Advances in
Heterocyclic
Chemistry
Volume 18
Editorial Advisory Board A. Albert A. T. Balaban J. Gut J. M. Lagowski J. H. Ridd Yu. N. Sheiiiker
H. A. Staab
M. TiSler
Advances in
HETEROCYCLIC CHEMISTRY Edited by A. R. KATRITZKY
A. J. BOULTON 01
School Chemical Srientt-s University ((East Atiglia Norwich, Etijland
Volume 18
Academic Press
.
New York
San Francisco
A Subsidiary of Harcourt Brace Jovanovtch, Publishers
London
.
1975
COPYIIIGHT 0 1975. BY ACADEMIC PRt-SS. 1NC. A L L HIGHTS RESERVED. UO I’AI
ACADEMIC PRESS, INC.
1 1 1 Fifth Avenue, New York, New York 10003
Urii/rd Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road. London NWI
LIBRARY OF CONGRFSS CAIALOG CARDNUMBER: 62-1 3037 ISI3N 0- 12 020618-8 P R I N T E D IN 1 H E UNIrFD STArES OF AMERICA
c011tents CONTRIBUTORS.
.
PREFACE .
.
vii
.
ix
. .
2 2 12
The Chemistry of Isatin FRAWK D. POPP I. Introduction . 11. Synthesis of Isatins . 111. N-Substit.lltrtl Isatins . 1V. I?,lectroplrilic Substitution and Rclatcd Reactions . V. Spectral Properties . 1‘1. 0xidat)ion and Kcduction .
.
.
. . . .
. VII. Itcm%ions with Ketone lteagont,s V11I. Itthactions nith Ainines . 1 9 . Condrnsations Involving Carbon at, C - 3 . S.Witzinger a ~ K ~ed l a t d Reactions XI. Polymers
.
. . . . .
.
,
16 19 20 24 37 45 51 56
Thiochronlalloncs and Related Compounds S. W. SCHNELLER I. Introduction . II. Thiochronians and Tliiochrornan-4-ones 111. Thiochroln0ric.s I V . Isothiochror~~ans and Isotliiochronlanones V. Benzothiopyrans . V1. Uenzothiopyryliiun Salts .
.
.
. .
60 61 79
84
. .
sa
. . .
100 100 102 126
. .
143
94
Thiourcas in the Synthesis of Heterocycles T. SCOTT (:RIFFIN, THOMAS S. \VOOIIS, I. Introduction . 11. Foiir-Memt)crccl Rings . 111. E’i\~e-McnlherctiRings TV. Sis-Membcrcd IZiIigs V. Seven-Mcinbcwd Rings 1‘1. Heteropolycyclic Kings
.
AND
DANIELL. KLAYMAN
.
.
. V
145
vi
CONTENTS
Advances in the Chcmistry of Chroin-3-enes LIJCIOMEKLINI
.L. lritrocluction 11. 111. IV. V. VI.
.
159 160 1 63 168 189 198
l’hysical l’ropcsrt icxs . Nat,iiral SubstancL>s . Synthcscs lieactions Applications .
Tautonicrisiii and Electronic Structure of Biological Pyrimidincs J. S. 1iwIAmowsnr A N D BERNAKD PULLMAN 200 I . Introciuci,ion . IT. Tautoincrisni of Cytosine . 202 227 111. Elcctronic St,ructurr of t,he Grountl State of Cytosines . 256 IV. Taiitomrrisin of Uracil and Thymine . . V. Elcctronic: Structure of t>he(:round State of Uracils and Thymines %t10 VI. Electronic Excited States of Cytosinc, Uracil, Thymine, and Their Ikrivativcs . 29 1 VII. Tautomerism, Elcxtronic Structures, and Spcctra of Rarc Pyrimidine Bascs of the Nricleic Acids 312 VIII. Miscellaneous Properties . 327
Recent Advances in the Clieniistry of Benzo[b]furan and Its Derivatives. Part I : Occurrence and Synthesis P. CAGNIANT A N D 1).CACNIANT I. Int,rodtict,ion . 11. The Prrsencc of Rcnzofiirans in Coal Tar and in Petroleum . 111. Nat>nralRenzofuran Derivatives IV. General Methods of Synthesis of Bcnzofurans . Appendix
338 853 356 361 473
.
CUMULATIVE INDEX OF TITLES
.
.
483
Coil tribu tors
*Pwwnt acldr(~sh:Institute of Phys~cs,Nicholas Copernicus University, Torun, Poland. VIi
This P a ge Intentionally Left Blank
Prefacc The present volume cmcompasses a \vide range of heterocyclic chemistry. Synt,lieses of heterocycles from tliioureas are reviewed by T. S. Griffin, T. S. Woods, and 1).I,. Klayman, while 8 . W. Schnellcr describes t h e chemistry of bmzotliiins and t licir derivatives (tliiochromans. thiocliromones, and thiocliromanones). Developments in chrorn-3-t.ric chemistry arc rcviewcd by L. Rierlini. F. I). Popp contributes a chapter on t h e isatins. A discussion of theoretical aspects of the tautomerisni of pyrimidines, by J. S. Kwiatkowski and 73. Pullman, follows u p a corresponding earlier contribution (Vol. 13) on tautomeric purines. I n the final chapter P. and I). Cagniant describe t h e natural occurrencc and synthesis of the benzofurans. A. R. KATRITZKY A. J. BOULTON
This P a ge Intentionally Left Blank
The Chemistry of Isatin PRANK D. POPP
Department of Chemistry, Clarkson College of Technology, Potsdam, New York
I. Introduction . 11. Synthesis of Isatins . A. RingClosure . B. Ring Contractions . C. From Indole Derivatives . . 111. N-Substituted Isatins A. Preparation from Isatin . . B. Reactions of N-Substituents . IV. Electrophilic Substitution and Related Reactions . A. Halogenation. . B. Other Electrophilic Sitbstitutions . C. Other Transformations . V. Spectral Properties . A. Infrared . B. Other Spectral Studies . VI. Oxidation and Reduction . A. Oxidation . B. Reduction . VII. Reactions with Ketone Reagents . A. Oximes B. Hydrazones . C. Thiosemicarbazones and Related Compounds . VIII. Reactions with Amines. A. Primary Amines . 1. Aromatic Primary Amines . 2. Aliphatic Primary Amines . B. Secondary Amines . IX. Condensations Involving Carbon at C-3 . A. Reactions Leading to 3-Hydroxy-3-substitutedOxindoles B. Reactions Leading to Isatylidene Derivatives . C. Miscellaneous Condensations . X. Pfitzinger and Related Reactions . X I . Polymers .
1
2 2 2 9
. .
. .
.
. .
. . .
. . . . . . . . .
. . . . . . . . . .
10 12 12 15 16 16
18 18 19 19 19 20 20 21 24 24 27 30 37 37 37 39 43 45 45 48 50 51 56
2
FRANK D. POPP
[Sec. 1I.A
I. Introduction Isatin (1) was the subject of a comprehensive review, containing 416 references, by Sumpter in 1944.l Since that time an even larger number
m: H
(1)
of papers have appeared concerning the preparation, properties, and reactions of isatin. Although isatin has been included as a small subtopic in several reviews concerned with indoles, no comprehensive review devoted to isatin has appeared since 1944. It is the purpose of this review to cover the literature of isatin from the previous review1 t o late 1974. As far as possible it will adopt the same format as the earlier review, and materials that only updates subjects covered in depth in that review1 will be listed, without extended comment.
II. Synthesis of Isatins A. RINGCLOSURE The most frequently used synthesis of isatins is the Sandmeyer procedure, which involves the formation of an isonitrosoacetanilide (3) from an aniline (2), chloral hydrate, and hydroxylamine. The isonitroso-
-
+JNH2 (2)
R 4 J N , H y H (3)
-4Xz: H
(4)
acetanilide (3)is converted into the isatin (4) on treatment with sulfuric ~ - ~ the Sandmeyer acid,l or less frequently polyphosphoric a ~ i d . Using a
W. C. Sumpter, Chem. Rev.34,407 (1944). J. Griponborg, E. Honkanen, and 0. Patoharju, Actu. Chem. Scund. 11, 1485 (1957).
F. Piozzi, Atti Accad. N u z . Lincei, CI. Sci. Pis., M a t . N u t . Rend. 22,629 (1957). F. Piozzi and G . Favini, Atti Accud. N u z . Lincei, CI. Sci. Fis., Mat. N u t . Rend. 18,647 (1955).
D. R&ilcanu and C . D. Nenitzcscu, Acud. Repub. P o p . R o m . S t u d . Cercet. Chim. 11, 19 (1963).
Sec. II.A]
THE CHEMISTRY OF ISATIN
3
reaction, o-substituted anilines have been converted into 7 - a I k ~ l , ~ . ~ - l l 7-rnethox~,~ 7-nitro,12 *~ 7-amino,13 7-carboxy,14 7-trifluoromethyl,15 and 7-halo4*16-20 isatins. Similarly p-substituted anilines have been used to prepare 5-alky1,4*6*8,9*21-23 5 - m e t h o ~ y , ~ 5-h * ~ydroxy,l3 ~-~~ 5-trifl~oromethy1,~~ 5-carboxy,14 5-csrbo~ymethy1,~~ 5 - a m i n 0 , ~5~ ace tam id^,^^ and 5-halo isatins. Although o - b r ~ m o o, ~- ~ h l o r o , ~ ,and ~ ~ o-iodo17 . ~ ~ . ~ anilines ~ give 7haloisatins, o-fluoroaniline has been reported 32 not to give an isatin. 2,CDifluoroaniline also fails to give an isatin 32 although cyclization 4*27*31932
F. Buscarons and J. M. Espinos, Chim. Anal. (Paris)48,336 (1966). N. P. Buu-Hoi and P. Jacquignon, J . Chem.SOC., 3095 (1959). H. Cassebaum, J . Prakt. Chem. 23,301 (1964). e A . L. Gershuns and A. A. Pavlyuk, Ukr. Khim. Zh. 30, 1086 (1964); Chem. Abstr. 62,5252 (1965). lo F.Piozzi and M. R. Langella, Gazz. Chim. Ital. 93, 1392 (1963). l1 V. A. Snieckus, T. Onouchi, and V. Boekelheide,J . Org. Chem. 37,2845 (1972). la E. R. Buchman, C. M. McCloskey, and J. A. Seneker, J . Amer. Chem. SOC. 69, 380 (1947).
E. Giovannini, P. Portmann, A. Johl, K. Schnyder, B. Knecht, and H. P. Zen-Ruffinen,Helv. Chim. Acta 40,249 (1957). l4 P. N. Stefanesau, Rev. Chim. (Bucharest)20,353 (1969). l5 P.M. Maginnity and C. A. Gaulin, J . Amer. Chem.SOC. 73,3579 (1951). 18 E. R. Buchman, H. Sargent, T. C. Myers, and J. A. Seneker, J . Amer. Chem. SOC. 68,2692 (1946). l1 M. B. Chaundhari and K. S. Nargund, J . Univ. Bombay 19, Sect. A . Pt. 3, Sci. No. 28,65 (1950); Chem. Abstr. 47, 1652 (1953). le M. C.Chiang, C. Li, and J. L. Li, Hua Hszceh Hsueh Pa0 22, 235 (1956); Chem. Abstr. 52, 10080 (1958). lo P.W. Sadler and R. L. Warren, J . Amer. Chem.SOC. 78, 1251 (1956). 2o P. Singh, K. S. Dhami, G. M. Sharma, and K. S. Narang, J . Sci. I d . Res. Sect. B 17, 120 (1958). a1 N. P.Buu-Hoi and D. Guettier, BUZZ.SOC. Chim. Fr. 586 (1946). aa N. P. Buu-Hoi, R. Royer, B. Eckert, and P. Jacquignon, J . Chem. SOC.,4867 l3
(1952).
R. Ponci, T. Vitali, F. Mossini, and L. Amoretti, Farmaco, Ed. Sci. 22, 999 (1967); Chem. Abstr. 68,114493 (1968). 24 M. Akahoshi, J . Pharm. SOC. Jap. 71, 710 (1951): Chem. Abstr. 46, 2047 (1952). 25 G..B. Bachman and G. M. Picha, J . Amer. Chem. SOC. 68,1599 (1946). 28 M. F. Bartlett, D. F. Dickel, and W. I. Taylor, J . Amer. Chem. SOC. 80, 126 a3
(1958).
M. Cirje, Rev. Roum. Chim. 18, 1013 (1973). 28 S. Pietra, Farmaco (Pavia),Ed. Sci. 13, 75 (1958): Chem. Abstr. 52, 13704 a7
(1958).
D. J. Bauer and P. W. Sadler, Brit.J . Pharmacol. 15,101 (1960). 30 A. Ermili and R. Giuliano, Gazz. Chim. Ital. 89,517 (1959). 31 R. N.Castle, K. Adachi, and W. D. Guither, J . Heterocyl. Chem. 2, 459 (1965). 3a V. Q. Yen, N. P. Buu-Hoi, and N. D. Xuong, J . Org. Chem. 23,1858 (1958). ae
4
[Sec. 1I.A
FRANK D. POPP
does occur when p-fluoroaniline 31,32 and 3,4-difluoroaniline 32 are used. Generally meta-substituted anilines give rise to a mixture of 4- and 6-substituted isatins9.13*19*33-37 although 4-trifl~oromethyl,l~*~~*~~.~ 4-nitro,13 4-amino,13 4-hydroxy,13 4-carboxy,13 6 - m e t h 0 x y , ~and ~ 6bromo isatins have been reported without the other isomer. The Sandmeyer method has been used with di- and trisubstituted aniline8 to prepare di-4.69139 1 4 * 19.32 938-55 and tri-5 19.30.56 substituted isatins. Although p-acetamidoaniline and 5-acetamido-2-aminotoluene gave 5-acetamido- and 5-acetamido-7-methylisatin, r e ~ p e c t i v e l y the ,~~ use of 4-acetamido-2-aminotoluene and 5-acetamido-2,4-dimethylaniline gave the appropriate a m i n o i ~ a t i n s . ~Other ~ . ~ ~ examples of hydrolysis during this cyclization are in the conversion of diethyl 5aminoisophthalate to isatin-4,6-dicarboxylic acid53 and 2-methyl-59
1 3 9
B. R. Baker, R. E. Schaub, J. P. Joseph, F. J. McEvoy, and J. H. Williams, J . Org. Chem. 17, 164 (1952). 3 4 A. Mangini and R. Passcrini, Gazz. Chim. Ital. 85, 840 (1955). 35 P. W. Sadler,J. Org. Chem. 21, 169 (1956). 36 A. E. Senear, H. Sargcnt, J. F. Mead, and J. B. Koepfli, J . Amer. Chem. SOC. 68, 2695 (1946). 37 H . Woxler, Acad. Repub. Pop. Romine, Filiala Iasi, Stud. Cercet. Stiint., Chim. 12,219 (1961);Chem. Abstr. 58,3379 (1963). 38 B. R. Baker and R. E. Schaub, British Patent 713,767 (1954); Chem. Abstr. 50, 14002 (1956). 38 B. R. Baker, J. P. Joseph, R. E . Schaub, F. J. McEvoy, and J. H. Williams, J . Org. Chem. 17, 157 (1952). 4 0 B. R. Baker, R. E. Schaub, J. P. Joseph, F. J. McEvoy, and J. H. Williams, J . Org. Chem. 17, 149 (1952). 41 E. Bullock and A. W. Johnson, J . Chem. Soc., 1602 (1957). 4 2 F. Buscarons and L. S. Moreno, Inform. Quim. Anal. 21, 191 (1967). 4 3 N. P. Buu-Hoi, B. Eckert, and R. Royer, C . R . Acad. Sci. 232, 1356 (1951). 44 H. Cassebaum and K . Liedel, J . Prakt. Chem. 12,91 (1960). 4 5 A. Ermili and R. Giuliano, Gazz. Chim. Ital. 89,517 (1959). 4 6 S. Gronowitz and G. Hansen, Ark. Kemi 27, 145 (1967). 4 7 M. Hashimoto and K . Hattori, Chem. Pharm. Bull. 14,1314 (1966). 4 8 R. Hodges, J. W. Ronaldson, A. Taylor, and E. P. White, J . Chem. SOC., 5332 (1963). 4 9 H. B. MacPhillamy, R. L. Dziemian, R . A. Lucas, and M. E. Kuehne, J . Amer. Chem. Soc. 80,2172 (1958). 5 0 F. G. Mann and J. H. Turnbull, J . Chem. SOC., 747 (1951). 51 H. Mix, Justus Liebigs Ann. Chem. 592, 146 (1956). 52 H. Mix and H. W. Krause, Chem. Ber. 89,2630 (1956). 53 H. Mix, H. W. Krause, and J. Reihsig,J. Prakt. Chem. 6, 174 (1958). 5 4 Y. Omote, H. Tazawa, Y . Fujinuma, and N. Sugiyama, Bull. Chem. SOC. Jap. 42, 3016 (1969). 55 H. Wexler and A. Caraculacu, An. Stiint. Univ. “A. T . Cum,” Imi, Sect. IC 13, 7 1 (1967);Chem. Abstr. 69, 106525 (1968). 5 6 R. Hodges and A. Taylor, J . Chem. SOC., 4310 (1964). 33
Sec. II.A]
5
THE CHEMISTRY OF ISATIN
cyanoaniline to 7-methylisatin-4-carbo~amide.~~ An N-methyl analog of 3 has been converted into an N - r n e t h y l i ~ a t i n . ~ ~ # ~ B Use of the appropriate tetrahydronaphthylamine has led to fused isatins such as 5 and 6,40 while diaminobiphenyls have given rise to
6x1 032: H
H
(5)
(6)
;
; $ e M
OITQ-Q~I:
0
H
H
0Me
MoO
(7)
Me
/
\
Ol:DonTI:
0
H
(9)
H
0
C0,H (8)
compounds of the type 714 and 8.514,4'-Diaminodiphenylether led to the isatin 9.59A number of m-phenylenediamines have been subjected to this sequence. Thus while m-phenylenediamine and 2,B-diaminotoluene gave 10 and 11 respectively,6o 2,4-diaminochlorobenzenegives 12.61 Finally, 2,4-diaminotoluene gives rise to 13 which has been postulated to arise in the alkali workup of 14.61 o-Nitroacetanilide and sulfuric acid or hydroffuoric acid gave a good yield of isatin-3-0xirne.~~ It is assumed that the cyclization took place via PhNHCOC(OH)=NOH. Treatment of anilines with oxalyl chloride followed by cyclization of the intermediate 15 is a useful isatin synthesis. Generally a Lewis acid F. Benington, R. D. Morin, and L. C. Clark, J . Org. Cfiem.23, 19 (1958). J. M. Z . Gladych and J. H. Hunt), S. African Patent 68 04,428 (1968); Chem. Abstr. 71, 81436 (1969). 59 I. Shopov, Dokl. Bolg. A k a d . Naulc 21, 241 (1968); Chem. Abstr. 69, 3207 (1968). 6o Z . J. Allan, Chein. Listy 46,228 (1952). Z . J. Allan, Chem. Listy 46, 224 (1952). 6 2 K. Wiechert, H. H. Heilrnann, and VV. Jacob, 2. Cliem. 1, 191 (1961). 57
58
[Sec. 1I.A
PRANK D. POPP
(10) R = H (11) H. = Mu
is used for the c y ~ l i z a t i o n , ~but ~ , ~in~ some - ~ ~ cases, for example 3,5d i m e t h ~ x y a n i l i n eno , ~ ~Lewis acid is needed. With 2,3-diclilorodiphenylamine, cyclization takes place onto the unsubstituted ring to give N-(2,3-di~hIorophenyl)isatin.~~ This method has also been applied to the synthesis of tetra hydro is at in^.^^,^^ Thus 16 and oxalyl chloride gave
R (15)
Ph (17)
H. E. Baumgartrn a n d J. L. Furnas, ,I. Org. Chem. 26, 1536 (1961). J. W. Cook, J. D. Loiidon, a n d P. McCloskry, J . Chem. Soc., 3904 (1052). 6G J. W. Cusic a n d W. E. Coyne, U.S. P a t e n t 3,509,149 (1970); Chem. Abstr. 73, 3931 (1970). 66 A. DaSettimo a n d E. Nannipieri, J . Org. Chem. 35,2546( 1970). 67 B. A. Hessand S. Corbino,J. Heterocycl. Chem. 8 , 161 (1971). 6 8 H. S. Lowrie, U.S. P a t e n t 3,265,693 (1966);Chem. Abatr. 65, 15395 (1966). 69 H. S. Lowrie, U. S. P a t e n t 3,297,694 (1967);Chem. Abstr. 66, 76020 (1967). 70 H. S. Lowrie,J. Med. Chem. 9 , 664 (1966). 71 M. S. Newman and W. H. Powel1,J. Org. Chem. 26,812 (1961). 7a A. Sallmann and R . Pfistrr, German P a t e n t 1,815,802 (1969); Chem. Abstr. 72, 12385. (1970). 73 A. Rallmann and R. Pfister, German P a t e n t 1,815,807 (1969);Chem. Abstr. 71, 101552 (1969). 74 R. A. Scherrrr, U.S. P a t e n t 3,238,201 (1966);Chem. Abstr. 64, 17614 (1966). 7 5 H. Newman and R. B. Angier, J . Org. Chem. 34,3484 (1947). 76 E. Ziegler, M. Eder, K. Belegratis, a n d E. Prewodourakis, Monatsh. Chem. 98, 2249 (1967). 77 E. Ziegler, F. Hradetzky, a n d M. Edcr, Monatah. Chem. 97, 1391 (1966). 63 64
Sec. II.A]
T H E CHEMISTRY O F I S A T I N
7
what was reported as 17.77Reaction of cyclohexanone and dimcthyloxalate gives a substituted gljroxylic ester which reacts with amines to form mils (18) which on acid hydrolysis give rise to similar compounds.7a-80Use of guanidine or urea as the amine with 2-oxocyclohexylglyoxylic acid gave quinazoline derivatives rather than 19.a1Infrared 7 9 , a 0
R
1C
and NMR studies support the taiitomeric structure 19 for these so-called tetrahydroisatins. The isatin derivative 20 was obtained from acridone by oxalate c y ~ l i z a t i o nThe . ~ ~ half ester-half acid chloride of oxalic acid has also been used in this synthesis.82 The ester of 2-oxocyclohexylglyoxylic acid arid 3,4-dimethoxyphenethylaminegave 18 (R = 3,4diniethoxyphenylethyl) 83-a6 which on treatment with phosphoric acid gave the hexahydroisatin derivative 21. 3-Acetoxy-2,4,5,6-tetrahydro2-oxobenzofuran and ammonia, ethylamine, or aniline gave 19 (R = H, Et, or Ph, r e s p e c t i ~ e l y )L.-P-n-GIuco~yranosides ~~ of isatins (21a) were L. Horwitz, J . Amer. Chem. Soc. 75, 4060 (1953). 1). G. O’Sullivan and P. W. Sadlcr, J . Chem. Soc., 876 (1959). 8o 1L. J. S. Beer and J. Hollowood, J. Chem. Soc., 991 (1964). 81 W. L. F. Armarego and B. A. Milloy, J . Ckem. Soc., Perkm Trans. 1, 2814
78 78
(1973).
L. Baiocchi, An71. Chinz. (Rome) 57, 492 (1967). 83 A. Mondon, German Patent 1,105,424 (1957);Chem. Abstr. 56, 7284 (1962). 84 A. Montlon,Justus Lzebzgs Ann. Chein. 628, 123 (1959). 8 5 A . Mondon and H. Witt, Chem. Rer. 103, 1522 (1970). 8 6 A. Mondon, I<. F. Hanscn, K. Bochme, H. P. E’aro, H. J. Nestler, H. G. Vilhuber, and I<. Bottcher, Chem. Ber. 103, 615 (1970). 8 7 R.J. S. Beer and R. W. Turner, J. Chem. Soc., 1648 (1965). 82
8
[Sec. 1I.A
FRANK D . POPP
prepared by condensation of the appropriate glucopyranosyl aniline derivatives with oxalyl chloride.87a The Martinet reaction is a somewhat similar method that makes use of the reaction of an aniline and oxomalonic ester to give 22, which on 0H
0
(23)
(22)
treatment with alkali in the presence of oxygen gives an isatin via a dio~iizdole.~~-~~ Treatment of potassium isatinate with sodium formate in aceticformic anhydride gave l - f o r m y l i ~ a t i n while , ~ ~ the sodium isatinate 23 was cyclized by treatment with acid to the expected 5-substituted i~atin.~~ o-Nitrobenzoyldiazomethanes have been cyclized by acid to N hydroxyisatins.lOO*lO1 Use of a I4C label in the diazo carbon led to an isatin with all of the I4C in the %position; the mechanism of this CO,H
OM0 (24)
87aM. N. Preobrazhenskaya, I. V. Yartseva, and L. V. Ektova, Dokl. Acad. Nauk SSSR 215, 873 (1974). W. T. Colwell, J . K. Horner, and N. A. Skinner, U.S. Dep. Corn., Ofjke Tech. Serw. A D 435,889 (1964);Chem. Abstr. 62, 11763 (1965). 89 W. Langenbeck, I<. Ruhlmann, H. H. Reif, and F. Stolze, J . Prakt. Chem. 4, 136 (1957). A. Martinet, C.R. Acad. Sci. 242, 2358 (1956). g1 J. R. Merchant and S. S. Salgar, J . Indian Chem.SOC. 4 0 , 2 3 (1963). 92 R. E. Schachat, E. 1. Becker, and A. D. McLaren, J . Org. Chem. 16, 1349 (1951). 93 F. Benington, R. D. Morin, and L. C. Clark, J . Org. Chem. 20, 1454 (1955). 94 V. H. Brown, W. A. Skinner, and J. I. DeGraw, J . Heterocyl. Chem. 6, 539 (1969). 95 N. P. Ruu-Hoi, P. Jacquignon, and E. Allegrini, J . Chem. SOC., 4836 (1961). 96 H. Cassobaum, Chem. Ber. 90, 2876 (1957). 97 J. W. Clark-Lewis and J. A. Edgar, J . Chem. SOC., 5551 (1965). g* W. L. F. Armarogo antl J. I. C. Smith, J . Chem. Soc. B, 449 (1967). g g J. Jarkovsky and Z. J. Allan, Collect. Czech. Chem. Commun. 26, 2940 (1961). looE. Giovannini and P. Portmann, Helw. Chim. Acta31, 1381 (1948). l o l E. C. Taylor antl D. R. Eckroth, Tetrahedron 20, 2059 (1964).
Sec. II.B]
THE CHEMISTRY O F ISATIN
9
conversion has been discussed.l o l Treatment of 24 with ammonium hydroxide followed by ferrous sulfate gave 6-chloro-7-methoxyisatin. l o 2 A number of ring closures have been reported that lead to 2- or 3substituted isatins. Thus, treatment of nitromalonbis-N-methylanilide with acid gives N-rnethylisatin-3-0xime.~~~ Reaction of 25 with cyclohexyl or t-butylisocyanide gives 26, which was hydrolyzed by acid to 27.1°4Heating of 28 gives, with oxidation, the isatin-2,3-dianil 29.1°5
B. RINGCONTRACTIONS
A number of so-called 2,4-dihydroxyquinolines, after the introduction of a 3-hydroxyimino,l06 3-nitroso,107.108 3-hydroxy-3-arnino,lo9 or more frequently 3,3-dihalo give isatins with sulfuric acid or sodium hydroxide. Treatment with sodium hydroxide of 3,3D. R. Eckroth, T. G. Cochran, and E. C. Taylor,J. Org. Chem. 31, 1303 (1966). J. W. Clark-Lewis and G. F. Katelrar, J . Chem. h’oc., 2825 (1959). l o 4 D. P. Deltsova, E. A. Avetisyan, N. P. Gambaryan, and I. L. Knunyants, Izv. Akad. N a u k S S S R , S e r . Khim., 355 (1973);Chem. Ahstr. 78, 147724 (1973). lo5 E. Ziegler, W. Kaufmann, and W. Klementschitz, Monatsh. Chem. 83, 1334 lo’
lo3
( 1952). R . Hardman and M. W. Partridge, J . Chem. SGC., 614 (1958). lo7F. N. Lahey, J. A. Lamberton, and J. R. Price, Aust. J . Sci. Res. Ser. A 3, 155 (1950). lo*J. A. Lamberton and J. R. Price, Aust. J . Chem. 6, 173 (1953). l o QT. Kappe, E. Lender, and E. Ziegler, Monatsh. Chem. 99, 2157 (1968). E. Ziegler and T. Kappe, Monatsh. Chem. 94, 698 (1963). ‘11 E. Ziegler and T. Kappo, Monatsh. Chem. 94, 73G (1963). 112 E. Ziegler, T. Kappe, and R. Salvador, Monatsh. Chem. 94,453 (1963). E. Ziegler, It. Salvador, and T. Kappe, Monatsh. Ch,em. 94, 941 (1963). E. Ziegler, R . Wolf, and T. liappe, Monatsh. Chem. 96, 418 (1965). lo6
10
FRANK D. POPP
[Sec. 1I.C
dichloro-2,4-dioxo-l,2,3,4-tetrahydroquinoline (30) labeled a t carbon 3 with 14Cresulted in 1OOyoloss of the activity as 14C0, and gave isatin which contained nol4C.ll5
(30)
7-Methoxy-2-methyl-1,4-dihydro-4-oxoquinoline was converted into 6-methoxyisatin by an oxidative ring opening followed by ring cloOxidation of 4-methyl-N-(2,3-dimethylphenyl)-carbostyil with alkaline permanganate gave N-(2,3-dimethylphenyl)i~atin.~~
Treatment of 31 with alkali gave 5,6-dimethylisatin in addition t o a quinoline derivative.l16
C. FROM INDOLE DERIVATIVES Chromic acid oxidation of a variety of indoles has been used as a synthetic route to i s a t i n ~ . ~ lA~ variety - l ~ ~ of other oxidative methods 115
T. Kappe, Personal Communication, 1973. W. Salzer, H. Timmler, and H. Andersag, Ber. 81, 12 (1948).
1158
A. H. Rees, J. Chem. Soc., 311 (1959). A. DaSettimo, M. F. Saettone, E. Nannipieri, and P. Barili, Gazz. Chim.Ital. 97, 1304 (1967). 118 E. Kambli, Helw. Chzm. Acta 47, 2155 (1964). l l S M. Kunori, Nkppon Kaguku Zasshi 81, 1431 (1960). lZo W. E. Noland and It. D. Riekc, J . Org. Cheni. 27,2250 (1962). lZ1 W. E. Noland and K. 1%. Hush, J . Org. Chem. 29,947 (1964). l Z 2A. P. Tercntcv and M. N. Proobrazhenskaya, Dokl. Akad. Nauk.SSSR 118,302 (1958);Chern. Abstr. 52, 11003 (1958). l z 3 A . P. Tercntcv and M. N. Preobrazhenskaya, Zh. Obshchei Khzm. 29, 317 (1969);Chem. Abstr. 53,21874 (1969). l Z 4A. 1’. Tcrentrv, M . N. Prcobrazhenskaya, A. S. Bobkov, and G. M. Sorolrma, Zh. Obshchez lihzni. 29,2541 (1959);Chem. Abstr. 54, 10991 (1960). 116
Sec. II.C]
T H E CHEMISTRY O F ISATIN
11
have also been employed.64~66*74~125-135a Thus, for example, treatment of 32 with oxygen in triethylamine gave i ~ a t i n . lVarious ~~ N,N’dialkylated indigo dyes have been oxidized with nitric acid to N a 1 k y l i ~ a t i n s . lOxidation ~~ of sporidesmin, a mold metabolic product, gave 5-chloro-B,7-dimethoxy-1-methylisatin.135
(32)
Dihalogenation of oxindole followed by alkaline hydrolysis of the 3,3-dihalooxindole has been applied to the synthesis of some isatins.66*126*136-137b A number of oxindoles have been treated with nitrous acid to give i ~ a t i n - 3 - o x i m e sReduction . ~ ~ ~ ~ ~ ~of~the oximes t o 3-aminooxindoles followed by ferric chloride oxidation gave is at in^.^^^.^^^ When this sequence was applied to 7-azaoxindole, the azaisatin 33 was
I-I (33)
Ac (34)
G. Berti, A . DaSettimo, and 0. Livi, Tetrahedron 20, 1397 (1964). E. Giovannml and P Portinam, Helv. ChLm. Acta 31, 1375 (1948). l Z 7 T. Lcsiak, Rocz Chewz. 37, 347 (1963);Chem. Abstr. 59, 6342 (1963). l Z 60. Neunhoeffer and G . Lchmann, Chem. Ber. 94, 2965 (1961). l Z 9A. Romeo, H. Corrodi, and E. Hartlegger, IIelv. Chzm. Acta 38,463 (1955). 130 S. I<. Saha, J . Indaan Chem. SOC., I d N e w s E d . 13, 178 (1950); Chem. Abstr. lZ5 lZ6
45, 8004 (1951). T. Sat0 and M. Ohto, Bull. Chem. SOC.J a p . 28, 480 (1955); Chem. Abstr. 50, 12018 (1956). 132 12. A. Schemer, Bclgian Patent 637,515 (1964); Chem. Abstr. 63,4307 (1965). 133 T. Hmo, M. Nakagawa, T. Hashizume, N. Yamaji, Y. Miwa, K. Tsunooka,and S . Akaboshi, Tetrahedron 27, 773 (1971). 134 R. Puinmcrcr and F. Mclnlnger, Justus Laebqs Ann. Clzem. 590, 173 (1954). 135 R.Hodges, J. W. Ronaldson, A. Taylor, and E. 1’. White, Chem. Ind. (London), 42 (1963). 135a 13. Hodges, J. W. Ronaldson, J. S. Shannon, A. Taylor, and E. P. White, J . Chern. Soc., 26 (1964). 136 R.J. Bass, T’etruhedron 27, 3263 (1971). 137 L. Simct, J . Org. Chem. 28, 3580 (1963). 137a T. A. Foglia and D. Swcrn, J . Org. Chem. 33, 4440 (1968). 137b DaSettimo. C. Mrnieagli, and E. Nannipicr, J . Org. Chem. 39, 1995 (1974). 138 E. Giovannmi and P. Portmann, Helu. Chzm. A c t a 31, 1392 (1948). 131
12
FRANK 1). POPP
[Xec. 1II.A
obtained.139 This appears to be the only report in the literature of an azaisatin. Reaction of N - a c e t y l i n d ~ x y l land ~ ~ 34141 with nitrous acid gave N-acetylisatin-2-oxime. A similar reaction takes place with indoxyl.140 Heating of N-methyloxindole and 35 in toluene gives 36 and Nm e t h y 1 i ~ a t i n .Il n~a~similar manner isatin was obtained from oxindole.142 The mechanism of these transformations has been discussed. The
c1,
Ac
(37)
spiroindole 37 has been converted to N-methylisatin and a number of other products.lo3
111. N-Substituted Isatins A.
PREPARATION FROM ISATIN
Isatin sodium or potassium salts react with dimethyl and acyl d i e t h ~ l lsulfate, ~~ a variety of alkyl halides,11*48*54p148-162 34958*143-146
139 140
141
H. Kagi, Helv. Chim. A c t a 24, 141E (1941). A. Etiennc, Rull.Soc. Chim.P r . , 651 (1948). D. Riiileanu, V. Daniel, E. Mosanu, and C. D. Nenitzescu, Rev. Roum. Chim.
12, 1367 (1967). Bruni and M. Poloni, Gazz. Chim.Ital. 100, 1119 (1970). 143 J . A. Ballantine, C. B. Barrett, R. J. S. Beer, B. G. Boggiano, K . Clarke, S. Eardley, B. E. Jonnings, and A. Robertson, J . Chem. Soc., 2222 (1957). 144 It. C. Eldorfield and H. H. ltembgos, J . Org. Chem. 32, 3809 (1967). 145 S . Piotra and G. Tacconi, 8'aT7YmCo (Pavza),Ed. S c i . 14, 854 (1959). 146 N. M. Turlievich and 0. F.Lymar, Metody Poluch. Khzna. Reaktzvov Prep., 117 (1971);C'hern.AbPtr. 78, 4063 (1973). 147 C. B. Hudson and A. V. Robertson, Aust. J . Chem. 20, 1521 (1967). 142 P.
Sec. III.A]
THE CHEMISTRY O F ISATIN
13
halides,152,153,163-166 and a 1 i 2 i y d r i d e s ~ ~to' ~give ~ ~ ,A7-alkyl ~ ~ ~ arid N acylisatins. Silver salts of isatin have also been used to prepare N alkylisatins. 148*149 In a similar manner 5-methylisatin and acrylonitrile
CH,C'H,CN (38)
with Triton B gave 38.169,170 Ketene has seen limited use in tho preWhen heated in water gramine and paration of N-a~ety1isatins.l~~ isatin gave N-skaty1i~at~in.l~~ A. E. Arbuzov and M. S Bastanova, lzv. A k a d . NaukSSSR, Otd. K l i z m . Nnuk, 459 (1952);Cheni. Abstr. 47,4876 (1933). 149 A. E. Arbuzov and 0. M. Shapshinskaya, T r . Kazan. Kham. T e k h n o l . Inst. 7m. S . &I. Karova, X o . 16, 11 (1951);('hem. Abstr. 51, 12065 (1957). 150 It. L. Autrey ancl F. C. Tahk, Tetrahedron 23,901 (1967). 15* I). J. Bauer and P. W. Sadler, British Patent 1,026,401 (1966); Cltem. Abstr. 65, 2224 (1966). 152 N. Hirose, S.Sohda, antl S. Toyoshima, Ynkuguku Zassha91, 1323 (1971). 153 R. Kikumoto antl T. liobayashi, Tetrahedron 22,3337 (1966). 154 F. Iinotz, Sca. Pharm. 38,20 (1970). 155 F. Iinotz,Sct. Pharm. 38,98 (1970). 156 F. Knotz,Sca. Pharni. 38, 163 (1970). 157 It. G. Johnston and D. Kidd, J . Chetn. SOC .4734 , (1964). 158 P. Lakshminarayana, K. K.Balasubramanian, and P. Shanmugam, J . Cltem. SOC. Perkzn Trans. 1 , 9 9 8 (1973). 159 A. Lindyuist, P. Lagerstrom, antl R. Dahlbom, Acta Pharm. Sscecica 9 , 93 148
(1972).
Patent 3,428,649 (1969);Chem. Abstr. 70,68150 (1969). H. Schafcr, Arch. Pharnz. 303,183 (1970). 162 G. Tacconi, 1'. P Mighetti, and ( i . Ucslmoni, J . I'rukt Chcm. 315, 339 (1973). 163 E. H. Huntress and J . Bornstcm, J . Amer. CIiem. SOC. 71, 745 (194'3). 164 R . Patcr, J . Heferocycl. Chem. 7, 11 13 (1970). 165 J . M. Muchowski, Can. J . Cheni. 48, 1946 (1970). 1 6 6 C . Runti and F. Collino, E'armaco, E d . S c i 24,577 (1969). 167 S. J. Holt, A . E. Kellie, 11. G. O'Sullivan, and P. W. Sadler, J. Cliene. S O C . , 1217 160 J. Plostnieks, U.S.
161
(1958). R . E. Lyle, D. E. Portloclr, &I. J . Kanc, and J. A. Bristol, J . Org. Chem. 37, 3967 (1972). 169 F.J . DiCarlo and H G Ltntlwall, .I. Amrr. Chcm. S O C .67, 199 (1945). 1 7 0 D. Waitr, J . Chein. SOC. C, 550 (1970). 171 1 ' . V. Svetkin, 211.Obslichez K h z n i . 26, 1216 (1936); Cheni. AOstr. 50, 16703 (1956). 172 A. Kainal, M. ilnluni, and 8 . Aziz, PwX. J . SIC?. Intl. Rrs. 9 , 323 (1966); C'hwi A h s f r .71, 3199 (1969). 168
14
[Sec. 1II.A
FRANK D. POPP
Isatin and triethylamine with methyl and phenylisocyanate has been reported to give 39 (R = Me and Ph, r e ~ p e c t i v e l y ) .I~n~ alkali, ~ however, isatin and phenylisocyanate of phenylisothiocyanate gave the qiiinazolines 40 ( X = 0 or S).174 Base-catalyzed reactions of isatins and ClSCPC1,,175C13CSH,176and C13CSC1177-179 gave 41 (R = SCE’Cl, and SCCl,, respectively), and reactjion of isatin with dimethylsulfoxide in acetic acid gave 41 (R = CH,SMe3).ln0
a:-; I
(’0,H
HO
ELIh
);J---JQ-,R R
H
(’ONHH
(39)
(40)
(41)
Isatin reacts with formaldehyde and a variety of amines in the Mannich reaction t o give compounds of type 42.181-193a A similar reaction takes place with isatin-3-thio~ernicarbazone,~~~*~~~ or 42 can react with thiosemicarbazide to give a similar product.lg2 I n the absence of an amine, isatin lE1 and substituted isatins157*193a with formL. Capiiano and M. Welter, Chern. Rer. 101, 3671 (1968). P. Ctyulai and I<. Lcmpcrt, I’errod. Polylech. Cheni. En g . 14, 13 (1970). 175 17,. Kuehlc, E. Klauke, F. Grewe, and H. Kaspers, Belgian Patent 621,711 (1963);Chem. Abstr. 59, 11510 (1963). 176 R. A r i ~ sFrench , Patent 1,492,948 (1967);Cheni. Abstr. 69, 59240 (1968). 177 Chimctron S.a.r.l., Belgian Patent 696,711 (1967); Chem. Abstr. 71, 101891 (1969). 170 C. Hcnnart, Bull. SOC. Chirn. Fr., 2968 (1967). 179 C. Hennart, French Patent 1,497,492 (1967);Chein. Abstr. 69, 106555 (1968). 180 H. H . Otto, Pharin. Zentralh. 107, 444 (1968); Chem. Abstr. 69, 106601 (1968). l E 1 N. P. Bou-Hoi, G. Salnt-t-Rllf,J. C. Perchc, and J. C. Bourgeade, Cham. Ther. 3 , 1 1 0 (1968). l o 2 Cibtt, Ltd., Netherlands Patcmt 6,507,422 (1965);Chem. Abstr. 65, 2227 (1966). l e 3 I t . C. l
174
Sec. III.B]
15
THE CHEMISTRY OF ISATIN
aldehyde gave 43. ('ornpounds such as Me,NCH,NHCOPh,lg4 and Et,NCH,CHPhOH18* (the latter by lead tetraacctate cleavage t o the iniiniiiin salt) also react to give Maiinich-type products (42). Michler's
('H,Nli.,
('H201f
(42)
(43)
(44)
hydro1 (p-Me,S(',H,),CHC) H , I g 5 gives an analogous condensation 1)roduct 141. rC = CH(C,H,NiMc,),]. Although isatin is generally itiiiirioiiietliylated at the NH-position, it also has been used as the clectrophilic component in the Blaniiich reaction,leg Thus isatin with R'COCH,R" and R,NH gavc 44.
B. REACTIONS OF N-SUBSTITUENTS N-Siibstitutcd isatins have also been prepared by reactions of some of thc compotiiids th at were described earlier. Reaction of N-hydroxyisatin n ith acetic arihytlride gave 45.l g 6 N-Hydroxyisatin has been converted into 45a by reaction with nietliyl isocyanate in th e presence
I
0
('
I1
I
nrv
0
~
('
~
NHMe
II
0
0
(45)
(45a)
(45b)
of a, catalytic amount of ~ , h e n g l d i r t z ~ i n e t l iReaction ~ n ~ . ~ ~of~ 45a ~ with cat;rlytic phenyldiazoinet hane in ethanol gave the oxadiazolo[2,3-a]indole 45b. 196a Hydrolysis of 38 gavc the corresponding propionic acid d e r i v n t i ~ e . ~N-Propargylisatin ~~.~"~ (46) has been used in the Mannich
I
C'H,-('rCH (46)
I
CH,-C=C--CH,NR (47)
13. Hcllmanri and G. Haas, Cheni. Ber. 90, 50 (1957). l q 5 71 FIcllinann and G. Opitz, Justrks Liebigs Ann. Chem., 604, 214 (1957). lgfi 1 3 . Eiitcrt, C:. Borggrefc, and H. Sclzcr, JaistuR Liebzgs Ann. C l m n . 725, 37 (1969). L. Capimno ant1 &I.Zander, Chem. Ber. 100, 3820 ( 1 9 6 7 ) . lQ4
16
[Sec. 1V.A
FRANK D. POPP
reaction to give 47.159 Isatin Mannich reaction products have been reacted with active hydrogen compounds. lg7Thus, for example, 42 and acetophenone gave isatin and PhCOCH,CH,NR,.197 The hydroxymethyl compound 43 with acyl halides gave esters of The acid 49 has reacted via the acyl chloride to give a the type 48.166 number of amides of the type 50.154*156 Thionyl chloride converts 43
CH,COR
CH,OCOII. (48)
(49) R = OH (50) R = NR,
into chloromethylisatin. lg8 Chloromethylisatin has proved to be a valuable reagent for the synthesis of N-substituted isatins. Reaction of chloromethylisatin with a large selection of compounds has led to a great variety of 1-isatinylmethyl derivatives. 198-203a
IV. Electrophilic Substitution and Related Reactions A. HALOGENATION Reagents such as N-bromosuccinimide,204 N-~hlorosuccinimide,~~~ N-bromocaprolactam,205sulfuryl chloride,206bromine,lls and t-butylhypochlorite 48 have been used to prepare 6-haloisatins. Isatin with IC1 gives 5 - i o d o i ~ a t i n . Chlorination ~~~ of 6-chloroisatin 40.208 and 4chloroisatin 40 gave 5,6- and 4,5-dichloroisatin, respectively. Various alkylisatins also undergo halogenation in the 5-position. l p 2 1 W. L. Nobles and N. D. Potti, J . Pharm. Sci. 57, 1097 (1968). F. Knotz, Sci. Pharm. 38, 227 (1970). lS9 H. Boehme and H. H. Otto, Arch. Pharm. (Weinheim)300, 922 (1967). H. Boehme and H. Schwartz, Arch. Pharm. (Weinheim)306, 684 (1973). 201 I?. Knotz, Scz. Pharm. 38, 26 (1970). 202 F. Knotz,Sci. Pharm. 41, 123 (1973). 203 W. Weridelin and F. Knotz, Monatsh. Chem. 103, 1632 (1972). 203a K. Issleib, W. D. Hepp, H. Oehme, and G. Erfurt, East German Patent 98,935 (1973);Chem. Abst. 80, 70697 (1974). 2 0 4 N. P. Buu-Hoi, Rec. Trav. Chzm. 73, 197 (1954). 205 B. Taub and J. B. Hino, J . Org. Chem. 25,263 (1960). 206 H. Junnge and H . J. Quadbeck-Seeger, German Patent 2,158,955 (1973); Chem. Abstr. 79,66169 (1973). 2 0 7 N. P . Buu-Hoi and P. Jacquignon, C.R. h a d . Sci. 244, 786 (1957). 2 0 8 M. M. Rapport, A. E. Benear, J. F. Mead, and J. B. Koepfli, J . Amer. Chem. lg7
lQ8
SOC. 68,2697 (1946).
Sec. IV.A]
17
THE CHEMISTRY O F ISATIN
If the 5-position is occupied, halogenation takes place in the 7 position. Bromination of 5-chloro or 5-methylisatin leads t o th e corresponding 7-bromo c o m p o ~ n d s and , ~ ~reaction ~ ~ ~ ~ of 4-chloro-5methoxyisatiri with X,N-dichlorourethane in refluxing acetic acid gave 4,7-dichloro-5-methoxyi~atin.~~~ I n aqueous acetic acid these latter Attempts t o introduce reactants gave 1,4-dichloro-5-metlio~yisatin.~~~ a second iodine i n 5-iodoisatin led t o the isolation of 51, which could be
(52)
(51)
hydrolyzed t o 5,7-diiodoisatin.210R,eaction of a number of 5-substituted ketnls (52) with IC1 led t o the isolation of 7-iodo-5-substituted ketals, which could be hydrolyzed to th e 7-iodo-5-substituted isatins.210 Although not electrophilic substitution, halogens have also been introduced into the 2- and 3-positions. Reagents such a s phosphorus pentachloride and chlorosulfonic acid214have been used t o introduce a halogen into the 2-position of isatins giving 2-chloro-3oxoindolenines. The products react further with reagents such as secondary aminrs,211 reactive aromatic and thiols212t o give compounds such as 53, 54, an d 55 respectively. 32*211-2139216
SMe
SMe
(55)
R. F. Coles, U.S. Patent 2,642,439 (1953);Chem. Abstr. 48,4004 (1954). J . Bass, Tetrahedron Lett., 1087 (1971). 211 J. vanAlphen, Rec. Trazj. Chim. 60, 138 (1941). 212 J. T. Baker and C. C. Duke, Tetrahedron Lett., 43 (1968). 213 E. Sawiclti, T. W. Stanley, T. R. Hauser, and R. Barry, Anal. Chem. 31, 1664 (1959). 214 W. Langrnbccli and D. Heuchcl, hfonatsh. Chem. 98,535 (1967). 215 E. Sawicki, T. W. Stanley and W. Elbert, Microchem. J . , Symp. Ser. 2, 633 (1961). 216 G . Palazzo and V. Rosnati, Gazz. Chim. Ital. 83, 211 (1953). 209
210 R.
18
[Sec. 1V.C
F R A N K D. P O P P
B. OTHERELECTROPHILIC SUBSTITUTIONS Nitration of 7-methyIi~atin,~ 4,7-dimethyli~atin,~~ and l - e t h y l i ~ a t i n lleads ~ ~ to the introduction of the nitro group into the 5-position. Nitration of 5-methylisatin gave 5-methy1-7-nitroi~atin."*~~ Reaction of isatin and haloisatins with chlorosulfonic acid gave 5chlorosulfonylisatins 219 which were then converted into sulfonamidcs.
C. OTHERTRANSFORMATIONS A number of reactions that do not reasonably fit in other categories are included in this section. The methoxy group in 7-meth0xy,~7-metho~y-6-methy1,~~ and 7-metho~y-4-rnethylisatin~~ has been cleaved to the corresponding hydroxy group with pyridine hydrochloride, while treatment with sodium hydroxide cleaves the 6-methoxy group of 5-chloro-6,7dimethoxy-l-methyli~atin.~~ 5-Acetamidoisatins have been hydrolyzed to 5 - a m i n o i ~ a t i n s .Isatin ~~ carboxylic acids have been converted to amides and esters by means of standard procedure^."^^^ A number of complexes of isatin and metal salts have been reported.220*221 Isatin and N-substituted isatins react with dialkyl phosphites to give 56 and with trialkyl phosphites to give 57.222The pyrolysis products of isatin have been as have those of N -
methyl is at in^.^^^^
R (56)
It (57)
W. C. Sumpter and W. F. Jones, J . Amer. Chem. SOC. 65, 1802 (1943) J. Taglianetti, An. Fac. Fawn. Odontol., Univ. Sao Paulo 7, 57 (1949); Cheni. Abstr. 45, 1997 (1951). S. Somasckhara, V. S.Dighc, G. K. Suthar, and S. L. Mukherjec, Curr. Sci. 34, 508 (1965). 2 2 0 R. C. Paul and S. L. Chadha,J. Inorg. Nucl. Chem. 31,2753 (1969). 221 R. C. Paul, S. K. Rohani, and S. L. Chadha, I n d i a n J . Chem. 8, 848 (1970). 222 A. Mustafa, M. M. Sidlry, and F. M. Solirnan, I'etrahedron 22, 393 (1966). 223 W. D. Crow and C. Wontrup, Chem. Corrmun., 1026 (1968). 223a C. Wentrup, Helw. Chzm. Acta 55, 1613 (1972). 217
218 M.
Sec. V.B]
THE CHEMISTRY O F I S A T I N
19
V. Spectral Properties A. INFRARED Extensive studies have been reported on infrared vibrational frequency correlations of isatin and a variety of substituted isatin.79,167,224-228 Infrared evidcrice supports structure 1 for isatin and gives no evidence for the lactiin or enol form.225*229 In contrast to isatin infrared studies indicate that the so-called 4,5,6,7-tetrahydroisatinsexist as the enol tautomer 19.19 In concentrated solution 7-methylisatin-4-carboxylicacid exhibits normal carboxylic acid dimerization, but in the solid state the lactol form 58 is present .228 Tnfrared studies indicate that hydrogen bonding as shown in 59 best represents the structure and mode of association of
(58)
(59)
isatin-3-0ximes.~~~ The infrared and hydrogen bonding of isatin-3thiosemicarbazones have been studied.230 An infrared study of the interaction of dimethylsulfoxide and isatin has appeared.231
B. OTHERSPECTRAL STUDIES A number of studies of the ultraviolet absorption spectra of isatins have appeared.34g232-235 The absorption curves of isatin and N-methylisatin are practically I). G. O’Sulliran, ,I. Che7n. Soc., 3278 (1960). U. G . O’Sullivan and 1’. W. Sadlcr, J . Chert%.Soc., 2202 (1956). 22G 1) G . O’Sullivan irnd 1’. IV. Sadlcr, J . Chem. Soc., 2839 (1957). 227 11. G. O’Sullivan and 1’. \V. Sadlrr, ,I. Org. Chem. 22, 283 (1957). P. W. Sadlcr, H. Mix, antl H. W. ICrausc, J . Cheni. Soc., 667 (1959). 229 K. Kiirosalri, N y i p o n K u g a k ~Z n s s h ~82, 1555 (1961); C / ~ e n iAbstr. . 58, 12088 (1863). 2’o P. LV. Sadler,J. C/tem.,Soc., 957 (1961). 231 R. C. Paul, P. Singh, and S. L. Chatlha, IiidianJ. Chem. 6, 673 (1968). 232 8 . J. Angyal, 13;. Rnllork, W. C . Hanger, W. C. Howell, antl A. W. Johnson, J . P h ~ mSoc., . 1592 (1957). 23J A. Mangini and R . l’asscrini, BoU. Scz. Fnc. Chzm. I d . Bologna 9 , 51 (1951); Chem. Abstr. 46, 330 (1952). 224 225
20
FRANK D. POPP
[Sec. V1.A
Isatin has been reported to fragment predominantly by successive loss of CO, HCN, and CO from the molecular ion on electron impact, and also by consecutive loss of two molecules of CO from the molecular ion followed by loss of HCN.236Use of 3-13C-labeled isatin shows that the initial loss of CO occurs entirely from the 2 - p o ~ i t i o n .Mass ~~~ spectral studies have also been carried out on a variety of derivatives of isatin.236-241 NMR studies have confirmed the enol tautomer 19 for the so-called tetrahydroisatins,81 and support the hydrazone structure for N methylisatin-3-phenylhydrazone .242
VI. Oxidation and Reduction A. OXIDATION The most frequently reported oxidation reaction of isatins is the oxidation with alkaline hydrogen peroxide to give anthranilic acids. This procedure has been both as a proof of structure of isatins and as a method of synthesis of anthranilic acids. The oxidation has been applied to alkyl,8,10.11.23,33.38-40,46,49,50,118halo ,11,18.35,36,36-40,47.106,118. 119.136,240 alkoXY,25,38,39.47,75, 107,118,136 trifluoromethyl 33,38,137 and , nitro8.120,217 isatins. Use of N-substituted isatins led to N-substituted anthranilic a ~ i d s . I n the ~ oxidation ~ ~ of ~ 5-bromo-l-(y~ ~ ~ carbethoxypropyl)-7-ethylisatin,60 was isolated after treatment with ethanol and acid.ll Oxidation of isatin derivatives 61 led, after treatment with diazomethane, to the acridine derivatives 62.67Application of this oxidation method to 7-hydroxyisatins gave rise to benzoxazolones (63).2*41 A. Mangini and R. Passerini, Boll. Sci. Fac. Chim. I n d . Bologna 12, 150 (1964); Chem. Abstr. 49, 8701 (1955). 235 R. Pummercr, F. Moininger, G . Schrott, and H. Wagner, Justus LieOigs Ann. Chem. 590,195 (1954). 236 J. A. Ballantine, R. G. Fenwick, and M. Alam, Org. Mass. Spectrom. 1, 467 (1968). 237 M. Butcher, Org. MassSpectrom. 5, 759 (1971). 238 J . A. Ballantine, R. G. Fenwick, and F. D. Popp, Org. Mas8 Spectrom. 5 , 1003 (1971). 239 F. D. Popp, J . Heterocycl. Chem. 6, 125 (1969). 2 4 0 F. D. Popp, J . Heterocycl. Chem. 9, 1399 (1972). 241 I<. Yamada, T. Konakahara, and H. Iida, Kogyo Kagaku Zasshi 73,980 (1970). 2 4 2 F. A. Snavely and C. H. Yoder, J . Org. Chem. 3 3 , 5 1 3 (1968). 2 4 3 C. Clerc-Bory, M. Clerc-Bory, H. Pacheco, and C. Mentzer, Bull. SOC. Chim.Fr. 1229 (1955). 234
~
~
Sec. VI.B]
21
THE CHEMISTRY O F ISATIN
Oxidation with chromium trioxide in acetic chromium trioxide in acetic anhydride-acetic acid,31 3-chloroperbenzoic acid in methylene chloride65 or benzene,74 or peracetic acid in acetic acidT4 gave rise t o isatoic anhydrides (64).
B. REDUCTION Sodium hydrosiilfite has been used t o reduce 5-bromo and 5,7dibronioisatin 244 as well as 5-niethoxy- 1-methylisatin57 to the corresponding dioxindole (65). Reduction of 1-benzylisatin with sodium hydrosulfite led t o the dioxindole (65, R = H , R' = CH,Ph)111,245a n d the isatide (66).245 1,7-Trimethyleneisatin1l0underwent a similar
E-ad(;0-n I
R' (65)
I
I
CH,Ph
CH,Ph (66)
reduction. 66 was also obtained from 65 an d l - b e n z y l i ~ a t i nSodium .~~~ borohydride also converted 1-benzylisatin t o th e dioxind01e.l~~ lxeduction of 5-chloroisatin with a zinc-copper couple led t o 5c h l o r o ~ x i n d o l eA . ~sodium-butanol ~~~ reduction of 4,B-dimethoxyisatin led to the corresponding i n d ~ l e . ~ ~ Lithium aluminum hyclride reduction of isatin gave mixtures of :~-hydroxyindoliric,indole, indigo, and indirubin with compositions depending upon the experimental conditions.246The latter three products 244
245 246
W. C. Sumptcr, J . Amer. Chem. SOC. 67, 1140 (1945). G. Hallmann, Chem. Ber. 95,1138 (1962). E Giovannini and T. Lorcnz, Helv. Chim. Acta 40, 1553 (1957).
22
[Sec. V1.B
FRANK D. POPP
were also obtained from a similar reduction of the 2- and 3-oximes of i s a t i ~ i .Lithium ~~~ aluminum hydride reduction of N-methylisatin gave N-methylindole and hT, "-dimethylindigo while N-methylisatin-3-oxime gave N-methylindole and N,N'-dimethylindirubi~i.~~~ In a similar manner 6-methylisatin gave 5,5'-diniethylindir~bin.~~~~~~~ Generally, however, lithium aluminium hydride reduction is used t o convert isatins to indoles. Thus, 4,5,6-trimethoxyi~atin,~~~ 5-bromoi ~ a t i n5-chloro-6-methoxy-l-methylisatin,253 ,~~~ 1-ethyl- and l-methyli ~ a t i nand ,~~ 4,6-dimethoxyisatin ~ g4 all gave the corresponding indoles. H
OH
1-Piperidinomethylisatin on lithium aluminum hydride gave the indoline 67 while sodium Forohydride reduction of the same isatin derivative gave a reductive dimerization to 68 and a reductionrearrangement to 69.255 Catalytic hydrogenation of isatin and N-methylisatin gave oxindole and N - m e t h y l o x i n d ~ l ewhile , ~ ~ ~similar reduction of 1-azidoacetylisatin gave l-aminoacetyloxindole.165 Catalytic hydrogenation over platinum oxide of N-methylisetin and isatin- 1-propionic acid gave 70. 16g A E. Giovannini and T. Lorenz, Helw. Chim. Acta 40, 2287 (1958). E. Giovannini and T . Lorenz, Ilelv. Chim. Acta 41, 113 (1958). 249 T. Ozawa and N. Kinae, Chem. Pharm. Bull. 18, 1293 (1970). 2 5 0 T. Ozawa and N. Kinae, Yakugaku Zasshi 93,8 (1973). 251 A. Carlsson, H. Corrodi, and T . Magnusson, Helv. Chim. Acta 46, 1231 (1963). 2 5 2 M. Julia, Y .Huang, and J. Igolen, C.R. Acad. Sci.,Ser. C . 265, 110 (1967). 263 H. Reimann and R. Jaret, Chem. Ind., (London) 2173 (1967). 254 C. B. Hudson and A. V. Robertson, Aust. J. Chem. 20, 1699 (1967). 2 5 5 H. J. Roth and H. H. Lausen, Arch. Pharm. ( Weinheim) 306, 775 (1973). 2 5 6 J. M. Muchowski, Can. J . Chem. 47, 857 (1969). 247
248
Xec. VLB]
T H E CHEMISTRY O F ISATIN
23
variety of substituted indoles have been obtained by diborane reduction of is at in^.^^^
Q D *
R
R
(70)
Isatin, N-methylisatin, and N-hydroxyisatin can be reduced to semidiones by treatment with the enolate anion of propiophenone in d i m e t h y l ~ u l f o x i d eNitroxides .~~~ are prepared from N-hydroxyisatin by treatment with lead dioxide in dioxan, while another nitroxide was formed spontaneously from N-hydroxyisatin in basic dimethyl sulfoxide solution in the presence of oxygen.z58 Stannous chloride reduction, in an acidic ethanol solution, of 1-(0nitrobenzoy1)isatin followed by treatment with base gave 71.153
(71)
~ ~ ~ a lead electrode and a Electrolytic reduction of i ~ a t i nusing saturated sodium carbonate solution as electrolyte gave dihydroxyindole, whereas a mercury cathode and lead anode in neutral sodium sulfate gave hydroxyindole. Electrolytic reduction of 1-methylisatin 260 using lead cathodes and 20 yo sulfuric acid gave l-methyldihydroxyindole; a mercury cathode and neutral sodium sulfate gave l-methylhydroxyindole. The polarographic behaviour of isatin,261-265 N - a l k y l i ~ a t i n , ~ ~ ~ H. Sirowcj, S.A . Khan, and H . Plimingcr, Syrztheszs, 84 (1972). G . A. Russell, C. L. Mycrs, P. Bruni, F. A. Nougcbaucr, and R. Blankespoor, J . A m e r . Cheni.Soc. 92, 2762 (1970). B. Sakurai, Bull. Chem. ,Sot. J a p . 17, 269 (1942). 260 B. Sakiirai, J . SAznshu U n i u . 1, 1 (1951);Ciiewi. Abstr. 48, 12580 (1954). 261 H. Casscbauni, 2 . Elektrochem. 58, 516 (1964). 262 W. Kemula, M. K . Kalinouski, and A. Girdwoyn, Rocz. Chew&. 41, 1975 (1967). 2 6 3 I. A. liorshunov, L. N. Sazanova, If. K. Shchcnnikova, and 0 . P. Malkova, Zaaod. Lab. 15, 1287 (1949);Chern. Abstr. 44, 3845 (1950). 264 W. C. Bumptcr, J. L. Williams, P. H Wilkenq, and B. L. Willoughby, J . Org. Cliem. 14,713 (1949). 265 W. C. Sumpter, P. H. Wilkcn, J . L. Williams, R. Wedemeyer, S. L. Boyer, and W. W. H u n t , J . Org. Chew&.16, 1777 (1951). 257 258
24
[Sec. VI1.A
FRANK D. POPP
i s a t i n - 3 - 0 x i m e , ~i s~a~t i, n~ -~3~- h y d r a ~ o n e3-phenyliminoo~indoles,~~~ ,~~~ 3-ben~ylideneindol-2(3H)-ones,~~~ l-(chl~roacetyl)isatin,~~~ and a variety of isatin derivatives 261 has been studied. A polarographic study of the alkaline hydrolysis of an isatin anil has been carried An analytical procedure for organotin hydrides has been based on the reduction of isatin t o o x i n d ~ l e . ~ ~ ~
VII. Reactions with Ketone Reagents
A. OXIMES A wide variety of substituted isatins have reacted with hydroxylamine to give isatin-3-oximes (72).6,26*42,51,92,107,126.169,274 0-Substitilted hydroxylamines also give this reaction.2755-Bromoisatin-3-oxime 0
1
(72)
(73)
has been prepared by reaction of 5-bromooxindole with sodium nitrite in acetic acid276and further examples of this reaction are included in Section II,C. N-Methylisat>in with 0-methylhydroxylamine gives 1methylisatin-3-0-methyloxime, while N-methylisatin and N-methyl hydroxylamine give 73.277Compound 73 can also be obtained from isatin-3-oxime with diniethyl sulfate and alkali.277 26G
R. Andruzzi, M. E. Cardinali, I. Carelli, and A. Trazza, Ann. Chim. (Borne)61,
415 (1971). C. Calzolari, Boll. Soc. Adriat. Sci., Nat. Trieste 45, 109 (1949);Chem. Abatr. 46, 3423 (1952). M. Cardinali, I. Carelli, and A. Trazza, Ric. Sci. 39, 647 (1969). 2 6 g A. Kosturiak and A. Nincakova, Petrochemia 13, 30 (1973). 270 L. C. Chatten, 1%.W . Daislcy, and C. J. Olliff, J . Chevn. SOC., Perkin T r a n s . 2 , 469 (1973). 271 Y. V. Svetkin and L. N. Andrecva, Zh. Obshchei Khim. 36, 8 (1966). 272 A. Kosturialr a n d R. Domansky, Chem. Zvest. 27,227 (1973). 273 M. Frankel, D. Wagner, D. Gortner, and A. Zilkla, Isr. J. Chem. 4, 183 (1966). 274 G. 1%. Btdford and M. W. Partriclge,J. Chena.Soc., 1633 (1959). 275 F.J. Villani, It. F. Tavares, a n d C. A. Ellis, J . Pharm. Sci. 58, 138 (1969). 276 W. C. Snmpter, M. Miller, and L. N. Hendrick, J . A m e r . Chem. Soc. 67, 1656 (1945). 2 7 7 R . Eistert, 12. Mnller, H. Selzer, and E. A. Hackmann, Chem. Ber. 97, 2469 (1964). 267
Kec. VII.A]
25
THE CHEMISTRY O F ISATIN
Isatin-3-oximes readily form complexes with a variety of metal ions.278,279 I n a number of cases, these have seen analytical applicat i o n ~ . ~ *Zsatin-2-oximesl ~ ~ * ~ ~ ~ also - ~ form ~ ~ metal com~~lexes.279~2Q4-2"7 Reduction of isatin-3-oximes t o the corresponding 3-aminooxindole has been carried out using stannous chloride in acetic acid51 or in hydrochloric 3-Aminooxindole has also been obtained I)v electrochemical reduction and cat>alytichydrogenation.lci9Reduction 0
/I
of isatin-3-oxirne with zinc in acetic acid-acetic anhydride gave 74, which was converted into 2-methylindolo[:1,2-d]thiazoleby phosphorus ~~entasulfide.2a9~2ag~ lsatin-3-oxime reacts with isocyanates t o give carbamoyloximinoisatins (75).290Irradiation of hT-methylis;Ltin-3-oxime causes syn-anti i s ( ~ ~ ~ i e r i z a t iwhile o i i , ~N-acetylindazolone ~~ is obtained from irradiation of N - a c e t y l i ~ a t i n d i o x i m e .Treatment ~~~ of this dioxime with acetic L. Divis, 8 6 . C.,ys. Sh. Chew>.-Technol.l'raze. A n a l . Chem., 3, 85 (1968); Chem. Abstr. 73, 10333 (1970). 279 K. Eckschlagcar, Clrewi. Lasty 56, 489 (1962). 2 8 0 F. Buscarons and A. I q u i c r d o , 1,lfoinr. Q u m . A n a l . 18, 103 (1964); Cheitr. Abstr. 62, 4615 (1965). 281 V. Ho1 orka, V. Sykora, anti <J.Voristik, Chl,n. A n a l . 29, 268 (1947). 2 8 2 A. Izquierdo and 0. Ranrrt, IrLform. QuLtn. Anal. 23, 161 (1969); chew^. Abstr. 72, 128318 (1970). 283 L. 8 . Malowan, CLencta 19, 119 (1959);Chew&.Abstr. 54, 7412 (1960). 284 L. Ilivis, S b . I'ys. S k . Crheni.-Technol.Praze, A n a l . Chewi., 5, 21 (1969);Chem. Abstr. 73, 126626 (1970). 2 8 5 L. Uivis a n d J . Skoda, Chern. Lzsty 48, 539 (1954). 286 V. Hovorka and L. Divis, Collect Czech. Chem. Cornmun. 14, 116 (1949). 287 V. Hovorka and L.Dir.15, Collect Czech. Chem. Cornmun. 14, 473 (1949). 2 8 8 €3,. Antiruzzi, M. E. Cardinali, ant1 A. Trazza, IClectroclt,zm. A c t a 17, 1624 (1972). 289 P. I. Abramenlto, Zh. I.'ses. Khwn. Obshchest. 16, 231 (1971); Chem. Abstr. 75, 5778 (1971). 289a 1 .' I. Abramcnko, Z h . T'ses. Kkiwb.Obshche.st. 18, 714 (1973); Chewi. Abst. 80, 95808 (1974). 290 M. (iiannella a n d M. Pigini, I"armaco, E d . Scz. 28, 157 (1973). 291 T. Sasaki and M. Takahashi, Yukz Gosez Kagwku Kyokas Shz 26, 899 (1968); Chem. Abstr. 70, 28746 (1969). 278
26
[Sec. VI1.A
FRANK D. POPP
anhydride causes cyclization to 76, which on hydrolysis with potassium hydroxide yielded the isatin derivatives 77 and 78.292
~
-
~
;
o
UN
~~--voH QJ-x! \ /
H
NCH,
'
N
N
Ac
0
(77)
(76)
(78)
Treatment of a number of isatin-3-oximes with sodium methoxide a t 140"293 or simply thermally 274*294 leads t o o-aminobenzonitriles.
Thermal treatment of isatin-2-oxime gave isatin and 79.294Beckman rearrangement of isatin-3-oximes resulted in the formation of o-cyanophenylis~cyanates.~~*~~~ With the Vilsmeier reagent, phosphorus 0
H (79)
(80)
oxychloride-dimethylformamide, isatin-3-oximes gave N,N-dimethyl8'-(o-cyanopheny1)formamidines This reaction probably proceeds through the o-cyanophenylisocyanates. The Schmidt reaction of isatin and hydrazoic acid in sulfuric acid gave anthranilamide (81), quinazoline-2,4-dione (79), and 2-(o-aminophenyl)-quinazolin-4-one (S2).297 A similar reaction has been reported
Takahashi, Bull. Chem. SOC. - p . 43,2986 (1970). Badischr Anilin-untl Soda-Fabrik A.-G., French Patent 2,014,431 (1970); Cheiri. Abstr. 74, 22571 (1971). 2 9 4 G. Bargc~llini and C. J. Turi, Gazz. Ckzm. Ital. 84, 157 (1954). 295 R . S. I'andit and S. Scshadri, lndaan J . Cfiem. 11,532 (1973). 296 M. N. Drshpandc and S. Seshadri, I n d ~ a J n. Cliem. 11,538 (1973). 297 ( i . Caronna and S. Palazzo, Gazz. G h m . Ital. 98, 911 (1968). 293
Sec. VII.B]
T H E CHEMISTRY O F ISATIN
27
to give simply anthranilamide from isatin and N - a ~ e t y l i s a t i n , ~ ~ ~ while N-ethylisatin gave o-ethylamin~benzamide.~~~ 4-Chloro-, 6chloro-, and 5-nitroanthranilamides were also prepared from the appropriate isatins although isatin-7-carboxylic acid failed t o react.299 2949298
B. HYDRAZONES A variety of arylhydrazines have been reacted with isatins t o give isatin-3-arvlligdrazorles (83).15,21,22~24*78,80,107,156.181.216.300-306 Similar reactions have also been carried out with isatins and a l k y l h y d r a z i n e ~ , ~ ~ ~ hy~razides,15~,186.304,305~308-312alld ~ydrazine21,156,157.216.313-315 to give 84, 85, and 86, respectively. Aldehyde hydrazones also react with
li-aTL,, N-NHH"
It'
(83)R" = i2romatic
(84) R" = Alkyl ( 8 5 ) R" = Aryl (86) R" = H
i ~ a t i n . ~ "Isatin-3-plienylhq.drazorics ,~~~ were prepared from oxindoles and benzenediazonium chloride276and from 3,3-dibromooxindoles and phenylhydrazinc.137b-276 Isatin-3-(2-nitrophenylhydrazone) has exhibited antineoplastic activity in an animal screening Tsatin-3-~~lienplliydrazonesand various metal salts give rise to G. Caronna, Gazt. ChLrri. Ital. 71, 585 (1941). W.G. H. E d w a r d s a n d V Pctrow, J . Chrvi. Soc., 1713 (1948). 300 E. Campaign(., I<.L. Thompson, a n d J. E. VanFVerth, J . Med. Pharrn. Cheni. 1,577 (1959). 301 L. Capuano antl W.Ebner, Chem. B e r . 104, 2221 (1971). 302 14'. Feigl a n d 11 Goldstclin, Talnnta 4, 209 (1960). 303 M. I h r n e l and S.A. Amin, U . A . E .J . Cherrh. 9, 139 (1966). 304 F.K n o t z , S o . I ' h a n ~ 38, . 222 (1970). 305 F.I). P o p p , J M e d . Phew/. 12, 182 (1969). 3 0 G H. V n n d c r l m ~ g lantl t M. Clac n, Bull. SOC. C / w n . Belg. 68, 47 (1959). 3 0 7 I{. H. Wilry and C:. lricli, J . O r y . Chern. 24, 1925 (1959). 308 F. T Brudcrlrin, U.S Patcnt 3,558,646 (1971);Cliem. Abstr. 75, 5689 (1971). 30g N. 1'. BL~u-HoI, N. 11. Xciong, N. H. Nam, F. Binon, and R. Royer, J . Chem. SOC., 1358 (1953) 310 V. 8. L)iniitrrilttia and 1'. S. I'clkis, Iiham. Geterotsrkl. Soedin. 7, 1050 (1971). 3 1 1 A . J r n s m ant1 0. R. Hanscn, ActrcChem. ~Scand. 6, 195 (1952). 312 &I. Sy, M. &4i>illt>t, arid J . Pages, Chim. T h e y . 5 , 216 (1970) 315 M. Alarn a n d J. A . FJallant In(,, J . Chrni. Soc. C , 255 (1968). 314 A. C. l'aclhyn, H. J. Mchta, V. S. Dighc, a n d S. Somasekhara, S C LCult. . 39, 55 (1973). 315 T . Sttsalu anti M. Tslrahashi, YZLICL Gosei Kagaku Kyokni Shi 26, 901 (1968); Clicni. Abstr. 70, 37502 (1969). 298
299
28
[Sec. VI1.B
FRANK D. POPP
c o n i p l e x e ~such ~ ~ ~as* 87 ~ ~(M ~ = Cu, Zn, Cd) and 88 (M = Hg, M a , Co). The complex formed from magnesium hydroxide and isatin-3-(4nitrophenylhydrazone) has been used as a spot test for i ~ a t i n . ~ ~ ~ NHPh
::M $:J@ -
PhNH
I
NHPh
C‘1
I
aTfjf(X-rJ
H
H
(87)
H
C1
(88)
Reduction of 83 (R = H, R’ = CH,Ph, R” = C6H4S03H) with Raney nickel alloy and sodium hydroxide gave 1-benzyldioxindole and with lithium aluminum hydride gave l - b e n ~ y l i n d o l i n e . ~ ~ ~ Alkylation of 83 (R’ = OH) takes a variety of paths including alkylation of the NOH to give 1-alkoxyisatins, alkylation of the NOH and the carbonyl group to give 1,2-dialkoxyindoles, alkylation a t the hydrazone group, and ring expansion to 2 - q ~ i n o l o n e sThe . ~ ~ course ~ of the reaction depends upon the nature of the substituent in the side chain.
a f ‘ d
OMe
-qJ-1° ‘ 0 I1
N
H
N-NH-C-C,H,X (90)
(89)
R‘ (91)
Reaction of 89 with hydrazides gave 90.310 The trans form was obtained and could be converted into the cis form thermally or photochemically and then reconverted by acid.310 Isatin-3-hydrazones react with aldehydes to give 91.157.314 Compound 91 (R = H, Ar = 2-(5-nitrofuryl)) has also been prepared by reaction of isatin with 5-nitrofurfuraldehyde h y d r a ~ o n eAmmonium .~~~ isothiocyanate, and 86 gave isatin-3-thio~emicarbazones.~~~ Heating of hydrazones 86 with sodium hydroxide gave oxindole and isatin a ~ i n e and , ~ ~heating ~ with sodium ethoxide gave oxindole, M. N. Sharma, Curr. Sci. 42,92 (1973). I. M. Taha and M. A. Khatab, U . A . R .J . Chem. 13,227 (1970). 318 V. P. Arya, Swiss. Patent 491,100 (1970);Chem. Abstr. 73, 109673 (1970). 319 W. Seibert, Chem. Ber. 80, 494 (1947). 316
317 F.
Sec. VII.B]
29
THE CHEMISTRY O F ISATIN
isoindigo, and 3 , 3 ' - b i o ~ i n d o l y 1 The . ~ ~ ~isoindigo probably arises from reaction of the oxindole and isatin while the bioxindolyl results from reduction of the isoindigo. Use of a stronger base, potassium t-biitoxide in dimethyl sulfoxide, gave only isatin a ~ i n e . ~The ~ O isatin 92 was
I
(93) 0H I
(94)
allowed t o react with hydrazine and then warm sodium ethoxide to give 93,73 s product of both reduction and ring opening. Isatin-3hydrazone was reduced with sodium in ethanol, and diethyl oxslate was added t o give 94.313 Heating of isatin azines gave compounds of th e type 95 (R' = H).321 Treatment of 1-methylisatin-3-tosylhydrazone 322 with sodium in
R'
R'
H
A. H. Jackson, Chem. Ind. (London), 1G52 (1965). N. P. Buii-Hoi arid G. Saint-Ruf, Bull. SOC. Chin&.Fr., 5036 (1968). 322 E. J . Moriconi ancl J. J . Murray, J . Org. Cheni. 29, 3577 (1934).
320
321
30
FRANK
I).
POPP
[Sec. VI1.C
ethylcne glycol gave a similar product 95 (R = H, R’ = Me).144Isatin3-tosylhydrazone with sodium hydroxide gave 3-diazooxindole (96).322,323Compound 96 was also prepared from 86 and mercuric oxide 3 2 2 and from isatin-3-oxime and chloramine.3223-Diazooxindoles in methanol solution with a suitable Lcwis acid provides a convenient, source of 3 - m e t , h o ~ y o x i n d o l e sPyrolysis .~~~ and photolysis of 96 have also been studied.322 Reaction of 96 with benzyne gave 96a324aA similar reaction takes place between 96 and diniethyl acetylenedicarbo~ylate.~~~~ Isatin-3-hydrazones (86) react with nitrosylsulfuric acid in glacial acetic acid to give, after dilution with water, the diazonium salt 97 as indicated by the formation of an azo dye with N,N-dimethylaniline.325*
C. THIOSEMICARBAZONES AND RELATED COMPOUNDS A very large variety of isatins reacted with thiosemicarbazides t o give isatin-3-thiost.micltrbazones (98).29,58.146.151.155.156,186.181.182. 1 9 2 . 1 9 3 a , ~ O % The irnpctus for the bulk of this work is the Fact
304,312*3159326-344
M. 1’. Cava, R. L Little, and D. R. Napier, J . Amer. Cheni. Soc. 80, 2257 (1958). 1’. L. Crogrr, J . Org. Chem. 30,3610 (1965). 324s T. Yarnazaki and H. Shechter, Tetrahedron Lett., 1417 (1973). 325 T. Vaidyanathan and S. Soshadri, I n d i a n J . Chem. 11,400 (1973). 326 D. J. Baurr and P. W. Sadler, Nature (London) 190, 1167 (1961). 327 D. J. l%aucr arid 1’. W. Sadler, British Patent 975,367 (1964);Chem. Abstr. 62, 323
324
6462 (1965). 11. J . lkaurr and P. W. Sadler, U.S. Patent 3,253,991 (1966);Chern. Abstr. 65, 8683 (1966). 329 J. Bornstein, H. L. Yale, K. Losre, M. Hoking, J . Martins, and W. A. Lott, J . Arner. Chem. Soc. 73, 906 (1951). 330 N. P. Bun-Hoi, N. D. Xuong, and E’. Binon, J . Chem. Soc., 713 (1956). 331 E. Campaigneand W. L. Archer,J. Amer. Chem. Soc. 74, 5801 (1952). 3 3 2 J . Daunis, It. Jacquicr, M. Rigail, and P. Viallofont, Bull. SOC. Clnm. F r . 2259 (1970). 333 G. Doleschall and K. Lcmport, Acta Chim. Acad. Sci. Hung. 64, 369 (1970). 334 L. Heiniscli and K. Kramarczyk, J . Prakt. Chern. 314, 682 (1972). 335 Z. Holzbecher, Chem. Lasty 44, 126 (1950). 336 I. S. Ioffo, A. B. Tomchin, and E. N. Zhukova, Zh. Obshch. Khina. 39, 70 (1969). 337 0. F. Lymar and N. M. Turkcvich, Meody. Poluch. Khim. IZeaktivovPrep., 115 (1971);Chem.Abstr. 78, 15950 (1973). 338 I). G. O’Sullivan, P. W. Sadlcr, and C. Webley, Chemotherapia 7, 17 (1963). 339 R . Prrscott, G. Jones, C. L. Peacock, and G. Caldes, Antzmacrob. A g . Chemofher., 275 (1969). 340 P. W. Sadler, ,7. Chem. Soc., 243 (1961). 341 S. Sallay and S. J. Childress, U.S. Patent 3,406,180 (1968); Chem. Abstr. 70, 11223 (1969). 342 A. W. Scott a n d M. A. McCall, J . Amer. Chem. Soc. 67, 1767 (1945). 328
Sec. VII.C]
THE CHEMISTRY O F ISATIN
31
exhibit significant antiviral that several of these thiosemicarbazon~~s a ~ t i v i t y . ~ ~ * ~ It~ has ~ also , ~ been ~ ~ claimed , ~ ~ that ~ , N-ethyl~ ~ ~ y ~ ~ ~ isatin-3-thiosemicarbazone has an eEect on tonic convulsions.362 Perhaps stimulated by the antiviral activity of isatin-3-thiosemicarbazone, isatin has been screened for a wide range of biological effects both ill animals 44,89,261,363-369 and in plants.370-375 A. B. Tonwhin, V. S. Dmitriilrha, T. N. Timofeeva, antl P. S. Pelkis, Zh. Org. Khim. 9,1988 (1973). 344 A . B. Tomchin, I. S. Toffe, V. V. Tretyakova, Y. V. Lepp, and A. I. Koltsov, Zh. Org. Kham. 9, 1537 (1973). 345 J . Aasen and G. Haiikcness, Actu Pathol MLcrobaol. Scand., Sect. B 80, 246 (1972);Chrm Abstr 77,37063 (1072). 346 M. Alcxantlrewii, L. Handruche, C. Murgcscii, and M. Duca, Rev. R o u m . Irlframicrobiol 6, 219 (1969); Chern. Abstr. 73, 11669 (1970). 347 M. Aleuandrtwu, C. Murgescu, L. Hantfrache, L. lonescii, and M. Duca, S t u d . Ceicet. InfrnmLcrobroZ. 20,263 (1969). 34R 1). J . Baiicr, U.S. Patcmt 3,636,226 (1972);Chem. Abstr. 76, 136008 (1972). 34q 11. J. 1 3 e i t c ~ ant1 K. Apostolov, Scaence 154,796 (1966). 350 I>. J . Bztuer, I<. Apostolov, and J. W. T. Sclway, Ann. N . Y . A c d . Sca. 173 (Art I), 314 (1970);Chem. Abstr. 73,75217 (1970). 3 G 1 1%. Gabriel, 137 ~ tJ.. E x p . I’at/iol. 52,271 (1971). 352 R . F. Haff, .I. J . Boyle, R. C. Stewart, R. J. Fcrlauto, J. M. Z. Gladycli, J. H . Hunt, and D. J a r k , Nuturr (London) 221,286 (1969). 3s1 D. H. Jones, I<. Slack, S . Syuircs, arid K. 1%.H. Wooldridge, J . M e d . Chem. 8, 676 (1965). 354 W. Levinson, 13. Wootlson, antl J. Jackion, Nature ( L o n d o n )232, 116 (1971). 355 L. G . Linitskaya, U. A. Ctalcgor, antl 1%. M. Rikbulator, V o p . T’arusoZ. 16, 155 (1971);Ciiern. Abstr. 75,47128 (1971). 356 W. E. Magcc and M. li.Hack, Ann. N . Y . Acad. Scz. 130,BO (1965). 357 (2. D. Pearson and E. F. Zimmt,rman, Vzrology 38,641 (1969). 3 5 8 0. I) Pearson and E. F. Ziminerman, BLocham. Baophys. Acta 195,246 (1969). 359 It. Pollikoff, 111. Lieb(~inan, N. E. Lem, anti E. J. Foley, J . I m m u n o l . 94,794 (1965);Chenr. Abstr. 63, 3505 (1965). 360 P. W. Sadlcar, A m N Y . Acad. Sca., 130,71 (1965). 361 R. Woodson and \V. K. Joklik, Proc. Nat. Acad. Scz. U.S. 54,946 (1963). 361a E. Katz, E. Mnrgalilli. and B Wincr, .I. Gen. Vzrol. 21. 477 (1973). 361b M. Tonow, E. Tonew, and L. Heinish, Acta Varol. (Engl. E d . ) 18, 17 (1974). 362 M Lieberman, 1%. Pollikoff, and A. M. Pascale, Antimmob. A g . Chemother., 531 (1966). 3 6 3 F. Bruns, ~ a ~ u r ~ ~ . ~ s e41, ~ 360 s c ~(1954). ~ ~ t e 7 ~ 364 J. Dcbat, German Patent 1,935,697 (1970);Chem. Abstr. 72,125053 (1970). 365 M. Murller and S. Schultrich, Acta Baol. M e d . Ger. 17,307 (1966); Chem. Abstr. 66,9718 (1967). 3Gf1 D. G. 0’Sullir an antl P. W. Sacllor, Arch. Rzochem. Biophys. 66, 243 (1957). 3 6 7 K. Sareen, 13 P. Kohli, M. I<. P. Amnia, and M. L. Gujral, Indian J . P h y s . Pharmacol. 6,87 (1962). 3fi8T. J . Smgh, IntE~a71V e t . J . 48,672 (1971);Chem. Abstr. 76, 81287 (1972). 343
32
[Sec. VI1.C
FRANK D . POPP
Met hods for the analysis of the antiviral N-methylisatin-3-thiosemicsrbazone have been reported.376Metabolic removal of the sulfur from N-methylisatin-3-thiosemicarbazonehas been reported 377 to give synand c~nti-h7-methylisatin-3-semicarbazone. A number of other analogs of 98, such as 99,378100,332,335 101,379-380a 102,381103,333,334,336,382*383 104,340and 105,343,384 have been prepared. X
S
N-NH-
11
II
C-NR;
N-- NH-C-NHR"
R+aLj rt'
x = so x=0
(99) (100) (101) X (105) X
= NH = S, R" = NHR"
I. Susheela, R . Singh, H. M. Dani, M. I<. P. Amma, and I<. Sareen, Enzymologia37,325 (1969);Chern. Abstr. 72,74963 (1970). 370 H. It. Chen, A. W. Galston, and L. Milstone, Plant. Physiol. 41, 1485 (1966). 371 J. L. Foster, Radiat. I'rot. Sensitization. Proc. lnt. Symp., Znd, 299 (1969); Chem,. Abstr. 74, 20057 (1971). 372 A. W. Galston and H. R. Chen, Plant Physiol. 40, 699 (1965). 3 7 3 E. Hambsch, German Patent 1,013,459 (1957);Chem. Abstr. 54, 16733 (1960). 374 S. Mukherji and T. Roy, I n d i a n J . Exp. Baol. 10, 395 (1972). 375 J. S. Weis, Nature ( L o n d o n )211, 1216 (1966). 376 J. C. Deavin and D. H. Mitchell, J . Pharrn. Pharmacol. 17,565 (1965). 377 L. A. Nutting, E. M. Wcber, and J . L. Tryon, J . VViroZ. 1, 650 (1967). 378 J. Krajowslti, Rocz. Chem. 46, 1177 (1972). 369
Sec. VII.C]
33
T H E CHEMISTRY O F ISATIN
An excess of isatin with thiocarbohydrnzide gives 106.384The syn isomer of isat,iri-3-tliioseiiiicarbazonepredominates while isatin-3semicarbazone exists in the anti form.385 Treatment with acid or warming converts this anti form into the syn isomer, while base causes the reverse i s o m ~ r i z a t i o n 4-Methylisatin-3-semicarbazone .~~~ exists as the syn isomer.344 A variety of metal complexes of isatin-3-thiosemicarbazones and isatin-3-semicarbazones have been prepared. A number of cyclization reactions have been carried out with isatin derivatives of this series. Isatin-3-thiosemicarbszone with chloroacetic acid, sodium acetate, acetic acid, and aldrhydes gave 107.392*393 Treatment of i s a t i n - 3 - t h i o s e m i c a r b a ~ o n e and ~ ~ ~ N-methyl~~~~~~~~ isatin-3-thiosemicarbazone 3 3 3 . 3 9 5 with 1X alkali gave 108 which on treatment wit11 alkali and iodine gave 109,395and with alkali and methyl iodide gave 110.333,396Ring opening also took place in the preparation of 108 (R = Me).333 Treatment of 108 (R = Me) with 2799386-390
2799391
F. Baiocchi, C. C. Chtng, W. ,J Haggcrty, L. R. Lewis, T. K. Liao, W. H. Nyberg, I). E. O’Rrien, antl E. G. I’odrebarac, .J. M e d Chenr. 6,431 (1963). 3Q0 I?. L). l’opp, J Plrarnz. Sci. 62, 679 (1973). mO*A. Lwoff, M Sy,M. Maillct, J Pages, and P. Ilavid, German Patent 2,020,230 (1970);C k e m . A6str. 74, 22687 (1971) 3 Q 1 S. D. Moshchitsl~ii, L. S. Sologub, A. F. I’avlcnko, and V. P. Akkerman, Zh. Orq K h m . 2 , 2 1 6 4 (1966). 3 Q 2 L. Heiniqch, M Toncw, and E Tonew, Gcrman Patcnt 2,034,644 (1971); Che7n. Abstr. 75, 1.51669 (1971). 383 L. Heinisch, M. Tonew, antl E. Toncw, British Patent 1,250, 598 (1971); Chem. Abstr. 76, 3693 (1972). 3Q4 A. B. Tomchin and I. S. Ioffe, Zh. Org. Khzm. 8, 199 (1972). 3Q5 A. B. Tomchin, I. S. loffc, Y. V. Lepp, and A I. Koltsov, Zh. Org. Chem. 9, 1081 (1973). 386 P. Barz and H. F. Fritz, 2.Nwturforsch 13.25, 199 (1970). 387 I. Grecu and M. Neamtu, Rev. Chzm. Mzner. 5, 813 (1968); Chem. Abstr. 70, 31995 (1969). 388 I Grecu and M. Neamtu, Rev. Chini. Mzner. 6, 625 (1969): Chem. Abstr. 71, 108368 (1969). 389 V. Hovorka and Z Holzbccher, Collect Czech. Chem. Commun. 14, 248 (1949). 390 G. N. Mitraand S S. U Sircar, J . IndaanC/zem. Soc. 32, 435 (1955). 391 V. Hovorka and Z Holzbecher, Collect Czech. C h n . Commun. 14, 186 (1949). 392 1.M. Kazanovslaya, Farm. %it ( K z f v )27, 59 (1972); Chem. Ahstr. 77, 61870 (1972). 393 N. M. TiirkeL ich and 0 . F.Lyinitr, Khim-Furm. Zh. 3 , 26 (1069);Chem. Ahstr. 71,30314 (1969). 394 1%. E. Hagenbach, E Hodcl, and 13. Gysin, Angew. Chem. 66, 359 (1964). 395 1.S. Ioffe, A . €3. Tomchin, and E N. Zhukova, Zh. Obshch. Khzm. 39, 78 (1969). 39Q I. S Ioffe, A, R. Tomchin, and E. N. Zhukova, Zh. Obshch. lihz7n. 39, 640 (1969). 379
34
[Sec. VI1.C
FRANK D. POPP
(109)
(110)
0 II
aNl:-NH-C=NH SMe I
QTL,N\JiC-Me N Me
R (112)
(111)
acetic anhydride gave a compound that probably was 111.333It is reported395that 108 exists as the thione in the crystalline state. A wide variety of substituted analogs of 108 have also been propared.58*397.398 Treatment of 112 under the same conditions that lead to the formation of 108 gave only isatin-3-semicarbazone 396 although heating in pyridine did lead to 110.333 N-methylisatin-3-semicarbazone could be cyclized to the 0x0 analog of 108,399but the cyelization of the thiosemicarbazone to 108 occurred much more easily.400Similar treatment of isatin-3-semicarbazone led to 113 via ring opening of the i~atin.~OO I n the N-acetyl series (98, R' =
q+-foQTpx H
Ac
NH2 0 (113)
0H (114)
Allcn & Hanburys Ltd., Nethorlancls I'atcnt 6,410,823 (1'365); Chem. Abstr. 63, 13295 (1965). 398 J . M. %. Gladych, It. Hornby, J. H. Hunt, D. Jack, J. J. Boyl, R. J. Ferlauto, I<.F. Haff, C. C : . Korinently, F.J . Stsnficld, and R. C. Stewart, J . Med. Chem. 15, 177 (1972). 399 A. B. Tomchin and I. S. loffe, Zh. Org. Khim. 8, 1740 (1972). 4oo I. S. Ioffc, A. B. Tornchin, and 13. A. Rusakov, Z h . Obsiich. Khim. 39, 2345 (1969). 397
Sec. VII.C]
35
THE CHEMISTRY O F ISATIN
COMe) the cyclization, in refluxing pyridine or acetic acid, gave 114,333 and the chemistry of this series has been discussed. The thiosemicarbazones 115 underwent cyclization 396 and ring that 113 and 117 are opening401 to give 116 and 117. It is formed by different, mechanisms in that 117 is formed from the tricyclic system while 113 is not. The analog 118 is obtained by treating isatin with potassium hydroxide and then s e n ~ i c a r b a z i d e and ~ ~ ~119 *~~ is ~ similarly obtainrd froni LV-nietliyli~atin.~~~ Treatment of 118 and 119 with acid or heat>gave 108,333while reaction of 118 with methyl iodide and sodium hydroxide followed by acid or heat gave 110.333Reaction of 105 (R = R’ = R”’ = H) with acid gave 106, while reaction with M t, N-N-C’
QTlo
NH2
QTXNX
II
R
R
(115)
R
I
NH
N
(116) 1%’
I
N-N
(117) K. = 1%’= Mc (118) R = R’ = H (119) R = MP. I<‘ = H
H (121)
sodium hydroxide gave a low yield of 120 in addition to 106 and isatin a ~ i n eReaction . ~ ~ ~ of 105 (R = R’ = H, R”’ = Ph) gave the thiadiazole 121. As might be expected 98 (R = R’ = H, R” = Me) did not undergo cyclizat ion but underwent ring opening with alkali.404 401
I. S. Ioffe, A . U. Torrichm, ant1 12. A. Rusakor, Zlr. Obshch. Khim. 40, 682
(1970). I. S. Ioffeantl A . B. ‘romchin, Zh. Obshch. Khim.40, 859 (1970). 403 A. B. To~ric~hin, 1. S. Ioffc., and E. A. ltiisalrov, Zh.Org. Khzna. 8 , 1791 (1971). 40‘1 A. H. Tomchin, Y. A . Kharit, and A. K. Kutscnko, K h m . Farm. Zh. 7, 10 (1973). 402
36
[Sec. VI1.C
FRANK D. POPP
The 0x0 analog of 108 undergoes alkylation in alkali to give 122,405 while alkylation of the silver salt gives 122,123,and 124.405 The amino analog can be obtained by heating the syn-3-guanylhydrazone (101)of isatin with ammonia or by slowly heating the anti isomer to 250" in a
(124)
(125)
high vacuum.4o6A variety of analogs of 125 have been prepared3g7as have analogs obtained from the 3-nitroguanylhydrazone of isatin-2oxime.407 The cyclization of certain 2-substituted isatin derivatives were studied so as to compare them with the above cyclizations. Thus, isatin-2-thiosemicsrbazone (126) and isatin-2-semicarbazone (127) underwcnt cyclization to 128 and 129 more easily than the corresponding cyclizations in the 3-~eries.~O* As in the 3-series the sulfur compound underwent cyclization more easily than the oxygen.408 In contrast t o
(126) X = S (127) X = 0
(130) 405
(128) X = S (129) X = 0
(131)
I. S. Iofft?, A. B. Tomchin, and E. N. Zhultova, Zh. Obshch. Khim. 39, 2339
(1969). H. King and J . Wright, J . Chenz. SOC., 2314 (1948). 407 IT. J. Lalor and . '!I L. Scot,l, J . Chem. SOC.C, 1034 (1969). 406 I. S. Ioffc, A. B . Tornchin, arid G. A. Shirokii, Zh. Org. Kham. 7, 179 (1971). 406
Sec. VII1.A.I ]
THE CHEMISTRY OF ISATIN
37
98, which was stable in acid, 126 on treatment with hydrochloric acid gave 130.409Reaction of isatin-2-anil with an excess of thiocarbohydrazide gzve 131,410while an excess of isatin gave the 2,2’-analog 106.410 A number of additional reports have appeared.410a-410e
VIII. Reactions with Amines
A. PRIMARY AMINES 1. Aromatic Primary Amines
A large variety of aromatic nmines react with isatins to give anils ( 132).169,232,269.305.312,411-413 The imine from isatin and o-hydroxyaiiiline forms complexes with copper acetate and zinc iodide.413
Reaction of these anils (132) with phenylhydrazine gives the isatin3 - ~ ~ l i e 1 i y l h y d r a z o nThe e . ~imine ~ ~ 132 (R = 5-Me, R’ = H, Ar = p-tolyl)
H‘ (132)
H (133)
has been prepared by reaction of dicliloroacetic acid with p-toluidine 414 or from ri-methylisatin and 133.161,162 Reaction of a variety of substituted isatins with o-phenylenediarnine gives indolo[2,3-D]qninoxalines (indoI’11enazines) ( 134).7.21,22,32.43,80,Q6, 107.154.16Y,193a.207.239,415-417 Substituted o-~~henylcnedinmines have also A . B. Tornchin, I . S. Zoffe, antl C:. A. Shir~kii,ZIL.0111. K l r z r t l 8, 870 (1972). A. B. Tomchin, I. S. Ioffc, anti (2.A. Shirokii, Zh. Org. Klram. 8, 400 (1972). 410a A. 13. Toincliin. I. 8. Iofft., -1. I. Iioltsov, and Y. V. Lcpp, Khzna. Geterotsikl. 409 410
S o e d / n . . 503 (1974). A. B. Toincliin. I S Ioffc., and G . A. Shirokii. Zlr. Org. K h m . 10, 103 (1974). 410c A. B. Tonicliin, I. S Ioffc, Y. V. Lcpp, and T. K. Tilnofwva, Zh. Org. Khzni. 10, 371 (1974). 410d A . l3. Tornchin. V. S. I h i t r u k h a , T. N. Timofrc\a, and 1’. 8.Pclliis, Zk. Org. J i / / i i t i . 10. 1519 (1974) 410e I3. Toinchin and Y. V. Lcpp. Zh. Orq. Khzm. 10, 1962 (1974). 411 C. B. Crippa and 8. Pictra, Gazz. Gh/ni. I f a l . 81, 19.5 (1951). 412 R . K. Granthain and 0 .Meth-Colin, Chem. Coznvtun., 500 (1968). *IJ G. Maneckc and J . (:aiigcr,Cheni. B e r . 101, 3336 (1968). 4 1 4 C. U . Crippn antl S. L’irtrd, C:uzz. Chztn. Ital. 78, 436 (1948). 415 G. M. Batlgc>rand P .J Ncllron, J Clrcni SOC., 3926 (1962). 416 N. 1 ’ Buu-Hoi, U 1’. Hien, ant1 (+ Saint-RnfC.R. A c a d . Scz., Ser. D 264, 2414 (1967). 411 Y. Kidani, IN.Matsuo, ant1 H. tioikc~.l’aLu@u Zasslia 90, 54 (1970). 410b
38
[See. VIII.A.l
FRANK D . POPP
been used to give compounds of the type 134.239,416-420a In cases where unsymmetrically substituted o-phenylenediarnines have been used, the structure has generally not been p r ~ v e d , although 135 has been used in such cascs to determine the structure.417
R(-aTL)3 R
a:L:n
~
Qz:l
(134)
Ph
~
(135)
~y/-L:~ I
CH,CH,NMU,
(136)
(137)
The preparation of compounds of type 134 is usually carried out by simply heating the diamine and isatin ; however, polyphosphoric acid has been used in some cases.423*424 Although 19 (R = Ph) does not react with aniline, it gives 136 with o-phenylenedia~nine.~~ A variety of reactions of indophenazines have been s t ~ d i e d . ~ ~ , ~ ~ ~ , ~ 417*425-426a N,N-Dimethylarninoethylindophenazine (137) has been reported to possess antimicrobial action. 154 I n some cases, a spiro structure (138)is obtained instead of, or in
N. P. Buu-FIoi and 1’. Jacquignon, C .R. A c i d . Set. 226, 2155 (1948). S. K. Guha, K. n. Bancrji, and K. K. Sen, J . I n d ~ a nCIiern. . SOC.50, 264 (1973). 420 G. Hanseke and W. Lemkc, Cheni. Ber. 91, 101 (1958). 4Z0a N. P. Bun-Hoi, G. Stunt-Nuf, and J. C. Arcos, Bull. SOC.Chzm. Fr., 838 418
418
(1969).
N. P. Bu~i-Iloi and G. Saint-Ituf, Bull. SOC.Chim.Fr., 1920 (1960). 4 2 2 E. M. Gal, Ezperzentia 7,261 (1951). 423 I. Shopov, Izv. Otd. Khim. Nauki, Bulg. Akad. Nauk. 3, 47 (1970); Chern. 421
424
Abstr. 74, 32028 (197 1). I. Shopov and N. Popov,J. Polym. Scz., Part A - 1 7, 1803 (1969).
Sec. VIII.A.21
39
T H E CHEMISTRY O F ISATIN
addition to, the linear structure 134,239*240*420 and such a structure may actually have been obtained in another case when a hydrate of 134 was claimed.422It is possible to convert 139 to 140 by refluxing in glacial acetic acid,239but no other such interconversions have been reported for other members of t>heseries. A number of ot,her aromatic diamines on reaction with isatin, while these diamines (not 0-)gave 141410.427.427a with 135 gave 142.429.430 A coml)arison of the infrared spectra of 141 arid 142 has been made.428
(142)
Q-x;
Although N-methylisatin and 143 in ethanol gives the expected reaction in acid can give 144 and 145.412A mechanism analogous to the Stevens rearrangement is proposed for the formation of 145.
&". 0 Qq-\ n \ (143)
MO
0
(144)
/
-
ND
Mc.
(145)
2. Aliphatic Primary Amines Primary aliphatic amines are also reported to give imines of the type 132 (where Ar now is aliphatic) with isatin,92,170*431-433 although the Y . Kidani, M. Matsuo, and H. Kolke, Y n k u g n k u Zasshz 90, 452 (1970). M. Matsuo, Y. Kidani, and H. Kotkc, Y a k u g a k u Zasshi 90, 601 (1970). 426a T. Kappe ant1 W. Lube, A1onut.d~.CllfWk.102, 781 (1971). 421 R. Vilceanu, 13. 11. Bndcr, M. Radulcscu, and M. Marinescu, Rev. R o u m . ClLzm. 425 426
18, 1225 (1973). A. Jindra, Collect Czech. Cliem. CommujL. 12, 541 (1947). 4 2 8 R. Bacaloglii antl I3. L). Brtder, Rev. Roum. Chom. 18, 275 (1973). 42g B. D. Badcr and R. Vilccanu, R e u . Roum. Chirn. 17, 1991 (1972). 430 J . Itaichcl, B. D. Badtbr, and R. Vilceann, Ilev. R o u n . Chem. 17, 1889 (1972). 431 P.G. Baddar antl %. Iskandcr, J . Chem SOC., 209 (1954). 4 3 2 K.M. Piccinlli and F.D. Popp, J . Heterocycl. Chem. 10, 671 (1973). 4 3 3 R. M. Piccirilli and F. D. Popp, J . Heterocycl. Chem. 10, 877 (1973). 427a
40
[Sec. VIII.A.2
FRANK D. POPP
tautomer 146 has been proposed, without proof, for the product froin isatin and b e n ~ y l a m i i i e .Reduction ~~ of these imines or reductive arnination of isatin gives 147.170
a7k= 03; It
CHPh
I
H
(147)
(146)
When an excess of primary aliphatic aniine is used with isatin, the situation becomes much more c o m p l i ~ a t e d . ~With ~ ~ *a~ ~10-fold ~ excess of cycloalkylaniines in ethanol in the presence of air, ring . ~ ~ ~ these same opening takes place to give 148 (R = ~ y c l o a l k y l )Under conditions other primary aliphatic amines gave purple gums which did not give crystalline p r o d n ~ t s . Isatin-3-imines ~ ~ ~ , ~ ~ ~ also undergo ring opening with an excess of cycloalkylaniines to give 148 in which both R groups are derived from the cycloalkyl residue.432The reaction of isatin or isatin-3-iniines, in the absence of a solvent, with an excess of ethylaniine gives a product which is believed to be 149.433
ad:-E& MH I
I
0
C I1 - - N H R
CH--NHEt
NH-C-NHB
I1 0
(148)
H (149)
Isatin has becn used in the Strecker degradation of a-amino acids to a l d e h y d e ~ , ~ and ~ ~ -in~ ~ the I formation of benzaldehydes froin benzylamines.431,435*438-440 These conversions have been the subject of a review, and mechanisms have been proposed.441 This formation of aldehydcs from primary amines may, in part, explain some of the E. Giovannini and P. Portmann, HeZv. Chim. Acta 31, 1361 (1948). A. Schonberg, R. Moubasher, and A. Mostafa, J . Chem. Soc. 176 (1948). 436 17. G. Raddar and Z.Iskandcr, Nature (London) 167, 1069 (1951). 437 F. G. Baddar and Z.Iskandcr, J . Chem. SOC., 203 (1954). 4J8 S. J. Angyal, P. J. Morris, R. C. Rassack, and J. A. Waterer, J . Chem. SOC., 2704 (1949). 439 W. G . Brouwer, W. A. Craig, J. A. D. Jeffreys, and A. Munro, J . Chem. SOC., Perkin Trans. 1 , 124 (1972). 440 A . Schonberg and R . Moubashcr, J . Chem. SOC., 1422 (19.50). 4 4 1 A. Schonborg and R. Moubashcr, Chem. Rev. 50,261 (1952).
434 435
Sec. VIII.A.21
41
THE CHEMISTRY O F ISATIN
results noted above in the reactions of isatin with an excess of primary aliphatic amines. An attempt to utilize this conversion of ariiines into aldehydes in an isoquinoline synthesis was not successful.43slristead, reaction between 2-( 3,4-dirnethoxyphenpl)cthglamine and isatin afforded orilp the spiro compound 150.433”Reaction hetween isatin and 2-(:l-hydroxy-4niethoxypheny1)ethylaniine gave a mixture of two spiro compounds, while a reaction of isatin, this amine, a i d henzplamine gave B-hydroxy7-niethoxy - 1-phenyl- 1,2,3,4-tetrahydroisoquinoline.4 3 y
0
0
n N L N - ( ” - N H MI1 e
lNH
:XI&
NH
‘ /.
H N
/ 0
\
R
0
\ (150)
(151)
(152)
Isatin and N-methylisatin can be reacted with ammonia t o give an imine (151). With methyl isocyanstc> these imines give 152 (R = CONHMe arid Jlc, rcspcctivcly) 123 Oxidation of the imine 151 (It = H) with hydrogen peroxide in aqueous ammonia. gave 153 while a siriiilar oxidation of isatin gave only arithranilic This ring opening can 0
(153)
(154)
0
(155)
be compared with the one rioted above for isatin and an excess of c y c l o a l k y l a r n i n e ~ .A~ ~similar ~ ring opening appears t o be involved when isatin and ammonia are reacted for three months in sunlight to give 154443and when 132 (R = R’ = H) is oxidized with alkaline peroxide to give 155.444 The structure of isamic acid, C,,H,,N30,~ H,O, obtained from ammonia and isatin or from sodium isatoate and 151 (R = H) has been studied for some time.445,446 In 1967 structure 156 was suggested for 442
443 444 445
446
G. ,Jacini, Gazz. C h h . Ital. 72, 510 (1942). S.Capuano and L. Uiammanco, Oazz. Chma. Ital. 86, 126 (1956). G . Jacini, Gnzz. Chim. Ifal.73, 85 (1943). G. Jacini, Gnzz. Cltim. Ital. 73, 306 (1043). C i . .Jacini, Gazz. C I L ~ VItnl. ) ~ . 77, 2‘3.5 (1947).
42
[Sec. VIII.A.2
FRANK D. POPP
but in 1969 this structure was challenged and the more isamic reasonable structure 157 was proposed.448
(156)
(157)
Although diaminomaleonitrile reacts with only 1 mole of isatin t o give 158,449*450 1,3-diaminopropane reacts to give 159.451The reaction of other diaminoalkanes appears to be more complicated.452I n related reactions 2-aminoethylthi01,~~~ 3-aminopropylthi01,~~~ and ethanedit h i 0 1 react ~ ~ ~ to give spiro compounds, such as 160. Raney nickel and 160 leads to oxindole and in the presence of alcohols to 3-alkyloxindoles.455 Mercaptodiphenylacetic acid and isatin in the presence of p-toluenesulfonic acid give 160a.455a CN CN
I
I
H ( 160a)
P. DeMayo and J. J. Ryan, Chem. Commun., 88 (1967). G. F. Field, Chem. Commun., 886 (1969). 449 H. Brcderrck and G. Schmotzcr, Justus Liebigs A n n . Chem. 600,95 (1956). 450 F. D. Popp,J. Heteromycl. Chem. 11, 79 (1974). 451 1%.H. MeDougall ant1 S. H. Malik, J. Chem. SOC. C, 2044 (1969). 4 5 2 F. D. Popp and L. Maicr, unpnblished results. 453 M. Wolf and A. A. Maseitti, U.S. Patent 3,458,525 (1969); Chem. Abslr. 72, 447
448
21715 (1970). M. Wolf, U.S. Patent 3,314,951 (1967);Chem. Abstr. 67, 90819 (1967). 455 E. Wenkert and N. V. Bringi, J. Amer. Chem. SOC. 80,5575 (1958). 455a A. Romo do Vivar a n d J. Romo, J. Org. Chem. 24,1490 (1959). 454
Sec. VIIT.B]
43
T H E CHEMISTRY O F I S ATI N
Notwithstanding an earlier report,456N-acetylisatin does not appear t o react with primary amines to give 3-imines. Instead ring opening takes place and 161 is obtained.457 When an excess of the primary amine reacts with N-acetylisatin, 162, which can also be obtained by reaction of 161 with the amine, is obtained.457A similar ring opening takes place between N-acylisatins and ammonia 458 and between N NR
0
It
CONH,
It
C:-CY)NHR
C-CONHR
NHAc
NHAc
(161)
(162)
(163)
acylisatins and a l ~ o h o l s . An ~ ~ excess ~ * ~ ~of~ ammonia with N-acylor with 161 (R = H)458leads to the quinazolines 163.
B. SECONDARY AMINES Isatin reacts with secondary heterocyclic amines to give 3,3-diaminooxindoles such as, for example, 164.460-462 Such compounds can also be .~~~ prepared by reaction of secondary amines with i ~ a t i n - 3 - a n i l sThese secondary amines can also react with isatin with ring opening to give
165.461
(165)
(164)
aTJy-n-QTx:yrfJ H
O
N
/
H
0
H N
H
(166)
F. Parisi, J . Amer. C j ~ e mSoc. . 75, 3848 (1953). 457 F.D. Popp and R. M. Piccirilli, J . Heterocycl. Chem. 8, 473 (1971). 4 5 8 F.J. Moyer, CIieni. Ber. 99, 3060 (1966). 4 6 9 It. Johnstone tlnd J . R. Price, A w t . J. Chem. 7,209 (1954). 4 6 0 Iiotlak S.A., Belgian Patcnt 533,980 (1960);Chem. Abstr. 55, 11157 (1961). 461 A. W. Johnson and U. J. McCaldin, J. Chem. Soc., 3470 (1957). 4 6 2 W. H . Lawton, Bclgian I’utcnt 655, 926 (1965);Cliem. Abstr. 65, 5577 (1966). 456
/
44
FRANK D. POPP
[Sec. VII1.B
Reaction of 164 with acetic anhydride, reaction of isatin with Lpipecolic acid, or reaction of pyrrolidine with isatin in acetic anhydride gives a substance known as isatin blue. Proline and isatin give the same product and the blue color is the basis of a color test for such comp o u n d ~ . The ~ ~ structure ~ - ~ ~ ~166 has been proposed for isatin blue,461 and other related compounds have also been prepared.461 In contrast to proline, 3,4-dehydro-~~-proline (167) does not give a color with i ~ a t i nThe . ~ reaction ~~ proceeds to give 168 and the mechanism of formation has been discussed.46gBoth cis- and trans-4-chloro-~proline 469 and A3-pyrroline470 also react with isatin t o give 168. A
O C O , ,
H
03.3 N
m
%
H
variety of 5-and 7-substituted isatiris react with 167 to give analogs of 168.147Reaction of 167 with N-substituted isatins in a buffer-alcohol mixture gave analogs of 168, but in buffer alone the reaction proceeded to give 169.l4I Although reductive amination of isatin with dimethylamine did not succeed, reaction of N-substituted isatins with dimethylamine in the presence of palladium on carbon and hydrogen gave 17O.l7O H
(170)
D. J . McCaldin, C a n . J . Chem. 38, 1229 (1960). F. N. Uoctor, Anal. Biochena. 43, 66 (1971). 465 R.P. Morozova, U k r . Biokhim. 2.37,290 (1965);Chem. Abstr. 63, 3294 (1965). 466 J. Noworytko and M. Sarnocka-Kcller, Acta Biochim. Pol. 2, 91 (1955); Chem. Abst. 50, 16631 (1956). 467 A. Saifer and I. Oreskes, Science 119, 124 (1954). 468 A. A. Titaev, Lub. Delo, 589 (1970);Chem. Abstr. 74,39034 (1971). 4Gg C. B. Hudsonand 4. V. Robertson, A u s t . J . Chem. 20, 1511 (1967). 470 C. B. Hudson and A. V. Robertson, Tetrahedron Lett., 4015 (1967). 4G3 464
Sec. IX.A]
THE CHEMISTRY O F ISATIN
45
IX. Condensations Involving Carbon at C-3 A.
REACTIONS
LEADINGTO
3-HYDROXY-3-SlJBSTITUTED OXINDOLES
Under mildly basic conditions, such as with piperidine or diethylamine as catalyst, isatins condense with a wide variety of ketone to give compounds of the type 171.144~145~150~169~232~471-490 These compoiinds have frequently been used t o prepare substituted tryptamines476*484*485.487 and also some 9H-pyridazino[3,4-b]indole R M a 2 r R - C O R "
R (171)
derivative^.^^^."^ I n the case of isatin and propiophenone, two diastereoisomers are ~ b t a i n e d . ~Although ~ ~ * ~ *mixtures ~ are obtained from methyl ethyl ketone and methyl n-propyl ketone, other methyl a k y l ketones condense a t the methyl rather than the methylene group. 473 It is possible to condense acetone and cyclohexanone 4 0 0 with two moles of isatin. 471
F. A . Al-Tai, A. M. El-Abbady, and A. S. Al-Tai U.A.R. J . Chem. 10, 339 (1967).
P. Barnfield, A . W. Johnson, and A. S Katner, J . Chem. Soc. C , 1028 (1966). 473 J. Rcrgman, Tetrahedron 27, 1167 (1971). 4 7 4 J . W. Cornforth, IC. H. Cornforth, C. Ei. Dalglicsh, and A. Nrubcrgrr, BzochewL. J . 48,591 (1951). 475 S. Davit1 and M. C. Doiicrt, BuZZSoc Chzm. Fr., 2152 (1967). 476 C. S. Franklin and A. C White, J . Chem. Soc , 1335 (1963). 477 C. S.Franklin antl A. C. White, British Patcnt 974,894 (1964); Chena. Abstr. 62, 472
9110 (1965). 478 47g
480 481
K. G. Holden, ZJ.S. Patent 3,631,177 (1971). (2. Kobayashi and S . Purulcnwa, Chem. PliarwL. BUZZ.12, 1129 (1964). R. E. Liitz and C. T. Clark, J . Orq. Chem. 25, 193 (1960). N N. Maxini and S.P e t r a ~ uC, . K. Acad. Sci. Roum. 8, 65 (1946);Cliem. Abstr.
43,1411 (1949) S. Pietra and G . Tacconi, Gazz. C h / m .Ital. 89, 2304 (1959). 483 S. Piotra and G. Tacconi, Furinaco (Pavia)E d . Scz. 15, 451 (1960). 4 e 4 S. Pietra antl C. Tacconi, fbrnzaco ( I ' a v ~ a Ed. ) Sc?. 16, 483 (1961). 485 8. Pictra and C:. Tacconi, Farmaco ( P a u m )Ed. &a. 13, 893 (1958). 4 a 6 S.Pietra and (2. Tacconi, Farmaco (f'avza)f
. Popp, unpuhlishrd rrsiilts.
482
46
[Sec. 1X.A
FRANK D . POPP
Other similar reagents such as nitro alkane^,^^^.^^^ methyl acetiinidate CH,C( = NH)OCH,,492 lactonitrile and d i b e n ~ y l a m i n e ,2-methyl~~~ ~ y r i d i n e ,and ~ ~ ~ 4-alkylpyridines 494a gave 172-175, respectively. Although active methylene compounds generally give rise to isatylidene derivatives, diethyl malonate 495 and ethyl ~ y a n o a c e t a t e have l ~ ~ been reported to give 3-substituted-3-hydroxyoxindoles. 0H
H (173) R = C(=NH)OMo (174) IL = CH(CN)N(CH,Ph), (175) R = 2- or 4-pyridyl
1U
Reaction of the Reissert compound anion 176 with isatin gave the ester 177.496
(176)
(177)
Isatin and its derivatives have reacted with both aryl and alkyl Grignard reagents to give 3-alkyl (or aryl) dioxindoles ( 178).232*497-500 Use of an excess of phenylmagnesium bromide with N - b e n ~ y l and ~~l G . Tacconi and S. Pietra, Farmaco (Pauia)Ed.Sci. 18,409 (1963). W. Ried and F. Kohlhaas, Justus Liebigs Ann. Chem. 701, 139 (1967). 493 A. Moyer and P. H. Payot, S. African Patent 68 07,093 (1969);Chem. Abstr. 72, 491
4Q2
43441 (1970). A. M. Akkerinan and H. Veldstra, Rec. Trav. Chim. 73, 629 (1954). 4Q4a G. Tacconi, S. Pietra, and M. Zaglio, Farmaco (Pauia)Ed. Sci. 20,470 (1965). 495 G . L. Papayan, Arm. Khim. Zh. 22,457 (1969); Chem. Abstr. 71, 70439 (1969). 4Q6 F. D. Popp, C. W. Klinowski, R. Piccirilli, D. H. Purcell, and R. F. Watts, J . Heterocycl. Chem. 8, 313 (1971). 4Q7 H. E. Baunigarten and P. L. Creger, J . Amer. Chem. SOC. 82,4634 (1960). 498 J. Bergman, Acta Chem. Scand. 25, 1277 (1971). 499 M. C. Bettembourg and S. David, Bull. SOC. Chim. Fr., 772 (1962). 5 0 0 B. Mills and K. Schofield,J . Chem. SOC., 558 (1961). 601 S. Sarel and J. T. Klug, Isr. J . Chem. 2 , 143 (1964). 494
Sec. IX.A]
47
THE CHEMISTRY O F ISATIN
N-methylisatin 5 0 2 , 6 0 3 has been reported to give the N-substituted 2 3 diphenylindoxyl ( 179) and 3,3-diphenyloxindole (180) rather than epoxides as claimed1 earlier. Phrnyllithium and isatin also give rise to 178 (R' = H, R = P11).504Zinc and ethyl bromoacetate also give products of the type 178.150*245,492 Ph
(178)
(179)
(180)
Isatin and N-substituted isatins react with diazoalkanes t o give a variety of products. Simple adducts of the type 181 have been obtained when N-substituted isatins react with methanol-free diazomethane and are reported to lose nitrogen and react further in methanol.505 Such adducts have also been reported in other cases.196*506-508 Ring enlargement to yuinolones (182; It is the R in RCHN, and R' is usually OH but sometimes O3Ie from diazoincthane) frequently occurs.123~196~50G-509 Finally, epoxides of the type 183 have sometimes been obtained from the diazoallianc reaction.123~24g*507~510 With diphenyldiazomethane, ring expansion does not take place and 183 (R = Ph) is the only
(181)
(182)
(183)
product. Hydrolysis of 183 ( R = Ph, R' = H, R" = 5-Me) with hydrocliloric acid gave i s o i n d i g ~Isatin . ~ ~ ~ with an excess of diphenyldiazoniethane for an extended reaction time gave 183 (R = Ph, R' = 502 W. C. Suniptrr and \V. W. Hunt, Trans. Kentucky Acnd. S c i . 17, 78 (1956); 503
505
507 508
Chem. abstr. 51, :1560 (1957). 13. Witkop antl A . Ek,J . Amer. Chrm. Soc. 73,5664 (1051).
J. M. Brrice,J Chem. Soc., 2366 (1959). B. Eistcrt antl 0. Ganster,Chem. Her. 104, 78 (1971). B. Eistcrt and G. Rorggrcfe,Justus Ltebigs A n n . Chem. 718,142 (1968). B. Eistert arid H Selzcr, Chem. B e y . 96, 1234 (1963). M. Regitz, W. Disteltlorf, V. Ecltstpin, and B. Wcber, Tetruhrdron Lett., 3979 (1972).
508 510
l3. Eistert and H. Sclzcr, Z . Nuturforsch. B 17, 202 (1962). A. Schonberg antl I<. Janghans, Ber. 96, 3328 (1963).
48
FRANK D . POPP
[Sec. 1X.B
CHPh,, R" = H), which was oxidized by sodium dichromate-acetic acid t o N - (diphenylmethy1)isatin. O
B. REACTIONS LEADING TO ISATYLIDENE DERIVATIVES Compounds of the type 171 can generally be easily dehydrated and many reactions of isatins lead directly t o isatylidene derivatives. Use of active methylene compounds such as malononitrile 511 and cyanoacetate 5,28.144*161*512.513gave compounds of the type 184. Various 4-thiazolidones have been condensed with isatin, generally under acidic conditions, to give 185.514-518Similar type compounds (186) have been obtained from thianaphthenes and isatin using acetic a ~ i d . These ~ ~ ~ - ~ ~ compounds (186) have been used as dyes. Other heterocyclic ketones
(186)
L. Capuano, V. Diehl, and W. Ebner, Chem. Ber. 105, 3407 (1972). 512 J. Harley-Mason and R. F. J. Ingleby, J . Chem. SOC., 3639 (1958). 513 R. G. Taborsky and W. M. McIsaac, J . M e d . Chem. 7 , 1 3 5 (1964). 514 B. Das and M. V. Roat, J . Sci. I n d . Res. Sect. B 14, 16 (1955). 515 R. P. Rao, Chem. Ber. 92, 2600 (1959). 516 R. P. Rao, J . Sci. I n d . Research, Sect. B 19,29 (1960). 517 R . P. Rao, Proc. Nut. Acad.Sci., I n d i a , S e c t . A 30, 181 (1961). 518 R. P. Rao and S. Raj, J . I n d . Chem. SOC. 50, 366 (1973). 519 Ciba, Ltd., British Patent 607,608 (1948);Chem. Abstr. 43,9470 (1949). 520 S. K. Guha and J. N. Chatterjea, J . I n d i a n Chem. SOC. 24,473 (1947). 521 S. K . Guha, J. N. Chatterjea, and A. K. Mitra, Chem. Ber. 94, 2295 (1961). m 2 K. Hoelzle and E. Kambli, U.S. Patent 2,463,225 (1948);Chem. Abstr. 43, 7706 511
(1949).
C. Shinomiya and K. Yamada, Kogyo K a g a k u Zasshi 67, 146 (1964); Chem. Abstr. 61, 5819 (1964). 624 A. K. Sinha, J . I n d i a n Chem. SOC. 31,463 (1954). 523
Sec. IX.B]
49
T H E CHEMISTRY OF ISATIN
also react to give compounds of the type 184.525-529The 2-isatylidene analogs of 186 have been obtained by using 135 in place of isatin.519.522 It is of interest to contrast the reaction of N-methylisatin and N -
methyloxindole under basic conditions144and A'-methylisatin and Nhydroxyoxindole under acidic conditions.525I n the former case 187 is obtained, and in the latter 188. A number of aliphatic aldoximes react with isatin to give 189.4E8 Although isatin and 2-methylpyridine give mainly 175 and only a small amount of 190 (R = H), use of 6-methylinicotinic acid494and its ester472gave only 190 (R = CO,H and CO,Et, respectively). Reaction
(190)
(189)
R'
Ar
R" (191)
Ac (191a)
L. Capuano and W. Ebner, Chem. Ber. 102,3691 (1969). J. A. Ballantine, R. J. S. Beer, D. J. Crutchley, G. M. Dodd, and D. R. Palmer, J . Chem. SOC., 2292 (1960). 527 F. E. King, T. tJ. King, and G. B. Thompson, J . Chem. SOC., 552 (1948). 5 2 8 G. Stofanovic and S. Miailovic, Glas. Khern. Drushtva, Beograd 22, 459 (1959); Chew,. Abstr. 56, 3442 (1962). 5 2 8 C. B. Barrett, K. J . S. Beer, G. M. Dodd, and A. Robertson, J . Chem. SOC., 4810 (1957). 525
526
50
PRANK
L).
POPP
[Sec. 1X.C
of isatin or N-methylisatin with 3-benzoylpropionamide or 4-( 3indolyl)-N-methyl-4-oxobutyramide under acidic condiions gave condensation and cyclization to 191.526A similar product (191, R = Ph, R’ = Me) was also obtained from isatin and N-methylisatin and 2hydroxy-l-methyl-5-oxo-2-phenylpyrrolidine.526 Islttin and P-aroylpropionic acids under Perkin conditions gave butenolides ( 191a).52ga The Wittig reaction and its various modifications have been used to prepare 184 (R = H; R’ = C02Et,150.160,530-532 R’ = ph,533 01 R’ = CNl6O). The literature contains many transformations of compounds of the type 184 and the 2-isatylidene analogs of 184; such compounds are ~~~,~~~ frequently prepared from oxindoles 533-53Q and i n d o ~ y l s ,rather than from isatins.
C. MISCELLANEOUSCONDENSATIONS Isatins condense with benzene,541 a l k y l b e n ~ e n e s , ~ and ~ ~ phen o l ~ ~under ~ * acidic ~ ~ conditions , ~ ~ ~ to give 192. Hydroquinone and N-methylisatin with sulfuric-acetic acid gave 193.55 Pyrroles 543 and in dole^^"*^^^ also condense with isatin under acidic 543 or basic 498 conditions. The well-known iiidopheninl has now been obtained from isatin and thiophene using polyphosphoric Condensation of N-methylisatin, glyoxal bisulfite, and sodium M. El-Abbady, M. A. Omnra, and N. C:. Kantlil, Rev. Rounk. Chenc. 19, 79 (1974). 530 R. L. Autrey and F. C. Tahk, Tetrahedron 24,3337 (1968). 531 H. A. Brandman, ,I.Heterocycl. Cheni. 10, 383 (1973). 532 J. Hollowood, British Patent 1,239,553 (1971);Chern. Abstr. 75, 98446 (1971). 533 R. Hodgcs, J. S . Shannon, W. D. Jamieson, and A. Taylor, Can. J . Chena. 46, 2189 (1968). 534 W. C. Anthony,J. Org. Chem. 31, 77 (1966). 535 G. Drsimoni, G. Tacconi, and F. Marinone, Gazz. Chim. Ital. 98, 1301 (1968). 536 C. C. 12ichards and M. 8 . F. Ross, Tetrahedron Lett., 4391 (1968). 537 G. Tacconi, A. Gamba, P. Marinone, and G . Dcsinioni, Tetrahedron 27, 561 (1971). 638 G. Tacconi and F. Marinone, Ric. S c i . 38, 1230 (1968). 539 M. Hooper and W. N. Pitkethly, J . Chem. Soc., P e r k m Trans. 1, 1607 (1972). 5 4 0 W. I. O’Sullivan and E. J. Rothcry, Chern. I t i d . ( L o n d o n ) ,849 (1972). 541 ,J. Wcgrnann and 11. Dahn, Helv. Chim. Acta 29, 415 (1940). 5 4 2 I<. Stcinriick, ( h m a n Patrnt 824,203 (1951);Chem. Abstr. 49, 7004 (1955). 543 G. Mullcr, J . Prukt. Chem. 4, 179 (19.57). 544 I. Shopov and C. Vodcnicharov, J-. Macrotnol. Sci., Chem. 4, 1027 (1970). 5291*A.
Sec. XI
51
THE CHEMISTRY O F ISATIN
HO
HO
OH
:gz+ (192)
(193)
OH
(194)
cyanide, in aqueous sodium carbonate followed b y neutralization, gave the tet)roiiiniide 194.545,546 Isatin, acetic anhydride, and pyridine gave a purple condensation product 195.547 Replacement of the acetic anhydride b y propionic anhydride caused the reaction to make a different path, a n d three
0
O )
N
Ac
/
az:-cxTD
0 ‘ (195)
I
I
COEt
COEt (196)
geometric isomers of 196 were obtained. 548 N-Propionylisatin also gave 196 and iV-acetylisatin was converted into the N-acetyl analog of 196.548
X. Pfitzinger and Related Reactions As was noted in Section IX,R, isatin reacts with ketoncs under mildly basic conditions to give 171. Under stronger basic conditions, such as concentxatcd sodiiiiii or potassium hydroxide, the reaction takes a completely diffcrent coursc. The isatin undergoes ring opening in the strong base and the alkali isatate (197) condenses with a ketone, such as 198, t o give a qiiinoline-4-carboxylic acid (a cinchoninic acid) (199). A detailed discussion of the scope of the Pfitzinger reaction is 545
R.G. Amiet, E’. W. Eastwood, and 1. D. Rae, Chern. Commun., 1614 (1971).
11. (iAniirt, . F. \Y. Ea5twootl, anti I. L). Rac, Aust. J . Ghern. 25, 1473 (1972). J. A. Ballantinc, A. LV. .Johnson, and A. 8. Katncr, J . Chena.SOC., 3323 (1964). 5 4 8 A. W. Johnson and A. S. Katncr, J . Chenz. SOC., 1455 (1965).
546 547
52
[Sec. X
FRANK D. POPP
coz- &I+
CO,H
I (!=O
Mt.
NH, (197)
i
0
--C--R’
II
(198)
~
~
-
~
l
i
(199)
beyond the scope of this review, but an attempt will be made to include a description of most of the examples. Methyl ketones (198) have given rise to a wide variety of compounds of the type 199.16~30,32~61.207.208~214,461~549-570b If ammoniuin hydroxide is used as the base, the aniide of 199 is ~ b t a i n e d , Use ’ ~ ~of~MeC~~~ ( = N H ) O E t with isatin gave the amide of 199 (R’ = OEt).571 Ketones of the type 200 (where R is not CH, or CH,) react with isatin to give cinchoninic acids of the type 201.557,572-5g3 I n a number of V. Ettel and Z . J. Allan, Chem. Listy 46, 249 (1952). A. S. Azaryan, 5. A. Avetyan, M. A. Kaldrikyan, and M. A. Iradyan, Sin. Geterotsikl. Soedin., 61 (1972); Chem. Abstr. 79, 146350 (1973). 551 R. F. Brown, J. Amer. Chern. SOC. 68, 2705 (1946). 552 R. J. Bass, Chem. Ind. (London),848 (1973). 553 E. R. Buchman, H. Sargent, T. C. Myers, and D. R. Howton, J . Amer. Chem. 54a
580
SOC. 68,2710 (1946).
N. P. Buu-Hoi and P. Cagniant, Rec. Traw. Chim. 64, 214 (1945). N. P. Buu-Hoi and P. Cagniant, Bull. SOC. Chim. F’r.,134 (1946). 5 5 6 N. P. Buu-Hoi and R. Royer, J . Chem. Soc., 106 (1948). 557 N. P. Buu-Hoi, R. Royer, N. D. Xuong, and P. Jacquignon, J . Org. Chem. 18, 1209 (1953). 5 5 8 A. L. Gcrshuns and P. Y. Pustovar, Kh,im. Geterotsikl. Soedin., 239 (1973). 559 J . S. Gillespie, R. J. Rowlett, and R. R. Davis, J . Med. Chem. 1 1 , 4 2 5 (1908). 660 H. Gilman, L. Tolrnan and S. 1’. Massie, J . Amer. Chem. Soc. 68, 2399 (1946). 561 A. L. Gsrshuns, A. N. Brizitskaya, and I?. Y . Pustovar, Khim. Geterotsikl. Soedcn., 1536 (1973). 562 H. R. Henzc and D. W. Carroll, J . Amer. Chem. SOC. 76,4580 (1954). 563 1%.E. L u t z , J . Amer. Chem.Soc. 68, 1813 (1946). 564 N. Okuda,J. Pharm. Soc.Jap. 71, 1275 (1951). 5 6 5 M. H. Palmer and R. 8. McIntyre, J . Chem. SOC.B, 539 (1969). V. Parrini, Gazz. ChCrn. Ital. 88, 24 (1958). 567 G. Y. Sarkis,J. Chem. Eng. Data 17, 388 (1972). 568 M. N. Scmtsova, P. L. Trakhtenberg, A. E. Lipkin, and T. B . Ryskina, Khim. Farm. Zh. 7,13 (1973). 569 I. Shopov and N. Kassabova, Izv.Otd. Khim. Nauki. Bulg. A k d . Nauk. 4, 619 (1971). 570 L. V. Thoi, Ann. Chim. (Paris)LO, 35 (1955). 570n S. A, Avotyan, A. S. Azaryan, and A. A. Aroyan, A r m . Khim. Zh. 26, 763 (1973); Chem. Abstr. 80, 70066 (1974). 570b J. Novotny, C. H. Collins, and F. W. Starks, J. P/mrm. S c i . 63, 1264 (1974). 571 A. Kei, K. Onami, H. Fukumi, and H. Matsushima, Japan Patent 72 37,187 (1972); Chem. Abstr. 78, 16060 (1973). 554
555
r
Sec. XI
THE CHEMISTRY O F ISATIN
53
cases mcthyl liet ones of tlip type 202 iuidergo condensation at the inethylene groiii) rat hcr than the methyl group t o give 201 (R =
CH3).556*565,694 5 q u Tllc factors ihat influence whether 199 or 201 is obtained have Iicen clibcuqsed. i56.i66, 5899597
B. 1 . Artlahc.v, 1 S Znrifyan. i i i i ( l :C G. ( ~ l i i l r h o \ c ~Kkini. t~, GeterotsLkl. S o r t l , n . , 525 ( 1 0 7 2 ) 6 7 J X . 1'. Burl-hoi,.I. C ' / r c , t / / Soc., 2 8 8 % (1940). 574 S . I' Hiiii-Hoi antl 1' ('tigniarit, /litZl.cVoc. ( ' / i t t i i . J'r., 123 (1!)46). 5 7 5 K I' l3iiii-Hoi a n i l X g i i \ c - i i - l I o m ~/ ? r e . T I U P( '.h i m . 67, 30!) (1948). 5 7 6 N. 1'. Riiii-Hoi a n i l 1C. lZovi.r, i I u 1 1 . ,Yoc. ( ' / i i t a . ff'r.,374 (1946). 577 hT.1'. Rini-Hoi ant1 1-1. liovixr, Ilirll. ,Yoc. C h i m . Fr., 820 (1947). 5 7 8 N t'. UiiwHoi, bl. Sy,diiil tJ lCicIi(t,? J . Ory/. C'lrrm. 22, 668 (1957). hcl. c'. A'. d c c d . ,Cci. 225, 15.5 (1047). 5 7 q P. C,igniant aivl \ . I k l r i 5 8 0 P. Cagniant aixl .I. I)c~liizarchc~, ('./i'. ; 3 r c z d . S c i . 223, 1148 (1946). . t'ac. Chitti. I t ! ( / t T t i t u . B o l o y ~ r i6, 26 (1048); CtLem. 572
H r i i i Hoi, C . 12. dcntl. Sci.227, 1251 ( 1 M 8 ) . M. 1)c~Clrrcqant1 Pi. 1'. Brcu-Hoi, P l l . Acad. Scr. 227, 1377 (1948). 5 8 4 A. 111. l.:l-;\bbaily, M . h. Ornara, anti N. G . Kandil, Hrcr. K o i m i . CILLVL. 18, 899 (1'373). 5 8 5 R.11. Garrett and H. R . H m z r , J . J i e d . Cheni. 9, 976 (1966). 58G A. I' Isbell ancl H. R . Henzc. J . A t t i e r . Chrin. SOC. 66, 2096 (1944). 5 8 7 J . .\. Knight, H. li.Porter, ant1 1'. I<. Calawaj, ,I. A m e r . Chem. Sot. 66, 1893 (1044). 58* L. C. 11larch, R'. =1. lioriiaiichlck, ( i . S.Ralaa, and M. &I. Joullir, J . J I r d . Cliem. 16, 337 (1973). 589 G . 1'. Mut.llcr a n t 1 I < E. Stobaiigh, cJ A t n ~ rC. " h e / u .SOC.72, 1.598 (1930). 5 9 0 Ngrcyc.n-Hoan ant1 X . 1'. L3iiii.hoi, C' I?. A c a t l . Scr. 224, 1363 (1947). 5g1 \\'. Ried and L'. I)!.B e t . . 104, 3341 (1971). novic, L. Lorcric, I<. 1. Miuiiiiziv, anii 31. L. Mihailovic, Tetmhedron 6,
583
304 (1958). A. &I. Llouell, €1. S. McCiiIloiigki, and 1'. I<. Calanay, J . Arner. Cheitz. SOC.70, 226 (1948). 59G H. H. Hrnze, J . lV. Mclton, anti E. 0. Eorman, ./. A m e r . Chtm. SOC. 70, 2622 (1948). 596 O.Nr\\ellanci€'. I<. Calaway,J. .~nic,..C/~ein.iSoc. 69, 116 (1947). 597 G . St(>fano\ic, X. Pa\ icic-\co\s, L. I,ortmc, miti 31. L. Mihailovic, Tetruhedron 6, 97 (1950). 594
54
FRANK D. POPE'
[Sec. X
Reaction of isatins with 3-chloro-2-butanone gave 205.9 1-(0-Toly1)isatins underwent a reaction similar to the Pfitziriger synthesis t o give 206.71 Although aldehydes have not been used, oximes have been used t o prepare 3-s~bstitut~ed quinoline-4-carboxylic acids.614 The dioxiine of R. L. Sublct,t ancl 1'. I<. Calaway, , J . d m e r . Che7n. Soc. 70, 674 (1948). N. P. Bnu-Hoi and P. Citgniant, Ber. 77, 118 (1944). 6oo N. P. Buu-Hoi, J . Chem. Soc., 795 (1'346). N. P. Biiu-Hoi and .'1 Cagniant, Bull. SOC.Chim. Fr., 343 (1944). N. P. Biiu-Hoi antl I<. lioyrr, Iiec. 2'rav. China. 66, 300 (1947). P. Cagniant antl A. I~kAitzarche,C . I<.Acad. Sci. 223, 808 (1'346). 604 J. Colongo and J . Cliainbion, C.R. Acrul. Sci. 224, 128 (1947). 605 P. Jacqitignon ant1 N. P. Uuii-Hoi,J . Ory. Cheni. 22, 72 (1957). L. E. I~lioloclov,G. 1'. Syrova, V. G . Yashunsltii, and Y. N. Shcinlter, Khim. Ceterotsilil. Soedin., 78 (1970). 607 R. Madhav and P. L. SoutJiwiclc,J . lleterocycl. Chern. 9, 443 (1'372). 6 0 8 F. G. Mann, Nuture ( L O I L ~164, O ~ 785 L ) (1949). E. 4.Markaryan and R. S. Ualayan, S i n . Geterotsikl. Soedin., 74 (1972);Chem. Abstr. 79, 146357 (1973). G1o N. 1'. Biiu-Hoi and R. Royer, C.R. Acad. Sci. 223, 806 (1946). 611 G. A. Kliinov, V. A. Stonik, antl M. N. Tilichcnko, 1ihi.m. Geterotsikl. Soedin., 821 (1973). 612 I. F. Tishchcnkova, L. E. Kholodov, and V. G. Yashunslri, Khirn. Geterotsikl. Soedin. 7, 102 (1971). 612a A. Hassnar and M. <J.Haddadin, J . Org. Chem. 27, 1911 (1962). G13 W. H. Linnell anti L. K. Sharp, Quart. J . Phar?n.I'harmucol. 21, 58 (1948). 614 M. Haring and G. Stillo, Helw. Chinz. Acta 44, 642 (1961). 598 599
Xec. X]
55
THE CHEMISTRY O F ISATIN
1,2-cyclopentaiiedionc and 1 ,kyclohexanedione undergo a modified Pfitzinger reaction to give 207.615
(207)
Treatment of N-acetylisatin with base gave the quiriolone 208,16*32.616-620n while N-propionylisatin gave the 3-methyl analog of COZH I
(208)
(209) CONH,
H (211)
(212) rt = H (213) R = Me
208,16Qand isatin with p-nitrophenylacetic anhydride gave the 3(p-nitrophenyl) analog of 208.620bThe use of 1-(chloroacetyl)isatin in this reaction has also been s t ~ d i e d ; i~t gives ~ ~ *2,4-dioxoquinoline ~ ~ ~ . ~ ~ ~ and 3-h~droxy-2-cjuinolone.N-(4-Chlorobutyry1)isatin gave 209 iii an abnormal example of this reaction.15QUse of 210 gave 2 l l . l Z 3Compounds similar to 211 have been obtained from isatin and allylisothiocyanates in the presence of Quinazolines 212 and 213 are also E. Uhlemann and P. Kurze, J. Prakt. Chem. 312, 1105 (1970). J. Buchi, H. Hurni, and R.Licberherr, Helv. Chim. Actu 32, 1806 (1949). 617 J. Buehi and X. Perlia, Arzneirnittel-Forsch. 10, 174 (1960). 618 R.A. Egli and C. Richter, Helv. Chim. Acta 40,499 (1957). K. Ohata, H. Frikunu, K. Kobayashi, H. Matsushima, and M. Icoromura, Japan Patent 72 16,477 (1972);Chem. Abstr. 77,164523 (1972). 6 2 0 C. R.Wetzal, J . R . Shanklin, and It. E. Lutz, J . Med. Chem. 16,528 (1973). woa H. Fukuini, K. Oohata, M . Matsnshima, and K. Arima, J . Pharnr. Soc. Japan 94, 768 (1974). 6 2 a b S. Yoshinia and A. Tanalra, J. Pharrn. Xoc. *7apan94, 267 (1974). 621 J. R. Price and L. W. Smith, Aust. J. Chem. 9, 139 (1956). 6 2 2 G. M. Sharma, I<. K. Soni, and K. S. Narang, Tetrahedron 18, 1019 (1962). 615
616
56
[Sec. XI
FRANK D . POPP
obtained from N-formyl and N-acetylisatin by treatment with sodium hydroxide and then ammonia.98 Pyruvic acid and isatins gave quinoline-2,4-dicarboxylica ~ i d s . ~ ~ . ~ ~ Use of malonic acid with isatins gave 2-quinolone-4-carboxylic a ~ i d s .Nitromethane ~ ~ ~ , ~ ~and ~ isatin with 50% potassium hydroxide gave 3-nitroquinoline-4-carboxylic A number of cinnolines have been obtained by alkali treatment of isatins. Thus, 214 gave 215,68-70 while isatin on treatment with base followed by hydrogen and palladium, diazotization, and reduction gave 3-hydro~ycinnoline.~~~ __f
"Q ' TL:
R , ~
' 0
N=CH--/
\
/
\
R
-R
(214)
(215)
XI. Polymers B,B'-Biisatin, 5,5'-methylenebiisatin, 5,5'-diisatylether, and 5,5'diisatylketones have proved to be useful compounds for the preparation of polymers. A series of polyindophenines (216-219) have been prepared by reaction of these isatins with thiophene under acidic condi-
(217) X = CH, (218) X = 0 (219) X = C = O 623
M. Colonna, Boll. Sci. Fac. Chim. I n d . Bologna, 89 (1941); Chem. Abstr. 37, 3096 (1943).
624
R.L. Zey, J . Heterocycl. Chem. 9 , 1177 (1972).
Sec. XI]
57
THE CHEMISTRY O F ISATIN
tioi~s.5s~544~625-62Q Polvpliosphoric acid is very effective for this polymerization.59*544*627~62Q These vat polymers can be reduced to the and their semiconductor properties have been leuco form,59,625.626*628 d i s c ~ s s e d Sulfuric . ~ ~ ~ ~acid-catalyzed ~~~ copolymerization of 220 and thiophene gave the polymeric vat dye 221.‘j30 In a manner similar to that noted above, pyrrole gave polypyrroleindophenines (222, X = 0, CH,, and a bond),631and o-diamines gave polyindoloyuinoxalines 223,424224,424,632 225,633226,423227,423and 228.423These latter compounds showed good thermal stability. Polymer
bnyJ---, H
\
H
n
(222)
(223) X = bond, Z = bond (224) X = 0, Z = C) (225) X = 0, Z = CH,
(226) X = CH,, Z = bond (227) X = CH,, Z = CH, (228) X = CH,, Z = 0
I. J. Levine, U.S. Patent 3,334,074 (1967);Chem. Abstr. 67, 82565 (1967). I. Shopov, Polymer Lett. 4, 1023 (1966). 627 I. Shopov, C.R. Acad. Bulg. Sci.21,439 (1968). 628 I. Shopov and K. Vodenicharov, Izv.Otd. Khirn. N a u k i , Bulg. Akad. N a u k 3, 625
626
445 (1970). 629
I. Shopov and K. Vodenicharov, Izv. Otd. Khim. N a u k i , Bulg. Akad. N a u k . 3, 233 (1970).
G. liossmehl and G. Manecke, Makromol. Chem. 113, 182 (1968). 631 I. Shopov, N. Kassabova, and M. Vodenicharova, Izv. Otd.K h i m . N a u k i , Bulg. Akud. Nauk. 4 , 6 2 9 (1971). 632 I. Shopov and N. Popov, Vysokomol. Soedin., Ser. B 9, 415 (1967); Chem. Abstr. 67, 82457 (1967). 633 M. Kurihara and N. Yoda, Japan Patent 70 40,552 (1970); Chem. Abstr. 74,
630
126522 (1971).
58
[Sec. XI
FRANK D. POPP
225 was prepared a t 150-250" rather than in the presence of polyphosphoric acid. The EPR spectra of several of the polyindoloquinoxalines have been reported.834 Polyphenylenequinolines (229) have been prepared through a Pfitzinger type reaction.56gUse of acetylated polystyrene with isatin in
+J
bXd ozi I
I1
n
(230)
the Pfitzinger reaction gave a cinchoninic acid derivative of polystyrene.635 The Sandmeyer isonitrosoacetanilide isatin synthesis has been applied to poly(m-aminostyrene) to give poly(6-vinylisatin) (230). 636*637 Polymer 230 has been converted into poly(6-vinylindirubine) and poly[(6-vinyl-3-indole)(2-thionaphthene)]indigo,and all three polymers were investigated with regard to t,heir redox capacity and standard redox p ~ t e n t i a l . " ~ . ~ ~ ' Note Added in Proof: Since the completion of this review the following additional reports have appeared. Section Ill: H. Boehme and H. Schwartz, Arch. Pharm. 307, 775 (1974); M. Furukawa, T. Suda, and S. Hayashi, Chem. Lett., 881 (1974). Section V I I : Y. S. Chough and K. 1. Kang, Yakhak Hoeji 17, 141 (1973): Chem. ADstr. 81, 151896 (1974);R . S. Pandit and S. Seshadri, Indian J . Chem. 12, 943 (1974);A. B. Tomchin and E. A. Rusakov, Khim.-Farm. Zg. 8, 23 (1974). Section V I I I : V. M. Dziomko, A. V. Ivashchenko, and R. V. Poponova, Zh. Org. Kh i m. 10, 1325 (1974); M. Furukawa, T. Yoshida, and S. Hayashi, Ghem. Pharm. Bull. 22, 2875 (1974);M. Seth, A. P. Bhaduri, N. M. Khanna, and M. L. Uhar, Indian J . C'hem. 12, 124 (1974). Section I X : B. Lal, P. Singh, and A. P. Bhaduri, IndianJ. Chem. 12, 906 (1974); G. I. Zhungietu and L. M. Reulets, Khim . aeterotsikl. Soedin., 1226 (1974). Section X : S . Petersen, Germ. Patent 2,314,242 (1974): Chem. Abstr. 82, 4296 (1975). I. Shopov and N. Iordanov, Dokl. Bolg. Akad. Nauk 22, 1123 (1969); Chem. Abstr. 72, 56038 (1970). 635 J. A. Blanchette, U.S. Patent 2,865,902 (1958); Chem. Abstr. 53, 7668 (1959). e 3 e G. Kossmehl and G. Manecke, Makromol. Chem. 115,285 (1968). 637 G. Manecke and G. Kossmehl, Makromol. Chem. 70,112 (1964). G34
Thiochromanones and Related Compounds 9. W. SCHNELLER
Department of Chemiatry, Univeraity of South Florida, Tampa, Florida
I. Introduction . . 11. Thiochromans and Thiochroman-4-ones . . A. Preparation of Thiochroman-4-ones . . . B. Preparation of Thiochromans . . C. Reactions of Thiochroman-4-ones . . D. Reactions of Thiochromans . . E. Physicochemical Properties of Thiochroman-4-ones and Thio. . chromans F. Uses of Thioclroman-4-ones and Thiochromans . . . 111. Thiochromones . A. Preparation of Thiochromones . . . B. Reactions of Thiochromones . C. Physicochemical Properties of Thiochromones . . D. Uses of Thiochromones . . IV. Isothiochromans and Isothiochromanones . . A . Preparation of Isothiochromanones and Isothiochromans . . B. Reactions of Isothiochromanones and Isothiochromans 1. Isot,hiochromanones . . . 2. Isothiochromans . . C. Physicochemical Properties of Isothiochromans . . D. Uses of Isothiochromans . . . V. Benzothiopyrans . . A. Preparation of 2H-1-Benzothiopyrans . . B. Preparation of 4H-1-Benzothiopyrans . . C. Preparation of 1H-2-Benzothiopyrans . . D. Reactions of 2H-1-Benzothiopyrans . . E. Reactions of 4H-1-Benzothiopyrans . . F. Reactions of 1H-2-Benzothiopyrans . . . G. Physicochemical Propcrties of Bcnzothiopyrans . . . H. Uses of Benzothiopyrans . . VI. Benzothiopyrylium Salts . . A. Preparation of Benzothiopyrylium Salts . . B. Reactions of Benzothiopyrylium Salts . . C. Physicochemical Properties of Benzothiopyrylium Salts . D. Uses of Benzothiopyrylium Salts .
59
60 61 61 63 66 74 76 77 79 79 81 82 83 84 84 85 85 87 88 88 88 88 89 90 90 92 92 93 93 94 94 95 96 96
60
[Sec. I
S . W. SCHNELLER
I. Introduction The scarcity of reviews1 and recent interest in thiochromanones and related compounds calls for a comprehensive summary of this area of heterocyclic chemistry. The apparent similarity between these systems and the naturally occurring chromanones, chromones (flavones), chromenes, etc., is responsible for the continued importance of these sulfur heterocycles. Chemical Abstracts (through November, 1973) has been employed as the principal reference source and nomenclature guide for this review. The focus will be directed t o five ring systems: thiochromans (l), thiochromones (2), isothiochromans (3), benzothiopyrans (4-6), and, benzothiopyrylium salts (7, 8). It is difficult completely t o segregate their chemistry since they are so interrelated; cross-references will be employed as often as possible. Thiocoumarins and thioxanthones are excluded since these molecules differ considerably from those reviewed here.
(1)
(2)
(3)
Thiochromans R = H,;H, OH Thiochrorrianones R = O
Thiochromones
Isothiochromans R = H,; H, OH Isothiochromanones R = O
(4) (5) (6) 2 H - 1 -Benzothiopyrans 4H-1 -Benzothiopyrans 1 H-2-Benzothiopyrans
X(7) 1 -Renzothiopyrylium salts
(8) 2-Benzothiopyrylium salts
D. S. Tarbell, in “Heterocyclic Compounds” (R. C. Elderfield, ed.), Vol. 2, Chapter 14. Wiley, New York, 1951.
Sec. II.A]
THIOCHROMANONES AND RELATED COMPOUNDS
61
11. Thiochromans and Thiochroman-4-ones A.
PREPARATION O F
THIOCHROMAN-4-ONES
Thiochroman-4-ones (1; R = 0) have been the most convenient synthetic entry into the thiochroman ring system. The most profitable of the various routes has been the acid-promoted cyclodehydration of p-arylmercaptopropionic acids (9) [Eq. (l)].The acids (9) result from
(9)
nucleophilic displacement of a thiophenoxide on a p-halopropionic acid2-6 or ester7 or nucleophilic ring opening of a p-propiolactones-l0 with alkyl oxygen cleavage. Sulfuric a ~ i d , ~ *polyphosphoric ~ , ~ . ~ ~ ~ ~ a ~ i d , ~ . l lphosphorus -l~ p e n t ~ x i d e , hydrogen ~.~ fluoride,14 and several Lewis acids15 catalyze the cyclization of (9). Variously substituted thiophenols and propionic acids or propiolactones may be used. Lewis acid15 catalysts frequently circumvent side reactions unavoidable with mineral acids [cf. Eq. (2)]. Lewis acids also cyclize the corresponding p-arylmercaptopropionyl halides to derivatives of 1 (R = 0).16 C . Finzi, Gazz. Chim. Ital. 56,539 (1926). V. Brllavita, Gazz. Chim. Ilal. 62, 655 (1932). * V. Bellavita, Gazz. Chirn. Ital. 70,594 (1940). N. Cagnoli, A. Ricci, and N. Ferli, Aun. Chim.( R o m e ) 47, 606 (1957);Chem. Abstr. 51, 16454 (1957). T. lkgtmi, R. Fochi, and G. Spunta, Boll. Sci. Fac. Chim. I d . Bologna 24, 75 (1966);Chem. Abstr. 66,46292 (1967). F.Krollpfeiffer and K. Schultze, Ber. 56B, 1919 (1923). * H. E. Zaugg, H. ,J. Glenn, R. J. Michaels, R. V. Shock, antl L. R. Swatt, J . Amer. Chem. SOC.79, 3912 (1957). A. B. Sen and S. L. Arora , J. Indian Chem. SOC.35, 197 (1958) l o €1. E. Zaugg, 11. J . Michaels, and H. J. Glenn, U.S. Patent 2,940,992; Chem. Ahstr. 54, 20990 (1960). l 1 C. D. Hurd and Shin Hayao, J . Amer. Chem. SOC. 76, 8065 (1954). l 2 G . Kunesch and P. M-essely, Monaish. Chem. 96, 1547 (196.5). l 3 h'. Cagnoli, A. Msrtani, antl C. Rossi, A m . C h k . ( R o m e ) 56, 1075 (1966); ('hem. -4bstr. 66, 55338 (1967). l4 D. 8. Tarbell, H. P. Hirschlsr, and T. J. Hall, J . Amer. Chem. SOC.75, 1985 (1953). l5 P. Cagniant and I). Cagniant, Bull. Soc. Chim. Fr. 3674 (1966). l6 W. E. Truce and J. P. Milionis, J . Amer. Chem. SOC. 74,974 (1952).
62
[Sec. 1I.A
S. W. SCHNELLER
Compound 9 has also been obtained via nucleophilic displacements by l ~ ~ Michael ~~ addition thioglycolic acids on activated h a l o b e n z e n e ~ and or a c r y l o n i t r i l e ~with ~ ~ subsequent hydrolysis. to acrylate 0
0
I
Further synthetic entries into the thiochromanone ring system have involved arylmercaptosuccinic acidsz0Pz1(10) as in Eq. (3) and the reaction of ethyl o-mercaptobenzoates with 2,3-diene carbonitriles 22 as in Eq. (4).3-Substituted thiochromanones (12) are prepared by the COOH I
l7
J. C. Petropoidos, M. A. McCall, and D. S. Tarbcll, J. Amer. Chem. SOC.75,
1130 (1963). F. Arndt, L. Locwo, and E. Ayca, Chem. Ber. 84,329 (1951). l9 A . P. Momsenko, Zh. Org. Khim.9, 775 (1973); Chem. Abstr. 79, 31797 (1973). 2 o J. Schmutz, H. Lavonor, R.Hirt, and M. Lanz, HeZw. Chim. Acta 34,767 (1951). 21 E . W. Bouquet, U.S. Patent 2,434,100; Chem. Abstr. 42, 2289 (1948). 22 I. T. Kay and N. Punja, J . Chem. SOC. C . 2409 (1970).
Sec. II.B]
THIOCHROMANONES A N D RELATED COMPOUNDS
63
alkylation of 3-carbalkoxythiochroman-4-ones(13) with subsequent saponification and d e c a r b o x y l a t i ~ n . ~ ~ H.
&
&R1
0,R2
(13)
(12)
B. PREPARATION OF THIOCHROMANS Thiochromans (1; R = H,) result from disproportionation of 2H-1benzothiopyrans (4) and also from thio-Claisen rearrangements of phenyl ally1 sulfides. The first pathway was discovered by Tilak and V a i d ~ a who , ~ ~ attempted to prepare one benzothiopyran (15) by cyclizing the /3-ketosulfide (14) in poiyphosphoric acid (PPA), but obtained the thiochroman (16) and a benzothiopyrylium salt as in Eq. ( 5 ) . This reaction involves 2 5 , 2 6 an acid-promoted disproportionation
(16)
via a hydride transfer in 15 (cf. Scheme l ) , which was expanded to a variety of thiochromans and thiocyanine dyes (from the benzothiopyryiium salts accompanying formation of 1, R = H2). J. It. Boissier and C. Malcm, French Patent 1,367,604; Ghem. Abstr. 61, 14642 (1964). 24 B. D. Tilak and V. M. Vaidya, Tetrahedron Lett., 487 (1963). 25 B. D. Tilak, R. B. Mitra, and V. D. Chandrakala, Tetrahedron Lett., 3569 (1965). 26 B. 1). Tilalr, H. S. Desai, C. V. Deshpande, S. K. Jain, and V. M. Vaidya, Tetrahedron. 22, 7 (1966). 23
64
S. W. SCHNELLER
[Sec. I1.B
Thiochroman (1; R = H2) is a product of the thio-Claisen rearrangement of ally1 phenyl sulfide, as reported in 1963;27 this reaction also produces 2,3-dihydrothiophenes as shown in Eqs. (6) and (7).28,29
0 SCH,CH=CHMo I
A ~
Similar reactions were carried out on 17,2918,30and 19.30The last gave thiochromans and 2,3-dihydrothiophenes from an apparent cyclization a t the ortho methyl substituent, but in fact involving a variety of hydrogen and methyl shifts. The route to the two main products [Eq. (7)] of the thio-Claisen rearrangement has been suggested to be via the thiirane intermediate (20).31 This rearrangement is also catalyzed by Lewis acids,32 but the products are more varied and this method is, therefore, less advantageous as a synthesis of thiochromans. C. Y .Moycrs, C. Rinaldi, and L. Bonoli, J . Org. Chem. 28, 2440 (1963). T. A. Danilova, T. Abdin, and E. A. Viktorova, Neftekhiwbiya 11, 444 (1971); Chem. Abstr. 75, 76324 (1971). 29 J. Tanaka, T. Katagiri, I<. Taltabo, and S . Takashita, Y u k i Oosei Kugaku KyokuiShi29,788 (1971); Chem. Abstr. 75 140636 (1971). 30 H. Kwart and M. H. Cohon, Chem. Commun., 1296 (1968). 31 H. Kwart and E. R. Evans,J. Org. Chem. 31,413 (1966). 32 S. Khushvakhtova, E. A. Vilttorova, and T. A. Danilova, Veatn. Mosk. Ul~iv., Khim. 2 4 , 9 9 (1969);Chem. Abstr. 72, 12260 (1970). 27 28
See. II.B]
THIOCHROMANONES AND RELATED COMPOUNDS
65
Thiochromans and thiochroman 1,l-dioxides arc readily prepared 3 3 - 3 5 from the corresponding thiochroman-4-one by catalytic hydrogenation in acetic acid/perchloric acid or via the Wolff-Kishner and Clemensen6p1' methods. Thermal decomposition of 21 produced thiochronian in 85% yield.36 Thiochroman and isothiochroinan occur in petroleum,37 and the completely saturated analog of the former (1-thiadecalin) was obtained 38-42 from propenyl 1-cyclohexenyl ketones in the presence of hydrogen sulfide and sodium acetate in ethanol.
33
J. R. Boissier and R. Ratorius, French Patent 1,574,139; Chem. Abstr. 72, 100522 (1970).
8. F. Birch, R. A. Dean, and E. V. Whitehead, J . I n s t . Petrol., London 40, 76 (1954);Cliem. ADstr. 49, 8243 (1955). 35 J. B. Campbell, E. R. Lavagino, It. B. Morin, and D. 0. Spry, Ann. N. Y . A c d . 34
Sca. 172, 261 (1970).
J . v. Braun, Ber. 43,3220 (1910). S. F. Birch, J . Inst. Petrol., London 39, 185 (1953); Chew&.Abstr. 47, 10211 (1953). 38 E. N. I<araulova, V. Sh. Shaikhrazieva, ant1 G. D. Gal'pern, Khim. Geterotsakl. Soediii., 51 (1967);Cherti. Abstr. 67, 64185 (19ti7). 39 V. Sli. Shaikhrazicva, E. K. Karaulova, C;. 1). Gal'pern, D. I<. Zhestkov, and I. V. Clicrcpanova, K h m . Seruorq. LSoedin., Soderzh. NeftyaX h Nejteprod. 8, 95 (1968);ChewL. Abstr. 71, 91222 (1969). 40 V. I. Dronov, V. P. Krivonogov, and V. S. Nikitina, KIiLm. Geterotsakl. Soedon., 335 (1970);Chtm. Abstr. 73, 66363 (1970). 4 1 V. I. Dronov and V. 1'. Krivonogov, USSR Patent 281,459; Chem. Abstr. 74, 87507 (1971). 42 V. G. Kharchenlro, N. M. Kupranrts, M. E. Stankevich, and M. N. Berezhnaya, USSR Patent 287,028; Chem. Abstr. 75, 35745 (1971). 36
37
66
[Sec. 1I.C
S. W. SCHNELLER
c. REACTIONSOF THIOCHROMAN-'&ONES Halogenation of thiochromanones is a fruitful entry into other systems. As shown in Scheme 2, bromination of 6-methylthiochroman4-one produces the perbromide (22), converted by water into the sulfoxide (23). Upon standing, 22 loses hydrogen bromide to form the 3-bromo compound (24), which yields the 3-amino analog and 6methylthiochrom-4-one with ammonia and dimethylaniline, respecti~ely.~~.~~
I R&NHz SCHEME
2
3-Bromothiochroman-4-ones are generally ring opened by hydroxide to thiosalicylic with formaldehyde they yield the corresponding 3-epoxy system (25) which can be converted into the 3-hydroxymethyl isomer (26).46Attempts to convert 25 into benzothiepins via acidmediated ring expansions have failed, yielding thiochromanones instead. 4 3 I?. Krollpfciffcr, H. Schultze, E. Schlumbohm, and E. Sommermeyer, Ber. 47948
58B,1654 (1925). W. Baker, J.Chem. SOC.127, 2349 (1925). 4 5 F. Krollpfeiffer, H. Schultze, and E. Sommermcyer, Ber. 58B,2698 (1925). 48 H. Hofmann, G. Salbeck, and B. Mcyer, Chem. Ber. 103,2084 (1970). 4 7 H . Hofmann, H. Westnacher, and H. J. Habcrstroh, Chem. Ber. 106, 349 (1973). 48 H. Hofmann and H. Wcsternacher, Chem. Ber. 102,205 (1969). 44
Sec. ILC]
THIOCHROMANONES AND RELATED COMPOUNDS
67
R (25)
(26)
Scheme 3 demonstrates similar reactions for thiochroman-4-one 1,l-dioxide (available from hydrogen peroxide oxidation of thiochroman 4-one).4 9
0 2
0 2
SCHEME 3
Chlorinationll of thiochroman-4-one is best achieved by cyclizing the requisite P-arylmercaptopropionic acid (9)with phosphorus oxychloride. Conversions related to this are presented in Scheme 4. l’hiochroman-4-ones are reduced to thiochroinan-4-01s by sodium borohydride and lithium aluminum h~dride.~O Lithium aluminum hydride reduction of thioflavan-4-ones (27) forms the 2,4-cis-thioflavan4-01s (28) as in Eq. (8). By contrast, deamination of 2,4-cis-4-aminothioflavans (29) with nitrous acid produced the trans- alcohol (30) as shown in Eq. (9).50 The alcohols obtained by the hydride reductions have 49 50
T. Nambara, Yakugaku Zawh%78, 624 (1958);Chem. Abstr. 52, 18392 (1958). Q. I?. Katekar, Au8t.J. Chem. 19, 1251 (1966).
68
S . W. SCHNELLER
/
[Sec. 1I.C
SO,CI,
frequently been employed for the preparation of 1-benzothiopyrylium salts by dehydration (potassium hydrogen sulfate, phosphorus pentoxide, etc.) to 2H-1-benzothiopyran (4) and subsequent hydride 10ss.6.51*52 (e.g., Section V1,A)
As mentioned (Section 11, B), thiochroman-4-ones are readily reduced to the methylene level ~ a t a l y t i c a l l y-,35~ ~under Clemmensen condition^,^^.^^ and, occasionally, with lithium aluminum h ~ d r i d eThe .~~ A . Luttring-haus and N. Englehard, Nuturwissenschuften 44,584 (1957). \$'. Bonthrono and U. H. Reid, Chem. I n d . (London), 1192 (1960). 6 3 C. Aiqylini, G. Grandohni, and L. Mignini, Ann. Chzm. (Rome) 46, 235 (1956); Chem. A b s f r . 51, 396 (1937). 51
52
Sec. II.C]
THIOCHROMANONES A N D RELATED COMPOUNDS
69
ketone moiety of 1 (R = 0) undergoes other typical reactions such as the formation of thiochroman-4-01s with organometallic reagents,17 (e.g., Grignard, organolithium) and oximes and hydrazones with hydroxylamine and various hydrazines, respectively. The 4-oximes are convenient intermediates. Reduction with zinc/ acetic acid,54hydrogen over palladium on c h a r c ~ a l or ~ ~ . ~ ~ or lithium aluminum h ~ d r i d e ,produces ~~ the 4-aminothiochroman. Interestingly, lithium aluminum hydride induces ring expansion to the
(32) SCHEME 5
2,3,4,5-tetrahydro-1,6-benzothiazepine (31), usually isolated as the p-toluenesulfonyl derivative 58-61 (Scheme 5). Compound 31 also results from t,he Beckmann rearrangement of the oxime to 32 and subsequent lithium aluminum hydride reduction (Scheme 5).58-60The C . M. Rennctt ancl W. B. Waddington, J . Chem. Soc., 1692 ( 1 9 3 1 ) . R . Bognar, M. Kakosi, and J. B a h t , Tetrahedron Lett., 137 ( 1 9 6 4 ) . 5 6 It. Bognar and M. 12ahos1,Justus Laebigs A n n . Chem. 693, 225 ( 1 9 6 6 ) . 57 N. V. Dudykina ancl V. A. Zagorcvskn, Sm. Prw. S o e d m . , I k h Analoy. Fragmentov, Akud. N a u k SSSR, Otd. Obshch. Tekhn. Kham., 139 ( 1 9 6 5 ) ;Chem. A b r t r . 65, 8866 ( 1 9 6 6 ) . 5 8 V. A. Zagorcvsbii arid N. V. Diitlykina, Zh. Obshch. Khrm. 33, 322 ( 1 9 6 3 ) ; Chem. Abstr. 59, 631 ( 1 9 6 3 ) . 59 V. A. Zagorevskii and N. V. Duciykina, Z h . Obshch. Kharri. 34, 2282 ( 1 9 6 4 ) ; C'hem. Abstr. 61, 11960 ( 1 9 6 4 ) . 6o N. V. Duclykina. anti V. 8 . Zagorcvskn, SLn. Praor. Soedzn. Ikh. Analog. E'rtcymetrtoz~,AXad h'aulz SSSIZ, Otd. Obshch. Tekhra. Khatn., 134 ( 1 9 6 5 ) ;Chem. Abstr 65, 683 ( 1 9 6 6 ) . V. A. Zagorevskii, N. V. Dudykina, and L. M. Mcscheryakova, Zh. Org. Kham. 5 , 1709 (1969);CI~ena. Abstr. 7 2 , 3316 ( 1 9 7 0 ) . 54 55
70
5. W. SCHNELLER
[Sec. 1I.C
Neber reaction produces the corresponding 3-aminothiochroman-4one.62Similar reactions have been conducted on the 8,s-dioxide oxime analogs .63 Ring expansion of thiochroman-4-ones to 5-oxo-2,3,4,5-tetrahydro1,4-benzothiazepines is accomplished by the Schmidt reaction, cf. Eq. (101.64
R@4@(10)
R'
Rl
Hydrazones of thiochroman-4-ones are converted into thiochromans under Wolff-Kishner-Huang conditions 6 5 and into the azo dimers by silver oxide.66Fisher indolization of the phenylhydrazones (33) gives G , 1l-dihydrobenz[b]indolo[2,3-d]thiopyrans(34), which by hydride loss form the thiopyrylium salts (35)) or on dehydrogenation produce the pseudoazulenes (36) (heterocyclic analogs of the carcinogen, benz[a]carbazole), as shown in Scheme 6.67-73 Thiochroman-4-one reacts with isatin in the presence of potassium hydroxide to form benzothiopyrano[4,3-b]quinoline-7-carboxylicacids as illustrated in Eq. (11).67J4J5 The carbethoxyhydrazone (37)is V. Dudykina and V. A. Zagorevslrii, Zh. Org. Khim. 2, 2222 (1966); Chem. Abstr. 66,75878 (1967). 63 W. E. Truco and J. A. Simms, J . Org. Chem. 22,617 (1957). 6 4 K. H. Wuensch, K. H. Stahnko, and A. Ehlers, Chem. Ber. 103,2302 (1970). 6 5 N. Bc4linger, D. Cagniant, and P. Cagniant, Tetrahedron Lett., 49 (1971). e6 F. Klages, M. Thuemmler, and M. Hocdl, Chem. Bey. 101,2153 (1968). 67 F. G. M a n n and B. B. Smith, J . Chem. SOC., 1898 (1951). 68 L. A. Aksanova, N. F. Kucherova, and V. A. Zagorevskii, Zh. Obshch. Khim. 33,220 (1963);Chem. Abstr. 59,2783 (1963). 69 N. F. Kucherova, L. A. Aksanova, and V. A. Zagorevskii, Z h . Obshch. Khirn. 33,3403 (1963);Chem. Abstr. 60,5471 (1964). lo A. Fravolini and A. Martani, Boll. Sci. Fac. Chim. Ind. Bologna 26, 227 (1968); Chem. Abstr. 70, 106414 (1969). l1 T. $2. Young and P. H. Scott, J . Org. Chem. 30,3613 (1965). 72 N. P. Buu-Hoi, A. Martani, A. Croisy, P. Jacquignon, and F. Porin, J . Chem. SOC. C, 1787 (1966). l 3 T. E. Young and P. H. Scott, U.S. Patent 3,388,133; Chem. Abstr. 69, 59213 (1968). l4 P. Cagniant and A. Deluzarche, C . R . Acad. Sci., 223,808 (1946). l5 A. Fravolini and C. Rodriguez Salazar, Ann. Chim. (Rome) 58, 1155 (1968); Chem. Abstr. 7 0 , 47334 (1969). 62
Sec. ILC]
71
THIOCHROMANONES A N D RELATED COMPOUNDS
R
converted into 4H-[ 1,2,3]thiadiazolo[5,4-c]benzothiopyran5,5-dioxides (38)with thionyl chloride76as shown in Eq. (12).
COOH
&
NNHC0,Et
0 2
(37)
N=N
so...&‘s
(12)
__f
0 2
(38)
3-Methoxymethylene thiochroman-4-one 7 7 with formamidine forms 5H-l-benzothiopyrano[4,3-d]pyrimidine, with o-phenylenediamine forms 5,T-dihydro- 1-benzothiopyrano[4,3-b][ 1,5]benzodiazepine, with 76
77
C. I).Hurd and R. I. Mori, J . Amw. Chem. S O C .77, 5359 (1955). A. E’ravolini, A. Mtlartani, and G . Grantlolini, 1301. Sca. Fac. Cham. I d . Bologna 26, 269 (1968);Chena. Bbstr. 70, 106482 (1969).
72
[Sec. 1I.C
S. W. SCHNELLER
hydroxylamine hydrochloride forms 411- 1-benzothioliyrano[ 3,4-d]isoxazole, with hydrazine hydrate forms 4H-l-benzothiopyr~~no[4,3-c]pq-razole, and with thiosemicarbazide forms I-thiocarbamoyl-9b-hydroxy3a,Bb-dihydro-4H- 1-benzothiopyranci[4,3-c]pyraz0le.~~ Thiochroman-4-ones with nialononitrile give the corresponding 4ylidenetrialo~ionitriles,~~ which undergo disproportionation when cyclized by sulfuric acid [Eq. (13)], provided a 6-methyl substituent is present to prevent ring sulfonation in preference to annelation to the kcto-ainide.80
E&NHz
+
E&NHz
R&NHz+
0
1
(13)
(39) It = C'H,
Extensive synthetic work with 7-metlioxythiocliro1na1i-4-one has led to a variety of 6-thiosteroids, particularly tI iio e s tr o g e ~ is ,* ~as, - ~ ~e.g., in Scheme 7 . 8 3 n
SCAE'MR 78
7
.
I<. C I ~ i i i p t ~ ~ and p i i ~C . I). Blanton, Trtrdietlroti Left 2489 (1964). I<:. Caiiipitignc~,H. H. Burton, C. 1).Blanton, and 8.V1'. Sclinellcr, J . Heterocycl. C'/zet)i. 8, 65 (1971). S. Fir. S(~1iiic~llcr ancl 1'. 1.2'.Clough, ,I. lfeterocycl. Cheni. 10, 1 3 1 (1973). J . C . IVtxbtra, 1\'.N . Spcckariip, U. K. I'andit, itntl 1%. 0 .Huisman, Tetraherlror~ Lett., 2781 (1966).
See. K C ]
THIOCHROMANONES
AND RELATED COMPOUNDS
73
Thiochronian-4-ones fragment on treatment \\ ith dimethylsulfoxonium iiiethylide [Ey. (14)].86 When R3 = H, both 40 and 41 are produced a t 50” I\ hereas only 40 is obtained a t room tenilwraturc; the process is believed t o involve 42.In a mechanistically siiiiilar reaction, 3-methylthiochroman-4-one yirlds 3,4,5,G-tctraliydro-3,.~,~-trimethyl3-[o-(methylthio)benzoyl]-2H- 1-benzotliiocin-&one (43).87
Photochemical react ions of thiochroman-4-one give mainly polymeric products,88 but irradiation of the corresponding sulfoxides 89 (44) and sulfonesgO(45) forms disulfides and pinacols [Eqs. (15) and (16)]. 82
83
84
85
T. Moriwakc,J. M e d . Chem. 9, 163 (1966). H. D. Hiusinan, J. (:. LVestra, W.N. Speckamp, and U. I<. Pandit, U.S. Patcnt 3,417,100; Chew Abstr. 70, 47700 (1!169). W.N. B. Kocnit, J. L. Van-Bruynsvoort, W. N. Speckamp, and H. 0. H u s man, Z’etiahedioii Lett., 2327 (1970). W. N. Spcckanip, J . G. Lt‘ostra, antl H. 0. Huisman, Tetrahedron 26, 2353 (1970).
W. N. Speckamp, J llijkink, <J A. Maasscn, and H. 0. Hirisman, Tetrahedron Lett., 2743 (1970). 87 I. W ,J Still, M S Cliaulian, antl M. T. Thoinas, Can J . Chem. 51, 839 (1973). 1’. Y. Johnson anti G. A . Bcrchtolt1,J Org. Chem. 35,584 (1970). 89 I . W.J . Still, M S Charihm, ant1 M. T Tliornas, l’ptrahedrort, Lett., 1311 (1973). 90 I . W. J. Still and M. T Thoinas, ,I. O n / . Chpvr~ 33,2730 (1968). 86
74
[Sec. 1I.D
S. W . SCHNELLER
D. REACTIONS OF THIOCHROMANS Bromination of thiochroman yields 91 the 6-bromo compound (46) which has been converted into various 6-substituted derivatives (Scheme 8). Friedel-Crafts acylation also occurs at the B - p o s i t i ~ n . ~ ~ . ~ ~ The #,&'-dioxide with N-bromosuccinimide yields 4-bromothiochroman
(46)
X = CN, COzH, COCI, COMo
SCHEME 8
1,l -dioxide.94The 8,s-dioxides with zinc/hydrochloric acidlacetic acid reform the reduced t h i o c h r ~ m a nTreatment .~~ of the thiochromans with sulfur is a route to 1,4-dithiochromanone~.~~~~~ Morin, Spry, and Muellerg8found that cyclic sulfoxides which do not possess an a-hydrogen undergo internal oxidation-reduction with oxidation of the carbon beta to the sulfur. Thus, 2,%dimethylthioP. Cagniant and Mme. P. Cagniant, C . R . Acad. Sci. 231, 1508 (1950). P. Cagniant a n d Mmo. P. Cagniant, Bull. SOC.Chim. Fr., 1560 (1961). 93 P. Cagniant and Mmc. P. Cagniant, C. R. Acad. Sci. 253,1702 (1961). 94 F. J. Lotspeich, J . Org. Chem. 30, 2068 (1965). 95 F. G. Bordwell a n d W. H. McKellin, J . Amer. Chem. SOC. 73,2251 (1951). 96 It. Maycr, Chem. Ber. 90, 2362 (1957). 97 R. Maycr and H. Damme, 2. Chem. 5, 150 (1965). 91
92
Sec. II.D]
THIOCHROMANONES AND RELATED COMPOUNDS
75
chroman 1-oxide (47) with acetic anhydride yields 48 whereas acetic anhydridelwater gave 48 and the rearrangement products 49 and 50 (Scheme 9).98Scheme 10 shows the effect of a /3-carbonyl group (51) on this r e a r r a n g e ~ n e n t .Cyclic ~~ sulfoxides with an a-hydrogen (e.g., 52) yield dehydration products via Pummerer rearrangement [Eq. (17)]. Photochemical rearrangement of 47 and 51 formed 2-isopropylbenzo[b]-
SCHEME 9
+
Ac 0 2
&Me 0 Me
\ Me SCHEME10
(52)
thiophene and 2-isopropylidenebenzo[b]thiophen-3-one, re~pectively.~~ Similar ring contraction of 3-bromothiochroman-4-01 to a benzo[b]thiophene occurslo0in aqueous dioxane. It. B. Morin, D. 0. Spry, and It. A. Mueller, Tetrahedron Lett., 849 (1969). R . A. Archer and R . S.Kii,chell, J . Amer. Chem. SOC. 88, 3462 (1966). l o oH. Hofmann and G. Salbeck, Angew. Chem., Int. E d . Engl. 8, 456 (1969). 98
99
76
S. W . SCHNELLER
E.
PHYSICOCHEMICAL
[Sec. 1I.E
THIOCHROMAN-&ONES THIOCHROMANS
PROPERTIESO F AND
The infrared spectra and dielectric constants,101*102 electr~nic,~~~-~~~ nuclear magnetic resonance (NMR),106*112-121 and mass122-126spectral data for these compounds have been analyzed. There exist numerous quantum mechanical calculations of the electronic transitions and involvement of the sulfur electron^.^^^^^^ Ultraviolet spectral determinations of the basicity of thiochroman-4-0nes~~~ allowed correlations with the corresponding chroman-4-ones. Nuclear magnetic resonance clarifies t,he conformation of the sulfurcontaining ring. Thus 3-halogen substituents in thiochroman-4-ones are G. F. Katekar and A. G. Moritz, A u s t . J . Chem. 22, 2337 (1969). A. Liittringhaus, It. Mocke, and J. Grohmann, Elektronentheor. Homoeopolaren Rindun,g Hauptjahrestag. Chem. Gee. Deut. Demokrat. Repub., 152 (1955); Chem. Abstr. 53, 3882 (1959). l o 3F.Krollpfeiffcr, Ber. 58B, 1677 (1925). l o 4M. J. Y. Folcy and N. H. 1 ’. Smith, J . Chem. Soc., 1899 (1963). lo5E. Rakosi-David, R. Bognar, and M. Raliosi, A c t a P h y s . Chim. Debrecina 10, 97 (1965); Chem. Abstr. 64, 1494 (1966). lo6D. Cagniant and 1’. Cagniant, B u l l . SOC. C h i m . Pr., 228 (1966). lo7J. Dehlor, H. Giovanelli, W. Amann, and W. Schneider, Ber. Bunsenges. P h y s . Chem. 71,655 (1967);Chem. Abstr. 68,25206 (1968). lo8G. Kresze and W. Amann, 8pectroch.im. Acta Part A 25, 393 (1969). l o gQ. Kraszc and W. Amann, Spectrochim. Acta Part A 26, 647 (1970). 110 D. E. Raltosi. M. Rakosi, J. Balint,,and R. Bognar, Acta P h y s . C h i m . Debrecim 15/16, 163 (1970); Clrem. Abstr. 75, 12884 (197 1). l l 1 K. H . Qiovanelli, J . Dohlor, and G. Hohlnoichcr, Ber. Bunsenges. P h y s . Chem. 75, 864 (1971); Chem. Abstr. 75, 135180 (1971). M. M. Dhingra, G. Govil, C. L. Khetrapal, and V. M. Vaidya, Tetrahedron Lett., 497 (1963). 113 G. F. Katokar and A . G. Moritz, A u s t . J . Chem. 20,2235 (1967). 114 A. 1%.Katritzky and B. Ternai, J . Heterocycl. Chem. 5, 745 (1968). 115 Q. Crandolini, A. Ricci, N. P. Buu-Hoi, and F. Perin, J . Heterocycl. Chem. 5, 133 (1968). 116 H. Hofmannand G. Salbecli, Tetrahedron Lett., 2587 (1969). 117 G. Kresze and W. Amann, Spectrochim. Acta Part A 26, 637 (1970). 118 M. Nishio, Chem. Pltarm. B u l l . 17, 274 (1969). 119 G. F. Katekar,J. Heterocycl. Ch,em.7 , 187 (1970). I z o J. B. Lambert, and F. R.Koeng, Org. M a g n . Reson. 3, 389 (1971). Iz1 A. Chatterjce and B. Bandyopadhyay, I n d i a n J . Chem. 11,446 (1973). l Z 2B. 1 ).Tilak, I<. G . Das, and H. M. El-Namaky, Ezperientia 23, 609 (1967). I z 3 E. S. Brodsltii, It. A. Khmel’nitsliii, A. A. Polyakova, and G. D. Gel’pern, Neftekhi,miya 9, 146 (1969);Chem. Abstr. 71, 2834 (1971). 12*A. G. Harrison, M. T. Thomas, and I. W. J. Still, Org. Mass. Spectrom. 3, 899 (1970). lZ5A. G. Loudon, A. Maccoll, and S. K. Wong, J . Chem. Soc. B , 1727 (1970). 12‘ A. G. Loiidon, A. Maccoll, and S . K. Wong, J . Chem. SOC. B, 1733 (1970). Io1
Io2
Sec. II.F]
THIOCHROMANONES AND RELATED COMPOUNDS
77
pseudo axially oriented, but 3-methyl groups are pseudo equatoria1.114*119*121 The vicinal coupling constants of the CH,-CH, moiety indicate120 the flattening of this ring. Finally, coupling between the H-3, H-4, and H-5 protons can be a valuable diagnostic indicator of the cistrans orientation of substituents in the sulfur ring.l16 l’olarographic reduction127 of thiochroman-4-one produces two waves, at 1.43 V and 1.31 V. An X-ray analysis120 of the lathr rat el^^ formed by 4-(p-hydroxyphenyl) -2,2,4-trimethylthiochroman has been reported.
F. U S E S O F THIOCHROMAN-4-ONES AND THIOCHROMANS A variety of thiochromans possess biological activity For example, 7-sulfamoylthiochroman 1,l-dioxides are effective d i u r e t i ~ s ; l ~ O - l ~ ~ thiochroman-6-acetic acids possess antiinflammatory, antipyretic, and analgesic activity;135-136 phcnethylamines from the Maiinich reactioii on thiochroman-4-ones are a - ~ y m p a t h o l y t i c land ~ ~ antidepressant ;138 4-substituted aminothiochromans are active as antihypertensives, as antidepressants, and as agents against angina pains;139-142 3,3dibromo-6-halothiochroman-4-one S-oxides exhibit antitumor characteristics;143 substituted 4-phenylthiochromari-4-01s have been prepared C. Angcllini and N. Frtli, Boll. C‘hzm. Furm. 97, 667 (1958); Chem. Abstr. 53, 11061 (1959). lZ8 I). n. MacNicol and F. R. Wilson, J . Chem. SOC. D,786 (1971). lZ9 D. D. MarNicol, J . Chem. SOC. D , 836 (196‘3). 130 J. R. Boissier and C. Malcn, Frciich Patent 1,365,504; Chcm. Abstr. 61, 14642 (1964). 131 J . R. Boissicr and C. Mulen, Frcnch Patent M2790; C h ~ m Abstr. . 62, 9113 (1965). 132 J . It. Boissier, C Dumont, J. Lcsbros, and C. Malcn, T h e m p i e 20, 1303 (1965). 133 J . T i . Boissirr, C. I h m o n t , J. Lchbros, and D. Moisy, Tlieiupze 22, 137 (1967). 134 J . R Boissier, C. Dumont, arid A . Gcradin, 4 n n . I’harin. F r . 28, 497 (1070); Chem. Abstr 74, 86038 (1971). 135 J. R. Boissier and 12. Hatouis, French Patent 2,126,182; Chem. Abstr. 78, 124449 (1973). 136 J. 12. Boissier and It. Rittouis, Gernian Patent 2,106,045; Chem. Abstr. 75, 15167.5 (1971). 137 W. Hansen, German Patent 1,913,199;Glrem. Abstr 74, 13005 (1971). 138 M. Nakanishi, T. Munakata, and S. Setogiichi, Grrman Patent 2,018,007; Chem. Abstr. 74, 13006 (1971). 139 (2. destevens, A. Halarnandarii, 1’. St rac.han, E. Donoghuc, L. Ilorfman, and C. F. Huebncr, J M e d . (‘h~na.6, 357 (1963). 140 J. R. Boissier and R Ratoilis, French Patent M7499; Chem. A6str. 75, 35743 (1971). 141 J. R. Boissier and It. Ratoilis, French Patcnt 1,584,755; Chem. Abstr. 74,11191 1 (1971). lZ7
78
S. W. SCHNELLER
[Sec. 1I.F
as oral antifertility agents; 144 and a hydantoin possessing the thiochromanone nucleus appears t o have anticonvulsant activity. 145 Many 3-dialkylaminomethyl- and 5-dialkylaminoalkylaminothiochroman-4-ones exhibit schistosomicidal a ~ t i v i t y , l ~and ~ - l a~ variety ~ of other aminothiochromans are a n t i a r n e b i ~ . l ~The ~ - ~thiochroman ~~ ring is also found in antimicrobial v i r u ~ i d e s ,insecti~~~.~~~ c i d e ~and , ~ acaricides,160 ~~ and antiedemic161and anti-inflammatory162 agents. Hexahydrothiochroman has been employed as a fuel additive,163 and several t-butyl thiochroman-4-ones have been studied for their 142
C. Malen, B. Danree, and M. Laubie, German Patent 2,017,902; Chem. Abstr.
143
M. Nishio, T. Ito, Y. Yarnada, K. Nagaoka, and N. Kanagawa, German Patent 1,958,238; Chem. Abstr. 73, 35224 (1970). R. R. Crenshaw, U.S. Patent 3,321,483; Chem. Abstr. 68,29601 (1968). H. Arnold, E. Kuohas, and N. Brock, German Patent 1,135,915; Chern. Abstr.
74, 22698 (1971).
144
58,3439 (1963). 146
S.-L. Chu and C.-C. Chang, H u a Hsueh Hsueh Pao, 24, 87 (1958);Chem. Abstr. 53, 7160 (1959).
147 S.-L.
Chu, W.-H. Chyan, and C.-C. Chang, H u a Hsueh Hsueh Pao 22, 371 (1956);Chem. Abstr. 52, 11044 (1958). 148 F. Bossert and R. Goennert, Med. Chem., Abbandl. Med.-Chem. Forschungsstaetten Hoechst. A.G. 1, 367 (1963);Chem. Abstr. 60, 9236 (1964). 148 A. B. Sen and Y. D. Kulkarni, J . Indian Chem. SOC. 34,687 (1967). 150 B. S. Kaushiva, Ann. Biochem. Exp. Med. 20, 493 (1960); Chem. Abstr. 58, 8254 (1963). 151 A. B. Sen and S. B. Singh, J . Indian Chem. S'oc. 43,521 (1966). 152 A. Mishra, A. Nayak, and M. K. Rout, J . Inst. Chem., Calcutta 42, 223 (1970); Chem. Abstr. 74, 108592 (1971). 153 H. A. Wagncr, U.S. Patent 3,158,619; Chem. Abstr. 62, 7748 (1965). 154 J. Crutze, K. Thomas, and D. Jerchel, South African Patent 6,808,173; Chem. Abstr. 72, 90290 (1970). 156 T. Ishii, and S. Ito, Japan Patent 7,019,299; Chem. Abstr. 73,66426 (1970). 156 C.Rufer,R.Albrecht,H.,J.Kesslor,andE. Schroeder,GermanPatent 1,935,685; Chem. Abstr. 74, 100049 (1971). 157 R. Albrecht, M. Muftir, and E. Schrooder, South African Patent 6,805,902; Chem. Abstr. 72, 12551 (1970). 15* M. Nishio, S. Ito, and N. Ishida, Japan Patent 7,013,816; Chem. Abstr. 7 3 45350 (1970). G. Hoerlein, G. Salbeck, K. D. Bock, and L. Emmel, German Patent 2,148,879; Chem. Abstr. 78, 159431 (1973). 160 M. D. Barker, German Patent 1,915,496;Chem. Abstr. 72,66799 (1970). 1°' M. Nishio, T. Koeda, T. Ito, and U. Shibata, German Patent 1,933,523; Chem. Abstr. 75,5709 (1971). M. Nishio, K. Ichuime, T. Ito, T. Koeda and U. Shibata, Japan Patent 7,026,099; Chem. Abstr. 73, 130890 (1970). R. A. Vere, A G A R D Conf. Proc. 1971, A G A R D -CP-84-71,11-1-1-13;Chem. Abetr. 75, 142483 (1971).
Sec. III.A]
THIOCHROMANONES AND RELATED COMPOUNDS
79
odorifero~sl~ charact,eristics ~*~~~ (the vapors of 6-t-butyl- and 6-tbut~yl-8-methylt~hiocliroman-4-o1ies resemble burning ~ a n d a l w o o d l ~ ~ ) . Thiochromans are found in some resins166 and dyes,167 thiochroman S-oxide has been used in uranium extractions,168 and 4-(p-hydroxyphenyl)-2,2,4-triniethylthiochroman forms a lathr rat el^^ with many solvents, usually in a 3 : l host to guest ratio for small molecules (ethanol or acetone) and 6:1 for larger molecules (e.g., toluene).
III. Thiochromones A. PREPARATION OF THIOCHROMONES
Two principal routes yield thiochromones. The first involves Michael addition of a thiophenol t,o a propiolic acid, followed by Friedel-Crafts cyclization of the chloride of the resultant /3-phenylmercaptoacrylic a ~ i d [Eq. ~ ~(1S)]. ~ -The ~ preferred ~ ~ cyclization catalyst is stannic
chloride (aluminum chloride can yield t h i o c ~ u m a r i n s ' ~or~ )a mixture of phosphorus peritoxide and phosphoric acid. The acrylic acid (53) has also been prepared by direct nucleophilic displacement of a chloride ion by thiophenol on P-chloroacrylic acid171 or of an ethoxide ion by N. 1'. Buu-Hoi, V. Belltivita, A. Ricci, and D. Balucani, Bull. SOC.Chim. Fr., 1210 (1966). 165 A. Ricci and N. P. Buu-Hoi, B d . SOC. Chim. Fr., 3634 (1967). 166 H. S. Bloch and H. E. Marnmen, U.S. Patent 2,657,193; Chem. Abstr. 48, 3724 (1958). I e 7 F. Arndt, W. Flemming, E. Scholz, and V. Lowensohn, Ber. 56B, 1269 (1923). 168 A. M. Rozen, Yu. I. Murinov, and Yu. E. Nikitin, Racliokhimiya 12, 355 (1970);Chem. ADstr. 73, 49060 (1970). 169 L;. Ruhemann, Rer. 46, 2188 (1913). 170 S. Ruhemann, 13er. 46, 3384 (1913). 171 S. Ruhemann, B e y . 47, 119 (1914). 172 F. Montanari and A. Negrini, Boll. Sci.Fac. Chim. Ind. Bologna 15, 50 (1957); Chem. Abstr. 51, 16451 (1957). 173 W. E. Truce and D. L. Goldhamer, J . Amer. Chem. SOC. 81,5795 (1959). lT4 N. Lozac'h, L. Legrand, and N. Bignebat, B u l l . SOC. Chim. Fr. 12, 3247 (1964). 164
80
5. W. SCHNELLER
[Sec. 1II.A
thiophenol on ethyl P - e t h ~ x y a c r y l a t e (to l ~ ~yield ~ ~ ~the ~ corresponding P-arylthioacryl ate), The second general method into the thiochrom-4-one ring involves the interaction of a thiophenol with compounds possessing a carbon atom bonded by a t least two electron withdrawing groups, usually in the presence of a dehydrating agent (phosphorus pentoxide or polyphosphoric acid). The first application of this was by Simonis and E l i a ~ land ~ ~ is illustrated in Eq. (19). The most successful active methylene substrates have been , k ? - k e t o e s t e r ~ , l/3-cyanokstones ~~-~~~ 83
diacylacetic acids,le4 acylmalonic acid esters,la5half-esters of malonic With this array of possibilities acid,186and a-acetamid~-~-ketoesters.~~~ a variety of thiochromones substituted in the sulfur ring is possible. Additionally, by changing the thiophenolic portion various benzo substituents can be realized. Thiochrom-&ones have also been prepared by the amine-promoted by elimination of hydrogen halide from 3-halothiochroman-4-ones,188 the Purnmerer reaction on thiochrornan-4-one S-oxides [Eq. ( 20)],g8 from a ring expansion of activated benz[b]thiophenes [Eq. (21)],l8’ by the reaction of o-mercaptoaryl alkyl ketones with ethyl esters of 175
W. J. Croxall and L. R. Frcimiller, U.S. Patent 2,532,291; Chem. Abstr. 45,
3421 (1951). L. Lcgrand and N. Lozac’h, Bull. SOC.Chirn. Fr., 953 (1958). 177 H. Simonis and A. Ellas, Ber. 49, 768 (1916). 178 Farbenfabrikcn Bayer Akt.-Ges., British Patent 803,803; Chem. Abstr. 53, 11412 (1959). 179 F. Bossert and H. Hanocka, Gorinan Patent 1,089,773; Chem. Abstr. 55, 27379 (1961). lQ0 F. Bosscrt, Justus Liebigs Ann. Chern. 680, 40 (1964). H. Sirnonis and A. Elias, J . Chem. SOC.110, 499 (1916). l a a F. Sauter and P. Stuctz, Monatsh. Chem. 98, 1962 (1967). 183 F. Bossert, Tetrahedron Lett., 4377 (1968). l Q 4 Farbenfabrikcn Bayer Akt.-Ges., British Patont 804,689; Chem. Abstr. 53, 11413 (1959). 1 8 5 F. Bossert, German Patent 1,095,842;Chern. Abstr. 57, 11170 (1962). 186 A. Ruwet, A. Pourvcur, and M. Renson, Bull. SOC. Chirn. Belge 79, 631 (1970). l Q 7 F. Bossert, Tetrahedrcm Lett., 555 (1971). F. Amdt, Ber. 58B, 2702 (1925). D. G. Hawthorne and Q. N. Porter, Aust. J . Chem. 19,1751 (1966). 176
Sec. III.B]
THIOCHROMANONES
AND RELATED COMPOUNDS
81
aliphatic or aromatic acids in the presence of sodium hydride,lg0from the rearrangements of dihydrothiocoumarirla,l"l and by the condensation of thiophenolic ethers with benzaldehyde.192 0
0
B. R'EACTIONS OF THIOCHROMONES 'I'hiochromones are readily brominated to the corresponding 2,3dibromothiochroman-4-ones,177~193 which are transformed back to thiochromones in ~ a t ~ eBoiling r . ~ ~alkalis ~ rupture the sulfur ring of thiochromones to form o-mercaptobenzoic acids;177phosphorus pentasulfide forms the thioketone analog [Eq. ( 2 2 ) ] . Furthermore, thiochroniones undergo typical condensation r e a c t i o n ~ l at ~ ~the ~~~~ carbonyl center (usually after conversion into the thioketone) as in the preparation of the esters (54) ; they form the 4,4-dichloro-4H-l-benzothiopyran ( 5 5 ) in the presence of dichloromethyl methyl ether,lg6 thionyl c h l ~ r i d e ,and ~ ~ oxalyl ~ . ~ ~ch10ride.l~~ ~ The chlorine atoms 55 are easily displaced by n ~ c l e o p h i l e or s ~removed ~ ~ ~ ~ by ~ ~copper bronze to yield197.199di(thioflavy1enes). Lewis acids convert thiochromones into thiocoumarins while alkylation affords 4-alkoxy-1-benzothiopyrylium salts [Eq. (23)].'01 G. Jongebreur, Pharm. Weekbl. 86, 661 (19.51);Chem. Abstr. 47, 2172 (1953). Herbertz, H. Waintioff, and F.Korte, 2. Naturforsch. B 23, 312 (1968). lg2 K. Auwers and F. Amdt, Ber. 42, 2706 (1909). l g 3 T. J. Speaker and P. J. Jannlte, J . f'harm. Sci. 54, 1073 (1965). l g 4 A. Schoenberg and E. Fresc, B e r . 96, 2420 (1963). l Q 5 E. Frese, German Patent 1,241,438; Chem. Abstr. 68,68887 (1968). lg6 I. Farkas, B. Costisella, M. Ralcosi, H. Gross, and R. Bognar, Chem. Ber. 102, 1333 (1969). l g 7 A. Schonberg and W. Asker, J . Chem. SOC., 272 ( I 942). l g 8 K. Jnnghans and A. Schoenberg, German Patent 1,295,548; Cliem. Abstr. 71, 38826 (1969). 19@ A. Schonborgand S. Nickel, Ber. 67B, 1795 (1934). 2oo G. P. Guillouzo and N. Lozac'h, Bull. SOC. Chim.Fr., 1624 (1962). 201 A . I. Kiprianov and A. I. Tolmachev, Z h . Obshch. Khim. 29, 2868 (1959); Chem. Abstr. 54,12126 (1960). lgO
l g 1G.
82
[Sec. 1II.C
S. W. SCHNELLER R
0
0
OMe
C. PHYSICOCHEMICAL PROPERTIES OF TRIOCHROMONES Infrared evidence of bond strengths and charge distributions 202 have been compared with similar data for 1-thiocoumarin, 1-selenocoumarin, 2-thiocoumarin, and 2 - s e l e n o c o ~ m a r i n .Ultraviolet ~~~ datazo4 have been correlated with extensive molecular orbital calculations.205-209 Such calculationszo9 indicate that electrophilic substitution should occur a t C-3 and nucleophilic or radical substitution a t C-2. Nuclear magnetic resonance 210*z11and mass spectral 212 data are available. As R. Mecko, R. Mocke, and A. Luttringhaus, 2. Naturforsch. B 10, 367 (1955). A. Ruwet and M. Renson, Bull. Soc. Chim. Belge 79, 89 (1970). 204 J. Schmutz, H. Lauener, R. Hirt, and M. Sane, Helv. Chim. Acta 34, 767 (1951). 2 0 5 J . Fabian, A. Mohlhorn, and R . Mayer, 2. Chem. 5 , 22 (1965). 208 P. H. Given, S. Guha, J. R. Jones, and R. Wedel, Nature (London) 206, 184
202
203
(1965). J. Fabian, A. Mehlhorn, J. Bormann, and R. Mayor, Wiss. 2. Tech. Univ. Dresden 14, 285 (1965);Chem. Abstr. 64, 9072 (1966). 208 G. Kresze and W. Amann, Spectrochim. Acta Part A 24, 1283 (1968); Chem. Abstr. 69, 72434 (1968). A. I. Tolmachev, G. G. Dyadyusha, and L. M. Shulezhko, Teor. Eksp. Khim. 6, 185 (1970);Chem. Abstr. 73,55511 (1970). 210 R. H . Martin, N. Defay, F. Geerts-Evard, P. H. Given, J. R. Jones, and R. W. Wedel, Tetrahedron 21, 1833 (1965). 211 G. Kresze and W. Amann, Spectrochim. Acta Part A 26, 637 (1970); Chem. Abstr. 72, 131894 (1970). 212 D. Schumann, E. Frese, and A. Schoenberg, Chem. Rer. 102, 3192 (1969). 207
Sec. III.D]
THIOCHROMANONES AND RELATED COMPOUNDS
83
in the thiochroman-4-one case (Section 11,E), thiochrom-&one S,Sdioxide exhibits two polarographic waves (-0.431 V and -1.096 V) assigned to reduction of the 2,3-double bond (first wave) and reduction of the carbonyl (second wave).213Spectrophotometric values have been determined for many t h i o c h r ~ m o n e s .The ~ ~ ~variation * ~ ~ ~ in the rates of hydrogen exchange a t the 3-, 6-, and 8-positions of thiochromone has been evaluated as a function of the acidity of the medium.216
D. TJSES
OF
THIOCHROMONES
A very significant application of thiochromones is the preparation of materials related to cyanine dyes217.218and pigments.219 The thiochronione ring system has been incorporated into s c h i s t o s o m i ~ i d a l ~ ~ ~ - ~ ~ ~ and bacteriostatic agents 226 and into materials potentially useful in the treatment of arterial pressure and systolic discharge,227 capillary allergic asthma and a n a p h y l a x i ~ , and ~ ~ ~hypoten*~~~ ion.^^^ Structures of the type 56 have been prepared from thiochromones for their potential estrogenic and antiestrogenic CHAr
(56) 213 214
N. Shinriki, Ynkugaku Zasshi 88, 1529 (1968);Chem. Abstr. 70, 73558 (1969). A. I. Tolmachcv, L. M. Sulezhko, and A. A. Kisilenko, Zh. Obshch. K h i m . 37,
367 (1967);Chem. Abstr. 67,53984 (1967). I. Degani, R. Fochi, and G. Sputa, Boll. S c i . Fac. C h i m . In,d. Bologna 26, 3 (1968);Chem.Abstr. 70, 3131 (1969). 21E A. R. Katritzky, U. Bressel, and J. R. Lea,J. Chem. Soc. B., 1 1 (1971). 217 A. I. Tolmachev and V.P. Stribnaya, Zh. Obshch. KIkim. 32, 383 (1962);Chem. Abstr. 58, 1446 (1963). 218 A . I. Tolmachev, Zh. Obshch. Khim. 30, 2884 (1960); Chem. Abstr. 55, 16538 215
(1961). 1). G. Wilkinson, British Patent 851,571; Chem. Abstr. 55, 10917 (1961). 2 2 0 17. Bossert and R. Gonnort, German Patent 954,599; Chem. Abstr. 53, 6257 (1959). 221 Farbenfabriken Baycr A.-G., British Patent 805,870; Chem. Abstr. 53, 12306 (1959). 222 F. Bossert, H. Henecka, and 1%.Gonnert, German Patent 1,024,981; Chem. Abstr. 54, 7740 (1960). 223 R. Gonnert, B u l l . WHO 25, 702 (1961). 2 2 4 K. Gonnert and H. Koelling, Drugs, Parasites, Hosts, Sylmp., Middle.sex Hosp. illed. School, 29 (1962);Chwn. Absfr.60, 7349 (1964). 2 2 5 J . l’ellegrino and J. Faria, A m e r . J . Trop. ilded. H y g . 14, 363 (1965); Chem. Abstr. 63, 1084 (1965).
219
84
[Sec. 1V.A
S. W . SCHNELLER
IV. Isothiochromans and Isothiochromanones
A. PREPARATION OF ISOTHIOCHROMANONES AND ISOTHIOCHROMANS Reaction between benzylmercapt,ans and haloacetic acids yield beiizylmercsptoacetic acids (57) which, via their acid chlorides, undergo an intramolecular Friedel-Crafts cyclization to produce isothiochromanones as in Eq. (24).233-235 Attempts to cyclize 57 with sulfuric acid, CH,SH
b
H
CH,SCH,COOH
+ XCH,COOH
- $$ R
1. ROC'lp 2. .4I(YJ/CS2
'
@ b 4 )
R (57)
as in the conversion of P-arylmercaptopropionic acids into thiochroman4-ones, produced resinous materials,233a characteristic of isothiochro-
manones in strong acid. Homoxylylene dibromide 236 (58)with potassium sulfide conveniently yields i s o t h i o ~ h r o m a n . ~Two ~ ~ -further ~ ~ ~ preparative routes t o isothiochromans involve a Friedel-Crafts procedure T. Narnbara, Y . Takcmori, and S. Okamoto, Yakugaku Zasshi 81, 1 (1961); Chem. Abstr. 55, 12392 (1961). 227 C Malen, B. Danreca, and M. Laubrie, German Patent 2,017,902; Chem. Abstr. 74,22698 (1971). 228 C. Malcn and P. Sesnoyrrs, British Patent 1,158,473; Chem. Abstr. 72, 43450 (1970). 229 It. Hazard and J. King, German Patent 2,004,125; Chem. Abstr. 73, 77057 (1970). 230 12. Hazard and J. King, German Patent 2,006,196; Chem. Abstr. 74, 42279 (1971). 231 C i . Jongebreucr, Arch. Int. Pharmacodyn. 90, 384 (1952);Chem. Abstr. 47, 760 (1953). 2 3 2 J. H. Fricd, U.S. Patent 3,506,654; Chem. Abstr. 73, 3812 (1970). 2 3 3 1'. Cagriiant and P. Cagniant, Bull. Soc. China. F r . , 1998 (1959). 214 R. 1,csscr and A. Mrhrlandor, Ber. 56B, 1642 (1923). 2 3 5 13r1stol-Mcycrs Co., Notherlands Patent 6,510,990; Chem. Abstr. 65, 8881 (1966). 2 3 6 J. V. Braun and F. Zobel, Ber. 56B, 2142 (1923). 237 V Q. Holliman and F. C . Mann, J . Chem. Soc., 34 (1945). 238 S.F. Birch, lt. A . Dcan, and E. V. Whitohcad, J . Inst. Petrol. 40, 76 (1954). 239 J . A . Paust and M. Hahyun, U.S. Patent 3,438,995; Chem. Abstr. 71, 13126 226
240
( 1 969). S. F. Birch, 1%.A. Dean, and E. V. Whitehead, J . Org. Chem. 19, 1449 (1954).
Sec. 1V.B.13
THIOCHROMANONES AND RELATED COMPOUNDS
85
[Eq. (Ei)],241 a nd an acid-promoted olefin cyclization [Eq. (26)].242-244 Finally, the photocycloatlditiori of thiobenzophenone with propiolic acids produced the 1-phenyl compounds 59.245
Ph
(58)
(59)
H. = CN, C02H, CH,OH, Ph
B. REACTIONS OF ISOTHIOCHROMANONES A N D ISOTHIOCHROMANS 1. Isothiochrorncmones Wolff-Kishner reduction of isothiochromanone 233 gives the expected isothiochroman; for Clemmcnsen conditions, conflicting reports indicate i s o t h i o c l ~ r o r n a nor~ ~1 ,~3-dil1ydro-l-methylbenzo~c]tl1iophene~~~ ~ as tdir products. Bromination may produce 3-bromoisothiochronianone, although this is not certain,234while Crignard reagents235 yield 4substituted isothiochroman-4-01. Scheme 11 summarizes other reactions of this ketone and indicates its versatility as a starting H. Boc,iimc, L. TIIS,mid R . IJntcdinlt, Bw. 97, 179 (1964). H . J . BaBernntlN.I)ost, H e r . Trtcv.C'him.68, 1 1 4 3 ( 1 9 4 9 ) . 243 €1. J . Bakernncl (;. J dcJong, Rec. Tiat'. C h ~ n ,70, . 377 ( 1 9 3 1 ) . 2 4 4 E. N. liaraulo\u, I ). Sh. Mtil,tnova, and G. I>. Gal'pern, k ' i ~ ? ?Seraorg. ,~. Sorlrrzh h'eftyakh p l o d . , A k a d . X a u k LSLSSI?., Bashkir. F ~ l z n l . , P / (!z'/?t'P/) ~!'altfh. Ufa, 164 (1937);Chem.Abstr 55, 1497 (1961). 245 , T. Koizwrii, Y. Ohnishi, ant1 G . Tsuchihashi, Japan Patent 7,301,077; bstr. 78, 147803 (1'373). 2 4 b , J . V. Brain and I<. iVcissbach, Uer. 62B, 2416 (1929). 241
242
86
S. W. SCHNELLER
[Sec. IV.B.l
SCHEME 11
The oxime (60) (Scheme 11) undergoes the Beckmann rearrangement t o 3,5-dihydr0-4,1-benzothiazepin-2(1H)-one.247 Several isotliiochroman-4-ones rearrange photochemically to thiochroman-3-ones (61) via the intermediate spiro-thietan-3-one (62) [Eq. (27)].248*249The ylid (63) is transformed into l - i n d a n ~ n ephoto~~~ chemically.
00
1
R
(63) 247 248
249 250
R. K. Hill and D. A. Cullisen, J . Amer. Chem.SOC.95, 2923 (1973). W. C. Lumma and G. A. Berchtold, J . Amer. Chern.SOC.89, 2761 (1967). W. C. Liirnma and G. A. Berchtold, J . Org. Chem. 3 4 , 3 4 (1969). It. H. Fish, L. C. Chow, a n d M. C. Caserio, Tetrahedron Lett., 1259 (1969).
Sec. IV.B.21
THIOCHROMANONES AND RELATED COMPOUNDS
87
Isothiochromanone is easily oxidized to its S,S-dioxide using potassium ~ e r m a n g a n a t e Reactions .~~~ of this sulfone are shown in Scheme 12.251 H
OH
0
COOH
CH2S02CH3
Me M e
SCHEME 12
2 . Isothiochromans
Chlorination or bromination of isothiochroman yields the corresponding 1-halo derivative^,^^^.^^^,^"^ which are intermediates for numerous isothiochromans since the halogen atoms are benzylic and, therefore, very susceptible t o nucleophilic substitution. Thus, l-chloroisothiochroman wth mercuric cyanide gives the 1-cyano derivative, which provides the 1-carboxylic acid, 1-ester, and the 1-amide.239~252 The remaining 1-H of the 1-cyano derivative is acidic and, with base,
251
(i. l’agani and S. Maiorana, Chzm. I d . ( M ~ l a n49,1347 ) (1967);Cheni. Abstr. 69,
2814 (1968). H. Boehrnc, L. Tils, and B. Unterhalt, Arch. I’hnrm. (Weinheim) 297, 325 (1964);Cherra. ADstr. 61, 8265 (1964). 253 H. Bochmr, I<.l’riesner, and B. Unterhalt, Arch. Pharm. ( Weinheim) 299, 931 (1966);Chem. Abstr. 66, 37728 (1967).
252
88
S. W . SCHNELLER
[Sec. V.A
forms a potent nucleophile susceptible to the usual reactions, e. g., as in Eq. (28), to produce materials useful in further ~ y n t h e s i s . ~ ~ ~ - ~ ~ ~ Isothiochroman undergoes simple alkylation a t the sulfur to form sulfonium salts,237is ring-opened and desulfurized with Raney and is ring-opened to 2-(0-toly1)ethyl mercaptan with Ca(NH3)6.258
C. PHYSICOCHEMICAL PROPERTIES OF ISOTHIOCHROMANS X-ray analysis demonstrates the boat conformation is preferred for isothiochroman S , S - d i o ~ i d e s .Ultraviolet,261 ~ ~ ~ * ~ ~ ~ NMR,262and mass spectral 263 data have also been reported.
D. USES OF ISOTHIOCHROMANS 1-Substituted and 1,l-disubstitutcd derivatives synthesized as discussed in Section IV,B,2 possess potential biological ( a n t i t u ~ s i v e , ~ " * ~ ~ ~ sedative,265muscle relaxant 265) a ~ t i v i t y . ~ ~ ~ . ~ ~ ~ * ~ ~ ~
V. Benzothiopyrans A. PREPARATION OF ~H-~-BENZOTHIOPYRANS Dehydration o f thiochroman-4-ols, generally with potassium hydrogen sulfate, is the most convenient preparation of 2H- l-benzothio[Eq. (29)]. Further met,hods to derivatives of 4 involve t,he pyrans,266*267 Vilsmeier formylation o f thiochroman-4-one to P-chlorovinyl aldehydes H. Boohmc and K. Lindenberg, Arch. Pharna. (Weirheim) 301, 544 (1968); Chem. Abstr. 69, 106524 (1968). 2 5 5 H. Boohmo, I<. Lindenberg, and B. Unterhalt, Arch. Pharm. ( W e i n h e i m ) 301, 580 (1968); Cliem. Abstr. 69, 106452 (1968). 256 H. Boehme, K. Lindcnbcrg, R. Pricsncr, and B. Unt,rrhalt, Arch. Pharm. (Wei7eheim)301, 326 (1968); CIiein. Abstr. 69, 51937 (1968). 257 H. Boehme and K . Lindenberg, Arch. Pharm. (Weinheint) 303, 229 (1970); Chem. Abstr. 73, 14621 (1970). 258 J. van Schooten, J . Knotnerus, H. Boer, and P. M. Duinker, Rec. Trav. Chim. 77, 935 (1958). 259 D. A. Whiting and D. A. Pulman, J . Chem.Soc. D., 831 (1971). 2 6 0 1). A. Pulman and D. A. Whiting, J . Cliem. Soc., Perkin Trans. 1, 410 (1973). 261 V. Georgian, Ckem. I d . (London,), 1480 (1957). 262 S. H. Smallcombe, R. J. Holland, 12. H . Fish, and M. C . Caserio, Tetrahedron Lett., 5987 (1968). m3 P. Natalis, Bull. C1. Sci., Acad. Roy. Belg. 48, 554 (1962); Chem. Abstr. 58, 405 (1963). 254
See. v.Bl
THlO(’HROMAN0NES A N D RELATED COMPOUNDS
89
of the type 64,268treatment of thiochronian-4-one S,S-dioxide LL ith sodium hydride followed by phcnyl isocyanate resulting in 65,269the cycloaddition of diniethyl acetylcnedicarboxplate with cycloheptatrieriethione forming the diestcr 66,270and the rc;xtion of aromatic a r n i n ~ s ~ ~ ~ arid tliiols 2 7 2 with 1 -bcnzothiopyrylium salts.
(29)
C1
OH
B. PREPARATION OF ~ H-~ -BEN Z O T H IO P Y R A N S Aryl Grignard reagents with 1-benzothiopyrylium salts yield 411- 1benzothiopyraris [Eq. ( 30)].271As mentioned in Section II,D, Pummercr I’h
reaction conditions convert 2-methylthiochroman S-oxide into 8methyl-411- 1-benzothiopyran9 8 while 411-1-benzothiopyrans have been 264
265 266
H. Bochme, Ckrman Patcnt 1,215,727; Cliena. Abstr. 65, 15337 (l!IG6). H. Bochmc and K. Lindenbvrg, Arch. Pharm. ( W e m h e m ) 301, 584 (1968); Chem. Abstr. 70, 3764 (1969). M. M. Dhingra, G. Govil, C. L. Khctrapal, and V. M. Vaidya, Tetrahedron Lett.,
497 (1963). S . Itossi and C . Pagani, Tetrahedron Lett., 2129 (1966). 268 M. Weissenfels, H. Schimg, and G. Huchsam, 2.Chem. 6, 471 (1966). 269 H. Zinncs and N. Lindo, German Patent 2,226,298; Chem. Abstr., 78, 124450 (1973). 270 T. Machiguchi, M Hoshino, S. Ebine, and Y. Kitahara, Chem. C07?ZWbun., 196 (1973). 271 A. Luttringhau5, N. Englrhard, anti A . Kolb, J u s t u s Loebigs Ann. Chetn. 654, 189 (1962). 272 13. 1). Tilalr and C . ‘I?. Panse, IrLdzan J . Chem. 7, 315 (1969); Chem. Abstr. 71, 21993 (1969). 267
90
9. W. SCHNELLER
[Sec. V.D
reported as ring tautomers of o-mercaptohydrocinnamonitriles [Eq. ( 31)].273 X I
X = CO,Et, CN
c.
PREPARATION O F
lH-2-BENZOTHIOPYRANS
The usual synthetic entry into this ring system ( 6 )is by the dehydration of isothiochromanols.274Compounds 6 are also available via the photochemical reaction of thiobenzophenone with acetylenic compound~.~~~
D. REACTIONS O F 2H-l-BENZOTHIOPYRANS 2H- 1-Benzothiopyrans with catalytic amounts of acid undergo disproportionation to thiochromans and benzothiopyrylium salts. I n the case of 3,4-dimethyl-2H- 1-benzothiopyran, intermolecular hydride transfer yields an 85:15 mixture of cis- and trans-3,4-dimethylthiochroman [Eq. (32)]276 and the 3,4-dimethylbenzothiopyryliumion. An intermediate bridged sulfonium ion has been suggested to be responsible for the stereochemical control of this reaction.276Bromination of 2H-1..Me
benzothiopyran S,S-dioxide in acetic acid yields the t r a n s - d i b r ~ m i d e . ~ ~ ~ Reaction of 4 with thionyl chloride followed by perchloric acid produces high yields of 1-benzothiopyrylium perchlorates 278 (e.g., Section V1,A). G. W. Stacy, D. L. Eck, antl T. E. Wollner, J . Org. Chem. 35,3495 (1970). C. C. Price, M. Hori, T. Parasaran, and M. Polk, J . Amer. Chem. SOC.85, 2278 (1963). 275 A. Ohno, T. Koizumi, Y. Ohnishi, and G. Tsuchihashi, Tetrahedron Lett., 2025 (1970). 276 B. D. Tilak, R. B. Mitra, antl Z . Muljiani, Tetrahedron 25, 1939 (1969). 277 G. Pagani, S. Maiorana, and S. Bradamante, Chim. I d . (Milan)53,363 (1971), Chem. Abstr. 75, 87999 (1971). 276 A . I. Tolmachev and V. P. Sribnaya, Z h . Obshch. Khim. 33, 3864 (1963); Chem. Abstr. 75, 13351 (1964). 273 274
Sec. V.D]
THIOCHROMANONES AND RELATED COMPOUNDS
91
4-Ethoxy-2H-1-benzothiopyranwith dichlorocarbene yields the dichlorocyclopropane (67),279*2n0 which in the presence of hot quinoline279produces the thiochromone (68), or with rnethoxidezn0forms the ring-expanded benzo[b]thiepin (69) and 2H-1-benzothiopyran (70), as in Scheme 13. Reaction of dichlorocarbene with the simple 2H-1-benzot>hiopyran(4) produces 281 the dichloromethyl derivatives (71) and (72) of Eq. (33).
(4)
(71)
(72)
Considerable work has been carried out on the aromatic character of the 2-anion (73).282The S,S-dioxide of 2H-1-benzothiopyran adds diazomet>haneto yield 74 which is converted into 75 upon bromination/ d e h y d r o b r o r n i n a t i ~ n .Compound ~~~ 75 also results from the hydrogen 279
280
281 2u2
2u3
W. E. Parham and M. D. Rhavsar, J . Org. Chem. 29, 1575 (1964). W. E. Parharn and D. G . Wcetman, J . Ory. Chem. 3 4 , 5 6 (1969). W. E. Parham and R. Koncos, J . Amer. Chem. SOC.83, 4034 (1961). S. Bradamante, S. Mttiorana, A. Mangia, and G. Pagani, J . Chem. SOC.B , 74 (1071). G . Pagani and S. Maiorana, Chim. I n d . (Mzlan)53,469 (1971);Chem. Abstr. 75, 48829 (1971).
92
S. W. SCHNELLER
[Sec. V.F
HN-N
(76)
(77)
peroxide oxidation of 76, itself obtainable from 3-formylthiochroman4-one and h y d r a ~ i n eCompound .~~~ 64 affords heterocyclic compounds, of which structure 77 is a typical example.284
E. REACTIONS O F 4H-1-BENZOTHIOPYRANS These reactions are virtually limited to molecules possessing an ylidene fuiictionality a t the 4-carbon, formally derived from thiochromone condensations with active methylene compounds (e.g., see Section III,B).194,195,285
F. REACTIONS OF IH-2-BENZOTHIOPYRANS Hydrogenation of 1,4-dimethyl-lH-2-benzothiopyranproduces, as expected, cis-1,4-dimethylisothiochroman,the S,S-dioxide of which exists in the boat conformation.26oAs with 2H-1-benzothiopyran, the anion formed from the 8,s-dioxide of 6 shows considerable delocalization and potential aromaticity.286Treatment of 1-substituted 1H-2benzothiopyrans with thionyl chloride followed by perchloric acid yields 1-substituted 2-benzothiopyrylium salts,287and Raney nickel desulfurization produces indane structure^.^^^^^^^ Finally, the enamine 284
285
28G 207
289
A. Ricci, D. Ralncani, C. Rossi, and A. Croisy, Boll. S c i . Pac. ChLm. Ind. Bologna 27,279 (1969);Chem. Abstr. 70, 111328 (1970). J. A. VanAllan, C. C. Petropoulos, G. A. Reynolds, and D. P. Maier, J . Heterooycl. Chern. 7,1368 (1970). S . Brrtdamnntr, A. Mangia, and G . I'ngani, J . Chem. SOC.B,546 (1971). C. C . Pricc and I). M. Follweilrr, J . Org. Chern. 34, 3302 (1969). D. J. 1)ijlrsnian cmd 0. T. Ncwhold, .I. Chem. SOC , 13 (1932). J . J. Broun a n d G . T. Ncwboltl, .I. Chern. SOC., 4397 (1952).
Sec. V.H]
THIOCHROMANONES A N D RELATED COMPOUNDS
93
(78) provides an uniisnal route to benzo[c]thiophenes, as in Eq. (34).290
G. PHYSICOCHEMIC’AL PROPERTIES OF BENZOTHIOPYRANS Ultraviolet spectra,zgl~zgz dipole moments,2g1 quantum chemical analysis,293~294 and photochromism 295 have been reported.
H. USES OF BENZOTHIOPYRANS Cyanine and polymethine benzothiopyran dyes (e.g., 79) have been prepared.296-298Thc polyrnethine dyes are particularly stable to heat and to light, possess higli infrared absorption coefficients, and have
5-
S
-(‘H
x
\V N. Spc,ckainp, F. H. M. Dcckcrs, and H. llulslnan, J . Chem.Soc. U , 1.521 (1O7O). 291 E. N. Kharlanlo\a, E N (:iir’p:tnova, and V. G. Kherchenko, Zh. Strukt. h’lr~nr 12, 637 (1971);( ’ l r ~ n t A h t r . 75, 166418 (1971). 2 q 3 J Iiabiun ant1 ( i I,aban, ’l’druhed/oti 25, 1441 (1969). 293 L. L i u i a ~and ~ i V ‘I‘:wl(l~~i,J.Jlol.Spectr.osc. 25, 113 (1968). 284 L. L i i n a u i and F T r l d ( l t - i , Cors, 8Ye/izcn.C‘hiin , 88 (1968);Gheni. ilbstr. 71, 69937 (1969). 295 I<.S. Heckcr and J . I
94
S . W . SCHNELLER
[Sec. V1.A
found use in “&-switching” of lasers.296Benzothiopyrans may possess insecticidal properties 299 and be useful as psychotropic agents 300,301 of general structure 80. CH(CH,),Y I1
VI. Benzothiopyrylium Salts A. PREPARATION OF BENZOTHIOPYRYLIUM SALTS The 1-benzothiopyrylium salts are best prepared from the easily The common accessible thiochroman-4-one [Eq. ( 35)].6*51.52*302-304 dehydrating agents include potassium hydrogen sulfate and phosphorus p e n t o ~ i d e ~ ~ * ~ ~ ~sulfuryl - ~ ~ ~ wchloride/perchloric hile a ~ i d ~ ~ * ~ and trityl perchlorate6 have been useful as hydride extractors. Another method involves the cyclization of p-ketosulfides (e.g., 81) or /I-arylthioacroleins (82) with perchloric acid [Eq. ( 36)].3059306
H. C. Patel, Diss. Abstr. B 30,5434 (1970). T. Tsujikawa,K. Tsukamura, Y. Nagawa, and Y. Saji, Japan Patent 7,364,471; Chem. Abstr. 78,111131 (1973). 301 T. Tsujikawa, K. Tsukamura, Y. Nagawa, and Y. Saji, Japan Patent 7,328,472; Ch,em.Abstr. 78,159428 (1973). 302 A. Luttringhaus and N. Engelhard, Naturwissenschuften 44,584 (1957). 303 A. Luttringhaus and N. Engelhard, Chem. Ber. 93,1525 (1960). 304 T. Hashimoto, I<. Kanai, H. Kitano, and K. Fukui, Nippon Kagaku Zusshi 86, 438 (1965); Chem. Abstr. 63,11497 (1965). 306 B. D. Tilak and G. T. Panse, IndianJ. Chem. 1, 191 (1969). 306 N. Engelhard and A. Kolb, Justus Liebigs Ann. Chem. 673,137 (1964). 29e
3oo
Sec. VI.B]
THIOCHROMANONES AND RELATED COMPOUNDS
95
PhSCH+'H('HO (82)
Similarly to Eq. (35) for the l-benzo series, 2-benzothiopyrylium salts are available from isothiochromanone.276~303~304 B. REACTIONS OF BENZOTHIOPYRYLIUM SALTS 1-Benzothiopyrylium salts with nucleophilic agents yield 2H-1- and 4 H - 1 - b e n z o t h i o p y r a n ~ ,while ~ ~ ~ phenyllithium gives l-thianaphthalenes308 (83) which, according Lo NMR spectra and dipole moments, are believed to be highly conjugated. l-Benzothiopyrylium salts (7) t
N Me, It
I
Ph
(83)
(84)
react with aromatic amines303 forming 84, are oxidized309 to thiochromones, thiocoumarins, and benzo[b]thiophenes with manganese dioxide, and condense with compounds possessing an active methylene or methyl group to yield dyes.310-313 307
A. Luttringhaus, N. Engelhard and A. Kolb, Justus Liebigs Ann. Chem. 654,
308
C. C. Price, M. Hori, T. Parasaran, and M. Polk, J . Amer. Chern. SOC.85, 2278
189 (1962). (1963).
I. Degani and R. Fochi, Ann. Chim. (Milan)58,251 (1968). 310A.I. Kiprianov and A. I. Tolmachev, Z h . Obshch. Khim. 30, 638 (1960);
300
Chem. Abstr. 54, 24703 (1960). A. I. Tolmachev and V. P. St,ribnaya, Zh. Obshch. Khim. 32,383 (1962);Chem. Abstr. 58, 1446 (1963). 312 B. 1). Tilak and S. K. Jain, In,dianJ. Chem. 7,17 (1968). 313 G. A. Reynolds and J . A. VanAllan, J . Heterocycl. Chem. 6, 623 (1969). 311
96
S. W. SCHNELLER
[Sec. V1.D
Phenyllithium also converts 2-benzothiopyrylium salts t o stable 2thianaphthalenes 274 (isomers of 83) which possess NMR spectra resembling that of an aromatic system. Formation of 1,l’-dihydro-2,2’dithia-1,l’-binaphthyl (85) is possible from the one-electron reduction o f 2-benzothiopyrylium salts.
C. PHYSICOCHEMICAL PROPERTIES OF BENZOTHIOPYRYLIUM SALTS Ultraviolet and NMR spectroscopic determinations are available of the pK and cationic stability of both isomeric (7 and 8) salts.315-318 The existence of a sulfonium sulfur in a conjugated system has been of molecular orbital interest, and some of these data have been correlated with electronic s p e ~ t r a . ~The ~ ”NMR ~ ~ ~spectral data 323.324 for both 7 and 8 have been reported, and in the former case the protons ct and y t o the sulfonium center are the most deshielded. Further, the NMR indicates considerable conjugation through the sulfur in the 1-benzothiopyrylium system.324
D. USESOF BENZOTHIOPYRYLIUM SALTS These salts have frequently been used to prepare thiocyanine C. C. Price, M. Siskin, and C. I<. Miao,J. Org. Chem. 36 974 (1971). J. Dcgani, R. Fochi, and G. Spunta, Boll. S c i . Pac. Cham. I n d . Bologna 23, 243 (1965);Chem. Abstr. 63, 13050 (1965). 316 J . Degani, R. Fochi, antl C. Vincenzi, Boll. S C I .Fac. Chim. I n d . Bologna 23, 21 (1965);Chem. Absfr.63,8137 (1965). 317 M. Renson and P. Pirson, Bull. SOC. Chem. Belges 75,456 (1966). 318 J. Degani, 12. Fochi, and G. Spunta, Gazz. Cham. Ital. 97,388 (1967). 319 T. E. Young and C. J. Ohnmacht, J . Org. Chem. 32,444 (1967). 3 2 0 J. Fabian, A . Mehlhorn, antl R. Zahradnlk, Theor. Chzm. Acta 12, 247 (1968). 321 J. Fabian, A. Mohlhorn, antl R. Zahradnik, J . P h y s . Chewi. 72, 3975 (1968). 322 J . Fabian, I<. Fabian, and H. Hartmann, Theor. Cham. Acta 15, 319 (1969). 323 R. Zahradnik and .J. Kontcclry, Collect. Czech. Chem. C o m m u n . 28, 1117 (1963). 324 T. E. Young and C. J. Ohnmacht, J . Org. Chern. 32, 1558 (1967). 314 315
Sec. Vl.D] THIOCHROMANONES A N D
RELATETI COMPOUNDS
97
H ,(' I
dyes325,326(e.g., 86) arid they have also found application as organic photoconductors 327 and electrophotographic sensitizers.328
325
B. 11. Tiluli, I n d . Chkm. Udge 32, 50 (1967); C'hrm. A6str. 70, 79132 (1969).
326
R.Wizlngrr, E.tperrerrtza 1, 2') (1943).
327
328
J. A. VanAllan, E'rcmcti Patcmt 2,005,060; C h ~ mAbstr. 73, 115063 (1970). G. A . Reynolds and ,J. A. VanAllan, U.S. Patent 889,023; Chem. Abstr. 75, 114836 (1971).
This P a ge Intentionally Left Blank
Thioureas in the Synthesis of Heterocycles T. SCOTT GRIFFIN, THOMAS S. WOODS, AND DANIEL L. KLAYMAN
Division of Medicinal Chemiatry, Walter Reed A m y Imtitute of Reaearch, Washington, D.C.
I. Introduction . 11. Four-Membered Rings . 111. Five-Membered Rings .
. .
.
A. Nitrogen-Containing Rings 1. Two Nitrogen Atoms . . 2. Three Nitrogen Atoms . 3. Four Nitrogen Atoms . B. Nitrogen- and Sulfur-Containing Rings . 1. One Nitrogen Atom and One Sulfur Atom . 2. Two Nitrogen Atoms and One Sulfur Atom . 3. One Nitrogen Atom and Two Sulfur Atoms . C. Nitrogen- and Oxygen-Containing Rings . . 1. One Nitrogen Atom and One Oxygen Atom . . 2. Two Nitrogen Atoms and One Oxygcn Atom. D. Oxygen- and Sulfur-Containing Rings . E. Miscellaneous Five-Membered Rings . IV. Six-Membered Rings . A. Nitrogen-Containing Rings . 1. One Nitrogen Atom . 2. Two Nitrogen Atoms . . 3. Three Nitrogen Atoms . 4. Four Nitrogen Atoms . 13. Nitrogen- and Sulfur-Containing Rings . . I . One Nitrogen Atom and One Sulfur Atom 2. Two Nitrogcn Atoms and One Sulfur Atom . 3. One Nitrogen Atom and Two Sulfur Atoms . C. Nitrogen- and Oxygen-Containing Rings . 1. One Nitrogen Atom and One Oxygen Atom . . 2. Two Nitrogen Atoms and One Oxygen Atom. . D. Miscellaneous Six-Mcmbcrcd Rings . . V. Seven-Membcrotl Rings VI. Hetcropolycyclic Rings . A. Quinazolines . . B. 4-Aniinoquinolines . C. Bcnzo- and Naphtho-Fused Five- and Six-Membered Hetorocyclic Rings . D. Miscellaneous Heterocycles .
99
100 100 102 102 102 106 109 109 109 120 122 124 124 124 125 125 126 126 126 127 130 134 134 134 139 140 141 141 142 142 143 145 145 147 150 153
100
T.
s. GRIFFIN,
T.
s. WOODS,
AND D. L. KLAYMAN
[Sec. I1
I. Introduction Of the many r e v i e w ~ l -dealing ~ with the chemistry of thioureas, none is devoted exclusively to their use in the preparation of heterocyclic compounds. This chapter will present the reactions and synthetic methods involved in these preparations and will illustrate the versatility of thioureas in the formation of heterocycles. Discussion will be limited to acyclic thioureas (1) and thiopseudoureas (2) in which the adjacent atoms of the substituent l-2-groups may be of any element other than R
\
/
I1
N-C-N
R'
1%"
/
\
R '"
(1)
R'
8R
\
/
,N-C
%R"
R" (2)
nitrogen. Thus thiosemicarbazides and imidazolidine-2-thiones,for example, are excluded from consideration, but thiobiurets and thiocarbamoyl isothiocyanates are not. Selenium-containing analogs of 1 and 2 which meet the above criteria are included. This review will not discuss the large body of literature concerning thiourea-induced sulfur insertions giving thiiranes from epoxides5 and from haloalcohols.6 I n this chapter, the heterocyclic systems prepared from thioureas are presented in order of increasing ring size and in order of increasing numbers of heteroatoms. The heteroatorns have been arranged in the following sequence: nitrogen, sulfur, oxygen, other elements. Heterocycles prepared from selenoureas and selenopseudoureas are presented together with their sulfur analogs. Heteropolycycles are discussed in a separate section and are grouped according to general ring type, rather than strictly by ring size.
11. Four-Membered Rings Thioureas are useful in the preparation of two four-membered ring systems: thietanes and 1,3-thiazetidin-4-ones. Thietanes (3) can be D. C. Schroeder, Chem. Rev. 55,181 (1955). E. G. Curphey, Chem. Prod. Chem. News 18,98 (1955).
I?. Kurzer, Chem. Rev. 56,95 (1956).
l?. ICurzer, Chem. Rev. 50, 1 (1952). D. D. Reynolds and D. F. Fields, in "Thc Chemistry of Hotorocyclic Compounds" (A. Woissberger, cd.) Vol. 19, Pt. 1, pp. 579-581. Wiley (Intcrscienco), New York, 1964. R. N. Kirnle, U.S. Patent 2,766,256 (1956).
SeC. 111
101
THIOUREAS IX THE SYNTHESIS O F HETEROCYCLES
prepared by reaction of 2-( 3-hydro~ylalkyl)-~ or 2-(3-chloroalkyl)-2thiopseudourea hydrobromides with base. The latter reaction has been reviewed by Etienne et 0 1 . ~ R
HNH
XCH,CHH(’HIi’ -8 4’ \ NH, .H B r
X
= OH, (’I
%
r,”i (3)
l (4)
Campbell indicated that %-oxa-G-t~hiaspiro[3.3]lieptane(4) was formed from 3,3-bis(chloromethyl)uxetanearid thiourea; however, no experimental details were given. The reaction between 1,3-diaryl-2-thioureas and phosgene or thiophosgene has been reported to 5 ield Z-aryliniino-3-ar31-1,3-thiazetidin4-ones (5)9 or thiones (6).1° Recent studies on the reaction between
(5) x = 0 (6) X = S
1-methyl or l-~-toluenesulfonyl-~-thioureas and phosgene suggested that the former must also be aryl-substituted at the 3-position in order to form the cyclic derivati17es.l~ Promnil2 proposed that 1,3-diazetidine-%-thioneswere the products of the reaction between dithiobiurets and aldehydes or ketones, which he called aldurcts and lieturets. respectively. These structures were subsequently shown to be hexahydrotriazines by Fairfull and Peak.l 3 I C ~ r z e rin , ~his review of dithiobiurets, summarized the structural work on aldurets and keturets. 1)ixon and Taylor14 claimed that 1,3-diazetidine-2-thiones were the products of the acid-catalyzed treatment of Y. Etienne, R. Soulas, arid H. T,mnbroso, ~n “Thc Chmiirtry of Heterocyclic Compoimds” (A. Wci\sbcrgcr, cd.), Vol. 19, Pt. 2, pp. 684-085. I\ilt,y (Intrrscience), New Yorlr, 1964. * T. A’. Campbcl1,J. Org Chem. 22, 1029 (1957). W. Will, Ber. 14, 1485 (1881). l o M. Frcund and H. U’olf, Ber. 25, 1456 (1892). l1 H. Ulrich, B. Tuckcr, and A. A. R.Sayigh, Tetrahedron 22, 1565 (19G6). l 2 E. Fromm, Jwslus Lzebigs A p ~ nChern. . 275, 20 (1893). l3 A. E. S. Fairfull and D. A . Pcak, J. Cheni. Soc., 803 (1955). l4 A. E. Dlxon and J. Taylor, J . Chew&.SOC. 109, 1244 (1916).
102
T. S. GRIFFIN, T. S. WOODS, AND D. L. KLAYMAN
[SeC. III.A.1
thioureas with aldehydes. However, this work has not been confirmed, and reactions between thioureas and aldehydes usually yield hexahydrotriazines (see Section IV, A, 3). F o e r s t e P reported that 2-phenylimino-3-phenyl-1,3-thiazetidine was formed by reaction of 1,3-dipheny1-2-thiourea with methylene iodide. Underwood and Dains16 repeated this reaction and obtained only a gummy product; however, they obtained crystalline 1,3-thiazetiand also from 1,5-diphenyl-2dines from 1,3-di-p-toly1-2-thiourea methyl-2,4-dithiopseudobiuret.Recently, Ried et al.I7 observed the formation in low yields of 1,3-thiazetidines from unsymmetrically disubstituted thioureas in the presence of triethylamine. They reported that 1-( 4-quinazolyl)-2-thioureas(7), which have an intramolecular hydrogen bond, react rapidly with methylene iodide in the presence of triethylamine to give the 1,3-thiazetidines (8) in high yields.17
H'
C.
II
'R
B,
ILI. Five-Membered Rings A. NITROOEN-CONTAINING RINGS 1. Two Nitrogen Atoms
Formation of imidazoles from thiourea derivatives has been limited largely to the 2-alkylthio or 2-aralkylthio-substituted rings (unsubstituted 2-mercaptoimidazoles will be classified as 4-imidazoline-2-thiones in this review). For example, the reaction of thiopseudoureas with phenacyl bromide was reported to yield 9.18,19 Gompper et aL20 were able to prepare (11) in nearly quanti4-amino-5-cyano- 1 -methyl-2-methylthioimidazole tative yield via ethoxide-promoted cyclization of 10. F. Foerster, Ber. 21, 1857 (1888). H. G. Underwood and F. B. Dains, J . Amer. Chem. SOC.57, 1769 (1935). l7 W. R i d , W. Merkel and 0. Miisinger, Justus Liebigs Ann. Chem. 1362 (1973). l a It. M. Dodson,J. Amer. Chem.Soc. 70,2763 (1948). l9 R. M. Dodson and F. Ross, J . Amer. Chem. SOC. 7 2 , 1478 (1950). 2 o R.Gompper, M. Giing, and F. Saygin, Tetrahedron Lett., 1885 (1966). l6 l6
Sec. III.A.11
THIOUREAS i~ THE SYNTHESIS OF HETEROCYCLES
103
Ph
Substituted 2-amino-2-imidazolines (13, R = H) may be prepared by a useful general method developed b y Bloom21 by the reaction of thiopseudourea hydriodides (12) with ethylenediamine. Another
procedure was reported b y Adcock and Lawson,22 who cyclized 1phenyl-3-(2-phenylaminoethyl)-2-thiourea (14), either directly with mercuric oxide or indirectly by treating 14 with iodomethane t o form the corresponding S-methiodide, which was in tu rn cyclized to 13 (Ar = R = Ph) by the action of base. Also Krasnitskaya et aLZ3were able t o generate 2-alkylthio-2-imidazolines (16) by reaction of unsaturated side-chain thiopseudoureas (15) with bromine and potassium acetate.
(15)
(16)
B. M. Bloom, U.S. Patcnt, 2,899,426 (1959); Chem. Abstr. 54, 588 (1960). 1%. Adcock and A. Lawson, J . Chem. SOC., 474 (1965). 2J ’3’. A. Krasnitskaya, I. V. Smolanlra, and A. L. Vais, Khim.Geterotsikl. Soedin., 424 (1973). 21
22
104
T.
s. GRIFFIN,
T. s. WOODS, A N D D . L. KLAYMAN
[Sec. III.A.l
The two general methods for preparation of 4-imidazoline-2-thiones are the reaction of acyloins with t h i o u r e a ~ and ~ ~ -the ~ ~acid hydrolysis of alkyl- or aryltliiureidoa~etals.~~~~* The above reactions have been summarized in a review by H ~ f r n a n n .Aren ~ ~ and Bite30 recently reported that the 2-phenyl-2-thiureido- 1,3-indanediones (17) undergo rearrangement in strong acid t o produce in high yield a series of 4-imidazoline-2-thiones (18).
Unsubstituted imidazolidine-2-thione, also known as ethylene thiourea, was one of the reported products (along with aniline, 2anilino-2-imidazoline, and hydrogen sulfide) which resulted from t,hermolysisof 1-(2-aminoethyl)-3-pheny1-2-thi0urea,~~ Cherbuliez e t ~ 1 . ~ ~ found that 1,3-diarylimidazolidine-2-thiones(20) were formed by treatment of the 1,3-diaryl-1-(2-hydroxyethyl)-2-tliioureas(19) with concciitrated hydrochloric acid. S
11
P h N H C --N
,,C!H,CH,OH COIIC.
\
Ar
HC1
,
LA:
Ar
A
Imidazolidin-4-one-2-thiones(21; R = H) are commonly known as thioliydantoins and the isomeric 2-iminothiazolidin-4-ones (22 ; R = H) have been frequently referred t o as pseudothiohydantoins. I n earlier 12. Anschutz and I<. Schwiclrerath, Justus Liebags Ann. Chern. 284, 9 (1895). A. Bassc and H. Klinger, Ber. 31, 1217 (1898). 26 H. Muller, Justus L a r b i p Ann. Chem. 284,25 (1895). 27 W. Marclrwalcl, Ber. 25,2354 (1892). 28 A. Wohl and W. Marcliwald, Ber. 22,568 (1889). 29 K. Hofmann, a n “The Chemistry of‘ Heterocyclic Compounds” (A. Weissbcrgcr, ocl.), Vol. G , pp. 77-82. Wiloy (Intcrscience), New York, 1953. Jo A. K. A r m and Dz. V. Bite, Kham. Geterotsakl.Soedzn., 329 (1968). 31 L. Hclgcn, 0. Stoutland, a n d C. L. Agre, J . Org. Chem. 24,884 (1959). 32 E. Cherbuliez, B. Willhalni, S. Jaocard, a n d J. Rabmowitz, Helv. Chim. Actu 24
25
50,2503 (1967).
See. 1II.A.I ]
‘I‘IIIOUIIEAS I N THE SYNTHESIS O F HETERO(’YCLE.9
105
literature (1877-1879) there occurred the assignment of structure 21 t o products of reactions between thiourea and cliloroacetic acid 33 or a-chloropropionic anhydride 34 when, in fact, the products had structure 22. This subject has beeii discussed in a general review of hydantoins by Ware.35 However, recently Achary and N a ~ a showed k ~ ~ t h a t 1(2-pyridyl)-2-thiourea produced a pseudothiohydantoin (22; It = 2pyridyl) when treated with chloroacetic acid in ethanol in the presence of sodium acetate, and a thiohydantoin (21; R = 2-pyridyl) when th e reaction was performed in p y id in e. General niethods for preparation of imidazolidin-4-one-2-thiones include the reaction of thioureas with a-dicarbonyl c o i n p o ~ n d s , ~ ~ * ~ ~ with ethyl p h c i i y l p r o p i ~ l a t e ,and ~ ~ with phcnyl chlorothiolacetate,40 and cyclization in acid of l-(carbethoxymcthyl)-2-thioureas.41 The analogous reaction of a-dioarbonyl coinpou I ids with selenoureas produce imidazolidin-4-0ne-d-selones.~~ Berlin and Levi 43 utilized the acidcatalyzed cyclization o i l-aryl-3-carballioxymethyl-2-thioureas to produce 3-arylimidazolidiii-4-on~-2-tliiones (23).
P. Claesson, Ber. 10, 1346 (1877). R. Freytag, J . Prakt. Chem. 20,380 (1879). 36 E. Ware, Chem. Rev. 46,403 (1950). 36 T. E. Achary and A. Nayak, Curr. Sci. 41, 539 (1972); Chem. Abstr. 77, 114305 33
34
(1972). H. Biltz, Ber. 42, 1792 (1909). 38 B. Sjolleina and L. Seoklcs, Rec. Trav. Chim. 44, 827 (1925);Chem. Abstr. 19, 3478 (1925). 39 S. Ruhemann and H. E. Staploton, J . Chem. SOC. 77,239 (1900). 40 C. E. Dalgliesh and F. G. Mann, J . Che7n. SOC., 559 (1947). 4 1 T. B. Johnson and A. G. Renfrew, J . Ainer. Chem. SOC. 47,240 (1925). 4 2 P. Bergmann, F. Pragst, and H. Paul, Arch. Pharm. (Weinheim) 299, 499 (1966). 43 A. Ya. Berlin and I. S. Lovi, Zh. Obshch. Khim . 33, 860 (1963). 37
106
T.
s. QRIFFIN,
T.
s. WOODS, AND
D. L. KLAYMAN
[Sec. III.A.2
Imidazolidine-4,5-dione-2-thiones (26), also known as thioparabanic acids, can be prepared by heating thioureas with oxalyl chloride 44.45 or diethyl ~ x a l a t e . ~Cyanogen ~.*~ may also be used if the reactants are heated in the presence of acid.4aS t ~ f f eand l ~ ~Ulrich and S a ~ i g have h~~ studied in detail the reaction of thioureas with oxalyl chloride and were able t o isolate intermediate thiazolidine-4,5-diones (25) which on (26). Thus, heating rearranged to the imidazolidine-4,5-dione-2-thiones in the mechanism proposed by S t ~ f f e l initial , ~ ~ attack of the oxalyl chloride is on sulfur t o form 24,which can cyclize to 25.Further heating then causes rearrangement of 25 t o 26. 0 0
1I I1
S
II
RNHCNHR
S-C--C-Cl
(co(’l)l
I
RNH-C=NR
-
(24)
2. Three Nitrogen Atoms 3,5-Diamino-l,2,4-triazoles(29)are readily formed by reaction of 2,4-dimethyl-(or diethyl)-2,4-dithiopseudobiurets(27) with hydrazine
hydrate 5 0 * 5 1 or aryl h y d r a z i n e ~ l-Aryl-3-cyano-2-methyl-2-thiopseu.~~ doureas (28)) which result from acid treatment of 27 (R = aryl, R’ = H), also react with hydrazine t o form 29.51When treated with hydrazine, dithiobiurets were reported to produce mixtures consisting of 3,5-diamino-l,2,4-triazoles and 3-arylamino-5-mercapto-1,2,4-triH. Biltz and E. Topp, Ber. 46, 1387 (1913). P. J. Stoffel, J . Org. Chem. 29,2794 (1964). 46 M. Nencki, Ber. 7 , 779 (1874). 47 A. Michael, J . Prakt. Chem. 49, 26 (1894). 4 8 T. Andreasch, Monatsh. Chem. 2 , 277 (1881). 4 9 H. Ulrich and A. A. R. Sayigh,J. Org. Chem. 30, 2781 (1965). 50 F. H. S. Curd, D. G. Davcy, D. N. Richardson, and R. de B. Ashworth, J . Chem. Soc., 1739 (1949). 51 J . S. Davidson, J . Chem.SOC. C , 194 (1969). 5 2 H. G. Underwood and F. B. Dains, Univ. KansmSci. Bull. 24, 5 (1936);Chem. Abstr. 32, 3399 (1938). 44 *5
Sec. III.A.21
THIOUREAS I N THE SYNTHESIS O F HETEROCYCLES
SCH,
107
SCH,
I
RN= C-NH-C
I
=NR'
+
R"-NHNH, (R" = H , Ar)
\
(27)
I" + I
SCH,
I RN=C--NHCN
+
H,NNH,
/
NHR' N
7
'
ANJ RNH
(29)
a ~ o l e s .D ~ a~ v. ~i d~ ~ o n and ~ ~ ,Werbel ~~ et al.56 were able to obtain 3arylamino-5-amino-1,2,4-triazolesexclusively by the reaction of l-aryl-4-methyl-2,4-dithiopseudobiuretswith hydrazine. I n addition, Davidson 57 studied the hydrazinolysis of a series of 2-methyl- 1phenyl-2,4-dithiopseudobiurets(30; R1,R2 = alkyl or aryl) and found that the predominant products, in yields up to 90%, were the 5mercapto-1,2,4-triazoles(31) when R2 was aliphatic, but when R2 was aromatic, mixtures of 31 and 32, in which the latter were predominant, resulted. Hydrazinolysis of 2-benzyl-1-phenyl-3-phenylamidino-2-thiopseudourea was reported to produce 3,5-diphenylamino- 1,2,4-triazole in 75% yield.58
Ph
R'
SMe
\
I
N-C=N-
/
S
II
-C-NHR2
+
H2NNHz
/
H (31) NR'Ph
53
F. Amdt, E. Milde, F. Tschenscher, F. Bielich, and G. Eckert, Ber. 55B, 12
'4
E. Fromm, L. ] h i c k , R. Runkol, and E. Mayrr, Justus Liebigs Ann. Chern.
(1922). 437,106 (1924).
J. S. Davidson,J. Chem. SOC.C, 2471 (1967). 56 L. M. Wcrbcl, E. F. Elslagor, and V. P. Chu, J . Heterocycl. Chem. 10, 631 (1973). 57 J. S. Davidson, J . Prakt. Chem. 314, 663 (1972). F. Kurzer and 1'. M. Sanderson, J. Chem. SOC.,3333 (1963).
55
108
T. s. GRIFFIN, T.
s. WOODS,
AND D . L. KLAYMAN
[Sec. III.A.2
Wheeler and B e a r d ~ l c ywere ~ ~ able to prepare the substituted 1,2,4triazoles (34) by reaction of 2-methyl-1-benzoyl-2-thiopseudoureas (33) with phenyl hydrazine. Similarly, Davidson 6 o treated hydrazine with
Ph (34)
(33)
2-methyl-l,l-dibenzoyl-2-thiopseudourea to produce 3-benzamido-5phenyl-1,2,4-triazole in 85% yield. If l-benzoyl-2-thioureas, rather than benzoyl-2-thiopseudoureas, are treated with hydrazines, the products as well as 3-amin0-1,2,4-triazoles.~~ A are 3-mercapto-l,2,4-triazoles variety of 3-amino- 1,2,4-triazoleshave also been prepared in moderately good yields via the reaction of hydrazides with t h i o p s e u d ~ u r e a s . ~ ~ , ~ ~ The intermediate N-anilinoamidino-2-thioureas, which result from the treatment of 3,5-diimino-1,2,4-dithiazolines (thiurets) with phenylhydrazine, were reported by Fromm 64-66 to cyclize to 3,5-diamino1,2,4-triazoles. Kurzer and co-workers, who had earlier reported the ,~~ this work cyclization of amidinothioureas to 1 , 2 , 4 - t r i a ~ o l e sextended to 1,3-bis(isopropylideneimino)-2-arylthiocarbamoylguanidines (35), NHAr
J=CMe, NCNHA~
(37)
II. L. Wheeler and A . 1’. Beardsley, Amer. Chern.,I. 29, 73 (1903). J. S. Davidson, Cliem. Ind. (London),464 (1972). 61 R.Sgarbi, Chim. Ind. (Milan)48, 18 (1966). 6 2 K. Uiemann and H. Bretschneidor, Monatsh. Chem. 89, 604 (1958). 63 E. Hoggarth, J . Chem. SOC., 612 (1950). 6 4 E. Fromrn and E. Vettor,.Justus Liebbgs Ann. Chem. 356, 178 (1907). 6 5 E. Proinrii and A. Wollor, Justus Liebigs Ann. Chem. 361, 302 (1908). 6 6 E. Frornm, Justus Liebigs Ann. Chem. 394, 258 (1912). 67 L. E. A. Godfrey and 17. Kurzer, J. Chem. SOC., 3437 (1960). 59
Sec. III.B.11
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
109
which they found would cyclize to 3-arylamino-5-hydrazono- 1,2,4triazoles (36) in base and to 3-hydrazono-5-mercapto-1,2,4-triazoles (37)in acid.68 3. Four Nitrogen Atoms 1-Alkyl (or aryl) 5-aminotetrazoles (38) can be prepared either from thioureas by reaction with sodium azide in the presence of lead carbonate 6 9 or from 2-thiopseudourea hydriodides by reaction with sodium azide. 70
B. NITROGEN-AND SULFUR-CONTAINING RINGS 1. One Nitrogen Atom and One Sulfur Atom The reaction between thioureas and a-halo ketones or aldehydes to form 2-aminothiazoles (39), first developed by Hantzsch 71 and TrauI E H ~ is ~ one , ~of~the * oldest ~ ~ and most important uses for thioureas in
the synthesis of heterocycles. When the thioureas are I ,3-disubstituted, the products are substituted 2-arnin0-4-thiazolines.~~ The a-halo ketones have also been replaced by a-diazo and by a,j3-epoxy ketones.74 A thorough discussion of the above reactions, including F. Kurmr and li. T)oiiraghi-Zatleh, J . Chem. SOC., 4448 (1965). 12. StollB, I<. Elirinann, L). Ricder, H. \Villc, H. Winter, aiic1 F.Hrnke-Stark, J . l’raXt. Chem. 134, 287 (1932). 7 0 W.1,. Garbrccht and R . M. I I w b s t , , I . Org. C h e m . 18, 1027 (1953). 71 A. Hantzsch and V. Trniimrtnn, IZer. 21, 938 (1888). 7 2 V. Traumarm,JudrIn Lrehzgs L4n~tC’hetn. 249, 31 (1888) 7 J L. C King and F.hZ R.ZilIi~r,.JAtnpr. C/iem.Soc 71, 3 6 7 (1949). l4 C. C. J. Culvenor, \V. D a \ ~ qJ. , A . Rlaclarcn, 1’ F Nclzon, arid W. E. Sitvige, J C h e m S o c . , 2573 (1949). 68
69
110
T.
s. GRIFFIN,
T.
s. WOODS,
AND I). L. ILLAYMAN
[Sec. ZII.B.l
methods for in situ generation of the reactive carbonyl compound, is contained in the general review of thiazoles by Sprague and Land75 which appeared in 1957. Numerous papers have appeared since 1957 on the use of tJheabove type reaction to prepare 2-aminothiazole derivatives for medicinal testing. The analogous reaction of a-halo aldehydes or ketones with selenoureas to produce 2-aminoselenazoles has been reviewed by Bulka76*77 and Shine.78 Dithiobiurets react with a-halo ketones 79-82 or aldehydes (generated in sit^)^^ to yield 2-thiureidothiazoles (40), which can be converted in two steps to 2-g~anidinothiazoles.~~ However, Beyer and Hantschela4 found that 2-gnanidinothiazoles could be more conveniently prepared via the reaction of 1-amidino-2-thiourea with a-halo ketones or aldehydes.
HCOCHR’
I
X
+
i i
H,NCNHCNH,
- ’’i R’,-
kNHCSNH2
(40)
Rartoszewski and J e r z m a n ~ w s k afound ~ ~ that mixtures of isomeric thiazolines were frequently produced by the reaction of various arylsubstituted unsymmetrical thioureas with chloroacetone. However, Murav’eva and Shchukina86*87observed that treatment of l-aryl-3J . M. Spraguo and A. H. Land, i n “Heterocyclic Compounds” (R. C. Elderfield, ed.), Vol. 5, pp. 484-723. Wiley, Now York, 1957. l6 E. Bulka, Advan. Heterocycl. Chem. 2 , 3 4 3 (1963). 77 E. Bulka, in “Organic Selenium Compounds: Their Chemistry and Biology” (D. L. Klayman and W. H. H. Gunther, eds.), pp. 459-496. Wiley, New Yorlt, 75
1973. 78
R. J. Shine, in “Organic Selenimn Compounds: Their Chemistry and Biology” (D. L. Klayman and W. H. H. Giinther, eds.), pp. 284-288. Wiley, New York, 1973.
E. Fromm and E. Philippe, Ber. 32, 835 (1899). 8o R. L. Sperry, U.S. Patent 2,470,585 (1949):Chem. Abstr. 43,5425 (1949). R. L. McKee and J . D. Thayer,J. Org. Chem. 17, 1494 (1952). 8 2 H. Beyer and I<. Pommerening, Chem. Ber. 99, 2931 (1966). 83 I. Iwataki, Bull. Chem.Soc. J a p . 45,3218 (1972). 8 4 H. Beyer and H. Hantschel, Chem. Ber. 95, 893 (1962). 8 5 J. Bartoszewski and Z. Jerinanowska, Rocz. Chem. 37, 1 1 (1963); Chem. Abstr. 59, 7510 (1963). 86 K. M. Murav’eva and M. N. Shchultina, Zh. Obshch. Khim. 30, 2327 (1960); ClLem. Abstr. 55, 9376 (1961). 87 I<. M. Murav’ova and M. N. Shchukina, Zh. Obshch. Khim. 30, 2334 (1960); Chem. Abstr. 55, 9376 (1961). 78
See. III.B.11
THIOUltEAS I N THE SYNTHESIS O F HETEROCYCLES
111
acyl-2-thioureas with a-halo ketones yiclded only the thiazoline isomer 41 with the acgl su h titu eiit on the exocyclic nitrogen. These authors also isolated the interniediate 4-hydroxythiazolidines (42) using milder conditions than were used for the formation of the thiazolines.
with acetone in th e The treatment of 1,3-d1~~heny1-2-tl~iourea presence of butylsulfenyl chloride was reported by Kopylova et aZ.88to vield tlie 5-butplthio-4-thiazolirie (43; isolated as a picrate). Another (44) produced interesting thiazoline is 2,2'-diamino-4,4'-spirobithiazoline from fusion of 1,3-dichloroacetone and t l ~ i o u r e a . ~ ~
Dodson and Turner were able t o prepare tlie 2,4-diaminothiazole (45) 1)sreaction of thiourea with a-cyanobenzyl benzenesulfonste. The
R. V. Kopylo\.a, M. N. Khasanova, R. Kh. Frcydlina, Uzb. Khim. Zh. 29 (2) (1968);C'heni. A6str. 70, (58240 (19GO). Q9 J. Harlcy-Mason. J . Clicm. SOC., 323 (1947). 90 K. M. Dodsonand H. \V. Tiimt=r,J.Amer. Chem.Soc. 73, 4617 (1951). OQ
112
T. S . GRIFFIN, T . S . WOODS, AND D. L. KLAYMAN
[Sec. III.B.1
reaction was further studied by Taylor et al., who found th a t l-phenyl?-thiourea gave 4-amino-3,5-diphenyl-2-irnino-4-thiazolineg1 and 1,3disubstituted thioureas gave th e corresponding t h i a z o l i n e ~ .A~ ~useful general method for the preparation of 2,5-diaminothiazoles (46) is the cyclization of 1-cyanomethyl-2-thiourea~.~~*~~
Several new syntheses of thiazoles from thioureas have been developed in recent years. Werbel 95 was able t o prepare 2-aminothiazoles by reaction of thioureas with bis(P-chloroethyl) ether. 1,3-Disubstituted thioureas, however, yielded disubstituted 4-thiazolines. I n a German patent, Reisinger 96 reported th at 2-aminothiazole was formed in 88% yield from thiourea and vinyl acetate in the presence of sulfuryl chloride. A method for the preparation of the 4-hydroxy-2-aminothiazole (47),which probably exists in the tautomer shown, has been developed by Delaby P t aLg7 via the reaction of thiourea with /I-aeylacrylic acid or its esters. Zbira19* has observed that, acylvinylphos-
phoniuni salts (48) will add thiourea to form thiopseudoureas which can cyclize t o 2-aminothiazolylmethylphosptmnium salts (49). Tile triE. C. Taylor, Jr., J. Woltnsky, a n d H.-H. Lee, J . Amer. Chem. SOC.7 6 , 1866 (1954). 92 E. (3. Taylor, Jr., (1. A. Berchtold, N. A. Goeckner, a n d F. C. Stroehmann, J . Org. Chem. 26, 2715 (1961). ‘33J . M. Ualqutst a n d F. J. Goetz, J . Heterocycl. Chem. 9, 937 (1972). 9 4 C. W. Capp. A. H. Cook, J. D. Downer, a n d 1. Heilbron, J . Chem. SOC., 1340 (1948). 95 L. M. Werbel, Chem. Ind. (London), 1634 (1966). gfi K. Iieisinger, West German P a t e n t 1,812,267 (1970);Chem. Rbstr. 73, 45498 (1970). 97 It. Delaby, S. Danton, a n d 1’. Chabrier, Bull. SOC. Chim. Fr., 2061 (1961). 98 E. Zbiral, Tetrahedron Lett., 5107 (1970).
Sec. III.B.11
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
113
plieiiylpliosphiiie moiety can bc removed from the latter by treatment with base t o produce 2-aminothiazoles (50).98
I NH2
0
It'
The acid-catalyzed cyclization of I-( 2-hydroxyethyl)-2-thioureashas been used extenbively for the preparation of 2-amino-2-tliiazoliries ( 51).9c"-101 Substituted 2-imiiiothiazolidines result if the thiourea is
further substituted on the nitrogen bearing the 2-hydroxyethyl g r ~ ~ p Iwakura . ~ ~ et~al.lo4 J ~studied ~ this cyclization reaction using a variety of acids and observed that mixtures of 2-amino-2-thiazoline and 2-arnino-2-oxazoline were frequently produced (see Section 111, C, 1). These workers also developed the proper acidic conditions for the preparation of either thiazoline or oxazoline exclusively.104Cherbuliez H. G. Soderbaum, Ber. 28, 1897 (1895). H. Dersin, Ber. 54, 3158 ( 1 9 2 1 ) . l o l A. Areschka, M. Prost, J. M. Maliaux, V. Van Cromphaut, F. Verbruggen, P.Binon, R. Charlier, G. IMaunois, M. Colot, J. Bauthier, and M. Polster, Bull. Chzna. T h e r . , 337 (1972). l o 2F. B. Dains, It. Q. Brcwstcr, I. L. Malm, A . W. Miller, R. V. Maneval, and J. A. Sultzabergrr, J . Attaer. Chent. S o r . 47, 1981 (1925). lo3L. Dashcn and 12. Q. Brewstor, T r n r ~ sK . a n s a s A c a d . Sci. 40, 103 (1937); Chem. A b s t r . 33, 5 3 9 4 (1939). I o 4 Y . Iwakure, K. Kurita, and F.Haj7an0,J. Polym. Sci., Part A - I , 7, 3075 (1969). 99
loo
114
T. S . QRIFFIN, T. S. WOODS, AND D . L. KLAYMAN
[SeC. III.B.1
et al.105-107found that the sulfate or phosphate esters of 1-(2-hydroxyethyl)-2-thioureas would readily cyclize with acid or base to 2-amino-2thiazolines. I n a further extension of this reaction, Ueutsch and Fantal0* found that the same 2-amino-2-thiazoline (53) produced in 90% yield by acid-catalyzed cyclization of l-phenyl-3-(2-hydroxyethyl)-2-thiourea was also formed in 91 yield by treatment of 1-(N-phenylthiocarbamoy1)aziridine (52) with concentrated hydrochloric acid. This reaction was f i s t reported by Gabriel and Stelzner,logwho erroneously formulated the aziridine (52) as l-phenyl-3-vinyl-2-thiourea. Iwakura and
(52)
(53)
NabeyallO found that the same reaction occurred in acetic acid, and Heine et aZ.lll reported that sodium iodide in acetone effectively promoted the rearrangement. Ti5ler1l2 utilized this procedure to produce a variety of 2-arylamino-2-thiazolines. I n a reaction first reported by Will in 1881,9 1,3-diaryl-2-thioureas heated with ethylene bromide yield 2-iminothiazolidines (54).1137114 Ar'
S
II
ArNHCNHAr'
+ HrCH&H,Br d < , N A r (54)
When Ar and Ar' were not identical, Foerster15 claimed to have isolated a single isomer of 54. However, Dashen and Brewsterlo3 studied a series of substituted 1,3-diphenyl-2-thioureas in this reaction and came to the conclusion that the phenyl group with more electron-donating lo5
E. Chcrbulioz, Br. Baehler, 0. Espejo, E. Frankenfeid, a n d J. Rabinowitz,
Helv. Ch.im. Acta 49,2G08 (1966). E. Chorbuliez, H. .Jindra, and J. Rabinowitz, Helv. Chim. Acta 49, 1951 (1966). Io7 E. Chcrbuliez, Br. Baehler, 0. Espejo, S. Jaccard, H. Jindra, a n d J. Rabinowitz, Helv. Chim. Acta 49, 2408 (196G). Io8 A. S. DeutJscha n d P. E. F a n t a , J . Org. Chem. 21, 892 (1956). log S. Gabriel a n d It. Stelznar, Ber. 28, 2929 (1895). 110 Y. Iwakura a n d A. Nabeya, Nippon Kagaku Zasshi 77, 773 (1956); Chem. Abstr. 52, 9028 (1958). 111 H. W. Hoine, W. G. Kenyon, a n d E. M. Johnson, J . Amer. Chem. SOC. 83, 2570 (1961) 112 M. Tigler, Arch. Pliarm. (Weidheim) 291, 457 (1968). 113 G . Noah, U e r . 23, 2195 (1890). 11* H. Erlenmeyer, H. Sehulthess, and H. Bloch, Helv. Chim.Acta 30, 1336 (1947). Io6
Sec. III.B.11
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
115
substituents would appear on the ring nitrogen in the product. Using the above reaction, Bradsher et nl.115 were able to prepare a variety of benzyl-substitutecl2-iminothiazolidines. Albert1lG reportedly formed 2-iminothiazolidinones by fusion of P-hydroxyalkylamines, such as ephedrine, with thiourea. Optical activity could be retained in the product from optically active phydroxyalkylamines. A useful synthesis of 5-exomethylene-2-iminothiazolidines(56) has been developed by Thieme and KOnig1l7 via cyclization of l-aryl-3(3-propynyl)-2-thioureas (55). R'
@ Zh);f
N H C N H - - '/ cC: - E- ~C~H
(55)
aCozM
- n=@12 (56)
Base-treatment of the compound proposed to be 1-(2-broinoethy1)-2thiourea (m.p. 173.6-174.2"), formed by the reaction of 2-bromoethylamine hydrobromide with potassium thiocyanate, was reported to yield 2-amin0-2-thiazoline;~~~ however, Klaymanllg has shown that the product of the thiocyanate reaction is actually 2-amino-2-thiazoline hydrobromide (m .p. 17 6- 177 " ) . 3-( 2,3-Dibromopropyl)-2-thioureas were apparently generated in situ by addition of bromine to a series of l,l-disubstituted-3-(2-propenyl)-2-thio~reas.~~~ The assumed dibromo intermediates then undergo rapid cyclization to the analogous 5 bromomethyl-2-amino-2-thiazolines. In another ring-closure reaction, Behringer and Zillikens121observed that the thiopseudourea derivative 57 cyclized in base to 1,3-thiazines when R was methyl (see Section IV, B, 1);however, when R was hydrogen, then the product was 2-amino2-thiazoline-4-carboxylic acid ( 5 8 ) in 70% yield.
(57)
(58)
C. K. Bradshcr, F.C. Brown, and E. F. Sinclair, J . Arner. Chem. SOC. 78, 6189 (1956). 116 W. Albert, D.D.R. Patcmt 10,792 (1955);C'hern. Abstr. 53, 3243 (1959). 117 P. Thienic and H. Konig, S!jr~thesis, 426 (1973). 11* E. J. Masters anti M. T. Bogmt, J. Amer. Chem. SOC. 64, 2709 (1942). 119 11. L. Klayman, unpublished results. lZo V. M. Fctloseev and Yii. M. Yevriokimov, Zh. ODshch. Khim. 34, 1551 (1964). H . Bchringcr and P. Zlllikenu, Justus Lie6zgs Ann. Chem. 574, 140 (1951). 115
T. s. GRIFFIN, T.
116
s. WOODS,
[Sec. lII.B.l
AND D. E. KLAYMAN
A frequently used method for the construction of the 2-amino-2thiazoline ring (60) involves the reaction between thiourea and 2bromoethylamine h y d r ~ b r o m i d e . l ~ If ~ - the l ~ ~amine nitrogen atom is BrCHCH,NH,-HBr
I
R
+ H,NCSNH,
-
H,N\
+
C-S-CHCH,NH, H2N
//
I
2Br-
R (59)
I
substituted, the products are 2-imino-3-substituted t h i a z o l i d i n e ~ . l ~ ~ * ~ ~ ~ The 2-(2-aminoethy1)thiopseudourea dihydrobromides ( 5 9 ) ,which are intermediates in the thiourea reaction, have also been used to produce 60 (or 2-imino-3-substituted thiazolidines).127.128I n an analogous reaction Chu and M a ~ t n e r prepared l~~ 2-amino-2-selenazoline from a selenopseudourca salt. A recent Australian patent states that iminothiazolidines are products of the acid treatment of 2-(2-substituted aminoethyl)thiopseudoureas, which were in turn prepared from thiourea and N-substituted aziridines.130 Fedoseev et ~ 1 . have ~ ~ ~ 9 A. Schobcrland C;. Hanscn,Chem. Ber. 91, 1239 (1958). V. M. Fedoseov and I. V. Fillppovich, Zh. Obshch. KhLm. 34, 1561 (1964). lZ4 D. G. Doherty, R. Shapira, and W. T. Burnett, Jr., J . Amer. Ghern. SOC. 79, 5667 (1957). l Z 5V. M. Fcdoseov, V. V. lvanenliov, and A. B. Silaev, Zh. Obshch. Kham. 30,3468 (1960). 126 W. Fiodler and G. Faust,J. Prakt. Chem. 21,131 (1963). lz7 T. Hino, K. Tana-ami, I<. Yamada, and S. Akaboshi, Chem. Pharm Bull. 14, 1193 (1966). l z 8 T. Hino, K. Tana-ami, K. Yarnada, and S. Akaboshi, Chem. Pharm. Bull. 14, 1201 (1966). lZ9 S.-H. Chi1 and H. C. Mautncr, J . Org. Chem. 27,2899 (1962). 130 A. Uaklien and J. Kolm, Australian Patent 414,415 (1971); Chern. Abstr. 77, 6440 (1972). 131 V. M. E’cdosoev, S. 1’. Kovalcnlio, A. B. Silaev, and A. N. Nesmeyanov, Zh. Obshch. Khzna. 29, 1703 (1959). 132 V. M. Fcdoscov, V. N. Bochkarcv, and A. B. Sdacv, Zh. Obshch. Kham. 31, 3929 (1961). 122
lz3
Sec. III.B.11
THIOUREAS IN THE SYNTHESIS O F HETEROCYCLES
117
shown that some bis(thiopseudourea) salts will cyclize to 2-amino-5(2-thiopseudoureidomethyl)-2-tl~iazoline dihydrobromides. KronrAd and K ~ z i i k lwcre ~ ~ able to make the labeled compounds 2-amino%thia~oline-Z-~~C hydrobromide and 2-arnino-Z-selena~oline-1-~~Se hydrobromide from the respective labeled 2-(2-aminoethy1)thio- and selenopseudourea dihydrobromides. I11 an interesting reaction reported by Salerni et u Z . , ~ the ~ ~ disulfide 61 was clcaved by iodomethane a t the -CH,-S- bonds with concomitant cyclization releasing dimethyl disulfide, forming the 2-iminothiazolidine 62.
One of the more important uses of thioureas has been in the preparation of 2-imino-4-thiazolidinones, first reported by M e ~ e r land ~~ A n d r e a ~ c h-13" , ~ ~via ~ reaction with a-halo acids or esters. This reaction lins h e n covered by in a review on 4-thiazolidinones which appeared in 1961, and, thcrcfore, will not be discussed in detail here. The corresponding reaction between a-halo acids or esters and sclenoiireax to produce 2-iininoseleriazolidin-4-ones is also known and has been reviewed.77*78 Bkerbloml4Ohas attempted t o clear up some of the confiision in the literature on whether 3-alky1-2-iminothiazolidin-4-ones (63) or 2-alkglamino-2-thiazolin-4-ones (64) are formed from 1-alkylthioureas and chloroacetic acid. She found that the reaction in water
L. I
134
118
T.
s. GRIFFIN,
T.
s. WOODS,
AND D . L . KLAYMAN
[Sec. III.B.l
with sodium acetate present produced only 64; whereas, in the absence of base, mixtures of 63 and 64 were obtained. Also 63 could be rearranged to 64 in base and the retro rearrangement could be induced in dilute acid.140 The reaction of 1-alkyl-3-arylthioureas (or selenoureas) with a-halo esters in the presence of base has been claimed to produce 3-alkyl-2arylirninothiazolidin-4-one~~~~-~~~ (and the selenium analogs).144 However, 0 r n a 1 - l ~recently ~ reported that a l-benzyl-3-phenyl-2thiourea, when treated with ethyl bromoacetate produced a thiazolidinone which has the alkyl side chain on the exo nitrogen, i.e., the 3-aryl2-benzyliminothiazolidin-4-one. Other preparations of 2-iminothiazolidin-4-ones which are discussed in the review by Brown139 utilize the reactions of thiourea with ahydroxy acids,146 ethyl d i a ~ o a c e t a t eglycidic ,~~ e ~ t e r ~cinnamic , ~ ~ * ~ ~ ~ unsaturated diacids (fumaric, maleic, and citraconic) or their ~ - l ~propiolic ~ esters.153v154There has been esters or i m i d e ~ , l ~ and considerable controversy in the literature surrounding the propiolic ester synthesis since many workers have proposed that the products are 1,3-thiazines (see Section IV, B, 1). The pertinent papers in this controversy have been summarized by Cain and Warrener. 155 N a g a ~ e ’ ~ ~ has recently settled the argument in favor of the 2-iminothiazolidin-4F. B. Dains, 1%.I). Coghill, anti S. S. Tihen, C J n i ~ i .Kansas Sci. Bull 24, 25 (1936);Chem. Abstr. 32, 3397 (1938). 142 F. B. Dains, L. M. Kinsett, C. 0. Holmbcrg, and C. C. Robinson, Uniw. Kansas Sc%.Bull. 24, 15 (1936);Chewh. Abstr. 32, 3396 (1938). 143 H. Najer, H . Giudicolli, C. Morel, and J. Monin, Bull. Soc. Chim. Fr., 1022 141
(1963). J. Monin, J.-F.Giudicolli, and H. Najer, C . R . Acad. Sci., Ser. C 262, 778 (1966). 145 A.M. M. E. Oinar, I’harmazie28, 110 (1973). 14G H. Dannenberg, and A. Rahman, Chem. Ber. 89, 1625 (1956). 147 J. A. Durden, Jr., H. A. Stansbury, Jr., and W. H. Catlette, J. Amer. Chem. SOC.81, 1943 (1959). 148 J. Bougault and P. Chabrier, C . R . Acad. Sci. 224,656 (1947). 149 R . Andreasch, Monatsh. Chem. 16, 789 (1895). 150 R . Andreasch, Monatsh. Chem. 18, 56 (1897). 151 D. H. Marrian, J . Chem. Soc., 1797 (1949). 152 A. N. Arakelian, H. Dunn, Jr., L. L. Gricshammcr, and L. E. Coleman, J . Org. Chern. 25, 465 (1960). 153 L. K. Miishkalo and G. Ya. Yangol, Ukr. Khim. Z h . 21, 732 (1955); Chem. Abstr. 50, 16751 (1956). 154 J. B. Hendrickson, R. Rees, and J. F. Templeton, J . Amer. Chem. Soc. 86, 107 (1964). 155 E. N. Cain and R. N. Warrenor, Aust. J. Chem. 2 3 , 5 1 (1970). 156 H. Nagase, Chem. Pharm. Bull. 21,270 (1973). 144
Sec. III.B.11
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
119
ones by structure proofs based on preparation of the products via unambiguous routes. 2-Iminothiazolidin-4-ones have also been prepared by the reaction or a-haloacetbetween thiourea and N-chloroa~etylanilines~~~-~~~ amides.160*161 In addition, these heterocycles are produced by treatment of thiourea with a-trichloromethylbenzyl alcohol162 and from thiopseudoureas and tliioglycolic acid.163 Iwataki 83 reported that l,l-dimethyl-2,4-dithiobiuretformed 3 - ( N , N-dimethylthiocarbamoyl)-2-iminothiazolidin-4-one upon reaction with chloroacetyl chloride in acetone in the presence of pyridine ; however, the same reaction with sodium acetate used as a base produced 2-(3,3dimethy1thiureido)-Z-thiazolin-4-0ne.~~ Goerdeler a d Jonas164have reported a useful method for the preparation of substituted 2-aminothiazoline-4,5-diones (65) by reaction of thioureas with oxnlyl chloride. Other diketo products in this series were prepared by cyclization of 2-(a-carbomethoxyalky1)-2-thiopseudourea hydrobromides in water to form the thiazolidine-2,4-diones 66 probably via hydrolysis of intermediate 2-iminothiazolidin-4-ones.165
Two reactions have been reported t o give thiazolinethiones from thioureas. Gregory and Mathes166prepared 4,5-dimethyl-4-thiazoline2-thione (67) via reaction of thiourea with the /3-ketothiocyanate 68. The other reaction was reported by Goerdeler and Ludke,167 who P. J. Meyer, Uer. 10, 1965 (1877). H. Taniyama and T. Yusa, J . Pharm. SOC.Jap. 75,5 (1955). 159 M. Masaki, T. Kitahara, H. Kurita, and M. Ohta, J . Amer. Chem. SOC. 90,4508 (1968). l 6 0 V. L. Vasilevskii, V. M. Fedosoev, and A. B. Silaov, Zh. Obshch. Khim. 32, 2269 (1962). K. A. Nuridzlianyan and C i . V. Kuznetsova, Khirn. Cfeterotsikl. Soedin., 908 (1970). IB2 W. Rceve and hI. Nees, J . Amer. Chem. SOC. 89, 647 (1967). IB3 C. Finzi and C. Angelmi, Ann. Cham. (Rorne)43, 832 (1953). 164 J. Goerdeler and K. Jonas, C!hem.Ber. 99, 3572 (1966). N. N. Suvorov and V. N. Buyanov, KhLm. Ceterotsikl. Soedzn., 377 (1970). I G 6 J. T. Grcgory and R. A . Mathes, J . Amer. Chem. SOC. 74,1719 (1952). 167 J. Uoerdeler and H. Lutlke, Ghem. Ber. 103, 3393 (1970). 157 158
120
T. s. GRIFFIN, T. s. WOODS, AND D . L. KLAYMAN
(68)
[Sec. III.B.2
(67)
observed t ha t thiocarbamoyl isothiocyaiiates (69) formed 2-amino-5imino-2-thiazoline-4-thiones (70) when treated with isocyanides.
2 . Two Nitrogen Atoms and One Sulfur Atom
The preparations of 1,2,4-thiadiazoles a n d 1,2,4-thiadiazolidines from thioureas are well known and have been summarized in three rcviews: t]hose of 1 3 a m b a ~ ,Sherman,169 ~~* arid K ~ r z e r . Contained l~~ in these reviews are discussions of the controversies th a t surrounded some of the products, notably “Hector’s bases,” which resulted from oxidation of substituted t l i i ~ u r e a s . Subjects ~ ~ ~ . ~ ~covered ~ in the above reviews, but too extensive to outline in detail here, are the oxidation of the amidinotliioureas t o 3,5-diamino-1,2,4-thiadiazoles(71),173,174 oxidation of p h e ~ i y l t h i o u r e aand ~ ~ ~of substituted a r n i d i n o t h i o u r e a ~ l ~ ~ to 3,5-diimino- 1,2,4-thiadiazolidines (72,Hector’s bases), the reaction of thiopseudoureas with tricliloromethariesirlfenyl chloride to form 3-alkylthio-5-chloro-1,2,4-thiadiazoles (73),177the reaction of thiopseudoureas with sodium thiocyanate and bromine178and the oxidation L. L. Uumbas, i n “The Chemistry of Heterocyclic Compountls” (A. Weissberger, ed.), Vol. 4, pp. 35-80. Wiloy (Intmscimce),New York, 1952. 160 W. R. Sherman, irk “Hctcrocyclic Compounds” (R. C. Eldcrficld, ed.), Vol. 7, pp. 541-626. Wiloy, New York, 1961. 170 F. Kurzer, Advan. Heterocycl. Chem. 5 , 119 (1965). 171 D. S. Hector, Ber. 22, 1176 (1889). 1 7 2 D. S. Hector, Ber. 23, 357 (1890). 173 F. Iiurzcr, J . Chem. Soc., 1 (1955). 174 F. Iiurzer, J. Chem. Soc., 2288 (1955). 175 C. P. Joshua, V. K. Vcrma, and I<. S. Surosh, Tetrahedron Lett., 663 (1961). 176 F. Kurzcr and P. M. Sanderson, J . Clkem. S O C .3336 , (1963). 177 J . Uocrdoler and G . Spcrlmg, Chern. Ber. 90, 892 (1957). 17* J. Gocrdeler and P. Lintlcn, Chem. Uer. 89,2742 (1956).
IG8
Sec. III.B.21
THIOUREAS I N T H E SYNTHESIS O F HETEROCYCLES
121
of d i t l i i ~ p s e i i d o b i u r e t sforniiiig ~~~ 3-alkyl(or aryl)thio-5-aniiiio-1,~,4thiutliazoles (74), the oxidation of thiobiuret derivatives t o S-alkoxy(or liydroxy)-5-ariiiiio-1,2.4-thiadiazoles (75),1009181 arid the oxidation of Il’-~c.iiziniidoyl-N’-ar~ltliioureasto 3-argI-5-arylamirio-l,~,4-thiadiazoles (76)182or, as was reported recently, to 2,3-diaryl-5-arylimino1,2,4-tliiadiazolines (77).lE3 R’
n (71)
NHR” (73) (‘I (74) NHR” (75) X H R ” (76) NHAr
H‘ NH, SR” SLt”
OH” Ar
(77)
Freund and Wolf l o reported that 2,4-diphenyl-l,2,4-thiadiazolidine3,5-dithione was formed Ly heating 1,3-diphenyl-Z-thiourea with thiophosgene in benzene ; whereas, a 1,%thiazetidine was produced at lower temperatures in ether (see Section 11). Chandela4 has reported are formed by the reaction of that 3,5-diarnino-1,2,4-thiadiazoles thiopseudonreas with carbon disiilfide in the presence of bromine. Use has also been made of tliioureas in the synthesis of 1,3,4-thiadiazolines (79) via reaction with the halohydrazones 78.185,106The analogous reaction with scleiioiireas was recently reported by Bulka and Ehlersla7 to yield 1,3,4-~elenadiazoline~. S
II
RNHCNH,
Ph
+ x
17y
\ C=NNHR’ /
N-NR’ __f
Ph4s
ANR
F.liurzer anti S.A. Taylor, J , Chem. Soc., 1064 (1939).
E’. liurzcr, Chena. I t d . (London),1482 (1936). F. K u r z c ~and S. A. Taylor, J . Chem. Soc., 379 (1958). 18L F. Kiirzcr and \V. Trrtink, J. Chem. Soc., 2851 (1959). l e 3G. Barnikow and H. Ebeling, 2. ChenL. 12, 130 (1972). 184 M. S. Chandc, IidLan J. C‘hem. 8, 137 (1970). 185 I t . Pusco, R e n d . 1st. Lo?ikburdo&’c&. 71, 425 (1938);Chem. Abstr. 34, 3267 (1940). 186 lt. Frisro and C. Musantc, Guzz. C ~ L ItuZ. ~ N .68, 147 (1938). E. Bulka and D. Ehlcrs, J . I’mkt. Chem. 315,510 (1973). I8O
Ie1
122
T. s. GRIFFIN, T.
s. WOODS,
AND D . L. KLAYMAN
[Sec. III.B.3
3. One Nitrogen Atom and Two Sulfur Atoms In a series of papers, Fromm and co-workers,12.64~188*189 beginning in 1893, showed that dithiobiurets could be oxidized with agents such as ferric chloride or halogens to salts of 3,5-diimino-1,2,4-dithiazolines (80) or 3-amino-5-imino-5H-1,2,4-dithiazoles (81). These heterocycles were named “thiurets” by Fromm, and that term has persisted in the later H HN+&HR’
s-s (80)
RRTN
x-
N)&FIR.
8-8
x-
(81)
literature. Verma and ~ o - w o r k e r s ~prepared ~ ~ - ~ ~ 80 ~ and 81 by oxidative debenzylation of 2-benzyl-2,4-dithiopseudobiurets.The formation and chemistry of thiurets was reviewed by Wuyts,lg3 Bambas,168and Kurzer3 in the early 1950’s and again by Kurzer170in 1965. B a m b a P 8 presented arguments in favor of a 5-amino-1,2,4thiadiazolin-3-thione structure for thiurets, but Kurzer170 disputed Uambas’ arguments, and later X-ray studies have confirmed the views of Kurzer in showing that thiuret hydriodide has structure 81 (R = R‘ - R” = H).lg4*lg5 The numerous other papers in which thiurets are prepared by previously reported methods will not be discussed here. However, it should be mentioned that tetrasubstituted dithiobiurets were oxidized by Divelylg6and by Oliver et a l l g 7to dithiazolium salts (82).
E. Fromm and E. Junius, Ber. 28, 1096 (1895). E. Fromm, Justus Liebigs Ann. Chem. 361,302 (1908). l g oV. K. Vorma, I n d i a n J . Chem. 1, 116 (1963). lgl C. P. J o ~ h u and a V. K. Verma, J . Indian Chem. SOC.38, 988 (1961). l g 2 S. N. Dixit and V. I<. Vorma, IndianJ. Chem. 1,487 (1963). l g 3 H. Wuyts, Traite Chem. Org. 21, 1053 (1953). lg4 0.Foss and 0. Tjomsland, Acta Chem. S c a d . 12,1799 (1958). lg5 P. F. Rodesiler and E. L. Amnia, ActaCr?/staZZogr.,Sect.B . 27, 1687 (1971). lQ6 W. R . Divoley, U.S. Patent 3,166,564 (1965);Chem. Abstr. 62,9145 (1965). lg7 J. E. Oliver, S. C . Chang, R. T. Brown, J. B. Stokes, and A. B. Bolkovec, J . Med. Chem. 15,316 (1972). lag
Sec. III.B.31
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
123
The reaction of thioureas with carbon disulfide in the presence of oxygen has been reported to give 3-amino-1,2,4-dithiazole-5-thiones (83).19* The same type of products could also be prepared by treatment of elemental sulfur with thiocarbamoyl isothiocyanates. lg9 Reaction of 3-amino-5-imino-l,2,4-dithiazoles with the latter type reagent was reported t o yield 84,the structure of which was postulated as possibly having significant contribution from a "no bond" resonance structure, 84b.200 However, X-ray studies indicate that structure 84a is the most important contributor.201A compound of type 84 was also observed as being one of several products, along with 1,2,4-dithiazoles, resulting from the air oxidation of 1,1,5,5-tetrarnethyl-2,4-dithiobi~ret.~~~
The reaction of benzoylthiourea with phosphorus pentasulfide was reported to yield 3-phenyl-l,2,4-dithiazolc-5-thione (85).203 Derocque et al. 204 observed that phosphorus pentasulfide converted 1,3-dibenzoyl2-methyl-2-thiopseudourea,s into 86a. However, in view of the X-ray results on the analogous st,ructure 84201 it may well be that structure 86b is a more important resonance contributor than 86a.
J. W. Clapp, T. A. Lies, and C. Lamb, U.S. P a t e n t 3,520,897 (1970); Chem. Abstr. 73, 120636 (1970). lg9 J. E. Oliver, 12. T. Brown, and N. L. Redfearn, J . Heterocycl. Chem. 9, 447 (1972). J. Coerdeler and J. Uhicn, Chem. Ber. 105,1568 (1972). 201 J. E. Oliver, J. L. Flippcn, and J. Karle, Chcm. Coinnzun., 1153 (1972). 202 J. E. Oliver and J. B. Stokes, I n f .J . Sulfur ClLem., A 2, 105 (1972). 203 J. Vialle, Quart. Rep. Sulfur Chern. 5 , 151 (1070); Chem. Sbstr. 73, 109715 (1970). 204 J.-L. Dorocquo, M. Pcrrier, and J. Viallr, BUZZ.S O C .Chine. Fr., 2062 (1968). lgB
124
T.
s. GRIFFIN,
T.
s. WOODS,
AND D . L. KLAYMAN
[Sec. III.C.2
c. NITROGEN- AND OXYOEN-CONTAINING RINOS 1. One Nitrogen Atom and One Oxygen A t o m Substituted 2-amino-2-oxazolines (88) have been prepared by a number of workers from 1-(2-hydroxyethy1)-2-thioureas (87). These
R’R2C’NHCSNHR4
I
R3CHOH
---+
R3R x k ” H R 4 H
cyclizations have been effected either directly with oxidizing agents102.205 or strong or indirectly via conversion of 87 to a 2-methyl-2thiopseudourea derivative and cyclization of the latter in base,22*206*207 or simply by heating in polar solvents if It4 is activating.208Weygand et aL2OEareported that treatment of ethyl lactate with thiourea in the presence of base yielded 5-methyloxazolidin-4-one-2-thione. 2. Two Nitrogen Atoms and One Oxygen Atom Two of the three possible isomeric ring systems of this type are reportedly formed from thioureas. Y ang and Johnson209 prepared the 1,2,4-oxadiazole 89 by treatment of 1-benzoyl-2-methyl-3-phenyl-2thiopseudourea with hydroxylamine. The unstable N-hydroxythioureas resulting from reaction of isothiocyanates with hydroxylamine were claimed by Guha and Chakladar210 to decompose to the unlikely 1,2,5-0xadiazoles 90.
Y. Iwakura, T. Kaya, and I<. Kurita, BUZZ.Chem. Soc. J a p . 43, 2531 (1970). B. Adcock and A. Lawson, J. Chem. Soc. C , 65 ( 1 966). 207 B. Adcock, A. Lawson, and D. H. Milas, J . Chem. Soc., 6120 (1961). 208 D. L. Klayman, R. J. Shine, and A. E. Murray, Jr., J . Pharm. Sci. 59, 1516 205
206
208a
(1970). F. Weygand, H. J. Bestmann, and F. Stedcn, Chern. Ber. 91,2537 (1958). S. T. Yang and T. B. Johnson, J . Arner. Chern.Soc. 54,2066 (1932). 1’. C. Ouha and M. N. Chaklatlar, Proc. IrLdian. S c i . Congr. 15th, 157 (1928); Chem. Abstr. 25,2999 (1931).
Sec. III.E]
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
125
D. OXYGEN-AND SULFUR-CONTAINING RINGS The single report of an oxygen- and sulfur-containing five-membered ring formed from a thiourea is that of Hartmann,211 who prepared the 1,3-oxathiolium salt 91 from a-bromoacetophenone and tetramethylthiourea.
E. MISCELLANEOUS FIVE-MEMBEREDRINGS A number of interesting five-membered ring heterocycles of other t)ypes have becn reported in the lit2eratureas having been derived from thioiircas. The I)yrrolitlin-.2-ones92 were formed by cyclization of 1(4-brornobutaiiog1)-2-thioiir~as.~~~ I n a relatcd reaction, Cherbuliezlo6 produced the pyrrolidine 93 by treatment of the sulfate ester of 1-(4hydroxybutyl)-3-phei~yl-2-thiourea with acid or base. S
S
(92)
(93)
ii
Tliiolaiies have been prepared by cyclizatiori of 2-( 3-hydroxyalky1)2-thio1)seudoiireas with base,6 a reaction which has also been used t o prepare thiiranes and tliietsnes (see previous sections.)6 Luttringhaus and Rrcchlin 2 1 3 rcymrtcd tlic formation of cis-2-tIiiahydrindrtne (94) by trentmrwl, of c i s - 1 ..’-l~is(l~ro~~io~iiethyl)cyclohexnne with 2 moles of thicirrrc~~ ‘I’hc t r u m tlilrouiidc. lioir cvcr, failed to give the analogous prod11c.t. \Vititc.rfc.ldt 2 1 4 tliscovcwd that one of the by-prodticts of the renctioii of tliiiict Iiylpro1)iolatc with 1,1,3,3-tetramethy1-2-thiouren was the thiophene 95. E L Hartniann, D.D.R. l’atent 77,732 (1970);Cheni. Abstr. 75, 151744 (1971). 1). N. Rcinhoritlt, Rcc. 7’mi~.C h m . 92, 20 (1973). 213 11. Luttringhniii a n d A. Brwhl~n, P h e m . n e r . 92, 2271 (1959). 212
*I4
13 W i i i t c r f ~ ~ l ~ Pl/t/.P / uIZer. . 100, 3679 (1967).
126
T. s. GRIFFIN, T .
s. WOODS,
AND D . L. KLAYMAN
[Sec. 1V.A.I
A single example of a phosphorus-containing heterocycle made from a t,hiourea is the 1,3,4-diazaphospholane (97) prepared in 80% yield via treat,ment of 96 witlh phosphorus t r i c h l ~ r i d e . ~ ~ ~ S
II
MeOCH,NRCNHR
+
PC1,
-
8
.,,KN/R
\
I
LP-Cl
II
0
IV. Six-Membered Rings
A. NITROGEN-CONTAINING RINGS 1. One Nitrogen Atom
The sole report in the literature of a pyridine nucleus prepared from thioiireas is that of Cottis arid Tieckelmann,216who obtained 2-amino3,5-dicyano-6-alkylthiopyridines(99) by treating 2-alkyl-2-thiopseudourea hydrogen sulfates with 1, I-dicyano-2-ethoxyethene (98). Careful attention to the concentration of 98 and base led to good yields of 99; otherwise, the products of the reaction were pyrimidines.216 + EtOCH=C
C ," \
CN (98) 215
216
+
HNH2
HS0,-
RSC \
NHZ
SR (99)
H. Petcrsrn, U.S. Patent 3,673,248 (1972);Chem. Abstr. 77, 101892 (1972). R. G . Cottis and H. TiccltclmcLnn,J. Org. Chern. 26, 7 9 (1961).
Sec. IV.A.21
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
127
2. Two Nitrogen Atoms
The preparation of pyrimidines and hydropyrimidines from thioureas is well established.139*217*218Since the latest review ( 1 962) covering this reaction,218 several reports of the preparation of heterocyclic compounds hy prcviously reported procedures have appeared in the literature. These involve reactions of thioureas with a$-unsaturated P - k e t o e s t e r ~ , ~aliphatic ~ ~ - ~ ~ ~k e t o n e ~ , ~ ~ P-dicar~-~~l bony1 and ethyl ethoxyn~ethylenecyanoacetate.~~~ Selenoureas have also been reported to react with P-ketoesters to give the analogous %-selc~iopyrimidines.~~~~~~~ Two reports have appeared of the cyclization of I -P-carboxyethyl-2-thioureasto hexahydropyrimidines in low yields in the presence of acetic a n h ~ d r i d e ; ~ ~ ~ , ~ ~ ? however, tetrahydrothiazines are the predominant products in these reactions. An innovation in the synthesis of pyrimidines was reported by Lacey 0 . W.Kenner and Sir Alexander Todd, in “Hctcrocyclic Compounds” (R. C. Eldrrfivld, ed.), 1’01. 6, pp. 234-323. Wilcy, Ncw York, 1957. 218 D. J . Brown, in “Thc Chcmistry of Hctmocyclic Compounds” (A. Weissbcxrger, c d . ) , Vol. 16, pp. 82-111. Wilcy (Intcrscicncc),New York, 1962. 219 R. Ziinmermann, Angew. ChewL. 75, 1124 (1963). 2 2 0 13. J. Nikawitz, L1.S.Patent, 3,152,122 (1964);Chem. Abstr. 62, 1670 (196.5). 221 A . E. Sammonrand M. El-Iiasaby, U . A . R . J . Chewa. 12, 17 (1969). 2 2 2 A . E. Sttmnioiir, M. 1. B. Selim, M. M. Nonr E l - h e n , and M. Abd-El-Halim, L‘.A.R. J . Clieiri. 13, 7 (1970);Chem. L4bstr.75, 5840 (1971). 2 2 3 l i . M. Iihachatryan and S. A. Vartanyan, Arm. Khim. Zh. 25, 338 (1972); C h e m . Abstr. 77, 125923 (1972). 224 A. E. Sammoix, M. 1. B . Sclirn, M. El-Kasaby, and F. Saied, J . Prakt. Chem. 314, 941 (1972). 2 2 5 H . 1vI. Foster, antl H. It. Snydcr, in “Organic Synthesos” (N. Rabjohn, ed.), Coll. Vol. 4, pp. 638-640. U’ilcy, Ncw York, 1963. 2 2 6 A. 0. Fitton and R . K. Smalley, “Practical Hcterocyclic Chemistry,” p. 104. Academic Press, Ncw Yorli, 1968. 2 2 7 13,.Ncidlein antl G. Menche, Arch Pharm. (Weiirheim)305, 596 (1972). G . Heinisch, Mo~iatsh.Chem. 104, 953 (1973). 229 H . Hartmann and I<. Mttyer, J . Prakt. Chem. 30, 87 (1965). 230 G . Jscnecke, Z . Chern. 6, 109 (1966). 231 G. Zigeuner, G. Gcibitz, and V. Eiscnrcich, Monatsh. Chem. 101, 1686 (1970). 2 3 2 T. Nagasawa, I<. Kuroiwa, I<. Narita, and Y . Isowa, Bull. Chem. SOC. J a p . 46, 1269 (1973). 233 T. L. V. Ulbricht, T. Okutla, and C. C. Price, in “Organic Syntheses” (N. Rabjohn, cd.), Coll. Vol. 4, p. 566. Wilay, New York, 1963. 234 H. G. Mautner, J . Amer. Chem. SOC. 78,5292 (1956). 235 H. G . Maiitncr and E. M. Clayton, J . Amer. Chem. SOC. 81, 6270 (1959). 236 M. Deriaj-Bizjak, S. Oblak and M. Tislur, J . Org. Chem. 27, 1343 (1962). 237 A. Proscn, B. St,anovnik,and M. TiBler,,I. Org. Chem. 29, 1624 (1964). 217
128
T. s. GRIFFIN, T. s. WOODS, AND D. L. KLAYMAN
[Sec. IV.A.2
i n l!)53238 and amplified in a subsequent paper.239 The reaction involves treatment of 2-alkyl-2-thiopseudoureas with diketene, usually in aqueous base, t o give 3,4-dihydro-2-alkylthio-6-methyl-4-pyrimidinones (100). Recent work by Veronese and D’Angeli240has indicated
ltSC”H \ NHH‘
+
J-y - oj----JS I
CH2
R’ (100)
that, if high temperatures are used, th e products are dihydro-1,3oxnzinones resulting from rearrangement of 100. Richter a n d Ulrich 241 have confirmed t h a t compounds of type 100 may be prepared from thioureas by this procedure. A useful preparation of pyrimidines from thioureas, which has recent ly been summarized in a monograph b y Taylor and M ~ K i l l o p , ~ ~ ~ involves the rcaction of ethoxymethylenemalonitriles (101) with 2~~lkyl-2-tliiopscudoureas to form 2-alkylthio-6-amino-5-cyanopyrimidim s (102). I n addition, the above-mentioned work243 critically
NCclS R I
CN
EtO
\
/
R/c=c
\CN
(101)
4- R’SC
gNH \
NH*
__t
H2N
(102)
evaluates the reaction of enaminonitriles (103) with thiourea t o give 1,2-dihydro-4-amino-2-pyrirnidinethiones (104). I n a variation of the P-carbonylester synthesis of pyrimidines from thioureas (see above), Fissekis and Sweet 244 recently reported the reaction of the methoxyacetalester 105 with thiourea in methanolic sodium methoxide t o give four new hydropyrimidines, 106-109, in low yield. When sodium t-butoxide was used, only 107 was produced. R. N. Lacey, British Patent 099,812 (1953);Chem. Abstr. 4 9 , 2 6 2 7 ~(1955). R. N. Lacey, J . Chern. Soc., 839 (1954). 240 A. C. Vrronesc and F. D’Angeli, Aim. Chim. (12ome) 6 0 , 3 7 4 (1970). 2 4 1 R. Richter and H. Ulrich, Chem. Ber. 106, 1501 (1973). 243 E. C. Taylor and A. MclCillop in “The Chemistry of Cyclic Enaminonitriles and o-Arninonit)riles,” pp. 113-1 18. Wilcy (Interscioncc),Now Yorli, 1970. 243 E. C. Taylor and A. McKillop, in “Tho Chcmistry of Cyclic Enaminonitriles and o-Aminonitroles,” p. 295. Wiloy, (Intorscionce),Now York, 1970. 244 J. D. Fissokis and F. Sweot, J . Org. Chem. 38, 1963 (1973). 238
239
Sec. IV.A.21
THIOUREAS IN THE SYNTIIESIS OF HETEROCYCLES
(106)
129
(107) H = -('H=CH, (108) rz = CHM~
I
OMC3 (109) 1C =
('H-hl~.
I
NHCNH,
II
8
Luknitsliii et nl.245reported preparation of the liexahydropyriinidin4-one-2-thione 110 by fusion of thiourea with 4-trichloromethyl-2oxetanone (111) a t 110- 130". Performing the reaction in ethaiiolic triethylamine gave an oxaziiie product instead. With selenopseudoureas, 111 gives 1,3-~eIenaziiies.~~~
A promising new method €or the preparation of thiobarbituric acids (112) involving the reaction of carbon suboxide with various arylt,liioureas was reported by Baranova et al.247 24B
246
F.I. Litknitskii, 11.0. Taubc, ancl U. A. Vovsi, ZIL.Org. Khina. 5 , 1844 (1969). F.1. Liiknitskii, U. 0. Tnubc, arid U. A. Vovsi, Uokl. Akncl. Nuuk SSSR 184, 355 (1969).
247
N. A. Baranova, V. G. Reilin, and L. B. Dashkevich, Z / L .Org. K/uim. 6, 1734 (1970).
130
T. s. QRIFFIN, T.
s. WOODS,
AND D. L. KLAYMAN
[Sec. IV.A.3
0
(112)
Only one report of a pyrazine-type compound apparently utilizing a thiourea has appeared. Tashika and Nitta248found that the iodine/ thiourea oxidation of a-aminoacetophenone hydrochloride gave 2,5diphenylpyrazine (113). The authors do not discuss the mechanism nor the function of the molar quantity of thiourea in the reaction.
3. Three Nitrogen Atoms
The chemistry leading to the formation of s-triazines from thioureas has been of considerable interest historically, and is well summarized in a monograph by Smolin and R a p o p ~ r t thus ~ ~ ~ the ; newer or less common aspects of these reactions will be dealt with here. One of the most convenient methods of preparing s-triazines from thioureas is by the action of acyl isothiocyanates on 2-thiopseudoureas, first studied by Johnson et al.250and later by Douglass and D a i n ~A. ~ ~ ~ recent report of this reaction was made by Goerdeler and N e ~ i T e r , ~ ~ ~ who prepared a series of s-triazinethiones (115) by treating 2-thiopseudoureas with benzoyl isothiocyanate (114, R = Ph). These authors 253 also studied the reaction of carbethoxy isothiocyanate (114, R = EtO) with 2-thiopseudoureas to prepare several 2-slkylthio-striazin-6-one-4-thiones (116). A unique s-triazine-producing reaction involving isothiocyanates was studied by Ghosh and G ~ h a who , ~ ~ ~ Y. Tashika and Y . Nitta, J . Phurm. SOC. Jup. 72, 1157 (1952). E. M. Smolin and L. Rclpoport, “Tho Chemistry of Heterocyclic Compounds” (A. Weissberger, ed.), Vol. 13. Wilcy (Intorscience),New York, 1959, 2 5 0 T. B. Johnson, H. S. Bristol, M. S. Elmer, and W. B. Cramer, Amer. G1~e.m. ,J. 30, 167 (1903). 251 I. B. Douglas and F. 13. Dains, J . Amer. Chem. SOC. 56, 719 (1934). 2 5 2 J. Goerdeler and J. Neuffer, Chem. Ber. 104, 1680 (1971). 253 J. Goerdeler and J. Neuffer, Chem. Ber. 104, 1606 (1971). 254 T. N. Ghosh and P. C. O;uha,J.Indian Chern.Soc. 7,2G3 (1930). 248
249
Sec. IV.A.31
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
131
0
A
N
,
RS ANAS H (116)
found that l-carbethoxy-3-aryl-2-thioureas (117) on treatment with isothiocyanates yield the dithiocyariuric acid derivatives 118.
S I1
ArNHCNHC0,Et
+
- LNR HN
RNCK
O A N A s
(117)
I
Ar
(118)
A useful preparation of s-triazines from thioureas which has received scant attention in the literatim is to be found in the work of who discovered that treatment of thiourea with aldehydes in the presence of amiries leads to hexahydro-s-triazinethiones (1 19) in high yields. The starting thiourea may be 1,3-disubstituted, and the amiries
k (119)
and aldehydes may be widely varied in structure without deterring the cyclization. Steindorff and Paquin 2 5 6 liad previoiisly proposed a 255 256
W.J. Burke,J. Amer. Cheni.Soc. 69, 2136 (1947). A. Stcxindorff and M. Paquin, U.S. Patent 2,01G,521 (1935); Ciicni. Abstr. 29, 8182 (1935).
132
T. s. GRIFFIN, T.
s. WOODS,
AND D . L. KLAYMAN
[Sec. IV.A.3
similar process leading to 119 (It’ = Me, R = H) by treating thiourea with the acetaldehyde-ammonia adduct. This reaction had been studied by N e n ~ k ini ~1874, ~ ~ who mistakenly formulated the product as “DiBthylidenesulfoharnstoff.” Furthermore, Ahmed and Subba Rao258 have reported that the reaction also proceeds with ammonium acetatte in place of the amine and with various aromatic aldehydes (R’CHO) to give 119 (R = H). Similar results were reported by Kr&ssig and Egar 259 when thiourea was heated with benzaldehyde without an amine present to give 119 (R’ = Ph, R = H) and an alcohol-insoluble polymer. When the reaction was carried out under a nitrogeii atmosphere the product was 120. Several groups have studied tlw formalion of products analogous to 120 by the interaction of aldeh j tlw with various mono-26oand d i t h i o b i u r c t ~in~the ~ ~ presence ~~~ of acid catalysts; thus, dithiobiuret itself would seem to be a likely internictliatc in the formation of 120. Davidson 51 has replaced the i~ldehydesin the dithiobiuret reactions with acetone and prepared the G,B-diniethyl ailslogs o f 120, as did Chase and Walker262in the thiopseudourea series. Foye and Hefferren 2 6 3 also studied the reaction of dithiobiuret with various aromatic aldehydes and with 1-propanal; however, they incorrectly assigned a linear Schiff base structure to the products. s-Triazines may also be prepared by treatment of arnidinothioureas 121 with cyanainide as reported by Kurzer and who found that the ratios of the three products 122, 123, and 124 could be controlled by varying temperature and solvent. The authors speculated
(122) x = s (123) X = NR 257 258
Lzg
M. Nenclci, Ber. 7, 158 (1874). I<. Ahmrd and N. V. Subba Rao, Proc. Indzan Acad. Sci., Sect. A 55, 284 (1962);Chem. Abstr. 58, 4569 (1963). 11. lirabsig and G . Egar, Makromol. Chem. 18/19, 195 (1956);Chem. Abstr. 51, 738 (1O67).
J . S.Daoidion, pcrsonal conimunication. L’,l 142, 14:. Siiiis5rnnn, (4.J. Hito, and Wr. 0. Foye, J . Org. Chem. 22, 824 (1957). xJ213. H. Cliasc. clli(L ,I. Walker, J . C‘henz. Soc., 4443 (1955). 26 M . 0. Fo) tl m d J. J . Hoffarren, J . Amer. I’harjn. Ass. 42, 31 (1953); CherrL. .4bstr. 47, 3524 (1963). I<’. ~ \ L I I L ( . Va r i c I R . 11. Pitchfork, J . Chenh.S’oc., 6296 (1965). lbo
Sec. IV.A.31
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
133
that formation of' the products was via an unisolated biguanidothionrea intermediate and have also reported the reaction of 121 (R = Ph) with diphenylcarbodiiniide to give the triphenyl derivative 125.265A novel reaction of an arnidinothiourea with carbon disulfide has been recently reported266to yield 126 in addition to a thiadiazine product. In the
Ph
(125)
earlier literature, Chase and Walker 2 G 2 studied the interaction of amidinothiourea with acetone in the presence of piperidiiie to give a similar product 127. Another useful triazine preparation from amidinothiourea (121) is detailed in the work of de Lannoy and NasielskiH i n l i e n ~who , ~ ~reported ~ the formation of 128 in 83% yield by treating 121 (R = H ) with ethyl formate in the presence of strong base. Another type of reaction leading to s-triazines from thioureas is that of Johnson and Nenge,2G8who reported that the imidothiocarbonate 129, when treated with %-ethyl-2-thiopseudourea,gave the triazine Ph
EtOCSEt
(130)
(129)
product 130. Another starting material was employed by Guha et aZ.,2G9 who prepared 132 by treating 131 with thiourea.
1; i EtOC'NHCOEt
+ HZNCSNH,
K N I i
+
EtO
iNAS H
(131)
(132)
E'. 1htr.wr and E. U. I'itclifork, J . C,'/ie)r~.SOC. C , 1878 (1967). J . D. U h a k u , J . It%dun,Chena.Soc.49, 1151 (1972). Zb7 J. dc L;~nnoy a n t l I< Naiirlslci-E-linken.;, BUZZ.SOC. Chain. Relqes 81, 387 (1'372). T. 13. Johnson an(i G . -\. Alcnge, i l m e r . Chern. J . 32,338 (1904). 269 1'. c'. Gtilia, $. l h o , ant1 ALSalctorw,J. I n d m 1 Chem. SOC. 6, 665 (1929).
OfiG
134
T.
s. GRIFFIN, T. s. WOODS, AND u. L.
KLAYMAN
[Sec. IV.B.l
4. Four Nitrogen Atoms The only report in the literature of the preparation of a tetrazine from a thiourea is that of Naik,270 who claimed to have isolated hexahydro-1,2,4,5-tetraphenyl-1,2,4,5-tetrazine-3,6-dithione (133) on treatment of 1,3-diphenyl-2-thiourea with sulfur monochloride in refluxing benzene. Since the only evidence presented for structure 133 S
phNKNPh S (133)
was an elemental analysis, alternative structures cannot be ruled out. Further work on this reaction is warranted.
B . NITROGENAND SULFUR-CONTAINING RINGS 1. One Nitrogen Atom and One Sulfur Atom The preparation of 1,3-thiazines utilizing thioureas has been reviewed271 and also is briefly summarized in a paper by Cain and W a r r e ~ i e r . The l ~ ~ 1,3-thiazine ring system may be prepared by intramolecular cyclization of variously substituted propylthioureas. Several groups have studied the behavior of 1-(2-carboxyethyl)-2-thiourea derivatives (134) on heating in the presence of acetic anhydride to give 135. claimed to isolate solely products of type 135 in good yield; whereas, DerBaj-Bizjak 236 and P r o ~ e nand ~ ~their ~ co-workers
obtained mixtures of 135 and pyrimidines, the former being favored by prolonged heating.236Behringer and Zillikens121 reported that treatI<. G. Naili,J. Chem.Soc. 119, 1166 (1921). It. C. Elderfield and E. E. Harris, a n “Hetrrocyclic Compounds” (R. C . Elderfiold, od.),Vol 6, pp. 601-623. Wiley, New York, 1987. 272 T. N. Ghosh, J . Indaan C‘hem.SOC. 1 1 , 2 3 (1934).
270
271
Sec. IV.B.11
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
135
nient of the thiopseudourea ester 136 with aqueous alkali gave the tctrnhydro-l,3-thiazines 137 (I3 = H, Et). 0
Several workers have studied other cyclization reactJions involving various leaving groups. Thus, compounds 138 have been shown to cyclize to 1,3-thiazines (139) under acidic or alkaline conditions. The earliest recorded reaction of this type is th at of K ; ~ h a nwho , ~ ~in~1897
reported the cyclization of 138 (R = P h or Et, R' = R" = Me, X = H, Y = OH) t o the analogous 139 in concentrated hydrochloric acid. Later workers 2 7 4 utilized the same reaction type t o prepare other compounds in the series, and in 1967 Cherbuliez et ~ 1 studied . ~these~ reactions and found by NMR model studies th a t on cyclization of various 138 (R' = R" = X = H, Y = OH), the exocyclic position of the C-N double bond is favored in the product if R is aromatic a n d the endocyclic positioii if R is aliphatic. Cherbuliez and his associates also reported cyclization of 138 where Y = OP0,H,lo5 and OS03H.lo6 Other ~ ~ ~ r k e have r s studied ~ ~ ~a similar , ~ ~process ~ * in ~ the ~ analogous ~ thiopseudourea series (Y = NH,) leading to 1,3-thiazines, including a n analysis of the kinetics of the c y ~ l i z a t i o n . ~ ~ ~ The 1,3-thiazine ring system may be prepared by treating various 273
RI. Kahan, Ber. 30, 1318 (1897).
F. B. Dams, It. Q. Wrciister, J . S. Blair, and W. C. Thompson, J . Amer. CILem. SOC.44, 2637 ( 1 9 2 2 ) . 2 7 5 E. Cherbuliez, Br. Baehler, 0 . Espcjo, 1%. Jindra, B. Willhalm, and 3 . IZabinowitz, Helv. Chzw~.Actu 50, 331 (1967). 276 V. M. Fcdoseev, G N. Shnlaeve, and V. I. Pershin, Zh. Org. Khzna. 4, 1791 274
277
(1968). V. M. Fedosccv and I. V. Filippovich, Zh. Obshch. IChim. 34, 1556 (1964). V. M. Fedosrw and V. 8. Churilin, Zh. Org. Kham. 8, 2434 (1972).
~
136
T. S. ORlFFJN, T. S. WOODS, A N D D. L. KLAYMAN
[Sec. IV.B.l
cr,P-unsaturated carboxylic acid derivatives (140) with thiourens. Using this reaction Noniura r t ~ 1 1 prepared . ~ ~ ~ tlie tetrahydroiminothiazinoiie 141 (1%= R’ = H, Y = C1) by treating thiourea with acryloyl chloride 0
(140)
(141)
(140, It = R’ = H, X = Cl). Taborsky280also used this method to prepnre the substituted 141 (R = Ph, R’ = E t , Y = HSO,) from actliylcinnamic acid (140, R = Ph, R’ = Et, X = OH); similar work was performed by ‘I‘akemoto et aZ.281These reaction typcs are discussed briefly in a review of 4-tliiazolidiiiones by Brown.139 Overberger and Friedrnan 2 R 2 were able to show th at 1,3-dipheny1-2-thiourea also undergoes this reaction to give the 3-phenyl-2-phenylimino analog of 141. Results similar to the abovc were reported b y Zimmeriiiann,2Q3 who prepared 141 [R = C0,R” (R” = various aliphatic groups), R’ = H , Y = C1 or Brl. Aknslii et aZ.2s4 studied a similar process in t>heir report of the interaction of 140 (R = H, R’ = CH,CO,H, X = OH) with thiourea t o give a n analog of 141 (R = H, K’ = CH,CO,H) which contains a 2-carbonyl rather th an 2-imino group. Also, triazincs are formed on BF, treatment of a,P-unsaturated carbonyl compounds and thiourea~.~~~ Many workers have employed P-halocarboxylic acids (142) to prepare tetrahydro- 1,3-thiazines (143) from thioureas. The halogen atom (X) 0
(142)
H (143)
M. Noniuru, Y . Nagano and l i . Terrtniura, Yukb Gosei Kagakii Klyokai Slii 30, 971 (1972); Chetn. Abstr. 78, 84342 (1973). K. G. Taborsky, J . Org. Chern. 23, 1779 (1958). 201 I<. Talccvrioto, H. Tahara, Y. Inaki, ant1 N. Uccln, Ghem. Lett., 767 (1972); C h e m Ab&. 77, 1 3 9 9 6 3 (1972). ~ 282 C. C . Ovcrborgcr, and 1%. A. Fricd~nan,J . Orq. Chern. 29, 1720 (1964). 283 R. Zimniormann,Angew. Che7n. I n t . Ed. Engl. 1, 663 (1962). 284 FI. Rkaihi, I?. Masutla, C. liutsutla, and T . Kobayashi, Mern. Fnc. Eng., Kobe Univ., 151 (1970);Client. Abstr. 73, 3433m (1970). 285 R . Hoff and A . P. Rlolr, Rec. Trav. Chim. 92, 631 (1973). 279
IV.B.11
&C.
137
‘L’HIOUREAS I N THE SYNTHESlS O F HETEROCYCLES
may be ~ l i l o r i n c b, ~r ~ ~ n ~i i~ n~ e~or , ~i o~ d~i i~i ~~, ~~ and *~~ ~the second P-substitilent ( R ) may be liydrogeri,~86.~D7~.289 ary1,28D or a r ~ y l (lY~of~ 143 may be Nfl or 0). I w o groups have reported pre1)aration of 1,3-tl.iiazines begiiiniiig with P-dicarbonyl compounds. The reaction of thiourea with 2-nitropropanedial 144 was reported by Hale arid Brillzg0to give 145. Similar r7
NOL
I
HC‘O(’H(’H0
+
H,N(’SNH,
-(’lNTL H
(144)
(145)
work involving both j3-di:ildehydes and P-diketones was reported later by H a r t i n ~ n n . ~Heterocyclcs ~’ containing only one douhle h i i d aiialogous t o 145 arc obtained when thioureas react with a,j3-unsaturated ketones or ~ - h y d r o x yketones 2g2 or with acetone 262 (probably via intermediate niesityl oxide). l’akamizawa ef a1.2g3,294 have reported the investigation of tho reaction of the unsaturated clicthers 146 with variously substitutcd thioureas t o give diliydrotliiaziuoiies 148. The snbstitnent m : b g be carbethoxy (X = C02Et)2g4 or cy:rno (X = CN),293and in the former case it was possible t o isolate the 2-imiiio intermediate 147 (X = C0,Et) I<
1%
- rAN, r< A, s
I3tOCH,(’=CHC)Me
I
x (146)
+ I%NH(’SNHit’
/
S
(147)
/
N/
H.O (-R’YH,)
‘S
N/
0
(148)
Other useful reagents for the preparation of tetrahydro- 1,j-thiazincs with a 5-hydroxy substitilent (149)are 3 - ~ h l o r o or - ~3-phthalimido-2g6 ~~ Y o . V. VladLimirskayn and N. M. Turltcvich, ddatrr. Peruogo L’seross. S’ezda Farwb. ( M o s c o w :M r d ) Sb., 298 (1962);Chena. Abstr. 63, 2967g (1965). 287 N. M. Turkovich, Ye. V. Vladzimirsltaya, and L. M. Venpnovlch, Khim. Geterotsikl. Soedur., 504 (1969). 2 8 8 I<. W. Wheeler and V. W. Gash, U. S. Patent 2,585,064 (1952); Chem. Abstr. 46, 7593 (1952). 289 N. A. Langlet, Rer. 24, 3848 (1891). 290 W. J. Hale and H. C. Brill, J . Amer. C h ~ mSoc. . 34, 295 (1912). 291 H. Hartmann, Tetrahedron Lett., 3977 (1972). 292 K. Zimmcrmann, Angetu. Chena. 75, 1023 (1963). 293 A. Takaniizawa, I<. IIirai, Y. Sato, and I<. Tori, .I. Or{].Chem. 29, 1740 (1964). 294 A. Takarnizawa antl I<. Hirai, J . Org. Chem. 30, 2290 (1965). 298 F. G. Moore antl F. R. Dams, U ~ L LKansas V. Sci. Bull. 18, 633 (1928); Chem. Abstr. 24, 2133 (1930). 286
138
T. s. ORIBBIN, T.
s. WOODS, AND
D. L. KLAYMAN
[Sec. IV.B.1
epoxides, which on reaction with thioureas produce the products 149 (R = HZg6or arylZg5).
An interesting rearrangement of thioureas leading to tetrahydro1,3-thiazines has been reported by TiBler,297*298 who found that 1trimethylene-3-aryl-2-thioureasundergo facile conversion to 150 in concentrated HC1. The same products (150) could also be prepared by treating the appropriately substituted thiourea with 1,3-dibrornopropane.298 A preparation of the thiazine ring system which should be investigated for generality is that of Baranova et al.,247who interacted the 1-aroyl-2-thioureas 151 with carbon suboxide to give 152. Compounds of structure similar to 152 were also obtained starting with 1,l-disubstituted t h i o u r e a ~Treatment .~~~ of other cumulenes 153, ketenes(X = 0)
i;r
H,NCNHCAr
+ O=C=C=C=O
-
i/
NHCAr
0 ’
(151)
(152)
and ketenimines (X = NR’), with thiocarbamoyl isothiocyanates (154) was reported by Goerdeler and Ludke167 to lead t o 155. They also found that bicyclic 1,3-thiazines were formed on treatment of 154 with cyclic e n a m i n e ~ . l ~ ~ S S R’
>,=C=X
II
+ (R3),NCNC8
R’ + ~2
X< 1 N ( R 3 ) ,
R2 (153)
(154)
(155)
There has been some controversy in the literature over the structiire of the products obtained from the reaction of thioureas with acetylenic V. M. Fedoseev and V. S. Churilin, Z h . Org. Khirn. 8,205 (1972). M . TiBlcr, Tetrahedron. Lett., 12 (1959). 290 M. TiBler, Arch. Pharm. (Weinheim)293165,621 (1960). 297
Sec. IV.B.21
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
139
esters. The vast majority of papers, even in the more recent literature, have referred to these products as 1,3-thiazines. The latest evidence indicates, however, that these products are actually iminothiazolidinones166(see Section 111,B, 1). 2 . Two Nitrogen Atoms and One Xulfur Atom
Only one kind of six-membered ring system containing two nitrogens and one sulfur has been prepared from thiourea-type starting materials, namely 1,3,5-thiadiazines. The first report of this sort of preparation is that of Fromm and W ~ d l e rwho , ~ ~ in 1908 found that the thiourea
(156)
(157)
156 cyclizes under the influence of alkali t o give 157. A more general process has recently been exploited by Dhake 266*299 to prepare compounds of type 159 (X = S, Y = NHR,) by treatment of the 1amidino-2-thiopseudoureas 158 with carbon disulfide. The thiadiazine products 159 are favored a t short reaction times, but s-triazines are Y
II
NH
II
NIX’
(158)
(15%
produced on prolonged heating of the mixture. Compounds of type 159 (X = S,Y = Me,N) may also be prepared by treating amidinothioureas witjh thiophosgene in the presence of triethyl amine.300Products of structure 159 (X = 0, Y = Me,N) may also be gained by treatment of amidiriothioureas with 1,l’-carbonyldiimidazole.301 Another procedure leading to similar products is the treatment of 2-methyl-2,4-dithiopseeudobiurets with phosgene to give 159 (X = 0, Y = SMe), with thiophosgene to give 159 (X = S , Y = SMe), or with p-tolueneaulfonylcarbonimidoyl dichloride to give 159 (X = N-p-tolyl, Y = SMe).83 J. D. Dhake, Indian J . Chem. 9, 1415 (1971). J. E. Oliver and A. B. DeMilo, J . Heterocycl. Chem. 8, 1087 (1971). 301 J . E. Oliver, B. A. Bierl, and J. M. I t u t h , J . Org. Chem. 37, 131 (1972). 299
300
140
T.
s. GRIFFIN,
T. s. WOODS, A N D D. L. KLAYMAN
[Sec. IV.B.3
Formaldehyde has been employed to prepare analogs of 159 with a higher degree of saturation. Thus 160 may be made by treating 1,1,5trimethyl-2,4-dithiobiuret with refluxirig aqueous formaldehyde,lS7and
(160)
(161)
the series 161 is formed on treatment of disubstituted thioureas with formaldehyde in the presence of hydrogen sulfide.302 A very useful preparation of 1,3,5-thiadiazine type rings involves the report of Goerdeler and L i i ~ i k e ~that ~ ? 154 undergoes reaction with phenyl isocyanate to give 162 (X = Ph, Y = 0) and with carbodiiiiiides to give 162 (X = R’, Y = NE’). Other compounds 163 may be prepared by treatment of 154 with benzaldehyde imines,16? a process which was also recently utilized by Kristian et aL303 S
H
(162)
(163)
Less useful preparations of 1,3,5-thiadiazines in which they are formed as components of mixtures include that of Chase and Walker.262 They isolated a thiadiazine as a product of the reaction of thiourea, bromine, and p-chlorophenylacetonitrile in acetone. The function of the nitrile, which was riot incorporated into the product, is not apparent. The product of a similar reaction, without the nitrile, was assigned a dithiazine structure by B a ~ m a n nOliver . ~ ~ ~and Stokes202also reported that a 1,3,5-thiadiazine is formed among the myriad of identified products of the 15-month air oxidation of 1,1,5,5-tetramethyl-2,4dithiobiuret . 3 . One Nitrogen Afom and Two Xulfur Atoms
The dihydro-1,3,5-dithiazinering system 165 can be prepared by treatment of thiourea or monosubstituted thioureas with geminal M. C. Sciclel and li’. E. Bocbttner, J . Hcterocycl. Ckern. 9, 231 (1972). I’. Kristian, D. Koscllc, and J. Bcmat, Chem. Zvestz 27, 280 (1973); Chem. Abstr. 79,53271 (1973). 304 E. Baumann, Her. 18, 883 (1885).
302
303
SeC. Iv.c.11
T H IOURE AS I N T H E S Y N T H E S I S OF H ETERO CY CLES
141
dihalidcs (164). The halides are usually unsubstituted (R' = H); however, one report using phenyldihalo- or methyldihalomethaiies has appeared.16 The halogen (X) of 165 may be chlorine,16 I ~ r o r n i n e , ~ ~ . ~ ~ ~ or iodine.16.305,306
C . NITROGEN-AND
OXYQE N~ONT AIN IN G
RINGS
1. One Nitrogen Atom and One Oxygen Atom
The preparation of dihytlro-4H- 1,3-oxazinones (166) from mono-239.240 or disubstituted 307 thiopseiidoureas has been accomplished by their reaction with diketene. In one case,239a 2-alkylthio intermediate in the
formation of 166 was isolated a t low temperatures. At higher temperatures, 166, resulting from elimination of thiol from the intermediate, was obtained along with some pyrimidine side product. Luknitskii et al.245prepared 167 by treatment of a thiopseudourea with 4-trichloromethyl-2-oxetanone(111). Interestingly, beginning with a selenopseudourea in this reaction, the product is the 1,3selenazine analog of 167,245having resulted from loss of the elements of ROH rather than RSeH as would have been expected from the example leading to 167. I n a different synthesis of the 1,3-oxazine ring system, Ignatova et al.308 reported preparation of 170 in yields of 70-93% by the reaction of C. H. Grogan ant1 I,. M. Rirc,J. 07g. Chem. 28, 248G (19G3). U. T. Ebayan and E. 14:. Ogancsyan, Uold. 31,ud. Nuul, AT/,L. S S R 31,87 (1960); C'hem.Abstr. 55, 104661 (19Gl). 307 R. N. Lacey, .I. C'lrern. S o c . , 845 (1964). 308 L. ,I.Ignatova, P. L. Ovcehltin, M. Z.Branzburg, A. Yo. Gckhman, and B. V. UnkovsBii, lilizm. Ceierotsikl. Soedm., 1037 (1972).
305
306
142
T.
s. GRIFFIN,
T.
s. WOODS, AND
D . L. KLAYMAN
[Sec. 1V.D
the hydroxypropyl thiourea 168 with iodomethane followed by treatment of the intermediate thiopseudourea 169 with alkali.
SMo (169)
2 . Two Nitrogen Atoms and One Oxygen Atom
The only preparation of a ring system of this type from thioureas, which has been reported in the literature, is the tetrahydro-1,3,5oxadiazine series of Seidel and B ~ e t t n e rwho , ~ ~synthesized ~ compounds 171 by treating thioureas with formaldehyde in the presence of p toluenesulfonic acid.
D. MISCELLANEOUS SIX-MEMBEREDRINGS A recent report of Winterfeldt 214 indicated that 2,3,5,6-tetracarbomethoxy-4H-thiin-4-one (172) is obtained, among other products, when 1,1,3,3-tetramethy1-2-thioureais treated with dimethyl acetylenedicarboxylate. 0
(172)
Perhaps the most unusual six-membered ring compound prepared from a thiourea analog is to be found in the report of Luknitskii et al.,248 who treated 2-ethyl-2-selenopseudourea with the trichloromethyl
Sec. V]
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
143
sultone 173 to give the novel tetrahydro-l,4,2-thiaselenazine-l, 1-dioxide 174.
H-j$
+ FtSC=NH
-
A , c NIT, ,
0-SO,
0,
cWJ;~NH H
(173)
(174)
V. Seven-Membered Rings The literature of seven-membered ring heterocycles prepared from thioureas is very limited, and some of the structural assignments that have been made are open to serious question. Ghosh309proposed that the reaction between 1-(2-aminophenyl)-3-substituted-2-thioureas and a-bromoacetophenone produced 2-bromomethyl-3,1,5-benzothiadiazepines. Pathak,310in refuting the structure proposed by Ghosh, asserted that the product could not contain bromine, but his alternative structures are somewhat tenuous. I n view of other work, Ghosh's product could be a 2-imino-4-thiazoline derivative of the thiourea (see Section 111, 13, 1). Ghosh309 proposed structure 175 (X = 0) for the reaction product between a 1-(2-aminopheny1)-2-thioureaand phosgene, S
II
@,t~NHR
+ COCI,
NHIt
7
N H
-4 X
(175)
although more recent work suggests that the product could be a 1,3thiazetidin-4-one (one possibility is 6, Ar = 2-aminophenyl, Ar' = R, X = 0) formed only from the thiourea portion of the molecule. Ghosh and G11ha311 reported a series of ring closure reactions of o-phenylenebisthioureas (176) to form the 1,2-dihydro-3,1,5-benzothiadiazepine-2-thiones (175, X = S). I n the case of the corresponding o-phenylenethiourea-ureas, the products were considered to be tetrahydro-l,3,5-benzotriazepinesif R was an aryl group or dihydro-3,1,5benzothiadiazepines if R was ally1 or methyl.311 T. N. Ghosh,J. 1ndianChem.Soe. 8, 71 (1931). K. B. Pathak, J . Indian Chem. SOC. 12,463 (1935). 311 T.N. Ghosh and P. C. Gtlha,J. IndianChem. SOC. 6,181 (1929). 309
310
144
T. S. GRIFFIN, T. s. WOODS, AND D . L. KLAYMAN
[Sec. V
S
II
R (176)
Johnson and Hill,312 on attempting to synthesize 6-allyl-2-thiobarbituric acid, reported formation of the 2-amino-4,5,6,7-tetrahydro- 1,3-thiazepin-4-one 177 from the reaction of thiourea with allyldiethylmalonate.
tLNH2q?"..
Et0,C"
N
0 (177)
N
0
Ph (178)
1,3-Diphenyl-2-thiourea, when heated under reflux in acetone with 4-bromobutanoyl chloride, was reported by Reinhoudt 212 to give a 19% yield of 2-phenylimino-3-phenylperhydro-l,3-thiazepin-4-one (178). I n addition, cyclization of the thiourea 179 gave the disubstituted 3-aminolH,AH-2,4-benzothiazepin-5-one (180; R1R2 = 0). Other derivatives (180; R1 = R2 = H, or R1R2= 0; R3 = R4 = CH,) could be prepared via cyclization of the thiopseudoureas 181. In this case, if R3 was phenyl and R4 was hydrogen, then the product was a 2-phenylimino modification of 180.212
312
T. B. Johnson und A. J. Hill, Amer. Chem. J . 45,356 (1911).
Sec. VI.A]
THIOLJREAS IN THE SYNTHESIS OF HETEROCYCLES
145
VI. Heteropolycyclic Rings
A. QUINAZOLINES (1yclohcxanones have been employed ill reactions with thioureas t o give quinazolines with varying degrees of saturation. For example, octahydroquinazoliriedithiones (182) have been pre1)nred froill :,y i - l o hexanone and symmetrical 313-315 or unsyinrnetrical 31 * disubstitutecl
(184)
(183)
(182)
thioureas. Similar compounds can be obtained from 2-carbalkoxycyclohexanones and thiourea to give 183 (R = H) or with a thiopseudourea t o give 183 (R = Me),316a process which has been extended to produce the benz~g]hexahydroquinazoline184.317A similar product is formed when thioureas are heated with 2-carbethoxy-l-amino~yclohexene.~~~ A more unusual leaving group was employed by Zigeuner et aZ.,318who prepwed an octahydroquinazoline by trcat,ing 2-(N,N-dimethylaminomethy1)cycloliexanone with thiourea in methanolic sodium methoxide. Another series of octahydroquinazolines (186) was synthesized b y Sammour et aZ.,319who treated the bisarylidenecyclohexanone 185 with various thioureas in etlianolic potassium hydroxide.
+ H,N(’SNHH
6 0 11
EtOH
CHAr (185)
(186)
J. Hohorn, Rocz. Chem. 29,849 (1955). J. Schoon, Rocz. CILena. 35, 967 (1961). 315 J. Schoen and K. Bogdanowicz, Rocz. Chem. 36, 1493 (1962). 316 F. H. S . Curd, L). N. l-hhardson, arid F. L. Rose,J. C‘hem. Soc., 378 (1946). 317 A. Rosowsky, El. I-’.Burrows, P. C. Huang, and E. J. Modest, J . Heterocycl. Chen~. 9 , 1239 (1972). 318 G . Zigcumer, V. Eiscnreich, and W. Irmnel, Monatsh. Chem. 101, 1743 (1970). 319 A. Haininour, A Marel, nncl M. H. i ll. Hnssein, U . A . R . J . Chew&.12, 451 (1969); Gliem. Abstr. 74, 53702 ( 1 9 7 1 ) . 313
314
146
T. s. QRIFFIN, T. s. WOODS, AND D. L. KLAYMAN
[Sec. V1.A
Many workers have employed anthranilic acid derivatives (187) to prepare tetrahydroquinazolines. Thus Deck and Dains 320 synthesized a series of tetrahydroiminoquinazolinones (188) by conducting the reaction with 2-thiopseudoureas in refluxing xylene, and two other ~ ~ ~ * 188 ~ ~ (R' ~ = H, R" = Ph, R" = H). groups of w ~ r k e r s prepared
Isatoic anhydrides have recently been employed 323*324 as anthranilic acid analogs to prepare additional compounds in the series. Similarly an intramolecular cyclization of 1- (2-cyanophenyl)-3-phenyl-2-thiourea, an anthranilonitrile derivative, was employed by Taylor and Ravindranathan 325 t o give an iminotetrahydroquinazoline. A similar process was studied by Soderbaum and Widman 326*327 in the intramolecular cyclization of 2-(3'-pheny1thiureido)benzylalcohol to give tetrahydroquinazolines. A series of unique quinazolines containing 1-hydroxyl substituents were also reported as resulting from N-hydroxythiourea derivatives of anthranilate esters.328 Spiroquinazolines have been synthesized by two groups. Gawlowski and Mirek329 recently reported the preparation of 189 from cyclo-
(189)
J. F. Deck and F. B. Dains, J. Amer. Chern.Soc. 55,4986 (1933). H. L. Wheeler, T. B. Johnson, D. F. McFarland, J . Amer. Chem. Soc. 25, 787 (1903). 322 N. A. Lange and F. E. Sheibley, J . Amer. Chem. Soc. 54, 1994 (1932). 323 Th. Kappe, W. Steiger, and E. Zieglor, Montash. Chem. 98, 214 (1967). 324 E. Zieglrr, W. Steiger, and Th. Kappc, MOna&h. Chem. 99, 1499 (1968). 326 E. C. Taylor and It. V. Ravindranathan, J . Org. Chem. 27,2622 (1962). 326 H. C. Soderbaum and 0. Widman, Ber. 22, 1665 (1889). 327 H. G. Sodcrbaum and 0. Widman, Ber. 22,2933 (1889). 328 R. Stoffel and H.-J.Brcsse, Arch. Pharm. (Weinheim)306,579 (1973). 320 321
Sec. VLB]
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
147
hexanone and thiourea under acidic conditions; similar results could be obtained beginning with 2-cyclohexylidenecyclohexanone329~330 or with 2-(l-chlorocyclohexyl)cyclohexanone.329 Also, the thiourea may be monosubstituted,330 in which case 1-substituted spiroquinazolines (189) are obtained. The most unusual preparation of quinazolines from thioureas is that of Dzieworiski et al.,331who fused P-naphthylamine and thiourea to give two products, the structures of which they suggested were 190 and 191 on the basis of elemental analyses and hydrolysis of the reaction
mixt8ureto give solely 1,2,3,4-tetrahydrobenzo[flquinazoline-2,4-dione (192); however, the hydrolysis of 191 to give 192 under these conditions is questionable.
B.
4-AMINOQUINOLINES
A useful preparation for heterocycles which has been perfected by Moszew, Dzieworiski, and Schoen, and co-workers, and which has received only scant attention in heterocyclic compendia,332involves the fusion of 1-aryl-2-thioureas containing a proton on the l-nitrogen atom and aldehydes or ketones with a-hydrogen atoms at 150-300” to give 4-amiiioquinoliiies. For example, Moszew 333 reported that reaction of acetophenone (193) and 1,3-diphenyI-2-thiourea (194) gives 4-anilino2-pheriylquinoline (195) and a quinolinoquinoline product. Various J. I?. Gawlowski and J . Mirek, Rocz. Chem. 46, 421 (1972). G. Jacnecke, Z . Chern. 8 , 3 8 3 (1968). 331 K. Dziewoliskl, L. Sternbach, and A. Strauchen, Rocz. Chem. 17, 1 (1937). 332 J. V. Crawforcl and E. T i . Wobster, in “Six-Mernbcred Heterocyclic Nitrogen Compounds with Four Condensed Rings” (C. F. H. Allen, ed.), pp. 114-116. Wilcy (Intcrscience),New York, 1951. 333 J. Moszew, Bull. I n t . Acud. Pol. Sci., Clusse Sci. Math. Nat. A1938, 98 (1938); Chem. Abstr. 33,4987 (1939). 329
330
148
T.
s. GRIFFIN,
T.
s. WOODS,
AND D. L . KLAYMAN
[Sec. V1.B
methylated isomers of 195 were prepared using methyl-substituted acetophenones 334.335 and/or (methylphenyl)thio~reas.~~~-~~~ Naphthylthioureas react with acetophenones to give b e n z o [ f ] q ~ i n o l i n e s ,and ~~~ NHPh I
(193)
(195)
(194)
other substituents have included cliloro on either or both reactants.337 Other carbonyl containing reactants which have been reported are methyl 2,2-diphenylethyl ketone,338 5,6,7,8-tetrahydro-2-acetylnaphtlialene,339 and p h e n y l a ~ e t a l d e h y d e which , ~ ~ ~ react with 194 t o give 4-anilino-2-(2,2-diphenylethyl)quinoline, 4-anilino-2-(2’-tetralyl)quinoline, and 4-anilino-3-phenylquinolinc, respectively. In a special case,336 deoxybenzoin, although lacking a carbonyl group, undergoes reaction with 194 to give 4-anilino-2,3-diphenylquinoline. The mechanism of these reactions has been suggested to involve initial decomposition of the thiourea to isothiocyanate and amine, and the latter reacts with the carbonyl compound to form a Schiff’s base. Condensation of the Schiff’s base with the isothiocyanate present, followed by loss of H,S gives the observed p r o d ~ ~ t s . ~ ~ ~ * ~ ~ ~ The carbonyl-containing reactant may be cyclic, in which case the products are fused quinolines. Thus if cyclohexanone reacts with 194, the product is the tetrahydroacridine 196,313y341or with 1,3-di-2-
(196)
(197)
K. Dziewonski, L. Gizler, and J. Moszew, Rocz. Chem. 15, 400 (1935); Glieni. Abstr. 30, 137tJ4 (1936). 335 li. llzieworiski a n d J. Moszew, B u l l . Int. Acud. Pol. Sci., Clnsse Sci.M a t h . Nut. A1936,258 (1936);Chem. Abstr. 31, 1812 (1937). 336 I<. Dzieworiski and J. Moszew, Rocz. Chem. 14, 1123 (1934). 337 I<. Dziewoliski a n d J. Mayer, Rocz. Chem. 14, 1157 (1934). 338 J . Moszew a n d W. %ankowska-Jasiriska, Rocz.Chem. 29, 541 (1956). 339 J. Moszew a n d M. Hala, B u l l . A c a d . Pol. Sci., S e r . S c i . Chim. 12,393 (1964). 340 J. Moszcw and H. Famielc6wna, Rocz. Chem. 22, 80 (1948). 341 K. Dzieworiski and J. Schoen, B u l l . Int. A c a d . Pol. Sci., Classe S c i . M a t h . Nut. 1934A, 448 (1034);Chem. AD&. 29,2958 (1935). 334
Sec. VI.B]
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
149
naphthyl-2-thiourea, cyclohexanone gives 12-(2-naphthylamino)-8,9, 10,l l-tctJrahydrobenz[n]acridine ( 197).342 a-Tetralone has been utilized in these reactions with 1,3-diphenyl-2thioureas to give dihydrobenz[c]acridiiies and with 1,3-di-2naphthyl-2-thiourea 342 to produce a dihydrodibenz[a,h]acridine (198). 3159341
P-Tetralone gives with 194,343or with 1,3-di-m-t~olyl-2-thio~rea,~~~ dihydrobciiz[a]acridiries (199, K = H, Me); this ketone, on reaction with 1,3-di-2-iiaphthyl-2-thiourea, gives a dihydr~dibenz[a,j]acridine.~~~ A ketone contained in a five-meinbered ring was also employed in these reactions when a-indanone was fused with 194 to give the indeno[3,2-6]cjuinoliiie 200 346 and with 1,3-di-2-naphthyl-2-thiourea to give thc indeno[3,2-h]-1-azaphenanthrene 201.
These reactions provide an important entry into the benzazine series. The parent rings can he prepared froin the products obtained by hydrolysis and dehydrogenntioii over zinc d i ~ s t . The ~ ~simplicity ~ * ~ ~ ~ * ~ ~ of the procedure is an attractive feature even though some of the fusion reactions proceed in poor yield. 342 J. Schocn
and l i . I%ogdnnowicz,Iloca. Chem. 34, 1339 (1960). J . Schocn anti IV. La.;kowslta, R o c z . Clieiri. 39, 1633 (1965). 344 J . Schocn and W. Laskowskn, Hoca. Chem. 40, 1315 (1966). 345 I<. I)zicwolislri, J Schocn, S. Ochab, and I<. Bogdanowicz, Rocz. Cliem. 37, 561 (1963). 346 J. Schocn ancl I<. Bogdanowicz, Rocz. C h ~ m36, . 44.5 (1962). 343
150
T.
S.
GRIFFIN, T.
S.
WOODS, AND
D . L. KLAYMAN
[SeC. v1.c
C. BENZO-AND NAPHTHO-FUSED FIVE-AND SIX-MEMBERED HETEROCYCLIC RINas 1-Aryl-2-thioureas (202) are a n important source of aromatic fusedring compounds. B y far the most frequently encountered conversion of 202 t o the latter are those leading to 2-aminobenzo[d]thiazoles (203),
oxidizing
a
Y
N
H
R
ngent
S
formed by treatment of the thioureas with oxidizing agents. Sprague and Land 75 provided a comprehensive survey of these reactions, covering the literature through 1957, involving oxidation with bromine, sulfuryl chloride, sulfur monochloride, and chlorine. Other oxidants which have been employed are thionyl chloride 347 and sulfur in conjunction with aromatic a m i n e ~ Reports, . ~ ~ ~ including those subsequent t o 1957, which do not present novel uses of the above reactions will be omitted. Other variations of these reactions have included th e formation of compounds of type 203 from bis(ary1amidino) d i s u l f i d e ~and ~ ~2-(2~ aminophenyl)thiopseudoureas.350The same product types 203 have been obtained on oxidation of dithiobiureta 351 or dithiopseudobiurets 352-354 with b r ~ m i n e , ~or ~iodine.353*354 ~ * ~ ~ ~An * interesting ~ ~ ~ product utilizing this reaction type has resulted from treatment of m-phenylenebis(thiourea) with bromine giving th e benzo[ 1,2-d: 5,4d’]bisthiazole 204.355
347
Y .Iwakura and K. Kurita, Bull. Chem.SOC. Jup. 43,2535 (1970).
348T. G. Levi, Atti Congr. Naz. Chim. Ind., 400 (1924); Chem. Abstr. 19, 1411 (1925). G. Barnikow and J. Bodeker, Chem. Ber. 100, 1394 (1967). 350 F. Kurzer and P. M. Sanderson, J . Chem.SOC., 230 (1962). 351 M. G. Paranjpe, IncEianJ. Chem. 6 , 132 (1968). 352 S. N. Dixit, J . Indian Chem. SOC. 40, 153 (1963); Chem. Abetr. 5 9 , 8 7 5 2 ~(1963). 353 V. K . Verma, IncZiunJ. Chem. 1, 300 (1963). 354 C. 1’. Joshua, J . Indian Chem.SOC. 38, 155 (1961). 365 G. Barnikow, H. Kunzek, and M. Hofmann, J . Prukt. Chem. 27,271 (1965). 348
Sec. VI.C]
151
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
A tetrahydrospiroberizothiazole 205 was produced in a different reaction type when an a-bromospiroketone was treated with t l ~ i o u r c a . ~ ~ ~ Similarly, tetrahydrobenzothiazoles arc formed when 6-bromo-2-carbethoxycyclohexanone reacts with monosubstituted t h i o ~ r e a sor , ~when ~~ 2-chlorocyclohexanone is treated with 1,3-disubstituted t h i o u r e a ~ . ~ ~ ~ Lau and Gompf 359 prepared a series of 2-amino-6-hydroxybenzo[d]thiazoles and corresponding naphtho[ 1,2-cl]thiazoles on treating 1,4benzoyuinone and 1,4-naphthoyuinone with thiourea in acidic media a t room temperature. At high temperature the products of the reaction with 1,4-benzoquinone are 5-hydroxybenz[d]- 1,3-oxathiol-2-ones 206.35y-361 With 1,4-naphthoquinones, the corresponding naphth[2,l-d]-1,3-oxathio1-2-ones 207 are formed;362 whereas, with tetrasubstituted thioureas and 1,4-benzoquinone, the benz[d]oxathiolium salts 208 are p r o d u ~ e d . ~ ~ ~ . ~ ~ ~
es 04)
H( R1@;=o ) R (206)
OH
(207)
s
HO
s-
(208)
Benzimidazoles arc obtained when thioureas are treated with o-phenylenediamine.320*365*366 Also a benzimidazole product 209 is formed (210) is oxidized with when 1-(2-aminophenyl)-3-phenyl-2-thiourea mercury(I1) or is heated in hydrochloric acid.311 Matsui et al.368 have recently found that 2-aminobenzimidazoles are produced 356
A. N. Nesmeyanov, K. A. Pcchcrskaya, and T. P. Tolstaya, Uch. Zap. Mosk. 00s. Univ. Im. M . 1.' Lomonosooa No. 132, Org. Khzm. 7, 66 (1950); Chem.
Abstr. 49, 3853d ( 1 966). P. H. L. Wei, U.S. Pattmt 3,694,450 (1972);Chem. Ahstr. 78, 16173 (1973). 358 G. de Stevens, H. A. Luts, and A. Halamandarrs, J . Org. Chem. 23, 114 (1953). 359 P. T. S. Lau and T. E. Gonipf, J . Org. Chern. 35,4103 (1970). 360 H. Burton and S ,B. David, J. Chem. Soc., 2193 (1952). 361 P. T. S. Lau and M. Kostner, J . Oiy. Chem. 33,4426 (1968). 362 D. E. Thurman and H. W. Stollings,J. Ileterocycl. Chem. 10, 117 (1973). 363 H. Hartmann, D.D.R. Patent 80,220 (1971);Chem. Ahstr. 75, 35994 (1971). 364 R.Hartmann, 2. Chem. 11, 381 (1971). 365 A. 12. Todd, F. Rergel, and Karimullah, Ber. 69, 217 (1936). 366 0. Kym,J. Prakt. Chem. 75, 323 (1907). 367 A. Mohsen and M. 14:. Omar, Pharmozze 27, 798 (1972); Chem. Abstr. 78, 72005p (1973). 357
152
T. s. GRIFFIN,
T. s. WOODS, A N D D. L. KLAYMAN
[Sec. V1.C
when 1-(2-aminopheny1)-3-carbethoxy-2-thiourea is heated in strongly protic solvents, or when 1,2-bis(3-carbethoxy-2-thiureido)benzene is treated with heavy metal ions or with alkaline hydrogen peroxide. Benzimidazolinones may be formed on treatment of 1,3-diaryl-2thioureas with sodium p e r o ~ i d e . Other ~ ~ ~ .products ~ ~ ~ reported by Ghosh from reaction of 210 with FeC1, or with nitrous acid were claimed to be 2,1,4-benzothiadiazines311 and b e n z o t r i a z ~ l e srespectively. ,~~~
Fused oxygen and nitrogen-containing rings may also be prepared in reactions with thioureas; thus, dihydrobenzoxazine products are obtained on treatment of salicyloyl chloride with thioureas3I1 or on fusion of salicylate esters with t h i o p s e u d o ~ r e a s When . ~ ~ ~ the thiopseudoureas are treated with o-aminophenol, the products are benzoxaz o l e ~ . ~A~ naphthyl O analog of a benzoxazole is produced on treatment of 1-(2-hydroxy-l-naphthyl)-2-thiourea with dimethyl sulfate.372 Stoffel and Bresse 328 have found that the cyclohexyl-N-hydroxythiourea derivative of anthranilic acid 21 1 undergoes cyclization in base t o give the dihydrobenz~c]isoxazolonecompound 212. With substituents other than cyclohexyl, however, the products of the reaction are quinazolines (see above).
3G8 T.
Matsui, M. Nagano, J. Tobitsuka, and I<. Oyamada, J . Pharm. SOC. J a p . 93, 977 (1978). 360 J. Shibasalti, T. Koizumi, and S. Matsumura, Y a k u g a k u Zasshi 88, 491 (1968). 370 J. Shibasaki, T.Koizumi, and S. Matsumura, Yakugaku Zasshi 88, 499 (1968). 371 E. Zieglcr, G. Kollcnz, and Th. Kappe, Monatsh. Chem. 100, 540 (1969). 372 B. Arvcntiov, M. Strul, H. Wcxlor, and D. Cahano, Acad. Repub. Pop. Rom. Filiala Iasi Stud. Cercet. Stiint. C h i m . 7, 25 (1956); Chem. Abstr. 53, 8083i (1959).
Sec. VI.D]
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
153
A six-membered nitrogen-sulfur heterocycle, namely, a 2,3-dihydro-2imino-4H-benzo[r]tliiitzin-4-onr, is produced on reaction of methyl 2-ctiloro-3,~-dinitro~~~1izoatc with thiourea in basic medium; 3 7 3 furthermore, a tetrahydrospirobc~izottiiazine213 is formed in addition t o its Iiexahydrospiroquiii~zoli~i~~ analog on interaction of cyclohexanone with thiourea in hydrochloric acid.329
Hazzaa et alS3l4 recently reported formation of a series of 3,4-dihydro6,7-dimethoxyisoquinolines(214) on treatment of dimethoxyphenethylthioureas with phosphoryl chloride followed b y oxidation with mercury(I1) chloride. Another use of a thioureit t o prepare a henzo-fused ring system is t h a t of lZeinhoudt,212 who treated the 1-(2-bromomethylbenzoyl)-2thiorireas 215 with sodium carbonate in acetone to give the isoindolin1-ones 216.
D. MISCELLANEOUSHETEROCYCLES A simple preparation of otherwise difficulty prepared heterocyclic ring systems is the cyclization of derivatives of type 217, resulting from reaction of carbethoxy isotliiocyanate with 2-aminoazaheterocycles t o give bridgehead-nitrogen heterobicyclic ,s-triazinonethiones 218. The hetero-rings of 217 which have been reportcd in this reaction are D. S. Dcorha and S. P. Sarren, J . Indian Chein. SOC.42, 97 (1965). A. A. 13. Hazzaa, A. M. M. E. Omar, and M. E. Ragab, P'harmazie 28, 364 (1073.) 375 L. Capuano and H. .J. Schrepfer, Chem. Ber. 104, 3039 (1971).
373
374
154
T.
s. GRIFFIN,
T.
s. WOODS,
AND D . L. KLAYMAN
[Sec. V1.D
S
NHCNHC0,Et (217)
(218)
3 - p y r a ~ o l y 1 3-( ,~~ 1,2,4-tria~olyl),~~~-~~~ ~ 2 - t h i a ~ o l y l , 2~ -~p~. -~~~~i ~ dyl,~~~ and 3 - p y r i d a ~ y l .A~ ~product ~ similar to these, 2,3,6,7-tetrahydro3-phenyl-2-phenyliminothiazolo[ 3,2-a]-s-triazine-4-thione (219), was reported by Klayman and Milne 384 to arise when l-phenyl-3-(2-thiazolin-2-yl)-2-thiourea (220) was treated with phenyl isothiocysriate. R
(220)
(219)
[ 1,2,4]-Triazolo[2,3-a]-s-triazines (221) were prepared by Bokaldere et aZ.3e5 by treating 1-( I,2,4-triazol-3-yl)-2-thiopseudoureas with triethyl orthoformate. The isomeric ring system [1,2,4]-triazolo[4,3-a]-striazine (222) was reported by DeMilo et al.386to arise when the thioureaNMe, 1
(221)
8 I,
(222)
A. Dc Milo, 8th Middlo Atlantic Regional Meeting, Amor. Chem. Soc., Org. Div. Jan. 17, 1973. 377 T. Hiratact, J . M. Tranmoh, H. B. Wood, A. Goldin, and .J. S. Driscoll, J . Heterocycl. Chem. 9, 99 (1972). 378 R. P. Bokaldcro and A. Ya. Liepin, Khim. Geterotaikl. Soedin., 276 (1973). 378 M. Nagano, T. Matsui, J. Tobitsuka, and K. Oyameda, Chem. Pharrn. R,ull. 21, 74 (1973). 380 M. Nagano, J. Tobitsuka, T. Matsui, and K. Oyamada, Chem. Pharm. Bull. 20,2618 (1972). 381 M. Nagano, T. Matsui, J. Tobitsuka, and K. Oyamada, Chem. P h a r m . Bull. 20,2626 (1972). 382 B. Stanovnik and M. TiBler, Synthesis, 308 (1972). 383 M. Zupan, B. Stanovnik, and M. TiRler, J . Org. Chem. 37, 2960 (1972). 384 D. L. Klayrnan and G. W.A. Milnc, Tetrahedron 25, 191 (1969). 3 R 8 1%. 1’. Bokaldore, A. Ya. Liepin, I. R. Mazhoika, I. S. Yankovska, and E. E. Liopin’sh, Khirn. Geterotsikl. Soedin., 419 (1973). 38G A. R. DeMilo, J. E. Oliver, and It. D. Gilardi, J . Heterocycl. Chem. 10, 231 (1973). 37G
Sec. VI.D]
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
155
like compound, 1,1’-thiocarbonyldiimidazole,reacted with a triazinylhydrazine compound. A myriad of types of fused-ring pyrimidines derived from thioureas h a w been reported in the litcrature. For example, Howard and Lindsey387reported the [ 1,3]-dithiin0[5,4-d]pyrimidine ring system 223, and other workers made the octahydrobenzo[b]thieno[2,3-d]pyrimidine 224 in 90% yield.388The formation of both of these products was via a base-promoted condensation of’ a thiourea with a carbethoxy group; however, in the former case the reaction was intermolecular and in the lather, intramolecular. Other unusual fused systems of this type have
included the i n d e n 0 [ 3 , 2 - d ] , ~oxin0[3,2-d],~~~ ~~.~~~ pyrirnidin0[4,5-d],~~~ imidaz0[4,5-e],~~~ and pyrimidino[2’,1’: 2,3]-[1,3]thiazino[5,6-d]394 pyrimidinonethione rings. Several groups have reported reactions giving thiazoloquinazoline compounds, probably the most interesting of which is the cyclizationring expansion of the aziridine thiourea derivative 225 to the dihydrothiazolo[2,3-b]quinazoline 226 in hydrochloric acid of Howard and Klein.395Other preparations of this ring system involve the treatment of l-(2-cerbethoxyphenyl)-2-thioureas with a-chloro 396-398 or abromo ketones or with viciiial ~ l i b r o m i d e s .Tetrahydro ~~~ salt 3969397
E. G . Howard and It. V. Lindsey, Jr., J. Amer. Cl~em. Soc. 82, 158 (1960). S. M. Khripak, A. A . Dobosh, and I. V. Srriolanka, Khim. Geterotsikl. Soedin., 567 (1973). 309 .J. Schocn and S. Fladro, Rocz. Chem. 39, 479 (1965). 390 S. Demerac, L. K . Dalton, anti R. C. Elrncs, Aust. J . Chem. 25, 2651 (1972). 391 H. Schulte, Chens. Be+. 87, 820 (1954). 392 I‘. Rergel antl A. I?,. Todd, J . Chem. Soc., 26 (1938). 393 A. A. Watson, S.C. Ncsnow, antl C?. B. Brown, J . Org. C h m . 38, 3046 (1973). 394 ‘1’. B. ,Johnson and N. A. Siwpard, Airier. Cheni. J . 46, 345 (1911). 3 9 8 J. C. Howard and G. K l c i n , J . Org. Chem. 27, 3701 (1962). 396 M. S. Dliatt antl I<. S.Narang, J . Org. Chem. 20, 302 (1955). 397 M. S. Illiatt aritl I<. S. Narang, 12es. B,ull. East Punjab Uniu. 36, 139 (1953); Chcm. Abstr. 49, 4AFOc (1956). 3 9 0 M. C. Khosltt, 0. 1’. Vig, I. S. Gupta, and K . S.Narang, J . Sci. I d . Res. 12B, 466 (1953); Chem. Abstr. 49, 1089 (1955).
307
300
156
T.
s. GRIFFIN,
T.
s. WOODS,
AND D . L. KLAYMAN
[Sec. V1.D
derivatives of this type may be prepared b y treatment of l-alkyl-3(cyclohexanon-2-ylmethyl)-2-thioureas with haloac acetone^.^^^
Interesting highly colored compounds were reported to be prepared by treatment of 2-substituted tropones with thiourea. Thus the orange or yellow 3-aza-1-thiaazulenes 227 400*401 are formed from 2-chlorotropones; however, the scarlet diazaazulene 228 402 was produced from a 2-mcthoxytropone under the influence of sodium ethoxide.
Reactions leading to two fused five-membered rings may be performed using thiourea-type reactants. Thus cyclization of 1-(N-carbethoxythiocarbamoy1)pyrrole (229)in hot quinoline gives 1,2-dihydropyrrolo[ 1,2-c]imidazolin-7-one-2-thione 403 (230) ; compounds of this type niay also be prepared from 1-(N-phenylthiocarbamoy1)pyrroleb y treatment with thiophosgene .404 A completely saturated analog of 230 has been reported as having been prepared from a thiourea by Stanovnik and TiSler.405Fused five-membered rings, the cyclopenta[d]imidazolines 406 G. Jaenccke and H. J. Mallon, Z . Chem. 8 , 4 6 3 (1968). I. Murata and T. Tozuka, Tohoku Duigaku Hi-sui Yoeki Kagaku Kenkyusho Hokoku 10,257 (1961);Chem. Abstr. 56,3483 (1962). 401 ‘I’. Nozor, S. Ito, K. Kitahara, and T. Ozoki, Tohoku Daigaku Hi-sui Yoeki Kagaku Kenkyusho Hokoku 10, 251 (1961);Chem. Abstr. 55, 25917 (1961). 4 0 2 H. Matsumuta, J . Chem. SOC. Japan (Nippon Kagaku Zasshz) 78, 669 (1957). 403 E. P. Papadopoulos, J . Org. Chem. 38, 667 (1973). 4 0 4 E. P. Papadopoulos, J . Org. Cltem. 31, 3060 (1966). 405 R . Stanovnik and M. Tigler, Croat. Chem. Acta 35, 167 (1963);Chem. Abstr. 60, 6840 (1964). 406 I. V. Smolanka, T. A. Krasnitskaya, and E. G. Mol’nik, Ukr. Khim. Zh. 38, 793 (1972);Chem. Abstr. 77, 152039 (1972). 399 400
Sec. VI.D]
THIOUREAS IN THE SYNTHESIS OF HETEROCYCLES
157
and t he cyclopeiita[d]thi~tzoliiies,407have been reported b y Smolanka and co -workers.
(229)
(230)
Tho reaction of thioiireas with terpenes has been employed to prepare an interesting series, the thiazabicyclo[4.2.2]dec-3-enes (232). The
rcaction, illustrated with liiiioneiie (231), has been studied with thiourea itself in the cases of none different starting tcrpenes all leading t o 232 (R = H)in yields of 26-44%.408 The reaction also leads t o ilr-subxtitutetltlcrivativcs of 232 (R = Me, Ph) with inorlosubstituted thioureas.409Anot)lier heterocyclic compound prepared froin thiourea arid a terpene starting material is the expected tricyclic pyrimidine derived froin ~ - ~ a r b e t h o s y c a r n ~ ~ l i o r . ~ ~ ~ Other ring types prqxwed froin tliioureas include those of Petersen and Heitzer, who prepared the iiaphthoxatliiolones 233 (X = 0, Y = OH) *11 from 2-(2-methylpropanal-2-yl)-1,4-naphthoquinone and 233 (X = NH, Y = H ) 4 1 2starting with a tctrahydrobenz[g]indol-6one, each through reaction with thiourea in hydrochloric acid. Kaushal and Nararig *13 prepared :t series of dihydrothiazolo[4,5-c]cinnolines 1. V. Smolanka and N. K. Man'o, Ukr. K h i m . 211.36, 589 (1970); Chem. Abstr. 73,98856 (1970). 408 L. C. Icing, L. -1 Sribliiskcy, ant1 13. \I7.Stcrn, J . Org. Chem. 21, 1232 (1956). 40q L C. King ant1 E. \V. S t r m i , ,7. Org. Chein. 23, 1928 (1958). 410 PrI. Polonovslri ant1 I).Libcrinann, Bull. Soc. Chzrn. Fr., 1073 (1947). 4 1 1 S. I'(-tersen and H. HeitzcLr, .J?Lstus Liehngs 9 n n . Chem. 764, 28 (1'372). 412 S. Prtcrsrn and 11.Heitzcr, Justus L z ~ h i g A s W L .Cliem. 764, 50 (1972). 413 A. N . Ktiushal aiid K. S. Narnng, Irtdinn J . Chrin. 10, 675 (1972); Chern. Abstr. 78, 4302s ( 1 ! ) 7 3 ) .
407
168
T. s. GRIFFIN, T. s. WOODS, AND D. L. KLAYMAN
[Sec. V1.D
(234) from 3-bromo-4-chlorocinnolirles and inonosubstituted thioureas. Another unusual lieterotricyclic system formed from thioureas is the t,hiazolo[3,4,fi-g,h]purine 235, which results in low yield o n treatment of 6-chloropurines with t h i o ~ ~ r e a s . ~ ~ ~ K'HN
(235)
TWOmodifications of the well-known benzothiazole preparation have 1 been employed to prepare unusual heteropolycycles. Kiinig et ~ treated 1-thiocarbamoyl-1,2,3,4-tetrahydroquinoline (236)with bromine in chloroform t o give the thiazolo[3,4,5-j,i]quinolinederivative 237. I n a process which requires disruption of the resonance stabilization of the pyridirie ring, Harris 416 reported th at treatment of 1-(2-pyridyl)-% thioureas with sulfuryl chloride or with bromine gives the hydrohalide salts of 2-irnino-2 H-[ 1,2,4]thiadiazolo[2,3-a]pyridines (238).
C. Tclnplc, J r . , ant1 J . A. Monlgomcry,J. Org. Chem. 31, 1417 (1966). \V. Konig, 1%'. Klrist, and J . Gotze, Rer. 64, 1664 (1931). 416 R. 1,. N. Harris, Aust. .I. Chewa. 25, 993 (1972).
414
415
.
~
Advances in the Chemistry of Chrom-3-enes LUCIO MERLIN1
Istituto tli Chimica, Politec.nico di Milano, Milano, Italy
I. Introduction . 11. Physical Properties . 111. Natural Substances . IV. Syntheses . . A . From a I’reformctl Hetero Ring B. Cyc1izat)ionof orfho-Alkyl Phenols and Dcrivativcs C. From Salicylaldehytlt: . 13. Misccllancous Syntheses . V. lieactions . A . Additions t o t,hc Doublc I3ontl . . B. Reactions in t,hc Presence of Acids . C. 13irig-O~)mingI < c w c - r ions . . VI. Applictttions .
1.59
.
160 I (i:t 168 1(i8 176 185
I88 IS!) 1S ! )
l!)d 197 1!JX
I. Introduction The aim of this review is to survey the advances in the chemistry of chroni-3-enes ( 2 H -1-benzopyrans, chrom-d3-enes, a-chromenes)l in the last decade. This subject was previously summarized by Wawzonek in 1!)51. ,2 brief hut clear treatment of chrom-3-ene chemistry can he found in Dean’s book3 (1!)63), where R detailed account is given of all the natural products ltnown a t that time. A section of a recent book on the synthesis of natural compounds has been dedicated to chrome~ies.~ The prcsent review will not deal with chroin-2-enes, nor with benzopyrylium salts, nor with ring-fused pyrano-heterocycles. The reader
2
Altho~cght h f x naiiic 2/f - I -1icnsopyran 1 5 prefmred by Clrernzcal A bstracls, the, niorc ~ o i n i n o nnorncnclaturr chroni-3 cmc u ill be used throughout this rc’view. S l F ~ i \ \ / n i i ( ~ l ,o. l 111 tcioc I I C ( ‘ ~ o l l l ~ ” ~ l l i l ~ l( .I < ( ’ E l l l ~ ~ l f l c ~ I Yll ~).l . ”01 2. 1) 2 7 7 \l’ilt%\, K(\ \ Ynrl,. 1!J51 F. M. I k a n , “Naturally Occurring Oxygen Ring Compounds,” Butterworth, l ~ o l l c l ~ ~1903 n.
F . M. Dean, zn “Tht. Total Synthr5ii of Natural Prodiicts” (J. ApSimon, ctl.), p. 467. W11ey (Intcrscicncc),New Yorlc, 1973. 159
160
LUCIO MERLIN1
[Sec. I1
interested in the preparation and applications of the numerous photochromic spiropyrans is referred to the recent book by B e r t e l ~ o n . ~ Surveys of the chemistry of hashish have also appeared.6 Literature has been searched through Volume 78 of Chemical Abstracts and through 1973issues of the most accessible journals.
II. Physical Properties No quantum mechanical calculation or similar theoretical treatment seems to have been dedicated to chrom-3-ene7 or to its simple derivatives. Interatomic distances and angles of two bromo derivatives of natural chromencs have been obtained by X-ray a n a l y s i ~ , The ~ * ~UV absorption, l o emission, l1 fluorescence, and fluorescence excitation spectral2 of some 2,2-dialkylchromenes have been studied in connection with their photochromic behaviour. The nuclear magnetic resonance (NMR) spectrum of chrom-3-ene (1) has been measured13 and the sign of coupling constants between protons on the hetero ring obtained from a study of double quantum t r a n ~ i t i 0 n s . lAn ~ inter-ring coupling (J4,8) has been detected.14-16 I n I
8
5
4
(1) ti
It. C. Bertclson, in “Teehniqucs of Chemistry” (A.Weissbcrger, cd.), VoZ. 111: Photoehromism. Wiloy, New York, 1971.
R. Mechoulam and Y. Gaoni, Fortschr. Chem. Org. Naturstofle 25, 175 (1967); Ciba Foundation Symposium on the Chemistry and Botany of Cannabis,” (C. R. B. Joyce and S. H. Curry, etls.). Churchill, London, 1970; “Abstract of Symposium on the Chcrnistry and Biological Activity of Cannabis,” Apotheker Societaten, Stockholm, 197 1 ; It. K. Razdan, in “Progress in Organic Chemistry” (J. Cook and W. Carruthers, eds.), Vol. 8, Butterworth, London, 1973. l’or t,hc sake of brevity, the numbering of the double bond will be omitted when not necessary. R.G. l’aton, 13. N. Maslcn, antl I<. J. Watson, Acta Crystallogr. 22, 120 (1967). W. L. Parkcr, J. 8 . E’lynn, and F. P. Bacr, J . A,ncer. Chert,. SOC. 90, 4723 (1968). l o N. V. Tycr arid 1C. S.Beekcr, J . Anier. C‘hem. SOC. 92, 1289 (1970). l 1 N. V. Tycr and I<,. 8 . Bockor, J . Anher. Chenz. SOC. 92, 1295 (1970). l 2 1%. s. &Y!lcc!r, E. 1)olan al1d 1). E. U d k e , J . CheWk. PhyS. 50, 239 (1969). l 3 L. Lunazzi antl F.Tatldei, J . illol. Spectrosc. 25, 113 (1968). l 4 J . A . !<:lvi<\ps i b ~ l ( LI I . (4. I”Ostr’I.. , J . {!/!t‘’)tk. S U ~ ’0.x. 1 (l!)(i4). l5 A. Arnone, G . Cardillo, L. Mcrlini, antl It. Mondclli, Tetrahedron Lett., 4201 (1967). l 6 E. V. Lassak and J. T. Pinhey, J . Chein. SOC. C , 2000 (19G7).
Set. 111
ADVANCES I N THE CHEMISTRY O F
CHROM-3-ENES
161
5-hydroxychromenes IT, is deshielded with respect to the parent compound, whereas acetylation of the OH group induces a marlred diamagnetic shift ( A S = 0.3-0.4).15 These effects, of steric origin,15 together with the 4,8 interaction, have hecn used b y rnany authors to distinguish between differently annellated pyran rings in polycyclic
natural products, as illustrated by the examples A,B,C (A: acetyl shift and J4.8; B: no acetyl shift but J4,8;C: acetyl shift, no J4,8).When the peri group is i~ methoxyl, or a n N-methyl, the nuclear Overhauser effect (NOE) reveals the interaction with 13-4.17-19 I n some flav-3-enes ( 2 phenylchrom-3-enes, 2) the ABX pattern of the 2,3,4 protons has been analyzed, and signs of the coupling constants were The magnitude (-2 Hz) of J2,4indicates a 90" angle between H, a n d H,, and supports the equatorial orientation of the phenyl group. The
absence of this allylic coupling in 3-acctoxyflavenes has heen invoked t o suggest that the pheiiyl is axial.21Solvent shift effects hclped in the assignment of the suhstituents on th e aromatic ring of natural chron~enes.~~,~~ l7
T. Torninatsu, M. Hashirrloto, T. Shinpu, and Ti. Tori, Tetrahedron 28, 2003
l9
J. Hlubiiccili, E. liltchic,, and W. C. Taylor, Aust. J . Cheiti. 23, 1881 (1070). II.I). Lockslcy, A . .T. Quillinan, and F. Schcinnmnn, J . Cherri. SOC. C , 3804
(1972).
(1971).
J . \V. Clark-Lenis, Aust. J . Chem. 21, 2039 (1968). 21 H. Aft, 13. R.Grant, and R. J. Molync~uu,Tetrahedron 23, 1963 (1967). 22 H. M'. Moore and K. Folltcrs, J . Amer. Clrem. SOC. 88, 564 (1966). 23 T. Anthonsen, Acta Chem. Scand. 22, 332 (1968). ao
162
[Sec. I1
LUCIO MERLIN1
Mass spectra of c h r ~ m e n e 2-alkylchromene~,~*-~~ ,~~ and flavenes 29 have been studied. The’fragmentation is dominated by the loss of one @
of the substituents on C-2, to give a stable benzopyrylium ion, which does not break down readily [Eq. (I)]. When R is H, and R’ is aryl or alkyl, hydrogen is lost preferentially. In the case of 6-hydroxy derivatives, quinonoid forms can be written for these ions.24*26 Much interest has been devoted to the photochromic behaviour of simple chromenes, especially because of practical applications of spiropyrans, particularly indolino~pirans.~ Kole and Becker 30 have been able to demonstrate the o-quinoneallide structure of the colored form 4,by producing it in THF at -75” and trapping by reduction with LiAlH,. It is ~ o n c l u d e dthat ~ ~ .the ~ ~ same intermediates occur when spiropyrans are irradiated, because only the pyran moiety has an
(5)
(6)
active role in the photochromism. Molecular orbital-self-consistent field (MO-SCF) calculation^^^ on the open form 4 suggest that the bonds are benzenoid-like, but no definite results were obtained on the differences between the cis and the trans forms. B. Willhalm, A. F. Thomas, and F. Gautschi, Tetrahedron 20, 1186 (1964). C. S. Barnes and J. L. Occolomita, A u s t . J . Chem. 17, 975 (1964). 26 H . Morimoto, T. Shima, I. Imada, M. Sasaki, and A. Ouchida, Justus LLebzgs Ann. Chem. 702, 137 (1967). 27 A. M. Duffiicld, Org. M a s s . Spectronl. 2 , 965 (1969). z8 W. J. Richter, J. G. Liohr, and P. Schulzic, Tetrahedron Lett., 4503 (1972). 29 A. Pelter and P. Stainton, J . Chem. SOC. C, 1933 (1967). 30 J. Kolc and R. S. Beclter, J . Phys. Chem. 71, 4045 (1967). 31 J. Kolc and 1%. S. Becker, Phofochern. Photobzol. 12, 383 (1970). 32 C. Balny, M. Hannezo, and A. Hinncn,J. Chim. Phys. 64, 1815 (1967). L. Edwards, *J. Kolc, and It. S. Bcckcr, I’hotochem. Photobiol. 1 3 , 4 2 3 (1971). 24
25
8eC. 1111
ADVANCES I N THE CHEMISTRY OF
CHROM-3-ENES
163
Data on tJhemolecular refraction and Raman absorption of chrorn-3ene have been reported.34
111. Natural Substances Almost every class of natural phenolic compounds contains examples of substances with a 2,%dialkylchromene ring, and the number of those that are discovcrcd increases every year. It would be difficult to give an exhaustive list of these compounds. Their chemistry will be discussed here only when it is related t o some particular behavior of the benzopyran ring. Examples include simple chromenes substituted in the aromatic ring,3*4*75-44 ben~odipyrans,~ diniers ~ ~ ~ of c l i r o m e r i c ~ , ~ ~ naphtl~opyrans,~ q~ u* i n~o~n e ~ ,f ~l a~v o ~ i e s ,f~l a~ v o n ~ l s ,c~h~a l c ~ n e s , ~ ~ f l a v a n o n e ~ , i~s~o f l a ~ o n o i d s , r~o~t e i ~ o i d s , p~ t~e r o ~ a r p a n s , ~couma~ 3 - a r ~ L - ~ - l i ~ d r o x ~ c o ~ i i4i -i ~ ~ r ihnesi ,i ~y ~ l ~ o u m a rchromnins,~~ r.i11~,”7351-j3 P. Maitte, Arm. C h i m . (Parzs)10, 431 (1953). F. Bohlmann and M Grenz, Ber. 103,90 (1970). 36 N. A. Sorcnscn, Abstr. Intern. Synip. h’atural Products, 3rd. Melbourne, 1960, p. 43. 37 L. F. Bjcldanes antl T. A. Geissman, Phytocliemzstry 8, 1293 (1969). 38 T. Anthonsrn, Acta C h e , , ~Scand. . 23, 3605 (1969). I<. Sliinia. S. Hiw1,t. 1 liiitgal,i, 17(i/;uqd,u Z:(LSR/)I 91. 1144 (1971); C”‘tewi. Abstr. 76, 14258. 4 0 D. R. Taylor and J. A. Wright, I’hytocltpmzutry 10, 1665 (1971). 41 W. L. Parker and B. Johnson, J . A m e r . Chenz. SOC. 90,4716 (1968). 4 2 R. D. Allan, R. L. Corrcll, and R. J. Wclls, TetrahedTon Lett., 4673 (1969). 43 A. M. Duffield and P. & Jcffrries, I. A u s t . ,J. Chein. 15, 812 (1962);16, 123 (1963). 4 4 I<. Makino, A. Yagi, and 1. Nishioka, Chem. Phnrm. Bull. 21, 149 (1973). 4 5 T. It. Kasturi antl Mani Thoma\, Tetrahedroii Lett., 2573 (1967); T. It. Kasturi, Mani Thomas, and E. M. Abraham, Ind~arrJ . Chern. 11, 91 (1973). 40 W. Sandermann and M. H. Simatupang, Ber. 97, 588 (1964). 47 A . R. Burnett and 1%. H. Thomson, J . Chem. Soc. C , 854 (1968). 4 8 R. H. Thomson, “Naturally Occurring Quinones,” Academic Press, New York, 34 35
1971. K. Venkataraman, I’hytoche,ntstry 11, 1571 (1972); L. Mcrlini, ibid. 12, 669 ( 1 973). 5 0 E. R’ong, Fortsclw. Chcin Org. A‘aturstoffe 28, 1 (1970). 51 W U. Whallcy, 1)7 “Clicnustry of Hetcrocyclic Compounds” (It. C. Elderfield etl.), Vol. 7, p. 1 . CZ’iley, New York, 1961. 5 2 H . I<. Arthur and \Y. 11. Ollis, J . Chern. SOC., 3910 (1963). 5 J M. Furer, T. 1%.Covindachari, and B. S . Joshi, I n d i a n J . Chem. 8, 198 (1970). 5 4 W. It. Chan, D. It. Taylor, and C. R. Willis, J . Chem. Soc. C, 2541 (1967);D. E. Games and N. J . Haskins, Cliem. C o m m u n . , 1005 (1971) and refs. quotcd tticrein. 49
164
LUCIO MERLIN1
[Sec. 111
c h r o m o n e ~ xitnthones,60 , ~ ~ * ~ ~ carbazole alkaloids,61quinoline alkaloids,62a c r i d i n e ~and , ~ ~a recent example of an indole alkaloid.64 All natural 2,2-dialkylchromenes are believed65to be derived in vivo from alkylation of a phenol or a suitable precursor with an ally1 pyrophosphate [Eq. ( S ) ] . Surprisingly, no biosynthetic work has been
carried on cliromenes, except for ubichromenol, which incorporates 2-14C-labeled mevalonic acid when this is injected into rats.66 A very recent c o m m u n i ~ a t i o ngives ~ ~ the first report of the biogenesis of a chromene from an isoprenoid precursor. Different pathways might be followed in the biosynthesis of pyranoand of the only catural 2-methylenechroquinones, such as 7 and niene.44Various mechanisms have been postulated or suggested for the E. Gucrreiro, G. Kunesch, and J. Polonsky, Pkytochemistry 10, 2139 (1971). G. H. Stout and I<. 11. Sears, J . Org. Chem. 33, 4185 (1968);G. H. Stout, G. K. Hickornell, and ti. D. Sears, ibid. 33,4191 (1968). 57 I. Carpcntcr, E. J. McUarry, and F. Schoinmann, J . Chem. SOC. C, 3783 (1971). 5 8 F. M. Dean and D. H. Taylor, J . Chem. SOC., 113 (1966); F. M. Dean and M. L. Robinson, I’liytochemistry 10, 3221 (1971). 5 9 D. R. Taylor and J. A. Wright, Rev.Latinoamer. Quim. 2, 84 (1971). 6 0 1 . Carpenter, M. D. Locksloy, and F. Scheinmann, Phytochemistry 8, 2013 (1969). 6 1 S. Kapil, in “The Alkaloids” (F.Manske, ed.), Vol. 13, p. 273, Academic Press, New York, 1971. 6 2 H. ‘r. Openshaw, in “The Alkaloids” (F.Manske, ed.), Vol. 9, p. 224. Academic Press, Now York 1967. 6 3 J. Schneider, E. L. Evans, E. Chinberg, and R. I. Fryer, J . Med. Chem. 15, 266 (1972)and refs. quoted therein. 6 4 B. Danioli, P. Manitto, F. Ronchetti, G. Russo, and G. Ferrari, Experientia 28, 250 (1972). 65 W. D. Ollis and I. 0. Sutherland, “Recent Developments in the Chemistry of Natural Phenolic Substances,” Porgamon, Oxford, 1961; W. D. Ollis, Ezperientia 22, 777 (1966); W. D. Ollis and 0. R. Gottlieb, Chem Commun., 1396 (1968). 66 T. Ramasarma and V. C. Joshi, Bull. Nut. Inst. Sci. India 28, 19 (1965) [Chem. Abstr. 66, 27120 (1967)l; V. C. Joshi, J. Jayaraman, and T. Ramasarma, Biochem. J . 92, 9C (1964); V. C. Joshi, J. Jayaraman, and T. Ramasarma, Indian J . E x p . Biol. 1, 113 (1963) [Chem.Abstr. 59, 10575 (1963)l;and Biochem. Biophys. Res. Comnlun. 12, 241 (1963). 67 K. T. Suzuki and S. Nozoe, Chem. Commun., 1166 (1972). 55
SB
SeC. 1111
ADVANCES I N THE CHEMISTRY O F CHROM-3-ENES
165
ring closure step [(Eq. ( a ) ] on the hasis of similar ist vitro reactions, although none of them is yet supported by in vivo experiments. These hypotheses are reported here, howrvcr, because they have been, and still can be stimulating suggestions for new synthetic work. I n th e first pathway t ha t was proposrd 6 5 (Scheme l ) ,an isoprenylated phenol may
(ii)
undergo a two-electron oxidation to the cation 9, which can lose a proton t o give tlie quinonemethitle 10 (i). The ring closure t o tjhe chromene occurs hy an electrocyclic reaction. ,4 more widely accepted variation of this hvpothesis 6* requires the abstraction of a hyclride ion 68
A . 13. Tarncr, QU(LYI‘. 12ev. 18, 347 (19G4).
166
LUCLO MERLIN1
[Sec. I11
from the beiizylic position by a quinonelike coenzymc (ii). Alternatively, oxidation of 5 at the benzylic positionG9could produce th e alcohol 11, which can give 3 by concerted elimination of water or through the
WHm””” -
m H .
H.
1
c‘ 3
__j
€1 OH (11)
(12)
intermediate benzylic cation. It hizs also been siiggcsted 7 0 t8hat this alcohol could be derived by condensation of citral 0s an eqiiivaleiit unit witjh a phenol. Again, t h e convcrsion of 11 into a tliene (12) has been The photooxidation of the allylic side chain of 5 has been
proposed72a s t,he oxidative step i n the ring closure sequence [Eq. ( 3 ) ] . l’hc cpoxidittion of the double lmid of 5 has also been p o ~ t i i l a t e d , ~ ~
probably by analogy with the behavior of quinolinc alkaloids 6 2 Eq. (4)l.
Most of thc natural 2,2-dialkylclirorneiies nrc derived from ;t single C, isoprenoid cliaiii (3, R = R’ = Mc). ltcmmtly, liowever, some polsisoprcnoid cliromcncs have been isolated : garnbogic acid ( 1 3 y 4 flemingins ( 1 4 p caiiiiabiclironiene (15) and carinabichronieiiic acid I t . Mcc.lioiilam ant1 Y. Gaoni, b’oitsc/rt Cheni. 0711.Xnturstoffe 2 5 , 201 ( l S ( i 7 ) . L. C‘roinbic itritl It. I’on\fortl, !i”(trr t o ) / Lctt., 4567 (1968) l 1 V. V. Ist,and J. T’oloniky, ! P ~ t i d e d r o26, ~ / 383‘3 (1970). 7 3 F. Bohlrnitnn i i i i t l M (:rcm/, I h . 103, 90 (197O). 7 4 W. D. Ollis, M. V. J. R:tni\dy, I . 0. Si~tlic~rland, ant1 $. M0ngli01~111<, Trtra hedrori 21, 1453 (1963). 75 G. Cartlillo, L. M ~ r l i n i ,ant1 I t . Moncic~Ili, 7’pt,aheu‘ion 24, 4!17 ( I Cnrdillo, 4. Ckmmro, L. Mvrlini, C. Nariiir, imtl S. Scrvi, I’h!yfoc/wrr B9
70
2027 (1073)
Set. 1111
167
ADVANCES I N THE CHEMISTRY O F CHROM-3-ENES
(16),6 arid many carbazole alkaloids61 contain a C,, chain, whereas the mold metabolitcs siccanocliromenc (17)76 and mycochromenic acid (l8)? respectively, contain or are derived 7* from a farnesylic chain.
-Oy''& 1 H2/Pd
2 RhIllOI
0
OH (13)
(21)
\ OH
H'
\H
/
o
\OH
/
(14) H , It' = H, OH
(16) It = C'OOH
168
LUCIO MERLIN1
[Sec. 1V.A
As for the 6-hydroxychromenes, such as ubichroinenol (19, n = 9) a n d plastochromenol (20, n = X), related to ubiquinones arid similar longchain q ~ i i n o n e s there , ~ ~ has been some controversy about their being true natmal products or artifacts.79All the qiiinones, with any value of n from zero t o 9, have been converted into the corresponding chromenols. The optical act,ivity of natural 2,2-dialkylchromenes with two diffcrent alkyl groups is difficult to assess with certainty, owing to the combined effects of difficnlty of purification (usually they are oils or low-melting solids) arid of the low intensity of the chromophore. The activity of ubichronienol and related compounds has been questioned, and i t seeins now certain th at caniiabicliroiiiene and cannabicyclol are inactive.G ‘The orilly unequivocal case is th a t of gambogic acid (13), which has been degraded to R(+ )-4,8-dimethyl-4-hydroxynonanoic acid lactorie (21) of high optical ~ ~ i i r i tThe y . ~point ~ could be of relevarice in connection with the biosynthesis. If the qiiinonemetliides (10) are iiitermcdiates, their cyclization to chromenes could occur without enzymic control, and thus give rise t o optically inactive conipounds.
IV. Syntheses Much progress has been made in the last, ten years in the synthesis of chrom-3-enes. Most of the activity has been stirniilated by the discovery of new natural prodiicts and by the suggestions of possible biosynthctic pathways (see Section TIT). For results prior t o 1963, the reader shonld consult Dean’s book and Wawzonek’s review.2
A . FROM A PREFORMED HETERO RING The reaction of coumarins with a Grignard reagent t o give 2 , 2 dialkylchromenes [Eq. (s)] has been known for a long t i n ~ e . ”This ~ synthesis has continued to be used, without modification, owing to the
79
I t . A. Morton, “The Biochemistry of Qiiinoiws,” Acadeniic Press, New York,
8o
G. Car(li1lo t m t l L. Mcbrlini, T ~ t r a h e d r o nLett., 2529 (1‘367).
1965.
SeC. IV.A]
ADVANCES I N T H E CHEMISTRY O F CHROM-3-ENES
169
accessibility of many coumarins.6*81-86With excess of the reagent and more forcing conditions, the ring can open t o give 2-(2-alkyl-~-liyvdroxy-) but-3-eiiylpheiiols (22),"2*86 from which the chromene can be recovered b y acid treatment,.87-8gThe same reaction has heen applied t o prcparc 2,2-diplienyl dcrivat ives, and occasionally i t has given 2.4-diphetiylchro~iienes.~~ C:liromeiies are easily obtained by dehvclration of 4-chromanols (24), in their turn readily available 1)yreduction of -&chromanones (23). Tlic parent conipouiid chrom-3-ene has been prqxwcd by this method 92 in 75-807" yield, via Meern ein-Poundorf reduction ant1 deh.vdration by azeotropic distillation over CuSO,. Other reducing agents are nictal
(23)
(24)
hydrides,g3*94 and dehydration can be performed cit,lier with p-toluenesulfonic : ~ c i d , " , a~ ~ i ~ i l d;rcc+jI or by licxating with A1,0,93 or KHS0497.9* or hy pyrolysis of the alcoliol itselfg6or of the A siinilnr sequence can he ci1,rriod out, start,ing from 3 clironinriones,lOO.lO1 but tliese are t~suallyless accessible inaterials than I-[. Fiilta.ini, M . Nirliayaiim.,antl 31.Nakajima, d g r . B i d . Chem. 25, 243 (1961). 13. I<. I b z t l a n , \\'. li. Thonipson, I-I. ( 2 . Pars, nntl F.E . (.:ranc:hc.lli, Tetruhedroiz I d / . , 3405 (1967). 83 C. R . Cook, 13. C. Corlcy, nnd M. 15. \ V > ~ l lJ, . O r ( / .Chrrrr. 30, 4114 (1!465). c. E. Cook and M. 1.:. LVa.11, ,I. 0 r . g . C//P?,/.33, 2!)98 ( 1 968). 8 5 J. Cot,t;trri antl I t . Livingst,oiir,,J.C"//e,)r.Soc., 5228 (1964). 86 # J . Cottani and It. Livinpstonc:, J . Chern. Sor.., 6046 (1965). 87 S. ltay, 1'. I<. (:rovw, an({zi. i2nantl. Iiidinli..J. Cliem. 8 , !Hi1 (1070). 8 8 C. E . Cook ancl C. E. 'hint:, Chenr. C " o ? i m 7 4 ~ 791 . , (1968). 8 9 (+.Cardillo, I<. C'ricchio, I,. hlcrlini, nntl ($. Xrtsini, Gazz. Chim. Ital. 99, 612 82
(1969). \A'. I>. Cottrrill and 13,. Liviiigst,onc.,J . Chet~i. Soc. C, 1758 (1970). 91 0 . A. Holmberg antl I1'. R.lalnii;trcim,Actu Clrena.Scund. 22, 995 (1968). 92 17. Baritnt,on, (i Pontainca, . itnil 1'. Prlaitt,cl, Bull. SOC. chin^. Fr., 4203 (1968). 93 It. Huls, R u l l . S o r ~ .Chim. Relges 66, 409 ( 1 9 5 7 ) ;67, 2%(1958); 68, 325 (1'35'3). 94 R f . L. Wolfrorn, 13. LV. Koos, and H. B. B h a t , J . O r g . Chem. 32, 1058 (1967). 90
R. Lixringstonc, J . C'hern. Soc., 76 (1962). N. I. Bntclmer m t l N . L. Rauld, J . 0 r . g . Chern,.37, 2359 (197%). 97 ( i . Canalini, J . Ut~gani,K. Fochi, ant1 G . Spunta, A r z ~Chin). . (Rome)57, 1045
g5
96
(1967). I).M o w a t and I t . ID. H. Murray, !L"rfrnh
lol
1'. 1C. Grovcr and N. h a n d , IridianJ. Chem. 7, 196 (1969).
170
LUClO MERLIN1
[Sec. 1V.A
the 4-isomers. If Grignard reagents react with 23, the process leads t o k u b s t i t u t e d chromenes (25).92*102,103 When the alkyl group in the Grignard reagent is greater than met,hyl, a mixture of 25 and of a 4alkylidenechromane (26)is obtained.9z Flavenes could not be obtained
by this reaction, owing t o their high sensitivity t o acids and rcady oxidation to pyrylium salts. On the other hand, this seems one of the preferred ways to prepare i s o f l a ~ - 3 - e n e s . ~A~ *similar - ~ ~ ~ reaction occiirs in the acid-induced cleavage of the pisatiii five-membered ring to give
pterocarpin [Eq. ( 6)]1°* and in the conversion of 4-aminoisoflavans into isoflaveiies by treatment>with HN02.109 The eliniination of watcr (or acetic acid) also occurs during reductive acetylatiori of flavonols, leading to 3-acetoxyflav-3-enes (27),which are converted into flavylium salts (28) in the acid medium. This reaction has been the subject of much study because of the complexity of the J. Colongr and A. Guyot, Hull. SOC.C h i m . Fr., 325 (1958). K. W e i n p , W. lialtcmhauser, M. D. Marz, E. Nadtxr, I?. Nader, J. Perncr, and 1).Scilcr, Justus Liebigs Ann. Chem. 711, 184 (1968). l o 4 L. R. How, A. 8 . R. Anjancyuln, and C. Sri lirishna, Curr. Sci. 32, 67 (1963); Tetrahedron 21,2677 (1965). l o 5N. Inouc, Bull. ChenL. SOC. Jup. 37, 606 (1964). l a GC. A. Anirudhan, W. B. Whallcy, and M. M. E. Bndran, J . Chem. SOC. C , 629 Io3
(1966). lo7
I<. H. Dudley, 1%. C. Corlcy, H. W. Millor, and M. E. Wall, J . Org. Chem. 32, 2312, 2317 (1967). C. W. L. Betan, A. J. Birch, B. Moore, and S . I<. Mukerjee, J. Cliern. SOC.,5991
lo8
(1864). log
S. Yaniaguchi, S. I t o , 1. Suzulri, and N. Inone, Bull. Chem. SOC.Jap. 41, 2073 (1968).
Sec. IV.A] H
O
\ OH
W 11
1
171
A D V s N C E S I N THE CHEMISTRY O F CHROM-3-ENES
1
( )I3
A
-
c
/ O
w
’
”
’
\
4 /r
O
\ +~
P
h
’
___,
O A ~
OAc
0
.
.
\
OAc
OAC
(27)
(28)
prodiicts.l10 LiAIH, reduction of 5-methoxyflavones gives a mixture of 3-methoxyflav-3-ents and of 3-inethoxyflav-2-enes. Acetic acid treatmerit converts the %-isomer into the 3-isomer.lll Elimination of HX (X = halogen) from 3- or 4-halochromanes (29) by action of bases has been used in the preparation of chromene112 and f I a ~ - 3 - e n e , ~of ~~.~’~ leucocyanidin acetate,’15 and of 4-halochromenes. 116 The elimination
H (X)
(29)
of HBr from 3,1-dibroxnochromanes seems rather sensitive t o t)he reacatiori conditions: 4-bromo-,116a mixturc of 3- and 4-bromo,l16 a n d ~ ~ - ~ r o i n o c l i r o n i ehave ~ i e sbeen ~ ~ ~obtained ~ ~ ~ ~ in different, instances. 3-Bromochromcnc~s can be prepared by dehydration of 3-bromo-4l i y d r ~ x y c h r o m a r i e s .Similar ~ ~ ~ eliminations occur in the pyrolysis of 4-ethoxychromaiie, of 3-alkylarnmonio~hromanes,~~~ of chromanes
I
OH
See Tominatqii l 7 a n d Iitcmturc qiiott’tl tht,rc,in. A. C. Wais.; ant1 L. C. Jtird, C/LW)L I n d . (Loitdoti),743 (1968) 1 1 2 If.Normant antl -1. Gabvrt,, C.R. Acacl. S c i . 235, 1047 (1952). K. G. Mnrathc, E. M. l’hlbtn, and T. J . Wlrwlcr, Chem. IrLd. (London), 1793 (19G2). 114 G . Descotrsantl D. Missos,S!inlhesis, 149 (1971). 1 1 5 A . I<. Ganguly antl T 12. Seshatlri, C‘urr. Scz. 29, 53 (1960); Cherrz. Ahstr. 54, 22605 (1960). 116 H . Ilofinann and (4. Salbcclr, Ber. 104, I68 (1!171). 1 1 7 It. It. Wittckind, T. CapIris, a n d S. Lazarus, .J. Heterocycl. Chem. 9, 1441 (1072).
110
111
172
[Sec. 1V.A
LUCIO MERLIN1
4-substituted with a n ortho or para hydroxyphenyl group [Eq. ( 7 ) ] ” * ~ ~ ‘ ~ and in the liomoallylic rearrangement of 3-spirocyclopropyl-4-hydroxychromanes [Eq. (8)].120
-
/\
\
OAc
H OH
Niicleophilic addition to benzopyrylium salts is another route to chromenes, but the attack may occur a t the positions 2 or 4, thus giving rise t o chrom-3-enes (30) or chrom-2-enes (31). Thus NaBI-I, reduces simple flavylium salts to flsv-2-enelz1 (wliich, in its turn, behaves as a nucleophile and gives rise to dimeric products 110) whereas 3-substituted
Nu (31)
salts undergo preferential addition at the 2 p o ~ i t i o n . Naphtho~~~,~~~ pyrylium salts give both isomers.lZ4 4-Chlorobenzopyrylium chloride has been shown by NMlt to be in equilibrium with 2,4-dichlorochrom3-ene in SO, s 0 1 u t i o n . l ~Phenols ~ attack this ion a t position 2 . l Z 5 2Aminochromenrs (and the 4-amino analogs) have been prepared W. Baker, A. J . Floyd, J. F. W. McOmir, G. Pope, A. S. Wearing, and J. H. Wiltl,J.ClLem.Soc., 2010 (1966). l l Q S. 1’. Starkov, L. V. Olushkova, Kham. Geterotszkl. Soedzn., 16 (1968) [Chem. Abstr. 69, 77054 (1968)l; G. U. Kontlrat’cva and M. N. Volliotrub, S L I ZIssled. . EJ. K/iLm. Dobnvol,, PolLm. Mat., 373 (1969) [Chem. Ahstr. 76, 59369 (1972)]. l Z oP. Bmncxtt, J . A. Donnelly, D. C. Moanc-y, and 1’. O’Boyle, J . Chem. SOC. Perlcsn Trapis. 1 , 688 (1973). l Z 1 G . A. lkynoltls and J. A. Van Allan, J . Orq. Chem. 32, 3616 (1967). l L 2 J. W. CI~XB-L(~WIS and M. I. Baig, Rust. J . Chena. 24, 2581 (1971). 123 I<. Wtlingrs, I t . Wild, and W. Kaltcnhausrr, Z. Lebensm. Unters. Forsch. 140, 129 (1969);Chem. Abstr. 71, 79931 (1969). l z 4 Z. Mulliani ant1 B D. Tllak, I?idLurL J . Chem. 7, 28 (1969). lZ5 B. Fohlisch and D. Krockmberger, Ber. 101,3990 (1968). 11*
Sec. IV.A]
ADVANCES IN THE CHEMISTRY OF C H R O M - ~ - E Y E S
173
starting from benzopyrylium salts and secondary amines.126*127 Alkaline hydro1ysis of benzopyrplium ~)crehlorate(32) gives 2-hydrosychroniene (33),which adds another moleciilc of the salt t o give the 2,2-dichrornenyl
ether (34).lZ8With 2-metliylbcrizopyrylinm salts, dehydration is the preferred course, giving ~-iiietliyleriecIiromene.l2" A conversion of a 2-chromene into a 3-chromcne occurs hy nneleophilic attack on 4,4dihalochrom-2-enes t o give h u b s t i t u t e d l-lialoeliroiii-3-enes [Eq. Normal attack a t 4 can also occur.
Another pathway that has attracted much attention is the dehydrogenation of cliromnnes. Broniination with ,~-hrornosncciiiimidefollowed by base treatment gives fair pields,1",81,131-137 but the rcaction may be of a 3 - or complicated by the formation, sometimes H. Hrnsc.1, J/rstu,sLiebigs AWILP h e m . 611, 97 (1958). It. Sritton. J . O~IJ. C ' h m . 37. IOC,!) (1972). 12* ,J. Dcgani, I t . Foahi, nnti ( 2 . Spuntu, 13011. S c i . Fuc. Chi,)?,.Ijid. L'IL~V. Bologna 23, 151 ( 1 0 6 5 ) ; C h e j ~Ahstr.63, . 13198 (10li5). l Z 9M . Miyano, S. Muraki, T. liusr~nolti,T. Morita, and M. Matsiii, N i p p o n h'ogeikczyuku Kniski 34, 683 (19tiO); ('hcni. Abstr. 59. 13!)20 ( l $ J f X 3 ) . 130 V. A. Zagortvskii, 1. I). Tsvctkova, antl E. I<. Orlova, Zh. Obshclr. K i i i m . 34, 1685 (1964); K h i ) ~ Geterotsikl. . Soedin., 786, 781 (1967); 422 (1969); E. K . Orlova, L. D. Tsvc%tsltovn,V. S. Troitskaya, V. C:. Vinokurov, and V. A. Zagorcvskii, ibid., 429 (1969). 1 3 1 H. li'ukami, J. Oda, ( i , Salmt,a, antl M. Nakajiinn, Ayr. B i d . C ' h e m . 25, 252 lZG
127
(1961). A . Jefferson and 3'. Soheinmann, J . C h i n . Soc. 0, 175 (1966). 133 F. Hoffinan-La llochu, Bclgian I'atcnt, 635,99!) (1964); Cheni. Abstr. 61, 13285 (1964). 134 C. Mcrcior, Anu. Chim. (Z'uris) 5 , 373 (1070); Compt. Rend. Acud. A%., C 270, 1422 (1970). 135 F. Piozzi, P. Vcnturella, and A. Bcllino, G'azz. Chirn. Iltnl. 99, 711 (1969). 136 M. F. Grundon anti K. ,J. James, Chem. C'o?umun., 1427 (1970). 1 3 7 A . C. J a i n , V. l i . Klianna. and '1'. I < . Swhn(lri. T&rrrhe,drorr 25. 2787 ( 1 9 6 9 ) . 132
174
[Sec. 1V.A
LUCIO MERLIN1
4-bromochromene [Eq. (1I)]. NMR evidence for a 3-bromochromene structure has been presented and a reasonable mechanism f0rmu1ated.l~~
Br
Earlier 4-bromo structural assignments should now be reversed. The 3-bromo derivative can be transformed into the desired chromene by zinc and a ~ i d . l ' * l ~ ~ A more direct way to attain the dehydrogenation is to allow a chromane to react with a high-potential quinone, such as chloranil or 2,3-dichloro-5,6-dicyanohcnzoquinone (DDQ13*) [Eq. (12)]. The reaction, usually carried on in benzene or dioxan, with yields in the
1)DO
\
\
/
range of 40%, was first used by a Swiss group,139who dehydrogenated a dimer of tocopherol. Their report, however, was apparently overlooked by all the following authors, who applied the reaction in the synthesis of a variety of In some cases the reaction 138
139
D. Walkcr and J. D. Hicbcrt, Chem. Rev. 67, 153 (1967). P. Schndrl, H. Moyur, J . Mctzgrr, rt. ltuegg, and 0 . Islor, H e h . Claim. Acta 46, 636 (1963).
G. Cartlillo, 12. Cricchio, and L. Mcrlini, Tetrahedron 24, 4 8 2 5 ( 1 9 6 8 ) . 141 A . R.Biirnctt a n d It. H . Thornson, J . CImn. SOC. C , 1261 (1967). 142 J . 12 RwA~, It. Kwok, It. N. Boolwr, A. C. Brown, L. E. Patterson, P. Pranc, 13. Rockry, itntl A. Pohland, J . Amer. Che7n. Soc. 90,4706 (1968). 143 1%.Mechoularn, B. Yapitinsky, arid Y. Gaoni, J . Amer. Clrem. SOC. 90, 2418 140
(1968). 144 145
146
A 12. Rurnctt and R . H. Thornson,J . Chewb. SOC.C, 850 (1968). M. Nakayama, S. Hayitshi, & Toukayarna, I. T. Horic, ant1 M.Masnrnura, Ctiem. Lrtt., 315 (1972);Cheni. Abstr. 77, 5284 (1972). S. Yamada, F Ono, T. Katagiri, and J . 'l'anaka, Ntppon Kaquku Kaishi, 1987 (1'372);Chem. Abstr. 78, 16070 (1'373).
Sec. IV.R]
ADVANCES I N THE CHEMISTRY OF CHROM-3-ENES
175
fails,19*137*142.147 hiit no sure explanation has been provided so far. The participation of L: 5-Iiydrox-y suhstituent, th a t could assist giving a quinonemethide, has lwen s i ~ g g e s t c d , 'but ~ ~ ~it~ contrasts with the succcssful dehydrogenation of unsuhstituted c l i r o r n a n e ~ .I~n ~rigid ~*~~~ systems, such ns t~ctralivdrocniiiinI,inols, stereoelectronic factors have been invoked t o explain the coiirsc of the The deliydrogenation of the ~-acctyl-Ci-liydroxychroin~~ic (35) gave the B-acetyl(37)148This result might be explained with the 5-livdrox~~chromcne sequence of Schemv 2 , or n it11 a similar one where the intermediate is a,
I OH (35)
I OH (36)
carbnniiim ion. hiit>in lwth cxscs th(. driving forcr shoiild be furnished 1)p t l i c nen 1y foriwd hydrogcii boiid &Isimilar rearrangement occurs in the natural 1)igniciit rottIerin.3 \I hich :~Isois a Ci-l1yclro~:4.-X-acylchroineiie. l'hc only other exaniple of this intcresting rearrarigenieiit is the recent coiirrersion of the alknloicl 1ihnl)lofoliiie (38) into f l i n d e r ~ i n e ( 3 9 ) ~ ~ ~ \vhicli adopts tlic. jirrferrcd ?--cpiiioloncstriic+ nre. 150
176
[Sec. 1V.B
LUCIO MERLIN1
B. CYCLIZATION OF O T ~ ~ O - A LPHENOLS KYL AND DERIVATIVES Chromenes (3) are valence tautomers of o-quinoneallides (4).Recent reports 31*32,151 have demonstrated the photochemical opening of the
(3)
(4)
chromene ring [Eq. (13)]: the o-quinoneallides are unstable, and thermal recyclization occurs even at very low temperature. The open forms have been trapped (see Section 11).Thus, if one assumes that the electrocyclic ring closure is an extremely facile process, any synthesis of oquinoneallides becomes a synthesis of c l i r o r n e r i e ~ . ~ ~ ~ ~ ~ ~ ~ Thermal cyclization of butadienylphenols (40), which are prepared from salicylsldehyde and a Wittig reagent, lias been shown to give c h r ~ r n e n e s .Deuteration ~ ~ ~ . ~ ~ ~confirmed the proposed mechanism, i.e., a [ 1,7] sigmatropic shift to a cpinoneallide [Eq. (14)].At temperatures
\
' c
-
A ,800
fnst
u
\
\
r
n
\
C
E
I
2
D (14)
/
(40)
higher than 210°, the cyclizatiori becomes reversible. The equilihrium is shifted toward the chromene, except for %benzylchromene, for which 45% of the corresponding trans,trans-butadienylphenolis present a t 210". 151
A. Padwa and G. A. Lee, Chem. Comrnun., 795 (1972).
152
G. Cardillo, L. Merlini, and S . Servi, Ann. Chim. (Rome)60, 564 (1970). R . Hug, H.-J Hansen, and H. Schmid, Helv. C I L L Acta ~ I . 55, 1675 (1972). R.Hug, H.-J. Hansen, and H. Schinid, Chsn~zu23, 108 (1969);Helv. C h m . Acta 55, 1828 (1972). E. E. Schwci7c~,11. M. Crouso, and D. L. Dalryrnplc, Chem. Commun., 364 (1969).
15' 154
155
Sec. IV.B]
ADVANCES I N T H E CHEMISTRY OF CH RO M - 3 - EN ES
177
The Claisen rearrangement of propargyl ethers of phenols (41) is one of the best syntheses of chromenes. The starting mat>erialsare easily prepared, and yields are usnally up to 80°/o or more. This reaction was introduced in 1962 by lwai and lde,156who prepared many chromenes and studied the effects on yields of substituents in the aromatic ring. It was later applied to the synthesis of 4-substituted c l ~ r o m e n e s but ,~~~ only in 1968 Schmid and c o - ~ o r k e r sformulated ~~~ it correctly as a Claisen rearrangement, followed by a [1,5] sigmatropic shift (Scheme 3). 2-Allenylphenol itself (42) gives chromene by heating.15EThe reaction
SCHEME 3
has been extended to the synthesis of a large iiiimber of natural 2 , 2 d i m e t ~ h y l c h r o m e ~ ~and c ~ shas , ~ ~now ~ ~ ~found ~ wide a c c e p t a n ~ e . l ~ ~ - ~ ~ ~ Benzodipyrans and naphthodipyrans are obtained from his ethers of i ~ ~ l . ~ ~ ~ the chromene is formed quinol and 2 , 7 - 1 i a ~ ~ l i t h a l e n e d Sometimes I. Iwai and J. Ide, C h e n . f’harrrk. Bull. 10, 926 (1962); 11, 1042 (1963). B. B. Thyagarajan, K. I<. Balasuhramanian, and K. Bhiiria Rao, Tetrah,edron 23, 1893 (1967); T i . C. Majiindar tind B. S. Thyagarajan, J . Heterocycl. Chern. 9, 489 (1972). 158 J. Zsindely anti H. Schmiti, Ilelv. Cihim. Acta 51, 1510 (1968). 159 J. It. H l ~ b ~ c tE. ~ kRit,chie, , and W. C. Taylor, Tetrahedron Lett., 1369 (1969); 156
157
A u s t . J . Chem. 24, 2347 (1971). J. A. Miller and H. C . S. Wood, British Patent 1,121,307 (1968); Chem. Abstr. 69, 96471 (1968). 161 S. K. Mukerjee, 8 . C. Sarkar, and T. 1%. Seshadri, IndianJ. Chem. 8, 861 (1970). 162 P. S. Sampath Kumar, V. V. S. Murti, and T. R . Scshadri, I n d i a n J . Chem. 9, 1319 (1971). 163 Y. Besace, I. Marszak, and J . Maisse, Bull. SOC. Cliirn. Fr., 2275 (1971). 164 F. Bohlmann and U. Biihmann, Ber. 105,863 (1972). 165 J . W.Huffmann and T. &I. Hsu, Tetrahedron. Lett., 141 (1972). 1 6 6 A. J. Quillinan and F. Scheinmann, J . Chem. Soc. P e r k i n T r a n s . 1, 1382 (1972). 167 M. Krishnamurty? K. 13. Sambhy, and T. I?,.Scshadri, I i u l i a n J . Chern. 10, 914 (1072). 16* F. Fujita, N. P;akat,ami, and M. Matsui, A y r . Rid. Ch,em. 37,1737 (1973). Ie9 B. J. Bajwa, P. Lid, and T. R. Seshadri, I n d i a n J . Chem. 9,17 (1971). I7O K. K. Ralasubrainanian ancl B. Vcnugopalan, Tetrahedron Lett., 2707 (1973). 160
178
[Sec. 1V.B
LUCIO MERLIN1
already in the alkylation step.18p165,166 A remarkable stereospecificity has been observed ,156*159 but in some cases of resorcinol derivatives both isomers are f ~ r i n e d . lThese ~ ~ *results ~ ~ ~ have now been rationalized by considering the stability of the transition state leading t o the dienoiie interrnediate.l7l When chelate or fused-ring stabilization compete for control of the regiospecificity , tlie formation of mixture can be foreseen (see later in this section). A detailed study of th e substituent effect and of thc increase in rate due to the gem-dimethyl effect has appeared recent1y.lI2 The us0 of o,o-dichlorohenzene instead of the usual N , N dimethylaniline as solvent increased the yields.172Catalysis by AgBF, or CF,COOAg in benzene or chloroform has been discovered.173 The silver ion rapidly forms a 7i-l)reecpiilibrium complex with th e acctylenic ether, which undergoes the slow [3s,3s] sigmatropic shift of the rearrangement, and also participates in the allenylphenol t o chromene step, doubling its rate at room tempcrature. A similar effect is shown by mercuric ions.174 Compounds at tlie same oxidation level of chromenes are o-isopentenylquinones (43). Their cyclization is obtained with bases, according t o the mechanism of Scheme 4.115 The first example of this
R m 0
W c H'
H H
cB -
A
-
@R HO
' H'
\
Y HO
\
/
It'
(43)
reaction dates back to Paternb,176 who cyclized lapachol with sodium acetate. However, the presence of an additional OH in lapachol gives rise t o ortho and para quinone isomers, so th a t the structure of the D. G. Clarltc, L. Crombic, and D. A. Whiting, Chem. Commun., 580 (1973). M. Hrtrfenist and E:. Thorn, , J . Orq. Chevi. 37,841 (1972). 173 U. Koch-Poincranz, H.-J Hansen, and H. Schniid, Helu. CILLWL. Acta 56, 2981 (1973). 174 I<. I(. Balasubramanian, I<. Virripalrsha Rrddy, and 1%. Nagarajan, Tetrahedrotb Lett., 5003 (1973). 175 B. 0. Linn, C. H. F;liitnk, E. L. Wong, and K. Folkers, J . Artier. Chew&.Soc. 85, 239 (1963). E. Paternb, c'wzz. ChattL. Ital. 12, 337 (1882); E. Paternb and G. Minunni, Lbld. 19,607 (1889). 17' 172
Sec. IV.B]
ADVANCES IN THE CHEMISTRY OF C H R O M - ~ - E N E S
179
products ~1as cstablishtd only much 1 a t ~ r . The l ~ ~cyclization of uLiqiiiiione [43, It = OMc. 1%'= Mr,,X = Me, Y = (CH,CH = CMcCH,),H] has lmw niuch studied, O M ing t o the biological importance of such substances. Recent applications to many types of polpisopreuylquirioncs have b ( ~ ~reported: n tmscs include alimiina,177 NaOH,178 NaH ~ ~ p r i d i ~ i e , "triethylamine.182 ~~~~~'~' Quinones as simple as 2-aIlylquirione Five the corresponding c h r o ~ n e n e sand , ~ ~dalbergiones ~ cyclize t o 4-~~hcnylcliroi~icrles ( n e o f l a v c n e ~ ) . l ~Photochemical ~-~~~ cyclization of 1 1 1 ) i q u i i i o n r ~and ~ ~ of vitninin Kls8 have also been obtained. Another reaction which requires o-quinoneallides as intermediates is the synthesis of chromenes from benzyne and qP-unsaturated aldehydes (Schcrne 5).la9The formation of the unstable benzoxete was confirmed by isotope labeling. Yields are in the range 4-40%. The same quinoneallides are probably involved in the reaction of 3,3dimethylallyltriplienylphosphoraue with o-benzoquinones (Scheme Ci),lj2which gives chromcnes, although in low yield. The c~clodehydrogcnatio~i of 2-( 3,B-dimethylally1)phenolswith DDQ or cliloranil (Schcine 7 ) has been envisaged 77 on the basis of a biogenetic ,q631759179
J . Links, Bioc//i))i.Biophys. Acta 38, 193 (19G0); J . Links and 0. Tol, i h d . 73, 349 (1963); c'. H . Shirnk, F. R. lioninszy, E. I,. LVong, N . 12. Trenner, U. H. Arison, and I<. Folkcrs, f1ioc:liertr. B i ~ p l / ? jRes. ~ . Commun., 3, 228 (1960); F.W. Hornining, It. A. Morton. and J. F. Ponnocli, Biochem. J . 80, 445 (1961). 178 H. H. Draper and A. S. Csallany, Biochem. Biophys. Res. Commun. 2, 307
177
(I9GO). A. F. Wagner, P. E. \Vit,trcaich, 13. Arison, N. 12. Trenner, and K. Folkers, J Amer. ('hem. A'oc. 85, 1178 (1063). L). McHale antl tJ. (:rccn, C'hein. Irrd. (London),1867 (1962). 181 I<. 1,. Stevens, L. ,Jard, and C. Manners, Tetrahedron Lett., 2955 (1973). 182 I. Tinada antl H. Morirnoto. Chem. I'harm. Bull. 13, 130 (19G5). 183 I). M c H a l ~ and J . Grepn,J. Chem. Soc., 5060 (1965). 184 W.11. Ollis, R. T. Redman, I t . J . Robcrt,s, I. 0. Suthtirland, and 0. R . Cothlirb, C'ltem. Comm7cr~.,1392 (1968); W. U. Ollis, in "Recmt Advances in Phytochemistry" ( J . T. Mabry et al. cds.), Vol. 2, p. 328. Appleton, New Yorlr, 1968. 185 S. K. M u l w r j w ~ 7'. , Saro,jiL. i i n ( l 7'.I t . S(:sh;ttlri, Tetr.clherlro)i27. 799 (1971). 1 8 6 I).M. S . Donnt,lly, P. J . Kavanagh, G . Iiunrsch, and J . Polonsky, d. Chem. Soc. Perkin Trans. 1, 965 (1973). 187 H. Morimoto and I. Imada, Chem. i'harm. Bull. 12, 739, 1042 (1964); H. W. Moore antl K. Folkors, A n n . 684, 212 (19G5); H. M. Cheng and J. E. Casida, J . Label. Compouiids 6, 67 (1970). la8 S. Fnjisawa, S. Kawubata, and It. Yamamoto, Yakugaku Zasshi 87, 1451 ( l W 7 ) ; Chem. Ahst,,. 69. 35874 (1968). H. Heaney and ,J. M. Jablonski, C/iem. Commun., 1139 (1968); H. Hoanoy, J . M. Jablonski, anti C. 7'.McCarty, J . Chem. SOC. Perkin Trans. 1, 2903 (1972). 179
180
LUCIO MERLIN1
SCHEME
[Sec. 1V.B
5
h y p o t h e ~ i s and ~ ~ , has ~ ~ been extended to a series of natural chromenes140,143 and flavenes.lgOYields rarely exceed 50%, but the method has found wide ap~~lication1s~57~135~150~16z~16g~1g1-204 especially in the conversion of naturally occurriiig isopentenylphenols into chromenes. The first step is supposed to be the abstraction of an hydride ion from the benzylic position, which leads t o a quinoneallide (see Scheme 1).
SCHEME 6
G. Cartlillo, 12.Cricchio, and L. Merlini, Tetrahedror~Lett., 907 (1969). I<. H.Dudley and 12. W. Chiang, J . Org. Chem. 34, 120 (1969). l o 2 G. Curdillo, 1%.Cricchio, L. Merlini, and G. Nasini, Qazz. Chim. ItaZ. 99, 308 (1969). l g 3A. C. .Jain, P. Lal, and T. R. Seshadri, I n d i a n J . Chem. 7, 1072 (1969). IQ4 8. Nozoe and K . T. Suzuki, Tetrahedron Lett., 2457 (1969). I g 5 I<. 12. Balaand T. R. Seshadri, Phytochem%stry10, 1131 (1971). Ig6 B. S. Bajwa, P. L. Khanna, and T. R. Seshadri, I n d i a n J . Chem. 9, 1322 (1971). l Q 7A. C. Jain and S. M. ,lain, Tetrrrhedrori 28, 981 (1972);8 . M . Anand and A. C. Jain, ibid. 28, 987 (1972); A. C. Jain and S. M. Jain, Tetruherlron Lett., 759 (1972); Tetrahedron 28,5063 (1972);ibid. 29,2803 (1973). l g 8 R.A. Finnegan and R. E. Merkel, Lloydia 32, 522 (1969). l g 9 A. C. Jain and T. R. Seshadri, Tetrahedron 26, 1977 (1970); A. C. Jain, V. K. Khanna, P. Lal, and T. R. Seshadri, I n d i a n J . Chem. 8 , 4 8 0 (1970). V. M. Deshpande, A. V. Rama Rao, B. Srinivasan, and K. Venkataraman, I n d i a n J . Chem. 10, 681 (1972). 201 F. Delle Monacho, 0. Gonpalves de Lima, J. F. cie Mollo, G. Delle Monache, and G. B. Marini-Bettblo, Gazz. C h i m . Ital. 103, 779 (1973). 202 J. L. Montero and I?. Winternitz, Tetrahedron 29, 1243 (1973). 203 A . C. Jainand M . K. Zutshi, Aust. J . Chem. 26, 641 (1973). 204 W. Steck,Can..J. Chem. 49,2297 (1971).
lgo lgl
Sec. IV.B]
ADVANCES I N T H E C H E M I S T R Y O F C H R O M - 3 - E N E S
181
SCHEME 7
The reaction is successful only if R and R' arc both alkyl, or when R = = P h , hut it can be performed also on a,P-unsaturated alkylphenols (Schcme 7 ) arid on alkylphenols LEg. ( 15)].147Depending on the conditions, o - p r o ~ ) e n ~ l ~ ) l i c n(44) o I s givc the chromene (45)205
H and It'
or the spiropyrans (46),'47most prohnhly via a vinylogous nucleophilic attack of one molecule of 44 on the o-qninoneallide, followed by two
1t
(44) R = H, O M e
(46) R = H , OMtr, R' = Mr (47) R = H , R' = H
dehydrogcnativc steps. Consistently with this hypothesis, 47 has also been obtained hy DUQ treatment of I,S-bis-(2-hydroxyyhenyl)-l,4pentadiene.205A strong influence of the solvent on the product of the reaction has been observed.147X neat regiospecific effect is observed when there is choicc. usual in the synthesis of natural products, of ring closurc onto a free or a chelatecl hydroxyl. The chclated hydroxyl never reacts, except when the chelation is loosened by another hydroxyl 205
L. Merlin1 and co-workers, unpublished.
182
6&
[Sec. 1V.B
LUCIO MERLIN1
ortho t o the carbonyl group. So far, reports of this last effect concern only compounds where there is a 2-methylpropanoyl or a 3-methylbutanoyl group between two OH, such aa in the synthesis of mammeigin from mammeisin 67*195*19Q or of the antibiotic iiliginosin B.20sTn this
H,\\\\q 0I
I
I -
v
o,
L)l>Q
R ‘
R‘
\ OH
0H
-
r& (16)
R\ OH
latter conipoiind, the unusually strong sl’ecific chelntion is substantiatxl by X-ray The unexpected formation of only one isomer [Eq. ( l G ) ] in this case is a good support for Cronibie and Whiting’s t h e 0 1 - y ~ ~ ~ of the regiospecificity of this aiid other relatcxl reactions, which rcquires the formation of the frcquently postiilated quinonemethide inter~ ~ i e d i a t e . ~The ~ . formation ~ ~ . ~ ~ of ~ .the ~ ~isomeric ~ qiiinoncmethide, involving the O H in 4, would mean t h e loss of the chelate staldization (see also later, this section). r, l h e ul)iqi.&ous o-quinoncal lidcs appear again in the thermal 1,4elimintttion o f water from o-hydroxyi)heriyI;Lllyl alcohols (48),153
@-[q/I]HO €t
It
R
(48)
hich have now I)chconie easily available from salic~vlaldehydeor ohydroxyacetol)liei~oii~~s and n vinylniagnesiuiii halide. ‘l’li(~ same mechanism prol)ably plt~,ysa role ill the similar pyrolj’sis of o-hydroxycinnnmyl alcohol (49, It = R’ = H), which, already employcd to prepare the parent ~ l i r o m e n e has , ~ ~Lwen ~ extended t o the siibstitutctl alcohols \T
SeC. IV.B]
ADVANCES I N THE CHEMISTRY O F CHROM-3-ENES
183
(49, R = R' = Me) which are obtained by photooxidation of the corresponding olefin. 7 2 The acid-induced cyelization of the same alcohols has been used: they are prepared from couniarins 87*88*185.186 or by base-promoted elimination from epoxides ( 50).150J64 The acidcatalyzed equilibrium between these alcohols and the corresponding
These latter, which are benzylic alcohols (48) has been shown t o acid-sensitive and prone to disproportionation, are also obtained by NaBH, reduction of the I n tlic reduction of 2-hydroxychalconcs, they were not isolated. but iinniecliately cyclized. this is one of the simplest syntheses o f flavenes.zq~20H~209 The benzylic alcohols (48) are probable intermediates in another very good synthesis, the condensation of a,P-unsaturated aldchydes with resorcinols in the presence of pyridine (Scheme X).210-213 Advantages of this procedure are the high yields and the use of the easily accessible 3-n~ethyl-3-hydroxyhutyntldeliyde d i ~ n e t l i y l a c e t a l instead ~~~ of the iinstable 3,3-dimethylacrolein. The method has been particularly useful
J . R'. Clark-Lcw 15, R. i V . Jtxmison, 11 C Skinglta nntl L. I<. U illinnis, Phern. ntl U. C. SLinglr, Aust. J . < ' h e m . Itrd (Lotrrlort), 1455 ( 1 9 0 7 ) ;J . jl' Clark-Lv 20, 21(iO ( 1 9 6 7 ) ,,I W Clark-Lrvis ant1 It. W ,Jcmi\on, tbzd. 21, 2247 ( 1 9 6 8 ) . 209 T Haw, Artn('ltrv)t S c w ~ d22, . 984.5 ( 1 9 6 8 ) . 210 1,. Crombic a n t i l < .Ponsfortl, J . Chp,n. S o r . C', 788 ( 1 9 7 1 ) . 211 I, C r o ~ n b ianti t ~ R I'on\forti, .I P l t r m . Sor P , 796 ( 1 9 7 1 ) Whiting, J . Cheni. S'oc. C, 8 0 4 212 I,. Crorribic, h .hl Bantlaranaynkc,, and 11. (1971). 213 V. V. Kane and It. I<. I t a z d a n , J A4uzer.Chrrtt. 8 o r . 90, (5551 ( 1 9 6 8 ) . 214 I,. Crombir, W. M. Bantlarnnayake, ant1 D. A. \Thiting, J Chem SOC. C , 811 (1971). 208
A\
184
[Xec. 1V.B
LUCIO MERLIN1
in the synthesis of a series of C,, derivatives (51, €3 = Me, R’ = CH2CH,CH = CMe,), starting from citral. The cyclization may occur via ring closure by elimination of watcr; or through a n o-quinoneallide.211 A different mechanism, involving a Michael addition of the phenol on the aldehyde, has been The formation of the intermediate quinoneallide has now been emphasized, as it provides the rationalization for the regiospecificity of the reaction.171When one o fth e hydroxyls is chelated, t,he chromenylation, being triggered by the acidic, unchelated OH, occurs a t the position such as t o allow retention of the stahilization energy of the chelate (Scheme 9, orientation A, not 23). A
g:j-w-q \
\
OCH
%/,H,o
%,H/o HPTi
If”. \
()\
\
OL‘H
o.,.H/o
H
\o
W
\
-
(A)
\ (B)
SCHEME 9
number of exaniplcs, including cases where the conflict between retention of the stabilization energy of the chelate and th a t of a fused ring explains the formation of mixtures, support this interpretation171 (we also above, this section). The only example of the use of ketones concrrns the reaction between mesityl oxide and 4 - h . y d r o s y ~ o u m a r i r i . ~ ~ ~ Other successful applications have been r e p ~ r t e d , ” ~ ~ l , ~but ~”~~~-~~ the reaction has failed so far with simple phenols or q u i n ~ l s . ~ l * A similar pathway was followed in the synthesis of siccanochromenes (e.g., 17), whcre t h e aldehyde was condensed with the lithio derivative d rcsorcinol. Treatment with oxalic acid gave directly the chromcne in 45% yield.220 More complicated from a mechanistic point of view is the recent 215
V. Kane and T. Graycck, Tetrahedron Lett., 3991 (1971).
216
W. .T (2 Uonnelly and 1’. V. R. Shannon, , J . Chem. Soc. l’erlczn Trans. 1 , 2 5 ( 197%j.
L17 218
21g 220
J. 1-L. Lcum anti J. 23. Etcary, ,I. Chern. SOC. C, 1062 (1970). C : . Coitibrs, J . C. Montcro, and I?. Wintcmitz, C . R . Acud. ,Vca., A’er. C . 274, 1313 (1972) I). W Hiitchinson and .J. A. Tomlinson, Z’rtralred~o~~ Lett., 5027 (1‘368). S. No7oc- and I<. H i m i , Tetrahedrou 27, GO73 ( 1 9 7 1 ) .
Sec. IV.C]
ADVANCES IN THE CHEMISTRY OF C H R O M - ~ - E N E S
185
synthesis of flavenes from cinriamaldehyde and phenoxymagnesium bromide [Ey. ( 17)].221A mixture of flav-2-ene and fiav-3-cne is ohtained but the latter re:Lrranges t o tho former on further treatment with the Grignard reagent.
c. FROM SALTCYLALDEHYDE A series of papers by Schweizer’s group 222-224 has indicated the possi1)ility of a general synthesis of chromenes in high yield kiy addition of the phenolate anion of salicylaldehyde to a vinylphosphonium salt CH,
“H, I/ PPh, +
a:A;ph, ll
0
0RCHEVI’. 10
and subsequent Wittig reaction (Scheme 10). When a n o-formylphenoxy trinirtIiy1enephosl)hoi~iumsalt (52) reacts with a base, the benzoxepin (54) or the cliromcne (57) are formed dcl)ending on thc solvcnt used. I n aprotic solvents the \\.ittig betaiiie (53) eliniinates Ph,PO to give the seven-membered compoiind. T n protic solvents. such as alcohols, protonation of the anion occurs, and elimination of n a t c r gives the Imizoxepin phosplioniuni derivative (55). This undergoes ring-opening, exactly as in the parent coinpoiiiid (54),lS5followed hy electrocyclic ring closiire t o tho chromene derivative (56). The same results, due t o the 6ame intermetliatcs, ; ~ r cohtained when salicylaldehydc sodium salt 2L1 222
C: Caiiraghi, ( i . Cayiiati, ancl G S,LIwno, ,I. (’iwn,. i’ioc. C , 2546 (1!)71). E E. S ( ~ h \ t t ~ i 7 ( ~, I rr r.iJe i Client Soc. 86, 2714 (1964);E. F:. S r h a i ~ t i r ~Jr., Lichr, 11. .J Monaco, J . Orq. (’hein 33, 241 (i(l!)(i8) , ‘P. M i n : i n i i , anil L). RI Croiisi,, .J. O r g Cherri 36, 4028 (1971) a n d precc~iltrigp t ~ p c r 1.~: . 1.: Sch\\(,t/il1.Al T. Wt.lir~~an, untl 11.M N
, C. J Bmningcr, and J . ( i . Thompson, J . O r g . < ‘ h e m . 33, 336 (1968).
186
LUCIO MERLIN1
[Sec. 1V.C
6-
// (57)
PPh,
(53)
I
T
O H - -Ph,PO
\ +
PPh, (55)
(56)
reacts with cyclopropyltriphenyl~hosphoiiiumsalts.224Notwithstanding the high yields, the synthesis has been used rarely.225 A similar rearrangement occurs when the endoperoxide (58) is treated with P(OMe), (Scheme 1 1).226
SCHEME 11 225
N. S.Narnsirnhnn, M. V. Pnradknr, and A. M. Gokhale, T&rahPdron Left., 1666 (1970).
J . E. Baldwin and 0. W. Lever, Chem. Commun., 344 (1973).
Sec. IV.C]
ADVANCES IN THE CHEMISTRY OF
187
CHROM-3-ENES
Condensation of salicylaldehydes with 2-chloro-3-formylbutene and analogs gave %-niethq.len~chroInnclic derivatives.227The direct reaction of salicylaldehyde with 2-methyl-2-chlorobutane or 2-mcthylbutene with catalysts to give ~,2,,3-trimethylchroiiieiieis reported in a patent228 The structure of the products from salicylaldehyde arid diphenylenes 2 2 9 - 2 3 0 has been revised. (see Section V,B).231 Salicylaldehyde is the starting nmterial for the preparation (Scheme 12) of most spirobenzopyrans, which are important photochromic compounds. The reader interested in their synthesis and properties is referred t o the recent excellent book by B e r t e l ~ o n . ~
X
Rq' 0
CHO
I
R
I
Y
R SCHEME12 227
M. Weissenfels, 1'. Schnoider, 11. Schmiedl, and H. Altmann, 2. Chem. 12, 263 (1972).
228 22g
230
J . T. Arrigo, 1J.S.Patemt. 2,987, 525 (1961); Chein. Abstr. 56, 3460 (1962). I<. Wizingcr, ilngezu. CJtrem. 52, 383 (1959). 1). Abson, I<. D. tjartle, J . Bryant, 12. Livingstone, and R. €3. Watson, J . Cheni. SOC.,
231
2978 (1965).
W. D. Cotterill, E. Bradley, R. Livingstonc, and M. Walshaw, J . Chenz. SOC.C, 3028 (1971) and rcfs. quotcd therein.
188
LUCIO MERLIN1
[Sec. 1V.D
D. MISCELLANEOUS SYNTHESES The ring expansion of furans by dichlorocarbene addition gives unstable 2,3-dichlorochromenes, which are trapped by nucleophilic displacement reactions (Scheme 1 3).232,233
SCHEME 13
A fascinating rearrangement ending into chromenes is the thermally allowed disrotatory (4n + 2 ) closure ~ of th e sultone ( 5 9 ) to a non-
SCHEME14 232
W. E. Parham, C. G. Fritz, R.W. Soeder, and lt. M. Dodson, J . Org. Chem. 28,
233
577 (1963). F. Nordol, J. Buddrus, W. Brodowski, P. Hontschel, D. Klamann, and P. Weycrstahl, Justus Liebigs Ann. Chem. 710, 36 (1967).
Sec. V.A]
A1)VANCES I N T H E (:HEMISTRY O F CHROM-3-ENES
189
isolated tricyclic intermediate. which loses SO, (Scheme 14).234 Compound 59 is obtained from tropoiie arid allylsulfonylchloride in the presence of triethylamine.
V. Reactions I n general the reactions of chromelies are those expected from styrene^.^ PerhalJs for this reason little attention has been paid to their chemical behaviour in recent pears. Hpdrogenation to chromanes, oxidative degradation, and oxidation to pyryliurn salts in acid medium have heen known for a long t i m e 3 A series of substituted benzopyrylium salts has been recently prepared by oxidation of cliromeries with tritylium p c r c h l ~ r a t e .Oxidation ~~ of 4phenylchromenes t o coumariris with Cr0,-pyridine complex or with SeO, in dioxan has been reported.lE6 A. ADDITIONS TO
THE
DOUBLE BOND
Osmium tetroxide or pernianganate 235 treatment of chromenes affords 3,4-cis-clirornanediols, which are converted into the trans .~~ give 2,:3-fransisomers by aqueous phosphoric acid at r e f l ~ xFlaverics 3,4-cis-flavaiidiol~.~~~ Further oxidation to 3-hydroxychroman-4-one The e p o ~ i d or e ~the ~ ~cisocmrs with OsO, -K10, mixed diol12, are obtained by action of peroxyacids on flavenes. Bromination or chlorination gives 3,4-dihalo derivatives in good yield.238-243Spontaneous dehydrobromination to 4-brornochromenes can, however, occur,238esp(wially in 7-methoxy derivatives.239Flavene gives a mixture of 2,:~-tra71s-3,4-trarLs-dibromoflavanand of 2,3-cis-3,4trans-dihromoflavan, and this is assumed t o be a proof of a 1)romonium 3392*235
234 235
W. E. Truco and C. M. Lin, J . Amer. Chem. SOC. 95,4426 (1973). F. BarantJon, G. Fontainc, and P. Muittr, (2.12.Acad. SCL.,Ser. C, 264, 410 (1967).
P. Colicnand I-'. Slairiont, Ijull ,Sot. Chirn. ff'r., 1164 (1967). 237 A. Nitta, Yok/iyciku Zassh/88, 8 1 b (1968); Chem. Abstr. 70, 37604 (1969). 23B 1C Livingstonc,, 1 ) Mlllrr, micl S Moriib, J . Chem. Soc., 3094 (1960). 239 * I . 11. l I t ' [ > W O l ' l h r L i i d TC.LI\ in#toiW, .I. CIW?n.LSOC.C , 2013 (1966). 2 4 0 13. J . IJolgw, I<. G . Mardthe, E. M. l'hilbin, T. S. Wheeler, and C. P. Lillpn, 236
241 242
243
T e t r a h d r o n 23, 341 (1867) ,J. Cottarn, 1%.I,ivirigbtone, a n d S. Morrib, J . Cliem. SOC., 5266 (1962). J B. .4bbott, C. J . France, R. Liviriptonc. and L). P. Pvlorrey, J . Chern. SOC. 1472 (1967). I_).Anker, J. A4ndrirwx,&I. Baran-Marszak, and D Molho, C.R. Acad. Sca., Ser C 274,650 (1'37%)
c,
190
LUCIO MERLIN1
[Sec. V.A
ion as intermediate.240N-Bromosuccinimide in sulfuric acid gives the corresponding pair of 4-brom0-5-hydroxyflavans.~~~ Hydroboration of chrom-3-enc, followed by H,O, oxidation, gives predominantly chroman-4-ol, with little 3 - i ~ o m e rThe . ~ ~same ~ happens for flavene, which gives a-flavan-4-ol,lz2but, when the aromatic ring bears elcctron-releasing substituents, boration occurs preferably at position 3.245 2,4-Dinitrophenylliydrazineadds to the double bond in the presence of acids, hut immediate dehydrogenation, apparently due t o the nitro group, takes place, giving 4-phenylazochromanes as find products.246 Addition of PhHgCl in the presence of Li2PdC14,followed by wateracetone treatment, gives 61 yo of trans-3-phenyl-4-1iydroxychromane and a small amount of the cis isomer.247The addition of (:rignard reagents t o 2-dicyanomethylenechromene affords 2-dicyanomethylcne4 - n l k y l ~ h r o m a r i c s .A~ ~niicleophilic ~ addition by the OH group of a phenol occiirs in the synthesis of munduserone [Eq. ( 18)].249
OMe
The addition of carbenes has attracted some attmtion. Chromcnc, 2nlkyl :tiid 4-cthoxycliron~ericsreact easily N ith dilialocarbcnes generated by standard methods, to give in FiO-80yo yield dihalocyclo~'ro~)a[c]chrc,nic.ii~s,wliirh can he reductively dehalogeriatrd with sodium arid ~~lc01i01.250~251 Tliernial hornoelectrocyclic ring opening, 999250-52
mtl E. ,J. McGarry, A ust. J . C h ~ m26, . 819 (1973). J . N7. Clark-Lowiiand E. J . McGarrv, Aust.J.Chem. 26, 809 (1973). '" I t . Livingstonc and I<.B. Watson, J . Chern. S o c . , 1509 (1!)57). 247 M .Ii
244
J.W. Clark- ILW
245
251
262
(1968). I t . Hug, (2. Fratcr, H.-J. Hanstm, and H. Srhrnitl, Helv. Chrm. Acta 54, 306 (1971). M. C. .Jacqiic%,13 Graffc, and P. Maittc, Hull. Soc. Ch?m.Yr., 2557 (1971).
SeC. V.A]
191
ADVANCES IN THE CHEMISTRY O F CHROM-3-ENES
followed by sigmatropic shifts, leads t o the %homologated chromene (Scheme 15).z51‘I’hc ratc of rcarrangement is remarkably dependent on the stereochemistry of the cyclopropa[c]chromenes (cis or trans t o t h e 2 s ~ i b s t ~ i t u e n tI)n. ~the ~ ~ cis compound, considerable steric hindrance appears in the disrotatory opening step.
A \
\
-c:x>.‘. \
/
SCHEME 15
A particular case of addition t o the double bond is the so-called “citrylidcne cyclization.”210 When 5-liydroxychromenes derived from citral arc heated in pyridine, they cyclize t o “citrylidene compounds” [Eq. (19)1. The clectrocyclic mechanism, r e ~ e n t ~ proposed,253 ly accounts
better than a previous oncz1O for the stereoselectivity of the reaction. The method is useful in the synthesis of natural compounds, such as bruceol. 21 O The photoaddition of 1)herianthrencc.juiIlone t o the double bond of 2,2-diniethylcIirotrieric gives a mixt lire of a ketooxetanc (l,Z-addition, 387,) arid of a I ,.l-dioxcnc (1,4-addition, 2570).253a 263
I).G. Clark(,, L. Crornbir, and L). A. \.Yhitmg, Chern. Conbrnur~., 582 (1973). C. H. Krauch, S. Fttritl, and C : . 0. Schrnck, FZer. 98, 310% (19(i5).
263s
192
[Sec. V.B
LUCIO MERLIN1
The only reaction in which a chromene appears t o react as a heterodiene and not likc a styrene is t h e addition of acetylene dicarboxylate to lapachenol, followed by thermal decomposition of the adduct (Scheme 1 6).254 The ready photodimerization of a chromerie has been reImrted recently. 255 (See also cannabicyclol, Section V,B.)
% MCO
I
C 00E t
\
/
111 I
coo 1St
SCHEME 16
B. REACTIONS IN
THE
PRESENCE OF ACIDS
Protonation of 4-mc+liylchromene by strong acids gives a carboniam ion, which can disproportionate by hydride ion transfer t o form 4methglenechromane and the pyryliiim salt [Eq. ( m)].256
\
/ Me
-q -q+q f{t
\
\
\
MR
Mr
/ (20)
hfv
The structures of the so-called 2,2-dimethplchromene and 2,2diphenylchrornene dimers have been much debated. I n 1000 Manuelli 257 discovered t h a t t h e natural compound lapachcnol, t o which later 258 the structure 60 was assigned, gave a dimeric product by treatment with acids. On the basis of a mechanistic suggestion of Woodward, Living254
255
256 267
258
M’. Saritlcrrnann and R. Castcn, Y’etiuhedron Lett., 1267 (19Ci3); s w a170 R A Ottc,r, S. S. Salrila, cmtl <J. J. Pox, J . Ovg. Chern. 37, 2858 ( 1 9 7 2 ) . R Rraz Pilho, M. dc J. Coutinho Lcmos, antl 0. It. Gottlieb, I’hytocheni/stry 12, 947 (1973). 13. I). Tilak antl Z Midjiani, T r t r n h d v o n 24, 949 (1968). C. Mnniiclli, Attz.Accad. N a z . Lzncei 9, 102, 314 (1900); 22, 686 (1913). It.Livirigitonc ant1 M. C. Whiting, J . Chern. SOC., 3631 (1955).
See. V.B]
ADVANCES IN THE CHEMISTRY OF C H R O M - ~ - E N E S
193
stone and Whitingzs8 assigned the structure 61 t o this dimer. This formulation was deemed unlikely by Barnes, Strong, and O c c o l o ~ i t z , ~ ~ ~
(60)
(61)
who investigated thc so-called ~ , ~ - d i ~ n e t l ~ y l c l ~ r odirner. m e n e They sssigiied the striictiirr arid stercochernistry (63) t o the latter on the basis of NMR rvidence. and attribiited the same skeleton, b y arialogy, t o lal~achenoltlimrr. The rneclianihrn which was proposed accounts for the fact that ~,:!-dimethylchruirierie dimer (63) is not obtained from the chromene itself, 1)utonly by reaction o f conmarin with ilIeLi or MebIgX. As, hov ever. lapchenol dimcr can be prepared directly from the chromene, not from the carbinol corresponding t o (62), the Austra1‘la11 aiitliors’ contention concerning its structure deserved f i i r t h r proof.
(62) 1%= MC
The structure. (64) lias now been suggested, on the basis of NMR and deuteratiun experiments, and a reasonable meclianisin formnlatcti.260 The same mechanism (Scheme 17) explains the formation of the dimrr of ageratochromme ith various acids.261Iodine in acid-free chloroform yields instead the dimer (65).261 C. S.B;Lr.nw,i\I I. Strong, and J. L. Occolowitz, TPl,d/edro,r 19, 839 (1SG3). \V D Cottwill. I<. L i r ing\tonc,, l i . D. Uartl(., and D. \V. Jonrs, !Z’etrci//edron 24, 1981 (10G8). 261 T. R. IGi~turi, E. M. Abraham, and P. Broun, J . Cliern. Suc. P e r k i n Trans. 1 , 2468 (1973).
269
z60
194
[Sec. V.B
LUCIO MERLIN1
The so-called 2,2-dipheiiylcliromene dimer (again the name is misleading) is obtJained in the reaction of coumarin with C,H ,MgBr, or from the carbinol (62, 1%= Ph). In this case the mechanism that requires tJhedehydration of the carbinol is not possible, and structure (66) has been proposed on the basis of the NMR spectrum.262This
/
Mrd
MrO
OMe
SCHEME 17 2E2
J. Cottarn, I<. Livingstone, M. Walshaw, 1C. I). Bartlo, and D. W. Jones, J . Chem. Soc., 5261 (1905).
Set. V.B]
195
ADVANCES I N THE CHEMISTRY O F CHROM-3-ENES
structure also explains the formation of 66 from a mixture of 2 , 2 diphenylchromene and 2,4-diplienylchrom-2-erie in acetic acid saturated with HCI. Another difficult problem has been the structural elucidation
of the product of the reaction hetween 2,2-diphenylchromene and 1,ldiphenylethylenc in acid which has been found to be identical t o that obtained from the latter and salicylaldehyde. Protonation of t h c chromene, ring opening, attack of the olefin by thc carboninm ion and ring closure (Scheme 18) lead t o the compound (67),
I
II
I
-I
II
I
Ph SCHEME 18
(67)
where the chromane ring is formed with the new 1,l-diphenylethylene moiety. Structure and mechanism are supported by deuteration experiments and independent synthesis.231 When the chromene has a side chain with a double bond in a suitable position, acids induce a n intramolecular cyclization. Thus for garnbogic acid 7 4 and caniiabichroniene t h e simplest product (68) comes from attack of the olefin on the benzylic carbonium ion [Eq. (Sl)]. 2119263
263
B. Yagen and 12. Mechoulam, l’et~ahedrorkLett., 5353 (1969). An additional rctluction htcp. most probably via intermolecular hydride transfer (scc abovc, t h i s section) is necessary t o account for the product 69.
196
LUCIO MERLIN1
3 \
/
\
II
A
M r Me
-
[Sec. V.B r (21)
q
\
I
II
A
M e Me
A
Mr, MIX
(68)
Depending on the acid, the medium, and the particular chromene, other pr~duct~s, such as 69 263 or the cyclobutane 70,211*263*264 are obtained. Cannabicyclol (70) is a natural product, and can also be prepared photochemically (45%)2 6 5 by heating in pyridine ( 1-2yo)211,266 or with
chlorariil .143 I t s structure, and consequently th a t of all the similar derivatives of other natural products,267has been matter of controhas versy.211.266*26* The structure 70, supported b y NMR data,211.26* been confirmed by X-ray analysis of a bromo derivative.269Whereas the photochemical cyclization is another example of a well-known process, the mechanism of the acid-catalyzed and thermal reaction is still It. K Razdan and B. A. Zttko, Tetrahedron Lett., 4947 (1969). I, Croinbie, 12. Ponsford, A. Sham, B. Yagnitinsky, and R. Mecl-ioulam, l’etrahedron Lett., 5771 (1968). 2 b b V. V. Kancsantl R. I<. IZaLdan, Tetrahedron Lett., 591 (1969). L67 S. P. Kwc rl, R 8. Kapil, and S. P. Popli, Tetrahedron Lett., 3857 (1969);Chem. I n d . (Loridon), 958 (1970). 268 V. V Knnc, l’ctralwdrovi Left., 4101 (1971). 260 M. J . l3rgli.y, I). U. Clarke, L. Croinbic, and 13. A. Whiting, Cltem. C o m m u n . , 264
205
1.547 (1970).
A stepwiw sc.qumce, involving the formation of a quinonernetl-id?,has been propo~ecl.~
Set.
v.cI
ADVANCES I N T H E CHEMISTRY O F CHROM-3-ENES
197
C. RTNC:-OT~ENINC REACTIONS The photocheniicnl ring opc~iiiigof cliroiiieiies t o the valence tautomers quiiioiitnllides lilts lwei1 described in Section 11. Similar results have bcen reported Ariotlier ring opening without change of the oxidation state occiirs when B-hydrosvchrornencs are treated with bases, such as sodium ethoxidc, to give y,y-diinethylallylqiiiiiories [E(i. ( 2 2 ) ] .A mechsnisni siiiiilar to that of the Birch reduction has been It R‘
advanced.271 \Vith LiLllH, or LiXID, there is further reduction, arid another meclianism can account for the dciiteratioii results.272 As chroinenes hrliave as aromatic others, the cleavage of the C - 0 bond has been achieved bp r n e t a l - a n i i n ~ n i aMg , ~ in ~ ~t ~e t~r~a ~h ~y ~ d r~o~f ~ r a n ~ ~ ~ or e1ectrocheniic:~lreduction [Eq. ( 2 3 ) With ~ ~ sonie ~ ~ dcrivatives, the
propeny1plieric)l has heen isolated besides the allylpl~eno1.275~z‘~7 Oxidation of a ~i-riiethoxychromcriewith A g 0 arid phosphoric acid in dioxan t o it surprisingly stable acetal (71) was followed by ring opening with bases.278
Mi.
Me (71)
H. Morimoto, I. Iinada, and G . Qoto, A n ) [ ,729, 171 (1969). I. Iniada anti H hloriinoto, Clieni. Phccrv,. nitll. 12, 1051 (1964);H. Morimoto, 1. Imacia, M. LVatanabt,,and H. Sugilirtrit, A n n . 715, 146 (1968). 2 7 3 A. J . Birch and M. hlnung, Trtmhrrlroti Lett., 3273 (1967); A. J. Birch, M. Maung, and A . I’t.1tt.r. Aust. ,I. C‘hc n i . 22, 1923 (1969). 274 E. Collins, I V . J (k. I)onnc~lly, anti 1’. V. It. Sliannon, C‘hem.Ind. (London), 120 r rraction gives a corriplev mixturix of products. (1972) rcportctl a caw ~ . h e rtlic, 2 7 5 A. MarcLer,J O r p i l o m e t . Chew/ 18,249 (1969). 276 V. G. hfairanoviLii. 0. 1. Vollio\,n, E. A. Obolnikova, and C .: I. Samokhvalov, I>oEl. A l , ~ z r l,4Xutl. . N a u k S W R 199, 829 (1971);Clrem. Abstr. 75, 136509 (1971). 277 11 I<. Rar/dm, LV. It. Thornpbon, E’. E. Granchelli, and H. C:. Pars, Abstr. Int. Synzp. Cheni. N n t . l’rod., 7 t h R t p . 1970 E-113. 278 N. I , Rtzultl nncl N. I. Hrrickncsr, ./. 01q.C f / i e w i 36, 4045 (1971). 271 272
198
LUCIO MERLIN1
[Sec. V I
VI. Applications Among chromenes, only the spiropyrans and their heterocyclic derivatives have found a wide practical application as photochromic substance^.^ 6,7-Chromenediols have been proposed as analytical reagents for the spect,rophot,ometric assay of rare earth cations.279 Chromenes witjh structure and activity similar to those of hashish A number of chromenes, mostly constituents have been with aryl substituents in positions 8,3, and 4 have been patented as biologically active substances.126.280-2~~o ACKNOWLEDGMENT The main p a r t of t,his revirw was writtrn during a sabbatical stay at Massachusetts Institute of Technology: t h e atithor is indobtccl t,o Professor 6. Biichi for hospitality and to NATO for financial support.
V. A. Nazarrnko a n d E. N. Poliirktova. Z h . A d . Khi,ttA. 23, 1658 (1968) [Chem. Ahntr. 70, 41350 (1!)68)]; V. A. Nazarcnko antl N. I. Makrinich, ibid. 25, 719 (1970) [C‘lrsni. Ahstr. 73, 7 2 7 7 5 (1970)l; N. S. Polticktov. M. A. Sander, and It. S. Larirr, ihirl. 25, 899 (1970)[ P h e m . A h t r . 73, 105191 (1970)j. I t . I<. ltaztlanand H . G . Pars, A t i t / .N . L’. A c a r l . S c i . 191, 15 (1971). E. Kaisrr, and 13. Ilornba, U.S. P a t e n t 3,122,563 (1964); Chem. Abstr. 60. 11990 (1964). 2 8 2 It. A. Michcli, A. N. Booth, A. L. Livingstone, antl E. M. Bickoff‘, J . Med. I’hurm. Chem. 5, 32 1 (1962). 283 E. Mwck A. (:., Nctherlands I’atcnt 6,617,021 (1966); Chern. Abstr. 66, 28657 (1967). 284 H. A. I)rWaltl, U.S. E’atrnt 3.436,3!)3 (19K!));Chem.Abstr. 71, 61216 (1969). 2 8 5 ‘I‘. Mrlt,on antl It. W. Tickit,, (irrman I’ut,. 2,050,496 (1971); Chem. Abstr. 75, 35760 (1971). 286 It. I<. Hazdim ancl W. It. ‘I’tiompson, Grrman Pat,ent, 2,122,643 (1971) [Cheni. Abstr. 76, 59455 (1972)l; (>crman Patcnt 2,135,521 (1972) [Chem. Abstr. 76, 9!)523 (1972)J;(ivrman I’atcnt 2,145,320 (1972) [Clrew.Ahstr. 77, 5343 (1972)l. 287 M . M ~ ~ r a k t t n iS. i . I
””
Tautomerism and Electronic Structure of Biological Pyrimidines"
+
J. S. KWIATKOWSKI AND BERNARD PULLMAN Institut dc Biologir Eli~~~~ico-('Ainiique, I,nhoratoire d c Biochinaic! Z'lte'orique associe' au C.N.B.S., Paris, Frcrrrce
I. Introduction . 11. Taiit,onicrism of Cytosine . A . The Basic Skeleton . B. Siibst,itiwnt Effects on Taut,orncric Eyriilibria of Cytosine . C . (~i~ant,uiii-Rlcrhaiiical St,utfit:s 111. Electronic Ktmicturc o f th(*(:round Stat,e of Cytosines . A. Thtl Gconiet,ry of Cytosine . . B. Vibrational Spectra o f Cytosine C. Itcstricted Lrgics: I
*
t
200 202 202 217 221 227 228 230 231 235
269 269 27 1 273 2x7
29 1 2!J 1 303 307 309
This work was supportccl by K.C.P. 173 of the Ccntrc National dc 1aKcchcrche Scicntifiqiic. o f 14'rancc. Present adtlrcss: Iristitrite of Physics, Nicholas Copcrnicus Univcrsit#y,Toruri, Poland. 199
200
J . S. KWIATKOWSKI AND BERNARD PULLMAN
[Sec. I
VII. Tautomerism, Electronic Structures, and Spectra of Rare Pyrimidine Bases of the Nucleic Acids . A. Geometrices . B. Tautomerism of Minor Pyrimidine Bases of the Nucleic Acids in Solution C. Distribution of Electron Densities . D. Molecular Orbital Energies: Electron-Donating and Electron-Accepting Properties E. Electronic Absorption Spectra . VIII. Miscellaneous Properties A. Inner Shells (ESCA) . B. NMR and NQR Spectroscopic Studies
.
.
. .
312 312 316 320 322 323 327 327 330
I. Introduction* The understanding of the tautomeric properties of the purine and pyrimidine bases of the nucleic acids and the determination of the electronic properties of the principal tautomers are of fundamental importance in molecular biology, in particular in connection with the theory of mutations (for general references see,e.g. refs. 1-6.) B. Pullman and A. Pullman have presented recently in these Advances3 a detailed review of the problem as it concerns the purine bases. The present paper
* Abbreviations used in this chapter: ESR, electron spin resonance; NMR, nuclear magnetic resonance; NQR, nuclear quadrupole resonance; PMR, proton magnetic resonance; CD, circular dichroism; IR, infrared; UV, ultraviolet; MO, molecular orbital; HOMO, highest occupied MO; LEMO, lowest empty MO; HMO, Huckel MO; EHT, extended Huckel theory; IEHT, improved EHT; SCF, self-consistent field; CNDO/2, complete neglect of differential overlap; INDO, intermediate neglect of differential overlap; CI, configuration interaction; STO, Slater-type orbital; AO, atomic orbital; LCAO, linear combination of AO; PCILO, perturbative configuration interaction over localized orbitals; ESCA, electron spectroscopy for chemical analysis; V-SCor w-technique, self-consistent wcharge; UHF, unrestricted Hartree-Fock. B. Pullman and A. Pullman, “Quantum Biochemistry.” Wiley (Interscience), New York, 1963. a A. Pullman, i n “Electronic Aspects of Biochemistry” (B. Pullman, ed.), p. 135. Academic Press, New York, 1964. B. Pullman and A. Pullman, Advun. Heterocycl. Chem. 13,77 (1971). B. Pullman, i n “Quantum Aspects of Heterocyclic Compounds in Chemistry and Biochemistry” (E. D. Bergmann and B. Pullman, eds.), p. 292. Israel Acad. Sci. Humanities, Jerusalem (distributed by Academic Press, New York), 1970. P. 0. Lowdin, Advun. Quunt.Chem. 2 , 2 1 3 (1964). V. I. Danilov and G. F. Kventsel, “Electronic Representations in the Point Mutation Theory” (in Russian). Naukova Dumka, Kiev, 1971.
Sec. I]
STRUCTURE O F BIOLOGICAL PYRIMIDINES
201
is an extension of this review to the pyrimidine bases. The quantummechanical methods commonly used in this type of study, having been described in Pullman and P ~ l l m a nwill , ~ not be repeated here. The principal tautomeric properties of the fundamental biological pyrimidines-cytosine, uracil, and thymine-are due to the presence in these N-heteroaromatic compounds of electron-donor substituents such as NH, and OH and of SH in some important analogs. The labile hydrogen may remain attached at the exocyclic 0, N, or S atom or migrate t o one of the ring nitrogens, giving rise to three principal types of tautomerism (Scheme 1): ,T’\,
Y\ N / C ‘XH
, ‘ \
F e (
?!
\
‘N H X = 0: lactim-lactam NH: amine-imine S : thiol-thione SCHEME 1
More explicitly, considering the two basic systems cytosine and uracil (thymine is 5-methyluracil and so its tautomerism is essentially analogous to that of uracil), these bases are capable of existing in six (aromatic) tautomeric forms 1-6 and 27-32, respectively. Nucleosides and nucleotides which are the biological building blocks may exist only in the three forms 2,4, and 6 or 28,30, and 32,as the result of the replacement of one ring NH of cytosine or uracil, respectively, by ribose or ribose phosphate. The same is true for some of the isomers or analogs of these compounds. The numbering of the heavy atoms adopted throughout this review is indicated in Fig. 1. Ionization of the pyrimidines (deprotonation or protonation) may occur in different ways resulting in the possibility of a number of tautomeric ionic (anionic and cationic) species. In the case of nucleosides, the number both of tautomeric conversions of the pyrimidines and of their molecular-ionic transformations is, smaller than in the case of the bases themselves.
R
FIG.1 Numbering of the heavy atoms.
202
J.
s.
KWIATKOWSKI AND BERNARD PULLMAN
[Sec. 1I.A
During recent years a very large amount of work has been carried out, both experimentally and theoretically, in order to elucidate the qualitative and quantitative aspects of pyrimidine tautomerism and to determine the physicochemical properties of the observable tautomeric forms of these molecules. Among the various methods, the determination of the tautomeric form of a molecule by X-ray diffraction technique is the most straightforward. Although the crystallographic parameters describing the positions of hydrogens in the heavy-atom structures are less accurate than those describing the other atoms and, although very often the position of the hydrogens are not directly determined, it is possible to infer these positions from consideration of bond distances and angles of the heavy atoms. For instance, one expects the CO bond length to be of the order of 1.22 A for a double bond on a ring but near 1.43A for a single bond7 (the latter value may be rather overestimated as recent X-ray crystallographic studies give the value of 1.33-1.35A for the C-0 bond lengths in the lactim forms of pyridinols8-10). All the other methods of investigation are based on comparative studies of the physicochemical properties of the molecules and of fixed models of their tautomeric forms (usually methylated derivatives). We present here a review of the experimental and theoretical information pertaining to two aspects of the problem: the evaluation of the nature and extent of pyrimidine tautomerism and the determination of the essential electronic characteristics of the most important tautomers of these bases.
II. Tautomerism of Cytosine A. THEBASICSKELETON Cytosine is generally represented in the lactam-amine form 2 both as a free molecule and in its nucleoside or nucleotide. This is also the form considered to be involved in the base-pairing scheme in DNA. An overwhelming amount of experimental evidence from nearly all the available techniques of physical chemistry seems nowadays t o confirm this assignment although the situation was not always clear-cut. D. Voet and A. Rich, Progr. Nucl. Acid Res. Mol. Biol. 10, 183 (1970).
d.Kvick and I. Olovsson, Ark. Kemi 30,71 (1968). J . Almlof, A. Kvick, and I. Olovsson, Acta Crpttallogr.Sect. B 27,1201 (1971). lo
L. H. Voight and J. G . Wirth, J . Amer. Chem.SOC. 93,6402 (1971).
Sec. II.A]
STRUCTURE OF BIOLOGICAL PYRIMIDINES
(5)
203
(6)
X-ray crystal results on cytosine itself loa-13 (anhydrous and monohydrate), its complexes with different p a r t n e r ~ , l ~cytidine,21 -~~ and cytidine 2',3'-cyclic phosphatez2all indicate its existence in the lactamamine form (2). In a number of crystals the cytosine ring is protonated, invariably at N-3.23-32In cytosine 5-acetic acid33half of the molecules Jeffrey and Kinoshita12have used a different numbering of the ring atoms of cytosine from that of Barker and Marsh,ll the latter being the same as the numbering used here. A superficial reading of the papers may lead to the erroneous c o n c l ~ s i o nthat ~ ~ cytosine in the crystals take on different tautomeric forms depending upon the solvent used for recrystallization. l1 D. L. Barker and R. E. Marsh, ActaCrystallogr. 17,1581 (1964). la G . A. Jeffrey and Y .Kinoshita, Acta Crystallogr. 16,20 (1963). l3R. J. McClure and B. M. Craven, Acta Crystallogr. Sect. B 29, 1234 (1973). l4D. L. Breen and R. L. Flurry, Theor. Chirn. Acta 23,138 (1971). l6 A. E. V. Haschemeyer and H. M. Sobell, Acta Crystallogr. 19, 125 (1965). l6 E. J. O'Brien, J . MoZ. Bio2.22,377 (1966). E. J. O'Brien, Acta Crystallogr. 2 3 , 9 2 (1967). l8 D. Voet and A. Rich, J . Arner. Chern. SOC. 91,3069 (1969). lo S. H. Kim and A. Rich, J . Mol. Biol. 42, 87 (1969). ao M. Sundaralingamand J. A. Carrabine,J . Mol. Biol. 61,287 (1971). 21 S. Furberg, C. S. Peterson, and C. Remming, Acta Crystallogr. 18, 313 (1965). 22 C. L. Coulter, J . Arner. Chem. SOC. 95,570 (1973). a3 E. Alver and S. Furberg, Acta Chern.Scad. 13,910 (1959). 24 R. F. Bryan and K. Tomita, Nature (London) 192,812 (1961). 25 R. F. Bryan and K. Tomita, Acta Crystallogr. 15,1174 (lSS2). 26 M. Sundaralingamand L. H. Jensen, J . Mol. Biol. 13,914 (1965). 2' M. Sundaralingamand L. H. Jensen, J . MoZ. Biol. 13,930 (1965). 28 C. E. Bugg and R. E. Marsh, J . MoZ. Biol. 25, 67 (1967). as E. Subramanian and H. K. Hunt, Acta CrystaZZogr.Sect. B 26,303 (1970). 30 B. L. Trus and R. Marsh, Acta Cry8tallogr. Sect. B 28, 1834 (1972). 31 C. Tamura, T. Hata, S. Sato, and N. Sakurai, Bull. Chern. SOC.Jap. 45, 3264 (1972). 32 J. S. Sherfbski and R. E. Marsh, Acta Crystallogr. Sect. B 29, 192 (1973). 33 R. E. Marsh, R. Bierstedt, and E. L. Eichhorn, Acta Crystallogr. 15,310 (1962). Ion
204
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s. KWIATKOWSKI AND BERNARD PULLMAN
[Sec. 1I.A
are randomly protonated at N-3 and the same system of half-protonated cytosine residues is found in the crystalline state of the helical polyribocytidylic whose structure in solution moreover seems similar to that in the solid ~ t a t e . ~ ~ . ~ ~ Early infrared (IR) spectroscopy studies were inconclusive; some 37*38 were considered to indicate that cytosine exists in the amine-lactim - ~ l it exists in the amine-lactam form (1) in the solid state, ~ t h e r s ~ gthat - ~ reviews, O see refs. 51, 52) on form (2 or 3). More recent s t ~ d i e s ~ ~(for cytidine, 5-halodeoxycytidines, sodium cytidylate, and polycytidylic acid in neutral H,O or D,O solution advocate, however, the structure 2 for the cytosine residue. Differences in the IR spectra of cytosine, cytidine, and cytidylic acid were considered by Angell.41 This author concluded that the cytidylic acids exist in the solid state in a zwitterion form with one of the hydrogen atoms from the phosphate group at N-3 of the cytosine ring ( ~ f . r e f s . ~Previously ~ , ~ ~ ) . Miles 44 postulated that the form 7a rather than the form 8 was the structure of cytidine in acid solution. This conclusion is essentially the same as that of Tsuboi et who proposed form 7b for the protonated form of cytidine, as 7a and 7b are two canonical forms of the same tautomer (7).
34
35
R.Langridge and A. Rich, Nature (London)198,725 (1963). E. 0. Akinrimisi, C. Sander, and P. 0. P. Ts’o, Biochemistry 2,340 (1963).
K. A. Hartmann, and A. Rich, J . Amer. Chem. SOC. 87,2033 (1965). E. R. Blout and M. Fields, J . Amer. Chem. SOC.72,479 (1950). 38 M. M. Stimson and M. J. O’Donnell, J . Amer. Chem. SOC. 74,1805 (1952). 39 H. W. Thompson, D. L. Nicholson, and L. N. Short, D i S C U S S . Paraday ~ 36
37
O C 9, .
222 (1950).
L. N. Short and H. W. Thompson, J . Chem. SOC.,168 (1952). C. L. Angel1,J. Chem. Soc., 504 (1961). 42 H. T. Miles, Biochim. Biophys. Acta 22,247 (1956). 4 3 E. M. Tanner, Spectrochim. Acta 8,9 (1956). 44 H. T. Miles, Biochim. Biophys. Acta 27,46 (1958). 45 H. T. Miles, Biochim. Biophy8. Acta 35,274 (1959). 46 H. T. Miles, Proc. Nat. Acad.Sci. U.S. 47,791 (1961). 40 41
47
M. Tsuboi, Y . Kyogoku, and T. Shimanouchi, Biochim. B i o p h p . Acta 55, 1 (1962).
H. T. Miles,J. Amer. Chem. SOC.85, 1007 (1963). 4 8 T. L. V. Ulbricht, Tetrahedron Lett. 16,1027 (1963). 5 0 H. FritzscheandM. Hartmann, 2.Chem. 11,69 (1971). 51 T. Shimanouchi, M. Tsuboi, and Y . Kyogoku, Advan. Chem. Phys. 7, 435 48
(1964).
I. Tinoco, and D. N. Holcomb, Annu. Rev. Phys. Chem. 15,371 (1964). 63 E. R. Blout and M. Fields, J . Biol. Chem. 178,335 (1949). 64 R. J. C. Harris, S. F. D. Orr, E. M. F. Roe, and J. F. Thomas, J . Chem. SOC.,
52
489 (1953).
&C.
11.A]
205
STRUCTURE OF BIOLOQICAL PYRIMIDINES
(7)
(7b)
(78)
(8)
I n general, the problem of tautomerism in nucleic acid bases has been approached by comparing the I R spectra of several isoelectronic model compounds. The model corresponding to the cytosine tautomers 4 or 5 have not yet been investigated. The I R spectroscopy studies cannot therefore definitely rule out these tautomers. It seems, however, that they do rule out form 6 for cytosine and cytidine and indicate that the dominant tautomer of the compounds in aqueous solution is the lactamamino form 2, and that the protonated cations have the structure 7. The conclusions from IR spectrosoopy have been confirmed by ~ ~the ,~~ constituent bases of recent Rumun spectroscopy ~ t u d i e s on RNA, their nucleosides and nucleotides, and on related model compounds. The Raman spectra of cytosines rule out the prevalence of the imine form 6 in solution and indicate that the neutral molecules have the structure 2. They also indicate that the removal of a proton from the free base leads to an anion of type 9,and that in the cation N-3 is the site of protonation.
(9)
The pyrimidine bases, their derivatives, nucleotides, and nucleosides have been extensively studied by N M R techniques including proton magnetic resonance (PMR), carbon-13, nitrogen-IS, and fluorine-I9 magnetic resonances as well as nitrogen- 14 nuclear q d r w p o l e resonance
(14NNQR). The first PMR s p e ~ t r aattributed ~ ~ . ~ ~ the tautomeric structure (7)to the cation of cytosine, in agreement with X-ray studies and IR data. For the preferred neutral form of cytosine in solution Kokko et aLSg R. C. Lord and G. J. Thomas, Spectrochina. Actu, Part A 23,2551 (1967). R. C. Lord and G. J. Thomas, Develop. AppLSpectrosc. 6,179 (1968). 57 C. D. Jardetzky and 0.Jardetzky, Federutim Proc. 17,380 (1968). 58 C. D. Jardetzky and 0. Jardetzky, J . Amer. Ch,em.Soc. 82,222 (1960). 6 0 J. P. Kokko, J. H. Goldstein, and L. Mandell, J . Amer. Chem. SOC. 83, 2909 56
66
(1981).
206
J.
s. KWIATKOWSKI AND BERNARD
PULLMAN
[Sec. 1I.A
originally suggested the zwitterionic form 10 in deuterated dimethyl sulfoxide and claimed that the same structure existed in water (for
(10)
cytosine cation they suggested the form 8). Later, however, Katritzky and Waxings0 showed that the predominant tautomer of cytosine in dimethyl sulfoxide and in aqueous solution has structure 2, and that cytosine undergoes protonation at N-3. The same form for the predominating tautomer of cytosine, its N- 1 and N-alkylamino derivatives and of cytidines, as well as the addition of the proton at the 3-position of these compounds, was confirmed by other PMR studies.61-ss The assignment of the N-3 position of the cytosine residue as the site of protonation is consistent with the recent NMR evidence that in the zinc complexes of cytidine the cytosine ring is bound to zinc through N-3s7.s8 (cf. reviewsg on sites of proton ionization and sites of metal ion coordination of DNA, RNA, and their constituents). A recent PMR studys5 demonstrates that double protonation of cytosine in FS0,H or FS03H-SbF5-S0, solution yields the structure 11.
H (11)
Gatlin and Daviss1 proposed that whereas cytidine existed in the amine form 2, 2’-deoxycytidine was the imine 6 . This interpretation because they did not measure cytidine or however, is incorrect 48949,s3
A. R. Katritzky and A. J. Waring, J . Chem.Soc., 3046 (1963). L. Gatlin and J. C. Davis, J . Amer. Chem.SOC.84,4464 (1962). 6a H. T. Miles, R. B. Bradley and E. D. Becker, Science 142,1569 (1963). 83 0. Jardetzky, P. Pappas, and N. G. Warde, J . Amer. Chem.SOC. 85,1657 (1963). 84 R. R. Shoup, H. T. Miles, and E. D. Becker, J . Amer. Chem. SOC.89, 6200 6o
I
(1967).
R. Wagner and W. Von Philipsborn, Helv. Chim. Acta 53,299 (1970). 66 W. Hutzenlaub and W. Pfleiderer, Chem. Ber. 106,665 (1973). S. M. Wang and N. C. Li, J . Amer. Chem.SOC.90,6069 (1968). 68 K. C. Tewari, J. Lee, and N. C. Li, Trans. Paraday Soc. 66,2069 (1970). 88 R. M. Izatt, J. J. Christensen, and J. H. Rytting, Chem. Rev. 71,439 (1971).
Sec. II.A]
STRUCTURE OF BIOLOGICAL PYRIMIDINES
207
deoxycytidine, but only their salts-cytidine hemisulfate and deoxycytidine hydrochloride. In fact, the two free bases are in the amine form 2, and the difference, between the PMR spectra of free deoxycytidine and its hydrochloride is attributed 48,49 to protonation of the cytosine ring in the acid salt, the result being consistent with IR data. The results of the above studies indicate that proportions of the other tautomeric forms, for instance the imine 6, are very small under ordinary conditions. Very recently new PMR studies 70-74 on cytosine, guanine, and their derivatives claimed to show that much higher fractions of the rare tautomers of cytosine and guanine were present at room temperatures in neutral aqueous solution. The unusually broad resonances of the cytosine-H-5 protons in the PMR spectra were examined as a function of temperature, concentration, and solution pD, as well as of the external magnetic field. The a ~ t h o r s ~considered l-~~ that the line broadening arose from chemical exchange between the amine and imine tautomers of cytosine, and from a detailed kinetic analysis of the problem they concluded that the imine tautomer of cytosine was present in the amount of 15 3% at room temperature in neutral aqueous solution. Such a result if true would have significant importance for the theory of mutation in genetic replication (abnormal adenine-cytosine base pairings). These findings, however, have been shown to be erroneous, being due to contamination by paramagnetic ions, a common source of line broadening.I6 Thus Wong et a1.76*77 presented evidence that the unusual broadening of the cytosine-H-5 protons was not reproducible with purified samples of cytidine 5’monophosphate. The broadening appeared with addition of paramagnetic impurities (Cu2+).This fact has since been acknowledged by the original authors 78. 70
71
B. W. Bangerter and S. I. Chan, J . Amer. Chem. SOC.91,3910 (1969). G. C. Y . Lee, J. H. Prestegard,and S. I. Chan, Biochem. Biophys. Rea. Commun. 43,435 (1971).
S. I. Chan and G. C. Y .Lee, i n “The Purines-Theory and Experiment” (E. D. Bergmann and B. Pullman, eds.), p. 277. Israel Acad. Aci. Humanities, Jerusalem (distributedby Academic Press, New York), 1972. 73 G. C. Y. Lee, J. H. Prestegard, and S. I. Chan. J . Amer. Chem. SOC. 94, 951 72
74
(1972). G. C. Y. Lee and S. I. Chan, J . Amer. Chem. SOC. 94,3218 (1972).
A. Abragam, “The Principles of Nuclear Magnetism.” Oxford Univ. Press, London and New York, 1962. 76 Y. P. Wong, K. L. Wong, and D. R. Kearns, Biochem. Biophys. Rea. Commun.
76
49,1580 (1972). 77 78
Y. P. Wong, J . Amer. Chem.Soc. 95,3511 (1973). M. Pieber, P. A. Goon, J. H. Prestegard, and S. I. Chan, J . Amer. Chem. SOC. 95,3408 (1973).
208
J. s. KWIATKOWSKI AND BERNARD PULLMAN
[Sec. 1I.A
Carbon-13 magnetic resonance spectra of the naturally occurring cytidines have been described in several papers. 79-82 The electronic structure of the compounds is reflected in the carbon-13 shifts. For instance, the observed chemical shifts for these and other pyrimidine and purine nucleosides were correlated, at least qualitatively, with the calculated charge densities (see Section VIII) and with the known reactivity of these molecules. It is difficult to draw conclusions from the carbon-13 spectra about the tautomerism of cytosine. NMR information on the electronic environment of the nitrogen and oxygen atoms in nucleic acid bases is of particular interest in view of the importance of base pairing. Only NMR spectra of nitrogen seem to have been reported. Early empirical correlations between the hybridization of nitrogen and the nitrogen-15 chemical shiftse3 and coupling constantse4 were expected to help in the identification of the tautomeric forms and of sites of protonation. The initial work dealt with l - m e t h y l c y t o ~ i n e and , ~ ~ led ~ ~ ~to an unambiguous proof that the predominant tautomeric form of 1-methylcytosine as well as of cytosine nucleosides was the amino form 2 and that in acid the ring was protonated at N-3. The results of related NMR s t ~ d i e s ~on~restricted * ~ ~ - ~ ~ rotation of the amino group, and the protonation, of several cytosines have been similarly interpreted. Some aspects of these studies will be discussed later (Section 111). Further support for structure 2 as the dominant tautomer of cytosine came from the analysis of the I4N NQR spectra of cytosine, cytidine, A. J. Jones, M. W. Winkley, D. M. Grant, and R. K. Robins, Proc. Nat. A d . Sci. U.S. 65,27 (1970). 8o A. J. Jones, D. M. Grant, M. W. Winkley, and R. K. Robins, J . Amer. Chem. SOC. 92,4079 (1970). A. J. Jones, D. M. Grant, M. W. Winkley, and R. K. Robins, J . Phys. Chem. 74, 'O
2684 (1970). 8a
O3
D. E. Dorman and J. D. Roberts, Proc. Nat. Acad. Sci. U.S. 65, 19 (1970). J. B. Lambert, G. Binsch, and J. D. Roberts, Proc. Nut. Acad.Sci. U.S. 51,735 ( 1964).
84
G. Binsch, J. B. Lambert, B. W. Roberts, and J. D. Roberts, J . Amer. Chem. SOC.86,5564 (1964). B. W. Roberts, J. B. Lambert, and J. D. Roberts, J . Amer. Chem. SOC.87,5439 (1965).
E. D. Becker, H. T. Miles, and R. B. Bradley, J . Amer. Chem. SOC. 87, 5575 (1965). 87
I. Adams, G. P. Jones, and J. M. Thomas, Trans. Paraday Soc. 66,1854 (1970). R. R. Shoup, E. D. Becker, and H. T. Miles, Biochem. Biophy.9. Res. Commun. 43,1350 (1971).
OQ O0
R . R. Shoup, H. T. Miles, and E. D. Becker, J . Phys. Chem. 76,64 (1972). R. R. Shoup, E. D. Becker, and M. L. McNeel, J. Phys. Chem. 76,71(1972).
Sec. II.A]
STRUCTURE OF BIOLOGICAL PYRIMIDINES
209
and some model compounds.91~92 The tautomeric form found for the cytosine ring was invariably the lactam-amine. The ionization constants of cytosine, cytidine, and their derivatives have been determined by spectrophotometry and by titration, at first without ascertaining their dependence on ionic strength or temperature, but later with the ionization constants determined over the range of 10-50") and the thermodynamic enthalpy and entropy changes for proton ionization e v a l ~ a t e d . ~ An~ -assumption ~~ is commonly used for structural analysis of organic compounds that the blocking of a protonacceptor center of a molecule, for example by a methyl group, does not significantly change the acid-base properties of the other acceptorcenters. Starting from the comparative study of the ionization constants of cytosine and of its several methylated derivatives (representing fixed models of tautomeric forms), it is evident (see Table I) that cytosine and cytidine exist in aqueous solution mainly in form 2 (cf. refs. 60, 96). It is true that no pK value is known for the methylated cytosine corresponding to the form 5, but the pK of the lactim-imine form 5 should certainly be considerably higher than that of the lactamamine form 2. From the comparison of ionization constants it was also deduced that both 1-methyl and 3-methyl cytosine5 exist predominantly in the The conclusions based lactam-amine forms 2 and 3, respectively.100*102 on a comparison of ionization constants have been confirmed by UV analysis (see below). The tautomeric ratios characterizing the complex scheme of tautomeric conversions of cytosine have not been evaluated. The only quantitative results concern the relative contributions of structures 2, D. T. Edmonds and P. A. Speight, J . Magn. Reson. 6,265 (1972). R. Blinc, M. Mali, R. Osredkar, A. Prelesnik, J. Seliger, I. ZupanEiE, and L. Ehrenberg, J. Chem. Phys. 57,5087 (1972). g3 S. Lewin and D. A. Humphreys, J . Chem.SOC. B, 210 (1966). g4 J. J. Christensen, J. H. Rytting, and R. M. Izatt, J. Phys. Chem. 71, 2700
91
g2
(1967).
J. J. Christensen, J. H. Rytting, and R. M. Izatt, J . Chem. SOC.B , 1643 (1970). g6 D. J. Brown and J. M. Lyall, A w l . J . Chem. 15,851 (1962). g7 A. R. Katritzky and A. J. Waring, J . Chem. SOC., 1540 (1962). g8 J. J. Fox and D. Shugar, Biochim. Biophys. Acta. 9, 369 (1962). gg B. I. Sukhorukov, A. S. Gukovskaya, L. N. Sukhoruchkina, and G. I. Lavreg5
nova, Biojizika 17, 5 (1972). W. Kenner, C. B. Reese, and A. R. Todd, J . Chem.SOC., 855 (1955). lol I. Wempen, R. Dusohinsky, L. Kaplan, and J. J. Fox, J . Amer. Chem. SOC. 83,
looG.
4755 (1961). 102
T. Ueda and J. J. Fox, J . Amer. Chem.SOC.85,4024 (1963).
COMPARISONOF THE pK VALUESFOR
TABLE I FWT IONIZATION OF CYTOSINESAND CYJXDINES
THE
pK valuesa
Type of tautomer
Compound
Ref:
98
99
1
2-Methoxycytosine 2-Methoxy-N8,N8-dimethylcytosine
5.3
5.41b
2
cytosinec
4.60b 4.61b
3
1-Methylcytosine CytidineO N8, N8-Dimethylcytosine 1-Methyl-N8,N8-dimethylcytosine 1-Methyl-N8-methylcytosine 3-Methylcytosine
4.45 4.55 4.1
4 6
100
94
101
4.57
4.5Sd
4.61e
60
102
103
7.49'
7.4
7.38
8.73
9.4 8.7
5 6.17 4.OSd 4.25e 4.20 4.47
4.3Sb 7.49b
l-Methyl-2-methoxycyt~sine 1,3-Dimethyl~ytosine 3-Methylcytidine 1,3-Dimethyl-N8-methylcytosine
96
N
9.33b
12.0 9.29
9.65b
Determined spectrophotometricaUyunless otherwise indicated. At 20°C; the accuracy of determination of pK values was & 0.66. For the collection of pK values determined a t various ionic strengths and temperatures, see Refs. 93 and 95. Potentiometridy determined values at 25%; the accuracy of determination of pK was & 0.01. The accuracy of determination of pK was & 0.05. f At 2OOC; titrated in 0.017 M solution. a
4 F w
Sec. II.A]
211
STRUCTURE OF BIOLOQICAL PYRIMIDINES
3, and 6 of cytosine in the molecular ground state as well as in the excited state. Since experimental evidence shows that cytosine, 1- and 3-methylcytosines, and 1,3-dimethylcytosine are protonated to give cations of similar structure, it was possible to evaluate the tautomeric ratios K?s3 = 213 (population of form 2/population of form 3) and Kfv6 = 216. Tautomeric ratios determined indicate that in aqueous solution tautomer 2 predominates over tautomers 3 or 6 by factors of about of lo3 or 104.6,respectively (see Table 11).Similarly, the lactam-amine form 2 of cytidine prevails over its lactam-imine tautomer 6 with a factor of lo6. Sukhorukov et al. gg measured the displacement of the near ultraviolet absorption bands of several cytosine8 upon transition from the neutral to the ionic form and evaluated the ionization constants in the excited state of the compounds. They concluded that on excitation there was no considerable shift in the tautomeric equilibrium of the forms 2 and 6 [(K:8,6 (in the excited state) = 1.55 x lo4]. They also attempted to evaluate the concentration of several molecular and
-
TABLE I1 TAUTOMERIC CONSTANTS AND THERMODYNAMIC PARAMETERS FOR CYTOSINE TAUTOMERS Experimental tautomeric ratios Method K8.3
Kf.3
Kf.6
lo=
60 100 62.8
6 x 103.0 104.0 5.26 x lo4
0.84 x 103
1.8 x 10 0.8 x 10
References
pK measurement in aqueous solution
W spectra measurementsb (at 30°, 50",and 70°, respectively)
97 994 104
Thermodynamic parameters . for conversion 2-6
1
From temperature Energy difference AEw 5.6 kcal/mole dependence of the Entropy difference ASow - 12 cal/mole .deg. K , values Free-energy difference AFw 6.73 kcal/mole Heat of tautomeric UV spectroscopy AH& 6.72 kcal/mole transition Calculated using pK = 7.4 for 3 - m e t h y l ~ y t o s i n e . ~ ~ ~ J ~ ~ * ~ ~ ~
* Uncertain evaluation (see text).
104
99
212
J.
s. KWIATROWSKI AND
BERNARD PULLMAN
[Sec. 1I.A
T B L E I11
CONCENTRATION OF MOLECULAR AND PROTONATED F O R MOF S ~CYTOSINE EVALUATED FROM IONIZATION CONSTANTSss
(t = 20", AQUEOUS SOLUTION)
Ground state Excited state
99.862 99.993
0.136 -
0.002
0.007
99.842
-
0.168 -
On the basis of the influence of the methyl group on the pK values of several derivatives of cytosine, it was postulatedss that the main proton-acceptor center for 2methoxycytosine was apparently N-1. A similar conclusion was postulatedloaon the basis of methylation studies of 2-methoxycytosinein which the 1-methiodiderather than the N-3 derivative was obtained.
protonated forms in the ground as well as in the excited state of It may be seen from Table I11 that the concentration of the cytosine.QQ lactam-imine form 6 both in the ground and in the excited state is small and that the dominant tautomer of protonated cytosine has hydrogen atoms at positions N-1, N-3, and N-8. However, the contributions of the other forms have not been taken into account. The figures quoted in Table I11 cannot thus be treated as definite values of the tautomeric concentrations. On the basis of the temperature dependence of the pK values, it was postulatedQQ that with rise in temperature the relative amount of form 2 diminishes, while those of forms 3 and 6 increase. An attempt has also been made to evaluate both the free energy change and the heat of the tautomeric conversion from form 2 to form 6 . These values were estimated as 6.73 and 5.72 kcal/mole, respectively. The near U V absorption spectra of cytosine, cytidine, and their derivatives have been measured in different solutions and in the solid state. Early works by Stimpson and O'Donnel13* were thought to confirm the previous conclusion from IR evidence that cytosine exists in the lactim-amine form 1. However, all later UV studies indicate that the predominating form both of cytosine and cytidine is lactam-amine P. Brookes and P. D. Lawley, J . Chem. Soc., 1348 (1962). H. Morita and S. Negakura, Theor. Chim. Acta 11,279 (1968). lo5I. Wempen and J. J. Fox, J . Amer. Chem.SOC. 86,2474 (1964). lo3 lo4
Sec. II.A]
STRUCTURE OF BIOLOGICAL PYRIMIDINES
213
2. For instance Shugar and Fox106 have shown that the spectrum of cytosine resembles that of 1-methylcytosine (form 2), not that of 2methoxycytosine (form 1). Similarly, Kenner et uZ.lo0 have established that lactam-imine forms 6 were unimportant both €or 1 -methylcytosine (thus also for cytosine itself) and for its aminoacetyl derivatives. Katritzky and Waring 6o have extended these studies and in particular showed that tautomers 3 and zwitterionic structures 10 were unimportant in'the tautomeric equilibrium in both aqueous and dimethyl sulfoxide solutions. Although these last comparisons were made with only two partially methylated cytosines still capable of tautomerism, the reported conclusions agree with those reached later by Brown and Lyall 96 on much wider evidence, As far as we are aware, the absorption spectrum of a model compound corresponding to the tautomer 5 of cytosine has not been measured, so it is difficult to eliminate the possibility of the existence of cytosine in form 5 on the basis of the UV spectra alone. This is ruled out, however, on pK consideration^.^^ It is interesting that the dominant form of 3-methylcytosine in aqueous solution has been establishedlo2 as form 3 rather than the imine forms 5 or 6. This conclusion agrees with that drawn from pK analysis (cf. the K , values in Table 111) that the concentration of tautomers 6 is smaller than that of tautomers 3. As to cytidine, it also is shown to exist mainly in form 2 (cf. e.g. ref. 107). The UV also provides a means of prediction of the anionic and cationic forms of cytosine and cytidine. It is known that there are no great differences between the spectra of amino-substituted aromatic hydrocarbons and the corresponding anions of molecules in which an amino group is replaced by a hydroxy group. The absorption bands of the anions are slightly shifted toward longer wavelengths and their intensities are somewhat stronger compared to those of the amino compounds. This analogy between the spectra of phenoxides and the corresponding amines is known as the Jones rule. This situation is different in the case of anionic forms of polyhydroxy N-heterocycles or systems with one hydroxy group and other easily ionized acidic substituents (e.g., mercapto groups) because the negative charge is here distributed between the ring nitrogens and oxygen (or sulfur). However, in the cases of simple compounds with one hydroxy group (e.g., monoxoazines or their amino, methoxy, or methylmercapto D. Shugar and J. J. Fox,Biochim. Biophys. Acta 9, 199 (1 952). W. C. Johnson,P. M. Vipond and J. C. Girod, Biopolymers 10,923 (1971).
lo6
lo7
214
J. 9. KWIATKOWSKI AND BERNARD PULLMAN
[Sec. 1I.A
derivatives), the opinion prevails that the anions conserve essentially their negative charge at the oxygen atom. Accordingly, one expects the analogies between the UV spectra of anionic forms of these hydroxy compounds and of the corresponding amino derivatives to be similar to those of aromatic hydrocarbons. Under these conditions, it is possible to correlate the spectrum of the cytosine anion with the spectra of 2methoxycytosine and 2,4-diaminopyrimidine(Table IV). As to the cationic structures of cytosine, the UV evidence60J02J08 shows that the cations of cytosine itself and of its 1- and 3-methyl derivatives all have structures of type 7. The UV spectra also give clear evidence that protonation of cytosine does not occur a t the amino group. There are appreciable differences between the spectra of amino compounds and the parent unsubstituted molecules. The spectra of the amines however, become closely similar to those of the unsubstituted molecules on cation formation at the
ANALOGIESBETWEEN
THE
TABLE IV SPECTRAOF MOLECULES WITH OH, NH,, SUBSTITUENTS
Bathoohromic effect of substituents: In aromatic hydrocarbons:
OH(0Me) << NH2
5
AND
0-
0-
QQQ 0-
e.g.
OH A,,,: (nm)
NHZ 28 1 230
270
211
In N-heteroaromaticmolecules:
287 235
OMe << NHp % 0OMe << 0 - NH,
e.g.3
Amax": (nm) a
The values of log
c
270 (3.86) 226 (3.90)
282 (3.84) 228 (3.97)
are given in parentheses.
lo8C . A. Dekker, Annu.
Rev. Biochem. 29,463 (1960).
282 (3.90) 224 (3.92)
Sec. I1.A]
STRUCTURE OF BIOLOGICAL PYRIMIDINES
215
amino group (NH,f)(see e.g. ref. 109). With a proton a t the amino group [form 71, the cytosine cation should have a spectrum resembling that of neutral 2-pyrimidone (12). This is not the case.6oIt is worth noting that
n
O
N
I
no monofunctional attack a t the amino group of cytidine has been found in the chelates of cytidine.l1° Similar considerations were used 60*96 to rule out the zwitterionic structure of cytosine as its main form in aqueous solution. As a zwitterion (10) cytosine ought to have a spectrum similar to that of the anion of 2-oxopyrimidine. The differences between the spectra of the two compounds indicate that this is not the case. UV spectroscopy is a sensitive tool for the elucidation of structures of molecules only if the different tautomers have distinct spectra. I n some cases, cytosine or cytidine and their alkylated analogs have similar spectra with seriously overlapping bands, and thus the application of UV spectroscopy to the elucidation of the tautomeric structures of the molecules is inconclusive. I n particular, the method is unreliable for the determination of tautomeric equilibria of cytosine (see below). Nevertheless the UV absorption spectra confirm the conclusions drawn from other studies as to the main form of cytosine and cytidine in aqueous solution a t room temperature. It has been ~ b ~ e r ~ e d however, , ~ ~ ~ that , ~ some ~ ~ of, these ~ ~ ~ - ~ ~ compounds undergo a large change in their electronic absorption spectra on going from aqueous to nonaqueous solution. Similar changes of the spectra have also been found upon heating aqueous solutions of these c o m p o ~ n d s . ~ ~These ~J~~ spectral J ~ ~ changes have been the “UV Atlas of Organic Compounds.” Butterworth, London, and Verlag Chemie, Weinheim. 110 S. Mansy, B. Rosenberg, and A. J. Thomson, J . Amer. Chem. SOC.95, 1633 (1973). ll1 C. HBIBne, A. Haug, M. Delbriick, and P. Douzou, C.R. Acad. Sci. 259, 3385 (1964). C. HBlBne, and P. DOUZOU, C.R. Acad. Sci. 259,4853 (1964). 113 C. HBlBne, Ph. D. Thesis, Univ. Paris, 1966. 114 E. Charney and M. Gellert, Biopolym. Symp. 1,469 (1964). 116 K.Berens and K. L. Wierzchowski, unpublished data.
log
216
J.
s. KWIATKOWSKI
AND BERNARD PULLMAN
[Sec. 1I.A
subject of controversy. Some authors have concluded that this behavior was connected with the change of tautomeric ratios between several tautomers caused by the nature of solvent and the temperature. HBlbne et uZ.111-113advanced the hypothesis that (i) in a n aqueous solution the dominant tautomer of cytosine, its 1-methyl derivative, and cytidine, is of type 2 and that tautomers 4 and 6 exist in small amounts, and (ii) the concentration of these last two tautomers increases with rise in temperature or with the change of solvent (for instance, from an aqueous solution to alcoholic). The spectral study of photoproducts of the c ~ m p o u n d l l l *was ~ ~ ~stated to confirm this conclusion. But no evaluation of the tautomeric ratio has been made because of overlapping of the absorption bands of several tautomers. However Morita and Nagakuralo4 concluded from similar studies that in aqueous solution cytosine exists as an equilibrium mixture of two forms, 2 and 6, only. According to these authors the first form predominates in trimethyl phosphate and water at room temperature, but the second prevails at high temperature. The imine form is considered to predominate also in acetonitrile. From the temperature dependence of the absorption spectrum of cytosine in aqueous solution, Morita and Nagakura estimated the tautomeric ratios Kfv6 to be equal to 33, 14, and 8 a t 30, 50, and 70°, respectively. The energy115&and entropy differences between the imine form 6 and the amine form 2 were evaluated as 5.5 kcal/mole and 12 cal/mole. deg., respectively. The evidence of Morita and Nagakura was the first experimental indication of a relatively large amount ( 3%) of the imine tautomer 6 of cytosine near room temperature in aqueous solution. Other workers have, however, proposed that the observed differences in the UV spectra of cytosine or cytidine with change in medium could be attributed to the existence of hydrogen-bonded solvent-solute comI n a paper quoted earlier,lo7 the spectra of cytidine, 3methyl-, and N,N-dimethylcytidine have been measured not only in aqueous solution but also in several other solvents differing in polarizability and dielectric constant. The observed spectral changes of cytidines showed that the imine tautomer of cytidine could not exist to an appreciable extent even in organic solvents. The differences between the spectra of cytidine in various solvents were attributed to hydrogen bonding and the equilibrium between the species found upon heating the aqueous solution of cytosine or cytidine was postulated to be a measure of the stability of the hydrogen-bonded complex. N
N
N
Morita and Nagakuralo4 have used the symbol AH", usually denoting the enthalpy difference, for the difference in energy between two tautomers. This misleading notation led t o the erroneous conclusionlo' that the difference in free energy between two tautomers has been measured to be 2 kcal/mole.
Sec. II.B.21
STRUCTURE OF BIOLOGICAL PYRIMIDINES
217
For comparison with the theoretical predictions, we have collected in Table 11, together with the previously discussed tautomeric constants, some thermodynamic parameters characterizing the tautomeric conversion of bytosine.
B. SUBSTITUENT EFFECTS ON TAUTOMERIC EQUILIBRIAOF CYTOSINE The shifts of the tautomeric equilibria (lactam + lactim, amine -+ imine, or thione -+ thiol) in N-heterocyclic molecules caused by substituents are of considerable interest. Several such studies are available for cytosines. 1. Halogen Substitution: Tautomeric Shift 2 --t 3
On the basis of the UV spectra of the neutral forms of cytosine and of the bathochromic and hypsochromic spectral shifts caused by protonation of cytosine and of its 1-methyl, 3-methyl, 5- and 6halogeno derivatives, Wempen and have concluded that 6-chloro and 6-fluorocytosine were best represented by the form 3 in which the dissociable proton was affixed to N-3. 5-Halogenocytosines by contrast occur mainly as form 2. 2. Aza-Substitution: Tautomeric Shift 3 + 6 The introduction of a nitrogen atom into cytosine (cytidine) yields 5-azacytosine (13) or 6-azacytosine (14). On the assumption that there
0
I
H (13)
I
H (14)
cannot be more than one labile hydrogen for an oxygen or nitrogen, the compounds are capable of existing in the forms similar to those of cytosine, namely 1-6. Additionally, 5-azacytosine can exist in the forms 15-17.
218
J.
s. KWIATKOWSKI
AND BERNARD PULLMAN
[Sec. II.B.3
The physicochemical properties of azacytosines, and the corresponding azacytidines and their derivatives have been s t ~ d i e d . l l ~ ~~~ It-was ~ ~ 6-azacytosine, ~-~~~~~~~ shown by I R , NMR, and UV s p e c t r o s c ~ p y that N,N-dimethyl-6-azacytosine, and their l-methyl derivatives as well as 6-azacytidine, possess the lactam-amine form 14, like cytosine itself. Similar studies118 have shown that 3-methyl-6-azacytosine possesses the lactam-imine form 6 , in contrast to 3-methylcytosine, which has the lactam-amine form 3.1°2 Experimental evidencelZ2shows that 5-azacytosine and 5-azacytidine exist in the lactam-amine form, type 13. Unfortunately, the tautomeric properties of 3-methyl-5-azacytosine have not been studies, so it is difficult to decide whether 5-aza-substitution in 3-methylcytosine causes a tautomeric shift toward the imine form. The tautomeric studies of azacytosines are not so complete as those of cytosine itself. The contribution of other tautomeric forms of azacytosines to the tautomeric equilibrium has not been evaluated (because of lack of model tautomeric compounds). It appears that 6-aza-substitution causes a tautomeric shift from form 3 of cytosine toward its imine form, 6 . Thus, upon 6-aza-substitution the contribution of the imine tautomers to the tautomeric equilibrium of cytosine increases, while that of tautomers 3 decreases. 3. Hydrogenation of Cytosine (5,6-Dihydrocytosine): Tautomeric Shift 2+6 The tautomeric properties of 5,6-dihydrocytosine and its alkyl derivatives have been studied by means of several spectroscopic methods (UV, I R , NMR) as well as by the pK e v a l u a t i ~ n . ~I R~ evidence ~J~~ shows that the tautomeric forms with a lactim hydroxy group at C-2 position are unimportant. On the other hand, NMR spectra show that structures of the lactam-amine type with two hydrogens a t the C-6 position and with a hydrogen at the N-3 atom were also unimportant. J. Pitha and J. BerBnek, Collect. Czech. Chem. Commun. 28,1507 (1963). J. Pifha and J. SemliEka,Collect. Czech. Chem. Commun. 29,410 (1964). 118 J. Gut, J. Jonas, and J. Pitha, Collect. Czech. Chem. Commun. 29, 1394 (1964). llQ A.Piskala and J. Gut, Collect. Czech. Chem. Commun. 28, 1681 (1963). l a o A.Piskala and J. Gut, Collect. Czech. Chem. Commun. 29,2794 (1964). lZ1 I.Flament, R.Promel, and R. H. Martin,BulZ.SOC.Chim. Belges 73,686 (1964). laa P. Pifhova, A. Pfskala, J. Pifha, and F. germ, Collect. Czech. Ghem. Commun. 117
30,1626 (1965).
T.L.V.Ulbricht,J . Chem. SOC.,6134 (1965). D.M.Brown and M. J. E. Hewlins, J . Chem.SOC.C , 2050 (1968).
la3
lZ4
l Z 6D.
M. Brown, Pure A w l . Chem. 18,187 (1969).
Sec. II.B.31
STRUCTURE OF BIOLOGICAL PYRIMIDINES
219
Brown and HewlinslZ4have concluded that only forms 18 and 19 are important for 1-alkyl-substituted 5,6-dihydrocytosine as for the parent molecule. Similar experimental evidence has shown that the dominant tautomer of 5,6-dihydrocytosine corresponds to a lactam-amine
structure (18), but the tautomeric constant of forms 18 with respect to 19 was comparatively small (Kt1*Jsz 25). The situation is different in chloroform: the IR spectra show that form 19 predominates in this solvent, although there is evidence of a small amount of form 18. It is worth noting that, although the change from the amine to the imine form upon change of solvent polarity is unusual in N-heterocycles, the tautomeric shift observed by Brown and Hewlins is comprehensible because of the small value of the tautomeric constant in aqueous solution. The tautomeric ratio of 25 in water for 5,6-dihydrocytosine should be compared with the value of lo5 for cytosine itself (see Table 11). It thus appears that the hydrogenation of cytosine causes a substantial shift toward the imine form. A further shift toward the imine is observed when 5,6-dihydrocytosine is substituted at the amino group by a hydroxy group. It was shown124 by UV spectra that 1-alkylexist in aqueous solution substituted N4-hydroxy-5,6-dihydrocytosines in the lactam(ox)imine form 20. N
R R = alkyl
J. s. KWIATKOWSKI AND BERNARD PULLMAN
220
[Sec. II.B.4
4. Substitution of a Hydroxy, Methoxy, or Amino Radical at the Amino
Qroup of Cytosine: Tautomeric Shift 2 -+ 6 One of the powerful chemical mutagens inducing point mutations is hydroxylamine, NH,OH, and its N- and 0-methyl d e r i v a t i v e ~ . l ~ ~ - l ~ ~ These react with the pyrimidine bases, and their reaction with cytosine (or cytidine) leads to the formation of several modified cytosines (or cytidines), among which are N4-hydroxycytosine (21, 22, R = R’ = H), and N4-methoxycytosine (21, 22, R = H, R’ = Me) and the HNOR’
0AN$ N
I
+/)
NOR‘ R = H, Me, or glycosic residue R’ = H or Me
I
R
R
(21)
(22)
corresponding cytidines. A similar although weaker mutagenic agent is hydrazine. It too reacts only with the pyrimidine bases. The reaction of hydrazine, with cytosine (cytidine) yields among other things N4aminocytosine (23,24). H,
,NH, N I
N Ha
s;T’ R = H or glycoaide residue
I
R
(23)
I
R (24)
Cytosines substituted at the amino group by hydroxy, methoxy, or amino groups are known to exist as mixtures of tautomers 21 or 23 and 22 or 24, respectively. The tautomeric properties of these cytosines were J. Phillips and D. M. Brown, Progr. Nucl. Acid. Res. Mol. Biol. 7 , 349 (1968). E. B. Freese, Radiat. Res. Suppl. 6, 97 (1966). 128 N. K. Koohetkov and E. I. Budowsky, Progr. Nucl. Acid. Res. Mol. Biol. 9, 126
127 E. Freese and
403 (1969).
C. Janion and D. Shugar, Acta Biochim. Pol. 12,337 (1965). 130 C. Janion and D. Shugar, Acta Biochim. Pol. 15,107 (1968). C . Janion and D. Shugar, Acta Biochim. Pol. 16,219 (1969). 132 C. Janion and D. Shugar,Acta Biochim. Pol. 18,403 (1971). 133 C . Janion and D. Shugtw, Biochem. Biophys. Res. Commun. 18,617 (1965). lae
Sec. II.C]
22 1
STRUCTURE OF BIOLOQICAL PYRIMIDINES
studied by I R , NMR, and UV spectroscopy as well as by ionization constant m e a ~ u r e m e n t s . ~From ~ ~ . ~NMR ~ ~ spectra by Brown and H e ~ l i n s the l ~ ~only possible forms for 1-substituted N4-hydroxy, N4methoxy ,or N4-aminocytosines are the 4-amine or 4-imine forms 21-24. The I R and UV spectra indicate that N4-hydroxy and N4-methoxycytosines exist in solution predominantly in imine form 22 while N4clminocytosine exists mainly in amine form 23. A comparison of the tautomeric constants in the series of N4substituted cytosines indicates an interesting trend. As seen above, in the case of cytosine itself, the ratio of the tautomers of the amine type 2 to those of the imine type 6 is about lo5. I n the case of N4:aminocytosine134 the amine form 22 predominates by a factor of about 30, while N4-hydroxy compounds have mainly the imine form 21 with 10 [i.e., K , (amine/imine) = lO-l]. Another tautomeric constant of this constant gave the value of 25 [K, (amine/imine) = 4 x lo-,] in favor of the imine. As we see, the contribution of the imine forms of N4-substituted cytosines to the tautomeric equilibrium becomes more important with respect to the amine forms with increase of the electronegativity of the N4-substituent in the series H, NH,, OH(0Me). I n Table V are compiled the experimental data on the predominant tautomers of cytosine itself and some of its derivatives. N
N
N
C. QUANTUM-MECHANICAL STUDIES We now discuss the results of quantum-mechanical calculations which have been performed in order to predict the most stable tautomeric structures of cytosines. This discussion requires the usual caution. Most important, the calculations refer in general to isolated molecules while the experimental data refer to the crystal or solution. A direct comparison between the two, although frequently made, must therefore be carried out with caution. This is particularly true when the different computed conformations differ little in energy, so that the effect of the environmental forces may be rather drastic. The same applies, a fortiori, to attempts at M. Brown and M. J. E. Hewlins, J . Chem. SOC.C , 1925 (1968). C. Janion, Acta Biochim. Pol. 19,261 (1972). 136 E. D. Sverdlov, A. P. Krapivko, and E. I. Budowsky, Khim. Qeterosikl. Soedin., in press (quoted by Budowsky et al.137). 13' E. I. Budowsky, E. D. Sverdlov, and T. N. Spasokukotskaya, FEBS Lett., 17, 134 D.
136
336 (1971).
TABLE V
PREDOMINANT TAWTOICERS OF CYTOSINES Compound Cytosine (cytidine)
5-Fluorocytosine, 5-chlorocytosine 6-Fluorocytosine, 6-chloroc ytosine 5-haCytOSine, 5-azacytidine 6-Azacytosine, 6-azacytidine 5,6-Dihydrocytosine
Environment
Type of predominant tautomer
Experimental evidence
Solid state
Lactam-amine (2)
Aqueous solution
Lactam-amine (2)
X-Ray crystallography,IR, and Raman spectroscopy IR, Raman, NMR, and W spectroscopy, pK measurements
Nonaqueous solution
Lactam-amine (2)
IR, UV spectroscopy
Acetonitrile (nonaq.sol.) Aqueous solution
Lactam-imine (6)
W spectroscopy
Lactam-amine (2)
W spectroscopy
Aqueous solution
Ladam-amine (3)
W spectroscopy
Aqueous solution
Lactam-amine (2)
IR, N M R , and W spectro-
Aqueous solution
Lactam-amine (2)
Aqueous solution
Lactam-amine (2)
Chloroform solution Lactam-imine (6) N4-Aminocytosin0 Aqueous solution Lactam-amine (2) N4-Hydroxy-cytosine, Aqueous solution Lactam-imine (6) N4~methox$cytosine N4-Hydroxy-5,6Aqueous solution Lactam-imine (6) dihydrocytosine
scopy IR, NMR, and UV spectroscopy IR, NMR, and W spectroscopy, pK measurements IR and W spectroscopy -
-
Remarks
z 104-105, tautomer 3 more stable than tautomer 6,alkylaminocytosines exist in form 2 Change of the proportions of tautomers on going from aqueous t o nonaqueous solution Uncertain evidence (see text) e . 6
Tautomer 6 more stable than tautomer 3 Kz.6 = 25
Sec. II.C]
STRUCTURE OF BIOLOGICAL PYRIMIDINES
223
correlation of the tautomeric ratios as measured, e.g., in solution, and the calculated energy differences between tautomeric forms. Calculations on biological pyrimidines have been performed by practically all the available quantum-mechanical procedures including the nonempirical ab initio methods. But only in a few cases have attempts been made to interpret the stability of pyrimidine tautomers. We present here theoretical attempts by several investigators as well as some new results by us from the CNDO/2 method. The first application of the quantum-mechanical methods to the study of the stabilities of the cytosine tautomers was based on the r-Huckel molecular orbital (‘IT-HMO)method. The method has been applied in particular to evaluate the variation of resonance energies upon tautomerization in the ground and excited state of c y t ~ s i n e , ~the . ~n-energy ~ ~ . ~ difference ~~ between forms 2 and 6140 and to deduce the influence of aza-substitution on the tautomeric e q ~ i l i b r i u m ’ (for ~ ~ *related ~ ~ ~ papers with an application of the ‘IT-HMOmethod see refs. 5, 140, 142, 143; and for ‘IT-SCF MO approach, see ref. 144). It must be emphasized that computations MO) are only signifilimited to the ‘IT-electronsystems (‘IT-HMO,‘IT-SCF cant to the problem of tautomerism if the energies of the a-bonds in tautomers are invariant. They may only be used, following a well documented procedure,l to give information on the relative tendencies of a series of related molecules, such as the nucleic acid bases, to undergo amine-imine (or lactam-lactim) tautomerism. Table VI collects the theoretical quantities appropriate to the description of the tautomeric stability of cytosine, computed by methods including both ‘IT- and a-electrons. We have added to it the results of a ‘IT-SCFMO approach (including a-polarization effects) on heats of atomization of different tautomeric forms of cytosine. Bodor et al.149 have related the heat of atomization to the stability of the tautomers, and found that the most stable structure of the molecule is the aminelactam 2 having the greatest heat of atomization (59.707 eV). They predict on this basis the following order of stability: 2 > 3 > 6 > 1. 138 B. Pullman and A. Pullman, Biochim.
Biophye. Acta 64,403 (1962). Biophye. Acta 74,269 (1963). 140 T. A. Hoffman and J. Ladik, Advan. Chem. Phys. 7 , 8 4 (1964). 141 A. Pullman, Biochim. Biophye. Acta 87,365 (1964). 142 V. I. Poltev and B. I. Sukhorukov, Bwjkika 1 6 , 5 (1971). 143 B. I. Sukhorukov and V. I. Poltev, Biofizika 9, 148 (1964). 144 N. Dupuy-Mamelleand B. Pullman, J . Chim.Phye.64,708 (1967). 145 H. Berthod and A. Pullman, Biopolymers 2,483 (1964). 148 H. Berthod and A. Pullman, J . Chim.Phys. 62,942 (1965). 147 B. Pullman, J. C h m . Phys. 43, S233 (1965). 148 V. I. Danilov, Bwjizika 12,540 (1967). 149 N. Bodor, M. J. S. Dewar, and A. J. Hart, J . Amer. C h m . SOC. 92,2929 (1970). 130 A. Pullman and B. Pullman, Biochim.
224
J.
s.
KWIATKOWSKI AND BERNARD PULLMAN
[Sec. 1I.C
TABLE VI
THEORETICAL QUANTITIES~ CHARACTERIZING TAUTOMERIC STABILITY OF CYTOSINE
Method
References
Quantityb (kcal/mole)
~~______
+
Berthod and P ~ l l m a n l ~ ~ -dEaSe ~ ~ ’ = - 8.0 T-HMO 0-Del R e AH8,be = 12.7, AH$: = 30.5 n-SCF MO + o-Del Re D a n i l ~ v l ~ * ~ ~ AH?;? = 25.3, A V : : = 20.4 TT-SCF MOC Bodor et ~ 4 Z . l ~ ~ AHE3 = -0.7 AHE6 = -2.2 A m 1 = -4.7 CND0/2d Present work AEa.1 = -2.01 AE8.s = - 10.65 AEs.6 = -13.90 A s s f - A@@ = -1.04 Bertrhn et al. lS0 CNDO/2 CI AE&f - A@@ = 0.93 ~
~~~
a
~
~
~~
For the theoretical interpretation (T-HMO, n-SCF MO) of the relative tendency of cytosines to undergo tautomerization see text. Abbreviations: AHkJ, difference between heats of atomization of tautomers ( i )and ( j ) ; AHSse, changes of enthalpy upon tautomeric conversion 2 6 ; AH‘.’, difference between the total ( n + o)-electron energies (n-HMO + o-Del Re) or total energies (CNDO/2) of tautomers (i) and (j). All values refer to the ground state of cytosine ( S o )unless otherwise indicated. The method includes cr-po1ari~ation.l~~ For other CNDO/2 calculations on tautomeric stability of cytosine, see refs. 14, 152, 153. I n all these calculations the same geometry of the ring has been used for different tautomers. --f
It is interesting that the calculated energy of the u bonds (including the lone-pair electrons) by means of the a-Del Re method146.154,156 favors slightly the imine form 6 of cytosine, but the summation of AE, and AE, leads t o the conclusion that the form 2 should be the most stable one.145-147 The PSCF MO method and the Del Re procedure for u-electrons have been applied by D a n i l o ~to l ~evaluate ~ the enthalpy changes on tautomeric conversion 2 + 6 in the ground state and the first excited singlet state for cytosine and its anionic and cationic forms. The results show that although in the ground state of cytosine the tautomeric J. BertriLn, 0. Chalvet, and R. Daudel, An. F k . 66,247 (1970). J. S. Dewar and T. Morita, J . Amer. Chem. SOC.91,796 (1969). 152 H. Fujita, A. Imamura, and C. Nagata, Bull. Chem. SOC. Jap. 42, 1467 (1969). 153 0. M. Sorarrain and E. A. Castro, Chem. Phys. Lett. 19,422 (1973). 1 B 4 G. Del Re, J . Chem. SOC., 4031 (1958). 166 G. Del Re, in “Electronic Aspects of Biochemistry” (B. Pullman, ed.), p. 221. Academic Press, New York, 1964. l50
lS1M.
Sec. II.C]
STRUCTURE OF BIOLOGICAL PYRIMIDINES
225
equilibrium already greatly favors the amine form, upon excitation or on going to ionic forms the equilibrium is shifted still more toward forms 2. This last result is in general agreement with the recent experimental evidence 99 indicating no considerable displacement in tautomeric equilibrium (strictly speaking experimental evidence 99 shows a slight shift toward forms 6, while the calculations148 indicate a slight shift toward forms 2). to evaluate CND0/2 CI calculations performed by Bertrdn et the variation of the tautomeric constant Kf,6 upon excitation do predict a shift toward the rare imine forms 6 in the first excited singlet state, and a shift toward the normal form 2 in the first triplet state. The CND0/2 method has also been applied by several investigators to the study of the stability of cytosine tautomers in their ground states.14J50J52J53At this point it is worth recalling the difficulty (see ref. 3) connected in such studies with the uncertainty as to the geometry of the rare tautomeric forms (because of lack of experimental data). The quantitative results of the CNDO/2 calculations depend appreciably on the assumed geometrical structures of these rare forms. Nevertheless, all CNDO/2 calculations (Table VI and refs. 14, 152, 153) predict lactam-amine tautomer 2 to be more stable than lactam-imine 6. The energy difference between these tautomers has been evaluated to be of the order of 13.9-26.6 kcal/mole, depending on the geometry of the structures. Breen and F1urry14 have investigated the stability of cytosine tautomers 1, 2, 3, and 6 by means of the CND0/2 method using different geometrical assumptions. Maintaining the same geometry (from Barker and Marshll) for the heavy atoms for all tautomers, they find the lactimamine tautomer 1 to be the most stable, tautomer 2 to be 0.024 eV less stable than 1 and lactam-imine tautomer 6 to be the least stable. Calculations performed on nonplanar tautomers having out-of-plane hydrogens of the amino group show the same order of stability. Calculations in which the exocyclic bonds C-0 and C-N were scaled, .but the angular geometries of the tautomers retained, gave again the same order of stability. Calculations performed with all the coordinates for each tautomer scaled gave, however, the tautomer 2 as the most stable. Lactim-amine tautomer 1 was the next, but higher in energy by 1.5 kcal/mole. The relative energetic positions of the other two tautomers were the same as in the unscaled tautomers. It is interesting that lactim-imine tautomers 5 and 4 appear to have considerably higher energies than tautomers 2 or even tautomer 6.156 lS6
B. L. Lesyng, M. Sci. Thesis, Univ. of Warsaw (1972), and unpublishedresults.
226
J. 8. KWIATKOWSKI AND BERNARD PULLMAN
[Sec. 1I.C
On the other hand, all CNDO/2 calculations predict that the tautomer
2 should be more stable than tautomer 3,and this last form more stable than the form 6. This prediction is in good agreement with the experimental evidence (Table 11). One point connected with these calculations deserves additional comment. As stated above, the results of the CNDO/2 energy calculations depend appreciably on the geometry assumed for the tautomeric unsatisfactory results were obtained forms. In a few cases14*15a*158*157 in predicting the position of the lactam-lactim equilibrium in N-heterocyclic molecules, owing to uncertainty in the geometry of the hydroxy g r ~ u p , i.e., ~ J the ~ ~C-0 and 0-H bond lengths. Usually, the calculations are performed with 1.4-1.46 8 and 0.9-1.0 8,respectively. Pullman and Pullman have made a study of the relative stability of the lactim form of guanine with respect to its lactam form as a function of the lengths of the G O and 0-H bonds. They showed that in order to interpret correctly the relative stabilities of guanine tautomers one has to use bond lengths 1.36 and 0.85 A, respectively (compare also the study of the lactam-lactim tautomerism in pyridones and pyrimid~nesl~'). More recently detailed crystallographic information beoame available about the geometry of the 0-H substituent in the lactim form of p y r i d i n o l ~ . ~ * ~ This geometry (rs0 z 1.33 and rO-* = 0.86 8)is close to that used in the Pullmans' studies on the lactim-lactam tautomerism of g ~ a n i n e . ~ The same values of the G O and 0-H bond lengths have also been used in our calculation on the lactim form of cytosine. Table VII contains the results of the CND0/2 calculation158on the energy of cytosine tautomers 2,3or 6 and of some derivatives. It can be seen that the calculated energy shifts are in agreement with the effect of substitution on the tautomeric equilibrium of cytosine discussed in Section 11, B. Thus, a 5-fluoro substituent causes a small tautomeric = 2.98 kcal/mole) or 6 shift toward forms 3 (AEE9F-cyt(AE2JF6F-Cyt - &?3%$ = 4.87 kcal/mole), while a 6-fluoro substituent causes a large shift toward form 3 (AE~LS,-,,,- AEg;t = 10.33 kcal/ mole) and a negligible shift toward form 6 , ( L I E ~ : B ,-- ~AE&!t ~ ~ = 1.63 kcal/mole). These conclusions have been confirmed by a very recent evaluation of the singlet-singlet transition energies159by means of the T-SCF MO CI method. These calculations predict that a 5-fluoro substituent in the cytosine tautomera 2, 3 and 6 should shift the first 167
lS8
M. Berndt, J. S. Kwiatkowski, J.Budzixiski, and B. Szczodrowska,Chem. Phys. Lett. 19,240(1973). J . S. Kwiatkowski and B. Pullman,Acta. Phys. Pol. A45,093 (1974). B. L. Lesyng, Studia Biophya., in press.
Sec. 1111
227
STRUCTURE O F BIOLOGICAL PYRIMIDINES
EFFECTOF STJBSTITUENT ON
THE
TABLE VII STABILITY OF TAUTOMERIC FORMS OF CYTOSINE
Theoretical dataa Substituent
None (cytosine itself) 6-Fluoro 6-Fluoro ~4-~mino N4-Hydroxy 6,6-Dihydro
AE2.3
AEz.6
- 10.65 - 7.87 - 0.32 -
- 13.90 - 9.03 - 12.27 - 1.62 - 0.07 - 1.Od
-
Experimental datab Kf.8
IQ.3 N
lo3
N
-
-
104.'
-
> 1c < 1c N
30 10-l-4 x 26(in water) 10-1 (in chloroform) N
Differences between CNDO/2 energies of tautomers 2, 3 and 2, 6, respectively. All values in kilocalories per mole. b Compere Table 11. Kf-1 stands for tautomeric ratio of forms (i) to (j). 0 Dominating tautomers 2 and 3 for 6-fluoro and 6-fluorocytosine,respectively. d From ref. 3. For cytosine itself the AEz.6 value was calculated3to be equal to - 16 kcal/mole. 4
absorption band of cytosine toward longer wavelengths (bathochromic effect), while a 6-Auoro substituent should cause a shift toward shorter wavelengths (hypsochromic effect). The magnitude of the bond shift is smaller in the latter case than in the former. Experimentally, Wempen and have measured the shifts upon both 5- and 6-fluoro substitution. The observed spectral shifts agree with the theoretical data only when the observed bands are attributed to the absorption of tautomers 2 in cytosine and 5-fluorocytosine, and to that of tautomer 3 in 6-fluorocytosine. Predicted tautomeric shifts also correlate satisfactorily with the experimental shifts observed in the cytosine, N4-amino- and N4hydroxycytosine series. I n accordance with the experimental evidence, the calculations predict a significant tautomeric shift toward imine form 6 upon amino or hydroxy substitution a t the amino group of cytosine. Previously reported calculations3 also gave a satisfactory interpretation of the tautomeric shift caused by hydration of cytosine.
III. Electronic Structure of the Ground State of Cytosines This section is devoted to the presentation of the essential physicochemical properties of cytosine and some of its derivatives and to the theoretical interpretation of these properties. Since the tautomeric
228
J.
s. KWIATKOWSKI
AND BERNARD PULLMAN
[Sec. 1II.A
equilibrium of cytosine is displaced very strongly toward the lactamamine form 2 and there is relatively very little experimental information available about the other tautomers, our discussion is in general restricted to this essential form. Some properties of the rare forms, however, are also presented.
A. THE GEOMETRY OF CYTOSINE Abundant information on the geometrical structure of cytosine, i.e., on the bond angles and lengths, is available from X-ray crystallographic investigations (for reviews, see refs. 7, 27, 160-168). Comparison of the crystal data from different publications shows that the different distances and angles differ significantly among themselves in the different studies compared with the evaluated standard deviations of these q ~ a n t i t i e sThe . ~ criterion of reliability choosen by Voet and Rich7 in the latest review was that the estimated standard deviations of the bond lengths and the bond angles of the reference molecules should be less than 0.05 A and 3 O , respectively. We have performed a similar averaging of the crystal data, in which, in addition to the crystallographic structures chosen by Voet and Rich, some more recent crystal structures were taken into consideration.20*22 These new calculated average values of the bond lengths and angles compare quite well with the averages determined by Voet and Rich.' The MO methods have been used to calculate the n-electronic bond orders in unprotonated cytosine, and the bond lengths have been calculated on the basis of these quantities in the customary way.lssa The qualitative agreement (Fig. 2) between the theoretical and experimental values is, in general, good, the best being obtained by means of the simple n-HMO method. The n-bond orders or total bond overlap populations calculated by different methods can be found in several papers: n-HMO calculations on cytosines, see reviews1~140.170-172; n-SC 160 M.
Spencer, Acta CrystaZZogr.12,50 (1959). M. Spencer, Acta CrystaZZogr.12, 66 (1959). laa L. Pauling and R. B. Corey, Arch. Biochem. Biophys. 65,164 (1956). 163 J. Kendrew and M. Perutz, Annu. Rev. Biochem. 26,327 (1957). 164 A. Rich and D. W. Green. Annu. Rev. Biochem. 30,93 (1961). 165 J. Kraut, Annu. Rev. Biochem. 34,247 (1965). 166 M. Sundarelingam, J . Amer. Chem.Soc., 87,699 (1965). D. R. Davies, Annu. Rev. Biochem. 36,321 (1967). J. Donohue, Arch. Biochem. Biophys. 128,591 (1968). leas Recent --SC HMO (improved w-technique) calculations16sdid not change the correlation between the calculated and experimental bond distances in cytosine.
Sec. III.A]
STRUCTURE OF BIOLOGICAL PYRIMIDINES
229
XI
I
1.3
1.21
I
I
I
1-2
1-6
2-3
I
2-7
I
3-4
4-5
- 1 - I
4-8
5-6 Bond
FIG.2. Comparison between experimental7 -( ) bond distances of cytosine ) and those calculated by means of the n-Huckel molecular orbital methodl ( and the n-self-consistent field MO rnethodl4O(- - - -).
. ...
HMO (w-technique) calculations169 on cytosine, forms 1 and 2, 1methylcytosine; T-SCF MO calculations on cytosine, forms 2,104*144*156, 171,173-180 6 104,144,156,177,178 3 104,156,178 1 4 and 5,156,178 5,6-dihy&.o, cytosine, forms 2 and 6,1449161 guanine-cytosine base pair171*175*182-186 9
9
Y. G. Smeyers and G. Delgado-Barrio, An. Real SOC. Espan. Pis. Quim. Ser. B 6 8 , 2 5 (1972). 170 J . I. Fernandez-Alonso, Advan. Chem. Phys. 7 , 3 (1964). 171 S. Fraga and C. Valdemoro, Struct. Bonding (Berlin)4,1(1968). 172 N. K. Kochetkov and E. I. Budovskii (eds.), “Organic Chemistry of Nucleic Acids,” Chapter 3. Plenum Press, London, 1971. 173 V. A. Kuprievich, V. I. Danilov, and 0. V. Shramko, Teor. Ekap. Khim. 2, 734 (1966). 17* A. Imamura, H. Fujita, and C. Nagata, Bull. Chem. SOC. J a p . 4 0 , 2 1 (1967). 175 A. Imamura, H. Fujita, and C. Nagata, Bull. Chem. SOC. Jap. 40,522 (1967). 176 A. Pullman, in “The Triplet State” (A. B. Zahlan, ed.), p. 515. Cambridge Univ. Press, London and New York, 1967. 177 T. Miyata, H. Suzuki, and S. Yomosa, J . Phys. SOC. Jup. 25, 1428 (1968). 178 T. L. Kunii and H. Kuroda, Rep. Computer Center, Univ. Tokyo 1, 227 (1968). 179 V. I. Danilov, 0. V. Shramko, and G. G. Dyadyusha, Biojkika 12, 544 (1967). C. Valdemoro and S. Fraga, Technical Report TC-6701, Dep. Chem. Univ. of Alberta (1967). 181B. Pullman and B. Dupuy, C.R. A d . Sci. 262,2773 (1966). lE2 R. Rein and J. Ladik, J . Chem. Phys. 40,2466 (1964). lE3 R. Rein and F. E. Harris, J . Chem. Phys. 41,3393 (1964). lE4 V. I. Danilov, V. A. Kuprievich, and 0. V. Shramko, Biojkika 12, 186 (1967). le6C. Valdemoro and S. Fraga, Technical Report TC-6702, Dep. Chem., Univ. of Alberta (1967). V. I. Danilov, N. V. Zheltovsky, V. V. Oglobin, and V. I. Pechenaya, J . Theor. Biol. 30,559 (1971). 16Q
230
J.
s. KWIATKOWSKI
AND BERNARD PULLMAN
[Sec. 1II.B
(for the T-bond orders of the C(5)-C( 6) bond in cytosine and &methylcytosine, see refs. 187-189); T-SCF MO + a-DeZ Re calculations1Q0on cytosine, form 6, and on four pairs of 2-aminopurine (amine and imine forms) with cytosine (forms 2 and 6); EHT calculations1Q1on cytosine and cytidine. Cytosine as well as the other heterocyclic nucleic acid bases are quasiaromatic compounds, expected to be planar. The experimental evidence shows that this is not strictly so, but the deviations of the ring atoms of cytosine from planarity are, in general, small, and in most cases within the limits of the experimental accuracy. Oxygen and amino groups, and the atoms of substituents, when present, appear to deviate more from planarity. In all the quantum-mechanical studies the cytosine ring has been assumed to be planar.
B. VIBRATIONAL SPECTRA OF CYTOSINE
As mentioned in Section I1 the IR and Raman spectra of cytosine and of some of its derivatives have been reported in detail. These, spectra have been particularly useful for the elucidation of the structure of the predominant tautomer. More recently, IR and Raman spectroscopy have been used by Susi et aZ.lQ2(cf. also ref. 193) to investigate the vibrations of cytosine and cytosine-d,, and assignments have been given for the in-plane fundamental modes. A valence force field for cytosine has also been proposed and employed to reproduce the observed frequencies with an average error of ca. 10 cm-l ( - 1.0%). Up to now, quantum-mechanical methods have not been applied to the study of the vibrational spectra of cytosine (see Section V, however, for an interpretation of the hydrogen bond vibrational spectra of the quanine-cytosinebase pair). G. G. Dyadyusha, V. I. Danilov, and 0. V. Shramko, Mol. Biol. 1,539 (1967). V. I. Danilov, Yu. A. Kruglyak, V. A. Kuprievich, and V. V. Oglogh, Theor. Chim. Acta 14,242 (1909). lagYu. A. Kruglyak, V. I. Danilov, V. A. Kuprievich, and V. V. Oglobin, Theor. Ek8p. Khim. 6,33 (1970). lgO V. I. Danilov, Yu. A. Kruglyak, V. A. Kuprievich, and 0. V. Shramko, Biofizika 12,726 (1907). lgl F. Jordan and B. Pullman, Theor.Chim. Acta 9,242 (1968). lea H. Susi, J. S. Ard, and J. M. Purcell, Spectrochim. Acta, Part A 29,725 (1973). V. Ya. Maleev and A. E. Stanevich, in “SpektroskopijaTverdowo Tela” (S. E. Frish, ed.), p. 95, Izd. “Nauka,” 1969. la’
Sec. 111.C]
231
STRUCTURE OF BIOLOQICAL PYRIMIDINES
C. RESTRICTED ROTATION ABOUT
THE
EXOCYCLIC C-N BOND
The amino groups of the nucleic acid bases may, in principle, undergo relatively free rotation. I n fact, however, they must be considered as having a significant amide character as a result of a partial double-bond character of the C-N bond due to resonance structures of types 25b and 25c.
(254
(25b)
(254
Rotational restriction of the amino group has been observed by the NMR spectroscopy technique in a number of cytosines in solution as measured well as in the crystalline state.64*86*88*89J94 Shoup et al. the activation parameters for the rotation of the dimethylamino group in N8-dimethylcytosine derivatives. With one exception, the range of activation energies is 15-1 8 kcal/mole. The activation energies found for 26a and 26b are about twice those reported by Martin and Reeselg5 for 26c. In this last case, however, the method by which the activation energy was obtained has not been described (usually approximate 89990
I
o d
x Me
Me
methods for obtaining rate constants from NMR spectra, give too low activation energies), so probably the values obtained by Shoup et al. are more reliable. Table VIII collects several activation parameters for the Ie4 R. R. Shoup, H. T.Miles, and E.D. Becker, Biochem. Biophys. Res. Commtm. 23, 194 (1966). lee
D. M. G.Martin and C.B. Reese, Chem. Commun., 1275 (1967).
TABLE VIII ACTIVATION P A R ~ T E FOR R STHE ~ ROTATION ABOUT Compound 1-Methylcytosine 1-N8,N8-!I’rimethylcytosine
(264
State Dimethylformamide-d, CDC1, CDSCN CD,OD
so2
N8,N8-Dimethyl-l-(2’,3‘,4’,6‘- CDCl, tet~aa03tyl-D -ghCO-
CD,CN
0
EXOCYCLIC C-N BONDOF CYTOSINES
E, (kcal/mole)
k298
AS*
(sec -l)
(e.u.)
-
138
-
-
-
17.6 15.1 15.7 11.5 17.3 18.1
90 123 48 1050 4.5 8.8
7.5 - 0.5 0.2 - 8.1 0.5 4.4
14.8 14.6 15.2 13.3 16.6 16.2
14.9 14.6 15.1 12.7 16.5 16.2
8.6
-
-
-
-
pyranosy1)cytosine (26b)
2’,3’-O-IsopropylideneN8,N8-dimethylcytidine(26c)
THE
Ap*298 AFc* References (kcal/mole) (kcal/mole)
88 89 -
89 -
195
56
u
Notation: E,, activation energy; kas8,rate constant at 298’K; A S , entropy of activation; AFaSe*and AB*, free energies of activation a t 298OK and at coalescence, respectively.
H I+
n
h
Sec. III.C]
STRUCTURE OF BIOLOGICAL PYRIMIDINES
233
rotation of the NR,R’, group in cytosine derivatives. Among these activation parameters, the activation energy E, was the subject of a theoretical treatment by means of the all valence-electrons methods. We have carried PCILO calculations for the barrier of rotation about the exocyclic C(4)-N(8) bond in several cytosines (Table IX). It can clearly be seen that the computations predict restricted rotation of the amino group in cytosine itself as well as in several methyl derivatives. It can also be seen that the barrier height to rotation is sensitive to methyl substitution a t positions C-5 or N-8, but not to substitution at position N-1 or C-6. The CND0/2 calculations predict the same dependence of the barrier heights on the position of substituent. The order of decreasing barrier heights in rotation in cytosine derivatives shown by both methods is cytosine > Ne-methylcytosine > N8,N8-dimethylcytosine. We can also see that the theoretical values of the barrier heights to rotation of the NMe, group in N8,N8-dimethylcytosine are 15-16 kcal/mole, in very good agreement with the experimental data (15-18 kcal/mole). An analysis of the NMR spectra of monomethylamino derivatives of cytosines shows that the rotation of the NHMe group is also restricted. From the corresponding peak heights of the NMR spectra, Shoup et aLE9 have evaluated the relative concentrations of 96/4 and 94.715.3 for the conformers of l-methyl-4-methylaminopyrimid-2-one and 2-methoxy1,5-dimethyl-4-methylaminopyrimidine having the NHMe group syn and anti to N-3. The corresponding associated free energy differences are 1.6 and 1.5 kcal/mole, respectively. Our calculations predict correctly that the syn conformers are more stable than the anti ones in the methylaminocytosines, and the calculated energy differenceAE between these two conformers of 1.0 and 0.9 kcal/mole for Ns-methyl and 6,Ne-dimethylcytosine, respectively, can be compared with the corresponding valuese9 of the free energy differences of 1.6 and 1.5 kcal/mole. The NMR evidenceeg shows that 5,N8-dimethylcytosine exists almost exclusively in one conformation, almost certainly with the N8-methyl syn to N-3. The energies of the conformers of the molecule calculated by the PCILO method predict correctly this experimental fact (see Table VIII). A conformational studylgS of N-6-substituted C. N. R. Rao, in “Conformation of Biological Molecules and Polymers” (E. D. Bergmann and B. Pullman, eds.),p. 107, Israel Acad. Sci. Humanities, Jerusalem (distributedby Academic Press, New York), 1973. lg7 K. G . Rao and C. N. R. Rao, J.Chem. SOC. Perkin Trans. 2,889 (1973). lg* H. Berthod and B. Pullman, C.R. A d . Sci. Ser. D 276,1767 (1973).
TABLE I X CALCULATED VALUESFOR BARRIEROF ROTATIONAND BARRIERHEIGHTS Energya (kcal/mole), with respect t o the individual global minimum, from PCILO calculation.c Angle of rotation, @(CPNS),in degrees Compound
0 ~
~
Cytosine 1-Methylcytosine 5-Methylcytosine 6-Methylcytosine Ne -Methylcytosine 5,N8-Dimethylcytosine 6,N8-Dimethylcytos~e N8,N8-Dimethylcytosie a
30"
60"
0 0 0 0 1.02 23.22 0.89 0
4.64 4.66 4.52 4.66 5.25 18.73 5.18 4.20
90" ~
~
13.66 13.70 13.41 13.73 13.25 13.98 13.34 12.01
18.04 18.10 17.73 18.13 17.38 17.01 17.50 15.83
120"
150" ~
~~
13.66 13.70 13.41 13.73 13.51 13.19 13.59 12.01
180"
Barrier heightsb t o rotation (kcal/mole) from CND0/2 calculation ( R ~ o ~ ~ ~ J ~ ~ )
~
4.64 4.66 4.52 4.66 4.83 4.74 4.85 4.20
0 0 0 0 0 0 0 0
25 20 16 20 17 17 15
Italicized figures are the barrier heights t o rotation. Barrier heights to rotation in l-N8-dimethylcytosinewas calculated1Qe*lQ7 as 17 kcal/mole. Calculations were obtained in collaboration with Dr. B. MBly.
U U
U
h
Sec. 1II.D.11
235
STRUCTURE OF BIOLOGICAL PYRIMIDINES
adenines by the PCILO method shows also that the conformers with the N6-methyl or N6-(dz-isopentenyl)syn to N-1 are the more stable ones.
D. DISTRIBUTION OF ELECTRON DENSITY IN CYTOSINES The ground-state wave function of cytosine has been calculated by practically all the semiempirical as well as nonempirical methods. Here, we shall discuss the application of these methods to interpret the experimental quantities that can be calculated from the molecular orbitals of cytosines and are related to the distribution of electron densities in the molecules. The simplest ‘IT-HMOmethod yielded a great mass of useful information concerning the structure and the properties of biological molecules including cytosines. The reader is referred to the book1 “Quantum Biochemistry” for the application of this method to interpret the physicochemical properties of biomolecules. Here we will MO and the all-valence restrict our attention to the results of the ‘IT-SCF or all-electron treatments of cytosines. 1 . Distribution of r-Electrons, a-Electrons, and the Total Electron Density Several methods of quantum chemistry have been applied to calculate the charge distributions in cytosine and some of its derivatives. The results can be found as follows: for ‘IT-HMOcalculations see ‘IT-SCHMO (improved w-technique) calculations169 reviews1~140~170-17z; on forms 1 and 2 of cytosine, l-methylcytosine; rr-SCF MO calculations on cytosine, forms 2,104,144,149,156,171~173-178,180,198-2066 104,140,144,149, 9
156*177*178 3,104*156*178 1, 4, and 5,104,156cationic and anionic forms of ~ y t o s i n e amine , ~ ~ and ~ ~imine ~ ~ forms ~ ~ ~of ~ 5,6-dihydrocyto~ ~ ~ ~ ~ 1-,3-, 5-methyl and N8-methylcytosine,z0*5- and 6-substitusine,144*181 ted cytosinezo5by F, C1, Br, I, OH, OCH,, SH, NH,, CH,, and COOH,
A. Veillard and B. Pullman, C . R .Acad. Sci. 253,2277 (1961). A. Veillard and B. Pullman, J . Theor. Biol.4, 37 (1963). 201 C. Nagata, A. Imamura, Y. Tagashira, and M. Kodama, BUZZ.Chem. SOC. Jap. lg9
38,1638 (1965).
J. Ladik and K. Appel, Theor. Chim. Acta 4, 132 (1966). V. A. Kuprievich, I n t . J . Quant. Chem. 1,561 (1967). 204 C. Nagata and 0.MBrtensson, J . Theor. Biol. 19, 133 (1968). 205 J. Ladik and G. Bicz6, Acta Chim. A d . Sci. Hung. 62,401 (1969). 2oe J. C. Parker, J. S. Avery, J. Ladik, and G. Bicz6, I n t . J . Quant. Chem. 3, 79 2oa
203
(1969).
V. A. Kuprievich, Theor. Ekap. Khim. 3 , 6 6 (1967). 208 A. Denis and H. Berthod, J . Chim. Phya. 65,1815 (1968). =07
236
J.
s.
KWIATKOWSKI AND BERNAFLD PULLMAN
[Sec. III.D.l
reaction products of cytosine with h y d r ~ x y l a m i n e 5-methyl ,~~~ and 5hydroxymethyl substituted cytosines and their 4-hydroxylaminoderi~ a t i v e s , ~guanine-cytosine O~ base pair175.182-188and its cation and anion209 (for the charge densities a t C-5 and C-6 positions in cytosine and 6-methylcytosine see s*1*7,1eg); TSCP MO + o-Del Re calculations on cytosine, form 6,lgo1-methylcytosine, forms 2 and 6,210 four pairs of 2-aminopurine (amine and imine forms) with cytosine (forms 2 and 6)lgO; EHT calculations on cytosine and cytidinelgl; IEHT calculations on cytosine 211-213 and its protonated form213;CNDO/Z calculations on cytosine form 2,156*1g7*214,215 1-, 5-, 6-, N8-methyl and N8-dimethylcytosinelg7(cf. also Labhart and Herrmann2ls on SCF MO calculations, including T and o electrons within electrostatic approximation, on cytosine), and see Figs. 5 and 6 for CNDO/2 calculations on different tautomers of cytosine and its derivatives, charges on atoms involved in hydrogen bonds of guanine-cytosine base pair 217; nonempirical calculations on cytosine.218-220 The charge distributions in cytosine have been previously reviewed These include the in several articles and books.1,81140.170-172,221-227 V. I. Danilov, V. A. Kuprievich, and 0. V. Shramko, Biojkika 12, 606 (1967). G. E. Bass and L. J. Schaad, J . Amer. Chem.SOC.93,4585 (1971). A. Pullman, E. Kochanski, M. Gilbert, and A. Denis, Theor. Chim.Acta 10,231 (1968). R . Rein, N. Fukuda, G. A. Clarke, and F. E. Harris, J . Theor. BioZ.21, 88 (1968). A. Denis and M. Gilbert, Theor. Chim. Acta 11,31 (1968). 214 C. Giessner-Prettre and A. Pullman, Theor. Chim. Acla 9,279 (1968). a15 H . Chojnacki and W. A. Sokalski, J . Mol. Struct. 15,263 (1973). 21e H . Labhart, and E. C. Hermann, in “Quantum Aspects of Heterocyclic Compounds in Chemistry and Biochemistry” (E. D. Bergmann and B. Pullman, eds.), p. 76. Israel Acad. Sci. Humanities, Jerusalem (distributed by Academic Press), New York, 1970. a17 A. C. Blizzard and D. P. Santry, J . Theor. Biol. 25,461 (1969). B. Mely, Ph. D. Thesis, Univ. Paris, 1968. a19 B. M61y and A. Pullman, Theor. Chim. Acta 13,278 (1969). E. Clementi, J. M. Andr6, M. C. Andr6, D. Klint, and D. Hahn, Acta P h p . Acad. Sci. Hung. 27,493 (1909). 221 A. Pullman, Int. J . Quant.Chena. 2s, 187 (1968). 222 A. Pullman and B. Pullman, Adwan. Qwnt.Chem. 4,267 (1968). 223 B. Pullman and A. Pullman, Progr. Nucl. Acid Res. Mol. Biol. 9,327 (1969). a24 A. Pullman, Ann. N . Y . Acad.Sci. 158,65 (1969). 225 B. Pullman, Int. J . Qwnt. Chem. 3s, 83 (1969). 22e A. Pullman, in “Quantum Aspects of Heterocyclic Compounds in Chemistry and Biochemistry” (E. D. Bergmann and B. Pullman, eds.), p. 9. Israel Acad. Sci. Humanities, Jerusalem (distributed by Academic Press, New York), 1970. a27A.Pullman, in “Sigma Molecular Orbital Theory” (0. Sinanoglu and K. Wiberg, eds.). p. 280. Yale Univ. Press, New Haven, Connecticut, 1970. 209 210
Sec. 1II.D. 11
STRUCTURE OF BIOLOGICAL PYRIMIDINES
237
comparison of the results obtained by different methods. Figures 3 and 4 give the net n- and (n + a)-charge distributions, respectively, for form 2 of cytosine. An analysis of all the results of semiempirical and nonempirical calculations shows that they predict net negative n-charges on atoms 0 - 7 , N-3, and C-5 (q, > q3 > q5),but the IEHT ca1culations2l1 predict also negative net n-charges on C-2, (3-4, and C-6. The IEHT method,228ahowever, is still in an evolving stage, and its results are frequently dubious. 0.197
NH2o"0.563 :%
I
0.184 0.241 (0.195)
- 0.438
- 0.297 - 0.548
- 0.214 - 0.373
N
(-0.2 79W. 335
-0.169 0.225 0.170 (0.133)
0.361 0.310 0.441 0.639
- 0.492 - 0.461 - 0.903 - 0.426 - 0.513 - 0.4161-0.326)
0.207 0.421 -0.256 0.208 0.108 10.042)
-0.169 -0.134 - 0.139 - 0.051 0.199 - 0 . 2 3 8 (-0216)
-
-
0.165 0.048 0.175 0.084 0.141 0.134 (0.133)
H
FIG.3. Net 8-charges in cytosine calculated by different methods (from top to bottom: W-HMO,T-SCF MO, EHT, IEHT, CNDO/2, nonempirical calculations). Data taken from Pullman and Pullman1~222*223~228 and from Clementi et aZ.220 (in parentheses).
All calculations (except the IEHT ones) predict the n-charge density on carbon C-5 to be higher than that on carbon C-6 and locate partial positive n-charges on C-2, C-4, and C-6, as well as on the amino group. Several discrepancies occurring in the calculations made by different workers are evidently due to the different approximations involved in 228
A. Pullman, Top. Curr. Chem. 31,45 (1972). The IEHT method with a different set of parameters has been applied by Rein et uZ.212to calculate the total charge distribution in cytosine and other nucleic acid bases (cf. Fig. 4). The 8-charges have not been indicated.
228a
238
J.
s. KWIATKOWSKI
AND BERNARD PULLMAN
[Sec. III.D.l
the methods. I n spite of these discrepancies, the methods give qualitatively similar results. The conclusions drawn from the results of calculations are highly significant for predicting the reactivity of the nucleio acid bases (see below). Several physicochemical properties of the bases, outstanding among which is the dipole moment, depend on both the n- and a-electrons of the molecule. Calculated total charges are indicated on Fig. 4. Those on the nitrogens are in the order N-3 > N-8 > N-1, with the exception of the nonempirical calculations giving the order N-8 > N-1 > N-3. Total
0.229 0.229
:::::
(0.123) 0 . 2 2 7 y ( 0 . 3 3 6 ) 0.394
2
-0.431 -0.324 -0.661 -0.134(-0.061) 2 2
0.229 0.229 0.349
/ 0":;' -":(y
(0.096)
0.371 (0.316)
0.19s 0.195 0.316 0.270 (0.097) 0.125 0.414 (0.369)
FIU.4. Total net charges in cytosine calculated by different methods (from top to bottom: n-HMO o-Del Re, n-SCF MO o-Del Re, EHT, IEHT, CND0/2, nonempirical calculations). Data taken from Pullman and Pullman,1*aa2*223*22'3 Rein et aLa12 (IEHT, in parentheses), and Clementi et aZ.2zo(nonempirical, in parentheses).
+
+
Sec. 1II.D.11
STRUCTURE OF BIOLOGICAL PYRIMIDINES
239
charges on C-5 are higher than on C-6. Similarly to the n-electronic charges, the total charges on C-2, C-4, and C-6 are partially positive. Unfortunately, it is not possible at present to compare theoretical charge distributions with the experimental results. Although, very recently, generalized X-ray scattering factors have been used 229 to estimate gross valence atomic populations in several N-heterocyclic compounds including uracil, a similar estimate for cytosine is not available. Figures 5 and 6 give the n- and total electronic charges calculated by the CNDO/2 method for several tautomeric forms of cytosine, 5-F and 6-F-cytosine, and of N8-amino and N8-hydroxy substituted cytosines. The last two compounds as discussed before are important in the theory of mutagenesis, being products of reaction between cytosine and hydrazine or hydroxylamine, respectively. It can be seen that the 5-F or 6-F substitutions change the rr- and total electronic charges mainly at the C-5 or C-6 atoms and in their surroundings. Substitution of the amine or hydroxy group at the N-8 atom does not change significantly the charge distribution in the cytosine ring. A more practical representation of the electron distribution in a molecule can be obtained from the probability density contour maps. Isodensity contours in the molecular plane and in a plane parallel to the molecular plane at an altitude of 0.8 atomic unit have been calculated230 for three nucleic acid bases (adenine, thymine, and cytosine) from nonempirical wave functions. The first type of contour gives an overall picture of a-bonding in the molecule, and the second characterizes the .rr-electrondensity. A comparison of the a-contours in cytosine (Fig. 7a) and other nucleic acid bases230 (cf. Fig. 14a for thymine) indicates a great constancy in the individual aspect of certain bonds, atoms, or groups of atoms in different environments, e.g., the characteristic shape of the C=O or NH, groups. Similarly, all the NH groups display a typical triangular form. All the pyridinelike nitrogens display another triangular distribution with the directional character of the lone pair clearly visible. On the other hand, the nonbonding electrons of the carbonyl oxygens are buried inside a nearly spherical distribution. The contours above the molecular plane (related to the .rr-electron densities) show neatly the differences between pyrrolic or amino-type and pyridinic nitrogen^^^^ (Fig. 7b; cf. Fig. 14b for thymine). The aaQ R. F. Stewart, J . Chem. Phys., 53,206(1970). 230
A. Pullman, M. Dreyfus, and B. Mely, Theor. Chim. Acta 17, 85 (1970).
240
J. 0.134
-0.346 I-0.3561
s.
KWIATKOWSKI AND BERNARD PULLMAN
[Sec.
III.D.l
0.127
N
0.424
0.i40
0.134
0.141
0.154
0.143
\ N - IZ(0.150 4
\N-Zs4
(0.299
-0.314) 0.214)
N
-0.396 (-0.484)
0.326
(-0.250)
(-0.4071
(-0.330)
0.098
(0.204
I
-0.389
-0.395 (-0.483)
I
1- 0.4791
(0.251)
0'02'
N-0.227 I (0.250
-0.94 (-0.476 )
1
0.152
-0.334
0.155
0.043
0.0Z6
-0.364 eo.ro31N
(-0J48l~/ 0.304
F$iZ]
/
0.022
-0.307
-0.110 -0.0791
(03 2 31
0.385 10.166
-0.275 (-0.235)
o tie
0.191
0.120
0.190
FIQ.5. Net total electronic charges in cytosine and fluorocytosine tctutomers calculated by the CNDO/2 method. The numbers in parentheses indicate IIcharges.
Sec. III.D.21
24 1
STRUCTURE OF BIOLOGICAL PYRIMIDINES 0.106 1-0.247
HNY
-0.103
t0.274fl
I
0.031
-0349 N
-0.41%
-0.003 I 0.146
0.;34
o.im
O . k
0.150
0.169
0.i47
FIG.6. Net total electronic charges in N*-amino and N4-hydroxysubstitkted cytosine tautomers calculated by the CNDO/2 method. The numbers in parentheses indicate a-charges.
carbon atoms of the rings appear very similar with the ‘exception of C-6 of pyrimidine. This result confirms the strong r-polarity of this particular atom. The reader is referred to the original paper 230 and reviews228*231 for the detailed discussion of the density contour maps. 2. Dipole Moments The dipole moment of cytosine has been calculated many times by different methods. Until very recently, no experimental data were available on this subject. A short time ago, an attempt was undertaken at the Institute of Biochemistry and Biophysics of the Polish Academy of Sciences, Warsaw, to measure the dipole moments of cytosine, of a number of its derivatives, and of gome cytidines. Table X collects the preliminary results of these measurements. As we see, the value of the dipole moment of cytosine is relatively large ( > 6.0 D), probably about Pullman and B. Pullman, in “The Purines-Theory and Experiment” (E. D. Bergmann and B. Pullman, eds.), p. 1. Israel Acad. Sci. Humanities, Jerusalem (distributedby Academic Press, New York), 1972.
231 A.
242
J.
s. KWIATKOWSRI AND
BERNARD PULLMAN
[Sec. III.D.2
FIU.7. Contours of constant values of electron density in the molecules plane of cytosine (a)and in a plane parallel to the molecular plane at 0.8 atomic unit from it (b),a30Values as indicated. 2 D higher than the dipole moment of uracil or thymine. All the quantum-mechanical calculations predicted a greater moment for cytosine (and guanine) than for uracil or thymine (and adenine). The agreement between the experimental dipole moment of cytosine and the values calculated by different methods is satisfactory (cf. Table XI) TABLE X
DIPOLE MOMENTSO
OF CYTOSINES AND CYTOSINE
Compound
1 -Cyclohexyl1-Cyclohexyl-N-8-methyl1,5-N-*-trirnethyl1-Ribosyl-
1-(2’,3‘,5’-Tri-O-methylribosyl)a
NUCLEOSIDES (AT 25’)
Dipole moment (D)
6.1 f 0.1 6.32 f 0.02 5.0b f 0.2 6.97 f 0.01 6.56 f O.OBb 5.9 f 0.1 6.06 f 0.02
Solution Dioxan Dioxan Benzene Dioxan Benzene Dioxan Dioxan
All figures presented for cytosines are unpublished data measured by I. Kdakowska and K. L. Wierzchowski, and those for cytosine nucleosides by I. Kubkowska and A. Rabczenko (Institute of Biochemistry and Biophysics, Polish Academy of Science, Warsaw). Uncertain value.
Sec. I11.D.31
STRUCTURE OF BIOLOGICAL PYRIMIDINES
243
provided that dipole moments calculated by EHT or IEHT are neglected, being always much higher than the experimental values. Moreover, the exact comparison of the calculated moments with the experimental value is difficult in the case of cytosine because of the uncertainty in the experimental value. It must also be remembered that in all the calculations (Tables X I and XII) the planarity of the molecule was assumed. In fact, the calculated dipole moments of amino compounds with the amino group lying in plane or out of plane of the molecule are significantly different (see, e.g., ref. 232). A very recent CNDO/2 of cytosine dipole moments has shown that it was significantly decreased (to about 7.2 D) when the NH, group was out of plane. From past e~perience,~ the direction of the calculated dipole moment of cytosine (see Tables X I and XII) is reliable. 3. Nolecular Isopotential Maps-Chemical Reactivity The study of the reactivity of the nucleic acid bases utilizes indices based on the knowledge of the molecular electronic structure. There are two possible approaches to the prediction of the chemical properties of a molecule, the isolated and reacting-molecule models (or “static” and “dynamic” ones, respectively). Frequently, at least in the older publications, the chemical reactivity indices for heteroaromatic compounds were calculated in the n-electron approximation, but in principle there is no difficulty to define similar quantities in the all-valence or allelectron methods. The subject is a very broad one, and we shall here mention only a new approach to chemical reactivity based on nonempirical calculations, namely the so-called molecular isopotential maps. The electrostatic potential V ( r , ) at a given point i created in the neighboring space by the nuclear charges and the electronic distribution of a molecule can be calculated from the molecular wave function (strictly speaking from the corresponding fist-order density function). As this quantity is directly obtainable from the wave function, it does not suffer from the drawbacks inherent in the classical population analysis. 33a J. E. Bloor and D. J. Breen, J . Phys. Chem. 72,716 (1968). ~ 4 H. 3 ~DeVoe and I. Tinoco, J . MoZ. Biol. 4,500 (1972). 234
235
H. Berthod and A. Pullman, C.R. Acad. Sci. 259,2711 (1964). H. Berthod, C. Giessner-Prettre, and A. Pullman, Theor. Chim. Acta 5, 53 (1966). S. Kang, J . MoZ. BioZ. 58, 297 (1971).
TABLE XI DIPOLEM O ~ N T OF S CYTOSINES~ CALCUIA~D BY D
~
N METHODS~ T
I
Dipole momentc Method *-HMOb a-SC HMO ( w -technique) a-HMO U-Del Re s-SCFMO u-DelRe
+
+
EHT IEHT
References
Tautomer of cytosine
Pn(aIJd
233 169'
2,1-CH32
6.9 (118) 3.91 (92)
1.7 (63)
8.0 (108) 5.55 (86)
2 2, 1-CH32 2, l-CH36, l,3-diCH,2
5.5 (97) 5.29 (96) 5.4 (113) 5.4 (112)
1.6 (95) 1.85 (99) 1.7 (99) 1.9 (99)
8.12 (127.4)
2.39 (106.0) 3.48 (90.0)h
7.0 (96) 7.14 (97) 7.1 (110) 7.2 (109) 5.22 16.5 (109) *17.3 (106) *12.43 (124.6)
234, 145' 1469 235,226 208 144 224,229 223 211 224 212
2 2
2 2
LLu(au)'
ptot(atot)'
n n
H
*12.9 (121) 6.69'
u 0
CNDOI2j
214
2
CNDO/B--Jaff6"
150
2
219,226 220
2 2
A b initio
6.39 (108)
1.29 (68)
1.78 ( - 89) 3.17 (84)h
5.76 (111)
*7.61 (102)
F6 ?
5.66 *8.27 6.76 (103) 6.4
Dipole moment of cytidine as a function of rotation about the glycosidic bond has been calculated by the INDO method by Kang236 (for the different puckerings of the sugar, (PC(4,)-c(5,)= 60' and 300") and by the PCILO method by Weiler-Feilchenfeldet al. 237 (for the Cj-endo gg conformation). Berthod and Pullman238using the PCILO method have calculated the dipole moments of anti and syn conformers of cytidine (C3-endogg) to be equal to 8.8 and 6.7 D, respectively, and those of deoxycytidine (C2-endogg) to be equal to 10.0 and 4.1 D, respectively. For the T-SCFMO dipole moment of cytosine see refs104*174*177.178. Cf. the reviews 1, 222-228. Dipole moment in Debye units; the angles (in degrees) with the axis N( 1)- C(4) (measured counterclockwise)are given in parentheses. n-Component of the dipole moment. e o-Component of the dipole moment (hydridization moment not included). f Total dipole moment (hybridization moment included (*) or not included). g Dipole moment of guanine-cytosine base pair has also been calculated. Hybridization moment. Including dipole moment of lone pairs. 'See Table XI1 for the dipole moments of different tautomers of cytosine and its derivatives as calculated in the present paper. For other CND0/2 calculations on dipole moment of cytosine, 888 refs. 153, 215,239. CNDO/2 method modified by Del Bene and Jaff6.a40*a41
H
H
H
u W
u
a
'
m 0 +4
246
[SeC.
J. 5 . KWIATKOWSKI AND BERNARD PULLMAN
III.D.3
TABLE XI1 CNDOIB DIPOLEMOMENTSOF CYTOSINEAND ITS DERIVATIVESO
I
H 7.70 D lOlD
0
I
I
H 5.76 D looo
H 8.64 D 146"
6.48 D 110"
I
I
H
H 7.14 D 156"
9.47 D 152"
H,
H\
0A
/OH
a
3.13 D 117'
H\
7.87 D 102O
H 5.01 D 69'
OH
,OH
I
/NH1
I
H
N H 6.11 D 112"
/NHI
I
I
H 3.50 D 66'
3.89 D 52"
5.21 D 68"
I
H 9.32 D 158'
3.06 D 64'
The angles are measured anti-clockwisewith respect to the axis N(l)-C(4).
Sec. III.D.31
STRUCTURE OF BIOLOGICAL PYRIMIDINES
247
Bonaccorsi et a1,242,243 have suggested an appropriate index for the study of chemical reactivity. The interaction energy between the molecular distribution (unperturbed) and an external point charge q placed at point i is qV(r,).This quantity is rigorously the first-order perturbation energy of the molecule in the field of the charge q. Taking q as a unit positive charge the interaction potential can be used for studying proton affinities (basicities) and in principle other electrophilic attacks. The study of the nucleic acid bases is interesting because they possess many possible sites of protonation or electrophilic attack. Isopotential maps have been constructed for adenine, cytosine, and thymine.244They may be used t o study theoretically the proton affinities of the different atoms in these molecules. It is well known that protonation of cytosine, its nucleotide or nucleoside, occurs at N-394*245-247 Nevertheless (cf. Section 11); alkylation also occurs at N-3.103.248*24g protonation of the oxygen of cytosine in DNA has been reported.250 The basic pK of cytosine is higher than that of adenine. The isopotential map in the molecular plane of cytosine (Fig. 8) shows that the potential well is deeper for N-3 than for 0 and the minimum for N-3 in cytosine is deeper than for any nitrogen in adenine. These maps, and their confrontation with the experimental facts have been discussed 228*244 H. Weiler-Felchenfeld, G. Zvilichovsky, E. D. Bergmann, B. Pullman, and H. Berthod, in “Conformation of Biological Molecules and Polymers” (E. D. B e r p a n n and B. Pullman, eds.), p. 311. Israel Acad. Sci. Humanities, Jerusalem (distributed by Academic Press, New York), 1973. 238 H. Berthod and B. Pullman, Biochem. Biophys. Res. Commun. 46, 125 (1972). 23BN, V. Zheltovsky and V. I. Danilov, “Quantum Mechanical Study of the Electronic Structure of the Nucleic Acids Bases by CNDOI2 Method.” Preprint Inst. Phys. Acad. Sci. Ukr. SSR, Kiev, 1973. 240 J. Del Bene and H. H. Jaff6, J . C h m . Phys. 48,1807 (1968). 241 J. Del Bene and H. H. Jaff6, J.Chem. Phys. 48,4050 (1968). 242 R. Bonaccorsi, C. Petrongolo, E. Scrocco, and J. Tomasi, in “Quantum Aspects of Heterocyclic Compounds in Chemistry and Biochemistry” (E. D. B e r p a n n and B. Pullman, eds.), p. 181. Israel Acad. Sci. Humanities, Jerusalem (distributed by Academic Press, New York), 1970. R. Bonaccorsi, E. Scrocco, and J. Tomasi, J . Chem. Phy3.52,5270 (1970). a44 R. Bonaccorsi, A. Pullman,E. Scrocco, and J. Tomasi, Theor. Chim. Acta 24, 51 (1972). 246 L. F. Cavalieri and B. H. Rosenberg, J . Amer. Chem.SOC. 79,5352 (1957). C.Zubay, Bioohim. Biophys. Acta 28, 044 (1958). a47 R. M. Izatt, J. J. Christensen, and J. H. Rytting, Chem. Rev. 71,439 (1971). 248 P. Brookes and P. D. Lawley, Biochim. Bwphys. Acta 26,450 (1957). 24B P. D. Lctwley, Progr. Nucl. Acid. Res. Mol. Bwl. 5 , 8 9 (1966). 250 N. F. Dove, F. A. Wallace, and N. Davidson, Biochim. Biophys. Res. Comm. 1, 312 (1959). 237
248
J.
s. KWIATKOWSKI
A N D BERNARD PULLMAN
[See. III.D.3
FIG.8. Elwtro\i ntir molcculnr potcntinl c-ncrgy maps for cytosine in thc ring plant, (top) :mtl i n 1 l i plane ~ perpmdlcular t o tlic. ring plnnch and passmg through atom5 itb inclictltc,cI (hot t o ~ n ) . ~ ~ ~
Sec. III.D.31
STRUCTURE OF BIOLOGICAL
PYRIMIDINES
249
(for isopotential maps for adenine and guanine calculated from CND0/2 wave functions, see ref. 251). Very recently Port and have made a theoretical study of the effect of the water environment on the structure of adenine, guanine, thymine, and cytosine. They calculated the electrostatic component of the interaction energy between the bases and water molecules. This part of the interaction energy plays the dominant role in hydrogen bonding and particularly in determining the relative orientations of the two partners at their equilibrium distance. The calculation of the interaction energy requires a knowledge of the wave function for the base and for water, The nonempirical wave functions were taken from previous calculations on the nucleic acid bases220 and on water (unpublished results of H. Berthod and A. Pullman). The water molecule was allowed to turn completely around the periphery of the base, a constant distance of 2.85 d being maintained between the oxygen of water and the atoms of the base. The calculations show (Fig. 9) that the
-0. I
-6.5
,,!’
-6.7 -6.8
k-
-5.2
/-
FIG.9. Hydration sites in cytosine.252Energies given in kilocalories per mole. Heavy lines, preferred hydration sites; full lines, coplanar arrangement of water and base; half-dashed, perpendicular arrangement of water with respect t o the plane of the base. 251 252
C. Giessner-Prettre and A. Pullman, C . R . Acad. Sci., Ser. C 272, 750 (1971). G. N. J. Port and A. Pullman, FEBS Lett. 31,70 (1973).
260
J.
s.
KWIATKOWSKI AND BERNARD PULLMAN
[Sec. 1 I I . E
N-3 atom was the most favorable hydration site in cytosine. A second hydration site is situated on the other side of the carbonyl group, between the oxygen and the hydrogen at N-1. There are no other regions of comparably strong attraction in cytosine. It is worth noting that the in-plane interactions are much more favorable than the out-ofplane ones. This has been illustrated252by calculations for a water molecule placed above the NH, group of cytosine (or adenine).
E. MOLECULARORBITAL ENERGIES : ELECTRON-DONATINU ELECTRON-ACCEPTING PROPERTIES A knowledge of the ionization potentials and electron affinities of the nucleic acid bases, or in general the understanding of the electron donor or acceptor properties of the bases, is important for the appreciation of charge transfer complexations and, together with the knowledge of the dipole moments of the bases, has a fundamental significance for the elucidation and evaluation of the intermolecular forces that govern the interaction of the bases with each other or with exogenous substances. The values of the ionization potentials of the bases were unknown experimentally until quite recently, and the electron affinities are still unknown. The first experimental determination of the ionization potentials of the pyrimidine bases (uracil, thymine), by Akopyan and vile so^,^^^ dates from 1965. Two years later Bergmann et al.254 measured the ionization potentials of some purine and pyrimidine bases including cytosine. The cytosine ionization potential as determined by mass spectrometry254was found to be 8.90 & 0.2 eV. On the other hand the potential determined from the “charge transfer’’ spectra by Pulton and Lyons255was 7.98 eV. The simplest method for calculating the ionization potentials and the electron affinities is the PHMO method. Such an evaluation is particularly suitable for the determination of the relative electron donoracceptor properties of the molecules. The appropriate indices are the energies of the highest occupied molecular orbitals ( H O M O ) for the electron donor capacity and the energies of the lowest empty molecular orbitals (LEMO) for the electron acceptor abilities. These simple theoretical predictions gave an excellent interpretation1*26sof the M. E. Akopyan and F. I. Vilesov, Dokl. Akad. NaukSSSR 161,1110 (1965). C. Lifschitz, E. D. Bergmann, and B. Pullman, Tetrahedron Lett., 4583 (1967). 255 H. Fulton and L. E. Lyons, A w l . J. Chem. 21,419 (1968). A. Pullman and B. Pullman, in “Quantum Theory of Atoms, Molecules, Solid State” (P. 0. Lowdin, ed.),p. 345. Academic Press, New York, 1966. 253 254
Sec. III.E]
251
STRUCTURE OF BIOLOGICAL PYRIMIDINES
electrochemical behavior of these biomolecules, including polarographic oxidizability and reducibility of the bases. For about ten years the theoretical values usefully replaced the lacking experimental ones in the study of a number of problems. Table XI11 collects the ionization potentials and electron affinities TABLE XI11 THE CALCULATEDwSCF MO IONIZATION POTENTIALS AND ELECTRON AFFINITIESOF CYTOSINE~
References
Compound
257c
2
235c 20F
2 2,l-CH33,3-CH32,5-CH32,N-8-diCH32 1 3 2
258
149
6 a
'
Ib (eV) 8.3 9Ad n(0-7) ll.Odn(N-3) 8.16 7.97 7.60 8.00 7.93 8.41e 8.0V
8.12e 9.25 9.68' 10.61 10.15'
Ab
(eV)
- 0.87 - 0.82 - 0.26 - 0.89 - 0.80 - 0.24e - 1.25e - 0.24e 1.17 1.20
The following papers may be consulted for the ionization potentials and electron affinities of cytosine and of its complexes with different partners: ~ y t o s i n e , " ~ ~ ' ~ ~ ~ ' ~ ' ~ 178,180.1~4.186.200,201,203.207,258.260 guan~ne~cytos~ne,171,1Ez-lS4,1ES 2-NHz-purine (amino form)-cytosine, 2-NH,-purine(imine form)-cytosineand 2-NHz-purine(amine form)-cytosine (form 6),lS0cytosine-cytosine and cytosine-cytosine-cytosine.'" Ionization potential (I)and electron affinity ( A ) were calculated from Koopmans' theorem, except those indicated. Using the corrected x-SCF MO procedure (an empirical diminution of the values of the atomic valence-state ionization potentials). The lone-pair ionization potentials calculated according to Nakajima and Corrected values (the energies of molecular orbitals were decreased by a constant value). Calculated by the "half-electron" method of Dewar et aZ.262These I-values correspond to the adiabatic ionization potential.
A. Pullman and M. Rossi, Biochim. Biophys. Acta 88,211 (1964). T. L. Kunii and H. Kuroda, Theor. Chim. Acta 11,97 (1968). 259 R. K. Nesbet, Biopolym. Symp. 1, 129 (1964). 2Eo S. Fraga and C. Valdemoro, Technical Report TC-6703, Dep. Chem., Univ. of Alberta (1967). 261 T. Nakajima and A. Pullman, J . Chim. Phys., 793 (1958). 262 M. J. S. Dewar, J. A. Hashmall, and G. G. Venier, J. Amer. Chem. SOC. 90, 1953 (1968). 25i
258
252
J.
s. KWIATKOWSKI AND BERNARD PULLMAN
[Sec. 1II.E
for cytosine and some of its derivatives calculated by means of the n-SCF MO method in a few representative papers. The n-SCF MO procedure, within the Pariser-Parr approximation using the ionization potentials of the atomic valence-states, yields values of molecular ionization potentials that are in general too high, sometimes by as much as 2 eV, with respect to experimental values. I n order to have a better value, two approaches are generally employed. According to the first one, the ionization potential of a molecule is calculated with respect to a reference compound (e.g., benzene) as the negative of the energy of the highest occupied molecular orbital diminished by the difference between the negative value of the highest occupied molecular orbital of the reference molecule and its experimental ionization potential. The second approach utilizes a n appropriately corrected n-SCF MO method, in which the effect of atomic reorganization energy upon bond formation is taken into account by an empirical decrease of the values of the atomic valence-state ionization potentials. The procedure reproduces correctly the experimental values of the molecular ionization potentials of a number of fundamental compounds. It can be seen from Table XI11 that the numerical values of the predicted potentials vary from one calculation to another. The relative order of the predicted potentials of the nucleic acid bases, however, is generally similar in all methods including the all-valence or all-electron ones and also similar to the order predicted originally by the n-HMO calculations. The “corrected” ionization potential of cytosine as determined by Pullman and R o s s ~and , ~ Kunii ~ ~ and K ~ r o d a , ~ ~ * are in good agreement with the experimental data (8.0-8.9 eV). Pullman and R ~ s s have i ~ attempted ~ ~ to evaluate also the nitrogen and oxygen lone-pair ionization potentials of the bases. Using a previously given expression 261 for the lone-pair ionization potentials they have evaluated the relative values of these potentials with respect to those of the nelectrons. I n cytosine the order of increasing ionization potentials is n < n ( 0 ) < n(N). As for the comparison among the nucleic acid bases, the predicted values of the ionization potentials indicated that cytosine It should is the best n(N)-donor and a better n(0)-donorthan also be added that all the quantum-mechanical calculations indicate that the purines are better n-donors than the pyrimidines. All-valence and all-electron methods (except IEHT) predict that the first ionization potential of cytosine and of several derivatives of a cytosine is of the n-type (Tables XIV and XV). An ionization potential of the r-type is the first one in all tautomers of cytosine. Similarly, the electron affinities in all cytosine tautomers should be of the n-type. The energies of the molecular orbitals of the guanine-cytosine base
Sec. III.E]
STRUCTURE OF BIOLOGICAL PYRIMIDINES
253
TABLE X I V
ENERGIES OF
THE LOWESTER~PTY (LEMO) AND THREEHIQHEST OCCUPIED IN CYTOSINES CALCULATED BY CNDO/2 METHOD (HOMO)MOLECULAR ORBITALS~
HOMO (eV)
LEMO Compound, tautomer Cytosine, 2 5-F-cytosine,2 fj-F-cytosine, 2 N4-Aminocytosine,2 N4-Hydroxycytosine, 2 Cytosine, 1 Cytosine, 3 5-F-cytosine,3 6-F-cytosine,3 N4-Hydroxycytosine, 3 Cytosine,b4 Cytosine,b5 Cytosine, 6 5-F-cytosine,6 6-F-cytosine,6 N4-Aminocytosine, 6 N4-Hydroxycytosine, 6
(eV) 2.85 2.30 2.61 2.86 2.75 4.05 2.87 2.29 2.63 2.81 3.21 2.61 3.05 2.63 2.82 3.03 2.94
- 10.79 - 10.98 - 11.12 - 10.71 - 10.85 - 11.56 - 10.48 - 10.50 - 10.97 - 10.46 - 9.73 - 9.89 - 11.26 - 11.32 - 11.49 - 10.24 - 10.73
- 11.820
- 12.190
- 12.340 - 11.780 - 11.900 - 11.760 -11.93~ - 12.310 - 12.540 - 11.970 - 11.270 - 11.930 - 12.66 - 12.89 - 13.05 - 12.54 - 12.500
- 13.30 - 13.33 - 13.72 - 12.25 - 12.79 - 13.12 - '.4.050 - 14.57~ - 14.130 - 13.89 - 14.49 - 13.990 - 12.680 - 12.990 - 13.150 - 12.770 - 12.68
Unlabeled orbitals are 7 levels. Data taken from Ref. 156.
pair have also been calculated in several papers using different methods.262aFor the energies of the highest occupied molecular orbital and the lowest empty one of the base pairs calculated by means of the PHMO method see refs. 1, 140, 171, 263. All calculations show that the molecular levels of the pairs correspond to slightly perturbed levels of the parent bases. The highest occupied molecular orbital of the pair originates from the corresponding molecular orbital of guanine, while the second highest occupied orbital of the pair originates from the HOMO of cytosine. Thus the electron-donor properties of the guaninecytosine pair depend on the electron-donor properties of guanine (perturbed by cytosine). On the other hand, the lowest empty molecular orbital of the guanine-cytosine pair, and the next one, correlate with the lowest empty molecular orbitals of cytosine and guanine, respectively. The electron-acceptor properties of the guanine-cytosine base See ref. 190 for the n-SCF MO ionization potential and electron affinity of the hydrogen-bonding pairs of cytosine-2-NH2-purine (amine form), cytosine-2NH,-purine (imine form), and cytosine (form 6)-2-NH,-purine (amine form). A. Pullman, C. R.Acad. Sci. 258, 5435 (1963).
262a
263
TABLE XV ENERGIES OF Method References LEMO (eV) HOMO (eV)
THE
LOWEST EMPTY(LEMO) AND THREEHIGHEST (HOMO) MOLECULARORBITALSOF CYTOSINE CALCULATEDBY DIFFERENT ALL-VALENCE OR ALL-ELECTRON METHODS EHT
224 - 12.50 n - 12.58 u - 13.51 71
Present calculations. Mainly localized on oxygen. Mainly localized on N-3.
IEHT 212 - 7.54 n - 8.5Fibu -9.12n - 9.61' u
A b initio
CNDOI2 211 - 9.07 u - 10.39 n - 10.54 T
214 - 10.78 n - 11.81 u - 13.21 T
a 2.85 n - 10.79 n - 11.82 u - 13.30 T
220 -
- 9.83 - 11.91 - 12.04
