Perhydropyrido thiazin-4-ones

A molecular mechanics prediction of the conformation of trans-%,9a-V - ,-phenyl-perhydropyrido[2,l-Z)][l,3]thiazin-6-one gave similar data as NMR experiments (00BAP19). 

Hydroxy group of rru -7,9u-H-7-(prepared from 7-formyl-2-(2-pyrimidyl)perhydropyrido[l,2-u]pyrazine by the treatment with MeOCH2P(Ph)3Cl in the presence of -Pr2NH in THF at 0°C, than with BuLi at room temperature (99MIP6). 

Oxidation of 6-oxopyrido[2,l-h][l,3]thiazine-4,9-dicarboxylates (85 n = 0, R = H, phthalamido) with 1 mol eq of 3-chloroperoxybenzoic acid yielded sulfoxides (85 n = 1, R = H, phthalamido) [83JCS(CC)199 92JCS(P1)621]. Oxidation of 2,3,4,6,7,llh-hexahydro[l,3]thiazino[2,3-a]-isoquinolin-4-ones with 3-chloroperoxybenzoic acid in dichloromethane gave sulfones (69FRP1552211). The appropriate sulfone was also prepared from perhydropyrido[2,l-h][l,3]thiazine (59AP165) and 3,4,7,8, 9,10-hexahydro-2//,6//-[ 1,3]thiazino[3,2-h] isoquinolin-6-one [79JAP(K)79/ 92996 81USP4284778]. 

Treatment of traras-8,9a-H-8-(2-methoxyphenyl)perhydropyrido[2,1-6][l,3]thiazin-6-one with 2.5 equiv of HSnBu3 in the presence of AIBN in boiling benzene for 1.5 h yielded 4-(2-methoxyphenyl)-l-[3-(tributylstan-nylthio)propyl]piperidin-2-one (01S13 5). 

Perhydropyrido[2,l-c][l,4]-thiazine-4,4-diphosphoric acid was prepared from its 4-one derivative by treatment with H3PO4, then PC13 at 100°C, followed by addition of H20 (88GEP3719513). 

AP(292)165]. Cyclization of ethyl 2-(2-piperidylmethylthio)acetate on the action of Na in boiling toluene afforded perhydropyrido[2,l-c][l,4]-thiazin-4-one [720MR(4)283], Ethyl 6-oxoperhydropyrido[2,l-c][l,4]thi-azine-4-carboxylate was obtained by cyclization of methyl 4-(5-ethoxycar-bonyl-l,4-thiazin-3-yl)butyrate in boiling toluene in the presence of (15)-(+)-10-camphorsulfonic acid [96MIP8]. 

Conformational analysis demonstrated that the predominant conformation of the cij-l,4a-H-l-phenyl, cis- and /ran5-3,4a-H-3-methyl, trans-4a,5-H-5-methyl, m-4a,8-H-8-methyl, and trans-4a,7-H-7-ethy derivatives of perhydropyrido[l,2-c][l,3]thiazine is the tram-fused one, whereas for the cw-4a,5-H-5-methyl and ds-4a,7-H-7-methyl derivatives it is the S-inside cw-fused conformation [70T3941 82OMR(20)239]. The chemical shift differences (1.13 and 0.49 ppm) between the C-8 methylene protons of trans-4a,7-H-7-ethyl- and cis-4a,7-H-7-ethylperhydropyrido[l,2-c][l,3]thiazines are in accord with exclusive existence in the tram-fused and in the cis-fused ring conformations, respectively [82OMR(20)239]. 

Differences between the stereochemistry of perhydropyrido[l,2-c] [l,3]thiazines and that of the closely related perhydropyrido[l,2-c][l,3] oxazines are expected to arise principally from the long C —S bond (181 pm) as compared with the C—O bond length of 141 pm, and also from differences in bond angles and in torsional interactions involving the heteroatoms. The longer C—S bonds in perhydropyrido[l,2-c][l,3]thiazine result in a lower interaction in the S-inside cis-fused conformer in comparison with the O analog, which increases the contribution of the S-inside cis-fused conformer to the equilibrium. The predominant conformation of perhydropyrido[l,2-c][l,3]thiazine (20, X = S) is the frans-fused one (Scheme 5) (70T3941). 

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