3.4- Dihydro-2//-pyrimido isoquinoline-2,4-diones

Cyclocondensation of a-aryl-2-pyridylacetamides and 2-(3,4-dihydroiso-quinolin-l-yl)acetamide with Et2C03 in the presence of NaOEt in boiling EtOH afforded 4-aryl-2,3-dihydro-l//-pyrido[l,2-c]pyrimidine-l,3-diones (99JHC389) and 6,7-dihydro-4//-pyrimido[6,1 -a]isoquinoline-2,4-dione (98MIP15), respectively. 

Treatment of pyrimidine-2-thione 184 with A1C13 yielded 6-oxo-6,7-dihydro-4//-pyrimido[6,l-tf]isoquinolin-4-thione 185 (Equation 37) <1998MI337>. Cyclization of 6,7-diethoxy-2-propylaminocarbonyl-l,2,3,4-tetrahydroisoquinoline-l-acetonitrile using NaOMe afforded 9,10-diethoxy-2-imino-3-propyl-l,2,4,6,7,l lb-hexahydropyrimido[6,l-tf]isoquinolin-4-one <1995S863>. Cyclization of l-(2-carboxyethyl)-l,2,3,4-tetrahydroquinazoline-2,4-dione 186 in polyphosphoric acid (PPA) afforded l,2,3,5,6,7-hexahydropyrimido[3,2,T /]quinazoline-l,3,7-trione 187 (Equation 38) <1997CHE96>. 

Reactions of 3,3-diethyl-3,4-dihydro-2//-pyrimido 2,l-a]isoquinoline-2,4-dione (65) with ethanol in the presence of hydrogen chloride and piperidine at 60-70°C afforded ethyl lV-(l-isoquinolyl)-2,2-diethylmalonamate (66) and l-(2-ethylbutyramido)isoquinoline (67), respectively (69YZ649). 

Oxidation of dimethyl l-phenyl-2-oxo-l,2-dihydro-llb//-pyrimido[2,l-a]-isoquinoline-3,4-dicarboxylate (64) by potassium permanganate either in acetone or in aqueous potassium hydroxide, followed by treatment with ethereal diazomethane, gave isocarbostyril and methyl oxanilate, respectively (67CB1094). Oxidation of 4-phenyl-2//-pyrimido[2,l-a]isoquinolin-2-one with potassium permanganate in a 1 5 mixture of pyridine and 2 N potassium hydroxide yielded 2-(2-carboxyphenyl)-6-phenylpyrimidin-4(3//)-one (72CB108). 2-Methyl-4//-pyrimido[2,l-a]isoquinolin-4-one and 3,4-dihydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione with potassium permanganate afforded phthalimide in low yield. 

Catalytic hydrogenation of 3,4-dihydro-2//-pyrimido[2,l-a]isoquinoline-2,4-diones (93) and 3,3-diethyl-9,10-dimethoxy-3,4,6,7-tetrahydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione (94) over Pt02 and Pd/C catalysts gave l,3,4,6,7,llb-hexahydro-2/7-pyrimido[2,l-a]isoquinoline-2,4-diones (95) [69YZ649 71JPP71/09466]. From the mother liquid of compounds 93 (R = H, R1 = Et and R = R1 = Et) 3-ethyl-2-hydroxy-6,7-dihydro-and -8,9,10,1 l-tetrahydro-4//-pyrimido[2,l-a]isoquinolin-4-ones, and 3,3-diethyl-l,3,4,llb-tetrahydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione, also could be isolated as minor products. Reduction of 3,3-diethyl-l,3,4,6,7,llfo-hexahydro-2//-pyrimido[2,l-a]isoquinoline-2,4-dione (95, R = R1 = Et, R2 = H) with LAH in tetrahydrofuran at 70°C for 9 h afforded 3,3-diethyl-l,3,4,6,7,llb-hexahydro-2//-pyrimido[2,l-a]isoquinoline (96). 

The reactions of l-aminocarbonylmethylene-3,4-dihydro- and 1,2,3,4-tetrahydroisoquinolines with lV,lV-dimethylcarboxamide diethyl acetals, triethyl orthoformate, and diethyl carbonate yielded 6,7-dihydro-2//-pyrimido[6,l-a]isoquinolin-2-ones [81KFZ(5)44 82KGS1095 84JMC1470] and 9,10-dimethoxy-3,4,6,7-tetrahydro-2//-pyrimido[6,l-n]isoquinoline-2,4-dione (84JMC1470), respectively. A mixture of l-ethoxycarbonyl-9,10-dimethoxy-3,4,6,7-tetrahydro-27/-pyrimido[6,l-fl]isoquinoline-2,4-dione and l-[cyano(ethoxycarbonyl)methylene]-l,2,3,4-tetrahydroisoquinoline was obtained when 6,7-dimethoxy-l-aminocarbonylmethylene-l,2,3,4-tetrahydroisoquinoline was reacted with ethyl chloroformate in methylene chloride in the presence of pyridine (84JMC1470). 

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