Isocyanates, synthesis, Curtius reactions, sodium azide

Activation of the carboxylic acid as the acyl chloride permits direct reaction with azide anion to form the acyl azide substrates for Curtius rearrangement. Sodium azide is commonly used, and the reaction has been used on the process chemistry scale for the synthesis of benzyl-A-vinyl carbamate. Acryloyl chloride was combined with sodium azide in a biphasic system with phase-transfer catalysis (PTC), providing acyl azide 25. Upon heating, Curtius rearrangement provided vinyl isocyanate, which was distilled directly into benzyl alcohol containing phenothiazine (27) to inhibit polymerization of 26 and triethylamine to catalyze addition of the alcohol to the isocyanate. The vinyl carbamate product 28 was isolated by crystallization. As the autiior clearly pointed out, preparation and reaction of acyl azides, particularly on large scales, require appropriate safety precautions. 

Goodman and Chorev 75 found that the required a-aminoacyl azides 14 are best prepared by reaction of the mixed anhydride of the amino acid with sodium azide. This method led to slightly better yields than the nitrosylation of TV-formylaminoacyl hydrazide. Curtius rearrangement of the a-aminoacyl azide 14 yielded the isocyanate 16, which was subsequently trapped as 17 or 18 as shown in Scheme 2. Comparable yields were obtained by nitrosylation with tert-butyl nitrite. 76 Other methods of acyl azide formation have rarely been employed for PMRI-peptide synthesis. Only Fincham et al. 11 reported the use of trimethylsilyl azide to synthesize an acyl azide en route to a PMRI-peptide. 

The Schmidt reaction of carboxylic acids with hydrazoic acid has the advantage over Curtius rearrangement that it is only one step from the acid to the amine, but the conditions are more drastic (usually sulphuric acid plus sodium azide). Under these harsh conditions, the isocyanate intermediate is rarely isolated. For these reasons, the Curtius rearrangement is frequently employed to convert acids to amines. The Schmidt reaction of ketones with hydrazoic acid is a powerful method for the synthesis of amides and lactams. TTiis process is somewhat related to the Beckmann rearrangement of oximes however, the Schmidt reaction is more succinct, allowing the conversion of ketones to amides in a single operation. Considering its widespread... 

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