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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Gewald K (1961) Reaction of ± -oxomercaptans with nitriles. Angew Chem 73:114–116
Gewald K (1965) Heterocycles from CH-acidic nitriles. VII. 2-Aminothiophene from α-oxo mercaptans and methylene-active nitriles. Chem Ber 98:3571–3577
Gompper R, Kutter E (1962) New thiophenes and thieno[2,3-b]thiophenes. Angew Chem 74:251–252
Gewald K, Schinke E (1966) Heterocycles from CH-acidic nitriles. X. Reaction of acetone with cyanoacetic ester and sulfur. Chem Ber 99:271–275
Huang H, Dömling A (2011) The Gewald multicomponent reaction. Mol Divers 15:3–33
Putevovd Z, Krutosikova A, Vegh D (2010) The Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes. ARKIVOC (i):209–246
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
Sabnis RW, Rangnekar DW, Sonawane ND (1999) 2-Aminothiophenes from the Gewald reaction. J Heterocyclic Chem 36:333–345
Dömling A (2006) Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev 106:17–89
Zavarzin V, Yarovenko VN, Shirokov AV, Smirnova NG, Es’kov AA, Krayushkin MM (2003) Synthesis and reactivity of monothio-oxamides. Arkivoc 13:205–223
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
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
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
Kathiravan MK, Shishoo CJ, Chitre TS, Mahadik RR, Jain KS (2007) Efficient synthesis of substituted 2-amino-3-carbethoxythiophenes. Synth Commun 37:4273–4279
Dömling A, Chi K-Z, Herdtweck E (2006) Derived isocyano amides useful as starting materials in IMCR. J Comb Chem 8:872–880
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
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
Kindler K (1923) Mechanism of chemical reactions. I. Reduction of amides and in oxidation of amines. Liebigs Ann Chem 431:187–207
Solovyev AY, Androsov DA, Necker DC (2007) One-pot synthesis of substituted 2-aminobenzo[b]thiophenes. J Org Chem 72:3122–3124
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
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)
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
Gladysz JA, Curran DP, Horvath IT, Horvath IT (eds) (2004) Handbook of fluorous chemistry. Wiley-VCH, Weinheim, pp 1–595
Crich D, Neelamkavil S (2001) Fluorous Swern reactions. J Am Chem Soc 123:7449–7450
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
Kaleta Z, Makowski BT, Soos T, Dembinski R (2006) Thionation using fluorous Lawesson’s reagent. Org Lett 8:1625–1628
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
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
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
Ma S (2003) Cationic cyclopentannelation of allene ethers. Acc Chem 36:284–290
Ma S (2005) Asymmetric synthesis of axially chiral allenes. Chem Rev 105:2829–2871
Ma S (2003) Acc Chem Res 36:701–712
Kim H, Williams L (2008) Recent developments in allene-based synthetic methods. J Curr Opin Drug Disc Dev 11:870–894
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
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
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
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
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
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
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
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
Godoi B, Schumacher RF, Zeni G (2011) Synthesis of heterocyclces via electrophilic cyclization of alkynes containing heteroatoms. Chem Rev 111:2937–2980
Mphahlele MJ (2009) Molecular iodine-mediated cyclization of tethered heteroatom-containing alkenyl or alkynyl systems. Molecules 14:4814–4837
Larock RC, Yue D (2001) Synthesis of benzo[b]thiophenes by electrophilic cyclization. Tetrahedron Lett 42:6011–6013
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
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
Yang F, Jin T, Bao M, Yamamoto Y (2011) Facile synthesis of 3,4-diiododihydrothiophenes via electrophilic iodocyclization. Tetrahedron Lett 52:936–938
Blenderman WG, Jouillie MM, Preti G (1979) The Birch reduction of thiophenes-2-carboxylic acid. Tetrahedron Lett 20:4985–4988
McIntosh JM, Goodbrand HB, Masse GM (1974) Dihydrothiophenes. II. Preparation and properties of some alkylated 2,5-dihydrothiophenes. J Org Chem 39:202–206
Mehta S, Larock RC (2010) Iodine/palladium approaches to the synthesis of polyheterocyclic compounds. J Org Chem 75:1652–1658
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
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
Seregin IV, Gevorgyan V (2007) Direct transition metal-catalyzed functionalization of heteroaromatic compounds. Chem Soc Rev 30:1173–1193
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
Perepichka IF, Perepichka DF (2011) Handbook of thiophenes-based materials. Wiley, Chichester
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
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
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
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
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
Zhong J (2003) Muscarine, imidazole, oxazole, and thiazole alkaloids. Nat Prod Rep 20:584–605
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
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
Nicolaus N, Franke PT, Lautens M (2011) Modular synthesis of napthothiophenes by Pd-catalyzed tandem direct arylation/Suzuki coupling. Org Lett 13 4236–4239
Bheeter CB, Bera JK, Doucet H (2011) Palladium-catalyzed direct arylation of thiophenes bearing SO2R substituents. J Org Chem 76:6407–6413
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
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
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights 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
DOI: https://doi.org/10.1007/7081_2012_75
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-31790-3
Online ISBN: 978-3-642-31791-0
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)