Hydrazine carboxylate, methyl ester

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]. 

Synthesis of 210 was started from preparation of chiral diamine 211 (Scheme 50) [172], In particular, D-serine methyl ester was converted to iV-benzyl derivative 212, which was transformed into carboxylic acid 212 using reaction with chloroacetyl chloride and subsequent hydrolysis. Carboxylic acid 212 was subjected to coupling with benzyl amine, reduction, reaction with ethyl oxalyl chloride and reductive cyclization to give bicyclic compound 213. Finally, 211 Two-step reduction of 213 led to the formation of diamine 211, which was isolated as dihydrochloride. Reaction of 211 with dichloro derivative 215 and then - hydrazine hydrate gave the product 216, which was coupled with carboxylic acid 217 and subjected to catalytic hydrogenation to give 210. 

The aminolysis of esters of pyrimidine occurs normally to yield amides. The reagent is commonly alcoholic ammonia or alcoholic amine, usually at room temperature for 20-24 hours, but occasionally under refiux aqueous amine or even undiluted amine are used sometimes. The process is exemplified in the conversion of methyl pyrimidine-5-carboxylate (193 R = Me) or its 4-isomer by methanolic ammonia at 25 °C into the amide (196) or pyrimidine-4-carboxamide, respectively (60MI21300), and in the butylaminolysis of butyl ttracil-6-carboxylate (butyl orotate) by ethanolic butylamine to give A-butyluracil-5-carboxamide (187) (60JOC1950). Hydrazides are made similarly from esters with ethanolic hydrazine hydrate. 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

Isocarboxazid Isocarboxazid, 2-benzylhydrazid-5-methyl-3-isoxazolecarboxylate (7.2.6), can be synthesized from acetylacetone, which on nitrosation with nitrous acid gives 5-methyl-isoxazol-3-carboxyhc acid (7.2.2). Esterification of this product gives the ethyl ester of 5-methyl-isoxazol-3-carboxyhc acid (7.2.3). The synthesized ester (7.2.3) is further reacted with benzylhydrazine, to give isocarboxazide (7.2.6), or with hydrazine, which forms 5-methyl-isoxazol-3-carboxylic acid hydrazide (7.2.4). Reacting the latter with benzaldehyde gives hydrazone (7.2.5), which is further reduced to the isocarboxazide (7.2.6) [46,47]. 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

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). 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

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