Methyl Isocyanide

(1; R = Me)

[593-75-9]  · C2H3N  · Methyl Isocyanide  · (MW 41.06) (2; R = n-Bu)

[2769-64-4]  · C5H9N  · Butyl Isocyanide  · (MW 83.15) (3; R = Cy)

[931-53-3]  · C7H11N  · Cyclohexyl Isocyanide  · (MW 109.19)

(reactive amphiphilic reagents for 1,1-additions to form heterocyclic N-t-butylimines, iminoyl halides, a-hydroxy amides, a,b-enals, a-acylamino amides via Passerini reactions, and polymethylene imines; oxidative additions to isocyanates and isothiocyanates1,2)

Physical Data: (1) bp 60 °C; d 0.75 g cm-3. (2) bp 123-124 °C; d 0.79 g cm-3. (3) bp 173-176 °C, 56-58 °C/11 mmHg; d 0.88 g cm-3.

Solubility: sol most organic solvents, e.g. methanol, ethanol, ether, toluene, dichloromethane.

Form Supplied in: pure liquids; methyl isocyanide is not commercially available; n-butyl and cyclohexyl isocyanides are commercially available.

Analysis of Reagent Purity: by GC.

Preparative Methods: the preparation of methyl isocyanide is well established.3

Handling, Storage, and Precautions: should be freshly distilled before use; foul smelling liquid; should be stored and used in a fume hood. Contaminated equipment should be washed with 5% methanolic sulfuric acid.

Heterocyclic Imines.2

[4 + 1] Cycloadditions of dimethyl tetrathiooxalate with alkyl isocyanides afford 2-imino-1,3-dithiolines under simple reaction conditions in good yields (eq 1).4 Iminodioxolidine derivatives are available in good yields from cyanoketimines (eq 2).5

Iminoyl Halides via 1,1-Additions.

Chlorination of cyclohexyl isocyanide (3) in THF containing HgCl2 incorporates the solvent in a ring-opening reaction (eq 3).6 Pivaloyl chloride reacts with methyl isocyanide (1) to give an a-keto iminoyl chloride (eq 4).7 N-Alkyl perfluoroalkylimidoyl iodides are easily accessible by copper-catalyzed condensation of iodo perfluoroalkanes and alkyl isocyanides in excellent yields. The products can be reduced by Sodium Borohydride to the corresponding secondary amines (eq 5).8

The Ugi four-component reaction between aldehydes, methyl isocyanide, and ammonium trifluoroacetate affords a-amino N-methylamides (eq 6).9 Nocardicine, a monocyclic b-lactam antibiotic, is synthesized in one step together with the b-lactam by an Ugi reaction (eq 7).10

Other Applications.

a,b-Unsaturated aldehydes are available in a one-pot reaction, zirconium catalyzed, with n-butyl isocyanide (2) and alkynes (eq 8).11

The reaction of methyl isocyanide with Titanium(IV) Chloride in CH2Cl2 affords an iminoyltitanium reagent which undergoes 1,2-addition to aldehydes and ketones. Hydrolysis of the adduct gives the homologous a-hydroxy-N-methylamide (eq 9).12

Isocyanides undergo formal [1 + 4] cycloaddition to cisoid a,b-enones in the presence of Diethylaluminum Chloride or Ethylaluminum Dichloride to give N-alkyl imines of b,g-butenolides (eq 10).13 The imines can be solvolyzed to g-keto esters or hydrogenated and hydrolyzed to g-butyrolactones.

Oxidative addition of oxygen, sulfur, and selenium to alkyl isocyanides affords isocyanates,14 isothiocyanates (eq 11),15 and, isoselenocyanates,16 respectively.

Polymerization of isocyanides with NiII catalysis leads to helical polymethyleneimine (M > 30 000 for n-butyl isocyanide, 75%).17

Related Reagents.

t-Butyl Isocyanide; Cyclohexyl Isocyanide; Ethyl Isocyanoacetate; Phenyl Isocyanide; 1,1,3,3-Tetramethylbutyl Isocyanide; p-Tolylsulfonylmethyl Isocyanide.

1. For general reviews on isocyanide chemistry, see: (a) Ugi, I. Isonitrile Chemistry Academic: New York, 1971. (b) Periasamy, M. P.; Walborsky, H. M. OPP 1979, 11, 295.
2. For applications of isocyanides in heterocyclic synthesis, see: Maraccini, S.; Torroba, T. OPP 1993, 25, 141.
3. Schuster, R. E.; Scott, J. E.; Casanova, J. OS 1966, 46, 75.
4. Hartke, K.; Kumar, A.; Henssen, G.; Quante, J.; Kampchen, T. CB 1982, 115, 3107.
5. Moore, H. W.; Yu, C.-C. JOC 1981, 46, 4935.
6. Yamazaki, T.; Wada, Y.; Tanimoto, S.; Okano, M. BCJ 1977, 50, 1094.
7. Tian, W. S.; Livinghouse, T. CC 1989, 819.
8. Tordeux, M.; Wakselman, C. T 1981, 37, 315.
9. Scholz, D.; Schmidt, U. CB 1974, 107, 2295.
10. Hatanake, M.; Noguchi, N.; Ishimaru, T. BCJ 1982, 55, 1234.
11. Negishi, E.; Swanson, D. R.; Miller, S. R. TL 1988, 29, 1631.
12. Schiess, M.; Seebach, D. HCA 1983, 66, 1618.
13. Ito, Y.; Kato, H.; Saegusa, T. JOC 1982, 47, 741.
14. Nemeth, S.; Simandi, L. I.; Drenth, W. ICA 1982, 64, L21.
15. (a) Hirao, T.; Yamada, A.; Hayashi, K.; Oshiro, Y.; Agawa, T. BCJ 1982, 55, 1163; (b) Fujiwara, S.; Shin-Ike, T. TL 1992, 33, 7021; (c) Fujiwara, S.; Shin-Ike, T.; Okada, K.; Aoki, M.; Kamle, N.; Sonoda, N. TL 1992, 33, 7021; (d) Tanaka, S.; Uemura, S.; Okano, M. BCJ 1977, 50, 2785.
16. Fujiwara, S.; Shin-Ike, T. TL 1991, 32, 3503.
17. Kamer, P. C. T.; Nolte, R. J. M.; Drenth, W. JACS 1988, 110, 6818.

Heiner Eckert, Alfons Nestl & Ivar Ugi

Technische Universität München, Germany

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