Nitrogen bridgehead compounds. Part 80 unusual reaction of ethyl 9-bromo-4-oxo-6,7,8,9-tetr ahydro-4h-pyrido[1,2-a]pyrimidine-3-carboxylates and N-Methylaniline

The acid-catalysed intramolecular nucleophilic addition of the phenyl ring to the C(9a) = N(1) double bond of ethyl 9-(N-methyl-N-phenyl)-4-oxotetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates, formed in the reactions of ethyl 9-bromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates and N-methylaniline, gave the first examples of a new tetracyclic pyrimido[1′,2′:1,2]pyrido[3,2-b]indole ring system ( 7 ). X-ray diffraction analysis of 7a revealed that the annelation of the pyrimidine and piperidine rings is transoid, while that of the piperidine and pyrroline rings is cis, the piperidine ring adopts an unusual ⁶T₈ twisted boat conformation, while the pyrroline ring has a ⁹T_8a conformation.     

Structural studies on 9-hydrazono-6,7,8,9-tetrahydro-4-oxo-4H-pyrido[1,2-a]pyrimidines by 1H, 13C and 15N NMR spectroscopy

¹H, ¹³C and ¹⁵N NMR studies demonstrated that 9-hydrazono-6,7,8,9-tetrahydro-4-oxo-4H-pyrido-[1,2-a] pyrimidlnes exist as an equilibrium mixture of Z-E isomers in the hydrazono–imino tautomeric form having an exocyclic double bond. Proton-catalysed Z-E interconversion is fast. Substituent and solvent effects revealed that the decisive factors controlling the Z:E ratio are internal hydrogen bonding in the Z-isomer, stabilization by solvation and steric interaction.     

Nitrogen bridgehead compounds. Part 76 Synthesis and stereochemistry of ethyl 9-benzylidene-6,7,8,9-tetrahydro-2-oxo-2H- and 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylates and their homologues

Ethyl 4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates 1–4 , their piperidine ring homologues 5–6 and their 2-oxo isomers 7–9 were reacted with benzaldehyde. At low temperature, kinetically stable addition products were formed. Thermodynamically stable condensation products were obtained at higher temperature, which were also formed when the addition products were refluxed in benzene. The 9-benzyl derivatives were prepared by the hydrogenation of the condensation products over Pd/C. The stereochemical features of the new compounds were determined via ¹H and ¹³C nmr chemical shift and coupling constant analysis and NOE measurements.     

Nitrogen bridgehead compounds. Part 86. Synthesis and reactivity of 7,12-dihydropyrimido[1′,2′;1,2]pyrido[3,4-b]indol-4(6H)-ones. Debenzologues of rutaecarpine alkaloids

A series of 7,12-dihydropyrimido[1′2′:1,2]pyrido[3,4-b]mdole-4(6H)-ones was prepared by Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrirmdin-4-ones. Quantum chemical calculations (ab initio and AM1) indicate that position 3 of 7,12-dihydropyrimido[1′,2′:1,2]pyrido-[3,4-b]indole-4(6H)-one can be involved in electrophilic substitutions, while position 2 is sensitive towards nucleophilic attack. Bromination of 6-methyl-7,12-tetrahydropyrimido[1′,2′:1,2]pyrido-[3,4-b]indol-4(6H)-one 16 with bromine afforded 3-bromo derivative 25 , which was reacted with cyclic amines to give 2-ammo-7,12-dihydropyrirmdo[1′2′:1,2]pyrido[3,4-b]indol-4(6H)-ones 26–30 in an addition-elimination reaction. Vielsmeier-Haack formylation of compound 16 gave 12-formyl 31 and 3,12-diformyl 32 derivatives (an N-formyl-1-deaza derivative of nauclefidine alkaloid 34 ) at 60° and 100°, respectively. 3,12-Diformyl compound 32 was oxidized to 3-carboxyl derivative 33 with potassium permanganate. The quaternary salt 35 , obtained from compound 16 with dimethyl sulfate, suffered a ring opening on the action of aqueous sodium hydroxide. The new compounds have been characterized by elemental analyses uv, ¹H nmr and in some cases by ¹³C ruler, CD spectra and X-ray investigations.     

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 45 [1]. Synthesis of 6-arylhydrazono-6,7,8,9-tetrahydro-11H-pyrido-[2,1-b]quinazolin-11-ones

A series of 6-arylhydrazono-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-ones 3–37 , conveneint starting materials for indolopyridoquinazolines, were prepared by diazonium coupling between aryldiazonium chlorides and 6,7,8,9-tetrahydro- 2 , 6-formyl-5,7,8,9-tetrahydro- 39 , 6-(dimethylamino)methylene-6,7,8,9- 38 or 6-carboxyl-5,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-ones 43 . The arylhydrazono derivatives were also prepared from 6-bromo- 45 or 6,6-dibromo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolines 46 with arylhydrazines. The structures of the 6-arylhydrazonopyridoquinazolines were characterized by uv and ¹H nmr spectroscopy. The 6-arylhydrazono derivatives show a solvent-dependent E-Z isomerism.     

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.     

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.     

Amino acids in the synthesis of heterocyclic systems. The synthesis of 4-oxo-4H-pyrido[1,2-a]pyridines and 4-oxo-4H-pyrido[1,2-a]pyrimidines

The pyridine and quinoline derivatives 2, 3 , and 6 with an activated methylene group atα-position in respect to the ring nitrogen atom were converted with 1, 8 , or 9 into fused pyrido[1,2-a]pyridine derivatives 4, 5, 7 , and 10 . In an analogous manner were the aminopyridines 16 and 17 transformed with thiazolone 9 into pyrido[1,2-a]pyrimidine derivatives 20, 21, 25 , and 26 .     

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 pyrimido[1,2-a]benzimidazoles from ethyl 2-ethoxymethylidene-3-oxo-3-(polyfluoroalkyl)propionates

Cyclization of ethyl 2-ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates with benzimidazol-2-amine in boiling 1,4-dioxane followed two concurrent pathways with participation of fluoroacyl and ethoxycarbonyl fragments and formation of, respectively, ethyl 4-hydroxy-4-polyfluoroalkyl-1,4-dihydropyrimido-[1,2-a]benzimidazole-3-carboxylates and 3-polyfluoroacylpyrimido[1,2-a]benzimidazol-4-ols. Dihydropyrimido[1,2-a]benzimidazole derivatives undergo dehydration to give ethyl 4-(polyfluoroalkyl)pyrimido[1,2-a]benzimidazole-3-carboxylates, whereas the hydroxy group in 3-polyfluoroacylpyrimido[1,2-a]benzimidazol-4-ols is capable of being replaced by the amino group of the second benzimidazole molecule with formation of 4-(1H-benzimidazol-2-ylamino)-3-polyfluoroacylpyrimido[1,2-a]benzimidazoles.     

Condensed heterocycles containing the pyrimidine nucleus

Continuing earlier studies designed to obtain derivatives of 1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one and of the isomeric 7-one of pharmacological interest, some novel compounds 2 and derivatives of 6,7,8,9-tetrahydro-5H-1,3,4-thiadiazolo[2,3-b]quinazolin-5-one ( 3 ) were prepared. Derivatives of pyrimido[2,1-b]benzothiazol-2-one ( 6 ) and of the isomeric 4-one derivatives 8 were also synthesized. Structural identification was obtained by ¹H-nmr, ir and mass spectra.     

Synthèse et étude physicochimique des 1,2,4-triazolo[4,3-a]-pyridines et des 1,2,4-triazolo[2,3-a]pyridines

The synthesis of 1,2,4-triazolo[4,3-a] and [2,3-a]pyridines 7, 8 was achieved by cyclization of 2-hydrazino-8-nitropyridine 3a with formic acid. The 4,5,6,7-tetrahydro-1,2,4-triazolo[2,3-a]pyridine 13 and 8-amino-1,2,4-triazolo[2,3-a]pyridine 9 were obtained by catalytic hydrogenation. The reduction of triazolo pyridine 8 using stannous chloride led to the intermediate compound 10 which with acetic anhydride afforded 8-acetylamino-5-chloro-1,2,4-triazolo[2,3-a]pyridine 10a . The structure of the derivatives was determined by ¹H-nmr (DMSO-d₆).     

A facile one-pot synthesis of 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones

Abstract  

The reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one or its 2-methylthio derivative with hydrazonoyl halides, in the presence of triethylamine, yielded 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The structure of the latter compounds was further confirmed by reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one with the appropriate active chloromethylenes followed by coupling of the products with benzenediazonium chloride to afford the non-isolable azo-coupling products which converted, in situ, to 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The reaction mechanism was proposed and the products were screened for their biological activity. Some of the newly synthesized compounds had a moderate effect against some bacterial and fungal species.     

Research on heterocyclic compounds. XXIII. Phenyl derivatives of fused imidazole systems

The reaction of various heteroarylamines with ethyl 2-benzoyl-2-bromoacetate was used to obtain some imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, imidazo[2,1-b]thiazoles and imidazo[2,1-b]benzothiazoles characterized by the presence of a phenyl moiety on the imidazole ring. In the case of thiazole and benzothiazole derivatives, unexpected by-products were isolated and their structures elucidated.     

Synthesis of 3-alkoxycarbonylaminomethylcarbonylamino-4-benzoyl-1,2-dihydropyridines and their cyclization to 5-phenyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones

The regiospecific reaction of 3-benzyloxycarbonylaminomethylcarbonylamino-4-benzoylpyridine (6a) , or 3-t-butoxycarbonylaminomethylcarbonylamino-4-benzoylpyridine (6b) , with either acetyl chloride or ethyl chloroformate, and either n-butylmagnesium chloride or phenylmagnesium bromide afforded the respective 1-acetyl (or ethoxycarbonyl)-2-n-butyl (or phenyl)-3-benzyloxy (or t-butoxy) carbonylaminomethylcarbonylami-no-4-benzoyl-1,2-dihydropyridines 7 in 60-75% yield. Reaction of 1-acetyl (or ethoxycarbonyl)-2-n-butyl (or phenyl)-3-t-butoxycarbonylaminomethylcarbonyl-4-benzoyl-1,2-dihydropyridines 7b, 7f, 7d, 7h with trifluoroacetic acid gave the corresponding 5-phenyl-8-acetyl (or ethoxycarbonyl)-9-n-butyl (or phenyl)-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones 8a, 8b, 8c, 8d respectively in 45–63% yield. N¹-Methylation of 5-phenyl-8-acetyl-9-n-butyl (or phenyl)-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones 8a, 8b using sodium hydride and iodomethane yielded the corresponding N¹-methyl derivatives 9a (48%) and 9b (54%). Oxidation of 5,9-diphenyl-8-ethoxycarbonyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-one (8d) using p-chloranil afforded 1,3-dihydro-5,9-diphenyl-2H-pyrido[3,4-e]-1,4-diazepin-2-one (10) . 5-Phenyl-8-acetyl-9-n-butyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-one (8a) and the corresponding 8-ethoxycarbonyl analog 8c exhibited weak anticonvulsant activity indicating that 8a and 8c may be acting at the same site as the 7-halo-1,4-benzodiazepin-2-one class of compounds.     

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.     

Synthesis of nitrogen heterocycles underlain by application of 3-(4-Acetyl[phenyl)-2H-coumarin

3-(4-Acetylphenyl)-2H-chromen-2-one was obtained from 4-acetylphenyldiazonium chloride in the conditions of Meerwein reaction. Reactions of 3-[4-(2-bromoacetyl)phenyl]-2H-chromen-2-one with pyridine, 4-methylpyridine, quinoline, benzo[f]quinoline, and triphenylphosphine afforded quaternary salts, and with thioacetamide, thiourea, 2-aminopyridine, 2-aminopyrimidine, and 6-aminopurine provided the corresponding derivatives of thiazole, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine, imidazo[2,1-i]purine. In the reaction of the same bromo derivative with thiosemicarbazide and aromatic aldehydes a thiazole ring is built and the corresponding hydrazones are formed.     

The synthesis of azahomotryptophane derivatives. The transformation of N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester into 4-(imidazo[1,2-a]azinyl-3)-4-oxohomoalanine derivatives

Azatryptophane homologues, 4-(imidazo[1,2-a]pyridinyl-3)- 9a-9f and 4-(imidazo[1,2-a]pyrimidinyl-3)-4-oxohomoalanine derivatives 9g-91 , were prepared from N,N-dimethyl-N′-(pyridinyl-2)- 6a-6f and N,N-dimethyl-N-(pyriniidinyl-2)formamidines 6g-6i , and (S)-N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester ( 2 ) and its (R,S)-isomer.     

Reactions of pyridinium or isoquinolinium ketene dithioacetals with aromatic N-imines and S-imines

Reactions of ketene dithioacetals, 1-[1-substituted 2,2-bis(methylthio)ethenyl]pyridinium 1a-i or -isoquinolinium 2a,b iodides with aromatic N-imines, 1-aminopyridinium 3a-1,1 -aminoquinolinium ( 4 ), and 2-amino-isoquinolinium ( 5 ) mesitylene sulfonates gave the corresponding 2-methylthioimidazo[1,2-a]pyridines 9a-k , 2-methylthiopyrazolo[1,5-a]pyridines 11a-q , 2-methylthioimidazo[2,1-a]isoquinoline derivatives 10a,b and 2-methylthiopyrazolo[1,5-a]quinoline ( 12 ). The benzoyl compounds, 1-[1-benzoyl-2,2-bis(methylthio)ethenyl]-pyridinium iodides 1g,h,i reacted with N-imine 3a to give the 3-benzoyl-2-methylthioimidazo[1,2-a]pyridines 9h-k . The reaction of pyridinium ketene dithioacetals 1a,f,g (R¹ = COOE_t, COPh, and CN) with substituted pyridinium N-imines having an electron-withdrawing group on the pyridine ring afforded only the corresponding pyrazolo[1,5-a]pyridine derivatives 11j-r in good yields. Reactions of ketene dithioacetals with various S-imines are also described. Possible mechanisms for the formation of 9 and 11 are described.