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.     

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.     

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 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 of derivatives of pyrazino[1,2-a]pyrimidin-4-ones

3-Alkoxy-2-aminopyrazines have been condensed with ethyl ethoxymethylenemalonate and isopropylidene methoxymethylenemalonate to afford 9-alkoxypyrazino[1,2-a]pyrimidin-4-ones substituted in the first case by an ethoxycarbonyl group at 3 position.     

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.     

Nitrogen bridgehead compounds. Part 65. Vilsmeier-haack formylation of 4H-pyrido[1,2-a]pyrimidin-4-ones. Part 6

2-Substituted 3-formyl-4H-pyrido[1,2-a]pyrimidin-4-ones can be synthethized by Vilsmeier-Haack formylation with the dimethylformamide-phosphoryl chloride complex only from those 4H-pyrido[1,2-a]pyrimidin-4-ones which contain a substituent with electron-releasing resonance effect in position 2. The products were characterized by uv, ir and ¹H nmr spectroscopy.     

A Three-Component Synthesis of trifluoromethylated hexahydropyrrolo[1,2-a]imidazol-5-ones and hexahydropyrrolo[1,2-a]pyrimidin-6-ones

Chemistry of Heterocyclic Compounds - A three-component reaction of ethyl trifluoropyruvate, methyl ketones, and ethylenediamine or 1,3-diaminopropane afforded...     

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.     

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.     

Condensation of substituted 2-aminopyridine with β-ketocarboxylic esters: 4H-pyrido[1,2-a]pyrimidin-4-ones and pyridin-2-ones

We report the condensation of substituted 2-aminopyridines 5 with β-ketocarboxylic esters in polyphosphoric acid. In this reaction were obtained together with the target compounds, 4H-pyrido[1,2-a]pyrirnidin-4-ones 6 also the pyridin-2-ones 7 . All the compounds 7 were tested for their calcium-antagonistic activity but failed to evoke any vasorelaxant response.     

Nitrogen bridgehead compounds VIII . Ring transformations IV . Synthesis and reactions of 2,3-Cycloalkylene-4H-pyrido [1,2-a] pyrimidin-4-ones

By condensing alicyclic β-ketocarboxylates with substituted 2-aminopyridines in polyphosphoric acid or phosphoryl chloride-polyphosphoric acid, numerous 2,3-tri-, tetra-, penta- and hexamethylene-4H-pvrido[1,2-a]pyrimidin-4-ones were synthesized for pharmacological purposes. The stability and several reactions of the title compounds were studied. The 6-substituted-4H-pyrido[1,2-a]pyrimidin-4-ones were transformed into 1,8-naphthyridines in good yields independent of the ring size of ring C . The characteristic differences in the ir and uv spectra of the pyrido-pyrimidines and the corresponding naphthyridines are discussed. Catalytic hydrogenation of the pyrido[1,2-a]pyrimidin-4-ones furnished the corresponding 6,7,8,9-tetrahydropyrido-[1,2-a]pyrimidin-4-one derivatives. It was found that the A and C rings attached to the pyrirnidinone ring in solutions of unsubstituted tetrahydropyrido[1,2-a]pyrimidin-4-ones are flexible, whereas in the 6-methyl derivatives the conformer containing the 6-methyl group in axial position predominates.     

Nitrogen bridgehead compounds. Part 50 . Vilsmeier-haack acylation of 6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones,Part 5

6-Methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-ones 1-5 were subjected to Vilsmeier-Haack acylation with complexes of phosphoryl chloride and different amides. Acylation at position 9 of the pyridopyrim-idines was successful with the iminium salt formed in situ from N-formylpiperidine, N-methylformanilide or N,N-diethylbenzamide, but unsuccessful with the iminium salt formed from N,N-diethylacetamide or N,N-di-ethylisobutyramide, respectively. The iminium salt formed from formanilide, N-methylpyrrolidinone or formamide reacted only with those tetrahydropyridopyrimidinones which contain a strongly electronegative substituent (e.g. CN or CO₂Et) in position 3. With the latter derivatives, the 9-phenylaminomethylene group could be introduced using N,N-diphenylformamide or in a “one-pot” procedure with aniline and triethyl orthoformate. Ethanolysis of 9-N-methyl-N-phenylaminomethylene derivatives 15 and 19 afforded 9-ethoxy-methylene compounds 26 and 27 in the presence of hydrogen chloride. The structures of the 9-substituted 6-methyltetrahydropyridopyrimidin-4-ones 14-25 were elucidated by means of uv, ¹H and ¹³C nmr spectroscopy. 9-Piperidinomethylene 14 , 9-(N-methyl-N-phenylaminomethylene 15-19 and 9-(N-methyl-2-pyrrolidinylidene) 21 derivatives exist as E geometric isomers. 9-Phenylaminomethylene-6-methyl-4-oxo-6,7,8,9-tetra-hydro-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile 20 displays a solvent-dependent E-Z isomerism. The bis-compound 25 contains both E and Z geometric exo C ? CH double bonds. 9-Benzoyl derivatives 23 and 24 exist predominantly as the 1,6,7,8-tetrahydropyridopyrimidin-4-one tautomer.     

Synthesis of some substituted pyrido[1,2-a]pyrimidin-4-ones and 1,8-naphthyridines

The substituted 4H-pyrido[1, 2-a]pyrimidin-4-ones (I) were obtained by the condensation of substituted 2-aminopyridines with δ-ketocarboxylic esters in PPA. Some of the derivatives I were transformed into the corresponding 1, 8-naphthyridines II and III.     

Isocyanate acting as a carbonyl precursor: pyridyl group-assisted formation of 4H-pyrido[1,2-a]pyrimidin-4-ones from ketimines and isocyanates

By the reactions of ketimines bearing a pyridyl or a picolyl group on a nitrogen atom of the imine moiety with tosylisocyanate, 4H-pyrido[1,2-a]pyrimidin-4-one derivatives could be obtained in quantitative yields. In these reactions, tosylisocyanate acts as a carbonyl precursor. The pyridyl or picolyl group is a key functional group because it is not only the constituent structure of the 4H-pyrido[1,2-a]pyrimidin-4-one framework but also the promoter of the formation of a ketene intermediate.     

Reactions of ethyl 4-chloro-5-pyrimidinecarboxylates with 2-aminopyridine. Synthesis of 5H-pyrido[1,2-A]pyrimido[5,4-e]pyrimidin-5-ones and 5H-pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones and rearrangement of the former to the latter

5H-Pyrido[1,2-a]pyrimido[5,4-e]pyrimidin-5-ones IVa,b and 5H-pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones Va,b were synthesized from ethyl 4-chloro-5-pyrimidinecarboxylate and 2-aminopyridine. The former compounds were obtained directly upon heating the reactants in ethanol, and the latter were prepared by the fusion of ethyl 4-(2-pyridylamino)-5-pyrimidinecarboxylates obtained as minor products from the above reaction. The angular fused cyclic compounds, IVa,b were rearranged to the linear tricycles, Vb-f upon heating with amines.     

A novel and convenient synthesis of thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones using Vilsmeier reagent

A novel route for the synthesis of thiazolo[3,2-a]pyrimidin-7-ones and pyrido[1,2-a]pyrimidin-2-ones from acetylated 2aminothiazoles and 2-aminopyridines under Vilsmeier conditions has been developed.The plausible mechanism has also been proposed.     

The reaction of 2-acetoacetamidopyridines with phosgene. A route to novel 3-Acetyl-2-chloro-4H-pyrido[ 1,2-a] pyrimidin-4-ones

2-(Acetoacetamido)pyridine, 1 , and its 5-methyl derivative, 2 , with phosgene, gave 3-acetyl-2-chloro-4H-pyrido[1,2-a]pyrimidin- 4 -one, 5 , and 3-acetyl-2-chloro-7-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one, 6 , respectively. The structures of these compounds followed from their elemental analyses, and interpretations of their uv, ir, pmr, and X-ray spectra. An alternative route to 5 and 6 , which sought first to react 1 and 2 with methyl - and benzyl chloroformates, was unsuccessful, and led, instead, to elimination of the acetoacetyl group with concomitant formation of the carbamate derivatives, 10 and 11 .