Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.     

Synthesis and properties of 3-arylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and related compounds: photo-induced autorecycling oxidation of some amines

Novel 3-phenyl- and 3-(4-nitrophenyl)cyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and the corresponding imino derivatives 5a,b and 6a,b were synthesized in modest to moderate yields by the abnormal and normal aza-Wittig reaction of 2-(1,3-diazaazulen-2-ylimino)triphenylphosphorane with aryl isocyanates and subsequent heterocyclization reaction with a second isocyanate. The related cationic compound, 1-methyl-3-phenylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-dionylium tetrafluoroborate 7a, was also prepared. The electrochemical reduction of these compounds exhibited more positive reduction potentials as compared with those of the related compounds of 3,10-disubstituted cyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1H,3H)-dione systems. In a search of the oxidizing ability, compounds 5a, 6a, and 7a were demonstrated to oxidize some amines to give the corresponding imines in more than 100% yield under aerobic and photo-irradiation conditions, while even benzylamine was not oxidized under aerobic and thermal conditions at 100 °C. The oxidation reactions by cation 7a are more efficient than that by 5a and 6a. Quenching of the fluorescence of 5a was observed, and thus, the oxidation reaction by 5a probably proceeds via electron-transfer from amine to the excited singlet state of 5a. In the case of cation 7a, the oxidation reaction is proposed to proceed via formation of an amine-adduct of 7a and subsequent photo-induced radical cleavage reaction.     

Alternative synthesis and novel oxidizing ability of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-dione derivatives

Synthesis of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-diones 7a-g was accomplished by ring opening and ring closure sequences of 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8,10(9H)-dione derivatives induced by several amines. Furthermore, alternative synthetic methodology for compounds 7a-e was also accomplished by single-step reaction of 2-chlorotropone with 6-aminouracil derivatives under mild conditions. X-ray crystal analysis of 7a was carried out to clarify the structural characteristics. The properties of 7a-e were studied by the UV-vis spectra and reduction potentials (−1.24 to −1.39 V vs Ag/AgNO₃). Novel photo-induced oxidation reaction of 7a-d toward some amines under aerobic conditions was carried out to give the corresponding imines in more than 100% yield [based on compounds 7a-d], suggesting the oxidation reaction occurs in an autorecycling process.     

Synthesis and rearrangement of cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones: an access to cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones

2-Substituted-4a-hydroxy-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 2a-c were synthesized by an one-step cyclocondensation from the 5-substituted-2-amino-2-oxazolines 1a-c with ethyl 2-oxocyclohexanecarboxylate in ethanol at room temperature, and easily dehydrated to provide 2-substituted-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 3. In refluxing xylene, the reaction conducted with various ethyl 2-oxocycloalkanecarboxylates led to the two isomeric 2-substituted-8/9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones 3 and 2-substituted-5H-cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones 4. The structure of some compounds was unambiguously established using X-ray crystallography. According to results from the DSC analysis of compound 2a, formation of the thermodynamically stable pyrimidinones 4 could be related to an intramolecular rearrangement of kinetically controlled pyrimidinones 3.     

A novel and convenient method for the synthesis of new derivatives of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione

A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine derivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via peptide coupling of l-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-pyridopyrrolodiazepines derivatives 5a-m, 6a-i, 7, and 8a-c. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.     

Studies on uracils: a facile one-pot synthesis of oxazino[4,5-d]-, pyrano[2,3-d]-, pyrido[2,3-d]- and pyrimido[4,5-d]pyrimidines using microwave irradiation in the solid state

N,N-Dimethyl-5-formylbarbituric acid 1 reacts with maleimide 2 and phenyl isocyanate/phenyl isothiocyanate 4 under microwave-assisted conditions in the solid phase to afford pyrano[2,3-d]pyrimidines 3 and oxazino[4,5-d]pyrimidines 5 in excellent yields. Under identical conditions, N,N-dimethyl-6-amino-5-formyluracil 6 reacts with 2 and 4 to give pyrido[2,3-d]pyrimidine derivative 7 and pyrimido[4,5-d]pyrimidines 8 in high yields.     

Microwave assisted synthesis of novel imidazo [2,1-b]thiazole derivative attached to quinoxalinones

3-(6-Phenylimidazo[2,1-b]thiazol-5-yl)quinoxalin-2(1H)-ones (qunoxalinone) (6a-q) have been synthesized by the reaction of ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) with suitably substituted o-phenylenediamines (5a-f) under microwave heating. The ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) were prepared by the reaction of 6-phenylimidazo[2,1-b]thiazoles (3a-e) with ethyl chlorooxoacetate in refluxing 1,4-dioxane whereas the thiazoles (3a-e) were synthesized by the reaction of 2-bromo-1-phenylethanones (2a-e) with thiazol-2-amine in refluxing acetone.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.     

Ring transformation of cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium ion to the corresponding pyrrole derivatives via troponeimine intermediates: photo-induced autorecycling oxidizing reactions of some amines

Ring transformation of 7,9-dimethylcyclohepta[b]pyrimido[5,4-d]furan- 8(7H),10(9H)-dionylium tetrafluoroborate 4⁺·BF₄⁻ to 7,9-dimethylcyclohepta[b]pyrimido[5,4-d]pyrrrole-8(7H),10(9H)-dionylium tetrafluoroborate 6a-d⁺·BF₄⁻ consists of the reaction of 4⁺·BF₄⁻ with amines and subsequent exchange of the counter-ion using aq. HBF₄. Reactions of 4⁺·BF₄⁻ with aniline and 4-substituted anilines afforded the corresponding pyrrole derivatives 6a-c⁺·BF₄⁻ directly in good yields. On the other hand, reaction of 4⁺·BF₄⁻ with benzylamine gave the troponeimine intermediate 9, which was not converted to 6d⁺·BF₄⁻ and reverted to 4⁺·BF₄⁻ by adding HBF₄; however, it was converted to 6d⁺·BF₄⁻ upon treatment with (COCl)₂ or SOCl₂, followed by exchange of the counter-ion. In a search for the characteristics of 9, inspection and comparison of the X-ray crystal analyses, NMR and UV-vis spectra, and CV measurement of 9 and N,N-disubstituted troponeimine derivatives 12 were carried out to suggest the remarkable structure of 12 having ionic C-O bonding between the imine-carbon atom and the oxygen atom of the barbituric acid moiety in the solid state. Thus, characteristics of 9 were ascribed to the sterically hindered and favorable conformation of N-protonated troponeimine intermediates. Furthermore, novel photo-induced oxidation reactions of a series of 4⁺·BF₄⁻, 5⁺·BF₄⁻, and 6a,e⁺·BF₄⁻ towards some amines under aerobic conditions were carried out to give the corresponding imines in 455-8362% yields [based on compounds 4⁺, 5⁺, and 6a,e⁺], suggesting the oxidation reaction occurs in an autorecycling process. Mechanistic aspects of the amine-oxidation reaction are also postulated.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Stabilization of (N-methyleneamino)imidoylketenes: synthesis of dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazines

Thermolysis of substituted methyl 1-methyleneamino-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates 2a,b led to substituted dimethyl 3,9-dioxo-1,5,7,11-tetrahydro-1H,7H-dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazine-1,7-dicarboxylates 4a,b and methyl 2,5-dihydro-5-oxo-1H-pyrazole-3-carboxylates 5a,b as minor products. The structure of compound 4a was determined by X-ray crystallography. The proposed mechanism of this conversion includes generation of (N-methyleneamino)imidoylketenes 6a,b and its intramolecular transformation to azomethine imines—5-oxo-2,5-dihydropyrazole-1-methylium-2-ides 7a,b, which undergo dimerization in head-to-tail manner yielding products 4a,b and partially hydrolyse to compounds 5a,b.     

One pot synthesis of imidazo[2,1-b]thiazoles and benzo[d]thiazolo[3,2-a]imidazoles

A series of imidazo[2,1-b]thiazole and benzo[d]thiazolo[3,2-a]imidazole analogues were synthesized by stirring an equimolar mixture of dibenzoylacetylene with imidazole/thiazole derivatives in toluene or acetonitrile at room temperature. The products were generated in good yields and characterized by standard analytical techniques such as IR, ¹H NMR, ¹³C NMR and mass spectrometry. The structure of products 19, 20, 22, 24 and 25 were also unambiguously confirmed by single crystal X-ray analysis.     

Synthesis and properties of 4,9-methanoundecafulvenes and their transformation to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones: photo-induced autorecycling oxidizing reaction toward amines

The synthesis and properties of 4,9-methanoundecafulvene [5-(4,9-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-trione] derivatives 8a,b were studied. Their structural characteristics were investigated on the basis of the ¹H and ¹³C NMR and UV-vis spectra. The rotational barrier (ΔG^‡) around the exocyclic double bond of 8a was found to be 12.55 kcal mol⁻¹ by the variable temperature ¹H NMR measurement. The electrochemical properties of 8a,b were also studied by CV measurement. Furthermore, the transformation of 8a,b to 3-substituted 7,12-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1H,3H)-diones 16a,b was accomplished by oxidative cyclization using DDQ and subsequent ring-opening and ring-closure. The structural details and chemical properties of 16a,b were clarified. Reaction of 16a with deuteride afforded C13-adduct 19 as the single product, and thus, the methano-bridge controls the nucleophilic attack to prefer endo-selectivity. The photo-induced oxidation reaction of 16a and a vinylogous compound, 3-methylcyclohepta[4,5]furo[2,3-d]pyrimidine-2,4(3H)-dione 2a, toward some amines under aerobic conditions were carried out to give the corresponding imines (isolated by converting to the corresponding 2,4-dinitrophenylhydrazones) with the recycling number of 6.1-64.0 (for 16a) and 2.7-17.2 (for 2a), respectively.     

Solvent-free reactions of N,N′-thiocarbonyldiimidazole with ferrocenylcarbinols

The efficient and simple routes for the synthesis of various ferrocenyl derivatives from ferrocenylcarbinols and N,N′-thiocarbonyldiimidazole (TCDI) are described. It involves grinding the two substrates in a Pyrex tube with a glass rod at room temperature. The reaction of ferrocenylmethanol (1a) provided S,S-bis(ferrocenylmethyl)dithiocarbonate (1b), whose crystal structure and a plausible mechanism for its formation are also reported. The reaction of 1-ferrocenyl-1-phenylmethanol (2a) and 1-ferrocenylbutanol (2b) gave the products 2c and 2d, respectively. The reaction of ω-ferrocenyl alcohols 4-ferrocenylphenol (3a) and 6-ferrocenylhexan-1-ol (3b) yielded the products 3c and 3d, respectively. Reaction of 1,1′-ferrocenedimethanol (3e) afforded 3f in moderate yield, and by contrast, it was not similar to 1b. Reaction of [4-(trifluoromethyl)phenyl]methanol (4a) provided the thiocarbonate 4b in good yield.     

Gas-phase pyrolysis of benzimidazole derivatives: novel route to condensed heterocycles

Gas-phase pyrolysis of N-(1H-benzimidazol-2-yl)-N′-arylidenehydrazines 1a-e gave the corresponding arylnitriles 2a-e, 2-aminobenzimidazole 3, 2,4,5-triphenylimidazole 4, 1,3-diphenyl-8H-2,3a,8-triazacyclopenta[a]indene 5, and 5,11-diphenyl-6H,12H-dibenzimidazo[1,2-a];1’,2’-d]pyrazine 6. The kinetics and analysis of the products of reaction are reported and used to elucidate the mechanism of the elimination process.     

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

A facile synthesis of pyrrolo[1,2-a]benzimidazoles and pyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazole derivatives

Reaction of 2-cyanomethylbenzimidazole 1 with hydrazonoyl halides 2 led to formation of pyrrolo[1,2-a]benzimidazole derivatives 7. Similar reaction of 1 with halides 3 afforded 5-amino-4-(benzimidazol-2-yl)pyrazole derivatives 11 or 1-amino-2-arylpyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazol-4-one 14 depending on the reaction conditions. The mechanisms of the studied reactions are discussed.     

2-Allyl-N-benzyl substituted α-naphthylamines as building blocks in heterocyclic synthesis. New and efficient syntheses of benz[e]naphtho[1,2-b]azepine and naphtho[1,2-b]azepine derivatives

A new series of 13-acetyl-7,12-dihydro-7-ethylbenz[e]naphtho[1,2-b]azepine (4a-d) and 2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepine derivatives (6a-d) have been synthesized from N-allyl-N-benzyl substituted α-naphthylamines (1a-d) by utilizing aromatic amino-Claisen rearrangement, intramolecular Friedel-Crafts alkylation and intramolecular dipolar 1,3-cycloaddition nitrone-olefin reactions.     

Regioselective Baeyer-Villiger lactonization of 2-substituted pyrrolidin-4-one. Synthesis of statine

Nine 2-substituted pyrrolidin-4-ones 4a-i were obtained via a series of functional group transformation of known prolinol 5 by facile six kinds of methodologies. The target structure of 1,3-amino alcohols 2a-i was constructed in the regioselective Baeyer-Villiger lactonization of ketones 4a-i and reduction of the resulting 4-substituted tetrahydro-1,3-oxazin-6-ones 3a-i. A new and straightforward synthesis of (3S,4S)-statine (6) has been established starting from trans-(2S,4R)-4-hydroxyproline (1).     

Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.