Phenyl Isocyanide1,2

[931-54-4]  · C7H5N  · Phenyl Isocyanide  · (MW 103.13)

(synthesis of heterocycles)

Physical Data: bp 54 °C/13 mmHg; d 0.98 g cm-3.

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

Form Supplied in: pure liquid; not commercially available.

Analysis of Reagent Purity: gas chromatography.

Preparative Methods: see Grundmann,3a Ugi and Meyr,3b and Obrecht et al.3c

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

Synthesis of Heterocycles.1,2

The pharmacologically interesting barbituric acid derivative 6-phenylaminofuro[2,3-d]pyrimidine-2,4(1H,3H)-dione can be synthesized from readily available benzylidene-N,N-dimethylbarbituric acid with phenyl isocyanide by Michael-type addition and cyclization with tautomerization (eq 1).4

Benzofuran derivatives can be prepared in a general procedure by an Ugi-type reaction from substituted o-hydroxybenzaldehydes and isocyanides (eq 2).5 The reaction of the intermediate iminium compound, from the aldehyde and the ammonium salt, with the isocyanide stops at the addition step of the Ugi reaction. The resulting amino group reacts with another equivalent of the aldehyde, because the phenoxy function, which behaves as an acid equivalent, cannot be cleaved as is usual in the Ugi reaction.

[4 + 1] Cycloaddition of dimethyl tetrathiooxalate with phenyl isocyanide leads to 2-imino-1,3-dithioles under simple reaction conditions in remarkably high yield (eq 3).6

Another [4 + 1] cycloaddition of kinetically stabilized azetes with phenyl isocyanide affords sterically hindered pyrrole derivatives (eq 4).7 A simple route to cyclopentane-fused quinolines involves [4 + 1] radical annulation of g-iodoalkynes with phenyl isocyanide.8

1,2-Benzo-4-boraimidazolines are available by [4 + 1] cycloaddition of dialkylboryl derivatives with 2-aminopyridine in high yields (eq 6).9 Another structurally interesting boron heterocycle, namely a borapyrrole derivative, can also be obtained by [4 + 1] cycloaddition and alkyl tautomerization (eq 7).10

Phenyl isocyanide is also an effective reagent to form a-(methoxycarbonylamino) amides from a-methoxy urethanes in reasonable yields. As shown in eq 8, a Lewis acid catalyzes formation of the a-methoxycarbonylvalinamide.11 The insertion of phenyl isocyanide into the C-O bond of N-(ethoxymethyl)piperidine gives the a-piperidino acetimidate shown in eq 9.12

Syntheses Based on the Passerini Reaction.

Cyclization of levulinic acid13a and o-formylbenzoic acids13b with phenyl isocyanide produces g-carbamoyl g-lactones (eqs 10 and 11). The Ugi four-component reaction between cycloalkanones, phenyl isocyanide, and ammonium formate affords a-formylamino N-phenylcarboxamides (eq 12).14

Other Applications.

Polymerization of isocyanides under the action of NiII catalysts leads to helical polymethyleneimines (eq 13).15 Oxidation of phenyl isocyanide by TlI-catalyzed reaction with dibenzoyl disulfide gives the isothiocyanate in excellent yield (eq 14).16 Also, the direct oxidation of phenyl isocyanide with elemental selenium gives phenyl isoselenocyanate in high yield (eq 15).17

Related Reagents.

t-Butyl Isocyanide; Cyclohexyl Isocyanide; Ethyl Isocyanoacetate; Isocyanomethyllithium; Methyl Isocyanide; 1,1,3,3-Tetramethylbutyl Isocyanide; o-Tolyl Isocyanide; p-Tolylthiomethyl Isocyanide.

1. For general reviews on isocyanide chemistry, see: (a) Isonitrile Chemistry; Ugi, I., Ed.; Academic: New York, 1971. (b) Periasamy, M. P.; Walborsky, H. M. OPP 1979, 11, 295.
2. For applications in heterocyclic synthesis, see: Marcaccini, S.; Torroba, T. OPP 1993, 25, 141.
3. (a) Grundmann, C. CB 1958, 91, 1380. (b) Ugi, I.; Meyr, R. OS 1961, 41, 101. (c) Obrecht, R.; Herrmann, R.; Ugi, I. S 1985, 400.
4. Figueroa-Villar, J. D.; Carnieiro, C. L.; Cruz, E. R. H 1992, 34, 891.
5. Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R.; Polo, C. S 1991, 999.
6. Hartke, K; Kumar, A.; Henssen, G.; Quante, J.; Kampchen, T. CB 1982, 115, 3107.
7. Hees, U.; Regitz, M.; Schneider, J.; Wagner, O. S 1990, 834.
8. Curran, D. P.; Liu, H. JACS 1991, 113, 2127.
9. Dorokhov, V. A.; Shagova, E. A. BAU 1987, 36, 1054.
10. Dorokhov, V. A.; Boldyreva, O.; Shashkov, A.; Mukhailov, B. H 1982, 18, 87.
11. (a) Shono, T.; Matsumara, Y.; Tsubata, K. TL 1981, 22, 2411. (b) Shono, T.; Matsumura, Y.; Hamaguchi, H. JACS 1975, 97, 4264.
12. Matsuda, O.; Ito, K.; Sekiya, M. CPB 1975, 23, 219.
13. (a) Passerini, M. G 1923, 331. (b) Passerini, M.; Ragni, G. G 1931, 61, 964; G 1926, 56, 826.
14. Bossio, R.; Marcaccini, S.; Paoli, P.; Papalco, S.; Pepino, R.; Polo, C. LA 1991, 843.
15. Kamer, P. C.; Nolte, R.; Dreuth, W. JACS 1988, 110, 6818.
16. Tanaka, S.; Okano, M.; Uemura, S. BCJ 1977, 50, 2785.
17. Fujiwara, S.; Tsutomu, S. TL 1991, 32, 3503.

Heiner Eckert, Alfons Nestl & Ivar Ugi

Technische Universität München, Germany

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