Hydrogen-Bond-Catalyzed Arylation of 3-(Aminoalkyl)indoles via C–N Bond Cleavage with Thiourea under Microwave Irradiation: An Approach to 3-(α,α-Diarylmethyl)indoles

Abstract

We have developed a simple and efficient method for the arylation of 3-(aminoalkyl)indoles with aryl alcohols and other aromatic nucleophiles through C–N bond cleavage under microwave irradiation to synthesize 3-(α,α-diarylmethyl)indoles. The method uses thiourea as catalyst, which is environmentally benign, water-tolerant and easy to handle. Notably, acid-sensitive substrates are tolerated under the reaction conditions. Thiourea activates the tertiary amine through double hydrogen bonding and converts it into a better leaving group. The reaction proceeds through the formation of vinylogous iminium ion as an intermediate.

Key words

hydrogen-bond-catalyzed - thiourea - microwave - indoles - vinylogous iminium ion

• References and Notes

• 1a López DR, López EM, Alcaine A, Merino P, Herrera RP. Org. Biomol. Chem. 2014; 12: 4503
• 1b Fang X, Li J, Wang C.-J. Org. Lett. 2013; 15: 3448
• 1c Kramer CS, Brase S. Beilstein J. Org. Chem. 2013; 9: 1414
• 1d Peterson EA, Jacobsen EN. Angew. Chem. Int. Ed. 2009; 48: 6328
• 1e Held FE, Tsogoeva SB. Catal. Sci. Technol. 2016; 6: 645
• 1f Kurono N, Ohkuma T. ACS Catal. 2016; 6: 989
• 1g Taylor MS, Jacobsen EN. Angew. Chem. Int. Ed. 2006; 45: 1520
• 1h Doyle AG, Jacobsen EN. Chem. Rev. 2007; 107: 5713
• 1i Zhang Z, Schreiner PR. Chem. Soc. Rev. 2009; 38: 1187
• 1j Takemoto Y. Chem. Pharm. Bull. 2010; 58: 593
• 1k Serdyuk OV, Heckel CM, Tsogoeva SB. Org. Biomol. Chem. 2013; 11: 7051

For reviews on microwave-assisted organic synthesis, see:
• 2a Gawande MB, Shelke SN, Zboril R, Varma RS. Acc. Chem. Res. 2014; 47: 1338
• 2b Moseley JD, Kappe CO. Green Chem. 2011; 13: 794
• 2c Microwaves in Organic Synthesis . 2nd ed. Loupy A. Wiley-VCH; Weinheim/Germany: 2006
• 2d Kappe CO. Angew. Chem. Int. Ed. 2004; 43: 6250
• 2e Lidstrom P, Tierney J, Wathey B, Westman J. Tetrahedron 2001; 57: 9225
• 2f Martinez AV, Invernizzi F, Leal-Duaso A, Mayoral JA, Garcia JI. RSC Adv. 2015; 5: 10102
• 2g Riemer M, Schmidt B. Synthesis 2016; 48: 1399
• 2h Rabiei K, Naeimi H. Green Chem. Lett. Rev. 2016; 9: 44
• 3a Sreejith P, Beyo RS, Divya L, Vijayasree AS, Manju M, Oommen OV. Indian J. Biochem. Biophys. 2007; 44: 164
• 3b Estevão MS, Carvalho LC, Ribeiro D, Couto D, Freitas M, Gomes A, Ferreira LM, Fernandes E, Marques MM. Eur. J. Med. Chem. 2010; 45: 4869
• 3c El-Mekabaty A, Etman HA, Mosbah A. J. Heterocycl. Chem. 2016; 53: 894
• 3d Grewal P, Mallaney M, Lau K, Sreedhara A. Mol. Pharmaceutics 2014; 11: 1259
• 3e Ates-Alagoz Z. Curr. Med. Chem. 2013; 20: 4633
• 4a Metwally MA, Shaaban S, Abdel-Wahab BF, El-Hiti GA. Curr. Org. Chem. 2009; 13: 1475
• 4b Hajicek J. Collect. Czech. Chem. Commun. 2007; 72: 821
• 4c Agarwal S, Cammerer S, Filali S, Frohner W, Knoll J, Krahl MP, Reddy KR, Knolker HJ. Curr. Org. Chem. 2005; 9: 1601
• 5a Walsh TF, Toupence RB, Ujjainwalla F, Young JR, Goulet MT. Tetrahedron 2001; 57: 5233
• 5b Jacotot B, Banga JD, Pfister P, Mehra M. Br. J. Clin. Pharmacol. 1994; 38: 257
• 6 Reddy BV. S, Reddy MR, Madan C, Kumar KP, Rao MS. Bioorg. Med. Chem. Lett. 2010; 20: 7507
• 7a Contractor R, Samudio IJ, Estrov Z, Harris D, McCubrey JA, Safe SH, Andreeff M, Konopleva M. Cancer Res. 2005; 65: 2890
• 7b Deng J, Sanchez T, Neamati N, Briggs JM. J. Med. Chem. 2006; 49: 1684
• 8 Lézé M.-P, Le Borgne M, Marchand P, Loquet D, Kogler M, Le Baut G, Palusczak A, Hartmann RW. J. Enzyme Inhib. Med. Chem. 2004; 19: 549
• 9a Chopade HN, Meshram JS, Pagadala R, Mungole A. Int. J. ChemTech Res. 2010; 2: 1823
• 9b Huang M.-H, Wa S.-N, Wang J.-P, Lin C.-H, Lu SI, Lian L.-F, Shen A.-Y. Drug Dev. Res. 2003; 60: 261
• 9c Shen AY, Tsai CT, Chen CL. Eur. J. Med. Chem. 1999; 34: 877
• 10 Wink M. Theor. Appl. Genet. 1988; 75: 225
• 11a Sakihama Y, Mano J, Sano S, Asada K, Yamasaki H. Biochem. Biophys. Res. Commun. 2000; 279: 949
• 11b Arora A, Nair MG, Strasburg GM. Free Radical Biol. Med. 1998; 24: 1355
• 11c Evans CR, Miller N, Paganga G. Trends Plant Sci. 1997; 2: 152
• 12 Kaim LE, Grimaud L, Oble J. Org. Biomol. Chem. 2006; 4: 3410
• 13 Yu L, Xie X, Wu S, Wang R, He W, Qin D, Liu Q, Jing L. Tetrahedron Lett. 2013; 54: 3675
• 14 Li ML, Chen D.-F, Luo S.-W, Wu X. Tetrahedron: Asymmetry 2015; 26: 219
• 15a Dutta P, Pegu CD, Deb ML, Baruah PK. Tetrahedron Lett. 2015; 56: 4115
• 15b Deb ML, Dey SS, Bento I, Barros MT, Maycock CD. Angew. Chem. Int. Ed. 2013; 52: 9791
• 16a Kumar A, Gupta MK, Kumar M. Green Chem. 2012; 14: 290
• 16b Kumar A, Gupta MK, Kumar M, Saxena D. RSC Adv. 2013; 3: 1673
• 16c Joachim GH, Michael A, Nikolaus R. Synthesis 1996; 883
• 16d Tamon M, Katsuaki H, Naoto Y. Synthesis 1980; 728
• 16e Snyder H, Smith C, Stewart J. J. Am. Chem. Soc. 1944; 66: 200
• 16f Albright JD, Snyder HR. J. Am. Chem. Soc. 1959; 81: 2239
• 16g Howe EE, Zambito AJ, Snyder HR, Tishler M. J. Am. Chem. Soc. 1945; 67: 38
• 16h Albertson NF, Archer S, Suter CM. J. Am. Chem. Soc. 1945; 67: 36
• 16i Somei M, Karasawa Y, Kaneko C. Heterocycles 1981; 16: 941
• 17 Synthesis of 3a: Typical Procedure: A solution of 1a (1 mmol, 250 mg), 2-naphthol (1 mmol, 144 mg) and thiourea (30 mol%, 23 mg) in MeCN (0.5 mL) was irradiated in a closed vessel in a microwave reactor at 100 °C for the specified time. The progress of the reaction was monitored by TLC. Upon completion of the reaction, solvent was removed under vacuum and the crude mixture was purified by column chromatography (hexane/EtOAc) to obtain the desired product 3a. Yield: 335 mg (96%); gray solid; mp 168–170 °C. IR (KBr): 3420, 3369, 3065, 2925, 1619, 1455, 1207, 747 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.5 Hz, 1 H), 8.04 (br s, 1 H), 7.80 (d, J = 8.1 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.45–7.14 (m, 10 H), 7.02 (d, J = 8.8 Hz, 1 H), 6.95 (t, J = 7.5 Hz, 1 H), 6.63 (s, 1 H), 6.50 (s, 1 H), 6.15 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 153.7, 141.5, 137.0, 133.0, 129.5, 129.4, 128.9, 128.8, 128.6, 127.0, 126.8, 124.0, 123.1, 123.1, 122.5, 120.1, 119.6, 118.5, 117.5, 111.4, 40.9. Anal. Calcd for C₂₅H₁₉NO: C, 85.93; H, 5.48; N, 4.01. Found: C, 85.82; H, 5.34; N, 4.09.
• 18 CCDC 1478603 (3h) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 19a Palmieri A, Petrini M, Shaikh RR. Org. Biomol. Chem. 2010; 8: 1259
• 19b Wang L, Chen Y, Xiao J. Asian J. Org. Chem. 2014; 3: 1036