Perhydropyrido thiazine

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). 

Perhydropyrido[l,2-h][l,2]thiazine-l,1-dioxide was prepared in 70% yield by the cyclization of 2-(3-chlorosulfonylpropyl)piperidine hydrochloride, obtained from 5-[3-(2-piperidyl)propyl]isothiourea dihydrochlorides with chlorine gas, on heating in toluene (62AP615). 

In a radical reaction of 2-iodomethylpiperidine (112) with tributyltin hydride, 2-(3-phenyl-2-propenyl)piperidine (113) and a 1 1 mixture of epi-mers of perhydropyrido[l,2-6][l,2]thiazine-l,1-dioxide (114) were obtained in 18 and 47% yield, respectively (77TL635). An identical mixture of 113 and the two epimers of 114 was also obtained from a 7 4 mixture of the Z and E isomers of 112, indicating that the starting C=C geometry is not maintained in the product 114. 

The nature of the ring fusion in quinolizidine derivatives may be determined from the 15N chemical shifts, which are to lower field in the transfused derivatives. This is shown for the indolo[a]quinolizidines 73 and 74 (chemical shifts to low field of external anhydrous liquid ammonia)115 and by the perhydropyrido[l,2-c][l,3]thiazines 8 66.9 trans conformer 312, 8 43.9 S-inside cis conformer 313.ll5a... 

However, in many other series results have been obtained that are compatible with those from other methods and that gave the dipole-moment method an appearance of general reliability now known to be unjustified. Such compatible results include spiropiperidines (Section III,A,4), tropanes (Section III,B,4), 2-alkyltetrahydro-l,2-oxazines (Section III,C,2), perhydro-pyrido[l,2-c][l,3]oxazines (Section III,D,IX perhydropyrido[l,2-c][l,3]thi-azines (Section III,D,2), dialkylhexahydropyrimidines and perhydropyrido-[l,2-c]pyrimidines (Section III,D,3), 5-alkyldihydro-l,3,5-dithiazines (Section III,G,3), 3,5-dialkyltetrahydro-l,3,5-thiadiazines (Section III,G,4) and, in part, l,2,4,5-tetraalkylhexahydro-l,2,4,5-tetrazines (Section III,H,4) as well as piperidines, tetrahydro-l,3-oxazines, and tetrahydro-l,3-thiazines containing an N-H group. 

Following the trend observed for the oxazine analog 296, the fusion of a benzene ring onto the [/] position of perhydropyrido[l,2-c][l,3]thiazine, as in 1,6,7,116-tetrahydro-2//,4//-[l,3]thiazino[4,3- ]isoquinoline 316, pushes the equilibrium almost exclusively to the S-inside cis conformation 317.284... 

The perhydropyrido[2,l-b][l,3]oxazine skeleton is a constituent part of macrocyclic xestospongine/araguspongine and aragupetrosine alkaloids isolated from different marine sponges. Pyrido[2,l-fo][l,3]oxazines, pyrido[2,l-fc][l,3]thiazines, and [l,3]oxazino[3,4-a]quinolines are also applied as key intermediates in the total syntheses of different alkaloids. Other examples of these ring systems have aroused much interest owing to their valuable pharmacological properties. 

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). 

Perhydropyrido[2,l-c][l,4]thiazine was prepared when 2-[(2-hydroxy-ethylthio)methyl]piperidine was treated with HBr in AcOH, and the evaporated reaction mixture was treated with NaOEt in EtOH [57N559 ... 

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]. 

Perhydropyrido[2,l-c][l,4]thiazine was prepared in the reaction of 1-(2-chloroethyl)-2-chloromethylpiperidine and Na2S (H20)9 in boiling aqueous EtOH (59CB1510). Cyclization of ethyl 7-substituted 6,8-difluoro-... 

Interatomic Distance (pm) and Bond Angles (°) in Two Hetero-Atom-Containing Rings of 1-(4-Bromophenyl) Derivative of Perhydropyrido[1,2-c][1,3]oxazine AND Perhydropyrido[1.2-c][13]thiazine (20, X = O, S) with ESD in Parentheses (73MI1, 73MI2)... 

The dipole moment of perhydropyrido[l,2-c][l,3]thiazine (20, X = S) was calculated from measurements in benzene at 25 C [76JCS(P2)418], These investigations indicated that perhydropyrido[l,2-c][l,3]thiazine exists as an 80 20 equilibrium mixture of the franj-fused and S-inside cis-fused conformers, the S-outside ds-fused conformer contributing only 1% to the equilibrium (Scheme 5). 

Pronounced Bohlmann bands in the region 2800-2600 cm of the IR spectra of perhydropyrido[l,2-c][l,3]thiazine and its ds-l,4fl-H-l-phenyl, cis- and franj-3,4a-H-3-methyl, trani-4a,5-H-5-methyl, d5-4a,8-H-8-methyl, di-l,4a-H-fram-5-H-5-methyl-l-phenyl, and trans-4a,7-H-7-ethyl derivatives indicate the predominance of the fram-fused conformation [70T3941 82OMR(20)239]. The absence of marked absorbance in the same region... 

S) and its trans- and ciy-4a,7-H-7-ethyl derivatives indicated that trans-4a,7-H-7-ethylperhydropyrido[l,2-c][l,3]thiazine and the ds-4a,7-H-7-ethyl analog exist exclusively in the rrans-fused and the S-inside cis-fused conformation, respectively, containing the ethyl group in the equatorial positions, whereas the parent perhydropyrido[l,2-c][l,3]thiazine in CDCI3 at 25°C is a ca. 25 75 mixture of the S-inside c/s-fused and tra/u-fused conformations. At -75°C, where the interconversion is slow in a 1 1 mixture of CS2 and THF-dg, the signals of both conformers of perhydropyrido[l,2-c][l,3] thiazine can be detected. The NMR spectrum shows the presence of 64% of the frans-fused and 36% of the S-inside cis-fused conformer [82OMR(20)239]. 

The reactions of 2-(2-mercaptoethyl)piperidines and aldehydes afforded perhydropyrido[l,2-c][l,3]thiazines [70T3941 82OMR(20)239]. In an exothermic reaction, l-(2-mercaptoethyl)-l,2,3,4-tetrahydroisoquinoline and 40% aqueous formaldehyde yielded l,2,4,6,7,llZ)-hexahydro[l,3] thiazino[4,3-fl]isoquinoline [77JCS(P2)370], The similar reaction with 4-nitrobenzaldehyde in boiling benzene furnished the c -4,llb-H-l-(4-nitrophenyl) derivative [760MR(8)258]. 

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