A simple and effective synthetic approach to pyrido[2,1-b]thiazines

Abstract

The reported methods for the synthesis of substituted pyrido[2,1-b] [1,3]thiazines are based on the reaction of 2-pyridinethiol with β-bromopropionic acid [1], reaction of tetrahydro-2-pyridinethione with benzylidenemalononitrile [2], reaction of 3,4-dihydropyridine-2(1H)-thione with epichlorhydrin [3], and acylation of 3,4-dihydro-2(1H)-pyridinethione with cinnamyl chloride [4].In the present work, we have found a simple and efficient method for preparing previously unreported substituted, partially hydrogenated pyrido[2,1-b][1,3]thiazines 1-4 consisting of the regioselective alkylation of 2-pyridinethiols 5-7 and 2-pyridinethiolate 8 by 1,3-dibromopropane in DMF in the presence of aqueous KOH.An X-ray diffraction structural analysis of 3a was carried out to establish the regioselectivity of the alkylation of 2-pyridinethiols 5-8 by 1,3-dibromopropane. We found that there are two symmetrically independent molecules A and B in the crystal of this compound. The major geometrical parameters of these molecules are given in Table 1, while a general view of these molecules is given in Figs. 1 and 2. The bond lengths and bond angles in 3a(A) and 3a(B) are virtually identical. In particular, N (1) in both molecules has planar trigonal configuration: the sum of the bond angles at this atom is 359.0(6)° in 3a(A) and 359.9(6)° in 3a(B). In both molecules, the N (1) -C (4) and N (1) -C (8) bonds are markedly shortened relative to the standard value for the pure N(sp 2 )-C(sp 2 ) single bond (1.45 Å) [5] due to n(N (1) )-π(C (4) =C (5) ) and n(N (1) )-π(C (8) =O (1) ) conjugation. On the other hand, the conformations of these molecules differ considerably, as indicated both by the endocyclic torsion angles (Table 2) and the modified Kramer-Pople parameters, S, θ, and Ψ [6]. Thus, while the S (1) N (1) C (1) C (2) C (3) C (4) heterocycle in molecule A has chair conformation (S = 0.99, θ = 12.2°, ψ = 8.8°), this heterocycle in molecule B has twist-boat conformation (S = 0.82, θ = 65.0°, Ψ = 10.0°). The central N (1) C (4) C (5) C (6) C (7) C (8) ring in molecule A has close to half-boat conformation (S = 0.71, θ = 53.2°, Ψ = 24.2°), while this ring in molecule B has a conformation intermediate between half-boat and half-chair (S = 0.77, θ = 64.8°, Ψ = 15.7°). Furthermore, the arrangement of the endocyclic substituents differs significantly. Thus, __________________________________________________________________________________________