Methyl Isocyanate1

MeN=C=O

[624-83-9]  · C2H3NO  · Methyl Isocyanate  · (MW 57.06)

(carbamoylates NH, OH, SH, and active CH compounds; converts epoxides to 1,2-amino alcohols via 2-oxazolidinones; undergoes [2 + x] cycloadditions to give rise to heterocycles; transforms aldoximes to nitriles2 and nitroalkanes to nitrile oxides3)

Alternate Name: MIC.

Physical Data: mp -17 °C; bp 39 °C; d 0.96 g cm-3.

Solubility: sol chlorinated, aromatic, ethereal solvents; reacts violently with H2O, basic, and protic solvents.

Form Supplied in: colorless liquid; no longer widely available. Usually prepared industrially in situ as needed.

Handling, Storage, and Precautions: Warning: Highly toxic! Lachrymator! Irritant! Extremely flammable! Use only in a fume hood. Wear protective gloves and preferably a NIOSH-approved respirator. All transfers and reactions should be carried out under anhydrous conditions. Store in a cool dry place, taking care to avoid contamination with protic, basic, or organometallic materials, as these may induce (exothermic) polymerization. Toxicity data for methyl isocyanate are available.1

N-Methylcarbamoylation.

The N-methylcarbamate (urethane) and N-methylurea moieties are common targets in organic synthesis, due to their function as pharmacophores in a stunning variety of compounds of pharmaceutical and agricultural interest. A typical method for their introduction makes use of the propensity of methyl isocyanate to add active hydrogen-bearing atoms (in either neutral or ionized form) to the central carbon atom.4 Reaction with alkyl-5 and arylamines,6,7 sulfonamides,8 and guanidines9 proceeds to give the ureas, often with high regioselectivity.6,7,10 Ring nitrogen atoms of heterocycles that bear a hydrogen (e.g. pyrazoles10) may also be carbamoylated under conditions mild enough even to avoid rupture of aziridines.11 Both alcohols12-14 and aryl hydroxys15 react readily with MIC, yielding the carbamates. Reaction of secondary alcohols is typically slow and incomplete, unless catalysts (usually basic) are used.16 A novel rearrangement of carbamate derivatives of hydroxamic acids affords N-methyl amino acids (eq 1).17

Thiols and thiocarbonyls that may be enolized react similarly;18 a protocol for the protection of peptidic SH groups as N-methylthiocarbamates has recently been developed.19 Malonates,20 cyanoacetates,20 and dithianes21 may be cleanly mono-N-methylcarbamoylated upon treatment with MIC.

Conversion of Oxiranes to 2-Oxazolidinones and 1,2-Amino Alcohols.

This transformation is very similar to that of simple epoxides to 2-oxazolidinones induced by p-Toluenesulfonyl Isocyanate. However, due to the lower reactivity of MIC, it is most often carried out in two or more steps via the epoxycarbamate derived from a-hydroxy epoxides (eq 2)12,22 or a-hydroxy esters.13 Hydrolysis of the 2-oxazolidinone yields the 1,2-amino alcohol.

Heterocycle Synthesis via Tandem Electrophilic-Nucleophilic Ring Closure.

The electrophilicity of the central carbon atom and latent nucleophilicity of the nitrogen atom endow MIC with the potential to form adducts with any other atomic array that exhibits a similar donor-acceptor character. Thus, a huge variety of heterocyclic products may be prepared with MIC (eq 3), and this list is not exhaustive.

Reaction with ynamines gives [2 + 2] adducts of single regiochemistry.23 Azomethine ylides derived from aziridines afford 4-imidazolinones by [2 + 3] cycloaddition highly regioselectively.24 Other [2 + 3] adducts are 1,2,4-triazol-5-ones (from hydrazides),25 imidazolin-5-imin-2-one-4-thiones (from cyanothioamides),26 1,2,4-triazolin-5-ones (from hydrazones),27 and 2-oxazolones (from ketols).28 Some examples of [2 + 4] adducts are 1,3-benzoxazines (from hydroxychalcones),29 1,2,4-oxathiazine S,S-dioxides (from alkynylsulfonamides),30 pteridineimines (from aminocyanodiazines),31 pyrazolopyrimidinones (from aminocyanopyrazoles),32 1,2,4-thiadiazin-3-one S,S-dioxides (from b-ketosulfonamides),33 triazinones (from 1,3-diazadienes),34 and 1,3-oxazine-2,4-diones (from 1,3-dioxan-4-ones).35 While most of these annulations are triggered or completed by base catalysis, a thermal reaction has also appeared in the literature (eq 4).35

Azaphosphoranes (from azides and phosphines) are easily converted to carbodiimides with MIC,36 and these also show a propensity for condensation with a variety of nucleophiles. An interesting strategy for [5 + 1] annulation utilizes intramolecular addition of the nucleophile (eq 5).37 Note that the NH group reacts with MIC before the azaphosphorane does.38

A number of unsaturated hydrocarbons react with MIC via the intermediacy of nickelacycles. Allenes give, after hydrolysis, 1:1 adducts with MIC (a-methyleneamides),39 as does styrene (N-methyldihydrocinnamide).40 Alkynes afford 2:1 adducts (2-pyridones) with MIC and this reaction is catalytic in nickel complex,41 unlike the styrene and allene reactions, which are stoichiometric in nickel.

Functional Group Interchanges.

Aldoximes are converted to nitriles in high yield upon treatment with MIC.2 In a very closely related reaction, alkyl nitro compounds yield nitrile oxides when subjected to reaction with MIC.3 These dipolar species are easily trapped intramolecularly, and this protocol provides an alternative to harsher reagents. Both functional group interchanges are dehydrations that exploit the high reactivity of MIC with H2O.

Related Reagents.

Phenyl Isocyanate; p-Toluenesulfonyl Isocyanate.


1. Anon. Dangerous Prop. Ind. Mater. Rep. 1989, 9, 68.
2. FF 1970, 4, 341.
3. Shigeno, K.; Ohne, K.; Yamaguchi, T.; Sajai, H.; Shibasaki, M. H 1992 33, 161.
4. (a) The Chemistry of Cyanates and Their Thio Derivatives; Patai, S., ed.; Wiley: New York, 1977; Part 2, pp 742-755. (b) MOC 1983, E4, 738.
5. Homma, H.; Watanabe, Y.; Abiru, T.; Murayama, T.; Numura, Y.; Matsuda, A. JMC 1992, 35, 2881.
6. Chern, J.-W.; Ho, C.-P.; Wu, Y.-H.; Runy, J.-F.; Liu, K.-C.; Cheng, M.-C.; Wang, Y. JHC 1990, 27, 1909.
7. Jean-Claude, B. J.; Just, G. JCS(P1) 1991, 2525.
8. Lee, M. J. C.; Eberling, J. A.; Nagasawa, H. T. JMC 1992, 35, 3641.
9. Tilley, J. W.; Ramuz, H.; Levitan, P.; Blount, J. F. HCA 1980, 63, 841.
10. Reiter, J.; Pongo, L.; Dvortsak, P. JHC 1987, 24, 1685.
11. Fishbein, P. L.; Kohn, H. JMC 1987, 30, 1767.
12. Aebi, J. D.; Deyo, D. T.; Sun, C. Q.; Guillaume, D.; Dunlap, B.; Rich, D. H. JMC 1990, 33, 999.
13. Kano, S.; Yuasa, Y.; Shibuya, S. H 1987, 26, 373.
14. (a) D'Amico, J. J.; Bollinger, F. G. JHC 1989, 26, 655. (b) Sauter, F.; et. al. M 1991, 122, 863 (CA 1992, 116, 173 969q).
15. (a) Kerdesky, F. A. J.; Holms, J. H.; Moore, J. L.; Bell, R. L.; Dyer, R. D.; Carter, G. W.; Brooks, D. W. JMC 1991, 34, 2158. (b) Massolini, G.; Carmellino, M. L. FES 1986, 41, 984 (CA 1987, 106, 151 469t).
16. Ibuka, T.; Chu, G.; Aoyagi, T.; Kitoda, K.; Tsukida, T.; Yoneda, F, CPB 1985, 33, 451.
17. Endo, Y.; Hizatate, S.; Shudo, K. SL 1991, 649.
18. Fukada, N.; Muri, T.; Muraoka, M.; Yamamoto, T.; Takeshima, T. BCJ 1988, 61, 4443.
19. Threadgill, M. D.; Gledhill, A. P. JOC 1989, 54, 2940.
20. (a) Capuano, L.; Boschat, P.; Heyer, H. W.; Wachter, G. CB 1973, 106, 312. (b) Capuano, L.; Zander, R. CB 1973, 106, 3670.
21. Page, P. C. B.; Van Niel, M. B.; Westwood, D. JCS(P1) 1988, 269.
22. Hart, T. W.; Vacher, B. TL 1992, 33, 3009.
23. Piper, J. U.; Allard, M.; Faye, M.; Hamel, L.; Chow, V. JOC 1977, 42, 4261.
24. Benhaoua, H.; Texier, F.; Carrine, R. T 1986, 42, 2283 (CA 1987, 106, 84 482b).
25. (a) Huber, E. W.; Kane, J. M. JHC 1990, 27, 1957. (b) Drummond, J. T.; Johnson, G. JHC 1988, 25, 1123.
26. Khattak, I.; Ketcham, R.; Schaumann, E.; Adiwidjaja, G. JOC 1985, 50, 3431.
27. Heitmann, M.; Zinner, G. CZ 1980, 104, 205 (CA 1980, 93, 220 667h).
28. Cascio, G.; Manghisi, E.; Fregnan, G. JMC 1989, 32, 2241.
29. Latif, N.; Assad, F. M.; Grant, N. S 1988, 246.
30. Hasegawa, K.; Hirooka, S.; Kawahara, H.; Nakayama, A.; Ishikawa, K.; Takeda, N.; Mukai, H. BCJ 1978, 51, 1805.
31. Tsuzuki, K.; Tada, M. JHC 1986, 23, 1299.
32. Quinn, R. J.; Scammells, P. J.; Kennard, C. H. L.; Smith, G. AJC 1991, 44, 1795.
33. Bender, A.; Guenther, D.; Wingen, R. LA 1985, 579 (CA 1985, 102, 203 947m).
34. Matsuda, I.; Yamamoto, S.; Ishii, Y. JCS(P1) 1976, 1528.
35. (a) Jaeger, G.; Wenzelburger, J. LA 1976, 1689. (b) Sato, M.; Katasiri, N.; Takayama, K.; Hirose, M.; Kaneko, C. CPB 1989, 37, 665. (c) Yogo, M.; Hirota, K.; Maki, Y. JCS(P1) 1984, 2097.
36. Knotz, H.; Zbiral, E. M 1986, 117, 1437.
37. Molina, P.; Aller, E.; Lorenzo, A. T 1991, 47, 6737.
38. Molina, P.; Lorenzo, A.; Aller, E. S 1992, 297.
39. Hoberg, H.; Suemmermann, K. JOM 1984, 275, 239.
40. Hernandez, E.; Hoberg, H. JOM 1986, 315, 245.
41. Hoberg, H.; Oster, B. W. S 1982, 324.

Erik P. Johnson

Ciba-Geigy Corporation, Summit, NJ, USA



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