Addition to Primary Amines Synthesis of Isonitriles

The Hofmann carbylamine synthesis of isonitriles by the reaction of chloroform and base with primary amines was first reported over 100 years ago, but the reaction was not preparatively useful. For this reason, the two step process involving formyla-tion of the amine followed by dehydration was the method of choice. The phase transfer carbylamine reaction is inexpensive and convenient and the yields are such that it is competitive with the dehydration technique in many cases [13—15]. 

The mechanism of the reaction (see Eq. 3.10) is believed to involve initial coordination of the electrophilic carbene to the nitrogen lone pair. The zwitterion thus formed undergoes proton transfer from nitrogen to carbon yielding an N-substituted aminodichloromethane. Base catalyzed beta-elimination of the elements of HQ followed by alpha-elimination of another mole of HCl yields the desired isonitrile. 

A series of isonitriles has been prepared by the Hofmann carbylamine reaction and several examples are recorded in Table 3.4. 

Methyl and ethyl are more conveniently prepared using dibromocarbene (from bromoform) and the yields reported are therefore for the bromoform case. 

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