Hydrazine carboxylic acid derivatives

Condensation of 3-ethoxycarbonyl-, 3-acetyl-, or 3-cyano-l,2,3,4-tetrahydropyridine -carboxylic acid derivatives 275-277 with hydrazine hydrate in boiling ethanol afforded the pyrido[3,4-r/ pyridazine derivatives 278-280, respectively (Equation 20) <2002PS1359>. 

The generation of azaamino add residues and their incorporation into the peptide chain can be accomplished by different methods that closely resemble the methods used for peptide coupling but are derived from the chemistry of semicarbazides. In principle, the formation of an azaamino acid residue takes place by the reaction of a hydrazine derivative (hydrazine or hydrazide) with carbonyl donors , different types of activated TV-carboxylic acid derivatives (Scheme 2). 

Allopurinol, 1,5-dihydro-4//-pyrazolo[3,4-d]pyrimidin-4-one (53), was first synthesized by Robins <56JA784> and by Schmidt <58HCA1052) from 5-aminopyrazole-4-carboxylic acid derivatives. Several syntheses starting from a simple acyclic intermediate have been reported. Thus, reacting ethyl alkoxymethylene cyanoacetate with hydrazine and formamide at 14(M80°C gave allopurinol in high yield. An acid catalyst lowers the temperature required for cyclization of the intermediate 4-alkoxycarbonyl-3-aminopyrazole and raises the purity and the yield of allopurinol <69BRPI 284084). 

The usual range of carboxylic acid derivatives can be prepared and interconverted. Both carboxylic acid and ester functions are capable of reduction by lithium aluminum hydride to alcohols, or by controlled potential reduction to aldehydes. Attempts to form the anhydride from imidazole-4,5-dicarboxylic acid by heating with acetic anhydride failed. Instead, compound (199) is formed. This product forms the monoester (200) when heated with methanol and the hydrazide (201) when treated similarly with hydrazine (Scheme 107) (75S162). The corresponding l-methyl-4,5-dicarboxylic acid loses the 4-carboxyl group when heated with acetic anhydride, but in boiling aniline it is transformed into the 1-methyl-4-carboxanilide (79H(12)186). 

A variety of one-carbon cyclizing agents have been used (71JOC10) to prepare 3-substituted l,3-thiazolo[2,3-c] 1,2,4-triazoles (111) from 2-hydrazino-l,3-thiazoles (110). The acid hydrazides (113) of these hydrazines, prepared either directly from 110 and carboxylic acid derivatives or indirectly from 1-acylthiosemicarbazides (112) and a-haloketones, also undergo facile dehydrative cydization to 111. [71JOC10 78JHC401 ... 

Usually decarboxylation is accomplished by heating the acids above their melting points, often in the presence of a copper-chromium catalyst. Imidazole-4,5-dicarboxylic acid can be monodecarboxylated by heating its monoanilide imidazole- and benzimidazole-2-carboxylic acids decarboxylate very readily indeed, so readily that the carboxyl function makes a useful blocking group in metallation procedures (see Scheme 7.2.1) [3-5]. A potentially useful method of preparation of imidazole-4-carboxylic acid derivatives heats the 4,5-dicarboxylic acid (2) with acetic anhydride to form (1), which is essentially an azolide and very prone to nucleophilic attack which cleaves the nitrogen-carbonyl bond (Scheme 8.3.1). With methanol the methyl ester (3) is formed with hydrazines the 4-hydrazides (4) result [6]. 

Wamhoff and Hendrikx prepared pyrimido[4,5-h]azepine-6-carboxylic acid derivatives 514 and 515 from carbodiimide 513 by reacting it with 5% sodium hydroxide solution or with hydrazine and i-propylamine in boiling... 

This hydrazine is available by catalytic reduction of acetone azine.1 Protection of carboxylic acids.2 The reagent reacts with carboxylic acid derivatives (the acyl chloride or mixed anhydride) to give a monoacylhydrazide, RCON(CHMe2)-NH(CHMe2). The derivatives are stable to both acids and bases. They are reconverted into carboxylic acids by selective oxidation, preferably with lead tetraacetate. The new method of protection has been used for penicillins. 

In most cases these C,N2 fragments are prepared by reaction of activated carboxylic acid derivatives (C, fragment), such as dithiocarboxylates 2, thioesters 3. nitriles 5, imidates 6, amidines 7, thioamides 8, selenoamides 9, selenoesters 11, orthocarboxylates 14, with hydrazine (N2 fragment) and are transformed to l,4-dihydro-l,2,4,5-tetrazines 17 without isolation. Therefore, these syntheses are treated as a (2 + 1 +2+1) fragment method. 

Dihydrotetrazines (340), which can easily be oxidized to 1,2,4,5-tetrazines, can be formed by dimerization of thiohydrazides (337) or amidrazones (338). The ring closure of hydrazidines (339) in a [5 + 1] fashion proceeds well with activated carboxylic acid derivatives such as imidates (341), orthocarboxylates (342) or dithiocarboxylates (343). The [4 + 2] procedure is found in the transformation of 1,3,4-oxadiazoles (346) or 1,4-dichloroazines (345) with hydrazine. Finally diazoalkanes (344) can be dimerized in a [3 - - 3] manner under the influence of a base the dimerization of diazoacetic ester is an early example, leading to 3,6-tetrazinedicarboxylate (48), which is frequently used in (4 -I- 2) cycloaddition reactions with inverse electron demand. Nitrile imines, reactive intermediates which are formed from many precursors, can dimerize in a [3 -I- 3] fashion to form 1,3,4,6-tetrasubstituted 1,4-dihydrotetrazines. These reactions are summarized in Scheme 57. 

Addition of antipyrene 39 to 38 affords the carboxylic acid derivative 40 that reacted with hydrazine and with phenylhydrazine in refluxing butanol to yield 42. The acyclic phenylhydrazone 41 was isolated from the reaction of 40 with hydrazine at room temperature (2003MOL322 Scheme 8). 

Pyrazole-3(5)-carboxylic acid esters derivatives are also another important motif of considerable pharmacological relevance and also represent useful synthetic building blocks in both organic and medicinal chemistry. The approach most often used to prepare these involves [3 + 2] cycloadditions between hydrazines and 1,3-diketoesters. In general, Claisen condensation of the enolate of a ketone 21 with diethyl oxalate is the method most commonly employed in the preparation of the 1,3-diketoesters, 22. These, in turn, constitute important building blocks for most of the pyrazole-3(5)-carboxylic acid derivatives 23 reported in the literature, some of which have been found to display important pharmaceutical activities. ... 

Carboxylic acid hydiazides are prepared from aqueous hydrazine and tfie carboxylic acid, ester, amide, anhydride, or halide. The reaction usually goes poody with the free acid. Esters are generally satisfactory. Acyl halides are particularly reactive, even at room temperature, and form the diacyl derivatives (22), which easily undergo thermal dehydration to 1,3,4-oxadiazoles (23). Diesters give dihydtazides (24) and polyesters such as polyacrylates yield a polyhydrazide (25). The chemistry of carboxyhc hydrazides has been reviewed (83,84). 

In an initial step triphenylphosphine adds to diethyl azodicarboxylate 5 to give the zwitterionic adduct 6, which is protonated by the carboxylic acid 2 to give intermediate salt 7. The alcohol reacts with 7 to the alkoxyphosphonium salt 8 and the hydrazine derivative 9, and is thus activated for a SN2-reaction ... 

A one-pot conversion of carboxylic acids into esters and amide derivatives from alcohols, amines or hydrazines has been reported [53], which involves the initial reaction of the acid with methane- or toluenesulphonyl chloride to yield a mixed anhydride. 

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