Stereoselectivity in the Addition of 1,3-Dipolarophiles to 6-Aryl-1,5-diazabicyclo[3.1.0]hexanes

Thermolysis of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes in the presence of N-arylmaleimides having a substituent in the ortho position of the aromatic ring leads to predominant formation of the corresponding trans-9-arylperhydropyrazolo[1,2-a]pyrrolo[3,4-c]pyrazole-1,3-diones. 6-Aryl-1,5-diazabicyclo[3.1.0]hexanes react with fumaric acid derivatives in a stereoselective fashion, affording perhydropyrazolo[1,2-a]pyrazoles with a trans,trans configuration.     

Diaziridine ring expansion in 6-aryl-1,5-diazabicyclo[3.1.0]hexanes upon reactions with activated olefins in ionic liquids

Reactions of 1,3-diphenylpropen-2-one and α-nitrostyrenes with azomethine imines, generated from 6-aryl-1,5-diazabicyclo[3.1.0]hexanes on catalysis with Et2O•BF3 in ionic liquids, were found to proceed with high regio- and stereoselectivity to afford the products of the diaziridine ring expansion, viz., [3-aryl-2-phenyltetrahydro-1H,5H-pyrazolo[1,2-a]pyrazol- 1-yl](phenyl)methanones, 1,3-diaryl-2-nitrotetrahydro-1H,5H-pyrazolo[1,2-a]pyrazoles and 5-aryl-6-(3-nitrophenyl)-2,3-dihydro-1H-pyrazolo[1,2-a]pyrazolium tetrafluoroborates (hexafluorophosphates). The reactions discovered are new, more simple methods for the syn- thesis of bicyclic structures.     

Ionic liquids on the basis of 2,3,4,6,7,8,9,10-octahydropyrimido-[1,2-a]azepine (1,8-diazabicyclo[5.4.0]undec-7-ene)

New ionic liquids containing alkyl and polyfluoroalkyl substituents and various anions were synthesized from 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepinium ion (1,8-diazabicyclo[5.4.0]undec-7-en-8-ium). Their NMR spectra and miscibility with water and organic solvents were studied.     

Synthesis of [1,2,3]Triazolo[1,5-a]quinoline-3-carboxamides Promoted by Organocatalyst and Base

We described here a simple and metal-free protocol to synthesize [1,2,3]triazolo[1,5-a]quinoline 3-carboxamides through a two-step synthetic strategy, in which the first step uses organocatalysis (10 mol % of diethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, while the second step involves the use of inorganic base (1.2 or 0.1 equiv. of potassium hydroxide). These reactions were performed between β-keto amides and o-carbonyl phenylazides in dimethylsulfoxide as solvent at 70 °C for 2 h. The synthetic protocol is ample, which thirteen examples of secondary [1,2,3]triazolo[1,5-a]quinoline 3-carboxamides were synthesized ranging from good to excellent yields (63-96 %), and six different tertiary [1,2,3]triazolo[1,5-a]quinolines 3-carboxamides were obtained ranging from moderate to good yields (48–76 %).     

Preparation and characterization of 6-substituted 1,8-diazabicyclo[5.4.0]undec-7-ene

The lithium 1,8-diazabicyclo[5.4.0]undec-6-ide ( 1 ) prepared from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and n-butyllithium reacts with alkyl halides and carbonyl compounds such as benzophenone, acetophenone, and benzaldehyde to give 6-substituted DBU derivatives in good yields. The reaction behavior of 6-substi-tuted DBU was also investigated.     

The synthesis of 7,8-dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]triazines

Cyclic hydrazino amidines were converted to the corresponding aminopyrazolyl derivatives. Ring closure between the amino groups of pyrazoline moieties and NH groups of cyclic amidines afforded the following ring systems: 7,8-Dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines.     

The reduction of 1,7-diazabicyclo[4,3,0]non-6-ene and of 2,3-dihydromidazo-[1,2-a]pyridine as azacyclic compounds with an amidine structure

It has been shown that the reduction of 1,7-diazabicyclo[4,3,0]non-6-ene and of 2,3-dihydroimidazo[1,2-a]-pyridine takes place with the hydrogenolysis of the C=N bond and the formation of 1-(-aminoethyl)piperidine or its 3,4-dehydro derivative.     

Syntheses of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines from methyl tetrahydro-4-oxo-3-thiophenecarboxylate and methyl tetrahydro-3-oxo-2-thiophenecarboxylate,respectively

A general synthesis of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]-thieno[3,2-d]pyrimidines is described. Methyl tetrahydro-4-oxo-3-thiophenecarboxylate ( 13 ) was condensed with 6-aminonicotinic acid ( 18 ) to give 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 19 ). Treatment of 19 successively with chlorotrimethylsilane, N-chlorosuccinimide and water gave 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 17 ). Methyl tetrahydro-3-oxo-2-thiophenecarboxylate ( 21 ) was converted to 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid ( 25 ) by an analogous route.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 8 . [1]Benzothieno[2,3-c]naphtho[1,2-h]quinoline and [1]benzothieno[2,3-c]naphtho[1,2-h][1,2,4]triazolo[4,3-a]quinoline

The previously unknown polycyclic heterocyclic ring systems, namely, [1]benzothieno[2,3-c]naphtho[1,2-h]-quinoline and [1]benzothieno[2,3-c]naphtho[1,2-h][1,2,4]triazolo[4,3-a]quinoline were synthesized via photocyclization of 3-chloro-N-(1′-phenanthryl)benzo[b]thiophene-2-carboxamide.     

Quino[1,2-c]quinazolines. I. Synthesis of quino[1,2-c]quinazolinium derivatives and the related indazolo[2,3-a]quinoline derivatives as analogs of the antitumor benzo[c]phenanthridine alkaloids

9,10-Dimethoxy-1,2,3,4,12,13-hexahydro-1-oxoquino[1,2-c]quinazolinium perchlorate, 1,2,3,4,13,24-hexahydro-1-oxo[1,3]dioxolo[4,5-g]quino[1,2-c]quinazolinium perchlorate, 6-methyl-2,3,9,10-tetramethoxyquino-[1,2-c]quinazolinium perchlorate and 2,3-dimethoxy-13-methyl[1,3]dioxolo[4′,5′:6,7]quino[1,2-c]quinazolinium perchlorate were synthesized as analogs of the potent antitumor benzo[c]phenanthridine alkaloids nitidine and fagaronine. The related 2,3,8,9-tetramethoxyindazolo[2,3-a]quinoline and 2,3-dimethoxy[1,3]dioxolo-[4,5-g]indazolo[2,3-a]quinoline were also synthesized. Further, the novel formation of 6,7-dimethoxy-2-(2-ethylamino-4,5-dimethoxyphenyl)quinoline via reductive alkylation with Raney nickel in refluxing ethanol is also reported.     

Polycyclic systems: Synthesis of isoindolo[2,1-b]-pyrrolo[1,2-d][2,4]benzodiazocine and isoindolo-[1,2-d]pyrrolo[1,2-a] [1,5]benzodiazocine

The synthesis of isoindolo[2,1-b]pyrrolo[1,2-d][2,4]benzodiazocine 7 and isoindolo[1,2-d]pyrrolo[1,2-a]-[1,5]benzodiazocine 13 are described starting from 2-(2-methoxycarbonyl)benzylphthalimide 1a and ethyl α-bromohomophthalate 9 respectively.     

Transformations of the pyrido[1,2-a]pyrazine ring system into imidazo[1,2-a]pyridines,imidazo[1,2-a]pyrimidines and 2-oxa-6a, 10c-diazaaceanthrylenes

Transformations of methyl 3-dimethylamino-2-(1-methoxycarbonyl-4-oxo-4H-pyrido[1,2-a]pyrazin-3-yl)acrylate with some cyanomethylenecarbonyl group containing compounds or cyanamide into imidazo-[1,2-a]pyridines, irmdazo[1,2-a]pyrimidines and 2-oxa-6a, 10c-diazaaceanthrylenes are described.     

Synthesis of novel imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines and pyrimido[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines

Several 1 1-amino-5H-pyrrolo[2,1-c][1,4]benzodiazepines have been used as starting material to prepare a number of derivatives of 9H-imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines and 10H-pyrimido[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepines. The imidazole nucleus was built by reaction of amidines with ethyl bromopyruvate or aminoacetaldehyde dimethylacetal. Several derivatives of imidazo[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine have been prepared by formylation of the pyrrole ring followed by formation of thioamides. Condensation of 11-amino-5H-pyrrolo[2,1-c][1,4]benzodiazepines with diethyl ethoxymethylenemalonate afforded intermediate diesters which were transformed into the corresponding 10H-pyrimido[1,2-a]pyrrolo[2,1-c]-benzodiazepines.     

Formylation of Furyl-substituted Imidazo[1,2-a]pyridine, Imidazo[1,2-a]pyrimidine and Imidazo[2,1-b]thiazole

Vilsmeier formylation of 2-(2-furyl)-substituted imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine, and also 6-(2-furyl)imidazo[2,1-b]thiazole with 1 mole of reagent occurs at the free position of the imidazole ring, while with an excess of the reagent it also occurs at the position 5 of the furyl group.     

The average structures of 2,3-diazabicyclo[2.2.1]hept-2-ene and 2,3-diazabicyclo[2.2.2]oct-2-ene

The average molecular structures of 2,3-diazabicyclo[2.2.1]hept-2-ene and 2,3-diazabicyclo[2.2.2] oct-2-ene have been determined by electron diffraction in the gas phase. The structural parameters were obtained by applying a least squares analysis on the molecular scattering intensity functions. For 2,3-diazabicyclo[2.2.1]hept-2-ene, C_s symmetry was assumed in calculating the geometry of the molecule. The parameters thus determined are: N₃=N₂ = 1.221 Å, N₃- C₄ = 1.445 Å, C₄-C₅ = 1.538 Å, C-H_(ave.) = 1.112 Å, < C₁N₂N₃ = 116.3°, < N₃C₄C₅ = 105.2°, < C₁C₄C₅ = 71.5°, C₄-C₇ = 1.547 Å, C₅-C₆ = 1.530 Å, < C₁C₇C₄ = 108.0°. For 2,3-diazabicyclo[2.2.2]oct-2-ene, C_2vsymmetry was assumed. The geometrical parameters are: N₃ = N₂ = 1.243 Å, N₃-C₄ = 1.473 Å, C₄-C₅ = 1.550 Å, C₅-C₆ = 1.516 Å, C-H_(ave.) = 1.119 Å,< C₁N₂N₃ = 115.1°, < N₃C₄C₅ = 109.1°, < C₆C₁C₄ = 71.6°.     

New heterocyclic structures. [1,3]Thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine

Derivatives of two new molecular structures, namely, [1,3]thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d]-[1,3]thiazino[3,2-a]pyrimidine, were synthesized together with other heterocyclic compounds. Retrosynthetic analysis of their molecular skeletons suggested a simple way of obtaining 3,4-dihydro-7,8-diamino-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one, which is a useful intermediate for their synthesis. This intermediate and the thiazole homologue were obtained directly by reaction of 5,6-diamino-2,3-dihydro-2-thioxo-4(lH)-pyrimidi-none with 1,3- or 1,2-dibromoalkane, respectively.     

A general and efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes

A convenient and efficient synthesis of N⁶-substituted 3,6-diazabicyclo[3.2.1]octanes (6a-c) has been achieved starting from suitably substituted lactams, which were converted to nitroenamines followed by reductive cyclization to afford 3,6-diazabicyclo[3.2.1]octane-2-ones in good yields. These bicyclic lactams were then reduced to the corresponding 3,6-diazabicyclo[3.2.1]octanes and converted to the required N³,N⁶-disubstituted 3,6-diazabicyclo[3.2.1]octanes (7a-h), which were screened for α₁-adrenoceptors antagonistic activities.     

Thermolyzed products of naphth[1,2-d]imidazo[2,1-b]-thiazole-2,3-dione

Themolysis of naphth[1,2-d]imidazo[2,1-b]thiazole-2,3-dione ( 1 ) in dimethylformamide gave an intermediate 2-isocyanatonaphtho[1,2-d]thiazole ( 2 ), which underwent [4 + 4] cyclodimerization to yield dinaphtho-[1″,2″:4,5;1′″,2′″:4′,5′]dithiazolo[3,2-a:3′,2′-e]-1,3,5,7-tetrazocine-9,19-dione ( 3 ). The possible [4 + 2] cycloadduct, 3-(2-naphtho-[1,2-d]-thiazolyl)naphtho[1′,2′:4,5]thiazolo[3,2-a]-1,3,5-triazine-2,4-dione ( 4 ), an usual dimer type of heterocyclic isocyanates was not produced. Discrimination between the two isomers was established on the basis of spectral analyses.     

The syntheses of 4b,5a-dihydro-5H-benzo[3,4]-phenanthro[1,2-b]azirine and 1a,11b-dihydro-6,11-dimethyl-1H-benz[3,4]anthra[1,2-b]azirine

The syntheses of the K-imine derivatives of carcinogenic benzo[c]phenanthrene and 7,12-dimethylbenz-[a]anthracene are described. Treatment of trans-5-azido-5,6-dihydrobenzo[c]phenanthren-6-ol ( 3 ) and trans-6-azido-5,6-dihydrobenzo[c]phenanthren-5-ol ( 5 ) with thionyl chloride yielded the corresponding β-chloro azides, which in turn, were reacted with lithium aluminium hydride to give 4b,5a-dihydro-5H-benzo[3,4]-phenanthro[1,2-b]azirine ( 2 ). In a similar manner trans-5-azido-5,6-dihydro-7,12-dimethylbenz[a]anthracen-6-ol ( 11 ) and trans-6-azido-5,6-dihydro-7,12-dimethylbenz[a]anthracen-5-ol ( 13 ) were transformed to the respective chloro azides and, converted into 1a,11b-dihydro-6,11-dimethyl-1H-benz[3,4]anthra[1,2-b]azirine ( 10 ).     

The syntheses of pyridazino[1,2-a] pyridazine derivatives of furan,pyridazine and pyrrole by diels-alder reactions

Diels-Alder adducts were formed in the lead tetraacetate oxidations of substituted cyclic hydrazides of furan, pyridazine and pyrrole dicarboxylic acids in the presence of 1,3-cyclo-hexadiene or 1,3-cyclopentadiene. The products resulting were furo[3,4-g]pyridazino[1,2-a]-pyridazine-6,10-diones, pyridazino[4,5-g]pyridazino[1,2-a]pyridazine-6,11-diones, and pyrrolo-[3,4-g]pyridazino[1,2-a]pyridazine-6,10-diones, respectively. Some hydrogenations and ring opening reactions were studied.