Furopyridines. I. Synthesis of furo[2,3-c]pyridine

The parent framework of furo[2,3-c]pyridine has been synthesized. 3-Furoic acid chloride ( 2 ) was reduced with bis(triphenylphosphine) copper(1) tetrahydroborate to afford 3-furaldehyde ( 3 ) which was condensed with malonic acid to give β-(3-furyl)acrylic acid ( 4 ). The acrylic acid 4 was converted to the acid azide ( 5 ), which in turn was cyclized to give furo[2,3-c]pyridin-7(6H)-one ( 6 ) by heating at 180° in diphenylmethane. The pyridone 6 was chlorinated with phosphorus oxychloride, followed by reduction with zinc and acetic acid to give furo[2,3-c]pyridine ( 8 ).     

Furopyridines. XIV. Synthesis of 2-aminoalkyl derivatives of furo[2,3-b]-, furo[3,2-b], furo[2,3-c]- and furo[3,2-c]pyridine

The preparation of 2-aminomethyl- 3a-d , 2-acetamidomethyl- 4a-d , 2-N,N-dimethylaminomethyl- 5a-d , 2-(1-hydroxy-2-nitroethyl)- 6a-d , 2-(1-hydroxyl-2-aminoethyl)- 7a-d and 2-(1-hydroxy-2-N,N-dimethylaminoethyl)- 8b-d derivatives of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine is described.     

Furopyridines. IX. Syntheses and properties of 3-ethoxy derivatives of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine

Reaction of ethyl 3-ethoxycarbonylmethoxyfuropyridine-2-carboxylates 2a-2d with sodium ethoxide afforded 3-ethoxy derivatives 3a-3d which converted to 3-ethoxyfuropyridines 5a-5d by hydrolysis and decarboxylation of the ester group. Vilsmeier reaction of 5a and 5b gave 2-formyl-3-ethoxy derivatives 6a and 6b and 2-formyl-3-chloro derivatives 7a and 7b , while 5c and 5d did not give any formyl compound. Bromination of 3-ethoxyfuropyridines with 1 equivalent mole of bromine gave 2-bromo-3-ethoxyfuropyridines 9a-9d , whereas reaction with 3 equivalents of bromine yielded 2,2-dibromo-3,3-diethoxy-2,3-dihydrofuropyridines ( 10a and 10b ) and/or 2-bromo-3,3-diethoxy-2,3-dihydrofuropyridines 11b , 11c and 11d . Treatment of compounds 5a-5d with n-butyllithium in hexane-tetrahydrofuran at ?70° and subsequent addition of N,N-dimethylformamide yielded 2-formyl derivatives 6a-6d .     

Furopyridines. VII. Preparation and hydrolysis of 2-cyano and 3-cyano derivatives of furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine

This paper describes the preparation and hydrolysis of 2-cyano and 3-cyano derivatives of furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine. Treatment of furopyridines 1a , 1b and 1c with n-butyllithium in hexane-tetrahydrofuran at -70° and subsequent addition of N,N-dimethylformamide yielded 2-formyl derivatives 2a , 2b and 2c. Dehydration of the oximes 4a , 4b and 4c of 2a , 2b and 2c gave 2-cyano compounds 5a , 5b and 5c , which were hydrolyzed to give 2-carboxylic acids, 6a, 6b and 6c , respectively. Reaction of 3-bromo compounds 7a , 7b and 7c with copper(I) cyanide in N,N-dimethylformamide afforded 3-cyano derivatives 8a , 8b and 8c. Alkaline hydrolysis of 8a , 8b and 8c gave compounds formed by fission of the 1-2 bond of furopyridines 9a , 9b and 9c , while acidic hydrolysis gave the corresponding carboxamides, 10a , 10b and 10c.     

Furopyridines. II. Bromination and nitration of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine

In order to reveal the reactivities of furopyridines, we undertook bromination and nitration of four furopyridines ( 1, 2, 3 and 4 ) whose chemical properties had been almost unknown. Bromination of 1, 2, 3 and 4 gave the corresponding trans-2,3-dibromo-2,3-dihydro derivatives 6, 8, 10 and 12 , respectively, which were converted to 3-bromofuropyridines 7, 9, 11 and 13 by treatment with sodium hydroxide in aqueous methanol. Nitration of 1 with a mixture of fuming nitric acid and sulfuric acid afforded a mixture of addition products 14a, 14b and 14c and 2-nitro derivative 15 . Both 14a and 14b were easily converted to 15 by treatment with sodium bicarbonate. Compound 2 was nitrated to give a mixture of cis- and trans-2-nitro-3-hydroxy-2,3-dihydro derivative 16a and 16b and 2-nitro derivative 17 . The cis isomer 16a was transformed to the trans isomer 16b by refluxing on silica gel in ethyl acetate. Compound 16b was dehydrated with acetic anhydride to give 17 . Nitration of 3 gave a nitrolic acid derivative 20 . Nitration of 4 gave a mixture of 2-nitro derivative 22 and 3-(trinitromethyl)pyridin-4-ol ( 23 ). The structures of 20 and 23 were established by single crystal X-ray analysis. The differences of behavior observed in these reactions are discussed in connection with the results of the determination of pKa values and the relative reactivities of deuteriodeprotonation of these furopyridines.     

Furopyridines. XXVII. Reactions of 2-methyl and 2-cyano derivatives of furo[2,3-b]-, -[3,2-b]-, - [2,3-c]- and -[3,2-c]pyridine

Bromination of 2-methylfuropyridines 1a-d-Me gave the 3-bromo derivatives 2a-d , while the 2-cyano compounds 1a-d-CN resulted in the recovery of the starting compounds. Nitration of 1a-d-Me and 1a-d-CN did not yield the corresponding nitro derivative, except for 1-c-CN giving 3-nitro derivative 3c in 7% yield. N-Oxidation of 1a-d-Me and 1b-d-CN with m-chloroperbenzoic acid yielded the N-oxides 4a-d-Me and 4b-d-CN , whereas 1a-CN did not afford the N-oxide. Cyanation of N-oxides 4a-d-Me and 4b-d-CN with trimethylsilyl cyanide gave the corresponding α-cyanopyridine compounds 5a-d-Me and 5b-d-CN . Chlorination of 4a-d-Me and 4b-d-CN with phosphorus oxychloride also gave the α-chloropyridine compounds 6b-d-Me and 6b-d-CN , accompanying formation of γ-chloropyridine 6a-Me, 6′b-Me and 6′b-CN , β-chloropyridine 6′b-CN , and α'-chloropyridine derivatives 6′c-Me and 6′c-CN . Acetoxylation of 4a-d-Me and 4b-d-CN with acetic anhydride yielded α-acetoxypyridine compounds 7a-Me and 7b-CN , pyridone compounds 11d-Me, 11c-CN and 11d-CN , 3-acetoxy compounds 8, 9b, 9c , and 2-acetoxymethyl derivatives 10b and 10c.     

Furopyridines. XII . Reaction of 3-bromo, 2-phenylthio and 2-phenylthio-3-bromo derivatives of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine with several alkyllithiums

This paper describes reactions of 3-bromo- 1a-d , 2-phenylthio- 5a-d and 2-phenylthio-3-bromofuropyridines 6a-d with n-butyl-, t-butyl- and methyllithium and lithioacetonitrile. Lithiation of compounds 1a-d with n-butyl- or methyllithium gave the parent furopyridines 2a-d and o-ethynylpyridinols 3a-d. Reaction of compounds 5a-d with methyllithium afforded o-(phenylthioethynyl)pyridinols 7a-d , which were also yielded by reaction of compounds 6a-d with t-butyl- or methyllithium. The phenylthio group in compounds 7a-d were substituted with t-butyl group by the reaction with excess t-butyllithium. In contrast, 2-phenylthio group in compounds 5a-d and 6a-d was substituted with cyanomethyl group by reaction with lithioacetonitrile to give compounds 11a-d and 10b, c respectively.     

Furopyridines. XXIII. Synthesis and reactions of chloropyridine derivatives of furo[2,3-b]-, -[2,3-c]- and -[3,2-c]pyridine

Chlorination of the N-oxides of furo[2,3-b]- 1a , -[2,3-c]- 1b and -[3,2-c]pyridine 1c with phosphorus oxychloride afforded compounds substituted normally at the α- or λ-position to the ring nitrogen, 2a, 2′a, 2b, 2c, 2′c and 2′c , and in addition, in the case of 1b , compounds substituted on the furan ring, 2′b and 2″b . The structures of these compounds were confirmed from their ir, nmr and mass spectra. The major chlorinated products 2a, 2b and 2c were converted to methoxy- 5a, 5b and 5c , N-pyrrolidyl- 7a, 7b and 7c , and phenylthiofuropyridines 8a, 8b , and 8c .     

Furopyridines. XXVIII. Reactions of 3-bromo derivatives of furo[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridine and their N-oxides

Bromination of 3-bromofuro[2,3-b]- 1a , -[3,2-b]- 1b and - [3,2-c]pyridine 1d afforded the 2,3-dibromo derivatives 2a, 2b and 2d , while the -[2,3-c]- compound 1c did not give the dibromo derivative. Nitration of 1a-d gave the 2-nitro-3-bromo compounds 3a-d . The N-oxides 4a-d of 1a-d were submitted to the cyanation with trimethylsilyl cyanide to yield the corresponding α-cyanopyridine compound 6a-d . Chlorination of 4a and 4d with phosphorus oxychloride gave mainly the chloropyridine derivatives 7a, 7′a and 7d , while 4b and 4c gave mainly the chlorofuran derivatives 7′b and 7′c accompanying formation of the chloropyridine derivatives 7b, 7′b and 7c . Acetoxylation of 4a and 4b with acetic anhydride yielded the acetoxypyridine compounds 8a, 8′a and 8b , while 4c and 4d gave the acetoxypyridine 8′c, 8′d and 8′d , pyridone 8c and 8d , acetoxyfuran 8′c and dibromo compound 9c and 9′c.     

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 ).     

Synthesis of furo[3,2-c]pyridine and furo[2,3-d]pyrimidine derivatives from butyrolactone diethylacetal

The reaction of butyrolactone acetal with CH acids was used to synthesize 2-methylenetetrahydrofuran derivatives. The latter react with dimethylformimide acetal to give a dieneamine that is capable of undergoing cyclization to furo [3,2-c]pyrimidine derivatives. This two-ring system was also synthesized by the reaction of cyanacetamide with 3-dimethylaminomethylenebutyrolactone acetal. The indicated acetal can also react with amidine components to give furo [2,3-d]pyrimidine derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 68–71, January, 1982.     

A New synthesis of 4,5,6,7-tetrahydrofuro[2,3-c]pyridines and furo[2,3-c]pyrrolidines

New syntheses of 4,5,6,7-tetrahydrofuro[2,3-c]pyridines and furo[2,3-c]pyrrolidine derivatives, starting from furan-3-carboxaldehyde, are reported.     

Furopyridines. XIX. Reaction of furo[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridine with acetic anhydride

Acetoxylation of N-oxide of furo[2,3-b]- 2a , -[3,2-b]- 2b , -[2,3-c]- 2c and -[3,2-c]pyridine 2d with acetic anhydride afforded compounds substituted normally at the α- or γ-position to the ring nitrogen, 3a, 4a, 4b, 3d, 4d, 8 and 9 , and in addition compounds substituted on the furan ring, 5a, 6a, 5b, 6b, 7b, 5c and 7c which were unexpected compounds. The structures of these compounds were established from the ir, nmr and mass spectra, and x-ray crystal analysis of 5b .     

Synthesis of 3-amino derivatives of benzo[b]furo[2,3-c]pyridines

The reaction of 1,7-dimethyl-3(2H)-benzo[b]furo[2,3-c]pyridone with phosphoric acid amides gave 1,7-dimethyl-3-dimethylamino (morpholino)benzo[b]furo[2,3-c]pyridines. A method for the synthesis of 3-amino derivatives of 4-nitrobenzo[b]furo[2,3-c]pyridines, which consists in heating 1,7-dimethyl-4-nitro-3(2H)-benzo[b]furo[2,3-c]pyridone with hexamethyldisilazane and secondary or primary amines in pyridine, was developed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1552–1555, November, 1991.     

Furopyridines. XXII. Elaboration of the C-substituents alpha to the heteronitrogen atom of furo[2,3-b] -, -[3,2-b] -, -[2,3-c]- and -[3,2-c]pyridine

The Grignard reaction of fused ring cyanopyridine derivatives 1a-d with methyl- and phenylmagnesium bromide yielded the corresponding acylpyridine compounds 2a-d and 3a-d . Furopyridine N-oxides 4a-d were converted into the compounds having a phenyl group at the α-position to the ring nitrogen 5a-d . Reduction of 1a-d and the carboxylic esters 6a-d with diisobutylaluminium hydride yielded the corresponding amines 7a-d and aldehydes 9a-d . The aldehydes were converted to nitroethanol derivatives 10a-d by condensation with nitromethane and acrylic ester compounds 11a-d by the Wittig-Horner reaction with methyl diethyl phosphonoacetate.     

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 .     

Condensed pyridine bases synthesis of some benzo[b]furo[2,3-c]-, benzo[b]- thieno[2,3-c]-, and benzo[b]selenopheno[2,3-c]-quinolines

Summary Condensation of benzo[b]furan-3(2H-one, benzo[b]thiophen-3(2H)-one and benzo[b]selenophen-3(2H)-one with dimedone gives 2-(3-heteryl)dimedones. Acylation of the latter leads to the corresponding tetracyclic pyrylium salts, from which condensed quinolines are obtained. Some condensed quinoline derivatives are obtained by reaction of 1-oxo-1,2,3,4-tetrahydroheterene[2,3-c]quinolines with sodium borohydride, hydrazine, and hydroxylamine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 321–326, March, 1994.     

Synthesis of furo[2,3-c]pyran and some properties of 2-amino derivatives of furo- and pyrrolo[2,3-c]pyrans

Thesynthesisof2-amino-5,5-dimethyl-3-cyano-4,5-dihydro-7H-furo[2,3-c]pyrananditspyrroleanalog was accomplished on the basis of 2,2-dimethyltetrahydro-4-pyranone. Their reaction with maleic anhydride, which leads to the formation of 3-amino-4-cyano-6,6-dimethyl-5,6-dihydro-8H-pyrano[c]-phthalic anhydride, was studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 316–318, March, 1991.     

Furopyridines. X. Synthesis of tricyclic heterocycles,furo[2,3-b:4,5-c']-, furo[3,2-b:4,5-c']-, furo[2,3-c:4,5-c']- and furo[3,2-c:4,5-c']dipyridine

This paper describes the synthesis of four tricyclic heterocycles, furo[2,3–6:4,5-c']- ( 5a ), furo[3,2-b:4,5-c']- ( 5b ), furo[2,3-c:4,5-c']- ( 5c ) and furo[3,2-c:4,5-c']dipyridine ( 5d ). Starting with 2-formylfuropyridines ( 1a-d ), β-(2-furopyridyl)acrylic acids 2a-d were obtained by condensing with malonic acid. The acrylic acids were converted to the acid azides by reaction with ethyl chloroformate and the subsequent reaction with sodium azide. Heating of the acid azides at 230–240° with diphenylmethane and tributylamine gave tricyclic pyridinones 3a-d , which were converted to the respective chloro derivatives 4a-d by reaction with phosphorus oxychloride. Reduction of the chloro compounds over palladium-charcoal yielded compounds 5a-d respectively. All the compounds 2 to 5 were characterized by elemental analysis and spectral data. The H and ¹³C nmr and electronic spectral features of the furodipyridines were discussed comparing with those of the parent furopyridines.