Methyl Cyanoformate1

(1; R = Me)

[17640-15-2]  · C3H3NO2  · Methyl Cyanoformate  · (MW 85.07) (2; R = Et)

[623-49-4]  · C4H5NO2  · Ethyl Cyanoformate  · (MW 99.10) (3; R = PhCH2)

[5532-86-5]  · C9H7NO2  · Benzyl Cyanoformate  · (MW 161.17)

(agent for the regioselective methoxycarbonylation of carbanions;1,2 reacts with organocadmium reagents to form a-keto esters;3 may function as a dienophile,4 dipolarophile,5 or radical cyanating agent6)

Physical Data: (1) mp 26 °C; bp 100-101 °C; d 1.072 g cm-3. (2) bp 115-116 °C; d 1.003 g cm-3. (3) bp 66-67 °C/0.6 mmHg; d 1.105 g cm-3.

Solubility: sol all common organic solvents; dec by H2O, alcohols, amines.

Form Supplied in: colorless liquid; methyl cyanoformate, as well as the ethyl and benzyl analogs, is available commercially.

Preparative Methods: small quantities of cyanoformate esters (up to 30 g) may be conveniently prepared from alkyl chloroformates by procedures employing phase-transfer catalysis with either 18-Crown-67 or Tetra-n-butylammonium Bromide,8 but several workers have found the products to be unsatisfactory when prepared on a larger scale.

Handling, Storage, and Precautions: store over 4Å molecular sieves; highly toxic; flammable; use in a fume hood.

Regioselective Methoxycarbonylation of Ketones.

Methyl cyanoformate gives generally excellent results in the regiocontrolled synthesis of b-keto esters by the C-acylation of preformed lithium enolates (eq 1)1,2 and is normally superior to the more traditional acylating agents such as acyl halides, anhydrides,9 and CO2,10 partly because these reagents afford variable amounts of O-acylated products.11 The enolates may be generated in a variety of ways, including direct enolization of ketones with suitable bases (eq 2),2 liberation from silyl enol ethers and acetates (eq 3),12 conjugate additions of cuprates to a,b-unsaturated ketones13 (eq 4),14 or by the reduction of enones by lithium in liquid ammonia (eq 5).1,12

Lithium enolates derived from sterically unencumbered cyclohexanones undergo preferential axial acylation (eq 6), whereas equatorial acylation is favored with D1(9)-2-octalones (eq 7),12 even in the absence of an alkyl substituent at C-10.15

For compounds in which the b-carbon of the enolate is sterically hindered, treatment with methyl cyanoformate may result in variable degrees of O-acylation, although this problem may be ameliorated by the use of diethyl ether as the solvent. In several cases a switch from predominantly O-acylation in THF to predominant C-acylation in diethyl ether has been observed (eqs 8-10).12

A comparative study of lithium, sodium, and potassium enolates indicated that the lithium derivatives reacted most satisfactorily.2 There may be substrates for which the thermodynamic enolates are required, however, and the sodium and potassium enolates may therefore be selected. Good results have been reported with these intermediates (eqs 11 and 12), although the latter afford significant amounts of O-acylated products.16,17 Quite apart from the issue of regioselectivity, the cyanoformate-based procedure is exceptionally reliable and makes it possible to prepare b-keto esters from ketones under especially mild conditions. It is not only the method of choice with sensitive substrates,16 but it will often ensure superior results with more robust compounds as well.

Methoxycarbonylation of Miscellaneous Carbon Acids.

The title reagent has also been applied to the methoxycarbonylation of esters (eq 13),18 lactones (eq 14),19 phosphonates (eq 15),20 imines (eq 16),21 and the N-acylation of lactams (eq 17).22

Higher Alkyl Cyanoformates.

A range of other alkyl cyanoformates has been successfully utilized for the acylation of enolate anions, including ethyl,23 allyl,24 benzyl,25 and p-methoxybenzyl,26 but not t-butyl cyanoformate, which appears to be insufficiently reactive. Enantiomerically enriched cyanoformates derived from (+)-menthol, (-)-borneol, and the Oppolzer alcohol were reported to furnish good chemical yields, but the level of enantioselectivity was disappointingly low (eq 18).27

Additions to the Nitrile Group.

Ethyl cyanoformate reacts with organocadmium reagents to afford a-keto esters (eq 19),3 and with malonate esters, b-keto esters, and other active methylene compounds to give a-aminoacrylates (eq 20).28 Both processes require catalysis with Lewis acids, of which Zinc Chloride has proven to be the most effective.

Cycloadditions.

Methyl and ethyl cyanoformate have been reported to undergo [4 + 2] cycloadditions, e.g. with cyclopentadienones4 and 2-alkyl-1-ethoxybuta-1,3-dienes to form pyridines (eq 21),29 and with cyclobutadienes to form Dewar pyridines (eq 22).30 Ethyl cyanoformate is also an effective dipolarophile, undergoing 1,3-dipolar addition to azides (eq 23)31 and cyclic carbonyl ylides (eq 24).5

Radical Cyanation.

The peroxide-initiated radical cyanation of cyclohexane and 2,3-dimethylbutane with methyl cyanoformate has been carried out in 72% and 77% yield, respectively.6

Related Reactions.

b-Keto ester formation from ketones may be achieved directly with dialkyl carbonates32 and dialkyl dicarbonates,33 or indirectly with dialkyl oxalates,34 methyl magnesium carbonate,35 and ethyl diethoxyphosphinyl formate.36 Regiocontrol is problematical, however, and is more reliably effected by trapping enolates with carbon dioxide,10 carbon disulfide,37 or carbon oxysulfide38 followed by methylation. In the latter cases, the dithio and thiol esters are converted into the parent carboxy esters by mercury(II)-catalyzed hydrolysis. The chemistry of acyl cyanides, but excluding cyanoformates, has been the subject of several reviews.39

Related Reagents.

Acetyl Cyanide; Carbon Dioxide; Carbon Oxysulfide; N,N-Carbonyldiimidazole; Diethyl Carbonate; Methyl Chloroformate; Methyl Magnesium Carbonate.


1. Crabtree, S. R.; Mander, L. N.; Sethi, S. P. OS 1991, 70, 256.
2. Mander, L. N.; Sethi, S. P. TL 1983, 24, 5425.
3. Akiyama, Y.; Kawasaki, T.; Sakamoto, M. CL 1983, 1231.
4. Padwa, A.; Akiba, M.; Cohen, L. A.; Gingrich, H. L.; Kamigata, N. JACS 1982, 104, 286.
5. Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.; Zhang, Z. J. JOC 1991, 56, 3271.
6. Tanner, D. D.; Rahimi, P. M. JOC 1979, 44, 1674.
7. Childs, M. E.; Weber, W. P. JOC 1976, 41, 3486.
8. Nii, Y.; Okano, K.; Kobayashi, S.; Ohno, M. TL 1979, 2517.
9. Caine, D. In Carbon-Carbon Bond Formation; Augustine, R. L., Ed.; Dekker: New York, 1979; Vol. 1, pp 250-258.
10. (a) Stork, G.; Rosen, P.; Goldman, N.; Coombs, R. V.; Tsuji, J. JACS 1965, 87, 275. (b) Caine, D. OR 1976, 23, 1.
11. (a) House, H. O. Modern Synthetic Reactions; Benjamin: Menlo Park, 1972; pp 760-763. (b) Black, T. H. OPP 1989, 21, 179. (c) Seebach, D.; Weller, T.; Protschuk, G.; Beck, A. K.; Hoekstra, M. S. HCA 1981, 64, 716. (d) cf. Ref. 5, p 258, footnote 69.
12. Crabtree, S. R.; Chu, W.-L. A.; Mander, L. N. SL 1990, 169.
13. (a) Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. JCS(P1) 1992, 865. (b) Haynes, R. K.; Katsifis, A. G. CC 1987, 340.
14. Hashimoto, S.; Kase, S.; Shinoda, T.; Ikegami, S. CL 1989, 1063.
15. cf. Mathews, R. S.; Girgenti, S. J.; Folkers, E. A. CC 1970, 708.
16. Ziegler, F. E.; Klein, S. I.; Pati, U. K.; Wang, T.-F. JACS 1985, 107, 2730.
17. Schuda, P. F.; Phillips, J. L.; Morgan T. M. JOC 1986, 51, 2742.
18. Ziegler, F. E.; Sobolov, S. B. JACS 1990, 112, 2749.
19. (a) Hanessian, S.; Faucher, A.-M. JOC 1991, 56, 2947. (b) Ziegler, F. E.; Cain, W. T.; Kneisly, A.; Stirchak, E. P.; Wester, R. T. JACS 1988, 110, 5442. (c) Leonard, J.; Ouali, D.; Rahman, S. K. TL 1990, 31, 739.
20. McLure, C. K.; Jung, K.-Y. JOC 1991, 56, 2326.
21. Bennet, R. B.; Cha, J. K. TL 1990, 31, 5437.
22. (a) Melching, K. H.; Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. TL 1986, 27, 4799. (b) Esch, P. M.; Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. H 1987, 26, 75. (c) Pirrung, F. O. H.; Rutjes, F. P. J. T.; Hiemstra, H.; Speckamp, W. N. TL 1990, 31, 5365.
23. Mori, K.; Ikunaka, M. T 1987, 43, 45.
24. Barton, D. H. R.; Donnelly, D. M. X.; Finet, J. P.; Guiry, P. J.; Kielty, J. M. TL 1990, 31, 6637.
25. Hashimoto, S.; Miyazaki, Y.; Shinoda, T.; Ikegami, S. CC 1990, 1100.
26. (a) Winkler, J. D.; Henegar, K. E.; Williard, P. G. JACS 1987, 109, 2850. (b) Henegar, K. E.; Winkler, J. D. TL 1987, 28, 1051.
27. Kunisch, F.; Hobert, K.; Welzel, P. TL 1985, 26, 5433.
28. Iimori, T.; Nii, Y.; Izawa T.; Kobayashi, S.; Ohno, M. TL 1979, 2525.
29. Potthoff, B.; Breitmaier, E. S 1986, 584.
30. (a) Krebs, A.; Franken, E.; Müller, S. TL 1981, 22, 1675. (b) Fink, J.; Regitz, M. BSF(2) 1985, 239.
31. Klaubert, D. H.; Bell, S. C.; Pattison, T. W. JHC 1985, 22, 333.
32. Deslongchamps, P.; Ruest, L. OS 1974, 54, 151.
33. Hellou, J.; Kingston, J. F.; Fallis, A. G. S 1984, 1014.
34. Snyder, H. R.; Brooks, L. A.; Shapiro, S. H. OSC 1943, 2, 531.
35. (a) Stiles, M. JACS 1959, 81, 2598. (b) Pelletier, S. W.; Chappell, R. L.; Parthasarathy, P. C.; Lewin, N. JOC 1966, 1747.
36. Shahak, I. TL 1966, 2201.
37. Kende, A. S.; Becker, D. A. SC 1982, 12, 829.
38. Vedejs, E.; Nader, B. JOC 1982, 47, 3193.
39. (a) Thesing, J.; Witzel, D.; Brehm, A. AE 1956, 68, 425. (b) Bayer, O. MOC 1977, 7/2c, 2487. (c) Hunig, S.; Schaller, R. AG(E) 1982, 21, 36.

Lewis N. Mander

The Australian National University, Canberra, Australia



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