Ethoxycarbonylmethylcopper1

EtO2CCH2Cu

[35756-99-1]  · C4H7CuO2  · Ethoxycarbonylmethylcopper  · (MW 150.65)

(reagent for improved yields of allylation of ethyl acetate2)

Preparative Methods: by the reaction of Ethyl Lithioacetate and Copper(I) Iodide in THF as a heterogeneous pale yellow solution at -110 °C or as a light brown homogeneous solution at -30 °C.

Handling, Storage, and Precautions: unstable above -30 °C; decomposes readily upon exposure to air or moisture. Use in a fume hood.

Characteristics.

Kuwajima and Doi2 reported the preparation of ethoxycarbonylmethylcopper by the reaction of the lithium enolate of ethyl acetate with copper iodide in THF at -110 °C. Upon warming the mixture to -30 °C a light brown homogeneous solution was obtained. Oxidative dimerization of the ethoxycarbonylmethylcopper resulted in the formation of diethyl succinate in 73% yield. The copper enolate did not react with butyl bromide or tosylate and did not add to pentanal; however, reaction with cyclohexenyl bromide resulted in a 69% yield of the alkylated product (eq 1).

Amos and Katzenellenbogen3 reported formation of a pale yellow heterogeneous reagent upon reaction of the lithium enolate of ethyl acetate and copper iodide at -78 °C, which turned dark brown upon warming to -30 °C. Oxidative coupling of the reagent prepared in this fashion also gave diethyl succinate, but in lower yield (29%). The nature of the species produced by reaction of the lithium enolate with copper iodide is not completely defined; however, the copper enolate exhibits dramatically different reactivity than the corresponding lithium enolate. The copper enolate appears to be a much softer nucleophile.

Reactions.

In the synthesis of sulfonium ion mimics of cationic intermediates involved in the squalene synthetase-catalyzed rearrangement of farnesyl pyrophosphate, alkylation of the lithium enolate of ethyl acetate with a thiosulfonate gave poor yields due to competing condensation reactions. Reaction of ethoxycarbonylmethylcopper and the thiosulfonate provided the desired product in reasonable yield (eq 2).4 Selective displacement of the allylic halide of 2,3-Dibromopropene has also been accomplished using the softer copper nucleophile (eq 3).5

Reaction of ethoxycarbonylmethylcopper with propargylic mesylates resulted in the formation of the allene ester product by an SN2 reaction while the corresponding lithium enolate provided only the alkynic product or did not react (eq 4).3 In contrast to the reaction with the propargylic electrophile, reaction with most allylic electrophiles generally proceeds by direct substitution without allylic transposition. The synthesis of 4, 8, and 12 nor analogs of geranylgeraniol was accomplished by direct displacement of allyl bromides with ethoxycarbonylmethylcopper.6 Reaction of ethoxycarbonylmethylcopper with farnesyl bromide provided the ester in 97% yield; allyl chlorides may also be employed in the alkylation reaction. The synthesis of the sex pheromone of Phtorimaea operculella was achieved without any indication of competing SN2 alkylation (eq 5).7

Regioselective 1,4-addition of ethoxycarbonylmethylcopper to cyclopentadiene monoepoxide has also been reported (eq 6).8 There has been an exception to the predominant mode of a alkylation of allylic electrophiles. A general method for the regioselective synthesis of 2-alkenenitriles by the g alkylation of 3-buten-2-one cyanohydrin diethyl phosphate included ethoxycarbonylmethylcopper as one of the nucleophiles.9 A more reactive, stabilized copper derivative is produced from iododifluoroacetate and copper powder.10 Ethoxycarbonyldifluoromethylcopper reacts with allyl, benzyl, alkenyl, alkynyl, and aryl halides.

Related Reagents.

Cyanomethylcopper.


1. (a) Posner, G. H. OR 1972, 19, 1. (b) Posner, G. H. OR 1975, 22, 253. (c) Lipshutz, B. H.; Sengupta, S. OR 1992, 41, 135. (d) Normant, J. F. S 1972, 63. (e) Yamamoto, Y. AG(E) 1986, 25, 947. (f) Posner, G. H. An Introduction to Synthesis Using Organocopper Reagents; Wiley: New York, 1980.
2. Kuwajima, I.; Doi, Y. TL 1972, 1163.
3. Amos, R. A.; Katzenellenbogen, J. A. JOC 1978, 43, 555.
4. Oehlschlager, A. C.; Singh, S. M.; Sharma, S. JOC 1991, 56, 3856.
5. Lawler, D. M.; Simpkins, N. S. TL 1988, 29, 1207.
6. Coates, R. M.; Ley, D. A.; Cavender, P. L. JOC 1978, 43, 4915.
7. Alexakis, A.; Cahiez, G.; Normant, J. F. TL 1978, 19, 2027.
8. Marino, J. P.; Fernandez de la Pradilla, R.; Laborde, E. JOC 1987, 52, 4898.
9. Yoneda, R.; Harasawa, S.; Kurihara, T. CPB 1987, 35, 913.
10. (a) Kitagawa, O.; Taguchi, T.; Kobayashi, Y. CL 1989, 389. (b) Taguchi, T.; Kitagawa, O.; Morikawa, T.; Nishiwaki, T.; Uehara, H.; Endo, H.; Kobayashi, Y. TL 1986, 27, 6103.

Russell J. Linderman

North Carolina State University, Raleigh, NC, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.