A. Kadushkin, I. F. Faermark, G. Shvarts
Nov 1, 1993
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Influential Citations
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Journal
Pharmaceutical Chemistry Journal
Abstract
The synthesis of new sulfur-containing derivatives of 4-aminopyridines has been undertaken in continuation of our investigations on the synthesis and study of biologically active compounds of this type of heterocycle. Initially 4-phenylamino-3-cyanopyridine-2-thione (I) was synthesized by a method developed previously for obtaining 4-amino substituted pyridine-2-thiones [2]. Cyanothioacetamide was taken as starting material and was reacted with the diethyl acetal of dimethylacetamide to give ot-cyano-/3-dimethylaminocrotonic acid thioamide (lIl) in good yield. The transamination of enamine (1/I) with aniline in acetic acid medium enabled the previously undescribed examine (IV) to be synthesized. The reaction of compound (IV) with an excess of the acetal of dimethylformamide (DMF) led to the pyridine intermediate (V) which was treated with aqueous alkali without isolation. Ring opening was accompanied by subsequent recyclization with the formation of the desired pyridinethione (I). Another approach to the synthesis of pyridine-2-thiones is by the reaction of 2-chloro-3-cyanopyridines (Via, b) with thiourea. The reaction was carried out in boiling toluene. After treatment of the intermediate isothiouronium salt with aqueous alkali the 4-phenylaminoand 4-dimethylaminopyridinethiones (I) and (VII) were obtained in yields of 63 and 72 %, respectively. Of the two existing syntheses of 4-amino substituted 3-cyanopyridine-2-thiones the direct replacement of a chlorine atom by a thione grouping is preferable since it uses thiourea, a sulfur-containing synthetic equivalent, which is more available than cyanothioacetarnide. Numerous examples are known in the literature of the use of 3-cyanopyridine-2-thiones in syntheses of derivatives of 3-aminothieno[2,3-b]pyridine [1], however 4-amino substituted 3-cyanopyridine-2-thiones have not as yet been used for this. Compounds (I) and (ID were alkylated with chloroacetic acid derivatives (ethyl ester, carbamide, nitrile) and with phenacyl and 4-nitrophenacyl bromides with the aim of synthesizing 4-phenylaminoand 4-dimethylaminothieno[2,3-b]pyridines. As a rule 3-cyanopyridine-2-thiones are used in alkylation reactions as the potassium salts in a medium of aqueous DMF. The S-alkylation reaction is most frequently accompanied by a spontaneous Torp-Ziegler cyclization with the formation of 3-aminothieno[2,3b]pyridine derivatives [i]. All the alkylation reactions of the potassium salts of 3-cyanopyridine-2-thiones (I, VID were carried out under standard conditions (aqueous DMF at 5-7~ in the present work with the aim of studying the effect of the nature of the amino substituent at the 4 position of the pyridine ring. It was established that in the case of the 4-phenylaminopyridine-2thione (I) the intermediate S-alkyl derivative (like VIII) is isolated under these conditions only in the case of R 3 = COOEt (VIIIa), In the remaining examples the alkylation is accompanied by a TorpZiegler cyclization with the formation of condensed thiophenes. The alkylation of 4-dimethylaminopyridine-2-thione (VII) under similar conditions gave the TorpZiegler cyclization product only in the case of R 3 = CN and COPh (IXh, i), i.e., the process of thiophene cyclization is slower when using (VII) compared to (I) which enables the pyridine intermediate (VIIIc, d) to be isolated. Such a difference in behavior of the intermediate S-alkyl derivatives is explained by the significantly larger electron-donating effect of the dimethylamino group compared with the aniline fragment in position 4 of the pyridine ring. It is understandable that such a positive mesomeric effect leads to an increase in the electron density on the carbon of the cyano group and correspondingly to a reduction of its ability