PROGRESS IN
HETEROCYCLIC CHEMISTRY Volume 19
Related Titles of Interest Books CARRUTHERS: Cycloaddition Reactions in Organic Synthesis CLARIDGE: High-Resolution NMR Techniques in Organic Chemistry FINET: Ligand Coupling Reactions with Heteroatomic Compounds GAWLEY & AUBÉ: Principles of Asymmetric Synthesis HASSNER & STUMER: Organic Syntheses Based on Name Reactions KATRITZKY: Advances in Heterocyclic Chemistry KATRITZKY & POZHARSKII: Handbook of Heterocyclic Chemistry, 2nd Edition LEVY & TANG: The Chemistry of C-Glycosides MATHEY: Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New Domain McKILLOP: Advanced Problems in Organic Reaction Mechanisms OBRECHT: Solid Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries PELLETIER: Alkaloids; Chemical and Biological Perspectives SESSLER & WEGHORN: Expanded Contracted and Isomeric Porphyrins WONG & WHITESIDES: Enzymes in Synthetic Organic Chemistry Major Reference Works BARTON, NAKANISHI, METH-COHN: Comprehensive Natural Products Chemistry BARTON & OLLIS: Comprehensive Organic Chemistry KATRITZKY & REES: Comprehensive Heterocyclic Chemistry I CD-Rom KATRITZKY, REES & SCRIVEN: Comprehensive Heterocyclic Chemistry II KATRITZKY, METH-COHN & REES: Comprehensive Organic Functional Group Transformations SAINSBURY: Rodd’s Chemistry of Carbon Compounds TROST & FLEMING: Comprehensive Organic Synthesis Journals BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS CARBOHYDRATE RESEARCH HETEROCYCLES (distributed by Elsevier) PHYTOCHEMISTRY TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS Full details of all Elsevier Science publications, and a free specimen copy of any Elsevier Science journal, are available on request at www.elsevier.com or from your nearest Elsevier Science office.
PROGRESS IN
HETEROCYCLIC CHEMISTRY Volume 19 A critical review of the 2006 literature preceded by two chapters on current heterocyclic topics Editors
GORDON W. GRIBBLE Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA and
JOHN A. JOULE The School of Chemistry, The University of Manchester, Manchester, UK
Amsterdam – Boston – London – New York – Oxford – Paris San Diego – San Francisco – Singapore – Sydney – Tokyo
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For information on all Elsevier publications visit our website at books.elsevier.com Printed and bound in the United Kingdom 08 09 10 11 12 10 9 8 7 6 5 4 3 2 1
v
Contents Foreword
x
Editorial Advisory Board Members
xi
Chapter 1:
1
Recent progress in the chemistry of 2,1-benzothiazines
Xuechuan Hong and Michael Harmata, Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri, USA 1.1 1.2 1.2.1 1.2.2 1.2.3 1.2.4 1.2.5 1.2.6 1.2.6.1 1.2.6.2 1.2.7 1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.6 1.3.7 1.3.8 1.4 1.5
Introduction The synthesis of 2,1-benzothiazines and related compounds Synthesis of 3,4-dihydro-2,1-benzothiazine 2,2-dioxide derivatives Synthesis of dibenzo[c,e][1,2]thiazine 5,5-dioxide derivatives Synthesis of 1H-2,1-benzothiazine 2,2-dioxide (sulfostyril) derivatives Synthesis of azathiabenzenes and azathiaphenanthrenes Synthesis of 1,2-thiazine S-oxide by cycloaddition of N-sulfinylaniline Synthesis of Harmata-type benzothiazines Lewis acid-mediated synthesis of 2,1-benzothiazenes Synthesis of enantiomerically pure 2,1-benzothiazines Heterocyclic ring-fused thiazines and ring-fused 2,1-benzothiazine derivatives Chemistry of 2,1-benzothiazines Reactions of 2,1-benzothiazine 2,2-dioxide Reactions of azathiabenzenes and azathiaphenanthrenes Functionalization of Harmata-type benzothiazines via a sulfoximine-stablized vinyl carbanion Indole Synthesis Aniline Synthesis Chiral ligands in asymmetric allylic alkylation New chiral benzothiazine ligand for catalysis and molecular recognition Application of 2,1-benzothiazines in natural products syntheses Acknowledgements References
Chapter 2:
1 1 1 5 7 9 10 12 12 14 20 25 25 26 31 31 32 34 36 36 40 40
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
44
Ana M. G. Silva and José A. S. Cavaleiro, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. 2.1 2.2 2.2.1 2.2.2 2.2.3 2.3 2.4 2.5
Overview of the cycloaddition reactions of porphyrins Porphyrins in cycloaddition reactions Porphyrins as dienophiles in Diels-Alder reactions Porphyrins as 1,3-dipoles in 1,3-dipolar cycloadditions Porphyrins as dipolarophiles in 1,3-dipolar cycloadditions Conclusions Acknowledgements References
Chapter 3:
44 45 45 49 58 67 67 67
Three-membered ring systems
70
Stephen C. Bergmeier and Damon D. Reed, Department of Chemistry & Biochemistry, Ohio University, Athens, Ohio, USA 3.1 3.2 3.2.1 3.2.2 3.3 3.3.1 3.3.2 3.4
Introduction Epoxides Preparation of epoxides Reactions of epoxides Aziridines Preparation of aziridines Reactions of aziridines References
Chapter 4:
70 70 70 74 80 80 85 90
Four-membered ring systems
92
Benito Alcaide, Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense de Madrid, Madrid, Spain and Pedro Almendros, Instituto de Química Orgánica General, CSIC, Madrid, Spain. 4.1 4.2 4.3
Introduction Azetidines, azetines, 3-azetidinones, and diazetines Monocyclic 2-azetidinones (β-lactams)
92 92 95
vi 4.4 4.5 4.6 4.7 4.8
Contents Fused and spirocyclic β-lactams Oxetanes, dioxetanes, oxetenes and 2-oxetanones (β-lactones) Thietanes, β-sultams, and related systems Silicon and phosphorus heterocycles. miscellaneous References
Chapter 5:
Five-membered ring systems
Part 1.
Thiophenes and Se/Te analogs
98 100 103 104 106
112
Tomasz Janosik and Jan Bergman, Department of Biosciences and Nutrition, Karolinska Institute, Novum Research Park, Huddinge, Sweden. 5.1.1 5.1.2 5.1.3 5.1.4 5.1.5 5.1.6 5.1.7 5.1.8
Part 2.
Introduction Thiophene ring synthesis Reactions of thiophenes Non-polymeric thiophene organic materials Thiophene oligomers and polymers Thiophene derivatives in medicinal chemistry Selenophenes and tellurophenes References
112 112 116 121 123 125 127 128
Pyrroles and benzo analogs
135
Erin T. Pelkey, Hobart and William Smith Colleges, Geneva, NY, USA and Jonathon S. Russel, St. Norbert College, De Pere, WI 54115, USA, 5.2.1 5.2.2 5.2.2.1 5.2.2.2 5.2.2.3 5.2.3 5.2.3.1 5.2.3.2 5.2.3.3 5.2.4 5.2.4.1 5.2.4.2 5.2.4.3 5.2.5 5.2.5.1 5.2.5.2 5.2.6 5.2.6.1 5.2.6.2 5.2.6.3 5.2.6.4 5.2.7 5.2.7.1 5.2.7.2 5.2.8 5.2.8.1 5.2.8.2 5.2.8.3 5.2.8.4 5.2.9 5.2.9.1 5.2.9.2 5.2.10
Part 3.
Introduction Synthesis of pyrroles Intramolecular approaches Intermolecular approaches Transformations of other heterocycles Reactions of pyrroles Substitution at nitrogen Substitution at carbon Functionalization of the side-chain Pyrrole natural products and materials Natural products and biologically active small molecules Macrocycles and oligopyrroles Non-oligomeric materials Synthesis of indoles Intramolecular approaches Intermolecular approaches Reactions of indoles Substitution at C–3/C–2 Substitution at nitrogen Functionalization of the benzene ring Functionalization of the side-chain Carbazoles and azaindoles Carbazole ring synthesis and annulation Azaindole ring synthesis Indole natural products Natural products isolation and characterization Indole alkaloid total synthesis β-Carboline and tetrahydro-β-carboline total synthesis Oxindole total synthesis Biochemical and medicinal chemistry Indole alkaloid biosynthesis Medicinal applications of indole alkaloids References
135 135 135 138 142 143 143 143 148 148 148 149 149 150 151 154 155 155 158 158 159 159 159 160 160 160 161 163 163 164 164 165 165
Furans and benzofurans
Xue-Long Hou, Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China, Zhen Yang, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, Department of Chemical Biology, College of Chemistry, Peking University, Beijing, China, Kap-Sun Yeung, Bristol-Myers Squibb Pharmaceutical Institute, Wallingford, CT, USA, and Henry N. C. Wong, Department of Chemistry, Institute of Chinese Medicine and Central Laboratory of the Institute of Molecular
176
vii
Contents
Technology for Drug Discovery and Synthesis, The Chinese University of Hong Kong, Hong Kong, China and Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, Shanghai, China. 5.3.1 5.3.2 5.3.2.1 5.3.2.2 5.3.3 5.3.3.1 5.3.3.2 5.3.3.3 5.3.3.4 5.3.4
Part 4.
Introduction Reactions Furans Di- and tetrahydrofurans Synthesis Furans Di- and tetrahydrofurans Benzo[b]furans and related compounds Benzo[c]furans and related compounds References
176 177 177 181 184 184 188 193 198 200
With more than One N Atom
208
Larry Yet, Albany Molecular Research, Inc., Albany, New York, USA. 5.4.1 5.4.2 5.4.3 5.4.4 5.4.5 5.4.6 5.4.7
Part 5.
Introduction Pyrazoles and ring-fused derivatives Imidazoles and ring-fused derivatives 1,2,3-Triazoles and ring-fused derivatives 1,2,4-Triazoles and ring-fused derivatives Tetrazoles and ring-fused derivatives References
208 208 219 226 231 233 235
With N and S (Se) atoms
242
Yong-Jin Wu, Bristol Myers Squibb Company, Wallingford, Connecticut, USA and Bingwei V. Yang, Bristol Myers Squibb Company, Princeton, New Jersey, USA 5.5.1 5.5.2 5.5.2.1 5.5.2.2 5.5.2.3 5.5.2.4 5.5.2.5 5.5.2.6 5.5.2.7 5.5.2.8 5.5.3 5.5.3.1 5.5.3.2 5.5.3.3 5.5.3.4 5.5.4 5.5.5 5.5.6 5.5.7
Part 6.
Introduction Thiazoles Synthesis of thiazoles Synthesis of fused thiazoles Synthesis of thiazolines Reactions of thiazoles and fused derivatives Thiazole intermediates in synthesis Thiazolium-catalyzed and -mediated reactions Thiazole-containing natural products Thiazole-containing drug candidates Isothiazoles Synthesis of isothiazoles Reactions of isothiazoles Isothiazoles as auxiliaries in organic syntheses Pharmaceutically interesting isothiazoles Thiadiazoles 1,3-Selenazoles, 1,3-selenazolidines and 1,2,3-selenadiazoles Acknowledgement References
242 242 242 245 247 249 254 258 261 262 263 263 266 268 270 271 272 273 274
With O and S (Se, Te) atoms
277
R. Alan Aitken and Lynn A. Power, University of St Andrews, UK. 5.6.1 5.6.2 5.6.3 5.6.4 5.6.5 5.6.6 5.6.7 5.6.8
Part 7.
1,3-Dioxoles and dioxolanes 1,3-Dithioles and dithiolanes 1,3-Oxathioles and oxathiolanes 1,2-Dioxolanes 1,2-Dithioles and dithiolanes 1,2-Oxathioles and oxathiolanes Three heteroatoms References
277 280 282 283 283 283 283 284
With O and N atoms
288
Stefano Cicchi, Franca M. Cordero and Donatella Giomi, Università degli Studi di Firenze, Italy. 5.7.1 5.7.2 5.7.3 5.7.4 5.7.5 5.7.6 5.7.7 5.7.8
Isoxazoles Isoxazolines Isoxazolidines Oxazoles Oxazolines Oxazolidines Oxadiazoles References
288 291 294 298 302 306 309 310
viii
Contents
Chapter 6:
Six-membered ring systems
Part 1.
Pyridine and benzo derivatives
314
Heidi L. Fraser, Darrin W. Hopper, Kristina M.K. Kutterer and Aimee L. Crombie, Chemical and Screening Sciences, Wyeth Research, Pearl River, New York, USA 6.1.1 6.1.2 6.1.2.1 6.1.2.2 6.1.2.3 6.1.3 6.1.3.1 6.1.3.2 6.1.4 6.1.4.1 6.1.4.2 6.1.5 6.1.5.1 6.1.6
Introduction Pyridines Preparation of pyridines Reactions of pyridines Pyridine N-oxides and pyridinium Salts Quinolines Preparation of quinolines Reactions of quinolines Isoquinolines Preparation of isoquinolines Reactions of isoquinolines Piperidines Preparations of piperidines References
314 314 314 318 322 325 325 328 330 330 332 333 334 343
353
Part 2 (2005) Diazines and benzo derivatives (2005) Michael P. Groziak, California State University East Bay, Hayward, CA, USA 6.2.1 6.2.2 6.2.3 6.2.3.1 6.2.3.2. 6.2.3.3 6.2.4 6.2.4.1 6.2.4.2 6.2.4.3 6.2.5 6.2.5.1 6.2.5.2 6.2.5.3 6.2.6
Introduction Reviews and general studies Pyridazines and benzo derivatives Syntheses Reactions Applications Pyrimidines and benzo derivatives Syntheses Reactions Applications Pyrazines and benzo derivatives Syntheses Reactions Applications References
353 353 354 355 356 356 357 360 365 367 370 371 372 373 374
383
Part 2 (2006) Diazines and benzo derivatives (2006) Keith Mills, Ware, Hertfordshire UK. 6.2.1 6.2.2 6.2.3 6.2.3.1 6.2.3.2 6.2.4 6.2.4.1 6.2.4.2 6.2.4.3 6.2.5 6.2.5.1 6.2.5.2 6.2.5.3 6.2.6
Part 3.
Introduction General studies Pyridazines and benzo derivatives Synthesis Reactions Pyrimidines and benzo derivatives Synthesis Reactions Applications Pyrazines and benzo derivatives Synthesis Reactions Applications and structural studies References
383 383 385 385 388 389 390 400 405 406 406 407 409 410
Triazines, tetrazines and fused ring polyaza systems
Pilar Goya and Cristina Gómez de la Oliva, Instituto de Química Médica (CSIC), Madrid, Spain. 6.3.1 6.3.1.1 6.3.1.2 6.3.1.3 6.3.2 6.3.3 6.3.3.1 6.3.3.2 6.3.4 6.3.5 6.3.6
Triazines 1,2,3-Triazines 1,2,4-Triazines 1,3,5-Triazines Tetrazines Fused [6]+[5] polyaza systems Triazino and tetrazino [6+5] fused systems Purines and related structures Fused [6]+[6] polyaza systems Miscellaneous References
414 414 415 416 420 422 422 423 427 428 429
414
ix
Contents
Part 4.
With O and/or S atoms
436
Chapter 7:
Seven-membered rings
437
John B. Bremner, Institute for Biomolecular Science and Department of Chemistry, University of Wollongong, Wollongong, NSW, Australia and Siritron Samosorn Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, Thailand. 7.1 7.2 7.2.1 7.2.2 7.2.3 7.2.4 7.3 7.3.1 7.3.2 7.3.3 7.4 7.4.1 7.5 7.6 7.7
Introduction Seven-membered systems containing one heteroatom Azepines and derivatives Fused azepines and derivatives Oxepines and fused derivatives Thiepines and fused derivatives Seven-membered systems containing two heteroatoms Diazepines and fused derivatives Dioxepines, dithiepines and fused derivatives Miscellaneous derivatives with two heteroatoms Seven-membered systems containing three of more heteroatoms Systems with N, S and/or O Seven-membered systems of pharmacological significance Future directions References
Chapter 8:
437 437 437 442 445 448 449 449 452 453 457 457 459 461 461
Eight-membered and larger rings
465
George R. Newkome, The University of Akron, Akron, Ohio, USA. 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10 8.11 8.12 8.13 8.14 8.15 8.16 8.17 8.18
Index
Introduction Carbon-oxygen rings Carbon-nitrogen rings Carbon-sulfur rings Carbon-oxygen/carbon-nitrogen rings Carbon-nitrogen-oxygen rings Carbon-nitrogen-sulfur rings Carbon-phosphorus-oxygen rings Carbon-phosphorus-sulfur rings Carbon-sulfur-oxygen rings Carbon-nitrogen-sulfur-oxygen rings Carbon-silicon/selenium/tellurium rings Carbon-metal rings Carbon-nitrogen-metal rings Carbon-oxygen-nitrogen-metal rings Carbon-silicon/germanium-nitrogen-metal rings Carbon-phosphorus-oxygen-metal rings Referencees
465 466 468 470 471 471 474 475 475 476 476 477 477 478 478 479 479 479
484
x Foreword
This is the nineteenth annual volume of Progress in Heterocyclic Chemistry, and covers the literature published during 2006 on most of the important heterocyclic ring systems.
References are
incorporated into the text using the journal codes adopted by Comprehensive Heterocyclic Chemistry, and are listed in full at the end of each chapter. This volume opens with two specialized reviews. The first, by Xuechuan Hong and Michael Harmata, covers ’Recent progress in the chemistry of 2,1benzothiazines’. The second, by Ana Silva and José Cavaleiro, discusses ‘Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions’. The remaining chapters examine the 2006 literature on the common heterocycles in order of increasing ring size and the heteroatoms present. In the previous volume, Vol. 18, it was not possible to include a chapter on ‘Six-membered ring systems: diazines and benzo derivatives’ so this volume has two chapters on this topic: chapter 5.4 (2005) covers the literature of 2005 and chapter 5.4 (2006) covers the publications of 2006. Due to unforeseen and
unfortunate circum stances, ‘Six-m embered ring system s: with O and/or S atom s’ does not appear in this volume; Volume 20 will include a double chapter on this topic, covering the literature of 2006 and 2007. The Index is not fully comprehensive – it includes only systematic heterocyclic ring system names. Thus, wherever a pyrrole is discussed, that would be indexed under 'pyrroles'; wherever 'pyrido[3,4-b]indoles' are mentioned an indexed entry under that name will be found; similarly 'aceanthryleno[1,2-e][1,2,4]triazines', 'azirines', '2H-pyran-2-ones', '1,2,4-triazoles', etc., etc. are listed. But, subjects like '4-ethyl-5-methylpyrrole', '5-acylazirines', '6-alkyl-2H-pyran-2-ones', '3alkylamino-1,2,4-triazoles', are not listed as such in the Index. 'Diels-Alder reaction' or 'Heck coupling' etc., are also not indexed. However, again this year, the Contents pages list all the subheadings of the chapters which we hope will considerably improve accessibility for readers. We are delighted to welcome some new contributors to this volume and we continue to be indebted to the veteran cadre of authors for their expert and conscientious coverage. We are also grateful to Joan Anuels of Elsevier Science for supervising the publication of the volume. We hope that our readers find this series to be a useful guide to modern heterocyclic chemistry. As always, we encourage both suggestions for improvements and ideas for review topics.
Gordon W. Gribble John A. Joule
xi
Editorial Advisory Board Members Progress in Heterocyclic Chemistry 2006 - 2007 PROFESSOR M. BRIMBLE (CHAIRMAN) University of Auckland, New Zealand
PROFESSOR D. ST CLAIR BLACK University of New South Wales Australia
PROFESSOR H. HIEMSTRA University of Amsterdam The Netherlands
PROFESSOR M.A. CIUFOLINI University of British Columbia Canada
PROFESSOR D.W.C. MACMILLAN California Institute of Technology USA
PROFESSOR T. FUKUYAMA University of Tokyo Japan
PROFESSOR M. SHIBASAKI University of Tokyo Japan
PROFESSOR A. FÜRSTNER Max Planck Institut Germany
PROFESSOR L. TIETZE University of Göttingen, Germany
PROFESSOR R. GRIGG University of Leeds UK
PROFESSOR P. WIPF University of Pittsburgh USA
Information about membership and activities of the International Society of Heterocyclic Chemistry (ISCH) can be found on the World Wide Web at http://webdb.uni-graz.at/~kappeco/ISHC/index.html
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1
Chapter 1 Recent progress in the chemistry of 2,1-benzothiazines
Xuechuan Hong and Michael Harmata∗ Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri 65211, USA
[email protected]
1.1 INTRODUCTION The study of the chemistry of 2,1-benzothiazines 1 started in the 1960s <65JOC3163; 81JHC73>. Subsequently, their preparation and intensive biological and physiological studies have been reported <66MI1; 66MI2; 66MI3; 67MI1; 67MI2; 67MI3; 67MI4; 68MI1; 69MI1; 71MI1; 77MI1; 84MI1; 89MI1; 92MI1>. In recent years, 2,1-benzothiazines 1, have been of enormous interest to synthetic chemists. The current review is intended to present the progress of synthetic procedures and applications of 2,1-benzothiazines 1 and related compounds. 5
4
6 7 8
N 1
3 S2
(1)
Figure 1. General structure of 2,1-benzothiazines 1 1.2 THE SYNTHESIS OF 2,1-BENZOTHIAZINES AND RELATED COMPOUNDS 1.2.1 Synthesis of 3,4-Dihydro-2,1-benzothiazine 2,2-dioxide Derivatives 3,4-Dihydro-2,1-benzothiazine 2,2-dioxide derivatives 2, a type of benzosultam, possess very strong biological activities and have been used as drugs for treating heart diseases and as lipoxygenase inhibitors <89MI1; 92MI1; 94MI1; 98MI1; 02MI1; 02MI2; 04MI1> (Figure 2). These remarkable biological activities have made the synthesis of the 3,4-dihydro-2,1benzothiazine 2,2-dioxide skeleton of interest. Several different methods of synthesis of 3,4dihydro-2,1-benzothiazine 2,2-dioxide derivatives are already established.
*∗ This review is dedicated to Professor Albert Padwa (Emory University) on the occasion of his 70th birthday
2
X. Hong and M. Harmata
R2 R3
R1= H, PhCH2 N R1
R2= H, alkoxyl, hydroxyl
SO2
R3= H, piperazinyl
(2)
Figure 2. 3,4-Dihydro-2,1-benzothiazine 2,2-dioxide derivatives. In 1965, the first 2,1-benzothiazine 2,2-dioxide was synthesized by Leov’s group <65JOC3163; 67MI1> through cyclization of 2-(ortho-aminophenyl)ethanesulfonic acid or its sodium salt with phosphorus pentachloride and acetyl chloride. They also demonstrated that 4-phenyl-3,4-dihydro-2,1-benzothiazine-2,2 dioxide (6) can be smoothly obtained by treatment of styrenesulfonanilide 5 with polyphosphoric acid (PPA) <67MI1>. Sianesi and co-workers <71CB1880> developed an alternative approach to prepare 4 in 73% yield by pyrolysis of the corresponding aminosulfonamide hydrochloride 7 (Scheme 1). NH 2
H N
PCl5, AcCl SO 3X
4
3: X= Na, H H N
5
SO2
H N
PPA
6
Ph
NH 2.HCl SO 2NH2
SO 2
~40%
Ph H N
o
200 C
SO 2
SO 2
73% 4
7
Scheme 1 In 1969, Hromatka et al. <69M928> found that the cyclization of 5-chloro-2-(Nmethyl-iodomethanesulfonamido)-benzophenone 8 with ammonia or alcoholic ammonia gave 6-chloro-4-hydroxy-1-methyl-4-phenyl-3,4-dihydro-2,1-benzothiazine 2,2-dioxide 9 and 6chloro-4-hydroxy-3-iodo-1-methyl-4-phenyl-3,4-dihydro-2,1-benzothiazine 2,2-dioxide 10 in 30% and 33% yields, respectively (Scheme 2).
3
Recent progress in the chemistry of 2,1-benzothiazines
CH 3 N SO2 CH 2 I O
Cl
CH3 N SO2
NH 3, CHCl3 30%
Cl
OH Ph
Ph 8
9 CH3 N SO 2CH2 I O
Cl
CH 3 N SO 2
NH 3, EtOH 33%
Cl
OH Ph
Ph 8
I
10
Scheme 2 Abramovitch and co-workers <75JA676> also synthesized 3,4-dihydro-2,1benzothiazine 2,2-dioxide 4 by flash vacuum pyrolysis of ȕ-arylethanesulfonyl azides 11. The 3,4-dihydro-2,1-benzothiazine 2,2-dioxide 4 was obtained in 13% yield at 300 oC along with some side products, such as dihydropyrindine, indoline, indole, and styrene. Although the reaction yield was low, this new approach appeared very promising for the synthesis of 2,1-benzothiazenes (Scheme 3). After an extension of this work reported by the same group, <78H(11)377; 81JA1525; 84JOC5124; 84MI1; 85JOC2066> the thermolysis of compound 11 (R1 = H; R2, R3 = OMe) at 400 oC in Freon 113 as solvent gave compound 12 in 46-62% yield. R2
R2 SO2N3
R3
H N
SO2
R3 R1
R1 4: R1= H, R2, R3= H
11
12: R1= H, R2, R3= OMe
Scheme 3 5-Hydroxy-3,4-dihydro-2,1-benzothiazine 2,2-dioxide 15 can be synthesized in a convenient manner <94TL2911>. Blondet and co-workers used a cyclization of an ortho(chloromethyl or carboxaldehyde) N-protected sulfonanilide 13 or 16 with sodium hydride in DMF to give the benzothiazine dioxide 14 or 17 in 35% and 47% yields, respectively (Scheme 4). Finally, removal of the methoxy group and hydrogenation led to the formation of 5-hydroxy-3,4-dihydro-2,1-benzothiazine 2,2-dioxide 15 in good yield over two steps.
4
X. Hong and M. Harmata
OCH 3
OCH 3 Cl
NaH, DMF
1. BBr3 , CH2 Cl2 , 77%
o N SO2 CH 3 60 C, 35%
13
N
Ph
14
SO2
2. H2 , Pd(OH)2 , 85%
NaH, DMF 25 o C, 47%
N H
15
Ph
OCH 3
OCH3 CHO
SO2
OH 1. BBr3 , CH 2Cl2, 65%
N
N SO 2CH3 16
OH
17
Ph
SO2
2. H 2, Pd(OH) 2, 82%
N H
15
Ph
SO2
Scheme 4 An improved synthesis of 3,4-dihydro-2,1-benzothiazine 2,2-dioxide was reported by Togo and co-workers using photochemical conditions <00JOC8391; 00JOC926>. Treatment of N-alkyl 2-(aryl)ethanesulfonamides 18 with (diacetoxyiodo)arenes under irradiation with a tungsten lamp at 20-30 oC afforded 2,1-benzothiazines 19 and 20. Chemical yields and selectivities were dependent upon the choice of solvents and the reactant’s substituents 18 (Table 1). When THF and EtOH were used as solvents, the reactions failed to give the cyclized products, since their Į-hydrogen was abstracted by the intermediate sulfonamidyl radical. Compound 20 was obtained as a major product when 1,2-dichloroethane was employed as a solvent. In contrast, in the case of EtOAc as solvent, compound 19 was obtained as the major product. Table 1. Formation of 3,4-dihydro-2,1-benzothiazine 2,2-dioxides with N-alkyl 2(aryl)ethanesulfonamides
R'
X'
I2 (1.0 eq), 20-30 oC
I
R'
SO2NHR PhI(OAc)2 (1.6 eq.) X'
W-hυ, 2 h 18
N R
SO2 +
R'
X'
19
N R
SO2
20
Entry
Solvent
R
Rƍ
Xƍ
Yield % of 19
Yield % of 20
1
THF
CH3
H
H
0
0
2
EtOH
CH3
H
H
0
0
3
AcOEt
CH3
H
H
81
10
4
ClCH2CH2Cl
CH3
H
H
6
89
5
ClCH2CH2Cl
Et
H
H
0
89
6
ClCH2CH2Cl
CH3
CH3
H
0
97
7
ClCH2CH2Cl
CH3
H
CH3
0
94
8
ClCH2CH2Cl
CH3
H
Cl
34
49
5
Recent progress in the chemistry of 2,1-benzothiazines
Table 2. Cyclization of N-methoxyl 2-(aryl)ethanesulfonamides
SO2NHOCH3
ArI(OH)OTs (1.1 eq.) 0 oC- rt. 20 min.
R
SO2 N OCH3
R
21
Entry 1 2 3
R H H H
22
Solvent CHCl3 AcOEt ClCH2CH2Cl
İ 4.7 6.0 10.4
o
Temp./ C
Time/min
Yield % of 22
o
20
18
o
20
29
o
20
73
o
0 C to rt 0 C to rt. 0 C to rt
4
H
CH3CN
37.5
0 C to rt
20
86
5
H
CH3CN
37.5
60-65
5
65
6
H
CH3CN
37.5
0
20
65
7
H
CH3CN
37.5
10-15
20
84
37.5
o
20
85
o
20
52
o
20
44
8 9 10
CH3 Cl F
CH3CN CH3CN CH3CN
37.5 37.5
0 C to rt 0 C to rt 0 C to rt
Togo’s group also reported the preparation of the 2,1-benzothiazines via an ionic pathway with hypervalent iodine compounds <03OBC1342>. Using this method, it was found to be far easier to synthesize five- or seven-membered benzosultams and avoid the difficult deprotection of the N-alkyl group in the six-membered benzosultams to give the free NH group. The reaction of N-methoxy 2-(aryl)ethanesulfonamides 21 with various hypervalent iodine reagents produced the cyclization products in various yields, which were dependent on the dielectric constant (ε) of solvents. The best yield of 2,1-benzothiazines 22 was 85% by treatment of N-methoxy 2-(aryl)ethanesulfonamides 21 with [hydroxy(tosyloxy)iodo] benzene in CH3CN solvent from 0 oC to room temperature for 20 minutes (Table 2). An electron-withdrawing group on the para position of the aromatic ring in 21 (e.g., Cl, F) reduced the yields of the cyclization reaction. In 2003, Togo and co-workers described a radical cyclization and ionic cyclization onto the aromatic rings of 2-(aryl)ethanesulfonamides 21 to produce 3,4-dihydro-2,1benzothiazine 2,2-dioxides with polymer-supported hypervalent iodine reagents in good yields <03ARK11>. 1.2.2 Synthesis of Dibenzo[c,e][1,2]thiazine 5,5-dioxide Derivatives Dibenzo[c,e][1,2]thiazine 5,5-dioxide derivatives 23 are pharmacologically interesting <91JMC2477; 93JMC2242; 99BMCL673>. Various methods for the construction of these biarylthiazines have been reported (Figure 3) <00SL475; 01T5915>.
6
X. Hong and M. Harmata
N R1
R1 = H, alkyl
SO2
23
Figure 3. Dibenzo[c,e][1,2]thiazine 5,5-dioxide derivatives
PhO2S
Pd(OAc)2, Na2CO3 N
PhO2S
N,N-dimethylacetamide reflux, 56%
24
N H
SO2
25
Scheme 5 Ames and Opalko have developed a palladium-catalysed cyclization of compound 24 to afford compound 25 in 56% yield (Scheme 5) <84T1919>. Glover and co-workers published a study involving the synthesis and photolysis of N-halogenobiphenyl-2-sulfonamides (26a or 26b) <86JCS(P2)645>. The photolysis of compound 26a or compound 26b in benzene formed an intermediate N-methylbiphenyl-2-sulfonamidyl radical, which resulted in compound 27a or 27b in 21% or 50% yield, respectively. In this procedure, the reaction only afforded the six-membered ring product 27(Scheme 6). R CH3 N hυ SO2 benzene
CH3 N SO2
SO2 N CH3
26a: R = I
27a: 21%
26b: R = Br
27b: 50%
Scheme 6 A reductive, intramolecular, free radical arylation using tributyltin hydride/AIBN was introduced by the Motherwell group <91CC877; 97TL137>. The reaction of 28 under radical conditions produced the direct addition product 29 and ipso-substitution product 30 in various yields, which depended on the ortho and para substituents. Electron-withdrawing groups favored the formation of compound 29, while the ortho carbomethoxy group, and even the CH3 group led to greatly improved yields of the ipso substitution product 30 (Scheme 7).
7
Recent progress in the chemistry of 2,1-benzothiazines
H3C
N
O2 S
R1
I
R2
(n-Bu)3SnH, AIBN, benzene, reflux
H3C
N
O2 S
R1
R1 NHMe R2
28
R2
29 29a: 39% 29b: 10% 29c: 44% 29d: 19% 29e: 0%
28a: R1= H, R2= CH3 28b: R1= H, R2= OCH3 28c: R1= H, R2= F 28d: R1= COOMe, R2= H 28e: R1= Me, R2= H
30 30a: 34% 30b: 33% 30c: 29% 30d: 65% 30e: 57%
Scheme 7
1.2.3 Synthesis of 1H-2,1-Benzothiazine 2,2-dioxide (sulfostyril) Derivatives The synthesis of 1H-2,1-benzothiazine 2,2-dioxide was pioneered by Loer and coworkers <66JOC3531> and also by the Rossi group <66AC(R)728; 66AC(R)741>. The general class of compounds is represented in Figure 4. R3 R2 N R1
SO2
R1= H, CH3 R2= H, ester, acid, ketone, arene R3= H, CH3, Phenyl
(31)
Figure 4. 1H-2,1-Benzothiazine 2,2-dioxide derivatives Compound 34 can be synthesized by a Bamford-Stevens procedure from compound 33. Loer explored the cyclization of 32 with polyphosphoric acid (PPA), followed by decomposition of the tosylhydrazone to form the desired 1H-2,1-benzothiazine 2,2-dioxide 34 in good overall yield (Scheme 8) <66JOC3531>. H N
SO2
PPA
H N
SO2
1)TosNHNH2
H N
2) Base
O OH
O
32
33
Scheme 8
34
SO2
8
X. Hong and M. Harmata
An improved synthesis of 1H-2,1-benzothiazine 4(3H)-one 2,2-dioxide 33 that results in a relatively high overall yield was developed by Lombardino’s group <71OPP33; 72JHC315>. This general method offered an easier entry into the 2,1-benzothiazine 2,2dioxide heterocyclic system <67JHC403>. Treatment of methyl N-benzyl-Nmethylsulfonylanthranilate 35 with sodium hydride led to 1-benzyl-4-oxo-1H-2,1benzothiazine-4(3H)-one 2,2-dioxide 36 in 68% yield. Reduction of 36 gave 4-oxo-1H-2,1Bn N SO2 CH3
Bn N
NaH
SO2
Pd/H2
SO 2
68%
68%
CO2 Me
H N
35
O
36
33
O
Scheme 9 benzothiazine-4(3H)-one 2,2-dioxide 33 in 68% yield (Scheme 9). Lombardino also reported the reaction of 37 with isocyanates in dimethyl sulfoxide to yield the 1H-2,1-benzothiazine3-carboxanilide 2,2-dioxide 38 in high yield (Scheme 10) <72JHC315>. CH 3 N SO 2
CH3 + RNCO
N
Et3 N
SO2
DMSO
O
NHR OH
37
O
38 R= alkenyl, arene
Scheme 10 Rossi and co-workers <66AC(R)741> independently reported the synthesis of 33 using the same method. Reduction of 33 with sodium borohydride, followed by dehydration afforded 34 in 80% yield. Compounds 40a and 40b were prepared from 39a and 39b with phosphorus oxychloride in 92% and 65% yields, respectively (Scheme 11) <66AC(R)741>.
R
H N
SO2
POCl3
R
H N
SO2
O Ph
Ph
39a: R = CH3
40a: R = CH3, 92%
39b: R = OCH3
40b: R = OCH3, 65%
Scheme 11 Rossi and co-workers <66AC(R)728> also showed that ortho-acyl methanesulfanilides 41 carrying an electron-withdrawing group at the α position of the sulfonyl group can readily
9
Recent progress in the chemistry of 2,1-benzothiazines
convert under basic conditions to 3,4-disubstituted 1H-2,1-benzothiazine 2,2-dioxides 42 in good to excellent yields (Scheme 12). Similar work was also reported by Sianesi and coworkers <67AC(R)1426>. R4 N R3
SO2 CH 2R 1
R4 N
NaOEt
COR2
SO 2
R3
R 2 = CH 3, Ph
R 1 R 3 = H, Cl R2
42
41
R 1 = ArCO, CO2 Et
R 4 = H, CH 3
Scheme 12 1.2.4 Synthesis of Azathiabenzenes and Azathiaphenanthrenes Cyclic sulfilimines are considered useful reagents in organic synthesis <00JOC8086; 03JOC9574>. The chemistry of cyclic sulfilimines has been studied extensively since the 1970s. Hori and co-workers accomplished the first synthesis of azathianaphthalene and azathiaphenanthrene in 1979 <79TL3969>. Their approach began with the formation of an olefin from ortho-nitrobenzaldehyde 43, via a Wittig reaction with an ylide and a subsequent reduction with zinc to afford cis and trans ortho-aminostyryl methyl sulfide 45. The cisolefin was then treated with NCS, AgClO4 and KOH to yield 2-methyl-1-aza-2thianaphthalene 47 in 41% yield. 9-Methyl-10-aza-9-thiaphenanthrene 48a and 9-ethyl-10aza-9-thiaphenanthrene 48b were obtained in a similar fashion in almost quantitative yields, whereas 6-benzyl-6H-dibenzo[c,e][1,2]thiazines 50 were isolated in moderate yields via a 1,2-rearrangement (Scheme 13) <90TL7021>. CHO
CH CHSCH 3
Ph3 P CHSCH 3 89%
NO 2
44
1. NCS 2.AgClO4
N H 46
41%
S
S
KOH CH 3
57%
N
Cl
2. KOH CH 2R
48a: R = H, 100% 48b: R = Me, 90%
NH2 45
S
CH3
47
1. NCS
1. NCS N
80%
NO2
43
CH CHSCH 3
Zn-CaCl2
SCH 2R NH 2
2. n-BuLi
49
S N CH 2Ar 50a: R = Ph, 50% 50b: R = pTol, 57%
Scheme 13
10
X. Hong and M. Harmata
Moody and co-workers independently reported the synthesis of azathiabenzenes by thermolysis <86JCS(P1)483>. Azides 51a and 51b were decomposed in boiling toluene to give the corresponding cyclic sulfimides 52a and 52b in 52% and 13% yields, respectively (Scheme 14). N3
N
SR
S R
CO2Et
CO2Et
51a: R = Ph
52a: R = Ph, 52%
51b: R = Me
52b: R = Me, 13%
Scheme 14 1.2.5 Synthesis of 1,2-Thiazine S-oxide by Cycloaddition of N-Sulfinylaniline The reaction of aryl sulfinylamines as heterodienes has been well documented in the literature <64JOC1688; 67JOC506; 67CB2151; 84JCS(P1)2429; 72JCS(P2)1134; 67CB2164; 86H(24)2739>. The first cycloaddition of N-sulfinylanilines, ArN=S=O 53, to an alkene was reported by Collins in 1964 and afforded the 1,2-thiazine S-oxide 54 in 82% yield (Scheme 15) <64JOC1688>. S
N
O
H O S NH toluene, reflux, 82%
H
53
54
Scheme 15 Several years later, Macaluso and Hamer extended the research to bicycloalkenes <67JOC506>. They also pointed out that this type of reaction occurred only when bridged bicyclic alkenes were used. However, Beecken <67CB2151> reported some cycloaddition reactions of heterocyclic sulfinylamino compounds to ethoxyacetylene. Hanson and Stone <84JCS(P1)2429> demonstrated that cycloadditions of compound 53 and substituted derivatives with certain hetero-bridged bicyclic alkenes, particularly with 1,4-epoxy-1,4dihydronaphthalene 55 are pericyclic reactions (Scheme 16) <83JCS(P2)1719>.
N
S
O O
H
55 O
H 53
56
Scheme 16
S O
NH
11
Recent progress in the chemistry of 2,1-benzothiazines
In order to explore the regioselectivity of aryl sulfinylamines as heterodienes, a variety of unsymmetrical (N-sulfinylamino)azines, such as (N-sulfinylamino)pyridines (57, 60, 63), were studied by Hanson <90JCS(P1)2089>. In refluxing toluene, 1,4-epoxy-1,4dihydronaphthalene 55 prefers to react at the C-2 position of 3-(N-sulfinylamino)pyridine 60. On the other hand, 2-(N-sulfinylamino)pyridine 63 reacted at the ring nitrogen with 1,4epoxy-1,4-dihydronaphthalene 55 to give only a single trans-exo-adduct 64 in 64% yield (Scheme 17). Hogeveen and co-workers <82JOC1909; 83JOC4275> also reported the synthesis of tricyclic sulfinamides by the reaction of cyclobutadiene aluminum halide ı complexes (65 or 66) with 53 at low temperature. Treatment of 65 or 66 with 53 at –60 oC resulted in the formation of 67 or 68 in 52% and 55% yields, respectively (Scheme 18).
N
O
S
N H
O 55%
N
H
57
S O
58 S
N
N
H
O
O
NH
H
S O
NH
59
5:1
O H
O
N H
O N H 60
61
S O
O
NH
H
S
S O
62 5.5%
75%
N
N
O H
O N
N
O 64%
H
63
S O
N
64
Scheme 17 H3C
H Al2Br6
H3C
CH3 65
H3C
H Al2Br6
H
CH3 66
Figure 5. Cyclobutadiene aluminum halide ı complexes.
NH
12
X. Hong and M. Harmata
N
S
O
CH3 H CH3
65 52%
S NH O
H3C 53 N
67 S
O
CH3 H H
66 55%
S NH O
H3C 53
68
Scheme 18
1.2.6 Synthesis of Harmata-type Benzothiazines Recently, the Harmata group developed several novel ways to synthesize 2,1benzothiazines represented by the general structures 69 and 70 (Figure 6) <87TL5997; 91JOC5059; 98JOC6845; 99AG(E)2419; 03JA5754; 04TL5233>. R1
R1
R2
R2 R3 N 69
S O Ar
R3 N
S O Ar
70
Figure 6. Harmata-type benzothiazines.
1.2.6.1 Lewis Acid-mediated Synthesis of 2,1-Benzothiazenes In 1987, the Harmata group reported a general and novel procedure for the synthesis of benzothiazenes during an attempt to synthesize alkynyl sulfoximines <87TL5997>. They demonstrated the Lewis acid-mediated electrophilic addition reaction of the N-aryl substituted sulfonimidoyl chlorides to alkynes. Intermediate vinyl carbocations may formed in the reaction, and converted into benzothiazenes by a Friedel-Crafts electrophilic substitution reaction. As an example, the reaction of N-phenylsulfonimidoyl chloride 71 with 1-trimethylsilyl-1-propyne and aluminum chloride in dichloromethane at –78 oC generated 72 in 75% yield (Scheme 19). This and other reactions took place with high Markownikov regioselectivity (Table 3). Whether the formation of the σ complexes 74 could be a concerted “cycloaddition” between the iminosulfonium “heterodiene” 73 and the alkyne dienophile or more likely a stepwise process, does not appear to have been established (Scheme 20) <91JOC5059>.
13
Recent progress in the chemistry of 2,1-benzothiazines
Cl N S O + R1C CR2 Ph pTol
R2 R1
AlCl3, CH2Cl2, -78 oC 75%
S O pTol
N
71
72: R1 = TMS, R2 = Me
Scheme 19 R2 Cl N S O Ph pTol
R1 O S N pTol
R1C CR2 AlCl3
71
73
R2
H
R1 N
S O pTol
74
R2 R1 N
S O pTol
75
Scheme 20 Table 3. N-Phenylsulfonimidoyl chlorides with alkynes in the presence of Lewis acids R2
Cl N S O + R1C CR2 Ph pTol
R1 N
S O pTol
Entry
R1
R2
Yield%
1
H
Ph
90
2
H
n-Bu
60
3
TMS
Me
75
An extension of this work was also reported by this group, <91JOC5059; 98JOC6845> in which the reaction was applied with success to alkenes, as shown in Scheme 21. The reaction not only proceeded with high Markownikov regioselectivity, but sometimes was very diastereoselective as well (Table 4).
14
X. Hong and M. Harmata
H Et Cl H N S O + Ph Et pTol
Et
78 oC, 74%,
H
Et H H Et
AlCl3 , CH2 Cl2 , N
121:1
76a
S O pTol
Et H
+ N 76b
S O pTol
Scheme 21 Table 4. Reaction of N-phenylsulfonimidoyl chlorides with alkenes Cl N S O + Ph pTol
R2
R3
R1
R4
Entry
R1
R2
1
H
H
2
H
3
R3 R2
N
R3
R4
R1 R4
R2 R3
S O pTol
N
76a
76b
R4 R1
S O pTol
Yield %
Ratio (76a : 76b)
-(CH2)4-
91
25:1
H
-(CH2)3-
81
5:1
H
H
-(CH2)5-
70
2.4:1
4
H
H
-(CH2)6-
76
2.1:1
5
H
Et
H
Et
85
122:1
6
H
H
Et
Et
85
2.3:1
7
H
Me
H
Me
62
45:1
8
H
H
Me
Me
78
2.3:1
9
H
Bu
H
H
77
1.6:1
10
H
Et
H
H
90
1.5:1
11
H
n-Pr
H
H
66
1.6:1
12
H
i-Pr
H
H
78
2.4:1
13
H
Ph
H
H
62
1.4:1
14
H
t-Bu
H
H
65
4.1:1
15
H
TMS
H
H
35
10:1
1.2.6.2 Synthesis of Enantiomerically Pure 2,1-Benzothiazines The Harmata group has also developed a route to enantiomerically pure 2,1benzothiazines. The process involves the N-arylation of sulfoximines using the BuchwaldHartwig reaction conditions, <02MI3; 99JOM(576)125> a reaction first reported by Bolm
15
Recent progress in the chemistry of 2,1-benzothiazines
<98TL5731>. The Bolm group has already made use of this reaction in the preparation of a variety of chiral ligands and unique cyclic sulfoximines <03OL427; 01SL1878; 02SL832>. Critical to the development of this reaction in the preparation of enantiomerically pure 2.1benzothiazines is the ready availability of enantiomerically pure sulfoximines 77a or 77b <97TA909>. NH S Ar O Me
NH S Ar Me O (R)-77a, Ar = pTol (R)-77b, Ar = Ph
(S)-77a, Ar = pTol (S)-77b, Ar = Ph
Figure 7. Enantiomerically pure sulfoximines. The Harmata group’s initial report concerned a one-pot, one-operation procedure <99AG(E)2419> for the synthesis of enantiomerically pure 2,1-benzothiazines via the Buchwald-Hartwig reaction reported by Bolm <98TL5731; 00JOC169> for sulfoximine Narylation. For example, treatment of ortho-bromobenzaldehyde 78 with enantiomerically pure N-H sulfoximine 77a in the presence of a palladium catalyst and base afforded the benzothiazine 79 in 78% yield (Scheme 22). Both C-N bond formation and condensation occurred during the reaction, a phenomenon that appears general for aldehydes like 78. pTol
CHO +
N S O H
Br
Me
5-10% Pd(OAc)2, 7.5%-15% BINAP, 1.8 eq. Cs2CO3, toluene,
(R)-77a
78
N
110 oC, 40 h, 78%
S O pTol
(R)-79
Scheme 22 Examples of coupling reactions of ortho-bromobenzoate ester 80 or orthobromobenzonitrile 87 with sulfoximine (R)-77a were also reported (Scheme 23a/b). In these cases only coupling occurred. However, the products could be converted into the 2,1benzothiazines 82 and 85 by treatment with a strong base. pTol CO2Me + N S O H Br Me
5% Pd(OAc)2, 7.5% BINAP, 1.4 eq. Cs2CO3, toluene, 115 oC, 40 h 84%
(R)-77a
80 CO2Me Me S O N pTol
OH 1.8 eq. KH, THF 0 oC to rt, 73%
(R)-81
N (R)-82
Scheme 23a
S O pTol
16
X. Hong and M. Harmata
pTol
CN +
Cs2CO3, toluene, 115 oC, 40 h
N S O H
Br
5% Pd(OAc)2, 7.5% BINAP, 1.4 eq. 94%
Me (R)-77a
83
NH2
CN N
Me S O
2.0 eq. n-BuLi, THF 0 oC to rt, 68%
N
pTol
(R)-84
S O pTol
(R)-85
Scheme 23b Enantiomerically pure bis-benzothiazines 87 and 89, are potentially useful templates for asymmetric catalysis. The Harmata group reported their syntheses from the corresponding dibromodialdehydes 86 and 88 under the reaction conditions used for the production of (R)79 (Scheme 24) <99AG(E)2419>. OHC
pTol
CHO +
Br
N S O H
Br
+ Br 88
O S
N
N S O H
Me
N
Tolp
S O pTol
(R, R)-87
pTol
CHO
OHC
48%
(R)-77a
86 Br
Me
Pd
Pd 41%
(R)-77a
pTol N O S N
S O pTol
(R, R)-89
Scheme 24 In 2003, the Harmata group reported a stereoselective, intramolecular Michael addition of sulfoximine carbanions to α,β-unsaturated esters as exemplified in Scheme 25 <03JA5754>. Preparation of sulfoximine 90 was conducted via the methodology introduced by Bolm as used in the initial studies of catalyzed benzothiazine synthesis <98TL5731; 00JOC169; 99AG(E)2419>. The sulfoximine 91 was transformed via treatment with LDA into 92. Importantly, 92 was formed as a single stereoisomer. This appears to be a general phenomenon for these types of reactions. Two procedures were reported for this cyclization. The first involved adding a THF solution of 2.0 equivalents of base in THF to the sulfoximine at -78 °C, but addition of the sulfoximine to base worked as well, and was occasionally absolutely necessary.
17
Recent progress in the chemistry of 2,1-benzothiazines
CO2Me
5% Pd(OAc)2, 7.5% BINAP 1.4 eq. Cs2CO3, 1.2 eq. (R)-77b toluene, reflux, 44 h
Br
91%
90 CO2Me
CO2Me
2.0 eq. LDA,THF -78 oC to -20 oC, 1 h
Me S O N Ph
92% N
91
S O Ph
92
Scheme 25 Two substrates could not be cyclized under normal addition conditions. An N-thienyl sulfoximine afforded benzothiazine 98 in good yield, but the corresponding the furanyl sulfoximine appeared to polymerize when base was added in the normal way. This problem was circumvented simply by adding the furan to a solution in base. The best reaction conditions involved adding a THF solution of the N-furanyl sulfoximine to 2.0 equivalents of LiHMDS in THF at –50 °C at a very slow rate. Stirring the solution for an additional 3 hours gave the benzothiazine 99 as a single stereoisomer in 85% yield. Similarly, the N-pyridyl sulfoximine also gave either decomposition or side products when treated with base. This problem was solved by addition of the sulfoximine to base coupled with degassing, and the desired benzothiazine 100 was obtained in 77% yield. The rationalization for the outcome of these cyclization reactions was based on minimizing steric interactions in the transition state leading to benzothiazine formation. For example, at least two possible transition states 101 and 102 could give rise to product 92 (or a diastereomer). Transition state 102 has gauche steric interactions that appear to be absent in the staggered transition state 101. This favors the latter and leads to the observed products 92 (Figure 8).
N S O H Ph
H H MeO2C H
101
N S O Ph H H H CO2Me
H
102
Figure 8. Possible transition state structures of the intramolecular Michael reaction of sulfoximine 91.
18
X. Hong and M. Harmata
Table 5. Reaction of sulfoximines with an amide base CO2Me
CO2Me LDA or LiHMDS (2.0 eq.)
Me S O N Ph
Entry
THF, -78 oC N
Yield (%)
Product
Entry
Product
CO2Me 1
BnO
91
5
93 S
S O N Ph 97
93
CO2Me
CO2Me 83
6
S
94
98 CO2Me
CO2Me
Me
3
S O N Ph
87
7
O
95
99 CO2Me
CO2Me O O
88 S O N Ph
96
85 S Ph N O
OMe
4
91 S Ph N O
S Ph N O
Me
Yield (%)
CO2Me
S Ph N O
2
S O Ph
8
77 N
S Ph N O 100
The Harmata group demonstrated that benzothiazine formation via the intramolecular Michael addition is stereospecific, at least in one case. When sulfoximine Z-103 was treated with 2.0 equivalents LDA the 2,1-benzothiazine 104 was obtained in 89% yield (Scheme 26) as the only product. Rationalizing this outcome was not straightforward. Transition state 106 suffers from gauche interactions and should be disfavored. However, the interaction of the ester group with a neighboring hydrogen (highlighted) in 105 was argued to be more severe. As it stands, these rationalizations are at best hypotheses that need to be investigated further.
19
Recent progress in the chemistry of 2,1-benzothiazines
CO2Me
MeO2C 2.0 eq. LDA,THF
Me S O N Ph
-78 oC to -20 oC
N
1 h, 89%
103
S O Ph
104
Scheme 26
N S O H Ph
HH MeO2C
H H
H H
HH
105
N S O Ph CO2Me
106
Figure 9. Putative transition states structures for the Michael reaction of sulfoximine 103. The Harmata group also found that certain ortho-bromocinnamates underwent a Michael addition during the course of the Buchwald-Hartwig reaction. This one-pot process produced the same products as the two step process and with the same, complete stereoselectivity. For example, this was first observed with bromocinnamate 107, where the reaction with (R)-77b afforded a 53% yield of sulfoximine 108 as well as a 36% yield of benzothiazine 95 under standard coupling conditions (Scheme 27). The cyclization was attributed to a buttressing effect of the ortho-methoxy in bromocinnamate 107. This presumably favored a conformation that placed the methyl group of its sulfoximine functionality near the β-carbon of the α,ѽβ-unsaturated ester, thus favoring cyclization. CO2Me Me
1.4 eq. Cs2CO3, 1.2 eq. (R)-77b Br
CO2Me
CO2Me
5% Pd(OAc)2, 7.5% BINAP
Me
toluene, reflux, 44 h OMe
OMe 107
Me S O N Ph
108: 53%
Me N
OMe
S O Ph
95: 36%
Scheme 27 Two other substrates, 109 and 111, exhibited this behavior. Most interesting was that the reaction of both 109 and 111 with (S)-77b under standard reaction conditions gave only benzothiazines 110 and 112, respectively, with no sign of the corresponding sulfoximine (Scheme 28). While using the argument of a buttressing effect may be useful, the Harmata group also reported that the reaction of bromocinnamate 113 with (S)-77b gave not only the sulfoximine 114, but the benzothiazine 96 as well (Scheme 28). There is no buttressing effect possible in this case and it is likely that other factors (e.g., electronic effects) can also favor direct benzothiazine formation.
20
X. Hong and M. Harmata
CO2Me
CO2Me
5% Pd(OAc)2, 7.5% BINAP 1.4 eq. Cs2CO3, 1.2 eq. (S)-77b toluene, reflux, 44 h, 61%
Br
N
109
S Ph O
110 CO2Me
CO2Me
5% Pd(OAc)2, 7.5% BINAP 1.4 eq. Cs2CO3, 1.2 eq. (S)-77b Br N CH3
toluene, reflux, 44 h, 82% N H3C
111
O
Br
S Ph O
112
CO2Me O
N
CO2Me
5% Pd(OAc)2, 7.5% BINAP 1.4 eq. Cs2CO3, 1.2 eq. (R)-77b
O
toluene, reflux, 44 h
O
113
Me S O N Ph
114: 60% CO2Me
O O
N
S O Ph
96: 25%
Scheme 28
1.2.7 Heterocyclic Ring-fused Thiazines and Ring-fused 2,1-Benzothiazine Derivatives The first synthesis of pyrazolo[5,1-c]-1,2,4-thiadiazines 116 and pyrazolo[3,4-c]-1,2thiazines 118 was reported by Aiello and co-workers <76JHC615>. Compound 115 was heated five degrees above its melting point to afford the novel ring system 116. However, compound 117 gave compound 118 when treated with triethylamine. Similar ring systems were prepared <97JHC1693> by Coppo and Fawzi from the reaction of substituted ethyl 5-[methyl(methylsulfonyl)amino]-1H-pyrazole-4-carboxylates 119 with sodium hydride. This gave the 7-substitued 1,7-dihydro-1-methylpyrazolo[3,4c][1,2]thiazin-4(3H)-one 2,2-dioxides 120 in fair to good yield (Scheme 30). They also extended this synthesis by treating methyl 2-[methyl(methylsulfonyl)amino]-6(trifluoromethyl)-3-pyridinecarboxylate 121 with sodium hydride in dimethylformamide to yield 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide 122 in 79% yield (Scheme 31) <98JHC499>.
Recent progress in the chemistry of 2,1-benzothiazines
R2
R2
R1
R1 N
N N H
N
NHSO2CH2COPh Ph
21
116a: R1 = Ph, R2= CH3
116b: R, R2 = (CH2)4 NH 116c: R1 = (CH2)3, R2 = (CH2)3 SO2
115 R1
Ph
R1 Et3N
N
118a: R1 = CH3
N
NHSO2CH2COPh
N Ph
N Ph
N H
SO2 118b: R1 = Ph
117
Scheme 29 CO2Et
O NaH/DMF
N N R1
NSO2CH3 CH3
N N R1
SO2 N CH3
120: R1 = Ar, CH3, 27-72%
119
Scheme 30 O
CO2CH3 NaH/DMF F3C
N
NSO2CH3 CH3
79%
121
F3C
N
SO2 N CH3
122
Scheme 31 The first synthesis of substituted 2,2-dioxo-1H-thieno[3,4-c][1,2]thiazines 124a and 124b was achieved by Fanghanel and co-workers <98JHC1449>. Reaction of the thiazinecarboxaldehydes 123a and 123b with Et3N in DMF at room temperature gave compounds 124a and 124b in 59% and 49% yields, respectively (Scheme 32). The methyl group of 125a,b is easily deprotonated by a base, such as NaOEt. The corresponding intermediate attacks the nitrile group to yield the benzo[c]thiazines 126a and 126b in 53% and 72% yields, respectively. This method is a very convenient way to prepare substituted 2,2-dioxo-benzo[c]1,2-thiazines (Scheme 33) <99JPR403>.
22
X. Hong and M. Harmata
CHO H3C X
S CH3
N S Ph O O
H3C
sulfur, triethylamine dimethylformamide
X
N S Ph O O
124a: X= SCH3, 59%
123a, b
124b: X= Cl, 49%
Scheme 32 R1
R1 H H3C MeS
NH2
R2 CH3
NaOEt, EtOH
H3C
N S Ph O O
N S Ph O O
X
126a: R1 = CO2Et, R2 = CN, 53%
125a, b
126b: R1 = CN, R2 = CN, 72%
Scheme 33 Moody and co-workers independently prepared the fused 1λ4,ѽ2-thiazines by mild thermolysis <86JCS(P1)483; 81CC927>. The thieno[3,2-c][1λ4,ѽ2]thiazines were successfully synthesized from the azides 127a-g in boiling toluene with varying yields (Scheme 34), which were generally good. Thermolysis of 127g gave a very poor yield of the corresponding sulfimide 128g, since product 128g lacks a stabilizing substituent, and thereby is unstable in refluxing toluene. Ethyl 2-phenyfuro[3,2-c][1λ4,ѽ2]thiazine-3-carboxylate 130 has been prepared by a similar procedure from 129 (Scheme 35). N3
N
S
S
RS
Z
127a-g
S
R Z
128a: R = Ph, Z = CO2Et, 90% 128b: R = Me, Z = CO2Et, 85% 128c: R = Et, Z = CO2Et, 30% 128d: R = Ph, Z = COMe, 90% 128e: R = Ph, Z = CHO, 75% 128f: R = Ph, Z = CN, 90% 128g: R = Me, Z = H, 4%
Scheme 34
23
Recent progress in the chemistry of 2,1-benzothiazines
N3 N O
O
70%
PhS
S
Ph CO2Et
CO2Et
129
130
Scheme 35 Chiacchio and co-workers <97T13855> reported a stereoselective synthesis of 133 via an intramolecular 1,3-dipolar cycloaddition. Intermediate 132 was generated in situ by the reaction of trans-N-(2-formylphenyl)-N-methyl-2-phenylethene-1-sulfonamide 131 with Nmethylhydroxylamine and afforded a tricyclic benzothiazine 133 in 51% yield (Scheme 36). Me
O
N H
Ph
N SO2 CH3
N3
Me N O H
MeNHOH
Ph
Ph
51%
131
N
O
H SO2
N SO2 CH3
N Me
132
N
O S O
Ph Ar
O
PPh3, THF, 25 oC
133
N PPh3
S O
Ph Ar
N O reflux, toluene,
Ph
5h N
S Ar
134a: Ar = pTol
135a: Ar = pTol, 91%
136a: Ar = pTol, 50%
134b: Ar = Ph
135b: Ar = Ph, 95%
136b: Ar = Ph, 48%
Scheme 36 Isoxazolo[4,3-c]-2,1-benzothiazine, a new heterocyclic system, was synthesized by an intramolecular aza-Wittig type ring closure process <04SL101>. This was the first example of the construction of a cyclic sulfimide using aza-Wittig chemistry. Treatment of 3-(oazidophenyl)-4-sulfoxyaryl-isoxazoles 134 with triphenylphosphine under Staudinger reaction conditions gave the corresponding aryliminophosphoranyl 4-sulfoxyaryl-isoxazoles 135a and 135b in the yields of 91% and 95%, respectively. A subsequent aza-Wittig type cyclization of 135a and 135b in refluxing toluene produced isoxazolo[4,3-c]-2,1benzothiazines 136a and 136b in the yields of 50% and 48%, respectively (Scheme 36). In order to study heterocyclic steroid analogues, such as the 7,11-dithiaazasteroid analogues, Fravolini developed the synthesis of new heterocyclic ring systems: tri- and tetracyclic 2,1-benzothiazines <82JHC1045>. Intermediate 137 was prepared from 1-methyl4-oxo-1H-2,1-benzothiazine-4(3H)-one 2,2-dioxide 37 and thioglycolic acid and could be converted into 6-methyl-4-oxo-3,4-dihydro-2H,6H-thiopyrano[3,2-c][2,1]benzothiazine 5,5dioxide 138 by cyclization with polyphosphoric acid. The reaction of 138 with dimethyl
24
X. Hong and M. Harmata
oxalate afforded the glyoxylate 139 in 60% yield. Condensation of the glyoxylate 139 in acetic acid with hydrazine hydrate and hydroxylamine hydrochloride respectively, furnished 5-methyl-1-carbomethoxyl-5H,11H-isoxazole[4,5-c]thiopyrano[3,2-c][2,1]benzothiazine 4,4dioxide 140a and 5-methyl-1-carbomethoxyl-5,11-dihydro-3H-pyrazolo[4,3c]thiopyrano[3,2-c][2,1]benzothiazine 4,4-dioxide 140b in the yields of 62% and 39%, respectively. Decarbonylation of 139 gave the β-keto ester 141 in 69% yield. Reduction of 141 afforded 5-methyl-1-hydroxy-5,11-dihydro-3H-pyrazolo[4,3-c]thiopyrano[3,2c][2,1]benzothiazine 4, 4-dioxide 142 in 40% yield (Scheme 37). O O
OH O
R
144a: R = 2-chloro-4-(methylsulfonyl), 68%
R
144b: R = 2-(2,4-Dichloro-phenyl)-vinyl, 17%
SO2 N CH3
SO2 N CH3
144c: R = 2-(2,6-Dichloro-phenyl)-vinyl, 40%
143
Ph
O O
S CO2H
O
64% N CH3 37
N CH3 137
SO2
N CH3
SO2 N CH3
146a: R = H, 31%
145a,b: 44-64%
57% S
S
O 60% SO2
O SO2 N CH3 139
N CH3 138
140a: X= O, 62%
69% CO2CH3
S N N H
N X
SO2 N CH3
OH S
146b: R = Me, 27% CO2Me
COCO2CH3
S
SO2 N CH3 142
O
R SO2
SO2
R
O
Ph
40%
140b: X= NH, 39%
O SO2
N CH3 141
Scheme 37 Recently, Coppo and Fawzi <98JHC983> reported the synthesis of tricyclic 2,1benzothiazines starting from compound 37 (Scheme 37). They discovered that the O-benzoyl compound 143 can rearrange to the C-benzoyl compounds 144a-c in the presence of acetone and triethylamine in fair to good yields. However, a rearrangement of 145a-b under similar reaction conditions resulted in the formation of novel tricyclic 2,1-benzothiazines 146a and 146b in the yields of 31% and 27%, respectively.
25
Recent progress in the chemistry of 2,1-benzothiazines
1.3 CHEMISTRY OF 2,1-BENZOTHIAZINES 1.3.1 Reactions of 2,1-Benzothiazine 2,2-dioxide As mentioned previously, 1H-2,1-benzothiazine 2,2-dioxide (34, R = H) can be converted into 3,4-dihydro-2,1-benzothiazine 2,2-dioxide 4 by hydrogenation <66JOC3531>. Alkylation and arylation of 4 occurred on the sulfonamide nitrogen to give compound 152 in high yield <65JOC3163; 71CB1880; 66JOC3531>. A similar reaction was further reported by the Loev group in which 2,1-benzothiazine 150 was formed from acrylonitrile and 34 via a Michael addition reaction, followed by a reduction <67MI3>. Electrophilic aromatic substitution reactions have been studied by Loev and Kormendy <65JOC3163> and by Sianesi <71CB1880> and co-workers. Bromination and nitration of 152 only afforded a 6mono-brominated product 153, whereas bromination and nitration of 4 gave a mixture of mono- and disubstituted products 151, where the yields are dependent upon the reaction conditions <65JOC3163; 67MI1>. Another interesting reaction has been reported by Rossi and Pagani <66AC(R)728>. Indole 148 and N-methylaniline 149 were isolated from treatment of 2,1-benzothiazine 147 with copper powder at around 300 oC (Scheme 38) <81JHC73>. R1 153: R =CH 3 R1 = Br, NO 2
CH2 CH 3
N R
SO2
NBS or
NHMe
HNO3
CH 3
149 CH 3
N
SO 2 N CH 3
Cu
N R 152
147
SO2
CH3 R 1 = CH 3
148 O
Me2 SO4
Base, RX
R1 H2
N H 33
SO2
N H
SO2 R1 = H
N H
SO2
4
34: R 1 = H or CH3 NBS or HNO3
1. CH 2=CHCN
R1 = H
2. H2 R1 N
SO2
(CH3 )3 NH 2 150
Scheme 38
R2
N H
SO2
151 :R 1, R2 = Br, NO 2
26
X. Hong and M. Harmata
1.3.2 Reactions of Azathiabenzenes and Azathiaphenanthrenes A further study of azathiabenzenes and azathiaphenanthrenes was reported by the Hori group <84CPB4360; 87CC385> and the Moody group <81CC927; 86JCS(P1)497; 86JCS(P1)501>. An interesting reaction of azathiabenzenes with electrophiles <91JCS(P1)1733; 94JCS(P1)1709> was observed as their compounds possess an ylidic structure <94JCS(P1)1709>. This structure was confirmed by spectral and some chemical evidence <91JCS(P1)1733>. For example, treatment of 52a with dimethyl acetylenedicarboxylate (DMAD) 154 in an aprotic solvent, such as dry benzene, at room temperature gave the adduct 157 in 47% yield. The proposed mechanism involves a fourcentered intermediate 156, which can arise from the first intermediate 155, which was formed by a nucleophilic addition of the ylide anion to DMAD (Scheme 39). When the solvent was changed to a protic solvent (e.g., methanol or ethanol), no thiazocine was observed, but adduct 160 (2:1) was isolated in 65% yield. The structure was determined by X-ray crystallography. It is possible that intermediate 155 was protonated by the protic solvent to give a relatively stable species 158. The next step requires intermediate 158 to be attacked by another molecule of 52a to result in the formation of intermediate 159, which afforded the final product 160 after deprotonation (Scheme 39) <84CPB4360; 82CC1060>. CO2Et
CO2Et S
N
N
Ph
52a
S
MeO2C
CO2Et PhH
Ph CO2Me
MeO2C
155
MeO2C CCO2Me
CO2Et N
S
Ph
MeO2C
H
158
CO2Et
CO2Et N
S
CO2Me 156
EtOH
154
S Ph
N
S Ph
Ph
CO2Me
N
52a
CO2Me
CO2Me
157: 47%
CO2Et
CO2Et CO2Me
S
Ph
N
N
H
N
MeO2C MeO2C
PhS
S Ph
N CO2Me
CO2Et
CO2Et
159
160: 65% 2:1
Scheme 39
SPh
27
Recent progress in the chemistry of 2,1-benzothiazines
Azathiaphenanthrenes can be oxidized by KMnO4 or m-chloroperbenzoic acid to the corresponding sulfoximines 163 in good yields. Azathiaphenanthrene 48a underwent a thermal ring expansion to afford 7H-dibenzo[d,f][1,3]thiazepine 163 in 26% yield by a Stevens-type rearrangment <79TL3969; 84CPB4360; 91JCS(P1)1733> while compound 48c underwent dealkylation to furnish compound 165 by cycloelimination via 164 (Scheme 40).
N
S
xylene
S
N H
CH2 R
48a: R = H 48c: R = alkyl
S
CH 2
N H 162 : R = H, 26%
161
KMnO4 xylene
N
S
CH2 H HC R' 164
S N CH2 R O 163
N H
S
165 . R= alkyl, ~40%
Scheme 40
S N CH2 R 48c RI ( R = Me, Et, et al.)
TMSCl
LDA N 48a
S
CH3
S
N
S CH2
Li 166
TMS 167
RCO 2Et
S
N
N H
R OH
168
Scheme 41
28
X. Hong and M. Harmata
The methyl hydrogen of 9-methyl-10-aza-9-thiaphenanthrene 48a is acidic. It can be readily deprotonated by LDA in THF <91TL4359>. The corresponding anion can be quenched by alkyl iodides to give various 9-alkyl-10-aza-9-thiaphenanthrenes 48c in fair yields (Scheme 41). However, none of the expected products were found when the anion was quenched by TMSCl or esters. Ring expansion product 167 was obtained via sulfonium ylide intermediate 170 derived from the expected product 169 by a 1,2-shift (Scheme 42) <01JA3830; 06JOC3650>. The novel spiro compound 168, the structure of which was confirmed by X-ray analysis, was generated by Sommelet-Hauser rearrangement (Scheme 43) <91JCS(P1)1733; 91TL4359>.
TMSCl
LDA N
S
CH3
N
S
CH2
166 Li
48a
N H
N
S
CH2TMS
169
S
S
S NH CHTMS
CHTMS
170
N H
171
TMS
167
Scheme 42
1. LDA N
S
2. RCO2Et CH3
N
48a
S
CH2COR
172
S
N H
S
CHCOR
173
S R
NH O 174
N
R OH
168
Scheme 43 Recently, Shimizu reported a novel polar cycloaddition of a 1,2-thiazinylium salt <99TL95>. Compound 175 was generated in situ from the reaction of compound 165 with trifluoroacetic anhydride and lithium tetrafluoroborate. It can undergo a cyclization reaction
29
Recent progress in the chemistry of 2,1-benzothiazines
with 1,3-butadienes in 1,2-dichloroethane to afford the corresponding cycloadducts 176 in good yields (Scheme 44). R1
R2
(CF3CO)2O N H
S
LiBF4
N
S
N
S
BF4 R2
BF4 R1
165
175
176
Scheme 44 Fused 1λ4-2-thiazines prepared by Moody and co-workers <81CC927; 86JCS(P1)497; 86JCS(P1)501> were expected to be photo-labile and indeed the sulfur-nitrogen bond was cleaved to give pyrrole products in good yields under irradiation in acetonitrile at 300 or 350 nm (Scheme 45 and Table 6) <81CC927; 86JCS(P1)497; 86JCS(P1)501>. N
S R
X
Z
H N
hu
MeCN
Z X SR
177a-f
178a-f
Scheme 45 Table 6. Photochemical rearrangement of fused 1λ4, 2-thiazines Entry
X
R
Z
Yield (%)
1
S
Me
CO2Et
50
2
S
Ph
CO2Et
83
3
S
Ph
COMe
77
4
S
Ph
CHO
75
5
O
Ph
CO2Et
32
6
CH=CH
Ph
CO2Et
75
The initial intermediates in the photolysis of the fused 1λ4, 2-thiazines, 177a-f were the nitrenes 179. Then electrocyclic ring closure of the resulting nitrenes 179 led to the nonaromatic fused 2H-pyrrole 180, followed by [1,5] sigmatropic shifts of –SR and hydrogen to give the pyrrole products 178a-f. It is very interesting that the observed products arose from the exclusive migration of the sulfur substituent in 180 in the presence of ester, ketone and aldehyde groups (Scheme 46) <86JCS(P1)497; 86JCS(P1)501>.
30
X. Hong and M. Harmata
N
S R
X 177a-f
N
hu
Z
SR
X
Z
179
Z X H
N SR
[1,5] shift
N
of -SR
Z
X
SR
180
181 2X[1,5]H shift
[1,5]Z shift
H N
N SR
Z
X
X 178a-f SR
Z
182 H
Scheme 46 On the other hand, thermal rearrangement of sulfimides gave completely different products, resulting from [1,4] shift <86JCS(P1)483; 86JCS(P1)491; 82CC884>. Usually, fused 1λ4, 2-thiazines are thermal stable up to 120 oC, but they were gradually consumed when they were heated in boiling xylene. They were found to rearrange to the 4aH-isomers 183a-g in good to excellent yield, with the exception of the benzo compound, which was thermally stable (Scheme 47 and Table 7). N X
N
S R X
Z
R
177a-g
S
Z 183a-g
Scheme 47 Table 7. Thermal rearrangement of fused 1λ4, 2-thiazines Entry
X
R
Z
Yield (%)
1
S
Me
CO2Et
40
2
S
Ph
CO2Et
94
3
S
Ph
COMe
80
4
S
Ph
CHO
54
5
O
Ph
CO2Et
98
6
CH=CH
Ph
CO2Et
-
7
S
Ph
CN
88
31
Recent progress in the chemistry of 2,1-benzothiazines
1.3.3 Functionalization of Harmata-type Benzothiazines via a Sulfoximine-Stablized Vinyl Carbanion Lithiation of to form 184 was reported by the Harmata group to be the first example of a sulfoximine-stabilized vinyl carbanion. The resulting organolithium species 184 reacted with various electrophiles to supply structurally diverse benzothiazines <88TL5229>. However, the diastereoselectivity of the reactions with aldehydes was low (Scheme 48). CH3 TMS CH3
N
S O pTol
CH3I 79%
N
S O pTol
3
EtCHO Et 83%, 1.9:1
Li
S O pTol
Br
pTol
TMSCl 89% C2Br2Cl4 CH 98%
CH3 OH
N
CH3
S O
N
CH3
N Ph2CO, 65%
184
CH3 OH Ph Ph S O N pTol
CH3
ClCO2C3H5 73%
S O pTol
CO2C3H5 N
t-BuCHO 76%, 2.4-2.8:1
S O pTol
CH3 OH
PhCHO 84%, 1.2:1
t-Bu N
CH3 OH
S O pTol
Ph N
S O pTol
Scheme 48 1.3.4 Indole Synthesis Harmata and Herron <91T8855>, discovered that the adducts from Lewis-acid mediated synthesis of 2,1-benzothiazines could have use in the synthesis of the other heterocyclic H
185
H S O N pTol
1. n-BuLi 2. MoOPH 3. KOH
N H 186 : 55%
Scheme 49
32
X. Hong and M. Harmata
systems. For example, benzothiazine 185 was reacted with n-BuLi followed by oxidation of the corresponding carbanion with MoOPH. A hydrolytic work-up gave tetrahydrocarbazole 186 in 55% yield (Scheme 49). 1.3.5 Aniline Synthesis Harmata and co-workers introduced a procedure for the reductive desulfurization of selected 2,1-benzothiazines with sodium amalgam, leading to the formation of the 2alkylanilines in high yields <94S142>. This method is regioselective and general. As an example, alkylation of 187 followed by treatment with Na/Hg resulted in the formation of the aniline 188 in 68% overall yield (Scheme 50). 1. n-BuLi TMS I N
S O pTol
TMS
2. Na/Hg NH2
68%
187
188
Scheme 50 Harmata and co-workers also discovered that 2,1-benzothiazines could be conveniently converted into 2-alkenylanilines by treatment with KDMSO in DMSO <91JOC5059; 91T8855>. For example, the reaction of benzothiazine 185 with KDMSO for 20 minutes at 70 oC resulted in the formation of the 2-alkenyl sulfinamide 189 in 90% yield (Scheme 51). H H N
2.0 eq. KDMSO 90%
S O pTol
NHSOpTol
185
189
Scheme 51 The 2-alkenyl sulfinamides appeared to be slightly unstable. They could, however, be quickly converted into anilines by base-catalyzed hydrolysis in good yields (Scheme 52) <91JOC5059; 91T8855>. This general route to 2-alkenyl anilines is regioselective, but not stereoselective. R2
R2 R3
1. KOH (2.0 eq.) +
2. H R1 NHSOpTol 190
R3 R1 NH2
191: R1, R2, R3 = H, alkyl, cycloalkyl 67-92%
Scheme 52
33
Recent progress in the chemistry of 2,1-benzothiazines
The Harmata group <95TL4769> also used the reductive desulfurization of 2,1benzothiazines to produce 2-alkenylanilines 192 in good yields (Scheme 53). This method is quite general, regioselective and stereoselective in some cases. R1
R1 R2
N
Na/Hg
R1 H
S O pTol
R2
+
R2 NH2
H NH2
(Z)-192 (major)
(E)-192 (minor)
R1, R2 = H, alkyl, TMS, phenyl 57%-92%
Scheme 53 A general route to allylanilines, reported by Harmata and co-workers <95TL4769> could be of value in organic synthesis. Deprotonation of 2,1-benzothiazines 193 with n-BuLi followed by alkylation with iodomethyltrimethylsilane, and subsequent desilylation with fluoride followed by hydrolysis led to allyl aniline 194 in good yields (Scheme 54). R1 R2
1. n-BuLi
R2
R1
2. TMSCH2I N
3. TBAF
S O pTol
4. KOH
NH2 194: R1, R2 = H, alkyl
193
Scheme 54 In 1998, Harmata and co-workers <98T9995> published a new synthesis of 2-alkenyl anilines. The silylated 2,1-benzothiazines 187 could be deprotonated by n-BuLi and alkylated by different electrophiles. The corresponding products could be desilylated by fluoride with concomitant cleavage of the carbon-sulfur bond to give 2-alkenylsulfinanilides that can then be hydrolyzed by base to the anilines 195 in good yields (Scheme 55). TMS
1. n-BuLi R
2. RX N 187
S O pTol
3. TBAF 4. KOH
Scheme 55
NH 2 195
34
X. Hong and M. Harmata
1.3.6 Chiral Ligands in Asymmetric Allylic Alkylation The development of sulfoximines as ligands for transition metal-catalyzed asymmetric organic reactions is only currently being realized <00S1>. Recently, Harmata and Ghosh <01OL3321> reported the preparation of both enantiomers of ligand 197 using the procedure mentioned earlier <99AG(E)2419> starting with the dialdehyde 196, as shown in Scheme 56. O S Ph N
CHO Ph
Br + Br
Pd(dba)2, rac-BINAP, Cs2CO3,
N S O H
toluene, 110 oC, 2 days, 68%
N S Ph O
Me
CHO (R)-77b
196
(R, R)-197
Scheme 56 OAc + CH2(CO2Me)2 Ph
Ph 198
2.5 mole% Pd, (R, R)-197, (10 mol%) solvent, BSA (3 eq.), KOAc (cat.)
MeO2C Ph
199
CO2Me
Ph (S)-200
Scheme 57 Table 8. Reacemic 1,3-diphenylallyl acetate with dimethyl malonate under various conditions Entry
Ligand
Pd source
Sovent
Time (h)
Yield (%)
Ee (%)
1
(R,R)-197
[Pd(allyl)Cl]2
THF
5
80
80
2
(S,S)- 197
[Pd(allyl)Cl]2
THF
3.5
90
80
3
(R,R)- 197
[Pd(allyl)Cl]2
benzene
3
90
82
4
(S,S)- 197
[Pd(allyl)Cl]2
benzene
3
85
82
5
(R,R)- 197
[Pd(allyl)Cl]2
toluene
3.5
85
78
6
(S,S)- 197
[Pd(allyl)Cl]2
toluene
3.5
70
78
7
(R,R)- 197
[Pd(allyl)Cl]2
CH2Cl2
4
30
0
8
(R,R)- 197
[Pd(allyl)Cl]2
CH3CN
5
45
0
9
(R,R)- 197
Pd2(dba)3
THF
3.5
75
86
10
(S,S)- 197
Pd2(dba)3
THF
3.5
69
86
11
(S,S)- 197
Pd(OAc)2
THF
7.5
67
73
12
(R,R)- 197
Pd(OAc)2
THF
7.5
68
73
13
(S,S)- 197
Ph(PPh3)4
THF
5
90
16
14
(R,R)- 197
Ph(PPh3)4
THF
5
79
6
Recent progress in the chemistry of 2,1-benzothiazines
35
They demonstrated that the C2-symmetric bis-benzothiazine (R,R)-197 was an effective ligand in the asymmetric allylic alkylation reaction. The best result in this case was the reaction of 198 and 199 in the presence of BSA, Pd2(dba)3 and (R,R)-197, which gave the product (S)-200 in 75% yield and 86% ee. More experimental data revealed that solvent effects are very important in this reaction (Scheme 57). Relatively nonpolar solvents resulted in good yields and enantiomeric excesses while reaction in CH3CN and CH2Cl2 gave only racemic products in moderate yields (Table 8).
O S N Cu N S O Ph Ph
201
Figure 10. X-ray structure of 201, a chiral, copper(I) complex of styrene Although the basis for the stereochemical outcome of asymmetric allylic alkylation reaction by bis-benzothiazine is not very clear <01OL3321>, bis-sulfoximines, the closely related bis-benzothiazines, and other ligands stereogenic at sulfur are important and potentially practical ligands for the future <03OL427; 01SL1878; 00S1; 01OL3321; 01JA3830; 03MI1>. In order to expand the scope of the chemistry associated with 197, the Harmata group has examined asymmetric cyclopropanation reactions using ligand (R,R)-197 <03JSMC349>. As a part of this research, the crystal structure of a chiral, copper(I) complex of styrene 201 was obtained, which suggested that edge-face interactions as well as stacking may be important in the recognition of enantiofaces of alkenes by chiral copper(I) complexes of 197 <03JSMC349>.
36
X. Hong and M. Harmata
1.3.7 New Chiral Benzothiazine Ligand for Catalysis and Molecular Recognition A new chiral benzothiazine ligand 205 was synthesized by Harmata and co-workers <06JOC3650>. It could be converted into a chiral molecular receptor 207 in a simple way. This chiral species 207 could be used as a new class of chiral molecular tweezers. The synthesis of 205 commenced with the protection of the commercially available compound 202, which was then coupled with (R)-sulfoximine 77b using the one-pot, one-operation procedure <99AG(E)2419> affording enantiomerically pure benzothiazine 204. This was followed by deprotection to produce benzothiazine 205 in good yield.
CHO
CHO 5% Pd(OAc) 2, 7.5% BINAP
5.0 eq. TEA, 0.5 eq. Br OH
THF, rt, 2 h
202
OMOM
93%
N OMOM
S O Ph
1.6 eq. Cs2 CO3 , 1.2 eq. (R)-77b
Br
NaI, 2.0 eq. MOMCl,
toluene, reflux, 48 h 89%
203
i-PrOH, THF, H2 O, rt, 3 h N
100% OH
204
S O Ph
205 N
Cl Cl
N H
Cl
2.3 eq. NaH, 2.1 eq. 205, DMF, 20 h, rt 89%
206
O N S Ph O
O N Ph 207
S O
Scheme 58 1.3.8 Application of 2,1-Benzothiazines in Natural Products Syntheses The Harmata group has shown that the benzothiazines prepared by the conjugate addition of sulfoximine carbanions to α,β-unsaturated esters <03JA5754> can be used as enantiomerically pure starting materials for the synthesis of natural products. The benzothiazine synthesis establishes a stereogenic center with complete fidelity at a postion alph to a benzene ring. There are a number of natural products that possess such stereogenic centers. The Harmata group has successfully applied the methodology to the synthesis of such compounds including (+)-curcumene 208 <03TL7261>, (+)-curcuphenol 209 <03TL7261>, erogorgiaene 210 <05TL3847>, pseudopteroxazole 211 <04OL2201; 05OL3581> and several related natural products.
37
Recent progress in the chemistry of 2,1-benzothiazines
Me
Me
Me
Me
Me Me H
Me Me
Me
R
Me Me H
Me N
208. R = H, S-(+)-curcumene
O
Me
209. R = OH, S-(+)-curcuphenol
210. erogorgiaene
Me
211. pseudopteroxazole
Figure 11. Natural product targets. Pseudopteroxazole 211 is a member of the amphilectane class of diterpenes and was isolated from a marine soft coral Pseudopterogorgia elisabethae <99OL527>. Pseudopteroxazole 211 possesses considerable inhibitory activity against M. tuberculosis H37Rv at a concentration of 12.5 ȝg/mL (97% growth inhibition). Given continuing global problems with respect to the treatment of tuberculosis, both the structure of 211 and its biological activity provide an impetus for syntheis. The total synthesis commenced with the coupling of ester 212 with (R)-sulfoximine (R)-77b to afford enantiomerically pure sulfoximine, which was then treated with LDA followed by a proton quench to produce benzothiazine 213 as a 10:1 mixture of diastereomers in good yield. Subjecting 213 to a twostep reduction/oxidation and spontaneous epimerization sequence afforded aldehydes 214a and 214b in a 1.6:1 ratio (Scheme 59). The mixture was treated with a Wittig reagent to provide 215a and 215b in 52% and 33% yields, respectively, as single stereoisomers. Me
CO2Et
Me
EtO 2C Me
a, b Br
N
OMe
OHC
Me H
OMe
212
H
Me
c, d
S O Ph
N OMe
213 Me
OHC Me
OMe
Me
Me
H
Me
+
S O N Ph
N OMe
214b
Me
Me e
S O Ph
214a
Me
Me H
Me
S O Ph
215a (52%)
H
Me N OMe
S O Ph
215b (33%)
(a) Pd(OAc)2, BINAP, (R)-sulfoximine, 81%; (b) LDA, 88%; (c) LAH; (d) Swern, 81%, 1.68:1, 2 steps; (e) Wittig
Scheme 59
38
X. Hong and M. Harmata
Interestingly, treatment of diene 215a with methanesulfonic acid afforded 216 as a single diastereomer in 88% yield, the structure of which was confirmed by X-ray analysis (Scheme 60). The transformation of 216 into 217 started with an alkylation, followed by reductive desulfurization and triazene formation to afford compound 217 in 92% yield. Upon treatment with diiodomethane, triazene 217 was smoothly converted to aryl iodide 218 in 75% yield. Pd-catalyzed intramolecular Heck coupling of 218 led to the desired product 219b in 62% yield. Me
Me
Me
Me Me H
Me 215a
a
H
Me N OMe
b, c, d
Me
S O Ph
OMe
216 Me
Me
Me
f
N N NEt2 217
Me Me H
e
Me
Me
Me Me H
Me Me
+
H
Me
I OMe 218
OMe CH2 219a (14%)
OMe Me 219b (62%)
(a) MsOH, 88%; (b) LiHMDS, allyl bromide; (c) Na/Hg, 92%, 2 steps; (d) HONO, Et2NH, 100%; (e) CH2I2, 20 h, 75%; (f) 2% Pd(OAc)2, 4% (o-Tol)3P, TEA, 120 oC, 38 h
Scheme 60
Stereoselective reduction of 219b was conducted using one of Pfaltz’s chiral catalyst to deliver compound 220 in 90% yield (Scheme 61). Demethylation of 220 with NaSEt afforded the phenol in 87% yield. Subsequent nitration of the phenol with concentrated HNO3 produced the corresponding nitrophenol in 84% yield. With the nitrophenol in hand, the last stage of the synthesis involved assembling the benzoxazole ring. Reduction of the nitrophenol with Zn dust, followed by treatment with methyl orthoformate and catalytic TsOH, completed the synthesis of pseudopteroxazole 211 in 65% yield for the last two steps (Scheme 61). After the successful synthesis of pseudopteroxazole 211, the synthesis of the structurally-related compound erogorgiaene 210, which also shows antituberculosis activity, was reported <01JNP100>. This synthesis was a formal synthesis of erogorgiaene using essentially the same methodology (Scheme 62) as that used for the synthesis of 211. Aniline 221 was converted into the iodide using triazene chemistry. A Sonogashira coupling reaction of the corresponding iodide followed by Swern oxidation and Wittig reaction afforded the
39
Recent progress in the chemistry of 2,1-benzothiazines
intermediate 222 in excellent yield. Hoveyda and co-workers<04JA96>. Me
219b
a
This compound was convered to erogorgiaene by
Me
Me Me H
Me
b, c, d, e
Me Me H
Me N
OMe Me
O 211
220
Me O (o-Tol)2P
Me
Me
CF3
O Ir
B
N
4 CF3
tBu
Pfaltz chiral catalyst
(a) 3% catalyst, 200 psi H2, rt, 1 h, CH2Cl2, 90%, 158:1; (b) 7.0 eq. NaH, 6.0 eq. EtSH, DMF, overnight, reflux, 87%; (c) HNO3, Hexanes, 1.5 min, 84%; (d) Zn, NH4Cl, 90% MeOH, rt, 1 h; (e) CH(OMe)3, TsOH (cat), 65%, two steps
Scheme 61
CO2 Me
Me
N
S
Me a, b
Ph
c, d, e, f, g Me
O
NH2 OH
94
221 Me
Me 12 steps
Me
H
Me 222
Me
TMS Me
Me
210; erogorgiaene ( tr an/ syn )
(a) LAH: (b) Na/Hg, (c) 4.5 eq. HCl, 3.4 eq NaNO2, 5.0 eq K2CO3, 5.0 eq. Et2NH, 90%; (d) CH3I, 130 o C, 0.5 h, 80%; (e) 0.12 eq PPh3, 0.06 eq PdCl2, 0.06 eq. CuI, Et3N, 2.0 eq. (trimethylsilyl)acetylene, 90%; (f) Swern oxidation, 96%; (g) Ph3PCH3, n-BuLi, THF, 98%.
Scheme 62
40
X. Hong and M. Harmata
In addition to these studies, the Harmata group also successfully achieved the total synthesis (+)-curcumene 208 and curcuphenol 209 utilizing the 2,1-benzothiazine chemistry <03TL7261>. The synthesis of (+)-curcuphenol was accomplished by reduction of benzothiazine 94, followed by protection, desulfurization, reductive deamination and deprotection to give diol 223 in good yield. The latter was then converted into (+)curcuphenol 209 (Scheme 63). The total synthesis of (+)-curcumene involved a similar approach to that of (+)-cucurphenol. CO2Me
Me a, b ,c, d, e
Me
N
S
Ph
OH Me
O 94
OH 223
a, f, g Me OBn Me
h, i, j, k
209 ; (+)-curcuphenol 208; (+)- curcumene
NH2 224
(a) LAH; (b) DHP, TsOH; (c) Na/Hg, 74%, three steps; (d) isoamyl nitrite, DMF, 50%; (e) H+ (f) NaH, BnBr; (g) Na/Hg; (h) HONO, NaBH3CN, 61%; (i) Pd/C, H2; (j) (Ph2PCH2-)2, Br2; (k) 2-methylpropene lithium
Scheme 63
1.4 ACKNOWLEDGEMENTS We are grateful to Prof. Paul A. Wender, Prof. Andreas Pfaltz, Prof. Abimael D. Rodriguez and Dr. Jeff Zablocki (CV Therapeutics) for their constant encouragement and informative conversations in the course of our work on benzothiazines. All those past and present members of our research group at the chemistry department at the University of Missouri-Columbia as well as all individuals whose names are included in the references are gratefully acknowledged. Our work in this area has been supported by the NIH (1R01AI59000-01A1) and the donors of the Petroleum Research Fund, sponsored by the American Chemical Society (38288-AC1 and others), to whom we are extremely grateful. 1.5 REFERENCES 64JOC1688 65JOC3163 66AC(R)728 66AC(R)741 66JOC3531 66MI1 66MI2
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66MI3 67AC(R)1426 67CB2151 67CB2164 67JHC403 67JOC506 67MI1 67MI2 67MI3 67MI4 68MI1 69M928 69MI1 71CB1880 71MI1 71OPP33 72JCS(P2)1134 72JHC315 75JA676 76JHC615 77MI1 78H(11)377 79TL3969 81CC927 81JA1525 81JHC73 82CC1060 82CC884 82JHC1045 82JOC1909 83JCS(P2)1719 83JOC4275 84CPB4360 84JCS(P1)2429 84JOC5124 84MI1 84T1919 85JOC2066 86H(24)2739 86JCS(P1)483 86JCS(P1)483 86JCS(P1)491 86JCS(P1)497 86JCS(P1)501 86JCS(P2)645 87CC385 87TL5997 88TL5229 89MI1 90JCS(P1)2089
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42 90TL7021 91CC877 91JCS(P1)1733 91JMC2477
91JOC5059 91T8855 91TL4359 92MI1 92MI1 93JMC2242
94JCS(P1)1709 94MI1 94S142 94TL2911 95TL4769 97JHC1693 97T13855 97TA909 97TL137 98JHC1449 98JHC499 98JHC983 98JOC6845 98MI1 98T9995 98TL5731 99AG(E)2419 99BMCL673
99JOM(576)125 99JPR403 99OL527 99TL95 00JOC169 00JOC8086 00JOC8391 00JOC926 00S1 00SL475 01JA3830 01JNP100 01OL3321 01SL1878 01T5915 02MI1
X. Hong and M. Harmata
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Recent progress in the chemistry of 2,1-benzothiazines
02MI2
02MI3 02SL832 03ARK11 03JA5754 03JOC9574 03JSMC349 03MI1 03OBC1342 03OL427 03TL7261 04JA96 04MI1 04OL2201 04SL101 04TL5233 05OL3581 05TL3847 06JOC3650
43
I. Yoshida, N. Yoneda, Y. Ohashi, S. Suzuki, M. Miyamoto, F. Miyazaki, H. Seshimo, J. Kamata, Y. Takase, M. Shirato, D. Shimokubo, Y. Sakuma, H. Yokohama, WO 2002088107, 2002; Chem. Abstr., 137, 353066. J.F. Hartwig, Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 1051. C. Bolm, M. Martin, L. Gibson, Synlett 2002, 832. K. Sakuratani, H. Togo, ARKIVOC. 2003, vi, 11. M. Harmata, X. Hong, J. Am. Chem. Soc. 2003, 125, 5754. J.T. Manka, F. Guo, J. Huang, H. Yin, J.M. Farrar, M. Sienkowska, V. Benin, P.Kaszynski, J. Org. Chem. 2003, 68, 9574. M. Harmata, S.K. Ghosh, C.L. Barnes, J. Supramol. Chem. 2003, 2, 349. M. Harmata, Chemtracts 2003, 16, 660. Y. Misu, H. Togo, Org. Biomol. Chem. 2003, 1, 1342. C. Bolm, M. Martin, O. Simic, M. Verrucci, Org. Lett. 2003, 5, 427. M. Harmata, X. Hong, C.L. Barnes, Tetrahedron Lett. 2003, 44, 7261. R.R. Cesati, J. De Armas, A.H. Hoveyda, J. Am. Chem. Soc. 2004, 126, 96. C. Yoakim, J. O'Meara, B. Simoneau, W.W. Ogilvie, R. Deziel, WO 2004026875, 2004; Chem. Abstr., 140, 303707. M. Harmata, X. Hong, C.L. Barnes, Org. Lett. 2004, 6, 2201. K. Hemming, C. Loukou, S. Elkatip, R.K. Smalley, Synlett 2004, 101. M. Harmata, X. Hong, S.K. Ghosh, Tetrahedron Lett. 2004, 45, 5233. M. Harmata, X. Hong, Org. Lett. 2005, 7, 3581. M. Harmata, X. Hong, Tetrahedron Lett. 2005, 46, 3847. M. Harmata, N.L. Calkins, R.G. Baughman, C.L. Barnes, J. Org. Chem. 2006, 71, 3650.
44
Chapter 2 Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions Ana M. G. Silva and José A. S. Cavaleiro* Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal E-mail:
[email protected]
2.1
OVERVIEW OF THE CYCLOADDITION REACTIONS OF PORPHYRINS
Interest in porphyrin chemistry started centuries ago with Man trying to understand why blood is red and plants are green <78MI1>. However it was only in 1929 that the macrocylic structure of a porphyrin was unambiguously demonstrated by Hans Fischer at his Munich school with the first synthesis of protoporphyrin IX. The iron complexes of such natural compounds play key roles in several vital functions (e.g., respiration and drug detoxification) and its magnesium complex is a precursor of chlorophyll a. As a result of this pioneering synthetic work Fischer was awarded the Nobel Prize in 1930 <94MI1>. Mainly after the second world war, chemists have looked for better synthetic methodologies leading to porphyrins and for the understanding of their biosynthesis, mode of action and catabolism. With the advent of synthetic porphyrins, potential applications in medicine, in catalysis and in other areas have become possible. Several research groups have been dedicating their efforts to the synthesis of simple porphyrins containing groups on meso- and/or betapositions of the macrocycle. Other topics of research have centred on the transformation of the periphery of the macrocycle via functionalization reactions including electrophilic substitutions, nucleophilic addition of alkyllithium reagents, peripheral reduction, oxidation and pericyclic reactions <00COC139; 00MI1>. Benzoporphyrins, chlorins (dihydroporphyrins) and bacteriochlorins (tetrahydroporphyrins) are important derivatives which can demonstrate significant medicinal applications. The search for new synthetic methodologies leading to such compounds is a target for many groups. Diels–Alder (DA) and 1,3-dipolar cycloaddition (1,3-DC) reactions are simple and very versatile transformations to introduce a wide range of substituents at the meso- and betapyrrolic positions of porphyrins, thus leading to promising derivatives obtained in many cases in one-pot transformations. The use of beta-vinylporphyrins as dienes in DA reactions has been known for decades and has been recently reviewed <03A107>. This review will focus only on the use of porphyrins as dienophiles in DA reactions as well as on the use of porphyrins and porphyrinic derivatives in 1,3-DC reactions.
45
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
2.2 2.2.1
PORPHYRINS IN CYCLOADDITION REACTIONS Porphyrins as dienophiles in Diels-Alder reactions
The possibility of using porphyrins as dienophiles in DA reactions emerged in 1997 when Cavaleiro and coworkers <97CC1199> found that meso-tetraarylporphyrins 1a-d can behave as dienophiles in the presence of o-benzoquinodimethane, a highly reactive diene generated in situ by the thermal extrusion of SO2 from a sulfone by refluxing in 1,2,4trichlorobenzene, TCB, giving chlorins 2a-d in moderate yields (Scheme 1). O2S Ar X NH
NH
N Ar
Ar N
Ar
TCB reflux
+
Ar HN
N
HN
Ar
X
N
Ar
Ar
1
2 a Ar= Ph, X=H b Ar= m-MeOC6H4, X=H c Ar= p-MeOC6H4, X=H d Ar= C6F5, X=H e Ar= Ph, X=NO2
Scheme 1. DA reactions of porphyrins 1 with o-benzoquinodimethane. As well as the synthesis of chlorins 2a-c, the DA reactions of porphyrins 1a-c with obenzoquinodimethane gave two naphthoporphyrins 3 and 4 (Figure 1) resulting from the diand tetradehydrogenation reactions of the corresponding chlorins. On the other hand, the reaction with porphyrin 1d having pentafluorophenyl groups in the meso positions, afforded the chlorin 2d and a diastereomeric mixture of two bacteriochlorin bis-adducts 5d and 6d (Figure 2), showing that the presence of electron-withdrawing groups at the meso-position of the porphyrin greatly improve the DA reactions with o-benzoquinodimethane.
Ar
NH
Ar
NH
N Ar
Ar N
HN
Ar
N Ar
Ar HN
N
3
Ar a Ar= Ph b Ar= m-MeOC6H4 c Ar= p-MeOC6H4
Figure 1. Naphthoporphyrins 3 and 4.
4
A.M.G. Silva and J.A.S. Cavaleiro
46
C6F5 NH
NH
N C6F5
F5C6
NH
N C6F5
F5C6
HN
N
Ph
C6F5
C6F5 5d
Ph HN
N
HN
N
N
Ph
C6F5
Ph
6d
7
Figure 2. Bacteriochlorins 5d and 6d and bis-naphthoporphyrin 7.
A beta-substituted porphyrin, such as beta-nitro-meso-tetraphenylporphyrin 1e, also reacts with o-benzoquinodimethane to give the corresponding nitrochlorin 2e, together with the naphthoporphyrin 4a and the bis-naphthoporphyrin (bisadduct) 7; the formation of these 4a and 7 derivatives imply HNO2 elimination and dehydrogenation reactions <06TL8437>. Subsequently, other publications have appeared involving the DA reactions of porphyrins with other dienes. For instance, the reaction of mesotetrakis(pentafluorophenyl)porphyrin 1d with the diene generated from pyrrole-fused 3sulfolene gave rise to the isoindole-fused chlorin derivative 8 accompanied by a mixture of stereoisomeric bacteriochlorins 9 (Scheme 2) <98CC2355>. NH
NH
O2S NH
NH
NH
N HN
Ar
TCB, reflux
NH
N Ar
N
Ar
CO2Et
Ar
Ar
Ar N
Ar
CO2Et
Ar
N Ar
Ar
+
N
HN
Ar
CO2Et
EtO2C
HN
Ar HN
1d Ar= C6F5
8 (32-39%)
9 (mixture of stereoisomers)
Scheme 2 DA Reaction of porphyrin 1d with a pyrrole-fused 3-sulfolene.
Furthermore, it was shown that porphyrin 1d can also react with a pyrazine o-quinodimethane derivative ( Scheme 3) <05TL2189>. However, in this case the reaction did not afford the expected DA adduct, the product being the porphyrin derivative 10 resulting from the tetradehydrogenation of the corresponding adduct. The porphyrin derivative 11 was also obtained although in minor amount; this product must result from a cyclization reaction between the beta-fused quinoxaline ring and the adjacent meso-aryl group. Also, bisadducts 12 and 13 were isolated; these are the result of site specific bisaddition to opposite pyrrolic rings followed by oxidative processes.
47
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
CN
CN
N Ar
Ar
NH
Br Br
N
N
CN
N
CN
NH
N
NH
N Ar +
Ar NaI, TCB, reflux
HN
N
CN
Ar
N
F
Ar
Ar
N
CN
N
F
Ar
HN
HN
N
F
Ar
Ar
F
Ar
10 (34%)
1d Ar= C6F5
N
11 (3%)
CN N
Ar
CN N
CN Ar
N
CN N F
NH
NH
N Ar +
Ar N N NC
N N NC
N NC
F
Ar
HN
Ar 12 (6%)
N HN F
F
Ar N 13 (1%)
NC
Scheme 3 DA reaction of porphyrin 1d with pyrazine o-quinodimethane derivative. C6F5
Ph
C6F5 N
NH N
C Ph
Ni
Ph
N
N
NH
N
N
HN
C6F5
C6F5
N C6F5
14
Ph
benzene, reflux
C6F5 16
1. benzene, reflux 2. DDQ
C6F5
Ph
C6F5 N
N N Ph
C Ph
Ni N
N
NH
N
N
HN
C6F5
C6F5
N Ph
15 (23%)
C6F5
C6F5 17 (55%)
Scheme 4. DA Reactions of N-confused porphyrin 14 and hexaphyrin 16 with obenzoquinodimethane.
A.M.G. Silva and J.A.S. Cavaleiro
48
The DA reactions with o-benzoquinodimethane have also been extended to nickel(II) Nconfused porphyrin 14 to yield nickel(II) N-confused isoquinoporphyrin 15 ( Scheme 4) <02CC1816>. The reaction occurred selectively in the peripheral carbonnitrogen bond, showing that this bond is more reactive than the other carbon-carbon double bonds. This can be understood by the resonance contributions to the overall structures. Figure 3 shows two such resonance structures. In the canonical form II the C=N is both “cross conjugated” and in an iminium form which is known to be electron-deficient and an active dienophile <02CC1816>. Ph
Ph NH
N
Ph
Ni
Ph
NH N
C
Ph
Ni
Ph
N
N
C N
N
Ph I
Ph II
Figure 3. Two canonical forms of N-confused porphyrin 14. Similarly, the DA reaction of o-benzoquinodimethane with the hexaphyrin 16, followed by treatment with DDQ, gave rise to the naphthohexaphyrin 17 <05AC(E)932>. This result revealed that the first addition of the diene took place selectively at the inner inverted betapyrrolic double bond, suggesting that this double bond is the most reactive position of the macrocycle. In minor amount the reaction also gave rise to a bisnaphthohexaphyrin. Curiously, this compound resulted from the selective addition of a second obenzoquinodimethane species to an outer beta-pyrrolic double bond of the naphthohexaphyrin 17, and is in agreement with the theoretical calculations that predicted that the second cycloaddition could not occur at the other side of the inner double bond of 17. C6F5
C6F5 N H N
N H N C6F5
C6F5 1d C6F5
C6F5
C6F5
C6F5
N H N
N H N
N
H N C6F5
N H N
C6F5 18d
8 h, 200 °C , 22% MW, 3x10 min, 200 °C , 83%
C6F5
C6F5 19d
heat, no reaction MW, 3x15 min, 180 °C , 23%
Scheme 5. DA Reaction of porphyrin 1d with pentacene and naphthacene.
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
49
It has also been shown that polycyclic hydrocarbon derivatives can react successfully with porphyrins. In fact, meso-mono-, meso-di- and meso-tetraarylporphyrins react with pentacene providing chlorin-type derivatives in moderate to good yields, depending on the number, steric hindrance and electron withdrawing character of the meso-aryl groups (Scheme 5) <00TL3065>. In the particular scenario of the DA reaction of mesotetrakis(pentafluorophenyl)porphyrin 1d with pentacene (after 8 h at 200 ºC), chlorin 18d was obtained in 22% yield. This yield was improved to 83% and the reaction time reduced to 30 minutes by performing the reaction under microwave irradiation (after 3x10 min at 200 ºC) <05TL4723>. Moreover, using microwave irradiation, the same porphyrin 1d reacted with naphthacene (after 3x15 min at 180 ºC) providing a synthesis of the corresponding chlorin 19d (as a mixture of isomers), which could not be obtained by a procedure using conventional heating. DA reactions with polycyclic hydrocarbon derivatives have also been applied to other macrocycles. Lukyanets and coworkers have explored this methodology by adding the unsubstituted tetraazaporphine 20 to a series of anthracene derivatives (Scheme 6). For instance, the reaction with naphthacene (after 6 h at reflux) afforded the chlorin 21 and a tetraazabacteriochlorin (bisadduct) in small amounts <00JPP525>.
N
N H
N
N N
N
N
H N
N C6H5Cl, reflux
N
N H
N
N N
H N
20
N 21 (39%)
Scheme 6. DA Reaction of the tetraazaporphine 20 with naphthacene.
The same strategy provides a useful tool to derivatize corrole 22 and sapphyrin 25 (Scheme 7). In the case of corrole 22, the reaction with pentacene (after 6 h at 200 ºC) afforded mainly the dehydrogenated adduct 23; this is formed from the selective addition of pentacene to the beta-pyrrolic double bond near to the direct pyrrole–pyrrole link and subsequent dehydrogenation <04S1291>. In minor amount, the reaction also gave rise to the dehydrogenated adduct 24 resulting from an unexpected thermal [4+4] cycloaddition reaction. In the reaction with sapphyrin 25, adduct 26 was produced with high selectivity (MW, 1 h, 200 ºC), showing once again that the beta-pyrrolic double bond close to the pyrrole-pyrrole link contains the most reactive position of this type of macrocycle <06TL3131>.
2.2.2 Porphyrins as 1,3-dipoles in 1,3-dipolar cycloadditions In 1995, Boyd and co-workers <95TL7971> covalently linked a porphyrin to fullerene C60 through a 1,3-dipolar cycloaddition reaction involving the porphyrinic azomethine ylide 28 (Scheme 8). The ylide was generated in situ from beta-formyl-meso-tetraphenylporphyrin 27 and N-methylglycine, and provided the porphyrin–C60 diad 29 in good yield.
A.M.G. Silva and J.A.S. Cavaleiro
50
C6F5 R HN
N
N C6F5
C6F5
N H N
NH HN
H N
22
25 R=(CH2)3OAc MW TCB, 200 °C
TCB 200 °C C6F5
C6F5 N
R
N H
N
HN C6F5
C6F5
+
R
HN C6F5
C6F5
N
NH HN
NH HN
23 (23%)
R
N H N H N
H N
26 (51%)
24 (13%)
Scheme 7. DA reactions of corrole 22 and sapphyrin 25 with pentacene.
Ph
N
CHO
N M
Ph N
Ph
+
HN CH2 CO2H
N
Me toluene reflux
Ph 27 (M= 2H) Ph
N
HC N CH2 Me N
M
Ph N
N
N
N N
C60 Ph
M
Ph
Ph Me
N Ph N
Ph Ph
28
29 (40%)
Scheme 8. 1,3-DC reaction of the porphyrinic azomethine ylide 28 with C60.
51
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
Subsequently, other research groups have used this strategy for the construction of other porphyrinic diads. As an example, the porphyrinic azomethine ylide 28 (M = Ni) has been successfully trapped in 1,3-DC reactions with a range of dipolarophiles including Nphenylmaleimide, dimethyl fumarate, dimethyl acetylenedicarboxylate, trans-β-nitrostyrene, 1,4-benzoquinone and 1,4-naphthoquinone. In general, the reactions afforded the expected adducts, e.g. 30, in very good yields (Scheme 9) <02JOC726>. Exceptions were found in the reactions with 1,4-benzoquinone and 1,4-naphthoquinone which only gave rise to the formation of the dehydrogenated adducts, e.g. 31. More recently, porphyrinic azomethine ylide 28 (M = Ni) has been trapped with isatin to give a spiro porphyrin derivative 32 (Scheme 9) <06SC2655>. O
O
N Ph
O N H
28
O
O
O
O Me N Ph
N
N Ph
Ph
Ph N
N
Ph
Ph
30 (96% mixture of diastereomers)
N H
N Ni
Ph
N
N
Ph
N
N Ni
Ph
N
N
O
O
N Ni
O
Me N Ph
Me N Ph
N Ph O
Ph
O
31 (94%)
32 (13%)
Scheme 9. 1,3-DC reactions of porphyrinic azomethine ylide 28 with different dipolarophiles It has also been demonstrated that in the absence of dipolarophiles, porphyrinic azomethine ylide 28 can participate in 1,5-electrocyclization reactions, to yield pyrroloporphyrins, e.g. 33 (Scheme 10) <01JCS(PT1)2752>. Ph
N 28
N N
Ph
Ni
Ph
Me
N
N
Ph
33 (55%)
Scheme 10. 1,5-Electrocyclization reaction of 28.
A.M.G. Silva and J.A.S. Cavaleiro
52
Numerous studies have been reported concerning the use of 1,3-DC reactions as powerful tools for the construction of other systems employing porphyrins or chlorins as electron donors and fullerene as electron acceptor, mimicking the photosynthetic reaction centres. One of these studies involves the preparation porphyrin-(C60)2 triads 34a and 34b from the 1,3-DC reaction of a porphyrin having two formyl groups in the para position of the 5,10- or 5,15phenyl groups, with N-methylglycine and C60 (Figure 4) <98CL605>. Ar N
N H H N
Ar N
Me
Me
N
N
Ar Me NH N
N
N
HN
N
Me Ar
34a
34b
Figure 4. Examples of porphyrin–(C60)2 triads 34.
N
1. pyridine, 100 ° C 2. 5% H2SO4, MeOH
N Mg N
N
O Phytyl
N HN
N
O
H3CO2C
O
NH
35
MeO
O 36 (90%)
O
OsO4, NaIO4
CHO
Me N NH N
MeO
O
N HN
O 38 (49%)
NH
N-methylglycine, C60 toluene, reflux
MeO
N
O
Scheme 11. Synthesis of phytochlorin-C60 diad 38.
N HN
O 37 (63%)
53
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
Hynninen and coworkers <99JCS(PT1)2403> used a similar approach to prepare phytochlorin-C60 diad 38 (Scheme 11). The protocol employed the pyrolysis of the natural chlorophyll a molecule 35, followed by transesterification and demetallation to furnish derivative 36. Subsequent oxidation of 36 with OsO4 and NaIO4 has allowed the synthesis of the formyl derivative 37, which was further used as precursor of the azomethinic ylide intermediate in the 1,3-DC reaction with C60 leading to the formation of diad 38. Photochemical studies revealed that this diad underwent a fast intramolecular photoinduced electron transfer in polar solvents such a benzonitrile <99JACS9378>. Based on studies showing that the close proximity between the porphyrin and the C60 is essential for the observation of an electron transfer process, Fukuzumi and co-workers have prepared the porphyrin-C60 diad 41, in which the C60-pyrrolidinyl moiety is directly connected to the meso position of the porphyrin macrocycle (Scheme 12) <03JPC(A)8834>. The strategy adopted for the synthesis of the starting porphyrin involved the 2+2 condensation of a meso-unsubstituted dipyrrylmethane with 3,5-di-tert-butylphenylsubstituted dipyrrylmethane and 3,5-di-tert-butylbenzaldehyde, to give 39, in 11.5% yield. Subsequent Ni(II) metallation, followed by Vilsmeier-Haack formylation and demetallation, gave rise to 40 which was used as the 1,3-dipole precursor; this dipole in the presence of Nmethylglycine and C60, yielded the expected diad 41.
Ar CHO +
NH HN
NH HN
NH
N
Ar
+
N
Ar=
HN 39
Ar
1. Ni(OAc)2, CHCl3, reflux 2. POCl3, DMF, CH2ClCH2Cl 3. CH3COONa (aq) 4. TFA, H2SO4, CHCl3
Ar Me
NH
N
Ar
N
Ar N
HN
NH
N-methylglycine, C60
N CHO
Ar Ar 41
toluene, reflux
N
HN
Ar
40
Scheme 12. Synthesis of porphyrin-C60 diad 41.
Similar protocols have been followed for the synthesis of other porphyrin-C60 diads where the linkage between C60 and porphyrin moieties occurs through the ortho, meta or para positions of the phenyl ring of the porphyrin macrocycle <00PP598, 03JPC(A)8834 and 06SC2135>.
A.M.G. Silva and J.A.S. Cavaleiro
54
Another interesting strategy for the construction of a porphyrin-C60 diad linked by a disilane chain was devised by Ito and coworkers (Scheme 13) <06BCSJ1338>. This method involves the use of the meso-iodo triphenylporphyrin 42, prepared by iodination of porphyrin 39 using a mixture of bis(trifluoroacetoxy)iodobenzene-iodine <00OL131>. An iodo porphyrin 42 was reacted with 1,2-diethynyl-1,1,2,2-tetramethyldisilane using Sonogashira coupling conditions to give rise to derivative 43; this compound then reacted with Ar
Ar
NH
I2, (CF3COO)2IPh, CHCl3
N
NH
Ar N
I N
HN
HN
Ar
39
Ar
N
Ar
42
Zn(OAc)2.2H2O, MeOH, CH2Cl2
Ar=
Me Me Si Si Me Me [PdCl2(PPh3)2], CuI, THF, NEt3
Ar
N
N
Me Me Si Si Me Me
Zn
Ar
N
N
Ar
43 I
Ar
N
Pd(PPh3)4, CuI, THF, NEt3 N
Me Me Si Si Me Me
Zn
Ar
N
N
CHO
Ar
CHO
44 N-methylglycine, C60 toluene, reflux
Ar
Me N
N
Me Me Si Si Me Me
Zn
Ar
N
N
Ar
N
45
Scheme 13. Synthesis of porphyrin-C60 diad 45.
55
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
p-iodobenzaldehyde using similar coupling conditions allowing the formation of porphyrin 44. This porphyrin was then allowed to react with N-methylglycine and C60, giving rise to the final diad 45. Fukuzumi and co-workers <03OL2719> have developed another strategy aimed at a synthesis of imidazoporphyrin-C60 diad 49 (Scheme 14). Using the Crossley approach <95JCSCC2379> as for the synthesis of 17,18-dioxochlorin 47, the Cu(II) complex of betanitro-meso-tetraphenylporphyrin 1e was demetallated and reduced to the beta-amino derivative 46, and this was photo-oxidised and hydrolysed to give 47. Condensation of 47 with the terephthalaldehyde in the presence of excess of NH4OAc in a refluxing 1:1 mixture of AcOH-CHCl3 for 2 h, gave the expected derivative 48, which, with N-methylglycine and in the presence of C60 produced the corresponding imidazoporphyrin-C60 diad 49. Interestingly, the Zn(II) complex of that imidazoporphyrin-C60 diad has shown the longest lifetime in solution of the charge-separated state ever reported for donor-acceptor-linked diads.
Ar
Ar N N
Cu
Ar
Ar N H
NO2 N
N
N
Ar
Ar 1e
N H
1. hυ, O2
H N
Ar
Ar
Ar 47
OHC NH4OAc AcOH/ CHCl3 Ar
Ar N H
Me N
N
N
N H
H N
N
N H
N CHO
N
N
N H
H N Ar
Ar 49
CHO
Ar
Ar N-methylglycine, C60 toluene, reflux
Ar
Ar
O
Ar
46
Ar=
O N
N
2. H+/ H2O or sílica gel
H N
N
Ar
Ar NH2
48
Scheme 14. Synthesis of porphyrin–C60 diad 49. In terms of synthetic methodologies for the preparation of porphyrinic azomethine ylides, the porphyrin moiety, in the examples above, was the carbonyl component. However, there are also examples where the porphyrin is used as the α-amino acid component. Lemmtyinen and coworkers <01JPP835> have devised a protocol, in which the phytochlorin 37 containing a formyl group was transformed into glycine derivative 50 via reductive amination (Scheme 15). In the final step, derivative 50 was reacted with benzaldehyde and C60, and gave rise to the phytochlorin–C60 diad 51.
A.M.G. Silva and J.A.S. Cavaleiro
56
CO2H HN
CHO
NH
N
O
MeO
37
O
NH
HN
N
Me O
1. GlyOt-Bu.HCl, NaBH3CN 2. TFA
N
N HN
O 50
O
benzaldehyde, C60 toluene, reflux
N
NH N
MeO
N HN
O O
51
Scheme 15. Synthesis of phytochlorin-C60 diad 51.
Ph
Ph N N
Ni
N
N Ph
1. HCl.NH2CH2CO2Me La(OTf)3, K2CO3, toluene, reflux CHO 2. NaBH , MeOH 4 CH2Cl2, 0 °C 3. NaOH (aq)
Ph
Ph N N
Ni N
Ph
Ph
N H
N
Ph 52
Ph
HCHO, dimethyl fumarate toluene, reflux
Ph N N
Ni
CO2Me N
N
CO2Me
N Ph
Ph 53
Scheme 16. Synthesis of diad 53.
CO2H
57
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
A convenient route to N-(porphyrin-2-ylmethyl)glycine 52 was described by Cavaleiro and coworkers <06JOC8352> (Scheme 16); it involves the coupling of the Ni(II) complex of beta-formyl-meso-tetraphenylporphyrin with an excess of glycine methyl ester hydrochloride followed by reduction of the product imine with sodium borohydride and alkaline hydrolysis. Once synthesized, the Ni(II) complex of N-(porphyrin-2-ylmethyl)glycine, 52 was used as an azomethine ylide precursor; the latter was generated in the presence of paraformaldehyde and dimethyl fumarate, allowing the formation of diad 53 in 74% yield. Besides the use of porphyrins as azomethinic ylide derivatives, the porphyrin macrocycle can also be used to generate porphyrinic nitrile oxides 55 (Scheme 17) <04RCB(E)2192>. Thus, the treatment of oxime 54 with N-bromosuccinimide in the presence of triethylamine, led to the formation of nitrile oxide 55, which was trapped in 1,3DC reactions with dimethyl maleate and 2,5-norbornadiene to afford 56 and 57, respectively. In the reaction with 2,5-norbornadiene, if an excess of 55 was used, then the corresponding bis-adduct was obtained in good yield.
N
N Ni
CH
NOH
NBS, NEt3
54
N Ni
N
N
N
N
C
N O
N
55 (92%) CO2Me CO2Me
N
N
N O
N
N
N
56 (91%)
CO2Me CO2Me
N
N O
Ni
Ni N
N
57 (97%)
Scheme 17. 1,3-DC Reactions of porphyrinic nitrile oxide 55 with dipolarophiles.
Another example with porphyrinic dipolar species uses pyridinium salt derivatives as precursors of porphyrinic pyridinium ylides (Scheme 18) <05TL5487>. The procedure involves the reaction of porphyrin 58 with methyl bromoacetate, in refluxing chloroform, to give pyridinium salt 59. The latter, in the presence of K2CO3, reacts with 1,4-benzoquinone to yield only the mono-addition compound 60. Notably, when the reaction was performed in the presence of DBU, bis-addition occurred and the porphyrinic dimer 61 was the only isolated addition product.
A.M.G. Silva and J.A.S. Cavaleiro
58
Ph
NH
N N
Ph HN
N
Ph
58
BrCH2CO2Me CHCl3, reflux
Ph
O NH
N NCH2CO2Me
Ph HN
N
Ph
+
Br
O
59 K2CO3 toluene, reflux
DBU toluene, reflux Ph Ph
Ph
O Ph
N NH
N
Ph N
HN
N
HN CO2Me
N
NH
O
N
NH
Ph
Ph
N
HN
Ph
O Ph 60 (16%)
N
N MeO2C
O
CO2Me
61 (23%)
Scheme 18. 1,3-DC reactions of porphyrinic pyridinium ylide with 1,4-benzoquinone.
2.2.3
Porphyrins as dipolarophiles in 1,3-dipolar cycloaddditions
Our first entry to the use of porphyrins as dipolarophiles in 1,3-DC reactions involved the reaction of porphyrins with azomethinic ylides, generated in situ from α-amino acids and aldehydes, to yield chlorins and isobacteriochlorins (bisadducts) <99CC1767, 05JOC2306>. In the particular scenario of the reaction of meso-tetrakis(pentafluorophenyl)porphyrin 1d with the azomethine ylide, generated in situ from N-methylglycine and paraformaldehyde, in refluxing toluene during 15 hours, the pyrrolidinochlorin derivative 62 was obtained as the main product (Scheme 19), together with a small amount of isobacteriochlorin 63 (bis-adduct, Figure 5).
59
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
H C O
+
HN CH2 CO2H
H
Me
C6F5 NH
N
H C N CH2 H Me
C6F5 +
C6F5 N
HN
C6F5
C6F5 NH
N
C6F5 HN
N
C6F5
1d
Me N
C6F5 + bisadduct (11%)
62 (61%)
Scheme 19. 1,3-DC Reactions of porphyrin 1d with azomethine ylide.
When a larger excess of the azomethine ylide precursors was used and the reflux was prolonged for 40 hours, the reaction afforded isobacteriochlorin 63 as the major adduct together with a small amount of bacteriochlorin 64 (Figure 5). This result demonstrates that the attack of the second azomethine ylide species to the chlorin macrocycle occurs preferentially at the adjacent β-pyrrolic double bond, yielding the isobacteriochlorin with high site selectivity. Me
C6F5
N N
Me
C6F5
N NH
N C6F5
C6F5
C6F5 63
N C6F5
C6F5 N
NH HN N Me
Me N
HN
C6F5 64
Figure 5. Bis-adducts obtained in 1,3-DC reaction.
This strategy has been successfully applied to other porphyrins, however the best yields were obtained with porphyrins having electron-withdrawing groups at the meso positions of the macrocycle <05JOC2306, 04JBCS923>. Knowing the great potential of such 1,3-DC with porphyrins, Gryko and co-worker <05OL1749, 06JOC5942> predicted that if two electron-withdrawing groups were placed in vicinal (β,β’) positions of the same pyrrolic unit of a porphyrin, then stable, locked chlorins could be synthesized in a regioselective way. As a result, they undertook the synthesis of a range of porphyrins to be used as starting materials in 1,3-DC reactions with azomethine ylides. The starting porphyrins were synthesised via 3+1 condensations of a tripyrrane (compound containing three pyrrolic units such as 65) with an α,α'-diformyl pyrrole. Thus, for the synthesis of the tripyrrane 65, they have performed the condensation of the aryl aldehyde with pyrrole (Scheme 20). On the other hand, the synthesis of the diformyl pyrrole 66 involved the dimerization of esters of acetoacetic acid using I2 or cerium ammonium nitrate (CAN) to give the corresponding 1,4-diketones; these, when treated with NH3, gave rise to an α,α'-dimethylpyrrole derivatives, which were then transformed into the required
A.M.G. Silva and J.A.S. Cavaleiro
60
diformylpyrroles 66 by selective oxidation of the methyl groups using CAN in MeCN/ H2O at room temperature (Scheme 21). Ar
Ar N H
TFA
ArCHO + N H
NH
HN 65
Scheme 20. Synthesis of the tripyrrane 65.
O
1. NaOMe 2. I2 or CAN
CO2R
RO2C
CO2R
O O
R= Me, Et, t-Bu
NH3aq or NH3, MeOH RO2C
CO2R
OHC
N H
CAN MeCN, H2O
RO2C
CHO
CO2R N H
66
Scheme 21. Synthesis of diformylpyrrole 66.
CO2R RO2C OHC
Ar
CO2R N H
CHO
Ar N H
+
NH
CO2R NH Ar
HN
N
66
N HN
65 Ar Me
RO2C NH
N
67
HCHO N-methylglycine toluene, reflux
CO2R
N
Ar N
HN
Ar
68
Scheme 22. Synthesis of locked chlorins 68. Finally, the condensation of the tripyrrane 65 with the diformyl pyrrole 66, in a TFA/CHCl3 solution, gave porphyrins 67. Such porphyrins were then used in 1,3-DC
61
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
reactions with azomethinic ylides affording the locked chlorins 68 (Scheme 22). The results obtained showed that if electron-withdrawing groups are introduced at β-pyrrolic positions, the presence of electron-withdrawing groups at meso positions is no longer necessary for the success of a 1,3-DC reaction. The usefulness of such 1,3-DC reactions was also demonstrated when C- and Nglycoconjugated pyrrolidine-fused chlorins 69 and 70 were synthesised via azomethinic ylide cycloadditions with meso-tetrakis(pentafluorophenyl)porphyrin 1d (Schemes 23 and 24) <05S857>. While the reaction of 1d with the azomethinic ylide, generated in situ from the galactosyl configured aldehyde and N-methylglycine, afforded a diastereomeric mixture of two chlorins 69, the reaction of 1d with the N-substituted symmetrical azomethinic ylide, generated in situ from the galactose-substituted glycine derivative with paraformaldehyde, gave chlorin 70 as the only isolable product. C 6 F5
O OHC
O O
O - + H2C N C H Me
N-methylglycine
O O
O O O
O
1d
HN
N C6F5
C6F5 NH
N
C6F5
* N Me O
O
O O O 69 (51% mixture of diastereomers)
Scheme 23. Synthesis of the C-glycoconjugated pyrrolidine-fused chlorin 69.
C6F5
O
O O
NH O CH2 CO2H
O
HCHO
H2C
+
O
N -
CH2
O O O
O
1d
N
HN
C6F5
C6F5 NH
N O C6F5
N O
70 (19%)
O O O
Scheme 24. Synthesis of the N-glycoconjugated pyrrolidine-fused chlorin 70.
Another example illustrating the versatility of 1,3-DC reactions is concerned with the reaction of [36]octaphyrin 71 with azomethine ylide generated in the usual way from Nmethylglycine and paraformaldehyde, to give mono- and bis-pyrrolidine-fused adducts 72 and 73 (Scheme 25) <06OL1169>
A.M.G. Silva and J.A.S. Cavaleiro
62
Ar
Ar
N Ar
NH
HN Ar
Ar
N
N
NH
N Ar
HN
71 Ar= C6F5
Ar
Ar
HCHO, N-methylglycine toluene, reflux Ar
Ar
Ar
N
NH
N
HN Ar
Ar
N
HN
Ar
72 (3%)
Ar
Ar
Ar
+
Ar
N N NH
N
Ar
N
NH N HN
N
HN
Ar
Ar
Ar
N N NH Ar
Ar
73 (7%)
Scheme 25. 1,3-DC Reaction of [36]octaphyrin 71 with azomethine ylide.
Ar H O N C Me H
NH
Ar
Ar N
Ar 74 (72%)
Ar
HN
Ar
Ar NH
HN O N Me
O
O
N Ar
N
O
1d, Ar= C6F5
N
Ar
O
HN
Ar
Ar
NH
N
O + O N C H Bn
N O * N
Ar
Bn O
O O
O
75 (66%)
Scheme 26. 1,3-DC reactions of porphyrin 1d with nitrones.
O
63
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
Reaction of porphyrins with nitrones has also been studied and the results obtained showed that this is a versatile approach leading to the synthesis of isoxazolidine fusedchlorins (Scheme 26). For instance, chlorin 74 was successfully prepared from the reaction of the N-methylnitrone, generated in situ from N-methyl hydroxylamine and paraformaldehyde, with porphyrin 1d <00JPP532>. It is important to note that bis-addition also took place, yielding exclusively bacteriochlorin type derivatives 76 and 77 (Figure 6). This result contrasts with those obtained in 1,3-DC reactions with azomethinic ylides where isobacteriochlorins were obtained preferentially. In an attempt to explain the different behaviour of azomethinic ylides and Nmethylnitrones in 1,3-DC reactions with porphyrins and chlorins, a theoretical study has been carried out. The results obtained showed that while in the cycloadditions of porphyrins and chlorins with azomethinic ylides the processes are irreversible and consequently are kinetically controlled, the cycloadditions of such macrocycles involving N-methylnitrone are clearly reversible, showing that the products from such reactions should be thermodynamically controlled <07MI1>. O N Me
C6F5 NH
NH
N C6F5
C6F5 N
Me
C6F5
N O
N C6F5
C6F5
HN
N
C6F5
O N Me
O N
76
HN
C6F5
Me
77
Figure 6. Bacteriochlorins 76 and 77. Ph
NH
NO2 N Ph
Ph N
HN
Ph
1e
N N CH2 H
Ph O2N N N NH
NH
N
N
Ph N
HN
Ph
78
+
Ph
Ph N
HN
Ph
N
NH
N
Ph + Ph
Ph
Ph O2N
N N
Ph
79
HN
Ph
DBU toluene, reflux
Scheme 27. 1,3-DC Reactions of porphyrin 1e with diazomethane.
80
A.M.G. Silva and J.A.S. Cavaleiro
64
Glycoconjugated isoxazolidine-fused chlorins and bacteriochlorins were also elegantly synthesised using a 1,3-DC approach (Scheme 26). For instance, the galactosylnitrone reacted with porphyrin 1d in a small volume of toluene, at 60 ºC, to yield chlorin 75, accompanied by a small amount of two related bacteriochlorins <02TL603>. Extension of the 1,3-DC approach to the synthesis of novel pyrazoline-fused chlorin 78 by the reaction of β-nitro-meso-tetraphenylporphyrin 1e with diazomethane has also been explored by Cavaleiro and co-workers (Scheme 27) <02S1155>. The resulting chlorin 78 could be further converted into the pyrazole-fused porphyrin 79 by treatment with DBU or into the methanochlorin 80 by refluxing in toluene. The same approach was subsequently used by Dolphin and co-workers <02CC2622> and also by Robinson and co-workers <03T499> to prepare pyrazoline cycloadducts from porphyrins and chlorins. Scheme 28 shows new chlorin derivatives (81 and 82) which have been obtained in this way. N N
NH
O
hν, heat
N
O
N HN
N
O
MeO
NH
HN
N
36
O
NH
N N CH2
HN
N
MeO
N
MeO
81
O 82
O
Scheme 28. 1,3-DC Reaction of phytochlorin 36 with diazomethane.
Carbonylic ylides represent other class of 1,3-dipolar reactive species to be used in 1,3DC reactions with porphyrins. For example, reaction of meso-tetraphenylporphyrin 1a with carbonyl ylide derived from tetracyanoethylene oxide gave chlorin 83 (Scheme 29) <02TL7281>. Moreover, a large range of 1,3-DC reactions with carbonyl ylides has been patented <04MI1>. The resulting adducts containing one or more cyano groups can be further derivatized aiming to obtain photosensitizing agents of interest in photodynamic therapy.
O NC NC
Ph
CN CN
Ph
Δ
NH
N Ph +
N
HN
Ph
1a
NC NC
CN CN
NH
O
Ph
NC CN O
CN CN
N
Ph
Ph N
HN
Ph
83 (20%)
Scheme 29. 1,3-DC Reactions of porphyrin 1a with a carbonyl ylide.
65
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
Nitrile oxides have been also widely applied in 1,3-DC reactions with porphyrins <05TL1555, 05S1030, 05S3632, 06H885>. The reactions using unstable nitrile oxides, such as benzonitrile oxide, have failed or have given products in low yields; however reactions using stable nitrile oxides usually gave good results. In this way, the addition of 2,6dichlorobenzonitrile, to meso-tetra(p-chlorophenyl)porphyrin 84 afforded chlorin 85, together with a minor amount of related bacteriochlorins (Scheme 30). Ar
NH
N
Ar
Ar N
Ar
O N C +
NH
Cl
Cl
N
Ar N
HN
Ar
O N
Cl Ar
HN
Ar
84, Ar= p-ClC6H4
Cl
85 (53%)
Scheme 30. 1,3-DC Reactions of porphyrin 84 with nitrile oxide.
Finally, it is important to mention that there are other related publications in which porphyrin macrocycles are not directly used as dipolarophiles but are transformed into new derivatives that can react with carbonyl ylides via ACE (alkene cyclobutene epoxide) reactions. This idea arose in 1997, when Russell and co-workers found that fused esteractivated cyclobutene epoxides 86 can be ring-opened to give carbonyl ylides 87, and that these can be trapped stereospecifically by ring-strained alicyclic dipolarophiles, such as 2,5norbornadiene, to form hetero-bridged norbornanes 88 in good yields, through ACE transformations (Scheme 31) <97CC1023>.
110 °C , 3 h
O
O 86
O E
E
E E
E 87
E 88
E= CO2Me
Scheme 31. A typical ACE (alkene cyclobutene epoxide) reaction.
Gunter and co-workers have applied this methodology to the condensation of norbornene derivative 90 (block A, Scheme 32) with epoxide 94 (block B, Scheme 33) <98S593>. Thus, using the Crossley porphyrin-α-dione 47, condensation with 1,2,4,5benzenetetramine tetrahydrochloride and then the product with a strained dione, gave 90 as block A.
A.M.G. Silva and J.A.S. Cavaleiro
66 -Cl+H
Ar
Ar N H
O
-Cl+H
N
N H N
NH3+Cl-
3N
N H
NH3+Cl-
3N
Ar
Ar
H N
O Ar 47
Ar
Ar
Ar
O
N
NH2
N
NH2
N
N
89
O Ar
Ar N H
N
N
N
N
N
N H N
Ar
Ar
90, block A
Scheme 32. Synthesis of block A.
Typically, the synthesis of block B involves the Diels-Alder reaction of 1,4naphthoquinone with cyclopentadiene, followed by reduction and OH methylation to give 92 (Scheme 33). The next step involves a Ru-catalysed [2+2] cycloaddition of 92 with dimethyl acetylenedicarboxylate (DMAD), followed by epoxidation (MeLi, ButOOH) to give 94 as block B. O
O + O
O
MeO
MeO
1. NaH, THF 2. MeI 91
MeO
DMAD RuH2CO(Ph3)3
MeO2C CO2Me MeO ButOOH, MeLi
MeO
92
CO2Me
-78°C O
MeO
93
CO2Me
94, block B
Scheme 33. Synthesis of block B.
Finally, the condensation of blocks A and B under thermal conditions gave 96, where the porphyrin ring is rigidly linked to the dimethoxynaphthalene chromophore, through an ACE reaction (Scheme 34). The ACE reaction has proved to be an extremely versatile method for linking other chromophores to porphyrin macrocycles through a rigid spacer <99JOC4218, 01M406, 02T3445>.
67
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
MeO
CO2Me
heat
94, B-BLOCK
90, block A
O MeO 95 MeO
O
MeO2C
CO2Me
Ar
MeO
N
MeO2C
Ar N H
N
N
N N Ar
H N
N Ar
96, ACE-coupled product
Scheme 34. ACE Reaction.
2.3 CONCLUSIONS This survey has highlighted the importance of cycloaddition reactions as powerful tools for the functionalisation of meso and beta-positions of a porphyrin macrocycle. As shown above, porphyrins can be used as dienophiles and as dipolarophiles in DA and 1,3-DC reactions with a wide range of reactive dienes and 1,3-dipoles to achieve monoadducts of the chlorin type, as the main products, or related compounds. Furthermore, under certain conditions, bis-adducts of the iso- or bacteriochlorin types can be obtained depending on the 4ʌ species used. Porphyrins can also be used as precursors of 1,3-dipolar species, and this has been widely explored, mainly when targets are concerned with the synthesis of porphyrinic diads. Several novel porphyrin derivatives can then be obtained by following the mentioned cycloaddition methodologies; many of the new products fulfil the requirements to be considered as potential new drugs mainly for the detection and treatment (PDT) of cancer situations and in the photo-inactivation of microorganisms.
2.4
ACKNOWLEDGEMENTS
Thanks are due to all colleagues and students who are co-authors in our cited publications. Thanks are also due to our University, to “Fundação para a Ciência e a Tecnologia” (FCT, Portugal) and POCI 2010 (FEDER) for funding the Organic Chemistry Research Unit. A.M.G.S. thanks FCT for her SFRH/BPD/8374/2002 grant.
2.5
REFERENCES
78MI1 94MI1 95TL7971 95JCSCC2379 97CC1199
D. Dolphin In The Porphyrins I; Dolphin, D., Ed.; Academic Press: New York, 1978; Vol. I, General Preface. R.A. Sheldon In Metalloporphyrins in Catalytic Oxidations; Sheldon, R.A., Ed.; Marcel Dekker: New York, 1994; p 6. T. Drovetskaya, C.A. Reed, P. Boyd, Tetrahedron Lett., 1995, 36, 7971. M.J. Crossley, L.J. Govenlock, J.K. Prashar, J. Chem. Soc., Chem. Commun., 1995, 2379. A.C. Tomé, P.S.S. Lacerda, M.G.P.M.S. Neves, J.A.S. Cavaleiro, Chem. Commun. 1997, 1199.
68 97CC1023 98CC2355 98CL605 98S593 99CC1767 99JACS9378 99JCS(PT1)2403 99JOC4218 00COC139 00JPP525 00JPP532 00MI1 00OL131 00PP598 00TL3065 01JCS(PT1)2752 01JPP835 01M406 02CC1816 02CC2622 02JOC726 02S1155 02T3445 02TL603 02TL7281 03A107 03JPC(A)8834 03OL2719 03T499 04JBCS923
04RCB(E)2192 04S1291 04MI1 05AC(E)932 05JOC2306 05OL1749 05S857 05S1030
A.M.G. Silva and J.A.S. Cavaleiro
R.N. Warrener, A.C. Schultz, D.N. Butler, S. Wang, I.B. Mahadevan, R.A. Russell, Chem. Commun. 1997, 1023. M.G.H. Vicente, M.T. Cancilla, C.B. Lebrilla, K.M. Smith, Chem. Commun. 1998, 2355. S. Higashida, H. Imahori, T. Kaneda, Y. Sakata, Chem. Lett. 1998, 7, 605. R.N. Warrener, M.R. Johnston, M.J. Gunter, Synlett 1998, 593. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, Chem. Commun. 1999, 1767. N.V. Tkachenko, L. Rantala, A.Y. Tauber, J. Helaja, P.H. Hynninen, H. Lemmetyinen, J. Am. Chem. Soc. 1999, 121, 9378. J. Helaja, A.Y. Tauber, Y. Abel, N.V. Tkachenko, H. Lemmetyinen, I. Kilpeläinen, P.H. Hynninen, J. Chem. Soc., Perkin Trans. 1 1999, 2403. R.N. Warrener, A.C. Schultz, M.R. Johnston, M.J. Gunter, J. Org. Chem. 1999, 64, 4218. M.G.H. Vicente, K.M. Smith, Curr. Org. Chem. 2000, 4, 139. E.A. Makarova, G.V. Korolyova, O.L. Tok, E.A. Lukyanets, J. Porphyrins Phthalocyanines 2000, 4, 525. A.C. Tomé, P.S.S. Lacerda, A.M.G. Silva, M.G.P.M.S. Neves, J.A.S. Cavaleiro, J. Porphyrins Phthalocyanines 2000, 4, 532. M.G.H. Vicente and L. Jaquinod in The Porphyrin Handbook; Kadish, K. M., Smith, K.M., Guilard, R., Ed.; Academic Press: San Diego, 2000; Vol. 1, p 149-238. F. Odobel, F. Suzenet, E. Blart, J.-P. Quintard, Org. Lett. 2000, 2, 131. J.L. Bahr, D. Kuciauskas, P.A. Liddell, A.L. Moore, T.A. Moore, D. Gust, Photochem. Photobiol. 2000, 72, 598. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, J.A.S. Cavaleiro, Tetrahedron Lett. 2000, 41, 3065. A.M.G. Silva, M.A.F. Faustino, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, J. Chem. Soc., Perkin Trans. 1 2001, 2752. A. Efimov, N.V. Tkatchenko, P. Vainiotalo, H. Lemmetyinen, J. Porphyrins Phthalocyanines 2001, 5, 835. M.R. Johnston, Molecules 2001, 6, 406. Z. Xiao, B.O. Patrick, D. Dolphin, Chem. Commun. 2002, 1816. A. Desjardins, J. Flemming, E.D. Sternberg, D. Dolphin, Chem. Commun. 2002, 2622. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, J. Org. Chem. 2002, 67, 726. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, J.A.S. Cavaleiro, Synlett 2002, 1155. M.R. Johnston, M.J. Gunter, R.N. Warrener, Tetrahedron 2002, 58, 3445. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, D. Perrone, A. Dondoni, Tetrahedron Lett. 2002, 43, 603. J. Flemming, D. Dolphin, Tetrahedron Lett. 2002, 43, 7281. J.A.S. Cavaleiro, M.G.P.M.S. Neves, A.C. Tomé, Arkivoc 2003, xiv, 107. N.V. Tkachenko, H. Lemmetyinen, J. Sonoda, K. Ohkubo, T. Sato, H. Imahori, S. Fukuzumi, J. Phys. Chem. A 2003, 107, 8834. Y. Kashiwagi, K. Ohkubo, J.A. McDonald, I.M. Blake, M.J. Crossley, Y. Araki, O. Ito, H. Imahori, S. Fukuzumi, Org. Lett. 2003, 5, 2719. A.N. Kozyrev, J.L. Alderfer, B.C. Robinson, Tetrahedron 2003, 59, 499. A.P.J. Maestrin, A.O. Ribeiro, A.C. Tedesco, C.R. Neri, F.S. Vinhado, O.A. Serra, P.R. Martins, Y. Iamamoto, A.M.G. Silva, M.G.P.M.S. Neves, A.C. Tomé, J.A.S. Cavaleiro, J. Braz. Chem. Soc. 2004, 15, 923. Y.V. Morozova, Z.A. Starikova, B.I. Maksimov, D.V. Yashunskii, G.V. Ponomarev, Russ. Chem. Bull., Int. Ed. 2004, 53, 2192. J.F.B. Barata, A.M.G. Silva, M.A.F. Faustino, M.G.P.M.S. Neves, A.C. Tomé, A.M.S. Silva, J.A.S. Cavaleiro, Synlett 2004, 1291. J.K. MacAlpine, E.D. Sternberg, D. Dolphin, USA Pat. 6,825,343 (2004) [http://www.freepatentsonline.com/6825343.html] H. Hata, H. Shinokubo, A. Osuka, Angew. Chem. Int. Ed. 2005, 44, 932. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, J. Org. Chem. 2005, 70, 2306. D.T. Gryko, M. GaáĊzowski, Org. Lett. 2005, 7, 1749. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, J.A.S. Cavaleiro, D. Perrone, A. Dondoni, Synlett 2005, 857. X. Liu, Y. Feng, X. Chen, F. Li, X. Li, Synlett 2005, 1030.
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
05S3632 05TL1555 05TL2189 05TL4723 05TL5487 06BCSJ1338 06H885 06JOC5942 06JOC8352 06OL1169 06SC2135 06SC2655 06TL3131 06TL8437 07MI1
69
L. Xingang, F. Yaqing, H. Xiaofen, L. Xianggao, Synthesis 2005, 3632. X. Li, J. Zhuang, Y. Li, H. Liu, S. Wang, D. Zhu, Tetrahedron Lett. 2005, 46, 1555. S. Zhao, M.G.P.M.S. Neves, A.C. Tomé, A.M.S. Silva, J.A.S. Cavaleiro, M.R.M. Domingues, A.J. Ferrer Correia, Tetrahedron Lett. 2005, 46, 2189. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, J.A.S. Cavaleiro, C.O. Kappe, Tetrahedron Lett. 2005, 46, 4723. S. Zhao, M.G.P.M.S. Neves, A.C. Tomé, A.M.S. Silva, J.A.S. Cavaleiro, Tetrahedron Lett. 2005, 46, 5487. H. Tsuji, M. Sasaki, Y. Shibano, M. Toganoh, T. Kataoka, Y. Araki, K. Tamao, O. Ito Bull. Chem. Soc. Jpn. 2006, 79, 1338. S. Ostrowski, P. WyrĊbek, A. Mikus, Heterocycles 2006, 68, 885. M. GaáĊzowski, D.T. Gryko, J. Org. Chem. 2006, 71, 5942. A.M.G. Silva, P.S.S. Lacerda, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, E.A. Makarova, E.A. Lukyanets, J. Org. Chem. 2006, 71, 8352. H. Hata, Y. Kamimura, H. Shinokubo, A. Osuka, Org. Lett. 2006, 8, 1169. M.E. Milanesio, E.N. Durantini, Synth. Commun. 2006, 36, 2135. X.G. Liu, Y.Q. Feng, C.J. Tan, H.L. Chen, Synth. Commun. 2006, 36, 2655. J.P.C. Tomé, D.-G. Cho, J.L. Sessler, M.G.P.M.S. Neves, A.C. Tomé, A.M.S. Silva, J.A.S. Cavaleiro, Tetrahedron Lett. 2006, 47, 3131. S. Ostrowski, P. WyrĊbek, Tetrahedron Lett. 2006, 47, 8437. G.J. Osés, A.M.G. Silva, A.R.N. Santos, A.C. Tomé, M.G.P.M.S. Neves, J. A.S. Cavaleiro, J.I. Garcia, unpublished results.
70
Chapter 3
Three-membered ring systems
Stephen C. Bergmeier and Damon D. Reed Department of Chemistry & Biochemistry, Ohio University, Athens, OH, USA
[email protected] and
[email protected]
3.1
INTRODUCTION
This review covers the chemical literature on epoxides and aziridines for the year 2006. As in previous years, this review is not comprehensive but rather covers a selection of synthetically useful and interesting reactions. Three-membered ring systems, epoxides and aziridines in particular, are excellent synthetic intermediates. This is largely due to their ability to be converted into other functional groups such as diols, diamines, and amino alcohols to name but a few. While the synthesis of aziridines and epoxides can be quite challenging, the rewards for a selective and high yielding synthesis can be substantial. The chapter has been divided into two sections, one covering epoxides and the other covering aziridines. Each of these sections has been further divided into two additional sections, one on the synthesis of the heterocycle and one on the reactions of the heterocycle. There is some overlap between methods for the synthesis of epoxides and aziridines and any overlap has been noted in the text. 3.2 3.2.1
EPOXIDES Preparation of Epoxides
Epoxides are possibly the most studied of the three-membered heterocycles. While a host methods for the synthesis of epoxides have been developed, work continues, especially in the development of more chemo-, regio-, and stereoselective methods. The development of new metal-based epoxidation catalysts continues to garner significant levels of activity. The use of the Mn-based catalyst, 1, with a water-soluble ligand provides excellent yields of the corresponding epoxides <06MI139>. A Mn-salen complex was modified by the addition of phosphonium groups at either end to render it water-soluble. The use of 5 mol% of this catalyst with NaIO4 as the oxidant provided a quantitative yield of cyclohexene oxide from cyclohexene.
71
Three-membered ring systems
NaIO4, 1 (5 mol%) 100%
Cl Ph3P
O
N
Cl
N
PPh3
Mn O
O 1
A number of additional metal-catalyzed epoxidations have been reported in the past year. Platinum is a rarely used catalyst in oxidation reactions. The use of chiral Pt-catalyst 2 in the epoxidation of terminal alkenes provides the epoxide products in moderate yield and enantiomeric excess <06JA14006>. The chiral hydroxamide 3 is used with a Mo catalyst to provide the epoxide product in excellent yields and moderate enantioselectivity <06AG(I)5849>. A bis-titanium catalyst, 4, has also been used to epoxidize the usual set of alkenes with H2O2 as the oxidant <06AG(I)3478>. Substrate
Product
Conditions
H
2 (2 mol%), H2O2
R
Yield, %ee R = C4H9, 48%, 83% ee R = CH2Ph, 75%, 66% ee
O
R O
79%, 98% ee
30% H2O2, 4 (5 mol%) H
O
47%, 82% ee
Ph
Ph
O [MoO2(acac)2] (2 mol%) 3, cumene hydroperoxide
82%, 87% ee H
Ph
Ph OH Pt P C6F5 Ph Ph
O
95%, 85% ee
Ph
Ph O
C(4-t-Bu-C6H4)3
P
N
CF3SO3 2
N 3
O
OH OH C(4-t-Bu-C6H4)3
H
H N
N Ti
O
O
Ph O
Ph 2
4
The use of supported catalysts to carry out epoxidation reactions has seen considerable activity in the past year. A primary rationale for the use of supported catalysts is the ease in the reuse of the catalyst. The solid supports used range from silica gel to polystyrene. Quinine and other Cinchona alkaloids were linked to a soluble PEG polymer to generate dimeric polymers such as 5 <06TA330>. Reaction of chalcone with 5 using t-BuOOH as the oxidant provides the product epoxide in good yield and with good enantioselectivity. The PEG-linked ligand was reused three times with only minimal degradation in the enantiomeric excess of the product.
72
S.C. Bergmeier and D.D. Reed
O
O
t-BuOOH, 5, KOH, 90%, 86% ee Ph
Ph
Ph
O
Cl
OMe N
H N
N
H N
OH
HO O
N
OMe
Cl PEG2000
Ph
O
5
N
Another method for generating an epoxidation catalyst on a solid support is to simply absorb or non-covalently attach the catalyst to the solid support <06MI493>. Epoxidation of olefin 6 with mCPBA and catalyst 8 provides 7 in quantitative yields and with 89% ee. The immobilization of 8 on silica gel improves the enantioselectivity of the reaction providing 7 with 95% ee. Recycling experiments with silica-8 show a decrease in both yield and the enantiomeric excess for each cycle (45% ee after 4 cycles). This is attributed to a leaching of the catalyst from the silica gel. Two other solid supports, a Mg-Al-Cl-LDH resin (LDH) and a quaternary ammonium resin (Q-resin) were also examined. It was expected that ionic attraction between 8 and the LDH or Q-resin would allow the catalyst to remain immobilized through multiple cycles better than with silica gel. Both of these resins showed improved catalytic properties upon reuse of the catalyst (92-95% ee after 4 cycles). O NC 6
8, mCPBA, 100%, 89% ee silica•8, mCPBA, 100%, 95% ee LDH•8, mCPBA, 100%, 93% ee Q-resin•8, mCPBA, 100%, 97% ee
N
O NC 7
O
N Mn
O3S
O t-Bu
O acac
SO3
t-Bu
8
Vinyl epoxides are highly useful synthetic intermediates. The epoxidation of dienes using Mn-salen type catalysts typically occurs at the cis-olefin. Epoxidations of dienes with sugarderived dioxiranes have previously been reported to react at the trans-olefin of a diene. A new oxazolidinone-sugar dioxirane, 9, has been shown to epoxidize the cis-olefin of a diene <06AG(I)4475>. A variety of substitution on the diene is tolerated in the epoxidation, including aryl, alkyl and even an additional olefin. All of these substitutions provided moderate yields of the mono-epoxide with good enantioselectivity.
73
Three-membered ring systems
O
O R
oxone, 9 (10-30 mol%), K2CO3
R
O
R = Ph, 66%, R = 85% ee R = nC5H11, 80%, 89%ee R = CO2Et, 64%, 94% ee R = CH=CHCO2Et (trans), 74%, 94% ee
O O
O
N
CH3
O O 9
An exploration of structural modifications on the activity of prolinol catalysts has been published <06T12264>. More electron-rich aromatic rings on the prolinol scaffold improve the activity in the epoxidation of α,β-enones. The reaction of 10 with an enone and t-BuOOH provides the epoxy-ketones with moderate levels of enantioselectivity. Iminoiodinanes are not normally used as epoxidation reagents. An organocatalytic route to epoxides using an iminoiodinane as the oxidant has been reported <06T11413>. The reaction of 11 and NsNIPh with α,β-unsaturated aldehydes provides the target epoxides in excellent yield and with excellent enantioselectivity. A number of other oxidants had been examined with iodosobenzene being the optimal oxidant. However the substrate scope of this oxidant was not ideal. NsNIPh was found to slowly generate iodosobenzene under the reaction conditions and provide wide substrate scope. O
O
Conditions R2
R1
O
R1
R2
Conditions
Substitution
% Yield, % ee
t-BuOOH, hexane, 10
R1 = Ph, R2 = Ph R1 = CH3, R2 = Ph R1 = Ph, R2 = CH2CH2Ph
93%, 89% ee 55%, 83% ee 80%, 71% ee
NsNIPh, 11•HClO4 (20 mol%) R1 = H, R2 = CH3 R1 = H, R2 = Ph R1 = H, R2 = n-C3H7 CH3
OH
O OCH3
N H H3C
88%, 93% ee 92%, 92% ee 72%, 88% ee
CH3 CH3 OCH3
H3C
N
Bn N H
t-Bu 11
10
Sulfur ylides are a classic reagent for the conversion of carbonyl compounds to epoxides. Chiral camphor-derived sulfur ylides have been used in the enantioselective synthesis of epoxy-amides <06JA2105>. Reaction of sulfonium salt 12 with an aldehyde and base provides the epoxide 13 in generally excellent yields. While the yield of the reaction was quite good across a variety of R groups, the enantioselectivity was variable. For example benzaldehyde provides 13 (R = Ph) in 97% ee while isobutyraldehyde provides 13 (R = i-Pr) with only 10% ee. These epoxy amides could be converted to a number of epoxide-opened
74
S.C. Bergmeier and D.D. Reed
products using fairly standard chemistry. In a particularly interesting transformation, amide 14 was converted to ketone 15 in excellent yield by treatment with an organolithium reagent. Me O S OMe
O
RCHO KOH R = Ph, 93%, 97% ee R = i-Pr, 79%, 10% ee
NEt2
12
R
CONEt2 13 O
O
RLi, -78 °C
O
CONEt2 Cl
R = Ph, 88% R = Me, 81%
14
R
Cl
15
A very interesting organocatalyzed one-pot Michael addition/aldol condensation/Darzens condensation has been reported for the asymmetric synthesis of epoxy-ketones <06JA5475>. An initial asymmetric Michael condensation between 16 and 17 is catalyzed by proline derivative 18. Intermediate 19 then undergoes an aldol condensation followed by a stereoselective Darzens condensation to provide epoxy-ketone 20 in moderate yield and with surprisingly good enantiomeric excess.
O O
+
O
O 18, AcONa
Cl
O
Cl
Oallyl
Oallyl
16
O
17
19 O K2CO3, DMF 57% yield 86% ee
O
CF3
TMSO Oallyl
O
N H
CF3
20 F3C
CF3 18
3.2.2
Reactions of Epoxides
The primary type of epoxide reaction remains the nucleophilic ring-opening reaction. Research on the development of novel catalysts or catalytic systems for epoxide opening continues to be a highly active area of study. Epoxides have been found to cleanly react with acetic anhydride to provide the diacetate under solvent-free conditions <06TL6865>. Treatment of epoxides with ammonium-12molybdophosphate and a slight excess of acetic anhydride (1.2 equivalents) provides the corresponding diacetate in excellent yields. A number of epoxides were examined and all worked quite well. It was also found that N-tosyl aziridines participate in this reaction providing the corresponding acetoxysulfonamides.
75
Three-membered ring systems
O
NTs
Ac2O, (NH4)3[PMo12O40]6 93%
OAc
Ac2O, (NH4)3[PMo12O40]6 93%
OAc
OAc
NHTs
The conversion of epoxides to other three-membered heterocycles is often a multi-step process involving an initial ring opening followed by a ring closure. Two recent reports detail a one step conversion of an epoxide to a thiirane. Treatment of an epoxide with KSCN in PEG-400 provides the corresponding thiirane in excellent yields <06TL8471>. A related solvent-free approach uses NH4SCN and catalytic cyanuric chloride to provide the thiirane in equally good yields <06TL4775>. O
PEG-400, KSCN, 93% or NH4SCN, cyanuric chloride (2 mol%), neat 90%
S
Typical epoxide ring-opening conditions with amine nucleophiles usually involves some type of acid catalyst. Consequently the development of milder catalysts for use with either sensitive epoxides or sensitive amines is of interest. Ring-opening reaction of epoxides with α-amino acid esters can be catalyzed by Ca(OTf)2 <06TL1733>. Reaction of 21 with an alanine ester provides the ring opened product 22 in moderate yields. Of note, the t-butyl ester is retained. This is a significant improvement over previously reported procedures in terms of yields. The products, 22, were prepared as hydroxyethylamine dipeptide isosteres. The use of Al(OTf)3 for the catalysis of epoxide opening by amines has also been reported <06TL6557>. O PhO 21
O
+ H N 2 O
R
Ca(OTf)2 PhO CH3CN R = Et, 68% R = t-Bu, 54% R = Bn, 61%
OH
H N
O O
R
22
A polymeric version of Jacobsen’s Cr-salen catalyst has also been reported <06TA1638>. This polymeric catalyst worked well with a variety of amines, showed excellent enantio- and diastereoselectivity with an enantiomeric excess of 90-98%. Most importantly the catalyst was reusable with no loss in stereoselectivity of the products. The synthesis of α,α-disubstituted amino acids is a difficult task and continues to attract attention. An efficient route that utilizes the ring-opening of an epoxide with azide has been reported <06TL9268>. Treatment of the sulfoxide substituted epoxide 23 with NaN3 provides intermediate azido aldehyde 24. This aldehyde was not isolated but oxidized to the acid and then the azide reduced to provide the α,α-disubstituted amino acid 25. The regioselectivity of this reaction was impressive with only one product reported.
76
S.C. Bergmeier and D.D. Reed
O S(O)tol
O O
N3 CHO
NaN3, MeOH/H2O O O
23
1) NaClO2, NaH2PO4 H2O2, 86% 2) H2, Pd/C, 98%
24 NH2 COOH
O O
25
The addition of Grignard reagents or other organometallic reagents to epoxides is a highly useful reaction for monosubstituted epoxides. However, when the epoxide is 2,3disubstituted, the selectivity of the addition is poor and overall yields are generally poor as well. A recent report on the addition of propenyl Grignard to epoxides identifies a set of conditions that improves regioselectivity <06JOC5826>. In addition, this method provides better yields than the corresponding alkynylalane. The reaction of 26 or 28 with an excess of propenyl magnesium bromide and catalytic CuI provides the ring-opened products 27 and 29 in excellent yield. The reaction, as expected, proceeds with inversion of stereochemistry. A large group, such as a TIPS, is necessary to provide good regioselectivity in the ring opening reaction. When the TIPS group in 26 was replaced with Bn, a 75:25 mixture of regioisomers was obtained.
TIPSO
TIPSO
26
CuI (130 mol%) MgBr (600 mol%)
O
TIPSO
OH 27, 63% TIPSO
28
O
OH
29, 70%
An epoxide ring opening followed by a ring closing has been found to form the important 3-hydroxypyrrolidine ring system <06CC3226>. Treatment of amido epoxide 30 with dimethylsulfoxonium methylide initially opens the epoxide ring. The amide anion then closes on the carbon bearing the sulfoxonium group to provide the 3-hydroxypyrrolidine ring 31. Spiro- and bicyclic hydroxypyrrolidines were also prepared from the corresponding cyclic amido epoxides. NHTs
30
O
Me3S(O)I, nBuLi 86%
TsN
31 OH
A Baylis-Hillman type product has been obtained through a ring-opening reaction of an epoxide with an allenoate <06OL2771>. The reaction of MgI2 with ethyl propiolate provides the iodo allenoate 32. This nucleophile reacts with an aryl epoxide to provide the homoallylic alcohol 33. The Z iodide is the major product formed.
77
Three-membered ring systems
CO2Me
MgO
O
OMe
O
Ar
MgI2
Ar
MeO
•
OH
I
I
Ar = Ph, 78%, 4:1 Z:E Ar = (4-OMe)C6H4, 74%, 5:1 Z:E Ar = 2-Cl-C6H4, 76%, 10:1 Z:E
33
32
The product of the previous reaction provides a Baylis-Hillman type product via an intermolecular addition of an allenoate to an epoxide. The first example of a true MoritaBaylis-Hillman reaction of an epoxide has recently been reported <06CC2977>. Treatment of enone 34 with Me3P provides a good yield of the epoxide-opened product 35. The reaction must be carried out at low concentrations in order to avoid the generation of a variety of side products. When the terminal end of the epoxide is substituted (e.g. 34) the exo-mode of cyclization is the only product observed. When the terminal end of the epoxide is unsubstituted (e.g. 36), the endo-mode of cyclization predominates providing 37. O
O
34
OH
O
35, 67%
Me3P, t-BuOH (0.025 M)
O
O
36
O
37, 60%
Epoxides will also participate in radical reactions and this usually results in ring opening of the epoxide. The addition of a radical derived from xanthate 38 to butadiene monoepoxide provides the addition product 39 in good yields as an E/Z mixture of olefins <06AG(I)6520>. This reaction presumably proceeds through the addition of the xanthate-derived radical to the olefin, which then opens the epoxide. O
O
O O S
38
OEt
O
O
Et3B, air 82%, E/Z 75:25 39
OH
Epoxides can also be reductively opened to form a radical. An example of an intramolecular cyclization of such a radical has recently been reported <06TL7755>. Treatment of 40 with Cp2TiCl generates an intermediate alkoxy radical, which then adds to the carbonyl of the formate ester. The product, 41, is formed as a 2:1 mixture of isomers at the anomeric carbon. This reaction is one of the first examples of a radical addition to an ester. The major byproduct of this reaction is the exo-methylene compound, 42, arising from a β-hydrogen elimination.
78
S.C. Bergmeier and D.D. Reed
OH
O Cp2TiCl O 40
OH
OH +
O
H O
O
H
42, 22% O
41, 66%, 2:1 mixture
β-Lactones are highly useful intermediates in organic synthesis and are components of a variety of biologically active molecules. One of the primary routes to β-lactones is the catalytic carbonylation of epoxides. Most carbonylation reactions require fairly high CO pressure (200-900 psi) in order to provide reasonable yields of product. These types of conditions make this reaction not particularly viable in the typical organic laboratory. A Crsalen catalyst has been developed that allows the carbonylation of epoxides to be carried out at only 1 atm. of CO pressure <06OL3709>. Catalytic carbonylation of epoxides were performed with only 1 mol % of 43 in 1-2 hours at 100 psi of CO. More impressively, the carbonylation could also be carried out at 1 atm of CO (a balloon) and slightly longer reaction times with 2 mol% of 43. This method was compatible with a number of functional groups including esters, ethers, halides and olefins. THF O
CO (1 atm) 43 (2 mol%) DME
R
O O R
N t-Bu
O
44
R = Me, 96% R = CH2OSiMe2t-Bu, 96% R = (CH2)2CH=CH2, 95%
43
t-Bu
Cr
Co(CO)4
N O
t-Bu
t-Bu THF
Lithiated epoxides have been found to react with a number of different activated electrophiles. A new study examines the reactivity of lithiated epoxides with nitrones to prepare β,γ-epoxyhydroxylamines, 46, and oxazetidine, 47 <06OL3923>. Upon deprotonation of styrene oxide, the lithiated reactant was then added to nitrone 45 to form the β,γ-epoxyhydroxylamine 46 in good yield as a single diastereomer. A number of additional nitrones were examined as well and all provided similar yields of the β,γepoxyhydroxylamines. Treatment of 46 with additional base provided the 1,2-oxazetidine ring system 47 in excellent yield. Interestingly, none of the five-membered isoxazolidines from the 5-endo-tet cyclization were formed in this cyclization.
O
Ph
sBuLi, TMEDA THF, -98 °C Ph
NaOH 60 °C 85%
O
Li
Ph
HO O N 47
Ph
t-Bu
t-Bu +
N
Ph 45
O
O 63%
t-Bu
Ph Ph N 46
OH
79
Three-membered ring systems
The aza-[2,3] Wittig rearrangement of aziridines is an excellent method for the synthesis of substituted piperidines. The analogous reaction of an epoxide has recently been examined <06TL7281>. Reaction of divinyl epoxide 48 with t-butyl diazo acetate provides the ylide intermediate 49, which then undergoes the [2,3] Wittig rearrangement to 50, Several catalysts were examined as catalysts for the formation of 49. It is noteworthy that the copper catalyst performed much better than the more widely used rhodium catalysts. CO2t-Bu
t-BuO2C
O
t-BuO2C
N2
O
O
Cu(hfacac)2 72%
48
49
50
The acid catalyzed rearrangement of an epoxide to an aldehyde or ketone is a useful and widely used reaction. Two useful examples of this rearrangement are reported below. An interesting conversion of a vinyl epoxide to a dihydropyridine has been reported using this rearrangement methodology <06OL3473>. Treatment of the ester substituted vinyl epoxide 51 with Sc(OTf)3 catalyzes a ring opening of the epoxide to form an intermediate enol. This enol adds to the imine which subsequently cyclizes to form the dihydropyiridine 53. This reaction is limited by the need for a non-enolizable imine. I
I
O
O
EtO CH3 51
+
Sc(OTf)3 (15 mol%) 5Å MS 51%
N Ph
H
H3C
N Ph CO2Et 53
52
An additional example of an oxonium ion generated via the acid catalyzed rearrangement has been used to prepare a dihydropyran <06TL6149>. The oxonium ion 54 generated by the reaction of an epoxide with ZrCl4 can be trapped by a nucleophile such as butynol to prepare dihydropyran 55. A variety of mono- and disubstituted epoxides have been used in this reaction. O
HO
ZrCl4
O
O
ZrCl3
54 Cl
O
67%
O 55
80
S.C. Bergmeier and D.D. Reed
3.3
AZIRIDINES
3.3.1
Preparation of Aziridines
Several reviews on the synthesis of aziridines have been published in the previous year. These publications include: a review on the silver catalyzed addition of nitrenes (among other intermediates such as carbene) across a double bond <06EJOC4313>; a review on sulfur ylide addition to imines to form aziridines <06SL181>; a review on nitrogen addition across double bonds <06ACR194>; a general review on functionalization of α,β-unsaturated esters with some discussion of aziridination <06TA1465> The addition of a nitrogen atom across a carbon-carbon double bond is a powerful method for the synthesis of aziridines in that two bonds are formed in a single step. The large amount of previous knowledge in the stereospecific synthesis of carbon-carbon double bonds also lends great utility to this general route of aziridine synthesis. The reactions of a nitrene, metal nitrene or nitrene equivalent with an olefin continues to attract attention. No doubt due to the potential payoff in terms of a generally universal aziridination method. The use of Rh2(NHCOCF3)4 has been shown to be exceptionally useful in the catalysis of aziridination reactions using trichloroethoxysulfonamide (TcesNH2) as the nitrogen source <06T11331>. The Tces group is readily removed from the final compound. In addition, this aziridination process works well on both styrene as well as aliphatic olefins. This reaction is rare in that similar aziridination methods only work well for styryl olefins. While nitrogen sources such as chloramine-T and PhI=NTs have been used for aziridination reactions, TsNCl2 has not been explored until now. The reaction of TsNCl2 with Pd(OAc)2 and K2CO3 provides the expected N-tosyl aziridines in good yields <06TL7225>. This reaction presumably proceeds through an initial amidohalogenation reaction catalyzed by palladium. The chloroamide is then converted to the aziridine via an intramolecular substitution reaction. Gold-based catalysis has attracted considerable attention in recent years. A gold-catalyzed aziridination reaction has recently been reported <06JOC5876>. A series of gold catalysts were examined for their ability to catalyze the aziridination of styrene with pnitrophenylsulfonamide (NsNH2). Styrene and phenyl-substituted styrenes provided the Nnosyl aziridines in good to excellent yields. Cinnamate however provided the aziridine product in only 25% yield. The use of other sulfonamides (e.g. tosyl, trichloroethyl) gave much lower yields of the aziridine product. Diphenylphosphorylazide (DPPA) has also been shown to be an excellent nitrene source in aziridination reactions <06JOC6655>. The reaction of styrene and substituted styrenes with DPPA and tetraphenylporphyrin cobalt (CoTPP) provided the N-diphenylphosphinyl aziridines in moderate yields. The use of metal-catalyzed aziridination methods with chiral ligands has also been reported. The copper-based system paired with ligand 56 provides the expected cinnamyl aziridine in good yield and excellent ee <06MI4568>. It is interesting to note that the t-butyl ester is obtained with 99% ee while the smaller methyl ester is obtained in only 88% ee. The binaphthyl ruthenium catalyst 57 has been found to aziridinate a number of olefins with moderate enantioselectivity <06TL1571>. Both p-nitrophenyl (Ns) and trimethylsilyloxy (SES) sulfonamides work well with this catalytic system. As is usually seen, the aziridination of aliphatic olefins proceeds in only 32% yield and 56% ee.
81
Three-membered ring systems
R2
R2 R1
conditions
R3 Conditions
R1
R3
N R4
Yield
Rh2(NHCOCF3)4 (1 mol%), PhI(OAc)2 R1 = Ph, R2 = H, R3 = Me, R4 = Tces, 85% Cl3CCH2OSO2NH2, MgO R1 = Me, R2 = Me, R3 = (CH2)2CH(Me)(CH2)2OH, 70% Pd(OAc)2 (2 mol%), K2CO3, TsNCl2
R1 = Ph, R2, R3 = H, R4 = Ts, 70%
[Au(tBu3Tpy)]OTf (3 mol%), NsNH2
R1 = Ph, R2, R3 = H, R4 = Ns, 88% R1 = Ph, R2 = H, R3 = CO2Me, R4 = Ns, 25%
CoTPP (10 mol%), (PhO)2P(O)N3
R1 = Ph, R2, R3 = H, R4 = P(O)(OPh)2, 50%
[Cu(MeCN)4]ClO4, 56, PhINTs
R1 = Ph, R2 = H, R3 = CO2tBu, R4 = Ts, 99%, 99% ee (2S,3R) R1 = Ph, R2 = H, R3 = CO2Me, R4 = Ts, 97%, 88% ee (2S,3R)
NsN3, 57 (0.1 mol%) NsN3, 57 (2 mol%) SESN3, 57 (0.1 mol%)
R1 = Ph, R2, R3 = H, R4 = Ns, 70%, 81% ee R1 = n-C6H13, R2, R3 = H, R4 = Ns, 32%, 56% ee R1 = Ph, R2, R3 = H, R4 = SES, 26%, 91% ee
O
O Ar = 3,5-Cl2-4-(CH3)3SiC6H2
Cl
N
N
Cl
N CO N Ru O O Ar Ar
Cl
Cl 56
57
Non-metal catalyzed aziridinations have also been reported. These methods are often more broadly applicable than the metal-catalyzed methods. The use of N-methylpyrrolidine-2-one hydrotribromide (MPHT) and chloramine-T is an effective route for the synthesis of N-tosyl aziridines <06MI16>. The aziridination of olefins using t-BuOI and sulfonamides appears to be a general method for aziridination <06CC3337>. The t-BuOI is prepared in situ from tBuOCl and NaI. This is a broadly applicable method in that a wide variety of sulfonamides (tosyl, nosyl, SES) can be used with roughly equivalent yields. R2
R2 conditions
R1 Conditions
R1
N R3 Yield
MPHT (10 mol%), Chloramine-T
R1 = Ph, R2, R3 = H, R4 = Ts, 85%
t-BuOCl, NaI, TsNH2 t-BuOCl, NaI, TsNH2 t-BuOCl, NaI, o-NsNH2 t-BuOCl, NaI, SESNH2
R1 = Ph, R2 = Me, R3 = H, R4 = Ts, 81% R1 = n-C6H13, R2, R3 = H, R4 = Ts, 77% R1 = Ph, R2, R3 = H, R4 = o-Ns, 66% R1 = Ph, R2, R3 = H, R4 = SES, 97%
82
S.C. Bergmeier and D.D. Reed
The ability to directly prepare N-H aziridines through the addition of nitrogen to an olefin is quite rare. A recent report provides a method for the conversion of chalcones to the corresponding N-H aziridines <06SL2504>. The use of the hydrazinium salt 58 as a nitrogen transfer agent in combination with base proved to be a synthetically useful method for the synthesis of aziridine 59. Hydrazinium salt 58 can be readily prepared as either the iodide or nitrate salt, although the iodide synthesis was more convenient. The counterion of the hydrazinium salt as well as the base used were shown to be important factors. For electronrich aryl groups the iodide salt and t-BuOK gave significantly better yields. O
O
O base
Ph
Ar
X
N H2N
CH3 58
Ar Ar Ph Ph p-MeOC6H4 p-MeOC6H4
X I NO3 I NO3
Ph 59 Yield (%) 61 95 56 2
HN
Base t-BuOK NaOH t-BuOK NaOH
Intramolecular aziridination reactions overcome many of the inherent limitations associated with intermolecular aziridinations. The ring strain associated with the resulting bicyclic aziridines leads to increased reactivity and instability. Sulfamate-linked bicyclic aziridines can be readily prepared using rhodium catalysis <06T11331>. Treatment of sulfamate 60 with Rh2(oct)4 and PhIO provides sulfamate-linked fused-ring aziridine 61. The stereoselectivity was moderate in this cyclization and was explained by a chair-like transition state that minimized gauche and A1,3 interactions. Interestingly the seven-membered ring 62 could also be formed in good yield and with improved diastereoselectivity.
O
O2 S
NH2
Me
Rh2(oct)4 (2 mol%) PhI(OAc)2, MgO 84%, 4:1
60 O
O2 S
Me 61
NH2
TBSO
O
O2 S
SiMe3
Rh2(NHCOCF3)4 (2 mol%) PhI(OAc)2, MgO 66%, 10:1
N H
O SO 2 N TBSO
H
SiMe3
62
Allylic carbamates have also been cyclized to carbamate-linked fused-ring aziridines. The cyclization of homoallylic carbamates to the corresponding aziridines has not been successful until a recent report <06CC4501>. The reaction of homoallylic carbamate 63 with a rhodium catalyst and iodosobenzene provides moderate yields of the fused-ring aziridine 64. The major byproduct of this reaction is the C-H insertion product 65. The relative amounts of the aziridine to the C-H insertion product could be modulated by the choice of rhodium catalyst. The use of Rh2(OAc)4 provides a 68:14 ratio of aziridine : C-H insertion product, while Rh2(oct)4 provides a slightly better 71:6 ratio.
83
Three-membered ring systems
O O
O NH2
O
O NH
N
63
64 Rh2(OAc)4, PhIO Rh2(oct)4, PhIO
O
H
65
68 71
14 6
The conversion of azidoformates to fused-ring aziridines via the thermal generation of a nitrene has previously been reported. More recently, the photolytic conversion of a sugarderived azidoformate has been used to prepare fused-ring aziridines <06JOC8059>. Photolysis of azidoformate 66 at 254 nm provides aziridine 67 in excellent yield. The resulting bicyclic aziridine was reduced to provide oxazolidinone 68 in 95% yield. Oxazolidinone 68 was subsequently converted to L-daunosamine. OCH3 O
OCH3
O O
hν (254 nm) 79%
O O
N3 66
O
N O
OCH3
O
H2, Pd/C 95%
NH O
67
68
The synthesis of aziridines though an aza-Darzens or Darzens-like approach is a conceptually useful method for the formation of two bonds of an aziridine ring in a single reaction step <06T3694, 06JOC5881>. There are of course a number of variations on this theme. One very useful approach is the addition of a sulfur ylide to an imine. The addition of S-allyl derived sulfur ylides has been shown to be a good route to diastereomerically pure vinyl aziridines <06CC1833>. The reaction of the chiral N-sulfinyl imine 69 with an S-allyl sulfur ylide provides aziridines 70 and 71 in good yield as a 25:75 mixture. The diastereomeric excess of the major isomer (71) was >95%. t-Bu
Me
N Ph
O
S tBu
69
S Me tBuOLi THF 72% ratio 70:71, 25:75
S N
O
t-Bu
Me
S N
O
Ph
Ph 70
71
The intramolecular addition of sulfur ylides to imines (e.g. 72) has proven to be an excellent route to fused-ring aziridines (e.g. 73) <06AG(I)7066>. The addition of a sulfonamide to a vinylsulfonium salt leads to the formation of the sulfur ylide 72. The ylide then undergoes an intramolecular addition to form the product fused-ring aziridine 73. This method has also been used for the synthesis of fused-ring epoxides.
84
S.C. Bergmeier and D.D. Reed
O
O N S t-Bu
O
S t-Bu NH
SPh2
S t-Bu N NHTs
N Ts
NaH
N
O S
t-Bu
68%
SPh2
N Ts
N Ts 72
73
The addition of halomethyl metal reagents provides another Darzens-like route to aziridines <06JOC9373>. Reaction of ICH2Cl with MeLi generates a chloromethyllithium reagent, which then adds to the imine 74. A subsequent intramolecular N-alkylation provides the aziridine 75. The isolation of a chloromethyl ketone byproduct demonstrated that the chloromethyllithium reagent is operative as opposed to a carbene.
OMe
N
ICH2Cl, LiBr, MeLi 97%, d.r. 87:13
O
N
OMe
N O
N
74
75
A new methodology for the synthesis of aziridines via an intramolecular cyclization reaction at nitrogen has been reported <06CC3513>. Typical ring closing methods for the formation of aziridines rely upon a basic nitrogen displacing a leaving group on a beta-carbon as in the approaches above. The conversion of a hydroxylamine to an O-acyl hydroxylamine renders this nitrogen relatively electrophilic. Formation of the enolate of 76 initiates a 3-exotet ring closure by reaction of the nucleophilic enolate carbon upon the electrophilic Oacylated nitrogen. The yields of this process are quite good. The reaction also proceeds with very good diastereoselectivity, providing 77 and 78 in a 90:10 mixture. The reaction has also been shown to proceed with a chloramine <06CC4338>.
Ph
N
76
Ph
OCOtBu LHMDS, -20 °C 93% CO2tBu
Ph N
N CO2tBu
77
90 : 10
CO2tBu 78
One of the most well used methods for the synthesis of aziridines involves a two (or sometimes more) step process in which an epoxide is opened by a nitrogen nucleophile. The resulting β-amino alcohol (e.g. 79) is then converted to an aziridine via a number of different processes. This method is generally not broadly applicable when a variety of different groups on the nitrogen of the aziridine are desired. A useful method to convert an epoxide to a number of different N-sulfonyl aziridines (e.g. 80) has been reported <06S425>. Simple addition of a sulfonamide to an epoxide provides high yields of 79 which is readily closed to form the aziridine.
85
Three-membered ring systems
1.2 equiv. RSO2NH2 0.1 equiv K2CO3 0.1 equiv BnNEt3Cl dioxane, 90 °C
O
OH N H
SO2R
79
R = 4-MeC6H4, 91% R = t-Bu, 83%
1) 5 equiv Pyridine 5 equiv MsCl CH2Cl2, reflux 2) 4 equiv K2CO3 CH3CN, 45 °C R = 4-MeC6H4, 82% R = t-Bu, 77%
N SO2R 80
A rather interesting approach to aziridines involves a reductive ring-opening of an azetidinone followed by ring closure <06OL1101>. Treatment of 81 with LiAlH4 leads to an intermediate amino alcohol. This is followed by the subsequent formation of the aziridine ring via displacement of the adjacent halogen to form 82. Cl BnO
OBn
5 equiv LiAlH4
HO
N O
H
R 81
3.3.2
N R
R = i-Pr, 57% R = Bn, 62% R = allyl, 43%
82
Reactions of Aziridines
The reactions of aziridines (like epoxides) are largely dominated by nucleophilic ring opening reactions. In the past year two reviews that cover ring opening reactions of aziridines have been published, including a review on ring opening reaction of aziridines with carbon nucleophiles <06EJOC4979>, and a review on the reactions of N-sulfonylaziridines <06JOC8993> which includes discussion of their ring opening reactions. The reaction of aziridines with oxygen nucleophiles is a common route to vicinal amino alcohols. The use of aldehydes as oxygen nucleophiles has been reported as a route to acyloxy amines <06OL1521>. N-Heterocyclic carbenes (NHC) have also been used to catalyze the ring opening of aziridines by carboxylic acid anhydrides to produce 83 in moderate yields <06EJOC4787>. The same NHC has also been reported to catalyze the opening of aziridines by TMSX reagents where X = N3, Cl, and I <06TL4813>. NHTs NHC, RCHO K2CO3 18-crown-6 50 °C, air R = Ph, 70% R = CH3, 75% NHC, (RCO)2O 80 °C R = CH3, 96% R = Ph, 91%
NTs
O O
R
NHC =
N
N
83
Amino sugars are important component of mono- and disaccharides that lend themselves well to synthesis through aziridine opening reactions. Glycal derived aziridines have been found to be useful intermediates for the synthesis of 4-amino-2,3-unsaturated sugars <06JOC1696>. Epoxide 84 was converted to the trans-dimesylate 85 through a series of standard transformations. Treatment of 85 with base and an excess of a glycosyl acceptor, 87, provides the glycoside 88 in excellent yield. The aziridine 86 was not isolated due to its
86
S.C. Bergmeier and D.D. Reed
reactive nature. A number of simply glycosyl acceptors such as MeOH and i-PrOH were examined in this reaction and provided the expected 1,4 addition products in high yield. It is quite impressive that the use of a monosaccharide such as 87 as the glycosyl acceptor also provides the product in very good yields. O
BnO
3 steps
O
BnO
84
85 O
HO
BnO O
O O
73%
MsN
NHMs
O
O
BnO
MsO
O
+
t-BuOK
86 O
O
O
O O
O
MsHN
O
87
88
Typically, the stereospecific formation of quaternary centers is as problematic as selective nucleophilic attack at the more substituted carbon of aziridines. Interestingly, a copper mediated methodology has been reported that does both <06OL5105>. Although N-tosyl aziridines show favorable results, N-nosyl aziridines gave the best results. The reaction of 89 with a variety of phenols yielded 90 in moderate yields. O OH N Ns
N H
CO2t-Bu + R
R
O
CuOAc, DBU toluene
O
R = H, 64% R = OMe, 59% R = CHO, 71%
89
N H NHNs
CO2t-Bu
90
Another problem with the reaction of phenols with aziridines is the selectivity between Oalkylation vs C-alkylation. A recent report has identified that the use of (ArO)3B selects for C-alkylation <06OL2627>. Most of the examples reported in this paper showed less than 5% of the O-alkylation product. What is interesting about this report is the stereochemistry of the product. While the mechanism is not known, the product is formally an SN1 type product. Generally less than 5% was the product of inversion of configuration (the SN2 product). In addition to the N-tosyl, both the N-Cbz and N-Dpp aziridines gave excellent yields of aziridine-opened product.
NTs Ph
B
O +
3
73% Ph
OH NHTs
Typically in ring-opening reactions of aziridines, the amine functional group is retained in the product molecule. An example of such a reaction where the amine group has been lost has recently been reported <06TL977>. An intramolecular Friedel-Craft reaction of aziridine 91 leads to the expected product as an intermediate. Under the rather drastic reaction conditions, the sulfonamide is lost leading to formation of the naphthalene ring.
87
Three-membered ring systems
CO2Me NTs
91
H3C
CO2Me
H2SO4 (300 mol%) benzene, reflux 85%
NHTs
92
H3C CO2Me
CO2Me
NHTs
CH3
93
94
CH3
It has been found that N-tosyl aziridines undergo oxidative addition to palladium complexes to form azapalladacyclobutanes <06JA15415>. Reaction of aziridine 95 with Pd2(dba)3 and 1,10-phenanthroline provides the palladacycle 96 in 45% isolated yield. This compound is an air stable solid. Treatment the palladacycle 96 with catalytic CuI is believed to open the palladacycle to form a copper intermediate, which cyclizes to cyclopentyl alkylpalladium intermediate 97. Loss of CuI then provides the product palladacycle 97 as an air stable solid. Several different aziridines were examined in this reaction. Only a limited set of olefin substituted aziridines provided the azapalladacyclobutanes (e.g. 96). NTs 95
(phen) Pd I N Cu Ts
Pd2(dba)3 (50 mol%) 1,10-phenanthroline (phen) 45%
Ts N
Pd(phen)
CuI (20 mol%) 72%
96
Pd(phen) I N Cu Ts
-CuI N Pd(phen) 97 Ts
A novel C-3 functionalization of methylene aziridines has also been reported <06T8447>. Selective deprotonation of 98 to form 99 and the reaction 99 with an electrophile yielded 100 in good yields. In this way, a variety of alkyl groups could be selectively placed on the aziridine. These researchers also found that (S)-α-methylbenzyl substituted methylene aziridines, 101, when deprotonated and reacted with a variety of electrophiles gave 102 in moderate yields and with good diastereoselectivity.
88
S.C. Bergmeier and D.D. Reed
Bn N
Bn N
s-BuLi, TMEDA
Bn N
Electrophile
Li
R
98
99
100 MeI PhCHO TMSCl Cl(CH2)4I
Me
H
Ph
Me
N
H
s-BuLi, TMEDA Electrophile
Ph
Electrophile R MeI Me Ph2CO Ph2COH TMSCl TMS
N R
101
R %Yield Me 79 PhCHOH 74 TMS 63 Cl(CH2)4 70
%Yield 47 43 80
%de 80 88 90
102
In an extension of previous work, additional examples of fused-ring aziridines were prepared through the cycloamination of olefins with an aziridine nitrogen <06JOC6067>. Fused-ring aziridines 104 and 105 were obtained through the cycloamination of aziridine 103. While 104 and 104 were obtained as an ~3:1 mixture, they were converted to exocyclic olefin 106 in excellent yields. These fused-ring aziridines will react with a variety of nucleophiles providing cyclic imine 107 in excellent yields. H O N ( )n 103
Br
Ph
N
H
( )n
N
Br
O
N
O
KOH MeOH/THF
104
105 Ph Ph n = 1, 98%, 104:105 = 74:26 n = 2, 88%, 104:105 = 78:22 O
H
( )n
H
( )n
NBS
Ph
( )n
Nu O H3C
106 Ph n = 1, 99% n = 2, 95%
N H 107
Nu
n = 1, TMSN3, Nu = N3, 99% n = 1, H2, Pd/C, Nu = H, 99% n = 1, MeOH, HBF4, Nu = OMe, 99% n = 2, TMSN3, Nu = N3, 81% n = 2, H2, Pd/C, Nu = H, 82%
In a related example, a cycloamination of an olefin was carried out with an N-t-butyl aziridine to prepare morpholine derivatives <06JOC4678>. Upon an initial bromoamination reaction an aziridinium ion 110 is formed. This readily undergoes ring opening with bromide to form dibromomorpholine 111. While this is an interesting reaction, it does not appear to be general, as other groups on the nitrogen provided little to no product. Br
Br NBS
N O
N O
O
Br 108
109
N
N
Br
110
43% Br
O 111
89
Three-membered ring systems
Researchers have found that the reduction of a variety of aziridine esters yields the corresponding aziridine aldehyde which dimerizes diastereoselectively <06JA14772>. The reduction of 112 with excess DIBAL yields the dimer 113, which is in equilibrium with the monomer 114. This molecule reacts as the monomer and both reduction to 115 or reductive amination to 117 proceed in quantitative yields. In a very interesting reaction, treatment of 113 with N-benzyl tryptamine provides the pentacyclic 116 in excellent yield. H N
H N Ph
CO2Et
DIBAL (200 mol%) 83%
Ph
112
H
H
H N
O OH
N
Ph H
113
CHO 114
Ph H N OH
Ph 115
NaBH4 100%
N-benzyltryptamine -20 °C, toluene 94% (20:1, syn:anti) Bn N H
NaCNBH3 aniline 100%
H N NHPh
Ph 117
H Ph
N
H
N H H 116
The reactions of N-acyl aziridines can sometimes involve nucleophilic attack at the acyl group rather than the aziridine ring. This change in the more typical pattern of reactivity is dependent on a number of factors. An example of this type of change in reactivity has recently been reported <06TL2065>. Treatment of 118 with benzylamine provided a low yield of 119, the product of nucleophilic attack at the carbonyl. An examination of reaction conditions found that the use of a Lewis acid and a coordinating solvent such as Et2O or THF provided significantly better yields of 119. O
OBn
O BnNH2
N F3C
CO2Et 118
Solvent (temp.) ClCH2CH2Cl (reflux) THF (reflux) Et2O (reflux)
Lewis acid Yield none 25% Yb(OTf)3 (20 mol%) 52% BF3•Et2O (100 mol%) 67%
NHBn N
F3C
CO2Et 119
In a highly unusual reaction, treatment of 120 with an organolithium reagent provides amine substituted homoallylic alcohol 122 <06JOC8510>. This reaction presumably proceeds via a metalation/ring opening sequence to generate intermediate 121. This then undergoes a beta-elimination to 122. A number of other examples were also reported.
90
S.C. Bergmeier and D.D. Reed
Li O
NTs
RLi
R
O NLiTs
120
3.4
121
R HO
NHTs
R = nBu, 82% R = Ph, 69% R = CH2SiMe3, 92%
122
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Three-membered ring systems
06OL3923 06OL5105 06S425 06SL181 06SL2504 06T3694 06T8447 06T11331 06T11413 06T12264 06TA330 06TA1465 06TA1638 06TL977 06TL1571 06TL1733 06TL2065 06TL4775 06TL4813 06TL6149 06TL6557 06TL6865 06TL7225 06TL7281 06TL7755 06TL8471 06TL9268
91
V. Caprlatl, S. Florlo, R. Lulsl, A. Salomone, C. Cuoccl, Org. Lett. 2006, 8, 3923. P. Li, E.M. Forbeck, C.D. Evans, M.M. Joullie, Org. Lett. 2006, 8, 5105. J. Huang, P. O'Brien, Synthesis 2006, 3, 425. X.L. Hou, J. Wu, R.H. Fan, C.H. Ding, Z.B. Luo, L.X. Dai, Synlett 2006, 181. A. Armstrong, D.R. Carbery, S.G. Lamont, A.R. Pape, R. Wincewicz, Synlett 2006, 2504. J.B. Sweeney, A.A. Cantrill, M.G.B. Drew, A.B. McLaren, S. Thobhani, Tetrahedron 2006, 62, 3694. C. Montagne, N. Prevost, J.J. Shiers, G. Prie, S. Rahman, J.F. Hayes, M. Shipman, Tetrahedron 2006, 62, 8447. K. Guthikonda, P.M. When, B.J. Caliando, J. Du Bois, Tetrahedron 2006, 62, 11331. S. Lee, D.W.C. MacMillan, Tetrahedron 2006, 62, 11413. A. Lattanzi, A. Russo, Tetrahedron 2006, 62, 12264. J. Lu, X. Wang, J. Liu, L. Zhang, Y. Wang, Tetrahedron: Asymmetry 2006, 17, 330. G. Guillena, D.J. Ramon, Tetrahedron: Asymmetry 2006, 17, 1465 R.I. Kureshy, S. Singh, N.H. Khan, S.H.R. Abdi, S. Agrawal, R.V. Jasra, Tetrahedron: Asymmetry 2006, 17,1638. K.Y. Lee, S.C. Kim, J.N. Kim, Tetrahedron Lett. 2006, 47, 977. H. Kawabata, K. Omura, T. Katsumi, Tetrahedron Lett. 2006, 47, 1571. A. Babic, M. Sova, S. Gobec, S. Pecar, Tetrahedron Lett. 2006, 47, 1733. G. Rinaudo, S. Narizuka, N. Askari, B. Crousse, D. Bonnet-Delpon, Tetrahedron Lett. 2006, 47, 2065. B.P. Bandgar, N.S. Joshi, V.T. Kamble, Tetrahedron Lett. 2006, 47, 4775. J. Wu, X. Sun, S. Ye, W. Sun, Tetrahedron Lett. 2006, 47, 4813. J.S. Yadav, K. Rajasekhar, M.S.R. Murty, Tetrahedron Lett. 2006, 47, 6149. D.B.G. Williams, M. Lawton, Tetrahedron Lett. 2006, 47, 6557. B. Das, V.S. Reddy, F. Tehseen, Tetrahedron Lett. 2006, 47, 6865. J. Han, Y. Li, S. Zhi, Y. Pan, C. Timmons, G. Li, Tetrahedron Lett. 2006, 47, 7225. K.J. Quinn, N.A. Biddick, B.A. DeChristopher, Tetrahedron Lett. 2006, 47, 7281. A. Fernandez-Mateos, P.H. Teijon, R.R. Clemente, R.R. Gonzalez, Tetrahedron Lett. 2006, 47, 7755. B. Das, V.S. Reddy, M. Krishnaiah, Tetrahedron Lett. 2006, 47, 8471. T. Satoh, M. Hirano, A. Kuroiwa, Y. Kaneko, Tetrahedron Lett. 2006, 47, 9268.
92
Chapter 4 Four-membered ring systems Benito Alcaide Departamento de Química Orgánica I. Facultad de Química, Universidad Complutense de Madrid, 28040-Madrid, Spain
[email protected] Pedro Almendros Instituto de Química Orgánica General, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain
[email protected] ______________________________________________________________
4.1
INTRODUCTION
The importance of four-membered heterocycles in many fields of Science (including Organic Chemistry, Inorganic Chemistry, Medicinal Chemistry, and Material Science) can hardly be overemphasized, and justifies a long lasting effort to work out new synthetic protocols. Condensing the vast amount of published material to less than 20 pages is an extremely demanding task. This, obviously, can only be done by strict selection and by applying a very dense style of writing. Oxygen- and nitrogen-containing heterocycles, in particular β-lactams, dominate the field in terms of the number of publications. This chapter covers selected relevant aspects in this area. 4.2
AZETIDINES, AZETINES, 3-AZETIDINONES, AND DIAZETINES
2-(1-Adamantyl)-2-methyl-azetidines have been synthesized and tested for their antiviral activity against influenza, being markedly active against influenza A H2N2 virus <06BMC3341>. The biological activities of an aqueous fraction extracted from Polygonatum odoratum of L-2-azetidinecarboxylic acid 1, purified from the extract, on the growth of several types of algae have been tested <06MI1>. Electrophilic amination of ketones and aldehydes in the presence of dibenzyl azodicarboxylate in dichloromethane, using L-2azetidinecarboxylic acid 1 as a catalyst, has been described <06TL1117>. The structure of 3fluoroazetidinium hydrochloride 2 has been explored both by X-ray diffraction analysis and DFT calculations, and the conformation of this molecule was shown to be significantly influenced by the through space C–F N+ interaction <06CC3190>. Aqueous phosphoric acid (85 wt%) is an effective, environmentally benign reagent for the deprotection of tert-butyl carbamates, including tert-butyl 1-benzhydrylazetidin-3-ylcarbamate 3 <06JOC9045>. The structure-property relationship of aminonitrofluorenes such as azetidine derivative 4, synthesized by copper-mediated Ullmann-type C–N bond formation between the free amine and the corresponding iodoarene, has been described <06S3425>. tert-Butyl hypoiodite (tBuOI) has been found to be a powerful reagent for the cyclization of N-alkenylamides leading to a variety of N-heterocycles, including 2-(iodomethyl)-1-tosylazetidine 5, under extremely mild conditions <06OL3335>.
93
Four-membered ring systems
F
CO 2H
BocHN
I N
+
N
N
N H H
1
2
H Cl
3
NO2
Ph
– Ph
N
Ts
5
4
N,N'-Carbonyldiimidazole-mediated cyclization of amino alcohols to substituted azetidines has been developed <06JOC4147>. N-Tosyl-3-halo-3-butenylamines underwent efficient Ullmann-type coupling with the catalysis of CuI/N,N'-dimethylethylenediamine to afford 2-alkylideneazetidines 6, which could be readily converted into the corresponding βlactams by oxidation with O3 <06OL5365>. 6-Vinyl oxazinanones undergo catalytic, diastereoselective, decarboxylative ring contraction to form vinyl azetidines 7 in good yield <06OL3211>. N-(Alkylidene or 1-arylmethylidene)-2-propenylamines have been regiospecifically functionalized to novel N-(alkylidene or 1-arylmethylidene)-3-bromo-2fluoropropylamines, which proved to be excellent precursors for 3-fluoroazetidines 8 <06JOC7100>. The one-pot formation of 1,3-disubstituted azetidines via the reaction of amine nucleophiles with in situ prepared bis-triflates of 2-substituted-1,3-propanediols have been demonstrated <06JOC7885>. O X
NHTs
Ts
i N
R
R
Ts
N
R2 O
R3
R4
6 (86–99%)
R1
R2
ii
R3
R1
H
R2
F
N
Ts
N
R1
8
R4 7 (60–93%)
o
Key: i) CuI, DMEDA, dioxane, 100 C. ii) 5 mol% Pd(PPh3)4, CH2Cl2, RT. The use of monochloroalane has been shown to be an efficient method for the reduction of 4-aryl-3,3-difluoro- as well as trans-2-aryl-3-chloro-β-lactams to their corresponding azetidines 9 <06SL2039; 06T6882>. The resulting chloroazetidines were excellent building blocks for the synthesis of different 3-substituted azetidines through nucleophilic substitution of the chlorine by different carbon, nitrogen, sulfur and oxygen nucleophiles in good to high yields <06T6882>. Azetidine-2-carboxylic acid 10 has been obtained by treating a trichloromethyl ketone-derived Mannich adduct with aqueous NaOH in 1,2-dimethoxyethane. The reaction is considered to proceed via a gem-dichlorooxirane intermediate. Intramolecular ring opening affords the azetidine ring <06AG(E)3146>. Enantio- and diastereomerically pure cis-2,3-disubstituted azetidinic amino acid derivatives have been obtained by intramolecular anionic ring-closure <06SL781>. The electroreduction of an aromatic imino ester prepared from (S)-glutamic acid in the presence of chlorotrimethylsilane and triethylamine afforded the four-membered cyclized product 11, a mixed ketal of cis-2,4-disubstituted azetidine-3-one, stereospecifically <06OL1323>. The application of N-ferrocenylmethyl azetidin-2-yl(diphenyl)methanol in the asymmetric ethylation and arylation of arylaldehydes has been described <06SL3443>. R2
X Y O
N
i Y
R1
O Ph2P
R2
X N
NH
OH
Ph
R1
CCl3
9 (82–97%)
Ph
TMSO
N HO2C
PPh2 O
N Ph
10 (72%) o
o
OMe
CO2Me
ii
Key: i) AlH2Cl, Et2O, 34 C (X = Cl), 0 C (X = F). ii) aq. NaOH, DME, RT.
11
Bz
94
B. Alcaide and P. Almendros
Pyranoid and furanoid spiro-N-mesyl azetidines, a new type of water-soluble spiro-Cnucleoside, have been prepared from easily available sugar spiroacetals <06T915>. The first results concerning thermally induced and silver-salt-catalyzed [2+2] cycloadditions of imines to (alkoxymethylene)cyclopropanes to afford spirocyclic azetidines 12 have been published <06AG(E)5176>. A two-step reaction sequence using a one-pot Į-aminoallylation reaction followed by ring-closing metathesis to make a diverse collection of spirocyclic diamines, including azetidines, has been developed <06TL8977>. The dominant secondary fragmentation of a series of 1,3-di- and 1,2,3-trisubstituted N-arylhexahydropyrimidines under electron impact has been described to involve loss of imines or azetidines <06ARK57>. The treatment of an oxopiperazino-β-lactam with BH3·SMe2 in THF under reflux gave rise to the bicyclic azetidine 13 as the major product <06TL8911>. The crystalline cis,cis,cis,cis-[5.5.5.4]-1-azafenestrane borane adduct 14 has been efficiently isolated using a Mitsunobu reaction as the key cyclization step followed by treatment with BF3·Et2O <06JA11620>. Triplet-sensitized irradiation of 8-thia-9-azatricyclo[7.2.1.0]dodeca2,4,6,10-tetraenes in acetone solution gives rise exclusively to tetracyclic sultams bearing a bridgehead azetidine ring <06JOC2456>. The synthesis of novel 1',2'-azetidine-fused bicyclic pyrimidine nucleosides and their transformations to the corresponding phosphoramidite building blocks for automated solid-phase oligonucleotide synthesis has been reported <06JOC299>. It has been shown that the reaction of azetidines with chloroformates gives highly functionalized γ-chloroamines in high yields and selectivities under mild reaction conditions <06OL5501>. The ring opening of activated cyclic amines, including fourmembered, followed by an intramolecular expansion of cyclopropanol to cyclobutanone via a carbocation intermediate has been reported. In the case of a N-tosylazetidine ester, the cyclobutanone 15 was formed by treatment of the crude Kulinkovich product with CaSO4 <06OL4335>. A formal [4+2] cycloaddition of 2-aryl-N-tosylazetidines with nitriles in the presence of Zn(OTf)2 has been described for the synthesis of substituted tetrahydropyrimidines <06TL5393>. N-Activated 2-phenylazetidines have been opened regioselectively at the benzylic carbon with various allylsilanes or propargylsilane in the presence of BF3·Et2O, providing amino olefins <06TL2205>. The carbonylative polymerization of azetidines catalyzed by [Co(CH3CO)(CO)3P(o-tol)3], and the participation of the tetrahydrofuran solvent in the polymerization to give ester units in the polymer products has been described
<06AG(E)129>. Insights into the regioselective nucleophilic ring-opening of azetidinium ions has been reported <06EJO3479>. It has been shown that efficient ring expansions, selectively leading either to pyrrolidines or to azepanes through [1,2] or [2,3] sigmatropic shifts, respectively, can be performed from 2-alkenylazetidinium salts <06EJO4214>. OR1
OR1
R2 +
H
R4
N
i
N R3
R2
N
OH
N
– BF3 +N
Bn
H
H
R3
ii N Ts
12 (71–97%)
13 o
14
NHTs ( )2
CO 2Et
O 15 (70%)
4
Key: i) 10 mol% Ag(fod), MeCN, 30 C. R = 2,5-Dimethoxyphenyl. ii) (a) ClTi(O-i-Pr)3, EtMgBr, THF, RT; (b) CaSO4, CH2Cl2, RT. The direct, stereoselective conversion of alkynes to N-sulfonylazetidin-2-imines 16 by the initial reaction of copper(I) acetylides with sulfonyl azides, followed, in situ, by the formal [2+2] cycloaddition of a postulated N-sulfonylketenimine intermediate with a range of imines has been described <06AG(E)3157>. The synthesis of N-alkylated 2-substituted azetidin-3-ones 17 based on a tandem nucleophilic substitution followed by intramolecular Michael reaction of primary amines with alkyl 5-bromo-4-oxopent-2-enoates has been
95
Four-membered ring systems
achieved <06EJO2440>. 1-Benzhydryl-3,3-difluoroazetidin-2-thione has been prepared and converted into γ-aminodithioesters <06S2327>. The [2+2] cycloaddition of an N-acyl-2azetine to dichloroketene has been described as a new entry to azetidines fused to cyclobutanes <06TL6377>. The conversion of 4-vinyl-substituted β-lactams into 4-vinylsubstituted 1-azetines 18 and their subsequent reaction with diphenylcyclopropenone resulted in the formation of a highly functionalized 7-azabicyclo[4.2.1]nonene <06TL425>. The Xray structure of an azetine-containing Ni(II) porphyrin derivative has been elucidated <06OBC4059>. The preparation of 1,2-diazetidines 19 from 1-(1-hydroxypropan-2yl)hydrazine-1,2-dicarboxylate under very mild conditions has been accomplished <06TL6835>. The regioselective acylation reactions of Δ2-1,2-diazetines 20 as well as their rearrangements into 4H-1,3,4-oxadiazines or pyridazines have been reported <06S514; 06S2885>. It has been proposed that azetine and Δ3-1,2-diazetine intermediates may be involved in the thermolysis of aza-enediynes <06OL1983>. A stereoselective synthesis of 4hydroxyalkyl-1,2-oxazetidines 21, based on the addition of α-lithiated aryloxiranes to nitrones and subsequent cyclization of the corresponding intermediates in a 4-exo-tet mode, has been described <06OL3923>. NSO2R4
R3 R
2
N
N
R 16
4.3
1
CO2R2
O
17
2
R1
R
N R1 18
HO R1
R2
SEt
1
ArHN
N N R
R
1
19
NHAr
R2 Ph
Ar
N N
O N
20
21
R3
MONOCYCLIC 2-AZETIDINONES (β-LACTAMS)
The polymer-supported and combinatorial synthesis of β-lactams has been reviewed <06MI109>. A review on the synthesis of new classes of heterocyclic C-glycoconjugates including C-glycosyl β-lactams by asymmetric multicomponent reactions has appeared <06ACR451>. The asymmetric synthesis of active pharmaceutical ingredients including βlactams such as ezetimibe and SCH 58053 has been reviewed <06CRV2734>. An overview on recent developments in isocyanide based multicomponent reactions in applied chemistry including β-lactam formation, has appeared <06CRV17>. Ketene chemistry including ketene-imine cycloadditions to form β-lactams, has been reviewed <06EJO563>. A review on the biocatalytic preparation of β-amino acids including the ring opening of β-lactams, has appeared <06T5831>. A convenient and general method of synthesis of NH-β-lactams via Grubbs’ carbene-promoted isomerization of the respective N-allyl β-lactam followed by RuCl3-catalyzed enamide cleavage has been developed <06CEJ2874>. The [2+2] carbonylative cycloaddition of substituted imines with allyl bromide leading to heteroaryl βlactams has been reported <06T1565> <06T12064>. The reaction of enantiopure 4oxoazetidine-2-carbaldehydes with unmodified ketones catalyzed by L-proline or D-proline has been reported to give the corresponding γ-amino-β-hydroxy ketones 22 <06JOC4818>. The synthesis of the novel carbapenem precursor (1'R,3S,4S')-3-[1'-(tertbutyldimethylsilyloxy)ethyl]-4-(cyclopropylcarbonyloxy)azetidin-2-one has been described <06EJO3755>. Ethyl difluoro(trimethylsilyl)acetate and difluoro(trimethylsilyl)acetamides have been used as precursors of 3,3-difluoroazetidinones <06EJO4147>. The activation of the C–Cl bond of (E)-α-chloroalkylidene-β-lactams via the Suzuki cross-coupling reaction to achieve 2-azetidinones 23 has been reported <06MI2114>. The diruthenium-catalyzed formation of β-lactams via carbenoid C–H insertion of α-diazoacetamides has been described <06MI2203>. The synthesis of novel N-sulfonyl β-lactams by Staudinger cycloaddition has
96
B. Alcaide and P. Almendros
been achieved <06MI49>. Results on chiral induction during photocyclization within achiral zeolites of α-oxoamides to β-lactams have been presented <06OBC4533>. A model that explains the relative stereoselectivity in the Staudinger reaction based on a kinetic analysis of the cis/trans ratios of reaction products has been proposed <06JA6060>. The effects of solvents, additives, and pathways of ketene generation on the stereoselectivity of the Staudinger reaction have been investigated <06JOC6983>. Staudinger reaction of ethoxycarbonyl(phenylthio)ketene with various imines and subsequent desulfurization reactions have been employed to synthesize 3-ethoxycarbonyl β-lactams <06JOC815>. The γ-heteroatom directed stereocontrolled Staudinger cycloaddition reaction of vinylketenes and imines has been achieved <06TL5993>. The diastereoselective synthesis of trans-β-lactams on soluble polymer support has been described <06S1829>. Functionalization of N[(silyl)methyl]-β-lactam carbanions with carbon electrophiles to give 2-azetidinones 24 has been reported <06JOC6368>. Experimental and theoretical evaluation of the unexpected four-membered (phosphono-β-lactams 25) over six-membered ring formation during the synthesis of azaheterocyclic phosphonates has been documented <06JA6368>. 2
R
H H
OH O
Ar 2
R
R3 N O
N
R1
O
22
X
2
R N
R1
E
O
23
O P(OR2)2
O
R1
Cl
1
N
R
Ph i
N
P(OR2)2 O
Ph
24
O
R1
25 (62–90%)
Key: i) NaH, THF, Δ. β-Lactam analogs of combretastatin A-4 have been synthesized and their cytotoxic effects have been evaluated in vitro against L1210 leukemia <06MI544>. The design, synthesis, and antibacterial activity of 4-alkylidene-azetidin-2-ones 26 as new antimicrobial agents against multidrug-resistant pathogens have been reported <06JMC2804>. (Benzothiazol-2'-yl)azetidin-2-one derivatives have been prepared and screened for antibacterial and antifungal activities <06IJC(B)1762>. Several pyrimidine-based 2azetidinones have been synthesized and tested for their antibacterial, antifungal and antituberculosis activities against different microorganisms <06IJC(B)773>. β-Lactam– dihydrofuran hybrids 27 have been prepared by a novel palladium(II)-catalyzed heterocyclizative cross-coupling of two different α-allenols <06AG(E)4501>. The synthesis of 3-(aryl)alkenyl-β-lactams by application of olefin cross-metathesis on solid support has been reported <06OL4783>. The synthesis of 3-phenylthio β-lactams has been carried out using α-diazocarbonyl compounds as precursors of ketenes <06S659>. A Lewis acidmediated method for the C3 epimerization of 3-halo-3-phenylthio-β-lactams has been developed <06H749>. The stereoselective synthesis of cis- and trans-3-alkoxy-3phenyl/benzylthioazetidin-2-ones has been described <06T8291>. β-Lactams 28 have been isolated as the major products of the reaction of dimethoxycarbene with isocyanates <06OL3121>. O MeO
O
O
RO
CO2Bn OMe
MeO OMe
H H 3
2
R
R
N
N H
O
O
26
Key: i) RN=C=O, chlorobenzene, heat.
1
R
27
4
R
N N
O
i
OMe OMe OMe N R O
MeO
28 (49–68%)
97
Four-membered ring systems
Azetidin-2,3-diones have been used as synthons for the stereoselective synthesis of cis- and trans-C3-alkyl/aryl azetidin-2-ones <06S115>. It has been reported that the threecomponent reaction of N-substituted hydroxylamines, aldehydes, and phenylacetylene catalyzed by Cu(I) under neat conditions afforded the corresponding β-lactams 29 <06MI203>. The reactions of nitrones with terminal alkynes (Kinugasa reaction), catalyzed by a chiral iPr-trisoxazoline/Cu(ClO4)2·6H2O complex in air, afforded β-lactams in reasonable yields with up to 85% ee <06JOC3576>. The direct, palladium-catalyzed, multicomponent synthesis of 3-amido-substituted β-lactams 30 from imines, acid chlorides, and carbon monoxide has been accomplished <06OL3927>. 4-Oxoazetidin-2-yl benzoate has been resolved by an inclusion complexation with a chiral host compound, (R,R)-(í)-trans4,5-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[4.5]decane <06TA2216>. The Rh(II)catalyzed intramolecular C–H insertion of diazoacetamides in water to afford β-lactams has been mentioned <06JOC5489>. The reaction of N-acylimidazoles possessing an electronwithdrawing group in the α position with diarylimines produces β-lactams 31 in high yields <06JOC5804>. Studies on the effects of the distance between the aromatic rings and the αstereogenic reaction center on the memory of chirality of β-lactams derived from phenylalanine have been performed <06TL5883>. The synthesis of C3 unsymmetrically disubstituted azetidin-2-ones by Lewis acid mediated functionalization of β-lactams as well as a mechanistic study have been published <06TL5255>. The generation of acyloxyketenes from unstable mesoionic 1,3-dioxolium-4-olates and their reaction with ketenophiles to give [2+2] cycloadducts, including β-lactams has been reported <06JOC5162>. A strategy for the synthesis of differently C3-substituted β-lactams involving the reaction of β-lactam carbocation equivalents with active substrates in the presence of a Lewis acid has been described <06T5054>. A new route to enantiopure 4-aryl-substituted β-lactams through lipase-catalyzed enantioselective ring cleavage of the corresponding racemic β-lactams has been developed <06MI917>. The enantioselective synthesis of trans-β-lactams using a chiral auxiliary under Reformatsky reaction conditions has been described <06SL1113>. A new class of glycoconjugated β-lactams has been accessed by direct glycosidation of a suitable 4alkylidene-azetidin-2-one acceptor with several perbenzylated (N-phenyl)trifluoroacetimidate donors activated by catalytic Yb(OTf)3 <06EJO69>. The synthesis and biological evaluation of azido- and aziridino-hydroxy-β-lactams through stereo- and regioselective epoxide ring opening have been reported <06JOC9229>. O
Ph
+ R1 CHO
i
3
R1
Ph
2 N O
Me
29 (55–95%)
R2
N
+ R 3COCl H
N
R
R1
ii
R1
R2 N O
R2
EWG
R1
O
30 (27–66%)
Ar N Ar 31
Key: i) MeNHOH·HCl, 5 mol % CuCl, 2,2'-bipyridine, KHCO3, NaOAc, neat, 70 oC. ii) 1.4 mol% Pd2(dba)3·CHCl3, iPr2EtN, MeCN/THF (1:1), 55 oC. β-Lactams have been used as a synthon for the preparation of a vast array of compounds. It has been reported that the reduction of 4-(haloalkyl)azetidin-2-ones with LiAlH4 is a powerful method for the synthesis of stereodefined aziridines and azetidines <06OL1101>. However, reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane afforded 2-(haloalkyl)azetidines, which were rearranged to 3,4-cis-disubstituted pyrrolidines and piperidines 32 <06OL1105>. During these rearrangements, bicyclic azetidinium intermediates were formed which were ring opened by halides. The synthesis of a peptide-
98
B. Alcaide and P. Almendros
deformylase inhibitor has been described using as the key transformation the aminolysis of a β-lactam <06SL3179>. Reductive ring opening of 2-azetidinones promoted by sodium borohydride gives 3-aminopropane-1,2-diols <06TL2209>. The stereoselective conversion of 2-azabicyclo[2.2.0]hex-5-en-3-one into aminodienes has been described <06S633>. Using a sodium methoxide/methanol system, an unprecedented domino β-lactam ring opening–allene cyclization reaction gives pyrroles 33 <06CC2616>. An enzymatic method has been developed for the synthesis of enantiomeric benzocispentacin and its six- and sevenmembered homologues through the lipase catalyzed enantioselective (E>200) ring opening of bicyclic β-lactams <06CEJ2587>. The ring opening of β-lactam-fused pinenes gave γ-amino alcohols, which have been used as catalysts for the enantioselective addition of diethylzinc to aldehydes <06TA199>. A novel procedure has been developed for the preparation of 2,3disubstituted 4,1-benzothiazepines, via the ring transformation of a β-lactam <06TL5665>. X X ( )n
R2O N O
R1
i ii
R2O
2
R ( )n
N R1
N O
OP
R3 H
Ph
iii
R1
32 (44–98%)
R2 MeOOC
Ph
R3 N R1
33 (50–54%)
Key: i) AlH2Cl, Et2O, RT. ii) MeCN, reflux. iii) MeONa, MeOH, RT.
4.4
FUSED AND SPIROCYCLIC β-LACTAMS
A review on antibacterial natural products including β-lactam formation has appeared <06AG(E)5072>. β-Lactamase nomenclature has been reviewed <06MI1123>. New approaches to the inhibition of metallo-β-lactamases <06AG(E)1022> as well as their use as novel weaponry for antibiotic resistance in bacteria have been reviewed <06ACR721>. A review on the application of alicyclic β-amino acids in peptide chemistry including enzymecatalyzed ring opening of cycloalkane fused β-lactams has been published <06CSR323>. An overview on free radical chemistry including fused β-lactams has appeared <06CC4055>. Large-scale oxidations in the pharmaceutical industry including β-lactams have been reviewed <06CRV2943>. The synthesis and biological activity of spiro β-lactams incorporating quinones have been reported <06PS2483>. The Cu(I)-catalyzed coupling of spiranic β-lactams with (E)-2-chlorovinyliodides or (E)-2-bromovinyliodides producing the corresponding β-haloenamides has been accomplished en route to chartellines <06OL1779>. In work directed toward a total synthesis of chartelline A, a strategy investigated to construct the 10-membered ring of this marine alkaloid was an intramolecular aldehyde/spiro-β-lactam cyclocondensation to form the macrocyclic enamide functionality <06JOC3159>. A biosynthetically inspired and strategically designed 10-step sequence synthesis of (±)chartelline C has been reported <06JA14028>. The synthesis of spiro-linked β-lactamdihydropyridines 34 through the cyclization of lithiated pyridine carboxamides has been achieved <06OL5325>. The utility of the spiro β-lactam 35 in the preparation of peptidomimetics as analogues of melanostatin was demonstrated <06JOC7721>. The chirospecific synthesis of spirocyclic β-lactams and their characterization as potent type II βturn inducing peptide mimetics have been accomplished <06JOC97; 06CEJ6315>. Thermolysis of spiro[β-lactam-4,2'-oxadiazolines] in the presence of aryl isocyanates
99
Four-membered ring systems
afforded both N-lactam and O-lactam substituted spiro[azetidine-2-one-4,3'-indol-2'-one] derivatives <06JOC4418>. O R N
R' Br
N
X
E
O
Cl X
N Br N H
N N
N
But Ph
Y
Ph
i ii
N O
Y
N H O
t
Bu
N
PMP
35
34 (39–91%) R = R' = Br (chartelline A) R = R' = H (chartelline C)
Key: i) LDA, –40 oC. ii) E–Cl. Spiranic β-lactams have been prepared by the reaction of N-protected cyclic keteneN,S-acetals with vinyl isocyanates <06SL201>. The synthesis of spiro-β-lactams through halogen-mediated intrasulfenyl cyclization of cis-3-benzylthio-3-(prop-2-ynyloxy/-enyloxy)β-lactams has been achieved <06EJO4943>. The one-pot three-component reaction for the direct conversion of certain alkylhydroxylamine hydrochlorides (alkyl = benzyl, pmethoxybenzyl, benzhydryl, tert-butyl), formaldehyde or an alkyl glyoxylate and bicyclopropylidene to furnish the 3-spirocyclopropanated 2-azetidinones 36 has been developed by microwave heating <06EJO1251>. The acid-catalyzed fragmentative rearrangement of tricyclic isoxazolidines yields cyclopropane-fused β-lactams <06SL1125; 06EJO5485>. The highly diastereoselective synthesis of fused oxopiperazino-ȕ-lactams 37 by Staudinger reaction between functionalized ketenes and 5,6-dihydropyrazin-2(1H)-ones has been carried out <06TL8911>.
R 1CHO + R 2 NHOH.HCl +
R1
R1
R2 N O
R2
R2
H
O N
i
N
N O
36 (49–78%)
O
Bn OTBDMS
1
R
37
Key: i) NaOAc, EtOH, MW. The synthesis of a series of macrocyclic bis-β-lactam derivatives via a highly stereoselective [2+2] cycloaddition has been described <06TL8855>. Di-exo-3-amino-7oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid, five aldehydes and two isocyanides were reacted both in methanol and in water to prepare a 10-membered ȕ-lactam library via a Ugi4-centre-3-component reaction <06TL9113>. 4-Formyl-1-(2- and 3-haloalkyl)azetidin-2-ones have been prepared as valuable starting materials for the synthesis of different optically active bicyclic azetidin-2-ones, such as piperazine and 1,4-diazepane annulated β-lactam derivatives 38 <06JOC7083>. A synthetic route to β-lactam-fused enediynes involved an intramolecular Kinugasa reaction <06CC2992>. A β-lactam-azasugar hybrid (polyhydroxylated carbacephem) has been designed and synthesized as a potent glycosidase inhibitor <06TL7923>. 7-Amino- and 2-ethoxycarbonyl-5-dethia-5-oxa-cephams were prepared from 1,3-alkylidene-l-erythritol <06T10928>. Synthetic approaches towards a new class of strained lactenediynes, compounds where a 10-membered enediyne ring is fused with a ȕ-lactam have been described <06ARK15; 06ARK261>. The stereoselective synthesis of functionalized tricyclic ȕ-lactams via intramolecular nitrilimine cycloaddition has been achieved <06TA1319>. Strained tricyclic β-lactams 39 were prepared via intramolecular
100
B. Alcaide and P. Almendros
[2+2] cycloaddition reactions in 2-azetidinone-tethered enallenols with control of the regioselectivity by choice of alkene substitution <06CEJ1539>.
R1 O N O
i
O
R 1O N
ii ( )n
X
N O
R2
R1 O
H H
OH
R2 iii
R 1O
N ( )n
H H
OH
R2
N
O
O
38 (41–87%)
39 (52–57%)
2
Key: i) R NH2, MgSO4, CH2Cl2, RT. ii) NaBH4, MeOH, reflux. iii) Toluene, 220 oC, sealed tube. New C-3' hydroxamate-substituted and more lipophilic cyclic hydroxamate cephalosporin derivatives were preppared as a potential new generation of selective antimicrobial agents <06OBC4178>. The positive effect of natural and negatively charged cyclodextrins on the stabilization of penicillins towards β-lactamase degradation due to inclusion and external guest–host association has been studied <06OBC1297>. The first step of the deacylation reaction of benzylpenicillin in the E. coli TEM1 β-lactamase has been modelled <06OBC206>. A strategy for the solid-phase synthesis of penicillin derivatives has been reported <06S3297>. Studies on the hydrolysis of oxacillin have been carried out <06CEJ7597>. A theoretical proposal for the synthesis of carbapenems from 4-(2propynyl)azetidinones promoted by [W(CO)5] as an alternative to the Ag+-assisted process has been reported <06CEJ7929>. A stoichiometric molecularly imprinted polymer for the class-selective recognition of β-lactam antibiotics in aqueous media has been described <06AG(E)5158>. An amide derived from penicillin V and racemic (R/S)-2-aminobutanol has been prepared and shows significantly higher toxicity than the pure diastereomers <06TL1737>. The synthesis and siderophoric activity of conjugates of methyl 6aminopenicillanate with biscatechol-hydroxamate chelators have been reported <06T7799>. An efficient method for the deprotection of tert-butyldimethylsilyl ethers was TiCl4-Lewis base complexes; it was applied in the synthesis of 1β-methylcarbapenems <06JOC5380>. The reactivity of cephalosporin sulfones has been studied <06JHC183>. 4.5 OXETANES, LACTONES)
DIOXETANES,
OXETENES
AND
2-OXETANONES
(β-
Ketene chemistry including ketene-aldehyde cycloaddition to form β-lactones and ketene-alkene cycloaddition to form oxetanes has been reviewed <06EJO563>. It has been reported that the attachment of the oxetane motif to molecular scaffolds results in remarkable improvements of key physicochemical characteristics and provides valuable opportunities for property-guided drug discovery <06AG(E)7736>. Oxetanes have also been utilized as synthons for the preparation of different compounds. The synthesis of 5-hydroxyfunctionalized 2-trifluoromethyl-1-alkenes was achieved by 1-(trifluoromethyl)vinylation via oxetane ring-opening <06S128>. A convenient route to tetrahydropyran-based liquid crystals from oxetane precursors has been described <06EJO3326>. The asymmetric synthesis of γhydroperoxyalkanols involved regiospecific and stereoselective acid-promoted opening of oxetanes with hydrogen peroxide. This was used as the core of the first asymmetric synthesis of 1,2-dioxolane-3-acetic acids 40 <06JOC2283>. An aniline glycosyl carbamate spacer linked to the 2'-OH of paclitaxel has been obtained <06JOC9628>. The synthesis of 7- and 10-spermine conjugates of paclitaxel and 10-deacetyl-paclitaxel were synthesised as potential
101
Four-membered ring systems
prodrugs <06TL2667>. Noncytotoxic taxanes as novel antituberculosis agents have been discovered <06JMC463>. A 4-methyl-5-oxo docetaxel analogue was prepared starting from 10-deacetylbaccatin III <06OL2301>. Bridging converts the noncytotoxic nor-paclitaxel derivative 41 into the cytotoxic analogue 42 by constraining it to the T-taxol conformation <06OL3983>. AcO O R
AcO
O OH
O OH
O O
8 steps
O
R OH
CO2 H
O O
H PhCH 2 OO
40 (12–36%)
O
OH
O
OAc
PhCH 2ON H
H PhCH 2OO
PhCH2 ON H
O O
O
41
42
A C,D-seco-paclitaxel derivative was prepared from taxine and tested for biological activity <06TL8503>. A 36-step synthesis has been carried out in automated synthesizers to provide a synthetic key intermediate for taxol <06MI370>. The bicyclic oxetane 43 which was obtained by the [2+2] photocycloaddition (Paternò-Büchi reaction) of a methylthymine derivative with benzaldehyde, showed, in model studies, efficient photosensitized splitting of thymine oxetane units by covalently linked tryptophan in high polarity solvents <06OBC291>. The Paternò-Büchi reaction of 1,3-dimethylthymine or 1,3-dimethyluracil with benzophenone and its six 4,4'-disubstituted derivatives generated two series of regioisomeric oxetanes, head-to-head and head-to-tail isomers <06EJO1790>. The efficient photosensitized splitting of the thymine dimer/oxetane unit on its modifying β-cyclodextrin by a binding electron donor has been reported <06OBC2576>. Thymine oxetanes have been tested as charge traps for chemical monitoring of nucleic acid mediated transfer of excess electrons <06AG(E)5376>. The pathways of excess electron transfer in DNA with flavindonor and oxetane-acceptor modified DNA hairpins 44 has been investigated <06CEJ6469>. A temperature effect on the stereoselectivity in the Paternò–Büchi reaction of 2,3dihydrofuran-3-ol derivatives with benzophenone was noted <06TL2527>. A new terpenoid, the tricyclic oxetane amentotaxone, has been isolated from Amentotaxus formosana <06OL753>. The spirocyclic oxetane lactone 45 has been synthetized <06T7747>. An oxetane-fused benzene was proposed as intermediate in the mass spectrometric fragmentation of even-electron negative ions from hydroxyphenyl carbaldehydes and ketones <06TL4601>. O
O HN O
i
HN O
N CO2Bn
O N
O
O
Ph H CO2Bn
43 (21%)
NH
O Ph Ph O
N
NH 44 G
O
H NH
G=
N
O
H O
R1O
OR
2
45
O O
Key: i) PhCHO, hν, MeCN, RT. An acid-catalyzed ring-closing ynamide-carbonyl metathesis, which would proceed through ring opening of an amide-substituted oxetene intermediate 46 formed through a stepwise hetero [2+2] cycloaddition pathway, has been described <06OL231>. The synthesis of tetrasubstituted enol ethers by E-selective olefination of esters with ynolates has been reported to occur via lithiated oxetene species <06JA1062; 06CEJ524>. A dioxetane-based selective chemiluminescent probe for singlet oxygen has been employed to detect and
102
B. Alcaide and P. Almendros
quantify singlet oxygen in the reactions of superoxide with organic peroxides <06JOC796>. The synthesis and fluoride-induced chemiluminescent decomposition of bicyclic dioxetanes substituted with a 2-hydroxynaphthyl group have been described <06T5808>. The synthesis of dioxetane 47 has been achieved during abortive attempts to synthesize ent-premnalane A <06T5313>. Bicyclic dioxetanes bearing a 2-hydroxy-1,1ƍ-binaphthyl-5-yl moiety are active towards intramolecular charge-transfer-induced chemiluminescent decomposition <06T12424>. Color modulation for intramolecular charge-transfer-induced chemiluminescence of bicyclic dioxetanes bearing a 3-hydroxy-5-naphthylphenyl moiety in the coordination sphere has been reported <06TL8407>. 4-(3-tertButyldimethylsilyloxyphenyl)-4-methoxyspiro[1,2-dioxetane-3,2ƍ-adamantane] was synthesised by two different approaches <06S1781>. The dioxetanone intermediate 48 was isolated in studies on the possible biogenetic precursors of pyrrole-2-aminoimidazole alkaloids <06OL2421>. A dioxetanone intermediate has been proposed as supporting the bioluminescence mechanism for the chemiexcitation process to generate the singlet-excited state of neutral oxyluciferin <06TL6057>. A spirocyclic dioxetanone intermediate was proposed in investigations of the unimolecular reactivities of a range of perbenzoate anions in the gas phase by electrospray ionization tandem mass spectrometry <06JOC7996>. R 3OC
O
N
O
R2
O
O
H O
O O
i Y
O
N
O O
R1
46
O N H
H
H
47
48
Key: i) O2, hν, CH2Cl2, RT. The structure and absolute configuration of the unusual fused β-lactone-type metabolite vibralactone 49, which was found to inhibit pancreatic lipase with an IC50 of 0.4 μg/mL, from the cultures of the Basidiomycete Boreostereum vibrans have been established by spectroscopic and computational methods <06OL5749>. A detailed mechanistic investigation of epoxide carbonylation by the catalyst [(salph)Al(THF)2]+ [Co(CO)4]– (salph = N,N'-o-phenylenebis(3,5-di-tert-butylsalicylideneimine), THF = tetrahydrofuran) to form βlactones has been carried out <06JA10125>. A readily prepared Cr–Co bimetallic catalyst is capable of effecting epoxide carbonylation to produce β-lactones at substantially lower CO pressures than previously reported catalyst systems <06OL3709>. A chiral oxazaborolidinecatalyzed enantioselective synthesis of β-lactones from ketene and aldehydes has been developed <06OL4943>. A catalytic asymmetric synthesis of 3,4-dialkyl-cis-β-lactones, inhibitors of the thioesterase domain of fatty acid synthase, via a sequential ketene dimerization/hydrogenation process has been achieved <06JOC4549>. 3-Alkylidene-oxetan2-ones 50 have been prepared in good to excellent yields, with high Z-selectivity, by olefin cross metathesis with 3-methyleneoxetan-2-ones in the presence of Ru-based second generation metathesis catalysts <06OL2139>. Molecular recognition of lactones, including βlactones, can be achieved by inclusion complexation with optically active hosts derived from tartaric acid <06TA1678>. The Walden cycle which interconverts the stereochemical configurations of chlorosuccinic and malic acids involves a β-lactone intermediate rather than an α-lactone intermediate because the Onuc C Cl angle in the transition structure for the former (174°) is more favorable than that for the latter (139°), as determined by a computational study <06CC1106>. An efficient chiron approach to the total synthesis of (–)-
103
Four-membered ring systems
tetrahydrolipstatin 51 starts from tri-O-acetyl-D-glucal, and uses copper-mediated C–C bond formation, Frater alkylation, and Barton-McCombie deoxygenation <06SL3888>. Stereoselective syntheses of (–)-tetrahydrolipstatin have been achieved via two divergent approaches through Prins cyclizations as the key steps <06TL4995>. The stereoselective synthesis of (–)-tetrahydrolipstatin via a radical cyclization based strategy has also been reported <06TL4393>. An expeditious enantioselective total synthesis of valilactone has been accomplished <06JOC5748>. Concise syntheses of valilactone and a two-carbon transposed orlistat derivative employed a tandem Mukaiyama aldol-lactonization process as a key step <06OL4497>. An efficient protocol has been developed using D-(2R)-Oppolzer sultam as a chiral auxiliary for generating anti/syn diastereomers with high enantiopurity and were utilized in an efficient synthesis of natural product belactosin C 52 and its synthetic congeners <06JOC337>. A concise and straightforward 14-step total synthesis of (±)salinosporamide A 53 has been described <06OBC2845>. Enantioselective total syntheses of lactacystin β-lactone 54 have been achieved <06JA6810; 06JOC1220; 06OBC193>. The reaction of acryloyl chloride with an amino ketone in the presence of pyridine produces a bicyclic β-lactone rather than the corresponding acrylamide, which can be the major product under other conditions <06OL1717>. A diastereoselective organonucleophile-promoted biscyclization process provides access to bicyclic- and tricyclic-β-lactones bearing tertiary carbinol centers and quaternary carbons and employed keto acid substrates <06OL4363>. A synthetic strategy for construction of the novel spiro-bicyclic ȕ-lactone-Ȗ-lactam system present in oxazolomycin has been demonstrated <06TL6031>. The ȕ-lactone nucleus has been used as a synthon for the preparation of different compounds such as (–)deoxyharringtonine <06JA10370>, the C7–C20 fragment of amphidinolide B <06OL7>, and (–)-pironetin <06JA7438>. SN2' Ring opening of a β-lactone has provided the requisite pyrrole-substituted allene for the enantioselective total synthesis of (–)-rhazinilam <06JA10352>, while ring opening of amino β-lactones yielded α-amino acids <06CC1757; 06TL1019; 06TL3701>. Yttrium initiators have been used for the polymerization of racemic β-butyrolactone <06AG(E)2782>. Different syntheses of functionalized β-keto esters have been carried out starting from 4-methyleneoxetan-2-one <06EJO1117; 06TA2672; 06T10497>. HO
nC6H13 1
R H
O
O
O
O
51 O
N H
H N HO2C
Cl
O NH
NH2 O
52
O
OHCHN
50 (55–94%)
O
O
nC11H23
O O
49
O
R
R2
i
O
O O
R2 +
1
OH
O 53
NH
H
O
OH
O 54
O
Key: i) 5 mol% Ru-based cat., CH2Cl2, reflux. 4.6
THIETANES, β-SULTAMS, AND RELATED SYSTEMS
A stereoselective one-pot synthesis of substituted 1,2-thiazetidine 1,1-dioxides (βsultams) 55 started from heterocyclic pentafluorophenyl (PFP) sulfonates <06OL5513>.
104
B. Alcaide and P. Almendros
Thermolysis of the pentacoordinate 1,2-thiazetidine 1-oxide 56, which was synthesized for the first time and characterized by X-ray crystallographic analysis, gave the corresponding aziridine 57 and a cyclic sulfinate almost quantitatively <06OL4625>. O
O S
HO O N
PFPO R
H H
i
F3 C
R
F3 C
O S N O 55 (26–58%)
H Ph CF3 CF3 O S N Ph O
F3C F3 C
+ Ph
57 (94%)
56 o
F3C CF 3
Ph N
ii
O S O (quant)
o
Key: i) Mo(CO)6, MeCN–H2O, 90 C. ii) Toluene, 160 C, sealed tube. Four-membered spironucleosides, including the spiroannulated thietane 58 were synthesized <06TL3875>. Various D- and L-thietanose nucleosides which have showed moderate anti-HIV activity were synthesized from D- and L-xylose <06JMC1635>. A synthesis of isothiazolidines 60 via sulfonium ylides formed by the reaction of thietanes 59 and nitrene has been achieved <06TL1109>. The 2-(diphenylmethylene)thietan-3-one 61 reacted with 1,2,4,5-tetrazines in KOH/MeOH/THF to give 4H-pyrazolo[5,1-c]thiazines <06TL7893>. A model for the prediction of the homolytic bond dissociation enthalpy and adiabatic ionization potential of fused four-membered heterocycles, including benzothiete 62, has been developed using calculations at B3LYP/LANL2DZ level <06OBC846>. S
Ph O
O O
BnO 58
Ar
Ar S
+ PhI NTs
59
O
Ph
i N Ts S 60 (56–67%)
S 61
S 62
Key: i) Cu(acac)2, benzene, reflux. 4.7
SILICON AND PHOSPHORUS HETEROCYCLES. MISCELLANEOUS
The preparation and reactivity of heterocyclic compounds with a silicon atom and another non-adjacent different heteroatom including 1,3-oxasiletane, 1,3-azasiletane, 1,3thiasiletane, and 1,3-phosphasiletane have been reviewed <06T7951>. An overview on novel silicon-based reagents for organic synthesis including silacyclobutanes and 1,3disilacyclobutanes has appeared <06CEJ1576>. 3,4-Dibromo-1,2,3,4-tetrakis(di-tertbutylmethylsilyl)cyclotetrasilene 63 was prepared in 81% yield by reduction of the corresponding tetrabromocyclotetrasilane with 2.1 equivalents of KC8 in THF <06AG(E)3269>. Calculations on a series of polycyclic silicon molecules confirm that the introduction of a double bond into four-membered cyclic silanes lowers the ring strain by the cyclic delocalization of π-electrons through hyperconjugation with the σ bonds <06T4491>. The first thermally stable four-membered heterocycle chlorosilylene 64 has been synthesised and characterized <06AG(E)3948; 06AG(E)4241>. The four-membered heterocycle 65 has been prepared and unambiguously identified by multinuclear NMR spectroscopy <06AG(E)1643>. Nickel-catalyzed ring opening reaction of silacyclobutanes 66 with aldehydes afforded the corresponding alkoxyallylsilanes 67, while ring expansion of benzodimethylsilacyclobutene with aldehydes occurred under nickel catalysis to give oxasilacyclohexenes <06OL483>. Oxidation of benzylidene acetals that incorporate a siletane ring at the para position creates a deprotection pathway without affecting other important chemical properties of the benzylidene acetal <06JOC420>.
105
Four-membered ring systems
t-Bu2 MeSi
Si
Si
Br Si t -Bu 2MeSi
SiMet -Bu2
Si Br SiMet -Bu 2
Tip Tip Tip Si Si
Cl
t -Bu N
Si N
Ph
t -Bu
63
64
R3
R2 Si R1 R1 66
Sn Si Tip Tip Tip
+ R 3CHO
65 Tip = 2,4,6-triisopropylphenyl
i
R1 Si R1
O
R2 67 (47–87%)
Key: i) Ni(cod)2, PPh2Me, toluene, 100 oC. The structure of a four-membered phosphapalladacycle has been established by a single-crystal X-ray structural analysis <06JA6376>. The thermal conversion of the cyclic carbodiphosphorane 68 into 1,2-λ5-azaphosphete 69 proceeds almost quantitatively and regioselectively <06AG(E)7447>. The reaction of aryl nitriles with [1,3,2,4]diselenadiphosphetane (Woollins' reagent) 70, followed by water affords a variety of primary arylselenoamides in 60–100% yield <06OL5251>. A single-crystal X-ray diffraction study of a bicyclic four-membered phosphorus-containing product showed the bicycle to adopt envelope-type topology <06AG(E)6685>. A 1,3,2-λ5-oxazaphosphetidine reaction intermediate, in which the P–O bond order is 0.47, has been found on studying the aza-Wittig reaction between phosphazenes and aldehydes <06JOC2839>. It has been postulated that betaine 71 can be formed upon treatment of the corresponding iminophosphorane with phenyl isocyanate through an abnormal aza-Wittig reaction <06EJO4170>. Various other fourmembered azaphosphaheterocyclic intermediates have also been proposed <06CEJ7178; 06T4128>. The fragmentation of C-amino four-membered phosphorus ylides to carbenes has been proposed <06JA459>. The preparation and characterization of the air-tolerant 1,3diphosphacyclobuten-4-yl radical 72 has been achieved <06AG(E)4341>. A fluorous analogue of Lawesson's reagent for thionation of carbonyl compounds has been developed and its use demonstrated on a series of amides, esters, and ketones <06OL1093>. Several structures of cationic P–S–halogen cages containing a four-membered heterocycle have been characterized <06CEJ1703>. R N – + – + NR2 P NR N P 2 N R Ph 68
N i
N P R Ph
R NR 2 P NR 2 N 69
Se Se P Ph Ph P Se Se 70
Me Me
CO2 Et
N PPh 3 N Ph O 71
t-Bu
Mes P P
Mes 72
o
Key: i) Benzene, 80 C, 60h. Mes = 2,4,6-t-Bu3C6H2. N-Sulfonyl aziridines underg oxidative addition to palladium(0) complexes resulting in azapalladacyclobutane complexes 73, which after intramolecular carbopalladation in the presence of copper(I) iodide gave azapalladabicyclo[3.2.1]octanes <06JA15415>. A titanacyclobutane has been proposed as intermediate in the olefin cyclopropanation with the Ti–Mg–CCl4 system <06JOC4325>. The existence of oxaarsetanes 74 during an arsa-Wittig reaction has been proved by 1H and 17O NMR spectroscopy <06EJO4934>. The syntheses, structures, and thermolyses of pentacoordinate 1,2-oxastibetanes, which are considered as formal [2+2]-cycloadducts in the reaction of a stibonium ylide and a carbonyl compound, have been described <06JOC659>. A tricyclic intermediate containing a four-membered metallacycle has been proposed for the Rh-catalyzed alkylation-cycloaddition of 3-haloalkyl1,6-enynes <06JA14818>. A planar metallacycle bearing a relatively short Hf–Sb bond has been study by X-ray diffraction <06CC4030>. Reversible alkene extrusion from platinaoxetanes has been reported <06JA12088>. Synthetic and structural studies of germanacycle 75 have been reported <06CC3978>. Homogeneus, titanocene-catalyzed
106
B. Alcaide and P. Almendros
dehydrocoupling of amine-borane adducts into four-membered azaboracycles has been accomplished <06JA9582>. Formation of (bistriphenylphosphine)-2-(2,2,4,4tetramethylpentan-3-ylidene)-1,3-dithiolato-platinum 76 and its X-ray crystallographic analysis have been carried out <06CEJ7742>. Synthesis and X-ray analysis of the 1,2dialuminacyclobutene 77 have been published <06AG(E)2245>. The synthesis of an Nheterocyclic carbene–Pd(II) four-membered complex and its application in the Suzuki and Heck-type cross-coupling reaction have been documented <06T6289>. Intramolecular C–H activation reactions of molybdenacyclobutanes have been performed <06JA9038>. Formation of aluminacyclobutenes via carbon monoxide and isocyanide insertion has been accomplished <06CC1763>. Experimental results have shown that Ti2 reacts with N2 to give a D2h-symmetric Ti2N2 molecule which has a planar, cyclic structure with alternating Ti and N atoms <06AG(E)2799>. Studies on ruthenium metallacycles derived from 14-electron complexes as possible olefin metathesis intermediates have been carried out <06JA16048>. The reaction of phosphaalkenes with electrophiles has provided an effective route to 1,3diphosphetanium salts containing a P2C2 ring <06JA15998>. Ph Pd(phen) AsPh3 N O R2 R1 Ph 73 74
Dipp N N Ge Dipp Cl 75
phen = 1,10-phenanthroline
Dipp = 2,6-i-Pr2C6H3
4.8
t-Bu
t-Bu
S Pt(PPh3)2 S
Me3Si
Ar Al Al
Me3Si
t-Bu 76
Ar 77
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110 06OL3983 06OL4335 06OL4363 06OL4497 06OL4625 06OL4783 06OL4943 06OL5251 06OL5325 06OL5365 06OL5501 06OL5513 06OL5749 06PS2483 06S115 06S128 06S514 06S633 06S659 06S1781 06S1829 06S2327 06S2885 06S3297 06S3425 06SL201 06SL781 06SL1113 06SL1125 06SL2039 06SL3179 06SL3443 06SL3888 06T915 06T1565 06T4128 06T4491 06T5054 06T5313 06T5808 06T5831 06T6289 06T6882 06T7747 06T7799 06T7951 06T8291 06T10497 06T10928
B. Alcaide and P. Almendros
S. Tang, C. Yang, P. Brodie, S. Bane, R. Ravindra, S. Sharma, Y. Jiang, J.P. Snyder, D.G.I. Kingston, Org. Lett. 2006, 8, 3983. S. Baktharaman, S. Selvakumar, V.K. Singh, Org. Lett. 2006, 8, 4335. H. Henry-Riyad, C. Lee, V.C. Purohit, Daniel Romo, Org. Lett. 2006, 8, 4363. G. Ma, M. Zancanella, Y. Oyola, R.D. Richardson, J.W. Smith, D. Romo, Org. Lett. 2006, 8, 4497. N. Kano, Y. Daicho, T. Kawashima, Org. Lett. 2006, 8, 4625. S.A. Testero, E.G. Mata, Org. Lett. 2006, 8, 4783. V. Gnanadesikan, E.J. Corey, Org. Lett. 2006, 8, 4943. G. Hua, Y. Li, A.M.Z. Slawin, J.D. Woollins, Org. Lett. 2006, 8, 5251. G. Arnott, J. Clayden, S.D. Hamilton, Org. Lett. 2006, 8, 5325. H. Lu, C. Li, Org. Lett. 2006, 8, 5365. M. Vargas-Sánchez, S. Lakhdar, F. Couty, G. Evano, Org. Lett. 2006, 8, 5501. A.K. de K. Lewis, B.J. Mok, D.A. Tocher, J.D. Wilden, S. Caddick, Org. Lett. 2006, 8, 5513. D.-Z. Liu, F. Wang, T.-G. Liao, J.-G. Tang, W. Steglich, H.-J. Zhu, J.-K. Liu, Org. Lett. 2006, 8, 5749. A.K. Khalafallah, N.A.A. El-Kanzi, H.A. Soleiman, M. Younis, Phosphorus, Sulfur Relat.Elem. 2006, 181, 2483. D.K. Tiwari, V.K. Gumaste, A.R.A.S. Deshmukh, Synthesis 2006, 115. R. Nadano, J. Ichikawa, Synthesis 2006, 128. J. Fleischhauer, R. Beckert, J. Weston, M. Schmidt, H.-J. Flammersheim, H. Görls, Synthesis 2006, 514. R. A. Youcef, C. Boucheron, S. Guillarme, S. Legoupy, D. Dubreuil, F. Huet, Synthesis 2006, 633. L. Jiao, Y. Liang, Q. Zhang, S. Zhang, J. Xu, Synthesis 2006, 659. E.L. Bastos, L.F.M.L. Ciscato, D. Weiss, R. Beckert, W.J. Baader, Synthesis 2006, 1781. S.-Z. Jian, Q. Yuan, Y.-G. Wang, Synthesis 2006, 1829. S. Lacroix, V. Rixhon, J. Marchand-Brynaert, Synthesis 2006, 2327. J. Fleischhauer, R. Beckert, W. Günther, H. Görls, Synthesis 2006, 2885. D.B. Boggián, E.G. Mata, Synthesis 2006, 3297. M. Sarkar, A. Samanta, Synthesis 2006, 3425. A. Zhou, L. Cao, H. Li, Z. Liu, C.U. Pittman Jr, Synlett 2006, 201. M. Sivaprakasam, F. Couty, G. Evano, B. Srinivas, R. Sridhar, K.R. Rao, Synlett 2006, 781. Q. Yuan, S.-Z. Jian, Y.-G. Wang, Synlett 2006, 1113. M. Marradi, A. Brandi, A. de Meijere, Synlett 2006, 1125. W. Van Brabandt, N. De Kimpe, Synlett 2006, 2039. X. Jiang, K. Prasad, M. Prashad, J. Slade, O. Repiþ, T.J. Blacklock, Synlett 2006, 3179. M.-C. Wang, W.-X. Zhao, X.-D. Wang, M.-P. Song, Synlett 2006, 3443. J.S. Yadav, K.V. Rao, A.R. Prasad, Synlett 2006, 3888. F.J. Sayago, M.A. Pradera, C. Gasch, J. Fuentes, Tetrahedron 2006, 62, 915. L. Troisi, L. Ronzini, C. Granito, L. De Vitis, E. Pindinelli, Tetrahedron 2006, 62, 1565. N. Kanomata, S. Yamada, T. Ohhama, A. Fusano, Y. Ochiai, J. Oikawa, M. Yamaguchi, F. Sudo, Tetrahedron 2006, 62, 4128. Y. Naruse, J. Ma, K. Takeuchi, T. Nohara, S. Inagaki, Tetrahedron 2006, 62, 4491. A. Bhalla, S. Madan, P. Venugopalan, S.S. Bari, Tetrahedron 2006, 62, 5054. I. Margaros, T. Montagnon, M. Tofi, E. Pavlakos, G. Vassilikogiannakis, Tetrahedron 2006, 62, 5313. N. Hoshiya, N. Fukuda, H. Maeda, N. Watanabe, M. Matsumoto, Tetrahedron 2006, 62, 5808. A. Liljeblad, L.T. Kanerva, Tetrahedron 2006, 62, 5831. T. Chen, J. Gao, M. Shi, Tetrahedron 2006, 62, 6289. B. Van Driessche, W. Van Brabandt, M. D'hooghe, Y. Dejaegher, N. De Kimpe, Tetrahedron 2006, 62, 6882. F.A. Macías, V.M.I. Viñolo, F.R. Fronczek, G.M. Massanet, J.M.G. Molinillo, Tetrahedron 2006, 62, 7747. R. Schobert, A. Stangl, K. Hannemann, Tetrahedron 2006, 62, 7799. G. Rousseau, L. Blanco, Tetrahedron 2006, 62, 7951. A. Bhalla, P. Venugopalan, S.S. Bari, Tetrahedron 2006, 62, 8291. B.L. Ashfeld, S.F. Martin, Tetrahedron 2006, 62, 10497. T.T. Danh, K. Borsuk, J. Solecka, M. Chmielewski, Tetrahedron 2006, 62, 10928.
Four-membered ring systems
06T12064 06T12424 06TA199 06TA1319 06TA1678 06TA2216 06TA2672 06TL425 06TL1019 06TL1109 06TL1117 06TL1737 06TL2205 06TL2209 06TL2527 06TL2667 06TL3701 06TL3875 06TL4393 06TL4601 06TL4995 06TL5255 06TL5257 06TL5393 06TL5665 06TL5883 06TL5993 06TL6031 06TL6057 06TL6377 06TL6835 06TL7893 06TL7923 06TL8407 06TL8503 06TL8855 06TL8911 06TL8977 06TL9113
111
L. Troisi, L. Ronzini, C. Granito, E. Pindinelli, A. Troisi, T. Pilati, Tetrahedron 2006, 62, 12064. N. Hoshiya, N. Watanabe, H.K. Ijuin, M. Matsumoto, Tetrahedron 2006, 62, 12424. Z. Szakonyi, Á. Balázs, T.A. Martinek, F. Fülöp, Tetrahedron: Asymmetry 2006, 17, 199. P. Del Buttero, G. Molteni, Tetrahedron: Asymmetry 2006, 17, 1319. K. Tanaka, D. Kuchiki, M.R. Caira, Tetrahedron: Asymmetry 2006, 17, 1678. Koichi Tanaka, Hiroko Takenaka and Mino R. Caira, Tetrahedron: Asymmetry 2006, 17, 2216. C. Chu, K. Morishita, T. Tanaka, M. Hayashi, Tetrahedron: Asymmetry 2006, 17, 2672. K. Hemming, P.A. O’Gorman, M.I. Page, Tetrahedron Lett. 2006, 47, 425. A. Schneider, O.E.D. Rodrigues, M.W. Paixão, H.R. Appelt, A.L. Braga, L.A. Wessjohann, Tetrahedron Lett. 2006, 47, 1019. V. Nair, S.M. Nair, S. Devipriya, D. Sethumadhavan, Tetrahedron Lett. 2006, 47, 1109. C. Thomassigny, D. Prim, C. Greck, Tetrahedron Lett. 2006, 47, 1117. P. Styring, S.S.F. Chong, Tetrahedron Lett. 2006, 47, 1737. M. Domostoj, I. Ungureanu, A. Schoenfelder, P. Klotz, A. Mann, Tetrahedron Lett. 2006, 47, 2205. P. Del Buttero, G. Molteni, M. Roncoroni, Tetrahedron Lett. 2006, 47, 2209. M. Abe, M. Terazawa, K. Nozaki, A. Masuyama, T. Hayashi, Tetrahedron Lett. 2006, 47, 2527. A. Battaglia, A. Guerrini, E. Baldelli, G. Fontana, G. Varchi, C. Samorì, E. Bombardelli, Tetrahedron Lett. 2006, 47, 2667. N. Valls, M. Borregán, J. Bonjoch, Tetrahedron Lett. 2006, 47, 3701. A. Roy, B. Achari, S.B. Mandal, Tetrahedron Lett. 2006, 47, 3875. J.S. Yadav, K.V. Rao, M.S. Reddy, A.R. Prasad, Tetrahedron Lett. 2006, 47, 4393. A. Attygalle, J. Ruzicka, D. Varughese, J. Sayed, Tetrahedron Lett. 2006, 47, 4601. J.S. Yadav, M.S. Reddy, A.R. Prasad, Tetrahedron Lett. 2006, 47, 4995. A. Bhalla, S. Rathee, S. Madan, P. Venugopalan, S.S. Bari, Tetrahedron Lett. 2006, 47, 5255. A. Bhalla, S. Rathee, S. Madan, P. Venugopalan, S.S. Bari, Tetrahedron Lett. 2006, 47, 5257. M.K. Ghorai, K. Das, A. Kumar, A. Das, Tetrahedron Lett. 2006, 47, 5393. P. Csomós, L. Fodor, J. Sinkkonen, K. Pihlaja, G. Bernáth, Tetrahedron Lett. 2006, 47, 5665. M.A. Bonache, C. Cativiela, M.T. García-López, R. González-Muñiz, Tetrahedron Lett. 2006, 47, 5883. A.L. Shaikh, V.G. Puranik, A.R.A.S. Deshmukh, Tetrahedron Lett. 2006, 47, 5993. D.K. Mohapatra, D. Mondal, R.G. Gonnade, M.S. Chorghade, M.K. Gurjar, Tetrahedron Lett. 2006, 47, 6031. Y. Takahashi, H. Kondo, S. Maki, H. Niwa, H. Ikeda, T. Hirano, Tetrahedron Lett. 2006, 47, 6057. A.C.B. Burtoloso, C.R.D. Correia, Tetrahedron Lett. 2006, 47, 6377. W. Miao, W. Xu, Z. Zhang, R. Ma, S.-H. Chen, G. Li, Tetrahedron Lett. 2006, 47, 6835. Y.F. Suen, H. Hope, M.H. Nantz, M.J. Haddadin, M.J. Kurth, Tetrahedron Lett. 2006, 47, 7893. G. Pandey, S.G. Dumbre, M.I. Khan, M. Shabab, V.G. Puranik, Tetrahedron Lett. 2006, 47, 7923. M. Matsumoto, K. Yamada, H. Ishikawa, N. Hoshiya, N. Watanabe, H.K. Ijuin, Tetrahedron Lett. 2006, 47, 8407. Z. Ferjancic, R. Matovic, Z. Cekovic, Y. Jiang, J.P. Snyder, V. Trajkovic, R.N. Saicic, Tetrahedron Lett. 2006, 47, 8503. N. Arumugam, R. Raghunathan, Tetrahedron Lett. 2006, 47, 8855. A. Viso, R. Fernández de la Pradilla, A. Flores, Tetrahedron Lett. 2006, 47, 8911. V. Gracias, A.F. Gasiecki, J.D. Moore, I. Akritopoulou-Zanze, S.W. Djuric, Tetrahedron Lett. 2006, 47, 8977. I. Kanizsai, Z. Szakonyi, R. Sillanpää, F. Fülöp, Tetrahedron Lett. 2006, 47, 9113.
112
Chapter 5.1
Five-membered ring systems: thiophenes and Se/Te analogues Tomasz Janosik and Jan Bergman Department of Biosciences and Nutrition, Karolinska Institute, Novum Research Park, SE141 57 Huddinge, Sweden
[email protected] (T. J.),
[email protected] (J. B.)
5.1.1 INTRODUCTION This chapter summarizes the advances in the chemistry of thiophenes, selenophenes and tellurophenes reported during the year 2006. The remarkable productivity in this field is manifested not only in all contributions devoted to fundamental reactivity and properties, but also by the numerous papers dealing with applications of thiophene containing molecules, for instance in medicinal chemistry and materials science. With the objective of providing an overview of general interest, selected examples illustrating the progress in these specialized areas will also be discussed briefly. However, the main focus will be directed towards general ring synthesis and reactions of thiophene derivatives. Several useful specialized reviews have appeared during the reporting period of this chapter. The chemistry of thienothiophenes <06AHC(90)125> and thienopyrimidines <06AHC(92)83> has been discussed in detail, whereas accounts of related interest highlight the field of thiaheterohelicenes <06OBC2518> as well as similar fused thiophene systems <06AG(E)8092>. 5.1.2 THIOPHENE RING SYNTHESIS The boronic ester 1, a useful partner for Suzuki couplings, has been prepared by exposure of the 2-fluorobenzaldehyde 2 to ethyl mercaptoacetate in the presence of a base under microwave irradiation <06JOC3959>. In addition, base induced reactions between ethyl mercaptoacetate and 2-aryl-1-chloroacrylonitriles <06RJO238>, hetarylacetonitriles <06CHC594>, or 6-chloropyrimidine-5-carbaldehydes <06JHC1629> resulted in series of ethyl 3-amino-5-arylthiophenene-2-carboxylates, 2-amino-3-hetaryl-4(5H)oxothiophenes, or thieno[2,3-d]pyrimidine-6-carboxylates, respectively. Annulation of 3-(phenylsulfonyl)pyrazine-2-carbonitrile with ethyl mercaptoacetate gave ethyl 3-aminothieno[2,3-b]pyrazine2-carboxylate in excellent yield <06T11124>. A stepwise sequence involving substitution of electron deficient 2-nitrobenzamides with methyl mercaptoacetate, followed by conversion of
113
Five-membered ring systems: thiophenes and Se/Te analogues
the amide unit to a nitrile and final base induced cyclization gave rise to substituted methyl 3aminobenzo[b]thiophene-2-carboxylates <06H(68)1109>. HS O
O B
CO2Et
K2CO3, MeCN μW, 140 °C, 30 min
CHO
O O B
74%
F
S
2
CO2Et
1
A one-pot variant of the Gewald thiophene synthesis involving aryl alkyl ketones provided a series of 2-amino-4-arylthiophene derivatives <06SL2559>, whereas new conditions for the Knoevenagel/Gewald sequence have also been established. This approach utilized hexamethyldisilazane and acetic acid for the condensation step, followed by treatment of the resulting intermediate with sulfur in the presence of NaHCO3, giving for instance 2-amino-3-cyanothiophene derivatives <06T11311>. The Gewald reaction has also been employed for preparation of 2-amino-5-(phosphonomethyl)thiophenes <06PSS601>. In addition, a variant using a functional ionic liquid as a soluble support leading to 2aminothiophene-3-carboxylates has been developed <06H(68)375>. Yet another “classical” thiophene synthesis, namely the reaction of 1,4-diketones with Lawesson’s reagent, has been employed for the construction of the indeno[1,2-b]thiophene skeleton <06JHC629>. The precursor 3 served as a starting material for a series of trisubstituted thiophenes in a study towards progesterone receptor modulators, giving for example the product 4 upon reaction with an appropriate bromoketone. The fact that rather complex thiophene derivatives could be prepared in a straightforward manner compensates for the low overall yields <06JHC1391>. N O N
Br
O
1. Et3N, 65 °C 2. p-TsOH, acetone reflux
S
N
N Cl
21%
Cl
S
N O
O
O O
4
3
An approach to dibenzothiophenes involving a benzyne intermediate has been developed, wherein the required precursor 5, which is available in three steps from 2-fluorothiophenol, underwent lithiation giving the species 6, which could thereafter be treated with various electrophiles rendering the final products 7 <06JOC6291>. E I
F S 5
t-BuLi (3.3 equiv) THF, -78 °C to 0 °C
Li S 6
E+, -78 °C to 20 °C 75-79% E = H, SPh, Br, 4-MeC6H4C(H)OH
S 7
Electrophilic cyclization of the precursors 8, which are available from 3(methylthio)pyridine by regioselective lithiation, followed by introduction of CBr4, and a subsequent Sonogashira coupling, has resulted in a series of thieno[3,2-b]pyridines 9
114
T. Janosik and J. Bergman
<06T6036>. It should also be mentioned that an isomeric series of thieno[2,3-b]pyridines has been prepared by base induced annulations involving for instance 2-mercaptopyridine-3carbonitrile precursors and ethyl chloroacetate <06SC97>. E+ (I2, Br2, or NBS) CH2Cl2, rt, 30 min
SMe N
E
N
42-88%
S
R
8
E = Br, I R = Ph, TMS
R
9
Intramolecular palladium catalyzed thio-enolate S-arylation has been used in a route to a set of fused benzo[b]thiophenes, as illustrated by the conversion of the substrate 10 into the product 11 <06T11513>. S Pd2(dba)3 (2.5 mol%), DPEphos (6 mol%) Cs2CO3, PhMe, 100 °C 57%
S
Br 10
11
A series of benzo[b]benzo[2,3-d]thiophen-6,9-diones 12 has been prepared in modest yields by palladium mediated cyclization of the precursors 13. However, the necessity to use stoichiometric amounts of the palladium source precludes cost effective preparation of the targets. The required substrates 13 may be constructed by palladium catalyzed reactions between the appropriate phenols with 2,3-dimethylbenzoquinone <06SC3319>. O R3
Me Me
R2
S O
13
O
Me Pd(OAc)2, AcOH reflux, 1 d
Me
R2
23-51%
S
O
R1
R3
R1 = H, F R2 = H, Cl R3 = H, Me, OMe, F, Cl
R1
12
Gold catalyzed reactions are currently enjoying considerable interest, and have also found applications in thiophene ring synthesis. A series of (Į-alkoxyalkyl)(o-alkynylphenyl) sulfides 14 was subjected to treatment with catalytic amounts of AuCl, giving the benzo[b]thiophenes 15 in excellent yields. Some additional, more complex examples were also provided <06AG(E)4473>. R OMe AuCl (2 mol%), PhMe, 25 °C
S 14
OMe
85%-quant.
S
R
R = Pr, Ph, cyclohexyl, t-Bu, CO2Et, 4-F3CC6H4, 4-MeOC6H4
15
The first gold catalyzed C–S bond formation was demonstrated in a route to the 2,5dihydrothiophene 16 via cycloisomerization of the allene 17 which occurred with high chirality transfer (d.r. > 95:5) <06AG(E)1897>.
115
Five-membered ring systems: thiophenes and Se/Te analogues
Me
Me
i-Pr
OBn
i-Pr
86%
SH
H
AuCl (5 mol%), CH2Cl2, rt
17
OBn S 16
The intriguing circulene 18 has been prepared from the precursor 19 by initial exhaustive C-2 metalation, followed by introduction of elemental sulfur, and quenching with aqueous hydrochloric acid. This set of operations resulted in a polythiol, which was eventually converted to the target heterocycle 18 by vacuum pyrolysis <06AG(E)7367>. S
S
S
S
1. LDA (16 equiv.), Et2O 2. S8, then aq. HCl 3. Vacuum pyrolysis
S
S S
S S
S S
S 19
18
A series of 3-oxothiophene derivatives has been prepared by intramolecular thia-antiMichael addition of a thiol anion to an enone functionality, resulting for instance in preparation of the target 20 by treatment of the precursor 21 with an amine <06JOC8006>. Cl
O
O
O NHPh
S
O
BnNH2, DMSO, 120 °C, 1 h
NHPh
87%
S
S
Cl
21
NHBn
20
It has been shown that Lewis acid catalyzed isomerization of thionolactones provides access to thiolactones. For example, exposure of the substrate 22 to catalytic amounts of BF3·OEt2 led to efficient conversion to the thiolactone 23. Such transformations were also found to give minor amounts of lactone or dithiolactone side products <06TL6067>. Substituted tetrahydrothiophene derivatives have also been obtained from 1,4-dithiane-2,5diol and 2-nitroethyl acetate derivatives by a base induced sequence featuring a Michael addition and a Henry reaction <06TL8087>.
S
O
C6H13
22 (98% ee)
BF3 Et2O (10 mol%) PhMe, reflux 70%
O
S
C6H13
23 (97% ee)
A series of functionalized tetrahydrothiophenes has been prepared by acid induced organocatalytic reactions involving Į,ȕ-unsaturated aldehydes and 2-mercapto-1phenylethanone 24. This procedure led to good yields of products displaying useful enantiomeric excess, as illustrated by construction of the target 25 in the presence of the catalyst 26 <06JA14986>.
116
T. Janosik and J. Bergman
O Pr
26 (10 mol%) PhCO2H, PhMe
CHO SH
Ph
74% (95% ee)
Pr
S
24
Ar
OH CHO
25
N H
Ar OTMS
26 Ar = 3,5-(CF3)2-C6H3
Formation of partially saturated thiophene derivatives has also been observed as products resulting from radical reactions of thiophenol with S-4-pentynylcarbamothioates <06JOC3192>, irradiation of the sultam 27 at 300 nm in hexane, which leads to the fused system 28 as the major product <06JOC8438>, or photoisomerization of 4-anisyl-4-methyl2,6-diphenyl-4H-thiopyran-1,1-dioxide <06JHC167>. Routes to L-ȕ-3ƍ-deoxy-3ƍ,3ƍ-difluoro4ƍ-thionucleosides <06OL6083> and a ketone analogue of biotin <06OL4593> have also been devised. H N
H S N O O
S O O
27
28
Generation and trapping of tropothione 29 with dienophiles has been utilized in an approach to partially saturated fused thiophene molecules. For example, treatment of tropone with Lawesson’s reagent in benzene, followed by introduction of N-phenylmaleimide gave the adduct 30 in excellent yield <06TL9329>. O
S O
Lawesson's reagent PhH, rt
Ph N
S
O
H
N Ph
H 90%
H
29
O
O
30
Heating of the sulfoxide 31 causes a Pummerer rearrangement generating the ylide 32, which could be trapped with dimethyl acetylenedicarboxylate (DMAD) giving the dihydrothiophene derivative 33 <06HC648>. TMS
S O
TMS
DMPU, 100 °C
31
DMAD
S 32
CO2Me
MeO2C
59%
S 33
5.1.3 REACTIONS OF THIOPHENES Again, the ease of bromine–lithium exchange at the 2-position of thiophenes has been demonstrated by conversion of the tetrabrominated trithiophene 34 (available by exhaustive bromination of the parent tricyclic compound) into the system 35, which is a useful building block for extended fused thiophene systems <06JOC3264>. Regioselective metalation has also been employed en route to 2,3-bis(phosphanyl)benzo[b]thiophene ligands for stereoselective transition metal catalyzed reactions <06EJO2100>. Metalated thiophenes have
117
Five-membered ring systems: thiophenes and Se/Te analogues
also been reacted with aromatic nitriles, followed by reduction with NaBH4, giving 2thienylmethylamine derivatives <06S1858>. Br
Br
Br
Br S
1. BuLi (2.1 equiv.) THF, -78 °C, 3 h 2. TMSCl (2.5 equiv.), -78 °C
TMS
TMS
80%
S
S
Br
Br
S
34
S
S 35
An interesting example of trilithiation has been reported, wherein 3(methylthio)thiophene 36 was exposed to the powerful base system LICKOR (tBuOK/BuLi), giving direct access to the products 37 after quenching of the intermediate 38 with suitable electrophiles. Reactions involving 2-(methylthio)thiophene gave 2,5disubstituted products resulting from a dilithiated intermediate <06S3855>. Li SMe
S LICKOR (6 equiv.) THF, -78 °C
Li
S 36
S
E S
1. E+ (6 equiv.), THF, -78 °C 2. H+
Li
E
48-84% E = Me, allyl, CO2H, CHO, TMS
38
S
E
37
Transition metal catalyzed coupling reactions constitute some of the most powerful and versatile tools for manipulation of thiophene derivatives and are clearly one of the most dominant fields in current thiophene chemistry. Several potentially useful strategies of this type have been elaborated during the past year. An interesting synthesis of 2,3diarylthiophenes has been described, wherein for instance the 3-thiophenemethanol derivative 39 was subjected to treatment with aryl bromides in the presence of a palladium catalyst, leading to the product 40, as well as many similar molecules. The series of events leading to this outcome features cleavage of the C–H and C–C bonds at the 2- and 3-positions of the thiophene substrates <06JOC8309>. Cl Ph
Ph OH
4-ClC6H4Br Pd(OAc)2, P(biphenyl-2-yl)(t-Bu)2 Cs2CO3, PhMe, reflux 86%
S 39
S
Cl 40
A tandem palladium catalyzed multi-component approach has been devised providing direct access to for instance trisubstituted thiophenes from the simple starting material 3iodothiophene 41. In a representative experiment, the substrate 41 was converted to the product 42 by treatment with ethyl acrylate and iodobutane in the presence of a catalytic system consisting of Pd(OAc)2, tri(2-furyl)phosphine (TFP), norbornene, and a base. A mechanistic rationale accounting for this outcome was also proposed <06OL3939>.
118
T. Janosik and J. Bergman
I
Pd(OAc)2 (10 mol%), TFP (20 mol%) BuI (10 equiv.), methyl acrylate (2 equiv.) norbornene (6 equiv.), Cs2CO3, CH3CN, 80 °C, 1 d
S 40
CO2Et
Bu Bu
S
96%
41
It has been demonstrated that bromothiophenes may undergo palladium catalyzed C–H homocoupling providing a new route to halogenated 2,2ƍ-bithiophenes, an important class of building blocks for oligothiophene synthesis. For example, the alcohol 42 could be converted to the 2,2ƍ-bithiophene derivative 43 in good yield, suggesting useful functional group tolerance <06JA10930>. (CH2)4OH
PdCl2(PhCN)2 (3 mol%) AgNO3/KF, DMSO, 60 °C
Br S 42
70%
(CH2)4OH
HO(H2C)4 Br
S
S
Br
43
Exposure of the benzo[b]thiophene derivative 44 to a palladium catalyst in the presence of tri(2-furyl)phosphine (TFP) as the ligand led to the product 45, which incorporated two heterocyclic units from the starting material. The mechanistic aspects of this transformation were also discussed, which appears to involve palladacycle intermediates <06JA722>.
Br S
Pd(OAc)2 (5 mol%), TFP (10 mol%) K2CO3, DMF, 105 °C, 20 h
CONHMe
75%
S
S O
44
N Me 45
The dithienyldienyne 46, which was prepared by sequential palladium catalyzed couplings, underwent intramolecular annulation to compound 47 in excellent yield. Similar cyclizations involving closely related substrates were also studied <06OL1197>. S S
Br 46
Pd(OAc)2 (0.2 equiv.), PPh3 (0.4 equiv.) Bu4NBr, K2CO3, DMF, 80 °C 87%
S
S
47
Palladium/copper catalyzed reactions of 3-iodothiophene-2-carboxylic acid 48 with two equivalents of a terminal alkyne gives selective access to 5-substituted 4-alkynylthieno[2,3c]pyran-7-ones, for example the system 49 <06TL83, 06T9554>.
Five-membered ring systems: thiophenes and Se/Te analogues
119
OPh OPh (2 equiv.)
I S
OPh
PdCl2(PPh3)2 (cat.), CuI (cat.) Et3N, DMF, 70-80 °C
CO2H
O
75%
S
48
O 49
Other new studies involving thiophenes in transition metal catalyzed couplings encompass generation and coupling of thiophene-3-boronic acid derivatives giving 3,4di(thien-3-yl)maleimides <06RJO1490>, and Suzuki couplings of 3,4-bis(5-iodo-2methylthien-3-yl)-2,5-dihydrothiophene <06SL737> or benzo[b]thiophene boronic acid <06TL3365>. Thiophene boronic esters have also been prepared by iridium catalyzed borylation, and were converted to regioregular poly(alkylthiophenes) using Suzuki reactions <06TL5143>. Synthetic sequences featuring Kumada and Suzuki reactions have also been used for construction of thiophenes bearing four thienyl substituents <06AFM917>. Negishi coupling involving 2-iodo-(3,4-ethylendioxythiophene) 5-carbaldehyde has been used during synthesis of a thiophene backbone amide linker for solid phase chemistry <06JOC6734>, whereas Negishi reactions of 2-bromothiophene have found use en route to fused thiophene– phenylene chromophores <06OL5033>. Applications of the Sonogashira reaction encompass coupling of brominated 2,2ƍ-bithiophenes leading to two-photon absorption chromophores containing a central 2,2ƍ-bithiophene motif <06T8467>, and preparation of oligo(2,5thienyleneethynylene) materials by repetitive Sonogashira reactions <06EJO405, 06S1009>. Sonogashira coupling of halothiophenes may also be conducted in water solution using palladium on charcoal as the catalyst in the presence of PPh3, CuI, and 2-aminoethanol <06BMCL6185>. A study on the reactivity of bromothiophene carboxylates in palladium catalyzed amination with hetaryl amines has also been conducted <06S2794>, whereas copper catalyzed reactions of thienylboronic acids with azo compounds gives rise to thienylhydrazine derivatives <06OL43>. Palladium catalyzed amination of 2,8dibromodibenzothiophene-S,S-dioxide with diarylamines provided access to materials for organic light emitting devices <06AM602>. Several bromothiophenes have also been aminated with various azoles in the presence of CuI in the ionic liquid [Bmim]BF4, as illustrated by the synthesis of compound 50 <06T4756>.
S
Br
benzimidazole CuI/L-proline,K2CO3 [Bmim]BF4, 105-115 °C 76%
S
N N 50
A protocol for palladium catalyzed direct C–H arylation of thieno[2,3-b]thiophenes has been developed <06SL2423>. Likewise, 3-cyanobenzo[b]thiophene 51 undergoes coupling with aryl bromides in the presence of a palladium catalyst to provide a series of 2-aryl derivatives, for example the product 52 <06SL2016>. Direct C–H arylation catalyzed by palladium acetate has also been carried out employing 3-methoxythiophene, leading to 2aryl-3-methoxythiophene derivatives. Extensions involving 2-bromothiophenes as the coupling partners enabled preparation of new oligothiophene systems <06TL9249> Thiophenes may also be arylated using aryl iodides in the presence of a rhodium catalyst <06JA11748>.
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T. Janosik and J. Bergman
CN
CN
3-(i-PrO)C6H4Br, Pd(OAc)2 (5 mol%) K2CO3, DCH-18-C-6, DMF, 140 °C
Oi-Pr S
82%
S 51
52
Irradiation of the readily available diamide precursor 53 in DMF solution gave the fused system 54 in excellent yield. This material could be subsequently chlorinated using POCl3, and dehalogenated by catalytic hydrogenation to the parent ring system bis[1]benzothieno[2,3-c:3ƍ,2ƍ-i][1,10]phenanthroline <06S1402>. Photocyclization reactions have also been employed in a route to new tetrathia[7]helicenes <06S3670>. Some other related helical aromatics have been prepared by intramolecular coupling of adjacent thiophene units via their 3-positions using FeCl3 in chloroform and nitromethane <06TL1551>.
Cl
Cl
S
S NH HN O
hν, DMF 90%
S
S
O
NH HN O
53
O 54
Interconversion of functional groups at the thiophene ring is a common strategy to access further useful derivatives. A set of thiophene-2-isocyanates has been obtained by N-silylation of the corresponding 2-aminothiophenes, followed by treatment of the resulting intermediates with phosgene <06RJG110>. Thiophene-2-carbaldehydes may be transformed to their corresponding 1,3-diselenanes <06RJG1123> or dithioacetals <06RJO256> by exposure to propane-1,3-diselenol or ethane-1,2-dithiol, respectively, in the presence of TMSCl. A study of Sharpless asymmetric dihydroxylation of thienyl- and (benzothienyl)acrylates has also been published <06TA2919>. Nucleophilic displacement of both bromine atoms in 3,3ƍdibromo-2,2ƍ-bithiophene with NaS(i-Pr), followed by S-dealkylation and oxidative cyclization of the resulting thiol functionalities gave dithieno[3,2-c:2ƍ,3ƍ-e][1,2]dithiin <06PSS191>. Studies on a synthesis of 4H-cyclopenta[2,1-b:3,4-bƍ]dithiophen-4-one resulted in isolation of the unexpected product bis[bis(2-iodo-3-thienyl)methyl]ether <06S1760>. Moreover, chiral diamino-thiophene derivatives have been prepared by reduction of imines generated from thiophenecarbaldehydes and (R,R)-1,2-cyclohexanediamine, and were investigated as ligands for asymmetric catalysis <06ASC1521, 06CEJ667>. Additional contributions worth mentioning in this context encompass preparation of [n](2,5)thiophenophane-1,n-diones <06JOC6516>, [3,3]dithiacyclophanes featuring thieno[2,3-b]thiophene motifs <06TL5599>, 3,4-dicycloalkoxy-2,5-diethoxycarbonylthiophenes <06TL4635>, a thieno analogue of a cooked food mutagen <06JHC101>, as well as synthesis of styryl substituted oligothienylenevinylenes using Wittig reactions <06T2190>. Additional studies featuring reactions of thiophene derivatives detail biohydrolysis of (S)3-(thiophen-2-ylthio)butanenitrile <06TL8119>, lipase catalyzed resolution of thiotetronic acids <06TL7163>, enzymatic kinetic resolution of 1,1-dioxo-2,3-dihydrothiophen-3-ol <06TL5273>, and efficient synthesis of 6-methyl-2,3-dihydrothieno[2,3-c]furan 55, a coffee
Five-membered ring systems: thiophenes and Se/Te analogues
121
aroma component <06TL787>. A new route to 5-vinyl derivatives of the thiotetronic acid natural product thiolactomycin has also been elaborated using Horner-Wadsworth-Emmons reactions for the key transformations <06TL3447>. It should also be mentioned that a study of 1,3-dipolar cycloadditions of benzo[b]thiophene-S,S-dioxide with azomethine ylides has been performed, leading to formation of partially saturated pyrrolo-fused benzo[b]thiophene derivatives, for instance 56, as mixtures of isomers <06TL5139>. Cyanation of thiophenes at C-2 has been achieved using TMSCN in combination with a recyclable polyvalent iodine(III) reagent based on an adamantane core <06CPB1608>. In addition, syntheses of several partially hydrogenated 4,6-dimethyldibenzothiophenes have been reported <06HCA1623>. H O S
N S
Me 55
H
O
H Ph O 56
Some theoretical aspects of thiophene reactivity and structure have also been discussed, for example the kinetics of proton transfer from 2,3-dihydrobenzo[b]thiophene-2-one <06JOC8203>, the configuration of imines derived from thiophenecarbaldehydes <06JOC7165>, and the relative stability of benzo[c]thiophene <06T12204>. The kinetics of nucleophilic aromatic substitution of some 2-substituted-5-nitrothiophenes in room temperature ionic liquids have also been investigated <06JOC5144>. 5.1.4 NON-POLYMERIC THIOPHENE ORGANIC MATERIALS The field of thiophene containing diarylethenes continues to attract considerable interest. Many of the structures display interesting properties, and could be useful in design of new electronic devices. For example, it has been shown that the photochromic properties of the system 57 may be modulated by addition of fluoride ions, which shifted the absorption maximum from 655 to 490 nm <06OL3911>. Diarylethenes featuring thiophene units bearing phenolic and pyridyl substituents have been prepared, and were demonstrated to exhibit pKa changes upon irradiation <06CEJ4283>. Self assembly at different temperatures was observed during studies of dithienylethenes possessing aryl substituents extended with hexaethylene glycol chains in aqueous solution, resulting from different aggregation properties of the open and closed forms of the system <06JOC7499>. Further extensions involve design of dithienylmaleimide switches incorporating ferrocene moieties controllable by irradiation or electrochemical redox reactions <06TL9227>, or molecular switches based on dithienylperfluorocyclopentene bearing imidazo[4,5-f][1,10]phenanthroline units <06T10072>. In addition, it has been demonstrated that photochromic cyclopentenes based on benzo[b]thiophene-S,S-dioxide units display high fatigue resistance <06CC1881, 06T5855>. Studies of the photochromic properties of an unsymmetrical perfluorocyclopentene bearing one benzo[b]thiophene system and an indene unit <06TL1267> or symmetrical systems with two thiophene units bearing fluorophenyl groups <06TL3167> have also been carried out.
122
T. Janosik and J. Bergman
UV Vis
(Mes)2B
S
B(Mes)2
S
(Mes)2B
S
B(Mes)2
S
57
The unsymmetrical system 58 incorporating donor and acceptor motifs has been prepared by sequential nitration, iodination, and Stille coupling from the parent 1,2-bis(2methylbenzo[b]thiophen-3-yl)perfluorocyclopentene, and was investigated as a device for photo induced electrochemical switching <06T6814>. Upon coordination of the 1,10phenanthroline ligand 59 to a rhenium(I) tricarbonyl complex, a system was obtained where the photochromism was extended from intraligand excitation to metal-to-ligand chargetransfer excitation <06CEJ5840>. The photochromic reactions in single crystals of 1,2-bis(5carboxyl-2-methyl-3-thienyl)perfluorocyclopentene, as well as co-crystals with bipyridines with intermolecular hydrogen bonding networks have also been studied <06CEJ4275>. Intramolecular hydrogen bonding has also been established to play a major role during diastereoselective cyclization of a dithienylhexafluoropentene carrying (R)-N-phenethylamide substituents <06OBC1002>. The fulvene 60 has been shown to participate in a Diels–Alder reaction with an electron deficient alkene, and the resulting adduct was thereafter locked by closing the dithienylethene unit by irradiation at 313 nm. The reverse reaction occurred upon opening the system by irradiation at wavelengths over 434 nm, whereupon the alkene was released <06AG(E)6820>. F
O
F
N
F
F
F
F
O S
S
NO2
S
N
S
58
Cl
S
S
59
S
Cl
60
The benzothieno[3,2-b]benzothiophene 61 is a new semiconductor for air stable organic field effect transistors (FET) <06JA12604>. A set of fused benzene–thiophene structures have been included in a study evaluating their vibronic coupling characteristics <06CEJ2073>. Likewise, the molecule 62 and two closely related structures have been investigated as materials for organic thin film transistors <06AFM426>. A series of related ring fused thiophenes have been investigated in connection with their solid state properties <06CM3470>. S
S Ph
Ph
S
S S
S
S 61
62
The dithieno[3,2-b:2ƍ,3ƍ-d]phosphole 63 has been designed as a very sensitive material for detection of fluoride ions <06OL495>. Cationic dithieno[3,2-b:2ƍ,3ƍ-d]phospholes alkylated at the phosphorus atom have also been prepared for application as building blocks
123
Five-membered ring systems: thiophenes and Se/Te analogues
for luminescent conjugated polyelectrolytes <06OL5893>. Derivatives of this skeleton bearing SiMe2H groups have also been studied <06OL503>. The impact on the electronic properties of di(2-thienyl)phospholes by modification of the phosphorus substitution has been monitored using Raman spectroscopy <06CEJ3759>. Some other examples of studies concerning thiophene containing materials encompass preparation of the donor–acceptor– donor type liquid crystal 64 <06OL4699>, evaluation of the properties of the thienoquinoid system 65 <06OL5235>, and probing of the solvatochromic behaviour of some thienylpyrroles, for example 66 <06OL3681>.
O
O B
S
S
C12H25
O B O
N N
O
Ph 63
O
64 O NC
NC
C12H25 O
O
O
P O
S
S
S
CN
S
S
CN N Pr
CN
CN 65
66
5.1.5 THIOPHENE OLIGOMERS AND POLYMERS Numerous studies have been devoted to 2,2ƍ-bithiophene based systems. Several diborylated structures, for example 67, have been included in a study investigating electronic communication between the boron centers and binding pyridine rings <06JA16554>. The synthesis and evaluation of the electronic properties of the dimer 68, as well as the corresponding trimer have been described <06CEJ2960>. 2,2ƍ-Bithiophenes bearing perfluoroaryl groups have also been prepared and studied as blue light emitting materials <06CM3261>. Other studies of related interest encompass push–pull 2,2ƍ-bithiophenes possessing amino and cyanovinyl groups <06JOC7509>, fluorescent indicators for Ca2+ based on the 2,2ƍ-bithiophene core substituted with the chelator o-aminophenol-N,N,Otriacetic acid <06T684>, and an octaethylporphyrin–dihexyl-2,2ƍ-bithiophene–pyridine system interlinked with diacetylene units <06TL5585>. F5 F5
O B
S S
O
B
S F5
S O
F5
67
O
68
Likewise, a number of terthiophenes have been prepared and studied. For example, radical cations of the system 69 end-capped by bicyclo[2.2.2]octane units have been found to form centrally attracted bent ʌ-dimers <06JA14470>. The trimer 70 has been included in a
124
T. Janosik and J. Bergman
systematic probing of the properties of a series of related molecules <06JA5792>. High resolution electronic spectra of several ethylenedioxythiophene oligomers, among others the silyl terminated compound 71, have been recorded and discussed <06JA17007>. A thiophene tetramer end-capped with 2-pyridyl units has also been reported in connection with syntheses of several related oligomers <06H(68)1349>. Incorporation of hexafluoropentene units in the system 72 enabled lowering of the LUMO level without disturbing the conjugation efficiency. The construction of this molecule involved preparation and coupling of 1,3dibromohexafluorocyclopenta[c]thiophene <06OL5381>. Other studies include Į,Ȧ-capped sexithiophenes bearing fluorenyl <06CM3151> or tricyanovinyl <06CEJ5458> units, whereas the self assembly of oligothiophenes with chiral oligoethylene chains attached via ester linkages has been investigated <06JA5923>. The parent sexithiophene has also been demonstrated to form inclusion complexes upon mixing with polysaccharides, in which the oligothiophene adapts a twisted conformation in the chiral channel formed by helical wrapping of the polysaccharide hosts <06OL235>. A one pot procedure for construction of symmetric octithiophenes from 4-(alkylthio)-2,2ƍ-bithiophene derivatives has also been described <06MAC8293>. Finally, several reports of various aspects of quinoid oligothiophene derivatives have appeared <06TL5375, 06JA10134, 06CM1539>.
S S
S
TMS
O
O S
O
F
70
TMS
S O
F F
F
F
S
O
S
F O
S
F
S S
69 O
F
F
F
F
O
71 C6F13
F
F F S
S
F F
F F F
S S
S
S
F
F F C6F13
72
There are also many examples of materials containing thiophenes in combination with other conjugated units, for instance decyl end-capped thiophene–phenylene oligomers with improved oxidation stability for semiconductor applications <06CM579>. A molecule incorporating octithiophene, quaterthiophene, and fullerene units linked by saturated fragments has been investigated as a long distance charge separation system <06JOC1761>. Liquid crystalline field effect transistors based on 5,5ƍƍ-bis(5-alkyl-2-thienylethynyl)2,2ƍ:5ƍ,2ƍƍ-terthiophenes have been devised <06JA2336, 06AM896>. The system 73 has been designed as a molecular wire which displayed electrochemical switching between an insulating and a conducting state <06OL183>. In addition, a synthetic route to monodisperse oligo[1,4-phenyleneethynylene)-alt-(2,5-thiopheneethynylene)] systems has been described <06T2576>.
125
Five-membered ring systems: thiophenes and Se/Te analogues
C6H13
C6H13 S
S
S
8
CN
8
C6H13
NC
73
Numerous publications include studies of thiophene containing polymers, for instance materials based on thieno[3,4-b]thiophene units <06MAC3118>, or the polymer 74 <06CEJ8075>. Visualization of enzymatic cleavage of single-stranded DNA has been achieved using the cationic polythiophene 75 <06JA14972>. The popular poly(3,4ethylenedioxythiophene) has been employed for design of transparent, plastic, low-workfunction electrodes <06CM4246>. A theoretical study has enabled accurate prediction of HOMO–LUMO gaps for polythiophene and polyselenophene based on extrapolation using long ( > 20-mer) oligomers <06OL5243>. The polymer 76 has been developed as a highmobility semiconductor for thin-film transistors <06AM3029>. A polymer composed of 1(thiophene-2-yl)benzothieno[2,3-b]benzothiophene units has also been prepared <06SM256>. Additional selected contributions to this field encompass for instance construction of postfunctionalizable phosphole modified polythiophenes <06AG(E)6152>, alternating thiophene–perfluoroarene copolymers <06JA2536>, regioregular copolymers containing 3-alkoxythiophene units <06JA8980>, a thiophene–benzobisthiazole copolymer <06SM38>, and a polythiophene containing cyclobutadiene cobalt cyclopentadiene complexes <06SM784>. The side chain conjugated material 77 displayed a very broad absorption band <06CC871>. C8H17 S
S NEt3 Me
O
Cl
C15H31
S S
S S 74
5.1.6
n
S 75
S
C15H31
n ∗
n
76
S
n
∗
77
THIOPHENE DERIVATIVES IN MEDICINAL CHEMISTRY
As in previous years, the thiophene moiety, which is a common isostere of benzene, has been incorporated in a great number of biologically active compounds targeting a wide variety of potential medical applications. For example, a series of 2-amino-3-(3ƍ,4ƍ,5ƍtrimethoxybenzoyl)-5-arylthiophenes <06JMC3906> or 3-amino-2-(3ƍ,4ƍ,5ƍ-trimethoxybenzoyl)-5-arylthiophenes <06JMC6425> has been identified as a new type of antitubulin agents, whereas it was shown that (S)-1-(2-aminocarboxyethyl)-3-(2-carboxythiophene-3ylmethyl)pyrimidine-2,4-dione displayed high potency towards GLUK5-containing kainate receptors <06JMC2579>. Other studies led to development of the molecule 78 as a hepatitis C virus polymerase inhibitor <06JMC1693>, 2-aminothiophene-3-carboxylates as adenosine A1 allosteric enhancers <06BMC2358>, N-glycolsyl-thiophene-2-carboxamides for proliferation of bovine aortic endothelial cells <06BMCL1316>, 5-(pyrazol-5-yl)thiophene2-carboxamides as selective calcium-release-activated calcium channel inhibitors
126
T. Janosik and J. Bergman
<06BMC4750>, 2-pyrimidyl-5-amidothiophenes as inhibitors of the kinase AKT <06BMCL4163>, and arylsulfonylthiophene-2-carboxamidine inhibitors of the serine protease C1s <06BMCL2200>. A series of monocyclic thiophenes, for instance 79, displayed activity as tyrosine phosphatase 1B inhibitors <06BMCL4941>. A related set of 5-substituted 3-aryl-4-cyanothiophene-2-carboxylic acids was designed as AMPA receptor allosteric modulators <06BMCL5057>. It should also be mentioned that 2,5-diphenylthiophene derivatives bearing hydroxy and amine substituents have been studied as compounds for ȕamyloid plaque imaging <06BMCL1350>. In addition, a theoretical investigation probing the structure–activity relationships in a series of nitrothiophenes has also appeared <06BMC8099>. OH N
H N OH
N
S
HO2C
S CO2H
O Br
O
NHCONHCH2(2-ClC6H4)
CO2H
HO2C 79
78
A number of benzo[b]thiophene compounds have also attracted attention. The system 80 has been studied as as a Į7 nicotinic receptor partial agonist <06JMC4374>, whereas the benzo[b]thiophene derivative 81 displayed antitumor effects < 06JMC3143>. A collection of benzo[b]thiophene-2-carboxamides was evaluated as antagonists of the human H3-receptor <06BMCL3162>. In addition, (arylamino) benzo[b]thiophenes were investigated as antioxidants <06BMCL1384>. It has also been shown that the molecule 82 displayed high affinity for the dopamine D3 receptor <06BMC5898>. Other related work involves design of benzothieno[2,3-c]pyran derivatives for inhibition of hepatitis C virus NS5B RNA-dependent RNA polymerase <06BMCL457>, 9-benzylidene-naphtho[2,3-b]thiophen-4-ones as antimicrotubule agents <06JMC7816>, and some cytotoxic thioaurone based structures <06CPB350>. Studies of tetrahydrobenzo[b]thiophene derivatives as inhibitors of hepatitis C virus NS5B polymerase <06BMCL100>, and 2-acylamino-tetrahydrobenzo[b]thiophene-3carboxamides as FLT3 tyrosine kinase inhibitors <06BMCL3282> have also appeared. MeO O N
O
OMe OH
N
Cl
S
Me
N
O
Cl
N
S
S 80
H N
MeO
81
82
There are also many fused thiophene derivatives incorporating other heterocyclic units which exhibit interesting pharmacological properties. The thieno[2,3-b]pyrrole 83 has been identified as an allosteric inhibitor of hepatitis C virus NS5B polymerase <06BMCL4026>, whereas a series of thienopyrroles has been investigated as glycogen phosphorylase inhibitors <06BMCL5567>. A study on thienopyrazole compounds as kinase inhibitors has also been reported <06BMCL96>. The thieno[2,3-b]thiophene fragment may be found in the antitumor compound 84 <06BMC2859>, and protein tyrosine phosphatase 1B inhibitors <06BMC2162>. Other interesting developments in this context include studies of 2-amino-3-
127
Five-membered ring systems: thiophenes and Se/Te analogues
aroyl-thieno[2,3-c]pyridine derivatives as allosteric enhancers at the adenosine A1 receptor <06BMCL5530>, antimicrobial 4-(phenylamino)thieno[2,3-b]pyridines <06BMC5765>, and 3-aminothieno[2,3-b]pyridine-2-carboxamide kinase inhibitors <06JMC2898>. The thieno[2,3-b]pyridone 85 represents a series of similar compounds that has been identified as inhibitors of [3H]glycine binding to the NMDA receptor <06JMC864>, whereas a set of thieno[2,3-b]pyridine-4-ones has been evaluated as non-peptide luteinizing hormonereleasing receptor antagonists <06JMC3809>. A nice example of bioisosterism was demonstrated by preparation of the thieno analogue 86 of the alkaloid febrifugine, which displayed potent antimalarial effects <06JMC4698>. Studies of related interest feature thienopyrimidine structures as melanin concentrating hormone receptor 1 antagonists <06JMC7108>, 06JMC7095>, antibacterial compounds <06BMCL4951>, or partial agonists for the thyroid stimulating hormone receptor <06JMC3888>. In addition, the molecule 87 was established to activate ATP-sensitive potassium channels of pancreatic beta cells <06JMC4127>. CH2CONMe2 N Ph HO2C
S
Cl HO
S S
O Cl
N
H N
HO O Cl
N
S
N H
O
S
S O
86
5.1.7
S
CN
84
83
OPh
NH N H 85
O
H N N
O 87
SELENOPHENES AND TELLUROPHENES
At present, the chemisty of selenophenes and tellurophenes is a relatively scantily studied area. Nevertheless, a number of new valuable contributions dealing with their chemistry have emerged. Electrophilic cyclization of 1-(1-alkynyl)-2-(methylseleno)arenes provides a route to a variety of 2,3-disubstituted benzo[b]selenophenes, as illustrated by the preparation of the system 88. Other useful electrophiles for similar reactions are I2 or NBS <06JOC2307>. Similar chemistry has also been employed in preparation of 2,3-disubstituted benzo[b]selenophenes on solid phase <06JCC163>. In addition, syntheses of 2,3dihydroselenolo[2,3-b]pyridines have been achieved using radical chemistry <06OBC466>.
SeMe
SePh
PhSeBr, CH2Cl2, rt 95%
Se
Ph
88
Selenation of the 1,4-dicarbonyl precursor 89 using the reagent (Me2Al)2Se gave the benzo[c]selenophene derivative 90 in good yield <06TL2887>. The synthesis and structural studies of 4,7-dimethoxybenzo[c]tellurophene have also been reported <06AG(E)5666>.
128
T. Janosik and J. Bergman
(Me2Al)2Se
Fe
O O
75%
Fe
Se
Fe
89
Fe
90
In similarity to their thiophene counterparts, halogenated selenophenes or tellurophenes are useful substrates for transition metal catalyzed reactions. Apart from a protocol for preparation of 2-arylselenophenes by Suzuki coupling of 2-iodo- or 2-bromoselenophene with aryl boronic acids, a route to 2-aroylselenophenes has been devised. For example, treatment of 2-iodoselenophene 91 with (4-methoxyphenyl)boronic acid under an atmosphere of carbon monoxide gave the product 92 in good yield <06JOC3786>. A copper mediated amidation protocol involving 2-iodoselenophene has also appeared <06JOC1552>. Moreover, it has been shown that variants of Sonogashira coupling of 2-bromo- or 2iodotellurophene derivatives offer efficient routes to a variety of 2-alkynyltellurophenes <06SL3161, 06TL2179>. It has also been demonstrated that homocoupling of 5-aryl or 5heteroaryl-2-bromoselenophenes in the presence of the system (Bu3Sn)2/Pd(PPh3)4 provides excellent yields of the corresponding 5,5ƍ-diaryl-2,2ƍ-diselenophenes and their heteroaryl substituted analogues <06TL795>. OMe
Se
I
4-(MeO)C6H4B(OH)2, Pd(PPh3)4 (cat.) Na2CO3, PhMe, CO
91
80%
Se O 92
5.1.8 REFERENCES 06AFM426 06AFM917 06AG(E)1897 06AG(E)4473 06AG(E)5666 06AG(E)6152 06AG(E)6820 06AG(E)7367 06AG(E)8092 06AHC(90)125 06AHC(92)83 06AM602 06AM896 06AM3029 06ASC1521
Y. Sun, Y. Ma, Y. Liu, Y. Lin, Z. Wang, Y. Wang, C. Di, K. Xiao, X. Chen, W. Qiu, B. Zhang, G. Yu, W. Hu, D. Zhu, Adv. Funct. Mater. 2006, 16, 426. X. Sun, Y. Li, S. Chen, W. Qiu, G. Yu, Y. Ma, T. Qi, H. Zhang, X. Xu, D. Zhu, Adv. Funct. Mater. 2006, 16, 917. N. Morita, N. Krause, Angew. Chem. Int. Ed. 2006, 45, 1897. I. Nakamura, T. Sato, Y. Yamamoto, Angew. Chem. Int. Ed. 2006, 45, 4473. M. Pittelkow, T. K. Reenberg, K. T. Nielsen, M. J. Magnussen, T. I. Sølling, F. C. Krebs, J. B. Christensen, Angew. Chem. Int. Ed. 2006, 45, 5666. M. Sebastian, M. Hissler, C. Fave, J. Rault-Berthelot, C. Odin, R. Réau, Angew. Chem. Int. Ed. 2006, 45, 6152. V. Lemieux, S. Gauthier, N. L. Branda, Angew. Chem. Int. Ed. 2006, 45, 6820. K. Yu. Chernichenko, V. V. Sumerin, R. V. Shpanchenko, E. S. Balenkova, V. G. Nenajdenko, Angew. Chem. Int. Ed. 2006, 45, 7367. T. Torroba, M. García-Valverde, Angew. Chem. Int. Ed. 2006, 45, 8092. V. P. Litvinov, Adv. Heterocycl. Chem. 2006, 90, 125. V. P. Litvinov, Adv. Heterocycl. Chem. 2006, 92, 83. T.-H. Huang, J. T. Lin, L.-Y. Chen, Y.-T. Lin, C.-C. Wu, Adv. Mater. 2006, 18, 602. O. Lengyel, W. M. Hardeman, H. J. Wondergem, D. M. de Leeuw, A. J. J. M. van Breemen, R. Resel, Adv. Mater. 2006, 18, 896. Y. Li, Y. Wu, P. Liu, M. Birau, H. Pan, B. S. Ong, Adv. Mater. 2006, 18, 3029. M. Bandini, M. Benaglia, T. Quinto, S. Tommasi, A. Umani-Ronchi, Adv. Synth. Catal. 2006, 348, 1521.
Five-membered ring systems: thiophenes and Se/Te analogues
06BMC2162
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T. Janosik and J. Bergman
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Five-membered ring systems: thiophenes and Se/Te analogues
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T. Janosik and J. Bergman
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Five-membered ring systems: thiophenes and Se/Te analogues
06S2794 06S3670 06S3855 06SC97 06SC3319 06SL737 06SL2016 06SL2423 06SL2559 06SL3161 06SM38 06SM256 06SM784 06T684 06T2190 06T2576 06T4756 06T5855 06T6036 06T6814 06T8467 06T9554 06T10072 06T11124 06T11311 06T11513 06T12204 06TA2919 06TL83 06TL787 06TL795 06TL1267 06TL1551 06TL2179 06TL2887 06TL3167 06TL3447 06TL3365 06TL4635 06TL5143 06TL5139 06TL5273 06TL5375 06TL5585 06TL5599
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134 06TL6067 06TL7163 06TL8087 06TL8119 06TL9227 06TL9249 06TL9329
T. Janosik and J. Bergman
J.-J. Filippi, X. Fernandez, E. Duñach, Tetrahedron Lett. 2006, 47, 6067. K. Toyama, T. Tauchi, N. Mase, H. Yoda, K. Takabe, Tetrahedron Lett. 2006, 47, 7163. A. Barco, N. Baricordi, S. Benetti, C. De Risi, G. P. Pollini, Tetrahedron Lett. 2006, 47, 8087. M. Gelo-Pujic, C. Marion, C. Mauger, M. Michalon, T. Schlama, J. Turconi, Tetrahedron Lett. 2006, 47, 8119. L. Sun, H. Tian, Tetrahedron Lett. 2006, 47, 9227. A. Borghese, G. Geldhof, L. Antoine, Tetrahedron Lett. 2006, 47, 9249. V. Nair, K. G. Abhilash, E. Suresh, Tetrahedron Lett. 2006, 47, 9329.
135
Chapter 5.2 Five-membered ring systems: pyrroles and benzo analogs Erin T. Pelkey Hobart and William Smith Colleges, Geneva, NY 14456
[email protected] Jonathon S. Russel St. Norbert College, De Pere, WI 54115
[email protected]
5.2.1
INTRODUCTION
The synthesis and chemistry of pyrroles, indoles, and additional fused pyrrole and indole ring systems reported during the past year (2006) are the subjects of this review. Pyrroles and indoles are amongst the most studied heterocyclic ring systems due to their diverse biological activity and materials science applications. Page restrictions limit this review to selected advances. In keeping with the past few years, pyrroles and indoles are treated separately. Review articles will be mentioned at the beginning of the relevant sections.
5.2.2
SYNTHESIS OF PYRROLES
Pyrrole syntheses have been organized systematically into intramolecular (type I) and intermolecular (type II) approaches and classified by the location of the new bonds that describe the pyrrole ring forming step (two examples illustrated below). type Ic N R
5.2.2.1
c d
b e
Intramolecular Approaches
Na R
type IIae Intermolecular Approaches
N R
Intramolecular Approaches
Intramolecular nucleophilic additions by nitrogen functional groups onto pendant alkynes and allenes represent an important class of type Ia approaches to functionalized pyrroles. A platinum-catalyzed (PtCl4) cyclization of homopropargyl azides provided an entry to 2,5disubstituted pyrroles and 4,5,6,7-tetrahydroindoles (fused pyrroles) <06OL5349>. The addition of a carbonylation step extended a pyrrole synthesis to pyrrole-2-acetic acid derivatives <06ASC2212>. Treatment of enyne amine 1 with palladium diiodide in the presence of CO and methanol produced pyrrole-2-acetic ester 2 via a 5-exo-dig cyclization, oxidative carbonylation, and isomerization.
136
E.T. Pelkey and J.S. Russel
Et
Et
PdI2 (cat.), KI CO, O2, MeOH
Et N Bu
63%
NH Bu
Bu
CO2Me
N Bu
Bu
CO2Me Bu
2
1
A ring opening reaction of β-lactams promoted by methoxide generated nitrogen nucleophiles in situ that subsequently added to proximal allenes producing trisubstituted pyrroles <06CC2616>. In the event, treatment of β-lactam 3 with MeONa led to pyrrole-2acetic ester 4 after cleavage of the amide bond, 5-exo-dig cyclization, and loss of methanol. The sequence was notable as no metal catalyst was required. OMe
PhO
OMe Ph MeONa
N R
O
MeOH 50%
PhO MeO2C
MeO
Ph NH
PhO
R
Ph
N R
MeO2C
Me
Ph PhO MeO2C
3 (R = p-OMePh)
N R
Me
4
A thermal ring opening reaction of an imine-substituted cyclopropene led to a mixture of 2,3,4-trisubstituted and 3,4,5-trisubstituted pyrroles <06TL5793>. Two type Ia syntheses of β-hydroxypyrroles have appeared. An aza-Nazarov cyclization of 1-azapenta-1,4-dien-3-ones produced β-hydroxypyrroles including 2,2’-bipyrroles <06EJO5339>. A second approach to a β-hydroxypyrrole involved an intramolecular N-H insertion into a rhodium carbene derived from the decomposition of a diazoketone <06JOC5560>. On the other hand, the photochemical decomposition of the diazoketone led to pyrrolidin-2-ones. Intramolecular condensation reactions of unsaturated γ-aminocarbonyl compounds provide regiospecific methods for the preparation of highly functionalized pyrroles. This strategy was utilized to prepare pyrrole-fused tetrathiafulvenes <06S2815>. In the event, a two-step reductive amination of aldehyde 5 gave sulfonamide 6. Treatment of 6 with Amberlyst 15 promoted an intramolecular condensation leading to fused pyrrole 7. Intramolecular condensation reactions of substituted γ-aminoacetals followed by oxidation with DDQ provided the corresponding pyrroles <06OL3585>. The former were prepared by nucleophilic additions of ketene silyl acetals onto imines. An intramolecular aza-Wittig reaction of unsaturated γ-azidoketones provided a regiospecific route to 4-amino- and 4alkyoxy-2-trifluoromethylpyrroles <06JOC6996>. Similarly, an aza-Wittig sequence involving γ-azido-β-hydroxyketones provided pyrrole-2-acetic esters <06JOC4965>. OHC
S S
EtO
S OEt
5
NHTs
1. TsNH2, MS, toluene 2. NaBH4, THF, EtOH 75% (2 steps)
S EtO
S OEt
6
S
Amberlyst 15 S
Ts N 99%
S S 7
α-Thioether pyrroles have been prepared utilizing a type Ib condensation <06T1708>. Treatment of ketene N,S-acetal 8 with the Vilsmeier-Haack reagent (POCl3 + DMF) led to 5-
137
Five-membered ring systems: pyrroles and benzo analogs
4-formylpyrrole-2-carboxylate 9 via an iminium-type cyclization. Interestingly, attempts to promote the cyclization with POCl3 alone or different Lewis acids did not yield any pyrrole products. On the other hand, treatment of 8 with the non-nucleophilic base DBU gave the 4unsubstituted pyrrole product 10. In a different study involving a structurally related vinylogous amide (no S), an acid-promoted (p-TsOH, AcOH, or POCl3) intramolecular condensation reaction produced a 2-benzoylpyrrole derivative <06T8243>. Cl
Cl
OHC
POCl3 DMF, 80 °C
EtS
CO2Me
N H
SEt MeO2C
88%
DBU toluene, Δ
N H
EtS
34% O
9
8
CO2Me
N H 10
Cl
A base-mediated type Ib cyclocondensation of imino chlorides, derived from treating the corresponding N-allylamides with triphenylphosphite-chloride, provided 2-aryl- and 2,3diarylpyrroles <06S995>. A novel intramolecular photocycloaddition involving vinylogous amides and allenes led to an interesting type Ib entry to functionalized pyrroles <06OL4031>. For example, photolysis of allene 11 provided fused pyrrole 12 via a [2+2] cycloaddition and retro-Mannich reaction. O
O O
hν N H
87%
N H
HN
11
12
Ring closing metathesis (RCM) continues to enjoy significant attention directed at the preparation of heterocycles including type Ic syntheses of pyrroles. 2-Phosphonopyrroles were prepared utilizing an oxidative RCM as the key step <06JOC4006>. For example, treatment of 4-aza-1,6-diene 13 with Grubbs’ second-generation catalyst in the presence of the oxidant, tetrachloroquinone (TCQ), produced pyrrole 14. Microwave-assisted RCM reactions involving diallylamines were utilized to provide amino acid pyrrole derivatives (i.e., 15) and N-arylpyrroles <06TL3893>. A synthesis of N-(3-fluorophenyl)pyrrole also was reported utilizing a RCM reaction <06S1823> Ph Grubbs 2nd Me TCQ, CH2Cl2
Me N Bn 13
P(OMe)2 O
84%
N N Bn 14
P(OMe)2 O
MeO O 15
138
E.T. Pelkey and J.S. Russel
A McMurry coupling reaction involving 3-aza-1,5-dicarbonyl compounds gave 2,5dihydro-3,4-diarylpyrroles <06SL490>. The latter were converted into the corresponding 3,4-diarylpyrroles by irradiation (Hg lamp, 500 W) in acetonitrile. Intramolecular condensation reactions involving enaminones and carbonyls (or their synthetic equivalents) provides another class of type Ic approaches to pyrroles. Treatment of enaminone 16 with TFA provided fused pyrrole 17 <06TL2151>. 16 was prepared utilizing an aza-Wittig reaction between 1,3-cyclohexanedione and 2-azido-1,1-diethyoxyethane. An alternate synthesis of 17 was achieved utilizing an oxidation of a β-hydroxy enaminone promoted by palladium(0) and mesityl bromide <06T8533>. A number of different fused pyrroles were prepared utilizing this methodology. O
O EtO
16
5.2.2.2
OEt
95%
N H
O
Pd(PPh3)4 MesBr, K2CO3, DMF
TFA, CH2Cl2
OH
63%
N H
18
17
N H
Intermolecular Approaches
No type IIab approaches were abstracted. A type IIac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis <06OL5837>. For example, treatment of iodoacrylate 19 and trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-2carboxylate 21 with excellent regioselectivity. 19 was prepared by iodinating (Niodosuccinimide) the corresponding commercially available dehydroamino ester.
SiMe3
I
Pd(OAc)2 LiCl, K2CO3 DMF, 65 °C
SiMe3
+ MeO2C
NHAc 19
81% Ph 20
MeO2C
N H
Ph
(> 25:1 regioselectivity) 21
A Knorr-type pyrrole synthesis involving the condensation between α-amino-β-ketoesters and β-ketonitriles provided β-cyanopyrroles <06OPRD899>. The former amine substrates were prepared by reduction of the corresponding α-isonitroso-β-ketoesters with Zn/HOAc. Following the communcation in 2004, a full report appeared that described type IIac cyclocondensation reactions between dihydroisoquinolines and α-nitrocinnamates leading to complex fused pyrroles <06JOC9440>. The latter were converted into the lamellarin alkaloids and related analogues. An oxidative radical coupling promoted by tetra-n-butylammonium cerium(IV) nitrate (TBACN) between β-aminocinnamate 22 and enamine 23 provided pyrrole-3,4-dicarboxylate 24 <06T2235>. Dimerization of the β-aminocinnamates provided symmetrical pyrroles.
139
Five-membered ring systems: pyrroles and benzo analogs
EtO2C
CO2Et + Ph
EtO2C
NH Ar
H 2N
22
CO2Et
TBACN, CHCl3 Ph
92%
Me 23
Me
N Ar 24
Two unique type IIad syntheses of pyrroles that were reported both involved cyclopropane fragmentations. The first allowed for a synthesis of 2-arylpyrroles <06SL2339>. In the event, treatment of stannylcyclopropane 25 with n-BuLi followed by benzonitrile produced 2-phenylpyrrole 26 via tin-lithium exchange, addition to the nitrile, ring fragmentation of ketimine intermediate, intramolecular condensation, and loss of dibenzylamine. 1. n-BuLi 2. PhCN 3. AcOH SnBu3 Bn2N
Ph
80% Bn2N
N H
NLi
25
Ph
26
The second IIad synthesis provided a route to 2,3,4-trisubstituted pyrroles <06CC2271>. Mixing cinnamaldehyde 27 with aminocarbene complex 28 in the presence of molecular sieves (MS) gave pyrrole 29. The authors proposed a mechanism that included a cyclopropane intermediate and subsequent fragmentation and intramolecular condensation.
Ph + HN
H
Cr(CO)5
MS 4Å toluene, Δ
Me
94%
Ph
Ph
OHC HN Me
N
proposed intermediate
29
Me
O 27
28
The preparation of 2-aminopyrroles was accomplished with type IIae zinc-catalyzed cyclocondensation reactions between β-cyanoketones and primary amines <06T1452>. Type IIae cyclocondensation reactions between primary amines and 1,4-dicarbonyl compounds (Paal-Knorr) or 2,5-dialkoxytetrahydrofurans (Clauson-Kaas) continue to remain the most utilized de novo approaches to functionalized pyrroles. An investigation into the utility of metal triflates in promoting the Paal-Knorr synthesis identified 1 mol% Sc(OTf)3 to be superior <06TL5383>. The preparation of a library of tetra-substituted pyrrole-3carboxamides was accomplished utilizing a Paal-Knorr cyclization within a parallel solutionphase sequence <06JCC491>. A few novel approaches for generating 1,4-dicarbonyl compounds appeared in reports aimed at preparing substituted pyrroles. The 1,4carbonylative addition reactions of arylboronic acids to methyl vinyl ketone catalyzed by a Rh(COD)2BF4 provided 1,4-diketones <06T11740), while the reductive ring opening of 3Hfuran-2-ones with DIBAL gave 1,4-ketoaldehydes <06H(68)1121>.
140
E.T. Pelkey and J.S. Russel
O
O O2 PdCl2, CuCl DMF/H2O
N
N PhO2S
O N O N
80% O
allylamine TiCl4 toluene
PhO2S
30
N Me
N
N
78% O
PhO2S
31
32
Pyrrole-substituted 1,4-diketones were prepared utilizing the Tsuji-Wacker oxidation of the corresponding homoallylic ketones <06OL6107>. The success of the reaction depended on protection of the pyrrole nitrogen as a sulfonamide. In the event, treatment of 2ketopyrrole 30 with PdCl2 and CuCl in an oxygen atmosphere gave 1,4-diketone 31. The latter underwent a cyclocondensation with allylamine in the presence of stoichiometric TiCl4 giving 2,2’-bipyrrole 32 which was converted into a 4-aminoprodigiosin analogue. The Paal-Knorr cyclocondensation has been exploited to prepare a number of biologically active 1,2-diarylpyrroles including analgesics <06AP670>, anti-inflammatory agents <06BMCL3657>, and antimycobacterial agents <06JMC4946>. The retro-Paal-Knorr ring opening reaction leading to 1,4-dicarbonyl compounds was accomplished by heating N-substituted pyrroles in a citrate buffer <06SL1428>. The sequence was coupled with a forward Paal-Knorr reaction enabling the exchange of the Nsubstituent on pyrroles. The Clauson-Kaas pyrrole synthesis was adapted to a soluble polyglycerol (PG) support <06OL403>. Electrochemical oxidation of furan 33 in the presence of methanol followed by hydrogenation gave 2,5-dimethoxytetrahydrofuran 34. Cyclocondensation with primary arylamines gave N-arylpyrroles 35. Removal from the PG support was then accomplished by treatment of 35 with LiOH which gave 2-pyrrolepropanoic acids 36. 1. MeOH dioxane electrolysis
PG O
O O 33
Ar-NH2 NaOAc AcOH
PG O
2. H2, Pt/C MeOH
O
O OMe 34
OMe
RO O
LiOH aq. dioxane
N Ar
35 R = PG support 36 R = H
A milder Clauson-Kaas pyrrole synthesis was reported that alleviated the need for acid or heat <06TL799>. The innovation involved the hydrolysis of 2,5-dimethoxytetrahydrofuran giving 2,5-dihydroxytetrahydrofuran. The latter was converted into pyrroles by treatment with primary amines in an acetate buffer. The Clauson-Kaas pyrrole synthesis was studied utilizing a K-10 montmorillonite acid catalyst and microwave irradiation <06OPP495>. Mild reaction conditions (cat. p-TsOH) allowed for the preparation of pyrrole-3-carboxaldehydes from 2,5-dimethoxytetrahydrofuran-3-carboxaldehydes <06S1494>. A mixture of metals was utilized to promote a type IIae synthesis of penta-substituted pyrroles <06OL2151>. Treatment of enyne 37 with a Ag(I) catalyst followed by BnNH2 and a Au(I) catalyst gave pyrrole 38 via a Claisen-type rearrangement and cyclocondensation.
141
Five-membered ring systems: pyrroles and benzo analogs
Ph
Ph CO2Et
O
AgSbF6
O
CO2Et
1. BnNH2 2. (Ph3P)AuCl
EtO2C Ph
Me Me
Me
N Bn
Me
38
37
A mixture of gold and silver reagents was also utilized in a type IIae cyclocondensation between β-alkynyl ketones and primary amines <06JOC4525>. For example, treatment of cyclopentanone 39 and benzylamine with AuCl and AgOTf gave fused pyrrole 40. A coppercatalyzed domino approach to complex pyrroles was developed <06AG(I)7079>. For example, treatment of iodoenyne 41 with BocNH2 in the presence of CuI and N,Ndimethylethylenediamine (DMEDA) gave fused pyrrole 42 via an amidation followed by a 5endo-dig cyclization. Several higher yielding examples were also reported. BnNH2, PPh3 AuCl, AgOTf ClCH2CH2Cl R2 N 1 R 40 R1 = Bn; R2 = Me 42 R1 = Boc; R2 = Ph
79%
O
BocNH2, CuI DMEDA Cs2CO3, THF
39
I
52% Ph
41
A type IIae cyclocondensation of silyloxy enynes catalyzed by TMSOTf produced highly substituted pyrrole-2-acetic esters <06OL3881>. The increasingly common theme of developing new pyrrole syntheses that involve cyclopropane fragmentations appeared in a type IIae pyrrole synthesis <06OL835>. Treatment of doubly activated cyclopropane 43 with benzylamine in the presence of magnesium sulfate led to complex pyrrole 44 via a nucleophilic cleavage of the cyclopropane ring, intramolecular condensation, and isomerization of the exocyclic π-bond.
CO2Et
Bn-NH2, MgSO4 CH3CN, Δ
C7H15
CO2Et
O
CO2Et
O
C7H15 Me 43
C8H17
NH Me
78% Bn
N Bn
Me
44
A type IIbc approach to pyrroles was employed in the synthesis of pyrrolo[2,1-b]thiazoles <06S1433>. The key step involved a formylation with the Vilsmeier-Haack reagent followed by a cyclocondensation of the putative iminium intermediate. Type IIbd pyrrole syntheses fall into three general categories: (1) Hinsberg-type; (2) azomethine ylide cycloadditions; and (3) isocyanide-based cyclocondensations. The Hinsberg pyrrole synthesis, the cyclocondensation between iminodiacetates and oxalates, has been further exploited in the total synthesis of the lamellarins <06T594, 06TL3755>. Azomethine ylide cycloadditions have been utilized to prepare a number of novel fused pyrroles including pyrrolo[2,1-a]isoquinolines <06CHJC279, 06TL1469> and pyrrolo[1,2b]pyridazines <06SL804>. Fused hydroxypyrroles were obtained in cycloaddition reactions with trimethylsilylketenes (TMS ketene) <06TL1469>.
142
E.T. Pelkey and J.S. Russel
S Bu3Sn
N Me
MeO2C Ph
S
CO2Me
N Me
benzene, Δ 81%
45
MeO2C
SnBu3 Ph
CO2Me N Me 46
Ph
The generation of azomethine ylides generated by the ring-opening of aziridines has been studied in supercritical CO2 <06TL5475>. The generation of non-stabilized azomethine ylides was realized utilizing an unprecedented 1,4-stannatropic shift <06CC526>. For example, heating thioamide 45 in the presence of DMAD produced pyrrole 46 via a cycloaddition of the azomethine ylide intermediate followed by loss of the sulfanyl group. Highly functionalized pyrroles continue to be prepared utilizing type IIbd cyclocondensation reactions between activated isocyanides and alkenes/alkynes. Cyclocondensations reactions involving tosylmethyl ioscyanide (TosMic) have been utilized to prepare pyrroles for study as reverse transcriptase inhibitors <06CMC1379> and neurotransmitters <06BMCL5203>. The preparation of 2-tosylpyrroles was realized via reactions between TosMic and alkynes run in the presence of triphenylphosphine <06HCA923>. An important solvent effect was discovered during an investigation into the Barton-Zard pyrrole synthesis (isocyanoacetates + nitroalkenes or β-nitroacetates) <06TL5481>. It appears that the THF stabilizing agent, BHT (butylated hydroxytoluene), inhibits this cyclocondensation. Much higher yields were obtained using distilled THF or MTBE as the solvent. Finally, the Barton-Zard pyrrole synthesis has been utilized to prepare pyrrole Weinreb amides <06JOC6678>, a useful precursor to pyrrole-2-carboxaldehydes and 3-pyrrolin-2-ones. The reaction between isocyanide 47 with nitroalkene 48 in the presence of DBU gave pyrrole Weinreb amide 49. The latter was converted into the corresponding pyrrole-2-carboxaldehyde 50 by treatment with LiAlH4. Oxidative cleavage of the formyl group gave 3-pyrrolin-2-one 51. Ph Me N OMe
CN O 47
Ph 48
NO2
DBU, THF 71%
Ph
Ph
N H 49
Me N OMe
LiAlH4 Ph THF
O
72%
Ph
N H 50
H
H2O2 Ph NaHCO3 80%
O
Ph
N H 51
O
Treatment of p-methoxyphenylethylamine with a stoichiometric amount of Cu(OAc)2 and in the presence of a catalytic amount of Pd(OAc)2 produced a 3,4-diarylpyrrole via an unexpected three-component cyclization process <06JACS12046>. Another threecomponent sequence was exploited to prepare 5-aryl-2-oxopyrrole derivatives via cyclocondensation reactions between malonates, aldehydes, and primary amines <06T6018>. 5.2.2.3
Transformations of other Heterocycles
A novel ring opening reaction of isoxazoles led to the formation of functionalized pyrroles <06S1021>. For example, treatment of isoxazole 52 with DBU led to the formation of pyrrole 53. A solid-phase synthesis of 3-amino-2,5-dicarboxylates was accomplished by transformation of pyrrol-3-one 54 <06JCC177>. The reaction between 54 and secondary amines led to the corresponding resin-bound aminopyrroles after enamine formation and loss
143
Five-membered ring systems: pyrroles and benzo analogs
of the phenylfluorenyl group. A similar solution-phase sequence was utilized to prepare pyrrole 30 <06OL6107>. HO
NHBn Ph
N
O
CO2Bu
MeO2C O
DBU THF, Δ
N
CO2Bu
OH
N Ph
55%
52
53
5.2.3
REACTIONS OF PYRROLES
5.2.3.1
Substitution at Nitrogen
CO2
Ph
N Bn
54
The introduction of N-protecting groups (i.e., Boc, sulfonyl, benzyl, trialkylsilyl, N-amino, and N-amido) attenuates the reactivity of the pyrrole nucleus and this topic has been extensively reviewed <06T11531>. The N-alkylation of pyrrole has been investigated in an ionic liquid (1-n-butyl-3-methylimidazolium tetrafluoroborate) using potassium carbonate as the base <06TL2435>. Treatment of pyrrole-2,4-dicarboxylates with chloramine (NH2Cl) in a biphasic system and in the presence of Aliquat 336 (phase-transfer agent) provided the corresponding N-aminopyrroles <06TL5341>. The conjugate addition of pyrrole to α,β-unsaturated esters catalyzed by potassium pyrrolate led to the formation of β-pyrrolyl esters <06SL77>. Nucleophilic aromatic substitution of N-pentafluorophenylpyrrole with the sodium salt of pyrrole provided the first access to hexapyrrolylbenzene derivatives <06ARK(ii)124>. The asymmetric allylic alkylation (AAA) reaction has been adapted for use with pyrrole nucleophiles <06JACS6054>. For example, treatment of pyrrole 55 and cyclopentene 56 with a palladium catalyst in the presence of a chiral additive gave pyrrole 57 in up to 92% ee. The latter was elaborated into piperazinone-pyrrole natural product, agelastatin A 94.
OBoc MeO2C
N H 55
Br
Pd2(dba)3•CHCl3 chiral additive Cs2CO3, CH2Cl2
+ 75%
MeO2C
N
OBoc 56 57
5.2.3.2
Br H
94 agelastatin A
OBoc
Substitution at Carbon
Functionalization of the electron-rich pyrrole ring is often accomplished utilizing standard electrophilic aromatic substitution reactions. N-bromosuccinimide (NBS) is the reagent of choice for preparing bromopyrroles <06BMC4627, 06BMC8162, 06BMCL5432, 06S3883, 06EJM1439>. The preparation of rhanzinal and related pyrrole natural products required the preparation of a 4-iodopyrrole-2-carboxaldehyde <06ARK(iii)163>. Introduction of the iodine was done by treatment of the corresponding pyrrole-2-carboxaldehyde with iodine and silver trifluoroacetate. The sulfonation of pyrrole 58 with chlorosulfonic acid in acetonitrile gave pyrrole-3-sulfonyl chloride 59 <06T1699>. Treatment of 59 with morpholine followed
144
E.T. Pelkey and J.S. Russel
by base-mediated removal of the protecting group gave pyrrole-3-sulfonamide 60. The preparation of anti-HIV 5-arylthiopyrroles was achieved utilizing arylsulfenyl iodide generated in situ by the combination of arylthiophenol, iodine, and potassium iodide <06CMC1367, 06CMC1379>. A method exploited for preparing 2-alkylthiopyrroles involved treating 2-thiocyanatopyrrole with an alkyl Grignard reagent <06JOC903>. Additional examples of the direct cyanation of pyrroles utilizing oxidative conditions (hypervalent iodine and trimethylsilyl cyanide) were reported <06CPB1608>. The preparation of formylpyrroles has been investigated with the Vilsmeier-Haack formylation (POCl3, DMF) <06OBC1032, 06TL3693>. With 2-(2’-thienyl)pyrrole <06T3493> and pyrrole-2-carboxylate <06TL4631>, this reaction proved to be unselective. O
HOSO2Cl, CH3CN N SO2Ph 58
O N S O
SO2Cl 1. morpholine, CH2Cl2 2. K2CO3, aq. MeOH N SO2Ph 59
46%
N H
77% (2 steps)
60
New electrophilic substitution reaction methods for the preparation of dipyrromethanes have been reported. The condensation of N-methylpyrrole with benzaldehyde leading to the corresponding dipyrromethane was promoted by the addition of the organic catalyst, pyrrolidinium tetrafluoroborate <06T12375>. The reaction between pyrrole and N-tosyl imines promoted by metal triflates gave dipyrromethanes whereas tripyrromethane byproducts were not observed <06T10130>. Different catalysts including bismuth-trichloride <06SC1373> and copper bromide <06TL7323> have been evaluated for promoting the Michael addition of pyrroles onto electron-deficient alkenes. Organic catalysts including azirdin-2-yl methanols <06TA3135> and chiral pyrrolidinium salts <06TA107> have been utilized for stereoselective conjugate addition reactions by pyrroles. For example, treatment of N-methylpyrrole 61 and (E)crotonaldehyde 62 in the presence of aziridin-2-yl methanol 63 gave alkylated pyrrole 64 with relatively good enantiomeric excess (ee). Me
+
Me
H
N Me 61
O 62
N H 63
Ph Ph OH
CH2Cl2, i-PrOH 51% (75% ee)
N Me
H Me
O
64
A Nazarov-type cyclization was exploited to prepare annelated pyrroles <06OL163>. Acylation of N-tosylpyrrole 65 with carboxylic acid 66 promoted by trifluoroacetic anhydride gave intermediate 2-ketopyrrole 67 which underwent a Nazarov-type cyclization to give cyclopenta[b]pyrrole 68. Another route to cyclopenta[b]pyrroles involved a novel cyclization involving pyrrole-substituted enones and isocyanides <06OL3975>.
Five-membered ring systems: pyrroles and benzo analogs
+
Me
(CF3CO2)2O
HO
N Ts 65
145
Me O
ClCH2CH2Cl, Δ 73%
66
N Ts 67
Me
N Ts 68
O
O
A gallium metal-mediated allylation of pyrrole led selectively to the formation of the 3substituted pyrroles <06TL3535>. In contrast, a palladium-catalyzed allylation of pyrrole with allylic alcohols performed in the presence of triethylborane led to 2-substituted pyrroles <06H(67)535>. Palladium-catalyzed cross-coupling reactions continue to play a central role for the preparation of highly substituted pyrroles and this subject has been reviewed <06EJO3043>. The regioselectivity in the cross-coupling of polybromopyrroles can be predicted from the 1 corresponding H NMR chemical shifts of the parent non-brominated parent systems <06CC299>. The positions containing protons that are shifted the farthest downfield in the 1 H NMR correspond to the more reactive bromine atoms in the cross-coupling reactions of polybromopyrroles. A one-pot, regioselective double Suzuki cross-coupling reaction appeared <06OL1537>. Sequential treatment of 4,5-dibromopyrrole 69 with p-methoxyphenylboronic acid and Pd(OAc)2 followed by p-fluorophenylboronic acid and Pd(PPh3)4 gave 4,5-diarylpyrrole 70. In a separate study, the regioselectivity of Suzuki reactions with 3,4-dibromo- and 2,4dibromopyrroles was evaluated <06S3883>. A two-step Negishi/Suzuki cross-coupling sequence provided a regioselective synthesis of 4,5-diarylpyrroles <06BMC4627> F
Br Br
1. p-OMePhB(OH)2 Pd(OAc)2, K2CO3, DMF N Et 69
CHO
2. p-FPhB(OH)2, Pd(PPh3)4 45%
MeO
N Et 70
CHO
Palladium-catalyzed cross-coupling reactions have been exploited for the preparation of the lamellarin natural products <06T594, 06TL3755> and related analogues <06JMC3257>. For example, the Suzuki cross-coupling of symmetrical bistriflate 71 with boronic acid 72 gave 3-arylpyrrole 73 <06TL3755>. A second Suzuki cross-coupling of 73 with boronic acid 74 then produced 3,4-diarylpyrrole 75 which was converted in several steps to lamellarin a 20-sulfate 76, a selective inhibitor of HIV-1 integrase.
146
E.T. Pelkey and J.S. Russel
MeO i-PrO TfO
B(OH)2
MeO
i-PrO
B(OH)2
OTf
OTf
MeO
BnO
OMOM
72 E
E
E
N
74 E
N
Pd(PPh3)4, Na2CO3, THF Ar
MeO
90%
Ar
E = CO2Me Ar = 3,4-diOMePh
71 MeO
Pd(PPh3)4, Na2CO3, THF
80%
73 MeO
OBn
MeO
OSO3Na
i-PrO
i-PrO OMOM E
O
MeO N
E
N
MeO
O
Ar 75
76
A total synthesis of the pyrrole natural product, rhazinal, utilized a Suzuki cross-coupling reaction to install a 3-aryl moiety <06ARK(iii)163>. Suzuki cross-coupling reactions were exploited for the preparation of a number of pyrrole materials including a prodigiosin analogue <06OL4951>, a bipyrrole building block <06TL2605>, fluorescent bis(pyrrol-2yl)arenes <06TL7541>, and BODIPY dyes <06EJO4658>. The Heck cyclization of bromopyrrole 77 and the corresponding oxidative Heck cyclization of desbromopyrrole 78 was studied <06SL3081>. While the Heck cyclization of 77 led to a mixture of [3.3.1]bicycle 79 and [3.2.2]bicycle 80 under a variety of conditions, the oxidative Heck cyclization of 78 led solely to the desired building block 79. The latter has previously been utilized in a total synthesis of dragmacidin F.
X
Me TBSO
for 77: Pd[P(t-Bu)3]2, Pd2dba3 Cy2NMe, THF
HO
O
77 X = Br 78 X = H
N SEM
for 78: Pd(OAc)2, t-BuOH AcOH, DMSO
TBSO
O H +
HO O
N SEM 79
Me
O HO O
N SEM 80
An enantiospecific, gold-catalyzed pyrrole annelation reaction was utilized in a total synthesis of rhazinilam 95 <06JACS10352>. Specifically, treatment of allene 81 with gold triflate – triphenylphosphine led to the formation of annelated pyrrole 82, which was subsequently converted into 95. A gold-catalyzed direct coupling of pyrroles with 1,3dicarbonyls led to the formation β-(pyrrol-2-yl)enones <06ASC331>.
147
Five-membered ring systems: pyrroles and benzo analogs
Me MeO2C
Me H PPh3 • AuOTf N
Et
97:3 (dr) 92%
MeO2C Et
81
95 rhazinilam
N 82
A regiochemical outcome of a palladium-catalyzed direct C-H bond functionalization of the pyrrole ring can be directed by choice of N-substitution with bulky groups directing to C3. The oxidative alkenylation of N-(Boc)pyrrole led selectively to a 2-vinylpyrrole whereas the same reaction with the N-(TIPS)pyrrole produced a 3-vinylpyrrole <06JACS2528>. A tandem coupling reaction/intramolecular direct C-H arylation leading to the pyrrolo[2,1a]isoquinoline ring system was investigated <06OL2043>. For example, treatment of Nbromoalkylpyrrole 83 and iodoarene 84 with the reagents shown provided fused pyrrole 85. The authors proposed a mechanism that includes a Heck reaction between norbornene and 84, an ortho C-H functionalization of the iodoarene, and a C-H arylation of the pyrrole ring. PdCl2, tri-2-furylphosphine Cs2CO3, norbornene, CH3CN
Me +
N
I
Me N
91% CO2Me 83 Br
CO2Me 85
84
A SmI2-induced reductive cyclization of N-(alkylketo)pyrroles provided an entry into medium ring 1,2-annelated pyrroles <06EJO4989>. An oxidative radical alkylation of pyrroles with xanthates promoted by triethylborane provided access to α-(pyrrol-2yl)carboxylic acid derivatives <06TL2517>. An oxidative coupling of pyrroles promoted by a hypervalent iodine(III) reagent provided bipyrroles directly <06OL2007>. Concerted reactions involving the π-bond of the pyrrole ring have been reported. The stereoselectivity in the cyclopropanation of pyrrole and other 5-membered ring heterocycles with rhodium carbenoids has been investigated <06JOC5349>. Diels-Alder cycloadditions of pyrroles (and indoles) with cyclopentadienone acetal gave the bicyclic cycloadducts in fairly good yields <06BCJ1288>. A synthesis of highly-substituted tetracenes was developed starting from isoindole (benzo[c]pyrrole) <06OL273>. For example, treatment of dibromonaphthalene 87 with phenyllithium in the presence of isoindole 86 followed by deamination of the intermediate cycloadduct provided tetracene 88. Separately, the synthesis and cycloaddition chemistry of oxadisilole-fused isoindoles was investigated <06SL2510>. F
OC6H13
F N Me F F 86
F
Br
1. PhLi 2. NaOH, CHCl3
F
Br
35%
F
+ OC6H13 87
OC6H13
F
OC6H13 88
Cycloaddition reactions involving dithione intermediates derived by the reductive extrusion of sulfur atoms from [1,2,3,4,5]pentathienopino[6,7-b]pyrroles provided access to 1,4-dithin-fused pyrroles (i.e., 89) <06OL4529>.
148
E.T. Pelkey and J.S. Russel
5.2.3.3
Functionalization of the Side-Chain
The preparation of 3-vinylpyrroles was investigated utilizing the Horner-WadsworthEmmons reaction with 3-formyl-N-tosylpyrrole <06S1494>. The intramolecular acylation of pyrrole-2-Weinreb amides provided access to novel indolizinone derivatives <06T6182>. The amidation of pyrrole-2-carbonyl chloride was utilized as a key step in the preparation of pyrrole-oxazole analogue 90 of the insecticide Pirate <06S1975>. A Mitsunobu reaction of 3,4-dihydroxypyrroles was utilized to prepare 3,4dialkylenedioxypyrroles (i.e., 91) <06TL3521>. Et Et O OMe
CO2Me
S
O
O
O N Me 89
S
N
N
N H
t-BuO
EtO 90
O
91
N H
OBn O
92
The large scale preparation of orthogonally protected pyrrole tricarboxylic acid derivatives (i.e., 92) was reported. A key step was the selective α-chlorination of a 2,4-dimethylpyrrole intermediate that was derived from the Knorr pyrrole synthesis.
5.2.4
PYRROLE NATURAL PRODUCTS AND MATERIALS
5.2.4.1
Natural Products and Biologically Active Small Molecules
Pyrrole rings are important structural subunits and recognition elements found in a number of bioactive materials including small molecule natural products and tetrapyrroles (i.e., porphyrins) and related macrocycles. The biosynthesis of naturally occurring pyrroles has been comprehensively reviewed <06NPR517>. The first five proteins involved in the biosynthesis of the prodigiosin pyrrole natural products have been identified <06JACS12600>. The total synthesis and anti-tumor activity of 3,4-diarylpyrrole natural products and related analogues have also been reviewed <06THC53, 06T7213>. Novel halogenated pyrrole natural products continue to be isolated from different marine organisms. Examples of recently isolated pyrroles include 4-bromopyrrole-2carboxyarginine <06JNP125> and the stylissadines (tetrameric dibromopyrrole-imidazoles) <06TL4675> from Stylissa caribica and agesamide A 93 from an Agelas sponge <06OL4235>. The combination of diverse biological activity and structural complexity make pyrrole natural products popular targets in the heterocyclic community. Selected highlights of developments in de novo pyrrole synthesis or reaction methodology developed en route to total syntheses of natural products have been mentioned in previous sections. Pyrrole marine natural product total syntheses that have been published during the last year include agelastatin A 94 <06JACS6054>, ageladine A <06OL1443, 06OL4083>, 12,12dimethylageliferin <06T10182>, cyclooroidin <06TL5561>, dibromophakellstatin <06JOC9431>, dragmacidin F <06CC3769, 06SL3081>, lamellarins (i.e., 76) <06T594,
149
Five-membered ring systems: pyrroles and benzo analogs
06TL3755, 06JOC9440>, manzacidin A <06JACS2174>, oroidin <06OL2961>, and the rigidins <06T8243>. The thermal cyclodimerization of oroidin provided a direct route to rac-cyclooroidin <06OL819>. Non-marine pyrrole natural product total syntheses that have been published during the last year include rhazinilam 95 <06ARK(iii)163, 06JACS10352>, rhazinal 96 <06ARK(iii)163>, and the polygonatines A and B <06OBC1032>. The total synthesis of the latter helped to confirm their structural assignment. Br O
Br H
N NH
O
Br H
N
H O NH HN
HO Me
O 93
N
NH H H NH O
94
BocHN
O NH Et
N
95 R = H 96 R = CHO
R
N H
CO2Me
97
Unnatural lamellarin analogues have been prepared and evaluated as anti-cancer agents <06BMC4627, 06JMC3257>. Additional small molecule pyrroles demonstrating anti-cancer activity include pyrrolopyrrolizinones <06BMC8162> and prodigiosin analogues <06OL4951>. Additional types of biological activity investigated include anti-HIV <06CMC1367, 06CMC1379>, anti-inflammatory <06BMCL3657, 06AP670>, and antimycobacterial <06JMC4946>. Syntheses of the rigid pyrrole amino acid derivatives 97 and the corresponding 5-amino congener were reported <06TL4631>. 5.2.4.2
Macrocycles and Oligopyrroles
The synthesis and biological evaluation of pyrrole macrocycles (i.e., porphyrins, expanded porphyrins, and calixpyrroles) and linear oligopyrroles comprise perhaps the largest body of work published each year that can be classified as pyrrole chemistry. Unfortunately, due to space limitations, the discussion of selected advances in this area could not be included. 5.2.4.3
Non-Oligomeric Materials
The preparation and evaluation of novel borondipyrromethane (BODIPY) derivatives continues to be well studied. Selected types of BODIPY that have been investigated include dyes <06EJO4658, 06CAJ176>, fluorescent sensors <06CC1503, 06JOC3093, 06OL4445, 06OBC776, 06JACS10640>, intracellular phospholipase activity sensors <06ACB65>, copper sensors (i.e., 98) <06JACS10, 06JOC2881>, DNA sequencers <06JACS2542>, photosensitizers <06CC4398>, and luminescent gels <06JACS4548>. To close out the pyrroles section, the pyrrole moiety has been incorporated into novel nonlinear optical chromophores (i.e., 99) <06JACS2142, 06OL3681>.
E.T. Pelkey and J.S. Russel
150 Et Me N F B F N
N
S S
CN
S
NC
S
S N
Me Et
5.2.5
99
98
SYNTHESIS OF INDOLES
As a distinct feature of mother nature’s fundamental amino acid scaffold, and emanating from a variety of biogenic processes, it is no surprise that the indole nucleus has been intimately woven into the diverse and evolving fabric of the natural world. And while a wealth of dedication and precision has been brought to bear by the community of synthetic chemists in efforts to prepare the elaborate interlacing frameworks in which nature has embedded the indole core, the simple five-six fused skeleton of the molecule also continues to inspire the development of creative strategies for its construction <00JCS(P1)1045>. The latter point is well illustrated in a recent series of reports by the Funk group whose imaginative approach to the indole ring system has the delicate aromatic materialize through a well conceived electrocyclic transformation of trienecarbamate precursors, e.g., 100-102 <06JACS4946, 06OL2643, 06OL3403, 06OL4775>. 1. TFA, 93% 2. K2CO3, DMF 100 °C
110 °C, 3h O
100
N BOC
O
DDQ, rt, 16h 88% 101
N BOC
ICH2CO2Me, 71% 3. 4 M NaOH; HCl 93%
N 102
This section of the chapter will highlight recent activity in the implementation of traditional methods and the development of novel strategies for the synthesis of indole alkaloids. A review of practical methods for indole synthesis has appeared <06CR2875>. A few special topics in indole chemistry that have been reviewed include heterocyclic synthesis via palladium-catalyzed oxidative addition <06CR4644>, 1-hydroxy-substituted indoles, tryptamines, and tryptophans <06THC77>, oxidative C-C bond formation in heterocyclic chemistry <06ARK(xi)310>, and monoterpene indole alkaloid biosynthesis <06NPR532>. Other brief monographs of topical interest have appeared including a discussion of the Nicholas approach to natural product hybrids <06CEJ6403> an overview of new principles in medicinal organometallic chemistry <06AG(I)1504>, an account of the synthesis of twelve fluoroindolecarboxylic acids <06EJO2956>, a survey of methoxy group directed augmentation of indoles <06ARK(vii)67>, the synthesis of indole derivatives via isocyanides <06OBC757>, and a kinetic study of indole nucleophilicity <06JOC9088>. Work by the Stoltz group on the synthesis of the pyrazinone dragmacidins has also been documented <06CC3769>. As with the corresponding section on pyrroles, indole syntheses have been categorized utilizing a systematic approach. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the indole forming step (2 examples shown below). In addition, the synthesis of azaindoles,
Five-membered ring systems: pyrroles and benzo analogs
151
and carbazoles will be treated separately. Oxindole synthesis will be covered in tandem with natural product synthesis. Intramolecular Approaches (type I) c
Intermolecular Approaches (type II) c
type Ia
d
d
b e N a H
5.2.5.1
c
type IIac d
b e N a H
b e N a H
Intramolecular Approaches
The classic intramolecular condensation of ortho-(2-oxoalkyl)anilines continues to be a useful strategy for accessing indoles via Ia type cyclization chemistry. Smith and co-workers employed acid-catalyzed cyclodehydration of ketoanilines on route to members of the nodulisporic acid family <06OL1665, 06OL1669>. For example, treatment of ketoaniline 103 with 1,1,1-trifluoroethanol at reflux provided mild access to 2-substituted indole 104, a precursor to the heptacyclic core of (–)-nodulisporic acid D <06OL1669>. A variation of this methodology has been reported by Butin who has prepared indoles via acid catalyzed cyclization of anilines onto ortho-pendant furans, which served as 1,3-diketone equivalents <06TL4113>. Kearney and Vanderwal observed the cyanogen bromide initiated intramolecular cyclization of pyridinyl anilines to afford substituted indoles <06AG(I)7803>. OH
OH
CF3CH2OH
• O
•
O NH2 103
H
reflux, 6h OBn
• O
H
•
OTES 104
N H
OBn OTES
Frejd and co-workers utilized a different tactic for aniline cyclization by first employing a Heck-Jeffery protocol under solvent-free conditions to prepare o-amino dehydrophenylalanine derivatives from o-aminoaryl iodides with the former undergoing a spontaneous Ia cyclization-elimination sequence to afford 2-methoxycarbonyl indoles <06S1183>. Dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST) was used by the Okuma group to promote the cyclization of o-vinyl-N-p-toluenesulfonylanilide to Ntosylindole <06CL1122>. A number of iodine promoted Ia type cyclization reactions have been utilized for indole ring construction. Iodocyclization of o-ethynylanilines, prepared by the Pd/Cu-catalyzed coupling of iodoanilines and terminal acetylenes, was employed by the Larock group in their synthesis of 3-iodoindoles <06JOC62>. Kobayashi and co-workers prepared 1-arylindoles via iodine-mediated endo-cyclization of 2-(arylamino)-α-methylstyrene derivatives <06BCJ1580>. An interesting solvent effect has been observed by Hessian and Flynn who reported selective 5-exo or 6-endo-digonal iodocyclization pathways leading to indoles 106 or quinolines 107, respectively, from common aniline precursors 105 <06OL243>.
E.T. Pelkey and J.S. Russel
152 R' I
107
HO
I2, CH3CN
N R Me I
R'
NMe2
R'
I2, EtOH
O
R
105
106
N Me
R
Several examples of metal-mediated intramolecular ring closures have been reported. Iwasawa and co-workers have accessed the tricyclic core of the mitosenes, e.g., 110, in one pot from N-(o-alkynylphenyl)imines 108 via [3+2] cycloaddition of the Pt(II) or Au(III)containing azomethine ylides 109 with electron rich alkenes <06OL289>. In a related investigation, tungsten-containing vinylazomethine ylides were used to generate indoles with a variety of pendant N- to C2 seven-membered ring systems <06OL895>. Ph N
108
O-t-Bu
N
MS5A, toluene 50 °C OTIPS
Ph
Ph
PtCl2 (3 mol %)
N O-t-Bu OTIPS
109
[Pt]
110
OTIPS
The Nakamura group was able to prepare 2,3-substituted indoles by the electrophilic trapping of indole C3-cuprates that had been generated by the sequential treatment of oalkynylanilines with n-BuLi, ZnCl2, then CuCN•2LiCl <06OL2803, 06AG(I)944>. In an alternative strategy, Lu and co-workers employed Pd(OAc)2 to facilitate a one-pot Sonogashira-Cacchi domino reaction between o-iodoanilines, terminal alkynes, and arylbromides in their preparation of 2,3-substituted indoles <06OL3271>. The Cacchi group made use of Pd2(dba)3 to couple o-(phenylethynyl)trifluoroacetanilide with aryl chlorides in their synthesis of 2,3-disubstituted indoles <06ASC1301>. A palladium catalyzed tandem Buchwald–Hartwig/Heck reaction provided Lautens and co-workers with efficient access to 2-vinylic indoles from gem-dibromovinyl aniline precursors <06OL4203>. Various strategies for indole ring synthesis have relied on the reductive cyclization of osubstituted nitroaryl groups. A synthesis of 7-formyl indoles from 3-methyl-2-nitrobenzyl alcohol has been reported by Satyam and co-workers that employs the Ia type Batcho– Leimgruber reductive cyclization <06SC1051>. The Belley group found that catalytic hydrogenation of (2-nitrophenyl)acetonitriles over Pd/C and (Ph3P)4Pd afforded N-hydroxy-2aminoindoles <06TL159>. An alternative path to N-hydroxyindoles has been reported by the Nicolaou group who observed SnCl2-promoted cyclization of nitroaromatic α,β-unsaturated ketoesters with the trapping of nucleophiles by the incipient α,β-unsaturated nitrone intermediates <06AG(I)5364>. The Hossain group has reported a nice complement to the Reissert indole synthesis that allows for access to 3-substituted, rather than 2-substituted, ethoxycarbonyl indoles. The synthesis proceeds via catalytic reduction of 2-nitroaryl-3hydroxypropenoic acid esters over Pd/C <06JOC4675>. Davawala and co-workers have prepared 3-allylindoles from o-nitrobenzaldehydes using a sequence of Wittig olefination of the aldehyde followed by a Claisen rearrangement in the presence of FeSO4 and NH3 <06TL1003>. As illustrated in the conversion of 111 to 112 below, a variety of indoles bearing chirality at C3 was accessed by O'Shea and co-workers by means of a (–)-sparteine directed enantioselective carbolithiation of 2-propenyl anilines, followed by electrophilic trappingcyclization of the lithio intermediates <06JACS10360>.
Five-membered ring systems: pyrroles and benzo analogs
Ph
153 Ph
NH 1. PhLi, rt, cumene 2. R2Li, (-)-spartene 3
N R3
R1
3. Electrophile (R -X) 4. 2 M HCl
R1
R2
111
112
A few type Ib intramolecular strategies for construction of the indole core have appeared. Opatz and Ferenc have prepared derivatives of indole-3-acetic acid via 5-exo-trig cyclization of α-deprotonated aminonitriles onto the ortho-pendant cinnamic acid side chains <06OL4473>. Minakata, Komatsu, and co-workers have accessed 2,3-substituted indoles from o-stannylmethylated thioanilides 113 or related o-stannylmethylated aryl isothiocyanates through a sequence of 1,5-dipole generation to 114 and subsequent intramolecular cyclization to indole 115 <06OL3693>. An interesting aza-Pauson–Khand reaction of alkynecarbodiimides has been employed by the Mukai group in an approach to the pyrrolo[2,3-b]indol-2-one system on route to (±)-physostigmine <06OL83>. R2
R2
SSnBu3
SnBu3
1
R
R1 N H
N
NH 113
R2
114 R1
S
115
S
The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of α-arylamino imine tautomers prepared from aniline derived α-arylamino ketones, has been used by Menéndez and co-workers for the preparation of 2-arylindoles <06SL91>. R3
R3
R3
I
R3
R3
R3 PdI
R2 R1 116
N H
R2 R1 117
N H
R2 R1 118
N H
Zhao and Larock have described the synthesis of carbazoles, indoles, and dibenzofurans 118 via a Ic type cyclization that follows a sequence of Pd-catalyzed cross-coupling of alkynes and aryl iodides 116, then nitrogen-directed palladium migration to an arylpalladium intermediate 117 that undergoes an intramolecular Mizoroki–Heck ring closure <06JOC5340>. A synthesis of 2-acyl and 2-alkoxycarbonyl-indoles was carried out by Tamariz and coworkers via an intramolecular Friedel–Crafts heteroannulation of enaminone precursors <06SL749>. A Iac type palladium-catalyzed intramolecular indolization of alkyne-tethered 2-chloroanilines has been reported by Lu and co-workers <06OL3573>. Taber and Tian have employed the Neber protocol to prepare α-aryl azirines that underwent thermal rearrangement to afford substituted indoles via a unique Ie type ring closure <06JACS1058>. A variety of substituted N-alkyl and N-aryl indoles have been prepared by Zhao and co-workers who observed Ie cyclization of 2-aryl-3-arylamino-2-
E.T. Pelkey and J.S. Russel
154
alkenenitriles promoted by phenyliodine bis(trifluoroacetate) <06OL5919>. A nice synthesis of stereodefined 3-aryl indolines has been reported by the Pineschi group that involves the intramolecular copper-mediated ring closure of sulfonamidic aryl triflates <06OL2627>. 5.2.5.2
Intermolecular Approaches
A vast array of type IIac ring syntheses have been reported. The Fischer indole synthesis, the tried and true acid catalyzed rearrangement of arylhydrazones derived from the intermolecular condensation of ketones or aldehydes with arylhydrazines, continues to find broad application in synthetic design. Zard and Sharp have applied the Fischer method in a total synthesis of (±)-aspidospermidine <06OL831>. The Rawal group made use of the Fischer protocol to prepare model vindoline substrates to assess a Pd cross-coupling strategy for the synthesis of C-15 vindoline analogues<06JOC7899>. A regioselective Fischer indole synthesis has been reported by Christoffers in which the regiochemistry across the 2,3-bond of the annulated indole products, 120 or 122, is dependent on the relative configuration (cis/trans) of the bicyclic starting ketones 119 or 121 respectively <06SL318>. Liu and coworkers have described a synthesis of 2,3-substituted indoles involving the rearrangement of 3,3-disubstituted indolenines generated from phenylhydrazine and α-disubstituted aldehydes. <06OL5769>. Microwave-assisted Fischer indolization using ZnCl2 in anhydrous triethylene glycol was applied by Lipinska and Czarnocki in their syntheis of 2-(2-pyridyl)indoles on route to derivatives of sempervirine <06OL367>. Microwave technology was also applied by Kapoor and co-workers in their silica-based, solvent-free approach to pyrazolines, tetrahydrocarbazoles, and indoles <06SC2727>. Novel access to arylhydrazones from aryllithiums and α-diazoesters has been reported by the Takamura group <06TL743>. O
NH a)
H
O
H
H
a)
CO2R
CO2R 119
120
HN H
CO2R
CO2R
( )n
( )n
121
122
a) PhNHNH2 (2 equiv), AcOH, TFA, 100 °C
Sonogashira cross-coupling reactions provided strategic entry into a few type IIac annulations. A heterogeneous palladium-catalyzed cross-coupling was used by Djakovitch and co-workers to prepare 2- and 2,3-substituted indoles from 2-iodoaniline and acetylene precursors <06ASC715>. Dorow and co-workers employed a 10:1 ratio of CuI:Cl2Pd(PPh3)2 in their preparation of pyrroloquinolones via Sonogashira coupling/heteroannulation methodology <06OPRD493>. McLaughlin and co-workers have described a one-pot copper-free Sonogashira alkynylation and base-mediated indolization reaction to access 1,2-disubstituted indoles 125 and azaindoles from o-chloroanilines 123 <06OL3307>. A ligand-, copper, and amine-free variant of the Sonogashira coupling was used by Srinivasan and co-workers to access 2substituded indoles <06T5109>. R1 Z 123
R2 NH Cl
H R3 PdCl2(MeCN)2 (1 mol %) X-Phol (3 mol %) K2CO3, MeCN
R2 NH
R1
KOt-Bu (50 mol %)
Z 124
R3
R1
R2 N R3
Z 125
Five-membered ring systems: pyrroles and benzo analogs
155
A few additional Pd-catalyzed schemes have been employed for IIac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of ohaloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. Other examples of type IIac indole syntheses include the Thummel group’s application of the Bartoli reaction for the synthesis of 7-bromoindole from 2-bromonitrobenzene and vinylmagnesium bromide <06JOC7611>, the use of Zn(OTf)2 by Kumar and Liu for the catalytic cyclization of propargyl alcohols with various substituted anilines <06JOC4951>, and the preparation of N-methoxyindoles by Penoni, Nicholas, and co-workers via treatment of nitrosoarenes and alkynes with K2CO3/(CH3)2SO4 <06JOC823>. Aoyama and co-workers have reported a unique entry into substituted indoles 128 from o-acyl-N-tosylanilines 126 that concludes with an intramolecular N-Li insertion of alkylidenecarbene intermediates 127 <06S1249>. O 2
R
R1
TMSCHN2 (1.2 equiv)
LDA or n-BuLi NHTs (2.2 equiv)
R3 126
R1 R2
+
C
R3 127
N Li Ts
E
R1
R2
E N Ts
R3 128
Select examples of Electrophiles = PhCHO, Ac2O, and allyl bromide
Gong and co-workers employed an intermolecular Nenitzescu reaction, a type IIce transformation, for the condensation of a β-amino-α,β-unsaturated ester with 1,4benzoquinone to afford a 5-hydroxyindole derivative <06BMC911>. A type IIae reaction has been reported by Willis and co-workers who prepared Nsubstituted indoles via Pd-catalyzed coupling of 2-(2-haloalkenyl)-aryl halides with a variety of amines <06ASC851>. In an alternative intermolecular approach to ring construction, Tang and Hu have reported a Pd-catalyzed coupling of o-alkynylhalobenzenes with amines to afford 1,2-disubstituted indoles <06ASC846>. 5.2.6 5.2.6.1
REACTIONS OF INDOLES Substitution at C-3/C-2
The development of asymmetric variants of the Friedel–Crafts alkylation at indole C3 has received considerable attention. In this regard, an assortment of chiral bisoxazolines have found steady use in conjunction with copper or zinc Lewis–Acid catalysts. Examples included the use of Zn(II) complexes for the alkylation of indoles with nitroalkenes <06JOC75, 06OL2115>, the use of Cu(II) complexes for promoting the addition of indoles to N-sulfonyl aldimines <06OL1621>, ethenetricarboxylates <06JOC739>, or benzylidene malonates as illustrated for the conversion of indole 129 to 130 with chiral azabisoxazoline ligand 131 <06OL6099>. A review of chiral bis(oxazoline) ligand chemistry has appeared <06CR3561>.
E.T. Pelkey and J.S. Russel
156
Ph
CO2Et Ph 129
N H
CO2Et
CO2Et
Cu(OTf)2/ligand EtOH, 20 °C
CO2Et
130
N H
H N
O N
O N
131 Example ligand
A collection of other chiral agents have been employed in efforts to install asymmetric side-chains at C3. Deng and co-workers made use of bifunctional cinchona alkaloids to promote the enantioselective Friedel–Crafts addition of indoles to aldehydes and α-ketoesters <06OL4063>. Cinchona alkaloid-catalyzed enantioselective addition of indoles to imines has also been reported <06JACS8156>. In an alternative approach to chiral indoles, the Evans group has employed a bis(oxazolinyl)pyridine-scandium(III) triflate complex to promote the enantioselective addition of 4,7-dihydroindole to α,β-unsaturated 2-acyl imidazoles <06OL2249>. In the latter case, oxidation of the substituted dihydroindole products with p-benzoquinone afforded the chiral indole products. Enantioselective Michael addition to α,β-unsaturated ketones was achieved using D-camphorsulfonic acid as a catalyst <06EJO5225>. Enantiomerically pure aziridin-2-yl methanols were used by Bonini and coworkers as organocatalysts for the C3 alkylation of N-methylindole with α,β-unsaturated aldehydes <06TA3135>. A variety of Pd-catalyzed couplings have been used to set new bonds at indole C3. Trost and Quancard employed Pd with an anthracene derived chiral ligand and trialkylboranes to promote the enantioselective C3 coupling of 3-substituted-1-H-indoles and allyl alcohols for the installation C3 quaternary centers <06JACS6314>. This methodology was applied in the synthesis of (–)-esermethole, a key intermediate on route to the Alzheimer’s drug candidate (–)-phenserine. The Ma group has employed Pd in the regiospecific C3 coupling of indoles to electron-deficient alkenes bearing a 2-acetoxymethyl group <06JOC9865>. The βhydroxytryptophan subunit of cyclomarin A was constructed by Spinella and co-workers via Pd-mediated vinylation of N-substituted indole to afford a key C3 acrylic ester <06SL1319>. An indolylboron species, prepared using Pd-catalyzed borylation of 3-iodoindole on solid support, was used by Kasahara and Kondo to prepare bisindolymaleimides <06H(67)95>. A number of other metal-mediated strategies for C3 functionalization have been described. Platinum was utilized by Han and Widenhoefer in the study of the intramolecular asymmetric hydroarylation of C2-tethered unactivated alkenes to generate 2,3-annulated indoles <06OL3801>. Related arylation/carboalkoxylation investigations with Pd have been disclosed <06CEJ2371>. Baba and co-workers used indium trichloride to promote the direct C3 coupling of indoles to benzyl or allylic alcohols <06AG(I)793>. Silver ion was used by the Banwell group to facilitate the coupling of N-methylindole to dibromocyclopropane derivatives in their approach to the polycyclic core structures of hapalindole and fischerindole alkaloids <06OL4959>. In an interesting variation of α-amido sulfone chemistry, the Petrini group has observed the formation of 3-(1-arylsulfonylalkyl) indoles via a clay-promoted Friedel–Crafts reaction <06OL4093>. Other reported routes to C3 substituted indoles include two independent reports of three-component aza-Friedel–Crafts reactions <06OL4939, 06SL96>, the Tudge group’s synthesis of 3-sulfenyl indoles using N-alkyl or arylphthalimides in the presence of catalytic MgBr2 <06OL565>, a photoinduced 1,4-addition of indoles to enones reported by Beauchemin and co-workers <06JOC676>, and the work of Tse and co-workers on the synthesis of bisindoles via ring opening of N-sulfonylaziridines <06OL5761>.
Five-membered ring systems: pyrroles and benzo analogs
157
The investigation of methods for the 2-arylation of indoles received significant attention. Examples include a report by Sanford and co-workers of a mild oxidative method for C2 aryl coupling that involves treatment of indoles 132 with [Ph-I-Ph]BF4 complex 133 under Pdcatalysis at room temperature <06JACS4972>, the use of palladium complexes of imidazolyl carbenes by the Sames group to arylate SEM-protected indoles <06OL1979>, and a report by Denmark and Baird on the cross-coupling of C2 silanolates with aryl iodides and bromides <06OL793>. In an approach that did not involve direct coupling at C2, Bremner and coworkers prepared 2-aryl-5-nitro-1H-indoles from N-acylated indoles via an intramolecular Pd-promoted oxidative cyclization to set the C2 bond, followed by hydrolysis of the isoindolo-indolone tetracyclic intermediates to free indole nitrogen <06BMC857>. BF4 N
H +
5 mol % PdII
I
AcOH, 25 °C
133
132
N 134
The synthesis of 2-vinylindoles continues to be of interest due to the vast potential of these species for further chemical elaboration. In developing a strategy for carbazole synthesis, a Michael-type addition of 4,7-dihydroindole to dimethyl acetylenedicarboxylate was employed to afford, after DDQ oxidation, functionalized 2-vinylindoles <06JOC7793>. In a metal-mediated approach, Nakao, Hiyama, and co-workers prepared propyl-substituted 2vinylindoles from N-protected 3-cyanoindoles via treatment with 4-octyne in the presence of catalytic nickel <06JACS8146>. Aryl, vinyl, and alkynyl substituents were installed by direct coupling with an N-protected 2-trifluoromethanesulfonyloxyindole, prepared from oxindole <06S299>. There have been various reports of efforts to construct indole fused polycyclic frameworks via annulation across N-C2 or C3-C2. Bergman, Ellman, and co-workers have disclosed details of the asymmetric cyclizations of N-allyl-substituted indoles bearing a C3 imine functionality. To promote the transformations, the N-C2 annulations were catalyzed by a chiral rhodium phosphoramidite complex <06OL1745>. The Frontier group made use of a heteroaromatic Nazarov type cyclization between C2 and a C3 pendent α,β-unsaturated βketoester functionality <06OL5661>. In a report by Beccalli and co-workers, seven and eight-membered lactam ring systems were fused across the indole 2,3-bond using Pdcatalyzed intramolecular cyclization of C3 tethered aryl amides <06S2404>. Ferrer and Echavarren employed a gold catalyst to prepare seven- and eight-membered ring systems from C3 tethered alkynes <06AG(I)1105>. X
..
X
X
X N
NCO 135
N Me 4 equiv.
X X N N
O
137
N Me
X X
O 136 X = OMe, SPr
The classic addition of C3 tethered amine derivatives onto C2 of indolium ions has been used to access hexahydropyrrolo[2,3-b]indole frameworks <06OL4303, 06OL6011>. An alternative and unique strategy for accessing similar pyrrolo[2,3-b]indole polycyclics 137 has
E.T. Pelkey and J.S. Russel
158
been investigated by Rigby and Burke who observed [4+1] cyclization of indole-2isocyanates 135 with carbenes <06H(67)643>. An oxidative coupling of an imidazole and a transient indolium ion has been exploited in a macrolactamization across the indole 2,3-π system <06OL1165>. Other annulation strategies are discussed below in the section on natural product synthesis. 5.2.6.2
Substitution at Nitrogen
The relative acidity of NH-indoles continues to stimulate the development of convenient protocols for protection-deprotection schemes. Chakrabarty and Kundu have reported the cleavage of N-Boc indoles under basic conditions using a methanolic solution of potassium carbonate <06SC2069>. The deprotection of N-tosylindoles using cesium carbonate has been reported by Bajwa and co-workers <06TL6425>. The Padwa group has described a method for the photodesulfonylation of indoles <06TL2409>. Alkylation at nitrogen has been achieved by treating indole or pyrrole with alkyl halides in ionic solutions of potassium carbonate in 1-n-butyl-3-methylimidazolium tetrafluoroborate [bmim][BF4] <06TL2435>. Bis-protection of 3,3’-diiodo-2,2’-biindoles with Me, Boc, CO2Et, or SO2Ph has been described by Roy and Gribble <06SC3487>. Me R3
Toluene reflux, 5h N Me
R2 138
HO Me R3
N Me
R2 139
Cr(CO)3
Me R3
N Me
Me H R2
140
Cr(CO)3
Cr(CO)3 3
R = 1,3-dioxolane
Single diastereomer
A few asymmetric transformations have been orchestrated between the indole ring and Nsubstituents. An intriguing stereoselective synthesis of N-aryl indole chromium complexes 138 with axially chiral N-C bonds has been reported by Kamikawa, Uemura, and co-workers <06OL1097>. Stereoselective chromium tricarbonyl migration from N-aryl 138 to the arene ring of indole 139 was observed, with subsequent installation of the asymmetric side-chain at indole C4 of 140 <06OL1097>. Arai and co-workers have employed 2-(ptolylsulfinyl)indoles bearing α,β-unsaturated enones at indole nitrogen as chiral auxiliaries for asymmetric Diels–Alder transformations <06H(68)1025>. An approach to N-C2 annulated indoles has been reported by Ishikura and co-workers that involved cyclization-intramolecular alkyl migration of N-tethered borates <06T1015>. A BF3•Et2O-promoted synthesis of 2-prenylindoles from N-prenylindoles has been described <06OBC3966>. Iodolactonisation used in tandem with a lactone-to-lactam rearrangement was employed by Joseph and co-workers for the conversion of N-allylindole-2-carboxylic acids to N-C2 cyclized diazepine derivatives <06SL2755>. Black and co-workers have achieved N-C7 annulation in the preparation of pyrrolo[3,2,1,hi]indazoles via base promoted cyclization of the 2,4-dinitrophenyl ethers of indole-7-ketoximes <06T6343>. 5.2.6.3
Functionalization of the Benzene Ring
The ability to selectively direct chemistry at indole positions C4 to C7 remains a synthetic challenge. Takayama and co-workers have developed a procedure for masking the 2,3-π bond of indole as a bridged ethylene glycol system that allowed for functionalization of the
Five-membered ring systems: pyrroles and benzo analogs
159
resulting indoline at C5 with halogen, NO2, or methoxy groups <06OL5705>. The ethylene glycol masking procedure was applied to the synthesis of corynanthe type opioid receptor agonists. Selective C-C bond formation at C4 has been achieved by Kita and co-workers who employed a Pummerer-type reaction between 5-sulfinyl indoles and a variety of carbon nucleophiles <06TL1881>. An Ir-catalyzed borylation strategy has been employed by Maleczka, Smith, and co-workers for the selective C7 arylation of NH indoles <06JACS15552>. A synthesis of 7-haloindoles via thallation of N-formylindoline has been described <06CPB788>. The Volk group has observed the formation 3-alkyl-7methyloxindoles during the reductive 3-alkylation of isatin with i-BuOH over Raney Ni <06H(68)539>. 5.2.6.4
Functionalization of the Side-Chain
The nucleophilicity of the indole core, coupled with the relative acidity of indole NH, continues to dictate a need for the development of delicate methods for selective side-chain functionalization. A sequence of hydroboration with 9-BBN followed by Suzuki–Miyaura Pd-coupling has been employed by Ferreira and Stoltz for the elaboration of 3-vinyl indole side-chains <06TL8579>. Gribble and co-workers have described the synthesis of indolylarylmaleimides and heteroaryl varients, staurosproine type indolocarbazole buildingblocks, via treatment of N-methylindole-3-glyoxylamide with methyl aryl acetates in solutions of potassium t-butoxide <06OL4975>. A report from the same group has appeared that describes the conversion of tryptamine to an intriguing bis(indolyl)oxazole analog of the pimprinaphine ring system <06S3948>. Indole-2- or indole-3-aldehydes were converted by Jaisankar and Srinivasan to the corresponding 2- or 3-cyanoindoles by treatment with sodium azide in the presence of aluminum chloride <06S2413>. A lipase-catalyzed enzymatic resolution has been used to generate an optically enhanced (R)-ester pendant on the cyclopentyl ring of a tricyclic 2,3-fused indole <06OPRD592>.
5.2.7
CARBAZOLES AND AZAINDOLES
5.2.7.1 Carbazole Ring Synthesis and Annulation Several reports of carbazole ring synthesis have appeared. A total synthesis of the biscarbazole alkaloid murrastifoline-A has been reported by the Chida group who employed a palladium-catalyzed double N-arylation of 2,2’-dibromobiphenyls to set the carbazole core <06T6792>. Structurally related murrayafoline-A has been prepared by Mai and co-workers via an anionic [4+2] cycloaddition of furoindolones onto methyl crotonate to set the tricyclic carbazole skeleton <06TL1071>. Fusion of an aryl-iron complex with a polyfunctional aniline afforded the central carbazole unit in the enantioselective synthesis of neocarazostatin B by the Knölker group <06CC711>. Oxidative cyclization of a diarylamine with catalytic Pd(II) was employed by the same group to afford several natural carbazole alkaloids bearing 7-hydroxy or –methoxy substituents <06OBC3215>. Lu and co-workers have reported the use of palladium-catalyzed intramolecular oxidative cyclization to access carbazoles from 3(3’-alkenyl)indoles <06OL1319>. Strategies for annulation of carbazole scaffolds have been investigated. Hexacyclic benzofuropyrano- or benzofurofurocarbazoles have been prepared by Chattopadhyay and coworkers via a cascade of sigmatropic rearrangements emanating from 2-hydroxycarbazole tethered aryloxy alkynyl ethers <06SL3358>. The same group reported the conversion of 2-
160
E.T. Pelkey and J.S. Russel
hydroxycarbazoles to a variety of C1-C2 oxepine or N-C1 azepine annulated carbazoles using a sequence of Claisen rearrangement from C2 O-allyl ethers followed by Grubbs’ olefin metathesis chemistry <06TL6895>. An interesting light- and base-meditated ring closure was used to access the aryl fused skeletons naphtho[a]carbazoles and benzo[c]carbazoles from 2- or 3-arylindole precursors <06T2820>. 5.2.7.2 Azaindole Ring Synthesis An intriguing synthesis of 7-azaindoles has been reported by Zheng and Kerr that involves the generation of a tristrifloxy pyridine derivative 142 that undergoes heteroannulation when treated with primary amines. Oxidation of the resulting azaindolines 143 with MnO2 afforded the fully aromatized ring system 144 <06OL3777>. OTf
O NH O 141
TfO Tf2O
N
OTf
pyridine
MnO2
RNH2
142
TfO
N 143
N R
TfO
N 144
N R
The Leimgruber–Batcho reaction was employed by Wang and co-workers to prepare 3substituted-4- and 6-azaindoles in one pot from o-methylnitropyridine, N,Ndimethylformamide dimethyl acetal, and electrophilic alkyl or acyl groups <06TL5653>. Synthesis of 4-substituted 7-azaindoles has been achieved by the Thutewohl group via Pdcoupling of anilines or phenols to C4 chlorides <06S629>. A synthesis of 7-azaserotonin from 7-azaindole has been reported by Chou and co-workers <06JACS14426>. 5.2.8 5.2.8.1
INDOLE NATURAL PRODUCTS Natural Products Isolation and Characterization
Isolation and characterization of new indole alkaloids remains a fruitful avenue for the discovery of agents with the potential for biomedical application. The virtues of this age-old process, in light of advances in combinatorial chemistry, were brought to the community as part of the 231st ACS National Meeting symposium, Modern Natural Products Chemistry and Drug Discovery <06ORGN467>. Examples of indole natural products that have recently been identified include the indoloquinone containing indoleamine-2,3-dioxygenase inhibitor exiguamine A from the marine sponge Neopetrosia exigua <06JACS16046>, the azepino-indole hyrtiazepine from the Red Sea marine sponge Hyrtios erectus <06JNP1676>, oxazinin-4, an isolate of the toxic mussel Mytilus galloprovincialis <06T7738>, the oxazolone tethered indole almazolone from the red alga Haraldiophyllum sp. <06T1165>, the cytotoxic, tripeptide-derived chaetominine from the Chaetomium fungus <06OL5709>, malbrancheamide, an brevianamide type indole with fused bicyclo[2.2.2]diazaoctane system from the fungus Malbranchea aurantiaca <06T1817>, the cytotoxic cytochalasan-type alkaloid chaetoglobosin U from endophytic fungus Chaetomium globosum <06JNP302>, an antiparasitic pyrimidine-linked β-carboline from the plant Annona foetida <06JNP292>, three bridged polycyclic terpenoid alkaloids from the stem-bark and root of Winchia calophylla <06JNP18>, three aspidospermidine-type alkaloids from the leaves of Kopsia officinalis <06HCA515>, the pentacyclic monoterpenoid arboflorine, isolated from the stem bark of Kopsia arborea <06OL1733>, four oxindole
161
Five-membered ring systems: pyrroles and benzo analogs
alkaloids from the bark of Cinnamodendron axillare <06JNP1517>, four related monoterpenoid oxindole alkaloids from the leaves of Gelsemium elegans <06OL3085, 06JNP715>, the unique spiro thiazole containing antifungal agent erucalexin, isolated from the leaves of the dog mustard Erucastrum gallicum <06OBC691>, and two indoloquinazoline alkaloids extracted from Wu-zhu-yu, the dried fruits of China's Evodia rutaecarpa <06H(68)1691>. 5.2.8.2
Indole Alkaloid Total Synthesis
The diversity of architectural types and vast array of biological activities continues to stimulate intense interest in the area of indole natural product total synthesis. A selection of completed works in total synthesis includes the DNA alkylating antitumor agents (+) and ent(–)-yatakemycin and duocarmycin SA <06JACS15683, 06JACS7136>, the bromo-indolinine chartelline C with spyrocyclic β-lactam and tethered imidazole functionality <06JACS14028>, the telomerase inhibitors dictyodendrin B, C, and E <06JACS8087>, the cyclic peptide stephanotic acid methyl ester <06OL1975>, cytotoxic (±)-subincanadine F with its distinctive 1-azabicyclo[4.3.1] skeleton <06JOC9495>, cytotoxic peduncularine with 6-azabicyclo[3.2.1]octene framework <06BCJ1552>, the ergot-alkaloids (+)-setoclavine, (+)isosetoclavine, and (–)-9,10-dihydroisosetoclavine <06H(67)291>, the isoquinuclidine containing (–)-(19R)-ibogamin-19-ol <06HCA542> and (+)-catharanthine <06AG(I)5334>, the antibacterial N-methyl-2,4-dibromoindole <06JNP1596>, the bis-indole alkaloids dragmacidin A, B, and C <06S49>, the neuronal cell protecting carbazomadurin B <06SL651>, the antioxidant (–)-neoechinulin A <06SL677>, and (S)-Cypridina luciferin <06TL753>.
N N N BnO N Me CO2Me O
MeO 145
O
O
O
N
N Et
MeO
MeO O
180 °C
N Me 146
Et OBn
OH N Me
Et OAc CO2Me
(−)-Vindoline 147
A virtue of the practice of indole natural product total synthesis is the concurrent development of general or fortuitous discovery of intriguing synthetic methodology. Boger and co-workers have disclosed the details of an intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles <06JACS10589> that has been employed in the total synthesis of (–)- and ent-(+)-vindoline <06JACS10596, 06AG(I)620>. For example, the inverse electron demand Diels–Alder cycloaddition ([4+2]) of the tethered oxadiazole 145 is followed, after loss of nitrogen, by a 1,3-dipolar cycloaddition ([3+2]) across the indole 2,3bond to stitch up the C ring of the core pentacyclic frame 146 of (–)-vindoline 147. In an alternative approach to annulation across the indole 2,3-π system, Padwa and coworkers have reported approaches to the pentacyclic and hexacyclic frameworks of the aspidosperma and kopsifoline alkaloids respectively that involve as the key step a Rh(II)promoted cyclization-cycloaddition cascade <06OL3275, 06OL5141>. As illustrated in their approach to (±)-aspidophytine 150, Rh2(OAc)4-catalyzed cyclization of a diazo ketoester 148 affords a carbonyl ylide dipole that undergoes [3+2]-cycloaddition across the indole 2,3-π bond to generate 149 <06OL3275>.
162
E.T. Pelkey and J.S. Russel
O
O N O MeO
CO2t-Bu
N N2 O OMe Me CO Me 2
O N
Rh(II)
N
O
MeO
N OMe Me
O
MeO
149
148
O
O
CO2t-Bu N H OMe Me Aspidophytine 150
In the course of their investigation of the enantioselective total synthesis of avarainvillamide and the stephacidins, the Baran group has developed a method for the dehydrogenation of tryptophan as well as a one-step tryptophan synthesis from pyroglutamate and substituted aniline precursors <06JACS8678>. On route to the Erythrina alkaloid 3-dimethoxyerythratidinone, Wang and Padwa encountered the interesting acid catalyzed rearrangement of lactam 151 to the tetracyclic hydroxyindole 153 via the lactone 152 <06OL601>. TBSO
O
CO2Me
HO OMe
O
O MeO
O
N
O
TfOH
H N
40 °C, 1h
MeO
OMe
N
OMe
OMe 152
151
153
The Bennasar group has reported a regioselective 6-endo reductive cyclization of 2indolylacyl radicals, generated from 154, to afford entry into the tetracyclic ring system 155 found within guatambuine 156 <06JOC1746, 06OL561>. Me N H
Me N
Me
Me N
n-Bu3SnH COSePh
AIBN
N Me 154
N Me 155
H O
(2:1 trans-cis)
N H
Me
Guatambuine 156
Strategies for the synthesis of the core structures of several natural products have been reported. In developing a biomimetic approach toward the synthesis of haplophytine, Corey and co-workers have investigated the direct coupling of two indole partners in the form of an aspidophytine mimic and a tetracyclic canthiphytine analog <06OL3117>. A selection of other studies include a biomimetic approach to the pentacyclic substructures of perophoramidine and communesin <06OL2187>, an aza-ortho-xylylene route to the communesin ring system <06OL3995>, synthesis of the tetracyclic core of tronocarpine <06OL4561>, a synthesis of the western half of the tremorgenic lolicines and lolitrems <06OL2209>, an approach to the bicyclo[4.3.1]decane skeleton of welwistatin <06OL5287>, a route to the tetracyclic core of koumine <06OL1081>, construction of the pentacyclic core of β-carboline subincanadine B <06OL115>, a synthesis of the tryptophan core of the celogentin/morodin family of cyclic peptides <06AJC819>, an enantioselective synthesis of
Five-membered ring systems: pyrroles and benzo analogs
163
the quaternary stereocenter bound to C7 of lyngbyatoxin A <06OBC4292>, an approach to the pentacyclic pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine framework of arnoamines A and B <06TL7819>, and a biomimetic approach to the furanobisindole core of phalarine <06TL4839>. 5.2.8.3 β-Carboline and Tetrahydro-β-carboline Total Synthesis The ubiquitous presence in nature and medicinal value of the tryptophan derived βcarbolines has prompted a wealth of synthetic activity. Recent efforts in carboline synthesis have been documented by Love <06THC93>. A review of strategies for the synthesis of the manzamine alkaloids has appeared <06THC255>. Martin and co-workers have described a general approach to corynanthe indole alkaloids, including a total synthesis of dihydrocorynantheol <06JOC6547>. A strategy for preparing zwitterionic sempervirine type indolo[2,3-a]quinolizine alkaloids has been documented <06T5736>. Other select examples of completed works in carboline and tetrahydro-β-carboline total synthesis include, (S)brevicolline <06OL3549>, (+)-macroline and alstonerine <06JOC8884>, (–)-normalindine <06JOC8761>, (–)-vincapusine <06JOC3768>, (–)-subincanadines A and B <06OL4605>, (±)-alloyohimbane <06OL3033>, ent-dihydrocorynantheol <06OL1533>, vallesamidine <06HCA249>, (+)-12b-epidevinlantirhine <06TL5737>, and (+)-Na-methylpericyclivine <06OL1017>. A few intriguing developments in the area of tetrahydro-β-carboline synthetic methodology include the report of a catalytic asymmetric Pictet–Spengler reaction <06JACS1086> and an enantioselective Pd-catalyzed intramolecular allylic alkylation of indoles <06JACS1424>. A one-step synthesis of 1-substituted-β-carbolines from Ltryptophan has appeared that bypassed the tetrahydro intermediate <06T10900>. 5.2.8.4
Oxindole Total Synthesis
Oxindoles and spirocyclic variants represent another general class of indole alkaloids that have received considerable attention as synthetic targets as well as key intermediates in natural product synthesis. Trost and Brennan have constructed the stereogenic quaternary center of deceptively simple horsfiline using a palladium-catalyzed asymmetric allylic alkylation of an oxindole nucleophile <06OL2027>. Weinreb and co-workers employed an oxindole spiro-β-lactam in their approach to chartelline A <06JOC3159, 06OL1779>. The Wood group has completed work on (±)-welwitindolinone A isonitrile <06JACS1448>. As illustrated below, the spiro-oxindole framework 159 was set via α-deprotonation of the isonitrile 158 with subsequent cyclization of the resulting anion onto the isocyanate <06JACS1448>. Other completed works in oxindole or spiroindole natural product synthesis include convolutamydines B and E <06OL677>, (±)-strychnofoline <06CEJ8208>, (±)dehaloperophoramidine <06AG4317>, (–)-flustramines A and B and (–)-flustramides A and B <06CC420>, (+)-alline <06TL5379>, and (R)-convolutamydine A.
164
E.T. Pelkey and J.S. Russel
Cl Me
Cl Me H O
H Me
N H
Me
COCl2
CN
Et3N, 0 °C
H
Cl Me H Me Me
R2N
THF -78 °C
158
H Me Me O
CN
N C O
NH2 157
LiHMDS
N H 159
Concurrent with efforts in the realm of oxindole natural products, a high density of work has been directed toward the development of supporting methodology for application to total synthesis. A selection from the multitude of reported works include the investigation of the diastereoselection in the formation of spirocyclic oxindoles by the intramolecular Heck reaction <06JOC2587, 06JOC2600>, the Lewis acid-catalyzed enantioselective C3 hydroxylation of oxindoles <06JACS16488>, the stereoselective alkylation of oxindole enolates <06JOC8559>, the tandem intramolecular Heck cyclization/carbonylation of acrylamides on route to perophoramidine and the communesins <06JOC8891>, the molybdenum-catalyzed asymmetric allylation of 3-alkyloxindoles for the formal synthesis of (–)-physostigmine <06JACS4590>, the addition of isatins to dimethoxycarbene-DMAD zwitterion to afford spirodihydrofurans <06JOC2313>, the diastereoselective synthesis of spirocyclic oxindoles via intramolecular Ullmann coupling and Claisen rearrangement <06AG(I)2274>, the rhodium-catalyzed asymmetric addition of aryl-and alkenylboronic acids to isatins <06AG(I)3353>, the synthesis of 2-phenylindoxyls via basic hydrolysis of 3acetoxy indoles <06ARK(xi)37>, the stereoselective synthesis of spiro-γ-butyrolactones from isatins <06OL507>, the synthesis of 3-acyloxindoles via CuI/L-proline-catalyzed intramolecular arylation of β-keto amides <06OL6115>, a domino carbopalladation/C-H activation/ C-C bond formation leading to the synthesis of unsymmetrically substituted 3(diarylmethylenyl)indolinones from anilides <06OL4927>, the asymmetric synthesis of spirocyclic oxindoles via chiral indole-2-sulfoxides <06OL4137>, the rhodium-catalyzed addition of arylboronic acids to isatins for the preparation of 3-aryl-3-hydroxyoxindoles <06OL2715>, and the synthesis of diversely functionalized oxaspirocyclic oxindoles using Barbier-type carbonyl-additions to isatins in sequence with metal mediated cyclization to spiro-dihydrofurans <06JOC2346>. 5.2.9 BIOCHEMICAL AND MEDICINAL CHEMISTRY 5.2.9.1 Indole Alkaloid Biosynthesis Indole alkaloids have had a rich history in the designs of chemists hoping to understand, mimic, and regulate a varied host of biochemical systems. Details regarding the biosynthetic pathway of the tryptophan derived antitumor agents rebeccamycin and staurosporine have been reported by the Walsh group <06JACS12289> as well as by Sherman and co-workers <06JACS724>. May and Stoltz have evaluated commonalities in the structure and biosynthetic origins of the cytotoxic calycanthaceous alkaloids, the communesins, and nomofugin <06T5262>. An investigation of the biosynthesis of the antitumor-antibiotic echinomycin has been disclosed <06OL4719>. Pedras and Okinyo have reported on the biosynthesis of erucalexin, a member of the crucifer phytoalexins, which have a putative role
Five-membered ring systems: pyrroles and benzo analogs
165
in the regulation of carcinogen metabolism <06CC1848>. Related investigations of the metabolism of crucifer phytoalexins have appeared <06OBC3526, 06OBC2581, 06BMC4958>. A reverse prenyltransferase has been investigated in conjunction with studies of the biosynthesis of the ergot alkaloid precursor fumigaclavine A <06CBC158>. 5.2.9.2
Medicinal Applications of Indole Alkaloids
In the realm of cancer chemotherapy, indoles have been screened as potential regulators of protein kinase activity <06JMC789, 06JMC1217, 06JMC2681, 06JMC3101, 06JMC4638, 06JMC4896, 06JMC7549>, as antimitotic agents <06JMC1910, 06JMC6273, 06CMC1106>, as angiogenesis inhibitors <06JMC1271, 06JMC2143>, antivascular agents <06BMC4410>, as regulators of DNA function <06JMC1442, 06JACS143, 06AG(I)6570>, and as ligands for various other protein and enzymatic targets <06JMC684, 06JMC6922, 06JMC7239, 06JMC7307, 06BMC464, 06BMCL6273>. A fundamental study of nucleophilic addition into a mitosene-like cyclopropyl quinone methide reductive alkylating agent has been described <06JOC5855>. Indoles have been investigated as potential regulators of a variety of other important disease states including Alzheimer’s disease <06JMC459, 06JMC7588>, diabetes <06JMC6421>, obesity <06JMC4023>, hypertension <06JOC2760, 06CMC96>, hepatitis B and C <06BMC911, 06JMC6950>, HIV <06JMC3172, 06BMC2106, 06BMC2109>, and malaria <06OL2591, 06OL3407>. Several studies of anti-inflammatory agents have been disclosed <06JMC135, 06JMC2611, 06JMC2858, 06JMC4512, 06JMC4327, 06JOC3718, 06BMCL3241, 06BMCL4483>. In the area of neuropsychiatric disorders, indoles were investigated as ligands for dopamine/serotonin receptors <06JMC760, 06JMC4785, 06JMC6408, 06H(68)713, 06BMC3794, 06TL943>, galanin receptors <06JMC3757>, GABA receptors <06JMC2489>, and melatonin receptors <06JMC3509, 06CMC1099>.
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Five-membered ring systems: pyrroles and benzo analogs
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06T8533 06T10130 06T10182 06T11531 06T11740 06T12375 06TA107 06TA3135 06THC53 06THC77 06THC93 06THC255 06TL159 06TL743 06TL753 06TL799 06TL943 06TL1071 06TL1469 06TL1881 06TL2151 06TL2409 06TL2435 06TL2517 06TL2605 06TL3521 06TL3535 06TL3693 06TL3755 06TL3893 06TL4113 06TL4631 06TL4683
E.T. Pelkey and J.S. Russel
R. Pathak, J.M. Nhlapo, S. Govender, J.P. Michael, W.A.L. van Otterlo, C.B. de Koning, Tetrahedron 2006, 62, 2820. M.M.M. Raposo, A.M.R.C. Sousa, A.M.C. Fonseca, G. Kirsch, Tetrahedron 2006, 62, 3493. S.S. Palimkar, P.H. Kumar, R.J. Lahoti, K.V. Srinivasan, Tetrahedron 2006, 62, 5109. J.A. May, B. Stoltz, Tetrahedron 2006, 62, 5262. T.M. Lipinska, Tetrahedron 2006, 62, 5736. B. Metten, M. Kostermans, G. Van Vaelen, M. Smet, W. Dehaen, Tetrahedron 2006, 62, 6018. J. Ruiz, E. Lete, N. Sotomayor, Tetrahedron 2006, 62, 6182. T.D. Wahyuningsih, K. Pchalek, N. Kumar, D.S. Black, Tetrahedron 2006, 62, 6343. T. Kitawaki, Y. Hayashi, A. Ueno, N. Chida, Tetrahedron 2006, 62, 6792. F. Bellina, R. Rossi, Tetrahedron 2006, 62, 7213. P. Ciminiello, C. Dell’Aversano, E. Fattorusso, M. Forino, S. Magno, F.U. Santelia, V.I. Moutsos, E.N. Pitsinos, E.A. Couladoouros, Tetrahedron 2006, 62, 7738. J.T. Gupton, E.J. Banner, A.B. Scharf, B.K. Norwood, R.P.F. Kanters, R.N. Dominey, J.E. Hempel, A. Kharlamova, I. Bluhn-Chertudi, C.R. Hickenboth, B.A. Little, M.D. Sartin, M.B. Coppock, K.E. Krumpe, B.S.Burnham, H. Holt, K.X. Du, K.M. Keertikar, A. Diebes, S. Ghassemi, J.A. Sikorski, Tetrahedron 2006, 62, 8243. Y. Aoyagi, T. Mizusaki, M. Shishikura, T. Komine, T. Yoshinaga, H. Inaga, A. Ohta, K. Takeya, Tetrahedron 2006, 62, 8533. B. Temelli, C. Unaleroglu, Tetrahedron 2006, 62, 10130. I. Kawasaki, N. Sakaguchi, A. Khadeer, M. Yamashita, S. Ohta, Tetrahedron 2006, 62, 10182. B. Jolicoeur, E.E. Chapman, A. Thompson, W.D. Lubell, Tetrahedron 2006, 62, 11531. H. Chochois, M. Sauthier, E. Maerten, Y. Castanet, A. Mortreux, Tetrahedron 2006, 62, 11740. C. Biaggi, M. Beaglia, L. Raimondi, F. Cozzi, Tetrahedron 2006, 62, 12375. P. Breistein, S. Karlsson, E. Hedenström, Tetrahedron Asymmetry 2006, 17, 107. B.F. Bonini, E. Capitò, M. Comes-Franchini, M. Fochi, A. Ricci, B. Zwanenburg, Tetrahedron Asymmetry 2006, 17, 3135. J.T. Gupton, Top. Hetercycl. Chem. 2006, 2, 53. M. Somei, Top Heterocycl Chem. Rep. 2006, 6, 77. Published online. B.E. Love, Top. Heterocycl. Chem. 2006, 2, 93. A. Nishida, T. Nagata, M. Nakagawa, Top. Heterocycl. Chem. 2006, 5, 255. M. Belley, E. Sauer, D. Beaudoin, P. Duspara, L.A. Trimble, P. Dubé, Tetrahedron Lett. 2006, 47, 159. E. Yasui, M. Wada, N. Takamura, Tetrahedron Lett. 2006, 47, 743. C. Wu, K. Kawasaki, S. Ohgiya, Y. Ohmiya, Tetrahedron Lett. 2006, 47, 753. B.S. Gourlay, P.P. Molesworth, J.H. Ryan, J.A. Smith, Tetrahedron Lett. 2006, 47, 799. C. Jin, J.P. Burgess, M.B. Gopinatha, G.A. Brine, Tetrahedron Lett. 2006, 47, 943. D. Mal, B. Senapati, P. Pahari, Tetrahedron Lett. 2006, 47, 1071. M. Kobayashi, M. Tanabe, K. Kondo, T. Aoyama, Tetrahedron Lett. 2006, 47, 1469. S. Akai, N. Kawashita, Y. Wada, H. Satoh, A.H. Alinejad, K. Kakiguchi, I. Kuriwaka, Y. Kita, Tetrahedron Lett. 2006, 47, 1881. E. Bellur, P. Langer, Tetrahedron Lett. 2006, 47, 2151. Hong, X.; J.M. Mejía-Oneto, S. France, A. Padwa, Tetrahedron Lett. 2006, 47, 2409. Y.R. Jorapur, J.M. Jeong, D.Y. Chi, Tetrahedron Lett. 2006, 47, 2435. M.A. Guerrero, L.D. Miranda, Tetrahedron Lett. 2006, 47, 2517. K. Dairi, S. Tripathy, G. Attardo, J.-F. Lavallée, Tetrahedron Lett. 2006, 47, 2605. K. Zong, L.B. Groenendaal, J.R. Reynolds, Tetrahedron Lett. 2006, 47, 3521. D. Prajapati, M. Goahin, B.J. Gogoi, Tetrahedron Lett. 2006, 47, 3535. A.I. Mikhaleva, A.B. Zaitsev, A.V. Ivanov, E.Y. Schmidt, A.M. Vasil’tsov, B.A. Trofimov, Tetrahedron Lett. 2006, 47, 3693. T. Yamaguchi, T. Fukuda, F. Ishibashi, M. Iwao, Tetrahedron Lett. 2006, 47, 3755. Q. Yang, X.-Y. Li, H. Wu, W.-J. Xiao, Tetrahedron Lett. 2006, 47, 3893. A.V. Butin, Tetrahedron Lett. 2006, 47, 4113. T.K. Chakraborty, S.P. Udawant, S. Roy, B.K. Mohan, K.S. Rao, S.K. Duta, A.C. Kunwar, Tetrahedron Lett. 2006, 47, 4631. C. Kalinski, M. Umkehrer, J. Schmidt, G. Ross, J. Kobl, C. Burdack, W. Hiller, S.D. Hoffmann, Tetrahedron Lett. 2006, 47, 4683.
Five-membered ring systems: pyrroles and benzo analogs
06TL4839 06TL5341 06TL5379 06TL5383 06TL5475 06TL5481 06TL5561 06TL5653 06TL5737 06TL5793 06TL6425 06TL6895 06TL7323 06TL7541 06TL7819 06TL8579
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C. Chan, C. Li, F. Zhang, S.J. Danishefsky, Tetrahedron Lett. 2006, 47, 4839. A. Bhattacharya, N.C. Patel, R.E. Plata, M. Peddicord, Q. Ye, L. Parlanti, V.A. Palaniswamy, J.A. Grosso, Tetrahedron Lett. 2006, 47, 5341. T. Kawasaki, W. Takamiya, N. Okamoto, M. Nagaoka, T. Hirayama, Tetrahedron Lett. 2006, 47, 5379. J. Chen, H. Wu, Z. Zeng, C. Jin, X. Zhang, W. Su, Tetrahedron Lett. 2006, 47, 5383. P.J.S. Gomes, C.M. Nunes, A.A.C.C. Pais, T.M.V.D. Pinho e Melo, L.G. Arnaut, Tetrahedron Lett. 2006, 47, 5475. A. Bhattacharya, S. Cherukuri, R.E. Plata, N. Patel, V. Tamez, Jr., J.A. Grosso, M. Peddicord, V.A. Palaniswamy, Tetrahedron Lett. 2006, 47, 5481. J. Patel, N. Pelloux-Léon, F. Minassian, Y. Vallée, Tetrahedron Lett. 2006, 47, 5561. J. Zhu, H. Wong, Z. Zhang, Z. Yin, N.A. Meanwell, J.F. Kadow, T. Wang, Tetrahedron Lett. 2006, 47, 5653. S.M. Allin, J.S. Khera, J. Witherington, M.R.J. Elsegood, Tetrahedron Lett. 2006, 47, 5737. H. Sato, K. Hiroi, Tetrahedron Lett. 2006, 47, 5793. J.S. Bajwa, G.-P. Chen, K. Prasad, O. Repic, T.J. Blacklock, Tetrahedron Lett. 2006, 47, 6425. S.K. Chattopadhyay, S.P. Roy, D. Ghosh, G. Biswas, Tetrahedron Lett. 2006, 47, 6895. R.S. Kusurkar, S.K. Nayak, N.L. Chavan, Tetrahedron Lett. 2006, 47, 7323. J.-i. Setsune, M. Toda, K. Watanabe, P.K. Panda, T. Yoshida, Tetrahedron Lett. 2006, 47, 7541. O.S. Radchenko, N.N. Balaneva, V.A. Denisenko, V.L. Novikov, Tetrahedron Lett. 2006, 47, 7819. E.M. Ferreira, B.M. Stoltz, Tetrahedron Lett. 2006, 47, 8579.
176
Chapter 5.3 Five-membered ring systems: furans and benzofurans Xue-Long Hou Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China.
[email protected] Zhen Yang Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry, Peking University, Beijing 100871, China.
[email protected] Kap-Sun Yeung Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, P.O.Box 5100, Wallingford, Connecticut 06492, USA.
[email protected] Henry N.C. Wong Department of Chemistry, Center of Novel Functional Molecules, Institute of Chinese Medicine and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis,† The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
[email protected] and Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China.
[email protected] † An Area of Excellence of the University Grants Committee (Hong Kong).
___________________________________________________________________________ 5.3.1 INTRODUCTION This article aims to review papers that were published in 2006 on reactions and syntheses of furans, benzofurans and their derivatives. Two reviews have summarized the syntheses of furans <06OBC1627> and tetrahydrofurans <06EJO1627>. Another review <06CJO1613> records the progress of transition metal-catalyzed asymmetric ring opening of oxabenzonorbornadienes. Like 2005, many new naturally occurring molecules containing tetrahydrofuran and dihydrofuran rings were identified in 2006. References on compounds whose biological activities were not mentioned are: <06HCA64; 06HCA73; 06JA3148; 06JNP1098; 06JNP1721; 06JNP1728; 06OL3613; 06P735; 06P759; 06P965; 06T4743; 06TL4623>. Articles on those naturally occurring compounds containing tetrahydrofuran or dihydrofuran skeletons whose biological activities were assessed are: <06CJO1667; 06JA11916; 06JNP274; 06JNP295; 06JNP671; 06JNP957; 06JNP1077; 06JNP1249; 06JNP1271; 06JNP1289; 06JNP1543; 06OL991; 06OL4513>.
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Five-membered ring systems: furans and benzofurans
References on those furan-containing compounds whose biological activities were not mentioned are: <06JNP1083; 06JNP1086; 06JNP1310; 06JNP1734; 06JNP1782; 06P965; 06T4988>. Naturally occurring compounds containing furan skeletons whose biological activities were assessed were mentioned in the following papers: <06JNP68; 06JNP113; 06JNP1749; 06OL701; 06OL4935; 06P452; 06P1957; 06P2288; 06TL4007>. References of those benzo[b]furan- or dihydrobenzo[b]furan-containing compounds whose biological activities were not mentioned are: <06HCA117; 06HCA1000; 06HCA1062; 06H(68)93; 06H(68)159; 06JNP876; 06OL2269; 06P459; 06P743; 06P2146>. References on those naturally occurring compounds containing benzo[b]furan or dihydrobenzo[b]furan skeletons whose biological activities were assessed are: <06HCA127; 06JNP121; 06JNP138; 06JNP229; 06JNP261; 06JNP299; 06JNP397; 06JNP1209; 06JNP1826; 06P307; 06TL1505; 06TL3685>. 5.3.2 REACTIONS 5.3.2.1 Furans Several examples reported in 2006 demonstrate that 2-substituted furans underwent spirocyclization at the 2-position. As illustrated in the scheme below, the reaction of a furan tethered at the 2-position to an iminium ion gave a spiro-2,5-dihydrofuran derivative as the sole diastereoisomer. This spirocyclization, which proceeded irrespective of the length of the carbon linker, was employed to construct the ABC tricyclic core of manzamine A <06OL27>. t
BuMe 2SiO
O
tBuMe
2SiO
HOAc OH
BsN
NBoc
PhMe r.t., 72 h 80%
O
OH
BsN NBoc
Spirocyclization was also the reaction pathway under radical conditions if furan was tethered to a radical precursor at the 2-position, as shown below <06CC665>. EtOSCS
O NtBu
O
O
Lauroyl peroxide MeO
ClCH2CH2Cl MeOH 76%
O
NtBu
When furans were tethered to silyl enol ethers at the 2-position, spiroannulation also occurred at the 2-position under electrochemical conditions <06CC194>, as exemplified below. The formation of the kinetic products is the result of the higher nucleophilicity of the furan C2-position.
Me3 SiO
O
carbon anode LiClO4 2,6-lutidine
H
MeOH− iPrOH
H
O
H
+
O
O
HO
i
O Pr 62%
OiPr 23%
178
X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
The scope of the ring-opening/recyclization of furan-containing substrates via the trapping of the transient oxonium ions, generated by the protonation of furan nucleus under strongly acidic conditions, by pendent nucleophiles was expanded <06TL4113; 06TL4117; 06JHC623; 06JHC1195>. A new example is illustrated below <06SL3431>. O
O NHNH2
N
N
p−TsOH Cl
Cl
O C6H6 reflux, 10 min 35%
O
O
2-Trimethylsilyloxyfurans were employed as C5-dianion equivalents in the spiroannulation with bi-functional ortho-esters to provide spirobutenolide derivatives <06OL3705>. When the second step was performed under radical conditions, instead of using base, cis-fused bicyclo[3.n.0]lactones were formed <06CC1200>. An interesting example is illustrated below. Br
+ Me 3SiO
O
ZnCl 2
EtO EtO
OEt
Br
O
CH 2Cl2 − 78 °C to r.t. 80%
O EtO
(Me 3Si)3SiH AIBN
OEt
C6 H6 reflux 90%
H O O
OEt H OEt
2-Triisopropylsilyloxyfurans were effective nucleophiles for the vinylogous Mannich addition to iminium ions that were formed by Rh2(cap)4-catalyzed oxidation of N-alkyl groups by THYDRO <06JA5648>. A stereoselective addition of 2-trimethylsilyloxyfurans to aryl aldehydes-derived aldimines employing a chiral phosphine/Ag complex as catalyst was developed <06AG(I)7230>. The prototypical example is shown below. tBu
N
H N
O (1 mol%) AgOAc (1 mol%) iPrOH (1.1 equiv.) PPh 2
MeO
+
N Ph
H
O
Me 3SiO
THF −78 °C, 18 h under air 82% > 98% de, 96% ee
OMe
MeO HN Ph O O
A Lewis acid-catalyzed vinylogous Mukaiyama aldol reaction between 2-trialkylsilyloxyfurans and α-substituted ketones proceeded diastereoselectively <06OL2909>. An organocatalytic addition of 2-trimethylsilyloxyfuran to aldehydes using 10 mol% of 1,3-bis(3-(trifluoromethyl)phenyl)urea provided adducts with modest threo selectivity <06TL8507>. A syn-selective, enantioselective, organocatalytic vinylogous Mukaiyama-Michael addition of 2-trimethylsilyloxyfuran to (E)-3trimethylsilyl-acrylaldehyde using MacMillan’s chiral amine catalyst was adopted to prepare a key butenolide intermediate in one formal total synthesis of
179
Five-membered ring systems: furans and benzofurans
campactin <06OL597>. A diastereoselective aldol addition of 2-trimethylsilyloxyfuran to an αchiral aldehyde, a key transformation in a total synthesis of (−)-rasfonin, was obtained by using a chiral oxazaborolidine as illustrated below <06JA11032>. H Ph(3,5-Me2) Ph(3,5-Me 2)
N
TfO H
O Me3 SiO
O
+ H
B 2-tol (48 mol%)
OH O
CH2Cl2 O −78 °C, 18 h 81% threo : erythro = 20:1 > 20:1 threo dr
Furan that was loaded on a soluble dendritic polyglycerol support could be efficiently oxidized electrochemically to a 2,5-dihydro-2,5-dimethoxyfuran, which served as an intermediate in the synthesis of a pyrrole library <06OL403>. 2,5-Diphenylfurans were found to oxidize to cis-enediones by Selectfluor in aqueous THF, presumably through the action of in situ-generated HOF <06TL6849>. 2-(5-Methoxyfuranyl)ruthenium complexes were readily oxidized by air to enediesters <06EJI649>. As shown below, the marine diterpene bipinnatin J was converted to intricarene by a biomimetic approach that involved an Achmatowicz-type oxidation of its 2-hydroxymethylfuran moiety to form an oxidopyrylium ion intermediate, which then participated in a transannular [5+2] cycloaddition with the butenolide ring <06OL5901, 06TL6401>. O AcO
OH O
2. Ac2O C5H5N DMAP 81%
O O
H O
1. m-CPBA
N H
H
DMSO 150 °C sealed tube 26%
O O
H O
O
O
O
The oxidation of 2,5-disubstuted furans by singlet oxygen was exploited for the synthesis of [5,5,5] and [6,5,6] bis-spiroketals <06OL1945>. An unusual regioselective photooxidation of 3-bromofuran to 2- and 3-bromo-γ-hydroxybutenolides, as depicted below, was reported. The mechanism for the observed base-dependent regioselective deprotonation of the endoperoxide intermediate was not determined <06OL4831>. O2, hv base
Br O
CH2Cl2 −78 °C 4.3 to 5.3 h
Br HO DBU Phosphaxene
Br
+ O
O
HO
O
O
78% 0 : 100 70% 80 : 20
A 2-aminofuran was converted into 4,4’-bipyrazole by reaction with two molecules of hydrazine <06TL8965>. Hydrogenation of 2-amylfuran under 5 atm of H2 as catalyzed by 10% Rh/C at 80 °C in water provided 2-amyltetrahydrofuran in 90% yield <06SL1440>. An advance in the area of enantioselective hydrogenation of furans, as reported by Pfaltz, is the hydrogenation of
180
X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
2-substituted furans using chiral iridium/pyridine-phosphinite complexes as catalysts, achieving ee of up to 93% <06AG(I)5194>. Another notable example is the Rh/butiphane-catalyzed enantioselective cis-hydrogenation of a furanylnucleoside as shown below <06OL4133>. H N
O MeO2C
O
O
N Me
H N
O
H2 (80 bar) (( R,R)- Pr-butiphane)Rh(COD)BF4 i
MeO2C
O
O
N Me
THF 80 °C 98% 99% de, 72% ee
2-Methoxyfurans reacted with ruthenium and platinum carbenoids, derived from tertiary propargyl carboxylates, regioselectively, leading to interesting triene systems, as represented by the example below <06OL1741>. OAc
OAc
[RuCl2(CO)2]2 (2.5 mol%)
+
ClCH2CH2Cl 50 °C, 18 h OAc
[Ru] O
OMe
O
OAc
+
89% 50 : 50
OMe
OMe O
The presence of a halogen substituent at the 5-position of N-alkenyl substituted 2furanyl amides markedly enhanced the rate of intramolecular Diels-Alder reaction and the yield of cycloadduct. This phenomenon, as determined by CBS-QB3 calculations, was attributed to the decreased activation energy and a greater stabilization of the cycloadduct imparted by the halogen substitution. The computation also suggested that a 5-methoxy group has the same favorable effect, and that substitution at the 5-position has a greater effect than that at the 3-position <06AG(I)1442; 06JOC5432>. The facile cycloaddition between furan and a 3,3-difluoro-2-propenoate as catalyzed by SnCl4 was determined by density functional theory calculations to have arisen from the high-energy barrier of cycloreversion. The transition state of this reaction was characterized as zwitterionic in nature <06JA13130>. The gold-catalyzed cycloisomerization of furans tethered to alkynes was adopted to the synthesis of interesting spiroannulated dihydrobenzo[c]furans containing pentofuranosides, hexofuranosides and hexopyranosides <06TL3307>. It was found that this type of cycloisomerization could occur even with furans bearing sterically demanding substituents at the 5-position, and that an ortho-methoxy group on the phenyl substituents had a strongly accelerating effect on the reaction rate <06CEJ6991>. An example is shown below.
O
NTs
AuCl3 (5 mol%)
O NTs
CD3CN 50 min. 88%
O
OH
The cyclopropanation of furan with methyl 4-bromophenyldizoacetate using the chiral dirhodium tetraprolinate was further studied, showing the initial bond formation occurred at the
181
Five-membered ring systems: furans and benzofurans
furan 2-position <06JOC5349>. 1,3-Dipolar cycloaddition of furanyltungsten complexes, in which furan function as a carbonyl ylide, was investigated <06OM435>. Furan participated in [4+3] and [3+2] cycloaddition reactions with 1-alkylidene-2-trimethylsilyloxyallyl and 1alkylidene-2-methoxyallyl cations respectively <06OL4113>. A [4+4] intramolecular photocycloaddition between a furan tethered to a pyran-2-one was used to construct the fused tricyclic [5-8-5] ring system of the fusicoccin diterpenoid traversianal <06OL4075>. A similar cycloaddition of a furan tethered to a 2-pyridone was examined for the synthesis of the tetraquinane crinipellin <06OL3367>. 5.3.2.2 Di- and Tetrahydrofurans The stereoselectivity of the Büchi-Paternò reaction between 3-hydroxy-2,3dihydrofuran and benzophenone was found to be influenced by solvent, temperature and steric effect <06TL2527>. A Dötz benzannulation involving a dihydrofuran chromium carbene complex and an alkyne was employed to form the aflatoxin B2 skeleton, providing the annulated product as the only regioisomer <06TL2299>. Cycloaddition involving 2,3dihydrofuran, 1-aminoanthraquinone and salicyaldehyde was catalyzed by triphenylphosphonium perchlorate to form cis-fused furanochromenylaminoanthraquinone <06TL9291>. New catalytic conditions for the cyclization between 2,3-dihydrofuran and imines using Me3SiCl <06SL1399>, phosphomolybdic acid <06TL4409>, SbCl3 <06TL5733> and iodine <06TL4509> to form furanotetrahydroquinolines were developed. A diastereoselective and enantioselective variant of this reaction was achieved by using a (R)BINOL derived phosphoric acid as illustrated below <06JA13030>. Ar O O H N OH
Ph
+
O
O P
OH O
Ar (Ar = 9-anthryl) (10 mol%) PhMe −10 °C 86% cis : trans = 99 : 1 90% ee
OH
N H
Ph
2-Benzoyl-4,5-dihydrofuran was readily oxidized by air, m-CPBA or DMDO to give a mixture of butyrolactone and tricyclic bis-acetal <06TL6285>. 2,3-Dihydrofurans were converted to butenolides by photo-oxygenation followed by dehydration of the intermediate hydroperoxides at room temperature <06T10688>. 2,3-Dihydrofuran underwent a radical group transfer reaction with xanthate to give an intermediate in which the anomeric xanthate further reacted with nucleophiles to provide 2,3-trans-disubstituted tetrahydrofurans <06JOC2352>. Group transfer reaction also occurred photo-chemically between 2,3dihydrofuran and difluoro(phenylseleno)acetate and phosphonate to provide 3-difluoromethyl substituted 2,3-dihydrofurans <06T3761>. In the absence of acetonitrile as an additive, the diastereoselective three-component coupling involving 2,3-dihydrofuran, N-tosyl imino ester and a nucleophile, as reported in 2005, provided trisubstituted pyrrolidines, as exemplified below <06OL4509>.
182
Ph
X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
O
+ TsHN
CO2Et
HO H
TiCl4
+ Me 3Si
CH2Cl2 −78 °C to 23 °C 72% 99:1 dr
Ph
N Ts
CO2Et
An interesting example of a triple electrophilic aromatic substitution between an oxonium ion, generated from a trisubstituted dihydrofuran, and phloroglucinol was exploited for the total synthesis of the C3-symmetric xyloketal A, as depicted in the scheme below <06OL1427; 06JOC1620>. H HO
OH
BF3.Et2O MgSO4
HO
+ O
OH
O
O
Et2O − 78 °C, 20 min 79% 80 : 20 dr
O O
H
H
O O
As exemplified below, an interesting rearrangement of fused 2,5-dihydrofurans to tricyclic lactones under strongly acidic conditions was observed <06JOC9544>. NHPh O
O O
HN O
N C 6H4-p -Me
O 85% H3 PO4 85 −100 °C, 2 h 88%
O O
O
N
N O
H
C6H4 -p-Me
Upon treatment with Me3SiOTf, the 2,5-dihydrofuran-containing 14-membered marine cembranoid sarcophytoxide was converted to a 10-membered ring product as shown below <06OL2957>. Presumably, the Lewis acid promoted the cleavage of the dihydrofuran ring to provide a transient allylic cation, leading to a transannular cyclization. O O
Me3 SiOTf (0.5 equiv.)
O
C6H 6 r.t., 30 min 15%
An intermolecular 1,5-oxygen migration of a cyclohexene-fused 7oxabenzonorbornadiene was induced by bromination <06T12318>. Double bond isomerization was minimized in a rhodium-catalyzed hydroformylation of 2,5-dihyfrofuran by using a phosphabarrelene ligand to produce 3-formytetrahydrofuran in 79% yield <06CEJ6931>. The Pd(OAc)2-catalyzed hydrophenylation of 7-oxabenzonorbornadiene was affected by the use of a triphenylphosphine-functionalized imidazolium carbene as a ligand <06SL1193>. The ringopening reaction of 7-oxabenzonorbornadienes was coupled to the ring-forming reaction of 2-
183
Five-membered ring systems: furans and benzofurans
iodoaryloxyallenes in a one-pot palladium-catalyzed process to provide interesting cis-2substituted-1-naphthalenols <06OL621>. Another example of a palladium-catalyzed reaction of 7-oxabenzonorbornadiene involved a three-component coupling with aryl iodides and benzynes, as illustrated below <06OL5581>. The regioisomer obtained is consistent with the insertion of the bicyclic alkene into the Pd-aryl bond before the benzyne. OMe
O
TfO
SiMe3
Pd(dba)2 P(2-furyl)3 CsF
OMe
O
+
+
MeCN r.t., 10 h 83%
The isomerization of 7-oxabenzonorbornadienes to 1-naphthols could be interrupted to obtain 1,2-naphthalene oxides by using Cp*Ru(cod)Cl as a catalyst and by careful work-up using neutral alumina, as shown below <06JA3514>. The regioselectivity of this reaction was consistent with the insertion of ruthenium into the more electron rich C−O bond. The C1 ester group of 7-oxa- and 7-oxabenzo-norbornadienes also induced a high regioselectivity in the ruthenium-catalyzed [2+2] cycloaddition with disubstituted alkynes <06TL7185>. However, the ruthenium-catalyzed reaction between 7-oxabenzonorbornadienes and propargylic alcohols in MeOH provided isochromenes <06EJO5449>. 7-Oxa- and 7-oxabenzo-norbornadienes could also be cyclopropanated by ruthenium carbenoids that were derived from tertiary propargyl carboxylates using a catalytic amount of CpRuCl(PPh3)4 <06JOC3569>. O
Cp*Ru(cod)Cl (5 mol%) ClCH2 CH2Cl 60 °C, 15 min neutral alumina 81%
CO2Me
MeO2C
O
2-Alkylidenetetrahydrofurans underwent a cyclo-condensation with amidines to give 4(3-hydroxyalkyl)pyrimidines, as can be seen below <06T5426>. Ph Ph
O
+
Br O
HN
Et3N NH 2
EtOH reflux, 12 h 91%
N
N Br OH
The formation of tetrahydrofuranyl ether from tetrahydrofuran and an alcohol via a tetrahydrofuran α-radical could be performed by using manganese(0) powder and CCl4 <06TL5111>. These conditions provided a high yield of the hindered tertiary alcohol, dimethylphenylcarbinol. Upon oxidation with cerium ammonium nitrate, 2tetrahydrofuranylstannanes generated transient tetrahydrofuranyl oxonium ions, which were captured intramolecularly by hydroxyl groups to provide furo[2,3-b]pyrans <06TL3607>, as illustrated below.
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X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
MeO2C
Ph OH
CAN (2 equiv.) MeCN 20 °C 54%
n
Sn Bu3
O
MeO2C O H
Ph
O
5.3.3 SYNTHESIS 5.3.3.1 Furans 3-Aryl furans were prepared in moderate yields by Rh-catalyzed regioselective hydroformylation of substituted propargylic alcohols followed by cyclization, and an example is shown below <06ASC545>. Rh(OAc)2 (5 mol%) PPh 3 (20 mol%) 700 psi CO/H2 (1:1) 4 Å MS, 65 °C 57%
O
Negishi coupling of 2-furylzinc chloride with vinyl telluride provided 2-substituted furan with (Z)-double bond in a stereoselective manner, which was used in the total synthesis of 1-(Z)-atractylodinol, a biologically active natural product as depicted in the following scheme <06TL8183> TMS
1. n-BuLi, THF, -78 °C O
2. ZnCl2, THF, -78 to 25 °C 3. PdCl2, CuI, THF, 25 °C, 30 h
O
O OH
BuTe 78%
1-(Z)-Atractylodinol TMS
As can be seen below, a retro-Diels-Alder strategy was used to prepare 2,3- and 2,4disubstituted furans with a SF5 group as one of the substituents, which was introduced into furan ring for the first time <06OL5573>. F 5S
O
F5S CN
150-160 °C 78%
O
Gold as an efficient catalyst has widely been used in furan synthesis. One example is shown below, in which the double hydroarylation of unactivated alkyne using 2-methylfuran afforded a difuranylmethane derivative in a moderate yield <06EJOC4340>. C5H 11 [(Mes3PAu)2Cl]BF4 (2.5 mol%) C5 H11 + O
50 °C, 7 d 42%
O
O
Five-membered ring systems: furans and benzofurans
185
2,5-Disubstituted furans were synthesized from 1,4-diketones, which were prepared from the reaction of methyl vinyl ketones with arylboronic acids in the presence of CO using rhodium catalyst as illustrated below <06T11740>. B(OH)2
1. RhH(CO)(PPh3) 3 (0.5 mol%) CO, MeOH
+
O
2. p-TsOH, PhMe 66%
O OMe
OMe
Diastereoselective Friedel-Crafts reaction of a 2-substituted furan with chiral glyoxylate regiospecifically gave chiral 2,5-disubstituted furans in high yields, and an example is shown in the scheme below <06OL5045>.
SnCl4
O BnOCH 2
+
O
O
O
CH2Cl2 – 78 °C 87%, >98 de
CHO
Ph
O
O
CH2OBn
OH
Ph
Functionalized hexanofuran shown below was provided as a 5.1:1 mixture of the desired diastereomer and its epimer by Pd-catalyzed cyclization of 3-iodo-4-substituted furan prepared from 3,4-diiodofuran through I-Li exchange, and was followed by trapping of the lithiated furan with an aldehyde. The modification of this procedure to produce diiodofuran using 1-methyl-2-pyrrolidinone as co-solvent was also reported <06JA17057>.
HO
Pd(OAc) 2 n-Bu 4NBr
I
Et3N MeCN-H2O 75 °C 75%
O
O
Addition of acyl anions generated from acylsilanes to α,β-unsaturated ketones using Nheterocyclic carbenes (NHCs) derived from thiazolium salts as catalyst produced 1,4diketones, which cyclized to form the corresponding furans in good yields under an acidic condition <06JOC5715>. 1. NHC (20 mol%) DBU
O
i
SiMe3 +
Ph
Ph O
Ph
PrOH, THF, 70 °C 2. HOAc 74%
Ph
O
A three-component, one-pot reaction of acyl chloride, propargylic alcohol derivatives and NaI using palladium as catalyst provided trisubstituted furans as depicted in the following scheme <06EJOC2991>. 3-Chloro-4-iodofurans can also be produced when ICl and NaCl are used in the second step.
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X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
1. Pd(PPh3 )2Cl 2 (2 mol%) CuI (4 mol%) Et3 N, THF, rt, 2h
OTHP
O
+ Ph
I
2. NaI p-TSA MeOH rt, 2 h 72%
Cl
Ph
O
As can be seen in the scheme below, the catalytic activity of gold species was also shown in a multi-substituted furan synthesis. Cyclization of allenones in the presence of Au(III)-porphyrin gave rise to the corresponding substituted furan in good to high yields. The catalyst can be recycled several times and still maintain the same catalytic activity <06OL325>. [Au(TPP)]Cl (1 mol%) CF 3CO2H (10 mol%)
O •
C4H 9
C5H11
acetone, 60 °C 90%
C5 H11
C4H9
O
Another example of Au-catalyzed was reported using alkynyl cyclopropyl ketones as a starting material. Trisubstituted furans were given in high yields under mild condition via a domino reaction process and an example is given below <06AG(I)6704>. n
O
n
Bu
Bu
O
[(PPh 3)Au]OTf (1 mol%) MeOH CH2Cl 2 86%
OMe
A Pt-catalyzed cyclization of an enynone as illustrated in the following scheme using a nucleophilic solvent afforded substituted furans in good to high yields. In this reaction, the solvent serves as a nucleophile to attack the β-position of the double bond <06TL5307>. The same reaction can also be catalyzed by Bu4N[AuCl4] in [bmim]BF4. It is noteworthy that the catalyst can be recycled several time and keep the catalytic activity unchanged <06SL1962>. n
O
n
Pr PtCl2 (5 mol%)
Pr
O
MeOH 40 °C 82%
OMe
Iodonium ylides reacted with electron-deficient alkynes or conjugated alkynes using Rh-catalyst to form trisubstituted furans in moderate yields as depicted in the scheme below <06SC1941>. O
O O
IPh
+ O
O
Rh 2(Opiv)4 43%
O
187
Five-membered ring systems: furans and benzofurans
Reaction of a tungsten carbene complex with alkynyllithium followed by treatment of aldehyde in the presence of Et3Al afforded trisubstituted furans in good to excellent yields <06AG(I)6874>. Dienes were the products without Et3Al. MeO
n
W(CO)5 PhMe2Si
Hex
THF, −78 °C
n
OMe
Li
n
(OC)5W
Hex
PhCHO
Li
Et3Al 89%
SiMe2Ph
Hex
Ph
O
SiMe 2Ph
Feist-Benary cyclo-condensation of (2,4-dioxobutylidene)-phosphoranes with αchloroacetone gave rise to substituted furfuryl phosphonium salts, which underwent subsequent Wittig reactions to afford alkenylfurans in good yields as can be seen below <06JOC8045>. 1. BuLi, THF, 0 °C O O
Cl
O PPh3
EtO
CO2 Et
2. nPrCHO, THF,
CO2Et
0 °C → 20 °C 80 °C 49%
O
PPh3 Cl
70% E:Z = 4:1
n
O
Pr
Fully substituted furan as depicted below was prepared from a Baylis-Hillman adduct in the presence of sulfuric acid in a moderate yield. Intermolecular Friedel-Crafts reaction is one of steps to give rise to the final tetrasubstituted furan <06T8798>. O 2N
CO2Et O
Ph
H2SO4 C6 H6 70-80 °C 43%
Ph
EtO2 C
Ph
O
Allenes as starting materials are still being explored. One example shown below is that the reaction of bromoallene with a 1,3-diketone under PTC condition provided a trisubstituted furan in high yield <06OL5061>. Cl
O
K 2CO3 n -Bu4NBr
O
+ Cl
acetone 65%
• Br
Cl O Cl O
The usefulness of allene derivatives has also been revealed in other examples. Thus, the annulated tetrasubstituted furan illustrated in the following scheme was delivered in a moderate yield using the diazoallene as precursor by a two-step reaction in the presence of Rhcatalyst <06S3605>. OEt N2
O 1. Rh2(OAc)4 (3 mol%) O
MeO
•
OMe
CH2 Cl2, 23 °C 73% 2. PhMe 120 °C 88%
OEt MeO
O O
MeO
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X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
Propargylic dithioacetals have been shown to be good starting materials for the synthesis of trisubstituted furans. Recently, a modification appeared, which demonstrated that these compounds could also be used to prepare tetrasubstituted furans in good yields <06SL1209>.
S n
1. nBuLi, THF, – 78 °C 2. iPrCHO, – 78 °C
S
Bu n
Bu
3. Hg(OAc)2 4. I2, KI, CH2Cl2 56%
n
i
Bu
Pr
I
O
n
Bu
Tandem reaction of aromatic aldehydes with electron-deficient acetylenes and dialkyl acetylenedicarboxylates in the presence of Et3N led to the formation of fully substituted furans in moderate yields. One appropriate example is shown below <06EJOC5174>. CHO
CO2Me
+
CO2Me
+ CO2Me
CO2Me
MeO2C
Et3N CH 2Cl2 – 10 °C 55%
MeO2C
O
Three-component reaction of thiazolium salt, ketene precursor, and dimethyl i acetylenedicarboxylate using Pr2Net as base gave rise to 1,4-thiazepine-fused furans in high yields, as can be seen in the following scheme <06AG(I)7793>.
+ N Et
Br
CO2 Me
COCl
S Ph
+ CO2 Me
Ph i
Pr2NEt
O
S
CH2Cl2 83%
N
CO2Me CO2Me
Et
As can be seen, the reaction between the anisyl derivative and the acetoacetate provided also tetrasubstituted furans. A subsequent demethylation cyclization delivered furo[3,4c]coumarins in a moderate yield <06JHC1699>. OMe
+
O
O
piperidine OEt
MeOH 40%
OMe CO2Et
O
O
O
HBr HOAc 50%
O
5.3.3.2 Di- and Tetrahydrofurans Haloetherification remains one of the most popular approaches towards tetrahydrofuran skeletons. Yus reported a double iodoetherification reaction promoted by a silver salt, affording 1,7-dioxaspiro[4.5]decanes, and an example is shown in the scheme below <06T2264>. Kumar and Singh also reported an iodoetherification pathway to form 2,3-diphenyltetrahydrofurans <06T4018>. A bromoetherification converted 3-butenols into bromotetrahydrofurans <06TL5751>.
189
Five-membered ring systems: furans and benzofurans
OH
I2 AgOTf
OH
O
Na 2CO3 THF r.t., 12 h 99%
O
Another general route from which tetrahydrofurans can be prepared is the Williamson ether synthesis. In this entry, many variations on leaving groups other than halides have been devised, e.g. mesylates <06AG(I)7072; 06JOC386; 06OL2831; 06OL5477>; tosylates <06JOC836; 06OL2635; 06T5421; 06T8095; 06TL3401>; epoxides <06AG(I)810; 06CAJ894; 06CC3444; 06EJO2403; 06JA9561; 06JOC926; 06JOC1416; 06OBC3220; 06OL4375; 06SL1177; 06SL2329> and water <06H(68)771; 06HCA3071; 06SL2035; 06T6107>. A bicyclic compound containing a tetrahydrofuran ring was synthesized, whose steps involved the opening of an epoxide intermediate, as shown below <06JOC1139>. SiMe 3 SiMe3 HO HO HO
CO2Et
1. MsCl Et3N CH2Cl2 –40 °C, 2 h
O
O
aq. sat. Ba(OH) 2
CO2R 2. K2CO3 MeOH HO 25 °C, 30 min R = Et and Me 99%
CO2H
50 °C, 24 h 100%
HO
4-Pentenols can be induced to undergo cyclization to form tetrahydrofurans under many conditions utilizing reagents such as mercury(II) acetate <06T2857; 06TL5943> and cerium(III) chloride <06T7466>. Hex-2-ene-1,6-diols also led to the formation of tetrahydrofurans upon treatment with an acid <06S3621>. Mukaiyama’s cobalt-catalyzed aerobic oxidative cyclization protocol has also been employed to from tetrahydrofurans from 4pentenols <06OL4379>. Other approaches involving 4-pentenols are the OsO4-catalyzed oxidative etherification <06JA13704> as shown in the scheme below, as well as a similar Pd(TFA)2-catalyzed oxidative version <06SL3533>.
H2 1C
O
OsO4 (5 mol%) Me 3NO
O
10
O
O
TFA cinnamic acid Me 2CO-H2O 77%
H21C1 0 HO
H
O
H
OH
HO
H
O
H HO
1,5-Hexadienes underwent an oxidative cyclization catalyzed by RuO4 <06OL3433> as illustrated in the following scheme <06T10989>.
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X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
H 21C10 HO RuO2•2H2O (20 mol%) OAc NaIO4 (4 equiv.) H 21C10 MeCN-EtOAc-H2O (3:3:1) 0 °C, 30 min
H21C10
O
OAc O
O
OH
+
OAc O
O
OH
+
H 21C10 HO
24%
14%
OAc O
O
O
9%
Palladium-catalyzed cyclization of bis-hydroxy-allyl alcohols unexpectedly gave dioxabicyclo[2.2.2]octanes <06TL3271>, while the adjacent bis(tetrahydrofuran) cores of annonaceous acetogenins can be obtained via a stereoselective palladium-catalyzed double cyclization of bis(allylic acetate)diols <06OL5637>. Palladium-catalyzed carboetherifications of substituted 4-pentenols in the presence of aryl bromides led to the formation of tetrahydrofurans bearing three stereocenters with moderate to good stereoselectivities <06TL2793>. A similar intramolecular version of this reaction gave also tetrahydrofurans in good stereo-control as shown below <06JA2893>. Pd2(dba)3 PCy3•HBF4 NaO-t-Bu
Br Ph OH
PhMe 105 °C 40% dr 92:5:2:1
H Ph H Major Diastereomer syn-addition trans-THF HO
Other obvious methods for generating tetrahydrofuran frameworks are via chemical transformations of lactols <06AG(I)6904; 06JNP1531; 06JOC1251; 06JOC6287; 06OL2039; 06TA3; 06TL6433>; acetals <06JOC1172; 06TL3979> and lactol acetate <06CC2720; 06TL4561; 06TL5905>. Radical cyclizations have also been employed to the formation of tetrahydrofurans <06AG(I)8018; 06EJO1547; 06OL2209; 06OL4481; 06SL1829>. Wender reported several rhodium-catalyzed cyclotrimerization of polyenes and dienecyclopropanes to lead to cyclic molecules embedded with tetrahydrofurans <06AG(I)2459; 06AG(I)3957; 06JA5354; 06JA6302>. In a study on the total synthesis of lactonamycin, the pivotal tetrahydrofuran ring was constructed via an intramolecular Michael addition reaction <06JOC2434>. Secosyrins 1 and 2 were also realized employing a Michael addition route <06SL3340>. An interesting transannular [2+2] photocycloaddition reaction of cyclic ether gave rise to the formation of a cyclobutane fused with two tetrahydrofuran rings <06TL733>. On the other hand, an approach to ophirin B and astrogorgin featured an intramolecular Diels-Alder cycloaddition as illustrated in the following scheme <06JA1371>. The total synthesis of (–)-cladiella-6,11-dien-3-ol, (+)polyanthellin A, (–)-cladiell-11-ene-3,6,7-triol and (–)-deacetoxyalcyonin acetate also made use of such intramolecular Diels-Alder strategy <06JA15851>. BnO
Me
1. C6H6 25 °C
H O H iPrO
2C
OSiiPr3
OSiiPr3
Et3 SiO Me
2. hν PhSSPh C6H6
Me H H O BnO iPrO C H H 2 Et3SiO Me
191
Five-membered ring systems: furans and benzofurans
Au(III)-mediated ring contraction of C-glycoside scaffolds provided highly substituted tetrahydrofurans <06OL5065>. Similarly, tetrahydrofuran-based γ-azido esters were prepared from 2-O-triflates of D-ribose and L-arabinose <06T4110>. It was uncovered by Makosza that enolates of γ-chloropropyl ketones reacted with aldehydes in protic media to generate aldoltype products that would cyclize to form tetrahydrofuran rings <06S1190>. Prins-type cyclization between homopropargylic alcohols containing terminal alkynes with aldehydes, forming tetrahydrofurans, was also observed by Cho <06OL3617>. Yadav developed an efficient synthetic method for highly substituted tetrahydrofurans via reactions of a vicinal tbutyldiphenylsilylmethyl-substituted cyclopropyl diester with aldehydes and ketones <06TL8043>. Lewis acid promoted rearrangement of 1,3-dioxolanyl-substituted 1,2-oxazines into novel molecules with 1,3,6-trioxa-7-azacyclopenta[cd]indene frameworks <06SL3498>. Lewis acid also mediated [3+2] cycloaddition reactions of chiral allylsilanes with an α-keto ester <06H(67)369> or an aldehyde <06JA15960> to afford silyltetrahydrofurans in good to high stereoselectivities. Another thermally induced [2+3] cycloaddition reaction between [60]fullerene and epoxides provided fullerenes fused with tetrahydrofurans <06JOC4346>. As can be seen below, a [5+2] approach towards the total synthesis of a naturally occurring molecule descurainin was reported by Snider <06T5171>. 1. Et3N CH 2Cl2 25 °C, 2 d 31%
O
O
H O
H
+
O
MeO
HO AcO
OMe OSi tBuMe 2
Enantiomerically pure reactions of 1,3-bis-silyl enol Rhodium complexes as the triethylphosphine to afford <06JA9642>. (Et3P)2Rh
O
2. C 5H5N•HF THF-C5H5 N 3. KOH MeOH-H 2O 87%
MeO HO
OAc OMe Descurainin
2-alkylidenetetrahydrofurans were prepared by TiCl4 mediated ethers with enantiomerically pure epichlorohydrin <06TA892>. one shown below reacted in solution in the presence of 2,2-disubstituted-5-methylenetetrahydrofurans in good yield
Me Me
PEt3 (10 equiv.)
O
Me Me
C6 D6 25 °C 68%
+ (Et3 P)4 RhH
3-Alkylidenetetrahydrofurans can be synthesized conveniently by many metal complex catalyzed cyclization procedures. In this connection, organometallic complexes of rhodium <06JA11766; 06JOC91; 06S4053; 06TL6361>, nickel <06JA2609>, indium <06T3582>, palladium <06TL8905>, iridium <06TA1238>, ruthenium <06JA9262> and gold <06AG(I)7427> are all known to catalyze cyclizations of allyl propargyl ethers to form 3alkylidenetetrahydrofurans via various mechanisms involving organometallic intermediates. Highly enantioselective reductive cyclization of alkynyl aldehydes via rhodium-catalyzed hydrogenation also provided 3-alkylidenetetrahydrofurans containing a stereogenic 4-hydroxy group <06JA10674>. A Rh(I)-catalyzed intramolecular [4+2] cycloaddition led to the formation of a bicyclic product featuring an alkylidenetetrahydrofuran scaffold is shown below <06JA12648>.
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X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
Me
O
[RhCl(diene*)]2 (5 mol%) (R ,R)-Et-DUPHOS (11 mol%) C6 H4-p -CF3 AgSbF 6 (20 mol%) O Me CH2Cl2 r.t., 1.5 h 97% 98% ee
Me
C6H4 -p-CF3 Me diene* = Me H
Me Me
3-Methylenetetrahydrofurans can also be realized by an intramolecular radical cyclization of bromoalkynes utilizing indium(I) iodide as a radical initiator <06TL2859>. 3Diiodomethylenetetrahydrofurans were also prepared from 1,ω-diiodo-1-alkynes in the presence of 1-hexynyllithium <06CC638>. Takikawa achieved the total synthesis of brevione B <06T39> and decaturin D <06TL4425>, both of which contain a spiro-fused 2,3-dihydrofuran ring. Their approach to these intriguing functionalities was by coupling a vinyl epoxide with a hydroxypyrone through a simple base-mediated SN2’-type epoxide opening, and was followed by a dehydrative O-alkylation step. A mild Ni(0)-catalyzed rearrangement of 1-acyl-2-vinylcyclopropanes was reported to give 2,3-dihydrofurans <06OL573>. 2,3-Dihydrofuran rings were realized by allowing βdiketones or β-ketoesters to react with 2-bromo-2-cyclopentenone in K2CO3-NaHCO3-mediated <06S1657> or Lewis acid catalyzed <06EJO2005> conjugate-addition-initiated-ring-closure (CAIRC) routes. β-Keto-diphenylphosphine oxides were found to cyclize to form optically active 2,3-dihydrofurans <06OBC3108>, while flash vacuum pyrolysis of vinyl epoxides gave cis2,3-dihydrofuran carboxylates as major products as illustrated in the scheme below <06OBC2912>. O
CO2Et
Ph
180 °C Sealed tube PhMe 80%
EtO2C Ph
EtO2C
+ O
Ph
O
10 : 1
A new domino lithium acetylide addition/rearrangement procedure on trans-1,2dibenzoyl-3,5-cyclohexadiene furnished 3-alkylidene-2,3-dihydrofurans via an intriguing mechanism involving three bond formations and two bond cleavages in one single operation <06SL1230>. The reaction of dimedone with meso-diacetoxycyclohexene in the presence of a palladium catalyst led to the formation of the tricyclic product as depicted below <06S865>. [Pd( η3-C3H5 )Cl]2 PPh 3 K 2CO3
O
+ AcO O
O
H
OAc THF r.t., 2.5 h 67%
O H
An obvious preparation of 2,5-dihydrofurans was by bis-allyl ether <06CC2489; 06JA1840> or by tandem allyl propargyl <06T5064> ring closing metathesis. Au(I) <06OL1957>, Au(III) <06EJO1387> and Pd(II) <06AG(I)4501> catalyzed cyclization of allenyl carbinols to form 2,5-dihydrofurans were recorded. Reactions of allenyl carbinols with KO-t-Bu or AgNO3 were also shown to lead to the formation of 2,5-dihydrofurans <06SL2383>. Coppercatalyzed rearrangement of vinyl oxiranes has been shown to lead to 2,5-dihydrofurans <06JA16054>. In the total synthesis of salviasperanol, the vinyl epoxide embedded in a cycloheptane ring rearranged to a 2,5-dihydrofuran skeleton upon treatment with a catalytic amount of trifluoroacetic acid <06OL2883>. Ga(III)-catalyzed cycloisomerization of enynes containing a cyclic alkene gave rise to the formation of eight-membered ring molecules fused with a 2,5-dihydrofuran <06OL5425>. As can be seen below, mercuric chloride mediated the
193
Five-membered ring systems: furans and benzofurans
cyclization of tethered alkynyl dithioacetals to form also 2,5-dihydrofuran frameworks <06OL313>. S i
Pr
Me
O
HgCl 2 (3 equiv.) CaCO3 (4 equiv.)
S O
Me Pri
MeCN-H2 O (4:1) 25 °C, 4 h 32%
Me
O
Me
5.3.3.3 Benzo[b]furans and Related Compounds The formation of a diverse array of five-membered ring heterocycles via the cycloaddition of isocyanides with furan- or pyrrole-based enones was reported. The reaction mechanism is discussed and an example is shown below <06OL3975>. O O
O
O
2,6-Me 2PhNC CaCl2 PhMe 25 °C 79%
Me
NH Me HN
Me
Me
4-Hydroxymethyl-4,8-dimethylfuro[2,3-h]chromen-2-one was realized in an efficient manner via a Claisen rearrangement of 4-(hydroxybut-2-ynyloxy)-4-methylchromen-2-one as depicted in the following scheme. Other examples with substitution of hydroxyl and with other substituents, such as chloro, amino, acetoxy were also reported <06JHC763>. A new approach for the synthesis of oxygenated benzo[b]furans was developed via epoxidation and cyclization of 2’-hydroxystilbene <06T4214>. Me
OH
O
Me
Microwave irradiation (540W)
O
N,N-diethylaniline 20-30 min 56%
O
O
O
Me
OH
O
The treatment of 2-fluorophenyl-2-iodophenyl ethers, amines, and thioethers with 3.3 equivalents of t-BuLi and further reaction with selected electrophiles gave rise to functionalized carbazoles, dibenzofurans, and dibenzothiophenes in a direct and regioselective manner. A selected example is illustrated below <06JOC6291>. Benzyl 2-halophenyl ethers was treated with t-BuLi, and then reacted with carboxylic esters to give 2,3-disubstituted benzo[b]furans <06JOC4024>.
F I O
1. t-BuLi (3.3 equiv) THF –78 °C to 0 °C 2. Ph 2S2 –78 °C to 20 °C 64% for two steps
SPh
O
p-Quinone monoimide was able to react with various azadienes in the absence of a Lewis acid to give 2,3-dihydrobenzo[b]furans, a motif that is present in numerous biologically active
194
X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
products, in moderate to excellent yields <06OL3919>. Three interesting and novel pentacyclic benzo[b]furan-based scaffolds were generated during a direct platinum-anodic oxidation of 2,4dimethylphenol, albeit in low yields <06EJO241>. Regioselective formation of benzo[b]furanbased spirocyclic compounds was accomplished by tri-n-butyltin hydride mediated aryl radical 4-exo-trig cyclization <06OL4059>. Synthesis of the racemic scaffold of 8-fluorogalanthamine was achieved by an oxidative coupling as illustrated below <06TL5701>. O K3[Fe(CN) 6] K2CO3
OH HO MeO
F
O MeO
N CHO
PhMe, H 2O 50 °C 40%
N CHO
F
A versatile and regioselective synthesis of benzo[b]furans, naphthalenes, indoles and benzothiophenes was achieved by reaction of o-alkynylarene and heteroarene carboxaldehyde derivatives in the presence of iodonium ions. The reaction mechanism was also discussed <06CEJ5790>. 1. IPy2 BF4, HBF4 CH2Cl2 0 °C, rt
Ph
OHC
O
Ph
O
Ph
2. PhHC=CH2, r.t. 36%
O
H
Several substituted benzo[b]furans were synthesized efficiently in one-pot procedures by reaction of salicyaldehydes and ethyl diazoacetate in the presence of HBF4•Et2O in high yields as shown below. A plausible mechanism was also given <06S1711>. Two types of naphtha[2,3-b]furan derivatives were made respectively by Lewis acid and HCl catalyzed ring cyclizations <06T8045>. AuBr3-catalyzed [4+2] benzannulation between enynal units and enol ethers was also applied to prepare benzo[b]furans <06JOC5249>. Cl
CHO
+ N2CHCO2Et
HBF4 •Et2O CH2 Cl2 r.t., 1 h 99%
OH Cl
CO2Et
Cl O Cl
2-Substituted 3-halobenzo[b]furans were afforded by the palladium-catalyzed annulation of 2-alkynylphenols in the presence of CuCl2 and Et3N•HCl as depicted in the scheme below <06OL3017>. Iodine-induced oxidative cyclization reaction of 2hydroxystilbenes was utilized in the synthesis of benzofurans <06SL1657>. Benzo[b]furan related furo[2,3-b]pyridine-4(1H)-one was also made effectively via iodocyclization <06OL1113>. A one-pot synthesis of benzo[b]furans was also reported by the Zn(OTf)2catalyzed cyclization of proparyl alcohols with phenols in high yield <06JOC4951>. Ph
PdCl2 CuCl2 Et3N•HCl
Cl Ph
Me
OH
DEC r.t. 78%
Me
O
Five-membered ring systems: furans and benzofurans
195
Asymmetric synthesis of the rocaglamides was accomplished by employing [3+2] photo-cycloaddition mediated by functionalized TADDOL based chiral Brønsted acids. The synthesis consisted of a [3+2] dipolar cycloaddition, a base-mediated α-ketol rearrangement and a hydroxyl-directed reaction <06JA7754>. Asymmetric synthesis of 1,2dihydrobenzo[b]furans was achieved by adamantylglycine derived dirhodium tetracarboxylate catalyzed C-H insertion <06OL3437>. OH
MeO HO
CO2Me
OMe O OH MeO
1. hv > 350 nm TADDOL, –70 °C PhMe, CH2Cl2
O
+ Ph
OMe COOMe
2. NaOH, MeOH 3. Me4NBH(OAc)3
O
MeO
(14% yield, 58%ee ) OMe exo-methyl rocaglamide MeO
O TADDOL =
Ar
OH CO2Me
OH
O Ar
Ar OH OH Ar = phenanthren-9-yl
O
MeO
Ar
(71% yield, 60% ee) OMe endo-methyl roc aglamide
Cationic palladium-catalyzed addition of arylboronic acids to nitriles for the formation of benzo[b]furans was reported <06OL5987>, an example of which is illustrated in the following scheme. The palladium-catalyzed cross coupling of alkynes with appropriately substituted aryl iodides for the synthesis of substituted dibenzofurans in moderate to excellent yields was also achieved <06JOC5341>. The benzo[b]furan core of heliannuls G and H were constructed by a palladium-catalyzed π-allyl cyclization reaction <06TL7353>. The palladiumcatalyzed oxidative activation of arylcyclopropanes was applied to the synthesis of 2substituted benzo[b]furans <06OL5829>. OMe CN MeO
O
Me
OMe
PhB(OH)2 [(bpy)Pd(μ-OH)]2 (OTf) 2
Ph Me
MeNO2 reflux, 9 h 82%
MeO
O
A metallative 5-endo-dig cyclization reaction of 2-ynylphenols generated by a sequential treatment of BuLi and ZnCl2 produced 3-zinciobenzo[b]furans in excellent yields. These intermediates were allowed to undergo a transmetallation route to form the corresponding cuprates, which reacted with electrophiles to produce a variety of 2,3disubstituted benzo[b]furans <06OL2803>. A similar strategy was utilized by the same team to construct the conjugated structures containing multiple benzo[b]furan units <06AG(I)944>.
196
X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
O
Ph
1. BuLi (1.0 eqiuv),PhMe, 0 °C to rt 2. ZnCl2 (1.0 equiv),120 °C Ph 3. CuCN 2LiCl, PhMe, –78 °C 4. I
OH
O (90% overall yield)
O
A palladium-catalyzed one-step synthesis of dihydrobenzo[b]furan-based fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes was reported, and an example is provided in the scheme below <06OL3601>. 2-Alkyl- or 2aryl-substituted benzo[b]furans were synthesized by a copper-TMEDA catalyzed intramolecular annulation from the corresponding ketones <06OL1467>.
+ Br O
O
Pd(OAc)2, PPh 3 Cs2CO3, norbomene
I O
CO2Et
CO2Et
DME 100 °C 45%
Br
O
2-Amino-2,3-dihydrobenzo[b]furans were obtained employing starting materials generated from Baylis-Hillman adducts <06TL3913>. O2N Ph
CO2Me CO2 Me
CF 3COOH H2SO4 (3.0 eqiev)
H2N CO Me 2 CO2Me O
C 6H6 60–70 °C, 3 h
Gold(I)-catalyzed synthesis of dihydrobenzo[b]furans from aryl allyl ethers was reported as depicted below <06SL1278>. Highly efficient AuCl3/AgOTf-catalyzed atomeconomical annulation of phenols with dienes was developed. This annulation generated various dihydrobenzo[b]furans under mild conditions <06OL2397>. MeO
O
OMe
Ph 3PAuCl (5 mol%) MeO AgOTf (5 mol%) CH2Cl2 40 °C 55%
Me O OMe
As can be seen in the following scheme, substituted (benzo[b]furan-3-yl)acetic acid was obtained in a high yield by heating substituted 4-chloromethylchromen with 2N NaOH solution <06T9258>. A benzo[b]furan core was also realized by a direct cyclization of Nef reaction products through an intramolecular cyclo-condensation <06SL567>. A facile synthesis of benzo[b]furoisocoumarins was reported by reaction of substituted phenols with ninhydrin in the presence of acetic acid, followed by treatment with a catalytic amount of Et3N in refluxing ethylene glycol <06SL207>. Various benzo[b]furans were made by N-heterocyclic carbene (NHC) catalyzed intramolecular nucleophilic substitution reaction from the corresponding aromatic aldehydes <06OL4637>.
197
Five-membered ring systems: furans and benzofurans
CH2Cl
MeO
O
CH2CO2H
NaOH (2.0 N) 80 °C 92%
O
O
MeO
A Dötz benzannulation reaction was utilized in the synthesis of the furo[2,3-b]furan core of aflatoxin B2 as illustrated below <06TL2299>. Synthesis of polynuclear aromatic compounds was achieved by using [5+5] cycloaddition of 2-alkynylarylcarbene complexes and enyne-aldehyde derivatives <06TL5303>. Cr(CO) 5
H
O
H
THF O H
O H
SiMe2 tBu
OEt + MeO
80 °C 31%
OH OMe SiMe2tBu
O OEt
A new triethylamine-catalyzed cascade reaction of aromatic aldehydes and propiolates was developed to prepare various benzo[b]furan-based polycyclic aromatics. Interestingly, the chemical outcome of this process depended on the reaction temperature and was selectively tailored by an appropriate choice of experimental conditions <06OL1241>. CO2 Me
CHO
O
Et3N (0.5 eqiuv)
+ H
CO2Me CH2Cl2 –40 °C, 3h
O
MeO2C
CO2 Me
As depicted in the following scheme, in the presence of sodium iodate and pyridine, several 5,6-dihydroxylated benzofuran derivatives were synthesized via an oxidation-Michael addition of β-dicarbonyl compounds to catechols in a one-pot procedure <06TL2615; 06JHC1673>. A novel additive Pummerer reaction of 2-benzo[b]furan sulfilimines with carbon nucleophiles derived from β-dicarbonyl compounds was also employed to the synthesis of 2,3disubstituted benzo[b]furans <06TL595>. HO
+
O
O
Me
HO
NaIO3 pyridine Me EtOH, H 2O 47%
O Me
HO
Me O
HO
An unexpected dimerization product was obtained in 30% yield during the palladiumcatalyzed hydrogenation of 2-(2-pyridylmethylene)-3(2H)-benzo[b]furan-3-one. A couple of similar types of substrates were investigated, indicating the scope of the substrates was limited <06T8425>. O
MeO
O
H O
H2 Pd–C N
EtOH 30%
MeO
H Py
OH O
H Py O OMe
198
X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
The benzo[b]furan-based core structure of galanthamine was constructed by a novel synthetic methodology making use of a NBS-initiated semi-pinacol rearrangement, leading to the desired products in high yields <06OL1823>. HO
O
MeO
O
NBS
O OSiMe 2tBu
CH2Cl2 0 °C 95%
OMe
O O
OHC
A practical method for the synthesis, resolution and determination of the absolute configuration of 9,9’-binaphtha(2,1-b)furanyl-8,8’-diol was reported as shown below <06TS1275>. A rearrangement of 4-acetoxy-9-furanylnaphtho[2,3-b]furans to tetracyclic naphthodifurans was achieved under acidic conditions <06TL4117>. O
O
OH
HO
FeCl3 OH
O I
H2O reflux 90%
The tetracyclic benzo[b]furan-based core structure of liphagal was efficiently assembled by an acid-initiated polyene cyclization reaction to form the pivotal fused 6,7 ring substructure as depicted in the following scheme <06OL321>. The acid-catalyzed dimerization of benzo[b]furans was also reported in the synthesis of a certain type of benzo[b]furan dimers <06SL1497>. A base-mediated condensation of benzo[b]furan-2-aldehyde with functionalized pyrans was applied to the synthesis of a new class of high-brightness red-light-emitting dopants for OLED <06OL2632>.
O
OMe
ClSO3H
OMe
–78 °C, 30 min 43%
OMe
H
OMe O
Br
Br
1,2-Bis(2-n-alkyl-1-benzo[b]furan-3-yl)perfluorocyclopentene derivatives were synthesized, and their photochromic performance was studied in solutions as well as in their single crystalline phases <06EJO3105>. F
F
F
F
F
F
F
hv
F
F
F
F
F R
R
hv# O R O
O R O
5.3.3.4 Benzo[c]furans and Related Compounds A quantitative study on local aromaticity based on n-center electron delocalization indices, where n is the number of atoms in the ring, was performed on benzo[c]furan and benzo[b]furan.
199
Five-membered ring systems: furans and benzofurans
The results show that benzo[b]furan is more stable by 14.4 kcal/mol due to a large decrease of aromaticity of the benzene ring in benzo[c]furan <06T12204>. A convenient one-step synthesis of various symmetrically substituted 1,3diarybenzo[c]furans was recorded, and an example is shown below <06SL2035>.
S
O
MgBr
S O
O THF 0 °C 85%
OMe
S
Two oxadisilole-fused benzo[c]furans illustrated below were prepared making use of Warrener’s tetrazine protocol <06JOC3512>. Their reactivities, photophysical, redox and thermal properties were all assessed. As shown below, an isocorannulenofuran was also synthesized, again by employing Warrener’s route, from readily accessible bromocorannulene <06OL5909>. O Si Si
Si O
O
O
Si
O
Si O Si
As can be seen in the scheme below, insertion reactions of aldehydes to the C–H bond of aromatic ketimines by using a rhenium catalyst provided benzo[c]furans via a mechanism involving consecutive steps of C–H bond activation, insertion of aldehyde, intramolecular nucleophilic cyclization, reductive elimination, and elimination of aniline <06JA12376>. Ph N
Ph
+ p-CF C H 3 6 4
Ph
[ReBr(CO)3(thf)]2 (2.5 mol%) 4Å MS
O H
O PhMe 115 °C, 24 h 93%
C6 H4-p -CF3
A rhodium-catalyzed intermolecular [2+2+2] cycloaddition of dipropargyl ethers with trimethylsilylynamides using (S)-xyl-BINAP as ligand led to the formation of 1,3dihydrobenzo[c]furans in high enantioselectivities, as depicted in the following scheme <06JA4586>. The same research team also prepared C2 symmetric and unsymmetric tetraortho-substituted axially chiral bis(1,3-dihydrobenzo[c]furans) employing a similar strategy <06OL3489>. It was found that when nitriles instead of alkynes were used, pyridine analogs of benzo[c]furans were obtained <06EJO3917>. O O Et
Ph
N
Ph
[Rh(cod)2]BF4 (10%) (S)-xyl-BINAP
Ph Et
N
Ph SiMe3
+
O Et
SiMe3
CH2Cl2 r.t. 62% 96%ee
Et O
200
X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
Yamamoto showed that Cp*RuCl(cod) was able to catalyze cyclotrimerization reactions between diynylboronate and monoalkynes to form 1,3-dihydrobenzo[c]furans as illustrated by an example below <06T4293>. By utilizing the same method, Yamamoto also prepared a number of spirocyclic C-arylribosides <06OL3565>. These organometallic-catalyzed [2+2+2] cycloaddition pathways were also used by Hocek <06OL2051> and Shibata <06TA614> in their quest for functionalized C-nucleosides and atropisomeric chiral o-diarylbenzene derivatives, respectively.
O O B O
Acetylene Cp*RuCl(cod) (10 mol%)
O
B
O
O CH2Cl2 r.t., 1 h 82%
Florio achieved a general method for the synthesis of hydroxyalkyl 1,3dihydrobenzo[c]furans from o-lithiated aryloxiranes and carbonyl compounds, and an example is depicted in the following scheme <06JOC3984>.
O Me
1. t-BuLi THF –78 °C 2. Me2 CO
Me
OH O
3. Heat 4. H+ 67% dr = >98/2
Br
Me
Me
As can be seen below, another route for the preparation of spiroannulated 1,3dihydrobenzo[c]furans (vide supra) was reported by Hotha, who made use of an AuCl3 promoted intramolecular Diels-Alder reaction <06TL3307>. O
O Ph
O BnO
OMe O
AuCl 3 (3 mol%)
O
MeCN 10 min 78% Me
O
O Ph
O BnO
OMe O OH Me
Acknowledgements: HNCW wishes to thank the Areas of Excellence Scheme established under the University Grants Committee of the Hong Kong Special Administrative Region, China (Project No. AoE/P-10/01) and an anonymous donor for financial supports. XLH acknowledges with thanks supports from the National Natural Science Foundation of China, National Outstanding Youth Fund, the Chinese Academy of Sciences, and Shanghai Committee of Science and Technology. KSY thanks Dr Nicholas A. Meanwell for support. 5.3.4 REFERENCES 06AG(I)810 06AG(I)944 06AG(I)1442 06AG(I)2459 06AG(I)3957 06AG(I)4501 06AG(I)5194
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X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
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06OL5573 06OL5581 06OL5637 06OL5829 06OL5901 06OL5909 06OL5987 06OM435 06P307 06P452 06P459 06P735 06P743 06P759 06P965 06P1957 06P2146 06P2288 06S865 06S1190 06S1657 06S1711 06S3605 06S3621 06S4053 06SC1941 06SL207 06SL567 06SL1177 06SL1193 06SL1209 06SL1230 06SL1278 06SL1399 06SL1440 06SL1497 06SL1657 06SL1829 06SL1962 06SL2035 06SL2329 06SL3340 06SL3431 06SL3498 06SL3533 06SL2383 06T39 06T2264 06T2857 06T3582 06T3761 06T4018 06T4110 06T4214
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W.R. Dolbier, Jr., A.Mitani, I. Ghiviriga, Org. Lett. 2006, 8, 5573. S. Bhuvaneswari, M. Jeganmohan, C.-H. Cheng, Org. Lett. 2006, 8, 5581. L.M. Wysocki, M.W. Dodge, E.A. Voight, S.D. Burke, Org. Lett. 2006, 8, 5637. Z. He, A. K. Yudin, Org. Lett. 2006, 8, 5829. P.A. Roethle, P.T. Hernandez, D. Trauner, Org. Lett. 2006, 8, 5901. A. Sygula, R. Sygula, P.W. Rabideau, Org. Lett. 2006, 8, 5909. B. Zhao, X. Lu, Org. Lett. 2006, 8, 5987. K.C. Bassett, F. You, P.M. Graham, W.H. Myers, M. Sabat, W.D. Harman, Organometallics 2006, 25, 435. M. Yamada, K.-i. Hayashi, H. Hayashi, S. Ikeda, T. Hoshino, K. Tsutsui, K. Tsutsui, M. Iinuma, H. Nozaki, Phytochemistry 2006, 67, 307. S.A.M. Abdelgaleil, M. Doe, Y. Morimoto, M. Nakatani, Phytochemistry 2006, 67, 452. A.F.K. Waffo, P.H. Coombes, D.A. Mulholland, A.E. Nkengfack, Z.T. Fomum, Phytochemistry 2006, 67, 459. I.C. de Pascoli, I.R. Nascimento, L.M.X. Lopes, Phytochemistry 2006, 67, 735. D. Arrieta-Baez, R.E. Stark, Phytochemistry 2006, 67, 743. A.J. Matich, B.J. Bunn, M.B. Hunt, D.D. Rowan, Phytochemistry 2006, 67, 759. R.R. Romero-González, J.L. Ávila-Núñez, L. Aubert, M.E. Alonso-Amelot, Phytochemistry 2006, 67, 965. R.B. Teponno, A.L. Tapondjou, D. Gatsing, J.D. Djoukeng, E. Abou-Mansour, R. Tabacchi, P. Tane, H. Stoekli-Evans, D. Lontsi, Phytochemistry 2006, 67, 1957. N. Tanaka, Y. Takaishi, Phytochemistry 2006, 67, 2146. N. Saewan, J.D. Sutherland, K. Chantrapromma, Phytochemistry 2006, 67, 2288. S. Tanimori, Y. Kato, M. Kirihata, Synthesis 2006, 865. M. Barbasiewicz, M. Makosza, Synthesis 2006, 1190. A. Mekonnen, R. Carlson, Synthesis 2006, 1657. M. E. Dudley, M. M. Morshed, M. M. Hossain, Synthesis 2006, 1711. T. Yao, A. Hong, R. Sarpong, Synthesis 2006, 3605. M.-C.P. Yeh, Y.-C. Lee, T.-C. Young, Synthesis 2006, 3621. D.E. Kim, C. Choi, I.S. Kim, S. Jeulin, V. Ratovelomanana-Vidal, J.-P. Genêt, N. Jeong, Synthesis 2006, 4053. Y.R. Lee, S.H. Yoon, Synth. Commun. 2006, 36, 1941. S. Das, R. Fröhlich, A. Pramanik, Synlett 2006, 207. B.-L. Zhang, F.-D. Wang, J.-M. Yue, Synlett 2006, 567. Y.-L. Chen, J. Jin, J.-L. Wu, W.-M. Dai, Synlett 2006, 1177. J. Zhong, J.-H. Xie, A.-E. Wang, W. Zhang, Q.-L. Zhou, Synlett 2006, 1193. J.-C. Tseng, J.-H. Chen, T.-Y. Luh, Synlett 2006, 1209. Y.-H. Liu, S.-L. Zhou, H.-F. Lu, Synlett 2006, 1230. N. W. Reich, C.-G. Yang, Z. Shi, C. He, Synlett 2006, 1278. S.V. More, M.N.V. Sastry, C.-F. Yao, Synlett 2006, 1399. T. Maegawa, A. Akashi, H. Sajiki, Synlett 2006, 1440. M. Dixut, A. Sharon, P. R. Maulik, A Goel, Synlett 2006, 1497. C. Pan, J. Yu, Y. Zhou, Z. Wang, M.-M. Zhou, Synlett 2006, 1657. E.J. Alvarez-Manzaneda, R. Chaboun, E. Alvarez, E. Cabrera, R. Alvarez-Manzaneda, A. Haidour, J.M. Ramos, Synlett 2006, 1829. X. Liu, Z. Pan, X. Shu, X. Duan, Y. Liang, Synlett 2006, 1962. F. Benderradji, M. Nechab, C. Einhorn, J. Einhorn, Synlett 2006, 2035. T.P. Heffron, T.F. Jamison, Synlett 2006, 2329. A.E. Koumbis, A.-A.C. Varvogli, Synlett 2006, 3340. A.V. Butin, A.S. Dmitriev, V.T. Abaev, V.E. zavodnik, Synlett 2006, 3431. F. Pfrengle, A. Al-Harrasi, H.-U. Reissig, Synlett 2006, 3498. D.C. Ebner, Z. Novák, B.M. Stoltz, Synlett 2006, 3533. M.A. Chowdhury, H.-U. Reissig, Synlett 2006, 2383. H. Takikawa, Y. Imamura, M. Sasaki, Tetrahedron 2006, 62, 39. F. Alonso, J. Meléndez, T. Soler, M. Yus, Tetrahedron 2006, 62, 2264. B.H. Fraser, R.J. Mulder, P. Perlmutter, Tetrahedron 2006, 62, 2857. A. Goeta, M.M. Salter, H. Shah, Tetrahedron 2006, 62, 3582. S. Murakami, H. Ishii, T. Tajima, T. Fuchigami, Tetrahedron 2006, 62, 3761. S. Kumar, P. Kaur, A. Mittal, P. Singh, Tetrahedron 2006, 62, 4018. A.A. Edwards, G.J. Sanjayan, S. Hachisu, R. Soengas, A. Stewart, G.E. Tranter, G.W.J. Fleet, Tetrahedron 2006, 62, 4110. S. N. Aslam, P. C. Stevenson, S. J. Phythian, N. C. Veitch, D. R. Hall, Tetrahedron 2006, 62, 4214.
206 06T4294 06T4743 06T4988 06T5064 06T5171 06T5421 06T5426 06T6107 06T7466 06T8045 06T8095 06T8425 06T8798 06T9258 06T10688 06T10989 06T11740 06T12204 06T12318 06TA3 06TA614 06TA892 06TA1238 06TA1275 06TL595 06TL733 06TL1505 06TL2299 06TL2527 06TL2615 06TL2793 06TL2859 06TL3271 06TL3307 06TL3401 06TL3607 06TL3685 06TL3913 06TL3979 06TL4007 06TL4113 06TL4117 06TL4409 06TL4425 06TL4509 06TL4561 06TL4623 06TL5111 06TL5303 06TL5307 06TL5701 06TL5733
X.-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. Wong
Y. Yamamoto, K. Hattori, J.-i. Ishii, H. Nishiyama, Tetrahedron 2006, 62, 4294. T. Kubota, Y. Matsuno, H. Morita, T. Shinzato, M. Sekiguchi, J. Kobayashi, Tetrahedron 2006, 62, 4743. M. Tori, K. Honda, H. Nakamizo, Y. Okamoto, M. Sakaoku, S. Takaoka, X. Gong, Y.-M. Shen, C. Kuroda, R. Hanai, Tetrahedron 2006, 62, 4988. K.P. Kaliappan, R.S. Nandurdikar, M.M. Shaikh, Tetrahedron 2006, 62, 5064. B.B. Snider, J.F. Gravowski, Tetrahedron 2006, 62, 5171. C. Ribes, E. Falomir, M. Carda, J.A. Marco, Tetrahedron 2006, 62, 5421. E. Bellur, P. Langer, Tetrahedron 2006, 62, 5426. Q. Wang, Y. Yang, Y. Li, W. Yu, Z.-J. Hou, Tetrahedron 2006, 62, 6107. M.-C.P. Yeh, W.-J. Yeh, L.-H. Tu, J.-R. Wu, Tetrahedron 2006, 62, 7466. A. V. Butin, V. V. Mel’schin, V. T. Abaev, W. Bender, A. S. Pilipenko, G. D. Krapivin, Tetrahedron 2006, 62, 8045. M.R. López, F.A. Bermejo, Tetrahedron 2006, 62, 8095. M. Mák, M. Nógrádi, Á. Szöllósy, Tetrahedron 2006, 62, 8425. K.Y. Lee, S. Gowrisankar, Y.J. Lee, J.N. Kim, Tetrahedon 2006, 62, 8798. A. M. Piloto, A. S. C. Fonseca, S. P. G. Costa, M. S. T. Goncalves, Tetrahedron 2006, 62, 9258. Y.-Z. Chen, L.-Z. Wu, M.-L. Peng, D. Zhang, L.-P. Zhang, C.-H. Tung, Tetrahedron 2006, 62, 10688. V. Picciaalli, T. Caserta, L. Caruso, L. Gomez-Paloma, G. Bifulco, Tetrahedron 2006, 62, 10989. H. Chochois, M. Sauthier, E. Maerten, Y. Castanet, A. Mortreux, Tetrahedron 2006, 62, 11740. M. Mandado, N. Otero, R.A. Mosquera, Tetrahedron 2006, 62, 12204. A. Menzek, A. Altundas, Tetrahedron 2006, 62, 12318. J.-C. Kim, K.-H. Kim, J.-C. Jung, O.-S. Park, Tetrahedron: Asymmetry 2006, 17, 3. T. Shibata, K. Tsuchikama, M. Otsuka, Tetrahedron: Asymmetry 2006, 17, 614. E. Bellur, D. Böttcher, U. Bornscheuer, P. Langer, Tetrahedron: Asymmetry 2006, 17, 892. F.Y. Kwong, H.W. Lee, W.H. Lam, L.-Q. Qiu, A.S.C. Chan, Tetrahedron: Asymmetry 2006, 17, 1238. A. V. Karnik, S. P. Upadhyay, M. G. Gangrade, Tetrahedron: Asymmetry 2006, 17, 1275. A. Padwa, S. Nara, Q. Wang, Tetrahedron Lett. 2006, 47, 595. S. Redon, O. Piva, Tetrahedron Lett. 2006, 47, 733. K. Kaniwa, T. Ohtsuki, Y. Yamamoto, M. Ishibashi, Tetrahedron Lett. 2006, 47, 1505. S. A. Eastham, S. P. Ingham, M. R. Hallett, J. Herbert, P. Quayle, J. Raftery, Tetrahedron Lett. 2006, 47, 2299. M. Abe, M. Terazawa, K. Nozaki, A. Masuyama, T. Hayashi, Tetrahedron Lett. 2006, 47, 2527. L-X. Pei, Y.-M. Li, X.-Z. Bu, L.-Q. Gu, A. S. C. Chan, Tetrahedron Lett. 2006, 47, 2615. M.B. Hay, J.P. Wolfe, Tetrahedron Lett. 2006, 47, 2793. B.C. Ranu, T. Mandal, Tetrahedron Lett. 2006, 47, 2859. A. Zawisza, D. Sinou, Tetrahedron Lett. 2006, 47, 3271. S.K. Maurya, S. Hotha, Tetrahedron Lett. 2006, 47, 3307. E. Ramu, G. Bhaskar, B.V. Rao, G.S. Ramanjaneyulu, Tetrahedron Lett. 2006, 47, 3401. M.R. Attwood, P.S. Gilbert, M.L. Lewis, K. Mills, P. Quayle, S.P. Thompson, S. Wang, Tetrahedron Lett. 2006, 47, 3607. P. Phuwapraisirisan, S. Surapinit, S. Sombund, P. Siripong, S. Tip-pyang, Tetrahedron Lett. 2006, 47, 3685. K. Y. Lee, J. Seo, J. N. Kim, Tetrahedron Lett. 2006, 47, 3913. T. Esumi, D. Hojyo, H.-F. Zhai, Y. Fukuyama, Tetrahedron Lett. 2006, 47, 3979. Y.-C. Shen, K.-L. Lo, Y.-C. Lin, A.T. Khalil, Y.-H. Kuo, P.-S. Shih, Tetrahedron Lett. 2006, 47, 4007. A.V. Butin, Tetrahedron Lett. 2006, 47, 4113. V.V. Mel’chin, A.V. Butin, Tetrahedron Lett. 2006, 47, 4117. K. Nagaiah, D. Sreenu, R.S. Rao, G. Vashishta, J.S. Yadav, Tetrahedron Lett. 2006, 47, 4409. S. Hosoe, T. Nakai, M. Sasaki, H. Takikawa, Tetrahedron Lett. 2006, 47, 4425. X.-F. Lin, S.-L. Cui, Y.-G. Wang, Tetrahedron Lett. 2006, 47, 4509. G.X. Chang, T.L. Lowary, Tetrahedron Lett. 2006, 47, 4561. H. Koshino, H. Satoh, T. Yamada, Y. Esumi, Tetrahedron Lett. 2006, 47, 4623. J.R. Falck, D.R. Li, R. Bejot, C. Mioskowski, Tetrahedron Lett. 2006, 47, 5111. Y. Zhang, J. W. Herndon, Tetrahedron Lett. 2006, 47, 5303. C.H. Oh, V.R. Reddy, A. Kim, C.Y. Rhim, Tetrahedron Lett. 2006, 47, 5307. P. Knesl, B. H. Yousefi, K. Mereiter, U. Jordis, Tetrahedron Lett. 2006, 47, 5701. G. Maiti, P. Kundu, Tetrahedron Lett. 2006, 47, 5733
Five-membered ring systems: furans and benzofurans
06TL5751 06TL5905 06TL5943 06TL6285 06TL6361 06TL6401 06TL6433 06TL6849 06TL7185 06TL7353 06TL8043 06TL8183 06TL8507 06TL8905 06TL8965 06TL9291
207
M. Honda, T. Mita, T. Nishizawa, T. Sano, M. Segi, T. Nakajima, Tetrahedron Lett. 2006, 47, 5751. G. Jalce, X. Franck, B. Seon-Meniel, R. Hocquemiller, B. Figadère, Tetrahedron Lett. 2006, 47, 5905. D.K. Mohapatra, S. Mohapatra, M.K. Gurjar, Tetrahedron Lett. 2006, 47, 5943. J. Robertson, A.J. Tyrrell, S. Skerratt, Tetrahedron Lett. 2006, 47, 6285. K. Mikami, S. Kataoka, K. Wakabayashi, K. Aikawa, Tetrahedron Lett. 2006, 47, 6361. B. Tang, C.D. Bray, G. Pattenden, Tetrahedron Lett. 2006, 47, 6401. J.-C. Jung, J.-C. Kim, H.-I. Moon, O.-S. Park, Tetrahedron Lett. 2006, 47, 6433. S.J. Blank, C.E. Stephens, Tetrahedron Lett. 2006, 47, 6849. R.R. Burton, W. Tam, Tetrahedron Lett. 2006, 47, 7185. S. Morimoto, M. Shindo, M. Yoshida, K. Shishido, Tetrahedron Lett. 2006, 47, 7353. A. Gupta, V.K. Yadav, Tetrahedron Lett. 2006, 47, 8043. J.M. Oliverira, G. Zeni, I. Malvestiti, R.H. Menezes, Tetrahedron Lett. 2006, 47, 8183. M. De Rosa, L. Citro, A. Soriente, Tetrahedron Lett. 2006, 47, 8507. J.T. Metza, Jr., R.A. Terzian, T. Minehan, Tetrahedron Lett. 2006, 47, 8905 M. Bakavoli, B. Feizyzadeh, M. Rahimizadeh, Tetrahedron Lett. 2006, 47, 8965. V. Gaddam, D.K. Sreenivas, R. Nagarajan, Tetrahedron Lett. 2006, 47, 9291.
208
Chapter 5.4 Five membered ring systems: with more than one N atom Larry Yet Albany Molecular Research, Inc., Albany, NY USA
[email protected]
______________________________________________________________________
5.4.1
INTRODUCTION
The synthesis and chemistry of pyrazoles, imidazoles, and 1,2,3-triazoles were actively pursued in 2006. A review on the cross-coupling reactions on azoles with two and more heteroatoms for pyrazoles and imidazoles has been published <06EJO3283>. Publications relating to 1,2,4-triazole and tetrazole chemistry were not particularly well represented this year. The solid-phase and combinatorial chemistry of these ring systems have not been investigated compared to past years. No attempt has been made to incorporate all the exciting chemistry or biological applications that have been published this year. 5.4.2
PYRAZOLES AND RING-FUSED DERIVATIVES
A short review has been published on the utilization of chiral enaminones and azomethine imines in the synthesis of functionalized pyrazoles <06ARK35>. Addition of hydrazines to 1,3-difunctional compounds is one of the most common methods employed for the preparation of pyrazoles. 1,3-Diketones were synthesized directly from ketones and acid chlorides and were then converted in situ into pyrazoles by the addition of hydrazine <06OL2675>. This method is extremely fast, general, and chemoselective, allowing for the synthesis of previously inaccessible pyrazoles and synthetically demanding pyrazolecontaining fused rings. A highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles based on the condensation of fluorinated 1,3-diketones with arylhydrazines has been described where N,N-dimethylacetamide is used as the solvent <06SL3267>. New bis-pyrazole derivatives were synthesized from aryl- and xylyl-linked bis(β-diketone)precursors with hydrazines <06SC707>. 3-Amino-5-trifluoromethyl-1H-pyrazoles were synthesized by cyclocondensation reactions of 4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-ones with hydrazines <06SL1485>. The application of microwave heating to a silica-assisted solution-phase synthesis technique has
209
Five membered ring systems: with more than one N atom
been utilized to develop a rapid and efficient two-step protocol for the preparation of pyrazoles 5 from aryl methyl ketone 1 and ethyl trifluoroacetate 2 with aryl hydrazine 4 via trifluoroketo enol 3 <06TL2443>. Treatment of ethyl 3,3-dicyano-2-methoxyacrylate with alkyl, aryl, heterocyclic and sulfonyl hydrazines led to the synthesis of N-1 substituted 3-acyl-4-cyano-5aminopyrazoles, which became versatile intermediates for the synthesis of many biologically active scaffolds <06TL5797>. 3-Arylhydrazono-4-polyfluoroalkyl-2,4-dioxobutanoates reacted with hydrazines to give ethyl 4-aryldiazeno-3-polyfluoroalkyl-1H-pyrazole-5-carboxylates <06RJOC887>. Microwave irradiation of substituted hydrazines and β-ketonitriles furnished 5aminopyrazoles, which were transformed to their corresponding N-carbonyl derivatives by treatment with an isocyanate or a chloroformate <06OBC4158>. CF 3 Me O Ar
O Me
+
O
NaH, DME, 160 °C F3C
OEt 2
1
microwave
OH
Ar
61-95%
NHNH 2 4 Si-TsOH, EtOH
Ar
N
N
160 ºC, microwave
CF3 3
48-95% Me 5
Cyclic β-bromovinyl aldehydes 6 are cyclized with phenylhydrazine in toluene in the presence of a palladium(II) acetate and a phosphorus chelating ligand together with sodium tertbutoxide to give 1-aryl-1H-pyrazoles 7 in moderate to good yields <06T6388>. This method also applied to other acyclic aldehydes and arylhydrazines. The reaction of ofluorobenzaldehydes 8 and their O-methyloximes 9 with hydrazine has been developed as a new practical synthesis of indazoles 10 <06JOC8166>.
CHO PhNHNH2, Pd(OAc)2 (5 mol%) ( )n
Br
PhMe, 125 °C
8
ref lux 29-82%
N Ph
7
Yield
1
20%
2
79%
3
65%
4
77%
N
CHO NH NH , DME 2 2 F
( )n
dppf (7.5 mol%), NaOt -Bu (2 eq)
6
R
N
n
NH 2NH 2, DME
R
N 10
N H
ref lux 69-94%
OMe H
R F 9
R = H, OMe, Cl, Br, F
(E)-N-methoxy-N-methyl-α-enaminoketoesters were employed as synthetic precursors for the regioselective condensations with hydrazines in a microwave-assisted synthesis of ethyl 1,5disubstituted-4-pyrazole carboxylate derivatives <06OL3219>. Protected N(1’)-substituted (S)3-(4-methoxycarbonyl-1H-pyrazol-5-yl)alanines were prepared by acid-catalyzed cyclocondensations of chiral enaminone, available from L-aspartic acid, with hydrazine hydrochlorides <06S2376>.
L. Yet
210
Hydrazones are also useful substrates in the preparation of pyrazoles. Reaction of Nmonosubstituted hydrazones with nitroolefins led to a regioselective synthesis of substituted pyrazoles <06OL3505>. 1H-3-Ferrocenyl-1-phenylpyrazole-4-carboxaldehyde was achieved by condensation of acetylferrocene with phenylhydrazine followed by intramolecular cyclization of the hydrazone obtained under Vilsmeier–Haack conditions <06SL2581>. A one-pot synthesis of oxime derivatives of 1-phenyl-3-arylpyrazole-4-carboxaldehydes has been accomplished by the Vilsmeier–Haack reaction of acetophenone phenylhydrazones <06SC3479>. Heterocycles can be employed as precursors for the synthesis of pyrazoles. Pyrazoles can be synthesized by three-membered ring substrates. For example, allyl amines 12 and pyrazoles 13 could be obtained by hydrazinolysis of 2-ketoaziridines 11 <06TL255>. Regioselective ring opening of 3-aryl-2-benzoyl-1,1-cyclopropanedicarbonitriles 14 with hydrazine provided a new process for the synthesis of 5-aryl-3-phenylpyrazoles 15 <06JHC495>. O R1
NH 2NH 2H 2O (10 eq) R3
N R2
KOH (2 eq), ethylene glycol, 100 °C
R1
R3
+
R1
12 0-69%
8-58%
Ar COPh 14
R 1 = t -Bu, Ph, Ar, CH 2CH 2CH=CH2 R 2 = H, phthalamide, R 3 = Me, Ph, Ar
Ph
CN CN
N
N H 13
11
HH
R3
NHR 2
NH2 NH 2 , DMF DME, reflux
Ar
N H
55-75%
N
15
Various five-membered ring heterocycles have been utilized in the preparation of pyrazoles. 1,2,3-Triazoles 16 underwent a Diels–Alder cycloaddition with dimethyl acetylene dicarboxylate under solvent-free conditions and microwave irradiation to afford pyrazole-3,4-dicarboxylates 18 with extrusion of the substituent on position 4 of the triazole intermediate 17 as a nitrile in the presence of silica-bound aluminum chloride <06TL8761>. A series of 6-substituted fluorinated indazoles 20 has been obtained through an ANRORC-like rearrangement (Addition of Nucleophile, Ring-Opening and Ring-Closure) of 5-tetrafluorophenyl-1,2,4-oxadiazoles 19 with hydrazine <06T8792>. Unexpected ring-opening of benzimidazoles with nitrilimines led to pyrazole derivatives <06TL8807>. 3-(p-Aryl)-4-cyanosydnone 21 underwent 1,3-dipolar cycloaddition with acrylic acid esters to give pyrazoloesters 22 and 23 in varying ratios
R1
N
DMAD, SiO 2-AlCl3 microwave, 80-130 °C
N N Ph
R2 16
20 min
Ph N R2
R1
CO2 Me
- R1
N N
MeO2C
35-94% CO 2Me
17 R 1 = H, Ph, CHO, CO2Me, Et R 2 = H, Me, Et, (CH 2) 3Me
CO2 Me
N R2
N N Ph 18
211
Five membered ring systems: with more than one N atom
<06SL901>. Reductive cleavage of 5-silyl, 3-, 4- and 5-silylmethylisoxazoles gave their corresponding silyl β-enaminones, which on reaction with hydrazines, provided regioselective syntheses of 3- or 5-silylpyrazoles and 3-, 4- or 5-silylmethylpyrazoles, respectively <06T611>. R
F
F
N O
X F
N
N
R = Me, Ph
F
19
20
OR PhCl, ref lux
NC O N
N H
X
X = NHMe, NMe 2, OMe
F
NH2
F
93-98%
O
EtO
F
NH2 NH 2, DMF, 25 °C
R = Et, t-Bu, Bn
RO
NC
N
O
N
NC
N
N
+
76-80%, 57:43 to 78:22 ratio
N O
OR O
R = CHPh2
21
85%, 100:0 ratio
OEt
OEt 23
22
A one-pot process to form 1,3,4-substituted pyrazoles 25 by Suzuki coupling of arylboronic acids to chromone 24, followed by condensation with hydrazine has been reported <06JCO286>. The synthesis of 3 or 5-o-hydroxyphenol-4-benzylpyrazoles has been accomplished by treatment of 3-benzylchromones, 3-benzylflavones and their 4-thiochromone analogs with hydrazine hydrate in hot pyridine <06EJO2825>. O R
I O 24
1. ArB(OH)2 , Pd(PPh3) 4 (2 mol%),
OH
N NH
K2CO3 (2 eq), THF, H 2 O, ref lux 2. NH2NH 2 (1.5 eq), 25 °C R = H, Me, OMe, Cl, NO2 48-95%
Ar R 25
Other miscellaneous type of reactions have been used in the synthesis of pyrazoles. Domino copper-catalyzed coupling/hydroamidation of iodoenynes 26 with bis(Boc)hydrazine led to a highly efficient synthesis of 3,4,5-trisubstituted pyrazoles 27 <06AG(E)7079>. A novel one-pot synthesis of pyrazoles has been accomplished by the reaction of β-formyl enamides with hydroxylamine hydrochloride catalyzed by potassium dihydrogenphosphate in acid medium <06TL43>. A new synthetic process approach to 4-(3-aminopropyl)-5-amino-1-methylpyrazole starting from 3-cyanopyridine has been developed <06OPRD159>. Microwave-assisted preparation of a wide range of 5-ethoxycarbonylpyrazoles and 3-pyrazoles by 1,3-dipolar cycloaddition of diazo compound to acetylenes has been reported <2006H(68)1961>. The regioselective, scaleable synthesis of three 4-(2-alkyl-5-methyl-2H-pyrazol-3-yl)piperidines has discussed <06TL1729>. Reaction of phenylhydrazine 28 with 1,3-dibromo-2-propanol 29 afforded 1-phenyl-1H-pyrazole 30 <06JOC135>. 1,3-Dipolar cycloaddition of
L. Yet
212
diphenylnitrilimine on olefins in the presence of porous calcium hydroxyapatite gave pyrazolines under solvent-free microwave irradiation <06SC111>. An enantioselective 1,3-dipolar cycloaddition reaction between diazoacetates and R-substituted acroleins, which gave 2pyrazolines with an asymmetric tetrasubstituted carbon center with titanium BINOL catalyst has been published <06JA2174>. Reaction of the Hüisgen zwitterion, derived from triphenylphosphine and dialkyl azodicarboxylates 31, with allenic esters 32 afforded highly functionalized pyrazoles 33 <06OL2213>. 1,3,5-Trisubstituted pyrazoles were synthesized from chalcones and hydrazines in the presence of iodine <06SC2189>. R1
R2
1. BocNHNHBoc, CuI (5 mol%),
I
R3 R 1 = H, n-Pr, Ph, Bn
N,N-dimethylethylenediamine (20 mol%), R2
R1
Cs 2 CO 3 (1.5 equiv), THF, 80 °C R3
26
2. TFA, CH 2Cl2, 25 °C 66-92%
NHNH 2 +
Br
28
R 1O2 C
CO2 R1 N N + 31
Br
R
OH
microwave
29
81%
PPh3 , DME, 25 °C
R2 32
CO2 Et
R 3 = Bn, n-Bu, n-Hex, CH2 COEt, (CH2 )nCl(or OBn)
K2 CO3, H2 O, 120 °C
35-72%
R
N N 30
R 1O 2C 2
R 2 = H, Et
N N H 27
OEt R 1 = Et, i-Pr
2
R3
N
N
R 2 = Me, Ph, Ar 1
CO2 R
R 3 = H, Ph
33
A one-step heterocyclization of o-nitrobenzylamines to 3-alkoxy-2H-indazoles in the presence of 5% potassium hydroxide in alcoholic solvents has been reported <06JOC2687>. The synthesis of a series of N,N’-disubstituted indazolone derivatives starting from methyl anthranilates in the presence of [phenyliodine(III)bis-(trifluoroacetate)] via an N-acylnitrenium intermediate has been presented <06JOC3501, 06T11100>. The Schiff bases, prepared from several amines and 2-nitrobenzaldehydes, were reacted with triethyl phosphite under microwave irradiation to generate nitrenes that underwent insertion reactions to give indazoles <06TL6795>. Lewis-acid promoted “coarctate” cyclization of ten 2-(phenylazo)benzonitrile derivatives furnished the isoindazole ring system <06JOC6619>. Several metal cross-coupling reactions have been applied to pyrazoles. C-H Arylation of aryl tosylates or chlorides could be achieved with a ruthenium catalyst at the C-2 phenyl position of 1-phenyl or 1-(p-tolyl)pyrazole 34 to give pyrazole 35 <06AG(I)2619>. Copper-catalyzed Narylation of pyrazole can be accomplished using air-stable copper(I) iodide as a copper source and 1,10-phenanthroline in the presence of potassium fluoride/alumina as a base <06SL2124; 06TL5203>. 1-Benzyl-4-bromo-1H-pyrazole can be cross-coupled with 3-pyridine-boronic acid in excellent yield <06AG(I)1282>. Heck cross-coupling reaction of 3-iodoindazoles with methyl 2-(acetylamino)acrylate provided a general route to new dehydro 2-azatryptophans and protected amino acid derivatives after catalytic hydrogenation <06S3506>.
213
Five membered ring systems: with more than one N atom
N
N N
ArOTs or ArCl
N Ar
[(RuCl2 )(p-cymene)2 ] (2.5 mol%) phosphoramide ligand (10 mol%)
(Me) H
K2CO3 , NMP
34
(Me) H 35
51-81%
N-Methylation at the pyrazole ring by sequential treatment of 5-tributylstannyl-4trifluoromethylpyrazole 36 with LDA and iodomethane regioselectively provided the Nmethylpyrazole 37 <06T6332>. The addition reaction of 5-lithiated-4-trifluoromethylpyrazole with a wide range of aldehydes or ketones allowed easy and high-yielding introduction of substituents on position 5 to give pyrazoles 38. Efficient preparation of 3-aryl-1H-pyrazoles 41 by reaction of 1-protected-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoles 40, prepared from pyrazole 39 with usual conditions, with (het)aryl halides has been described <06TL4655>. The SEM protecting group was difficult to remove in the presence of the carboxylate derivatives and often required drastic refluxing conditions and excess tetrabutylammonium fluoride. The choice of THP protecting group was found to alleviate these shortcomings. The C-3 position of isoindazoles is readily functionalized by metalation with lithium diisopropylamide followed by reaction with a variety of electrophiles <06SC285>. Indazole 42 can be regioselectively protected at N-2 by a SEM group using novel conditions (Scheme 12) <06JOC5392>. The SEM group of 43 efficiently directed regioselective C-3 lithiation and the resulting nucleophile reacted with a wide range of electrophiles to generate novel indazole derivatives 44 after the SEM group was removed by treatment with tetrabutylammonium fluoride in tetrahydrofuran or by aqueous hydrochloric acid in ethanol. 1(p-Methoxybenzyl)pyrazole, when treated with either n-butyllithium or lithium diisopropylamide, underwent metalation at the exocyclic -position but mutated to the 5-lithio species in the course of few minutes or hours <06EJO2417>. Trapping the intermediates with a rapidly reacting electrophile such as chlorotrimethysilane or carbon dioxide offered selective access to either of the two possible regioisomers. N-Arylation of 3,5-disubstituted-pyrazoles with 4-fluoro and 2-fluoronitrobenzene under microwave irradiation conditions with and without solvent compared to the classical heating afforded N-arylation regioisomers in yields depending on the method used <06ARK138>. F3 C Bu3Sn
F3 C
F3 C N H 36
N
1. LDA, THF, -78 °C 2. MeI
Bu3 Sn 93%
N N Me 37
1. n-BuLi, THF, -78 °C 2. RCHO or RCOR 46-96% R = H, alkyl, aryl
R R HO
N N Me 38
L. Yet
214 1. NaH, SEMCl, THF
1. ArX, Pd(PPh 3) 4 (5 mol%).
2. n-BuLi, THF
N H
O
3. B(Oi-Pr) 3
N
B O
4. pinacol 5. HOAc, THF
39
NaHCO 3 (2 eq), DME,
N
N SEM
H 2O, reflux (40-93%) 2. TBAF, THF, reflux (60-95%)
41
Cyhex2 NMe THF 94%
42
E
1. n-BuLi, THF, -78 °C
SEMCl
N
N
N H
40
75%
N H
Ar
N SEM N 43
2. E (72-98%)
N
3. TBAF, THF, reflux or HCl, EtOH, reflux
44
N H
>94%
Substitution reactions on pyrazoles have been reported. Reaction of a pyrazolyl disulfide 45 with bromotrifluoromethane and ethyl bromide in the presence of sodium dithionite at room temperature afforded pyrazolyl sulfides 46, followed by oxidation with hydrogen peroxide in trifluoroacetic acid afforded sulfenylpyrazoles 47 in excellent yields <06JFC948>. βChloropyrazole-4-carbaldehyde 48 has been utilized in the efficient synthesis of thiopyrano[5,6c]coumarin/[6,5-c]chromones through intramolecular domino Knoevenagel hetero Diels–Alder reactions with 4-hydroxy coumarin and its benzo analogs <06TL2265> and a rapid synthesis of mono- and bis-tetrahydropyrazolo[4’,3’:5,6]thiopyrano[4,3-b]quinolines via imino Diels-Alder reactions <06TL7571>. 3-Methylindazole 49 was Boc-protected followed by radical bromination with N-bromosuccinimide to give bromoindazole 50, which then underwent nucleophilic substitution by the carbanion of diethyl acetamidomalonate followed by decarboxylation and hydrochloride salt formation to yield a synthesis of 2-azatryptophan 51 <06T7772>. A simple and efficient protocol for the synthesis of 3-methoxy-4-arylmethyleneand 3-methoxyheteroarylmethylenepyrazoles 53 have been reported from the reaction of 4pyrazolomethyl alcohols 52 with either alcohols, thiols, aryl and heterocyclic (furanyl, indolyl and pyrrolyl) compounds in the presence of camphorsulfonic acid (CSA) <06TL817>. These reactions are believed to proceed via a Friedel-Crafts-type carbocation type mechanism. S H2 N
CN
N
RS CF3 Br or EtBr
N
Cl
Na 2S2 O4 , Na2 HPO4
Cl
DMF, H 2 O, 25 °C
H2 N
N
N
Cl
2
H2 O2 , TFA Cl
R = CF3 (96%), Et (95%)
R = CF3 (51%), Et (96%) CF3 45
O RS
CN
CF3 46
H2 N
CN
N
N
Cl
Cl
CF3 47
Five membered ring systems: with more than one N atom
R
215
CHO Me
N
S
N Ph
Me
48 CO2Et Br 1. AcNHCH(CO Et) , Na, 2 2
Me 1. Boc O, DMAP, 2 N N H 49
CH 3CN (97%)
N N 50 Boc
2. NBS, MCPBA, CCl4, 85 °C (61%)
N N Me
N
2. NaOH, EtOH, H 2O, reflux 3. HCl, reflux (70%)
OMe Condition A: ROH or RSH,
HO
NH 2· HCl
EtOH, 70 °C
51
N H
OMe
R
CSA (0.1 eq), 25 °C
R = OR, SR (50-100%)
N N Me
Condition B: ArH or HetH, CSA (0.1 eq), CH2 Cl2 , 25 °C
52
R = Ar, Het (50-85%)
53
Alkylation on the nitrogen of pyrazoles has been investigated. Microwave-assisted organic synthesis in nonpolar solvents utilizing cylinders of sintered silicon carbide (SiC) as chemically inert and strongly microwave absorbing materials as passive heating elements (PHEs) was demonstrated for the alkylation of pyrazole 39 with phenylethylbromide to give pyrazole 54 <06JOC4651>. The synthesis of 2,2-dichlorotrifluoromethyl pyrazole derivatives 56 from pyrazoles 55 by the interaction of N-sodium salts with Freon-113 has been carried out in the presence of tetrabutylammonium iodide (TBAI) as the catalyst <06SC1967>. 1,1’-Di(4-nitro or 2-nitrophenyl)-5,5’-disubstituted-3,3’-bipyrazoles have been prepared in one step by N,Narylation of 5,5’-disubstituted-3,3’-bipyrazoles with 4-fluoro and 2-fluoronitrobenzene under microwave irradiation and classical heating <06ARK46>. phenylethylbromide, SiC heating element, NaHCO 3
N
N H
PhMe, microwave, 250 °C
N
Ph
88%
39
54
R
R 1. NaH, DMF, 25 °C R
N
N H 55
N
2. ClF2CCFCl2 , TBAI R = H (72%), Me (70%)
R
N N CF2CFCl2 56
L. Yet
216
Fused pyrazole compounds have been prepared from N-alkyl substituted pyrazoles. For example, a palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp2 C-H functionalization as the key step has been described, in which an alkyl-aryl bond and an aryl-heteroaryl bond were formed in one pot <06OL2043>. A variety of highly substituted six-membered annulated pyrazoles 59 were synthesized in a one-step process in moderate yields from N-bromoalkyl pyrazoles 57 and aryl iodides 58. R N
+
N
R = Me (54%)
tri-2-furylphosphine (22 mol%)
= F (49%)
N N
Cs2 CO 3 (2 eq), norbornene (2 eq)
Br 57
R
Pd(OAc) 2 (10 mol%)
I
= CF3 (42%)
MeCN, 90 °C
58
59
Some electrophilic reactions on pyrazoles have been reported. 1-Ethylpyrazole-4carbaldehyde 61 was prepared from 1-ethylpyrazole 60 by the Vilsmeier reaction <06RJOC550>. Bromination of 3-(3-arylpyrazol-4-yl)acrylic acids 62 led to the formation of 2bromo-3-(3-arylpyrazol-4yl)acrylic acids 63 which were converted to 3-(3-arylpyrazol-4yl)propionic acids 64 by treatment of of potassium hydroxide with an alcoholic solution <06RJOC701>. 3-Aryl-1-phenyl-4-mercaptomethylpyrazoles reacted with monochloroacetic acid to give 3-aryl-1-phenyl-4-pyrazolylmethylsulfanylacetic acids whose oxidation with hydrogen peroxide in acetone or acetic acid solution led to 3-aryl-1-phenyl-4pyrazolylmethylsulfinyl- and sulfonylacetic acids, respectively <06RJOC703>. The nitration of 5-chloropyrazoles 65 with a mixture of 100% nitric acid and 65% oleum or a mixture of 60% nitric acid and polyphosphoric acid gave substituted 5-chloro-4-nitropyrazoles 66 <06RJOC901>. 4-Acyl-5-hydroxy-1-phenyl-3-trifluoromethylpyrazoles 69 were prepared by reaction of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol 67 with trimethyl orthoacetate, triethyl orthopropionate and triethyl orthobenzoate, respectively, followed by hydrolytic cleavage of the primarily formed condensation products 68 <06H(68)1825>. R R
N Et
N
1. POCl3
OHC R
R = H (77%) = Me (69%)
60
HO2 CHC=HC
HO2 CBrC=HC
Ar N N Ph 62
Br2 CHCl3
R
2. H 2O N Et 61
N
Ar N N Ph 63
HO 2CC C KOH EtOH 47-66%
Ar N N Ph 64
217
Five membered ring systems: with more than one N atom
R2 Cl
N R1 65
or HNO3/PPA
N
N R1 66
R1 = Me, Et, n-C 7 H15, R2 = Me, n-Pr, i-Pr, Ar
O
OR 2 R1 R1 C(OR 2)
N N Ph
N
Cl
45-91%
CF3 HO
R2
O 2N
HNO3 /SO3 -H 2 SO 4
3,
110-140 °C
R 1 = Me, Et, Ph
67
R 2 = Me, Et
CF3
HCl, H 2 O
N N Ph 68
O
46-96%
R1
CF3
HO
EtOH
N N Ph 69
Microwave irradiation provided a general methodology for the generation of oquinodimethanes derived from dibromopyrazole 70 in the presence of excess sodium iodide in DMF <06SL579>. The cycloaddition reactions with electron-deficient dienophiles such as Nmethylmaleimide afforded the corresponding heteropolycyclic adduct 71. Dimethyl acetylenedicarboxylate, diethyl azodicarboxylate and p-benzoquinone were other successful dienophiles employed in this reaction. N-Acetyl-styrylpyrazoles underwent Diels–Alder cycloaddition reactions with N-methylmaleimide under solvent-free conditions to give the corresponding tetrahydroindazoles in good yields and high selectivity <06SL1369>. O N Me Br N
O
Br N Ph 70
O
(2 eq) N
NaI (3 eq), DMF microwave
N Me
N Ph
O 71
80%
An efficient route to 4-aryloxy pyrazoles 74 bearing a trifluoromethyl group has been developed from 4-hydroxypyrazole 72 under basic conditions with 3,5-dicyanofluorobenzene 73 with concomitant removal of the silyl group to give pyrazoles 75 <06SL1404>. Fries-type NC
CN
NC
CN NC
O
F F3C
N 72
N
OTBS
CN
73
HO
K2 CO 3, DMF, 90 °C 85%
F3C
1. MsCl, Et3N, CH2 Cl2 N 74
N
O
2. NaCN, DMF, 70 °C OH
65%
F3C
N 75
NH
L. Yet
218
rearrangement of 3-acyloxypyrazoles led to 1-acyl-1,2-dihydro-3H-pyrazol-3-ones in the presence of titanium(IV) chloride or tin(IV) chloride <06JHC859>. A series of 2-(5-aryl-3-styryl-4,5-dihydro-1H-pyrazol-1-yl)-4-(trifluoromethyl)-pyrimidines 78 was synthesized by the cyclocondensation of 5-aryl-1-carboxamidino-3-styryl-4,5-dihydro1H-pyrazoles 76 with 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones 77 <06S2349>. Ar Ar
Ar H 2N
N
N
O +
NH· HCl 76
F3 C
OMe R
77
Ti(Oi-Pr)4 or BF3 ·OEt 2 (cat) EtOH, 25 ºC
Ar
60-90% R = H, Me, Ph, Ar, 2-f uryl, 2-thienyl,
N N
N N
R
CF3 78
1,3,5-Trisubstituted pyrazolines were converted to the corresponding pyrazoles efficiently by the treatment of a catalytic amount of HIO3 or I2O5 in water <06TL9283>. 1,3,5-Trisubstituted pyrazolones were oxidized to the corresponding pyrazoles in high yields by molecular oxygen in the presence of catalytic amount of N-hydroxyphthalimide and Co(OAc)2 in acetonitrile at room temperature <06T2492>. Many pyrazole fused ring systems have been reported. N-Substituted 5-pryazolones underwent thermal condensation with esters of -keto acids, losing water and alcohol molecules, to form N-substituted pyrano[2,3-c]pyrazol-6-ones 79 <06CHE326>. Ethyl 5-amino-3trifluoromethyl-1H-pyrazole-4-carboxylate was utilized as an useful reactant for the synthesis of trifluoromethylated pyrazolo[1,5-a]pyrimidine 80 <06JFC409>. Regioisomeric syntheses of polyfluoroalkylpyrazolo[1,5-a]pyrimidines 81 and 82 was accomplished from 3-amino-5methylpyrazole <06RJOC142>. Simple methods for the preparation of phosphorus-containing fused pyrimidine analogues such as pyrazolo[3,4-c][1,5,2]diazaphosphinine systems 83 and 84 from amidine derivatives of pyrazoles have been reported <06S1613>. A series of substituted 1H,6H-pyrano[2,3-c]pyrazol-6-ones 85 were synthesized from one-pot cyclocondensation of hydrazine derivatives or 1H-pyrazol-5-one derivatives with various β-keto esters under solventfree conditions using microwave irradiation <06SC51>. 1-Chloro-2-formyl-3,4dihydronaphthalene reacted with various aminopyrazoles to deliver 6,7-dihydro-pyrazolo[2,3a]benzo[h]quinazolines 86 <2006SC1601>. A one-pot and convenient synthesis of multisubstituted pyrazolo[3,4-b]pyridines 89 has been achieved by a two-step reaction of 5azido-1-phenylpyrazole-4-carboxaldehydes 87 to ketones 88 in ethanolic potassium hydroxide <06SC1549>. A convenient regioselective one-pot approach to pyrazolo[1,5-a]pyrimidine derivatives from α,β-unsaturated imines generated in situ with amino heterocycles has been reported <06TL2611>. One-step intermolecular aza-Wittig synthesis of pyrazolo[1,5derivatives from 5a]pyrimidine and imidazo[1,2-b]pyrazole (triphenylphosphoranylideneamino)-3-phenylpyrazoles and α-chloroketones has been reported <06JHC523>. Pyrazolo [3,4-b]pyridines were prepared from 2-tosyloxy-3-acylpyridines in the 1,3-Dipolar cycloaddition of dimethylacetylene presence of hydrazine <06CC726>. dicarboxylate to sydnones was exploited in the synthesis of 1-aryl-4,5-dihydro-1H-pyrazolo[3,4d]pyridazine-3,6-diones <06JHC827>.
219
Five membered ring systems: with more than one N atom
Me
Me
Me
R2
F3 C
N N R1
O
N N
O
N
H
N
Me
EtO2C
RF
F3 C N
O
N
81
82
R1 O OH Me P N
Me N N Ph
N
R R P N
Me N N Ph
Ar
83
N
O NH Me
Me
80
79
RF
F 3C
N N
R
R2
R2
1
N N
N
N N R3
Ar
84
O
O 85
86 R1
OHC
N
N3
N Ph
+
R2
R3
R 1 = Me, Ph
KOH, EtOH
N
reflux 88
R1
R2
O
R3
65-92%
N 89
87
N Ph
R 2 = H, Ac
(66)
R 3 = Me, Ph, Ar, -(CH 2) n-
A convenient one-step transformation of primary and secondary amines into the corresponding unprotected guanidines using 4-benzyl-3,5-dimethyl-1H-pyrazole-1carboxamidine 90 and its polymer-bound variant were described <06S461>. 1,3-Dipolar cycloaddition of polymer-bound alkynes to azomethine imines generated in situ from Naminopyridine iodides followed by aromatization of the cycloadducts gave polymer-bound pyrazolopyridines that were released from the resin as carboxylic acids with trifluoroacetic acid or as methyl esters with sodium methoxide <06JCO344>. Me R Me
N
ClH·H2 N 90
5.4.3
R = Ph,
N NH
IMIDAZOLES AND RING-FUSED DERIVATIVES
Trisubstituted imidazoles have been synthesized from 1,2-diketones or α-hydroxyketones with ammonium acetate in very short reaction times with excellent yields in the presence of 1,1,3,3-N,N,N’,N’-tetramethylguanidinium trifluoroacetate as an ionic liquid <06SC65>. Iodine acted as an efficient catalyst in the synthesis of 1,2,4,5-tetraarylimidazoles 93 using benzoin 91,
L. Yet
220
aromatic aldehydes 92 and benzylamine in the presence of ammonium acetate <06TL5029>. A variety of aromatic, aliphatic, and terpenoidal aldehydes underwent condensation with ammonium acetate or amines to give 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles in high yields using zirconium(IV) chloride as an efficient catalyst at room temperature <06SC2991>. A highly versatile method for the preparation of enantiopure 1-substituted-1,2disubstituted and 1,4,5-trisubstituted imidazoles was developed by using the cyclocondensation reaction of a 1,2-dicarbonyl compound, an aldehyde, a 1,2-amino alcohol and ammonium acetate <06T8199>.
Ph
BnNH2 , NH4 OAc (2 eq)
OH +
Ph
ArCHO
O
I2 (10 mol%), EtOH, reflux 94-98%
92
Ph
N
Ph
N 93 Ph
Ar
91
2-Imidazolines 96, prepared from the reaction of aldehydes 94 and ethylenediamine 95 with molecular iodine in the presence of potassium carbonate, were smoothly oxidized to the corresponding imidazoles 97 in good yields using (diacetoxyiodo)benzene at room temperature <06SL227>. Similarly, the preparation of 2-imidazolines 96 was performed by cyclization of nitriles 98 with ethylenediamine 95 under microwave irradiation in solvent-free conditions followed by aromatization to imidazoles 97 under microwave irradiation in toluene and using manganese oxide or MagtrieveTM as the oxidant <06S5868>. The system, I2/KI/K2CO3/H2O, oxidized carbon–nitrogen bonds for the synthesis of imidazolines and benzimidazoles from aldehydes and diamines under anaerobic conditions in water at 90 ºC has also been reported <06TL79>. Rapid and efficient preparation of 2-imidazolines and bis-imidazolines by reaction of ethylenediamine with nitriles in the presence of catalytic amounts of sulfur under ultrasonic irradiation has been reported <06TL2129>. NH2 95
H 2N RCHO 94
I2 , K2CO3 (3 eq)
H 2N RCN 98
NH2 95
microwave solvent-f ree 74-98%
PhI(OAc) 2, K2 CO 3
DMSO, 25 ºC N 38-83% 96 R = Ar, cyclohexyl, 2-furyl
t -BuOH, 70 ºC 50-100%
H N
R
H N R N 96
MnO2 or Magtrieve TM PhMe, microwave 56-64%
H N
R
N 97
R
H N N 97
R = pyrazolyl-type
A microwave-assisted, one-pot, two-step protocol was developed for the construction of polysubstituted 2-aminoimidazoles 101 via the sequential formation of imidazo[1,2a]pyrimidinium salts from readily available 2-aminopyrimidines 99 and α-bromocarbonyl compounds 100, followed by opening of the pyrimidine ring with hydrazine <06OL5781>. A
Five membered ring systems: with more than one N atom
221
single-pot novel synthesis of varied substituted 4-hydroxyimidazoles 103 by SeO2-mediated oxidation of 1-aryl-2-phenyl/thiomethyl/secondary amino-4-N,N-dimethylamino-4-methyl-1,3diazabuta-1,3-dienes 102 has been reported <06SL2199>. Reaction of tetracyanoethylene, ammonium acetate and carbonyl compounds afforded 2-[5-amino-2,3-dihydro-4H-imidazol-4ylidene]malononitriles <06TL1445>. 2-Aminoimidazol-4-carbaldehyde derivatives were prepared by the reaction of tert-butoxycarbonylguanidines with 3-bromo-1,1dimethoxymethylpropan-2-one <06SL2836>. Addition of lithiated methoxyallene to imines provided allenyl amines, which upon reaction with iodine and nitriles furnished dihydroimidazole derivatives <06SL1683>. Addition of allyl amines to isocyanates afforded Nallylureas, which are converted to imidazolidin-2-ones with generation of two bonds and up to two stereocenters when treated with aryl bromides and catalytic amounts of Pd2(dba)3/Xantphos in the presence of sodium tert-butoxide <06OL2531>. An efficient route to 4-aryl-5pyrimidinylimidazoles via sequential functionalization of 2,4-dichloropyrimidine has been published <06OL269>. 1. MeCN, 130-150 ºC, N
+
R 3 2. 60% NH 2NH 2 (5 eq),
R2
NHR1
N
microwave
Br
O
99
100
R2
N
R3
N R1
NH2
MeCN, 100 ºC, microwave
101
R 1 = Me, Et, Bn, n-C5 H11, cyclopropyl, cyclopentyl R 2 = H, Me, Bn, Ar R 3 = H, Ar
38-96%
Ar R
N N
Me
50-55 ºC NMe 2 102
Ar N
SeO2 dioxane, H2 O 51-69%
R N
OH
R = Ph, piperidinyl, pyrrolidinyl, thiomethyl
103
Metal-mediated approaches to the synthesis of imidazoles have been reported. The palladium-catalyzed coupling of imines and acid chloride was used to provide a new, one-step method to synthesize imidazoles <06JA6050>. A new efficient copper-catalyzed preparation for 1,4-disubstituted imidazoles 106 via the cross-cycloaddition between isocyanides 104 and 105 has been published <06JA10662>. [3+2]-Cycloaddition of aziridines 107 with various nitriles in the absence of organic solvent catalyzed by Sc(OTf)3 afforded the corresponding imidazolines 108 in good to excellent yields under extremely mild reaction conditions <06TL1509>. Cu(OTf)2 or Zn(OTf)2 mediated [3+2] cycloaddition reactions of various α-alkyl or α-aryl substituted N-tosylaziridines with nitriles has also been described for the syntheses of substituted imidazolines <06TL5399>.
L. Yet
222
Cu 2O (10 mol%) ArNC
+
NC
104
EWG 105
Ar
1,10-phenanthroline
N
(20 mol%)
N 106
THF, 80 ºC
EWG
88-98%
R
RCN, Sc(OTf) 3 (25 mol%)
Ts N
solvent-f ree, 25 ºC, air
Ar
51-94%
107
R = Me, n-Pr, Ar
N
N Ar
Ts
108
Multicomponent reactions have been described for several syntheses of imidazoles. Highly efficient methods for the syntheses of spiroimidazolinones via microwave-assisted threecomponent one-pot sequential reactions or one-pot domino reactions have been described <06JOC3137>. Multicomponent reactions between 2-aminopyrimidine, aldehydes and isonitriles afforded imidazo[1,2-a]pyrimidines <06TL947>. Two novel one-step microwave mediated syntheses of arrays of 3-iminoaryl-imidazo[1,2-a]pyridines and imidazo[1,2-a]pyridyn3-ylamino-2-acetonitriles were synthesized by multicomponent reactions under microwave condition in methanol by simply mixing α-aminopyridines, aldehydes, and trimethylsilylcyanide catalyzed by polymer-bound scandium triflate <06TL2989>. 3-Aminoimidazo[1,2-a]pyridines have been synthesized via the multicomponent reaction of aldehydes, isocyanides and 2aminopyridines in the presence of the ionic liquid 1-butyl-3-methylimidazolium bromide [bmim]Br <06TL3031>. A radical phosphination reaction of organic halides and alkyl imidazole-1-carbothioate has been reported <06JA4240>. 4-Arylsulfonylmethyl-5-nitroimidazoles were prepared by reacting four chloromethylaryl sulfones with 5-nitroimidazole derivatives via a vicarious nucleophilic substitution (VNS) of hydrogen reaction <06SC3639>. Application of palladium-catalyzed π– allyl chemistry to 4-allylimidazoles 109 provided entry to substituted imidazoles 110 without allylic transposition <06T10555>. The multi-gram scale polybromination of variously substituted imidazoles was performed using a stoichiometric amount of the bromine–DMF complex <06TL1949>. In some nucleophilic substitution reactions of 2-cyano-3nitroimidazo[1,2-a]pyridine, nitrogen and oxygen nucleophiles underwent substitution of the 2cyano group, while sulfur nucleophiles underwent substitution of the 3-nitro group <06JHC565>. O N N PG
O
Pd2 (dba) 3, PPh 3 X
NuH or Nuc, solvent 62-98%
109
PG = Bn, MOM X = Me, OEt, Ot-Bu
N N PG
Nuc
110
223
Five membered ring systems: with more than one N atom
A new reaction of the efficient difluorocarbene-generating reagent trimethylsilyl fluorosulfonyldifluoroacetate (TFDA) is reported in which molecules containing an Nalkylimidazole 111 or benzimidazole structure underwent an unexpected one-pot conversion to N-difluoromethylthioureas 112 <06OL5549>. Thermolysis of 1,2-dialkynylimidazoles 113 in benzene solution afforded 7-phenyl-5H-cyclopentapyrazines 114, which presumably formed by solvent trapping of cyclopentapyrazine carbene intermediates <06TL353>.
R N
TFDA (4 eq), NaF (cat)
N
R = Bn (63%), Me (52%)
DME, 105 ºC
111
R N S N CF2 H 112
R2 PhH, 80-100 ºC N
R1 = H, Ph
N R1
113
Ph N
38-88%
R2 = H, Ph, n-Pr,
R2 N 114
R1
Ar, CH 2OMe
A basic ionic liquid, 1-methyl-3-butylimidazolium hydroxide ([bmIm]OH) and 1-butyl-3methyl-methylimidazolium tetrafluoroborate ([bmim]BF4), has been introduced as a catalyst and reaction medium for the Markovnikov addition of imidazoles 116 to vinyl esters 115 under mild conditions to give imidazoesters 117 <06JOC3991; 06TL1555>. A series of (nitroimidazolyl)succinic esters and diacids were prepared from the Michael-type addition of the nitroimidazole to the α,β-unsaturated ester <06S3859>. H (NO2) H(NO 2)
O R
N O
115
+
N H 116
N
[bmim]BF4 or [bmim]OH, 50 ºC 81-98%
R = Me, i-Pr, n-C 4H 9, Ph
O R
N O
Me
117
Several reports of the synthesis and chemistry of benzimidazoles have been published. The most common methods involved the condensation of 1,2-phenylenediamine with a carbonyl group. 2-Substituted benzimidazoles were prepared from 1,2-phenylenediamine and esters under microwave conditions <06SC2597>. A highly selective synthesis of 2-aryl-1-arylmethyl-1H1,3-benzimidazoles from the reaction of 1,2-phenylenediamines and aromatic aldehydes in the presence of silica sulfuric acid in ethanol or water has been reported <06TL2557>. Microwaveassisted one-step high-throughput synthesis of benzimidazoles from phenylenediamine and carboxylic acids in the presence of triphenyl phosphite has been disclosed <06TL2883>. A
L. Yet
224
simple and environmentally friendly synthesis of 2-substituted benzimidazoles was developed using a small-pore-size zeolite <06SC3625>. Condensation of aldehydes with 1,2phenylenediamine and catalytic iodine in water provided a convenient synthesis of benzimidazoles <06JHC773>. 2-Substituted benzimidazoles 119 were prepared by reaction of 2-azidoaminobenzenes 118 with aldehydes under thermal conditions <06SC3425>. The reaction probably proceeded via a sequential imine formation, azide decomposition forming a nitrene, and electrocyclization. The treatment of benzylidene(2-nitroaryl)amines 120, prepared by the reaction of o-nitroaniline and benzaldehydes, with carbon monoxide in the presence of a catalytic amount of selenium under basic conditions, afforded 2-aryl-1H-benzimidazoles 121 <06SL109>. Hydrogenation of Nsubstituted 2-nitroanilines with palladium on carbon as catalyst in the presence of trimethyl orthoformate and catalytic pyridinium p-toluenesulfonate at room temperature provided the corresponding disubstituted benzimidazoles <06TL5359>. A liquid phase PEG-ester resin, derived from the commercially available 4-fluoro-3-nitrobenzoic acid, was used in the multistep synthesis of specifically functionalized bis-benzimidazoles where microwave irradiation through ten steps involved ipso-SNAr reaction, neutral reduction and acid cyclization <06TL2601>. Using carbodiimide reagents [1,3-diisopropylcarbodiimide or N-(3-dimethylaminopropyl)-N’ethylcarbodiimide hydrochloride (EDC)], a mild, generalized, one-pot method that delivered N2-arylaminobenzimidazole esters from commercially available aryl isothiocyanates and 1,2phenylenediamines has been developed <06JCO907>. Homonuclear Diels–Alder dimerization of various 5-ethenyl-2-phenylsulfanyl-1H-imidazoles provided a novel highly regio- and stereoselective route to the preparation of multifunctionalized 4,5,6,7-tetrahydrobenzimidazoles <06T10182>. R 2CHO NH 2
HOAc, EtOH
R1
N
reflux
N3
N H 119
44-96%
118
N NO 2 120
Ar
R2
R1
R1 = H, Cl, Me, OMe R2 = i-Pr, n-C6 H13 , Ph, Ar
N
CO, Se (10 mol%), 3A MS
Ar
DBU, 1,4-dioxane, 120 °C 76-99%
121
N H
Imidazoles and fused-derivatives have participated in a myriad of cross-coupling reactions. The reaction of protected 4,5-diiodoimidazoles with (PhMe2CCH2)2CuLi regioselectively provided 5-cuprated imidazoles, which readily reacted with various electrophiles furnishing functionalized imidazoles in good yields <06CC2170>. Remarkably, these resulting monoiodoimidazoles underwent again an iodine–copper exchange reaction in the presence of sensitive functional groups like an aldehyde or a ketone. In the presence of copper(I) bromide, 2aminopyrimidine-4,6-diol, and tetrabutylammonium fluoride, a variety of imidazoles underwent the N-arylation reaction with aryl and heteroaryl halides <06JOC8324>. 4,7-Dimethoxy-1,10phenanthroline was found to be an efficient ligand for the copper-catalyzed N-arylation of imidazole with aryl iodides and bromides under mild conditions <06OL2779>. Copper-
Five membered ring systems: with more than one N atom
225
catalyzed N-arylation of imidazole and benzimidazole can be accomplished using air-stable copper(I) iodide as a copper source and 1,10-phenanthroline in the presence of potassium fluoride/alumina as a base <06SL2124; 06TL5203>. By using copper(I) iodide as the catalyst and L-Proline as the ligand, the Ullmann-type coupling reactions of aryl/heteroaryl bromides and imidazoles in [Bmim]BF4 at 105–115 ºC gave the corresponding N-arylimidazoles/Nheteroarylimidazoles in good yields <06T4756>. A general and efficient method for the coppercatalyzed cross-coupling of amides and thiophenols with 6-halogenoimidazo[1,2-a]pyridines has been reported <06T6042>. C-H Arylation of imidazoles and benzimidazoles has appeared recently in the literature. The first palladium- and copper-mediated C-2 arylations of imidazole 122 with aryl iodides under ligandless and base-free conditions to give 2-arylimidazoles 123 has been described <06EJO1379>. This system worked for benzimidazole also and no N-arylation products were observed for both imidazole and benzimidazole. Efficient palladium-catalyzed microwaveassisted arylation of 2-substituted imidazo[1,2-a]pyrimidines has been disclosed <06JCO659>. The sterically-hindered imidazolyl carbene ligand complex 125 catalyzed the efficient C-H arylation of imidazo[1,2-a]pyridines 124 to give 126 <06OL1979>. Palladium-catalyzed direct arylation and heteroarylation of imidazo[1,2-a]pyridines at the 3-position where comparisons between classical heating and microwave irradiation has been described <06SL3237>. N N H 122
ArI, Pd(OAc)2 (5 mol%)
N
CuI (2 eq), DMF 140 ºC
N H 123
Ar
53-89%
CsOAc (2 eq) N N 124
CO2 Et
N
125 (2.5 mol%) ArX, DMA, 125 ºC 51-98%
CO2 Et
N 126
Ar
N
N
O 125
N
Me
Me Pd(I)2 PPh 3
Many ring-fused imidazole derivatives have been synthesized by various methods. 3Bromoimidazo[1,2-a]pyridine derivatives have been directly synthesized from reaction of 2aminopyridines with α-haloketone derivatives followed by DMSO oxidation <06CL270>. The synthesis of dipyrido[1,2-a:2’,3’-d]imidazole and hitherto unknown benzo and aza analogues has been described <06JOC260>. An efficient new route for the synthesis of benzimidazo[1,2a]quinolines has been developed via the palladium catalyzed intramolecular Buchwald-Harwtig aryl amination of newly synthesized 2-(2’-bromoanilino)quinolines <06JOC1280>. Iodinemediated, oxidative desulfurization promoted cyclization of N-2-pyridylmethyl thioamides served as an efficient and versatile method for the preparation of imidazo[1,5-a]pyridines <06OL5621>. Methyl 2-trimethylsiloxycyclopropanecarboxylates, 2-aminopyridine and isonitriles were combined in a one-pot reaction to provide a series of novel δ-amino acids incorporating an imidazo[1,2-a]pyridine backbone <06S2677>. A highly efficient one-pot methodology has been developed to synthesize a class of substituted 1-pyridylimidazo[1,5a]pyridines, using Brönsted acidic ionic liquid 1-butylimidazolium tetrafluoroborate, [Hbim]BF4 <06S2849>. 5H-imidazo[5,1-a]isoindoles were prepared from intramolecular C-H arylation
226
L. Yet
palladium-catalyzed reactions <06SL3170>. Thermolysis of 1,2-dialkynylimidazoles in chlorinated solvents led to 5-chloroimidazo[1,2-a]pyridine products <06T3798>. The synthesis of polyfunctional imidazo[1,5-a]pyridines via the reactive species generated in situ from Nsubstituted lactams and Viehe’s salt has been reported <06TL1395>. A series of 5,7,8polysubstituted imidazo[1,2-a]pyridines were synthesized regioselectively from in situ generated α,β-unsaturated imines and dianions derived from methyl azolyl acetates in a one-pot procedure <06TL2941>. Fused imidazo-pyridine and -azepine derivatives were synthesized using a sequential van Leusen/intramolecular Heck protocol <06TL3225>. A concise route to access fused imidazole rings employing the van Leusen three-component reaction followed by a palladium/copper catalyzed intramolecular C-arylation has been reported <06TL8873>. Synthesis of some 4,5-dihydro-2H-benzo[g]indazoles and 8,9-dihydro-2H-benzo[e]indazoles via the Vilsmeier-Haack reaction under thermal and microwave irradiation conditions has been reported <06JHC389>.
5.4.4
1,2,3-TRIAZOLES AND RING-FUSED DERIVATIVES
A microreview on the copper(I)-catalyzed alkyne–azide “click” cycloadditions from a mechanistic and synthetic perspective has been written <06EJO51>. Click chemistry includes a range of reactions that proceed in high yield under ambient conditions, preferably in water, with regioselectivity and a broad tolerance of functional groups. The copper-catalyzed 1,3-dipolar cycloaddition reaction of azides and acetylenes to give 1,2,3triazoles is known as the “cream of the crop” of all click reactions. β-Tosylethylazide (TSE-N3), which could be prepared in one step from p-tolyl vinyl sulfone and sodium azide/sulfuric acid, underwent copper(I)-catalyzed 1,3-dipolar cycloadditions with alkynes in the presence of sodium ascorbate to produce TSE-protected 1,2,3-triazoles where the protecting group could be removed using potassium tert-butoxide <06TL3035>. Primary, secondary, and aromatic azides underwent 1,3 dipolar cycloaddition-coupling with an excess of alkyne in the presence of Cu(CH3CN)4PF6 as catalyst, N,N,N’-trimethylethylenediamine as ligand, molecular oxygen, and 4methoxymorpholine N-oxide (NMO) as co-oxidant to afford 1,4,5-trisubstituted-1,2,3-triazoles <06T6405>. Copper(II) acetate-promoted regioselective synthesis of 1,4-disubstituted-1,2,3triazoles in water has been reported <06SL957>. The use of methylene chloride as a co-solvent with water in the copper(I)-catalyzed 1,3-dipolar cycloaddition of organic azides and alkynes increased reaction rates and provided the corresponding 1,2,3-triazoles in excellent yields compared to other organic co-solvent systems <06TL5105>. A series of orthogonally protected 1,4-disubstituted-1,2,3-triazoles were prepared from the corresponding alkynols and trialkylsilylpropargyl azides via 1,3-dipolar cycloaddition <06TL6971>. A polymer-supported benzyldimethylamino catalyst for the Hüisgen’s [3+2] cycloaddition reaction between azides and alkynes to give 1,4-disubstituted-1,2,3-triazoles was prepared from copper(I) iodide and Amberlyst A-21 <06OL1689>. A three-step solid-phase-supported sequence involving reductive amination by N-phenylpiperazinyl-substituted alkylamines, N-acylation by alkynoic acids, and azide-alkyne [3 + 2] cycloaddition parallel synthesis of 1,2,3-triazole carboxamides has been reported <06JCO252>. A three-component coupling was used to prepare a series of 1,4-disubstituted-1,2,3-triazoles 129 from the corresponding acetylated Baylis–Hillman adducts 127, sodium azide and terminal alkynes 128 <06TL3059>. This same reaction was also carried out in either water or in
227
Five membered ring systems: with more than one N atom
polyethylene glycol as a solvent in the presence of copper(I) iodide <06TL3055>. A copper(I) catalyst in a mixture of the ionic liquid [bmim][BF4] and water effected three-component reaction of halides, sodium azide and alkynes to form 1,4-disubstituted 1,2,3-triazoles <06TL1545>. R1
OAc EWG
1
R
R2
+
NaN3 , Cu, CuSO 4 EtOH, 80 ºC
128
72-92%
127
EWG N
R 1 = Ph, Ar, 3-furyl, n-C5 H 11
N N
R 2 = Ph, n -C 5H 11 , CH2 CH2 OH EWG = CO2 Me, CO2 Et, CN
R2
129
Tandem azidination– and hydroazidination–Hüisgen [3 +2] cycloadditions of ynamides are regioselective and chemoselective, leading to the synthesis of chiral amide-substituted 1,2,3triazoles <06OBC2679>. A series of diversely 1-substituted-4-amino-1,2,3-triazoles 132 were synthesized by the copper-catalyzed [3+2] cycloaddition between azides 130 and ynamides 131 <06T3837>. Cu(OAc)2 , sodium ascorbate R N3 +
Bn
t-BuOH, H2 O
Bz
38-96%
N
130
131
N N R N
R = alkyl, Bn, carbohydrate
132
Bn N Bz
[3+2]-Cycloadditions of alkyl azides 134 with various unsymmetrical internal alkynes 133 in the presence of Cp*RuCl(PPh3)2 as catalyst in refluxing benzene led to 1,4,5-trisubstituted-1,2,3triazoles 135 and 136, whereas alkyl phenyl and dialkyl acetylenes underwent cycloadditions to afford mixtures of regioisomeric 1,2,3-triazoles and acyl-substituted internal alkynes reacted with complete regioselectivity <06JOC8680>. In addition, propargyl alcohols and propargyl amines were found to react with azides to afford single regioisomeric products. Coppercatalyzed [3+2] cycloaddition of azides to mono- and disubstituted alkynes with N-heterocyclic carbene ligands have been found to be a versatile and highly efficient reaction in which an internal alkyne was successfully shown to work for the first time <06CEJ7558>. R3 *
R1
R2 133
+
R 3 N3 134
Cp RuCl(PPh 3) 2 PhH, 80 ºC 10-100%
N N N 1
R 135
R2
R3 +
N N N
R1
R2 136
“Click” chemistry has been particularly active in various fields this year. For example, ample applications of click chemistry have been seen in carbohydrate chemistry. Various pseudo-oligosacchardies and amino acid glycoconjugates were synthesized via an intermolecular 1,3-dipolar cycloaddition reaction using easily accessible carbohydrate and amino acid derived azides and alkynes as building blocks <06JOC364>. The iterative copper(I)-catalyzed
228
L. Yet
cycloaddition between an ethynyl α-C-mannoside and alkyl 6-azido-α-C-mannoside derivatives was suited to the (1,6)-ligation between α-D-mannose units through 1,4-disubstituted triazole bridges, thus resulting in the formation of linear oligomers with alternating triazole and mannose fragments up to a triazolo-pentamannose derivative <06OBC3225>. Cu(I)-catalyzed 1,3-dipolar cycloaddition between azido-2’-deoxyribose and terminal alkynes. afforded quantitatively 4substituted 1,2,3-triazolyl-nucleosides under solvent-free microwave irradiation <06TL4807>. Click chemistry in the area of peptide and protein chemistry has also been seen. A small library of protein tyrosine phosphatase (PTP) inhibitors was synthesized by the Cu(I)-catalyzed 1,3-dipolar alkyne-azide cycloaddition reactions <06OL713>. A panel of 1,2,3-triazole metalloprotease inhibitors was assembled by reacting eight zinc-binding hydroxamate alkynyl warheads with 12 azide building blocks <06OL3821>. Similar cycloadditions of azidoalkynes having ester, furanoside and peptidic tethers led to the formation of monomeric triazolophanes of higher ring sizes. Peptidotriazoles, unnatural oligomers with alternating amide and triazole linkages, were synthesized efficiently on solid support <06TL665>. A practical approach toward proline derived triazolopeptides employing [3+2] azide–alkyne cycloadditions as the key reaction step and the analysis of their cis/trans prolyl ratios has been reported <06T8919>. Cu(I)-catalyzed 1,3-dipolar cycloaddition ‘click chemistry’ was used to prepare 18F-radiolabeled peptides <06TL6681>. “Click” cyclization was employed in the efficient route to well-defined macrocylic polymers <06JA4238>. α-Isocyano acetamide-based three-component reaction followed by a coppercatalyzed intramolecular [3+2] cycloaddition of alkyne and azide afforded complex macrocycles <06OL4145>. A strained monomeric 12-membered triazolophane was formed by the Cu(I)catalyzed intramolecular cycloaddition of an azide to an alkyne having a constrained tether incorporating an aromatic ring and a furanoside ring <06TL2775>. Novel fluconazole/bile acid conjugates were designed and their regioselective synthesis was achieved in very high yield via Cu(I)-catalyzed intermolecular 1,3-dipolar cycloaddition <06T11178>. A new fluorous F17CLICK-TEMPO catalyst for the oxidation of alcohols to aldehydes was prepared by a facile approach using the copper-catalyzed azide-alkyne cycloaddition as the ligation method <06SL2767>. Conjugated tetra-1,2,3-triazoles were synthesized by the coupling reaction of terminal alkynes <06SL645>. New nonlinear compounds containing 1,4-diaryl-[1,2,3]-triazole were prepared using a straightforward and efficient method for the regioselective synthesis of [1,2,3]-triazoles <06SC951>. Potassium azidoalkyltrifluoroborates reacted with various alkynes in a copper(I)-catalyzed reaction to give 1,4-disubstituted organo-[1,2,3]-triazol-1-yltrifluoroborates <06OL2767>. 1,2,3-Triazoles with 1-position substituents, derived from tocopherol (vitamin E), were synthesized by 1,3-dipolar cycloaddition reactions of 5α-azido- tocopheryl acetate with alkynes <06EJO2081>. The reaction of benzyl azide with terminal di-, tri-, and tetraynes appended with a range of functional groups proceeded regioselectively to give terminal 1,2,3-triazole products <06OL6035>. The addition of azide or diazo reagents to activated substrates is also another method of preparing 1,2,3-triazoles. Palladium-catalyzed synthesis of 1H-triazoles 138 from alkenyl halides 137 and sodium azide in the presence of xantphos ligand has been reported <06AG(I)6893>. A regiospecific 1,3-dipolar cycloaddition of 2-diazopropane to iminoethers afforded in two steps the corresponding 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles <06TL6685>. 4,5-Dihydro-1H-1,2,3-triazoles can also be prepared from the 1,3-dipolar cycloaddition of 2diazopropane to imidates <06JHC499>. An efficient and regioselective procedure for the
Five membered ring systems: with more than one N atom
229
synthesis of 1,2,3-triazoles via a [3+2] cycloaddition of polymer-bound vinyl sulfone and sodium azide under microwave irradiation has been described <06OL3283>. NaN 3 , Pd2 (dba) 3 xantphos, dioxane
Br
R
or DMSO, 90-110 ºC 137
R
R = Ph, Ar, 2-furyl, CH 2 OBn
N N NH 138
45-94%
Other non-traditional preparations of 1,2,3-triazoles have been reported. The rearrangement in dioxane/water of (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole into (2-aryl-5phenyl-2H-1,2,3-triazol-4-yl)ureas was investigated mechanistically in terms of substituents on different pathways <06JOC5616>. A general and efficient method for the preparation of 2,4diaryl-1,2,3-triazoles 140 from α-hydroxyacetophenones 139 and arylhydrazines is reported <06SC2461>. 5-Alkylamino-1H-1,2,3-triazoles were obtained by base-mediated cleavage of cycloadducts of azides to cyclic ketene N,N-acetals <06S1943>. Oxidation of N(alkylamino)pyrazolones is a good and general strategy for the preparation of monocyclic 1,2,3triazin-4-ones, which upon photochemical reaction resulted in the loss of carbon monoxide and rearrangement to a 2-alkyl-2H-1,2,3-triazole <06EJO3021>. A new simple and efficient approach to 2,4-disubstituted-1,2,3-triazoles-5-amines from the reaction of 2arylhydrazononitriles and hydroxylamine has been described <06ARK53>. Reaction of Nfluoropyridinium fluoride generated in situ with a series of isonitriles and diazo compounds led to the formation of the corresponding (pyridine-2-yl)-1H-1,2,3-triazoles in good yields <06TL2631>. O OH
Ar2 R 139
Ar2NHNH2, CuCl2 AcOH, reflux 52-86% R = H, Ph
Ar2 R
N N Ar2 N 140
A variety of triazole-based monophosphines (ClickPhos) 141 have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes and their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides <06JOC3928>. A novel P,N-type ligand family (ClickPhine) is easily accessible using the Cu(I)-catalyzed azide-alkyne cycloaddition reaction and was tested in palladium-catalyzed allylic alkylation reactions <06OL3227>. Novel chiral ligands, (S)-(+)-1-substituted aryl-4-(1-phenyl) ethylformamido-5-amino-1,2,3-triazoles 142, R 2P N
Ar
N Ph N 141 R = Ph, t-Bu, Cy
Me Ph
*
O NH 2
HN N
N
142
N Ar
L. Yet
230
were prepared were used as catalytic chiral ligands in the silver (I)-promoted enantioselective allylation reaction of aldehydes with allyltributyltin <06SC1063>. Benzotriazole-related methodology publications appeared in 2006. Reaction of 1formylbenzotriazole with triphenylphosphine/carbon tetrachloride afforded 1-(2,2dichlorovinyl)benzotriazole, where lithiation followed addition of electrophiles gave a variety of functionalized N-(ethynyl)benzotriazoles <06T3794>. Novel mono- and symmetrical di-Nhydroxy- and N-aminoguanidines were readily prepared from the reaction of diverse hydroxylamines or hydrazines with reagent classes di(benzotriazol-1-yl)methanimine, (bisbenzotriazol-1-yl-methylene)amines, benzotriazole-1-carboxamidines, benzotriazole-1carboximidamides, and N’-hydroxy-1H-1,2,3-benzotriazole-1-carboximidamide <06JOC6753>. α-Carbolines were prepared from benzotriazoles and azines bearing a leaving group at the C2 position through the modified Graebe-Ullmann reaction under microwave irradiation <06OL415>. A one-pot synthesis of unsymmetrical disulfides from 1-chlorobenzotriazole has been described <06JOC8268>. Michael addition of benzotriazole or 1,2,3-triazole to nitroolefins, promoted by a cinchona alkaloid, gave Michael adducts in moderate to high enantioselectivities <06OL1391>. Stable and easily accessible N-acylbenzotriazoles, derived from a variety of aliphatic, unsaturated, (hetero)aromatic, and N-protected-R-amino carboxylic acids, were reacted with Grignard and heteroaryllithium reagents to afford the corresponding ketones <06JOC9861>. Some interesting fused 1,2,3-triazole ring systems have been reported. A series of 5piperidyl-substituted 7-hydroxy-3H-1,2,3-triazolo[4,5-d]pyrimidines 143 has been synthesized from pipecolinate esters, benzylazides, and cyanoacetamide <06CHE246>. 4-Alkylidene-5,6dihydro-4H-pyrrolo-[1,2-c][1,2,3]triazoles 144 were prepared from alkylidenecyclopropanes via diiodogenation/Cu(I)-catalyzed 1,3-dipolar cycloaddition/intra-molecular Heck reaction sequence <06SL1446>. 6,6-Dimethyl-2-phenyl-4,5,6,7-tetrahydro-2H-benzotriazol-4-one 145 were prepared from N-(5,5-dimethyl-3-oxocyclohexenyl)-S,S-diphenylsulfilimine and benzenediazonium chloride <06SC2087>. A tandem aza-Wittig reaction of an iminophosphorane with acyl chlorides afforded 3,5-dihydro-1,2,3-triazolo[4,5-d]-1,2,4triazolo[1,5-a]pyrimidin-9-ones 146 <06OBC130>. N-Acyl and N-alkoxycarbony derivatives 147 of 1H-1,2,3-triazolo[4,5-c]pyridine have been prepared and applied in the protection of amines and amino acids <06JHC417>. Two series of compounds, 3-aryl- and 3-methyl-7aryl[1,2,3]triazolo[1,5-a]pyridines have been synthesized by Suzuki cross-coupling reactions, with a triazolopyridine halide and an aryl or heteroaryl boronic acid in moderate to good yields <06TL8101>. OH N
N N
N N H
O N
Ar 143
N
N N
R3 144
O
O N Ph
Me R2
R1
N
Me 145
N N Ph
R N N
N
N
N
R
N N
Ar 146
N N N
147
231
Five membered ring systems: with more than one N atom
5.4.5
1,2,4-TRIAZOLES AND RING-FUSED DERIVATIVES
A comprehensive review on the chemistry of mercapto- and thione-substituted 1,2,4triazoles and their utility in heterocyclic synthesis has been published <06ARK59>. The thermodynamic parameters, ΔΔH# and ΔΔS#, were determined for the interception of an intermediate, with the structural characteristics of an aziridinium imide, by nucleophilic solvents during the reaction of 2-methyl-2-butene with N-phenyltriazolinedione <06TL2961>. Acyl hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. Reaction of acyl hydrazides 149 with imidoylbenzotriazoles 148 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 150 <06JOC9051>. Treatment of N-substituted acetamides with oxalyl chloride generated imidoyl chlorides, which reacted readily with aryl hydrazides to give 3-aryl-5-methyl-4-substituted[1,2,4]triazoles <06SC2217>. 5-Methyl triazoles could be further functionalized through α-lithiation and subsequent reaction with electrophiles. (E)-N’-(Ethoxymethylene)hydrazinecarboxylic acid methyl ester 152 was applied to the one-pot synthesis of 4-substituted-2,4-dihydro-3H-1,2,4triazolin-3-ones 153 from readily available primary alkyl and aryl amines 151 <06TL6743>. An efficient synthesis of substituted 1,2,4-triazoles involved condensation of benzoylhydrazides with thioamides under microwave irradiation <06JCR293>. HOAc, microwave N N
+
N R1
R 1 = Me, Bn, p-Tol
O NR2
R3
NHNH2 149
151
R3 = Me, Ph, p-tol
R3 N
R1
N
77-100%
148
RNH2 +
R2 N
R2 = p-Tol, 4-OMeC6 H 4
150
EtO
N
NHCO 2Me
152
EtOH, 50 ºC then NaOMe, MeOH, 75 ºC 34-94%
N NH N R 153
O
The methyl ester of N-tert-butoxycarbonyl-(Z)- -bromo- -(1,2,4-triazol-1-yl)dehydroalanine was prepared by treatment of the methyl ester of N-tert-butoxycarbonyl-(E)- -(1,2,4-triazol-1yl)dehydroalanine with N-bromosuccinimide, followed by triethylamine <06EJO3226>. A convenient approach to 4,5-disubstituted-3-hydroxymethyl-1,2,4-triazoles as well as to the corresponding 3-chloromethyl and 3-carboxaldehyde derivatives was developed starting from 3mercapto-1,2,4-triazoles which can, in turn, were readily obtained from acyl hydrazines and isothiocyanates <06S156>. 1,2,4-Triazole nucleoside analogues bonded at N-1 of the base were synthesized by addition of N-halo-3,5-dibromo-1,2,4-triazoles to 1,2-unsaturated carbohydrate N,N,N’,N’-Tetrabromobenzene-1,3-disulfonylamide (TBBDA) or derivatives <06S496>. trichloromelamine (TCM) were used as effective oxidizing agents for the oxidation of urazoles and bisurazoles to their corresponding 1,2,4-triazolinediones under mild and heterogeneous conditions <06S1631>. The first cross-coupling reactions on halogenated 1H-1,2,4-triazole nucleosides has been described <06T3301>. Bromination of 2-aryl-1-[1,2,4]triazol-1-ylalk-3-
L. Yet
232
yn-2-ols afforded 6-bromo-7-hydroxy-5-alkyl-7-aryl-7,8-dihydro-[1,2,4]triazolo[1,2-a]pyridazin4-ylium salts, which were converted to 3-alkyl-5-arylpyridazines on treatment with strong alkali <06T8966>. The reactions of urocanic acid methyl esters with singlet oxygen and 4-methyl1,2,4-triazoline-3,5-dione were explored <06T10700>. Aryltriazole nucleosides with various aromatic groups in the 5-position on the 1,2,4-triazole ring were synthesized via a Suzuki reaction starting with bromotriazole nucleoside under microwave irradiation <06TL6727>. A facile method for the synthesis of 3-allyl-4-(1,2,4-triazolo-3,5-dione)cyclopentenes 156 from bicyclic 1,2,4-triazolo-3,5-diones 154 by the Pd/Lewis acid catalyzed reaction of allyltributyltin 155 in ionic liquid has been described <06TL3997>. 1-Methyl-1,2,4-triazole underwent direct silylation at the C-5 position with bromotrimethylsilane in the presence of triethylamine <06S1279>. SnBu3 N N N
O
155 O
[Pd(allyl)Cl] 2 (5 mol%), dppe (10 mol%)
O 154
O
N NH
I 2 (2 mol%), [bmim]PF 6, 60 ºC R
R N
76-95% R = Ph, Bn, Cy, CH 2 Ar
156
N-Phenyl-1,2,4-triazole-3,5-dione 157 has been found to be an efficient and chemoselective reagent for the oxidation of thiols to their corresponding symmetrical disulfides <06TL9211>. N-4-(p-Chloro)phenyl-1,2,4-triazole-3,5-dione 158 has been used as an effective oxidizing agent for the oxidation of 1,3,5-trisubstituted pyrazolines to their corresponding pyrazoles under mild conditions at room temperature <06TL833>. The asymmetric synthesis of hydrobenzofuranones via desymmetrization of cyclohexadienones using the intramolecular Stetter reaction has been accomplished with 1,2,4-triazolium salt catalyst 159 <06JA2552>. 1,2,4-Triazolium salt catalysts 160 and 161 were employed in the highly enantioselective azadiene Diels-Alder reactions <06JA8418>. Dimethyl-2-(3-nitro-1,2,4-triazol-1-yl)-2-pyrrolidin-1-yl-1,3,2diazaphospholidinium hexafluorophosphate (MNTP) has been developed as a powerful condensing reagent for phosphate and phosphonate esters <06T3667>. N N O
N R
O
157 R = Ph 158 R = 4-ClC6 H 4
Me N N PF6 P N N N NO 2 Me N
N
O N
N R
159 160 R = 4-OMeC 6H 4, BF4 161 R = 2,4,6-MeC6 H 2, Cl
Several interesting 1,2,4-triazole fused-ring systems have been reported. A facile synthesis of 3,5-dihydro-6H-imidazo[1,2-b]-1,2,4-triazol-6-ones 162 was obtained by an iminophosphorane-mediated annulation <06EJO4170>. 8-Trifluoromethyl-1,2,4-triazolo[4,3b]pyridazines 163 has been prepared from 4-trifluoromethyl-4,5-dihydropyridazin-3-one
233
Five membered ring systems: with more than one N atom
<06S103>. Arene carbaldehyde-3-methylquinoxalin-2-yl hydrazones, obtained by the condensation of 2-hydrazino-3-methylquinoxaline with various aromatic aldehydes, on treatment with iodobenzene diacetate in dichloromethane, underwent oxidative cyclization to exclusively afford 1-aryl-4-methyl-1,2,4-triazolo[4,3-a]quinoxalines 164 <06SC1873>. 2-Aminofuran-3carbonitriles reacted were converted to 2-amino-furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines in three steps <06ARK68>. The synthesis of fused [5,5]-1,2,4-triazoles via a tandem cyclopropane rearrangement–cyclization sequence has been described <06SC3377>. A convenient two-step preparation of [1,2,4]triazolo[4,3-a]pyridines 165 from 2-hydrazinopyridine and carboxylic acids has been reported <06TL7591>. The Groebke-type multi-component reaction between 3-amino1,2,4-triazole, aromatic aldehydes and benzylic isonitriles has been studied from the viewpoint of convenient generation of combinatorial arrays of imidazo[1,2-b][1,2,4]triazoles 166 <06TL6891>. One-pot three-component synthesis of highly functionalized 2,3-dihydro-1,3dioxo-1H,5H-pyrazolo[1,2-a][1,2,4]triazoles has been reported <06HCA1176>.
Me Me
N
N N N
Ar
CF3
O
N Ph 162
NHR
Ar
N
N
N
N N
N NH2
163
R2
N N
N
Me
N
N R
164
165
N N
R1 N H
N
166
A solution-phase synthesis for the preparation of substituted 2-(1,2,4-triazol-3yl)benzimidazoles from 1,2,4-triazole-3-carbaldehydes and ortho-phenylenediamines has been developed for the purpose of producing diverse lead generation libraries <06TL8025>. The syntheses of metabolites of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1ylmethyl)quinoline-3-carboxylate (TAK-603), a disease-modifying antirheumatic drug, has been disclosed <06T8707>. Efficient microwave-assisted synthesis of 1-(1H-indol-1-yl)-2-phenyl-3(1H-1,2,4-triazol-1-yl)-propan-2-ols as antifungal agents has been reported <06T6479>.
5.4.6
TETRAZOLES AND RING-FUSED DERIVATIVES
A review has been published on the methods of functionalization of tetrazoles for the period 2001 to mid 2005 <06RJOC469>. The search for new radical structures having both low selectivity and high reactivity toward the addition reaction onto alkenes has led to a new tetrazole-derived thiyl radical <06JOC9723>. A series of 1-substituted 1H-1,2,3,4-tetrazoles 168 have been synthesized in good yields from amines 167, triethyl orthoformate, and sodium azide through the catalyzed reaction with Yb(OTf)3 <06EJO2723>. Zinc hydroxyapatite (ZnHAP) is an effective heterogeneous catalyst for the [2 + 3]-cycloaddition of sodium azide with nitriles 169 to afford 5-substituted 1Htetrazoles 170 <06SC1809>. A practical synthesis of 5-(4’-methylbiphenyl-2-yl)-1H-tetrazole from 2-fluorobenzonitrile has been described as a key intermediate in the synthesis of several angiotensin II receptor antagonists <06JHC1353>. Sterically hindered 2,4-disubstituted 3-(5tetrazolyl)pyridines were synthesized from corresponding nicotinonitriles using microwave
L. Yet
234
technology <06T1849>. 1-Isocyanomethylbenzotriazole and 2,2,4,4-tetramethylbutylisocyanide smoothly underwent Ugi type reaction to afford 1,5-disubstituted aminomethyl tetrazoles, which could cleaved under acidic conditions to yield substituted α-aminomethyl tetrazoles <06TL4289>. HC(OEt)3 , NaN 3 Yb(OTf) (20 mol%) RNH2 167
R = Ph, Ar, phenylethyl
N N N N R
71-91%
168
MeOCH2 Ch2OH 100 ºC
NaN 3, ZnHAP ArCN 169
DMF, 120 ºC 71-86%
N N N N H 170
Ar
Photolysis of 4-allyl-tetrazolones resulted in molecular nitrogen elimination with formation of 3,4-dihydropyrimidinones <06JOC3583>. The reactions of 1,4-bis[2-(tributylstannyl)tetrazol5-yl]benzene with α,ω-dibromoalkanes were carried out in order to synthesize pendant alkyl halide derivatives of the parent bis-tetrazole <06T9577>. A range of 5-amino-1-aryltetrazoles was obtained directly from the corresponding 1-aryltetrazoles in one pot by consecutive ringopening, azidation and intramolecular cyclization <06S1307>. The synthesis and characterization of 5-(1-(2-(1H-tetrazole-5-yloxy)naphthalen-1-yl)naphthalen-2-yloxy)-1Htetrazole (BIZOL) as the first bis-tetrazole BINOL-type ligands has been described <06TL3929>. Alkylation of 1-aryl-4,5-dihydro-1H-tetrazol-5-ones and 1-phenyl-4,5-dihydro1H-tetrazole-5-thione with tetrakis(2-chloroacetoxymethyl)methane in refluxing acetonitrile in the presence of potassium bromide and triethylamine gave tetrakis[2-(4-aryl-5-oxo-4,5-dihydro1H-tetrazol-1-yl)acetoxymethyl]methanes and tetrakis[2-(1-phenyl-1H-tetrazol-5ylsulfanyl)acetoxymethyl]methane, respectively <06RJOC1056>. A practical, safe, high-yielding and efficient synthesis of (S)-pyrrolidin-2-yl-1H-tetrazole 171 has been developed, which avoided the generation of ammonium azide in the cyclisation step and the use of a 9:1 acetic acid–water mixture as the solvent in the hydrogenation <06SL889>. (S)-5-Pyrrolidin-2-yltetrazole 171 has been employed in the sequential, organocatalyzed asymmetric reaction to give chiral 1,2-oxazines from achiral ketone starting materials <06CC3211>, in the asymmetric addition of malonates to a range of enones <06CC66>, in the asymmetric conjugate addition of nitroalkanes to enones <06OBC2039>. N N H
N HN N 171
Pyridine N-oxides were converted to tetrazolo[1,5-a]pyridines 172 by heating in the presence sulfonyl or phosphoryl azides and pyridine in the absence of solvent <06JOC9540>. 3-R-5Trinitromethyltetrazolo[1,5-a]-1,3,5-triazin-7-ones 173 have been prepared from the alkylation of 5-trinitromethyltetrazolo[1,5-a]-1,3,5-triazin-7-one silver salt with different alkylation agents <06CHE417>. The use of 2-fluorophenylisocyanide in the combinatorial Ugi-tetrazole reaction followed by a nucleophilic aromatic substitution afforded tricylic tetrazolo[1,5-a]quinoxaline 174 in good yields and with high diversity <06TL2041>.
Five membered ring systems: with more than one N atom
O R N N N N 172
5.4.7
N N
N (O2 N) 3C
N 173
R N
N R
1
235
R2 R 3 N
N N N
N
174
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238 06S1613 06S1631 06S1943 06S2349 06S2376 06S2677 06S2849 06S3506 06S3859 06SC51 06SC65 06SC111 06SC285 06SC707 06SC951 06SC1549 06SC1063 06SC1601 06SC1809 06SC1873 06SC1967 06SC2087 06SC2189 06SC2217 06SC2461 06SC2597 06SC2991 06SC3377 06SC3425 06SC3479 06SC3625 06SC3639 06SL109 06SL227 06SL579 06SL645 06SL889 06SL901 06SL957 06SL1369 06SL1404 06Sl1446 06SL1485 06SL1683
L. Yet
D.M. Volochnyuk, S.A. Kovaleva, A.N. Chernega, N.G. Chubaruk, A.N. Kostyuk, A.M. Pinchuk, A.A. Tolmachev, R. Schmutzler, Synthesis 2006, 1613. M.A. Zolfigol, R. Ghorbani-Vaghei, S. Mallakpour, G. Chehardoli, A.G. Choghamarani, A.H. Yazdi, Synthesis 2006, 1631. H. Quast, M. Ach, T. Hergenröther, D. Regnat, Synthesis 2006, 1943. D.C. Flores, G.F. Fiss, L. S. Wbatuba, M.A.P. Martins, R.A. Burrow, A.F.C. Flores, Synthesis 2006, 2349. U. Urši , D. Bevk, S. Pirc, L. Pezdirc, B. Stanovnik, J. Svete, Synthesis 2006, 2376. I. Veljkovic, R. Zimmer, H.-U. Reissig, I. Brüdgam, H. Hart, Synthesis 2006, 2677. S.A. Siddiqui, T.M. Potewar, R.J. Lahoti, K.V. Srinivasan, Synthesis 2006, 2849. F. Crestey, V. Collot, S. Stiebing, S. Rault, Synthesis 2006, 3506. J. Pacheco-Torres, E. Pérez-Mayoral, E. Soriano, P. López-Larrubia, O. Ouari, A. González-Cortés, S. Cerdán, P. Ballesteros, Synthesis 2006, 3859.ï M.M. Mojtahedi, M.R. Jalali, M. Bolourtchian, Synth. Commun. 2006, 36, 51. A. Shaabani, A. Rahmati, B. Aghaaliakbari, J. Safaei-Ghomi, Synth. Commun. 2006, 36, 65. R. Atir, S. Mallouk, K. Bougrin, M. Soufiaoui, A. Laghzizil, Synth. Commun. 2006, 36, 111. A. Bunnell, C. O’Yang, A. Petrica, M.J. Soth, Synth. Commun. 2006, 36, 285. M.J. Hayter, D.J. Bray, J.K. Clegg, L.F. Lindoy, Synth. Commun. 2006, 36, 707. G. Conte, R. Cristiano, F. Ely, H. Gallardo, Synth Commun. 2006, 36, 951. A. Zheng, W. Zhang, J. Pan, Synth. Commun. 2006, 36, 1549. M. Chen, Y. Zheng, S. Fan, G. Gao, L. Yang, L. Tian, Y. Du, F. Tang, W. Hua, Synth. Commun. 2006, 36, 1063. S. Bondock, W. Khalifa, A.A. Fadda, Synth. Commun. 2006, 36, 1601. M.L. Kantam, V. Balasubrahmanyam, K.B.S. Kumar, Synth. Commun. 2006, 36, 1809. R. Aggarwal, G. Sumran, Synth. Commun. 2006, 36, 1873. K.I. Petko L.M. Yagupolskii, Synth. Commun. 2006, 36, 1967. M. Takahashi, S. Onda, N. Matsumoto, Synth. Commun. 2006, 36, 2087. S. Ponnala, D.P. Sahu, Synth. Commun. 2006, 36, 2189. J. Lindstrom, M.H. Johansson, Synth. Commun. 2006, 36, 2217. W.-J. Tang and Y.-Z. Hu, Synth. Commun. 2006, 36, 2461. X. Jing, Q. Zhu, F. Xu, X. Ren, D. Li, C. Yan, Synth. Commun. 2006, 36, 2597. G.V.M. Sharma, Y. Jyothi, P.S. Lakshmi, Synth. Commun. 2006, 36, 2991. C.N.D Marco, S.D. Kuduk, Synth. Commun. 2006, 36, 3377. J.M. Wallace, B.C.G. Soderberg, J.W. Hubbard, Synth. Commun. 2006, 36, 3425. O. Prakash, K. Pannu, R. Naithani, H. Kaur, Synth. Commun. 2006, 36, 3479. A. Hegedus, Z. Hell, A. Potor, Synth. Commun. 2006, 36, 3625. M.D. Crozet, V. Remusat, C. Curti, P. Vanelle, Synth. Commun. 2006, 36, 3639. Y. Nishiyama, M. Fujimoto, N. Sonoda, Synlett 2006, 109. M. Ishihara, H. Togo, Synlett 2006, 227. A. Díaz-Ortiz, M.A. Herrero, A. de la Hoz, A. Moreno, J.R. Carrillo, Synlett 2006, 579. Y.-M. Wu, J. Deng, Q.-Y. Chen, Synlett 2006, 645. V. Franckevi ius, K.R. Knudsen, M. Ladlow, D.A. Longbottom, S.V. Ley, Synlett 2006, 889. E.-M. Chang, T.-H. Chen, F.F. Wong, E-C. Chang, M.-Y. Yeh, Synlett 2006, 901. K.R. Reddy, K. Rajgopal, M.L. Kantam, Synlett 2006, 957. V.L.M. Silva, A.M.S. Silva, D.C.G.A. Pinto, J.A.S. Cavaleiro, Synlett 2006, 1369. L.H. Jones, C. Mowbray, Synlett 2006, 1404. W.-l. Chen, C.-l. Su, X. Huang, Synlett 2006, 1446. M.A.P. Martins, W. Cunico, S. Brondani, R.L. Peres, N. Zimmermann, F.A. Rosa, G.F. Fiss, N. Zanatta, H.G. Bonacorso, Synlett 2006, 1485. M. Gwiazda, H.-U. Reissig, Synlett 2006, 1683.
Five membered ring systems: with more than one N atom
06SL2124 06SL2199 06SL2581 06SL2767 06SL2836 06SL3170 06SL3237 06SL3267 06T611 06T1849 06T2492 06T3301 06T3667 06T3794 06T3798 06T3837 06T4756 06T5868 06T6042 06T6332 06T6405 06T7772 06T6388 06T8199 06T8707 06T8792 06T8919 06T8966 06T9577 06T10182 06T10555 06T10700 06T11100 06T11178 06TL43 06TL79 06TL255 06TL353 06TL655 06TL817 06TL833
239
R. Hosseinzadeh, M. Tajbakhsh, M. Alikarami, Synlett 2006, 2124. V. Kumar, A. Anand, M.P. Mahajan, Synlett 2006, 2199. M. Joksovi , Z. Ratkovi , M. Vuki evi , R.D. Vuki evi, Synlett 2006, 2581. A. Gheorghe, E. Cuevas-Yañez, J. Horn, W. Bannwarth, B. Narsaiah, O. Reiser, Synlett 2006, 2767. N. Ando, S. Terashima, Synlett 2006, 2836. N. Arai, M. Takahashi, M. Mitani, A. Mori, Synlett 2006, 3170. J. Koubachi, S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet, Synlett 2006, 3237. F. Gosselin, P.D. O’Shea, R.A. Webster, R.A. Reamer, R.D. Tillyer, E.J.J. Grabowski, Synlett 2006, 3267. M. Calle, L.A. Calvo, A. Gonzalez-Ortega, A.M. Gonzalez-Nogal, Tetrahedron 2006, 62, 611. S.M. Lukyanov, I.V. Bliznets, S.V. Shorshnev, G.G. Aleksandrov, A.E. Stepanov, A.A. Vasil’ev, Tetrahedron 2006, 62, 1849. B.Han, Z. Liu, Q. Liu, L. Yang, Z.-L. Liu, W. Yu, Tetrahedron 2006, 62, 2492. S. Wille, M. Heim, R. Miethchen, Tetrahedron 2006, 62, 3301. N. Oka, M. Shimizu, K. Saigo, T. Wada, Tetrahedron 2006, 62, 3667. A.R. Katritzky, S.K. Singh, R. Jiang, Tetrahedron 2006, 62, 3794. A.K. Nadipuram, S.M. Kerwin, Tetrahedron 2006, 62, 3798. M. IJsselstijn, J.-C. Cintrat, Tetrahedron 2006, 62, 3837. X. Lv, Z. Wang, W. Bao, Tetrahedron 2006, 62, 4756. A. de la Hoz, A. Dıaz-Ortiz, M.C. Mateo, M. Moral, A. Moreno, J. Elguero, C. FocesFoces, M.L. Rodrıguez, A. Sanchez-Migallon, Tetrahedron 2006, 62, 5868. C. Enguehard-Gueiffier, I. Thery, A. Gueiffiera, S.L. Buchwald, Tetrahedron 2006, 62, 6042. T. Hanamoto, M. Egashira, K. Ishizuka, H. Furuno, J. Inanaga, Tetrahedron 2006, 62, 6332. B. Gerard, J. Ryan, A.B. Beeler, J.A. Porco Jr., Tetrahedron 2006, 62, 6405. F. Crestey, V. Collot, S. Stiebing, S. Rault, Tetrahedron 2006, 62, 7772. C.S. Cho, D.B. Patel, Tetrahedron 2006, 62, 6388. Y. Matsuoka, Y. Ishida, D. Sasaki, K. Saigo, Tetrahedron 2006, 62, 8199. M. Mizuno, M. Yamashita, Y. Sawai, K. Nakamoto, M. Goto, Tetrahedron 2006, 62, 8707. A.P. Piccionello, A. Pace, I. Pibiri, S. Buscemi, N. Vivona, Tetrahedron 2006, 62, 8792. A. Paul, H. Bittermann, P. Gmeiner, Tetrahedron 2006, 62, 8919. P.J. Crowley, S.E. Russell, L.G. Reynolds, Tetrahedron 2006, 62, 8966. A.D. Bond, A. Fleming, F. Kelleher, J. McGinleyc, V. Prajapati, Tetrahedron 2006, 62, 9577. I. Kawasaki, N. Sakaguchi, A. Khadeer, M. Yamashita, S. Ohta, Tetrahedron 2006, 62, 10182. P. Krishnamoorthy, R. Sivappa, H. Du, C.J. Lovely, Tetrahedron 2006, 62, 10555. R. Roa, K.E. O’Shea, Tetrahedron 2006, 62, 10700. A. Correa, I. Tellitu, E. Domınguez, R. SanMartin, Tetrahedron 2006, 62, 11100. V.S. Pore, N.G. Aher, M. Kumar, P.K. Shukla, Tetrahedron 2006, 62, 11178. A. Saikia, M.G. Barthakur, M. Borthakur, C.J. Saikia, U. Bora, R.C. Boruah, Tetrahedron Lett. 2006, 47, 43. P. Gogoi, D. Konwar, Tetrahedron Lett. 2006, 47, 79. G. Chen, M. Sasaki, A.K. Yudin, Tetrahedron Lett. 2006, 47, 255. A.K. Nadipuram, S.M. Kerwin, Tetrahedron Lett. 2006, 47, 353. Z. Zhang, E. Fan, Tetrahedron Lett. 2006, 47, 655. B. Cottineau, J. Chenault, G. Guillaumet, Tetrahedron Lett. 2006, 47, 817. M.A. Zolfigol, D. Azarifar, S. Mallakpour, I. Mohammadpoor-Baltork, A. Forghaniha, B. Malekia, M. Abdollahi-Alibeik, Tetrahedron Lett. 2006, 47, 833.
240 06TL947 06TL1395 06TL1445 06TL1509 06TL1545 06TL1555 06TL1729 06TL1949 06TL2041 06TL2129 06TL2265 06TL2443 06TL2557 06TL2601 06TL2611 06TL2631 06TL2775 06TL2883 06TL2941 06TL2961 06TL2989 06TL3031 06TL3035 06TL3055 06TL3059 06TL3225 06TL3929 06TL3997 06TL4289 06TL4655 06TL4807 06TL5029 06TL5105 06TL5203 06TL5359 06TL5399 06TL5451 06TL5797 06TL6201 06TL6479 06TL6681 06TL6685
L. Yet
V.Z. Parchinsky, O. Shuvalova, O. Ushakova, D.V. Kravchenko, M. Krasavin, Tetrahedron Lett. 2006, 47, 947. A.S. Kiselyov, Tetrahedron Lett. 2006, 47, 1395. A.V. Eremkin, O.V. Ershov, Y.S. Kayukov, V.P. Sheverdov, O.E. Nasakin, V.A. Tafeenko, E.V. Nurieva, Tetrahedron Lett. 2006, 47, 1445. J. Wu, X. Sun, H.-G. Xia, Tetrahedron Lett. 2006, 47, 1509. Y.-B. Zhao, Z.-Y. Yan, Y.-M. Liang, Tetrahedron Lett. 2006, 47, 1545. J.-M. Xu, W.-B. Wu, C. Qian, B.-K. Liu, X.-F. Lin, Tetrahedron Lett. 2006, 47, 1555. O. Dirat, A. Clipson, J.M. Elliott, S. Garrett, A.B. Jones, M. Reader, D. Shaw, Tetrahedron Lett. 2006, 47, 1729. M. Bahnous, C. Mouats, Y. Fort, P.C. Grosb, Tetrahedron Lett. 2006, 47, 1949. C. Kalinski, M. Umkehrer, S. Gonnard, N. Jager, G. Rossa, W. Hiller, Tetrahedron Lett. 2006, 47, 2041. V. Mirkhani, M. Moghadam, S. Tangestaninejada, H. Kargar, Tetrahedron Lett. 2006, 47, 2129. J. Jayashankaran, R.D.R.S. Manian, R. Raghunathan, Tetrahedron Lett. 2006, 47, 2265. P.S. Humphries, J.M. Finefield, Tetrahedron Lett. 2006, 47, 2443. P. Salehi, M. Dabiri, M.A. Zolfigol, S. Otokeshb, M. Baghbanzadeh, Tetrahedron Lett. 2006, 47, 2557. C.-H. Wu, C.-M. Sun, Tetrahedron Lett. 2006, 47, 2601. A.S. Kiselyov, L. Smith, II, Tetrahedron Lett. 2006, 47, 2611. A. S. Kiselyov, Tetrahedron Lett. 2006, 47, 2631. A. Ray, K. Manoj, M.M. Bhadbhade, R. Mukhopadhyay, A. Bhattacharjya, Tetrahedron Lett. 2006, 47, 2775. S.-Y. Lin, Y. Isome, E. Stewart, J.-F. Liu, D. Yohannes, L. Yu, Tetrahedron Lett. 2006, 47, 2883. A.S. Kiselyov, Tetrahedron Lett. 2006, 47, 2941. Z. Syrgiannis, Y. Elemes, Tetrahedron Lett. 2006, 47, 2961. T. Masquelin, H. Bui, B. Brickley, G. Stephenson, J. Schwerkosked, C. Hulme, Tetrahedron Lett. 2006, 47, 2989. A. Shaabani, E. Soleimani, A. Maleki, Tetrahedron Lett. 2006, 47, 3031. A.H. Yap, S.M. Weinreb, Tetrahedron Lett. 2006, 47, 3035. B. Sreedhar, P.S. Reddy, N.S. Kumar, Tetrahedron Lett. 2006, 47, 3055. S. Chandrasekhar, D. Basu, C. Rambabu, Tetrahedron Lett. 2006, 47, 3059. X. Beebe, V. Gracias, S.W. Djuric, Tetrahedron Lett. 2006, 47, 3225. H.A. Dabbagh, A. Najafi-Chermahini, S. Banibairami, Tetrahedron Lett. 2006, 47, 3929. V.S. Sajisha, M. Smitha, S. Anas, K.V. Radhakrishnan, Tetrahedron Lett. 2006, 47, 3997. A. Domling, B. Beck, M. Magnin-Lachaux, Tetrahedron Lett. 2006, 47, 4289. A.-L. Gerard, A. Bouillon, C. Mahatsekake, V. Collota, S. Raulta, Tetrahedron Lett. 2006, 47, 4655. R. Guezguez, K. Bougrin, K.E. Akria, R. Benhida, Tetrahedron Lett. 2006, 47, 4807. M. Kidwai, P. Mothsra, Tetrahedron Lett. 2006, 47, 5029. B.-Y. Lee, S. R. Park, H. B. Jeon, K. S. Kim, Tetrahedron Lett. 2006, 47, 5105. R. Hosseinzadeh, M. Tajbakhsh, M. Alikarami, Tetrahedron Lett. 2006, 47, 5203. K.R. Hornberger, G.M. Adjabeng, H.D. Dickson, R.G. Davis-Ward, Tetrahedron Lett. 2006, 47, 5359. M.K. Ghorai, K. Ghosh, K. Das, Tetrahedron Lett. 2006, 47, 5399. G. Pawar, W.M. De Borggraeve, K. Robeyns, L. Van Meervelt, F. Compernolle, G. Hoornaert, Tetrahedron Lett. 2006, 47, 5451. M. Ge, E. Cline, L. Yang, Tetrahedron Lett. 2006, 47, 5797. J.D. Ha, S.J. Lee, S.Y. Nam, S.K. Kang, S.Y. Cho, J.H. Ahn, J.-K. Choi, Tetrahedron Lett. 2006, 47, 6201. N. Lebouvier, F. Giraud, T. Corbin, Y.M. Na, G. Le Baut, P. Marchanda, M. Le Borgne, Tetrahedron Lett. 2006, 47, 6479. J. Marik, J.L. Sutcliffe, Tetrahedron Lett. 2006, 47, 6681. B. Toumi, A. Harizi, Tetrahedron Lett. 2006, 47, 6685.
Five membered ring systems: with more than one N atom
06TL6727 06TL6743 06TL6795 06TL6891 06TL6971 06TL7199 06TL7571 06TL7591 06TL7653 06TL8025 06TL8101 06TL8761 06TL8807 06TL8873 06TL9211 06TL9285
241
J. Wan, R. Zhu, Y. Xia, F. Qu, Q. Wu, G. Yang, J. Neytsc, L. Peng, Tetrahedron Lett. 2006, 47, 6727. N. Shao, C. Wang, X. Huang, D. Xiao, A. Palani, R. Aslanian, N.-Y. Shih, Tetrahedron Lett. 2006, 47, 6743. D.J. Varughese, M.S. Manhas, A.K. Bose, Tetrahedron Lett. 2006, 47, 6795. V.Z. Parchinsky, V.V. Koleda, O. Shuvalova, D.V. Kravchenko, M. Krasavin, Tetrahedron Lett. 2006, 47, 6891. O.D. Montagnat, G. Lessene, A.B. Hughes, Tetrahedron Lett. 2006, 47, 6971. S.A. Laufer, A.J. Liedtke, Tetrahedron Lett. 2006, 47, 7199. R.D.R.S. Manian, J. Jayashankaran, R. Ramesh, R. Raghunathan, Tetrahedron Lett. 2006, 47, 7561. A. Moulin, J. Martinez, J.-A. Fehrentz, Tetrahedron Lett. 2006, 47, 7591. A.R. Katritzky, Z. Wang, M. Tsikolia, C.D. Hall, M. Carman, Tetrahedron Lett. 2006, 47, 7653. N.V. Ivanova, S.I. Sviridov, A.E. Stepanov, Tetrahedron Lett. 2006, 47, 8025. B. Abarca, R. Aucejo, R. Ballesteros, F. Blancoa, E. Garcıa-Espana, Tetrahedron Lett. 2006, 47, 8101. A. Dıaz-Ortiz, A. de Cozar, P. Prieto, A. de la Hoz, A. Moreno, Tetrahedron Lett. 2006, 47, 8761. B. El Azzaoui, B. Rachid, M.L. Doumbia, E.M. Essassi, H. Gornitzkab, J. Bellan, Tetrahedron Lett. 2006, 47, 8807. V. Gracias, A.F. Gasiecki, T.G. Pagano, S.W. Djuric, Tetrahedron Lett. 2006, 47, 8873. A. Christoforou, G. Nicolaou, Y. Elemes, Tetrahedron Lett. 2006, 47, 9211. L. Chai, Y. Zhao, Q. Sheng, Z.-Q. Liu, Tetrahedron Lett. 2006, 47, 9285.
242
Chapter 5.5 Five-membered ring systems: with N and S (Se) atoms Yong-Jin Wua and Bingwei V. Yangb a Bristol Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492-7660, USA b Bristol Myers Squibb Company, PO Box 4000, Princeton, NJ 08543-4000, USA
[email protected] and
[email protected]
5.5.1 INTRODUCTION This review chapter focuses on the syntheses and reactions of these 5-membered heterocyclic ring systems containing nitrogen and sulfur (or selenium) (reported during 2006). The importance of these π-rich heterocycles in medicinal chemistry and natural products is also covered. 5.5.2
THIAZOLES
5.5.2.1 Synthesis of Thiazoles The Hantzsch reaction discovered in 1889 remains one of the most reliable routes to thiazoles and numerous applications of this reaction appeared during the past year <06BMCL2773; 06BMCL5317; 06JA2995; 06JMCAC235; 06JOC5031; 06JOC8302; 06T66; 06T1110; 06T11592; 06TL239; 06OL3057>. For example, the Hantzsch reaction of α-bromomethyl ketone 1 with thioamide 2 is utilized to construct one of the two thiazole rings in a recent total synthesis of myxothiazols <06OBC2906>. OMe
OMe O
S N S
O Br
1
i-Pr
+ H2N Me
NaHCO3; TFA, Py 59%
2
Me
O N
N
S
i-Pr S
3
Another frequently used method for construction of thiazoles consists of cyclization of compounds containing C(=S)-NH-CH-C(=O) or C(=S)-NH-CH-C(=S) fragment (with loss of water or hydrogen sulfide). The requisite thioamides are prepared from their corresponding amides using phosphorus pentasulfide, Belleau’s reagent, Lawesson’s reagent or the recently developed fluorous Lawesson’s reagent, which can be easily removed by a simple filtration through fluorous reverse phase silica <06OL1625>. For example, 2-N-acylglycinamides 4 undergo dithionation followed by trifluoroacetic acid anhydride (TFAA)-mediated cyclization to furnish a series of trifluoroacetamides 6 in moderate yields <06TL2361>. Interestingly, the analogous reaction of the corresponding monothionated acetamide 7 results in an approximately equal mixture of thiazole 8 and oxazole 9.
243
Five-membered ring systems: with N and S (Se) atoms
O
Ph
R
Lawesson's reagent or Belleau's reagent
NH2
N H 4
R
O S
S P
OY
P S
S
Ph
N H
Ph N
TFAA Ph
O
TFAA
NH2
N
21-46% R
S
O CF3
N H
S 6
Lawesson's reagent: Y = Me Fluorous Lawesson's reagent: Y = (CH2)4(CF2)5CF3 Belleau's reagent: Y = Ph
Ph NH2
Ph
Ph N H 5
R = alkyl, aryl
YO
S
S
Ph
O CF3
N H
S
N +
Ph
CF3
N H
O 9
8
7
O
The thionation of 1,4-dicarbonyl compounds and their subsequent cyclization can be carried out in two steps as described above, but frequently the two-step sequence can be combined in one single operation. Thus, treatment of N,N-diformylaminomethyl aryl ketones 11 with phosphorus pentasulfide and triethylamine gives arylthiazoles 12 directly <06SL460>. It is unclear whether the formyl group is lost before or after thiazole formation. The thiazole-based dipeptides 14 are also obtained from β-ketoamides 13 via cyclization upon treatment with the Lawesson’s reagent on solid phase <06OL2417>. Similar transformations (15 to 16) have been carried out using the fluorous Lawesson’s reagent as described above <06OL1625>. Ar
Br
50-95%
O
O
Bn
O NH
O 13
Ar
O
Lawesson's reagent
O
Bn
S
O N
RHN
R1
N
12
11
10
RHN
CHO P2S5, Et3N N 61-83% CHO
NaN(CHO)2 Ar
15 O O R2 Fluorous Lawessons' 48-82% reagent R1
O
S
Me R = CBZ, Fmoc, Boc, Alloc
14
H N
N S
Me
16
R2
2-Aminothiazoles are frequently synthesized by the reaction of aromatic or aliphatic amines with α-thiocyanatoketones, which are prepared from α-haloketones by treatment with potassium thiocyanate. These two operations can be performed in one pot using a supported reagents system, KSCN/SiO2-RNH3OAc/Al2O3 <06T3201>. This method provides a direct synthesis of 2-aminothiazoles 20 from α-haloketones 17 and amines, thus obviating the isolation of intermediate α-thiocyanatoketones 18. O R
X
1
KSCN/SiO2, R3NH3OAc/Al2O3
O R
SCN
1
R2 17
R2 18
R1 R2
OH N S 19
H 2N R 3
-H2O
R1
39-99% R2
N NHR3 S 20
Oxidation of thiazolines represents another approach to thiazoles. This method has been applied to the synthesis of N-Boc-L-thiazole methyl ester 22 <06JA10513>. Conversion of resin-bound thiazolines 23 to thiazoles 24 is also reported <06OL2417>.
244 Me
Y.-J. Wu and B.V. Yang
Et
HN Boc
DBU, BrCCl3
O N
O 87% Me
S
Me
Et N
HN Boc
O Me
S
21
Bn
O
O N
HN R
DBU, BrCCl3
O
87%
S 23
22
Bn HN R
O N
O
S 24
R = Cbz, Fmoc
A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Bocprotected L-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 : 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. R MeO2C
N
C
BF3
H
O 26
R
BF3•Et2O
MeO2C
N
OBF3
MeO2C
S
NMe2 HS Me 25
O
Me
N O Me Me 27
N
R = BocHN
Me
N Me Me 28
O
R OAc
MeO2C
O S
R
i-Pr
R
H N
-Me2NH
MeO2C
40%
S
N SH N Me Me
30
OAc
29
A series of 2-(thiazol-5-yl)acetamides and acetates 35a/b has been prepared in one pot from the reactions of benzotriazolylthione derivatives 32 with N,N-dimethyl-4-N’,N’bis(trimethylsilyl)aminobut-2-yne amide 31a and ethyl 4-N,N-bis(trimethylsilyl)aminobut-2ynoate 31b, respectively <06TL8661>. Presumably, the initial adducts 33a/b undergo intramolecular thia-Michael addition to give 34a/b, which isomerize to thiazoles 35a/b. C(O)X R TMS N TMS 31a: X = NMe2 31b: X = OEt
C(O)X
S
32
THF, MeOH; Et3N
C(O)X
C(O)X
Bt
S R
S N 33a/b
N N N
S R
R
N TMS
Bt =
40-93% H 34a/b
R = aryl, alkyl, alkoxy, phenoxy, Bt
N 35a/b
245
Five-membered ring systems: with N and S (Se) atoms
A novel synthesis of iodothiazole 38 takes advantage of Wiemer’s protocol for the synthesis of vinyl iodides from ketones <06JOC5031>. The thiazolyl phosphate 37, prepared from 2-isopropylaminothiazoline-4-one 36, is converted to the desired iodothiazole 38 upon treatment with in situ generated trimethylsilyl iodide. This iodide is a key intermediate in the synthesis of the quinolone substructure of the protease inhibitor BILN 2061. i-Pr
H N
N
O
KHMDS, (PhO)2POCl
S 36
H N
i-Pr
N
O
S
83%
OPh P OPh O
NaI, TMSCl
i-Pr
H N
55%
N
I
S 38
37
5.5.2.2 Synthesis of Fused Thiazoles A series of 2-arylbenzothiazoles 41 has been synthesized via microwave irradiation of 1 : 1 mixture of ortho-aminothiophenols 39 and alkyl or aryl acylacetonitriles <06JHC1609>. This reaction appears to be more efficient than that of ortho-aminothiophenols with βketoesters to form substituted benzothiazoles reported previously <05H(65)2119>. O NH2 R1
-MeCN
SH
H N
CN
R
R1
SH
39
O
N
77-98%
R
R
-H2O
40
S
R1
R1 = H, Cl R = aryl, alkyl
41
Benzothiazoles can be obtained from ortho-haloanilides under strong basic conditions as exemplified by the formation of 5-bromo-2-(3,4-dimethoxyphenyl)benzothiazole 43 from dibromide 42 <06JMC179>. A Cu(I)-catalyzed version of this transformation has been developed <06JOC1802>. Treatment of ortho-haloanilides 44 with cesium carbonate in the presence of copper(I) iodide and a ligand furnishes benzothiazoles 45 in good yields. This cyclization involves an intramolecular C-S cross-coupling of the ortho-haloanilides and presumably proceeds via an oxidative insertion/reductive elimination pathway through a Cu(I)/Cu(III) manifold. Both 1,10-phenanthroline (1,10-phen) and N,N’-dimethylethylenediamine provide ligand acceleration, but 1,10-phen shows greater substrate tolerance. Br Br 42
S
NaH
Br
S
51% N N Br H Ar 43 Ar = 3,4-di-OMe-Ph
Ar 44
N H
S
CuI (5 mol%), Cs2 CO3 1,10-Phen (10% mol)
S
>99% (Ar = Ph) Ar 93% (Ar = 4-OMe-Ph)
N
Ar 45
The Jacobson thioanilide radical cyclization chemistry has been extensively used for the synthesis of benzothiazoles as shown by the preparation of 4-fluoro-2-(3,4-dimethoxyphenyl)benzothiazole 47 <06JMC179>. The harsh reaction conditions (K3Fe(CN)6, NaOH,
246
Y.-J. Wu and B.V. Yang
S 46
F
R
Y
N H
48
K3Fe(CN)6 55% NaOH
S Ar
R
Ar
R
N
Ar
N 50
49
O
S
O I OAc AcO OAc DMP
Y N 47 F
N H
.
HS
S
Y = 3,4-di-OMe-Ph
S Ar
R
85-95%
.
R
S Ar N
N 51
52
H2O, EtOH, 90°C) can be overcome by using the Dess-Martin periodinane (DMP) (CH2Cl2, 25°C) <06JOC8261>. The reaction probably proceeds via thiyl radical 50, which undergoes 1,5-homolytic radical cyclization followed by aromatization of radical 51 to give 2arylthiazole 52. A modified Pictet-Spengler reaction has been applied to the synthesis of thiazoloquinolines 58 <06T3228>. Condensation of anilines 53 with aryl aldehydes 54 followed by endo cyclization results in the formation of thiazoloquinolines 58 under a variety of traditional Pictet-Spengler protocols such as 2% trifluoroacetic acid in dichloromethane. Ar S
ArCHO 54
NH2
R1HN
S R1HN
H S
NH
R1HN
NH
N
N
N
Ar
TFA 53
56
55 Ar S
R1HN
Ar NH
75-85%
S R1HN
N
N
57
58
N R1 = phenyl, benzyl
A novel series of 5H-thiazolo[3,2-a]pyridine-5-ones 64 is prepared by addition of malonic esters 59 to 2-alkynylthiazoles 60 <06H(67)523>. A plausible reaction mechanism involves an intramolecular cyclization of the initial adduct 61 to give the cyclobutenoxide intermediate 62. Ring-opening of this intermediate and subsequent cyclization lead to 5H-thiazolo[3,2a]pyridine-5-one 64.
247
Five-membered ring systems: with N and S (Se) atoms
R
1
R1
R2
CO2Me
N
+
CO2Me
•
R2
60 61 O R1 R2
R1 OMe
MeO2C
NaH
S
59
O MeO2C
N
R
O OMe
2
N
S
S 62
O
OMe 48-83%
N S CO2Me 63
R1 R
N S
2
R1 = Me, allyl R2 = Ph, n-Bu
CO2Me 64
5.5.2.3 Synthesis of Thiazolines Cyclodehydration of the compounds bearing C(=O)-S-C-C-NH2 moiety is a common approach to thiazolines. This method has been used repetitively to form the thiazoline moiety in a recent synthesis of chiral cyclic oligothiazolines <06CC1757>. Exposure of thioester 65 to trifluoroacetic acid results in cyclodehydration to give thiazoline 66, a doubly protected dimer unit. This dimer is converted to carboxylic acid 67 via basic hydrolysis and thiol 68 by the activation of the thiazolidinone ring with a Boc group and subsequent base-induced ring opening. Acid 67 is coupled with thiol 68, and the resulting thioester is treated with trifluoroacetic acid to furnish tetramer 69, which undergoes double deprotection to provide thiocarboxylic acid 70. Di- and tri-merization of this acid in a head-to-tail fashion produce a 1.8 : 1 mixture of macrocyclic thioesters 71a and 71b in 63% yield. Boc deprotection of 71a and 71b and subsequent cyclodehydration give cyclic octathiazoline 72a and dodecathiazoline 72b, respectively.
248
Y.-J. Wu and B.V. Yang
Boc HN Me O H Me CO2Me N S S 65
O
Me N H Me N
TFA 96% O
Me CO2R
S
Boc2O, 91%; NaOMe, 81%
S NaOH 78%
Boc Me N HN HS
CO2Me S
68
66 R = Me 67 R = H Me
67,BOPCl, Et3N, 77%; TFA, 93%
Me N Me N N H Me N
S
Boc Me N HN
Boc2O, 90%; NaOH, 81%
S
S
Me
Me N S
N Me O NHBoc
S
63%
S
S TFA
Me
Me
N Me
N
N
N
S
79% (a) 77% (b)
S
N
N S
S
Me S 71a/b
Me
Me
Me
N
N
Me
S
S
N
S
70
S
N BocHN O Me
CO2H
S
HS
69 S
BOPCl, Et3N
Me N
S
O
Me Me N
CO2Me
S Me S
N
N
Me
Me
S
n a: n = 1; b: n = 2
Me S 72a/b
n
Compounds bearing C(=S)-NH-C-C-OH fragment (β-hydroxy thioamide) can also undergo cyclodehydration to form thiazoline derivatives. The utility of this strategy has been demonstrated in the synthesis of halipeptins A and D <06JA4460>. Exposure of 73a/b with (diethylamino)sulfur trifluoride (DAST) brings about intramolecular cyclization to provide thiazolines 74a/b, which are advanced precursors to halipeptins A and D. Me
OMe
O
n-Pr
Me H Me O N
Me S Me O O
Me 73a/b
Me
OH
R
N
N CO2Me DAST Me
OMe
85% N3
Me
Me
n-Pr a: R = (CH2)2OTBDPS b: R = Et
O
Me S Me O O
Me 74a/b
Me O
R
N CO2Me Me
N3
Me
Kelly’s biomimetic methodology, first reported in 2003 <03AG(E)83>, has become one of the most reliable routes to thiazolines. In this approach, the phosphorus-activated amide carbonyl group undergoes nucleophilic attack by the cysteine thiol group to provide the thiazoline moiety (see 76). Kelly’s thiazoline formation has been applied to the total syntheses of three complex natural products: halipeptin A (75 to 77) <06TL1081>, apratoxin A (78 to 79) <06OL531> and (R)-telomestatin <06OL4165>. The typical protocol in Kelly’s
249
Five-membered ring systems: with N and S (Se) atoms
methodology involves triphenylphosphine oxide and triflic anhydride, but the cyclodehydration and deprotection of S-t-Bu group in 80 is carried out with addition of anisole, which drives the reaction to completion. Kelly’s approach is also utilized in the solid-phase synthesis of thiazoline-based peptides 82 from resin-bound dipeptides 81 <06OL2417>. Me HN Fmoc
O
Ph3P(O), NH CO2allyl Tf2O Me
Me FmocHN (TfO)Ph3P
STr
75
Me N
CO2allyl
75%
Me
O S Tr
CO2Allyl
N
HN Fmoc
Me
S 77
76 CO2Allyl
Me NH
O
Troc Me
t-Bu O
STr
O
O Me
Ph3P(O), Me Fmoc Tf2O N
N
O
Troc Me
t-Bu O
S
O Me
78
O
HN N
N N
N
Ph3P(O), O Tf2O, Me anisole O
N O
20%
N
N
N
N
N
O
N
N
Me O
Me Ph3P(O), Tf2O
O Me
O telomestatin
80
O
O 81 TrS
O
N
NH
RHN
R
N
Bn
O
O
O
S
O
St-Bu
Fmoc N
79 Bn
O
O N
CO2allyl
O
O N
RHN
O
S
82 R = CBZ, Fmoc
5.5.2.4 Reactions of Thiazoles and Fused Derivatives The first practical, large-scale synthesis of 2-amino-5-fluorothiazole 84 employs the reaction of dilithiated 2-butoxycarbonylaminothiazole 83 with N-fluorobenzenesulfonimide (NFSi) <06OPRD346>. This reaction generates a 70 : 15 mixture of the desired fluorinated thiazole 84 and the sulphone 85, and after three consecutive recrystallizations thiazole 84 is isolated in 35-40% yield. This procedure has been utilized to prepare multikilogram quantities of 84, which is a heterocyclic amine component of a series of glucokinase inhibitors. BocHN
S N 83
t-BuLi; NFSi 36% (84)
BocHN
S N 84
F
+
BocHN
S
SO2Ph
N 85
A regioselective generation of thiazol-2-yl and benzo[d]thiazol-2-yl magnesium chlorides (87 and 89) uses 2,2,6,6-tetramethylpiperidyl MgCl•LiCl (TMPMgCl•LiCl), readily available by reacting iso-propyl MgCl•LiCl with 2,2,6,6-tetramethylpiperidine
250
Y.-J. Wu and B.V. Yang
<06AG(E)2958; 06CC583>. This mixed Mg/Li amide, which has excellent solubility in THF (1.2 M) and is stable for more than six months as THF solution at 25°C, allows the regioselective functionalization of various aromatic and heteroaromatic compounds. Thus, both thiazole and benzothiazole undergo smooth C-2 magnesiation with TMPMgCl•LiCl at 25°C, and the resulting magnesium chlorides are trapped with benzaldehyde and iodine, respectively, to furnish adducts 88 and 90. Me
Me
S + N
N MgCl•LiCl
THF, 25°C
N 87
Me Me TMPMgCl•LiCl 86 S
THF, 25°C
N
S
PhCHO MgCl
S
TMPMgCl•LiCl
N
S
94%
OH
S
I2 MgCl
Ph
N 88
98%
I
N 90
89
A new methodology for direct phosphonation of thiazoles has been developed <06OL5291>. Reaction of substituted thiazoles 91 with dimethyl or diethyl phosphates in the presence of manganese (III) acetate dihydrate provides 5-dimethyl or diethylphosphonothiazoles 95. The high C-5 regioselectivity is rationalized by comparing the two intermediates 93 and 94, which result from the attack of phosphonyl radical 92 to the thiazole ring at the C-4 and C-5 position, respectively. The radical in intermediate 94 is next to an imine as opposed to a sulphur as in the case of 93, and therefore, 94 is more stable than 93. As a result, the C-5 phosphonation involving 94 is favored. In the case of unsubstituted thiazole, the C-2 and C-5 phosphonations proceed in a ratio of 78 : 10, indicating that the C-2 position of thiazole is most reactive for phosphonation, followed by the C-5, and the C-4 is the least. R2 5
4
Mn(OAc)3
N
S 2 91
R1
R1 = H R2 = H N
HP(O)(OR)2 • P(O)(OR)2 92
R2 • 1
R
2 XR =H
O O P(OMe)2 + (MeO)2P
S 97 (78%)
O 2 (RO)2P R N • S 93
N
S 98 (10%)
(RO)2P O
R2
80-92%
N R1
S 94
N (RO)2P O
S
R1
95
1
O (MeO)2P
N S 96
R1
R = Me, Et, OMe, OEt, H, acetyl R2 = Me, Ph, H R = Me, Et
A mild and efficient α-heteroarylation of simple esters and amides via nucleophilic aromatic substitution has been described <06OL1447>. Treatment of 2-chlorobenzo[d]thiazole 99 with tert-butyl propionate in the presence of NaHMDS under nitrogen furnishes tert-butyl 2-(benzo[d]thiazol-2-yl)propanoate 100. When the same reaction is preformed initially under nitrogen and then exposed to air, the hydroxylation product 101 is obtained. This method offers two desirable features that are either complementary or improvements to the palladium-catalyzed α-arylation reactions. First, heteroaryl chlorides
251
Five-membered ring systems: with N and S (Se) atoms
may be used; Second, the reactions can be conducted at ambient temperature as opposed to the elevated temperature usually required by palladium-catalyzed α-arylation reactions. S N 101
CO2t-Bu OH Me
NaHMDS, EtCO2t-Bu,
S Cl
air, 84%
NaHMDS, EtCO2t-Bu, N2, 91%
N 99
S
CO2t-Bu
N 100
Me
The palladium- and copper-mediated C-2 arylation of thiazole with 4-iodoanisole under ligandless and base-free conditions provides 2-(4-methoxyphenyl)thiazole in good yield <06EJOC1379>. However, the scope of this selective C-2 arylation has not been disclosed. N MeO
I
+
Pd(OAc)2 (5 mol%) CuI (2 equiv)
N MeO
84%
S
S
Several palladium-catalyzed C-5 arylations of thiazoles have been reported. For example, 2,5-diarylthiazole 104 is prepared via arylation of thiazole 102 at C-5 with aryl iodide 103 using PdCl2(PPh3)2 as a catalyst and silver(I) fluoride as an activator <06T9548>. The selectivity in the arylation of 4-methylthiazole with biphenyl triflate 105 depends on the choice of base: cesium carbonate favors the C-2 arylation, while the C-5 arylation dominates with potassium carbonate <06H(68)1>. The C-2 selectivity issue is overcome by using 2trimethylsilylthiazoles, which serve as efficient counterparts for palladium-catalyzed crosscoupling reactions with aromatic triflates (without any fluoride anion source) to afford 2-aryl thiazoles. For example, mono-thiazoles 110a/b are obtained from triflate 108 using 2trimethylsilylthiazoles 109a/b. N S 102
Ar
1
PdCl2(PPh3)2 (3 mol%), AgF Ar2I 103
N Ar2
Ar1 = 4-OMe-Ph; Ar2 = 4-CO2Et-Ph
OTf OH
Pd(OAc)2, PPh3, K2CO3, LiCl R N
S 104
Ar1 46%
108
Pd(OAc)2, PPh3, base
N S
N
OH
TMS
S 109a (R = H) 109b (R = Me)
OTf 105
Ph
110a (71%) 110b (73%)
Ph S 106
N Me
S
Me
+ Me
Ph
S
N
1.6 : 1 (Cs2CO3) 107 1 : 3.5 (K2CO3)
A cobalt-catalyzed method for arylation of heteroarenes including thiazole and benzothiazole was reported in 2003 <03OL3607>. According to this report, the direct C-5 arylation of thiazole with iodobenzene was carried out in the presence of cobalt catalyst [Co(OAc)2/IMes] and cesium carbonate, and a complete reversal of arylation from C-5 to C-2 was observed with the bimetallic Co/Cu/IMes system. This report has been retracted as the laboratory of the senior author has not been able to reproduce the key results disclosed in the communication <06OL2899>.
252
Y.-J. Wu and B.V. Yang
N Ph
S
Ph-I, IMes (10 mol%) X Co(OAc)2 (5 mol%), Cs2CO3, 64%
Ph-I, IMes (10 mol%) X Co(OAc)2 (5 mol%), CuI, Cs2CO3, 84%
N S
N Ph
S
A parallel synthesis of a library of 2-aryl-6-chlorobenzothiazoles 112 involves a regioselective palladium-catalyzed Suzuki coupling reaction of 2,6-dichlorobenzothiazole 111 with arylboronic acids (1.1 equiv) under microwave irradiation <06TL3091>. When excess phenylboronic acid is used, Pd(PPh3)4 still provides 2-phenyl-6-chlorobenzothiazole exclusively, while 2-dicyclohexylphosphinobiphenyl 113 generates 2,6diphenylbenzothiazole as the major product.
Cl
S Cl
Me2N
ArB(OH)2, Pd(PPh3)4, Na2CO3, dioxane/H2O
Cl
S Ar
57-79%
N
N PCy2 113
112
111
The synthesis of 4-bromo-2'-chloro-2,5'-bis(thiazole) 117 from 2-chlorothiazole via palladium-catalyzed cross-coupling reactions has been reported <06JOC3754>. Among the three coupling methods (Negishi, Suzuki and Stille), the Stille coupling route proves to be the best. Lithiation of 2-chlorothiazole with LDA and subsequent quenching with tributyltin chloride give 2-chloro-5-tributylstannylthiazole 114, which is coupled with 2,4-dibromothiazole 116 to give bis(thiazole) 117. This compound can also be prepared by the Suzuki coupling reaction of 2,4-dibromothiazole with the first known thiazoleboronic acid ester 115, but the yield is much lower. The Negishi coupling protocol suffers from substantial side reactions and results in an inseparable mixture of products. The transition-metal-catalyzed cross-coupling reactions on various azole systems including thiazoles and benzothiazoles have been summarized in a recent review <06EJOC3283>. S
LDA, Bu3SnCl Cl
95%
N
LDA, B(O-iPr)3; pinacol; HOAc 95%
Bu3Sn
Br S
Stille (81%)
Cl N 114 Me O Me B Me O Me 115
Br
N
S N
S
117
N
Cl Br
S 116 S Cl
Suzuki (12%)
N
A synthesis of the eastern fragment of the thiazole peptide GE2270 relies on a regioslective bromine-lithium exchange reaction of thiazoles and Negishi cross-coupling reaction <06JOC4599>. 2,4-Dibromothiazole 116 undergoes the known regioselective bromine-lithium exchange to give 4-bromo-2-thiazolyl lithium 118, the TBS protected (S)mandelate 119 is added, and the resulting adduct is reduced stereoselectively to provide threo alcohol 120. This alcohol is converted the Boc protected amine 121 in a four step sequence. Bromine-lithium exchange of 121 and subsequent transmetalation to zinc are followed by a regioselective Negishi cross-coupling with 2,4-dibromothiazole 116 to furnish bis(thiazole) 122. This compound could serve as a building block for the synthesis of thiazolyl peptide GE2270.
253
Five-membered ring systems: with N and S (Se) atoms
Br
1.
Br N
n-BuLi
N
Br S 116
Li S 118
EtO2C
Ph
119 OTBS 92%
Br N
Ph OTBS
S 2. L-selectride, 86%
OH
120
4 steps
Br N
1. t-BuLi, ZnCl2 Br 2. 116, [PdCl2(PPh3)2]
S N S 122
Ph OTBS NHBoc
44%
N S 121
Ph OTBS NHBoc
The cycloaddition of 2-aminothiazoles with dimethyl acetylenedicarboxylate (DMAD) has been thoroughly investigated <06JOC5328>. Treatment of thiazoles 123 with DMAD in acetonitrile leads unexpectedly to 6-(dimethylamino)-3,3-pyridinedicarboxylates 128. According to the proposed mechanism, nucleophilic attack of the thiazole at C-5 to DMAD gives the zwitterionic intermediate 124, which cyclizes to the fused cyclobutene 125, the formal [2 + 2] adduct. Thermal disrotatory opening of 125 leads to all-cis 1,3-thiazepine 126, which undergoes a symmetry-allowed disrotatory 6π-electrocyclic ring closure to give 7-thia2-azanorcaradiene 127. Desulfurization of 127 gives rise to pyridine 128. Alternatively, the zwitterionic intermediate 124 could lead to 7-thia-2-azabicyclo[2.2.1]hepta-2,5-diene 129, the formal [4 + 2] cycloadduct, through the attack of its carbanionic center to the C-2 of thiazole moiety. Further sulphur extrusion in 129 would provide the regioisomeric pyridine 130. This pathway proves to be operative, although in low extension, only in rare instances. The zwitterionic intermediates can be trapped when the reactions are carried out in methanol instead of acetonitrile. For example, exposure of thiazole 131 to 1 equiv of DMAD in methanol gives a 24 : 76 mixture of (E)- and (Z)-isomer 132 and 133. In the case of thiazole 134, the fused cyclobutene intermediate 135 is isolated in 52% yield, and it cleanly transforms into pyridine 136 under thermal conditions.
254
Y.-J. Wu and B.V. Yang
NMe2 S 123 N
NMe2 S N
R
R
E
E
N
E
solid arrow
Me
E
N
E
R 125
E
N
N
N
R
E +
N
R = 4-Tol
Me
N 132
R
H 52% Me
S
Me Me
N
E E
R 127 S
Me N
N 133
N
Me 135
R
E
Me
E
Me
90%
E
E
N
Δ
N
N 134
DMAD
N
R
Me
Me2N S
H
E
S
Me
90%
126
S
E
E
N
70-91% Me
128
130 DMAD
E
R
Me
Me R
S
E
N
Me
E
N
R
Me
E = CO2Me; R = CH=CH-Ar, Ar
Me2N
131
S
Me N S
N
E
Me
S
129
Me
Me E
N
[2+2]
dashed arrow
E
Me
E
124 [4+2]
Me
H
N
E
136 Me
Oxidation of thiazoles 137 with HOF•MeCN provides easy access to the family of thiazole N-oxides 138 <06CC2262>. The readily made HOF•MeCN complex, considered to be one of the best oxygen transfer agents in chemistry, transfers an oxygen atom directly to thiazole-containing compounds without affecting the double bonds of the thiazole moiety. A small amount of N,S,S-trioxide 139 is also formed in this oxidation. R2
R2 R3
S 137
R1
R2
O N
HOF•MeCN
N
R3
S
O N
R1
138 (78-91%)
+
R3
S
R1
O O 139 (3-10%)
R1 = H, Me R2 = Me, aryl R3 = H, Me, Ac, (CH2)2OAc
5.5.2.5 Thiazole Intermediates in Synthesis An enantioselective synthesis of both (R)- and (S)-α-alkylcysteines 144 and 147 is based on the phase-transfer catalytic alkylation of tert-butyl esters of 2-phenyl-2-thiazoline-4carboxylic acid and 2-ortho-biphenyl-2-thiazoline-4-carboxylic acid, 142 and 145 <06JOC8276>. Treatment of 142 and 145 with alkyl halides and potassium hydroxide in the presence of chiral catalysts 140 and 141 gives the alkylated products, which are hydrolyzed to (R)- and (S)-α-alkylcysteines 144 and 147, respectively, in high enantioselectivity. This method may have potential for the practical synthesis of chiral α-alkylcysteines.
255
Five-membered ring systems: with N and S (Se) atoms
X
Et Br
X
CO2t-Bu
N S
N
CO2t-Bu
S Ph
141
140 (1 mol%), RX, KOH 42-99% yield 67-99% ee
142
O allyl
N
140 X = 3',4',5'-trifluorophenyl
Ph
CO2t-Bu R
N Ph
H
S
143 R = alkyl, allyl, benzyl, propargyl
141 (1 mol%), RX, CsOH
CO2t-Bu R
N
CO2H R
H2N HS
144
CO2H R
H2N
H
S
77-99% yield 68-88% ee
145
N
HS
Ph
147
146
The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is amply demonstrated in a recent enantioselective synthesis of FD-891, a 16-membered macrolide <06JA3128>. This synthesis features four thiazolidinethione propionate aldol reactions for controlling the configuration of 8 of 12 stereogenic centers. For example, addition of aldehyde 149 to the enolate solution of N-propionyl thiazolidinethione 148 produces aldol product 150 with excellent selectivity (dr > 20:1) for the Evans syn isomer. Compound 148 also undergoes diastereoselective aldol addition with 3-butenal to give the non-Evans syn aldol product 152 under different conditions (dr > 15:1). Both aldol products are incorporated into FD-891. Asymmetric aldol reactions using thiazolidinethione chiral auxiliaries are also applied to the synthesis of bistramide <06JA4936>, (+)-SCH 351448 <06OL2887> and salinomycin <06OL527>. OTBS
Bn Me N
S
TiCl4, (-)-sparteine, NMP, CH2Cl2, 78%
Bn N
S
TiCl4, Me (-)-sparteine, CH2Cl2, 73%
OHC
S
O OH 150
149
OTBS
S
O
148
OHC
151
Bn Me N
S S
O
OH
152
The stereoselective addition of the titanium enolate of N-acetyl-4-phenyl-1,3-thiazolidine2-thione 153 to the cyclic N-acyl iminium ion 154 is utilized in the synthesis of (-)stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed anti-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide.
256
Y.-J. Wu and B.V. Yang
Ph
Me
N
S
TiCl4, DIPEA N
Me + AcO
S O 153
O
92%
Me MgBr•Et2O, TMSCl, Et3N; HCl
Ph
S
154
O
N
N
S
O
156 CHO 74%
H 155
Me
N NH
S
Ph
O
Ph
S
O
Ph OH 157
N-(Alkoxy)thiazole-2(3H)-thiones 158 are precursors to alkoxyl radicals which can participate additions, β-fragmentations and remote functionalizations <06OBC2313>. For example, microwave irradiation of 158 in the presence of tributytin hydride or bromotrichloromethane affords tetrahydrofurans 162a and 162b, respectively. Conceivably, the alkoxyl radical 160, generated under microwave conditions, undergoes 5-exo-trig cyclization to give a cyclized radical 161. Hydrogen (Bu3SnH) or bromine atom transfer (BrCCl3) onto radical 161 leads to tetrahydrofuran derivatives 162a/b. Ar
Ar S Me
N O
S
X-Y μW
Me
N• 159 O•
S
X-Y
S
Ar
S
Me
N O
5-exo-trig
163 •
Ph 158
Ph
Ph 160
161
SY
X -Y = H-SnBu3, Br-CCl3 Ar = 4-OMe-Ph X
64% (X = H) 68% (X = Br)
O Ph 162a (X = H) 162b (X = Br)
The synthesis of a series of piperidine imino-C-glycosides 169 involves a stereoselective addition of 2-thiazolylmagnesium bromide 165 to a N-glycosylhydroxylamine 163, a hidden open-chain sugar nitrone 164 <06JOC7574>. The resulting N-thiazolylalkylhydroxylamine 166 is reduced to a secondary amine, which, upon mesylation, transforms into a substituted piperidine 167 via a SN2 intramolecular cyclization. Cleavage of the thiazole ring to formyl group is carried out by a one-pot, three-step reaction sequence consisting of microwaveassisted N-methylation of the thiazole ring by methyl iodide, reduction of the Nmethylthiazolium salt with sodium borohydride, and mercury chloride-promoted hydrolysis of the resulting thiazolines. The crude piperidine aldehyde is further reduced to the primary alcohol 168, and removal of the O-Bn and N-Bn groups in 168 affords a pair of 2,6-dideoxy2,6-iminoheptitol hydrochlorides 169.
257
Five-membered ring systems: with N and S (Se) atoms
O
BnO
OH NBn
OH BnO BnO
OBn
BnO
BnO
OBn
(ThMgBr) 80%
S
164
H2 N
BnO
N
OBn
OBn 163
Cl
O NBn
OH
Pd(OH)2/C, HCl, H2
BnO
92%
OBn
MgBr 165
BnO
6
BnO
OBn OBn
6S/6R = 3/1
166
1. Cu(OAc)2•H2O, Zn, HOAc (74%) 2. MsCl, Et3N (80%)
Bn N
MeI; NaBH4; OH HgCl2; NaBH4
BnO
56%
OBn
Bn N
BnO BnO
OBn 168
OBn 169
OH NBn
HO Th
Th OBn
OBn 167
6-Nitro-2-benzothiazolyl α-manniside 170 has been identified as an efficient mannosyl donor in the direct β-selective mannosylation of glucosamine derivatives <06BCSJ479>. Mannosylation of 171 with 170 using HB(C6F5)4 as a promoter proceeds smoothly to give a 4 : 1 mixture of β- and α-mannosides 172. This represents the first example of direct βselective mannosylation with the chitobiose acceptor 171. The β-trisaccharide 172 serves as a key building block for the synthesis of the pentasaccharide core commonly present in the Nlinked glycans.
OBn AllylO
OAllyl OBn O
+
HO AllylO
OBn AllylO
N
OBn O PhthN
O S 170 O BnO 171
NO2 HB(C6F5)4 (20 mol%) 5A° MS
OBn O PhthN
N3
OAllyl OBn O O AllylO
OBn O PhthN
O BnO
172 95% (α/β = 1/4)
OBn O PhthN
N3
The Julia olefination reaction involving alkylsulfonyl benzothiazoles remains one of the most effective methods for the stereoselective formation of olefins. The power of Julia olefination is demonstrated in the total synthesis of cystothiazole A <06T11592> and FR901464 <06T1378>. Coupling of sulfone 173 with aldehyde 174 using LHMDS proceeds stereoselectively to give a 14 : 1 mixture of cystothiazole A and its Z-isomer in 64% yield. Epoxyaldehyde 175 also undergoes E-selective Julia olefination with sulfone 176 to give the desired diene 177, which is converted to FR901464 in four steps. The Julia olefination reaction involving alkylsulfonyl benzothiazoles is also applied to the synthesis of phorboxazole A <06OL6043>, iejimalide B <06AG(E)5832>, (-)-codonopsinine <06TA1380>, myxothiazols <06OBC2906>.
258
Y.-J. Wu and B.V. Yang
O O S N
S N
S
CHO
+
S
R
Me 174
173 Me
O
CHO
MeO 175 O
OTBS
176
Me Me
O
O
MeO
Me OTBS O
Me Me O
E/Z = 14/1 R
Me
O
i-Pr
N
N
R = CO2Me
S O O Me S N
+
OMe OMe
LiHMDS 64%
OMe OMe
i-Pr
N
S
S
cystothiazole A
Me Me O
OTBS
LiHMDS 68%
Me
N H
OTBS
N H
177
There are several new methodologies based on the Julia olefination reaction. For example, 2-(benzo[d]thiazol-2-ylsulfonyl)-N-methoxy-N-methylacetamide 178, prepared in two steps from 2-chloro-N-methoxy-N-methylacetamide, reacts with a variety of aldehydes in the presence of sodium hydride to furnish the α,β-unsaturated Weinreb amides 179 <06EJOC2851>. An efficient synthesis of fluorinated olefins 182 features the Julia olefination of aldehydes or ketones with α-fluoro 1,3-benzothiazol-2-yl sulfones 181, readily available from 1,3-benzothiazol-2-yl sulfones 180 via electrophilic fluorination <06OL1553>. A similar strategy has been applied to the synthesis of α-fluoro acrylates 185 <06OL4457>. S O O O Me S N N OMe 178 S O O S N Ar 180 S O O S N t-BuO2C 183
NaH, RCHO R 44-72% R = alkyl, aryl, sugar
LDA, NFSi 90% NaH, Selectfluor 73%
S O O S F N Ar 181 S O O S F N t-BuO2C 184
O
Me N OMe 179 LHMDS, R1R2C(O) 62-98%
R1
Ar
R2
F 182
RCHO, DBU
t-BuO2C
R
F
H
70-99% 185
5.5.2.6 Thiazolium-Catalyzed and -Mediated Reactions The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the direct nucleophilic addition of acyl anions to nitroalkenes using silyl-protected thiazolium carbinols <06JA4932>. In the presence of a fluoride anion, carbinol 186 is not cleaved to an aldehyde
259
Five-membered ring systems: with N and S (Se) atoms
and thiazolium zwitterion, but instead, it acts as nucleophlic acyl reagent, thereby selectively accessing carbonyl anion 189 presumably via a 1,2-hydrogen shift of the initial adduct 188. Treatment of carbinol 186 with tetramethylammonium fluoride (TMAF) and thiocarbanilide in the presence of nitroalkenes 187 provides β-nitroketones 190. In the absence of the thiourea additive, the yield is significantly lower. The incorporation of chiral thiourea 193, derived from quinine, into the reaction with (E)-(2-nitrovinyl)cyclohexane 191 produces βnitro ketone 192 in 74% ee. This fluoride-activated acyl anion strategy is divergent from the typical combinations of heteroazolium salts and bases, and therefore reactive nitroalkenes can be used as substrates (nitroalkenes decompose rapidly upon exposure to amine bases). Y
OTES Ar
N I Me Me 186 TMAF 193
Me
NO2
Ar
O 192
Ar
H
Me
N
Me
Ar = 4-Cl-Ph Y = alkyl, aryl
191
OH
188
N Me Me 189
N
F3C
N H
O
OMe
N H 193
Me
56-80%
O
67% yield 74% ee R = cyclohexyl
S
Ar
Me
CF3
NO2
1,2-H shift
S
(PhNH)2C=S
R
R
O
NO2 187 Me4N•F
S
Ar N
NO2 Y 190
H
The conjugate addition of acylsilanes to unsaturated esters and ketones utilizing Nheterocyclic carbenes derived from thiazolium salt 200 (Sila-Stetter reaction), first communicated in 2004 <04JA2314>, has been described in full detail <06JOC5715>. The proposed reaction pathway starts with the deprotonation of the thiazolium salt 200 with DBU to yield thiazol-2-ylidene 201, a nucleophilic carbene. Addition of this carbene to acylsilane 194 generates intermediate 196, which undergoes a 1,2-silyl group migration from carbon to 195 O Ph
Ar TMS
194
N
O
TMS Ph
Ar'
200 (30 mol%) DBU (30 mol%)
Et
Y
Brook
HN
H
P(O)Ph2 Ph
Ar O 203
S Ph
Y
N
50-82%
Y
N Br
Me 200
O 198 RNH2, acid
S
DBU N Et
Ph Ar'
Me 197 acyl anion
S Et
O Ar
Et
Me
196 Y = (CH2)2OH
P(O)Ph2
200 (30 mol%) DBU (30 mol%) 77-94%
OTMS S N
202 Ar
O
Me Br 201
Y
Ph Ar
R N
Ar'
199
to oxygen (Brook rearrangement). This thermodynamically driven migration results in acyl anion equivalent 197, which adds to the α,β-unsaturated ketones 195. This carbonyl anion methodology provides easy access to various 1,4-diketones 198, which are well known precursors to polysubstituted furans and pyrroles. The thiazolium-catalyzed additions of
260
Y.-J. Wu and B.V. Yang
acylsilanes have also been extended to N-phosphinoylimines 202 to give α-aminoketones 203. The N-heterocyclic carbene (NHC) catalyzed carbonyl anion addition reactions have been extensively investigated, but in contrast, the corresponding nucleophilic substitution reactions have received considerably less attention. Recently, NHCs generated in situ from thiazolium salts 205 have been applied to intramolecular nucleophilic substitution reactions <06OL4637>. For example, treatment of aldehydes 204 with 205 (25 mol%) and DBU (70 mol%) at 160°C provides benzopyrones 208. In the case of aldehydes 209, benzofuranones 212 are obtained exclusively. Presumably, the reaction involving aldehyde 204 proceeds via SN2 pathway, while aldehyde 209 undergoes SN1 reaction, where the initial carbon cation 210 rearranges to give the more stable intermediate 211, thus leading to benzofuranones 212. Y
Y
Me
Y
Me
S
N Me
S
N Me OH
S Me CHO
205 I
R
X
O
204 Y = (CH2)2OH; X = I, OTs
CHO
X
DBU 48-76%
HO O 206
R
Ar
O R
R
O 208
O 207
Y
Me
Y
Me
S
N Me
S
N Me
205
R O
N Me
O Ar R
OTs DBU 45-86% R
HO O 210
209
R Ar
O
HO Me O Ar 211
Me
212
Benzotetramisole 213 has been identified as an effective catalyst for kinetic resolution of sec-benzylic and propargylic alcohols 214 to give 215 in excellent enantioselectivity <06OL1351; 06OL4859>. The benzotetramisole-catalyzed kinetic resolution has been extended to 2-oxazolidinone 217 via enantioselective N-acylation <06JA6536>. (RCO)2O DIPEA,
OH R1 R2 214 O HN
213 (4 mol%)
OH R1 R2 215
(EtCO)2O, DIPEA, O
Ph 217
213 (4-10 mol%) 15-50%
OC(O)R +
R1
R2 216
R1 = phenyl, propargyl R2 = alkyl R = i-Pr, Et
O
O N
O O
+
HN
S O
Et Ph 218 (92-99% ee)
Ph 219 (17-99% ee)
N 213
N Ph
Asymmetric hydrogenation of trisubstituted aryl alkenes and aryl alkene esters using iridium-phosphine thiazole complexes 220 have been reported <06JA2995>. The tetrahydrobenzo[d]thiazole complex (220b) delivers higher enantioselectivity than the cyclopenta[d]thiazole and cyclohepta[d]thiazole counterparts (220a and 220c), and replacement of thiazole moiety with oxazole dramatically reduces the enantioselectivity. The
261
Five-membered ring systems: with N and S (Se) atoms
iridium-N-heterocyclic carbene-tetrahydrobenzo[d]thiazole complex 221 is also synthesized, but only moderate enantioselectivity is obtained <06TL7477>. Ph BArF
N
Ph2 P Ir
N
N
Ir
R3
R1
H H2, 220 or 221 (0.5 mol%)
>98% ee(220) 34-90% ee (221)
N Ph
Ph
S
S
220a/b/c a: n=0; b: n=1; c: n=2
221
( )n
R2 BArF
R2 H R1
BArF = tetrakis(3,5-di-trifluoromethylphenyl)borate
R3 H H
The C2-symmetric bifunctional tridentate bis(thiazoline) 222 has been shown to promote the zinc(II)-catalyzed asymmetric Michael addition of nitroalkanes to nitroalkenes in high enantioselectivity <06JA7418>. The corresponding bis(oxazoline) ligand provides comparable enantioselectivity but higher product yield. The same bis(thiazoline) ligand has also been evaluated in the enantioselective Friedel-Crafts alkylation of indoles, but the enantioselectivity is moderate <06OL2115>.
NO2
Ph 223
N H S
N
N
Ph Ph 222
EtNO2 222 (25 mol%) Et2Zn (25 mol%) Ti(Oi-Pr)4
S Zn(OTf)2 (5 mol%) 222 (5 mol%)
Ph Me
NO2
NO2 224 syn/anti = 11.7/1 54% yield, 95% ee Ph *
N H
NO2 N H
99% yield 78% ee
225
5.5.2.7 Thiazole-Containing Natural Products During the past year, there have been numerous reports on the synthesis of thiazolecontaining natural products, including halipeptin A <06JA4460; 06TL1081>, halipeptin D <06JA4460>, obyanamide <06T9966>, tubulysin D <06JA16018>, tubulysin U and V <06AG(E)7235>, apratoxin A <06OBC2906>, cystothiazole <06T11592; 06H(69)231>, myxothiazol A and Z <06OBC2906>, bistratamide <06TL239>, (R)-telomestatin <06OL4165; 06S1289> and GE 2270 <06JOC4599>. The relative and absolute stereochemistry of antimitotic macrolide archazolid A and B, originally isolated in the early nineties, has been determined on the basis of extensive highfield NMR studies, molecular modelling and chemical derivatization <06OL4751>. The proposed structures have yet to be confirmed by total synthesis. The E stereochemistry at Δ14,15 of (-)-mycothiazole has been revised to Z, and a closely related analog, mycothiazole-4,19-diol, has also been isolated from Cacospongia mycofijiensis <06JNP145>. Studies on a recent collection of the Red Sea sponge Negombata magnifica have led to the discovery of latrunculin T, a new member of the latrunculin family <06JNP219>.
262
Y.-J. Wu and B.V. Yang
Ar
OMe n-Pr Me O
HN
O H
O Me
Me
Me
N
Me
N
NH Me Me N O
Me O Me
S
S
Me
Et
N
N R1
S
i-Pr
N
Me
OMe OMe
Me
O O
NH
O Bn
i-Pr O
N
4
S
S
N H N Me Me N O
MeO 4
O
19
OH OH
N
N
N
N
N N
HN
N
O
telomestatin
Me Me
O O i-Bu
O
mycothiazole-4-19-diol
S
Me
Me MeO
H N
O
O
Me
OH
15
15
Me
Me
O Et
mycothiazole
14
O
N
Me
Me Me R
MeHN
S Me Me
N
O
O OH
S
Me
i-Pr
14
Me Me
19
S CH2OMe i-Pr GE 2270
Me
N
obyanamide
S
NH N
O
myxothiazol A (R = NH2); myxothiazol Z (R = OMe)
O
N S
N
S
MeO
H N
O
Me
OH
O
Me O
N
HN
CO2H
S
S cystothiazole
Ph O
N O
O N
OH
S
Me
O
NH2
S
N
Bn HN
OMe OMe
ROC
N
S
Me t-Bu apratoxin (Ar = 4-MeO-Ph) MeHN
N
O
N
N
OH
tubulysin D (R1 = CH2OC(O)i-Bu, R2 = Ac) tubulysin U (R1 = H, R2 = Ac) tubulysin V (R1 = H, R2 = H)
MeO2C
Me
O
i-Pr OR2
N
N
Et
O
O
O
S
O
O
O
Me
halipeptin A (R = OH) halipeptin D (R = H)
N Me
Me
OO Me N
N
(CH2)2R
H N
O
Me N
N
O
O S archazolid A (R = Me) archazolid B (R = H) OH R Me
Me
latrunculin T (R = CO2H)
5.5.2.8 Thiazole-Containing Drug Candidates A number of biologically important thiazole analogs have been disclosed, including SSR125543 (CRF1 antagonist as antidepressant, phase I) <06DF282>, tebipenem and its prodrug, tebipenem pivoxil (broad-spectrum antibacterial agents, phase II) <06DF676>, BMS-605541 (antitumor agent) <06JMC3766>, GW610 (antitumor agent) <06JMC179>, BAL-4815 (antifungal agent, phase I) <06DF187>, and AF267B (M1 muscarinic receptor
263
Five-membered ring systems: with N and S (Se) atoms
agonist for Alzheimer’s disease, phase I) <06N671>. The discovery of the second generation epothilones as antitumor agents, including fludelone (preclinical), has been reviewed <06JOC8329>. S
OMe
Me
Me
O
N
fludelone Me
N N
O
Me Me O OH MeO
OMe
F
S GW 610
CN
NMe N H H Me
N
S AF267B
Et S N
S
N
O
CO2R tebipenem (R = H) tebipenem pivoxil (R = OCH2OC(O)t-Bu)
BAL-4815
H N
O
SSR-125543
Me
N F
5.5.3
Cl
HO
S
F
N
N
N
N Me
HO
S
Me
OH Me
Me
F3C
Me F
F
F
S
HN
NH
N H
N
O
BMS-605541
ISOTHIAZOLES
5.5.3.1 Synthesis of Isothiazoles A novel synthesis of alkylsulfanylisothiazoles 230 starts with sodium α-cyanoketene dithiolates 227, obtained by the reaction of cyanoacetamides 226 with carbon disulfide in the presence of sodium ethoxide <06SC825>. Treatment of 227 with sulphur and piperidine acetate generates sodium isothiazole-3,5-dithiolates 229. The formation of 229 is assumed to arise from the addition of anionic sulphur to the nitrile group in 227 to give the intermediate 228, which cyclizes upon elimination of anionic sulphur to yield 229. Salts 229 are readily alkylated to furnish 3,5-bis(alkylthio)isothiazole derivatives 230. Ar HN O 226
NaS
NaOEt, CS2 CN 95%
Ar
SNa
H N
CN O
NaS
piperidine, HOAc sulfur
Ar
N O
227
S 228
-Sn S
RS H N
R = alkyl, aryl Ar
N SR
O 230
S Sn
H N
R-X
NaS
70-85%
H N Ar
75% S
N SNa
O 229
A novel synthesis of isothiazolidines involves sulfonium ylides, formed by the reaction of thietanes and nitrenes <06TL1109>. Exposure of N-(p-tolylsulfonyl)imino)phenyliodinane 232 with excess of thietanes 231 (5 equiv) in the presence of a catalytic amount of Cu(II)
264
Y.-J. Wu and B.V. Yang
acetylacetonate affords cis-isothiazolidines 234. One plausible explanation for the cis selectivity is that the cis isomer of the diastereomeric mixture of thietane 231 selectively reacts with 232 to form the sulfimide intermediate 233, which undergoes [1,2]-sigmatropic rearrangement to give the cis product 234. R1 S R2 231
PhI=NTs 232
R1
R1
Cu(acac)2
56-75% R2
S
R2
NTs 233
R1 = aryl, alkyl R2 = aryl, H
S
N Ts 234
A series of benzisothiazolone derivatives 238 has been prepared from methylthiosalicylate 235 <06OL4811>. The key cyclization step features the formation of a N-acylnitrenium ion 237, generated by the hypervalent iodine reagent, phenyliodine(III)bis(trifluoroacetate) (PIFA). This ion cyclizes to benzisothiazol-3-one 238 upon intramolecular trapping of the thiol moiety. O OMe
N R H SH
63-95%
SH 235
O
O
AlMe3, RNH2
236
O N R
PIFA
R = aryl, benzyl, Me
60-78% N R S
SH 237
238
Radical cyclization of acyclic sulfinamides 239 provides easy access to cyclic sulfinamides 241 <06AG(E)633>. Conceivably, the reaction pathway involves thiophilic attack by the aryl radical with a concomitant or successive expulsion of the p-tolyl or tertbutyl radical. R1 239
N R2 X S O Y
Bu3SnH, AIBN
31-86% N R2 -Y • S O Y 240 R1 = OMe, F, H; R2 = H, Me; X = Br, I; Y = Ts, t-Bu R1
R1
•
241
N R2 S O
A practical synthesis of the bicyclic dienyl sultam 246 has been reported <06JOC6573>. The key step of the ring-closing metathesis (RCM) represented by conversion of 243 to 244 has to be implemented prior to the sultam formation (244 to 245). Bicyclic sultam is converted to dienyl sultam 246 in two steps. O O 4 steps S O 242
Cl
H N
S O O 243
RCM
Cl
98% 244
NH S O O
NaOH Et3N 95%
O
O S
2 steps
O
O S
N
N
245
246
An efficient synthesis of N-alkylated-4-substituted isothiazolidine-dioxides (sultams) 251 has been developed utilizing epoxides 248 <06TL4245>. Addition of a secondary sulphonamide 247 to epoxide 248 in hot 1,4-dioxane affords the amino alcohol 249, which is
265
Five-membered ring systems: with N and S (Se) atoms
converted to the benzensulfonate 250. Treatment of 250 with n-BuLi leads to the formation of N-alkylated-4-substituted sultam 251. Chiral 4-substituted sultams are easily accessed using the chiral epoxide. The chirality is faithfully translated to the product through the inversion at the sulfonate-bearing carbon as a result of cyclization occurring exclusively via a SN2 pathway. O O 247 S 2 Me NHR + O
K2CO3, Et4NCl 86-97%
248
R1
Me O OH S O N 2 R R1 249
PhSO2Cl pyridine
Me O BsO S O N 2 R R1 250
n-BuLi 1 72-83% R (2 steps)
O S O N R2 251
R1 = Ph, alkyl; R2 = Bn, Ph; Bs = PhSO2
An asymmetric synthesis of chiral 3-substituted sultams 256 makes use of a diastereoselective nucleophilic addition reaction <06EJOC1271>. The nucleophilic 1,2addition of various organo-cerium reagents to the C=N double bond of ω-SAMP-hydraznosulfonate 252 gives hydrazines 253 in good to excellent diastereoselectivity. Removal of the chiral auxiliary by reductive N,N-bond cleavage and Cbz protection of the primary amine leads to aminosulfonates 254. After ester hydrolysis and chlorination, the resulting aminosulfonyl chlorides 255 are cyclized under basic conditions to afford 3-substituted sultams 256. MeO N YO
S
O O
MeO
RMgBr or RLi CeCl3
N
78-99%
H
HN YO
S
BH3•THF; CbzCl,K2CO3
N
50-99%
R
O O
NHCbz
EtOH, H2O; NaOAc;
Cl
S O O
COCl2 72-83%
R
O O HN S
HBr, HOAc; Et3N R
255 ee = 78-93%
S O O
R
254 ee = 78-93%
253 de = 78->96%
252
NHCbz YO
Y = cyclohexyl R = alkyl, Ph
256 ee = 78-93%
Chiral N-substituted benzisothiazole-3-one-1,1-dioxide (saccharin) derivatives 258 are synthesized via the direct ortho-lithiation of 3-N-arylsulfonyloxazolidine-2-ones 257 using LDA and HMPA <06TL6405>. Compounds 257 are readily prepared from (L)-amino acids. O
O
O
R
S
O S
LDA, HMPA
R N
R1
O R2
257
O
62-71%
OH
1
R
R2
O 258
R = Me, i-Pr, s-Bu, Bn R1, R2 = H, H; or CH=CH-CH=CH
Various saccharin derivatives 260 have been prepared by chromium (VI) oxide catalyzed H5IO6 oxidation of substituted ortho-toluenesulfonamides 259 <06T7902>. The reaction presumably proceeds through a benzylic radical intermediate 261 generated from the
266
Y.-J. Wu and B.V. Yang
abstraction of a benzylic hydrogen by chromium oxo and peroxo species. Subsequent intramolecular hydrogen transfer leads to the formation of the N-centered radical intermediate 262. This radical is easily oxidized to the carbonyl diradical 263 which cyclizes to afford the saccharin skeleton 260. Alternatively, radical 262 can undergo a second hydrogen atom abstraction to give an alkyl diradical 264, which undergoes intramolecular coupling to give sultam intermediate 265. This intermediate can be readily oxidized to 260. The excess H5IO6 used is to regenerate the high-valence chromium species to force the reaction to completion. Further development of this methodology culminates in the direct synthesis of substituted N-tert-butyl saccharin analogs 267 from their corresponding substituted toluene derivatives 266 via a one-pot, three-step sequence: chlorosulfonation with chlorosulfonic acid, trapping the sulfonyl chloride with tert-butyl amine and the oxidative cyclization of the resulting ortho-toluenesulfonamide. O
Cr(n)
O S 2
1
R
259
NHR CH3
Cr(n-1)
O
O S
H5IO6
H-atom transfer
NHR2 • CH2
1
R
R
O [O] R1
N R2
265
ClSO3H; t-BuNH2, Et3N; H5IO6 (7 equiv), CrO3 (10 mol%),
R3
O S NR2 • • CH2 264
R1
N R2
O
260
[O]
-H+, -e O
O S
O
O
O S
R1 •
NR2 •
O 263
O S
R3
NR2 •
CH3 262
R1 = H, halogen, CF3, NO2 etc. R2 = H, alkyl
O S
O S
1
261
O R1
O
-H+, -e
H5IO6 (8 equiv), CrO3 (10 mol%)
12-92%
HIO3
N t-Bu
Me Ac2O (7 equiv), 38-79%
R3 = H, halogen, CF3, t-Bu
267 O
266
5.5.3.2 Reactions of Isothiazoles A highly stereoselective synthesis of the β-substituted β-amino sulfone 271 involves the addition of a sulfonyl anion, derived from N-PMB sultam 268 upon treatment with NaHMDS, to chiral N-sulfinyl imine (S)-269 <06OL789>. Removal of the N-sulfinyl followed by basic workup affords amine 271. The stereochemical outcome of the adduct 270 was established via proton NMR analysis of the Mosher’s amide derived from 271. t-Bu PMB N
S O O
268
N
S (S)-269 O
Ar PMB N
NaHMDS 91% Ar = p-tolyl
S O O 270
H N
S t-Bu O dr >99:1
Ar
TFA; NaHCO3
PMB N
S O O 271
NH2 t-Bu
The Diels-Alder reaction between isothiazole-dioxides and various dienes represents an attractive approach toward a range of bi- and tricyclic derivatives containing the fused
267
Five-membered ring systems: with N and S (Se) atoms
heterocyclic nucleus <06EJOC4285>. In all the cycloadditions evaluated, Sc(OTf)3 appears to be the most effective catalyst which affords high yields under mild conditions. The two dienophiles 272a and 272b exhibit different endo/exo selectivity in reactions with cyclopentadiene and furan. The 4-aryl substituted isothiazole-dioxide 272b gives a mixture of exo and endo adducts in all cases, with the latter being preferred (endo/exo: 5/1 with furan and 8/1 with cyclopentadiene, reaction not shown). However, a major selectivity is found with isothiazole-dioxide 272a, and the selectivity depends on the nature of the diene: cyclopentadiene delivers the endo adduct 273 (X = CH2) exclusively, whereas the exo addition product 274 (X = O) is the sole product from furan. X
O O S N
X Sc(OTf)3
70% (X = CH2) NHBn 88% (X = O)
O O S N
X
H OO + S H N
Ar
H NHBn H
BnHN 273
272a
O O S N NEt2 272b
274
Ar = p-MeO-C6H4
endo/exo: 99/1 (X = CH2); 0/100(X = O)
The 1,3-dipolar cycloaddition of diazoalkanes 276 and nitrile oxides 279 to isothiazole dioxides 275 provides an easy entry into fused bicyclic isothiazole systems 277 and 280, respectively <06JHC1045>. The adducts from 4-bromoisothiazole (R1 = Br) are labile and undergo spontaneous debromination to form the aromatic bicyclic pyrazolo-isothiazoles 278 and isoxazolo-isothiazoles 281. O O S N
R2CH2N2 276 90%
R1 NHBn 275
Ar
Ar C N O 279
N
O O S N
O
R2
R1 = Br -HBr
N H NHBn 278
Ar
R1 = Br -HBr
N
R1 NHBn 280
O O S N
N
74% (from 275) N 2 H R1 NHBn R = CO2Et 277 O O S N
N
85-90%
R2
87% (from 275) Ar = 2,6-diMe-Ph
R1= H, Br R2= CO2Et, Ph Ar = Ph, 2,6-diMe-Ph
O O S N
O NHBn 281
The regioselective ozonation of alkylidene-sultams 282 followed by reaction with diazomethane leads to the formation of highly reactive bicyclic trioxo-isothiazolidine 284 <06HCA971>. MeO
CO2Me
MeO
O3 R
SO2 N Me 282
57 -75%
O
CO2Me SO2 N Me 283
MeO
CO2Me
CH2N2 88%
O
SO2 N Me
R = H, Me
284
3,5-Dichloro- and 3,5-dibromoisothiazole-4-carbonitriles 285a/b undergo regioselective Stille, Negishi, Sonogashira coupling reactions at C-5 to provide 3-halo-5-substituted
268
Y.-J. Wu and B.V. Yang
isothiazoles <06OBC3681>. However, the analogous couplings with 3-chloro- or 3-bromo5-phenylisothiazoles 286a/b at C-3 fail to yield any desired products. To this end, the first 3iodo-5-phenylisothiazole-4-carbonitrile 291 is prepared via Sandmeyer iodination of the 3amino analog 290, available from 3,5-dichloroisothiazole-4-carbonitrile 286a in two steps. This iodide shows sufficient reactivity in the palladium-catalyzed coupling reactions, and the C-3 coupling products 287 and 292 are obtained in good yields. The cross-coupling reactions on azoles with two and more heteroatoms including isothiazoles have been reviewed <06EJOC3283>.
NC X
X
N S 285a/b
Suzuki or Stille
X
N or Negishi Ph S a: X = Cl 286a/b b: X = Br
Sonogashira 69-91% NC
R
NC
X S
N
288a/b
Suzuki X or Stille
BnNH2 (X = Cl)
NC
NHBn
Br2, AIBN
N
90%
S 289
Ph
R
Ph NC
N S 287
Ph
S
Suzuki 80% or Stille 90%
90%
Ph
NC
NC Ph
NH2 N S 290
i-amyl nitrite, I2 85%
N
292
Sonogashira 70-100% NC Ph
I N S 291
5.5.3.3 Isothiazoles as Auxiliaries in Organic Syntheses Oppolzer’s camphor sultam, a well known chiral auxiliary, has been utilized in the asymmetric [2,3]-sigmatropic rearrangement of glycine-derived allyl ammonium ylides. These reactions are known to be highly selective in terms of relative and absolute stereocontrol with substrates bearing acyclic alkene moiety <05JA1066>. For example, the [2,3]-rearrangement of N’N’N’-allyldialkyl glycinoyl (2S)-sultam salts 293 gives the allyl glycine derivatives 295 with a high level of diastereoselectivity, in favour of the (2’R)-isomer (dr > 96 : 4). However, when the chiral camphorsultams of the ylides derived from Nmethyltetrahydropyridine (NMTP) undergo rearrangement, the reactions proceed with exclusive cis-stereoselectivity but no absolute stereocontrol as exemplified by the formation of 1 : 1 diastereomers of pyrrolidine carboxylates 297 and 298 from the NMTP (2S)camphorsultam salt 296 <06T11506>. The lack of diastereoselectivity in the cyclic series suggests that the sigmatropic rearrangements of N-chiral ammonium ylides are controlled by nitrogen stereogenicity.
269
Five-membered ring systems: with N and S (Se) atoms
Me
Me
Xs
O
NaH
1
R N
2
N
R2 Br
R1 N R2 294
10
S 293 O O
1
2
H
64-99% R1 N R2
H
O
2'
R
NaH S
S
N Me
s
X
O O
+
R
O
53%
N 296
O
Me
O
Br
Xs
2'R/2'S = 96/4 to >99/1
R , R = allyl, Bn, Me; X = (2S)-camphor sultam
N Me
2'
(2'S)-295
(2'R)-295
s
Me
H
Xs + R1 N R2 O
O
S s
X (45 : 55)
297
N Me
298
The camphor sultam auxiliary has been applied to the asymmetric aziridine synthesis via aza-Darzens reaction of N-diphenylphosphinylimines. Reaction of the chiral enolates derived from N-bromoacetyl (2R)-camphorsultam 299 with N-diphenylphosphinyl aryl and tertbutylimines 300 generates (2’R,3’R)-cis-N-diphenylphosphinyl aziridinoyl sultams 301 in high diastereoselectivity <06T3681>. However, the stereoselectivity of this reaction depends on the structure of the imine substituents: arylimines substituted in the ortho-position usually give mixtures of cis- and trans-aziridines, and exclusively trans-configured products 306 are obtained from ortho-bromo, iodo, and trifluoromethylphenylimines <06T3694>. Me
P(O)Ph2
Me R N S O O 299
Br
+
NaHMDS NP(O)Ph2
40-78% dr > 95 : 5
H N H R
X
R O 301 exclusive XR = (2R)-camphor sultam; R = aryl, heteroaryl, vinyl, t-Bu O
Me
300
N O
X
R O
302 none P(O)Ph2
NP(O)Ph2
H N H
H N H LiHMDS
+ S O O 303
H N H R
P(O)Ph2
Me R
Br
P(O)Ph2
69-72%
304 Xs = (2S)-camphor sultam
s
s
X
X
O
R 305 exclusive for R = H, NO2
O
R 306 exclusive for R = Br, I, CF3
An elegant application of Oppolzer’s sultam in the asymmetric [C+NC+CC] coupling reaction provides convenient access to a variety of pyrrolidines 312 in a single step <06OL3647>. Simply mixing aldehyde 307, chiral amine derived from glycyl (2R)camphorsultam 308, and electron-deficient alkene 309 in THF in the presence of a catalytic amount of silver acetate results in the clean production of highly functionalized pyrrolidines 312. The reaction proceeds through imine 310 formed from aldehyde 307 and amine 308. The subsequent [3+2] cycloaddition with alkene 309 leads to 2,5-cis disubstituted pyrrolidines, presumably via the intermediacy of a metalated (E, E)-azomethine ylide 311. The Oppolzer’s chiral glycyl sultam serves several important roles: (1) it reduces the nucleophilicity of the amine component, thus preventing unwanted Michael addition; (2) it
270
Y.-J. Wu and B.V. Yang
facilitates azomethine ylide formation by enhancing the α-acidity of the imine; (3) it controls the diastereofacial selectivity of the 1,3-dipolar cycloaddtion in a predicable maner, i.e. alkene approaching from the endo-Re face of the (E,E)-azomethine ylide as depicted by 311. H R2 + H2N
COXR
O AgOAc (5 mol%)
Z
309
X
N R R1
H
Me
R
H 2
H H 308 + H H Y
endo-Re Me
307 CHO
R1
O Ag
N O
63-94% S O
H R2 H N R1 H
XR O
dr: 7:1 to 19:1
Y Z N H R2 312 311 R1 H H R1= Bn, BnO, alkyl; R2 = H, NHBoc; Y = CO2Me, SO2Ph; Z = H, CO2Me or Y, Z = CON(Ph)C(O); XR =(2R)-camphor sultam H
H 310
Other applications of Oppolzer’s sultams include diastereoselective allylation of glyoxylic oxime ethers <06TL611>, asymmetric aldol reactions in the syntheses of macrolide FD-891 <06OL2695> and antitumor antibiotic belactosin and its analogs <06JOC337>, silver (I) promoted asymmetric halomethoxylation of α, β-unsaturated carboxylic acid derivatives <06TA210>, Lewis acid-catalyzed [4+2] cycloaddition of α, β-unsaturated carboxylic acid derivatives to cyclopentadiene and cyclohexadiene <06TA822>, dialkylboron triflatepromoted anti addition of acylated Oppolzer’s sultam to aldehydes <06TA1152>, and BaylisHillman reaction with Oppolzer sultam derived acrylamide <06EJOC4731>. 5.5.3.4 Pharmaceutically interesting isothiazoles Several biologically active isothiazoles and their saturated and/or oxygenated analogs have been reported in 2006. Isothiazoles have been incorporated into TrkA kinase inhibitor 313 <06BMCL3444> and the allosteric MEK1 (MAP kinase/ERK kinase) inhibitor 314 <06BMCL5561>, sultams into the selective TACE (TNFα converting enzyme) inhibitor 315 (IC50: TACE 5.9 nM, MMP-1, 2, 9, 13 > 2128 nM) <06BMCL1028> and human melanocortin subtype-4 receptor (MC4R) selective agonists 316 <06BMCL1130>. Compounds containing isothiazole moiety that are currently in clinical development include STA-5312 (rosabulin), a tubulin binder for the treatment of drug-resistant cancers (Phase I) <06BMCL5164>, and CP-547632, a potent, selective and orally bioavailable vascular endothelial growth factor (VEGF) receptor-2 tyrosine kinase inhibitor for cancer therapy (phase II) <03CR7301>
271
Five-membered ring systems: with N and S (Se) atoms
OH H2N
N S
O HN O
Me
OH HN
NH OH
O
S O N O
O
NH
S N
H2N
HN
H N
HN O N
S
O Cl
O
313
Cl
Me
314
Cl CN
N
316 R = H, Me
N 315 H N
N
O S
HN
N H N O
S
H2N
N
CP-547632
Me STA-5312
N
F
O O
O
R R S O O
F
Br
5.5.4 THIADIAZOLES A practical α-heteroarylation of simple esters or amides has been developed via nucleophilic aromatic substitution. Exposure of chlorothiadiazoles 317 and 319 to NaHMDS and tert-butyl acetate or N,N-dimethylacetamide leads to the formation of functionalized 1,3,4-thiadiazole 318 and 1,2,4-thiadiazoles 320, respectively <06OL1447>. Cl N N
S
CO2t-Bu
MeCO2t-Bu, N NaHMDS N 79%
Ph 317
S
Cl N S
Ph 318
N
MeC(O)R NaHMDS
C(O)R N S
N
69-87%
R = Ot-Bu, NMe2
Ph 320
Ph 319
Direct electrophilic silylation of thiadiazole 321 with bromotrimethylsilane (TMSBr) under basic conditions provides easy access to C-silyl thiadiazole 322, which can serve as a synthetic equivalent of an organometallic intermediate or a silyl-protected azole <06S1279>. N N Ph
S 321
TMSBr, Et3N pyridine-toluene 72%
N N Ph
S 322
TMS
Reaction of N,N-dimethylsulfamoyl aziridines 323 and 325 with primary amines furnishes substituted 1,2,5-thiadiazolidine 1,1-dioxides 324 and 326, respectively, in a regioselective manner <06SL833>. Aziridine 325 is made from (1R,6S,Z)-bicyclo[4.2.1]non3-en-9-one in two steps: N,N-dimethylsulfamoyl imine formation using dimethylsulfamide and subsequent reaction with trimethylsulfoxonium ylide. The product from the reaction with 4-methoxy-benzyl amine can be subsequently manipulated (debenzylation and derivatization) to give the alternative nitrogen substitution pattern in a controlled manner.
272
Y.-J. Wu and B.V. Yang
Cyclic sulfamides 326 serve as key intermediates in the synthesis of a series of potent and selective γ-secretase inhibitors with potential for the treatment of Alzheimer’s disease.
Me2N
O S O
O O S N HN
RNH2
N
O
R
Me2NSO2NH2, Ti(OEt)4, 50%
Me2N
O S O
R
N
RNH2
64-87%
Bn
Bn
323
60-87%
Me3S(O)I, NaH 87%
324
R = alkyl, ArCH2
O N S O NH
325
326
5.5.5 1,3-SELENAZOLES, 1,3-SELENAZOLIDINES AND 1,2,3-SELENADIAZOLES A series of 5-acyl-2-amino-1,3-selenazoles 331 are prepared from selenazadienes 327 upon treatment with α-haloketones 328 in hot methanol or acetonitrile. In the presence of triethylamine, reaction of selenoazadienes 332 with 1,3-dichloro-propan-2-one (5 equiv) affords the bis(selenazoyl) ketones 333 in high yields, whereas the same reaction without base produces the corresponding selenazoles 331 (R3 = CH2Cl) preferentially <06S31>. R1 R N
R1 R N
O
2
2
X
Se
328
N
R1 R2 N
Se
329
O Se
Et3N 82-91%
NMe2
332
Cl
R1 N R2
Se
N
COR3
330 NMe2
NMe2
Se
Se N
O
Cl
N
COR3
N
X = Br, Cl
NMe2
327
R3
R1 R N 2
N
R1 N 2 R
-Me2NH
68-100%
R1 R2 N
Se COR3
N 331
333
Reaction of N,N-unsubstituted selenoureas 332 with methyl vinyl ketone in the presence of ferric chloride in refluxing ethanol gives 2-amino-5-(1-ethoxy)-1,3-selenazoles 335 <06H(68)2145>. This approach obviates the use of lachrymatory halo carbonyl compounds frequently utilized in the synthesis of 1,3-selenazoles. Me R1 R2 N
Se NH2
332
O FeCl3, EtOH
R1 R N 2
Se N
333 Me
R1 R N 2
Se
R1 77-89% R N 2
334 Me
Se
H -FeCl2 -HCl
N OEt
N
OEt Me 335
A novel synthesis of 1,2,3-selenadiazoles 338 starts with the Michael addition of 2nitropropane to α,β-unsaturated ketones 336 under basic conditions <06JHC149>. The resulting adducts are treated with semicarbazide hydrochloride to give semicarbazones 337, which are converted to 1,2,3-selenadiazoles 338 by reaction with selenium dioxide in THF (the choice of the solvent appears to be important in this case).
273
Five-membered ring systems: with N and S (Se) atoms
Ar
NH2
H N
1. Me2CHNO2, NaOMe 2. NH2NHC(O)NH2
O
N
NO2
Ar'
Ar Ar'
336
337
N
SeO2
O Me Me
N
Se NO2
Ar
62-73%
Me Me
Ar' 338
Alkylisoselenocyanates 339 are versatile starting materials for the synthesis of various selenium-containing heterocycles. Reaction of 339 with allylamine yields N-allylselenoureas 340 which undergo intramolecular cyclization in the presence of hydrogen chloride to afford 5-methyl imino-selenazolidines 341 <06CL626>. When propargylamines 342 are used instead of allylamine, 5-methylidene-selenazolidines 343 are obtained directly <06H(68)1607>. Addition of 339 with sodium hydroselenide generates the intermediate Nalkyldiselenocarbamates 344, which react with bromoacetylbromide 345 to provide oxoselenazolidines 346 <06S2738>. Se
H2N R-N=C=Se 339
R
N H
89-97%
H N
HCl, EtOAc
N H
81-100%
N Se R 341
Me
340 1 342 NHR
65-97%
R = aryl, cycloalkyl
NaHSe R2 O
R1 N Se 343
3
R
Se
R = aryl, Bn, N cycloalkyl R R1 = H, Me
R
N H
Se
Se
Br Br 345
R
10-37%
O
344
N
Se R3
R2 346
Alkylisoselenocyanates 339 are also used in the synthesis of 2-methylidene-1,3selenazolidine derivatives <06T3344>. Nucleophilic addition of the carbanion derived from malononitrile 347 to 339 leads to an intermediate keten-N, Se-acetal 348, which reacts with 2haloacetate ester and 1,2-dibromoethane to provide 1,3-selenazolidin-4-ones 350 and 1,3selenazolidines 352, respectively. R N
CN
R1 Se 352
Br
Br(CH2)2Br, Et3N
R N Se 351
31-62%
R1CH2CN 347 + R-N=C=Se 339
R = aryl, cycloalkyl R1 = CN, CO2Et
CN R
Br(CH2)2Br
1
Se
34-86%
O
R N
R2
Se 350
2
Et3N R HN
R2CH(X)CO2R3, Et3N
CN R1 348
R = H, Me X = Cl, Br R3 = Me, Et R2CH(X)CO2R3
R3 O
CN R1
R N
CN
Se
R1
O R2
349
5.5.6 ACKNOWLEDGMENT We thank Dr. Richard Hartz of Bristol-Myers Squibb for critical reading of this review.
274
Y.-J. Wu and B.V. Yang
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Five-membered ring systems: with N and S (Se) atoms
06JA2995 06JA3128 06JA4460 06JA4932 06JA4936 06JA6536 06JA7418 06JA10513 06JA16018 06JHC149 06JHC1045 06JHC1609 06JMC179 06JMC3766
06JMCAC235 06JNP145 06JNP219 06JOC337 06JOC1802 06JOC3287 06JOC3754 06JOC4599 06JOC5031 06JOC5328 06JOC5715 06JOC6573 06JOC7574 06JOC8261 06JOC8276 06JOC8302 06JOC8329 06N671 06OBC2313 06OBC2906 06OBC3681 03OL3607 06OL527 06OL531 06OL789 06OL1351 06OL1447 06OL1553 06OL1625 06OL2115 06OL2417
275
C. Hedberg, K. Kallstrom, P. Brandt, L.K. Hansen, P.G. Andersson, J. Am. Chem. Soc. 2006, 128, 2995. M.T. Crimmins, F. Caussanel, J. Am. Chem. Soc. 2006, 128, 3128. K.C. Nicolaou, D.E. Lizos, D.W. Kim, D. Schlawe, R.G.de Noronha, D.A. Longbottom, M. Rodriquez, M. Bucci, G. Cirino, J. Am. Chem. Soc. 2006, 128, 4460. A.E. Mattson, A.M. Zuhl, T.E. Reynolds, K.A. Scheidt, J. Am. Chem. Soc. 2006, 128, 4932. M.T. Crimmins, A.C. DeBaillie, J. Amer. Chem. Soc. 2006, 128, 4936. V.B. Birman, H. Jiang, X. Li, L. Guo, E.W. Uffman, J. Am. Chem. Soc. 2006, 128, 6536. S. Lu, D. Du, J. Xu, S. Zhang, M, J. Am. Chem. Soc. 2006, 128, 7418. B. Wagner, D. Schumann, U. Linne, U. Koert, M.A. Marahiel, J. Am. Chem. Soc. 2006, 128, 10513. H.M. Peltier, J.P. McMahon, A.W. Patterson, J.A. Ellman, J. Am. Chem. Soc. 2005, 128, 16018. S. Saravanan, A. Nithya, S. Muthusubramanian, J. Heterocycl. chem. 2006, 43, 149. F. Clerici, M.L. gelmi, C. Monzani, D. Pocar, A. Sala, J. Heterocycl. chem. 2006, 43, 1045. S. Kamila, B. Koh, E.R. Biehl, J. Heterocycl. chem. 2006, 43, 1609. C.G. Mortimer, G. Wells, J. Crochard, E.L. Stone, T.D. Bradshaw, M.F.G. Stevens, A.D. Westwell, J. Med. Chem. 2006, 49, 179. R.M. Borzieri, R.S. Bhide, J.C. Barrish, C.J. D’Arienzo, G.M. Derbin, J. Fargoli, J.T. Hunt, R. Jeyaseelan, Sr., A. Kamath, D.W. Kukral, P. Marathe, S. Mortillo, L. Qian, J.S. Tokarski, B.S. Wautlet, X. Zheng, L.J. Lombardo, J. Med. Chem. 2006, 49, 3766. B. Das, V.S. Reddy, R.R. Ramu, J. Molecular Catal. A: Chemical 2006, 252, 235. R.N. Sonnenschein, T.A. Johnson, K. Tenney, F.A. Valeriote, P. Crews, J. Nat. Prod. 2006, 69, 145. K.A. El Sayed, D.T.A. Youssef, D. Marchetti, J. Nat. Prod. 2006, 69, 219. G. Kumaraswamy, M. Padmaja, B. Markondaiah, N. Jena, B. Sridhar, M.U. Kiran, J. Org. Chem. 2006, 71, 337. G. Evindar, R.A. Batey, J. Org. Chem. 2006, 71, 1802. H.F. Olivo, R. Tovar-Miranda, E. Baragan, J. Org. Chem. 2006, 71, 3287. P. Stanetty, M. Schnurch, M.D. Mihovilovic, J. Org. Chem. 2006, 71, 3754. O. Delgado, G. Heckmann, H.M. Muller, T. Bach, J. Org. Chem. 2006, 71, 4599. N. Haddad, J. Tan, V. Farina, J. Org. Chem. 2006, 71, 5031. M. Alajarin, J. Cabrera, A. Pastor, P. Sanchez-Andrada, D. Bautista, J. Org. Chem. 2006, 71, 5328. A.E. Masson, A.R. Bharadwaj, A.E. Zuhl, K.A. Scheidt, J. Org. Chem. 2006, 71, 5715. A.J. Preston, J.C. Gallucci, L.A. Paquette, J. Org. Chem. 2006, 71, 6573. A. Dondoni, A. Nuzzi, J. Org. Chem. 2006, 71, 7574. D.S. Bose, M. Idrees, J. Org. Chem. 2006, 71, 8261. T. Kim, Y. Lee, B. Jeong, H. Park, S. Jew, J. Org. Chem. 2006, 71, 8276. J. Guo, G.A. Erickson, R.N. Fitzgerald, R.T. Matsuoka, S.W. Rafferty, M.J. Sharp, B.R. Sickles, J.C. Wisowaty, J. Org. Chem. 2006, 10, 8302. R.M. Wilson, S.J. Danishefsky, J. Org. Chem. 2006, 71, 8329. A. Caccamo, S. Oddo, L.M. Billings, K.N. Green, H. Martinez-Coria, A. Fisher, F.M. LaFeria, Neuron 2006, 49, 671. J. Hartung, K. Daniel, T. Gotteald, A. Grob, N. Schneiders, Org. Biomol. Chem. 2006, 4, 2313. J.M. Clough, H. Dube, B.J. Martin, G. Pattenden, K.S. Reddy, I.R. Waldron, Org. Biomol. Chem. 2006, 4, 2906. I.C. Christoforou, P.A. Koutentis, Org. Biomol. Chem. 2006, 4, 3681. B. Sezen, D. Sames, Org. Lett. 2003, 5, 3607. I. Larrosa, P. Romea, F. Urpi, Org. Lett. 2006, 8, 527. J. Doi, Y. Numajiri, A. Munakata, T. Takahashi, Org. Lett. 2006, 8, 531. F. Velazquez, A. Arasappan, K. Chen; M. Sannigrahi, S. Venkatraman, A.T. McPhail, T.-M. Chan, N.-Y. Shih, F.G. Njoroge, Org. Lett. 2006, 8, 789. V.B. Birman, X. Li, Org. Lett. 2006, 8, 1351. H.C. Shen, F. Ding, S.L. Colletti, Org. Lett. 2006, 8, 1447. A.K. Ghosh, B. Zajc, Org. Lett. 2006, 8, 1553. Z. Kaleta, B.T. Makowski, T. Soos, R. Dembinski, Org. Lett. 2006, 8, 1625. S. Lu, D. Du, J. Xu, Org. Lett. 2006, 8, 2115. E. Biron, J. Chatterjee, H. Kessler, Org. Lett. 2006, 8, 2417.
276 06OL2695 06OL2887 06OL2899 06OL3057 06OL3647 06OL4165 06OL4457 06OL4637 06OL4751 06OL4811 06OL4859 06OL5291 06OL6043 06OPRD346 06S31 06S1279 06S1289 06S2738 06SC825 06SL460 06SL833 06T66 06T1110 06T1378 06T3201 06T3228 06T3344 06T3681 06T3694 06T7902 06T9548 06T9966 06T11506 06T11592 06TA210 06TA822 06TA1152 06TA1380 06TL239 06TL611 06TL1081 06TL1109 06TL2361 06TL3091 06TL4245 06TL6405 06TL7477 06TL8661
Y.-J. Wu and B.V. Yang
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277
Chapter 5.6 Five-membered ring systems: with O & S (Se, Te) atoms
R. Alan Aitken* and Lynn A. Power University of St. Andrews, UK (e-mail:
[email protected])
5.6.1
1,3-DIOXOLES AND DIOXOLANES
The conversion of 1,2-diols into the corresponding 2,2-dimethyl-1,3-dioxolanes has been achieved by reaction with acetone and polymer-supported Ph3P/I2 <06SL305>, while highly stereoselective conversion of trans epoxides 1 into the cis dioxolanes 2 has been reported using acetone with either a Lewis Acid <06EJO3007> or photocatalytically with a pyridinium salt catalyst <06H(68)1861>. Conversion of non-enolisable aldehydes and ketones, R1R2C=O, into dioxolanes 3 can be carried out in excellent yield by slow addition of KOBut to a mixture of the compound and 2-chloroethanol in DMF <06OL3745>. An interesting dioxolane to dioxolane rearrangement is involved in the conversion of 4 into 5 upon acid-catalysed treatment with ethanediol <06OBC2218> and the stereospecific rearrangement of 6 to give 7 has also been described <06JOC1537>. Palladium-catalysed coupling of aryl halides with 2-hydroxyethyl vinyl ether gives either of the isomeric dioxolanes 8 or 9 depending on the catalyst and ligands used <06EJO765>.
O R1
O R2
R1
1
O
O
R1 R2
O
R2
O
O
68%
S Ph
O
5
O2N
O R
CO2Me
O
10
CO2Me
O O
11
R1 R2
7 R
12
CO2
O
Ar
O
9
8 O
CHR3
Ar
O
O
O
O
6
O
S
4
Ph BF3•Et2O
O2N
O
TsOH
3
2
OH
HO
O
O
O R
O
13
278
R.A. Aitken and L.A. Power
Reaction of substituted catechols with DMAD and 0.1 equiv. DABCO directly gives the benzodioxoles 10 <06S2286> and photochemical addition of 1,3-dioxolan-2-yl radicals to alkynes in acetonitrile affords products 11 <06CC4300>. New studies on the industrially important carboxylation of epoxides 12 to give dioxolan-2-ones 13 include catalysis by silica-supported quaternary phosphonium salts <06CC1664>, quaternary ammonium saltterminated polyethyleneglycol <06TL1271> and tris(dibutylamino)bromomethane with ZnBr2 <06JMOC(250)30. The formation of 1,3-dioxolan-2-ones from 1,2-diols and diphosgene is efficiently promoted by activated charcoal <06S885>. A variety of routes to dioxolanones involving metal-promoted cyclisation of alkenyl and alkynyl carbonates and other esters has been described and these include copper triflatecatalysed reaction of α-allyloxy acids to give dioxolan-4-ones <06EJO3554>, palladiummediated rearrangement and cyclisation of hexa-2,4-diene-1,6-diol monocarbonates to give dioxolan-2-ones <06T11218>, and cyclisation of propargyl carbonates and esters to afford 4alkylidenedioxolan-2-ones using mercuric triflate <06TL8369, a gold(I) complex <06OL515> or a palladium catalyst <06T2545>. More unusual methods leading to dioxoles and dioxolanones include Wolff rearrangement of the Meldrum's acid diazirine 14 to give 15 <06RJOC1213>, reaction of succinimide with methyl 2-diazoacetoacetate to give 16 <06TL2643> and SnCl4-promoted reaction of the fluorinated carbamate 17 with furan to give 18 among the products after hydrolytic work-up <06JA13130>. O O
N N
O
14
hν, MeOH
O
O
O
CO2Me
O
R2
O
CHCO2H
O
20
O
F
NEt2 CO2Et
17
O O
R
O F
16
O O
CO2Me
N O H
O
15
R1
19
O
O
ButCHO R OMe
SnCl4 O
O O
21
But
HO
O F
O F EtO2C
O
18 A patent procedure for formation of compounds 19 from simple tartaric acid derivatives has appeared <06USP047129> and various new routes to chiral dioxolanones include synthesis of dioxolan-2-ones either by transition metal-mediated asymmetric synthesis <06T1864> or enzyme-mediated kinetic resolution <06H(68)1329> and a new synthesis of the chiral dioxolan-4-ones 21 from lactic or mandelic acid involving initial formation of intermediates 20 with trimethyl orthoformate in cyclohexane followed by reaction with pivalaldehyde <06S3915>. Newly reported conditions for hydrolysis of 2,2-disubstituted dioxolanes to give the corresponding aldehydes or ketones include treatment with I2 formed in situ from CuSO4 and NaI in acetone <06SL215>. Electrochemical fluorination of 1,3-dioxolan-2-one to give 22 has been reported <06MI2477> while loss of SPh and either radical addition or substitution results when 23 is photolysed in the presence of alkenes or arenes respectively <06SL1015>. Both cis and trans divinyldioxolanones 24 have been prepared by reductive coupling of acrolein followed by cyclisation with diethyl carbonate, and used for palladium-catalysed asymmetric alkylation <06JA3931>. A Barbier-type allylation in water results when 2-aryl-1,3-dioxolanes are treated with allyl bromide, zinc and ammonium chloride in the presence of β-cyclodextrin to give ArCH(OH)CH2CH=CH2 <06TL2133>. Treatment of the ferrocenyl dioxolane 25 with
279
Five-membered ring systems: with O & S (Se, Te) atoms
alkyllithiums, RLi, gave not the expected ortho-metallation but the two products 26 and 27 <06T9038>. A review of silylated heterocycles as formyl anion equivalents includes mention of compounds such as 28 <06CC4881>. F F
F
O O
O
O
PhS
O
23 O O
TMS
O
O
22
O O
O
O
28
24 O
OMe OMe
OH
O
RLi
Fe
R
+
Fe
25
Fe
27
26
Various new studies on the asymmetric reactions of chiral hydroxy acid-derived dioxolan4-ones 21 have appeared, including Michael addition of their anions to ethyl crotonate and butenolide <06ARK(vii)292>, to enones <06T9174> and 2-benzylidene-1,3-diones <06T8069> and to sugar-containing chiral N-sulfinylimines <06JOC6785>. Addition of achiral dioxole anions to chiral N-sulfinylimines was also described <06OL5729>. The [2+2] cycloaddition of chiral 5-alkylidene-1,3-dioxolan-4-ones to dichloroketene has also been reported <06T4153>. New applications of dioxolane compounds include the formation of polymers containing spiro-2,2-bis dioxolane units <06MI2875>, and a variety of polymers with different uses containing fluorinated dioxole and dioxolane monomer units <06MM7591, 06JPS(A)1613, 06MI1017, 06MI1703, 06MI1873, 06JPS(B)1385>. New TADDOL derivatives 29 have been made <06S2159>, and used as catalysts both as such <06JOC1359> and in the form of derivatives like 30 which acts as a ligand for Pd-catalysed coupling of aryl chlorides <06CC1419>. The behaviour of bicyclic dioxolanes such as 31 <06S3122> and 32 <06SL331> as peptidomimetics has been reviewed. A variety of bicyclic dioxolane compounds 33 have been useful for treating conditions associated with blood platelet aggregation or activation <06WOP105529> and the tricyclic dioxolane 34 has been patented as a fragrance ingredient <06USP128604>. Ar
R
O
OH
O
OH Ar
Ph O O Ph
R
29
R1
Ph O O P H O Ph
RN O HO2C
31
30
O
O
X O R2
33 X = O, S, NH, CH2
O
34
O
R3 R1 N O
O CO2R2
32
280
5.6.2
R.A. Aitken and L.A. Power
1,3-DITHIOLES AND DITHIOLANES
New catalysts and conditions for the reaction of carbonyl compounds with ethanedithiol to give 2-substituted 1,3-dithiolanes include HClO4 on silica <06S2497, 06S2767>, a 1:3 mixture of SiO2 and P2O5 without solvent <06PS(181)387>, anhydrous CuSO4 in CH2Cl2 or solvent-free <06PS(181)1445>, SnCl2 under solvent-free microwave conditions <06TL5155> and catalytic ZnCl2, NiCl2 or CuCl2 supported on natural phosphate rock <06ARK(ii)31>. New synthetic approaches to dithioles include cycloaddition of thiiranethione 35 with DMAD to form 36 and with benzyne to give the corresponding benzodithiole <06CEJ7742>, benzoyl isothiocyanate, PhC(=O)NCS, with DMAD in the presence of Ph3P to give 37 <06TL2953>, and formation of 39 by treatment of 38 with S8 and its subsequent reaction with DMAD to give 40 <06H(68)2243>. Further results on the generation of thiocarbonyl ylides by reaction of thioketones with diazo compounds and their cycloaddition with thiocarbonyls to afford 1,3-dithiolanes have appeared <06T7776, 06HCA1910>. S But But
DMAD
S
But But
S
Ph
CO2Me
N N H
S8 S
38
39
OC12H25
OC12H25
Li MeO2C
S S
R1 R2
+ S
S
CO2Me
S
S
R
CN
43
42 N
CO2Me
40
CN
S
41
S
S
S S
S
S
37
DMAD
S
S
S
S
S
S
Ph
S
36
35
O
MeO2C
CO2Me
S
N
O
O
Ar
S S
MeO2C S
S
O
44 45 A 1,3-dithiol-2-thione 41 bearing lactic acid-derived long chain chiral groups has been prepared <06T3370>, and reaction of 2-cyanomethylene-1,3-dithiolane with aldehydes or ketones and TiCl4 to give products 42 has been reported <06S3009>. A new synthetic route to the propargylic dithioacetals 43 has appeared <06SL3173> and, while the dithiolane anion 44 undergoes straightforward Michael addition to an enone, use of an excess in the presence of the non-deprotonated dithiolane gives adducts such as 45 <06TL1961>. Work on electroactive TTF-type compounds has continued at a high level and synthesis of such compounds based upon 1,3-dithiolane-2,4,5-trithione oligomer has been reviewed <06CHE423>. TTF derivatives with pendant mercaptoalkyl chains have been prepared and their electrochemistry as monolayers on a gold surface examined <06T4419>. New dithiole and TTF-type donors prepared and studied include 46 <06T11106>, 47 <06S2815> and 48 <06H(67)655> while the calculated and experimental Raman spectra of 49 and its Z-isomer have been compared <06SM(156)75>. Salts of formula (50)2I3 have been studied
281
Five-membered ring systems: with O & S (Se, Te) atoms
<06MCLC(455)65> and superconducting and metallic materials based upon donors such as 51 <06JA1456>, 52 <06CC1592>, and 53 <06IC3275> have been reported. S
S
S S
O
S
O
46
S
Se
S
Se
S
S
O
S
Se
Se
Se
S
Se
S
S
O
Se
O
Se
Se
O
S
S
Se
O
S
S
50
S
S
S
S
N
Se
Se
I
N
Se
Se
I
Se
I
S
Se
Se
I
S
Se
S
49 S
S
Se
S
S
Se
51
54
S
Se
S
Se
52
Se
O
Se
O
Se
Br/I
Se
Br/I
55
Se
I
S
Se
Se
I
S
Se
57
56
S
48
53 O
Se
47
S S
Se NH
HN
S
Br
S
Br
58
A series of papers describing detailed studies on dibromo- and diiododithiadiselenafulvalene and tetraselenafulvalene derivatives has appeared including examples such as 54 <06JMAC4110>, 55 <06JMAC3381>, 56 and 57 <06JMAC162> and 58 <06T8152>. Further studies on extended and dimeric or trimeric TTF derivatives with a variety of spacer groups have appeared <06JA10484, 06CEJ2709, 06SM(156)1271> and these include methylantimony-linked compounds such as 59 and 60 <06TL8937>, TTF-containing molecular wires <06TL5059>, and a field-effect transistor based on benzodi-TTFs 61 <06CC2750>. Trimeric donor-acceptor systems based on quinoxalino-TTFs have been examined <06CC1878> as have hybrid structures containing a TTF in conjunction with a cyclodextrin <06T9701>, a crown ether <06TL3431, 06H(67)665, 06T1998>, a porphyrin <06JA2444> or a phthalocyanin <06T3545>. New materials showing conductivity and superconductivity based on non-aromatic TTF analogues such as 62 and 63 have been described <06CC1331, 06SM(156)991, 06SM(156)1043>.
S
S
S
S
Sb
S
S
Se
Se
Sb
Se
Se
S
S
Se
Se
Sb
Se
Se
59 RS
S
S
RS
S
S
S
S
S
S
S
S
S
S
S
S
S
S
62 60
61
S
S
SR
S
S
SR
S
S
S
S
63
Deprotection of 2,2-disubstituted-1,3-dithiolanes to give carbonyl compounds can be ® achieved using Oxone with KBr in aq. MeCN <06TL8559> and a review of silylated heterocycles as formyl anion equivalents includes reference to 64 <06CC4881>. A method for transformation of propargylic dithiolanes 43 into tetrasubstituted furans has been reported <06SL1209> and Michael addition of enolates to the chiral dithiolane dioxide 65 takes place
282
R.A. Aitken and L.A. Power
with variable diastereoselectivity <06SL2043>. A variety of carbonyl-containing alkylidenedithiolanes undergo rearrangements on treatment with simple amines as illustrated by conversion of 66 into 67 <06JOC8006> and 68 into 69 <06ASC1986>. Oxidation with rearrangement of 70 to give 71 brought about by Cu(II) and water has been reported for R = SCH2CH2CN or SeCH2CH2CN <06TL3123>. TMS
O
O S
S R
R1
S
NHR2
S O
64
S
65 O
O Ph
S
S
Ph
72
S
S
R
S
S
S
R
S
O S
Ar
S
S
NEt
70
CO2H
S
S
S
S
S
S
S
S
S
S
S S
S
73
N
R
S
71 O
N
68
S
NHR3
67
69
S
NHR2
R1
S
O
EtNH2
S
S
O
R3NH2
66
O
Ar
O
R Pri
S
N
S
PPh2
74
Self assembly of halogen adducts of carboxylic acid 72 and similar compounds in the solid state has been examined <06POL989> and the X-ray structure of compound 73 has been reported to show an interesting supramolecular stacking <06AX(E)o5469>. A chiral TTF 74 containing both oxazoline and phosphine groups has been found to be an effective ligand for Pd-catalysed asymmetric allylation of malonates <06T11942>.
5.6.3
1,3-OXATHIOLES AND OXATHIOLANES
New catalysts for the reaction of carbonyl compounds with 2-mercaptoethanol to give 2substituted-1,3-oxathiolanes include HClO4 on silica <06S2497>, and either iodine <06CL542> or phosphotungstic acid <06JMOC(247)14> under solvent-free conditions. A new method for conversion of 2-hydroxyalkyl tert-butyl sulfides into 2-tert-butyl-1,3oxathiolanes involving treatment with ButCHO, PhSH and BF3•Et2O has been described <06T931>. 1,3-Oxathiolan-5-ones have been prepared by a new method using Al(OTf)3 <06EJO3554> and used to provide a -CH(SH)CO- unit in fused ring systems <06T5464>, while 1,3-oxathiolan-2-ones are formed directly from epoxides, sulfur and CO in a process catalysed by NaH <06T5803>. Although generally not isolated, spiro 1,3-oxathiolanes are postulated as key intermediates in the reaction of terpene-derived thiones with vinyloxirane to give a variety of products <06HCA456>. Cleavage of 2-substituted 1,3-oxathiolanes back to the carbonyl compounds canbe achieved with IBX and catalytic β-cyclodextrin in water <06SC3771>. A variety of reactions between diazo esters and 1,3-oxathiolanes leading to ring-expanded products have been described <06RCB1464, 06T829, 06T3610>. Treatment of the simple oxathiolanone 75 with Lawesson's reagent unexpectedly led to the 1,2-dithietane 76 which underwent thermolytic ring expansion to 77 under FVP conditions at 850 °C <06HCA991>. Electrochemical fluorination of 1,3-oxathiolan-2-one to give the 4-fluoro product has been reported <06MI2477>.
283
Five-membered ring systems: with O & S (Se, Te) atoms
5.6.4
1,2-DIOXOLANES
A few new compounds of this type have been obtained by ozonolysis of suitable substrates and typical examples include 78 <06TL771> and 79 <06EJO2174>. O Ph
PhCH
LR
O S
S S
75
76
5.6.5
O
CHPh
FVP
O
O
S S
O
OOH
O O
77
79
78
1,2-DITHIOLES AND DITHIOLANES
An important paper describing the properties of cyclic compounds containing silicon and tin includes many sulfur-, selenium- and tellurium-containing compounds and describes the preparation of both 80 and 81 from I-(CH2)3SAc <06JA14949>. The preparation of 1,213 diselenolane 82 by a new route has also been described and its C NMR spectrum reported <06RJGC229>. Further chemistry of substituted 1,2-dithiole-3-thiones 83 has been described including their preparation <06RCB147>, and reaction with chromium carbenes <06JOC808> and Na2S <06JFC(127)774>. Reductive cleavage of the S-S bond in 84 using * LiEt3BH followed by reaction with Cp MCl2 gives rise to a series of metal derivatives 85 <06POL823>. Anti-inflammatory activity has been claimed for substances like 86 that release H2S into biological tissues by virtue of the dithiolethione group <06WOP111791>. S Se
S Te
80
Se Se
82
81
R1
S S
S
O Cl
O
O Ph
Cl
86
O AcO
O
OMe O O
O S
85 O or R R1 S 2 R O
But
Br/I H
O
H
89
5.6.6
84
S O
H N
S
83
S
Cp* M S S
S S
R2
87
S
88
O S O
S S OMe
H
90
1,2-OXATHIOLES AND OXATHIOLANES
The cyclic sulfinates 87 and 88 have been prepared by radical cyclisation of the corresponding haloalkyl tert-butylsulfinates as shown <06AG(E)633.
5.6.7
THREE HETEROATOMS
The unusually stable cross-ozonide 89 has been reported <06TA1780>, and a range of isomeric mono- and disulfoxides of the E-cyclooctene-derived 1,2,3-trithiolane 90 have been prepared <06T5441>.
284
5.6.8
R.A. Aitken and L.A. Power
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Five-membered ring systems: with O & S (Se, Te) atoms
06USP047129 06USP128604 06WOP105529 06WOP111791
287
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288
Chapter 5.7
Five-membered ring systems with O & N atoms
Stefano Cicchi, Franca M. Cordero, Donatella Giomi Dipartimento di Chimica Organica ‘Ugo Schiff’, HeteroBioLab, Università di Firenze, Italy
[email protected]
5.7.1
ISOXAZOLES
Isoxazoles are privileged aromatic heterocycles due to their wide spectrum of biological activities and their use as versatile building blocks in organic synthesis. Recent progress in the field of transition-metal-catalyzed cross-coupling reactions on isoxazole systems has been summarized and discussed <06EJO3283>. Reductive cleavage of 5-silyl-, 3-, 4-, and 5-silylmethylisoxazoles 1 gave silyl βenaminones 2, useful synthons in the regioselective synthesis of silyl- and silylmethylpyrazoles 3, as well as pyrrole-, pyrimidine-, and pyridine derivatives <06T611>. R2 3
R
R1
R1
O
N
2
H2 [Ni] EtOH, rt
R
R3
1
R2 4 NH2 R NHNH2
O 2
EtOH, rt
3
R
R1
N R4
3
N
R1
R2
R3
Me
H
TMS
Me CH2TMS Me
R4 Et
2 Yield 3 Yield 91%
91%
CONH2 89%
78%
Me H CH2SiMePh2 Et CH2TBDPS H Ph Ph
90% 96%
93% 34%
The Pd/C assisted hydrogenolysis of substituted 3-(2-nitrophenyl)isoxazoles 4 results in the formation of substituted 4-aminoquinolines 5 through reduction of the nitro to an amino group, followed by isoxazole ring cleavage and concomitant ring closure. In contrast, similar catalytic hydrogenation of 3-nitrophenyl-4,5-dihydroisoxazoles led to reduction of the nitro group with retention of the isoxazoline ring <06S1995>. N O R
R2 1
4
R NO2
NH2 R1
10% Pd/C, H2 MeOH, 40 psi 79-93%
R N
R2
R = H, Cl, OMe R1= H, Me, CF3, CH2OH R2= H, CHO, CO2Me
5
On the other hand, 4-alkoxycarbonyl- and 4-aminocarbonyl-substituted isoxazoles 6 undergo unusual conjugate reduction with sodium borohydride and sodium
289
Five-membered ring systems with O & N atoms
trifluoroacetoxyborohydride, respectively, to give 4,5-dihydroisoxazoles 7 and 8. They are also alkylated at C-5 through sonication with secondary and tertiary alkyl iodides, in the presence of zinc dust and copper(I) iodide, leading to compounds 9. This behavior, analogous to that of acrylates and acrylamides, is characteristic of 4-substituted isoxazoles but not of the 5-substituted regioisomers. These processes generally afford trans-4,5-disubstituted isoxazolines and the incorporation of chiral auxiliaries into the ester function allows one to perform alkylations with a good level of stereocontrol (86-88% yields, 93 to 98% de). This methodology provides a complementary approach to nitrile oxide cycloadditions to alkenes for the asymmetric synthesis of 4,5-dihydroisoxazoles <06JOC3221>. R1
HOH2C Ar
N
O
R = OMe
R1
ROC
NaBH4 (15 equiv) Ar EtOH, reflux
N
7 61-91%
O
6
R1
H2NOC
R = NH2
NaBH4 (15 equiv) O Ar N CF3CO2H (15 equiv) 8 90-92% THF, rt
Zn, CuI, R2I R = OMe, NH2 Ar = 2,4,6-Me3C6H2 aq. MeOH R1 = H R1 = H, Me, Ph, CH2OH sonicate, 5 °C - rt R2 = Et, t-Bu, i-Pr, c-C6H11, ROC R2 adamantyl Ar
N
O
9 25-100%
Treatment of Baylis-Hillman (BH) derivatives 10, obtained from 3-(2-bromophenyl)-5methyl-4-isoxazolecarbaldehyde, with tributyltin hydride allowed a straightforward synthesis of isoxazolo-benzazulene systems 11 along with minor amounts of the debrominated products 12 <06TL7043>. BH adducts made from 5-isoxazolecarbaldehydes were converted in moderate yields into pyrrole derivatives by reaction with primary amines and then DBU <06S1021>. N O
N O R
N O
Bu3SnH, AIBN
R + toluene, reflux EWG EWG R = H, OH, OAc EWG = CO2R, CN 11 40-50%
Br 10
R 12 11-33%
EWG
Catalytic enantioselective crossed aldehyde-ketone benzoin cyclizations of ketoaldehydes, such as 13, readily obtained from an aryl nitrile oxide and a 1,3-diketone, were studied in order to perform the synthesis of complex molecules. Significant asymmetric induction was observed with chiral triazolium salts such as 14, in the presence of DBU as base, leading to compound 15 in high yield and with 99% ee in favor of the R enantiomer <06AG(E)3492>. MOMO
N
MOMO
O
N
O
14 (10 mol%) DBU (10 mol%) O
O
13
THF, rt
OH O 15 87% 99% ee
Ph
ClN N N
14
O
290
S. Cicchi, F.M. Cordero, and D. Giomi
A one-pot synthesis of 3-methyl-5-aryl-4H-pyrrolo[2,3-d]isoxazoles was performed in high yields by Sharpless epoxidation of 4-amino-3-methyl-5-styrylisoxazoles <06TL4957>. 1,2,4,5-Tetrazines were condensed with isoxazolylcyclobutanones in methanolic KOH to give conformationally restricted 6-isoxazol-5-yl-6,7-dihydro-5H-[1,2]diazocin-4-ones <06JOC2480>. HO2C NO2 N
O Ar 17
O 16
a), b)
N X
a)
NO2
+ NH2XH
+
+
O
O 18
Ar
19
N
X = O, NH, NPh
20 61-95%
Ar
O
N X 21 48-90% Reagents and conditions: a) piperidine (0.1 equiv), EtOH, 60 °C; b) H2O, NaOH (4 equiv), reflux.
A four component one-pot procedure (4-MC) was developed for the synthesis of 3heteroarylpropionic acids 20 and 4-nitroisoxazolyl derivatives 21 from commercially available starting materials 16-19, in high yields and without chromatographic purification <06OL5157>. 5-Aminoisoxazoles 22 have been synthesized by nucleophilic addition of lithiated alkyl nitriles to α-chloroximes <06OL3679>. The cyclization of oxime dianions with diethyl oxalate afforded isoxazole-5-carboxylates 23 by acid-mediated dehydration of intermediate hydroxyisoxazolines <06S2515>. N R1
OH Cl
R2
N O
CN
t-BuLi THF, -78 °C
R1
N
NH2
R2 22 34-91% R1 = Ar, c-C6H11, n-Pr, 3-thienyl, 2-pyridyl R2 = H, Me, Ph, Bn, i-Pr, cyclopropyl
Ar
OH
N O
(CO2Et)2 i, ii
CO2Et
Ar 23 68-96%
i, BuLi, THF, -78 °C - rt ii, TsOH.H2O, toluene, reflux
Functionalized isoxazoles were obtained in good yields from activated acetylenes and alkyl 2-nitroethanoates in the presence of triphenylphosphine <06TL1627>. The use of PPh3/DDQ offers a neutral and highly efficient method for the conversion of 2-hydroxyaryl aldoximes and ketoximes to 1,2-benzisoxazoles in excellent yields at room temperature <06TL8247>. Isoxazole (as well as isoxazoline, and isoxazolidine) analogues of C-nucleosides related to pseudouridines 25 and 27 have been regioselectively synthesized by 1,3-dipolar cycloaddition (1,3-DC) of nitrile oxides (and nitrones) derived from uracyl-5-carbaldehyde 24 and 2,4-dimethoxypyrimidine-5-carbaldehyde 26 respectively <06T1494>.
291
Five-membered ring systems with O & N atoms
O
O CHO
HN O
O
MeO
b)
26
b)
80%
N
O
OCOPh N ( )7
O
25
OMe N O OCOPh
N MeO
N O
HN
OMe CHO a)
N
O OCOPh
N ( )7
OMe N
O
HN
a) N ( )7 24
N
N N
90%
MeO
OCOPh N
27
Reagents and conditions: a) NH2OH.HCl, Na2CO3, EtOH/H2O, 20 °C; b) NaOCl, CH2Cl2/H2O, 0-20 °C.
1,3-DC of carbohydrate dipolarophiles with cerium(IV) ammonium nitrate CAN(IV) in acetone, acetophenone, or pinacolone as solvent yielded regioselectively the corresponding 3,5-disubstituted isoxazoles as stable pharmacophores for glycomimetic syntheses. For instance, peracetylated propynyl β-D-galactoside 28 gave derivatives 29 in satisfactory yields <06SL1739>. Some derivatives provided inhibitory properties against galectins-1 and -3 <06CC2379>. AcO
O
OAc O
AcO
AcO R O
OAc 28
AcO CAN(IV) MeCN, reflux R = Me, Ph, CMe3
OAc O
O N O
OAc
O R
29 78-92%
A solid-phase synthesis of 3-substituted isoxazoles 31 in good yields and purities was achieved by 1,3-DC of polymer-supported vinyl selenide with in situ generated nitrile oxides; treatment of intermediate isoxazolines 30 with an excess of hydrogen peroxide resulted in the release of isoxazoles 31 while the use of MeI/NaI led to 3-substituted 5-iodoisoxazolines <06S2293>.
Se
RCH=NOH NCS, NEt3 CHCl3, rt
Se O
H2O2 N 30
R = Ar, 2-furyl, n-Pr, PhCH2CH2
R
THF, rt
+ R N 31 78-88% > 95% purity
O
SeOOH
A DFT-HSAB study provides a quantitative rationalization of regioselectivity in 1,3-DC of 4-substituted benzonitrile oxides towards methyl propiolate not amenable to FMO and electron-demand theory <06CEJ1156>. 5.7.2 ISOXAZOLINES New applications of nitrile oxide 1,3-DC have been reported. Soluble, single-wall carbon nanotubes (SWNT) 32 functionalized with pentyl esters at the tips and pyridyl isoxazoline rings along the walls were prepared using pentyl ester-SWNT as dipolarophile. The complex
292
S. Cicchi, F.M. Cordero, and D. Giomi
of SWNT 32 with a zinc porphyrin was studied and compared with the corresponding complex with pyridyl isoxazoline-functionalized [60]-fullerenes <06JA6626>. N N
N
RO2C RO2C
1. NEt3 Cl
N OH
O
CO2R
n
CO2R CO2R CO2R CO2R CO2R CO2R
RO2C
2. pentyl ester-SWNT 1,2-Cl2C6H4 mw (150 W, 45 min)
RO2C RO2C RO2C
R = n-pentyl
32
25,27-Diallyloxycalix[4]arene 33 reacted with isophthaldinitrile oxide through a 1+1 double 1,3-DC to give the calix[4]arene 34 having an aryl-1,3-diisoxazoline cap on the lower rim. Under the same conditions, 5,17-diallylcalix[4]arene gave the corresponding 1+1 upper rim capped calix[4]arene <06TL8383>. Calix[4]arenes isoxazole and isoxazolines underwent molybdenum hexacarbonyl-mediated N-O bond cleavage in the presence of water to afford calix[4]arenes decorated respectively with α,β-unsaturated-β-amino ketones and β-hydroxy ketones <06TL9077>. Cl
NOH
+ O
OHOH
MeOH reflux NOH 24 h
O
Cl
33
A (R = X) R1 R2
RO O 35 +
ArC N O
H2O 25 °C
B (R = H) THF 25 °C
O
NEt3
27%
O O
CO2X Ar
R2 + O 38
X = β-cyclodextrin substituted at a C6-position; Ar = 4-t-BuC6H4
34
R2 R1
O
C N O 40
CO2H Ar
R1 N
R1 R2 N CO2H O 39
N
O
R1
Ar
N
OH
R1 R2 + N N CO2X O R2 O 37 36 1. NaOH 2. pH 1
Ar
O
OH
R1 R2 H H Me H H Me
38:39 (path A) (path B) 20: 1 1: 20 1:10 <1:100 >100: 1 1: 1
Polymeric isoxazolines were prepared by cycloaddition of nitrile oxides to norbornadiene followed by ring-opening metathesis polymerization (ROMP) <06PLM3292; 06MM3147>. Isoxazolines 38 and 39 were obtained in different ratios by direct cycloaddition of 4-tbutylbenzonitrile oxide with acids 35 (R = H, path B) and by the intermediate formation of cyclodextrin derivatives 36 and 37 followed by basic hydrolysis and acidification (path A). The reversed regioselectivity as well as an increased rate of the cycloaddition step could be explained through the temporary association of the nitrile oxide with the cyclodextrin to give the inclusion complex 40 <06CEJ8571>.
293
Five-membered ring systems with O & N atoms
3-Nitroisoxazolines were prepared from N-alkoxy-3,3-dinitroisoxazolidines by thermally induced β-elimination. For example, isoxazolidines 42 synthesized by a three-component reaction of tetranitromethane with two equivalents of alkenes 41, were converted into isoxazolines 43 by heating in boiling chlorobenzene <06S706>.
R1
R2
+ C(NO2)4
O2N O2N N O O 1 R 42 R2 NO2
PE rt
41 PE =petroleum ether
R1
O2N R1 R2
N
PhCl reflux
R1
R2
yield
Ph H BuO H -(CH2)5OAc H
O R2 43
71% 73% 74% 72%
2-Isoxazolines 47 were prepared from O-propargylic hydroxylamines via tandem rearrangement-cyclisation reactions by heating in methanol. The proposed mechanism involves an initial 2,3-sigmatropic rearrangement to give the N-allenic hydroxylamine 44 followed by rearrangement to 45. Then, oxime 45 undergoes a 5-endo-trig cyclization to 3isoxazoline 46 which isomerizes to the more stable product 47 <06SL463>. HOMe
R2
ONH2 HCl R1
K2CO3
O
H2N
R2
MeOH reflux
R2 MeOH R1 HOMe N • HO HN R1 45 R2 OH 44
R1 HN
R1 N
R2
O
46 R1 2-ClC6H4, 3-MeOC6H4, 4-ClC4H4, 3,5-(CF3)2C6H3, n-Pr, Et2NCH2, R2 = H; R1 = Ph, R2 = Me, i-Pr; R1 = H, R2 = Ph, n-pentyl.
O
R2
47 60-84%
R1 =
A detailed study of the role of the base in the formation of 2-isoxazolines by condensation of primary nitro compounds with alkenes in the presence of the tertiary diamine 1,4diazabicyclo[2.2.2]octane (DABCO) was published <06EJO4852; 06EJO3016>. Isoxazolines N-oxides have been synthesized from primary aliphatic nitro compounds and alkenes by a two-step procedure consisting of 1,3-DC of a 1-halo-substituted silyl nitronate followed by halosilane elimination <06S2265>. O CO2Me Nu (10 mol%)
OMe •
Nu R1 R1 48 49 R1 = n-C5H11, Nu = PPh3
Ph
Bn N O LiCl H2O 40 °C
Bn Ph
R1
Bn
OMe
N O Nu 50
O
Nu
Ph
N O
CO2Me
R1 51 68%
4-Isoxazolines were synthesized by a new regioselective and organocatalyzed nitrone 1,3DC with conjugated alkynoates in water. Both tertiary amines and phosphines catalysed the reaction which did not occur in absence of the catalyst or in organic solvents. For example, C-phenyl N-benzyl nitrone reacted with alkynoate 48 in H2O/LiCl in the presence of 10 mol% of PPh3 to give 4-isoxazoline 51 in 68% yield. In the proposed mechanism, the catalyst (PPh3) adds to 48 to generate the zwitterionic allenoate 49 which is the reactive dipolarophile. Regioselective 1,3-DC of 49 with the nitrone affords the primary cycloadduct 50 which evolves to 51 by elimination of a molecule of the catalyst <06CC2798>. New theoretical calculations of mechanisms of isoxazoline syntheses have been reported.
294
S. Cicchi, F.M. Cordero, and D. Giomi
In particular, the reactions of electrophilically activated benzonitrile N-oxides with 3methylenephthalimidines with formation of 2-isoxazolines and oximes and the cycloaddition between alkynyl metal(0) Fischer carbenes and nitrones leading to 4-isoxazolines have been investigated by density functional theory methods <06JOC9319; 06JOC6178>. Naturally occurring dimeric spiroisoxazolines (+)-aerothionin (52) and (+)-calafianin (53) have been synthesized in enantiopure form and their configuration unambiguously assigned <06TL727; 06OL927>. O N H
N O
HO
O
( )2
O
N H
N O
O
OH
( )2
N H
N O
O Br
Br OMe
Br
Br
52 (+)-aerothionin
Br
OMe
N H
N O
O Br
53 (+)-calafianin
O
O
5.7.3 ISOXAZOLIDINES O H
H
N
SO3 O
OH O N
O
O
NH HN
HO
MeO
O N
NH
NH 54 O cylindrospermopsin CONHX
OH
N X O
O
H
Bn HN O N
N CO2H H 56 (2S,4S)-pipecolic acid OH HO H CO2Me HO
OH X = (R)-PhMeCH
O
H
Bn N O
Ph O HO H N
OH
HO
MeO
OH N
Ph
55 H haouamine A HO H N CO2H N H 57
OH OH HO
OH
O
PO(OEt)2 HCl
HO 58 OH H
N 60 OH HO N (−)-1-homoaustraline 61 CO2Me HCl O 59 (−)-7a-epi-cronatecine Isozazolidine rings and the final product moieties deriving from them are shadowed.
Cl
N
O HO
N
N N
N
OH 62
OH
Isoxazolidines are valuable intermediates for the synthesis of natural products and other bioactive compounds. Recent literature shows more and more examples of the versatility and usefulness of this class of heterocycles. For example, isoxazolidine derivatives have been used as key intermediates in the synthesis of the natural alkaloids 54 and 55 <06T4549; 06OL2309>, the cyclic amino acids 56 and 57 <06EJO3235; 06TA1863>, the pyrrolidine fucosidase inhibitor 58 <06EJO2384> the pyrrolizidine alkaloid analogues 59 and 60 <06JOC1614; 06CAR2005>, the hydroxyindolizidine 61 <06TA292> and the nucleoside analogue 62 <06TL8821>. Typically, isoxazolidines are employed as masked β-amino alcohols which can be released under mild reduction conditions, but other different transformations leading to a variety of useful functionalities are also available as shown by some of the following examples. The
295
Five-membered ring systems with O & N atoms
conversion of a vinyl group into a γ-hydroxy-α-keto acid moiety was accomplished by diastereoselective 1,3-DC with N-tert-butyl C-ethoxycarbonyl nitrone and subsequent ring opening under basic conditions. The process was applied to the synthesis of some sialic acid derivatives. For example, the 3-alkoxycarbonyl isoxazolidine 63 was converted into the L-Nacetylneuraminic acid (64) in 60% yield via C-3 deprotonation followed by N–O cleavage and imine hydrolysis <06AGE7417>. OH OH NHAc + t-Bu
OH OH
N
E
dioxane OH OH 30 °C
O
90% 91% ds
OH OH NHAc
NHAc
1. NaOH MeOH
E 2. H2O OH OH O N 60% 63 t-Bu OH OH NHAc
E OH OH OH N
CO2H OH OH OH O
t-Bu
OH OH
NHAc
E OH OH O N t-Bu HO OH HO O AcHN CO2H HO OH 64
E = CO2 Et
N-Unsubstituted isoxazolidines such as 65 undergo facile decarboxylative peptide couplings with α-keto acids <06JA1452>. The use of water as solvent or cosolvent was particularly beneficial for the formation of amides in high yields. The methyl α-keto esters obtained could be saponified to the corresponding α-keto acids, and the β-peptide chain could then be extended by reaction with another isoxazolidine. HN O
O + CO2H
Bn 65
O
OMe CO2Me
t-BuOH/H2O (0.5 M) 40 °C, 1 h
Bn N H
O OMe O
93%
1,2-Thiazetidine 1,1,-dioxides (β-sultams) 67 were directly synthesised from pentafluorophenyl (PFP) isoxazolidine-4-sulfonates 66 under mild reducing conditions [Mo(CO)6, MeCN, H2O, reflux]. The process is stereoselective and goes through N–O bond cleavage followed by intramolecular displacement of the PFP group by the amine <06OL5513>. O
O S
PFPO
Mo(CO)6 O
R
MeCN, H2O N 90 °C Me 66
O O S N Me
OH
R 67
R = 2-naphthyl (58%), 4-MeOC6H4 (53%), 4-allylOC6H4 (52%), 4-BrC6H4 (50%), 2-ClC6H4 (47%), Ph (37%), 4-ClC6H4 (37%), 2-BrC6H4 (27%), c-C3H5 (27%), 3-BrC6H4 (26%)
5-Spirocyclopropane isoxazolidines are versatile intermediates for the synthesis of different classes of heterocycles. Highly strained 3-spirocyclopropane β-lactam 71 (n = 2) was obtained by acid-catalyzed fragmentative rearrangement of bis-spirocyclopropane isoxazolidine 70 (n = 2) prepared by intramolecular cycloaddition of 69 (n = 2). Under the same conditions, the lower homologue 71 (n = 1) could not be isolated as it underwent ring opening to give the β-amino acid 72 <06EJO5485>.
296
HO
S. Cicchi, F.M. Cordero, and D. Giomi
( )n a), b)
O
N O
( )n
b)
O
n=1
HO2C
MeN MeN ( )n ( )n N H F3C H H Me 68 69 70 O 71 n = 1 58% 72 71% n = 1, 2 n = 1, 2 n = 2 66% n = 2 58% Reagents and conditions: a) PCC, CH2Cl2, 25 °C, 3 h; b) MeNHOH.HCl, NEt3, 3 Å MS; c) TFA, MeCN, reflux, 15 min.
Similarly, 3-spirocyclopropane monobactams 74 were prepared by a one-pot threecomponent cascade reaction of alkylhydroxylamine hydrochlorides, aldehydes and bicyclopropylidene. In particular, microwave heating of mixtures of the three components in the presence of sodium acetate in EtOH furnished the products 74 through nitrone formation, 1,3-DC and acid-catalyzed rearrangement of isoxazolidine 73 <06EJO1251>. 4'Chlorospiro[cyclopropane-1,5'-isoxazolidines] prepared by 1,3-DC of pyrroline N-oxides with 2-chloro-2-cyclopropylideneacetates underwent a cascade ring enlargement process in the presence of a base affording 5-oxo-indolizidinone derivatives <06JOC2417>. H HCl + R2CHO + 1N R OH
R1 N
NaOAc EtOH, mw 80-100 °C
O
O
N R1 R2 74 49-78% 73 R1 = Bn, PMB, Ph2CH, t-Bu, R2 = H; R1 = Bn, t-Bu, R2 = CO2Et; R1 = PMB, R2 = CO2Me R2
Nitrone 1,3-DC reactions are still the most general approach to isoxazolidines. The stereocontrol is usually achieved by the use of chiral nitrones and/or dipolarophiles, but new interesting achievements on Lewis acid catalyzed cycloadditions are also frequently reported. Tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanatedionate) europium(III) [Eu(fod)3] selectively activated the Z-isomer of C-alkoxycarbonyl nitrone 75 existing as an E,Zequilibrium mixture by forming the (Z)-75-Eu(fod)3 complex. (Z)-75-Eu(fod)3 reacted with electron-rich dipolarophiles such as vinyl ethers to give the trans-adducts with excellent diastereoselectivity <06T12227>. E
E
N N R R O O (E)-75 (Z)-75 E = CO2Me R = CHPh2
OEt (20 equiv) ClCH2CH2Cl
O
R N
E
+
O
R N
OMe E
EtO trans-76 EtO cis-76 no additive, 36 h, 89% 72 : 28 Eu(fod) (1 equiv), 7 h, quant >98 : 2
O R
N
O
Eu(fod)3
(Z)-75-Eu(fod)3
Bis(oxazolinyl)pyridine-Ce(IV) triflate complex 78 catalyzed the enantioselective 1,3-DC of acyclic nitrones with α,β-unsaturated 2-acyl imidazoles. For example, C-phenyl N-benzyl nitrone reacted with 77 in the presence of 78 to give the adduct 79 with excellent diastereoand enantioselectivity. Isoxazolidine 79 was then converted into β'-hydroxy-β-amino acid derivatives by hydrogenation of the N-O bond in the presence of Pd(OH)2/C and cleavage of the 2-acyl imidazole with MeOTf in MeCN <06OL3351>.
297
Five-membered ring systems with O & N atoms
Bn
N
N
N
Ph
78 (5 mol%)
NMe + O
EtOAc, 4 Å MS 0 °C, 17 h 97%
O 77
N Me Ph
O
Ph O
N Bn >99% ds, 99% ee
Ph
79
N N N Ce (OTf)4
O
Ph Ph
78
The 1,3-DC of nitrone 80 with maleimide 81 is a new example of recognition-mediated reaction. The association between the urea moiety in 80 and the carboxylate ion in 81c and 81d triggers a pseudointramolecular cycloaddition resulting in increased reaction rate and diastereoselectivity. A slower reaction with essentially no stereocontrol was observed using dipolarophiles lacking the carboxylate recognition site such as 81a and 81b. The recognition site on maleimide could be switched ‘on’ and ‘off’ in situ by the addition of base and acid, respectively <06CC3684>. t-Bu HN
Z
t-Bu
O
t-Bu
HN
HN
O
O
HN
O
HN
HN
Z Z + O O d -acetone N O O 6 12.5 mM H O H O N 10 °C Ar O Ar N Ar N N N 36 h 80 81a-d O O Ar = 4-t-BuC6H4 H O 82a-d H O 83a-d Z = a OMe; b OH; c O HNEt3; d O NBu4 a and b: 40-41% conversion; 82/83 = ca. 1: 1 +
c and d: 67-70% conversion; 82/83 = ca. 4: 1
3-O-Allyl carbohydrate nitrones prepared from aldehydes 84 with PhNHOH in aqueous media in the presence of the cationic surfactant cetyltrimethylammonium bromide (CTAB) underwent highly regio- and stereoselective intramolecular cycloaddition at room temperature. In all cases the exclusive formation of a single isomer was observed. In particular, the more substituted prenyl derivatives gave pyran derivatives such as 87, whereas the corresponding allyl and crotyl compounds afforded the bridged isoxazolidines 85 and 86 containing an oxepane ring <06JOC345>. No reaction was observed in water without CTAB or under neat conditions, whereas in conventional organic solvents a mixture of isomers was generally obtained. Ph R1 N H H O O H
O
O H O H 85 R1 = H 84% 86 R1 = Me 85%
PhNHOH R1 CTAB 2 H2O, rt R 2
R =H
OHC
O O
O 84
O
PhNHOH CTAB H2O, rt 1
2
R = R = Me
Ph O N H HO H
O H
O O
87 78%
A B3LYP/6-31G* study was performed on both thermal and BH3-catalyzed 1,3-DC of nitrones with methacrolein <06JOC9831>. A new stereodivergent synthesis of optically pure 4-alkylisoxazolidin-4-ols starting from enantiopure 2-(alkyloxiran-2-yl)methanols has been reported. In particular, the (2R)-glycidyl
298
S. Cicchi, F.M. Cordero, and D. Giomi
tosylate and nosylate R-88 were respectively converted into the enantiomeric isoxazolidines S-91 and R-91. Treatment of the tosyl derivative 88 (R=Ts) with PhthNOH caused the selective opening of the epoxide ring with formation of R-89 that cyclised to S-90 upon addition of methanol and NEt3. On the contrary, the nosyl group in 88 (R=Ns) underwent direct displacement by PhthNOH with conservation of the oxirane ring, which was then opened with HCl. Eventually, chlorohydrin S-92 gave R-90 by treatment with NEt3 in MeOH <06TL7635>. HO
HO O c) O b) Cl N N 59% O 75% H Ar PhthN HCl O R-91
R-90
OH R = Ns d), e) O 59%
RO R-88
S-92
HO
R = Ts HO a)
OTs b)
O PhthN
O
HO c)
N
72%
Ar O S-90 41%
R-89
O
N H HCl S-91
Ar = 2-MeO2CC6H4; TsOH = 4-MeC6H4SO3H; NsOH = 3-O2NC6H4SO3H; PhthNH = phthalimide Reagents and conditions: a) PhthNOH, NEt3, 1,4-dioxane, 50 °C, 48 h; b) MeOH, NEt3, 50 °C, 2 h; c) HCl, H2O, 95 °C, 4 h; d) PhthNOH, NEt3, CH2Cl2, 24 h; e) conc HCl, 1 h.
New examples of palladium-catalyzed cyclization of O-homoallylhydroxylamines to isoxazolidines have been reported <06TL927; 06SC1247>. 5.7.4 OXAZOLES Several new methods for the synthesis of the oxazole nucleus were published. A new consecutive three-component oxazole synthesis by an amidation-coupling-cycloisomerisation sequence was developed. The synthesis started from propargylamine 92 and acyl chlorides. To extend this process, a four component sequence involving a carbonylative arylation by substitution of one acyl chloride with an aryl iodide and a CO atmosphere was also performed <06CC4817>. O Ar
1
+ Cl
O
H2N
+
Ar
2
PdCl2(PPh3)2, CuI
N
Cl NEt3, THF, 0° C
Ar1
92
O
O Ar2
O
O Ar2
NH
Cl
1
Ar
O NH
Ar2
Ar1 Pd(II), Cu(I) 1
O
2
Ar , Ar = Aryl, Heteroaryl 49-75%
Conceptually interesting is the synthesis of the oxazole system 94 through a Beckmann rearrangement of α-formyl ketoxime dimethyl acetals 93 which demonstrated the possibility of a non-amino acid pathway in the biosynthesis of marine derived oxazoles <06CC1742>.
299
Five-membered ring systems with O & N atoms
HO
n-Bu
N
n-Bu
n-Bu
N
polyphosphoric acid n-Bu
Beckmann rearrangment MeO
OMe 94
93
O 97%
A new approach to the synthesis of 2,4,5-trisubstituted and 2,5-disubstituted oxazoles, 97 and 98, used 1-(methylthio)acetone 95 with nitriles in the presence of trifluoromethanesulfonic anhydride. The proposed mechanism involves an unstable 1(methylthio)-2-oxopropyl triflate 96 which was detected using NMR spectroscopy <06JOC3026>. O
O
Tf2O
S
R-CN
S
O
R
Raney-Ni N
95
Base
R-CN
O
N 98 R = alkyl, aryl
97 S
96 OTf
R
70-90%
S
S
O N
N C R
O R
The use of Zn(OTf)2 with a Ru complex, TpRuPPh3(MeCN)2PF6, proved useful for the cyclization of propargyl alcohols 99 with amides. The reaction proceeded through the intermediate 100 which was also isolated from the reaction mixture when only the Zn catalyst was used. Upon heating with the mixture of the two catalysts, compound 100 was completely converted into the final oxazole 101 <06JOC4951>.
2
R1
Zn(OTf)2 TpRuPPh3(MeCN)2PF6
O
OH R
NH2
99
Toluene, 100° C, 5h
Zn(OTf)2 R1 2
R (O)CHN
O 100
N R1 =aryl R1 101 O 88-95% R2 =aryl, alkyl Zn(OTf)2 TpRuPPh3(MeCN)2PF6
R2
N R2 O 101
R1
Application of the Ritter reaction conditions on γ-hydroxy-α,β-alkynoic esters, 102, produced ethyl 5-oxazoleacetates 103 or γ-N-acylamino-β-keto ester 104 by reaction with aryl or alkyl nitriles respectively. The γ-N-acylamino-β-keto ester 104 can also be transformed into oxazole derivatives using an additional step involving POCl3 <06TL4385>.
300
S. Cicchi, F.M. Cordero, and D. Giomi
OEt
O Alk-CN
O
Ar OH
Ar
H2SO4, 0° C
102
104
O OEt Alk 55-78%
HN O
POCl3
H2SO4, 0° C ArCN 44-70%OEt Ar O N O
DMF 70° C 84-92%
103 Y Y = aryl, alkyl
A new method for the solid phase synthesis of oxazole-containing peptides 105 was developed, based on cyclodehydration followed or preceded by oxidation in a biomimetic fashion. The oxazole nucleus was obtained starting from threonine or serine and the method is compatible with most protecting groups <06OL2417>.
R
Ph
Ph
Ph H N
N H
Dess-Martin Periodinane
O O
O HO
CH2Cl2, 2 h
R
N H
H N O
O
PPh3, I2, DIEA R O
O
N H
O N O
O 105
80-93%
R= Cbz, Fmoc, Alloc, H
A microwave assisted Cornforth rearrangement of oxazole-4-carboxamides 106 efficiently afforded 5-aminooxazole-4-carboxylates 107. This procedure was applied to the formal synthesis of a natural antibiotic derived from pseudomonic acid <06TL4698>. O N Ph
O
O
EtO NR2
OEt 106
OEt
O Ph
N
N O
mw R2N
Ph
NR2 107 NR2= primary and secondary alkyl amines 19-99% O
A parallel synthesis of novel pyrrole-oxazole analogues of the insecticide PirateTM was performed through the dehydration of acylaminoketones with POCl3<06S1975>. A multipurpose mesofluidic flow reactor was developed for the automated synthesis of libraries of 4,5-disubstituted oxazoles. The process was based on the known reaction of alkylisocyanoacetates and acylchlorides <06OL5231>. Considering the reactivity and the transformations of the oxazole nucleus, some examples of new reactivity were described as well as the application of known reactions to the oxazole nucleus. The ceric ammonium nitrate (CAN) promoted oxidation of oxazoles with various substitution patterns was investigated and yielded the corresponding imides 108 in good yields, tolerating a wide variety of functional groups and substituents on the oxazole moiety <06OL5669>.
301
Five-membered ring systems with O & N atoms
R2
O R
N
R1 N H 108
rt
R3
O
O
CAN
1
R1, R2, R3 = Aryl, Alkyl, Alkenyl
O
+ 2
R3
R
OH
50-90%
An N-heterocyclic carbene 110 catalyzed the rearrangement of the O-acyl carbonates 109 into their corresponding C-acylated isomers 111, generating a C-C bond and a quaternary stereocenter with high efficiency <06OL3785> The same reaction can be performed enantioselectively using TADMAP 112 <06JA925>. OR1 O
O
R2
N N
O
110
N R1O N Ph R2
O
N
O
H CPh3 OAc
O
N 67-84% THF, rt, 5 min 111 Ar Ar R1= Me, Bn, Ph R2 = Me, Bn, CHMe2, CH2CHMe2
N
109
TADMAP 112
2-Aryl-4-trifloyloxazoles 113 undergo rapid, microwave assisted coupling with a range of aryl and heteroaryl boronic acids in good to excellent yields. The same procedure is also effective using 4-aryl-2-chlorooxazoles and can be extended to the synthesis of homo- and heterodimeric 4,4'-linked dioxazoles <06OL2495>. Analogous results were obtained using oxazol-4-ylboronates with aryl and heteroaryl halides <06SL555>. O Ar1
O Pd(0), Ar2B(OH)2 Ar1 N
mw, dioxane N OTf 113
Ar2
114 75-94%
Ligand and base free conditions for the arylation of azoles were developed, although with a modest yield especially for oxazole, affording 2-substituted oxazoles <06EJOC1379>. With the aim of finding new antagonists for the type 5 metabotropic glutamate receptor (mGluR5) for use in the treatment of drug abuse, two new 4-arylethynyl-2-methyloxazole derivatives 116 and 117 were synthesized starting from 2-methyloxazole-4-carboxaldehyde 115 <06S243>. I O
1) CBr4, PPh3 (86%) 2) NaHMDS, MeLi, Me3SiCl
N
O
115 H
Y
O N
O
X
N 84%
Y SiMe3
X 116 Y = F X = CH 85% 117 Y = H X = N 52%
A review concerning the cross-coupling reactions of azoles with two and more heteroatoms was published <06EJOC3283>. Several reports on the synthesis of oxazole containing natural compounds or their analogues appeared in 2006. The synthesis of telomestatin 118 was performed <06OL4165> as well as several analogues as 119 <06BMCL3891> and others <06S1289; 06TL7897;
302
S. Cicchi, F.M. Cordero, and D. Giomi
06JA13662> The synthesis of bengazole A 120, a marine bisoxazole natural products with antifungal properties was completed. This synthesis was the first to produce a single stereoisomer <06AG(E)6714>. A new synthesis of phorboxazole B was published <2006CEJ1185>. Towards the synthesis of diazonamide A a biomimetic approach to the indole bis-oxazole fragment by oxidation of a TyrValTrpTrp tetrapeptide was reported <06CC2397>. The first total synthesis of inthomycin B 121 was performed. The synthesis was based on the Stille coupling of a stannyl-diene with an oxazole vinyl iodide <06TL549>. Oxazoles substituted on C-2 with a carbonyl group and a long chain revealed interesting inhibitors of fatty acid amide hydrolase (FAAH) enzymes <06JA14004>. N O
S N O
N
N
O N
N
O O
N
N O
O
NH
OH
O
O
O
O
OH OH OH
N
bengazole A 12
N O
N N
N
O O
N
O
O
HN N
O N
N
119
telomestatin 118
O
O
O
O
120
inthomycin B
HO
NH2
121
5.7.5
OXAZOLINES
New simple methodologies for the synthesis of variously substituted 2-oxazolines exploit aldehydes and amino alcohols as starting materials. For instance, the reaction of aromatic or aliphatic aldehydes with amino alcohols in the presence of N-bromosuccinimide as oxidizing agent allowed the one-pot preparation of compounds 122 under mild reaction conditions and in high yields <06S2996>. Analogously, treatment of aromatic aldehydes and 2-aminoethanol with pyridinium hydrobromide perbromide (PHPB) in water led to 2-aryl-4,5dihydrooxazoles 123 <06SL1479>. The copper(I)-catalyzed reaction of aldehydes and methyl isocyanoacetate afforded ester derivatives 124 in almost quantitative yields and high diastereoselectivity in favor of the trans diastereomer <06TL8641>. 2
R R3 R1 R = Ar, pyridyl, a) stiryl, t-Bu, C9H19 N O 1 2 3 R , R , R = H, Me, R Et, i-Pr, Ph, Bn 122 30-96% NC RCHO +
CO2Me
RCHO +
R1
R2
H2N MeO2C c) R = Ar, i-Pr
N
R3 OH R
b) R = Ar R1= R2= R3= H
N
O
Ar 123 58-95%
trans/cis ratio from 86:14 to >99:1 O 124 >99%
Reagents and conditions: a) 4Å MS, CH2Cl2, rt, 14 h, then NBS, rt, 0.5 h; b) PHPB-H2O, rt; c) 10 mol% iPr2EtN, 5 mol% CuCl, 10 mol% PPh3, CH2Cl2, 40 °C, 2 h.
303
Five-membered ring systems with O & N atoms
O O R1= Ar, CH3(CH2)n, PhCH2CH2 R2 = H, Me
N
O
R1CO2R2
( )n H2N
a)
R1
OH
a) n = 1-3
125 64->99%
N
O
( )n OH 126 52->99%
Reagents and conditions: a) Zn4(OCOCF3)6O (1.25 mol%), toluene, reflux.
A direct catalytic conversion of esters, lactones, and carboxylic acids to oxazolines was efficiently achieved by treatment with amino alcohols in the presence of the tetranuclear zinc cluster Zn4(OCOCF3)6O as catalyst, essential for condensation and cyclodehydration reactions. For example, the use of (S)-valinol allowed the easy synthesis of oxazolines 125 and 126 in satisfactory yields <06CC2711>. A one-pot direct preparation of various 2substituted oxazolines (as well as benzoxazoles and oxadiazoles) was also performed from carboxylic acids and amino alcohols (or aminophenols or benzhydrazide) using Deoxo-Fluor reagent <06TL6497>. Bromoamidation of cyclic olefins allowed the synthesis of bicyclic oxazolines. For instance, treatment of cyclohexene with N-bromoacetamide as the halogen source and different nitriles at 0 °C, in the presence of SnCl4 or BF3.Et2O and water, led to oxazolines 128 through intermediate trans-bromoamides 127. The scope of the bromoamidation appears quite broad with regard to olefinic and nitrile components <06JA9644>.
Br
a)
CCl3
H O
b)
NHCOR R = t-Bu, Ph 127 75-77%
CCl3 Au[P(C6F5)3]SbF6 (1-2 mol %) NH O N
O R
N H 128 92-93%
ClCH2CH2Cl, 0 °C
R 129
R R = H, c-C6H11, n-C7H15, 130 74-98% i-Pr, t-Bu, Bn
Reagents and conditions: a) MeCONHBr, RCN (15 equiv), H2O (1.2 equiv), BF3.Et2O (0.4 equiv), CH2Cl2, 0 °C; b) NEt3 (2 equiv), DBU (0.2 equiv), DMF, reflux.
Cyclization of N-alkenylamides to 2-oxazolines was achieved in very mild conditions with tert-butyl hypoiodite <06OL3335>. The 5-exo-dig gold(I)-catalyzed cyclization of propargylic trichloroacetimidates 129 proceeded with remarkably efficiency under very mild conditions to give 4-methylene-4,5-dihydrooxazoles 130 in good yields. The mildness of the protocol was clearly responsible for the lack of isomerization of the final products to the corresponding, thermodynamically more stable, oxazoles <06OL3537>. O R1
F3C 131
NsONHCO2R2 F3C CaO
O 1
CH2Cl2, rt R1 = Ph, OEt R2 = Et, t-Bu
132
F3C
F3C
N R CO2R2
O
N CO R2 2 R1
O
N CO R2 2
R1 133 52-58%
CF3-Enones 131 showed different reactivity in amination reactions to nosyloxycarbamates. In particular, 4-oxazolines 133 were synthesized operating in the
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S. Cicchi, F.M. Cordero, and D. Giomi
presence of CaO or NaH as base probably through a domino sequence involving a fast rearrangement of unstable trifluoroacetyl aziridines 132 <06JOC6295>. Tripodal oxazolines 136a,b were synthesized from protected (3-hydroxyphenyl)glycinol 134 and tricarboxylic acids 135a,b in a one-pot reaction. Deprotection followed by generation of the corresponding phenoxide ions and subsequent treatment with 4bromomethylpyridine afforded preorganized C3 symmetric pyridyl-oxazolines 137a,b in 62 and 53% overall yields, respectively. Mixing 137b and trans-Pd(OTf)2(PEt3)2 in a 2:3 molar ratio gave homochiral dimeric cage 138b with two well-defined internal binding sites for molecular recognition of ammonium and enantiomeric α-chiral organoammonium ions <06CC1136>. Analogous tripodal oxazoline-based artificial receptors were synthesized and exploited for dopamine recognition in water <06JOC38> while related bis(oxazolinyl)phenols 139 were applied as fluorescence sensors towards primary amines even capable of enantio-discriminating α-chiral amines <06T11645>. N
R'O HO2C
NH2
R
N
R'O
CO2H
N
OR' OH + OTBS
a) R
R HO2C
134
135a,b
c)
b) R' = TBS R = Me, Et
N
O N O
N R R
R 136a,b Pd
N
N
O
O
O O
O
Et3P PEt3 O
O
d)
6+
O N
O N
O O
N O
138b
O
O
R
137a R = Me 62% R = Et b R = Et 53% e) R
N O
N R R
O N PEt 3 N Pd Pd N Et3P N Et3P PEt3
N O
N
O N
N
O
R O
N
R = Ph, Me HO
N O 139
Reagents and conditions: a) (COCl)2, NEt3, CH2Cl2; b) MsCl, NEt3, DMAP, CH2Cl2; c) aq. NaOH, MeOH, rt; d) NaH, DMF, 4-bromomethylpyridine, CH2Cl2, rt; e) 137b and trans-Pd(OTf)2(PEt3)2 in 2:3 ratio, CH2Cl2, rt.
O
N
N N 1 140a R2 R R3 R3 O
O
N 1
R
140b
N R2
R1
2 R2 R OH O S N
141 R3
O
O
N
O N
O PPh2
N
N 2 R1 R 142
N PAr2 143
R
N PPh2 R 144
305
Five-membered ring systems with O & N atoms
Great attention is still devoted to the synthesis and applications of enantiopure oxazoline ligands and recent results related to the use of C2-symmetric bis-oxazoline ligands in asymmetric catalysis have been reviewed <06CRV3561>. Concerning mono-oxazoline derivatives, two libraries of chiral N-heterocyclic carbene-oxazoline ligands 140a,b have been synthesized and their iridium(I) complexes successfully tested in the asymmetric hydrogenation of olefins <06CEJ4550>. A series of enantiopure thiophene mono-oxazoline N,O-ligands 141 with three sites of diversity were also prepared in two steps from the corresponding thiophene carbonitriles and applied to the enantioselective phenyl transfer reaction of aldehydes <06TA2442>. A new family of optically active phosphine-oxazoline P,N-ligands 142 has been synthesized and evaluated in asymmetric allylic alkylation (AAA) reactions (ees up to 97%) <06T11470>. Different regioisomers of aromatic-substituted phosphinyl-oxazolinyl-[2.2]paracyclophanes <06JOC4609> and some aza-paracyclophaneoxazoline N-oxides <06TL8611> were prepared and tested in AAA reactions and allylation of aldehydes, respectively. Novel planar chiral PHOX ligands with a pentamethylferrocene backbone were synthesized and applied in Pd-catalyzed AAA reactions (ees up to 94%) <06JOC2486> while the use of P,N-ferrocenyl-oxazoline ligands with electron-rich or electron-deficient aryl groups on the P atom allowed high diastereoselectivity and excellent enantioselectivity (up to 98%) in Cu(I)-catalyzed asymmetric 1,3-DC of azomethine ylides to nitroalkenes <06AG(E)1979>. New chiral phosphine-oxazoline ligands 143 (SIPHOX) with a rigid and bulky spirobiindane scaffold were prepared in four steps in 40-64% overall yields: the corresponding iridium complexes catalyzed the hydrogenation of acyclic N-aryl ketimines (ees up to 97%) <06JA12886>. Excellent results (ees up to 99%) in the iridium-catalyzed hydrogenation of imines and olefins were also obtained with 2-aza-norbornane-phosphineoxazoline ligands <06CEJ2318>. Potentially tridentate P,N,N-quinazoline-oxazolinecontaining ligands 144 have been synthesized and applied to Pd(0)-catalyzed AAA reactions <06OL5109>.
O t-Bu
N
N
O
O
N
O NH HN
t-Bu
O
O
N
N
Ar O
145
R
146
R
O
O
N
N
R
147
R
Ar O
The synthesis of different C2-symmetric bis-oxazoline ligands, such as 145, with an axialunfixed biaryl backbone has been reported as well as their diastereomeric equilibrium in solution and their application to Cu-catalyzed cyclopropanation of styrene with diazoacetate <06TA767>. A three-step procedure allowed the synthesis of C2-bis-oxazoline-amide ligands 146, tested in Pd-catalyzed AAA (ee’s up to 98%) <06JOC6451>. Chiral C2- and C1symmetric bis-oxazolines with a cyclopentane backbone have been prepared and studied in transfer hydrogenation, cyclopropanation and Diels-Alder reactions <06TA620>. The synthesis of highly modular N,Y,Z,Y,N-pentadentate bis-oxazolines (Y = N, O, S; Z = N, NO, OH, OMe) such as 147 led to a variety of ligands in diastereo- and enantiomerically pure form exploited for the construction of helical metal complexes with predetermined chirality <06T9973>. Single enantiomer, chiral donor-acceptor metal complexes were synthesized via the self-discriminating Zn(II)-complexation of a pseudoracemic mixture of donor/acceptorsubstituted bis-oxazoline derivatives <06OL2759>. Chiral pyridyl-bis-oxazolines (Pybox)
306
S. Cicchi, F.M. Cordero, and D. Giomi
were successfully applied in scandium(III)-catalyzed Sakurai additions to glyoxyamide <06OL2071>, pyrrole alkylations <06OL2249> and cerium(IV)-catalyzed nitrone cycloadditions of α,β-unsaturated 2-acyl imidazoles <06OL3351>. Metal-complexes of azabis-oxazolines efficiently catalyzed the addition of indoles to benzylidene malonates <06OL6099> and to nitroalkenes <06OL2115> (up to 98-99% ee) as well as addition of nitroalkanes to nitroalkenes <06JA7418>. Aldol reactions of pyridine N-oxide aldehydes were performed in high yields and diastereoselectivity and in excellent enantioselectivity in the presence of chiral copper(II)-bis(oxazoline) complexes <06CEJ3472>. A novel route to cyclopropane derivatives has been described from 2-(1,1dimethylalkyl)dimethyloxazolines 148a (R1 = Me): conversion into 1,3-diiodides 149 via Pdcatalyzed sequential C-H activation and then radical cyclization led to 2-(1alkylcyclopropyl)dimethyloxazolines 150 in satisfactory yields <06OL5685>. The corresponding aryl derivatives 148b (R2 = Ph) were subjected to Pd-catalyzed alkylation of aryl C-H bonds with sp3 organotin reagents using benzoquinone as a crucial promoter to give derivatives 151 <06JA78>. I
R2
I
cat. Pd(OAc)2 R1 R1 (PhCO2)2 IOAc a) N N R2 R2 C6H6, Δ 2 EtOAc, Δ O O R = Ph 148a,b R1 = Me, (CH2)n R1 = Me 149 70-83%
N
O 150 81-91%
R1 R1 N O 151 62-88%
R2= alkyl, CH2X, ester, OTBS, NPhth Reagents and conditions: a) cat. Pd(OAc)2, Me4Sn, Cu(OAc)2, benzoquinone, MeCN, reflux.
Unusual C-2 and C-4 regioselective lithiation of 3-bromo-5-(4,4'dimethyl)oxazolinylpyridine 152 using LTMP versus LDA was observed providing compounds 153 and 154, precursors of highly substituted nicotinic acid derivatives <06OL6071>. Bicyclic 2-piperidinones 155 were obtained from 2-(butyn-4-yl)oxazolines through free-radical-mediated carbonylation and 6-endo cyclization of the resultant acyl radicals onto the oxazoline nitrogen <06JA7712>. Sugar oxazolines were exploited in the synthesis of glycoproteins <06OL3081> and glycosaminoglycans <06CEJ5962>.
N Br R
O N 153 45-77%
1. LTMP, THF, -78 °C 2. Electrophile 3. NH4Cl
N Br
O N
152
1. LDA, THF, -78 °C 2. Electrophile 3. NH4Cl
R = Cl, I, TMS, CO2Et, CH(OH)Ar, CH(NTs)Ar
R Br
N
O O
R R' N
N 154 51-89%
O 155
5.7.6 OXAZOLIDINES Some new methods for the synthesis of the oxazolidine ring were published offering new ways to exploit the rich chemistry of these compounds. In aqueous media α-ketoamides 156 with phenolic substituents (Y = CN, CF3, H) undergo photocleavage and release of the phenol with formation of 5-methyleneoxazolidin-4-ones 158. The zwitterionic intermediate eliminates the phenolate leaving group and the resultant iminium ion 157 undergoes cyclization <06JOC4206>.
307
Five-membered ring systems with O & N atoms
O
H
4-YC4H4O
R2 N
156
R1
hν hydrogen transfer
R2 OH
4-YC4H4O
O
O
R2 OH N
R1 - 4-YC H O6 4 157
R2 O N
N R1
R1 158
O
O 17-60 %
R1, R2 = alkyl
Although the synthesis of the oxazolidinone 159 appeared to be well established, the scale-up of the reaction gave poorly reproducible results. The synthesis was much more efficient using diphosgene and a catalytic amount of activated charcoal <06S885>.
Ph
OH
H2N
Ph Ph
O
ClCO2CCl3 activated charcoal
O
NH 159 Ph
Ph Ph
THF, overnight
25 g, 89%
Another synthesis of 5-methylene-1,3-oxazolidin-3-ones can be achieved using Au(I) to catalyze the cyclization of N-propargyl carbamates 160. The reaction proceeds under very mild conditions and was applied to a large number of compounds <06SL2727>. O t-BuO
R3 N 2 1 O R R 160
PPh3AuNTf2
R3 N
5 min-20 h
R2 R1,
O
65-99%
R1 = aryl, alkyl R3 = H, Me
R2
A previously described process – the synthesis of stannylated oxazolidines and their ring opening to afford N-(α-tributylstannylorgano)-(R)-phenylglycinol carbamates 161 – was completed by the transformation of these latter compounds into stannylated oxazolidinones 162. The ring closure of compounds 161 can be achieved by treatment with two equivalents of NaH or by mesylation of the primary alcohol. The applicability of this process was demonstrated by the use of the stannylated oxazolidinones as precursor of organolithium reagents <06S4151>.
O
R22CuLi
Bu3Sn N O
OR1
Ph
OR1
O Bu3Sn 161 R2
O NaH or MsCl
O N
N
OH Ph
Ph Bu3Sn 2 50-93% R 162 1 R = Me, t-Bu R2 = alkyl
The formation of 1,3-oxazolidin-2-ones by the reaction of phosgene or diphosgene with amino alcohols is a well established reaction, proceeding with retention of configuration of the stereocenters of the original amino alcohol. However exceptions were found with substrates containing the (2,3-anti)-3-amino-1,2-diol moiety. As an example, the reaction of amino alcohol 163 with phosgene and diphosgene was described. The two reactions gave
308
S. Cicchi, F.M. Cordero, and D. Giomi
different results since for phosgene the major product was the cis-oxazolidinone 164 while with diphosgene the major one was the trans isomer 165 <06T6392>.
Ph
HO
O
OH
Ph
Cl
Cl N
NH 163 HO
NEt3
O
76%
164 O
O NEt3
Cl
OCCl3 HO
Ph N
Ph
OH NEt3
OH OCCl3
OH
Ph O
N O-
OCCl3
N - CCl3O-
O
O
N
O
O45% O
O
165
A high degree of selectivity can be obtained in the base catalysed epimerization of 1,3oxazolidin-2-ones 166 and 167. Through a proper choice of the base and substituents a selectivity up to 99:1 can be obtained for both the trans and cis isomers <06JOC5008>. CO2Me Bn N
O O
R=H
N LHMDS R
166
CO2Me
CO2Me
R = Bn
O
LHMDS
HN 167
O
dr > 99:1
O O
dr > 99:1
Some reactions in which a preformed 1,3-oxazolidine ring is transformed into another oxazolidine derivative were described. A detailed study of the enantioselective reduction of N-tosyl-4-alkylidene-1,3-oxazolidin-2-ones under the catalysis of Rh salts and chiral ligands, was published <06T9237>. S
O (EtO)2P(S)H O
N
DPSO
AIBN
O O
168
P
OEt OEt
N 75% DPSO
1,3-Oxazolidin-2-ones were employed as nucleophiles in a new multicomponent reaction called UFU (Ullman-Finkelstein-Ullman). This reaction allowed the one-pot synthesis of dissymmetrical para-disubstituted benzene scaffolds from 1-bromo-4-iodobenzene and two nucleophiles <06TL4973>. The 1,3-oxazolidin-2-one ring was used as scaffold for a radical cyclization to obtain compound 168, in a synthetic process towards the synthesis of substituted quinuclidines <06JOC3656>.In a similar way, the 1,3-oxazolidin-4-one ring was used as a scaffold for a ring closing metathesis useful for the synthesis of azepinones and azocinones <06TL3625>.
309
Five-membered ring systems with O & N atoms
Several examples of the use of α,β-unsaturated imides of chiral, or non chiral, 1,3oxazolidin-2-ones were published. These compounds were used in Michael additions <06JOC8572; 06TL1291> and Diels-Alder reactions <06OL539; 06T12398; 06T3095>. (NVinyl)-1,3-oxazolidin-2-ones were used as dipolarophiles in 1,3-DC reactions with nitrones <06SL3255>. A fluorinated α-bromo imide was used in a stereoselective Reformatsky-type reaction with imines <06CC3628>. Concerning natural and bioactive compounds, a short synthesis of cytoxazene 169 was reported <06T9349>. O HN
O OH cytoxazene 169
MeO
O
H N
O O
N O
O
O
O N H
O
O
H N
N O 170
O
O N
O
O
O N
N H
O
O
OBn O
Three sets of oligomers containing the 4-carboxy-5-methyloxazolidin-2-one moiety, one example is compound 170, were synthesized with the aim of verifying if these systems are able to give a β-bend ribbon spiral <06JA2410>. 5.7.7
OXADIAZOLES
5-Alkyl- and 5-aryl-2-amino-1,3,4-oxadiazoles were prepared by tosyl chloride/pyridinemediated cyclization of thiosemicarbazides in good yields (79-99%). Interestingly, thiosemicarbazides exhibited a higher rate of cyclization than the corresponding semicarbazides. For example, 171 (X=S) was converted to oxadiazole 172 within 5 h <06JOC9548>. O Ph
H N
N H X 171
TsCl (1.2 equiv) Ph pyridine (2.1 equiv) THF, 65-70 °C
H N
N N Ph
O
N H
Ph X = O: 23% conv after 20 h X = S: 99% conv after 5 h
172
O
O
N
N
N N RZ CO2Me
o-Cl2C6H4, 180 °C
O 173
N Me
[4+2] cycloaddition
O N
N O RZ N N RE Me CO2Me
RE
or TIPB, 230 °C 61-94% RZ, RE = H, Me, CH2OTBS, Ph, OBn, CO2Me, CN
O
RZ RE CO2Me
N 174 Me [3+2] cycloaddition
O N
-N2 N Me TIPB = 1,3,5-triisopropylbenzene
O
RZ RE CO2Me
A systematic exploration of a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was conducted in which the tethered initiating dienophile, the tethered
310
S. Cicchi, F.M. Cordero, and D. Giomi
dipolarophile, the 1,3,4-oxadiazole C-2 and C-5 substituents, the tether lengths and sites, and the central heterocycle were examined. For instance, derivatives 173, bearing a tethered indole as the dipolarophile trap of the in situ generated carbonyl ylide and different tethered dienophiles, were successfully exploited leading in each case to a single diastereomer of the cycloadducts 174 <06JA10589>. Treatment of acylated adenosine-N-oxides with carboxylic acid anhydrides in the presence of thiophenol produced 4-(5-substituted-1,2,4-oxadiazol-3-yl) nucleoside analogues. For example, 175 was converted to 176 by treatment with acetic anhydride followed by deprotection of the amino group at C-5 with I2 (0.5 mol equiv) in hot MeOH <06OL4565>. N O AcO AcO
NH2 1. PhSH, (MeCO)2O 2. I2, MeOH
N
OAc 175
N
N
O
3. NEt3, CH2Cl2
N O AcO AcO
N
N
NH2 N O OAc 176 98%
The rearrangement mechanisms of 5-perfluoroalkyl-1,2,4-oxadiazoles such as the five-tosix membered ring-rearrangements by hydrazinolysis and the photoinduced competitive rearrangements have been investigated <06JOC8106; 06JOC2740>.
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Five-membered ring systems with O & N atoms
06EJO3016 06EJO3235 06EJO3283 06EJO4852 06EJO5485 06JA78 06JA925 06JA1452 06JA2410 06JA6626 06JA7418 06JA7712 06JA9644 06JA10589 06JA12886 06JA13662 06JA14004 06JOC38 06JOC345 06JOC1614 06JOC2417 06JOC2480 06JOC2486 06JOC2740 06JOC3026 06JOC3221 06JOC3656 06JOC4206 06JOC4609 06JOC4951 06JOC5008 06JOC6178 06JOC6295 06JOC6451 06JOC8106 06JOC8572 06JOC9319 06JOC9548 06JOC9831 06MM3147 06OL539 06OL927 06OL2115 06OL2249 06OL2309 06OL2417
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312 06OL2495 06OL2701 06OL2759 06OL3081 06OL3335 06OL3351 06OL3537 06OL3679 06OL3785 06OL4165 06OL4565 06OL5109 06OL5157 06OL5231 06OL5513 06OL5669 06OL5685 06OL6071 06OL6099 06PLM3292 06S243 06S706 06S885 06S1021 06S1289 06S1479 06S1975 06S1995 06S2265 06S2293 06S2515 06S2996 06S4151 06SC1247 06SL463 06SL555 06SL1739 06SL2727 06SL3255 06T611 06T1494 06T3095 06T4549 06T6392 06T9237 06T9349 06T9973 06T11470 06T11645
S. Cicchi, F.M. Cordero, and D. Giomi
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Five-membered ring systems with O & N atoms
06T12227 06T12398 06TA292 06TA620 06TA767 06TA1863 06TA2442 06TL549 06TL727 06TL927 06TL1291 06TL1627 06TL3625 06TL4385 06TL4698 06TL4957 06TL4973 06TL6497 06TL7043 06TL7635 06TL7897 06TL8247 06TL8383 06TL8611 06TL8641 06TL8821 06TL9077
313
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314
Chapter 6.1
Six-membered ring systems: pyridine and benzo derivatives Heidi L. Fraser, Darrin W. Hopper, Kristina M. K. Kutterer, Aimee L. Crombie Chemical and Screening Sciences, Wyeth Research, Pearl River, NY, USA
[email protected],
[email protected],
[email protected], and
[email protected]
6.1.1 INTRODUCTION The presence of pyridines in an abundant number of natural products <06JA11799; 06JOC8384; 06TL6183; 06EJO4916; 06OL2309; 06TL3489> and pharmaceutically active compounds <06JMC607; 06BMC4466; 06JMC971; 06JMC1939; 06JMC7278; 06JMC4698> continues to fuel the desire to develop new and improved methods for their synthesis as well as the synthesis of their benzo derivatives. Azacoumarins have been shown to be versatile biodynamic agents <06CUMC2795>. There have also been reviews on quinoline derivatives and their antibiotic properties in multidrug resistant Enterobacter Aerogenes isolates <06CDC843>. A number of important reviews highlighting the preparation of pyridines and their benzo derivatives have been published in 2006, including the synthesis of quinolines using the Skraup and Doebner-Miller methods <06CHC701>. Fallahpour et al. discussed the utilization of oligopyridines as ligands in coordination chemistry <06COS19>. The reaction of triallylboranes with pyridines and isoquinolines, as well as other heterocycles, was reviewed as a versatile approach to the construction of bicyclic and polycyclic nitrogen heterocycles <06PAC1357>. This chapter includes a summary of the methods developed for the syntheses and reactions of pyridines, quinolines, isoquinolines, and piperidines that were disclosed in the literature in 2006. It will cover selected advances in the field and will serve as an update to the review published last year in this volume.
6.1.2
PYRIDINES
6.1.2.1 Preparation of Pyridines Cyclocondensations are one of the most widely used methods for preparing pyridines and dihydropyridines. The reaction is routinely employed in the synthesis of biologically important pyridines <06JMC607; 06TL1261; 06T2799; 06JHC101; 06OL899; 06BMC4466; 06JMC3244; 06BMC5481; 06JMC3809; 06BMC8176; 06JHC1169; 06SC97; 06SC1549; 06S1664> and those of interest in material sciences <06JOC1009; 06S1295; 06JOC4862; 06S2873; 06SC1721; 06TL837; 06JHC1177>. In general, cyclocondensations are catalyzed by base, Brønsted, and Lewis acids (e.g., Yb(OTf)3 <06TL1261>, AlCl3 <06BMC8176>, and Sc(OTf)3 <06OL3473>). Recently, efforts have been focused on employing multicomponent cyclocondensation reactions as one-pot procedures to conveniently synthesize diverse arrays
315
Six-membered ring systems: pyridine and benzo derivatives
of pyridine derivatives in an efficient, cost effective, and often times environmentally friendly manner <06JMC607; 06JHC985; 06OL899; 06S2873; 06SC1721; 06TL837>. For example, a one-step, three-component cyclocondensation procedure for the synthesis of pyridines and 1,4-dihydropyridines has been described <06OL899>. As shown below, structurally diverse aldehydes 1 combine with two equivalents of malononitrile 2 and various thiols 3 to form 2-amino-3,5-dicyano-6-sulfanylpyridines 4 and the corresponding 1,4dihydropyridines 5 in good yields. R1
R1
R1
NC
NC
CN
R2SH
CN
CN
or EtOH reflux, 2 h
H 1
NC
Base
O
H2N
2 3 R1, R2 = Alk, Ar, or HetAr
H2N
R2 N 4 20-48%
N R2 H 5 62-96%
The Hantzsch synthesis of pyridines is a cyclocondensation method of considerable importance. This route traditionally involves the condensation of four components, including two molecules of ȕ-carbonyl compounds, an aldehyde, and ammonia to form 1,4dihydropyridines, which can be aromatized into pyridines <06JOC1725; 06SC665; 06JCO829>. The reaction has conveniently been adapted to solid supported synthesis <06SC665> and liquid-phase synthesis <06JCO829>. In a novel solution phase approach, the preparation of dihydropyridine 6 has been achieved by reacting ionic liquid-phase bound ȕ-oxo ester 7 with dimedone 8 and aldehyde 9 in good yields and high purities. Additional adaptations have been made to improve the Hantzsch 1,4-dihydropyridine synthesis. These modified routes generally involve the addition of enones with ȕ-enaminones under conventional thermal conditions <06BMC4842; 06H2087; 06JHC1217> and microwave assisted conditions <06OBC3664; 06OBC3980>.
IL O
O
O
7
Ar
8 N
Ar 11
H
neat, 90 °C 96%
9
O
MeOH, reflux, 18 h 80% Ar = 3,4-(CH2O2)C6H3
O IL O
Ar 6
O
N
1 equiv NaOMe
HO O
O
H N
1.5 equiv NH4OAc
O
O
O IL O
Ar 10
O
1.1 equiv DDQ CH2Cl2 reflux, 2 h 80%
As improvements in Hantzsch 1,4-dihydropyridine syntheses have occurred, attention has also been focused on advancing the aromatization processes used to produce pyridines from these precursors. The utility of several oxidizing agents has been explored, including DDQ <06JFC865>, iodoxybenzoic acid (IBX) <06S451>, sodium periodate catalyzed by Mn(III)salophen complex <06BMC2720> or polystyrene-bound Mn(III) porphyrin <06CJC1>, molecular oxygen catalyzed by N-hydroxyphthalimide and Cu(OAc)2 <06T2492>, and silica gel-supported bis(trimethylsilyl)chromate <06SC77>. Other improvements in the aromatization process have led to a rapid microwave-assisted reaction using commercially available manganese dioxide (in the absence of an inorganic support) <06S1283> and to a more environmentally friendly, yet effective oxidizing method utilizing methanesulfonic acid
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H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
and sodium nitrite in the presence of wet SiO2 under heterogeneous and solvent free conditions <06JHC199>. Several related polar cyclization processes have also been reported for the synthesis of pyridines <06T8398; 06BMC2837; 06JA4453; 06T6222; 06SL1437> and pyridinones <06JOC1094; 06T3959; 06S2777; JHC1105; 06BMCL5668; 06JOC9895; 06JOC8146>. In some cases, the Vilsmeier reagent is used to effect the cyclization <06T8398; 06BMC2837>. As shown below, several chloronicotinaldehydes 12 are synthesized via the reaction of enamides 13 with the Vilsmeier reagent, generated by three different methods and at varying concentrations <06T8398>. R2 1
R
13
N R3
O
POCl3 or Triphosgene or Diphosgene
0 °C → rt → 75 °C
R2
88-94%
R1
CHO
DMF N
Cl
R1 = H, Ph, or CO2Me R2 = H, Alk, Ar, or CO2Et R3 = H or Bz
12
In addition to polar cyclization processes, pericyclic reactions are also used to produce pyridines and hydropyridines. Many of the most current strategies employ [4+2] cycloadditions to produce dihydropyridines, which can easily be converted to pyridines in a number of ways including oxidation or elimination processes. The nitrogen of the pyridine ring can be incorporated either via the diene (e.g., 1- or 2-azadienes <06H975; 06JOC3494; 06T5454; 06JA11799; 06H815; 06T1095; 06SC1521; 06T7661; 06JOC8384>, oxazoles <06BMC2209>, 1,2,4-triazines <06TL869; 06T5736; 06TL7025>, or pyrazines <06BMCL4537>) or via the dienophile (activated imine or nitrile <06S2551>). The utility of this hetero-Diels–Alder approach to pyridines is demonstrated by its application in several syntheses of natural products as the key regioselective step <06H975; 06JA11799; 06SC1521; 06JOC8384; 06T5736>. The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels– Alder reactions has expanded to include 3-phosphinyl-1-aza-1,3-butadienes, 3-azatrienes, and 1,3-bis(trimethylsiloxy)buta-1,3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively <06T1095; 06T7661; 06S2551>. In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-1-aza-1,3-butadiene 15 (conveniently prepared from ȕ-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields <06T5454>. Me 2.5 equiv TBDMSOTf TBDMSO 2.6 equiv EtiPr2N
O Me 16
N OH
CH2Cl2, 0 °C, 5-18 h
Me
2.0 equiv DMAD toluene N OTBDMS μW (180 °C), 2 h 15 56%
TBDMSO Me
CO2Me N 14
CO2Me
Likewise, an efficient one-pot multicomponent synthesis of annelated 2-amino pyridines (e.g., 17) utilizing [4+2] cycloadditions has been described <06JOC3494>. The process involves the in situ generation of 1-aza-1,3-butadiene from a palladium-catalyzed couplingisomerization reaction of aryl halides (e.g., 18) with propargyl N-tosylamines (e.g., 19). The resulting butadiene then undergoes cycloadditions with N,S-ketene acetals (e.g., 20) to form annelated pyridines (e.g., 17).
317
Six-membered ring systems: pyridine and benzo derivatives
NHTs
Ar = p-MeOPh
2. 5.0 equiv MeS THF N reflux, 12 h 20 Me 64%
Ar Br 18
CN
1. 2 mol% (Ph3P)2PdCl2 1 mol% CuI Et3N, THF reflux, 24 h
CN
19
Ar
N 17
N Me
Another pericyclic transformation commonly used to synthesize pyridines is the cyclotrimerization reaction <06ASC2307>. Traditionally, this approach involves a transition metal-catalyzed [2+2+2] cycloaddition of diynes with nitriles. A variety of catalysts are capable of effecting this transformation, including cobalt <06T968; 06CC1313>, ruthenium <06OL3565; 06JA4592>, rhodium <06EJO3917; 06OL3489>, and nickel <06JOC5834> complexes and with the appropriate catalyst system (i.e., cationic rhodium(I)/modifiedBINAP complex), the aza-cyclotrimerization can be achieved chemo-, regio-, and enantioselectively <06EJO3917; 06OL3489>. Aza- [2+2+2] cycloadditions of diynes with nitriles can lead to a variety of fused pyridines, including those that are highly substituted and sterically hindered <06T968; 06OL3565; 06EJO3917; 06OL3489; 06JOC5834>. Additionally, non-fused pyridines can be available via this route, as demonstrated by a solid-supported, cobalt-catalyzed cyclotrimerization shown below <06CC1313>. Various alkynes 21 and nitriles 22 were combined with polymer bound propargylic alcohol 23 to rapidly construct libraries of diverse pyridines 25 in good yields and purities. R1
TrtO
CpCo(CO)2 TMAO
R3 N
R2 21
23 1
R = Alk or Ar R2 = H or Alk R3 = Alk or Ar
N
toluene 80 °C, 48 h
22
R1
HO N
R2 3
R 25
R1
TrtO
1% TFA CH2Cl2 rt, 1 h
24
R2 R3
43-85% yield >90% purity
Recently, a method for synthesizing substituted pyridines incorporating 3-azadienynes as substrates in ruthenium-catalyzed cycloisomerizations was described <06JA4592>. This route is a two-step process that first converts readily available N-vinyl or N-arylamides (e.g., 26) to the corresponding C-silyl alkynyl imines (e.g., 27) and subsequent rutheniumcatalyzed protodesilylation and cycloisomerization results in the formation of the corresponding substituted pyridines (e.g., 28). 1. 1.2 equiv Tf20 4.0 equiv 2-Cl-pyr CH2Cl2
O Ph
N H 26
O
2. 2.7 equiv TMSC≡CCu Ph THF, -78 °C → 0 °C 99%
O
N
10 mol% CpRu(PPh3)2Cl 10 mol% SPhos 1 equiv NH4PF6 toluene, 105 °C 70%
27
TMS
O
N Ph 28
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H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
In addition to the examples above, several other interesting methods for synthesizing pyridines, hydropyridines, and pyridinones have recently been described. Routes involving pericyclic reactions as the key step include tandem [2+2] cycloadditions/electrocyclic ring openings <06JOC5328>, 1,3-dipolar cycloadditions <06T6398>, electrocyclic ring closures <06OL2611; 06BMC4341>, aza-Cope rearrangements <06S2085>, and aza-Wittig reactions <06JOC6020; 06T4128>. Additionally, palladium-mediated Heck reactions <06TL3225; 06JOC8602>, electrophilic aromatic substitution reactions <06CC2586; 06BMC5765>, and 6-endo N-lithioketimine cyclizations <06JOC8565> have been employed to produce pyridine derivatives. 6.1.2.2 Reactions of Pyridines Palladium reactions have continued to dominate the reactions of pyridines in the literature of 2006. Material scientists have utilized the palladium chemistry of pyridine to assemble various core structures <06TL3471; 06CC4744; 06JOC4155; 06S1141; 06CC2071>. Medicinal chemists have also utilized a large assortment of palladium chemistry in the construction of pyridine-containing targets. Many Sonogashira reactions have been performed on halopyridines <06BMCL4788; 06BMCL4792; 06EJM847; 06BMCL2270; 06JMC3581; 06S243; 06JOC8673; 06T2465>. While Suzuki reactions use both pyridylboronic acids <06AG(I)1282; 06SL53> and halopyridines <06JOC2000; 06T11734; 06S2855; 06BMCL4283; 06JMC7450; 06JMC2210; 06T6945>. Two different groups have examined Suzuki-Miyaura coupling reactions of amino-chloropyridines with various substitution patterns <06AG(I)3484; 06OL1787>. Stille reactions employ both halo<06BMC6202; 06BMCL3150; 06BMCL3740; 06JHC1311; 06BMCL3209> and stannylpyridines <06OL2123; 06BMCL6832; 06BMCL3424; 06JMC2673> in cross-coupling reactions to obtain compounds of interest. Moreover, Heck reactions incorporate vinylpyridines as substrates <06BMCL3201> in addition to halopyridines <06JOC6302; 06BMCL4048; 06JOC2922; 06BMCL5378>. All of these palladium reactions may be used in concert to incorporate a large amount of diversity into a heterocycle very efficiently <06BMCL1175; 06TL8917; 06BMCL1679; 06BMCL2000; 06EJO4257; 06JMC5324; 06OL3549; 06BMCL4567; 06BMCL3197; 06TL2337; 06T5862>. Scott and Maes separately utilized tandem palladium-catalyzed amination cyclization sequences to prepare imidazopyridiones and dipyridoimidazoles, respectively <06JOC260; 06SL2083>. Likewise, Cvetovich and Chung synthesized naphthyridinone via palladium-catalyzed Heck-lactamization <06JOC8610; 06JOC8602>. Beebe et al. utilized a sequential van Leusen–Heck reaction to prepare a fused imidazopyridine <06TL3225>. The regioselectivity of Suzuki cross-coupling reactions of 2,4-dibromopyridine 29 have been examined by Cid et al. <06T11063>. They report two catalytic systems for the Suzuki coupling of 2,4-dibromopyridine 29 and arylboronic acids, which lead to a highly selective method for the preparation of 30 or 31. This illustrates that the C-Br bond at the 2-position of the pyridine ring is more reactive toward palladium insertion than the C-Br bond at the 4position. The scheme below exemplifies how the alteration of ligands, solvent, and additives can modify the major product of this reaction. Anhydrous conditions facilitate high selectivity for preparation of 4-bromo-2-arylpyridine 30. Conversely, for the preparation of the symmetrical 2,4-diarylpyridine 31, the presence of water is instrumental in the optimization of the reaction.
319
Six-membered ring systems: pyridine and benzo derivatives
Ph
N 31
Br
Ph
.
Pd2dba3, 2-BDBP K3PO4 1.5 H2O PhB(OH)2 82%
N 29
Br
Pd(PPh3)4, TlOH(aq), THF, Pd2dba3/PCy3, K3PO4/dioxane Br PhB(OH)2 43%
N
Ph
30
In addition to being substrates for palladium reactions, pyridines are also utilized as ligands for palladium <06H1233>. Pleixats et al. exploited the complexation of pyridine to palladium to create a silica-bonded, reusable catalysts for Suzuki coupling reactions <06TL2399>. Organ and co-workers developed a series of NHC-PdCl2-3-chloropyridine (NHC = N-heterocyclic carbene) complexes that are easily reduced to a highly active Pd0NHC species, readily prepared in large scale and air stable <06CEJ4743>. Yu et al. developed two new types of unsymmetrical pyridyl-supported pyrazolyl-NHC ligands for the assembly of transition metal catalysts <06JOC5274>. The application of these ligands as palladium complexes was explored; they exhibited good to excellent catalytic activity in the Suzuki–Miyaura reactions. Furthermore, palladium chemistry has also been used to form C-N and C-O bonds on pyridines. The latter has been utilized in the synthesis of oxygen substituted biologically active pyridines <06EJM640; 06TL5333>. In the formation of C-N bonds this chemistry has also been used to prepare compounds of biological interest that contain amino-pyridine moieties <06BMCL3249; 06JOC7322> in addition to amino-substituted terpyridines <06S2585; 06TL5079>, and pyridines that contain macrocycles <06TL2691>. Moreover, a palladium-catalyzed amidation reaction was used in the preparation a 2,3-fused pyridyl urea a potential drug target <06S2716>. Yu and Che reported a catalytic amidation based on a cascade chelation-directed cyclopalladation approach <06JA9048>, illustrated in the preparation of amide 32 from 2-phenylpyridine 33 via the cyclic palladium intermediate 34. O 5 mol% Pd(OAc)2
N 33
K2S2O8, H2NCOCF3, DCE 80 °C, 7 h, 92%
HN
N AcO Pd
CF3
N 2
34
32
Some amination reactions, while unsuccessful under palladium conditions, are accomplished via copper-catalyzed reaction <06BMCL5309; 06JMC3753; 06TL6011; 06T4756; 06BMCL2689; 06JMC3719; 06BMCL4400>. Yu and co-workers capitalized on the extensive literature of pyridyl as a directing group in C-H activation in a copper-catalyzed acetoxylation and halogenation of aryl C-H bonds to yield 35 and 36, respectively <06JA6790>. This new reaction can also be applied to cyanation to form 37, amination, esterification, and thioesterification of C-H bonds. Selected examples are shown in the scheme below. The broad scope of this reaction is postulated to be a result of the mechanism. The authors propose a single electron transfer to the pyridine, leading to a radical-cation intermediate. The radical-cation intermediate then reacts with available nucleophiles and facilitates formation of many possible products.
320
H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
OAc 10 mol% Cu(OAc)2 HOAc-Ac2O, O2 130 °C, 48 h, 37%
Br N
1 equiv Cu(OAc)2 Br2CHCHBr2 65%
36
N
1 equiv Cu(OAc)2 CH3CN, TMSCN 42%
33
N 35 CN N 37
Fluorine containing pyridines are of interest in medicinal chemistry due to their unique electronic effects <06JOC9420>. Two groups over the last year have attempted to improve both electrophilic and nucleophilic fluorination of pyridines. Hoyte et al. enhanced the nucleophilic fluorination of pyridines using microwave conditions <06BMCL3454>. Kinetic experiments showed an average relative rate ratio of 3:1 for microwave versus conventional heating methods. Similarly, Sanford and co-workers describe the development of the first palladium-catalyzed C-H activation/C-F bond-forming reaction with electrophilic fluorine under oxidative conditions, utilizing microwave irradiation <06JA7134>. This has been illustrated with the ortho-fluorination of 2-phenylpyridine 38 generating difluoro 39 in good yield. F N
10 mol % Pd(OAc)2 0.5 mL CH3CN in CF3C6H5 μW, 150 °C, 1.5 h F N
38
BF4
N Cl 69%
2
F N F 39
Additional publications from Sanford et al. describe the full exploration of palladiumcatalyzed chelate-directed chlorination, bromination, and iodination of arenes using Nhalosuccinimides as the terminal oxidant <06T11483>. Moreover, an electrophilic fluorination of dihalopyridine-4-carboxaldehydes was reported by Shin et al. <06JFC755>. This was accomplished via transmetalation of the bromo derivative, followed by treatment with N-fluorobenzenesulfinimide as the source of electrophilic fluorine. Several groups have studied the free radical chemistry of pyridines. Schiesser and coworkers used a free radical rearrangement of 2-selenopyridines to prepare seleniumcontaining antioxidants <06OBC466>. Additionally, Burgos and co-workers examined the radical cyclization and atom transfer reactions of pyridyl radicals in the preparation of annulated pyridines <06TL8343>. Pyridylmethyl radicals, prepared by direct selenation of 2methylpyridines, have also been shown to undergo 5-exo-trig and 6-exo-trig cyclization under standard free-radical conditions <06TL553>. Zard et al. presented a more unique free radical reaction of pyridines <06CC4422>. An unprecedented radical ring closure onto the pyridine nitrogen was observed when certain protecting groups were present in close proximity to the pyridine nucleus. This result was obtained upon changing the protecting group of the 2-aminopyridine 40 from acetyl to the more versatile t-butoxycarbonyl (Boc) group. Under otherwise identical conditions, alteration of the protecting group resulted in the formation of a different product. It was determined by X-ray and other spectroscopic means that the unexpected product 41, was formed from ring closure onto the pyridine nitrogen followed by electron transfer of the resulting radical to the peroxide generating a radical anion, quenching of the radical anion leads to a tetrahedral intermediate, which then collapses to give the observed pyridone 41.
321
Six-membered ring systems: pyridine and benzo derivatives
O
Lauroyl peroxide DCE, reflux N R R = Boc; 55% Cl
N O
C(S)OEt S N 40
41
N R
Lauroyl peroxide DCE, reflux R = Ac; 50% Cl
O
N 42
N R
O
Sulfur containing pyridines have been shown to display interesting chemistry. Pyridine disulfides have been used as a sulfenylating agent with a phosphine-promoted desulfurative allylic rearrangement to fuctionalize thiols <06OL3593>. Tanaka and co-workers have reported an N-glycosylation, which uses a newly designed glycosyl donor bearing a pyridylmethyl group on the sulfur <06TL5147>. This moiety facilitates C-S bond cleavage via bidentate coordination of S and N atoms to Lewis acid activators. N-2-Pyridylmethyl thioamides have been reported to participate in an iodine-mediated oxidative desulfurization cyclization, which is an efficient method for preparation of 2-azaindolizines <06OL5621>. Pyridinedithioesters were used as a proficient heterodienophile when complexed with BF3 <06OL1033>. A hetero-Diels–Alder reaction using 3-pyridinedithioester 43 was used to generate a key intermediate 44 in the synthesis of racemic Aprikalim 45 as illustrated below. S S N 43
1. BF3 2. CH2Cl2 35 °C, 24 h 91%
N
N S
S
O S S
3:1
S
44
HN
N
Aprikalim 45
Due to their electron deficient character, pyridines are susceptible to nucleophilic attack. Rudler et al. has studied the reaction of pyridines with bis(trimethylsilyl)ketene acetals <06TL4553; 06TL4561>. In one instance, they examine the reaction of bis(trimethylsilyl)ketene acetals with 2-phenylpyridines activated with chromium tricarbonyl to give pyridine-substituted bicyclic -lactones. This reaction allows for the formation of up to five stereogenic centers in two-steps. A second report describes successive double nucleophilic additions of bis(trimethylsilyl)ketene acetals to pyridines. Modification of substituents on the ketene acetal and starting lactones makes it possible to drive the addition reactions either toward formation of tetrahydropyridines or the formation of highly substituted piperdines stereoselectively. O
O
N
PMP 1. LiHMDS, THF -78 °C, 5 min N 2. CH3OCOCl O 99%, dr = 94/6 O 46 t-Bu
H PMP
N O
OLi
N O
47 t-Bu
O
PMP
O N O
N O
CO2t-Bu 48
Clayden and co-workers reported the dearomatiztion of an electron-deficient pyridine ring via intramolecular cyclization of an enolate shown in the scheme above <06OL5325>. Generation of the amino acid derived enolate of 46, with simultaneous activation of the pyridine ring by N-acylation, leads to a stereoselective transition state 47. The authors postulate that the stereoselectivity arises from the manner in which the bulky PMP (p-
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methoxy phenyl) group controls the approach of the enolate. This results in an enantiomerically enriched diazaspirocyclic amino acid derivative such as 48. 6.1.2.3 Pyridine N-Oxides and Pyridinium Salts Pyridinium salts continue to be targets of interests for several different applications. Bererine derivatives, which originated from Chinese herbal medicine, have been synthesized for examination of their antihyperglycemic activity <06BMCL1380>. These natural products are also of interest for their interactions with G-quadruples DNA structures <06BMCL1707>. The inhibitory activity of pyridinium salts towards acetylcholinesterase was also reported recently <06BMC472>. Moreover, Köck reported the first total synthesis of viscosamine, a natural product containing a pyridinium salt moiety <06S2580>. Material science applications of pyridinium salts include non-linear optics <06T7817; 06EJO2727; 06ACR3838> and chiral room-temperature ionic liquids <06JOC9857; 06JFC159; 06EJO3791>. Additionally, their unique physicochemical and photophysical properties make pyridinium salts important compounds for electron transfer sensitizers <06JOC315>, photosensitizers <06JA7510>, and self-assembled films <06JA2142>. Over the past year, the dearomatization of pyridinium salts has been implemented in the synthesis of indoles <06AG(I)7803> and less obviously triazolyldienes <06JOC7805>. Typically, pyridinium salts are prepared through reaction of an intact pyridine with electrophiles. Marazano et al. used a three-component process as entry into 3-substituted pyridinium salts for the preparation of 49 as shown below <06TL5503>. O
N R1
O X
O
R2 50
51
R3 LDA X THF 20 - 80%
O O
n-BuNH2 HCl/ MeSO3H MeOH, reflux 60 - 65%
R2 O
52
R2 CH3SO3 N n-Bu 49
R1 = H, Si(CH3)3 R2 = CH3, n-Bu, H R3 = n-Bu, t-Bu X = -C(CH3)2-, -CH2-
3-Substituted pyridinium salts of this nature were difficult to obtain by other methods. This sequence is initiated with condensation of the anions of imine 50 with malonaldehyde monoacetals 51 to access glutaconaldehyde monoacetals 52. The monoacetal-aldehyde was then reacted with primary amines (n-BuNH2) to give 3-substituted pyridinium salts 49. When the silylimino derivative (R1=Si(CH3)3) was used, substantially higher yields of intermediate glutaconaldehydes were obtained. The utilization of solid-support pyridinium salts in the synthesis of bicyclic pyridines has been reported. Yue et al. synthesized 1,2,3,7-tetrasubstituted indolizines using poly(ethyleneglycol)bound pyridinium salts <06JHC781>. The PEG-bound pyridinium salts 53 were reacted with alkenes or alkynes in the presence of Et3N, via 1,3-dipolar cycloaddition, to give polymer-bound indolizines 54 and 55, respectively. Liberation of the heterocycle with KCN/MeOH afforded 1,2,3,7-tetrasubstituted indolizines 56 and 57 in good to excellent yield. O
O R1CH=CHR2 Br N 53
O
R1
O
Et3N, TPCD DMF, 90 °C 96-99%
O
R2
N 54
O
R
O KCN/CH3OH rt, overnight O 50-90% R = CH3, Ph R1 = COCH3, CN, COPh R2 = H, aryl, heteroaryl
R1 R2
N 56
O
R
323
Six-membered ring systems: pyridine and benzo derivatives
O R4
R3
O
Et3N
53
R3 R4
N
DMF, 90 °C 97-99% 55
O
R
O KCN/CH3OH rt, overnight O 62-75% R = CH3, Ph R3 = COCH3, H R4 = COCH3
R3 R4
N 57
R
O
Similarly, Yli-Kauhaluoma and co-workers have studied the 1,3-dipolar cycloaddition of polymer-bound alkynes to azomethine imines, generated in situ from N-aminopyridine iodides, in the synthesis of pyrazolopyridines <06JCC344>. Dudley and co-workers have designed pyridinium triflate reagent 58 for the preparation of benzyl ethers <06JOC3923>. This reagent is easily prepared in two steps with good yield. Since it is also bench-stable and preactivated, the benzylation reaction occurs upon warming 58 in the presence of an alcohol with no need for acidic or basic promoters. R Cl
N
KOH, BnOH 18-c-6, PhMe reflux, 95% BnO
N
MeOTf, PhMe 0 °C to rt 86-91% BnO
N
OTf 58
OH
R
OBn
R = 1°, 2°: Yield> 80% HO R = 3°, aryl: Yield ≤ 80%
OTf
N
A key reaction of pyridinium salts continues to be nucleophilic addition to form dihydropyridines or pyridinones. Specifically, the reaction of Grignard reagents with Nacylpyridinium salts has been used to generate pivotal pyridinone intermediates in the total synthesis of (-)-Barrenazines <06OL2985> and (-)-FR901483 <06JOC9393>. Lavilla et al. examined the addition of isocyanides to pyridinium salts 59 as an efficient entry into substituted nicotinonitrile derivatives 60 <06OL5789>. The electron-withdrawing group helps to stabilize the nitrilium intermediate. The carboxamido group also undergoes dehydration in the generation of the observed product 60. CN
H2N(O)C
H2N(O)C
R1Cl N
Br
R1 = Bn, CO2CH3, Fmoc, Alloc R2 =2,6-dimethylphenyl, t-Butyl, Cyclohexyl
N R1 59
R2N=C NaOAc/ MeOH Yield over 2 steps: 60 - 71%
O R1 N NH R2 60
Another classic reaction of pyridinium salts is reduction of the pyridine ring. Donohoe and co-workers reported the partial reduction of N-alkylpyridinium salts <06OBC1071>, which is accompanied by subsequent alkylation and hydrolysis to furnish a range of 2,3dihydropyrid-4-ones. This sequence has the potential to introduce a variety of functional groups at the C-2 position of 2,3-dihydropyrid-4-ones. Reduction of pyridinium ylides with sodium borohydride has also been reported in fair to good yields <06JHC709>. Both pyridinium salts and pyridine N-oxides are of increased interest as chiral catalysts in organic reactions. Connon and Yamada independently designed and examined pyridinium salts as chiral catalysts in the acylation of secondary alcohols <06OBC2785; 06JOC6872>. These two catalysts can be used for kinetic resolution of various sec-alcohols and dl-diols in good to moderate enantiomeric excess. Pyridine N-oxides have been utilized as asymmetric catalysts in the allylation of aldehydes <06JOC1458> and in the Strecker reaction <06T4071>. In the latter, the chiral Noxides played a key role in the initial activation of the Si-C bond by coordinating an O atom to the Si atom of silyl cyanide and stabilizing the three-membered complex proposed by the
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H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
authors. The preparation of these types of chiral N-oxide catalysts by oxidative dimerization has been examined by Denmark et al. and demonstrated in the synthesis of many chiral pyridine N-oxides <06TA687>. Alternatively, Sanfilippo and co-workers have examined the enzymatic kinetic resolution of pyridine N-oxides to produce several chiral N-oxides <06TA12>. Pro-chiral pyridine N-oxides have also been used as substrates in asymmetric processes. Jørgensen and co-workers explored the catalytic asymmetric Mukaiyama aldol reaction between ketene silyl acetals 61 and pyridine N-oxide carboxaldehydes 62 <06CEJ3472>. The process is catalyzed by a copper(II)-bis(oxazoline) complex 63 which gave good yields and diastereoselectivities with up to 99% enantiomeric excess.
R
catalyst OTMS CH Cl , -40 °C 2 2
H +
N O
OMe
O 62
64 - 92% 77 - 99% ee
61
O
R
O
N O
OH O
O N
t-Bu
Cu
TfO 63
R = H, 6-Br, 6-Ph, 5-Br, 5-Ph
N
OTf
t-Bu
Pyridine N-oxides have been exploited in the reaction with silylaryl triflates 64 to prepare 3-(2-hydroxyphenyl)pyridines 65 regioselectively, as illustrated below <06JOC4689>. Treatment of the silylaryl triflate 64 with cesium fluoride generates the benzyne intermediate 66, which in turn undergoes 1,3-dipolar cycloaddition with the pyridine N-oxide 67 forming intermediate 68. Rearrangement of 68 to bicyclic 69 occurs rapidly; this intermediate is then deprotonated at the C-3 position to give the 3-phenyl regioisomer 65. Isomer 65 is observed when bicyclic 69 is substituted with electron-donating or electron-neutral group. The influence of electron-withdrawing groups on the pyridine ring (R = CN) facilitates deprotonation at the C-2 carbon resulting in the 2-phenyl isomer 70. N R O N
R
R 67 CH3CN CsF 66
TfO 64
R
fast N O
TMS
H
R = CN, EWG R = CN; 42%
N 68
H O 69
70 HO
R HO R = H, CH3 52 - 80% N 65
Over the past year, two additional methods were reported to reduce pyridine N-oxides to the corresponding pyridines. Sandhu and co-workers have presented an efficient and general method for the deoxygenation of N-oxides using Zn(OTf)2 and Cu(OTf)2 <06SL395>. Similarly, Fernandes et al. have developed a novel reduction method, with wide functional group tolerance, using a silane (PhSiH3) in the presence of a catalytic amount of MoO2Cl2 to produce pyridines in excellent yield.
325
Six-membered ring systems: pyridine and benzo derivatives
6.1.3
QUINOLINES
6.1.3.1 Preparation of Quinolines The development and use of environmentally friendly methods for the synthesis of quinolines and dihydroquinolines were represented in variety of publications in 2006. Many of the reports incorporated solvent free conditions. Perurnal et al. showed that silicasupported NaHSO4 as a heterogeneous catalyst for the cyclization of 2-amino-chalcones 71 under solvent free microwave conditions results in a variety of 2,3-dihydroquinolin-4-ones 72 in high yields <06CJC1079>. Lier et al. also utilized a silica supported TaBr5 catalyst to cyclize 2-amino-chalcones 71 forming a variety of 2,3-dihydroquinolin-4-ones 72 under solvent free thermal conditions <06TL2725>. The use of silica gel supported TaBr5 under solvent free thermal conditions showed considerable improvement in yield for this cyclization compared to the reaction conducted in organic solvents.
NH2
NaHSO4-SiO2 μW 2 min
O
O
1
Ar R1
71
R = H, 80 - 95% TaBr5-SiO2 140 - 150 °C, 3 - 5 min
R1 72
R1 = H, 70 - 92% Br, 70 - 75%
N H
Ar
Wang et al. reported two different reaction conditions for a solvent free Friedländer quinoline synthesis. Initially, they reported the reaction of 2-acetyl anilines 73 with a variety of β-diketoesters 74 using p-TsOH as the catalyst under microwave conditions to form substituted quinolines 75 <06OBC104>. They also reported the same reaction using BiCl3 as the catalyst under thermal conditions <06LOC289>. Both sets of conditions afford high yields and simpler experimental procedures. p-TsOH, μW 15 - 60 s
R1 O NH2 73
EtO2C
R1
87 - 96%
+ R2
O 74
BiCl3 74 - 178 °C 2-5h 89 - 96%
CO2Et N
R2
R1 = 4-FC6H4, Me R2 = Me, Et, i-Pr
75
In addition to their work with solvent free systems, Wang and co-workers reported a water mediated Friedländer quinoline synthesis using hydrochloric acid and conventional heating to synthesize a variety of substituted quinolines in high yields <06TL1059>. Additionally, Rivkin and co-workers synthesized a variety of 4-hydroxy-3phenylquinolin-2-(1H)-ones under solvent free microwave conditions using an activated arylmalonate <06TL2395>. Reacting the desired substituted aniline with di-(2,4,6trichlorophenyl)-2-phenyl-malonate at 250 °C with microwave irradiation for 15 min resulted in a variety of 4-hydroxy-3-phenylquinolin-2-(1H)-ones in good yields. They also demonstrated the utility of this method in the synthesis of type I fatty acid synthase inhibitors <06BMCL4620>. Kumar et al. have reported a variation of the Friedländer quinoline synthesis. They highlight the use of CeCl3•7H2O as a reusable catalyst in the reaction of 2-
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H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
aminoarylketones 76 with ketones 77 in acetonitrile at room temperature to form a variety of substituted quinolines 78 <06TL813>. R1 R2
O + NH2 O 76
R1
CeCl3·7H2O CH3CN, rt
R2
65 - 95%
R3 77
N
R3
78
R1 = C6H5 R2 = CH3, CO2CH3, CO2CH2CH3, COCH3 R3 = CH3, CH2CH3, CH2OCH2CH2NPht R2 - R3 = COCH2C(CH3)2CH2, (CH2)6, CH2CH(t-butyl) CH2CH2
Xie and co-workers developed a simple route for the synthesis of 3-aryl-1,2,3,4tetrahydroquinolines 79 using a direct intramolecular reductive ring closure strategy <06TL7191>. The yields for the key reductive ring closure were moderate; however, the simplicity of their route leads to an efficient synthesis of a variety of tetrahydroquinolines 79. R1 R
R3
R1
1. ArCH2CN Na, C2H5OH 2. NaBH4
O
2
2
R
CN NO2
R3
NO2
R1 H2, Pd/C Ar THF, CH3OH
R4
R2
Ar
R3
7 - 74 %
N H 79
R4
4
R
A novel reaction for the synthesis of 4-amino-substituted quinolines 80 or 4-quinolones 81 was reported. Reaction of various ketones, such as 82 and 83, with o-oxazoline-substituted anilines 84 and 85 in the presence of a catalytic amount of p-toluenesulfonic acid (p-TSA) in dry n-butanol led to 80 and 81, respectively <06T9365>. To the authors’ surprise, the reaction of acetophenones 82 lead to a different outcome than that of the cyclic or acyclic ketones 83 containing more than one carbons α to the ketone. 1
R
R5 O
NH2 N
R2
4
R
O
+ R3
10 mol% p-TSA n-butanol, reflux 24 h
HN HO
75 - 89%
84
82
R5 R6 R6
R4
O
NH2 N
R7
Ph
O
+ 83
85
R6
R2
N 80 O
5
R
R1
10 mol% p-TSA n-butanol, reflux 24 h
R3 R7
88% 81
N H
Ph
The use of cerium(IV) ammonium nitrate (CAN) as a catalyst for an aza-Diels–Alder reaction was reported in two different publications. In one report Perumal and co-workers react a variety of anilines 86 and aldehydes 87 with enamine 88 in the presence of 5 mol% CAN to form a series of tetrahydroquinolines 89. The reactions were performed at room temperature with very short reaction times and in good yields. In addition, the resulting tetrahydroquinolines could be oxidized to the corresponding substituted quinolines using 2.5 eq of CAN in high yields <06TL3589>.
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Six-membered ring systems: pyridine and benzo derivatives
R1 +
H2N
R2 + O 87
86
N 88
5 mol% CAN H2O or aq CH3CN rt
O
H N
R2
N
O
R1
82 - 86% R1 = H, Cl; R2 = H, Me, OMe
89
Yu and co-workers also used CAN to catalyze an aza-Diels–Alder reaction <06TL3545>. Aryl imines were reacted with N-vinylpyrrolidin-2-one or N-methyl-N-vinyl-acetamide in the presence of 10 mol% CAN resulting in the desired 2,4-cis-tetrahydroquinolines in good yields. An efficient high yielding synthesis of 3-substituted 2,3-dihydroquinolin-4-ones 90 was developed by using a one-pot sequential multi-catalytic process <06TL4365>. The scheme below shows the one-pot sequential multi-catalytic Stetter reaction of aldehyde 91 and α,βunsaturated esters 92, resulting in the formation of the desired dihydroquinolines 90. Cl O
OH S 20 - 30 mol%
N + NHMs
1
AcO
R 92
91
O R1
5 mol% Pd(OAc)2 12 mol% PPh3, 5 equiv i-Pr2NEt t-BuOH (0.1 M), 50 °C
N Ms
98 - 99%
R1 = CO2Et, CO2t-Bu, CN
90
A novel metal free approach for the synthesis of substituted quinolines 93 was reported using a HCl(cat)-DMSO system <06JOC800>. A catalytic amount of HCl in DMSO activates aldehydes 94, which react with benzylideneanilines 95 to form substituted quinolines 93.
1
2
R
94
R O
+
N 95
R3
5 mol% HCl DMSO, air
R
55 - 82%
R1
3
N R2 93
R1 = (CH2)5CH3, (CH2)2Ph, CH2Ph R2 = H, 4-BrPh, 4-OCH3Ph, 4-CO2H, furan, Ph; R3= H, 4-BrPh, 4-OCH3Ph, 4-CO2H, 2-OCH3, Ph
In a similar one-pot synthesis of substituted quinolines, Wang et al. used molecular iodine (1 mol%) to catalyze the reaction between enolizable aldehydes and imines in refluxing benzene. The advantage of this method is that it is metal free, takes place with short reaction times, and produces good yields <06TL3127>. Metal-catalyzed methods for the synthesis of quinolines continue to be of interest. In an alternate new strategy, SnCl2 was used to mediate tandem reactions for the synthesis of highly functionalized quinolines 96, derived from Baylis-Hillman adducts <06T8740>. The reduction of the nitro group of 97 initiates a highly regioselective intramolecular cyclization involving the amino and carbonyl group, which is introduced through a SN2 substitution reaction as shown in the scheme below.
328
H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
O R2 + R1
1. DABCO rt, 15 min (80 - 86%) 2. AcCl, pyr, CH2Cl2 2-3 h (78 - 84%)
O
O R1
O
O 3
OAc
R4
R3
2
R
R1
R4 R2
R
DABCO 68 - 85%
NO2 NO2
NO2 97
SnCl2, MeOH reflux
50 - 86% R2
R1 = H, 5-Cl, 3,4-OCH2O R2 = CO2Me, CN R3 = Me, Ph, OEt R4 = Ph, OEt
1
R
O R3
96
N
R4
In another metal-catalyzed quinoline synthesis, NiBr2(dppe) was used to catalyze the reaction of 2-iodoanilines with aroylalkynes in acetonitrile at 80 °C <06JOC7079>. The resulting 2,4-disubstituted quinolines were synthesized in good yields and this method was reported to tolerate a broad range of functional groups. Konakahara and co-workers reported the first direct synthesis of a quinoline skeleton 99 via homodimerization of ethynylanilines 98 in the presence of InBr3 in refluxing methanol <06JOC3653>. R1 InBr3, MeOH, reflux, 24 h
1
R
R2 98
NH2
56 - 89% R1 = H, Me, F, CN, NO2 R2 = H, Me
R2 R1
N R2
99
H2N
6.1.3.2 Reactions of Quinolines A novel approach for the direct conversion of quinoline N-oxides to 2-aminoquinolines was developed using an isocyanate intermediate <06OL1929>. This regioselective conversion was achieved by treating a primary amide 100 with oxalyl chloride and reacting the resulting isocyanates with quinoline N-oxides 101 to give the desired 2-amidoquinolines 102 in good yield. R1
1. oxalyl chloride CH2Cl2
O NH2
2.
R2
100 N O 101
O R1 N H
N 102
R2 R1 = H, R2 = 3-CN, 91% R1 = H, R2 = 6-CO2Et, 82% R1 = 3-CF3, R2 = H, 81% R1 = 4-OMe, R2 = H, 79%
The synthesis of N-heterocyclic isothiocyanates has been a difficult challenge due to their propensity to oligomerize by autocatalysis. In an attempt to alleviate this issue, silver thiocyanate was used in a novel synthesis of 4-quinolyl isothiocyantes <06TL2161>. Reaction of 4-chloroquinoline with silver thiocyanate in refluxing anhydrous toluene for 12 h results in the desired product in quantitative yields and excellent purity. The asymmetric hydrogenation of quinoline continues to be of interest. Li et al. reported the asymmetric hydrogenation of a variety of 2-substituted-quinolines to the corresponding tetrahydroquinolines using an Ir-catalyst with a BINOL-derived diphosphonite ligand
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Six-membered ring systems: pyridine and benzo derivatives
<06CC2159>. The use of this catalytic system gave enantiomeric excesses ranging from 7396% with conversions of >96% in most cases. In another report involving an asymmetric hydrogenation of 2-substituted-quinolines, a [{IrCl9cod)}2]/(S)-segphos catalyst was used to achieve good enantiomeric excesses <06AG(I)2260>. In this reaction, which provides a new approach for the hydrogenation of heteroaromatic systems, the quinoline was first activated with chloroformates forming the N-acylpyridinium salt. Using a metal free Brønsted Acid catalyzed transfer hydrogenation Rueping et al. reported a new organocatalytic reduction of quinolines <06S1071> and its application in the synthesis of alkaloids <06AG(I)3683>. 2Substituted quinolines 103 are reduced in the presence of Hantzsch dihydropyridine 104 and catalyst 105 in benzene at 60 °C to give the desired tetrahydroquinolines 106 in good to high yields and high enantiomeric excess. EtO2C
CO2Et N H 104 Ar
R
N 103
N H 106
O O P O OH
R = 2-naphthyl, 93% yield, >99% ee 3-bromophenyl, 92% yield, 98% ee R 1,1'-biphenyl-4-yl, 91% yield, >99% ee 2-furyl, 93% yield, 91% ee n-pentyl, 88% yield,90% ee Ar = 9-phenanthryl
105 Ar
A one-pot synthesis of pyrano[3,2-c]quinolin-2,5(6H)-dione 107 was reported through the condensation reaction of chlorocarbonyl ketenes 108 with 4-hydroxyquinolin-2(1H)-ones 109. This simple procedure was shown to be a convenient synthesis of pharmacologically active compounds in high yields <06S435>. OH + Cl N 109 R
O
anhyd CHCl3 20 - 30 min, rt
Ph C O
O 108
O
R = Et; 90% Me; 85% Ph; 92%
O Ph
N R
O
OH 107
Kappe and co-workers developed two general microwave methods for the synthesis of symmetrical (hetero)-biaryls 110 from 4-chloroquinolin-2(1H)-one 111 <06JOC1707>. The two methods include either a Pd(0)- or Ni(0)-mediated homocoupling, as exemplified below. Cl R4 R3 R2
N R1
111
Method 1 O PdCl2(dppf), [B(pin)]2, KOH, BuCl R1 N μW, 130 - 145 °C, 35 min 68 - 91 % R2
R4
Method 2 NiCl2, PPh3, Zn, DMF μW, 205 °C, 25 min 41 - 98%
N
R3 R2
O R3 R4
110
R1 O R1 = Me, Ph R2, R3, R4 = H, OMe
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H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
6.1.4 ISOQUINOLINES 6.1.4.1 Preparation of Isoquinolines The Pictet-Spengler reaction continues to be a popular area of research for the synthesis of isoquinolines. In one report it was shown that α-amino acids like L-DOPA can be reacted with benzaldehyde to form the corresponding isoquinoline in quantitative yield <06SL1903>. This Pictet-Spengler reaction was conducted under very mild conditions, allowing the reaction to take place in the presence of unstable functional groups. In another version of the Pictet-Spengler reaction, AuCl3/AgOTf was used to catalyze the cyclization of imines 112 to a variety of tetrahydroisoquinolines 113 in good yields <06JOC2521>. MeO N
MeO 112
R
1 mol% AuCl3, 2 mol% AgOTf,
MeO
1 equiv AcCl, 1 equiv 2,6-lutidine, CH3CN, rt, 12 h
MeO 113
R = CO2Et, 81% p-NO2C6H4,78% N Ac p-MeOC6H4, 82% Ph, 73% R
Chen et al. reported a more environmentally friendly version of the Pictet-Spengler reaction <06H1651>. In this report, a series of 2-phenylsulfonyl-1,2,3,4tetrahydroisoquinoline-1-carboxylic acid ethyl ester derivatives 114 were synthesized in good yields through the cyclization of N-phenylsulfonyl-β-phenethylamines 115 with α-acyl sulfide 116 using phenyliodine(III) bis(trifluoroacetate) (PIFA) in ionic liquid ([bmin]PF6). The use of the ionic liquid allows for a simple purification and [bmin]PF6 can conveniently be recycled. R1 R2
PhO2S CO2Et NH + S
PIFA, [bmin]PF6 50 °C, 1 h [bmin]PF6 = PF6 N
R3
N n-Bu
R1 R2 R3
116
115
114
R1, R2, R3 = H, 88% R1, R2 = H, R3 = OMe, 78% R1= H, R2, R3 = OMe, 85% N SO2Ph 1 2 R , R = H, R3 = Cl, 75% CO2Et
Kobayashi and co-workers have described a new synthesis of a range of 1,4-disubstituted isoquinoline derivatives 117 <06S2934>. Initially, a lithium halogen exchange of 118 was performed to form 119, followed by treatment with a variety of nitriles 120 resulting in 1,4disubstituted isoquinolines 117. R2 R1
R2 OMe
Br 118
n-BuLi R1 Et2O, 0 °C Li 119
R2 3 OMe R CN, 120 0 °C
R1 N
36 - 73% 117
3
R
Kobayashi and co-workers have also reported an alternate synthesis of 1,4-disubstituted isoquinolines and a new synthesis of 1,3,4-dihydroisoquinoline derivatives <06BCJ1126; 06S2934>. The 1,4-disubstituted isoquinolines 121 are synthesized in good yields by reacting a variety of organolithiums 122 with different benzonitriles 123. In addition, a variety of lithium dialkylamides 124 were also reacted with different benzonitriles 123 to form 1-amino-4-substituted isoquinolines 121 in moderate yields.
331
Six-membered ring systems: pyridine and benzo derivatives
Ph R1
Ph
R2Li 122 or LiNR32 124
OMe
R1 N
-78 °C to rt 41 - 76%
CN 123
R1 = H, OMe R2 = Ph, s-Bu, N(R3)2 R3 = i-Pr, Et
2
121 R
Additionally, Kobayashi and co-workers demonstrated the reaction of 125 with phenyl lithium, followed by treatment with different electrophiles results in 1,3,4-trisubstituted dihydroisoquinolines 126, as shown below <06BCJ1126>. Ar R1
Ar 1. PhLi, -78 °C to 0 °C 2. R1X
N
CN
R1 = H, 69% Me, 59% Bn, 62%
126 Ph
125
Bravo et al. synthesized a series of 1-alkyl- and 1-aryl-3-aminoisoquinolines 127 <06JHC235>. Treatment of 2-acylphenyl-acetonitriles 128 with amines 129 and a catalytic amount of trifluoroacetic acid results in the formation of 1-alkyl or 1-aryl-3aminoisoquinolines 127 in a single reaction step and in good yields. CN O + R1
128
NHR2 R1 = Et, R2 = Me, 92% R1 = Et, R2 = Ph, 86% N R1 = Ph, R2 = Ph, 76%
H R2NH2 EtOH, Δ 129 127
R1
An improved method for the synthesis of 4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3carboxylic acid derivatives 130 was presented <06S1971>. This improved three-step method efficiently converts phthalic anhydride 131 to the desired dihydroisoquinolines 130 in high yields over three steps with only one purification. O O 131
O
1. R1NHCH2COR2 2. CH2N2
O O N
R1 = Me, t-Bu R2 = OMe, OEt, NHEt, N(Me)Ph, NEt2
O
R1
O R2
NaOR1 R1OH 64 - 83%
OH O R2 N
R1
130 O
In a facile and rapid stereoselective, three-component, one-pot reaction, a series of cisisoquinolonic acids 132 were synthesized using silica supported sulfuric acid to catalyze the reaction between homophthalic anhydride 133 with different aldehydes 134 and amines 135. This three-component cyclocondensation offers a variety of advantages including high yields, easy experimental work-up, and the use an inexpensive, non-toxic, readily available, and recyclable catalyst <06JHC187>. R2CHO 134 R1NH2 135
O O O 133
SiO2·H2SO4 CH3CN, rt 81 - 90%
O N
HO2C
H
R1 H R2 132
R1 = Ph, 4-ClC6H4, 4-MeC6H4, PhCH2, PhCH2CH2, benzimidazole R2 = Ph, 4-ClC6H4, 4-NO2C6H4, 4-BrC6H4, 3-ClC6H4, 2-BrC6H4
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Chang et al. and Yamamoto et al. reported two notable intramolecular hydroaminations of alkynes to form tetrahydroquinolines. Chang and co-workers were able to synthesize a tetrahydroisoquinoline system using a catalytic one-pot procedure in good yield <06JA12366>. In an enantioselective approach, Yamamoto et al. have developed a palladium-catalytic intramolecular asymmetric hydroamination of alkynes using a chiral catalyst derived from Pd2(dba)3•CHCl3 and (R,R)-renorphos to form tetrahydroisoquinolines in high yield and good enantiomeric excess <06JOC4270>. 6.1.4.2 Reactions of Isoquinolines The asymmetric addition of different types of nucleophiles at the C-1 position of 3,4dihydroisoquinolines were highlighted in a number of publications. Schreiber et al. described an enantioselective addition of terminal alkynes 136 to 3,4-dihydroisoquinolinium bromide 137 in the presence of triethylamine, catalytic copper bromide, and QUINAP <06OL143>. The resulting 1-substituted tetrahydroquinolines 138 were isolated in high yield and high enantiomeric excess in most cases. OMe MeO N
MeO 137
Br
+ R1 Br
136
5 mol% CuBr, 5.5 mol% QUINAP, MeO 1 equiv Et3N, CH2Cl2, -55 °C H MeO 71 - 91% yield 94 - 99% ee
R1 = Ph, Si(Me)3, OEt, CH2OMe
OMe
* N 138
Br
R1
Two recent publications highlight the first catalytic allylation of cyclic imines. In a formal total synthesis of (-)-Emetine, Itoh et al. describe a catalytic asymmetric allylation of 3,4-dihydro-6,7-dimethoxyisoquinoline using CuCl, (R)-tol-BINAP (10 mol%) and TBAT (10 mol%) as the catalyst to achieve moderate to high yields in moderate enantiomeric excess <06OL1295>. Chong et al. detailed a general asymmetric methodology for the synthesis of 1-substituted tetrahydroquinolines 139 via an enantioselective allylation of 3,4dihydroquinolines 140 with the allylboronate 141. High yield and high ee were achieved using this method and its utility was highlighted by its application to the synthesis of various known alkaloids (crispine A, coniine•HCl, ent-corynantheidol) <06JA9646>. R1
141 N
R2 140
R1
R1, R2 = H, 92%, 95% ee R2 R1, R2 = H, 78%, 98% ee R1, R2 = OCH2O, 86%, 95% ee R1, R2 = Cl, 88%, 95% ee R1 = H, R2 = NO2, 90%, 99% ee
3,5-(CF3)2-C6H3 NH 139
O B O 141 3,5-(CF3)2-C6H3
A Pd(II)-catalyzed asymmetric addition of malonates to dihydroisoquinolines was also reported <06JA14010>. This method provides highly optically active C-1-substituted tetrahydroisoquinolines in good yields. An efficient asymmetric hydrocyanation of 6,7dimethoxy-3,4-dihydroisoquinoline to yield 1-cyano-1,2,3,4-tetrahydroisoquinoline was also described <06SL1595>. This asymmetric Strecker reaction, which utilizes Jacobsen’s thiourea-containing catalyst, resulted in high yield and high enantiomeric excess of tetrahydroisoquinolines. In another report, the enantioselective addition of vinylzinc reagents
333
Six-membered ring systems: pyridine and benzo derivatives
to 3,4-dihydroisoquinoline N-oxides were shown to produce the desired 1-substituted 1,2,3,4tetrahydroisoquinolines in good yields and high enantiomeric excess. However, to achieve these high enantiomeric excesses, 1.2 equivalents of chiral ligand must be used <06OL3979>. An asymmetric hydrogenation of isoquinolines that were first activated with chloroformates was reported by Zhou and co-workers using an [{IrCl9cod)}2]/(S)-segphos catalyst to synthesize 1,2-dihydroisoquinolines with good enantiomeric excesses <06AG(I)2260>. In another asymmetric hydrogenation, 1-substituted-3,4-dihydroisoquinolines were reduced using a water soluble ruthenium(II)complex catalyst in water with sodium formate as the hydrogen source. This environmentally friendly method resulted in high yields and high enantiomeric excess of the desired tetrahydroquinolines <06CC1766>. Kundu et al. developed a mild and efficient one-pot protocol for the synthesis of dihydroindazoloisoquinolines 142 via an unprecedented SnCl2-mediated intramolecular cyclization of nitro-aryl substrates 143 <06OL1525>. As illustrated below, the cyclization occurs via the hydroxylamines 144 and leads to the formation of dihydroindazoloisoquinolines 142 in high yield and purity. R1O
R1O R2O
R3 143 R4
1. SnCl2·H2O,PhSH, TEA, CH3CN, rt, N 15 min NO2 R1, R2 = CH3, -CH2R3 = H, CH3, OCH3 R4 = H, Cl, OCH3
R1O N OH
R2O
NH R3 144 R4
N
R2O 2. TsCl, rt 15 min 88 - 91 % 142
R3
N
R4
A one-pot procedure was developed by Bai and co-workers for the ring enlargement of αchloromethyl N-containing heterocycles <06JHC321>. Chloromethyl tetrahydroisoquinoline 145 was treated with alkylbromides and potassium carbonate in refluxing acetonitrile resulting in good yields of desired 2,3-dihydro-1H-benzo[d]azepine-5-carboxylate 146. The proposed transformation involves the formation of aziridinium salts 147 followed by bond breaking between the nitrogen and the tertiary carbon atom. EtO NH
EtO H3CO2C
Cl
RBr, K2CO3, CH3CN reflux R = Bn, 71% Allyl, 85%
145
EtO
EtO
N R N R
EtO H3CO2C 147
EtO H3CO2C 146
6.1.5 PIPERIDINES There have not been any comprehensive reviews related to piperidines published in the past year. A review on sulfur-nitrogen containing compounds such as sulfinimines (Nsulfinyl imines) and N-sulfonyloxaziridines includes the use of N-sulfinyl imines in the synthesis of di-, tri-, and tetra-substituted 4-piperidones <06JOC8993>. Another account describes chiral cyclic imide-based synthetic methodologies for the asymmetric synthesis of naturally occurring or pharmaceutically interesting hydroxylated heterocyclic derivatives including (S)-6-alkyl-5-hydroxy-2-piperidinones and 2-alkyl-3-piperidinols <06SL1133>.
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6.1.5.1 Preparation of Piperidines The application of olefin metathesis to the synthesis of piperidines continues to be widely employed. The use of ring closing metathesis (RCM) in the synthesis of fluorovinylcontaining α,β-unsaturated lactams 148 and cyclic amino acid derivatives 149 is shown below. A key improvement in these reactions is the addition of the Grubbs’ 2nd generation catalyst (G2) in small portions during the reaction to compensate for catalyst decomposition that occurs at elevated reaction temperatures <06EJO1166>. 7 mol% G2, F toluene, Bn 100 °C, 4 h R1 80% - 99% O N F R1 = H or O CH2OC(O)C(F)CH2
N Bn 148
R1
R2
N R
R N Ph
Ru Cl Cy3P
1
R
Cl
N
N R1 O 149
R2
R1 = Boc or Ts, R2 = OMe or substituted benzylamine
F
R = 2,4,6-triMePh
2.5-5 mol% G2, F toluene, 100 °C, O 30-60 min 74% - 99%
Two RCM reactions were employed in a new and efficient route to a key chiral intermediate, isoquinuclidine 150, in the synthesis of alkaloid (+)-catharanthine <06AG(I)5334>. The first RCM makes use of chiral enone 151, derived from L-serine, to generate a chiral dihydropyridinone 152. Intramolecular alkene metathesis of dialkenyl piperidine 153 generates 150, which represents the first example of the use of RCM in the generation of an azabicyclo[2.2.2]alkene system. O O O
N 151
O 10 mol% G2, CH2Cl2, reflux, 18 h 87%
O
O
N
MeO2C
O 152
O
N 153
MeO2C N 10 mol% G2, CH2Cl2, reflux, 20 h O 84%, >99% ee 150
O
Additional RCM reactions have been reported for the synthesis of piperidines and related lactams. Pearson et al. have reported the use of RCM as the key step in the generation of the piperidine ring in a synthesis of trans-3,4 iminosugars <06BMCL3262>. A RCM reaction has also been employed in the generation of fused bicyclic derivates from the octahydroquinolizine chemical class of compounds <06JMC7278>. Grubbs’ first generation Ru catalyst (G1, PhCH=RuCl2(Pcy3)2) was used in the preparation of a lactam structural analogue of the polyketide passifloricin lactone <06T4086>. Niida et al. reported the generation of diastereomeric lactams utilizing mild RCM reactions at room temperature <06JOC4118; 06OL613>. In the synthesis of cyclic β-amino esters 154 and 155, via RCM, Grubbs’ second-generation catalyst was superior, leading to lower reaction temperature and higher yields compared to those achieved with the first generation catalyst <06JOC3317>. O HN
CO2Me
5 mol% G1 or G2, CH2Cl2, 2 h O G1 (rt) = 79% G2 (rt) = 85%
O N H
BocN OMe
154
CO2Me
5 mol% G1 O or G2, CH2Cl2, 4 h N OMe G1 (reflux) = 45% Boc 155 G2 (rt) = 92%
Another form of olefin metathesis widely used for piperidine formation is ring-rearrangement metathesis (RRM), as shown below. The versatility of this reaction can be seen in its ability
335
Six-membered ring systems: pyridine and benzo derivatives
to produce piperidines from different sized cyclo-ene rings (e.g. cyclopentene 156 and cyclooctadiene 157). The RRM reaction proceeds in high conversion and with good diastereomeric ratios <06AG(I)1302>. O
O
O
2 mol% A, O
N
ethylene, rt 89%, d.r. = 5:1 156
N
PCy3 Cl Ru Cl
MeO2C
O iPr A IH2Mes Cl Ru Cl Ph Cy3P B
5 mol% B, MeO2C ethylene, Δ TsN 95%, d.r. = 14:1, trans/cis
TsN
157
A new approach to piperidines via cyclization of dienes, such as 158, employs a phosphorus hydride mediated radical addition/cyclization reaction <06JOC3656>. This reaction proceeds with complete regioselectivity to create the 6-exo-trig product 159, although as an inseparable mixture of two of the four possible diastereomers. O N O 158
O (EtO)2P(S)H, AIBN, cyclohexane, 80 °C O 75% ODPS DPS = tert-butyl diphenylsilane
P(S)(OEt)2
N
ODPS 159
Other radical cyclization approaches to the synthesis of piperidines include a CANmediated stereoselective cyclization of epoxypropyl cinnamyl amines <06TL705> and a cyclization of ¢−trimethylsilylmethylamine radical cation, generated via a photoinduced electron transfer reaction to a tethered -functionality <06JOC8481>. The scheme below depicts the novel use of a carbonyl ene cyclization (A, Lewis acidcatalyzed) and a closely related Prins cyclization (B, Brønsted acid-catalyzed) to generate predominantly trans (cyclization condition A) or cis (cyclization condition B), di and tri substituted piperidines 160 and 161 <06JOC2460; 06OBC51>. Of note, in the formation of di-substituted derivatives, R1 = H and R2 = Ph, no reaction occurs under cyclization condition B and the cis isomer 160 is obtained exclusively under cyclization condition A. In the case of tri-substituted derivatives, when bulky substituents at the 2-position (R1 = t-Bu or Ph) are present the trans diastereomer 161 is obtained almost exclusively under cyclization condition A, while no diastereoselectivity is seen under cyclization condition B. R1
Ts N R2 O
R2
A. MeAlCl2, CHCl3, 61 °C, 16 -27 h 64 - 84%, up to 2:98 cis:trans B. HCl, CH2Cl2, -78 °C, 16 h 73 - 94%, up to >98:2 cis:trans R1
R2 =
= H; H, CH3, -(CH2)n- [n=2,3,4] R1 = CH3, Bn, i-Pr; R2 = H
R1
Ts N
R1
Ts N R2
R2 OH
R2 160 - cis
OH
R2 161 - trans
Hydroamination of olefins has received considerable attention this year as a route to functionalized piperidines and spiropiperidines, particularly in regard to the investigation of new catalysts. In the synthesis of spiro-piperidines, two new mild and more general intramolecular hydroamination protocols were developed this year. One protocol uses a cationic gold-phosphine complex (Au[P(tBu)2(o-biphenyl)]Cl) as the catalyst
336
H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
<06AG(I)1747> and the other makes use of an ytterbium ate complex [Li(THF)n][Yb[(R)C20H12N2(C12H22)]2] <06JOC2514>, both generating spiro-piperidines in high yield. The utility of a new lanthanide catalyst 162 for hydroamination and hydrosilylation is highlighted below<06CC874>. Application of this new lanthanide catalyst resulted in excellent yields of piperidines such as 163 and 164 with reduced reaction times. NH2
NH2 Ph
2.2 mol% 162 60 °C, 22 h quantitative yield
2 mol% 162 100 °C, 4 h
163 N
164
Ph TMS P N N(SiHMe2)2 La N(SiHMe2)2 P N Ph 162 TMS Ph Ph 2 mol% 162 Ph
NH
Ph
PhSiH3, rt, 4 h 99% yield for 2 steps
N SiH2Ph
Chang et al. reported a mild tandem intramolecular hydroamination of yne amines to form an endo-adduct intermediate, which reacts with electron-deficient azides to produce cyclic amidines <06JA12366>. Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination <06JA8134>. H 2 mol% Pd(TFA)2, 4 mol% Xantphos + H2N R RH2N 10 mol% PhCO2H PhMe, 110 °C, 5-48 h 166
N R
PdLn
165
R = Ph, 80% R = 3-pyridyl, 41% R = Bn, 68% R = phenethyl, 72%
Hydroamination of olefins under most catalytic conditions proceed with Markovnikov addition of the N-H bond across the olefin. Shown below is a rhodium-catalyzed intramolecular, anti-Markovnikov, hydroamination developed for the synthesis of 3arylpiperidines 167 <06JA6042>. Further evaluation of this reaction as a synthesis of multisubstituted piperidines revealed that substrates with substituents α or γ to the amino group did not produce the expected piperidine, however, substrates with a substituent β to the amino group produce piperidines in high yield. 5 mol% [Rh(COD)(DPPB)]BF4,
β Ar
γ
α
NHMe
THF, 80 °C, 24 h 71 - 83%
N Ar
Ar = Ph, 4-OMePh, 3,4-OMePh, 4-FPh, 3,4-FPh
167
An interesting example of a gold-catalyzed cycloisomerization of β-aminoallene 168 to tetrahydropyridine 169 is depicted below <06OL4485>. Patil et al. report a similar goldcatalized hydroamination of allenes to produce 2-vinyl piperidine 170 in good yield <06TL4749>.
337
Six-membered ring systems: pyridine and benzo derivatives
5 mol% AuCl, 5 mol% pyridine nBu HN CH2Cl2, rt, 6 d 76%
nBu H2N 168
5 mol% AuCl, C5H11 THF, rt, 24 h 80% NHCbz
N Cbz
169
C5H11 170
Palladium-catalyzed (PdCl2(PPh3)2) decarboxylative carbonylation reactions for the formation of lactams are known to proceed under carbon monoxide at a pressure of 60 atmospheres. The scheme below highlights a new procedure utilizing a different Pd catalyst, where the formation of lactams 171 from oxazolidinones 172 takes place at atmospheric pressure <06S227>. O
O
NTs R
172
5 mol% Pd2 (dba)3 10 mol% Ph3P CO (1 atm), benzene, 60 °C, 4 h
R
R = i-Pr, 74% R = Ph, 77% R = Bn, 75% R = CH2OTBDMS, 71%
TsN O 171
A report on a regiospecific 6-exo radical cyclization for the generation of lactams 173 highlights a remarkable halogen-substitution effect on the direct reactions of unsaturated N-H amides on vinylic halogen substituents <06OL2647>. O X
NH2
O
Pb (OAc)4 / I2, CH2Cl2, rt hv, 4 h, 70 - 89% X = Cl, Br, I
I
H N
X 173
The following two schemes exemplify the synthesis of piperidines via 1,4-addition of amines. In the first scheme below, a one-pot Stille coupling/double Michael addition, starting from readily available vinyl stannanes, is used to generate piperidinones 174 <06SL547>. An example of the reduction of piperidinone 174 to piperidine 175 is also highlighted. R3
0.5 mol% [allylPdCl]2
R2-NH2, THF 60 °C, 2 h COCl 52 - 70% R3 R1 2 1 R = Me, Ph R = CH2CO2t-Bu, CH2Ph, CH2CH=CH2
Bu3Sn
R1
O 1 mol% PPh3 THF, 60 °C, 3 h
N
R2
R1
HO NaBH4, i-PrOH H2O, rt, 1 d
N
R2
3
R 174 175 R3 = NHPhth, CH(NHTFA)CO2t-Bu
An interesting synthesis of enantiopure cis-decahydroquinolines, which involves enol ether hydrolysis, double bond isomerization, and intramolecular 1,4-addition of an amino group across a cyclohexenone has been reported <06T9166>. The process is stereoselective, with the exclusive formation of both cis-isomers 176 (43% over 3 steps) and 177 (17% over 3 steps) of the decahydroquinoline ring. OH
OH O
Bn2N
O
H2N
H 2N HCl 70 °C, 3.5 h
O
N H H
H
OH 176 O
OH 177
N H H
Other routes to piperidines involving 1,4-addition reactions include the incorporation of a Michael addition reaction as the piperidine ring formation step in the total synthesis of Histrionicotoxin <06JA12656> and the use of an intramolecular 1,4-addition, 6-endo-dig ring
338
H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
closure of a nonattenuated amine into a pendant ynone in excellent yields, as demonstrated in the synthesis of enaminones <06JA8702>. Bargiggia and Murray reported a novel double 1,4-addition of hydroxylamine to a bis ¢,£-unsaturated diester to afford predominantly the cis isomer of a N-hydroxypiperidine <06TL3191>. Another route to the formation of piperidine heterocycles is cyclization via reductive amination utilizing various hydride sources. The scheme below depicts a bis reductive amination, using sodium triacetoxyborohydride as the hydride source, to generate exo-178 and endo-179 azabicyclo[3.2.1]octane amino acids in moderate yields <06JOC8467>. RO2C OHC
OHC
NHCOMe
RO2C MeOCHN
CHO p-methoxybenzylamine, NaBH(OAc)3, AcOH (cat.), CHO ClCH2CH2Cl, 25 °C CO2R NHCOMe
HN
R = Me; (±)-(1S*,5S*,6S*)-exo-178; 61% R = (-)-8-Phenylmenthyl; (-)-(1S, 5S,6S)-exo-178; 57%
178 NH NHCOMe R = Me; (±)-(1R*,5R*,6S*)-endo-179; 53% CO2R R = (-)-8-Phenylmenthyl; (-)-(1R, 5R,6S)-endo-179; 58% 179
Gheorghe et al. make use of sodium cyanoborohydride as a hydride source in the synthesis of 5-arylpiperidines <06OL1653>. Kellehar and Kelly report the formation of a spiro ¥-lactam using sodium borohydride in the key reductive amination step <06TL3005>. A number of reports have been published this year that describe the use of hydrogenation over various catalysts as a process to generate the source of hydride ion in reductive amination. Palladium catalysts used in these types of synthesis of various piperidines include Pd/C <06SL487; 06H2129>, Pd/CaCO3 <06OL1569>, and Pd(OH)2 <06T9942>. Reductive amination can also be performed via hydrogenation in the absence of catalyst, as reported by Calderón et al. <06JOC6258>. Finally, a one-pot hydroformylation reductive amination sequence was reported using a rhodium catalyst (HRh(CO)(PPh3)3) and XANTPHOS under microwave irradiation conditions to form cyclic enamides in good yields <06OL3725>. Nucleophilic displacement of leaving groups, such as mesylates, tosylates, triflates, or halogens, as well as nucleophilic ring opening of epoxides, cyclic sulfates, cyclic hemiacetals, or lactones is still a common route to piperidine cores. Nucleophilic displacement of mesylates, tosylates, or triflates have been used to generate diverse piperidine containing cores such as imidazolo[1,2-a]-L-arabino-piperidinoses <06EJO610>, (S)-3-hydroxypiperidin-2-one <06T7459>, trans-4-hydroxypipecolic acids <06EJO3235>, 2,3-disubstituted piperidines <06OL4051>, 2,3,4,5-substituted piperidines <06JMC2989>, a bicyclic diamine <06TL2581>, iminosugars <06S2242>, bicyclic iminosugars <06S827>, and a 2'-deoxy-2'-N,4'-C-ethylene-bridged nucleoside <06JA15173>, generally in excellent yields. An interesting variation on nucleophilic displacement of halogens includes the use of Nsulfinylamide 180 to generate optically pure 2-(1-hydroxybenzyl)piperidine 181 <06S687>.
TolOS
Cl TolOS 1. LDA, THF, NH -78 °C 2. -78 °C to rt, 16 h O OTIPS OTIPS TolOS N S Tol ( ) Cl 3 180
TolOS
H
N 2 steps TolOS
OTIPS 66%
N
Ph OH 181
339
Six-membered ring systems: pyridine and benzo derivatives
An effort to improve the efficiency of the nucleophilic displacement of halogens in a cyclocondensation reaction of primary amines with alkyl dihalides for the synthesis of Nphenylpiperidine through the use of microwave irradiation (80-100 W, 120 °C, 20 min, 96% yield) was reported this year <06JOC135>. Stereocontrolled nucleophilic opening at the C1-position of epoxides to furnish substituted piperidine 182 was accomplished through the use of Lewis acids TMSOTf or Sc(OTf)3 <06CC2156>. Ts
O Ph
H N
TMSOTf, DCM, rt, 2 d, 98% or Sc(OTf)3, DCM, rt, 3 d, 92%
Ts N
182 OH
Ph
The synthesis of enantiomerically pure D-manno and L-gluco iminosugars 183 and 184, respectively, was achieved via reduction of an isoxazoline to an amine, which subsequently acts as a nucleophile in a spontaneous opening of the cyclic sulfate moiety <06JOC894>. O N
O O S O O
1. H2, Pd/C, Na2CO3, MeOH, rt, HO 5 h, 77% OBn 2. H2O, H2SO4, dioxane, 40 °C, HO 36 h, 93%
OBn NH 183
HO HO
OBn NH 184
The scheme below depicts a reduction of an azide on a sugar moiety followed by nucleophilic ring opening of the sugar to obtain either an aza-sugar piperidine 185 <06TA2006> or an aza-sugar lactam 186 <06HCA635>. HO
HO 1. TFA, H2O, 40 °C, 2 h O 2. H2, PtO2, 20 bar, rt, 12 h O 3. H2, Pd/C, HO O 5 bar, rt, 24 h 80%
N3 H BnO
H H N
EtO2C H OH
N3 O
BnO
OH 185
1. H2 (1 bar), EtO2C O 10% Pd/CaCO3, EtOH, 4 h HO 2. N2, 12 h OBn 65%
H N
O OBn
OBn 186
Other examples of nucleophilic ring opening of a sugar to generate an aza-sugar piperidine include the synthesis of 1-deoxy-homonojirimycin analogues <06OBC3675> and 1-deoxynojirimycin <06S1035>. Likewise, Kikuchi et al. report the nucleophilic opening of a cyclic hemiacetal to generate a 2,3-substituted piperidine <06JMC4698>. Amide bond formation as a route to piperidine lactams continues to be widely employed. Formation of the amide bond can be effected through the use of coupling reagents such as dicyclohexylcarbodiimide/4-pyrrolidinopyridine <06TL5317>, N-hydroxysuccinimide/EDCI <06T10815>, or by direct cyclization of an amine on a methyl or ethyl ester <06T4011; 06CC674; 06TL2257; 06TL8667; 06BMCL417; 06T4907; 06AG(I)1722; 06T8731; 06BMC2620>. Bicyclic lactam 187 was generated via a Staudinger reaction to reduce the azide, followed by thermal cyclization of the amine on the ester <06SL271>. EtO2C OTBS
1. PH3P, H2O, 1,4-dioxane, reflux, 40 h 2. xylene, reflux, 6 h, 95%
N3 Ph
O 187 OTBS
HN Ph
340
H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
Intermolecular or intramolecular cyclizations via alkylation of an enolate with a large variety of electrophiles continues to have widespread usage. One form of these cyclizations involves displacement of a halogen or mesylate. Pu and Ma have reported the use of alkylative cyclization involving displacement of an iodide under mild conditions to generate a bicyclic enone in excellent yield <06JOC6562>. Kropf et al. report an intramolecular cyclization involving alkylation of an enolate, an ¢-/¢'-unsubstituted cyclohexanone, and a tethered 4-alkyl electrophile to form bicyclo[3.3.1]nonane ring systems in good yields <06JOC2046>. Double intermolecular alkylation with a dibromide on methyl cyanoacetate or a bis-mesylate on indene was used to generate the piperidine core of ¢,¢-cyclic-£aminohydroxamic acids <06BMCL2699> or spiropiperidine fused indenes <06JMC4801>, respectively. Other electrophiles used in intramolecular cyclizations with enolates include esters and alkenes. Esters were utilized in the generation of 5,6-dihydro-4-hydroxy-2pyridones <06H555> and £-keto lactams via Dieckmann condensation <06JOC4969>. Hanessian et al. report anion cyclization onto a terminal alkene and the formation of a chain extended piperidine through concomitant trapping with allylbromide <06JMC4544>. Intramolecular Mannich reactions have been used in the synthesis of piperidines. An intramolecular Mannich-type reaction was used as the key step in a highly diastereoselective and concise preparation of novel trifluoro-substituted analogues of di- and trisubstituted piperidine alkaloids <06EJO3421>. In the scheme below, an intramolecular Mannich reaction is shown as the key step in the asymmetric synthesis of the 2,3,6-trisubstituted piperidine core 188 of the antitumor Nuphar alkaloids <06JOC4222>. O N O O
TsOH•H2O, benzene, 60 °C, 6 h 76%
188 O
N H
N O
The application of [4+2] cycloaddition reactions for the synthesis of piperidines has received a considerable amount of attention this year. Palacios et al. have reported the hetero-Diels–Alder reaction of 3-azatrienes with enamine pyrrolidinecyclohexanone affording hexahydroisoquinolines in 42% yield <06T7661>. Denmark and Montgomery reported the first [4+2] cycloaddition of an N-vinyl nitrone with a tethered dienophile providing a somewhat unstable tetrahydropyridine N-oxide in 86% yield <06JOC6211>. Another interesting route to a tetrahydropyridine core enlisted an inverse electron demand Diels–Alder reaction of an electron-deficient N-sulfonyl-1-azabutadiene with an electron-rich dienophile <06JA11799>. A number of aza Diels–Alder reactions using imines as azadienes have been reported. Alves et al. reacted 3-(3-(tert-butyl-dimethylsilyloxy)buta-1,3-dienyl)oxazolidin-2-one with 2Hazirines at room temperature for 4-5 days with no catalyst to obtain cycloadducts in moderate to good yield <06T3095>. Venkatraman et al. reported the hetero Diels–Alder reaction of a chiral imine with cyclopentadiene, using catalytic BF3•O(C2H5)2, generating an azabicyclo[2.2.1]heptene derivative <06BMCL1628>. A [4+2] cycloaddition was used in the synthesis of piperidones via a Yb(OTf)3 catalysed reaction of an imine with Danishefsky’s diene <06BMC5955>. Boglio et al. reported an improved catalyst, a weaker POM-Yb Lewis acid (TBA5H2[¢1-YbP2W17O61]) <06AG(I)3324>. An aza Diels–Alder reaction of optically active sulfinimines with the Rawal diene and catalyzed by TMSOTf is reported to lead to enantiomerically enriched dihydropyridones with enantiomeric excesses up to 90% <06TA1420>. Dandapani et al. reported a scandium triflate-catalyzed [4+2] aza-annulation
341
Six-membered ring systems: pyridine and benzo derivatives
in the synthesis of pipecolates <06JOC8934>. Takasu et al. studied the synthesis of substituted piperidin-4-ones 189 via an imino Diels–Alder reaction catalyzed by triflic imide. They then expanded this reaction to a one-pot multicomponent reaction of 2-siloxy-1,3butadiene 190 with in situ generated aldimines as depicted below <06T11900>. TBSO
R2 NH2
2 mol% Tf2NH, MS 4Å, CH2Cl2, 0 °C, 4 h
O 190 Ph
R1
R1
TBSO N
189
R2
R1 = Ph, R2 = Ph, 78%, trans-cis (80:20) R1 = Bn, R2 = Ph, 74%, trans-cis (80:20) R1 = Bn, R2 = iPr, 16%
Ph
Other multicomponent reactions are exemplified in the following two schemes. A new highly diastereoselective four-component reaction was developed for the synthesis of dihydropyridones 191 substituted with an isocyanide functionality <06OL5369>, thereby generating a synthetically useful complex isocyanide for use in further reactions. In this strategy, a phosphonate, a nitrile, and an aldehyde are used to generate an azadiene intermediate 192, which is trapped by an isocyanoacetate in the same pot. R2
O EtO P EtO R1 2
R
n-BuLi, THF CN -78 °C to rt, 5 h CHO
MeO2C R1
R2
R3
N
R1 = Ph, i-Pr, 2-furan R3 2 = aromatic, R NC heteroaromatic, and α,βO unsaturated aldehydes N H R3 = H, Ph, p-chlorophenyl 191
NC R1
32 - 98%
192
Raja and Perumal reported the synthesis of novel 2,6-diaryl-3-(arylthio)piperidin-4-ones via a four-component reaction consisting of arylthioacetones, 2-substituted aromatic aldehydes and methylamine or ammonium acetate <06CPB795>. Further elaboration of this four component reaction to a novel five component tandem Mannich-enamine-substitution sequence involving the reaction of ethyl 2-[(2-oxopropyl)sulfanyl]acetate, two equivalents of a substituted aromatic aldehyde, and two equivalents of ammonium acetate is shown below <06T4892>. When this five-component tandem reaction involves para-substituted benzaldehydes, the cis (193) and trans (194) diastereomers of thiazones are obtained. Alternatively, ortho-substituted benzaldehydes form only the trans (194) diastereomer along with an air-oxidized product 195. O
O
O S
O 2 NH4OAc
HN
EtOH, rt, 5-7 d 42 - 74%
2 Ar CHO Ar = Ph, p-Cl-Ph, p-CH3-Ph, p-F-Ph, oCl-Ph, o-CH3-Ph, o-OCH3-Ph
N H 193
HN
HN S
Ar
O
O
Ar
S
S Ar
N H 194
Ar
Ar
N H 195
Ar
Another frequently used method for preparing piperidines is via reduction of the corresponding pyridine. These reductions can be accomplished through catalytic hydrogenation with platinium(IV) oxide <06JMC4116; 06BMCL395; 06BC248; 06TL1729>. Chong et al. reported the use of rhodium on alumina to generate enantiomerically pure cis-2,6-piperidinedicarboxylic acid from the corresponding 2,6pyridinedicarboxylic acid <06JMC2055>. Ohigashi reported an improved reduction of 3cyanopyridine to its tetrahydropyridine derivative utilizing a NaBH4-ethanol reduction system <06OPRD159>.
342
H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
The conversion of pyridines to their tetrahydropyridine or pyridinone derivatives is frequently accomplished via a pyridinium salt intermediate. Bennasar et al. reported the use of a Grignard reaction to generate a pyridinium salt, followed by reduction with NaBH4 producing a substituted tetrahydropyridine in excellent yield <06JOC1746>. The Grignard reaction of a 4-methoxypyridinium salt, followed by acidic hydrolysis of the intermediate methyl enol ethers, to generate pyridinone derivatives has been reported in three separate instances <06OL2985; 06OBC1071; 06AG(I)932>. Bräckow and Wanner reported the conversion of 4-substituted pyridines to their corresponding 4,4-disubstituted piperidines by trapping 4-substituted N-silylpyridinium ions with dialkylmagnesium reagents, followed by NaCNBH3 reduction <06T2395>. Xu et al. reported a regio- and diastereoselective double dinucleophilic addition of bis(OTMS) ketene acetals to pyridine to generate lactones <06TL4541; 06TL4553>. The remaining section highlights various other methods of generating piperidine cores. The scheme below depicts a simple route to piperidines heterocycles, such as 196, via an intramolecular Horner–Emmons cyclization of phosphonate 197 <06JA12743>. O (EtO)2P 197
O
O N H Ph
Ph
Ph
MeONa, MeOH rt, 16 h 61%
O HN
Ph 196
Thompson et al. reported the use of a [3+2] cycloaddition reaction on an N-alkyl pyridine salt to generate an azabicyclic core with varied substitution on the bridge <06BMCL811>. A remarkable four-step, one-pot reaction, starting from azide building block 198 and utilizing a Horner–Wadsworth–Emmons [3+2]-1,3-dipolar cycloaddition cascade to generate the pivotal piperidine core 199 in an expeditious stereoselective synthesis of (−)-Cassine 200, is shown in the scheme below <06OBC524>. O O O
O
O 1. CH3CN, DIPEA, P rt, 3 d OEt n OEt 2. Rh2(OAc)4, rt, n = 7 OAc 12 h, 74% N3
OAc
O N H
nO
O
O
198
OH
199 n = 7
n
N H 200 n = 9
An elegant synthesis of the spiroaminal containing domain of azaspiracids 201 makes use of a Staudinger-aza-Wittig reaction in a cascade sequence to generate the spiroaminal 202 <06T5338; 06JA15114>. N3 O O TES O TBS
Et3P, PhH rt, 6 h 75%
HO TES
O
O
OO N R
TBS
N H TES 202
TES
O 201
R'
Reggelin et al. reported the application of methylated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines 203 for the synthesis of highly substituted aza(poly)cyclic ring systems 204 under complete stereocontrol <06JA4023; 06S2224>.
343
Six-membered ring systems: pyridine and benzo derivatives
O S N
1. n-BuLi, -78 °C 2. ClTi(Oi-Pr)3, -78 °C to 0 °C 3. 205, toluene, 0 °C H OTBS O NPhth 205
H
OH
H
OH
hydrazine NPhth -78 °C to rt S1a
S1a
203
N H 204
A novel route to 3,4-disubstituted piperidines 206 via ring transformation of 2(haloalkyl)azetidines 207 is shown below. During these reactions, bicyclic azetidinium intermediates are formed and then ring opened by a variety of nucleophiles generating stereospecific substituted piperidines in excellent yields <06OL1105>. Br
R2O N 1 207 R
CH3CN, Δ, 3h
R2 O
H N R1
OH R2 O N 206 R1
Other routes to piperidines, lactams, and piperidine diones include the conjugate addition of 1,2-ethanedithiol onto a 1,5-amino-ynal, followed by cyclization to a piperidine aminal <06JOC2715>. Calvet-Vitale et al. reported the formation of new N-substituted ȕ-enamino ester piperidines featuring an exocyclic tetrasubstituted double bond through the intramolecular cyclization of linear amino-ȕ-keto-esters <06JOC2071>. A biomimetic approach to the pentacyclic substructures of indole alkaloids perophoramidine and communesin has been reported. This approach proceeds via intramolecular cyclopropanation followed by nucleophilic ring opening of the resulting activated cyclopropane ring, with an in situ generated aniline, to form both the tetrahydropyridine and lactam rings of the pentacyclic substructure <06OL2187>. Amat and co-workers reported the cyclocondensation of (R)phenylglycinol with racemic methyl 4-formylhexanoate stereoselectively affording a bicyclic cis-lactam derivative in good yield <06TA1581>. Chen et al. reported a [3+3] annulation of α-sulfonyl acetamide with α,β-unsaturated esters in the synthesis of bicyclic glutarimides <06OL3033>. Lastly, Ge et al. made use of a condensation of a protected amino acid with bromoacrylamide to generate a piperidine dione intermediate <06EJO4106>.
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H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
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Six-membered ring systems: pyridine and benzo derivatives
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350 06OPRD159 06PAC1357 06S227 06S243 06S435 06S451 06S687 06S827 06S1035 06S1141 06S1283 06S1295 06S1664 06S1971 06S2085 06S2224 06S2242 06S2551 06S2580 06S2585 06S2777 06S2855 06S2873 06S2934 06SC77 06SC97 06SC665 06SC1521 06SC1549 06SC1721 06SL53 06SL271 06SL395 06SL487 06SL547 06SL1071 06SL1133 06SL1437 06SL1595 06SL1903 06SL2083 06SL2716 06T968 06T1095 06T2395 06T2465 06T2492 06T2799 06T3095 06T3959 06T4011 06T4071 06T4086 06T4128 06T4756
H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
A. Ohigashi, K. Temmaru, N. Hashimoto, Org. Process Res. Dev. 2006, 10, 159. Y.N. Bubnov, N.Y. Kuznetsov, M.E. Gurskii, A.L. Semenova, G.D. Kolomnikova, T.V. Potapova, Pure Appl. Chem. 2006, 78, 1357. J.G. Knight, I.M. Lawson, C.N. Johnson, Synthesis 2006, 227. Y. Iso, A.P. Kozikowski, Synthesis 2006, 243. H. Sheibani, M.H. Mosslemin, s. Behzadi, M.R. Islami, K. Saidi, Synthesis 2006, 3, 435. J.S. Yadav, B.V.S. Reddy, A.K. Basak, G. Baishya, A.V. Narsaiah, Synthesis 2006, 451. J.L.G. Ruano, J. Aleman, M.B. Cid, Synthesis 2006, 687. P. Maier, S.M. Andersen, I. Lundt, Synthesis 2006, 827. A. Roy, B. Achari, S.B. Mandal, Synthesis 2006, 1035. U.B. Vasconcelos, A.A. Merlo, Synthesis 2006, 1141. M.C. Bagley, M.C. Lubinu, Synthesis 2006, 1283. L.J. Nurkkala, R.O. Steen, S.J. Dunne, Synthesis 2006, 1295. J. Boivin, F. Carpentier, R. Jrad, Synthesis 2006, 1664. M.M. Blanco, M.S. Shmidt, C.B. Schapira, I.A. Perillo, Synthesis 2006, 12, 1971. U. Wittmann, F. Tranel, R. Froehlich, G. Haufe, Synthesis 2006, 2085. M. Reggelin, J. Kuehl, J.P. Kaiser, P. Buehle, Synthesis 2006, 2224. Y.-L. Chen, R. Leguijt, H. Redlich, Synthesis 2006, 2242. T. Emmrich, H. Reinke, P. Langer, Synthesis 2006, 2551. C. Timm, M. Koeck, Synthesis 2006, 2580. O. Johansson, Synthesis 2006, 2585. C. Castera-Ducros, M.D. Crozet, P. Vanelle, Synthesis 2006, 2777. D. Blachut, Z. Czarnocki, K. Wojtasiewicz, Synthesis 2006, 2855. A. Winter, A.M.J. van den Berg, R. Hoogenboom, G. Kickelbick, U.S. Schubert, Synthesis 2006, 2873. K. Kobayashi, K. Hayashi, K. Miyamoto, O. Morikawa, H. Konishi, Synthesis 2006, 17, 2934. M. Heravi, F. Derikvand, H. Oskooie, R. Hekmat Shoar, Synth. Commun. 2006, 36, 77. A. Abdelhamid, A. Al-Atoom, Synth. Commun. 2006, 36, 97. E. Rajanarendar, P. Ramesh, M. Srinivas, K. Ramu, G. Mohan, Synth. Commun. 2006, 36, 665. B.C. Hong, M. Hallur, J.H. Liao, Synth. Commun. 2006, 36, 1521. A. Zheng, W. Zhang, J. Pan, Synth. Commun. 2006, 36, 1549. M. Cooke, J. Wang, I. Theobald, G. Hanan, Synth. Commun. 2006, 36, 1721. T. Cailly, F. Fabis, A. Bouillon, S. Lemaitre, J. Sopkova, O. de Santos, S. Rault, Synlett 2006, 53. P. Raubo, J.J. Kulagowski, G.G. Chicchi, Synlett 2006, 271. A. Saini, S. Kumar, J.S. Sandhu, Synlett 2006, 395. P. Dewi-Wuelfing, J. Gebauer, S. Blechert, Synlett 2006, 487. S. Doerrenbaecher, U. Kazmaier, S. Ruf, Synlett 2006, 547. M. Rueping, T. Theissmann, A.P. Antonchick, Synlett 2006, 7, 1071. P.Q. Huang, Synlett 2006, 1133. N. Nishiwaki, T. Nishimoto, M. Tamura, M. Ariga, Synlett 2006, 1437. T. Kanemitsu, Y. Yamashita, K. Nagata, T. Itoh, Synlett 2006, 10, 1595. N. de la Rifuera, S. Fiol, J.-C. Fernándex, P. Forns, D. Fernándex-Forner, F. Albericio, Synlett 2006, 12, 1903. J.P. Scott, Synlett 2006, 2083. M.E. Popkin, R.K. Bellingham, J.F. Hayes, Synlett 2006, 2716. R. Hrdina, I.G. Stara, L. Dufkova, S. Mitchel, I. Cisarova, M. Kotora, Tetrahedron 2006, 62, 968. F. Palacios, D. Aparicio, Y. Lopez, J.M. de los Santos, J.M. Ezpeleta, Tetrahedron 2006, 62, 1095. J. Brackow, K.T. Wanner, Tetrahedron 2006, 62, 2395. Y. Luo, H. Gao, Y. Li, W. Huang, W. Lu, Z. Zhang, Tetrahedron 2006, 62, 2465. B. Han, Z. Liu, Q. Liu, L. Yang, Z.-L. Liu, W. Yu, Tetrahedron 2006, 62, 2492. A. Herrera, R. Martinez-Alvarez, M. Chioua, R. Chatt, R. Chioua, A. Sanchez, J. Almy, Tetrahedron 2006, 62, 2799. M.J. Alves, A.G. Fortes, F.T. Costa, Tetrahedron 2006, 62, 3095. T. Brunin, L. Legentil, J.-P. Henichart, B. Rigo, Tetrahedron 2006, 62, 3959. R.K. Singh, S. Jain, N. Sinha, A. Mehta, F. Naqvi, N. Anand, Tetrahedron 2006, 62, 4011. Z. Su, C. Hu, S. Qin, X. Feng, Tetrahedron 2006, 62, 4071. W. Cardona, W. Quinones, S. Robledo, I.D. Velez, J. Murga, J. Garcia-Fortanet, M. Carda, D. Cardona, F. Echeverri, Tetrahedron 2006, 62, 4086. N. Kanomata, S. Yamada, T. Ohhama, A. Fusano, Y. Ochiai, J. Oikawa, M. Yamaguchi, F. Sudo, Tetrahedron 2006, 62, 4128. X. Lv, Z. Wang, W. Bao, Tetrahedron 2006, 62, 4756.
Six-membered ring systems: pyridine and benzo derivatives
06T4892 06T4907 06T5338 06T5454 06T5736 06T5862 06T6222 06T6398 06T6945 06T7266 06T7459 06T7661 06T7817 06T8398 06T8731 06T8740 06T9166 06T9365 06T9650 06T9942 06T10815 06T11063 06T11483 06T11734 06T11900 06TA12 06TA687 06TA1420 06TA1581 06TA2006 06TL553 06TL705 06TL813 06TL837 06TL869 06TL1059 06TL1261 06TL1729 06TL2161 06TL2257 06TL2337 06TL2395 06TL2399 06TL2581 06TL2691 06TL2725 06TL3005 06TL3127 06TL3191 06TL3225 06TL3471 06TL3489
351
V.P.A. Raja, S. Perumal, Tetrahedron 2006, 62, 4892. A.S. Paraskar, A. Sudalai, Tetrahedron 2006, 62, 4907. S. Nguyen, J. Xu, C.J. Forsyth, Tetrahedron 2006, 62, 5338. M.D. Fletcher, T.E. Hurst, T.J. Miles, C.J. Moody, Tetrahedron 2006, 62, 5454. T.M. Lipinska, Tetrahedron 2006, 62, 5736. T. Cailly, F. Fabis, S. Rault, Tetrahedron 2006, 62, 5862. M.G. Ferlin, V.B. Di Marco, A. Dean, Tetrahedron 2006, 62, 6222. A. Hamid, H. Oulyadi, A. Daiech, Tetrahedron 2006, 62, 6398. W.T. McElroy, P. DeShong, Tetrahedron 2006, 62, 6945. Z.M. Zhao, P.S. Mariano, Tetrahedron 2006, 62, 7266. C.-G. Feng, J. Chen, J.-L. Ye, Y.-P. Ruan, X. Zheng, P.-Q. Huang, Tetrahedron 2006, 62, 7459. F. Palacios, E. Herran, C. Alonso, G. Rubiales, Tetrahedron 2006, 62, 7661. F. Jara, M. Dominguez, M.C. Rezende, Tetrahedron 2006, 62, 7817. B. Gangadasu, P. Narender, S.B. Kumar, M. Ravinder, B.A. Rao, C. Ramesh, B.C. Raju, V.J. Rao, Tetrahedron 2006, 62, 8398. V. Singh, G.P. Yadav, P.R. Maulik, S. Batra, Tetrahedron 2006, 62, 8731. S. Madapa, V. Singh, S. Batra, Tetrahedron 2006, 62, 8740. M. Mena, N. Valls, M. Borregan, J. Bonjoch, Tetrahedron 2006, 62, 9166. F.-T. Luo, V.K. Ravi, C. Xue, Tetrahedron 2006, 62, 9365. A.C. Fernandes, C.C. Romao, Tetrahedron 2006, 62, 9650. S.R.V. Kandula, P. Kumar, Tetrahedron 2006, 62, 9942. A.-L. Johnson, J. Bergman, Tetrahedron 2006, 62, 10815. C. Sicre, J.L. Alonso-Gomez, M.M. Cid, Tetrahedron 2006, 62, 11063. D. Kalyani, A.R. Dick, W.Q. Anani, M.S. Sanford, Tetrahedron 2006, 62, 11483. A.S. Voisin, A. Bouillon, I. Berenguer, J.-C. Lancelot, A. Lesnard, S. Rault, Tetrahedron 2006, 62, 11734. K. Takasu, N. Shindoh, H. Tokuyama, M. Ihara, Tetrahedron 2006, 62, 11900. C. Sanfilippo, N. D'Antona, G. Nicolosi, Tetrahedron Asymmetry 2006, 17, 12. S.E. Denmark, F. Yu, Tetrahedron Asymmetry 2006, 17, 687. R. Kawecki, Tetrahedron Asymmetry 2006, 17, 1420. M. Amat, C. Escolano, A. Gomez-Esque, O. Lozano, N. Llor, R. Griera, E. Molins, J. Bosch, Tetrahedron Asymmetry 2006, 17, 1581. G. Le Bouc, C. Thomassigny, C. Greck, Tetrahedron Asymmetry 2006, 17, 2006. J. Ward, V. Caprio, Tetrahedron Lett. 2006, 47, 553. V. Nair, K. Mohanan, T.D. Suja, E. Suresh, Tetrahedron Lett. 2006, 47, 705. D.S. Bose, R.K. Kumar, Tetrahedron Lett. 2006, 47, 813. A. Kumar, S. Koul, T.K. Razdan, K.K. Kapoor, Tetrahedron Lett. 2006, 47, 837. D.N. Kozhevnikov, V.N. Kozhevnikov, A.M. Prokhorov, M.M. Ustinova, V.L. Rusinov, O.N. Chupakhin, G.G. Aleksandrov, B. Koenig, Tetrahedron Lett. 2006, 47, 869. G.-W. Wang, C.-S. Jia, Y.-W. Dong, Tetrahedron Lett. 2006, 47, 1059. N. Sakai, D. Aoki, T. Hamajima, T. Konakahara, Tetrahedron Lett. 2006, 47, 1261. O. Dirat, A. Clipson, J.M. Elliott, S. Garrett, A. Brian Jones, M. Reader, D. Shaw, Tetrahedron Lett. 2006, 47, 1729. B. Zhong, R.S. Al-Away, C.Shih, J.H. Grimes Jr., M. Vieth, C. Hamdouchi, Tetrahedron Lett. 2006, 47, 2161. A. Mitchinson, W.P. Blackaby, S. Bourrain, R.W. Carling, R.T. Lewis, Tetrahedron Lett. 2006, 47, 2257. V. Mamane, Y. Fort, Tetrahedron Lett. 2006, 47, 2337. A. Rivkin, B. Adams, Tetrahedron Lett. 2006, 47, 2395. M. Trilla, R. Pleixats, M.W.C. Man, C. Bied, J.J.E. Moreau, Tetrahedron Lett. 2006, 47, 2399. F.H.V. Chau, E.J. Corey, Tetrahedron Lett. 2006, 47, 2581. A.D. Averin, O.A. Ulanovskaya, A.A. Borisenko, M.V. Serebryakova, I.P. Beletskaya, Tetrahedron Lett. 2006, 47, 2691. N. Ahmed, J.E. van Lier, Tetrahedron Lett. 2006, 47, 2725. F. Kelleher, S. Kelly, Tetrahedron Lett. 2006, 47, 3005. X.-F. Lin, S.-L. Cui, Y.-G. Wang, Tetrahedron Lett. 2006, 47, 3127. F.C. Bargiggia, W.V. Murray, Tetrahedron Lett. 2006, 47, 3191. X. Beebe, V. Gracias, S.W. Djuric, Tetrahedron Lett. 2006, 47, 3225. P. Gavina, S. Tatay, Tetrahedron Lett. 2006, 47, 3471. Y. Yoshimura, J. Inoue, N. Yamazaki, S. Aoyagi, C. Kibayashi, Tetrahedron Lett. 2006, 47, 3489.
352 06TL3545 06TL3589 06TL4365 06TL4541 06TL4553 06TL4749 06TL5079 06TL5147 06TL5317 06TL5333 06TL5503 06TL6011 06TL6183 06TL7025 06TL7191 06TL8343 06TL8667 06TL8917
H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie
B. Han, X.-D. Jia, Z.-L. Jin, Y.-L. Zhou, L. Yang, Z.-L. Liu, W. Yu, Tetrahedron Lett. 2006, 47, 3545. B. Savitha, P.T. Perumal, Tetrahedron Lett. 2006, 47, 3589. T. Nemoto, T. fukuda, Y. Hamada, Tetrahedron Lett. 2006, 47, 4365. Y. Xu, H. Rudler, B. Denise, A. Parlier, P. Chaquin, P. Herson, Tetrahedron Lett. 2006, 47, 4541. Y. Xu, E. Aldeco-Perez, H. Rudler, A. Parlier, C. Alvarez, Tetrahedron Lett. 2006, 47, 4553. N.T. Patil, L.M. Lutete, N. Nishina, Y. Yamamoto, Tetrahedron Lett. 2006, 47, 4749. J.-D. Cheon, T. Mutai, K. Araki, Tetrahedron Lett. 2006, 47, 5079. K. Mitsudo, W. Matsuda, S. Miyahara, H. Tanaka, Tetrahedron Lett. 2006, 47, 5147. J.M. Andres, R. Pedrosa, A. Perez-Encabo, Tetrahedron Lett. 2006, 47, 5317. P.S. Humphries, S. Bailey, Q.Q.T. Do, J.H. Kellum, G.A. McClellan, D.M. Wilhite, Tetrahedron Lett. 2006, 47, 5333. M.D. Sanchez-Salvatori, A. Lopez-Giral, K. Ben Abdejelil, C. Marazano, Tetrahedron Lett. 2006, 47, 5503. V.S.C. Yeh, P.E. Wiedeman, Tetrahedron Lett. 2006, 47, 6011. S. Hosokawa, S. Kuroda, K. Imamura, K. Tatsuta, Tetrahedron Lett. 2006, 47, 6183. D.N. Kozhevnikov, O.V. Shabunina, D.S. Kopchuk, P.A. Slepukhin, V.N. Kozhevnikov, Tetrahedron Lett. 2006, 47, 7025. W.Chen, B. Liu, C. Yang, Y. Xie, Tetrahedron Lett. 2006, 47, 7191. A. Sanchez, A. Nunez, C. Burgos, J. Alvarez-Builla, Tetrahedron Lett. 2006, 47, 8343. Y.D.V. K. Jayakanthan, Tetrahedron Lett. 2006, 47, 8667. M.-Y. Jang, S. De Jonghe, L.-J. Gao, P. Herdewijn, Tetrahedron Lett. 2006, 47, 8917.
353
Chapter 6.2 (2005)
Six-membered ring systems: diazines and benzo derivatives (2005) Michael P. Groziak California State University East Bay, Hayward, CA, USA
[email protected]
__________________________________________________________________________
6.2.1 INTRODUCTION The diazines pyridazine, pyrimidine, pyrazine, and their benzo derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine once again played a central role in many investigations. Progress was made on the syntheses and reactions of these heterocycles, and their use as intermediates toward broader goals. Some studies relied on solid-phase, microwave irradiation, or metal-assisted synthetic approaches, while others focused attention more on the X-ray, computational, spectroscopic, and natural product and other biological aspects of these heterocycles. Reports with a common flavor have been grouped together whenever possible.
6.2.2 REVIEWS AND GENERAL STUDIES One review covered the functionalizations and synthetic applications of pyridazin-3(2H)ones <05JHC353>, while another on the reactions of pyrimido[4,5-c]pyridazine-5,7(6H,8H)diones with nitrogen nucleophiles highlighted their ability to undergo nucleophilic substitution of hydrogen <05JHC375>. The synthesis and heterocyclizations of 3-alkynyl6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones and their lumazine analogs was reviewed <05JHC413>, as was the synthesis of functionalized compounds containing pyridazine rings <05JHC361>. In the medicinal arena, pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as A3 adenosine receptors ligands were covered in a review <05MI1319>, as were biologically active pyridazinoquinoxalines <05JHC387>. Finally, the history of the discovery of the diarylpyrimidine anti-HIV drug Rilpivirine {R278474, 4-[[4-[[4-[(1E)-2cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile} was covered <05JMC1901>. Homoheteraryl coupling mediated by Pd(OAc)2 was used to form the aryl-aryl bonds in new diazines <05JHC1423>. The pyrazine alkaloids botryllazine A and B from Botryllus leachi and related compounds (1a-c) were prepared by a regioselective metalation/crosscoupling approach starting from chloropyrazine <05JOC2616>. The pyridine ring of the
M.P. Groziak
354
pyridin-2-yldiazines 2-4 was used as an ortho-directing group for metalation <05T9637>. The regioselectivity observed was similar to that found for 2H incorporation (percentages shown next to ring positions) after generating the anions with 3-4 eq. LTMP in THF at -78 ˚C for 15 min. The 35Cl NQR and 1H NMR relaxation times in a 1:2 hydrogen-bonded (chloranilic acid)-(1,3-diazine) complex 5 were measured, giving an indication of partial Htransfer to the diazines <05BCJ1241>. Aryl substituted diazines 6 and 7 were obtained by Stille cross-coupling of Bu3Sn-substituted precursors, themselves prepared via nucleophilic substitution of halodiazines with Bu3SnLi <05T2897>. The metalation/functionalization of 2bromopyrazine, 2,4-dibromopyrimidine, and 3-bromo-6-phenylpyridazine was reported, together with an improved preparation of these halodiazine starting materials <05JHC509>. The ring metalation of cinnoline, quinazoline, and quinazolinone sulfoxides was found to be effective, but curiously that of a quinoxaline sulfoxide was not <05T8924>. R1
N
R2
21%
O 1a, R = R = H; 1 2 b, R1 = H, R2 = 4-HOC6H4CO; c, R1 = 4-HOC6H4CO, R2=H
N HO
14%
N
N 81%
N
19%
N
N 16%
100%
2
N
N
N 11%
N
89%
3
4
OH N
Cl N H O
O
(N)
N
N O H N
O
N N
N
N
N
N N
N
N
N
Cl
5
7
6
6.2.3 PYRIDAZINES AND BENZO DERIVATIVES X-ray crystallography continued to expand our knowledge of the solid state structures of pyridazines. The crystal structures of 6a-methyl-7-phenylsulfonyl-6-phenylsulfonylmethyl7,7a-dihydro-6aH-cyclopropa[d][1,2,3]triazolo[4,3-b]pyridazine <05AX(E)o2142>, 3,6-bis(4-methoxybenzyloxy)pyridazine <05AX(E)o2486>, and ethyl 3-methyl-6-oxo-5-[3-(trifluoromethyl)phenyl]-1,6-dihydro-1-pyridazineacetate <05AX(E)o1561> were determined. In the organometallics field, neutral Cu4N12 and Ag4N12 metallacycles with a para-cyclophane framework were prepared by treating Cu(I) and Ag(I) pyrazolates with pyridazine, and three of these were solved crystallographically <05CC1619>. Finally, [pyridazin-3(2H)-one-6-yl]ferrocenes 8 were prepared and characterized by a wide variety of methods, including IR, 1D and 2D NMR, and X-ray <05JOM802>. O Fe
N
N
N
N
O Q 8
Q = -(CH2)n-, (E)-CH=CH-,
(N)
Six-membered ring systems: diazines and benzo derivatives (2005)
355
6.2.3.1 Syntheses Condensation approaches to the synthesis of pyridazines were once again popular. A microwave-assisted cyclocondensation reaction involving -diketones and hydrazine in the presence of DDQ produced 3,4,6-trisubstituted pyridazines <05SL2743>. New tricyclic pyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-ones were prepared from 2,3-dihydrothiopyrano[2,3-b]pyridin-4(4H)-ones via condensation with glyoxylic acid followed by hydrazines. Their binding affinity at the benzodiazepine receptor was studied <05AP126>. Hydrazonoyl halides were used to access many heterocycles, including pyrazolo[3,4-d]pyridazines <05JHC527, 05SC249>, pyrrolo[1,2-b]pyridazines were among the many heterocycles accessed using -(cyanomethyl)benzylidene-malononitrile as a starting material <05SC2251>, and methyl 3,3,3-trifluoropyruvate was used in a two-step synthesis of 4trifluoromethyl-(2H)-pyridazin-3-ones <05SL1907>. Pyridazino[3,4-a]carbazoles 9 were obtained by the reaction of substituted 2-benzylidene-1,2,3,4-tetrahydrocarbazol-1-ones and thiocarbohydrazide or thiosemicarbazide <05CCC223>. R
R (H2NNH)2C=S N H
N H
KOH, EtOH
O
N 9
N
A new tetraazaheterocyclic system was accessed when substituted pyridazino[4,5-b][1,8]naphthyridin-6(7H)-ones like 10 were prepared from 1,8-naphthyridine-3-carboxylates <05H(65)329>. A regioselective synthesis of pyridazines 11 was developed from the cycloaddition of phosphorylated 1,2-diaza-1,3-butadienes with olefins. Cycloadduct formation occurs via an endo transition state with styrene, cyclopentadiene, and dihydrofuran, but via an exo one with norbornadiene <05EJO1142>. The regioselective cycloaddition of tetrazines and alkynylboronic esters gave highly substituted pyridazine boronic esters 12 <05AG(I)3889>. Pyridazine derivatives 13a-c were formed via Diels-Alder reaction of di(benzoyl)acetylene and 1,1,2,2-tetra(cyano)ethylene <05CJC57>, and pyridazino[4',3':4,5]thieno[3,2-d]-1,2,3-triazines were prepared along a heterocyclization route <05PS591>. Ph NC EtO
CO2Et N
Br
N
NC EtO
N
Br R1
R1
N
NH N
R2
B(OR)2 N N –N2
B(OR)2 R1
12
O
N
Me
PhOC
CO2Et N O
Me O PPh2
10 R1
N R2 N
N N
CO2Et N N +
O
Ph
O PPh2 11
COPh
N N
+ Ar C N N C Ar H H
Ar PhMe Δ
PhOC
Ar COPh
13a-c, R = Me, OMe, Cl
Some unusual pyridazine syntheses were reported. A dye-sensitized photooxygenation reaction of ribofuranosyl furans gave a new entry to pyridazine C-nucleosides 14
M.P. Groziak
356
<05JOC6503>, and new pyridazino-psoralens 15 were prepared via a furan ring expansion reaction <05T4805>. The reaction of 3-acetylcoumarins with alloxan followed by NH2NH2 easily produced 3-(2-oxo-2H-chromen-3-yl)-6H,8H-pyrimido[4,5-c]pyridazine-5,7-diones <05JHC1223>. Furano- and pyrano[2,3-c]pyridazines 17 and 18a,b as well as substituted quinolines were conveniently prepared from pyridazinone 16 and vinyl- and allyltriphenylphosphonium salts <05HAC56>. Me Me O
O
1O
1. 2 2. Et2S
N N
O
RO
RO OR
RO
Me
3. NH2NH2•HCl
RO
O
O
Me OR 14 CO2Me N + N
N N
CO2Me N N Δ
O
O 15
CO2Me O
O CN Ph3P
O N
N H
O CN
O N
O
N
+
X
O N
O 17 (39%)
16
O
Me
N O Me 18a, X = NH (13%) b, X = O (19%)
6.2.3.2 Reactions Removal of the MOM group from 5-alkynyl-2-methoxymethylpyridazin-3(2H)-ones 19 with HCl gave, with certain alkynyl substituents, 5-(2-chloroalkenyl)pyridazin-3(2H)-ones like 20a-d <05T4785>. 4-Cyano-5,6-dimethylpyridazine-3(2H)-thione was transformed into thieno[2,3-c]pyridazines and pyrimido[4',5':4,5]thieno[2,3-c]pyridazines <05PS413>. Alkyl/aryl pyridinazinyl ethers were prepared from the corresponding halopyridazinones <05JHC639>. O MOM
O HCl
N N Ph
R
HN N
Cl
Ph
20a, R = H, b, R = CH2OH, R c, R = CH(OH)Me, d, R = CH2Cl
19
6.2.3.3 Applications Pyridazines continued to play a central role in the construction of new biologically active compounds. 2,7-Dihydro-3H-pyridazino[5,4,3-kl]acridin-3-ones were synthesized as cytotoxic agents <05BMC1969> and 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-
Six-membered ring systems: diazines and benzo derivatives (2005)
357
pyridazin-3-one and related compounds were prepared as aldose reductase inhibitors <05JMC6326>. Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones were examined as PDE5 inhibitors <05BMCL2381>, pyrazolo[3,4-c]pyridazines as cyclin-dependent kinase (CDK2) inhibitors <05JMC6843>, pyrazolo[3,4-d]pyridazines as antibacterials and antifungals <05EJM401>, and polyfunctionally substituted pyridazines and their fused derivatives <05HEC89> and certain pyrrolopyridazine cycloadducts <05H(65)1871> were all prepared as antimicrobials. Some pyridazines were developed as inhibitors of p38 MAP kinase <05BMCL2409>, others as acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors <05JHC395>, and still others as GABA-α receptor ligands <05JMC6004, 05JMC7089>. Finally, certain 3(2H)pyridazinones were prepared as fungicides and herbicides <05JHC427>.
6.2.4 PYRIMIDINES AND BENZO DERIVATIVES We have learned more about the physicochemical properties of pyrimidines through some detailed investigations. For example, the electronic structures of 15 substituted pyrimidines like 21a-d were studied by computational methods <05EJO522>, and mono- and multinuclear Mn(II), Co(II), and Cu(II) complexes of bisazo-dianils containing a pyrimidine moiety were synthesized and examined by a variety of spectroscopic methods (IR, electronic absorption, ESR) <05JCC683>. The intramolecular stacked conformation of pyrazolo[3,4-d]1 pyrimidines tethered by a trimethylene linker was documented in solution by H NMR and in the solid state by X-ray <05JMS179>, and complexes between the tautomers of the RNA pyrimidine bases and L-leucine were characterized by ab initio computational methods <05TC31>. Tautomerism in N-methyl regioisomers of uracil, 5-fluorouracil, and thymine was also examined this way <05TC201>. 4,5,6,7-Tetrahydro-2-methyl-2,4-diphenyl4,7a,12b-triazadibenzo[e,g]azulene-1,3,8-triones 22 were prepared as members of a pyrimidine-annulated pyrrolobenzodiazepine ring system related to Aspergillus alkaloids <05EJO1781>, and their prototropic tautomerism was studied by 1H NMR <05H(65)625>. The 4,9-methanoundecafulvene-related [5-(4,9-methanocycloundeca-2',4',6',8',10'-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-triones] 23 were prepared, and their physical properties were examined by UV-Vis, cyclic voltammetry, and NMR. The rotational barrier about the exocyclic C=C was determined to be 12.55 kcal•mol-1, by a VT-NMR study <05T7384>. In a similar fashion, a set of 5-[bis(1-heteroazulen-3-yl)methylidene]pyrimidine-2,4,6(1,3,5H)triones 24 was prepared by reaction of bis(1-heteroazulen-3-yl)methyl cations with barbituric acid followed by chloranil-mediated oxidation, and these too were extensively characterized by NMR, UV-Vis, cyclic voltammetry, MO computations, and X-ray crystallography <05T8616>. R3
O
R4
R2 N
N
N R1
21a, R1 = H, C≡CH, NH2, NMe2; b, R2 = H, Me, Cl, OH, OMe, NMe2; c, R3 = H, C≡CH, Me, iPr; d, R4 = H, Me, Cl, OMe
N
N Ph
O Me
Ph 22
O
M.P. Groziak
358 O
O
H
O +
O O
H
O
N
N N R
H N
O Ac2O, 120 °C, 1h
O
X
N R
O 23
O
N R
X OO
O O
R N
R N
O OO
O
N R
X
O O 24a, X = O b, X = NMe
N R
X
There was again a large number of X-ray crystallographic determinations of pyrimidinebased structures. 1,3-Bis(pyrimidin-2-ylsulfanyl)propan-2-one (25) <05AX(E)o594>, 2,3bis[(pyrimidin-2-ylsulfanyl)methyl]quinoxaline <05AX(E)o2746>, 2,4,6-tris(pyrimidin-2-ylsulfanyl)-1,3,5-triazine <05AX(E)o1133>, 4-(2-naphthyl)pyrimidine <05AX(E)o2256>, and 2-chloro-4-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine <05AX(E)o1821> were among the simpler ones. Others were 3-(4-fluorophenyl)-2-(4-methylphenoxy)-5,8,9-trimethylthieno[3',2':5,6]pyrido[4,3-d]pyrimidin-4(3H)-one <05AX(E)o2663>, 10''-(4-chlorobenzylidene)5''-(4-chlorophenyl)-4'-(2,4-dichlorophenyl)-1'-methyl-2,3,2'',3'',7'',8'',9'',10''-octahydro-1H, 5''H,6''H-indole-3-spiro-2'-pyrrolidine-3'-spiro-2''-cyclohepteno[1,2-d]thiazolo[3,2-a]pyrimidine-2,3''-dione <05AX(E)o1411>, 2-diisopropylamino-3-phenylbenzo[4,5]furo[3,2-d]pyrimidin-4(3H)-one <05AX(E)o2649>, and 10''-(4-methoxybenzylidene)-5'',4'-bis(4methoxyphenyl)-1'-methyl-2,3,2'',3'',7'',8'',9'',10''-octahydro-1H,5''H and 6''H-indole-3-spiro2'-pyrrolidine-3'-spiro-2''-cyclohepteno[1,2-d]thiazolo[3,2-a]pyrimidine-2,3''-dione <05AX(E)o2086>. Still others were 3-methyl-6,8-di(2-pyridyl)-[1,2,3]triazolo[5',1':6,1]pyrido[2,3-d]pyrimidine <05ARK71>, 4-(o-methoxyphenyl)-1,3,4,4a,5,6,7,8a-octahydro-2Hpyrano[2,3-d]pyrimidine-2-thione <05AX(E)o1228>, 4-(E)-2-[3-(3-[(E)-2-(4-cyanophenyl)1-diazenyl]hexahydro-1-pyrimidinylmethyl)hexahydro-1-pyrimidinyl]-1-diazenylbenzonitrile <05MI297>, 4,7-bis(4-methoxyphenyl)-1,3,7-triphenyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolo[2,3-d]pyrimidine-2,5,6-trione (26) <05AX(E)o635>, and the related 4-p-tolyl1,3,4,4a,5,6,7,8a-octahydro-2H-pyrano[2,3-d]pyrimidin-2-one (27) <05AX(E)o1049>. O N N
Ph
N S
O
O
N
S
N O 25
MeO
Ph
Me
OMe
N
N O
Ph 26
H N
HN O
27
In addition to these, 5-methyl-2-methylsulfanyl-7-phenylpyrazolo[1,5-a]pyrimidine-3carbonitrile <05AX(E)o2506>, 7''-benzyl-9''-benzylidene-4'-[4-(dimethylamino)phenyl]-1'methyl-5''-phenyl-2'',3'',6'',7'',8'',9''-hexahydro-1H-indole-3(2H)-spiro-2'-pyrrolidine-3'-spiro2''-pyrido[4,3-d]thiazolo[3,2-a]pyrimidine-2,2''-dione <05AX(E)o1830>, ethyl 3-cyano-7methylpyrazolo[1,5-a]pyrimidine-6-carboxylate <05AX(E)o1459>, methyl 2-[2-(5,7dimethyl-1,2,4-triazolo[1,5-a]pyrimidin-2-ylsulfanylmethyl)phenyl]-3-methoxyacrylate <05AX(E)o1992>, and methyl 4-((E)-2-{3-[(3-{(E)-2-[4-(methoxycarbonyl)phenyl]-1-
Six-membered ring systems: diazines and benzo derivatives (2005)
359
diazenyl}-5,5-dimethylhexahydro-1-pyrimidinyl)methyl]-5,5-dimethylhexahydro-1-pyrimidinyl}-1-diazenyl)benzoate <05MI307> were also analyzed by X-ray crystallography. The isostructural compounds 5-methyl-2-(4-methylphenyl)- (28), 2-(4-chlorophenyl)-5methyl-, and 2-(4-bromophenyl)-5-methyl-7,8-dihydro-6H- cyclopenta[g]pyrazolo[1,5-a]pyrimidines displayed chains linked by a single CH•••π(arene) H bond, but the 5-methyl-2-ptolyl- derivative was found linked by a single CH•••NH bond into chains, which themselves were linked into sheets by a π-π stacking interaction <05AX(C)o452>. 7-Hydroxy-3methoxy-4-methyl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidin-1(9H)-one 29 was shown to have a planar pyrimidine ring involved in three CH•••π interactions <05AX(C)o158>. 5-(4Methoxybenzoyl)-4-(4-methoxyphenyl)-1-(1-(4-methoxyphenyl)-ethylideneamino) <05AX(E)o622> and 5-(4-methoxybenzoyl)-1-(4-methoxybenzylideneamino)-4-(4methoxyphenyl)- <05AX(E)o637> pyrimidin-2(1H)-one (30a and b, respectively) were each solved crystallographically. OMe O N Me
N
Me
N HO
N N
Me
28
O
OMe MeO
N N OMe
N O R
29
30a, R = Me; b, R = H
In the organometallic field, a complicated nonanuclear Ni(II) complex containing the 7,8dihydro-1,2,4-triazolo[4,3-a]pyrimidin-7-one anion 31 as a ligand was characterized by Xray <05EJI2779>, as were bis(pyrimidine-2-thiolato)bis(triphenylphosphine)ruthenium(II) 32 <05AX(E)m714>, cis,cis,trans:N,N;P,P;S,S-[bis(triphenylphosphine)][bis(pyrimidine-2thiolato)]ruthenium(II) <05JCC429>, and catena-poly[[[(acetonitrile- N)silver(I)]- bis(pyrimidin-2-ylsulfanyl)methane- 2N1:N1'] tetrafluoroborate] 33 <05AX(E)m1658>. In the biological-medicinal field, pyrimidines solved crystallographically included 3-bromo-1(2-deoxy- -D-erythro-pentofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 34, a DNA duplex stabilizing nucleoside <05AX(C)o67>, the herbicide isopropyl 2-(5,7-dimethyl-1,2,4triazolo[1,5-a]pyrimidin-2-yloxy)benzoate <05AX(E)o2079>, and 2-methyl-7-oxo-5,6,7,8tetrahydropyrimido-[4,5-d]pyrimidin-3-ium chloride 35, from the thermal decomposition of the HCl salt of nimustine {1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-(2-chloroethyl)-3nitrosourea, 36}, an antitumor DNA cross-linker for treating malignant glioma <05AX(E)o544>. N
Ph3P PPh3 O
N
N N
Ru
S N
N
N
N
32
Ag
S N
31
N
S
S N
N
CH3CN 33
nBF4– n
360
M.P. Groziak
NH2
Br
Cl
N
N N
N
H NH2
O
OH
N
Me
NH N
34
OH
N H
NH2
H N
Cl
O N N
Me
O
Cl
N
35
HN
O 36, nimustine
6.2.4.1 Syntheses Cyclization routes to pyrimidines continued to be a rather popular approach for preparing these heterocycles. 3,6-Dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones like 37 were prepared via cyclization of guanidine intermediates <05CL1022>, and 3-substituted 4-oxo3,4,5,6,7,8-hexahydropyrido[4',3',4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid esters were prepared along a heterocyclization route <05PS95>. A new route to pyrido[4,3-d]pyrimidines like 39 relied upon an intramolecular cyclization of 4-amino-5-(tert-butyliminomethyl)-2(methylthio)-6-(phenylethynyl)pyrimidine 38 <05CHE268>, and a regioselective, radical cyclization-based synthesis of pyrimidine-annulated spiro-heterocyclic compounds was reported <05SC1961>. Using a photo-induced oxidative cyclization reaction, areno[b]pyrimido[5,4-e]pyran-2,4(1,3H)-dionylium perchlorates and tetrafluoroborates 41 were prepared from alkylidenated barbituric acids 40, and were characterized by NMR, UV-Vis, and X-ray <05T4919>. O N
N
N N Ph
H2N
Ph
CHCl3
38
hν, Ac2O 60% HClO4
N N Me
N N
MeS O
O
N Ph
N
37
Me
H2N AgNO3
NHEt
N
N
40
39
O Me
or 42% HBF4, O aerobic, r.t.
O
N MeS
N N Me
O 41 ClO4(BF4-)
2-Amino-5-methyl-7H-1,3,4-thiadiazolo[3,2-a]pyrimidin-7-ones in a sequence beginning with the condensation of 2-bromo-5-amino-1,3,4-thiadiazole and diketene <05JHC1105>. A three-component condensation route to 5-aryl-5,8-dihydroazolo[1,5-a]pyrimidine-7carboxylic acids was developed, and the solvent effect on regioisomer production was studied <05S2597>. A condensation approach to pyrrolylthieno[2,3-d]pyrimidines and thieno[2,3-d][4,5-d]dipyrimidines was described <05PS633>, as was the preparation of pyrimidines by condensation of N-substituted lactams and Viehe's salt (dichloromethylenedimethylammonium chloride) <05TL1177>. Carbonylative alkynylation followed by cyclocondensation constituted a new four-component pyrimidine synthesis of 42 (variolin B) and 43 (variolin D), tricyclics related to the meridianins 44 <05AG(I)6951>, and condensation of
Six-membered ring systems: diazines and benzo derivatives (2005)
361
6-[(dimethylamino)methylene]aminouracil with aryl isocyanates and isothiocyanates gave pyrimido[4,5-d]pyrimidines upon loss of Me2NH from the initial adduct <05TL1433>. The diketo 2-(2-oxocyclohexylcarbonyl)benzoic acid ester was condensed with NH2NH2 to give an indazole, which was subsequently transformed into a fused pyrimidine <05PS163>. H2N OH
N
N
H2N OH
R1 N
N
CO2Me
N
H2N
R3 R4
H2N 42, variolin B
N
R2
N N
N
N
43, variolin D
N H
44, meridianins R1-R4 = H/OH/Br
The use of microwave acceleration in pyrimidine syntheses continued to grow. For example, a microwave assisted synthesis of pyrimidines from ketones and formamide in the presence of HMDS was reported <05TL7889>, as was one which generated pyrazolo[1,5-a]pyrimidines from enaminones and 5-amino-1H-pyrazoles <05JHC925>. A microwaveassisted Michael addition of pyrimidines to α,β-unsaturated esters generated carbocyclic nucleoside analogs <05S419>, and a microwave-assisted one-pot synthesis of 2-amino-6,7disubstituted-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one from 2,6-diaminopyrimidin-4-one, aldehydes, and acyclic 1,3-dicarbonyl compounds was found to proceed in very good yields in the absence of a catalyst <05ARK76>. Microwaves accelerated the synthesis of imidazo- and pyrimidopyrido[4',3':4,5]thieno[2,3-d]pyrimidines from a thienopyridinecarboxylate and pyridothienopyrimidine <05ZN(B)221>, and an improvement in the microwave-assisted synthesis of 1,2,4-triazolo[4,5-a]pyrimidin-5-ones was noted when a paste-like medium was employed <05S2833>. The use of microwave acceleration in combination with solid-phase approaches was used as well. Tetrahydropyrimidinones were obtained via microwave assisted, solid-phase intramolecular cyclization <05TL5747>, and a microwave-assisted solid support synthesis of dihydropyrido[2,3-d]pyrimidines was also described <05TL1345>. Resin-bound amidines were condensed with -dicarbonyl compounds to give 2-alkyl/aryl-pyrimidines and related 3H-pyrimidin-4-ones <05JCO517>. Solid-phase approaches to pyrimidines were used both to generate libraries of compounds and simply for convenience. A combinatorial library of 3,5,6-trisubstituted pyrrolo[3,2-d]pyrimidines (9-deazapurines) was generated by a solid-phase synthetic approach <05JCO977>, and the solid phase preparation of pyrido[2,3-d]pyrimidin-7-ones was described <05TL8749>. Solid-phase approaches to trisubstituted 1H-pyrido[2,3-d]pyrimidin4-ones <05JCO96>, 3-substituted pyrrolo[3,2-d]pyrimidine-6-carboxylates <05JCO589>, and 3H-imidazo[1,2-a]pyrimidin-7-ones, 1,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidin-2ones, and 3,4,6,7,8,9-hexahydro-1H-pyrimido[1,2-a][1,3]diazepin-2-ones were developed <05TL5289>. A solid-phase synthesis of N-(pyrimidin-2-yl)amino acid amides relied upon nucleophilic aromatic substitution using 2-fluoropyrimidine <05ARK172>, and a traceless solid-phase sulfone linker approach was used to prepare 3,4-dihydropyrimidin-2-ones <05JCO721>. Solid-phase approaches were not solely used to generate libraries, however. A large number of 7-trifluoromethyl-substituted pyrazolo[1,5-a]pyrimidines were prepared via parallel solution-phase synthesis <05JCO236>.
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M.P. Groziak
Efficiency in pyrimidine synthesis was sometimes achieved by the use of metal-catalyzed reactions. 4-Substituted and bicyclic pyrimidines were prepared via a Pd-catalyzed reaction of -Me and -methylene ketones with formamide. Among the products obtained, 5,6dihydrobenzo[h]quinazoline and 4-naphth-2-ylpyrimidine were characterized by X-ray methods <05H(65)2593>. 6-[(Phosphonomethoxy)alkynyl- and alkyl]pyrimidines 45 and 46 were prepared via Sonogashira coupling <05CCC247>, and the Pd-C/CuI/PPh3-catalyzed Sonogashira coupling of 3-iodopyrazolo[1,5-a]pyrimidines with propargylic and homopropargylic reagents followed by catalytic hydrogenation gave -functionalized 3-(3dimethylaminopropyl)pyrazolo[1,5-a]pyrimidines <05S131>. OH (NH2)
OH (NH2)
N H2N
N N
H2N 45
O
n = 1,2
N
PO3H2
46
O n
PO3H2
Often, simply conducting several steps in a one-pot fashion or using more than two components in a reaction was found to generate pyrimidines efficiently. A one-pot preparation of pyrimidines relied on the condensation of α,β-unsaturated imines and amidines or guanidines <05TL1663>, and another of 2-arylimidazo[1,2-a]pyrimidines from ketones, [hydroxy(tosyloxy)iodo]benzene, and 2-aminopyrimidine was found to be accelerated by the use of an ionic liquid as solvent <05SC1741>. A one-pot synthesis of substituted 1,2,3,4-tetrahydropyrimidines from N,S-acetals, formaldehyde, and diamines was reported <05JHC975>, as was a one-pot, three-component, KF/alumina-catalyzed synthesis of pyrido[2,3-d]pyrimidines <05SC1921>. A one-step synthesis of 2-amino-7-chlorothiazolo[5,4-d]pyrimidines 48 from 4,6-dichloro-5-aminopyrimidine (47) gave a ready entry to 2,7diaminothiazolo[5,4-d]pyrimidines 49 <05JOC10194>, and -dicarbonyl compounds were found to add regioselectively to 2-ethoxymethyleneaminonitriles in a one-pot, [5+1]-annulation synthesis of quinazolines and fused pyrimidines <05S1083>. A one-pot synthesis of 3,4dihydropyrimidin-2-(1H)-ones developed using Bi(III) nitrate as catalyst represents an improvement over the classical Biginelli reaction conditions <05ARK74>. A three-component, base-mediated reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones 50 with p-cyanophenol and 2-mercaptopyrimidine (51) gave 2,4,5-trisubstituted-pyridazin-3(2H)-ones like 52a-d, together with 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-e]4H-thiopyran-1,6-diones <05T5389>. Finally, tri- and tetrasubstituted pyrimidines like 53 were prepared by a four-component coupling reaction involving a silane, two aryl nitriles, and an acetal <05OL4705>. Cl
Cl NH2
N N
Cl 47
R1NCS base
NHR2 N
N
R1NH2 NHR1
S
N 48
H+ or base MW, 150 °C
N
N
NHR1 S
N 49
363
Six-membered ring systems: diazines and benzo derivatives (2005)
Cl
OH
SH
Cl O
N N R 50
+
+
N
Y base
X
CH3CN
O
N
N R
51
CN
52a, X = Cl, Y = SAr; b, X = SAr, Y = OAr; c, X = OAr, Y = SAr; d, X = Y = SAr
N
OR4 R1CH2SiMe3 + BuLi
R2CN
R1
R3CN
R2
NH2 N
R1
(R4O)4C
R3
N N
R2
53 R3
The preparation of 2-substituted thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones by isomerization of the corresponding [4,3-c] isomers was reported <05H(65)2683>, and was that of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines, pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[1,6-a]benzimidazoles, and related fused polyheterocycles <05JHC1069>. 2,3Dihydroimidazo[1,2-a]pyrimidin-5(1H)-ones 54a-c were generated by a sterically induced multihetero-retro-ene fragmentation of the 8-alkoxyimidazo[1,2-a]pyrimidin-5(3H)-ones 55a-c initially formed by reacting 2-alkoxyiminoimidazolidines and acetylenedicarboxylates <05T5303>. 3-Formyl- and 3-cyano coumarin N-functionalized amidines were used as starting materials for the preparation of [1]benzopyrano[4,3-b]- and -[4,3-d]pyrimidin-5-ones like 56 <05T4957>, and 6-hydroxy-4H-4-oxo[1]-benzopyran-3-carboxaldehyde was shown to be a versatile starting material for the preparation of pyrimidines like 58a,b when condensed with barbituric or thiobarbituric acid (57a or 57b, respectively) <05HAC20>. H N
OCH2R1 R2 N
H N
CO2R3
N or
N R3OH
N H
N
N
R2
O
O
54a-c, R1 = H; R2 = Me, Ph, CO2R O OHC
R1 N
OCH2R1 N R2
55a, R1 = R2 = H; b, R1 = Ph, R2 = H; c, R1 = H, R2 = Me O
O
CH3CO2–
NH4+
PhMe, Δ
N
N R1
O N 56
O O
O HO
NH
O + O
O
N H
O
O
X
57a,b, X = O,S
HO
NH O
O
N H
X
58a,b, X = O,S
A tandem aza-Wittig/heterocumulene-mediated annulation route was developed for the efficient production of 6,7,8,9-tetrahydro-benzothieno[2,3-d]-1,2,4-triazolo[1,5-a]pyrimidin10(3H)-ones <05S1601>, and an amine oxide rearrangement was key to the regioselective preparation of pyrrolo[2,3-d]pyrimidines <05S1164>. Hexahydro-2-phenacylidenepyrimidines gave -lactam fused 8-aroyl-2,3,4,5-tetrahydro-7-hydroxy-6H-pyrrolo[1,2-a]pyrimidine-6-ones when treated with (COCl)2 in the presence of NaH <05IJH87>, and methyl
364
M.P. Groziak
N-methyl-N-(6-substituted-5-nitro-4-pyrimidinyl)aminoacetates underwent base-catalyzed ring closure and rearrangement to 6-substituted 4-methylamino-5-nitrosopyrimidines or 9methylpurin-8-ones <05TL1841>. Pyrrolo[2,3-d]pyrimidine-2,4-diones were prepared from N-(5-vinyluracil-6-yl)sulfilimines by sunlight-mediated photolysis <05TL5551>, and thieno[2,3-d]pyrimidine-6-carboxaldehydes were prepared for the first time by oxidation of thieno[2,3-d]pyrimidin-6-ylmethanols with I2 <05CHE800>. A general approach to 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-ones from 4-amino-1alkyl-3-propylpyrazole-5-carboxamides was developed <05JHC751>, a reaction of carbodiimides and secondary amines or alcohols was found to give 5-dialkylamino or 5alkoxy 7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones <05S2544>, the new ring systems indeno[1,2-d]pyrimidinone, indeno[1,2-e]pyrrolo[1,2-a]pyrimidinone, and indeno[1,2-e]pyrimido[1,2-a]isoindole were accessed via ring expansion of azetidinone and ring closure of amino esters and 1,3-diamines <05ARK416>, and substituted pyrazolo[4,3-d]pyrimidin-7ones were prepared from pyrazole-5-carboxylic acid precursors <05JHC1085>. Enaminones were used to access pyrazolo[1,5-a]pyrimidines <05JHC307>, sulfone-containing pyrazolo[1,5-a]pyrimidines were obtained <05JHC609>, and tetrahydro2(1H)quinazolinones and cyclopenta[d]-2(1H)pyrimidinones were prepared from alkoxyvinyl trifluoromethyl ketones <05SC3055>. Triazolino[4,3-a]pyrimidines were among the various heterocycles prepared using hydrazonoyl halides <05PS149>, and new naphtho[2,1-b]furo[3,2-d]pyrimidines were prepared and examined for biological activity <05IJH189>. As for biologically-related pyrimidines, a chemoenzymatic asymmetric total synthesis of the polycyclic pyrazolo[3,4-d]pyrimidine analogs 59 of a phosphodiesterase (PDE) inhibitor was reported <05JOC2824>, and the conversion of 2-amino-4,6-dichloro-5pyrimidinecarboxaldehyde to methyl 2-amino-4-(methoxy)thieno[2,3-d]pyrimidine-6carboxylate for obtaining antifolates was optimized <05JHC1305>. Heptadienes containing pyrimidine nucleic acid bases were prepared as building blocks for carbocyclic oligonucleotide analog synthesis <05SC1003>, pyrimidine-based 1',3'-anhydro- -D-psicoand -sorbo-furanosyl nucleosides were obtained from O2,3'-anhydro- -D-fructofuranosyluracil <05SL1683>, and the total synthesis of N-malayamycin A and related pyrimidine nucleosides 60a-c was achieved <05JOC6721>.The preparation of 1,3dimethylcyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1,3H)-dionylium ions like 62, models for NAD+/NADH, were reported <05JOC9780>. The dionylium ion 62 can be reduced with NaBH4 to give an NADH-like H– delivery agent (61) effective at reducing ketones to 2˚ alcohols. O
O Ph N
H2N
N
N N
N Bn
59 (and enantiomer)
NH H
O
R1 R2
O H
O N OH
NH O
60a, R1 = OMe, R2 = Me; b, R1 = F, R2 = H; c, R1 = OMe, R2 = H
Six-membered ring systems: diazines and benzo derivatives (2005)
O Me N
Ph N
H H
Ph N
R1
Me N
O
OH R2
R1
O N
Me
R2
Me N
Ph N +
Me
Me N O
N Me
O
61
Ph N
O
N O
365
N O
O
62
NaBH4
Me
6.2.4.2 Reactions Cyclization reactions of pyrimidines were studied, for instance, the reactivity of tetrahydropyrido[4,3-b]pyrimidines with DMAD leading to dihydropyrimidinylethylamines <05TL1975> and pyrimido[4,5-d]pyrimidines obtained efficiently by hetero Diels-Alder cycloaddition of methyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5carboxylate (64), a Biginelli compound, with N-arylidine-N'-methylformamidines to form 63 and N-arylidine guanidines to form 65. The mechanism of this cycloaddition was probed using semiempirical MO methods <05T4237>. Acetylenic pyrimidines underwent microwave-assisted intramolecular hetero-Diels Alder reactions to form fused bicyclic pyridines <05TL3423>. Ar
H Ph N H N CO2Me Me HN Ar Me N N Me 63
S
S
N
HN
H Ph N H
HN
Ar N
H Ph N H CO2Me HN Ar Me HN N 65 NH2
S
H2N
CO2Me Me 64
Nucleophilic addition/substitution reactions of pyrimidines were investigated as well. The selectivity of nucleophilic substitution in 2,4-disulfanyl-substituted thieno[2,3-d]pyrimidin-6carboxylic acids was studied <05JHC841>, as was the SN(ANRORC) reactivity of substituted 5-ethoxycarbonylpyrimidines <05JHC557>. Selective disubstitution of 2,4-dichloropyrido[2,3-d]pyrimidine with nucleophiles by SNAr and Suzuki and Stille cross-couplings was achieved <05TL5851>. The regioselectivity of conjugate additions to 3-(pyridin-3-yl or pyrimidin-2-yl)-propenoates and their N-oxides (66) to give 67a,b was studied by a combination of theoretical and experimental methods <05EJO3297>, and 4-azido-2pyrimidinone nucleosides 68 were shown to react with nucleophiles at the modified base's C2 position, giving tetrazole nucleosides 69 <05JOC1961>, contrary to a previous report. N CO2Et
N N N N
CO2Et R1
PrSH O
R2
O N
N 66
NaOEt, EtOH
N
N
O
N
NuH
AcO
68
N NH Nu
O
O
N
AcO
AcO 67a, R1 = H, R2 = SPr b, R1 = SPr, R2 = H
N
AcO
69
O
366
M.P. Groziak
Rearrangements of pyrimidine compounds were also reported. 9H-Cycloalka[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones were found to undergo intramolecular rearrangement in refluxing xylene to give cycloalkyl-fused oxazolo[3,2-a]pyrimidin-7- and -5-ones (70 and 71, respectively) <05T4453>. A regioselective thio-Claisen rearrangement starting from 5-prop2-ynyl/enyl-sulfanyl pyrimidinones generated thienopyrimidinones 72a,b <05T10774>, and O
O N
RCH2 O
CO2Et
+
n = 1, 0
NH2
n
N
RCH2 O
n
N
R3SCH2CO2H N
Me2N
N
N 71
n
N N
S
N
R1 pTsCl, Et3N, anhyd. CH2Cl2 r.t.
O
O
N 70
R2 R2
N
+ RCH2
R1
R
N
O
73a,b, R = H, Me
SR3
72a-b, R3 = CH2C≡CH, CH2CH=CH2
an acid-catalyzed O-N-type Smiles rearrangement reaction was noted in 2-pyrimidinyloxy-Narylbenzylamines, giving the corresponding phenols <05SL1239>. Ru(II) complexes containing hemilabile 2-(pyridin-2-ylmethylthio)pyrimidine ligands 73a,b were shown to interconvert between N,S- and N-coordinated species <05EJI2423>. In the first example of catalytic C-C coupling involving activation of a C-F bond in the presence of a C-Cl one, 5-chloro-2,4,6-trifluoropyrimidine (74) reacted with arylboronic acids in the presence of a Ni(II) catalyst to generate 5-chloro-2-fluoro-4,6-diarylpyrimidines 75 <05OM4057>. A theoretical and experimental investigation of the structure and reactivity of 4-(4-chlorophenyl)pyrimidinium ylides was undertaken <05ARK7>, and the structure, stability, and reactivity of 4-methyl- and 4-(halophenyl)pyrimidinium (4halobenzoyl)methylides (76a-d and 76e-h, respectively) were examined by theoretical and experimental methods <05HCA2747>. The Biginelli 3,4-dihydropyrimidin-2(1H)-one 77 was converted in two steps to a variety of multifunctionalized pyrimidines with general structure 78 <05JOC1957>. In a more biological light, N,N'-bis(3-aminopropyl)-2,7-diamino1,8-naphthyridine was found to stabilize a single pyrimidine bulge in dsDNA <05BMC4507>. Finally, separate enantioselective microbial reductions of 6-oxo-8-[4-[4-(2pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione 79 generating either of the 2˚ alcohol epimers (80a,b) was reported <05TA2778>. N
F 10%
F
R N
N Cl
F N
F
F
Ph3P Ni PPh3 F
N F Cl 74
THF, Cs2CO3 PPh3, PhB(OH)2
N Ph
N
O N
X Ph
Cl 75
76a-d, R = Me, X = F, Cl, Br, I e-h, R = 4-ClC6H4, X = F, Cl, Br, I
367
Six-membered ring systems: diazines and benzo derivatives (2005)
Ph HN O
N H
Me
CO2Me
N
N PBr PF6
77
O
Ph
1. [O] 2. NuH, base
CO2Me
Nu
NR
Me
N
O
78
3
O NR
[H]
O
HO
O
79, 6-keto Buspirone 80a,b R = 4-(pyrimidin-2-yl)piperazin-1-yl
6.2.4.3 Applications Some interesting non-medical applications were found for pyrimidines. The combination of Pd(OAc)2 and 2-aminopyrimidine-4,6-diol 81 was discovered to form a stable, efficient catalytic system for the Suzuki-Miyaura cross coupling of arylboronic acids and aryl halides <05SL1897>, and it rendered the Sonogashira cross-coupling of aryl halides with terminal alkynes efficient and copper-free <05EJO4256>. New rhodium 1,3-dialkyl-3,4,5,6tetrahydro-2-pyrimidinylidene complexes 82 prepared as aromatic aldehyde arylation catalysts were characterized by multinuclear NMR <05JOM5849>. Supramolecular systems were constructed from complexes of 2,6-disubstituted 1-oxa-4-thia-3,5-diazine 4,4-dioxides with symmetric triazines <05RJO289>. 6-Substituted 2,4-bis(acrylamido)pyrimidines 83 were used as the key pieces in the construction of optically responsive imide receptors <05JOC2729>, and N-(4-amino-1-methyl-5-nitroso-6-oxo-1,6-dihydropyrimidin-2-yl)-N'[bis(2-aminoethyl)]ethylenediamine 84 was synthesized and characterized by multinuclear NMR methods. It's use as an ion receptor was investigated by assessing it’s ability to adsorb Zn(II) and Cd(II) out of aqueous solution when anchored to activated carbon <05EJI3093>. A set of 1-dimensional coordination polymers [M(NO3)2(pyrimidine)(H2O)2]∞ (M = Mn, Co, Ni, or Zn) like 85 was prepared and their phase purity was determined <05EJI1572>. The pressure-sensitive magnetism of guest-tunable weak ferromagnets of the type [Fe{N(CN)2}2(pyrimidine)](guest) (guest = EtOH or pyrimidine) was studied <05CL974>. Metal complexes with the new ditopic ligand 4-[6-(2-pyridyl)-2-pyridyl]-6-(2pyridyl)pyrimidine 86 were shown to self-assemble into 2×2 grid complexes which had encapsulated NO3– ions. These complexes were characterized by X-ray <05EJI894>. HO
R R' N N
N cat.
R1 I (Br)
HO
+
O
HN
N R2
NO3N
N N
O
NH2
84
N
N H2O
-O
85
O N H N
N
N N
3N
O
N
N
OH2 Mn2+ N
83
N N R' R 82
1
cat. Pd(OAc)2 CsCO3, CH3CN
R2
Me
NH2 N 81 R
O
N H
N H N
O N
Bn
N 86
N(CH2CH2NH2)2
As for nucleic acid applications, the syntheses and fluorescent properties of the DNA nucleobase replacements like the 1,2,3-triazolo[4,5-d]pyrimidine 2'-deoxyribofuranosides 87
368
M.P. Groziak
were reported <05HCA751>. A 4-(2'-pyridyl)-pyrimidinone deoxyriboside was prepared and was shown to form a self-pair in the presence of Ni(II), stabilizing dsDNA as in 88 <05CC1342>. Chiral 2-(aminoalkoxy)-substituted 4-(2-thienyl)pyrimidines and 4,6-bis(2thienyl)pyrimidines were prepared as dsDNA intercalators. Their binding constants showed up to a 2.4:1 discrimination of the (S)-enantiomers over the (R)-counterparts <05BMCL2720>. Finally, DNA-intercalating annelated pyrrolo-pyrimidines were prepared from substituted 2-amino-3-cyanopyrroles and 3-amino-4-cyanopyrroles <05BMC1545>. O N
HN N
Ni2+ N
N
HO
N 87
N
N
N N O
O
O
OH
N
88
1- and 2-Alkyl-4-aminopyrazolo[3,4-d]pyrimidines were developed as adenosine deaminase inhibitors <05JMC5162>, 2-(2-furanyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin5-amines were developed as adenosine A2a antagonists <05BMCL3670, 05BMCL3675>, pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines were prepared as human A3 adenosine receptor antagonists <05JMC152>, and 4-substituted 5-phenyl-7-(5-deoxy- -Dribofuranosyl)pyrrolo[2,3-d]pyrimidines (diaryltubercidins) <05JMC7808>, 6,7-disubstituted 4-aminopyrido[2,3-d]pyrimidines <05BMCL2803>, and 5-(3-bromophenyl)-7-(6-morpholin4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine <05BMC3705> were prepared as inhibitors of adenosine kinase. Pyrimidine-based compounds continue to be of interest as antimalarial agents. Among the ones synthesized for this bioactivity were 2,4,6-trisubstituted pyrimidines <05BMC4645> and 4-pyrido-6-aryl-2-substituted aminopyrimidines <05BMC6226>. Libraries of 2,4,6trisubstituted pyrimidines were prepared and screened for antimalarial activity <05BMCL1881, 05BMCL3130> and also for topoisomerase II activity <05BMCL47>, while other libraries of 6-aryl-2-substituted pyrimidin-4-ylphenols <05BMCL4923> and trisubstituted pyrimidines <05BMCL5218> were prepared and screened for antimalarial and antitubercular activities. 5-Substituted pyrimidine nucleosides were examined as antimycobacterial agents <05JMC7012, 05BMC6663>, spiro-pyrazolo-3,3'-thiopyrano[2,3-b]pyridines were prepared as antifungal and antibacterial agents <05JHC221>, a set of pyrimidine-based antifungal agents was synthesized <05AAC2226>, and some unusual [1,2,4]triazolo[1,5-a]pyrimidine-based triorganotin(IV) complexes 89 were prepared and characterized by IR and Mossbauer spectroscopy and quantum chemical calculations <05JOM4773>. These had good antifungal and antibiofilm activities. Bu
Bu O
O Sn O Bu Bu HN
Sn
O
Bu Bu
N N N
89
N- and O-Substituted terpenyl pyrimidines <05EJM552> as well as dihydropyrido[2,3-d]pyrimidines <05BMC6678> were prepared as antileishmanial agents. 5-Alkynyl- and 6alkyl-furo[2,3-d]pyrimidine acyclic nucleosides <05BMC1239>, acyclic furo- and
369
Six-membered ring systems: diazines and benzo derivatives (2005)
pyrrolo[2,3-d]pyrimidine nucleosides <05JMC4690>, and bicyclic furano pyrimidine nucleosides were synthesized as antiviral agents <05AAC1081>. Other bioactivities sought were pyrimidine-5-carboxamides as tyrosine kinase inhibiting anti-allergic agents <05BMC4936>, mono, bi and tricyclic pyrimidines as analgesics and anti-inflammatory agents <05BMC6158>, and 2,4,6-trisubstituted pyrimidines as pregnancy interceptive agents <05BMC1893>. Substituted pyrimidines containing a thiazolidinedione moiety were investigated as hypoglycemic and hypolipidemic agents <05EJM862>. Pyrimidine heterocycles were examined as receptor site agonists or antagonists. Among these were 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides for the benzodiazepine receptor <05BMC4821>, 3-arylpiperazinylalkylpyrrolo[3,2-d]pyrimidine-2,4-diones for the α1-adrenoceptor <05JMC2420>, bicyclic oxazolino- and thiazolino[3,2-c]pyrimidine-5,7diones, prepared by treating 2-methyloxazolines or -thiazolines with chlorocarbonyl isocyanate, for the hGnRH receptor <05BMCL1407>, piperidinyl- and 1,2,3,6tetrahydropyridinyl-pyrimidines selective for the 5-HT1α receptor <05BMCL2990>, and substituted 3H-pyrimidin-4-ones for the calcium receptor <05BMCL2537>. Pyrimidines were also prepared as enzyme inhibitors. Many of these were kinase inhibitors, including 2anilino-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-ones <05BMCL1931> and pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines <05BMCL3778> as kinase inhibitors, 4-aminofuro[2,3-d]pyrimidines as tyrosine kinase inhibitors <05BMCL2203>, pyrazolo[1,5-a]pyrimidines as inhibitors of human cyclin-dependent kinase 2 (CDK2) <05BMCL863>, pyrido[2,3-d]pyrimidin-7-ones as inhibitors of cyclin-dependent kinase 4 (CDK4) <05JMC2371>, and substituted aminobenzimidazole pyrimidines as inhibitors of cyclin-dependent kinase <05BMCL1973>. A short synthesis of 3-{4-[2-(3-chlorophenylamino)pyrimidin-4-yl]pyridin-2-ylamino}propanol, a protein kinase C inhibitor, relied on the Negishi crosscoupling reaction of a pyridine zincate and 2,4-dichloropyrimidine (90) to generate the key intermediate 91 <05JOC5215>. N
ZnI + N
Cl N
F
Cl
90
N Pd[PPh3]4, THF, reflux, 4 h F 90%
N N 91
Cl
2-Amino-3-nitropyrazolo[1,5-a]pyrimidines were prepared as inhibitors of coxsackievirus B3 replication <05BMCL37>, fused pyrimidines as PDE7 inhibitors <05BMCL1829>, and pyrimidinetriones as inhibitors of MMPs <05BMCL1807>. Methylated 3H-pyrrolo[2,3-d]pyrimidin-2(7H)-one nucleoside analogs 92 incorporated into triplex-forming oligonucleotides were shown to selectively bind CG inversions <05CC2555>, and pyrimidine-linked biphenyl anionic RSV fusion inhibitors were found to be less active than their corresponding triazine-linked counterparts <05BMCL427>. R 92
N
N
Me
N O H
H N H O
N N
N H N N
N O H N H
370
M.P. Groziak
In the anticancer field, 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-ones <05BMCL4731> and 6-[1-(2,6-difluorophenyl)ethyl]pyrimidinones <05JMC6776> were prepared as cytotoxic/antitumor agents, pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides <05BMCL1591> and thieno[2,3-d]pyrimidin-4(1H)-ones <05BMCL3763> were prepared as tumor cell antiproliferative agents, and 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines <05BMC5475>, trimethylene-bridged 2,4-diaminopyrrolo[2,3-d]pyrimidines <05JHC1127>, 2,4-diamino-6-methyl-5-substituted pyrrolo[2,3-d]pyrimidines <05JHC589>, and pyrrolo[2,3-d]pyrimidines <05JMC7215> were prepared as dihydrofolate reductase (DHFR) inhibitors. 5-Substituted furo[2,3-d]pyrimidines and 6-substituted pyrrolo[2,3-d]pyrimidines <05JMC5329>, 2-amino-4-oxo-5-arylthio-substituted pyrrolo[2,3-d]pyrimidines <05BMCL2225>, and 2-amino-4-oxo-5-substituted benzylthiopyrrolo[2,3-d]pyrimidines <05JHC165> were all synthesized as antifolate inhibitors of thymidylate synthase.
6.2.5 PYRAZINES AND BENZO DERIVATIVES Our understanding of the physicochemical properties of pyrazines has deepened. The internal rotation and IR spectrum of 2,5-pyrazinedicarboxamide were studied by quantum chemical calculations <05TC73>, and ab initio MO calculations at the MP2/6-31++G(**) level were used to explain the electronic and vibrational properties of complexes of pyrazine and HX linear acids <05JMS2822>. MM and MO calculations were used to investigate the conformational and electronic properties of odor-active pyrazines <05JMS169>, and NMR, IR, X-ray, and DFT methods were used to examine the structures of pyrido[1,2-a]pyrazinium bromide <05JMS7>. The amino-imino tautomerism in 2,3-disubstituted pyrazines in both solution and the solid state was investigated by NMR and X-ray methods <05JMS67>. Metal complexes containing a pyrazinecarboxamide ligand were investigated by a variety of spectroscopies <05JCC1241>. Pyrazine-based heterocycles examined by X-ray crystallography included 5,10-dihydroxy-5H,10H-diimidazo[1,2-a:1',2'-d]pyrazine 93 <05AX(C)o361> and 7-ethyl-2methyl-4-phenylhexahydropyrazino[1,2-a]pyrazin-3-one <05TL51>. Those within an organometallic complex included a Ca(II) complex with pyrazine-2,3-dicarboxylate ligands <05JCC891>, a Ag(I) complex containing the trans-2-(2-phenylethenyl)pyrazine ligand <05JMS37>, catena-bis( -pyrazine-2,3-dicarboxylato-N,O,O')zinc(II) <05JCC931>, diaqua(pyrazine-2,3-dicarboxylato-N,O:O',O'')calcium(II) <05JCC963>, and Ni(II) complexes containing pyrazine-2-carboxylate ligands <05JCC1429>. In addition, X-ray crystallography was used to examine the one-dimensional coordination polymer 94 of Cu(II) with 2-pyrazinecarboxylate <05AX(E)m499>, osmium clusters like 95 containing 2,3-bis(2pyridyl)pyrazine as a chelating ligand <05JOM622>, and pyrazine-bridged benzyl dicobaloximes 96a,b, which were also characterized by cyclic voltammetry <05JOM3746>.
371
Six-membered ring systems: diazines and benzo derivatives (2005)
R
OH N
R
N O
R
OH N
N O
OH
O N
N
N
N
N
N
OH
OH2
N
N Cu O N 94 O
N
O
93
OC n
R R
N
Os(CO)4
OC Os
CH2Ar O N Co N HO N
Os 95 (CO)4
N O
R
Co
O N
R
N HO CH2Ar
R
96a,b, R = Me, Ph
6.2.5.1 Syntheses A modified Ugi four-component condensation route was used to prepare substituted 4oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-6-carboxamides <05JCO806>. Microwaveassisted reactions enhanced the synthesis of substituted 2(1H)-pyrazinones via "click chemistry" <05JCO490>, and 6,8-diarylimidazo[1,2-a]pyrazines were prepared from 1-(2aryl-2-oxoethyl)-2-aryloylimidazoles using NH4OAc/AcOH under microwave conditions <05JHC319>. A regioselective one-pot synthesis of 9-alkyl-6-chloropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazines 98 from 2,3-dichloropyrido[2,3-b]pyrazine (97) was reported <05JOC2878>, and a solid-phase synthesis of substituted 2(1H)-pyrazinones was developed for future generation of libraries of these heterocycles <05JCO90>. Furoxano[3,4-b]pyrazines were prepared by treating 2-alkoxy-3,5-dinitro-6-chloropyrazines with NaN3 <05JHC691>. Polyfunctional tetrahydropyrido[3,4-b]pyrazines like 99 were prepared in a one-pot reaction using C5F5N and diamines <05JOC7208>, while the sequential reaction of C5F5N with sodium phenylsulfinate and a diamine generated polyfunctional tetrahydropyrido[2,3-b]pyrazines like 100 <05JOC9377>. O N N
N 97
Cl Cl
R
N
NHNH2
Δ
Cl
Me F
N 98
N R
N N
MeO
PhSO2 F
N N N 99
H N
Me
NEt2
F
N
N H
100
Pyrazino[1,2-a]indoles 101 and 102 were prepared by intramolecular cyclization of 2acyl-1-propargylindoles and NH3 <05JOC4088>. Pyrrolo[1,2-a]pyrazin-1-ones 103 were obtained from 2-acylpyrroles <05T1077>. Pyrazines doubly activated with MeO2CCl in the presence of bis(TMS)ketene acetals generated polycyclic -lactone products <05TL3449>. Tetramethylpyrazine reacted with SeO2 to give 2,5-dimethylpyrazine-3,6-dicarboxaldehyde, which in turn reacted with (iPr)2NH to give 2,5-dimethyl-3,6-bis[(2,6-diisopropylphenylimino)methyl]pyrazine, a chelating ligand for transition metal complexes <05ZN(B)22>.
372
M.P. Groziak
Finally, trialkyl-substituted pyrazines 104 were prepared in a regiocontrolled manner from nitroketones by reaction with -amino ketones <05OL5529>. R N
R
NH3 N
O R'
101 O N H
N R
R +
Pd(OAc)2
N
N CH2R'
O
R1
NO2
N R
R2
O
N CHR'
102 O
R3 octylviologen
R1
N
R2
N
R3
N
NaOAc Bu4NCl DMSO
Na2S4O6 K2CO3
Cl–
H3N
103
104
6.2.5.2 Reactions Palladium-catalyzed reactions on pyrazines were the subject of quite a few investigations. 3,5-Dichloropyrazinones 105 were shown to undergo regioselective Suzuki and Heck reactions to give 3-substituted products, while the less reactive 5-position could be functionalized only after transhalogenation to the corresponding 5-bromo or -iodo derivatives <05T3953>. The Suzuki, Sonogashira, Heck, and Buchwald-Hartwig reactions were explored using 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine as the key starting material <05S1345>. Functionalized, symmetric bi-2(1H)-pyrazinones were obtained by homocoupling in a Suzuki-type reaction involving an in situ generated boronic acid <05SL777>, while highly substituted bipyrazines like 107 were obtained by a Suzuki cross-coupling approach from 2amino-5-bromopyridazine (106) <05JOC388>. The Pd-catalyzed heteroannulation of N-(3chloropyrazin-2-yl)methanesulfonamide with alkynes was used to prepare 6,7-disubstituted5H-pyrrolo[2,3-b]pyrazines <05TL1845>. OMe
R Cl
Bn (Ph) O N N 105
Cl
(HO)2B H 2N
N N 106
OMe
B(OH)2
MeO Br Pd[PPh3]4, Na2CO3 THF, reflux, 24 h 56%
N
N
H 2N
NH2 N
N MeO 107
Olefinic pyrazines like 108 were shown to react with C6H6 in the superacid TfOH to give anti-Markovnikov addition products like 109 <05OL2505>. The orientation observed is presumed to be due to the multiply charged heterocycle adjacent to the olefin. Pyrazine oquinodimethanes underwent Diels-Alder condensation with meso-tetraarylporphyrins to give new π-extended porphyrins <05TL2189>. A one-pot formation of polycyclic - and lactones like 111 was developed using the reaction of pyridine and pyrazine (110) with bis(trimethylsilyl)ketene acetals. Many of them were characterized by X-ray <05EJO3724>.
373
Six-membered ring systems: diazines and benzo derivatives (2005)
N
CF3SO3H
N
N
C6H6, 80 ° C 96%
N
108
N
Ph
Me
N MeO2C
O
Me
1. Me2C=C(OSiMe3)2
N 110
109
MeO2C N
2. ClCO2Me
O 111
6.2.5.3 Applications The non-medicinal applications reported for pyrazine-based compounds were extremely diverse. By studying substituent effects, the rate-determining step for chemiluminescence in 6-arylimidazo[1,2-a]pyrazin-3(7H)-ones was indicated to be a single electron transfer from the anion to triplet O2 <05TL7701>. Reaction of the diamide ligands N,N'-bis(2pyridylmethyl)pyrazine-2,5-dicarboxamide and N,N'-bis[2-(2-pyridyl)ethyl]pyrazine-2,5dicarboxamide 112 with Cu(BF4)2•4H2O gave dinuclear Cu(II) complexes which were characterized by EPR <05EJI1530>. The Cu(II) complex [Cu2(pyrazine-2,5dicarboxylato)(1,10-phenanthroline)4](NO3)2•10H2O 113 was examined by X-ray crystallography, and the magnetic exchange through the pyrazine bridge was studied <05EJI2586>. The colorimetric sensor properties of solvatochromic substituted 2phenylimidazo[1,2-a]pyrazin-3(7H)-ones 114a-e were examined by UV/Vis and SM1COSMO computations <05T10073>. Pyrazine itself was found to bind to the cavities formed in Mn(II), Fe(II), Ni(II), and Cu(II) complexes bridged with squarate molecules, forming a supramolecular network. The X-ray crystal structure of a similar Zn(II) complex was determined <05BCJ445>. Two axially chiral quinazoline-equipped phosphinamine ligands, 2-(2-pyridyl)quinazolinap 115a and 2-(2-pyrazinyl)quinazolinap 115b, were prepared, resolved, and their diastereomeric palladacycles were examined crystallographically <05T9808>. Other related quinazolines like 116a-f were also prepared. A total of 27 volatile pyrazines such as 117-120 were isolated and characterized from the myxobacterium Chondromyces crocatus and marine bacteria <05EJO4141>. N O HN O N
N n = 1 or 2
Cu2+ N
N N
O
N Cu2+
N
Me N
N
N
O
N
N
O
N
NH 112
N
O
N
n
O
n
R 114a-e, R = NMe2, OMe, H, Cl, CN
113
N X
N
N N
N
N
N PPh2
MeO
N
R
N
PPh2
N 117
119
MeO N
115a, X = CH; b, X = N
116a-f, R = Ph, Me, Pri, But, H, Bn
Me
N 118
N
Me
N
SMe
120
374
M.P. Groziak
In medicinal applications, [1,2,4]triazolo[1,5-a]pyrazines have been examined as adenosine A2α receptor antagonists <05H(65)2321, 05BMCL4809>, pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazines were prepared from 1-phenyl-5-(pyrrol-1-yl)-1H-pyrazole-3carboxylic acid azide as antibacterials and antifungals <05M217>, and pyrazinones were examined as inhibitors of the TF/VIIa complex <05BMCL3006> and as non-nucleoside reverse transcriptase inhibitors (NNRTIs) <05JMC1910>. New thrombin inhibitors were built around a pyrazinone core <05EJM782>, pyrazinone monoamides were prepared as ascaspase-3 inhibitors <05BMCL1173>, and 5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazines as dipeptidyl peptidase IV (DPP-IV) inhibitors <05JMC141>. A QSAR study on 1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone as aldose reductase inhibitors was conducted <05BMC1445>, the synthesis <05JMC1886> and SAR <05JMC4892> of pyrazine-pyridine biheteroaryls as vascular endothelial growth factor (VEGF) receptor-2 inhibitors were reported, and the effect of L-pyrazinylalanine as a phenylalanine replacement in a somatostatin was explored <05JMC4025>. Finally, the susceptibility <05AAC804> and resistance <05AAC444, 05AAC2210> of Mycobacterium tuberculosis to pyrazinamide was further investigated.
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376 05BMC4821 05BMC4936 05BMC5475 05BMC6158 05BMC6226 05BMC6663 05BMC6678 05BMCL37 05BMCL47 05BMCL427 05BMCL863
05BMCL1173
05BMCL1407 05BMCL1591 05BMCL1807
05BMCL1829 05BMCL1881 05BMCL1931 05BMCL1973 05BMCL2203 05BMCL2225 05BMCL2381 05BMCL2409 05BMCL2537 05BMCL2720 05BMCL2803 05BMCL2990 05BMCL3006
05BMCL3130
M.P. Groziak
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M.P. Groziak
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Six-membered ring systems: diazines and benzo derivatives (2005)
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380 05JMS67 05JMS169 05JMS179 05JMS2822 05JOC388 05JOC1957 05JOC1961 05JOC2616 05JOC2729 05JOC2824 05JOC2878 05JOC4088 05JOC5215 05JOC6503 05JOC6721 05JOC7208 05JOC9377 05JOC9780 05JOC10194 05JOM622 05JOM802 05JOM3746 05JOM4773 05JOM5849 05M217 05MI297 05MI307 05MI1319 05OL2505 05OL4705 05OL5529 05OM4057 05PS95 05PS149 05PS163 05PS339 05PS413 05PS591 05PS633 05RJO289 05S131 05S419 05S1083 05S1164
M.P. Groziak
M.A. Farran, R.M. Claramunt, C. Lopez, E. Pinilla, M.R. Torres, J. Elguero, J. Mol. Struct. 2005, 741, 67. K. Shimazaki, T. Inoue, H. Shikata, K. Sakakibara, J. Mol. Struct. 2005, 749, 169. K. Avasthi, S. Aswal, R. Kumar, U. Yadav, D.S. Rawat, P.R. Maulik, J. Mol. Struct. 2005, 750, 179. J.B.P. Da Silva, M.R. Silva Junior, M.N. Ramos, S.E. Galembeck, J. Mol. Struct. 2005, 2822. A.E. Thompson, G. Hughes, A.S. Batsanov, M.R. Bryce, P.R. Parry, B. Tarbit, J. Org. Chem. 2005, 70, 388. F.-A. Kang, J. Kodah, Q. Guan, X. Li, W.V. Murray, J. Org. Chem. 2005, 70, 1957. F. Peyrane, P. Clivio, J. Org. Chem. 2005, 70, 1961. F. Buron, N. Ple, A. Turck, G. Queguiner, J. Org. Chem. 2005, 70, 2616. P. Manesiotis, A.J. Hall, B. Sellergren, J. Org. Chem. 2005, 70, 2729. M.X.-W. Jiang, N.C. Warshakoon, M.J. Miller, J. Org. Chem. 2005, 70, 2824. A. Unciti-Broceta, M.J. Pineda-de-las-Infantas, J.J. Diaz-Mochon, R. Romagnoli, P.G. Baraldi, M.A. Gallo, A. Espinosa, J. Org. Chem. 2005, 70, 2878. G. Abbiati, A. Arcadi, A. Bellinazzi, E. Beccalli, E. Rossi, S. Zanzola, J. Org. Chem. 2005, 70, 4088. P. Stanetty, G. Hattinger, M. Schnuerch, M.D. Mihovilovic, J. Org. Chem. 2005, 70, 5215. F. Cermola, M.R. Iesce, G. Buonerba, J. Org. Chem. 2005, 70, 6503. S. Hanessian, G. Huang, C. Chenel, R. Machaalani, O. Loiseleur, J. Org. Chem. 2005, 70, 6721. G. Sandford, R. Slater, D.S. Yufit, J.A.K. Howard, A. Vong, J. Org. Chem. 2005, 70, 7208. A. Baron, G. Sandford, R. Slater, D.S. Yufit, J.A.K. Howard, A. Vong, J. Org. Chem. 2005, 70, 9377. S.-i. Naya, J. Nishimura, M. Nitta, J. Org. Chem. 2005, 70, 9780. J. Liu, R.J. Patch, C. Schubert, M.R. Player, J. Org. Chem. 2005, 70, 10194. R.A. Machado, M.C. Goite, A.J. Arce, Y. De Sanctis, A.J. Deeming, L. D'Ornelas, D.A. Oliveros, J. Organometal. Chem. 2005, 690, 622. A. Csampai, A. Abran, V. Kudar, G. Turos, H. Wamhoff, P. Sohar, J. Organometal. Chem. 2005, 690, 802. D. Mandal, B.D. Gupta, J. Organometal. Chem. 2005, 690, 3746. M.A. Girasolo, C. Di Salvo, D. Schillaci, G. Barone, A. Silvestri, G. Ruisi, J. Organometal. Chem. 2005, 690, 4773. I. Oezdemir, S. Demir, B. Cetinkaya, E. Cetinkaya, J. Organometal. Chem. 2005, 690, 5849. A.-R. Farghaly, H. El-Kashef, Monatsh. Chem. 2005, 136, 217. B. Peori, K. Vaughan, V. Bertolasi, J. Chem. Crystallogr. 2005, 35, 297. S.L. Moser, V. Bertolasi, K. Vaughan, J. Chem. Crystallogr. 2005, 35, 307. P.G. Baraldi, M.A. Tabrizi, R. Romagnoli, F. Fruttarolo, S. Merighi, K. Varani, S. Gessi, P.A. Borea, Curr. Med. Chem. 2005, 12, 1319. Y. Zhang, J. Briski, Y. Zhang, R. Rendy, D.A. Klumpp, Org. Lett. 2005, 7, 2505. N. Sakai, Y. Aoki, T. Sasada, T. Konakahara, Org. Lett. 2005, 7, 4705. T.A. Elmaaty, L.W. Castle, Org. Lett. 2005, 7, 5529. A. Steffen, M.I. Sladek, T. Braun, B. Neumann, H.-G. Stammler, Organometallics 2005, 24, 4057. E.K. Ahmed, F.F. Abdel-latif, M.A. Ameen, Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 95. A.O. Abdelhamid, M.A.M. Alkhodshi, Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 149. Z.V. Voitenko, O.A. Pokholenko, I.S. Kondratov, V.O. Kovtunenko, C. Andre, J.G. Wolf, Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 163. A. Mobinikhaledi, N. Foroughifar, B. Ahmadi, Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 339. A.M.K. El-Dean, M.S.A. El-Gaby, A.M. Gaber, H.A. Eyada, A.S.N. Al-Kamali, Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 413. A. Deeb, M. Kotb, M. El-Abbasy, Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 591. M.I. Abdel Moneam, Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 633. A.V. Shishulina, E.N. Sazhina, A.A. Michurin, Russ. J. Org. Chem. 2005, 41, 289. L. Yin, J. Liebscher, Synthesis 2005, 131. A. Khalafi-Nezhad, A. Zarea, M.N.S. Rad, B. Mokhtari, A. Parhami, Synthesis 2005, 419. S.K. Chattopadhyay, R. Dey, S. Biswas, Synthesis 2005, 1083. K.C. Majumdar, A. Biswas, P.P. Mukhopadhyay, Synthesis 2005, 1164.
Six-membered ring systems: diazines and benzo derivatives (2005)
05S1345 05S1601 05S2544 05S2597 05S2833 05SC249 05SC1003 05SC1741 05SC1921 05SC1961 05SC2251 05SC3055 05SL777 05SL1239 05SL1683 05SL1897 05SL1907 05SL2743 05T1077 05T2897 05T3953 05T4237 05T4453 05T4785 05T4805 05T4919 05T4957 05T5303 05T5389 05T7384 05T8616 05T8924 05T9637 05T9808 05T10073 05T10774 05TA2778 05TC31 05TC73 05TC201 05TL51 05TL1177 05TL1345 05TL1433 05TL1663 05TL1841 05TL1845
381
L. Yin, J. Liebscher, Synthesis 2005, 1345. M.-W. Ding, N.-Y. Huang, H.-W. He, Synthesis 2005, 1601. J.-F. Zhao, C. Xie, M.-W. Ding, H.-W. He, Synthesis 2005, 2544. V.A. Chebanov, Y.I. Sakhno, S.M. Desenko, S.V. Shishkina, V.I. Musatov, O.V. Shishkin, I.V. Knyazeva, Synthesis 2005, 2597. G. Bratulescu, Synthesis 2005, 2833. C. Moustapha, N.A. Abdel-Riheem, A.O. Abdelhamid, Synth. Commun. 2005, 35, 249. K.H. Bouhadir, J.-L. Zhou, P.B. Shevlin, Synth. Commun. 2005, 35, 1003. Y.-Y. Xie, Synth. Commun. 2005, 35, 1741. X.-S. Wang, Z.-S. Zeng, D.-Q. Shi, S.-J. Tu, X.-Y. Wei, Z.-M. Zong, Synth. Commun. 2005, 35, 1921. K.C. Majumdar, T.K. Das, M. Jana, Synth. Commun. 2005, 35, 1961. F. Abdelrazek, Synth. Commun. 2005, 35, 2251. H. Bonacorso, M. Costa, I. Lopes, M. Oliveira, R. Drekener, M. Martins, N. Zanatta, A. Flores, Synth. Commun. 2005, 35, 3055. W.M. De Borggraeve, P. Appukkuttan, R. Azzam, W. Dehaen, F. Compernolle, E. Van der Eycken, G. Hoornaert, Synlett 2005, 777. H.-Y. Wang, Y.-X. Liao, Y.-L. Guo, Q.-H. Tang, L. Lu, Synlett 2005, 1239. T.I. Kulak, O.V. Tkachenko, S.L. Sentjureva, J. Vepsaelaeinen, I.A. Mikhailopulo, Synlett 2005, 1683. J.-H. Li, X.-D. Zhang, Y.-X. Xie, Synlett 2005, 1897. D.A. Sibgatulin, D.M. Volochnyuk, A.N. Kostyuk, Synlett 2005, 1907. G. Minetto, L.R. Lampariello, M. Taddei, Synlett 2005, 2743. E.M. Beccalli, G. Broggini, M. Martinelli, G. Paladino, Tetrahedron 2005, 61, 1077. M. Darabantu, L. Boully, A. Turck, N. Ple, Tetrahedron 2005, 61, 2897. R. Azzam, W.M. De Borggraeve, F. Compernolle, G.J. Hoornaert, Tetrahedron 2005, 61, 3953. P. Sharma, A. Kumar, N. Rane, V. Gurram, Tetrahedron 2005, 61, 4237. O.-S. Adetchessi, J.-M. Leger, J. Guillon, I. Forfar-Bares, J.-J. Bosc, C. Jarry, Tetrahedron 2005, 61, 4453. A. Coelho, H. Novoa, O.M. Peeters, N. Blaton, M. Alvarado, E. Sotelo, Tetrahedron 2005, 61, 4785. J.C. Gonzalez-Gomez, L. Santana, E. Uriarte, Tetrahedron 2005, 61, 4805. S.-I. Naya, M. Miyagawa, M. Nitta, Tetrahedron 2005, 61, 4919. E.M. Beccalli, A. Contini, P. Trimarco, Tetrahedron 2005, 61, 4957. J. Saczewski, Z. Brzozowski, M. Gdaniec, Tetrahedron 2005, 61, 5303. J.-W. Park, J.-J. Kim, H.-K. Kim, H.-A. Chung, S.-D. Cho, S.G. Lee, M. Shiro, Y.-J. Yoon, Tetrahedron 2005, 61, 5389. S.-i. Naya, Y. Yamaguchi, M. Nitta, Tetrahedron 2005, 61, 7384. S.-i. Naya, K. Yoda, M. Nitta, Tetrahedron 2005, 61, 8616. N. Le Fur, L. Mojovic, N. Ple, A. Turck, F. Marsais, Tetrahedron 2005, 61, 8924. C. Berghian, M. Darabantu, A. Turck, N. Ple, Tetrahedron 2005, 61, 9637. S.P. Flanagan, R. Goddard, P.J. Guiry, Tetrahedron 2005, 61, 9808. Y. Takamuki, S. Maki, H. Niwa, H. Ikeda, T. Hirano, Tetrahedron 2005, 61, 10073. C. Mohan, P. Singh, M.P. Mahajan, Tetrahedron 2005, 61, 10774. R. Patel, L. Chu, V. Nanduri, J. Li, A. Kotnis, W. Parker, M. Liu, R. Mueller, Tetrahedron: Asymmetry 2005, 16, 2778. Y. Zhao, L. Zhou, THEOCHEM 2005, 726, 31. V. Timon, M.I. Suero, M.J. Martin Delgado, V. Botella, A. Hernandez-Laguna, THEOCHEM 2005, 714, 73. H. Yekeler, THEOCHEM 2005, 713, 201. T.V. Lukina, S.I. Sviridov, S.V. Shorshnev, G.G. Aleksandrov, A.E. Stepanov, Tetrahedron Lett. 2005, 47, 51. A.S. Kiselyov, Tetrahedron Lett. 2005, 46, 1177. A. Agarwal, P.M.S. Chauhan, Tetrahedron Lett. 2005, 46, 1345. D. Prajapati, A.J. Thakur, Tetrahedron Lett. 2005, 46, 1433. A.S. Kiselyov, Tetrahedron Lett. 2005, 46, 1663. I. Susvilo, A. Brukstus, S. Tumkevicius, Tetrahedron Lett. 2005, 46, 1841. C.R. Hopkins, N. Collar, Tetrahedron Lett. 2005, 46, 1845.
382 05TL1975 05TL2189 05TL3423 05TL3449 05TL5289 05TL5551 05TL5747 05TL5851 05TL7701 05TL7889 05TL8749 05ZN(B)22 05ZN(B)221
M.P. Groziak
L.G. Voskressensky, T.N. Borisova, I.S. Kostenev, I.V. Vorobiev, A.V. Varlamov, Tetrahedron Lett. 2005, 46, 1975. S. Zhao, M.G.P.M.S. Neves, A.C. Tome, A.M.S. Silva, J.A.S. Cavaleiro, M.R.M. Domingues, A.J. Ferrer Correia, Tetrahedron Lett. 2005, 46, 2189. B. Shao, Tetrahedron Lett. 2005, 46, 3423. H. Rudler, B. Denise, Y. Xu, J. Vaissermann, Tetrahedron Lett. 2005, 46, 3449. R. Pathak, A.K. Roy, S. Kanojiya, S. Batra, Tetrahedron Lett. 2005, 46, 5289. N. Matsumoto, M. Takahashi, Tetrahedron Lett. 2005, 46, 5551. X. Wang, S. Dixon, N. Yao, M.J. Kurth, K.S. Lam, Tetrahedron Lett. 2005, 46, 5747. G. Lavecchia, S. Berteina-Raboin, G. Guillaumet, Tetrahedron Lett. 2005, 46, 5851. H. Kondo, T. Igarashi, S. Maki, H. Niwa, H. Ikeda, T. Hirano, Tetrahedron Lett. 2005, 46, 7701. S. Tyagarajan, P.K. Chakravarty, Tetrahedron Lett. 2005, 46, 7889. M. Angiolini, D.F. Bassini, M. Gude, M. Menichincheri, Tetrahedron Lett. 2005, 46, 8749. H. Schumann, H.-K. Luo, Z. Naturforsch., B: Chem. Sci. 2005, 60, 22. E.K. Ahmed, M.A. Ameen, F.F. Abdel-Latif, Z. Naturforsch., B: Chem. Sci. 2005, 60, 221.
383
Chapter 6.2 (2006)
Six-membered ring systems: diazines and benzo derivatives (2006)
Keith Mills Ware, Hertfordshire UK
[email protected] ___________________________________________________________________________
6.2.1 INTRODUCTION The chemistry of diazines remains an area of intense interest, both academic and industrial, with applications in many areas, from biomedical to materials science and electronics. They are versatile, having very varied reactivity, giving many opportunities for manipulation of substituents. Nucleophilic substitutions, electrophilic substitution in oxy and amino derivatives, organometallic and transition metal-catalysed coupling reactions are all subjects of substantial research effort. There are obvious similarities in reactivity of the three diazine systems but also many interesting and practically important, often subtle, differences. All three systems are amenable to sequential substitutions, giving opportunities for use as scaffolds and also, particularly for pyrimidines, rapid muticomponent, often “one pot”, ring constructions are possible. Both these features give great potential for combinatorial chemistry and library construction. The main emphasis of this review will be on the synthetic and reactivity aspects of the three diazine systems and their benzo-derivatives, although some other interesting and significant applications will also be covered. Generally one or two representative examples of reactions or syntheses will be given and it is understood that further examples will usually be found in the original paper. However, this is flexible and generic reactions or products may be shown if this is considered more appropriate. 6.2.2
GENERAL STUDIES
The Negishi coupling reactions of a number of amino-chlorodiazines have been reported. The aminopyrazine 1 was used as the substrate for optimisation but examples involving the other diazines were also given. Dialkylzincs and alkylzinc halides reacted successfully and a particularly useful in situ formation of primary alkylzinc halides by exchange of an alkyl halide with diethylzinc could be carried out. Fortuitously, this alkylzinc exchange was catalysed by the nickel catalyst used for the following coupling <06TL341>.
384
K. Mills
N Cl
NH2
N
R = Pr, 92%; cyclopentyl, 46%; PhCH2CH2*, 42%; PhCH2* , 50%
N
RZnX, NiCl2.(dppp) R
N
(* prepared in situ from RBr + Et2Zn)
NH2
1 NH2
similar couplings with (e.g.): N
Cl
Br
N
Me
N
H2N
N
H2N
N
N
Cl
A study of the Į-arylation of diazine mono N-oxides, under Heck-like conditions, also gave emphasis to pyrazines but a number of examples using pyrimidines and pyridazines were also described (Scheme 1). A wide range of aryl chlorides, bromides and iodides was used and the products were easily deoxygenated by catalytic reduction. An interesting feature was the use of a copper additive, which was only required for the pyrimidine reactions, to give a very substantial improvement in yield <06AG(I)7781>. Pd(OAc)2, t-Bu3P.HBF4 K2CO3, dioxane, 110 °C
N
N
ArX
N O
N
H2, Pd or HCO2NH4, Pd
N O
N
Ar
Ar
86% yield
75% yield
Ar = 4-tolyl for optimisation studies similarly: N
N N O
N O
68% yield
N
N
N O
Ar
N
Ar
N
N O
73% yield
Ar
N O
standard conditions, 17% yield with 10 mol% CuCN, 61% yield
N O
Scheme 1 A metal-iodine exchange has been carried out on all three diazine systems under very mild conditions using lithium tri-n-butyl magnesate, although only one substrate from each system was used: 3-iodo-6-phenylpyridazine, 4-iodo-2-methylthiopyrimidine and 2-iodopyrazine. The pyridazine example was most problematic, possibly due to solubility problems. Aldehydes, benzophenone and diphenyl disulfide were used as the electrophiles <06SL1586>. N N
1) n-Bu3MgLi, THF, −10 °C I 2) PhSSPh, −10 °C to r.t.
N N
SPh
N SPh
86% yield
similarly
MeS
N
85% yield
SPh
Ph
N
N
62% yield
385
Six-membered ring systems: diazines and benzo derivatives (2006)
The copper-catalysed N-arylation of diazinones by aryl halides, but mainly using 2-fluoro-4iodoaniline, was described as part of a paper devoted primarily to pyridones. Pyrazin-2-one, pyrimidin-4-one and pyridazin-3-one all reacted successfully but pyrimidin-2-one failed to give any product <06TL7677>. N
NH2 F
N N H
CuI, 8-hydroxyquinoline, K2CO3, DMSO, 130 °C
N
N O
similarly prepared
O
O
N Ar
O
28%
Me
I
43% yield
F
N
NH2
6.2.3
N Ar
59%
PYRIDAZINES AND BENZO DERIVATIVES
The relatively rare discovery of a new pyridazine natural product – azamerone 2 – has been reported <06OL2471>. O
O Cl
N N
O OH
Cl OH
2 azamerone
6.2.3.1 Synthesis A number of pyridazines have been prepared by standard condensations of enediones with hydrazine but a general synthesis of the intermediate enediones is notable. This involved iodine-copper exchange of an iodoenone 3, followed by reaction of the resulting cuprate with acid chlorides. However, only a few of these enediones were actually converted into pyridazines <06OL1941>. O O R Ph
I 3
1) Npthyl2CuLi, THF −100 °C 2) O
COCl
Ph
Et
R R O
N2H4.H2O, EtOH reflux
O R = pentyl, 78% yield
Ph
N N O
Me3Si similarly prepared
N N S
96% yield
The one-pot synthesis of the dibromopyridazinone 4 has been optimised up to a 22 kg scale in a process research project. One key feature was the use of hydrobromic acid, rather than
386
K. Mills
hydrochloric acid, for the diazotisation step to avoid partial halide exchange in the final condensation <06TL8733>. Br
Br
Br Br
F
F NaNO2, HBr; SnCl2
F
HO
F
O
O
O
N NHNH2
NH2
N
F F
4
82% yield
Useful variations on another standard synthesis of pyridiazines by Inverse-ElectronDemand Diels–Alder reactions included the regioselective reactions of 1,2,4,5-tetrazine sulfoxides with enols, enamines and alkynes (Scheme 2). These sulfoxides have greater reactivity than the previously used sulfides but, more importantly, showed a reversed (complementary) regioselectivity. The reactions of the sulfoxide 5 appeared to be totally regioselective apart from one case (with 2,3-dihydrofuran). The Cbz amine 6 also reacted with high regioselectivity in most cases but there were several exceptions <06JOC185>. Ph N Me
S O
N N
SMe Me
N
Ph dioxane, 100 °C, 1 h
or
90% yield
5
Ph NHCbz
S O
94% yield
OTMS
Ph
Me
Ph
CH2Cl2, 25 °C, 1 h
SMe
N
N
Me
OTMS
N
CH2Cl2, 25 °C, 2 h Me
83% yield
S O
S O
NHCbz
N N
N
Me NHCbz
OEt
CH2Cl2, 25 °C, 6 h Me
N
N
6
S O
N
58% yield
N
Me Me
S O
NHCbz N
7% yield
N
The use of an alkynylboronate 7 as the dienophile allowed the synthesis of pyridazin-4ones <06OBC4278>. Cl O
B
O
7
N N
N N Cl
R R = H, Bu, Ph, TMS
O O xylene reflux
R
B
O
H2O2, Na2CO3 Cl
N Cl N 63% yield, R = H 86% yield, R = TMS
R Cl
Cl N H
N
73-85% yield
387
Six-membered ring systems: diazines and benzo derivatives (2006)
In a study of the use of microwave irradiation for the preparation of pyridazines by the cycloaddition of alkynes to 3,6-bis-(2-pyridyl)-1,2,4,5-tetrazine 8, it was found incidentally that acetone reacted, via its enol, with this tetrazine, also giving a pyridazine. Aldehydes reacted similarly but with variable yields and other ketones gave mixtures of products derived from both possible enols. In the one example (acetone) where it was tried, conventional heating gave an only marginally lower yield than microwave heating <06JOC4903> (The room temperature, base-catalysed, addition of aldehydes to tetrazines has previously been reported but this may be mechanistically different <79JOC629>). 2-py
2-py N N
Me2CO
N N
2-py
MW, 150 °C, 30 min; 75% yield
Me
N N
Conventional heating, 150 °C, 30 min; 69% yield
2-py
8
Conversion of other heterocyclic systems into pyridazines has also been used, for example the reaction of 3-aminopyrone 9 with hydrazine, followed by oxidative aromatisation <06T9718> and the more unusual utilisation of a 1,2,4-triazole 10 as the source of the N-N unit <06T8966>. In this latter transformation, the intermediate quaternary salt 11 was isolable. An even more unusual example was the reaction of the diazetidine 12 with enolates <06S2885>. NH2 O
CONHNH2
N2H4.H2O
O
N H 88% yield
9
Cl
N
Li
2) triazole
OH N
N
98% yield
Br
Ar 1) R
O
N
R
Ar
CO2Me
CAN, MeOH
Br2
Ar
N N
R N
NaOH
Ar
N
R N
N
N
10
11
NTol NHTol N N Me
NTol 12
O
R2
LiHMDS, THF
R1
−78 °C to rt
R2
NHTol
N N Me R1 = Me, R2 = H; 93% yield R1
In a paper concerned with the synthesis of fused pyridazines, the isoxazole 13 was used as a masked amino alcohol, which was eventually used to construct a fused pyridine ring. A standard hydrazine reaction, followed by hydrogenolysis of the isoxazole of the intermediate
388
K. Mills
14 gave the required pyridazine amino alcohol. The sequence is interesting, despite the low yield, which was due in part to instability of the bicyclic intermediate 14 <06TL2257>. F N N
O OHC N
O
NH2
Ar
N2H4.H2O O
H2, Pd
N
N
O
N 9% yield (2 steps)
14
13
Ph
Ar
HO
N N
N H
Ar
A cyclocondensation involving the carbonyl of a benzoquinone was used for the synthesis of a cinnoline 15 of interest as a potential anti-fungal agent <06BMCL1850>. O
O
CN
Me
Cl
Me
Cl
CO2Me EtOH, NH4OH, rt
O
Cl
Me
Cl
N2H4.H2O, EtOH CO2Me
Me
31% yield
O
HO
CO2Me NH2
Me
N
reflux
CN
Me
N
46% yield
15
Improved conditions for the cyclisation of 2-alkynyl diazonium salts to cinnolines, using aqueous sodium chloride, have been described <06OPPI476>
6.2.3.2 Reactions A review of the palladium-catalysed reactions of halo-pyridazines has been published <06SL3185>. The regioselective O-sulfonylation of 4-bromopyridazine-3,6-dione 16, using a hindered sulfonyl chloride, allowed efficient sequential boronic acid couplings. 2,4,6-Triisopropylbenzenesulfonyl chloride was the only sulfonyl chloride to give essentially complete regioselectivity, whereas the corresponding 4-phenyl pyridazinedione gave a highly selective reaction even with tosyl chloride. <06TL6125>. Br
Br O
O
N H
NH
Ar O
ArSO2Cl, py ArSO2O
16
NH
Suzuki
N 90% yield, >95% regioselectivity
ArSO2O
Ar O
N
O
NH Ar'
N
NH
ArSO2 = 2,4,6-triisopropylbenzene sulfonyl
A paper concerned with the synthesis of pyridazino[3,4-b]indoles 18 included a study of various conversions of 4,5-dichloro-2-methylpyridazin-3-one 17 including nucleophilic substitutions, Suzuki reactions and electrophilic substitution (nitration), combined with reductive dehalogenation, and usefully summarised previous work <06T121>.
389
Six-membered ring systems: diazines and benzo derivatives (2006)
Cl O N
Cl
Cl
Cl N
N2H4 H2NHN
O
Me
N
N
O
CuSO4 N
Me
N
NH2 O
via Suzuki
Me
79% N
17
N
Me
POCl3 71%
Cl
I O
Cl N
O2N
N
Me
N O2N
N
N
4
3
O
NaI
also prepared 4-Br 3-NO2 compounds
Me
18
N Me
N
The divergence of oxidative addition and nucleophilic substitution was shown by the reaction of the dichloropyridazinone 19 with phenoxide, which displaced the 6-chlorine, vs. a Suzuki coupling, which showed selectivity for the C-3 halide <06OBC4278>.
O R PhO
O Cl
PhONa, THF
N N CH2Ph
R
O Cl PhB(OH)2, Pd
N N CH2Ph
Cl
Cl
19
70% yield, R = Bu
R
Ph N N CH2Ph
62% yield, R = Bu
The microwave-assisted dipolar cycloaddition of pyridazinyl quaternary salts such as 20 was shown to be substantially better than the reaction using conventional heating. Novel regioselective reactions using monosubstituted dipolarophiles were also included <06SL804>.
N N
MeO2C
CO2Me Et3N, PhH CO2Me
MeO2C
N 20
58% yield 30% yield
N
CO2Me
N N
Et3N, PhH
CO2Me MW, 5min
(previous thermal conditions)
MeO2C
CO2Me CO2Me
59%yield 30% yield
6.2.4 PYRIMIDINES AND BENZO DERIVATIVES A useful discussion of the metallation of pyrimidines is to be found in a more general review on metallation <06EJO1593>. A full issue of Chemical Reviews was concerned with DNA damage and repair, parts of which may be of interest relating to pyrimidine reactivity
390
K. Mills
<06CRV213>. Biginelli compounds were included in an account of heterocyclic glycolconjugates <06ACR451>. Other reviews cover the chemistry of quinazoline alkaloids <06T9787> and pyrimidine chemistry in crop protection <06H561> 6.2.4.1 Synthesis The ever-popular Biginelli synthesis of dihydropyrimidines, by condensation of urea with a keto ester and an aldehyde, and variations on it, has been applied in a number of areas. R'
R'CHO
EtO2C
Biginelli reaction
NH2
R
H 2N
O
EtO2C
O
NH
R
O
N H
New variations in conditions include the use of antimony trichloride as a catalyst for the synthesis of monastrol analogues, with modifications in the aryl ring and replacement of thio by oxo <06BOC173>. The use of ionic liquids <06SC1503> and microwave enhancement <06BMCL4893> have also been reported. Nanosynthesis (single bead reaction) has been carried out <06AG(I)3102> and highly enantioselective reactions have been achieved using the catalyst 21 <06JACS14802>. 5-Nitro-dihydropyrimidines such as 22 have been prepared using Į-nitroacetophenone in place of the usual keto ester and shown to have potential as antiarrythmic agents <06BMCL1418>.
OH
Ph
N
O P
EtO2C
O O2N
O OH
NH
NH
monastrol Me
N R
S
Ph
Ph 21
N H
O 22
A surprisingly infrequent use of Biginelli compounds to make aromatic pyrimidines has also been reported. Dehydrogenation with ceric ammonium nitrate gave pyrimidinones 23 or pyrimidinediones 24, depending on conditions <06T9726>. Ph EtO2C O 24
CAN, AcOH 80 °C
NH N H
O 61% yield
Ph EtO2C R
NH N H
CAN, aq.Me2CO −5 °C
Ph EtO2C R
O 83% yield
N N H
O 23
A general method for the guanidine analogue of the Biginelli reaction has been developed using the two reagents 25 and 26, which overcome some of the limitations of the direct
391
Six-membered ring systems: diazines and benzo derivatives (2006)
guanidine condensation. The choice between the two reagents depended on the acid-stability of the substrate <06JOC7706>. RCHO CO2Et Me
EtO2C
R' NH2
HN
O
R
R
Me
EtO2C
N
Me
R'
N H
NH N
NH2
strong acid for 25 or Boc2O; NH3; TFA for 26
O Me R' HN
N
N
Me or
=
N
NH2
N
25 HN
HN
NH2
N 26 NH2
A number of alternative preparations of Biginelli-type compounds and similar dihydropyrimidines have been described. A route to N-1-substituted compounds 27, which are difficult to make by the standard Biginelli reaction, involved reaction of an Į-chlorobenzyl isocyanate with N-substituted aminocrotonates <06SL375>. EtO2C
ArCHO
EtO2CNH2 H2SO4 cat., 150 °C
ArCH(NHCO2Et)2
PCl3
NCO Ar Cl
Ar = Ph, 68% yield
Ar NHR
EtO2C
CH2Cl2, reflux
Me
Me
NH N R
O 27
Ar = Ph, R = Me, 64% yield Ar = Ph, R = 4-ClC6H4, 63% yield
Another multicomponent synthesis giving N-3-substituted compounds 28 consisted of the sequential reaction of metallated phosphonoacetates, in one pot, with a nitrile then an aldehyde and finally an isocyanate. This was an extensive study of the scope and limitations of the different substituents on all the components. The most important feature was that, for good yields, the isocyanate should bear an electron-withdrawing group – tosyl was the most successful. However, an exchange reaction could be carried out by reaction of the tosyl products with aryl isocyanates under microwave irradiation, giving the N-3-aryl derivatives 29 <06CEJ7178>.
392
K. Mills
R3
1) BuLi 2) R2CN
P(O)(OEt)2
R1
R1
3) R3CHO 4) R4NCO All reactions between -78 and rt
R2
N N H
R4 O
R1 = H, alkyl, aryl, CO2Et, P(O)(OEt)2 R2 = S-alkyl, aryl R3 = (alkyl), aryl R4 = Ts, RCO, (Ar)
28 (R4 = Ts) ArNCO, MW
R3 R1 via R2
N
R3
R4 NH
R1
O
R2
N N H
Ar O
29
The dihydropyrimidinethione 30 has been obtained by microwave-induced rearrangement of a dihydrothiazine, using silicon carbide as a passive heating element <06JOC4651>. Ph
Ph EtO2C Me
MW, SiC, toluene, 220 °C
S N H
NH
EtO2C Me
NH N H
S 30
68% yield
There has been significant emphasis on the use of pyrimidine thio ethers for further selective functionalisation by nucleophilic displacements of either the alkylthio or alkylsulfone and general syntheses of pyrimidines often include methylthio as one of the representative substituents. The reaction of enolisable ketones with nitriles under the influence of triflic anhydride is a useful general method for the synthesis of 2,4-“symmetrically” substituted pyrimidines. Reaction of 1-tetralone with aryl cyanides or methyl thiocyanate, followed by aromatisation with DDQ gave good yields of benzoquinazolines. The further transformation of the methylthio product 31, via oxidation and selective sequential nucleophilic substitution of the resulting sulfones, illustrates the utility of this substituent. 2-Tetralone reacted similarly but substantial amounts of by-products were formed <06T2799>.
393
Six-membered ring systems: diazines and benzo derivatives (2006)
O N
Tf2O, MeSCN
SMe
N
DDQ
N
CH2Cl2, rt
SMe N
31
SMe 70% yield
SMe
93% yield mCPBA
N
OMe
NaOMe, MeOH, refl.
NH3, rt
85%
N
N
74%
NH2
SO2Me N
85% yield
SO2Me
The same general method has been applied using N-benzylpiperidone 32 as the ketonic component (note the cleavage of the benzyl group) <06TL5463>. O Tf2O, RCN
R
N TfN
N CH2Ph
N
R = Me, Tol, MeS (45-65% yield)
R
32
The use of alkyl esters in place of ketones resulted in the formation of alkoxypyrimidines 33 which could be converted in high yields, via selective sequential nucleophilic substitutions, into amino dialkoxy and trialkoxy pyrimidines 34 <06EJO3332>. SMe RCH2CO2Et MeSCN
Tf2O
R
Nu 3 steps
N
EtO
N
SMe
33 R = alkyl, Ph (not H)
42-71% yield
R EtO 34
N N
Nu'
e.g. Nu = NH2, OMe; Nu' = OMe
The condensation of anilides or enamides with nitriles was developed as a general method for the synthesis of pyrimidines or quinazolines such as 35 and 36 <06JACS14254>.
394
K. Mills
Cy MeO
Tf2O NHCOPh
N
Cl
MeO
N
−78 °C to 45 °C
CN
N
Ph
35
90% yield R
similarly
O
O
N Ph N 36
NHCOPh
A process research investigation on p38 MAP kinase inhibitors examined the synthesis (on 7 mol scale) of a group of closely related pyrimidinones such as 37, by condensation of a number of arylacetic esters with 4-cyanopyridine and methyl isothiocyanate. Other nitriles were also examined but were much less successful than 4-cyanopyridine: 3-cyanopyridine gave a much lower yield and both benzonitrile and 2-cyanopyridine failed completely <06T11714>. Me CN
Me
O add KOt-Bu
Ar py
N
CO2Et
Add MeNCS then MeI
N
NH
N
CO2Et
N Reaction carried out on 7 mol scale
Me SMe
37
51% yield
Cyclobutane-fused pyrimidinones 39, precursors to quinone methide intermediates, have been prepared by reaction of amidines with the cyclopropane ester 38 <06EJOC2753>. Cl
38
R
CO2Me
HN
N
Et3N, dioxane, rt NH2
NH 39
R = aryl, MeS
R
O
43-83% yield
PhSO2 175 °C
N
R NH
PhSO2 O
39-84% yield
The synthesis of a pyrimidine 40 by reaction of an amidine with an isoxazole is an interesting example of interconversion of heterocycles <06TL3209>. In another heterocycle interconversion, the reaction of 3-amino-5-phenyl-1,2,4-oxadiazole with hexafluoropentane dione gave a mixture of the hydroxaminopyrimidine 41 and aminopyrimidine N-oxide 42. This was in contrast to previous work where pentanedione gave a high yield of only the corresponding amino N-oxide. The mechanism of the reaction was discussed, based on the isolated by-products <06T1158>.
395
Six-membered ring systems: diazines and benzo derivatives (2006)
Me
Me
Ph HN
N
N
NH2.HCl
N Ph
O
N Ph
N
K2CO3, MeCN
N
Ph N
31% yield Me
N Ph
O
O
NH2 N
Me
O
F3C
CF3
CF3
N
N
CF3 F3C
HClO4, MeCN
40
N
F3C
NHOH
41 39% yield
N O
NH2
42 21% yield
Pyrimidin-2-ones 43 with fluorinated substituents have been prepared by reaction of metallated imines with fluorinated nitriles, followed by cyclisation with triphosgene <06T1444>. O
Rf Me R1
NH2 Cl3CO
LDA, RfCN N R2
R1
Rf OCCl3
N R2
R1 mainly aryl, R2 alkyl or aryl or R1,R2 = (CH2)3 Rf = CF2Ph or C7F15
N R1
N O R2 43 70-94% yield
69-87% yield
A straightforward preparation of pyrimidinones and pyrimidinethiones 45 involved reaction of isocyanates or isothiocyanates with the readily available starting material 44, which had previously been described by the same authors. A particularly interesting application was the use of sugar isothiocyanates to give nucleosides. Nucleophilic displacements of the sulfur groups in the products were also reported <06EJO634>. SMe SMe MeS
NH
NMe2 44
RNCX, Et3N
N R = alkyl, aryl, sugar O = S, O
N N R 45
N
S
BzO
X
O
Nu−
including e.g. OBz OBz
Nu N N R
X
The nickel-catalysed co-trimerisation of acetylenes with isocyanates gave good yields of uracils 46, depending on the isocyanate substituents, pyridones being unwanted by-products
396
K. Mills
in some cases. Trimethylsilyl and tri-n-butyltin were favoured as the acetylene substituent, the latter being carried through to an in situ Stille coupling <06T7552>. O Me
TMS
Ni cat.
TMS
N
R
N O R 46 Yields up to 83% Me
RNCO
Me
Similar reaction with
SnBu3
followed by in situ Stille coupling (75% overall, R = Et)
An efficient preparation of 5-cyanouracils started from N-ethoxycarbonylcyanoacetamide 47, the carbonyl of the urethane finally being incorporated into the uracil ring <06BMC3399>. O O (EtO)3CH, MeCN
O NC
RNH2
NC
NHCO2Et
NC NHCO2Et
Et3N
N O R generally >70% yields overall
RHN
47
NH
Uracil 5-carboxylates 48 were prepared by reaction of aminomethylene malonates with chlorosulfonyl isocyanate. The reaction was greatly accelerated by microwave irradiation (1h vs. 2-3 d in refluxing toluene), although the microwave yields were somewhat lower than those from the thermal reactions. The chlorosulfonyl group was lost during work-up and chromatography. The method was compatible with sugar residues <06TL1989>.
O EtO2C
CO2Et NHR
ClSO2NCO
EtO2C
MW, benzene 1 h or toluene reflux 2-3 d
NH N R
R = Ph, yield 60% (thermal), 44% (MW) OAc
O 48
R=
O
AcO OAc
yield 70% (thermal) 58% (MW)
OAc
An improved synthesis of 11C-2 thymine 49, for use in PET scans, was made possible by an efficient and rapid synthesis of 11C-phosgene, previously reported <02NMB345> by the same authors. 11C is a particularly interesting challenge due to its very short half life (20 minutes) and the whole sequence and purification from the end of the bombardment took 16 minutes. The scale was necessarily small (0.2 mg) <06TL5321>.
397
Six-membered ring systems: diazines and benzo derivatives (2006)
O
O EtO2C
Me
Me
H2N
3 steps
KOt-Bu, DME
HN C N O H
Me
11
CHO
HN COR
11COCl
2
49
14N
2
+ H2
18 MeV proton beam
11CH
11CCl
4
4
10 min
16 min
A number of new conditions and catalysts have been used for the synthesis of quinazolinones 50 from anthranilic acids, amines and ortho esters, including bismuth trifluoroacetate with an ionic liquid <06TL3561>, lanthanum nitrate or tosic acid under solvent-free conditions at room temperature <06TL4381> and Nafion-H <06SL2507>. O CO2H
R1NH
2 3 2, R C(OR )3
NR1
NH2
N
50
R2
Quinazolines 51 have been prepared by the condensation of N-aryl carbamates with hexamine, followed by aromatisation of the dihydro intermediate. A variety of mono- and disubstituted anilides were used, meta-substituted starting materials giving 7-substituted quinazolines <06T12351>. Benzoquinazolines were also prepared similarly from naphthylamine carbamates <06OL255>.
Me
Me
hexamine, TFA NHCO2Et
N
K3Fe(CN)6, KOH
Me
N 51
reflux
N CO2Et
N 49% yield
The convenient synthesis of dichloroquinazolines 52 from anthranilonitriles by reaction with diphosgene was also applied to fusion of pyrimidine rings onto other heterocyclic aminonitriles <06SL65>. Cl CN NH2
Cl3COCOCl
N
MeCN, 130 °C
N
52 Cl
86% yield Cl CN N N Bn
NH2
Cl3COCOCl MeCN, 100 °C
N
N
N Cl N Bn 51% yield
Yields for 6-substituted compounds range from 41% (CF3) to 80% (Me)
398
K. Mills
The reaction of 2-isothiocyanato benzonitrile with aryl acetonitrile anions was used to prepare quinazoline thione derivatives 53 <06S3067>. NC CN
Ar
ArCH2CN, NaH
NH
NCS
N H
53
S
Quinazoline diones 54 were also available from 2-bromobenzoates via a palladiumcatalysed N-arylation of ureas<06OL5089>. O Cl
CO2Me H 2N
Br
NHBu
Pd2(dba)3, Xantphos, Cs2CO3
O
dioxan, 100 °C
Cl
N N H 85% yield
Bu 54
O
Substituted and aza analogues of febrifugine have been prepared in the search, with a certain amount of success, for a better anti-malarial activity/ toxicity balance <06BMCL1854>. A number of analogues of rutaecarpine, including substituents in and fusion onto ring D were prepared by condensation reactions on iminothio ethers 55 <06TL1777>. N
HO O N
O
N H
febrifugine
R N SMe
N H 55
CO2H
O AcOH
N
NH2 reflux 24h
N H
N
R
rutaecarpine (R =H) 85% yield
Malayamycin A has been synthesised by a lengthy route, starting with the reaction of a protected ribonolactone with a lithiated pyrimidine <06T5201>. A much shorter synthesis of the fused quinazoline asperlicin D involved direct cyclisation of a diamide <06TL693>.
399
Six-membered ring systems: diazines and benzo derivatives (2006)
O OMe
O O
O
OMe O
Li
O
N N
O
O NH
O
3 steps
NH
O H OH malayamycin A
N
NH2 O NH
O
NH H
O OMe
H N
H N
H2N MeO
22 steps
MgCl2, DMF CO2Me
O
130 °C
O
NH
N
O
O 35% yield
N H
N H
asperlicin D
The synthesis of both enantiomers of vasicinone has been carried out using almost entirely polymer-supported reagents. The route was based on functionalisation of deoxyvasicinone by a highly selective bromination then via enantioselective reduction of the derived ketone <06SL2609>. O
O
O PPh2
N
N
N 98% yield
N3
O
NMe3+Br3−
N
N Br
99% yield
3 steps O
O N
similarly 10S-vasicinone N OH 10R-vasicinone
NaBH4, TMSCl
N
Polymer-supported chiral ligand
N
Me2N
N
OMe
O HN
NH2.HCl
BnHN
N OH
N
N N
N
N
O
.
79% yield
N BnHN
OH
N
variolin B2
N N NH2
N
NH2
NH2
N
N
N H2N
NH2
N
K2CO3
N
N
N
OMe
NH2 NMe2
O
87% yield
N H2N 56
N N NH2
400
K. Mills
Some analogues of the marine alkaloid variolin B2 were prepared as potential cytotoxic agents. The compound 56 is particularly interesting as its synthesis included the simultaneous formation of two pyrimidine rings <06JMC1217>.6.2.4.2 Reactions Two examples of pyrimidines 57, 58 were included in a study of direct magnesiation of heterocycles. Both of these metallated selectively at C-4 using “inverse addition” i.e. substrate added to the metallating agent <06AG(I)2958>.
Br
57
N MgCl.LiCl
N
−55 °C to −40 °C (inverse addition)
N
I
MgCl.LiCl Br
I2
N
Br
67% yield N
N
Ar
MgCl.LiCl
similarly N 58
N
N
OH
4-C6H4CHO
N Cl
N
Cl
N N
68% yield Cl
Conditions for the magnesium-iodine exchange in 5-(4-iodophenyl)pyrimidine with isopropylmagnesium chloride have been optimised. It was found that addition of bis-[2-(N,Ndimethylamino)ethyl] ether greatly inhibited the major side reaction, addition to the pyrimidine ring <06OL3141>. Selective halogen exchange at C-5 of 5,6-dibromo-2,4dimethoxypyrimidine 59 was carried out using isopropylmagnesium chloride. The second bromine also exchanged, but much more slowly, allowing a clean “one pot” sequential replacement of both <06OL3737>.
OMe Br Br
OMe i-PrMgCl, rt; RCHO then i-PrMgCl; R'COCl
N N
OMe
"one pot conversion"
HO
N
O
N N
59 OMe
69% yield
O
Nucleophilic substitution of leaving groups is probably the most important area in pyrimidine reactivity and, in particular, the differential reactivity of C-2 and C-4 is the most investigated topic. The displacement of 2- and 4-sulfide and sulfone groups is referred to in the synthesis section. The selective hydrolysis of 4-amino-2-chloropyrimidines under acidic conditions has been studied in great detail by a process research group <06OPRD921>. The selective displacement of the 4-chlorine in 2,4-dichloro compounds can be capricious but a much better result was obtained starting with 4-chloro-2-methylthiopyrimidine 60. A displacement of chlorine was followed by oxidation of the methylthio to sulfone and displacement of sulfone <06BMCL5633>
401
Six-membered ring systems: diazines and benzo derivatives (2006)
Me
Me HN
Cl RNH2, MW
N
5-azabenzimidazole K2CO3
mCPBA
N N
SMe
N
HN
Ph
N
N N
SMe
N
76% yield
88% yield
60
Ph
N
A number of palladium-catalysed reactions of the triflate 61 have been reported but the nucleophilic displacement with primary aliphatic amines was, surprisingly, very slow in refluxing THF (24-92h). However, under microwave irradiation the reactions were very rapid and gave high yields, although even with microwaves, secondary amines and anilines failed to react <06TL4437>. Me N O
N 61
Me N
RNH2, MW
N
5-12 min
OTf
O
N N
NHR
A useful investigation has been published on the comparison of the reactions of 6-aryl-2,4dichloropyrimidines towards nucleophilic substitution with amines vs. palladium-catalysed amination. In many cases, the nucleophilic reactions showed moderate selectivity (ca. 4:1) while the corresponding palladium reactions were highly selective (often 98-99%) for C-4, although this was quite ligand-sensitive, with dppb being the ligand of choice <06OL395>. Another study showed modest selectivity for C-4 in 2,4-dichloropyrimidine 62 using tbutylamine, while the Sonogashira reaction showed high selectivity <06OL269>. TMS Cl Sonogashira
N
N
Cl
N
87% yield
62
N
Cl
NHt-Bu t-BuNH2
Cl
N
N
reflux
N
N
Cl
65% yield
NHt-Bu
26% yield
Another example with the same substrate was a highly C-4-selective Negishi coupling (ArZnCl/ Pd) <06T2380>. Cl
n-BuLi, ZnCl2
I
NHBoc
N
NHBoc ArZnCl
N
62 Cl 75% yield
Pd cat
N N
Cl
402
K. Mills
A detailed study of the regioselectivity of Suzuki couplings on 2,4-dihalo- and 2,4,5trihalopyrimidines and some related substrates under microwave conditions has been reported <06TL4415>. In another paper, Sonogashira reactions on the 5-bromo-4-chloropyrimidines 63 were, surprisingly, found to be selective for the chlorine, although for the corresponding 5iodo compounds normal selectivity (I>Cl) returned <06TL3923>. Another investigation in this area showed that the Suzuki coupling of 5-bromo-2-chloro-4-piperidinylpyrimidine was selective for the C-5 bromine <06SL861>. R Cl Br Me
N
63
Br
Sonogashira
N
Me
X
N N
X
X = NH2 or MeS
There is always interest in the photochemistry of the pyrimidine nucleic acid bases and related simple pyrimidinones, due to its importance in genetic mutation. In addition to damaging DNA, photo-induced reactions may also repair the damage, as in the reduction, by FADH, of the thymine glycol 64 back to thymine <06JACS10934>. Another report related to repair of DNA involved a model study, by means of the linked dimer 65, of the involvement of tryptophan in the electron-transfer leading to reversion of thymine oxetane adducts <06OBC291>. O O HN O
O
Me OH
N
OH
DNA
64
HN
Me
FADH hν
HN O
N
O N
Me O Ph H R O
HN
DNA
65 MeO2C
RN
Other model studies related to DNA photo damage include the photocyclisation of 5 and 6benzyluracils 66, 67 <06OL681> and the related cyclisation of 5-phenylthio uridine, incorporated into a dinucleotide 68 <06OL2527>. O HN O
O Ph
N H 66
hν
HN O
O
O hν
HN N H
O
N H 67
Ph
HN O
N H
403
Six-membered ring systems: diazines and benzo derivatives (2006)
O
O SPh
HN N
O 68
hν
N
O
O
S
HN
O OH
OH
O
P O HO O dGuanosine
O P O HO O dGuanosine
A computational study was concerned with the effect of solvation on the radical ion involved in CDP photolyase enzyme-catalysed reversion of thymine and uracil cyclobutane dimers stimulated by visible light <06T6490>. Photo-induced conversions are also important synthetically. The photocycloaddition of 5substituted uracils 69 with ethylene has been used for the synthesis of 2aminocyclobutanecarboxylic acids. The addition reaction worked well with carbon and fluorine substituents and also with a Cbz-protected amino. However, uracils with other 5nitrogen substituents (NH2, NHBn and NO2) failed, only starting material being recovered. The sequence also worked for the 6-isomers but somewhat less consistently <06SL1394>. O R
H2C CH2
NH N H
O
R
NH
hν aq. Me2CO
69
O
N H R Me Ph F NHCbz CO2H
R
0.5M NaOH
CO2H
r.t.
O
R
NaNO2, HCl
CO2H
NH O
Yield 85% 36% 80% 81% 80%
NH2
NH2
R Yield(2 steps) Me 65% Ph 30% F 74%% NHCbz 36% N.R. CO2H (The CbzNH comound also gave 31% amine)
An unusual C-5-alkylation of 6-chlorouracil occurred on attempted displacement of the chlorine by the aminoindane 70. The reacting species was thought to be the stabilised carbonium ion 71, generated by loss of the amino group <06JOC7053>.
O NH Cl
N H
O
Me2N Me2N
NH
Et3N, DMSO
O 70
NH2
130 °C-140 °C, 4h
Cl
N H 75% yield
Me2N via
O 71
404
K. Mills
Surprisingly mild conditions, using a multi-component reaction with aldehyde, amine and isocyanide, were sufficient for replacement of oxygen by amine at C-2 or C-4 of pyrimidinones. The reaction was thought to proceed via O-alkylation followed by a Smiles rearrangement 72. The method also works with 2-ones and 2-thiols <06OL4019>. A more regular direct replacement of oxygen by amines in uracil and other pyrimidinones used BOP 73 as the activating agent <06OL2425>. Cy
Et O
Cy CyNC, R2NH2, EtCHO
N Me
N H
R1
N O
R2 N
MeOH, 60 °C Me
N
N
Et R R1
O NH
via ?
89% yield R1 = Ph; R2 = 4-Cl benzyl
N N
72
O O NH N R1
O
NHR2
RNH2 BOP, DBU rt to 60 °C
N
Br N H
N
(Me2N)3P
N
NH Cl
N N O
N
O
N O R1 e.g. R1=Bn, R2=n-Bu 73% yield
N
NH
similarly with
PF6
O
73 BOP
An efficient method has been developed for the conversion of pyrimidine-2-thiol into the sulfonyl chloride 75, which was reacted in situ with amines. A modified method gave the rather more stable (and storable) sulfonyl fluoride 74 <06JOC1081>. NaOCl, KHF2
N N 74
SO2F
NaOCl, HCl
N N
SH
−25 °C
RNH2
N N
SO2Cl
N N
SO2NHR
75
The use of more polar solvents (acetonitrile, DMF) improved the N:O ratio Mitsunobu alkylation of 3-benzoyl thymine with cyclopentanol <06SL324>. N selectivity in the alkylation of 2-pyrimidinones has been investigated and the rationalised on the HSAB principle <06T6848>. 2-Phenylthioethyl has been used as a protecting group for N-3 of thymidine manipulation of the sugar. It was removed via oxidation to the sulfone <06SL845>.
in the vs. Oresults during
The reaction of N-methyl nitropyrimidinone 76 with aminocrotonates has been used for the synthesis of 4-aminonicotinates. The only example using a dialkylamino crotonate gave a similar yield, but the equivalent reactions using aminoenones and 4-substituted aminocrotonates gave only very modest yields <06SL1437>.
405
Six-membered ring systems: diazines and benzo derivatives (2006)
O O2N
N
NHR
EtO2C
Me
Me
N
NHR
R Pr Ph CH2CH2OH
CO2Et
MeOH reflux
N
76
Yield 88% 48% 80%
(10 other examples)
6.2.4.3 Applications The 5-anthranylpyrimidinone 77 was designed to be a selective sensor for fluoride ion <06JOC2143>
O N Me
N H
O N H
N H
n-Bu
77
Amino pyrimidine-terminated oligothiophenes such as 78 were components of donor-acceptor photovoltaic devices <06T2050>. O
NH2 N H 2N
N
N
N
S
S
S
S
S N
H2N
O
H 2N
NH2
N
NH2
78
Some peptide sensors were based on binding to the zinc chelate of ligands such as 79, with specific quenching of the fluorescence of nearby tryptophan residues in the peptide <06T12191>. HO2C HO2C
R N
CO2H
N
H N
R N N H
O
N
H N O
N N H
NHBoc
79
A study of the interaction of 6-pyridinium substituted uracil mesomeric betaines 80 with nucleic acid has been reported <06OBC3056>.
406
K. Mills
O NH N R2N
O
N 80
2-Amino 4,6-dihydroxypyrimidine is a useful ligand for copper-catalysed arylations of other heterocyclic NH <06JOC8324>.
6.2.5
PYRAZINES AND BENZO DERIVATIVES
A review discussed the use of 3,5-dichloropyrazin-2-one as a versatile scaffold for synthesis <06S2799>. A feature article was concerned with the synthesis of dragmacidins <06CC3769>. 6.2.5.1 Synthesis A variation on the usual synthesis of pyrazines, reaction of 1,2-diones with diamines, was the use of the diazabutadiene 81 in place of the dione <06JOC5897>. In another paper, the same diaza compound 81 reacted with sarcosine methyl ester, in a complex set of reactions, to produce quite good yields of 5-oxy-pyrazine-2-carboxamides 82. The N-methyl was lost and direct aromatisation occurred, presumably, due to cleavage of the N–N bond <06SL2403>. R1 R2O2C
N
R3
NH2
R4
NH2
N
81
Me
dihydropyrazine mixture
benzoquinone or Pd-C
R3
N
R1
R4
N
Me
R1 = CO2Me, CONMe2, P(O)(OEt)2 etc NHMe CO2Me
R1 = CONMe2 R1 R2O
2C
N H
NaOEt
N Me
N Me
CO2Me
THF, reflux
Me2NOC
N 82
Me
O N H 44% yield
The thermal rearrangement of 1,2-dialkynylimidazoles gave intermediate cyclopentapyrazine carbenes 83, which then trapped the solvent (benzene) to give a phenylsubstituted products 84 <06TL353>.
407
Six-membered ring systems: diazines and benzo derivatives (2006)
Ph N
PhH
N R2
R2 80-100 °C
N
:
N
N
38-88% yields
R2 N
R1 83
R1
84
R1
Quinoxalines 85 have been prepared by the reaction of diols with benzene-1,2-diamines in the presence of a ruthenium catalyst <06TL5633>. Iodobenzene diacetate has been suggested as a less toxic alternative to lead tetraacetate for the oxidative cyclisation of iminooximes to quinoxaline N-oxides 86 <06TL4969>.
NH2
HO
R
HO
R'
OH N
Ph
N
Ph
R
N
R'
85
Ru cat., KOH
NH2
N
PhI(OAc)2
O N
Ph
CH2Cl2, rt
N
Ph
86
A route to an intermediate 87 containing the core system of dragmacidin has been described, which involved the three-point fusion of an indole onto the seven-membered ring <06OL4775>. OTIPS
NTs
OTIPS
NTs
N
N N N I
OMe
OMe
O
BnO
N Ac
87
6.2.5.2 Reactions The reaction of pyrazine and quinoxaline with methyl chloroformate and bis-silyl enol ethers gave fused tetrahydropyrazine lactones 88, in an extension of previous work. There was little consistency with the variation of R in the stereochemistry of the products <06T12084>.
408
K. Mills
OTMS R
N
CO2Me R N
OTMS
CO2Me R N O
O N CO2Me
MeO2CCl
N
O
similarly O N CO2Me
88
An interesting iridium-catalysed 5-CH boronation of 2,3-dimethylpyrazine was reported incidentally in a paper mainly devoted to the reaction of pyridines. The product 89 was used in a Suzuki coupling <06AG(I)489>. Selective mono coupling of 2,6-dichloropyrazine with boronic acids, followed by amine displacement of the second chlorine has been used to prepare potential anti-cancer compounds <06JMC407>. A full paper has been published on the chelation-driven selective Suzuki coupling of the pyridinium ylides 90 <06TL6457>. N
Me
B2pin2, [Ir(cod)(OMe)]2 (2.5 mol%)
N
Me
N
O
Me
L=
B O
t-Bu
t-Bu
Br
S
L (5 mol%), hexane, rt, 16 h N
Me
Pd
N
Me
N
Me
S 89
34% yield
N
N
N N
N
Br
N
Suzuki Br
N N
N
Ar
N
Br
90
An abnormal (tele) substitution of chlorine in both 2,3- and 2,6-dichloropyrazines 91, 92 occurred on reaction with dithiane anion, while morpholine gave the normal ipso-substitution <06TL31>. Another paper described the highly selective ipso monosubstitution of the 2,3dichloro compound by enolates in toluene <06T9919>. S N N
Li S
S
Cl
−78 °C
Cl
91
N
N
N
Cl
N
N O
S
similarly
S
N
Cl
S morpholine
N
73% yield
Cl
N 92
Cl
N
Cl
69% yield
409
Six-membered ring systems: diazines and benzo derivatives (2006)
6.2.5.3 Applications and structural studies Quinoxaline bis-N-oxides have been investigated as potential anti-cancer agents 93 <06BMC6917> and anti-trypanosomal agents 94 <06BMC5503>. In the latter case, a vanadyl complex was prepared in order to increase bioavailability. O O N N O
N
O N
NH Ar
N O
93
CN NH2 V O
2
94
Several papers were concerned with the synthesis of and mechanism of luminescence of Cypridina luciferin and its analogues <06T6272; 06TL753; 06TL6057>. The binding of the diuretic amiloride 95 to DNA has been studied <06CC1185>. The chiral camphor-derived pyrazine ligand 96 showed monomeric coordination to Cu and Zn, in contrast to the bidentate polymeric behaviour of related earlier compounds <06ARK218>. NH2 HN Cl
N
H2N
N
NH O
N 96
amiloride 95 N
NH2
There has been continued interest in the potential of pyrazines for use in materials science and electronics. Studies of the solid state behaviour have been carried out on pyrazine perchlorate and tetrafluoroborate <06JACS15775> and of alkyl-substituted pyrazine bis-Noxide-TCNE complexes <06TL4569>. The crystallisation and self-assembly of derivatives of hexaazatriphenylene (hat) 97, were also of interest, such as the copper complex 98 <06JACS15799> and tri-benzo compound 99 <06JACS13042>. Fluorescent hexakis (biphenyl) derivatives have been investigated as “light-harvesting” systems <06JOC5752>. CN
CN N
CN
N
N
N
NC
N
N
N
N
NC
N
N
N
97
hexaazatriphenylene (hat)
N
Cu1, EtOH
CN CN
L2Cu
OEt
N
EtO
N
N
NC
N
N
CuL2 L2Cu 98
N
CN OEt
410
K. Mills
R N R
N
O
N R=
N
N
N H
N
n-octyl
R 99
The quinoxaline 100, with self-contained donor-acceptor properties, has potential in optoelectronic <06JACS10992>. Electroactive dendrimeric bis-quaternary salts have been prepared by direct quaternisation of pyrazine using dendrimeric benzyl bromides <06TL4711>. R N N R R = C6H4R' or NMeAr 100
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06TL3561 06TL3923 06TL4381 06TL4415 06TL4437 06TL4569 06TL4711 06TL4969 06TL5321 06TL5463 06TL5633 06TL6057 06TL6125 06TL6457 06TL7677
06TL8733
413
A.R. Khosropour, I. Mohammadpoor-Baltork, H. Ghorbankhani, Tetrahedron Lett. 2006, 47, 3561 M. Pal, V.R. Batchu, N.K. Swamy, S. Padakanti, Tetrahedron Lett. 2006, 47, 3923 M. Narasimhulu, K.C. Mahesh, T.S. Reddy, K. Rajesh, Y. Venkateswarlu, Tetrahedron Lett. 2006, 47, 4381 S.C. Ceide, A.G. Montalban, Tetrahedron Lett. 2006, 47, 4415 S. El Kazzouli, G. Lavecchia, S. Berteina-Raboin, G. Guillaumet, Tetrahedron Lett. 2006, 47, 4437 T.J. Kucharski, J.R. Oxsher, S.C. Blackstock, Tetrahedron Lett. 2006, 47, 4569 P. Rajakumar, K. Ganesan, Tetrahedron Lett. 2006, 47, 4711 R. Aggarwal, G. Sumran, A. Saini, S.P. Singh, Tetrahedron Lett. 2006, 47, 4969 K. Ohkura, K. Nishijima, K. Sanoki, Y. Kuge, N. Tamaki, K. Seki, Tetrahedron Lett. 2006, 47, 5321 A. Herrera, R. Martínez-Alvarez, R. Chioua, J. Almy, Tetrahedron Lett. 2006, 47, 5463 C.S. Cho, S.G. Oh, Tetrahedron Lett. 2006, 47, 5633 Y. Takahashi, H. Kondo, S. Maki, H. Niwa, H. Ikeda, T. Hirano, Tetrahedron Lett. 2006, 47, 6057 J.X. de Araújo-Júnior, M. Schmitt, P. Benderitter, J-J. Bourguignon, Tetrahedron Lett. 2006, 47, 6125 M.J. Reyes, R. Castillo, M.L. Izquierdo, J. Alvarez-Builla, Tetrahedron Lett. 2006, 47, 6457 K.J. Filipski, J.T. Kohrt, A. Casimiro-Garcia, C.A. Van Huis, D.A. Dudley, W.L. Cody, C.F. Bigge, S. Desiraju, S. Sun, S.N. Maiti, M.R. Jaber, J.J. Edmunds, Tetrahedron Lett. 2006, 47, 7677 J. Zhang, H.E. Morton, J. Ji, Tetrahedron Lett. 2006, 47, 8733
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Chapter 6.3
Triazines, tetrazines and fused ring polyaza systems Pilar Goya and Cristina Gómez de la Oliva Instituto de Química Médica (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain e-mail:
[email protected]
6.3.1
TRIAZINES
6.3.1.1 1,2,3-Triazines Computational studies of hydrogen bonding complexes between 1,2,3-triazine and water have been carried out <06JST83; 06MI401; 06MI209>. A theoretical study of 1,2,3-triazine in water has been reported <06JST87>. Ternary complexes of europium(III) ions and triazine have been prepared. A complex containing 5,6-diphenyl-(2-pyridyl)-1,2,3-triazine produced efficient electroluminiscence <06MI489>. Oxidation of 1-(alkylamino)pyrazolones 1 allowed the preparation of monocyclic 1,2,3triazin-4(3H)-ones 2, which are a new class of heterocycles <06EJO3021>. Ph
O
Me Me
H N N O NHR 1
R=H
Ph
O R
N H
N NH
Cu(OAc)2 , MeOH 60-76%
Me Ph
N 2
N N
R
The reaction of 1,2,3-triazolium-1-aminides 3 with propiolate esters led to fluorescent 2,5-dihydro-1,2,3-triazine derivatives 4 in one pot, involving a Huisgen cycloaddition followed by a sequence of rearrangements <06JOC5679; 06TL1721>. These reactions can be carried out in acetone, in water, or under solvent-free conditions.
415
Triazines, tetrazines and fused ring polyaza systems
X X
Ph
Ph O
O
N N N N
H OMe
N
Ph
MeO
30-50%
Ph
N
N N
4
X
X 3
6.3.1.2 1,2,4-Triazines A convenient way to modity calix[4]arenes, based on the direct C-C coupling reactions of their phenol moiety with 1,2,4-triazines has been reported <06JOC8272>. A theoretical study of the tautomerism of 6-substituted 1,2,4-triazin-3-thion-5-one has been carried out <06JST123>. A new complex derived from 5-methoxy-5,6-diphenyl-4,5-dihydro-2H[1,2,4]triazine-3-thione (LH2OCH3) with methylmercury chloride was synthesized and characterized <06POL1464>. Complexes of the types LPtCl2 and [L2Pt]X-2 (L=substituted 3(pyridin-2-yl)-1,2,4-triazine) were synthesized and characterized for the first time by X ray crystallography <06IC7182>. A one-pot procedure for preparing 3-pyridyl-5-substituted 1,2,4-triazines 7 from αhydroxyketones 5 and 2-pyridyl amidrazone 6 has been described <06TL3865>. R
O
H2N
OH
H2N
5
Py N
R
MnO2, Δ 60-70%
N N
6
Py N
7
Substituted 1,2,4-triazines were conveniently prepared in one pot by the condensation of amides and 1,2-diketones followed by cyclization with hydrazine hydrate <06MI67>. A new class of cyclic dipeptidyl ureas, namely 3-hydroxy-6-oxo[1,2,4]triazin-1-ylalaninamides 12, have been synthesized using the Ugi reaction. This reaction involved an αketo-acid acid 8, an isocyanide 9 and semicarbazones 10 to give the Ugi adducts 11, wich were then stirred with sodium ethoxide <06JOC4578>. O Ar
O R3NC
HO
O 8
9
HN N
NH2 R2 R1 10
Ugi reaction MeOH 3 days 46-73%
Ar O O HN
O
NH2 O
N NH R2 R1 R3 11
Ar
N
O O
N
EtONa EtOH 12 h 53-84%
HN
OH N R2 R1
R3 12
Several 3-mercapto-1,2,4-trizines have been synthesized through the condensation of thiosemicarbazide with diketones under microwave irradiation in a solventless system <06PS87>. The synthesis and cyclocondensation reactions of 3-substituted-5-(2aminobenzyl)-1H-[1,2,4]triazin-6-ones have been reported <06JHC613>.
416
P. Goya and C.G. de la Oliva
The reactivity and use of 1,2,4-triazine 4-oxide have been described <06OM2972>. Thus, readily available (3-pyridyl)-1,2,4-triazine 4-oxides 13 were used to prepare 2,2'bipyridines 15. The reaction course involves a nucleophilic substitution of hydrogen and an aza Diels–Alder (DA) reaction <06TL869>. Ar H
N
N
N O
NuH RCOCl 28-56%
Py
Ar
N
Nu
N
Ar
2,5-norbornadiene
N
Nu
82-90%
Py
14
N
Py
15
13
The first case of the use of amino acids as chiral auxiliaries in nucleophilic addition to triazinones was employed in the reaction of C-nucleophiles with 3-aryl-1,2,4-triazin-5(4H)ones 16 and N-protected amino acids 17, to form 1-acyl-6-Nu-3-aryl-1,6-dihydro-1,2,4triazin-5(4H)-ones 18 in high diastereomeric excess <06TL7485>.
O
H N N
OH
Ar O
N
H N
R2
R1
16
O
H N
Nu
N
NuH 14-18%
Ar N H N
O
17
R2
1
R 18
Chiral 4-(1-arylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones were synthesized easily through enantioselective diethylzinc addition to the exocyclic C=N double bond of 4-arylidenamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones <06TA2617>. The pyrolysis in the gas phase of 4-benzylidenamino- and 6-styryl-1,2,4-triazine-3,5(2H, 4H)-diones and 6-styryl-2,3-dihydro-3-thioxo-1,2,4-triazin-5(4H)-ones has been studied <06T1182; 06T6214>. The DA reaction of 5-acetyl-3-methylthio-1,2,4-triazine with cyclic enamines has been used in the total synthesis of new indazolo[2,3-a]quinolizine alkaloids <06T5736>. Novel agonist 5HT1A receptor position emission tomography (PET) ligands derived form 1,2,4-triazine-3,5-dione 19 have been synthesized and evaluated in vivo <06JMC125; 06BMCL2101>.
O
CH 3 O N N
H 3 11 C
N
O
N N 19
6.3.1.3 1,3,5-Triazines The product of an episulfonium ion-mediated cyclotrimerisation previously reported as a 15-membered ring trilactam has now been shown to be a 1,3,5-triazine <06OBC3120>. The tautomerism of 2,4-di(benzyloxy)-1,3,5-triazin-6(5H)-one has been studied <06MI561>.
417
Triazines, tetrazines and fused ring polyaza systems
Theoretical studies on the nonlinear optical properties of octupolar tri-s-triazines have been carried out <06MI808>. The azide-tetrazole isomerism in several polyazido 1,3,5-triazines and diazido-1,2,4,5tetrazines has been investigated by ab initio quantum chemical methods <06EJI2210>. The tridentate ligand 2,4,6-tri(2-pyridyl)-1,3,5-triazine has continued to be the basis for different complexes, among other with copper <06IC7119>, iron <06MI1150>, manganese, zinc and cadmium <06POL2550>, and with lanthanoids <06POL1057>. A novel ligand N,N'di(2-pyridyl)-2,4-diamino-6-phenyl-1,3,5-triazine (dpdapt) has been synthesized and its reactions with CuCl2 studied <06POL195>. A new versatile family of chelating agents based on bis(hydroxyamino)-1,3,5-triazines, BHTS, has been described <06MI1285>. The synthesis of 2,4,6-trisubstituted-1,3,5-triazines has been reviewed <06MI81>. Reaction of an activated form of carboxylic acids 20 with zinc dimethyl imidodicarbonimidate 21 led to 4,6-dimethoxy-1,3,5-triazines 22 in high yields <06S2845>. OMe
MeO O
N
NH
R
Zn
R
N
X
NH
74-95%
N
H2O
OMe
MeO
20
1/2 ZnCl2
N
2
22
(0.5 equiv) 21
1,3,5-triazapentadienes have been used as nucleophilic building blocks with different electrophilic reagents. In the case of aldehydes, the corresponding 1,2-dihydrotriazines were obtained whereas with ketones, depending on the substitution of the starting compounds, either 1,3,5-triazahexa-1,3,5-trienes or dihydrotriazines were obtained <06EJO3923>. The dealkylative functionalization of tertiary amines 23 with electron deficient heteroaryl chlorides including triazinyl chloride 24 has been published <06TL2229>. Efficient and practical reaction conditions were determinated for a range of substrates.
R1
N 3
R2
R Ph R 1 = Me, Et, Bn 23
N
N N 24
N Cl
92-96%
Ph
N N 25
N R3
R2
R 1 Cl
Recent applications of 2,4,6-trichloro-1,3,5-triazine and its derivatives in organic synthesis have been reviewed <06T9507>. The selective replacement of chlorine in cyanuric chloride by the 3,7-dioxa-r-1azabicyclo[3,3,0]oct-5-yl-methoxy group through the Williamson method has been described <06T7319>. The reactions of cyanuric chloride with some amine nucleophiles have been described under very mild conditions <06H807>. Synthetic strategies to generate 2-aryl- 27, 2-alkyl- 28 and 2-acetylenyl- 29 -substituted 4,6-diamino-1,3,5-triazines from the corresponding 2-chloro compound 26 have been reported <06TL5973>.
418
P. Goya and C.G. de la Oliva
Ar
Cl N
N
Cl
R
Cl O O
EtO
diethyl malonate NaH 0 ˚C to 20 ˚C 25%
N
OEt
3-chloroaniline K2CO3, THF
N N
O
EtO OEt
Cl
R
27
N
N N
HN
14%
R
R
28
26 R=N
N N
HN
80 ˚C, 62%
R
O
Cl N
N
Cl
3-chloroaniline, K2CO3 acetone-water 40 ˚C , 94%
N
N N
HN
DME, Pd(PPh3)4 K2CO3, ArB(OH)2
Cl
O
Ph
Ph H toluene, DIPEA CuI, Pd(PPh3)4, 20 ˚C, 71%
Ph
N
3-chloroaniline K2CO3, THF
N
N HN
33% Cl
R
N
N N
R
29 Cl
The base and acid hydrolysis of sym-triazine mononitriles has been studied <06CHE642>. The potassium salt of 2-amino-4-methoxy-6-dinitromethyl-1,3,5-triazines 30 with N2O4 afforded the nitroformaldoximes 31 and the 1,2,5-oxadiazole N-oxides 32 <06CHE1096> <06CHE557>. R2
N
N MeO
R1 N
N 30
R2 N 2O 4
N
N C(NO 2) 2K
MeO
R2
R1 N
O N
N N 56-67% 31
N
N MeO
O
R1
R2
N
N
N
N
N N
N
R1
OMe
N O
O 24-32% 32
OH
N-alkyl-2,4-dioxohexahydro-1,3,5-triazines 33 were oxidized easily with oxygen to the corresponding cyanuric acid derivatives 34 <06M185>. R N
O R
N
O N
33
R
O2 60-85%
R N
O R
N
O N
O 34
R
419
Triazines, tetrazines and fused ring polyaza systems
The wide spectrum of potential activity of 1,3,5-triazines is reflected in the number of publications which have again appeared in 2006. Thus, there have been reports dealing with the in silico discovery of -secretase inhibitors among which s-triazine derivatives were promising lead candidates <06JA5436>. The socalled ADATS, 6-alkylthio-4-[1-(2,6-difluorophenyl)-alkyl]-1H-[1,3,5]triazin-2-ones, have been identifed as novel regulators of cell differentation <06MI1073>, 2,4-diamino- and 2amino-4-alkenyl-1,3,5-triazines have shown antitumor activity <06EJM219; 06EJM611>. The optimization of triazinyl amines as non-nucleoside inhibitors of HIV-1 reverse transcriptase has been published <06BMCL5664>. 1,3,5-Triazin-2,4,6-trione scaffolds have been employed as templates to incorporate the pharmacophore requirements of cytosolic phospholipase A2α substrate mimetics <06BMCL2978>. Screening of a chemical library in a DNA helicase assay provided the lead for the synthesis of triaminotriazines with antibacterial activity <06BMCL1286>. The synthesis and antibacterial activity of substituted s-triazines <06EJM1240> and the SAR of novel antibacterial 3,5-diamino-piperidinyl triazines have been described <06BMCL5451>. A series of 2,4,6-trisubstituted triazines has been synthesized and screened for antileishmanial activity <06BMC7706; 06EJM106>. The application of cyanuric chloride in different organic reactions has been the subject of several papers, including a review <06SL2156>. It has been used as a dehydrating agent for the synthesis of isomaleimides <06T937; 06T3557> and for the synthesis of bicyclic isoxazolines and isoxazoles <06OBC2851>. It has also been employed as catalyst for the synthesis of thiiranes and oxiranes in solvent-free conditions <06TL4775>; together with nBu4NNO2 for the converssion of alcohols, thiols and trimethylsilyl ethers to alkyl nitriles <06MI220>; for the synthesis of homoallylic alcohols and amines <06TL9103> and to generate in situ HCl, used as an efficient catalyst for the solvent-free Hantzsch synthesis of new dihydropyridines <06S55>. An efficient single-step procedure for the synthesis of 4,6-diarylpyrimidin-2(1H)-ones 35 promoted by cyanuric chloride and Zn(OTf)2 or Bi(OTf)3 under solvent-free microwave irradiation conditions has been developed <06H1551>. Cl N O
O Ar1
H
Ar2
O
N
O Cl CH 3
H 2N
NH 2
N
N
Cl
Zn(OTf ) 2 or Bi(OTf) 3 microwave
NH
Ar1
Ar2 35
64-94%
Fluorous 2,4-dichloro-1,3,5-triazines have been used as nucleophilic scavengers <06MI728> and as amide coupling agents <06MI724>. The preparation of t-butyl 4,6dimethoxy-1,3,5-triazinylcarbonate (Boc-DMT) and 9-fluorenylmethyl 4,6-dimethoxy-1,3,5triazinylcarbonate (Fmoc-DMT) and their usefulness as N-protecting reagents for amines has been rerported <06S1931>. The use of 1,3,5-triazine-based synthons in supramolecular chemistry has been reviewed <06EJI29>. The synthesis of bis(triazine) molecules capable of acting as synthetic receptors for barbiturate guest molecules has been described <06EJO1444>. Two series of triazine-based dendrons were efficiently prepared by a convergent method and their properties studied <06OL1541>. A practical syntheis of [1,3,5]triazine dendritic molecules on solid supports has been described <06MI2248>.
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P. Goya and C.G. de la Oliva
A number of tetraazacalix[2]arene[2]triazines bearing substituents on the bridging atoms were synthesized using a fragment coupling strategy <06OL5967>. Nonmesomorphic as well as mesomorphic V-shaped acids with a structure similar to banana liquid crystals, have been complexed to a 2,4,6-triamino-1,3,5-triazine derivative <06JA4487>. The organic inclusion compound 2,4,6-tris-(4-bromophenoxy)-1,3,5-triazine was used to create an ordered arrangement of endohedral fullerenes in a crystalline host matrix <06CPL327>. Organic-inorganic hybrid gels based on s-triazine have been prepared from chlorosilanes by exchange reactions <06CC4741>. 1,3,5-Triazines having oligo(1,4-phenylvinylene) chains in the 2-, 4- and 6-positions have been synthesized and exhibit strong push-pull effects <06EJO2609>. The synthesis and crystal structures of di- and triorganotin(IV) derivatives with 6-amino1,3,5-triazine-2,4-dithiol have been reported <06JOM1606>. Self-assembled hexanuclear arene ruthenium metallo-prisms with 2,4,6-tripyridyl-1,3,5triazine (ppt) subunits showed unexpected double helical chirality <06CC4691>.
6.3.2
TETRAZINES
A new electrofluorescent switch was prepared with an electroactive fluorescent tetrazine blend of polymer electrolyte <06CC3612>. The structure and magnetic properties of the stable oxoverdazyl free radical 6-(4-acetamidophenyl)-1,4,5,6-tetrahydro-2,4-dimethyl1,2,4,5-tetrazin-3(2H)-one has been reported <06POL2433>. The synthesis and characterization of two new tetrathiafulvalene (TTF) derivatives bearing pyridine-based substitutents and 1,5'-dimethyl-6-oxoverdazyl radicals have been described <06JOC2750>. New high-nitrogen materials with 3-amino-6-nitroamino-tetrazine (ANAT) as the anion have been synthesized and their properties studied <06CC4007>. The reaction of 3,6-diaryl-1,2,4,5-tetrazines (aryl = phenyl, 2-furyl or 2-thienyl) with 2 equivalents of Ru(acac)2(CH3CN)2 resulted in reductive tetrazine ring opening to yield diruthenium complexes <06IC821>. Complexes involving the 3,6-bis(2-pyridyl)-1,2,4,5-tetrazine (bptz) ligand have been obtained <06JA5895; 06MI1498>. The unusual reaction of cyanoacetic acid esters with s-triazine monoazides afforded derivatives of a novel coupled heterocyclic system: 2-[1,3,5]triazin-2-yl-1,2dihydro[1,2,3,4]tetrazine-5-carboxylic acid esters <06CHE965>. A series of tetrahydro-1,2,4,5-tetrazinan-3-ones have been prepared by the reaction of carbonic acid bis(1-methylhydrazide) with aromatic aldehydes <06JCR(S)515>. The synthesis, structure analysis and antitumor activity of 3,6-disubstituted-1,4-dihydro1,2,4,5-tetrazine 36 derivatives have been described <06BMCL3702>. R sulf ur RCN
N 2 H4 x H2 O
EtOH
N HN
NH N
R 32-85% 36
Δ EtOH
N N R
R Cl Cl
N 2 H4 x H2O
421
Triazines, tetrazines and fused ring polyaza systems
The inverse electron demand DA reaction of 1,2,4,5-tetrazines has continued to be the most important reaction of this system. The cycloaddition reactions of the novel 3-methylsulfinyl-6-methylthio- 37 and 3(benzyloxycarbonyl)amino-6-methylsulfinyl- 38 -1,2,4,5-tetrazine to afford the corresponding pyridazines 39-40 proceeded with a regioselectivity opposite to expected and complementary to that observed for the corresponding sulfides <06JOC185>. O H3 C S
SCH3
SCH3
R 54-96% R 39
R2 N R2 O
R
N N
H3 C S
N N
H3 C S
N N 37 O
O
OR 1
N N
NHCbz
R
N N 38
N N
H3 C S
NHCbz R 34-83% 40
The cycloaddition of acetylenes to 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazines to give the corresponding di(pyridin-2-yl) pyridazines was considerably accelerated under microwave assisted conditions <06JOC4903>. The [4+2] cycloaddition of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 41 with ketene N,O-acetals or cyanamide yielded tetrafunctionalized pyridazines 42 or 1,2,4-triazine 43 respectively. Treatment of 42-43 with zinc dust in AcOH afforded pyrrole 44 or imidazole 45 derivatives <06S1513>. EWG
CO2 Me N N
N N CO2 Me 41
EtO
NH2
N N
MeO 2C Zn/AcOH
NH 2 CO2 Me
12-98% H2 N
CO2 Me EWG
EWG HN
42
N
44
CO2 Me 93% N N
MeO 2C Zn/AcOH
N
HN NH 2
CO2 Me 43
NH 2
MeO2 C
N
87%
NH 2
MeO2 C 45
Other examples of the use of 1,2,4,5-tetrazine derivatives in [4+2] cycladditions have been reported <06T8169; 06EJO3358>. Conformationally restricted 6-isoxazol-5-yl-6,7-dihydo-5H-[1,2]diazocin-4-ones were synthesized from 1,2,4,5-tetrazines and isoxazolylcyclobutanone <06JOC2480>. The reaction of thietan-3-one 46 with 1,2,4,5-tetrazines 47 gave 4H-pyrazolo[5,1c]thiazines 48 via a rare anti-Michael addition <06TL7893>.
422
P. Goya and C.G. de la Oliva
Ph
Ar N N
S
O
Ph
O
Ph
ROH
N N
S
Ar 47
46
S
N N
Ph
KOH
Ph OH
Ph
Ar
Ar
N N Ar 52-56% 48
Ar
The hetaryl displacement in 3,6-disubstituted 1,2,4,5-tetrazines with anhydro bases of Nmethylquinaldiniums has been described <06MI99>.
6.3.3
FUSED [6]+[5] POLYAZA SYSTEMS
6.3.3.1 Triazino and tetrazino [6+5] fused systems The synthesis and biological activity, as vascular endothelial growth factor (VEGF) inhibitors, of a series of substituted pyrrolo[2,1-f][1,2,4]triazine derivatives have been reported <06JMC2143>. Novel synthetic routes for the preparation of previously inaccesible 2,3,7-trisubstituted pyrazolo[1,5-d][1,2,4]triazines have been described and their affinity for the GABAA benzodiazepine binding site studied <06BMCL3550; 06BMCL872>. Imidazo[1,2-b][1,2,4]triazines, imidazo[1,2-d][1,2,4]triazin-8-ones and imidazo[2,1f][1,2,4]triazin-8-ones have also been synthesized as agonists of the GABAA benzodiazepine receptor <06JMC1235; 06BMCL1477; 06BMCL1582>. The synthesis, crystal structure and anticancer activity of derivatives of ethyl and methyl (tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl) formate and acetate have been reported <06EJM539; 06EJM1373>. The synthesis of the pyrazolo[4,3-e][1,2,4]triazine 52-53 family of natural products, fluvine A, pseudoiodinine and nostocine A have been reported <06JA5646>.
N
H N
O
N
CO2Et
H 2N
POCl3, PhNMe2 [PhCH2NMe3]+Cl-
N
MeCN, Δ
N
Cl
N
CO2Et
Boc
H N Boc
N
EtOH, Δ
49
i. CF3CO2H CH2Cl2 ii. KOH, MeOH
N
N
H N NH
N 35% O 51
TMSCHN2 MeOH:MeCN 4:9
N
N
H N N
N
H N NH
CO2Et N 47% 50 Me N N
N OMe 18% 52 Identical to fluviol A and normethylpseudoiodinine
N NH
N O 4% 53 Identical to nostocine A
Pyrazolo[4,3-e][1,2,4]triazine derivatives have been prepared from oximes of 5-aryl- and 5-formyl-1,2,4-triazines <06MI191>. Novel pyrazolo[5,1-c][1,2,4]triazines incorporating an N-(2-oxoethyl)phthalimide moiety have been reported <06JCR(S)6>.
423
Triazines, tetrazines and fused ring polyaza systems
The synthesis and structures of 6-amino-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one derivatives <06MI169; 06MI444> and of dihydrotetrazolo[5,1-c][1,2,4]triazines have been described <06H1595>. Pyrazolo[1,5-a][1,3,5]triazines 58 were obtained by an efficient one-step reaction from iminodithiocarbonates 54 and pyrazole 55, or by an alternative two-step reaction form the aroyl isothiocyanates 56 and pyrazole 55 <06TL5441>. O Ar
HN N
SEt N
SEt
54
Me
H 2N
DMF, Δ 61-90%
55
Ar
O Ar
N C S 56
HN N
Δ Me MeCN
H 2N 55
70-96%
N HN H N NH
Ar O
S
N N
N
Me i.NaH, EtBr DMF, rt ii. DMF, Δ
EtS
Me
N 58
75-90%
57
The synthesis and biological activity of 1,2,4-triazolo[1,5-a][1,3,5]triazines (5-azapurines) has been reviewed <06H1723>. Novel three-component reactions of thiazole Schiff bases, ammonium acetate and aromatic aldehydes under solvent-free microwave irradiation conditions yielded diastereoselectively thiazolo-s-triazines <06GC455>. Aminomethylation of 2-amino-5,5-bis(hydroxymethyl)-1,3-thiazol-4(5H)-one and its spiro analogs gave the corresponding [1,3]thiazolo[3,2-a][1,3,5]triazine derivatives <06CHE1086>. Condensed tetrazolo[1,5-a][1,3,5]triazin-7-ones have been prepared from the corresponding 4-azido-1,3,5-triazines <06CHE1051>. 6.3.3.2 Purines and related structures The number of publications under this heading is considerable, even through purine nucleosides and related structures have not been included. A general and efficient solid-phase synthesis of N-9-substituted 2,8-diamino purines 62 has been described. The key synthetic transformation uses a carbodiimide-mediated cyclization of a thiourea 60. The reaction was performed using microwave reaction conditions on solid phase <06TL8897>.
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P. Goya and C.G. de la Oliva
H N
S NH 2
N L
N
N R1
R2
N
CH 2Cl2, 80 ºC microwave
L
N R
N 1
59
N
N L
N H
ArNCS, DMF
N
N
R1
N R2
Ar NH TFA, CH CN 3 HN R1
61
N H
DIC, CH 2Cl2
R2
DMF, EtOH, 25 ºC
60
N
N
25 ºC
Ar
NH
N
Ar NH
N R2
55-81% 62
A regiospecific strategy to N-7-substituted purines 65 and its application to a library of 2,6,8-trisubstituted purines has been reported. The three-step synthetic strategy involves cyclization reactions of suitably substituted pyrimidines 63 with either a carboxylic acid or an aldehyde <06JCO410>. SAr N R
N
H N
SAr R1
NH 2
R 2 CO2 H or R 2CHO
N R
64
N
R4
i. mCPBA R2
N
N
61-95%
63
R3
R1 N
N ii. R3 R4 NH
R
R1 N R2 N
N
33-90%
65
A practical synthesis of 2-arylamino-6-alkylaminopurines from 2,6-dichloropurine by base-assisted substitution of the 6-chloro substituent with cyclobutylamine followed by a new trimethylsilyl chloride-catalyzed displacement of the 2-chloro group in the intermediate purine with an aromatic amine has been published <06OPRD799>. Suzuki-type Pd(0) coupling reactions have been used for the synthesis of 2-arylpurines <06BMCL3144>. A microwave-assisted method to prepare novel 8-mercapto-3-methyl-7-alkyl xanthines 68 has been reported. Compared to conventional synthetic routes, the new method has significantly shortened synthetic steps and reaction time <06TL775>. O
O Br O
NH2 CH3 66
RNH 2 microwave, 120 ºC, 10 min O 71-81%
CH3 67
O NHR
EtOC(O)SK
NH2
microwave, DMF, 120 ºC, 10 min 73-97%
R N SH N
O CH3 68
Direct C–H arylation of purines in position 8 by diverse aryl iodides has been achieved with Pd catalysis in the presence of CuI and Cs2CO3. The methodology is general and efficient and was applied in the consecutive regioselective synthesis of 2,6,8-trisubstituted purines bearing three different C-substituents in combination with two cross-coupling reactions
425
Triazines, tetrazines and fused ring polyaza systems
<06OL5389>. Treatment of 6-(heteroaryl)purines 69 with NaH followed by alkyl iodides gave regiospecific N9 alkylation derivatives 70 <06JOC8901>. N X
N X R
N
N ii. R1 I
N H
N
H
N
i. NaH, DMF
N
N Y
R
H
N
Y
N R1
N
83-97%
69
70
The selective magnesiation of chloro-iodo purines which represents an efficient approach to new purine derivatives has been published. Both 6-chloro-2-iodo-purine 71 and 2-chloro-6iodo-purine 72 undergo a selective I/Mg exchange reaction with i-PrMgCl at -80 ºC, thus, 6chloro-2-(phenylhydroxymethyl)-purine 73 and 2-chloro-6-(phenylhydroxymethyl)-purine 74 were synthesized. However, the reaction course at 0 ºC was different. Magnesiation of 6chloro-2-iodo-purine 71 proceeded with the migration of magnesium to the 8 position of the purine nucleus. In the case of 2-chloro-6-iodo-purine 72, substitution of iodine by an alkyl group from the Grignard reagent together with a Cl/Mg exchange reaction took place. Finally, the reaction with aldehydes afforded the corresponding alcohols 6-chloro-8(phenylhydroxymethyl)-purine 75 and 6-alkyl-2-(phenylhydroxymethyl)-purine 76 <06OL1291>. Cl N R1
N OH
N R
ii. R1 CHO 48-85%
N N
N 74 R
N
N
N R
N
I
71
OH
N Cl
N
73
R1
Cl
Cl i. i PrMgCl, THF -80 ºC
I i. i PrMgCl, THF -80 ºC ii. R1 CHO 50%
N Cl
N 72
i. i PrMgCl, THF 0 ºC
N
ii. R1 CHO
N
47%
N
i. R 1MgCl, THF -80 ºC to 0 ºC
N R
ii. R2 CHO 54-68%
N
R1
N R
OH
75
R1 N
N HO
N R2
76
N R
The cyclization and rearrangement products from the coupling reactions between terminal O-ethynyl(hydroxymethyl)benzene and 6-halopurines have been described <06T6121>. In a report dealing with the synthesis and anticancer activity of (6'-substituted)-7- and 9(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)purines, transformations of N9'-alkyl-6'-halopurines have been described <06T11724>. Several reports have dealt with biological properties of purine derivatives: a general review <06BMC3987>; 2-arylpurines as CdK inhibitors <06BMCL3144>; 2,6-disubstituted and 2,6,8-trisubstituted purines as adenosine receptor antagonists <06JMC2861>; 2,8,9trisubstituted purines as TNF-α inhibitors <06BMCL4360>; 6-substituted purines as antileishmanial agents <06EJM1>; purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors <06BMC5742> and purine-based derivatives as inhibitors of the heat schock protein 90 <06JMC381; 06JMC817; 06JMC5352>.
426
P. Goya and C.G. de la Oliva
Several papers dealing with xanthine-based compounds as adenosine A receptor antagonists have been published: 1,3,8- and 9-substituted 9-deazaxanthines as human A2B adenosine receptor antagonists <06JMC282>; 1,3-dipropyl-8-(1-heteroarylmethyl-1Hpyrazol-4-yl)xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists <06BMCL302>; norbornyllactone substituted xanthines as adenosine A1 receptor antagonists <06BMC3654>; 1- and 3-[1-(2-hydroxy-3-phenoxypropyl)]xanthines as A1 and A2 adenosine receptor antagonists <06BMC2697>; tricyclic imidazoline derivatives as potent and selective adenosine A1 receptor antagonists <06JMC7132> and tricyclic arylo-, imidazo-, pyrimido- and diazepinopurinediones with affinity for the adenosine A2A receptor <06BMC7258>. A convenient regioselective one-pot approach to pyrazolo[1,5-a]- and imidazolo[1,2a]pyrimidine derivatives 79 from aminoheterocycles 78 and α,β-unsaturated imines 77, generated in situ, has been described <06TL2611>.
EtO O P EtO 1
Ar CN
Ar 2
NH Ar
R
Ar2 CHO
1
O
P
H N N
NH 2 78
N
R N
OEt OEt
Ar 2
Ar 1
NH 77
52-76%
N
Ar 1 79
Microwave-assisted regiospecific shyntesis of 2-trifluoromethyl-7-trihalomethylated pyrazolo[1,5-a]pyrimidines has been reported <06MI358>. A one-step synthesis of pyrazolo[1,5-a]pyrimidine via an intermolecular aza-Witting reaction has been achieved <06JHC523>. The synthesis of new pyrazolo[3,4-d]pyrimidine derivatives and their activity as potent antiproliferative and proapoptopic agents has been reported <06JMC1549>. A series of antimicrobial pyrazolo[3,4-d]pyrimidines containing 8(trifluoromethyl)quinoline have been synthesized from 5-amino-1-[8(trifluoromethyl)quinolin-4-yl]-1H-pyrazole-4-carboxylate and 4-carbonitrile <06BMC2040>. A test library with three novel p38α inhibitory activity has been prepared, among them pyrazolo[3,4-d]pyrimidine and pyrazolo[3,4-b]pyrazine with potent in vivo activity <06BMCL262>. A convenient route for the synthesis of pyrazolo[3,4-d]pyrimidine involving Friedländer condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide has been reported <06JHC1169>. A facile synthesis of pyrazolo[3,4-d]pyrimidines and pyrimido[4,5-d]pyrimidin-4-one derivatives has been published <06SC2963>. Pyrazolo[4,3-d]pyrimidines have been prepared as inhibitors of coagulation factor Xa <06BMCL5176; 06BMCL3755>, as cannabinoid receptor CB1 antagonists <06BMCL731>, as selective PDE5 inhibitors <06JMC3581> and as analogues of myoseverin with antiproliferative activity <06EJM1405>. Triazolino[4,3-a]pyrimidines, pyrazolo[3,4-d]pyridazines and isozazolo[3,4-d]pyridazines have been synthesized from hydrazonoyl chlorides <06SC97>. A novel tricyclic piperidine-fused pyrazolo[1,5-a]pyrimidin-7-(4H)-one has been synthesized with regioselective formation of the tricyclic core structure <06MI715>.
427
Triazines, tetrazines and fused ring polyaza systems
6.3.4
FUSED [6]+[6] POLYAZA SYSTEMS
Molecular orbital calculations have been used to analyze the stabilities of dihydropterins <06H1705>. The photochemistry of 6-(hydromethyl)pterin in aqueous solution has been investigated <06HCA1090>. A new synthesis of pterins based on the acylation of 4-amino-5-nitrosopyrimidines with dienoic acid chlorides, followed by a high-yielding intramolecular hetero DA cycloaddition and cleavage of the N⎯O bond has been reported <06HCA1140>. Several new substituted pterins have been obtained in an efficient one-pot procedure using N,N'dimethyldichloromethyleniminium chloride (phosgeniminium chloride) and a suitable pyrazine <06H933>. Pteridines have been prepared in good yields from 6-amino-5-nitrosouracils with Meldrum’s acid in the presence of piperidine as catalyst under thermolytic conditions <06SC3085>. Novel 6-formylpterin derivatives have been synthesized and their neuroprotective effects studied <06OBC1811>. The synthesis of 4-trifluoromethylpyrimido[4,5-c]pyridazin-5,7-diones from 6hydrazinouracils and 1,1,1-trifluoropropane-2,3-dione monohydrates has been reported <06H1875>. Novel pyrimido[4,5-c]pyridazines have been synthesized and investigated as inhibitors of lymphocyte specific kinase <06BMCL4257; 06H2037>. Reaction of 3-alkylamino-6,8-dimethylpyrimido[4,5-c]pyridazin-5,7-diones 80 with cyclohexyl and cycloheptylamines afforded novel cycloalkano bis(pyrrolo[2,3c]pyrimido[5,4-e]pyridazines 81 <06T652>. NH2 Me O
Me N O
O
O
H N
N N Me 80
N
N
R
n n = 1,2 AgPy 2MnO4 6-13%
Me
O
Me N
n
N N
N
N R
N R
O N
N
Me
N
81
Electron-rich 6-[(dimethyl(amino)methylene)amino uracil 82 underwent [4+2] cycloaddition reactions with various in situ generated glyoxylate imine and imine oxides to afford novel pyrimido[4,5-d]pyrimidine derivatives 83-84 after elimination of dimethylamine from the (1:1) cycloadducts and oxidative aromatization. This one-pot procedure yielded excellent yields when carried out in the solid state and under microwave irradiation <06BMCL3537>.
428
P. Goya and C.G. de la Oliva
O
OEt
O
H
O Me
ArNH 2 O Me O
Δ microwave 83-95%
N Me N Me
N Me 82
O
Et
N
N N Me
O
Ar
N 83
Δ microwave
O
Ar
Me N
Pn O 80-90%
O
Ar
N
N N Me
Ph
N 84
Within an SAR study of p38 MAP kinase inhibitors, a series of 3,4-dihydropyrimido[4,5d]pyrimidin-2-ones and 3,4-dihydropyrido[4,3-d]pyrimidin-2-ones were prepared <06BMCL4400>. Coordination frameworks of pyridazino[4,5-d]pyridazine have revealed a pronounced ability for anion π interactions <06CC4808>. In a report dealing with novel classes of GABAA receptor benzodiazepine binding site ligands, pyrazino[2,3-d]pyridazines were prepared using an aza Wadsworth-Emmons cyclization as the key step <06TL2257>. The formation of pyridazino[4,5-c]pyridazine derivatives upon [4+2] cycloaddition of 4-phenyl-1,2,4-triazoline-3,5-dione to crossconjugated monoferrocenyltrienes has been reported <06JHC1115>.
6.3.5
MISCELLANEOUS
Pyrimido[3',2':4,5]thieno[3,2-d]pyrimidinones reacted with hydrazonoyl halides in dioxane and triethylamine to give the corresponding tetracyclic fused tetrazines <06JHC935>. The electrochemical oxidation of catechols in the presence of 6-methyl-1,2,4-triazin-3thion-5-one and 4-amino-6-methyl-1,2,4-triazin-3-thion-5-one as nucleophiles in aqueous solutions provided an efficient electrosynthesis of thiazolo[3,2-b][1,2,4]triazin-7-one and 1,2,4-triazino[3,4-b]1,3,4-thiadiazine derivatives respectively <06TL1713> <06TL8553>. Isoindolo[2,1-c]benzo[1,2,4]triazines 85 have been described as a new ring system with antiproliferative activity <06BMC343>. R1
O H H O
CN R 4 2
H 2N
R
NaNO 2
KCN R2
N H 2N R
4
CN R 4
R3
R3 NaHSO3 40-95%
H2 N
R1
AcOH 84-98%
R3 R2
N N N 85
R1
Structurally related sets of triazinoquinoline, triazinoisoquinoline and pyridotriazine derivatives have been synthesized and their binding to benzodiazepine receptors studied <06EJM445>. Pyridazino[3’,4’:3,4]pyrazolo[5,1-c]-1,2,4-triazines have been prepared and their antimicrobial activity evaluated <06PS809> <06PS2505>.
Triazines, tetrazines and fused ring polyaza systems
429
An efficient one-pot synthesis of tetracyclic fused 1,2,3triazine[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]-1,2,3-triazines has been described <06JHC1051>. The synthesis and biological studies of a new series of pyrazolo[4,3-e][1,2,4]triazolo[1,5c]pyrimidines as antagonists of the human A3 adenosine receptor have been reported <06JMC1720>. The solid phase parallel synthesis of tetrahydroimidazo[1,2-a][1,3,5]triazepin-2-thiones and 2-imines has been reported starting from resin-bound peptides <06JCO127>. Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazinones with potent and selective phosphodiesterase 5 (PDE5) inhibitory activity have been described <06JMC5363>
6.3.6
REFERENCES
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<06BMCL872>
<06BMCL1286> <06BMCL1477>
<06BMCL1582> <06BMCL2101>
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430 <06BMCL2978> <06BMCL3144> <06BMCL3537> <06BMCL3550> <06BMCL3702> <06BMCL3755> <06BMCL4257>
<06BMCL4360>
<06BMCL4400> <06BMCL5176> <06BMCL5451> <06BMCL5664> <06CC3612> <06CC4007> <06CC4691> <06CC4741> <06CC4808> <06CHE557> <06CHE642> <06CHE965> <06CHE1051> <06CHE1086> <06CHE1096> <06CPL327> <06EJI29> <06EJI2210> <06EJM1> <06EJM106>
P. Goya and C.G. de la Oliva
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Triazines, tetrazines and fused ring polyaza systems
<06EJM219> <06EJM445> <06EJM539> <06EJM611> <06EJM1240> <06EJM1373> <06EJM1405> <06EJO1444> <06EJO2609> <06EJO3021> <06EJO3358> <06EJO3923> <06GC455> <06H807> <06H933> <06H1551> <06H1595> <06H1705> <06H1723> <06H1875> <06H2037> <06HCA1090> <06HCA1140> <06IC821> <06IC7119> <06IC7182> <06JA4487> <06JA5436> <06JA5646> <06JA5895> <06JCO127> <06JCO410> <06JCR(S)6> <06JCR(S)515> <06JHC523>
431
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432 <06JHC613> <06JHC935> <06JHC1051> <06JHC1115> <06JHC1169> <06JMC125> <06JMC282>
<06JMC381> <06JMC817>
<06JMC1235>
<06JMC1549>
<06JMC1720> <06JMC2143>
<06JMC2861> <06JMC3581>
<06JMC5352>
<06JMC5363> <06JMC7132> <06JOC185> <06JOC2480> <06JOC2750> <06JOC4578> <06JOC4903> <06JOC5679>
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434 <06POL1057> <06POL1464> <06POL2433> <06POL2550> <06PS87> <06PS809> <06PS2505> <06S55> <06S1513> <06S1931> <06S2845> <06SC97> <06SC2963> <06SC3085> <06SL2156> <06T652> <06T937> <06T1182> <06T3557> <06T5736> <06T6121> <06T6214> <06T7319> <06T8169> <06T9507> <06T11724> <06TA2617> <06TL775> <06TL869> <06TL1713> <06TL1721> <06TL2229> <06TL2257> <06TL2611> <06TL3865> <06TL4775>
P. Goya and C.G. de la Oliva
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Chapter 6.4 Six-membered ring systems: with O and/or S atoms
Unfortunately, due to unforeseen and unfortunate circumstances, the regular chapter on ‘Six-membered ring systems: with O and/or S atoms’ does not appear in this volume. We apologise for this omission. We anticipate that PHC 20 will include a double chapter on this area, covering the literature of 2006 and 2007.
437
Chapter 7
Seven-membered rings John B. Bremner Department of Chemistry, University of Wollongong, Wollongong, NSW 2522, AUSTRALIA
[email protected] Siritron Samosorn Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, THAILAND
[email protected]
7.1
INTRODUCTION
The chemistry and biological activities of seven-membered heterocyclic systems continued to command significant attention in 2006. In this chapter both fused and non-fused heterocycles are addressed with an emphasis on N, O, and S as the heteroatoms in the seven-membered ring components. Reviews which include some treatment of these heterocyclic derivatives have been published covering ring-closing metathesis of heteroatom substituted dienes <06H(70)705>, and a review of the pyrrolo[1,2-a]azepine-based Stemona alkaloids <06MI99>. A detailed review on synthetic approaches to oxepines has also been published <06T9301>.
7.2
7.2.1
SEVEN-MEMBERED SYSTEMS CONTAINING ONE HETEROATOM
Azepines and derivatives
Detailed computational studies have been reported on 5-azatropolone and 1H-azepine-4,5dione and related isoelectronic homologues and isomers <06JPC(A)1600>. A novel electrophilic reaction of the 2-methoxyazepinium ion 2, formed in situ from 1 on treatment with TiCl4,was observed in the presence of benzene to give 3, 4 and 5. The kinetics of the isomerisation (k1, k2, k3) of the 4H-azepine 3 to 8 via 6 and 7 were also reported <06EJO3803>.
438
J.B. Bremner and S. Samosorn
Ph
TiCl4
Ph-H +
iPr
O
N
N
OMe
OMe
N
2
1
OMe
3, 43% Ph
+ N
Ph
N
OMe
4, 49%
Ph
Ph
N
5, 3%
Ph
Ph
k2
k1 N
OMe
k3 N
OMe
N
OMe
7
6
3
OMe
OMe
8
Satake et al. reported further detailed studies on the chemistry of 2H-azepines highlighting a [1,5] sigmatropic hydrogen shift and also an unusual [1,5] sigmatropic propylthio shift on heating 9 to afford 10 and 11 respectively; kinetic measurements were consistent with a concerted process for the propylthio shift <06OL5469>. R
R
R
Δ H PrS
N
OMe
PrS
9
SPr
+ N
N
OMe
10
a: R = t-Bu b: R = Me
OMe
11
Access to the 4,4´-disubstituted azepine derivatives 14 was achieved in good yield by ring closing metathesis on the dienes 12 using the Grubbs II catalyst 18; the diene precursors 12 could be made in racemic or optically enriched form from α,α´-disubstituted lactone precursors <06S1437>. Removal of the N-protecting group and reduction of the double bond in 13 by hydrogenation then resulted in the azepanes 14. (i) R2 R1
N CBz
(ii) N CBz
R2 R1
14
13
12 R1 a: Me b: Ph
R2 H Me
NH
R2 R1
75% 83%
R1 a: Me b: Ph
R2 H Me
100% 90%
Reagents: (i), ClCH2CH2Cl, Grubbs II Ru cat., N2, reflux, 82 °C, 5 h; (ii), Pd/C, H2, 50 psi, AcOH, 20 °C, overnight.
439
Seven-membered rings
The power of ring closing metathesis for seven-membered ring synthesis continued to be realised as exemplified by the preparation of the tetrahydroazepines 16 (X = CH2) or 2azepinones 16 (X = CO) from the appropriately substituted precursors 15. Yields were generally good to high (particularly with Grubbs II ruthenium catalyst 18). However, as noted in other 1 2 reactions of this type, amine functionality (15a, R = Bn, R = H, X = CH2) compromised the metathesis process, and a very low yield of 16 was obtained with Grubbs I catalyst 17 and no product at all with the second generation Grubbs catalyst (Table 1); starting material 15 was reisolated in both cases <06T1777>. R1 X N
MeO
(i)
X
MeO
O
O
R2
R2 16
15
P(Cy)3 Cl
R1 N
N
Ru
Cl
N
Cl Ru
Ph
Cl
P(Cy)3 17
Ph P(Cy)3 18
Reagents: (i), Grubbs I or II cat., DCM, 40 °C.
Table 1 Substrate
R
15a 15b
Bn Bn
1
R
2
X
H H
CH2 C=O
Grubbs I cat. 16 yield (%) 8 88
Grubbs II cat. 16 yield (%) 0 90
Inclusion of the amide in oxazolidinone functionality can be used to overcome diene statial disposition issues, for example in the conversion of 19 into 20; yields of 20 were generally high (Table 2). Ring opening of the oxazolidine moiety with or without loss of the mandelic acid moiety then afforded the corresponding azepin-2-ones <06TL3625>. TBSO O Ph
5 mol% Grubbs cat.
N O
R
TBSO O Ph
N
CH2Cl2 (abt 10-2 M)
19 Reagents: (i), Grubbs cat. (5 mol %), DCM (ca 10-2 M).
O
R 20
440
J.B. Bremner and S. Samosorn
Table 2 19 19a 19b
R H i-Bu
Catalyst 17 18
20, Yield (%) 20a, 91 20b, 78
Other N-substituted and reduced 2-azepinone derivatives 22 can also be accessed in high yields (Table 3) by ring closing metathesis on the precursors 21 using Grubbs II catalyst 18. A variety of N-heteroaryl substitutent groups were tolerated in this reaction <06TL3295>. O BocHN
O
R1 BocHN
N R3
R3
Grubbs cat.
R2
R2
21
Table 3 R1 O
R1 N
22
R2 H
R3 H
H
H
10
88
H
H
10
92
Grubbs II cat. (mol%) 5
Yield (%) 90
N
A compact synthesis of the azepinones 24 has been developed based on ring closing metathesis reactions of the α-amino enones 23 <06H(67)549>. High yields of products were 2 1 2 obtained (for example, 24, R = H, R = Boc, 90%) from (23, R =H, R = Me, R = Boc). The 2 azepinone derivative 24 (R = H, R = (2-Pyr)SO2) was converted into a cathepsin K inhibitor. R N P
R1
O
(i)
O
23 Reagents: (i), Grubbs II cat. (2.5-5 mol%), DCM, heat, 12 h.
R
N P 24
Azepanes and azepanones continue to attract attention synthetically because of their incorporation in compounds of biological significance. A new diastereoselective and enantioselective lithiation – addition methodology has been described to provide access to the azepine precursors 25 (Ar1 = p-BrPh, Ar = p-MeOPh)); these were then converted into 27 via 26, and subsequently to the further substituted azepan-2-ones 30 via 28 and 29 <06JA2178>.
441
Seven-membered rings
CH3
CH3
H3C
(i)
Ar Boc CO2Et N
Ar
Ar
H3C N
Ar
(ii)
Ar Boc
CH3 N Ar 27
O O
NH 26 Ar
25
CH3
(iii) Ph
CH3
Ph
CH3
ArH2C
(v)
Ph
CH3 CH3
ArH2C
CH3
(iv)
CH3
N O N Ar Ar 30 28 29 Reagents: (i), Me3Al, p-anisidine, DCM, 83%; (ii), HCl (aq.), CHCl3, 86%; (iii), H2, Pd(OH)2, EtOH, benzene, 96%, dr = 94:6; (iv), a. LDA. b. p-BrC6H4CH2Br, THF, 94%, dr = 98:2; (v), CAN, MeCN, H2O, 62%, dr = >99:1. O
N H
O
As part of the development of an efficient synthetic strategy for the synthesis of the little known 3,5- and 3,6-disubstituted tetrahydro-1H-azepines, ring-closing metathesis of the diene 31 to 32 in high yield was reported <06JOM5406>. Boc N
Boc N
MeO O
(i)
MeO O
OTBS
OTBS
31 Reagents: (i), Grubbs II cat., 2.5 mol%, 90%.
32
The synthesis of the N-protected 7-methylazepine derivative 34 was achieved in 89% yield by a ring-closing metathesis reaction on 33 mediated by Grubbs I ruthenium catalyst. This azepine was an important precursor for the preparation, via epoxidation of the double bond, of a number of 7-methylazepanone derivatives for evaluation as cathepsin K inhibitors <06JMC1597>. Me
Me
(i)
NCbz
NCbz 33 Reagents: (i), Grubbs I cat., DCM.
34
A two-carbon ring expansion reaction of 5-membered cyclic enamines gave 6,7-dihydro-1Hazepines on reaction with dimethyl acetylenedicarboxylate <06ZN(B)385>.
442
J.B. Bremner and S. Samosorn
The synthesis of the D-gulonolactam 36 was based on an intramolecular cyclisation /ring enlargement strategy involving reduction of the azido group in 35 followed by intramolecular nucleophilic attack on the lactone moiety to afford 36 in excellent yield <06T7455>. H N
OH O
N3 O
(i)
O
O HO
O
O
HO
35 Reagents: (i), 10% Pd/C, HCO2NH4, EtOAc.
7.2.2
O
36
Fused azepines and derivatives
A palladium-catalysed intramolecular hydroamidation (using 39 as the catalyst) with the amido alkyne 37 proceeded regioselectively in the presence of base (KOH or NaOEt) to provide access to the 3-benzazepin-2-one 38. This reaction can also accommodate other alkynes <06TL3811>.
(i)
O
N Me O
NHMe
37
38, 82%; KOH 80%; NaOEt
Reagents: (i), Pd(PPh3)2(OAc)2 39, base, DMF, 60 °C, 16 h. CO2Me Et F
N N H 40
CO2Me
F
N Et
CO2Me
Me H O
MeOH
F
δ+
N H
N H B
A
74% MeO2C N
F N H 41
Et
δ+ N Et
443
Seven-membered rings
Reduced fused azepines (e.g. 40) have been used in a new ring expansion strategy to afford fuse
