Phosphorylthioacetamides in the synthesis of annulated quinoxalines

Abstract

Diethoxyphosphorylthioacetamide in the reaction with 2,3 dichloroquinoxaline acted as a thionating reagent, giving diethoxyphosphorylacetonitrile and 2 chloro 3 [(3 chloro 2 quinoxalinyl)thio]quinoxaline. Reactions of phosphorylthioacetamides with N methylquin oxalinium iodide in alcohol media in the presence of a base proceeded stereoselectively to afford cis 3 phosphoryl 1,3,3a,4,9,9a hexahydro 2H pyrrolo[2,3 b]quinoxaline 2 thiones.Key words: phosphorylthioacetamides, 2,3 dichloroquinoxaline, N methylquinoxalinium iodide, annulation, 1,3,3a,4,9,9a hexahydro 2H pyrrolo[2,3 b]quinoxaline 2 thiones.Thioamides of carboxylic acids are widely employed as key precursors for the synthesis of various five and six membered heterocycles. 1 In particular, azines con taining two and more heteroatoms are known to undergo annulation in the presence of thioamides of carboxylic acids (and some other bisnucleophilic reagents). This abil ity of azines is behind convenient routes to complex fused heterocyclic systems that are of particular interest from the viewpoint of biological activity. 2-4However, publications devoted to the reactivities of phosphorylthioacetamides are scarce. 5-8 To the best of our knowledge, they are mainly concerned with (1) alky lation reactions that occur at the sulfur atom 5,6 and sub sequently afford biologically active amidines, (2) the Hantzsch synthesis of phosphorus containing thiazoles, 7 and (3) regioselective condensation with dimethyl acetylenedicarboxylate yielding phosphorus containing thiazolidin 4 ones. 8 Limited data on the chemical prop erties of compounds of this class are largely due to the lack of convenient methods for their preparation.A recently developed, convenient method for the syn thesis of phosphorylthioacetamides with various types of the surrounding of the P atom made these organophos phorus compounds easily accessible. 9 Here we present data on their application as annulating agents in reactions with azines. Diethoxy and diphenylphosphorylthio acetamides 1a,b were chosen as the starting organophos phorus substrates and easily accessible 2,3 dichloro quinoxaline and N methylquinoxalinium iodide, as azine components.Condensation of thioamides RC(S)NH 2 (R = H, Me, and Ph) with 2,3 dichloroquinoxaline has been re ported 10-12 to give 2 substituted thiazolo[4,5 b]quinoxa lines, although the physicochemical constants of the re sulting 2 methyl derivative do not coincide (the melting points of the samples differ by more than 200 °C). Sur prisingly, thioamide 1a in a reaction with 2,3 dichloro quinoxaline 2 acted as a thionating agent. As a result of the reaction of equimolar amounts of the reactants in ethanol in the presence of triethylamine as an acceptor of HCl, 2 chloro 3 (3 chloroquinoxalin 2 ylthio)quin oxaline 3, the starting thioamide 1a, and diethoxy phosphorylacetonitrile were isolated instead of the ex pected thiazolo[4,5 b]quinoxaline (Scheme 1). Scheme 1