Acyl Azides from Mixed Anhydrides

3 Acyl Azides by Direct Conversion of Carboxylic Acids 

Bandgar et al. reported a general route for the synthesis of acyl azides from aryl, heteroaryl, alkylaryl and alkyl acids with cyanuric chloride (297) in the presence of sodium azide and (V-methylmorpholine. Acid activation can also be achieved using triphosgene. In fact, aromatic and aliphatic carboxylic acids react with triphosgene in the presence of sodium azide and triethylamine giving acyl azides in good yield (e.g. synthesis of 301). 

The reaction of carboxylic acids with diphenylphosphoryl azide (DPPA) and subsequent Curtins rearrangement can be used for the conversion of malonic esters 304 into protected (/ )-2-methylcysteine 308. Monomethylation of dimethyl malonate followed by alkylation with t-butylchloromethyl sulfide gives the achiral diester 305. Enantioselec- 

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It should be mentioned at this stage that instead of acyl chlorides, mixed anhydrides may also be used for the synthesis of acyl azides. From carboxylic acids and chloroformates/triethylamine, mixed anhydrides are formed, which can directly react with azide ions. Sterically hindered acids fail in this procedure (equation 31)." " The similar synthesis of /-butyl azidoformate by reaction of /-butylcarbonic diethylphosphoric anhydride with KN3 is described in Organic Syntheses. ... 

Section A of Scheme 10.15 contains a number of examples of Curtius rearrangements. Entry 1 is an example carried out in a nonnucleophilic solvent, permitting isolation of the isocyanate. Entries 2 and 3 involve isolation of the amine after hydrolysis of the isocyanate. In Entry 2, the dihydrazide intermediate is isolated as a solid and diazotized in aqueous solution, from which the amine is isolated as the dihydrochloride. Entry 3 is an example of the mixed anhydride procedure (see p. 948). The first stage of the reaction is carried out in acetone and the thermolysis of the acyl azide is done in refluxing toluene. The crude isocyanate is then hydrolyzed in acidic water. Entry 4 is a reaction that demonstrates the retention of configuration during rearrangement. 

Peptide bond formation involves activation of the carboxyl group of an amino acid residue, followed by aminolysis of the activated residue by the amino group of a second amino acid residue. Two types of activated molecules are recognized those that are not detectable but are postulated and those that are detectable and can be isolated. Postulated intermediates are necessary to account for the formation of the detectable intermediates. The postulated intermediates are consumed as fast as they are formed, either by aminolysis by an amino group or by nucleophilic attack by an oxygen nucleophile, which produces activated molecules that are also immediate precursors of the peptide. More than one activated compound may be generated by a postulated intermediate. Activated esters, acyl halides and azides, and mixed and symmetrical anhydrides are isolatable activated compounds that are generated from postulated intermediates. Peptides are produced by one of three ways ... 

Mixed carboxylic-carbonic anhydrides, prepared from carboxylic acids and alkyl chloioformates in the presence of base, are easily converted to acyl azides by the action of sodium azide. Since the reaction sequence from carboxylic acids to acyl azides proceeds under mild conditions, it has a broad applica-... 

The Curtius rearrangement has been extensively utilized for the synthesis of numerous cyclo-propylamines 4 from cyclopropanecarboxylic acids 1. The necessary acyl azides 2 are most conveniently obtained by reaction of sodium azide with the mixed anhydride of the cyclopropanecarboxylic acid and ethyl chloroformate. ... 

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