Nitrous acid reaction with hydrazides

Curtius rearrangement of a-oximino acid azides is reported as a new method of synthesis for 3-substituted 5-hydroxyoxadiazoles. In this method, the oxime of an a-ketoester is converted to the acid hydrazide, which in turn is converted to the azide by reaction with nitrous acid 115a). 

Preparation. Hiis stable, crystalline white solid is readily prepared as shown, starting with the condensation of benzhydrol and methyl chlorothiolcarbonate to produce the ester (1). The crude ester is treated in ether with hydrazine in methanol to form the hydrazide (2) and this is converted into the azide (3) by reaction with nitrous acid. 

Hydrazides —> Azides. The acid azide method of peptide synthesis, for example of the protected dipeptide (3), has the advantage that no racemization of the peptide vomptments occurs. However, conversion of N-carbobenzoxy-S-benzyl-u-cysteine hydni/.lde (I) into the azide by reaction with nitrous acid under normal conditions (ITor ls considerable amide as by-product (Rt ONHNHNO — RCONH> + fiBaNHaOl. Amide formation can be lUDoraiiad hv onaratlna at hlah aoiditv and... 

Hydrazide— azide. In the synthesis of putrescine dihydrochloride, diethyl adipate is converted into the dihydrazide, which on reaction with nitrous acid affords... 

The racemic acid (78) was converted into the acid chloride (80) by reaction of its sodium salt with oxalyl chloride in benzene. Compound (80) was treated with anhydrous hydrazine to afford the hydrazide (81). Reaction with nitrous acid followed by photolysis of the resulting azide (82) gave the desired 5-lactam (83). 

Sulfonic acid hydrazides, RSO2NHNH2, are prepared by the reaction of hydraziae and sulfonyl haUdes, generally the chloride RSO2CI. Some of these have commercial appHcations as blowiag agents. As is typical of hydrazides generally, these compounds react with nitrous acid to form azides (26), which decompose thermally to the very reactive, electron-deficient nitrenes (27). The chemistry of sulfonic acid hydrazides and their azides has been reviewed (87). 

The Cunius degradation of acyl azides prepared either by treatment of acyl halides with sodium azide or trimethylsilyl azide [47] or by treatment of acyl hydrazides with nitrous acid [f J yields pnmarily alkyl isocyanates, which can be isolated when the reaction is earned out in aptotic solvents If alcohols are used as solvents, urethanes are formed Hydrolysis of the isocyanates and the urethanes yields primary amines. 

As noted above, a convenient pathway to cinno-lines consists of intramolecular condensation of a diazonium group with a ketonic methyl group, or alternately with a double bond. The analogous reaction with an amide nitrogen leads to 1,2,3-benzotriazines, such as 198. Reaction of isatoic anhydride with N-aminomorpholine affords the hydrazide 196 then, treatment with nitrous acid yields initially the diazonium salt (197). Under the reaction conditions... 

Sugar lactones react readily with hydrazine to give crystalline derivatives useful for isolation and identification (127). Thus, addition of hydrazine to a reaction mixture containing an aldonolactone facilitates isolation of the product. The lactone may be regenerated from the hydrazide by treatment with nitrous acid (128). The phenylhydrazides obtained on treatment of aldonolactones with phenylhydrazine are also useful for characterization (129,130). 

If primary or secondary amines are used, AT-substituted amides are formed. This reaction is called aminolysis. Hydrazines yield the corresponding hydrazides, which can then be treated with nitrous acid to form the azides used in the Curtius rearrangement. Hydroxyl amines give hydroxamic acids. 

The instability of tert-butyl chioroformate limits its use for preparing Boc derivatives.102 /ert-Butyl fluoroformate (bp 40-42 aC/23.3 kPa)103104 is more stable than the chloro derivative and more reactive than rm-butyl azidoformate (HAZARD). Both reagents should be prepared afresh. rm-Butyl azidoformate (bp 36.5-37.5 °C/1.3 kPa)105 has the added frisson of being explosive hence, it should be prepared in situ from the reaction of Boc-hydrazide with nitrous acid and used without purification. Moreover, the by-product of aqueous workup, hydrazoic acid, is highly toxic. 

As described earlier (Section 4.4.1.1), the intermediates of the Curtius reaction are acyl azides, which themially rearrange to isocyanates. One of the classical procedures for the preparation of acyl azides consists of the formation of hydrazides from esters and hydrazine, followed by treatment of the hydrazides with nitrous acid, generated from sodium nitrite and acetic, hydrochloric or sulfuric acid. Acyl azides are commonly used in the crude state or in solution since they are thermally unstable and potentially explosive. 

Acid azides are obtainable by reaction of the respective hydrazides with nitrous acid or of acid chlorides with sodium azide.302 378 Curtius degradation of 2-phenyloxazole-4-carbonyl azide (236) in boiling xylene... 

The other method of preparing 5-cyanotetrazole is based on treatment of 1-cyanoformimidic acid hydrazide with nitrous acid. The intermediate 1-cyanoformimidic acid hydrazide could be prepared by the reaction of cyanogen and hydrazine [18, 19]. 

Acid azides are commonly prepared by treating acid hydrazides in cold, aqueous solution with nitrous acid. The required hydrazides are prepared from esters hy reaction with hydrazine. Acid azides can also be made by treatment of acid chlorides with sodium azide. In Curtius ... 

Saturated Monocarboxylic Acids. Azides of saturated acids can be prepared almost equally well by reaction of the hydrazides with nitrous acid or by reaction of the acid chlorides with sodium azide. The latter method is superior for very low-molecular-weight acids, whose hydrazides and azides are difficult to extract from water by this method acetyl chloride is converted to methyl isocyanate through the azide in 60-72% yields. From lauroyl chloride, 86% of undecyl isocyanate is obtained by the sodium azide method. The reaction of acid an-... 

From Hydrazides. All the techniques for converting hydrazides into azides are based on the reaction of the hydrazide with nitrous acid, with the exception of the rarely used diazonium method. The principal variables are solvent, method of isolating the azide, pH, and the order of the addition of the reactants. The reaction is nearly always carried out at ice-bath temperatures. 

Since the reaction of nitrous acid with hydrazides is rapid and exothermic, the reactants should be brought together no faster than the heat can be dissipated a rise in temperature is likely to lower the 3ddd by decomposition of nitrous acid or of flie azide or of both. Slow addition provides time for the interaction of the azide with unchanged hydrazide to produce the secondary hydrazide rapid addition lessens the extent of this side reaction. For effective cooling, ice is generally added directly to the reaction mixture the addition of Dry Ice to the supernatant ether layer has been recommended as being even more efficient. ... 

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