Perhydropyrido pyrazines reactions

The 7-(2-oxoethyl) derivative was prepared from 7-formyl-2-(2-pyrimidyl)perhydropyrido[l,2- ]pyrazine by the treatment with MeOCHzP(Ph)3Cl in the presence of Pr 2NH in THF at 0°C, then with BuLi at room temperature < 1999WO99/020622>. Reaction of a 7-mesyloxymethyl group in perhydropyrido[l,2-tf Ipyrazine with NaCN in DMF at 110°C gave a 7-cyanomethyl derivative, which was converted into a 2-oxoethyl group by treatment first with DIBAL-H, then with 2M HC1. The 2-oxoethyl group was reacted with 4-FC6H4MgBr in THF at — 10°C to yield a... 

Perhydropyrido[l,2- ]pyrazin-l-one was prepared in the reaction of methyl pipecolinate and ethylene imine in boiling EtOH <19951JSP5461047>. Cyclocondensation of ethyl 2-amino-2-(2-pyridyl)acetate with DMAD, followed by treatment of reaction mixture with NaOMe, gave the 2-(l-methoxycarbonyl)-4-oxo-47/-pyrido[l,2- ]pyrazin-3-yl)acetate <1996JHC639>. 

Cyclocondensation of 2-aminomethylpiperidine 395 and (C02Me)2 yielded perhydropyrido[l,2-tf]pyrazine-3,4-dione 396 (Equation 73) <2000T1005>. Reaction of a 2-(tosylamino)methylpyridine with (CH2Br)2 afforded a... 

Reactions of perhydropyrido[l,2-flJpyrazine with aldehydes in the presence of NaB(OAc)3H and NaBH3CN in AcOH (05USA2005/ 0282811) and in acidified EtOH (07USA2007/0117839) afforded 2-substi-tuted derivatives. 2-(l-Diphenylmethylazetidin-3-yl) derivative was obtained in the reaction of perhydropyrido[l,2-a]pyrazine and diphenyl-methyl-3-azetidin-3-one in the presence of (polystyrylmethyl) trimethy-lammonium cyanoborohydride in MeOH containing 10% AcOH at 120 °C for 5 min under microwave irradiation (06WOP2006/137791). 

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). 

Reaction of cis-6H,9aH-2-(ferf-butoxycarbonyl)perhydropyrido[l,2-fl] pyrazine-6-aldehyde with ylide, formed from (3-chlorobenzyl)(triphe-nyl)phosphonium bromide with BuLi, furnished 6-[(E)-2-(3-chlorophe-nyl)vinyl] derivative (07USA2007/037817). The treatment of cis-6H,9aH-... 

The Mitsunobu reaction of perhydropyrido[l,2-a]pyrazine-l,4-dione 230 at ambient temperature gave dehydrated product 231 in 15% yield. When the reaction was carried out with excess PBu3 and diethyl azodicar-boxylate at 40 °C the incipient 231 spontaneously underwent enolization and tautomerization, [4+2] aza-Diels-Alder reaction to provide a 2.4 1 mixture of diastereomers 232 and 233 (07T6124). No reaction occurred when isolated 231 was treated under similar conditions. 

Perhydropyrido[l,2-fl]pyrazin-l-one N-oxide 167 was formed from 1-hydroxypipecolic acid amide 261 by reverse Cope elimination by heating in CHCI3. Similar reaction of 1-hydroxypipecolinate 262 resulted an 1 5 30 equilibrium mixture of 262, 263, and 264 (07TL1683). 

The reaction of 2-benzoylmethyl-3,5,6,7-tetrahydropyrido[l,2,3-de]-quinoxalin-3-ones with H2NNH2 and subsequent cyclization of the reaction products in AcOH gave tetracyclic compounds 133 [78KFZ(7)89], Heating l-oxo-3-hydroxy-2-[2-(3-indoyl)ethyl]perhydropyrido[l,2-a]-pyrazine and the isomeric l-hydroxy-3-oxo derivative in cone. HC1 gave a mixture of cis and trans pentacyclic derivatives 134 and 135 (91T1065). 

Reaction of 2-(benzisoxazol-3-yl)-7-[2-(3,3-tetramethylenegluta-rimido)ethyl]perhydropyrido[l,2- ]pyrazine with sodium bis(trimethyl-silyl)amide in THF at -70°, then with (+)-(camphorsulfonyl)oxaziridine gave a diastereomeric mixture of 7-[2-(2fl-hydroxy-3,3-tetramethyleneglu-trimido)ethyl] derivatives (93MIP1). 

Benzylperhydropyrido[l,2-a]pyrazin-6-one was prepared through the cyclization of 287, obtained from 285 via 286 (93JOC690). From the reaction mixture of 2,3-di(2-tetrahydrofuryl)piperazine, treated with HBr gas in AcOH at 90-95°C, then with KOH, l-(2-tetrahydrofuryl)-9-hydroxy-perhydropyrido[l,2-a]pyrazine could be isolated (61BSF2135). Cyclization of 2-(l,2,3,4-tetrahydroxylbutyl)quinoxalines in an acidic media gave 8H-pyrido[l,2-a]quinoxalin-8-ones together with a small amount of their 9-... 

Thionyl chloride has been used to convert the alcohol 56 into the cyclized quaternary salt 57. Reduction of the nitrile 58 with Raney nickel and hydrogen gave the 1-oxo compound 60 (R = H), ° presumably by way of the intermediate 59. This intermediate is also involved in the preparation of compound 60 (R = H) by treatment of the ester 61 with ethyleneimine. The optically active ester 61 has been converted by this route into perhydropyrido[l,2-a]pyrazines of known configuration. When this reaction was repeated with the methyl-substituted piperidine... 

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