4- perhydropyrido oxazines, reaction with

The reaction of m-fused perhydropyrido[2,l-6][l,3]oxazines (31) with diethyl cyanophosphonate in the presence of a catalytic amount of ZnCl2 or ZnBr2 provided 2-cyanopiperidines (32) [88H(27)1575 91SL44, 91SL878]. 

Catalytic reduction of compound 467 over Pd(OH)2/C catalyst in MeOH for 1 h, then reaction with L-lysine derivative 468 for 24 h gave an inseparable mixture of perhydropyrido[2,l-c][l,4]oxazin-3-one 215 and piperidine 469 (08BMC10216). 

Reaction of (25,55)- and (2i ,55)-2-[5-(terc-butyldimethylsilyloxy)piper-idin-2-yl]ethanols with phenylglyoxal monohydrate in the presence of 4 A molecular sieves in boiling CH2CI2 overnight gave (15,4n5,7i )- and (2i ,4ni ,7i )-l-benzoyl-7-(terc-butyldimethylsilyloxy)perhydropyrido[l,2-c][l,3]oxazines 97 and 100, respectively, in good yield (99MI19). Both products were accompanied by unidentified minor isomers. 

Reaction of 3-(3-bromopropy])-3-(4-biphenyl)perhydropyrido[l,2-c][l,4]oxazine with AgN03 in a boiling solvent yielded 3-[(4-biphenyl)per-hydropyrido[l,2-c][],4]oxazin-3-yl]propyl nitrate (00MI9). 

Phenyl-9-(2-propoxycarbonylamino)perhydropyrido[2,l-c][l,4]oxazin-1-one was prepared from methyl 4 phenyl-l-oxoperhydropyrido[2, l-c][l,4]oxazine-9-carboxylate (98MIP12). First, the methyl ester was hydrolyzed into 9-carboxylic acid by heating in 6N HCl, then the carboxylic acid was reacted with (Ph0)2P(0)N3 in benzene in the presence of NEt3 at 22 °C for 45 min, then at reflux for 50 min. After addition of -PrOH the reaction mixture was boiled for 20 h to yield a 9-(iso-propoxycarbonylamino) derivative. 

Reaction of ot-diazoester 413 with several copper carboxylate catalysts afforded azocyclooctene 414 along with perhydropyrido[2,l-r ][l,4]oxazin-l-one 415 (Equation 77) <1996TL2165>. 

Hydrogenation of 4-cyano-4-(methoxymethoxy)butyrate in the presence of HO(CH2)2NH2 and (CH2NH2)2 over a Pd/C catalyst gave a mixture of diastereomers of 9-(methoxymethyl)perhydropyrido[2,l-A [l,3]oxazin-6-ones and 5-(methoxymethyl)-l-(3-hydroxypropyl)piperid-2-one, and furthermore a diastereomeric mixture of 9-(methoxy-methyl)perhydropyrido[l,2- ]pyrimidin-6-ones <2003ASC483>. Reaction of 535 with TsOH in the presence of H20, followed by treatment with saturated aqueous NaHC03, yielded a mixture of 536 and 537 (Equation 90) <1995JOC2989>. 

Reaction of 4-aryl-3,4,6,7,8,9-hexahydro- and -perhydropyrido[2,l-c] [l,4]oxazin-6-ones with ( Pr)2NLi in THF at 0 °C, then with 3-methoxy-4-(4-methyl-l H-imidazol-1 -yl)benzaldehide afforded 7-( [3-methoxy-4-(4-methyl-1 H-imidazol-1 -yl)phenyl] hydroxymethyl derivatives, which were dehydrated by treatment first with MeSC Cl and NEt3, then with a solution of NaOMe in MeOH to provide (E)-7- [3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]methylene -4-aryl-3,4,6,7,8,9-hexahydro- and -perhydropyrido[2,l-c][l,4]oxazin-6-ones (07USA2007/0117859). 

Reaction of 4-aryl-7-iodoperhydropyrido]2,l-c][l,4]oxazin-6-ones (07USA2007/0117839, 08WOP2008/013213) and 7-iodo-6-oxo-4-(3,4,5-tri-fluorophenyl)perhydropyrido[2,l-a]pyrazine-2-carboxylate (07USA2007/ 0117839) with P(OEt)3 at 120 °C for 2 h afforded 7-phosphonic acid diethyl esters. 3-Hydroxy-6-arylperhydropyrido[2,l-c][l,4]oxazin-4-ones first were reacted with triphenylphosphonium bromide in refluxing MeCN, then with 3-methoxy-4-(4-methyl-lH-imidazol-l-yl)benzaldehyde at ambient temperature in the presence of NEt3 to provide (Z)-3- l-[3-methoxy-4-(4-methyl-lH-imidazol-l-yl)phenyl]methylidene] derivatives (07USA2007/ 0117798, 08USA2008 /0207900). 

The reaction of 1,3-disubstituted perhydropyrido[l,2-c][l,3]oxazines (69) and 7-(benzothiazol-l-yl)-6,7-dihydro-17/,3//,5//-pyrido[3,2,l-iy][3,l]benz-oxazine with Grignard reagents led to 2-(/V-substituted 2-piperidyl)ethanols (70) (50JA358 58CLY2081) and l-benzyl-4-(benzotriazol-l-yl)-8-hydroxy-methyl-l,2,3,4-tetrahydroquinoline (95JOC3993), respectively. 

Perhydropyrido[l,2-c][l,3]oxazin-l-ones were prepared in the reaction of the appropriate 2-(2-piperidyl)ethanols and ethyl chloroformate (63AP38) in the presence of sodium ethylate in boiling benzene, or when 2-(2-piperidyl)ethanol was reacted with dimethyl carbonate in the presence of sodium methylate (91X1311). l-Hydroxymethyl-9,10-dimethoxy-l,2,4,6,7,llb-hexahydro-[l,3]oxazino[4,3-fl]isoquinoline-4-oneand 4-thione were prepared from l-[bis(hydroxymethyl)methyl]-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline with ethyl chloroformate in the presence of sodium methylate, and thiophosgene in the presence of NEts, respectively... 

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