Facile rearrangement of 2-amino-3-carbethoxy-4-ethylfuro[3,2-b]pyridinium cation to 2-oxo-3-cyano-4-ethyl-4H-furo[3,2-b]pyridine

The rearrangement of 2-amino-3-carbethoxy-4-ethylfuro[3,2-b]pyridinium iodide in basic solution was studied. The reaction product is 2-oxo-3-cyano-4-ethyl-4H-furo[3,2-b]pyridine which was obtained also by alkylation with ethyl iodide and sodium hydride in dimethylformamide of 2-oxo-3-cyano-3H-furo[3,2-b]-pyridine or of p-nitrophenyl-3-acetoxypyridine-2-cyanacetate.     

Synthesis of 4H-furo[3,2-b]indole derivatives A new heterocyclic ring system

4H-Furo[3,2-b]indole (III) was prepared from deoxygenation of 2-(2-nitrophenyl)furan (II) with triethyl phosphite and thermolysis of 2-(2-azidophenyl)furan (VI). 4H- or 4-alkylfuro [3,2-b]indole-2-carboxaldehydes (VIII, IXa-c) were obtained by Vilsmeier formylation of the corresponding furo[3,2-b]indoles (III, VIIa-c). 4H-Furo[3,2-b]indole-2-carboxaldehyde (VIII) was submitted to the Cannizzaro, Wittig and reduction reactions. The Shiff's bases were obtained by the reaction of 4-ethylfuro[3,2-b]indole-2-carboxaldehyde (IXb) with amines. J. Heterocyclic Chem., 14, 975 (1977)     

Synthesis of 4H-furo[3,2-b]indoles. II. Bromination,acylation and nitration of 4H- and 4-benzoylfuro[3,2-b]indoles

Monobromination and monoacylation at the 2-position of 4H-furo[3,2-b]indole ring (III) were facilitated by the benzoyl group in the 4-position; subsequent nitration attempts were unsuccessful.     

Furopyridines. III. A new synthesis of furo[3,2-b]pyridine

A convenient synthesis of furo[3,2-b]pyridine and its 2- and 3-methyl derivatives from ethyl 3-hydroxypiconate ( 1 ) is described. The hydroxy ester 1 was O-alkylated with ethyl bromoacetate or ethyl 2-bromopropionate to give the diester 2a or 2b . Cyclization of compound 2a afforded ethyl 3-hydroxyfuro[3,2-b]pyridine-2-carboxylate ( 3 ) which in turn was hydrolyzed and decarboxylated to give furo[3,2-b]pyridin-3-(2H)-one ( 4a ). Cyclization of 2b gave the 2-methyl derivative 4b . Reduction of 4a and 4b with sodium borohydride yielded the corresponding hydroxy derivative 5a and 5b respectively, which were dehydrated with phosphoric acid to give furo[3,2-b]pyridine ( 6a ) and its 2-methyl derivative ( 6b ). 2-Acetylpyridin-3-ol ( 8 ) was converted to the ethoxycarbonylmethyl ether ( 9 ) by O-alkylation with ethyl bromoacetate, which was cyclized to give 3-methylfuro[3,2-b]pyridine-2-carboxylic acid ( 10 ). Decarboxylation of 10 afforded 3-methylfuro[3,2-b]pyridine ( 11 ).     

Straightforward method for the synthesis of 2H-furo[3,2-b]pyran-2-one derivatives starting from allomaltol

We developed a facile approach for the preparation of a rare 2H-furo[3,2-b]pyran-2-one system. The suggested method is based on a two-step process using unsubstituted allomaltol as a starting compound. The key stage of the considered route is a condensation of 2-(2-aryl-2-oxoethyl)-3-hydroxy-6-methyl-4H-pyran-4-ones with 1,1-carbonyldiimidazole. The advantages of the presented method are commercially available starting materials and convenient experimental procedures including simple isolation of the target compounds. The structure of one of the 2H-furo[3,2-b]pyran-2-ones was confirmed by x-ray diffraction.     

Novel pyrano[3,2-b]indole derivatives: synthesis and some properties

Acid treatment of β-(3-acetoxyindol-2-yl)-α-cyanoacrylic acid derivatives (ethyl ester and nitrile) with aqueous or gaseous HCl afforded novel 3-substituted 2-oxo-2,5-dihydropyra-no[3,2-b]indoles. 2-Oxo-2,5-dihydropyrano[3,2-b]indole-3-carbonitrile was converted into ethyl 2-oxo-2,5-dihydropyrano[3,2-b]indole-3-carboximidate.     

2-[3-(Trifluoromethyl)phenyl]furo[3,2-b]pyrroles: synthesis and reactions

The synthesis and reactions of methyl 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole-5-carboxylate (1a) are described. Upon reaction with methyl iodide, benzyl chloride, or acetic anhydride, this compound gave N-substituted products 1b-d. By hydrolysis of compounds 1a-c, the corresponding acids 2a-c were formed, or by reaction with hydrazine-hydrate, the corresponding carbohydrazides 3a-c were formed. By heating 2-[3-(trifluoromethyl)phenly]-4H-furo[3,2-b]pyrrole-5-carboxylic acid (2a) in acetic anhydride, 4-acetyl-2-[3-(trifluoromethyl)phenyl]furo[3,2-b]pyrrole (4) was formed. By hydrolysis of 4, 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole (5a) was formed, and reactions with methyl iodide or benzyl chloride gave N-substituted products 5b-c. The reaction of 4 with dimethyl butynedioate gave substituted benzo[b]furan 6. Compound 3a reacted with triethyl orthoesters giving 7a-c, which afforded with phosphorus (V) sulphide the corresponding thiones 8a-c. The thiones 8a-c reacted with hydrazine hydrate to form hydrazine derivatives 9a-c. The reaction of triethyl orthoformiate with compounds 9a-c led to furo[2′,3′: 4,5]pyrrolo[1,2-d][1,2,4]triazolo[3,4-f][1,2,4]triazines 10a-c. Hydrazones 11a-c were formed from 3a-c and 5-[3-(trifluoromethyl)phenyl]furan-2-carboxaldehyde. The effect of microwave irradiation on some condensation reactions was compared with “classical” conditions. The results showed that microwave irradiation shortens the reaction time while affording comparable yields.     

2,2′-Bifurylidene-5,5′-diones,Coumarins, 3a, 7a-dihydro-1H-inden-1-ones,and 5H-furo[3,2-b]pyran-5-ones from propyne and carbon monoxide

The [Co₂ (CO)₈]-catalyzed reaction between propyne and CO in acetone at 110° and 170 bar was re-investigated. There are five major products: (E)-3,4′-dimethyl-2,2′-bifurylidene-5,5′-dione ( 4 ), 3,5,8-trimethylcoumarin ( 8 ), 3a, 7a-dihydro-2,4,7,7a-tetramethyl-1H-inden-1-one ( 9 ), 2,6-dimethyl-5H-furo [3,2, -b]- pyran-5-one ( 11 ), and 2,7-dimethyl-5H-furo 3,2-b-pyran-5-one ( 12 ); of these, only one, 4 . had previously been recognized. In parallel experiments were obtained 2,6-dipentyl-5 H-furo[3,2-b]pyran-5-one ( 13 ), 2,7-dipentyl–5H-furo[3,2-b]pyran-5-one ( 14 ), 3a, 7a-dihydro-2,4,7,7a-tetrapentyl-1H-inden-1-one ( 15 ). And 3a, 7a-dihydro-2,4,6,7a-tetrapentyl-1H-inden-1-one ( 16 ) from hept-1-yne, and two further types of products from two atypical 1-alkynes: 3,6,9-tri(tert-butyl)-1-oxaspiro[4.4]nona-3,6,8-trien-2-one ( 20 ) from (tert-butyl)acetylene and the exo-dimer 21 of 2,5-bis(trimethylsilyl)cyclopenta-2,4-dien-1-one ( 22 ) from (trimethylsilyl)acetylene. Compounds 11,12 , and 20 were identified by X-ray analysis.     

Furopyridines. XX. Wittig-horner reaction of a phosphonate of reissert analogues of furo[3,2-c]-, -[2,3-c]- and -[3,2-b]pyridines

Furo[3,2-c]-( 1a ), -[2,3-c]- ( 1b ) and -[3,2-b]pyridine ( 1c ) were reacted with isopropyl chloroformate and trimethyl phosphite to give dimethyl 5-isopropoxycarbonyl-4,5-dihydrofuro[3,2-c]pyridine-4-phosphonate ( 2a ), dimethyl 6-isopropoxycarbonyl-6,7-dihydrofuro[2,3-c]pyridine-7-phosphonate ( 2b ) and dimethyl 4-isopropoxycarbonyl-4,7-dihydrofuro[3,2-b]pyridine-7-phosphonate ( 2c ) as unstable syrups. Reaction of 2b and 2c with n-butyllithium and then with benzaldehyde, p-methoxybenzaldehyde, p-cyanobenzalde-hyde or propionaldehyde afforded the normal Wittig reaction products 5b-H, 5b-OMe, 5b-CN, 5b-Et, 5c-H, 5c-H, 5c-OMe and 5c-CN , except for 2b with propionaldehyde. While, the same reactions of compound 2a and the reaction of 2b with propionaldehyde afforded the unexpected products, 5-isopropoxycar-bonylfuro[3,2-c]pyridinio-4-aryl-(or ethyl)methoxides 3a-H, 3a-OMe, 3a-CN and 3a-Et , 4-(1′-aryl(or ethyl)-1′-hydroxymethyl)furo[3,2-c]pyridines 4a-H, 4a-OMe, 4a-CN and 4a-Et accompanying formation of the normal products. Treatment of the normal Wittig reaction products with lithium diisopropylamide and then with acetone gave the derivatives alkylated at the 2-or the benzylic positions.     

Tetrahydrocyclopenta[e]pyrido[3,2-b][1,4]diazepine and -cyclopenta[e]pyrido[2,3-b][1,4]diazepine derivatives

In pursuing the study on compounds obtained by condensation of N-monoalkylated aromatic and hetero-aromatic diamines with α- and β-ketoesters, 7,8,9,10-tetrahydrocyclopenta[e]pyrido[3,2-b][1,4]diazepin-6(5H)-ones 4a, 4b and 5,7,8,10-tetrahydrocyclopenta[e]pyrido[2,3,-b][l,4]diazepin-9H)-ones 5a, 5b were prepared starting from 2,3-diaminopyridine or 2,3-diamino-5-chloropyridine and ethyl 2-oxo-cyclopentanecarboxylate. Compounds 4a,b and 5a,b suffer thermally induced ring contraction to the imidazolone derivatives 8a,b and 7a,b respectively and are unsuitable for preparing diazepinone derivatives. Thus the methylated diazepinones 15, 17 and 18 , stable on heating, were prepared. Compound 17 was transformed into the clozapine analogue 22 , through the diazepinthione 20 and its S-methyl derivative 21 .     

Convenient synthesis and anticancer evaluation of novel pyrazolyl-thiophene,thieno[3,2-b]pyridine,pyrazolo[3,4-d]thieno[3,2-b]pyridine and pyrano[2,3-d]thieno[3,2-b]pyridine derivatives

The newly synthesized 3-(3-amino-5-(phenylamino)-4-(phenylcarbamoyl)thiophen-2-yl)-3-oxopropanoate was utilized as a precursor for the synthesis of pyrazolyl-thiophene derivative, which undergoes cyclization upon treatment with benzaldehyde derivatives to provide pyrazolo[3,4-d]thieno[3,2-b]pyridines. Basic treatment of pyrazolyl-thiophene derivative with phenyl isothiocyanate followed by subsequent addition of chloroacetone and/or ethyl bromoacetate yielded the thiazolylidene-pyrazolyl thiophenes. In addition, the building block 3-(3-amino-5-(phenylamino)-4-(phenylcarbamoyl)thiophen-2-yl)-3-oxopropanoate was converted into the corresponding thieno[3,2-b]pyridine compounds through its reactions with (DMF-DMA) and/or heating in sodium ethoxide. Moreover, the reaction of 7-hydroxy-5-oxo-N-phenyl-2-(phenylamino)-4,5-dihydrothieno[3,2-b]pyridine-3-carboxamide with 2-arylidenemalononitrile produced the new annulated pyrano[2,3-d]thieno[3,2-b]pyridines. The prepared thiophene-based compounds were evaluated against HepG2, PC3, and MCF-7 cancer cells, and normal fibroblast cell (WI38). The pyrazolo[3,4-d]thieno[3,2-b]pyridine and pyrano[2,3-d]thieno[3,2-b]pyridine compounds substituted with chlorophenyl group presented promising cytotoxic activities against HepG2 cancer cell line without any human toxicity. Docking study for the synthesized thiophene compounds delivered valuable insights about the binding interactions with the crystal structure of NS5B enzyme with PDB ID (4TLR).     

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®.     

Furopyridines. XVII . Cyanation,chlorination and nitration of furo[3,2-b]pyridine N-oxide

The N-oxide 2 of furo[3,2-b]pyridine ( 1 ) was cyanated by the Reissert-Henze reaction with potassium cyanide and benzoyl chloride to give 5-cyano derivative 3 , which was converted to the carboxamide 4 , carboxylic acid 5 , ethyl ester 6 and ethyl imidate 8 . Chlorination of 2 with phosphorus oxychloride yielded 2-9a , 3- 9b , 5- 9c and 7-chloro derivative 9d . Reaction of 9d with sodium methoxide, pyrrolidine, N,N-dimethylformamide and ethyl cyanoacetate afforded 7-methoxy- 10 , 7-(1-pyrrolidyl)- 11 and 7-dimethylaminofuro[3,2-b]pyridine ( 14 ) and 7-(1-cyano-1-ethoxy-carbonyl)methylene-4,7-dihydrofuro[3,2-b]pyridine ( 12 ). Nitration of 2 with a mixture of fuming nitric acid and sulfuric acid gave 2-nitrofuro[3,2-b]pyridine N-oxide ( 15 ).     

Synthesis of novel dihydrothiazolo[3,2-a]pyrimidinone derivatives

Condensation of 2-amino-4-hydroxy-2-mercaptopyrimidine (2) hydrate and ethyl 4-bromocrotonate gave a mixture of ethyl 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a]pyrimidine-3-acetate (4) and 2a,3-dihydro-1-thia-5,8,8b-triazaacenaphthylene-4,7(2H)-dione (5) whereas reaction of 2 with 4-bromocrotononitrile afforded only 7-amino-2,3-dihydro-5-oxo-5H-thiazolo[3,2-a] pyrimidine-3-acetonitrile. Reaction of the tricycle 5 (which was isolated as a hemihydrate) with excess methyl iodide/potassium carbonate in dimethylformamide resulted in both ring hydrolysis and methylation to give 3,4-dihydro-1,7-dimethyl-4- [(methylthio)methyl]-2H-pyrimido[1,6-a]pyrimidine-2,6,8(1H,7H)-trione (10). Methylating 5 with excess methyl iodide/sodium methoxide in methanol also resulted in ring fragmentation and methylation but instead afforded methyl 7-methyl-amino-2,3-dihydro-5-oxo-7H-thiazolo[3,2-a]pyrimidine-3-acetate. The mechanistic aspects of these reactions are discussed.     

Furo[3,2-e]pyrrolo[1,2-α][1,4]diazepine and derivatives

The 5,10-dihydro-4H-furo[3,2-e]pyrrolo[1,2-α][1,4]diazepin-5-one ( 7 ) and furo[3,2-e]pyrrolo[1,2-α][1,4]diaze-pine ( 10 ) are synthesized from suitable isocyanates 3a,b in acetic acid. The reactivity of 10 (C- and N-alkyla-tion) is investigated.     

First synthesis of 4H-furo[3,2-f]pyrrolo[1,2-a][1,4]diazepines

The synthetic pathway leading to 4-H-furo[3,2-f]pyrrolo[1,2-a][1,4]diazepines is described in five steps starting from 2-hydroxyketones via 2-amino-3-furonitriles.     

Furopyridines. XXI. Synthesis of cyano derivatives of furo-[2,3-b]-, -[2,3-c]- and -[3,2-c]pyridine and their conversion to derivatives having another carbon-substituent

Cyanation of furo[2,3-b]-, -[2,3-c]- and -[3,2-c]pyridine N-oxides 1a, 1b and 1c by the Reissert-Henze method, reaction with benzoyl chloride and trimethylsilyl cyanide in dichloromethane and the reaction with trimethylsilyl cyanide and triethylamine in acetonitrile afforded 6-cyanofuro[2,3-b]- 2a , 7-cyanofuro[2,3-c]- 2b and 4-cyanofuro[3,2-c]pyridine 2c in moderate to excellent yield. The cyano group in 2a, 2b and 2c was converted to carboxamides 3a, 3b and 3c , ethyl imidates 5a, 5b and 5c and ethyl carboxylates 6a, 6b and 6c . Reaction of the N-oxides with trimethylsily bromide in acetonitrile gave the deoxygenated furopyridine 7a and 7d , bifuropyridyl 8b and 8c , and the N-oxide 9 of 8c .     

5H-Thiazolo [3,2-b]- and 2H-Thiazolo [2,3-c]-as-triazines

Derivatives of the 5H-thiazolo[3,2-b]- and 2H-thiazolo[2,3-c]-as-triazine systems were synthesized via condensation of tetrahydro-I-methyl-as-triazine-3(2H)-thione with ethylene dibromide and ethyl bromoacetate, respectively. An hypothesis is given for the formation of the [3,2-b] system in one of these reactions and the [2,3-c] system in the other. Structure proof was accomplished by an unequivocal synthesis of one of the [2,3-c] derivatives.     

Indole esters as heterocyclic synthons. III. Preparation and reactions of furo[3,2-b]indoles

The preparation of furo[3,2-b]indoles via Dieckmann cyclization is described. The precursor diesters were obtained from 3-hydroxy-1H-indole-2-carboxylic acid esters and methyl or ethyl bromoacetate. Reactions of the furo[3,2-b]indole enolic esters prepared are discussed.     

The synthesis of 5,10-dihydro- and 2,3,5,10-tetrahydrothiazolo-[3,2-b] [2,4]benzodiazepines, 1,2,3,4,7,12-hexahydrobenzothiazolo-[3,2-b] [2,4] benzodiazepine,and 9,14-dihydro-6H-[1]benzothiopyrano-[4′,3′:4,5]thiazolo[3,2-b] [2,4] benzodiazepine via 1,2,4,5-Tetrahydro-3H-2,4-benzodiazepine-3-thione

Catalytic reductive scission of phthalazine (II) utilizing a two-stage palladium-Raney nickel procedure afforded o-xylene-α,α′-diamine (III) in 97% yield. Treatment of III with carbon disulfide gave [o-(aminomethyl)benzyl]dithiocarbamic acid (IV), which upon thermal cyclization furnished 1,2,4,5-tetrahydro-3H-2,4-benzodiazepine-3-thione (V). Reaction of V with 1,2-dibromoethane, chloro-2-propanone, ethyl 2-chloroacetoacetate, ethyl chloroacetate, and ethyl 2-bromohexanoate gave 2,3,5,10-tetrahydrothiazolo[3,2-b][2,4]benzodiazepine (VII) and substituted 5,10-dihydrothiazolo[3,2-b][2,4]benzodiazepines (Villa and b, IX, and X), respectively. Condensation of V with 2-chlorocyclohexanone and 3-bromothiochroman-4-one afforded 1,2,3,4,7,12-hexahydrobenzothiazolo[3,2-b][2,4]benzodiazepine (XII) and 9,14-dihydro-6H-[1]benzothiopyrano[4′,3′:4,5]thiazolo[3,2-b][2,4]benzodiazepine(XIll). None of the compounds possessed appreciable biological activity.