Structure and reactivity of 2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one

It has been shown that the alkylation of 2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one takes place at the oxygen atom, but electrophilic substitution takes place mainly at position 8 of the molecule (the ortho position relative to the hydroxy group).Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1660–1666, December, 1992.     

Potential ambifunctionality of 2-azidopyrido[1,2-a] pyrimidin-4-one

2-Azidopyrido[1,2-a]pyrimidin-4-one can exit only in the azido form and undergoes cyclo-addition reaction with 1,3-dicarbonyl compounds to form 1,2,3-triazole derivatives. Under the influence of bases or hydrochloric acid the carbonyl group is attacked with subsequent opening of the pyrimidine ring. This causes an immediate cyclization of the azide group to give a tetrazolo derivative. In a similar way a triazole ring can be formed from the appropriate hydrazino derivatives of pyrido[1,2-a]pyrimidin-4-one.     

9-Hydroxy-2-methyl-4H-pyrido[1,2-α] pyrimidin-4-one and its derivatives

2-Amino-3-(o-bromobenzyloxy)pyridine ( 1 ) and ethyl acetoacetate gave 9-(o-bromobenzyl-oxy)-2-methyl-4H-pyrido[1,2-α]pyrimidin-4-one ( 2 ) in 2% yield. When 1 and methyl β-amino-crotonate ( 3 ) were reacted, benzyl ether cleavage occurred and the products were 9-hydroxy-2-methyl-4H-pyrido[1,2-α]pyrimidin-4-one ( 4 ) and its ammonium salt ( 5 ). These observations led to an alternative synthesis in which 2-amino-3-pyridinol ( 6 ) and either 3 or methyl acetoacetate, ( 8 ) in diethylbenzene at 185° gave 4 in 86 and 87% yields, respectively, and the anion of 4 and o-bromobenzyl bromide gave 2 in 61% yield. Even in diethylbenzene at 185°, 1 and 8 gave only trace amounts of 2 . Thus, o-bromobenzylation of the 3-hydroxyl group in 6 markedly decreased the reactivity of the amino group in 6 toward reactions with acetoacetic esters.     

Synthesis of 6-amino-2-aryl-1,2-dihydro-3H-pyrido[2,3-d]pyrimidin-4-one derivatives

This paper reports the synthesis of new pyrido[2,3-d]pyrimidin-4-one derivatives as diuretic agents. Starting with 1,2-dihydro-5-nitro-2-oxo-3-pyridinecarboxylic acid 1 , ethyl 2-ethoxy-5-nitro-3-pyridincarboxylate 4 was obtained. Compound 4 reacts with ammonia, methylamine or S-methylpseudothiourea to give the respective 2-amino-5-nitro-3-pyridinecarboxamide derivatives 5 and 6 or 2-methylthio-6-nitro-3H-pyrido[2,3-d]pyrimidin-4-one 8. Treating carboxamide 5 with arylaldehydes and zinc dichloride, new 2-aryl-1,2-dihydro-6-nitro-3H-pyrido[2,3-d]pyrimidin-4-ones 9 were synthetised. These compounds reduced with iron(II) hydroxide gave 6-amino-2-aryl-1,2-dihydro-3H-pyrido[2,3-d]pyrimidin-4-ones 10 as expected.     

Synthesis of new heterocyclic phenols: 9-Hydroxypyrido[1,2-a]pyrimidin-4-one and Derivatives

9-Hydroxypyrido[1,2-a]pyrimidin-4-one ( 5 ) was prepared by condensation of 2-amino-3-hydroxypyridine with isopropylidene aminomethylenemalonate. The reaction first led to an enaminoester intermediate which underwent cyclization by heating at 250° affording the new heterocyclic phenol 5 . A similar condensation performed on 2-amino-3-benzyloxypyridine yielded the corresponding benzylic ether which can be easily debenzylated to 5 by hydrogenolysis. Furthermore 2-amino-3-benzyloxypyridine condensed with diethyl ethoxymethylenemalonate gave 9-benzyloxy-3-ethoxycarbonylpyrido[1,2-a]pyrimidin-4-one which was also debenzylated to the corresponding free phenol.     

Nitrogen bridgehead compounds. Part 51 Autoxidation of 9-aminotetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones. Synthesis and stereochemistry of 9-amino- and 9-hydroxy-6,7-dihydro-4H-pyrido[1,2-a]-pyrimidin-4-ones

In solution the 9-phenylaminotetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones 1-5 were oxidized into the 9-aminodihydro compounds 15-19 by atmospheric oxygen at ambient temperature. Autoxidation is most probably a free-radical chain process, which takes place with ground-state triplet oxygen via the radical cation of the enamine form. The 9-aminodihydro derivatives were also prepared from 9,9-dibromo compounds 10 and 11 and from 9-hydroxydihydro compounds 12-14 . The 9-hydroxydihydro derivatives, obtained from the 9-amino compounds 16, 19 and 21 by acidic hydrolysis, showed a solvent-dependent and R¹ substituent-dependent oxo-enol tautomerism. The enol form was stabilized by electron-withdrawing R¹ groups and a polar solvent. However, for the 9-aminodihydropyrido[1,2-a]pyrimidines 15-26 only the enamine tautomer (E) could be identified independently of the substituent and the solvent. The chemical structures of the synthesized products were studied by uv, ir, ¹H- and ¹³C-nmr spectroscopy.     

Tetrahydro- and octahydropyrido[1,2-a]pyrimidin-4-ones

The catalytic hydrogenation of 2-methyl-, 1 2,8-dimethyl-, 2 , 2,9-dimethyl-, 3 , 9-methyl-2-propyl-, 4 , 2,3,9-trimethyl-, 5 , 9-methyl-2-phenyl-, 6 , 9-hydroxy-2-methyl-, 7 , 9-acetoxy-2-methyl, 8 , 9-carboxy-2-methyl-, 16 , 9-carboethoxy-2-methyl-, 17 , 9-carbomethoxy-2-methyl-, 18 , and several 9-carboxamido-2-methyl-, 19, 20 , and 21 , derivatives of the pyrido[1,2-a]pyrimidin-4-one heterocycle has led to a series of novel 6,7,8,9-tetrahydro- and fully saturated, octahydro analogs. In deuteriochloroform or DMSO-d₆ solution, the pmr spectra of the tetrahydro derivatives derived from 1-7 revealed only the 6,7,8,9-tetrahydro structures. In the pmr spectra of 16-21 , there was evidence of a facile 1,3-prototropic shift of the proton from position-9 to position-1, resulting in equilibria between tautomeric species, i.e., . The ratio of tautomers present at equilibrium, with the esters, favored the enamine conformation, whereas, with both the carboxylic acid and the amides, the imine structure predominated. Supportive evidence for the enamine structure with the esters was derived also from the ir spectra. Alkylation of the anion derived from the tetrahydro 9-carbomethoxy derivative with sodium hydride led exclusively to derivatives of 6,7,8,9-tetrahydro system.     

Synthesis of pyrido[2,3-d]pyrimidin-4-one derivatives

This paper describes one-pot synthesis of 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidin-5-one 4 , 5H-dipyri-do[1,2-a:3′,2′-e]pyrimidin-5-one 10 and 5H-pyrido[3,2-e]pyrimido[1,2-a]pyrimidin-5-one 15 and some of their derivatives, starting with 2-chloro-3-pyridine carboxilic acid 1. Compounds 4 and 10 reacted with phosphorus pentasulfide to give the respective 5-thione analogues, 5 from 4 and 11 from 10 . Boiling the 5-thione derivatives with hydrazine hydrate, the respective 5-hydrazono derivatives 6 from 5 and 12 from 11 were obtained. The 5-acetyl hydrazono, 7 , and the 5-isopropylidenehydrazono, 8 , derivatives were also prepared from 6 , and the 5-propionylhydrazono derivatives, 13 , from 12 . Compound 4 reacted with hydrazine to give an adduct with two molecules of hydrazine and the probable structure 16 . Treating this adduct with acetone a monohydrazone 17 was obtained. Boiling a suspension of this adduct in DMF, it gave 6,10-dihydro-6H-pyrido[3′,2′:5,6]pyrimido[2,1-c][1,2,4]triazin-5-one 20 .     

Electronic structure of 4H-pyrido[1,2-a]pyrimidin-4-ones

The characteristic features of ir and uv spectra of 43 4H-pyrido[1,2-a]pyrimidin-4-one derivatives with electron donor or acceptor groups in position 3, and positions 6, 7, 8, or 9, respectively, have been systematically studied. On the basis of the spectra some conclusions have been drawn for the molecular structure. The negative solvent effect of the lowest-energy π → π* transition is investigated by the PPP method.     

Synthesis of 1-Benzoyl-3-aryl-4-hydroxy-4-phenylimidazolidin-2-thiones

l-Benzoyl-3-aryl-4-hydroxy-4-phenylimidazolidin-2-thiones can be synthesized readily from the cyclization of 1-benzoyl-3-arylthioureas with bromine-acetophenone in the presence of excess triethylamiqe.