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.     

3-Benzoyl-2-hydroxy-9-methylpyrido[1,2-A] pyrimidin-4-one

The single aberrant product of the reaction between 2-amino-3-methylpyridine ( 2 ) and ethyl benzoylacetate ( 4 ) in diethylbenzene at ca. 180° was 3-benzoyl-2-hydroxy-9-methylpyrido-[1,2-a]pyrimidin-4-one ( 5 ). When administered to naive rats, 5 induced behavioral effects strikingly similar to those manifested by morphine-addicted rats who have been deprived of that analgetic.     

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.     

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.     

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.     

Stereochemistry and 13C NMR investigation of 9-halotetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones

It was shown that the halogen atom occupies the quasi-axial position in the predominant conformer of the 9-halo derivatives of tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones. When R³ = Me, the conformational equilibrium is determined by the latter substituent which is always quasi-axial. The effects of the methyl group and the halogen atoms on the ¹³C chemical shifts (SCS values) were used for the identification of cis and trans isomers. Interesting non additivity of substituent effects was found in derivatives bearing quasi-axial substituents at C-6 and C-9: and this was caused by the ring flattening.     

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.     

Suzuki-Miyaura cross-coupling reactions of halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-ones

The palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one with (het)arylboronic acids allow easy access to (het)aryl and vinyl derivatives of this bicycle in good to excellent yields, even from chloro derivatives. The sequence of reactivity of the halogen in the different positions of the ring system was also investigated. 6-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one could be prepared by thermal cyclization of isopropylidene (6-phenylpyrid-2-ylamino)methylenemalonate, together with a small amount of 7-phenyl-1,4-dihydro-1,8-naphthyridin-4-one.     

Synthesis and nuclear magnetic resonance spectra of 2H-pyrido [1,2-a] pyrimidin-2-ones

Reaction of ethyl phenylpropiolate with several 2-aminopyridines afforded the corresponding 2H-pyrido[1,2-a] pyrimidin-2-ones in good yields. Analysis of the nmr spectra of these compounds and their hydrobromides were based on comparing their spectra with their 3-deuterated analogues. It was found that in these 2-oxo compounds, the proton at position-7 is shielded and absorbs together with the olefinie proton at position-3 in the region of 5 6.35-6.70 ppm. The latter proton could be used for differentiating these compounds from the corresponding 4-oxo isomers which have already been identified by the deshielded proton at pusition-6 near § 9.0 ppm. The ir and nmr spectral data for all these compounds are tabulated and discussed.     

Synthesis,characterization and cytotoxic activity of diorganotin (IV) complexes with 4H-pyrido[1,2-a]pyrimidin-4-one derivatives

The coordination behaviour of the diorganotin (IV) compounds R₂SnCl₂ (where R = Me, Ph) with 4H-pyrido [1,2-a] pyrimidin-4-one derivatives (L) has been described. The complexes R₂SnCl₂ · L obtained have been characterized physicochemically and spectroscopically. The pyrimidin-4-one ligands were found to coordinate with R₂SnCl₂ species in a monodentate fashion, mainly via the oxygen atom of the 4-one group or possibly via the nitrogen atom of the (SINGLE BOND)C(DOUBLE BOND)N linkage (the less sterically hindered nitrogen of the pyrimidine derivative) to give pentacoordinate tin complexes. Of the complexes selected to be screened against five tumour cell lines, some exhibited significant in vitro activity.     

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.     

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.     

A chelate method for the synthesis of 2H-pyrido[l,2-a]pyrimidin-2-one derivatives

Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 1, p. 229, January, 1990.     

Nitrogen bridgehead compounds. Part 77. Addition reaction of 9-methylene-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones

Addition of bromine or thioacetic acid onto 6-methyl-9-methylenetetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones is stereoselective and gives the cis 6-Me,9-CH substituted products. Addition is also stereoselective in respect to the C(9) and C(10) centers, and gives as the primary product the erythro diastereomer, which may then undergo epimerization to the threo isomer. Relative configuration and predominant conformation of the products were determined by 1D and 2D nmr methods.     

Synthesis of 5H-pyrido[2,3-a]phenoxazin-5-one and 5H-pyrido[3,2-a]phenoxazin-5-one derivatives

The 5H-pyrido[2,3-a]phenoxazin-5-one derivatives and 5H-pyrido[3,2-a]phenoxazin-5-one derivatives were prepared by the condensation of substituted 2-aminophenols with 6,7-dibromo-5,8-quinolinequinone followed by dehalogenation in the presence of sodium hydrosulfite dissolved in aqueous pyridine under a nitrogen atmosphere.     

Nitrogen bridgehead compounds. Part 71. Chiroptical properties of 9-halo derivatives of 6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one and its 3-carboxy derivative

Earlier assignments [2] relating to the CD bands of 6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones were utilized to explain the chiroptical properties of their 9-halogenated derivatives. The signs of the most characteristic CD bands proved to be determined by the axial substituents in the benzylic position to the inherently achiral pyrimidinone chromophore.