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.     

Nitration of dithieno[3,2-b:3′,2′-d]pyridine and dithieno[3,2-b:3′,4′-d]pyridine

Nitration of dithieno[3,2-b:3′,2′-d]pyridine ( 4 ) and dithieno[3,2-b:3′,4′-d]pyridine ( 5 ) has been studied. Nitration of 4 occurred in both positions of the C ring, while 5 was predominantly substituted on the 3,4-fused ring. The structures of the nitro derivatives were proven by extensive use of ¹H and ¹³C nmr spectroscopy.     

Heteroaromatic boron compounds. XV. Deuteriodeprotonation in some borazarothienopyridines and thienopyridines

Deuteriodeprotonation of some substituted 4,5-borazarothieno[2,3-c]pyridines (I) and 7,6-borazarothieno[3,2-c]pyridines (II) has been studied by the nmr technique. Exchange occurred predominantly in the 3-position, and the effect of methyl substitution on rate is discussed. The rates of exchange in some derivatives of I and II were compared with those of the isoelectronic thieno[2,3-c]pyridines (III) and thieno[3,2-c]pyridines (IV). Similar rates were obtained, confirming the aromatic nature of I and II. The deuteriodeprotonation of 4-methyl-4,5-borazaro-thieno[2,3-c]pyridine (Ie), 7-methyl-7,6-borazarothieno[3,2-c]pyridine (IIe), 4-methylthieno-[2,3-c]pyridine (IIIe), and 7-methylthieno[3,2-c]pyridine (IVe) were measured at different concentrations of deuteriosulfuric acid and different temperatures, showing that the protonated heterocycles are substrates in the deuteriodeprotonation reaction. Standard rates at p0 H and 100° were calculated for these systems.     

Tandem transformations of tetrahydropyrrolo[3,2-<Emphasis Type="Italic">c</Emphasis>]pyridines under the action of dimethyl acetylenedicarboxylate. A novel route to pyrrolo[2,3-<Emphasis Type="Italic">d</Emphasis>]azocines

Reactions of substituted tetrahydropyrrolo[3,2-c]pyridines with dimethyl acetylenedicarboxylate in protic and aprotic solvents were studied. A novel single-step method for the synthesis of pyrrolo[2,3-d]azocine derivatives was developed. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2513–2519, November, 2005.     

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.     

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 .     

Chlorination of 1H-pyrrolo[3,2-c]pyridin-4,6(5H,7H)dione (3,7-dideazaxanthine) and its 5-methyl derivative

The chlorination of 1H-pyrrolo[3,2-c]pyridin-4,6(5H, 7H)dione (3,7-dideazaxanthine) ( 2 ) and 5-methyl-1H-pyrrolo[3,2-c] pyridin4,6(5H,7H)dione (1 -methyl-3,7-dideazaxanthine) ( 3 ) with phenylphosphonic dichloride has yielded 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine (2,6-dichloro-3,7-dideazapurine) ( 1 ). A mechanism for the demethylation of the 5-methyl derivative under these conditions is proposed. Ammonolysis of 4,6-dichloro-1H-pyrrolo[3,2-c] pyridine was unsuccessful while catalytic reduction of this dichloro derivative produced 1H-pyrrolo[3,2-c]-pyridine ( 4 ).     

Synthesis of 4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine

4-Methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine ( 3 ) was synthetized from 2-acetylfuro[3,2-f]benzo[b]furan ( 4 ) or from 2-acetyl-5,6-dihydrofuro[3,2-f]benzo[b]furan ( 10 ). The key step involves a rearrangement-cyclization of azides 6 and 12 to form 4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridin-1(2H) one ( 7 ) and 8,9-dihydro-4-methylfuro[3′,2′:5,6]benzofuro[3,2c]pyridin-1(2H)-one ( 13 ). Introduction of an aminoalkyl chain on carbon 1 was effected by substitution of 1-chloro-4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine ( 8 ).     

Synthesis of substituted pyrido[3´,2´:4,5]thieno[3,2-c]isoquinolin-5(6H)-ones and their sulfinyl and sulfonyl derivatives

A method for the synthesis of previously unknown pyrido[3´,2´:4,5]thieno[3,2-c]isoquinolin-5(6H)-ones was suggested, which includes a condensation reaction of substituted 3-cyanopyridine-2(1H)-thiones with methyl 2-(chloromethyl)benzoate and subsequent treatment of the condensation products with potassium tert-butoxide. The oxidation of the condensation products to sulfoxides or sulfones and subsequent treatment of these compounds with potassium tert-butoxide led to substituted pyrido[3´,2´:4,5]thieno[3,2-c]isoquinolin-5(6H)-one 11-oxides or substituted pyrido[3´,2´:4,5]thieno[3,2-c]isoquinolin-5(6H)-one 11,11-dioxides.

     

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 .     

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.     

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 and reactions of 2,3-dimethylfuro[3,2-c]pyridines

Summary A number of substituted 2,3-dimethylfuro[3,2-c]pyridines was synthesized. 3-(4,5-Dimethyl-2-furyl)propenoic acid (1) was converted to the acid azide2, which in turn was cyclized to give 2,3-dimethyl-5H-furo[3,2-c]pyridine-4-one (3) by heating at 240°C in Dowtherm. The pyridone3 was chlorinated with phosphorus oxychloride to give4, which was reduced with zinc and acetic acid to 2,3-dimethylfuro[3,2-c]pyridine (5). Treatment of4 with several secondary heterocyclic amines led to compounds6a–6c. Reaction of pyridone3 with phosphorus pentasulfide rendered the thione7, which was methylated to8a. The 4-methoxy derivative8b was obtained from4 with sodium methoxide. 2,3,5-Trimethylfuro[3,2-c]pyridine-4-one (9) was obtained by reaction of3 with methyl iodide.Dedicated to Professor Dr.Fritz Sauter on the occasion of his 65th birthday     

4-Amino-6-hydroxy-1H-pyrrolo[3,2-c] pyridine (3,7-dideazaisoguanine)

The preparation of 4-amino-6-hydroxy-1H-pyrrolo[3,2-c]pyridine (3,7-dideazaisoguanine) ( 1 ) in five steps from 1H-pyrrolo[3,2-c]pyridin-4,6(5H,7H) dione (3,7-dideazaxanthine) ( 2 ) is described. Furthermore, prolonged treatment of 1 with 10% aqueous sodium carbonate solution is reported to lead to ring opening of the pyridine of 1 resulting in 3-carboxamidopyrrole-2-acetic acid ( 3 ).     

Chemistry of thienopyridines. XXXVI. Further studies on nitration in the thieno[2,3-b]- and thieno[3,2-b]pyridine systems

Three compounds, thieno[3,2-b]pyridine 4-oxide, 7-nitrothieno[3,2-b]pyridine 4-oxide ( 1 c), and 6-cyano-thieno[2,3-b]pyridine, undergo nitration by means of a mixture of nitric and sulfuric acids to yield 3,7-dinitro-thieno[3,2-b]pyridine (3%), 3,7-dinitrothieno[3,2-b]pyridine 4-oxide ( 1d ) (26%), and 6-carbamoyl-5-nitrothieno[2,3-b]pyridine ( 6b ) (11%), respectively. Structures of the products were ascertained by spectral means, notably infrared, ¹H nmr, and ¹³C nmr. It is proposed that 1d exists (at least in part) as a tricyclic structure and that 6b may result from an intramolecular mechanism of nitration. An attempt to de-N-oxygenate 1c with excess triphenylphosphine removes more than one oxygen atom per molecule (as triphenylphosphine oxide) without producing an identified thienopyridine product.     

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.     

Angular heterocycles. A convenient synthesis of azabenzophenothiazines

The acid-catalysed reaction of substituted 1,4-naphthoquinones with o-aminoheterocyclic thiones in alcoholic solution afforded substituted monoazabenzo[a]phenothiazin-5-ones 4,5 and substituted benzo[a][1,4]diazabenzothiazino[3,2-c]phenothiazin-5-one ( 6 ). Some of the resulting compounds were subjected to dehalogenation. The structures of the products were assigned by elemental analysis, ¹H-nmr, and other spectral analysis.     

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.     

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.     

Synthesis of some heterocyclic skeletons via organoiron complexes. Crystal and molecular structure of (5a,6,7,8,9,9a-η6-1,4-benzoxathiino[3,2-b]pyridine)(η5-cyclopentadienyl)iron hexafluorophosphate

Synthesis of the heterocyclic skeletons of some biologically active compounds from (η⁶-o-dichlorobenzene)(η⁵-cyclopentadienyrl)iron hexafluorophosphate in a two step procedure is described. Cyclopentadienyliron hexafluorophosphate complexes of 1,4-benzodioxino[2,3-b]pyridine, 1,4-benzoxathiino[3,2-b]pyridine, 10H-pyrido[3,2-b]benzoxazine, benzo[b]naphtho[2,3-e][1,4]dioxin, 4-methylbenzo[b]benzopyran-2-one[7,6-e][1,4]dioxin and benzo[b]anthracen-9,10-diono[1,2-e][1,4]dioxin were isolated and characterized. Upon pyrolytic sublimation of these complexes the free heterocycles were obtained and characterized. (η⁶-1,4-Benzoxathiino[3,2-b]pyridine)(η⁵-cyclopentadienyl)iron hexafluorophosphate crystalizes in the orthothombic system, space group Pbca; the dihedral angle between the planes of outer rings was found to be 176.8 (1).