Lithium Cyano(methyl)cuprate

MeCuCNLi

[41753-78-0]  · C2H3CuLiN  · Lithium Cyano(methyl)cuprate  · (MW 111.55)

(regioselective organocuprate reagent for the 1,4-addition of a methyl group to vinyl epoxides and enones)

Solubility: sol ether at -20 °C; precipitates from solution at -78 °C.

Preparative Method: an ether solution of low-halide Methyllithium is added to 1 equiv of anhyd Copper(I) Cyanide at -78 °C;1 in order to maximize the 1,4-addition mode of lithium cyano(methyl)cuprate to vinyl epoxides, commercial methyl lithium with no halide present should be used.

Handling, Storage, and Precautions: thermally stable up to a temperature of about 0 °C; more stable than most organocuprates at rt or 0 °C; oxygen- and moisture-sensitive.

Ring Opening Reactions of Epoxides.

One of the first reports of the use of the cyano ligand in cuprates came from the work of Acker2 in the ring opening of simple epoxides (eq 1). As predicted, the cuprates added regiospecifically to the less-substituted carbon atom of the epoxide.

The regioselectivity of cyanocuprates can be further demonstrated with the reaction of the reagent (1) with the bis-epoxide (2).3 With 1 equiv of reagent at -78 °C, the less-hindered pendent epoxide is opened selectively to form (3), which can then undergo intramolecular ring openings of the cyclic oxirane to produce the bicyclic ether (eq 2).

In an interesting ring opening of an epoxide derived from an allylic alcohol, 3 equiv of (1) reacted with the epoxy alcohol (4) to produce the diol (5), which was an intermediate in the synthesis of (+)-exo-brevicomin (eq 3).4

While it had been well known that homoorganocuprates add in a 1,4-manner to acyclic vinyl epoxides,5 reactions of Lithium Dimethylcuprate with cyclic vinyl epoxides gave mixtures of 1,2 and 1,4 ring-opened products.6 The greater reactivity of cyclic vinyl epoxides usually resulted in the competitive 1,2 ring opening. In 1979 it was recognized that the cyanoalkylcuprates in ether regioselectively added 1,4 to cyclic vinyl epoxides.1 A typical example of this selectivity is shown for the reaction of (1) with 1,3-cycloheptadiene monoepoxide (eq 4). These reactions must be done in ether and not THF in order to observe the selective 1,4-addition.

In the case of the 1,3-cyclohexene monoepoxide, only the 1,4-adduct is observed with trans stereochemistry. Lithium methyl acrylate cuprates transfer a methyl group to these epoxides with even greater regioselectivity (97:3). The conclusion reached is that the strongly electron-withdrawing cyano and acrylate ligands are responsible for this enhanced regioselectivity.1 This ligand effect exhibited by the cyano group is general for all cyanoalkylcuprates.

Other examples of the 1,4-addition of (1) include the exo-methylene epoxide (6) (eq 5).7 The product of this reaction (7) was used as an intermediate in the synthesis of the pheromone a-multistriatin.8

The unique ability of the cyano group to direct the ring openings of cyclic vinyl epoxides in a trans-1,4 manner provided new methodology for the synthesis of chiral molecules. The reiterative sequence of cyclohexadiene monoepoxides reacting with cyanocuprates allowed for the introduction of three stereocenters within the cyclohexene ring, as outlined in eq 6.9

A further variation in the 1,4-additions of cyanocuprates to vinyl epoxides comes from the use of enol ethers derived from a,b-epoxy ketones as the vinyl component of the vinyl epoxide system.9 This strategy places an alkyl group a to a ketone in an umpolung manner, as illustrated for a,b-epoxycyclohexanones in eq 7.10

The use of a silyl enol ether in a cyclopentanone epoxide system was the basis for a synthesis of prostaglandins.11 A simple version of this ring opening is shown in eq 8 for (1) and enol ether epoxide (8) to give the hydroxycyclopentanone (9).

In addition to the silyl enol ethers of ketones, enol phosphates of epoxy ketones undergo the regioselective 1,4 ring openings with (1).11 In the epoxycyclopentanone system, the enol phosphate (10) is prepared from the ketone with Lithium Diisopropylamide and Diethyl Phosphorochloridate at -78 °C. Reaction of (10) with (1) gives exclusively the 1,4-product (11) in 94% yield (eq 9).

An additional advantage of the enol phosphates is that the phosphate unit may be reductively removed to produce an alkene.8 This last process was used in the synthesis of a-multistriatin via intermediate (12) (eq 10).

Reactions with Allylic Acetates.

The reagent (1) is also very effective in the allylations of allylic acetates and benzoates in an SN2 sense. The reaction of (1) with the allyl acetate (13) proceeds in high yield to produce a mixture of the substituted enyne (14) and the allene (15) (eq 11).12 The latter product results from addition of the cyanocuprate to the propargyl acetate system.

In another example, (1) added cleanly to the bis-allyl benzoate (16) to give the diene (17) (eq 12).13

An example of the cyanocuprate (1) undergoing a conjugate addition to an allenyl sulfone is shown in eq 13. The allenyl p-tolyl sulfone is converted to the allyl sulfone (18) in good yield.14

Related Reagents.

Lithium Butyl(cyano)cuprate; Lithium Cyano(dimethylphenylsilyl)cuprate.


1. Marino, J. P.; Floyd, D. M. TL 1979, 675.
2. Acker, R.-D. TL 1977, 3407.
3. Acker, R.-D. TL 1978, 2399.
4. Page, P. C. B.; Rayner, C. M.; Sutherland, I. O. CC 1988, 356.
5. Anderson, R. J. JACS 1970, 92, 4978.
6. Staroscik, J.; Rickborn, B. JACS 1971, 93, 3046.
7. Marino, J. P.; Abe, H. S 1980, 872.
8. Marino, J. P.; Abe, H. JOC 1981, 46, 5379.
9. Marino, J. P.; Hatanaka, N. JOC 1979, 44, 4467.
10. Marino, J. P.; Jaén, J. C. JACS 1982, 104, 3165.
11. Marino, J. P.; Fernández de la Pradilla, R.; Laborde, E. JOC 1987, 52, 4898.
12. Keinan, E.; Bosch, E. JOC 1986, 51, 4006.
13. Newman, M.; Hussain, N. S. JOC 1982, 47, 2837.
14. Berlan, J.; Koosha, K. JOM 1978, 153, 107.

Joseph P. Marino & David P. Holub

University of Michigan, Ann Arbor, MI, USA



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