Methyl Chloroformate

[79-22-1]  · C2H3ClO2  · Methyl Chloroformate  · (MW 94.50)

(protecting agent for many functional groups;1-16 activates N-heteroaromatic rings and carboxylic acids toward nucleophilic attack;17-26 methoxycarbonylating agent for organometallic reagents and enolates27-39)

Alternate Name: MCF.

Physical Data: bp 70-72 °C; d (20 °C) 1.223 g cm-3; n20D 1.3870.

Solubility: slightly sol water with slow decomposition; miscible with alcohols, benzene, chloroform, ether, etc.

Form Supplied in: colorless liquid; widely available.

Handling, Storage, and Precautions: flammable liquid; vesicant; its vapors are highly toxic, lachrymatory, and strongly irritating to the eyes. It should be handled with caution in a fume hood using protective gloves.

Functional Group Protection.

The protection of alcohols1 and phenols2 as their methyl carbonates can be achieved using methyl chloroformate under basic conditions (eq 1). Primary and secondary alkylamines are readily protected as their methyl carbamates using MCF, typically in the presence of Et3N,3,4 Na2CO3,5 K2CO3,6 or NaHCO3.7 Selective N-protection of amino alcohols can be achieved under these conditions (eq 2).5

Methyl carbonates are more resistant to basic hydrolysis than simple esters; however, both alcohol-1c and phenol-derived2 methyl carbonates can be selectively hydrolyzed under mildly basic conditions in the presence of a methyl carbamate derivative, allowing for the overall selective N-protection of amino alcohols and amino phenols (eq 3).

MCF is also useful for the N-protection of a-amino acids (Schotten-Baumann conditions),8 primary arylamines (using pyridine as base),1b,9 amides (using Triethylamine/4-Dimethylaminopyridine as base),10 and pyrrole and indole ring nitrogens (using NaH or KH as base).11 N-Silylpyrroles can be converted to the corresponding methyl carbamates under milder conditions than are required for the direct N-protection of pyrroles.12 ortho-Phenylenediamines are readily converted to the corresponding benzimidazole-2-carbamates using MCF in the presence of MeSCH(NH2)=NH.13 The forcing conditions that are often required for removal of a methyl carbamate protecting group (e.g. Hydrazine, KOH,14 or aq Ba(OH)2)15 have limited the utility of this N-protecting group when compared with other carbamates; although milder N-deprotection conditions have been reported (Iodotrimethylsilane, CHCl3, 50 °C; then MeOH),16 this chemistry has not seen widespread use. Lithium Aluminum Hydride reduction of methyl carbamates affords the corresponding N-methylamines,3,4 providing an attractive method for the overall N-methylation of primary and secondary amines (eq 4).

Activation of N-Heteroaromatic Rings Toward Nucleophilic Attack.

Pyridine, quinoline, and isoquinoline rings are activated by MCF toward in situ nucleophilic attack, leading to the formation of 1,2- and/or 1,4-dihydropyridines, -quinolines, or -isoquinolines. The addition of alkyl Grignard reagents proceeds with variable and often poor regioselectivity.17 However, alkenyl- and alkynyl-Grignard reagents (eq 5),17b unhindered allylic18 and allenylic19 stannanes, cyanide ion,20 and Sodium Borohydride (in MeOH at -70 °C21) all add with high 1,2-selectivity. Highly 1,4-selective addition reactions are observed using alkylcopper reagents (eq 6),17a,22 dialkylcuprates,17b,23 silyl enol ethers,22 and benzylic stannanes.24 The 1,4-addition of aryllithium reagents,25 and methyllithium and methylmagnesium bromide,26 to chiral 3-oxazolinylpyridines proceeds with high regio- and diastereofacial selectivity (eq 7). Removal of the chiral auxiliary affords chiral 4-substituted dihydropyridines in high ee.

Methoxycarbonylation of Organometallic Reagents and Enolates.

Deprotonation of terminal alkynes (typically using n-BuLi,27 LDA,28 or EtMgBr29), followed by trapping the resulting alkynyllithium or -Grignard reagent with MCF, offers an excellent route to methyl alkynoates (eq 8) (see 2,2,2-Trichloroethyl Chloroformate if subsequent cleavage to the carboxylic acid is desired). A related approach to methyl alkynoates proceeds via homologation of an aldehyde to the corresponding a,a-dibromoalkene. Dehydrobromination and halogen-metal exchange followed by trapping the resultant alkynyllithium with MCF provides the methyl alkynoate in high overall yield (eq 9).30 Aryllithium31 and alkenylaluminium32 species are also effectively methoxycarbonylated by MCF, but the trapping of simple primary alkyllithiums with MCF appears to be of little synthetic utility.33 The in situ trapping of a simple phosphonium ylide with MCF followed by deprotonation provides a convenient synthetic approach to a-methoxycarbonylphosphonium ylides (eq 10).34

The C-methoxycarbonylation of lithium ester35 and amide36 enolates can be effectively accomplished using MCF. Addition of n-BuLi to a chiral 1-oxazolinylnaphthalene followed by trapping the resulting azaenolate with MCF affords the C-acylation product with high diastereoselectivity (eq 11).37 In contrast, reaction of copper38 and potassium39 ketone enolates with MCF typically results in O-acylation to afford the corresponding enol carbonates (eq 12). The weak nucleophilicity of enol carbonates (they are stable to peroxy acids and Ozone)38a makes them useful masked enolate equivalents.

Activation of Carboxylic Acids as Mixed Anhydrides.

Activation of N-(alkoxycarbonyl)-a-amino acids as mixed anhydrides using MCF/N-methylpiperidine in CH2Cl2 minimizes urethane byproduct formation and racemization during peptide bond formation.40 Reaction of these mixed anhydrides with N,O-Dimethylhydroxylamine followed by LiAlH4 reduction provides an attractive route to the corresponding N-(alkoxycarbonyl)-a-amino aldehydes (eq 13).41 Attempts to generate mixed anhydrides from N-acyl-a-amino acids using MCF result in cyclization to the corresponding 5(4H)-oxazolones.42,43

a-Diazo ketones may be conveniently prepared by reaction of a mixed anhydride with Diazomethane; the mixed anhydrides are typically prepared either by treatment of the parent carboxylic acid with MCF/Triethylamine44 or by treatment of the corresponding methyl ester with potassium silyloxide and then MCF.45 Attack by amines46 or N-silylamines47 on such mixed anhydrides provides a useful approach to amide synthesis (eq 14), while acyl azides are prepared in excellent yield by reaction of the mixed anhydride with Sodium Azide.48

While the mixed anhydrides derived from the reaction of carboxylic acids with methyl chloroformate using Et3N as base are relatively stable, the addition of catalytic amounts of 4-Dimethylaminopyridine or N-methylmorpholine results in facile conversion to the corresponding methyl esters under very mild reaction conditions that are compatible with sensitive functionality.49

Related Reagents.

Benzyl Chloroformate; 2,2,2-Trichloroethyl Chloroformate.

1. (a) Eren, D.; Keinan, E. JACS 1988, 110, 4356. (b) Trost, B. M.; Kuo, G. H.; Benneche, T. JACS 1988, 110, 621. (c) Fang, J.-M.; Cherng, Y.-J. JCR(M) 1986, 1568.
2. Schwartz, M. A.; Pham, P. T. K. JOC 1988, 53, 2318.
3. Yamada, F.; Hasegawa, T.; Wakita, M.; Sugiyama, M.; Somei, M. H 1986, 24, 1223.
4. Somei, M.; Yamada, F.; Makita, Y. H 1987, 26, 895.
5. Knapp, S.; Sebastian, M. J.; Ramanathan, H.; Bharadwaj, P.; Potenza, J. A. T 1986, 42, 3405.
6. Corey, E. J. et al. TL 1978, 1051.
7. Patjens, J.; Ghaffari-Tabrizi, R.; Margaretha, P. HCA 1986, 69, 905.
8. Itaya, T.; Mizutani, A.; Watanabe, N. CPB 1989, 37, 1221.
9. Takai, H. et al. CPB 1985, 33, 1129.
10. Kubo, A.; Saito, N.; Yamato, H.; Masubuchi, K.; Nakamura, M. JOC 1988, 53, 4295.
11. Somei, M.; Saida, Y.; Komura, N. CPB 1986, 34, 4116.
12. Keijsers, J.; Hams, B.; Kruse, C.; Scheeren, H. H 1989, 29, 79.
13. Akhtar, M. S.; Seth, M.; Bhaduri, A. P. IJC(B) 1986, 25B, 395.
14. Shono, T.; Matsumura, Y.; Uchida, K.; Tsubata, K.; Makino, A. JOC 1984, 49, 300.
15. Wovkulich, P. M.; Uskokovic, M. R. T 1985, 41, 3455.
16. (a) Jung, M. E.; Lyster, M. A. CC 1978, 315. (b) Wender, P. A.; Schaus, J. M.; White, A. W. JACS 1980, 102, 6157.
17. (a) Gosmini, R.; Mangeney, P.; Alexakis, A.; Commercon, M.; Normant, J. F. SL 1991, 111. (b) Yamaguchi, R.; Nakazono, Y.; Matsuki, T.; Hata, E.-i.; Kawanisi, M. BCJ 1987, 60, 215.
18. Yamaguchi, R.; Moriyasu, M.; Yoshioka, M.; Kawanisi, M. JOC 1985, 50, 287; Yamaguchi, R.; Moriyasu, M.; Yoshioka, M.; Kawanisi, M. JOC 1988, 53, 3507.
19. Yamaguchi, R.; Moriyasu, M.; Takase, I.; Kawanisi, M.; Kozima, S. CL 1987, 1519.
20. Uff, B. C. et al. JCR(S) 1986, 206.
21. Fowler, F. W. JOC 1972, 37, 1321.
22. Akiba, K.; Ohtani, A.; Yamamoto, Y. JOC 1986, 51, 5328.
23. Piers, E.; Soucy, M. CJC 1974, 52, 3563.
24. Yamaguchi, R.; Moriyasu, M.; Kawanisi, M. TL 1986, 27, 211.
25. Meyers, A. I.; Oppenlaender, T. CC 1986, 920.
26. (a) Meyers, A. I.; Oppenlaender, T. JACS 1986, 108, 1989. (b) Meyers, A. I.; Natale, N. R.; Wettlaufer, D. G. TL 1981, 22, 5123.
27. Mori, K.; Fujiwhara, M. T 1988, 44, 343.
28. Marshall, J. A.; Andrews, R. C.; Lebioda, L. JOC 1987, 52, 2378.
29. Earl, R. A.; Townsend, L. B. OS 1981, 60, 81.
30. Boeckman, R. K., Jr.; Perni, R. B. JOC 1986, 51, 5486.
31. Uemora, M.; Take, K.; Isobe, K.; Minami, T.; Hayashi, Y. T 1985, 41, 5771.
32. Zwiefel, G.; Lynd, R. A. S 1976, 625.
33. Rucker, C. JOM 1986, 310, 135.
34. Marshall, J. A.; DeHoff, B. S.; Cleary, D. G. JOC 1986, 51, 1735.
35. Hersloef, M.; Gronowitz, S. CS 1985, 25, 257.
36. Ackermann, J.; Matthes, M.; Tamm, C. HCA 1990, 73, 122.
37. Meyers, A. I.; Roth, G. P.; Hoyer, D.; Barner, B. A.; Laucher, D. JACS 1988, 110, 4611.
38. (a) Danishefsky, S.; Kahn, M.; Silvestri, M. TL 1982, 23, 703; however, see also: (b) Trost, B. M.; Hiemstra, H. T 1986, 42, 3323.
39. Earley, W. G.; Jacobsen, E. J.; Meier, G. P.; Oh, T.; Overman, L. E. TL 1988, 29, 3781.
40. Chen, F. M. F.; Steinauer, R.; Benoiton, N. L. JOC 1983, 48, 2939.
41. Goel, O. P.; Krolls, U.; Stier, M.; Kesten, S. OS 1989, 67, 69.
42. Chen, F. M. F.; Benoiton, N. L. Int. J. Pept. Protein Res. 1988, 31, 396.
43. Chen, F. M. F.; Slebioda, M.; Benoiton, N. L. Int. J. Pept. Protein Res. 1988, 31, 339.
44. Padwa, A.; Fryxell, G. E.; Zhi, L. JACS 1990, 112, 3100.
45. Padwa, A.; Krumpe, K. E.; Kassir, J. M. JOC 1992, 57, 4940.
46. Rao, A. V. R.; Chavan, S. P.; Sivadasan, L. T 1986, 42, 5065.
47. Balogh, D. W.; Patterson, L. E.; Wheeler, W. J. SC 1988, 18, 307.
48. Tius, M. A.; Thurkauf, A. TL 1986, 27, 4541.
49. (a) Kim, S.; Kim, Y. C.; Lee, J. I. TL 1983, 24, 3365. (b) Burke, S. D.; Pacofsky, G. J.; Piscopio, A. D. TL 1986, 27, 3345. (c) Davis, M.; Wu, W.-Y. AJC 1987, 40, 223.

Paul Sampson

Kent State University, OH, USA

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