Hydrazides, acyl, with alcohols

In general the synthesis of suitably protected amino acid and peptide hydrazides from the corresponding alkyl or aryl esters by reaction with hydrazine hydrate is carried out in alcohols or DMF at ambient temperature.P However, with C-terminal branched amino acids such as valine or isoleucine, or larger peptides, more vigorous conditions are required, i.e. higher temperature (25-80°C) and longer reaction times. To avoid formation of symmetrical bis(A-acyl-aminoacyl)hydrazides an excess of hydrazine hydrate or hydrazine is recommended, which also enhances the reaction rates. In this context, the solvent is known to play an important role, with alcohols being more appropriate than DMFP 0 or solvent mixtures such as dioxane/methanol.f l The use of hydrazine hydrate without any solvent has also been reported. ... 

HMBA resin, an aminomethyl polystyrene resin acylated with 4-(hydro-xymethyl)benzoic acid. It is completely resistant towards treatment with acids (even liquid HE), and enables on-resin side-chain deprotection. The highly versatile linker is cleaved by a variety of nucleophiles such as hydroxide ions (to give peptide acids), alcohols (to give esters), ammonia or amines (to give amides), hydrazine (to give peptide hydrazides), or UBH4 (to give peptide alcohols) [R. C. Sheppard, B. J. Williams, Int.J. Pept. Protein Res. 1982, 20, 451]. 

The third group of xenobiotics modifications is represented by conjugations , which include acylation of alcohols, phenols, amines, amides, hydrazides, etc., with sulfuric, acetic, glucuronic, glutamic and other acids, alkylation, and other synthetic... 

Hydrazides. Acyl halides, esters, and amides react with hydrazine to form hydrazides which are themselves useful synthetic intermediates. Treatment of the hydrazide with nitrous acid yields the acyl azide which, upon heating, gives isocyanates (Curtius rearrangement). Di- or trichlorides are obtained upon reaction with Phosphorus(V) Chloride Crotonate and other esters have been cleaved with hydrazine to liberate the free alcohol (eq 10). ... 

The Cunius degradation of acyl azides prepared either by treatment of acyl halides with sodium azide or trimethylsilyl azide [47] or by treatment of acyl hydrazides with nitrous acid [f J yields pnmarily alkyl isocyanates, which can be isolated when the reaction is earned out in aptotic solvents If alcohols are used as solvents, urethanes are formed Hydrolysis of the isocyanates and the urethanes yields primary amines. 

Much more important than these reactions, however, are the reactions of CDI and its analogues with carboxylic acids, leading to AAacylazoles, from which (by acyl transfer) esters, amides, peptides, hydrazides, hydroxamic acids, as well as anhydrides and various C-acylation products may be obtained. The potential of these and other reactions will be shown in the following chapters. In most of these reactions it is not necessary to isolate the intermediate AAacylazoles. Instead, in the normal procedure the appropriate nucleophile reactant (an alcohol in the ester synthesis, or an amino acid in the peptide synthesis) is added to a solution of an AAacylimidazole, formed by reaction of a carboxylic acid with CDI. Thus, CDI and its analogues offer an especially convenient vehicle for activation of... 

The acyl-azide method of coupling (Figure 2.13) has been available for about a century, but it is not attractive for routine use because it involves four distinct steps that include two stable intermediates that require purification. In addition, aminolysis of the azide is slow. The first step involves preparation of the ester (see Section 3.17), which can be methyl, ethyl, or benzyl. The ester is converted to the hydrazide by reaction in alcohol with excess hydrazine at ambient or higher... 

Syntheses of quaternary l-alkyl-3-perfluoroalkyl-4,5-dimethyl-l,2,4-triazolium iodides have led to the disclosure of a variety of new quaternary salts <04JOC1397>. Arylation of 3-alkylthio-5-aryl-l,2,4-triazoles under basic conditions gave 5-alkylthio-l,3-diaryl-l,2,4-triazoles in moderate yields <04JHC201>. Acyl hydrazides 155 reacted with imidates 156 to yield 1,2,4-triazoles 157 followed by Mitsunobu reactions with amino alcohols 158 to give regioisomeric... 

Bergmann has employed the azides of acylated amino acids for the stepwise degradation of peptides, as illustrated by the conversion of hippurylalanine to hippuramide and acetaldehyde. Hippurylalanine is converted through its ester and hydrazide to its azide, which is heated with benzyl alcohol to give 1-hippuramido-l-carbobenzoxyaminoethmie. This upon hydrogenation is cleaved to hippuramide mid acetaldehyde. ... 

A very versatile polymeric scaffold for site-specific double PPM is poly( 1 -aceto-l-pentalluorophenoxycarbonyl-2-vinylcyclopropane) [poly(APVCP)] (see Scheme 8) [139]. In this case, the two-step modification is performed in a sequential batch process. Following aminolysis by treatment with various primary amines, the ketone can be converted in the presence of hydrazide or hydroxylamine derivatives. Fmthermore, the ketone can be reduced to the secondary alcohol, which is subsequently converted into the ester or carbamate through the use of different acyl halides and isocyanates. 

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