6.7.8.9- Tetrahydro-11 -oxo-pyrido

Vilsmeier-Haack formylation of 2-(4-methyl-l-piperazinyl)-4//-pyrido-[l,2-n]pyrimidin-4-one with a mixture of POCI3 and DMF at 95°C gave a 3-formyl derivative (93FES1225) while ethyl 4-oxo-6,7,8, 9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-2-acetate at 50 °C yielded a 9-dimethylaminomethylene-3-formyl derivative (01MI4). 3-Formyl-2-hydroxy-8-[2-(4-isopropyl-l,3-thiazol-2-yl)-l-ethenyl]-4//-pyrido[l,2-n]pyri-midin-4-one was obtained from the 3-unsubstituted derivative with oxalyl chloride-DMF reagent in CH2CI2 at room temperature for 3h (OlMIPl). 

Reaction of l-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimi-din-l-ium-2-olate (148) with tetracyanoethylene afforded 3-substituted derivative 149 (95H(40)681). 

The A-substituted derivatives of 4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxamides and -3-acetamides and l,6-dimethyl-4-oxo-1,6,7,8-tetrahy-dro-4//-pyrido[l,2-n]pyrimidine-3-carboxamide were prepared by treatment of the appropriate 3-carboxylic acids and acetic acid, first with an alkyl chloroformate in the presence ofNEt3 in CHCI3 below — 10°C, then with an amine (98ACH515). A-Phenethyl and A-[2-(3,4-dimethoxyphenyl)ethyl] derivatives of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetamide were obtained in the reaction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-3-acetic acid and phenethylamines in boiling xylene under a H2O separator. Hydrazides of 4-oxo-4//- and 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic acid were prepared from the appropriate ester with H2NNH2 H2O in EtOH. Heating 4-oxo-4//- and 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic hydrazides in EtOH in the presence of excess Raney Ni afforded fhe appropriafe 4-oxo-6,7,8,9-fefrahydro-4//-pyrido[l,2-n]pyrimidine-3-acefa-mide. In the case of the 4-oxo-4// derivative, in addition to N-N bond... 

Meszaros, Hermecz et al. transformed the quaternary 6,7.8,9-tetrahydro-pyrido[1.2-u]pyrimidinium salts (204) with acid to the carboxylic acids (205 R1 = H)257 and with sodium hydrogen carbonate solution to the l,6,7,8-tetrahydropyrido[l,2- ]pyrimidines (205 R = alkyl).7x2 8 From the alkaline hydrolysis reaction mixture, compounds 206 and 207 were also isolated.133 The quaternary salt (204 R = Me) was transformed with hydrazine hydrate to 6-methylpiperidone and with ammonia to 6-methyl-4-oxo-6.7,8,9-tetrahydro-4//-pyrido[1.2- ]pyrimidine-3-carboxamide and its A-methyl derivative.133... 

With aromatic and heteroaromatic aldehydes,193 4-oxo-6,7,8,9-tetra-hydro-4T/-pyrido[l,2-a]pyrimidines yielded the 9-arylmethylene derivatives,133,266 whereas with glyoxylic acid the 9-carboxymethylene derivative was formed.266,267 The primary addition product (237) could be isolated from the reaction mixture of ethyl 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidine-3-carboxylate and benzaldehyde. On dehydration the addition product (237) gave the 9-benzylidene compound.266 The 9-carboxymethylene derivatives may be transformed by catalytic hydrogenation to the 9-acetic acids, which can be esterified.266,267... 

Depending on the work-up conditions, Vilsmeier-Haack formylation of 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidines gave various 9-sub-stituted pyrido[l,2-a]pyrimidines (240 -242).284,319 The 9-aminomethylene derivatives (240) were transformed by hydrolysis in 0.5 N hydrochloric acid to the 9-formyl compounds (241 R3 = H), by ethanolic hydrogen chloride to... 

Conformational analysis of 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidine-3-acetates and -3-carboxylates 30 (R = H) and their mono-methylated (R = Me, R1 = H) and 6,9-, 7,9-, and 8,9-dimethylated derivatives were carried out by H and l3C NMR spectroscopy (86JOC394). At ambient temperature the 6-methyl derivatives predominantly adopt the energetically most favorable half-chair conformation with a pseudoaxial methyl group. In the other half-chair conformation a serious 1-3 allylic strain exists between the pseudoequatorial methyl group and the adjacent carbonyl group. At the 7- and 8-methyl derivatives the half-chair conformations with equatorial methyl group occur almost exclusively, but the 9-... 

Hydroxyimino-6,7,8,9-tetrahydro-4//-pyrido[ 1,2-a]pyrimidin-4-ones 532 were obtained when 6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidin-4-ones 531 reacted with sodium nitrite in aqueous hydrochloric acid at 0°C or in aqueous sulfuric acid first at 60°C, then at 80°C (if R1 = NH2) (83JMC1494). The hydroxy group of 9-hydroxyimino-6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[ 1,2-a]pyrimidine-3-carboxylate 533 (R = Me)... 

A 1,4-dipolar cycloaddition between tetrahydropyrido[l,2-a]pyrimidi-none 114 (R = Me) and 4-methyl-l, 2,4-triazoline-3,5-dione 666gave stable adduct 667 in acetonitrile or in acetic acid at room temperature for 1 hour (Scheme 44) (85CB4567). When ethyl cyanoformate was used as dienophile in boiling toluene for 20 hours, ethyl 3-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[ 1,2-a]pyrimidine-2-carboxylate 669 was obtained (86CB1445). Pyrido[l,2-a]pyrimidine-2-carboxylate 669 was formed from the initial adduct 668 by elimination of phenyl isocyanate. Reaction of tetrahydropyr-ido[l,2-a]pyrimidinone 114 (R = Me) with l-(diethylamino)-l-propyne in... 

Attempts to reduce the quaternary salts of 4-oxo-4//-pyrido[l,2-a]-pyrimidines with sodium borohydride or lithium aluminum hydride remained unsuccessful. At the same time the 6,7,8,9-tetrahydro quaternary salts may readily be reduced with sodium borohydride to the 1-alkyl-1,6,7,8,9,9a-hexahydro derivatives. " Sodium borohydride reduction of the 1,6- and 1,7-dimethyl-3-carbamoyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyrimidinium salts proceeds stereoselectively and yields the thermodynamically controlled product. The l-methyl-3-carbamoyl-4-oxo-l,6,7,8,9,9a-hexahydropyrido[l,2-a]pyrimidines were also prepared by the catalytic (Pd/C) hydrogenation of the 1,6,7,8-tetrahydro deriva-tives, ° but this reaction led to a diastereoisomeric mixture. ... 

If the reaction of 9-halo-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l,2-a]pyri-midines and amines was carried out in the absence of air, the 9-amino-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidines were isolated, which could be oxidized by air to the 6,7-dihydro analogs. The latter were directly prepared from 9,9-dihalo-4-oxo-6,7,8,9-tetrahydro- or 9-hydroxy-4-oxo-6,7-dihydro-4/f-pyrido[l,2-a]pyrimidines ° with amines. 

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