4-Phenylperhydropyrido oxazines

Perhydro derivatives of pyrido[l,2-7)][l,2]oxazines are frequently applied in the total synthesis of various alkaloids to control the stereochemistry, and pyrido[l,2-c][l,3]oxazines and [l,3]oxazino[3,4-u]quinolines were also used in the stereoselective syntheses of different alkaloids. Perhydropyrido[l,2-c][l,3]oxazines and their benzologs are formed form 2-(2-hydroxyethyl) piperidines and from their benzologs to justify the stereochemistry of 2-(2-hydroxyethyl) derivatives. Different optically active pipecolic acids can be prepared via 4-phenylperhydropyrido[2,l-c][l,4]oxazin-l-ones. 

Irradiation of 4-(3-benzoylpropionyl)-1,4-morpholine (267) yielded an epimeric mixture of 9-hydroxy-9-phenylperhydropyrido[2,l-c][l,4]oxazin-6-ones 268 and 269 via hydrogen abstraction from the position 3 of the morpholine moiety of 267 (98T2529). It was assumed that the steric hinderance between the phenyl group and the hydrogen atoms of 5-methylene group of 267 in the biradicals contributed to the observed selectivity. 

A single stereoisomer of 4-methyl-3-phenylperhydropyrido[2,l-c][l,4]oxa-zine 279, containing a fused bicycle, was obtained by the cyclization of l-(2-hydroxyethyl)-2-piperidinemethanol 235 in CH2CI2 on the action of cone. H2SO4 (97JHC1813). Similarly, l-phenylperhydropyrido[2,l-c][l,4] oxazine 281 was obtained from l-(2-hydroxyethyl)-2-[(phenyl)hydroxy-methyljpiperidine 280. 

Treatment of 3-phenylperhydro[l, 3]oxazolo[3,2-a]pyridine-5-carboxylates 303 and 304 with BF3 Et20 in THE, followed by reduction with NaBD4 afforded 6-deutero-4-phenylperhydropyrido[2,1 -c][l, 4]oxazin-1 -ones 220 and 222 (97JA6446). 

Reaction of 40% glioxal with silylated compounds 308 (97SL799, 99SL1094, OOJOC4435) and 310 (97SL799) gave a diastereomeric mixture of l-hydroxy-4-phenylperhydropyrido[2,l-c][l,4]oxazines 309 and 311, respectively. Similarly, diastereomeric mixtures of 8-substituted l-hydroxy-4-phenylperhydropyrido[2,l-c][l,4]oxazines were prepared (01EJOC2385). 

A single isomer of 4-phenylperhydropyrido[2,l-c][l,4]oxazin-l-one 319 was isolated from a reaction mixture of 2-bromocyclohexane and 2-azido-2-phenylethanol. The formation of 319 was deduced from azepino[l,2-i]... 

Treatment of 3-phenylperhydropyrido[ 1,2-/ 1,3 oxazin-l -one with LAH gave a 1 9.5 mixture of 3-phenylphenylper-hydropyrido[l,2-c][l,3]oxazine and l-methyl-2-(2-phenyl-2-hydroxyethyl)piperidine <20050BC520>. Reduction of ds- >,4a- I-/ra .v-8-H-3-incthyl-8-pentyIperhydropyrido[ 1 1,3 oxazin-6-onc with NaBH4 at room temperature... 

Treatment of tert-butyl (2/. )-2-(2-propcny lidene (piperidine-1-carboxylate with McjSil and PhOH yielded 3-substituted-3,4,7,8-tetrahydro-l//,6//-pyrido[l,2-c][l,3]oxazin-l-ones <2005T1595>. Reaction of l-(benzoxycarbonyl)2-styrylpiperidin-4-one with I2 resulted in the formation of r-3,4a-//-/ra r-4-//-4-iodo-3-phenylperhydropyrido[l,2-d-[l,3]oxazine-l,6-dione <2002JOC1972>. A diastereomeric mixture of 3-iodomethylperhydropyrido[ 1,2 z [ 1,3]oxazin-l-ones (e.g., 178) was obtained by intramolecular iodocarbamation of l-(alkoxycarbonyl)-2-allylpiperidines (e.g., 177) with I2 (Equation 34) <1999JOC8402, 2002OL3459>. 

Mild acidic hydrolysis of amino nitrile 369 gave m-4,9a-/7-rra r-9-7/-9-benzyloxy-4-phenyl-3,4,9,9a-tetrahydro-17/,67/-pyrido[2,l-d[l,4]oxazin-l-one <1996TL4001>. (2A)-2-Cyano-l-[(lR)-2-hydroxy-l-phenylethyl]piperidin-6-one, on standing for 20 days in ethanol saturated with HC1 gas, afforded (4/ ,9aA)-4-phenylperhydropyrido[l,2-4[l,4]oxazine-l,6-dione, which was sometimes accompanied by the unstable (26 )-l-[(l/ )-2-hydroxy-l-phenylethyl]-... 

Reduction of 6,8-diazabicyclo[3,2,l]oct-6-enes 411, prepared from 410 with alkyl- or phenyllithium, with NaBH3CN gave 1-amino-l-substituted 4-phenylperhydropyrido[2,l-f][l,4]oxazines 412 (Equation 76) <1996JOC6700>. The 1-methyl derivative of 412 (R1 = Me) was accompanied by 10% of the C-l epimer. A 3 7 mixture of 4-phenylperhy-dropyrido[2,l-r ][l,4]oxazin-l-one was obtained from 410 by treatment with HC1 in the presence of Si02, then with Zn(BH4)2 <2003JOC1401>. 

The 3-methyl- and 3-phenylperhydropyrido[l,2-c][l,3]oxazines all adopt the trans-fused conformation (274—277).135 The two 4-methyl derivatives 278 and 279 also adopt the trans conformation (Jgem — 7.8 Hz in both isomers) but 279 shows an enhanced Aae (0.87 ppm) (cf. 0.59 ppm in 278) which cannot be due to changes in cis trans conformational equilibria.279... 

The relative configuration of the 2-phenyl group in trans-fused cis-2,9a-H-2(5)-phenylperhydropyrido[2,l-h][l,3]oxazine was established in NOE experiments (94TL1715). The cis isomer 23 could be equilibrated with the trans isomer 22 in the presence of triethylamine in CDC13 at 80°C (94JA2617). 

Optically active pipecolic acids, and their 2-substituted derivatives were prepared by the catalytic hydrogenation of the respective optically active 4-phenylperhydropyrido[2,l-c][l,4]oxazin-l-ones and their 9a-substituted derivatives over Pearlman s catalyst in good yields (05TA3858). 

The epimerization of (4R,9aR)-4-phenylperhydropyrido[2,l-c][l,4]oxazin-1-one at C9a carbon could be achieved by treatment with KN(SiMe3)2 in THF at 78 °C for 30 min to yield effectively the (4R,9aS) epimer (05TA3858). NaN(SiMe3)2 and LiN Pr2 proved to be less appropriate than KN(SiMe3)2, as they gave only 10% and 50% conversion, respectively. 9a-Substituted derivatives were obtained by alkylation of (4R,9flR)-4-phenyl-perhydropyrido[2,l-c][l,4]oxazin-l-one with alkyl iodides, allyl and benzyl bromides in THF in the presence of KN(SiMe3)2/ and HMPA at —78 °C for 1.5 h in 61-83% yields. 

THF at room temperature for 220 min to give 4-phenylperhydropyrido [2,1 -c][1,4Joxazin-6-one (07USA2007/0117839). Reduction of ethyl 1-[1-aryl-2-hydroxyethyl]-6-oxopipeperidine-2-carboxylates with NaBH4 in MeOH at 0 °C for 80-100-min-yielded l-hydroxy-4-arylperhydropyrido [2,1 -c] [ 1,4] oxazin-6-ones. 

Alkoxy-3-phenylperhydropyrido[2,l-c][l,4]oxazines were formed from the 3-hydroxy derivative 25 (R = OH) in boiling alcohols via an intermediate carbenium-oxonium ion, stabilized by the 3-phenyl group [78JMC460 90AP(323)53],... 

Cyclization of methyl 4-(c/s-3,5-H-2-oxomorpholin-5-yl)butyrate in boiling toluene provided c/s-4,9a-H-4-phenylperhydropyrido[2,l-c][l,4]ox-azine-3,6-dione [95H(41)1931], Heating l,4-oxazin-2-one 163 afforded [l,4]oxazino[4,3-a]quinoline-4,6-dione 164 (94IZV299, 94JFC119). The reaction of carboxylic acid 165 with l.l -carbonyldiimidazole in the presence of 4-methylmorpholine afforded pyrido[2,l-c][l,4]oxazin-4-one (61)... 

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