Synthesis of Tetrahydroisoquinolines by Visible-Light-Mediated 6-exo-trig Cyclization of α-Aminoalkyl Radicals

Abstract

Starting from the respective tertiary α-silylmethyl amines, the intramolecular cyclization of α-aminoalkyl radicals to Michael acceptors produced tetrahydroisoquinolines. The reaction conditions included the use of 5 mol% of an iridium photoredox catalyst, dimethylformamide as the solvent, and equimolar amounts of water and cesium carbonate as the additives. 13 substrates were synthesized from ortho-alkylbenzaldehydes in a three-step procedure involving a carbonyl condensation, a radical bromination, and a substitution by a secondary α-silylmethyl amine. After optimization of the photocyclization, the reaction delivered tetrahydroisoquinolines in moderate to high yields (41–83%). A facial diastereoselectivity (dr ≅ 80:20) was observed with chiral substrates and a crystal structure provided evidence for the relative configuration of the major diastereoisomer. A catalytic cycle with direct electron transfer to the photoexcited metal catalyst is proposed.

Key words

catalysis - cyclization - electron transfer - iridium - photochemistry - radical reaction

• References and Notes


Reviews:
• 1a Nakajima K, Miyake Y, Nishibayashi Y. Acc. Chem. Res. 2016; 49: 1946
• 1b Renaud P, Giroud L. Synthesis 1996; 913
• 1c Pandey G. Synlett 1992; 546
• 1d Yoon UC, Mariano PS. Acc. Chem. Res. 1992; 25: 233
• 2a Pienta NJ, McKimmey JE. J. Am. Chem. Soc. 1982; 104: 5501
• 2b Dunn DA, Schuster DI. J. Am. Chem. Soc. 1985; 107: 2802
• 2c Dinnocenzo JP, Banach TE. J. Am. Chem. Soc. 1989; 111: 8646
• 2d Miyake Y, Nakajima K, Nishibayashi Y. J. Am. Chem. Soc. 2012; 134: 3338
• 3a Chu L, Ohta C, Zuo Z, MacMillan DW. C. J. Am. Chem. Soc. 2014; 136: 10886
• 3b Fan L, Jia J, Lefebvre HQ, Rueping M. Chem. Eur. J. 2016; 22: 16437
• 3c Zuo Z, Cong H, Li W, Choi J, Fu GC, MacMillan DW. C. J. Am. Chem. Soc. 2016; 138: 1832
• 4 Ashley MA, Yamauchi C, Chu JC. K, Otsuka S, Yorimitsu H, Rovis T. Angew. Chem. Int. Ed. 2019; 58: 4002
• 5a Yoon UC, Kim JU, Hasegawa E, Mariano PS. J. Am. Chem. Soc. 1987; 109: 4421
• 5b Hasegawa E, Xu W, Mariano PS, Yoon UC, Kim JU. J. Am. Chem. Soc. 1988; 110: 8099
• 5c Xu W, Yoon TJ, Hasegawa E, Yoon UC, Mariano PS. J. Am. Chem. Soc. 1989; 111: 406
• 5d Pandey G, Kumaraswamy G, Bhalerao UT. Tetrahedron Lett. 1989; 30: 6059
• 5e Jung YS, Swartz WH, Xu W, Mariano PS, Green NJ, Schultz AG. J. Org. Chem. 1992; 57: 6037
• 5f Pandey G, Reddy GD, Kumaraswamy G. Tetrahedron 1994; 50: 8185
• 5g Jonas M, Blechert S, Steckhan E. J. Org. Chem. 2001; 66: 6896
• 5h Cho DW, Yoon UC, Mariano PS. Acc. Chem. Res. 2011; 44: 204
• 6 Nakajima K, Kitagawa M, Ahida Y, Miyake Y, Nishibayashi Y. Chem. Commun. 2014; 50: 8900
• 7 Wayner DD. M, Dannenberg JJ, Griller D. Chem. Phys. Lett. 1986; 131: 189
• 8a Das J, Kumar JS. D, Thomas KG, Shivaramayya K, George MV. J. Org. Chem. 1994; 59: 628
• 8b Das J, Kumar JS. D, Thomas KG, Shivaramayya K, George MV. Tetrahedron 1996; 52: 3425
• 9a de Alvarenga ES, Mann J. J. Chem. Soc., Perkin Trans. 1 1993; 2141
• 9b de Alvarenga ES, Cardin CJ, Mann J. Tetrahedron 1997; 40: 3169
• 9c Bertrand S, Glapski C, Hoffmann N, Pete J.-P. Tetrahedron Lett. 1999; 40: 3169
• 9d Bertrand S, Hoffmann N, Pete J.-P. Eur. J. Org. Chem. 2000; 2227
• 9e Bauer A, Westkämper F, Grimme S, Bach T. Nature 2005; 436: 1139

For nonfunctionalized amines, see:
• 10a McNally A, Prier CK, MacMillan DW. C. Science 2011; 334: 1114
• 10b Ruiz Espelt L, Wiensch EM, Yoon TP. J. Org. Chem. 2013; 78: 4107
• 10c Zhu S, Das A, Bui L, Zhou H, Curran DP, Rueping M. J. Am. Chem. Soc. 2013; 135: 1823
• 10d Dai X, Cheng D, Guan B, Mao W, Xu W, Li X. J. Org. Chem. 2014; 79: 7212
• 10e Dai X, Mao R, Guan B, Xu X, Li X. RSC Adv. 2015; 5: 55290
• 10f Murphy JJ, Bastida D, Paria S, Fagnoni M, Melchiorre P. Nature 2016; 532: 218

For silylated amines, see:
• 11a Miyake Y, Ashida Y, Nakajima K, Nishibayashi Y. Chem. Commun. 2012; 48: 6966
• 11b Lenhart D, Bach T. Beilstein J. Org. Chem. 2014; 10: 890
• 11c Ruiz Espelt L, McPherson IS, Wiensch EM, Yoon TP. J. Am. Chem. Soc. 2015; 137: 2452
• 11d Lenhart D, Bauer A, Pöthig A, Bach T. Chem. Eur. J. 2016; 22: 6519

Recent reviews:
• 12a Schultz DM, Yoon TP. Science 2014; 343: 1239176
• 12b Reckenthäler M, Griesbeck AG. Adv. Synth. Catal. 2013; 355: 2727
• 12c Xi Y, Yi H, Lei A. Org. Biomol. Chem. 2013; 11: 2387
• 12d Prier CK, Rankic DA, MacMillan DW. C. Chem. Rev. 2013; 113: 5322
• 12e Tucker JW, Stephenson CR. J. J. Org. Chem. 2012; 77: 1617
• 12f Zeitler K. Angew. Chem. Int. Ed. 2009; 48: 9785
• 13a Pictet A, Spengler T. Ber. Dtsch. Chem. Ges. 1911; 44: 2030
• 13b Cox ED, Cook JM. Chem. Rev. 1995; 95: 1797

Key publications:
• 14a Rueping M, Zhu S, Koenigs RM. Chem. Commun. 2011; 47: 12709
• 14b Rueping M, Vila C, Koenigs RM, Poscharny K, Fabry DC. Chem. Commun. 2011; 47: 2360
• 14c Rueping M, Zhu S, Koenigs RM. Chem. Commun. 2011; 47: 8679
• 14d Pan Y, Wang S, Kee CW, Dubuisson E, Yang Y, Loh KP, Tan C.-H. Green Chem. 2011; 13: 3341
• 14e Zhao G, Yang C, Guo L, Sun H, Chen C, Xia W. Chem. Commun. 2012; 48: 2337
• 14f Freeman DB, Furst L, Condie AG, Stephenson CR. J. Org. Lett. 2012; 14: 94
• 15 Condie AG, González-Gómez JC, Stephenson CR. J. J. Am. Chem. Soc. 2010; 132: 1464
• 16 Kohl P, Jadhav D, Pandey G, Reiser O. Org. Lett. 2012; 14: 672
• 17 Liu X, Bureš F, Liu H, Jiang Z. Angew. Chem. Int. Ed. 2015; 54: 11443
• 18 Nakamura Y, O-kawa K, Minami S, Ogawa T, Tobita S, Nishimura J. J. Org. Chem. 2002; 67: 1247
• 19 Xue Q, Mao Z, Shi Y, Mao H, Cheng Y, Zhu C. Tetrahedron Lett. 2012; 53: 1851
• 20 Jeong HC, Lim SH, Cho DW, Kim SH, Mariano PS. Org. Biomol. Chem. 2016; 14: 10502
• 21 Juris A, Balzani V, Barigelletti F, Campagna S, Belser P, von Zelewesky A. Coord. Chem. Rev. 1988; 84: 85
• 22 Lowry MS, Goldsmith JI, Slinker JD, Rohl R, Pascal RA, Maillaras GG, Bernhard S. Chem. Mater. 2005; 17: 5712
• 23 Böhm A, Bach T. Chem. Eur. J. 2016; 22: 15921
• 24 Cyclization Reaction; General Procedure Substrate (1.00 equiv), Cs₂CO₃ (1.00 equiv), H₂O (1.00 equiv), and photoredox catalyst [Ir{dF(CF₃)ppy}(dtbpy)]PF₆ [Ir(dF)] (0.05 equiv) were dissolved in dry DMF (ca. 2 mL/0.1 mmol substrate). The yellow mixture was degassed by repeating a freeze-pump-thaw cycle (3×) and irradiated for 14 h with 30 W blue LED lamps (λ = 455 nm) at r.t. whilst continuously stirring under an argon atmosphere. After 14 h, water (ca. 5 mL/0.1 mmol) was added. The layers were separated and the aqueous layer was extracted with diethyl ether (3× ca. 6 mL/0.1 mmol). The combined organic layers were washed with brine and dried with Na₂SO₄. After filtration, residual solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain the photoproduct. Representative NMR data (1a): ¹H NMR (500 MHz, CDCl₃): δ = 7.40–7.34 (m, 2 H, 2× meta-C_Ph-H), 7.34–7.28 (m, 2 H, 2× ortho-C_Ph-H), 7.27–7.21 (m, 1 H, para-C_Ph-H), 7.17–7.07 (m, 3 H, H-6, H-7, H-8), 7.00–6.94 (m, 1 H, H-5), 4.13–3.99 (m, 2 H, CH ₂CH₃), 3.80 (d, ² J = 14.9 Hz, 1 H, CHH-1), 3.71 (d, ² J = 13.1 Hz, 1 H, Ph-CHH), 3.58 (d, ² J = 13.1 Hz, 1 H, Ph-CHH), 3.42 (d, ² J = 14.9 Hz, 1 H, CHH-1), 3.38–3.31 (m, 1 H, H-4), 2.88 (dd, ² J = 16.0 Hz, ³ J = 9.7 Hz, 1 H, CHHCO₂Et), 2.80 (ddd, ³ J = 11.7 Hz, ⁴ J = 3.2, 1.3 Hz, 1 H, CHH-3), 2.61–2.58 (m, 2 H, CHH-3, CHHCO₂Et), 1.20 (t, ³ J = 7.1 Hz, 3 H, CH₂CH ₃). ¹³C NMR (101 MHz, CDCl₃): δ = 172.9 (s, CO₂Et), 138.7 (s, CH₂-C _Ph), 137.6 (s, C-4a), 135.3 (s, C-8a), 129.1 (d, meta-CH_Ph), 128.4 (d, C-8), 128.4 (d, ortho-CH_Ph), 127.2 (d, para-CH_Ph), 126.7 (d, C-6*), 126.5 (d, C-7*), 126.2 (d, C-5), 62.8 (t, CH₂-C_Ph), 60.4 (t, CH ₂CH₃), 56.5 (t, C-1), 54.7 (t, C-3), 41.2 (t, CH₂CO₂Et), 35.8 (d, C-4), 14.3 (q, CH₂ CH₃). * Assignment is interconvertible. Major diastereoisomer (1i): ¹H NMR (400 MHz, CDCl₃): δ = 7.39–7.36 (m, 2 H, 2× meta-C_Ph-H), 7.33–7.29 (m, 2 H, 2× ortho-C_Ph-H), 7.27−7.22 (m, 1 H, para-C_Ph-H), 7.22–7.13 (m, 4 H, H-5, H-6, H-7, H-8), 4.10 (d, ² J = 13.6 Hz, 1 H, Ph-CHH), 3.75 (q, ³ J = 6.3 Hz, 1 H, H-1), 3.55 (s, 3 H, CO₂CH₃), 3.40 (d, ² J = 13.6 Hz, 1 H, Ph-CHH), 3.26 (dq, ³ J = 9.0 Hz, ³ J = 5.0 Hz, 1 H, H-4), 2.90–2.80 (m, 2 H, CHH-3, CHHCO₂CH₃), 2.66 (dd, ² J = 16.0 Hz, ³ J = 5.0 Hz, 1 H, CHHCO₂CH₃), 2.62–2.56 (m, 1 H, CHH-3), 1.53 (d, ³ J = 6.3 Hz, 3 H, CH₃). ¹³C NMR (101 MHz, CDCl₃): δ = 173.2 (s, CO), 140.4 (s, C-8a), 139.6 (s, CH₂-C _Ph), 137.7 (s, C-4a), 128.9 (d, meta-CH_Ph), 128.3 (d, ortho-CH_Ph), 128.1 (d, C-8*), 127.3 (d, C-5*), 127.0 (d, para-CH_Ph), 126.4 (d, C-6**), 126.1 (d, C-7**), 58.9 (t, CH₂-C_Ph), 57.8 (d, C-1), 51.5 (q, CO₂ CH₃), 50.9 (t, C-3), 39.9 (t, CH₂CO₂H3), 35.1 (d, C-4), 21.9 (q, CH₃). */** Assignments are interconvertible. Minor diastereoisomer (1i): ¹H NMR (400 MHz, CDCl₃): δ = 7.39–7.35 (m, 2 H, 2× meta-C_Ph-H), 7.33–7.28 (m, 2 H, 2× ortho-C_Ph-H), 7.27–7.22 (m, 1 H, para-C_Ph-H), 7.17–7.09 (m, 3 H, H-6, H-7, H-8), 7.06–7.00 (m, 1 H, H-5), 4.10 (q, ³ J = 6.6 Hz, 1 H, H-1), 3.83 (d, ² J = 13.1 Hz, 1 H, Ph-CHH), 3.63 (d, ² J = 13.1 Hz, 1 H, Ph-CHH), 3.52 (s, 3 H, CO₂CH₃), 3.23–3.17 (m, 1 H, H-4), 3.00 (d, ² J = 10.6 Hz, 1 H, CHH-3), 2.88 (dd, ² J = 16.2 Hz, ³ J = 10.1 Hz, 1 H, CHHCO₂CH₃), 2.55–2.45 (m, 2 H, CHH-3, CHHCO₂CH₃), 1.28 (d, ³ J = 6.6 Hz, 3 H, CH₃). ¹³C NMR (101 MHz, CDCl₃): δ = 173.5 (s, CO), 141.4 (s, C-8a), 139.4 (s, CH₂-C _Ph), 137.5 (s, C-4a), 129.2 (d, meta-CH_Ph), 128.8 (d, C-8), 128.3 (d, ortho-CH_Ph), 127.4 (d, para-CH_Ph), 127.0 (d, C-5), 126.4 (d, C-6*), 126.2 (d, C-7*), 58.4 (t, CH₂-C_Ph), 56.0 (d, C-1), 51.5 (q, CO₂ CH₃), 45.8 (t, C-3), 41.1 (t, CH₂CO₂CH₃), 35.9 (d, C-4), 14.8 (q, CH₃). * Assignment is interconvertible.
• 25 Hoffmann RW. Chem. Rev. 1989; 89: 1841
• 26 Cooper BE, Owen WJ. J. Organomet. Chem. 1971; 29: 33