1070-3632/05/7503-0425 2005 Pleiades Publishing, Inc. Russian Journal of General Chemistry, Vol. 75, No. 3, 2005, pp. 425 431. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 3, 2005, pp. 461 467. Original Russian Text Copyright 2005 by Golovchenko, Pil’o, Brovarets, Chernega, Drach. Transformations of Acylation Products of Functionally 4-Substituted 2-Alkyl(aryl)-5-hydrazino-1,3-oxazoles into 1,3,4-Oxadiazole Derivatives A. V. Golovchenko, S. G. Pil’o, V. S. Brovarets, A. N. Chernega, and B. S. Drach Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine Received August 6, 2003 Abstract 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 , -disubsti- tuted enamides I III with hydrazine hydrate, initiated recently [1 3] 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 IV VI containing in 4-position various electron-withdraw- ing groups: C(O)OAlk, P(O)(OAlk) 2 , and C N. The 1 H NMR and IR spectra of these products are consist- ent with their suggested structures (Table 1). Trans- formations I IV, II V, and III VI are similar to the extensively studied cyclocondensations of en- amides I III with primary and secondary amines (see references in [4]). Therefore, there is no doubt that compounds IV VI are, indeed, the 5-hydrazino-1,3- oxazole derivatives differently reacting with carboxyl- ic acid chlorides in the presence of bases. The reaction pathway essentially depends on the structure of elec- tron-withdrawing substituents in 4-position of the heteroring and on the acylation conditions. In particu- lar, 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 -acylation prod- ucts VII and VIII containing the HtNHNHCO frag- ment, 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 -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 -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 N H pro- tons in the HtNHNHCO group. The structural similarity of -acylation products VII IX was proved not only by spectroscopy, but also by the fact that, in contrast to the isomeric -acylation products, compounds VII IX after approoriate treatment transformed into 1,3,4-oxa- diazole derivatives. In particular, substrates VII and VIII, when heated in acetic acid or ethanol, recyclize (see scheme) into the corresponding de- rivatives of 1,3,4-oxadiazol-2-ylglycine (X) or its phosphonyl analog (XI) (Table 2). The presence of the CHNH and PCHNH groups in X and XI is confirmed by the 1 H NMR spectra in the regions of 6.1 6.4 and 9.6 9.8 ppm (Table 1). The signals were reliably assigned by comparison of the 1 H NMR spectra of compounds X and those of the related 1,3,4-oxadiazole derivatives C (see below) whose structure was proved by single crystal X-ray diffraction [2]. It should be noted that compounds VII do not transform into X even upon prolonged heating when acetic acid or ethanol as solvent is replaced by