Methyl Formate

(1; R1 = H, R2 = Me)

[107-31-3]  · C2H4O2  · Methyl Formate  · (MW 60.06) (2; R1 = H, R2 = Et)

[109-94-4]  · C3H6O2  · Ethyl Formate  · (MW 74.09) (3; R1 = H, R2 = Pr)

[110-74-7]  · C4H8O2  · Propyl Formate  · (MW 88.12) (4; R1 = H, R2 = Bu)

[592-84-7]  · C5H10O2  · Butyl Formate  · (MW 102.15) (5; R1 = H, R2 = t-Bu)

[762-75-4]  · C5H10O2  · t-Butyl Formate  · (MW 102.15) (6; R1 = D, R2 = Me)

[23731-38-6]  · C2H3DO2  · Methyl Formate  · (MW 61.06)

(formylating agent for carbonyl compounds;1-3 electrophile for organometallic agents4)

Physical Data: (1) bp 34 °C; d 0.974 g cm-3. (2) bp 52-54; d 0.917 g cm-3. (3) bp 80-81 °C; d 0.904 g cm-3. (4) bp 106-107 °C; d 0.892 g cm-3. (5) bp 82-83 °C; d 0.872 g cm-3. (6) bp 32.1 °C; d 0.990 g cm-3.

Solubility: partially sol water; miscible with alcohol, ether.

Form Supplied in: liquid; widely available in 97-99% purity.

Handling, Storage, and Precautions: most formates are colorless, flammable, irritant, and moisture-sensitive liquids. Inhalation of methyl formate vapor produces nasal and conjunctional irritation, retching, narcosis, death from pulmonary effects. Ethyl formate is irritating to skin, mucous membranes, and, in high concentrations, narcotic. Use in a fume hood.

Among all the formates listed, methyl and ethyl formate are the most widely used agents in organic synthesis. These formates are mainly used as a formylating agent for carbonyl compounds. As shown in eq 1, cyclohexanone (7) is converted into the enolate (8) in the presence of either Sodium Ethoxide or Sodium Hydride and condensed with ethyl formate to give 2-hydroxymethylene cyclohexanone (9) or its tautomer, 2-formylcyclohexanone (10).1i

To generate enolate (8) from the carbonyl compounds, sodium alkoxide1 or sodium hydride (or Potassium Hydride)2 is generally used. Examples for using Potassium t-Butoxide are also reported.3 The solvent can be either benzene, toluene, ether, dimethoxyethane, or THF. Caution: gas evolution has been cited in the formylation of cyclopentanone with ethyl formate in a solution of potassium t-butoxide in THF.3 Among the carbonyl compounds, ketones are the most commonly used substrates for the formylation. A few examples for formylating lactones5 and esters6 are also reported.

A classic example of the synthetic utility is illustrated (eq 2) in the formylation of a cyclic ketone to block one a-position (11 to 12 to 13a-c) and alkylating the a-position (13a-c to 14a-c). The blocking group is then removed (14a-c to 15 to 16).1b,1c,1g

Organometallic agents are combined with the formates to give alcohols or aldehydes.4 For example, treatment of an ethereal solution of 5-pentenylmagnesium bromide with methyl formate at 0 °C gives undeca-1,10-dien-6-ol in 86% yield (eq 3).4c

The carbanion generated from the deprotonation of O,S-acetal (17) reacts with ethyl formate at -80 °C to give the aldehyde (18) in 89% yield (eq 4).4d

The formates are also reported to react in the following unusual transformations. Nitrobenzene is reacted with the formates, catalyzed by PdCl2(PPh3)2, together with Bu3PO/KBr under carbon monoxide atmosphere, to give N-phenylcarbamates in 29-63% yield (eq 5).7

Benzylic, aryl, and alkyl halides react with the formates under carbon monoxide atmosphere, in the presence of (RhLCl)2 (L = 1,5-hexadiene), KI, and, optionally, Pd(PPh3)4, to give the corresponding carboxylate esters in 20-94% yield (eq 6).8

The formates add regioselectively to alkenes or alkynes, such as p-methylstyrene, catalyzed by Tetrakis(triphenylphosphine)palladium(0) and 1,4-Bis(diphenylphosphino)butane under carbon monoxide atmosphere, to give the linear isomer and the branched isomer (6.5:1 ratio) in 67% yield (eq 7).9

1. (a) Prelog, V.; Geyer, U. HCA 1945, 28, 1677. (b) Birch, A. J.; Robinson, R. JCS 1944, 501. (c) Johnson, W. S.; Posvic, H. JACS 1947, 69, 1361. (d) Johnson, W. S.; Petersen, J. W.; Gutsche, C. D. JACS 1947, 69, 2942. (e) Wilds, A. L.; Shunk, C. H. JACS 1950, 72, 2388. (f) Frank, R. L.; Varland, R. H. OSC 1955, 3, 829. (g) Ireland, R. E.; Marshall, J. A. CI(L) 1960, 1534; JOC 1962, 27, 1615, 1620. (h) Clinton, R. O.; Manson, A. J.; Stonner, F. W.; Neumann, H. C.; Christiansen, R. G.; Clarke, R. L.; Ackerman, J. H.; Page, D. F.; Dean, J. W.; Dickinson, W. B.; Carabateas, C. JACS 1961, 83, 1478. (i) Ainsworth, C. OSC 1963, 4, 536. (j) Schenone, P.; Bignardi, G.; Morasso, S. JHC 1972, 9, 1341. (k) Boatman, S.; Harris, T. M.; Hauser, C. R. OSC 1973, 5, 187.
2. (a) Weisenborn, F. L.; Remy, D. C.; Jacobs, T. L. JACS 1954, 76, 552. (b) Corey, E. J.; Cane, D. E. JOC 1971, 36, 3070. (c) Eaton, P. E.; Jobe, P. G. S 1983, 796. (d) Denmark, S. E.; Habermas, K. L.; Hite, G. A. HCA 1988, 71, 168. (e) Peet, N. P.; LeTourneau, M. E. H 1991, 32, 41.
3. Myers, A. G.; Harrington, P. M.; Kuo, E. Y. JACS 1991, 113, 694.
4. (a) Coleman, G. H.; Craig, D. OSC 1943, 2, 179. (b) Barbot, F.; Miginiac, P. JOM 1977, 132, 445. (c) Cresp, T. M.; Probert, C. L.; Sondheimer, F. TL 1978, 3955. (d) Boehme, H.; Sutoyo, P. N. AP 1983, 316, 505. (e) Katritzky, A. R.; Akutagawa, K.; Jones, R. A. SC 1988, 18, 1151.
5. (a) Rakhit, S.; Gut, M. JOC 1964, 29, 229, 859. (b) Harmon, A. D.; Hutchinson, C. R. TL 1973, 1293. (c) Yamada, K.; Kato, M.; Hirata, Y. TL 1973, 2745. (d) Murray, A. W.; Reid, R. G. CC 1984, 132. (e) Lehmann, J.; Neugebauer, M.; Marquardt, N. AP 1990, 323, 117.
6. (a) Holmes, H. L.; Trevoy, L. W. OSC 1955, 3, 300. (b) Thenappan, A.; Burton, D. J. JFC 1990, 48, 153.
7. Lin, I. J. B.; Chang, C. S. J. Mol. Catal. 1992, 73, 167.
8. Buchan, C.; Hamel, N.; Woell, J. B.; Alper, H. CC 1986, 167.
9. (a) Alper, H.; Saldana-Maldonado, M.; Lin, I. J. B. J. Mol. Catal. 1988, 49, L27. (b) Lin, I. J. B.; Alper, H. CC 1989, 248.

Chiu-Hong Lin

The Upjohn Company, Kalamazoo, MI, USA

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