Chemistry of thienopyridines. XVII. Direct halogenation of thieno[2,3-b]pyridine

Thieno [2,3-b] pyridine (Ia) was converted into its 3-chloro, 3-bromo, and 3-iodo derivatives by means of elemental halogen, silver sulfate, and sulfuric acid. Bromine in a buffered chloroform solution of la also gave the 3-bromo compound (57% yield). Chlorine plus a refluxing mixture of Ia, chloroform, and water produced both the 3-chloro and the 2,3-dichloro derivatives. Various transformation products of these halothienopyridines (including the 2-nitro-3-halo compounds) are described and mass spectral fragmentation patterns are presented.     

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.     

Chemistry of thienopyridines. XIX. Further studies on chlorination and S-oxidation in the thieno[2,3-b] pyridine system

Treatment of thieno [2,3-b] pyridine (1a) with chlorine gas in chloroform (plus water) gave a mixture of two 2,3-dichloro-2,3-dihydrothieno[2,3-b] pyridine 1-oxides [trans-syn (IIa), and cis-anti (IIb)) [and 2,3,3-trichloro-2,3-dihydrothieno[2,3-b]pyridine syn-1-oxide (IVa), as well as a non-isolated fourth product (prohably the anti isomer of IVa) and sometimes a small amount of thieno[2,3-b]pyridine 1,1-dioxide (III). Treatment of Ia in a solvent (water, chloroform-water, or THF-water) with sulfuric acid and sodium hypochlorite gave a mixture of IIb and III. Effects of variations of reaction conditions on the composition of the product mixture were ascertained through chemical isolation and/or pmr analysis. Products formed were rationalized in terms of the chlorine-water-hypochlorous acid equilibrium, plus attack of chlorine variously at positions 1 (S-atom), 2, and 3 of 1a, but of hypochlorous acid only at position 1. Thermal and chromatographic limitations on isolation procedures for some of the products were established. Stereochemistries of IIa, IIb, and IVa were assigned by means of pmr spectrometry with the aid of the shift reagent Eu(fod)₃. Spin-spin couplings between the proton at position 2 and those at positions 4 and 6 were observed at high resolution. In exploratory runs, 5-ethyl-la was converted into isolable 2,3-dichloro-5-ethyl-2,3-dihydrothieno[2,3-b]pyridine 1-oxide, and 5-acetyl-Ia yielded 3-chloro-5-acetylthieno] 2,3-b]pyridine. Mass spectral fragmentation patterns for the various products are presented.     

Chemistry of thienopyridines. VIII. Substitution products derived from thieno[2,3-b] pyridine 7-oxide

Thieno[2,3-b]pyridine (I) was concerted to the N-oxide (II, 53%) by means of hydrogen peroxide and acetic acid. Nitration of II in sulfuric acid gave 4-nitrothieno[2,3-b]pyridine 7-oxide (III, 50%), while nitration in acetic acid formed the isomeric 5-nitrothieno[2,3-b]pyridine 7-oxide (IV, 54%). Compounds III and IV were reduced to the corresponding 4- and 5-aminothieno[2,3-b]pyridines, respectively. Treatment of III with acetyl chloride gave 4-chlorothieno-[2,3-b]pyridine 7-oxide (XI, 81%), convertible in two steps to 4-(N-substituted amino)thieno-[2,3-b]pyridines (especially of the 4-dialkylaminoalkylamino type) for screening as potential antimalarial drugs. 4-Aminothieno[2,3-b]pyridine reacted with aromatic aldehydes to give Schiff's bases and other products. Mechanisms for some of the reactions are suggested. NMR spectral data are reported for various 4-substituted thieno[2,3-b]pyridine compounds.     

Chemistry of thienopyridines. XV. Syntheses of thieno [3,4-b] - and thieno[3,4-c] pyridines

Thieno [3,4-b] pyridine (5) was synthesized by means of the successive steps of (a) photochlorination of 2,3-dimethylpyridine to the bis(chloromethyl) compound, (b) condensation with sodium sulfide, (c) oxidation to the sulfoxide, and (d) catalytic dehydration by means of alumina. Thieno[3,4-c]pyridine (6) was obtained in an analogous manner. Spectral properties indicate that 5 and 6 have aromatic character.     

Electrophilic substitution in benzo[b]thieno[2,3-c]pyridine. Acylation

A study has been made of the acetylation and benzoylation of substituted benzo[b]thieno[2, 3-c]pyridines. It has been shown that acetylaton proceeds exclusively at position 8, whereas benzoylation leads to a mixture of products of substitution at positions 6 and 8. The molecules in question have been calculated in the PPP and MNDO approximations.L. M. Litvinenko Institute of Physical Organic Chemistry and Coal-Tar Chemistry, Academy of Sciences of the Ukraine, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 701–705, May, 1994. Original article submitted March 3, 1994.     

A simple synthesis of thieno[2,3-b]pyrazine and thieno[2,3-b] pyridine

A facile synthesis of thieno[2,3-b]pyrazine (1) and thieno[2,3-b]pyridine (9) is reported. Furthermore, convenient preparations of a variety of synthetically useful compounds derived from these ring systems is also presented.     

The synthesis and chemical reactivity of thieno[2,3-c]- and thieno[3,2-c] pyridines

The syntheses and reactions of various thieno[2,3-c]- and thieno[3,2-c] pyridines are described. Molecular orbital calculations were performed on thieno[2,3-c]pyridine (1) in order to determine the most susceptible sites to electrophilic and nucleophilic attack. Superdelocalizability values, S_r- are reported for each position in this molecule to give relative orders of reactivity towards the two types of reactions. Electrophilic attack was found to occur experimentally at C-3 in all the thienopyridines studied. Peracid oxidation of thieno[2,3-c]- and thieno[3,2-c]pyridines produced only the N-oxide. The lack of reactivity of certain thienopyridines under Vilsmeier formylation and Friedel-Crafts acetylation conditions was related to their basicities. The dissociation constants of various thienopyridinium salts are reported.     

Chemistry of thienopyridines. IV. Syntheses of 5-substituted thieno[2,3-b] pyridines

Chemical transformations on 5-acetylthieno[2,3–6] pyridine produced 5-NH₂, 5-CO₂H, and 5-CH₂ CO₂H substituents. The 5-amino compound underwent facile diazotization (plus Sand-meyer reaction), Schiff's base formation, and acylation. Treatment of the derived 5-bromo compound with potassium amide in liquid ammonia gave a mixture of 4-amino (major) and 5-amino isomers. Nmr spectral data are reported for the 5-substituted thieno [2,3-b] pyridine system.     

Chemistry of thienopyridines. XXXI. A new synthesis of thieno[3,2-b]pyridine and studies on direct substitution into its thiophene ring

Thieno[3,2-b]pyridine ( 1 ) is synthesized in 65% overall yield for two steps which consist of addition of toluene-α-thiol to 2-ethynylpyridine plus vacuum pyrolysis of the addend ( 7 ). Cis and trans forms of 7 are described. Compound 1 undergoes (a) electrophilic substitution at C-3 to give chloro, bromo, and iodo derivatives (44–57% yields) and (b) lithiation at C-2 (to give 1a ). Intermediate 1a is converted into derivatives of 1 with halo (19–48%), formyl (54%), acetyl, and hydroxymethyl (40%) substituents at C-2. Also described are 2-cyano and 2,3-dibromo derivatives of 1 . Structural assignments are based on chemical transformations plus ¹H and ¹³C nmr spectral data. The substitution pattern of 1 is compared with predictions made on the bases of analogous ring systems and molecular orbital calculations.     

A convenient synthesis of the thieno[3,2-c]pyridine nucleus

The unsubstituted thieno[3,2-c]pyridine ring system was prepared from thiophene-3-carboxaldehyde in 4 steps. The sequence is suitable for scale-up.     

Chemistry of thienopyridines. XXXII. Direct introduction of C-substituents gamma to the heteronitrogen atom in the thieno[2,3-b]pyridine system

Treatment of the N-oxide 1a of thieno[2,3-b]pyridine ( 1 ) with either (a) acetic anhydride and ethyl cyanoacetate or (b) benzoyl chloride and an enamine of cyclohexanone (Hamana reactions) serves to introduce a C-substituent at the 4-position of 1 . In case (a) one obtains a yellow, isolable vinylogous N-ylide 5 (23% yield), which undergoes facile transformation into ethyl 2-(4-thieno[2,3-b]pyridyl)cyanoacetate ( 1e ) (88–93 %). Acetic anhydride reconverts 1e to 5 (95%). Case (b) produces 2-(4-thieno[2,3-b]pyridyl)cyclohexanone (39%), hydrolyzable to 6-(4-thieno[2,3-b]pyridyl)hexanoic acid (45%). The hydrochloride of 1a is also reported. Structural formulations are based on spectral studies (including ¹³C nmr data for 1 and 1e ) and chemical transformations. Major contrasts (plus some similarities) between the systems 1 and quinoline in the Hamana reactions are discussed.     

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.     

Preparation of reissert compounds derived from the thieno[3,2-c]pyridine,thieno[2,3-d]pyridazine and the thieno[2,3-d]pyrimidine ring systems

The use of tributyltin cyanide, trimethylsilyl cyanide and potassium cyanide in the Reissert reaction is contrasted in the furo[3,2-c]pyridine, thieno[3,2-c]pyridine, thieno[2,3-dpyridazine, and thieno[2,3-d]pyrimidine ring systems.