Hydrazides Hydrazines

MAO Inhibitors. MAO is an enzyme which oxidizes a variety of monoamines. Among the substrates of this enzyme are tyramine, tryptamine, 5-hydroxytryptamine, histamine, and short chain aliphatic monoamines ( ). Oxidation of histamine to imidazoleacetaldehyde can be carried out by DAO as well as MAO. is also responsible for the conversion of N -MH, the product of HMT, to N -MIAA. Many MAO inhibitors have been identified they are conventionally divided into hydrazides, hydrazines and amines (44). Some MAO inhibitors, e.g. the hydrazines, are non-selective they also inhibit DAO. 

Pyridine reacts with sodium hydrazide in the presence of hydrazine to yield 2-hydrazinopyridine in the absence of free hydrazine a hydrazo compound is formed (Scheme 88) (64AG(E)342). A difference between hydrazination and amination is the formation of 1,4-adducts which cannot be rearomatized even on heating. This is reflected in the behaviour of quinoline, which gives only a 0.5% yield of a -hydrazino product, whereas 4-methylquino-line is hydrazinated in 76% yield (64AG(E)342). Acridine behaves differently with sodium hydrazide/hydrazine, 9,10-dihydroacridine is formed almost quantitatively, but reaction in the absence of hydrazine yields 9-aminoacridine (65%). An even higher yield of 9-amino-acridine is obtained when sodium Af.AC-dimethylhydrazide is used (Scheme 89). Good evidence for intermediacy of (151) comes from the isolation of (152) on hydrolysis of (151). 

The reaction of sodium alkylamides with pyridine gives 2-amino-pyridine derivatives,301 but this does not appear to have been exploited with substituted pyridines. Similarly, pyridine gives 2-hydrazinopyridine on treatment with sodium hydrazide/hydrazine followed by hydrolysis.301 ... 

Isopropanolamine 2-Mercaptoethanol 1-Methyl-3-phenyl-5-[3-(trifluoromethyl) phenyi]-4(1 H)-pyridinone a-Naphthylamine Nitrosophenylhydroxylamine ammonium salt Phenyl benzoate m-Phenylenedimaleimide N-Phenylmaleimide Phenyl mercuric bromide Potassium carbonate Potassium N-hydroxymethyl-N-methyldithiocarbamate Pyridine Silica, fused Tetrachlorophthalic acid Thiourea p-Toluic acid , N-Tridecyl-2,6-dimethylmorpholine Trimethyl phosphate agric. chemicals, maleic hydrazide Hydrazine agric. sprays Zinc sulfate monohydrate agric., biodegradable Poly (hydroxybutyrate-hydroxyvalerate) agriculture... 

Sodium amide/hydrazine Reductions with sodium hydrazide/hydrazine NaNH IHsN NH ... 

Synonyms Benzenesulfonic acid, 4-methyl-, hydrazide Hydrazine, p-tolylsulfonyl- p-Toluenesulfonhydrazide p-Toluenesulfonic acid, hydrazide p-Toluenesulfono-hydrazide p-Toluenesulfonyl hydrazide N-Toluolsulfonyl hydrazine Tolylsulfonyl hydrazine Tosyl hydrazide... 

Acid hjdrazides from esters. Meth and ethyl esters react with hydrazine to give acid hydrazides ... 

Place 1 0 ml. of hydrazine hydrate (CAUTION corrosive chemical) in a test-tube fitted with a short refiux condenser. Add 10 g. of the methyl or ethyl ester dropwise (or portionwise) and heat the mixture gently under refiux for 15 minutes. Then add just enough absolute ethanol through the condenser to produce a clear solution, refiux for a further 2-3 hours, distil oflF the ethyl alcohol, and cool. Filter oflF the crystals of the acid hydrazide, and recrystallise from ethanol, dilute ethanol or from water. 

The independent preparation of potassium phthabmide (from a solution of phthalimide in absolute ethanol and potassium hydroxide in 75 per cent, ethanol) may be avoided in many cases by boiling phthalimide with the halide in the presence of anhydrous potassium carbonate. The N-substituted phthalimide (I) is frequently cleav with difficulty this is often facilitated by reaction with hydrazine hydrate to give an intermediate product, which is easily decomposed by hydrochloric acid to 3deld the insoluble hydrazide of phthaUc acid (II) and the primary amine (III) ... 

Benzylatnine. Warm an alcoholic suspension of 118-5 g. of finely-powdered benzyl phthalimide with 25 g. of 100 per cent, hydrazine hydrate (CAUTION corrosive liquid) a white, gelatinous precipitate is produced rapidly. Decompose the latter (when its formation appears complete) by heating with excess of hydrochloric acid on a steam bath. Collect the phthalyl hydrazide which separates by suction filtration, and wash it with a little water. Concentrate the filtrate by distillation to remove alcohol, cool, filter from the small amount of precipitated phthalyl hydrazide, render alkaline with excess of sodium hydroxide solution, and extract the liberated benzylamine with ether. Dry the ethereal solution with potassium hydroxide pellets, remove the solvent (compare Fig. //, 13, 4) on a water bath and finally distil the residue. Collect the benzylamine at 185-187° the 3ueld is 50 g. 

Thus esters were converted to hydrazides with an excess of hydrazine hydrate in alcohol with a yield of 84% (66). 

Thiazolecarboxylic acid hydrazides are prepared by the same general methods used to prepare amides, that is, by treating acids, esters, amides, anhydrides, or acid halides with hydrazine or substitued hydrazines. For example, see Scheme 21 (92). The dihydrazides are obtained in the same way (88). With diethyl 2-chloro-4,5-thiazoledicarboxylate this reaction gives the mono hydr azide monoester of 2-hydrazine-4,5-... 

The conversion of esters to hydrazides and of hydrazides to the sulfonyl derivatives occurs in good yield in the McFadyen-Stevens synthesis, but the decomposition of sulfonyl derivatives gives low yields of the desired products, for example, thiazole hydrazide (28) with 10% excess of PhSOjCl in pyridine gave a 75% yield of l-phenylsulfonyl-2-(4-methyl-5-thiazo ecarbonyl)hydrazine (29) (66). The Newman-Caflish modification of the McFadyen-Stevens synthesis gave 37% 4-methyl-5-thiazole-carboxaldehyde (30) (Scheme 27). 

This reaction forms the basis of one method of terminal residue analysis A peptide is treated with excess hydrazine in order to cleave all the peptide linkages One of the terminal amino acids is cleaved as the free amino acid and identified all the other ammo acid residues are converted to acyl hydrazides Which amino acid is identified by hydrazmolysis the N terminus or the C terminus ... 

Acid-Base Reactions. Anhydrous hydrazine undergoes self-ionization to a slight extent, forming the hydrazinium, N2H5, and the hydrazide, N H7ions ... 

Hydrazinium salts, N2H5 X, are acids in anhydrous hydrazine, metallic hydrazides, N2H, are bases. Neutralization in this solvent system involves the hydrazinium and hydrazide ions and is the reverse of equation 7. Metal hydrazides, formally analogous to the metal amides, are prepared from anhydrous hydrazine and the metals as well as from metal amides, alkyls, or hydrides. (The term hydrazide is also used for organic compounds where the carboxyUc acid OH is substituted with a N2H2.) Sodium hydrazide [13598-47-5] is made from sodium or, more safely, from sodium amide (14) ... 

The ionic hydrazides are extremely sensitive and explode on contact with ak or upon heating. The alkaline-earth hydrazides, which have the general formula M(N2H2), appear to be less sensitive (15). Hydrazides such as aluminum hydrazide [25546-96-7] Al(N2H2)3, have also been made (16). The hydrazide anion is more nucleophilic than hydrazine and undergoes reactions not possible using hydrazine itself (17). Thus, styrene in ethyl ether solution at 0°C is... 

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). 

All the sulfonic acid hydrazides are made from hydrazine or semicarbazide and the appropriate sulfonyl chloride in the presence of an HCl acceptor such as ammonia. 

Pharmaceuticals. The tuberculostatic dmg isoniazid [54-85-3] (60), the hydrazide of 4-pyridinecarboxyhc acid, was one of the eadiest hydrazine-based dmgs introduced in the United States. It is made by the reaction of hydrazine and an isonicotinic acid ester (219). 

Pyridazinecarbohydrazides are prepared in the normal way from an ester or acid chloride and hydrazine or a substituted hydrazine, generally in good yields. Pyridazines with two ortho alkoxycarbonyl groups give cyclic hydrazides with hydrazine, which are pyridazinopyridazines. 

The most useful syntheses of pyridazines and their alkyl and other derivatives begins with the reaction between maleic anhydride and hydrazine to give maleic hydrazide. This is further transformed into 3,6-dichloropyridazine which is amenable to nucleophilic substitution of one or both halogen atoms alternatively, the halogen(s) can be replaced by hydrogen as shown in Scheme 110. In this manner a great number of pyridazine derivatives are prepared. 

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. 

Maleic hydrazide (149), produced on a large scale as a herbicide, can be obtained, according to a patent, from a simple diaziridine, which on an industrial scale could be less expensive than hydrazine hydrate. In the proposed manufacture of diamide (150) from a diaziridine and urea it must be taken into account that the reaction of urea is preceded by solvolytic hydrazine formation, which probably proceeds under the reported conditions (several hours, 70-80 °C, acidic media) (79AHC(24)63). 

Sulfobenzyl esters were prepared (cesium salt or dicyclohexylammonium salt, Na03SC6H4CH2Br, DMF, 37-95% yield) from A -protected amino acids. They are cleaved by hydrogenolysis (H2/Pd), or hydrolysis (NaOH, dioxane/water). Treatment with ammonia-or hydrazine results in formation of the amide or hydrazide. The ester is stable to 2 M HBr/AcOH and to CF3SO3H in CF3CO2H. The relative rates of hydrolysis and hydrazinolysis for different esters are as follows ... 

Classically, amides and hydrazides have been prepared from an ester or an acid chloride and an amine or hydrazine, respectively they can also be prepared directly from the acid as shown in eqs. 1-3. 

The dihydro-bases of type (I) yield on treatment with hydrazine the expected (—)-dihydro-d-wolysergic acid (I) hydrazide, but on hydrolysis with alkali the reduced isolysergic acid residue is irreversibly isomerised to the dihydrolysergic acid residue and the product obtained is (—)-dihydro-d-lysergic acid (c/. p. 532). 

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