Introduction

Thieno[2,3-b]pyridine derivatives are an important class of heterocyclic compounds due to their pharmacological and biological utility, including anticancer, antidermatophytic, antimalarial, anti-Alzheimer's, antifungal, anti-inflammatory, insecticidal, and antiviral activities.1 Thieno[2,3-b]pyridines were also reported as Pim-1 kinase inhibitors and multidrug resistance modulators.2 Therefore, many efforts have been made to synthesize these important heterocycles.3

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2-Thioxopyridine-3-carbonitrile-based reactions

There are many recent papers devoted to the synthesis of thieno[2,3-b]pyridines using substituted 2-thioxopyridine-3-carbonitrile or 3-cyanopyridine-2-thiolate as starting material or key intermediate.4 Dyachenko et al. described multicomponent synthesis of functionalized thieno[2,3-b]pyridines 5 starting from compounds 1–4 through 3-cyanopyridine-2-thiolate intermediate.5

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The reaction between 4-(chloromethyl)-5-hydroxycoumarins 6 and 2-thioxopyridine-3-carbonitriles 7 in the presence of a base leads to pyrano[4”,3”,2”:4',5']chromeno[2',3':4,5]thieno[2,3-b]pyridin-2-ones 8 in two synthetic steps.6

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Seyed Sajad Sajadikhah was born in 1982 in Mamasani, Fars province, Iran. He obtained his BSc in pure chemistry from the University of Isfahan in 2006, MSc and PhD in organic chemistry under supervision of Prof. M. T. Maghsoodlou from the University of Sistan and Baluchestan, Zahedan in 2009 and 2013, respectively. Currently he is an assistant professor at the Department of Chemistry at the Payame Noor University, Iran. His research focuses on organic synthesis, heterocyclic chemistry and catalysts.

Ghasem Marandi was born in 1973 in Khoy, Iran, and received his BSc degree in chemistry from the Payame Noor University in 1999. To complete MSc degree in organic chemistry, he joined the University of Sistan and Baluchestan in 2002. He earned PhD degree in organic chemistry in 2009. His research projects for MSc and PhD degrees were supervised by Prof. M. T. Maghsoodlou. From 2011, he is an assistant professor at the Science Faculty of Urmia University. His research interests focus on synthesis and methodology, he is a coauthor of more than 50 papers.

2-Thioxopyridine-3-carbonitrile-based reactions (continued)

Leung et al. developed a practical synthesis of cycloalkylthienopyridine-2-carboxamides 12 starting from cycloalkanones 9, methyl formate, 2-cyanoethanethioamide (2), followed by the reaction of 2-thioxopyridine-3-carbonitrile intermediate 10 with N-aryl-2-bromoacetamides 11. Anticancer activity of compounds 12 was investigated.7

The Bohlmann–Rahtz reaction of α,β-acetylenic ketones 13 with 2-cyanothioacetamide 2 followed by a tandem S-alkylation/Thorpe–Ziegler cyclization reaction with chloroacetamide leads to thieno[2,3-b]pyridines 14.8

Yahya et al. reported the synthesis of new progesterone derivatives 17 bearing thieno[2,3-b]pyridine substituent. Starting enaminone 15 was obtained from the reaction of progesterone with dimethylformamide–dimethylacetal in dry xylene under reflux. Condensation of compound 15 with 2-cyanoethanethioamide (2) gave 2-thioxopyridine-3-carbonitrile 16. Subsequent S-alkylation and cyclization produced thienopyridine 17. Synthesized products 17 were tested for the cytotoxic effect against human breast cancer cells.9

The reaction of malononitrile (18), H2S, and aldehydes in the presence of Et3N afforded 4H-thiopyran 19. Recyclization of compound 19 under alkaline conditions led to 3-cyanopyridine-2-thiolate intermediate. Its S-alkylation with α-halocarbonyl compounds 4 and subsequent intramolecular cyclization afforded thieno[2,3-b]pyridines 20. Further reaction of the vicinal amino and carbamoyl groups with cyclohexanone in glacial AcOH gave spiro compound 21.10

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An efficient route for the synthesis of thieno[2,3-b]pyridines 23 was reported by Alinaghizadeh et al.11 One-pot three-component reaction of aldehydes 1, malononitrile (18), and thiophenol in the presence of catalysts (Et3N, high surface area or nanosized MgO) in EtOH led to 2-amino-4-aryl-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile, which was reduced by Na2S to compounds 22. Sodium alkoxide-catalyzed S-alkylation of 2-amino-4-aryl-6-mercaptopyridine-3,5-dicarbonitriles 22 followed by cyclization reaction gave thienopyridines 23.

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Cascade heterocyclization of tetracyanopropenide

Highly substituted thieno[2,3-b]pyridines 26 were obtained through cascade heterocyclization of 2-acyl-1,1,3,3-tetracyanopropenide salts 24 with mercaptoacetate 25 in refluxing pyridine.12 Use of a mixture of pyridine–H2O, 4:1, as a solvent led to pyrrolo[3,4-d]thieno[2,3-b]pyridines 27 in 49–57% yields.13

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Cu-catalyzed cyclization

Li et al. reported an efficient approach to 2-acylthienopyridines 30 from (2-fluoropyridin-3-yl)alkynols 28 through nucleophilic thiolation, Cu-catalyzed thioester cleavage, 5-endo-dig cyclization, and oxidation reaction cascade. Two equivalents of potassium ethyl xanthate (29) were used as sulfur source and probably as facilitator of oxidation process via coordination with Cu complexes.14

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Thiophene-based reactions

Vilsmeier–Haack reagent was used to produce 4-chlorothieno[2,3-b]pyridines 34 and formylated 4-chlorothieno[2,3-b]pyridines 35 from N-protected 3-acetyl-2-aminothiophenes 33. The reaction was performed at 65 or 100°C with different amounts of Vilsmeier–Haack reagent (6 and 12 equiv). Thiophenes 33 were synthesized via Gewald reaction from compounds 31 and 32.15

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Mohareb and Ibrahim reported another strategy for the synthesis of thieno[2,3-b]pyridine derivatives 38.16 Thiophenes 37, synthesized from 3-oxo-3-propanenitriles 36, were reacted with ethyl cyanoacetate affording 2-(N-cyanoacetamido) thiophene. The latter underwent cyclization in the presence of NaOEt to give the final products 38. Compounds 38 were tested for anticancer activity and showed good results.

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