The synthesis of monomethoxy[1]benzothieno[2,3-c]quinolines

A series of monomethoxy[1]benzothieno[2,3-c]quinolines 24-28 were prepared by photocylization of the appropriate 3-chloro-N-phenylbenzo[b]thiophene-2-carboxamides 9–13 to [1]benzothieno[2,3-c]quinolin-6(5H)-ones 14-18 followed by chlorination to 6-chloro[1]benzothieno[2,3-c]quinolines 19-23 then dechlorination resulting in the title compounds except for 25 which was achieved by direct reduction of 15 . Reaction of 24-28 with methyl iodide provided the corresponding N-methyl quaternary salts 29-33 . Also, conversion of 4-meth-oxy[1]benzothieno[2,3-c]quinolin-6(5H)-one 16 to 4-methoxy-6-methylthio[1]benzothieno[2,3-c]quinoline 35 and 4,6-dimethoxy[1]benzothieno[2,3-c]quinoline 36 is described.     

The synthesis of dimethoxy- and trimethoxy[1]benzothieno[2,3-c]quinolines

Three dimethoxy[1]benzothieno[2,3-c]quinolines 24–26 were prepared by photocyclization of the appropriate 3-chloro-N-phenylbenzo[b]thiophene-2-carboxamides 15–17 to [1]benzothieno[2,3-c]quinolin-6(5H)-ones 18–20 followed by chlorination to 6-chloro[1]benzothieno[2,3-c]quinolines 21–23 and then dechlorination resulting in the title compounds. Reaction of 24–26 with methyl iodide furnished the corresponding N-methyl quaternary salts 27–29 . Sodium methoxide readily converted 21–23 to trimethoxy[1]benzothieno[2,3-c]quinolines 30–32 .     

Synthesis and structure of N-methylated azacalix[4]pyridines and azacalix[1]arene[3]pyridines

Reaction of azacalix[4]pyridine and azacalix[1]arene[3]pyridine with methyl iodide afforded N-methylated products selectively and highly efficiently. Crystal structures revealed that the modified electronic nature of the pyridines could change the conjugation between the bridging nitrogen and the neighbouring aromatics.     

[1+1] and [2+2] crown ethers derived from N,N-bis(2-hydroxyalkylbenzyl)alkylamine and their inclusion phenomena with metal ions

N,N-bis(2-hydroxyalkylbenzyl)alkylamine (HBA) is a derivative obtained from a single time ring opening of benzoxazines. For HBA with methyl group at ortho and para positions, and at N atom, the reaction between this derivative and ditosylated compound gives [1+1] dibenzo-monoaza-crowns. For HBA without methyl group at ortho position, the compound gives [2+2] macrocyclic ethers. The studies on inclusion phenomena using Pedersen’s and molar ratio techniques clarify the alkali metal ion guest inclusion to be 2:1 for [2+2] and 5:2 for [1+1] macrocycles.     

Unusual formation of a novel pyrrolo[1′,2′:1,2]pyrido[3,4-b]indole

Reaction of 1-methyl-3,4-dihydro-β-carboline 1 with methyl glycidate 4 gave the novel tetracyclic conjugated γ-lactam, 2-methylpyrrolo[1′,2′:1,2]pyrido[3,4–6]indol-3-one 5 . The same compound 5 was obtained in higher yield when 1 was treated with methyl 2-methoxyacrylate 7 . Sodium borohydride treatment of 5 resulted in the cleavage of lactam to yield the unexpected alcohols 8 and 9 .     

On triazoles XLIV [1]. synthesis of new ring systems containing imidazo[2′,1′:3,4] [1,2,4] triazolo [1,5‐a]pyrimidine and imidazo[1′,2′:2,3][1,2,4]triazolo[1,5‐a]pyrimidine skeleton

Dedicated to Dr. János Császár on the occasion of his 70^th birthday Ring transformation of 2‐cyanoimido‐3‐methyl‐1,3‐oxazolidine ( 10 ) yielded 5‐amino‐3‐[N‐(2‐hydrox‐yethyl)‐N‐methyl]amino‐1H‐1,2,4‐triazole ( 6 ) that was ring closed with different β‐keto esters to 2‐[N‐(2‐hydroxyethyl)‐N‐methyl]amino‐1,2,4‐triazolo[1,5‐a]pyrimidinones ( 4 ). Cyclisation of derivatives 4 led to imidazo[2′,1′:3,4][1,2,4]triazolo[1,5‐a]pyrimidines ( 2 ) and imidazo[1′,2′:2,3][1,2,4]triazolo[1,5‐a]pyrim‐idines ( 3 ) representing 10 novel ring systems. Besides spectroscopical evidence of structure of derivatives 2 and 3 X‐ray diffraction analysis of derivative 2b was also performed.     

Synthesis of 1-azabicyclo[3.3.0]octane derivatives and their effects as piracetam-like nootropics

A useful pharmaceutical intermediate, 5-nitromethyl-1-azabicyclo[3.3.0]octane (1), was prepared in one step from 1,7-dichloro-4-heptanone (4) under mild conditions. Catalytic hydrogenation of 1 over Raney Ni in the presence of sodium hydroxide afforded 5-aminomethyl-1-azabicyclo[3.3.0]octane (2) in high yield. Piracetam analogues 20-23, which were pyrrolidine derivatives involving a 1-azabicyclo[3.3.0]octane ring, were synthesized. Pharmacological tests showed that N-[(1-azabicyclo[3.3.0]octan-5-yl)methyl]-2-oxo-1-pyrrolidineacetamid e (20) improves cerebral function.     

Antibacterial properties of 3 H-spiro[1-benzofuran-2,1'-cyclohexane] derivatives from Heliotropium filifolium

A re-examination of cuticular components of Heliotropium filifolium allowed the isolation of four new compounds: 3'-hydroxy-2',2',6'-trimethyl-3H-spiro[1-benzo-furan-2,1'-cyclohexane]-5-carboxylic acid(2), methyl 3'-acetyloxy-2',2',6'-trimethyl-3H-spiro[1-benzofuran-2,1'-cyclohexane]-5-carboxylate (3), methyl 3'-isopentanoyloxy-2',2',6'-trimethyl-3H-spiro[1-benzofuran-2,1'-cyclohexane]-5-carboxylate (4) and methyl 3'-benzoyloxy-2',2',6'-trimethyl-3H-spiro[1-benzofuran-2,1'-cyclohexane]-5-carboxylate (5).Compounds 2-5 were identified by their spectroscopic analogies with filifolinol (1), and their structures confirmed by chemical correlation with 1. The antimicrobial properties of the compounds were tested against Gram positive and Gram negative bacteria. Some of them proved to be active against Gram positive, but inactive against Gram negative bacteria. In searching for structure-activity relationships from the obtained MIC values, lipophilicity was shown to be an important variable.     

A Mild and Efficient Synthesis of Novel Isoxazolyl‐Benzo[d]Pyrazino[2,1‐b] [1,3]Oxazoles

Synthesis of novel 2‐3‐methyl‐5‐[(E)‐2‐aryl‐1‐ethenyl]‐4‐isoxazolyl‐4,10a‐diaryl‐1,10a‐dihydro‐2H‐benzo[d]pyrazino[2,1‐b][1,3]oxazoles 5 were simply achieved by the reaction of 2‐[3‐methyl‐5‐[(E)‐2‐aryl‐1‐ethenyl]‐4‐isoxazolyl(2‐oxo‐2‐arylethyl)amino]‐1‐aryl‐1‐ethanones 3 with o‐aminophenol 4 in the presence of CAN catalyst. The intermediates, 2‐[3‐methyl‐5‐[(E)‐2‐aryl‐1‐ethenyl]‐4‐isoxazolyl(2‐oxo‐2‐arylethyl)amino]‐1‐aryl‐1‐ethanones 3 , were prepared by the reaction of 4‐amino‐3‐methyl‐5‐styrylisoxazole 1 , with phenacylbromides 2 in ethanol in the presence of K₂CO₃. The structures of the newly synthesized compounds 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h , 3i , 3j , 3k , 3l and 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j , 5k , 5l have been confirmed by analytical and spectral data.     

C- and N-alkylation of 4,5-dihydro-1H-indeno[1, 2-b]pyridine derivatives

2-Methyl-4-aryl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridine derivatives react with methyl iodide in an aprotic medium in the presence of alkaline agents to give C- and N-alkylation products, viz., 2,4a-dimethyl- and 1,2-dimethyl-4-aryl-5-oxo-4,5-dihydroindeno[1,2-b]pyridines, and with dimethyl sulfate or methyl p-tosylate under the same conditions to give N-methylation products.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 393–398, March, 1984.     

The synthesis of [1]benzothieno[2,3-c]quinolines, [1]benzothieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline,and [1]benzothieno[2,3-c]tetrazolo[1,5-a]quinoline

Photocyclization of 3-chloro-N-phenylbenzo[b]thiophene-2-carboxamide 10 afforded [1]benzothieno[2,3-c]-quinolin-6(5H)-one 11 which was chlorinated to 6-chloro[1]benzothieno[2,3-c]quinoline 12 followed by dechlorination to give [1]benzothieno[2,3-c]quinoline 5 . A series of 6-substituted alkoxy and thioalkoxy[1]benzothieno[2,3-c]quinoline derivatives were prepared along with the N-methyl quaternary salt 13 of 5 . 6-Chloro[1]-benzothieno[2,3-c]quinoline 12 was converted into 6-hydrazino[1]benzothieno[2,3-c]quinoline 23 which upon treatment with formic acid yielded [1]benzothieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline 6 . Treatment of 23 with nitrous acid resulted in [1]benzothieno[2,3-c]tetrazolo[1,5-a]quinoline 7 . Compounds 6 and 7 are novel heterocyclic ring systems.     

Smiles rearrangement for the synthesis of 5-amino-substituted [1]benzothieno[2,3-b]pyridine

The Smiles rearrangement was successfully applied to 4-hydroxybenzo[b]thiophene furnishing a facile entry to the 4-amino derivative. The rearrangement was extended to 5-methoxy-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine obtained via aza-Wittig/electrocyclization reaction of novel N-(4-methoxybenzothiophen-2-yl)iminomethyldiphenylphosphorane with methyl trans-4-oxo-2-pentenoate. The preparation of a novel 5-amino-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine, which is of interest as a potential secondary peptide structure mimic, was successfully achieved.     

Chemistry of 1,2,3-thiadiazole. IV. Synthesis of [1]benzoxepino-[3,4-d][1,2,3]thiadiazole, [1]benzothiepino-[3,4-d][1,2,3]thiadiazole, [1]benzoxepino[4,3-d][1,2,3]thiadiazole, [1]benzoxepino[4,3-d]oxazole and [1]benzoxepino[4,3-d]oxazole. Four novel heterocycles

Starting from the readily available 4-bromomethy-5-carbethoxy 1,2,3-thiadiazole (V), 5-bromomethy-4-carbethoxy-1,2,3-thiadiazole (IX) and ethyl 2-aryl-5-bromomethyloxazole-4-carboxylate (XIV), 4,10-dihydro-10-oxo[1]benzoxepino[3,4-d][1,2,3]thiadiazole (Ia), 4,10-dihydro-10-oxo[1]benzothiepino[3,4-d][1,2,3]thiadiazole (Ib), 4,10-dihydro-4-oxo[1]benzothiepino[4,3-d] [1,2,3]thiazole (II), 2-aryl-4,10-dihydro-4-oxo[1]benzoxepino[4,3-d]oxazoles (XIXa-XIXc) and 2-aryl-4,10-dihydro-4-oxo[1]benzothiepino[4,3-d]oxazoles (XIXd-XIXf) were prepared.     

Alkylation of 1-hydroxy-1H-[1,2,3]triazolo[4,5-e][1,2,3,4]tetrazine 5,7-dioxide

Alkylation of 1-hydroxy-1H-[1,2,3]triazolo[4,5-e][1,2,3,4]tetrazine 5,7-dioxide 1 and its silver salt 10 with different alkylating agents (diazomethane, diazoacetone, bromoacetone, α-bromoacetophenone, methyl iodide, methyl vinyl ketone) was studied. Alkylation of compound 1 with diazo compounds and salt 10 with halocompounds results predominantly in O-alkylation products, 1-alkoxy-1H-[1,2,3]triazolo[4,5-e][1,2,3,4]tetrazine 5,7-dioxides. The Michael reaction of compound 1 with methyl vinyl ketone involves the triazole nitrogen atom to give 1-(3-oxobutyl)-1H-[1,2,3]triazolo[4,5-e][1,2,3,4]tetrazine 3,4,6-trioxide. The structures of the compounds synthesized were established by ¹H, ¹³C, ¹⁴N NMR spectroscopy and mass spectrometry.     

1,2,4-Triazoles—XXXIV: Photodimerization of some 1,2,4-triazo[4,3--]quinoline and 1,2,4-triazolo[3,4-a]isoquinoline derivatives

Irradiation of 1,2,4-triazolo[4,3-a]quinoline and several Me derivatives at 300 nm afforded the cisoid-fused, head-to-tail cyclobutane dimers 7bα,7cα,14bα,14cα - tetrahydro - 1,2,3a,8,9,10a - hexaazadibenzo [c,i]dicyclopenta[a,g]biphenylenes. However, 1,2,4 - triazolo[3,4-a]isoquinolines gave analogous cisoid-fused, head-to-head dimers except for the 5-Me derivative where the head-to-tail dimer was obtained.Codimerization occurred when 1 - methyl - 1,2,4 - triazolo[4,3-a]quinoline and 5 - methyl - 1,2,4 -triazolo[3,4-a]isoquinoline were irradiated at 300 nm, affording a cisoid-fused head-to-tail cyclobutane co-dimer as the single photoproduct. However, irradiation of their 5-Me substituted derivatives at 300 nm afforded the cisoid-fused, head-to-head, cyclobutane codimer and also a minor amount of the dimer derived from 5 - methyl -1,2,4- triazolo[4,3-a] quinoline. Irradiation of equimolar quantities of 2(1H)-quinolinone and 5 - methyl - 1,2,4 -triazolo [4,3-a]quinoline at 300 nm gave the known 2(1H)-quinolinone dimer and a minor amount of a cisoid-fused co-dimer of undetermined configuration.     

Reaction of Substituted Methyl 2,3,7-Triazabicyclo[3.3.0]oct-3-ene-4-carboxylates and 1,2,7-Triazaspiro[4.4]non-2-ene-3-carboxylates with Iodinating Agents

Substituted methyl 2,3,7-triazabicyclo[3.3.0]oct-3-ene-4-carboxylates and 1,2,7-triazaspiro[4.4]non-2-ene-3-carboxylates react with N-iodosuccinimide (or the system iodine-silver trifluoroacetate) to give, respectively, methyl 6-iodo-3-azabicyclo[3.1.0]hexane-6-carboxylates or methyl 1-iodo-4,6-dioxo-5-azaspiro[2.4]heptane-1-carboxylates as mixtures of exo and endo isomers.     

Synthesis, structure and properties of N-acetylated derivatives of methyl 5-amino-1H-[1,2,4]triazole-3-carboxylate

Methyl 5-amino-1H-[1,2,4]triazole-3-carboxylate hydrochloride (1). and free ester (2). were obtained and 2 was reacted with Ac(2)O to give the acetylated products 3-6. Compounds 1-6 were studied using HPLC, GC-MS, FTIR and multinuclear NMR spectroscopy, including the cross-polarisation magic angle spinning (CPMAS) technique. The results of the acetylation of 2 were compared to those of the acetylation of 5-amino-1H-[1,2,4]triazole, and for 2 a significant decrease in the susceptibility to acetylation was found. The reaction of 2 with Ac(2)O at 20 degrees C, regardless of the amount and the concentration of the latter, including neat Ac(2)O, proceeds fully regioselectively and leads to one product: methyl 1-acetyl-5-amino-1H-[1,2,4]triazole-3-carboxylate (3). In sharp contrast to 5-amino-1H-[1,2,4]triazole, neither an additional monoacetylated isomer, whether annular or exocyclic, nor any diacetylated derivative could be detected. The diacetylation of 2 requires the process to be carried out in neat boiling Ac(2)O and, as in the case of 5-amino-1H-[1,2,4]triazole, gives two diacetylated isomers. These are methyl 1-acetyl-3-(acetylamino)-1H-[1,2,4]triazole-5-carboxylate (4) and 1-acetyl-5-(acetylamino)-1H-[1,2,4]triazole-3-carboxylate (5). Hypothetical pathways of their formation have been suggested. A mixture of 4 and 5 upon hydrolysis of the ring acetyl group gives the monoacetylated derivative methyl 5-(acetylamino)-1H-[1,2,4]triazole-3-carboxylate (6). The spectroscopic, structural and conformational characteristics of compounds 1-6 have been given and methods for their preparation have been provided.     

达比加群酯中间体3-【【【2-{[(4-氰基苯基)氨基]甲基}-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯的合成

以对氨基苯腈为起始原料,经胺化反应制得N-(4-氰基苯基)甘氨酸(4);4与N-[3-氨基-4-(甲基氨基)苯甲酰基]-N-2-吡啶-β-丙氨酸乙酯(5)经酰胺化后经闭环反应,合成了达比加群酯的关键中间体——3-【【【2-{[(4-氰基苯基)氨基]甲基}-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯,总收率79.6%,其结构经~1H NMR和ESI-MS确证。     

Synthesis of 4‐(1‐phenyl‐1H‐pyrazol‐3‐yl)‐[1,2,4]triazolo[4,3‐a]quinoxalines and their 4‐halogenopyrazolyl analogs

Synthesis of {3‐[1‐(ethoxycarbonyl)‐[1,2,4]triazolo[4,3‐a]quinoxalin‐4‐yl]‐1‐phenyl‐1H‐pyrazol‐5‐yl}methyl ethyl oxalate ( 2 ), ethyl 4‐[5‐(acetoxymethyl)‐1‐phenyl‐1H‐pyrazol‐3‐yl]‐[1,2,4]triazolo[4,3‐a]quioxaline‐1‐carboxylate ( 4 ), [4‐halo‐1‐phenyl‐3‐(1‐phenyl‐[1,2,4]triazolo[4,3‐a]quioxalin‐4‐yl)‐1H‐pyrazol‐5‐yl]methyl acetate ( 11 ), {4‐halo‐3‐[1‐methyl‐[1,2,4]triazolo[4,3‐a]quinoxalin‐4‐yl]‐1‐phenyl‐1H‐pyraz‐ol‐5‐yl}methyl acetate ( 13 ), and [3‐([1,2,4]triazolo‐[4,3‐a]quinoxalin‐4‐yl)‐4‐halo‐1‐phenyl‐1H‐pyrazol‐5‐yl] methyl formate ( 15 ) was accomplished. The structural investigation of the new compounds is based on chemical and spectroscopic evidences. J. Heterocyclic Chem., (2011)     

Enantiospecific synthesis of annulated nicotine analogues from D-glutamic acid. 7-Azabicyclo[2.2.1]heptano[2.3-c]pyridines

The conformationally restricted nicotinoid (1S,4S)-7-methyl-7-azabicyclo[2.2.1]heptano[2,3-c]pyridine dihydrochloride has been prepared enantiospecifically from D-glutamic acid. The method involved a lithium cis-2,6-dimethylpiperidide-mediated intramolecular anionic cyclization of (2S,5R)-N-(tert-butyloxycarbonyl)-5-[3-(4-N-chloropyridinyl]proline methyl ester in tandem with a standard decarboxylation sequence. Reductive amination afforded the desired N-methylated [2.2.1]bicyclonicotinoid. Cyclization of the corresponding iodopyridinylproline methyl ester, obtained via ultrasound-facilitated chloro-iodo exchange, was also effected.