Perhydropyrido benzoxazines

Enantiopure (7 )-3-alkylpiperidines (38, R = Me, Et) were obtained when perhydropyrido[2,l-Z)][l,3]benzoxazin-9-ones (37, R = H, Me) were treated first with an excess of AIH3, then with PCC, followed by a 2.5 N solution of KOH (99TL2421). Treatment of optically active perhydropyr-ido[2,l-Z)][l,3]benzoxazines 39 and 40 with LAH in the presence of AICI3 and DIBALH (if R = COOEt) yielded 3-substituted piperidines 41 (00TA2809). 

Radical cyclization of perhydro-l,3-benzoxazines 64, promoted by Bu4SuH in the presence of AIBN gave a mixture of perhydropyrido[2,l-6][1,3]benzoxazin-9-ones 65 and 66 and seven membered tricyclic derivatives 67 and 68, formed in a 6-exo and 7-endo cyclization process, respectively (99TL2421). Cyclization of parent acrylamide 64 (R = R = H) occured with moderate regioselectivity (6-exo/7-endo ratio 65 35) and poor stereoselectivity (65/66 ratio 42 43). The presence of a /3-methyl group in... 

Diastereoseleetive 6-exo-trig radieal eyelization of (-)-perhydro-l,3-benzoxazines 69, 71, 74 with Bu3SnH and AIBN gave a diastereomerie mixture of perhydropyrido[2,l-Z)][l,3]-benzoxazines 39, 70, and 72, 73, and 40, 75, respeetively (00TA2809). 

Chiral 3-alkylpiperidines were prepared through perhydropyrido[2,I-Z)][],3]benzoxazines (99TL242I, 00TA2809). 5u-Pentyl-5u,6,7,8,9,H-hexa-hydropyrido[2,I-Z ][l,3]benzoxazin-9-ones 31, 33 (R CsHn) and 34 were used in the total synthesis of racemic and natural (—)-(R) forms of adalinine alkaloid (99SL37, 99TL739). 

Radical cyclization of perhydro-l,3-benzoxazines 518, promoted by Bu vSnI I in the presence of 2,2 -azobis(2-methylpro-pionitrile) (AIBN) gave a mixture of perhydropyrido[2,T ][l,3]benzoxazin-9-ones 519 and 520 and the seven-membered tricyclic derivatives 521 and 522, formed by a 6-exo- and a 7-rwr/o-cyclization process, respectively (Scheme 54) < 1999TL2421 >. Cyclization of parent acrylamide 518 (R = R1 = H) occurred with moderate regioselectivity (()-exo/7-endo ratio = 65 35) and poor stereoselectivity (519/520 ratio = 42 43). The presence of a [1-methyl group in crotylamide 518 (R = Me, R1 = H) disfavored the 7-/w/ -cyclization process, but did not influence the stereoselectivity of the cyclization (519/520 ratio = 66 34). The presence of an a-methyl group in methylacrylamide 518 (R=H, R1 Me) caused a retardation of the 6-oeo-attack, favoring the 7-/w/ -cyclization with a higher stereoselectivity (521/522 ratio = 75 12). 

The H-NMR spectra of perhydropyrido[l,2-c][l,3]oxazines and Bohl-mann-band measurements (Section II,E,1) show the predominance of the trans-fused conformer 265,135 and comparison of -NMR chemical shifts in the locked perhydropyrido[3,2,l-i/][3,l]benzoxazines 269 and 270,45 taken as models for the trans- and cis-fused conformers, indicates 90% 265 in the equilibrium at 25°C (AG° 1.3 kcal mol-1). This is lower than that (AG° 2.6 kcal mol ) for the corresponding quinolizidine equilibrium. This estimate is consistent with the results of dipole moments, which indicate predominantly trans conformer,61 and of a low-temperature H-NMR study of ci s(4a-H,7-H)-7-ethylperhydropyrido[l,2-c][l,3]oxazine (271 272),61... 

The conformations of tri- and tetracyclic compounds containing the per-hydropyrido[l,2-c][l,3]oxazine system have been determined by H-NMR spectroscopy. The four perhydropyrido[3,2,l-i/][3,l]benzoxazines 269, 270, 280, and 281 have been isolated, and the O-outside cis-conformational analog of 266, which has not been observed in the bicyclic series, was shown to possess the same Jtem (—7.5 Hz) for the NCH20 protons as that of the... 

The treatment of 8-hydroxymethylperhydroquinolines 134 with (HCHO) and pTsOH H20 in boiling CHC13 gave perhydropyrido[3,2,l-ij] [3,1 [benzoxazines 135 (09JOC2290, 09OL1515). 

Methiodide and ethiodide salts were prepared from perhydropyrido[2,l-c][l,4]oxazines [58N516 60AP(293)74 63AP(296)38], from 1,3,4,6,7, llh-hexahydro-[l,4]oxazino[3,4-a]isoquinolines (67BRP1094470, 67NEP 6611733 85AJC1591), and from perhydropyrido[l,2,3-de]-l,4-benzoxazine (44HCA1756) with alkyl iodides. 

Conformational analysis of perhydropyrido[l,2-c][l,3]benzoxazines (21-24) (Scheme 6) by a modification of the MM285 force field predicts that the trans conformation of the heterocycles is the most stable for the r-... 

Stereochemically locked all-chair conformations of perhydropyrido [3,2,l-i ][3,l]benzoxazines (25-28) are useful models for the investigation of the conformational equilibria of the mobile perhydropyrido[l,2-... 

Some H NMR Data on Stereochemically Locked Perhydropyrido[3,2,I-i/][1,3]benzoxazines (25-28) in CDCl, at 270 MHz [80JCS(P2)I778]... 

NMR Data of trans and O-inside cis Conformations of Perhydropyrido[1,2-c][1,3]oxazine(20, X = O) in CD2CI2-CFCI3 at 203 (92MRC129) AND Its Hydrochloride Salt in CDCI3 at Room Temperature (88MRC748), and Those of Stereochemically Locked Perhydro[3,2,1-i ][1,3]benzoxazines (25-28) in CDCI3 at Room Temperature (92MRC129) (ppm)... 

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