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.     

Some novel heterocyclic systems derived from 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-α]benzimidazole and the corresponding diamine

The preparation of 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-a]benzimidazole from 1,4-diacetamido-2,3-dinitrobenzene is described. Reaction of this compound with 2,5-dimethoxytetrahydrofuran produces 2,3-dihydro-8-nitro-7-N-pyrrolo-1H-pyrrolo[1,2-a]benzimidazole, which can be cyclised to produce two new heterocyclic ring systems, 9,10-dihydro-8H-pyrrolo[1,2-a]pyrrolo(1′,2′:1,2]imidazo[5,4-f]quinoxaline and 9,10-dihydro-8H-pyrrolo[2,1-c]pyrrolo[1′,2′:1,2]imidazo[4,5-h][1,2,4]benzotriazine. The corresponding diamine, 7,8-diamino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole undergoes a variety of condensation reactions to produce several new heterocyclic systems, for example, with formic acid, 1,7,8,9-tetrahydroimidazo-[4,5-e]pyrrolo[2,1-6]benzimidazole is formed and with diacetyl, 9,10-dihydro-2,3-dimethyl-8H-pyrrolo-[1′,2′:1,2]imidazo[5,4-y]quinoxaline is obtained.     

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.     

5,6-Dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4,4-diacetic acid diethyl ester,an useful synthon for the synthesis of new polycyclic nitrogen systems of pharmacological interest

This report describes the synthesis of derivatives of two nitrogen tetracyclic ring systems, respectively 9H,11H-pyrimido[4,3-c]pyrrolo[1,2-a][1,4]benzodiazepine and spiro[piperidine-4,4′-[4H]pyrrolo[1,2-a][1,4]-benzodiazepine], by the use of the diethyl ester of 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4,4-diacetic acid as a synthon. This compound was obtained by condensation of 1-(2-aminomethylphenyl)-1H-pyrrole with diethyl 1,3-acetonedicarboxylate in acid medium. Pyrimidopyrrolobenzodiazepine derivatives were obtained by treating either the pyrrolobenzodiazepine 4,4-diacetate or the related 4-methyl-4-acetate with phenylisocyanate in boiling diethyl ether in the presence of sodium metal. The structure of 12,13-dihydro-11,13-dioxo-12-phenyl-9H,11H-pyrimido[4,3-c]pyrrolo[1,2-a][1,4]benzodiazepine, a product formed by loss of an acetate unit when 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4,4-diacetate, sodium metal and phenyl-isocyanate reacted in boiling xylene, was proved by catalytic reduction to 11,13-dioxo-12-phenyl-12,13,14,14a-tetrahydro-9H,11H-pyrimido[4,3-c]pyrrolo[1,2-a][1,4]benzodiazepine, which was synthesized by unambiguous pathway via 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4-acetate. The 2,6-dioxospiro[piperidine-4,4′-[4H]pyrrolo[1,2-a][1,4]benzodiazepine] derivatives were synthesized from the N-BOC derivative of 5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepine-4,4-diacetic acid diethyl ester, by hydrolysis followed by treatment with 2 equivalents of 1,1′-carbonyldiimidazole (CDI) and then with aniline or benzylamine. Removal of BOC from the N-phenyl-2,6-dioxopiperidine derivative was obtained by heating the related spiroderivative in toluene in the presence of p-toluenesulphonic acid. Similar reaction failed when the N-benzyl-2,6-dioxopiperidine analog was used as substrate.     

Synthesis of (5aS)-2-benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-diones

A convenient method was developed for the combinatorial synthesis of substituted (5aS)-2-benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]-diazepine-5,10-diones. The structure and the most probable conformation of (5aS)-2-benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-dione in solution was established by NMR spectroscopy and calculations using the Gaussian program.

     

Synthesis of 9-arylamino- and (Z)-9-arylimino-9H-pyrrolo[1,2-a]indoles by reactions of 2-(pyrrol-1-yl)benzaldehydes with aryl amines

Heating mixtures of 2-(pyrrol-1-yl)benzaldehydes and aryl amines under argon afforded 9-arylamino-9H-pyrrolo[1,2-a]indoles, via cyclization of the resulting 2-(pyrrol-1-yl)benzaldimine intermediates. Heating in the presence of oxygen afforded (Z)-9-arylimino-9H-pyrrolo[1,2-a]indoles, which were successfully hydrolyzed with hydrochloric acid to give pyrrolo[1,2-a]indol-9-ones.     

A convenient route to diazepines by intramolecular cyclisation of carbonylazides

The appropriate substituted carbonylazides I treated with warm acetic acid give the corresponding acetamide IV or the cyclic lactam VI . This is a convenient route to 10,11-Dihydro-5H-pyrrolo[1,2-a][1,4]-benzodiazepin-11-one and 10,11-Dihydro-4H-thieno[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10-one.     

Novel heterocyclic β-nitroenamines-based on a one-pot three-component reaction: a facile synthesis of fully substituted 1H-pyrrolo[1,2-a]-fused-1,3-diazaheterocycles

A one-pot multicomponent synthesis of a novel class of 2,3-dihydro-1H-pyrrolo[1,2-a]imidazoles, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidines, and 2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,3]diazepines, starting from simple and readily available inputs including diveres diamines, l,l-bis(methylthio)-2-nitroethen and diaroylacetylene, in excellent yields is described.     

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

The reactions of methyl α-(2-formyl-1H-pyrrol-1-yl)carboxylates with N-substituted aliphatic 1,2-, 1,3-, and 1,4-diamines afford new pyrrole-containing heterocyclic systems: 1,2,3,10b-tetrahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazin-5(6H)-ones, 1,3,4,11b-tetrahydro-2H-pyrrolo[2′,1′:3,4]pyrazino[1,2-a]pyrimidin-6(7H)-ones, and 1,2,3,4,5,12b-hexahydro-pyrrolo[2′,1′:3,4]pyrazino[1,2-a][1,3]diazepin-7(8H)-ones. The reduction of these compounds with different reagents was studied.     

Synthesis,Antibacterial and Antifungal Activity of New 3-Aryl-5H-pyrrolo[1,2-a]imidazole and 5H-Imidazo[1,2-a]azepine Quaternary Salts

A series of novel 3-aryl-5H-pyrrolo[1,2-a]imidazole and 5H-imidazo[1,2-a]azepine quaternary salts were synthesized in 58–85% yields via the reaction of 3-aryl-6, 7-dihydro-5H-pyrrolo[1,2-a]imidazoles or 3-aryl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepines and various alkylating reagents. All compounds were characterized by ¹H NMR, ¹³C NMR, and LC-MS. The conducted screening studies of the in vitro antimicrobial activity of the new quaternary salts derivatives established that 15 of the 18 newly synthesized compounds show antibacterial and antifungal activity. Synthesized 3-(3,4-dichlorohenyl)-1-[(4-phenoxyphenylcarbamoyl)-methyl]-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-1-ium chloride 6c possessed a broad activity spectrum towards Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Cryptococcus neoformans, with a high hemolytic activity against human red blood cells and cytotoxicity against HEK-293. However, compound 6c is characterized by a low in vivo toxicity in mice (LD₅₀ > 2000 mg/kg).     

Five-membered 2,3-dioxo heterocycles: LXXIV. Recyclization of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones by the action of benzohydrazides. Crystalline and molecular structure of N-[2,4-dihydroxy-5-oxo-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]benzamide

Recyclization of 3-aroyl-1H-pyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones by the action of benzoic acid hydrazides gave N-[2,4-dihydroxy-5-oxo-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-2-aryl-2,5-dihydro-1H-pyrrol-1-yl]benzamides whose structure was proved by X-ray analysis.     

Novel pyrrolo[1,2-a][3.1.6]benzothiadiazocine ring synthesis. Unusual Truce-Smiles type rearrangement of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl(or sulfinyl)}acetone

Reaction of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfonyl}acetone with sodium hydroxide with or without zinc gave 1-(2-nitrophenyl)(1H-pyrrol-2-ylsulfonyl)methane by a Truce-Smiles type of transformation and 1-(2-nitrophenyl)-2-methylsulfonylpyrrole by deacetylation. Similar treatment of 1-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfinyl}acetone gave only 1-(2-nitro-phenyl)(1H-pyrrol-2-ylsulfinyl)methane. 1-{[1-(2-Nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}acetone, 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}-1-phenyl-ethan-1-one or 2-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]sulfanyl}acetonitrile were reductively cyclised with sodium borohydride and 5% palladium-on-carbon into 6-methyl(or phenyl)-5,6-dihydro-7H-pyrrolo[1,2-a][3.1.6]benzothiadiazocin-7-ol or 6-amino-5H-pyrrolo[1,2-a][3.1.6]benzothiadiazocine-7-oxide, respectively.     

Pyirolothieno[1,4]diazepines. Part IV. First synthesis of pyrrolo-[1,2-a]thieno[2,3-f][1,4]diazepine Derivatives

Treatment of 3-(2-formyl-1H-pyrrol-1-yl)-2-thiophenecarboxamide by various nucleophiles like methyl ketones, amines, alcohols, thiols or acetates led to new 5,6-dihydro-4H-pyrrolo[1,2-a]thieno-[2,3-f][1,4]diazepines.     

Synthesis and epimerization of 10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-(11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione

The reaction of the 1,2:3,4-di-O-isopropylidene-6-O-tosyl-α-d-galactopyranose 2 with (11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-dione 1, prepared from l-proline and isatoic anhydride, gave two products which were previously reported as conformational isomers. In this work, an X-ray crystallographic study showed these to be the diastereomeric pair (11aS)- and (11aR)-10-N-(6-deoxy-1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)-pyrrolo[2,1-c][1,4]benzodiazepin-5,11-diones as a consequence of C(11a) epimerization in the benzodiazepine moiety during glycosylation under basic reaction conditions. The hydrosolubility of the deprotected products were compared with those of the analogous benzodiazepine derivatives.     

Novel synthesis of tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones via decarboxylative cyclization reaction of α-amino acids and α-ketoamides

An efficient and practical method was developed for the synthesis of tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones based on the decarboxylative cyclization reaction of α-ketoamides and proline. In most cases, tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones were obtained with perfect diastereoselectivity to give trans-isomer in excellent yield.     

Five-membered 2,3-dioxoheterocycles: XCVI. Reactions of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5h)-triones with substituted 1,3,3-trimethyl-2-azaspiro[4.5]dec-1-enes

3-Aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones react with 1,3,3,7,9-pentamethyl-2-azaspiro-[4.5] deca-1,6,9-trien-8-one and 2′,5′,5′-trimethyl-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-4-one providing 3-aroyl-2-hydroxy-3a-{(3,3,7,9-tetramethyl-8-oxo-2-azaspiro[4.5]deca-1,6,9-trien-1-yl)methyl}pyrrolo[1,2-a-quinoxaline-1,4(3a H,5H)-diones and 3-aroyl-2-hydroxy-3a-{(5′,5′-dimethyl-4-oxo-4′,5′-dihydro-4H-spiro[naphthalene-1,3′-pyrrol]-2′-yl)methyl}pyrrolo[1,2-a]-quinoxaline-1,4(3aH,5H)-diones.     

Pyrrolothieno[1,4]diazepines part III: Synthesis of amino,hydrazino and mercapto derivatives

Treatment of 2-(2-formyl-1H-pyrrol-1-yl)-3-thiophenecarbonitrile by sodium percarbonate afforded, in a one-pot sequence and on a multigram scale, 5,6-dihydro-6-hydroxy-4H-pyrrolo[1,2-a]thieno-[3,2-f][1,4]diazepin-4-one whose reactivity towards various nucleophiles like amines, hydrazines and thiols was evaluated.     

Synthesis of pyrimido[1,2-a]benzimidazoles from ethyl 2-ethoxymethylidene-3-oxo-3-(polyfluoroalkyl)propionates

Cyclization of ethyl 2-ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates with benzimidazol-2-amine in boiling 1,4-dioxane followed two concurrent pathways with participation of fluoroacyl and ethoxycarbonyl fragments and formation of, respectively, ethyl 4-hydroxy-4-polyfluoroalkyl-1,4-dihydropyrimido-[1,2-a]benzimidazole-3-carboxylates and 3-polyfluoroacylpyrimido[1,2-a]benzimidazol-4-ols. Dihydropyrimido[1,2-a]benzimidazole derivatives undergo dehydration to give ethyl 4-(polyfluoroalkyl)pyrimido[1,2-a]benzimidazole-3-carboxylates, whereas the hydroxy group in 3-polyfluoroacylpyrimido[1,2-a]benzimidazol-4-ols is capable of being replaced by the amino group of the second benzimidazole molecule with formation of 4-(1H-benzimidazol-2-ylamino)-3-polyfluoroacylpyrimido[1,2-a]benzimidazoles.     

One-pot synthesis of polycyclic heterocyclic compounds by condensation of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium salts with pyridine-2, 3, and 4- and quinoline-4-carboxaldehydes

A one-pot synthesis of new polycyclic heterocyclic compounds was carried out via the condensation of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium chloride with pyridine- and quinolinecarboxaldehydes. The heating of the aforementioned 3H-indolium salts with 1 eq. of pyridine-2, 3, and 4- or quinoline-4-carboxaldehyde in ethanol in the presence of piperidine as a catalyst provided 9a-[2-(pyridyl)ethenyl]- or 9a-[2-(quinolyl)ethenyl]-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one derivatives as the main products. However, reaction outcome was dramatically different for the analogous reactions in acetic acid. In this case, the heating of the chloride with 2 eq. of pyridine-2-carboxaldehyde afforded derivatives of 9a-[3-(pyridin-2-yl)indolizin-2-yl]-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one as the major product, while the use of 2 eq. of pyridine-3 and 4- or quinoline-4-carboxaldehyde led to the formation 2-heteroaryl-1-heteroarylmethyl-9H-pyrrolo[1,2-a]indole-3-carboxamides. Plausible pathways for the cyclization reactions are discussed. The structural assignments were based on ¹H, ¹³C and ¹⁵N NMR spectroscopy, HRMS and single-crystal X-ray diffraction data.     

Five-membered 2,3-dioxo heterocycles: LIII. Reaction of 3-Aroyl-1<Emphasis Type="Italic">H</Emphasis>-pyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazine-1,2,4-triones with substituted 1,3,3-trimethyl-3,4-dihydroisoquinolines. A new approach to 13-aza analogs of steroids

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with substituted 1,3,3-trimethyl-3,4-dihydroisoquinolines to give the corresponding 3-aroyl-4-hydroxy-1-(2-hydroxyphenyl)-5′,5′-dimethyl-5′,6′-dihydro-1H-spiro[pyrrole-2,2′-pyrrolo[2,1-a]isoquinoline]-3′,5-diones. 7′,8′-Benzo derivatives of the latter may be regarded as 13-azagonane analogs having a spiro-fused pyrrole ring at C¹⁶.