Synthesis of Polysubstituted 3-Chalcogenated Indoles through Copper(I) Iodide-Catalyzed Three-Component Domino Reactions

Abstract

Polysubstituted 3-chalcogenated indoles were synthesized by a three-component, one-pot, domino reaction of a N-(2-bromophenyl)trifluoroacetamide, a 1-alkyne, a disulfides or diselenides, CuI, and proline in DMF. In this process, tandem Sonogashira coupling, N-cyclization, and sulfenyl/selenyl electrophilic substitution occurred sequentially and smoothly to form the anticipated products in good to excellent yields (20 examples; 65–96%). Notably, no palladium catalyst was used in this catalytic system, supporting its cost effectiveness and potential industrial application.

Key words

indoles - copper catalysis - Sonogashira reaction - cyclization - electrophilic substitution - One-pot reaction

• References and Notes

• 1a Humphrey GR, Kuethe JT. Chem. Rev. 2006; 106: 2875
• 1b Cacchi S, Fabrizi G. Chem. Rev. 2005; 105: 2873
• 1c Bartoli G, Bencivenni G, Dalpozzo R. Chem. Soc. Rev. 2010; 39: 4449
• 1d Bandgar BP, Sarangdhar RJ, Viswakarma S, Ahamed FA. J. Med. Chem. 2011; 54: 1191
• 1e Choi Y, Kim Y, Park S, Lee KW, Park T. J. Nutr. Biochem. 2012; 23: 1732
• 1f Sashidhara KV, Kumar M, Sonkar R, Singh BS, Khanna AK, Bhatia G. J. Med. Chem. 2012; 55: 2769
• 2a Kolasa T, Gunn DE, Bhatia P, Woods KW, Gane T, Stewart AO, Bouska JB, Harris RR, Hulkower KI, Malo PE, Bell RL, Carter GW, Brooks CD. W. J. Med. Chem. 2000; 43: 690
• 2b Ragno R, Coluccia A, Regina GL, De Martino G, Piscitelli F, Lavecchia A, Novellino E, Bergamini A, Ciaprini C, Sinistro A, Maga G, Crespan E, Artico M, Silvestri R. J. Med. Chem. 2006; 49: 3172
• 2c La Regina G, Edler MC, Brancale A, Kandil S, Coluccia A, Piscitelli F, Hamel E, De Martino G, Matesanz R, Diaz JF, Scovassi AI, Prosperi E, Lavecchia A, Novellino E, Artico M, Silvestri R. J. Med. Chem. 2007; 50: 2865
• 2d Funk CD. Nat. Rev. Drug Discov. 2005; 4: 664
• 2e Wen Z, Xu J, Wang Z, Qi H, Xu Q, Bai Z, Zhang Q, Bao K, Wu Y, Zhang W. Eur. J. Med. Chem. 2015; 90: 184
• 3a Atkinson JG, Hamel P, Girard Y. Synthesis 1988; 480
• 3b Matsugi M, Murata K, Gotanda K, Nambu H, Anilkumar G, Matsumoto K, Kita Y. J. Org. Chem. 2001; 66: 2434
• 3c Tudge M, Tamiya M, Savarin C, Humphrey GR. Org. Lett. 2006; 8: 565
• 3d Schlosser KM, Krasutsky AP, Hamilton HW, Reed JE, Sexton K. Org. Lett. 2004; 6: 819
• 3e Campbell JA, Broka CA, Gong L, Walker KA. M, Wang J.-H. Tetrahedron Lett. 2004; 45: 4073
• 3f Yadav JS, Reddy BV. S, Reddy YJ. Tetrahedron Lett. 2007; 48: 7034
• 3g Maeda Y, Koyabu M, Nishimura T, Uemura S. J. Org. Chem. 2004; 69: 7688
• 3h Pezzella A, Palma A, Iadonisi A, Napolitano A, d’Ischia M. Tetrahedron Lett. 2007; 48: 3883
• 3i Wu G, Liu Q, Shen Y, Wu W, Wu L. Tetrahedron Lett. 2005; 46: 5831
• 3j Yadav JS, Reddy BV. S, Krishna AD, Reddy CS, Narsaiah AV. Synthesis 2005; 961
• 3k Chakrabarty M, Sarkar S. Tetrahedron Lett. 2003; 44: 8131
• 3l Shirani H, Stensland B, Bergman J, Janosik T. Synlett 2006; 2459
• 4a Larock RC, Yum EK. J. Am. Chem. Soc. 1991; 113: 6689
• 4b Chen Y, Cho C.-H, Larock RC. Org. Lett. 2009; 11: 173
• 4c Chen Y, Cho C.-H, Shi F, Larock RC. J. Org. Chem. 2009; 74: 6802
• 5a Guo Y.-J, Tang R.-Y, Li J.-H, Zhong P, Zhang X.-G. Adv. Synth. Catal. 2009; 351: 2615
• 5b Du H.-A, Tang R.-Y, Deng C.-L, Liu Y, Li J.-H, Zhang X.-G. Adv. Synth. Catal. 2011; 353: 2739
• 6 Liu J, Li P, Chen W, Wang L. Chem. Commun. 2012; 48: 10052
• 7 Liu F, Ma D. J. Org. Chem. 2007; 72: 4844
• 8a Sang P, Chen ZK, Zou JW, Zhang YH. Green Chem. 2013; 15: 2096
• 8b La Regina G, Gatti V, Famiglini V, Piscitelli F, Silvestri R. ACS Comb. Sci. 2012; 14: 258
• 8c Bettanin L, Saba S, Doerner CV, Franco MS, Godoi M, Rafique J, Braga AL. Tetrahedron 2018; 74: 3971
• 9 Ma D, Liu F. Chem. Commun. 2004; 1934
• 10 Okuro K, Furuune M, Enna M, Miura M, Nomura M. J. Org. Chem. 1993; 58: 4716
• 11 2-Phenyl-3-(phenylthio)-1H-indole (3a); Typical ProcedureA sealable reaction tube equipped with a magnetic stirrer bar was charged with 2-N-(2-bromophenyl)-2,2,2-trifluoroacetamide (1ab; 1 mmol), ethynylbenzene (2a; 1 mmol), Ph₂S₂ (0.5 mmol), Cs₂CO₃ (2 mmol), CuI (0.1 mmol), proline (0.3 mmol), and DMF (2 mL). The reaction vessel was placed in an oil bath at 100 °C under N₂, and the mixture was stirred at this temperature for 12 h. The cap was then opened and the mixture was stirred at the same temperature for another 12 h. It was then cooled to r.t., diluted with EtOAc, and washed with H₂O and brine, then dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, hexane–EtOAc (10:1)] to give a pale-yellow solid; yield: 265 mg (88%); mp 139–141 °C.¹H NMR (500 MHz, CDCl₃): δ = 8.56 (s, 1 H), 7.80 (d, J = 7.2 Hz, 2 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.48 (m, 3 H), 7.42 (t, J = 7.2 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 7.21 (m, 3 H), 7.17 (d, J = 7.5 Hz, 2 H), 7.10 (t, J = 7.2 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 140.84, 139.11, 135.97, 134.65, 131.20, 129.83, 129.42, 129.05, 125.71, 124.98, 123.66, 121.47, 120.10, 111.45, 99.97. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₁₅NNaS⁺ = 324.0817; found: 324.0819.