Visible-Light-Driven Sulfonylation/Cyclization to Access Sulfonylated Benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-ones

Visible-light-driven sulfonylation/cyclization of N-methacryloyl-2-phenylbenzoimidazoles has been successfully developed. Using commercially available sulfonyl chloride as sulfonylation reagent, a wide range of sulfonylated benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-ones with potential antitumor activity were provided in acceptable to excellent yields. This method has the advantages of mild reaction conditions and outstanding functional group tolerance, and provides a new strategy for the development of potential antitumor lead compounds.     

The synthesis and transformations of 9H-imidazo[1,2-b]pyrazolo[4,3-d]-pyridazine and 9H-pyrazolo[4,3-d]-s-triazolo[4,3-b]pyridazine derivatives

The nucleophilic and electrophilic substitutions of 6-substituted 9,9-dimethyl-9H-imidazo[1,2-b]pyrazolo- [4,3-d]pyridazines 2 , nucleophilic substitutions of 6-substituted 9,9-dimethyl-9H-pyrazolo[4,3-d]-s-triazolo- [4,3-b]pyridazines 7 and some other transformations to give compounds 3 and 8 , respectively, were studied. It was shown that both heterocyclic systems are stable under the conditions employed in these transformations.     

Synthesis of heterocycles. Part VII Synthesis and antimicrobial activity of some 7H-s-triazolo[3,4-b][1,3,4]thiadiazine and s-triazolo[3,4-b][1,3,4]thiadiazole derivatives

The cyclization of 4-amino-5-aryl-3-cyanomethylthio-1,2,4-triazoles II in the presence of concentrated sulfuric acid yields 7H-6-amino-s-triazolo[3,4-b][1,3,4]thiadiazines III . Cyclization of 4-amino-5-aryl-1,2,4-tria-zole-3-thiones I with phenacyl chloride yields 7H-3-aryl-6-phenyl-s-triazolo[3,4-b][1,3,4]thiadiazines IV . Similarly, compounds I condensed with cyanogen bromide, phenyl isothiocyanate and carbon disulfide to give the corresponding cyclized products 6-amino-3-aryl-s-triazolo[3,4-b][1,3,4]thiadiazoles V , 3-aryl-6-phenyl-amino-s-triazolo[3,4-b][1,3,4]thiadiazoles VI and 3-aryl-striazolo[3,4-b][1,3,4]thiadiazol-6(5H)thiones VII , respectively. Also in the presence of phosphoryl chloride, compounds I underwent cyclization with monocarbo-xylic acids and oxalic acid to 3,6-diaryl-s-triazolo[3,4-b][1,3,4]thiadiazole VIII and 6,6′-bis(3-aryl-s-triazolo-[3,4-b][1,3,4]thiadiazoles) IX . The above compounds were screened for their antimicrobial activity.     

The synthesis of 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles,11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles and 1,2,4-triazolo[3,4-f]-1,2,4-triazino[4,5-a]indoles

This paper describes the synthesis of the previously unknown 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles (2) and 11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles (3) from 4-hydrazino-5H-pyridazino[4,5-b]indoles (1) , as well as the synthesis of 1,2,4-triazolo[3,4-f]-1,2,4-triazino-[4,5-a]indoles (10) from 2-indolecarbohydrazide (4) . Compounds 2 were obtained by acylation of compounds 1 , followed of thermal cyclization and compounds 3 by treating compounds 1 with nitrous acid. The reactions of compound 4 with formic acid or ethyl orthoformiate gave 1,2-dihydro-1-oxo-1,2,4-triazino[4,5-a]indole (6) . Treating this last compound with phosphorus oxychloride or phosphorus pentasulfide, followed by hydrazine, gave 1-hydrazino-1,2,4-triazino-[4,5-a]indole (9) . Acylation of this last compound, followed of cyclization gave compounds 10 . All the compounds were characterized by elemental analysis and ir and ¹H-nmr spectra.     

The photo cycloaddition of alkenes to s-triazolo[4,3-b] and [2,3-b]pyridazines

s-Triazolo[4,3-b]pyridazine (I) reacted with cyclohexene under the influence of ultraviolet light to yield 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[1,5-a]indole (IV) and 9-cyanomethyl-4a,5,7,8,8a,9-hexahydro-6H-s-triazolo[1,5-a]indole (V). These products were formed by the addition of the alkene to the 1,8 positions of I with a concurrent cleavage of the N₄? N₅ bond. Similar additions were observed with cyclopentene and 2,3-dimethyl-1,3-butadiene. The isomeric s-triazolo[2,3-b]pyridazine (III) reacted with cyclohexene to form an isomer of IV, 4a,5,7,8,8a,9-hexahydro-9-methylene-6H-s-triazolo[4,3-a]indole (XV) and two [2 + 2] cycloadducts (XVI and XVII).     

Synthesis of 3-aryl-6H-isoxazolo[3,4-d]pyrazolo[3,4-b]pyridines and 3-aryl-6H-isoxazolo[5,4-d]pyrazolo[3,4-b]pyridines

The synthesis and characterization of a number of 3-aryl-6H-isoxazolo[3,4-d]pyrazolo[3,4-b]pyridines and 3-aryl-6H-isoxazolo[5,4-d]pyrazolo[3,4–6]pyridines from common precursors, 5-benzoyl-4-chloro-1H-pyrazolo-[3,4-b]pyridines, has been described. The structures were determined by unambiguous chemical synthesis and by isolation and ¹³C nmr analysis of some key, isolated, intermediates. The ability of these compounds to displace [3H]flunitrazepam from CNS binding sites was also observed.     

A new method for the synthesis of 6H,11H-indolo[3,2-c]-isoquinolin-5-ones/thiones and their reactions

The synthesis of 8-substituted and unsubstituted 6H,11H-indolo[3,2-c]isoquinolin-5-ones/thiones 3a-c and 4a-c and their derivatives viz, ethyl (8-substituted-6H,11H-indolo[3,2-c]isoquinolin-5-on-6-yl)acetates 5a-c , (8-substituted-6H,11H-indolo[3,2-c]isoquinolin-5-on-6-yl)acetyl hydrazides 6a-c , 3,5-disubstituted-pyrazoles 7a-c and 8a-c , 3-substituted-pyrazol-5-ones 9a-c and 5-(8-substituted-6H,11H-indolo[3,2-c]isoquinolin-5-on-6-yl)methyl-1,3,4-oxadiazole-2-thiones 10a-c , also ethyl (8-substituted-11H-indolo[3,2-c]isoquinolin-5-ylthio)ace-tates 11a-c , (8-substituted-11Hindolo[3,2-c]isoquinolin-5-ylthio)acetyl hydrazides 12a-c , 3,5-disubstituted-pyrazoles 13a-c and 14a-c , 3-substituted-pyrazol-5-ones 15a-c and 5-(8-substituted-11H-indolo[3,2-c]isoquin-olin-5-yl)thiomethyl-1,3,4-oxadiazole-2-thiones 16a-c is described.     

Homophtalonitrile for Multicomponent Reactions: Syntheses and Optical Properties of o-Cyanophenyl- or Indol-3-yl-Substituted Chromeno[2,3-c]isoquinolin-5-Amines

Malononitrile is a useful reagent for multicomponent reactions with hundreds of methods developed. In this paper, we suggest α-(cyano)-o-tolunitrile (homophtalonitrile) to work as a vinylogous malononitrile. Thus, a organocatalytic pseudo-three-component reaction of homopthalonitrile (2 equiv) and o-hydroxybenzaldehyde, leading to the diastereoselective formation of 5-amino-12H-chromeno[2,3-c]isoquinolin-12-yl)(cyano)methyl)benzonitriles, was discovered. The possibility to employ other nucleophiles was demonstrated for indoles, and a sequential three-component reaction of homophtalonitrile, o-hydroxybenzaldehyde, and (aza)indole, giving 12-(1H-Indol-3-yl)-12H-chromeno[2,3-c]isoquinolin-5-amines, was developed. The photophysical properties of the synthesized compounds have been studied, revealing high fluorescence quantum yields (42–70 %) for indol-3-yl substituted 12H-chromeno[2,3-c]isoquinolin-5-amines and reversible fluorescence quenching under acidic conditions.     

Synthesis of arylsulfonyl-substituted indolo[2,1-a]isoquinolin-6(5H)-one derivatives via a TBAI-catalyzed radical cascade cyclization

We have developed a metal-free radical cascade reaction of N-substituted 2-aryl indoles with readily available sulfonyl hydrazides for the rapid construction of arylsulfonyl-substituted indolo[2,1-a]isoquinolin-6(5H)-one derivatives. With the TBAI–TBHP catalytic system, a broad series of structurally diverse indolo[2,1-a]isoquinolin-6(5H)-one derivatives were obtained in moderate to excellent yields. The reaction features mild reaction conditions, operationally easiness, scaled-up feasibility, and high functional-group-tolerance.     

Heterocyclic derivatives of naphthalene-1,8-dicarboxylic anhydride. Part I. Nitro-7H-benzimidazo[2,1-a]benz[de]isoquinolin-7-ones

Condensation of o-phenylenediamine with 2-, 3- and 4-nitronaphthalene-1,8-dicarboxylic anhydrides gives, in each case, an isomer mixture. Separation of the mixtures into the six isomeric mononitro-7H-benzimidazo[2,1-a]benz[de]isoquinolin-7-ones is described and the isomers characterised in respect of previously reported data on some isomers; ir and mass spectrum data are reported, the latter showing fragmentation ions which may be used in characterising dyes based on this chromophore. Other new derivatives of 7H-benzimidazo[2,1-a]benz[de]isoquinolin-7-one are also described.     

Synthesis of 1H-pyrazolo[3,4-c]isoquinolin-1-ones by the condensation of cyclohexanone derivatives with 3-amino-1-phenyl-1H-pyrazol-5(4H)-one

The synthesis of 1H-pyrazolo[3,4-c]isoquinolin-1-ones was carried out by reacting 3-aryl(heteryl)-2,4-diacetyl-5-hydroxy-5-methylcyclohexanones with 3-amino-1-phenyl-1H-pyrazol-5(4H)-one. The structure of the 7-acetyl-2,4,6,7,8,9-hexahydro-8-hydroxy-5,8-dimethyl-2-phenyl-6-(fur-2-yl)-1H-pyrazolo[3,4-c]isoquinolin-1-one obtained was proved by X-ray diffraction analysis.     

Condensed Isoquinolines. 18. Enamine Properties of Benzimidazo[1,2-b]isoquinolin-11(5H)-one in the Michael Reaction

The reaction of benzimidazo[1,2-b]isoquinolin-11(5H)-one with activated olefins has been studied. The derivatives of 3,10-dioxo-3H,10H-benzimidazo[1,2,3-ij]benzo[c][1,8]naphthyridine formed are the result of an initial Michael reaction at C₍₆₎ followed by intramolecular heterocyclization.     

The photochemical synthesis of novel heterocyclic compounds from s-triazolo[4,3-b]pyridazine (II)

s-Triazolo[4,3-b Jpyridazine (I) photochemically reacted with dihydropyran; 2,3-dihydro-p-dioxin; 2,5-dihydrofuran; 2,5-dimethoxy-2,5-dihydrofuran; and 1,3-dioxep-5-ene to give a new series of substituted pyrrolo[1,2-b]-.s-triazoles (II-IX). In most reactions, two or more products were formed. The following compounds have been prepared from I: 9-methylene-4a,5,6,7,8a,9-hexahydropyrano[2,3 :4,5]pyrrolo[1,2-b]-s-triazole (Ha), the corresponding 9-cyanomethyl product (III), and 9-methylene-4a,7,8,8a-tetrahydro-6H,9H-pyrano[3′,2′:4,5]pyrrolo[1,2-b]-s-triazole (IIb) from dihydropyran; 9-methylene-4a,6,7,8a-tetrahydro-9H-p-dioxino[2′,3′:4,5]-pyrrolo[1,2-6]-s-triazole (IV) from 2,3-dihydro-p-dioxin; 8-methylene-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]pyrrolo[1,2-b]-s-triazole (V) and the corresponding 8-cyanomethyl product (VI) from 2,5-dihydrofuran; 8-cyanomethyl-5,7-dimethoxy-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]-pyrrolo[1,2-6]-s-lriazole (VII) from 2,5-dimethoxy-2,5-dihydrofuran; and 10-methylene-4a,5,9a,10-tetrahydro-9H-[1,3]dioxepino[5′,6′:4,5]pyrrolo[1,2-b]-s-triazole (VIII) and the corresponding 10-cyanomethyl product (IX) from 1,3-dioxep-5-ene. The addition of several other compounds (1,2,3,6-tetrahydropyridine, 1-acetylimidazole, 3-sulfolene, 2,3-dihydro-p-dithiin, and vinylene carbonate) was attempted, but no reactions were observed.     

The identification of 10 and 11 substituted 7H-benzimidazo[2,1-a]benz[de]isoquinolin-7-ones through 1N NOE studies on their methyl p-toluenesulfonate salts

The spectral similarities of 10 and 11 substituted 7H-benzimidazo[2,1-a]benz[de]isoquinolin-7-ones hinder the identification of the individual isomers. Preparation of the 13-methyl p-toluenesulfonate salts of these compounds has allowed the assignment by the use of NOE techniques. Saturation of the N-methyl caused an NOE at H-12. The coupling pattern of H-12 then provides identification of the compound.     

A straightforward synthesis of indazolo[3,2-a]isoquinolin-6-amines

4-Substituted 1-bromoisoquinolin-3-amines were subjected to Suzuki coupling with o-nitrophenylboronic acid to yield 1-(2-nitrophenyl) isoquinolinamines, which participated in Cadogan cyclization with triethyl phosphite under microwave irradiation in a sealed vial to yield fluorescent indazolo[3,2-a]isoquinolin-6-amines. The new compounds were also functionalized by transformation of the amino group.     

Condensed Isoquinolines. 17. Enamine Properties of Benzimidazo[1,2-b]isoquinolin-11(5H)-one in Alkylation Reactions

The alkylation of benzimidazo[1,2-b]isoquinolin-11(5H)-one has been studied. This occurs at N₍₅₎ or C₍₆₎ depending on the type of alkylating agent and the reaction conditions. It was shown that C₍₆₎ alkylation is effected in reactions with reactive alkyl halides. A repeat alkylation occurs preferentially at the same position. Interaction with o-xylylidene dibromide leads to spiro[benzimidazo[1,2-b]-isoquinolin-6,2'-indan]-11-one and 1,6-dihydro-11H-6a,11b-diazobenzo[b]benzo[5,6]cyclohepta[1,2,3-l,m]fluoren-11-one, which are derivatives of new heterocyclic systems.     

Novel polycyclic heterocycles. XI. Synthesis of 11,12-dihydropyrido[2,1-b] [1,3]benzodiazepines, 6H-pyrido[1,2-c] [1,3,5]benzoxadiazepines,and 6H-Pyrido[1,2-c] [1,3,5]benzothiadiazepines

An unusually facile dehydrobromination, involving the ortho-bromine atom and the = NH proton of a 2-imino-1-(phenethyl)-, 2-imino-1-(phenoxymethyl)-, or 2-imino-1-(phenylthiomethyl)-pyridine ( 2a-e ) has led to the synthesis of three novel bridgehead nitrogen tricyclic systems: 11,12-dihydropyrido[2,1-b] [1,3]benzodiazepines ( 3a,b ), 6H-pyrido[1,2-c] [1,3,5]benzoxadiazepines ( 3c,d ) and 6H-pyrido[1,2-c][1,3,5]benzothiadiazepines ( 3e ). As anticipated, these cyclizations required a base, e.g., potassium carbonate, and a catalyst, e.g., copper bronze. What was unusual, was that these reactions occurred in methanol or n-propanol, under reflux, either under anhydrous conditions, or in the presence of large amounts of water. The pmr spectra of these compounds are discussed.     

Pyrido[2′1′:2,3]imidazo[4,5-c]isoquinoline and the alkylation of pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one

The reaction of 2-aminopyridine, o-phthaldehydic acid and potassium cyanide gave pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one, which upon treatment with propargylbromide, yielded both O and N alkylated products. 2-Aminopyridine, o-phthaldehyde and potassium cyanide gave 1-cyano-2-(2-pyridyl)isoindole which rearranged in acid to give the previously unreported parent pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinole. Structures were confirmed using uv, ir, nmr and x-ray spectroscopy.     

6H-indeno[1,2-b]pyrido[3,2-e]pyrazines. A new heterocyclic ring system

Condensation of 1,2-indanedione and 1,2,3-indanetrione hydrate (ninhydrin) with 2,3-diamino-pyridines gave a number of compounds belonging to the hitherto unknown 6H-indeno[1,2-b]-pyrido[3,2-e]pyrazine ring system. The unsymmetrical nature of the reactants can theoretically result in isomeric ring closure products. Assignment of the 6H- ring system was based upon the identity of 6H-indeno[1,2-b]pyrido[3,2-e]pyrazin-6-one obtained from 2,3-diaminopyridine and ninhydrin with material prepared by unequivocal synthesis. The direction of cyclization of ninhydrin and 1,2-indanedione with the diamines was shown to be the same by reduction of the indenopyridopyrazinones to the corresponding indenopyridopyrazines. Some physical, chemical, and tumor growth-inhibitory properties of the products are reported.     

Synthesis of some new derivatives of 4-hydrazino-5H-pyridazino[4,5-b]indole

This paper describes the synthesis of 1-chloro-4-hydrazino-5H-pyridazino[4,5-b]indole ( 4 ) and some of the triazoles ( 6–8 ), tetrazoles ( 10–11 ), triazolotetrazoles ( 9 ) and bis-tetrazoles ( 12 ) derived from it. All of these were previously unknown compounds. Treating 1,4-dioxo-1,2,3,4-tetrahydro-5H-pyridazino[4,5-b]indole ( 1 ) with phosphorus oxychloride gave 1,4-dichloro-5H-pyridazino[4,5-b]indole ( 2 ), which reacts regioselectively with hydrazine to give compound 4 . The reactions of 4 with formic and acetic acids gave 6-chloro-11 H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles ( 6a-6b ), respectively. Reaction of compound 6a with hydrazine gave 6-hydrazino-11H-1,2,4-triazolo[4,3–6]-pyridazino[4,5,-b]indole ( 8 ). This with nitrous acid gave 6-azido-11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]-indole ( 9 ). Compound 4 reacted with nitrous acid to give 6-chloro-11H-tetrazolo[4,5-b]pyridazino[4,5-b]-indole ( 10 ), which gave 1,4-diazydo-5H-pyridazino[4,5-b]indole ( 12 ), through successive reactions with hydrazine and nitrous acid. All compounds were characterized by elemental analysis, ir and ¹H-nmr spectra.