Hydrazides reaction with aromatic compounds

An ester group at C-3 or C-5 is not different in function from any ester in aliphatic or aromatic compounds. The ester can be converted into an amide or a hydrazide, or it may be hydrolyzed. The hydrazide can be converted into an acid azide and rearranged to an isocyanate which in turn will form a carbamate or can be hydrolyzed to an amine. However, the amine group can be replaced with chlorine by diazotization in hydrochloric acid, not an ordinary pattern of behavior (76AHC(20)65) although similar reactions do occur in the 1,2,4-triazole ring system. 

The reaction has been shown to be of very broad scope with a multitude of nucleophiles Nu such as imides.23,24,29,32,33,36,37,42 amines,10,32 cyanide,25,32 hydroxide,10,32 alkox-ide,10,26,32 electron-rich isocyclic or heterocyclic aromatic compounds,28 carboxamides,31 lactams,31 ureas,31 sulfonamides,31 cyanate,31 formate (to give products with Nu = H),34 C-H acidic compounds,35 hydrazines and hydrazides,38 and sulfinates.38 The amino group NR R2 of cyclopropane-1,1-diamines and the nucleophile Nu in bicycles 8, 9 or 12, respectively, can be easily replaced with other nucleophiles Nu, such as water,10,32,33 alkoxide,10,32-34,42 Grignard compounds,27,42 amines,29,30,36,37,42,43 cyanide,29,33,42,44 hydride,34,42,44 and C-H acidic compounds39-41,43,44 (see Section 5.2.1.). Therefore, it is currently the most important method for the preparation of substituted bicyclic cyclopropylamines. The toxic and costly reagent methyl fluorosulfate can be avoided in a modified synthetic route, which instead of the fluorosulfate 5 proceeds via the corresponding tetraphenylborate, hexafluorophosphate, or (most conveniently) via the tosylate.23 The different steps of the method can often be combined in a one-pot procedure. Results are summarized in Table 3. 

Indoloquinoxaline 693 was obtained in 83-90% yield by irradiating a mixture of isatin with o-phenylenediamine in acetic acid in an MW oven in either an open flask or closed Teflon vessel for 1-2 min. Carbethoxymethylation of isatin with ethyl chloroacetate in the presence of K2CO3 and Nal was carried out under MWI to give compound 694 in 70% yield within 4min. It could be converted into 695 by reaction with o-phenylenediamine in acetic acid in either an open flask (2 min) or closed Teflon vessel (Imin) (Scheme 134). Alternatively, carbethoxymethylation of 693 under MWI for 6 min afforded a 53% yield of 695. Reaction of 695 with hydrazine hydrate in ethanol under MWI gave the hydrazide 696 in 84% yield. MWI has been also used to condense 696 with aromatic aldehydes and monosaccharides to yield the hydrazone derivatives 697 in 58-99% yields (Scheme 134) (05JCR(S)299). 

Thiophene- and benzo[6]thiophene-carboxylic acids undergo all the normal reactions of an aromatic carboxylic acid (63AHC(1)1, 70AHC(11)177). They can be converted to acid chlorides, amides and esters the esters can be used to make hydrazides. Benzo[6]thiophene-2-carboxylic acid chloride has been converted to the methyl ketone with dimethylcadmium and to the diazoketone with diazomethane. Bromodecarboxylation of the silver salts (Hunsdiecker reaction) has been used to prepare the dibromo compounds (340) and (341). 

Acetylation is an important route of metabolism for aromatic amines, sulphonamides, hydrazines and hydrazides and there is a wide variety of substrates. This metabolic reaction is one of two types of acylation reaction and involves an activated conjugating agent, acetyl CoA. It is hence a type 1 reaction. Acetylation is notable in that the product may be less water soluble than the parent compound. This fact gave rise to problems with sulphonamides when these were administered in high doses. The acetylated metabolites, being less soluble in urine, crystallized out in the kidney tubules, causing tubular necrosis (table 4,1). The enzymes which catalyse the acetylation reaction, acetyltransferases, are cytosolic and are found in the liver, in both hepatocytes and Kupffer cells, in the gastrointestinal mucosa and in white blood cells. The enzyme has been purified and its mechanism of action extensively studied and is now well understood. This involves first acetylation of the enzyme by acetyl CoA... 

Direct amination of 3(2//)-pyridazinones occurs when they are heated with hydrazine hydrate and this is a convenient route to many 4-amino-6-substituted-3(2//)-pyridazinones (Scheme 11). The reaction generally gives high yields and amination is regiospecific when the 6-position is occupied by an aromatic or heteroaromatic ring, but the parent 3(2/ -pyridazinone gives a mixture of the 4- and 5-amino-3(2//)-pyridazinones. The reaction tolerates jV-methyl substitution of the pyridazinone, but is sensitive to steric factors the presence of a 5-substituent causes a marked reduction in reaction rate, and amination does not occur with 4-phenyl-3(2//)-pyridazinone. With maleic hydrazide 4-hydrazination occurs, possibly by displacement of an intermediate amino compound or by oxidation of an intermediate 4,5-dihydro-4-hydrazino adduct both 4-hydrazino- and... 

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