Truly Catalytic Gewald Synthesis of 2-Aminothiophenes Using Piperidinium Borate (Pip Borate), a Conjugate Acid–Base Pair

Abstract

The Gewald reaction has been well-known for more than half a century as an excellent method to provide bioactive 2-aminothiophene heterocycles from the reaction of carbonyl compounds, α-cyanoacetates, and elemental sulfur, in the presence of amines, in stoichiometric amounts. This work describes the use of salts of boric acid as conjugate acid-base pairs in a truly catalytic amount for the cyclocondensation of ketones with active methylenes such as malononitrile, ethyl cyanoacetate, and benzoyl acetonitrile with sulfur to give 2-aminothiophenes via the Gewald reaction. The present protocol is also applied for synthesizing Tinoridine, an anti-peroxidative NSAID, with excellent yield. Additionally, the catalyst has great recyclability and reusability.

Key words

conjugate acid-base catalyst - Gewald reaction - 2-aminothiophenes - recyclable - piperidinium borate

• References

• 1 Abd-El-Aziz AS, Afifi TH. Dyes Pigm. 2006; 70: 8
• 2 Sridhar M, Rao RM, Baba NH, Kumbhare RM. Tetrahedron Lett. 2007; 48: 3171
• 3 Gewald K. Angew. Chem. 1961; 73: 114
• 4 Hung K, Liu Y, Simon O, Zhang L, Lu P, Yeung BK, Yokokawa F. Synlett 2022; 33: 464
• 5 Valant C, Aurelio L, Devine SM, Ashton TD, White JM, Sexton PM, Scammells PJ. J. Med. Chem. 2012; 55: 2367
• 6 Rossetti A, Bono N, Candiani G, Meneghetti F, Roda G, Sacchetti A. Chem. Biodivers. 2019; 16: e1900097
• 7 Romagnoli R, Prencipe F, Oliva P, Cacciari B, Balzarini J, Liekens S, Gambari R. Molecules 2020; 25: 1690
• 8 Wilson R, Kumar P, Parashar V, Vilchèze C, Veyron-Churlet R, Freundlich JS, Alland D. Nat. Chem. Biol. 2013; 9: 499
• 9 Hartkoorn RC, Ryabova OB, Chiarelli LR, Riccardi G, Makarov V, Cole ST. Antimicrob. Agents Chemother. 2014; 58: 2944
• 10 Huang Y, Dömling A. Mol. Diversity 2011; 15: 3
• 11 Bymaster FP, Rasmussen K, Calligaro DO, Nelson DL, DeLapp NW, Wong DT, Moore NA. J. Clin. Psychiatry 1997; 58: 28
• 12 Kazuhiro G, Masao H, Hiroshi I. Biochem. Pharmacol. 1977; 26: 11
• 13 Li X, Conklin D, Pan HL, Eisenach JC. J. Pharmacol. Exp. Ther. 2003; 305: 950
• 14 Podolin PL, Callahan JF, Bolognese BJ, Li YH, Carlson K, Davis TG, Roshak AK. J. Pharmacol. Exp. Ther. 2005; 312: 373
• 15 Mariño EL, Dominguez-Gil A. Int. J. Clin. Pharmacol., Ther. Toxicol. 1986; 24: 482
• 16 Langley MS, Clissold SP. Drugs 1988; 35: 104
• 17 Sabnis RW, Rangnekar DW, Sonawane ND. J. Heterocycl. Chem. 1999; 36: 333
• 18 Romagnoli R, Baraldi PG, Carrion MD, Cara CL, Preti D, Fruttarolo F, Hamel E. J. Med. Chem. 2007; 50: 2273
• 19 Mahdavi B, Hosseyni-Tabar SM, Rezaei-Seresht E, Rezaei-Seresht H, Falanji F. J. Iran. Chem. Soc. 2020; 17: 809
• 20 Abu-Hashem AA, Abu-Zied KM, El-Shehry MF. Monatsh. Chem. 2011; 142: 539
• 21 Al-Mousawi S, Moustafa MS, Elnagdi MH. ARKIVOC 2008; (x): 17
• 22 Abaee MS, Cheraghi S. J. Sulfur Chem. 2014; 35: 261
• 23 Kaki VR, Akkinepalli RR, Deb PK, Pichika MR. Synth. Commun. 2015; 45: 119
• 24 Shaabani A, Hooshmand SE, Afaridoun H. Monatsh. Chem. 2017; 148: 711
• 25 Moeinpour F, Omidinia R, Dorostkar-Ahmadi N, Khoshdeli B. Bull. Korean Chem. Soc. 2011; 32: 2091
• 26 Rajagopal R, Jyothi TM, Daniel T, Srinivasan KV, Rao BS. Synth. Commun. 2001; 31: 3113
• 27 Gavali KD, Kudale PR, Chaturbhuj GU. Tetrahedron Lett. 2023; 154537
• 28 Elnagdi MH, Erian AW. Liebigs Ann. Chem. 1990; 1215
• 29 Abaee MS, Cheraghi S. Turk. J. Chem. 2014; 38: 650
• 30 Nakanishi M, Tahara T, Araki K, Shiroki M, Tsumagari T. J. Med. Chem. 1973; 16: 214
• 31 Gill RK, Kaur R, Kumar V, Gupta V, Singh G, Bariwal J. MedChemComm 2016; 7: 1966
• 32 Li L, Ruan B, Zhang Z, Huang L, Xu C. Heterocycles 2021; 102: 2007
• 33 Mojtahedi MM, Abaee MS, Mahmoodi P, Adib M. Synth. Commun. 2010; 40: 2067
• 34 Aurelio L, Valant C, Figler H, Flynn BL, Linden J, Sexton PM, Scammells PJ. Bioorg. Med. Chem. 2009; 17: 7353
• 35 van der Klein PA, Kourounakis AP, IJzerman AP. J. Med. Chem. 1999; 42: 3629