Available 2‐acylamino‐3,3‐dichloroacrylonitriles, when treated with hydrazine hydrate, provide 2‐alkyl‐ or 2‐aryl‐5‐hydrazino‐1,3‐oxazole‐4‐carbonitriles that readily add alkyl or aryl isothiocyanates and the adducts formed recyclize on heating. Finally, the synthesis results in 5‐alkyl(aryl)amino‐1,3,4‐thiadiazol‐2‐yl(acylamino)acetonitriles or the products of their further cyclization, 2‐(5‐amino‐1,3‐ oxazol‐2‐yl)‐1,3,4‐thiadiazole derivatives. The structures of the novel substituted 1,3,4‐thiadiazoles are corroborated spectroscopically as well as by X‐ray diffraction method. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:454–458, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20041

It has been shown that the derivatives of diethyl 5‐amino‐2‐phthalimidoalkyl‐1,3‐oxazol‐4‐ylphosphonates can be employed in the synthesis of phosphorylated peptidomimetics containing the phosphonoglycine residue. The reaction of diethyl 5‐alkylamino‐2‐aminoalkyl‐1,3‐oxazol‐4‐ylphosphonates with unsaturated azlactones was utilized to obtain phosphorylated peptidomimetics with dehydroamino acid moieties. The double bond in the latter was reduced with zinc in acetic acid to provide the corresponding saturated peptidomimetics containing a diethoxyphosphoryl group in the side chain.

Acylation products of 2-aryl-5-hydrazino-4-X-1,3-oxazoles [X = C(O)OAlk, P(O)(OAlk) 2 ], when heated in acetic acid or ethanol, undergo recyclization and transform into the derivatives of 1,3,4-oxadiazol-2-ylglycine or its phosphonyl analog. A similar rearrangement also occurs in the reactions of 2-alkyl(aryl)-5-hydrazino-1,3-oxazole-4-carbonitriles with carboxylic acid chlorides in pyridine, but it is accompanied by additional cyclization involving the amide residue and nitrile group, yielding 2-(5-amino-1,3-oxazol-4-yl)-1,3,4-oxadiazole derivatives.A systematic study of the reactions of b,b-disubstituted enamides I3III with hydrazine hydrate, initiated recently [133] and continued in this work, showed that the possible applications of this polycondensation are fairly wide, and it is indispensable for preparative synthesis of 5-hydrazino-1,3-oxazole derivatives IV3 VI containing in 4-position various electron-withdrawing groups: C(O)OAlk, P(O)(OAlk) 2 , and C=N. The 1 H NMR and IR spectra of these products are consistent with their suggested structures (Table 1). Transformations I 6 IV, II 6 V, and III 6 VI are similar to the extensively studied cyclocondensations of enamides I3III with primary and secondary amines (see references in [4]). Therefore, there is no doubt that compounds IV3VI are, indeed, the 5-hydrazino-1,3-oxazole derivatives differently reacting with carboxylic acid chlorides in the presence of bases. The reaction pathway essentially depends on the structure of electron-withdrawing substituents in 4-position of the heteroring and on the acylation conditions. In particular, acylation of the hydrazino group in alkyl esters of 2-aryl-5-hydrazino-1,3-oxazole-4-carboxylic acids IV and their phosphonyl analogs V in acetonitrile in the presence of an equimolar amount of triethylamine mainly occurs at the nitrogen atom more remote from the oxazole ring. The reaction yields b-acylation products VII and VIII containing the HtNHNHCO fragment, as indicated by the 1 H NMR spectra (Table 1).At the same time, 2-aryl-5-hydrazino-1,3-oxazole-4-carbonitriles VI structurally related to IV and V react with carboxylic acid chlorides in the presence of triethylamine quite differently, yielding mainly the a-acylation products HtN(COR 2 )NH 2 whose structure was unambiguously proved by spectral and chemical methods [2]. The acylation pathway of substrates VI changes if the acylation with carboxylic acid chlorides is performed in pyridine. The b-acylation products IX formed in the first step are difficult to isolate pure, because they readily undergo further transformations (see scheme). However, we were able to isolate one of these compounds (X = CN, R 1 = R 2 = 4-CH 3 C 6 H 4 ) and to record its 1 H NMR spectrum. The spectrum contained two broadened singlets at 10.43 and 10.93 ppm, assignable to two different N3H protons in the HtNHNHCO group.The structural similarity of b-acylation products VII3IX was proved not only by spectroscopy, but also by the fact that, in contrast to the isomeric a-acylation products, compoun...

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