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CONTENTS
CHAPTER
1.
2.
PAGE
THE CATALYTIC ASYMMETRIC STRECKER REACTION Masakatsu Shibasaki, Motomu Kanai, and Tsuyoshi Mita . . . . . . . .
1
THE SYNTHESIS OF PHENOLS AND QUINONES VIA FISCHER CARBENE COMPLEXES Marcey L. Waters and William D. Wulff . . . . . . . . . . . . . . . . . . . 121
CUMULATIVE CHAPTER TITLES BY VOLUME . . . . . . . . . . . . . . . . . . . . . . . 625 AUTHOR INDEX, VOLUMES 1–70 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639 CHAPTER AND TOPIC INDEX, VOLUMES 1–70 . . . . . . . . . . . . . . . . . . . . . . 645
ix
CHAPTER 1
THE CATALYTIC ASYMMETRIC STRECKER REACTION MASAKATSU SHIBASAKI, MOTOMU KANAI, and TSUYOSHI MITA Graduate School of Pharmaceutical Sciences, The University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
CONTENTS INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . MECHANISM AND STEREOCHEMISTRY SCOPE AND LIMITATIONS . . . . . . . . . . . . Imine Synthesis . . . . . . . . . . . . . Catalytic Enantioselective Strecker Reaction of Aldimines . . . . . Enantioselective Strecker Reaction of Aldimines Catalyzed by Chiral Organocatalysts . . . . . . . . . . . . Enantioselective Strecker Reaction of Aldimines Catalyzed by Chiral Metal Complexes . . . . . . . . . . . . Catalytic Enantioselective Strecker Reaction of Ketimines . . . . . Catalytic Enantioselective Reissert Reaction . . . . . . . . APPLICATIONS TO SYNTHESIS . . . . . . . . . . . COMPARISON WITH OTHER METHODS . . . . . . . . . . Chiral Auxiliary-Controlled Asymmetric Strecker Reaction . . . . . Catalytic Asymmetric Hydrocyanation of Hydrazones . . . . . . Catalytic Asymmetric Hydrogenation . . . . . . . . . Catalytic Asymmetric Introduction of the Side Chain through C–C Bond Formation . . . . . . . . . . . . . . Asymmetric Phase-Transfer-Catalyzed Reactions . . . . . . Asymmetric Allylic Substitution Catalyzed by Chiral Transition Metal Complexes Reactions . . . . . . . . . . Catalytic Asymmetric Addition to Imino Esters . . . . . . . Oxazole as a Glycine Enolate Equivalent . . . . . . . . Catalytic Asymmetric Electrophilic Amination of Enolates . . . . . . . . . . . . . . . . EXPERIMENTAL CONDITIONS Toxicity of Cyanide Compounds . . . . . . . . . . Isolation of Amino Acids . . . . . . . . . . . EXPERIMENTAL PROCEDURES . . . . . . . . . . . Allyl-(4-tert-butylbenzylidene)amine [General Procedure for Preparation of Simple Amine-Derived Aldimines] . . . . . . . . .
[email protected] Organic Reactions, Vol. 70, Edited by Larry E. Overman et al. 2008 Organic Reactions, Inc. Published by John Wiley & Sons, Inc. 1
PAGE 3 3 10 10 12 .
12
.
15 19 20 23 27 28 30 30 31 31
.
32 34 37 38 39 39 39 40
.
40
2
ORGANIC REACTIONS
N -(2-Isopropylcyclopent-2-en-1-ylidene)-P,P-diphenylphosphinic Amide [General Procedure for Preparation of N-Phosphinoyl Ketimines] . . . . . Cyclohexanecarboxaldehyde N-(Mesitylenesulfonyl)imine [General Procedure for Preparation of N-Sulfonyl Imines] . . . . . . . . . N-allyl-N-((4-tert-butylphenyl)(cyano)methyl)-2,2,2-trifluoroacetamide [General Procedure for Catalytic Enantioselective Strecker Reaction of Aldimines Using a Urea-Based Catalyst] . . . . . . . . . . . N-(Mesitylenesulfonyl)-α-(cyano)cyclohexylmethylamine [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using a Phase-Transfer Catalyst] . . . . . . . . . . . . . . Chiral (Salen)Al(III) Complex [Catalyst Preparation] . . . . . . (S)-N -Allyl-N -(phenyl(cyano)methyl)-2,2,2-trifluoroacetamide [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst] . . . . . . . . . . . . . . N-(9-Fluorenylamino)phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst: Condition A] . . . . . . . . . . . . . N -(9-Fluorenylamino)phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst: Condition B] . . . . . . . . . . . . . N-(9-Fluorenylamino)phenylacetonitrile [General Procedure for Catalytic Enantioselective Strecker Reaction of Aldimines Using a Solid-Supported Aluminum Catalyst] . . . . . . . . . . . . . . 2-(2-Hydroxyphenyl)amino-2-phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using a Zirconium Catalyst] . . . . . . . . . . . . . . 1-(2-Hydroxy-6-methylphenyl)aminononane-1-carbonitrile [General Procedure for the Catalytic Enantioselective Three-Component Strecker Reaction Using a Zirconium Catalyst] . . . . . . . . . . . . . . 2-Benzhydrylamino-2-phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction Using a Titanium Catalyst] . . . . 2-Benzylamino-2-(4-bromophenyl)propionitrile [General Procedure for Asymmetric Strecker Reaction of Ketimines Using a Urea Catalyst] . . . . . N-[1-Cyano-2-isopropylcyclopent-2-en-1-yl]-P ,P -diphenylphosphinic Amide [General Procedure for the Asymmetric Strecker Reaction of Ketimines Using a Gadolinium Catalyst] . . . . . . . . . . . . . . 4-(4-Chlorophenyl)-4-methyl-2-phenyl-4H -oxazol-5-one [General Procedure for the Catalytic Enantioselective Strecker Reaction of Ketimines Using a Gadolinium Catalyst: Combination of TMSCN and HCN] . . . . . . . N -(2-Furoyl)-2-cyano-6,7-dimethoxy-1,2-dihydroquinoline [General Procedure for the Catalytic Enantioselective Reissert Reaction of Quinolines] . . . . 1-Cyano-1-phenyl-1,2-dihydroisoquinoline-2-carboxylic Acid Vinyl Ester [General Procedure for Generating Quaternary Stereocenters by Catalytic Enantioselective Reissert Reaction of Isoquinolines] . . . . . . . . . 2-Cyano-5-diisopropylcarbamoyl-2H -pyridine-1-carboxylic Acid 9H -Fluoren-9-ylmethyl Ester [General Procedure for the Catalytic Enantioselective Reissert Reaction of Pyridine Derivatives] . . . . . . . . 4-Chloro-2-cyano-5-diisopropylcarbamoyl-2H -pyridine-1-carboxylic Acid 2,2-Dimethylpropyl Ester [General Procedure for the Catalytic Enantioselective Reissert Reaction of a Halide-Substituted Pyridine Derivative] . . . . . . . . . ADDITIONAL CONTRIBUTIONS AFTER MANUSCRIPT SUBMISSION . . . . . . . . . . . . . TABULAR SURVEY Chart 1. Catalysts and Ligands Used in Tables . . . . . . . Table 1. Catalytic Enantioselective Strecker Reactions of Aldimines . . .
40 41
42
43 43
44
44
45
45
46
47 47 48
48
50 51
52
52
53 54 58 59 62
THE CATALYTIC ASYMMETRIC STRECKER REACTION Table 2. Catalytic Table 3. Catalytic Table 4. Catalytic Aug. 2007 . Table 5. Catalytic Aug. 2007 . . REFERENCES
Enantioselective Enantioselective Enantioselective . . . Enantioselective . . . . . .
Strecker Reactions of Ketimines . . Reissert Reactions . . . . . Strecker Reactions of Aldimines: Nov. 2006 to . . . . . . . . . Strecker Reactions of Ketimines: Nov. 2006 to . . . . . . . . . . . . . . . . . .
3 . .
88 95
.
99
. .
110 115
INTRODUCTION
α-Amino acids are important building blocks for proteins, peptides, and pharmaceuticals. Among a wide variety of methods to synthesize optically active α-amino acids,1 – 6 the Strecker reaction7 is one of the simplest and the most powerful. This reaction consists of three steps (Eq. 1): (1) condensation of an aldehyde or a ketone with an amine to produce an imine, (2) nucleophilic attack of cyanide on the imine to produce an amino nitrile, and (3) hydrolysis of the amino nitrile to the corresponding α-amino acid. These three steps can be conducted in one pot. Conversion of the nitrile group to amide, amine, or aldehyde functionalities is also possible. + H2NR3
O R
1
R
2
– H2 O
N R
1
R3 R
2
asymmetric catalyst CN
–
hydrolysis and deprotection
R3NH
CN
R1
* R2 H 2N
(Eq. 1) CO2H
R 1 * R2
The catalytic promotion and enantiocontrol of cyanide addition to imines is the main focus of the catalytic asymmetric Strecker reaction. Therefore, isolated and purified imines are normally used as substrates. The catalyst turnover efficiency and enantioselectivity of this step are intimately related to the electronic and steric characteristics of the substrate imines, with the nitrogen substituent greatly contributing to these factors. However, since optically active α-amino acids are generally the synthetic target of a catalytic asymmetric Strecker reaction, the accessibility of the starting imines and ease of final deprotection of the product are also important considerations. Due to the importance of catalytic enantioselective Strecker reactions, there have been several reviews on this topic to date.8 – 10 This chapter focuses on catalytic enantioselective Strecker reactions (and Reissert reactions) and the Tables cover all of the references through August 2007. For enzymatic reactions, the reader is directed elsewhere.11 MECHANISM AND STEREOCHEMISTRY
Many of the catalysts for the asymmetric Strecker reaction (and the Reissert reaction) appear to promote the reaction through dual activation12 – 15 of the
4
ORGANIC REACTIONS
electrophilic imine and the nucleophilic cyanide, either trimethylsilyl cyanide (TMSCN) or hydrogen cyanide (HCN).16 This type of asymmetric catalysis was initially postulated in the closely related catalytic asymmetric cyanosilylation of aldehydes. A dual activation mechanism was first proposed for chiral tin (II)–cinchonine catalyst 1.17 In this reaction, the alkoxytin triflate and the tertiary amine of the quinuclidine are believed to act as a Lewis acid to activate the aldehyde, and as a Lewis base to activate TMSCN, respectively. Although high enantioselectivity (90% ee) was obtained, the catalyst turned over only twice (catalyst loading = 30 mol%, product yield = 63%), and the result for only one substrate (cyclohexanecarboxaldehyde) was reported. H TfOSnO N
N H
O
SiMe3
H
R
CN
1
A synergistic combination catalyst was reported for an enantioselective cyanosilylation of aldehydes. Magnesium bisoxazoline 2 acted as a chiral Lewis acid to activate the aldehyde, and uncomplexed bisoxazoline 3 as a Brønsted base to activate HCN as shown in complex 4.18 HCN was generated in a catalytic amount from TMSCN and moisture, and regenerated after TMS trapping of the intermediate cyanohydrin by TMSCN. Only aliphatic aldehydes produced high enantioselectivities in this report. Ph O
N + H N O
Mg
H – N C
O R
O N
Cl
Ph
CN N O
Ph 2
Ph 3
4
Extensive mechanistic studies of an asymmetric cyanosilylation of aldehydes and ketones catalyzed by a salen–titanium complex revealed that the actual catalyst is a bimetallic complex bridged by a µ-oxo atom (5).19,20 One titanium atom acts as a Lewis acid to activate the substrate, while the other titanium atom
THE CATALYTIC ASYMMETRIC STRECKER REACTION
5
generates titanium cyanide (or isocyanide) via transmetalation with TMSCN. It was proposed that the reaction proceeds through an intramolecular cyanide transfer from one titanium to the substrate activated by the other titanium (5).21,22 Only aromatic aldehydes led to high enantioselectivity.
+ N
t-Bu t-Bu t-Bu t-Bu
N Ti O O +N C−
O O
Bu-t Bu-t
O
Ph
Ti
N O
N
H
5
Asymmetric catalyst 6 (prepared from Et2 AlCl and the corresponding BINOLderived ligand) promotes cyanosilylation of aromatic and aliphatic aldehydes with excellent enantioselectivities (Eq. 2).23,24 This catalysis is believed to occur via a dual activation mechanism, in which the aluminum provides a Lewis acidic site to activate the aldehyde and the internal phosphine oxide acts as a Lewis base to activate TMSCN as in intermediate 7. The additive phosphine oxide (R 3 PO) coordinates to the aluminum, and modulates the Lewis acidity and geometry of the aluminum to be optimal for the dual activation pathway. This mechanism was supported by the following: (1) the reaction rate increased according to the electron density of the internal phosphine oxide (a nucleophile activator) at the 3,3 -positions of the BINOL scaffold, (2) an IR absorption derived from the activated ionic cyanide was observed (ν = 2057 cm−1 ; cf. TMSCN, ν = 2192 cm−1 )25 when the bifunctional catalyst 6 was mixed with TMSCN, while a monofunctional Lewis acid aluminum catalyst (generated from BINOL and Et2 AlCl) did not produce this absorption, and (3) a control reaction with a monofunctional catalyst containing diphenylmethyl groups at the 3,3 -positions of BINOL, instead of the Lewis basic phosphine oxide, produced the enantiomer of the products that were obtained using the bifunctional catalyst 6. Catalyst 6 was later applied to a catalytic enantioselective Strecker reaction.26,27 Based on the mechanism of the catalytic enantioselective cyanosilylation of aldehydes using 6, the Strecker reaction was proposed to proceed through a dual activation mechanism illustrated by intermediate 8. These models (7 and 8) can explain the absolute configuration of the products.
6
ORGANIC REACTIONS
O R
6 (9 mol%), R'3P(O) (36 mol%)
+ TMSCN
OTMS (86-100%) 83-99% ee
CH2Cl2, –40°
H
R
CN
P(O)Ph2 O Al Cl O P(O)Ph2 6
Ph
Ph P
O O
Me3 R Si
O O
(Eq. 2)
P
H O
Al Cl
Me3 Si CN
Ph
Ph CN
O
O R''
H N R
Al Cl
(O)PR'3 7
P(O)Ph2
8
P(O)Ph2
A dual activation mechanism illustrated by complex 9 was proposed for the catalytic enantioselective Strecker reaction of aldimines using a titanium–peptide complex.28,29 This transition state model was based on the mechanistic information obtained from kinetic studies, observation of a kinetic isotope effect, measurement of the activation enthalpy and entropy, and molecular modeling studies.30 The titanium acts as a Lewis acid to activate the imines, while the terminal amide carbonyl oxygen acts as a Brønsted base to activate HCN, which is generated in situ from TMSCN and the additive i-PrOH. Specifically, the observed large negative entropy of activation (S= = −45.6 ± 4.1 kcal/K•mol) supports the notion that the reaction proceeds through the highly ordered transition state 9. Ph
H
C N H R N Ph t-Bu O H NBu N N + H Ti O O OBu-t i-PrO OPr-i 9
Chiral organocatalysts now provide an important class of reagents for asymmetric catalysis.31 Two significant asymmetric organocatalysts for the Strecker reaction have been reported, and both of these studies presented mechanistic proposals. One of the organocatalysts is the chiral thiourea catalyst 10, which is one
THE CATALYTIC ASYMMETRIC STRECKER REACTION
7
of the most useful asymmetric catalysts for the Strecker reaction of aldimines and ketimines.32 – 35 Detailed NMR and molecular modeling studies of the catalyst–imine complex demonstrated that the E- and Z-imine geometrical isomers of acyclic imines rapidly interconvert in the presence of the thiourea catalyst, and that the reaction proceeds from the Z-imine complexed to the thiourea moiety of the catalyst through hydrogen bonding as in 11 (Y = S).36 In accord with this pre-transition-state model, a cyclic Z-imine (3,4-dihydroisoquinoline) is an excellent substrate for the Strecker reaction, producing the product in quantitative yield with 89% ee. The absolute stereoinduction from the cyclic Z-imine is identical to that of all of the Strecker adducts derived from acyclic imines that exist predominantly as E isomers. In addition, high-level calculations suggested that the catalyst binds to the starting imine more strongly than to the product; the energy of formation of the thiourea catalyst–imine complex is 10.0 Kcal/mol, while that of the catalyst–product complex is 6.3 Kcal/mol. Thus, product inhibition is unlikely to occur. RL t-Bu S Ph
O O
N H
N
N H
N
HO
RS H N
H t-Bu N
t-Bu
Y
OCOBu-t
10
O
HO
O (Y = O or S)
Ph
OCOBu-t
N
H
t-Bu
11
The other useful organocatalyst for the Strecker reaction is the chiral C-2-symmetric bicyclic guanidine catalyst 12.37 This catalyst was proposed to promote the Strecker reaction through a dual activation mechanism as shown in intermediate 13. The nucleophile HCN is deprotonated by the basic guanidine, while the substrate imine undergoes hydrogen bonding to the protonated guanidine catalyst. A proximal phenyl group of the catalyst can undergo π-stacking with one of the benzhydryl phenyls of the imine. This well-organized pre-transition state model defines the approach of cyanide to the activated imines, and can explain the absolute configuration of the product.
N
Ph N
N
Ph N H
Ph
N +
12 N
N H
H – C
Ph 13
N H
Ph
8
ORGANIC REACTIONS
Ketimines are generally much less reactive than aldimines. Therefore, an asymmetric catalyst with higher activity is required to promote the enantioselective Strecker reaction of ketimines. Chiral thiourea catalyst 10 can promote this type of reaction38 through a similar mechanism to that shown in complex 11. Chiral gadolinium catalyst 18 can promote the asymmetric Strecker reaction of N -diphenylphosphinoyl ketimines.39 – 41 The active catalyst was generated from Gd(OPr-i)3 and D-glucose-derived chiral ligand 14 in a 1 : 2 ratio (Scheme 1). Protic additives such as 2,6-dimethylphenol or HCN dramatically accelerated the reaction, as well as improved the enantioselectivity. Based on ESI-MS studies, the active catalyst was proposed to be a 2 : 3 complex (18) of gadolinium and 14, which was generated through reaction of initially formed alkoxide complex 16 with TMSCN giving compound 17, followed by protonolysis. The Strecker reaction should proceed through an intramolecular transfer of a cyanide to the activated imine by the second Lewis acidic gadolinium (19). The proton in the asymmetric catalyst should accelerate the dissociation of the product from the catalyst (from 19 to 16), and thus accelerate the catalytic cycle. Regeneration of the active catalyst 18 from 16 requires TMSCN. Direct conversion of 16
O Gd(OPr-i)3
+
P Ph2 HO
O
14: X = F 15: X = Cl
O
X
HO
X
(Gd:14 or 15 = 1:2) O H N PPh2
NC R1
R2
O O O
Gd O
O O O
O
Gd O H
O
= 14 or 15 O O Gd O O
16
O
O Gd O CN O O PPh2 N
R1
N R1
O O O
O PPh2 R2
O
Gd
O O Gd O
O CN NC O TMS
R2
19
2 TMSCN (cat.)
O O O
O
Gd O H
O O Gd O
CN 18
Scheme 1
O
HCN 2 TMSCN (cat.)
TMS
17
THE CATALYTIC ASYMMETRIC STRECKER REACTION
9
to 18 through protonolysis by HCN did not occur, and no reaction proceeded in the absence of a catalytic amount of TMSCN. When HCN was used as the additive in combination with a catalytic amount of TMSCN, TMSCN was regenerated at the protonolysis step (17 to 18). Therefore, only a catalytic amount of TMSCN (and a stoichiometric amount of HCN) is required. Labeling studies using TMS13 CN and kinetic studies revealed that the actual nucleophile is not TMSCN, but rather the gadolinium cyanide generated through transmetalation from TMSCN.42 A catalytically active species was crystallized and its structure was elucidated by X-ray crystallography using the dichlorocatechol-containing ligand 15.43 The crystal, however, was not the 2 : 3 complex 16 (active catalyst prepared in situ), but a 4 : 5 complex (20) of gadolinium and 15. Although both polymetallic complexes contain the chiral ligands with the same absolute configuration, crystal 20 (4 : 5 complex) produced the enantiomers of the Strecker products compared to those obtained by using the in situ prepared 2 : 3 complex (16) (Eq. 3). These results demonstrated the importance of the higher order assembly structure of the polymetallic asymmetric catalyst for its function. Due to the structural complexity of the catalysts, three-dimensional models for enantioinduction have yet to be clarified. O O O
Gd O
ligands with the same chirality
O
O O Gd
O
S-isomer
O
16 (2:3 complex) 3D structure unknown
but complex with different assembly state
R-isomer
20 (4:5 complex) elucidated by x-ray crystallography
(Eq. 3)
The Reissert reaction44 is an acyl cyanation of N -heteroaromatic compounds using a combination of an acylating reagent (such as acyl halide or halo carbonate) and a cyanating reagent (such as TMSCN or NaCN). This reaction is very important for the synthesis of biologically active compounds containing N -heterocycles.45,46 The reaction proceeds through an initial N -acylation followed by a dearomatizing cyanation (Eq. 4). Because the amide bond of the N -acylated heteroaromatic intermediates 21 (such as acylquinoliniums, acylisoquinoliniums, and acylpyridiniums) are conformationally flexible, it is essential to define the positions of both the electrophile and the nucleophile by the asymmetric
10
ORGANIC REACTIONS
catalyst to realize high enantioselectivity. All the reported catalytic enantioselective Reissert reactions47 – 50 to date have utilized Lewis acid–Lewis base bifunctional aluminum complexes similar to 6 as the catalysts. In a typical proposed transition-state model (22), the N -acylquinolinium intermediate is activated by the aluminum, and the TMSCN is activated by the phosphine oxide of the catalyst. Due to steric factors, the reaction via the s-trans N -acylquinolinium 22 should be more favorable than that via the s-cis isomer 23. Thus, the reactive conformer with regard to the amide bond is influenced by the asymmetric catalyst.
4
RCOCl TMSCN
6
+ N
N
Cl–
N O
*
2
R
O
CN
R
21
Ar Ar
P
O
Ar Ar
O O
O
Me3 Si CN
Me3 Si CN + N Cl– R
Al
+ N
O O
Cl–
R
O O
Cl P(O)Ar2
P
Al Cl
22
P(O)Ar2
23
(Eq. 4) The catalytic enantioselective Reissert reaction of pyridine derivatives presents additional difficulties. There are three similarly electrophilic carbon centers on the acyl pyridinium intermediate (C-2, 4, and 6 of 21). Therefore, an asymmetric catalyst needs to facilitate one specific pathway out of a possible six (three positions × two faces) to produce one specific regioisomer with high enantioselectivity. As will be discussed below, a finely tuned bifunctional asymmetric catalyst is able to elegantly solve this problem.50 SCOPE AND LIMITATIONS
Imine Synthesis There are mainly two types of imines that have been utilized in catalytic enantioselective Strecker reactions: (1) simple amine-derived imines such as N -allyl, N -benzyl, N -benzhydryl, and N -fluorenyl imines, and (2) activated imines containing electron-withdrawing groups on the nitrogen atom, such as N -phosphinoyl and sulfonyl imines. Simple amine-derived aldimines are the most readily prepared by mixing the aldehydes and amines in the presence of desiccant. Many of
THE CATALYTIC ASYMMETRIC STRECKER REACTION
11
these simple amine-derived imines are labile to purification using silica gel column chromatography or during distillation at high temperature; therefore, imines purified by recrystallization are preferred. The substrate purity is generally very important for catalytic enantioselective reactions, because trace amounts of impurities might have detrimental effects on the asymmetric catalyst. There is, however, an example of using in situ-generated aldimines as substrates for the catalytic enantioselective Strecker reaction (see the chiral Zr-catalyzed threecomponent reaction).51 On the other hand, N -phosphinoyl imines and N -sulfonyl imines require multistep syntheses from the corresponding aldehydes or ketones. Although N -phosphinoyl aldimines have not been utilized as substrates for the catalytic asymmetric Strecker reaction, N -phoshinoyl ketimines are excellent substrates.39 – 43 N -Phosphinoyl ketimines can be synthesized in two steps from the corresponding ketones (Eq. 5)52 via oxime formation followed by treatment with R2 PCl. The reaction of ketoximes with R2 PCl at low temperature produces unstable O-phosphinyl oximes 24 as the initial products, which undergo rearrangement to give N -phosphinoyl imines 25 at higher temperature through a radical-cage mechanism.53,54 Interestingly, E/Z geometrical isomerization of phosphinoyl ketimines is very fast even at low temperature based on NMR studies.39 This characteristic is important for the induction of high enantioselectivity from substrates having a wide variety of substituents, because imine geometrical isomers (with regard to the C=N bond geometry) produce enantiomeric products. The cyanation should proceed from the more reactive imine geometry, and so the thermodynamic stability of (E) and (Z) N -phosphinoyl imines (E/Z ratio of imines) is not related to the enantioselectivity. Although N -phosphinoyl imines are more electrophilic than simple aminederived imines, they are generally quite stable to silica gel purification. In addition, many of the aromatic ketone-derived phosphinoyl imines are crystalline.
O R1
NOH
H2NOH R2
R1
R2
N
Ph2PCl Et3N
R1
R2 24
OPPh2
OPPh2
N R1
N R2
R1
O PPh2 R2
25
(Eq. 5) N -Sulfonylimines are the most activated (electron-deficient) imines. N Sulfonylimines derived from aromatic aldehydes or aliphatic aldehydes bearing no enolizable α-protons are relatively easy to prepare. For example, condensation of an aldehyde with a sulfonamide in the presence of a Lewis acid (e.g. TiCl4 , BF3 •OEt2 , (EtO)4 Si)55,56 or a Brønsted acid (e.g. p-TsOH, amberlyst-H+ , HCO2 H)57 affords the target imines. Aliphatic N -sulfonyl aldimines have been prepared in situ without purification in two steps (Eq. 6):58 (1) condensation of an aldehyde, an arenesulfinic acid sodium salt, and a sulfonamide in the presence of formic acid and water to form the corresponding sulfonamide sulfone 26, then (2) treatment of the isolated sulfone with a mild base such as sodium bicarbonate.
12
ORGANIC REACTIONS
Due to their lability, the aliphatic N -sulfonylimines are used in further reactions without purification. O R
NHSO2Ar
HCO2H
+ p-TolSO2Na + ArSO2 NH2
H2O
H
SO2Tol-p
R 26
(Eq. 6)
NSO2Ar
NaHCO3 H2O/CH2Cl2
R
H
Catalytic Enantioselective Strecker Reaction of Aldimines The catalytic enantioselective Strecker reaction of aldimines can be categorized into two classes: (1) reactions promoted by chiral organocatalysts and (2) reactions promoted by chiral metal catalysts. Enantioselective Strecker Reaction of Aldimines Catalyzed by Chiral Organocatalysts. The first example of a catalytic enantioselective Strecker reaction was reported using organocatalyst 27,59 which was developed based on the structure of a previously reported asymmetric catalyst that promotes cyanosilylation of aldehydes.60 – 63 Catalyst 27, containing guanidine and (S)-phenylalanine moieties, can promote Strecker reactions of aromatic aldimines with high to excellent enantioselectivity (Eq. 7). Heteroaromatic and aliphatic imines afforded products with only low enantioselectivities (up to 32% ee). The products can be converted to optically active α-amino acids via a one-step acid hydrolysis. N R
CHPh2
27 (2 mol%), HCN (2 eq) MeOH, –75° to –25°
H
H N
O
NH2 NH
HN Ph
HN R
CHPh2 CN
(71-97%) <10 to >99% ee
(Eq. 7)
NH O 27
A more general asymmetric organocatalyst class for the Strecker reaction was developed using urea or thiourea as the activating moiety of imines, giving thiourea catalysts 28–30. Optimization of each structural module of the catalyst by a combinatorial approach led to the identification of catalysts that produce excellent enantioselectivity and catalyst activity with a wide range of aldimines containing aromatic and aliphatic substituents (Eq. 8).32,33 The enantioselectivity is not affected by the size of the nitrogen protecting group, and allylamine-derived and benzylamine-derived imines produced comparable enantioselectivity. This tendency can be explained based on model 11. Resin-bound asymmetric catalyst 30 is as effective as the soluble catalysts 28 and 29. Additional advantages of using
THE CATALYTIC ASYMMETRIC STRECKER REACTION
13
catalyst 30 are facile catalyst recovery and product isolation by simple filtration. The filtered catalyst was reusable for at least ten cycles without any loss of enantioselectivity or catalyst activity. The products were converted to enantiomerically pure α-amino acids through protection of the nitrogen atom with a formyl group, recrystallization, nitrile hydrolysis to a carboxylic acid, deformylation, and removal of the N -benzyl group. A typical conversion process is shown in Eq. 9. N R
R1
cat. 28-30 (1–4 mol%), HCN toluene, –78°, 15–20 h
H
R3 t-Bu Y N R2 N N H H O
HN
R1 (65-99%) 77-99% ee CN
R
R = aryl, alkyl R1 = benzyl, allyl
(Eq. 8) 28: R2 = PhCH2, R3 = H, Y = O 29: R2 = R3 = Me, Y = S 30: R2 = polystyrene–CH2, R3 = H, Y = S
N
HO t-Bu
OCOBu-t
O HN t-Bu
Ph CN
1. Ac2O, formic acid
H
2. recrystallization
N
Ph
t-Bu 1. H2SO4, (65% w/v) 45°, 20 h
>99% ee
CN
(Eq. 9)
NH2•HCl
2. HCl (conc), 70°, 12 h 3. H2, Pd/C, MeOH
t-Bu
CO2H
(84% overall from imine) >99% ee
Although substrate generality is not as broad as for the thiourea catalysts 28–30, chiral C-2-symmetric guanidine 12 is a simple yet highly enantioselective organocatalyst for the Strecker reaction of N -benzhydryl aldimines.37 The sterically bulky N -benzhydryl group is essential for high enantioselectivity. Aromatic aldimines produced high enantioselectivity, while aliphatic aldimines produced less satisfactory results (Eqs. 10a & 10b). The enantioselectivity reversed depending on the substrates, with aromatic imines affording products in the R-configuration and aliphatic imines affording S-configurational products. The absolute configuration of the products from aromatic ketimines can be explained using model 13. N
CHPh2 H
Ar
12 (10 mol%), HCN (2 eq) toluene, –40°, 20 h
N 12 N R
CHPh2 H
R = alkyl
Ar
CHPh2 (80-99%) 50-88% ee CN
(Eq. 10a)
N
Ph
HN
Ph N H
12 (10 mol%), HCN (2 eq) toluene, –40°, 22 h
HN R
CHPh2 CN
(~95%) 63-84% ee
(Eq. 10b)
14
ORGANIC REACTIONS
Chiral ammonium salt 31 is an effective catalyst for the asymmetric Strecker reaction of N -allyl aromatic aldimines (Eq. 11).64 The reaction was proposed to proceed through the attack of cyanide on the imine, which is activated by hydrogen bond formation to the ammonium proton of the catalyst. The reaction should occur in the U-shaped pocket constructed by the three aromatic groups of the catalyst. Bulky substrates containing N -benzyl or N -benzhydryl protecting groups produced less satisfactory enantioselectivities. In addition, aliphatic aldimines were poor substrates in this reaction. 1. 31 (10 mol%), HCN (2 eq), CH 2Cl2, –70°, 24-48 h
N Ar
HN
2. (CF3CO)2O
H
Ar
CN
(86-98%) 79 to >99% ee
OMe
(Eq. 11)
N N
H +N
H O
N N
H
O
N
CF3CO2– 31
BINOL-derived chiral phosphates are versatile Brønsted acid organocatalysts.65,66 A highly enantioselective catalytic Strecker reaction was reported using catalyst 32 (Eq. 12).67 Only aromatic imines produced high enantioselectivities. The activation of the substrate aldimine occurs in the chiral environment through protonation by the phosphate. N Ar
Bn H
32 (10 mol%), HCN (1.5 eq) toluene, –40°, 48–72 h
O O P O OH
HN Ar
Bn CN
(59-97%) 85-99% ee
(Eq. 12)
32
Chiral quaternary ammonium salt 33 is a useful asymmetric phase-transfer catalyst for the Strecker reaction of aliphatic N -sulfonyl aldimines (Eq. 13).68 Inexpensive and easy-to-handle KCN can be used as a cyanide source. Generally, enantioinduction from aliphatic aldimines is more difficult than from aromatic
THE CATALYTIC ASYMMETRIC STRECKER REACTION
15
aldimines. This phase-transfer-catalyzed reaction, however, is notable because aliphatic aldimines produced better results than aromatic aldimines. N R
SO2Mes
33 (1 mol%), 2 M aq. KCN (1.5 eq)
HN
toluene–H2O, 0°, 2-8 h
H
R = alkyl Mes = 2,4,6-Me3C6H2
SO2Mes CN
R
(81-98%) 88-97% ee
Ar
Ar Me + N
(Eq. 13) I–
Me Ar Ar 33: Ar = 4-CF3C6H4
Enantioselective Strecker Reaction of Aldimines Catalyzed by Chiral Metal Complexes. The (salen)aluminum(III) complex 34 is an excellent catalyst for the enantioselective Strecker reaction between aromatic aldimines and HCN (Eq. 14).69 Aliphatic imines afford products with moderate enantioselectivities (37–57% ee). The reaction is best performed at very low temperature (−70◦ ) to avoid competing background reactions. Catalyst 34 is easily prepared on a large scale and appears to have an indefinite shelf-life even when stored under ambient conditions.70 The products can be converted to enantiomerically pure α-amino esters through methanolysis of the cyanide followed by N deprotection (Eq. 15). 1. 34 (2–5 mol%), HCN (1.2 eq), toluene, –70°
N Ar
CF3
2. TFAA
H
O
Ar
N t-Bu
(91-99%) 79-95% ee
N CN
(Eq. 14)
N
Al O Cl O Bu-t
Bu-t
t-Bu 34
HN
MeOH/HCl, reflux, 8 h CN
78%
HN CO2Me
93% ee dimethylbarbituric acid, Pd(PPh3)4 (5 mol%) CH2Cl2, rt, 3 h
NH2•HCl CO2Me (60%), >99% ee recrystallized
(Eq. 15)
16
ORGANIC REACTIONS
Asymmetric bifunctional catalyst 6 was developed as a general catalyst for the Strecker reaction of aldimines, and high enantioselectivities have been observed using this catalyst with both aromatic and aliphatic substrates.26,27 Catalyst 6 acts in a bifunctional manner: aluminum activates the imine as a Lewis acid, and the phosphine oxide activates TMSCN as a Lewis base (8 in Eq. 2).71 The N -protecting group of the substrate has a large effect on the enantioselectivity, and N -fluorenylimines gave optimal results. Slow addition of a catalytic amount (20 mol%) of phenol into the reaction mixture containing a stoichiometric amount of TMSCN dramatically increased the reaction rate (condition A), and the reaction was completed in less than 68 hours. Alternatively, a more atom-economic combination of a catalytic amount of TMSCN and a stoichiometric amount of HCN can be used (condition B). Both conditions produced comparable enantioselectivity. The N -fluorenyl group of the product could be removed through oxidative treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or manganese dioxide to generate the corresponding fluorenone-derived imine, followed by acidic hydrolysis (Eq. 16). A recyclable, solid-supported asymmetric catalyst 35 was developed by connecting catalyst 6 to JandaJ EL72 (Eq. 17).73 Catalyst 35 produced slightly lower enantioselectivity than the soluble catalyst 6, and the catalyst activity decreased significantly after the fourth recycle. A: 6 (9 mol%), TMSCN (2 eq), PhOH (20 mol%), slow addition over 17 h or B: 6 (9 mol%), TMSCN (20 mol%), HCN (1.2 eq), slow addition over 24 h CH2Cl2, –40°, 24-68 h
N R
H 1. HCl, H2CO2H 2. DDQ, THF 3. 1 N HCl 4. Amberlyst A-21
NH2 R
CONH2
(91%) 4 steps, R = Ph
HN R
CN (66–98%) 70–96% ee
1. MnO2, CH2Cl2 2. HCl, THF 3. 12 N HCl
NH2•HCl R
CO2H
(79%) 3 steps, R = t-Bu
P(O)Ph2 O Al Cl O P(O)Ph2 6
(Eq. 16)
THE CATALYTIC ASYMMETRIC STRECKER REACTION
35 (10 mol%), TMSCN (4 eq), t-BuOH (1.1 eq) CH2Cl2, –50°, 41-66 h
N R
(96-100%) 83-87% ee
HN CN
R
H
(Eq. 17)
O
Ph2(O)P
3
3
17
JandaJEL
O Cl Al O Ph2(O)P 35
Corey’s oxazaborolidine14 catalyst was utilized in the catalytic enantioselective Strecker reaction of aldimines. Enantioselectivity was, however, only moderate (up to 71% ee, Eq. 18).74 N R
Ph H
oxazaborolidine catalyst (20 mol%), HCN (1.5 eq) toluene, –25° H Ph N
HN
Ph (82-95%) 39-71% ee
R
CN
Ph
O
B Me oxazaborolidine catalyst
(Eq. 18)
Other metals that are utilized in catalytic enantioselective Strecker reactions of aldimines are the Group 4 metals titanium and zirconium. The complex generated from Zr(OBu-t)4 , 6,6 -dibromo-1,1 -bi-2-naphthol (36) or 3,3 -dibromo-1,1 -bi2-naphthol (37), and N -methylimidazole (NMI) is a general asymmetric catalyst that produced high enantioselectivity in the reactions between aldimines and (n-Bu)3 SnCN (Eq. 19).51,75 The structure of the asymmetric catalyst was proposed as 38 based on NMR studies. The free phenolic group of the imine is essential for high enantioselectivity as well as high chemical yield. This reaction was extended to a three-component catalytic enantioselective Strecker reaction. Thus, the Strecker products were obtained with high enantioselectivity from a mixture of aldehydes, o-hydroxyaniline derivatives, and HCN in the presence of 1–5 mol% of the chiral Zr catalyst (Eq. 20).51,76 The products were converted to amino acid derivatives through methylation of the phenolic OH, conversion of the nitrile to the methyl ester, and oxidative removal of the N -protecting group.
18
ORGANIC REACTIONS
HO +
N
(n-Bu3Sn)CN (1.1 eq)
Zr(OBu-t)4 (10 mol%), (R)-6-Br-BINOL (36: 10 mol%), (R)-3-Br-BINOL (37: 10 mol%), NMI (30 mol%)
HN
toluene/benzene (1/1) –65° to 0°, 12 h
H
R
HO
CN R (72-98%) 74-92% ee
Br
Br
(Eq. 19)
Br
OBu-t O O Zr O L
L O
Zr
O
O OBu-t
Br
Br
Br
38 HO
HO RCHO +
38 (1–5 mol%)
+ HCN
H 2N
CH2Cl2, –45°, 12 h R1
R1 CN
R
1. MeI, K2CO3 2. HCl/MeOH
(76-100%) 84-94% ee
HN
(Eq. 20)
NH2•HCl (24-38%) 4 steps
3. Ce(NH4)2(NO3)6, TFAA 4. HCl/MeOH
CO2Me
R
Titanium catalysts derived from peptide 39 promoted the enantioselective Strecker reaction of N -benzhydryl aldimines and TMSCN (Eq. 21).28 – 30 The catalyst can be systematically tuned, and the optimal catalyst structure is different depending on the substrate. Slow addition of i-PrOH to the reaction mixture dramatically accelerated the reaction rate. The protic additive generated the actual nucleophile, HCN, in situ from TMSCN, and also facilitated the catalyst turnover step. The reaction was proposed to proceed through a dual activation mechanism as depicted in model 9. Ph Ph
N R
H
+ TMSCN
Ti(OPr-i)4 (10 mol%), peptide ligand 39 (10 mol%)
Ph HN
i-PrOH, slow addition for 20 h, toluene, –20° to 4° t-Bu Ar
N O
H N
R
O N H O OBu-t
OMe
Ph
(93-100%) 76-97% ee
CN
(Eq. 21)
39 Ar (e.g.) = 2-HO-5-MeOC6H3, 2-HO-3,5-Br2C6H2 , 2-HO-3,5-Cl2C6H2, 2-HO-1-naphthyl
A chiral titanium complex generated from an easily accessible N -salicylβ-aminoalcohol 40 can also promote a highly enantioselective Strecker reaction of aromatic aldimines (Eq. 22).77
THE CATALYTIC ASYMMETRIC STRECKER REACTION
Ti(OPr-i)4 (10 mol%), ligand 40 (10 mol%)
Ph Ph + TMSCN
N Ar
19
Ph HN
i-PrOH (1 eq), toluene, 0°
H
Ar
Ph
(80-85%) 83 to >98% ee
CN
Ph N H OH 40
OH
(Eq. 22)
Catalytic Enantioselective Strecker Reaction of Ketimines α,α-Disubstituted amino acids are important chiral building blocks for biologically active compounds, such as enzyme inhibitors and conformationally restricted peptide mimetics.78 The catalytic enantioselective Strecker reaction of ketimines is a very useful reaction for the synthesis of enantiomerically enriched α,α-disubstituted amino acids. Normally, ketimines are much less reactive than aldimines. In addition, differentiation of the two substituents (aryl vs. aryl, aryl vs. alkyl, or alkyl vs. alkyl groups) on the prochiral carbon of ketimines is much more difficult compared to those on aldimines (aryl or alkyl vs. hydrogen). Therefore, asymmetric catalysts that can promote the Strecker reaction of ketimines need to be more active and enantioselective than those promoting reactions of aldimines. Chiral urea 28 and its solid-supported derivative are efficient catalysts for enantioselective Strecker reactions of aryl methyl ketimines (Eq. 23).38 Aliphatic ketimines and ethyl-substituted ketimines react with moderate (41–69% ee) enantioselectivity. N Ar
Ph
+ HCN
Me H Bn
28 (2 mol%)
NC
toluene, –75°, 24-90 h
Ar
t-Bu
N O
N H
NHBn
(45-100%) 42-95% ee
O N H
(Eq. 23) N
HO t-Bu
OCOBu-t
28
Chiral titanium catalyst 41 derived from BINOL79 and heterobimetallic catalyst 4280 have been shown to promote the asymmetric Strecker reaction of an acetophenone-derived ketimine (Eq. 24). However, this was the only substrate studied in these reactions.
20
ORGANIC REACTIONS Ph
N Ph
+ TMSCN
catalyst 41 or 42 (10 mol%)
NC
toluene, –20°
Ph
Me
NHBn
41, 1 h: (80%) 56% ee 42, 9 h: (>95%) 88% ee i-PrO O Ti O i-PrO
(Eq. 24)
Li
Me2 N
O
N Me2
O
O Sc
41
O 42
A synthetically useful catalyst for the enantioselective Strecker reaction of ketimines is a gadolinium complex derived from ligand 14 (Scheme 1).39 – 41 This catalyst was prepared from Gd(OPr-i)3 and 14 in a 1 : 2 ratio. Excellent enantioselectivities were obtained from a wide range of N -diphenylphosphinoyl ketimines (aromatic, heteroaromatic, and aliphatic) in the presence of minimal catalyst loadings (0.1–2.5 mol%). The reaction can be performed either in the presence of a stoichiometric amount of TMSCN and 2,6-dimethylphenol40 or the combination of a catalytic amount of TMSCN and a stoichiometric amount of HCN (Eq. 25).41 Using the latter combination, excellent catalyst turnover (up to 1000) was observed. The N -diphenylphosphinoyl group was easily removed under acidic conditions.
N R1
O PPh2 R2
Gd(OPr-i)3 (1-2.5 mol%)–14 (2-5 mol%), TMSCN (1.5 eq), 2,6-dimethylphenol (1 eq), EtCN, –40°, 2.5–67 h or Gd(OPr-i )3 (0.1-1 mol%)–14 (0.2-2 mol%), TMSCN (2.5-5 mol%), HCN (1.5 eq), EtCN, –40°, 3-54 h
O NC HN PPh2 R1
R2
(73-99%) 80-99% ee
(Eq. 25) O
P Ph2 HO
O
O
F
HO
F
14
Catalytic Enantioselective Reissert Reaction The catalytic enantioselective Reissert reaction is very useful for the synthesis of biologically active compounds containing N -heterocycles. The reaction requires the use of strong electrophiles such as acyl chlorides. In addition, TMSCl is generated during the course of the reaction when TMSCN is used as a cyanide source. Therefore, an asymmetric catalyst should be tolerant toward these strong electrophiles. The catalytic enantioselective Reissert reaction of quinolines was developed using BINOL-derived Lewis acid–Lewis base bifunctional catalyst 43 (Eq. 26).47,48 The use of 2-furoyl chloride and methylene chloride/toluene mixed
THE CATALYTIC ASYMMETRIC STRECKER REACTION
21
solvent gave the best results with the fewest side-products. In addition, ligand 43 containing di(o-tolyl)phosphine oxide as a Lewis base to activate TMSCN produced slightly improved enantioselectivity compared to the original bifunctional catalyst 6 containing diphenylphosphine oxide. Generally, quinolines containing electron-donating substituents resulted in higher yields and enantioselectivities as compared to those containing electron-withdrawing substituents. This tendency is consistent with the following results obtained from mechanistic studies: (1) the rate-determining step of the Reissert reaction is the catalyst-independent acyl quinolinium formation, and (2) the catalyst-independent background cyanation of an acyl quinolinium intermediate is faster for electron-deficient substrates. The reaction was conducted using the JandaJ EL-supported catalyst 44; the enantioselectivity, however, was slightly lower than with the soluble catalyst 43. The solid-supported catalyst 44 was recyclable and the aluminum was retained, although the enantioselectivity decreased with each run (from 86% ee in the first run using 44 to 64% ee in the fourth run). Z Z
W
Y X
43 (1-9 mol%), 2-furoyl chloride (2-4 eq), TMSCN (2-4 eq)
Y
CH2Cl2–toluene, –40°, 40-112 h
X
N R
W
N O O (57-99%) 67-96% ee
P(O)(tol-o)2 O Al Cl O
CN
(Eq. 26)
P(O)(tol-o)2 43: R = H 44: R = (CH2)3CH=CH(CH2)3OCH2–JandaJEL
Taking advantage of the multifunctionality of the quinolinium products, several subsequent useful transformations were possible. An enantiomerically enriched tetrahydroquinoline-2-carboxylate derivative 46 was synthesized from the Reissert product 45 via rhodium-catalyzed hydrogenation followed by hydrolysis and methyl esterification, without any loss of enantiopurity (Eq. 27). In addition, epoxidation of cyanoquinoline derivative 47 proceeded selectively from the side opposite to the nitrile (Eq. 28). After conversion of the nitrile to an amide, regioselective epoxide ring-opening with water using ceric ammonium nitrate (CAN) followed by cleavage of the N -furoyl amide produced functionalized tetrahydroquinoline 48 containing three contiguous stereocenters. 1. LiO2H, H2O–MeOH
H2, Rh/C N Ph
CN O
45
AcOEt 71%
N Ph
CN O
2. 6 N HCl 3. CH2N2
N CO2Me H 46 (58%) 3 steps
(Eq. 27)
22
ORGANIC REACTIONS O m-CPBA
CN
N
N
CH2Cl2, 15 h (71%)
O O
O CN
O
aq. H2O2, Na2CO3, (n-Bu)4HSO4
N
CH2Cl2, 1.5 h (62%)
O
O
47
O
OH
OH
OH
OH
sat. NH3
CAN (10 mol%) N
aq. MeCN, 1 h (66%)
CONH2
CONH2 O
i-PrOH, 40°, 6 h (73%)
N H 48
O
CONH2
(Eq. 28) The catalytic enantioselective Reissert reaction was applied to the synthesis of quaternary stereocenters by tuning the bifunctional catalyst (Eq. 29).49 To overcome the attenuated reactivity of substrate 49, catalyst 50 containing an enhanced Lewis acidity was developed. The Lewis acidity of aluminum in complex 50 should be higher than in the previous catalysts 6 or 43 due to the electronwithdrawing bromine substituents on the BINOL core and the electronegativity of the triflate anion. Excellent enantioselectivity was obtained from a number of highly substituted isoquinolines. The reaction was utilized as a key step in the catalytic asymmetric synthesis of several biologically active compounds (see “Applications to Synthesis”). R1 N
R1 R
50 (1-2.5 mol%), CH2=CHOCOCl (1.8 eq), TMSCN (2 eq) CH2Cl2, –40° to –60°, 48 h
49 Br
P(O)Ph2
R1 N
R1 R
O
CN O
(62-98%) 73-95% ee
(Eq. 29)
O Al OTf O P(O)Ph2
Br 50
Chiral piperidines are among the most important building blocks for biologically active compounds. The catalytic enantioselective Reissert reaction of pyridine derivatives can produce such chiral building blocks. An asymmetric catalyst prepared from Et2 AlCl and chiral ligand 51 in a 1 : 2 ratio promotes the enantioselective Reissert reaction of nicotinamide derivatives 54 with excellent regio- and enantioselectivity (Eq. 30).50 The electron-withdrawing amide functional group at the 3-position of the substrates is essential for high conversion and enantioselectivity, and the configuration of the sulfoxides at the 3,3 -positions of
THE CATALYTIC ASYMMETRIC STRECKER REACTION
23
the ligand is also critical for the observed high selectivity. The aluminum complexes derived from the C-2-symmetric ligands 52 and 53 are poor catalysts in terms of catalyst activity, enantioselectivity, and regioselectivity. On the basis of structural studies of the active catalyst using mass spectroscopy, a 2 : 3 complex of aluminum and ligand 51 is proposed to be the active enantioselective catalyst. Proper configurational matching between the axial chirality of the BINOL core and central chiralities of the two sulfoxides is essential for the stabilization of the active bimetallic catalytic species, and thus for the high regio- and enantioselectivity. Ligands 52 and 53 did not generate the corresponding 2 : 3 complexes. A different type of enantioselective bifunctional catalyst, generated from Et2 AlCl and phosphine sulfide-containing ligand 55 in a 1 : 1 ratio, was the optimal catalyst for slightly different substrates 56 containing a halogen substituent at the 4-position of the pyridine core (Eq. 31).50 O
Et2AlCl (5 mol%), 51 (10 mol%), FmocCl (1.4 eq), TMSCN (2 eq)
O NR2
CH2Cl2, –60°, 5 h
NC
N 54 R = Me or i-Pr
NR2
+ Z S Y OH OH + Z' S Y'
N Fmoc
(89-98%) 93-96% ee
51: Z, Y' = Ph; Z', Y = O– 52: Z, Z' = O–; Y, Y' = Ph 53: Z, Z' = Ph; Y, Y' =O –
(Eq. 30) X
O N(Pr-i)2
N 56 X = Cl or Br
Et2AlCl (10 mol%), 55 (10 mol%), neopentyl–OCOCl (1.4 eq), TMSCN (2 eq)
X
O N(Pr-i)2
N
NC
CH2Cl2, –60°, 27-36 h
t-Bu P(S)Ar2 OH OH
O
O
(89-92%) 86-91% ee
P(S)Ar2 55: Ar = 2-EtC6H4
(Eq. 31)
APPLICATIONS TO SYNTHESIS
The importance of catalytic enantioselective Strecker and Reissert reactions is demonstrated by their effective use in the synthesis of biologically active compounds. The catalytic enantioselective three-component Strecker reaction of aldehyde 57, aniline derivative 58, and HCN using 2.5 mol% of chiral zirconium catalyst
24
ORGANIC REACTIONS
38 produced the corresponding product 59 in 80% yield with 91% ee. This product was converted to D-pipecolic acid methyl ester (60) in three steps (Eq. 32).51 HO CHO
TBSO
HCN, 38 (2.5 mol%)
+
CH2Cl2, –45°
H2N
57
58
(Eq. 32)
HO NH HN TBSO
CO2Me 60
CN 59 (80%) 91% ee
Sorbinil (63) is a highly potent aldose reductase inhibitor, considered to be a pharmaceutical lead for the treatment of diabetic neuropathy.81 Sorbinil contains a spirohydantoin structure with a quaternary stereocenter. A concise catalytic enantioselective synthesis of sorbinil was achieved using the catalytic enantioselective Strecker reaction of ketimine 61 as the initial key step (Eq. 33).40 Product 62 was obtained in quantitative yield with 98% ee using 1 mol% of the gadolinium complex derived from ligand 14. Enantiomerically pure 62 was obtained through one recrystallization. Synthesis of 63 was completed in three steps from intermediate 62.
N F
O PPh2
Gd(OPr-i)3 (1 mol%), 14 (2 mol%), TMSCN (1.1 eq), 2,6-dimethylphenol (1 eq) F
EtCN, –40°, 83 h
O
O 61
O H N PPh2
NC
62 (100%) 98% ee (93%) >99% ee, recryst. from CHCl3-hexane HN F
O NH
O O 63
(Eq. 33)
Lactacystin (66) is a potent and selective proteasome inhibitor isolated from Streptomyces by Omura and coworkers.82 It contains a quaternary stereocenter in a highly substituted γ -lactam ring. Due to its challenging structure, many synthetic chemists have studied and achieved the total synthesis of lactacystin.83 – 85 The catalytic enantioselective Strecker reaction using a gadolinium catalyst was applied to construct the quaternary stereocenter (C-5) of lactacystin starting from N -phosphinoyl imine 64 (Eq. 34).86 The catalyst prepared from Gd[N(TMS)2 ]3 and ligand 14 in a 1 : 1.5 ratio gave the best results. The reaction was completed
THE CATALYTIC ASYMMETRIC STRECKER REACTION
25
in two days using 2.5 mol% of catalyst, and produced chiral product 65 in quantitative yield and 98% ee. The chiral catalyst prepared from Gd(O-Pr-i)3 and 14 in a 1 : 2 ratio as used in Eq. 33 produced less satisfactory results. Three of the other stereogenic centers (C-6, 7, and 9) of lactacystin, except for the one derived from cysteine, were controlled by the configuration of the quaternary stereocenter at C-5 with excellent stereoselectivity.
N
O PPh2
Gd[N(TMS)2]3 (2.5 mol%), 14 (3.75 mol%), TMSCN (2 eq), 2,6-dimethylphenol (1 eq) i-Pr
EtCN, –40°, 48 h
i-Pr
O H N PPh2
NC
64
65 (>99%) 98% ee HO2C
NHAc
(Eq. 34)
O NH
7 6
5
S O
9
Pr-i
HO HO 66
L-689,560 (70) is a potent NMDA (N -methyl-D-aspartate) receptor antagonist identified by the Merck group.87 The synthesis involved the catalytic enantioselective Reissert reaction of quinoline 67 using 1 mol% of aluminum catalyst 43 (Eq. 35).48 When the Reissert reaction was complete, intermediate enamine 68 was reduced in situ by subsequent addition of NaBH3 CN, AcOH, and MeOH. This one-pot catalytic enantioselective Reissert reaction–reduction protocol selectively (>20 : 1) produced 69, with the cyanide trans to the amine, in 91% yield and 93% ee. Subsequent functional group transformations and enantioenrichment by recrystallization furnished 70 in enantiomerically pure form. Solid-supported catalyst 44 was also utilized in the Reissert reaction of 67; the enantioselectivity was 86% ee using 3 mol% of 44. Cl Cl
N(allyl)2
CH2Cl2, –40°, 40 h Cl
N(allyl)2
43 (1 mol%), TMSCN (2 eq), 2-furoyl chloride (2 eq) Cl
N
N
CN O
67
O 68 Cl
N(allyl)2
NaBH3CN AcOH–MeOH
Cl
N O O 69 (91%) 93% ee
(Eq. 35)
O Cl HN
NHPh
N H
CO2H
CN Cl
70
26
ORGANIC REACTIONS
MK801 (dizocilpine, 73), which contains a quaternary stereocenter,88 is another highly potent NMDA receptor antagonist. The synthesis of this agent involved the catalytic enantioselective Reissert reaction of isoquinoline 71 using 2.5 mol% of the enantiomer of catalyst 50 (ent-50) to form 72 in 62% yield and 95% ee.49 Subjecting 72 to radical cyclization conditions using (n-Bu)3 SnH and AIBN produced the tetracyclic core. Synthesis of MK801 was completed through a series of functional group transformations (Eq. 36). ent-50 (2.5 mol%), TMSCN (2 eq), CH2=CHOCOCl (1.8 eq)
N Br
N
O
CN O
CH2Cl2, –40°, 48 h
Br 71
72 (62%) 95% ee
(Eq. 36)
O O (n-Bu)3SnH
HN
N
AIBN 73
NC (85%)
Anticonvulsant phenytoin analogues 78 and 7989 were synthesized using the catalytic enantioselective Reissert reaction of compounds 74 and 75, respectively (Eq. 37).49 Thus, the Reissert reaction of these two substrates in the presence of catalyst ent-50 produced the corresponding products 76 and 77 with high enantioselectivity. These compounds were converted to the target molecules 78 and 79 through hydrogenation and hydrolysis of the nitrile.
N R 74: R = Me 75: R = Ph
ent-50 (2.5 mol%), TMSCN (2 eq), CH2=CHOCOCl (1.8 eq)
N
CH2Cl2, 48 h
R
Temp –60° –40°
O
CN O
76: (88%) 89% ee 77: (95%) 95% ee
N R
(Eq. 37)
O
NH
O 78: R = Me 79: R = Ph
The catalytic enantioselective Reissert reaction of isoquinoline 80 was utilized as a key step for the synthesis of biosynthetic intermediate 8190 of a dopaminederived alkaloid salsolinol (Eq. 38).49 The Reissert reaction of 80 proceeded with excellent yield and enantioselectivity using ent-50 as the catalyst.
THE CATALYTIC ASYMMETRIC STRECKER REACTION
PhCO2
ent-50 (2.5 mol%), TMSCN (2 eq), CH2=CHOCOCl (1.8 eq)
PhCO2
CH2Cl2, –60°, 48 h
PhCO2
N
PhCO2
27
O
N CN O (94%) 94% ee
80 HO + NH Cl– 2
HO
CO2H 81
(Eq. 38)
An asymmetric formal synthesis of a dopamine D4 − receptor-selective antagonist CP-293,019 (85)91 was achieved using the catalytic enantioselective Reissert reaction of pyridine derivative 82 as a key step (Eq. 39).50 The Reissert reaction of 82 using a catalyst derived from Et2 AlCl and a chiral sulfoxide-containing ligand 51 in a 1 : 2 ratio produced the corresponding product 83 in 98% yield with 91% ee. The known key intermediate 84 was synthesized from 83 in several steps.
NMe 2 N
O
Et2AlCl (5 mol%), 51 (10 mol%), MeOCOCl (1.4 eq), TMSCN (2 eq)
O
NMe 2
CH2Cl2, –60°, 5 h
NC
N Fmoc 83 (98%) 91% ee
82
F OH
O
N
N
BocN
N
N 84 F
N
85
(Eq. 39)
COMPARISON WITH OTHER METHODS
Due to the importance of α-amino acids in a variety of fields, a number of excellent stereoselective methods have been developed for their synthesis.1 – 6 As shown in Scheme 2, there are mainly four types of retrosynthetic bond disconnection. Any non-stereoselective reactions for the synthesis of α-amino acids can theoretically be extended to asymmetric synthesis using the chiral auxiliary method. Asymmetric synthesis of α-amino nitriles through the chiral auxiliary method is the main focus of this section. However, given the importance of and current emphasis on developing catalytic enantioselective reactions, three other types of catalytic enantioselective methods for chiral α-amino acid synthesis are also discussed in some detail.
28
ORGANIC REACTIONS
alkylation Mannich-type reaction etc.
R1 H2N
hydrogenation (R2 = H)
R2 CO2H
amination
Strecker reaction
Scheme 2
Chiral Auxiliary-Controlled Asymmetric Strecker Reaction It is possible to control the stereochemistry of the Strecker reaction by introducing a chiral auxiliary to the amine moiety of substrates. There are two main features of this methodology: (1) the diastereoinduction is reliable and predictable, and (2) the enantiomeric purity of the target compounds can be easily enriched through separation of the intermediate diastereomers even if the initial stereoselectivity is not completely satisfactory. Disadvantages of the chiral auxiliary method are that a stoichiometric amount of a chiral source is always required, and that chiral auxiliaries normally decompose during the deprotection of the nitrogen atom to obtain final target amino acids. Therefore, the use of inexpensive chiral auxiliaries is essential. Imines derived from 1-phenylethylamine (or its analogues)81,92 – 105 and chiral N -sulfinyl imines106 – 111 are two representative chiral substrates used in the asymmetric Strecker reaction. The diastereoselectivity of 1-phenylethylamine-derived imines is normally moderate (ca. 1.5 : 1 to 4 : 1),93,94,95,100 with some exceptions. When high diastereoselectivity was obtained (Eq. 40), reversible cyanide addition occurred concomitantly with fractional crystallization.81 The desired diastereomer 87 was obtained from 86 as a single isomer in 82% yield. The product is a key synthetic intermediate of an aldose reductase inhibitor. N
Ph HCN, EtOH, 0°
F
F
Ph
O 86
H N
NC
(82%) single isomer
O 87
(Eq. 40)
Chiral N -sulfinyl ketimines afford high diastereoselectivity in the Strecker reaction (Eq. 41).108 The chiral auxiliary is removed under acidic conditions, and α,α-disubstituted amino acid derivatives are obtained with high enantiomeric purity.
THE CATALYTIC ASYMMETRIC STRECKER REACTION
p-Tol
O S
Et2AlCN (1.5 eq), i-PrOH (1 eq)
N
p-Tol
THF, –78°
O S
NH
t-Bu
Bu-t
29
(95%) 99:1
CN
(Eq. 41) To highlight the utility of the chiral auxiliary-controlled method, two recent examples of the asymmetric Strecker reaction of trifluoromethyl ketone-derived imines are described. A diastereoselective Strecker reaction of chiral oxazolidine 88 containing a phenylglycinol auxiliary proceeded with moderate to low selectivity in the presence of 1.5 eq of BF3 •OEt2 (Eq. 42).112 The resulting diastereomers 89 and 90 were separable by silica gel column chromatography. The diastereomerically pure 89 was converted to trifluoromethylalanine hydrochloride (91) through acid hydrolysis in 60% yield.
HN CF3
Ph
TMSCN (1.5 eq), BF3•OEt2 (1.5 eq)
Ph
CH2Cl2
O
HN CF3
88
OH
HN +
CN 89
89
Ph OH
CF3
(91%) 89:90 = 54:46
CN 90
NH2•HCl
conc. HCl, reflux, 14 h CF3
CO2H
91 (60%)
(Eq. 42)
Highly diastereoselective Strecker reactions of trifluoromethyl-substituted N -sulfinyl imine 92 have been reported (Eq. 43).113 Imine 92 can be synthesized through condensation between trifluoromethylketones and the corresponding enantiomerically pure sulfonamide in the presence of an excess amount (1.5 eq) of Ti(OPr-i)4 .114,115 Trifluoromethyl-substituted sulfinyl amides 92 are not very stable, and should be generated and purified quickly prior to use. The diastereoselectivity of this Strecker reaction was strongly dependent on the solvent. When non-coordinating hexane was used as a solvent, isomer 93 was obtained as the major diastereomer. However, the other isomer 94 was the major product when highly coordinating DMF was used as a solvent. The authors attributed this dramatic solvent effect to the switch of the transition state from cyclic (in hexane) to acyclic (in DMF). In hexane, the oxygen atom of the sulfinyl amide acts as a Lewis base to activate TMSCN. On the other hand, the oxygen atom of DMF activates TMSCN, thus liberating the oxygen atom of the sulfinyl amide from coordination to silicon. Isolated diastereomer 94 was converted to amino acid 95 via acid hydrolysis. Currently, there is no
30
ORGANIC REACTIONS
catalytic enantioselective Strecker reaction that is effective with trifluoromethylsubstituted aldimines and ketimines. Therefore, the diastereoselective methods are the only asymmetric approaches to access chiral trifluoromethyl-substituted amino acids. O S
N CF3
TMSCN
Bu-t
HN
(69-92%)
R 92
O S
R
HN
Bu-t +
CN CF3
CF3
93
Solvent Temp hexane rt DMF –35°
R
O S
Bu-t
CN 94
(Eq. 43)
93:94 = 7:1 to 99:1 93:94 = 1:6 to 1:19 NH2
conc. HCl 94
CF3
CO2H R 95 R = Ph
(80%)
Catalytic Asymmetric Hydrocyanation of Hydrazones Hydrazones can be considered to be stable surrogates for imines. Despite the existence of several examples of racemic cyanation of hydrazones,116,117 including a Lewis acid catalyzed reaction,118 there is only one catalytic enantioselective variant reported (Eq. 44).119 An ErCl3 –PhPyBox (96) complex was used as an asymmetric catalyst (5 mol%). Hydrazones derived from aromatic aldehydes afforded high enantioselectivity (76–97% ee). Aliphatic substrates and ketone-derived hydrazones, however, produced only moderate enantioselectivity. O N R1
O
Ph NH
96 (5 mol%), TMSCN (2 eq) MeOH (2 eq), CHCl3, 0°
R2
HN Ph NC NH R1
O
96
(Eq. 44)
O
N N ErCl3
Ph
R2
(85-100%) 31-97% ee
N Ph
Catalytic Asymmetric Hydrogenation Asymmetric hydrogenation of dehydroamino acids 97 by chiral rhodium or ruthenium catalysts is one of the most general and reliable methods for the synthesis of α-amino acid derivatives (Eq. 45). Because this reaction is fundamental
THE CATALYTIC ASYMMETRIC STRECKER REACTION
31
and has been extensively reviewed,120 – 128 it will not be discussed here in detail. Excellent catalyst turnover rates, catalyst turnover numbers, and enantioselectivities are generally obtained. This method is used practically for large-scale syntheses of chiral α-amino acids. α,α-Disubstituted amino acids, however, cannot be synthesized using this method. CO2R1
R
NHCOR2 97
chiral catalyst + H2
R
1 * CO2R
NHCOR2
(Eq. 45)
A potentially important but much less studied catalytic asymmetric hydrogenation route to chiral α-amino acids is the reductive amination of α-keto acids 98. A catalytic enantioselective hydrogenative amination of 98 in the presence of N -benzylamine and 1 mol% of a chiral rhodium complex derived from 99 proceeded with moderate to excellent enantioselectivity (Eq. 46).129 The reaction conditions were tolerant of the carboxylic acid functional group.
O R
CO2H 98
+ BnNH2
[Rh(COD)2]BF4 (1 mol%), 99 (1.1 mol%), H2 (60 bar) MeOH, rt, 3-24 h
NHBn R
CO2H
(19-99%) 19-98% ee
PPh2 BnN PPh2 99
(Eq. 46)
Catalytic Asymmetric Introduction of the Side Chain through C–C Bond Formation Asymmetric Phase-Transfer-Catalyzed Reactions. The asymmetric alkylation of glycine-derived Schiff base ester 100 using chiral phase-transfer catalysis is an alternative approach to chiral α-amino acids.5,130,131 Phase-transfer catalysis generally offers the following advantages: (1) mild reaction conditions, (2) simple reaction procedures, and (3) the use of safe and inexpensive reagents and solvents. Thus, the reaction can be easily conducted both on small and large scales. Chiral phenylglycine derivatives, however, cannot be synthesized using the phase-transfer methodology. Since the first report of catalytic enantioselective alkylation of 100 using cinchona alkaloid-derived phase-transfer catalyst 101,132 the efficiency has been significantly improved by modifying the catalyst structure (Eq. 47). Specifically, N -9-anthracenylmethyl catalyst 102133,134 and a catalyst containing two cinchona alkaloid moieties (103)135 are highly effective asymmetric catalysts.
32
ORGANIC REACTIONS Ph N Ph
Ph
catalyst CO2Bu-t
N
R-X, base
Ph
100 R = Bn Catalyst mol% Solvent Temp 101 rt CH2Cl2 10 102 –78° 10 CH2Cl2 103 1 toluene-CH2Cl2 0° 104 0° 0.2 toluene
H
+ N Br– R1 OR2
Time 9h 23 h 10 h 12 h
CO2Bu-t R
Yield (75%) (87%) (95%) (81%)
% ee 64 94 97 98
101: R1 = benzyl, R2 = H 102: R1 = 9-anthracenylmethyl, R2 = allyl 103: R1 =
(Eq. 47)
, R2 = allyl
N Ar Br – N+
Ar 104: Ar = 3,5-Ph2C6H3 105: Ar = 3,4,5-F3C6H2
The most useful asymmetric phase-transfer catalysts in terms of enantioselectivity, substrate generality, and catalyst activity are the binaphthyl-derived quaternary ammonium salts 104 and 105.136,137 It is noteworthy that the method can be applied to a catalytic asymmetric synthesis of α,α-dialkyl-substituted amino acids using sterically less crowded prenucleophile 106 (Eq. 48). The absolute configuration of the quaternary stereocenter can be controlled by the order of addition of the alkylating reagents. Br (1 eq), CsOH•H O (5 eq), 2 toluene, –10°, 3.5 h 2. PhCH2Br (1.2 eq), 0°, 30 min 1.
Ar
N
CO2Bu-t
106 + 105 (1 mol%) Ar = 4-ClC6H4
H2N
CO2Bu-t Ph
3. 10% citric acid (80%) 98% ee
(Eq. 48) Asymmetric Allylic Substitution Catalyzed by Chiral Transition Metal Complexes. The catalytic asymmetric allylic substitution by azlactone 107
THE CATALYTIC ASYMMETRIC STRECKER REACTION
33
produces enantiomerically enriched precursors of α,α-disubstituted amino acids. Two kinds of constitutional isomers can be formed selectively, depending on the asymmetric catalyst used (Eqs. 49 and 50). Using the palladium catalyst containing chiral diphosphine ligand 108, substitution occurs at the C-1 position having the acetoxy leaving group.138,139 Using a molybdenum catalyst derived from ligand 109, the substitution occurs at C-3.140 High enantio- and diastereo selectivities are obtained in both reactions. The product azlactone was solvolyzed in basic methanol to give the amino acid derivative 110 in quantitative yield.
Ph
1
2
OAc
[Pd(η3-C3H5)Cl]2 (2.5 mol%), 108 (7.5 mol%), NaH (2 eq)
O
OAc
3
+ R
O
DME, 0° to rt, 2-24 h
N
OAc O O
Ph R N
Ph 107 (2.25 eq) R = alkyl
Ph (60-91%) 83-99% ee dr = 4.4:1 to >19:1 O
O NH
HN
PPh2 Ph2P 108
OCO2Me + 1
3
Ar
2
C7H8Mo(CO)3 (10 mol%), 109 (15 mol%), NaH (2 eq)
O R
(Eq. 49)
O
Ar
O
THF, 65˚, 3-6 h
N
O
R N
Ph 107 (2.25 eq) R = alkyl
Ph (76-92%) 85-99% ee dr = 97:3 to >98:2 Ar
K2CO3, MeOH
R
O
O
OMe NH2 110
(100%)
O NH HN
N
N 109
(Eq. 50)
An asymmetric allylic substitution by zinc enolates (such as 111) derived from N-protected glycine esters catalyzed by a chiral palladium complex and ligand 112 has been reported (Eq. 51). The substrate generality of this reaction is not very broad.141
34
ORGANIC REACTIONS OCO2Me
+
Ph
Ph
CF3OCN Zn O
[Pd(η3-C3H5)Cl]2 (1.2 mol%) OBu-t
112 (3 mol%), THF
CF3CONH
CO2Bu-t
Ph Ph (62%) 94% ee dr = 95:5
111 O N
PPh2
112
(Eq. 51)
Catalytic Asymmetric Addition to Imino Esters. Imino esters (113, 118, or 121) are reactive electrophiles, and they have been used in various catalytic asymmetric carbon–carbon bond-forming reactions (e.g. the Mannich-type reactions) using diverse nucleophiles. Enol silyl ethers react with 113 in the presence of the chiral cationic palladium catalyst 116 with high enantioselectivity (Eq. 52).142 The binuclear µ-hydroxo complex 116 was prepared from ˚ the mononuclear dicationic palladium complex 114 through treatment with 4 A molecular sieves in acetone. The dicationic complex 114 did not induce any enantioselectivity in the Mannich-type reaction shown in Eq. 52. This reaction was recently extended to the direct addition of β-ketoesters to imino esters using dicationic 115 as an asymmetric catalyst (Eq. 53).143 Interestingly, binuclear complex 117 was an unsatisfactory catalyst for this reaction. A three-component reaction involving a glyoxalate, an amine, and a β-ketoester was also reported in which the enantioselectivity was high, but the diastereoselectivity was moderate. Similarly, addition of nitroalkanes was developed with high diastereo- and enantioselectivity from imino ester 113 using cationic copper (II)–chiral bisoxazoline complexes.144,145
N i-PrO2C
Ar + H
113 Ar = 4-MeOC6H4
2
OTMS
116 (3-5 mol%), DMF
R
28°, 17-24 h
2 eq
Ar Ar OH2 4 Å MS P Pd ++ 2 BF4– acetone P Ar OH2 –2 H2O, –2 BF4– Ar 114: Ar = p-TolC6H4 115: Ar = Ph
Ar
NH O
i-PrO2C R (62-95%) 53-90% ee 2 BF4– Ar Ar Ar H Ar P P O Pd+ Pd+ O P P Ar H Ar Ar Ar 116: Ar = p-TolC6H4 117: Ar = Ph
(Eq. 52)
THE CATALYTIC ASYMMETRIC STRECKER REACTION
N EtO2C
Ar
CO2Bu-t
+ Ac
H
Ar
115 (5 mol%) THF, rt, 35 h
NH CO2Bu-t
EtO2C
Ar = 4-MeOC6H4
35
Ac
(70%) 86% ee/55% ee dr = 74:26
(Eq. 53)
N -Acyl imino esters 118 can be synthesized through elimination of HBr from the corresponding 2-bromoglycine derivative using a polymer-supported amine. The chiral copper(II) triflate–diamine complex 119 catalyzed the asymmetric addition of enol silyl ethers (Eq. 54),146,147 alkyl vinyl ethers,145 and acyl enamides148 to 118. Reactions using propionate-derived enol silyl ethers also proceeded with high enantio- and diastereoselectivity. Syn-isomer 120 was produced from both E- and Z-enolates. The catalytic asymmetric Mannich-type reactions149 and allylation reactions150 proceeded in aqueous media (H2 O/THF = 1 : 9) using more stable N -acylhydrazono esters as substrates. A combination of zinc fluoride (50 mol%), chiral diamine (related to 119), and triflic acid (1 mol%) was used as the catalyst. The hydrazine moiety of the products was converted to the amine by reduction with samarium diiodide.
N
+
R1 O
R2OC
COR2
OTMS R3
R4
Cu(OTf)2–119 (10 mol%) CH2Cl2, 0° to –78°, 12-18 h
O 118 Ph
Ph
NH O
R 1O
R4
R3 O 120 (44-97%) 42-96% ee
NH HN 119
(Eq. 54)
N -Tosylimino esters 121 should be more electrophilic than N -acylimino esters, considering the strong electron-withdrawing ability of the tosyl group. The chiral cationic copper(I) complex derived from Tol-BINAP and copper(I) perchlorate is a useful asymmetric catalyst for Mannich-type reactions using enol silyl ethers, ene reactions using alkenes, and allylation reactions using allylsilanes and substrate 121.151 More recently, a catalytic asymmetric Staudinger-type β-lactam formation (Eq. 55) was reported.152 A ketene generated in situ from an acid chloride and proton sponge was nucleophilically activated by benzoylquinine (122). Addition of 10 mol% of indium triflate, acting as a Lewis acid to activate imine 121, dramatically accelerated the reaction without affecting the excellent diastereo- and enantioselectivity.
36
ORGANIC REACTIONS
N
Ts
Cl
122 (10 mol%), In(OTf)3 (10 mol%), proton sponge (1 eq)
O
+
EtO2C
toluene, –78°, 16 h
R
O N
EtO2C R (91-98%) 96-98% ee dr = 9:1 to 60:1
1 eq
121
Ts
OMe
(Eq. 55)
N N OBz 122
Organocatalysts can promote direct asymmetric Mannich-type reactions of ketones or aldehydes to imino esters.153 – 163 Generally, proline-catalyzed or dinuclear zinc-catalyzed164 direct asymmetric Mannich-type reactions between imino esters and α-substituted ketones or aldehydes result in syn products with excellent diastereo- and enantioselectivity. Through logical consideration of the transition state structure, an anti-selective direct asymmetric Mannich-type reaction between imino esters and aldehydes producing 124 was developed using 3-pyrrolidinecarboxylic acid derivative 123 as a catalyst (Eq. 56).165 N
Ar
Ar
CHO
+
DMSO
R
EtO2C Ar = 4-MeOC6H4
NH O
123 (1-5 mol%)
2 eq CO2H
EtO2C
H R 124 (57-92%) 97 to >99% ee dr = 95:5 to 98:2
(Eq. 56)
N H 123
The organocatalyzed direct asymmetric Mannich-type reaction was extended to the synthesis of quaternary stereocenters using a special keto imino ester 125 as a substrate (Eq. 57).166 The proline-derived diamine 126 produced high diastereoand enantioselectivity in the reactions between 125 and aldehydes. O O R1
O N CO2Et
CHO
+ R
126 (5 mol%)
O R1
Et2O, 0°, 20 h
R2
R2 R3
125
2 eq
NH CO2Et CHO R
(Eq. 57)
R3 N H
N
(72-99%) 83-98% ee dr = 4:1 to >20:1
126
The catalytic enantioselective nucleophilic alkylation of imino esters is much less studied than Mannich-type reactions. N -Benzyloxycarbonyl (Cbz) imino esters
THE CATALYTIC ASYMMETRIC STRECKER REACTION
37
127 can react with electron-rich aromatic compounds through a Friedel-Crafts type alkylation under the catalysis of a cationic copper(I)-chiral phosphine complex (Eq. 58).167,168 This reaction directly generates enantiomerically enriched N -Cbzprotected α-aryl amino esters, which are common intermediates for peptide synthesis. Catalytic enantioselective addition of dialkylzinc to imino esters has been recently reported.169 The enantioselectivity, however, was in the moderate range. O N
EDG OBn
+
CuPF6-(R)-Tol-BINAP (5-20 mol%)
Cbz
CH2Cl2 or THF, –78°
EtO2C
NH
EDG
(Eq. 58)
EtO2C EDG = electron donating group
127
(44-88%) 52-98% ee
Oxazole as a Glycine Enolate Equivalent. Oxazole derivatives can be utilized as a glycine enolate equivalent.170,171 Two catalytic enantioselective variants have been reported. First, the chiral nucleophilic pyridine derivative 128 catalyzed the enantioselective rearrangement of O-acylated azlactone 129 to α,α-disubstituted amino acid derivatives 130 with excellent enantioselectivity and broad substrate generality (Eq. 59).172 The products were directly converted to protected dipeptides (e.g., 131) in high chemical yield. Second, chiral aluminum catalyst 132 promoted the addition of 133 to aromatic aldehydes in the presence of a catalytic amount of lithium perchlorate, and the subsequent one-pot rearrangement of 134 afforded cis-β-hydroxy-α-amino acid derivatives 135 with excellent diastereo- and enantioselectivity (Eq. 60).173 When R=H, the products were isomerized to trans-136 by treatment with 5% 1,8-diazabiclo[5.4.0]undec7-ene (DBU), allowing for the synthesis of both syn- and anti-β-hydroxy-α-amino acid derivatives. In addition, application to α,α-disubstituted amino acid synthesis was possible using a dicationic copper-bisoxazoline complex as a catalyst and methyl-substituted 137 as a nucleophile. O BnO R
O
O
128 (2 mol%), t-amyl alcohol 0°, 2-6 h
O
N Ar 129 Ar = 4-MeOC6H4
O
BnO
O R N Ar
H2N
CO2Me
130 (93-95%) 88-91% ee O BnO2C N CO2Me R NH H COAr 131 (95%) R = Me
N N
128
Fe
(Eq. 59)
38
ORGANIC REACTIONS MO R Ar'
N
3 Å MS, toluene, rt, 20 h
OMe
O
Ar
132 (5-10 mol%), LiClO4 (20 mol%)
N
ArCHO +
Ar'
133: R = H 137: R = Me Ar' = 4-MeOC6H4 N
CO2Me
R O Ar 135: R = H (58-100%) 91 to >99% ee dr = 73:27 to >99:1
OMe O + 134 M = metal
N
5% DBU
Ar'
R
CO2Me
Ar'
R=H
O
Ar 136
t-Bu
Bu-t N + O Al O N
SbF6– Bu-t
132
t-Bu
(Eq. 60)
Catalytic Asymmetric Electrophilic Amination of Enolates Azodiacarboxylates are excellent nitrogen electrophiles in catalytic asymmetric amination of enolate derivatives. Direct organocatalytic asymmetric α-amination of aldehydes has been reported (Eq. 61).174 – 176 Excellent enantioselectivity is achieved from a wide range of aldehydes using L-proline as catalysts. The products are converted to amino acid derivatives by oxidation of the aldehyde and reduction of the hydrazine using Raney nickel. The proline-catalyzed asymmetric amination of aldehydes was applied to the syntheses of biologically active pharmaceutical leads.177,178
R1 O2 C
N N
CO2R1
CHO
+ R
L-proline (10 mol%)
CH2Cl2, rt
R1O2C 1
R O2C
NH CHO N
R (57-92%) 89-95% ee
1.5 eq
1. KMnO4 2. TMSCHN2 3. TFA 4. H2, Raney Ni 5. Boc2O, DMAP
R1O2C
H N
CO2Me R
(Eq. 61)
THE CATALYTIC ASYMMETRIC STRECKER REACTION
39
Chiral cationic copper(II)–bisoxazoline complex 138 catalyzes a general and highly enantioselective α-amination of α-substituted β-ketoesters (Eq. 62).179 – 181 Enantiomerically enriched α,α-disubstituted amino acid derivatives can be synthesized using this reaction. An asymmetric organocatalyzed synthesis of quaternary stereocenters is also possible using α-cyanoacetates as nucleophilic substrates.182,183
N N
O
CO2Bn
BnO2C 1.2 eq
+
O
R1
OR3 R2
Cu(OTf)2 (0.2-0.5 mol%), 138 (0.2-0.5 mol%)
BnO2C
CH2Cl2, 16 h
BnO2C
O
O N Ph
138
NH CO2R3 N
COR1 R2 (70-98%) 87-99% ee
N Ph
(Eq. 62)
EXPERIMENTAL CONDITIONS
Toxicity of Cyanide Compounds Cyanide compounds (TMSCN, HCN, and KCN) used in the Strecker reaction are highly toxic, and should be handled very carefully in a well-ventilated hood.184 The toxicity of cyanide is attributed to its extremely high affinity to the iron(III) ion of the mitochondrial cytochrome oxidase enzyme (50% inhibitory concentration = 10−8 M). Through the inhibition of this enzyme, the reduced form of cytochrome c, a key electron transporting membrane protein, cannot be converted to the oxidized form, and the respiratory system of cells is blocked. The fatal concentration of HCN for humans after 10 minutes of exposure is 0.2 mg/L, and concentrations over 0.3 mg/L cause instantaneous death. To prevent any exposure to cyanide, use of appropriate personal protective equipment (gloves, eye glasses, respirator, and HCN gas detector) is indispensable. All solutions containing cyanide should be kept and treated under basic pH. The cyanide waste should be discarded by a special facility, or after oxidative treatment with sodium hypochlorite solution (available chlorine >5%) overnight. If the latter method is used, the remaining cyanide concentration in the treated waste solution should be confirmed by commercial CN− test paper to be below the detection limit before that solution is discarded. Isolation of Amino Acids Due to their high polarity, free amino acids synthesized after acid hydrolysis of the Strecker products are generally difficult to isolate and purify using silica gel column chromatography. Taking advantage of the ionic feature of amino acids, however, they can be isolated relatively easily using ion-exchange column chromatography.40 The crude mixture after acid hydrolysis of the Strecker products usually contains the target amino acid, a residue derived from the nitrogen protecting group, and ammonium chloride. This mixture is loaded onto an acidic
40
ORGANIC REACTIONS
resin (such as acidic Dowex), and the non-charged organic byproduct derived from the nitrogen protecting group is first eluted using methanol. Next, the target amino acid is eluted from the column as the corresponding ammonium salt by changing the eluent to aqueous ammonia. During evaporation of the eluent, the ammonia that is generated through equilibration of the weak acid (carboxylic acid) with the weak base (ammonia) salt is eliminated. Thus, the free amino acid can be obtained. EXPERIMENTAL PROCEDURES
Preparation of the catalysts referred to in the preceding text and in the experimental procedures may be found by consulting information within references cited. O H
+
NH2
N
3 Å MS
(—)
H
t-Bu
t-Bu
Allyl-(4-tert-butyl benzylidene)amine [General Procedure for Preparation of Simple Amine-Derived Aldimines].33 To a flame-dried 50-mL round˚ molecular sieves (2 g) and CH2 Cl2 bottom flask, were added activated 3 A (20 mL, freshly distilled from CaH2 ). To this solution, the substrate benzaldehyde (20 mmol) was added followed by a syringe addition of allylamine (1.3 eq, 26 mmol). After 4 hours, the sieves were removed by filtration and washed with CH2 Cl2 (2 × 10 mL). The filtrate was collected and the solvent was removed in vacuo. Further purification was accomplished by vacuum distillation to yield the target aldimine. IR (thin film) 2955, 1650, 1462, 1372 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 8.28 (s, 1H), 7.71 (d, J = 10.4 Hz, 2H), 7.45 (d, J = 10.4 Hz, 2H), (s, 1H), 6.06 (ddd, J = 5.6, 10.3, 17.1 Hz, 1H), 5.24 (dappq, J = 1.5, 17.1 Hz, 1H), 5.16 (dappq, J = 1.5, 10.3 Hz, 1H), 4.26 (dappq, J = 1.5, 5.6 Hz, 2H), 1.35 (s, 9H); 13 C NMR (100 MHz, CDCl3 ) δ 161.7, 153.9, 135.9, 133.4, 127.9, 125.4, 115.6, 63.4, 34.7, 31.1; HRMS (m/z): [M+ ] calcd for C14 H19 N, 201.1517; found, 201.1528.
O i-Pr
N
1. pyridine, NH2OH•HCl, 4˚ 2. 60°, 12 h
i-Pr
OH
Ph2PCl, Et3N –40° to rt
(79%)
N
O PPh2 (55%)
i-Pr 64
N -(2-Isopropylcyclopent-2-en-1-ylidene)-P,P-diphenylphosphinic Amide [General Procedure for Preparation of N-Phosphinoyl Ketimines].39,52,86 Pyridine (20.8 mL, 0.26 mol) and hydroxylamine hydrochloride (16.8 g, 0.24 mol) were added to the starting ketone (20 g, 0.16 mol) in EtOH (268 mL)
THE CATALYTIC ASYMMETRIC STRECKER REACTION
41
at 4◦ . After stirring for 15 minutes at 4◦ , the reaction mixture was warmed to 60◦ and stirred for 12 hours. Concentration and purification by flash column chromatography (EtOAc/hexane = 1 : 10 to 1 : 5) afforded the corresponding oxime (17.7 g, 79%) as a white solid. To a solution of Et3 N (18.4 mL, 0.13 mol) and the oxime (16 g, 0.12 mol) in CH2 Cl2 (96 mL) and hexane (96 mL), chlorodiphenylphosphine (27.1 g, 0.13 mol) in CH2 Cl2 (38 mL) was added slowly over 1 hour at −40◦ . The reaction mixture was warmed gradually to room temperature, CH2 Cl2 (100 mL) was added, and the insoluble salt was removed by filtration through a celite pad. The filtrate was concentrated in vacuo. The solid residue was purified by flash column chromatography (CH2 Cl2 /MeOH = 50 : 1 to 20 : 1; EtOAc/MeOH = 20 : 1) to afford the target ketimine (37.4 g) as a white solid. Toluene (75 mL) was added to 64 (37.4 g) and the solution was warmed to 70◦ , at which point hexane (75 mL) was added. The solution was gradually cooled to room temperature, and the resulting precipitate was collected by filtration to afford pure title compound (25.7 g, total yield 55%) as a white solid, mp 133–134◦ ; IR (neat) = 2959, 1634, 1609, 1192 cm−1 ; 1 H NMR (500 MHz, CDCl3 ) δ 7.89–7.94 (m, 4H), 7.36–7.43 (m, 6H), 6.99–7.00 (m, 1H), 2.95–2.97 (m, 2H), 2.86 (sept, J = 7.0 Hz, 1H), 2.50–2.51 (m, 2H), 1.16 (d, J = 7.0 Hz, 6H); 13 C NMR (125 MHz, CDCl3 ) δ 194.2 (d, J = 4.9 Hz), 154.2, 154.1, 152.1, 135.7, 134.7, 131.5, 131.5, 131.4, 131.4, 131.1, 131.1, 128.3, 128.3, 128.2, 128.2, 34.3 (d, J = 4.9 Hz), 29.4, 25.3, 21.5; 31 P NMR (CDCl3 ) δ 20.7; LRMS–FAB (m/z): 324 [M + H]+ ; HRMS–FAB (m/z): [M + H]+ calcd for C20 H23 NOP+ , 324.1512; found, 324.1524. MesSO2NH2, p-TolSO2Na
O H
HCO2H, H2O, rt, 12 h (Mes = 2,4,6-Me3C6H2)
HN
SO2Mes NaHCO3 SO2Tol-p
(96%)
N
SO2Mes H
(67%)
Cyclohexanecarboxaldehyde N-(Mesitylenesulfonyl)imine [General Procedure for Preparation of N-Sulfonyl Imines].58,68 A mixture of cyclohexanecarboxaldehyde (363 µL, 3.0 mmol), mesitylenesulfonamide (598 mg, 3.0 mmol) and sodium p-toluenesulfinate (481 mg, 3.0 mmol) in HCO2 H (4.5 mL) and H2 O (4.5 mL) was stirred for 12 hours at room temperature. The resulting white precipitate was filtered off, and washed with H2 O and hexane. The precipitate was then recrystallized from EtOAc/hexane to obtain the intermediate N -(mesitylenesulfonyl)-α-(p-toluenesulfonyl)cyclohexylmethylamine (301 mg, 2.01 mmol, 67%) as a crystalline material; IR (thin film) 3401, 3285, 3028, 2928, 2855, 1599, 1566, 1450, 1331, 1302, 1155, 1123, 1082, 903, 853, 814, 733 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.52 (d, J = 8.3 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 6.81 (s, 2H), 5.27 (d, J = 10.7 Hz, 1H), 4.53 (dd, J = 3.0, 10.7 Hz, 1H), 2.50–2.40 (m, 1H), 2.42 (s, 6H), 2.34 (s, 3H), 2.29 (s, 3H), 2.11 (d, J = 12.3 Hz, 1H), 1.81–1.60 (m, 4H), 1.38–1.28 (m, 2H), 1.19-1.02
42
ORGANIC REACTIONS
(m, 3H); 13 C NMR (100 MHz, CDCl3 ) δ 144.4, 141.7, 137.5, 135.7, 134.2, 131.6, 129.3, 128.3, 77.5, 37.5, 30.7, 27.2, 26.2, 25.8, 25.7, 22.9, 21.7, 21.0. The sulfonamide sulfone obtained above (901 mg, 2.01 mmol) was dissolved in CH2 Cl2 (2 mL). Then, saturated aqueous sodium bicarbonate solution (1 mL) was added and the mixture was stirred for 1 hour. Phases were separated and the aqueous phase was extracted with CH2 Cl2 . The combined organic phase was dried over sodium bicarbonate and concentrated under vacuum to yield the target imine (566 mg, 1.93 mmol, 96%); IR (thin film) 3026, 2930, 2853, 1624, 1603, 1566, 1450, 1319, 1155, 1057, 853, 797, 777, 750 cm−1 ; 1 H NMR (400 MHz, CD2 Cl2 ) δ 8.40 (d, J = 4.0 Hz, 1H), 6.98 (s, 2H), 2.58 (s, 6H), 2.43 (m, 1H), 2.31 (s, 3H), 1.88-1.66 (m, 5H), 1.38–1.20 (m, 5H); 13 C NMR (100 MHz, CD2 Cl2 ) δ 179.8, 143.7, 140.4, 132.1, 131.9, 44.0, 28.9, 26.2, 25.6, 23.1, 21.2; HRMS–ESI–TOF (m/z): [M + H]+ calcd for C16 H24 NO2 S, 294.1522; found, 294.1522. O N
t-Bu
CF3
1. 28 (2 mol%), HCN, –70° H
2. (CF3CO)2O
N
(89%) 97% ee CN
t-Bu
N-allyl-N-((4-tert-butylphenyl)(cyano)methyl)-2,2,2-trifluoroacetamide [General Procedure for Catalytic Enantioselective Strecker Reaction of Aldimines Using a Urea-Based Catalyst].33 In a flame-dried 5-mL round-bottom flask equipped with a stirring bar, catalyst 28 (5 mg, 2 mol%, 0.008 mmol) and toluene (1.6 mL) were combined. The substrate (0.4 mmol, 200 mM final concentration) was added by syringe. The reaction mixture was stirred at ambient temperature until the catalyst completely dissolved. The reaction flask was cooled to −70◦ by means of a constant temperature bath and then a toluene solution of HCN (1.54 M, 340 µL, 0.52 mmol, 1.3 eq) was added slowly by syringe. After 20 hours, the reaction mixture was left to warm to ambient temperature and quenched with trifluoroacetic anhydride (103 µL, 0.73 mmol, 1.5 eq). The solvents were removed under vacuum and the resulting residue was purified by flash chromatography (hexanes/CH2 Cl2 = 3 : 2) to afford the Strecker adduct as a clear oil (89% yield, 97% ee); HPLC (Chiralcel AD, 0.6% i-PrOH/hexane, 1 mL/min) tr = 9.0 min (major), tr = 11.4 min (minor); [α]23 D −61.4◦ (c 1.0, CH2 Cl2 ); IR (thin film) 2966, 1704, 1213, 1154 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.47 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.60 (s, 1H), 5.69 (m, 1H), 5.21 (d, J = 10.4 Hz, 1H), 5.15 (d, J = 17.2 Hz, 1H), 4.16 (dd, J = 4.7, 17.0 Hz, 1H), 3.92 (dd, J = 6.2, 17.0 Hz, 1H), 1.33 (s, 9H); 13 C NMR (100 MHz, CDCl3 ) δ 157.7 153.5, 131.2, 127.7, 127.0, 126.3, 120.1, 117.4, 115.4, 49.5, 48.4, 34.7, 31.1; HRMS (m/z): M+ calcd for C17 H19 F3 N2 O, 324.1449; found, 324.1436.
THE CATALYTIC ASYMMETRIC STRECKER REACTION
N
SO2Mes
HN
33 (1 mol%), 2 M aq. KCN (1.5 eq) H
SO2Mes CN
toluene–H2O, 0°
43
(89%) 95% ee
N-(Mesitylenesulfonyl)-α-(cyano)cyclohexylmethylamine [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using a Phase-Transfer Catalyst].68 A mixture of the starting imine (58.7 mg, 0.20 mmol), chiral ammonium iodide catalyst 33 (2.6 mg, 0.002 mmol) in toluene (1 mL), and H2 O (3 mL) was cooled to 0◦ and an aqueous KCN solution (2 M, 150 µL, 0.3 mmol) was added dropwise. The reaction mixture was stirred vigorously at this temperature for 2 hours, saturated aqueous NH4 Cl solution was added, and the mixture was extracted with CH2 Cl2 . The combined extracts were dried over Na2 SO4 . Evaporation of solvents and purification of the crude products by flash column chromatography on silica gel (EtOAc/hexane = 1 : 4) gave the title compound (57.0 mg, 0.178 mmol, 89% yield, 95% ee); HPLC (Daicel Chiralpak AD-H, 2-propanol/hexane = 1 : 10, 0.5 mL/min, λ = 254 nm), tr = 13.3 min (R) and 14.7 min (S); [α]29 D − 18.9◦ (c 1.00, CHCl3 , 95% ee); IR (thin film) 3275, 3028, 2930, 2855, 2253, 1602, 1566, 1450, 1330, 1157, 1091, 1057, 904, 852, 731 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 6.99 (s, 2H), 5.37 (d, J = 9.1 Hz, 1H), 3.92 (dd, J = 6.7, 9.1 Hz, 1H), 2.65 (s, 6H), 2.31 (s, 3H), 1.86-1.67 (m, 6H), 1.29–1.06 (m, 5H); 13 C NMR (100 MHz, CDCl3 ) δ 143.0, 139.0, 132.7, 132.1, 116.5, 49.5, 41.2, 29.0, 28.4, 25.7, 25.4, 25.3, 23.0, 21.1; HRMS–ESI–TOF (m/z): [M + Na]+ calcd for C17 H24 N2 O2 SNa, 343.1454; found, 343.1451. Bu-t
Bu-t
t-Bu
t-Bu OH N OH N
t-Bu
O N Cl Al O N
Et2AlCl CH2Cl2, toluene, 2 h
(95%)
t-Bu
Bu-t
Bu-t 34
Chiral (Salen)Al(III) Complex [Catalyst Preparation].69 In a flame-dried 100-mL round-bottom flask equipped with a stir bar were combined and stirred salen ligand (1.52 g, 2.78 mmol) and CH2 Cl2 (20 mL, freshly distilled from CaH2 ). A toluene solution of diethylaluminum chloride (1.8 M, 1.54 mL, 2.78 mmol) was added slowly to the stirring solution at ambient temperature. After stirring for 2 hours, the solvents were removed under vacuum and the resulting yellow solid was rinsed with 50 mL of hexane. The solid was dried
44
ORGANIC REACTIONS
under vacuum to yield catalyst 34 (1.59 g, 95% yield) as a yellow solid, mp >350◦ (dec); IR (KBr) 2966, 2953, 2867, 1640, 1544, 848 cm−1 ; 1 H NMR (400 MHz, C6 D6 ) δ 7.84 (s, 2H), 7.77 (s, 2H), 7.61 (s, 2H), 3.51 (m, 2H), 1.91 (s, 18H), 1.39 (s, 18H) 1.36 (m, 4H), 0.59 (m, 4H); 13 C NMR (100 MHz, CD2 Cl2 ) δ 162.7, 141.2, 139.3, 131.4, 128.7, 128.4, 118.7, 64.6 (broad), 35.9, 34.4, 31.6, 30.0, 28.2, 24.1. Anal. Calcd for C36 H52 AlClN2 O2 : C, 71.20; H, 8.42; Al, 4.44; Cl, 5.84; N, 4.61. Found: C, 71.05; H, 8.63; Al, 4.49; Cl, 5.73; N, 4.56. 1. 34 (2–5 mol%), HCN (1.2 eq), toluene, –70°
N Ph
CF3
2. (CF3CO)2O
H
O N Ph
(91%) 95% ee CN
(S )-N -Allyl-N -(phenyl(cyano)methyl)-2,2,2-trifluoroacetamide [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst].69 In a flame-dried 5-mL round-bottom flask equipped with a stir bar, 34 (12 mg, 5 mol%, 0.02 mmol) and toluene (1.4 mL) were combined. The reaction mixture was stirred at ambient temperature until the catalyst had completely dissolved. The reaction flask was cooled to −70◦ by means of a constant-temperature bath, and a toluene solution of HCN was added (0.85 M, 690 µL, 0.59 mmol, 1.2 eq). After 5 minutes, N-allyl benzylimine (71 mg, 0.49 mmol) was added in one portion by syringe. After 15 hours, the reaction was quenched with trifluoroacetic anhydride (103 µL, 0.73 mmol, 1.5 eq) and left to warm to ambient temperature. The solvents were removed under vacuum, and the resulting residue was purified by flash chromatography (hexane/CH2 Cl2 = 3 : 2) to afford the title product as a clear oil (119 mg, 91% yield, 95% ee); Chiral GC (γ TA, 112◦ for 23 min, 3◦ /min to 123◦ ) tr = 21.5 min (major), tr = 23.9 min (minor); [α]23 D 57.7◦ (c 1.0, CH2 Cl2 ); IR (thin film) 2936, 2249, 1701 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.45 (m, 5H), 6.65 (s, 1H), 5.66 (m, 1H), 5.19 (d, J = 10.2 Hz, 1H), 5.13 (d, J = 17.0 Hz, 1H), 4.15 (dd, J = 4.7, 17.0 Hz, 1H), 3.91 (dd, J = 6.0, 17.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3 ) δ 157.9 (q, J = 38 Hz), 131.1, 130.1, 130.0, 129.4, 127.8, 120.3, 117.5, 115.2, 49.8, 48.6; HRMS (m/z): [M + NH4 ]+ calcd for C13 H11 F3 N2 O, 286.1167; found, 286.1163. A: 6 (9 mol%), TMSCN (2 eq), PhOH (20 mol%), slow addition over 17 h CH2Cl2, –40°
N Ph
H
HN Ph
CN
(92%) 95% ee
N-(9-Fluorenylamino)phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst: Condition A].26,27 The chiral substituted BINOL ligand precursor (13 mg, 18 µmol) was placed in a flame-dried flask and dissolved in CH2 Cl2
THE CATALYTIC ASYMMETRIC STRECKER REACTION
45
(0.5 mL). To this solution was added a hexane solution of diethylaluminum chloride (0.96 M, 17 µL, 16 µmol) under argon. The resulting mixture was stirred at room temperature for 1 hour to give a clear solution of the BINOL-derived catalyst 6. To the thus-prepared catalyst solution, a solution of the starting fluorenyl imine (0.17 mmol) in CH2 Cl2 (0.6 mL) was added at −40◦ , followed by the addition of TMSCN (45 µL, 0.34 mmol). After 30 minutes, a solution of phenol (3 µ, 34 µmol) in CH2 Cl2 (0.2 mL) was slowly added over 17 hours. The reaction mixture was stirred for an additional 44 hours. The reaction was quenched with aqueous saturated NaHCO3 , and the mixture was diluted with Et2 O. The organic layer was separated, and the water layer was extracted with Et2 O. The combined organic layers were washed with water and dried over Na2 SO4 . Further purification was performed by flash column chromatography on silica gel to afford the target fluorenyl aminonitrile (92% yield, 95% ee); HPLC (Daicel Chiralpak AS, hexane/i-PrOH = 90 : 10, 1.0 mL/min) tr = 13.3 min and 25.0 min; [α]24 D − 14.0◦ (c 1.0, CHCl3 ); 1 H NMR (CDCl3 ) δ 7.78–7.68 (m, 3H), 7.53–7.26 (m, 10H), 5.14 (s, 1H), 4.57 (s, 1H), 2.34 (bs, 1H); 13 C NMR (CDCl3 ) δ 143.6, 143.5, 141.1, 140.7, 135.8, 129.01, 128.98, 128.9, 128.8, 127.6, 127.4, 125.7, 125.0, 120.2, 120.1, 119.6, 62.2, 50.3. B: 6 (9 mol%), TMSCN (20 mol%), HCN (1.2 eq), slow addition over 24 h CH2Cl2, –40°
N Ph
H
HN Ph
CN
(92%) 95% ee
N -(9-Fluorenylamino)phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using an Aluminum Catalyst: Condition B].26,27 To a CH2 Cl2 solution (1.0 mL) of catalyst 6 (33 µmol) prepared as described above, a solution of the starting imine (0.352 mmol) in CH2 Cl2 (1.0 mL) and TMSCN (70 µmol) were added at −40◦ . To this mixture, a solution of HCN (0.422 mmol) in CH2 Cl2 (0.26 mL) was slowly added over 24 hours. After 12 hours (total 36 hours), the reaction was worked up as described above to yield the title compound in 92% yield and 95% ee. 35 (10 mol%), TMSCN (4 eq), TMSCN (4 eq), t-BuOH (1.1 eq) CH2Cl2, –50°
N Ph
H
HN Ph
CN
(98%) 87% ee
N-(9-Fluorenylamino)phenylacetonitrile [General Procedure for Catalytic Enantioselective Strecker Reaction of Aldimines Using a Solid-Supported Aluminum Catalyst].73 To the corresponding swollen polymersupported ligand (19.1 mg, loading level = 0.52 mmol/g, 10 mmol) in CH2 Cl2
46
ORGANIC REACTIONS
(0.4 mL), a hexane solution of diethylaluminum chloride (0.95 M, 10 µL, 9.5 mmol) was added at ambient temperature, and the mixture was stirred for 1 hour to prepare catalyst 35. The catalyst mixture was cooled to −50◦ , then the starting imine (27 mg, 0.1 mmol) in CH2 Cl2 (0.25 mL), TMSCN (54 µL, 0.4 mmol), and tert-butanol (0.11 mmol) in CH2 Cl2 (0.25 mL) were added successively with 10 minute intervals between additions. After 60 hours, saturated aqueous NaHCO3 (1 mL) was added. The usual workup and purification by silica gel column chromatography afforded pure title compound in 98% yield and 87% ee. Catalyst recycling experiments were performed as follows: Instead of quenching the reaction with NaHCO3 , after the reaction was completed, dry Et2 O (five times the volume of CH2 Cl2 ) was added and the reaction mixture was left for 3 hours. The supernatant containing the Strecker product was then decanted by syringe, and catalyst 35 was washed with dry Et2 O five times under an inert atmosphere. After drying the catalyst under reduced pressure for 30 minutes, CH2 Cl2 , imine, TMSCN, and tert-butanol were added at −50◦ to start the new cycle. HO
HO 38 (5 mol%), NMI (30 mol%) + (n-Bu)3SnCN
N Ph
H
toluene–benzene (1:1), –65° to 0°
HN Ph CN (92%) 91% ee
2-(2-Hydroxyphenyl)amino-2-phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction of Aldimines Using a Zirconium Catalyst].51,75 To Zr(OBu-t)4 (0.04 mmol) in toluene (0.25 mL) was added (R)-6-Br-BINOL (0.04 mmol), (R)-3-Br-BINOL (0.04 mmol), and N -methylimidazole (NMI; 0.12 mmol) in toluene (0.75 mL) at room temperature. The mixture was stirred for 1 hour, and then cooled to −65◦ to generate catalyst 38. A benzene solution (1.0 mL) of the imine (0.4 mmol) and tributyltin cyanide (0.44 mmol) were added. The mixture was stirred and warmed from −65◦ to 0◦ over 12 hours, and then saturated aqueous NaHCO3 was added to quench the reaction. The aqueous layer was extracted with CH2 Cl2 . After the usual workup, the crude product was chromatographed on silica gel to give the desired adduct (92%, 91% ee); HPLC (Daicel Chiralcel OD, hexane/isopropyl alcohol = 9 : 1, 1.0 mL/min) tr = 40.0 min (major) and 49.7 min (minor); 1 H NMR (CDCl3 ) δ 7.61–7.43 (m, 6H), 6.93–6.72 (m, 4H), 5.40 (d, 1H, J = 7.2 Hz), 4.43 (br, 1H); 13 C NMR (CDCl3 ) δ 144.5, 134.0, 133.3, 129.5, 129.3, 127.2, 121.5, 120.7, 118.4, 114.9, 114.2, 50.6. Since some of the products from this method were unstable, they were characterized after methylation of the phenolic OH group as follows: The product was treated with 20% MeI–Me2 CO (5 mL) and K2 CO3 (200 mg). After the mixture was stirred at room temperature for 6 hours, saturated aqueous NH4 Cl was added to quench the reaction. After extraction of the aqueous layer with CH2 Cl2 , the crude product was purified by chromatography on silica gel to afford the corresponding methylated product (quantitative yield).
THE CATALYTIC ASYMMETRIC STRECKER REACTION HO
HO C8H17CHO +
38 (1 mol%) + HCN
H2N
47
CH2Cl2, –45°
HN C8H17
CN
(86%) 84% ee
1-(2-Hydroxy-6-methylphenyl)aminononane-1-carbonitrile [General Procedure for the Catalytic Enantioselective Three-Component Strecker Reaction Using a Zirconium Catalyst].51 To a CH2 Cl2 solution (3.0 mL) of (R)-6Br-BINOL (0.04 mmol), (R)-3-Br-BINOL (0.04 mmol), and N -methylimidazole (0.12 mmol) was added a CH2 Cl2 solution (1.0 mL) of Zr(OBu-t)4 (0.04 mmol) at room temperature. After the mixture was stirred for 1 hour, a CH2 Cl2 solution (0.2 mL) of HCN (0.8 mmol) was added at 0◦ , and the mixture was further stirred for 3 hours at the same temperature. The resulting solution was then added to a mixture of nonaldehyde (0.4 mmol) and 2-amino-3-methylphenol (0.4 mmol) in CH2 Cl2 (1 mL) at −45◦ . After the mixture was stirred for 12 hours, HCN was added if the reaction was not yet completed. Saturated aqueous NaHCO3 was then added to quench the reaction, and after the usual workup, the crude product was purified by chromatography on silica gel to give the desired adduct (86%, 84% ee); HPLC (Daicel Chiralpak AD, hexane/isopropyl alcohol = 19 : 1, 1.0 mL/min) tr = 10.4 min (major) and 13.0 min (minor); 1 H NMR (CDCl3 ) δ 6.93–6.70 (m, 3H), 4.00 (t, J = 7.3 Hz, 1H), 2.33 (s, 3H), 1.92 (dt, J = 7.3, 7.7 Hz, 2H), 1.70-1.20 (m, 12H), 0.89 (t, J = 6.7 Hz, 3H); 13 C NMR (CDCl3 ) δ 150.1, 134.5, 130.6, 125.2, 123.0, 120.4, 113.4, 49.7, 34.2, 31.7, 29.1, 29.0, 25.6, 22.6, 17.7, 14.0; HRMS (m/z): M+ calcd for C17 H26 N2 O, 274.2047; found, 274.2045. Ph
Ph N Ph
Ph H
+ TMSCN
Ti(OPr-i)4 (10 mol%), 39 (10 mol%) i-PrOH, slow addition for 20 h, toluene, 4°
HN Ph
Ph CN
(99%) 97% ee
2-Benzhydrylamino-2-phenylacetonitrile [General Procedure for the Catalytic Enantioselective Strecker Reaction Using a Titanium Catalyst].28 The reaction was set up inside of a glove box under a nitrogen atmosphere. Chiral ligand 39 (49 mg, 0.10 mmol) was placed into a flame-dried round-bottomed flask, and dissolved in toluene (5 mL). The flask was charged with a toluene solution of Ti(OPr-i)4 (0.5 M, 0.2 mL, 0.1 mmol), and the yellow solution was stirred for 10 minutes at 22◦ . Subsequently, N-diphenylmethylbenzalimine (271 mg, 1.0 mmol) was added. The reaction vessel was capped with a septum, sealed with teflon tape, removed from the glove box, and placed in a room maintained at 4◦ . TMSCN (267 µL, 2.0 mmol) was added to the stirred solution. Isopropyl alcohol (153 µL, 2.0 mmol) in toluene (2 mL) was added over 20 hours with additional stirring for 10 hours. The crude reaction mixture was passed through a plug of silica with CH2 Cl2 (5 mL) and concentrated under vacuum. The crude reaction mixture showed 99% conversion and 97% ee by HPLC
48
ORGANIC REACTIONS
(Chiralpak AD). The pale yellow solid was recrystallized from hexane/CH2 Cl2 (5 : 1) to afford the title compound (228 mg, 82%, >99% ee); [α]24 D − 64.2◦ (c 5.0, CHCl3 ); IR (CCl4 ) 3327, 3087, 3069, 3031, 2848, 2231, 1948, 1879, 1810, 1608, 1501, 1451, 1187, 929 cm−1 ; 1 H NMR (CDCl3 , 400 MHz) δ 7.58–7.20 (m, 15H), 5.24 (s, 1H), 4.59 (d, J = 12.0 Hz, 1H), 2.14 (d, J = 12.0 Hz, 1H); 13 C NMR (CDCl3 , 100 MHz) δ 243.4, 242.7, 235.6, 129.7, 129.6, 129.4, 128.6, 128.4, 128.1, 127.9, 127.7, 119.4, 66.2, 53.0; HRMS (m/z): [M + H]+ calcd for C21 H18 N2 , 299.1548; found, 299.1549. Anal. Calcd for C21 H18 N2 : C, 84.53; H, 6.08; N, 9.39. Found: C, 84.22; H, 6.19; N, 9.28. N
Ph +
HCN
NC
28 (2 mol%)
NHBn (99%) 93% ee
toluene, –75° Br
Br
2-Benzylamino-2-(4-bromophenyl)propionitrile [General Procedure for Asymmetric Strecker Reaction of Ketimines Using a Urea Catalyst].38 A 10-mL round-bottom flask equipped with a stir bar was charged with catalyst 28 (3.7 mg, 0.006 mmol, 0.02 eq), toluene (2 mL), and the starting ketimine (0.3 mmol). The reaction mixture was cooled to −75◦ by means of a constant temperature bath. In a separate 2-mL flask equipped with a stir bar, toluene (1 mL) and TMSCN (50 µL, 1.25 eq) were combined. After cooling the solution to 5◦ , MeOH (15 µL, 1.25 eq) was added. The solution was stirred for 2 hours at 5◦ , cooled to −78◦ , and then added to the reaction flask by syringe. When conversion of the starting material exceeded 99% as monitored by either 1 H NMR or HPLC, the solvents were removed under vacuum. The crude product was obtained as a solid (quantitative as a mixture with catalyst, 93% ee). Recrystallization from hexanes afforded pure title product as white needles (76% overall yield, >99.9% ee), mp 79.9–80.1◦ ; HPLC (Chiralcel OD, i-PrOH/hexanes (3%), 1 mL/min) tr = 15.9 min (major), tr = 19.5 min (minor); [α]23 D −58.6◦ (c 1.0, CH2 Cl2 ); IR (thin film) 3323, 2224 cm−1 ; 1 H NMR (400 MHz, CDCl3 ) δ 7.65 (d, J = 6 Hz, 2H), 7.59 (d, J = 6 Hz, 2H), 7.42–7.26 (m, 5H), 3.93 (d, J = 10 Hz, 1H), 3.58 (m, 1H), 2.02 (d, J = 5 Hz, 1H), 1.80 (s, 3H); 13 C NMR (400 MHz, CDCl3 ) δ 139.4, 139.1, 132.4, 128.9, 128.6, 127.8, 127.8, 123.0, 121.2, 60.4, 49.8, 31.5; EI–HRMS (m/z): M+ calcd for C16 H15 BrN2 , 314.0418; found, 314.0414.
N i-Pr
O PPh2
Gd[N(TMS)2]3 (2.5 mol%), 14 (3.75 mol%), TMSCN (2 eq), 2,6-dimethylphenol (1 eq) EtCN, –40°
NC
O H N PPh2
i-Pr (94%) 98% ee
N-[1-Cyano-2-isopropylcyclopent-2-en-1-yl]-P,P -diphenylphosphinic Amide [General Procedure for the Asymmetric Strecker Reaction of Ketimines Using a Gadolinium Catalyst].86 A solution of tris[N ,N -bis(trimethylsilyl)
THE CATALYTIC ASYMMETRIC STRECKER REACTION
49
amide]gadolinium in THF (0.2 M, 2.0 mL, 0.40 mmol) was added to a solution of ligand 14 (276 mg, 0.6 mmol) in THF (16 mL) at 4◦ , and the mixture was stirred at 50◦ for 1 hour. The solvent was evaporated, and the residue was dried under vacuum for 2 hours at room temperature. The resulting amorphous material was dissolved in propionitrile (18.7 mL), cooled to −40◦ , and TMSCN (4.3 mL, 32 mmol) and 2,6-dimethylphenol (1.95 g, 16 mmol) in THF (6 mL + 2 mL for wash) were added. The mixture was stirred for 0.5 hours at −40◦ , the imine substrate (5.2 g, 16 mmol) was added, and the reaction mixture was stirred for about 2.5 days at −40◦ . Silica gel (50 g) was added at −40◦ to quench the reaction. (Caution! HCN generation! The reaction was quenched in a well-ventilated hood, and the generated HCN was trapped into a saturated NaHCO3 bubbler.). The slurry was filtered and the solid washed with a mixture of CH2 Cl2 (400 mL) and MeOH (20 mL). The combined filtrate was concentrated under vacuum. The solid residue was partially purified by flash column chromatography (EtOAc/hexane = 2 : 1 to EtOAc/MeOH = 20 : 1) to afford the expected product as a white solid (5.9 g) containing chiral ligand 14. To remove ligand 14, toluene (117 mL) was added to the mixture (5.9 g), the mixture was warmed to 80◦ , and to the resulting solution hexane (47 mL) was added. The solution was cooled gradually to room temperature, and the precipitate was filtered off to afford the pure amide product (4.6 g) as a white solid. The filtrate was concentrated under vacuum and toluene (30 mL) was again added at 80◦ , followed by the addition of hexane (12 mL). After gradually cooling to room temperature, the precipitate was filtered to afford an additional crop of amide product (0.7 g). These two crops were combined, and the pure title product was obtained as a white solid [5.3 g, 94% yield, 98% ee (unaffected by the washing process)], mp 132−133◦ ; [α]23 D + 12.9◦ (c 0.51, CHCl3 ); IR (neat) 2230, 1590, 1437, 894 cm−1 ; 1 H NMR (500 MHz, CDCl3 ) δ 7.99 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.56–7.44 (m, 6H), 5.77 (m, 1H), 3.24 (d, J = 5.8 Hz, 1H), 2.73–2.69 (m, 1H), 2.59 (sept, J = 8.2 Hz, 1H), 2.47–2.44 (m, 1H), 2.40–2.34 (m, 1H), 1.22 (d, J = 7.0 Hz, 3H), 1.18 (d, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, CDCl3 ) δ 149.5, 133.6, 132.5, 132.5, 132.4, 132.2, 131.4, 131.3, 131.1, 129.8, 128.8, 128.7, 128.7, 128.6, 120.4, 62.2, 40.2, 29.4, 26.9, 22.9, 22.7; 31 P NMR (CDCl3 ) δ 20.9; LRMS–FAB(m/z): [M + Na]+ 373; HRMS–FAB (m/z): [M + H]+ calcd for C21 H24 N2 OP, 351.1621; found, 351.1635. Chiral ligand 14 was recovered as follows: The filtrate solution containing the ligand was evaporated, and concentrated aqueous HCl (20 mL) was added to the residue. The mixture was heated at 100◦ for 5 hours and poured into water (50 mL). Ligand 14 was extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (30 mL), dried (Na2 SO4 ), and concentrated. Pure ligand 14 was recovered in 90% yield through silica gel column chromatography (EtOAce/hexane = 1 : 1).
50
ORGANIC REACTIONS
NC
O H N PPh2
O
1. conc. HCl 2. PhCOCl, pyridine, DMAP
i-Pr
Ph (—) 98% ee
N
O i-Pr
The enantiomeric excess of the Strecker product was determined by its conversion to the corresponding oxazoline according to the scheme above. Concentrated HCl (1 mL) was added to the cyclopentenyl amide product (10 mg), and the mixture heated at 100◦ for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. Pyridine (0.5 mL), benzoyl chloride (20 µL), and 4-N ,N -dimethylaminopyridine (DMAP, 5 mg) were added at room temperature. After stirring for 1 hour, the reaction mixture was poured into saturated aqueous NH4 Cl (5 mL). The products were extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (5 mL), dried (Na2 SO4 ), and concentrated. Purification by silica gel preparative TLC (EtOAc/hexane = 1 : 4) gave the oxazoline in 98% ee. The enantiomeric excess was determined by chiral HPLC (Daicel Chiralcel OJ-H, i-PrOH/hexane = 1 : 99, 1.0 ml/min) tr = 6.3 min (minor) and 7.2 min (major); [α]23 D +1.5◦ (c 0.95, CHCl3 ); IR (neat) 3436, 2965, 1813, 1650 cm−1 ; 1 H NMR (500 MHz, CDCl3 ) δ 8.03–7.99 (m, 2H), 7.58–7.45 (m, 3H), 5.92 (brt, J = 2.3 Hz, 1H), 2.68–2.55 (m, 2H), 2.44–2.37 (m, 1H), 2.35–2.28 (m, 1H), 2.18–2.09 (m, 1H), 1.03 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H); 13 C NMR (125 MHz, CDCl3 ): δ 180.6, 160.4, 148.2, 132.7, 130.5, 128.8, 127.9, 126.0, 81.4, 36.8, 30.6, 27.5, 22.2, 22.2; LRMS–ESI (m/z): [M + Na]+ 278.0.
N
O PPh2
Gd(OPr-i)3 (0.1 mol%), 14 (0.2 mol%), TMSCN (2.5 mol%), HCN (1.5 eq)
NC
O H N PPh2
EtCN, –40° Cl
Cl
O 1. conc. HCl
O N
2. PHCOCl, pyridine, DMAP
(99%) 93% ee
Ph (—) 93% ee
Cl
4-(4-Chlorophenyl)-4-methyl-2-phenyl-4H -oxazol-5-one [General Procedure for the Catalytic Enantioselective Strecker Reaction of Ketimines Using a Gadolinium Catalyst: Combination of TMSCN and HCN].41 A THF solution of gadolinium triisopropoxide (0.2 M, 18.8 µL, 3.8 µmol) was added to a solution of ligand 14 (3.5 mg, 7.6 µmol) in THF (75 µL) in an ice bath. The mixture was stirred for 40 minutes at 45◦ , and then the solvent was evaporated. After drying the resulting pre-catalyst under vacuum (5 mmHg) for 1 hour, the substrate ketimine (1.33 g, 3.8 mmol) was added as a solid in one portion. Propionitrile (1 mL) was added at −40◦ , and after 30 minutes, TMSCN (12.5 µL,
THE CATALYTIC ASYMMETRIC STRECKER REACTION
51
0.094 mmol) was added. After 5 minutes, a propionitrile stock solution of HCN (4 M, 1.4 mL, 5.6 mmol) was added to start the reaction. After 54 hours at −40◦ the reaction was complete, and silica gel was added. The mixture was carefully concentrated until no HCN gas remained as determined by monitoring with an HCN sensor. The silica gel was removed by filtration, and the filtrate was washed with MeOH/CHCl3 (1 : 9). The combined liquids were removed by evaporation, and the resulting residue was purified by silica gel column chromatography to give the diphenylphosphinic amide intermediate (99% yield). The enantiomeric excess of the product was determined to be 93% after converting to the corresponding oxazoline, 4-(4-chlorophenyl)-4-methyl-2-phenyl-4H -oxazol-5-one, as described above. HPLC (Daicel Chiralcel OJ-H, hexane/i-PrOH = 499 : 1, 1.0 ml/min) tr = 18.7 min (minor) and 22.4 min (major); [α]22 D +120.5◦ (c 1.37, CHCl3 ); IR (neat) 1820, 1656, 1007 cm−1 ; 1 H NMR (CDCl3 ) δ 8.09 (d, J = 8.3 Hz, 2H), 7.62–7.50 (m, 5H), 7.36 (d, J = 8.5 Hz, 2H), 1.86 (s, 3H); 13 C NMR (CDCl3 ) δ 178.8, 160.4, 137.3, 134.3, 133.0, 128.8, 128.1, 126.9, 125.7, 70.2, 27.3; EIMS (m/z): M+ 285; EI–HRMS (m/z): M+ calcd for C16 H12 ClNO2 , 285.0557; found, 285.0564.
43 (9 mol%), 2-furoyl chloride (2 eq), TMSCN (2 eq)
MeO MeO
N
MeO MeO
N
CH2Cl2–toluene, –40°
CN O
O (—) 91% ee
N -(2-Furoyl)-2-cyano-6,7-dimethoxy-1,2-dihydroquinoline [General Procedure for the Catalytic Enantioselective Reissert Reaction of Quinolines].47,48 Diethylaluminum chloride in hexane (30 µL, 0.029 mmol) was added at ambient temperature to a solution of the corresponding ligand (22 mg, 0.029 mmol) in CH2 Cl2 (2.5 mL) and the resulting solution was stirred for 1 hour. This catalyst solution of 43 was cooled to −40◦ , and a solution of 6,7-dimethoxyquinoline (60.5 mg, 0.32 mmol) in CH2 Cl2 (0.5 mL) was added, followed by the addition of 2-furoyl chloride (63 µL, 0.64 mmol). After adding toluene (2.5 mL), TMSCN (85 µL, 0.64 mmol) in toluene (0.5 mL) was added slowly over 24 hours at −40◦ . A saturated aqueous solution of NaHCO3 was added after 40 hours, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated NaCl and dried over Na2 SO4 . Evaporation of the solvent and purification of the resulting crude product by silica gel column chromatography (EtOAc/hexane = 1 : 4) gave pure title compound in 91% ee; HPLC (Daicel Chiralpak AS, hexane/i-PrOH = 70 : 30, 1.0 mL/min) tr = 15.7 and 20.8 min; [α]23 D +267◦ (c 1.0, CHCl3 ); IR (KBr) 3447, 2234, 1655 cm−1 ; 1 H NMR (CDCl3 ) δ 7.41 (m, 1H), 6.92 (d, J = 3.4 Hz, 1H), 6.78–6.72 (m, 2H), 6.47 (m, 1H), 6.43 (brs, 1H), 6.10 (d, J = 6.7 Hz, 1H), 5.96 (dd, J = 6.7, 9.1 Hz, 1H), 3.91 (s, 3H), 3.62 (s, 3H); 13 C NMR (CDCl3 ) δ 158.2, 148.9, 147.4, 146.3, 145.1, 129.2, 127.3, 112.8, 117.7, 116.0, 111.9, 109.4, 107.7, 56.2, 56.0, 42.5;
52
ORGANIC REACTIONS
EIMS (m/z): M+ 310; EI–HRMS (m/z): M+ calcd for C17 H14 N2 O4 , 310.0943; found 310.0957.
N Ph
50 (1 mol%), CH2=CHOCOCl (1.8 eq), TMSCN (2 eq) CH2Cl2, –50°
N Ph
O
CN O
(88%) 95% ee
1-Cyano-1-phenyl-1,2-dihydroisoquinoline-2-carboxylic Acid Vinyl Ester [General Procedure for Generating Quaternary Stereocenters by Catalytic Enantioselective Reissert Reaction of Isoquinolines].49 To a CH2 Cl2 solution (3 mL) of ligand 50 (13.1 mg, 0.015 mmol), a hexane solution of trimethylaluminum (0.98 M, 15.3 µL, 0.015 mmol) was added at ambient temperature and the resulting solution was stirred for 1 hour. A CH2 Cl2 solution of freshly distilled triflic acid (0.0585 M, 250 µL, 0.146 mmol, 97.5 mol% to trimethylaluminum) was then added and the mixture was stirred for 30 minutes. To the catalyst solution was added a solution of 1-phenylisoquinoline (308 mg, 1.5 mmol) in CH2 Cl2 (2.5 mL) at −50◦ , followed by TMSCN (400 µL, 3.0 mmol) and vinyl chloroformate (230 µL, 2.7 mmol). After 48 hours, 5% aqueous NH3 was added. The solution was extracted with CH2 Cl2 and purified by silica gel column chromatography (hexane/EtOAc) to give the title product (88%, 95% ee); HPLC (Daicel Chiralpak AD, hexane/2-propanol = 98 : 2, 1.0 mL/min) tr 12.1 min and 14.3 min; [α]25 D +195◦ (c 0.60, CHCl3 ); IR (neat) 1737, 1652, 1495, 1453, 1382, 1323, 1259, 1194, 1143, 943, 876, 762, 695 cm−1 ;1 H NMR (CDCl3 ) δ 7.62–7.60 (m, 2H), 7.37–7.28 (m, 3H), 7.22–7.03 (m, 5H), 5.83 (d, J = 8.2 Hz, 1H), 4.86 (d, J = 13.4 Hz, 1H), 4.55 (dd, J = 6.6, 2.1 Hz, 1H); 13 C NMR (CDCl3 ): δ 149.5, 142.2, 141.2, 130.3, 129.3, 128.8, 128.7, 128.4, 128.1, 126.9, 125.7, 125.0, 123.4, 117.7, 105.3, 98.2, 62.9; EIMS (m/z): M+ 302; EI-HRMS (m/z): M+ calcd for C19 H14 N2 O2 , 302.1055; found, 302.1055.
N(Pr-i)2 N
O
Et2AlCl (5 mol%), 51 (10 mol%), FmocCl (1.4 eq), TMSCN (2 eq)
O
CH2Cl2, –60°
N(Pr-i)2 NC
N Fmoc (98%) 96% ee
2-Cyano-5-diisopropylcarbamoyl-2H -pyridine-1-carboxylic Acid 9H Fluoren-9-ylmethyl Ester [General Procedure for the Catalytic Enantioselective Reissert Reaction of Pyridine Derivatives].50 Ligand 51 (0.02 mmol) was dried under reduced pressure for 1 hour, and dissolved in CH2 Cl2 (0.5 mL). A hexane solution of diethylaluminum chloride (0.98 M, 10.2 µL, 0.01 mmol) was added and the mixture stirred at room temperature for 1 hour. The resulting mixture was cooled to −60◦ , and a CH2 Cl2 solution of N ,N -diisopropylnicotine amide (0.4 M, 0.5 mL, 0.2 mmol), 9-fluorenylmethoxycarbonyl chloride (FmocCl,
THE CATALYTIC ASYMMETRIC STRECKER REACTION
53
2.8 mmol), and TMSCN (53.3 µL, 4.0 mmol) were added successively. After the reaction was completed, water was added. The products were extracted three times with CH2 Cl2 . The organic phase was washed with brine, dried over Na2 SO4 and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give the title product (98%, 96% ee); HPLC (Daicel Chiralpak AD–H, hexane/2-propanol = 9 : 1, 1.0 mL/min, λ 254 nm) tr = 38.5 min, tr = 42.1 min (minor); [α]20 D −153.33◦ (c 0.93, CHCl3 ); IR (neat) 3462, 3092, 2958, 1736, 1653, 1624, 1442, 1371, 1297, 1255, 1211 cm−1 ; 1 H NMR (DMSO-d6 , 50◦ ) δ 7.86 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 6.4 Hz, 2H), 7.41 (t, J = 7.3 Hz, 2H), 7.33 (t, J = 7.3 Hz, 2H), 6.53 (brd, 1H), 6.26 (d, J = 8.9 Hz, 1H), 5.98 (d, J = 5.8 Hz, 1H), 5.77 (t, J = 8.9 Hz, 1H), 4.74 (brd, 1H), 4.64 (brd, 1H), 4.40 (t, J = 5.8 Hz, 1H), 3.71 (m, 2H), 1.21 (brd, 12H); 13 C NMR (CDCl3 ) δ 166.7, 152.0, 142.9, 142.8, 141.3, 128.0, 127.3, 124.7, 124.6, 120.2, 120.1, 115.7, 69.3, 46.8, 42.8, 21.0, 20.8; ESI–MS (m/z): [M + H]+ 456, [M + Na]+ 478; HRMS–FAB (m/z): [M + H]+ calcd for C28 H30 N3 O3 , 456.2287; found, 456.2285. Cl
N(Pr-i)2 N
Cl
Et2AlCl (10 mol%), 55 (10 mol%), neopentyl–OCOCl (1.4 eq), TMSCN (2 eq)
O
CH2Cl2, –60°
O N(Pr-i)2
NC t-Bu
N O
O
(92%) 91% ee
4-Chloro-2-cyano-5-diisopropylcarbamoyl-2H -pyridine-1-carboxylic Acid 2,2-Dimethylpropyl Ester [General Procedure for the Catalytic Enantioselective Reissert Reaction of a Halide-Substituted Pyridine Derivative].50 Ligand 55 (0.02 mmol) was dried under reduced pressure for 1 hour, and dissolved in CH2 Cl2 (1.5 mL). A hexane solution of diethylaluminum chloride (0.98 M, 20.4 µL, 0.02 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was cooled to −60◦ , and 4-chloro-N ,N -diisopropylnicotinamide in CH2 Cl2 (0.4 M, 0.5 mL, 0.2 mmol), neopentyl chloroformate (2.8 mmol), and TMSCN (53.3 µl, 4.0 mmol) were added successively. After the reaction was completed, water was added. The products were extracted three times with CH2 Cl2 . The organic phase was washed with brine, dried over Na2 SO4 , and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give the title compound (92% yield, 91% ee); HPLC (Daicel Chiralpak OD–H, hexane/ i-PrOH = 20 : 1, 1.0 mL/min, λ 254 nm) tr = 24.4 min (major), tr = 17.3 min (minor); [α]23 D −175.0◦ (c 0.68, CHCl3 ); IR (neat) 3452, 2076, 1634, 759 cm−1 ; 1 H NMR (DMSO-d6 , 50◦ ) δ 6.92 (s, 1H), 6.15 (d, J = 6.9 Hz, 1H), 5.97 (d, J = 6.9, 1H), 4.1-3.5 (brd, 2H), 4.0 (d, J = 10.3 Hz, 1H), 3.9 (d, J = 10.3 Hz, 1H), 1.27 (s, 12H), 0.96 (s, 9H); 13 C NMR (DMSO-d6 ) δ 162.7, 151.5, 128.8, 126.0, 123.5, 116.1, 112.0, 76.5, 50.8, 45.2, 44.4, 31.2, 25.9, 20.0; ESI–MS (m/z): [M + Na]+ 304; HRMS–FAB (m/z): [M + H]+ calcd for C19 H29 ClN3 O3 , 382.1897; found 382.1893.
54
ORGANIC REACTIONS ADDITIONAL CONTRIBUTIONS AFTER MANUSCRIPT SUBMISSION
Due to high interest in the catalytic asymmetric Strecker reaction, several important papers have been published after this manuscript was submitted. In this section, the latest contributions in this field (from November 2006 to August 2007) are surveyed.185 Quinine-derived quaternary ammonium salt 139 catalyzed an asymmetric Strecker reaction using α-amido sulfones 140 as aldimine precursors and acetone cyanohydrin as a cyanide source (Eq. 63).186 Highly reactive aliphatic N -Boc imines were generated in situ in the presence of a stoichiometric base (aqueous K2 CO3 ). Aliphatic substrates, including unstable linear aliphatic substrates, resulted in moderate to high enantioselectivity. Analogous reactions involving aromatic substrates, however, were not described. HN
Boc +
R
HO
CN
139 (10 mol %)
HN
aq. K2CO3–toluene, –20°, 42 h
SO2Tol-p 140
Boc CN
R
(85-95%) 50-88% ee Br–
H HO
N
(Eq. 63)
+ CF3
MeO N 139
A similar approach was reported using chiral phase-transfer catalyst 33 and KCN (1.05 eq) was used as a cyanide source (Eq. 64).187 Chemical yields and enantioselectivities improved compared to the reactions starting from the preformed aldimines.68
HN R
SO2Mes
33 (1 mol%), 2 M aq. KCN (1.05 eq)
SO2Tol-p
toluene–H2O, 0°, 1-2 h
HN R
SO2Mes CN
(93-99%) 85-99% ee
Ar
(Eq. 64) Ar Me + N
I–
Me Ar Ar 33: Ar = 4-CF3C6H4
THE CATALYTIC ASYMMETRIC STRECKER REACTION
55
Jacobsen’s chiral thiourea catalyst (ent-29) was applied to a catalytic asymmetric acylcyanation of N -benzyl aldimines using acylcyanide (141) as acyl and cyanide sources.188 This reaction was later extended to a three-component reaction involving in situ imine generation from aldehydes and amines (Eq. 65).189 Both aromatic and aliphatic substrates resulted in excellent enantioselectivities. Whether the reaction proceeds through initial acylation of the imine by acylcyanide followed by enantioselective cyanation, or initial enantioselective cyanation of the imine by a trace amount of contaminated HCN followed by trapping the resulting amine with acyl cyanide to regenerate HCN, is not clear. The fact that the same enantiomer was produced as the Jacobsen’s Strecker reaction32,33 suggests mechanistic similarities between these two reactions. O O R
1
+ H
R2NH2
O
+ R3
(1 eq)
ent-29 (5 mol%)
R3
CH2Cl2, 5 Å MS, –40°, 36 h
CN
141 (1 eq)
Me t-Bu S N Me N N H H O
N R1
R2
(46-97%) 74-94% ee
CN
N
HO t-Bu ent-29
OCOBu-t
(Eq. 65)
Chiral urea catalyst 142, related to 28 and 29, was synthesized from glucosamine and applied to a catalytic asymmetric Strecker reaction of aromatic aldimines and a ketimine (Eq. 66).190 Enantioselectivity and substrate generality, however, are less satisfactory than with 28 and 29. N Ar
R2
142 (2 mol%), HCN (2 eq)
NC HN R2
toluene, –50°, 24 h
R1 Ar (60-98%) 50-95% ee
R1
OAc AcO AcO
O
H N
N HO O
H N
O
Bu-t Bu-t
N H
Ph
(Eq. 66)
OPiv 142
A significant protecting group effect was observed in the asymmetric Strecker reaction of N -sulfonyl aldimines catalyzed by Mg(OTf)2 –box 143 complex (Eq. 67).191 Although N -p-tosylimines afforded no enantioselectivity, enantioselectivity increased up to 84% by using N -(2-pyridylsulfonyl)imines 144.
56
ORGANIC REACTIONS
The marked difference was attributed to the two-point binding of imine 144 to magnesium with the pyridine nitrogen and sulfonyl oxygen atoms. O N
O S
N
Mg(OTf)2 (10 mol%), 143 (11 mol%), TMSCN (1.3 eq)
O HN
ClCH2CH2Cl, rt
N
CN Ar (99%) 73-84% ee
Ar 144 O
O S
(Eq. 67)
O N
N
Ph
Ph 143
Chiral vanadium–salen complex 145, which was proven to be an efficient catalyst for cyanosilylation of aldehydes, can promote the Strecker reaction of aromatic aldimines and a ketimine with moderate enantioselectivity (Eq. 68).192 N
145 (10 mol%), HCN (1.2 eq)
Ph
Ar
NC HN R2
toluene, –40°, 4 h
R1
t-Bu t-Bu
N O N V+ O O O H H
Ar
R1
(48-100%) 41-81% ee
EtOSO3–
(Eq. 68)
Bu-t Bu-t
145
Although the enantioselectivity and substrate generality are not comparable to those obtained using chiral thiourea catalysts 28 or 29 and the chiral gadolinium catalyst derived from 14, two organocatalysts that promote asymmetric Strecker reactions of ketimines have been reported recently. First, chiral phosphate 146 can activate simple amine-derived ketimines through hydrogen bond formation. The Strecker reaction proceeded at −40◦ giving the corresponding products with moderate enantioselectivity (Eq. 69).193 Only results for aromatic substrates were described. N Ar
Ph
146 (5 mol%), HCN (1.5 eq) toluene, –40°, 3 d
HN Ar
Ph CN
(69-95%) 56-80% ee
CF3
O O P O OH
146
CF3
(Eq. 69)
THE CATALYTIC ASYMMETRIC STRECKER REACTION
57
Bis(pipecolic acid)-derived N -oxide catalyst 147 promotes an enantioselective Strecker reaction of N -phosphinoyl ketimines with high enantioselectivity (Eq. 70).194 A dual activation transition state model is proposed, in which oxygen atoms of the N -oxide act as Lewis bases to activate TMSCN and an amide hydrogen atom acts as a Brønsted acid to activate the imine. A related organocatalyst 148 has been developed for a catalytic enantioselective Strecker reaction of N -tosyl ketimines (Eq. 71).195 The enantioselectivity of catalyst 148 was in the moderate range.
N R1
O PPh2
147 (5 mol%), TMSCN (1.5 eq) toluene, –20°
O NC HN PPh2 R1
R2
(90-99%) 72-92% ee
R2
(Eq. 70) O
HN
NH + N
O−
−
O
+ N O
147
N R1
Ts
148 (5 mol%), 2,5-di-(1-adamantyl)hydroquinone (20 mol%)
NC
R2 R (90-99%) 61-91% ee
TMSCN (1.5 eq), toluene, -20°
R2
O
O + N
NH
HN
O−
NHTs
1
(Eq. 71)
+ N
−O
148
Jacobsen’s catalytic asymmetric Strecker reaction was applied to the synthesis of several isoquinoline alkaloids, such as (−)-calycotomine, (−)-salsolidine, and (−)-carnegine. The chiral stereogenic center was constructed in high efficiency using the catalytic asymmetric Strecker reaction (Eq. 72).196 MeO MeO
N
1. 29 (5 mol%), HCN (1 eq), toluene, –70°, 40 h
MeO
2. TFAA, –60°, 2 h
MeO
N
CF3
CN O 86%, 95% ee MeO MeO
MeO NH
HO (–)-calycotomine
MeO
MeO NH
(–)-salsolidine
MeO
NMe
(–)-carnegine
(Eq. 72)
58
ORGANIC REACTIONS TABULAR SURVEY
The literature has been surveyed up to August 2007. The reactions in the Tables are arranged in order of increasing carbon number of the imines, excluding the protecting group of the nitrogen atom. The reactions of aldimines are listed in Table 1. The reactions of ketimines are listed in Table 2. The catalytic enantioselective Reissert reactions are listed in Table 3. The catalytic enantioselective Strecker reactions of aldimines and ketimines reported in the literature disclosed after submission of this manuscript (from November 2006 to August 2007) are listed in Table 4 and Table 5, respectively. Yields of the products are included in parentheses; (—) indicates that the yield was not reported. Enantiomeric excesses (ee) of the products are also listed. The following abbreviations have been used in the Tables: BINOL BINAP Bn Boc DAHQ Flu Fm fur FmocCl HMDS Mes Mtr Mts naph Ph PMB TADDOL t-Bu Tf TFAA TMS TMSCN Tol Ts
binaphthol 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl benzyl tert-butoxycarbonyl 2,5-di-(1-adamantyl)hydroquinone 9-fluorenyl fluorenylmethyl furyl 9-fluorenylmethoxycarbonyl chloride hexamethyldisilazide mesityl (2,4,6-trimethylphenyl) 4-methoxy-2,3,6-trimethylbenzenesulfonyl 2,4,6-trimethylphenylsulfonyl naphthyl phenyl p-methoxybenzyl [5-(hydroxydiphenylmethyl)-2,2-dimethyl[1,3]dioxolan-4-yl]-diphenylmethanol tert-butyl trifluoromethanesulfonyl trifluoroacetic anhydride trimethylsilyl trimethylsilyl cyanide tolyl p-toluenesulfonyl
59 O
H N N H O
Ph2(O)P
O
8
3
5d: Ar = 2-HO-1-naphthyl
5c: Ar = 2-HO-5-MeOC6H3
O
N H
Y
t-Bu
HO
N H N
3
OMe
O JandaJEL
t-Bu t-Bu
N
6
HN
t-Bu
Ph
O Cl O
N Al
OCOBu-t
2c: R1 = polystyrene–CH2, R2 = H, Y = S
5b: Ar = 2-HO-3,5-Cl2C6H2
Cl Al
O
t-Bu
2b: R1 = R2 = Me, Y = S
OBu-t
O
N
2a: R1 = PhCH2, R2 = H, Y = O
R
1
5a: Ar = 2-HO-3,5-Br2C6H2
t-Bu
P(O)Ph2
Al Cl
N
Ph2(O)P
Ar
1
O
O
P(O)Ph2
R2
O
O
Bu-t
3
NH
H N
CHART 1. CATALYTS AND LIGANDS USED IN TABLES
NH
9
O
O
P
Ph
NH2
OH
O
N 7
N N H
Ph
4: Ar = 4-CF3C6H4
Ar
Ar
Ar Me +N I– Me
Ar
60
HO
P Ph2
O O P(O)(Tol-o)2
Al Cl
P(O)(Tol-o)2
F
HO 13
F
O
O
OH
N
CF3CO2–
16b: R = (CH2)3CH=CH(CH2)3OCH2–JandaJEL
16a: R = H
R
O
10
OH
N H
Ph
Br
Br
+ N O
11
H
H
17
14
Ti
O
O
O i-PrO
O
P(O)Ph2
N Me2
Me2 N
N
P(O)Ph2
Al OTf
N
H
i-PrO O
N N
OMe
CHART 1. CATALYTS AND LIGANDS USED IN TABLES (Continued)
15
12
Sc
Li
+ S
OH
OH
Ph
O–
O–
Ph
P(S)Ar2
P(S)Ar2
OH + S
OH
O
O
18: Ar = 2-EtC6H4
O
O
61
MeO
Ph
O N
HO
22
19
N
H
N
+
Ph
O
N CF3
Br–
t-Bu
O
25
O
O
23
P
–O
OH
O
+ N
O
CF3
Bu-t
EtOSO3–
CF3
Bu-t
+ N
20
H
O
HN
O–
H
O
NH
t-Bu
O
N O N V+
AcO AcO
+ N
O
O–
H N
24
21
OPiv
HO O
NH
N
O
OAc
O + N –O
HN
O
Bu-t Bu-t
H N N H
Ph
62
C4
C3
N
N
N
N
N
N
H
Bn
H
SO2Mes
H
Flu
H
CHPh2
H
Bn
H
Flu
Aldimine
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene–H2O, 0°, 3 h
2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),
CH2Cl2, –40°, 36 h
TMSCN (20 mol%), catalyst 1 (9 mol%),
HCN (1.2 eq, slow addition for 24 h),
catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h
phenol (20 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
MeOH, –75°
HCN (2.0 eq), catalyst 3 (2 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h
phenol (20 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
Conditions
CF3
CN
Bn
I
CN
NHFlu
CN
NHCHPh2
N
O
HN
N
CN
Bn
CN
SO2Mes
I (92), 71
CF3
O
CN
NHFlu
(89), 91
(85), 93
(89), 72
(81), <10
(74), 79
(84), 70
Product(s) and Yield(s) (%), % ee
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES
33
68
26, 27
26, 27
59
33
26, 27
Refs.
63
C5
t-Bu
R
N
t-Bu
H
H
CHPh2
H
CHPh2
N
H
H
Bn
SO2Mes
N
N
N
toluene, –78°, 15 h; then Ac2O, formic acid
polymer-supported catalyst 2c (4 mol%),
HCN (1.3 eq),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene–H2O, 0°, 3 h
2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene, –70°, 15 h; then TFAA
HCN (1.2 eq), catalyst 6 (5 mol%),
toluene, –20°
Ti(OPr-i)4 (15 mol%), ligand 5a (15 mol%),
n-BuOH (1.5 eq, slow addition for 10 h),
TMSCN (2.0 eq),
toluene, –20°
Ti(OPr-i)4 (15 mol%), ligand 5a (15 mol%),
n-BuOH (1.5 eq, slow addition for 10 h),
TMSCN (2.0 eq),
O
t-Bu
H
O
N
CN
CN
CN
Bn
CN
Bn
N
CN
t-Bu
CF3
R
HN
N
N
SO2Mes
t-Bu
CF3
O
t-Bu
CF3
O
CN
NHCHPh2
CN
NHCHPh2
(82), 88
(94), 94
(98), 93
(88), 96
i-Bu
t-Bu
R
(75), 95
(69), 37
(80), 95
(84), 85
33
33
68
33
69
29
29
64
C5
R
O
t-Bu
t-Bu
t-Bu
H
N
N
N
H
Flu
H
+
CHPh2
H
Bn
H2N
HO
Aldimine Ph
O (20 mol%), B Me
N-methylimidazole (15 mol%), CH2Cl2, –45°
(R)-3-BINOL (5 mol%),
(R)-6-BINOL (5 mol%),
HCN (2.0 eq), Zr(OPr-n)4 (5 mol%),
CH2Cl2, –40°, 36 h
TMSCN (20 mol%), catalyst 1 (9 mol%),
HCN (1.2 eq, slow addition for 24 h),
catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h
phenol (20 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
1,1,1-trichloroethane, 4°
Ti(OPr-i)4 (10 mol%), ligand 5a (10 mol%),
n-BuOH (1.5 eq, slow addition for 20 h),
TMSCN (2.0 eq),
toluene, –40°, 22 h
HCN (2.0 eq), catalyst 7 (10 mol%),
MeOH, –75°
HCN (2.0 eq), catalyst 3 (2 mol%),
toluene, –25°, 24 h
HCN (1.5 eq),
N
H Ph
Conditions
I
CN
NHCHPh2
CN
Bn
I
CN
R
HN
HO
CN
I (98), 77
t-Bu
NHFlu
I (100), 85a
I (95), 84
t-Bu
t-Bu
HN
i-Bu
t-Bu
R
(97), 78
(80), 17
(82), 39
(94), 91
(quant), 88
Product(s) and Yield(s) (%), % ee
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
51
26, 27
26, 27
28
37
59
74
Refs.
65
O
O
O N
N
N
N
H
CHPh2
H
Bn
H
Flu
H
CHPh2
toluene, 0°
Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),
TMSCN (2.0 eq), 2-propanol (1.0 eq),
MeOH, –75°
HCN (2.0 eq), catalyst 3 (2 mol%),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
CH2Cl2, –50°, 66 h
polymer-supported catalyst 8 (10 mol%),
TMSCN (4 eq), t-BuOH (1.1 eq),
CH2Cl2, –40°, 36 h
TMSCN (20 mol%), catalyst 1 (9 mol%),
HCN (1.2 eq, slow addition for 24 h),
catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h
phenol (20 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
toluene, –20°
Ti(OPr-i)4 (15 mol%), ligand 5b (15 mol%),
n-BuOH (1.5 eq, slow addition for 10 h),
TMSCN (2.0 eq),
I
CN
Bn
I
CN
NHCHPh2
I (82), 91
O
O
HN
I (97), 86
I (92), 87
O
CN
NHFlu
CN
NHCHPh2
(94), 32
(84), 89
(92), 90
(86), 94
77
59
67
73
26, 27
26, 27
29
66
C6
C5
R
H
O
N
HO
S
S
S
O
N
N
N
N
N
H
Bn
H
Flu
H
CHPh2
H
Bn
H
Flu
Aldimine
Bn
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
toluene–benzene, –65° to 0°
O
CN
(85), 92
—
HN
12 h 2-thienyl
N-methylimidazole (30 mol%),
HN
Time
(90), 89
(83), 98
i-Bu CN
CN
NHFlu
CN
(77), 95
(93), 79
R
R
CN
Bn
NHCHPh2
HN
CN
(R)-3-BINOL (10 mol%),
HO
S
S
S
O
NHFlu
(89), 92
(79), 83
Product(s) and Yield(s) (%), % ee
(R)-6-BINOL (10 mol%),
(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),
catalyst 1 (9 mol%), CH2Cl2, –40°, 58 h
phenol (20 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
toluene, 0°
Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),
TMSCN (2.0 eq), 2-propanol (1.0 eq),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h
phenol (20 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
Conditions
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
67
51, 76
26, 27
77
67
26, 27
Refs.
67
C7
t-Bu
N
N
N
N
H
H
Bn
H
N
N
H
CHPh2
H
Bn
CHPh2
CH2Cl2, –70°, 36 h; then TFAA
HCN (2.0 eq), catalyst 11 (10 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene, –70°, 15 h; then TFAA
HCN (1.2 eq), catalyst 6 (5 mol%),
toluene, –20°
Ti(OPr-i)4 (15 mol%), ligand 5c (15 mol%),
n-BuOH (1.5 eq, slow addition for 10 h),
TMSCN (2.0 eq),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
MeOH, –75°
HCN (2.0 eq), catalyst 3 (2 mol%),
N
O
O
N
I
N
CF3
O
I (95), 92
CF3
CF3
t-Bu
CF3
N
CN
Bn
CN
CN
(74), 95
(91), 95
(95), 89
(69), 78
(85), 90
(86), <10
NHCHPh2
N
CN
O
CN
Bn
CN
NHCHPh2
64
33
69
29
33
33
59
68
C7
N
N
N
N
PMP
H
Flu
H
CHPh2
H
H
Bn
Aldimine
N
O (20 mol%), B Me
Ph
catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h
phenol (20 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
toluene, –40°, 20 h
HCN (2.0 eq), catalyst 7 (10 mol%),
toluene, 0°
Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),
TMSCN (2.0 eq), 2-propanol (1.0 eq),
toluene, 4°
Ti(OPr-i)4 (10 mol%), ligand 5c (10 mol%),
2-propanol (1.5 eq, slow addition for 20 h),
TMSCN (2.0 eq),
MeOH, –25°
HCN (2.0 eq), catalyst 3 (2 mol%),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
toluene, –25°, 24 h
HCN (1.5 eq),
H Ph
Conditions
CN
CN
Bn
PMP
I
CN
NHFlu
CN
NHCHPh2
I (85), 96
I (99), 97b
I
CN
NHCHPh2
HN
HN
(92), 95
(96), 86
(97), >99
(87), 89
(94), 71
Product(s) and Yield(s) (%), % ee
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
26, 27
37
77
28
59
67
74
Refs.
69
F
F
O
N
HO
N
N
H
H
H
CHPh2
H
+ H 2N
HO
toluene, –40°, 23 h
HCN (2.0 eq), catalyst 7 (10 mol%),
CH2Cl2, –70°, 24 h; then TFAA
HCN (2.0 eq), catalyst 11 (10 mol%),
N-methylimidazole (30 mol%), CH2Cl2, –45°
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
HCN (2.0 eq), Zr(OBu-t)4 (10 mol%),
toluene–benzene, –65° to 0°, 12 h
N-methylimidazole (30 mol%),
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),
CH2Cl2, –50°, 60 h
polymer-supported catalyst 8 (10 mol%),
TMSCN (4 eq), t-BuOH (1.1 eq),
CH2Cl2, –40°, 36 h
TMSCN (20 mol%), catalyst 1 (9 mol%),
HCN (1.2 eq, slow addition for 24 h),
F
F
CF3
I (80), 86
O
I
HN
HO
I (98), 87
I (92), 95
CN
CN
NHCHPh2
N
CN
(97), 86
(96), 89
(92), 91
37
64
51
51, 75
73
26, 27
70
C7
Cl
Cl
Cl
Cl
Cl
N
N
N
N
N
H
Flu
H
CH2Cl2, –50°, 59 h
polymer-supported catalyst 8 (10 mol%),
TMSCN (4 eq), t-BuOH (1.1 eq),
catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h
phenol (20 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
toluene, –20°, 20 h
HCN (2.0 eq), catalyst 7 (10 mol%),
MeOH, –75°
HCN (2.0 eq), catalyst 3 (2 mol%),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
toluene, –70°, 15 h; then TFAA
HCN (1.2 eq), catalyst 6 (5 mol%),
Conditions
I (98), 85
Cl
Cl
Cl
Cl
Cl
Cl
CF3
I
N
CN
PMP
CN
NHFlu
CN
NHCHPh2
CN
NHCHPh2
HN
CN
Bn
CN
(92), 95
(88), 81
(94), >99
(60), 86
(69), 85
(92), 81
Product(s) and Yield(s) (%), % ee
HN
O
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
PMP
CHPh2
H
H
Bn
H
Aldimine
73
26, 27
37
59
67
67
69
Refs.
71
Br
Cl
Cl
Cl
N
N
H
H
N H
CHPh2
H
CHPh2
N
HO
CH2Cl2, –70°, 40 h; then TFAA
HCN (2.0 eq), catalyst 11 (10 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene, –70°, 15 h; then TFAA
HCN (1.2 eq), catalyst 6 (5 mol%),
toluene, 0°
Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),
TMSCN (2.0 eq), 2-propanol (1.0 eq),
toluene, 4°
Ti(OPr-i)4 (10 mol%), ligand 5b (10 mol%),
2-propanol (1.5 eq, slow addition for 20 h),
TMSCN (2.0 eq),
MeOH, –75°
HCN (2.0 eq), catalyst 3 (2 mol%),
toluene-benzene, –65° to 0°, 12 h
N-methylimidazole (30 mol%),
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),
I
CF3
CF3
O N
N
CN
O
Cl
I (88), 85
Br
Br
CN
CN
I
CN
(80), >99
(90), 88
(89), 89
(93), 79
(96), 93c
NHCHPh2
CN
NHCHPh2
I (84), 97
Cl
Cl
HN
HO
64
33
69
77
28
59
51, 75
72
C7
F
F
NO2
Br
N
Br
N
Br
N
N
N
H
H
Bn
CHPh2
H
CHPh2
H
H
Aldimine
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
MeOH, –75°
HCN (2.0 eq), catalyst 3 (2 mol%),
toluene, 0°
Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),
TMSCN (2.0 eq), 2-propanol (1.0 eq),
toluene, 4°
Ti(OPr-i)4 (10 mol%), ligand 5b (10 mol%),
2-propanol (1.5 eq, slow addition for 20 h),
TMSCN (2.0 eq),
toluene, –70°, 36 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
Conditions
O
I
F
O2N
F
CN
N CN
HN
Br
CN
CN
Bn
CN
(87), 90
(59), 98
(71), <10
(99), 94d
(88), 95
NHCHPh2
NHCHPh2
Br
N
CF3
I (80), >98
CF3
Br
O
Product(s) and Yield(s) (%), % ee
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
67
59
77
28
33
33
Refs.
73 O
N
N
N
N
H
H
+ H 2N
HO
SO2Mes
H
CHPh2
H
Bn
H
N-methylimidazole (30 mol%), CH2Cl2, –45°
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
HCN (2.0 eq), Zr(OBu-t)4 (10 mol%),
toluene–H2O, 0°, 2 h
2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),
toluene, –40°, 22 h
HCN (2.0 eq), catalyst 7 (10 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene, –70°, 15 h; then TFAA
HCN (1.2 eq), catalyst 6 (5 mol%),
CF3
CF3
CF3
CN
Bn
CN
CN
HN CN
CN
NHSO2Mes
CN
NHCHPh2
N
N
N
HO
O
O
O
(95), 94
(89), 95
(95), 76
(85), 87
(88), 86
(77), 57
51
68
37
33
33
69
74
C8
C7 N
N
H
Bn
H
N
N
N
H
Flu
H
Flu
H
toluene, –70°, 15 h; then TFAA
HCN (1.2 eq), catalyst 6 (5 mol%),
catalyst 1 (9 mol%), CH2Cl2, –40°, 24 h
phenol (50 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
CH2Cl2, –40°, 36 h
TMSCN (20 mol%), catalyst 1 (9 mol%),
HCN (1.2 eq, slow addition for 24 h),
CH2Cl2, –40°, 24 h
TMSCN (2.0 eq), catalyst 1 (9 mol%),
toluene, –40°, 22 h
HCN (2.0 eq), catalyst 7 (10 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
Conditions
N
CF3
O
I (75), 81
CF3
O
I
N
I
CN
Bn
CN
CN
NHFlu
CN
NHFlu
CN
(95), 63
(66), 86
(80), 80
(99), 94
NHCHPh2
(90), 91
Product(s) and Yield(s) (%), % ee
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
CHPh2
Aldimine
69
26, 27
26, 27
26, 27
37
33
Refs.
75 N H
N
N
N
H
Flu
H
CHPh2
H
Bn
CH2Cl2, –70°, 40 h; then TFAA
HCN (2.0 eq), catalyst 11 (10 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
CH2Cl2, –50°, 64 h
polymer-supported catalyst 8 (10 mol%),
TMSCN (4 eq), t-BuOH (1.1 eq),
toluene, –40°, 20 h
HCN (2.0 eq), catalyst 7 (10 mol%),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
CH2Cl2, –70°, 36 h; then TFAA
HCN (2.0 eq), catalyst 11 (10 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
CF3
CF3
N
O
CN
Bn
CN
N
N
CN
CN
CN
NHFlu
CN
NHCHPh2
HN
O
I (94), 87
CF3
O
(98), >99
(97), 96
(100), 83
(96), 80
(55), 87
(99), 95
64
33
73
37
67
64
33
76
C8
PMP
N H
N
HO
N
N
H
H
H
CHPh2
Aldimine
toluene, –70°, 15 h; then TFAA
HCN (1.2 eq), catalyst 6 (5 mol%),
toluene–benzene, –65° to 0°, 12 h
N-methylimidazole (30 mol%),
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),
CH2Cl2, –70°, 40 h; then TFAA
HCN (2.0 eq), catalyst 11 (10 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene, 0°
Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),
TMSCN (2.0 eq), 2-propanol (1.0 eq),
toluene, –40°, 12 h
HCN (2.0 eq), catalyst 7 (10 mol%),
Conditions
O
N
N
I
N
HN
HO
O
PMP
CF3
CF3
CF3
O
CN
CN
CN
CN
CN
NHCHPh2
CN
NHCHPh2
(93), 91
(96), 89
(86), 89
(96), 95
(84), 98
(88), 50
Product(s) and Yield(s) (%), % ee
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
69
51, 75
64
33
77
37
Refs.
77
PMP
PMP
N
N
H
CHPh2
H
Bn
N
Ph
toluene, 0°
Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),
TMSCN (2.0 eq), 2-propanol (1.0 eq),
toluene, 4°
Ti(OPr-i)4 (10 mol%), ligand 5b (10 mol%),
2-propanol (1.5 eq, slow addition for 20 h),
TMSCN (2.0 eq),
toluene, –40°, 28 h
HCN (2.0 eq), catalyst 7 (10 mol%),
MeOH, –75°
HCN (2.0 eq), catalyst 3 (2 mol%),
O (20 mol%), B Me
H Ph
toluene, –25°, 24 h
HCN (1.5 eq),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
CH2Cl2, –70°, 36 h; then TFAA
HCN (2.0 eq), catalyst 11 (10 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
I
I
CN
I (85), 91
CN
NHCHPh2
I (99), 94
PMP
PMP
CN
NHCHPh2
I (95), 40
PMP
HN
CN
Bn
N
I (95), 90
PMP
CF3
O
(99), 84
(90), 96
(97), 93
(98), 95
77
28
37
59
74
67
64
33
78
C8
N
HO
OMe
OMe
PMP
PMP
N
N
N
H
H
H
CHPh2
H
Flu
Aldimine
MeOH, –75°
HCN (2.0 eq), catalyst 3 (2 mol%),
CH2Cl2, –70°, 40 h; then TFAA
HCN (2.0 eq), catalyst 11 (10 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene–benzene, –65° to 0°, 12 h
N-methylimidazole (30 mol%),
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),
CH2Cl2, –50°, 41 h
polymer-supported catalyst 8 (10 mol%),
TMSCN (4 eq), t-BuOH (1.1 eq),
catalyst 1 (9 mol%), CH2Cl2, –40°, 44 h
phenol (20 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
Conditions
I
MeO
MeO
MeO
PMP
CF3
O
O
CN
CN
CF3
HN
HO
I (98), 83
PMP
NHFlu
CN
CN
CN
NHCHPh2
N
N
(97), 76
(93), 93
(82), 80
(96), >99
(99), 93
Product(s) and Yield(s) (%), % ee
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
59
64
33
51, 75
73
26, 27
Refs.
79
O
O
CF3
CF3
NC
H
H
N
N
N
N
H
Bn
H
H
Bn
H
CHPh2
OMe
N
OMe
N
PMP
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
CH2Cl2, –70°, 24 h; then TFAA
HCN (2.0 eq), catalyst 11 (10 mol%),
toluene, 0°
Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),
TMSCN (2.0 eq), 2-propanol (1.0 eq),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
O
O
CF3
CF3
NC
CF3 CN
O N
HN
HN
HN
OMe
CN
CN
Bn
CN
CN
Bn
CN
NHCHPh2
OMe
N
CF3
O
PMP
(88), 93
(53), 96
(75), 97
(92), 80
(84), 83
(93), 77
67
67
67
64
77
33
80
C9
C8
Ph
Ph
O
O
N
HO
N
N
N
H
H
H
SO2Mes
H
CHPh2
H
N
HO
Aldimine
toluene–benzene, –65° to 0°, 12 h
N-methylimidazole (30 mol%),
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),
toluene–H2O, 0°, 2 h
2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),
toluene, –40°, 16 h
HCN (2.0 eq), catalyst 7 (10 mol%),
CH2Cl2, –70°, 48 h; then TFAA
HCN (2.0 eq), catalyst 11 (10 mol%),
toluene–benzene, –65° to 0°, 12 h
N-methylimidazole (30 mol%),
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),
Conditions
Ph
Ph
O
O
CF3 CN
CN
HN
HO
CN
CN
SO2Mes
CN
NHCHPh2
N
HN
O
HN
HO
(55), 83
(81), 90
(96), 79
(88), 90
(89), 80
Product(s) and Yield(s) (%), % ee
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
51, 75
68
37
64
51, 75
Refs.
81
Ph
Ph
Ph
NO2
N
N
O +
N
H
Flu
H
H2N
H
CHPh2
CHPh2
H
HO
toluene, –20°, 24 h
Ti(OPr-i)4 (10 mol%), ligand 5a (10 mol%),
2-propanol (1.5 eq, slow addition for 10 h),
TMSCN (2.0 eq),
CH2Cl2, –50°, 66 h
polymer-supported catalyst 8 (10 mol%),
TMSCN (4 eq), t-BuOH (1.1 eq),
CH2Cl2, –40°, 36 h
TMSCN (20 mol%), catalyst 1 (9 mol%),
HCN (1.2 eq, slow addition for 24 h),
catalyst 1 (9 mol%), CH2Cl2, –40°, 41 h
phenol (20 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
toluene, 4°, 24 h
Ti(OPr-i)4 (10 mol%), ligand 5d (10 mol%),
2-propanol (1.5 eq, slow addition for 20 h),
TMSCN (2.0 eq),
N-methylimidazole (15 mol%), CH2Cl2, –45°
(R)-3-BINOL (5 mol%),
(R)-6-BINOL (5 mol%),
HCN (2.0 eq), Zr(OBu-t)4 (5 mol%),
NO2
I (96), 83
I (78), 92
Ph
Ph
Ph
CN
I
CN
NHCHPh2
CN
NHFlu
CN
NHCHPh2
HN
HO
(>98), 90f
(80), 96
(>98), 84e
(85), 94
29
73
26, 27
26, 27
29
51
82
C9
n-C8H17
n-C8H17
O
N
HO
N
N
N
H
H
H 2N
H
SO2Mes
H
+
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene-H2O, 0°, 2 h
2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
N-methylimidazole (6 mol%), CH2Cl2, –45°
(R)-3-BINOL (2 mol%),
(R)-6-BINOL (2 mol%),
HCN (2.0 eq), Zr(OBu-t)4 (2 mol%),
toluene–benzene, –65° to 0°, 12 h
N-methylimidazole (30 mol%),
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),
Conditions
CF3
n-C8H17
n-C8H17
N
CN
N O
CN
CF3
SO2Mes
CN
CN
CN
HN
O
HN
HO
HN
HO
(88), 91
(88), 97
(65), 90
(86), 84
(72), 74
Product(s) and Yield(s) (%), % ee
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
HO
Aldimine
33
68
33
51
51, 75
Refs.
83
C11
C10
Ph
OMe
N
H
CHPh2
H
N
N
H
Bn
H
SO2Mes
N
N
Ph
O (20 mol%), B Me
H Ph
toluene, –25°, 24 h
HCN (1.5 eq),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
toluene, –20°, 1 h
HCN (2 eq), catalyst 12 (10 mol%),
CH2Cl2, –70°, 40 h; then TFAA
HCN (2.0 eq), catalyst 11 (10 mol%),
toluene, –70°, 15 h; then TFAA
HCN (1.2 eq), catalyst 6 (5 mol%),
toluene–H2O, 0°, 8 h
2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),
toluene, 4°, 24 h
Ti(OPr-i)4 (10 mol%), ligand 5d (10 mol%),
2-propanol (1.5 eq, slow addition for 20 h),
TMSCN (2.0 eq),
I
CF3
I (93), 68
I
I (95), 79
Ph
HN
OMe
N
HN
HN
O
CN
SO2Mes
CN
Bn
CN
Bn
CN
CN
(94), 78g
(71), 85
(80), 86
(93), 93h
(95), 98
NHCHPh2
74
67
80
64
69
68
29
84
C11
N
N
N
H
H
toluene, 0°
Ti(OPr-i)4 (10 mol%), ligand 10 (10 mol%),
TMSCN (2.0 eq), 2-propanol (1.0 eq),
toluene, 4°
Ti(OPr-i)4 (10 mol%), ligand 5c (10 mol%),
2-propanol (1.5 eq, slow addition for 20 h),
TMSCN (2.0 eq),
toluene, –20°, 12 h
HCN (2.0 eq), catalyst 7 (10 mol%),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
toluene, –70°, 15 h; then TFAA
HCN (1.2 eq), catalyst 6 (5 mol%),
toluene, 4°
Ti(OPr-i)4 (10 mol%), ligand 5c (10 mol%),
2-propanol (1.5 eq, slow addition for 20 h),
TMSCN (2.0 eq),
Conditions
CN
CN
Bn
I
CN
NHCHPh2
CN
NHCHPh2
HN
N
I (91), 98
CF3
O
CN
NHCHPh2
(93), 90j
(90), 76
(85), 99
(95), 93
(100), 93i
Product(s) and Yield(s) (%), % ee
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
CHPh2
CHPh2
H
Bn
H
N
Aldimine
77
28
37
67
69
28
Refs.
85
t-Bu
t-Bu
N
HO
O
N
HO
N
N
N
H
H
H
H
Flu
H2N
H
CHPh2
H
+
HO
toluene, –40°, 72 h
HCN (2.0 eq), catalyst 7 (10 mol%),
toluene, –70°, 20 h; then TFAA
HCN (1.3 eq), catalyst 2a (2 mol%),
toluene–benzene, –65° to 0°, 12 h
N-methylimidazole (30 mol%),
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),
N-methylimidazole (30 mol%), CH2Cl2, –45°
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
HCN (2.0 eq), Zr(OBu-t)4 (10 mol%),
toluene–benzene, –65° to 0°, 12 h
N-methylimidazole (30 mol%),
(R)-3-BINOL (10 mol%),
(R)-6-BINOL (10 mol%),
(n-Bu)3SnCN (1.1 eq), Zr(OBu-t)4 (10 mol%),
catalyst 1 (9 mol%), CH2Cl2, –40°, 68 h
phenol (20 mol%, slow addition for 17 h),
TMSCN (2.0 eq),
t-Bu
t-Bu
CF3
O
HN
HO
HN
HO
HN
HO
CN
CN
(80), 85
(89), 97
(85), 87
(83), 85
(98), 91
(95), 89
NHCHPh2
N
CN
CN
CN
CN
NHFlu
37
33
51, 75
51
51, 75
26, 27
86
C13
C12
C11
TBSO
MeO
TBSO
Me2N
N
3
O
H
N
N
H
+ H 2N
HO
H
CHPh2
H toluene, –40°, 38 h
HCN (2.0 eq), catalyst 7 (10 mol%),
toluene, –40°
HCN (1.5 eq), catalyst 9 (10 mol%),
N-methylimidazole (15 mol%), CH2Cl2, –45°
(R)-3-BINOL (5 mol%),
(R)-6-BINOL (5 mol%),
HCN (2.0 eq), Zr(OBu-t)4 (5 mol%),
toluene-H2O, 0°, 8 h
2 M aq KCN (1.5 eq), catalyst 4 (1 mol%),
toluene, –20°, 24 h
Ti(OPr-i)4 (15 mol%), ligand 5a (15 mol%),
n-BuOH (1.5 eq, slow addition for 10 h),
TMSCN (2.0 eq),
Conditions
TBSO
MeO
TBSO
Me2N
HN
CN
Bn
HN
HO
CN
(80), 91
(93), 76
(98), 88
(70), 94
CN
(98), 97
NHCHPh2
HN
CN
SO2Mes
CN
NHCHPh2
Product(s) and Yield(s) (%), % ee
TABLE 1. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES (Continued)
CHPh2
H
Bn
SO2Mes
N
Aldimine
37
67
51
68
29
Refs.
87
After recrystallization from hexanes, the product yield was 55%, >99% ee.
After recrystallization, the product yield was 87%, >99% ee.
j
g
After recrystallization, the product yield was 80%, >99% ee.
After recrystallization, the product yield was 61%, 97% ee.
f
i
After recrystallization, the product yield was 87%, 97% ee.
e
h
After recrystallization, the product yield was 93%, >99% ee.
After recrystallization, the product yield was 80%, 97% ee.
d
After recrystallization, the product yield was 82%, >99% ee.
After recrystallization, the product yield was 85%, >99% ee.
c
After recrystallization, the product yield was 97%, 85% ee.
b
a
88
C6
C5
t-Bu
S
N
S
O
N
P(O)Ph2
P(O)Ph2
P(O)Ph2
Bn
N
N
N
P(O)Ph2
Ketimine
toluene, –75°, 15 h
HCN (1.25 eq), catalyst 2a (2 mol%),
CH3CH2CN, –40°, 10 h
Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
CH3CH2CN, –40°, 3 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
HCN (1.5 eq), TMSCN (5 mol%),
CH3CH2CN, –40°, 21 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
CH3CH2CN, –40°, 6 h
Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
CH3CH2CN, –40°, 2.5 h
Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
Conditions
t-Bu
I
S
CN
NHBn
NC NHP(O)Ph2
I (99), 99
S
NC NHP(O)Ph2
O
NC NHP(O)Ph2
NC NHP(O)Ph2
(98), 70
(94), 96
(93), 93
(98), 98
(91), 80
Product(s) and Yield(s) (%), % ee
TABLE 2. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES
38
40
41
40
40
40
Refs.
89
C8
C7
N
N
N
N
P(O)Ph2
Bn
P(O)Ph2
N
toluene, –20°, 9 h
TMSCN (2 eq), catalyst 12 (10 mol%),
toluene, –20°, 1 h
TMSCN (2 eq), catalyst 14 (10 mol%),
toluene, –75°, 24 h
HCN (1.25 eq), catalyst 2a (2 mol%),
toluene, –75°, 30 h
HCN (1.25 eq), catalyst 2a (2 mol%),
CH3CH2CN, –40°, 0.25 h
Gd(OPr-i)3 (5 mol%), ligand 13 (10 mol%),
HCN (1.5 eq), TMSCN (20 mol%),
CH3CH2CN, –40°, 16 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
CH3CH2CN, –40°, 43 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
I
I (>95), 88
I
I (99), 94
N
CN
NHBn
CN
NHBn
CN
NH
NC NHP(O)Ph2
(80), 56
(97), 90
(97), 85
(90), 95
NC NHP(O)Ph2 (73), 90
80
79
38
38
41
40
40
90
C8
Cl
O2 N
N
N
N
N
CH3CH2CN, –40°, 54 h
ligand 13 (0.2 mol%),
Gd(OPr-i)3 (0.1 mol%),
HCN (1.5 eq), TMSCN (2.5 mol%),
CH3CH2CN, –40°, 13 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
toluene, –75°, 80 h
HCN (1.25 eq), catalyst 2a (2 mol%),
CH3CH2CN, –40°, 19 h
ligand 13 (0.2 mol%),
Gd(OPr-i)3 (0.1 mol%),
HCN (1.5 eq), TMSCN (5 mol%),
CH3CH2CN, –40°, 30 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
toluene, –75°
HCN (1.25 eq), catalyst 2a (2 mol%),
Conditions
I (97), 90
I (99), 93
Cl
O2N
CN
N
CN
NHBn
I
Time 36 h 50 h 30 h 40 h
R OMe CF3 t-Bu Br
(93), 95
(quant), 93b
(94), 92
R
NC NHP(O)Ph2
I
NC NHP(O)Ph2
H
Product(s) and Yield(s) (%), % ee
TABLE 2. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES (Continued)
R
P(O)Ph2
Bn
P(O)Ph2
Ketimine
(95), 92a
(95), 89
(95), 92
(97), 93
41
40
38
41
40
38
Refs.
91
Br
Br
N
N
Br
N
N
Bn
P(O)Ph2
P(O)Ph2
Bn
Bn
N
CH3CH2CN, –40°, 2 days
ligand 13 (3.75 mol%),
Gd(HMDS)3 (2.5 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (2.0 eq),
CH3CH2CN, –40°, 3 days
Gd(OPr-i)3 (5 mol%), ligand 13 (10 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
CH3CH2CN, –40°, 52 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
toluene, –75°, 90 h
HCN (1.25 eq), catalyst 2a (2 mol%),
toluene, –75°, 60 h
HCN (1.25 eq), catalyst 2a (2 mol%),
toluene, –75°, 80 h
HCN (1.25 eq), catalyst 2a (2 mol%),
Br
I
NC NHP(O)Ph2
(quant), 93c
(94), 96
(99), 97
(45), 42
(97), 91
NC NHP(O)Ph2
CN
NHBn
CN
NHBn
Br
I (99), 98
Br
CN
NHBn
86
86
40
38
38
38
92
C9
CF3
MeO
N
N
N
N
Bn
Bn
P(O)Ph2
N
N
P(O)Ph2
Bn
Ketimine
CH3CH2CN, –40°, 31 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
toluene, –75°, 17 h
HCN (1.25 eq), catalyst 2a (2 mol%),
toluene, –75°, 65 h
HCN (1.25 eq), catalyst 2a (2 mol%),
toluene, –75°, 60 h
HCN (1.25 eq), catalyst 2a (2 mol%),
CH3CH2CN, –40°, 38 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
toluene, –75°, 80 h
HCN (1.25 eq), catalyst 2a (2 mol%),
Conditions
CF3
MeO
NC NHP(O)Ph2
CN
NH
CN
NHBn
CN
NHBn
NC NHP(O)Ph2
CN
NHBn
(97), 95
(96), 69
(quant), 95a
(98), 88
(89), 87
(98), 91
Product(s) and Yield(s) (%), % ee
TABLE 2. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES (Continued)
40
38
38
38
40
38
Refs.
93
C10
Ph
Ph
F
N
N
P(O)Ph2
N P(O)Ph2
O
N
P(O)Ph2
N
P(O)Ph2
CH3CH2CN, –40°, 38 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
toluene, –75°, 17 h
HCN (1.25 eq), catalyst 2a (2 mol%),
CH3CH2CN, –40°, 48 h
Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
CH3CH2CN, –40°, 1.3 h
ligand 13 (1 mol%),
Gd(OPr-i)3 (0.5 mol%),
HCN (1.5 eq), TMSCN (5 mol%),
CH3CH2CN, –40°, 83 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.1 eq),
CH3CH2CN, –40°, 8 h
Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
Ph
Ph
CN
NH
NHP(O)Ph2
O
NC NHP(O)Ph2
NC
I
NC NHP(O)Ph2
I (96), 93
F
(93), 96
(98), 41
(98), 97
(100), 98d
NC NHP(O)Ph2 (94), 88
40
38
40
41
40
40
94
C12
C10
N
P(O)Ph2
P(O)Ph2
CH3CH2CN, –40°, 16 h
Gd(OPr-i)3 (2.5 mol%), ligand 13 (5 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
toluene, –75°, 65 h
HCN (1.25 eq), catalyst 2a (2 mol%),
CH3CH2CN, –40°, 67 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
CH3CH2CN, –40°, 22 h
Gd(OPr-i)3 (1 mol%), ligand 13 (2 mol%),
2,6-dimethylphenol (1.0 eq),
TMSCN (1.5 eq),
After recrystallization from hexanes, the product yield was 79%, >99.9% ee.
After recrystallization from hexanes, the product yield was 76%, >99.9% ee.
After recrystallization from CHCl3–hexane, the product yield was 93%, >99% ee.
b
c
d
After recrystallization from hexanes, the product yield was 75%, >99.9% ee.
N
N
P(O)Ph2
Conditions
NC NHP(O)Ph2
CN
NH
(73), 53
(97), 89
(99), 86
(92), 92
NC NHP(O)Ph2
NC NHP(O)Ph2
Product(s) and Yield(s) (%), % ee
TABLE 2. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES (Continued)
a
N
Ketimine
40
38
40
40
Refs.
95
C10
C9-10
C8
C7
O
O
R
N
N
4.0 4.0 2.0
Br MeO CH2Cl2–toluene
CH2Cl2
CH2Cl2–toluene
CH2Cl2–toluene
40 h
112 h
64 h
64 h
Time
CH2Cl2–toluene, –40°, 64 h
2-furoyl chloride (2.0 eq),
2. Catalyst 16a (9 mol%),
1. TMSCN (2.0 eq), slow addition for 12 h
4.0
Cl
Solv
2-furoyl chloride (x eq), –40˚
TMSCN (x eq), catalyst 16a (9 mol%),
CH2Cl2, –60°, 5 h
ligand 15 (10 mol%), ROCOCl (1.4 eq),
TMSCN (2.0 eq), Et2AlCl (5 mol%),
H
N
Me
CH2Cl2, –60°, 5 h
ligand 15 (10 mol%), FmocCl (1.4 eq),
x
N
Me
N
OMe
TMSCN (2.0 eq), Et2AlCl (5 mol%),
Conditions
O
O
R
NC
NC
O
N
N
OR
O
(74), 89
(63), 67
(57), 67
N
N
O
CN
CN
Me
O
O Me
OMe
OCH2Flu
(91), 85
O
O
N
O
(89), 93
(98), 91
(77), 83
Fm
Me
R
(85), 57a
Product(s) and Yield(s) (%), % ee
TABLE 3. CATALYTIC ENANTIOSELECTIVE REISSERT REACTIONS
R
O
O
Substrate
47, 48
47, 48
50
50
Refs.
96
C11
C10
Me2N
MeO
MeO
N
N
N
N
N
Substrate
CH2Cl2–toluene, –40°, 40 h
2-furoyl chloride (2.0 eq),
2. Catalyst 16a (9 mol%),
1. TMSCN (2.0 eq), slow addition for 12 h
CH2Cl2–toluene, –40°, 40 h
2-furoyl chloride (2.0 eq),
2. Catalyst 16a (9 mol%),
1. TMSCN (2.0 eq), slow addition for 12 h
CH2Cl2, –60°, 48 h
vinyl chloroformate (1.8 eq),
TMSCN (2.0 eq), catalyst 17 (2.5 mol%),
CH2Cl2, –78°, 24 h
acetyl chloride (1.1 eq),
TMSCN (2.0 eq), catalyst 16a (9 mol%),
CH2Cl2–toluene, –40°, 40 h
2-furoyl chloride (2.0 eq),
TMSCN (2.0 eq), catalyst 16a (9 mol%),
Conditions
MeO
MeO
MeO
O
O
O
O
N
N
O
O
O
CN
CN O
N
N
O
CN
N
CN
CN
(73), 75
(71), 54
(72), 89
(99), 91
(88), 89
Product(s) and Yield(s) (%), % ee
TABLE 3. CATALYTIC ENANTIOSELECTIVE REISSERT REACTIONS (Continued)
47, 48
47, 48
49
47, 48
48
Refs.
97
C15
C12
C11-12
Cl
N
X
N
Cl
O
O
R
N
N(allyl)2
N(Pr-i)2
N(Pr-i)2
R
N
N
CH2Cl2, –40°, 40 h
2-furoyl chloride (4.0 eq),
polymer-supported catalyst 16b (3 mol%),
TMSCN (4.0 eq),
CH2Cl2, –40°, 40 h
2-furoyl chloride (2.0 eq),
TMSCN (2.0 eq), catalyst 16a (1 mol%),
CH2Cl2, –60°, 27 h
neopentyl-OCOCl (1.4 eq),
ligand 18 (10 mol%),
TMSCN (2.0 eq), Et2AlCl (10 mol%),
CH2Cl2, –60°, 5 h
ligand 15 (10 mol%), ROCOCl (1.4 eq),
TMSCN (2.0 eq), Et2AlCl (5 mol%),
CH2Cl2, –60°, 48 h
vinyl chloroformate (1.8 eq),
TMSCN (2.0 eq), catalyst 17 (2.5 mol%),
CH2Cl2, –60°, 48 h
vinyl chloroformate (1.8 eq),
TMSCN (2.0 eq), catalyst 17 (2.5 mol%),
O
O
Cl
N
X
N
I (92), 86
Cl
NC
NC
R
R
O N(Pr-i)2
N(Pr-i)2
O
O
O
N
I
O
CN
N(allyl)2
OCH2Bu-t
R
O
CN O
N
CN O
N
(88), 87
(80), 84
(84), 73
(98), 88
36 h
27 h
Time
(91), 93
Br
Cl
X
Fm
(89), 86
(92), 91
(98), 96
neopentyl (98), 93
R
Me
H
R
CH2OMe
Et
R
48
48
50
50
49
49
98
C24
C16
C15
a
Ph
N
N Br
N CH2Cl2, –60°, 48 h
vinyl chloroformate (1.8 eq),
TMSCN (2.0 eq), catalyst 17 (2.5 mol%),
CH2Cl2, –60°, 48 h
vinyl chloroformate (1.8 eq),
TMSCN (2.0 eq), catalyst 17 (2.5 mol%),
CH2Cl2, –40°, 72 h
vinyl chloroformate (1.8 eq),
TMSCN (2.0 eq), catalyst 17 (1 mol%),
CH2Cl2, –50°, 48 h
vinyl chloroformate (1.8 eq),
TMSCN (2.0 eq), catalyst 17 (1 mol%),
Conditions
PhC(O)O
PhC(O)O
Ph
Ph
CN O
N
CN O Br
N
CN O
N
O
O
O
N CN O
O
(95), 92
(59), 93
(88), 95
(94), 94
Product(s) and Yield(s) (%), % ee
TABLE 3. CATALYTIC ENANTIOSELECTIVE REISSERT REACTIONS (Continued)
After recrystallization, the product yield was 42%, >99% ee.
PhC(O)O
PhC(O)O
Ph
N
Substrate
49
49
49
49
Refs.
99
C5
C4
C3
C2
t-Bu
SO2Tol-p
Boc
HN
O + PhCH2NH2
SO2Tol-p
Boc
H
H
N Bn
SO2Tol-p
HN Mts
HN
SO2Tol-p
Boc
SO2Tol-p
Boc
HN
HN
Substrate
toluene–H2O, –20°, 42 h
catalyst 19 (10 mol%),
Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),
toluene, –40°, 36 h
catalyst ent-2b (5 mol%),
Acetyl cyanide (1.5 eq),
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
toluene–H2O, 0°, 1.5 h
KCN (1.05 eq), catalyst 4 (1 mol%),
toluene–H2O, –20°, 42 h
catalyst 19 (10 mol%),
Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),
toluene–H2O, –20°, 42 h
catalyst 19 (10 mol%),
Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),
toluene–H2O, –20°, 42 h
catalyst 19 (10 mol%),
Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),
Conditions
I
N
CN
Bn
CN
Mts
t-Bu
CN
NHBoc
I (92), 92
O
HN
CN
NHBoc
CN
NHBoc
CN
NHBoc
(85), 88
(87), 95
(99), 97
(92), 82
(88), 80
(85), 78
Product(s) and Yield(s) (%), % ee
TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007
186
189
188
187
186
186
186
Refs.
100
C5
N
O + PhCH2NH2
Ph
SO2Tol-p
Boc
H
H
H
H
N Bn
SO2Tol-p
HN Mtr
SO2Tol-p
HN Mts
HN
n-Bu
i-Bu
i-Bu
i-Bu
t-Bu
t-Bu
t-Bu
N Bn
Substrate
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
toluene–H2O, 0°, 1 h
KCN (1.05 eq), catalyst 4 (1 mol%),
toluene–H2O, 0°, 1 h
KCN (1.05 eq), catalyst 4 (1 mol%),
toluene–H2O, –20°, 42 h
catalyst 19 (10 mol%),
Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),
toluene, –40°, 4 h
HCN (1.2 eq), catalyst 20 (10 mol%),
toluene, –40°, 36 h
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
Conditions
N
N
N
HN
HN
n-Bu
CN
CN
Bn
CN
Bn
Ph
CN
Bn
CN
Mtr
CN
Mts
CN
NHBoc
HN
O
i-Bu
i-Bu
i-Bu
t-Bu
t-Bu
O
t-Bu
O
(76), 94
(99), 93
(96), 91
(90), 68
(85), 16
(46), 94
(62), 96
Product(s) and Yield(s) (%), % ee
TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007 (Continued)
188
187
187
186
192
189
188
Refs.
101
C7
C6
C5
t-Bu
t-Bu
n-Bu
O
O
H
O
SO2Tol-p
Boc
H
H
N Bn
N
H
+ PhCH2NH2
+ PhCH2NH2
N Bn
H
HN
O
toluene–H2O, –20°, 42 h
catalyst 19 (10 mol%),
Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),
toluene, –40°, 36 h
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
toluene, –70°, 24 h
HCN (2 eq), catalyst 21 (2 mol%),
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
toluene, –40°, 36 h
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
N
I
N
CN
NHBoc
CN
Bn
CN
CN
Bn
CN
Bn
HN
O
O
O
O
N
I (97), 92
t-Bu
n-Bu
O
(95), 50
(87), 96
(87), 50
(94), 89
(75), 88
187
189
188
190
188
189
102
C7
H
N Bn
H
N Bn
H
N Bn
HN SO2Tol-p
Boc
Substrate
SO2Tol-p
HN Mts
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
toluene–H2O, –20°, 42 h
catalyst 19 (10 mol%),
Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
toluene, –50°, 24 h
HCN (2 eq), catalyst 21 (2 mol%),
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
toluene–H2O, 0°, 1.5 h
KCN (1.05 eq), catalyst 4 (1 mol%),
Conditions
N
O
O
N
N
HN
O
HN
CN
Bn
CN
Bn
CN
Bn
CN
Bn
CN
Mts
(94), 96
CN
NHBoc
(82), 98
(60), 47
(88), 92
(99), 97
(95), 72
Product(s) and Yield(s) (%), % ee
TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007 (Continued)
188
186
188
190
188
187
Refs.
103
Ph
Ar
Ar
O
N
N
H
N
O
H
H
Bn
N
+ PhCH2NH2
+ RNH2
H
S
O
toluene, –40°, 36 h
catalyst ent-2b (5 mol%),
n-C6H13COCN (1.5 eq),
toluene, –40°, 36 h
catalyst ent-2b (5 mol%),
Acetyl cyanide (1.5 eq),
22 (11 mol%), ClCH2CH2Cl, rt
TMSCN (1.3 eq), Mg(OTf)2 (10 mol%),
toluene, 24 h
catalyst 21 (2 mol%),
HCN (2 eq),
toluene, –40°, 4 h
catalyst 20 (10 mol%),
HCN (1.2 eq),
Ph
Ph
5
O
O
CN
CN
Bn
N
CN
R
HN
N
HN
O
Ar
Ar
HN
CN
Bn
CN
S
O
(95), 94 (93), 94 (92), 94 (83), 80
4-MeOC6H4CH2 4-ClC6H4CH2 1-naphCH2 2-furCH2
(76), 74
(88), 88
(67), 0
4-O2NC6H4
–50°
n-C5H11
allyl
R
(77), 84
4-BrC6H4
–50°
(99), 75
(83), 74
3-BrC6H4
–50°
(84), 88
N
(69), 72
(72), 84
Ph 2-BrC6H4
Ph
–50° –50°
(86), 95
Ar
(48), 41
4-ClC6H4
–70°
(76), 57
3-ClC6H4
Temp
(88), 75
Ph
Ar
189
189
191
190
192
104
C7
Cl
Cl
Cl
Cl
H
N Bn
N
O
O
N
H
S
H
H
Bn
O N
+ PhCH2NH2
Substrate
O
O
Ph
Ph
Ph
OH OH
Ph
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
22 (11 mol%), ClCH2CH2Cl, rt
TMSCN (1.3 eq), Mg(OTf)2 (10 mol%),
toluene, –40°, 36 h
catalyst ent-2b (5 mol%),
Acetyl cyanide (1.5 eq),
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
TADDOL =
toluene, –40°, 3 d
HCN (1.5 eq), TADDOL (10 mol%),
Conditions
Cl O
O
N
CN
Bn
HN
I
O
Cl
N
I (78), 92
Cl
Cl
HN
O
CN
S
CN
Bn
CN
Bn
(86), 98
N
(87), 98
(—), 32
(99), 72
Product(s) and Yield(s) (%), % ee
TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007 (Continued)
188
191
189
188
193
Refs.
105
C8
R
Ph
Ph
Ph SO2Tol-p
Boc
SO2Tol-p
6
N
O
N
H
S
H
Bn
SO2Tol-p
HN Mtr
6
HN Mts
O
SO2Tol-p
HN Mtr
SO2Tol-p
HN Mts
HN
N
22 (11 mol%), ClCH2CH2Cl, rt
TMSCN (1.3 eq), Mg(OTf)2 (10 mol%),
toluene, –40°, 3 d
HCN (1.5 eq), TADDOL (10 mol%),
toluene–H2O, 0°, 1 h
KCN (1.05 eq), catalyst 4 (1 mol%),
toluene–H2O, 0°, 1 h
KCN (1.05 eq), catalyst 4 (1 mol%),
toluene–H2O, 0°, 1 h
KCN (1.05 eq), catalyst 4 (1 mol%),
toluene–H2O, 0°, 1 h
KCN (1.05 eq), catalyst 4 (1 mol%),
toluene–H2O, –20°, 42 h
catalyst 19 (10 mol%),
Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),
R
Ph
Ph
Ph
6
HN
6
HN
CN
Mtr
CN
Mts
HN
O
HN
CN
Mtr
CN
Mts
HN
HN
CN
NHBoc
O
CN
S
CN
Bn
N
(68), 30
(96), 89
(96), 84
(86), 86
(93), 85
(95), 79
(99), 72 (99), 84
Me MeO
R 191
193
187
187
187
187
186
106
C8
Ar
Ar
N
N
MeO
MeO
MeO
H
H
Ph
O
N
N
H + PhCH2NH2
H
Bn
H
Bn
Substrate
toluene, –40°, 4 h
HCN (1.2 eq), catalyst 20 (10 mol%),
toluene, –50°, 24 h
HCN (2 eq), catalyst 21 (2 mol%),
toluene, –40°, 36 h
catalyst ent-2b (5 mol%),
Acetyl cyanide (1.5 eq),
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
toluene, –40°, 3 d
HCN (1.5 eq), TADDOL (10 mol%),
Conditions
Ar
Ar
HN
HN
CN
CN
I (88), 92
MeO
MeO
Ph
I
O N
HN
CN
Bn
CN
Bn
(98), 64 (96), 66 (79), 82
2-MeOC6H4 3-MeOC6H4 4-MeOC6H4
(46), 52 (70), 59 (50), 51 (65), 31
3-MeOC6H4 4-MeOC6H4 3-CF3C6H4
(77), 74 3-MeC6H4 2-MeC6H4
(65), 70 4-MeC6H4
Ar
(83), 75
(93), 78
3-MeC6H4 4-MeC6H4
(81), 69
2-MeC6H4
Ar
(95), 96
(93), 22
Product(s) and Yield(s) (%), % ee
TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007 (Continued)
192
190
189
188
193
Refs.
107
C9
Ph
Ph
Ph
Ph
Ph
Ph
SO2Tol-p
Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),
Cbz
O
N
H
H
Bn
+ PhCH2NH2
SO2Tol-p
HN Mts
SO2Tol-p
HN Mtr
SO2Tol-p
toluene, –40°, 36 h
catalyst ent-2b (5 mol%),
Acetyl cyanide (1.5 eq),
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
toluene–H2O, 0°, 2 h
KCN (1.05 eq), catalyst 4 (1 mol%),
toluene–H2O, 0°, 1 h
KCN (1.05 eq), catalyst 4 (1 mol%),
toluene–H2O, 0°, 1 h
KCN (1.05 eq), catalyst 4 (1 mol%),
toluene–H2O, –20°, 42 h
catalyst 19 (10 mol%),
toluene–H2O, –20°, 42 h
catalyst 19 (10 mol%),
Acetone cyanohydrin (2 eq), K2CO3 (5.0 eq),
SO2Tol-p
Boc
HN Mts
HN
HN
N
HN
HN
O
CN
CN
Bn
CN
Mts
CN
Mtr
CN
Mts
CN
NHCbz
HN
I (82), 92
Ph
Ph
Ph
Ph
Ph
NHBoc
(83), 94
(99), 98
(98), 96
(99), 94
(79), 40
(95), 68
189
188
187
187
187
186
186
108
C11
Ar
N
O
H
S
N
O
H
N
N
N
O
N
H
H
H
H
Bn
+ PhCH2NH2
Ph
Substrate
toluene, –50˚, 24 h
HCN (2 eq), catalyst 21 (2 mol%),
22 (11 mol%), ClCH2CH2Cl, rt
TMSCN (1.3 eq), Mg(OTf)2 (10 mol%),
toluene, –40˚, 4 h
HCN (1.2 eq), catalyst 20 (10 mol%),
toluene, –50°, 24 h
HCN (2 eq), catalyst 21 (2 mol%),
toluene, –40°, 36 h
catalyst ent-2b (5 mol%),
Acetyl cyanide (1.5 eq),
toluene, –40°
catalyst ent-2b (1 mol%),
Acetyl cyanide (1.5 eq),
Conditions
Ar
HN
O
O
I
N
CN
N
HN CN
CN
CN
Bn
Ph
(78), 80
1-naph (99), 75
2-naph (99), 73
Ar
(46), 72
(73) , 76
(92), 96
Product(s) and Yield(s) (%), % ee
HN
HN
CN
S
I (92), 94
O
TABLE 4. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF ALDIMINES: NOV. 2006 TO AUG. 2007 (Continued)
190
191
192
190
189
188
Refs.
109
C14
C12
Cbz
MeO
MeO
MeO
t-Bu
N
N
N
H
H
Bn
N
H
Ph
SO2Tol-p
HN Mts
N
toluene–H2O, 0°, 1 h
KCN (1.05 eq), catalyst 4 (1 mol%),
toluene, –40°, 3 d
HCN (1.5 eq), TADDOL (10 mol%),
2. TFAA
toluene, –70°, 40 h
1. HCN (1.5 eq), catalyst 2b (5 mol%),
toluene, –50°, 24 h
HCN (2 eq), catalyst 21 (2 mol%),
toluene, –50°, 24 h
HCN (2 eq), catalyst 21 (2 mol%),
toluene, –40°, 4 h
HCN (1.2 eq), catalyst 20 (10 mol%),
Cbz
MeO
MeO
MeO
MeO
MeO
t-Bu
N
HN
O
CN
Bn
CN
Mts
CN
N
NH
CN
Ph
CN
HN
CN
HN
HN
(86), 95
(99), 99
(93), 22
CF3
(97), 86
(82), 84
(82), 34
187
193
196
190
190
192
110
C8
C7
C6
Ph
Ph
N
t-Bu
t-Bu
N
N
S
O
N
N
N
N
N
P(O)Ph2
Ts
P(O)Ph2
Ph
Ts
P(O)Ph2
Br
Substrate
toluene, –40°, 4 h
HCN (1.2 eq), catalyst ent-20 (10 mol%),
toluene, –50°, 24 h
HCN (2 eq), catalyst 21 (2 mol%),
toluene, –20°, 196 h
TMSCN (1.5 eq), catalyst 23 (5 mol%),
toluene, –20°, 80 h
catalyst 24 (5 mol%),
TMSCN (1.5 eq), DAHQ (20 mol%),
toluene, –20°, 120 h
TMSCN (1.5 eq), catalyst 23 (5 mol%),
toluene, –20°, 70 h
catalyst 24 (5 mol%),
TMSCN (1.5 eq), DAHQ (20 mol%),
toluene, –20°, 108 h
TMSCN (1.5 eq), catalyst 23 (5 mol%),
Conditions
Ph
Ph
HN
CN
NHBn
CN
(63), 50
(91), 72
(92), 81
(92), 77
(95), 77
(98), 80
(92), 43
Br
NC HN P(O)Ph2
S
NC HN Ts
O
NC HN P(O)Ph2
N
t-Bu
NC HN Ts
t-Bu
NC HN P(O)Ph2
Product(s) and Yield(s) (%), % ee
TABLE 5. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES: NOV. 2006 TO AUG. 2007
192
190
194
195
194
195
194
Refs.
111
C9
Br
X
Ph
Ar
N
N
N
Ts
N
PMB
Ts
PMB
N
N
Ts
PPh2
O
toluene, –40°, 3 d
HCN (1.5 eq), catalyst 25 (5 mol%),
toluene, –20°, 68 h
catalyst 24 (5 mol%),
TMSCN (1.5 eq), DAHQ (20 mol%),
toluene, –40°, 3 d
HCN (1.5 eq), catalyst 25 (5 mol%),
toluene, –20°, 80 h
catalyst 24 (5 mol%),
TMSCN (1.5 eq), DAHQ (20 mol%),
toluene, –20°, 68 h
catalyst 24 (5 mol%),
TMSCN (1.5 eq), DAHQ (20 mol%),
toluene, –20°
TMSCN (1.5 eq), catalyst 23 (5 mol%),
NHP(O)Ph2
Br
X
Ph
(92), 91 (95), 88 (94), 88 (98), 81
4-BrC6H4 3-ClC6H4 3-O2NC6H4 2-FC6H4
(88), 68
(90), 76
(99), 85
NC HN PMB
NC HN Ts
NC HN PMB
Br
Cl
(90), 71
(91), 71
(98), 89
4-ClC6H4
X
(95), 90
(91), 90
4-FC6H4
Ph
Ar
(99), 85
NC HN Ts
NC HN Ts
Ar
NC
193
195
193
195
195
194
112
C9
O
O
MeO
MeO
R
N
N
N
N
Ts
PMB
PPh2
O
N
N
PPh2
O
Ts
Substrate
Br
toluene, –20°
TMSCN (1.5 eq), catalyst 23 (5 mol%),
toluene, –20°, 80 h
catalyst 24 (5 mol%),
TMSCN (1.5 eq), DAHQ (20 mol%),
toluene, –40°, 3 d
HCN (1.5 eq), catalyst 25 (5 mol%),
toluene, –20°
TMSCN (1.5 eq), catalyst 23 (5 mol%),
toluene, –20°, 80 h
catalyst 24 (5 mol%),
TMSCN (1.5 eq), DAHQ (20 mol%),
toluene, –40°, 3 d
HCN (1.5 eq), catalyst 25 (5 mol%),
Conditions
O
O
MeO
MeO
R
NHP(O)Ph2
NC
NHP(O)Ph2
NC HN Ts
(89), 70
(97), 92
(91), 89
(92), 76
(92), 56
Me
MeO (93), 89
R
Br
(94), 61
NC HN PMB
NC
NC HN Ts
NC HN
Product(s) and Yield(s) (%), % ee
TABLE 5. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES: NOV. 2006 TO AUG. 2007 (Continued)
194
195
193
194
195
193
Refs.
113
C10
MeO
MeO
MeO
MeO
Cl
N
N
N
P(O)Ph2
P(O)Ph2
Ts
N
Ts
P(O)Ph2
Ts
N
N
P(O)Ph2
N
toluene, –20°, 80 h
catalyst 24 (5 mol%),
TMSCN (1.5 eq), DAHQ (20 mol%),
toluene, –20°, 196 h
TMSCN (1.5 eq), catalyst 23 (5 mol%),
toluene, –20°, 80 h
catalyst 24 (5 mol%),
TMSCN (1.5 eq), DAHQ (20 mol%),
toluene, –20°, 196 h
TMSCN (1.5 eq), catalyst 23 (5 mol%),
toluene, –20°, 70 h
catalyst 24 (5 mol%),
TMSCN (1.5 eq), DAHQ (20 mol%),
toluene, –20°, 144 h
TMSCN (1.5 eq), catalyst 23 (5 mol%),
toluene, –20°, 72 h
TMSCN (1.5 eq), catalyst 23 (5 mol%),
NC HN Ts
NC HN P(O)Ph2
(99), 61
(91), 78
(96), 65
(99), 88
(95), 91
NC HN P(O)Ph2
NC HN Ts
MeO
MeO
MeO
NC HN Ts
(97), 76
(91), 90
HN P(O)Ph2
NC HN P(O)Ph2
MeO
Cl
NC
195
194
195
194
195
194
194
114
C12
Ph
Ph N
N
N
N
N
PMB
P(O)Ph2
PMB
Ts
Substrate
Br toluene, –40°, 3 d
HCN (1.5 eq), catalyst 25 (5 mol%),
toluene, –40°, 3 d
HCN (1.5 eq), catalyst 25 (5 mol%),
toluene, –20°, 168 h
TMSCN (1.5 eq), catalyst 23 (5 mol%),
toluene, –40°, 3 d
HCN (1.5 eq), catalyst 25 (5 mol%),
toluene, –20°, 80 h
catalyst 24 (5 mol%),
TMSCN (1.5 eq), DAHQ (20 mol%),
Conditions
Ph
Ph NC HN
NC HN PMB
(90), 92
Br
(95), 72
NC HN P(O)Ph2
(82), 60
(98), 71
NC HN PMB
NC HN Ts
(69), 80
Product(s) and Yield(s) (%), % ee
TABLE 5. CATALYTIC ENANTIOSELECTIVE STRECKER REACTIONS OF KETIMINES: NOV. 2006 TO AUG. 2007 (Continued)
193
193
194
193
195
Refs.
THE CATALYTIC ASYMMETRIC STRECKER REACTION
115
REFERENCES 1 2 3 4 5 6 7 8 9 10 11
12 13 14 15 16 17 18 19
20
21
22
23 24 25 26
27
28
29
30
31 32 33 34 35 36 37 38 39
40 41
Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889. Duthaler, R. O. Tetrahedron 1994, 50, 1539. O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron 1994, 50, 4507. Kreuzfeld, H. J.; Doebler, C.; Schmidt, U.; Krause, H. W. Amino Acids 1996, 11, 269. Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013. Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290. Strecker, A. Ann. Chem. Pharm. 1850, 75, 27. Gr¨oger, H. Chem. Rev. 2003, 103, 2793. Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875. Enders, D.; Shilvock, J. P. Chem. Soc. Rev., 2000, 29, 359. For an example of an enzyme-catalyzed asymmetric Strecker reaction, see: Lee, T.; Ahn, Y. Bull. Korean Chem. Soc. 2002, 23, 10. Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49. Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1236. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 1986. Rawlands, G. J. Tetrahedron 2001, 57, 1865. Ma, J.-A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566. Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. Chem. Lett. 1991, 541. Corey, E. J.; Wang, Z. Tetrahedron Lett. 1993, 34, 4001. Belokon’, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.; Tararov, V. I. Tetrahedron Lett. 1999, 40, 8147. Belokon’, Y. N.; Caveda-Cepas, S.; Green, B.; Ikonnikov, N. S.; Khrustalev, V. N.; Larichev, V. S.; Moscalenko, M. A.; North, M.; Orizu, C.; Tararov, V. I.; Tasinazzo, M.; Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc. 1999, 121, 3968. Belokon’, Y. N.; Green, B.; Ikonnikov, N. S.; Larichev, V. S.; Lokshin, B. V.; Moscalenko, M. A.; North, M.; Orizu, C.; Peregdov, A. S.; Timofeeva, G. I. Eur. J. Org. Chem. 2000, 2655. Belokon’, Y. N.; Blacker, A. J.; Carta, P.; Clutterbuck, L. A.; North, M. Tetrahedron 2004, 60, 10433. Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 2641. Hamashima, Y.; Sawada, D.; Nogami, H.; Kanai, M.; Shibasaki, M. Tetrahedron 2001, 57, 805. Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989. Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 2000, 39, 1650. Takamura, M.; Hamashima, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Chem. Pharm. Bull. 2000, 48, 1586. Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 4284. Porter, J. R.; Wirschun, W. G.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 2657. Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 11594. Houk, K. N.; List, B., Eds. Acc. Chem. Res. 2004, 37, 487. Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed. Engl. 2000, 39, 1279. Wenzel, A. G.; Lalonde, M. P.; Jacobsen, E. N. Synlett 2003, 1919. Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. Engl. 2006, 45, 1520. Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012. Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157. Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634. Kato, N.; Suzuki, M.; Kanai, M. Shibasaki, M. Tetrahedron Lett. 2004, 45, 3147. Kato, N.; Suzuki, M.; Kanai, M. Shibasaki, M. Tetrahedron Lett. 2004, 45, 3153.
116 42
43
44 45 46 47 48 49 50
51 52 53
54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70
71
72 73 74 75 76
77 78 79 80 81 82
83 84 85
ORGANIC REACTIONS
Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908. Kato, N.; Mita, T.; Kanai, M.; Therrien, B.; Kawano, M.; Yamaguchi, K.; Danjo, H.; Sei, Y.; Sato, A.; Furusho, S.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 6768. Reissert, A. Chem. Ber. 1905, 38, 1603. Popp, F. D. Heterocycles 1973, 1, 165. McEwen, W. E.; Cobb, R. L. Chem. Rev. 1955, 55, 511. Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6327. Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 6801. Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 10784. Ichikawa, E.; Suzuki, M.; Yabu, K.; Albert, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 11808. Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762. Krzyzanowska, B.; Stec, W. J. Synthesis 1978, 5, 521. Kruglyak, Y. L.; Landau, M. A.; Leibovskaya, G. A.; Martynov, I. V.; Saltykova, L. I.; Sokalskii, M. A. Zhur. Obshch. Kim. 1969, 39, 215. Brown, C.; Hudson, R. F.; Maron, A.; Record, K. A. F. J. Chem. Soc, Chem. Commun. 1976, 663. Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561. Love, B. E.; Raje, P. S.; Williams, II, T. C. Synlett 1994, 493. Glass, R. S.; Hoy, R. C. Tetrahedron Lett. 1976, 1781. Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75. Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910. Oku, J.; Inoue, S. J. Chem. Soc., Chem. Commun. 1981, 229. Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem. 1990, 55, 181. Danda, H. Synlett 1991, 263. Danda, H.; Nishikawa, H.; Otaka, K. J. Org. Chem. 1991, 56, 6740. Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027. Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566. Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. Rueping, M.; Sugiono, E.; Azap, C. Angew. Chem., Int. Ed. 2006, 45, 2617. Ooi, T.; Uematsu, Y.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2548. Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315. For other utilities of the chiral (salen)Al(III) catalyst, see: Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313. For a review about other utilities (cyanosilylation of aldehydes and Reissert reactions) of the BINOL-derived Lewis acid-Lewis base bifunctional asymmetric catalysts, see: Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491. Reger, T. S.; Janda, K. D. J. Am. Chem. Soc. 2000, 122, 6929. Nogami, H.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2001, 42, 279. Berkessel, A.; Mukherjee, S.; Lex, J. Synlett 2006, 41. Ishitani, H.; Komiyama, S.; Kobayashi, S. Angew. Chem., Int. Ed. Engl. 1998, 37, 3186. For other utilities (Mannich reaction, aza Diels-Alder reaction, Mukaiyama aldol reaction, and hetero Diels-Alder reaction) of chiral zirconium catalysts, see: Kobayashi, S.; Ueno, M. Saito, S.; Mizuki, Y.; Ishitani, H.; Yamashita, Y. Proc. Natl. Acad. Sci. USA 2004, 101, 5476. Banphavichit, V.; Mansawat, W.; Bhanthumnavin, W.; Vilaivan, T. Tetrahedron 2004, 60, 10559. Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517. Byrne, J. J.; Chavarot, M.; Chavant, P. Y.; Vall´e, Y. Tetrahedron Lett. 2000, 41, 873. Chavarot, M.; Byrne, J. J.; Chavant, P. Y.; Vall´ee, Y. Tetrahedron: Asymmetry 2001, 12, 1147. Sarges, R.; Howard, H. R.; Kelbaugh, P. R. J. Org. Chem. 1982, 47, 4081. Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi, R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44, 113. Corey, E. J.; Li, W. Z. Chem. Pharm. Bull. 1999, 47, 1. Masse, C. E.; Morgan, A. J.; Adam, J.; Panek, J. S. Eur. J. Org. Chem. 2000, 2513. Shibasaki, M.; Kanai, M.; Fukuda, N. Chem. Asian J. 2007, 2, 20.
THE CATALYTIC ASYMMETRIC STRECKER REACTION 86
87
88
89 90 91
92 93 94 95 96 97 98
99 100 101 102 103 104
105 106 107 108 109 110 111
112 113 114 115 116 117 118 119 120
121
122 123
117
Fukuda, N.; Sasaki, K.; Sastry, T. V. R. S.; Kanai, M.; Shibasaki, M. J. Org. Chem. 2006, 71, 1220. Leeson, P. D.; Carling, R. W.; Moore, K. W.; Moseley, A. M.; Smith, J. D.; Stevenson, G.; Chan, T.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp, J. A.; Marshall, G. R.; Hoogsteen, K. J. Med. Chem. 1992, 35, 1954. Thompson, W. J.; Anderson, P. S.; Britcher, S. F.; Lyle, T. A.; Thies, J. E.; Magill, C. A.; Varga, S. L.; Schwering, J. E.; Lyle, P. A.; Christy, M. E.; Evans, B. E.; Colton, D.; Holloway, M. K.; Springer, J. P.; Hirshfield, J. M.; Ball, R. G.; Amato, J. S.; Larsen, R. D.; Wong, E. H. F.; Kemp, J. A.; Tricklebank, M. D.; Singh, L.; Oles, R.; Priestly, T.; Marshall, G. R.; Knight, A. R.; Middlemiss, D. N.; Woodruff, G. N.; Iversen, L. L. J. Med. Chem. 1990, 33, 789. Brouillette, W. J.; Brown, G. B.; DeLorey, T. M.; Liang, G. J. Pharm. Sci. 1990, 79, 871. Dostert, P.; Varasi, M.; Della Torre, A.; Monti, C.; Rizzo, V. Eur. J. Med. Chem. 1992, 27, 57. Sanner, M. A.; Chappie, T. A.; Dunaiskis, A. R.; Fliri, A. F.; Desai, K. A.; Zorn, S. H.; Jackson, E. R.; Johnson, C. G.; Morrone, J. M.; Seymour, P. A.; Majchrzak, M. J.; Faraci, W. S.; Collins, J. L.; Duignan, D. B.; Di Prete, C. C.; Lee, J. S.; Trozzi, A. Bioorg. Med. Chem. Lett. 1998, 8, 725. Patel, M. S.; Worsley, M. Can. J. Chem. 1970, 48, 1881. Harada, K.; Okawara, T.; Matsumoto, K. Bull. Chem. Soc. Jpn. 1973, 46, 1865. Ojima, I.; Inaba, S.; Nagai, Y. Chem. Lett. 1975, 737. Stout, D. M.; Black, L. A.; Matier, W. L. J. Org. Chem. 1983, 48, 5369. Inaba, T.; Fujita, M.; Ogura, K. J. Org. Chem. 1991, 56, 1274. Fadel, A. Synlett 1993, 503. Tulinsky, J.; Cheney, B. V.; Mizsak, S. A.; Watt, W.; Han, F.; Dolak, L. A.; Judge, T.; Gammill, R. B. J. Org. Chem. 1999, 64, 93. Fondekar, K. P.; Volk, F.-J.; Frahm, A. W. Tetrahedron: Asymmetry 1999, 10, 727. Daga, M. C.; Taddei, M.; Varchi, G. Tetrahedron Lett. 2001, 42, 5191. Warmuth, R.; Munsch, T. E.; Stalker, R. A.; Li, B.; Beatty, A. Tetrahedron 2001, 57, 6383. Wang, Q.; Quazzani, J.; Sasaki, N. A.; Potier, P. Eur. J. Org. Chem. 2002, 834. Volk, F.-J.; Wagner, M.; Frahm, A. W. Tetrahedron: Asymmetry 2003, 14, 497. Badorrey, R.; Cativiela, C.; Diaz-de-Villegas, M. D.; Diez, R.; Galbiati, F.; Galvez, J. A. J. Org. Chem. 2005, 70, 10102. Hazelard, D.; Fadel, A.; Girard, C. Tetrahedron: Asymmetry 2006, 17, 1457. Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. Davis, F. A.; Zhou, P.; Chen, B.-C.; Chem. Soc. Rev. 1998, 27, 13. Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem. 2000, 65, 8704. Mabic, S.; Cordi, A. A. Tetrahedron 2001, 57, 8861. Davis, F. A.; Kavirayani, R. P.; Carroll, P. J. J. Org. Chem. 2002, 67, 7802. Avenoza, A.; Busto, J. H.; Corzana, F.; Francisco, P.; Peregrina, J. M.; Sucunza, D.; Zurbano, M. M. Synthesis 2005, 575. Huguenot, F.; Brigaud, T. J. Org. Chem. 2006, 71, 7075. Wang, H.; Zhao, X.; Li, Y. Lu, L. Org. Lett. 2006, 8, 1379. Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913. Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9948. Ziegler, F. E.; Wender, P. A. J. Org. Chem. 1977, 42, 2001. Chiba, T.; Okimoto, M. Synthesis 1990, 209. Manabe, K.; Oyamada, H.; Sugita, K.; Kobayashi, S. J. Org. Chem. 1999, 64, 8054. Keith, J. M.; Jacobsen, E. N. Org. Lett. 2004, 6, 153. Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric Synthesis; Ojima, I. Ed.; VCH: New York, 2000; pp 1–110. Brown, J. M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Heidelberg, 1999; pp 121–182. Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons, Inc.: New York, 1994. Halpern, J. In Asymmetric Synthesis, Vol. 5 ; Morrison, J. D., Ed; Academic Press: New York, 1985; pp 41–68.
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125
126 127 128 129
130
131 132 133 134 135
136 137 138 139 140 141 142 143
144
145
146 147
148 149 150 151
152
153
154
155 156
157 158
159
160
ORGANIC REACTIONS
Koenig, M. D. In Asymmetric Synthesis, Vol. 5 ; Morrison, J. D. Ed; Academic Press: New York, 1985; pp 71–98. Burk, M. J.; Gross, M. F.; Harper, T. G. P.; Kalberg, C. S.; Lee, J. R.; Martinez, J. P. Pure Appl. Chem. 1996, 68, 37. Noyori, R. Adv. Synth. Catal. 2003, 345, 15. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998. Kadyrov, R.; Riermeier, T. H.; Dingerdissen, U.; Tararov, V.; B¨orner, A. J. Org. Chem. 2003, 68, 4067. O’Donnel, M. J. In Catalytic Asymmetric Synthesis; Ojima, I. Ed.; VCH: New York, 2000; pp 727–755. O’Donnell, M. J. Acc. Chem. Rec. 2004, 37, 506. O’Donnell, M. J.; Bennett, W. D. J. Am. Chem. Soc. 1989, 111, 2353. Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414. Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595. Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-K.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-S. Angew. Chem., Int. Ed. 2002, 41, 3036. Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519. Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139. Trost, B. M.; Ariza, X. Angew. Chem., Int. Ed. Engl. 1997, 36, 2635. Trost, B. M.; J¨akel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125, 4438. Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256. Weiß, T. B.; Helmchen, G.; Kazmaier, U. Chem. Commun. 2002, 1270. Hagiwara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474. Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005, 44, 1525. Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843. Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A. Angew. Chem., Int. Ed. Engl. 2001, 40, 2992. Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org. Lett. 2002, 4, 143. Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507. Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 1679. Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002, 124, 5640. Hamada, T.; Manabe, K. Kobayashi, S. Angew. Chem., Int. Ed. 2003, 42, 3927. Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J.; Ryzkov, L.; Taggi, A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67. France, S.; Shah, M.; Weatherwax, A.; Wack, H.; Roth, J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206. C´ordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1842. C´ordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1866. Chowdari, N. S.; Suri, J. T.; Barbas, C. F., III Org. Lett. 2004, 6, 2507. Notz, W.; Watanabe, S.; Chowdari, N. S.; Zhong, G.; Betancort, J. M.; Tanaka, F.; Barbas, C. F., III Adv. Synth. Catal. 2004, 346, 1131. Kano, T.; Yamaguchi, U.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 16408. Franz´en, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T.; Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84. Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362.
THE CATALYTIC ASYMMETRIC STRECKER REACTION 161
162 163
164 165
166 167 168 169 170 171 172 173 174
175 176
177 178 179 180
181 182 183 184
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187 188 189 190 191
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Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 2896. Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed. 2005, 44, 4077. Cheong, P. H.-Y.; Zhang, H.; Thayumanavan, R.; Tanaka, F.; Houk, K. N.; Barbas, C. F., III Org. Lett. 2006, 8, 811. Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338. Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 1040. Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 4476. Saaby, S.; Fang, X.; Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 4114. Saaby, S.; Bay´on, P.; Aburel, P. S.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 4352. Basra, S.; Fennie, M. W.; Kozlowski, M. C. Org. Lett. 2006, 8, 2659. Steglich, W.; H¨ofle, G. Tetrahedron Lett. 1970, 4247. Suga, H.; Ikai, K.; Ibata, T. J. Org. Chem. 1999, 64, 7040. Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532. Evans, D. A.; Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew. Chem., Int. Ed. 2001, 40, 1884. Bøgevic, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790. List, B. J. Am. Chem. Soc. 2002, 124, 5656. For an example of metal-catalyzed asymmetric electrophilic amination, see: Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452. Chowdari, N. S.; Barbas, C. F., III Org. Lett. 2005, 7, 867. Suri, J. T.; Steiner, D. D.; Barbas, C. F., III Org. Lett. 2005, 7, 3885. Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1367. Foltz, C.; Stecker, B.; Marconi, G.; Bellemin-Laponnaz, S.; Wadepohl, H.; Gade, L. H. Chem. Commun. 2005, 5115. Huber, D. P.; Stanek, K.; Togni, A. Tetrahedron: Asymmetry 2006, 17, 658. Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167. Hartung, R. In Patty’s Industrial Hygiene and Toxicology; Clayton, G. D., Clayton, F. E., Eds.; Wiley: New York, 1994; Vol. II, Part D, Chapter 33. For the latest review of catalytic asymmetric addition to imines, see: Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541. Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Fini, F.; Pettersen, D.; Ricci, A. J. Org. Chem. 2006, 71, 9869. Ooi, T.; Uematsu, Y.; Fujimoto, J.; Fukumoto, K.; Maruoka, K. Tetrahedron Lett. 2007, 48, 1337. Pan, S. C.; Zhou, J.; List, B. Angew. Chem., Int. Ed. 2007, 46, 612. Pan, S. C.; List, B. Org. Lett. 2007, 9, 1149. Becker, C.; Hoben, C.; Kunz, H. Adv. Synth. Catal. 2007, 349, 417. Nakamura, S.; Nakashima, H.; Sugimoto, H.; Shibata, N.; Toru, T. Tetrahedron Lett. 2006, 47, 7599. Blacker, J.; Clutterbuck, L. A.; Crampton, M. R.; Grosjean, C.; North, M. Tetrahedron: Asymmetry 2006, 17, 1449. Rueping, M.; Sugiono, E.; Moreth, S. A. Adv. Synth. Catal. 2007, 349, 759. Huang, J.; Liu, X.; Wen, Y.; Qin, B.; Feng, X. J. Org. Chem. 2007, 72, 204. Huang, X.; Huang, J.; Wen, Y.; Feng, X. Adv. Synth. Catal. 2006, 348, 2579. Kanemitsu, T.; Yamashita, Y.; Nagata, K.; Itoh, T. Synlett 2006, 1595.
CHAPTER 2
THE SYNTHESIS OF PHENOLS AND QUINONES VIA FISCHER CARBENE COMPLEXES MARCEY L. WATERS Department of Chemistry, The University of North Carolina, Chapel Hill, North Carolina 27599 WILLIAM D. WULFF Department of Chemistry, Michigan State University, East Lansing, Michigan 48824
CONTENTS ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . INTRODUCTION MECHANISM AND OVERVIEW . . . . . . . . . . . . . . . . . SCOPE AND LIMITATIONS Benzannulation . . . . . . . . . . Product Isolation . . . . . . . . . Regioselectivity . . . . . . . . . . Alkenyl, Aryl, and Alkynyl Chromium Complexes . . . Alkyne Components . . . . . . . . . Heteroatom Stabilizing Substituents . . . . . . Reaction Media and Conditions . . . . . . . Metal and Ligand Complement . . . . . . . Diastereoselectivity . . . . . . . . . Intramolecular Reactions . . . . . . . . Heteroannulation . . . . . . . . . . Cyclohexadienone Annulation . . . . . . . Two-Alkyne Annulation . . . . . . . . Ortho-Benzannulation/Cyclization of Doubly Unsaturated Complexes . . . . . . . . APPLICATIONS TO SYNTHESIS . . . . . . COMPARISON WITH OTHER METHODS . . . . . . . PREPARATION OF CARBENE COMPLEXES . . . . . . . . EXPERIMENTAL CONDITIONS . . . . . . . . EXPERIMENTAL PROCEDURES
[email protected] Organic Reactions, Vol. 70, Edited by Larry E. Overman et al. 2008 Organic Reactions, Inc. Published by John Wiley & Sons, Inc. 121
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PAGE 123 123 124 131 131 131 135 140 150 160 164 170 173 175 179 181 185 188 192 199 204 207 208
122
ORGANIC REACTIONS
2-Butyl-4-methoxy-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)naphthalen-1-ol (Benzannulation with an Alkynylborane). . . . . . . . . 2,3-Diphenyl-1,4-naphthoquinone (Comparison of Thermal Reaction in THF Solution with Solid-Phase Reaction on Silica Gel). . . . . . . . . {tert-Butyl-[2-tert-butyl-4-(2-isopropyl-5-methylcyclohexyloxy)naphthalen-1yloxy]dimethylsilanyloxy}tricarbonylchromium(0) (Asymmetric Benzannulation of O-Menthyloxy Complexes). . . . . . . . . . . 2,3-Diethyl-4,4,5-trimethoxy-4H -naphthalen-1-one (Oxidative Workup to Quinone Monoacetals). . . . . . . . . . . . . . 4-Methoxy-2-phenylphenanthren-1-yl Acetate (Benzannulation and In Situ Protection as an Aryl Acetate). . . . . . . . . . . . . 2-Acetyl-11-hydroxy-6,7-dimethoxy-2,3,4,4a,12,12a-hexahydro-1H -naphthacen-5-one and 8-Acetyl-7,8,9,10-tetrahydro-11-hydroxy-1-methoxytetracene-5,12-dione (One-Pot Benzannulation/Friedel-Crafts Reactions Followed by Oxidation). . Tricarbonyl[6-(tert-butyldimethylsilanyloxy)-2 -(tert-butyldimethylsilanyloxymethyl)-3methoxy-2,5-dimethylbiphenyl]chromium(0) (Simultaneous and Stereoselective Creation of Axial and Planar Elements of Chirality). . . . . . . {tert-Butyl[4-methoxy-2-methyl-6-(1-trityloxyethyl)phenoxy]dimethylsilanyloxy} tricarbonylchromium(0) (Central to Planar Chirality Transfer from a Chiral Propargyl Ether). . . . . . . . . . . . . 4-Methoxy-6-methyl-6-(3-methylbut-3-enyl)-2-(3-methyl-1-trityloxyhepta-2,6dienyl)cyclohexa-2,4-dienone (1,4-Asymmetric Induction in Cyclohexadienone Formation). . . . . . . . . . . . . . {[2-(4-Benzenesulfonylbutyl)-4-methoxy-6,7-dimethyl-5,8-dihydronaphthalen-1-yloxy]tert-butyldimethylsilanyloxy}tricarbonylchromium(0) (Tandem Diels-Alder/ Benzannulation Reaction). . . . . . . . . . . . 7-Methoxy-10-oxospiro[4.5]deca-6,8-diene-1-carbonitrile and 5-(tertButyldimethylsilanyloxy)-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile (Tandem Benzannulation/Aromatic Nucleophilic Substitution). . . . . Methyl 5-{1-[(tert-Butyldimethylsilyl)oxy]ethyl}-6-ethoxy-4-hydroxy-7-methoxyindole and its Acetate (Benzannulation of a Heteroaryl Carbene Complex). . . . N-{3-[1-Methoxy-4a-(2-methoxymethoxyethyl)-9-methyl-4-oxo-4a,9-dihydro4H-carbazol-3-yl]propyl}benzamide (Cyclohexadienone Annulation of an Aryl Carbene Complex). . . . . . . . . . . . . Ethyl 3,4-Diethyl-2-hydroxy-5-(1-pyrrolidinyl)benzoate (Phenol Formation from an Activated Aminocarbene Complex). . . . . . . . . . {[4-(tert-Butyldimethylsilanyloxy)-2-methyl-5-propylphenyl] dimethylamino}tricarbonylchromium(0) (Generation of an Aniline Chromium Tricarbonyl Complex). . . . . . . . . . . . 2-Hydroxymethyl-3,6-dimethyl-1,4-naphthoquinone (Intramolecular Benzannulation with an In Situ Generated Tether). . . . . . . . . . 5,17-Dimethyl-11,23,26,28-tetramethoxy-25,27-dihydroxycalix(4)arene (Calix[4]arene Formation via a Triple Annulation). . . . . . . . . . 6-Methyl-4-(trimethylsilanyl)indan-5-ol (Regioselective Two-Alkyne Phenol Annulation). . . . . . . . . . . . . . 3-(tert-Butyldimethylsilanyloxy)-12-methyl-7,15,16,17-tetrahydro-6H cyclopenta[a]phenanthren-11-ol (Tandem Diels-Alder Two-Alkyne Phenol Annulations). . . . . . . . . . . . . . N-Benzyl-1-heptyl-4-methoxy-2-methyl-9H -carbazol-3-ol (Photoinduced ortho-Benzannulation). . . . . . . . . . . . . . . . . . . . . . . . . TABULAR SURVEY Table 1. Phenyl(alkoxy)chromium Carbene Complexes with Internal Alkynes . Table 2. Phenyl(alkoxy)chromium Carbene Complexes with Terminal Alkynes . Table 3. Aryl(alkoxy)chromium Carbene Complexes with Internal Alkynes . .
209 209
210 211 211
212
214
215
216
217
217 219
220 220
221 222 223 223
224 225 225 228 261 283
THE SYNTHESIS OF PHENOLS AND QUINONES Table 4. Aryl(alkoxy)chromium Carbene Complexes with Terminal Alkynes . Table 5. Alkenyl(alkoxy)chromium Carbene Complexes with Internal Alkynes Table 6. Alkenyl(alkoxy)chromium Carbene Complexes with Terminal Alkynes Table 7. Heteroaryl(alkoxy)chromium Carbene Complexes with Internal Alkynes Table 8. Heteroaryl(alkoxy)chromium Carbene Complexes with Terminal Alkynes Table 9. Amino and Imino Chromium Carbene Complexes with Internal Alkynes Table 10. Amino and Imino Chromium Carbene Complexes with Terminal Alkynes . . . . . . . . . . . . . Table 11. Sulfur-Stabilized Chromium Carbene Complexes with Alkynes . Table 12. Arylmolybdenum Carbene Complexes with Internal Alkynes . . Table 13. Arylmolybdenum Carbene Complexes with Terminal Alkynes . Table 14. Alkenylmolybdenum Carbene Complexes with Internal Alkynes . Table 15. Alkenylmolybdenum Carbene Complexes with Terminal Alkynes . Table 16. Aryltungsten Carbene Complexes with Internal Alkynes . . . Table 17. Aryltungsten Carbene Complexes with Terminal Alkynes . . Table 18. Alkenyltungsten Carbene Complexes with Internal Alkynes . . Table 19. Alkenyltungsten Carbene Complexes with Terminal Alkynes . . Table 20. Carbene Complexes of Non-Group VI Metals with Alkynes . . Table 21. Carbene Complexes with Tethered Alkynes . . . . . Table 22. Non-Heteroatom-Stabilized Carbene Complexes with Alkynes . Table 23. Cyclization of Doubly Unsaturated Complexes . . . . Table 24. Miscellaneous Reactions of Carbene Complexes . . . . . . . . . . . . . . . . . REFERENCES
123 . . . . . .
312 345 375 434 443 454
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472 487 491 494 498 501 503 508 511 513 517 524 557 568 597 612
ACKNOWLEDGMENTS
We express our gratitude to our coworkers at Michigan State University for assistance in proofreading this chapter. We also thank the many students and postdoctoral fellows who have contributed over the years to much of the original research that we cite. We are grateful to the National Science Foundation and National Institutes of Health for financially supporting the study of the chemistry of carbene complexes conducted in our laboratories over the last twenty-three years. Finally, we certainly extend our thanks to Bob Joyce (now deceased) and Linda Press for their invaluable help in assembling the tables, and to Scott E. Denmark for his patience, encouragement, and professional oversight of this chapter. INTRODUCTION
Fischer carbene complexes can be broadly defined as those transition-metal carbene complexes that have a low oxidation state, have an electrophilic carbene carbon, and usually have a heteroatom-stabilizing substituent on the carbene carbon. The reactivity of Fischer complexes of the type 1 is consistent with the resonance structures 1a and 1b (Scheme 1). These complexes were first prepared by E. O. Fischer and were, in fact, the first examples of any type of transitionmetal carbene complexes to be reported.1 The reaction of a Fischer carbene complex with an alkyne was first reported by D¨otz and was found to give a chromium tricarbonyl complexed 4-alkoxy-substituted phenol (Scheme 1).2 The
124
ORGANIC REACTIONS OH (CO)5Cr
OMe R2 R3
+
R
S
L
R =H
R3 RS (CO)3Cr OMe 2
1
(CO)5Cr
R3 1a
R1
RL
R
R1
OMe R2
R1
2
(CO)5Cr
OMe R2 R3 1b
R1
R1
O C
R3 OMe
RL
RS
Scheme 1
outcome was unexpected because the reaction was anticipated to give a cyclopropene by transfer of the carbene ligand to the alkyne.3 The reaction of Fischer carbene complexes with alkynes is facile, occurring just above ambient temperature, and resulting in the assembly of a benzene ring from the three carbons of the α,β-unsaturated carbene complex, the two carbons of the alkyne, and the carbon of a carbon monoxide ligand (Scheme 1). The synthetic value of this reaction stems from its broad scope, the generally high yields for the process, and the fact that the products can function as intermediates for the synthesis of a variety of aromatic compounds including para-quinones. It is the most synthetically valuable of the large number of reactions of Fischer carbene complexes that have been developed for applications in synthetic organic chemistry. Most of the previous reviews of the reactions of Fischer carbene complexes with alkynes have appeared as part of larger reviews on the applications of Fischer carbene complexes in organic synthesis that include a number of different reactions.4 – 41 The first major review was published only a few years after the discovery of the reaction,10 and shortly thereafter a detailed review appeared which focused on the work of a single research group.16 The literature on the reaction of Fischer carbene complexes with alkynes up to 1988 is roughly contained in three reviews that cover all reactions of Fischer carbene complexes.10,16,20 A comprehensive review has appeared that includes the reaction of Fischer carbene complexes with alkynes for the period 1988 to 1993.24 This chapter is the first comprehensive review that is limited to the synthesis of phenols and quinones from the reactions of Fischer carbene complexes with alkynes. The literature is covered as cited in Chemical Abstracts up to September, 2004. MECHANISM AND OVERVIEW
The mechanism by which (4-alkoxyphenol)chromium tricarbonyl complexes 2 are produced from the reaction of Fischer carbene complexes is not known in complete detail. A summary of the current understanding of the reaction of α,βunsaturated Fischer carbene complexes 1 with alkynes is presented in Scheme 2.
THE SYNTHESIS OF PHENOLS AND QUINONES
(CO)5Cr
OMe R2 R3
– CO
R1 1
R R1 β α
R3
R
S
R
L
R1 3
3
1 R2 R
OMe
R2
RS
O • RL
(CO)4Cr
OMe 2 α βR
Cr(CO)3
(E)-5
R3 R1 β α 3 OMe S R2 L 2 R R 1 Cr(CO)4 (E)-4 OH
O
R3
RL
OMe RS Cr(CO)3 6
125
2
R =H
R1
RL
R3 (CO)3Cr
RS OMe 2
Scheme 2
The first and rate-limiting step of the reaction was long ago proposed on the basis of kinetic studies to be a carbon monoxide dissociation from the starting carbene complex to give the 16-electron unsaturated species 3.42 Subsequent reaction with the alkyne is suggested to give the η1 ,η3 -vinyl carbene-complexed intermediate (E)-4. Recently, this view has been called into question by a theoretical study that concluded that the first step is an insertion of the alkyne to give a pentacarbonyl species and then a rate limiting loss of CO to give the unsaturated vinyl carbene complex (E)-4.43 This report is controversial44 because it is inconsistent with kinetic studies that demonstrated that the first step of the reaction is loss of CO, and that the second step depends on the alkyne concentration.42 The η1 ,η3 -vinyl carbene-complexed intermediate (E)-4 has been suggested to exist in a number of different forms. Most early mechanistic proposals include a [2 + 2] cycloaddition of the alkyne and carbene complex to give a metallacyclobutene intermediate that undergoes subsequent electrocyclic ring opening to give an η1 -vinyl carbenecomplexed intermediate related to (E)-4 (see structure (E)-17 in Scheme 6) but not having the chromium coordinated to carbons 2 and 3.5,9 It was suggested in 1987 that the η1 -complex (E)-17 is coordinatively unsaturated and may prefer to exist as the 18 e− (η1 ,η3 -vinyl)carbene complex (E)-4.13 Subsequently, extended H¨uckel calculations found that the η1 - and η1 ,η3 -vinyl carbene complexes are of comparable energy and also ruled out a metallacyclobutene intermediate as a precursor to (E)-4.45,46 The intermediate 4 must have an E-configuration about the C2-C3 double bond to enable phenol formation, and evidence suggests that this configuration is favored by the electron-releasing methoxy group.47 One recent density functional theory calculation (DFT) found that the η1 ,η3 -complex (E)4 is more stable,48 while another recent DFT study found that the η1 complex (E)-17 (Scheme 6) is more stable.49,50 It has been experimentally shown that the η1 ,η3 and η1 forms can interconvert.51,52 A third isomeric form of (E)-4 has been proposed recently on the basis of spectroscopic evidence in which the chromium is coordinated to a carbon-carbon double bond originally present in an alkenyl carbene complex.53,54 The intermediacy of this species in the formation of phenols has been supported by DFT calculations that find this configuration to
126
ORGANIC REACTIONS
be the most stable of the isomers of 4.49,50,55 An η1 ,η3 -vinyl carbene-complexed intermediate has been isolated from the reaction of a cationic tungsten carbene complex bearing a Cp ligand.56 The insertion of CO was originally proposed to give the (η4 -vinyl) ketene complex (E)-5 which upon electrocyclic ring closure and tautomerization gives the observed phenol complexes 2.57 DFT studies support the intermediacy of vinyl ketene complex (E)-5 for aryl complexes.48 However, for the same studies on alkenyl carbene complexes there is no local minimum for the vinyl ketene complex but rather CO insertion and electrocyclic ring closure occur in the same step.48 – 50 The isolation of (η4 -vinyl) ketene complexes has been reported for the reaction of alkynes with carbene complexes that do not have an α,β-unsaturated substituent.58,59 The last step in the reaction is proposed to be the tautomerization of cyclohexadienone complex 6, and support for this intermediate comes from the isolation of a non-tautomerized (R2 = H) complex from a molybdenum carbene complex.60 Metal-free and metal-complexed cyclohexadienones can be obtained from these reactions if tautomerization is not possible (R2 , R1 = H).61,62 Information about the rates and reversibility of these processes has been difficult to obtain because a rate-limiting CO dissociation is followed by rapid conversion into product, which also explains the inability to detect reaction intermediates.63,64 One DFT study suggests that both the alkyne insertion and CO insertion steps should be irreversible.48 Another DFT study finds that the alkyne insertion should be irreversible, but information on the CO insertion step was not provided.49,50 A detailed study of the reaction of a (2-furyl) carbene complex with 1-pentyne concludes that at least one of these steps must be irreversible.65 More recent studies on the reaction of a 2-methoxyphenyl complex finds that the constitutional isomers of the vinyl carbene complex (E)-4 (see structures 4 and 7, Scheme 3) undergo interconversion faster than CO insertion although it could not be determined if this interconversion takes place by reversible insertion of the alkyne or some other mechanism.66 Unsymmetrical acetylenes react with α,β-unsaturated Fischer carbene complexes to give two constitutionally isomeric phenol products as represented by compounds 2 and 8 (Scheme 3). In most reaction scenarios, the predominant product can be predicted on the basis of the steric bulk of the alkyne substituents such that the major product has the largest substituent of the alkyne incorporated adjacent to the hydroxy group of the phenol.67 – 70 With internal alkynes, mixtures of isomers that vary with the sizes of the substituents are observed. With terminal alkynes the reaction generally proceeds with greater than 100 : 1 selectivity, but lower selectivities are occasionally observed (10 : 1). The source of the steric influence of the alkyne substituents on regioselectivity has been suggested to result from the interaction of these substituents with carbon monoxide ligands in the η1 ,η3 -vinyl carbene complexed intermediate (Scheme 3, 4 vs. 7). Extended H¨uckel calculations reveal that the substituent ˚ closer to its nearest CO ligand at the 2-position of this intermediate is at least 1 A than the substituent on the 1-position.46 It is not clear whether the preference for isomer 4 over 7 is a result of kinetic or thermodynamic control. Perturbation of
THE SYNTHESIS OF PHENOLS AND QUINONES
R1 R
L
S
R
2
R
R3
3
OMe 2
RL 1
RS
OH R2
=H
OC Cr CO OC CO OMe R2
(CO)4Cr
R3
R1 R1
3 RS
RL
R2
R3
3
RS 1
2
R
RL
2 major product OH
OMe 2
RL
OC Cr CO OC CO (E)-7 R1
R1
R3 RS (CO)3Cr OMe
(E)-4
RL larger than RS
127
R3
R2 = H
R1
RS
R3 RL (CO)3Cr OMe 8 minor product
OMe RL +
RS – OC Cr CO OC CO (E)-4a
Scheme 3
the regioselectivity by electronic effects has been reported rarely. To date, only ketone71 and tributylstannyl72,73 substituents on the alkyne are known to influence regioselectivity to the point that electronic factors predominate over steric factors. The source of these electronic effects have been interpreted in terms of the resonance structure (E)-4a for the η1 ,η3 -vinyl carbene complexed intermediate. A recent report describes the regioselective reaction with internal boryl alkynes, which may be due to electronic rather steric effects.74,75 Even if the key intermediates in the reaction are those shown in Scheme 2, this information is usually not sufficient to predict the product distribution. The reactions are quite sensitive to solvent, temperature, concentration, the nature of the metal and its ligands, and on any functionalities present in either the carbene complex or the alkyne. The optimal conditions for a given carbene complex and alkyne are best determined experimentally with the aid of the known set of reactions that are presented in the Tabular Survey. One of the main problems in the reaction of α,β-unsaturated Fischer carbene complexes with alkynes is the large number of chemical structures that are possible products. The chemoselectivity, or the selectivity for a certain product type, has been carefully examined and the number of products that have been reported for this reaction are too numerous to list here, but are included in the Tabular Survey. However, for those reactions targeting phenols, the most common structures observed as co-products are furans,65,76,77 vinylcyclopentadienones,78
128
ORGANIC REACTIONS
cyclobutenones,76,13 indenes (cyclopentadienes),76,79 and two-alkyne phenols, which are phenols derived from the carbene carbon, a carbon monoxide ligand, and two equivalents of the alkyne.80,81 The mechanistic origin of each of these side-products will be briefly discussed below to the extent that such information is known. A mechanistic accounting for the formation of the vinylcyclopenten-1,3-dione product 10 and the furan product 13 is presented in Scheme 4. These products result from the insertion of the alkyne to give the Z-isomer of the η1 ,η3 -vinyl carbene complexed intermediate 4. The alkyne normally inserts to give the Eisomer of 4 and this preference has been shown to be a result of the electronic influence of the methoxy group.47 Consequently, the vinylcyclopenten-1,3-dione 10 and furan product 13 are usually observed in less than 20% combined yield, although under certain circumstances they are the major products of the reaction. Furan formation results from insertion of a carbon monoxide ligand to give the Z-isomer of the vinyl ketene complex 5, and then attack of the methoxy group on the ketene to give the zwitterion 11. Carbon-oxygen bond fragmentation gives the non-stabilized carbene-complexed intermediate 12, which is not observed but is presumably attacked rapidly by the carbonyl oxygen with subsequent loss of chromium to give the furan.65,77 Although two reasonable possibilities have
OMe R2
(CO)4Cr
R3 3
RL
R1
3
R
L
R3
R1 R
R
S
RS
O RS
R3
R2
(Z)-5
O
R RL (Z)-5 O
RL
RL OMe
R2 RS
R1
O RS
RL
RS 11
Cr(CO)n
R2
R3
R1
10
R1 R2
RS
Cr(CO)3
9 3 Me R O
RL
S
O •
Cr(CO)4
(CO)n M RL OMe
R1
MeO
2
(Z)-4 RL
RS
Cr(CO)4 (E)-4
MeO
RS
OMe
R2 R L
R3 RL
R3
R1
RS
R3 O
MeO RL
R2 Cr(CO)n RS
12
Scheme 4
R1
R3 O
MeO RL
R1 RS
13
R
2
THE SYNTHESIS OF PHENOLS AND QUINONES
129
been suggested for the formation of the vinylcyclopenten-1,3-dione 10, the most likely pathway is thought to involve a reductive coupling of the carbon-carbon double-bond of the ketene with a second molecule of the alkyne to give metallacyclopentenone 9. Subsequent CO insertion and reductive elimination would render the observed product 10.78,60 For many reactions of interest, the formation of the indene product can be the most detrimental, decreasing the yields of the desired phenol product. The indene product results from the failure of carbon monoxide to insert into the vinyl carbene-complexed intermediate (E)-4 to produce the vinyl ketene complexed intermediate (E)-5 (Scheme 5). Instead, cyclization occurs to give a five-membered ring (14), which upon loss of the metal gives the cyclopentadiene 15. This product is actually rarely seen with alkenyl-substituted chromium carbene complexes and is usually only observed as a side-product in the reaction of aryl complexes, where it is often isolated as the metal-free indene 16. The phenol to indene (cyclopentadiene) ratio is more favorable for phenol formation with chromium than with molybdenum and tungsten complexes.60,63,71,82 Phenol formation is also more often seen with electron-poor complexes than with electron-rich complexes,79,83 and in less polar solvents rather than in more polar
R3
R1
R1
RS
R2
R2 RL (E)-4
R3
OMe
OMe
R1
RS L
R
Cr(CO)4
R2
Cr(CO)4
14
OMe
R2 RL
R
R
S
RS
R1
O R1
R3
RL •
RS
RL Cr(CO)3
3 O R
RL
R1 R2
OMe RS
RS
RL
RL R3
RS Cr(CO)4
20 R1
R1
RS
RS
R2
21 R1
R3
R3 OMe
R2 O •
OH R3 RL
RL
RL
19
(E)-4
RS
18
RS
MeO
RL 16
R2
Cr(CO)4 (E)-17 R2
RS
RL 15
MeO L
O
R2 OMe
RS RL Cr(CO)3 (E)-5
Scheme 5
OMe
R4
OMe RS
R3
R1 (E)-4
R3
RL
RS 22
130
ORGANIC REACTIONS
solvents.13 Concentration and temperature can also influence this ratio such that lower temperatures and higher concentrations favor phenol formation.84 The two-alkyne phenol product 21 results from the incorporation of two equivalents of the alkyne. It is believed that the formation of this product begins with the decomplexation of the double-bond in the saturated 18-electron η1 ,η3 vinyl carbene complexed intermediate (E)-4 to give the unsaturated 16-electron η1 -analog (E)-17 (Scheme 5).80 Calculations have shown that these two intermediates are nearly identical in energy and that the barrier to their interconversion is quite low45,46 This observation has been confirmed experimentally.51,52 The site of unsaturation in (E)-17 makes possible the reaction with a second alkyne to give the η1 ,η3 -vinyl carbene complexed intermediate 18 that has two equivalents of the alkyne incorporated. CO insertion would give the vinyl ketene complex 19 and electrocyclic ring closure would give the cyclohexadienone 20, which can sometimes be isolated but is usually reduced in situ by chromium(0) to give phenol 21. This mechanism suggests that the formation of two-alkyne phenols is concentration dependent and experiments reveal that the phenol 21 is most often significant as a side-product at high concentrations and with sterically unencumbered alkynes. Just as the η1 ,η3 -vinyl carbene complexed intermediate (E)-4 can decomplex from the double bond to give the η1 -vinyl carbene complexed intermediate (E)-17 and then insert an alkyne, so can the η1 ,η3 -vinyl carbene complexed intermediate 18. This process is presumably the mechanism by which Group 6 carbene complexes, especially those of tungsten, can cause oligomerization and polymerization of alkynes.85 Finally, the cyclobutanone product 22 is thought to be the result of an electrocyclic ring closure of the vinyl ketene complex (E)-5. The formation of this product is often maximized in acetonitrile where coordination of the solvent to the metal may foster cyclization.13 It has not been determined whether the two-alkyne phenol product 21 and the cyclobutanone product 22 can be formed from the E-η1 ,η3 -vinyl carbene complexed intermediate 4, or formed from the Z-isomer, or from both. The formation of the phenol product can often be sensitive to the concentration of the reactants. Extensive investigation revealed that this dependency is linked to the concentration of the alkyne and not to that of the carbene complex.13,60,84 Increased concentration of the alkyne leads to increased proportions of the phenol product relative to the indene (cyclopentadiene) product. An explanation was put forth that involves the coordination of a molecule of the alkyne to the metal center in the 16 electron η1 -vinyl carbene complexed intermediate (E)-17, which already has a molecule of the alkyne incorporated. Because an alkyne can be either a 2or 4-electron donor ligand, the coordination of alkyne 23 is proposed to facilitate the insertion of a carbon monoxide ligand (Scheme 6). The alkyne can switch from a 2-electron donor in 24 to a 4-electron donor in 25, and thus maintains a saturated, 18-electron metal center during the CO insertion step. Electrocyclic ring closure and loss of the acetylene would then produce the phenol chromium tricarbonyl complex 2 as the product. This alkyne-promoted enhancement of phenol formation is termed the “allochemical effect”84 if the alkyne 23 is the
THE SYNTHESIS OF PHENOLS AND QUINONES R3
R1 2
R R
L
Cr(CO)4
R1
R
23
OMe
R2 (CO)4Cr
RS
R
Cr(CO)4 (E)-17
OMe
1 R2 R
O
RS RL
4
R5 24
R3
25
OH 2
R =H
RS
RL Cr(CO)3 5
R2
R3
R1
R5
R3
R2 O • R4
R4
OMe RL
RS
(E)-4
R3
R1 OMe
131
RL
OMe RS
Cr(CO)3
6
R1
RL
R3 (CO)3Cr
RS OMe 2
Scheme 6
same as the first alkyne that has already been incorporated into (E)-17, and the “xenochemical effect”86 if the two alkynes are different. This allochemical effect and the process that leads to the formation of the 2-alkyne phenol product 21 (Scheme 6) are closely related. In the former the alkyne coordinates to the metal of (E)-17 but does not insert and in the latter the alkyne inserts into (E)-17 to give the intermediate 18. SCOPE AND LIMITATIONS
Benzannulation Product Isolation. The primary product of the reaction between an alkyne and an α,β-unsaturated Fischer carbene complex (e.g., 26) is an arene chromium tricarbonyl complex with the chromium coordinated to the newly formed benzene ring. The phenoxy function present in these products renders the molecule sensitive to air and special precautions are needed to isolate these complexes. The arene complex 27 is isolated in 45% yield by purification on silica gel at −15◦ under an inert atmosphere (Eq. 1).87 However, this result does not represent the actual yield because naphthol 28 can be isolated in 66% yield after oxidation in air60 and quinone 29 is obtained in 73% yield after an oxidative workup with ceric ammonium nitrate (Eq. 2).13 The lower yield of complex 27 is due to air oxidation which occurs despite the precautions taken. Most arene chromium tricarbonyl complexes from this reaction are quite air-sensitive and will lose the metal within minutes upon exposure to atmospheric conditions. This air-sensitivity is in contrast to that of Fischer carbene complexes, which are normally stable to air and only undergo extensive air oxidation when left in solution for a day or more. Relatively air-stable arene chromium tricarbonyl complexes are obtained from reactions of carbene complexes with acetylenes
132
ORGANIC REACTIONS
bearing large substituents as illustrated in the isolation of complex 30 in 79% yield (Eq. 3).68 Many such arene complexes with hindered substituents adjacent to the phenol are quite stable to air and some will survive chromatography on silica gel at room temperature in the presence of air with little or no decrease in yield.88 OH 1. Cr(CO)5
Pr-n
Pr-n, n-Bu2O, 45°
(Eq. 1)
2. silica gel, N2, –15°
OMe 26
(CO)3Cr OMe 27 (45%) OH Pr-n
THF, 80° 2. air Cr(CO)5
1.
OMe
Pr-n
28 (66%) O
OMe 26
(Eq. 2) Pr-n
THF, 45° 2. CAN O 29 (73%) OH 1. Cr(CO)5
OMe 26
Bu-t
Bu-t , n-Bu2O, 45°
(Eq. 3)
2. silica gel, N2, –15° (CO)3Cr OMe 30 (79%)
The reaction of complex 26 with diphenylacetylene at 45◦ produces the arene complex 31 with the chromium tricarbonyl group on the newly formed benzene ring.2 This product results from kinetic control because heating this complex to 70◦ results in migration of the chromium tricarbonyl group to the other ring of the naphthalene nucleus giving complex 32. This observation requires that the chromium remains bound to the organic fragment during the entire course of the reaction. Complex 31 is also used to demonstrate a method for removal of the chromium tricarbonyl unit from the product that does not involve an oxidation of the metal. Ligand displacement with carbon monoxide can effectively provide the metal-free phenol 33 in good yield (Eq. 4).76 A related ligand displacement method with triphenylphosphine has been reported.90 Another important aspect of deprotection with CO in addition to the mild conditions is that this method sequesters the chromium as its hexacarbonyl complex in high yield, thus providing for a convenient recycling of the chromium (chromium hexacarbonyl is the starting material from which most Fischer carbene complexes are produced).
THE SYNTHESIS OF PHENOLS AND QUINONES
133
Because chromium hexacarbonyl is relatively insoluble in ether, it can be recovered by simple filtration. OH Ph Bu2O, 70° Ph
OH
(CO)3Cr
Ph
OMe 32
Ph
(Eq. 4)
OH
(CO)3Cr OMe
Ph
50 atm CO
31
+ Cr(CO)6
Et2O, 70°
Ph OMe 33 (80%)
In most synthetic applications the metal-free organic product is desired and the method of workup is chosen to provide a clean and rapid removal of the metal as well as to provide the product in a particular oxidation state or particular form of functional group differentiation, as illustrated in the reaction of the cyclohexenyl complex 34 with diethylacetylene (Scheme 7).69 Oxidative workup with ferric chloride-DMF removes the metal from complex 35 but does not oxidize the hydroquinone mono-ether, resulting in product 36. Pyridine N -oxide has also been used for this purpose.91 Oxidation with ceric ammonium nitrate removes the metal and oxidizes the product to the quinone 37. Cerium(IV) oxidation in methanol gives the quinone mono-acetal 38. Other oxidants that have been
OH Et
FeCl3-DMF complex
Et OMe 36 (64%) O
OH Et Cr(CO)5 OMe 34
Et
Et
THF, 45°
Et
CAN
Et
Et O 37 (65%)
(CO)3Cr OMe 35
O Et
CAN/MeOH
Et MeO OMe 38 (59%)
Scheme 7
134
ORGANIC REACTIONS
used include lead oxide,92 nitric acid,76 silver oxide,93 and iodine.67 The ferric chloride-DMF complex is not selective in the oxidation of naphthol chromium tricarbonyl complexes, removing the metal and oxidizing the product to a naphthoquinone. Other than air, no oxidant has been reported that will selectively remove the metal from a naphthol chromium tricarbonyl complex without also oxidizing the naphthol to a naphthoquinone. Air oxidation is usually effective for obtaining naphthols from naphthol complexes but exposure to air for extended times, or additional irradiation with ultraviolet light may be required for certain complexes. Ligand displacement with CO can be a useful alternative for the clean isolation of naphthols. In general, it has been possible to efficiently protect the phenoxy function while retaining the chromium tricarbonyl group in products from the reactions of alkenyl complexes. However, this process has not been as successful for the reactions of aryl complexes, probably because of the increased lability of naphthol chromium tricarbonyl complexes toward ligand displacement compared to that of phenol chromium tricarbonyl complexes. For example, the reaction of phenyl complex 26 with 1-hexyne in the presence of acetic anhydride and triethylamine gives the acetylated product 39, which has lost the metal (Eq. 5).94 In contrast, cyclohexenyl complex 34 undergoes benzannulation with 1-pentyne followed by in situ acylation to give tricarbonyl(O-acetoxyarene)chromium complex 40 in 64% yield (Eq. 6).95 O-Acetyl complexes can sometimes be obtained from aryl carbene complexes if the naphthyl chromium tricarbonyl complexes are first isolated.73 Whereas O-acetoxynaphthalene chromium tricarbonyl complexes cannot be obtained by the one-pot method, the in situ acylation of these products is useful because O-acylated naphthols are often less sensitive to air oxidation than their corresponding naphthols. For this reason, in situ acylation is often used to produce acylated products from both alkenyl and aryl complexes and the transformation indicated in Eq. 5 has been developed as an Organic Syntheses procedure.94 With alkenyl complexes, the metal-free O-acylated products are obtained from a tandem process in which the benzannulated product is exposed to air before the acylating reagents are added.
OH Bu-n
Bu-n, THF, reflux Cr(CO)5 OMe 26
Ac2O, Et3N, DMAP (CO)3Cr OMe
(Eq. 5)
OAc Bu-n
OMe 39 (68%)
THE SYNTHESIS OF PHENOLS AND QUINONES
135
OAc Pr-n
Pr-n, THF, 50° Cr(CO)5
(Eq. 6)
AcBr, (i-Pr)2NEt
OMe
(CO)3Cr OMe 40 (64%)
34
Several other methods for derivatization of the phenoxy function have been reported for the direct preparation of differentially-protected (hydroquinone)chromium tricarbonyl complexes. The silylated chromium tricarbonyl complex 4295 and the triflated complex 4396 have both been prepared from carbene complex 41 and 1-pentyne (Eq. 7). The yields of these complexes are approximately the same for both one-step and two-step processes. Silylated complexes can also be obtained from aryl complexes in a one-pot process with certain alkynes.73,97 Other electrophiles that have been used include triisopropylsilyl triflate and methoxymethyl chloride.95 Two reports of functionalization of the phenol by an intramolecular Mitsunobu reaction have been described.98,99 In the reaction of the octalin carbene complex 44, the metal is retained in product 45, which is formed as a single diastereomer (Eq. 8).99 OTBS Pr-n
THF, 50° 2. TBSCl, Et3N, rt Cr(CO)5
1.
(CO)3Cr OMe
Pr-n
42 (65% )
OMe
(Eq. 7)
OTf
41
Pr-n
CH2Cl2, 50° 2. Tf2O, (i-Pr)2NEt, rt (CO)3Cr OMe 43 (66% )
(CO) 5Cr
OEt
EtO
Cr(CO)3 (CH2)4OH
44
Cr(CO)3
DEAD
(CH2)4OH OH
THF, 60° H
EtO
H
O
Ph3P H 45 (50%)
(Eq. 8) Regioselectivity. In general, the regioselectivity of the reaction is controlled by steric effects and the level of regioselectivity is related to the difference in steric bulk of the two alkyne substituents.67 – 70 The major isomer derives from the incorporation of the larger substituent into the position adjacent to the phenolic hydroxy group. The largest difference in substituent sizes occurs when one of them is hydrogen, and thus the highest selectivities are found with these alkynes.
136
ORGANIC REACTIONS
The regioselectivity with terminal alkynes is almost always extremely high with both aryl and alkenyl complexes alike. This high selectivity is illustrated by the reaction of phenyl complex 26 with phenylacetylene, which gives at least a 179 : 1 selectivity for phenol 46 in preference to phenol 47 (Eq. 9).100 Likewise, reaction of cyclohexenyl complex 34 with 1-pentyne gives phenol 48 in preference to phenol 49 with at least 250 : 1 selectivity (Eq. 10).101 OH 1. Cr(CO)5
OH Ph +
Ph, THF, 45°
2. air
Ph
OMe
OMe
26
(Eq. 9)
OMe
46
47 (87%) 46:47 ≥ 179:1 OH
OH 1.
Cr(CO)5
Pr-n +
Pr-n, THF, 50°
2. FeCl3-DMF
Pr-n
OMe
(Eq. 10)
OMe OMe 48 49 (55%) 48:49 ≥ 250:1
34
The pair of reactions of carbene complexes 41 and 50 with 1-pentyne provides a direct comparison of the regioselectivity of these complexes with the same alkyne because these two reactions share the same set of two possible isomeric quinones (but not phenols) (Eq. 11).69 Interestingly, whereas the trans1-propenyl complex 50 gives the typically high regioselectivity observed with terminal alkynes, the 2-propenyl complex 41 only gives a 93 : 7 selectivity for quinones 51 and 52. This ratio represents the lowest regioselectivity that has been observed in the reaction of an alkenyl complex with a non-electronically perturbed terminal alkyne and no explanation for it has been offered. The regioselectivity of this reaction can be increased to 97 : 3 if the reaction is performed with 1-tributylstannyl-1-pentyne.72 Cr(CO)5
+
Pr-n
OMe 41 Cr(CO)5
O
O Pr-n
1. THF, 45°
+
2. CAN +
Pr-n O 51
Pr-n
O 52
(Eq. 11)
OMe 50
Complex 41 50
51 + 52 (51%) (75%)
51:52 93:7 1:99
The effect of the difference in steric size of the two alkyne substituents on the regioselectivity of the reaction is illustrated in Eq. 12.67 2-Pentyne gives a 1.5 : 1 mixture of the isomeric quinones 54 and 55 upon reaction with the
THE SYNTHESIS OF PHENOLS AND QUINONES
137
2-methoxyphenyl complex 53 (Eq. 12). This ratio is increased to 4.8 : 1 with 4-methyl-2-pentyne. On the basis of the difference in the size of the two substituents, higher regioselectivity was expected for the reaction with 1-phenylpropyne and the value of 41 : 1 has been recorded for this reaction.66 This selectivity drops to 18 : 1 when the temperature is increased from 45◦ to 90◦ . This is the only example in which regioselectivity as a function of temperature has been reported.
O OMe MeO
1.
O R
R, THF, 45°
+
2. CAN
R
Cr(CO)5
MeO
53
O 54
R Et i-Pr Ph Ph
Temp 45° 45° 45° 90°
MeO
O 55
(Eq. 12)
54:55 1.5:1 4.8:1 41.0:1 18.0:1
Regioselectivity is rarely influenced by electronic perturbations of the alkyne. Very small differences in the regioselectivity of the reaction of complex 26 with substituted diphenylacetylenes 56 are found where nearly equal ratios of phenol complexes 57 and 58 are observed despite significant electronic differences in the two arene rings of 56 (Eq. 13).42 Electronic factors can, under some circumstances, exert a strong influence on regioselectivity.71 – 73 If the alkyne is substituted by a stannyl group, the regioselectivity of incorporation of the alkyne occurs as if the stannyl group were not present. Occasionally the regioselectivity is enhanced over that observed for the terminal alkyne. For example, the reaction of complex 41 with 1-tributylstannyl-1-pentyne gives, after oxidative workup, a 97 : 3 mixture of quinones 51 and 52 (Eq. 11).72 The reaction of tributylstannylacetylene with complex 59 followed by in situ protection with tert-butyldimethylsilyl triflate gives the stannyl-substituted chromium tricarbonyl complex 60 in 40% yield, and the destannylated complex 61 in 27% yield (Eq. 14).72 The major product 60 has the stannyl group incorporated adjacent to the methoxy group (3-position). This orientation is opposite to the regioselectivity previously seen with all terminal acetylenes. Minor product 61 could have resulted from loss of the stannyl group in either the 2- or 3-position. The reaction with 2-deuterio-1-tributylstannylacetylene proceeds with a 2 : 1 selectivity in favor of the “abnormal” isomer 60. The origin of this effect is attributed to β-stabilization of the positive charge on C1 of the vinyl carbene complexed intermediate (E)-4a when the stannyl group is on C2 of (E)-4a (Scheme 3). Although silicon has a lesser ability to stabilize β-carbocations than does tin,102
138
ORGANIC REACTIONS
it is nonetheless surprising that a similar electronic effect has not been observed for silicon.69,72,73 +
Cr(CO)5
R2
OMe
26
Bu2O, 45°
R1 56 R
OH
1
R2
OH
+
(Eq. 13) (CO)3Cr
OMe
(CO)3Cr OMe
R2
57
R1
58 R1 H H Me
R2 Me CF3 CF3
57 + 58 57:58 (52%) 0.82:1.00* (66%) 1.22:1.00* (62%) 1.17:1.00
* constitution not assigned OTBS TMS
1. Cr(CO)5
Sn(Bu-n)3, THF, 50°
2. TBSOTf, Et3N
OMe 59
OTBS
+ TMS Sn(Bu-n)3 TMS (CO)3Cr OMe (CO)3Cr OMe 60 (40% ) 61 (27%)
(Eq. 14) A disubstituted alkyne with a ketone function in conjugation with the alkyne reacts with high regioselectivity to give products in which the ketone function is introduced into the phenol adjacent to the methoxy group (Eq. 15).71 Reaction of complex 62 with hex-3-yn-2-one gives products 63 and 64, both as a result of the same regiochemical incorporation of the alkyne. Compound 64 is formed via cyclization of the vinyl ketene in a crossed fashion. Ester functions do not impart a strong enough effect when conjugated with an alkyne to influence the regioselectivity and as a result mixtures of isomers are observed.47,70 It is curious that a ketone, which is separated from the alkyne by two methylenes, has an effect on the regioselectivity, albeit to a lesser extent than is observed with conjugated ketones (Eq. 47).103 A recent report on the regiochemical outcome of the reactions of internal boryl alkynes may involve electronic control of the regioselectivity by boron.74,75 OH Et OMe
O
Cr(CO)5 62
THF, 50°
O
Et
Ac
+ O
Ac
OMe 63 (33%)
O Et
O OMe 64 (32%)
(Eq. 15)
THE SYNTHESIS OF PHENOLS AND QUINONES
139
Site selectivity in reactions of unsymmetrically substituted phenyl carbene complexes has been examined to some extent. In all of the reactions of 3-substituted phenyl carbene complexes 65, the major isomer 66 results from cyclization away from a meta substituent (Eq. 16).67 A very curious observation is that the magnitude of the site-selectivity observed with the 3-methoxy complex 65b is highly dependent on whether a terminal or internal alkyne is used.67 The reaction with 3-hexyne is four times less selective than the reaction with 1-pentyne. An explanation for this behavior has not been advanced. The electronic nature of the meta substituent also has a strong effect. The 3-trifluoromethylphenyl complex 65c is ten times as selective as the 3-methoxy complex 65b. The same reaction with the 3-methyl complex 65a gives a 1.2 : 1 mixture of 66a and 67a. Because the trifluoromethyl group is not significantly different in size than a methyl or methoxy group, it is clear that a strongly electron-withdrawing group directs the cyclization to the more remote para position. Two isomers are also possible in the cyclization of the 2-naphthyl complex 68. However, reaction with diphenylacetylene affords only a single isomer, namely a phenanthrene rather than an anthracene (Eq. 17).104 The actual chemical yield of this reaction is likely to be quite high and the low yield of 69 is likely a consequence of the air instability of this arene chromium tricarbonyl complex containing an unprotected phenolic hydroxy group. Cyclization to the 1-position of the naphthalene is a typical reactivity pattern for various types of cyclizations of 2-substituted naphthalenes because this option disrupts the aromaticity in only one of the naphthalene rings. This direction of cyclization of 2-substituted naphthyl carbene complexes has been confirmed in a different system by X-ray crystal structure analysis.105 OMe
(CO)5Cr
O 1. Et
R
65 65a 65b 65c
R Me OMe CF3
66 + 67 (79%) (81%) (55%)
Ph
Ph
Bu2O, 45° 68
Et
Et MeO OMe 66
Et MeO OMe 67
(Eq. 16)
66:67 1.2:1 2.1:1 25.5:1
Ph
Cr(CO)5 OMe
O
+
2. CAN/MeOH R
R Et
Et, THF, 45°
HO
Ph OMe Cr(CO)3
(Eq. 17)
69 (19%)
The normal site selectivity of the reaction of Fischer carbene complexes with alkynes can be reversed if the alkyne is tethered through the heteroatomstabilizing substituent. Either isomer of the quinone from the reaction of 4-methylphenyl carbene complex and 3-butynol can be obtained cleanly as shown
140
ORGANIC REACTIONS
in Eqs. 18 and 19.86 Carbene complex 70 and the free alkyne give the expected quinone isomer in 76% yield. The regiochemical outcome is reversed for the tethered complex 71 because the vinyl carbene complexed intermediate 72 in this reaction has the unsubstituted end of the alkyne at the C1 position. Note that in the absence of a tether, a terminal alkyne will preferentially be incorporated to give vinyl carbene intermediate (E)-4 rather than (E)-7 (Scheme 3) for the reasons discussed above. It is interesting to note that the intramolecular reaction of complex 71 gives high yields only in the presence of ten equivalents of diphenylacetylene. This phenomenon is observed for a number of intramolecular examples and is termed the xenochemical effect.86 The xenochemical effect is related to the allochemical effect84 in that the product distribution is a function of the alkyne concentration, but it differs in that the distribution is a function of the concentration of an alkyne that does not become incorporated into the product (Scheme 6). 1. Cr(CO)5 OMe 70
Cr(CO)5 O 71
O
(CH2)2OTHP, hexane, reflux
2. CAN 3. MeOH, HCl
O OH (76%)
(Eq. 18)
O
1. Ph Ph (10 eq), hexane, reflux
O (60%)
2. CAN
OH
Si Me2
O R3
R1
O
(Eq. 19)
R2 OC
Cr CO OC CO 72
Alkenyl, Aryl, and Alkynyl Chromium Complexes. The only alkenyl chromium carbene complex that will not react with alkynes to give useful yields of annulated products is the unsubstituted parent vinyl carbene complex 73 (Scheme 8). The reaction of complex 73 with 1-pentyne gives approximately a 13% yield of phenol 74.106 The origin of the failure of this reaction is not understood but it is known that complex 73 is unstable with respect to polymerization and can only be isolated in pure form below its melting point (15◦ ).107 – 109 The α-silyl-substituted vinyl complex 59 (Scheme 8) has been developed as a synthetic equivalent for the parent vinyl complex.110 The reaction of 59 with 1-pentyne followed by exposure to air and trifluoroacetic acid affords phenol 74 in 60% yield. Both the 2-propenyl and trans-1-propenyl complexes react with alkynes to give useful yields of the cyclized product (Eq. 11). The cis-1-propenyl
THE SYNTHESIS OF PHENOLS AND QUINONES
141
OH Cr(CO)5 OMe
Pr-n
Pr-n
(~13%)
CH2Cl2, 50°
73
OMe 74 OH
TMS Cr(CO)5 OMe 59
1.
Pr-n
Pr-n
CH2Cl2, 50°
2. air/CF3CO2H
74 (60%)
TMS (CO)3Cr OMe 75
Scheme 8
complex also reacts with alkynes to give phenol products but the cis- and trans1-propenyl complexes could not be compared since the former isomerizes to the trans complex at a rate competitive with the reaction with 1-pentyne.69 Interestingly, β,β-disubstituted complexes do not isomerize during their reactions with alkynes.111 The β-silyl-substituted complex 76 can also serve as a synthetic equivalent for the parent and has the additional advantage that the silicon migrates to the phenolic oxygen both obviating the need for protodesilylation and producing an air-stable arene chromium tricarbonyl complex directly from the reaction (Eq. 20).110 This process occurs because migration of silicon to oxygen is faster than tautomerization of the hydrogen in intermediate 78. Benzannulation of a β-silyl-substituted carbene complex can be coupled with a Diels-Alder reaction of an alkynyl carbene complex as illustrated in the one-step preparation of the dihydronaphthyl complex 81 (Eq. 21).95,112 In this process, the diene reacts with alkynyl complex 79 faster than with the alkyne to give the Diels-Alder adduct 80, which then reacts with 1-pentyne with silyl migration to give the arene complex 81 in 80% yield.
Pr-n
Cr(CO)5
TBS
OMe
OTBS Pr-n
CH2Cl2, 50° (CO)3Cr OMe
76
77 (72%) O Pr-n
TBS
(CO)3Cr OMe 78
(Eq. 20)
142
ORGANIC REACTIONS
OMe (CO)5Cr + 79
+
THF, 50°
Pr-n
TMS Pr-n
OMe (CO)5Cr
TMS
MeO
(Eq. 21)
OTMS
(CO)3Cr 80
81 (80% )
A wide range of substituents on the phenyl ring in an aryl carbene complex can be tolerated in the reaction. The introduction of a methyl group at the 2-position (82) has very little effect on the yield of quinone product (Eq. 22 vs. Eq. 23).84 However, the methyl substituent does have some effect on the reaction run at lower concentration and higher temperatures where both quinone and indene products are observed. A methoxy group at this position has an even greater effect (Eq. 24).84 Even if the reaction of the 2-methoxyphenyl complex 53 is run at high concentration and low temperature to maximize the six-membered ring product, indenes 84 and 85 are still formed in a combined 23% yield. More dramatically, at low concentrations and high temperatures only a trace of the quinone is observed. The yield of quinone 83 can be improved (77–91%) by utilizing a large excess of alkyne or employing a less coordinating solvent (benzene or 2,5-dimethyltetrahyrofuran).84
Cr(CO)5 OMe 26 [26] 0.1 M 0.005 M
1. Et Et, THF, temp
+
Temp 45° 110°
OMe
(88%) (87%)
(Eq. 22)
(≤0.3%) (≤1.0%)
O
Et Et +
2. CAN
Et O
Temp 45° 110°
Et
Et O
OMe 82 [82] 0.5 M 0.005 M
Et Et
2. CAN
1. Et Et, THF, temp Cr(CO)5
O
(87%) (58%)
Et OMe
(≤1.0%) (16%)
(Eq. 23)
THE SYNTHESIS OF PHENOLS AND QUINONES O
1. Et Et, THF, temp
OMe Cr(CO)5
Et
Et
Et +
2. CAN
Et
Et
OMe 53
OMe OMe 84
OMe O 83
[53] 0.5 M 0.005 M
143
Temp 45° 110°
(61%) (trace)
(18%) (65%)
+
Et OMe O 85 (5%) (10%)
(Eq. 24) The effect of the methoxy group at the 2-position may be due to a combination of coordination, electronic, and steric effects. Interestingly, the 4-methoxyphenyl complex 86 displays a different sensitivity to concentration and alkyne substitution than the does the 2-methoxyphenyl complex 53 and thus the effects of the methoxy group cannot be strictly electronic (Eq. 25).84 The 4-methoxy complex reacts with 1-pentyne to give a 30% yield of quinone 87 along with indene 88 and keto ester 89, whereas, the reaction of the 2-methoxyphenyl complex under the same conditions gives the quinone as the predominant product (not shown).84 The keto ester 89 is not a primary product of the reaction but rather results from air oxidation of furan 90, which is often seen as a by-product in this reaction but is usually difficult to isolate.65,76,77 The influence of the 4-methoxy group can only be electronic and the degree of its effect is significant because the reaction of the unsubstituted phenyl complex 26 gives a 73% yield of the quinone 29 (Eq. 2) and the 4-acetoxy complex 91 gives a 61% yield of the quinone 92 (Eq. 26).84 1.
MeO Cr(CO)5
Pr-n, THF, 45°
O
Pr-n MeO
Pr-n
MeO
+
+
2. CAN
OMe
OMe
O 87 (30%)
86 (0.5 M)
88 (37%) O O
MeO n-Pr
OMe 89 (9%)
OMe MeO
O
n-Pr 90
(Eq. 25)
144
ORGANIC REACTIONS 1.
AcO Cr(CO)5
Pr-n, THF, 45°
O Pr-n
AcO
(Eq. 26)
2. CAN
OMe
O 92 (61%)
91 (0.5 M)
Almost all of the substituent effect studies that have been carried out on the reaction of substituted phenyl complexes involve alkyl or alkoxy groups. Complexes bearing electron-withdrawing groups have rarely been studied because they are not available by the standard methods of synthesis. Fischer carbene complexes are typically prepared by reaction of chromium hexacarbonyl with the corresponding aryllithium compounds. Thus, functionality that is not compatible with an organolithium reagent cannot be easily introduced into an arylcarbene complex. A recent study provides one of the few direct comparisons of the effects of electron-withdrawing and electron-donating groups on the reactions of phenyl carbene complexes (Eqs. 27 and 28).113 Reactions of a number of para-substituted complexes with 1-pentyne were examined in benzene. The complex bearing the electron-releasing methoxy group gives low yields of quinone product and an equal amount of the indanone product (the distribution is slightly different in benzene and THF; Eqs. 25 vs. 27). The effect of the bromo substituent is negligible, whereas the trifluoromethyl group has a dramatic effect, affording a 95% yield of the quinone. The observation of a positive effect of an electron-withdrawing group was anticipated from published mechanistic studies.47 However, the yield from the 4-acetylphenyl complex is not consistent with these studies and this may be because of the instability of this complex. The reaction of the phenyl complex bearing a trifluoromethyl group in the 2-position with 1-pentyne gives a much reduced yield of quinone.113 In fact, all 2-substituted phenyl complexes give reduced yields independent of the electronic nature of the substituent. The larger the substituent the more the yield decreases (methyl vs. iso-propyl).113 The reduced yields observed with 2-substituted complexes could be the result of steric destabilization of the planar conformation of the vinyl ketene complex (E)-5 that is necessary for cyclization (Scheme 2).
1.
R Cr(CO)5 OMe 0.1 M
Pr-n, benzene, 80°
O R
Pr-n Pr-n
R +
2. CAN R OMe H Br Ac CF3
O
O (36%) (78%) (75%) (63%) (95%)
(Eq. 27) (40%) (1%) (—) (—) (—)
THE SYNTHESIS OF PHENOLS AND QUINONES 1. OMe
O
Pr-n, benzene, 80°
145 Pr-n
Pr-n +
2. CAN R Cr(CO)5 0.1 M
R
R H OMe CF3 Me i-Pr
O
R
(78%) (60%) (64%) (66%) (49%)
O
(Eq. 28)
(1%) (—) (—) (—) (11%)
The reactions of a number of internally coordinated tetracarbonyl carbene complexes have been investigated but the effects of such coordination on product distribution have not been carefully determined in many systems. Given the sensitivity of the reactions of the 2-methoxy-substituted phenyl carbene complex 53 to concentration, temperature, and solvent (Eqs. 24 and 28), it is necessary that comparisons be made with full awareness of the exact reaction conditions. One system in which a comparison under precise control of conditions has been made is the reaction of the 2-methoxy-4-acetoxyphenylcarbene complex 94 (Eq. 29).84 The chelated complex 94 can be generated in high yield by heating 93 in THF. The reaction of both complexes at 110◦ , and at 0.005 M in carbene complex with 1.5 equivalents of alkyne gives an essentially identical profile of the three products. From this experiment it can be concluded that it makes no difference whether 2-O-substituted phenyl carbene complexes are used as either the pentacarbonyl or the coordinated tetracarbonyl complexes. Often, the transient formation of an internally coordinated complex can be observed during the course of a reaction of a non-coordinated complex with an alkyne. AcO
1.
AcO Cr(CO)5
or
OMe MeO
OMe OMe 93
2. CAN
Cr(CO)4
94 O AcO
Pr-n
OMe O (41%) (41%)
AcO
AcO
Pr-n +
93 94
Pr-n THF, 110°
Pr-n
+ OMe O (12%) (14%)
OMe O O
OMe
(18%) (14%)
(Eq. 29) Although the reactions of complexes 93 and 94 demonstrate that the product distribution is not dependent on whether the methoxy group is coordinated prior to the reaction, the results in Eqs. 24 and 30 suggest that coordination by the methoxy group at some point in the reaction may take place. The chromium should be much less able to coordinate to a tert-butoxy group than to a methoxy
146
ORGANIC REACTIONS
group. Thus, if coordination of the methoxy group is responsible for the differences in the reactions of phenyl complex 26 and the 2-methoxyphenyl complex 53 (Eqs. 22 and 24), then the reaction of the 2-tert-butoxyphenyl complex 95 (Eq. 30) should have a product distribution more similar to that of 26 than to that of 53. On the other hand, if the effect is strictly electronic, then the two oxygenated complexes 53 and 95 should produce the same distribution. The result is intermediate between these extremes. It is clear that hindered protecting groups on the oxygen substituent allow preferential formation of the quinone product. The reaction of 2-tert-butoxyphenyl complex 95 with 3-hexyne at 0.5 M and 45◦ affords a 96% yield of the quinone with less than 1% of the indene (Eq. 30), whereas under the same conditions the 2-methoxyphenyl complex 53 affords only a 61% yield of the quinone and 23% of the indene (Eq 24).84 Note that the data in Eq. 28 predict that the yield of quinone from the reaction of complex 95 would be less than that for 53 (Eq. 24) given the size of the 2-substituent. However, the reactions in Eq. 28 are performed in a different solvent and are carried out on a terminal alkyne. Internal and terminal alkynes can have quite different product distributions (see below).
OMe
O
1. Et Et, THF, temp
+
2. CAN t-BuO
Cr(CO)5 95 [95] 0.5 M 0.005 M
Et Et
Et t-BuO
Temp 45° 110°
Et Et
O
(96%) (7%)
t-BuO
OMe
(≤1%) (54%)
+ t-BuO
Et O
(—) (8%)
(Eq. 30) The sulfur-coordinated complex 97 has been prepared and its reaction with 4-pentyn-1-ol has been compared with that of the non-coordinated complex 96 (Scheme 9).91 The reactions are carried out by adsorption on silica gel and the internally coordinated complex gives a 39% yield of the phenol 98, double that of the non-coordinated complex. No other products are reported for this reaction and the fate of the remainder of the substrate is not known. The coordinated complex is more stable than the non-coordinated complex, and thus the increased yield may be due to competing decomposition of complex 96. It is likely that the loss of sulfur arises from an in situ reduction of the cyclohexadienone 99 by chromium(0) to give 98.80 A variety of heteroaryl Fischer carbene complexes give good yields of annulated phenols and quinones. The reaction of the 2-furyl complex 100 with 3hexyne provides the quinone 101 in 85% yield after oxidative workup with CAN (Eq. 31).114 The reaction of the 3-furyl complex 102 gives the same quinone in 77% yield with no detectable amount of an isobenzofuran that would result from the alternate siteselectivity in the cyclization.104,114 The furan complex 100 reacts with the functionalized alkyne 104 in the presence of acetic anhydride to give
THE SYNTHESIS OF PHENOLS AND QUINONES
147
OMe (CO)5Cr O
S Ph 96
1. 45o, benzene (76%)
OH
(CH2)3OH silica gel, 80°
OH
2. pyridine N-oxide
O OMe
OMe
98 (19%) from 96 (39%) from 97
(CO)4Cr O
S Ph
Ph S O
97
OH O OMe 99
Scheme 9
the benzannulated product 105 (Eq. 32).115 The same reaction of the 2-pyrrolyl complex 103 is more efficient, providing the highly functionalized indole 106 in 62% yield.115,116
O
Cr(CO)5 O
1. Et Et, THF, 70°
OMe 100
Et
2. CAN O
O
Et
(Eq. 31)
O
Cr(CO)5
101 (85%) from 100 (77%) from 102
OMe 102
OAc OTBS X
Cr(CO)5 OMe
100 X = O 103 X = NMe
OTBS
+ EtO
THF, 65° Ac2O, NEt3
104
X
OEt OMe 105 X = O (43%) 106 X = NMe (62%)
(Eq. 32)
The site selectivity of the annulation of a 3-pyrrolyl carbene complex can be reversed by blocking the 2-position. This was demonstrated in the reaction of the 2,5-dimethyl-3-pyrrolyl complex 107 with diphenylacetylene to give a substituted isoindolequinone (Eq. 33).117 The synthetic utility of indole-substituted
148
ORGANIC REACTIONS
carbene complexes is illustrated in the reaction of the 2-indolyl complex 108, which reacts with 3-hexyne to give a carbazoloquinone in 81% yield (Eq. 34).62 Pyridylcarbene complexes have proved difficult to make118 – 120 and for this reason dihydropyridyl complexes of the type 109 were developed as synthetic equivalents for 2-pyridyl complexes (Eq. 35).121 Subsequent to annulation with an alkyne, the pyridine ring may be reoxidized with trityl tetrafluoroborate, which also oxidizes the hydroquinone ring to give substituted quinolinoquinones. 1. Ph Ph, toluene, 95°
Me N Cr(CO)5
O Ph Me N
2. air
OMe 107
Cr(CO)5 N Me
OMe
O (44 %) O
1. Et Et, THF, 50°
OMe
N Boc Cr(CO)5 109
Pr-n, THF, 60°
2. air
Et
(Eq. 34)
Et
2. CAN
N O Me (81%)
108 1.
(Eq. 33)
Ph
OH
O Pr-n
N Boc OMe (58%)
Pr-n
Ph3C+ BF4– N O (70%)
(Eq. 35) There have been occasional reports of the benzannulation of Fischer carbene complexes bearing heteroatoms at a position beta to the carbene carbon. Examples already discussed include the β-silyl substituted complexes 76 and 80 (Eqs. 20 and 21)112,110 and a β-thio ether complex 96 (Scheme 9).91 The sulfone complex corresponding to 96 also undergoes benzannulation with loss of the sulfone to give phenolic products related to 98 where the sulfur is lost in the aromatization.91 Only two examples of cyclization of complexes bearing β-oxygen substituents are known. In the first, the β-methoxyalkenyl complex 110 reacts with 1-pentyne to give phenol 111 in 64% yield (Eq. 36).122 The loss of the methoxy group from the cyclohexadiene complex 112 is likely a result of reduction by chromium(0) to give a chromium(II) phenolate complex.80 The second example is the reaction of the internally coordinated naphthyl complex 113 with the alkyne 114 to give the substituted phenanthrene 115 (Eq. 37).105 This example demonstrates the strong preference for cyclization of a 2-naphthyl complex to the α-position. With complex 113, this preference is strong enough to force cyclization to occur ipso to the methoxy despite the fact that the other ortho position is unsubstituted. An amino group in the β-position leads to the exclusive formation of cyclopentadiene products. This reaction has been examined extensively and is illustrated by the
THE SYNTHESIS OF PHENOLS AND QUINONES
149
reaction of complex 116 which gives the cyclopentadiene 117 in 77% yield (Eq. 38).123 Depending on the conditions and substrates, a variety of products have been observed from the reaction of β-amino complexes.30
MeO
β
1.
α
Cr(CO)5
OH
Pr-n, MeCN, 50°
Pr-n
2. air
OMe 110
OMe MeO
(Eq. 36)
111 (64%)
O Pr-n
(CO)3Cr OMe 112 OMe OMe + OMe MeO
OMe
1. t-BuOMe, 50° CO2Me 2. PPh3, acetone, CO2Me Ac 2O, NEt3
Cr(CO)4
113
114
AcO
115 (44%)
CO2Me CO2Me
(Eq. 37) NMe2
NMe2
Pr-n n-Pr
EtO
(Eq. 38)
THF, 52° Cr(CO)5 116
OEt 117 (77%)
Cyclization occurs onto an α,β-unsaturated carbene complex that bears a β-halogen substituent. The two known examples involve fluorine and chlorine substituents. The β-chloroalkenyl complex 120 reacts with phenylacetylene to give a significantly higher yield of the quinone 119 than the corresponding unchlorinated complex 118 (Eq. 39).124 The α,β-difluoro complex 121 reacts in a similar fashion to afford (after cyclization and reductive cleavage of the fluorine) phenol 122 in 35% yield (Eq. 40).125 Cyclization does not occur if the βfluoro substituent is on a benzene ring.126 The reaction of the 2,6-difluorophenyl complex 123 with diphenylacetylene affords the cyclobutenone 124 as the major product (Eq. 41).126 A second product, 125, results from cyclization, not onto the phenyl group of the carbene complex, but onto the phenyl group of the alkyne. Both products from this reaction are obtained as chromium tricarbonyl complexes but in each case it was not determined which of the aryl rings is coordinated.
150
ORGANIC REACTIONS Cr(CO)5 O
BnO
OEt
Ph, SiO 2, 80°
O O
BnO
2. CAN
R
BnO
1.
BnO
BnO 118 R = H 120 R = Cl
Cr(CO)5
n-Bu
OMe 121
F MeO
F 123
(Eq. 39)
OH
1. Ph Ph, t-BuOMe, 55°
n-Bu
Ph
F
Ph
2. FeCl3-DMF
(Eq. 40)
OMe 122 (35%)
1. Ph Ph, n-Bu2O, 100°
O
OMe
F • Cr(CO)3
2. air
(CO)5Cr
O
119 (19%) from 118 (48%) from 120
F
F
Ph BnO
Ph
+
Ph F 124 (30%)
(Eq. 41) F
F OMe Ph
• Cr(CO)3
125 (—)
The benzannulation of α-alkynyl complexes has been reported and is illustrated in Scheme 10.127 Mechanistically, this reaction must be quite distinct from that of alkenyl- and arylcarbene complexes (Scheme 1). Intramolecular reaction of the pendant alkyne in complex 126 and carbon monoxide insertion is proposed to give an alkynyl-substituted vinyl ketene complex of the type 127. Cyclization of this vinyl ketene complex then gives a diradical intermediate, which upon hydrogen abstraction gives a benzannulated product. Note that the indoline 129 obtained from thermolysis of complex 126 is the same product that could be produced from the alkenyl complex 131 by the normal mechanism. However, complexes of the type 131 do not give phenols but rather cyclize without CO insertion to give a cyclopentadiene unit that is embedded into an azabicyclo[3.3.0]octane.128 The indoline 129 cannot be isolated as its chromium tricarbonyl complex. However, if the reaction of 126 is carried out in the presence of triethylsilane as hydrogen donor, the silyloxyindolinylchromium tricarbonyl complex 130 is isolated in 41% yield. Recently, an alternative entry to diradical intermediates of the type 128 from saturated carbene complexes has been reported, and the synthetic utility of these intermediates has been further explored.129,130 Alkyne Components. The reactions of α,β-unsaturated Fischer carbene complexes with alkynes will tolerate a broad range of functional groups present in the alkyne. Less tolerant are alkynes that are conjugated to strongly electronwithdrawing or electron-donating groups and also alkynes that are very bulky.
THE SYNTHESIS OF PHENOLS AND QUINONES
γ-terpinene, Ac2O, NEt3
(CO)5Cr N Me
Ph
O
.
• N Me Cr(CO)3
THF, 85° Ph
126
151
O
.
Ph
127
128
Et3SiH THF, 85°
H source
Et3SiO
AcO
(CO)5Cr N Me Cr(CO)3
Ph
N Me Cr(CO)3
N Me
Ph
130 (41%)
Ph
131
N Me
129 (53%)
Scheme 10
Coordination of functional groups on the alkyne to the metal can lead to sideproduct formation. Functional groups on the alkyne that survive under the reaction conditions include alkenes, alkynes (hindered), halides, silanes, stannanes, ethers, thio ethers, seleno ethers, acetals, epoxides, ketones, esters, amides, nitriles, nitro groups, sulfoxides, and sulfones. Alcohols can be tolerated by the reaction in some instances (see below). The reaction of Fischer carbene complexes with acetylene fails to give useful amounts of the normal benzannulation product. For example, the reaction of complex 26 with two equivalents of acetylene affords a 1% yield of naphthol 132 and a 36% yield of the two-alkyne phenol 133 (Eq. 42).131 The two-alkyne phenol results from incorporation of the carbene carbon, a carbon monoxide ligand, and two equivalents of the alkyne. The primary product is the cyclohexadienone complex of the type 134, which is reduced by chromium(0) to the phenol.80 The yield of the two-alkyne phenol drops sharply with substituted alkynes. The reaction of 26 with propyne provides useful yields of the naphthols and only 4% of the two-alkyne phenol corresponding to 133.131 OH OH
(2 eq) Cr(CO)5
+
THF, 45°
OMe
OMe 132 (1%)
26 O
OMe Ph
(CO)3Cr 134
133 (36%)
(Eq. 42)
152
ORGANIC REACTIONS
Trimethylsilylacetylene can serve as a synthetic equivalent for acetylene because it affords high yields of the normal benzannulated product and can be subject to clean proto-desilylation (Eq. 43, Scheme 8).69,101,110 Bulky silylsubstituted alkynes can lead to the isolation of vinyl ketenes that are stabilized by the α-silyl substituent.57,61,132 – 134 Thus, reaction of phenyl complex 26 with phenyl(triisopropylsilyl)acetylene gives the vinyl ketene in 88% yield (Eq. 44).134 Whereas stannyl-substituted alkynes do not yield stable vinyl ketenes, they have been reported to cause a reversal in the site selectivity of alkyne incorporation into phenolic products (Eq. 14).72,73 OH
R2 R1
R2
TMS
OMe
OH TMS
R2
+
H
(Eq. 43)
R1
Cr(CO)5
R1 OMe
OMe O
Cr(CO)5
Ph
TIPS
Ph
benzene, 80°
OMe
TIPS
•
(Eq. 44)
(88%)
OMe Cr(CO)3
26
The efficiency of phenol formation from unfunctionalized alkynes is quite different for internal and terminal alkynes. The reactions of 4-substituted phenyl carbene complexes in benzene with 3-hexyne (Eq. 45) are compared to the same reactions with 1-pentyne (Eq. 27).113 Reactions with 3-hexyne produce greater than 90% yields of quinone products for all 4-substituted phenyl complexes including those with electron-deficient as well as electron-donating substituents. The yields are also generally higher for reactions of ortho-substituted complexes with 3-hexyne compared to 1-pentyne (Eq. 46 and Eq. 28). However, as in the reaction of 1-pentyne (Eq. 27), the yields from reactions of 3-hexyne with orthosubstituted complexes are also suppressed relative to those of the unsubstituted phenyl complex (Eqs. 45 and 46). There are two reports of the reactions of cyclic alkynes, and the example shown in Eq. 47 is of interest because it reveals that a carbonyl group separated from an alkyne function by two methylenes can influence the regioselectivity.103,135 R OMe
1. Et Et, benzene, 80°
O R
R OMe H Br CF3
R +
2. CAN Cr(CO)5
Et Et
Et
Et O
O
(93%) (96%) (93%) (96%)
(—) (<0.7%) (<1%) (—)
(Eq. 45)
THE SYNTHESIS OF PHENOLS AND QUINONES
OMe
O
1. Et Et, benzene, 80°
Et Et +
2. CAN R
Et
Et
Cr(CO)5
R
R H OMe CF3 Me
153
R
O
O
(Eq. 46)
(<0.7%) (7%) (—) (—)
(96%) (77%) (74%) (58%)
O O
R
Cr(CO)5
O
1. THF, 45°
OMe +
O +
2. CAN O
R
O
R H OMe CF3
R
I I + II (89%) (69%) (42%)
O
II
(Eq. 47)
I :II (—) 2.3:1.0 1.5:1.0
Although alkenes react with Fischer carbene complexes to produce cyclopropanes,136 they do so too slowly to compete with the benzannulation reaction. Thus, the reaction of Fischer carbene complex 34 with (Z)-1-methoxybut-1-en-3yne results in a good yield of the phenol (Eq. 48).69 The compatibility of alkenes with the benzannulation reaction has also been demonstrated in an intermolecular competition experiment. The yield of the quinone from the reaction of complex 53 and 3-hexyne (Eq. 24) is unchanged (58%) when carried out in the presence of four equivalents of ethyl vinyl ether137 even though, in the absence of 3-hexyne, ethyl vinyl ether gives good yields of cyclopropane.138 MeO Cr(CO)5 OMe 34
OH
O
(2 eq),
TsOH
(Eq. 48)
OMe
THF, 45° OMe (68%)
OMe (70%)
Conjugated 1,3-diynes react with one equivalent of a Fischer carbene complex to provide the benzannulated product in which one of the alkynes has been incorporated in a process that is unaffected by the presence of the other alkyne. After decomplexation of the metal from the phenol 135 by exposure to air, a second benzannulation can be carried out to give biaryl product 136 in good yield (Eq. 49).100 Interestingly, product 136 cannot be obtained by direct reaction of the diyne with an excess of the carbene complex. It thus appears that the presence of a chromium tricarbonyl group on the mono-annulated product 135 hinders subsequent reaction with a second equivalent of carbene complex. The reactions
154
ORGANIC REACTIONS
of conjugated 1,3,5-triynes are complicated by the ability of a carbene complex to react either with the central alkyne unit or with one of the two terminal alkyne units. Steric interactions predict that the reaction would be selective for the central alkyne. The cyclohexenyl complex 34 reacts at the central alkyne with 1,3,5-triynes that are capped with triisopropylsilyl groups. Surprisingly, the triyne capped with a phenyl group gives rise to exclusive incorporation of a terminal alkyne unit (Eq. 50).139 1. Ph THF, 66° Cr(CO)5
OH
Ph,
Ph
1. 34, THF, 70°
2. air
2. air
OMe
OMe 135 (67%)
34
Ph
(Eq. 49)
OH Ph
Ph OMe
MeO
HO
136 (56%)
Cr(CO)5 OMe 34
1. R THF, 55°
R
2. air OH R
OH
R
OMe
R
(Eq. 50)
or OMe R (43%) R = Ph
(70%) R = TIPS
Heteroatom-substituted alkynes do not always react with Fischer carbene complexes to give phenolic products. Ynamines are reactive towards Fischer carbene complexes and react below room temperature to give simple non-cyclized insertion products.140,141 This reaction occurs by a mechanism that is different from that for simple alkynes. The reaction is first order in both carbene complex and ynamine.141 The insertion products undergo a thermally induced cyclization that leads to indene products and not to phenols, presumably due to the electronrich nature of α,β-unsaturated complexes of type 137 (Eq. 51).142 In contrast to ynamines, alkoxy-substituted alkynes such as 104 do react with carbene complexes to give phenols (Eq. 32). Terminal alkoxy acetylenes also yield insertion products analogous to 137.143 Alkynyl thio ethers do not react with chromium carbene complexes in the same way as either ynamines or alkoxy acetylenes, but rather give very unusual dienyne products that are unprecedented in all
THE SYNTHESIS OF PHENOLS AND QUINONES
155
the reactions of carbene complexes with alkynes (Eq. 51).144 Tungsten complexes react with thioalkynes to give insertion products analogous to 137.145 Haloacetylenes react with Fischer carbene complexes to generate complex mixtures of products.72,146 MeO n-Bu
Bu-n
Ph
SMe
(39%)
Ph
hexane, 80˚ n-Bu
MeO
OMe
(Eq. 51)
Cr(CO)5 Ph 26
NEt2
NEt2
(CO)5Cr
Ph
hexane, 20° 137
(70%)
OMe
The presence of an alcohol function on the alkyne can sometimes be tolerated, but can also lead to intramolecular trapping of the complexed vinyl ketene intermediate to give lactones. This behavior is dependent on the length and substitution of the tether between the alkyne and the alcohol function and on the nature of the carbene complex. A dramatic example of this dependence is the reaction of the two propargylic alcohols shown in Eqs. 52 and 53. Propargyl alcohol gives only the phenol (Eq. 53),147 whereas substituted propargylic alcohols give β-lactones as the exclusive products (Eq. 52).148 This divergence has been attributed to the Thorpe-Ingold effect.148 Interestingly, alkynes similar to 138 that contain a 4-membered ring can afford either ring-expanded or cyclobutenone products.149 OH
Ph +
(CO)5Cr
O
O THF, reflux
Ph
Ac2O, NEt3
OMe 26
138
(52%)
(Eq. 52)
OMe
OH OH Cr(CO)5 OMe 26
+
OH
t-BuOMe
(Eq. 53)
45° OMe (60%)
Homopropargylic alcohols afford substantial amounts of lactone product with aryl complexes but not with alkenyl complexes.147 Whereas the reaction of 4methylphenyl complex 70 affords naphthol 139 in only 17% yield along with the lactone 140 in 33% yield (Eq. 54a), the reaction of alkenyl complex 141 with 3-butyn-1-ol affords phenol 142 in good yield (Eq. 54b).147 Lactone 140 is depicted as the Z-enol ether rather than as the E-enol ether that was originally reported. Subsequent work established that the enol ether from the reaction
156
ORGANIC REACTIONS
of 4-pentyn-1-ol with complex 70 was assigned incorrectly as the E-enol isomer and thus it is considered likely that the enol ether configuration of 140 was also incorrectly assigned as the E-isomer.65 The Z-isomer of the complexed vinyl ketene intermediate 143 cannot cyclize to the naphthol 139. Because the E-isomer of 140 is not observed, it can be assumed that for the E-isomer of ketene complex 143, intramolecular trapping of the ketene by the hydroxy group cannot compete with cyclization to phenol 139. Longer-chain alcohols give much less of the ketene-trapped product. The reactions of complex 70 with 4-pentyn-1-ol and 5-hexyn-1-ol give the corresponding naphthols in 44 and 75% yields, respectively.147
OH
OH
OH +
Cr(CO)5
t-BuOMe, 45°
OMe
OMe 70
O O
OMe 139 (17%)
140 (33%)
(Eq. 54a) OH
OH OH
Cr(CO)5 t-BuOMe, 45°
OMe
OMe
141
142 (76%)
(Eq. 54b)
Cr(CO)3 Cr(CO)3
MeO • O (E)-143
OH OMe
• O
OH
(Z)-143
The presence of a propargyl ether function can be detrimental to benzannulation especially for the reaction of electron-rich aryl carbene complexes. Whereas the tert-butyldimethylsilyl ether of 1-hexyn-3-ol reacts with complex 144 to give only the naphthol product 145, the corresponding methyl ether gives a mixture of naphthol 145 and furan 146 (Eq. 55).150 These examples suggest that coordination of the propargyl oxygen to chromium during the reaction is somehow responsible for the formation of furans. An increase in the level of substitution at the propargylic position is also detrimental to the reaction but not as a result of furan formation. For example, the indene product 147 is formed in 28% yield from the reaction of complex 144 with the quaternary TBS-protected propargyl ether prepared from 3-methyl-1-hexyn-3-ol.150 This steric effect is also observed for alkynes that do not bear propargylic oxygen substituents.84
THE SYNTHESIS OF PHENOLS AND QUINONES R1
OMe Cr(CO)5
157
Pr-n
OR2
OMe
THF, 60° OMe 144
R1 Pr-n
OMe OH OR2 R1 Pr-n +
R2O MeO
OMe
OMe
(Eq. 55)
O
146 R1 H H Me
R2 Me TBS TBS
OR2
+ OMe OMe
OMe OMe 145
R1 Pr-n
OMe 146 (16%) (—) (—)
145 (24%) (46%) (30%)
147 147 (—) (—) (28%)
Propargyl ether functions can lead to high yields of naphthol products if the oxygen carries a tert-butyldimethylsilyl group and the aryl ring of the carbene complex is not electron-rich. This behavior is illustrated in the reaction of phenyl complex 26 with bis-propargyl ether 148, which provides the naphthol 149 in 85% yield (Eq. 56).151 The phenol functionality is not acetylated, but if acetic anhydride is not present the reaction falls. Alkenyl complexes are much less susceptible to side product formation with propargyl ethers. The reaction of carbene complex 76 with propynal diethyl acetal gives a 53% yield of the chromium tricarbonyl complex 150 (Eq. 57).110 Complexation of the propargyl ether oxygen is not a problem for the reaction of trans-1-propenyl complex 50 as it is for the reaction of the aryl complex 144 (Eq. 55) given that an 82% yield of the phenol complex 151 is produced in this reaction (Eq. 58).88 Homopropargyl ether functions can also interfere with the benzannulation reaction.152 TBSO OBn Cr(CO)5
OTBS OH
Ac2O
+
OBn OTBS
heptane, 80°
OMe 26
148
OMe OTBS 149 (85%)
(Eq. 56) TBSO TBS
Cr(CO)5 OMe 76
OEt +
CH2Cl2, 50°
OEt OEt
OEt
(53%)
(CO)3Cr OMe 150
(Eq. 57)
158
ORGANIC REACTIONS OMe
TBSO Cr(CO)5
OMe
CH2Cl2, 50°
+
(82%) dr = 85:15
TBSOTf, 2,6-lutidine
OMe 50
(CO)3Cr OMe 151
(Eq. 58)
Propargylsilanes react to give phenols but only if they are unsubstituted at the propargylic carbon. The reaction of the phenyl complex 26 with 1-trimethylsilyl2-propyne gives the normal phenol product in 62% yield (Eq. 59).153 However, phenols are not observed if an additional substituent is present in the 1-position of the propyne.154,155 These propargylsilanes stereoselectively produce only the E,Edienes. This type of product may be formed when the normal cyclization process is thwarted by a β-silyl elimination from the intermediate η1 ,η3 -vinyl carbene complexed intermediate 152 with subsequent reductive elimination resulting in the formation of a carbon-silicon bond. R
R Cr(CO)5
TMS
TMS
solvent, reflux
OMe 26
Solvent dioxane dioxane THF
OH R
MeO TMS
+ OMe
R Ph n-Pr H
(82%) (75%) (—)
TMS
Ph
(—) (—) (62%)
(Eq. 59)
OMe Cr(CO)4
R 152
Reactions of alkynes that are conjugated to ketone or ester groups do give phenol products but in diminished yields when compared to unfunctionalized alkynes. The reaction of phenyl complex 26 with 3-butyn-2-one affords the naphthol product in 42% yield (Eq. 60).70 No other products are reported from this reaction. The reaction of the same complex with ethyl propynoate affords the naphthol in 41% yield.70 These are the highest yields reported to date with any alkoxy carbene complex having a terminal alkynone or alkynoate ester; however, there is a high-yielding reaction of ethyl propynoate and an amino complex.156,157 Higher yields of naphthols can be obtained from conjugated alkynyl esters if the alkyne is internal.70 The ester functionality has little influence on regioselectivity when the alkyne is internal. The reaction of conjugated alkynyl ketones in an internal alkyne also gives higher yields but of two predominant products, as illustrated by the reaction of 62 where an unusual tricyclic lactone 64 is produced along with the normal product 63 (Eq. 15).71 Both products are formed by the same regiochemistry of incorporation of the alkyne. The reaction of complex 53
THE SYNTHESIS OF PHENOLS AND QUINONES
159
with alkyne 153 illustrates that the presence of non-conjugated ketone and ester groups is usually tolerated (Eq. 61).158 OH O
O Cr(CO)5
+
R
THF
R
65° OMe
R Me (42%) OEt (41%)
(Eq. 60)
OMe
26
OH
OMe
Ac
Cr(CO)5
+
45°
MeO2C
OMe
Ac
benzene CO2Me OMe (81%)
153
53
(Eq. 61) Alkynyl borate esters participate in the benzannulation reaction. The reaction of phenyl complex 26 with alkynylborate 154 affords a single isomer of the naphthol 155 along with a small amount of the protiodeboronated product 156 (Eq. 62).74,75 This reaction has considerable synthetic potential because it represents an example of a regioselective insertion with an internal alkyne. Moreover, the pinacol boronate products are suitable for Suzuki cross-coupling reactions. OH
n-Bu Cr(CO)5
B O O
+
THF B O OMe O
45°
OMe 26
OH
Bu-n
154
Bu-n + OMe 156 (15%)
155 (73%)
(Eq. 62) The benzannulation reaction is also compatible with a number of groups that could coordinate to the metal and interfere with the reaction such as thio ethers91,114,159 (Scheme 9) and nitriles. Interestingly, the reaction of the cyclohexenyl complex 34 with the 6-cyano-1-hexyne (Eq. 63)12,159 occurs to give a slightly higher yield of the desired product than does the reaction of this complex with 1-pentyne (Eq. 10). OTIPS Cr(CO)5 + OMe 34
(CH2)4CN
CN
TIPSOTf, 2,6-lutidine CH2Cl2, 50° (CO)3Cr OMe 157 (76%)
(Eq. 63)
160
ORGANIC REACTIONS
Heteroatom Stabilizing Substituents. The most thoroughly studied class of non-oxygen-stabilized carbene complexes is that of the amino carbene complexes. These complexes are more electron-rich and as a consequence have stronger bonds to the carbon monoxide ligands, which in turn leads to decreased proportions of products that incorporate carbon monoxide. The reactions of amino carbene complexes with alkynes in DMF have been developed as an efficient method for the synthesis of indenes.79 The effect of solvent on this reaction is illustrated in the combination of the morpholine complex 158 with 1-hexyne. In THF, the phenol and indanone products are formed in 18% and 43% yields, respectively, whereas in DMF the latter is favored over the former by a factor of 13 : 1 (Eqs. 64a and 64b).160 The indanone is a secondary product of the reaction that results from hydrolysis of the indene 159 upon purification on silica gel. The highest yield of the naphthol (50%) is obtained when the reaction is run in hexane. The efficiency of indene formation is highly dependent on the nature of the substituents on nitrogen. Reaction of the pyrrolidino complex 160 with 1-hexyne in DMF gives the indanone in 49% yield (Eq. 64b),79 whereas reaction of the dimethylamino complex corresponding to 160 with 1-pentyne in DMF gives only a 32% yield of the indanone product.83 Internal alkynes usually give higher proportions of indenes than do terminal alkynes. However, with morpholino carbene complex 158 there is not much difference. The reaction of this complex with 1hexyne in DMF gives a 90% yield of the indenone product (Eq. 64a) and under the same conditions it gives a 96% yield of indanone product with 3-hexyne.79 OH Cr(CO)5
Bu-n
N
+
120°
+ N
O O 158
Solvent DMF MeCN THF hexane
O
Bu-n
Bu-n
N O O
O (7%) (9%) (18%) (50%)
(90%) (71%) (43%) (13%)
Bu-n
(—) (3%) (7%) (12%)
(Eq. 64a)
Bu-n
N O 159
Bu-n Cr(CO)5 N
Bu-n
(49%)
DMF, 120° O
160
(Eq. 64b)
THE SYNTHESIS OF PHENOLS AND QUINONES
161
Phenols can be obtained from the reaction of amino carbene complexes bearing non-aromatic substituents.54,83 Reaction of the cyclohexenyl complex 161 with 1-pentyne in benzene affords the phenol 162 in 66% yield with no detectable amount of the five-membered ring product 163 (Eq. 65).83 The formation of phenols from aminoalkenyl complexes is limited to terminal alkynes. The reaction of complex 161 with 3-hexyne gives a complex mixture of products, none of which is the expected phenol.83 Reactions of amino complexes with alkynes can give a number of unusual products that are derived from internal trapping of the vinyl ketene complex by the amino group.22 This trapping leads to zwitterionic species of the type 165, which can be isolated from the reaction of complex 164 with diphenylacetylene in refluxing cyclohexane (Eq. 66).161 Many other reactions of this type lead to products that result from a Stevens-type rearrangement of this zwitterionic intermediate that gives rise to lactams. This rearrangement is usually seen with groups of greater migratory propensity than methyl. An example is the reaction of the pyrrolidino carbene complex 160 with 1-phenylpropyne to give the bicyclic lactam 166 in 38% yield (Eq. 67).77 OH Cr(CO)5
Pr-n
Pr-n
Pr-n
+
solvent, 80°
NMe2 161
162 Solvent benzene THF DMF
162 (66%) (57%) (25%)
O
NMe2
163
163 (≤2%) (12%) (13%) Me O
(CO)5Cr Ph NMe2
(Eq. 65)
Me
N
Ph
Ph
C6H12, 80°
(Eq. 66)
Ph Cr(CO)3
164
165 (55%) Ph Cr(CO)5 N
Ph
N
benzene, reflux
O
(Eq. 67)
(CO)3Cr 160
166 (38%)
The propensity of amino complexes to give indenes instead of phenols can be alleviated by installing a carbonyl group on the nitrogen162,163 or by incorporating the nitrogen atom into a pyrrole.164 Both of these modifications attenuate the electron-donating capacity of the nitrogen atom to the carbene carbon. The tertbutyl carbamate complex 167 reacts with 3-hexyne to give predominantly the
162
ORGANIC REACTIONS
phenol-derived product 168 in 56% yield along with an 11% yield of the indene 169 (Eq. 68)162 Similar reaction of the methoxy complex 26 gives the quinone in 88% yield (Eq. 22).84 Although the reaction of an N ,N -dialkylamino complex corresponding to 167 has never been investigated under these conditions with 3-hexyne, no N ,N -dialkylamino aryl carbene complex has ever been reported to react with an internal alkyne in any solvent to give a phenol. Alternatively, electron density can be removed from an amino complex through the carbon substituent to give enhanced yields of phenols. The alkenyl amino complex 170 bearing an ester group gives good to excellent yields of phenols even with internal alkynes as illustrated by the formation of phenol 171 in 75% yield (Eq. 69).156,157 In the absence of electron-withdrawing groups, alkenylamino complexes fail to give phenols with internal alkynes.83 In contrast to the carbamate complex 167, certain N -acyl complexes react with alkynes to give pyrroles. Complex 172 reacts with methyl propiolate to give the pyrrole 174 in a process that has been shown to involve a [3 + 2] cycloaddition of the alkyne with in situ generated munchnone 173 (Eq. 70).165 (CO)4Cr
N Bn
OAc
1. Et Et, toluene, 55°
O
Et
Et
Et
+
OBu-t 2. Ac O, Et N 2 3 3. FeCl3-DMF
Et N CO Bu-t 2 Bn 169 (11%)
N Bn CO2Bu-t 168 (56%)
167
(Eq. 68) OH EtO2C
Cr(CO)5 N
1. Et Et, THF, 60°
EtO2C
Et
(Eq. 69)
Et
2. SiO2
N
170 171 (75%) O
O
(CO)4Cr
N Me 172
Ph
THF, rt
CO2Me O
CO (30 psi) Ph
N Me 173
CO2Me Ph
Ph
N Me
Ph
(Eq. 70)
174 (80%)
A limited number of reports have described the reactions of sulfur-stabilized Fischer carbene complexes with alkynes. Although it has been reported that this reaction can proceed without the assistance of a Lewis acid,166 most of the studies have employed boron trifluoride etherate to afford the best, albeit still low, yields.167,168 The thiomethyl phenyl complex 175 reacts with 3-hexyne in the presence of five equivalents of boron trifluoride etherate and five equivalents of acetic anhydride to give the acetylated phenol 176 in 13% yield (Eq. 71).167 The reaction of 175 with 1-hexyne under the same conditions is more efficient, giving the acetylated phenol 177 in 45% yield.167 It is interesting to note that
THE SYNTHESIS OF PHENOLS AND QUINONES
163
the reaction of the thioethyl analog of 175 with 3-hexyne in THF affords a 46% yield of the naphthol in the absence of Lewis acids.166 OAc Et
Et
Et
(13%) Et
Cr(CO)5
SMe 176
Ac2O, Et3N, BF3•OEt2
(Eq. 71)
THF, 65°
SMe
OAc Bu-n
n-Bu
175
(45%) SMe 177
The benzannulation of alkoxy carbene complexes has been carried out almost universally on either methoxy or ethoxy complexes. There is little data available on the effect of the alkoxy group on either the yield or the product distribution from reactions with alkynes. When the same reaction has been reported with two different alkoxy groups, the results often conflict.88,91,100,159 In the only systematic study on the effect of the size of the alkoxy group, it was found that the yields of quinone product are higher for isopropoxy groups compared to methoxy groups in reactions of aryl complexes with 1-pentyne (Eq. 72).113 This effect was not general because no difference is seen for electron-donating substituents in the 4-position or for any type of substituent in the 2-position. The deleterious consequences of 2-substitution in an aryl complex (Eq. 28) cannot be offset by substitution of isopropoxy for methoxy.113 The benzannulation of aryloxy carbene complexes provides yields similar to those of alkoxy complexes, however, there has been no direct comparison.47,169 1.
R2 Cr(CO)5 R1 Me i-Pr Me i-Pr
OR1 R2 H H Br Br
Pr-n, benzene, 80°
R2
O R
2
Pr-n
n-Pr
O
+
2. CAN
R 1O O (78%) (90%) (75%) (91%)
O
Pr-n
(Eq. 72)
(7.5%) (<5%) (5%) (<5%)
Given the thermal instability of acetoxy complexes,170,171 it is surprising that complex 179,172 in this example generated from complex 178, reacts with 1-hexyne (Eq. 73) to give the same yield of the benzannulation product as does the reaction of the corresponding methoxy complex 26 (Eq. 5).94 Other acetoxy complexes fail to provide any cyclized product upon reaction with alkynes.114 The only class of complexes that has two carbon substituents on the carbene
164
ORGANIC REACTIONS
carbon and which are isolable are those bearing two aryl groups. The reactions of these complexes generally give low yields of phenols upon reaction with alkynes.47,87,143 In contrast, the dibenzocycloheptatriene complex 180 reacts with 1-hexyne to give a 55% yield of the benzannulation product after protection as its TBS ether (Eq. 74).173,174
AcCl
Cr(CO)5 O–
NMe4
Cr(CO)5
+
O
1. Bu-n, THF, 65°
Bu-n (71%)
2. CAN
OAc
178
O
179 (35%)
(Eq. 73) 1.
Bu-n, t-BuOMe, 20°
(55%)
(Eq. 74)
2. TBSCl, Et3N Cr(CO)5
TBSO Bu-n
180
Reaction Media and Conditions. The nature of the solvent can have a significant effect on the product distribution from reactions of Fischer carbene complexes with alkynes. This effect is most often observed for the reaction of aryl alkoxy carbene complexes and is rarely seen for alkenyl alkoxy carbene complexes, although the reactions of alkenyl amino carbene complexes are sensitive to the nature of the solvent (Eq. 65).83 The general observation of the correlation between efficiency of phenol formation and the nature of the solvent is that the highest chemoselectivity for phenol formation is found in non-polar and/or non-coordinating solvents.12,13,60,84 The effects of solvent on the benzannulation reaction is usually more pronounced for internal alkynes than for terminal alkynes. As an example, the reaction of phenyl complex 26 with 3-hexyne gives higher yields of the naphthol in THF and in benzene than in acetonitrile, in which an indene is formed as a mixture of double-bond isomers in 25% yield along with a cyclobutenone in 7% yield (Eq. 75).60 The use of polar solvents in combination with other changes can lead to reactions that give high selectivity for products other than phenols. For example, reactions of amino carbene complexes in DMF can give synthetically useful yields of indenes (Eq. 64a).79,160 OH Cr(CO)5 OMe 26
Et
+
solvent, 80°
MeO Et
Et OMe
Solvent THF MeCN benzene
Et Et
Et
(97%) (32%) (97%)
OMe (1.3%) (25%) (≤0.7%)
+
O
Ph Et
Et (—) (7%) (—)
(Eq. 75)
THE SYNTHESIS OF PHENOLS AND QUINONES
165
Reactions of 2-methoxyphenyl complex 53 are much more sensitive to the solvent than those of the unsubstituted phenyl complex 26. The product distribution from the reaction of complex 53 with 3-hexyne is especially responsive to the ability of the solvent to coordinate to the metal during the course of the reaction (Eq. 76).84 Non-coordinating solvents such as hexane and benzene give significantly higher yields of the quinone than does THF. Furthermore, the yield of the quinone drops precipitously in acetonitrile where the cyclobutenone is the major product and is isolated in 78% yield. An indication of the importance of the coordination of the solvent to the metal during the reaction can be seen in the data from the reaction in 2,5-dimethyltetrahydrofuran (DMTHF) in which the yield of quinone is significantly higher than it is in THF. 1. Et Et, solvent, 45°
OMe
2. CAN OMe Cr(CO)5 53
O
Et Et + Et
Solvent DMTHF hexane benzene THF MeCN
OMe O
Et Et +
OMe OMe
(88%) (83%) (77%) (61%) (6%)
(6%) (—) (2%) (18%) (5%)
MeO Et
+
OMe O
O
Ar
(Eq. 76)
Et Et Ar = 2-MeOC6H4
(—) (—) (5%) (5%) (6%)
(—) (—) (—) (—) (78%)
The rule that non-polar and non-coordinating solvents give the highest chemoselectivity for phenols is rarely violated. One exception is the reaction of the 2,5-dimethoxyphenyl complex 144 with 1-pentyne, which gives a 76% yield of phenol in acetonitrile and only a 59% yield in THF (Eq. 77).175 Even more surprising is the drop in yield to 14% when the reaction is performed in hexane. Another exception is the reaction of the phenyl complex 26 with diphenylacetylene, which in heptane76 gives an equal mixture of phenol and indene products, but in THF84 affords the phenol almost exclusively. The solvent can also have profound effects on the intramolecular reactions of carbene complexes with alkynes leading to products not seen in intermolecular reactions.176 OMe
1. OMe
OMe Cr(CO)5 144
Pr-n, solvent, 45°
OMe OH Pr-n
2. air Solvent hexane THF MeCN
OMe OMe (14%) (59%) (76%)
(Eq. 77)
166
ORGANIC REACTIONS
Reactions of Fischer carbene complexes with alkynes have also been examined without solvent.177,178 As an example, the reaction of phenyl complex 26 with 1.5 equivalents of diphenylacetylene is performed by dissolving the two reactants in ether, adding silica gel, and removing the solvent to leave a dry powder which is heated under nitrogen at 40–50◦ for 3 hours (Eq. 78). The yield of the quinone 181 after oxidation is comparable to the yield reported for the same reaction in THF.84 The reaction of complex 26 with 1.5 equivalents of phenylacetylene carried out in the same manner gives the quinone 182 in 81% yield, which is comparable to the yield reported for this reaction in THF where the corresponding naphthol 46 was isolated (Eq. 9).100 This technique has not been widely examined; however, a few dry-state reactions on silica gel give improved yields of phenolic products compared to the same reactions performed in solution,91,98,124,179 whereas it is less effective for other reactions.75,180 O Ph
Ph
Ph
(86%) 40-50°
Cr(CO)5 OMe 26
Ph O 181
1. alkyne, SiO2, heat 2. CAN
(Eq. 78)
O Ph
Ph
(81%)
60-65° O 182
The distribution of products from the reaction of Fischer carbene complexes with alkynes can be dependent on the concentration such that the preference for the phenolic product increases at higher concentrations.13,60,84 The sensitivity of the product distribution on the concentration is greater for aryl complexes than for alkenyl complexes, and greater for internal alkynes than for terminal alkynes. One system that is particularly sensitive to concentration is the reaction of the 2-methoxyphenyl complex 53 with 3-hexyne.84 At 1.0 M in alkyne the distribution between phenol and indene products is not particularly sensitive to the concentration of the carbene complex (Eq. 79).84 However, the distribution is strongly dependent on the concentration of the alkyne as can be seen from the data at 0.005 M in carbene complex where a 100-fold increase in the concentration of the alkyne increases the yield of quinone from 5% to 81%. An additional increase in concentration of the alkyne to 8.8 M (neat 3-hexyne) affords the quinone as the exclusive product. A careful analysis of the concentration dependence of the reaction of a molybdenum complex also reveals that the product distribution is a function of the concentration of the alkyne and not of the carbene complex.60 This phenomenon has been termed the allochemical effect and is explained by an alkyne-assisted insertion of carbon monoxide into the vinyl carbene intermediate to give the vinyl ketene intermediate (Scheme 6).84 The η1 ,η3 -vinyl carbene complexed intermediate (E)-4 is an 18-electron complex and coordination of an
THE SYNTHESIS OF PHENOLS AND QUINONES
167
alkyne must be preceded by a dissociation of the double-bond to generate the η1 vinyl carbene intermediate (E)-17 (Scheme 6). An alkyne can be either a 2- or 4electron donor and because carbon monoxide insertion results in the formation of an unsaturated complex, it has been proposed84 that the alkyne ligand in complex 24 can accelerate the CO insertion if it switches from a 2- to a 4-electron donor during the process such that 25 is a saturated 18-electron complex (Scheme 6).
OMe Cr(CO)5
MeO 53
1. Et Et, THF, 45° 2. CAN O
Et
Et
MeO
Et +
Et +
Et
Et OMe O [53] 0.005 0.05 0.005 0.05 0.5 0.05
[Alkyne] 0.01 0.1 1.0 1.0 1.0 8.8
(5%) (46%) (81%) (84%) (61%) (91%)
OMe OMe (66%) (42%) (5%) (5%) (18%) (<1%)
OMe O (9%) (1%) (<1%) (1%) (5%) (<1%)
+
O
Ar Et Et Ar = 2-MeOC6H4 (—) (3%) (5%) (2%) (—) (—)
(Eq. 79) A related phenomenon, termed the “xenochemical effect”, has been observed in which the yield of phenolic product from reaction with an alkyne is dependent on the concentration of a second added alkyne that does not become incorporated into the product.86 This is schematically indicated in Scheme 6. The xenochemical effect is a special case of the allochemical effect where the alkyne R4 CCR5 is not the same as the alkyne that has already been incorporated (RL CCRS ). Thus far it has only been observed in intramolecular reactions, and a dramatic example is in the reaction of complex 183 to give the quinone 184 and indanone 185. The yield increases from 33 to 83% if 10 equivalents of diphenylacetylene are added to the reaction mixture (Eq. 80). The yield of quinone 184 could be increased somewhat by employing 3-hexyne as the xenochemical agent. However, competition is seen with the intermolecular benzannulation of 3-hexyne at the expense of the intramolecular benzannulation. Examples have also been reported for an intramolecular reaction of manganese carbene complexes (see Eq. 89 in the following section).181,182 One might expect to find intermolecular examples of the xenochemical effect if the two alkynes were of much different reactivity. Finally, concentration is also an important factor in the distribution between phenolic products and products resulting from the incorporation of more that one alkyne. Examples include the formation of two-alkyne phenols (21 in Scheme 5),80,81 vinylcyclopentenediones (10 in Scheme 4),60,78 and polyacetylene.85
168
ORGANIC REACTIONS
Cr(CO)5 Me2Si
O
O
1. additive, hexane, reflux, 1 h
OH OH
2. CAN
+ O
O 184
O 183 Additive none Ph Ph (10 eq) Ac2O (1.5 eq)
184 (33%) (83%) (26%)
185
(Eq. 80)
185 (—) (3%) (2%)
Another interesting additive effect that has not been widely reported, but which nonetheless could be synthetically quite important, is the effect of added acetic anhydride.116,183 This effect is illustrated by the reaction of complex 26 with alkyne 186, which fails to give any of the phenolic product in refluxing heptane, but in the presence of one equivalent of acetic anhydride affords the expected product in 66% yield (Eq. 81). Note that the product is not acetylated. Acetic anhydride does not have any effect on the yield of quinone from the intramolecular reaction of 183.86 The effect of acetic anhydride has only been reported for a small number of reactions and while it certainly does not work in all reactions,84 or may not even work on a majority of reactions, when it does work the effect can be substantial and thus should be considered when optimizing a benzannulation reaction. An even less well studied additive is carbon monoxide. Small increases in the yield of quinone product can be observed for some complexes when the reaction is performed under a carbon monoxide atmosphere,184 as has been observed for 2-alkoxyaryl carbene complexes (10-15% increase). OH OTBS OTBS Cr(CO)5 OMe 26
+ TBSO
additive, heptane 80°
186
Additive none Ac2O (1.5 eq)
OMe OTBS (—) (66%)
(Eq. 81) The effect of temperature on chemoselectivity has been examined for some reactions. The reaction of complex 53 with 3-hexyne over a 135◦ temperature range reveals that, whereas the mass balance is fairly consistent over this range, the proportion of phenolic product varies dramatically (Eq. 82).84 In these studies, phenolic products are favored at lower temperature and are increasingly replaced by indene products as the temperature is raised. The unsubstituted phenyl complex 26 and the 2-methylphenyl complex 82 are not as sensitive to changes in temperature, but the latter is sensitive to a combination of temperature and concentration (Eqs. 22 and 23).84 The effects of temperature on the reactions of alkenyl complexes have not been extensively studied.60 The effect of temperature on the regioselectivity of the reaction of Fischer carbene complexes with
THE SYNTHESIS OF PHENOLS AND QUINONES
169
alkynes has only been examined in one example and it was found that the level of the regioselectivity drops by a factor of two for a 45◦ increase in temperature (Eq. 12).66
OMe
1. Et Et, benzene, temp
O
53
Et OMe O
Temp 45° 110° 180°
Et Et +
+
2. CAN OMe Cr(CO)5
Et Et
(77%) (29%) (16%)
OMe OMe (2%) (6%) (12%)
Et OMe O
(Eq. 82)
(5%) (37%) (44%)
Although lower temperatures favor the formation of phenols compared to indenes, there is a limit to which the temperature can be lowered to achieve reasonable rates. The rate-limiting step is the loss of a CO ligand (Scheme 2).42 For most pentacarbonyl chromium carbene complexes, a reasonable rate for the thermal reaction can only be achieved at temperatures no lower than approximately 40–50◦ . Reactions of amino carbene chromium complexes79 and alkoxy carbene tungsten complexes60,63 require higher temperatures than those of alkoxy carbene chromium complexes and both give a greater proportion of indene. This phenomenon has been attributed to the slower initial CO dissociation for amino complexes.48 This shift in product distribution to indenes for these reactions may be due to a combination of electronic effects in the carbene complexes and the temperature of the reaction, but these effects have not been sorted out. Molybdenum complexes react faster than chromium complexes and also give a higher proportion of indene products.185,60 Thus, for molybdenum complexes it is clear that the increased propensity for indene formation is due to the nature of the metal. Other methods for facilitating the loss of CO include photolysis, ultrasound irradiation, and microwave irradiation, and all three have been examined for the reaction of carbene complexes with alkynes. Photolysis has been used to probe for reactive intermediates in this reaction for both chromium and tungsten complexes.63,64 The effect of photolysis of chromium carbene complexes on the yield of phenol products is variable. The reaction of complex 26 with 3-hexyne is mediated by irradiation with a 450 Watt Hg lamp and occurs at reasonable rates at 15◦ and at −78◦ , but the highest reported yield of the quinone is 54% at 15◦ (Eq. 83).13 It is clear that ultraviolet irradiation can do more than just lower the barrier of CO dissociation since the photo-induced reaction of the 2methoxyphenyl complex 53 with 3-hexyne gives no trace of phenolic product and instead the indene product is obtained in 49% yield. This result is in contrast to the thermally-induced reaction in the same solvent (Eq. 79).13 Much higher yields of phenolic products have been reported from the photolysis of heteroaryl complexes and heteroaryl-substituted alkenyl complexes.186 The photo-induced reaction of complex 187 with 3-hexyne affords the phenolic product in 81% yield and is important because reactions of complexes of this type provide the only known
170
ORGANIC REACTIONS
examples of a successful photo-induced benzannulation of a chromium complex in which the corresponding thermal reaction fails (Eq. 84).187,188 Photolysis is also known to greatly facilitate or make possible the benzannulation reactions of manganese complexes in inter- and intramolecular reactions.181,182 The photolysis of β,β-disubstituted iminocarbene complexes in the presence of alkynes leads to the formation of 2H -pyrroles.189,190 1. Et Et, 450-W Hg lamp, vycor, THF, 15°, 3 h
OMe
O +
2. CAN
Et
Et
Cr(CO)5
R
Et Et
R
26 R = H 53 R = OMe
OMe
R
O (54%) (—)
(—) (49%)
(Eq. 83) Ph
Ph Et (CO)5Cr
125-W Hg lamp, quartz, THF, –20°, 2 h
O 187
OH
Et
(81%) O
Et
(Eq. 84)
Et
There are also a few examples of ultrasound-promoted reactions, an illustration being the reaction of complex 34 with 1-pentyne (Eq. 85).177 This reaction provides the quinone product in essentially the same yield as the corresponding thermal reaction,13 but the time and temperature are greatly reduced. Other reports include improvement in yields and rate for the benzannulation of aryloxy complexes169 and similar improvements in the key step in the synthesis of parvaquone.191 1. OMe
Pr-n ultrasound, n-Bu2O, rt, 10 min
O Pr-n (75%)
2. CAN Cr(CO)5 34
(Eq. 85)
O
The synthesis of phenols from the reactions of Fischer carbene complexes with alkynes has also been facilitated with microwave irradiation in a commercial reactor at 130◦ for 5 minutes.192 Despite the relatively high temperatures employed, the reactions give yields comparable to the corresponding thermal reactions. Other agents that have been reported to mediate the reaction of carbene complexes with alkynes include [(COD)RhCl]2 ,which has been reported to facilitate the reaction of β-aminovinyl complexes with alkynes,193 – 195 and boron trifluoride etherate, which has been reported to facilitate the benzannulation of thio carbene complexes (Eq. 71).167,168 Metal and Ligand Complement. Fischer carbene complexes are known for a large number of transition-metals and the reactions of many of these have been
THE SYNTHESIS OF PHENOLS AND QUINONES
171
investigated with alkynes. However, of the Group 6 metals, chromium remains the metal of choice for the synthesis of phenols and quinones. The reactions of tungsten and molybdenum carbene complexes with alkynes are much less chemoselective for the phenolic product60,63,82,185 as exemplified by the reaction of unsubstituted phenyl complexes 188 and 189 with 1-pentyne (Eq. 86).60 The situation can be quite different with alkenyl complexes. For example, higher yields of the phenols can be obtained for certain molybdenum and tungsten alkenylcarbene complexes than with the corresponding chromium complexes.60 One disadvantage of molybdenum complexes is that they are less stable than the chromium complexes. Nonetheless, molybdenum complexes can be employed without special precautions if used immediately after preparation. Tungsten complexes are more stable than the chromium complexes but suffer from the fact that alkyne polymerization63,85 can be a serious side-reaction, thus requiring significant excesses of the alkyne. The reactions of tungsten and molybdenum alkenyl complexes with internal alkynes are not as chemoselective for phenols as are their reactions with terminal alkynes and thus these reactions usually give mixtures of products.60
OMe
Pr-n benzene, 80°
M(CO)5 OH
Pr-n
Pr-n
Pr-n + OMe 26 M = Cr 188 M = Mo 189 M = W
(59%) (3%) (6%)
+ OMe (1%) (80%) (60%)
Ph
n-Pr
O Pr-n OMe
+ O
(8%) (3%) (5%)
(Eq. 86)
OMe O
Ph
(6%) (3%) (6%)
A few non-Group 6 Fischer carbene complexes have been investigated for their reactivity with alkynes but none provide for a synthesis of phenols that is as general as that of chromium complexes. Iron tetracarbonyl carbene complexes such as 190 give only phenols upon reaction with dimethyl acetylenedicarboxylate (Eq. 87).196 The more typical outcome of the reaction of iron complexes with alkynes is the production of furans196,197 or the formation of pyrones (Eq. 87).198 A ruthenium Fischer carbene complex has been reported to give a quinone.199 The reaction of stannyl tricarbonyl cobalt carbene complexes (e.g., 191) with alkynes gives 2-alkoxyfurans as the only observable products as in the reaction of stannyl complex 191 with 3-hexyne (Eq. 88). This process has been used in the synthesis of bovolide.200 Cyclopentadienyl dicarbonyl manganese carbene complexes will only react with alkynes upon ultraviolet irradiation and then only with non-carbon groups on the oxygen substituent of the carbene carbon. The intramolecular reaction of the siloxycarbene complex 192 gives a quinone upon photolysis and oxidative workup (Eq. 89). However, if the siloxy group is
172
ORGANIC REACTIONS
replaced by a methyl group, no quinone formation is detected either by thermolysis or photolysis.181,182 Note that intramolecular benzannulation of the manganese complex 192 is facilitated by the xenochemical effect (Scheme 6). The yields are approximately doubled by the addition of 5 equivalents of diphenylacetylene. O Ph
O
(100%)
CH2Cl2, 55 psi CO, 70°
OEt
(Eq. 87)
Fe(CO)4 OH
OEt
MeO2C
190
CO2Me
CO2Me
(21%)
THF
CO2Me OEt
OMe Ph3Sn(CO)3Co Ph
Et
benzene, 50°
Et
Et
Et
Ph
O
(Eq. 88)
OMe
191 (93%) Mn(CO)2(η5C5H4CH3) O Me2Si O 192
1. Ph Ph (5 eq), CH2Cl2, 150-W xenon lamp
O
2. CAN
OH
(Eq. 89)
O (56%)
Replacing one of the carbon monoxide ligands of a Fischer carbene complex with a phosphine affects the benzannulation reaction with alkynes.87,13,201 Only a small effect is seen in the reaction of phenyl complex 26 with 3-hexyne when a CO ligand is replaced with a tri-n-butylphosphine (Eq. 90).201 In a related study with diphenylacetylene, replacement of a CO ligand by either the electron-rich tri-n-butylphosphine or with the electron-poor tris-(para-fluorophenyl)phosphine also has only a minor effect on the outcome of the reaction.201,87 In contrast, a trin-butylphosphine ligand greatly affects the reaction of the phenyl molybdenum complex 188 with 3-hexyne (194, Eq. 90).133,201 The major product changes from the indene with the pentacarbonyl complex 188 to the quinone with the tri-n-butylphosphine complex 194. The origin of this effect has not been determined, but this is one of only three known examples of phenol formation from an aryl molybdenum carbene complex.60,82,185,201 In principle, the use of phosphine ligands could provide a method to lower the temperature requirement of the benzannulation reaction. It has been demonstrated that a triphenylphosphine (but not trialkylphosphine) dissociates faster than CO from a Fischer carbene complex.202 Although there are no known examples of the benzannulation
THE SYNTHESIS OF PHENOLS AND QUINONES
173
of tetracarbonyl(triphenylphosphine) aryl or alkenyl complexes, the two-alkyne annulation reaction has been reported for an alkyl carbene complex with a triphenylphosphine ligand and a rate acceleration was observed (see section on Two-Alkyne Annulation).133 L M(CO)4 OMe M 26 Cr 193 Cr 188 Mo 194 Mo
1. Et Et, THF, 80°
O +
2. CAN
L CO (n-Bu3)P CO (n-Bu3)P
Et Et Et
O (97%) (79%) (9%) (43%)
Et + Ph OMe (1.3%) (≤3 %) (67%) (≤1 %)
Et
Et OMe
O (≤1%) (8%) (5%) (2%)
(Eq. 90) There are many more examples in which a carbon monoxide ligand has been replaced by an oxygen or sulfur donor atom as the result of the coordination of an alkoxy group, a thio ether, or a carbonyl oxygen. Some examples include the methoxy-chelated complexes 94 (Eq. 29)84 and 113 (Eq. 37),105 the thioetherchelated complex 97 (Scheme 9),91 and the carbonyl-chelated complexes 167 and 172 (Eqs. 68 and 70).162,165 Only one example is known in which a carbon monoxide ligand is replaced by an isonitrile ligand, and an indene product results from reaction of this complex with an alkyne.203 Diastereoselectivity. A new stereogenic element is formed when the arene chromium tricarbonyl group is created. There are three modes of stereoinduction involving diastereoselective installation of the chromium tricarbonyl group. These three possibilities arise when the stereocenter of the arene chromium tricarbonyl group is created in the presence of stereocenters that already exist either on the alkyne, on the oxygen substituent of the carbene carbon, or on the carbon substituent of the carbene carbon. The development of stereoselective benzannulation procedures is dependent on the invention of a general method for the protection of the phenol function and the resulting production of air-stable arene chromium tricarbonyl complexes.95 The only success that has been achieved with a carbene complex bearing a chiral alcohol is illustrated by the reaction of the phenyl [(−)-menthyloxy]carbene complex 195 with 3,3-dimethyl-1-butyne to give a 10 : 1 mixture of the diastereomers 196 and 197 (Eq. 91).97,204 Although this reaction does give a similar selectivity with 3-hexyne,73 it gives low selectivity with 1-pentyne.205 The corresponding reactions of alkenyl [(−)-menthyloxy]carbene complexes fail to give significant stereoselectivity with a number of acetylenes including tertbutylacetylene.97,205
174
ORGANIC REACTIONS
Cr(CO)5 O
1.
Bu-t, t-BuOMe, 55°, 45 min
2. TBSCl, NEt3
OTBDMS Bu-t
OTBDMS Bu-t
195
(Eq. 91)
+ (CO)3Cr O
(CO)3Cr O
196 (50%)
197 (5%)
Another mode of stereocontrol involves asymmetric induction from a stereogenic center on the alkyne to the newly formed planar element of chirality. Very high asymmetric induction is observed for the reaction of certain alkenyl carbene complexes with propargyl ethers. The reaction of the β-substituted vinyl carbene complex 50 with alkyne 198 (R = CPh3 ) gives the arene chromium tricarbonyl complex 199 in 68% yield and ≥96 : 4 stereoselectivity (Eq. 92).88 The high stereoselectivities observed may have a stereoelectronic origin as revealed by variations in the ether substituent of the propargyl ether 198 and by the fact that the alkyne 200 gives nearly an equal mixture of diastereomers upon reaction with complex 50.88,206 This stereoinduction is limited to β-substituted alkenyl carbene complexes. The same reaction with alkenyl carbene complexes bearing an α-substituent gives low stereoselectivity. The third mode for stereoinduction in the benzannulation reaction involves chiral carbene complexes that have a stereogenic center in the carbon substituent of the carbene carbon. This reaction has been examined for cyclohexenyl complexes bearing substituents in the 3- and 6-positions and the diastereoselectivity varies from low to modest.207 High diastereoselectivity has been observed from the reaction of complex 44 with 5-hexyn-1-ol which gives a single diastereomer of 45 after an intramolecular Mitsunobu cyclization (Eq. 8).99 Other examples of this mode of stereoselection include the use of the benzannulation reaction in the formation of cyclophanes,208 chiral biaryls,209 annulenes,98 and carbohydratederived carbene complexes.210 TBSO
R Cr(CO)5 OMe 50
i-Pr2NEt, TBSCl, CH2Cl2, 60°
OTr (68%) ≥96:4 dr
(CO)3Cr OMe
198 R = OCPh3 (OTr) 200 R = Bu-t
(Eq. 92)
199
Asymmetric induction is also observed in reactions where the chromium tricarbonyl unit is not retained in the newly formed arene ring. In a study directed
THE SYNTHESIS OF PHENOLS AND QUINONES
175
to the synthesis of allocolchicinoids, the reaction of the carbene complex 201 with 1-pentyne selectively gives the benzannulated product 203 in which there is central to axial stereoinduction leading to the preferential formation of one of the two possible atropisomers 202 and 203 (Eq. 93).211 Another example of this type of asymmetric induction is presented in the next section (Eq. 98).100 MeO MeO
OMe 201
MeO MeO
Pr-n
MeO MeO
Pr-n
Cr(CO)5 benzene, 55-58° 36 h
OH
MeO
OMe MeO
Pr-n
202 +
MeO MeO MeO
OH OMe
MeO 202 + 203 (73%) 202:203 7:93
203
(Eq. 93) Asymmetric induction can also be achieved from the newly formed plane of chirality of the arene chromium tricarbonyl complex to an axis of chirality formed in the same reaction. The combination of α,β-unsaturated carbene complexes with 2-substituted aryl acetylenes simultaneously generates planar and axial elements of chirality.212 As an example, if the reaction of complex 50 and aryl propyne 204 is carried out in toluene at 50◦ in the presence of tert-butyldimethylsilyl chloride and (i-Pr)2 NEt, the arene chromium tricarbonyl complex 206 is obtained in an 89 : 11 mixture of syn- to anti-isomers (Scheme 11). This diastereoselectivity can be reversed to give a 97 : 3 ratio in favor of the anti-isomer if the benzannulation and silylation steps are carried out sequentially. These observations are consistent with a kinetic formation of the syn-phenoxy complex 205. Under simultaneous silylation conditions the phenol is silylated before rotation about the chiral axis can occur to give the anti-phenoxy complex 205. Under sequential silylation conditions, complete isomerization to the anti-phenoxy complex can occur if the first step is performed at 80◦ (the two step reaction at 50◦ gives a 95 : 5 mixture of anti:syn isomers). Subsequent silylation then yields the silylated complex anti206. The reactions of aryl acetylenes of the type 204 with a chiral substituent replacing the methyl group on the benzene can give rise to asymmetric induction from the stereocenter in the alkyne to a newly formed axis of chirality in the benzannulated product.213 Intramolecular Reactions. The most thoroughly studied intramolecular reactions of α,β-unsaturated Fischer carbene complexes involve those in which the alkyne is tethered through the heteroatom substituent (Type A). The thermolysis of the complexes 207 provides good yields of fused cyclic aryl ethers for the generation of dihydrobenzofurans, dihydrobenzopyrans, and
176
ORGANIC REACTIONS
Cr(CO)5 OMe 50
OC CO OC Cr HO
204
rotation
OC CO OC Cr HO
TBSCl, i-Pr2NEt, toluene MeO syn-205
MeO anti-205
TBSCl
TBSCl
OC CO OC Cr EO
OC CO OC Cr EO
MeO
MeO
syn-206
E = TBS syn + anti (63%) (62%)
one pot, 50° TBSCl, i-Pr2NEt added in 2nd step, 80°
anti-206
syn:anti 89:11 3:97
Scheme 11
tetrahydrobenzoxepins, respectively (Eq. 94).214 The extension to formation of eight-membered rings has not been reported. There are a few examples of intramolecular cyclizations wherein the alkyne is tethered to an alkenyl or aryl substituent of the carbene carbon (Type B).215,216 These reactions do not always give the normal phenolic products, but often good yields of the phenol can be obtained (Eq. 95). If the alkyne is tethered to the β-carbon of an alkenyl complex as in 208, the product of the reaction is a metacyclophane.215 The yield of the phenol is modest for the cyclophane with an eight-methylene bridge (43%), but above that, the yield increases and levels off at 60%. If the alkyne is connected to the α-carbon, and if it is sufficiently long, then paracyclophanes are formed, but the strain introduced with shorter tethers can lead to the formation of products that are unprecedented in intermolecular reactions including bicyclo[3.1.0]hexenones and m-alkoxyphenols.217,176 OMe
OMe
O
R
R1
(CO)5Cr
R1
R
O (CO)5Cr
R2 R1
R2
R OH
Type A Intramolecular Benzannulation
R1 R
OH
Type B Intramolecular Benzannulation
THE SYNTHESIS OF PHENOLS AND QUINONES
O n
n
n 0 1 2
THF, 35°
O (CO)5Cr
OH
207
177
(81%) (62%) (62%)
(Eq. 94)
OMe OMe (CO)5Cr
n 0 2 5 9
THF, 100° OH
n+8
208 n
(43%) (58%) (65%) (60%)
(Eq. 95)
A significant difference between the two modes of intramolecular cyclization (especially with terminal alkynes) is that the regiochemistry is reversed in Type A but is normal in Type B reactions. A consequence is that terminal alkynes do not give as high yields of phenols for the Type A process as for Type B. These low yields can be overcome by capping the alkyne with a trimethylsilyl group.114 Intramolecular benzannulation with alkynes attached through removable tethers has been used to control the regiochemistry of reactions of internal alkynes (Eq. 19). A synthesis of deoxyfrenolicin featured the intramolecular benzannulation of carbene complex 209, which upon oxidative workup gives a naphthoquinone, and upon workup involving a ligand displacement gives a naphthol (Eq. 96).86,90,218 An intermolecular reaction with a similarly functionalized alkyne gives the opposite constitutional isomer.90 MeO
O
1. THF, 35° MeO
O
O
Pr-n
OH
O Pr-n
2. DDQ
(51%)
O
(Eq. 96)
Cr(CO)5 MeO 209
O
O
1. THF, 35° Pr-n
2. (n-Bu)3P, acetone
(48%)
OH
Intramolecular benzannulations also impact the chemoselectivity of the reaction. For intermolecular reactions, alkenyl amino carbene complexes and alkynes can sometimes yield phenolic products (Eq. 65),83 but aryl amino carbene complexes rarely afford phenols as the major product and instead usually afford indenes.79,160 However, as illustrated by the reaction of complex 210, the intramolecularity of a benzannulation reaction can cause a switch from indenes to phenols for amino carbene complexes (Eq. 97).219 Other examples of intramolecular
178
ORGANIC REACTIONS
reactions of amino complexes give phenolic products,23,128,220,221 whereas others give indene products.128,222 O Ph
H N
OH Ph
benzene
Ph +
reflux
Cr(CO)5
(Eq. 97)
N (54%)
210
N (23%)
Intramolecular benzannulations have also been demonstrated in the reactions of bis(carbene) complexes with bis(alkynes). The first benzannulation from the reaction of the bis(carbene) complex 211 and 1,4-diphenylbutadiyne is intermolecular but the second step must be intramolecular (Eq. 98).100 The intramolecularity of the second step leads to the formation of a C2 -symmetric product unlike that observed for the product from the intermolecular reaction (Eq. 49).100 Despite the low yields observed for the reaction of complex 211, this reaction has potential for the asymmetric synthesis of chiral biaryls given that only a single diastereomer of the binaphthol 212 is formed (Eq. 98). A bis(carbene) complex can also be employed in a double-benzannulation of a non-conjugated diyne as a route to calix[4]arenes. The reaction of bis(carbene) complex 213 with diyne 214 gives calix[4]arene 215 in 41% yield in a process in which two of the benzene rings of the calixarene are made at the same time as the macrocycle. (Eq. 99).223
(CO)5Cr
Cr(CO)5 O
O Ph
Ph
Ph
OH
Ph Ph
HO Ph
O
THF, 75°
O
H
211
H
(Eq. 98)
212 (23%) one diastereomer
Ph OMe
Ph OMe
(CO)5Cr
+
Cr(CO)5 OMe 213
OMe 214 MeO
Ph Ph
OMe
THF, 100°
HO MeO
OMe OH
215 (41%)
(Eq. 99)
THE SYNTHESIS OF PHENOLS AND QUINONES
179
Heteroannulation Heteroaromatic rings containing a hydroxyl function have been produced from the reaction of α,β-unsaturated carbene complexes by two routes (Scheme 12). In reactions with carbene complexes of type 216, substitution of one of the triplybonded carbon atoms of the alkyne with a heteroatom leads to the heterocycles 217. Alternatively, heterocycles 219 can be formed by the reactions of alkynes with carbene complexes of the type 218 in which the α-carbon of the α,βunsaturated substituent has been replaced by a heteroatom. Although the latter approach has been proven so far to be the more general, the following discussion will begin with the reactions of “hetero-alkynes.” OH
R2 R
Cr(CO)5
R1
3
Y
R2
R3 Y
R1
OMe
OMe 217
216
OH
R2
R3 Y
R4
R2
Cr(CO)5
R3 Y
R1 218
R4 R1 219
Scheme 12
Reaction of aryl carbene complexes with nitriles do not produce functionalized isoquinolines. Instead, imidatocarbene complexes such as 220 result from the insertion of the nitrile function into the chromium-carbon bond of the starting carbene complex (Scheme 13).224,225 At higher temperatures (138◦ ) the only products formed are the oxazole 221 and the alkene 222.226,227 The latter is likely due to thermal decomposition of phenyl complex 26, which is formed by expulsion of benzonitrile from complex 220.228 OH Ph
Ph
N
Cr(CO)5
N
OMe 26
26
Ph
OMe
Ph
N
benzene, 80°
MeO
Ph N
n-Bu2O Cr(CO)5
138°
220 (85%)
Scheme 13
MeO
O N
Ph 221 (12%)
Ph
Ph
Ph
+ MeO
OMe
222 (12%)
180
ORGANIC REACTIONS
Whereas the reaction of carbene complexes with nitriles does not produce six-membered heterocycles, these products can result from reactions of carbene complexes with phosphaalkynes.229 – 231 Reaction of the 1-naphthyl carbene complex 223 with 2,2-dimethylpropylidynephosphane gives a phosphabenzene chromium tricarbonyl complex in 82% yield (Eq. 100).229,231 The metal can be removed in quantitative yield by ligand exchange with toluene. Despite the high yield observed for this reaction, significant yields of phosphaarenes could not be obtained with other carbene complexes. The predominant product from most of these reactions are oxaphospholes. (CO)5Cr
MeO
OMe t-Bu
P
Bu-t
MeO
P
Bu-t
toluene
P OH Cr(CO)3
t-BuOMe, 50°
OH
140-170°
(82%)
223
(Eq. 100)
(100%)
Although thermolysis of complex 220 does not produce a six-membered heterocycle (Scheme 13), its reaction with alkynes gives 3-hydroxypyridines.226,232 The 3-hydroxypyridine 224 is produced in 51% yield along with the non-CO inserted pyrrole 226 (Eq. 101).232 A third product (225) is formed by cyclization to the phenyl group on the carbene carbon in 220 rather than to the imino group. This complication does not exist for complex 227; however, its reaction with 1pentyne only gives five-membered ring products containing nitrogen (Eq. 102).226 The naphthalene product from this reaction results from extrusion of tert-butyl nitrile to give phenyl complex 26, which then undergoes reaction with 1-pentyne. This reaction is carried out in tert-butyl nitrile as solvent to suppress extrusion. The same reaction in THF gives only the naphthalene product.233 Extrusion of tert-butyl nitrile from complex 228 would give a non-stabilized carbene complex and this apparently disfavors extrusion since a naphthalene is not observed from the reaction of complex 228 with 1-pentyne (Eq. 103).232 The observation that the more electron-deficient complex 228 gives a six-membered ring product incorporating a CO ligand while the more electron-rich complex 227 only gives non-CO inserted products is consistent with the differences observed for reactions of alkoxy- and aminocarbene complexes. OH OH
OMe N
Ph (CO)5Cr
Ph
Pr-n hexane, 70°
Pr-n Pr-n +
N
N
Ph
OMe
(CO)5Cr 227
N H
t-BuCN, 70°
+ Ph
Ph
(Eq. 101)
226 (4%) OH
n-Pr Pr-n Bu-t
Ph
OMe 225 (31%)
224 (51%)
N
Ph
Ph
220
Ph
n-Pr
+
Bu-t N H (54%)
n-Pr MeO Ph
Pr-n + N (23%)
Bu-t (18%)
OMe
(Eq. 102)
THE SYNTHESIS OF PHENOLS AND QUINONES OH
OAc Pr-n
N
Ph (CO)5Cr
Ph
181
Pr-n
n-Pr
Pr-n
+
+
hexane, 70°
N
Bu-t
Ph
Bu-t N H (26%)
Bu-t (37%)
228
Ph
Bu-t N H (13%)
(Eq. 103) The imino complex 229 (Eq. 104) gives a higher proportion of 3-hydroxypyridine product than does the imidato complex 228 (Eq. 103).232 – 236 Chromium imino complexes of the type 229 produce mixtures of 3-hydroxypyridines and pyrroles, whereas the tungsten analogs give only pyrroles in a highly chemoand regioselective synthesis of these heterocycles (Eq. 104).234 The reaction of β,β-disubstituted imino complexes of the type 229 (obtained from ketones) with alkynes has been reported to give 2H -pyrroles under photolytic conditions.189,190 The only examples of heteroannulation onto a heterocylic substituent of a carbene complex involve the reactions of pyrazole complexes of the type 230 (Eq. 105).237 Moderate yields of pyrazolopyridinoquinones are obtained upon reaction with alkynes. The intramolecular assembly of a 3-hydroxypyridine from the complex 231 affords a 53% yield of a ring-fused 3-hydroxypyridine (Eq. 106).232 OH N
Pr-n
(CO)5M 229 M = Cr M=W
hexane, 70°
Ph
Ph
Pr-n + N
OMe hexane, rt
Ph
N H (9%) (≤1%)
OMe TMSCHN2
+ Ph
(51%) (—)
(CO)5Cr
Pr-n
n-Pr
(CO)5Cr NH N
(40%) (74%)
1. Et Et THF, 45° 2. CAN
Et Et
(Eq. 105)
OH
OMe
(CO)5Cr
O N N O (45%)
230 (76%)
Ph
(Eq. 104)
N H
hexane, 70°
N
Ph N
(53%)
(Eq. 106)
231
Cyclohexadienone Annulation Cyclohexa-2,4-dienones can be the predominant products from the reactions of alkynes with α,β-unsaturated carbene complexes of the type 232 that bear two carbon substituents in the β-position (Scheme 14).61 Complexes of the type 232 with YR = R3 Si give silylated phenols of the type 233 in high yield, often as their chromium tricarbonyl complexes (Eqs. 20 and 21).95,110,112,159 These products result from the carbon to oxygen migration of the silicon substituent in
182
ORGANIC REACTIONS
R2 R1
OP
YR Cr(CO)5
RL
RS
YR = H, TMS
OMe 232
OH
R2
RL
R1 RS (CO)3Cr OMe 233
P=H
R2
RL
R1
RS OMe 237
P = H, TMS
232
R
L
R
S
YR = R3
R3
O RL
R2 R1
RS
OMe 234 R3 = alkyl, aryl
232
RL
RS
R1
R2 NR2 RL
YR = NR2 RS
MeO 235
232
RL
RS
YR = OR, SR, F
RY R2
O RL 237
R1 RS (CO)3Cr OMe 236
Scheme 14
intermediate 236. If the carbene complex bears an oxygen, sulfur, chlorine, or fluorine substituent in the β-position, phenol 237 is produced by cleavage of the carbon-YR bond in intermediate 236 shown in Scheme 14 (Scheme 9,91 Eq. 36,122 Eq. 37,105 Eq. 39,124 Eq. 40125 ). The reactions of complexes bearing β-amino substituents do not give phenols or cyclohexadienones but rather yield predominantly cyclopentadienes of the type 235 (Scheme 14).123,30 Given the higher reduction potential of carbon-carbon bonds and the lower migratory propensity of carbon versus silicon or hydrogen, the reaction of complexes of the type 232 with YR as a carbon substituent usually give the cyclohexadienone product 234, although carbon migration may occur (see below). The reactions of complexes 238, 241, and 242 illustrate the versatility of the cyclohexadienone annulation (Eqs. 107–109). The reaction of hindered complex 238 with keto alkyne 239 gives the decalindienone 240 in 70% yield (Eq. 107).238 The quaternary carbon that is produced in the cyclohexadienone annulation becomes a spirocyclic center if the carbene complex is derived from a methylidenecycloalkane such as complex 241 (Eq. 108).239 The tetracyclic cyclohexadienone 243 is constructed from simple starting materials utilizing a
THE SYNTHESIS OF PHENOLS AND QUINONES
183
Diels-Alder reaction of a Fischer carbene complex as well as the cyclohexadienone annulation (Eq. 109).240 O O OMe
OBu-t
+
O OBu-t
THF, 50° Pr-i
Pr-i
Cr(CO)5 238
OMe 240 (70%)
239
(Eq. 107) OMe (CO)5Cr
+
TMS
TMS
THF, 50°
O (71%)
(Eq. 108)
MeO
241 OEt
Cr(CO)5
(CO)5Cr
OEt
Ph OEt
rt Pr-c
(Eq. 109)
THF, 50°
Pr-c
c-Pr O
Ph
243 (33%)
242
The cyclohexadienone annulation reaction can produce a new stereogenic center at the quaternary carbon if the two β-substituents of the carbene complex are not the same, as illustrated in Eq. 109.240 In such reactions the potential exists for relative asymmetric induction between the preexisting stereocenters in either the carbene complex or the alkyne and the newly formed stereocenter in the cyclohexadienone. Although the stereoselectivity of these reactions has not been extensively examined, examples of both types of induction can be found in the literature. Reaction of the 2,6-dimethylcyclohexenyl complex 244 gives a 90 : 10 selectivity for the trans-configured cyclohexadienone (Eq. 110),61 in contrast to the reaction of the 2,3-dimethylcyclohexenyl complex 245, which renders a nearly equal mixture of isomers (Eq. 111).207 A proposal to account for this difference in stereoselectivity has been presented. Significant levels of 1,4-asymmetric induction are observed for reactions with propargyl ethers (Eqs. 112 and 113).111 This reaction is stereospecific as demonstrated by the reaction of the Z- and E-isomers of carbene complex 246. The E-isomer gives a 92 : 8 mixture of diastereomers, whereas the Z-isomer gives a 9 : 91 mixture of the same cyclohexadienones. This result requires that the Z- and E-isomers of the β,β-disubstituted carbene complex 246 do not isomerize under the reaction conditions, which is surprising in light of the fact that the cis- and trans-1-propenyl carbene complexes have been found to isomerize under the reaction conditions.69 O OMe Cr(CO)5 244
O Bu-n
Bu-n
Bu-n +
(Eq. 110)
THF, 50° OMe
OMe (78%) 90:10
184
ORGANIC REACTIONS O
O Pr-n OMe
Pr-n
Pr-n +
hexane, 60°
Cr(CO)5 245
(Eq. 111)
OMe
OMe (83%) 56:44
O
OTr
Et OMe
OTr
Cr(CO)5
OMe
(E)-246
O
OTr
Et OMe
OTr
(Eq. 112)
(73%) 92:8
OTr
Et
OMe
O
OTr
+
Et
heptane, 55°
O
+
Et
heptane, 90°
Et
Cr(CO)5 (Z)-246
OMe
(Eq. 113)
(66%) 9:91
OMe
The reactions of aryl carbene complexes that have all-carbon substituents in positions beta to the carbene carbon often do not give cyclohexadienone products. For example, the reaction of the 2,6-dimethylphenyl carbene complex 247 with diphenylacetylene gives a 96% yield of the indene product, which is isolated as a mixture of the metal-free indene and its chromium tricarbonyl complex (Eq. 114).241,242 Although this reaction does not give a naphthol in which the methyl group has migrated to oxygen, this reaction does give an indene in which the methyl group has undergone a 1,5-sigmatropic rearrangement. Part of the driving force for this migration is the restoration of the aromaticity of the benzene ring that was lost when cyclization occurred to give the intermediate 249 (R = H, Eq. 115). A recent study finds that the 1,5-sigmatropic migration of methyl can be prevented by a keto-enol tautomerization in intermediate 249 (R = OH).243 An example of this tautomer-arrested annulation is the reaction of complex 248 with 3-hexyne, which affords the highly functionalized indenone 250 in 75% yield (Eq. 115). Some intramolecular variants of these reactions lead to CO insertion and the formation of vinyl ketene intermediates, which upon cyclization give cyclohexadienone products.243 Ph Ph Cr(CO)5
Ph
Ph
benzene, 110° (CO)3Cr
OMe 247
Ph +
OMe
Ph
(96%) 45:55
Et
HO
R Et Cr(CO)5 OMe 248
(Eq. 114)
OMe
Et
benzene, 110°
Et O
Et Cr(CO)3 OMe 249 R = OH
Et OMe 250 (75%)
(Eq. 115)
THE SYNTHESIS OF PHENOLS AND QUINONES
185
Cyclohexadienones can be obtained in good yields from other β,β-blocked aryl carbene complexes. Both 2-indolyl and 3-indolyl carbene complexes that have carbon substituents beta to the carbene complex give moderate to high yields of cyclohexadienone annulation products.62 As an example, the 2-indolyl complex 251 reacts with alkyne 252 to give the 4H -carbazol-4-one 253 in 59% yield (Eq. 116). The only example of an asymmetric cyclohexadienone reaction involving a chiral auxiliary on the carbene complex has been reported for an indolyl carbene complex. The reaction of chiral carbene complex 254 with 1pentyne gives the 4H -carbazol-4-one 255 with a greater than 96 : 4 selectivity for the diastereomer shown (Eq. 117).244 OMOM
MOMO
O
NHBz OMe N Me
Cr(CO)5
NHBz
252
(Eq. 116)
benzene, 50°
N Me
251
OMe
253 (59%)
Me N
MeN
O N (CO)4Cr Me N
Ph
Pr-n MeCN, 45-50°, 24 h
O Me N
N
Ph (61%) dr = ≥ 96:4
(Eq. 117)
Pr-n O
254
255
Two-Alkyne Annulation The original discovery of the formation of phenols from the reaction of Fischer carbene complexes with acetylenes involved the incorporation of only one molecule of alkyne. However, phenolic products can also be formed from the reaction of a Fischer carbene complex with two molecules of an alkyne. This structural type was first observed as a minor product in the cyclohexadienone annulation.61 An example of the competition between the formation of the two different phenolic products is presented in the reaction of phenyl complex 26 with propyne to give naphthol 256 along with phenol 257, which is derived from two molecules of propyne (Eq. 118).131,245 The yield of the “two-alkyne” phenol 257 initially increases with the number of equivalents of alkyne employed in the reaction and then falls off, presumably because of competing polymerization of the alkyne. The two-alkyne phenol is the major product with acetylene under all conditions (Eq. 42).131 The unsaturated substituent of the carbene complex is not incorporated into the two-alkyne phenol and thus alkyl-substituted carbene complexes such as 258 can also give “two-alkyne” phenol products. The
186
ORGANIC REACTIONS
latter reacts with propyne to give the phenol 259, which is likely formed via the intermediate vinylcarbene complex 260 into which a second molecule of alkyne inserts (Eq. 119).131 A more thorough presentation of the mechanistic path to the two-alkyne phenol product can be found in Scheme 5. OH
OH
(x eq) Cr(CO)5
+
THF, 45°
OMe
OMe 256
26 x 2 40 neat
256 (45%) (10%) (0.3%)
257
(Eq. 118)
257 (4%) (44%) (28%)
OH OMe Cr(CO)5
(10 eq) THF, 45°
258 OMe
259 (33%)
(Eq. 119)
Cr(CO)4 260
The utility of the intermolecular “two-alkyne phenol” annulation is limited by typically poor yields as indicated in Eqs. 118 and 119. Furthermore, this variant is limited to small alkynes such as propyne or acetylene (Eq. 42). More success has been achieved with intramolecular variations of this process (Eqs. 120–123). The possibilities for intramolecular reaction are three-fold: (1) the tethering of the carbene complex to one of the alkynes, (2) the tethering together of the two alkynes, and (3) the tethering of both alkynes to the carbene complex. The first combination is limited in its ability to produce the two-alkyne phenol product as illustrated by the formation of phenol 262 from the reaction of complex 261 with 1-pentyne (Eq. 120).246 This particular intramolecular variation in benzene can produce good to moderate yields of 2-vinylcyclopentenedione 263, a rather complex product derived from the incorporation of two equivalents of alkyne and two equivalents of carbon monoxide (Scheme 4).78 Also observed in this reaction is the isomeric “two-alkyne phenol” 264, which results from incorporation of the carbon monoxide into the benzene ring para to the carbon derived from the carbene carbon. Increased amounts of this para “two-alkyne phenol” are observed at lower substrate concentrations78,246 and with amino carbene complexes.58
THE SYNTHESIS OF PHENOLS AND QUINONES OMe 1.
(CO)5Cr
Pr-n (10 eq), solvent, 80°
OH
Pr-n
O
n-Pr +
n-Pr
187
OMe +
2. TiCl3, LiAlH4
HO
O 261
262 Solvent THF benzene MeCN
262 (7%) (8%) (15%)
263
263 (23%) (41%) (≤1 %)
264
264 (≤0.3%) (2.0%) (≤0.5%)
(Eq. 120) Synthetically useful yields of “two-alkyne phenols” can be obtained from the reaction of Fischer carbene complexes with diynes. This feature is illustrated by the reactions of complexes 258 and 268 with 1,6-heptadiyne (265) which, depending on the solvent, gives mixtures of the phenol 266 and the cyclohexadienone 267 (Eq. 121).80,133 The cyclohexadienone 267 can be reduced to the phenol 266 by chromium(0), supporting the mechanism proposed for phenol formation (Scheme 5). The phenol is the major product in THF, but in acetonitrile increased amounts of the cyclohexadienone are isolated. This outcome is thought to be attributable to the ability of acetonitrile to sequester the chromium(0). Good yields of the cyclohexadienone product can be obtained with the phosphine-substituted complex 268, which can react with the diyne without the need for heating. In a related process, phenols of the type 266 can also be produced by the reaction of diynes and Fischer carbyne complexes.81 The double intramolecular reaction of carbene complexes bearing tethered diynes can give good yields of tricyclic phenols as illustrated by the thermolysis of complex 269 in acetonitrile (Eq. 122).245,247 1. OMe
, solvent, temp
OH
O
265
(CO)4Cr
2. silica gel
L
266 258 258 268
L CO CO Ph3P 267
OMe
+
Solvent THF MeCN MeCN
Temp 70° 70° 22°
(CO)5Cr-THF
267
(Eq. 121)
266 267 (57%) (0%) (39%) (26%) (6%) (54%)
266 (47%)
OMe OH
(CO)5Cr 1. MeCN, 70° 2. silica gel
O +
(72%) 43:57 269
OMe
(Eq. 122)
188
ORGANIC REACTIONS
A tandem Diels-Alder/“two-alkyne annulation” has been developed as a strategy for the synthesis of steroid analogs.245,247 Diels-Alder reaction of endiynyl carbene complex 270 with 2-methoxybutadiene proceeds at room temperature to give the cycloadduct 271 in 84% yield (Eq. 123). The tungsten complex is employed because the double intramolecular two-alkyne annulation of chromium complexes gives lactone side products, the amount of which is dependent on the geometric constraints of the tether. Tungsten complexes require higher temperatures for reaction but, nonetheless, give good yields of two-alkyne phenols. Thermolysis of 271 in THF produces the cyclohexadienone in 72% yield as a 3 : 1 mixture of diastereomers.245 W(CO)5
(CO)5W
MeO
TMS
TMS OMe
MeO rt, 23 h
(84%)
MeO
270
271 TMS O H
THF, 110°
TMS +
O H
R MeO
R MeO
H (72%) 72:28
H
R = OMe
(Eq. 123) Ortho-Benzannulation/Cyclization of Doubly Unsaturated Complexes The penultimate intermediate in the formation of phenols from the thermal reaction of Fischer carbene complexes with alkynes is a doubly unsaturated ketene complex of the type 274 (Scheme 15). The typical reaction involves the carbene complex 272 and an alkyne to give the 4-methoxyphenol 275. On the basis of the extensive photochemical studies of Fischer carbene complexes,248,249,37 it was anticipated that an alternative method for access to ketene complex 274 would be the photolysis of the doubly unsaturated carbene complex 273.250,251 Photolysis should promote a CO insertion to give ketene complex 274, and subsequent cyclization would then lead to the 2-methoxyphenol 276. These two methods would thus be complementary as to the substitution patterns in the phenol product. Recently, the thermal conversion of certain types of complex 273 into phenols 276 has been observed.252,253 Photo-induced ortho-benzannulation of carbene complex 278 (prepared by a Diels-Alder reaction of alkynyl complex 277 with cyclopentadiene) gives the ring-fused 2-methoxynaphthol 279 in 18% yield (Eq. 124).250,251 The yield of this reaction is dramatically improved (93%) when the reaction is carried out in a Pyrex vessel under an atmosphere of carbon monoxide.254 2-Methoxyanilines
THE SYNTHESIS OF PHENOLS AND QUINONES
R5
R5 R1
MeO
189
O •
R2
R4 Cr(CO)5
R1 (CO)3Cr
272
OH R4 R3
R1 R3 = OMe
R5
R2
R2
R4 OMe
274
275 OH
OMe R5
(CO)5Cr
R5
MeO
hn or heat 274
R2
R4
R2
R3
R4 R3 276
273
Scheme 15
and 2-methoxyaminonaphthalenes are produced by thermal reaction of doubly unsaturated carbene complexes with isonitriles.255 This reaction presumably proceeds via the iminoketene analog of 274 (Scheme 15). For example, complex 280 reacts with tert-butyl isonitrile to give the aminonaphthalene 281 in 89% yield, and with ethyl 2-cyanoacetate to give 282 in 80% yield, in contrast to photo-induced CO insertion into 280, which gives the naphthol 283 in 42% yield (Eq. 125). OMe
Cr(CO)5
(CO)5Cr
OMe OH
THF, hν OMe
rt Ph
Ph 277
278 (98%)
279 (18%) (93%, CO atm, Pyrex filter)
(Eq. 124) OMe NHR
CNR rt-65°
Ph
Cr(CO)5
281 R = t-Bu 282 R = CH2CO2Et
OMe
(89%) (80%)
Ph 280
OMe hn
OH
CO Ph 283 (42%)
(Eq. 125)
190
ORGANIC REACTIONS
The photo-induced ortho-benzannulation reaction is not generally extendable to dialkylamino-substituted carbene complexes. The photolysis of complex 284 in the presence of CO does not give any detectable amount of the amino naphthol 285 (Eq. 126).256 However, if the amino group of the carbene complex is incorporated as a carbamate, photolysis of complexes such as 286 give amino naphthols like 287 (Eq. 127).256 A similar observation has been made for the scope of the thermal benzannulation of amino complexes with alkynes (Eq. 68).162,163 The most general method for the synthesis of 2-amino phenols from this reaction is the thermolysis of isonitriles.255,257 For example, the amino carbazole 289 is obtained in 86% yield from thermal reaction of indole carbene complex 288 with tert-butyl isonitrile,258 compared to the 65% yield of alkoxy carbazole 290 that was obtained from the photolysis of 288 in the presence of CO (Eq. 128). Both the CO and isonitrile insertion/cyclization products from indolyl carbene complexes of the type 288 were used in the total synthesis of carbazoquinocin C.258 Cr(CO)5
hn, CO
NMe2
NMe2 OH
284 (CO)4Cr
(Eq. 126)
Ph
Ph 285 O N Bn
O O-Bu-t
hn
t-BuO
N
Bn
(Eq. 127)
OH
CO
Ph
Ph 286
287 (33%)
MeO
NHBu-t
t-BuNC MeO
Cr(CO)5
THF, reflux
C7H15-n N Bn 288
C7H15-n N Bn 289 (86%) MeO
OH
(Eq. 128)
hn CO, THF
N Bn
C7H15-n
290 (65%)
The formation of ortho-alkoxy phenols from doubly unsaturated carbene complexes can be effected thermally in good yield with certain complexes.252,253 Whereas thermolysis of complex 278 in refluxing heptane affords only the o-methoxyphenol 279 in 29% yield (Eq. 124),254 thermolysis of complex 291
THE SYNTHESIS OF PHENOLS AND QUINONES
191
in THF produces the o-methoxyphenol 292 in 93% yield (Eq. 129). This thermal reaction was found to be synthetically viable only for a variety of cyclobutenylcarbene complexes, presumably because of the strain in the four-membered ring.253 These cyclobutenyl complexes are also unique in that their reactions with alkynes produce eight-membered ring compounds like 293.54 MeO OH
O
(93%)
MeO Cr(CO)5
O
292
THF, reflux
(Eq. 129)
MeO 291
Ph
O
Ph
O
(71%)
293
An alternative entry into dienyl ketenes of the type 274 (Scheme 15) involves reactions of Fischer carbene complexes with alkynes that are conjugated to doubly unsaturated groups.51,129,130,259,260 The reaction of complex 258 with (Z)-4-phenyl-3-buten-1-yne gives the naphthalene derivative 297 in 80% yield (Scheme 16).51 In these reactions, the vinyl ketene intermediate 295 is formed by addition of the carbene complex 258 to the terminal alkyne function to give the new complexed vinyl carbene intermediate 294. Subsequent CO insertion to give 295 followed by cyclization affords phenol 296, which is isolated as cyclized product 297.51
MeO
O •
(CO)4Cr Cr(CO)5
dioxane, reflux, 4 h
MeO
MeO
258
(CO)3Cr 295
294 MeO
OMe O
OH
297 (80%)
296
Scheme 16
192
ORGANIC REACTIONS APPLICATIONS TO SYNTHESIS
A large number of reactions of Fischer carbene complexes have been employed in organic synthesis and undoubtedly the reaction that has been most widely used in organic complex molecule synthesis is the benzannulation reaction with alkynes. The benzannulation reaction has been used in the total syntheses of a variety of natural products including vitamins K3 and K1(20) ,261 vitamins in the K1 and K2 series,262 vitamin E,263 nanaomycin A and deoxyfrenolicin,86,90,152,218 7-ethoxyprecocene,69 khellin,264,115 sphondin,114 thiosphondin,114 heratomin,114 angelicin,114,265 visnagan,167 12-O-methylroyleanone,266 5-lipoxygenase inhibitors,267 fredericamycin A,151,183,268,269 egonol,270 parvaquone,191 calphostins A, B, C, and D,271,272 shikonin,273 – 275 7-methoxyeleutherin,276 bis-N -dimethylmurryquinone,75 carbazoquinocin C,258 and landomycinone.277 The benzannulation reaction has also been used for the synthesis of the anthracyclinone antitumor antibiotics including the formal synthesis of daunomycinone278,12,112 and 11-deoxydaunomycinone158,279 – 281 . An alternate strategy for the formal synthesis of daunomycinone and 4-demethoxydaunomycinone has also been reported,279,281 – 284 but subsequently this synthesis has been called into question.105 Strategic models have been examined for the synthesis of several natural products including frenolicin and granaticin,214 olivin and chromomycinone,285,286,113,265 aspidosperma alkaloids,62,242 mitomycin A,287 taxodione,238 nogalarol,288 11-ketosteroids,245,247 oxasteroids,289 gilvocarcins,290 anthracyclines,159 angucyclinone SF 2315A,103 berberine alkaloids,291 indolocarbazole natural products,292,293 benzocarbazole natural products,220 modified carbohydrates,294,124 C-arylglycosides,295,296 menogaril,175,297 rubromycin,298 and allocolchicinoids.299,211 A selected set of total syntheses that feature the reaction of Fischer carbene complexes with alkynes is presented below and in each example the presentation begins with the key benzannulation step. The synthetic target is usually a natural product, but one example highlights benzannulation in the synthesis of a ligand for use in asymmetric catalysis. The examples were chosen to illustrate the utility of the benzannulation of alkenyl, aryl, and heteroaryl complexes, the intramolecular benzannulation, and the ortho benzannulation. The syntheses of 12-O-methylroyleanone266 and vitamin K1(20) 262 result directly from the benzannulation of alkenyl complex 299 and phenyl complex 26, respectively (Eqs. 130 and 131). Decalenyl complex 299 is prepared from the hydrazone 298 upon in situ generation of the corresponding vinyllithium. The reaction of this complex with 1-methoxy-3-methyl-1-butyne gives the target quinone 300 in 37% overall yield from 298. The synthesis of vitamin K1(20) is actually quite straightforward once the phytyl chain is appended to the proper alkyne function. The reaction of alkyne 301 with the phenyl carbene complex 26 gives a 56% yield of vitamin K1(20) after oxidation of the 4-methoxyphenol product with silver oxide.262 The same alkyne can be used in the synthesis of vitamin E.300
THE SYNTHESIS OF PHENOLS AND QUINONES
N
NHSO2Ar
EtO
1. n-BuLi (2.2 eq), –78° to –20° 2. Cr(CO)6 3. Et3O+ BF4–
H
Cr(CO)5
193
1. MeO Pr-i THF, reflux 2. CAN/H2O
H 299
298
MeO O
Pr-i
(Eq. 130)
O H 300 (37%) from 298 12-O-methylroyleanone 1. Cr(CO)5
R, t-BuOMe, 50°, 1 h 301
2. Ag2O, Et2O
OMe 26
R=
(Eq. 131)
3
O
O
(56%) vitamin K1(20)
Alkenyl and aryl carbene complexes have both been used in the synthesis of anthracycline antitumor antibiotics. Daunomycinone and 11-deoxydaunomycinone are aglycones of members of the anthracycline family of antitumor antibiotics, which include agents that are among the clinically most important compounds in cancer chemotherapy (Eqs. 132 and 133). The syntheses of daunomycinone278,12 and 11-deoxydaunomycinone158 via Fischer carbene complexes are illustrative of the power of the benzannulation reaction to solve two of the most significant problems related to the synthesis of this family of compounds: (1) the control of the relative orientation of the A vs. D rings, and (2) a convergent method to both the 11-oxy and 11-deoxy members of the anthracycline family.301 The construction of the tetracyclic quinone 305 from carbene complex 302 and alkyne 303 represents a formal synthesis of daunomycinone because its synthesis from 305 has been previously reported.302 This reaction gives a single constitutional isomer of 304 and locks in the correct relative regiochemistry of two ends of the tetracyclic target 305. The regioselectivity is expected to be quite high because the related reaction of the cyclohexenyl complex 34 with 1-pentyne gives greater than 250 : 1 selectivity (Eq. 10).
194
ORGANIC REACTIONS
OH
O O
MeO
O
1. THF, 45°
+
O
O
2. FeCl3-DMF
OMe O
(CO)5Cr 302
OMe O
303 O
O OMe
304 (72-74%)
OH
O
OH
B
C
O
O A
OMe O OH 305 (61-65%)
MeO
D
OH
O OH OH daunomycinone
(Eq. 132) The synthesis of 11-deoxydaunomycinone is accomplished with an inverted strategy compared to that for daunomycinone in that it incorporates the aromatic A-ring in the carbene complex and the saturated D-ring in the alkyne (Eq. 133).158 A tetracyclic intermediate can be made in a one-pot process involving a tandem benzannulation/Friedel-Crafts sequence of carbene complex 53 and alkyne 306. Benzannulation is carried out in benzene and after completion, the reaction mixture is opened to air to oxidatively liberate product 307 from the metal. Triflic anhydride and sodium acetate are added to protect the phenol and then triflic acid is added to effect the Friedel-Crafts cyclization. Final adjustments to the oxidation state give the tetracyclic target 308 in 61% overall yield from alkyne 306. Intermediate 308 has been previously converted into 11-deoxydaunomycinone in four steps.303 The complete synthesis of 11-deoxydaunomycinone, including the four additional steps from intermediate 308, is achieved in 8.5% overall yield from commercially available starting materials. This synthesis clearly demonstrates the efficiency of the benzannulation reaction of Fischer carbene complexes in organic synthesis. OH
O OMe OMe Cr(CO)5
O
1. C6H6, 75°
+
2. air, 10 min
O
O OMe OMe
OBu-t 306
53 O
OBu-t
307 O
O
O OH
OMe O
OH
308 (61% from 306)
MeO
O
OH OH
11-deoxydaunomycinone
(Eq. 133)
THE SYNTHESIS OF PHENOLS AND QUINONES
195
The synthesis of fredericamycin A is a formidable task not only due to the complexity of the molecule but also because a highly oxygenated aryl carbene complex is required (Eq. 134). Depending on the substitution pattern and the nature of the substituents, these complexes can be problematic in the benzannulation reaction.151,183,268,269 The 2,3,5-trioxygenated phenyl carbene complex 309 is no exception. In fact, the importance of the “acetic anhydride” effect (Eq. 81)116 was made apparent in the course of this synthesis. The key benzannulation in the synthesis of fredericamycin A is the reaction of complex 309 with alkyne 310 to give the desired phenol 311 in 35% yield. In the absence of acetic anhydride no product is observed. OTBS MOMO MeO
Cr(CO)5 OMe
+
TBSO BnO
Ac2O (1-2 eq) n-heptane, 50°, 48 h
EtO MOMO 309
N
310
MOMO MeO
OMe OTBS
MOMO
OH OTBS BnO
O
OH
O
O OH HO
MeO
EtO 311 (35%)
N
O
O
N H fredericamycin A (28% from 311)
(Eq. 134) The synthesis outlined in Eq. 135 is not of a natural product, but rather of a compound that was designed and synthesized for the purpose of serving as the chiral ligand VAPOL for catalytic asymmetric synthesis. The synthesis begins with the benzannulation reaction of the 1-naphthylcarbene complex 312 and phenylacetylene,89 which is carried out on a 250-gram scale to give a 72% yield of phenanthrene 313 after acetylation of the phenol.304 Cleavage of the methyl ether occurs with simultaneous reduction of the acetoxy group to give 2-phenyl4-phenanthrol (314) in 81% yield. Heating 314 in the presence of air at 185◦ gives the VAPOL ligand directly as a product of oxidative phenolic coupling. The racemic VAPOL can be resolved into its enantiomers by salt formation of a cyclic phosphoric acid derivative with (−)-cinchonidine. VAPOL has found general use in asymmetric catalysis.305 – 309
196
ORGANIC REACTIONS 1.
(CO)5Cr
OMe
Ph THF, 60°, 17 h
AcO
2. Ac2O, Et3N, THF, 60°, 24 h
Ph
312 250-g scale
185°
Ph Ph
neat, air
AlCl3, n-PrSH
resolution
OH OH
Cl(CH2)2Cl, rt, 12 h Ph
OMe 313 (72%)
Ph Ph
(±)-VAPOL (80-89%)
OH 314 (81%)
OH OH
(S)-VAPOL
(Eq. 135) The structural features of deoxyfrenolicin are sufficiently seductive to have inspired one formal and two total syntheses utilizing the benzannulation reaction. Since deoxyfrenolicin has a naphthalene core that is substituted in both the 2- and 3-positions, retrosynthesis to an aryl carbene complex requires a benzannulation reaction with an internal alkyne, a reaction known not to be regioselective. The first total synthesis solved the regiochemistry problem by tethering the alkyne 316 to the aryl carbene complex 315 via a β-alkoxyethoxy group that serves as the heteroatom stablizing group (Eq. 136).90,214,218 The key intermediate is the carbene complex 317, which upon thermolysis and oxidative workup gives naphthoquinone 318 as a single constitutional isomer. –+ ONMe4
1. AcCl, –20° 2. 316
OMe Cr(CO)5 315
MeO
O
O
O 317 (88%)
O
O
2. DDQ Pr-n
O CO2H
Pr-n OMe O
1. Et2O, 35°
Cr(CO)5
Pr-n OH
OMe O
318 (51%)
OH
OMe O deoxyfrenolicin
319
HO
O
O
Pr-n
316
(Eq. 136)
THE SYNTHESIS OF PHENOLS AND QUINONES
197
This synthesis can be shortened and improved in overall efficiency by employing the silicon tether in carbene complex 321, generated in situ from complex 315 and chloro(alkynyloxy)silane 320. Complex 321 is heated in hexane to give the key intermediate 319, which undergoes several subsequent steps to complete a formal synthesis of deoxyfrenolicin (Eq. 137).86 Note that in this intramolecular reaction the product can be liberated from the silicon tether without oxidation at the alcohol function. A second total synthesis of deoxyfrenolicin has been reported in which the problem of regiochemistry is circumvented by employing a terminal alkyne. The substitutent in the 3-position is introduced by an oxa-Pictet-Spengler reaction.152
–+ ONMe4
320
1. n-hexane, reflux
Cr(CO)5
CH2Cl2, –23°
MeO
OMe Cr(CO)5 315
2. CAN
O Si Me Me Pr-n O
321 (100%) O
O
CO2H O
Pr-n OMe O
OH OMe O 319 (49%)
deoxyfrenolicin
ClMe2SiO Pr-n 320
(Eq. 137)
The total synthesis of sphondin has been achieved by both an inter- and intramolecular benzannulation. The intramolecular approach involves the 3-furyl carbene complex 322 that has the alkyne tethered through the oxygen substituent of the carbene complex (Eq. 138).114,265 Thermolysis of 322 leads to in situ formation of the arenechromium tricarbonyl complex 323, which is methylated, proto-desilylated, and finally oxidatively liberated from remaining metal fragments to afford the benzofuran 324 in yields that range from moderate to excellent. The presence of the trimethylsilyl group in the intramolecular benzannulation is critical because extremely poor yields are observed for this reaction with terminal alkynes.90,114,214 A more efficient synthesis of sphondin can be achieved by an intermolecular benzannulation of the 2-furyl complex 100 and alkyne 325 to generate the benzofuran 326 in 55% yield (Eq. 139).114 Oxidation of 326 with DDQ produces sphondin in 40–57% yield.
198
ORGANIC REACTIONS
SPh
TMS O (CO)5Cr
SPh
O
2. MeI, K2CO3
1. THF, 75-85°
3. TFA 4. FeCl3-DMF
O TMS (CO)3Cr OH
O 322
323 O
SPh
O
O
O
O OMe
OMe sphondin (40%)
324 (56-92%)
(Eq. 138) 1.
O
OMe
CO2Me
O
325 THF, 85°
O
(Eq. 139)
2. air, 85°, 3 Å MS Cr(CO)5 100
O OMe 326 (55%)
The calphostin family of natural products are potent inhibitors of protein kinase C. The synthesis of calphostin A illustrates a situation where the thermal isonitrile insertion/cyclization is superior to the photo-induced CO insertion/cyclization procedure (Eq. 125).255 The presence of adjacent oxygenated carbons in one of the rings in these molecules suggested an approach utilizing the ortho-benzannulation of a Fischer carbene complex (Eq. 140).271,272 The key intermediate for this synthesis is the 2-alkenyl substituted aryl complex 327. The central disconnection in the retrosynthetic analysis leads to the ortho-quinone intermediate 329. The photo-induced ortho-benzannulation fails to provide a synthetically viable synthesis since photolysis of complex 327 gives low yields of the ortho-methoxy phenol 330. However, the alternative procedure involving the thermal reaction of complex 327 with an isonitrile gives the o-methoxynaphthylamine 328 in 60% yield. After protection of the alcohol function, 328 is oxidized to the o-quinone 329 in 87% yield. Quinone 329 is dimerized with trifluoroacetic acid in the presence of oxygen to give an intermediate, which upon deprotection affords calphostin A. The synthetic strategy developed for the synthesis of calphostin A has also been applied to the synthesis of calphostins B, C, and D.271,272
THE SYNTHESIS OF PHENOLS AND QUINONES MeO
Cr(CO)5
MeO
OMe OTIPS
OMe NHBu-t OH
1. t-BuNC 2. TBAF
MeO
199
1. BzCl, pyr 2. DDQ
MeO 327
328 (60%) OH O
MeO
OMe OBz
O O
MeO MeO
OBz
(Eq. 140)
MeO
OBz OMe
329 (87%) OH O calphostin A MeO
OMe OH OTIPS
MeO 330
COMPARISON WITH OTHER METHODS
The synthesis of phenols and quinones by the reaction of Fischer carbene complexes with alkynes is broadly applicable, and provides good to excellent overall synthetic efficiency for a range of substituted phenols, naphthols, and higher polycyclic phenols. There are many other methods for construction of aromatic ring systems in general, and also for phenols and quinones in particular.310 A few of these methods are closely related mechanistically to the benzannulation of carbene complexes in that they involve electrocyclic ring closure of a dienyl ketene intermediate that, however, is not coordinated to a metal center. Most of these processes involve the generation of cyclobutenones of the type 331, and their electrocyclic ring opening to a dienyl ketene and subsequent cyclization (Eq. 141). R1
O O R5
R2
R3 331
R4
heat or light
R1
OH
• R5
R2 R3
R4
R1
R5
R2
R4
(Eq. 141) R3
Many of the methods for the construction of cyclobutenones involve the [2 + 2] cycloaddition of a ketene with an alkyne (332 to 331, Scheme 17). This reaction can be synthetically useful with stable ketenes such as diphenylketene,311,312 but not generally with simple alkynes and ketenes. One example involves the reaction of phenylacetyl chloride with phenylacetylene.313 Thermally induced elimination of HCl at 180◦ produces phenylketene, which undergoes cyclization to the cyclobutenone 334. Under the reaction conditions, 334 undergoes ring
200
ORGANIC REACTIONS R5
N2 R3
R
light
4
O O
R5
R5
O
base
•
R4
R4
Cl O
R5
R3
R4
R3 332 heat or light
R1
Y
R1
R2 X R2
O R5 R3 R 333
332
4
– HY
R1
R2
R1
O
R2
R3
R5 R4
331 R1
O Cl
R2
+
R3Sn
R5 R4
R3 Ph
CH2COCl
Ph
180°, 16 h
Ph
O
KOH 335 (56%)
Ph
O
Ph 334
OH 335
Ph
O 336
Scheme 17
opening and then cyclization to afford naphthol 335, which in the presence of the acid chloride is acylated to provide ester 336. Hydrolysis gives a 56% yield of naphthol 335. The limitation of the [2 + 2] cycloaddition of ketenes with alkynes can be overcome in a two-step process involving the [2 + 2] cycloaddition of a ketene with an enol ether to provide 333 (Y = OR), followed by elimination of an alcohol to generate the phenol precursor 331.314,315 An alternative approach to cyclobutenones of the type 331 is the installation of the unsaturated substituent on the sp3 carbon by a Stille coupling reaction of chlorocyclobutenones.316 A synthetically reliable synthesis of phenols via cyclobutenones has been developed on the basis of the [2 + 2] cycloaddition of ketenes with alkynyl ethers, thio ethers, and ynamines.317,318 This process involves the cascade of
THE SYNTHESIS OF PHENOLS AND QUINONES
201
four pericyclic reactions and has been utilized in syntheses of a number of natural products. The synthesis of royleanone outlined in Eq. 142 involves a cascade of three pericyclic reactions beginning with the [2 + 2] cycloaddition of alkyne 338 with a ketene generated from the Wolff rearrangement of the diazo ketone 337.319 This reaction affords phenol 339 in 64–67% yield and subsequent silyl deprotection and oxidation completes the synthesis of royleanone. This synthesis is to be compared with the synthesis of O-methyl royleanone from carbene complex 299 (Eq. 130).266 The synthetic route to the methyl ether via the carbene complex is a few steps shorter and proceeds with somewhat higher overall yield.319 Pr-i
N2 O
i-Pr
OTIPS
TIPSO
TIPSO Pr-i
O
338 OH
hn 337 339 (64-67%)
(Eq. 142)
OH O
Pr-i
1. TBAF 2. Fremy's Salt
O
royleanone (49%)
A flexible synthesis of 4-alkoxyphenols and quinones grew out of the synthesis of phenols from cyclobutenones as outlined in Scheme 18.320 – 325 Alkoxyphenols would be the expected products when R3 in cyclobutenone 331 is an alkoxy group, that is, when cyclobutenones of the type 340 are employed (Scheme 18). Cyclobutenones 340 bearing an alkoxy substituent on the sp3 carbon tend to give higher yields of phenols upon thermolysis because the alkoxy group has a propensity for outward rotation in the electrocyclic ring opening. Thus, the unsaturated substituent preferentially undergoes inward rotation to give the ketene intermediate 341 having the correct geometry for cyclization to phenol 342.326 Cyclobutenones of the type 340 are best prepared from squaric acid.327,328 One of the key advantages of this quinone synthesis is the regiocontrolled construction of quinones as exemplified in the synthesis of quinone 344 in an overall yield of 90% from the intermediate 343 (Scheme 19).329 The synthesis of the same quinone from the reaction of a 4-methylphenyl-substituted Fischer carbene complex with 2-heptyne would give a mixture of isomers in which quinone 344 would be expected as the minor isomer. Thus, although this quinone synthesis is longer than the one involving Fischer carbene complexes, it offers a much higher level of regiochemical control that is not possible with Fischer carbene complexes. Much of the work on methods for quinone synthesis involving cyclobutenones and cyclobutenediones described above grew out of an earlier method that featured an oxidative addition of a transition-metal to a cyclobutenedione to give a metalla-cyclopentadienone followed by coupling with an alkyne to produce
202
ORGANIC REACTIONS HO
O
HO
O
i-PrOH
i-PrO
O
i-PrO
O (86%)
R5
Li
R1
R4
O R
2. MeX
O
i-PrO
O
2. 12 N HCl
benzene
1.
R1
1. R1Li
i-PrO
OMeR
R1
1. R2Li
5
R5
2. TFA
4
R2
O R1
O
OR R 340
4
OH
•
R2
R5
R1
R4
R2
OR
R5 R4 OR 342
341
Scheme 18
i-PrO
O
i-PrO
O
i-PrO
(72%) i-PrO
O (89%)
OMe
OH
O n-Bu
O
1. Li 2. MeX
2. 12 N HCl
1. n-BuLi 2. TFA
O
1. MeLi
O
140° xylene
OMe
CAN n-Bu
n-Bu OMe
O 344 (90%) from 343
343 (55%)
Scheme 19
quinones (Eq. 143).330,331 This method can be extended to cyclobutenones where, depending on the nature of the metal, either metallacyclopentenones332 or vinyl ketene complexes of the type 346 can be isolated (Eq. 144).333 Subsequent reaction of complex 346 with an alkyne gives a mixture of constitutionally isomeric phenols. R1
O
MLn
R1
O
O R3
R4
R1
R4
R2
R3
ML(n-1) R2
O
R2 O 345
O
(Eq. 143)
THE SYNTHESIS OF PHENOLS AND QUINONES
203
OH O R1
(C9H7)Co(PPh3)2
O
R2
•
R3
Co
R3 +
COD (2 eq), 100°
R2
OH R4
R4 R1
R1
R3 R2
R1
R4 R2
346
(Eq. 144) The reaction can also be performed catalytically with substoichiometric amounts of bis(cyclooctadiene)nickel resulting in facile formation of the same phenols at much reduced temperatures (Eq. 145).334 Reactions of the isolated vinyl ketene complexes 346 with alkynes give good to moderate yields of phenols (Eq. 144). However, the regioselectivity is low as indicated in the reaction of 347 with 1hexyne, which gives a 2.5 : 1 mixture of phenols 348 and 349 (Eq. 146).333 OH O
R
R
OH R3
R4
4
R1
R1
R3
•
R4
R2
R2
OH O
(Eq. 145)
+
Ni(COD)2 (10-20 mol%), 0°
R2
R1
3
Co
Bu-n
OH Bu-n +
(Eq. 146)
COD (2 eq), 100° Ph Bu-n 349 (45%)
Ph Ph
348 (18%)
347
Reactions of cyclobutenones with alkynes catalyzed by Ni(0) fail to give phenolic products with terminal alkynes, but afford good to high yields with internal alkynes. The steric difference between the two substituents of the alkyne has essentially no impact on regioselectivity as noted in the reaction of cyclobutenone 350 with 4-methyl-2-pentyne, which gives an equal mixture of the two possible isomeric products (Eq. 147).334 O Ph
Ni(COD)2 (10-20 mol%) 350
OH
OH Pr-i
Pr-i Ph
(40%) + Ph
(40%)
(Eq. 147)
Pr-i
The most widely studied of the organometallic-based quinone syntheses is that involving metallacyclopentenediones of the type 345 derived from cyclobutenediones (Eq. 143). Application of this process to the synthesis of an intermediate for the natural product royleanone is illustrative (Eq. 148).335 Reaction of cyclobutenedione 351 with tris(triphenylphosphine)chlorocobalt gives the corresponding metallacycle in 46% yield. Replacement of the phosphine ligands in the metallacycle with dimethylglyoxime produces the more reactive (toward alkynes)
204
ORGANIC REACTIONS
complex 352.336 The key step in the synthesis is the reaction of complex 352 with alkyne 353 to give the quinone 354 as a 5 : 1 mixture of constitutional isomers. i-Pr
O
MeO
O
O i-Pr
Cl Co PPh3 PPh3 MeO O (46%)
ClCo(PPh3)3
351
O
O i-Pr
DMG
OH N
Co
pyridine
MeO
N L O OH 352 (86%) L = pyridine
(Eq. 148)
OH
OMe O
OTBS 353
Cl
Pr-i
Pr-i
CoCl2•6H2O
O
O OTBS 354 (81%) 5:1 mixture of constitutional isomers
H royleanone
PREPARATION OF CARBENE COMPLEXES
The most widely used method for the synthesis of Fischer carbene complexes remains the original method reported by Fischer, which involves the addition of an organolithium reagent to a metal carbonyl complex (Scheme 20).1 The alkoxy complexes 356 can be obtained directly from the metal acylate 355 by in situ alkylation with trialkyloxonium salts,337 alkyl fluorosulfonates,338 or alkyl trifluoromethanesulfonates.339 The carbon monoxide ligands in lithium acylates will rapidly exchange with free carbon monoxide and also with the acyl carbon, thus providing an efficient method for the preparation of isotopically-labeled compounds.340 The reactions of acylate complexes 355 with less reactive electrophiles such as methyl iodide are not generally useful, although the direct preparation of complexes 356 with alkyl iodides in a two-phase system has been developed.341 Reactivity toward a given electrophile can be increased by conversion of the lithium acylate 355 to the tetraalkylammonium acylate 359. This enhancement is illustrated by the reaction of 359 with acid halides to generate the acyloxy complexes 360.170 These complexes are not generally stable to isolation under ambient conditions, but their reactivity can be utilized in the preparation of a variety of complexes by substitution reactions with alcohols, amines, and thiols.171 The preparation of complexes of the type 356 via the acyloxy complexes 360 is more efficient when the latter are generated with an acid halide from the ammonium salt 359 than from the lithium salt 355. Fischer was the first to demonstrate that amino and thio complexes of the type 357 could be prepared by the direct treatment of alkoxy complexes with amines and thiols.9 The alkylation of 355 with dimethyl sulfate is slow and inefficient. However, high yields have been reported with this inexpensive alkylating agent from the reaction of the potassium acylate generated in situ from the hydroxy complex 358 and potassium
THE SYNTHESIS OF PHENOLS AND QUINONES O C OC
O C
H+
OH (CO)5M
Cr CO
C O C O
R1
358 R1Li
OLi (CO)5M
R1
355
CH2N2 or K2CO3/Me2SO4 R2Y + or R2I, Et4NBr–/H2O
+ O– (R3)4 N R1 359
OR2 HXR3
(CO)5M
R1
356
+ (R3)4 NBr–
(CO)5M
205
YR3 (CO)5M
R1 357 YR3 = SR3, N(R3)2
HOR2 O
R4COY
O (CO)5M
HYR3
R4
R1 360
Scheme 20
carbonate.89 Alkylation of the hydroxy complex with diazomethane was, in fact, the first method by which a Fischer carbene complex was produced.1 A number of “non-Fischer” methods for the synthesis of Group 6 pentacarbonyl carbene complexes have been developed and, while a comprehensive discussion of these methods is not possible here, a few select examples are shown (Eqs. 149–151). The most important of these involves the reaction of the pentacarbonyl Group 6 metal dianions with acid halides342 and amides,343 which can lead to efficient synthesis of alkoxy and amino carbene complexes (Eq. 149). Although these methods were originally developed with disodium salts, the dipotassium salt is the preferred choice because of the ease of purification of the resulting carbene complex.344 Fischer carbene complexes can be prepared efficiently by the reaction of diazo compounds with metal pentacarbonyl derivatives of the type 361 that have an easily dissociable ligand (Eq. 150).345 This method does not appear to be applicable to the preparation of complexes that have oxygen substituents on the carbene carbon.346 Although Grignard reagents and other organometallic reagents less reactive than organolithiums do not provide useful yields of carbene complexes by the Fischer procedure, these reagents can potentially lead to Fischer complexes by addition to the more reactive metal precursors of the type 361 that have a labile ligand. Such a process has been reported for organozinc compounds.347 After the addition of diphenylzinc to 361 (L = THF), the resulting chromium pentacarbonyl monoanion is exposed to an atmosphere of CO, presumably leading to the formation of the zinc acylate corresponding to 355, which upon subsequent alkylation gives phenyl complex 26 (Eq. 150). Finally, a rather interesting synthesis of the stablized complex 363 has
206
ORGANIC REACTIONS
been reported from the reaction of the vinyllithium derivative 362 and complex 361 (L = PPh3 ) in which the addition product suffers a conjugate elimination of triisopropylsiloxide to give the α,β-unsaturated complex 363 (Eq. 151).143 O (R3)2N
R1
TMSCl
N(R3)2 (CO)5M
M(CO)6
2 M (0)
R1
357
1
(Eq. 149)
(M1)2M(CO)5 O
M1 = Li, Na, K Cl
R1
OR2
R2X
(CO)5M
R1
356
OMe C6H4OMe-4 N2 C6H4OMe-4 L = cyclooctene M(CO)6
L
(CO)5Cr
L M(CO)5
hn
3. Me3O+ BF4– L = THF
OMe
(66%)
1. Ph2Zn 2. CO (1 atm)
361
(Eq. 150)
OMe (CO)5Cr
26 (35%) OTIPS
OTIPS L M(CO)5
+
TIPSO
M = Cr O
L = PPh3
361 TIPSO
Li 362
TIPSO
O
(Eq. 151)
Cr(CO)5 363 (56%)
Another important route to α,β-unsaturated Fischer carbene complexes is the conversion of one carbene complex into another. It is not possible to even summarize the large number of classes of reactions in this category. The examples provided illustrate the types of transformations resulting in α,β-unsaturated Fischer carbene complexes that could serve in the preparation of phenols and quinones (Eqs. 152–155). The first method (Eq. 152) involves the Diels-Alder reaction of an alkynyl carbene complex that provides cycloadduct 80, which has been used to produce a benzannulated product (Eq. 21).112 Certainly one of the most important reactions in this category is the aldol condensation of alkyl carbene complexes to give trans-1-alkenyl complexes as is illustrated by the synthesis of complex 364 (Eq. 153).348 A number of useful procedures for this process have been developed over the years.156,239,348 – 351 The carbene complex 366 obviously could not be directly prepared by the standard Fischer procedure
THE SYNTHESIS OF PHENOLS AND QUINONES
207
starting with 4-bromobenzaldehyde (Eq. 154).113 The metal-halogen exchange in the 4-bromophenyl carbene complex 365 is only successful if the isopropoxy group is present to prevent attack on the carbene carbon.352 Finally, the metathesis reaction of electron-rich alkenes can be a useful method for the synthesis of either amino-353 or alkoxy-substituted354 Fischer carbene complexes (Eq. 155). TMS
TMS Cr(CO)5
Cr(CO)5
50°, 4 h
(Eq. 152)
OMe
OMe 79
80 (89%)
OMe (CO)5Cr
1. n-BuLi 2. C(CH2)6CHO /SnCl4
OMe (CO)5Cr
3. MsCl, Et3N
258
364 (57%)
(Eq. 153) OPr-i
OPr-i 1. n-BuLi
(CO)5Cr
2. DMF
(CO)5Cr
(Eq. 154)
Br
CHO
365
366 (49%)
O N O
OMe
OMe N
(CO)5Cr
(69%)
(Eq. 155)
+
THF, 66° (CO)5Cr 26
EXPERIMENTAL CONDITIONS
The reactions of Fischer carbene complexes with alkynes are best performed in non-polar solvents at temperatures of 45−80◦ under an inert atmosphere. Lower concentrations are usually required for intramolecular reactions and also to inhibit certain side-products in intermolecular reactions. However, most side-processes can be avoided by higher reaction concentrations. Many of the published procedures include deoxygenation of the reaction mixture by the freeze-thaw method. This procedure is usually taken for precautionary reasons when exploring a new reaction and looking for all primary products. For example, the 2-alkoxyfuran side-products are quite sensitive to air and often do not survive prolonged exposure. Deoxygenation by the freeze-thaw method is usually not needed for most reactions. Instead, flushing the flask with nitrogen is sufficient. In many reactions
208
ORGANIC REACTIONS
where the yields have been compared with and without careful deoxygenation, only slight if any differences have been noted. This observation is particularly important in the development of large-scale reactions where deoxygenation by the freeze-thaw method would be impractical (see the experimental procedure for the preparation 4-methoxy-2-phenylphenanthren-1-yl acetate). Most Fischer chromium carbene complexes are only slightly sensitive to air and can be purified by chromatography on silica gel in the presence of air with negligible losses. In large-scale preparations, purification can be accomplished by crystallization because many complexes are solids. Crystallized complexes can be stored in a refrigerator in a vial or bottle flushed with nitrogen for indefinite periods, sometimes up to several years. For some of the more air-sensitive complexes, reactions are most successful if the complex is purified just prior to use by chromatography on silica gel in the presence of air. It is extremely rare to encounter a complex that is so air sensitive that chromatography on silica gel under an inert atmosphere is required. Air oxidation of chromium carbene complexes produces chromium(III) and even trace amounts can cause broadening in the NMR spectra. Filtration through a short plug of silica gel with CDCl3 directly into an NMR tube removes the contaminant sufficiently enough to produce high quality spectra even when the filtration is done in air. Some complexes produce trace amounts of chromium(III) upon reaction with CDCl3 and thus C6 D6 is the preferred solvent in that event. CAUTION: Although chromium is an essential element in the +3 oxidation state, high levels of chromium(III) are toxic. In addition, the reaction of chromium carbene complexes with alkynes can produce chromium hexacarbonyl as a product of the reaction. This compound is a toxic and relatively volatile solid. Thus, these reactions should be carried out in ventilated hoods taking the normal precautions for handling toxic materials.
EXPERIMENTAL PROCEDURES
The following set of experimental procedures was chosen to illustrate a number of facets of the reactions of Fischer carbene complexes with alkynes. Methods for product isolation, of particular importance in most applications of the procedure, are reviewed in the section on Scope and Limitations. As is more fully illustrated by the following Experimental Procedures, there is a range of experimental protocols available for the production of a diverse set of functionalized products from these reactions including phenols, protected phenols, quinones, quinone acetals, arene chromium tricabonyl complexes, and cyclohexadienones. The reaction of Fischer carbene complexes with alkynes can be a very complicated reaction that can lead to a vast array of products, potentially detracting from its synthetic utility for generating phenols and quinones. The identity of the products reflects both the choice of reaction conditions and the actual protocol employed. In most of the following procedures, the procedure and conditions have been optimized for the normal benzannulation product.
THE SYNTHESIS OF PHENOLS AND QUINONES O B O THF, 45°, 16 h
OH
1. n-Bu Cr(CO)5
209
OH
Bu-n B O OMe O
2. air
OMe
Bu-n +
OMe (15%)
(73%)
2-Butyl-4-methoxy-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)naphthalen-1-ol (Benzannulation with an Alkynylborane).75 To a solution of pentacarbonyl(methoxyphenylmethylene)chromium (102 mg, 0.327 mmol) in THF (6.4 mL) was added 2-(hex-1-ynyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (204 mg, 0.980 mmol) via syringe under nitrogen. The reaction mixture was stirred at 45◦ for 14 hours and concentrated by rotary evaporation. Purification of the resulting residue by silica gel chromatography provided 4-methoxy-2n-butyl-1-naphthol (11 mg, 15%) and the title compound (85 mg, 73%). The latter was crystallized from hexanes to provide an amber solid, mp 116–116.5◦ : IR 3445, 2991, 2977, 1662, 1142 cm−1 ; 1 H NMR (250 MHz, CDCl3 ) δ 0.96 (t, J = 7.3 Hz, 3H), 1.42 (s, 12H), 1.47–1.72 (m, 4H), 2.73 (app t, J = 7.9 Hz, 2H), 3.91 (s, 3H), 4.93 (br s, 1H), 7.39–7.53 (m, 2H) 7.95–8.03 (m, 1H), 8.05–8.13 (m, 1H); 13 C NMR (62.9 MHz, CDCl3 ) δ 14.1, 24.7, 24.9, 30.2, 33.0, 63.5, 84.0, 121.6, 122.0, 124.3, 125.2, 125.9, 126.6, 144.4, 153.9. Anal. Calcd for C21 H29 BO4 : C, 70.80; H, 8.20. Found: C, 70.67; H, 8.36. O Cr(CO)5
1. Ph
Ph
Ph
2. CAN/H2O
OMe Method A (solid state) Method B (solution)
Ph O (86%) (94%)
2,3-Diphenyl-1,4-naphthoquinone (Comparison of Thermal Reaction in THF Solution with Solid-Phase Reaction on Silica Gel).84,177 Method A. A suspension of pentacarbonyl(methoxyphenylmethylene)chromium (65 mg, 0.208 mmol), silica gel (2.58 g), and diphenylacetylene (46 mg, 0.258 mmol) in hexane or Et2 O was stirred for 5 minutes at room temperature and the solvent was removed in vacuo. The round-bottomed flask containing the resulting orange powder was purged with nitrogen, immersed in a heated oil bath, and the contents were stirred at 40–50◦ until all the complex had been consumed (as indicated by TLC analysis of extracts of small aliquots of solid mixture, 3 hours). On completion of the reaction, the adsorbent was extracted with Et2 O and the extracts filtered through a pad of Kieselguhr. The resulting crude phenol product was taken up in Et2 O (10 mL) and treated with an aqueous cerric ammonium nitrate solution (8 eq) for 30 minutes at room temperature. The quinone was purified on a silica gel column with a 3 : 2 mixture of petroleum ether/CH2 Cl2 as eluent. 2,3-Diphenyl-1,4-naphthoquinone was obtained as a yellow crystalline
210
ORGANIC REACTIONS
solid (56 mg, 86%), mp 139–140◦ (lit.355 mp 141–142◦ ): FTIR (CH2 Cl2 )1670, 1601 cm−1 ; 1 H NMR (CDC13 ) δ 7.10 (m, 4H), 7.23 (m, 6H), 7.81 (m, 2H), 8.21 (m, 2H). Method B. A solution of pentacarbonyl(methoxyphenylmethylene)chromium (0.156 g, 0.500 mmol) and diphenylacetylene (0.178 g, 1.00 mmol) in THF (1.0 mL) was deoxygenated by the freeze-thaw method and heated at 70◦ for 12 hours under an argon atmosphere. The reaction mixture was diluted with THF (10 mL) and water (10 mL) and then ceric ammonium nitrate (1.8 g) was added. After 20 minutes the aqueous layer was extracted twice with Et2 O and the combined organic fractions were washed with water and brine, then dried over Mg2 SO4 . The crude reaction mixture was chromatographed on a silica gel column with a mixture of Et2 O, CH2 Cl2 , and hexanes (1 : 1 : 10) to give 0.146 g (0.47 mmol) of the title compound as a yellow solid in 94% yield. OTBS Cr(CO)5 O +
Bu-t
1. t-BuOMe (0.4 M), 55°, 55 min Bu-t 2. silica gel 3. TBSCl (4 eq), Et3N (4 eq), rt, 3 h
(CO)3Cr O
(55%)
{tert-Butyl-[2-tert-butyl-4-(2-isopropyl-5-methylcyclohexyloxy)naphthalen-1-yloxy]dimethylsilanyloxy}tricarbonylchromium(0) (Asymmetric Benzannulation of O-Menthyloxy Complexes).97 A solution of pentacarbonyl [[[(1S,2R,5S)-5-methyl-2-(1-methylethyl)cyclohexyl]oxy]phenylmethylene] chromium (2 mmol) and of 3,3-dimethyl-1-butyne (8 mmol) in tert-butyl methyl ether (5 mL) was degassed in three cycles and warmed at 55◦ for 55 minutes. After cooling to room temperature and filtration over silica gel, (tertbutyl)chlorodimethylsilane (8 mmol) and triethylamine (8 mmol) were added and the solution was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether/CH2 Cl2 = 5 : 1, −10◦ ) to give 0.66 g (1.1 mmol, 55%) of the title arene complex as a red solid: Rf = 0.27 (petroleum ether/CH2 Cl2 = 5 : 1); dr = 91 : 9 (based on 1 H NMR signals for H-3: 5.71 (s)/5.60 (s) ppm); [α] = −690◦ (c = 0.9, CHCl3 ); IR (petroleum ether) 1958, 1890, 1877 cm−1 ; 1 H NMR (500 MHz, CDCl3 ) δ 0.34, 0.53 (s, 6H), 0.80, 0.93, 1.01 (d, J = 7.0 Hz, 3H), 1.09 (s, 9H), 1.52 (s, 9H), 1.15–1.70 (m, 3H), 1.75 (m, 2H), 2.11 (qd, J = 7.0, 2.6 Hz, 1H). 2.65 (m, 1H), 4.00 (ddd, J = 10.6, 9.8, 5.3 Hz, 1H), 5.60 (s, 1H), 7.33 (ddd, 1H, J = 9.1, 6.5, 1.0 Hz, 1H), 7.45 (ddd, J = 8.9, 6.5, 1.0 Hz, 1H), 8.05 (m, 2H); 13 C NMR (100 MHz, CDCl3 ) δ −1.0, 0.4, 16.9, 20.8, 22.2, 19.9, 23.6, 26.0, 27.0, 30.9, 31.5, 34.2, 34.9, 39.3, 48.1, 76.9, 79.7, 99.0, 101.0, 108.6, 123.4, 125.4, 126.6, 127.8, 128.9, 130.6, 234.4; MS (70 eV) m/z (% relative intensity): 604 (5, M+ ), 548 (1, M+ −2 CO), 520 (100, M+ −3 CO), 468 (1, M+ −Cr(CO)3 ). Anal. Calcd for C33 H48 O5 SiCr: C, 65.53; H, 8.00. Found: C, 65.43; H, 7.91.
THE SYNTHESIS OF PHENOLS AND QUINONES
MeO
O
1. Et Et, THF, 45°, 24 h
Cr(CO)5
211
Et (72%)
2. CAN / MeOH
OMe
Et MeO OMe OMe
2,3-Diethyl-4,4,5-trimethoxy-4H -naphthalen-1-one (Oxidative Workup to Quinone Monoacetals).12 A solution of pentacarbonyl[methoxy(2-methoxyphenyl)methylene]chromium (0.690 g, 2.02 mmol) and 3-hexyne (0.207 g, 2.52 mmol) in THF (20 mL) was deoxygenated by the freeze-thaw method (−196◦ /0◦ , 3 cycles). The mixture was stirred under argon at 45◦ and monitored by TLC. The crude mixture was poured into a solution of ceric ammonium nitrate (7.5 eq) in anhydrous MeOH (100 mL) and stirred over powdered anhydrous Na2 CO3 (1 g). After 30 minutes the solution was diluted with of 2% aqueous Na2 CO3 (200 mL) then extracted with several portions of Et2 O. After removal of the volatiles the crude product was purified by chromatography on activity IV basic alumina with a mixture of Et2 O/CH2 Cl2 /hexanes (1 : 1 : 4, Rf = 0.13) to give the title compound in 72% yield as a white solid, mp 88–89.5◦ (ether/hexane); 1 H NMR (CDCl3 ) δ 1.14 (t, J = 7.5 Hz, 3H), 1.24 (t, J = 7.5 Hz, 3H), 2.51 (q, 2H), 2.57 (q, 2H), 2.92 (s, 6H), 3.94 (s, 3H), 7.15 (d, J = 8.6 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H); 13 C NMR (CDCl3 ) δ 13.3, 14.0, 19.4, 20.0, 51.2, 56.1, 99.5, 115.2, 118.5, 125.l, 130.0, 134.4, 142.1, 154.8, 157.3, 183.2; MS m/z (% relative intensity): 290 (18, M+ ), 275 (16), 261 (100), 259 (52), 231 (78), 135 (78), 115 (85), 91 (60), 77 (88). OAc Cr(CO)5 MeO
1.
Ph
Ph, THF, 55°, 4 h
(72%)
2. Ac2O, Et3N, THF, 55°, 17 h OMe
4-Methoxy-2-phenylphenanthren-1-yl Acetate (Benzannulation and In Situ Protection as an Aryl Acetate).304 An oven-dried, 3-L, three-necked, roundbottomed flask equipped with a mechanical stirrer, a reflux condenser, and a septum was charged with pentacarbonyl(methoxy-1-naphthalenylmethylene)chromium (250 g, 0.69 mol). To this was added dry THF (1.4 L) via cannula under an inert nitrogen atmosphere. The resulting dark-red solution was purged with nitrogen for 30 minutes. The septum was replaced by a pressure-equalizing dropping funnel containing a nitrogen purged solution of phenylacetylene (91 mL, 0.83 mol) and dry THF (29 mL). The flask and its contents were heated to 55◦ with a heating mantle and then the phenylacetylene solution was added dropwise over a 3-hour period. The reaction mixture was stirred at 55◦ for an additional 1 hour or until TLC indicated that the chromium carbene complex was totally consumed. At this point triethylamine (289 mL, 2.07 mol) and acetic anhydride (196 mL, 2.07 mol) were added to the flask and the resultant mixture was stirred at 55◦ for 17 hours. The dark brown reaction mixture was cooled to ambient
212
ORGANIC REACTIONS
temperature, decanted into a 2-L round-bottomed flask, and the volume reduced to 1/4 of the original volume under reduced pressure (rotary evaporator). The greenish yellow precipitate was collected by filtration on a 13-cm B¨uchner funnel under reduced pressure and washed with EtOAc (3 × 200 mL) to afford the first crop of the yellow product. The green solid remaining in the 3-L flask was washed with EtOAc (3 × 100 mL) and the solvent decanted. The solid residue remaining was discarded, the decanted EtOAc washings were combined with the filtrate from the first crop, and the combined organic layers washed with 1 L of water and 1 L of brine. The organic layer was suction filtered through a 3-cm bed of wet packed silica gel in a 12-cm diameter B¨uchner funnel to remove the green chromium residue. The brown filtrate was reduced to 1/4 of its original volume under reduced pressure and the resultant precipitate was collected by filtration and washed with EtOAc (3 × 50 mL) to afford a second crop of the product as a yellow solid. The filtrate was then further concentrated to afford a third crop. The three crops were combined to provide the title compound as a light yellow solid (171 g, 72% yield based on the carbene complex). The product was further purified by flash column chromatography using EtOAc/hexane (1 : 9) to give a white solid, mp 160–161◦ ; Rf = 0.23 (EtOAc/hexane = 1 : 9); IR (neat) 3056, 2929, 2844, 1762, 1598, 1498, 1451, 1367, 1213, 1196, 1174, 1157, 1100, 1049, 815, 745, 700 cm−1 ; 1 H NMR (CDCl3 ) δ 2.19 (s, 3H), 4.14 (s, 3H), 7.13 (s, 1H), 7.36 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.53–7.63 (m, 4H), 7.70 (d, J = 8.9 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 9.62 (d, J = 8.8 Hz, 1H); 13 C NMR (CDCl3 ) δ 20.7, 56.0, 109.6, 119.5, 120.9, 126.3, 126.9, 127.5, 127.6, 128.3, 128.4, 128.6, 129.1, 129.3, 130.1, 131.9, 132.5, 137.3, 138.0, 156.6, 169.7; MS m/z (% relative intensity): 342 (8, M+ ), 300 (100), 285 (46), 268 (8), 255 (6), 239 (10), 226 (12), 191 (2), 155 (27), 126 (18); exact mass (m/z) calcd for C23 H18 O3 , 342.1256; found, 342.1253. Anal. Calcd for C23 H18 O3 : C, 80.68; H, 5.30. Found: C, 80.76, H, 5.42. O Cr(CO)5 MeO
+
O
OMe
OBu-t
OH
1. benzene, 75°, 12 h 2. air, 15 min, rt 3. TFAA, NaOAc, 1 h 4. TFA, 2 h, rt 5. 2 N NaOH, rt
O
O
O
1. AgO, HNO3
MeO MeO
O (56%)
2. O2, DMF, 100°, 3 h (75%)
MeO
O
OH
2-Acetyl-11-hydroxy-6,7-dimethoxy-2,3,4,4a,12,12a-hexahydro-1H -naphthacen-5-one and 8-Acetyl-7,8,9,10-tetrahydro-11-hydroxy-1-methoxytetracene-5,12-dione (One-Pot Benzannulation/Friedel-Crafts Reactions Followed by Oxidation).158 A solution of pentacarbonyl[methoxy(2-methoxyphenyl)
THE SYNTHESIS OF PHENOLS AND QUINONES
213
methylene]chromium (0.176 g, 0.516 mmol) and tert-butyl 4-acetyl-2-(prop-2ynyl)cyclohexanecarboxylate (0.163 g, 0.619 mmol) in benzene (6 mL) was deoxygenated by the freeze-thaw method (−196◦ to room temperature, 3 cycles). The reaction mixture was heated under an argon atmosphere at 60◦ for 30 hours and then opened to air for 15 minutes. A major spot on TLC (Rf = 0.34, CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1) indicated the presence of the benzannulated product. NaOAc (98.0 mg, 0.715 mmol) was added and the mixture was stirred at room temperature for 5 minutes before trifluoroacetic anhydride (2.0 mL) was introduced. The acetylation reaction was complete in one hour after stirring at room temperature (Rf = 0.42, CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1). Trifluoroacetic acid (3 mL) was added and the resulting mixture was stirred at room temperature for 2 hours to effect the Friedel-Crafts cyclization. Only one spot was present on TLC (Rf = 0.29, CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1). To hydrolyze the trifluoroacetate, NaOH solution (4 M) was slowly added until the solution became basic (pH > 11). After the mixture was stirred at room temperature for a half hour, HCl was added to neutralize the reaction mixture (Rf = 0.13, CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1). The mixture was extracted with Et2 O (6 × 30 mL) and the organic phases were combined and dried over MgSO4 . After removal of the volatiles, 2-acetyl-2,3,4,4a,12,12a-hexahydro-11-hydroxy6,7-dimethoxytetracen-5(1H )-one was isolated by flash chromatography (CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1) in 56% overall yield. The tetracenone intermediate was not characterized, but rather directly oxidized by treatment with silver oxide (1.28 g, 10.3 mmol) and nitric acid (2.0 N, 10.3 mL, 20.6 mmol) in acetone (20 mL) at room temperature for 30 minutes (Rf = 0.14). After addition of buffer solution (pH 7, 10 mL) and CH2 Cl2 (50 mL), the organic phase was washed with brine and water, and dried over MgSO4 . Evaporation of the volatiles under reduced pressure gave an orange residue which was aromatized by a gentle purge with oxygen in DMF (10 mL) at 100◦ for 2 hours. After removal of the DMF by heating under reduced pressure, the product was purified by flash chromatography (CH2 Cl2 /Et2 O/hexane = 1 : 1 : 1, Rf = 0.44) to give the title compound (0.109 g, 0.311 mmol, 75% yield) as an orange solid and as the sole product; mp 222–225◦ (lit.356 mp 222–225◦ ). If the tetracenone intermediate is not purified, the final product was isolated in 61% overall yield from the alkyne in a one-pot seven step process. IR (neat) 2957, 2921, 2854, 1701, 1665, 1622, 1585, 1460, 1436, 1415, 1384, 1353, 1287, 1269, 1260, 1249, 1235, 1213, 1176, 1053 cm−1 ; 1 H NMR (CDCl3 ) δ 1.71–1.82 (m, 1H), 2.23–2.31 (m, 1H), 2.27 (s, 3H), 2.69–2.84 (m, 2H), 2.95–3.08 (m, 3H), 4.06 (s, 3H), 7.33 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 13.35 (s, 1H); 13 C NMR (CDCl3 ) δ 22.8, 24.5, 28.2, 31.5, 46.8, 56.7, 114.0, 118.0, 119.5, 120.1, 120.9, 129.7, 132.7, 135.6, 135.9, 144.2, 160.8, 160.8, 182.7, 188.8, 210.1; MS m/z (% relative intensity): 350 (100, M+ ), 335 (6), 308 (30), 307 (97), 306 (12), 304 (25), 291 (12), 290 (12), 289 (15), 275 (5), 189 (6), 178 (4), 166 (4), 115 (5), 77 (4), 69 (5); exact mass (m/z) calcd for C21 H18 O5 , 350.1154; found, 350.1169.
214
ORGANIC REACTIONS
OMe (CO)5Cr
TBSO
(CO)3Cr
TBSO
(CO)3Cr
OTBS
+ MeO
Method A Method B
OTBS
syn + anti (53%) (58%)
syn
OTBS MeO
anti
syn:anti >99:1 6:94
Tricarbonyl[6-(tert-butyldimethylsilanyloxy)-2 -(tert-butyldimethylsilanyloxymethyl)-3-methoxy-2,5-dimethylbiphenyl]chromium(0) (Simultaneous and Stereoselective Creation of Axial and Planar Elements of Chirality).212 Method A. A magnetic stir bar was placed in a flame-dried, single-necked flask that had been modified by replacement of the 14/20 joint with a 10-mm threaded high-vacuum stopcock. The stopcock was replaced by a rubber septum and the flask was back-filled with argon. N ,N -diisopropylethylamine (0.162 g, 1.25 mmol, distilled from KOH and freshly filtered through basic alumina) was added via syringe. Pentacarbonyl[(2Z)-1-methoxy-2-butenylidene]chromium (0.102 g, 0.37 mmol, freshly purified or freshly prepared) was added to the reaction flask followed by a solution of (2-(prop-1-ynyl)benzyloxy)(tert-butyl)dimethylsilane (0.065 g, 0.25 mmol) in toluene (1.0 mL) and then (tert-butyl)chlorodimethylsilane (0.113 g, 0.75 mmol) was added via syringe. The septum was replaced by the threaded stopcock and the reaction mixture was deoxygenated using the freeze-thaw method (three cycles). The reaction flask was left to warm to room temperature, after which it was back-filled with argon, sealed with the stopcock, covered with aluminum foil, and heated to 50◦ for 24 hours. After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator and subjected to silica gel chromatography. Elution with a mixture of pentane and CH2 Cl2 (3 : 1) gave the title compound (88 mg, 53% yield) as a yellow oil which was determined by 1 H NMR to be ≥99 : 1 syn:anti. 1 H NMR (CD2 Cl2 , 400 MHz) δ−0.64 (s, 3H), −0.17 (s, 3H), 0.17 (s, 6H), 0.80 (s, 9H), 0.97 (s, 9H), 1.86 (s, 3H), 2.22 (s, 3H), 3.78 (s, 3H), 4.97 (d, J = 7.8 Hz, 1H), 5.34 (d, J = 7.8 Hz, 1H), 5.72 (s, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.82 (d, J = 7.0 Hz, 1H). Method B. A magnetic stir bar was placed in a flame-dried, single-necked flask that had been modified by replacement of the 14/20 joint with a 10-mm threaded high-vacuum stopcock. The stopcock was replaced by a rubber septum and the flask was back-filled with argon. Pentacarbonyl[(2Z)-1-methoxy-2butenylidene]chromium (105 mg, 0.38 mmol) was added together with a solution of (2-(prop-1-ynyl)benzyloxy)(tert-butyl)dimethylsilane (65 mg, 0.25 mmol) in toluene (1.0 mL). The septum was replaced by the threaded stopcock and the reaction mixture was deoxygenated using the freeze-thaw method (−196◦ to room temperature, three cycles). At the end of the third cycle (room temperature), the reaction flask was back-filled with argon, sealed with the stopcock,
THE SYNTHESIS OF PHENOLS AND QUINONES
215
covered with aluminum foil, and heated in an oil bath at 50◦ for 48 hours. After cooling to room temperature, the reaction flask was placed under a positive flow of argon, and N ,N -diisopropylethylamine (0.218 mL, 1.25 mmol) and (tert-butyl)chlorodimethylsilane (0.113 g, 0.75 mmol) were added to the reaction flask. The flask was deoxygenated by the freeze-thaw method (−196◦ to room temperature, two cycles) and heated for an additional 24 hours at 50◦ . After being cooled to room temperature, the reaction mixture was concentrated on a rotary evaporator and the product was purified by silica gel chromatography (pentane/CH2 Cl2 = 3 : 1) to provide the title compound as a yellow oil (92 mg, 58%). The product was determined by 1 H NMR to be a 96 : 4 mixture of anti to syn diastereomers. The same ratio was found in the 1 H NMR of the crude reaction mixture. The diasteromers are not separable by TLC or silica gel chromatography. Anti-isomer: IR (neat) 2930, 2857, 1955, 1880, 1463, 1409, 1255, 1159, 1119, 1077, 914, 837, 778 cm−1 ; 1 H NMR (CD2 Cl2 , 400 MHz) δ −0.49 (s, 3H), −0.04 (s, 3H), −0.03 (s, 3H), 0.04 (s, 3H), 0.73 (s, 9H), 0.85 (s, 9H), 1.80 (s, 3H), 2.20 (s, 3H), 3.70 (s, 3H), 4.28 (d, J = 13.6 Hz, 1H), 4.56 (d, J = 13.6 Hz, 1H), 7.40 (m, 2H), 7.50 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H). TBSO OMe (CO)5Cr
OTr +
TBSCl, (i-Pr)2NEt,
(68%) dr ≥ 96:4
CH2Cl2, 60°, 12 h (CO)3Cr
OTr
OMe
{tert-Butyl[4-methoxy-2-methyl-6-(1-trityloxyethyl)phenoxy]dimethylsilanyloxy}tricarbonylchromium(0) (Central to Planar Chirality Transfer from a Chiral Propargyl Ether).88 Pentacarbonyl[(2Z)-1-methoxy-2-butenylidene] chromium (0.263 mmol) and a small magnetic stir bar were placed in a flamedried, single-necked flask that had been modified by replacement of the 14/20 joint with a 10-mm threaded high-vacuum stopcock (Kontes No. 826610). The stopcock was replaced with a rubber septum and the flask was evacuated and back-filled with argon. One half of the volume of anhydrous CH2 Cl2 required for a 0.05 M solution of the carbene complex, optically pure (S)-(but-3-yn2-yloxy)triphenylmethane (1.9 eq), N ,N -diisopropylethylamine (5.0 eq, freshly distilled or passed through a pipette-size basic alumina column), (tert-butyl)chlorodimethylsilane (3.0 eq), and the remaining solvent were added via syringe. The septum was replaced with the threaded stopcock, and the reaction mixture was degassed using the freeze-thaw method (three to four cycles). Then the reaction flask was back-filled with argon, sealed with the stopcock, and the reaction mixture was heated at 60◦ for 6–20 hours or until all the carbene complex was consumed. After cooling to room temperature, the reaction mixture was analyzed by TLC (CH2 Cl2 /hexane = 1 : 1, UV/PMA), concentrated under reduced pressure, and subjected to column chromatography (gradient elution from 0–75% CH2 Cl2 in hexane or pentane, column size 1.5 × 30 cm) to give the title compound (239.7 mg, 68% yield) as a yellow waxy foam,
216
ORGANIC REACTIONS
Rf = 0.42 (CH2 Cl2 /hexane = 1 : 1). The diastereomeric purity was determined to be greater than 96 : 4 by 1 H and 13 C NMR analysis with the aid of samples of each diastereomer. [α]20 436 −298.3◦ (c 5.70 × 10−5 , CH3 OH); [α]20 D −114.0◦ (c 5.70 × 10−5 , CH3 OH); IR (neat) 2928, 2855, 1941, 1858, 1452, 1429, 1235, 1153, 1041, 1026, 893, 829 cm−1 ; 1 H NMR (CDCl3 ) δ 0.14 (s, 3H), 0.15 (s, 3H), 0.76 (s, 9H), 1.51 (d, J = 6.3 Hz, 3H), 2.05 (s, 3H), 3.52 (s, 3H), 4.82 (d, J = 2.5 Hz, 1H), 4.85 (q, J = 6.3 Hz, 1H), 5.51 (d, J = 2.5 Hz, 1H), 7.12 (t, J = 7.0 Hz, 3H), 7.16 (t, J = 7.7 Hz, 6H), 7.36 (d, J = 7.5 Hz. 6H); 13 C NMR (CD2 Cl2 ) δ −2.9, 17.7, 18.8, 25.8, 26.7, 56.2, 66.3, 81.6, 83.3, 88.3, 99.1, 114.1, 127.5, 127.6, 128.0, 128.1, 129.1, 129.3, 136.0, 144.6, 235.5; EIMS m/z (% relative intensity): 675 (11, M+ + 1), 590 (56), 538 (10), 347 (3), 330 (4), 289 (3), 243 (100), 228 (3), 207 (3), 183 (9), 165 (34), 126 (5), 105 (28); exact mass (m/z) calcd for isomer C38 H42 CrO6 Si: 674.2156, found 674.2143.
OTr
O
Cr(CO)5 OMe
MeCN, 55°, 14 h
OMe
OTr
(88%) dr 98:2
4-Methoxy-6-methyl-6-(3-methylbut-3-enyl)-2-(3-methyl-1-trityloxyhepta2,6-dienyl)cyclohexa-2,4-dienone (1,4-Asymmetric Induction in Cyclohexadienone Formation).357 Pentacarbonyl[methoxy-1-(2,5-dimethylhexa-1,5-dienyl)methylene]chromium (0.552 mmol) and ((E)-5-methylnona-4,8-dien-1-yn3-yloxy)triphenylmethane (0.28 g, 0.718 mmol, 1.3 eq) were placed in a 100-mL, flame-dried, single-necked flask that had been modified by replacement of the 14/20 joint with a 10-mm threaded high-vacuum stopcock. The stopcock was replaced by a rubber septum and the flask was evacuated and back-filled with argon. To this flask was added MeCN (50 mL), the septum was replaced by the threaded stopcock, and the reaction mixture was deoxygenated by the freezethaw method (three cycles). The flask was back-filled with argon, sealed with the stopcock at room temperature, and heated to 55◦ for 14 hours. After cooling to room temperature, the reaction mixture was opened to the air, the solvent was changed to Et2 O, and the solution was stirred for 3 hours in air. The crude mixture was concentrated, and the product purified by column chromatography (silica gel, hexane/CH2 Cl2 = 1 : 1) to yield the title compound (0.28 g, 88% yield) as a light yellow solid, dr = 98 : 2 as determined by 1 H and 13 C NMR analysis with the aid of a sample of a mixture of diastereomers. Rf = 0.31 (hexane/CH2 Cl2 = 1 : 1); IR (neat) 1646, 1598, 1448, 1384 cm−1 , 1 H NMR (CDCl3 ) δ 0.94 (s, 3H), 1.32 (m, 3H), 1.53 (s, 3H), 1.59 (s, 3H), 1.81 (m, 1H), 2.01 (m, 2H), 2.13 (m, 2H), 3.48 (s, 3H), 4.46 (s, 1H), 4.55 (s, 1H), 4.69 (d, J = 3 Hz, 1H), 4.93 (d, J = 10.1 Hz, 1H), 5.01 (d, J = 16.8 Hz, 1H), 5.07 (d, J = 9 Hz, 1H), 5.33 (d, J = 9 Hz, 1H), 5.77 (m, 1H), 6.66 (d, J = 3 Hz, 1H), 7.71 (m, 9H), 7.47 (d, J = 8 Hz, 6H); 13 C NMR (CDCl3 ) δ 17.0, 22.4, 27.1, 32.2, 32.3, 39.0, 41.2, 48.5, 54.5, 66.9,
THE SYNTHESIS OF PHENOLS AND QUINONES
217
87.8, 109.3, 109.5, 114.4, 125.3, 127.0, 127.6, 128.8, 136.0, 136.2, 138.3, 138.5, 144.6, 145.4, 150.4, 202.8.
TBS Cr(CO)5
3
,
OTBS
SO2Ph
SO2Ph (74%)
THF, 50°, 4 d
OMe
(CO)3Cr OMe
{[2-(4-Benzenesulfonylbutyl)-4-methoxy-6,7-dimethyl-5,8-dihydronaphthalen-1-yloxy]-tert-butyldimethylsilanyloxy}tricarbonylchromium(0) (Tandem Diels-Alder/Benzannulation Reaction).95 Pentacarbonyl[3-[(1,1-dimethylethyl)dimethylsilyl]-1-methoxy-2-propynylidene]chromium (0.388 g, 1.037 mmol) and 1-(hex-5-ynylsulfonyl)benzene (0.166 g, 1.55 mmol) were combined in a mixture of THF (10 mL) and 2,3-dimethylbutadiene (3.5 mL). The solution was degassed (four cycles), and heated at 50◦ under argon for six days. Concentration and chromatographic purification on silica gel (Et2 O/CH2 Cl2 /hexanes = 1 : 1 : 6) gave the title compound as a yellow solid (0.409 g, 0.764 mmol, 74% yield), mp 136.5 − 138.0◦ : Rf = 0.23 (Et2 O/CH2 Cl2 /hexanes = 1 : 1 : 4); IR (neat film) 1946, 1860, 1463, 1355, 1306, 1257, 1150, 1133 cm−1 ; 1 H NMR (CDCl3 ) δ 0.28 (s, 3H), 0.34 (s, 3H), 0.94 (s, 9H), 1.65 − 1.85 (m, 4H), 1.73 (s, 3H), 1.75 (s, 3H), 2.24 (dt, J = 13.8, 7.0 Hz, 1H), 2.61 (dt, J = 13.8, 7.0 Hz, 1H), 3.07−3.13 (m, 5H), 3.20−3.30 (m, 1H), 3.67 (s, 3H), 4.87 (s, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.87 (d, J = 7.1 Hz, 2H); 13 C NMR (CDCl3 ) δ −3.1, −2.1, 18.4, 18.5, 18.7, 22.4, 25.9, 28.9, 29.8, 30.8, 32.5, 55.8, 56.0, 73.8, 96.8, 102.0, 103.6, 121.4, 122.0, 125.9, 127.9, 129.3, 133.8, 136.2, 138.9, 234.7; MS m/z (% relative intensity): 650 (10, M+ ), 566 (45), 514 (100), 457 (100), 372 (20), 331 (20), 317 (75). Anal. Calcd for C32 H47 CrO7 SSi: C, 59.06; H, 6.50. Found: C, 58.67; H, 6.14. O TBS
Cr(CO)5 OMe
1.
OTBS
CN or
2. LDA
Method A Method B
CN OMe (50%) (—)
OMe CN (—) (46%)
7-Methoxy-10-oxospiro[4.5] deca-6,8-diene-1-carbonitrile and 5-(tert-Butyldimethylsilanyloxy)-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile (Tandem Benzannulation/Aromatic Nucleophilic Substitution).159 Method A. Pentacarbonyl[(2E)-3-[(1,1-dimethylethyl)dimethylsilyl]-1-methoxy-2-propenylidene]chromium (0.2125 g, 0.565 mmol), 6-cyano-1-pentyne (0.0666 g, 0.621 mmol), and a small stir bar were placed in a 100-mL flask that had been modified by replacement of the 14/20 joint with a 10-mm
218
ORGANIC REACTIONS
threaded high-vacuum stopcock. The contents of the flask were dissolved in anhydrous CH2 Cl2 (11.3 mL) and deoxygenated by the freeze-thaw method. The flask was back-filled with argon at room temperature, the stopcock was replaced, and the flask sealed and heated at 65◦ under argon for 20 hours. The reaction flask was cooled to 0◦ and opened to high vacuum to strip the volatiles, followed by 2 hours at room temperature under high vacuum. The crude benzannulated product was taken up into THF (30 mL), then the flask was degassed and back-filled with argon. Under an argon stream, the threaded stopcock was replaced with a rubber septum. The flask was then cooled to −78◦ . A deoxygenated THF solution of lithium diisopropylamide (0.847 mmol, 1.5 eq) was cooled to −78◦ and added by cannula. The reaction mixture was stirred at −78◦ for 1.5 hours. A −78◦ degassed THF solution of iodine (1.15 g, 4.52 mmol, 8.0 eq) was added to the reaction mixture. After stirring the resulting solution for 1 hour at −78◦ , the cold bath was removed. After 2.5 hours of stirring at room temperature, the mixture was poured into Et2 O/10% aqueous Na2 S2 O3 . The aqueous layer was extracted once with Et2 O. The combined organic layers were dried with brine and MgSO4 , filtered, and concentrated. Chromatography on silica gel (Et2 O/CH2 Cl2 /hexanes = 1 : 1 : 6) gave two separable diastereomers of the spirocyclic title compound in a combined yield of 50%; major (0.0298 g, 0.147 mmol) and minor (0.0234 g, 0.115 mmol). If the arene chromium tricarbonyl complex produced by the benzannulation reaction was first purified (69%) and then subjected to the aromatic nucleophilic addition in a second step, then the major diastereomer of the spirocyclic product was obtained in 33% overall yield and the minor in 17% overall yield. The major isomer was isolated as a colorless solid, mp 88−90◦ : Rf = 0.19 (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 4); IR (neat film) 2240, 1670, 1641, 1582, 1453, 1408, 1250, 1032, 824 cm−1 ; 1 H NMR (CDCl3 ) δ 1.83 (quint, J = 6.3 Hz, 1H), 1.94−2.00 (m, 2H), 2.04−2.16 (m, 2H), 2.39−2.46 (m, 1H), 3.31 (t, J = 9.1 Hz, 1H), 3.66 (s, 3H), 5.27 (d, J = 2.5 Hz, 1H), 6.09 (d, J = 10.1 Hz, 1H), 6.90 (dd, J = 10.1, 2.7 Hz, 1H); 13 C NMR (CDCl3 ) δ 23.9, 30.8, 39.6, 40.8, 55.1, 57.9, 105.9, 119.7, 126.6, 142.3, 150.9, 201.7; MS m/z (% relative intensity): 203 (70, M+ ), 188 (15), 175 (25), 171 (10), 161 (30), 147 (90), 137 (100), 133 (50), 122 (40), 117 (40), 105 (50), 91 (65), 77 (90); exact mass (m/z) calcd for C12 H13 NO2 , 203.0946; found 203.0915. The minor isomer was isolated as an amber oil: Rf = 0.14 (Et2 O/CH2 Cl2 / hexane = 1 : 1 : 4); IR (neat film) 2240, 1669, 1642, 1585, 1464, 1408, 1242 cm−1 ; 1 H NMR (CDCl3 ) δ 1.74 − 1.78 (m, 1H), 1.83−1.91 (m, 1H), 2.12− 2.19 (m, 2H), 2.21−2.29 (m, 1H), 2.38−2.46 (m, 1H), 2.76 (t, J = 9.5 Hz, 1H), 3.63 (s, 3H), 4.93 (d, J = 2.6 Hz, 1H), 6.04 (d, J = 10.1 Hz, 1H), 6.83 (dd, J = 10.2, 2.8 Hz, 1H); 13 C NMR (CDCl3 ) δ 23.4, 30.1, 38.5, 40.5, 55.0, 58.5, 107.6, 119.5, 126.7, 141.5, 151.3, 202.0; MS m/z (% relative intensity) 203 (45, M+ ), 188 (10), 175 (15), 171(5), 161 (25), 147 (25), 137 (90), 121 (25), 107 (40), 91 (45), 77 (100); exact mass (m/z) calcd for C12 H13 NO2 , 203.0946; found 203.0948.
THE SYNTHESIS OF PHENOLS AND QUINONES
219
Method B. Pentacarbonyl[(2E)-3-[(1,1-dimethylethyl)dimethylsilyl]-1-methoxy-2-propenylidene]chromium (0.1555 g, 0.414 mmol) and 6-cyano-1-pentyne (0.071 g, 0.66 mmol) were combined as described in Method A and heated at 65◦ for 21 hours. The procedure for the nucleophilic addition was the same as for the one-pot conversion to spirocycle, except that (1) the annulation residue was taken up into only 8.5 mL of THF (∼0.05 M), and (2) 10 minutes after the addition of lithium diisopropylamide to the reaction mixture, the dry ice/acetone bath was replaced with an ice-water bath. After 1 hour at 0◦ , a deoxygenated solution of iodine (0.79 g, 3.11 mmol, 7.5 eq) in THF (5 mL) was added at 0◦ . The mixture was stirred at room temperature for 3 hours prior to workup as described above. Chromatography (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 10) yielded the tetrahydronaphthalene title compound in 38% yield (0.0497 g, 0.157 mmol). If the arene chromium tricarbonyl complex from the benzannulation reaction was first purified (69%) and then subjected to the aromatic nucleophilic addition in a second step, the tetrahydronaphthalene product was obtained in 46% yield for the two steps. The product was a colorless solid, mp 72−74◦ : Rf = 0.52 (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 4); IR (neat film) 2237, 1594, 1476, 1252, 1090, 905, 861 cm−1 ; 1 H NMR (CDCl3 ) δ 0.22 (s, 3H), 0.23 (s, 3H), 1.02 (s, 9H), 1.80–1.84 (m, 1H), 1.88–1.94 (m, 1H), 1.95–2.04 (m, 1H), 2.25 (br d, J = 13.0 Hz, 1H), 2.47 (ddd, J = 17.7, 11.4, 5.7 Hz, 1H), 2.86 (br d, J = 17.4 Hz, 1H), 3.84 (s, 3H), 4.06 (br s, 1H), 6.59 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H); 13 C NMR (CDCl3 ) δ −4.2, 18.2, 19.1, 23.6, 25.0, 25.7, 26.1, 55.7, 107.6, 117.1, 119.9, 121.7, 129.3, 147.2, 151.3; MS m/z (% relative intensity) 317 (65, M+ ), 261 (20), 233 (100), 218 (10), 159 (15), 144 (5), 129 (5), 115 (10); exact mass (m/z) calcd for C18 H27 NO2 Si, 317.1811; found 317.1828. TBSO (CO)5Cr
MeO
OTBS N Me
+
EtO
OR
Ac2O (1.1 eq) THF, 65°, 5 h EtO R=H R = OAc
N OMe Me (26%) (41%)
Methyl 5-{1-[(tert-Butyldimethylsilyl)oxy]ethyl}-6-ethoxy-4-hydroxy-7methoxyindole and its Acetate (Benzannulation of a Heteroaryl Carbene Complex).115,116 A solution of pentacarbonyl[methoxy(1-methyl-1H -pyrrol2-yl)methylene]chromium (1.0 g, 3.2 mmol), (4-ethoxybut-3-yn-2-yloxy)(tertbutyl)dimethylsilane (1.5 g, 4.8 mmol), and acetic anhydride (0.3 mL, 3.2 mmol) in THF (150 mL) was heated at 65◦ under argon for 5 hours. The mixture was cooled, and the solvent was removed by rotary evaporation to give a black oil. Purification by flash column chromatography (silica gel, 250 g, Et2 O/hexanes = 3 : 7) gave the title compound as a brown oil (309 mg, 26% yield) and its corresponding acetate as a brown oil (553 mg, 41% yield). Spectral data for the 4-acetoxyindole: IR (neat) 3334, 1637, 1494, 1324, 1288, 1056 cm−1 ; 1 H NMR
220
ORGANIC REACTIONS
(CDCl3 ) δ −0.07 (s, 3H), 0.16 (s, 3H), 0.92 (s, 9H), 1.41 (t, J = 7.0 Hz, 3H), 1.51 (d, J = 6.3 Hz, 3H), 3.85 (s, 3H), 3.93 (s, 3H), 4.09 (q, J = 7.0 Hz, 2H), 5.45 (q, J = 6.3 Hz, 1H), 6.49 (d, J = 3.1 Hz, 1H), 6.78 (s, J = 3.1 Hz, 1H), 8.86 (s, 1H); MS m/z: 379 (M+ ), 363, 247, 218. Anal. Calcd for C20 H33 NO4 Si: C, 63.28; H, 8.76; N, 3.69. Found: C, 63.25; H, 8.81; N, 3.52. OMOM
MOMO
(CH2)3NHBz
O
(CH2)3NHBz Cr(CO)5 N Me
(59%)
benzene, 50°, 17 h N Me
OMe
OMe
N-{3-[1-Methoxy-4a-(2-methoxymethoxyethyl)-9-methyl-4-oxo-4a,9-dihydro-4H-carbazol-3-yl]propyl}benzamide (Cyclohexadienone Annulation of an Aryl Carbene Complex).62 Pentacarbonyl[methoxy[3-[2-(methoxymethoxy)ethyl]-1-methyl-1H -indol-2-yl]methylene]chromium (121 mg, 0.27 mmol) was combined with N -(pent-4-ynyl)benzamide (76.8 mg, 0.41 mmol) in benzene (27.0 mL). The mixture was deoxygenated by the freeze-pump-thaw method and then was stirred at 50◦ under argon for 17 hours. Once cool, the flask was opened to air and stirred for 1 hour at room temperature. The solution was concentrated and the residue was chromatographed on 60 mL of silica gel (Et2 O/hexane = 9 : 1). The principal deep purple band was collected to afford the title compound (77 mg, 0.16 mmol, 59% yield) as a viscous oil: IR (CHCl3 ) 2929, 2851, 1653, 1609, 1580, 1547, 1488, 1464, 1363, 1101, 993, 913 cm−1 ; 1 H NMR (CDCl3 ) δ 1.73 −1.87 (m, 2H), 2.09 (br t, J = 6.8 Hz, 2H), 2.33–2.42 (m, 2H), 3.21 (s, 3H), 3.33 (t, J = 6.8 Hz, 2H), 3.34–3.50 (m, 2H), 3.50 (s, 3H), 3.64 (s, 3H), 4.39 (d, J = 6.4 Hz, 1H), 4.40 (d, J = 6.4 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 7.3 Hz, 1H), 6.96 (s, 1H), 7.03 (br s, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.38 (t, J = 7.7 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 7.3 Hz, 1H); 13 C NMR (CDCl3 ) δ 25.6, 29.4, 31.2, 38.6, 46.4, 55.1, 60.9, 61.5, 63.2, 96.3, 107.0, 120.2, 122.3, 125.1, 126.9, 127.3, 128.2, 128.3, 128.4, 129.5, 131.0, 134.7, 141.8, 146.7, 167.2, 201.6; Anal. Calcd for C28 H32 N2 O5: C, 70.57; H, 6.77; N, 5.88. Found: C, 70.26; H, 7.03; N, 5.76. OH Cr(CO)5
EtO2C N
1. Et Et, THF, 60°, 48 h
EtO2C
Et Et
2. air
(75%)
N
Ethyl 3,4-Diethyl-2-hydroxy-5-(1-pyrrolidinyl)benzoate (Phenol Formation from an Activated Aminocarbene Complex).156 – 157 To a solution of pentacarbonyl[(2E)-4-ethoxy-4-oxo-1-(1-pyrrolidinyl)-2-butenylidene]chromium
THE SYNTHESIS OF PHENOLS AND QUINONES
221
(74 mg, 0.2 mmol) in THF (7 mL) was added an excess of diethylacetylene. The mixture was stirred at 60◦ for 48 hours and then cooled to room temperature and stirred with silica gel (1 g) for 30 minutes. The solid was filtered off and the solvent and excess alkyne were removed under reduced pressure. The resulting residue was subjected to flash chromatography on silica gel (hexane/EtOAc = 3 : 1) to yield the title compound (44 mg, 75% yield) as a yellow oil: 1 H NMR (CDC13 ) δ 1.22 (m, 6H), 1.42 (t, J = 7.1 Hz, 3H), 1.93 (m, 4H), 2.77 (m, 4H), 3.00 (m, 4H), 4.40 (q, J = 7.1 Hz, 2H), 7.52 (s, 1H), 10.94 (s, 1H); 13 C NMR (CDC13 ) δ 14.1, 14.3, 15.3, 19.5, 21.3, 24.5, 53.9, 61.0, 109.4, 118.3, 131.2, 141.1, 147.7, 156.5, 170.5. Anal. Calcd for C16 H21 NO5 : C, 62.53; H, 6.89; N, 4.56. Found C, 62.69; H, 6.72; N, 4.53.
Cr(CO)5 NMe2
Pr-n TBSCl, (i-Pr)2NEt, benzene, 80°, 18 h
OTBS Pr-n (65%) (CO)3Cr NMe2
{[4-(tert-Butyldimethylsilanyloxy)-2-methyl-5-propylphenyl]dimethylamino}tricarbonylchromium(0) (Generation of an Aniline Chromium Tricarbonyl Complex).83 Pentacarbonyl[1-(dimethylamino)-2-methyl-2-propenylidene]chromium (75.0 mg, 0.26 mmol) and a small magnetic stir bar were placed in a flame-dried, single-necked flask that had been modified by replacement of the 14/20 joint with a 10-mm threaded high-vacuum stopcock (Kontes No. 826610). The stopcock was replaced with a rubber septum and the flask was evacuated and back-filled with argon. One-half of the total amount of anhydrous benzene (1.0 mL) required for a 0.25 M solution of the carbene complex, 1pentyne (48.5 µL, 0.49 mmol, 1.9 eq), N ,N -diisopropylethylamine (135.3 µL, 0.78 mmol, 3.0 eq, freshly distilled and/or passed through a pipette-size basic alumina column), (tert-butyl)chlorodimethylsilane (78.1 mg, 0.52 mmol, 2.0 eq), and the remaining solvent were added via syringe. The septum was replaced with the threaded stopcock, and the reaction mixture was deoxygenated using the freeze-thaw method (−196◦ to room temperature, three to four cycles). The reaction flask was back-filled with argon at the end of the last cycle, sealed with the stopcock, and heated at 80◦ for 17 hours. After cooling to room temperature, the reaction mixture was analyzed by TLC (CH2 Cl2 /hexane = 1 : 1, UV/PMA), concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel (10-50% CH2 Cl2 in hexane) to give the title compound as a yellow solid (74.8 mg, 65% yield), mp 74−75◦ . Recrystallization from Et2 O:pentane gave yellow needles: Rf = 0.43 (CH2 Cl2 /hexane = 1 : 1); IR (neat) 2959, 2932, 2861, 1951, 1868, 1473, 1364, 1266, 1172, 945, 862, 842, 784 cm−1 ; 1 H NMR (CD2 Cl2 ) δ 0.31 (s, 3H), 0.41 (s, 3H), 1.02 (s, 9H), 1.03 (t, J = 7.5 Hz, 3H), 1.59 (m, 2H), 2.19 (m, 1H), 2.24 (s, 3H), 2.61 (s, 6H), 2.63 (m, 1H), 5.05 (s, 1H), 5.50 (s, 1H); 13 C NMR (CD2 Cl2 ) δ −4.2, −3.8, 14.3, 18.4, 18.6, 24.8, 25.8, 32.7, 45.1, 86.1, 89.5, 102.0, 106.1, 126.5, 135.8, 236.0;
222
ORGANIC REACTIONS
EIMS m/z (% relative intensity): 443 (46, M+ ), 387 (25), 359 (100), 307 (64), 250 (9), 120 (14); exact mass (m/z) calcd for C21 H33 CrNO4 Si, 443.1584; found, 443.1566. Anal. Calcd for C21 H33 CrNO4 Si: C, 56.86; H, 7.50; N, 3.16; Cr, 11.73. Found C, 56.64; H, 7.84, N, 3.05; Cr, 11.56.
1. Me2SiCl2 2. vacuum 3. OH
Cr(CO)5
O
O– Me4N+
4. Ph Ph (3 eq), hexane, 69°, 1 h 5. CAN/H2O
(83%) O
OH
2-Hydroxymethyl-3,6-dimethyl-1,4-naphthoquinone (Intramolecular Benzannulation with an In Situ Generated Tether).86 2-Butyn-1-ol (500 mg, 7.1 mmol) was added dropwise at room temperature to neat dichlorodimethylsilane (9.10 g, 70.5 mmol). Immediate removal of HCl and excess dichlorodimethylsilane in vacuo provided (but-2-ynyloxy)chlorodimethylsilane in quantitative yield and requiring no additional purification. The in situ preparation of pentacarbonyl[[[(2-butynyloxy)dimethylsilyl]oxy](4-methylphenyl)methylene] chromium was accomplished by dropwise addition of a solution of (but-2-ynyloxy)chlorodimethylsilane (84 mg, 0.52 mmol) in CH2 Cl2 (3 mL) to a stirred solution of [tetramethylammonium][(4-(1-methylphenyl)oxidomethylene]pentacarbonyl chromium (200 mg, 0.52 mmol) in CH2 Cl2 (20 mL). After several minutes, tetramethylammonium chloride was removed by filtration and the solvent was removed in vacuo to give the siloxy carbene complex in quantitative yield. This complex was taken up in hexane (50 mL, [Cr] = 0.01 M) and diphenylacetylene (922 mg, 5.2 mmol, 10.0 eq) was added. The reaction mixture was heated to reflux with stirring and monitored by IR spectroscopy until the carbonyl ligand stretching bands of the starting siloxycarbene complex disappeared (∼1 hour). The reaction mixture was left to cool to room temperature under an inert atmosphere after which the solvent was removed by rotary evaporation in air. The residue was taken up in Et2 O (40 mL) and treated with a solution of ceric ammonium nitrate (0.5 M, 10 mL) in 0.1 N aqueous nitric acid (10 eq). The combined aqueous and organic layers were stirred vigorously for 10 minutes. The aqueous phase was then extracted with Et2 O (3 × 25 mL), and the combined organic extracts were dried over MgSO4 and concentrated. The products were separated by flash chromatography (petroleum ether/EtOAc = 65 : 35). The excess diphenylacetylene eluted rapidly and was recovered quantitatively. Further elution gave the title compound (93 mg, 83% yield): IR (CDCl3 ) 1665, 1622, 1602 cm−1 ; l H NMR (CDCl3 ), δ 2.21 (s, 3H), 2.46 (s, 3H), 4.72 (s, 2H), 6.76 (br s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H); 13 C NMR (CDCl3 ) δ 12.2, 21.8, 58.0, 126.4, 126.9, 129.4, 131.8, 134.5, 141.9, 144.7, 145.2, 185.4, 186.0. Anal. Calcd for C13 H12 O3 : C, 72.21; H, 5.59. Found: C, 72.14; H, 5.91.
THE SYNTHESIS OF PHENOLS AND QUINONES
OMe
MeO
223
+ Cr(CO)5
(CO)5Cr OMe
OMe OMe
MeO ClCH2CH2Cl
(36%)
100° HO MeO
OMe OH
5,17-Dimethyl-11,23,26,28-tetramethoxy-25,27-dihydroxycalix(4)arene (Calix[4]arene Formation via a Triple Annulation).223 1,3-Bis-[2 -propenyl (methoxy)methylene pentacarbonylchromium (0)]-2-methoxy-5-methylbenzene (0.188 g, 0.28 mmol) and 2-methoxy-5-methyl-1,3-di(prop-2-ynyl)benzene (0.055 g, 0.28 mmol) were dissolved in 1,2-dichloroethane (112 mL) in a flamedried, 250-mL Schlenk flask under argon. The solution was deoxygenated by the freeze pump thaw method (−196◦ to room temperature, three cycles) and then backfilled with argon at ambient temperature. The flask was sealed with a threaded high-vacuum Teflon stopcock and heated to 100◦ for 20–40 minutes during which time the deep red solution turned yellow. The yellow solution was stirred overnight exposed to air to facilitate demetalation of the arene chromium tricarbonyl complex. The solvent was removed under vacuum, the residue dissolved in EtOAc (50 mL), and the solution filtered through a short pad of silica gel. Further washing of the silica gel pad with EtOAc and evaporation of the solvent gave the crude calixarenes. Purification was accomplished by flash chromatography on silica gel (EtOAc/hexanes = 1 : 3), giving the title calix(4)arene (0.054 g, 0.101 mmol, 36% yield) as a white solid and as a single conformer. This compound was crystallized from acetonitrile and subjected to single crystal X-ray diffraction analyses that revealed that it exists as the cone conformer, mp >298◦ (dec.) Rf = 0.32 (EtOAc/hexanes = 1 : 3); IR (CH2 Cl2 ) 3297, 3055, 2988, 2937, 2835, 1600, 1481, 1433, 1285, 1228, 1124, 1055, 1009 cm−1 ; 1 H NMR (CDCl3 , 300 MHz) δ 2.03 (s, 6H), 3.27 (d, J = 13.2 Hz, 4H), 3.74 (s, 6H), 3.93 (s, 6H), 4.27 (d, J = 12.9 Hz, 4H), 6.61 (s, 4H), 6.72 (s, 4H), 7.59 (s, 2H,); 13 C NMR (CDCl3 , 75 MHz) δ 20.9, 31.5, 55.8, 63.5, 113.7, 129.1, 129.7, 132.7, 134.3, 146.9, 151.3, 152.2; HRMS (m/z): calcd for C34 H36 O6 , 540.2512; found 540.2512. Anal. Calcd for C34 H36 O6 : C, 75.53; H, 6.71. Found: C, 75.62; H, 6.60.
Cr(CO)5 OMe
TMS +
TMS 1. THF, 70° 2. air
HO
(73%)
6-Methyl-4-(trimethylsilanyl)indan-5-ol (Regioselective Two-Alkyne Phenol Annulation).80 A deoxygenated solution of pentacarbonyl[methoxy(methyl) methylene]chromium (164 mg, 0.67 mmol) and (hepta-1,6-diynyl)trimethylsilane
224
ORGANIC REACTIONS
(108 mg, 0.66 mmol) in THF (7 mL) was heated at 50◦ for 20 hours. The mixture was then stirred in air at room temperature for 1 hour followed by filtration through a bed of Celite. After removal of the volatiles from the filtrate, the crude product was purified by chromatography on silica gel (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 50) to first give the recovered carbene complex (14 mg) and then the title compound (106 mg, 0.48 mmol, 73% yield): IR (CHCl3 ) 3600, 2970, 1560, 1400 cm−1 ; 1 H NMR (CDCl3 ) δ 0.37 (s, 9H), 2.02 (m, 2H), 2.20 (s, 3H), 2.78 (t, J = 7.3 Hz, 2H), 2.92 (t, J = 7.2 Hz, 2H), 4.73 (s, 1H), 7.01 (s, 1H); MS m/z (% relative intensity) 220 (30, M+ ) 205 (30), 204 (100), 189 (50); exact mass (m/z) calcd for C13 H20 OSi, 220.1283; found 220.1287. Anal. Calcd for C13 H20 OSi: C, 70.88; H, 9.09. Found: C, 71.20; H, 9.23. TBSO OMe (CO)5W
1.
OMe , 1 atm CO, MeCN, rt, 16 h
HO (62%)
2. 110°, 23 h TBSO
3-(tert-Butyldimethylsilanyloxy)-12-methyl-7,15,16,17-tetrahydro-6H cyclopenta[a]phenanthren-11-ol (Tandem Diels-Alder Two-Alkyne Phenol Annulations).245 A 100-mL, single-necked flask equipped with a threaded highvacuum stopcock was charged with pentacarbonyl(1-methoxy-2,6,11-tridecatriynylidene)tungsten (0.147 g, 0.28 mmol), ((E)-4-methoxybuta-1,3-dien-2-yloxy) (tert-butyl)dimethylsilane (0.0902 g, 0.42 mmol), and MeCN (5.6 mL). The solution was deoxygenated three times via the freeze-thaw method, the flask was back-filled with 1 atm of carbon monoxide and sealed, and the contents of the flask were stirred at room temperature for 16 hours. The flask was opened and the reaction mixture was diluted with MeCN (50.6 mL). The solution was degassed twice using the freeze-thaw method, and then the flask was back-filled with one atmosphere of carbon monoxide at room temperature, sealed, and placed in an oil bath at 110◦ for 23.5 hours. The crude reaction mixture was filtered through Celite, and after removal of solvents, the product was purified by flash chromatography on silica gel (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 30, then 1 : 1 : 4) to give the title compound as a colorless oil (0.0635 g, 0.17 mmol, 62% yield); Rf = 0.38 (Et2 O/CH2 Cl2 /hexane = 1 : 1 : 16); IR (neat) 3567, 3028, 2952, 2894, 2857, 1608, 1495, 1471, 1419, 1287, 1247, 1224, 1169, 1073, 999, 969, 852, 839, 781 cm−1 ; 1 H NMR (CDCl3 ) δ 0.25 (s, 6H), 1.02 (s, 9H), 2.10 (quintet, J = 7.5 Hz, 2H), 2.23 (s, 3H), 2.65 (m, 2H), 2.68 (m, 2H), 2.88 (quintet, J = 7.5 Hz, 4H), 5.20 (s, 1H), 6.74 (m, 1H), 6.76 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H); 13 C NMR (CDCl3 ) δ −4.1, 12.6, 18.2, 24.6, 25.7, 26.5, 30.0, 31.3, 32.2, 117.8, 118.2, 119.3, 119.9, 126.4, 126.6, 132.0, 132.7, 140.7, 142.8, 149.2, 154.0; MS m/z (% relative intensity): 380 (100, M+ ), 339 (14), 323 (36), 161 (8), 75 (29), 57 (14); exact mass (m/z) calcd for C24 H32 O2 Si, 380.2173; found, 380.2162. Anal. Calcd for C24 H32 O2 Si: C, 75.74; H, 8.48. Found: C, 75.36; H, 8.58.
THE SYNTHESIS OF PHENOLS AND QUINONES MeO
C7H15-n N Bn
MeO
Cr(CO)5
225
OH
hn
(65%)
CO, THF N Bn
C7H15-n
N-Benzyl-1-heptyl-4-methoxy-2-methyl-9H-carbazol-3-ol (Photoinduced ortho-Benzannulation).258 A solution of pentacarbonyl[[2-(1-ethylideneoctyl)1-(phenylmethyl)-1H -indol-3-yl)methoxymethylene]chromium (472 mg, 0.815 mmol) in THF (150 mL) in a quartz photoreactor was purged with nitrogen for 15 minutes and then purged with carbon monoxide for another 15 minutes. The solution was irradiated with a 450 W medium-pressure mercury lamp for 30 minutes at room temperature. The resulting solution was kept under a carbon monoxide atmosphere for 12 hours. The solvent was then evaporated to give a red oily residue. The residue was purified by column chromatography (EtOAc/hexanes = 3 : 97) to give the title compound (223 mg, 65% yield) as a light brown solid, mp 102−104◦ : IR (CH2 Cl2 ) 3544, 2959, 2928, 2857 cm−1 ; 1 H NMR (500 MHz, CDCl3 ) δ 0.91 (t, J = 6.9 Hz, 3H), 1.20–1.40 (m, 8H), 1.42–1.64 (m, 2H), 2.38 (s, 3H), 2.74–2.84 (m, 2H), 4.06 (s, 3H), 5.65 (s, 1H), 5.66 (s, 2H), 7.04 (d, J = 6.8 Hz, 2H), 7.19–7.30 (m, 5H), 7.34–7.40 (m, 1H), 8.20 (dd, J = 7.8, 1.3 Hz, 1H); 13 C NMR (125 MHz, CDCl3 ) δ 12.0, 14.1, 22.6, 28.2, 29.1, 29.8, 31.8, 31.8, 48.7, 60.5, 108.8, 114.7, 119.2, 121.0, 122.1, 123.0, 124.3, 125.4, 127.1, 128.8, 134.2, 138.7, 138.8, 140.6, 142.1; EIMS m/z (% relative intensity) 415 (65), 330 (20), 240 (80), 91 (100). Anal. Calcd for C28 H33 NO2 : C, 80.93; H, 8.00; N, 3.37. Found C, 81.23; H, 7.84; N, 3.48. TABULAR SURVEY
The literature coverage includes that cited in Chemical Abstracts up to midSeptember of 2004, but some additional references past this time have been included. All reactions in the literature that involve the reaction of an α,βunsaturated Fischer carbene complex with an alkyne are included whether or not a phenol or quinone product was formed in the reaction, i. e., every example is included where a phenol or quinone product could have been produced. Not all reactions of saturated alkyl carbene complexes with alkynes are included; only those where reaction occurs to give a phenol product or phenol-derived product. The reactions of alkyl carbene complexes that give phenol products are largely the two-alkyne phenol products, which are to be found in Table 24 on miscellaneous reactions, or in Table 21 on carbene complexes with tethered alkynes. The product distribution from the reactions of carbene complexes with alkynes can often be very sensitive to the concentration and, thus, for purposes of comparison, the concentration of the carbene complex and the number of equivalents of alkyne are given in the tables when they are reported. Most of the tables are organized by the carbon number of the alkyne that appears in the first column and then by the carbon number of the carbene complex that appears in the second
226
ORGANIC REACTIONS
column. Tables 21 and 23 are organized by the carbon number of the carbene complex which appears in the first column. In some instances, the carbene complex that participates in the reaction is generated in situ and the organization is by the carbon number of the precursor carbene complex. The tables are subdivided by the nature of the metal, whether the alkyne is terminal or internal, and by the type of heteroatom-stabilizing group on the carbene complex. Thus the reactions of chromium, tungsten, and molybdenum complexes occur in separate tables. The reactions of chromium complexes are also separated into oxygen-, aminoand imino-, and sulfur-stabilized complexes. The exceptions to this organization are the tables on intramolecular reactions (Table 21), non-heteroatom-stabilized complexes (Table 22), and doubly unsaturated complexes (Table 23), where all examples of different metals and/or heteroatom complexes appear. The yields for the reactions are given in parentheses, followed by a ratio of product if applicable. A dash (—) indicates that no yield is reported in the reference. The following abbreviations have been used in the tables: Ad Bn Boc Bz CAN CC COD Cp Cp DBU de DEAD DDQ DMAP DME DMF DMTH dr ds EE HMPA LAH MEM MOM naphth N-morph PMB PMP
adamantyl benzyl tert-butoxycarbonyl benzoyl ceric ammonium nitrate carbene complex 1,5-cyclooctadiene cyclopentadienyl methylcyclopentadienyl 1,8-diazabicyclo[5.4.0]undec-7-ene diastereomer excess diethylazodicarboxylate 2,3-dichloro-5,6-dicyano-f-benzoquinone N ,N -dimethylaminopyridine 1,2-dimethoxyethane N ,N -dimethylformamide 2,5-dimethyltetrahydrofuran diastereomeric ratio diastereomer selectivity 2-ethoxylethyl hexamethylphosphoric triamide lithium aluminum hydride methoxyethoxymethyl methoxymethyl naphthyl N -morpholino p-methoxybenzyl p-methoxyphenyl
THE SYNTHESIS OF PHENOLS AND QUINONES
pyr TBAF TBS TBDPS Tf THF THP TIPS TMS Tol Tr tr Ts
pyridine, pyridinyl tetrabutylammonium fluoride tert-butyldimethylsilyl tert-butyldiphenylsilyl trifluoromethanesulfonyl (triflyl) tetrahydrofuran 2-tetrahydropyranyl triisopropylsilyl trimethylsilyl tolyl triphenylmethyl (trityl) trace p-toluenesulfonyl
227
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C4
Refs.
OH Cr(CO)5 Ph excess
(n-Bu)2O, 45°, 2 h
OMe 0.27 M
(68)
87
(CO)3Cr OMe O
C5 Cr(CO)5
Et Ph 1.7 eq
OMe 0.3 M
O Et
1. Solvent, 45°
+
I
II
2. CAN, MeOH
67
Et MeO OMe
MeO OMe Time
I + II
I :II
2h
(51)
2.2:1
(n-Bu)2O 24 h
(70)
2.0:1
THF
(66)
2.2:1
Solvent (n-Bu)2O
228
24 h
OH Cr(CO)5 1.5 eq Ph
Et (n-Bu)2O, 45°, 2 h
(60)
358
OMe 0.33 M
(CO)3Cr
OMe OH
Cr(CO)5
1.5 eq Ph
OH Et
t-BuOMe, 45-50°, 2-5 h
OMe 0.2 M
+
I
II
68
Et (CO)3Cr
OMe
(CO)3Cr
OMe
I + II (56), I:II = 2.2:1 NMe2
Cr(CO)5 NMe2
Hexane, rt, 1 h Ph
1 eq
(CO)5Cr
Ph
OMe 0.3 M
(2-65) E:Z = 45:1
359, 142
OMe
OMe Cr(CO)5 1. Hexane, rt, 1 h Ph 1 eq
OMe
2. Decane, 125°, 3 h
0.3 M
O
(CO)3Cr OH
Cr(CO)5
2 eq
OMe
(CO)3Cr
(24)
C6
Ph
(—)
(CO)3Cr
(20)
O
Me
(n-Bu)2O, 40-60°, 2 h
0.33 M
142
+
93
OMe OH Pr-n
Cr(CO)5 Ph
229
1.25 eq
OMe
(n-Bu)2O, 45°, 2 h
0.27 M
(CO)3Cr
I (58)
87
I (80)
68
OMe
OH Pr-n(Me)
Cr(CO)5 t-BuOMe, 45-50°, 2-5 h
1.5 eq
Ph
OMe
Me(Pr-n)
0.2 M
(CO)3Cr
OMe
OH Cr(CO)5 Et
Et Ph 1-4 eq
OMe 0.3-0.3 M
Et (n-Bu)2O or t-BuOMe,
(65-72)
45-55°, 1-2 h
Et (CO)3Cr
OMe
87, 73
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) O
C6 Et
Et
Cr(CO)5
Et
OMe
Et
I +
Et Ph
Refs.
Et II
+
OMe
O Et
Ph
O Et
III
OMe
+ Et
O
IV
+
Et OH
Et
Et
Et V
230
Ph
O
+
VI
OMe
Et OMe
Alkyne (eq)
CC (M)
3.0
0.12
1. THF, 45°, 16-24 h
I
II
III
IV
V
VI
(88)
(≤0.3)
(≤0.3)
(0)
(—)
(—)
13, 84
(97.4)
(1.3)
(0)
(0)
(≤1)
(—)
60
(44)
(—)
(—)
(—)
(—)
(—)
13
(54)
(—)
(—)
(—)
(—)
(—)
13
(96.6)
(1.7)
(0)
(0)
(1.3)
(—)
60
(87)
(≤1)
(≤1)
(0)
(—)
(—)
60
(96)
(—)
(—)
(—)
(—)
(—)
67
(96.5)
(≤0.7)
(0)
(0)
(≤1)
(—)
60
(95.7)
(≤0.6)
(0)
(0)
(<0.9)
(—)
60
(84)
(—)
(—)
(—)
(—)
(—)
13
(57)
(tr)
(—)
(23)
(—)
(—)
84
(38)
(14)
(—)
(23)
(≤1)
(—)
84
(—)
(25)
(—)
(7)
(≤2)
(32)
60
(37)
(5)
(5)
(24)
(—)
(—)
84
(24)
(14)
(15)
(19)
(—)
(—)
84
(—)
(65)
(—)
(11)
(1)
(12)
60
2. CAN 2.0
1. THF, 80°, 47 h
0.1
2. CAN 2.0
1. THF, –78°, 13.5 h
0.021
UV photolysis 2. CAN, –78° 2.0
1. THF, –15°, 13.5 h
0.021
UV photolysis 2. CAN 2.0
1. THF, 80°, 34 h
0.005
2. CAN 2.0
1. THF, 110°, 1-2 h
0.005
2. CAN
1.5
0.3
1. THF, 50°, 20 h 2. CAN
1.9
0.1
1. Benzene, 80°, 46 h 2. CAN
1.9
0.005
1. Benzene, 45°, 64 h 2. CAN
3.0
0.1-0.2
1. Hexane, 45°, 24 h 2. CAN
2.0
0.5
1. MeCN, 45°, 16-24 h 2. CAN
2.0
0.1
1. MeCN, 45°, 17 h 2. FeCl3-DMF
2.0
1. MeCN, 80°, 20 h
0.1
2. Air/SiO2 2.0
0.05
1. MeCN, 45°, 16-24 h
231
2. CAN 2.0
0.005
1. MeCN, 45°, 44 h 2. CAN
2.0
0.005
1. MeCN, 80°, 48 h 2. Air/SiO2
(n-Bu)3P
Cr(CO)4
Ph
OMe
Alkyne (eq)
CC (M)
2.2
0.05
I + II + III + IV + V + VI
1. THF, 50°, 20 h
I
II
III
IV
V
VI
(64)
(—)
(—)
(—)
(—)
(—)
133
(79)
(<3)
(—)
(—)
(8)
(—)
201
2. CAN 1.9
0.1
1. THF, 80°, 20-40 h 2. CAN
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OAc
C6 Ac2O (1.1 eq),
Cr(CO)5 Et
Ph 2.8 eq
Et
NEt3 (1.1 eq),
Et OMe 0.03 M
THF, 65°, 2 h
(75)
267, 360
(94)
73
Et OMe OTBS Et
1. t-BuOMe, 55°, 1 h
Cr(CO)5
2. TBSCl (4 eq),
4 eq Ph
OMe
Et
Et3N (4 eq), rt, 4 h
0.4 M
(CO)3Cr
OMe O
Et 1.5 eq
Et
232
+ Bu-n 1.5 eq
Ph
O Et
Cr(CO)5
1. Benzene, 40°, 22 h
OMe
I
2. CAN
Bu-n II
+
361
Et
0.1 M
O
O I + II (78), I:II = 4:96 Ph
Cr(CO)5 Et
THF, –20° to rt, 15 h
Et Ph 1.9 eq
(≤5)
Ph
Ph
(≤5)
+
OAc
+
114
(<5)
+
Ph
0.14 M Ph
Ph
+
(≤5)
Ph
Ph (≤5) +
OAc
O Ph
+
(<5)
Ph
Ph
Ph (≤5)
Ph (CO)3Cr
O
Et Et
Cr(CO)5 2 eq
Benzene, 80°, 16 h Ph
(97)
OPr-i
+
Et (≤0.5)
0.1 M
O
O O
Et 1.5 eq
Et
+ Bu-n 1.5 eq
O Et
Cr(CO)5 Ph
113
Et
1. Benzene, 40°, 22 h
OPr-i
Bu-n I
2. CAN
+
II
361
Et O
0.1 M
I + II (75), I:II = 1:99
O
OTBS (CO)5Cr
Et
Ph 1. t-BuOMe, 55°, 4 h
O
233
Et
Et
Et
2. TBSCl (4 eq), Et3N (4 eq), rt, 3 h
(CO)3Cr
(44) 85% de
73
O
0.4 M
4 eq R1O
OR1
R1O
OR1
1. TBSCl (5 eq), Et3N (10 eq), R2O THF, 55°, 3h R2O 2. CAN
6 eq
OR2 362
(80) OR2 TBSO
Ph
Et
R2 =
R1 = (CO)5Cr
Et
0.022 M OH MeO2C 1 eq
CO2Me
CO2Me
Cr(CO)5
(7)
THF, 65°, 3 h Ph OMe 0.03 M
CO2Me OMe
183
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) OH
C7
Refs.
Et
Cr(CO)5 (n-Bu)2O, 40-60°, 2 h
Et
Ph 2 eq
(—)
93
OMe 0.33 M
OMe
(CO)3Cr
OH
OH Bu-t
Cr(CO)5 t-BuOMe, 45-50°, 2-5 h
Bu-t Ph
0.2 M
1.5 eq
I
OMe
+
(CO)3Cr OMe
II Bu-t
68
II (23)
13
(CO)3Cr OMe
I + II (59), I:II = 98:2 O
234
1.5 eq OMe
2. FeCl3-DMF
OMe
t-Bu
0.1-0.2 M "
Ph
I (32) +
1. Hexane, 45°, 24-48 h Ph
O
Bu-t
Cr(CO)5
O 1. THF, 45°, 24-48 h
I (26) +
II (14)
13
2. FeCl3-DMF "
1. MeCN, 45°, 24-48 h
II (27)
13
2. FeCl3-DMF OH Pr-n(Et)
Cr(CO)5 Et
t-BuOMe, 45-50°, 2-5 h
Pr-n Ph
(CO)3Cr OMe
OAc Cr(CO)5 2 eq
OAc Pr-n
1. THF, 55°, 12 h
OMe 0.1 M
Et I
2. Ac2O, NaOAc, Ph
68
Et(Pr-n)
0.2 M
1.5 eq
(62) one isomer
OMe
+
II
Et
THF, 55°, 12 h
363
Pr-n
OMe
OMe I + II = (96), I:II = 52:48
OAc Cr(CO)5 Et
CO2Et
OAc Et
Ac2O (2.5 eq), Et3N (2 eq),
CO2Et I
THF, 65°, 5 h Ph
OMe
+
II
CO2Et OMe
0.03 M
70
Et OMe
I + II (38), I:II = 1.1:1 Ph n-Bu
Cr(CO)5 n-Bu
SMe
OMe
Hexane, 79°, 16 h
235
Ph
OMe
(39) MeO
144
Bu-n Ph NEt2
Cr(CO)5 NEt2
Ph
1 eq
OMe
Hexane, rt, 0.5 h
(CO)5Cr
Ph
0.3 M
"
I (62-70) E:Z = 14.5:1
Octane, 30.2°
140, 359 142, 141
OMe
I (—)
364 O
C8
Pr-n
Cr(CO)5
n-Pr
(35)
1. (n-Bu)2O, 40-60°, 2 h Ph 2 eq
OMe 0.33 M
2. O2/SiO2 O
93
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) OH
C8
Refs.
Me
Cr(CO)5 (85)
t-BuOMe, 45-55°, 1 h Ph
(CO)3Cr
0.29 M
1.15 eq
262
OMe OMe OH Bu-t
Cr(CO)5 Et
Bu-t
Ph
1.5 eq
OMe
t-BuOMe, 45-50°, 2-5 h
(66)
0.2 M
(CO)3Cr OMe O
236
Pr-i Ph
2 eq
OMe
Pr-i Pr-i
Cr(CO)5 i-Pr
68
Et
1. Solvent, heat
+
I
Pr-i II
84
Pr-i
2. CAN
O II
O CC (M)
I
Solvent Temp
0.5
THF
45°
(78)
(<1)
0.5
heptane
45°
(71)
(<1)
0.5
THF
110°
(65)
(<1)
0.005
THF
110°
(45)
(21)
O Cr(CO)5
1.5 eq
OMe
2. CAN O OH
0.2 M
OMe
Cr(CO)5
OMe
Heptane, 80°, 84 h Ph
TMS 1.8 eq
135
(49)
1. THF, 66°, 5 h Ph
OMe
(0)
183
(0)
183
TMS
0.4 M
OMe
OAc OMe
Cr(CO)5 2.1 eq Ph
OMe
Ac2O (1.5 eq), Et3N (1.5 eq), heptane, 80°, 19 h
TMS
0.4 M
OMe O
Cr(CO)5 TMS
TMS Ph 1.25 eq
OMe 0.4 M
•
O
TMS
(n-Bu)2O, 50°, 2 h
(52)
Ph
TMS
+
Cr(CO)3
•
TMS
OMe
C9
TMS Ph
(20)
57, 132 365
OMe
OH Cr(CO)5 n-Pr
Bu-n
Ph
1.5 eq
OMe 0.2 M
Bu-n(Pr-n) (62) single isomer
t-BuOMe, 45-50°, 2-5 h
68
Pr-n(Bu-n) (CO)3Cr
OMe
237
OH Ph
Cr(CO)5 t-BuOMe, 45-50°, 2-5 h
Ph
Ph
0.2 M
1.5 eq
(73) single isomer
OMe (CO)3Cr
68, 42
OMe O
Cr(CO)5 5 eq
Ph
OMe 0.05 M Cr(CO)5
1. Microwave,
Ph
OMe 0.05 M
I (70)
192
2. CAN O 1. Microwave, THF, 130°, 300 s
5 eq
Ph
(n-Bu)2O, 130°, 300 s
2. CAN
I (86)
192
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
C9
O
Cr(CO)5 t-Bu
CO2Et
Product(s) and Yield(s) (%)
OMe
1. THF, 65°, 6 h Ph
1.5 eq
OMe 0.06 M
2. Air
Refs.
Ph
t-Bu
(93)
70
(33)
93
CO2Et OH Bu-n
Cr(CO)5
n-Bu Ph 2 eq
OMe 0.33 M
1. (n-Bu)2O, 40-60°, 2 h 2. Air, silica gel OMe OH
O
Cr(CO)5
B
THF, 45°, 2-16 h
238
O
Ph
3 eq
C10
B
OMe
(53)
O
75
OMe O
0.05 M
OAc Bu-n
Cr(CO)5 n-Bu
Bu-n
Ph
2 eq
OMe
Ac2O (2 eq), NEt3 (2 eq),
(48)
THF, 65°, 10 h,
267
Bu-n OMe
0.03 M O
OH
O
Cr(CO)5 Ph
MeO2C
OMe
151, 183
(0)
THF, 65°, 24 h CO2Me
0.2 M
1.5 eq
OMe
O Cr(CO)5 1. THF, 45°, 24 h Ph
O
OMe 0.3 M
1 eq
Ph n-Bu
Ph
OMe
O
MeO THF, 65°, 4 h
149
(—)
OH n-Bu
0.12 M
0.83 eq
OMe
Cr(CO)5 (16) +
Ac2O (2 eq), Et3N (2 eq),
EtO
Ph
OMe
Ph
O
OAc
HO
O
(21)
148, 191
OEt
THF, reflux, 16 h
OEt OMe
239
1.2 eq
OAc Cr(CO)5 n-C5H11
103
O
Cr(CO)5
OH
(89)
O
2. CAN
CO2Et
Ph
OMe
Ac2O (2.5 eq), Et3N (2 eq),
I
THF, 65°, 5 h
CO2Et +
II
CO2Et
0.03 M
1.5 eq
OAc C5H11-n
70, 267
C5H11-n
OMe
OMe
I + II (49-60), I:II = 1.6-2.0:1 NEt2
Cr(CO)5 Et2N
NEt2
Ph
OMe
Hexane, 14°, 4 d
(CO)5Cr
Ph
Et2N
(52)
366, 367
OMe
0.13 M
3 eq
NEt2
Cr(CO)5 1 eq
(n-Bu)2O, 70°, 4 h Ph
(CO)4Cr
Ph
OMe 0.33 M
Et2N
OMe
(39)
366, 367
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C10
Refs.
NEt2 Cr(CO)5 Et2N
NEt2 Ph 1 eq
OMe 0.33 M (step 1)
1. (n-Bu)2O, 70°, 4 h
NEt2
(23)
367
(0)
183
(0)
183
2. Decane, 125°, 2 h (CO)3Cr
OMe
0.09 M (step 2)
C11
O
OH
O
Cr(CO)5 Ph
TMS
OMe
Heptane, 80°, 17 h TMS
1.4 eq
0.4 M
OMe OH
O
O
240
Cr(CO)5 Hexane, 45°, 17 h Ph MeO
OMe OMe
0.02 M
1.5 eq
OMe
MeO Ph
OAc CO2Et
Ph
1.5 eq
OMe 0.03 M
CO2Et
Ph
Cr(CO)5 Ph
Ph
+
(22)
Ac2O (1.2 eq), Et3N (1.3 eq), THF, 65°, 6 h
O
O
(50)
70
Ph
CO2Et OMe
CO2Et Ph OH
MeO
Cr(CO)5
n-Bu
O OH
THF, 65°, 4 h Ph 0.83 eq
OMe
149
(—)
n-Bu
OMe 0.12 M
C12
OAc OTBS OTBS
Cr(CO)5
1.5 eq
OMe 0.033 M
70, 115
(54)
Ac2O (1.5 eq), Et3N (1.5 eq), Ph
EtO
THF, 65°, 3 h
OEt OMe OAc OTBS
OH
OTBS
Cr(CO)5 1.5 eq
Ac2O (1.1 eq), Ph
OMe
+
THF, 65°, 4 h
115
OEt
0.03 M
OEt
OMe
OMe
I (12)
II (52)
Cr(CO)5 1.5 eq
Ph
OMe
AcOH (1 eq),
I (0), II (50)
115
THF, 65°, 6 h
0.033 M
241
MeO Cr(CO)5 1.5 eq
Ph
OMe 0.03 M
EtO Et3N (1.0 eq),
OH I (29)
O
THF, 65°, 4 h
115
OEt OMe Cr(CO)5 1.5 eq
Ph
OMe 0.03 M
THF, 65°, 4 h
I (88)
115, 368
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C12 R
Refs.
R
O Cr(CO)5 1. Silica gel, 100°, 2 h Ph
n-Bu
OMe
2. CAN
I
369
I
369
Bu-n
1.2 eq O R
I
NH2
(38)
NO2
(0)
Cl
(71)
O Cr(CO)5
242
n-Bu
Ph
R
OMe
1. Silica gel R Bu-n
2. CAN
1.2 eq
O R
Temp
Time
I
NO2
125°
12 h
(0)
Cl
100°
2h
(79)
OH Cr(CO)5 n-Bu
Ph
NH2
OMe
Silica gel, 100°, 2 h
369
(13) NH2 Bu-n
1.2 eq
OMe OH Bu-n O
n-Bu
Cr(CO)5
B Ph
O 3 eq
THF, 45°, 2-16 h
75
(73)
O
B
OMe 0.05 M
OMe O
C13 OH Cr(CO)5 t-BuOMe, 45-55°, 1 h Ph
(91)
OMe 0.29 M (CO)3Cr
1.15 eq
262
Me OMe O
Cr(CO)5 1. Silica gel Ph n-Bu 1.2 eq
OMe
R
I
O
243
Temp
Time
I
Me
100°
2h
(64)
OMe
80°
20 h
(57)
CHO 100°
2h
(0)
CHO
Cr(CO)5 Ph
n-Bu
R
O
CHO
369
R Bu-n
2. CAN
OMe
1. Silica gel, 120°, 20 h
(24)
2. CAN
369
Bu-n
1.2 eq
O
C14
OH Ph
Cr(CO)5 Ph
Ph
Ph
1 eq
OMe 0.31 M
(n-Bu)2O, 45°, 3 h
(62)
2
(53)
360
Ph (CO)3Cr
OMe OAc Ph
Cr(CO)5 1.8 eq
Ph
OMe 0.04 M
Ac2O (1 eq), Et3N (1 eq), Ph
THF, 45°, 2 h OMe
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C14
OH
OH (20) +
Heptane, 80°, 0.5 h
Ph 1 eq
Ph
Ph
Cr(CO)5 Ph
Refs.
Ph OMe 0.33 M
(18)
(CO)3Cr OMe
OMe
(CO)3Cr
Ph
Ph
OMe
244
Ph
Ph
O
Ph
OMe
Ph
I
Ph
O
(—)
+
Ph
Ph Ph
1. THF, 45°, 24-48 h
O
OMe
Ph
Ph
Ph
III +
O
0.1-0.2
II
+
OMe
O
CC (M)
+
Ph
Ph
Ph
Cr(CO)5
3.0
•Cr(CO)3 (2) OMe
OMe
+
(10) OMe
O
Alkyne (eq)
+
(CO)3Cr
C23H18O2•Cr(CO)3
Ph
Ph (4)
Ph (26) +
+
Ph
76
Ph
Ph
IV
I
II
III
IV
(59)
(—)
(—)
(—)
13
(65)
(—)
(—)
(—)
177
(94)
(—)
(3)
(3)
84
(89)
(—)
(8)
(3)
84
(94)
(—)
(6)
(—)
84
(64)
(—)
(24)
(7)
84
(41)
(—)
(38)
(4)
84, 13
(—)
(19)
(—)
(51)
13
(36)
(—)
(—)
(21)
13
(86)
(—)
(—)
(—)
177, 178
(77)
(—)
(—)
(—)
177, 178
(15)
(—)
(—)
(—)
177, 178
(—)
(83)
(—)
(—)
79
2. CAN 1.5
1. (n-Bu)2O, 5°, 0.33 h
0.04
ultrasound 2. CAN 2.0
1. THF, 70°, 12 h
0.5
2. CAN 2.0
1. THF, 70°, 15 h
0.005
2. CAN 2.0
1. THF, 110°, 0.5 h
0.5
2. CAN 2.0
1. THF, 110°, 4 h
0.005
2. CAN 3.0
1. Heptane/hexane, 45°, 24 h
0.16
245
2. CAN 3.0
1. MeCN, 45°, 24 h
0.16
2. CAN 3.0
1. Benzene, 45°, 24 h
0.16
2. CAN 1.2
1. Silica gel, 40-50°, 3 h
—
2. CAN 1.0
1. MgSO4, 50°, 1.5 h
—
2. CAN 1.2
1. Al2O3, 60-65°, 10 min
—
2. CAN —
DMF, 90°
— (n-Bu)3P
Cr(CO)4
Ph
OMe
1.0 eq 0.04 M
1. (n-Bu)2O, 90°, 3 h 2. CAN
I (48) + II (—) + III (6) + IV (—)
133
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OH
C14
Ph Ph
(CO)5Cr Ph
1. THF, 45°, 36 h
Ph
Br
O
2 eq
(93)
Ph
2. Air, 30 min
O
169
Br
0.03 M
OH Ph (CO)5Cr 2-3 eq
Ph
R 1. THF, 45°, 36 h
O
2. Air, 30 min
246
0.02 M
OMe (86)
Ph
t-Bu
O
169
(70)
R R OH
L Cr(CO)4
1 eq
Ph
Ph (n-Bu)2O, heat, 2.5 h
87
•Cr(CO)3
OMe
Ph
0.05-0.08 M
OMe Temp
L (4-FC6H4)3P
60°
(61)
(n-Bu)3P
90°
(11)
OH Cr(CO)5 Dioxane, 100°, 26 h Ph
n-Bu 1.2 eq
OMe
(57)
260
I
369
Bu-n
0.015 M
OMe
O Cr(CO)5 R
n-Bu
Ph
OMe
1. Silica gel, heat, time
R Bu-n
2. CAN O
1.2 eq
R
R
Temp
Time
I
Ac
120°
12 h
(0)
CO2Me
100°
2h
(0)
R
O
R
Cr(CO)5 Ph
n-Bu
OMe
(54)
1. Silica gel, 80°, 20 h
Ac
2. CAN
CO2Me (56)
Bu-n
1.2 eq
369
O OTBS
247
Ph Cr(CO)5
OTBS Ph
1. t-BuOMe, 55°, 1.5 h
Ph +
2. CH2Cl2, TBSCl, Et3N, Ph 2 eq
CO2Et
OMe
rt, 3 h
(CO)3Cr
CO2Et
(35) O Cr(CO)5 Ph
Benzene, 80°, 12-24 h
TBS 1.2 eq
Ph
(CO)3Cr
OMe
0.33 M
370 OMe (8.5)
CO2Et
TBS •
(CO)3Cr
TBS Ph
Ph
+
OMe OMe (55)
OMe
(CO)3Cr (19)
134
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C14
O
Refs. O
Ph O Ph
Cr(CO)5
B Ph
O 3 eq
OMe 0.5 M
Ph
1. THF, 45°, 16 h 2. CAN
O
B
74
+
O
O
O (12)
(57) OH Ph Cr(CO)5
3 eq Ph
THF, 45°, 14 h OMe O
0.5 M
C15
248 Ph Ph
1.2 eq
Ph
t-BuOMe, 45°, 6 h
42, 68
+
OMe
Ph
0.26 M
OH
R
OH
R Cr(CO)5
75
(64)
O
B
OMe
(CO)3Cr
(CO)3Cr
OMe
R
OMe I
II
R
I + II
I:II
CF3
(66)
55:45 (not assigned)
Me
(52)
53:47 (not assigned)
O R
Cr(CO)5 1. Silica gel, 80°, 20 h Ph
R
Ph
OMe
2. CAN
R
Ph
1.2 eq
Me
(65)
OMe
(57)
369
O
O Cr(CO)5 Ph
OMe
CH(Me)OMe
n-Bu
1. Silica gel, 50°, 2 h
CH(Me)OMe Bu-n
2. CAN
1.2 eq
213
(76) 0% de
O OH
O
O
Cr(CO)5 (0)
THF, 65°, 24 h Ph TBSO
1.5 eq
i-PrO
O
0.03 M
OMe OTBS O i-PrO
Cr(CO)5 Pr-n i-PrO
151, 183
OMe
Pr-n (72)
1. THF, reflux, 4 h Ph
OH
OMe
2. HCl (cat), CH2Cl2, rt
372, 149
O
i-PrO
249
O Ph
0.12 M
0.83 eq OH
Ph
Ph Ph
Cr(CO)5
O Ph
Ph 3 eq
Ph (39) +
Dioxane, reflux, 6 h OMe
(16)
Ph
0.26 M
OMe
OMe
+ Ph C16
Ph
(5)
OH p-Tol
Cr(CO)5
Ar Ph 1.2 eq Ar =
CF3
OMe 0.26 M
OH Ar
t-BuOMe, 45°, 6 h
Tol-p 42, 68
+ Tol-p (CO)3Cr
371
OH
OMe I
Ar (CO)3Cr
I + II (62), I:II = 46:54
OMe II
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C16 O Cr(CO)5
(42)
1. Silica gel, 100°, 2 h
n-Bu
O
Ph
O
OMe
369
CHO Bu-n
2. CAN O
1.2 eq OH
OTBS
OTBS OAc
Cr(CO)5
+
THF, 65°, 24 h MeO2C
Ph
OMe 0.3 M
1.5 eq
250
Cr(CO)5
1.5 eq Ph
OMe
151
CO2Me CO2Me
OMe I (22)
OMe
II (0)
Ac2O (1.5 eq), Et3N (1.5 eq), I (10) + II (8)
151, 183
heptane, 80°, 19 h
0.1 M
TBSO
HO TBSO O
O
O
O
Cr(CO)5 Ac2O (1.1 eq), Et3N (1.1 eq), Ph
EtO
OMe
THF, 65°, 5 h
0.03 M
1.5 eq
(45)
115
(45)
70
OEt OMe
AcO TBSO
O
O
Cr(CO)5 Ac2O (1.5 eq), Et3N (1.5 eq),
1.5 eq Ph
OMe 0.03 M
THF, 65°, 7 h
OEt OMe
O Ph
Cr(CO)5 Ph
(42)
1. THF, 105°, 2 h
Ph Ph 1.0 eq
OMe
100
2. CAN
0.21 M
O
Ph
OH
O
Cr(CO)5 1.0 eq
Ph
THF Ph
+
I
II
OMe
Ph
Ph
251
CC (M)
Temp
Time
I
II
0.03
60°
24 h
(20)
(21)
0.03
70°
23 h
(44)
(—)
0.5
70°
24 h
(16)
(—)
0.21
105°
3h
(12)
(—)
0.21a
105°
3h
(—)
(—)
O
O (53)
1. THF, 50°, 17 h OBu-n
+
(21)
O
Ph
Ph
OH Solvent, 70°, 24 h Ph
O I
+
II Ph
OBu-n 0.03 M
OBu-n Ph
Ph
Cr(CO)5 1.0 eq
100
Ph
2. CAN
0.03 M
OBu-n Ph
Ph
Cr(CO)5 Ph
100
Ph
OMe
1.0 eq
OMe
Ph
OBu-n Solvent
Ph
Ph
I
II
THF
(61)
(—)
benzene
(40)
(—)
hexane
(31)
(—)
100
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C16
Ph
O
O
OH
THF
Ph (CO)5Cr
Ph Ph
HO
Ph
Ph
+
I
100
Cr(CO)5 O
0.9 eq
O Ph Ph
HO
II O
O
252
CC (M)
Temp
Time
I
II
0.005
80°
16 h
(12)
(21)
0.024
80°
16 h
(23)
(13)
0.029
105°
4h
(19)
(25)
0.16
45°
16 h
(19)
(7)
0.20
105°
4h
(7)
(13)
0.84 eq (CO)5Cr
O
O
Ph Ph
HO
Ph
Ph
OH (23)b
THF, 75°, 17 h
100
Cr(CO)5 O O Ph Ph
HO 0.03 M +
O
+
O
Ph
(21)b
Ph
Ph Ph
Ph THF, 75°, 5 h
(CO)5Cr
O
O
Cr(CO)5
O
(22)b Ph
O
Ph (29)
0.84 eq
O
O
100
O
0.03 M
C17
O Cr(CO)5 Ph
Benzene, 80°, 12-24 h
TIPS Ph
•
TIPS
(CO)3Cr
(88)
134
OMe
1.2 eq
OMe
O Cr(CO)5
253
Ph
OMe
2. CAN
CH(Pr-i )OMe
n-Bu
213
O
1.2 eq
C18
(68) 0% de CH(Pr-i)OMe Bu-n
1. Silica gel, 75°, 2 h
O Cr(CO)5 n-Bu
O
O
Ph
OMe
(39) 0% de
1. Silica gel, 125°, 2 h
213
CHO Bu-n
2. CAN O
1.2 eq
O Cr(CO)5 213
1. Silica gel, temp, 2 h Ph
OMe
CH(t-Bu)OMe Bu-n
2. CAN
CH(t-Bu)OMe
n-Bu
O
1.2 eq Temp
% de
75°
(60)
47
50°
(40)
52
213
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C18
Refs.
OH Cr(CO)5 n-Bu
Ph
SOPh
OMe
1. Silica gel, 75°, 2 h
SOPh Bu-n
2. Air
1.2 eq
(44) 67% de
213
(—)
213
OMe
OH Cr(CO)5 1. Silica gel, 75°, 2 h n-Bu
Ph
SO2Ph
OMe
SO2Ph Bu-n
2. Air
1.2 eq
OMe
254
OTBS
Ph
OTBS Ph
Cr(CO)5
Ph
1. t-BuOMe, 55°, 1.5 h +
2. TBSCl, Et3N,
(CO)5W
OMe Ph 0.33 M
OMe
CH2Cl2, rt, 3 h
(CO)3Cr
(CO)5W
2 eq
370 (CO)3Cr
OMe
OMe
(CO)5W
OMe
(28)
OMe
(7)
OH
Ph
Ph Cr(CO)5 Benzene, 90°, 24 h Ph 1 eq
Ph
(3)
373
OMe OMe
0.04 M
Ph
O
C19 Cr(CO)5 1. Silica gel, 100°, 2 h n-Bu
CON(Pr-i)2
Ph
OMe
CON(Pr-i)2 Bu-n
2. CAN
1.2 eq
(44)
369
O O Cr(CO)5 1. Silica gel, 100°, 2 h Ph
NHBz
n-Bu
OMe
(44)
NHBz Bu-n
2. CAN
369
O
1.2 eq
NHBz
O
NHBz Cr(CO)5
(34)
1. Silica gel, 100°, 2 h Ph
OMe
n-Bu
2. CAN
369
Bu-n
255
O
1.2 eq
H
C20 HO
H Cr(CO)5 t-BuOMe, 45-55°, 1 h 3
Ph
3
OMe
0.29 M
1.15 eq
(CO)3Cr
(90)
262
Me OMe O
Cr(CO)5 Ph CH(OMe)Ph
n-Bu 1.2 eq
OMe
1. Silica gel, 100°, 2 h
CH(OMe)Ph Bu-n
2. CAN O
(0)
213
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C20
Refs.
O Cr(CO)5 1. Silica gel, 100°, 2 h n-Bu
N(Me)Bz
Ph
OMe
369
(50) N(Me)Bz Bu-n
2. CAN
1.2 eq
O NMeBz
O
NMeBz Cr(CO)5
(72)
1. Silica gel, 100°, 2 h Ph
OMe
n-Bu
2. CAN
369
Bu-n O
1.2 eq C21
O
256
Cr(CO)5 1. Silica gel, 80°, 12 h Ph
CON(Pr-i)2
Ph
OMe
2. CAN
Ph
CON(Pr-i)2
(0)
369
O 1.2 eq OH Sn(Bu-n)3
Sn(Bu-n)3
Cr(CO)5
TBSO
Ph 1.9 eq
183
(0)
THF, 65°, 4 h OMe
OTBS
0.03 M
OMe OH
OTBS
OTBS
OH
Cr(CO)5 I +
Additives, solvent, Ph TBSO
0.7-3.0 eq
OMe
II
151, 183
heat, 3-24 h
0.3 M
OMe OTBS
OMe OTBS
I
II
heptane
80°
1.0
0
(66)
(—)
heptane
80°
1.0
1.0
(68)
(—)
heptane
80°
1.0
1.0
(67)
(—)
heptane
80°
1.0
1.0
(63)
(—)
heptane
80°
1.0
1.0
(65)
(—)
heptane
80°
1.0
1.0
(66)
(—)
heptane
80°
1.0
1.0
(67)
(—)
heptane
80°
0
1.0
(30)
(17)
heptane
80°
0
0
(—)
(74)
heptane
40°
0
0
(48)
(—)
THF
65°
1.0
0
(29)
(—)
acetone
55°
0
0
(24)
(—)
heptane,
54°
1.5
1.5
(44)
(—)
56°
0
0
(51)
(26)
Temp Ac2O (eq) Et3N (eq)
Solvent
ultrasound
257
heptane, ultrasound C23
HO Cr(CO)5 Ph 3
1.15 eq
t-BuOMe, 45-50°, 1 h
+
3
OMe
0.29 M
(CO)3Cr
I
OMe HO
(CO)3Cr
3
OMe II
I + II (92), I:II = 63:37
262, 68
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C23
Refs.
O Cr(CO)5 OMe
Ph 3
1. t-BuOMe, 60°, 1 h
261
(48)
3
2. Ag2O/Et2O, 1 h
0.17 M
O
2.5 eq
O Cr(CO)5 OMe
Ph CH(Me)OTIPS
n-Bu
1. Silica gel, 100°, 2 h
(43) 60% de
CH(Me)OTIPS Bu-n
2. CAN
213
O
1.2 eq
O
258
Cr(CO)5 N(Bu-t)Bz
n-Bu
OMe
Ph
1. Silica gel, 100°, 2 h
369
O
1.2 eq C24
(0)
N(Bu-t)Bz Bu-n
2. CAN
TIPS
TIPS
TIPS
Cr(CO)5 THF, 90°, 24 h TIPS 0.05 M
1.0 eq
(69)
373
OMe
Ph
Ph
OMe
O
C25 OH
Ph
Ph Ph
HO Cr(CO)5
Ph MeO
Benzene, 80°, 24 h
(16)
OMe
Ph
MeO
0.05 M
3 eq
OMe
HO
Ph Ph
HO
Cr(CO)5
OMe
THF, 80°, 24 h OMe
Ph 3 eq
+
I MeO
100
100
HO
HO
Ph II MeO
+
OMe Ph
OH Ph Ph MeO O
III
Ph OMe
259
Alkyne (M)
I
II
III
0.1
(35)
(11)
(16)
0.05
(17)
(8)
(29)
0.006
(19)
(23)
(32)
C26 OH OTBDPS Cr(CO)5 Ph
MeO2C
OMe
OAc +
Et3N (1.5 eq), heptane, 80°, 19 h
151
CO2Me OMe
0.1 M
1.5 eq
OTBDPS
Ac2O (1.5 eq),
Ph2P
(7)
OMe
CO2Me (6)
Cr(CO)4
Cr(CO)5 Ph2P
Octane, 90°, 4 h
PPh2 Ph 1.2 eq
PPh2
OMe 0.06 M
OMe
(78)
374
TABLE 1. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
C30
Product(s) and Yield(s) (%)
Refs.
O Cr(CO)5 n-Bu
CH(Me)OTBDPS
Ph
OMe
1. Silica gel, 100°, 2 h
CH(Me)OTBDPS Bu-n
2. CAN
1.2 eq
(67) 50% de
213
O
OH
Cr(CO)5
OBn
Heptane, 80°
BnO
Ph
TBSO
OTBS
OTBS
OMe 0.3 M
1 eq
Time
151, 183
OMe OTBS
260
Ac2O (1 eq)
3h
(85-89)
—
20 h
(0) R
C54
O
R Cr(CO)5 1. THF, 60° 2 d OMe Ph 0.008 M
n-Bu 1.25 eq
p-Tol
N
N
N
N
R=
Tol-p
p-Tol a
The carbene complex was added slowly.
b
Only one diastereomer was observed.
3-R (73)
2. PbO2, CH2Cl2
Bu-n O
4-R (75)
375, 376
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne
Carbene Complex
Conditions
C2
Product(s) and Yield(s) (%)
Refs.
OH OH
Cr(CO)5 THF, 45° Ph
I
OMe
0.07-0.13 M
OMe
Alkyne
Ph
+
I
II
2 eq
(1)
(36)
20 eq
(1)
(27)
1 atm
(2)
(34)
C3
OH
OH Ph
Cr(CO)5 Solvent, 45° Ph
131
II
+
I
131, 377,
II
OMe
245
261
0.07-0.2 M Alkyne
OMe I
II
(45)
(4)
Solvent
2 eq
THF
40 eq
THF
(10)
(44)
neat
—
(0.3)
(26-28)
O Cr(CO)5 saturated solution Ph
C4
OMe 0.25 M
1. (n-Bu)2O, 55°, 2 h
(66) O OH
O
261
2. AcOH, HNO3, 0.5 h
O
Cr(CO)5 (28-42)
THF, 65°, 5 h Ph 1.5 eq
OMe 0.03 M
70, 183
OMe
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) OH
C4 O
Cr(CO)5 OMe
OMe
THF, 65°, 6 h Ph
1.25 eq
Et
OMe 0.27 M
(n-Bu)2O, 45°, 2 h
Cr(CO)5 OEt Ph
262
4 eq
183
OMe OH
Cr(CO)5 Et Ph
(32)
OMe 0.08 M
1.5 eq
Refs.
O
OEt 0.25 M
Et2O, 0-4°, 24 h
(35) (CO)3Cr OMe OEt Ph (CO)5Cr
87
E:Z = 10:1
(48)
378
OEt OH OH
Cr(CO)5
OH
(0) + (CO)5Cr
1. THF, reflux, 16 h Ph 3 eq
OEt
O (38) 289
2. Air OEt OH
C5 O OEt 1.1-1.5 eq
Additive (1.1-1.5 eq), THF, Ph
OMe
Ph
CO2Et
Cr(CO)5
I
60-65°, 4-6 h
0.03-0.05 M
OMe
+
MeO RO2C
CO2R' II
I
R
R1
II
none
(41)
Et
Et
(9)
—
70
EtOH
(0)
Et
Et
(83)
6:1
379
t-BuOH
(0)
t-Bu
t-Bu
(16)
4:1
379
t-BuOH
(0)
Et
t-Bu
(35)
4:1
379
t-BuOH
(0)
Et
Et
(18)
3:1
379
(i-Pr)2NH
(0)
Et
N(Pr-i)2 (50)
Z >> E
379
Additive
E:Z
OH Cr(CO)5
Pr-n 1.2-1.5 eq
Pr-n
(n-Bu)2O or t-BuOMe,
(45)
45-50°, 2-5 h
Ph OMe 0.2-0.27 M
68, 87
(CO)3Cr OMe O
1. See table
Cr(CO)5
Pr-n
2. CAN Ph
OMe
I
Alkyne (eq)
CC (M)
Solvent hexane
O
Temp Time 45° 24-48 h
0.1-0.2 0.04
3
0.1-0.2
2
—
5
0.05
(n-Bu)2O 130°
5
0.05
THF
130°
263
3 1-1.5
(n-Bu)2O
rt
15 min
—
(80)
13
ultrasound
(67)
177
THF
45° 24-48 h
—
(73)
13
—
60°
silica gel
(51)
177, 178
300 s
microwave
(91)
192
300 s
microwave
(68)
192
10 min
n-Pr O
Ph
Cr(CO)5
1. MeCN, 45°, 24-28 h
3 eq Ph
OMe
O
I (53) +
O
(45)
Pr-n
13
2. CAN
0.1-0.2 M O Pr-n Cr(CO)5
1. Benzene, 80°, 16 h
3 eq Ph
2. CAN
OR
O n-Pr
I
+
Pr-n OR III
+
II O
CC (M)
R
Ph
O
I
II
III (11)
0.005
Me
(82)
(—)
0.1
Me
(78)
(1)
(8)
0.1
i-Pr
(90)
(<1)
(<5)
113
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
OH
Pr-n Pr-n
Cr(CO)5 Ph
OR 0.1 M
+
+
1. Benzene, 80°, 16 h
Pr-n 2 eq
Refs.
113
2. Air II
I OR
OR
O n-Pr
R
Pr-n OR
I
II
III
Me
(76)
(1)
(8)
i-Pr
(90) (≤1) (<5)
Ph
O III OR
264
I: R = H MeO O II: R =
Pr-n
Cr(CO)5 1. Solvent, 45-80°, 20-70 h
1.5-1.9 eq Ph
OMe
Ph
+
2. Air Pr-n
OMe O
OH
MeO O +
III
Pr-n O
+
n-Pr
V OMe
Pr-n
+ Ph Ph VI OMe
OMe Ph
+ OMe
O VII OH
Ph
Pr-n
O
IV
O
O n-Pr
+
MeO
O Pr-n
Ph
Pr-n
+ VIII
IX Pr-n
CC (M)
Solvent
I
II
III
IV
V
VI
VII VIII
IX
0.1
MeCN
(48)
(31)
(5)
(0)
(4)
(2)
(0)
(0)
(0)
13
0.1
THF
(84) (<1.5) (0)
(0)
(2)
(0)
(10)
(0)
(0.5)
60
0.005
THF
(62)
(0)
(0)
(12) (0)
(7)
(0)
(0.5)
60
0.1
benzene
(64) (<1.5) (0)
(0)
(1)
(0)
(4)
(10)
(1)
60
0.005
benzene
(59)
(0)
(0)
(0)
(1)
(0)
(8)
(5)
(3)
60
0.1
MeCN
(60)
(12)
(0) (<1.5) (9) (0.5) (19)
(0)
(2)
60
0.005
MeCN
(76) (<1.5) (0) (<1.5) (3)
(0)
(5)
60
—
hexane
(80)
(—) (—) (—) (12) (—)
78
(0)
(—)
(—)
(—)
(3)
OTBS
OTBS Pr-n
(CO)5Cr O Ph
4 eq
(1)
Pr-n
1. t-BuOMe, 58°, 2.5 h Cr(CO)3
+
2. TBSCl (4 eq), O
Et3N (4 eq), rt, 12 h
205
O
265
0.4 M I (17)
II (25) dr = 6.4:1
(CO)5Cr O
4 eq Ph
I (32) + II (25) dr = 6.1:1
TBSCl (2 eq),
205
EtN(Pr-i)2 (3 eq), CH2Cl2, 58°, 2.5 h
0.05 M O O
Cr(CO)5
HO
Et3N (x eq) Ph
Ph
OMe I
OMe
x
Solvent
Temp Time
I
Isomer ratioa
Ac2O (2 eq)
3
THF
reflux
7h
(26)
2:1
148
Ac2O (2 eq)
2
THF
reflux
7h
(40)
3:1
148
ultrasound
3
benzene
—
1.5
(35)
4:1
380
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
Refs.
OH OEt OH
(CO)5Cr
OH 1. THF, 60°, 15 h
Ph
3 eq
(50)
289
2. Air OEt OH
O TMS
Cr(CO)5 (n-Bu)2O, 50°, 1.5 h
TMS Ph 1.7 eq
(76)
OMe 0.37 M
•
TMS
+
OMe (4)
+
57
•Cr(CO)3 Ph
OMe O
•
TMS OMe
266
Ph
(2)
Cr(CO)3
OTBS Cr(CO)5 4 eq
TMS
1. t-BuOMe, 55°, 1 h 2. TBSCl (4 eq),
Ph
OMe 0.4 M
(92)
73
(61)
169
Et3N (4 eq), rt, 3 h (CO)3Cr
OMe OH TMS
Cr(CO)5 4 eq
1. THF, 45°, 24 h Ph
OPh 0.04 M
2. Air OPh OH
Cr(CO)5 THF, 65°, 16 h OMe 2.8 eq
Ph
OMe 0.2 M
OMe OMe
(0)
183
OAc Cr(CO)5 OMe 2.3 eq
Ph
OMe 0.2 M
Ac2O (1.5 eq), Et3N (1.5 eq), heptane,
183
(43)
OMe
80°, 21 h OMe OH
C6
Bu-n
Cr(CO)5 (n-Bu)2O, 45°, 2 h
Bu-n Ph 1.25 eq
OMe 0.27 M
(45) (CO)5Cr
87
OMe OH Bu-n
Cr(CO)5 1.0 eq
(94)
THF, 65°, 2 h Ph
OMe 0.03 M
267
OMe
267
OR Cr(CO)5
Ac2O (1.1 eq),
I: R = Ac
Bu-n
Et3N (1.1 eq),
1.5 eq Ph
OMe
II: R =
O
+
OMe
381
THF, 65°, 3 h Bu-n Ph
OMe Bu-n
MeO
n-Bu
O
O
H
+
Pr-n
Pr-n
I (65), II (18), III (0), IV (0) Cr(CO)5
1. THF, 65°, 1 h 2. Ac2O (1.1 eq),
Ph
OMe
Et
O
III
OMe
1.5 eq
OAc
IV
OMe
I (56), II (0), III (10), IV (10)
381
pyridine, rt
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C6
Refs.
OAc Cr(CO)5 Bu-n
Ac2O (2.2 eq), Et3N (1.1 eq),
Bu-n
DMAP (0.16 eq), Ph
1.5 eq
OMe 0.1 M
I (68)
94
THF, 65°, 1 h OMe
Cr(CO)5 2.7 eq Ph
OMe 0.04 M
Ac2O (1 eq), Et3N (1 eq),
I (82)
267, 360
THF, 60°, 1 h O
Bu-n +
1.5 eq
1. Benzene, 40°, 22 h Et 1.5 eq
Et
O Bu-n
Cr(CO)5 Ph
OMe 0.1 M
I
Et +
II
361
Et
2. CAN O
O
268
I + II (78), I:II = 96:4 Cr(CO)5 1. Benzene, 40°, 22 h Ph
OPr-i 0.1 M
2. CAN
Cr(CO)5
1. THF, rt, 20 h
Bu-n
I + II (75), I:II = 99:1 O Bu-n
2. 50°, 2 h Ph
3 eq
OAc 0.1 M
361
(71)
172
(60)
169
3. CAN O OH Bu-n
Cr(CO)5 1. THF, 45°, 24 h
2 eq Ph
OPh 0.05 M
2. Air, 30 min OPh
OH Bu-t
Cr(CO)5 t-BuOMe, 45-50°, 2-5 h
Bu-t
Ph
1.5 eq
148
(79)
OMe 0.2 M (CO)3Cr
OMe OTBS
Cr(CO)5 4 eq
1. Solvent, 55°, 55 min
OTBS Bu-t
Bu-t
2. TBSCl (4 eq), Ph
OR* 0.4 M
I
+
II
204, 97
Et3N (4 eq), rt, 2 h (CO)3Cr
(CO)3Cr
OR*
OR*
269
R*
Solvent
I + II
dr
de
(–)-menthyl
t-BuOMe
(55)
10:1
82
(–)-menthyl
benzene
(50)
5.6:1
70
(–)-menthyl
pet ether
(52)
3.7:1
57
(+)-menthyl
t-BuOMe
(55)
1:9.2
80
(–)-8-phenylmenthyl
t-BuOMe
(65)
3:1
50
endo-(–)-bornyl
t-BuOMe
(65)
2.3:1
40
endo-(+)-fenchyl
t-BuOMe
(80)
7:1
75
(±)-1-phenylethyl
t-BuOMe
(71)
3:1
53
(±)-naphthylethyl
t-BuOMe
(51)
2.3:1
40
(±)-1-phenyl-2-methylpropyl
t-BuOMe
(45)
3:1
50
O HO
Cr(CO)5 Ph
i-Pr
OMe
O
Ac2O (2 eq), Et3N (3 eq), THF, reflux
Ph
I (33)b
148
i-Pr OMe
Cr(CO)5 Et3N (3 eq), ultrasound, Ph
OMe
I (20)c > 2 isomers
380
benzene, 1.5 h
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
C6
Product(s) and Yield(s) (%)
Refs.
OH
3 eq
OH
Cr(CO)5
OH
1. THF, 60°, 15 h Ph
OEt
(40)
289
2. Air OEt OH
Cr(CO)5 TMS
TMS
1. THF, reflux Ph
0.83 eq
OMe 0.12 M
2. Air
Cr(CO)5
1. THF, rt, 20 h
C5H11-n
2. 50°, 2 h
270
Ph 3 eq
OAc 0.1 M
153
OMe O
C7 C5H11-n
(62)
(58)
172
3. CAN O OH
Cr(CO)5 t-BuOMe, 45-55°, 1 h Ph 1.2 eq
OMe 0.3 M
(60)
262
(CO)3Cr OMe OH Ph
Cr(CO)5 +
THF, 70°, 1.5 h 1.2 eq
Ph
OH OMe O
C8 Cr(CO)5 C6H13-n 3 eq
OAc 0.1 M
(24)
(41)
C6H13-n
1. THF, rt, 20 h
(47)
2. 50°, 2 h Ph
16
OMe
3. CAN O
172
O
Ph
C6H11-c
1. See table
Cr(CO)5
C6H11-c
191
2. CAN
OR O
Alkyne (eq)
R
Temp
Time
1.8
Me
(n-Bu)2O
70°
14 h
(72)
2.8
Me
silica gel
50°
4h
(68)
1.4
Me
ultrasound, THF,
—
25 min
(83)
1.8
Et
silica gel
60°
2h
(51)
1.4
Et
ultrasound, THF
—
40 min
(91) OAc Ph
1. Ac2O (2.2 eq),
Cr(CO)5 Ph
Et3N (2) eq),
271
Ph 2.7 eq
OMe 0.5 M
(93)
2. THF, 60°, 4 h
OMe OH *
Cr(*CO)5 2 eq
OH
OMe 0.1 M
*C =
13
*
Ph
THF, 45°, 21 h Ph
89
THF, 45°, 12 h
I
+
II
100
Ph
C OMe
OMe
I + II (87), I:II 179:1
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
C8
Product(s) and Yield(s) (%)
Refs.
O Cr(CO)5
1. Microwave, solvent,
Ph
130°, 300 s
Ph Ph
OMe
192
2. CAN O
272
Alkyne (eq)
CC (M)
1
0.01
(n-Bu)2O
(68)
1
0.05
(n-Bu)2O
(88)
1
0.5
(n-Bu)2O
(65)
5
0.05
(n-Bu)2O
(91)
210
0.05
(n-Bu)2O
(47)d
1
0.01
THF
(70)
1
0.05
THF
(73)
1
0.5
THF
(64)
5
0.05
THF
(78)
1
0.05
toluene
(58)
1
0.05
CH2Cl2
(36)
1
0.05
MeOH
(50)
1
0.05
EtOH
(54)
1
0.05
HO(CH2)2OH
(58)
1
0.05
H2O
(0)
1
0.05
THF
(73)
1
0.05
Et2O
(82)
1
0.05
(n-Bu)2O
(88)
Solvent
I
Cr(CO)5 1. See table Ph
OMe
I
2. CAN
Alkyne (eq)
CC (M)
Time
I
3.0
0.1-0.2
—
THF
45°
24-48 h
(67)
13
3.0
0.1-0.2
—
hexane
45°
24-48 h
(57)
13
1-1.5
0.04
ultrasound n-Bu2O
—
10 min
(66)
177
2.0
—
silica gel
—
60-65° 90 min
(81)
177, 178
2.0
—
MgSO4
—
60-70° 90 min
(18)
177, 178
Solvent Temp
OMe Ph
Cr(CO)5 1 eq
1. THF, 48°, 12 h Ph
OMOM 0.2 M
(58)
100
(88)
169
2. NaH, Me2SO4 OMOM
273
OH Ph
Cr(CO)5 2 eq
1. THF, 45°, 24 h Ph
OPh
2. CAN
0.04 M
OPh
Cr(CO)5
O
THF, 60°, 12 h O
OMe
Ph
O
MeO
OH OMe
+
OMe
Ph
150 O
1 eq
OMe
OMe
(38)
(38)
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C8
Refs.
O
OH
O
Cr(CO)5 Ph
OMe
Ph
Ac2O (2 eq), Et3N (3 eq),
(52) 3:2 mixture of isomersa
148
THF, reflux, 2.5 h OMe
I Cr(CO)5 Et3N (3 eq), ultrasound, Ph
OMe
I (36) 9:1 mixture of isomersa OH
O
380
benzene, 1.5 h O
Cr(CO)5 (0)
Hexane, 45°, 3 h
183
Ph OMe 0.1 M OMe
1.5 eq
274
OH Cr(CO)5
O
THF, 45°, 2-16 h
B Ph
O 3 eq
O B
O
(50)
75
OMe
0.05 M OMe
C9 TMS
TMS Ph
Cr(CO)5 Dioxane, 100°
n-Pr
Ph
OMe
OMe
I + 2 isomers (II and III)
154
n-Pr I + II + III (75), I:II:III = 56:25:19 OH
CF3
Cr(CO)5
1. Photolysis, 3-methylpentane, 95 K
Ph
OMe
CF3
(—)
2. 200-235 K (CO)3Cr
OMe
64
O Cr(CO)5
1. Microwave, solvent,
Solvent
130°, 5 min Ph 2 eq
OMe
2. CAN
0.05 M
THF
(75)
(n-Bu) 2O
(73)
192
O
C10
OH C8H15-n
Cr(CO)5 C8H15-n Ph 1.5 eq
OMe
(59)
t-BuOMe, 45-50°, 2-5 h
0.2 M
(CO)3Cr
OMe OR
OTBS
68
OTBS
Cr(CO)5 Ac2O (1.5 eq), Et3N (1.5 eq), Ph
OMe
0.3 M
1.5 eq
R = Ac (74)
I
183
heptane, 80°, 1 h
275
OMe
Cr(CO)5 1.5 eq
Heptane, 80°, 43 h
I R = H (0)
183
Ph OMe 0.3 M OH
C11
Ph
Cr(CO)5 Benzene, 45°, 12 h Ph OMe 2 eq
0.05 M
382
(76)
OMe
OMe OMe OAc
OAc Ph
Cr(CO)5 Ph OMe 2 eq
Ac2O (2.5 eq), Et3N (5 eq), OCD3
OMe
Ph
+
0.05 M
OCD3
382
OCD3
benzene, 45°, 12 h OMe
I
II
I + II = (53), I:II = 1:1
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) Cl
OH
Cl
Refs.
Cr(CO)5 Benzene, 45°, 12 h Ph OMe
+
I
382
OMe
OCD3 0.05 M
OCD3
2 eq
OH
Cl
Ph II OCD3 OMe
I + II (68), I:II = 1:1
OH
O
276
Cr(CO)5 Ph
OMe
Ph +
(25)
Dioxane, reflux
(45)
51
O
0.29 M
OMe
1.1 eq OMe
MeO
OMe OH
Cr(CO)5
O
O
O
O +
THF, 60°, 12 h Ph
OMe
O
OAc OMe
Ph
288
MeO
OAc
OAc 1.0 eq
O
O (34)
(43)
Ph Ph MeO2C CO2Me 1.3 eq
Cr(CO)5 O–Li+ 0.7 M
THF, reflux, 12 h
(66)
O MeO2C
CO2Me
383
C12 Cr(CO)5
OAc
O
OAc
OAc
OAc Ph
TMS
1. THF, 50-55°, 16-36 h
OMe
295
OMe TMS Ph Dioxane, 100°
Ph
(low)
CH2Cl2, rt, 16-24 h
Cr(CO)5 Ph
OAc
O
2. Ac2O, pyr, DMAP,
I + 2 isomers (II and III)
OMe
OMe
154
I + II + III (82), I:II:III = 63:20:17
Ph O
Cr(CO)5 Fe
Fe
1. THF, 65°, 2 d Ph OMe 0.58 M
1 eq
(71)
92
2. PbO2, CH2Cl2 O
C13
Ph
277
Cr(CO)5 Ts
N Ph 0.83 eq
OEt
1. MeCN, 70°, 1 h
(79)
O
2. 10% HCl
384
Ts N H
0.12 M O Cr(CO)5 Se
Ph
Se
See table. OR
179
NO2
NO2 O R
Solvent
Temp Time
Me
—
THF
heat
—
(18)
Et
—
THF
heat
—
(22)
Me
ultrasound
benzene
—
—
(0)
Et
ultrasound
benzene
—
—
(0)
Me
silica gel
—
55°
—
(27)
Et
silica gel
—
55°
—
(23)
Me
silica gel
—
rt
3d
(51)
Et
silica gel
—
rt
3d
(66)
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
Ph
C14
O Cr(CO)5 Ph Ph
OMe
(78)
Dioxane, reflux
51
0.29 M 1.1 eq O
Ph
OMe
O Cr(CO)5 Ph Ph
O Dioxane, 100°, 26 h
+
O
OMe 0.007 M
260 (2)
(52)
1.1 eq
278
OAc OTBS OTBS
Cr(CO)5 Ph
1.4 eq
OMe
Ac2O (1.5 eq), (47)
Et3N (1.5 eq),
151, 183
heptane, 80°, 1 h
0.3 M
OMe O
3
1.8 eq
CO2Et Ph
Cr(CO)5 OMe 0.11 M
3
1. THF, 45°, 24 h 2. CAN O
CO2Et
(25)
385
O
Ph Ph
Cr(CO)5 Ts
1. MeCN, 70°, 41 h
N
Ph OEt 0.12 M
2. 10% HCl
O
+
O Ts N
Ts N
(32)
0.83 eq
+
384
(25)
Ts N (12)
O OH Sn(Bu-n)3
Cr(CO)5 THF, 45°, 4 h
Sn(Bu-n)3 Ph 1.5 eq
(0)
183
OMe 0.4 M OMe
279
OTBS Cr(CO)5 4 eq
OTBS Sn(Bu-n)3
1. t-BuOMe, 55°, 1 h +
2. TBSCl (4 eq), Ph
OMe 0.4 M
+
73
Sn(Bu-n)3
Et3N (4 eq), rt, 3 h (CO)3Cr
(CO)3Cr OMe
OMe
(45)
(6)
OH
(15) Sn(Bu-n)3 (CO)3Cr Ph
C19 Ts
Ph
Cr(CO)5 1. MeCN, 70°, 41 h
N
Ph
OEt 0.12 M
OMe
Ts N
(69)
O
2. 10% HCl
384
0.83 eq
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
EtO
C21
Ph Ts
Ph
N
Ph
Cr(CO)5 1. Solvent, heat, 17-30 h OEt 0.12 M
Ts N
2. [FeCl4][FeCl2(DMF)3]
Ph +
O
+
Ts N
OEt
386, 387
II
I Ph
0.33 eq
O Ts
O
N
III
280
Solvent
Temp
I
II
III
THF
reflux
(22)
(9)
(22)
EtOH
70°
(21)
(14)
(21)
MeCN
70°
(14)
(16)
(7)
CH2Cl2
reflux
(27)
(0)
(22)
benzene
70°
(19)
(5)
(18)
toluene
70°
(0)
(17)
(27)
DMF
70°
(0)
(23)
(0)
i-PrOH
70°
(13)
(12)
(20)
70°
(13)
(3)
(12)
reflux
(20)
(0)
(20)
acetone THF, PPh3 (0.39 eq) C24
OAc OTBDPS OTBDPS
Cr(CO)5
Ac2O (1.5 eq), (32)
Et3N (1.5 eq), Ph 1.5 eq
OMe 0.1 M
heptane, 80°, 3 h OMe
151, 183
C49
R
O
R
Cr(CO)5 (72)
1. THF, 60°, 2 d Ph 1.25 eq
OMe 0.008 M
375, 376
2. PbO2, CH2Cl2 O O
Cr(CO)5
R
1. THF, 60°, 2 d R
Ph
1.25 eq
OMe 0.008 M
2. PbO2, CH2Cl2
375, 376
(74) p-Tol
O N
N
N
N
R=
Tol-p
281
p-Tol C52
R O N
N
Cr(CO)5
R
R N
Ph
N
OMe 0.04 M
Por (69)
1. THF, 60°, 2 d
376
2. DDQ, MeOH, reflux, 1 h O
4
R 0.8 eq
N
N
N
N
Por =
R=
TABLE 2. PHENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C56
Refs.
OTBDPS OTBDPS Cr(CO)5
OTBDPS OTBDPS
O
Ph
OMe
1. THF, 50-55°, 16-36 h
OTBDPS
OAc
2. Ac2O, pyr, DMAP,
OTBDPS
O
(low)
295
CH2Cl2, rt, 16-24 h OMe OTBDPS
OTBDPS Cr(CO)5
OTBDPS O
OTBDPS
Ph
OMe
1. THF, 50-55°, 16-36 h 2. Ac2O, pyr, DMAP,
O
CH2Cl2, rt, 16-24 h
282
OMe a
Isomers were not specified.
b
Only one isomer of unreported configuration was obtained.
c
More than two isomers were obtained as products from this reaction.
d
The starting alkyne provided the solvent for this reaction.
OTBDPS
OAc
OTBDPS
(62)
295
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C4
Refs.
O OMe
1. THF, 45°, 24 h
1.5 eq
(68)
13
2. CAN
OMe Cr(CO)5
MeO
0.1-0.2 M
O O
OMe
3 eq
+
(3)
1. MeCN, 45°, 24 h
(9) +
2. CAN
OMe Cr(CO)5
MeO
0.1-0.2 M
OMe
MeO
O MeO O
+
(30)
283
OMe
(11) OMe
MeO C5
13
O
O Et
OMe
Et
1. THF, 45°, 24 h
OMe Cr(CO)5 0.3 M
1.5 eq
+
I
II
67
Et
2. CAN MeO
O
MeO
O
I + II (81), I:II = 1.5:1 O
MeO MeO OMe
OEt 4.3 eq 0.1 M
OMe Cr(CO)5
276
(22)
1. THF, 62°, 34 h OEt
2. CAN MeO
O
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C6
O
F
Refs.
O
Et Et
Et 1.5 eq
Cr(CO)5
F
OMe
0.3 M
1. THF, 45°, 24 h 2. CAN, MeOH
Et +
I F
Et
II
67
+
84
Et
MeO OMe
MeO OMe
I + II (70), I:II = 7.5:1 O
Et Et
2.0 eq
Cr(CO)5
1. THF, heat
I
Et
+
II
Et
2. CAN
OMe
OMe
O Et
284
III
Et O CC (M)
Temp
Time
I
II
III
0.5
45°
16-24 h
(87)
(<1)
(<1) (<1)
0.5
110°
30-40 min
(77)
(<1)
0.005
110°
1-2 h
(58)
(16)
(1)
0.001
110°
14 h
(37)
(17)
(<1)
R 2.0 eq
Cr(CO)5
1. Benzene, 80°, 16 h 2. CAN
OR 0.1 M
I + III
I
III
Me
(58)
(—)
i-Pr
(59)
(6)
113
O
Et Et
Cr(CO)5 CF3
1. Benzene, 80°, 16 h
+
I
2. CAN
OR
Et
II
+
113
Et CF3
0.1 M
O
Et CF3
O
CF3
Et
III R
OR
I
II
III
Me
(74) (—) (—)
i-Pr
(36) (20) (26)
O
Et Et
Cr(CO)5 OMe OMe
Et
+
1. Solvent, heat, additive Et
2. CAN
285
MeO
I
OMe
MeO
O Et
MeO
III
O
O
+
Et
+ II
MeO MeO
Et
IV
Et
Alkyne (eq)
CC (M)
Temp
Time
Additive
I
II
III
IV
2.0
0.5
THF
45°
24 h
—
(61)
(18)
(5)
(—)
84, 13
2.0
0.5
THF
45°
24 h
—
(70)
(—)
(—)
(—)
13
2.0
0.5
THF
45°
24 h
—
(72)
(—)
(—)
(—)
67
1.5
0.2
THF
45°
24 h
—
(55-65)
(18-26)
(4)
(<3)
67
3.4
0.1
THF
55°
34 h
—
(52)
(27)
(4)
(—)
13
3.4
0.1
THF
55°
48 h
PPh3 (1 eq)
(33)
(48)
(9)
(—)
13
1.7
0.1
THF
55°
48 h
PMe2Ph (1 eq)
(27)
(4)
(—)
(—)
13
2.0
0.1
THF
55°
43 h
OPPh3 (1 eq)
(32)
(50)
(6)
(—)
13
Solvent
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
C6
Et
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Et
Refs.
I + II + III + IV (continued from previous page)
286
Alkyne (eq)
CC (M)
Solvent Temp
Time
Additive
I
II
III
IV
2.0
0.1
THF
55°
55 h
OPPh3 (1 eq)
(27)
(30)
(5)
(—)
13
2.0
0.1
THF
55°
48 h
Me2S (1 eq)
(39)
(43)
(4)
(—)
13
2
0.05
THF
45°
11 h
—
(46)
(42)
(1)
(3)
84
20
0.05
THF
45°
11 h
—
(84)
(5)
(1)
(2)
84
176
0.05
neat
45°
12 h
—
(91)
(<1)
(<1)
(—)
84
2
0.005
THF
45°
48 h
—
(5)
(66)
(9)
(—)
84, 13
200
0.005
THF
45°
37 h
—
(81)
(5)
(<1)
(5)
84
4
0.1-0.2
THF
45°
40 h
EtOCH=CH2 (4 eq) (58)
(—)
(—)
(—)
137
2
0.5
THF
110°
30 min
—
(29)
(53)
(10)
(—)
84
2
0.5
THF
110°
20 min
—
(26)
(54)
(10)
(—)
84
2
0.5
THF
110°
40 h
CO (1 atm)
(28)
(47)
(<1)
(—)
84
2
0.05
THF
110°
1h
—
(9)
(68)
(11)
(—)
84
20
0.05
THF
110°
1h
—
(38)
(46)
(7)
(—)
84
2
0.005
THF
110°
2h
—
(tr)
(65)
(10)
(—)
84
2
0.005
THF
110°
2h
CO (1 atm)
(8)
(62)
(10)
(—)
84
2
0.005
THF
110°
—
C5H6 (200 eq)
(0)
(73)
(12)
(—)
84
2
0.005
THF
110°
—
isoprene (200 eq)
(0)
(55)
(16)
(—)
84
200
0.005
THF
110°
12 h
—
(45)
(31)
(8)
(—)
84
2
0.5
THF
180°
5 min
—
(13)
(38)
(18)
(—)
84
2
0.5
DMTHF 45°
36 h
—
(88)
(6)
(tr)
(—)
84
2
0.005
DMTHF 45°
58 h
—
(28)
(52)
(2)
(—)
84
2
0.5
benzene 45°
24 h
—
(77)
(2)
(5)
(—)
84
2
0.005
benzene 45°
48 h
—
(21)
(—)
(37)
(—)
84, 13
2
0.5
benzene 110°
30 min
—
(29)
(6)
(37)
(—)
84
2
0.05
benzene 110°
13 h
—
(5)
(8)
(53)
(—)
84
287
2.0
0.005
benzene
110°
2h
—
(<1)
(3)
(68)
(—)
84
2.0
0.5
heptane
45°
—
—
(81)
(<2)
(<4)
(—)
84
2.0
0.5
heptane
110°
50 min
—
(54)
(9)
(35)
(—)
84
2.0
0.5
heptane
110°
25 min
—
(60)
(1)
(38)
(—)
84
2.0
0.5
heptane
110°
25 min
Ac2O (1.5 eq) (36)
(tr)
(30)
(—)
84
1.5
0.1-0.2
hexane
45°
24 h
—
(83)
(—)
(—)
(—)
13
2
0.5
MeCN
45°
24 h
—
(6)
(5)
(6)
(78)
84
2
0.05
MeCN
45°
24 h
—
(3)
(24)
(12)
(44)
84
2
0.005
MeCN
45°
48 h
—
(tr)
(31)
(25)
(25)
84
1.5
0.12
MeCN
45°
24 h
—
(<2)
(17)
(—)
(43)
13
3
0.1-0.2
CH2Cl2
45°
24 h
—
(65)
(—)
(—)
(—)
12,13
2
0.5
isoprene
45°
24 h
—
(80)
(—)
(4)
(—)
84
1.5
0.1-0.2
dioxane
45°
24 h
—
(70)
(—)
(—)
(—)
13
1.5
0.1-0.2
MeNO2
45°
24 h
—
(60)
(—)
(—)
(—)
13
1.5
0.1-0.2
MeOHa
45°
24 h
—
(51)
(20)
(—)
(—)
13
1.5
0.1-0.2
HMPA
45°
24 h
—
(12)
(21)
(—)
(29)
13
(16) +
13
O
O
Et Et
Cr(CO)5
3 eq
OMe OMe 0.1-0.2 M
1. DMF, 45°, 24 h
O MeO
+
(12)
Et
Et
2. CAN MeO
MeO
O Et (12)
Et O
MeO
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OTBS
C6
Et
Cr(CO)5
Et 4 eq
OMe OMe 0.4 M
Et
1. t-BuOMe, 55°, 1 h 2. TBSCl (4 eq), Et3N (4 eq), rt, 3 h
Et
(63)
73
MeO OMe (CO)3Cr Et
3 eq
Cr(CO)5 OMe OMe 0.1-0.2 M
Et
1. DMF, 45°, 24 h
MeO MeO
O +
I
II
OMe
MeO
Et
Et
I
II
air
(5)
(25)
air, S8
(19)
(28)
Oxidant
288
Et
CO2Me
1. UV photolysis, Cr(CO)5
1.5 eq
OMe OMe
13
2. Oxidant
THF, 15°, 2 h
Et +
I (49) +
MeO
13
2. Air, silica gel MeO
0.02 M
(2)
(2)
Et
Et Et +
+ MeO
Et MeO
(5)
O (4)
O Et OMe
1.2 eq MeO
Cr(CO)4
(58)
1. THF, 45° Et
2. CAN MeO
O
13
O
R
O
Et 1.5 eq
Cr(CO)5
R
+
I
2. CAN, MeOH
OMe
0.3 M
Et
1. THF, 45°, 24 h R
II
Et MeO OMe
MeO OMe
R
I + II
I:II
Me
(79)
1.2:1
OMe
(81)
2.1:1
CF3
(55)
25.5:1
(70)
7.5:1
F
O
OMe O Et
2 eq
Cr(CO)5
MeO
1. THF, heat
Et +
I
2. CAN
MeO
II
289
O I:II
O Temp
84
Et
Et
OMe CC (M)
67
Et
Time
I + II
0.5
45°
16-24 h
(94)
2:1
0.5
110°
30-40 min
(94)
1.6:1
0.005
110°
1-2 h
(94)
1.3:1
O
R2 R2 Cr(CO)5
2 eq
113
2. CAN
OR1
0.1 M
Et
1. Benzene, 80°, 16 h Et O
R1
R2
Me
Br
(93)
i-Pr Br
(98)
Me
CF3
(96)
i-Pr CF3
(99)
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
C6
Carbene Complex
Conditions
Product(s) and Yield(s) (%) O
RO Et
Et Et
RO
Et
Cr(CO)5
+
1. Solvent, heat 2. CAN
1.5-2 eq
RO +
Et
Et
OMe
O
OMe
I Et
RO Et III R
Refs.
Et
OMe
Et
O
II
+
O
OR IV
290
CC (M)
Solvent
Temp
Time
I
II
III
IV
Me
0.12
hexane
45°
1-2 d
(80)
(—)
(—)
(—)
13
Me
0.12
MeCN
45°
1-2 d
(44)
(19)
(—)
(4)
13
Me
0.5
THF
110° 3-40 min
(85-93)
(—)
(—)
(—)
84, 13
Me
0.5
THF
110° 3-40 min
(88)
(—)
(—)
(—)
84
Me
0.005
THF
110°
1-2 d
(64)
(—)
(—)
(—)
84
Ac
0.5
THF
45°
16-24 h
(94)
(—)
(—)
(—)
84
Ac
0.5
THF
110° 30-40 min
(80)
(—)
(—)
(—)
84
O
Et Et
Cr(CO)5
2 eq MeO
OMe
1. THF, heat
Et
+
2. CAN
+
84
Et MeO
O
OMe I
MeO Et Et O
MeO
II Et
III
+
Et OMe
IV
CC (M)
Temp
Time
I
II
III
IV
0.5
45°
16-24 h
(74)
(tr)
(—)
(—)
0.5
110°
30-40 min
(59)
(17)
(—)
(9)
0.005
110°
1-2 h
(6)
(37)
(16)
(5)
O Et 2 eq
Cr(CO)5
MeO
OMe OMe CC (M)
+
1. THF, heat MeO
2. CAN Temp
I
OMe O II
0.5
45°
16-24 h
(45)
(14)
0.5
110°
30-40 min
(37)
(—)
0.005
110°
1-2 h
(<4)
(—)
OMe
OMe 84
Et
Time
OMe
O
O Et
I
Et
II
OTBS Et
1. t-BuOMe, 55°, 1 h
291
4 eq
Cr(CO)5
MeO
OMe OMe 0.4 M
2. TBSCl (4 eq),
(70)
Et3N (4 eq), rt, 3 h
MeO
73
Et OMe OMe Cr(CO)3 O
MeO MeO Cr(CO)5 OMe OMe
Et MeO
Et
1. THF, heat 2. CAN
+
Et
I
II
Et
OMe
OMe O
O
84
Et
MeO Et
+
CC (M)
Temp
Time
I
OMe II
OMe
0.5
45°
16-24 h
(83)
(<2)
(<2)
0.5
110°
30-40 min
(15)
(19)
(34)
0.005
110°
1-2 h
(<2)
(54)
(<2)
III
III
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
C6
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
MeO Et
Et
OMe
2-3 eq MeO
1. Solvent, 45°
I + II + III
2. CAN
Cr(CO)4
CC (M)
Solvent
0.03
t-BuOMe
0.005
THF
Time
I
II
III
8h
(20)
(—)
(—)
276
48-72 h
(24)
(31)
(<2)
84
O
AcO Cr(CO)5
2 eq
OMe OMe
Et AcO
Et
AcO
Et
+
1. THF, heat
84
Et
2. CAN
292
OMe
I
OMe O
O
II
Et AcO +
Et III OMe
CC (M)
Temp
Time
I
II
III
0.5
45°
16-24 h
(60)
(tr)
(10)
0.5
110°
30-40 min
(35)
(8)
(42)
0.005
110°
1-2 h
(—)
(12)
(70)
OMe
OTBS Et
1. t-BuOMe, 55°, 1 h 4 eq
Cr(CO)5 OMe 0.4 M
(92)
2. TBSCl (4 eq), Et
Et3N (4 eq), rt, 3 h OMe
Cr(CO)3
73
OMe
OMe OH
OMe
1. THF, heat
2 eq
Cr(CO)5
Et
Et +
I
2. Oxidant
Et
OMe OMe
OMe OMe
OMe
Et
Et
Et III +
Temp
Time
0.5
45°
16-24 h
0.005
45°
48-72 h
Et
OMe
OMe CC (M)
0.5
IV
II
III
air
(52)
(<2)
(<2)
(9)
air
(<4)
(<7)
(20)
(43)
293
(11)
(tr)
(31)
(46)
FeCl3-DMF
(<1)
(<1)
(34)
(54)
1-2 h
OMe
IV
OMe
OMe
I
Oxidant
110° 30-40 min FeCl3-DMF 110°
84
O
OMe
OMe
0.005
+
II
Et
OMe OTBS Et
1. t-BuOMe, 55°, 1 h 4 eq
Cr(CO)5 OMe OMe
(67)
2. TBSCl (4 eq),
73
Et
Et3N (4 eq), rt, 3 h
0.4 M
OMe OMe Cr(CO)3 Et
Et 2 eq
Cr(CO)5 OMe
Et I
1. Benzene, 110°, 13 h 2. Air
(CO)3Cr
OMe
1.0 M
Et
+
II
242
OMe
I + II (100), I:II = 65:35 OTBS
Cr(CO)5 MeO
4 eq
OMe 0.4 M
MeO
1. t-BuOMe, 55°, 1 h
MeO
Et
MeO
Et
(73)
2. TBSCl (4 eq), Et3N (4 eq), rt, 3 h
73
OMe Cr(CO)3
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
C6
Carbene Complex
Conditions
Refs.
Et
HO Et
Product(s) and Yield(s) (%)
O
Et
Cr(CO)5
2 eq
Benzene, 110-125°
OMe
(75)
243
Et
(37)
243
OMe
0.5-1.0 M O
HO 2 eq
Et
Cr(CO)5
O
(i-Pr)2NEt (0.1 eq), MeCN, 60°, 29 h OMe
OMe
0.5-1.0 M
Et
O
Et Et
294
Cr(CO)5
2 eq R
+
Et
2. CAN
OMe
Et
+
1. THF, heat R
O
I
OMe
R
II
Et Et R
O
O
OMe
Et
Et
R
+ III
IV
CC (M)
Temp
Time
I
II
III
IV
CH2CH2OMe
0.5
45°
16-24 h
(82)
(—)
(—)
(—)
84
CH2CH2OMe
0.5
110°
30-40 min
(76)
(tr)
(—)
(—)
84
CH2CH2OMe
0.005
110°
1-2 h
(50)
(22)
(4)
(—)
84
OBu-t
0.5
45°
16-24 h
(96)
(<1.3)
(—)
(—)
84
OBu-t
0.5
110°
30-40 min
(52)
(21)
(6)
(—)
84
OBu-t
0.005
110°
1-2 h
(7)
(54)
(8)
(—)
84
OBu-t
0.12
45°
1-2 d
(72)
(<6)
(—)
(—)
13
R
Cr(CO)5
2 eq t-BuO
0.12 M
OMe
1. MeCN, 45°, 1-2 d
I (24) + II (18) + III (—) + IV (23)
Bu-n OAc
OAc Et
Ac2O (1.1 eq), 2.8 eq
Cr(CO)5
n-Bu 0.03 M
OMe
13
2. FeCl3-DMF
Et +
(26)
Et3N (1.1 eq), Et
THF, 65°, 5 h
n-Bu
OMe TMS
(9)
12
II
84
Et
Et
Cr(CO)5
267
OMe
OTMS
TMS
(26) Et
THF, 45°
Et
+
(0) Et
OMe OMe
OMe
OMe OMe
OMe
295
O
Et Et
Cr(CO)5
2 eq t-BuO
OMe
1. THF, heat
Et
I +
2. CAN
Et OMe
O
t-BuO
t-BuO Et
+
III
Et OMe
CC (M)
Temp
Time
I
II
III
0.5
45°
16-24 h
(87)
(—)
(—)
0.5
110°
30-40 min
(71)
(—)
(—)
0.005
110°
1-2 h
(44)
(13)
(8)
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C6
Et
HO Et
Refs.
O OMe
Et 2 eq
Et
Benzene, 90°, 4 h
Cr(CO)5
(60)
243
(58)
98
(41)
98
(44)
98
OMe
0.5 M
(CO)5Cr
Et
OMe
1.8 eq
MeO
Et
1. THF, 60°, 20 h OH
2. O2, Et2O, rt 0.05 M
296
(CO)5Cr
Et
OMe
O
Et
1. THF, 60°, 9 h
1.6 eq
O
2. CAN 0.05 M (CO)5Cr
Et
OMe
1.5 eq
O
Et
1. Silica gel, 60°, 5 h
O
2. CAN Br (CO)5Cr
Br OMe
2 eq
MeO
Et
Et2O, rt 2. FeCl3-DMF
Et
+
2. Ac2O, Et3N, DMAP,
0.1 M
(CO)3Cr Et MeO
Et 1. THF, 60°, 5 h
OAc (59)
98 OAc (6)
(CO)5Cr
Et
OMe
MeO
1. THF, 60°, 5 h
Et (63)
2. Ac2O, Et3N, DMAP,
2 eq
Et2O, rt 0.2 M
98
OAc
3. FeCl3-DMF
Br
Br Et (CO)5Cr
MeO
OMe
Et OH
10 eq
1. Silica gel, 60°, 6 h
(31)
HO
98
2. O2, Et2O, rt (CO)5Cr
Et
OMe
OMe Et
297
(CO)5Cr OMe
OTBS OTBS
1. t-BuOMe, 50° 2. TBSCl (10 eq),
3 eq
O
Et
O
Et
+
388
Et3N (10 eq), rt, 12 h
O
Et Et
0.04 M
(CO)3Cr
OMe
(30)
OMe
(39)
O Et
Cr(CO)5 10 eq Me Me
(48)
1. Hexane, reflux, 1 h Si
O
86
Et
2. CAN O
OBu-n
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C6 Et
MeO
Cr(CO)5 Et
Et
1. THF, 55°, 3 h
Et OMe
4 eq
(34)
208
OTBS
2. TBSCl, Et3N, rt, 3 h (CO)3Cr
0.05 M (CO)3Cr MeO +
Et Et
(18)
OTBS Et OMe
1.3-1.5 eq
298
MeO
Et
Toluene, 70°, 0.75-3 h
203
Cr(CO)3 0.04 M
CNR
(CO)2(RNC)Cr
OMe
OMe
R 2,6-Me2C6H3
(68) (48) Et TBSO
Cr(CO)5
Et Cr(CO)5
OMe OMe 5 eq
OMe
OMe OMe
1. THF, 66°, 2 h
OMe 0.1 M
Cr(CO)5
(29) 1.4:1 mixture of isomers
OMe
2. TBSCl, Et3N, rt, 2 h
OMe Cr(CO)5 TBSO
Et Et
209
Et O
Cr(CO)5
Et
OMe
O
OMe
1. THF, reflux, 2 h
OMe
OMe
2. CAN
OMe
OMe
209
O
Cr(CO)5
0.1 M
(56)
O
Et Et O
O R
1. THF, 45°, 24 h
R
Cr(CO)5 1.5 eq
+
I
2. CAN
13, 67
II R
0.3 M
299
OMe OMe
OMe O
OMe O
R
I + II
I:II
n-Pr
(64)
2.9:1
i-Pr
(61)
4.8:1
O
O OMe
Cr(CO)5
OMe
1. Hexane, reflux, 1 h
+
2. CAN
MeO
O
CF3
C7
86
OMe O I I + II (79), I:II = 1:2.5
II
CF3 NEt2
Et2N
Hexane, 20°, 0.5 h 1 eq MeO
(67)
Cr(CO)5
Cr(CO)5
141
MeO
0.075 M
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C8
EtO2C
CO2Et
OMe
(CO)5Cr
MeO
CO2Et
CO2Et (2)
1. THF, 60°, 17 h
2.1 eq
Refs.
0.04 M
98
OH
2. Air, Et2O, rt O
Pr-i Pr-i
i-Pr
Cr(CO)5
Pr-i
Pr-i
+
1. THF, 45°, 70-115 h Pr-i I
2. CAN
OMe OMe
MeO
O
OMe
MeO
Pr-i
300
Pr-i O
MeO
III
O
+
84
II
MeO MeO
+ i-Pr
Pr-i
Alkyne (eq)
CC (M)
I
II
III
IV
20
0.05
(29)
(36)
(9)
(11)
2
0.5
(21)
(43)
(8)
(12)
IV
O MeO
MeO Cr(CO)5
2 eq 0.5 M
OMe
Pr-i (83)
1. THF, 45°, 44 h
84
Pr-i
2. CAN O Pr-i
Cr(CO)5
2 eq
OMe 0.5 M
Pr-i
1. Benzene, 110-130°, 34 h 2. FeCl3-DMF
OMe
(79)
242
HO TMS
Pr-i
HO
Pr-i
Cr(CO)5
2 eq
2,6-di-tert-butylpyridine (1 eq),
(51)
243
benzene, 110-125°
OMe
O
0.5 M
O
O
• OMe TMS
TMS
TMS
TMS
n-Bu2O, 2 h, 50°
(CO)5Cr
1.25 eq
• TMS
MeO
R
0.4 M
TMS
+
57. 365
MeO I
R
R
(CO)3Cr R
I
II
CF3
(0)
(41)
Me
(43)
(27)
OMe
(—)
(—)
301
C9
II
O Ph Cr(CO)5
Ph 1.5 eq
OMe OMe
1. THF, 45°, 24 h
(78)
67
2. CAN OMe O
0.3 M
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C9
O Ph
1. Solvent, heat, 2-24 h OMe
Ph 2 eq
MeO
Cr(CO)4
Refs.
O
additive
+
IA
IB
+
OMe O
OMe O
Ph
Ph IIB +
IIA + OMe Ph
OMe
OMe
OMe
Ph IIIB +
IIIA +
302
O
OMe
OMe
Ph
O
IV
MeO MeO O CC (M)
Solvent
66
Ph
2. CAN
Temp Additive
I
A:B
A:B
III
A:B
IV
0.5
THF
45°
none
(70)
38:1
(13) 1.1:1
II
(1)
1.0:1
(7)
0.005
THF
45°
none
(23)
49:1
(53) 1.1:1
(11)
1.1:1
(0)
0.5
THF
45°
PPh3 (2 eq)
(29) ≥27:1
(24) 1:1.5
(4)
1.6:1
(15)
0.005
THF
45°
PPh3 (2 eq)
(13) ≥35:1
(67) 1.2:1
(6)
1.2:1
(2)
0.05
DMTHF
90°
none
(34)
18:1
(59) 1.3:1
(3)
1:1.1
(—)
0.005
DMTHF
90°
none
(5)
18:1
(74) 1.4:1
(9)
1:1.1
(—)
0.05
DMTHF
90°
PPh3 (2 eq)
(17)
16:1
(69) 1.3:1
(2)
1:1.1
(—)
0.005
DMTHF
90°
PPh3 (2 eq)
(8)
19:1
(81) 1.3:1
(5)
1:1.6
(—)
O 1. Microwave, (n-Bu)2O, 2 eq
Cr(CO)5
Ph
130°, 300 s
(54)
192
2. CAN
OMe
O
0.05 M
Ph
HO
O
O Cr(CO)5
Ph
+
Benzene, 110-125°
OMe
OMe
OMe (17)
(61)
0.5-1.0 M
OMe
OMe OMe
243
HO Cr(CO)5
Benzene, 100°, 8 h
O
HO +
TMS
243 TMS
OMe
TMS
303
2 eq
0.5-1.0 M
(40)
OMe
R1
R2
R1
O
1. Solvent, 45°, 24 h Cr(CO)5
O
O
+
O
O
103
2. CAN
R2 OMe 0.2-0.4 M
1.5-2 eq
(4)
OMe
R1
R1
R2
Solvent
CF3
H
OMe
H
OMe
O
R2
I I
II
THF
(25)
(17)
THF
(48)
(21)
H
benzene
(53)
(25)
OMe
H
n-heptane
(57)
(20)
OMe
H
DMTHF
(56)
(24)
OMe
OMe
THF
(27)
(—)
O
II
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OH
C10
Pr-i i-Pr
Pr-i Cr(CO)5 1 eq
Me
Cr(CO)5
2 eq
100
Pr-i
OR
OR 0.03 M
C5H11-n
(53)
n-Bu (65)
C5H11-n
1. Benzene, 110-145°, TMS
R
THF, 50°, 16 h
TMS
33-39 h 2. FeCl3-DMF
OMe 0.5 M
TMS
(78)
OMe
C5H11-n
+ OMe
R1
HO 2 eq
Cr(CO)5
304
+ R2 (8)
benzene, 110-125°
0.5 M
OMe
pentyl-n
HO
O 2,6-Di-tert-butylpyridine (1 eq),
243 (63) O
OMe
C11
242
(6)
1 : 1 mixture R1 = TMS (n-C5H11); R2 = n-C5H11 (TMS) TMS
Cr(CO)5
Ph
1. THF, 45°
Complex mixture
146
2. CAN
OMe OMe
O Ph Me3Sn
Cr(CO)5
Ph
1. THF, 45°
(20)
146
2. CAN
OMe OMe
t-Bu OMe O
C12
O
Bu-t n-BuO
Cr(CO)5 t-Bu
Bu-t 1 eq
t-Bu
1. THF, 50°, 16 h OBu-n
+
2. CAN
Bu-t
0.03 M (6)
O
100 O (72)
C13 Cr(CO)5 O OMe
TMS O OMe
0.94 eq
1. Dioxane, 60°, 32 h
(47)
O O F Ph
F Ph
OMe
0.025 M
C14
Cr(CO)5
Ph 1.2 eq
F
270
O
2. Iodine
F •Cr(CO)3 Ph +
(n-Bu)2O, 100°, 1 h
OMe
126
F MeO
OMe 0.2 M
•Cr(CO)3
F Ph
O (30)
(—)
OH
R
R Cr(CO)5
1.6 eq
R
Ph
(n-Bu)2O, 45-60°, 2 h
305
Ph
OMe
Me
(40)
CF3
(25)
104
(CO)3Cr OMe
0.1-0.2 M
O Ph
1. Ultrasound, (n-Bu)2O, Cr(CO)5
1-1.5 eq
177
Ph
2. CAN
OMe 0.04 M
O
Cr(CO)5
1.4 eq
I (69)
20 min
1. Silica gel, 50°, 3 h
I (70)
177, 178
2. CAN
OMe
OH Ph Cr(CO)5
3 eq
1. THF, 45°, 36 h
(76)
OPh 0.02 M
169
Ph
2. Air, 30 min OPh
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C14
Ph Ph
Cr(CO)5
Ph 2 eq
OMe
Ph
Ph
Solvent, 100-110°, 2-20 h
0.5 M
OMe
+ OMe Cr(CO)3
I
Solvent
I + II
I:II
(n-Bu)2O
(52)
65:35
benzene
(96)
55:45
2 eq
Cr(CO)5 OMe
Ph
HO
O Solvent, 100-125°
II 241, 242
Ph
HO
Refs.
Ph
Ph
+
Ph
243
additive OMe
OMe
I
0.5-1.0 M
306
Solvent
Additive
I + II
I:II
benzene
none
(88)
49:51
THF
none
(64)
38:62
MeOH
none
(74)
46:54
benzene
2,6-di-tert-butylpyridine (76)
72:28
benzene
pyridinium tosylate
(39)
92:8
II
OH Ph 1.1 eq Cr(CO)5 OMe
Cr(CO)3 Ph
(n-Bu)2O, 70°, 2.5 h
Cr(CO)5
OMe Ph
OMe (n-Bu)2O, 60°, 2.5 h
Cr(CO)3 (19) Ph
0.3 M
104
OMe
0.3 M
1.3 eq
(21.5)
OH
104
(CO)5Cr
Ph
OMe
MeO
Ph X
1. THF, 65°, 16 h
1.8 eq
OH
2. O2, Et2O, rt
H
(50)
Br
(32)
98
0.07 M
X
X
(CO)5Cr
OMe 1. THF, 60°, 4 h
2 eq
Ph
MeO
Ph
2. Ac2O, Et3N, DMAP, 0.1 M (CO)5Cr
98
(39)
389
(51)
98
3. FeCl3-DMF Ph
OMe
O
1 eq
Ph
1. (n-Bu)2O, 45°, 4 h O
2. HNO3
307
(50) OAc
Et2O, rt
0.1 M (CO)5Cr
Ph
OMe
O
1.4 eq
Ph
1. Silica gel, 60°, 6 h
O
2. CAN Br
Br (CO)5Cr
1.1 eq
OMe O
Ph Cr(CO)3 Ph
HO
(30)
1. (n-Bu)2O, 50°
0.2 M
+
OMe
2. TBSCl, Et3N, rt
TBSO
O
Ph Cr(CO)3 Ph
388 (1)
OMe O
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C14
Ph
Ph
EtO Cr(CO)5
2.2 eq
OH
OEt
(CO)5Cr THF, 45°, 3.5 h
Ph
(CO)5Cr
(42) (CO)3Cr
OEt
0.09 M
391
Ph
OEt
OEt
OEt Ph
(CO)5Cr
OH
(s-Bu)2O, 50°, 2.5 h
2.0 eq
Ph
Ph OEt
0.08 M
(CO)3Cr
OH
391
Ph (CO)3Cr
308
Cr(CO)5 OMe Cr(CO)5
(51)
OMe
OEt
OEt
OEt Ph 1.2 eq
(32) β:α = 1.9:1.0
1. Heptane, 76-80°, 1 h
MeO2C
MeO2C
0.08 M
(CO)3Cr Cr(CO)5 Ph
OMe
TBS OMe
390
Ph
2. Air, 40 h
O TBS
• Benzene, 80°, 12-24 h
+
TBS OMe
MeO
Ph MeO OMe
(57)
(12)
134
C14
(CO)3Cr
O
MeO Ph
TBS
• Cr(CO)5
TBS
MeO +
TBS
Benzene, 80°, 12-24 h MeO
OMe
Ph OMe
(CO)3Cr OMe
(53)
(18)
O Ph
O
Ph
O B
Cr(CO)5
1. THF, 65°
O 3 eq
B
2. CAN
OMe
Ph +
O
75
O
O (45)
0.05 M
134
O
(15)
OMe (CO)5Cr
309
1. Dioxane, reflux, 24 h TMS
O
CO2Me
(40)
O
270
O
2. Iodine
O
CO2Me
O 0.05 M
0.84 eq C15
O
OH
O Cr(CO)5
OMe 3 eq
(40)c one isomer
1. THF, 55°, 14 h
90
2. CAN
OMe OMe 0.02 M
OMe O OH
C16
Ph Ph
Cr(CO)5
Ph 1 eq
R
THF, 50°, 16 h
0.03 M
OR
OR
Me
(61)
n-Bu
(82)
100
Ph
TABLE 3. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
C16
Carbene Complex
OTBS
Conditions
Product(s) and Yield(s) (%)
OBn
OBn OH
(53) OBn OMe OTBS (CO)3Cr
C17
TIPS
O •
(CO)5Cr Ph
R TIPS
Benzene, 80°, 12-24 h
MeO
298
MeO
0.17 M OBn Cr(CO)5
OTBS
OTBS
Ac2O (1 eq), THF, 50°, 17 h
OMe
MeO
3 eq
Refs.
3-MeO (84)
R MeO C23
134
4-MeO (87) R
310
HO OH
(CO)5Cr
Pr-i
Pr-i Pr-i
OMe
OMe
THF, 75°, 40 h OMe 1 eq C26
Pr-i
PPh2 1.2 eq
100
0.03 M Ph2P
R Ph2P
(32)
MeO HO
R Cr(CO)5 OMe
Cr(CO)4 PPh2
Octane, 90°, 4 h
R Me
(85)
CF3 (74) OMe
374
C26
Ph2P
OEt (CO)5Cr Ph2P
PPh2
EtO
MeO
PPh2
Cr(CO)4
1. Heptane, reflux, 4 h 2. Air
1.2 eq
MeO
(7)
MeO
+
(30)
390
CO2Me CO2Me
0.03 M
C32
CO2Me OH
OH
Ph
Cr(CO)5 OBu-n
Ph
Ph OBu-n
1. THF, 67°, 3 d OBu-n
0.04 M
311
BnO MOMO
TBSO
MOMO
Cr(CO)5
MeO 0.5 eq
MOMO
OMe
N
80°, 2 d
0.2 M
(48)
MOMO
EtO MOMO
MeO MOMO
a
OMe OTBS
R
BnO TBSO Cr(CO)5 OMe
0.34 eq R=
Oxidation was carried out using FeCl3-DMF.
b
The product was a single isomer.
c
The carbene complex was recovered in 30% yield.
0.5 M
N
BnO HO TBSO
Heptane, 50°, 47 h Additive Ac2O (1.5 eq) —
268
MeO
OMOM
OTBS
BnO HO TBSO
Ac2O (1.5 eq), heptane,
OTBS EtO
100
Ph
0.77 eq
C 42
(48)c
OBu-n
2. 85°, 1 d
269 MeO MOMO
OMe OTBS
(35) (0)
3:1 mixture of diastereomers
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C3
Refs.
OH Cr(CO)5
OH 2 eq 0.22 M
OH
t-BuOMe, 45°, 2-4 h
(60)
147
OMe OMe OMe
OMe OMe Cr(CO)5
1.5 eq
Ac2O (2 eq), Et3N (3 eq),
OMe OMe 0.009 M
I (45) one isomer
O
OMe
THF, reflux, 4.5 h
148
O
OMe Cr(CO)5
312
2.2 eq
I (41) one isomer
O
OMe
Et
1. THF, rt, 20 h Et
Cr(CO)5
3 eq
2. 50°, 2 h
(35) OMe O OMe
OMe Cr(CO)5 OH
Ac2O (2 eq), Et3N (3 eq), THF, reflux, 3.5 h
OMe OMe
OMe OMe O
0.01 M
(48) >2 isomers
148
>2 isomers
380
O
OMe
OMe Cr(CO)5
2.2 eq
172
3. CAN
OAc 0.01 M
1.5 eq
380
benzene, 3 h
OMe OMe 0.01 M
C4
Ultrasound, Et3N (3 eq),
Ultrasound, 1-4 h
OMe OMe 0.01 M
OMe OMe O
313
Solvent
Ac2O
Et3N
THF
0 eq
0 eq
(55)
THF
0 eq
3 eq
(0)
THF
1.5 eq
0 eq
(0)
THF
2 eq
3 eq
(0)
(n-Bu)2O
0 eq
0 eq
(29)
(n-Bu)2O
0 eq
3 eq
(27)
(n-Bu)2O
1.5 eq
0 eq
(0)
(n-Bu)2O
2 eq
3 eq
(25)
benzene
0 eq
0 eq
(20)
benzene
0 eq
3 eq
(89)
benzene
1.5 eq
0 eq
(0)
benzene
2 eq
3 eq
(72)
O
OH
2.0 eq
O
OH
OH
Cr(CO)5
t-BuOMe, 45°, 2-4 h
+
0.22 M OMe
p-Tol
(17)
OMe
O
MeO
+ O
Cr(CO)5
147
(33)
(—)
O Cr(CO)5 OMe t-BuOMe, 45°, 2-4 h
2.0 eq
O
MeO
MeO
MeO
(46)
0.22 M
+ O
OMe OMe
Cr(CO)5
(—)
147
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) O
C5
Refs.
Pr-n Pr-n
Cr(CO)5
Pr-n
1. THF, heat
2 eq
+
I
2. CAN
OMe
II
+
84
O
O
CC (M)
Temp
Time
I
II
III
0.5
45°
16-24 h
(59)
(—)
(—)
0.5
110°
30-40 min
(55)
(—)
(—)
0.005
110°
1-2 h
(77)
(—)
(7)
O
O
III OMe
n-Pr
314
Cr(CO)5
2 eq
I +
+
II
113
Pr-n O
2. CAN
OR R
1. Benzene, 80°, 16 h
IV
CC (M)
I
II
Me
0.1
(66)
(—)
(3)
i-Pr
0.1
(66)
(—)
(—)
Me
0.005
(78)
(4)
(—)
OR
IV
OH Cr(CO)5
2 eq
1. Benzene, 80°, 16 h 2. Air
Pr-n Pr-n
I + IV
+
OR 0.1 M
113 OR
OR V I
IV
Me
(3)
(3)
i-Pr
(19)
(—) (48) (—)
R
VI V
VI
(62) (—)
O Pr-n Cr(CO)5
2 eq
1. Benzene, 80°, 16 h
CF3
CF3
113
O O Pr-n
1. Microwave, (n-Bu)2O, Cr(CO)5
2 eq 0.05 M
(64)
i-Pr (60)
OR
0.1 M
R Me
2. CAN
OMe
130°, 5 min
(85)
192
2. CAN O O
Pr-n
OH 3 eq
Cr(CO)5
315
OMe OMe 0.1-0.2 M
OMe Pr-n
1. MeCN, 45°, 24 h
O Pr-n
+
2. CO (650 psi),
MeO
THF, rt, 36 h OMe OMe (57)
OMe OMe
(18-23)
13
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) O
C5
Refs.
Pr-n Pr-n
Cr(CO)5
Pr-n
1. Solvent, heat
I
+
OMe O
+
II
2. CAN
OMe OMe
O
OMe
MeO O O
III
MeO Alkyne
CC (M)
2 eq
0.5
3 eq
n-Pr
316
Temp
Time
I
II
III
THF
45°
16-24 h
(64)
(—)
(11)
84
0.1
THF
45°
24 h
(74)
(—)
(—)
13
2 eq
0.5
THF
110° 30-40 min
(57)
(—)
(11)
84
2 eq
0.005
THF
110°
1-2 h
(23)
(41)
(6)
84
3 eq
0.1
CH2Cl2
45°
24 h
(71)
(—)
(—)
13
1-1.5 eq
0.04
(n-Bu)2O, ultrasound —
5 min
(61)
(—)
(—)
177
2 eq
0.5
benzene
45°
16-24 h
(60)
(—)
(tr)
84
3 eq
0.1-0.2
benzene
45°
24 h
(90)
(—)
(—)
13
2 eq
0.5
benzene
110° 30-40 min
(52)
(—)
(—)
84
2 eq
0.5
n-heptane
45°
16-24 h
(56)
(—)
(—)
84
3 eq
0.1-0.2
n-hexane
45°
24 h
(88)
(—)
(—)
13
3 eq
0.1-0.2
MeCN
45°
24 h
(—)
(—)
Solvent
(57-69) OTBS
13 OTBS
Pr-n Cr(CO)5
1.5 eq
amine (2.5 eq), 45°
OMe OMe 0.05 M
Pr-n +
TBSX (1.5 eq), I
II
OMe OMe X
Amine
Solvent
Cl
Et3N
Cl
Et3N
OMe OMe I
II
THF
only
(—)
n-heptane
(—)
(34)
(86)
(tr)
OTf 2,6-lutidine CH2Cl2
O
OMe O Pr-n
2 eq
Cr(CO)5
MeO
OMe
95
•Cr(CO)3
1. THF, heat
Pr-n +
I
II +
MeO
2. CAN
O
OMe
O
O O MeO
III
n-Pr CC (M)
Temp
Time
I + II
I:II
0.5
45°
16-24 h
(74)
11.3:1
(7)
84
0.3
45°
24 h
(76)
10.5:1
(—)
67
0.5
110°
30 min
(80)
5.6:1
(9)
84
0.005
110°
1-2 h
(84)
5.0:1
(—)
84
III
O
317
CF3
CF3 Cr(CO)5
2 eq 0.1 M OR
Pr-n
Me
2. CAN
i-Pr (98)
CF3 Cr(CO)5 OR
Pr-n
Me
2. Air
i-Pr (98)
Br
0.1 M OR
(96)
113
OR O
Cr(CO)5
R
1. Benzene, 80°, 16 h
0.1 M
2 eq
113
(95)
O OH
CF3 2 eq
R
1. Benzene, 80°, 16 h
1. Benzene, 80°, 16 h
Br
Br
O
Pr-n +
2. CAN O
113 RO n-Pr II O
I R
I
II
Me
(75)
(5)
i-Pr
(91) (≤5)
Pr-n
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne C5
Carbene Complex
Conditions
Product(s) and Yield(s) (%) OH
Br
Br
Pr-n
Cr(CO)5
2 eq
O
Pr-n +
1. Benzene, 80°, 16 h
113 RO n-Pr
2. Air
OR
Refs.
Br
OR
I
0.1 M
II R
I
II
Me
(72)
(5)
i-Pr
(90)
(≤5)
O
MeO Cr(CO)5
2 eq
318
OMe
O
Pr-n
MeO
1. Additive (1.5 eq),
Pr-n
MeO
Pr-n +
solvent, heat
+
84
2. CAN I
II
O
O
O O MeO
OMe III
n-Pr Temp
Time
I
II
THF
45°
16-24 h
(30)
(37)
(9)
none
THF
110°
30 min
(41)
(39)
(13) (—)
Additve
Solvent
0.5
none
0.5 0.5
CC (M)
III
TBSCl
THF
110°
25 min
(46)
(28)
0.005
none
THF
110°
1-2 h
(41)
(25)
(7)
0.5
none
benzene
45°
16-24 h
(36)
(40)
(Tr)
0.5
none
benzene
110°
30 min
(50)
(23)
(2)
0.5
none
heptane
110°
0.5 h
(50)
(23)
(2)
0.5
TBSCl
heptane
110°
0.5 h
(55)
(26)
(2)
0.5
TMSCl
heptane
110°
0.5 h
(52)
(22)
(—)
0.5
Ac2O
heptane
110°
0.5 h
(26)
(12)
(9)
0.5
BF3•OEt2
heptane
110°
0.5 h
(56)
(20)
(—)
MeO 1. Benzene, 45°, 16 h
2 eq
Cr(CO)5 0.5 M
2. CAN
I (29) + II (59)
113
OPr-i OH
MeO
MeO Cr(CO)5
Pr-n (46) + II (28) +
Hexane, 45°
OMe
78
OMe MeO
O (15) MeO n-Pr
Pr-n O
OH
HO
319
1. Tf2O, pyridine, benzene Cr(CO)5
2 eq 0.1 M
OR
TfO
Pr-n +
2. Alkyne, benzene, 80°, 16 h
O
113
Pr-n
3. Air
OR O
OR TfO
Pr-n
OR R Me
I
II
(80) (≤5)
i-Pr (82)
(6)
OTf
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
Refs.
O
Pr-n Pr-n
Cr(CO)5
Pr-n 2 eq
MeO
1. THF, heat
+
I
II +
2. CAN
OMe
O
MeO
84
O MeO O O
MeO
III
n-Pr
MeO
320
CC (M)
Temp
Time
I
II
III
0.5
45°
16-24 h
(56)
(—)
(—)
0.5
110°
30-40 min
(63)
(<6)
(7)
0.005
110°
1-2 h
(59) (<18)
(5)
O
AcO Cr(CO)5
2 eq
OMe
0.5 M
Pr-n
AcO
1. THF, heat
84
2. CAN Temp
Time
45°
16-24 h
(61)
110°
30-40 min
(50)
O
OH
AcO
Pr-n
AcO Cr(CO)5
2 eq OR
0.1 M
R
1. Benzene, 80°, 16 h
Me
(60)
2. Air
i-Pr
(60)
113
OR
O
Ac
Ac Cr(CO)5
2 eq
Pr-n (63)
1. Benzene, 80°, 16 h
113
2. CAN
OMe
O
0.1 M
O
Pr-n Pr-n
2 eq
Cr(CO)5
MeO
OMe OMe
+ MeO
1. THF, heat MeO
2. CAN
+ OMe O II
OMe O I
O
MeO
O
OMe
OMe
321
Pr-n CC (M)
Temp
Time
I
II
III
0.5
45°
16-24 h
(60)
(—)
(10)
0.5
110°
0.5 h
(53)
(tr)
(9)
0.005
110°
1-2 h
(39)
(10)
(10)
III
84
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
Refs.
O
MeO
Pr-n
MeO Cr(CO)5
Pr-n 2 eq
OMe OMe
MeO
Pr-n
+
1. Solvent, heat
+ OMe O II
OMe O I MeO
MeO O
O
O
+
MeO
OMe O n-Pr
OMe
IV
322
Temp
Time
I
II
III
IV
16-24 h
0.5
THF
45°
(46)
(<16)
(<10)
(<2)
0.5
THF
110° 30-40 min
(43)
(12)
(3)
(—)
0.005
THF
110°
1-2 h
(<6)
(43)
(<2)
(—)
0.5
benzene
45°
16-24 h
(47)
(14)
(<2)
(10)
0.5
benzene
110°
40 min
(35)
(8)
(4)
(—)
0.5
hexane
45°
16-24 h
(49)
(7)
(<2)
(16)
OMe
OMe OH
Cr(CO)5
OMe
OMe
Pr-n
Pr-n +
1. Solvent, heat
Pr-n O
Pr-n
III Solvent
CC (M)
84
2. CAN
Pr-n +
+
2. Air
OMe OMe
OMe OMe I
O
OMe
OMe III
II
OMe
OMe
OMe +
Pr-n
Pr-n +
OMe O IV
OMe OMe V OMe
O
O
MeO OMe VI Solvent
Temp
Time
I
II
III
IV
V
VI
0.5
THF
45°
16-24 h
(71)
(2)
(—)
(<1)
(—)
(<2)
84
0.5
THF
110° 30-40 min
(52)
(—)
(17)
(8)
(—)
(10)
84
0.005
THF
45°
2-3 d
(65)
(13)
(—)
(4)
(—)
(<3)
84
0.005
THF
110°
1-2 h
(15)
(—)
(36)
(—)
(20)
(—)
84
0.5
THF
45°
24 h
(59)
(—)
(—)
(—)
(—)
(—)
175
0.5
hexane
45°
24 h
(14)
(—)
(—)
(—)
(—)
(—)
175
0.5
MeCN
45°
24 h
(76)
(—)
(—)
(—)
(—)
(—)
175
CC (M)
323
OH
HO
1. Tf2O, pyridine, benzene Cr(CO)5
2 eq
OMe OMe 0.5 M
TfO
Pr-n (62)
2. Alkyne, benzene, 45°, 16 h OMe OMe
OMe
OMe O Br
Br Cr(CO)5 OMe OMe 0.5 M
113
3. Air
OMe 2 eq
Pr-n
Br Pr-n O
+
1. THF, 45°, 24 h 2. CAN OMe O (24)
(23)
175
O
OMe
OMe n-Pr
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
O
Refs. Pr-n
Pr-n Cr(CO)5
Pr-n 2 eq
1. Benzene, 80°, 16 h
+
(49)
(11)
113
2. CAN
Pr-i OMe 0.1 M
Pr-i
O
Pr-i
O O
AcO
Pr-n
AcO Cr(CO)5
2 eq
OMe OMe
AcO
Pr-n +
1. THF, heat
+
84
2. CAN O
OMe
OMe O I
II
AcO
AcO
324
O
Pr-n
O
OMe
OH
+ OMe
OMe Pr-n
III
IV
CC (M)
Temp
Time
I
II
III
IV
0.5
45°
16-24 h
(67)
(<2)
(<15)
(<2)
0.5
110°
30 min
(41)
(12)
(18)
(—)
0.5
110°
30 mina
(52)
(9)
(13)
(—)
0.005
110°
1-2 h
(25)
(24)
(12)
(—)
Pr-n
AcO OMe
2 eq
Cr(CO)5
MeO
I + II + III + IV
1. Solvent, heat
Temp
Time
I
II
III
IV
0.5
Solvent THF
45°
16-24 h
(68)
(<2)
(<15)
(<2)
0.5
THF
110°
40 min
(41)
(14)
(14)
(—)
0.005
THF
110°
1-2 h
(37)
(24)
(23)
(—)
0.5
benzene
45°
16-24 h
(51)
(10)
(26)
(—)
0.5
benzene
110°
30 min
(47)
(11)
(14)
(—)
CC (M)
Pr-n
HO
O Cr(CO)5
2 eq 0.5-1.0 M MeO
(9)
Benzene, 110-125°
OMe
Cr(CO)5
t-BuOMe, 55°, 0.5 h
(57)
MeO
MeO OMe OMe
TMS
TMS
325
OMe OMe 0.25 M OMe
2 eq
93
Cr(CO)3
OMe OH
Cr(CO)5 OMe OMe 0.5 M
O
243
OMe OH MeO OMe Pr-n
OMe
1.1 eq
3 eq
84
2. CAN
OMe Cr(CO)5
175
2. Air Solvent
OMe OMe
hexane
(20)
THF
(46)
MeCN
(42)
1. t-BuOMe, 50° 0.04 M
Pr-n
1. Solvent, 45°, 24 h
2. TBSCl (10 eq),
OTBS O
O Pr-n
+ OMe
Et3N (10 eq), rt, 12 h (CO)3Cr
OMe (15)
TBSO Pr-n (15)
388
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
O
C5 1. THF, 45°, 36 h Cr(CO)5 1.5 eq
2. CAN, MeCN/H2O,
(52)
218, 90
rt, 0.5 h
OMe OMe 0.1 M
OMe O OH
Cr(CO)5
1.5 eq
OMe
O OMe OMe (46) O
326
Cr(CO)5
1.5 eq
+
1. THF, 45°, 36 h 2. Silica gel
OMe OMe 0.1 M
90
OMe (20)
(54)
1. THF, 45°, 36 h
218
2. DDQ, MeOH, 0°, 2 h
OMe OMe 0.1 M
MeO MeO OMe OH Cr(CO)5
OH 2 eq
OH
t-BuOMe, 45°, 2-4 h
147, 65
+ O
OMe OMe (44)
0.25 M
Cr(CO)5
(18) O +
O OMe (20)
Cr(CO)5
MeO 3 eq
MeO
OH
1. THF, 60°, 17 h 0.05 M
Cr(CO)5
MeO
98
MeO
1. THF, 60°, 4 h 2. DEAD, PPh3,
2 eq
(41)
OH
2. O2, Et2O, rt
(29)
O
THF, rt, 18 h
98
0.5 M OMe
OMe Cr(CO)5 OH
Et3N (3 eq) OMe OR
0.01 M
OMe OR
O O Isomer Ratio b
R
Additive
Me
Ac2O (2 eq)
THF, reflux
(58)
4:1
148
Et
Ac2O (2 eq)
THF, reflux
(72)
3:1
148
Me
none
benzene, ultrasound
(67)
3:1
380
O •
327
Cr(CO)5
TMS 2 eq
OMe 0.09 M MeO
(69)
61
(61)
98
MeO
Cr(CO)5
MeO
TMS
1. THF, 50°, 6 h
2 eq
TMS
THF, 45°, 64 h
OH
2. O2, Et2O, rt 0.1 M O
C6
Bu-n
1. THF, rt, 20 h Cr(CO)5
Bu-n 3 eq
OMe OAc 0.1 M
2. 50°, 2 h
(80)
3. CAN OMe O
172
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OAc
C6
Bu-n Bu-n
Cr(CO)5
2 eq
Ac2O (2 eq), Et3N (2 eq),
(44)
267
THF, 65°, 4 h
OMe 0.03 M
OMe O
MeO
Bu-n
MeO OMe
2.3 eq MeO 0.1 M
Cr(CO)4
MeO
Bu-n (6)
1. THF, 45°, 12 h
(19)
+
276
2. CAN OMe
OMe O
O
OAc Bu-n
328
2 eq
Cr(CO)5
n-Bu
OMe
0.03 M
(51)
Ac2O (2 eq), Et3N (2 eq), THF, 65°, 4 h
267
n-Bu OMe OAc Bu-n
2 eq
Cr(CO)5
Ac2O (2 eq), Et3N (2 eq),
OMe 0.03 M
267
(19)
98
OMe O
Cr(CO)5
MeO
(51)
THF, 65°, 20 h
Bu-n
1. THF, 60°, 9 h
1.8 eq
O
2. CAN 0.07 M
Bu-n O
Cr(CO)5 OMe OMe 5 eq
OMe
O OMe
1. THF, 66°, 2 h
OMe 0.1 M
(36)
OMe
2. CAN
209
O
Cr(CO)5
O Bu-n
OMe
R
OMe OH
OMe
R R
Cr(CO)5
1 eq
OMe
329
OMe OMe
OMe OMe I
R
O
+
THF, 60°, 12 h
I
OMe
II
150
II
(67) (3)
s-Bu
(82) (9)
t-Bu OTBS
Bu-t OR
Bu-t 4 eq
MeO
Cr(CO)5
1. t-BuOMe, 55°, 1 h
Cr(CO)3
(48) dr = 9.5:1
OMe OR
0.4 M R = (–)-menthyl
OH
OH Bu-t
Cr(CO)5
1.5 eq
73
2. TBSCl (4 eq), Et3N (4 eq)
Bu-t +
THF, 60°, 17 h
89
OMe
Cr(CO)3 OMe
OMe
0.5 M (78)
(13)
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C6
OH
1. t-BuOMe, 50° O
Bu-t
2. TBSCl (10 eq),
5 eq
Bu-t
(23) +
(20) OMe
Et3N (10 eq), rt, 12 h
OMe 0.4 M
O
O
Cr(CO)5
(CO)3Cr
388
TBSO
OMe
Bu-t 1. THF, 50°, 2 h
MeO
2. Et3N (4 eq), TBSCl (4 eq),
4.4 eq OMe
Bu-t
THF, rt, 2 h
(50)c
208
OTBS (CO)3Cr
330
(CO)5Cr 0.05 M OH
OH
Cr(CO)5
OH
t-BuOMe, 45°, 2-4 h
(75)
147
OMe
2 eq
OMe
0.22 M
OMe
OMe
OH
Cr(CO)5
Et3N (3 eq), 3.5 h
0.01 M
O
OMe OR
OMe OMe
O Additive Ac2O (2 eq)
THF, reflux
(77)d
148
none
benzene, ultrasound
(77)d
380
C7
O C5H11-n
1. THF, rt, 20 h Cr(CO)5
C5H11-n 3 eq
OMe OAc 0.1 M
(51)
2. 50°, 2 h OMe O
MeO OMe OH
OMe OMe
1 eq
Pr-n
OMe Pr-n
Cr(CO)5
Pr-n
172
3. CAN
THF, 60°, 12 h
OMe OMe
+
O
(24)
150
(16)
OMe OMe
OMe OMe
OMe MeO OMe OH
OMe OMe
Et
331
Cr(CO)5
Et 1 eq
THF, 60°, 12 h
OMe OMe
+
O
OMe OMe (11)
OMe OMe
OMe
OMe
+
150
(12)
OMe Et
+
(41)
OMe
OMe
OMe OH
OMe
Et
OMe
OMe CO2Me
CO2Me 1 eq
Cr(CO)5 OMe OMe
+
THF, 60°, 12 h
150
CO2Me OMe OMe (65)
OMe
OMe (5)
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C7
Refs.
OH R
OR 1. t-BuOMe, 45-65° CO2Me
1.3 eq
Cr(CO)5
RO 0.2 M
2. PPh3, acetone, rt, 15 h
CO2Me
RO
Me
(53)
Ac
(47)
105
OMe
OMe
MOMO
MOMO
O
OH
O O O
Cr(CO)5 MOMO
See table
275
OMe
MOMO
OMe
332
Temp
Time
THF
50°
14 h
(36)
hexane
55°
64 h
(30)
—
CH2Cl2
70°
4h
(39)
0.05
—
heptane
90°
12 h
(33)
1.2
0.05
ultrasound THF
—
—
(23)
5
0.05
ultrasound hexane
—
—
(31)
2.6
0.5
—
CH2Cl2
70°
3h
(20)
2.4
0.3
—
hexane
50°
20 h
(28)
Alkyne (eq)
CC (M)
Solvent
1.2
0.05
—
1.2
0.05
—
1.2
0.05
1.2
OMe
O
OMe OH
O Cr(CO)5
See table
275
OMe OMe
OMe OMe
Alkyne (eq)
CC (M)
1.2
0.05
THF
50°
12 h
(18)
2.2
0.05
THF
50°
12 h
(34)
3.5
0.1
THF
50°
12 h
(42)
2.2
0.05
CH2Cl2
70°
1h
(23)
10
0.05
CH2Cl2
70°
1h
(59)
20
0.05
CH2Cl2
70°
1h
(76)
Solvent Temp Time
C7
OMe OTBS Cr(CO)5 CN 2 eq
OMe OTBS +
2,6-lutidine, TBSOTf, heptane or CH2Cl2, 45°
OMe OMe 0.3 M
95
(22)
(tr)
OMe OMe CN
OMe OMe CN •Cr(CO)5
O
C8
C6H13-n
1. THF, rt, 20 h
333
Cr(CO)5
C6H13-n 3 eq
172
3. CAN
OMe OAc 0.1 M MeO
(33)
2. 50°, 2 h OMe O
O
Cr(CO)5
C6H13-n
1. Silica gel, 60°, 4 h
1.5 eq
O
O
+
C6H13-n
98
2. CAN (30)
(7) O Ph
1. Microwave, (n-Bu)2O, Ph 5 eq
Cr(CO)5 0.05 M OMe
130°, 300 s
(52)
2. CAN O
192
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OAc
C8
OAc Cr(CO)5
Ph 1.2-2.0 eq
Ph Ph
1. Solvent, 60°, 17 h
+
2. Ac2O (2 eq), Et3N (3 eq),
89
I
solvent, 60°, 17 h
OMe
II
OMe CC (M)
Solvent
E-II
Z-II
THF
(79)
(<1.2)
(—)
0.03
THF
(65)
(8)
(—)
0.05
THF
(66)
(<13)
(—)
0.5
THF
(38)
(32)
(—)
0.5
THF
(74)
(8)
(<0.5)e
0.5
benzene
(36)
(25)
(<1.7)
0.5
MeCN
(22)
(18)
(<2.8)
334
I
0.005
1. THF, 60°, 17 h
OMe
Ph
2. Ac2O (2 eq), Et3N (3 eq), Cr(CO)5
1.2 eq
THF, 60°, 24 h
(69)
3. AlCl3, EtSH,
OMe
89
OMe
CH2Cl2, rt, 12 h O
Cr(CO)5
MeO
Ph R
1.5 eq
O
1. Silica gel, 60°, 5 h
R MeO
R MeO
Cr(CO)5
1.8 eq
(50)
OH
98
2. O2, Et2O, rt
Cr(CO)5
MeO
98
Ph
1. THF, 60°, 21 h 0.07 M
H (22) Br (24)
2. CAN
MeO
Ph
1. THF, 60°, 5 h 2 eq
2. Ac2O, Et3N, 0.2 M
OAc
3. FeCl3–DMF
Cr(CO)5
Et3N (3 eq) O
OMe OR
OMe OR
O Z:E
0.01 M Additive
R
98
OMe
OMe
OH
(25)
DMAP, Et2O, rt
Me
Ac2O (2 eq) THF, reflux
(74) 3:1
148
Et
Ac2O (2 eq) THF, reflux
(77) 7:3
148
Me
—
(79) 7:3
380
benzene, ultrasound
OMe
OMe
335
Cr(CO)5
Silica gel, 50-60°, 3 h
OMe OMe
(71)
380
OMe OMe
C9
O 1. Microwave, (n-Bu)2O, Cr(CO)5 5 eq
130°, 300 s
(57)
0.05 M
O O OH
1. Hexane Cr(CO)5
OTHP
192
2. CAN
OMe
2. CAN
(76)
86
3. MeOH, HCl (1 M)
OMe
O OH OMe O 1.5 eq
O
1. t-BuOMe, 40°, 1 h
O
MeO
Cr(CO)4
2. CO (75 bar), O
CH2Cl2, 70°, 48 h 0.1 M
279 (75)
OMe OMe
280 281
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C9 OH O
Cr(CO)5
O
O
O
O
150
OAc OMe
1 eq
O
+
THF, 60°, 12 h
OAc OMe
O
(30-50)
OMe (—)
OAc OMe
OMe OH 1. t-BuOMe, 50°, 1 h
CO2Me OMe
CO2Me 1.1 eq
(76)
CO2Me
Et2O, 70°, 72 h MeO 0.2 M
282, 283,
CO2Me
2. CO (75 bar),
Cr(CO)4
281, 279, 284
OMe OMe
336
O OMe O
1. t-BuOMe, 50°, 16 h 1.1 eq
OMe
CO2Me
2. CO (82 bar),
(20)
105
Et2O, 70°, 84 h MeO
MeO
Cr(CO)4
OMe
0.2 M OMe 1.1 eq
OR
OMe
2. See table MeO
CO2Me
1. t-BuOMe, 50°, 16 h MeO
Cr(CO)4
0.2 M
105
CO2Me OMe
Step 2
R
NaOMe (9 eq), MeOH, rt, 2 h
OH
Ac2O (3.2 eq), Et3N (9.5 eq),
OAc (44)
(27)
PPh3 (7.5 eq), acetone
OMe
OMe OH 1. t-BuOMe, 50°, 1 h
1.1 eq
OMe
CO2Me
2. CO (75 bar), CH2Cl2, 70°, 72 h
MeO MeO 0.2 M
C10
Cr(CO)4
OMe OMe OMe O
MeO
MeO OMe
OTHP 2 eq
281, 279
(79)
CO2Me
MeO
Cr(CO)4
1. Hexane, 50°, 3.5 h
OH
2. CAN
(10)
+
276 O
OMe O
0.11 M
MeO
O H
(22)
OMe O O
337
Cr(CO)5
CO2Bu-t 1.5 eq
OMe OMe 0.3 M
CO2Bu-t
1. THF, 45°, 24 h
(66)
67
(66)
12
2. CAN OMe O OH
Cr(CO)5
1.5 eq
OMe OMe
CO2Bu-t
1. THF, 45°, 24 h 2. Air OMe OMe
0.2 M 1. CH2Cl2, 40°, 36 h
OH
2. Air, rt, 15 min 1.5 eq
Cr(CO)5 OMe OMe 0.18 M
(64)
3. (CF3CO)2O, NaOAc 5. NaOH
12, 13, 265
4. CF3CO2H, 45 min OMe OMe O
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C10
Conditions
Product(s) and Yield(s) (%)
RO
RO
1. Solvent, 45°, 24 h OMe
CO2Bu-t
1.5 eq
Me
0.01 M
hexanes
1.2 eq
Ac
0.5 M
CH2Cl2
OMe OMe
Solvent
Cr(CO)5
CONHBu-t
(47) O
(67) CONHBu-t (70)
1. THF, 45°, 24 h
67
2. CAN
OMe OMe
OMe O
0.3 M
C11
286
CH2Cl2, rt, 14 h
MeO R
Cr(CO)4
CO2Bu-t
2. TF2O, pyridine,
Alkyne
1.5 eq
Refs.
OTf
338
OH O
O
1. t-BuOMe, 40°, 1 h OMe
O O
MeO 1.5 eq
O
2. CO (75 bar),
Cr(CO)4
279, 280,
(76)
O
CH2Cl2, 70°, 48 h
281
OMe OMe
0.1 M
O CN
CN Cr(CO)5 OEE
R
OMe
OMe O
O
Cr(CO)5 R1
OAc
12
R2 OMe
2
R2 O
(76)
OEE
2. CAN
OMe OMe 0.3 M
1.5 eq
1. THF, 45°, 36 h
O
O
OH
OMe
O +
THF, 60°, 12 h
O
R1
OAc OMe R
1 eq
1
O
AcO
OMe I
II
OMe
OMe R2 O
R1
R2
OMe OAc OAc
OAc
OAc R1
I
II
III
OMe
(—)
(24)
(24)
(—)
H
(—)
(—)
(—)
(30-50)
OAc
(16)
(30)
(—)
(21)
OMe
O
+
III
MeO R1
O
OH
O +
C12
OMe 150, 288
OMe OH
OTBS
OMe
IV
IV
OTBS Pr-n
Cr(CO)5
Pr-n 1 eq
150
(46)
THF, 60°, 12 h
339
OMe OMe
OMe OMe
OMe
OMe OH
TBSO
OTBS
MeO
Et
OTBS Cr(CO)5
Et 1 eq
Et
THF, 60°, 12 h
OMe OMe
OMe OMe
(30)
+
(28)
150
OMe
MeO
OTBS SO2Ph 1 eq
SO2Ph Cr(CO)5 OMe OMe
TBSCl, Et3N,
(—)
95
heptane, 45° OMe OMe O
Fe
Cr(CO)5 OMe OMe
Fe
1. THF, 65°, 48 h 2. PbO2, CH2Cl2 OMe O
(63)
92
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C12
Conditions
R2
R1
Product(s) and Yield(s) (%) R1
Refs.
R2 O
1. THF, reflux, 19-25 h
Fe OMe 1.2 eq
(57)
Fe
392
2. PbO2, CH2Cl2
0.05 M OMe Cr(CO)5 R1, R2 = CH2
OMe O
R1 = CH2OMe, R2 = Me MeO OH
C13 MeO Cr(CO)5
Heptane, 70°, 10 h
OMe OMe 0.1 M
340
CO2Me 1.5 eq
(43)
OMe OMe OH
OMe
OMe Cr(CO)5
1. Solvent, 50°, 48 h 2. Air
MeO2C
OMe OMe 0.08 M
0.85-1.2 eq
OMe
Cr(CO)5
MeO MeO2C 1.1 eq
OMe
0.5 M
+
I
II
MeCN
(53)
(—)
hexane
(34)
(—)
benzene
(54)
(9)
benzene
(60)
(10)
OMe OMe O OMe MeO2C II
OMe OH OMe
TMS 1. MeCN, 45°, 36 h
(66)
2. Air
Ac Cr(CO)5
1. Solvent, 45°, 24 h 2. Air, silica gel
OMe OMe 0.1 M
1.1 eq
341
OMe
1.1 eq
MeO Cr(CO)4 0.1 M
C14
175
MeO2C OMe OMe OH
Ac MeO2C
297
MeO2C OMe OMe I
Solvent
OMe
TMS
290
CO2Me
Solvent
I
II
MeCN
(74)
(0)
benzene
(81)
(9)
1. Benzene, 50°, 48 h
158, 393
+ MeO2C OMe OMe I Ac
OMe O OMe MeO2C II
I (73) + II (10)
158, 393
2. Air, silica gel
MOMO
MOMO
OH
OTBS
OTBS Cr(CO)5 MOMO
t-BuOMe, 55-60°, 10-24 h
OMe
(—) MOMO
C15
274
OMe OH OBn
OBn Cr(CO)5 OR OMe OMe
1. Solvent, 60°, 15 h
OR
2. Air, silica gel OMe OMe
R
Solvent
OMOM
THF
(25)
OMOM
benzene
(22)
OAc
THF
(74)
152
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C16
Conditions
OMe
Product(s) and Yield(s) (%) OMe OH
OTBS
OMe
TBSO
THF, 60°, 12 h
Cr(CO)5
OMe 1 eq
R
OMe OMe
OMe
(15)
OMe OMe
Ac
(40)
150
OMe
OMe
OMe O
OH
2. Air, 10 min, rt Cr(CO)5
t-BuO2C
3. (CF3CO)2O, NaOAc
1.2 eq
(56)
5. NaOH
OMe OMe O
342
OMe OH
OMe OBn
Cr(CO)5 OMe OMe
(62)
1. MeCN, 45°, 24 h 2. Air
O OMe OMe
0.5 M MOMO
MOMO
OTBS
OBn
TMS
TMS
1.1 eq
158
4. CF3CO2H, 1.5 h, rt
OMe OMe 0.1 M
C19
MeO2C
R
+
OMe
R= 1. Benzene, 75°, 12 h
Refs. OTBS
175
OMe
OH OTBS
OAc
Cr(CO)5 2.8 M OMe
1.0 eq MOMO
OTBS
THF, 55°, 12 h MOMO MeO MOMO
MOMO
1.0 eq OAc
Cr(CO)5 3.2 M OMe
MOMO
277
(38)
OAc
O
OTBS
(35-40)
1. Heptane, 55°, 14 h
277
2. CAN MOMO
O
OAc
C21 O
1. Tf2O, pyridine, CH2Cl2 O
Cr(CO)5 OMe OMe 0.14 M
OTBS
OMe
OAc
HO OMe
O O
TfO
(40)
2. Alkyne (1.05 eq),
113
OTBS
CH2Cl2, 45°, 24 h 3. Ac2O, DMAP
OMe OMe
C23 OMe
1. CH2Cl2, 45°, 22 h
O
MeO2C
OPMB
OMe Cr(CO)4
MeO 0.5 M
1.04 eq
O (42) MeO2C OMe OMe TBSO OTBS
OMe
343 O
OMe Cr(CO)5
O
O O
THF, 60°, 12 h
OMe OMe
OMe
1 eq
O
(40)
150
OMe
OH
OMe
OMe Cr(CO)5
CO2CHPh2
285
OPMB
DMAP, rt, 5 h
O TBSO
O
AcO
3. Ac2O, (i-Pr)2EtN,
C25 OTBS
OMe
OAc
AcO
O
OMe OMe
(56-60)
MeCN, 50°, 15 h OMe OMe
CO2CHPh2
12
TABLE 4. ARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C49
Refs.
R
O R Cr(CO)5
0.8 eq
1. THF, 60°, 2 d
375, 376
(75)
2. PbO2, CH2Cl2
OMe OMe
OMe O
0.01 M Tol
N
N
N
N
R=
Tol
Tol
R
O
344
Br Br Cr(CO)5
0.8 eq 0.01 M
OMe
(76)
1. THF, 60°, 2 d
375, 376
2. PbO2, CH2Cl2 O O
Cr(CO)5 R 0.8 eq
a
OMe OMe 0.01 M
R
1. THF, 60°, 2 d 2. PbO2, CH2Cl2
The reaction mixture was not deoxygenated.
b
Isomers were not specified.
c
Only one isomer of unreported configuration was obtained.
d
More than two isomers were obtained as products from this reaction.
e
Alkyne added via syringe pump.
OMe O
(74)
375, 376
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OH
C4 Cr(CO)5
t-BuOMe, 40-60°, 2-4 h
OMe 0.2 M
1.2 eq
(68) (CO)3Cr
NMe2
OMe
R
NMe2
R Pyridine
x eq
300
(CO)5Cr OEt
OEt
x
y
3
0.05
R Me
Temp Time
4
0.1
n-Pr 55°
80° 1.5 h (56)
394
78 h (95)
yM Br
Br NMe2
NMe2
345
3 eq
Pyridine, 70°, 72 h
(79)
394
(36)
395
(CO)5Cr OEt
OEt
0.05 M Me
Me
N
N O
2-4 eq
O
OH
1. Pyridine, 80°, 6 d 2. HCl, DME, 80°, 14 h
(CO)5Cr
O
OEt 0.05 M O
O
R NMe2
O 2-4 eq
R
O
R
NMe2
Pyridine, 80°, 3 d (CO)5Cr OEt
0.05 M
H
(87)
Me
(75)
395
OEt
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
C4
Carbene Complex
Conditions
TBSO
Product(s) and Yield(s) (%) TBSO
NMe2
NMe2
Pyridine, 80°, 1.5 h 3 eq
Refs.
(91)
(CO)5Cr
394
OEt
OEt 0.05 M O O
NMe2
O
NMe2
Pyridine, 80°, 3 d
O
1:1 mixture
(72)
398
of isomers (CO)5Cr OEt
OEt
346
O
O
O
O
NMe2
O
NMe2
Pyridine, 80°, 3 d
O +
398 Me2N
(CO)5Cr (38)
OEt
O
NBn2 Pr-n
C5
Pr-n
[(Naphthalene)Rh(cod)]-
Z:E = 64:36
397
CO2Me
[SbF6] (10 mol%), O 1.5 eq
(78)
O OMe
MeO
OEt
OEt
(CO)5Cr O
(27)
NBn2
THF, 50-55°, 4 d
OEt
(CO)5Cr
OEt
CH2Cl2, rt, 12-36 h 0.05 M
(81) O
396
C6
O Et
Cr(CO)5 Et
Et
1. THF, 45-60° OMe
(<5)
110, 399
(~10)
110, 399
Et
2. CAN O OH
Et
Cr(CO)5 1. CH2Cl2, 45-60° OMe
Et
2. Air OMe
OTBS Cr(CO)5
1.5 eq
Et
1. THF, 50°
(59)
2. TBSCl (1.5 eq), OMe
(CO)3Cr
0.05 M
95
Et
Et3N (2.5 eq), rt, 6-12 h
OMe
347
O Et
Cr(CO)5 1.5 eq
Solvent
1. Solvent, 45-55°, 24 h OMe
Et
2. Air
0.1 M
THF
(39)
MeCN
(42)
61
OMe OH THF, –-20°, photolysis, 2 h
5 eq Cr(CO)5
O
OMe
1.5 eq
Et
O
Et
O
Et
1. THF, 45°, 24 h 2. CAN
O
187
O
Cr(CO)5 O
(35)
Et O
(58)
69
O
0.3 M
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
O
C6
OMe Et
Et
Et
Cr(CO)5
(37)
1. THF, 45°, 24 h
1.5 eq
69
Et
2. CAN O
0.3 M
O Et 1.5 eq
OMe
O
Cr(CO)5
Solvent
1. Solvent, 45°, 24 h 2. CAN
Et
O O
THF
(73)
hexane
(79)
benzene (73)
0.3 M
MeCN
(64)
OH
348
1.5-2.0 eq
OMe
O
Cr(CO)5
69, 13
Et Et
1. THF, 45-50°, 24-96 h
I
2. Air O
+
Et
Et
II
O O
OMe CC (M)
I
II
0.3
(80)
(—)
69
0.5
(73)
(<0.1)
60
0.005
(75)
(<1.0)
60
OTBS Et
1. THF, 50° 1.5-2.0 eq
Cr(CO)5
TMS
OMe 0.05 M
(38)
2. TBSCl (1.5 eq), Et3N (2.5 eq), rt, 6-12 h
TMS (CO)3Cr
Et OMe
95
OH Et 1.5 eq
Cr(CO)5
TMS
TMS
2. Air
OMe
(33)
1. THF, 50°, 26 h
95
Et
0.05 M
OMe OH
Et Et
Cr(CO)5
1.5-2.0 eq
+
1. Solvent, 45-50°, 18-42 h
OMe
I Solvent
CC (M)
Et
Et
2. Conditions
II
OMe
Conditions
I
O
II
349
0.5
THF
air, TsOH, H2O/THF
(67)
(≤3)
60
0.3
THF
FeCl3-DMF
(64)
(—)
69
0.005
THF
air, TsOH, H2O/THF
(60)
(≤1)
60
0.5
n-heptane
air, TsOH, H2O/THF
(58)
(≤0.1)
60
0.005
n-heptane
air, TsOH, H2O/THF
(73)
(≤0.1)
60
0.5
MeCN
air, TsOH, H2O/THF
(41)
(≤1)
60
0.005
MeCN
air, TsOH, H2O/THF
(23)
(22)
60
O Et Cr(CO)5
1.5 eq
Et
2. CAN
OMe
Solvent
1. Solvent, 45°, 24 h
THF
(65)
MeCN
(56)
69, 13
O O
0.3 M
Et Cr(CO)5
1.5 eq
1. THF, 45°, 24 h
(59)
69
Et MeO OMe
2. CAN/MeOH
OMe 0.3 M
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C6
Refs.
OTBS Et
1. THF, 50° Et
Cr(CO)5
Et 1.5 eq
2. TBSCl (1.5 eq), (CO)3Cr
0.05 M
95
(65) Et
Et3N (2.5 eq), rt, 6-12 h
OMe
OMe O
P(Bu-n)3 Cr(CO)4
5 eq
Et 1. THF, 60°, 12 h
133
(33) Et
2. CAN
OMe
O O
0.1 M TBS
Cr(CO)5
350
OMe
O
TBS
Et
Et
1. THF, 45-60°
(<6)
2. CAN
+
(<6)
Et
110
Et
O
O OTBS
TBS
Et
Cr(CO)5 CH2Cl2, 65°, 15 h
1.5 eq
(43)
OMe (CO)3Cr
0.05 M
OMe OTBS
TBSCl (2 eq), Cr(CO)5
1.9 eq
OMe 0.05 M
110
Et
(i-Pr)2NEt (3 eq), CH2Cl2, 60°, 10-12 h
OTBS Et
Et (48) +
Et OMe Cr(CO)3
(35) Et OMe Cr(CO)3
207
OH
1. 2,3-Dimethyl-1,3-buta-
TMS Cr(CO)5
1.5 eq
OMe
0.03 M
Et
diene (80 eq),
112
(52)
THF, 70°, 48 h Et
2. Air OMe
O
O NMe2
O
O 2-4 eq
NMe2
Pyridine, 80°, 4 d
(78)
Et
395
(CO)5Cr OEt
Et
OEt
Ph
OH
Ph 5 eq
Photolysis, THF, –20°, 2 h
Et
351
Cr(CO)5 O 0.05 M
187
(36)
188
Et Ph OH
Ph Photolysis, THF,
5 eq Cr(CO)5
O
(81)
O
Et
O
–20°, 0.5 h
Et Bu-n
n-Bu
OH Et
1. THF, 60°, 42 h
Cr(CO)5
N Boc
Et
Boc
OMe O
O
OMe O
O
NMe2
O
121
(12) N
2. Air
O
NMe2
Pyridine, 80°, 3 d
Et
+
Et
(CO)5Cr OEt
398
Me2N Et
(37)
Et
OEt
OEt (18)
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
C6
Conditions
Product(s) and Yield(s) (%)
OBn MeO Et
Et
MeO
Cl
MeO Cr(CO)5
O
2.2 eq
THF, 80°
Et Et
O
OEt
OEt
TIPSO
OTIPS
OH
TIPSO
O
Et
t-BuOMe, 55°, 7 h O
O
Cr(CO)5
O
124
(42)
MeO
O 10 eq
Refs.
OH
O
Et
+
Et 210, 400
O
O Et (CO)3Cr OMe
OMe
OMe 0.07 M
OH
O
(33)
352
(46) 3:1 mixture of isomers
OTIPS
TIPSO
TIPSO
TIPSO
OH
TIPSO
10 eq
Cr(CO)5
O OTIPS 0.07 M
Et
OH
TIPSO +
Et
THF or t-BuOMe, OTIPS
OMe
O
Et
O
50-55°, 2.5-6 h
Et
143, 294, 210, 400
OMe OTIPS (CO)3Cr
OMe (30-31)
(39-40)
OH
OH Pr-n
Pr-n 1.2 eq
Cr(CO)5
t-BuOMe, 40-60°, 2-4 h
(52)
+
0.2 M
(13) Pr-n
OMe (CO)3Cr OMe
(CO)3Cr OMe
300
O Pr-i MeO
Cr(CO)5
Pr-i
OMe
3 eq
1. THF, reflux, 4 h
(≥28)
266
(≥37)
266
OMe
2. CAN O O
Pr-i
H
Cr(CO)5
3 eq
OMe
H
1. THF, reflux, 4 h
OMe
2. CAN O OH
Ac
Cr(CO)5
Et
THF, 50°
353
1.5-2 eq
+
(18)
(39) OMe
OMe OH
Cr(CO)5
O
Solvent, heat
R 0.05 M
+
I
R
R R
Solvent
OMe OMe 1-morpholino
II
O
Et
Ac
O
H
O
O
Et 1.5-2 eq
71
Et
Ac
OMe 0.05 M
H
O
O
Et
Temp
I
II
THF
50°
(33)
(32)
71
MeCN
50°
(35)
(31)
71
THF
70°
(18)
(63)
401
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) OH
C6
O
Et
O
Cr(CO)5
O Ac
Et
O
1. Solvent, 50°, 14-15 h
O
O
2. FeCl3-DMF
2 eq
O
Et
+
Ac
Refs.
47 O
I
II
0.05 M
R
R
Solvent
CF3 CF3
R
R
354
I + II
I:II
THF
(56)
71:29
benzene
(67)
74:26
CF3
MeCN
(37)
68:32
CF3
CH2Cl2
(51)
72:28
Cl
THF
(57)
65:35
H
THF
(63)
49:51
OMe
THF
(59)
53:47
NMe2
THF
(51)
39:61
OH CO2Me MeO2C
Cr(CO)5
CO2Me 1.5 eq
1. THF, 45°, 24 h
(8) OMe
C7
Et2N Ph
Cr(CO)5
Et2N OEt 1.5 eq
0.5 M
69
CO2Me
2. Iodine
OMe 0.3 M
Pet ether/hexanes (1:1), 0-20°
Ph
(30) + OEt
EtO
Cr(CO)5 Ph
Cr(CO)5 (29)
NEt2
402
NEt2
Ph 1 eq
Ph
(CO)5Cr 0.05 M
Hexane, rt, 3 h
Ph
(CO)5Cr
(64)
Ph
403
OMe
OMe OH
Ac
Cr(CO)5
TMS 1.5-2 eq
THF, 50°
(25)
OH
OH Pr-n
MeO2C
Pr-n
Cr(CO)5
O
1.5-2 eq
O
(33) O
OMe
0.05 M
355
C8
CO2Me
(35) + CO2Me
THF, 50°
OMe
71
OMe
OMe
0.05 M
H
+ TMS
(8) Ac
OMe
O
O
TMS
47
Pr-n OMe
O O
NMe2 O
O
NMe2
Pyridine, 80°, 4 d
(65)
395
(CO)5Cr OEt
2-4 eq 0.05 M
OEt
Ph
N Ph
3 eq
N
Pyridine, 80°, 1.5 h
(51)
(CO)5Cr
394
OEt OEt
0.05 M
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
C8
Conditions
Product(s) and Yield(s) (%)
R (CO)5Cr
NBn2
R
Z:E
n-Pr
THF, 50-55°, 4 d
OEt
(75) 67:33
OEt OH Pr-n
Cr(CO)5
TMS
TMS (56) +
1. THF, 45°, 24 h TMS
2. FeCl3-DMF
OMe
397
c-C3H5 (62) 90:10
R OH
n-Pr
Refs.
O
NBn2
(20)
101
(23)
72
Pr-n
OMe
OMe
OH
OH Pr-n
Cr(CO)5
1.5 eq
(48) +
1. THF, 50°, 18 h
356
Pr-n
2. TFA, CH2Cl2, rt, 0.5 h
OMe 0.05 M
OMe
OMe
O
O
1. THF, 50°, 16 h n-Pr
Cr(CO)5
SnMe3 1.5 eq
Pr-n
2. HCl (aq)
I O
I + II (—), I:II = 34.3:1
O
Pr-n
TMS
THF, 50-55°, 4 d
OEt
72
(0)
Pr-n TMS
O
NBn2
TMS
(CO)5Cr
II Pr-n
NBn2 TMS
+
3. CAN
OMe 0.07 M
397
OEt OH Ph
Ph
I
O
Cr(CO)5 OMe
(0)
THF, 60° I
O OMe
146
C9
HO
Cl TBS
Cr(CO)5
OMe
TBS
SiO2, 80°
OMe
O
(39)
404
(31)
404
O
OEt
OEt HO
Cl Cr(CO)5
TBS
THF, 80° OMe
O OMOM
O OMOM OH Ph
H Ph 1.5-2 eq
O
Cr(CO)5
O
THF, 50°
357
OMe 0.05 M
O
Cr(CO)5
–20°, 0.5 h
Ph +
187 O C7H15-n (10) Ph
Ph
Ph
OH
OH +
Photolysis, THF, O
Cr(CO)5
–20°, 0.5 h
71
OH
C7H15-n O (30)
5 eq
(62)
OMe
OH
Photolysis, THF, O
+
(4)
Ph
Ph
n-C7H15 5 eq
H H
OMe O
Ph
C10
H
O
O
O
C7H15-n
O
188 O
(28)
(7)
C7H15-n
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C10 Cr(CO)5
TBSCl (3 eq),
(CO)3Cr
TBSO
(CO)3Cr +
TBSO 212
(i-Pr)2NEt (5 eq), OMe 0.25 M
1.5 eq
toluene, 50°, 24 h
I
MeO
MeO
II
I + II (63), I:II = 89:11 1. Toluene, 80°, 24 h Cr(CO)5 1.5 eq
212
I + II (62), I:II = 3:97
toluene, 80°, 24 h
0.25 M
358
Cr(CO)5
1.5 eq
2. TBSCl (3 eq), (i-Pr)2NEt (5 eq),
OMe
TBSCl (3 eq),
(CO)3Cr
TBSO
TBSO
(i-Pr)2NEt (5 eq),
212 I
toluene, 50°, 3 h
OMe
(CO)3Cr +
II MeO
MeO
0.25 M
I + II (61), I:II = 22:78 1. Toluene, 120°, 24 h Cr(CO)5
1.5 eq
2. TBSCl (3 eq),
I + II (63), I:II = 2:98
toluene, 120°, 24 h
0.25 M
(CO)3Cr
TBSO
(CO)3Cr +
Cr(CO)5
TBS
212
(i-Pr)2NEt (5 eq),
OMe
TBSO
Toluene, 50°, 24 h
1.5 eq
212
OMe 0.25 M
I MeO I + II (73), I:II≤ 3:97
MeO
II
1.5 eq
HO
(CO)3Cr t-Bu
Cr(CO)5
t-Bu
+
Toluene, heat, 24 h
HO
(CO)3Cr t-Bu
212
OMe MeO
0.25 M
Cr(CO)5
I + II
I:II
50°
(69)
65:35
120°
(60)
1:99
TfO
(CO)3Cr
TfO
(CO)3Cr
2. Tf2O (3 eq),
+
(i-Pr)2NEt (5 eq), OMe
II
MeO
Temp
1. Toluene, 80°, 24 h 1.5 eq
I
toluene, 80°, 24 h
I
MeO
0.25 M
212 II
MeO
I + II (86), I:II ≤1:99
359
TBSCl (3 eq), Cr(CO)5
1.5 eq
(CO)3Cr
TBSO
II
MeO
Temp
I + II
I:II
50°
(77)
21:79
80°
(66)
23:77
Temp
Time
I + II
I:II
50°
24 h
(75)
14:86
(i-Pr)2NEt (5 eq),
50°
48 h
(66)
≤1:99
toluene, heat, 24 h
80°
24 h
(74)
2:98
1. Toluene, heat, time
OMe 0.25 M
212
I
MeO
Cr(CO)5
TBSO
+
(i-Pr)2NEt (5 eq), toluene, heat, 24 h
OMe 0.25 M
1.5 eq
(CO)3Cr
2. TBSCl (3 eq),
I + II
212
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C10 (CO)3Cr
TBS Cr(CO)5
2,3-Dimethyl-1,3-butadiene, MeO
Ac
O
O
(73)
THF, 50° OMe
1.5-2 eq
71
Ph OMe
0.05 M
OH Ph Cr(CO)5
1.5-2 eq
212
(29)
0.07 M Cr(CO)5
Ph
TBSO
THF, 50°, 14 d
OMe 1.5 eq
H
O
O (5) +
THF, 50°
(70)
Ac
360
OMe 0.05 M
OMe
OMe Ph
O
Cr(CO)5
(6) + Ac
O
71
O (62) ≥98% ds
THF, 70°
47
Ph
OMe 0.05 M
OMe
Cr(CO)5 O 1.5 eq
(87)
OMe
OMe
Cr(CO)5
CO2Me
O Ph
O 1.5-2 eq
H
O
O
THF, 50°
OMe 0.05 M
71
Ph
OH
1.5-2 eq
Refs.
OMe
[(Naphthalene)Rh(cod)]-
O (85)
[SbF6] (10 mol%), CH2Cl2, rt, 12-36 h
CO2Me
0.05 M O
396
C11
O Ph
Cr(CO)5 Ph
TMS
1. THF, 45-60°, 19-38 h OMe
2 eq
(70)
146
TMS
2. CAN
0.044 M
O O Ph
2 eq
Cr(CO)5
O
1. THF, 45-60°, 19-38 h
OMe 0.044 M
O O Ph
Cr(CO)5
Ph 2 eq
Ph
1. THF, 45-60°, 19-38 h OMe
361
O OH Ph
CO2Et
Cr(CO)5
O
1.5-2 eq
THF, 50°
EtO O
O (43) +
OEt
O
OMe
Cr(CO)5
[(Naphthalene)Rh(cod)]-
71
OMe
O
Ph (75)
[SbF6] (10 mol%), OMe
(27)
O
OMe O
O
H
Ph
0.05 M
1.5 eq
146
(60) TMS
2. CAN
0.044 M
Ph
146
(66) TMS
O
2. CAN
CH2Cl2, rt, 12-36 h
396
CO2Et
0.05 M O
TBSCl (3 eq), Cr(CO)5 CO2Me
TBSO R
(CO)3Cr
TBSO
+
(i-Pr)2NEt (5 eq),
212
R
I
toluene, 50°, 24 h
OMe
1.5 eq
(CO)3Cr
II
MeO MeO I + II = (74), I:II <2:98 R = CO2Me
0.25 M
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C12
Cr(CO)5
(CO)3Cr
TBSO Pr-i
I MeO I + II = (56), I:II = 94:6
MeO 1. Toluene, 120°, 24 h 2. TBSCl (3 eq), (i-Pr)2NEt (5 eq),
OMe 0.25 M
212
II
I + II = (33), I:II ≤1:99
212
toluene, 120°, 24 h Cr(CO)5
362
1. Pyridine, 80°, 60 h 2. H2O NMe2 0.05 M
2 eq
TBSO i-Pr
toluene, 50°, 12 h
Cr(CO)5
EtO
(CO)3Cr +
(i-Pr)2NEt (5 eq),
OMe 0.25 M
Pr-i 1.5 eq
TBSCl (3 eq),
O (47)
405
Me2N
OMe
O
Cr(CO)5 THF, 50°, 36 h
O OMe 1.5 eq
Ph
(8) O
O
0.04 M
+
Ph
401
(37)
O OMe
Ph
C12-14
R OH
R
n-Pr
Pr-n O
2 eq
O
Cr(CO)5
1. THF, 50°, 14-15 h 2. FeCl3-DMF
OMe
R +
O OMe O
0.05 M I
O
47
O O
n-Pr II
OMe
R
I + II
I:II
CF3
(70)
37:63
Cl
(56)
51:49
H
(67)
61:39
OMe
(68)
74:26
NMe2
(75)
79:21
O
C13
Ph Ph
TMS
Cr(CO)5
O
1. THF, 60°, 28 h
OMe
TBSCl (3 eq), Cr(CO)5
363
1.5 eq
+
Bu-t
212
II
MeO I + II = (75), I:II 57:43
1. Toluene, 120°, 24 h 2. TBSCl (3 eq),
I + II = (67), I:II ≤1:99
212
(i-Pr)2NEt (5 eq),
OMe
toluene, 120°, 24 h
0.25 M
Cr(CO)5
TBSCl (3 eq),
(CO)3Cr
TBSO
(CO)3Cr +
(i-Pr)2NEt (5 eq),
TBSO 212
toluene, 50°, 24 h
OMe 0.25 M
1. Toluene, 120°, 24 h 2. TBSCl (3 eq),
OMe 0.25 M
II
I MeO I + II = (57), I:II = 89:11
MeO
Cr(CO)5 1.5 eq
146
TBSO
I
MeO
Cr(CO)5
1.5 eq
(CO)3Cr
(i-Pr)2NEt (5 eq),
0.25 M
1.5 eq
Bu-t
TBSO (CO)3Cr
toluene, 50°, 24 h
OMe
complex mixture
TMS
O
0.05 M
Bu-t
+
(5) O
2. CAN
I + II = (47), I:II ≤1:99
212
(i-Pr)2NEt (5 eq), toluene, 120°, 24 h
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C14
Refs.
OH Ph Ph
Cr(CO)5
Ph 1.1 eq
(n-Bu)2O, 70°, 1.5 h
(26)
104
Ph
OMe 0.14 M
(CO)3Cr OMe OH Ph
Cr(CO)5
1.5 eq
1. (n-Bu)2O, 70°
(36)
69
(66)
13
(67)
69
Ph
2. FeCl3-DMF
OMe 0.3 M
OMe OH Ph
1.5 eq
Cr(CO)5
364
O
1. Hexane, 45°, 24 h O
2. FeCl3-DMF
OMe
Ph OMe
0.3 M
OH OEt
Ph Cr(CO)5
1.5 eq
1. THF, 45°, 24 h 2. FeCl3-DMF
OMe
Ph
EtO OMe
0.3 M E:Z = 1.6:1.0 O TMS 1.5 eq
O Ph
Cr(CO)5 1. THF, 50°, 46 h
0.03 M
OMe
TMS (25) +
Ph (27)
Ph
2. CAN
406
Ph
O
O O
TMS
Cr(CO)5 THF, 50°, 46 h
1.5 eq 0.03 M
Ph TMS
OMe Ph
OMe
(11)
406, 110
OH F n-Bu
1.5 eq
Cr(CO)5 F
n-Bu
Ph
F
Ph
(35)
1. t-BuOMe, 55°, 18 h 2. FeCl3-DMF
OMe
125
OMe OH Ph Cr(CO)5
1.5 eq
1. THF, 45°, 24 h
Me2N
Cr(CO)5
4 eq
13
OMe
Pr-n
Me2N
(89) Ph
2. FeCl3-DMF
OMe 0.3 M
Pyridine, 55°, 78 h
OEt
Pr-n
Ph
(80)
Ph
0.1 M
394
OEt
365
OH Ph
Cr(CO)5
Ph
Ph
t-BuOMe, 40-60°, 2-4 h
1.2 eq
(90)
OMe
300
Ph
0.2 M
OMe
(CO)3Cr
O Cr(CO)5
TBS
1. THF, 50°, 46 h
1.5 eq
O
TBS
Ph
OMe
Ph (35)
2. CAN
+
(17)
Ph
0.05 M
O
O
OTBS TBS
110
Ph
O Ph
Cr(CO)5
1.5 eq
Ph (26) +
CH2Cl2, 50° OMe
TBS
(8)
110
Ph
0.05 M
(CO)3Cr
Ph
OMe
OMe
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Me
C14
N
R Ph
Ph 2-4 eq
Conditions Ph
R
N Ph
2. HCl, DME, 80°, time 2
O R Cr(CO)5
4 eq
OEt
20 h (42)
395
R
R
Ph Ph
H
Time Time 5d
(81)
Me 4 d
(51)
395
OEt
OEt
366
(CO)5Cr
1. Pyridine, 80°, 60 h
2 eq NMe2 0.05 M
O
Ph
Ph Cr(CO)5
O
(0)
405
2. H2O Ph
Me2N
OH
O
MeO
36 h (50)
3d
O
Me2N Pyridine, 80°, time
0.05 M
1.5 eq
7d
n-Pr
O
O Me2N
Time 1 Time 2
Me OH
O
OEt 0.05 M
Refs.
Me
R
O 1. Pyridine, 80°, time 1
(CO)5Cr
Product(s) and Yield(s) (%)
O
Toluene, 70°, 5 h
Ph
Ph
(52)
407
Ph
0.2 M
OMe OH
Ph
Ph Cr(CO)5
5 eq O
Ph
Photolysis, THF, –20°, 0.5 h
(14) Ph O
188
NMe2 Pyridine, 80°, 3 d (CO)5Cr
O
O Me2N
(46)
Et
O
OEt
398
O Et
EtO O Cr(CO)5
R
THF, 50-55°, 4 d
NBn2
Ph
Ph
TIPSO
367
OMe
O OTIPS
(0)
OH Ph
Cr(CO)5
OH
Ph
Ph
O
CO2Me
+
Photolysis, THF, –20°, 2 h Cr(CO)5
210
OTIPS OMe (CO)3Cr (46)
OMe (7)
Ph
Ph
O
OH
CO2Me
OH Ph
Ph
OTIPS
C13
5 eq
—
+ O
Ph
397
TIPSO
t-BuOMe, 55°, 3.5 h
0.2 M Ph
75:25
TIPSO
TIPSO
2 eq
(68)
c-C3H5 (59) >95:<5
OEt
OTIPS
Z:E
n-Pr
R
NBn2 OEt
TIPSO
R
Ph
Ph
(44)
O
187
(22)
O
CO2Me C14 Cr(CO)5
O
THF, 50° 0.05 M
Ph
(50)
O
OMe
O
Ph
1.5-2 eq
71
OMe
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) O
C14
O
Ph
Ph
O B
Cr(CO)5
Ph
O 0.05 M
3 eq
OMe
1. THF, 45°, 14 h
B
2. CAN
+
O
75
O
O
O
(83)
C15 TBSCl (3 eq), Cr(CO)5 OTBS
OMe
1.5 eq
RO RO
(CO)3Cr
(CO)3Cr +
(i-Pr)2NEt (5 eq),
(14)
RO 212
I
toluene, 50°, 24 h
0.25 M
Refs.
II
RO MeO
MeO
I + II = (70), I:II <1:99 R = TBS
368
OH
Cl
OMe MeO
Sn(Bu-n)3
Cr(CO)5
O
O OEt
Ph
OEt OH
OMe
Ph
0.83 eq
OMe i-PrO
Cr(CO)5 OMe
THF, reflux, 6 h
O Pr-n
i-PrO
Pr-n
+ OMe i-PrO
i-PrO O
OH
371
(8) Ph
O O
Ph
+
Ph
0.26 M
Pr-n i-PrO
MeO (48)
Dioxane, reflux, 6 h
O
i-PrO
OH Ph
Cr(CO)5
0.77 eq
404
(20)
SiO2, 80°
OMe O
0.1 M (39) 2.8:1 mixture of isomers
(21) E:Z = 2.5:1
372, 149
C16
OH
OH
Ph
Ph Ph
Cr(CO)5
Ph
+
55-70°, 10-30 h
OMe OMe Alkyne (eq)
CC (M)
1.0
100
I
Solvent
Additive
0.05
THF
1.0
0.5
1.0
0.05
0.4
1.2
II
Ph
Ph
OMe I
II
none
(73)
(2.4)
THF
none
(73)
(2.8)
benzene
none
(44)
(<1.3)
THF
(n-Bu)3P (3 eq)
(74)
(<1.3)
OH Ph Cr(CO)5
0.4 eq
THF, 66-70°
Ph OMe
+
I
OMe HO
369
OMe 1.2 M
Time
I
9h
(67)
(4)
60 h
(5)
(0.6)
100 III
III
Cr(CO)5
EtO
O
Ph
1. Pyridine, 80°, 72 h
2 eq NMe2 0.05 M
2. H2O
405
(60) Me2N Ph OMe
OMe O
1. Dioxane, 85° 2. MeO2C
(CO)5Cr
CO2Me ,
0.75 eq Ph
CO2Me
Ph
0.02 M
408
(61)
O
dioxane, 85°, 1-2 h
CO2Me
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
C16 Cr(CO)5
TBSCl (3 eq),
Product(s) and Yield(s) (%) (CO)3Cr
TBSO R
(CO)3Cr
1.5 eq
OMe 0.25 M
Cr(CO)5
toluene, 50°, 24 h
C17
I + II = (58), I:II 6:94
Sn(Bu-n)3
Cr(CO)5
R = CH2OTBS
212
toluene, 50°, 24 h O Pr-n
1. THF, 50° 2. HCl (aq)
+
370
I
3. CAN
OMe
R = CH2OTBS
(i-Pr)2NEt (5 eq), O
n-Pr
II
MeO
I + II = (53), I:II = >99:1
1. Toluene, 50°, 48 h
212
R
I
MeO
2. TBSCl (3 eq), OMe 0.25 M
TBSO
+
(i-Pr)2NEt (5 eq), CH2OTBS
Refs.
Pr-n
O
72
II
O
I + II = (68), I:II = 34.1:1 OH OH Pr-n
Cr(CO)5
I +
1. CH2Cl2, 50° OMe
I
2. I2
72
I
Pr-n
II
OMe OMe I + II = (50), I:II > 20:1 OH
OH Pr-n
Cr(CO)5 OMe
+
1. Hexanes, 50°, 18 h 2. HCl (aq)
I OMe OMe I + II = (77), I:II > 99:1
72 Pr-n
II
Ph
Cr(CO)5
EtO
O
Ph
1. Pyridine, 80°, 56 h CO2Et 2 eq
NMe2 0.05 M
405
(66) Me2N
2. H2O
CO2Et
C18
OH OH
Ph
Ph
Ph Cr(CO)5
Ph
1. THF, 55°, 24 h
+
2. Air Ph
OMe Ph
I
II
CC (eq)
I
II
1
2
(29)
(32)
1
5
(0)
(69)
5
1
(43)
(0)
371
Alkyne (eq)
Ph
EtO
O
Ph
2. H2O
NMe2 0.05 M
Ph (48)
Ph MeO
OMe
TMS OMe
TMS
1. Dioxane, 85° 2. MeO2C
(CO)5Cr
CO2Me ,
0.02 M
CO2Me
+
O
dioxane, 85°, 1-2 h Ph 0.75 eq
405
Me2N
TMS
O
MeO
Cr(CO)5 1. Pyridine, 80°, 56 h
2 eq
OH 139
OMe
OMe 0.1 M
Ph
408
O
CO2Me
CO2Me
CO2Me (5)
Ph (62)
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
C19
Carbene Complex
Conditions n-Bu
Bu-n OMe
n-Bu
2. MeO2C
CO2Me ,
Ph
OMe
(3) MeO n-Bu
1. Dioxane, 85° 2. MeO2C
(CO)5Cr
CO2Me ,
372
CO2Me
CO2Me (56)
O
(19)
O
1. Dioxane, 85° 2. MeO2C
Ph
OMe
n-Bu OMe
408
O
CO2Me
Ph
0.02 M
CO2Me
+
O
dioxane, 85°, 1-2 h
(CO)5Cr
Ph
OMe
n-Bu
0.75 eq
CO2Me
CO2Me (76)
0.02 M
408
O
CO2Me
Ph
0.75 eq
CO2Me
+
O
dioxane, 85°, 1-2 h 0.75 eq
Refs.
MeO
1. Dioxane, 85°
(CO)5Cr
O
Product(s) and Yield(s) (%) OMe
CO2Me ,
0.02 M
408
(39)
O
dioxane, 85°, 1-2 h
CO2Me
Ph
CO2Me C21 OMe (CO)5Cr
O Ar
0.02 M
Ar = O
n-Bu
1. Dioxane, 85° 2. MeO2C
CO2Me , Ar
CO2Me
+
O
dioxane, 85°, 1-2 h 0.75 eq
MeO
OMe
n-Bu
Bu-n
CO2Me CO2Me (45)
O CO2Me Ar
(30)
408
OH
C23 Cr(CO)5 R
OH R
t-BuOMe, 47°, 3.5 h
+
R
263, 409
OMe
1.1 eq
(CO)3Cr
0.23 M R=
OMe (41)
(CO)3Cr
OMe (18)
2
C24 TIPS
TIPS
OH
OMe (CO)5Cr
Solvent 1. Solvent, 55°, 24 h
THF
(70)
2. Air
toluene
(81)
TIPS
TIPS
1.1 eq
139
OMe
0.1 M
C25
OH
373
OH Ph
Ph OMe
THF, 70-74°, 12 h
(CO)5Cr OMe
Ph
OMe
(56)
100
MeO HO
Ph
0.37 eq
1.7 M O Ph
OMe 0.37 eq
Ph O
1. Benzene, 70-74°, 12-34 h
(CO)5Cr
2. CAN
O
CC (M)
100
O
0.016
(16)
0.16
(42)
1.7
(60)
TABLE 5. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C26 OH R
R Cr(CO)5
1 eq
R
OMe
(41)
1. THF, 55°, 24 h 2. Air
+
139
OMe
0.1 M
R OH R
R=
R OH
OMe
374
MeO
(23)
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OH
C2
OH Cr(CO)5 1 atm
THF, 50°
(15)
OMe 0.22 M
+
(33)
131
OMe
C3
O Cr(CO)5 1. THF, 45-55°, 24 h OMe
I (59)
0.1 M
1.5 eq
61
2. Air OMe
Cr(CO)5 1.5 eq
1. MeCN, 45-55°, 24 h OMe
I (62)
61
2. Air
375
0.1 M
O
1.5 eq
Cr(CO)5
OH
1. THF, 45°, 24 h
+
(44)
(7)
61
2. Air OMe 0.1 M
OMe
trans:cis = 91:9
O 2.4 eq
Cr(CO)5
O (26)
Hexane, 60°, 24 h
OMe
+
(20)
OMe
+
207
OMe
0.05 M
OH (1-2)
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C4
Conditions
OEt
MeO
(CO)5Cr
2.5 eq
Product(s) and Yield(s) (%)
Refs.
MeO NHBn
THF, 70°, 12 h
(CO)5Cr
N Bn
Bu-n
0.1 M
(46)
410
Bu-n O
O
N Cr(CO)5
N Ph
OEt
Ph (76)
RhCl3•3H2O (2 mol%), THF/MeOH (4:1), 20°
194
MeO
0.25 M
OEt OH OH Cr(CO)5
376
OH 2 eq
OMe 0.22 M
1.5 eq
OMe
O
O
CH2Cl2, rt, 12-36 h
147
OMe
[(Naphthalene)Rh(cod)][SbF6] (10 mol%),
O
(76) (CO)3Cr
Cr(CO)5 Ac
t-BuOMe, 45°, 2-4 h
(64)
396
(22)
69
Ac
0.05 M OH Cr(CO)5
CO2Me
OMe 1.5 eq
CO2Me 1. THF, 45°, 24 h 2. Iodine OMe CO2Me
0.3 M [(Naphthalene)Rh(cod)]-
1.5 eq
O
OMe
Cr(CO)5 0.05 M
[SbF6] (10 mol%), CH2Cl2, rt, 12-36 h
(89) O O
396
O 1.5 eq
R
[(Naphthalene)Rh(cod)]-
Cr(CO)5
R
OMe 0.05 M
[SbF6] (10 mol%),
Ph
(75)
CH2Cl2, rt, 12-36 h
p-MeOC6H4
(81)
2-furyl
(88)
ferrocenyl
(71)
n-Bu
(70)
C5
R
CO2Me
396
OH Pr-n
Cr(CO)5 n-Pr
CH2Cl2, 50°
(~13)
110, 399
OMe OMe O
O Pr-n
Cr(CO)5
1.5 eq
1. THF, 50°, 24 h
377
Pr-n (66)
2. Tf2O (1.5 eq), (i-Pr)2NEt (2.5 eq), CH2Cl2, rt, 24 h
0.05 M
96
Cr(CO)3
OMe
OTBS Cr(CO)5
Pr-n
TBSOTf (1.5 eq), base (2.5 eq), 50°, 18-22 h
OMe
69
O
1. CH2Cl2, 50°, 1 d
OMe
1.5 eq
(4) Pr-n
O OTf
Cr(CO)5
1.5 eq
+
(47)
2. CAN
OMe 0.3 M
0.05 M
Cr(CO)3
OMe
Solvent
Base
THF
2,6-lutidine
(73)
CH2Cl2
2,6-lutidine
(77)
THF
(i-Pr)2NEt
(55)
95
OTBS Cr(CO)5
1.5 eq
Pr-n
1. THF, 50°, 18-22 h 2. TBSCl (1.5 eq),
(65)
Et3N (2.5 eq),
OMe 0.05 M
THF, rt, 6-12 h
95
Cr(CO)3
OMe
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) OTBS
C5 (i-Pr)2NEt (3 eq),
R1 =
OR* R3 =
Ph R2 =
R4 =
378
Ph Cr(CO)5 1.5 eq OMe
Pr-n +
I
CH2Cl2, 60°, 14-19 h
OR* 0.05 M
1.9 eq
Pr-n
TBSCl (2 eq),
Cr(CO)5
n-Pr
II
Cr(CO)3 I
II
dr I
R1
(69)
(23)
60:40
R2
(83)
(—)
50:50
R3
(68)
(—)
58:42
R4
(77)
(—)
55:45
OH Pr-n (60)
2. (n-Bu)3P, rt, 36 h
69
3. MeOH, CCl4 OMe O
O Pr-n
Cr(CO)5 1. THF, 50°, 24 h OMe
205
OR*
R*
1. THF, 50°, 24 h
0.3 M
1.5 eq
Refs.
OTBS
I
+
II Pr-n
2. CAN
0.3 M
O
69
O I + II (75), I:II≥ 99:1
O Pr-n
Cr(CO)5 1. THF, 50°, 24 h
1.5 eq OMe 0.3 M Z:E = 2.2:1.0
(—)
2. CAN O
69
OTBS Cr(CO)5
Pr-n
TBSOTf (1.5 eq), 2,6-lutidine (2.5 eq),
1.5 eq OMe
(74)
CH2Cl2, 50°, 18-22 h
0.05 M
OMe
95
Cr(CO)3
OTBS Pr-n Cr(CO)5 O
1.5 eq
TBSCl (2 eq), Cr(CO)3
(i-Pr)2NEt (3 eq),
(82)
O
CH2Cl2, 60°, 14 h
205
57:43 mixture of diastereomers
0.05 M OH Pr-n Cr(CO)5
379
1.2 eq
t-BuOMe, 40-60°, 2-4 h
(75)
OMe OMe
0.2 M
300
Cr(CO)3 OH
5 eq
Photolysis, THF, –20°, 2 h Cr(CO)5
O
0.2 M MeO
187
(24)
Pr-n O OH Pr-n
Cr(CO)5 MeCN, 50°, 24 h
(64)
122
OMe OMe O
O 1.5 eq
O OMe
O
Cr(CO)5
Pr-n
1. THF, 45°, 24 h
69
(38) O
2. CAN
O
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
O
C5 EtO
Pr-n Cr(CO)5
n-Pr 1.5 eq
OMe 0.3 M E:Z = 1.6:1.0
1. THF, 45°, 24 h 2. CAN
(40)
69
EtO O OH Pr-n
Cr(CO)5
1.5 eq
OMe 0.3 M
1. THF, 45°, 24 h
60. 69
(54)
2. FeCl3-DMF complex OMe OH
O
n-Pr
Pr-n
Pr-n Cr(CO)5
1.5 eq
380
OMe 0.3 M
OMe (51)
1. Hexane, 45°, 24 h
+
2. Air, TsOH, THF/H2O
(9)
60, 246
O OMe OH
Pr-n Pr-n
2 eq
Cr(CO)5
O
OMe 0.005 M
(57)
1. THF, 50°, 21 h 2. Air, TsOH, THF/H2O
+
(≤0.2)
60
O
O
O
OMe O Pr-n
1.5 eq
Cr(CO)5
O
(67)
1. THF, 45°, 24 h
OMe 0.3 M
2. CAN
Cr(CO)5
1. CH2Cl2, 50°
69, 13
O O OH
TMS
Pr-n
OMe
(60)
2. Air, CF3CO2H OMe
110
OTf TMS
1. CH2Cl2, 50°, 24 h Cr(CO)5
Pr-n (81)
2. Tf2O, (i-Pr)2NEt CH2Cl2, rt, 12-15 h
OMe
TMS
96
Cr(CO)3 OMe OTBS
TMS
Pr-n Cr(CO)5
50°, 18-22 h
0.05 M
TMS Cr(CO)5
OMe I
Base
Solvent
TBSCl
Et3N
THF
(44)
TBSCl
(i-Pr)2NEt
THF
(37)
TBSOTf
2,6-lutidine CH2Cl2
Silane
95, 72
I TMS
OMe
1. THF, 50°, 18-22 h
Cr(CO)3
(79)
I (60)
95
381
2. TBSCl, Et3N
OMe 0.05 M
O
TMS
Pr-n Cr(CO)5
2 eq
1. Heptane, 50°, 24 h
95
(76) TMS
2. CAN
OMe
O
0.05 M
OH
Pr-n Pr-n
Cr(CO)5
1.5-2 eq
OMe
1. Solvent, 45-50°, 18-24 h
+
I
II
2. Oxidant, solvent O
OMe CC (M)
Solvent 1
Oxidant, Solvent 2
I
II
0.5
THF
air, TsOH, THF/H2O
(69)
(≤2)
60
0.005
THF
air, TsOH, THF/H2O
(65)
(≤6)
60
MeOH
FeCl3-DMF complex
(72)
(—)
13
0.3
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
OH
Refs.
OH Pr-n
Cr(CO)5
n-Pr
THF, 45°, 24 h
+
I
II
101
Pr-n
OMe OMe
OMe I + II (55), I:II≥250:1
OE
OH Pr-n
Pr-n Cr(CO)5
EX, (i-Pr)2NEt, 50°, 24 h
Cr(CO)3 OMe I
OMe
OMe
II OMe
EX
Solvent
Tf2O
CH2Cl2
(43)
(23)
96
AcBr
THF
(64)
(—)
95
382 Cr(CO)5
+
I
1. THF, 50°
I
2. EX, base
II
EX
Base
I
TBSCl
Et3N
(65)
95
MEMCl (i-Pr)2NEt (68) O Pr-n
Cr(CO)5
1.5 eq
OMe
1. Solvent, conditions 2. CAN O Solvent
Conditions
0.3
THF
45°, 24 h
(61)
69
0.3
MeCN
45°, 24 h
(69)
13
0.08
(n-Bu)2O ultrasound, rt,
(75)
177
CC (M)
10 min
OTBS Cr(CO)5
1.9 eq
CH2Cl2, 60°, 10-12 h
OMe
Pr-n +
I
(i-Pr)2NEt (3 eq), OMe
II
Cr(CO)3
OMe
207
Cr(CO)3
I + II (65), I:II = 60:40
0.05 M
OTBS
R Cr(CO)5
R
Pr-n +
I
(i-Pr)2NEt (3 eq), CH2Cl2, 60°, 10-12 h
OMe
OTBS
R Pr-n
TBSCl (2 eq), 1.9 eq
OTBS Pr-n
TBSCl (2 eq),
OMe
0.05 M
II
Cr(CO)3
OMe
R
I + II
I:II
Me
(50)
76:24
OMe
(48)
94:6
207
Cr(CO)3
OH
383
Pr-n Cr(CO)5
1.5 eq
(66)
1. THF, 45°, 24 h
69
2. FeCl3-DMF complex
OMe 0.3 M
OMe EtO
Cr(CO)5
R 3.5-7 eq
EtO
THF, 52°, 14 h R
Pr-n
NMe2
R NMe2 I
0.04 M EtO
i-Pr
(14)
c-Pr
(77)
411, 412
Pr-i THF, 52°, 14 h
3.5-7 eq (CO)4Cr
I R = i-Pr (30)
411
NMe2
0.04 M
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C5
Conditions
Product(s) and Yield(s) (%) EtO
Cr(CO)5 EtO
n-Pr
NMe2
n-Pr
NMe2
NMe2
n-Pr +
Pr-n +
See table.
n-Pr
Refs.
O
Pr-n
EtO
n-Pr
I O
NMe2 III
Pr-n + OEt III O
NMe2
n-Pr
+
O
n-Pr Pr-n
Et OEt
NMe2
IV
V
384
Alkyne (eq)
CC (M)
Solvent
Time
Temp
Additive
I
II
III
IV
V
4.5
0.01
hexane
90 h
55-60°
none
(11)
(0)
(10)
(0)
(0)
412
4
0.1
hexane
20 h
55-60°
none
(26)
(tr)
(27)
(0)
(0)
412
34
0.1
hexane
20 h
55-60°
none
(24)
(tr)
(25)
(0)
(0)
412
101
0.1
1-pentyne 20 h
55-60°
none
(22)
(tr)
(24)
(0)
(0)
412
4
0.1
THF
60 h
55-60°
none
(20)
(tr)
(47)
(0)
(0)
412
34
0.1
THF
22 h
55-60°
none
(22)
(tr)
(37)
(0)
(0)
412
3.5-7
0.04
THF
14 h
52˚
none
(9)
(—)
(—)
(—)
(—)
411
4
0.1
DMF
144 h
55-60°
none
(27)
(tr)
(0)
(0)
(28)
412
34
0.1
DMF
48 h
55-60°
none
(25)
(tr)
(0)
(0)
(27)
412
4
0.1
MeCN
72 h
55-60°
none
(40)
(14)
(0)
(26)
(0)
412
34
0.1
MeCN
14 h
55-60°
none
(13)
(2)
(1)
(45)
(0)
412
4
0.1
DMF
90 h
55-60°
Ph3P (1 eq)
(42)
(10)
(0)
(6)
(6)
412
4
0.1
DMF
72 h
55-60°
Ph3P (10 eq)
(50)
(12)
(0)
(0)
(0)
412
60
0.1
DMF
60 h
55-60°
Ph3P (1 eq)
(21)
(5)
(0)
(0)
(24)
412
4
0.1
pyridine
88 h
55-60°
none
(68)
(11)
(0)
(3)
(0)
412
1.5
0.05
pyridine
7h
80°
none
(78)
(15)
(0)
(0)
(0)
412
4
0.1
hexane
7h
55-60°
MeCN (1.8 eq)
(6)
(tr)
(13)
(59)
(0)
412
O
O Pr-n
1.9 eq
Cr(CO)5
Pr-n +
Solvent, 60°, 24 h
+
207
I OMe 0.05 M
III
OMe
OMe OH
I
II
III
THF
(27)
(25)
(—)
hexane
(46)
(37)
(<3)
MeCN
(43)
(17)
(—)
Solvent
n-Pr
III
Pr-n
O Cr(CO)5
Pr-n
THF, 50°, 24 h
OMe
(47)
112
(65)
95
MeO
0.05 M
385
OTBS TBS
Pr-n
2,3-DimethylCr(CO)5
1.5 eq
butadiene (50 eq), THF, 50°, 7 d
OMe
Cr(CO)3 OMe
0.07 M O Cr(CO)5
TBS
O
TBS
Pr-n
1. THF, 45-60° 2. CAN
OMe
Pr-n +
(<5) O
OTBS Pr-n
Cr(CO)5
110
O
OH TBS
(<5)
Pr-n +
(0)
CH2Cl2, 50°
(72)
110
OMe OMe
OMe
Cr(CO)3
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
C5
Carbene Complex
Conditions
n-Pr
EtO
3.5-7 eq
t-Bu
Product(s) and Yield(s) (%) OEt n-Pr
EtO
(CO)5Cr
Pr-n (0)
THF, 52°, 14 h to 7 d NMe2
0.04 M
t-Bu
Refs.
+
(43)
NMe2
411, 413
Bu-t
O n-Pr
O Pr-n Cr(CO)5
(67)
THF, 50°, 24 h
112
0.05 M
OMe
OMe O
O
TBS TBS
Cr(CO)5
Pr-n
1. THF, 45°, 24 h
(<5)
2. CAN
386
OMe
O
THF, 55°
Pr-n (CO)5Cr
OEt
(63) E:Z = 2:1
412
Pr-n 0.1 M
OEt O
Pr-n
O
n-Pr
See table
Pr-n
N-morph Alkyne (eq)
95
N
n-Pr
OEt (CO)5Cr
(<62) O
O
N 4 eq
Pr-n +
N-morph Solvent
Temp Time
6
DMF
55°
36 h
(52)
3
THF/H2O (99:1)
80°
3h
(54)
414
O
N-morph 4 eq
(CO)5Cr
Pr-n
THF, 80°, 3 h
O
N-morph
n-Pr
+
Pr-n
OEt
OEt (13)
O 3 eq
DME, 65°, 15 h (CO)5Cr
414, 412
OEt (56) Pr-n
N-morph
n-Pr
N-morph
n-Pr
(66)
Pr-n
415
N-morph OEt
OEt 0.05 M O
Pr-n 3 eq
(CO)5Cr
N-morph
THF/MeCN (9:1), 65°, 15 h
N-morph
n-Pr
(82)
OEt
415
OEt
387
0.05 M N-morph
c-Pr
N-morph n-Pr 4.5 eq
(CO)5Cr
Pr-c
412
(67)
THF, 55°
OEt
OEt
0.05 M n-Pr
OEt (CO)5Cr
NHMe
N Me
(CO)5Cr
THF, 65° OTBS
OEt 8 eq
416
OTBS n-Pr
OEt
(CO)5Cr
(25)
EtO (66)
THF, 52°, 7 d O
NMe2
OEt
n-Pr
0.05 M
413
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
C5
Carbene Complex
Conditions
(CO)5Cr
Refs.
n-Pr OEt
n-Pr 8 eq
Product(s) and Yield(s) (%) EtO
THF, 52°, 7 d
413
O n-Pr
EtO
OH
Ph Ph
Pr-n
Photolysis,
5 eq O
(17)
OEt
0.05 M
Me2N
(37)
187
THF, –20°, 0.5 h
Cr(CO)5
O OH
Cr(CO)5
388
TMS OMe MeO
Pr-n
THF, 50°, 24 h
(56)
112
0.05 M MeO MeO OMe OH
OMe
Pr-n 1.1 eq
OEt MeO MeO
t-BuOMe, 55°, 30 min MeO OMe OMe n-Pr
(CO)5Cr OEt Me2N
+
Ph
n-Pr
OTMS
Pr-n Ph
n-Pr
(21)
THF, 55°, 36 h O
0.05 M n-Pr
(0)
411, 413
NMe2 Pr-n
OEt Me2N
OEt Me2N
EtO (19)
O
(CO)5Cr 4 eq
Cr(CO)3
OEt
THF, 52°, 14 h to 7 d 0.04 M
Ph
279
0.25 M
Cr(CO)4
3.5-7 eq
417, 418, (57)
OEt
+
OTMS
(38) 416 Cr(CO)3
OH
Ph
Ph Cr(CO)5
5 eq
Pr-n
THF, –20°, 0.5 h
(30)
188
photolysis
O
O OTMS
TMS
Pr-n
OMe
1.5 eq
(97)
THF, 45°, 24 h
12, 95, 112
0.05 M Cr(CO)5
OMe
(CO)3Cr
OH 1. THF, 45°, 24 h
Cr(CO)5
Pr-n
2. Silica gel
389
TMS OMe 0.05 M
(95)
112
MeO
O
OH
O 1. THF, 45°, 12 h
O
Cr(CO)5
Pr-n (64)
O
2. Air
12
OMe
OMe O
TMSO
O OMe
Pr-n (33)
THF, 50°, 24 h
OMe Cr(CO)5 0.05 M
112
OMe OH Pr-n 1. THF, 60°, 42 h
Cr(CO)5
N Boc
(60)
121
N
2. Air OMe
Boc
OMe
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
C5
Carbene Complex
Conditions
Product(s) and Yield(s) (%) TBSO
OTBS
OTBS
n-Pr
CH2Cl2, 60°, 10-12 h
0.05 M
OMe
OTBS Pr-n
+
(i-Pr)2NEt (3 eq),
Cr(CO)5
1.9 eq
TBSO Pr-n
TBSCl (2 eq),
Refs.
(CO)3Cr
207
I
(CO)3Cr
OMe
II OMe
OTBS Pr-n +
I + II (<2); III (79) (CO)3Cr
TBSO
OTBS
III OMe
O
O Pr-n
390
1.9 eq
(47)
1. CH2Cl2, 60°, 10-12 h
Cr(CO)5
(11)
207
2. CAN
0.05 M
OMe
Pr-n +
O
O
OH Pr-n 3 eq
1. Hexanes, 50°, 24 h Cr(CO)5 OMe OMe
(65)
299
(58)
121
2. Air OMe OMe
0.15 M
OH Pr-n 1.5 eq N Boc
Cr(CO)5 OMe
0.04 M
1. THF, 60°, 42 h 2. Air
N Boc
OMe
O
OEt (CO)5Cr
6 eq
Ph
DMF, 55°, 45 h
O
n-Pr
(39)
Ph
N-morph
414
N-morph OH 1. 2-Trimethysiloxy-1,3-
TMS 1.5 eq
O
Pr-n
butadiene (15 eq),
Cr(CO)5
(58)
THF, 50°, 36 h OMe
0.03 M
2. Silica gel, air
OEt
OMe Me2N
(CO)5Cr
4 eq
OTBS
Hexanes, 55°, 24 h
OTBS
n-Pr
NMe2
0.1 M
391
Cr(CO)5
0.04 M
394
OH
O
O
(92)
OEt
O 1.2 eq
112
1. THF, 45°, 48 h
Pr-n (60)
O
12
2. FeCl3-DMF OMe
TMS OMe
Bu-n
n-Bu
OH Pr-n
1.5 eq
Cr(CO)5
N Boc
(47)
1. THF, 60°, 42 h
OMe
Boc
OMe
R
R
Me2N
R
NMe2
n-Pr
n-Pr Pyridine, 80°, 3 d
OEt
121
N
2. Air
+
(41)
Cr(CO)5
(21)
Me2N
OEt
398
OEt
R= O
O
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C5
Conditions
Product(s) and Yield(s) (%) 1
R 1O
Refs.
1
OR OH
OR OH Pr-n
(CO)5Cr
n-Pr 3 eq
+
1. Benzene, 55-58°, 36 h
1.0 M
OMe OMe
MeO
392 OMe
0.33 M
OMe
R2
I + II
I:II
Me
Me
(40)
II only
Me
Et
(43)
II only
Me
i-Pr
(47)
II only
Me
t-Bu
(50)
II only
Et
Me
(73)
1:13.2
i-Pr
Me
(72)
1:12.5
OMe
MeO
OMe OH Pr-n
Pr-n
+
I
OR2
II
OMe
OMe OH Cr(CO)5 1. Benzene, 55-58°, 36 h 2. Air
OR1
MeO
R1
MeO
3 eq
OR2 OMe
I
OMe
OMe
MeO
211
OR2 OMe
2. Air
R2O MeO
Pr-n
2 OR1 OR
II 2 OR1 OR
R1
R2
I + II
I:II
Me
Me
(53)
3.0:1
Me
Et
(45)
2.4:1
Me
i-Pr
(51)
2.4:1
Me
t-Bu
(48)
2.0:1
Et
Me
(45)
2.1:1
i-Pr
Me
(45)
2.1:1
i-Pr
t-Bu
(48)
3.4:1
211, 299
OEt 4 eq
O
OTBS
(CO)5Cr
THF/H2O (99:1), 80° 3 h
O
n-Pr OTBS
N-morph OEt N-morph DME, 65°, 15 h
3 eq 0.05 M
4
OTBS
(62)
415
4
OTBS OEt OTBS Pr-i CH2Cl2, 65°, 20 h
OMe
i-Pr 2 eq
Cr(CO)5 R
0.1 M
(68) (CO)3Cr
393
Pyridine, 80°, 3 d Cr(CO)5 R= O
R + Me2N
(24)
(20)
OEt
398
OEt
O c-Pr Hexane, 55°, 24 h
EtO
NMe2
c-Pr (95)
0.1 M
Cr(CO)5 R
110
i-Pr
i-Pr
NMe2
c-Pr
OMe NMe2
R
NMe2
EtO
4 eq
N-morph
n-Pr
TBS
c-Pr
414
N-morph O
(CO)5Cr
(50)
OEt R
NMe2 Pyridine, 80°, 3 d
EtO
394
Cr(CO)5
R
NMe2
c-Pr(H) (36) H(c-Pr)
+
c-Pr Me2N
(24)
OEt
398
OEt
R= O
O
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OH
C5
(CO)5Cr OMe 1.5 eq
1. THF, 45°, 24 h
Cr(CO)5
2 eq
1. Pyridine, 80°, 45 h 0.05 M NMe2 R2N
2. H2O
O
(73)
OEt
394
0.25 M Cr(CO)5
Ph
RhCl3•3H2O (2 mol%), OEt
N-morph Ph +
THF, 60°, 12 h
OMe 0.05 M
193
(10)
N-morph
OEt TBSO
MeO 1.9 eq
(74) NR2 = morpholine
N-morph Ph
Cr(CO)5
194
(76) NR2 = NMe2
THF/MeOH (4:1), 20°
Ph EtO (CO)5Cr
405
Me2N R 2N
Ph
1.5 eq
69
OMe
0.3 M EtO
1.5 eq
(57)
2. FeCl3-DMF
(25)
OEt TBSO
OMe
2,6-Lutidine, TBSOTf,
OMe
+
CH2Cl2, 60°, 12-24 h
(70) (CO)3Cr OMe OH
(CO)3Cr OMe
88 (12)
OMe Cr(CO)5
1.5 eq
OMe 0.3 M
1. THF, 45°, 24 h
OMe
2. SiO2, air OMe
(68)
12, 69
OH
Cl
OH
OEt
HO
Silica gel, 80°
(20)
404
(32)
404
O
O Cr(CO)5
3 eq
OH
Cl
OH
OEt
O
I
OEt
Silica gel, 80° O
Cr(CO)5
OEt O 1. THF, reflux
OEt
(41)
2. Ph3P, DEAD,
395
Cr(CO)5
289
THF, 20° (CO)3Cr OEt
SPh OEt
8 eq
1. Silica gel, 80°
O Cr(CO)5
I (19)
91
I (39)
91
2. Pyridine-N-oxide
Ph S 8 eq
Cr(CO)4 O
1. Silica gel, 80° 2. Pyridine-N-oxide
OEt O H
OEt
3 eq
1. THF, reflux
OH
H
(≥34)
2. CAN Cr(CO)5
289
O
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
Refs.
O 1. THF, reflux
H
OEt
HO Cr(CO)5
3 eq
2. PPh3, DEAD, THF, 20°
(≥7)
H
289
3. Air, benzene, hn OEt
OEt
O
(CO)5Cr 1. THF, reflux 3 eq
(≥31)
2. PPh3, DEAD, THF, 20° 3. Air, benzene
O O
O O O
396
O
O
Cr(CO)5
O
1. MeCN, 45-55°, 24 h
O OMe 1.5 eq
(55)
61
2. Air
0.1 M
OMe OH Cr(CO)5
1.5 eq
289
OEt
OMe 0.3 M
O O (33)
1. THF, 45°, 24 h
69
2. FeCl3-DMF OMe O TMS
Cr(CO)5 TMS
Solvent, 45-55°, 24 h 1.5 eq
OMe 0.1 M
OMe
Solvent THF
(50)
MeCN
(73)
61
OH
Cl
TMS OEt
Silica gel, 80°
(36)
404
O
O Cr(CO)5
OEt OTBS
TMS
TMS Cr(CO)5
1.5 eq
1. THF, 50°, 22 h 2. TBSCl, Et3N, rt, 16 h
OMe 0.05 M
TMS (CO)3Cr
(40)
72
(71)
69, 13
(71)
239
OMe OH TMS
Cr(CO)5
1.5 eq
1. THF, 45°, 24 h 2. Air
397
OMe 0.05 M
OMe O TMS
Cr(CO)5 THF, 50°, 36 h OMe OMe
OAc 1. THF, 50-55°, 16-36 h Cr(CO)5
O
OMe
TMS
O
2. Ac2O, pyr, DMAP,
(—)
295
CH2Cl2, rt, 16-24 h OMe
Me2N
Me2N
Pr-n OEt
2 eq
Pr-n
TMS MeCN, 80°, 8 h
(53)
Cr(CO)5
394
OEt
0.05 M
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
O
O TMS
Cr(CO)5
TMS 1.5 eq
Refs.
TMS +
THF, 45°, 24 h
61
OMe 0.1 M
I
OMe
II
OMe
I + II (75), I:II = 92:8 H
O
O
H OMe
(37) 2:1 mixture of isomers O
H
Cr(CO)5
H
398
OMe 2.2 eq
TMS
MeO +
THF, 80°
124
O OMe
Cr(CO)5
OMe
OMe OH
MeO OEt
O
419
OMe OMe OH
Cl
MeO
TMS
THF, 55°, 24 h
O I
OMe
OEt
TMS II
OEt
I + II (28) O O O
O
O
R
NMe2
2-4 eq
Pyridine, 80°, 4 d
O
NMe2
R TMS
NMe2
R
+
395
EtO Cr(CO)5 0.05 M
TMS
OEt I
OEt II
R
I
II
H
(40)
(9)
Me
(45)
(9)
MeN n-Pr O
2-4 eq
Me N
n-Pr
O Pyridine, 80°, 40 h
O
TMS
(56)
O
EtO Cr(CO)5 0.05 M Ph
395
OEt Ph
Ph
O
O 3 eq
+ TMS
THF, reflux O
OMe
O
MeO
420
Cr(CO)3
(13) (50) 1.4:1 mixture of isomers
0.07 M OEt
O
N-morph
399
THF/MeCN (9:1), 75°
N-morph OTBS
TMS
(—)
415
OEt
TBSO OTBDPS
OTBDPS
TBDPSO
TBDPSO
OAc
1. THF, 55°, 28 h 3 eq
TMS
MeO
Cr(CO)5
(CO)5Cr
O
2. Ac2O, pyr, DMAP,
O OMe
OTBDPS
TBDPSO
TMS
O
(—)
295
CH2Cl2, rt, 16-24 h
Cr(CO)5
OMe
C6
O OMe
Bu-n
(CO)5Cr
n-Bu
0.1 M
1.5 eq
Solvent
Solvent, 45-55°, 24 h
THF
(60)
MeCN
(80)
61
OMe
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C6
O
O Bu-n
Cr(CO)5
n-Bu 1.5 eq
Refs.
THF, 45°, 24 h
Bu-n I
+
II
61
OMe OMe
0.1 M Cr(CO)5
Bu-n
OEt
THF, 60°, 2 h
(66) Ph
NH2
Ph
OMe OH Cl
2.2 eq
MeO
400
OEt
O
Bu-n
THF, 80°
(42) OMe
OEt R
Cr(CO)5
Cr(CO)5
Bu-n OEt
2.5 eq Ph
124
O
Cr(CO)5
OMe
410
N
OMe MeO
OMe
I+II (78), I:II = 90:10
THF, 70°, 12 h Ph
NHR 0.1 M
N R
Me
(54)
i-Pr
(48)
Ph
(42)
Bn
(46)
410
Cr(CO)5
Cr(CO)5
Bu-n OEt
2.5 eq
THF, 70°, 12 h
(71) n-Bu
n-Bu NHBn 0.1 M
O
SO2Ph 8 eq
O
OMe
Bu-n 1. Silica gel, 70° 2. CAN
Cr(CO)5
410
N Bn
(37) O O
91
H O 3 eq
(70)
THF, reflux OMe
O 0.07 M
O
Bu-n
Cr(CO)5
420
3:1 mixture of isomers
MeO
Ph
Ph O
3 eq
THF, reflux
0.07 M
420
(57) O
OMe
O
Bu-n
5:1 mixture of isomers
MeO
Cr(CO)5
H O 3 eq
THF, reflux
401
OMe
MeO
OMe THF, reflux OMe
MeO OMe
15:1 mixture of isomers
MeO
OMe MeO
3 eq
Bu-n
Cr(CO)5
0.07 M
420
(53) MeO
MeO
O
MeO
Bu-n
420
(52) OMe MeO
Cr(CO)5
0.07 M Ar 3 eq
O
Ar OMe
O
Bu-n
Ar
THF, reflux
Ph O
Cr(CO)5
0.07 M
420
(45)
PMP (62) OMe
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C6
Conditions
Product(s) and Yield(s) (%)
R
R2
R1 t-Bu
Refs.
OTBS
2
Bu-t
A: TBSCl (2 eq),
O
(CO)5Cr
R1
(i-Pr)2NEt (3 eq),
1.9-4.0 eq
Cr(CO)3 O
CH2Cl2, 60°, 14 h B: 1. t-BuOMe, 55°, 55 min R1
R2
CC (M)
Me
H
0.4
H
Me
0.05
Method
2. Filter through SiO2 3. TBSCl (4 eq), NEt3 (3 eq), rt, 3 h
% de
(63)
57:43
14
97
A
(78)
52:48
4
205
—(CH)4—
0.05
A
(90)
55:45
10
205
—(CH)4—
0.4
B
(59)
58:42
16
97
402
O
Cr(CO)5 OEt Me2N
THF, 60°, 20 h
Pr-i
Pr-i
Me2N
Pyridine, 80°, 2 d
t-Bu Pr-i (9)
0.05 M
O
OEt Ph N-morph
DMF/H2O (99:1), 55°, 36 h
Cr(CO)3 Pr-i
N Me (11)
(15) R = NMe2 O O
Pr-i
(CO)5Cr
+ t-Bu
R (47) R = OEt
OEt
2 eq
OEt
O
t-Bu
Cr(CO)5
6 eq
dr
B
t-Bu
421
O
+
Pr-i
421
N Me
OEt
(60)
O
t-Bu Ph N-morph
(54)
414
O
OEt 3-6 eq
(CO)5Cr
Pr-n N-morph
Solvent/H2O (99:1),
O
Solvent
t-Bu Pr-n
55-80°, 3-36 h
THF
(51)
DMF
(30)
414
N-morph O 1. THF, reflux
H
OEt
HO
Cr(CO)5
2. PPh3, DEAD,
(50)
H
Cr(CO)3
OEt
5 eq OMe MeO
OMe OH Cl
2.2 eq
MeO OEt
O
403
OMe
99
THF, –10° to –20°
THF, 80°
OH (16)
MeO
+
124
O
Cr(CO)5
OEt OMe MeO
Cl
O H
MeO
(18)
O
O OEt
O
Cl
OH
1. THF, 80°, 16 h
OEt
O
2. PPh3, DEAD
Cr(CO)5
2 eq Me2N
OEt
MeCN, 80°, 8 h
(53)
394
Pr-n
TMS
0.05 M Cr(CO)5
2 eq
404
OEt Me2N
Pr-n
TMS
(33) O
OEt
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C7
Conditions
Product(s) and Yield(s) (%)
SO2Ph n-C5H11
O
C5H11-n
1. Silica gel, 70°
OEt
8 eq
Refs.
O
2. CAN
(49)
91
O
Cr(CO)5
O OH
OEt Cr(CO)5
1.5 eq
(23)
1. THF, 45°, 24 h 2. Air
OMe
69
EtO OMe
0.3 M EtO
Cr(CO)5 O (43)
404
1. Pyridine, 80°, 60 h 2 eq
2. H2O
NMe2 0.05 M
Me2N
TBSO EtO
OEt
Cr(CO)5
TBS
OEt CH2Cl2, 65°, 20 h
EtO 2 eq
405
(53)
110
OMe 0.05 M
OMe
Cr(CO)3
TBSO
OTMS
TBSO
OTMS
Cr(CO)5 +
(i-Pr)2NEt, TBSCl, TMSO 1.9 eq
OMe 0.05 M
CH2Cl2, 60°, 12-24 h (CO)3Cr OMe
I
(CO)3Cr OMe
I + II (75), I:II = 90:10
88 II
Me2N O
Cr(CO)5
Me2N Me2N
Pyridine, 80°, 2 d 2 eq
Pr-i
OEt
Pr-i
(58)
421
(76)
95
(47)
95
N
0.05 M
Me O CN
Cr(CO)5 NC
2. CAN
OMe 0.5 M
2 eq
1. Heptane, 50°, 24 h O OTf CN
Cr(CO)5
1.5 eq
Tf2O, 2,6-lutidine, CH2Cl2, 50°
OMe
OMe
0.05 M
Cr(CO)3
405
OTBS Cr(CO)5
1.5 eq
CN
TBSOTf (1.5 eq),
Me
CH2Cl2, 50-65°, 15-24 h
OR
R
2,6-lutidine (2.5 eq),
159, 95
c-C6H11 (75)
Cr(CO)3
OR
0.05 M
(73)
OTBS 1. THF, 50° 1.5 eq
Cr(CO)5
CN
2. TBSCl (1.5 eq),
(67)
Et3N (2.5 eq), rt, 6-12 h
OMe 0.05 M
OMe
95
Cr(CO)3
O CN Cr(CO)5
2 eq
1. Heptane, 50°, 24 h
(57)
95
2. CAN
OMe 0.5 M
O
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OR
C7 Cr(CO)5
CN
ROTf (1.5 eq), 2,6-lutidine (2.5 eq),
NC 1.5 eq
OMe 0.05 M
R TBS
CH2Cl2, 50-65°, 15-24 h OMe
(73)
159, 95
TIPS (68)
Cr(CO)3
OTBS Cr(CO)5
CN
1. THF, 50° 2. TBSOTf (1.5 eq),
1.5 eq OMe
(22)
Et3N (2.5 eq), rt, 6-12 h
0.05 M
OMe
95
Cr(CO)3
OE CN
406
1.5 eq
Cr(CO)5 OMe 0.05 M
EX (1.5 eq), base (2.5 eq),
159, 95
solvent, 50-65°, 15-24 h OMe
Cr(CO)3
EX
Solvent
Base
TBSOTf
CH2Cl2
2,6-lutidine
(72)
TIPSOTf
CH2Cl2
2,6-lutidine
(76)
AcBr
THF
(i-Pr)2NEt
(55)
OE CN
1. Solvent, 50° 1.5 eq
Cr(CO)5 OMe 0.05 M
159, 95
2. EX (1.5 eq), base (2.5 eq), rt, 6-12 h OMe
Cr(CO)3
Solvent
EX
THF
TBSCl
Et3N
(65)
CH2Cl2
TIPSOTf
2,6-lutidine
(72)
THF
Ac2O
Et3N
(31)
Base
OTBS TMS
CN
1. THF, 50° Cr(CO)5
1.5 eq
2. TBSCl (1.5 eq), Et3N (2.5 eq), rt, 6-12 h
OMe 0.05 M
(52) TMS OMe
95
Cr(CO)3
OTBS CN
Cr(CO)5
TBS 2 eq
CH2Cl2 or THF, OMe 0.05 M
(68-69)
45-65°, 11-24 h OMe
110
Cr(CO)3 OH
OTBS
TBS Cr(CO)5
TBS
159, 95,
4 CN
THF, 45°, 24 h
OMe OMe
4
(<5) +
Cr(CO)3
OMe
CN
(43)
95
Cr(CO)3
407
OTBS TBS
CN Cr(CO)5
1.5 eq
2,3-Dimethyl-
(68)
butadiene (50 eq), OMe 0.07 M
C8
THF, 50°, 6 d
OMe O
Cl n-C6H13
95
Cr(CO)3
C6H11-n
1. Silica gel, 80°
OEt
O
2. CAN
Cr(CO)5
404
(52)
404
O O
Cl
C6H11-n
1. Silica gel, 80°
OEt
O
(31) O
2. CAN
O
Cr(CO)5
O
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C8
Conditions
Product(s) and Yield(s) (%)
SPh n-C6H13
C6H11-n
OEt
O
Refs.
O I (9)
1. Silica gel, 80° 2. CAN
Cr(CO)5
91
O O
PhS Cr(CO)4
O
1. Silica gel, 80°
I (18)
91
2. CAN
OEt
TBSO
Bu-t
Cr(CO)5
t-Bu
(i-Pr)2NEt, TBSCl,
408
1.9 eq
OMe 0.05 M
CH2Cl2, 60°, 12-24 h
(79) 55:45 mixture of isomers
88
(CO)3Cr OMe TBSO
TBS
Cr(CO)5 CH2Cl2, 65°, 19 h
(40)
110
OMe 2 eq
0.05 M
(CO)3Cr OMe
Me2N
Cr(CO)5 O OEt
2 eq
1. Pyridine, 80°, 60 h 2. H2O
(40)
405
Me2N
0.05 M R2N R2N
Ph NR2
Cr(CO)5 RhCl3•3H2O (2 mol%),
1.5 eq Ph 0.25 M
OEt
THF/MeOH (4:1), 20°
NMe2 OEt
(72)
N-morpholino (73)
194
N-morph Ph
N-morph (CO)5Cr
1.5 eq
Pr-i OEt
THF, 60°, 12 h
(26)
Pr-i
Ph
193
OEt O Ph
Cr(CO)5 Ph OMe
THF
(55)
2. Air
MeCN
(81)
0.1 M
1.5 eq
Solvent
1. Solvent, 45-55°, 24 h
61
OMe O Ph
4 eq
OEt
O
Medium
1. Medium, 70° O
2. CAN
Cr(CO)5
Silica gel
(2)
THF
(2)
91
O
409
OH Ph OMe
1.5 eq
1. THF, 45°, 24 h
(76)
69
2. FeCl3-DMF
Cr(CO)5 0.3 M
OMe NMe2
NMe2 Ph 3.5-7 eq
(2)
THF, 52°, 14 h Cr(CO)5
EtO
411
OEt
0.04 M O Ph 2 eq
1. THF, 50°, 9 h
OMe
O
2. CAN
(60)
146
O
Cr(CO)5
O
0.04 M
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C8
Refs.
O Ph
1. (n-Bu)2O, 130°, 300 s, OMe
Ph 2 eq
microwave
c-Pr 3.5-7 eq
NMe2
192
I (62)
411
O NMe2
c-Pr
EtO
THF, 52°, 14 h Cr(CO)5
(75)
2. CAN
0.05 M Cr(CO)5
Ph
0.04 M
OEt
c-Pr NMe2 3.5-7 eq
THF, 52°, 14 h Cr(CO)4
410
EtO
I (72)
i-Pr
i-Pr NMe2
3.5-7 eq
THF, 52°, 14 h Cr(CO)4 EtO t-Bu
3.5-7 eq
411
0.04 M NMe2
Ph
(27)
0.04 M
OEt
NMe2
t-Bu
EtO
411
THF, 52°, 14 h to 7 d
Ph
OEt
Ph
NMe2 (0)
+
(52)
0.04 M Cr(CO)5
OEt
(CO)5Cr Ph
R 3-6 eq
EtO
EtO Me2N
Ph R
Ph
R
Ph
EtO
TMS
Ph R R
Ph
+
THF, 55°, 4 d R
NMe2
422, 423 R
Ph I
411, 413
Bu-t
O
NMe2 Ph
R
I + II
I:II
H
(62)
1.8:1
D
(64)
1.8:1
II
O
O Ph
OMe
1.5 eq
(3)
OMe
OMe
OMe
O
H
Ph
THF, 55°, 16 h
(21) 2.5:1 mixture of isomers O
Cr(CO)5
H
1.5 eq
O
TBS
Cr(CO)5
Ph
Ph
1. THF, 65°, 17 h 0.02 M OMe
424
OMe O
TBS
61
2. Air
Cr(CO)5 0.1 M
O
Ph (55) +
1. THF, 45°, 24 h
+
(<5)
(54)
110
2. CAN O
O
411
OTBS Ph
Cr(CO)5
TBS 1.5 eq
CH2Cl2, 65°, 19 h
(44)
110
OMe 0.05 M
(CO)3Cr
OMe
(CO)5Cr R1 2.5 eq
Ph
Cr(CO)5 THF, 70°, 12 h
NHR2 OMe
R1
0.1 M
(CO)5Cr
R2
Ph
Me
(34)
Ph
Bn
(19)
n-Bu Bn
(57)
R THF, 52°, 7 d
OEt 0.05 M
410
OEt
Ph
R
8 eq
N R2
R1
O
OEt
OEt
Ph
OEt
(27)
NMe2
(51)
413
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
C8
Carbene Complex
Conditions Ph
OEt
(CO)5Cr
Product(s) and Yield(s) (%)
Ph
THF, 52°, 7 d OEt 0.05 M NMe 2
8 eq
3 eq Pr-n
(41)
413
Ph O THF/MeCN (9:1),
(CO)5Cr
OEt
O
N-morph
OEt
Refs.
OEt
65°, 15 h
N-morph
Ph
(97)
415
Et
0.05 M OEt n-Pr 2 eq
N
n-Pr MeCN, 80°, 8 h
412
EtO
(95)
0.05 M
(CO)5Cr
OEt
OEt
Ph
THF, 50°, 20 h
Cr(CO)5
(33)
240
EtO O
Y
Ph OR
O
394
Pr-c O
Pr-c
8 eq
N
Ph
1. Medium, 70-80°
Cr(CO)5
2. CAN
91 O
I O
R
Y
Medium
Et
SPh
silica gel
Et
SPh
THF
(0)
Et
SO2Ph
silica gel
(47)
Me
SO2Ph
silica gel
(69)
(21)
SPh 8 eq
Cr(CO)4
O
1. Medium, 70-80°, 2. CAN
OEt
2 eq
1. Pyridine, 80°, 68 h
OEt Me2N 0.05 M
Cr(CO)5
I
silica gel
(68)
THF
(45)
O
91
(88)
Me2N
Ph
Ph
NMe2
405
OEt
Ph
Ph
EtO
(0) +
THF, 52°, 14 h to 7 d 0.04 M
Cr(CO)5
Ph
411, 413
(24) O
OEt
NMe2
Ph
413
1.5 eq
Medium
2. H2O
NMe2
Ph 3.5-7 eq
I
Ph
Ph
NMe2
Ph
EtO
(73)
RhCl3•3H2O (2 mol%), 0.25 M
Cr(CO)5
THF/MeOH (4:1), 20°
194
OEt
H O 3 eq
(71)
THF, reflux OMe
O
Ph
0.07 M
(CO)5Cr
OEt 1.5 eq
O MeO
morph-N
Ph Pr-i
(CO)5Cr
420
1.2:1 mixture of isomers
THF, 60°, 12 h
Ph
Ph
Pr-i
N-morph
(34)
193
OEt
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C8
Conditions
Product(s) and Yield(s) (%)
OBn BnO
R
Ph
BnO 1. Silica gel, 80°
OEt
O
Ph O O
OAc
1. Silica gel, 80° 2. Pyridine N-oxide, CH2Cl2, 20°
Cr(CO)5
(28) O
N-morph
TBS
414
THF/MeCN (9:1), (CO)5Cr
N-morph
TBS
(72)
415
65°, 15 h OEt
0.05 M O OEt 3 eq
91
O
O OEt 3 eq
124
O
OMe
O
(19)
Cl (48)
Cr(CO)5 SO2Ph
AcO
R H
BnO
2. CAN
OBn
Refs.
OBn O
N-morph OTBS
(CO)5Cr
4
THF/MeCN (9:1),
N-morph
TBS 3
65°, 15 h
0.05 M
(69)
OTBS
415
OEt
O O O
O NMe2
2-4 eq
Pyridine, 80°, 4 d
O NMe2 (42)
TBS
O +
NMe2 (6)
EtO Cr(CO)5 0.05 M
OEt
TBS
OEt
395
O OEt
R
3 eq (CO)5Cr
N-morph
THF/H2O (99:1),
R R
80°, 12-20 h
N-morph
C9
Me2N
O
TBS
n-Pr
(62)
Ph
(48)
414
O OEt
1. Pyridine, 80°, 60 h 2. H2O
405
(26) Me2N
Cr(CO)5 0.05 M
2 eq
TBSO Cr(CO)5
TBS
CH2Cl2, 65°, 20 h
(57)
OMe
415
I 1.5 eq
110
I
0.05 M
(CO)3Cr
OMe PMP
PMP EtO
Cr(CO)5
TMS PMP
PMP
EtO
PMP
(26) +
THF, 55°, 4 d NMe2 OEt
(11)
NMe2
3-6 eq
422, 423
NMe2
PMP
PMP
H O
TBSO
THF, reflux OMe
O
1.3:1 mixture of isomers
Cr(CO)5 3 eq
420
(59) O OTBS
MeO
0.07 M NMe2
NMe2 EtO
3 eq
Pyridine, 80°, 1.5 h
NMe2 +
(86)
TBSO
Cr(CO)5 0.05 M
(7)
TBSO
OEt
394
OEt
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C9
O i-Pr
Refs.
O
O OMe
THF, 50°, 24 h
Cr(CO)5 0.05 M
1.5 eq
O OMe
OMe OH O Ph
1. THF, 45°, 24 h
(17)
2. I2
Ph 1.5 eq
Cr(CO)5
O
O
OMe
416
OH
THF, 50°, 24 h OMe
O 238 Pr-i MeO
(49)
OH
(8)
O
O OBu-t
O
+
Pr-i
Cr(CO)5 0.05 M
1.5 eq
TMS
O
OH
O
1.5 eq
69
OMe
0.3 M i-Pr
238
(66)
Pr-i
OBu-t OMe
N
(43)
1. THF, 60°, 42 h 2. Air
Boc Cr(CO)5 0.04 M
121
N Boc
OMe
OMe
OMe (70)
THF, reflux, 6 h Cr(CO)5
Pr-n
Pr-n TMS
E,E is major
OMe
OMe Cr(CO)5
155
5.1:1:1 mixture of isomers;
(72)
THF, reflux, 6 h Pr-n TMS
155
11.5:4.2:1 mixture of isomers; E,E is major
OMe O
OMe
O
Pr-n
Cr(CO)5
TMS
0.01 M
C10
Cr(CO)5
1.9 eq
Ph
(i-Pr)2NEt, TBSCl,
(74) 55:45 mixture of isomers
CH2Cl2, 60°, 12-24 h
OMe 0.05 M
88
(CO)3Cr OMe Ar OEt
Ar
EtO
NMe2
Ar
Ar
(CO)5Cr
EtO
Ar
(30) +
THF, 55°, 4 d
3-6 eq
155
E,E is major
TBSO Ph
(79) 5.25:1 mixture of isomers;
THF, reflux, 6 h
TMS
(18)
NMe2 Ar
Ar = 3,5-Me2C6H3
422, 423
NMe2 Ar
417 NMe2 OEt
1. Pyridine, 80°, 52 h 2. H2O
EtO
405
(50) Me2N
0.05 M
2 eq
O
Cr(CO)5
OEt OMe O
OMe Ph 1.1 eq
(80)
Dioxane, reflux
(CO)5Cr
51
0.03 M O
1. THF, reflux 2. TBAF (1 eq), THF, 20°
TBSO OEt
3. Ph3P, DEAD, THF, 20°
Cr(CO)5
(≥9)
289
4. Photolysis, air, OEt
benzene, 20°
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C10
Conditions
Product(s) and Yield(s) (%) O
1. THF, reflux OTBS
2. TBAF (1 eq), THF, 20°
H
OEt Cr(CO)5
3. Ph3P, DEAD, THF, 20°
H
( 7) OEt TBSO
TBSO
OTBS
OTBS
Cr(CO)5
OTBS
(i-Pr)2NEt, TBSCl, OR 0.05 M
88
+
CH2Cl2, 60°, 14 h
I
(CO)3Cr OR
418
I + II
I:II
Me
(70)
91:9
i-Pr
(80)
91:9
Cr(CO)5
TBSO
OTBS
(i-Pr) 2NEt, TBSCl,
OTBS
+
CH2Cl2, 60°, 14 h
OMe 0.05 M
II
(CO)3Cr OR
R
TBSO 1.9 eq
289
4. Photolysis, air, benzene, 20°
1.9 eq
Refs.
(CO)3Cr OMe
I
88 (CO)3Cr OMe
II
I + II (41), I:II = 57:43 TBSO OMe
1.9 eq
Cr(CO)5 0.05 M
OTBS
TBSO
OTBS
+
(i-Pr) 2NEt, TBSCl, CH2Cl2, 60°, 14 h (CO)3Cr OMe
I
88 (CO)3Cr OMe
I + II (87), I:II = 72:28
II
OH
t-Bu
OH
OTBS
t-Bu OMe
1.9 eq
(i-Pr) 2NEt, TBSCl, 0.05 M
Cr(CO)5
OTBS
t-Bu +
CH2Cl2, 60°, 14 h
I
(CO)3Cr OMe
88 II
(CO)3Cr OMe
I + II (74), I:II = 91:9 O
Ph OMe
1.3 eq
Additive (3 eq),
OTBS
Ph
II
OMe
OMe
Additive
I + II
I:II
none
(73)
82:18
(n-Bu)3P
(49)
66:34
O
419
O
OEt
OMe OEt
Cr(CO)5
1.5 eq
THF, 50°, 24 h 0.05 M
238
(68)
Pr-i OMe O
i-Pr
111
I
O i-Pr
OTBS
+
heptane, 90°, 18 h
Cr(CO)5
O
Ph
O OMe
O OMe
THF, 50°, 24 h
Cr(CO)5
1.5 eq
OMe
C11
O
NMe2 Pr-n
1. Pyridine, 80°, 64 h
EtO 0.05 M
2 eq
238
(62)
Pr-i
0.05 M
OMe
(87)
405
Me2N
2. H2O
Cr(CO)5
Pr-n
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C11 EtO
Ar 3 eq
THF, 60°, 7 d
Me2N
Ar = 2,4,6-Me3C6H2
TBSO
Ar
OTBS
R
NMe2
(22)
R
NMe2
421
NMe2
R Pyridine, 80°, 1.5 h
EtO
+
(77)
0.05 M
(8)
R OEt R = (CH2)3OTBS
Cr(CO)5
3 eq
Cr(CO)3 TMS
N Me
TMS
3
OH OMe
OCD3
420
OMe
OCD3
+
Benzene, 45°, 48 h
Cr(CO)5 0.05 M
394
OEt
OH
2 eq
Refs.
OEt
Cr(CO)5
52 I
OCD3
OCH3
II
I + II (77), I:II = 1:1; E:Z I = 1:3, E:Z II 1:3 OMe OH
OMe OMe O
O
1. THF, 45°
O
O
(39)
Cr(CO)5
OMe O 1.1 eq
O 0.1 M
16
2. FeCl3-DMF
1. Solvent, 45-50°, 18 h OMe Cr(CO)5
2. FeCl3-DMF
O
O
Solvent THF MeCN
OMe OH
O
OMe (72-76) (69)
O
278, 12
OMe
OMe 1. 2-TMSO-1,3-butadiene
(CO)5Cr
OH
O
(15 eq), THF, 50°, 72 h
1.5 eq
O
O
O
2. Me2C(CH2OH)2, TMSCl
112
(23)
TMS
0.03 M
OMe OH
Cl
MeO2C
OEt
O
CO2Me
Silica gel, 80°
Cr(CO)5
(40)
MeO2C CO2Me
O
404
OEt O CO2Me
Cl
O
n
OEt
O
421
MeO2C
CO2Me
1. Silica gel, 80° 2. DBU, THF
Cr(CO)5
n
n
O
1
(38)
2
(48)
404
OEt R OEt
Pyridine, 80°, 1.5 h
Br MeO2C
CO2Me
NMe2
(CO)5Cr
3 eq
NMe2
n-Pr
Br MeO2C
CO2Me
1-Ad OEt 1-Ad
O
O
Pr-i
Pr-i
Pyridine, 80°, 2 d (CO)5Cr
2 eq
NMe2
N Me
0.05 M
(69)
394
(CH2)3OTBS (51)
OEt
0.05 M
C12
R
R
+
O
1-Ad Pr-i
421
OEt (19)
(50)
OTIPS SPh OMe
PhS
Cr(CO)5 0.05 M
TIPSOTf, 2,6-lutidine,
(65)
THF, 50° OMe
95
Cr(CO)3
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C12
O
Cl
n
n
OEt
O
OTs
Refs.
Cr(CO)5
n
1. Silica gel, 80° 2. Cs2CO3, DMF
1 (25)
O
404
2 (26) OEt O
SO2Ph
1. Silica gel, 80°
OEt
O
Cr(CO)5
2. Pyridine N-oxide, CH2Cl2, 20°
(26)
91
O
2. Cs2CO3, DMF, 20°
OEt O
Ph S
422
OTs 8 eq
O
Cr(CO)4
(49)
1. Silica gel, 80° 2. Pyridine N-oxide
91
O
OEt
O OTBS
TBS
SO2Ph Cr(CO)5
SO2Ph
OMe 0.07 M
1.5 eq
O 1.2 eq
butadiene (50 eq), OMe
THF, 50°, 4 d
TMS
OMe
OAc
Cr(CO)5 0.05 M
1. THF, 55°, 18 h O
2. Ac2O, pyr, DMAP, CH2Cl2, rt, 16-36 h
TMS OMe
95
Cr(CO)3
OAc
OAc OAc
(74)
2,3-Dimethyl-
OAc (59)
295
OAc
O 1.2 eq
OMe
TMS
2. CAN
Cr(CO)5
OAc
O
1. THF, 55°, 18 h
(61)
295
TMS
0.05 M
O O
CO2Et CO2Et NHAc
OMe
O
CO2Et CO2Et
1. THF, 45°, 24 h
69
O
0.3 M
1.5 eq
(71)
NHAc
O
2. CAN
Cr(CO)5
O
Fe
423
OMe
1. THF, 65°, 2 d
Cr(CO)5 0.06 M
2. PbO2, CH2Cl2
O
1 eq
(55)
Fe O O
Ph
Ph OMe
1 eq
1. THF, 65°, 2 d
Cr(CO)5
92
O TBSO
OSiMe2R
(62)
Fe
2. PbO2, CH2Cl2
0.06 M
TBSO
OSiMe2R
(i-Pr)2NEt, TBSCl,
OMe Cr(CO)5
OSiMe2R
+
CH2Cl2, 60°, 14 h 1.9 eq
92
O
(CO)3Cr OMe I
88
I + II
(CO)3Cr OMe II I:II
Ph
(40)
85:15
C6F5
(32)
62:38
PMP
(56)
88:12
0.05 M R
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C13
TBSO
OTIPS
TBSO
Refs. OTIPS
OTIPS OMe Cr(CO)5
1.9 eq
+
(i-Pr)2NEt, TBSCl, CH2Cl2, 60°, 14 h
I
(CO)3Cr OMe
0.05 M
88
(CO)3Cr OMe
II
I + II (87), I:II = 95:5 O OEt Br
OTBS
(CO)5Cr
OTBS 3 eq
THF/MeCN (9:1), 80°, 1.5 h
4
Br
3
OTBS
424
MEMO O
(78)
415
OTBS
OEt
0.05 M
O
MeO
N-morph
N-morph
OMe
O
O
OMe
1. CH2Cl2, 50°
(65)
95
2. MEMCl, (i-Pr)2NEt, rt
Cr(CO)5
MeO Cr(CO)3 O O
O OBu-t
Pr-i OMe
t-BuO 1.5 eq
THF, 50°, 24 h
O Pr-n
Br EtO2C 3 eq
CO2Et
238
OMe
OEt (CO)5Cr
(70)
Pr-i
Cr(CO)5 0.05 M
N-morph
THF (1% H2O), 80°, 7 h
O Pr-n
Br EtO2C
CO2Et
N-morph
(26)
414
Me2N
NMe2
R
R OEt
2-4 eq
Pyridine, 80°, 3 d
0.05 M Cr(CO) 5
(48)
Br EtO2C
CO2Et
395
OEt
O
R = (CH2)2
C14
O TMS
Ar
NMe2
EtO
OEt
Ar 3 eq Ar = 4-PhC6H4
Ar
THF, 55°, 4 d
395, 423
(34) NMe2
Cr(CO)5
4.5:1 mixture of isomers
Ar OTBS
(n-Bu)3Sn
OMe
TMS
1.5 eq
0.07 M
425
Me2N TMS
MeO2C CO2Me 3 eq CO2Et
TMS (CO)3Cr
rt, 16 h
Me2N
(27) TMS (CO)3Cr
OMe
Pr-n OEt
+
(40) Sn(Bu-n)3
2. TBSOTf, Et3N,
Cr(CO)5
72
OMe
Pr-n
Pyridine, 80°, 1.5 h
(81)
394
MeO2C CO2Me
TMS
0.05 M Cr(CO) 5
OEt OH
Z
Z
3
OMe
Y
0.9 eq
OTBS
1. THF, 50°, 22 h
3
Benzene, 70°, 2 h Y
Cr(CO)5 0.003 M Y Z
I
II
O
O
(38)
(3)
O
CH2
(41)
(3)
CH2
CH2
(53)
(3)
+
385
H
I
OMe
CO2Et
OMe Y
CO2Et
Z II
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C14
Refs.
OH CO2Et 3
0.9 eq C15 OTBS Ph
OMe
TMS
Cr(CO)5
1.9 eq
OMe TBSO OTBS Ph
(i-Pr)2NEt, TBSCl, CH2Cl2, 60°, 14 h
I
(CO)3Cr OMe
0.05 M
TIPSO
426
1.9 eq
(46)
385
TBSO
OTBS Ph
+
88
(CO)3Cr OMe
II
I + II (81), I:II = 71:29
Pr-n
OMe
(i-Pr)2NEt, TIPSCl,
Cr(CO)5
CH2Cl2, 60°, 14 h
0.05 M
TIPSO
OTIPS
OTIPS Pr-n
CO2Et
TMS
Cr(CO)5 0.003 M
OMe
3
Benzene, 70°, 2 h
I
(CO)3Cr OMe
OTIPS Pr-n
+
88 II
(CO)3Cr OMe
I + II (68), I:II = 93:7 MeO
OMe 1. Dioxane, 85° O
OMe Cr(CO)5
Ph
2. MeO2CC CCO2Me,
CO2Me
Ph
CO2Me (72) OH O
O
CO2Me
+
O
dioxane, 85°, 1-2 h
408
O CO2Me Ph
(9)
Solvent OMe O OMe NEt2
Cr(CO)5
1. Solvent, 45°
O
2. Iodine OMe
NEt2 OMe
THF
(17)
MeCN
(30)
278
C17 O
Me2N OEt 2 eq
Pr-n
1. Pyridine, 80°, 60 h 2. H2O
405
(15)
Me2N
Cr(CO)5 0.05 M
Pr-n OR R
OMe Cr(CO)5 0.05 M
SPh OMe 1.3 eq
ROTf, 2,6-lutidine, CH2Cl2, 50-65°, 15-24 h
(76)
TIPS
(77)
OAc
OMe R
OMe
427
(67)
TBSO
OTr
CH2Cl2, 60°, 12-24 h
I
(CO)3Cr OMe
0.05 M
OTr
+
(i-Pr)2NEt, TBSCl,
Cr(CO)5
1.9 eq
OH
OMe TBSO
OMe
139
R
C23 OTr
R=
MeCN, 55°, 24 h
Cr(CO)5 0.12 M
OMe 0.5 eq
159
SPh OMe
(CO)3Cr OMe
OAc
TBS
88 II
(CO)3Cr OMe
I + II (89), I:II = 55:45 TBSO OMe
1.9 eq
OTr
TBSO
(i-Pr)2NEt, TBSCl,
Cr(CO)5
88
+
CH2Cl2, 60°, 12 h
I
(CO)3Cr OMe
0.05 M
OTr
II
(CO)3Cr OMe
I + II (68), I:II ≥ 96:4
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
C23
Conditions
Product(s) and Yield(s) (%) TBSO
TBS
TBSO
OTr
Refs. OTr
OTr OMe
OMe
428
R1
+
R1 Heptane, additive (3 eq),
R2 +
OMe E:Z
Additive
Temp
I + II
I:II
Et
≥98:2
none
90°
(73)
92:8
Et
Me
≤2:98
none
55°
(66)
91:9
Me
Ph
≥98:2
none
90°
(72)
90:10
Me
Ph
≥98:2
(n-Bu)3P
90°
(68)
80:20
Me
Ph
60:40
none
90°
(65)
68:32
Cr(CO)5 0.05 M
1. THF, 55°, 22 h CH2Cl2, rt, 16-24 h
O TMS OMe
111 II
OBn
OAc 2. Ac2O, pyr, DMAP,
OTr
OMe
Me
OMe
O
R1
I
0.01 M R2 R1
OBn
1.2 eq
88 II
(CO)3Cr OMe
OTr
R2
Cr(CO)5
O
O
16-18 h
TMS
OTr
I + II (88), I:II = 58:42
OMe
OBn
TBSO
I
(CO)3Cr OMe
0.05 M
1.3 eq
OTr
CH2Cl2, 60°, 14 h
Cr(CO)5
R2
II
(CO)3Cr OMe (CO)3Cr OMe I + II (65), I:II = 69:31 TBSO
1.9 eq
88
I
Cr(CO)5 0.05 M
1.9 eq
+
CH2Cl2, 60°, 14 h
OBn (53)
295
TIPSO
C25
Pr-n 1.9 eq
TIPSO
OTr
OTr
Pr-n
OMe
TIPSCl, (i-Pr)2NEt,
Cr(CO)5
CH2Cl2, 60°, 14 h
Pr-n
+
I
(CO)3Cr OMe
0.05 M
OTr
(CO)3Cr OMe
+
88
II
I + II (72), I:II = ≥ 96:4 OH
OTr Pr-n
(13)
III
OMe C29 O
OTr
OTr O
429
OMe
+
See table.
Cr(CO)5
OTr 357
OMe
0.01 M
OMe II
I Solvent
Temp
I + II
I:II
MeCN
55°
(88)
98:2
MeCN
90°
(72)
95:5
heptane
90°
(60)
94:6
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OBn
C36 OBn
BnO OH
Ph OBn
BnO
R O 2 eq
t-BuOMe, 60°, 26 h
Ph
O
OBn Cr(CO)5 0.15 M
R
R O O
(88) O
O
O O O
430
O
(85)
O
O
O O O O
O
O
(76) O
O
O O
O
O
(67)
O O
O O O O
O
O
OBn
(80)
OBn
425
C36-56
OBn BnO OAc
OBn OBn
BnO
OMe
TMS OBn
O
Cr(CO)5
1. THF, 55°, 16 h 2. Ac2O, pyr, DMAP,
OBn
O
(54)
295
CH2Cl2, rt, 16-24 h TMS
0.27 M
1.1 eq
OBn
OMe
C49 R
O
Ph Ph OMe R
Cr(CO)5
1. THF, 60°, 2 d
375, 376
(71)
375, 376
O
0.008 M
1.25 eq
(73)
2. PbO2, CH2Cl2
431 O
Ph Ph OMe Cr(CO)5
R
2. PbO2, CH2Cl2 O
0.008 M
1.25 eq
R
1. THF, 60°, 2 d
p-Tol
N
N
N
N
R=
Tol-p
p-Tol
TABLE 6. ALKENYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
C52
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
R Ph
Ph N
O
N
R
R N
N
OMe Cr(CO)5
1. THF, 60°, 2 d
376
O
2. DDQ, MeOH, reflux, 1 h
0.04 M R 0.8 eq
O
O
N
N
N
N
Ph
R=
432
Ph
O
O
O O
Ph (68)
C56 OTBDPS TBDPSO OTBDPS O
OMe (CO)5Cr
OTBDPS
O
295
CH2Cl2, rt, 16-24 h
TMS
1.1 eq
1. THF, 55°, 22 h 2. Ac2O, pyr, DMAP,
OTBDPS
OTBDPS
OAc
TMS
0.05 M
OMe (32) 7:1 mixture of β:α anomers OTBDPS
TBDPSO OTBDPS O
433
1.05 eq
OMe (CO)5Cr
OTBDPS TMS 0.05 M
OTBDPS
OAc
1. THF, 55°, 24 h 2. Ac2O, pyr, DMAP,
O
CH2Cl2, rt, 16-24 h TMS OMe
OTBDPS
(56)
295
TABLE 7. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C4
Refs.
OAc MeO
N 4 eq
OMe
Ac2O (1 eq), Et3N (1 eq), N
THF, 70°, 6 h
Cr(CO)5
287
(—)
287
OMe
0.1 M
C5
(—) OMe
OAc EtO
N 4 eq 0.1 M
OMe
Ac2O (1 eq), Et3N (1 eq), N
THF, 70°, 6 h
Cr(CO)5
OEt OMe
C6
OH
O
Et
434
Et
Et
OMe
O
2. Air, silica gel
Cr(CO)5 0.08 M
1.5 eq
(82) +
1. THF, 85°, 10 h O
(4)
Et
Et
I OMe MeO
1.5 eq
OMe
O
1. MeOH, 85°, 10 h
+
I (82)
Cr(CO)5 0.08 M
(3)
Et
65
Et
O
MeO2C
2. Air, silica gel
O
MeO
65
Et
O Et
1.6 eq
OMe
O
1. THF, 75°, 18 h 2. CAN
Cr(CO)5 0.17 M O
1. THF, 75°, 18 h
114
Et O
OMe
1.6 eq
(85) O I
I (77)
114
2. CAN
Cr(CO)5 0.17 M
O
OAc
1.0 eq
CH2Cl2, –20° to rt, 1 h
O
(3)
O
0.22 M Cr(CO)5
114
OAc Et
2-4 eq
OMe
N
Ac2O (2 eq), Et3N (2 eq),
Me Cr(CO)5 0.03 M
THF, 65°, 3 h
N Me
H N N
(45)
237
Et
1. THF, 45°, 18 h
OMe
116, 360
OMe O
N N
1.5 eq
(42-48) Et
Et
2. CAN 0.1 M Cr(CO)5
O O Et
435
1.5-2.5 eq
N Me
1. Solvent, 50°, 24 h
OMe
Me
Cr(CO)5 CC (M)
Cr(CO)5 OMe N Me
I
O
0.2
THF
(81)
0.01
hexane
(79)
0.2
benzene
(79)
0.01
MeCN
(29)
1. Hexane, 80°, 9-20 h
I (78)
62
2. CAN 0.01 M Me
N
1. Hexane, 50°, 24 h OMe
0.01 M
Et
Solvent
Me 1.1 eq
62 N
2. CAN
Cr(CO)5
O Et
N
(76)
2. Air
Et OMe
62
TABLE 7. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C6
O
Refs. O
Et Et
Et
OMe
N
1.1 eq
Me 0.01 M
N
2. Air
Me
Cr(CO)5
Et
(75) + Et
1. Hexane, 50°, 24 h
(20) 62 Et OMe Cr(CO)4
N Me
OMe OH CO2Me
MeO2C
CO2Me
OMe
N Me
2.4 eq
(36)
THF, 65°, 5 h N
Cr(CO)5
Me
0.04 M
116
CO2Me OMe OAc
OAc TMS
TMS
OMe
N
436
4 eq
Cr(CO)5
Ac2O (1 eq), Et3N (1 eq),
+
(32) N
THF, 70°, 6 h
N
0.1 M
OMe OAc
C7
(tr) TMS
287
(20) Bu-n
116
OMe OAc
Bu-n n-Bu
OMe
N
Me Cr(CO)5 0.04 M
2.4 eq
Ac2O (1.5 eq), Et3N (1 eq), THF, 65°, 5 h
+
(31) N
N
Me
Me
OMe O
OMe
Pr-n EtO
Pr-n
OMe
N
3.2 eq
1. Hexane, 50°, 24 h N
2. Air
Me 0.01 M
Me
Cr(CO)5
(49)
62
(78)
62
OEt OMe O TMS
EtO
TMS
OMe
N
2.5 eq
N
2. CAN
Me 0.2 M
H N
1. THF, 50°, 24 h OEt
Me
Cr(CO)5
O
O 1. THF, 45°, 48 h
N
1.5 eq
OMe
N
N (16)
2. CF3CO2H, 0.5 h
Ph
Cr(CO)5
Ph
O
0.1 M
C8-9
R
2
R
Fe
R2
+
R1
Fe
Fe
R2
O 426
Alkyne (eq)
II
I
II (15)
n-Pr n-Pr
1.5
(0)
n-Pr n-Pr
2.5
(18) (21)
Ph
Me
1.5
(13)
Ph
Me
2.5
(29) (10)
437
C8
R1
R2
I
0.05 M R1
O
OMe Dioxane, 100°, 5 h
OMe
OMe
O
Cr(CO)5 1
237
OEt
3. CAN
(0)
O Y
Y
Y OMe
1.5 eq
0.2 M
Cr(CO)5
1. THF, 66°, 5 h
S
2. CAN
NMe (28)
(56)
135
O O
C9
Ph
1. (n-Bu)2O, 130°, 300 s, Ph
OMe
O 2 eq
microwave 2. CAN
Cr(CO)5 0.05 M
(64)
192
O O O
O B O 3 eq
N Me 0.05 M
OMe
1. THF, 45°, 16 h 2. CAN
Cr(CO)5
N Me
B O
O
O
(64)
75
TABLE 7. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C10
OH
Refs. Bu-n
Bu-n n-Bu
Bu-n
O
1.5 eq
OMe Cr(CO)5
Bu-n
+
1. DMF, 120°, 5 h O
2. 1 N HCl, MeOH
O
(37)
OMe
427
O
Bu-n
(34)
Bu-t O
Bu-t
OMe Cr(CO)5
1.5 eq
1. DMF, 120°, 5 h
427
(72) O
2. 1 N HCl, MeOH
O
C11
OH
Ph Ph
O
438
Ph
OMe Cr(CO)5
1.5 eq
+
1. DMF, 120°, 5 h
427
O
2. 1 N HCl, MeOH
O O (36) trans:cis = 2.6:1 Ph
(14)
OMe OH
C12
Ph Ph
Bu-n
O
1.5 eq
OMe Cr(CO)5
Bu-n
+
1. DMF, 120°, 5 h O
2. 1 N HCl, MeOH
O (51) trans:cis = 1:2.6
(15)
OMe
427
O
Bu-n OH Ph
O
OMe Cr(CO)5
1. THF, 65°
427
(51) O
2. 1 N HCl, MeOH
Bu-n OMe Bu-t
O O
O Bu-t
OMe Cr(CO)5
1.5 eq
O
1. DMF, 125°, 5 h
427
(60)
O
2. 1 N HCl, MeOH
O
OAc OTBS x
TBSO OEt 1.5 eq
O
OMe
Cr(CO)5 0.03 M
Ac2O (2 eq), Et3N (x eq), O
THF, 65°, 10 h
OEt OMe OH
2
(43)
0
(36)
115, 264
OAc OTBS
OTBS
Ac2O (x eq), Et3N (y eq), N
OMe
Me Cr(CO)5 0.03 M
+
AcOH (z eq), N
THF, 65°, 5-10 h
115, 116 N
OEt
Me
Me
I I
OMe
y
z
1.1
0
0
(26) (41)
1.1
1.1
0
(0)
(46)
2.4
1.5
1.5
0
(0)
(62)
1.5
0
0
1
(19) (—)
Alkyne (eq)
x
1.5 1.5
439
OMe
N Me
OMe Cr(CO)5
Et3N (x eq),
O
THF, 65°, 4-5 h
OH
MeO
0.03 M
Me N x
N
Me
II
OMe
II
EtO 1.5 eq
OEt
1.0
(13)
0
(68)
115
OEt O
O Bu-n
O B O
Bu-n 3 eq
O
OMe
Cr(CO)5 0.03 M
1. THF, 65°, 16 h
O
O
B
2. CAN
Bu-n (47) +
O
O
(30)
74, 75
O O
OH
C14
Ph Ph
Ph 1.1 eq
O
OMe
Cr(CO)5 0.17 M
(n-Bu)2O, 80°, 2.5 h
(19) O (CO)3Cr OMe
Ph
104
TABLE 7. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) OH
C14
Ph Ph
R Ph
Refs.
Ph
OMe
O
Cr(CO)5
1.5 eq
1. DMF, 120°, 5 h
R
R
+ O
2. 1 N HCl, MeOH
Ph O
I OMe
R
I
H Me
427
O
Ph II
II
cis:trans II
(8) (61)
1.5:1
(9) (56)
1.3:1
O Ph 1.3 eq
OMe
O
Medium
1. Medium, 50-80°, 2-3 h O
2. CAN
Cr(CO)5
Ph
silica gel
(74)
MgSO4
(43)
177, 178
O
440
OH O
Ph
O OMe
1.25 eq
(n-Bu)2O, 70°, 2 h
(62)
104
(28)
104
Ph
Cr(CO)5 0.2 M
(CO)3Cr OMe OH Ph (n-Bu)2O, 80°, 1.5 h
1.3 eq OMe
S
S
Ph
(CO)3Cr OMe
Cr(CO)5 0.18 M
OAc Ph 2-4 eq
OMe
N Me
Cr(CO)5 0.04 M
Ac2O (1-2 eq), Et3N (1-2 eq),
(22-24) N
THF, 65°, 2-24 h
116, 267,
Ph
Me
360
OMe
C14
O Ph Ph
Ph
Ph
N
OMe
1. Toluene, 95°, 15 h
Ph
N
(44)
2 eq
Cr(CO)5
0.1 M H N
O O
N
Ph
N N
1.5 eq
R
1. THF, 45°, 18 h
OMe R
117
Ph
2. Air
Ph
2. CAN Cr(CO)5 0.1 M
R
Me
(41)
237
O
Me
Ph
N OMe
(51)
Ph
O
N 1.5 eq
Me
1. Hexane, 50°, 24 h
(52)
62
Ph
2. CAN
441
Cr(CO)5
O
0.01 M O
Cr(CO)5 1.5 eq
Fe
OMe
(n-Bu)2O, 80°, 4 h
Fe Ph
OMe (45)
Ph Cr(CO)3
428
0.11 M O
Ph
O
Cr(CO)5 Fe
Alkyne (eq)
OMe
0.05 M
+
Dioxane, 100°, 5 h Fe
OMe 426
Fe
OMe Ph I
Ph
I
II
1.5
(38)
(—)
2.5
(43)
(20)
Ph II
TABLE 7. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C14
O
O
Ph O B
Ph
OMe
O
O 3 eq
Cr(CO)5 0.05 M
1. THF, 65°, 16 h
O
B
2. CAN
Ph (35) +
O
(42)
74, 75
O
O
O
Refs.
O
C14-17 O Ph
R
OMe
O
1.2 eq
Benzene, 80°, 12-24 h
•
R
R
(CO)3Cr O
Cr(CO)5
TBS
(36)
TIPS
(62)
134
OMe
C16 AcO TBSO
442
OTBS O O
OEt
OMe
O
Cr(CO)5
1.0 eq
THF, 65°, 72 h
O
N
(28)
264, 115
(38)
115
OEt OMe HO TBSO
Me
O
Ac2O (2 eq), Et3N (2 eq),
0.03 M
1.5 eq
O
OMe
Cr(CO)5 0.03 M
O
Ac2O (1.1 eq), Et3N (1.1 eq), THF, 65°, 8 h
N Me
OEt OMe
O
TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C4
HO
O
O OMe
Y
THF, 65°, 20 h Y
x eq
x
y
Time
O
—
—
20 h (13)
264, 115,
0.03
4 h (39)
116
OMe
yM
C5
Y
NMe 2.4
Cr(CO)5
Refs.
O Pr-n n-Pr
1. THF, 75°, 18 h
OMe
O
2. CAN
1.5 eq
(51) O
Cr(CO)5 0.17 M
114
I O
1. Ultrasound, (n-Bu)2O, OMe
O
443
1.3 eq
rt, 25 min
I (45)
177
I (72)
192
2. CAN
Cr(CO)5 0.1 M
1. Microwave, (n-Bu)2O, OMe
O
2 eq
130°, 300 s 2. CAN
Cr(CO)5 0.05 M
OH Pr-n OMe
Y
x eq
Y
(n-Bu)2O, 70°, 2 h Y
Cr(CO)5
Cr(CO)3
yM
x
y
Temp Time
O 1.1 0.35
70°
S
80°
1.2 0.5
2h
(23)
104
1.5 h (40)
OMe
TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne C5
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
O
H N N
Pr-n
N N
n-Pr
OMe
1.5 eq
0.01
(10)
2. CAN
0.1
(31)
1.0
(27)
Cr(CO)5
xM
x
1. THF, 45°, 18 h O
237
OAc
H N N
Pr-n
N N
1.5 eq
Ac2O (1.5 eq),
OMe
(11)
237
THF, 45°, 36 h Cr(CO)5
OMe
0.1 M
O
O
444
Pr-n 1.1-1.5 eq
1. Hexane, 50°, 24 h N
OMe
Me 0.01 M
Cr(CO)5
2. CAN
+
62
N
N
Me I
Me
Pr-n
Me
O
I + II (68), I:II ≥ 350:1
II
O
N 2 eq
OMe
1. Hexane, 80°, 9-20 h
I + II (73), II:I ≥110:1
62
2. CAN Cr(CO)5 0.1 M O Pr-n 1.1 eq
N
OMe
Me 0.01 M
Cr(CO)5
1. Hexane, 50°, 24 h 2. Air
(85) N Me
OMe
62
Me
O
Me
N
Pr-n
N OMe
1.1-1.5 eq
1. Hexane, 50°, 24 h
62
(48)
2. Air Cr(CO)5
0.1 M
OMe OTBS
OTBS
O Pr-n 1.1 eq
1. Hexane, 55°, 1.5 h N
OMe
Me 0.01 M
Cr(CO)5
(53)
2. Air
Me
OMe
OTBS
1.1 eq
OTBS
O Pr-n
1. Hexane, 55°, 48 h
445
OMe
N Me
242
N
(38)
242
N
2. Air
Me
Cr(CO)5
OMe
0.01 M OH H OMe
O
HO 1.2 eq
Cr(CO)5
1. Solvent, 80°, 14 h
+
I
O
65
OMe II
OMe
Solvent
O
O
O
2. Air
0.1 M
I
(Z)-II (E)-II
THF
(22)
(48)
(0)
MeCN
(32)
(20)
(5)
H
O OMe
S EtO
OH
3
1.5 eq
Cr(CO)5 0.05 M
EtOH (1.5 eq),
CO2Et
S
THF, 60° , 4-6 h
(81) E:Z = 1:2
379
OMe CO2Et
TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) OH
C5
H
O OMe
O EtO
Refs.
O
1.5 eq
Cr(CO)5 0.05 M
OEt
EtOH (x eq), THF, 60-65, 3-20 h
OMe CO2Et OMe I
II I
N
II (E:Z)
(—) (80)
1:1.2
0
(21) (20)
—
446
Cr(CO)5
264, 115
H +
N
OMe
CO2Et
N Me
OMe CO2Et
Me I
0.05 M
379
CO2Et
EtOH (x eq), THF, 60-65°, 3-6 h
Me
II
1.5
O 2-4 eq
CO2Et
O
O
x
OMe
+
II
x
I
1.5 0
II
II (E:Z)
(—) (87) E only
379
(51)
116
(5)
—
C6
MeO
Bu-n n-Bu
Y
OMe Cr(CO)5
Additives (1.1 eq), THF, 60-65°, 6-24 h
Bu-n
Y
OR +
O
OMe
O Bu-n
Y Y
I
II OMe
Alkyne (eq)
Y
Additive
R
I
II
1.5
O
none
H
(33)
(35)
381
2.6
O
none
H
(76)
(—)
360
1.5-2.5
O
Ac2O, Et3N
Ac
(68)
(—)
381, 267,
1.5
S
none
H
(33)
(10)
381
1.5
S
none
H
(44)
(—)
360
1.5
S
Ac2O, Et3N
Ac
(66)
(—)
381, 360
360
OAc Bu-n
1. THF, 85°, 20 h 1.5 eq
OMe
O
2. Ac2O, NaOAc,
O (29)
65
O
THF, 85°, 6 h
Cr(CO)5 0.08 M
O
MeO +
(60)
n-Bu OMe OH
447
Bu-n Cl
3 eq
O
O
Conditions O
1. THF, 53°, conditions
Cl
2. Air, 30 min
O
40 h
(42)
ultrasound, 2 h
(59)
169
Cr(CO)5 0.03 M OAc Bu-n 2.4 eq
OMe
N Me
Cr(CO)5
Ac2O (1.5 eq), Et3N (1 eq),
(34)
116
N
THF, 65°, 2 h
Me
OMe OAc Bu-n
4 eq
OMe
N
Cr(CO)5
Ac2O (1 eq), Et3N (1 eq),
287
(22) N
THF, 70°, 6 h
0.1 M
OMe
TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OAc
C6
Bu-n n-Bu
OMe
N 4 eq 0.1 M
Cr(CO)5
Ac2O (1 eq), Et3N (1 eq),
287
(18) N
THF, 70°, 6 h
OMe O OH O
R MeO2C 1.0-2.1 eq
O
OMe Cr(CO)5
1. Solvent, 78-85°, 12-20 h
114, 65
+
+ O
2. Workup
I
0.08-0.17 M
O
OMe
II OMe
O
MeO
448
O R
+
III R
O MeO R
O MeO
+
O
O R
CO2Me
IV
V
O R = (CH2)2CO2Me
OMe
Solvent
Workup
I
II
III
IV
V
THF
air, SiO2
(15)
(37)
(22)
(—)
(—)
THF
TsOH, benzene, 85°
(—)
(55)
(—)
(—)
(—)
hexane
air, SiO2
(6)
(39)
(15)
(—)
(—)
MeOH
air, SiO2
(47)
(—)
(—)
(24)
(—)
benzene
(n-Bu)3P, acetone
(30)
(—)
(30)
(—)
(—)
MeCN
air, SiO2
(12)
(—)
(—)
(—)
(42)
1. MeOH, 85°, 18 h OMe
1.1 eq
O
CO2Me
OH
O
O
O
2. (n-Bu)3P, acetone,
(51)
O
+
(8)
Cr(CO)5
OMe
OMe
S
O
1. THF, 85°, 10 h 2. Air, SiO2
Cr(CO)5 0.17 M
OMe O
CO2Me
OH 1.5 eq
114
rt, 1 h
+
(5)
114
(37)
S
S OMe
OMe MeO
+
O S
(30)
MeO2C
449
O O 1. MeOH, 85°, 2 h 2. Cl3CCO 2H, benzene,
O
O
114
(35) O
reflux
Cr(CO)5
O
0.1 M O
C8
Ph
1. Microwave, (n-Bu)2O, Ph
OMe
O 2 eq
130°, 300 s
(29)
192
(73)
169
O
2. CAN
Cr(CO)5 0.05 M
O OH Ph
1.2 eq
1. THF, 45°, 36 h
OPh
O
2. Air, 30 min
Cr(CO)5 0.02 M
O OPh
TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C8
Refs.
OAc Ph Ph
OMe
N 2.4 eq
Me H N
Cr(CO)5
Ac2O (2 eq), Et3N (2 eq),
(45) Me
N
OMe O Ph
N N
1.5 eq
OMe R
116
N
THF, 65°, 4 h
R
1. THF, 45°, 18 h
Me
(22)
2. CAN
TMS
(10)
Cr(CO)5
R
237
O
0.1 M
O Ph
450
1. Benzene, 50°, 24 h
2.5 eq
N
OMe
Me 0.2 M
Cr(CO)5
(61)
2. CAN
62
N Me
O O Ph
1. Hexane, 50°, 24 h
1.1 eq
OMe
N Me
2. Air
(80)
62
(0)
192
N Me
Cr(CO)5
OMe
0.01 M C9
O 1. Microwave, (n-Bu)2O, O 2 eq
OMe
Cr(CO)5 0.05 M
130°, 300 s 2. CAN
O O
OH
C10
OBn BnO
Cl O
O 1.2 eq
1. THF, 55°, conditions
O
Conditions
Cl
2. Air, 30 min
O
33 h
(25)
ultrasound, 5 h
(55)
169
Cr(CO)5 0.03 M
C11
O TsO OMe
N
Me
Cr(CO)5
0.01 M
C12 CO2Et
OMe
HO OMe
O
62
N
2. K2CO3, NaI, 80°, 6 h
Me
1.1-1.5 eq
(42)
1. Hexane, 50°, 24 h
CO2Et
Benzene, 70°, 2 h
(37)
385
451
I
O
Cr(CO)5
OMe THF, 100°, 2 h
OMe
O
I (10)
385 O
Cr(CO)5 MeO2C
OMe
O
3. Air, SiO2
O
MeO (23) +
2. (n-Bu)3P, acetone
Cr(CO)5
1.1 eq
SPh
O
1. Toluene, 85°, 18 h
SPh
O (8)
MeO2C
O
114
PhS OMe Boc OH N
O
O OPh
O
N Boc
1. THF, 50-55°, conditions 2. Air, 30 min
Cr(CO)5 0.03-0.05 M
169 O
Conditions
OPh
1.5
21 h
(53)
3.0
ultrasound, 2 h
(59)
Alkyne (eq)
TABLE 8. HETEROARYL(ALKOXY)CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C12
OH
O NHBoc
EtO
1. THF, 45°, 17-36 h 2. Air, 30 min
Cr(CO)5 1.2 -2.0 eq
O OEt
OAr
O
NHBoc
O
ArO II I
II
2-ClC6H4
(34)
(—)
2-MeOC6H4
(26)
(—)
4-IC6H4
(43)
(—)
3-CF3C6H4
(35)
(—)
OMOM
452
OMOM
O
O
1. Benzene, 50°, 17 h OMe
N Me
169
O
OAr I
0.01-0.05 M
O N H 1.5 eq
Boc
N
+
O
Ar
Ph
Refs. OEt
O
N H
2. Air
Ph
(59)
62
N Me
Cr(CO)5
OMe
0.01 M C13
BnO
O
O
O
Et N H
1.5 eq
N Me 0.05 M
OMe
1. Xylenes, 55°, 1.5 h 2. 140°, 1 h
Cr(CO)5
Et N Me
OMe
N H
OBn (61)
242
C14
OH CO2Et 3
OMe
O
Cr(CO)5 0.83 eq
3
Benzene, 70°, 2 h
CO2Et
(52)
O OMe
0.0025 M
H
+
OMe O
CO2Et
(10)
385
453
TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C4 NH2 1.3 eq
MeO
Argon (5 bar), MeCN, 80°, 15 min
Cr(CO)4
OMe H
0.24 M
NHMe
1.3 eq MeO
Argon (5 bar), MeCN, 80°, 15 min
Cr(CO)4
(48)
431
(73)
431
N Cr(CO) 5
N Me Cr(CO)4
MeO
0.24 M H N
Ph
454
5 eq
Benzene, reflux, 12 h
(52)
429
(CO)4Cr O
(CO)3Cr (CO)5Cr
N
Ph THF or cyclohexane,
1.5 eq Ph
Ph
0.33 M H N 3.2 eq
Cr(CO)4
Argon (5 bar),
(51)
N
THF, 70°, 1 h
N Me2 NMe2
NH2 Benzene, 20°, 2 h
(CO)5Cr
1.0 eq
Ph
0.3 M
432
Cr(CO)4
0.08 M
Me2N
235, 236
Ph
N Me2 C5
(48)
Ph
N H
80°, 1-3 h
N
(79)
Et
(CO)5Cr
Et
C6 Et
Cr(CO)5
Et 2 eq
Benzene, 80°, 18 h
NMe2
Et +
Et NMe2
0.25 M
(10)
Et Et +
Et
(10)
(5)
NMe2
EtO2C
Cr(CO)5 N
Et
THF, 60°, 48 h
156, 157
(75)
Et N
0.03 M
Et Ph
NMe2
83
OH
EtO2C 4 eq
430
Ph
Et
Cr(CO)5
3 eq
Et
Solvent, 2.5-5 d
Et +
+
13
NMe2 0.1 M
455
I Solvent
NMe2
O II
Temp
I
II
III
THF
95°
(13)
(46)
(15)
THF
115°
(31)
(22)
(14)
toluene
95°
(2)
(2)
(19)
toluene
115°
(22)
(14)
(22)
5 eq
O
Et
N Me
Ph
III
Et
H N
Ph
Et
Et
Benzene, reflux, 6 h
(71)
429
(CO)4Cr
1.5-2.0 eq
Et
Cr(CO)5
Ph N
O
(CO)3Cr
0.08 M
Et
1. DMF, 120-125°, 5 h 2. 90-95°, 15 h O
(52)
79
TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
Et
C6 Cr(CO)4
Ph Et
1. DMF, 120-125°, 5 h
Et
Et
2. 90-95°, 15 h
N-morph
79
(59)
432
(67)
162, 163
N-morph Et
1.5-2.0 eq H N
Ph
1.2 eq
Et THF, 70°, 1 h
Cr(CO)4
N
N Me2
Cr(CO)4 N Me2 OAc
0.1 M
456 2 eq
N
Bn
2. Ac2O, Et3N, DMAP,
Et
rt, 3.5 h
O
3. FeCl3-DMF, 20 min
OBu-t
0.1 M
Et
1. Toluene, 55°, 4 h
Cr(CO)4
N
Bn
O OBu-t OH
O
Pr-n
Et
N 2 eq
(96)
n-Pr
N
n-Pr
Toluene, 100°
N
p-Tol
p-Tol
Et
Et
Et
+
(17)
Cr(CO)4
Et
Et
(14)
OH
433
p-Tol
0.25 M Et H N
Et
Tol-p
1.2 eq
Toluene, 70°, 1 h
Cr(CO)4
Et
(CO)3Cr
N Me2
(36)
(5) NMe2
OAc
Et p-Tol
Et
Cr(CO)4
R
N
1. Solvent, 55-60°, 2-3 h
O
Et +
2. Ac2O, Et3N, DMAP, rt, 0.5-2 h
OBu-t
R
Solvent
Workup
R
I
II
THF
none
H
(54)
(—)
0.26
toluene
FeCl3-DMF
Bn Et
(11)
(56)
Ph N
Hexane, 85-90°, 24 h
Cr(CO)5
Et
R
457
3 eq
Ph
O II
232
Et R
Hexane, 70-90°, 1-3 d
Cr(CO)5
N
(84)
Ph
N H
0.014 M
N
OBu-t
0.05
Et
R
I
OBu-t
162, 163
Et
O
N
3. Workup
CC (M)
3 eq
432 NH
NMe2
0.09 M
2 eq
Et
+ (CO)3Cr
N
0.014 M
Ph
N H
R
Ph
(97)
Me
(81)
t-Bu
(85)
232
N NH 0.05 M
(n-Bu)2O, 90°, 3 h
(40)
208
(66)
392
Et Et
Cr(CO)5
Cr(CO)3
Et 2.2 eq
DMF, 120°, 3 h
Et
N-morph OMe Cr(CO)5 0.06 M
OMe
N-morph
TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
CO2Me
C6 Cr(CO)4
MeO2C
(CO)4Cr
CO2Me
CO2Me
CH2Cl2, –20°, 24 h N-morph 0.1 M
1 eq
N-morph
Cr(CO)5
RO2C
R CO2Me
THF, 60°, 16 h
N
458
Cr(CO)5
N 0.005 M
hexane, rt, 4-11 h
157
CO2Me (23)
Ph
Photolysis (pyrex),
(81)
(1R,2S,5R)-menthyl (67)
MeO2C
Ph Ph
Et
N
0.03 M
10 eq
54
CO2Me
RO2C
1.2 eq
(73)
189, 190
N
Ph
CO2Me R1
Cr(CO)4
1 eq
CH2Cl2, –20°, 24 h R2
N-morph
CO2Me R1 R2
N-morph
MeO2C
CO2Me
0.1 M O 2 eq
Ph
Cr(CO)4
N Me
R1
(CO)4Cr
CO (30 psi), THF, rt, 25 h
Ph
Ph
(54)
—CH2CH2CH2O—
(95)
CH2OMe
Me
54, 53
(69)
I (90)
Ph
N Me
R2
—CH2CH2CH2—
165
0.03 M Cr(CO)5
O 2 eq
CO (30 psi), THF, rt, 5 d
Ph
N Me
Ph
165
I (78)
0.03 M
1. n-BuLi, THF, –78°, 10 min Cr(CO)5
R
MeO2C
CO2Me
R
Ph
R
2. PhCOCl, –78 to 0°,
2 eq
15 min
NHMe 0.17 M
N Me
3. Alkyne (2 eq),
Ph
(72)
Me
(23)
165
CO (30 psi), rt, 2 d CO2Me
O
(CO)4Cr Cr(CO)5
1 eq
NR2
0.05 M
Photolysis, THF,
NR2 CO2Me
O
–40° to rt, 12 h
NH2
(9)
NHMe
(10)
54
NR2 CO2Me
O
(CO)4Cr
1. Photolysis, THF, –40° Cr(CO)5
1 eq 0.05 M
NMe2
2. Alkyne (1 eq),
CO2Me
O
54
(35)
–40° to rt, 12 h NMe2
459
CO2Me Cr(CO)5
R 1 eq
1. Photolysis, THF, –40°
CO2Me
2. Alkyne (1 eq), N-morph 0.05 M
–40° to rt, 12 h
Et
Ph
3 eq
N 0.014 M
R
Cr(CO)5 R
Hexane
Pr-n 3 eq
0.014 M
(50)
54
Ph Temp
Time
Me
80°
24 h
Ph
70°
2-3 d
N H
Cr(CO)5
Hexane, 80°, 24 h
Ph
II Ph
R I
II
(95)
(≤1)
(98)
(0)
N H
EtO
OEt (73) N H
O
+
I
n-Pr N
(55)
2-furyl
Et
Et
O
C7 Ph
Ph
N-morph R
O
EtO
R
(CO)4Cr
+
Ph
234, 232
R
Pr-n (≤1) N H
234
TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
C7
Product(s) and Yield(s) (%) EtO
EtO
Pr-n
Hexane, 70°, 2-3 d Ph 0.014 M
3 eq
Pr-n
Cr(CO)5
N
Ph
Ph
Benzene, 20°, 2 h Ar
0.3 M
232
NEt2
(CO)5Cr 1 eq
(94)
Ph
N H
NH2 Et2N
Refs.
Ar
N Et
(CO)5Cr Ar
Ph
(81)
4-ClC6H4
(96)
430, 435
NEt2 (CO)4Cr
Cr(CO)5 1 eq
Benzene, 60°, 2 h Ph
MeHN
Me
0.3 M
460
(63)
403
(26)
235, 236
N Ph NEt2
Ph THF or hexanes, Ph
N
Cr(CO)5
80°, 1-3 h
Ph
Ph
N H I
NEt2 Ph 1 eq
THF, 20°, 1 h Ph
N
Ph
+
I (16)
N
+
(33)
434
Cr(CO)5
0.33 M Ph
NEt2 +
(34) Ph
N
Cr(CO)5
NEt2 Ph
(10)
Ph
N
Cr(CO)3
OEt
Et2N Et2N
Ph
4 eq
THF, 80°, 30 min Ph
N
NEt2 O
EtO
(tr) +
(CO)2Cr
Cr(CO)5
0.33 M
Et2N
(15)
436
+
227
Cr(CO)3
NEt2 EtO
+
Ph
N
Ph
O
(86) Ph
N
Ph
NEt2
NEt2 O
O O N
2 eq
Ph
O
+
Et2O, 20°, 1 h
Ph
(CO)5Cr
N
O
N
O
Ph Ph
(CO)5Cr
Ph Ph
Ph
0.33 M
Ph
(28)
(16) NEt2
461
NEt2 (CO)5Cr
(CO)5Cr
Ph O
O N
N H (8) C8 (CO)4Cr
MeO2C
Bu-n
2 eq
Ph
N Me 0.03 M
Ph
CO (30 psi), THF, rt, 25 h Ph
N Me
R 1.2 eq
N
165
(36)
R CO2Et
THF, 60°, 16 h N
0.03 M
Ph
(16) Ph
R
EtO2C
EtO2C
Ph
Cr(CO)5
EtO2C
O
Ph
Bu-n
MeO2C
O
Ph
+
CO2Et
(77)
n-Pr
(61)
157
TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C9 Ph
Ph
(CO)4Cr
+
Benzene, reflux, 6 h
Ph N H
Ph 5 eq
O
(CO)3Cr
0.08 M
O
(CO)3Cr
Ph
(CO)5Cr 1.9 eq
429 (22)
(30)
Benzene, reflux, 12 h
N
Ph
N
Ph (CO)3Cr
0.1 M
Ph +
N
Ph
(38)
O
77 (—)
O
462
OH EtO2C
Cr(CO)5
EtO2C 4 eq
Ph 156, 157
(70)
THF, 60°, 48 h
N
N
0.03 M
R1 R1
Cr(CO)5
Ph
R2 1.5-2 eq
R1 R2
1. DMF, 120-125°, 5 h 2. 90-95°, 15 h
N-morph
R2
+ I
79 II
N-morph
O
R1
R2
Ph
Me
(41) (52)
Bu-t
CO2Et
(31) (58)
I
II
Bu-t EtO2C
Bu-t
+ CO2Et
DMF, 120°, 3 h N-morph
2.1 eq 0.05 M
OMe Cr(CO)5
O
OMe
(54)
392 H (6)
OMe O
C9-11
Ph
R
DMF, 120°, 3 h
R
0.05 M
SMe
392
Ph
N-morph
2.1 eq
OMe Cr(CO)5
O
OMe
(3) (low)
TMS C10
463
Bu-n Ph n-Bu
Bu-n
Bu-n
1. DMF, 120-125°, 5 h N-morph
1.5-2 eq
Bu-n
Cr(CO)5 Bu-n
+
(28) O
C11
(67)
Cr(CO)5
Ph
N
CO2Et
THF, 60°, 16 h
(70)
157
N
1.2 eq
0.03 M n-Bu
C12 Ph
N-morph
Ph
EtO2C EtO2C EtO2C
79
2. 90-95°, 15 h
Bu-n
O
1.5 eq
Cr(CO)5 NMe2
0.08 M
Ph
DMF, 120°, 5 h O O
NMe2
(21)
427
TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C12
Fe
DMF, 120°, 3 h
Fe
392
(50)
N-morph 1.5 eq
0.05 M
OMe Cr(CO)5
O
OMe
C14
OH Ph Ph
Cr(CO)5
Ph
Benzene, reflux, 15 h
2 eq
437
(15.4) Ph
N
N
464
Ph
O NMe2
1.5 eq
DMF, 120-125°, 5 h
Ph
O
Ph
O N-morph
1.5 eq
1. DMF, 120°, 5 h
Ph
Ph
O
Ph
+
N-morph
O
2. 1 N HCl, MeOH
Cr(CO)5
427
(44)
NMe2
O
Cr(CO)5
427
O
(20)
(27)
O
cis:trans = 1:1 S 1.1 eq
N
1. Benzene, reflux, 12 h
Cr(CO)5
2. Pyridine, reflux, 6 h
S
Ph
N +
(44)
S
(46) 77 N
Ph Ph
Ph
0.1 M
O
Ph
1.1 eq
Ph
Ph
N
S
N
1. Benzene, reflux, 12 h Cr(CO)5
2. Pyridine, reflux, 6 h
+
(1)
S (44) 77
Ph
N
S
0.1 M
O OH EtO2C
Cr(CO)5
EtO2C 1.5 eq
N
Ph
THF, 60°, 48 h
156, 157
(57)
Ph
0.03 M
N
Cr(CO)3 Ph
Cr(CO)5
Ph 1.2 eq
Ph
Benzene, reflux, 12 h
465
NMe2
– O
Ph Ph
(55)
161
(59)
438
Ph N Me + Me Ph
Cr(CO)5
1.2 eq
Cyclopentadiene (10 eq), NMe2
O
Ph
N
benzene, reflux, 24 h
Me Ph Ph 2 eq
(CO)5Cr
N
1. Benzene, reflux, 12 h
Ph
Ph
Ph (24) +
N O Ph
Cr(CO)5
Ph N
N
(2)
77
Ph Ph
2 eq
Ph
2. Pyridine, reflux, 6 h
0.12 M
Benzene, reflux, 2 h
N
Ph (CO)3Cr
Ph O
Ph
(18-23)
439, 440a
TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C14 Ph
Ph Ph
Ph 2 eq
N
S
Cr(CO)5
Ph
O O +
Benzene, reflux, 12 h S
N
N
S
Ph
O (42)
Ph
Ph
(7)
Ph
Ph Ph
+ O
(7) Ph 1.9 eq
N
Cr(CO)5
Ph
+ (11) O
Ph
Ph Benzene, reflux, 12 h
Ph
Ph
466
Ph (CO)3Cr
0.1 M
(42)
77
O
Ph
Ph +
N
+
(14)
Ph
N
77
Ph
N
Ph
(16)
O Ph 1.9 eq
N
Ph
Ph Cr(CO)5
Benzene, reflux, 12 h
Ph
Ph
+
N Ph
Ph
O
(0-2) Ph
+
N
77, 440a
(50-62)
Ph
Ph
N
(CO)3Cr O (0-33)
OH Ph
Ph Ph
Cr(CO)5
0.9 eq
Ph
1. THF, reflux
N
(57) +
Ph
2. Air
(13)
164
N
N 0.03 M c-Pr 1.25 eq
N
Me Cyclohexane, Cr(CO)5
Ph
reflux, 12 h
c-Pr + Me N Ph – Ph
0.07 M
+
O Ph
c-Pr
Ph
1.5-2.0 eq
Ph 161, 441
+
Ph
Cr(CO)3 O
Cr(CO)3 (14)
(21) Ph
1. DMF, 120-125°, 5 h Ph
2. 90-95°, 15 h
467
N-morph
Ph
Ph
N
Cr(CO)3 (42-47) Ph Cr(CO)5
Ph
Me
O
Ph
+
79
3. Acid N-morph
I
II N-morph Ph
Acid I no
II
III Ph
+
(34) (55) (0)
yes (34) (0) (52) (CO)5Cr 2.0 eq
Ph
Ph Bu-s N H
1. Toluene, reflux, 18 h 2. Pyridine, 6 h
HN H
1. Benzene, reflux, 12 h 2. Pyridine, 6 h
441
N Bu-s Me
Cr(CO)5
O
(32) 1:1 mixture of isomers Ph
Ph 2.0 eq
III
Ph
O
N
Ph Ph (23)
a
H Ph
Ph
Ph
+ Ph
O Ph (41)
+ O
(11)
441
TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C14 Ph
Cr(CO)5 Ph
Ph
Ph
1. Benzene, reflux, 8 h
N
Ph
Ph
Ph
(—) +
N
Ph
Ph
(—)
N
440a
2. Pyridine, reflux O
0.17 M
O Me
Me
Me
N
O
N
Ph
1. Benzene, reflux, 48 h
1.5 eq Ph
(CO)5Cr
+
2. Pyridine, reflux, 12 h
Ph
Ph
440b
Ph
Ph (7)
(62)
468
Me
N
Ph
O Cyclohexane, reflux
(CO)5Cr
Ph
Me + Ph N Ph –
Ph
Ph
N
O
(—)
442
Ph
Cr(CO)3 Ph
Cr(CO)5
Ph
N
THF, 80°, 1-3 h
Ph
Ph
Ph
N
1.5 eq Ph
Cyclohexane, reflux
Cr(CO)5 0.1 M
+ N
O
(41)
235, 236
(65)
440b
Ph
N H
Ph
– Ph
Ph
Cr(CO)3
n
1.2 eq N
Benzene, reflux, 22 h
n
N
O
Ph
n
N
O
+
Ph
437
+
(CO)5Cr Ph
Ph
Ph
Ph
I
Ph
N
Ph
II
Cr(CO)3
n
Ph
N
Ph
Ph
Ph
Ph
III
IV
Ph
Ph Ph
469 V
Ph
+
O
VI
O Ph
Ph
Ph
Ph +
+
N
N
n
IX
VIII
VII I
II
III
IV
(47) (0.7) (0)
V
VI
VII VIII
IX
(9.7)
(0)
(0)
(0)
(0)
2 (10) (32.6) (0.6) (1.5) (23)
(0) (17.9) (3.9)
3 (11) (37.4) (0)
(0)
(0)
4
(0) (11.3) (3.9) (1.9)
(0)
N
(CO)3Cr
n
n
1 (6.7)
+
Ph
Ph
n
+
n
O
+
(31)
(0)
(8)
(0)
(4.6) (5.2) (5.8) (0) (12.3)
TABLE 9. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
C14
(CO)4Cr Ph
Ph
Product(s) and Yield(s) (%)
O
N Me 0.03 M
CO (30 psi), THF, rt, 25 h
Ph
Ph
165
(12)
Ph
N Me
OH
Ph
Ph
Cr(CO)5
2 eq
Refs.
Ph
Ph
Ph
2 eq
Conditions
Benzene, reflux, 10 h
N
CN
Ph
Ph
+
(53.3)
(19.4)
437
Ph N Ph
Ph
H N
Ph
470
1.0 eq
Toluene, 75°, 1 h (CO)4Cr
(CO)3Cr
Ph
Ph Ph
1. Benzene, reflux, 12 h
(3)
Ph (3.6) +
+
O O
O Me
Ph
N
O
Ph Ph
Ph
Ph Photolysis (pyrex), Cr(CO)5
N
hexane, rt, 4-5 h
0.005 M
Me
(42.6) +
Ph
O
Ph
Ph
N
Ph H
Ph
(4.1)
Ph
R
Ph
Me (51) N
Ph Me
N
R
Ph (5.8) +
Ph
Ph
Ph Ph
10 eq
Ph
(0.7) +
O
Ph
440b
2. Pyridine, reflux, 12 h
Ph
Ph
NH NMe2 (10)
Ph
N
(CO)5Cr
432
(CO)3Cr
NMe2 (42)
Me 2.3 eq
N
N Me2
0.1 M
Ph +
R
189, 190
Ph (49)
Ph DMF, 120°, 3 h
1.5 eq
Ph
N-morph OMe Cr(CO)5
OMe
(85)
392
N-morph
0.05 M MeO
C15
(CO)4Cr
(CO)5Cr Ph MeO
471
2 eq a
Ph
O N Me
Ph Ph
Cr(CO)5
CO (30 psi), THF, rt, 2.25 h
0.03 M
This product was formed with retention of configuration of the s-butyl group.
(65) Ph
N Me
Ph
165
TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C3
DMF, 120°, 1 h
392
(50)
N-morph 0.05 M
OMe Cr(CO)5
O
OMe CN
Cr(CO)5
Ph NC
1. Photolysis, THF, –40° 2. Alkyne (1 eq),
N-morph 0.05 M
C4
–40° to rt, 12 h
(CO)4Cr Ph
472
(73)
190
(38-55)
235, 236
N-morph
Ph Photolysis (pyrex), Ph
54
OEt
EtO 10 eq
(22)
Cr(CO)5
N 0.005 M
hexane, rt, 5 h
Ph N
Ph MeO
Ph
MeO
THF, MeCN or C6H12, Ph
N
Cr(CO)5
80°, 1-3 h
Ph
0.3 M
1.5 eq
N H
Ph
N
Ph
MeO Ph
Ph THF, 80°, 1.5 h
1.5 eq BzO
N
Cr(CO)5
BzO
(11)
236
Bz
0.3 M OH
CO2Me
O
Cr(CO)4
MeO
CH2Cl2, –20°, 24 h
N-morph 0.1 M
1 eq
(25)
54
(36)
236
Cr(CO)3 N-morph
MeO2C Ph 1 eq
THF or MeCN, 80°, 1-3 h Ph N 0.3 M
Cr(CO)5
Ph
N H
Ph
N
Ph
MeO2C Ph
Ph 1 eq
THF, 80°, 1.5 h Cr(CO)5
N
BzO
BzO
Ph
N Me 0.03 M
CO (30 psi), THF, rt, 13 h
Ph
Ph
N Me
C4-5
OH EtO2C
473
1.5 eq
Ph
165
O
EtO2C
Cr(CO)5 N
R
(80)
MeO2C
Cr(CO)4
O
O
236
Bz
0.3 M
2 eq
(18)
R
R Me
THF, 60°, 48 h
0.03 M
156, 157
OMe (89)
N
OEt
C5
(63) (94)
OH Pr-n Cr(CO)5
n-Pr
Benzene, 80°, 24 h
(57)
83
(65)
83
NMe2 2 eq
NMe2
0.25 M
OTBS Pr-n Cr(CO)5
3 eq
NMe2 0.25 M
TBSCl, (i-Pr)2NEt, benzene, 80°, 17 h Cr(CO)3
NMe2
TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OTBS
C5
Pr-n Cr(CO)5
n-Pr 2 eq
TBSCl, (i-Pr)2NEt, benzene, 80°, 14 h
NMe2 0.25 M
(42)
83
(57)
83
Cr(CO)3 NMe2 OH Pr-n
Cr(CO)5 2 eq
Benzene, 80°, 16 h NMe2 0.25 M
NMe2 OTBS
R4
474
2 eq
R4
Cr(CO)5 N
R2
R1 0.05 M
TBSCl, (i-Pr)2NEt, benzene, 80°, 14-18 h
OTBS R4
Pr-n +
R3O
205
R3O
Cr(CO)3
N
Pr-n
N
anti R1 = H, R2 = CH2OR3 syn R1 = CH2OR3, R2 = H
II
I
R3
R4
anti:syn
I
II
dr
% de
Me
Me
≤17:83
(49)
(—)
55:45
10
Me
Me
≥83:17
(34)
(—)
55:45
10
Me
Ph
26:74
(40)
(13)
52:48
4
TBS
Me
14:86
(51)
(—)
55:45
10
TBS
Me
86:14
(48)
(—)
59:41
18
Cr(CO)5 N
2 eq
Ar—Cr(CO)3
Ar
N
N
+
TBSCl, (i-Pr)2NEt, benzene, 80°, 20 h
O 0.05 M
OTBS Pr-n Ar =
O
205
O (12)
(51) dr = 55:45
OH R
EtO2C
EtO2C
Pr-n R
Cr(CO)5
1.5 eq
N
THF, 60°, 48 h
R N
0.03 M
H
(72)
D
(72)
OH
156, 157
Pr-n Pr-n
Cr(CO)5
4 eq
NMe2
1. Solvent, 80°, 36-47 h
I
+
II
83
2. HX, THF/H2O O
NMe2
475
CC (M)
Solvent
I
II
0.5
heptane
(66)
(<2)
0.5
benzene
(64)
(<1)
0.5
THF
(57)
(12)
0.005
THF
(<22)
(19)
0.5
CH2Cl2
(18)
(<7)
0.5
MeCN
(<5)
(13)
0.5
DMF
(25)
(13)
OTBS Pr-n 4 eq
Cr(CO)5 NMe2
TBSOTf, 2,6-lutidine,
83
80°, 42-64 h NMe2
CC (M)
Solvent
0.5
heptane
(50)
0.5
benzene
(40)
0.05
CH2Cl2
(33)
Cr(CO)3
TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
Refs.
OTf Pr-n
1. Benzene, 80°, 84 h Cr(CO)5
n-Pr 4 eq
NMe2
0.5 M
2. Tf2O, (i-Pr)2NEt,
83
(25)
rt, 1 d NMe2
Cr(CO)3
OH
O Pr-n
Cr(CO)5
2 eq
1. Solvent, 80°, 20 h
Pr-n +
2. Oxidative workup NMe2
+
NMe2 I
0.25 M
83
II
O
Pr-n
O
O
Pr-n
Pr-n
476
O
MeN
+
+
III
Ph
IV
NMe2
V O
Ph
Solvent
Workup
I
II
III
IV
V
benzene
CAN
(—)
(<4)
(—)
(25)
(<4)
THF
none
(—)
(<2)
(12)
(15)
(19)
THF
CAN
(—)
(<2)
(—)
(—)
(—)
DMF
none
(<1)
(—)
(<1)
(<1)
(32)
OTBS
OTBS Pr-n
Cr(CO)5
1.9 eq
NMe2
Pr-n (21) +
TBSCl, (i-Pr)2NEt, benzene, 80°, 10-12 h NMe2
0.25 M
(20)
Cr(CO)3
NMe2
OTBS
Cr(CO)3
OTBS Pr-n
1.9 eq
Cr(CO)5
TBSCl, (i-Pr)2NEt,
NMe2
NMe2
(4)
+
Cr(CO)3
NMe2
OTBS
OR
OR
Pr-n (35)
benzene, 80°, 10-12 h
OR
Cr(CO)5
Cr(CO)3
Pr-n +
TBSCl, (i-Pr)2NEt, benzene, 80°, 10-12 h
I
NMe2
NMe2
0.25 M
207
OTBS
Pr-n 1.9 eq
207
+
Cr(CO)3
II
NMe2
207
Cr(CO)3
OTBS Pr-n
R
I
II
(32)
(2)
(9)
TBS (25)
(4)
(29)
Me III
477
NMe2
Cr(CO)3
III
O Pr-n OMe
n-Pr
HO 1. THF, 70°, 4 d
2 eq Ph
N
Cr(CO)5
2. Air/silica gel
0.16 M
(21) Ph
+
OMe (18) 406 N
N
Ph Pr-n
n-Pr
Pr-n R 3 eq
Solvent, 70-80°, 24 h Ph
N
Cr(CO)5
0.014 M
Ph
R
N H I
+
Ph
N H II
R
Solvent
I
II
III
Me
hexane
(40)
(9)
(51)
Ph
hexane
(64)
(—)
(28)
t-Bu
hexane
(94)
(≤1)
(5)
t-Bu
MeCN
(20)
(61)
(14)
R
+
HO 234, 232 Ph
N III
R
TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5 OR1
R2
n-Pr
Hexane, 70° Ph
N
Cr(CO)5
1
R
Me
Ph
Ac
Ph
Ac
t-Bu
R
Ph
+
R2
N H I
Refs. Pr-n
n-Pr
Pr-n
Ph
R2
I
N H II II
(0)
(4)
(51)
(0)
(9)
(31)
(13)
(26)
(37)
2
HO + Ph
234 N III
R
2
III
O Pr-n
OMe Bu-t 2 eq
1. THF, 70°, 24 h Ph
N
Cr(CO)5
0.08 M
478
(41)
224, 233
(38)
224
2. CAN O OH Pr-n
OMe Bu-t 1. THF, 70° Ph
Cr(CO)5
N
2. Air OMe OH
Cr(CO)5
Ph
OH
Ph
2 eq
Pr-n
Ph
NMe2
2. Workup
II
NMe2
NHMe I
Workup
(39) (—)
air, benzene
(23)
(8)
O
N
Pr-n
O N (CO)4Cr
Ph
N
MeCN, 45-50°, 24 h
244, 205
(40-61) >96% de
Me
0.005 M
N
Me
II
air, silica gel
Me
N O Ph N Me
Me
O
N
Pr-n
O N 1.5 eq
83
I
0.25 M
1.5 eq
Pr-n
+
1. Benzene, 84°, 17 h
(CO)4Cr
Ph Me N
N
MeCN, 45-50°, 24 h
244, 205
(22-33) >96% de
Me
N O Ph
0.005 M
479
N Me TMS Ph
HO
TMS
(60) +
THF or MeCN, 80°, 1-3 h Ph
Cr(CO)5
N
Ph
0.3 M
1.5 eq
TMS
N
Ph
Ph
N H
Ph
(10)
236
O O
Ph
Cr(CO)5
1. Photolysis, THF, –40° 2. Alkyne (1 eq),
Me2N
N-morph 0.05 M
–40° to rt, 12 h
NMe2 (CO)4Cr
(54)
Ph N-morph
54
TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OH
C6
n-Bu 4 eq
EtO2C
Cr(CO)5
EtO2C
Bu-n
THF, 60°, 16 h
N
N
0.03 M
Ph 1.5-2 eq
156, 157
(88)
Bu-n
Cr(CO)5 1. DMF, 120-125°, 5 h
N
(49)
2. 90-95°, 15 h
79
O OH
Bu-n
480
1.0 eq
Bu-n +
+
1. Solvent, temp, 4 h N-morph
2. 90-95°, 15 h I
N-morph
Solvent
Temp
I
II
III
DMF
120°
(7)
(90)
(—)
MeCN
120°
(9)
(71)
(3)
THF
120°
(18)
(43)
(7)
hexane
90°
(50)
(13)
(12)
1. DMF, 120-125°, 5 h N-morph
Ph
160 N-morph
III
II (95)
79
2. 90-95°, 15 h Bu-n
Ph
n-Bu
HO THF or MeCN, 80°, 1-3 h
Ph
N
(30)
O
+
Cr(CO)5 Ph
Ph
O
II
O
Cr(CO)5
Ph
2 eq
O
Bu-n
Cr(CO)5
Ph
Ph
N Me
Ph
N H
Ph
(56)
236
n-Bu
Cr(CO)4
N Me 0.03 M
N
Ph
CO (30 psi), THF, rt, 13 h
Ph
Ph
165
(27)
Bu-t
t-Bu
(n-Bu)2O, 90°, 3 h
NH
O Cr(CO)3
Cr(CO)5
R 2-4 eq
208
(40)
4 eq
Bu-t DMF, 120-125°, 3-3.5 h
O N
R H
(53)
Me
(20)
392
R
481
OMe Cr(CO)5 0.04-0.06 M
OMe
OMe
O
OMe Bu-t
2 eq
O
(8)
DMF, 125°, 3 h
392
N OMe Cr(CO)5
OMe
O
0.09 M OH EtO2C TMSO 4 eq
N 0.03 M
EtO2C
Cr(CO)5
OTMS
THF, 60°, 16 h
(73) N
156, 157
TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C7
Refs.
OAc
N
n-C5H11
OBu-t
OAc
C5H11-n
1. Toluene, 55°, 2.5 h
Bn
C5H11-n
2. Ac2O, Et3N, DMAP,
+
rt, 3.5 h O
(CO)4Cr
2 eq
3. FeCl3-DMF, 20 min
N
Bn
O
0.03 M
(46)
162, 163
(19) C5H11-n
OBu-t R C5H11-n
1.2-2 eq
DMF, 120-125°, 3 h R
482
OMe Cr(CO)5
0.05 M
O
OMe
NH2
(17)
NHMe
(22)
NMe2
(51)
N-aziridinyl
(0)
N-pyrrolidinyl
(7)
N-piperidinyl
(75)
392
(17)
N C7 OH EtO2C
THF, 60°, 16 h
N 4 eq
EtO2C
Cr(CO)5
156, 157
(82) N
0.03 M
C8 C6H13-n (CO)4Cr
n-C6H13
(n-Bu)2O/THF (10:1), N H
Ph
(45)
443
90°, 1 h O
(CO)3Cr
OH EtO2C
Cr(CO)5
EtO2C 4 eq
C6H13-n
THF, 60°, 16 h
N
1.2 eq
N
Tol-p 1. Toluene, 120°, 1 h
R 0.06 M
O
MeO2C
H N
MeO2C
156, 157
(66)
0.03 M
Cr(CO)5
R
N
2. rt, 20 h p-Tol
O
MeO2C C6H13-n
+
R
p-Tol
I
R
I + II
I:II
Me
(45)
58:42
Bn
(26)
—
OH
C6H13-n
N
444
II
Ph
483
Ph Cr(CO)5
Ph 2 eq
I (42)
THF, 66°, 1 h
+
II (40)
54
N-morph
Cr(CO)4
2 eq
N-morph
N-morph
0.05 M
THF, 66°, 1 h
I (20) + II (20)
54
N-morph 0.05 M N-morph Cr(CO)4
2 eq
N-morph 0.05 M
(CO)5Cr CH2Cl2, rt, 1 h
(46)
54
TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C8
Refs.
OH
R
Ph
Ph R
THF, 60°, 16 h
N
4 eq
EtO2C
Cr(CO)5
EtO2C
R
0.03 M
N
H
(95)
D
(80)
156
OTBS
Ph
Ph (70)
1. THF, 60°, 16 h
N 4 eq
EtO2C
Cr(CO)5
EtO2C
2. TBSCl, Et3N
0.03 M
156
Cr(CO)3
N
484 Ph Ph
Ph
HO THF, MeCN or cyclohexane,
1.5 eq Ph
N
Cr(CO)5
80°, 1-3 h
0.3 M
Ph
N
Ph
Ph
10 eq
Photolysis (pyrex), N
Cr(CO)5
hexane, rt, 4-5 h
0.005 M
Ph
Ph
(41)
235, 236
189, 190
(43) N
Ph Ph
Ph
THF, 80°, 1-3 h BzO
Ph
Ph
1.5 eq N
Cr(CO)5
BzO
Ph (38)
N
+
Ph
Bz
0.3 M
Me
(CO)4Cr
Ph
(12)
236
Ph
O N
N H
O
N
1.5 eq
N H
Ph
Ph Ph
+
(0-12)
Ph Me N
N
MeCN, 45-50°, 24 h
(40) >95% de
Me
N
244
O
Ph N Me
0.01 M
C9
OH
THF, 60°, 16 h
N 4 eq
EtO2C
Cr(CO)5
EtO2C
156, 157
(58) N
0.03 M
485 Ph
N
Ph
Ph
Ph
4 eq
THF or MeCN, 80°, 1-3 h N
Ph
Cr(CO)5
(15)
HO
H N
Ph (43)
236
p-Tol
p-Tol C11
+
O
TsO 4 eq
N 0.03 M
EtO2C
Cr(CO)5
EtO2C
(68)
THF, 60°, 16 h N
156, 157
TABLE 10. AMINO AND IMINO CHROMIUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OH
C12 EtO2C
Cr(CO)5
EtO2C
Fe N
Fe
(85)
THF, 60°, 16 h
0.03 M
156, 157
N
4 eq
DMF, 120°, 3 h
1.5 eq
Fe
N-morph
486
0.05 M
OMe Cr(CO)5
OMe
O
(50)
392
TABLE 11. SULFUR-STABILIZED CHROMIUM CARBENE COMPLEXES WITH ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OH
C5 Ph
Cr(CO)5
n-Pr
2. Air
SEt 0.02 M
2 eq
Pr-n 1. THF, 46°, 48 h
(36)
377
(32)
377
SEt OH Pr-n SEt
2 eq
1. THF, 46°, 48 h 2. Air
MeO Cr(CO)5 0.02 M
SEt OAc
MeO
C6
Bu-n
BF3•OEt2 (5 eq), n-Bu
SMe
O
487
Cr(CO)5
2 eq
THF, 65°
O
(48)
167
O n-Bu SMe OAc
0.03 M Cr(CO)5
Ph
O
MeS
(28) +
Ac2O (5 eq), Et3N (5 eq),
Bu-n
BF3•OEt2 (5 eq), Ac2O (5 eq), Et3N (5 eq),
2 eq SMe
(45)
167
(21)
168
(41)
167
THF, 65° SMe OH
0.03 M
Bu-n SPr-n
1.9 eq
BF3•OEt2 (5 eq), toluene, 65°
MeO
Cr(CO)5
SPr-n OAc
MeO
0.18 M
Et
BF3•OEt2 (5 eq), Et
Et
SMe
O
2 eq
Cr(CO)5 0.03 M
Ac2O (5 eq), Et3N (5 eq), THF, 65°
O
Et SMe
TABLE 11. SULFUR-STABILIZED CHROMIUM CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OAc
C6 Cr(CO)5
Ph Et
Et
Et
BF3•OEt2 (5 eq), Ac2O (5 eq), Et3N (5 eq),
2 eq
SMe 0.03 M
2 eq SEt
SEt Cr(CO)5
Cr(CO)5
NEt2 Petroleum ether
n-PrS
488
1 eq
377, 166
Et
2. Air
0.02 M
Et2N
(46)
Et 1. THF, 46°, 48 h
C7
167
SMe OH
Cr(CO)5
Ph
(13) Et
THF, 65°
n-PrS
0.1 M Y
Y O
(58)
S
(54)
168
Y R
Cr(CO)5 Cr(CO)5 Et2O, 20°
2 eq Ph
Et2N
SR 0.5 M
SR
Ph
Cr(CO)5 Cr(CO)5 1 eq RS
Ar RS
0.1 M
C8
NEt2
Petroleum ether Ar
allyl
(82)
t-Bu
(75)
Ph
(79)
c-C6H11 (79) R
Ar
n-Pr
Ph
(67)
Me
4-MeC6H4
(60)
n-Pr
4-MeOC6H4 (63)
Ph
O 2 eq
SMe
Ph
Cr(CO)5 0.03 M
THF, 65°
Ph
Ph
(32) +
Ac2O (5 eq), Et3N (5 eq),
(32)
O SMe
168
O
OAc BF3•OEt2 (5 eq),
445
O
SMe
167
OAc Ph
Ph
BF3•OEt2 (5 eq),
Cr(CO)5
Ac2O (5 eq), Et3N (5 eq),
2 eq SMe 0.03 M
(42)
167
(45)
377
THF, 65° SMe OH
Ph
Ph
Cr(CO)5
2 eq
1. THF, 46°, 48 h SEt 0.02 M
2. Air SEt OAc Bu-t
BF3•OEt2 (5 eq), MeO2C
Bu-t
SMe
O
Ac2O (5 eq), Et3N (5 eq), THF, 65°
Cr(CO)5
2 eq
O
167
(25)
167
SMe
0.03 M
489
(55) CO2Me
C9
OAc Ph
BF3•OEt2 (5 eq), Ph
SMe
O 2 eq
Ac2O (5 eq), Et3N (5 eq), THF, 65°
Cr(CO)5
O SMe
0.03 M
OAc Ph
Ph
BF3•OEt2 (5 eq),
Cr(CO)5
Ac2O (5 eq), Et3N (5 eq),
2 eq SMe
(9)
167
THF, 65°
0.03 M
SMe OAc BF3•OEt2 (5 eq),
TMSO OEt
SMe
O
Ac2O (5 eq), Et3N (5 eq), THF, 65°, 96 h
Cr(CO)5
2 eq
(33) O
167
OEt SMe
0.03 M
TABLE 11. SULFUR-STABILIZED CHROMIUM CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OAc
C11
Ph
BF3•OEt2 (5 eq), EtO2C
Ph
SMe
O
Ac2O (5 eq), Et3N (5 eq), THF, 65°
Cr(CO)5 0.03 M
2 eq
O
(52)
167
(43)
167
CO2Et SMe OAc
Ph
Ph
BF3•OEt2 (5 eq),
Cr(CO)5
Ac2O (5 eq), Et3N (5 eq),
2 eq SMe
CO2Et
THF, 65°
0.03 M
SMe
C12 OMe
OMe O
490
BF3•OEt2 (5 eq), Et3N (5 eq),
Fe SEt 2 eq
0.03 M
(3)
392
Fe
THF, reflux, 19 h
OMe Cr(CO)5
OMe O
C14 OAc Ph
BF3•OEt2 (5 eq), Ph
Ph 2 eq
O
SMe Cr(CO)5 0.03 M
Ac2O (5 eq), Et3N (5 eq), THF, 65°
(23) O
Ph SMe
167
TABLE 12. ARYLMOLYBDENUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C6
OH Et
O
1. Additive (2 eq), solvent,
L Mo(CO)4 Et
80°, 20-50 h Ph
OMe
Refs.
2. Workup
Et
Et +
Et +
Et
Et
OMe
Et + OMe
O I
II
III
Et Et Et
Et
+ Ph
O
Ph
+ OMe
O V
OMe
IV
OMe
Et
Et VI
491
Alkyne (eq)
CC (M)
L
Solvent Additive Workup
I
II
III
IV
V
VI
1.9
0.1
CO
THF
none
air
(9)
(—)
(66)
(1)
(5)
(—)
60
1.9
0.005
CO
THF
none
air
(3)
(—)
(71)
(0)
(2)
(—)
60
1.9
0.1
(n-Bu)3P
THF
none
CAN
(—)
(43)
(—)
(—)
(—)
(—)
201
1.9
0.1
(n-Bu)3P
THF
none
air
(—)
(—)
(<1)
(—)
(2)
(—)
201
7.8
0.056
(n-Bu)3P
THF
none
CAN
(—)
(36)
(—)
(—)
(—)
(—)
201
7.8
0.056
(n-Bu)3P
THF
none
air
(—)
(—)
(≤1)
(—)
(4)
(—)
201
1.9
0.1
CO
THF
(n-Bu)3P CAN
(—)
(≤5)
(0)
(—)
(0)
(—)
201
1.9
0.1
CO
benzene none
air
(6)
(—)
(74)
(0)
(15)
(—)
60
1.9
0.005
CO
benzene none
air
(5)
(—)
(66)
(0)
(8)
(—)
60
7.8
0.1
CO
MeCN
none
air
(—)
(—)
(—)
(—)
(6)
(16)
60
7.8
0.1
CO
MeCN
none
CAN
(—)
(39)
(>5)
(1)
(—)
(—)
60
7.8
0.005
CO
MeCN
none
air
(—)
(—)
(—)
(—)
(6)
(3)
60
7.8
0.005
CO
MeCN
none
CAN
(—)
(67)
(>5)
(1)
(—)
(—)
60
TABLE 12. ARYLMOLYBDENUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C6
Et
Et
p-Tol
1.2 eq
Et
O
(CO)4Mo
OBu-t
N
1. Solvent, temp, 1 h
p-Tol
Temp
R
I
II
60°
H
(11)
(—)
toluene
80°
Bn
(—)
(13)
Et
p-Tol
492
N
Solvent, temp, 2-3 h
R
p-Tol N HO R I
I
II
n-Pr
(18)
(—)
toluene
80°
Bn
(9)
(10)
(CO)5Mo
Ph
OMe
O
433
(63)
359
(83)
430
OMe
NEt2 Benzene, 20, 2 h
Ph
N
NEt2 Hexane, rt, 1 h
(CO)5Mo 0.3 M
Et
R II R
NH2 1 eq
p-Tol
60°
Ph (CO)5Mo
+
O
Temp
C7
0.3 M
Et
Et
THF
Solvent
1 eq
163
N
0.06 M
NEt2
OR
CO2Bu-t II
THF
R
Et
N
I Solvent
1.2 eq
p-Tol
CO2Bu-t
0.06-0.1 M
(CO)4Mo
+
O
N
2. Air, 3-12 h
R
Et
Et
N (CO)5Mo
Et Ph
C8-9 OMe R1
OMe
O
(CO)5Mo
O O OMe
R2
Dioxane, 100°, 5 h
2.5 eq
0.05 M
R2
Fe
Fe
Fe
R1 I
R1
R2
n-Pr
n-Pr
(10) (17)
Me
Ph
(40) (19)
I
II
426 R1
R2
II
C14 O Ph
HN
Ph 1.2 eq
Ph
Benzene, reflux, 3 h
N Mo(CO)4
Ph
N
N
(40)
446
(27)
426
Ph
Ph
493
0.1 M OMe Alkyne (eq)
O
Ph
(CO)5Mo
1.5
Dioxane, 100°, 5 h
2.5
Fe 0.05 M
Fe
OMe Ph
(37)
TABLE 13. ARYLMOLYBDENUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
OH
Pr-n Ph
+
+
1. Solvent, 80°, 26-60 h OMe
1.9 eq
Pr-n
Pr-n
Mo(CO)5
n-Pr
Refs.
Ph
2. Air, silica gel
I
II
OMe
OMe
60
OH
O n-Pr
OMe
O III
Pr-n
Ph
OMe
Pr-n
+
Ph O Ph
IV
MeO + CO2Me Ph
MeO O + Ph
O
O
O
494
Pr-n
Pr-n
Pr-n
VII
VI Solvent
V
Pr-n
OMe
VIII
I
II
III
IV
V
VI
VII
VIII
0.1
THF
(21)
(5)
(25)
(0)
(20)
(20)
(0)
(0)
0.005
THF
(27)
(12)
(27)
(0)
(6)
(11)
(0)
(0)
0.1
benzene
(62)
(4)
(2)
(1.3)
(21)
(2.5)
(0)
(0)
0.005
benzene
(80)
(3)
(3)
(3)
(6)
(1)
(0)
(0)
0.1
MeCN
(10)
(18)
(16)
(0)
(4)
(30)
(3)
(0)
0.005
MeCN
(3)
(9)
(2)
(0)
(2)
(1)
(2)
(27)
0.1
MeOH
(19)
(2)
(0.2)
(0)
(25)
(41)
(0)
(0)
CC (M)
O TMS Mo(CO)5
TMS
OMe
1.3 eq
(69)
1. Toluene, 90°, 5 min
82, 185
2. CAN O
0.07 M
C6
Bu-n OMe
n-Bu 1.3 eq 0.07 M
Mo(CO)5
1. Toluene, 90°, 5 min
(53)
82, 185
(27)
185
2. CAN O O Bu-n
1.3 eq
O
OMe Mo(CO)5 0.07 M
1. Toluene, 90°, 90 min 2. CAN
O O Bu-t
OMe
t-Bu
Mo(CO)5
1.3 eq
O O OMe
+
1. Toluene, 90°, 5 min 2. CAN O
0.07 M
185
Bu-t (34)
(15)
Bu-t
495
O OMe
1.3 eq
Mo(CO)5
+
1. Toluene, 90°, 5 min 2. Air
(17)
O
0.07 M R
Bu-t
R O OMe
1.3 eq
Mo(CO)5
OMe
1. Toluene, 90°, 5 min 2. Air
OMe
Bu-t
185 (55)
R H
(33)
185
OMe (34)
0.07 M C6H13-n
C8 OMe
n-C6H13 1.3 eq
Mo(CO)5 0.07 M
1. Toluene, 90°, 5 min
(69)
2. Air O
185
TABLE 13. ARYLMOLYBDENUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C6H13-n
C8 OMe
n-C6H13 1.3 eq
Mo(CO)5
1. Toluene, 90°, 5 min
82, 185
(60)
2. CAN
O
0.07 M O
C6H13-n OMe
O
1.3 eq
Mo(CO)5
1. Toluene, 90°, 90 min O
0.07 M
C9 Ph
TBSO
OTBS
OMe
Ph
Benzene, 100°, 1.5 h Mo(CO)5
496
1.7 eq
185
(35) O
2. CAN
(66)
447
OMe
0.04 M
C12 EtO2C
OH OMe
O
CO2Et
See table
0.9 eq
+
385
O
Mo(CO)5
I
OMe
0.003 M
H
H CO2Et
CO2Et +
OMe
OMe
O
O
II
III
Temp
Time
I
II
III
THF
55°
4h
(tr)
(12)
(—)
THF
67°
0.33 h
(—)
(10)
(—)
THF
67°
2h
(—)
(40)
(—)
THF
100°
2h
(tr)
(42)
(—)
benzene
25°
56 h
(19)
(8)
(17)
benzene
70°
4h
(12)
(8)
(16)
benzene
100°
2h
(17)
(5)
(10)
1,4-dioxane 102°
2h
(tr)
(34)
(—)
Solvent
C14
H EtO2C 3
497
0.9 eq
OMe
O
1,4-Dioxane, reflux, 2 h
Mo(CO)5 0.003 M
OMe
CO2Et
OMe
CO2Et
(42)
385
O H
Mo(CO)5 0.83 eq
(33)
THF, reflux, 2 h Ph
OMe
0.003 M
+
385
Ph H (17) OMe Ph
CO2Et
TABLE 14. ALKENYLMOLYBDENUM CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C6
OH Et
Et
O
OMe Mo(CO)5
Et
+
1. Additive, solvent, temp 2. Air, TsOH, THF/H2O
Et
H
Et O
O
Et
H
OMe I
Refs.
+
60
O
II H
O Et
O
Et Et
OMe Et
Mo Et
CO Et III
498 Alkyne (eq)
CC (M)
I
II
III
2
0.5
THF
rt
none
(49)
(12)
(3-5)
Solvent Temp Additive (eq)
499
2
0.05
THF
rt
none
(31)
(33)
(3-5)
20
0.05
THF
rt
none
(58)
(16)
(3-5)
2
0.05
THF
60°
none
(16)
(36)
(—)
2
0.05
THF
110°
none
(6)
(25)
(—)
3
0.05
THF
rt
MeCN (10)
(10)
(59)
(—)
2
0.05
THF
rt
MeCN (100)
(tr)
(6)
(—)
2
0.05
THF
60°
Ph3P (1)
(14)
(47)
(—)
2
0.05
THF
60°
(n-Bu)3P (1)
(—)
(—)
(—)
2
0.05
THF
60°
(MeO)3P (1)
(—)
(—)
(—)
2
0.05
THF
60°
CO (1 atm)
(33)
(11)
(—)
2
0.005
THF
rt
none
(8)
(59)
(—)
200
0.005
THF
rt
none
(36)
(10)
(—)
2
0.005
THF
rt
MeCN (100)
(7)
(58)
(—)
2
0.5
n-heptane rt
none
(69)
(<3)
(—)
2
0.05
n-heptane rt
none
(68)
(<5)
(—)
2
0.005
n-heptane rt
none
(69)
(<1)
(—)
2
0.05
benzene
rt
none
(65)
(—)
(—)
2
0.05
benzene
rt
MeCN (2)
(54)
(6)
(—)
3
0.05
benzene
rt
MeCN (4)
(24)
(34)
(—)
3
0.05
benzene
rt
MeCN (10)
(16)
(33)
(—)
3
0.05
benzene
rt
MeCN (38)
(7)
(46)
(—)
3
0.05
benzene
rt
MeCN (114)
(7)
(43)
(—)
2
0.05
CH2Cl2
rt
none
(53)
(—)
(—)
2
0.05
DMTHF
rt
none
(28)
(36)
(—)
3
0.05
MeCN
rt
none
(5)
(25)
(—)
2
0.05
DME
rt
none
(57)
(14)
(—)
2
0.05
DMF
rt
none
(9)
(14)
(—)
2
0.05
MeOH
rt
none
(11)
(40)
(—)
2
0.05
MeNO2
rt
none
(<10)
(<10)
(—)
OH
H
Et 2 eq
OMe Mo(CO)5
+
1. Solvent, temp, 8-19 h 2. Air, TsOH, THF/H2O
Solvent
Et
Et I
CC (M)
H
OMe
II
Temp
I
II
0.5
THF
50°
(48)
(22)
0.005
THF
50°
(6)
(64)
0.5
n-heptane
50°
(33)
(7)
0.005
n-heptane
50°
(33)
(9)
MeCN
25°
(5)
(27)
0.1
Et
O
60
TABLE 14. ALKENYLMOLYBDENUM CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C6
OH
OH
Refs. O
Et
O Et
OMe
O
+
Solvent, rt O
Mo(CO)5
1.5-2 eq
+ Et
O
I OMe O
0.05 M
OMe H
I
II
III
THF
(23)
(—)
(44)
MeCN
(<10) (26)
(7)
Solvent
O O
O
III Et
C10
OMe
OH
H Ph
O
OMe
500
Ph
(11) +
THF, 50°
C14
Ph Photolysis (pyrex), Ph 10 eq
N 0.005 M
Mo(CO)5
hexane, rt, 7 h
Ph Ph
(59)
71
OMe
Ph
Ph Ph
O Ph
OMe O
0.05 M
Ph
O
Mo(CO)5
1.5-2 eq
71
II
(21) N
190
TABLE 15. ALKENYLMOLYBDENUM CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
Refs.
OH Pr-n OMe
n-Pr 2 eq
Mo(CO)5 0.1 M
(80)
1. THF, rt, 14 h
60
2. Air, TsOH, THF/H2O OMe OH
2 eq
OMe
O
Mo(CO)5
+
1. THF, rt, 24-28 h 2. Air, acid, THF/H2O
60 O
O
H
OMe I
501
Acid
I
II
0.05
TsOH
(51)
(10)
0.005
none
(35)
(14)
OH
Mo(CO)5
+
1. Solvent, temp, 15-45 h
60
2. Air, TsOH, THF/H2O
H
OMe I
CC (M)
Solvent
0.5
THF
0.005
THF
Pr-n
H
Pr-n OMe
O
II
CC (M)
2 eq
Pr-n
H
Pr-n
O
II
Temp
I
II
rt
(86)
(<0.2)
rt
(77)
(—)
0.5
n-heptane
50°
(72)
(<0.8)
0.005
n-heptane
50°
(80)
(<3)
TABLE 15. ALKENYLMOLYBDENUM CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
C14 3
1 eq
OMe
O
THF, 67°, 2 h
O
Mo(CO)5 0.003 M
0.7 eq
OMe
O
THF, 67°, 2 h
CO2Et O
502
0.01 M
CO2Et
THF, 100°, 2 h TMS
Mo(CO)5
(34)
385
3.4:1 mixture of isomers
OMe OH OMe
385
O
0.004 M
TMS
(72)
H
Mo(CO)5
1 eq
Refs.
OMe
EtO2C
O
EtO2C
Product(s) and Yield(s) (%)
385
(30) OMe OH
0.9 eq
OMe
CO2Et
THF, 67°, 12 h (24)
Mo(CO)5 0.003 M
OMe
+
CO2Et (35) O
3:1 mixture of isomers
385
TABLE 16. ARYLTUNGSTEN CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C4 W(CO)5
Ph
Photolysis, toluene, rt
+ polymer
(<10)
63
OMe OMe C6
OH Et
Et Et
W(CO)5
Ph
1. THF, 80°, 42-75 h
Et
Et
+
2. Air, silica gel
OMe
60
Et I OMe Et
1.9 eq
OMe
II Et
Et
+
Et
+ Ph
O
O
503
III
Ph
Et
OMe
O IV
Et
+ Bz
CO2Me
V
CC (M)
I
II
III
IV
V
0.1
(6)
(53)
(—)
(33)
(—)
0.005
(8)
(57)
(17)
(—)
(9)
OH
Et Et
W(CO)5
Ph
1. MeCN, 80°, 62 h
1.9 eq
Et (7) +
+
(4)
2. Air, silica gel
OMe
60
Et
0.005 M
OMe
OMe Et
MeO
Et +
(2) Ph
OMe
O
O
Ph
(3)
Et
Et
TABLE 16. ARYLTUNGSTEN CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Ph
C6 Et
Et
Ph
3 eq
Et
N
W(CO)5
Hexane, 80°, 24 h
(86) Ph
0.014 M
234
Ph
N H O
Ph
W(CO)5
1.9 eq
Et Et
1. Benzene, 80°, 42-73 h
Et
+
2. Workup
OMe
Refs.
Et
+
60
Et I
II
O
O
Et Et Et
Ph
504
III Workup
CC (M)
Et
+
O
O
OMe
IV
I
II
III
IV
0.1
air, silica gel
(—)
(—)
(—)
(6)
0.1
CAN
(3)
(42)
(44)
(—)
0.005
air, silica gel
(—)
(—)
(—)
(1)
0.005
CAN
(2)
(31)
(36)
(—)
Et OMe
4 eq
W(CO)5
Et
1. Benzene, 80°, 46 h 2. Silica gel
(40)
448
O
0.1 M
C7
O
NEt2 O Petroleum ether, 20°, 2 h
NEt2 1 eq
(CO)5W
(72)
(CO)5W SC3H5 0.1 M
SC3H5
168
NEt2
NH2 1 eq
N
Benzene, 20°, 2 h
(CO)5W
(91)
Et
(CO)5W
Ph
430
Ph
0.3 M R
R
R NEt2
1 eq
Hexane, 20°, 2 h
(CO)5W
(CO)5W
OMe I
OMe 0.33 M
I
E:Z
OMe
(61)
10:1
Me
(78)
100:0
H
(74)
100:0
Br
(45)
5:1
CF3
(69)
100:0
359, 141
O NEt2
SR (CO)5W
2 eq
(CO)5W
Et2O, 20°
Ph
Ph
SR
I
0.5 M
+
+ II
505
O
S
445
W(CO)5
R
O + SR
III R
IV
I
II
III
IV
allyl
(82)
(4)
(0)
(0)
Ph
(69)
(0)
(3)
(1)
CH2Ph
(70)
(0)
(22)
(7)
TABLE 16. ARYLTUNGSTEN CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C7
NEt2
Ph
(CO)5W
(CO)5W
NEt2 1 eq
Ph +
Pet ether/ether, 20°, 0.5 h
N
+
N
Ph
0.22 M
Refs.
NEt2
Ph
(82)
(10)
NEt2 Ph
N
Ph NEt2
Ph +
(CO)5W
Ph N Ph
W(CO)5 (3) C9-14
434
N
(3)
Ph Ph
506
Ph
W(CO)5
R
R
Toluene or benzene
63
OMe R
OMe Recovered CC
Temp Time
Me
photolysis
Me
—
Ph
photolysis
Ph
—
rt
72 h
(—)
(50)
100°
18 h
(>90)
(—)
rt
6-10 d
(<10)
(—)
100°
3h
(90)
(—) Ph
C9 Ph
Ph
OR
R=
Toluene, 110°, 1.5 h
(60) (CO)3W
C10
1 eq
(CO)5W 0.25 M
(n-Bu)2O, 90°, 6 h OMe
+
OR
(30) (CO)3W
449
OR
NEt2
Ph NEt2
NEt2
Ph
W(CO)5
(CO)4W Et2N
Ph OMe
(19)
366
H N
C14 Ph
O N
N
Ph
Ph
N
(51)
1. THF, 45°, 18 h
OMe
1.5 eq
237
Ph
2. CAN W(CO)5 0.1 M OMe (CO)5W
O O p-Xylene, 138°, 5 h
0.05 M
OMe
O +
OMe Ph
Fe
Fe
Ph
426
Ph
Fe Ph
(34)
(30)
Ph OMe
4 eq
Ph
Benzene, 80°, 66 h
W(CO)5
(19)
448
OMe
507
0.1 M Ph (CO)3W
EtO (CO)5W 2.2 eq
Ph
EtO
Toluene 2
+
(CO)5W
I
Ph (CO)3W
0.06 M Temp
Time
I
II
70°
3h
(30)
(46)
75°
4h
(0)
(70)
391
OEt Ph
EtO OEt II
Ph Ph OMe
C26
(CO)4W
OMe Ph2P
PPh2
(CO)5W
1 eq
Ph Hexane, 100°, 4 h
Ph
Ph
Ph2P W(CO)4
0.085 M MeO
PPh2
(78)
374
TABLE 17. ARYLTUNGSTEN CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne
Carbene Complex
C3
Conditions
Product(s) and Yield(s) (%)
Refs.
OMe (CO)5W
40°, 45 h
OEt
OEt
C4 EtO
(CO)5W 2 eq
85
Polymer (44)
Ph
100 eq
(CO)5W
Et2O, 0-4°, 24 h
0.25 M
OEt
Ph
(80) E:Z = 9:1
Ph OH
C5 Ph
378
Pr-n Pr-n
Pr-n
W(CO)5
n-Pr
+
1. Solvent, 80°, 30-240 h OMe
2. Air, silica gel
I
+ Ph II
OMe
OMe
OMe
OH
508
O n-Pr
60 O III
Pr-n
+
Ph
OMe
Pr-n
+
+
Ph O
Pr-n V
IV
OMe Ph
MeO CO2Me Pr-n
O
O
Ph
VI
Pr-n
VII
Alkyne (eq)
CC (M)
I
II
III
IV
V
VI
VII
30
0.1
THF
(6)
(6)
(37)
(0)
(10)
(18)
(0)
3.8
0.005
THF
(10)
(9)
(38)
(0)
(7)
(20)
(4)
20-30
0.1
benzene
(7)
(57)
(12)
(1.2)
(19)
(2)
(0)
3.8
0.005
benzene
(6)
(60)
(5)
(6)
(14)
(1)
(0)
3.8
0.005
MeCN
(10)
(9)
(5)
(0)
(1)
(5)
(5)
Temp, 18-22 h
Polymer
C6-8
Solvent
+
OMe (CO)5W
R
85, 63
Ph Alkyne (eq)
Temp
50
40°
R n-Bu
(45)
100
60°
t-Bu
(28)
50
40°
Ph
(55)
Polymer
C8 OMe Cycloalkene (100 eq),
(CO)5W
Ph
Ph
Ph
450, 451
Ph
50°, 21-312 h n
m
509
Alkyne (eq)
Cycloalkene
n
10
cyclopentene
1
(19)
3
cyclopentene
1
(4.9)
2.25
cyclopentene
1
(4.2)
1.75
cyclopentene
1
(7)
1
cyclopentene
1
(15.8)
0.75
cyclopentene
1
(20.3)
0.3
cyclopentene
1
(36.7)
10
cycloheptene
3
(16)
1
cycloheptene
3
(16)
10
cyclooctene
4
(7)
1
cyclooctene
4
(8) Ph
OMe
4 eq
W(CO)5 0.1 M
1. Benzene, 80°, 96 h 2. Silica gel
(40) O
448
TABLE 17. ARYLTUNGSTEN CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C16 OMe (CO)5W
Toluene, 75°, 18-24 h
452
Ph
CC (M)
Alkyne (eq) 1
0.05
(50)
100
0.001
(31)
C17 OMe (CO)5W
Toluene, 75°, 18-24 h
E:Z = 22:78
452
(24)
452
510
Ph E:Z = 44:56 Alkyne (eq)
CC (M)
1
0.05
(41)
100
0.001
(26)
C18 OMe (CO)5W
Toluene, 75°, 18 h Ph
0.001 M 100 eq
TABLE 18. ALKENYLTUNGSTEN CARBENE COMPLEXES WITH INTERNAL ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%) OH
C6
Refs.
Et Et
Et
Et
O
2 eq
OMe
2. Air, TsOH, THF/H2O
Et
+
1. THF, 90°, 24-48 h
W(CO)5
OMe
60
O
Et
O
O
I
CC (M)
I
II
0.5
(58)
(<3)
0.05
(65)
(<3)
0.005
(77)
(<2)
OH
II
Et Et
2 eq
511
OMe
1. Solvent, 90°, 18-32 h
W(CO)5
2. Air, TsOH, THF/H2O
O
I
OMe Solvent
CC (M)
Et
+
I
II (7)
0.1
THF
(45)
0.005
THF
(56)
(8)
0.1
n-heptane
(51)
(23)
0.005
n-heptane
(50)
(38)
0.1
MeCN
(24)
(24)
0.005
MeCN
(8)
(47)
OH Et
O OMe
Et
II
H
O
O (36) +
THF, 80°
(20) 71 Et
W(CO)5
1.5-2 eq
60
Et
OMe
OMe O
0.05 M
TABLE 18. ALKENYLTUNGSTEN CARBENE COMPLEXES WITH INTERNAL ALKYNES (Continued) Alkyne
Carbene Complex
C7
Conditions
Product(s) and Yield(s) (%) NEt2
OEt (CO)5W
Et2N 1 eq
Cyclohexane, 0° 0.5 M
NEt2
Ph
(CO)5W (37) +
(CO)5W
Refs.
OEt (1)
OEt
Ph
Ph OEt
OEt +
(CO)5W Ph
(CO)4W (22) +
Et2N
NEt2
Ph
OEt (CO)5W
512
+
Ph (16)
Et2N
(1)
402
TABLE 19. ALKENYLTUNGSTEN CARBENE COMPLEXES WITH TERMINAL ALKYNES Alkyne C4
Carbene Complex R 2N
Conditions
Product(s) and Yield(s) (%) R2N
Ph Catalyst (2-2.5 mol%),
MeO
OEt 1.5 eq
THF/MeOH (4:1),
MeO
20°, 36 h
W(CO)5
Catalyst
Ph
OEt
0.25 M
OEt
morph-N R1
(CO)5W
THF/EtOH (5:1), R2
NR2
[(COD)RhCl]2 NEt2
(63)
[(COD)RhCl]2 N-morph
(61)
[(CO)2RhCl]2
NEt2
(77)
[(CO)2RhCl]2
N-morph
(74)
RhCl3•3H2O
NEt2
(77)
RhCl3•3H2O
N-morph
(77)
194
R1
[(COD)RhCl]2 (2.4 mol%),
1.5 eq
Refs.
R2
MeO
193
20°, 36-38 h OEt
N-morph 0.25 M
513
R1
R2
1-cyclohexenyl Me
(53)
Ph
Me
(63)
Ph
i-Pr
(59)
Ph
(70) n-Pr
Pr-n
C5
R n-Pr
Hexane, 80°, 24 h W(CO)5
N
Ph 3 eq
Ph
0.014 M
+
R
N H I
Ph
Pr-n OMe W(CO)5 0.005 M
1. THF, 80°, 61 h
I
II
Me
(74)
(<1)
Ph
(76)
(0)
R
OH 2 eq
234
R
N H II
(87)
60
2. Air, TsOH, THF/H2O OMe
TABLE 19. ALKENYLTUNGSTEN CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
OH
H
Pr-n
n-Pr 8 eq
OMe
O
1. THF, 80°, 108-120 h 2. Air, TsOH, THF/H2O
W(CO)5
Refs.
Pr-n
+
60 O
O I OMe
CC (M)
I
II
0.5
(43)
(≤0.4)
0.005
(54)
(—)
H II
O
O Pr-n OMe
4 eq
W(CO)5
1. THF, 80-90°, 38-64 h
60
2. CAN O
514
CC (M) 0.1
(88)
0.005
(96)
R 2N
Ph Catalyst (2-2.5 mol%), OEt W(CO)5
1.5 eq
0.25 M
R2N
Ph
NR2
Catalyst
NMe2
[(COD)RhCl]2
(53)
THF/MeOH (4:1),
N-morph [(COD)RhCl]2
(58)
20°, 36 h
NMe2
[(CO)2RhCl]2
(74)
N-morph [(CO)2RhCl]2
(75)
NMe2
RhCl3•3H2O
(78)
NEt2
RhCl3•3H2O
(74)
N-morph RhCl3•3H2O
(76)
NHMe
[(CO)2RhCl]2
(0)
NHEt
[(CO)2RhCl]2
(0)
NHMe
RhCl3•3H2O
(0)
NHEt
RhCl3•3H2O
(0)
OEt
194
N-morph R1
OEt R1
(CO)5W
[(COD)RhCl]2 (2.4 mol%),
1.5 eq
R2
THF/EtOH (5:1), R2
193
(59)
20°, 28-36 h OEt
N-morph 0.25 M R1
R2
1-cyclohexenyl Me
(59)
Ph
Me
(68)
Ph
i-Pr
(68)
Ph
(71)
C8 R 2N
Ph OEt
Ph
THF/MeOH (4:1),
194
20°, 36 h
515
W(CO)5
1.5 eq
R2N
Catalyst (2-2.5 mol%),
0.25 M
OEt
Catalyst
NR2
[(COD)RhCl]2
NEt2
(61)
[(COD)RhCl]2
N-morph
(60)
RhCl3•3H2O
NMe2
(73)
RhCl3•3H2O
NEt2
(71)
RhCl3•3H2O
N-morph
(71)
N-morph Ph
OEt (CO)5W
[(COD)RhCl]2 (2.4 mol%),
Ph
1.5 eq R
R R
THF/EtOH (5:1), 20°, 30-32 h
Me
(62)
i-Pr
(59)
193
OEt
N-morph 0.25 M
TABLE 19. ALKENYLTUNGSTEN CARBENE COMPLEXES WITH TERMINAL ALKYNES (Continued) Alkyne C8
Carbene Complex R 2N
Product(s) and Yield(s) (%) R2N
Ph RhCl3•3H2O (2 mol%), OEt
Ph 1.5 eq
Conditions
(CO)5W
Refs.
Ph NR2
Ph
THF/MeOH (4:1),
NMe2
(76)
20°, 36 h
NEt2
(77)
OEt
194
0.25 M Ph
OEt 2.5 eq
NHMe
(CO)5W
THF, 70°, 12 h
NMe
(CO)5W
Ph
0.1 M
morph-N [(COD)RhCl]2 (2.4 mol%),
516
1.5 eq
THF/EtOH (5:1),
Ph OEt
(CO)5W
410
Ph
R
morph-N
(53)
0.25 M
Ph
Ph
193
R
20°, 36 h OEt
R Me
(69)
i-Pr
(71) (69)
C11 TMSO
morph-N
morph-N Ph (CO)5W
1.5 eq
0.25 M
Ph
[(COD)RhCl]2 (2.4 mol%),
OEt
THF/EtOH (5:1), 20°, 38 h
(61)
TMSO OEt
193
TABLE 20. CARBENE COMPLEXES OF NON-GROUP VI METALS WITH ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C4
Refs.
Ph H
PF6–
Cp(CO)2Fe 3 eq
+
+
CH2Cl2, –78° to rt
Ph
PF6– I
+ Cp(CO)2Fe CH2Ph (—)
Cp(CO)2Fe PF6–
I + II = (75)
453
II
O Ph
10 eq
(89)
198
EtO
Fe(CO)4
EtO
Ph
O
CH2Cl2, 78°, 1 h
Fe(CO)3
O
Fe(CO)4 4.9 eq
60°, 1 h
517
Ph
Ph
NMe2 0.2 M
NMe2
O
Ph
O
+
I
II +
197
Me2N Fe(CO)3
O O
Fe(CO)3
+
III
IV
Me2N (OC)3Fe
Ph Fe(CO)3 Atmosphere
Solvent
I
II + III
III
CO (55 psi)
CH2Cl2
(47)
(13)
(0)
(20)
(47)
(0)
CO (650 psi) (CH2)2Cl2 Ar (40 psi)
CH2Cl2
(73)
(0)
(21)
Ar (15 psi)
THF
(62)
(0)
(4)
CO2Et N
EtO2C
Ph
2 eq
Ph
N
Photolysis, Et2O, 20°
(79)
454
Ph
Ph
(CO)3Fe
(CO)3Fe
0.01 M
TABLE 20. CARBENE COMPLEXES OF NON-GROUP VI METALS WITH ALKYNES (Continued) Alkyne C4
Carbene Complex Ph3Sn
Conditions
Product(s) and Yield(s) (%)
Co(CO)3 Benzene, 50°, 6 h
Ph 2.5 eq
Refs.
Ph
OMe 0.007 M
(75)
200
(33)
198
OMe
O O
Fe(CO)4 Et
Ph
O CO (55 psi),
EtO
Ph
CH2Cl2, 70°, 1 h
10 eq
EtO Et Fe(CO)3 MeO2C
Fe(CO)4 MeO2C
CO2Me
THF EtO
Ar
I EtO
4.9 eq
O
+
Ar
518
Ar
I
II
Ph
(15)
(4)
2-MeOC6H4
(78)
(0)
3-MeOC6H4
(22)
(1)
4-MeOC6H4
(42)
(11)
CO2Et N
2 eq (CO)3Fe
CO2Et
Ph Photolysis, Et2O, 20° Ph
N Fe(CO)3
Ph
Ar
O
Ph
CO2Et
Ph
N
(38) MeO2C
+
Ph MeO2C
CO2Et Ph N+
0.01 M +
455
II EtO
Ph
O (CO)3Fe CO2Me
(11)
(44)
454
C5 n-Pr Ph
ClCH2CH2Cl, 60°, 1 h
NMe2
4.9 eq
n-Pr
n-Pr
Fe(CO)4
Ph
0.2 M
+
(64) NMe2
O
(4) Ph
197
Pr-n
O Fe(CO)4 MeO2C
EtO
Ph
O CO (55 psi), CH2Cl2,
Ph
(15) Fe(CO)3
MeO2C
Ar
THF
OEt
519
Ar
I
II
Ph
(25)
(42)
2-MeOC6H4
(0)
(79)
3-MeOC6H4
(30)
(19)
4-MeOC6H4
(0)
(80)
455
OEt
O
CO2Me (73)
ClCH2CH2Cl, 60°, 1 h
NMe2 0.2 M
Ph
Et
197
NMe2
O Et
Fe(CO)4 Et
II Ar
OEt
O
Fe(CO)4
C6
+
I Ar
4.9 eq Ph
MeO2C
CO2Me
Fe(CO)4 4.9 eq
198
EtO
70°, 1 h
10 eq
Et
Solvent, 60°, 1 h Ph
4.9 eq
NMe2
Ph3Sn
NMe2
O
Solvent
0.2 M
2.5 eq
197 Ph
THF
(45)
ClCH2CH2Cl
(74) Et
Co(CO)3
Et (93)
Benzene, 50°, 6 h Ph
Ph OMe 0.007 M
200
OMe
O
TABLE 20. CARBENE COMPLEXES OF NON-GROUP VI METALS WITH ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
R2
C6
1. Photolysis, pyrex filter, n-Bu
R2
+
520
Et Et
181
I
2. CAN O
II
O
R2
R 1O R1
R2
I
II
Me
H
(0)
(5-10)
TiCp2Cl
H
(30)
(5-10)
TiCp2Cl
Me
(28)
(5-10)
OC
R2
O
Bu-n
THF, 20°, 5 h MnCp'(CO)2
5 eq
Refs.
O
Ph
OC
Ru OMe H B B Cl B H Co
O Bu-n (18)
1. Toluene, reflux, 3 h
199
2. CAN O
0.04 M
MeO2C 4.9 eq
OEt
CO2Me
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
+
THF CO2Me
R
R
CO2Me
OH
Fe(CO)4
OEt
455 CO2Me
I
R
R in I
H 2-OMe
I
II
H
(21)
(9)
5-OMe
(5)
(5)
3-OMe
6-OMe
(33)
(2)
4-OMe
7-OMe
(93)
(<1)
II
CO2Me
C6
MeO2C
Fe(CO)4 MeO2C
CO2Me NMe2
Ph Solvent
CO2Me CO2Me
II
CH2Cl2
(50)
(0)
ClCH2CH2Cl
(35)
(24)
THF
(16)
(13)
Ph Ph Photolysis, Et2O, 20°
N
E*
Ph
Ph (62)
(11)
+
E*
Ph
E
E
E
II
Ph
E*
N
Ph
(CO)3Fe
MeO2C I
CO2Et N
CO2Me 197
NMe2
O I
0.2 M
2 eq
MeO2C +
Solvent, 60°, 1 h Ph
4.9 eq
CO2Me
0.01 M
454
E
N
521
+
Ph
O (CO)3Fe NEt2
Ph Et2N
Cp'(CO)2Mn 1 eq
Hexane, 70°, 22 h
Cp'(CO)2Mn
Ph
OMe
0.4 M
Benzene, 80°, 2 h NH2
430
Et
Cp'(CO)2Mn
NEt2
NH2 Benzene, 20°, 2 h Ph
0.3 M
(66)
N Ph
(CO)5Mn(CO)4Mn
1 eq
456
NEt2
Ph 0.3 M
(76) E:Z = 10:1
OMe
Cp'(CO)2Mn
1 eq
E* = CO2Et
E
E
C7
E = CO2Me
(7)
N
(83)
Et
(CO)5Mn(CO)4Mn
430
Ph
TABLE 20. CARBENE COMPLEXES OF NON-GROUP VI METALS WITH ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
O
C8 Fe(CO)4 Ph
Ph
O CO (55 psi), CH2Cl2,
EtO
10 eq
Ph
70°, 1 h
(74) EtO Ph
Fe(CO)3 Ph
Ph
Fe(CO)4 4.9 eq
+
Solvent, 60°, 1 h Ph
198
NMe2
Ph
197
NMe2
O
Ph
I
II
O Ph
Ph
522 N
2 eq (CO)3Fe
III
Solvent
I
II
III
IV
CH2Cl2
(18)
(0)
(0)
(0)
ClCH2CH2Cl
(16)
(15)
(0)
(30)
THF
(12)
(13)
(18)
(0)
EtO2C
Ph
N
Ph
IV
Ph
Photolysis, Et2O, 20°
(74) Ph
Ph
Ph
+ Ph
CO2Et
Ph
Me2N
+
Ph OH
454
Ph Fe(CO)3
0.01 M C10
OBu-t t-BuO
Fe(CO)4 t-BuO 4.9 eq
OBu-t Ph
NMe2 0.2 M
OH OBu-t
CH2Cl2, 60°, 1 h
(6) t-BuO
OBu-t OBu-t
t-BuO
Ph
t-BuO
(5) 197 OBu-t
+
OBu-t
C13 OMe MeO2C
OMe Cp'(CO)2Mn
MeO2C
CH2Cl2, 60°, 1 h Ph
MeO2C
Ph (68)
457
(93)
198
MeO2C
C14
O Fe(CO)4 Ph
Ph 10 eq
EtO
70°, 1 h
Ph
Ph3Sn 1.2 eq Ph
Ph
O
CO (55 psi), CH2Cl2, EtO
Ph Ph Fe(CO)3
Ph Co(CO)3 OMe
0.007 M
Ph
Heptane, 50°, 6 h
(58) Ph
O
OMe
200
523
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C13
R
OH
R1
1. RC CH (3 eq),
(CO)5Cr
MeO
R
R
benzene, 70°, 12-24 h
+
78
+
2. Silica gel
0.005 M
Refs.
OH I
O III
II O
R1
R
OMe OMe
I
II
III
IV
H
(9) (10) (8)
(34)
Me
(6)
(54)
(2)
(3)
R
OMe
+ O
IV
OH
C13-16
Pr-n
1. n-PrC CH (x eq),
524
solvent, 60-85°, 4-24 h
+
I + II + IV R = n-Pr +
2. Workup
VI
V 1
CC (M)
x
Solvent
Workup
I
II
IV
V
VI
OMe
0.005
3
benzene
silica gel
(3)
(15)
(55)
(—)
(—)
OMe
0.005
3
benzene
Zn/HOAc
(2)
(12)
(—)
(—)
(—)
OMe
0.005
3
benzene
silica gel
(—)
(—)
(54)
(—)
(—)
OMe
0.5
3
benzene
TiCl3/LAH
(7)
(5)
(—)
OMe
0.5
3
benzene
silica gel
(—)
(—)
(14)
(—)
(—)
OMe
0.05
3
benzene
TiCl3/LAH
(5)
(11)
(—)
(<0.1)
(0.6)
OMe
0.05
3
benzene
silica gel
(—)
(—)
(38)
(—)
(—)
OMe
0.005
3
benzene
TiCl3/LAH
(2)
(13)
(—)
OMe
0.005
3
benzene
silica gel
(—)
(—)
(53)
OMe
0.05
10
benzene
TiCl3/LAH
(8)
(2)
(—)
OMe
0.05
10
benzene
Silica gel
(—)
(—)
(41)
(—)
(—)
OMe
0.05
10
THF
TiCl3/LAH
(7)
(<0.3)
(—)
(<0.1)
(<1)
OMe
0.05
10
THF
silica gel
(—)
(—)
(23)
(—)
(—)
OMe
0.05
10
MeCN
TiCl3/LAH
(15)
(<0.5)
(—)
OMe
0.05
10
MeCN
silica gel
(—)
(—)
(<1)
(—)
(—)
OMe
0.08
3
MeCN
silica gel
(41)
(—)
(—)
(—)
(—)
OMe
0.005
2.5
MeCN
silica gel
(17)
(—)
(—)
(—)
(—)
OMe
0.08
2
hexane
silica gel
(4)
(—)
(43)
(—)
(—)
OMe
0.01
2
hexane
silica gel
(10)
(9)
(56)
(—)
(—)
OMe
0.005
2
hexane
silica gel
(10)
(10)
(57)
(—)
(—)
OMe
0.004
1.2
hexane
silica gel
(2)
(2)
(24)
(—)
(—)
N-pyrrolidinyl
0.05
10
THF
TiCl3/LAH
(2)
(16)
(—)
(<1.0)
(7)
N-pyrrolidinyl
0.05
10
THF
silica gel
(—)
(—)
(16)
(—)
(—)
N-pyrrolidinyl
0.05
10
benzene
TiCl3/LAH
(2.4)
(14)
(—)
(<0.2)
(3)
N-pyrrolidinyl
0.05
10
benzene
silica gel
(—)
(—)
(17)
(—)
(—)
N-pyrrolidinyl
0.5
10
benzene
TiCl3/LAH
(3)
(11)
(—)
(<1.0)
(5)
N-pyrrolidinyl
0.5
10
benzene
silica gel
(—)
(—)
(11)
(—)
(—)
N-pyrrolidinyl
0.05
10
MeCN
TiCl3/LAH
(<0.3)
(<0.2)
(—)
N-pyrrolidinyl
0.05
10
MeCN
silica gel
(—)
(—)
(<1)
R
58, 246 OH
Pr-n
(<0.8) (<1.2)
(<0.3) (<1.0) (—)
(—)
(<0.2) (<0.6)
(<0.5) (<0.5)
525
(<0.2) (<0.3) (—)
(—)
C13 OMe (CO)5Mo
1. n-PrC CH (3 eq), benzene, 60-85°, 4-24 h
I + II + IV + V + VI R = n-Pr
58, 246
2. Workup CC (M)
Workup
I
II
IV
0.5
TiCl3/LAH
(36)
(<0.4)
(—)
0.5
silica gel
(—)
(—)
(1)
0.05
TiCl3/LAH
(43)
(<0.5)
(—)
0.05
silica gel
(—)
(—)
(5)
0.005
TiCl3/LAH
(48)
(<0.5)
(—)
0.005
silica gel
(—)
(—)
(20)
V
VI
(<0.4) (<0.4) (—)
(—)
(<0.5) (<0.4) (—)
(—)
(<0.5) (<1.0) (—)
(—)
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C13 OMe (CO)5W
1. n-PrC CH (3 eq), benzene, 60-85°, 4-24 h
I + II + IV + V + VI R = n-Pr
58, 246
2. Workup Workup
I
II
0.5
TiCl3/LAH
(17)
(<0.5)
CC (M) 0.5
silica gel
(—)
(—)
0.05
TiCl3/LAH
(27)
(<3.0)
526
0.05
silica gel
(—)
(—)
0.005
TiCl3/LAH
(29)
(<1.0)
0.005
silica gel
(—)
(—)
OMe
1. n-PrC CH (3 eq), MeOH (x eq), benzene,
(CO)5Cr
60-85°, 12-24 h 0.005 M
IV
V
(<0.5) (—) (<0.5) (—)
(—)
(—) (<1.0) (<2.0) (0.2)
(—)
(—)
OMe O I + II + IV R = n-Pr +
246
VII OMe
2. Silica gel x
I
II
IV
VII
0
(2)
(12)
(54)
(—)
5
(—)
(—)
(41)
(1)
10
(—)
(—)
(42)
(4)
20
(4)
(9)
(35)
(8)
50
(2)
(4)
(34)
(9)
100
(1)
(3)
(11)
(49)
200
(3)
(3)
(12)
(49)
500
(3)
(1)
(4)
(74)
OMe
1. RC CH (3 eq),
O
R +
MeOH, 45°, 36-42 h I CC (M)
R
246
OMe
2. Silica gel II
I
II
III
0.21
n-Pr
(18)
(18)
(11)
0.07
n-Bu
(21)
(27)
(13)
0.005
n-Pr
(9)
(12)
(45)
R OMe O
+ OMe III
OH
O
1. TMSC CH (3 eq), 0.005 M
(—)
(—) (<0.5) (<0.5)
OH OMe (CO)5Cr
VI
(—) (<0.5) (<0.5)
TMS
TMS
OMe
(8) +
benzene, 70°, 12-24 h
(46)
78
(27)
78
2. Silica gel O
527
MeO
1. EtC CEt (3 eq), 0.005 M
Et
O Et
Et
benzene, 70°, 12-24 h 2. Silica gel
OMe
+
(11)
Et
O
O O 1. RC 0.005 M
3
CH (3 eq),
benzene, 70°, 12-24 h 2. Silica gel
O OH
1. PhC CH (3 eq),
MeO
Ph
solvent, 15-36 h
H
(36)
TMS
(39)
Ph
OMe
+
458, 78, 246
O I
II
Temp
I
THF
45°
(7)
benzene
70°
(16) (20) (54)
MeCN
45°
(43) (—) (—)
II
III
(—) (—)
78
CO2Bu-t (41) O
Ph
+
2. Silica gel Solvent
R
OMe R
O
III
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C13
OH OMe
1. n-BuC CH (3 eq),
(CO)5W
Refs.
Bu-n Bu-n
THF, 85°, 48 h
+
(26)
(42)
458
+
246
Bu-n
2. Silica gel n-Bu OH OMe
1. R1C CPh (2-3 eq),
(CO)5Cr
OMe R1
Ph
R2OH, 45°, 48 h
OR2
R1
2. Silica gel I
0.07 M
II
2
I
II
III
H
Me
(36)
(40)
(12)
H
i-Pr
(37)
(14)
(<1)
Ph
Me
(5)
(<1)
(41)
R
1
R
528
1. RC CPh (3 eq),
(CO)5W
Ph
OMe O OR2 III
OH OMe
O
+
Ph
O
Ph +
solvent, 85°, 48 h 2. Silica gel
Ph
+
O
458
R I
0.07 M
II
Ph
Solvent
R
I
II
III
THF
H
(50)
(24)
(—)
MeCN
H
(8)
(—)
(40)
THF
Ph
(7)
(—)
(—)
C14
Ph
R
III
O OMe
1. n-PrC CH (3 eq),
(CO)5Cr
n-Pr
OMe
benzene, 70°, 12-24 h
+
(37)
(30) O
2. Silica gel
78
OMe
O
0.005 M
C15 O
1. THF, 75°, 14 h
O
2. (n-Bu)3P, acetone, 50°, 5 h
(CO)5Cr
(12-14)
3. MeOH, CCl4
114
O
O 0.5-0.005 M
OH
O (CO)5Cr
1. CH2Cl2, –20°
O
2. –20° to 25°
(tr) O
114
O
O C16-17
O
O O SiMe2
1. PhC CPh (10 eq),
R1
2. CAN
R3
hexane, reflux, 1 h
(CO)5Cr
86
529
R2
OH O
R1 2-propenyl 2-furyl
CC (M)
R2
R3
—
Me
H
0.01l
—OCH=CH—
C16-19
OAc R O
(CO)5Cr
1. Et2O, 25-35°, 20-44 h 2. PPh3, Ac2O, Et3N
Ph 0.04 M
n
R
O
n
(62) (75) R
n
H
1
(16)
H
2
(18)
H
3
(38)
Me
1
(81)
Me
2
(62)
Me
3
(62)
214, 90
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C16-18
3 R1 R
R1
H N (CO)5Cr
R2 R3
H
Toluene, 110°, 2-2.5 h
C17
222, 221 N
R2
MeO 0.03 M
Refs.
OMe
R1
R2
R3
H
H
H
H
Me
H
(0)
Me
H
H
(50)
Et
H
H
(50)
Me
H
D
(—)a
Cr(CO)3
(0)
530
OMe
OMe
O
O
(CO)5Cr
Benzene, 70°, 16-24 h
245, 247
(41)
0.005 M C17-20
OH
OMe
245, 247
Solvent, 110°, 16-24 h
(CO)5W m
0.005 M
m
n
n
m
n
Solvent
1
1
benzene
(30)
1
1
MeCN
(48)
1
2
MeCN
(61)
1
3
MeCN
(38)
2
2
MeCN
(36)
2
3
MeCN
(—)
OMe
C17-28 (CH2)n
MeO
OMe
OMe (CO)5Cr Solvent, 16-24 h
(CH2)n
OH HO OH
(CH2) n OH OH
+
(CH2)n
(CH2) n +
n
0.005 M
I
OMe
II (CH2) n
OMe
OH +
III
OMe
531
n
Solvent
Temp
I
II
III
6
hexane
60°
(4)
(10)
(—)
6
benzene
60°
(4)
(14)
(—)
6
CH2Cl2
60°
(14)
(26)
(—)
6
MeCN
60°
(19)
(27)
(—)
6
THF
60°
(9)
(36)
(—)
6b
THF
60°
(9)
(19)
(—)
6
THF
100°
(18)
(39)
(—)
8
THF
100°
(2)
(15)
(43)
10
THF
100°
(—)
(5)
(58)
13
THF
100°
(—)
(—)
(65)
17
THF
100°
(—)
(—)
(60)
215, 459
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C17-27 (CH2)n
OMe (CO)5Cr
OH
O
Solvent, 12-22 h
+
n
+
I
0.002 M
(CH2)n
(CH2)n
OH
+
II
OMe
176, 217
III
OMe
OMe (CH2)n
(CH2)n
OH MeO
HO
IV
(CH2)n
532
OMe
C17-18
OMe
+
HO
V
n
Solvent
Temp
I
II
III
IV
V
6
THF
100°
(—)
(—)
(—)
(—)
(36)c
6
benzene
100°
(—)
(—)
(—)
(—)
(28)c
10
THF
70°
(8)
(31)
(30)
(—)
(10)
10
THF
100°
(4)
(42)
(15)
(tr)
(8)
10
MeCN
100°
(17)
(11)
(24)
(—)
(5)
10
CH2Cl2
100°
(22)
(—)
(<2)
(17)
(12)
10
hexane
100°
(22)
(—)
(—)
(29)
(8)
10
benzene
100°
(40)
(—)
(tr)
(21)
(12)
13
THF
65°
(1)
(40)
(20)
(—)
(6)
13
THF
100°
(5)
(38)
(16)
(2)
(10)
13
benzene
100°
(14)
(—)
(—)
(18)
(26)
16
THF
100°
(56)
(2)
(1)
(—)
(10)
16
benzene
100°
(48)
(—)
(—)
(2)
(9)
OAc
Me N
γ-Terpinene (100 eq),
(CO)5Cr
0.02 M
R
TMS
(—)
THF, 85°
t-Bu
(31)
N
R
C18
R
Ac2O (3 eq), Et3N (4 eq),
127
Me OH
O
1. THF, 75°, 14 h
(CO)5Cr TMS
O (76)
2. (n-Bu)3P, acetone, 50°, 5 h
114
3. CCl4, MeOH, rt, 16 h 0.2 M
O
O
O O O SiMe2
R2
533
(CO)5Cr R1
Ar 0.01 M
R1
1. Solvent, reflux, 1 h
86
OH
2. CAN O
R1
Ar
Solvent
Additive
R2
Me
Ph
THF
none
H
(24)
Me
Ph
hexane
none
H
(34)
H
4-MeC6H4
THF
none
Me
(14)
H
4-MeC6H4
hexane
PhC CPh (10 eq)
Me
(40) OMe
OMe
R
OMe
R
(CO)5Cr +
t-BuOMe, 55°, 2 h
460
R R
R
(CO)3C r
OMe
OMe
R n-Pr
(30)
(30)
TMS
(—)
(—)
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C19 Bu-t
OMe OMe
(CO)5Cr t-BuOMe, 55°, 2 h
(38)
461
MeO
t-Bu t-Bu
O
O O
(CO)5Cr
O +
(20)
Benzene, 60°, 1.5 h
(51)
O
243
O
OH
534
OAc
O
1. Additive (10 eq),
(CO)5Cr
solvent, reflux, 1 h 2. PPh3 0.01 M
3. Ac2O, pyridine
O
TBSO
OMe (CO)5Cr
1.
Solvent
Additive
THF
none
(38)
hexane
none
(40)
hexane
PhC CPh
(39)
HO
HO
, OMe MeCN, rt, 16 h, CO (1 atm)
245, 247
+ (10)
(52)
2. 110°, 23 h HO H
86
TBSO TMS
TMS N
(CO)5Cr
Benzene, 87°, 12 h
(40)
128
(22)
128
N
0.25 M (E:Z = 1:1)
(CO)5Cr
OH
H
Ph
N (CO)5Cr
Benzene, 85°, 12 h 0.25 M Ph
(E:Z = 3.5:1)
H
O O SiMe2
N O OH
1. Additive (x eq), solvent,
(CO)5Cr
reflux, 1 h
OH
2. CAN
+
+
I
O
86
II
O
O
0.01-0.3 M
R1 + O
III
R2 IV
535
Additive
x
Solvent
I
II
III
IV
O R1
none
—
THF
(17)
(8)
(10)
(0)
—
—
none
—
benzene
(19)
(2)
(16)
(0)
—
—
none
—
hexane
(33)
(0)
(0)
(0)
—
—
2,6-di-tert-butylpyridine
—
hexane
(28)
(0)
(0)
(0)
—
—
Ac2O
1.5
hexane
(26)
(2)
(0)
(0)
—
—
diphenylacetylene
10
THF
(26)
(—)
(—)
(—)
—
—
diphenylacetylene
2
hexane
(50)
(6)
(—)
(—)
—
—
diphenylacetylene
5
hexane
(70)
(8)
(—)
(—)
—
—
diphenylacetylened
5
hexane
(61)
(4)
(—)
(—)
—
—
diphenylacetylene
10
hexane
(83)
(3)
(—)
(—)
—
—
diphenylacetylened
10
hexane
(85)
(3)
(—)
(—)
—
—
diphenylacetylene, CO (1 atm) 10
hexane
(45)
(6)
(—)
(—)
—
—
1-hexyne
10
hexane
(31)
(4)
(—)
(24)
n-Bu H
3-hexyne
2
hexane
(39)
(6)
(—)
(22)
Et
Et
3-hexyne
5
hexane
(48)
(4)
(2)
(21)
Et
Et
3-hexyne
10
hexane
(51)
(11)
(4)
(19)
Et
Et
R2
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
C19
O O SiMe2
Conditions
Product(s) and Yield(s) (%) O
Refs.
O
1. Additive, solvent,
(CO)5Cr
Et +
reflux, 1 h 2. CAN
0.01-0.3 M
I
Additive
Solvent
none none
86
OH
Et
II
O
O
536
I
II
THF
(23)
(0)
benzene
(24)
(0)
none
hexane
(26)
(0)
2,6-di-tert-butylpyridine
hexane
(22)
(0)
diphenylacetylene (2 eq)
benzene
(22)
(0)
diphenylacetylene (10 eq)
hexane
(60)
(0)
3-hexyne (10 eq)
hexane
(41)
(14)
OAc 1. THF, reflux, 1 h 2. TBAF, Et2O
0.01-0.3 M
(33) OAc
3. TMSCl, MeOH 4. Ac2O, pyridine
O O SiMe2
+
OAc (6)
86
O
OAc O MeO
(CO)5Cr 1. CH2Cl2, reflux
Ar Ar = 4-MeOC6H4
86
(26) OH
2. CAN O O 1. PhC CPh (10 eq), hexane, reflux, 1 h
Ar = 2-MeOC6H4
(41)
86
OH
2. CAN MeO
O
O O SiMe2
O 1. Additive (10 eq), hexane,
(CO)5Cr
MeO
MeO +
reflux, 1 h 0.01-0.03 M
+
I O
II
OH
O
OMe
O Additive
O O SiMe2
Et
MeO
I
II
III
none
(21)
(tr)
(0)
PhC CPh
(39)
(tr)
(0)
EtC CEt
(29)
(tr)
(14)
Et III O
O Additive
1. Additive (10 eq), hexane,
(CO)5Cr
none
reflux, 1 h
(38)
86
PhC CPh (62)
2. CAN
MeO
86
OH
2. CAN
537
0.01 M
MeO
O
OH
O O O SiMe2
OH 1. Solvent, reflux, 1 h
(CO)5Cr
+
2. Workup Ph
0.01 M
I
O
86 II
OH
Solvent
Workup
I
II
THF
CAN
(27)
(6)
benzene
TBAF, HCl, CAN
(25)
(3)
OH
O
OMe (CO)5Cr
Benzene, 70°, 16-24 h 0.005 M
O
(24) +
O O (19)
245, 247
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
Conditions
Product(s) and Yield(s) (%) OH
C19-20
MeO
OMe (CO)5Cr
+
Solvent, 70°, 16-24 h
Refs.
O
245, 247
n
0.005 M
n
n
n
Solvent
I
II
1
benzene
(57)
(—)
1
(n-Bu)2O
(50)
(5)
1
THF
(61)
(7)
1
MeCN
(31)
(41)
1
DMF
(10)
(16)
2
benzene
(33)
(0)
538
C20-23 O
1. PhC CPh (5 eq),
O n O SiMe2
R
150 W Xe Arc
Cp'(CO)2Mn
(345 nm filter),
n
O
2. CAN R
182
OH
CH2Cl2, 20°
R
n
H
1
(30)
Me
1
(20)
Me
2
(22)
Me
3
(23)
C20 O O
OMe
(39)
Benzene, 70°, 16-24 h
(CO)5Cr
245, 247
0.005 M O O SiMe2 (CO)5Cr
O 1. Additive (10 eq), solvent, reflux
86 OH
2. CAN O 0.01-0.3 M
539
Additive
Solvent
none
THF
(15)
PhC CPh
hexane
(48) OAc
O O (CO)5Cr Ph
1. Et2O, 35°, 20 h
(65)
2. PPh3, Ac2O, Et3N, 17.5 h O
O
214
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
C20
O O SiMe2
Conditions
Product(s) and Yield(s) (%)
Refs.
O OH
1. Additive (x eq),
(CO)5Cr 0.01-0.03 M
+
+
solvent, reflux
86
OH
2. CAN I
O
II
O
O
R1 R2 III O
540
Additive none none nonee none none diphenylacetylene diphenylacetylene diphenylacetylene 1-hexyne 3-hexyne 3-hexyne
x — — — — — 5 10 10 10 5 10
Solvent THF benzene benzene toluene hexane THF benzene hexane hexane hexane hexane
II (4) (5) (5) (—) (0) (6) (—) (5) (0) (10) (0)
I (30) (27) (25) (25) (27) (29) (55) (65) (54) (61) (75)
III (0) (0) (0) (0) (0) (0) (0) (0) (15) (6) (9)
R1
R2 — — — — — — — — H Et Et
— — — — — — — — n-Bu Et Et
OAc OAc
1. Solvent, reflux +
2. TBAF, Et2O
86
OAc
3. TMSCl, MeOH I
4. Ac2O, pyridine Solvent
II
OAc I
II
THF
(38)
(7)
hexane
(40)
(4)
O O SiMe2
O
O
HO
MeO
1. Additive (10 eq),
(CO)5Cr
MeO
OH
+
+
solvent, reflux
86
2. CAN I OMe
Additive
O O SiMe2
Solvent
II
O I
II
O O
III
none
THF
(20)
(6)
(0)
none
hexane
(31)
(0)
(0)
PhC CPh
hexane
(55)
(0)
(0)
EtC CEt
hexane
(40)
(4)
(7)
MeO
Et Et III O
O 1. PhC CPh (10 eq),
(CO)5Cr
hexane, reflux
541
MeO
86
(59) OH
2. CAN OMe O O O SiMe2
O MeO
(CO)5Cr 1. THF, reflux
OH
(30)
86
2. CAN O OMe OMe
OH
N (CO)5Cr
Ph
Hexane, 70°
(53) N
462
Ph
Ph 1. PhC CPh (10 eq),
N (CO)5Cr
Ph
benzene, reflux 2. Air, silica gel Ph
N
Ph
(31) +
Ph
CN
(48)
219
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
Me
C20
N
OH
(CO)5Cr
Solvent
1,4-Cyclohexadiene (100 eq), N
solvent, 80°
0.01 M
Ph
Me
Ph
THF
(25)
toluene
(15)
MeCN
(6)
127
OAc
Hydrogen source, Ac2O (3 eq), Et3N (4 eq),
127 N
THF, 85° Hydrogen Source
CC (M)
Ph
Me
1,4-cyclohexadiene (100 eq)
(43)
0.01
1,4-cyclohexadiene (10 eq)
(34)
0.01
1,4-cyclohexadiene (100 eq)
(63)
0.02
1,4-cyclohexadiene (100 eq)
(49)
0.02
γ-terpinene (100 eq)
(53)
542
0.005
(CO)3Cr 0.02 M
OSiEt3
HSiEt3 (100 eq),
(41) N
THF, 85°, 13 h
127
Ph
Me (CO)3Cr 0.02 M
(CO)3Cr
OSiEt3 (7)
DSiEt3 (100 eq), N
THF, 85°, 13 h
OSiEt3
+
(2.2) N
Ph
Me
Me
127
Ph D
Me N
γ-Terpinene (100 eq),
(CO)5Cr
R = 1-cyclohexenyl
OAc
Ac2O (3 eq), Et3N (4 eq),
(41) N
THF, 85° 0.02 M
C21
Me
R
O O SiMe2 Cp'(CO)2Mn
127
R
1. PhC CPh (5 eq),
O
150 W Xe Arc (345 nm filter),
(45)
OAc
CH2Cl2, 20° 2. CAN
182
O
3. Acetylation OMe
OMe
(CO)5M
M
(CO)4M Photolysis, Et2O, –44°
Ph
Ph
OMe
Cr
(—)
W
(51)
463
OMe
(CO)5Mo
(CO)4Mo 10–3
mbar, 45°
543
Ph
463
(—) Ph OMe Ph
OMe (CO)5Cr 1. t-BuOMe, 55°, 2 h Ph
463
(55)
2. Air Ph OMe O O SiMe2
(CO)5Cr MeO
O 1. PhC CPh (10 eq), hexane, reflux
OH
2. CAN OMe O
(65)
86
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C21 O O SiMe2
O 1. Additive (10 eq),
(CO)5Cr
O
R
R
Et
86
OH
2. CAN
R
I
O
Et
Additive
Me
PhC CPh
(50)
(0)
Me
EtC CEt
(25)
(14)
OMe
PhC CPh
(37)
(0)
I
O
II
R
O O SiMe2
Et
+
hexane, reflux
II
O 1. EtC CEt (10 eq),
(CO)5Cr
hexane, reflux
+
Et
+ Et
544
2. CAN OH
O
(53)
(17)
86
O
O Et Et (9)
Et
O
O O SiMe2
1. PhC CPh (10 eq), hexane, reflux
(CO)5Cr
+
(73)
Et
Et
2. CAN MeO
MeO H
O
O
MeO
OH
(4)
86
O
TMS
TMS N
(CO)5Cr
Benzene, 88°, 12 h
Ph
(57)
128
N Ph
0.25 M
Cr(CO)5
TMS TMS Benzene, 80°, 12 h
N H
Ph
(60)
128
N
(CO)5Cr
Cr(CO)5 Ph
0.25 M C21-22 OMe (CO)5Cr
Y
Y
OH THF, 65°, 3 h Y 0.02 M
O
(25)
NMe
(20)
CH2
(38)
464, 216
(CO)3Cr OMe
545
C21-26 O O SiMe2
O
1. PhC CPh (5 eq), 150 W Xe Arc
Cp'(CO)2Mn R2
R1
R2
(345 nm filter),
OH
CH2Cl2, 20° R1
O
2. CAN
C22
R1
R2
H
Me
(75)
H
Et
(51)
H
Ph
(60)
Me
Me
(75)
Me
Et
(79)
Me
TMS
(32)
OMe
Me
(48)
182
OMe (CO)5Cr 1. (n-Bu)2O, 90°, 2 h
O (40)
2. CAN 0.04 M O
216
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C22
Refs.
OH
H
Ph
N (CO)5Cr
TMS (29)
Benzene, 85°, 12-17 h
128
TMS Ph 0.25 M E:Z = 1:15.5
H
N
C23
O
OH
H
Ph N
Ph
Benzene, reflux, 12 h
(CO)5Cr
+
(54)
(23)
219
Ph
Ph
N
546
O O SiMe2
N O
1. PhC CPh (5 eq), 150 W Xe Arc
Cp'(CO)2Mn
(345 nm filter), O
2. CAN
C23-24
182
(56) OH
CH2Cl2, 20° n-Pr OH N
R
Pr-n +
Solvent, 105°, 1 h
(CO)5Cr
I
R
C23-26
Pr-n
R
H
R
Solvent
H Me
465 II
N
H
H
I
II
(n-Bu)2O
(34)
(14)
(n-Bu)2O
(39)
(10)
H
toluene
(21)
(18)
Me
toluene
(23)
(16)
Ar
N
OH Ar
H
Ar
Toluene, 110°, 2 h
N (CO)5Cr
N H
Ph
(19)
4-MeC6H4
(18)
2,4,6-Me3C6H2
(17)
220
C24 5
(CO)5Cr
Cr(CO)5
OMe 0.005 M
MeO
HC C(CH2)6C CH,
MeO
OH
HO
OMe
(31)
215
THF, 100°, 0.2-4 h
PhS O
SPh
1. THF, 80°, 8 h
547
O
2. FeCl3-DMF
(CO)5Cr TMS
3. TFA/AcOH (1.5:1) CCl4, rt, 15 min
O
(51)
114, 265
(56-94)
114
O OH
0.13 M 1. THF, 80°, 8 h
O
SPh
2. MeI, K2CO3, Me2CO 0.13 M
3. TFA/AcOH (1.5:1), CCl4, rt, 15 min
O
4. Air or FeCl3-DMF
OMe OH
O O (CO)5Cr MeO 0.05 M
n-Pr
1. Et2O, 35-37°, 64 h
Pr-n
2. PPh3, acetone MeO
O
O
(48)
218, 90
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
C24
Conditions
Product(s) and Yield(s) (%) O
O O
1. Et2O, 35-37°, 64 h
n-Pr
(CO)5Cr
(51)
O
2. DDQ, MeCN/H2O
MeO
Refs.
0.05 M
MeO
Pr-n
O
Pr-n
218, 90
OH
HO
O
O O SiMe2
1. Additive (10 eq), hexane, reflux
(CO)5Cr
Pr-n
+
OH
Pr-n
+
86
2. CAN MeO
MeO
O
Pr-n
O
MeO
I
II I
II
III
none
(40)
(9)
(40)
PhC CPh
(53)
(3)
(—)
EtC CEt
(51)
(4)
(40)
Additive
548 C24-25
O O SiMe2
O R
1. Additive (10 eq),
(CO)5Cr
solvent, reflux, 1 h
R
OH
2. CAN O
III
R
Additive
Solvent
Ph
none
THF
(25)
Ph
none
hexane
(19)
Ph
PhC CPh
hexane
(43)
n-C7H15 none
hexane
(48)
n-C7H15 PhC CPh n-C7H15 EtC CEt
hexane
(51)
hexane
(56)
86
C24-30 OMe
OH
OH
(CO)5Cr
R
THF, 100°, 0.2-4 h 13
0.005 M
+
R R I
OMe
R
I + II
I:II
H
(>65)
(<1:30)
TMS
(31)
(39:61)
Ph
(66)
(80:20)
215
II
OMe
OH
Ph
Me
Ph N
Ph TMS
+
(30)
Benzene, reflux, 12 h
(CO)5Cr Ph
Me
(17)
(CO)3Cr
N
Me OH
OH TMS
H N (CO)5Cr
219
N
TMS
Cr(CO)3
See table N
(CO)3Cr
I
H TMS
+
+ N
II
H •
23
O TMS
•
O
+
549
N
N
H (CO)3Cr
H
III
Solvent
Temp
Time
I
II
III
IV
hexane
reflux
3h
(13)
(10)
(43)
(0)
MeCN
reflux
0.5 h
(0)
(0)
(0)
(71)
toluene
70°
2h
(0)
(0)
(80)
(10)
t-Bu •
t-Bu
IV
O
Ar
H
Solvent, 85°, 1 h
465
N
N
(CO)5Cr
H Ar
Ar
Solvent
Cr(CO)3
Ph
(n-Bu)2O
(70)
4-MeC6H4
(n-Bu)2O
(82)
Ph
toluene
(20)
4-MeC6H4
toluene
(57)
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
Et
C25 O O
O
1. PhC CPh (5 eq),
SiMe2
150 W Xe Arc
Cp'(CO)2Mn
(345 nm filter),
182
(51)
Et
CH2Cl2, 20° OH
O
2. CAN O O SiMe2
O MeO
(CO)5Cr C7H15-n
C7H15-n
1. Hexane, reflux
86
(36)
OH
2. CAN O
550
OMe O O SiMe2
O C7H15-n
1. Additive (10 eq),
(CO)5Cr
hexane, reflux
C7H15-n
OH
2. CAN
MeO
Additive none
(55)
PhC CPh
(49)
86
O
MeO
OH
H
Ph
N (CO)5Cr
Ph
Benzene, 85°, 12-17 h
(59)
128
Ph Ph
H
0.25 M E:Z = 11:1
N Ph O
Ph N
f
(CO)5Cr
1. Benzene, reflux
NC
2. Air, silica gel
+
(16)
N
(7)
Cr(CO)3
C26
TMS
OMe
TMS
O
(CO)5W
H
+
(43)
THF, 110°, 20 h
(17)
MeO MeO
OMe
O
H
CO (1 atm), TMS
219
Ph
245
MeO MeO
H
H
O H
CO (1 atm),
O (19)
MeCN, 110°, 20 h MeO TMS H N
Toluene, 110°, 2 h
•
O
Ph
(29)
551
H (CO)3Cr
Ph Ar
OH Ar
H
Toluene, 90°, 2 h N N
(CO)5Cr
H
Ph C26-33
220
N
(CO)5Cr
C26-29
TMS
H
TMS
245
t-Bu
R
t-Bu
n-(Bu)2O, 85° N
(CO)5Cr Tol-p
•
Ar Ph
(28)
4-MeC6H4
(24)
2,4,6-Me3C6H2
(65)
2,6-(MeO)2C6H3
(42)
3,4,5-(MeO)3C6H2
(43)
220
O R
p-Tol N R (CO)3Cr
H
(82)
Me
(85)
Bn
(63)
465
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
C27-30
Conditions
Product(s) and Yield(s) (%)
Refs.
Ar OH Ar
H N
See table
(CO)5Cr
+
I
II = I-Cr(CO)3
220
N H
552
Ar
Solvent
Temp
Time
I
II
Ph
toluene
90°
1h
(26)
(—)
4-MeC6H4
toluene
90°
1h
(25)
(—)
2,4,6-Me3C6H2
toluene
90°
1h
(70)
(—)
2,4,6-Me3C6H2
t-BuOMe
55°
4.5 h
(25)
(22)
2,4,6-Me3C6H2
THF
68°
3h
(57)
(15)
2,4,6-Me3C6H2
MeCN
82°
40 min
(63)
(0)
2,4,6-Me3C6H2
(n-Bu)2O
75°
1h
(45)
(28)
2,4,6-Me3C6H2
(n-Bu)2O
85°
35 min
(49)
(30)
2,6-(MeO)2C6H3
toluene
90°
1h
(43)
(—)
3,4,5-(MeO)3C6H2
toluene
90°
1h
(45)
(—)
C28-38
R2
R1
OMe
OMe
(CO)5Cr
R1
MeO
R3
OMe
Cr(CO)5
R3
0.0025 M
223 R4 (1.0 eq), 1,2-dichloroethane,
OH
100°, 20-40 min
R2
HO
R4
553
R1
R3
R
2
R4
Me
Ph
Me
Ph
(35)
Me
n-C6H13
Me
n-C6H13
(22)
Me
OMe
Me
OMe
(36)
Ph
OMe
Ph
OMe
(41)
Me
OMe
Me
Ph
(31)
Ph
OMe
Me
Ph
(35)
Me
OMe
Me
n-C6H13
(22)
Me
n-C6H13
Ph
OMe
(35)
Me
OMe
Ph
OMe
(40)
C29-30
O
R HO
(CO)5Cr
O
1. Benzene, temp, 18-19 h
MeO
+
247, 245
2. Workup TBSO
OTBS 0.005 M
R
Temp
I I
II
OMe
75°
air
(30)
(23)
NMe2
120°
TiCl3/LAH
(10)
(—)
OMe
O
(CO)5Cr CO (1 atm),
MeO
MeCN, 80°, 27 h 0.005 M
II
TBSO
Workup
OTBS
TBSO
O (28)
245
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
C29
Conditions
Product(s) and Yield(s) (%)
Refs.
OMe HO
(CO)5W
HO
Additive,
+
247, 245
solvent, 110°, 19 h I
TBSO
OTBS
II
THF
(53)
(0)
benzene
(51)
(0)
none
heptane
(48)
(0)
0.005
none
MeCN
(63)
(0)
0.05
none
MeCN
(50)
(0)
0.005
CO (1 atm)
MeCN
(47)
(31)
Additive
Solvent
0.005
none
0.005
none
0.005
II
HO
I
CC (M)
554
Pr-n C33 O
Pr-n
H N
N
(CO)5Cr
H (n-Bu)2O, 85°, 1.5 h
MeO
466
(7)
MeO
0.06 M
OMe
OMe
C36-43 R O
OBu-n
H N
R
N (n-Bu)2O, 85°, 1.5 h
R
N
H
(CO)5Cr
H
+
MeO
466
MeO
MeO
II
I
OMe 0.05 M
OMe
R
555
C37
OMe I
II
TMS
(14)
(—)
Ph
(8)
(7)
ferrocenyl
(16)
(8)
2-pyridinyl
(3)
(3)
t-Bu O
O
OBu-n
OH
H N
N
Bu-t
Solvent, 85°, 1.5-2 h
MeO
Bu-t
N
H
(CO)5Cr
+
MeO
H 466
MeO I
OMe 0.02-0.05 M
Solvent (n-Bu)2O toluene
OMe
II
I
II
(low)
(0)
(0)
(17)
OMe
TABLE 21. CARBENE COMPLEXES WITH TETHERED ALKYNES (Continued) Carbene Complex
C38
Conditions
Product(s) and Yield(s) (%)
Refs.
n-C5H11 O H N
N
C5H11-n
H
(CO)5Cr (n-Bu)2O, 85°, 2 h
(44)
MeO
MeO
OMe 0.04 M
556
a b c d
OMe
There was greater than 90% deuterium incorporation in the product. The concentration of the starting carbene complex was equal to 0.025 M. A trimer was also isolated in 9-13% yield. The concentration of the starting carbene complex was equal to 0.001 M.
e
The concentration of the starting carbene complex was equal to 0.006 M.
f
This product was a mixture of two diastereomers.
466
TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
OH
C2 Cr(CO)5
Ph
Et2O, rt, 2 h
(9)
87
Ph
1.6 eq
(CO)3Cr
Ph
C3 W(CO)5
Ph
Alkyne (100 eq), Ph
Polymer (75)
85
40°, 22 h OH
C4 Cr(CO)5
Ph
Et2O, rt, 2 h
(12)
87
Ph
1.6 eq
557
(CO)3Cr + BF – 4
1. CO (1 atm), CH2Cl2, –78°
H
S
Ph OH
2. Air
W(CO)2Cp
(33)
467
S
0.006 M + BF – 4
OH
1. CO (1 atm), CH2Cl2, –78°
H
56, 467
(62)
2. Air W(CO)2Cp 0.006 M + BF – 4
O WCp(CO) 2
+ BF – 4
CO (1 atm),
H
(73) dr = 1.2:1
56
CH2Cl2, –10° W(CO)2Cp 0.006 M
TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne
Carbene Complex
C4
Conditions
H (CO)5W
EtO
Product(s) and Yield(s) (%)
CH2Cl2, –78° to –25°
(CO)5W
(21)
Ph
18 eq
Refs.
OEt 468
Ph Cr(CO)5
Cr(CO)5 OEt 1 eq
CH2Cl2, –20°, 2 h
(47)
345
(41)
345
0.05 M Cr(CO)5 Cr(CO)5 OEt 1 eq
CH2Cl2, –20°, 2 h
558
O O
0.05 M
Cr(CO)5 Cr(CO)5 OEt
1 eq
CH2Cl2, –20°, 2 h
(36)
0.05 M
C5 Ph
E:Z = 1.6:1
345
OH Pr-n
Cr(CO)5
n-Pr
Et2O, rt, 2 h
(11)
87
Ph 1.5 eq
(CO)3Cr + BF – 4
R
H
OH R
CH2Cl2, –78° 2. Air, 24 h
W(CO)2Cp 0.006 M
Ph
1. CO (1 atm),
R
n-Pr
(34)
i-Pr
(67)
467
Cr(CO)5 1. t-BuOMe, 20°, 1-2 h
(CO)5Cr
HO
+
2. TBSCl, Et3N, 20°, 2 h
4 eq 0.1 M
+
O
(46)
O
173
(59)
(<5)
TBSO (CO)5Cr
4 eq
O
O
1. t-BuOMe, 40°, 1-2 h
(68)
173
2. TBSCl, Et3N, 20°, 2 h TBSO
0.1 M
TBSO
559
(CO)5Cr
4 eq
Cr(CO)5
(CO)3Cr
1. t-BuOMe, 20°, 1-2 h
+
2. TBSCl, Et3N, 20°, 2 h
0.1 M
173
O
(33)
TBSO (46) Me3P (1 eq),
H (CO)5W
CH2Cl2/pentane (1:2), Ph
1.1 eq
PMe3 (CO)5W Ph
(11)
469
(—)
469
–50°, 3-5 min
0.02 M SMe
H
(CO)5W
(CO)5W CH2Cl2/pentane (1:2),
MeS
–50°, 30 min
1.1 eq
0.02 M
TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
MeO
n-Bu
(CO)5Cr
1. t-BuOMe, 20°, 1-2 h
4 eq
Refs.
OTBS
OMe
C6
Bu-n
(62)
(CO)3Cr
173
2. TBSCl, Et3N, 20°, 2 h 0.1 M
OMe
OMe
OMe
OTBS
OTBS MeO 4 eq
+
1. t-BuOMe, 20°, 1-2 h
560
(CO)5Cr
Bu-n Bu-n 173
(CO)3Cr
(CO)3Cr
2. TBSCl, Et3N, 20°, 2 h
0.1 M
(40)
(25) OMe
4 eq
(CO)5Cr
1. t-BuOMe, 20°, 1-2 h
(78)
173
2. TBSCl, Et3N, 20°, 2 h 0.1 M OTBS
OTBS
n-Bu 4 eq
(CO)5Cr
O
(42) +
1. t-BuOMe, 40°, 1-2 h 2. TBSCl, Et3N, 20°, 2 h
0.1 M
Bu-n
O
(26) 174, 173 O
Cr(CO)3
(CO)3Cr (CO)5Cr
4 eq
1. t-BuOMe, 20°, 1-2 h 2. TBSCl, Et3N, 20°, 2 h
0.1 M
174, 173
(55) n-Bu TBSO
(CO)3Cr (CO)5Cr
4 eq
+
1. t-BuOMe, 20°, 1-2 h 2. TBSCl, Et3N, 20°, 2 h
0.1 M
173 n-Bu
n-Bu
RO
TBSO (27) + BF – 4
561
t-Bu
R = H (26) R = TBS (<5)
OH 1. CO (1 atm), CH2Cl2, –78°
H
(49)
2. Air, 24 h
Bu-t
W(CO)2Cp
0.006 M
467
Ph (CO)5W
100 eq
40°, 15 h
85
Polymer (15)
Ph + BF – 4 R
OH
OH
1. CO (1 atm),
R
CH2Cl2, –78°
H
+
467
2. Air, 24 h
R
W(CO)2Cp
0.006 M
R
I
I
II
n-Pr
(28)
(33)
i-Pr
(16)
(49)
II
TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne
Carbene Complex
C6
+ BF – 4 Et
Et
Conditions
Product(s) and Yield(s) (%) OH
1. CO (1 atm),
Et
CH2Cl2, –78°
H
(34)
2. Air, 24 h 0.006 M NMe2
NMe2
(CO)5W
CH2Cl2, –50° Ph
C7 Cp'(CO)2Mn 1 eq
W(CO)5
+
(CO)5W Me2N
Cp'(CO)2Mn
Ph
Ph
0.4 M
(8)
(25)
470a
Ph
NEt2 Hexane, 70°, 22 h
(52)
456
Ph
562
NEt2
Ph 1 eq
NMe2
(CO)5W Me2N
Ph Et2N
467
Et
W(CO)2Cp H
Me2N
Refs.
(CO)5W
Hexane, –60° to rt
(CO)5W
Ph
Ph
359
(50)
Ph
0.7 M NEt2 (CO)5Cr 1 eq
(CO)5Cr
CH2Cl2, –60°, 5 min
(51)
345
(52)
345
0.05 M
NEt2 (CO)5Cr (CO)5Cr 1 eq 0.05 M
O
CH2Cl2, –60°, 5 min
O
NEt2 (CO)5Cr 1 eq
CH2Cl2, 20°, 1 h
(CO)5Cr
345
(27) syn/anti = 4.6
0.05 M NEt2
Ar (CO)5Cr
1 eq
CH2Cl2, –20°, 1 h
(CO)5Cr
PMP
0.05 M
Ar
Ar
Ph
(58) E:Z = 5.6:1
345
PMP (65)
PMP NEt2 (CO)5Cr
(CO)5Cr 1 eq
CH2Cl2, –60°, 5 min
(73) E:Z = 3.4:1
345
563
0.05 M
C8 (CO)5W
H (CO)5W Ph 0.02 M
1.1 eq
NMe2
1. CH2Cl2/pentane (1:2), –40°
(14)
469
2. MeC CNMe2 (1.2 eq)
OH Ph
Cr(CO)5
Ph Ph
(27)
Et2O, rt, 2 h
87
Ph
1 eq
Cr(CO)3
Ph Ph (CO)5W
50 eq
40°, 46 h
Polymer (49)
85
Ph
TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C8 H (CO)5W
Ph
Ar
1 eq
H
Ph CH2Cl2, –80° to –10°
Refs.
Ar
(CO)5W
(—) +
(CO)5W
(—) Ph
470b
Ar
Ph Ar
H
+
(CO)5W
TMS
TMS
(CO)5Cr
(—)
Ar = Ph, 4-MeC6H4
W(CO)4
t-BuOMe, 20°, 1-2 h
(82)
+ O
(<5)
173
4 eq
564
0.1 M TMS
TMS
Cr(CO)5 t-BuOMe, 40°, 1-2 h
4 eq
(44)
O
173
O
0.1 M
O •
Cr(CO)5 TMS t-BuOMe, 20°, 1-2 h
4 eq
TMS
(—)
173
0.1 M NEt2
H
Et2N
(CO)5W
CH2Cl2/pentane (1:2), Tol-p
1.1 eq
0.02 M
–40°, 30 min
(CO)5W
(78) Tol-p
469
C10 1. CH2Cl2/pentane (1:2),
H (CO)5W
–50°, 1.5 h Ph
1.0 eq
Ph
Ph NEt2
(CO)5Cr
Hexane/benzene (3:1), Ph
rt, 30 min
0.2 M
1.5 eq
Ph
(10)
469
2. Me3P (1 eq)
0.02 M
Et2N
+ PMe3
– (CO)5W
O
Ph
471
(16)
Et2N
NEt2 OH
C11 EtO2C
Ph
Cr(CO)5
Ph Ph
Et2O, rt, 2 h
(7)
Ph
87
CO2Et
1 eq
(CO)3Cr Ph OMe
C12
565
MeO OH
MeO O
Cr(CO)5
Ph
MeO
OMe
1. THF, 20°, 1 h Ph
MeO
OMe
O
296
2. Silica gel, 10°
OMe
(30) dr = 1.25:1
(CO)3Cr
Ph
C14 + BF – 4 Ph
H
Ph 1 eq 0.006 M
+ BF – 4
Tol-p
(89)
CO (1 atm), CH2Cl2, –78°
W(CO)2Cp
56
Ph
Cp(CO)2W
Ph
TABLE 22. NON-HETEROATOM-STABILIZED CARBENE COMPLEXES WITH ALKYNES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C14
Refs.
OH
Ph
Ph
Ph
(CO)5Cr Ph
(n-Bu)2O, 40°, 2 h O
1.4 eq
Ph
(22)
104
(20)
87
(CO)3Cr O
0.1 M OH
Ph
Cr(CO)5
Ph
Et2O, rt, 2 h
1 eq Ph
Ph (CO)3Cr Ph OH
566
CF3
CF3 Cr(CO)5
1.2 eq
(18)
104
Ph
Tol-p
0.4 M
Ph
(n-Bu)2O, rt, 2 h (CO)3Cr
Tol-p OH Ph
OH
CF3 Cr(CO)5
1.5 eq
1. (n-Bu)2O, rt, 2 h
CF3
Ph +
2. Air Tol-p (14)
(4) CF3
OH Ph
Cr(CO)5
2-naphth
(n-Bu)2O, rt, 1 h
1.2 eq
(11)
Ph 0.25 M
47
Ph
Tol-p
0.05 M
Ph
Ph (CO)5Cr
naphth-2
104
C16 W(CO)5
Ph
(18)a
Toluene, 50°, 16 h
452
Ph 0.001 M I
100 eq W(CO)5
Ph 1.0 eq
Toluene, 50°, 16 h
I (51)
452
Ph 0.05 M
C17
W(CO)5
Ph
(19)a
Toluene, 50°, 16 h
452
Ph 0.001 M
567
I
100 eq W(CO)5
Ph 1 eq
Toluene, 50°, 16 h
I (40)
452
Ph 0.05 M
C18
W(CO)5
Ph
Toluene, 50°, 16 h Ph 0.001 M 100 eq a
The yield was based on starting alkyne.
(24)a
452
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES Carbene Complex or Precursor Complex
C13
Conditions
Product(s) and Yield(s) (%)
Refs.
OMe OMe
N-morph
(CO)5Cr +
THF, rt, 12 h
morph-N
O
(38)
O
472
morph-N
C14 OMe (CO)5Cr MeO
OMe
1. CNBn (2 eq),
+
THF, rt, 15 min 2. Silica gel
(52)
473
NHBn
O OMe
C15
568
OEt
EtO
(CO)5W +
R2PH
EtO
O
+
Pentane, 0° PR2
(CO)5W
+ PR2
(CO)5W I
R
I
(CO)5W
474 PR2
II III
IV
t-Bu
I + II + III (80)
II
(0)
c-C6H11
(30)
III EtO +
(7) (22) (36) IV
(CO)5W PR2 OH
OMe (CO)5Cr
OMe
Photolysis, CO, THF
(0)
254
Ph
OMe
OMe
(CO)5W +
+
(10)
Neat, 50°, 4 h
(5)
475, 472
Ph OMe
Ph
Ph
OMe
(CO)5W +
MeCN, rt, 72 h MeO
Ph
(51)
475, 472
MeO
C15-16 OMe (CO)5W
O +
+
THF, rt
569
morph-N R
OMe
O
I
475, 472
morph-N
R
Time
I
II
Cl
12 h
(36)
(0)
H
10 min
(0)
(95)
Me
15 min
(0)
(90)
2d
(0)
(95)
R
OMe
R
OMe
OMe OMe
(CO)5W +
(CO)5W
Ph
THF, rt, few min
(95) OMe
morph-N Ph
II
N-morph
472
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
C15-16
Conditions
Product(s) and Yield(s) (%)
OMe
OMe (CO)5W + Ar
THF, rt
472 morph-N
morph-N
Ar
R
Time
R
Ph
5 min
H
(95)
4-MeC6H4
15 min
Me
(97)
OMe
(94)
4-MeOC6H4
Refs.
OMe OMe
8h
OMe +
THF, rt
472
570
morph-N
morph-N
R
Time
R
15 min
H
(92)
15 min
Me
(95)
OMe
(96)
10 h C15
OTMS OMe
OTMS
OMe (CO)5W + Ph
(83)
THF, rt, 10 min
472
O
morph-N
OMe (CO)5Cr +
O
O
1. THF, rt, 10 min 2. TsOH, toluene, 110°
morph-N
Ph
OMe
472
(58) morph-N
OMe
N-morph
(CO)5Cr +
THF, –10°, 6 d morph-N
Ph
(34)
472
morph-N
OMe (CO)5Cr
OMe
OMe +
THF, rt, 3 d
OMe
OMe 3 eq
+
OMe
(59)
571 +
OMe
THF, rt, 2 d morph-N
+
MeO
OMe
(85)
472
morph-N
morph-N
C3H5O
OC3H5 THF, rt, 4 d morph-N
472
OMe
THF, rt, 6 d
+
(86) morph-N
OMe
2 eq
472
TMSO
OMe
2 eq
OMe
THF, rt, 3 d TMSO
2 eq
472
(64) TMSO
TMSO
1 eq
OMe
OMe
OMe (54)
O
472
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
C15
Conditions
Product(s) and Yield(s) (%)
OMe
OMe
(CO)5Cr
OMe
O
O
+
Refs.
(87)
THF, rt, 12 h
472
morph-N
morph-N 2 eq
OMe
N-morph +
2 eq
OMe
THF, rt, 12 h
+
(57) morph-N
morph-N
472
MeO MeO
Cr(CO)5
(9)
572 morph-N OMe
OMe
OMe
+
1 eq
OMe
THF, rt, 3 d
TMSO
(90)
472
(76)
472
TMSO
OMe
OMe
OMe
+
1 eq
OMe
OMe
OMe
THF, 40°, 2 d
morph-N
morph-N
C15-16 OMe
OR2
(CO)5M +
OMe
OMe
OR2 Toluene or benzene, 45°
+
OR2 R1
C16
476 R1
1
R
M
R1
R2
Cr
H
TBS
Cr
H
W
H
Cr
OMe
OR2 I
OR2 I
II
(73)
(25)
TMS
(9)
(80)
TBS
(35)
(55)
TBS
(65)
(5)
II
OMe (CO)5Cr Photolysis, THF, CO
(23)
OH
254
573
OMe C17-18 NHR
CO2Me
CO2Me
(CO)4Cr CO2Me
O
H O
0.1 M
C17
CO2Me
(35)
54
Me (44)
NHR
OMe
O
R
CH2Cl2, rt, 8 h
N2 purge, THF, reflux, 9 h
(79)
252, 253
OH
O OMe
W(CO)5 0.02 M H
OEt
OEt R
(CO)5M
Et2O, 20°, 12-14 h NMe2
W (89) (CO)5M –
NMe2 +
Cr (85)
474
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C17 O
O Photolysis, CO, THF
Cr(CO)5
(65)
477
OH OMe
OMe
O CNBu-t (3 eq),
(78)
255
NHBu-t
toluene, reflux OMe O
O
574
CNR, solvent,
Cr(CO)5
reflux, 12-24 h
NHR
Solvent
R
toluene
t-Bu
(72)
THF
CH2CO2Et
(64)
255, 257
OMe
OMe OMe
OMe
(CO)5M +
THF, rt, 20-30 min
OMe 472
(95)
Ph
Ph
morph-N morph-N
2 eq Ph M = Cr, W OMe
MeO
(CO)5M +
MeO
OMe
O (30)
THF, rt, 2.5 min
2 eq Ph
472
Ph
Ph O
morph-N
M=W
OMe M = Cr 1 eq
+ morph-N
N
CCl3
OMe
OMe
Cr(CO)5
OMe
THF, rt, 48 h
Ph
(85)
472
morph-N
1. CNBu-t (2 eq),
N
OMe
CCl3
THF, 60°
N 478
(60)
N
NHBu-t
2. Silica gel OMe
OMe C18 Ph OMe
CNBu-t (2 eq),
(90)
ether, reflux
Cr(CO)5
255
NHBu-t OMe
575 1. N2 purge, THF, reflux, 4-9 h OMe
O 0.02 M
2. Workup
O
OH
THF, reflux, 6 h OMe R 0.02 M
2. Air, sunlight, 12 h
1. N2 purge,
0.02 M
OMe W(CO)5
none
Me
MeO
OH
252, 253
(77)
2. Air, sunlight, 12 h
(72)
253
OMe (0)
OMe
O
THF, reflux, 6 h O
air, sunlight, 12 h (56)
W
R R
Cr(CO)5
O
Workup
Cr OMe
M(CO)5
1. N2 purge, MeO
M
(65) O
OH OMe
253
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C18 M CNBn (2 eq), OMe
O
THF, rt, 15-60 min
O
NHBn
CNBu-t (2 eq),
(86)
473
NHBu-t
MeO
OMe
Cr(CO)5 OMe
OMe
576
(CO)5W +
THF, rt, 4 d morph-N
2 eq
473
(85)
THF, rt, 15 min OMe
0.05 M
(78)
Cr
OMe
0.05 M M(CO)5
MeO
W
OMe 472
(67)
Ph
Ph morph-N
Ph OMe
OMe
OMe +
2 eq
THF, rt, 1 d morph-N
N
CCl3
1. CNBu-t (2 eq), N
OMe Ph
M(CO)5
morph-N
N
CCl3
2. Silica gel
Sealed tube, THF, 80°, 18 h
(93)
472
M NHBu-t
Ph
OMe
W
(72)
Cr
(68)
478
N
CCl3 M = Cr
O
N
THF, 60°, 12 h
Ph
Ph
MeO
478
(70)
N OMe
C18
N-morph
N-morph CO2Me
CO2Me
CH2Cl2, rt, 8 h
54
(68)
0.1 M (CO)4Cr
CO2Me
CO2Me
C19 R R
R OMe Ph
Photolysis, THF, CO OH
Cr(CO)5
H
(90)
OH
(78)
254
OMe Ph R=H
O
CNBu-t (2 eq),
NHBu-t
ether, reflux
577
(CO)5Cr THF, reflux, 36 h
(90)
479
OMe Cr
OMe
Time
R
CNR, reflux Ph
255
OMe O C OC
OMe
(85)
Cr(CO)5 NHR
t-Bu
t-BuOMe
48 h
(71)
CH2Ts
ZnCl2, THF
5h
(84)
257
OMe
1. N2 purge, THF, reflux, 6 h O 0.02 M
OMe Cr(CO)5
2. Air, sunlight, 12 h
(46) O
OH OMe
252, 253
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
R
C19 (CO)5Cr
OMe R
R
Photolysis, solvent, CO
OH R
Solvent
F Cl
+
477 OH
I
OMe
OMe
I
II
THF
(11)
(55)
THF
(6)
(83)
OH
THF
(30)
(35)
F
toluene
(<2)
(58)
Cl
toluene
(<3)
(89)
OH
toluene
(63)
(12)
II
578 1. Conditions, time O 0.02 M
M(CO)5
252, 253
2. Workup, 12 h
OMe M
Conditions
O OMe Workup
Time
Cr
THF, reflux, N2 purge
8h
air, sunlight, 12 h
(72)
Cr
THF, reflux
12 h
air, sunlight, 12 h
(26)
Cr
THF, 40°
28 h
air, sunlight, 12 h
(20)
Cr
hexane, reflux
24 h
air, sunlight, 12 h
(25)
Cr
MeCN, 65°
8h
air, sunlight, 12 h
(25)
Cr
THF, reflux, CO atm
9d
air, sunlight, 12 h
(—)
W
THF, reflux, N2 purge
9h
none
(59)
W
THF, reflux
20 h
none
(58)
W
THF, 40°
48 h
none
(15)
W
hexane, reflux
48 h
none
(19)
W
MeCN, 65°
10 h
none
(32)
1. N2 purge,
O
OH
O
THF, reflux, 4 h OMe
O 0.02 M
253
(67) O
2. Air, sunlight, 12 h
OH OMe
Cr(CO)5 O CNBu-t (2 eq),
0.05 M
473
(78) O
THF, rt, 15 min
NHBu-t OMe
C20 Ph OMe
See table OH
Cr(CO)5
579
OMe Conditions
Temp
photolysis, THF
—
(18)
251
photolysis, THF, CO
—
(93)
254
reflux
(29)
254
heptane, CO
80°
(75)
480
THF
80°
(41)
480
THF, CO
80°
(87)
480
benzene
80°
(51)
480
benzene, CO
80°
(92)
480
heptane
Ph Photolysis, MeOH, CO
CO2Me
(6)
+
(67) OH
OMe
OMe
254
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C20 Ph CNR1
OMe
255, 257 NHR2
Cr(CO)5
OMe
580
R1
Solvent
Temp
t-Bu
Et2O
reflux
8h
t-Bu
(83)
n-Bu
t-BuOMe reflux
12 h
n-Bu
(70)
Bn
THF
rt
21 h
Bn
(85)
CH2CO2Et
THF
reflux
8h
CH2CO2Et
(81)
2,6-Me2C6H3
CH2Cl2
reflux
8h
2,6-Me2C6H3
(86)
TMS
THF
rt
2h
H
(56)
CH=CHMe
THF
reflux
1h
H
(68)
Time
Ph OMe
O
Photolysis, THF, CO
(50) O
Cr(CO)5
254
OH OMe R
R
R
Photolysis, solvent, CO
+
477
OH
Cr(CO)5
OH
OMe OMe
OMe I
II
Solvent
R
I
II
THF
OMe
(9)
(61)
THF
Me
(39)
(32)
THF
CHO
(30)
(41)
THF
CF3
(<2)
(69)
toluene
Me
(7)
(89)
toluene
CHO
(22)
(66)
Ph
Ph CNBu-t (2 eq), OMe
(44)
NHBu-t
t-BuOMe, reflux
255
OMe
Cr(CO)5 n-Pr 1. CNBu-t (2 eq), MeO
MeO
Pr-n
THF, reflux, 40 h
581
Cr(CO)5
(73)
O
2. CAN
272
OMe O
OMe OMe
1. THF, reflux, 9-12 h OMe
O
2. Air, sunlight, 12 h
(69) with N2 purge OH
O OMe
Cr(CO)5
OMe OMe
Cr(CO)5
253
(44) without N2 purge
1. N2 purge, THF, reflux, 3 h 2. Air, sunlight, 12 h
(95) OMe
OH OMe
253
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C20 OMe
OMe
1. N2 purge,
MeO
MeO
THF, reflux OMe
MeO OMe
2. Air, sunlight, 12 h
(0) MeO OMe
Cr(CO)5
253
OH OMe
OMe
OMe
MeO
MeO CNBu-t (2 eq), OMe
MeO OMe
THF, rt, 15 min
(85) MeO OMe
Cr(CO)5 O
582
OMe
OMe
473
NHBu-t OMe O
MeO
MeO
(97)
CNBu-t (2 eq), OMe
MeO OMe
THF, rt, 15 min
MeO OMe
Cr(CO)5
473
NHBu-t OMe
O
O CNBn (2 eq), OMe
O
(67) O
THF, rt, 15 min
473
NHBn OMe
Cr(CO)5 O C OC
NMe2 (CO)5Cr Dioxane, reflux, 52 h
NMe2 Cr
(29)
479
H O Photolysis, CH2Cl2
(45)
256
Ph OEt
OEt
(CO)5Cr
OEt O
Pr-c
N
THF, 50-55°
Pr-c N
R
Pr-c
R
+
0.03 M
Pr-c
R
N
Pr-c
I R
583
(CO)4Cr
I
II
n-Pr
(22)
(63)
c-Pr
(0)
(81)
t-Bu
(0)
(92)
Ph
(21)
(45)
CH2Cl2, rt, 8 h
CO2Me
N-morph 0.1 M (CO)4Cr
(74)
54
N-morph CO2Me
CO2Me CO2Me
O
II
CO2Me
CO2Me CO2Me
481
Pr-c
CH2Cl2, rt, 8 h
O
N-morph
CO2Me
(62)
54
N-morph
0.1 M MeO
(CO)4Cr
CO2Me N-morph 0.1 M
N-morph
CO2Me
CO2Me
CH2Cl2, rt, 8 h MeO
CO2Me
(65) 60:40 mixture of isomers
54
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
Ph
Conditions
CN
Ph 1. THF, rt, 9 h
(20)
2. Air, sunlight N-morph
54
N-morph
0.05 M
M
1. CO (1 atm),
W
THF, 65°, 6 h O
O
Refs.
OH
CN
(CO)4Cr
Product(s) and Yield(s) (%)
2. Air, sunlight, 12 h
O O
M(CO)5
253
(49)
Cr (55) O
0.02 M C21
584
OMe
OMe
(CO)5Cr Ph
HO Photolysis, THF, CO
(42)
254
Ph OMe CNR
R2HN
1
255, 257 Ph
O
R1
Solvent
t-Bu
t-BuOMe
Temp
Time
R2
32°
12 h
CH2CO2Et
t-Bu
(89)
THF
reflux
8h
CH2CO2Et
(80)
TMS
THF/PhMe
reflux
24 h
H
(32)
CH=CHMe
Et2O
reflux
2h
H
(76)
1. N2 purge, O
THF, reflux, 3 h OMe
O 0.02 M
2. Air, sunlight, 12 h
O
(77)
252, 253
OH OMe
Cr(CO)5 1. N2 purge,
(70)
THF, reflux, 9 h OMe OMe
2. Air, sunlight, 12 h OMe
W(CO)5
253
OH OMe
0.02 M OMe
OMe MeO
CNBn (2 eq), OMe
585
MeO OMe
THF, rt, 15 min
MeO (76) MeO OMe
Cr(CO)5
473
NHBn OMe
Ph Photolysis, CO, THF, 8 h
(75)
255, 256
(92)
54
(32)
54
Cr(CO)5 Me2N
Ph
Me2N
(CO)4Cr
OH
OH
CO2Me
CO2Me
Ph 1. THF, rt, 9 h
N-morph
2. Air, sunlight N-morph
0.05 M
OH
1. MeLi (1 eq), THF, –80° 2. H3O+, –60°
Ph
CO2Me
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
C21
Conditions
Product(s) and Yield(s) (%) H
OEt
Refs.
OEt
(CO)5M
M Et2O, 20°, 5 h N
MeO
(CO)5M –
OEt (CO)5M
N +
OMe
W
(92)
Cr
(86)
OEt
H
474
OEt
H
NHPh +
Toluene, 50°, 4 h H
H
N
M(CO)5
Ph
(CO)5M
I
586
O
OBu-t
I
II
W
(30)
(59)
Cr
(44)
(45)
474
II
OH N(Me)CO2Bu-t
NMe
(CO)4Cr
N Ph
M
Photolysis, THF, CO
256
(81)
O
O
CH(OMe)2
C22
CH(OMe)2 Cr(CO)5
CH(OMe)2
Photolysis, solvent, CO
+
477
OH
OMe
OH
I
OMe Solvent
I
II
OMe
II
THF
(30) (44)
toluene
(<4) (92)
Ph Ph
1. N2 purge, OMe
O
2. Air, sunlight, 12 h 0.02 M
M R = OH
THF, reflux, 7-12 h O
R
I
W
(89)
Cr
(72)
252, 253
OMe
M(CO)5
M CNBu-t (2 eq),
0.05 M
I R = NHBu-t
THF, rt, 15 min Ph
W
(88)
Cr
(94)
Ph 1. THF, reflux, 7-12 h
OMe
O 0.02 M
2. Air, sunlight, 12 h
(56) with N2 purge O
OH
587
1. N2 purge,
M
THF, reflux, 3-12 h OMe 0.02 M
2. Air, sunlight, 12 h
OMe
M(CO)5 Ph
O OMe
O
252, 253
(32) without N2 purge
OMe
Cr(CO)5
OMe
473
CNBu-t (2 eq),
OH
(83)
Cr
(90)
253
OMe
O
Ph
O
NHBu-t
THF, rt, 15 min
W
(98)
473
OMe
Cr(CO)5 0.05 M
CNBn (2 eq), OMe
TMSO OMe 0.05 M
Cr(CO)5
THF, rt, 15 min
(59) TMSO OMe
NHBn OMe
473
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
C22
O
Conditions
OMe CNBu-t (2 eq), OMe
THF, rt, 15 min
(92)
MeO
Cr(CO)4
NHBu-t
morph-N
Ph
THF, rt, 9 h
CONMe2
Cr(CO)5
588
Se
OEt
(CO)3Fe THF, reflux, 2.5 h
Se
(CO)3Fe
Se
Cr(CO)3
EtO
(24)
CH2Ph
Se
482
Ph
Cr(CO)5 (CO)3Fe
(CO)3Fe
Se
Ph
Se
54
(45)
OH
CONMe2
0.05 M
473
OMe
Cr(CO)5 Ph
(CO)3Fe
MeO
OMe
morph-N
(CO)3Fe
O
OMe
MeO
OEt
(CO)3Fe THF, reflux, 2 h
(CO)3Fe
Se
Cr(CO)3
EtO +
(25)
CH2Ph
Se
Ph
483
Ph
0.13 M
(CO)3Fe
Se
(CO)3Fe
Se
Ph OEt Se Fe(CO)3 EtO
Se
Ph (CO)3Fe
(CO)3Fe
OEt
Se
THF, 85°, 3 h
(CO)3Fe
Cr(CO)5
Se (15)
+
Se
(CO)3Fe
Se
(CO)3Fe
Se
(18)
O
(CO)3Fe
Se
(CO)3Fe
Se
(19)
Se Fe(CO)3
Ph (CO)3Fe
Refs.
O
O
MeO
OMe
Product(s) and Yield(s) (%)
484
OH OEt
(70)
Toluene, reflux, 3 h
484
OH OEt
S
(CO)3Fe
Ph (CO)3Fe
(CO)3Fe
OEt
Se
THF, 85°, 3 h
S
(CO)3Fe
Se
Cr(CO)5
Toluene, 85°, 3 h S
(CO)3Fe
Te
Se
484 OH
I (23) OEt 484
589
(CO)3Fe
S
(CO)3Fe
Te
Ph
THF, reflux, 2 h
Cr(CO)5
0.09 M
(CO)3Fe
I (34)
Ph OEt
S
O
(11)
(CO)3Fe
(CO)3Fe +
OEt
+
(17)
(CO)3Fe
S
(CO)3Fe
Te
483 Ph OEt Te Fe(CO)3 (9) EtO Ph
(CO)3Fe
S
(CO)3Fe
Te
S
Fe(CO)3
Solvent
Solvent, reflux, 2 h OH
THF
(21)
toluene
(38)
484
OEt Ph Cr(CO)4 Photolysis, THF, CO MeN
O OBu-t
(83) OH N(Me)CO2Bu-t
256
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C23 OMe (CO)5Cr Photolysis, solvent, CO
+
(76)
(7)
477
OH OH
OMe OMe
Ph Ph
1. N2 purge, OMe
O
M
THF, reflux, 6-12 h O
2. Air, sunlight, 12 h
OH
W
(60)
Cr
(55)
252, 253
OMe
M(CO)5 Ph 1. N2 purge,
590
O OMe
O
O
Ph
O
OH
THF, reflux, 6 h 2. Air, sunlight, 12 h
Ph
OMe
(82)
473
Ph
MeO
MeO CNBn (2 eq), OMe
MeO
473
OMe
Cr(CO)5 OMe
(72)
THF, rt, 15 min
MeO
NHBn
OMe 0.05 M Cr(CO)5
OMe
N-morph
N-morph
CO2Me
OMe
CO2Me
CH2Cl2, rt, 8 h
(52) 71:29 mixture of isomers
54
Ph (CO)4Cr
CO2Me
Ph
CO2Me Ph
0.1 M 1. MeLi (1 eq), THF, –80° 2. H3O+
MeO2C
(71)
OH
54
CO2Me
C23 OEt
Ph
(CO)5W
Petroleum ether, 20°, 3 d
– W(CO)5
+ Et2N
NEt2
(—)
Ph
NEt2
485
OEt – W(CO)5
Ph
(CO)5W
Petroleum ether, 20°, 3 d
EtO
Ph
OEt
(66)
485
(82)
485
NEt2 + O
Ph
1. Toluene, 45°, 5 h NEt2
2. aq HCl C23-26
591
OEt (CO)5Cr
Ph N Pr-c
0.05 M
R
Ph
N
R
Pr-c
THF, 50-55°, 16-24 h
R
OEt
C24
n-Pr
(88)
c-Pr
(97)
t-Bu
(85)
Ph
(62)
481
Ph Ph
1. N2 purge, OMe OMe
THF, reflux, 2 h 2. Air, sunlight, 12 h
OMe
Cr(CO)5
(90)
253
(—)
253
OH OMe
1. N2 purge, THF, reflux, 2 h O
OBn Cr(CO)5
2. Air, sunlight, 12 h
O
OH OBn
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C24 (t-Bu)2P
Cr(CO)5
(t-Bu)2P
CNR (2 eq), Ph
OEt
(96) R = t-Bu, c-C6H11
cyclohexane, 60°, 1 h
486
NHR
0.16 M
OEt M(CO)5
M(CO)5
(t-Bu)2P
(t-Bu)2P
(t-Bu)2P
M(CO)5
(t-Bu)2P
+
Pyridine (0 or 1 eq), 3-35 h Ph
+
486
OEt EtO
592
M
Solvent
Temp
Cr
benzene
60°
no
Cr
benzene
80°
no
Cr
benzene
80°
W
heptane
W
heptane
W
heptane
EtO
I
Pyridine
EtO
II II
III
(>90)
(0)
(0)
(0)
(>90)
(0)
yes
(0)
(0)
(>90)
55°
no
(91)
(0)
(0)
80°
no
(0)
(86)
(0)
80°
yes
(0)
(0)
(>90)
I
III
C25 Cr(CO)4 Photolysis, THF, CO
256
(28)
OH
O
BnN
N(Bn)CO2Bu-t OBu-t C25-27 Conditions R1
R2
MeO
OMe
(CO)5Cr
A: Photolysis, toluene, CO or B: CNBu-t, toluene,
NR1
N Me
NR1
reflux, 5 h
N Me
R2
A
Me
OH
(51)
A
allyl OH
(58)
B
Me
B
allyl NHBu-t (58)
292, 293
NHBu-t (89)
C26 Cr(CO)5 (c-C6H11)2P
Ph
Cr(CO)5
(c-C6H11)2P OEt
(c-C6H11)2P +
Heptane, 2 h
Cr(CO)5
EtO
486 EtO
I
Temp
I
II
80°
(>80)
(>10)
100°
(0)
(>90)
II
Ph Ph CNBu-t (2 eq), OMe
MeO TMSO
THF, rt, 15 min
(65) TMSO OMe
Cr(CO)5
473
NHBu-t OMe
0.05 M
593
C26-29 Ph R
Ph R
N
N
Ph Ph
THF, 50-55°, 15-18 h OEt
OEt Cr(CO)5 0.05 M
C28
R n-Pr
(88)
c-Pr
(96)
t-Bu
(99)
Ph
(80)
481
N-morph [(COD)RhCl]2 (2.5 mol%),
Ph
N-morph Ph
THF, 20°, 36 h OEt OEt W(CO)5
(76)
195
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C28-30 MeO
OMe
(CO)5Cr
OH R
Photolysis, toluene, CO N R
293
allyl (63)
N
N
MOM
Boc
N
R
(71)
MOM
MeO
NHBu-t R 292, 293
allyl (74)
CNBu-t, toluene, reflux, 5 h N R
C29
Boc
N
(68)
MOM
Cr(CO)5
594
MeO
MeO MeO OTIPS
Photolysis, CO, OTIPS
271, 272
(36)
OH
THF or toluene
OMe OMe
0.03 M
OMe
MeO 1. CNBu-t (2 eq), THF, OH NHBu-t
reflux, 24 h
0.75 M
2. TBAF
(60)
271, 272
OMe OMe TIPSO
MeO
MeO
1. CNBu-t (2 eq), THF, OTIPS
reflux, 16 h
+
271, 272
O
2. CAN
OMe O I
CC (M) 0.4 0.1
I
II
(82)
(0)
OMe O II
(57-62) (20-25)
Ph Cr(CO)4
Atmosphere Photolysis,
O
BnN
atmosphere, THF
OH
OBu-t
C30
(40)
CO
(62)
256
N(Bn)CO2Bu-t
Me
Me
Ph
N
N2
N
Ph
Photolysis, CO, THF
OMe
Ph
(51)
165
(33)
256
OH
Ph
Cr(CO)5
Ph
OMe
C31 Ph Ph Cr(CO)4
595
Photolysis, CO, THF
OH
O
BnN
N(Bn)CO2Bu-t OBu-t C31-36 W(CO)5 EtO [(COD)RhCl]2 (2.5 mol%),
R1 R3 R2
toluene, 70°, 12 h
N Me
R3 R2
R1
N Me OEt
0.1 M E:Z = 95:5 R1
R2
R3
Ph
Me
Me
(71)
Ph
Me
H
(74)
Ph
Ph
H
(76)
cyclohex-1-enyl
Ph
H
(73)
195
TABLE 23. CYCLIZATIONS OF DOUBLY UNSATURATED CARBENE COMPLEXES (Continued) Carbene Complex or Precursor Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C32-33 C7H15-n
R
C7H15-n
R
N
R
N Photolysis, CO, THF
Bn
Cr(CO)5
OH
C7H15-n
Bn
C7H15-n
Bn
N
R
N CNBu-t (7 eq), Cr(CO)5
596
OR
258
OMe
0.005 M
MeO
(65)
PMB (62)
Me NHBu-t
THF, 75°, 18 h
(86)
258
MOM (72)
OR
1.2 M
C39 RhCl(COD) EtO Toluene, 70°, 4 h
Ph Ph
N Me
0.1 M E:Z = 95:5
Ph Ph
N Me OEt
(63)
195
TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES Alkyne
Carbene Complex
C2
Conditions
Product(s) and Yield(s) (%)
OEt (CO)4W
Refs.
OH 487
(8)
Hexane, rt, 2 d
105 Pa 0.07 M C4
H
Ph
(CO)5W
9 eq
W(CO)5
H
Ph
CH3
CH2Cl2, 20°, 6 h
+
(CO)5W
Ph 488, 489
W W (CO)3 (CO)3
W(CO)4 (28)
(23)
+ poly-2-butyne (—)
597
H (CO)5W
excess
Pentane, –78° to rt
(CO)5W
Ph
+ Ph
Ph
+ Me2C2[C(H)Ph]a
+ n-C H 5 11
Ph
489
Me2C2[C(H)Ph]2a
+
+ (Me2C2)2(CO)[C(H)Ph]a OH
C5 t-Bu
Bu-t
Argon (4 bar), t-BuOMe,
P
Cr(CO)5
1.1 eq
(extremely low)
100°, 2 h
231
P
OMe 0.1 M
(CO)3Cr OMe
TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5
OH t-Bu
P
Argon (4 bar), t-BuOMe,
+
(minor)
P
70°, 7 h
1.1 eq
OMe Cr(CO)5
Argon (9 bar), DME, 90°, 3 h
MeO
598
OEt Cr(CO)5 0.04 M
Argon (9 bar), Et2O, 90°, 3 h
(4)
P
S (CO)3Cr
231
t-Bu
Bu-t S
O O
OH 1.3 eq
(43)
+
OMe
0.08 M
231
P
(9)
P
O
(22)
t-Bu
Bu-t O
231
O
OMe OH
1.3 eq
(5)
•
OMe 0.25 M
Cr(CO)5 OMe P
t-Bu
Bu-t Cr(CO)5
Refs.
P +
EtO
O S
OEt OH
1.2 eq
Argon (5 bar), DME, OMe 0.02 M
t-Bu
Bu-t
Cr(CO)5
Ph
P
(6)
80°, 5 h
+ MeO
P O
(35)
231
Ph
OMe
t-Bu (CO)4Cr 1.2 eq
MeO
OMe
P Argon (5 bar), CH2Cl2, rt, 8 h
0.02 M
MeO O
OMe (60)
230, 231
OH
MeO 1.2 eq
MeO Cr(CO)5
MeO 0.08 M
+
(25)
P
MeO
70°, 4 h
OMe
Bu-t
Argon (5 bar), DME,
OMe
231
t-Bu P
OMe (50)
MeO
O OMe
t-Bu
OMe
(CO)4Cr
P MeO EtO
1.3 eq
Cr(CO)3
Argon (5 bar), Et2O,
EtO
230, 231
(77)
O
70°, 1 h
Cr(CO)3
0.04 M OH
599
1.4 eq
Bu-t
Bu-t
Cr(CO)5
2-naphth
OMe
P
+
Argon (5 bar), t-BuOMe, P
50°, 5 h
0.17 M
230, 231
2-naphth
(CO)3Cr OMe (19)
OMe
O (9)
(CO)5Cr
Bu-t P
+ 2-naphth
(8) OMe
O
OH Cr(CO)3
OH
Bu-t Cr(CO)5
1.0 eq
Argon (5 bar), t-BuOMe, P
50°, 2 h
Bu-t +
II
OR 0.4 M
229, 231
P
I
OR
OR
R
I
II
Me
(82)
(7)
Et
(72)
(0)
TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C5-6
OH Cr(CO)3 t-Bu
OH Bu-t
Bu-t
P Cr(CO)5
+ t-Bu
OEt 1:1
Refs.
Alkyne (1 eq), argon (5 bar),
+
P
P
231
Et2O, 60°, 2 h OEt
OEt I
0.19 M
II
OH Bu-t
I + II + III (—), OEt
C5
Cr(CO)3
I:II:III = 27:3:5
III t-Bu (CO)4Cr
600 t-Bu
P
OMe
OMe
P MeO
MeO
O
Argon (5 bar), t-BuOMe,
(11)
231
70°, 3 h 0.06 M OMe C6
OMe
H (CO)5W
t-Bu
Alkyne (excess)
polymer (—)
489
Ph OMe (CO)5Cr
(3)
THF, 50°, 41 h
1.2 eq
1.2 eq
490
OH I
Br(CO)4M
Toluene, –10° to rt, 10 min
I
M
I
Cr
(12)
W
(16)
81
OH
OMe O
(CO)5Cr
O
THF, 70°, 9 h
(31)
80
0.0044 M
1.1 eq C7
OH
OMe (CO)5Cr 1.2 eq
THF, 70°
80
I
CC (M)
Time
0.0044
6.5 h
(57)
0.1
2h
(20)
0.1
84 hb
(52) O
OMe (CO)5Cr
1.2 eq
I (39) +
MeCN, 70°, 6.5 h
(26)
80
OMe
II
0.0044 M
601
OMe (CO)4Cr
Solvent, 2-12 h
I + II
133
L 0.006 M L
Solvent
Temp
I
II
2.8
(n-Bu)3P
THF
70°
(48)
(0)
3.2
(n-Bu)3P
MeCN
70°
(49)
(0)
2.0
Ph3P
THF
21°
(61)
(0)
0.8
Ph3P
MeCN
22°
(8)
(55)
Alkyne (eq)
OMe (CO)5Cr
OH THF, 70°, 6 h
1.2 eq
(71)
491
0.0044 M
TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne
Carbene Complex
C7
Conditions
Product(s) and Yield(s) (%) OH
OMe (CO)5Mo 3.5-4 eq
+
Solvent, 70°, 1-4 h
80
I
0.0044 M
OMe
II I
II
THF
(62)
(5)
MeCN
(29)
(10)
Solvent
Refs.
O
OMe (CO)5W
See table
0.0044 M
I + II
80
Time
I
II
5
—
THF
95°
59 h
(56)
(0)
5
—
MeCN
95°
44 h
(8)
(23)
rt
4h
(56)
(0)
95°
133 hb
(71)
(0)
Alkyne (eq)
Solvent Temp
602
2.5
photolysis THF
6
—
THF
OH
OMe 7 eq
THF, 95°, 65 hb
(CO)5W
(71)
Bu-n 0.0044 M
OH 1.2 eq
Br(CO)4M
R
Toluene, –10° to rt, 10 min R
0.1 M
(CO)5W
–78° Ph
R
M
Me
Cr
(50)
Me
W
(54)
Ph
W
(18)
81
NEt2
H Et2N
80
Bu-n
(CO)5W
(57) Ph
489
C6H13-n
C8 n-Bu
n-Bu
Mo(CO)5
n-C6H13 OMe
C5H11-n (5)
(20) +
Benzene, 100° n-Bu
C6H13-n
447
MeO
OH OH Ph Cr(CO)5 Ph
(n-Bu)2O, 80°, 1 h OMe 2.2 eq
(12)
492
(CO)3Cr
0.5 M OMe OH
Ph
Ph
O Cr(CO)5 2.2 eq
Ph
+
Hexane, 70-80°, 8-20 h
+
603
OH (22)
0.05 M
OMe (7)
Hexane, 80°, 24 h Ph
N
M(CO)5
Ph
0.014 M
(12)
Ph
Ph 2.2 eq
406
Ph
OMe
+ N H I
Ph
+ N H II
I
II
III
Cr
(20)
(25)
(18)
W
(65)
(≤1)
(0)
OMe
HO 234 N III
Ph
M
OMe Ph
OH
(CO)5Cr
(n-Bu)2O, 70°, 6 h
(61)
246
Pr-n 1.1 eq
Pr-n
0.006 M
TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
C8 Br(CO)4M
M
OH
Toluene, –10° to rt, 10 min
0.1 M
Refs.
Cr
(46)
W
(52)
81
1.2 eq OH
OMe (CO)5M
M
THF, 50-95°, 32-50 h
0.0044 M
Cr
(32)
W
(50)
80
1.2-4 eq OMe
OMe
n-Pr
(40)
THF, reflux, 6 h
(CO)5Cr
TMS
n-Pr
Ph
155
Ph
TMS
604
10:3.3:1 mixture of diastereomers; E,E-major
C10 TMS OMe (CO)5M
OH THF, 70-95°
TMS 1.2-10 eq
M Cr
(73)
W
(61)
80
0.0044 M
Ph
OMe (CO)5Cr 1.1 eq
O
Dioxane, reflux, 6 h
OMe
(80)
51
0.02 M OMe OMe (CO)5Mo
OMe
OMe
Benzene, 60°, 4.5 h Bu-n
OH Bu-n
(9)
493
C11 MeO2C Br(CO)4M MeO2C
Toluene, –10° to rt,
M
MeO2C
10 min
0.1 M
OH
MeO2C
Cr
(52)
W
(60)
81
1.2 eq C12 OMe (CO)5Cr Pr-n
0.83 eq
1. PhCl, 100° 24 h
0.05 M
C13
Ph Ph Br(CO)4M . 0.1 M
1.2 eq
+
(2)
O
(10)
O
130
2. Iodine
M
OH
Toluene, –10° to rt, 10 min
Cr
(31)
W
(42)
81
Cl
605
OMe (CO)5Cr
1. Solvent, reflux
+
O
2. TsOH, rt
+ O
I
129
II
Bu-n Solvent
I
II
III
dioxane
(34)
(0)
(26)
dioxane/CDCl3 (49:1)
(29)
(7)
(26)
III O
OMe (CO)5Cr
0.83 eq
1. Solvent, 100°, 24 h
O
I + II +
0.05 M
130
IV
O
2. Iodine Solvent
I
II
IV
PhCl
(60)
(0)
(5)
PhCl/CCl4 (9:1)
(20)
(45)
(0)
TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne
Carbene Complex
OMe (CO)5Cr
Conditions
Product(s) and Yield(s) (%)
1. Dioxane, reflux
129
+
+
2. TsOH, rt
Refs.
O
O
O (13)
(54)
(4)
Bu-n OMe (CO)5Cr Bu-n
1. Dioxane, reflux, 26 h
O
(71)
259
O
(84)
259
2. Iodine
0.03 M
0.83 eq
606
Bu-n OMe (CO)5Cr
1. Dioxane, reflux, 26 h 2. Iodine
0.03 M
n-Bu
0.83 eq OMe
EtO2C (CO)5M
OH
EtO2C
THF
EtO2C
80
EtO2C 0.0044 M Alkyne (eq)
M
Temp
Time
1
Cr
70°
15.5 h
(57)
5.5
W
95°
65 h
(72) CO2Me
MeO2C N
MeO2C (CO)5Cr 1.3 eq
0.7 M
Toluene, 120°, 1 h
MeO2C CO2Me
(48) O
O
494
CO2Me MeO2C Toluene, 120°, 1 h
N
MeO2C 1.3 eq
494
MeO2C CO2Me
(CO)5Cr
O
(59)
O
0.7 M OEt Ts
N
solvent, 65-80°, 1-4 h
(CO)5Cr
OH
1. Additive (4 eq), Ts
N
291
2. FeCl3-DMF 1 eq
607
CC (M)
CC (eq)
Solvent
Addtive
0.13
1.0
MeCN
none
(17)
0.13
1.0
benzene
none
(31)
0.13
1.0
THF (sealed tube)
none
(59)
0.13
1.0
THF
none
(40)
0.013
1.0
THF
none
(56)
0.006
1.0
THF
none
(57)
0.006
2.0
THF
none
(60)
0.006
2.0
THF
Ph3P
(71)
0.006
1.0
benzene/hexane (1:1)
Ph3P
(74)
0.006
2.0
THF
DMAP
(19)
0.006
2.0
THF
(PhO)3P
(71)
0.006
2.0
THF
(n-Bu)3P
(27)
C14 Ph
R
OMe (CO)5Cr
Me (61)
Dioxane, reflux, 6 h R
O
0.02 M
1.1 eq
51
c-Pr (68) OMe
R
TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C14 Ph O
Ph
OMe (CO)5Cr
Solvent, 100°
+
I
R
II
260
O
0.02 M
OMe
O
1.1 eq R
Solvent
Me c-Pr
OMe
R
I
II
dioxane
(22)
(26)
dioxane/H2O (99:1)
(26)
(50)
Bu-n OMe (CO)5Cr
1. PhCl, 100°, 24 h
608
0.05 M
Bu-n 0.83 eq TMS
TMS
OMe 1. Dioxane, reflux
OH
2. TsOH, rt
OEt N 1 eq
Ts
(CO)5Cr
2. FeCl3-DMF
OEt (CO)5Cr
1 eq
1. THF, reflux
0.006 M
N
0.006 M
130
n-Bu
(CO)5Cr
Ts
(14)
O
2. Iodine
(20)
155
OH Ts
(71)
N
OH 1. THF, reflux 2. FeCl3-DMF
Ts
Ts +
N (25)
291
OH
N
291 (25)
C15 Ph OMe (CO)5Cr
Dioxane, reflux, 6 h
(54)
51
O 0.02 M
1.1 eq
OMe
OMe (CO)5Cr
(30)
1. PhCl, 100°, 24 h
0.05 M
130
O
2. Iodine
0.83 eq CO2Me
CO2Me
609
OMe (CO)5Cr
1. Dioxane, reflux, 26 h
0.03 M
Bu-n
259
(61)
O
2. Iodine n-Bu
0.83 eq OH
OEt Ts
N
(CO)5Cr
1. THF, reflux
N
(0)
291
2. FeCl3-DMF
0.006 M
1 eq
Ts
C15-16 R OEt Ts
N
(CO)5Cr R
1. THF, reflux 2. FeCl3-DMF
0.006 M
1 eq
R
OH Ts
N
CO2Me
(16)
TMS
(84)
291
TABLE 24. MISCELLANEOUS REACTIONS OF CARBENE COMPLEXES (Continued) Alkyne
Carbene Complex
Conditions
Product(s) and Yield(s) (%)
Refs.
C17 OMe (CO)5Cr
+
1. PhCl, 100°, 24 h
0.05 M
2. Iodine
O
1. PhCl, 100°, 24 h
O
130 O
(50)
(5)
0.53 eq 6
OMe (CO)5Cr
(40)
130
2. Iodine
0.05 M 0.53 eq C18
610
Ph
OMe Ph
(CO)5Cr
1. PhCl, 100°, 24 h
(31)
O
130
2. Iodine
0.05 M 0.53 eq C19
Ph
Ph OMe (CO)5Cr Bu-n
1. Dioxane, reflux, 26 h
O
(81)
259
(63)
259
2. Iodine
0.03 M
n-Bu
0.83 eq Ph Ph
OMe (CO)5Cr
1. Dioxane, reflux, 26 h
O
2. Iodine Bu-n 0.83 eq
0.03 M
n-Bu
CO2Me CO2Me
6
OMe
(CO)5Cr
1. PhCl, 100°, 24 h
(35)
O
130
2. Iodine
0.05 M 0.53 eq
TMS TMS Ts
N
OH
OEt (CO)5Cr
1. THF, reflux
TMS
N
(10)
291
2. FeCl3-DMF
0.006 M
1 eq
Ts
TMS Ph OEt
Ts
N
(CO)5Cr
1. THF, reflux
Ph
2. FeCl3-DMF
1 eq
(83)
291
611
Ts
Ts
N
N
OEt OMe
(CO)5Cr 0.006 M
1 eq
OMe
OMe
1. THF, reflux OMe
2. FeCl3-DMF
(34)
OH
These products arise from the coupling of 2-butyne with one or two C(H) Ph fragments, or two 2-butyne molecules with one C(H)Ph fragment and one CO
molecule. b
N
0.006 M
C23
a
OH Ts
The alkyne was added slowly.
291
612
ORGANIC REACTIONS REFERENCES
1
Fischer, E. O.; Maasb¨ol, A. Angew. Chem., Int. Ed. Engl. 1964, 3, 580. D¨otz, K. H. Angew. Chem., Int. Ed. Engl. 1975, 14, 644. 3 D¨otz, K. H., Rheinische Friedrich-Wilhelms-Universit¨at Bonn, D-53121, Bonn, Germany. Personal communication. 4 Brown, F. J. Prog. Inorg. Chem. 1980, 27, 1. 5 Casey, C. P. In Reactive Intermediates; Jones, M.; Moss, R. A., Eds.; Wiley-Interscience: New York, 1981; Vol. 2, pp 135–174. 6 Semmelhack, M. F. Pure Appl. Chem. 1981, 53, 2379. 7 Semmelhack, M. F., Sato, T.; Bozell, J.; Keller, L., Wulff, W.; Zask, A.; Spiess, E. In Current Trends in Organic Synthesis; Nozaki, H., Ed.; Pergamon: New York, 1982; p 303. 8 D¨otz, K. H. Pure Appl. Chem. 1983, 55, 1689. 9 D¨otz, K. H.; Fischer, H.; Hofmann, P.; Kreissl, F. R.; Schubert, U.; Weiss, K. Transition Metal Carbene Complexes; Verlag Chemie: Deerfield Beach, FL, 1983; p. 153. 10 D¨otz, K. H. Angew. Chem., Int. Ed. Engl. 1984, 23, 587. 11 Casey, C. P. In Reactive Intermediates; Jones, M.; Moss, R. A., Eds.; Wiley-Interscience: New York, 1985; Vol. 3, pp 109–150. 12 Wulff, W. D.; Tang, P.-C.; Chan, K.-S.; McCallum, J. S.; Yang, D. C.; Gilbertson, S. R. Tetrahedron 1985, 41, 5813. 13 Chan, K.-S.; Peterson, G. A.; Brandvold, T. A.; Faron, K. L.; Challener, C. A.; Hyldahl, C.; Wulff, W. D. J. Organomet. Chem. 1987, 334, 9. 14a D¨otz, K. H. In Organometallics in Organic Synthesis: Aspects of a Modern Interdisciplinary Field; tom Dieck, H. ; de Meijere, A., Eds.; Springer: Berlin, 1988; p 85. 14b Schore, N. E. Chem. Rev. 1988, 88, 1081. 15 D¨otz, K. H. In Advances in Metal Carbene Chemistry; NATO ASI Ser., Ser. C, 1989; Vol. 269, p 199. 16 Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, pp 209–393. 17 Harrington, P. J. Transition Metals in Total Synthesis; Wiley: New York, 1990; p 346. 18 D¨otz, K. H. Nouv. J. Chem. 1990, 14, 433. 19 McQuillin, F. J.; Parker, D. G., Stephenson, G. R. Transition Metal Organometallics for Organic Synthesis; Cambridge University Press: Cambridge, 1991. 20 Wulff, W. D. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 5, p 1065. 21 Mulzer, J.; Altenbach, H.-J.; Braun, M.; Krohn, K.; Reissig, H.-U. Organic Synthesis Highlights; VCH: Weinheim, 1991; p 186. 22 Rudler, H. Chem. Soc. Rev. 1991, 186. 23 Grotjahn, D. B.; D¨otz, K. H. Synlett 1991, 381. 24 Wulff, W. D. In Comprehensive Organometallic Chemistry II ; Abel, E. W., Stone, F. G. H., Wilkinson, G., Eds.; Pergamon: New York, 1995; Vol. 12, pp 469–576. 25 Harvey, D. F.; Sigano, D. M. Chem. Rev. 1996, 96, 271. 26 Wulff, W. D. Organometallics 1998, 17, 3116. 27 D¨otz, K. H., Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187. 28 Herndon, J. W. Coord. Chem. Rev. 1999, 181, 177. 29 D¨orwald, F. Z. Metal Carbenes in Organic Synthesis; Wiley-VCH: New York, 1999. 30 de Meijere, A.; Schirmer, H.; Duetsch, M. Angew. Chem., Int. Ed. 2000, 39, 3964. 31 Herndon, J. W. Coord. Chem. Rev. 2000, 206–207, 237. 32 Sierra, M. A. Chem. Rev. 2000, 100, 3591. 33 Barluenga, J. Pure Appl. Chem. 2002, 74, 1317. 34 D¨otz, K. H.; Stendel, J. Jr. In Modern Arene Chemistry, Didier, A., Ed.; Wiley-VCH: New York, 2002; pp 250–296. 35 Sola, M.; Duran, M.; Torrent, M. Catalysis by Metal Complexes 2002, 25, 269. 36 Barluenga, J.; Fananas, F. J. Tetrahedron 2000, 56, 4597. 2
THE SYNTHESIS OF PHENOLS AND QUINONES 37
38
39
40
41 42 43 44 45 46 47
48 49 50 51 52 53
54
55 56
57 58 59
60
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77
78
613
Hegedus, L. S. In Metal Carbenes in Organic Synthesis; D¨otz, K. H., Ed.; Springer: New York, 2004; p 157. Wu, Y.-T.; de Meijere, A. In Metal Carbenes in Organic Synthesis; D¨otz, K. H., Ed.; Springer: New York, 2004; p 21. Minatti, A.; D¨otz, K. H. In Metal Carbenes in Organic Synthesis; D¨otz, K. H., Ed.; Springer: New York, 2004; p 123. Barluenga, J.; Rodriguez, F.; Fananas, F. J.; Florez, J. In Metal Carbenes in Organic Synthesis; D¨otz, K. H., Ed.; Springer, New York: 2004; p 59. Barluenga, J.; Santamaria, J.; Tomas, M. Chem. Rev. 2004, 104, 2259. Fischer, H.; M¨uhlemeier, J.; M¨arkl, R.; D¨otz, K. H. Chem. Ber. 1982, 115, 1355. Torrent, M.; Duran, M.; Sola, M. Organometallics 1998, 17, 1492. Fischer, H.; Hofmann, P. Organometallics 1999, 18, 2590. Hofmann, P.; H¨ammerle, M. Angew. Chem., Int. Ed. Engl. 1989, 28, 908. Hofmann, P.; H¨ammerle, M.; Unfried, G. Nouv. J. Chem. 1991, 15, 769. Waters, M. L.; Brandvold, T. A.; Isaacs, L.; Wulff, W. D.; Rheingold, A. L. Organometallics 1998, 17, 4298. Gleichmann, M. M.; D¨otz, K. H., Hess, B. A. J. Am. Chem. Soc. 1996, 118, 10551. Torrent, M.; Duran, M.; Sola, M. Chem. Commun. 1998, 999. Torrent, M.; Duran, M.; Sola, M. J. Am. Chem. Soc. 1999, 121, 1309. Herndon, J. W.; Hayford, A. Organometallics 1995, 14, 1556. Waters, M. L., Wulff, W. D., The University of Chicago, Chicago, IL, unpublished results. Barluenga, J.; Aznar, F.; Martin, A.; Garcia-Granda, S.; Perez-Carreno, E. J. Am. Chem. Soc. 1994, 116, 11191. Barluenga, J.; Aznar, F.; Gutierrez, I.; Martin, A.; Garcia-Granda, S.; Llorca-Baragano, M. A. J. Am. Chem. Soc. 2000, 122, 1314. Torrent, M.; Sola, M.; Frenking, G. Chem. Rev. 2000, 100, 439. Garrett, K. E.; Sheridan, J. B.; Pourreau, D. B.; Feng, W. C.; Geoffroy, G. L.; Staley, D. L.; Rheingold, A. L. J. Am. Chem. Soc. 1989, 111, 8383. D¨otz, K. H.; F¨ugen-K¨oster, B. Chem. Ber. 1980, 113, 1449. Anderson, B. A.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1990, 112, 8615. Chelain, E.; Parlier, A.; Rudler, H.; Daran, J. C.; Vaissermann, J. J. Organomet. Chem. 1991, 419, C5. Wulff, W. D.; Bax, B. M; Brandvold, T. A.; Chan, K.-S.; Gilbert, A. M.; Hsung, R. P.; Mitchell, J.; Clardy, J. Organometallics 1994, 13, 102. Tang, P.-C.; Wulff, W. D. J. Am. Chem. Soc. 1984, 106, 1132. Bauta, W. E.; Wulff, W. D.; Pavkovic, S. F.; Zaluzec, E. J. J. Org. Chem. 1989, 54, 3249. Foley, H. C.; Strubinger, L. M.; Targos, T. S.; Geoffroy, G. L. J. Am. Chem. Soc. 1983, 105, 3064. Knorr, J. R.; Brown, T. L. Organometallics 1994, 13, 2178. McCallum, J. S.; Kunng, F.-A.; Gilbertson, S. R.; Wulff, W. D. Organometallics 1988, 7, 2346. Waters, M. L.; Bos, M. E.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 6403. Wulff, W. D.; Tang, P.-C.; McCallum, J. S. J. Am. Chem. Soc. 1981, 103, 7677. D¨otz, K. H.; M¨uhlemeier, J.; Schubert, U.; Orama, O. J. Organomet. Chem. 1983, 247, 187. Wulff, W. D.: Chan, K.-S.; Tang, P.-C. J. Org. Chem. 1984, 49, 2293. Yamashita, A.; Toy, A. Tetrahedron Lett. 1986, 27, 3471. Brandvold, T. A.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1990, 112, 1645. Chamberlin, S.; Waters, M. L.; Wulff, W. D. J. Am. Chem. Soc. 1994, 116, 3113. D¨otz, K. H.; Szesni, N.; Nieger, M.; N¨attinen, K. J. Organomet. Chem. 2003, 671, 58. Davies, M. W.; Johnson, C. N.; Harrity, J. P. A. Chem. Commun. 1999, 2107. Davies, M. W.; Johnson, C. N.; Harrity, J. P. A. J. Org. Chem. 2001, 66, 3525. D¨otz, K. H. J. Organomet. Chem. 1977, 140, 177. Parlier, A.; Rudler, M.; Rudler, H.; Goumont, R.; Daran, J.-C.; Vaissermann, J. Organometallics 1995, 14, 2760. Xu, Y.-C.; Challener, C. A.; Dragisich, V.; Brandvold, T. A.; Peterson, G. A.; Wulff, W. D.; Willard, P. G. J. Am. Chem. Soc. 1989, 111, 7269.
614 79 80 81 82 83 84
85 86 87 88 89
90
91 92 93 94 95 96 97 98 99 100
101
102 103 104 105
106 107 108
109
110 111
112 113 114 115 116 117 118
119 120 121
ORGANIC REACTIONS
Yamashita, A. Tetrahedron Lett. 1986, 27, 5915. Wulff, W. D.; Kaesler, R. W.; Peterson, G. A.; Tang, P. C. J. Am. Chem. Soc. 1985, 107, 1060. Sivavec, T. M.; Katz, T. J. Tetrahedron Lett. 1985, 26, 2159. D¨otz, K. H.; Larbig, H. J. Organomet. Chem. 1991, 405, C38. Wulff, W. D.; Gilbert, A. M.; Hsung, R. P.; Rahm, A. J. Org. Chem. 1995, 60, 4566. Bos, M. E.; Wulff, W. D.; Miller, R. A.; Chamberlin, S.; Brandvold, T. A. J. Am. Chem. Soc. 1991, 113, 9293. Katz, T. J.; Lee, S. J. J. Am. Chem. Soc. 1980, 102, 422. Gross, M. F.; Finn, M. G. J. Am. Chem. Soc. 1994, 116, 10921. D¨otz, K. H.; Dietz, R. Chem. Ber. 1977, 110, 1555. Hsung, R. P.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1994, 116, 6449. Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C.; Whitcomb, M. C.; Yeung, S.-M.; Ostrander, R. L.; Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 3392. Semmelhack, M. F.; Bozell, J. J.; Keller, L.; Sato, T.; Spiess, E. J.; Wulff, W.; Zask, A. Tetrahedron 1985, 41, 5803. Painter, J. E.; Quayle, P.; Patel, P. Tetrahedron Lett. 1995, 36, 8089. Chan, K.-S.; Zhang, H. Synth. Commun. 1995, 25, 635. D¨otz, K. H.; Pruskil, I. Chem. Ber. 1980, 113, 2876. Timko, J. M.; Yamashita, A. Org. Synth. 1992, 71, 72. Chamberlin, S.; Wulff, W. D.; Bax, B. Tetrahedron 1993, 49, 5531. Gilbert, A. M.; Wulff, W. D. J. Am. Chem. Soc. 1994, 116, 7449. D¨otz, K. H.; Stinner, C. Tetrahedron: Asymmetry 1997, 8, 1751. Neidlein, R.; G¨urtler, S.; Krieger, C. Helv. Chim. Acta 1994, 77, 2303. Beddoes, R. L.; King, J. D.; Quayle, P. Tetrahedron Lett. 1995, 36, 3027. Bao, J.; Wulff, W. D.; Fumo, M. J.; Grant, E. B.; Heller, D. P.; Whitcomb, M. C.; Yeung, S.-M. J. Am. Chem. Soc. 1996, 118, 2166. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 258. Hagen, G.; Mayr, H. J. Am. Chem. Soc. 1991, 113, 4954. Gordon, D. M.; Danishefsky, S. J.; Schulte, G. K. J. Org. Chem. 1992, 57, 7052. D¨otz, K. H.; Dietz, R. Chem. Ber. 1978, 111, 2517. Semmelhack, M. F.; Ho, S.; Cohen, D.; Steigerwald, M.; Lee, M. C.; Lee, G.; Gilbert, A. M.; Wulff, W. D.; Ball, R. G. J. Am. Chem. Soc. 1994, 116, 7108. Chan, K. S.; Ph.D. Dissertation, The University of Chicago, 1986. Wilson, J. W.; Fischer, E. O. J. Organomet. Chem. 1973, 57, C63. Macomber, D. W.; Hung, M. H.; Liang, M.; Verma, A. G.; Madhukar, P. Macromolecules 1988, 21, 1187. Wulff, W. D.; Bauta, W. E.; Kaesler, R. W.; Lankford, P. J.; Miller, R. A.; Murray, C. K.; Yang, D. C. J. Am. Chem. Soc. 1990, 112, 3642. Chamberlin, S.; Wulff, W. D. J. Org. Chem. 1994, 59, 3047. Hsung, R. P.; Quinn, J. F.; Weisenberg, B. A.; Wulff, W. D.; Yap, G. P. A.; Rheingold, A. L. Chem. Commun. 1997, 615. Wulff, W. D.; Yang, D. C. J. Am. Chem. Soc. 1984, 106, 7565. Liptak, V. P.; Wulff, W. D. Tetrahedron 2000, 56, 10229. Wulff, W. D.; McCallum, J. S.; Kunng, F.-A. J. Am. Chem. Soc. 1988, 110, 7419. Yamashita, A.; Toy, A.; Scahill, T. A. J. Org. Chem. 1989, 54, 3625. Yamashita, A.; Scahill,T. A.; Toy, A. Tetrahedron Lett. 1985, 26, 2969. D¨otz, K. H.; Gl¨anzer, J. Z. Naturforsch. B: Chem. Sci. 1993, 48, 1595. Kalinin, V. N.; Shilova, O. S.; Petrovskii, P. W.; Kovredov, A. L. Organomet. Chem. (USSR) 1989, 2, 520. Barluenga, J.; Tomas, M.; Lopez-Pelegrin, J. A.; Rubio, E. Tetrahedron Lett. 1997, 38, 3981. Aumann, R.; Yu, Z.; Fr¨olich, R. J. Organomet. Chem. 1997, 549, 311. Peterson, G. A.; Wulff, W. D. Tetrahedron Lett. 1997, 38, 5587.
THE SYNTHESIS OF PHENOLS AND QUINONES 122
123 124 125 126 127 128 129 130 131
132 133 134 135 136
137 138 139 140 141 142 143 144 145 146 147 148
149 150 151 152 153 154 155 156 157 158 159 160 161
162 163
164 165 166
167 168
615
Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 369. De Meijere, A. Pure Appl. Chem. 1996, 68, 61. Hallett, M. R.; Painter, J. E.; Quayle, P.; Ricketts, D.; Patel, P. Tetrahedron Lett. 1998, 39, 2851. D¨otz, K. H.; Gl¨anzer, J. J. Chem. Soc., Chem. Commun. 1993, 1036. D¨otz, K. H.; Sturm, W. J. Organomet. Chem. 1986, 310, C22. Rahm, A.; Wulff, W. D. J. Am. Chem. Soc. 1996, 118, 1807. Rahm, A.; Wulff, W. D. Tetrahedron Lett. 1995, 36, 8753. Herndon, J. W.; Wang, H. J. Org. Chem. 1998, 63, 4562. Zhang, Y.; Herndon, J. W. Tetrahedron 2000, 56, 2175. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 349. D¨otz, K. H. Angew. Chem., Int. Ed. Engl. 1979, 18, 954. Xu, Y.-C.; Wulff, W. D. J. Org. Chem. 1987, 52, 3263. Moser, W. H.; Sun, L.; Huffman, J. C. Org. Lett. 2001, 3, 3389. Zimmer, R.; Reissig, H.-U. J. Prakt. Chem. 1998, 340, 755. Doyle, M. In Comprehensive Organometallic Chemistry II ; Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Eds.; Pergamon Press: New York, 1995; Vol. 12, p 421. Wulff, W. D.; Hyldahl, C., The University of Chicago, Chicago, IL, unpublished results. Fischer, E. O.; D¨otz, K. H. Chem. Ber. 1972, 105, 3966. Jiang, M. X.-W.; Rawat, M.; Wulff, W. D. J. Am. Chem. Soc. 2004, 126, 5970. D¨otz, K. H.; Kreiter, C. G. J. Organomet. Chem. 1975, 99, 309. Fischer, H.; D¨otz, K. H. Chem. Ber. 1980, 113, 193. D¨otz, K. H.; Pruskil, I. Chem. Ber. 1978, 111, 2059. D¨otz, K. H.; Ehlenz, R.; Paetsch, D. Angew. Chem., Int. Ed. Engl. 1997, 36, 2376. Katz, T. J.; Yang, G. X.-Q.; Rickman, B. H.; Iwashita, T. J. Am. Chem. Soc. 1993, 115, 2038. Fischer, H.; Meisner, T.; Hofmann, J. J. Organometal. Chem. 1990, 397, 41. Chan, K. S.; Mak, C. C. Tetrahedron 1994, 50, 2003. D¨otz, K. H.; Sturm, W. J. Organomet. Chem. 1985, 285, 205. Harrity, J. P. A.; Heron, N. M.; Kerr, W. J.; McKendy, S.; Middlemiss, D.; Scott, J. S. Synlett 1996, 1184. Zora, M.; Herndon, J. W.; Li, Y.; Rossi, J. Tetrahedron 2001, 57, 5097. Semmelhack, M. F.; Jeong, N.; Lee, G. R. Tetrahedron Lett. 1990, 31, 609. Boger, D. L.; Jacobson, I. C. Tetrahedron Lett. 1989, 30, 2037. Xu, Y.-C.; Kohlman, D. T.; Liang, S. X.; Erikkson, C. Org. Lett. 1999, 1, 1599. Patel, P. P.; Zhu, Y.; Zhang, L.; Herndon, J. W. J. Organomet. Chem. 2004, 689, 3379. Herndon, J. W.; Patel, P. P. J. Org. Chem. 1996, 61, 4500. Herndon, J. W.; Zhu, Y. Tetrahedron Lett. 1998, 39, 7443. Barluenga, J.; Lopez, L. A.; Martinez, S.; Tomas, M. J. Org. Chem. 1998, 63, 7588. Barluenga, J.; Lopez, L. A.; Martinez, S.; Tomas, M. Tetrahedron 2000, 56, 4967. Wulff, W. D.; Xu, Y.-C. J. Am. Chem. Soc. 1988, 110, 2312. Chamberlin, S.; Wulff, W. D. J. Am. Chem. Soc. 1992, 114, 10667. Liptak, V.; Wulff, W. D., The University of Chicago, Chicago, IL, unpublished results. Chelain, E.; Goumont, R.; Hamon, L.; Parlier, A.; Rudler, M.; Rudler, H.; Daran, J.-C.; Vaisserman, J. J. Am. Chem. Soc. 1992, 114, 8088. D¨otz, K. H.; Grotjahn, D.; Harms, K. Angew. Chem., Int. Ed. Engl. 1989 28, 1384. Grotjahn, D. B.; Kroll, F. E. K.; Sch¨afer, T.; Harms, K.; D¨otz, K. H. Organometallics 1992, 11, 298. Merino, I.; Hegedus, L. S. Organometallics 1995, 14, 2522. Merlic, C. A.; Baur, A.; Aldrich, C. C. J. Am. Chem. Soc. 2000, 122, 7398. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 238. Yamashita, A.; Toy, A.; Ghazal, N. B.; Muchmore, C. R. J. Org. Chem. 1989, 54, 4481. D¨otz, K. H.; Leue, V. J. Organomet. Chem. 1991, 407, 337.
616 169
ORGANIC REACTIONS
Pulley, S. R.; Sen, S.; Vorogushin, A.; Swanson, E. Org. Lett. 1999, 1, 1721. Fischer, E. O.; Selmayr, T.; Kreiss, F. R. Chem. Ber. 1977, 110, 2947. 171a Connors, J. A.; Jones, E. M. J. Chem. Soc. (A) 1971, 3368. 171b Connors, J. A.; Jones, E. M. J. Chem. Soc. (A) 1971, 1974. 172 Yamashita, M. Ohishi, T. Bull. Chem. Soc. Jpn. 1993, 66, 1187. 173 Pfeiffer, J.; Nieger, M.; D¨otz, K. H. Chem. Eur. J. 1998, 4, 1843. 174 D¨otz, K. H.; Pfeiffer, J. Chem. Commun. 1996, 895. 175 Su, J.; Wulff, W. D.; Ball, R. G. J. Org. Chem. 1998, 63, 8440. 176 Wang, H.; Huang, J.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 2003, 125, 8980. 177 Harrity, J. P. A.; Kerr, W. J.; Middlemiss, D. Tetrahedron 1993, 49, 5565. 178 Harrity, J. P. A.; Kerr, W. J.; Middlemiss, D. Tetrahedron Lett. 1993, 34, 2995. 179 Caldwell, J. J.; Colman, R.; Kerr, W. J.; Magennis, E. J. Synlett 2001, 1428. 180 Anderson, J. C.; Denton, R. M.; Hickin, H. G.; Wilson, C. Tetrahedron 2004, 60, 2327 181 Balzer, B. L.; Cazanoue, M.; Sabat, M.; Finn, M. G. Organometallics 1992, 11, 1759. 182 Balzer, B. L.; Cazanoue, M.; Finn, M. G. J. Am. Chem. Soc. 1992, 114, 8735. 183 Boger, D. L.; Jacobson, I. C. J. Org. Chem. 1990, 55, 1919. 184 Wu, H.; Wulff, W. D., Michigan State University, East Lansing, MI, unpublished results. 185 D¨otz, K. H.; Larbig, H. Bull. Soc. Chim. Fr. 1992, 129, 579. 186 Choi, Y. H.; Rhee, K. S.; Kim, K. S.; Shin, G. C.; Shin, S. C. Tetrahedron Lett. 1995, 36, 1871. 187 Weyershausen, B.; D¨otz, K. H. Eur. J. Org. Chem. 1998, 1739. 188 Weyershausen, B.; D¨otz, K. H. Synlett 1999, 231. 189 Campos, P. J.; Sampedro, D.; Rodriquez, M. A. Organometallics 2000, 19, 3082. 190 Campos, P. J.; Sampedro, D.; Rodriquez, M. A. J. Org. Chem. 2003, 68, 4674. 191 Harrity, J. P. A.; Kerr, W. J.; Middlemiss, D.; Scott, J. S. J. Organomet. Chem. 1997, 532, 219. 192 Hutchinson, E. J.; Kerr, W. J.; Magennis, E. J. Chem. Commun. 2002, 2262. 193 Aumann, R.; G¨ottker-Schnetmann, I.; Fr¨ohlich, R.; Meyer, O. Eur. J. Org. Chem. 1999, 2545. 194 G¨ottker-Schnetmann, I.; Aumann, R. Organometallics 2001, 20, 346. 195 G¨ottker-Schnetmann, I.; Aumann, R.; Bergander, K. Organometallics 2001, 20, 3574. 196 Ur-Rahman, A.; Schnatter, W. F. K.; Manolache, N. J. Am. Chem. Soc. 1993, 115, 9848. 197 Semmelhack, M. F.; Park, J. Organometallics 1986, 5, 2550. 198 Semmelhack, M. F.; Tamura, R.; Schnatter, W.; Springer, J. J. Am. Chem. Soc. 1984, 106, 5363. 199 Stockman, K. E.; Sabat, M.; Finn, M. G.; Grimes, R. N. J. Am. Chem. Soc. 1992, 114, 8733. 200 Wulff, W. D.; Gilbertson, S. R.; Springer, J. P. J. Am. Chem. Soc. 1986, 108, 520. 201 Hsung, R. P.; Xu, Y.-C.; Wulff, W. D. Tetrahedron Lett. 1995, 36, 8159. 202 Casey, C. P.; Cesa, M. C. Organometallics 1982, 1, 87. 203 D¨otz, K. H.; Christoffers, C. Chem. Ber. 1995, 128, 163. 204 D¨otz, K. H.; Stinner, C.; Nieger, M. J. Chem. Soc., Chem. Commun. 1995, 2535. 205 Hsung, R. P.; Wulff, W. D.; Chamberlin, S.; Liu, Y.; Liu, R.-Y.; Wang, H.; Quinn, J. F.; Wang, S. L. B.; Rheingold, A. L. Synthesis 2001, 200. 206 Lorsbach, B. A.; Prock, A.; Giering, W. P. Organometallics 1995, 14, 1694. 207 Hsung, R. P.; Wulff, W. D.; Challener, C. A. Synthesis 1996, 773. 208 Longen, A.; Nieger, M.; Airola, K.; D¨otz, K. H. Organometallics 1998, 17, 1538. 209 Tomuschat, P.; Kr¨oner, L.; Steckhan, E.; Nieger, M.; D¨otz, K. H. Chem. Eur. J. 1999, 5, 700. 210 D¨otz, K. H.; Otto, F.; Nieger, M. J. Organomet. Chem. 2001, 621, 77. 211 Vorogushin, A. V.; Wulff, W. D.; Hansen, H.-J. J. Am. Chem. Soc. 2002, 124, 6512. 212 Fogel, L.; Hsung, R. P.; Wulff, W. D.; Sommer, R. D.; Rheingold, A. L. J. Am. Chem. Soc. 2001, 123, 5580. 213 Anderson, J. C.; Cran, J. W.; King, N. P. Tetrahedron Lett. 2003, 44, 7771. 214 Semmelhack, M. F.; Bozell, J. J. Tetrahedron. Lett. 1982, 23, 2931. 215 Wang, H.; Wulff, W. D. J. Am. Chem. Soc. 1998, 120, 10573. 216 D¨otz, K. H.; Gerhardt, A. J. Organomet. Chem. 1999, 578, 223. 217 Wang, H.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 2000, 122, 9862. 218 Semmelhack, M. F.; Bozell, J. J.; Sato, T.; Wulff, W.: Spiess, E. J.; Zask, A. J. Am. Chem. Soc. 1982, 104, 5850. 170
THE SYNTHESIS OF PHENOLS AND QUINONES 219
220 221 222 223 224 225 226 227 228 229
230 231 232
233
234 235 236 237 238 239 240
241
242 243 244
245
246
247 248 249
250 251
252 253 254 255 256 257 258 259 260 261
617
Chelain, E.; Parlier, A.; Audouin, M.; Rudler, H.; Daran, J.-C.; Vaissermann, J. J. Am. Chem. Soc. 1993, 115, 10568. D¨otz, K. H.; Leese, T. Bull. Soc. Chim. Fr. 1997, 134, 503. D¨otz, K. H.; Sch¨afer, T. O.; Harms, K. Synthesis 1992, 146. D¨otz, K. H.; Sch¨afer, T.; Harms, K. Angew. Chem., Int. Ed. Engl. 1990, 29, 176. Gopalsamuthiram, V.; Wulff, W. D. J. Am. Chem. Soc. 2004, 126, 13936. Yang, D. C.; Dragisich, V.; Wulff, W. D.; Huffman, J. C. J. Am. Chem. Soc. 1988, 110, 307. Fischer, H. J. Organomet. Chem. 1980, 197, 303. Dragisich, V., Ph.D. Thesis, The University of Chicago, 1990. Aumann, R.; Heinen, H.; Kr¨uger, C.; Betz, P. Chem. Ber. 1990, 123, 605. Fischer, E. O.; Heckl, B.; D¨otz, K. H.; M¨uller, J.; Werner, H. J. Organomet. Chem. 1969, 16, P29. D¨otz, K. H.; Tiriliomis, A.; Harms, K.; Regitz, M.; Annen, U. Angew. Chem., Int. Ed. Engl. 1988, 27, 713, D¨otz, K. H.; Tiriliomis, A.; Harms, K. J. Chem. Soc., Chem. Commun. 1989, 788. D¨otz, K. H.; Tiriliomis, A.; Harms, K. Tetrahedron 1993, 49, 5577. Dragisich, V.; Murray, C. K.; Warner, B. P.; Wulff, W. D.; Yang, D. C. J. Am. Chem. Soc. 1990, 112, 1251. Wulff, W. D.; Dragisich, V.; Huffman, J. C.; Kaesler, R. W.; Yang, D. C. Organometallics 1989, 8, 2196. Dragisich, V.; Wulff, W. D.; Hoogsteen, K. Organometallics 1990, 9, 2867. Aumann, R; Heinen, H. J. Organomet. Chem. 1990, 391, C7. Aumann, R; Heinen, H. J. Organomet. Chem. 1990, 389, C1. Chan, K. S.; Wulff, W. D. J. Am. Chem. Soc. 1986, 108, 5229. Gilbertson, S. R.; Wulff, W. D. Synlett 1989, 47. Wulff, W. D.; Gilbertson, S. R. J. Am. Chem. Soc. 1985, 107, 503. de Meijere, A. In Organometallics in Organic Synthesis 2 ; Werner, H.; Erker, G., Eds.; SpringerVerlag: New York, 1989; p 273. D¨otz, K. H.; Dietz, R.; Kappenstein, C.; Neugebauer, D.; Schubert, U. Chem. Ber. 1979, 112, 3682. Quinn, J. F.; Bos, M. E.; Wulff, W. D. Org. Lett. 1999, 1, 161. Bos, M. E.; Wulff, W. D.; Wilson, K. J. Chem. Commun. 1996, 1863. Quinn, J. F.; Powers, T. S.; Wulff, W. D.; Yap, G. P. A.; Rheingold, A. L. Organometallics 1997, 16, 4945. Bao, J.; Wulff, W. D.; Dragisich, V.; Wenglowski, S.; Ball, R. G. J. Am. Chem. Soc. 1994, 116, 7616. Anderson, B. A.; Bao, J.; Brandvold, T. A.; Challener, C. A.; Wulff, W. D.; Xu, Y.-C.; Rheingold, A. L. J. Am. Chem. Soc. 1993, 115, 10671. Bao, J.; Dragisich, V.; Wenglowski, S.; Wulff, W. D. J. Am. Chem. Soc. 1991, 113, 9873. Hegedus, L. S. Tetrahedron 1997, 53, 4105. Hegedus, L. S. In Comprehensive Organometallic Chemistry II ; Abel, E. W.; Stone, F. G. H.; Wilkinson, G., Eds.; Pergamon: New York, 1995; Vol. 12, pp 549–576. Yang, D. C., Ph. D. Thesis, University of Chicago, IL, 1986. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 336. Barluenga, J.; Aznar, F.; Palomero, M. A.; Barluenga, S. Org. Lett. 1999, 1, 541. Barluenga, J.; Aznar, F.; Palomero, M. A. J. Org. Chem. 2003, 68, 537. Merlic, C. A.; Xu, D. J. Am. Chem. Soc. 1991, 113, 7418. Merlic, C. A.; Burns, E. E.; Xu, D.; Chen, S. Y. J. Am. Chem. Soc. 1992, 114, 8722. Merlic, C. A.; Xu, D.; Gladstone, B. G. J. Org. Chem. 1993, 58, 538. Merlic, C. A.; Burns, E. E. Tetrahedron Lett. 1993, 34, 5401. Rawat, M.; Wulff, W. D. Org Lett. 2004, 6, 329. Herndon, J. W.; Zhang, Y.; Wang, H.; Wang, K. Tetrahedron Lett. 2000, 41, 8687. Jackson, T. J.; Herndon, J. W. Tetrahedron 2001, 57, 3859. D¨otz, K. H.; Pruskil, I. J. Organomet. Chem. 1981, 209, C4.
618 262 263 264 265 266 267
268 269 270 271
272
273
274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293
294 295 296 297 298 299 300 301
302 303 304
305 306 307
ORGANIC REACTIONS
D¨otz, K. H.; Pruskil, I.; M¨uhlemeier, J. Chem. Ber. 1982, 115, 1278. D¨otz, K. H.; Kuhn, W. Angew. Chem., Int. Ed. Engl. 1983, 22, 732. Yamashita, A. J. Am. Chem. Soc. 1985, 107, 5823. Peterson, G. A.; Kunng, F.-A.; McCallum, J. S.; Wulff, W. D. Tetrahedron Lett. 1987, 28, 1381. King, J.; Quayle, P.; Malone, J. F. Tetrahedron Lett. 1990, 31, 5221. Yamashita, A.; Schaub, R. G.; Bach, M. K.; White, G. J.; Toy, A.; Ghazal, N. B.; Burdick, M. D.; Brashler, J. R.; Holm, M. S. J. Med. Chem. 1990, 33, 775. Boger, D. L.; Jacobson, I. C. J. Org. Chem. 1991, 56, 2115. Boger, D. L.; H¨uter, O.; Mbiya, K.; Zhang, M. J. Am. Chem. Soc. 1995, 117, 11839. Zhang, J.; Zhang, Y.; Zhang, Y.; Herndon, J. W. Tetrahedron 2003, 59, 5609. Merlic, C. A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian, A. J. Am. Chem. Soc. 2000, 122, 3224. Merlic, C. A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian, A.; Mammen, J. J. Org. Chem. 2001, 66, 1297. Papageorgiou, V. P.; Assimopoulou, A. N.; Couladouros, E. A.; Hepworth, D.; Nicolaou, K. C. Angew. Chem., Int. Ed. 1999, 38, 270. Shimai, Y.; Koga, T., Japanese Patent 63,156,741 (1988). Pulley, S. R.; Czako, B. Tetrahedron Lett. 2004, 45, 5511. D¨otz, K. H.; Donaldson, W. A.; Sturm, W. Synth. Commun. 2000, 30, 3775. Roush, W. R.; Neitz, R. J. J. Org. Chem. 2004, 69, 4906. Wulff, W. D.; Tang, P.-C. J. Am. Chem. Soc. 1984, 106, 434. D¨otz, K. H.; Popall, M.; M¨uller, G. J. Organomet. Chem. 1987, 334, 57. D¨otz, K. H.; Popall, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 1158. D¨otz, K. H.; Popall, M. Chem. Ber. 1988, 121, 665. D¨otz, K. H.; Popall, M. J. Organomet. Chem. 1985, 291, C1. D¨otz, K. H.; Popall, M. Tetrahedron 1985, 41, 5797. D¨otz, K. H. German Patent 3,407,632 (1985). Gilbert, A. M.; Miller, R.; Wulff, W. D. Tetrahedron 1999, 55, 1607. Miller, R. A.; Gilbert, A. M.; Xue, S.; Wulff, W. D. Synthesis 1999, 80. Flitsch, W.; Lauterwein, J.; Micke, W. Tetrahedron Lett. 1989, 30, 1633. Semmelhack, M. F.; Jeong, N. Tetrahedron Lett. 1990, 31, 605. King, J. D.; Quayle, P. Tetrahedron Lett. 1991, 32, 7759. Parker, K. A.; Coburn, C. A. J. Org. Chem. 1991, 56, 1666. Mori, M.; Kuriyama, K.; Ochifuji, N.; Watanuki, S. Chem. Lett. 1995, 615. Merlic, C. A.; McInnes, D. M.; You, Y. Tetrahedron Lett. 1997, 38, 6787. Merlic, C. A.; You, Y.; McInnes, D. M.; Zechman, A. L.; Miller, M. M.; Deng, Q. Tetrahedron 2001, 57, 5199. D¨otz, K. H.; Ehlenz, R. Chem. Eur. J. 1997, 3, 1751. Pulley, S. R.; Carey, J. P. J. Org. Chem. 1998, 63, 5275. Paetsch, D.; D¨otz, K. H. Tetrahedron Lett. 1999, 40, 487. Wulff, W. D.; Su, J.; Tang, P.-C.; Xu, Y.-C. Synthesis 1999, 415. Xie, X.; Kozlowski, M. C. Org. Lett. 2001, 3, 2661. Vorogushin, A. V.; Wulff, W. D.; Hansen, H.-J. Org. Lett. 2001, 3, 2641. D¨otz, K. H.; Kuhn, W. J. Organomet. Chem. 1983, 252, C78. For an alternative synthesis of 11-deoxydaunomycinone involving carbene complexes, see references 281, 279, and 280. An alternate synthesis of daunomycinone has been published but has been called into question. See reference 105. Kende, A. S.; Tsay, Y. G.; Mills, J. E. J. Am. Chem. Soc. 1976, 98, 1967. Kimball, S. D.; Walt, D. R.; Johnson, F. J. Am. Chem. Soc. 1981, 22, 3711. Grant, E. B.; Yeung, S.-M.; Balasubramanian, S.; Antilla, J.; Wulff, W. D.; Ding, Z.; Pulgam, V. R., Michigan State University, East Lansing, MI, unpublished results. Bao, J.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1993, 115, 3814. Heller, D. P.; Goldberg, D. R.; Wulff, W. D. J. Am. Chem. Soc. 1997, 119, 10551. Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem., Int. Ed. 2001, 40, 2271.
THE SYNTHESIS OF PHENOLS AND QUINONES 308 309 310 311 312 313 314 315 316 317 318
319 320 321 322
323
324 325
326
327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351
352
353 354
619
Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518. Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675. Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley-VCH: New York, 1999. Smith, L. I.; Hoehn, H. H. J. Am. Chem. Soc. 1939, 61, 2619. Druey, J.; Jenny, E. F.; Schenker, K.; Woodward, R. B. Helv. Chim. Acta 1962, 71, 600. Kipping, V. C.; Schiefer, H.; Sch¨onfelder K. J. Prakt. Chem. 1973, 315, 887. Mayr, H. Angew. Chem. Int. Ed. Engl. 1975, 14, 500. Mayr, H.; Huisgen, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 499. Krysan, D. J.; Gurski, A.; Liebeskind, L. S. J. Am. Chem. Soc. 1992, 114, 1412. Danheiser, R. L.; Gee, S. K. J. Org. Chem. 1984, 49, 1672. Dudley, G. B.; Takaki, K. S.; Cha, D. D.; Danheiser, R. L. Org. Lett. 2000, 2, 3407 and references cited therein. Danheiser, R. L.; Casebier, D. S.; Firooznia, F. J. Org. Chem. 1995, 60, 8341. Liebeskind, L. S.; Iyer, S.; Jewell, C. F., Jr. J. Org. Chem. 1986, 51, 3065. Perri, S. T.; Foland, L. D.; Decker, O. H. W.; Morre, H. W. J. Org. Chem. 1986, 51, 3067. Moore, H. W.; Yerxa, B. R. Adv. Strain Org. Chem.; JAI Press Inc.: Grenwich, 1995; Vol. 4, p 81. Tiedemann, R.; Heileman, M. J.; Moore, H. W.; Schaumann, E. J. Org. Chem. 1999, 64, 2170, and references therein. Hergueta, A. R.; Moore, H. W. J. Org. Chem. 1999, 64, 5979, and references therein. Liu, H.; Tomooka, C. S.; Xu, S. L.; Yerxa, B. R.; Sullivan, R. W.; Xiong, Y.; Moore, H. W. Org. Synth. 1998, 76, 189. Houk, K. N.; Spellmeyer, D. C.; Jefford, C. W.; Rimbault, C. G.; Wang, Y.; Miller, R. D. J. Org. Chem. 1988, 53, 2125. Liebeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. J. Org. Chem. 1988, 53, 2482. Liu, H.; Tomooka, C. S.; Moore, H. W. Synth. Commun. 1997, 27, 2177. Liebeskind, L. S.; Granberg, K. L.; Zhang, J. J. Org. Chem. 1992, 57, 4345. Liebeskind, L. S.; Baysdon, S. L.; South, M. S. J. Am. Chem Soc. 1980, 102, 7397. Yin, J.; Liebeskind, L. S. J. Org. Chem. 1998, 63, 5726. Huffman, M. A.; Liebeskind, L. S.; Pennington, W. T. Organometallics 1990, 9, 2194. Huffman, M. A.; Liebeskind, L. S. J. Am. Chem. Soc. 1990, 112, 8617. Huffman, M. A.; Liebeskind, L. S. J. Am. Chem. Soc. 1991, 113, 2771. Liebeskind, L. S.; Chidambaram, R.; Nimkar, S.; Liotta, D. Tetrahedron Lett. 1990, 31, 3723. Liebeskind, L. S.; Baysdon, S. L.; Goedken, V.; Chidambaram, R. Organometallics 1986, 5, 1086. Aumann, R.; Fischer, E. O. Chem. Ber. 1968, 101, 954. Casey, C. P.; Cyr, C. R.; Boggs, R. A. Syn. Inorg. Met. Org. Chem. 1973, 3, 249. Harvey, D. F.; Brown, M. F. Tetrahedron Lett. 1990, 31, 2529. Lee, I.; Cooper, N. J. J. Am. Chem. Soc. 1993, 115, 4389. Hoye, T. R.; Chen, K.; Vyvyan, J. R. Organometallics 1993, 12, 2806. Semmelhack, M. F.; Lee, G. R. Organometallics 1987, 6, 1839. Imwinkelried, R.; Hegedus, L. S. Organometallics 1988, 7, 702. Schwindt, M. A.; Lejon, T.; Hegedus, L. S. Organometallics 1990, 9, 2814. Pfeiffer, J.; D¨otz, K. H. Organometallics 1998, 17, 4353. Chaloner, P. A.; Glick, G. D.; Moss, R. A. J. Chem. Soc., Chem. Commun. 1983, 880. Stadmueller, H.; Knochel, P. Organometallics 1995, 14, 3163. Wang, H.; Hsung, R. P.; Wulff, W. D. Tetrahedron Lett. 1998, 39, 1849. Casey, C. P.; Boggs, R. A.; Anderson, R. L. J. Am. Chem. Soc. 1972, 94, 8947. Aumann, R.; Heinen, H. Chem. Ber. 1987, 120, 537. Baldoli, C.; Buttero, P. D.; Licandro, E.; Maiorana, S.; Papagni, A.; Zanotti-Gerosa, A. Synlett 1993, 935. Barluenga, J.; Trabanco, A. A.; Florez, J.; Garcia-Granda, S.; Martin, E. J. Am. Chem. Soc. 1996, 118, 13099. Barluenga, J.; Aznar, F.; Martin, A. Organometallics 1995, 14, 1429. D¨otz, K. H.; Haase, W. C.; Klumpe, M.; Nieger, M. Chem. Commun. 1997, 1217.
620 355 356 357 358 359 360 361 362 363
364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380
381 382
383 384 385 386 387 388 389 390 391 392 393 394 395
396
397
398 399 400 401 402
ORGANIC REACTIONS
Beringer, F. M.; Galton, S. A. J. Org. Chem. 1963, 28, 3250. Hauser, F. M.; Mal, D. J. Am. Chem. Soc. 1983, 105, 5688. Liu, Y.; Wulff, W. D., The University of Chicago, Chicago, IL, unpublished results. D¨otz, K. H.; Dietz, R.; von Imhof, A.; Lorenz, H.; Huttner, G. Chem. Ber. 1976, 109, 2033. D¨otz, K. H. Chem. Ber. 1977, 110, 78. Yamashita, A.; Johnson, H. G. U.S. Patent 4,737,519 (1988); Chem. Abstr. 1989, 110, 23565. Wulff, W. D.; Wu, C., Michigan State University, East Lansing, MI, unpublished results. Quast, L.; Nieger, M.; D¨otz, K. H. Organometallics 2000, 19, 2179. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 219. Schneider, K. J.; Neubrand, A.; van Eldik, R.; Fischer, H. Organometallics 1992, 11, 267. D¨otz, K. H.; M¨uhlemeier, J. Angew. Chem., Int. Ed. Engl. 1982, 21, 929. D¨otz, K. H.; Kreiter, C. G. Chem. Ber. 1976, 109, 2026. D¨otz, K. H.; Neugebauer, D. Angew. Chem., Int. Ed. Engl. 1978, 17, 851. Yamashita, A.; Scahill, T. A.; Chidester, C. G. Tetrahedron. Lett. 1985, 26, 1159. Anderson, J. C.; Cran, J. W.; King, N. P. Tetrahedron Lett. 2002, 43, 3849. Kretschik, O.; Nieger, M.; D¨otz, K. H. Organometallics 1996, 15, 3625. Zora, M.; Herndon, J. W. Organometallics 1994, 13, 3370. Zora, M.; Herndon, J. W. J. Org. Chem. 1994, 59, 699. Jiang, M. X.-W.; Rawat, M.; Wulff, W. D. J. Am. Chem. Soc. 2004, 126, 5970. D¨otz, K. H.; Pruskil, I.; Schubert, U.; Ackermann, K. Chem. Ber. 1983, 116, 2337. Chan, C.-S.; Mak, C. C.; Chan, K. S. Tetrahedron. Lett. 1993, 34, 5125. Chan, C.-S.; Tse, A. K.-S.; Chan, K. S. J. Org. Chem. 1994, 59, 6084. Peterson, G. A., Ph. D. Thesis, University of Chicago, IL, 1987. Aumann, R.; Hinterding, P. Chem. Ber. 1991, 124, 213. Yamashita, A.; Scahill, T. A. Tetrahedron Lett. 1982, 23, 3765. Caldwell, J. J.; Harrity, J. P. A.; Heron, N. M.; Kerr, W. J.; McKendry, S.; Middlemiss, D. Tetrahedron Lett. 1999, 40, 3481. Yamashita, A.; Timko, J. M.; Watt, W. Tetrahedron Lett. 1988, 29, 2513. Waters, M. L.; Wu, C.; Wulff, W. D., Michigan State University, East Lansing, MI, unpublished results. Hoye, T. R.; Rehberg, G. M. J. Am. Chem. Soc. 1990, 112, 2841. Watanuki, S.; Mori, M. Organometallics 1995, 14, 5054. Harvey, D. F.; Grenzer, E. M.; Gantzel, P. K. J. Am. Chem. Soc. 1994, 116, 6719. Watanuki, S.; Ochifuji, N.; Mori, M. Organometallics 1994, 13, 4129. Watanuki, S.; Ochifuji, N.; Mori, M. Organometallics 1995, 14, 5062. Jahr, H. C.; Nieger, M.; D¨otz, K. H. J. Organometal. Chem. 2002, 641, 185. Neidlein, R.; Rosyk, P. J.; Kramer, W.; Suschitzky, H. Synthesis 1991, 123. Cambie, R. C., Rutledge, P. S.; Tercel, M.; Woodgate, P. D. J. Organomet. Chem. 1986, 315, 171. Huy, N. H. T.; Lefloch, P. J. Organomet. Chem. 1988, 344, 303. Woodgate, P. D.; Sutherland, H. S.; Rickard, C. E. F. J. Organometal. Chem. 2001, 627, 206. Xu, Y.-C., Ph. D. Thesis, The University of Chicago, IL, 1988. Flynn, B. L.; Funke, F. J.; Silveira, C. C.; de Meijere, A. Synlett 1995, 1007. Schirmer, H.; Funke, F. J.; M¨uller, S.; Noltemeyer, M.; Flynn, B. L.; de Meijere, A. Eur. J. Org. Chem. 1999, 2025. Barluenga, J.; Vicente, R.; Lopez, L. A.; Rubio, E.; Tomas, M.; Alvarez-Rua, C. J. Am. Chem. Soc. 2004, 126, 470. Duetsch, M.; Vidoni, S.; Stein, F.; Funke, F.; Noltemeyer, M.; de Meijere, A. J. Chem. Soc., Chem. Commun. 1994, 1679. Milic, J.; Schirmer, H.; Flynn, B. L.; Noltemeyer, M.; de Meijere, A. Synlett 2002, 875. Chan, K. S.; Wulff, W. D., The University of Chicago, Chicago, IL, unpublished results. D¨otz, K. H.; Jakel, C.; Haase, W.-C. J. Organomet. Chem. 2001, 617, 119. Brandvold, T. A.; Wulff, W. D. J. Am. Chem. Soc. 1991, 113, 5459. Aumann, R.; Heinen, H.; Hinterding, P.; Str¨ater, N.; Krebs, B. Chem. Ber. 1991, 124, 1229.
THE SYNTHESIS OF PHENOLS AND QUINONES 403
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D¨otz, K. H.; F¨ugen-K¨oster, B.; Neugebauer, D. J. Organomet. Chem. 1979, 182, 489. Eastham, S. A.; Herbert, J.; Painter, J. E.; Patel, P.; Quayle, P. Synlett 1998, 61. 405 Wu, Y.-T.; Schirmer, H.; Noltemeyer, M.; de Meijere, A. Eur. J. Org. Chem. 2001, 2501. 406 Challener, C. A.; Wulff, W. D.; Anderson, B. A.; Chamberlin, S.; Faron, K. L.; Kim, O. K.; Murray, C. K.; Xu, Y.-C.; Yang, D. C.; Darling, S. D. J. Am. Chem. Soc. 1993, 115, 1359. 407a Christoffers, J.; D¨otz, K. H. J. Chem. Soc., Chem. Commun. 1993, 1811. 407b Christoffers, J.; D¨otz, K. H. Chem. Ber. 1995, 128, 157. 408 Luo, Y.; Herndon, J. W.; Cervantes-Lee, F. J. Am. Chem. Soc. 2003, 125, 12720. 409 Dotz, K. H. German Patent 3,221,506 (1983). 410 Aumann, R.; Hinterding, P. Chem. Ber. 1992, 125, 2765. 411 Duetsch, M.; Lackmann, R.; Stein, F.; de Meijere, A. Synlett 1991, 5, 324. 412 Flynn, B. L.; Schirmer, H.; Duetsch, M.; de Meijere, A. J. Org. Chem. 2001, 66, 1747. 413 Stein, F.; Duetsch, M.; Lackmann, R.; Noltemeyer, M.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1991, 30, 1658. 414 Flynn, B. L.; Funke, F. J.; Noltemeyer, M.; de Meijere, A. Tetrahedron 1995, 51, 11141. 415 Flynn, B. L.; Silveira, C. C.; de Meijere, A. Synlett 1995, 10, 812. 416 Stein, F.; Duetsch, M.; Noltemeyer, M.; de Meijere, A. Synlett 1993, 7, 486. 417 D¨otz, K. H.; Popall, M.; M¨uller, G.; Ackermann, K. Angew. Chem., Int. Ed. Engl. 1986, 25, 911. 418 D¨otz, K. H.; Popall, M.; M¨uller, G.; Ackermann, K. J. Organomet. Chem. 1990, 383, 93. 419 Faron, K. L.; Wulff, W. D. J. Am. Chem. Soc. 1988, 110, 8727. 420 Barluenga, J.; Aznar, F.; Palomero, M. A. Angew. Chem., Int. Ed. 2000, 39, 4346. 421 Schirmer, H.; Labahn, T.; Flynn, B.; Wu, Y.-T.; de Meijere, A. Synlett 1999, 2004. 422 Schirmer, H.; Duetsch, M.; Stein, F.; Labahn, T.; Knieriem, B.; de Meijere, A. Angew. Chem., Int. Ed. 1999, 38, 1285. 423 Schirmer, H.; Flynn, B. L.; de Meijere, A. Tetrahedron 2000, 56, 4977. 424 Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 329. 425 Janes, E.; Nieger, M.; Saarenketo, P.; D¨otz, K. H. Eur. J. Org. Chem. 2003, 2276. 426 Zora, M.; Gungor, E. U. Tetrahedron Lett. 2001, 42, 4733. 427 Yamashita, A.; Toy, A.; Watt, W.; Muchmore, C. R. Tetrahedron Lett. 1988, 29, 3403. 428 D¨otz, K. H.; Dietz, R.; Neugebauer, D. Chem. Ber. 1979, 112, 1486. 429 Alvarez, C.; Parlier, A.; Rudler, H.; Yefsah, R.; Daran, J. C.; Knobler, C. Organometallics 1989, 8, 2253. 430 D¨otz, K. H. Chem. Ber. 1980, 113, 3597. 431 D¨otz, K. H.; Rau, A. J. Organomet. Chem. 1991, 418, 219. 432 D¨otz, K. H.; Rau, A.; Harms, K. J. Organomet. Chem. 1992, 439, 263. 433 D¨otz, K. H.; Kroll, F.; Harms, K. J. Organomet. Chem. 1993, 459, 169. 434 Aumann, R.; Heinen, H.; Goddard, R.; Kr¨uger, C. Chem. Ber. 1991, 124, 2587. 435 D¨otz, K. H. J. Organomet. Chem. 1976, 118, C13. 436 Aumann, R.; Heinen, H.; Kr¨uger, C.; Betz, P. Chem. Ber. 1990, 123, 599. 437 Lafolle-Bezzenine, S.; Parlier, A.; Rudler, H.; Vaissermann, J.; Daran, J.-C. J. Organomet. Chem. 1998, 567, 83. 438 Bouancheau, C.; Rudler, M.; Chelain, E.; Rudler, H.; Vaissermann, J.; Daran, J.-C. J. Organomet. Chem. 1995, 496, 127. 439 Denise, B.; Parlier, A.; Rudler, H.; Vaissermann, J. J. Organomet. Chem. 1995, 494, 43. 440a Rudler, H.; Parlier, A.; Yefsah, R.; Denise, B.; Daran, J.-C.; Vaissermann, J.; Knobler, C. J. Organomet. Chem. 1988, 358, 245. 440b Rudler, H.; Parlier, A.; Rudler, M.; Vaissermann, J. J. Organomet. Chem. 1998, 567, 101. 441 Bonancheau, C.; Parlier, A.; Rudler, M.; Rudler, H.; Vaissermann, J.; Daran, J.-C. Organometallics 1994, 13, 4708. 442 Rudler, H.; Parlier, A. Goumont, R.; Daran, J.-C.; Vaisserman, J. J. Chem. Soc., Chem. Commun. 1991, 1075. 443 D¨otz, K. H.; Erben, H.-G.; Harms, K. J. Chem. Soc., Chem. Commun. 1989, 692. 444 D¨otz, K. H.; Weber, R. Chem. Ber. 1991, 124, 1635. 404
622 445
ORGANIC REACTIONS
Aumann, R.; Schr¨oder, J.; Heinen, H. Chem. Ber. 1990, 123, 1369. Denise, B.; Dubost, P.; Parlier, A.; Rudler, M.; Rudler, H.; Daran, J. C.; Vaissermann, J.; Delgado, F.; Arevalo, A. R.; Toscano, R. A.; Alvarez, C. J. Organomet. Chem. 1991, 418, 377. 447 Harvey, D. F.; Neil, D. A. Tetrahedron 1993, 49, 2145. 448 Neidlein, R.; G¨urtler, S.; Krieger, C. Synthesis 1995, 11, 1389. 449 Barluenga, J.; Trabanco, A. A.; Florez, J.; Garcia-Granda, S.; Llorca, M.-A. J. Am. Chem. Soc. 1998, 120, 12129. 450 Katz, T. J.; Lee, S. J.; Nair, M.; Savage, E. B. J. Am. Chem. Soc. 1980, 102, 7940. 451 Katz, T. J.; Lee, S. J.; Nair, M. J. Am. Chem. Soc. 1980, 102, 7942. 452 Katz, T. J.; Sivavec, T. M. J. Am. Chem. Soc. 1985, 107, 737. 453 Brookhart, M.; Humphrey, M. B.; Kratzer, H. J.; Nelson, G. O. J. Am. Chem. Soc. 1980, 102, 7802. 454 Aumann, R.; Trentmann, B.; Kr¨uger, C.; Lutz, F. Chem. Ber. 1991, 124, 2595. 455 Rehman, A.; Schnatter, W. F. K.; Manolache, N. J. Am. Chem. Soc. 1993, 115, 9848. 456 D¨otz, K. H.; Pruskil, I. J. Organomet. Chem. 1977, 132, 115. 457 Hoye, T. R.; Rehberg, G. M. Organometallics 1990, 9, 3014. 458 Wulff, W. D.; Xu, Y.-C. Tetrahedron Lett. 1988, 29, 415. 459 Wang, H.; Wulff, W. D., The University of Chicago, Chicago, IL, unpublished results. 460 Hohmann, F.; Siemoneit, S.; Nieger, M.; Kotila, S.; D¨otz, K. H. Chem. Eur. J. 1997, 3, 853. 461 D¨otz, K. H.; Siemoneit, S.; Hohmann, F.; Nieger, M. J. Organometal. Chem. 1997, 541, 285. 462 Wulff, W. D. In Comprehensive Organometallic Chemistry II ; Abel, E. W., Stone, F. G. H., Wilkinson, G., Eds.; Pergamon: New York, 1995; Vol. 12, p 509. 463 D¨otz, K. H.; Sch¨afer, T.: Kroll, F.; Harms, K. Angew. Chem., Int. Ed. Engl. 1992, 31, 1236. 464 D¨otz, K. H.; Mittenzwey, S. Eur. J. Org. Chem. 2002, 39. 465 Leese, T.; D¨otz, K. H. Chem. Ber. 1996, 129, 623. 466 Woodgate, P. D.; Sutherland, H. S. J. Organomet. Chem. 2001, 629, 131. 467 Garrett, K. E.; Feng, W. C.; Matsuzaka, H.; Geoffroy, G. L.; Rheingold, A. L. J. Organomet. Chem. 1990, 394, 251. 468 Casey, C. P.; Polichnowski, S. W.; Shusterman, A. J.; Jones, C. R. J. Am. Chem. Soc. 1979, 101, 7282. 469 Fischer, H.; Volkland, H.-P.; Stumpf, R. Anal. Quim. Int. Ed. 1996, 92, 148. 470a Hartbaum, C.; Mauz, E.; Roth, G.; Weissenbach, K.; Fischer, H. Organometallics 1999, 18, 2619. 470b Fischer, H.; Hofmann, J.; Mauz, E. Angew. Chem., Int. Ed. Engl. 1991, 30, 998. 471 D¨otz, K. H.; Dietz, R. J. Organomet. Chem. 1978, 157, C55. 472 Barluenga, J.; Aznar, F.; Barluenga, S.; Fernandez, M.; Martin, A.; Garcia-Granda, S.; PineraNicolas, A. Chem. Eur. J. 1998, 4, 2280. 473 Barluenga, J.; Aznar, F.; Palomero, M. A. Chem. Eur. J. 2002, 8, 4149. 474 Aumann, R.; Fr¨ohlich, R.; Prigge, J.; Meyer, O. Organometallics 1999, 18, 1369. 475 Barluenga, J.; Aznar, F.; Barluenga, S. J. Chem. Soc., Chem. Commun. 1995, 1973. 476 Barluenga, J.; Fernandez-Rodriguez, M. A.; Aguilar, E. Org. Lett. 2002, 4, 3659. 477 Merlic, C. A.; Roberts, W. M. Tetrahedron Lett. 1993, 34, 7379. 478 Barluenga, J.; Lopez, L. A.; Martinez, S.; Tomas, M. Synlett, 1999, 219. 479 Merlic, C. A.; Xu, D.; Khan, S. I. Organometallics 1992, 11, 412. 480 Lian, Y.; Wulff, W. D., Michigan State University, East Lansing, MI, unpublished results. 481 Funke, F.; Duetsch, M.; Stein, F.; Noltemeyer, M.; de Meijere, A. Chem. Ber. 1994, 127, 911. 482 Mathur, P.; Ghosh, S., Sarkar, A.; Rheingold, A. L.; Guzei, I. A. Organometallics 1998, 17, 770. 483 Mathur, P.; Ghosh, S.; Sarkar, A.; Rheingold, A. L.; Guzei, I. A. J. Organomet. Chem. 1998, 566, 159. 484 Mathur, P.; Ghosh, S.; Sarkar, A.; Rheingold, A. L.; Guzei, I. A. Tetrahedron 2000, 56, 4995. 485 Aumann, R.; Heinen, H.; Dartmann, M.; Krebs, B. Chem. Ber. 1991, 124, 2343. 486 Aumann, R.; Jasper, B.; Fr¨ohlich, R. Organometallics 1995, 14, 231. 487 Parlier, A.; Rudler, H.; Platzer, N.; Fontanille, M.; Soum, A. J. Chem. Soc., Dalton Trans. 1987, 1041. 488 Fischer, H.; Schmid, J.; Riede, J. J. Organomet. Chem. 1988, 355, 219. 446
THE SYNTHESIS OF PHENOLS AND QUINONES 489 490
491
492 493 494
623
Fischer, H.; Schmid, J. J. Mol. Catal. 1988, 46, 277. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 354. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, 1989; Vol. 1, p 356. Dietz, R.; D¨otz, K. H.; Neugebauer, D. Nouv. J. Chem. 1978, 2, 59. Harvey, D. F.; Lund, K. P.; Neil, D. A. J. Am. Chem. Soc. 1992, 114, 8424. Hoye, T. R.; Rehberg, G. M. Organometallics 1989, 8, 2070.
AUTHOR INDEX, VOLUMES 1-70
Volume number only is designated in this index
Adam, Waldemar, 61, 69 Adams, Joe T., 8 Adkins, Homer, 8 Agenet, Nicolas, 68 Agcr, David J., 38 Albertson, Noel F., 12 Allen, George R., Jr., 20 Angyal, S. J., 8 Antoulinkis, Evan G., 57 Apparu, Marcel, 29 Archer. S., 14 Arseniyadis, Simeon. 31 Aubcrt, Corinnc, 68 Bachmann, W. E., 1,2 Baer. Donald R.. 11 Banfi. Luca. 65 Baudoux, Jerome. 69 Baxter. Ellen W.. 59 Beauchemin, 58 Behr, Lyell C , 6 Behrman. E. J., 35 Bergmann, Ernst D., 10 Berliner, Ernst, 5 Biellmann, Jean-Francois, 27 Birch, Arthur J., 24 Blatchly, J. M., 19 Blatt. A. H.. 1 Blickc, F. F., 1 Block, Eric, 30 Bloom, Steven H., 39 Bloomfield, Jordan J., 15, 23 Bonafoux. Dominique, 56 Boswell, G. A., Jr., 21
Brand, William W., 18 Brewster, James H., 7 Brown, Herbert C , 13 Brown, Weldon G., 6 Bruson, Herman Alexander, 5 Bublitz. Donald E.. 17 Buck, Johannes S.. 4 Bufali, Simone, 68 Buisine, Olivier, 68 Burke, Steven D., 26 Butz. Lewis W., 5 Cahard, Dominique, 69 Caine, Drury, 23 Cairns, Theodore L., 20 Carmack, Marvin. 3 Carpenter, Nancy E., 66 Carreira, Eric M.. 67 Carter. H. E., 3 Cason, James, 4 Castro, Bcrtrand R., 29 Casy. Guy, 62 Chamberlin, A. Richard, 39 Chapdelaine, Marc J.. 38 Charette, Andre" B., 58 Chen, Bang-Chi, 62 Cheng, Chia-Chung. 28 Ciganek, Engelbert, 32, 51, 62 Clark, Robin D., 47 Confalone, Pat N., 36 Cope, Arthur C , 9, 11 Corey, Elias J., 9 Cola, Donald J.. 17 Cowden, Cameron J., 51
Organic Reactions, Vol. 70, Edited by Larry E. Ovemian et al. © 2008 Organic Reactions. Inc. Published by John Wiley & Sons. Inc. 639
640
AUTHOR INDEX. VOLUMES 1-70
Crandall, Jack K., 29 Crich, David, 64 Crimmins, Michael T., 44 Crouch, R. David, 63 Crounse, Nathan N., 5 Daub, Guido II.. 6 Dave, Vinod, 18 Davies, Huw M. L., 57 Davis, Franklin A., 62 Denmark. Scott E., 45 Denny, R. W.. 20 DeLucchi, Ottorino, 40 DeTar, DeLos R, 9 Dickhaut, J., 48 Djerassi, Carl, 6 Donai lima. L. Guy, 11 Drake, Nathan L., 1 DuBois. Adrien S., 5 Ducep, Jean-Bernard, 27 Dunogues, Jacques, 37 Eliel, Ernest L., 7 Emerson, William S., 4 Engel, Robert, 36 England, D. C. 6 Fan, Rulin, 41 Farina, Vittorio, 50 Ferrier. Robert J., 62 Fettes, Alec, 67 Fieser, Louis F., I Fleming, Ian, 37 Folkers, Karl, 6 Fuson. Reynold C, 1 Gadamasctti, Kumar G., 41 Gandon, Vincent, 68 Gawley, Robert E., 35 Geissman, T. A.. 2 Gensler, Walter J.t 6 Giese, B., 48 Gilman, Henry, 6, 8 Ginsburg, David, 10 Gobcl, T., 48 Govindachari, Tuticorin R.. 6 Grieco, Paul A., 26
Grierson, David, 39 Gschwend, Heinz W., 26 Gung, Benjamin W., 64 Gutsche, C. David. 8 Habermas, Karl L., 45 Hageman, Howard A., 7 Hamilton. Cliff S., 2 Hamlin, K. E., 9 Hanford, W. E., 3 Hanson, Robert M., 60 Harris. Constance M., 17 Harris, J. F., Jr., 13 Harris, Thomas M, 17 Hartung, Walter H., 7 Hassan, C. H., 9 Hauser, Charles R., 1,8 Hayakawa, Yoshihiro, 29 Heck, Richard F., 27 Heldt, Walter Z., 11 Heintzelman, Geoffrey R., 65 Henne, Albert L., 2 Hofferberth. John E.. 62 Hoffman, Roger A., 2 Hoiness, Connie M., 20 Holmes. H. L., 4, 9 Houlihan, William J., 16 House. Herbert O., 9 Hudlicky\ MiloS, 35 Hudlicky\ Tom«, 33, 41 Hudson, Boyd E., Jr., 1 Hughes, David L., 42 Huie, E. M., 36 Hulce, Martin, 38 Huyscr, Earl S.. 13 Hyatt. John A., 45 Idacavage. Michael J., 33 Ide, Walter S.. 4 Ingersoll. A. W., 2 Itsuno, Shinichi, 52 Jackson, Ernest L., 2 Jacobs. Thomas L., 5 Jahangir, Alam, 47 Jakka, Kavitha, 69 Johnson. John R., 1 Johnson. Roy A., 63 Johnson, William S.. 2. 6
AUTHOR INDEX, VOLUMES 1-70
Jones. Gurnos. 15, 49. 56 Jones, Reuben G., 6 Jones, Todd K., 45 Jorgenson, Margaret J., 18 Kanai, Motomu, 70 Kappe, C. Oliver, 63 Katsuki, Tsutomu, 48 Kende, Andrew S., 11 Kloetzel, Milton G„ 4 Knochel, Paul, 58 Kobayashi, Shu. 46 Kochi, Jay K., 19 K op pi nil. B., 48 Kornblum, Nathan, 2, 12 Kosolapoff, Gennady M., 6 Kreider, Eunice M.. 18 Krimcn, L. I., 17 Krishnamurthy, Vcnkat, 50 Krow, Grant R., 43 Kuhlmann, Heinrich, 40 Kulicke. K. J.. 48 Kulka, Marshall, 7 Kutchan, Toni M., 33 Kylcr, Keith S., 31
Lane, John F., 3 Leffler, Marl in T., 1 Letavic, Michael A., 66 Lim, Linda B. L.. 64 Link, J. TM 60 Little, R. Daniel, 47 Lipshutz, Bruce 11.. 41 Luzzio, Frederick A., 53 Malacria, Max, 68 McCombie, Stuart W., 66 McElvain, S. M., 4 McKeever, C. H., 1 McLoughlin, J. I., 47 McMurry, John E., 24 McOmie, J. F. W., 19 Maercker. Adalbert, 14 Magerlein, Barney J., 5 Mahajan, Yogesh R., 65 Malek. Jaroslav, 34. 36 Mallory, Clelia W., 30 Mallory, Frank B., 30
Manske, Richard H. F., 7 Marcinow, Zbigniew, 42 Marti, Christianc, 67 Martin, Elmore L., 1 Martin, Victor S., 48 Martin, William B., 14 Masjedizadeh, Mohammad R.. 47 Meigh, Ivona R., 65 Meijer, Egbert W.. 28 Melikyan. G. G., 49 Mikami, Koichi, 46 Miller. Joseph A., 32 Millot, Nicolas, 58 Miotti, Umberto, 40 Mita, Tsuyoshi, 70 Modena, Giorgio, 40 Molander, Gary, 46 Moore, Maurice L., 5 Morgan, Jack F., 2 Moriarty, Robert M.. 54, 57 Morton, John W., Jr., 8 Mosettig, Erich, 4, 8 Mozingo, Ralph, 4 Mukaiyama, Teruaki, 28, 46
Nace, Harold R., 12 Nagata, Wataru, 25 Nakai, Takeshi, 46 Nakamura, Eiichi, 61 Naqvi, Saiyid M., 33 Negishi. Ei-Ichi, 33 Nelke, Janice M.. 23 Nelson, Todd D., 63 Newman, Melvin S., 5 Nickon, A., 20 Nielsen, Arnold T.. 16 Noe. Mark C , 66 Noyori, Ryoji, 29
Ohno, Masaji, 37 Ojima, Iwao, 56 Otsuka, Masami, 37 Overman, Larry E., 66 Owsley, Dennis G, 23 Pappo. Raphael, 10 Paquette. Leo A.. 25. 62 Parham, William E., 13
641
642
AUTHOR INDEX, VOLUMES 1-70
Parmerter, Stanley M., 10 Pasto, Daniel J., 40 Paterson, Ian, 51 Pettit, George R., 12 Phadke, Ragini, 7 Phillips, Robert R., 10 Pierini, Adriana B., 54 Pigge, F. Christopher, 51 Pine, Stanley R, 18,43 Pinnick, Harold W., 38 Porter, H. K., 20 Posner, Gary H., 19, 22 Prakash, Om, 54, 57 Price, Charles C, 3
Rabideau, Peter WM 42 Rabjohn, Norman. 5, 24 Rathke, Michael W., 22 Raulins, N. Rebecca, 22 Raynolds, Peter W., 45 Reed. Josephine W., 41 Reich, Hans J., 44 Reinhold, Tracy L., 44 Reitz, Allen B., 59 Rhoads, Sara Jane, 22 Rickborn, Bruce, 52, 53 Rigby. James H., 49, 51 Rinehart, Kenneth L., Jr., 17 Ripka, W. C, 21 Riva, Renata, 65 Roberts, John D., 12 Rodriguez, Alain L., 58 Rodriguez, Herman R., 26 Roe. Arthur, 5 Rondcstvcdt, Christian S., Jr., 11,24 Rossi, Roberto, 54 Ruh-Polenz. Carmen, 55 Rytina, Anton W., 5 Saha-Moller, Chantu R., 61 Santiago, Ana N., 54 Saner. John C, 3 Schaefer, John P., 15 Schore, Neil E., 40 Schulenberg, J. W., 14 Schweizer, Edward E., 13 Scott, William J., 50
Scribner, R. M.. 21 Seeberger, Peter H., 68 Semmelhack, Martin F., 19 Sengupta, Saumitra, 41 Sethna, Suresh, 7 Shapiro, Robert R, 23 Sharts. Clay M., 12, 21 Sheehan, John C, 9 Sheldon, Roger A., 19 Sheppard, W. A., 21 Shibasaki, Masakatsu. 70 Shirley, David A., 8 Shriner. Ralph L., 1 Simmons, Howard E., 20 Simonoff, Robert, 7 Slowinski, Franck, 68 Smith, Lee Irvin, 1 Smith, Peter A. S., 3. 11 Smithers, Roger, 37 Snow, Sheri L., 66 Spielman, M. A., 3 Spoerri, Paul E., 5 Stacey. F. W., 13 Stadler, Alexander, 63 Stanforth, Stephen P., 49, 56 Stetter, Hermann, 40 Struve, W. S., 1 Suter, C. M.. 3 Swamer, Frederic W., 8 Swern, Daniel, 7
Takai, Kazuhiko, 64 Tarbell. D. Stanley, 2 Taylor, Richard J.K., 62 Taylor, Richard T., 40 Thoma, G., 48 Tidwell, Thomas T., 39 Todd, David. 4 Touster, Oscar, 7 Trach, F., 48 Truce, William E., 9, 18 Trumbull, Elmer R., 11 Tsai, Chung-Ying. 56 Tucker. Charles E., 58 Tullock, C. W., 21 Tzamarioudaki, Maria, 56
Ucmura, Motokazu, 67
AUTHOR INDEX, VOLUMES 1-70
van Leusen, Albert M., 57 van Leusen, Daan, 57 van Tamelen, Eugene E., 12 Vedejs, E., 22 Vladuchick, Susan A., 20 Vorbriiggen, Helmut, 55 Wadsworth, William S., Jr., 25 Walling, Cheves, 13 Wallis, Everett S., 3 Wallquist, Olof, 47 Wang, Chia-Lin L., 34 Warnhoff, E. W., 18 Waters, Marcey L., 70 Watt, David S., 31 Weinreb, Steven M., 65 Weston, Arthur W., 3, 9 Whaley, Wilson M., 6 Wilds, A. L., 2 Wiley, Richard H., 6
Williamson, David H., 24 Wilson, C. V., 9 Wilson, Stephen R., 43 Wolf, Donald E., 6 Wolff, Hans, 3 Wollowitz, Susan, 44 Wood, John L., 3 Wulff, William D., 70 Wynberg, Hans, 28 Yam ago, Shi gem. 61 Yan, Shou-Jen, 28 Yoshioka, Mitsuru, 25 Zaugg. Harold E., 8, 14 Zhao, Cong-Gui, 61,69 Zhou, Ping, 62 Zubkov, Oleg A., 62 Zweifel, George, 13, 32
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
Many chapters contain brief discussions of reactions and comparisons of alternative synthetic methods related to the reaction that is the subject of the chapter. These related reactions and alternative methods are not usually listed in this index. In this index, the volume number is in boldface, the chapter number is in ordinary type. Acetoacetic ester condensation, 1, 9 Acetylenes: cotrimerizations of, 68, 1 oxidation by dioxirane, 69, 1 reactions with Fischer carbene complexes, phenol and quinone formation, 70, 2 synthesis of, 5, 1; 23, 3; 32, 2 Acid halides: reactions with esters, 1, 9 reactions with organometallic compounds, 8, 2 α-Acylamino acid mixed anhydrides, 12, 4 α-Acylamino acids, azlactonization of, 3, 5 Acylation: of esters with acid chlorides, 1, 9 intramolecular, to form cyclic ketones, 2, 4; 23, 2 of ketones to form diketones, 8, 3 Acyl fluorides, synthesis of, 21, 1; 34, 2; 35, 3 Acyl hypohalites, reactions of, 9, 5 Acyloins, 4, 4; 15, 1; 23, 2 Alcohols: conversion to fluorides, 21, 1, 2; 34, 2; 35, 3 conversion to olefins, 12, 2 oxidation of, 6, 5; 39, 3; 53, 1
replacement of hydroxy group by nucleophiles, 29, 1; 42, 2 resolution of, 2, 9 Alcohols, synthesis: by allylstannane addition to aldehydes, 64, 1 by base-promoted isomerization of epoxides, 29, 3 by hydroboration, 13, 1 by hydroxylation of ethylenic compounds, 7, 7 by organochromium reagents to carbonyl compounds, 64, 3 by reduction, 6, 10; 8, 1 from organoboranes, 33, 1 Aldehydes, additions of allyl, allenyl, propargyl stannanes, 64, 1 Aldehydes, catalyzed addition to double bonds, 40, 4 Aldehydes, synthesis of, 4, 7; 5, 10; 8, 4, 5; 9, 2; 33, 1 Aldol condensation, 16; 67, 1 catalytic, enantioselective, 67, 1 directed, 28, 3 with boron enolates, 51, 1 Aliphatic fluorides, 2, 2; 21, 1, 2; 34, 2; 35, 3 Alkanes, by reduction of alkyl halides with organochromium reagents, 64, 3 oxidation of, 69, 1
Organic Reactions, Vol. 70, Edited by Larry E. Overman et al. 2008 Organic Reactions, Inc. Published by John Wiley & Sons, Inc. 645
646
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
Alkenes: arylation of, 11, 3; 24, 3; 27, 2 asymmetric dihydroxylation, 66, 2 cyclopropanes from, 20, 1 cyclization in intramolecular Heck reactions, 60, 2 from carbonyl compounds with organochromium reagents, 64, 3 dioxirane epoxidation of, 61, 2 epoxidation and hydroxylation of, 7, 7 free-radical additions to, 13, 3, 4 hydroboration of, 13, 1 hydrogenation with homogeneous catalysts, 24, 1 reactions with diazoacetic esters, 18, 3 reactions with nitrones, 36, 1 reduction by alkoxyaluminum hydrides, 34, 1 Alkenes, synthesis: from amines, 11, 5 from aryl and vinyl halides, 27, 2 by Bamford-Stevens reaction, 23, 3 by Claisen and Cope rearrangements, 22, 1 by dehydrocyanation of nitriles, 31 by deoxygenation of vicinal diols, 30, 2 from α-halosulfones, 25, 1; 62, 2 by palladium-catalyzed vinylation, 27, 2 from phosphoryl-stabilized anions, 25, 2 by pyrolysis of xanthates, 12, 2 from silicon-stabilized anions, 38, 1 from tosylhydrazones, 23, 3; 39, 1 by Wittig reaction, 14, 3 Alkene reduction by diimide, 40, 2 Alkenyl- and alkynylaluminum reagents, 32, 2 Alkenyllithiums, formation of, 39, 1 Alkoxyaluminum hydride reductions, 34, 1; 36, 3 Alkoxyphosphonium cations, nucleophilic displacements on, 29, 1 Alkylation: of allylic and benzylic carbanions, 27, 1 with amines and ammonium salts, 7, 3 of aromatic compounds, 3, 1 of esters and nitriles, 9, 4
γ -, of dianions of β-dicarbonyl compounds, 17, 2 of metallic acetylides, 5, 1 of nitrile-stabilized carbanions, 31 with organopalladium complexes, 27, 2 Alkylidenation by titanium-based reagents, 43, 1 Alkylidenesuccinic acids, synthesis and reactions of, 6, 1 Alkylidene triphenylphosphoranes, synthesis and reactions of, 14, 3 Allenylsilanes, electrophilic substitution reactions of, 37, 2 Allylic alcohols, synthesis: from epoxides, 29, 3 by Wittig rearrangement, 46, 2 Allylic and benzylic carbanions, heteroatom-substituted, 27, 1 Allylic hydroperoxides, in photooxygenations, 20, 2 Allylic rearrangements, transformation of glycols into 2,3-unsaturated glycosyl derivatives, 62, 4 Allylic rearrangements, trihaloacetimidate, 66, 1 π-Allylnickel complexes, 19, 2 Allylphenols, synthesis by Claisen rearrangement, 2, 1; 22, 1 Allylsilanes, electrophilic substitution reactions of, 37, 2 Aluminum alkoxides: in Meerwein-Ponndorf-Verley reduction, 2, 5 in Oppenauer oxidation, 6, 5 Amide formation by oxime rearrangement, 35, 1 α-Amidoalkylations at carbon, 14, 2 Amination: of heterocyclic bases by alkali amides, 1, 4 of hydroxy compounds by Bucherer reaction, 1, 5 Amine oxides: Polonovski reaction of, 39, 2 pyrolysis of, 11, 5 Amines: from allylstannane addition to imines, 64, 1
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
oxidation of, 69, 1 synthesis from organoboranes, 33, 1 synthesis by reductive alkylation, 4, 3; 5, 7 synthesis by Zinin reaction, 20, 4 reactions with cyanogen bromide, 7, 4 α-Aminoacid synthesis, via Strecker Reaction, 70, 1 α-Aminoalkylation of activated olefins, 51, 2 Aminophenols from anilines, 35, 2 Anhydrides of aliphatic dibasic acids, Friedel-Crafts reaction with, 5, 5 Anion-assisted sigmatropic rearrangements, 43, 2 Anthracene homologs, synthesis of, 1, 6 Anti-Markownikoff hydration of alkenes, 13, 1 π-Arenechromium tricarbonyls, reaction with nitrile-stabilized carbanions, 31 η6 -(Arene)chromium complexes, 67, 2 Arndt-Eistert reaction, 1, 2 Aromatic aldehydes, synthesis of, 5, 6; 28, 1 Aromatic compounds, chloromethylation of, 1, 3 Aromatic fluorides, synthesis of, 5, 4 Aromatic hydrocarbons, synthesis of, 1, 6; 30, 1 Aromatic substitution by the SRN 1 reaction, 54, 1 Arsinic acids, 2, 10 Arsonic acids, 2, 10 Arylacetic acids, synthesis of, 1, 2; 22, 4 β-Arylacrylic acids, synthesis of, 1, 8 Arylamines, synthesis and reactions of, 1, 5 Arylation: by aryl halides, 27, 2 by diazonium salts, 11, 3; 24, 3 γ -, of dianions of β-dicarbonyl compounds, 17, 2 of nitrile-stabilized carbanions, 31 of alkenes, 11, 3; 24, 3; 27, 2 Arylglyoxals, condensation with aromatic hydrocarbons, 4, 5 Arylsulfonic acids, synthesis of, 3, 4 Aryl halides, homocoupling of, 63, 3
647
Aryl thiocyanates, 3, 6 Asymmetric aldol reactions using boron enolates, 51, 1 Asymmetric cyclopropanation, 57, 1 Asymmetric dihydroxylation, 66, 2 Asymmetric epoxidation, 48, 1; 61, 2 Asymmetric Strecker reaction, 70, 1 Atom transfer preparation of radicals, 48, 2 Aza-Payne rearrangements, 60, 1 Azaphenanthrenes, synthesis by photocyclization, 30, 1 Azides, synthesis and rearrangement of, 3, 9 Azlactones, 3, 5 Baeyer-Villiger reaction, 9, 3; 43, 3 Bamford-Stevens reaction, 23, 3 Barbier Reaction, 58, 2 Bart reaction, 2, 10 Barton fragmentation reaction, 48, 2 B´echamp reaction, 2, 10 Beckmann rearrangement, 11, 1; 35, 1 Benzils, reduction of, 4, 5 Benzoin condensation, 4, 5 Benzoquinones: acetoxylation of, 19, 3 in Nenitzescu reaction, 20, 3 synthesis of, 4, 6 Benzylic carbanions, 27, 1; 67, 2 Biaryls, synthesis of, 2, 6; 63, 3 Bicyclobutanes, from cyclopropenes, 18, 3 Biginelli dihydropyrimidine synthesis, 63, 1 Birch reaction, 23, 1; 42, 1 Bischler-Napieralski reaction, 6, 2 Bis(chloromethyl) ether, 1, 3; 19, warning Borane reduction, chiral, 52, 2 Borohydride reduction, chiral, 52, 2 in reductive amination, 59, 1 Boron enolates, 51, 1 Boyland-Sims oxidation, 35, 2 Bucherer reaction, 1, 5 Cannizzaro reaction, 2, 3 Carbenes, 13, 2; 26, 2; 28, 1 Carbene complexes in phenol and quinone synthesis, 70, 2
648
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
Carbenoid cyclopropanation, 57, 1; 58, 1 Carbohydrates, deoxy, synthesis of, 30, 2 Carbo/metallocupration, 41, 2 Carbon-carbon bond formation: by acetoacetic ester condensation, 1, 9 by acyloin condensation, 23, 2 by aldol condensation, 16; 28, 3; 46, 1; 67, 1 by alkylation with amines and ammonium salts, 7, 3 by γ -alkylation and arylation, 17, 2 by allylic and benzylic carbanions, 27, 1 by amidoalkylation, 14, 2 by Cannizzaro reaction, 2, 3 by Claisen rearrangement, 2, 1; 22, 1 by Cope rearrangement, 22, 1 by cyclopropanation reaction, 13, 2; 20, 1 by Darzens condensation, 5, 10 by diazonium salt coupling, 10, 1; 11, 3; 24, 3 by Dieckmann condensation, 15, 1 by Diels-Alder reaction, 4, 1, 2; 5, 3; 32, 1 by free-radical additions to alkenes, 13, 3 by Friedel-Crafts reaction, 3, 1; 5, 5 by Knoevenagel condensation, 15, 2 by Mannich reaction, 1, 10; 7, 3 by Michael addition, 10, 3 by nitrile-stabilized carbanions, 31 by organoboranes and organoborates, 33, 1 by organocopper reagents, 19, 1; 38, 2; 41, 2 by organopalladium complexes, 27, 2 by organozinc reagents, 20, 1 by rearrangement of α-halosulfones, 25, 1; 62, 2 by Reformatsky reaction, 1, 1; 28, 3 by trivalent manganese, 49, 3 by Vilsmeier reaction, 49, 1; 56, 2 by vinylcyclopropane-cyclopentene rearrangement, 33, 2 Carbon-fluorine bond formation, 21, 1; 34, 2; 35, 3; 69, 2 Carbon-halogen bond formation,
by replacement of hydroxy groups, 29, 1 Carbon-heteroatom bond formation: by free-radical chain additions to carbon-carbon multiple bonds, 13, 4 by organoboranes and organoborates, 33, 1 Carbon-nitrogen bond formation, by reductive amination, 59, 1 Carbon-phosphorus bond formation, 36, 2 Carbonyl compounds, addition of organochromium reagents, 64, 3 Carbonyl compounds, α,β-unsaturated: formation by selenoxide elimination, 44, 1 vicinal difunctionalization of, 38, 2 Carbonyl compounds, from nitro compounds, 38, 3 in the Passerini Reaction, 65, 1 oxidation with hypervalent iodine reagents, 54, 2 reductive amination of, 59, 1 Carbonylation as part of intramolecular Heck reaction, 60, 2 Carboxylic acid derivatives, conversion to fluorides, 21, 1, 2; 34, 2; 35, 3 Carboxylic acids: synthesis from organoboranes, 33, 1 reaction with organolithium reagents, 18, 1 Catalytic enantioselective aldol addition, 67, 1 Chapman rearrangement, 14, 1; 18, 2 Chloromethylation of aromatic compounds, 2, 3; 9, warning Cholanthrenes, synthesis of, 1, 6 Chromium reagents, 64, 3; 67, 2 Chugaev reaction, 12, 2 Claisen condensation, 1, 8 Claisen rearrangement, 2, 1; 22, 1 Cleavage: of benzyl-oxygen, benzyl-nitrogen, and benzyl-sulfur bonds, 7, 5 of carbon-carbon bonds by periodic acid, 2, 8 of esters via SN 2-type dealkylation, 24, 2
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
of non-enolizable ketones with sodium amide, 9, 1 in sensitized photooxidation, 20, 2 Clemmensen reduction, 1, 7; 22, 3 Collins reagent, 53, 1 Condensation: acetoacetic ester, 1, 9 acyloin, 4, 4; 23, 2 aldol, 16 benzoin, 4, 5 Biginelli, 63, 1 Claisen, 1, 8 Darzens, 5, 10; 31 Dieckmann, 1, 9; 6, 9; 15, 1 directed aldol, 28, 3 Knoevenagel, 1, 8; 15, 2 Stobbe, 6, 1 Thorpe-Ziegler, 15, 1; 31 Conjugate addition: of hydrogen cyanide, 25, 3 of organocopper reagents, 19, 1; 41, 2 Cope rearrangement, 22, 1; 41, 1; 43, 2 Copper-Grignard complexes, conjugate additions of, 19, 1; 41, 2 Corey-Winter reaction, 30, 2 Coumarins, synthesis of, 7, 1; 20, 3 Coupling reaction of organostannanes, 50, 1 Cuprate reagents, 19, 1; 38, 2; 41, 2 Curtius rearrangement, 3, 7, 9 Cyanation, of N-heteroaromatic compounds, 70, 1 Cyanoborohydride, in reductive aminations, 59, 1 Cyanoethylation, 5, 2 Cyanogen bromide, reactions with tertiary amines, 7, 4 Cyclic ketones, formation by intramolecular acylation, 2, 4; 23, 2 Cyclization: of alkyl dihalides, 19, 2 of aryl-substituted aliphatic acids, acid chlorides, and anhydrides, 2, 4; 23, 2 of α-carbonyl carbenes and carbenoids, 26, 2 cycloheptenones from α-bromoketones, 29, 2 of diesters and dinitriles, 15, 1
649
Fischer indole, 10, 2 intramolecular by acylation, 2, 4 intramolecular by acyloin condensation, 4, 4 intramolecular by Diels-Alder reaction, 32, 1 intramolecular by Heck reaction, 60, 2 intramolecular by Michael reaction, 47, 2 Nazarov, 45, 1 by radical reactions, 48, 2 of stilbenes, 30, 1 tandem cyclization by Heck reaction, 60, 2 Cycloaddition reactions, of cyclenones and quinones, 5, 3 cyclobutanes, synthesis of, 12, 1; 44, 2 cyclotrimerization of acetylenes, 68, 1 Diels-Alder, acetylenes and alkenes, 4, 2 Diels-Alder, imino dienophiles, 65, 2 Diels-Alder, intramolecular, 32, 1 Diels-Alder, maleic anhydride, 4, 1 [4 + 3], 51, 3 of enones, 44, 2 of ketenes, 45, 2 of nitrones and alkenes, 36, 1 Pauson-Khand, 40, 1 photochemical, 44, 2 retro-Diels-Alder reaction, 52, 1; 53, 2 [6 + 4], 49, 2 [3 + 2], 61, 1 Cyclobutanes, synthesis: from nitrile-stabilized carbanions, 31 by thermal cycloaddition reactions, 12, 1 Cycloheptadienes, from divinylcyclopropanes, 41, 1 polyhalo ketones, 29, 2 π-Cyclopentadienyl transition metal carbonyls, 17, 1 Cyclopentenones: annulation, 45, 1 synthesis, 40, 1; 45, 1 Cyclopropane carboxylates, from diazoacetic esters, 18, 3
650
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
Cyclopropanes: from α-diazocarbonyl compounds, 26, 2 from metal-catalyzed decomposition of diazo compounds, 57, 1 from nitrile-stabilized carbanions, 31 from tosylhydrazones, 23, 3 from unsaturated compounds, methylene iodide, and zinc-copper couple, 20, 1; 58, 1; 58, 2 Cyclopropenes, synthesis of, 18, 3
Darzens glycidic ester condensation, 5, 10; 31 DAST, 34, 2; 35, 3 Deamination of aromatic primary amines, 2, 7 Debenzylation, 7, 5; 18, 4 Decarboxylation of acids, 9, 5; 19, 4 Dehalogenation of α-haloacyl halides, 3, 3 Dehydrogenation: in synthesis of ketenes, 3, 3 in synthesis of acetylenes, 5, 1 Demjanov reaction, 11, 2 Deoxygenation of vicinal diols, 30, 2 Desoxybenzoins, conversion to benzoins, 4, 5 Dess-Martin Oxidation, 53, 1 Desulfurization: of α-(alkylthio)nitriles, 31 in alkene synthesis, 30, 2 with Raney nickel, 12, 5 Diazo compounds, carbenoids derived from, 57, 1 Diazoacetic esters, reactions with alkenes, alkynes, heterocyclic and aromatic compounds, 18, 3; 26, 2 α-Diazocarbonyl compounds, insertion and addition reactions, 26, 2 Diazomethane: in Arndt-Eistert reaction, 1, 2 reactions with aldehydes and ketones, 8, 8 Diazonium fluoroborates, synthesis and decomposition, 5, 4 Diazonium salts: coupling with aliphatic compounds, 10, 1, 2
in deamination of aromatic primary amines, 2, 7 in Meerwein arylation reaction, 11, 3; 24, 3 in ring closure reactions, 9, 7 in synthesis of biaryls and aryl quinones, 2, 6 Dieckmann condensation, 1, 9; 15, 1 for synthesis of tetrahydrothiophenes, 6, 9 Diels-Alder reaction: intramolecular, 32, 1 retro-Diels-Alder reaction, 52, 1; 53, 2 with alkynyl and alkenyl dienophiles, 4, 2 with cyclenones and quinones, 5, 3 with imines, 65, 2 with maleic anhydride, 4, 1 Dihydrodiols, 63, 2 Dihydropyrimidine synthesis, 63, 1 Dihydroxylation of alkenes, asymmetric, 66, 2 Diimide, 40, 2 Diketones: pyrolysis of diaryl, 1, 6 reduction by acid in organic solvents, 22, 3 synthesis by acylation of ketones, 8, 3 synthesis by alkylation of β-diketone anions, 17, 2 Dimethyl sulfide, in oxidation reactions, 39, 3 Dimethyl sulfoxide, in oxidation reactions, 39, 3 Diols: deoxygenation of, 30, 2 oxidation of, 2, 8 Dioxetanes, 20, 2 Dioxiranes, 61, 2; 69, 1 Dioxygenases, 63, 2 Divinyl-aziridines, -cyclopropanes, -oxiranes, and -thiiranes, rearrangements of, 41, 1 Doebner reaction, 1, 8 Eastwood reaction, 30, 2 Elbs reaction, 1, 6; 35, 2 Electrophilic fluorination, 69, 2 Enamines, reaction with quinones, 20, 3
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
651
Enantioselective aldol reactions, 67, 1 Ene reaction, in photosensitized oxygenation, 20, 2 Enolates: Fluorination of, 69, 2 α-Hydroxylation of, 62, 1 in directed aldol reactions, 28, 3; 46, 1; 51, 1 Enone cycloadditions, 44, 2 Enzymatic reduction, 52, 2 Enzymatic resolution, 37, 1 Epoxidation: of alkenes, 61, 2 of allylic alcohols, 48, 1 with organic peracids, 7, 7 Epoxide isomerizations, 29, 3 Epoxide formation, 61, 2 migration, 60, 1 Esters: acylation with acid chlorides, 1, 9 alkylation of, 9, 4 alkylidenation of, 43, 1 cleavage via SN 2-type dealkylation, 24, 2 dimerization, 23, 2 glycidic, synthesis of, 5, 10 hydrolysis, catalyzed by pig liver esterase, 37, 1 β-hydroxy, synthesis of, 1, 1; 22, 4 β-keto, synthesis of, 15, 1 reaction with organolithium reagents, 18, 1 reduction of, 8, 1 synthesis from diazoacetic esters, 18, 3 synthesis by Mitsunobu reaction, 42, 2 Ethers, synthesis by Mitsunobu reaction, 42, 2 Exhaustive methylation, Hofmann, 11, 5
Gattermann aldehyde synthesis, 9, 2 Gattermann-Koch reaction, 5, 6 Germanes, addition to alkenes and alkynes, 13, 4 Glycals, fluorination of, 69, 2 transformation in glycosyl derivatives, 62, 4 Glycosides, synthesis of, 64, 2 Glycosylating Agents, 68, 2 Glycosylation on polymer supports, 68, 2 Glycosylation, with sulfoxides and sulfinates, 64, 2 Glycidic esters, synthesis and reactions of, 5, 10 Gomberg-Bachmann reaction, 2, 6; 9, 7 Grundmann synthesis of aldehydes, 8, 5
Favorskii rearrangement, 11, 4 Ferrocenes, 17, 1 Fischer carbene complexes, 70, 2 Fischer indole cyclization, 10, 2 Fluorinating agents, electrophilic, 69, 2 Fluorination of aliphatic compounds, 2, 2; 21, 1, 2; 34, 2; 35, 3; 69, 2 of carbonyl compounds, 69, 2 of heterocycles, 69, 2
Halides, displacement reactions of, 22, 2; 27, 2 Halide-metal exchange, 58, 2 Halides, synthesis: from alcohols, 34, 2 by chloromethylation, 1, 3 from organoboranes, 33, 1 from primary and secondary alcohols, 29, 1
Fluorination: by DAST, 35, 3 by N-F reagents, 69, 2 by sulfur tetrafluoride, 21, 1; 34, 2 Formylation: by hydroformylation, 56, 1 of alkylphenols, 28, 1 of aromatic hydrocarbons, 5, 6 of aromatic compounds, 49, 1 of non-aromatic compounds, 56, 2 Free radical additions: to alkenes and alkynes to form carbon-heteroatom bonds, 13, 4 to alkenes to form carbon-carbon bonds, 13, 3 Freidel-Crafts catalysts, in nucleoside synthesis, 55, 1 Friedel-Crafts reaction, 2, 4; 3, 1; 5, 5; 18, 1 Friedl¨ander synthesis of quinolines, 28, 2 Fries reaction, 1, 11
652
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
Haller-Bauer reaction, 9, 1 Halocarbenes, synthesis and reactions of, 13, 2 Halocyclopropanes, reactions of, 13, 2 Halogen-metal interconversion reactions, 6, 7 α-Haloketones, rearrangement of, 11, 4 α-Halosulfones, synthesis and reactions of, 25, 1; 62, 2 Heck reaction, intramolecular, 60, 2 Helicenes, synthesis by photocyclization, 30, 1 Heterocyclic aromatic systems, lithiation of, 26, 1 Heterocyclic bases, amination of, 1, 4 in nucleosides, 55, 1 Heterodienophiles, 53, 2 Hilbert-Johnson method, 55, 1 Hoesch reaction, 5, 9 Hofmann elimination reaction, 11, 5; 18, 4 Hofmann reaction of amides, 3, 7, 9 Homocouplings mediated by Cu, Ni, and Pd, 63, 3 Homogeneous hydrogenation catalysts, 24, 1 Hunsdiecker reaction, 9, 5; 19, 4 Hydration of alkenes, dienes, and alkynes, 13, 1 Hydrazoic acid, reactions and generation of, 3, 8 Hydroboration, 13, 1 Hydrocyanation of conjugated carbonyl compounds, 25, 3 Hydroformylation, 56, 1 Hydrogenation catalysts, homogeneous, 24, 1 Hydrogenation of esters, with copper chromite and Raney nickel, 8, 1 Hydrohalogenation, 13, 4 Hydroxyaldehydes, aromatic, 28, 1 α-Hydroxyalkylation of activated olefins, 51, 2 α-Hydroxyketones: rearrangement, 62, 3 synthesis of, 23, 2 Hydroxylation: of enolates, 62, 1 of ethylenic compounds with organic peracids, 7, 7
Hypervalent iodine reagents, 54, 2; 57, 2 Imidates, rearrangement of, 14, 1 Imines, additions of allyl, allenyl, propargyl stannanes, 64, 1 additions of cyanide, 70, 1 as dienophiles, 65, 2 synthesis, 70, 1 Iminium ions, 39, 2; 65, 2 Imino Diels-Alder reactions, 65, 2 Indoles, by Nenitzescu reaction, 20, 3 by reaction with TosMIC, 57, 3 Isocyanides, in the Passerini reaction, 65, 1 sulfonylmethyl, reactions of, 57, 3 Isoquinolines, synthesis of, 6, 2, 3, 4; 20, 3 Jacobsen reaction, 1, 12 Japp-Klingemann reaction, 10, 2 Katsuki-Sharpless epoxidation, 48, 1 Ketene cycloadditions, 45, 2 Ketenes and ketene dimers, synthesis of, 3, 3; 45, 2 α-Ketol rearrangement, 62, 3 Ketones: acylation of, 8, 3 alkylidenation of, 43, 1 Baeyer-Villiger oxidation of, 9, 3; 43, 3 cleavage of non-enolizable, 9, 1 comparison of synthetic methods, 18, 1 conversion to amides, 3, 8; 11, 1 conversion to fluorides, 34, 2; 35, 3 cyclic, synthesis of, 2, 4; 23, 2 cyclization of divinyl ketones, 45, 1 synthesis from acid chlorides and organo-metallic compounds, 8, 2; 18, 1 synthesis from organoboranes, 33, 1 synthesis from α,β-unsaturated carbonyl compounds and metals in liquid ammonia, 23, 1 reaction with diazomethane, 8, 8 reduction to aliphatic compounds, 4, 8 reduction by alkoxyaluminum hydrides, 34, 1
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
reduction in anhydrous organic solvents, 22, 3 synthesis from organolithium reagents and carboxylic acids, 18, 1 synthesis by oxidation of alcohols, 6, 5; 39, 3 Kindler modification of Willgerodt reaction, 3, 2 Knoevenagel condensation, 1, 8; 15, 2; 57, 3 Koch-Haaf reaction, 17, 3 Kornblum oxidation, 39, 3 Kostaneki synthesis of chromanes, flavones, and isoflavones, 8, 3 β-Lactams, synthesis of, 9, 6; 26, 2 β-Lactones, synthesis and reactions of, 8, 7 Leuckart reaction, 5, 7 Lithiation: of allylic and benzylic systems, 27, 1 by halogen-metal exchange, 6, 7 heteroatom facilitated, 26, 1; 47, 1 of heterocyclic and olefinic compounds, 26, 1 Lithioorganocuprates, 19, 1; 22, 2; 41, 2 Lithium aluminum hydride reductions, 6, 2 chirally modified, 52, 2 Lossen rearrangement, 3, 7, 9 Mannich reaction, 1, 10; 7, 3 Meerwein arylation reaction, 11, 3; 24, 3 Meerwein-Ponndorf-Verley reduction, 2, 5 Mercury hydride method to prepare radicals, 48, 2 Metalations with organolithium compounds, 8, 6; 26, 1; 27, 1 Methylenation of carbonyl groups, 43, 1 Methylenecyclopropane, in cycloaddition reactions, 61, 1 Methylene-transfer reactions, 18, 3; 20, 1; 58, 1 Michael reaction, 10, 3; 15, 1, 2; 19, 1; 20, 3; 46, 1; 47, 2 Microbiological oxygenations, 63, 2 Mitsunobu reaction, 42, 2 Moffatt oxidation, 39, 3; 53, 1
653
Morita-Baylis-Hillman reaction, 51, 2 Nazarov cyclization, 45, 1 Nef reaction, 38, 3 Nenitzescu reaction, 20, 3 Nitriles: formation from oximes, 35, 2 synthesis from organoboranes, 33, 1 α,β-unsaturated: by elimination of selenoxides, 44, 1 Nitrile-stabilized carbanions: alkylation and arylation of, 31 Nitroamines, 20, 4 Nitro compounds, conversion to carbonyl compounds, 38, 3 Nitro compounds, synthesis of, 12, 3 Nitrone-olefin cycloadditions, 36, 1 Nitrosation, 2, 6; 7, 6 Nucleosides, synthesis of, 55, 1 Olefins, hydroformylation of, 56, 1 Oligomerization of 1,3-dienes, 19, 2 Oligosaccharide synthesis on polymer support, 68, 2 Oppenauer oxidation, 6, 5 Organoboranes: formation of carbon-carbon and carbon-heteroatom bonds from, 33, 1 isomerization and oxidation of, 13, 1 reaction with anions of α-chloronitriles, 31, 1 Organochromium reagents: addition to carbonyl compounds, 64, 3; 67, 2 addition to imines, 67, 2 Organohypervalent iodine reagents, 54, 2; 57, 2 Organometallic compounds: of aluminum, 25, 3 of chromium, 64, 3; 67, 2 of copper, 19, 1; 22, 2; 38, 2; 41, 2 of lithium, 6, 7; 8, 6; 18, 1; 27, 1 of magnesium, zinc, and cadmium, 8, 2; of palladium, 27, 2 of tin, 50, 1; 64, 1 of zinc, 1, 1; 20, 1; 22, 4; 58, 2
654
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
Osmium tetroxide asymmetric dihydroxylation, 66, 2 Overman rearrangement of allylic imidates, 66, 1 Oxidation: by dioxiranes, 61, 2; 69, 1 of alcohols and polyhydroxy compounds, 6, 5; 39, 3; 53, 1 of aldehydes and ketones, Baeyer-Villiger reaction, 9, 3; 43, 3 of amines, phenols, aminophenols, diamines, hydroquinones, and halophenols, 4, 6; 35, 2 of enolates and silyl enol ethers, 62, 1 of α-glycols, α-amino alcohols, and polyhydroxy compounds by periodic acid, 2, 8 with hypervalent iodine reagents, 54, 2 of organoboranes, 13, 1 of phenolic compounds, 57, 2 with peracids, 7, 7 by photooxygenation, 20, 2 with selenium dioxide, 5, 8; 24, 4 Oxidative decarboxylation, 19, 4 Oximes, formation by nitrosation, 7, 6 Oxochromium(VI)-amine complexes, 53, 1 Oxo process, 56, 1 Oxygenation of arenes by dioxygenases, 63, 2 Palladium-catalyzed vinylic substitution, 27, 2 Palladium-catalyzed coupling of organostannanes, 50, 1 Palladium intermediates in Heck reactions, 60, 2 Passerini Reaction, 65, 1 Pauson-Khand reaction to prepare cyclopentenones, 40, 1 Payne rearrangement, 60, 1 Pechmann reaction, 7, 1 Peptides, synthesis of, 3, 5; 12, 4 Peracids, epoxidation and hydroxylation with, 7, 7 in Baeyer-Villiger oxidation, 9, 3; 43, 3 Periodic acid oxidation, 2, 8 Perkin reaction, 1, 8 Persulfate oxidation, 35, 2
Peterson olefination, 38, 1 Phenanthrenes, synthesis by photocyclization, 30, 1 Phenols, dihydric from phenols, 35, 2 oxidation of, 57, 2 synthesis from Fischer carbene complexes, 70, 2 Phosphinic acids, synthesis of, 6, 6 Phosphonic acids, synthesis of, 6, 6 Phosphonium salts: halide synthesis, use in, 29, 1 synthesis and reactions of, 14, 3 Phosphorus compounds, addition to carbonyl group, 6, 6; 14, 3; 25, 2; 36, 2 addition reactions at imine carbon, 36, 2 Phosphoryl-stabilized anions, 25, 2 Photochemical cycloadditions, 44, 2 Photocyclization of stilbenes, 30, 1 Photooxygenation of olefins, 20, 2 Photosensitizers, 20, 2 Pictet-Spengler reaction, 6, 3 Pig liver esterase, 37, 1 Polonovski reaction, 39, 2 Polyalkylbenzenes, in Jacobsen reaction, 1, 12 Polycyclic aromatic compounds, synthesis by photocyclization of stilbenes, 30, 1 Polyhalo ketones, reductive dehalogenation of, 29, 2 Pomeranz-Fritsch reaction, 6, 4 Pr´evost reaction, 9, 5 Pschorr synthesis, 2, 6; 9, 7 Pummerer reaction, 40, 3 Pyrazolines, intermediates in diazoacetic ester reactions, 18, 3 Pyridinium chlorochromate, 53, 1 Pyrolysis: of amine oxides, phosphates, and acyl derivatives, 11, 5 of ketones and diketones, 1, 6 for synthesis of ketenes, 3, 3 of xanthates, 12, 2 Quaternary ammonium N-F reagents, 69, 2 salts, rearrangements of, 18, 4
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
Quinolines, synthesis of, by Friedl¨ander synthesis, 28, 2 by Skraup synthesis, 7, 2 Quinones: acetoxylation of, 19, 3 diene additions to, 5, 3 synthesis of, 4, 6 synthesis from Fischer carbene complexes, 70, 2 in synthesis of 5-hydroxyindoles, 20, 3
Ramberg-B¨acklund rearrangement, 25, 1; 62, 2 Radical formation and cyclization, 48, 2 Rearrangements: allylic trihaloacetamidate, 66, 1 anion-assisted sigmatropic, 43, 2 Beckmann, 11, 1; 35, 1 Chapman, 14, 1; 18, 2 Claisen, 2, 1; 22, 1 Cope, 22, 1; 41, 1, 43, 2 Curtius, 3, 7, 9 divinylcyclopropane, 41, 1 Favorskii, 11, 4 Lossen, 3, 7, 9 Ramberg-B¨acklund, 25, 1; 62, 2 Smiles, 18, 2 Sommelet-Hauser, 18, 4 Stevens, 18, 4 [2,3] Wittig, 46, 2 vinylcyclopropane-cyclopentene, 33, 2 Reduction: of acid chlorides to aldehydes, 4, 7; 8, 5 of aromatic compounds, 42, 1 of benzils, 4, 5 of ketones, enantioselective, 52, 2 Clemmensen, 1, 7; 22, 3 desulfurization, 12, 5 with diimide, 40, 2 by dissolving metal, 42, 1 by homogeneous hydrogenation catalysts, 24, 1 by hydrogenation of esters with copper chromite and Raney nickel, 8, 1 hydrogenolysis of benzyl groups, 7, 5 by lithium aluminum hydride, 6, 10
655
by Meerwein-Ponndorf-Verley reaction, 2, 5 chiral, 52, 2 by metal alkoxyaluminum hydrides, 34, 1; 36, 3 of mono- and polynitroarenes, 20, 4 of olefins by diimide, 40, 2 of α,β-unsaturated carbonyl compounds, 23, 1 by samarium(II) iodide, 46, 3 by Wolff-Kishner reaction, 4, 8 Reductive alkylation, synthesis of amines, 4, 3; 5, 7 Reductive amination of carbonyl compounds, 59, 1 Reductive cyanation, 57, 3 Reductive desulfurization of thiol esters, 8, 5 Reformatsky reaction, 1, 1; 22, 4 Reimer-Tiemann reaction, 13, 2; 28, 1 Reissert reaction, 70, 1 Resolution of alcohols, 2, 9 Retro-Diels-Alder reaction, 52, 1; 53, 2 Ritter reaction, 17, 3 Rosenmund reaction for synthesis of arsonic acids, 2, 10 Rosenmund reduction, 4, 7 Samarium(II) iodide, 46, 3 Sandmeyer reaction, 2, 7 Schiemann reaction, 5, 4 Schmidt reaction, 3, 8, 9 Selenium dioxide oxidation, 5, 8; 24, 4 Seleno-Pummerer reaction, 40, 3 Selenoxide elimination, 44, 1 Shapiro reaction, 23, 3; 39, 1 Silanes: addition to olefins and acetylenes, 13, 4 electrophilic substitution reactions, 37, 2 oxidation of, 69, 1 Sila-Pummerer reaction, 40, 3 Silyl carbanions, 38, 1 Silyl enol ether, α-hydroxylation, 62, 1 Simmons-Smith reaction, 20, 1; 58, 1 Simonini reaction, 9, 5 Singlet oxygen, 20, 2 Skraup synthesis, 7, 2; 28, 2
656
CHAPTER AND TOPIC INDEX, VOLUMES 1–70
Smiles rearrangement, 18, 2 Sommelet-Hauser rearrangement, 18, 4 SRN 1 reactions of aromatic systems, 54, 1 Sommelet reaction, 8, 4 Stevens rearrangement, 18, 4 Stetter reaction of aldehydes with olefins, 40, 4 Strecker reaction, catalytic asymmetric, 70, 1 Stilbenes, photocyclization of, 30, 1 Stille reaction, 50, 1 Stobbe condensation, 6, 1 Substitution reactions using organocopper reagents, 22, 2; 41, 2 Sugars, synthesis by glycosylation with sulfoxides and sulfinates, 64, 2 Sulfide reduction of nitroarenes, 20, 4 Sulfonation of aromatic hydrocarbons and aryl halides, 3, 4 Swern oxidation, 39, 3; 53, 1 Tetrahydroisoquinolines, synthesis of, 6, 3 Tetrahydrothiophenes, synthesis of, 6, 9 Thia-Payne rearrangement, 60, 1 Thiazoles, synthesis of, 6, 8 Thiele-Winter acetoxylation of quinones, 19, 3 Thiocarbonates, synthesis of, 17, 3 Thiocyanation of aromatic amines, phenols, and polynuclear hydrocarbons, 3, 6 Thiophenes, synthesis of, 6, 9 Thorpe-Ziegler condensation, 15, 1; 31 Tiemann reaction, 3, 9 Tiffeneau-Demjanov reaction, 11, 2 Tin(II) enolates, 46, 1 Tin hydride method to prepare radicals, 48, 2 Tipson-Cohen reaction, 30, 2 Tosylhydrazones, 23, 3; 39, 1 Tosylmethyl isocyanide (TosMIC), 57, 3 Transmetallation reactions, 58, 2 Tricarbonyl(η6 -arene)chromium complexes, 67, 2
Trihaloacetimidate, allylic rearrangements, 66, 1 Trimethylenemethane, [3 + 2] cycloaddition of, 61, 1 Trimerization, co-, acetylenic compounds, 68, 1 Ullmann reaction: homocoupling mediated by Cu, Ni, and Pd, 63, 3 in synthesis of diphenylamines, 14, 1 in synthesis of unsymmetrical biaryls, 2, 6 Unsaturated compounds, synthesis with alkenyl- and alkynylaluminum reagents, 32, 2 Vilsmeier reaction, 49, 1; 56, 2 Vinylcyclopropanes, rearrangement to cyclopentenes, 33, 2 Vinyllithiums, from sulfonylhydrazones, 39, 1 Vinylsilanes, electrophilic substitution reactions of, 37, 2 Vinyl substitution, catalyzed by palladium complexes, 27, 2 von Braun cyanogen bromide reaction, 7, 4 Vorbr¨uggen reaction, 55, 1 Willgerodt reaction, 3, 2 Wittig reaction, 14, 3; 31 [2,3]-Wittig rearrangement, 46, 2 Wolff-Kishner reaction, 4, 8 Xanthates, synthesis and pyrolysis of, 12, 2 Ylides: in Stevens rearrangement, 18, 4 in Wittig reaction, structure and properties, 14, 3 Zinc-copper couple, 20, 1; 58, 1, 2 Zinin reduction of nitroarenes, 20, 4
