Amine from acyl azides

Acyl azide, amines from, 935 Acyl carrier protein, function of, 1 140 Acyl cation, electrostatic potential map of, 558... 

The Curtius rearrangement of the acyl azide derived from optically pure a-methoxy-a-(trifluoro-methyl)phenylacetic acid (MTPA 48) also proceeds with retention of configuration, giving a-methoxy-a-(trifluoromethyl)benzyl isocyanate (49 equation 26). The isocyanate (49) is useful for the determination of the enantiomeric composition of optically active primary and secondary amines. 

The Curtius rearrangement can be catalyzed by Lewis acids or protic acids, but good yields are often obtained also without a catalyst. From reaction in an inert solvent (e.g. benzene, chloroform) in the absence of water, the isocyanate can be isolated, while in aqueous solution the amine is formed. Highly reactive acyl azides may suffer loss of nitrogen and rearrange already during preparation in aqueous solution. The isocyanate then cannot be isolated because it immediately reacts with water to yield the corresponding amine. 

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. 

Reactions of pyrimido[4,5-3] [l,4]thiazines were discussed in CHEC-II(1996) <1996CHEC-II(7)737> more recently, reported reactions of this system involve nucleophilic substitution in a number of guises. Hemiaminals at C-3 react with ammonium acetate to form aminals (Equation 166) <1999CHE97>. The formation of acyl hydrazides from pyrimido[4,5-3][l,4]thiazine-2-carboxylic acids, along with their subsequent conversion to acyl azides and Curtius... 

The reaction sequence - including subsequent reaction with water which leads to amines - is named the Curtius Reaction. This reaction is similar to the Schmidt Reaction with acids, differing in that the acyl azide in the present case is prepared from the acyl halide and an azide salt. 

The conversion of an acid to an amine of one less carbon may be conveniently accomplished by way of the azide and rearrangement to the isocyanate. The azide may be obtained either from the acyl chloride and sodium azide or from an ester by treatment with hydrazine and subsequent diazotization. An excellent review including scope and limitations of the reactions, selection of experimental conditions and procedures, and a tabulation of compounds prepared thereby has been presented. ... 

Sample preparation Mix 300 pL of a 30 pM solution in dichloromethane with 10 pL 20 mM l-(6-methoxy-2-naphthyl)ethyl isothiocyanate in anhydrous dichloromethane and 50 pL 0.1% triethylamine in dichloromethane, vortex thoroughly, heat at 50° for 1.5 h, inject an aliquot. (Synthesize l-(6-metho -2-naphthyl)ethyl isothiocyanate as follows (protect from light). Dissolve 500 mg (S)-(+)-naproxen in 50 mL dry toluene, slowly add 5 mL freshly distilled thionyl chloride, reflux for 1 h, evaporate to dryness under vacuum, dry the acyl chloride (mp 87.5°) under vacuum over KOH for 2 days. Dissolve 0.5 mmoles acyl chloride in 5 mL acetone, stir at 0°, add 0.6 mmoles sodium azide dissolved in ice water, stir at 0° for 30 min, add 10 mL ice-cold water, filter, dry solid in a desiccator under vacuum. Dissolve the solid in 1 mL toluene or dichloromethane (dried over 3 A molecular sieve), reflux for 10 min, evaporate, store resulting isocyanate (mp 51°) under vacuum over a desiccant. Dissolve 0.5 mmole isocyanate in 5 mL acetone, add 20 mL 8.5% phosphoric acid, heat to 80° for 1.5 h, adjust to pH 13, extract with diethyl ether dichloromethane 4 1. Wash the organic layer twice with water, dry over anhydrous sodium sulfate, evaporate to dryness, dissolve in 1 mL toluene, evaporate to give the amine from... 

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