Studies on the benzo[1,2]cyclohepta[3,4,5-d,e]isoquinoline ring system

The syntheses of various oxidation states of the novel benzo[1, 2]cyclohepta[3, 4, 5-d, e]-isoquinoline ring system is described. The ring system was obtained by the Schmidt rearrangement, with exclusive alkyl migration, of 1, 6, 7, 11b-tetrahydro - 2H - dibenz-[cd,h]azulen-2-one and by a Bischler-Napieralski reaction of suitable derivatives of 10, 11-dihydro-5H-dibenzo[a, d]cycloheptene - 5 - methylamine. 4, 5, 10, 11 - Tetramethoxy derivatives of the new ring system were best prepared by a Pictet-Spengler reaction of the appropriate amine.     

Synthesis of New Heterocyclic Systems on the Basis of 7-Benzyl-3-chloro-1-(morpholin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthiridine-4-carbonitrile

Methods have been developed for the synthesis of new 8-amino-3-benzyl-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4′,5′: 4,5]thieno[2,3-c][2,7]naphthyridine starting from 7-benzyl-3-chloro-1-(morpholin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile. 8-Hydrazinyl-3-benzyl-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4′,5′: 4,5]thieno[2,3-c][2,7]naphthyridine has been converted to isomeric pentacyclic structures with a triazole ring fused through the [c] side of the pyrimidine ring, and their Dimroth rearrangement has been accomplished in both acidic and basic media. New heterocyclic systems containing pyrrolo[1,2-a]pyrimidinone and pyrimido[1,2-a]azepinone fragments were obtained on the basis of the thieno-[2,3-c][2,7]naphthyridine derivative.     

Synthesis of 3-(2-Phenylquinolin-4-yl)/3-(l-p-Chlorophenyl-5-methyl-1, 2,3-triazol-4-yl)-s-triazolo[3,4-b]-1, 3,4-thiadiazine Derivatives

s-Triazolo[3, 4-b]-1,3,4-thiadiazine derivatives constitute an important class of organic compounds with diverse biological activities. 2-Phenylquinoline and 1,2, 3-triazole derivatives are very attractive heterocyclic systems due to their wide use in medicine, agriculture and industry^[1]. Incorporation of 2-phenylquinoline and 1,2,3-triazole moiety into the 3-position of s-triazolo[3,4-b]-l, 3,4-thiadiazine ring system may enhance their biological activity. In light of the above findings, we synthesized some new s-triazolo[3, 4-b]-1, 3, 4-thiadiazine derivatives 2a-b~6a-b by the condensation of 4-amino-5-mercapto-3-(2-phenylquinolin-4-yl)/3-(1-p-chlorophenyl-5-methyl-1, 2,3-triazol-4-yl)-1, 2, 4-triazoles 1a-b with chloroacetalde-hyde, ω-bromo-ω-(1H-1, 2, 4-triazol-1-yl)acetophenone, chloranil, 2-bromocyclohexanone, 2, 4'-dibromoacetophenone, respectively.     

The synthesis of 4H-imidazo[5,1-c][1,4]benzothiazine derivatives

A facile synthesis of the 4H-imidazo[5,1-c][1,4]benzothiazine ring system is described. The synthesis utilized the annulation of an imidazole ring onto a 2H-1,4-benzothiazin-3(4H)-one via the addition of the anion of ethyl isocyanoacetate. Methods for the functionalization of the 1-, 3-, 4-, and 5-positions of the ring system are presented.     

On triazoles XVIII. . an unexpected rearrangement observed during the reaction of 5-amino-1,2,4-triazoles with N-heterocyclic β-oxo-esters

In the course of the synthesis of pyrido[4,3-d]-1,2,4-triazolo[1,5-a]pyrimidine derivatives 3c representing a novel ring system an unexpected rearrangement of the intermediate enamines to yield 5 was observed. A mechanism of the formation of 5 was suggested. The isomeric pyrido[4,3-e]-1,2,4-triazolo[1,5-a]pyrimidine derivatives 4c containing also a new ring system were obtained, too. The structure of products obtained was proved with the help of their uv, cmr and X-ray spectra.     

A convenient approach to heterocyclic building blocks: synthesis of novel ring systems containing a [5,6]Pyrano[2,3-c]pyrazol-4(1H)-one moiety

Starting from commercially available educts, a straightforward synthetic route to new heterocyclic building blocks is exemplified with the one- or two-step synthesis of tri-, tetra-, or pentacyclic ring systems. Representatives of the following novel ring systems are prepared from 3-methyl-1-phenyl-2-pyrazolin-5-one and the corresponding o-halo-arenecarbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane: pyrimidino[4',5':5,6]pyrano[2,3-c]pyrazol-4(1H)-one, thieno[3',2':5,6]pyrano[2,3c]pyrazol- 4-(1H)-one, thieno[3',4':5,6]pyrano[2,3-c]pyrazol-4(1H)-one, thieno[3',2':4',5']thieno[2',3':5,6]-pyrano[2,3-c]pyrazol-4(1H)-one, [1,3]dioxolo[5',6'][1]benzothieno[2',3':5,6]pyrano-[2,3-c]- pyrazol-4(1H)-one, pyridazino[4',3':5,6]pyrano[2,3-c]pyrazol-4(1H)-one and pyrazolo-[4',3':5',6']pyrido[3',4':5,6]pyrano[2,3-c]pyrazol-4(1H)-one. While the latter two ring systems are directly obtained due to a spontaneous intramolecular substitution reaction, in the other reactions uncyclised 4-aroylpyrazol-5-ols are produced, which are cyclised into the target heterocycles in a subsequent synthetic step (i.e. treatment with NaH in DMF). Detailed NMR spectroscopic investigations ((1)H-, (13)C-, (15)N-) with the obtained compounds were undertaken to unambiguously prove the new structures.     

Nitration of 2- and 4-[2-(2-furyl)vinyl]thiazole derivatives

Nitration of 4-methyl-2-[2-(nitro-2-furyl)vinyl]thiazole with a mixture of concentrated nitric and sulfuric acids leads to 4-methyl-5-nitro-2-[2-(3,5-dinitro-2-furyl)vinyl]thiazole. Under the same conditions 2-methyl- and 2-acetamido-4-[1-R-2-(5-nitro-2-furyl)vinyl]thiazoles (R=CH₃, Cl) are nitrated in the 3 position of the furan ring, 2-amino-4-[1-chloro-2-(5-nitro-2-furyl)vinyl]thiazole is nitrated in the 5 position of the thiazole ring and 2-acetamido-5-nitro-4-[2-(2-furyl)vinyl]thiazole undergoes profound changes. Under the influence of a mixture of of nitric acid and acetic anhydride the latter compound is converted quantitatively to the 5-nitro derivative (with respect to the furan ring), whereas 4-[2-(5-nitro-2-furyl)vinyl]thiazole derivatives do not undergo reaction.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 314–317, March, 1977.     

Synthesis of Heterocyclic Compounds from 2-Phenyl-l,2,3-Triazole-4-Formylhydrize

Many compounds containing the 1,3,4-oxadiazole and/or1,2,3(or 4)-triazole and thiadiazole ring system are reported to possess antibacterial^[1], antiinflammatory^[2], anticonrulsant^[3],CNS stimulant^[4] and pesticidal^[5] activities and excellent anthelmintic properties^[6,7]. In view of this and the results of the combined different nuclei system in a molecular always enhancing the therapeutic activities,the present work deals with the synthesis of the combined different pharmacologically active nuclei system mentioned above in a molecular through some new method.     

Condensed pyridazines. Part III. Rearrangement and ring cyclization during the thermolysis of (z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate

The thermolysis of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate ( II ) provides a new synthetic route to pyrrolo[2,3-c-]pyridazines, specifically, methyl 3-chloro-1,6-dimethyl-4-oxo-1,4-dihydro-7H-pyrrolo[2,3-c]pyridazine-5-carboxylate ( III ) in 91% yield. Treatment of III with ozone provides an entry into the novel pyridazino[3,4-d][1,3]oxazine ring system, specifically, 3-chloro-1,7-dimethylpyridazino[3,4-d][1,3]oxazine-4,5-dione ( IV ) in 73% yield. Compound IV is smoothly hydrolyzed into 6-acetylamino-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( V ) which is readily recyclized into IV by dehydration with acetic anhydride. Furthermore, IV undergoes a facile reductive ring opening reaction with sodium borohydride to give 3-chloro-6-ethylamino-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( VI ) in 95% yield.     

Synthesis of 3,4-Dihydro-2-methyl-3-oxo-N-aryl-2H-[1]benzothieno[3,2-e1,2-thiazine-4-carboxamide 1,1-Dioxides

A novel synthesis of the title compounds, representing a new heterocyclic ring system, is described. Chlorosulphonation of 3-methylbenzo[b]thiophene followed by reaction with methylamine gave sulfonamide, 4 . Lithiation of 4 , followed by quenching with carbon dioxide yielded acetic acid, 5 . Cyclodehydration of 5 to benzothienothiazine 6 followed by reaction with aryl isocyanates afforded the desired benzothieno[3,2-e]-1,2-thiazine-4-carboxamides 1a-f.     

Synthesis of the new ring system,Pyrazolo[3,4-d][1,3]diazepine. A novel route for the synthesis of azolo[1,3]diazepines

A reduction of the nitrile group of 5-amino-4-cyano-1-methylpyrazole ( 3 ) has provided the very versatile compound 5-amino-1-methylpyrazole-4-carboxaldehyde ( 4 ). The amino group of 4 was protected using di-methylformamide dimethylacetal and the aldehyde group was then reacted with trimethylsilyl cyanide to afford the moisture sensitive compound 5-[[(dimethylamino)methylene]amino]-4-[cyano(trimethylsiloxy)-methyl]-1-methylpyrazole ( 10 ). The cyano group of the cyanohydrin 10 was reduced using a cobalt boride catalyst to afford an intermediate aminomethyl group which was involved in an in situ annulation. This reaction provided 1-methyl-1,4,5,6-tetrahydropyrazolo[3,4-d][1,3]diazepin-4-ol, a derivative of the new ring system, pyrazolo[3,4-d][1,3]diazepine.     

A new strategy for the construction of the imidazo[1,5-a]quinoxalin-4-one ring system and its application to the efficient synthesis of BMS-238497, a novel and potent Lck inhibitor

A new efficient strategy was developed for the construction of the imidazo[1,5-a]quinoxalin-4-one ring system. The new method involves condensation of o-nitroaniline with glyoxylate in methanol followed by treatment of the resulting alpha-(o-nitroanilino)-alpha-methoxy acetate with tosylmethyl isocyanide (TosMIC) reagent to give 1-(o-nitrophenyl)imidazole-5-carboxylate. Reductive cyclization of the nitro imidazole carboxylate afforded imidazo[1,5-a]quinoxalin-4-one in three steps and 60% overall yield. The new method was successfully applied to the synthesis of BMS-238497, a novel and potent Lck inhibitor.     

Synthesis of ethyl 4,5-disubstituted 2-azido-3-thiophenecarboxylates and use in the synthesis of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-ones

New heterocyclic azides, ethyl 2-azido-4-R¹-5-R²-3-thiophenecarboxylates, were synthesized by diazotization of 2-aminothiophenes and subsequent treatment with sodium azide. The reactions of these heterocyclic azides with β-ketoesters and activated acetonitriles were studied. The derivatives of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine, a new ring system, were prepared in high yields via an anionic hetero-domino reaction.     

Cyclization of 5-diazoimidazole-4-thioamide

Cyclization of 5-diazoimidazole-4-thioamide and -4-methylthioamide gives derivatives of a new heterocyclic system — imidazo[4,5-e]-2,3,4-thiadiazine — which are readily recyclized to 2-azapurines. 4-Methylthioimidazo[4,5-d]-1,2,3-triazine was synthesized, and its reactions with amines and hydrazines were studied.     

Synthesis of analogs of 5(4)-aminoimidazole-4(5)-carboxamide and purines

4-Chloroimidazo[4,5-d]-1,2,3-triazine was obtained by oxidative chlorinatlon from imidazo[4,5-d]-1,2,3-triazine-4-thione, and its reaction with nucleophilic agents and cleavage of the triazine ring to give 5-diazoimidazole-4-carbonitrile were studied. The newly synthesized diazoimidazole was subjected to C- and N-diazo coupling. It was established that 3-methylimidazo[4,5-d]-1,2,3-triazine-4-imine, formed by reaction of the diazo compound with methylamine, is capable of recyclization to 4-methylaminoimidazo[4,5-d]-1,2,3-triazine.See [1] for communication IV.Translated from Khimiya Getereotsiklicheskikh Soedinenii, No. 4, pp. 556–559, April, 1976.     

Reaction of tricarbonyl[(1-4-η)-2-methoxy-5-vinylidene-cyclohexa-1,3-diene]iron derivatives with carbene: (2+1) cycloaddition for the rapid synthesis of spiro[2,5]octane

Tricarbonyl[(1-4-η)-2-methoxy-5-methylene-cyclohexa-1,3-diene]iron (1a) and tricarbonyl[(1-4-η)-2-methoxy-5-isopropylene-cyclohexa-1,3-diene]iron (1b) complexes are unstable 4-vinylidene cyclohexanone equivalents and these react regio- and stereoselectively with carbenes and metallocarbenes to give spiro[2,5]octane ring system. The (2+1) cycloaddition reaction provides a rapid entry into spiro[2,5]octane ring system. In cases where the carbene and metallocarbene contain a good bulky leaving group or an electron-withdrawing group, the cyclopropane ring-opening products are obtained.     

Nucleophilic and Electrophilic Properties of Carbenes,II. 4-Biphenylyl-4-pyridylcarbene

Flash pyrolysis of 4-biphenylyl-4-pyridyldiazomethane ( 4 gave 7-phenyl-2-azafluorene) 5 , which was also synthesized from 3-mesitoylpyridine in four steps. 4-Biphenylyl-4-pyridyl-[¹³C]-diazomethane ( 9 ) was prepared from isonicotinic [¹³C]-acid chloride in three steps. Flash pyrolysis of 9 established that 4a- and 4b-[¹³C]-7-phenyl-2-azafluorenes are formed in a carbene-carbene rearrangement in which ring expansion of the biphenyl part dominates over that of the pyridine ring. These results support the postulate that carbene-carbene rearrangements are favoured by a nucleophilic interaction between the filled singlet carbene sp² (σ) orbital and the lowest unoccupied molecular orbital (LUMO) of the aromatic ring.     

The synthesis and transition temperatures of 5-(4-alkyl- and 4-alkoxy-phenyl)-2-cyanobenzo[b]furans and a 5-(4'-alkylbiphenyl-4-yl)-2-cyanobenzo[b]furan: a comparison with their biphenyl and terphenyl analogues

The synthesis and transition temperatures of a series of 5-(4-alkyl- and 4-alkoxy-phenyl)2-cyanobenzo[b]furans and a 5-(4'-alkylbiphenyl-4-yl)-2-cyanobenzo[b]furan are presented. The 2-cyanobenzo[b]furans show similar mesophase types to the analogous biphenyl and terphenyl compounds, which are obtained by replacing the benzo[b]furan unit with a phenyl ring. The transition temperatures for the 2-cyanobenzo[b]furan compounds are always higher than for their biphenyl and terphenyl counterparts, but they are much lower than for the corresponding phenylnaphthalenes. Five mesogenic benzo[b]furans without a cyano group were prepared as intermediates and these compounds have lower clearing points than their biphenyl analogues.     

Tetrasilacyclobutadiene ((t)Bu(2)MeSi)(4)Si(4): a new ligand for transition-metal complexes

The anionic complex of [tetrakis(di-tert-butylmethylsilyl) tetrasilacyclobutadiene]dicarbonylcobalt, [(R4Si4)Co(CO)2]-.K+ (R = SiMetBu2) 2-.K+, was synthesized by the reaction of tetrasilacyclobutadiene dianion dipotassium salt [R4Si4]2-.2K+ 1 with an excess of CpCo(CO)2 in THF. X-ray analysis of 2-.[K+(diglyme)2(THF)] showed an almost planar Si4 ring of rectangular shape with an in-plane arrangement of the silyl substituents. 2- was also prepared as a free anion with the [K+[2.2.2]cryptand] counterion by complexation with [2.2.2]cryptand and as a dimer {2-.[K+(THF)3]}2 without complexing reagents in THF. Such a tetrasilacyclobutadiene fragment represents a new type of ligand for Co complexes, being the first example of a cyclobutadiene containing only heavier group 14 elements.     

Synthesis of a 4H-anthra[1,2-b]pyran derivative and its antimicrobial activity

The five-step synthesis of the new 4H-anthra[1,2-b]pyran derivative 1 is reported. The key steps in this approach included a Marschalk alkylation of 1,4-dihydroxyanthraquinone followed by a Baker-Venkataraman reaction and then an acid-catalyzed cyclization of ring A to form the 4H-anthra[1,2-b]pyran system. Two compounds, the 4H-anthra[1,2-b]pyran 1 and the anthraquinone derivative 6 were evaluated for antimicrobial activity and showed moderate antialgal, antifungal, and antibacterial activities.