A short route to 3-alkynyl-4-bromo(chloro)cinnolines by Richter-type cyclization of ortho-(dodeca-1,3-diynyl)aryltriaz-1-enes

Cleavage of ortho-(dodeca-1,3-diynyl)triazenes in HCl or HBr medium and subsequent cyclization of the resulting diazonium salts is investigated. In the absence of a strong electron-withdrawing substituent, the reaction affords 3-alkynyl-4-bromo(chloro)cinnolines as the only product. A methoxycarbonyl group promotes hydrolysis of 4-halocinnolines which results in the formation of by-products: furo[3,2-c]cinnoline and cinnolinone. Substitution of bromine in 3-(alk-1-ynyl)-4-bromocinnolines is achieved with methylamine, Na₂S and ethynylbenzene affording pyrrolo[3,2-c]cinnoline, thieno[3,2-c]cinnoline and 3,4-diethynylcinnoline, respectively.     

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.     

Reaction of 2-alkylthio-6-amino-pyrimidin-4(3H)-ones with ethyl bromopyruvate. Synthesis of furo-[2,3-<Emphasis Type="Italic">d</Emphasis>]-pyrimidine and furo[3,2-<Emphasis Type="Italic">e</Emphasis>]imidazo-[1,2-<Emphasis Type="Italic">c</Emphasis>]pyrimidine carboxylates

Reaction of 2-alkylthio-6-aminopyrimidin-4(3H)-ones with ethyl bromopyruvate to give ethyl 2-alkyl-thio-4-aminofuro[2,3-d]pyrimidine-5-carboxylates has been shown to proceed under neutral or acidic conditions. The obtained furo[2,3-d]pyrimidines underwent further cyclocondensation reaction with ethyl bromopyruvate to afford diethyl 5-alkylthiofuro[3,2-e]imidazo[1,2-c]pyrimidine-2,9-dicarboxy-lates. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 440–443, March, 2009.     

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

(E)-3-{5-[3-(Trifluoromethyl)phenyl]furan-2-yl}propenoic acid (I) was prepared from 5-[3-(tri-fluoromethyl)phenyl]furan-2-carbaldehyde under the Doebner’s conditions. The obtained acid was converted to the corresponding azide II, which was cyclized by heating in diphenyl ether to 2-[3-(trifluoromethyl)phenyl]-4,5-dihydrofuro[3,2-c]pyridin-4-one (III). This compound was aromatized with phosphorus oxychloride to chloroderivative IV which was reduced with H₂NNH₂-Pd/C to the title compound V. 2-[3-(Trifluoromethyl)phenyl]furo[3,2-c]pyridin-5-oxide (VI) was synthesized by reaction of V with 3-chloroperoxybenzoic acid in dichloromethane. On treatment of VI with benzoyl chloride and potassium cyanide (Reissert-Henze reaction), corresponding 2-[3-(trifluoromethyl)phenyl]furo[3,2-c]pyridine-1-carbonitrile (VII) resulted. 5-Amino-2-[3-(trifluoromethyl)phenyl]furo[3,2-c]pyridin-5-ium-4-methylbenzene sulfonate (VIII) was prepared by direct N-amination of the title compound V with 1-[(aminooxy)sulfonyl]-4-methylbenzene in dichloromethane. Then, VIII was transformed to a non-isolated zwitterionic N-imid IX which afforded the corresponding furo[3,2-c]pyrazolo[1,5-a]pyridine carboxylic acid esters X, XI by 1,3-dipolar cycloaddition reactions with dimethyl but-2-ynedionate (DBD) or ethyl propiolate. The structures of all compounds were confirmed by their IR and NMR spectra. Presented at the 1st International Conference “Applied Natural Sciences” on the occasion of 10th anniversary of the University of St. Cyril and Methodius, Trnava, 7–9 November 2007.     

Synthesis and reactions of 2-and 4-substituted furo[3,2-c]pyridines

Substituted furopropenoic acids were prepared from appropriate aldehyde under the Doebner’s conditions. Obtained acids were converted to the corresponding azides, which were cyclized by heating in Dowtherm to furopyridones. These compounds were aromatized with phosphorus oxychloride to chloro derivatives of furo[3,2-c]pyridine (Va, Vb). Chloro derivative Vb was reduced with hydrazine hydrate to 2-(4-aminophenyl)furo[3,2-c]pyridine in ethanol and Pd/C as a catalyst. Chloro derivative Va was converted to 4-amino-2-(3-pyridyl)furo[3,2-c]pyridine under the same conditions. The chlorine atom in other chloro derivatives (VIIa, VIIb) was replaced by nucleophilic substitution with alkoxides (sodium ethoxide, propoxide, and isopropoxide) and the corresponding alkoxy derivatives were formed. By reaction of VII with cyclic secondary amines (morpholine, piperidine, and pyrrolidine) 4-substituted furopyridines were prepared.     

Synthesis and Reactions of 4-Oxiranylmethylfuro[3,2-b]pyrroles and Their Benzo Derivatives

Methyl 4-oxiranylmethyl-4H-furo[3,2-b]pyrrole-5-carboxylates 2a-c and methyl 1-oxiranylmethyl-1H-benzo[4,5]furo[3,2-b]pyrrole-2-carboxylate (2d) were prepared by reaction of the appropriate starting compounds 1a-d with excess chloromethyloxirane. The compounds 2a-d undergo oxirane ring opening by heterocyclic amines (morpholine, pyrrolidine, piperidine or 4-methylpiperazine) giving N-2-hydroxy-3-heteroaminopropyl-substituted compounds 3a-f or substituted 4,5-dihydrofuro[2',3':4,5]pyrrolo[2,1-c][1,4]oxazin-8-ones 4a-e.     

Furopyridines. XI. 13C NMR Spectra of 2- or 3-Substituted Furo[2,3-b]-, Furo[3,2-b]-, Furo[2,3-c]- and Furo[3,2-c]pyridine

The ¹³C nmr spectra of 2- or 3-monosubstituted furo[2,3-b]- 1a-1j , furo[3,2-b]- 2a-2j , furo[2,3-c]- 3a-3j and furo[3,2-c]pyridine derivatives 4a-4j are reported. Effects by change in annelation and substituent effects on ¹³C chemical shifts and carbon-proton coupling constants are discussed. The spectra of benzo[b]furan derivatives 5a-5j having the corresponding substituent are also reported for comparison.     

Heteroyohimbane a noyau furannique. Nouvelle voie d'acces aux derives de la furo[3,2-c]pyrone et de la furo[3,2-c]pyridine

3,4-Dicarbomethoxyfuran bearing an acetonyl or a phenacy group in the 2 position w3as prepared by pyrolysis of the dihydrocyclo adduct from methyl acetylendicarboxylate and 2-acetonyl- or 2-phenacylfuran. Condensation of 2-acetonyl-3,4-dicarbomethoxyfuran with tryptamine gave a new heteroyohimbane with a furan ring, indolo[2,3-a]furo[3,2-c]quinolizine, a potential precursor of yohimbane. Ketodiacids from saponification allow one to obtain derivatives of the following heterocyclic ring systems, namely 4H-furo[3,2-c]pyran-4-one and furo[3,2-c]pyridine.     

Modified coumarins. 24. Synthesis of cycloheptane-annellated tetracyclic furocoumarins

Substituted 2,3,4,5-tetrahydrocyclohepta[c]furo[3,2-g]chromen-6-ones, modified psoralen analogs containing a cycloheptane ring annellated to the 5,6-positions of a furo[3,2-g]chromen-7-one, were synthesized from 3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6-ones. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 534–540, November–December, 2006.     

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.     

Synthesis of substituted furo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines and furo[3,2-e]tetrazolo[1,5-c]pyrimidines

A series of substituted furo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines and furo[3,2-e]tetrazolo[1,5-c]pyrimidines were obtained from reactions of substituted 2-dimemylamino-4-hydrazmofuro[2,3-d]pyrimidines with orthoesters or sodium nitrite in acetic acid, respectively.     

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. 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.     

Copper-catalyzed radical/radical cross-coupling of ketoxime carboxylates with 4-hydroxycoumarins: A novel synthesis of furo[3,2-c]-coumarins

A novel and efficient strategy for the synthesis of furo[3,2-c]coumarins has been developed via copper-catalyzed radical/radical cross-coupling of ketoxime carboxylates with 4-hydroxycoumarins. This redox-neutral reaction allows smooth and selective synthesis of 2-substituted, 3-substituted, 2,3-disubstituted and 2,3-fused polycyclic furo[3,2-c]coumarins.     

A New method for the synthesis of 4-oxo-4,5-dihydrofuro[3,2-c]quinoline

A new method for the synthesis of 4-oxo-4,5-dihydrofuro[3,2-c]quinoline is the Pd(0)-catalyzed coupling of o-bromonitrobenzene with 3-formyl-2-tributylstannylfuran, followed by reductive ring closure to furo[3,2-c]quinoline N-oxide and rearrangement.     

Electrophilic substitution of furo[3,2-c] pyridine

Furo[3,2-c] pyridine (I) was nitrated to give 2-nitrofuro[3,2-c]pyridine (II). Bromination and chlorination of I gave, respectively, 2,3-dibromo-2,3-dihydrofuro[3,2-c]pyridine (III) and 2,3-dichloro-2,3-dihydrofuro[3,2-c]pyridine (IV). Oxidation of I with hydrogen peroxide afforded furo[3,2-c]pyridine 5-oxide (V) which was converted to I by phosphorus trichloride and to 4-chlorofuro[3,2-c]pyridine (VI) by phosphorus oxychloride.     

1,4-Cyeloaddition reactions. IV. preparation of Cyclopenta[g]furo[3,2-c]quinolines,Cyclopenta- [f]furo[3,2-c]quinolines,Benzo[H]furo[3,2-c]quinolines,and Furo- [3,2-c]indeno[1,7-gh] quinolines from 2,3-Dihydro-5-methylfuran and schiff bases

The boron trifluoride catalyzed 1,4-addition of 2,3-dihydro-5-methylfuran to N-(p-methoxybenzylidene)-5-indanamine (VI) gave 2 pairs of epimers, dl-3,3a,4,5,7,8,9,10b-octahydro-4-(p-methoxyphenyl)-10b-methyl-2H-cyclopenta[g]furo[3,2-c]quinoline (VIIa and b) and dl-3,3a, 4,-5,8,9,10,10c-octahydro-4-(p-methoxyphenyl)-10c-methyl-2H-cyclopenta[f]furo[3,2-c]quinoline (VIIIa and b). When 4-(benzylideneamino)-1-naphthol (IXa) was condensed with 2,3-dihydro-5-methylfuran in an analogous manner, a mixture of two isomers of dl-1,2,2a,3,4,5a-hexahydro-5a-methyl-2-phenylbenzo[h]furo[3,2-c]quinolin-7-ol [Xa and b (R ? H)] was obtained. Likewise, 4-[(p-hydroxybenzylidene)amino]-1-naphthol (IXb) and 4-(p-methoxybenzylidene)amino]-1-naphthol (IXc) gave a mixture of two isomers of dl-1,2,2a,3,4,5a-hexahydro-2-(p-hydroxyphenyl)-5a-methylbenzo[h]furo[3,2-c]quinolin-7-ol [Xa and b (R ? OH)] and dl-1,2,2a,3,4,5a-hexahydro-2-(p-methoxyphenyl)-5a-methylbenzo [h]furo[3,2-c]quinolin-7-ol [Xa and b (R ? OCH₃)], respectively. The condensation of N-(p-methoxybenzylidene)-5-acenaphthenamine (XI) with 2,3-dihydro-5-methylfuran afforded a mixture of two isomers of dl-2,3,3a,4,5,9,10,-11b-octahydro-4-(p-methoxyphenyl)-11b-methylfuro[3,2-c]indeno[1,7-gh]quinoline (XIIa and b). Structural assignments for all of the products were made from NMR spectra. None of these compounds possessed appreciable biological activity.     

New synthetic approach to epoxyisoindolo[2,1-a]quinolines based on cycloaddition reactions of 2-furyl-substituted tetrahydroquinolines with maleic anhydride and acryloyl chloride

A procedure was developed for the synthesis of hydrogenated furyl-substituted furo[3,2-c]quinolines, pyrano[3,2-c]quinolines, and 4-ethoxy-and 4-(2-oxopyrrolidin-1-yl)quinolines. The reactions of these compounds with acryloyl chloride and maleic anhydride produce epoxyisoindolo[2,1-a]quinoline derivatives through successive acylation at the quinoline nitrogen atom and intramolecular exo-[4+2]-cycloaddition at the furan moiety. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1023–1038, May, 2007.     

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.     

Furannes et pyrroles disubstitués en 2,3. XVI synthèse de furo[3,2-c]pyranones-4 et nouvelle voie d'accès aux furo[3,2-c]pyridines

Treatment of 4-hydroxy-6-methylpyran-2-one with chloracetalhyde in basic aqueous medium gave 6-methylfuro[3,2-c]pyran-4-one. This compound reacted with ammonium hydroxide and some primary amines to form the corresponding N-substituted furo[3,2-c]pyrid-4-ones which may also be obtained from 4-hydroxy-α-pyridones. Furo[3,2-c]pyran-4-one was acylated at the 2 position and 4-chloro-6-methylfuro[3,2-c]pyridine easily gave 4-substituted derivatives by displacement of the halogen atom.