Polycondensed heterocycles. II. A new preparative route to 11-Oxo-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine

6-Methylthio-10-oxo-5H,10H-pyrrolo[1,2-b]isoquinoline 11 was isolated in an attempted synthesis of 11-oxo-5H,11H-pyrrolo[2,1-c][1,4]benzothiazepine 1 from 1-(2-methylthiobenzyl)pyrrole-2-carboxylic acid chloride 9 , obtained using as starting material o-methylthiobenzyl bromide 3 and passing through 1-(2-methylthiobenzyl)pyrrole-2-carbonitrile 5 , by cyclization with aluminum chloride. However the successful demethylation with sodium in dimethylacetamide of 1-(2-methylthiobenzyl)pyrrole-2-carboxyamide 12 , formed by hydrolysis of nitrile 5 , allowed us to prepare by another way the corresponding thiol 13 and consequently the 1-(2-mercaptobenzyl)pyrrole-2-carboxylic acid 14 , which when subjected to intramolecular ring closure by CDI in place of DCC gave 1 in higher yield, 69% instead of 43%. Finally, the direct cyanation of 1-(2-ethoxycarbonylthiobenzyl)pyrrole 16 , prepared utilizing the 1-(2-mercaptobenzyl)pyrrole 15 obtained by demethylation of the corresponding thioanisol 4 which was carried out as above, afforded the unexpected 1-(2-ethylthio-benzyl)pyrrole-2-carbonitrile 17 .     

Reactivity of sarcosine and 1,3-thiazolidine-4-carboxylic acid towards salicylaldehyde-derived alkynes and allenes

The reaction of sarcosine and 1,3-thiazolidine-4-carboxylic acid with salicylaldehyde-derived alkynes and allenes opened the way to new chromeno[4,3-b]pyrrole and chromeno[2,3-b]pyrrole derivatives. Tetrahydro-chromeno[4,3-b]pyrroles were obtained from the reaction of these secondary amino acids with O-propargylsalicylaldehyde. Interestingly, sarcosine reacted with ethyl 4-(2-formylphenoxy)but-2-ynoate to give a monocyclic pyrrole resulting from rearrangement of the initially formed 1,3-dipolar cycloadduct. Decarboxylative condensation of ethyl 4-(2-formylphenoxy)but-2-ynoate with 1,3-thiazolidine-4-carboxylic acid afforded in a stereoselective fashion the expected chromeno-pyrrolo[1,2-c]thiazole, which structure was unambiguously established by X-ray crystallography. However, the 1H,3H-pyrrolo[1,2-c]thiazole resulting from the opening of the pyran ring was also isolated. The reaction with O-buta-2,3-dienyl salicylaldehyde afforded 3-methylene-hexahydrochromeno[4,3-b]pyrrole. O-Allenyl salicylaldehyde reacted with sarcosine and 1,3-thiazolidine-4-carboxylic acid to give a new type of chromeno-pyrroles. A mechanism proposal for the synthesis of these chromeno[2,3-b]pyrroles has been presented.     

Reaction of organozine reagents derived from dialkyl 2,2-dibromomalonates and methyl 4,4-dibromo-3-oxoalkanoates with 2-oxochromene-3-carboxamides

Organozinc compounds obtained by treatment of dialkyl 2,2-dibromomalonates with zinc reacted with N-substituted 2-oxochromene-3-carboxamides to give dialkyl 1a-R-carbamoyl-2-oxo-1a,7b-dihydro-2H-cyclopropa[c]chromene-1,1-dicarboxylates or alkyl 2-R-1,3,4-trioxo-2,3-dihydro-1H,9bH-chromeno[3′,4′:1,3]-cyclopropa[1,2-c]pyrrole-9c-carboxylates. Reactions of N-substituted 2-oxochromene-3-carboxamides with zinc enolates derived from methyl 4,4-dibromo-3-oxoalkanoates led to the formation of the corresponding 9c-alkyl-2-R-2,3-dihydrochromeno[3′,4′:1,3]cyclopropa[1,2-c]pyrrole-1,3,4-triones.     

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 of thio- and furan-fused heterocycles: furopyranone,furopyrrolone, and thienopyrrolone derivatives

We report herein the synthesis of a novel class of compounds, ethyl 4-oxo-4H-furo[3,2-c]pyran-6-yl carbonate, (7E)-7-[(dimethylamino)methylene]-4H-furo[3,2-c]pyran-4,6(7H)-dione, 5-oxo-N-phenyl-2,5-dihydro-4H-furo[3,2-b]pyrrole-4-carboxamide, and 5-oxo-N-phenyl-5,6-dihydro-4H-thieno[3,2-b]pyrrole-4-carboxamide starting from the corresponding acid derivatives. Intramolecular cyclization in the presence of thionyl chloride formed the target fused ring systems. Additional transformation was seen in the cyclization of furan-fused heterocycle. A mechanism was proposed based on experimental and computational findings.     

Cyclopropanation of N-substituted 3-aryl-2-cyanoprop-2-enamides and derivatives of 5,5-Dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylic acid and 2-oxochromene-3-carboxylic acid with bromine-containing zinc enolates

Zinc enolates derived from 1-aryl-2,2-dibromoalkanones react with N-substituted 3-aryl-2-cyanoprop-2-enamides and 5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylic and 2-oxochromene-3-carboxylic acid derivatives to give, respectively, N-substituted 2-alkyl-3-aryl-2-aroyl-1-cyanocyclopropane-1-carboxamides, 6-(4-bromobenzoyl)-4,4,6-trimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylic acid ethyl ester and morpholide, and 1-alkyl-1-aroyl-2-oxo-1a,7b-dihydrocyclopropla[c]chromene-1a-carboxylic acids as a single geometric isomer. Treatment of 1-alkyl-1-aroyl-2-oxo-1a,7b-dihydrocyclopropa[c]chromene-1a-carboxylic acids with carboxylic acid anhydrides leads to the formation of the corresponding 9c-alkyl-1-aryl-3,4-dioxo-9b,9c-dihydro-2,5-dioxacyclopenta[2,3]cyclopropa[1,2-a]naphthalen-1-yl carboxylates.     

Transformations of 3,3,4-tricyano-3,4-dihydro-2<Emphasis Type="Italic">H</Emphasis>-pyran-4-carboxamides. Synthesis of pyrano[3,4-<Emphasis Type="Italic">c</Emphasis>]pyrrole derivatives

A procedure has been developed for the synthesis of polyfunctional pyrano[3,4-c]pyrrole derivatives via intramolecular cyclization involving vicinal cyano and carboxamide groups on a pyran ring. 3-Amino-1-oxo-1,3a,4,7a-tetrahydropyrano[3,4-c]pyrrole-3a,7a-dicarbonitrile thus obtained react with organic amines to give stable ammonium salts and undergo hydrolysis to 1,3-dioxo-1,2,3,3a,4,7a-hexahydropyrano[3,4-c]pyrrole-3a,7a-dicarbonitriles in the presence of sulfuric acid.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Synthesis of 2-[3-(trifluoromethyl)phenyl]furo[3,2-<Emphasis Type="Italic">c</Emphasis>]pyridine derivatives

2-[3-(Trifluoromethyl)phenyl]-4,5-dihydrofuro[3,2-c]pyridin-4-one (I) was prepared by a three-step synthesis. Its reaction with phosphorus sulfide rendered thione II which was methylated to 2-[3-(Trifluoromethyl)phenyl]-4-methylsulfanylfuro[3,2-c]pyridine (III). 5-Methyl-2-[3-(trifluoromethyl)phenyl]-4,5-dihydrofuro[3,2-c]pyridin-4-one (IV) was obtained by the reaction of I with methyl iodide in PTC conditions. The chlorine atom in derivate V was replaced with heterocyclic secondary amines via nucleophilic substitution and 4-substituted furopyridines VIa and VIb were thus prepared. 2-[3-(Trifluoromethyl)phenyl]furo[3,2-c]pyridine-4-carboxylic acid (VII) was obtained by hydrolysis of the corresponding carbonitrile Va.     

A facile synthesis and highly atom economic 1,3-dipolar cycloaddition of hexahydropyrido[3,4-c][1,5]benzothiazepines with nitrile oxide: stereoselective formation of hexahydro[1,2,4]oxadiazolo[5,4-d]pyrido[3,4-c][1,5]benzothiazepines

A series of new 2-methyl-11-aryl-4-[(E)-arylmethylidene]-1,2,3,4,11,11a-hexahydropyrido[3,4-c][1,5]benzothiazepines were obtained by the reaction of o-aminothiophenol and (E)-1-methyl-3,5-bis(arylidene)-4-piperidones in the presence of a catalytic amount of acetic acid under solvent-free microwave irradiation. These dipolarophiles undergo a highly atom economic 1,3-dipolar cycloaddition with nitrile oxide to afford a series of novel 6-methyl-1-phenyl-8-aryl-4-[(E)-arylmethylidene]-4,5,6,7,7a,8-hexahydro[1,2,4]oxadiazolo[5,4-d]pyrido[3,4-c][1,5]benzothiazepines stereoselectively.     

An intramolecular oxo Diels-Alder approach to 1-oxo-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl esters

The diastereoselective synthesis of a series of 1-oxo-1,2,3,3a,4,7a-hexahydro-pyrano[3,4-c]pyrrole-4-carboxylic acid ethyl esters via an oxo Diels-Alder reaction is described. Ab initio calculations predicted the products of the exo cycloaddition to be the thermodynamic products while the products resulting from the endo cycloaddition were predicted to be the kinetic products. The calculations were born out by experimental data.     

Synthesis and Structure of 4-Indolyl-5-(thieno[3,2-<Emphasis Type="Italic">b</Emphasis>]pyrrol-6-yl)imidazoles

A procedure was proposed for regioselective acylation of methyl 2-methyl-4H-thieno[3,2-b]-pyrrole-5-carboxylate with 2-(3-indolyl)-2-oxoacetyl chloride. Reactions of the resulting methyl 6-[2-(3-indolyl)-1,2-dioxoethyl]-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate with aromatic aldehydes and ammonium acetate in acetic acid afforded the corresponding methyl 6-[2-aryl-4-(3-indolyl)imidazol-5-yl]-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylates. The structure of methyl 6-[2-(4-chlorophenyl)-4-(3-indolyl)imidazol-5-yl]-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate was studied by X-ray analysis.     

Facile ionic liquid-mediated,three-component sequential reactions for the green,regio- and diastereoselective synthesis of furocoumarins

An environmentally friendly approach to the diastereoselective synthesis of trans-4-oxo-3-aryl-3,4-dihydro-2H-furo[3,2-c]coumarin-2-carbonitriles, trans-2-benzoyl-3-(aryl)-2H-furo[3,2-c]chromen-4(3H)-ones and trans-ethyl-4-oxo-3-(aryl)-3,4-dihydro-2H-furo[3,2-c]chromene-2-carboxylates in good yields is described. The method is based on the sequential multicomponent reactions of 4-hydroxycoumarin, aromatic aldehydes and in situ generated cyanomethylpyridinium, phenacylpyridinium/(2-ethoxy-2-oxoethyl)pyridinium ylides, in the presence of the ionic liquid [BMIm]OH, which functions both as a catalyst and the reaction medium.     

Cyclization of substituted 3,4-diaminopyridines into 1H-[1,2,3]triazolo[4,5-c]pyridine 2-oxide derivatives during the nitration process

The nitration of pyridine-3,4-diamine, its N,N′-diacetyl derivative, and N ⁴-alkylpyridine-3,4-diamines with excess nitric acid in concentrated sulfuric acid at 60°C was accompanied by cyclization with formation of the corresponding 1-substituted 4-nitro-1H-[1,2,3]triazolo[4,5-c]pyridine 2-oxides. 4-Chloro-1H-[1,2,3]triazolo[4,5-c]pyridine 2-oxide derivatives were obtained under analogous conditions from 2-chloropyridine-3,4-diamine, its N,N′-diacetyl derivative, and 2-chloro-N ⁴-methylpyridine-3,4-diamine. The nitration of these compounds at 80–90°C gave 4-chloro-7-nitro-1H-[1,2,3]triazolo[4,5-c]pyridine 2-oxides.     

Synthesis of spiro-fused (C5)-pyrazolino-(C6)-triazinones, a new heterocyclic system

Reaction of 4-hydrazinoquinazoline with 2,4-diketoesters gives the corresponding 3-acylmethyl-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones in a one-step procedure via cyclocondensation-Dimroth-like rearrangement. Spectroscopic studies as well as X-ray analysis reveal that the obtained triazinoquinazolines exist in their ketoimine tautomeric form. Treatment of these compounds with hydrazine hydrate affords 3′-(2-aminophenyl)-3-(het)aryl-spiro[pyrazoline-5,6′(1′H)-1,2,4-triazin]-5′(4′H)-ones or 5-(het)arylpyrazole-3-carboxylic acid hydrazides depending on the reaction conditions. The structure of the spiro-heterocycles was elucidated by means of single-crystal X-ray analysis and confirmed by spectroscopic investigations.     

Synthesis of 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1<Emphasis Type="Italic">H</Emphasis>-imidazo-[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acids

Nitration of 2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one gave its 5-nitro derivative which was subjected to alkylation with dimethyl sulfate, diethyl sulfate, and benzyl(dimethyl)phenylammonium chloride. The resulting 1,3-dimethyl-, 1,3-diethyl-, and 1,3-dibenzyl-5-nitro-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones were reduced to the corresponding 1,3-dialkyl-5-amino-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-ones, and the latter reacted with itaconic acid to produce 1-(1,3-dialkyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acids. 1-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-5-oxopyrrolidine-3-carboxylic acid was obtained by analogous reaction with 5-amino-2,3-dihydro-1H-imidazo[4,5-b]-pyridin-2-one.     

Synthesis of 3-(trifluoromethyl)indeno[2,1-c]pyran-1,9-diones from 4-aryl-3-carbethoxy-6-(trifluoromethyl)-2-pyrones and their reaction with sodium azide leading to new carbostyril derivatives

Treatment of ethyl 4-aryl-6-(trifluoromethyl)-2-oxo-2H-pyran-3-carboxylates, prepared from 4,4,4-trifluorobutane-1,3-diones, PCl₅ and sodium diethyl malonate, with sulfuric acid afforded the intramolecular Friedel–Crafts acylation products, 3-(trifluoromethyl)indeno[2,1-c]pyran-1,9-diones, from which 2-(trifluoromethyl)-6H-pyrano[3,4-c]quinoline-4,5-diones were obtained via the Schmidt reaction in moderate yields. The latter reacted with sodium azide to give 2-oxo-4-(5-trifluoromethyl-1,2,3-triazol-4-yl)-1,2-dihydroquinoline-3-carboxylic acids in good yields.     

Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol-4(1H)-ones

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′,3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.     

Synthesis and nmr spectra of the six isomeric thieno[c]-fused 1,7- and 1,8-naphthyridines

Through the use of Pd(0)-catalyzed coupling between 2- and 4-formyl-3-thiopheneboronic acid and 4-iodo-3-aminopyridine ( 1 ) and 3-bromo-2-aminopyridine, convenient one-pot procedures for the preparation of thieno[2,3-c]-1,7-naphthyridine ( 2 ), thieno[3,4-c]-1,7-naphthyridine ( 3 ), thieno[2,3-c]-1,8-naphthyridine ( 6 ) and thieno[3,4-c]-1,8-naphthyridine ( 7 ) have been developed. Thieno[3,2-c]-1,7-naphthyridine ( 4 ) and thieno[3,2-c]-1,8-naphthyridine ( 8 ) were obtained through the coupling of 2-tri-n-butylstannyl-3-thiophenaldehyde with 2,2-dimethyl-N-(4-iodo-3-pyridinyl)propanamide and 3-bromo-2-acetamidopyridine ( 1 ). The yield of 8 was further increased when copper(II) oxide was used as the co-reagent. The ¹³C nmr spectra of the six isomeric thieno[c]-fused 1,7- and 1,6-naphthyridines are discussed.     

Synthesis of tetra- and pentaaza heterocyclic systems and benzimidazo[1,2-c]quinazoline derivatives

5,6-Dihydropyrimido[5′,4′: 5,6]pyrido[1,2-a]benzimidazole and pyrimido[4′,5′: 4,5]pyrimido[1,6-a]-benzimidazole derivatives were synthesized starting from 3-[4-hydroxy-6-methyl(hydroxy)-2-phenylpyrimidin-5-yl]propanoic and 4-hydroxy-2-phenylpyrimidine-5-carboxylic acids. New 6-sulfanyl-substituted benzimidazo-[1,2-c]quinazolines were also prepared.