o-Tolyl Isocyanide1,2

[10468-64-1]  · C8H7N  · o-Tolyl Isocyanide  · (MW 117.16)

(synthesis of N-heterocycles and azomethines)

Physical Data: bp 75 °C/16 mmHg; d 0.97 g cm-3.

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

Analysis of Reagent Purity: by gas chromatography.

Preparative Method: see Ugi and Meyr.3

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

Introduction.

o-Tolyl isocyanide can be used to synthesize a great variety of compounds.1,2 The aromatic o-methyl group can be lithiated to create a bifunctional isocyanide reagent (eq 1).4

Indole Synthesis.

Reaction of o-tolyl isocyanide with Lithium Diisopropylamide followed by alkylation5,6 or acylation7-9 and then cyclization gives 3-substituted indoles (eqs 2-4).

Synthesis of Other Heterocycles.

b,g-Butenolide imines can be made in reasonable yields by Lewis acid-catalyzed [4 + 1] cycloaddition (eq 5).10 The azetidine ring system, otherwise very difficult to obtain, results in reasonable yield in a one-step [2 + 2 + 2] cycloaddition using o-tolyl isocyanide (eq 6).11

Azomethines.

Nucleophilic attack of organozinc compounds on the isocyanide carbon leads to the corresponding Schiff bases (eq 7).12 Similarly, Pd0 catalysis effects insertion of o-tolyl isocyanide into the Si-Si bond of bis-silyl compounds (eq 8).13

Related Reagents.

t-Butyl Isocyanide; Cyclohexyl Isocyanide; Ethyl Isocyanoacetate; Isocyanomethyllithium; Methyl Isocyanide; Phenyl Isocyanide; 1,1,3,3-Tetramethylbutyl 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. Ugi, I.; Meyr, R. OS 1961, 41, 101.
4. Ito, Y.; Kobayashi, K.; Saegusa, T. JOM 1986, 303, 301.
5. Ito, Y.; Kobayashi, K.; Seko, N.; Saegusa, T. BCJ 1984, 57, 73.
6. Ito, Y.; Kobayashi, K.; Seko, N.; Saegusa, T. CL 1979, 1273.
7. Ito, Y.; Saegusa, T.; Kobayashi, K. TL 1979, 1039.
8. Ito, Y.; Saegusa, T.; Kobayashi, K. JOC 1979, 44, 2030.
9. Ito, Y.; Kobayashi, K.; Saegusa, T. JACS 1977, 99, 3532.
10. Ito, Y.; Saegusa, T.; Kato, H. JOC 1982, 47, 741.
11. Burger, K.; Thenn, W.; Schickaneder, H. JFC 1975, 6, 59.
12. Ito, Y.; Murakami, M.; Ito, H. JOC 1988, 53, 4158.
13. Ito, Y.; Nishimura, S.; Ishikawa, M. TL 1987, 28, 1293.

Heiner Eckert, Alfons Nestl & Ivar Ugi

Technische Universität München, Garching, Germany



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