Skip to main content
SpringerLink
Log in

Recent Advances in the Synthesis of Thiophenes and Benzothiophenes

  • Chapter
  • First Online:
Metalation of Azoles and Related Five-Membered Ring Heterocycles

Part of the book series: Topics in Heterocyclic Chemistry ((TOPICS,volume 29))

Abstract

The use of thiophenes in medicinal chemistry and materials sciences has grown enormously during the past several years. For example, thiophene is the backbone of several important pharmaceuticals such as Reloxifen, duloxetine (Cymbalta), tiotropium (Spiriva), Cosopt (dorzolamide), etc. Importantly, the syntheses the aforementioned drugs use simple thiophenes as starting materials. The quest for these exotic small molecules has been brought forth by either modification of classical methods and, more importantly, novel synthesis by highly creative synthetic chemists. Likewise attention has been drawn to the efficient synthesis of thiophenes-containing organic materials due to the importance of atom-economics and green chemistry. Due to the facile synthesis of thiophene derivatives much progress has been made in thiophenes containing organic materials with respect to light-emitting diodes, firld-effect transistors, solar cells, etc. This report details the major synthetic methods for the synthesis of thiophenes and benzo[b]thiophenes including Gewald reaction, Wilgerodt-Kindler reaction, Paul-Knorr reaction, fluorous synthetic protocol, sulfur-assisted reactions, electrophilic cylization and direct arylation methods. Where possible, the reactions will be categorized. However, in several cases major overlapping of two or more synthetic methods have prevented such categorizations.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 379.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Gewald K (1961) Reaction of ± -oxomercaptans with nitriles. Angew Chem 73:114–116

    Article  CAS  Google Scholar 

  2. Gewald K (1965) Heterocycles from CH-acidic nitriles. VII. 2-Aminothiophene from α-oxo mercaptans and methylene-active nitriles. Chem Ber 98:3571–3577

    Article  CAS  Google Scholar 

  3. Gompper R, Kutter E (1962) New thiophenes and thieno[2,3-b]thiophenes. Angew Chem 74:251–252

    Article  CAS  Google Scholar 

  4. Gewald K, Schinke E (1966) Heterocycles from CH-acidic nitriles. X. Reaction of acetone with cyanoacetic ester and sulfur. Chem Ber 99:271–275

    CAS  Google Scholar 

  5. Huang H, Dömling A (2011) The Gewald multicomponent reaction. Mol Divers 15:3–33

    Article  CAS  Google Scholar 

  6. Putevovd Z, Krutosikova A, Vegh D (2010) The Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes. ARKIVOC (i):209–246

    Google Scholar 

  7. Gewald K, Schinke H, Boettcher H (1966) Heterocycles from C–H acidic nitriles VIII. 2-Aminothiophenes from methylene active nitriles, carbonyl compounds, and sulfur. Chem Ber 99:94–100

    Article  CAS  Google Scholar 

  8. Sabnis RW, Rangnekar DW, Sonawane ND (1999) 2-Aminothiophenes from the Gewald reaction. J Heterocyclic Chem 36:333–345

    Article  CAS  Google Scholar 

  9. Dömling A (2006) Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev 106:17–89

    Article  Google Scholar 

  10. Zavarzin V, Yarovenko VN, Shirokov AV, Smirnova NG, Es’kov AA, Krayushkin MM (2003) Synthesis and reactivity of monothio-oxamides. Arkivoc 13:205–223

    Google Scholar 

  11. Feroci M, Chiarotto I, Rossi L, Inesis A (2008) Activation of elemental sulfur by cyanomethyl anion: synthesis of substituted 2-aminothio-phenes by the Gewald reaction. Adv Synth Catal 350:2740–2746

    Article  CAS  Google Scholar 

  12. Forero JSBF, de Carvalho EM, Jones J, da Solva FM (2011) A new protocol for the synthesis of 2-aminothiophenes through the Gewald reaction in solvent-free conditions. Heterocyclic Lett 1:61–67

    Google Scholar 

  13. Tormyshev VM, Trukusikova A, Rogozhnikova Olga Y et al (2006) Aryl alkyl ketones in a one-pot Gewald synthesis of 2-aminothiophenes. Synlett 16:2259–2564

    Google Scholar 

  14. Kathiravan MK, Shishoo CJ, Chitre TS, Mahadik RR, Jain KS (2007) Efficient synthesis of substituted 2-amino-3-carbethoxythiophenes. Synth Commun 37:4273–4279

    Article  CAS  Google Scholar 

  15. Dömling A, Chi K-Z, Herdtweck E (2006) Derived isocyano amides useful as starting materials in IMCR. J Comb Chem 8:872–880

    Article  Google Scholar 

  16. Balamurugan K, Perumal S, Reddy ASK, Yogeeswari P, Sriram D (2009) A facile dominoprotocol for the regioselective synthesis and discovery of novel 2-amino-5-arylthieno[2,3-b]thiophenes as antimycobacterial agents. Tetrahedon Lett 50:6191–6195

    Article  CAS  Google Scholar 

  17. Willgerodt K (1888) Conversion of ketones and aldehydes into acids and acid amides by means of ammonium sulphide. Ber Dtsch Chem Ges 431:534–536

    Article  Google Scholar 

  18. Kindler K (1923) Mechanism of chemical reactions. I. Reduction of amides and in oxidation of amines. Liebigs Ann Chem 431:187–207

    Google Scholar 

  19. Solovyev AY, Androsov DA, Necker DC (2007) One-pot synthesis of substituted 2-aminobenzo[b]thiophenes. J Org Chem 72:3122–3124

    Article  CAS  Google Scholar 

  20. Androsov DA, Solovyev AY, Petrov ML, Butcher RJ, Jasinski JP (2010) A convenient approach towards 2- and 3-aminobenzo[b]thiophenes. Tetrahedron 66:2474–2485

    Article  CAS  Google Scholar 

  21. Sakya SM (2005) Hurd–Mori 1,2,3-thiadiazole synthesis. In: Li JJ, Corey EJ (eds) Name reactions in heteocyclic chemistry. Wiley, Hoboken, pp 199–206 (Review)

    Google Scholar 

  22. Minetto G, Raveglia LF, Sega A, Taddei M (2005) Microwave-assisted Paal-Knorr reaction – synthesis of polysubstituted furans, pyrroles and thiophenes. Eur J Org Chem 24:5277–5288

    Article  Google Scholar 

  23. Gladysz JA, Curran DP, Horvath IT, Horvath IT (eds) (2004) Handbook of fluorous chemistry. Wiley-VCH, Weinheim, pp 1–595

    Google Scholar 

  24. Crich D, Neelamkavil S (2001) Fluorous Swern reactions. J Am Chem Soc 123:7449–7450

    Article  CAS  Google Scholar 

  25. Hao X, Yamazaki O, Yoshida A, Nishikido J (2003) Tin(IV) bis(perfluoroalkane-sulfonyl)amide complex as a highly selective Lewis acid catalyst for Baeyer–Villiger oxidation using hydrogen peroxide in a fluorous recyclable phase. Tetrahedron Lett 44:4977–4980

    Article  CAS  Google Scholar 

  26. Kaleta Z, Makowski BT, Soos T, Dembinski R (2006) Thionation using fluorous Lawesson’s reagent. Org Lett 8:1625–1628

    Article  CAS  Google Scholar 

  27. Guo H-F, Shao H-Y, Yang Z-Y et al (2010) Substituted benzothiophene or benzofuran derivatives as a novel class of bone morphogenetic protein-2 up-regulators: synthesis, structure-activity relationships, and preventive bone loss efficacies in senescene accelerated mice (SAMP6) and ovariectomized rats. J Med Chem 53:1819–1829

    Article  CAS  Google Scholar 

  28. Hao L, Zhan Z-P (2011) The construction of five-membered heterocycles by transition metal-catalyzed cyclization of propargylic compounds. Cur Org Chem 15:1625–1643

    Article  CAS  Google Scholar 

  29. Zhou H, Xie L, Ren L, Su R (2010) Sulfur-assisted five cascade sequential reactions for the convenient and efficient synthesis of allyl thiophen-2-yl acetates, propionates, and ketones. Org Lett 12:356–359

    Article  CAS  Google Scholar 

  30. Ma S (2003) Cationic cyclopentannelation of allene ethers. Acc Chem 36:284–290

    Article  Google Scholar 

  31. Ma S (2005) Asymmetric synthesis of axially chiral allenes. Chem Rev 105:2829–2871

    Article  Google Scholar 

  32. Ma S (2003) Acc Chem Res 36:701–712

    Article  CAS  Google Scholar 

  33. Kim H, Williams L (2008) Recent developments in allene-based synthetic methods. J Curr Opin Drug Disc Dev 11:870–894

    CAS  Google Scholar 

  34. Xu G, Chen K, Zhou H (2010) Sulfur-assisted propargyl-allenyl isomerization and intramolecular cyclization for the synthesis of tricyclic thiophenes derivatives. Tetrahedron Lett 51:6240–6242

    Article  CAS  Google Scholar 

  35. Iwai I, Ide J (1964) Intramolecular anionic diels-alder reactions of 1-aryl-4-oxahepta-1,6-diyne systems in DMSO. J Chem Pharm Bull 12:1094–1100

    Article  CAS  Google Scholar 

  36. Zhou H, Zhu D, Huang H, Wang K (2010) Ga(OTf)3-promoted sequential reactions via sulfur-assisted propargyl-allenyl isomerizations and intramolecular [4 + 2] cycloaddition for the synthesis of 1,3-dihydrobenzo[c]thiophenes. J Org Chem 76:2706–2709

    Article  Google Scholar 

  37. Paull DH, Abraham CJ, Scerba MT, Alden-Danforth E, Lectka T (2008) Bifunctional asymmetric catalysis: cooperative lewis acid/base systems. Acc Chem Res 41:655–663

    Article  CAS  Google Scholar 

  38. Murahashi SC, Takaya H (2000) Low-valent ruthenium and iridium hydride complexes as alternatives to Lewis acid and base catalysts. Acc Chem Res 33:225–233

    Article  CAS  Google Scholar 

  39. Spence HJ, Skabara PJ, Giles M et al (2005) The first direct experimental comparison between the hugely contrasting properties of PEDOT and the all-sulfur analogue PEDTT by analogy with well-defined EDTT–EDOT copolymers. J Mater Chem 15:4783–4792

    Article  Google Scholar 

  40. Roncali J, Blanchard P, Frere PJ (2005) 3,4-Ethylenedioxythiophene (EDOT) as a versatile building block for advanced functional π-conjugated systems. J Mater Chem 15:1589–1610

    Article  CAS  Google Scholar 

  41. Das S, Dutta K, Panda S, Zade SS (2010) 3,4-Ethylenedioxythiophene and 3,4-ethylenedioxyselenopheneL synthesis and reactivity of C–Si bond. J Org Chem 75:4868–4871

    Article  CAS  Google Scholar 

  42. Godoi B, Schumacher RF, Zeni G (2011) Synthesis of heterocyclces via electrophilic cyclization of alkynes containing heteroatoms. Chem Rev 111:2937–2980

    Article  CAS  Google Scholar 

  43. Mphahlele MJ (2009) Molecular iodine-mediated cyclization of tethered heteroatom-containing alkenyl or alkynyl systems. Molecules 14:4814–4837

    Article  CAS  Google Scholar 

  44. Larock RC, Yue D (2001) Synthesis of benzo[b]thiophenes by electrophilic cyclization. Tetrahedron Lett 42:6011–6013

    Article  CAS  Google Scholar 

  45. Cho C-H, Heuenswander B, Larock RC (2010) Diverse methyl sulfone-containing benz[b]thiophenes library via iodocyclization and palladium-catalyzed coupling. ACS Comb Sci 12:278–285

    CAS  Google Scholar 

  46. Cho C-H, Neuenswander B, Lushington GH, Larock RC (2009) Solution-phase parallel synthesis of a multi-substituted benzo[b]thiophenes library. ACS Comb Sci 12:900–906

    Google Scholar 

  47. Yang F, Jin T, Bao M, Yamamoto Y (2011) Facile synthesis of 3,4-diiododihydrothiophenes via electrophilic iodocyclization. Tetrahedron Lett 52:936–938

    Article  CAS  Google Scholar 

  48. Blenderman WG, Jouillie MM, Preti G (1979) The Birch reduction of thiophenes-2-carboxylic acid. Tetrahedron Lett 20:4985–4988

    Article  Google Scholar 

  49. McIntosh JM, Goodbrand HB, Masse GM (1974) Dihydrothiophenes. II. Preparation and properties of some alkylated 2,5-dihydrothiophenes. J Org Chem 39:202–206

    Article  Google Scholar 

  50. Mehta S, Larock RC (2010) Iodine/palladium approaches to the synthesis of polyheterocyclic compounds. J Org Chem 75:1652–1658

    Article  CAS  Google Scholar 

  51. Ikeda T, Kawamote M, Lee S-M et al (2004) Oxadiazolyindole trimmers, tetrazolylindole trimmers, their manufacturing liquyid crystal compositions, and organic electroluminescent devices. Jpn Kokai Tokkyo Hoho, JP 2004224774 2004

    Google Scholar 

  52. Ohta A, Akia T, Ohkuwa T, Chiba M et al (1990) Palladium-catalyze arylation of furan, thiophene, benzo[b]furan and benzo[b]thiophene. Heterocycles 31:1951–1958

    Article  CAS  Google Scholar 

  53. Seregin IV, Gevorgyan V (2007) Direct transition metal-catalyzed functionalization of heteroaromatic compounds. Chem Soc Rev 30:1173–1193

    Article  Google Scholar 

  54. Roger J, Gottumukkala AL, Doucet H (2010) Palladium-catalyzed C3 or C4 direct arylation of heteroaromatic compounds with aryl halides by C–H bond activation. ChemCatChem 2:20–40

    Article  CAS  Google Scholar 

  55. Perepichka IF, Perepichka DF (2011) Handbook of thiophenes-based materials. Wiley, Chichester

    Google Scholar 

  56. Liu C-Y, Zhao H, H-h Yu (2011) An efficient synthesis of 3,4-ethylenedioxy-thiophene (EDOT)-based functional π-conjugated molecules through direct C–H bond arylations. Org Lett 13:4068–4071

    Article  CAS  Google Scholar 

  57. Schipper DJ, Fagnou K (2011) Direct arylation as a synthetic tool for the synthesis of thiophenes-based organic electronic materials. Chem Mater 23:1594–1600

    Article  CAS  Google Scholar 

  58. Roquet S, Cravino A, Leriche P et al (2006) Triphenylamine-thienylenevinylene hybrid systems with internal charge transfer as donor materials for heterojunction solar cells. J Am Chem Soc 128:3459–3466

    Article  CAS  Google Scholar 

  59. Mushrush M, Facchetti A, Lefenfeld M, Katz He, Marks TJ (2003) Easily processable phenylene-thiophene-based organic field-effect transistors and solution-fabricated nonvolatile transistor memory elements. J Am Chem Soc 125:9414–9423

    Article  CAS  Google Scholar 

  60. Baghbanzadeh M, Pilger C, Kappe CO (2011) Palladium-catalyzed direct arylation of heteroaromatic compounds: improved conditions utilizing controlled microwave heating. J Org Chem 76:8138–8142

    Article  CAS  Google Scholar 

  61. Zhong J (2003) Muscarine, imidazole, oxazole, and thiazole alkaloids. Nat Prod Rep 20:584–605

    Article  Google Scholar 

  62. Gompel M, Leost M, De Kier EB et al (2004) Meridianins, a new family of protein kinase inhibitors isolated from the ascidian Aplidium meridianum. Bioorg Med Chem Lett 14:1703–1704

    Article  CAS  Google Scholar 

  63. Chen L, Roger J, Bruneau C, Dixneuf PH, Doucet H (2011) Palladium-catalyzed direct arylation of thiophenes tolerant to silyl groups. J Chem Commun 47:1872–1874

    Article  CAS  Google Scholar 

  64. Nicolaus N, Franke PT, Lautens M (2011) Modular synthesis of napthothiophenes by Pd-catalyzed tandem direct arylation/Suzuki coupling. Org Lett 13 4236–4239

    Google Scholar 

  65. Bheeter CB, Bera JK, Doucet H (2011) Palladium-catalyzed direct arylation of thiophenes bearing SO2R substituents. J Org Chem 76:6407–6413

    Article  CAS  Google Scholar 

  66. Zhang Y-M, Fan X, Yang S-M, Scannevia RH, Burke SL, Rhodes KJ, Jackson PF (2008) Syntheses and in vitro evaluation of arylsulfone-based MMP with heterocyclic-derived zinc-binding groups. Biorg Med Chem Lett 18:405–408

    Article  CAS  Google Scholar 

  67. Shiozaki M, Imai H, Maeda K et al (2009) Synthesis and SAR of 2-phenyl-1-sulfonylaminocyclopropane carboxylates as ADAMTS-5 (Aggrecanase-2) inhibitors. Bioorg Med Chem Lett 19:6213–6217

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Southern Methodist University, Dallas, TX, 75275, USA

    Edward R. Biehl

Authors
  1. Edward R. Biehl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward R. Biehl .

Editor information

Editors and Affiliations

  1. Dept. Chemistry, Dartmouth College, Burke Laboratory 6128, Hanover, 03755, New Hampshire, USA

    Gordon W. Gribble

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Biehl, E.R. (2012). Recent Advances in the Synthesis of Thiophenes and Benzothiophenes. In: Gribble, G. (eds) Metalation of Azoles and Related Five-Membered Ring Heterocycles. Topics in Heterocyclic Chemistry, vol 29. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7081_2012_75

Download citation

Publish with us

Policies and ethics

Search

Navigation