Acyl azides from acid hydrazides

Alkyl nitrites and nitrogen tetroxide together with acid are also effective for the formation of acyl azides from hydrazides under anhydrous conditions. As shown in Scheme 16, the Curtius reaction is especially suitable for the formation of complex reactive molecules. 

Acyl azides (see Section 2.13) The acyl-azide method of coupling is unique for two reasons. First, it is the only case in which the immediate precursor of the activated form of the peptide is not the parent acid. The starting material is the peptide ester that is obtained from the amino acid ester by usual chain assembly (Figure 2.25, path A). Second, it is the only method that just about guarantees production of a peptide that is enantiomerically pure, provided scrupulous attention is paid to details of procedure. There is no danger for loss of chirality during conversion of the ester to the hydrazide and then the azide, but care must be taken to avoid contact of... 

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... 

A closely related reaction of general applicability is the Curtius rearrangement222 of acyl azides. The rearranging species in the Schmidt reaction (see p. 898) is in fact also a protonated acyl azide these azides are readily prepared by the action of nitrous acid on acyl hydrazides which are themselves formed from esters and hydrazine (Section 9.6.17, p. 1269). On heating in aprotic solvents the acyl azides decompose to yield the corresponding isocyanates in good yield. 

Z-Glu(OtBu)-Ala-Glu(OtBu)-OPcp [(from EtOAc) yield 78% mp 132-133 C [a]o -13.2 (c 2, CHCI3)] and Z-Glu(OtBu)-Ala-OPcp [(from MeOH) yield 64% mp 171-172 C mp 173-174 C after three crystallizations, [a]o —18.5 (c 1.33, CHCI3)] were prepared from the acid and HOPcp using DCC according to Section 3.2.1.1.3.The protected tripeptide ester had the same specific rotation as that prepared by coupling the protected dipeptide hydrazide and the amino add ester by the acyl azide method. The two esters prepared by direct esterification were demonstrated by indirect optical rotation measurements to be >99.6 and 98% enantiomerically pure, respectively. 

As described earlier (Section 4.4.1.1), the intermediates of the Curtius reaction are acyl azides, which themially rearrange to isocyanates. One of the classical procedures for the preparation of acyl azides consists of the formation of hydrazides from esters and hydrazine, followed by treatment of the hydrazides with nitrous acid, generated from sodium nitrite and acetic, hydrochloric or sulfuric acid. Acyl azides are commonly used in the crude state or in solution since they are thermally unstable and potentially explosive. 

Acyl azides are obtained from hydrazides by the action of nitrous acid or alkyl nitrites 269... 

Acyl azide method, one of the oldest coupling methods in peptide synthesis, introduced by Theodor Curtius in 1902. Starting compounds are amino acid or peptide hydrazides (R-CO-NH-NH2), easily accessible from the corresponding esters by hydrazinolysis, which are transformed into azides (R-CO-N3) by N-... 

In the early literature, including the pioneering studies of Curtius himself, acyl azides were prepared from carboxylic acids via treatment of the derived acid hydrazides with nitrous acid. This method is less commonly used in contemporary synthesis but still appears occasionally in the literature. Examples were shown for compounds 1, 7, 17, and 21 in the earlier sections above. 

Special reactions of hydrazides and azides are illustrated by the conversion of the hydrazide (205) into the azide (206) by nitrous acid (60JOC1950) and thence into the urethane (207) by ethanol (64FES(19)105Q) the conversion of the same azide (206) into the N-alkylamide (208) by ethylamine the formation of the hydrazone (209) from acetaldehyde and the hydrazide (205) and the IV-acylation of the hydrazide (205) to give, for example, the formylhydrazide (210) (65FES(20)259). It is evident that there is an isocyanate intermediate between (206) and (207) such compounds have been isolated sometimes, e.g. (211). Several of the above reactions are involved in some Curtius degradations. 

The two reaction pathways studied involve a route from the carboxylic acid to the isocyanate via the acyl chloride and azide (Sodium Azide Pathway, Pathway A), Figure 4 and a route from the carboxylic acid to the isocyanate via the hydrazide (Hydrazide Pathway, Pathway B), Figure 5. The reactions were monitored by isolating the intermediate reaction products and characterizing them by melting points, elemental composition, or IR spectroscopy. 

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