3- perhydropyrido pyrimidine

Perhydropyrido[l,2-a]pyrimidin-2-one was A -alkylated with 1,4-dibro-mobutane to yield a 1-(4-bromobutyl) derivative (94MIP6). 6-Methyl-4-oxo-4/f-],6,7,8,9,9a-hexahydro-4//-pyrido[],2-a]pyrimidine-3-carboxylate 138 was alkylated with alkyl chlorides 139 to give 1-substituted derivatives 140 (97MIP2). 

Reaction of perhydropyrido[l, 2-n]pyrimidine with BrCN in the presence of MgO in a 1 1 mixture of CHCI3 and MeOH at 40 °C resulted in the formation of the ten-membered 6-methoxy-3,4,7,8, 9,10-hexahydro-l,5-diazecine-l,5-(2//,6//)-dicarbonitrile. Similar reaction of perhydropyrido[l, 2-n]pyrimidin-2-one led to the nine-membered 6-methoxy-4-oxo-2,3,4,5,6,7,8,9-octahydro-l//-l,5-diazonine-l-carbonitrile (99AJC1131). 

Dehydrogenation of piperidine derivative 329 with Hg(II)-EDTA reagent afforded a mixture of perhydropyrido[l,2-n]pyrimidin-2-one 330 and pyrido[],2-c][],2,5]oxadiazine 331 (99ZN(B)632). 

CO were used only perhydropyrido[l,2-u]pyrimidine (398, R = H) formed from compound 397 (R = H). 

Acidimetric, spectrophotometric and HPLC assays were developed for determination of 2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyrimidine-l,3-diones 135 (98M133). Its solubility properties were also characterized. Resolution of the enantiomers of 4-phenyl-2- 4-[4-(2-pyrimidinyl)piperazi-nyl]butyl perhydropyrido[l,2-c]pyrimidine-l,3-dione was achieved on hep-takis(2-N, V-dimethylcarbamoyl)- 6-cyclodextrines (01 JC(A)249). 

Characteristic H NMR data of (4a/ ,55)- and (4n5,5R)-2-substituted 5- [A-(/e/ /-butoxycarbonyl)-L-tryptophyl]amino perhydropyrido[l,2-c]pyri-midine-l,3-diones were tabulated (01JMC2219). C CPMASS NMR data of 4-(4-methoxyphenyl)perhydropyrido[l,2-c]pyrimidine were reported (00JST73). C NMR data were reported for eight 4-aryl-2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyrimidin-l,3-diones in the solid state and in CDCI3 solution (00JPO213). The structure of 4-aryl-3,4-dihydro-2//-pyrido [l,2-c]pyrimidine-l,3-diones and their 2,3,5,6,7,8-hexahydro derivatives were characterized by H and C NMR data (99JHC389). Conformational analysis of 6-methyl-2,3,4,6,7,ll/)-hexahydro-l//-pyrimido[6,l-n]isoquino-lin-2-ones 138 and 139 were carried out by H and C NMR studies (97LA1165). 

Perhydropyrido[l,2-c]pyrimidine was N-arylated with 6-bromo-l-(2-propyl)indole in the presence of DBU, NaO/-Bu, (/-Bu)3P, and Pd(OAc)2 in boiling xylene (01MIP6). 

Reaction of perhydropyrido[l,2-c]pyrimidin-l-one 149 with Mc2C(OMe)2 in the presence of CSA afforded tricyclic derivative 150 (01JA8851). 

Cyclization of l-(A -substituted aminocarbonyl)-3-[(tert-butoxycarbonyl) amino]- and -3- [Ai -(tert-butoxycarbonyl)tryptophyl]amino -2-(ethoxycar-bonylmethyl)piperidines (e.g. 188) on the action of NaH gave 2-substituted 5-(substituted amino)perhydropyrido[l,2-c]pyrimidine-l,3-diones (e.g. 159 and 189) (97JMC3402, 97MIP16, 98MI63, 0UMC2219). Cyclization could be also carried out in the presence of DBU (01JMC2219). 

Under the circumstance of catalytic hydrogenation of piperidine derivatives 190 in MeOH over Pd/C catalyst afforded an isomeric mixture of perhydropyrido[l,2-c]pyrimidines 174-177 (98TL7021, 00JA5017). The main product was 174 (66%). 

Perhydropyrido[l,2-r]pyrimidin-l,3-ones were applied in the total synthesis of cyanobacterial hepatotoxin 7-epicylindrospermopsin (01JA8851). 

The bromine atom of 4-aryl-2-(4-bromobutyl)-2,3,5,6,7,8-hexahydro-177- ancj -perhydropyrido[l,2-c]pyrimidine-l,3-diones was displaced with 4-substituted piperazines <2002FES959, 2004APH139, 2004PHA99>. Heating 3-hydroxymethyl derivatives of epimeric 6-methyl-l,3,4,6,7,llb-hexahydro-277-pyrimido[6,l-,2]isoquinolin-2-ones 152 resulted in the formation of the 3-unsubstituted derivatives 153 by loss of CH20 (Equation 26) <1997LA1165>. 

JOC3790>, perhydropyrido[l,2-r]pyrimidin-l-ones <2002JA4950, 2005JOC1963>, 1,6,7,1 1 b-tetrahydro-2//,4//-... 

Reduction of 3-benzyl-8-chloro-4-oxo-4//-pyrido[l,2- ]pyrimidine-2-carboxylate <2004W004/064741> and 2-methyl-4-oxo-4//-pyrido[l,2-tf]pyrimidine-3-carboxylate <2003T4123> with DIBAL-H afforded 2- and 3-formyl derivatives, respectively. Reduction of /V-(4-fluorobenzyl)-3-hydroxy-8-[methoxy(methyl)amino]-4-oxo-6,7,8,9-tetra-hydro-4//-pyrido[l,2- ]pyrimidine-2-carboxamide with Zn-dust in aqueous AcOH afforded the 8-methylamino derivative, which was acylated with AcOH in the presence of Hiinig s base, HOBt, and l-(3-dimethylaminopro-pyl)-3-ethylcarbodiimide-HCl <2004W004/058756>. 3-(Perhydropyrido[l,2- ]pyrimidin-2-yl)propylamine was obtained by catalytic hydrogenation of 2-(perhydropyrido[l,2- ]pyrimidin-2-yl)propionitrile over a Pt02 catalyst <2003FRP1275647>. 

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>. 

Rhodium-catalyzed reaction of iV-butenyl-l,3-propanediamines 538 with a mixture of H2 and CO gave a mixture of hydroformylated 539, 540, and carbonylated products 541, 542 in the presence of a phosphine (PPI13, PBU3, P(C6Hn)3, PO-toDj) (Equation 91) <1997T 17449, 1997TL4315>. When the hindered biphosphite, BIPEPHOS, and a 9 1 or 1 1 mixture of H2 and CO were used, only perhydropyrido[l,2- ]pyrimidine 539 (R = H) was formed from 538 (R = H). 

This effect is also shown by comparison of the coupling constants in the perhydropyrido[l,2-c]pyrimidines 35 and 36,65 trans-fused dibenzo-[a,/]quinolizidine (29) (J6ai,6eq — 12.7 Hz),51 and quinolizidine (Jgem — 11.3 Hz).66 The similar coupling constants of the C-l and C-3 methylenes in the... 

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. 

Bohlmann absorption is also characteristic of the trans-fused but not of the cis-fused conformations of the 1,3-heterocyclic systems 87,135 88, ss and 89.136 Bohlmann bands are intense in the trans-syn-lrans-perhydropyrido-[l,2-c 2, l -/]pyrimidine 90,137 and these are markedly reduced in the 6,6-dideutero derivative,138 showing the contribution of the interheteroatomic C-6—Hax to the formation of Bohlmann bands in 1,3-heterocyclic systems. 

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