Hydrazides from esters

Amides are stable compounds. The lower-melting members (such as acetamide) can be readily purified by fractional distillation. Most amides are solids which have low solubilities in water. They can be recrystallised from large quantities of water, ethanol, ethanol/ether, aqueous ethanol, chloroform/toluene, chloroform or acetic acid. The likely impurities are the parent acids or the alkyl esters from which they have been made. The former can be removed by thorough washing with aqueous ammonia followed by recrystallisation, whereas elimination of the latter is by trituration or recrystallisation from an organic solvent. Amides can be freed from solvent or water by drying below their melting points. These purifications can also be used for sulfonamides and acid hydrazides. 

The esters 35 are obtained by reaction of hydrazides 34 with chloroformate esters or carbonic diesters 3 23 28 42 as previously discussed for the special case of the activated esters (see Section 10.4.2). The amides 36, on the other hand, are formed from hydrazides 34 with isocyanic acid 3,43,44 or with trimethylsilyl isocyanate 42 (Scheme 10). 

The usual procedure of preparing acid azides, which involves treating an acid chloride with sodium azide, - suffers from the disadvantage that it is often difficult to obtain pure acid chlorides in good yields from acids which either decompose or undergo isomerization in the presence of mineral acids. Synthesis of the azide by way of the ester and hydrazide has been used to circumvent this difficulty but is much less convenient. The present procedure permits ready formation of acid azides in excellent yields from mixed carboxyhc-carbonic anhydrides and sodium azide under very mild conditions. 

Carboxylic acid azides are prepared from carboxylic acid halides or from amino acid/peptide esters via hydrazides, followed by nitrosylation with nitrous acid in water or with alkyl nitrites in organic solvents.Also, the aforementioned diphenylphosphorazidate cf. Section 2.3.1.1.2.2.ii.e) is often used in this preparation method starting from carboxylic acids. 

Figure 28 Electrokinetic separation of the niacin derivatives in the presence of SDS. Conditions applied voltage, 15 kV sample injection, injected by raising the positive end of the capillary about 4 cm higher than the other end capillary, a polyimide-coated fused-silica (70 cm X 50 xm i.d.) micellar solution, 0.15 M SDS in 0.02 M borate-0.01 M KOH (pH 9.1) detection wavelength, 210 nm. 1, Isonicotinic acid hydrazide 2, Nam 3, pyri-dine-3-methanol 4, 6-AN 5, MNA 6, pyridine-3-aldehyde 7, pyridine 8, 3-acetylpyri-dine 9, thionicotinamide 10, NiA 11, pyridine-3-sulfonic acid 12, P-picoline 13, nicotinic acid ethyl ester. (From Ref. 71.)...

Curtius transformation An alternative to the Hofmann transformation for obtaining an amine from an ester via the hydrazide, azide and isocyanate. Thus ethyl ethanoate is converted into melhylamine by the following series of reactions ... 

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. 

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). 

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 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. 

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. 

Aminosalicylic acid (5-amino-2-hydroxybenzoic acid) [89-57-6] M 153.1, m 276-280 , 283 (dec), pK 2.74 (CO2H), pK 5.84 (NH2). Cryst as needles from H2O containing a little NaHS03 to avoid aerial oxidation to the quinone-imine. The Me ester gives needles from C6H6, m 96°, and the hydrazide has m 180-182° (From H2O). [Fallab et al. Helv Chim Acta 34 26 1951, Shavel J Amer Pharm Assoc 42 402 1953.]... 

Simple isothiazole-4-carboxylic acids have been made from the corresponding nitriles, which are available in turn from the halogeno derivatives, or directly by the olefin route.5-Aminoiso-thiazole-4-esters and -nitriles are readily obtained by the thioamide route. The 4-acids behave normally and form acid chlorides, esters, amides, and hydrazides. In contrast to the 5-series... 

The A-substituted derivatives of 4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxamides and -3-acetamides and l,6-dimethyl-4-oxo-1,6,7,8-tetrahy-dro-4//-pyrido[l,2-n]pyrimidine-3-carboxamide were prepared by treatment of the appropriate 3-carboxylic acids and acetic acid, first with an alkyl chloroformate in the presence ofNEt3 in CHCI3 below — 10°C, then with an amine (98ACH515). A-Phenethyl and A-[2-(3,4-dimethoxyphenyl)ethyl] derivatives of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetamide were obtained in the reaction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-3-acetic acid and phenethylamines in boiling xylene under a H2O separator. Hydrazides of 4-oxo-4//- and 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic acid were prepared from the appropriate ester with H2NNH2 H2O in EtOH. Heating 4-oxo-4//- and 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic hydrazides in EtOH in the presence of excess Raney Ni afforded fhe appropriafe 4-oxo-6,7,8,9-fefrahydro-4//-pyrido[l,2-n]pyrimidine-3-acefa-mide. In the case of the 4-oxo-4// derivative, in addition to N-N bond... 

Dehydrogenation of the hydrazide derivative 33 with mercuric oxide in the presence of ethylene diamine tetraacetic acid (EDTA) gave 34 and 35 (77AP588). The latter (35) was prepared from a reaction of ester 36 with the appropriate lactam 37 (Scheme 11). 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

Certain 1,3,4-oxadiazole and 1,2,4-triazole glyphosate derivatives have been conveniently prepared in a faster, more efficient manner by heating the thionoester intermediates 73 with the appropriate acid hydrazide (61). These versatile thionoesters 73 have been synthesized in nearly quantitative yield from the readily available nitrile 31a, described previously, through the intermediate imidate ester 72. The oxadiazole products such as 70 obtained using this procedure were identical to those obtained from the HHT approach. 

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