Ethyl Lithioacetate

(R = Et)

[56267-15-3]  · C4H7LiO2  · Ethyl Lithioacetate  · (MW 94.05) (R = Me)

[57570-85-1]  · C3H5LiO2  · Methyl Lithioacetate  · (MW 80.02) (R = t-Bu)

[53503-61-0]  · C6H11LiO2  · t-Butyl Lithioacetate  · (MW 122.11) (R = Bn)

[71010-30-5]  · C9H9LiO2  · Benzyl Lithioacetate  · (MW 156.12)

(two-carbon nucleophile in ester enolate alkylation, condensation, conjugate addition, and transmetalation reactions)

Solubility: sol THF.

Form Supplied in: white solids.

Analysis of Reagent Purity: the 1H and 13C NMR spectra (C6D6/THF solutions) for t-butyl lithioacetate have been reported.1

Preparative Methods: solutions of lithioacetates are prepared by addition of the appropriate ester to a 1 M THF solution of Lithium Diisopropylamide maintained at -78 °C. Enolate formation is complete within 15 min and the solutions are normally used directly.2 Enolization of t-butyl acetate in hexane produces a precipitate of amine-free enolate.1,3 Solutions of the ester enolates are stable at -78 °C, but Claisen ester condensation products form rapidly at 25 °C, perhaps via a ketene intermediate.4 This instability requires that reactions of the ester enolates be completed at as low a temperature as possible and is perhaps the major limitation to their use.

Alkylation Reactions.5

Alkylation of lithioacetates with primary organic halides generally occurs without significant problems of dialkylation or O-alkylation.6 Typically, HMPA is added so that alkylation can be completed at low temperatures. Alkylation procedures with a-chloroboronic esters,7 a-halo esters,8 triflates,9 and halo epoxides10 have been reported. In at least one case, alkylation with an epoxide has been achieved (eq 1).11a In the case of cyclohexene epoxide, the yield is improved by using the diethylaluminum derivative.11b Arylation or vinylation can be achieved by photostimulated reaction with aryl halides,12 by means of a nickel catalyst,13 and by reaction with arenetricarbonylchromium complexes (eq 2).14

Aldol Condensations.2

Aldol condensations of lithioacetates usually proceed rapidly and stable lithium aldolates are obtained with both aldehyde and ketone substrates at -78 °C. If reaction mixtures are allowed to warm prior to quenching, lower yields of b-hydroxy esters may be obtained.15 Diastereoselective reactions with a variety of chiral aldehydes have been reported.2,16 Relatively high selectivity (13:1) is obtained with epoxy aldehydes (eq 3).16a Condensation of lithioacetates with imine substrates has been used to prepare b-lactams.17

Acylation Reactions.18

The acylation of lithioacetates with a variety of acylating agents is possible, including esters,19 acid chlorides,20 acyl imidazoles,21 anhydrides,22 and thionolactones.23 In most cases, yields are limited by proton exchange of the acidic b-keto ester product with the starting enolate. This is usually allowed for by using an excess of amide base,20 or, more commonly, an excess of the lithioacetate (eq 4).19a

Conjugate Additions.24

Conjugate additions of lithioacetates to unsaturated esters,25 thioamides,26 acyl ylides,27 sulfonium salts,28 and ketones,29 and to ketene thioacetal monoxides,30 have been reported. Exceptionally bulky Lewis acids have been used to favor conjugate addition over carbonyl addition to unsaturated ketones.31 The enolate product of conjugate addition reactions can be used for subsequent alkylation (eq 5)32 or alkenation (eq 6)25a reactions.

Transmetalation Reactions.

Lithioacetates have been transmetalated by a variety of metal compounds including Cerium(III) Chloride,33 Tri-n-butylchlorostannane,34 titanium alkoxides,35 Diethylaluminum Chloride,11b and complexes of nickel and palladium.36 Reaction of lithioacetates with Chlorotrimethylsilane gives a mixture of C-silylated and O-silylated products (eq 7).6

Related Reagents.

t-Butyl a-Lithiobis(trimethylsilyl)acetate; t-Butyl a-Lithioisobutyrate; t-Butyl Trimethylsilylacetate; Dilithioacetate; Ethyl Bromozincacetate; Ethyl Lithio(trimethylsilyl)acetate; Ethyl Trimethylsilylacetate; Phenoxyacetic Acid.

1. Kim, Y-J.; Bernstein, M. P.; Roth, A. S. G.; Romesberg, F. E.; Williard, P. G.; Fuller, D. J.; Harrison, A. T.; Collum, D. B. JOC 1991, 56, 4435.
2. Heathcock, C. H. COS 1991, 2, Chapter 1.6.
3. Rathke, M. W.; Sullivan, D. F. JACS 1973, 95, 3050.
4. (a) Seebach, D.; Amstutz, R.; Laube, T.; Schweizer, W. B.; Dunitz, J. D. JACS 1985, 107, 5403. (b) Sullivan, D. F.; Woodbury, R. P.; Rathke, M. W. JOC 1977, 42, 2038.
5. (a) Caine, D. COS 1991, 3, Chapter 1.1. (b) Bos, W.; Pabon, H. J. J. RTC 1980, 99, 141. (c) Petragnani, N.; Yonashiro, M. S 1982, 521.
6. Rathke, M. W.; Sullivan, D. F. SC 1973, 3, 67.
7. Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. JACS 1986, 108, 810.
8. Petragnani, N.; Yonashiro, M. S 1980, 710.
9. Al-Abed, Y.; Zaman, F.; Shekhani, M. S.; Fatima, A.; Voelter, W. TL 1992, 33, 3305.
10. Paterson, I.; Boddy, I.; Mason, I. TL 1987, 28, 5205.
11. (a) Wender, P. A.; Erhardt, J. M.; Letendre, L. J. JACS 1981, 103, 2114. (b) Danishefsky, S.; Kitahara, T.; Tsai, M.; Dynak, J. JOC 1976, 41, 1669.
12. Semmelhack, M. F.; Bargar, T. JACS 1980, 102, 7765.
13. Millard, A. A.; Rathke, M. W. JACS 1977, 99, 4833.
14. (a) Semmelhack, M. F.; Clark, G. R.; Garcia, J. L.; Harrison, J. J.; Thebtaranonth, Y.; Wulff, W.; Yamashita, A. T 1981, 37, 3957. (b) Semmelhack, M. F. COS 1991, 4, 517.
15. Rathke, M. W. JACS 1970, 92, 3222.
16. (a) Escudier, J.-M.; Baltas, M.; Gorrichon, L. TL 1991, 32, 5345. (b) Hanson, G. J., Baran, J. S.; Lindberg, T. TL 1986, 27, 3577. (c) Heathcock, C. H.; Flippin, L. A. JACS 1983, 105, 1667. (d) Guanti, G.; Banfi, L.; Narisano, E.; Thea, S. SL 1992, 311.
17. (a) Ha, D.-C.; Hart, D. J.; Yang, T.-K. JACS 1984, 106, 4819. (b) Fujioka, H.; Yamanaka, T.; Matsunaga, N.; Fuji, M.; Kita, Y. SL 1992, 35.
18. Davis, B. R.; Garratt, P. J. COS 1991, 2, Chapter 3.6.
19. (a) Lynch, J. E.; Volante, R. P.; Wattley, R. V.; Shinkai, I. TL 1987, 28, 1385. (b) Ohta, S.; Shimabayashi, A.; Hayakawa, S.; Sumino, M.; Okamota, M. S 1985, 45. (c) Robl, J. TL 1990, 31, 3421.
20. Rathke, M. W.; Deitch, J. TL 1971, 2953.
21. Harris, B. D.; Bhat, K. L.; Joullie, M. M. TL 1987, 28, 2837.
22. (a) Gilbreath, S. G.; Harris, C. M.; Harris, T. M. JACS 1988, 110, 6172. (b) Montforts, F.-P.; Ofner, S. AG(E) 1979, 18, 632.
23. Nicolaou, K. C.; McGarry, D. G.; Somers, P. K.; Kim, B. H.; Ogilvie, W. W.; Yiannikouros, G.; Prasad C. V. C.; Veale, C. A.; Hark, R. R. JACS 1990, 112, 6263.
24. Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1989, 19, 227.
25. (a) Tanaka, J.; Kanemasa, S.; Ninomiya, Y.; Tsuge, O. BCJ 1990, 63, 466. (b) Cooke Jr, M. P. JOC 1986, 51, 1637. (c) Yamaguchi, M.; Tsukamoto, M.; Hirao, I. TL 1985, 26, 1723.
26. Tamaru, Y.; Harada, T.; Nishi, S.; Yoshida, Z. TL 1982, 23, 2383.
27. Cooke Jr., M. P.; Goswami, R. JACS 1977, 99, 642.
28. Takaki, K.; Negoro, K.; Agawa, T. JCS(P1) 1979, 1490.
29. Fischer, A.; Henderson, G. N. TL 1983, 24, 131.
30. Herrmann, J. L.; Kieczykowski, G. R.; Romanet, R. F.; Schlessinger, R. H. TL 1973, 4715.
31. Maruoka, K.; Itoh, T.; Sakurai, M.; Nonoshita, K.; Yamamoto, H. JACS 1988, 110, 3588.
32. Yamaguchi, M.; Tsukamoto, M.; Hirao, I TL 1985, 26, 1723.
33. Nagasawa, K.; Kanbara, H.; Matsushita, K.; Ito, K. TL 1985, 26, 6477.
34. Zapata, A.; Acuña, C. A. SC 1984, 14, 27.
35. Comins, D. L.; Brown, J. D. TL 1984, 25, 3297.
36. Burkhardt, E. R.; Bergman, R. G.; Heathcock, C. H. OM 1990, 9, 30.

Michael Rathke & Robert Elghanian

Michigan State University, East Lansing, MI, USA

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