Synthesis and alkylation of pyrazolo[3,4-c]isoquinolines and hexahydrocyclohepta[d]pyrazolo[3,4-b]pyridines

The condensation of 1-acyl-2-(morpholin-4-yl)cycloalkenes with 3-amino-1-phenyl-1H-pyrazol-5(4H)-ones gave the corresponding 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]isoquinoline and 3,6,7,8,9,10-hexahydrocyclohepta[ d]pyrazolo[3,4-b]pyridine derivatives. Alkylation of 2,3,6,7,8,9-hexahydropyrazolo[3,4-c]-isoquinolines with alkyl halides occurred at the nitrogen atom in the 3-position. The structure of 7-methyl-2,5-diphenyl-2,3,6,7,8,9-hexahydro-1H-pyrazolo[3,4-c]isoquinolin-1-one was proved by X-ray analysis.     

Imidazo- und Diazino-Anellierungen an das [1]Benzothieno[2,3—d]pyrimidin-System

Derivatives of the following six ring systems were synthesized:

1. 3,10-Dihydro-[1]benzothieno[2,3-d]imidazo[1,5-a]-pyrimidine (I)
2. 6H-[1]Benzothieno[2,3-d]pyrazino[1,2-a]pyrimidine (II)
3. 1,5-Dihydro-[1]benzothieno[2,3-d]imidazo[1,2-a]-pyrimidine (III)
4. 6H-[1]Benzothieno[2,3-d]pyrimido[1,2-a]pyrimidine (IV)
5. 1,5-Dihydro-imidazo[1,2-a]thieno[2,3-d]pyrimidine (V)
6. 4H-Pyrimido[1,2-a]thieno[2,3-d]pyrimidine (VI)

The first four types are new heterocyclic systems. 2-Aminomethyl-5,6,7,8-tetrahydro-[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (5), which was used as intermediate for typesI andII, was synthesized by various methods. TypesIII andIV were prepared from 2-methylthio-5,6,7,8-tetrahydro-[1]-benzothieno[2,3-d]pyrimidin-4(3H)-one via the corresponding 2-benzylamino derivatives, followed by ring closure.     

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.     

Synthesis of substituted [1,3]thiazolo[4,5-b]pyridines and [1,3]thiazolo[4,5-d][1,2,3]triazines

In this work, we described an easy preparation of substituted 4-amino-5-cyano-1,3-thiazoles. These compounds have been used as starting materials to obtain two classes of compounds. New substituted [1,3]thiazolo[4,5-e]pyridines were synthesized in one step via Friedländer reaction. Diazotation of 4-amino-5-cyano-1,3-thiazoles afforded 4-chloro[1,3]thiazolo[4,5-d][1,2,3]triazines in one step. The later was substituted by a secondary amine to obtain substituted 4-amino[1,3]thiazolo[4,5-d][1,2,3]triazines.     

Efficient synthesis of 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinoline 4,4-dioxide

A new efficient and versatile synthesis to obtain different substituted 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinolone 4,4-dioxide was developed. The four cyclic systems are achieved by a three-step synthesis proceeding under mild conditions in high yields.     

Synthesis and electrochemical evaluation of substituted imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine scaffolds

Substituted 4-(2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazoles were prepared from 5-amino-1-aryl-4-cyanoformimidoylimidazoles and cyanoacetamide, under mild experimental conditions. The pyrrolyl-imidazoles were cyclized to the corresponding 7,8-dihydroimidazo[4,5-b]pyrrolo[3,4-d]pyridines by reflux in ethanol, with catalysis by DBU. The same pyrrolyl-imidazoles were reacted with orthoesters, at room temperature and in the presence of sulfuric acid, to generate 3,7-dihydro-8H-imidazo[4,5-d]pyrrolo[3,2-f]diazepines in very good yield. Electrochemical studies of the imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine derivatives were carried out. The reduction potential of 7-ethyl-3-(4-methoxyphenyl)-8-oxo-7,8-dihydro-3H-imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine-9-carbonitrile was in the adequate range for presenting bioreduction properties.     

Pyrazoles as building blocks in heterocyclic synthesis: Synthesis of pyrazolo [3,4-d]pyrimidine, pyrazolo[3,4-e][1,4]diazepine, pyrazolo [3,4-d][1,2,3]triazine and pyrolo [4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives

Several new pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-e][1,4]diazepine, pyrazolo[3,4-d][1,2,3]triazine and pyrolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives were prepared by the reaction of the corresponding 5-amino-pyrazole-4-carbonitrile derivative with different organic reagents under different reaction conditions. Using IR, ¹H NMR, and mass spectra we have characterized all new compounds.     

New method for the synthesis of substituted thieno[3,2-b]pyridines and 5H-pyrano[2,3-d]thieno[3,2-b]pyridines derived from them

A new highly selective method was developed for the synthesis of substituted thieno[3,2-b]-pyridines based on the domino reaction of monopotassium salt (rather than dipotassium one) of carbamoylcyanodithioacetic acid with ethyl 4-chloroacetoacetate. Substituted 5H-pyrano[2,3-d]-thieno[3,2-b]pyridines were synthesized based on these thieno[3,2-b]pyridines.     

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.     

New syntheses of [1,2,5]oxadiazolo[3,4-e][1,2,3,4]tetrazine 4,6-dioxide

New methods were developed for the synthesis of [1,2,5]oxadiazolo[3,4-e][1,2,3,4]tetrazine 4,6-dioxide from 4-(tert-butyl-NNO-azoxy)-N-nitro-1,2,5-oxadiazol-3-amine or its alkali metal salts and acid anhydrides (or chlorides) in the presence of strong acids. The yield of [1,2,5]oxadiazolo[3,4-e][1,2,3,4]tetrazine 4,6-dioxide in acetic anhydride in the presence of sulfuric acid or sulfuric anhydride at 20°C in 20 min attained 83%. A general mechanism was proposed for the reactions under study. Acetyl group behaved for the first time as departing group in the synthesis 1,2,3,4-tetrazine 1,3-dioxides, and [1,2,5]oxadiazolo[3,4-e][1,2,3,4]tetrazine 4,6-dioxide was obtained in 47% yield from N-[4-(acetyl-NNO-azoxy)-1,2,5-oxadiazol-3-yl]acetamide.     

Synthesen von basisch substituierten ([1]Benzo-)Thieno-[2,3—d]pyrimidin-Derivaten und von ([1]Benzo-)Thieno-[2,3-d]-1,2,4-triazolo[4,3-a]pyrimidin-Derivaten

Reaction of 2-methylthio-thieno[2.3-d]pyrimidin-4(3H)-ones with heterocyclic secondary amines, ethanolamine and hydrazine, resp., gave the corresponding derivatives with a basic substituent in position 2. Cyclization of the hydrazino compounds with formic acid gave derivatives of thieno[2.3-d]-1.2.4-triazolo[4.3-a]pyrimidine and [1]benzothieno[2.3-d]-1.2.4-triazolo[4.3-a]pyrimidine, two new heterocyclic systems.     

Synthesis and some properties of N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]pyrazinones

Reactions of methyl 2-(2-formyl-1H-pyrrol-1-yl)alkanoates with unsubstituted aliphatic 1,2-, 1,3-, and 1,4-diamines gave N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]-pyrazinones. Some of them show ring-chain tautomerism. Transformations of these compounds led to a number of novel heterocyclic systems: 2,10-dihydro-3H,5H-imidazo[1,2-a]-pyrrolo[1,2-d]pyrazines, 2,3,4,11-tetrahydro-6H-pyrrolo[1??,2??:4,5]pyrazino[1,2-a]pyrimidines, 1,2,3,5,6,10b-hexahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazines, 1,3,4,6,7,11b-hexahydro-2H-pyrrolo[2??,1??:3,4]pyrazino[1,2-a]pyrimidines, and 2,3,4,5,6,7-hexahydro-1H-pyrrolo[2,1-c]-[1,4,7]triazacycloundecin-8(9H)-one.     

A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.     

Chemical reactivity of [1,2,3]triazolo[1,5-a]- and [1,5-c]-pyrimidinium salts

The chemical reactivity of the [1,2,3]triazolo[1,5-a]- and [1,5-c]-pyrimidinium salts towards morpholine, water and sodium methoxide have been studied. Among others, new 1-aza and 2-azabutadienes substituted by a [1,2,3]-triazole ring were obtained in the course of the opening of the positively charged pyrimidine ring.     

Microwave assisted synthesis of 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones using Mn(OAc)3

2-Hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one 2a and 7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one 2b, were obtained in high yields under mild conditions from the cyclization reactions of bis-(2,4,6-trichlorophenyl) malonate and 2-aminobenzothiazole or 2-aminothiazole, respectively. A new class of compounds, 2,3-dihydro-4H-benzo[4,5]thiazolo[3,2-a]furo[2,3-d]pyrimidin-4-ones and 6,7-dihydro-5H-furo[2,3-d]thiazolo[3,2-a]pyrimidin-5-ones, were synthesized via the microwave assisted radical addition of compounds 2a and 2b to various alkenes using manganese(III) acetate. A preliminary acetylcholine esterase (AchE) inhibition test of compound 4e showed excellent (92%) inhibitory potential, comparable with the standard drug Donapezil®.     

Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid, Part VI [1]. Synthesis and X-ray structure of model indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylic esters

Cyclocondensation reaction of ethyl 7,8-diamino-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate with 1-methylisatin produced a separable mixture of the corresponding indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates, of which the latter isomer predominates. On the other hand, interaction with 1H-isatin or 5-chloroisatin gave the respective indolo[2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates as the sole regiospecific products. The structures of these new pentacyclic derivatives are based on microanalytical, spectral (IR, MS, and NMR) and X-ray crystal structure data.     

Synthesis of [1,2,4]triazolo[4,3-b]-s-tetrazines with incorporated furazan ring

Furazancarboxylic hydrazides can serve as nucleophiles to substitute for one dimethylpyrazole fragment in bis(3,5-dimethylpyrazol-1-yl)-s-tetrazine, giving the corresponding N??-[6-(3,5-dimethylpyrazol-1-yl)-s-tetrazin-3-yl]-4-R-furazan-3-carbohydrazides in good yields. Dehydration of the indicated carbohydrazides in polyphosphoric acid for the first time gave rise to [1,2,4]triazolo[4,3-b]-s-tetrazines containing the furazan ring as a substituent at the triazole ring.     

Reactions of tetrahydropyrido[4,5-d][1,2,4]triazolo[1,5-a]-pyrimidin-4-ones with activated alkynes. Synthesis of [1,2,4]triazolo[1′,5′:1,2]pyrimido[4,5-d]azocines

Triazolo[1′,5′:1,2]pyrimido[4,5-d]azocines were synthesized by the tandem expansion of the tetrahydropyridine ring in tetrahydropyridotriazolopyrimidines by the action of activated alkynes. Under these conditions, triazolopyridopyrimidines benzylated at the nitrogen atom of the pyrimidine moiety undergo the Hofmann cleavage of the tetrahydropyridine ring to form 5-vinyltriazolo[1,5-a]pyrimidines.     

Short and efficient access to imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives

Access to N-protected or N-free imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives as potential antiviral compounds was achieved in good yields from N-protected 7-amino-8-halo-2-methylimidazo[1,2-a]pyridines by catalytic coupling of terminal acetylenes under mild conditions using [PdCl₂(PPh₃)₂] or [Cu(Phen)(PPh₃)₂]NO₃.     

A modular approach to 4,5-diaminopyrrolo[2,3-d]pyrimidines and 2,4,5-triaminopyrrolo[2,3-d]pyrimidines

A short and highly modular approach to various 4,5-diaminopyrrolo[2,3-d]pyrimidines and 2,4,5-triaminopyrrolo[2,3-d]pyrimidines was developed starting from 4-chloro-5-halopyrrolo[2,3-d]pyrimidines and 5-bromo-2,4-dichloropyrrolo[2,3-d]pyrimidine, respectively. Direct amination at the 5-position was achieved without the use of transition metals or other catalysts in 32-86% yield. Ten examples are given.