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Synthesis of Amido-Containing Heterocyclic Compounds

V.N. Yarovenko,* S.A. Kosarev, I.V. Zavarzin, and M.M. Krayushkin.

N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 117913 Moscow, Russian Federation

Abstract: A convenient approach to the synthesis of amido-containing 1,3,4-oxadiazoles, tetrazoles, isoxazolines, isoxazoles, and oxathiazoles was suggested.


    We suggested an approach to the synthesis of several amido-containing heterocyclic compounds using heterocyclization of carbamoylhydroxymoyl chloride fragments (D) obtained by the successive modification of accessible chaloracetamide groups according to Scheme 1.

Scheme 1


(D) R= Ph 


    Monothiooxamides (B) are formed in the reactions of different a-substituted derivatives of acetamide 1 with preliminarily prepared solutions of elemental sulfur in amines. a-Chloracetamides (1a) and their pyridinium salts (1e) react most smoothly.

    A possibility to obtain monothiooxamides by the reactions of chloracetamides with sulfur and amines has been previously shown in the literature using several examples. However, no preliminarily prepared solutions of sulfur in amines were used in these processes, and a high temperature was used in the reactions. Our attempts to obtain several monothiooxamides by the method described resulted in the synthesis of the target products only in insignificant amounts. We showed that when sulfur and amine are simultaneously added to chloracetamides, an aminomethylene derivative (2) is mainly formed and then it can react with sulfur only at a high temperature.

    We showed that the reactions of monothiooxamides in pyridine with an excess of hydroxylamine, which plays the role of the reducing agent in this reaction as well, afford carbamoylamidoximes in high yields. The reaction proceeds via the stage of formation of substituted amidoxime 3, which can be isolated in high yield when the reaction is carried out at room temperature

    It is noteworthy that the synthesis of nonsubstituted amidoximes from N(S)-substituted thioamides has not been described previously.

    We also showed that carbamoylamidoximes can be synthesized in sufficiently high yields in one flask by the reaction of the corresponding chloracetamide with elemental sulfur and amine in pyridine followed by the treatment of the reaction mass with hydrochloric hydroxylamine without intermediate isolation of the monothiooxamide formed.

    We established that when hydrochloric acid is added to an aqueous suspension of carbomoylamidoximes, water-soluble salts are formed, which are rapidly transformed under the action of sodium nitrite at room temperature into hydroxymoyl chlorides.

    The reactions of hydroxymoyl chlorides with different nucleophiles make it possible to synthesize different heterocyclic compounds.

    Thus, we developed an approach, which allows one to synthesize different amido-containing heterocyclic compounds by several simple modifications of amino group.