Carbamate acyl azide

Employing this method, enantioenriched phenol esters 68, amides 69, and carbamates 70 (after Curtius rearrangement of the intermediate acyl azide) were prepared in yields often greater than 90% with ee-values reaching up to 97% (generally 80-95%, see Fig. 37). 

Support-bound aliphatic alcohols react smoothly with isocyanates in the presence of catalytic amounts of a base to yield carbamates (Table 14.7). In an interesting variant of this reaction, isocyanates were generated in situ by Curtius degradation of acyl azides (Entry 2, Table 14.7). 

Support-bound isocyanates can be conveniently prepared from carboxylic acids by Curtius degradation. Because the reaction of the intermediate acyl azides with alcohols to yield esters is slow, Curtius degradation can be conducted in the presence of alcohols to yield carbamates directly (Entries 4 and 5, Table 14.8). 

Reaction of carboxylic acids gives acyl azides, which rearrange to isocyanates, and these may be hydrolyzed to carbamic acid or solvolysed to carbamates. Decarboxylation leads to amines. 

The isocyanate can he isolated if the Curtius degradation is carried out in an inert solvent. The isocyanate also can be reacted with a heteroatom-nucleophile either subsequently or in situ. The heteroatom nucleophile adds to the C=N double bond of the isocyanate via the mechanism of Figure 8.12. In this way, the addition of water initially results in a carbamic acid. However, all carbamic acids are unstable and immediately decarboxylate to give amines (see Figure 8.5). Because of this consecutive reaction, the Curtius rearrangement represents a valuable amine synthesis. The amines formed contain one C atom less than the acyl azide substrates. It is due to this feature that one almost often refers to this reaction as Curtius degradation, not as Curtius rearrangement. 

Figure 14.44 also shows how the Curtius degradation of an acyl azide can be combined with the addition of ferf-butanol to the initially obtained isocyanate. This addition gives a carbamate. In the present case a fert-butoxycarbonyl-protected amine ( Boc-protected amine ) is formed. 

Guichard et al. [168] have reported the preparation of optically active O-succinimidyl-ethylcarbamate derivatives 105 and their use as activated monomers in the solid-phase synthesis of oligoureas. Boc- and Fmoc-pro-tected j8-amino acids 102 were first converted to the corresponding acyl azides 103 (Scheme 28). Intermediate isocyanates 104 obtained by Curtius rearrangement of 103 were immediately trapped with / /-hydroxysuccinimide in the presence of pyridine to afford the corresponding carbamates 105 (51-... 

Because of its stability and storability, carbamate 29, or derivatives thereof, should be useful building blocks for further library development. However, for the target in question, a more direct conversion to the fumarate amide would be desirable. Fortunately, we found that the carboxylic acid formed fi om the t-butyl ester could be converted directly into acyl azide 27... 

With no fear, we pushed on to the Curtius rearrangement sequence needed to transform ferf-butyl ester 44 into the amide needed for sorbicillactone A. In the same fashion as the model substrate, the ester was first converted into acyl azide 45. Heating the acyl azide in a solution of f-BuOH under microwave conditions gave the rearranged product as ferf-butyl carbamate 46. Alternatively, and more directly, the rearrangement of acyl azide 45 to the isocyanate could be performed in THF. Subsequent hydrolysis with aqueous K2CO3 afforded the amine, which was acylated with fumarate 30 to give amide 47. 

Alkyl-, vinyl-, and aryl-substituted acyl azides undergo thermal 1,2-carbon-to-nitrogen migration with extrusion of dinitrogen — the Curtius rearrangement — producing isocyantes. Reaction of the isocyanate products with nucleophiles, often in situ, provides carbamates, ureas, and other A-acyl derivatives. Alternatively, hydrolysis of the isocyanates leads to primary amines. 

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. 

Carbamates are also formed by one-stage, two-step processes involving isocyanates as intermediates and precursors. Thus, carbamates are prepared under modified Hofmann rearrangement conditions, using NBS/NaOMe as the reagent [443], by Curtius rearrangement of the acyl azide if the reaction is carried out in alcohol, by the reaction of amides with lead tetraacetate [444], or by the Lossen rearrangement, if the carbamates are not sensitive to the presence of base. 

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