Five-membered 2,3-dioxo heterocycles: CI. Reaction of 3-aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with arylhydrazines. Crystal and molecular structure of substituted 2-hydrazonopyrrolo[2,1-c][1,4]benzoxazine

A new direction of nucleophilic attack was revealed in the reactions of 3-aroylpyrrolo[2,1-c][1,4]-benzoxazine-1,2,4-triones with o-tolylhydrazine and 2-hydrazinylbenzoic acid hydrochloride, which afforded the corresponding hydrazones at the C²=O carbonyl group, substituted 2-(2-o-tolylhydrazono)pyrrolo[2,1-c]-[1,4]benzoxazine-1,4(2H)-diones and pyrrolo[2,1-c][1,4]benzoxazin-2(4H)-ylidenehydrazinylbenzoic acids. The structure of (Z)-2-{2-[3-benzoyl-1,4-dioxo-1H-pyrrolo[2,1-c][1,4]benzoxazin-2(4H)-ylidene]hydrazinyl}-benzoic acid was determined by X-ray analysis.     

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.     

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.     

Five-membered 2,3-dioxo heterocycles: CII. Spiro heterocyclization of 3-aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones by the action of tetrahydroquinoline

3-Aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with 1,2,3,4-tetrahydroquinoline to give 3-aroyl-4-hydroxy-1-(2-hydroxyphenyl)-5′,6′-dihydrospiro[pyrrole-2,1′-pyrrolo[3,2,1-ij]quinoline]-2′,5(1H,4′H)-diones.     

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.     

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.     

Five-membered 2,3-dioxo heterocycles: XCII. Reaction of 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with ethyl (2Z)-(3,3-dimethyl-8-oxo-2-azaspiro[4.5]deca-6,9-dien-1-ylidene)ethanoate. Synthesis of bridged analogs of pyrrolizidine alkaloids

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with ethyl (2Z)-(3,3-dimethyl-8-oxo-2-azaspiro[4.5]deca-6,9-dien-1-ylidene)acetate to give ethyl 6′-aryl-2′-(2-hydroxyphenyl)-11′,11′-dimethyl-3′,4,4′,13′-tetraoxospiro[2,5-cyclohexadiene-1,9′-(7′-oxa-2′,12′-diazatetracyclo[6.5.1.0^1,5.0^8,12]tetradec-5′-ene)]-14′-carboxylates whose structure was confirmed by X-ray analysis. The products may be regarded as bridged analogs of pyrrolizidine alkaloids, 7′-oxa-2′,12′-diazatetracyclo[6.5.1.01,5.08,12]tetradecanes.     

Research on nitrogen containing heterocyclic compounds. XVIII. Synthesis of 9H-pyrrolo[2,1-c]-s-triazolo[4,3-a][1,4]benzodiazepine,a novel tetracyclic ring of pharmaceutical interest

Reaction of di-4-morpholinylphosphinic chloride on 5,10-dihydro-9H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one 9 afforded 11-(di-4-morpholinylphosphinyloxy)-5H-pyrrolo[2,1-c][1,4]benzodiazepine 10 . Displacement of di-4-morpholinylphosphinyloxy group of 10 by formylhydrazine with concomitant intramolecular cyclization led directly to 9H-pyrrolo[2,1-c]-s-triazolo[4,3-a][1,4]benzodiazepine 7, a novel nitrogen heterocyclic ring of pharmaceutical interest. A new procedure for the synthesis of 9 is also described.     

Condensation of 2-naphthylamine or N-benzyl-2-naphthylamines with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexane-3-carboxylate

Condensation of 2-naphthylamine with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexanecarboxylate afforded depending on the reaction conditions methyl 9,9-dimethyl-11-oxo-8,9,10,12-tetrahydro-7H-benzo[a]acridine-10-carboxylate or 4-alkoxymethyl-1,4-dihydro-2??,6??-dioxo-4??,4??-dimethyl-2??H,3H,6??Hspirobenzo[f]quinoline-2,1??-cyclohexyl-3??-carboxylate. The condensation of N-benzyl-2-naphthylamines with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexanecarboxylate provided with the quantitative yield the corresponding methyl 4-benzyl-1,4-dihydro-2??,6??-dioxo-4??,4??-dimethyl-2??H,3H,6??H-spirobenzo[f]quinoline-2,1??-cyclohexyl-3??-carboxylates.     

Novel synthesis of the pyrrolo[2,1-c][1,4]benzodiazocine ring system via a Dieckmann condensation

A novel four-step synthesis to the pyrrolo[2,1-c][1,4]benzodiazocine ring system is described. 1H-Pyrrole-2-carbaldehyde was alkylated with ethyl or methyl bromoacetate and the resulting ethyl or methyl (2-formyl-1H-pyrrol-1-yl)acetates oxidised with potassium permanganate to the corresponding 1-[(2-ethoxy or methoxy)-2-oxoethyl]-1H-pyrrole-2-carboxylic acids. The latter was converted into their acid chlorides by reaction with thionyl chloride and without isolation transformed into the respective methyl 2-({[1-(2-ethoxy or methoxy-2-oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoates by reaction with methyl anthranilate. Dieckmann condensation of methyl 2-({[1-(2-methoxy-2-oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoate provided the pyrrolo[2,1-c][1,4]benzodiazocine.     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

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.     

Five-membered 2,3-dioxo heterocycles: LXII. Reaction of 3-aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with N,N′-dihydroxycyclohexane-1,2-diamine. Unusual rearrangement in the spiro[quinoxaline-2,2′-pyrrole] system

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with N,N′-dihydroxycyclohexane-1,2-diamine to give 3-aroyl-1′,4,4′-trihydroxy-1-(2-hydroxyphenyl)-4a′,5′,6′,7′,8′,8a′-hexahydro-1′H-spiro[pyrrole-2,2′-quinoxaline]-3′,5(1H,4′H)-diones which underwent rearrangement into 1′-aroyloxy-4,4′-dihydroxy-1-(2-hydroxyphenyl)-4a′,5′,6′,7′,8′,8a′-hexahydro-1′H-spiro[pyrrolidine-2,2′-quinoxaline]3′,4,5(4′H)-triones via [1,4]-migration of the aroyl group. The product structure was proved by X-ray analysis.     

Five-membered 2,3-Dioxoheterocycles: LIX. Reaction of 3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with Acyclic β-Enaminoesters. Crystal and Molecular Structure of Ethyl 3-Benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,3-dihydro-1H-pyrrolo-2-spiro-3′-(5-methyl-2-oxo-2,3-dihydro-1H-pyrrolo-4-carboxylate)

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones react with substituted alkyl 3-amino-2-propenoates to form substituted alkyl 3-aroyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrrole-2-spiro-3′-(2-oxo-2,3-dihydro-1H-pyrrole-4-carboxylates). Crystal and molecular structure of ethyl 3-benzoyl-4-hydroxy-1-o-hydroxyphenyl-5-oxo-2,5-dihydro-1H-pyrrole-2-spiro-3′-(5-methyl-2-oxo-2,3-dihydro-1H-pyrrole-4-carboxylate) was investigated.     

Microwave-assisted generation and reactivity of aza- and diazafulvenium methides: heterocycles via pericyclic reactions

Azafulvenium methides and diazafulvenium methides have been generated under microwave irradiation from 2,2-dioxo-1H,3H-pyrrolo[1,2-c]thiazoles and 2,2-dioxo-1H,3H-pyrazolo[1,5-c]thiazoles, respectively. Pericyclic reactions of these 1,7-dipole intermediates, namely, sigmatropic [1,8]H shifts, 1,7-electrocyclization or [8π+2π] cycloaddition led to the synthesis of a range of pyrrole and pyrazole derivatives. The first evidence for the azafulvenium methides by intermolecular trapping via [8π+2π] cycloaddition is reported.     

Five-membered 2,3-dioxo heterocycles: LVI. 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 acyclic enamino ketones

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones react with 4-arylaminopent-3-en-2-ones and 3-amino-1,3-diphenylprop-2-en-1-ones to give substituted 4-aroyl-3-hydroxy-1-(o-hydroxyphenyl)-1,7-diazaspiro[4.4]nona-3,8-diene-2,6-diones.     

Interaction of 3-p-toluoyl-1,2-dihydro-4H-pyrrolo-[2,1-c][1,4]benzoxazine-1,2,4-trione with benzylamine. Synthesis and crystal and molecular structure ofZ-3-(1-benzyl-2-hydroxy-4,5-dioxo-2-p-tolyltetrahydropyrrol-3-idene)-3,4-dihydro-2H-1,4-benzoxazin-2-one

3-p-Toluoyl-1,2-dihydro-4H-pyrrolo-[2,1-c][1,4]benzoxazine-1,2,4-trione reacts with benzylamine to yieldZ-3-(1-benzyl-2-hydroxy-4,5-dioxo-2-p-tolyltetrahydropyrrol-3-idene)-3,4-dihydro-2H-1,4-benzoxazin-2-one. The crystal and molecular structure of the latter compound was studied by X-ray structural analysis. Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 3, pp. 566–569, March, 1997.     

Chemistry of Acyl(imidoyl)ketenes: IX. Synthesis and Thermolysis of 3-Aroyl-8-chloro-1,2-dihydro-4<Emphasis Type="Italic">H</Emphasis>-pyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazine-1,2,4-triones

Reactions of 3-Z-aroylmethylene-6-chloro-3,4-dihydro-2H-1,4-benzoxazine-2-ones with oxalyl chloride afford 3-aroyl-8-chloro-1,2-dihydro-4H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones and Z-3-(2-aryl-2-chlorovinyl)-6-chloro-2H-1,4-benzoxazine-2-ones. Aroyl(imidoyl)ketenes generated by decarbonylation of pyrrolobenzoxazinetriones undergo dimerization through [4+2]-cycloaddition to form 4-aroyl-3-aroyloxy-2-(2-oxo-2H-1,4-benzoxazin-3-yl)-1H, 5H-pyrido[2,1-c][1,4]benzoxazine-1,5-diones.     

A convenient approach to the synthesis of 2-(2-aminoethyl)pyrroles and their heterocyclization into hydrogenated pyrrolopyridines and related pyrroloindolizines

2-(2-Aminoethyl)pyrroles and 2-(2-succinimidoethyl)pyrroles were prepared from acetals of ethyl 4-oxoalkanoates via latent vinyl 1,4-dicarbonyl compounds as the key intermediates. The Pictet-Spengler condensation of 2-(2-aminoethyl)pyrroles with aromatic aldehydes gave 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines in good yields. 4,5,7,8,9,9a-Hexahydro-3H-pyrrolo[2,3-g]indolizines were prepared in a similar way starting from 2-(2-succinimidoethyl)pyrroles.     

[4 + 2]-Cycloaddition of vinyl acetate to pyrrolobenzoxazinetriones. Diastereoselective synthesis of angularly fused pyrano[4,3-<Emphasis Type="Italic">b</Emphasis>]pyrroles

[4 + 2]-Cycloaddition of vinyl acetate to 3-aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones afforded (10R*,11aR*)-8-aryl-6,7,12-trioxo-6,7,10,11-tetrahydropyrano[4′,3′:2,3]pyrrolo[2,1-c][1,4]benzoxazin-10-yl acetates with high diastereoselectivity.