Dilithium Trimethylcuprate1


[61278-42-0]  · C3H9CuLi2  · Dilithium Trimethylcuprate  · (MW 122.53)

(organometallic methylating agent for ketones,2 enones,3,4 halides,5 and hydrazones6 and for cross-coupling reactions with mercury(II) chlorides7)

Physical Data: in Et2O, Li2CuMe3 exists in equilibrium with MeLi and LiCuMe2.8 In THF, however, it has been shown by 7Li NMR that Li2CuMe3 is not a discrete species, but an equilibrium mixture of more complex organocuprates which may be more accurately represented as a MeLi-to-MeCu ratio.9 In this article, Li2CuMe3 is employed to represent a 3:1 ratio of MeLi to CuI. It is additionally important to recognize that the varied modes of reaction of Li2CuMe3 suggest that different species or mechanisms of reaction may occur under specific conditions with certain reactants. In some cases the course of reaction indicates an initial metal ion-oxygen complexation followed by the addition of MeLi, while in others the reaction of a higher order cuprate appears likely.

Solubility: sol ether and THF to -100 °C.

Preparative Method: to Copper(I) Iodide (30 mmol) suspended in 100 mL anhydrous ether or THF at 0 °C is added Methyllithium (90 mmol, 2 M in THF or ether) and the light tan solution is stirred for 10 min before cooling and use.

Handling, Storage, and Precautions: Li2CuMe3 should be used immediately following preparation to obtain optimal yields.

Addition to Ketones.

The addition of an organolithium or Grignard reagent to an unhindered cyclohexanone generally leads to the predominant formation of the axial alcohol.10 However, the 3:2 mixture of LiCuMe2 and MeLi to form the Li2CuMe3 complex adds to 4-t-butylcyclohexanone to give 94% trans-4-t-butyl-1-methylcyclohexanol in 91% yield (eq 1).2 Similar results have been observed with 4a-methyl-trans-2-decalone and 2-methylcyclohexanone (eq 2), as well as with various C(3)-substituted cyclohexanones (eq 3).11

Comparable stereoselectivity resulted from the slow addition of MeLi to a solution of ketone and LiCuMe2 and the use of Lithium Perchlorate and Lithium Bromide in solution with MeLi.12 These results suggest a complexation of the ketone by LiCuMe2 followed by rapid addition by MeLi from the least hindered face. Interestingly, Li2CuMe3 showed no stereochemical advantage over MeLi in the reaction with 2-methylcyclopentanone.2 However, methylation of racemic 2-methyl-2-phenyl-1-indanone gave addition predominantly from the least hindered face (eq 4).13

Addition to Enones.

Li2CuMe3 provides exclusive 1,4-addition to a,b-unsaturated carbonyl compounds.3,4 While the Li2CuMe3 complex has a similar reaction rate to LiCuMe2 for conjugate addition to b-monosubstituted enones in THF, Li2CuMe3 yields mostly 1,2-addition for sterically hindered b-disubstituted enones. This regioselectivity is presumably due to the more rapid 1,2-addition by MeLi relative to the sterically demanding 1,4-addition by Li2CuMe3. The use of ether as solvent results in an increase in the overall rate of reaction at the cost of a decrease in regioselectivity. This loss of selectivity is presumably a result of 1,2-addition by MeLi (eq 5).4

The reaction of Li2CuMe3 with (Z)-hexenolide in ether at 0 °C gave a mixture of 4-alkenoic acid and 4-methyl 5-hexenoic acid in 89% total yield (eq 6).14

Substitution of Halides.

Li2CuMe3 generally shows higher reactivity and enhanced yields compared with LiCuMe2 and Li2Cu3Me5 in the substitution of alkyl, allylic, vinylic, and aryl halides (eqs 7 and 8).5

The rate of halogen reactivity was I > Br > Cl > F; THF proved to be the most efficacious solvent investigated, except for substitution of fluorine in which ether was proven to be more effective. Notable exceptions to this generally successful reaction are bromo- and chlorocyclohexane, chloro- and fluorobenzene, and p-chloroanisole. These compounds showed either no reaction with any cuprate investigated or halogen-metal exchange which resulted in reduction.

The reaction of 6-substituted 1-heptenes with Li2CuMe3 led to varied products, depending on the leaving group, implicating a complex reaction mechanism for this displacement reaction (eq 9).15 The 6-iodo-substituted compounds produced a reaction profile of products which supports the possibility that the displacement of iodide by Li2CuMe3 may proceed through an electron transfer mechanism, while leaving group displacement in the other 6-substituted electrophiles occurs via an apparent SN2 mechanism.

Boron Trifluoride Etherate catalyzes the substitution reaction of Li2CuMe3 with N-benzoyl-3-bromo-2,3-didehydrohomoserine-g-lactone to give the 3-methylbut-2-enoic acid-g-lactone in 78% yield (eq 10).16

Activation of C-N.

It has been shown that Li2CuMe3 provides a source of CuI which activates C-N bonds in hydrazones toward nucleophilic attack by MeLi in ether.6 The reaction fails in THF due to the preferential complexation of CuI by THF. The final result is a gem-dialkylated product. In a subsequent publication,17 it was shown that addition of Li2CuMe3 to aldehyde tosylhydrazones resulted in the formation of hindered cuprates which react smoothly with alkyl halides in the normal cuprate fashion (eq 11).

The reaction of tosylhydrazones from secondary or tertiary aldehydes give acceptable yields, while unbranched tosylhydrazones result in low yields. The reaction proceeds through an initial 1,2-addition to the C-N bond, followed by selective secondary or tertiary ligand transfer.

Cross-Coupling Reactions with Organomercurials.

The addition of 5 equiv of Li2CuMe3 to aryl mercury(II) chlorides in ether followed by quenching with MeLi and oxygen resulted in effective methylation (eq 12).7,18 In addition, organomercurials produced via oxymercuration of alkenes react readily with Li2CuMe3 (eq 13). A compilation of all the reaction types revealed the order of reaction efficiency to be aryl- > vinyl- > primary alkyl- > secondary alkylmercurial. The reactions are proposed to proceed via an initial mercury-copper transmetalation to generate a mixed diorganocopper species which then undergoes a thermal or oxidative elimination to produce the cross-coupled product. The highly stereoselective nature of the reaction is inconsistent with a radical anion chain mechanism for the cross coupling.

Related Reagents.

Dilithium Pentamethyltricuprate; Lithium Dimethylcuprate.

1. Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. T 1984, 40, 5005.
2. Macdonald, T. L.; Still, W. C. JACS 1975, 97, 5280.
3. Macdonald, T. L.; Still, W. C. TL 1976, 31, 2659.
4. Ashby, E. C.; Lin, J. J.; Watkins, J. J. JOC 1977, 42, 1099.
5. Ashby, E. C.; Lin, J. J. JOC 1977, 42, 2805.
6. Bertz, S. H. JOC 1979, 44, 4967.
7. Larock, R. C.; Leach, D. R. TL 1981, 22, 3435.
8. Lipshutz, B. H.; Kozlowski, J. A.; Breneman, C. M. JACS 1985, 107, 3197.
9. (a) Ashby, E. C.; Watkins, J. J. CC 1976, 784. (b) Ashby, E. C.; Watkins, J. J. JACS 1977, 99, 5312.
10. (a) Houlihan, W. J.; JOC 1962, 27, 3860. (b) Ashby, E. C.; Chao, L.-C.; Laemmle, J. JOC 1974, 39, 3258.
11. Cieplak, A. S.; Tait, B. D.; Johnson, C. R. JACS 1989, 111, 8447.
12. (a) Ashby, E. C.; Noding, S. A. JOC 1979, 44, 4371. (b) Ashby, E. C.; Lin, J. J.; Watkins, J. J. TL 1977, 18, 1709.
13. Berlan, J.; Auvray, P.; Besace, Y.; Cresson, P. T 1985, 41, 5011.
14. Fujisawa, T.; Umezu, K.; Kawashima, M. CL 1984, 1795.
15. Ashby, E. C.; Depriest, R. N.; Tuncay, A.; Srivastava, S. TL 1982, 23, 5251.
16. Olsen, R. K.; Hennen, W. J.; Wardle, R. B. JOC 1982, 47, 4605.
17. Bertz, S. H. TL 1980, 21, 3151.
18. Larock, R. C.; Leach, D. R. OM 1982, 1, 74.

Timothy J. Guzi & Timothy L. Macdonald

University of Virginia, Charlottesville, VA, USA

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