Synlett 2020; 31(09): 916-924
DOI: 10.1055/s-0040-1707995
letter
© Georg Thieme Verlag Stuttgart · New York

Palladium-Catalyzed Decarboxylative Formal (4+2) Cycloaddition of Vinyl Benzoxazinanones with 3-Nitroindoles

Melissa J. Bird
,
Steven M. Wales
,
,
The authors thank the University of Wollongong and the Australian Research Council (DP180101332) for the generous funding for this research.
Further Information

Publication History

Received: 29 November 2019

Accepted after revision: 26 February 2020

Publication Date:
20 March 2020 (online)


Abstract

A diastereoselective palladium-catalyzed dearomative formal (4+2) cycloaddition between vinyl benzoxazinanones and 3-nitroindoles has been developed. This reaction provides a concise route to tetrahydro-5H-indolo[2,3-b]quinolines in excellent yield (up to 94%) and diastereoselectivity (up to >98:2), with versatile functional handles including vinyl, nitro, and free NH groups.

Supporting Information

 
  • References and Notes

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  • 19 General Procedure for the Synthesis of Cycloadducts 3/3′ To an oven-dried Schlenk flask under N2 was charged vinyl benzoxazinanone 1ag (1.20–2.00 equiv), indole 2at (1.00 equiv), Pd2(dba)3·CHCl3 (7.5 mol%) and phenanthroline (15 mol%). Anhydrous tetrahydrofuran (0.1 M) was then added, and the reaction mixture left to stir at room temperature for 1–24 h. The crude mixture was then transferred to a clean round-bottom flask using dichloromethane, and the solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (EtOAc/n-hexanes) to yield the cycloadducts 3/3′. (±)-(5aR,10bR)-10b-Nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3aa) White solid (18.9 mg, 88% yield, dr 90:10). 1H NMR (500 MHz, CDCl3): δ = 7.58 (d, J = 8.5 Hz, 2 H), 7.52–7.47 (m, 2 H), 7.29 (ddd, J = 8.4, 7.4, 1.3 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 2 H), 7.13 (tdd, J = 7.6, 1.5, 0.8 Hz, 1 H), 7.03 (td, J = 7.6, 1.1 Hz, 1 H), 6.94 (d, J = 7.5 Hz, 1 H), 6.87 (dd, J = 7.9, 1.2 Hz, 1 H), 6.81 (td, J = 7.5, 1.2 Hz, 1 H), 6.24 (dt, J = 17.0, 10.1 Hz, 1 H), 6.14 (d, J = 2.5 Hz, 1 H), 5.40 (dd, J = 10.1, 1.3 Hz, 1 H), 5.33 (d, J = 16.9 Hz, 1 H), 5.17 (d, J = 2.5 Hz, 1 H), 4.35 (d, J = 9.9 Hz, 1 H), 2.35 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3): δ = 145.3, 143.0, 141.4, 133.6, 131.8, 130.7, 130.2, 128.8, 128.6, 127.2, 126.1, 124.4, 124.2, 123.8, 122.8, 121.7, 116.8, 114.9, 101.2, 79.9, 50.3, 21.7 ppm. IR (ATR): ν = 3367, 2978, 2923, 2853, 1595, 1550, 1354, 1170, 1086, 989, 959, 812, 751, 705, 660, 576 cm–1. HRMS (ESI): m/z calcd for C24H22N3O4S [M + H]+: 448.13255; found: 448.13253. (±)-(5aR,10bR)-10b-Nitro-6-[(4-nitrophenyl)sulfonyl]-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3ab) White solid (15.7 mg, 69% yield, dr 91:9). 1H NMR (500 MHz, CDCl3): δ = 8.25 (d, J = 8.6 Hz, 2 H), 7.89 (d, J = 8.7 Hz, 2 H), 7.53–7.47 (m, 2 H), 7.37–7.28 (m, 1 H), 7.15 (app. t, J = 7.7 Hz, 1 H), 7.10 (app. t, J = 7.7 Hz, 1 H), 6.97 (d, J = 7.5 Hz, 1 H), 6.87–6.82 (m, 2 H), 6.24–6.17 (m, 2 H), 5.42 (d, J = 10.1 Hz, 1 H), 5.35 (d, J = 17.0 Hz, 1 H), 5.10 (d, J = 2.6 Hz, 1 H), 4.38 (d, J = 9.8 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 150. 9, 142.2, 142.1, 140.9, 132.1, 130.3, 128.9, 128.7, 128.4, 126.3, 125.1, 124.7, 124.31, 124.25, 123.2, 122.0, 116.7, 114.8, 100.9, 80.3, 49.8 ppm. IR (ATR): ν = 3366, 3100, 1535, 1464, 1347, 1251, 1173, 992, 855, 793, 767, 750, 679, 602, 570, 523, 458 cm–1. HRMS (ESI): m/z calcd for C23H17N4O6S [M – H]: 477.08743; found: 477.08742. (±)-(5aR,10bR)-6-(Methylsulfonyl)-10b-nitro-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3ac) White solid (14.6 mg, 65% yield, dr 80:20). 1H NMR (500 MHz, CDCl3): δ = 7.66 (d, J = 8.1 Hz, 1 H, cis), 7.59 (d, J = 7.8 Hz, 1 H, trans), 7.35–7.32 (m, 3 H, 2 H trans and 1 H cis), 7.29–7.27 (m, 1 H, cis), 7.18–7.04 (m, 4 H, 2 H trans and 2 H cis), 7.00 (d, J = 7.5 Hz, 1 H, trans), 6.95 (d, J = 7.4 Hz, 1 H, cis), 6.86–6.82 (m, 2 H, trans), 6.76–6.71 (m, 2 H, cis), 6.65 (d, J = 1.7 Hz, 1 H, cis), 6.25–6.09 (m, 3 H, 2 H trans and 1 H cis), 5.44–5.36 (m, 2 H, trans), 5.34 (d, J = 16.9 Hz, 1 H, cis), 5.19 (d, J = 10.1 Hz, 1 H, cis), 5.11 (d, J = 2.9 Hz, 1 H, trans), 4.77 (s, 1 H cis), 4.55 (d, J = 8.8 Hz, 1 H, cis), 4.49 (d, J = 9.8 Hz, 1 H, trans), 3.00 (s, 3 H, cis), 2.92 (s, 3 H, trans) ppm. 13C NMR (126 MHz, CDCl3): δ = 142.8 (trans), 142.4 (cis), 141.1 (trans), 140.4 (cis), 132.61 (cis), 132.59 (cis), 132.2 (trans), 131.0 (trans), 129.1 (cis), 128.9 (trans), 128.5 (cis), 128.4 (trans), 126.6 (trans), 126.3 (cis), 125.7 (cis) 125.0 (cis), 124.5 (trans), 124.3 (trans), 123.8 (trans), 122.9 (cis), 122.7 (trans), 121.9 (trans), 121.8 (cis), 120.4 (cis), 116.8 (trans), 116.5 (cis), 114.0 (cis), 113.7 (trans), 101.1 (trans), 99.4 (cis), 80.2 (trans), 76.5 (cis), 51.6 (cis), 49.8 (trans), 38.0 (cis), 37.0 (trans) ppm. IR (ATR): ν = 3398, 3352, 2927, 2852, 1599, 1549, 1464, 1339, 1151, 969, 748, 539, 508 cm–1. HRMS (ESI): m/z calcd for C18H18N3O4S [M + H]+: 372.10125; found: 372.10079. (±)-Methyl (5aR,10bR)-10b-nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline-9-carboxylate (3ak) White solid (20.4 mg, 85% yield, dr 86:14). 1H NMR (400 MHz, CDCl3): δ = 8.27 (d, J = 1.8 Hz, 1 H, cis), 8.14 (d, J = 1.8 Hz, 1 H, trans), 7.99–7.93 (m, 2 H, trans and cis), 7.73 (d, J = 7.9 Hz, 2 H, cis), 7.60 (d, J = 8.0 Hz, 2 H, trans), 7.52 (d, J = 8.6 Hz, 1 H, trans), 7.48 (d, J = 8.6 Hz, 1 H, cis), 7.26–7.20 (m, 4 H, 2 H trans and 2 H cis), 7.14 (app. t, J = 7.7 Hz, 1 H, trans), 7.07 (app. t, J = 5.8 Hz, 1 H, cis), 6.96–6.92 (m, 2 H, 1 H trans and 1 H cis), 6.87 (d, J = 7.8 Hz, 1 H, trans), 6.84–6.73 (m, 3 H, 1 H trans and 2 H cis), 6.67 (d, J = 1.8 Hz, 1 H, cis), 6.27 (dt, J = 16.9, 10.1 Hz, 1 H, trans), 6.19 (d, J = 2.5 Hz, 1 H, trans), 6.10 (dt, J = 17.9, 9.6 Hz, 1 H, cis), 5.49 (d, J = 10.2 Hz, 1 H, trans), 5.39 (d, J = 16.9 Hz, 1 H, trans), 5.29 (d, J = 17.0 Hz, 1 H, cis), 5.22 (d, J = 2.5 Hz, 1 H, trans), 5.15 (d, J = 10.1 Hz, 1 H, cis), 5.00 (s, 1 H, cis), 4.44 (d, J = 9.0 Hz, 1 H, cis), 4.37 (d, J = 10.0 Hz, 1 H, trans), 3.89 (s, 6 H, 3 H trans and 3 H cis), 2.37 (s, 3 H, cis), 2.36 (s, 3 H, trans) ppm. 13C NMR (101 MHz, CDCl3): δ (one C Ar trans ‘missing’ due to overlap) = 166.0 (trans), 165.8 (cis), 146.7 (trans), 146.1 (cis), 145.7 (trans), 145.6 (cis), 141.1 (trans), 140.3 (cis), 134.3 (cis), 134.1 (cis), 133.61 (trans), 133.55 (trans), 132.6 (cis), 130.4 (trans), 130.34 (trans), 130.27 (cis), 130.1 (trans), 129.2 (cis), 128.9 (trans), 128.6 (cis), 127.7 (cis), 127.2 (cis), 127.1 (trans), 126.6 (cis), 126.3 (cis), 126.2 (trans), 124.3 (trans), 123.8 (trans), 123.6 (trans), 122.9 (cis), 122.2 (cis), 122.0 (trans), 120.3 (cis), 116.9 (overlapping trans and cis), 114.0 (trans), 113.6 (cis), 100.6 (trans), 98.9 (cis), 80.7 (trans), 77.4 (cis), 52.45 (overlapping trans and cis), 52.41 (cis), 50.1 (trans), 21.77 (cis), 21.75 (trans) ppm. IR (ATR): ν = 3366, 2920, 1726, 1553, 1479, 1267, 1168, 956, 750, 658, 536 cm–1. HRMS (ESI): m/z calcd for C26H24N3O6S [M+H]+ 506.13803; found: 506.13800. (±)-(5aR,10bR)-10b-Nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline-9-carbonitrile (3al) White solid (16.7 mg, 75% yield, dr 84:16). 1H NMR (500 MHz, CDCl3): δ = 7.90 (s, 1 H, cis), 7.78 (s, 1 H, trans), 7.73 (d, J = 8.4 Hz, 2 H, cis), 7.60 (d, J = 8.4 Hz, 2 H, trans), 7.55 (d, J = 1.3 Hz, 2 H, trans), 7.52 (d, J = 1.1 Hz, 2 H, cis), 7.29 (d, J = 8.7 Hz, 2 H, cis), 7.26–7.24 (m, 2 H, trans), 7.17 (app. t, J = 7.6 Hz, 1 H, trans), 7.12–7.08 (m, 1 H, cis), 6.96 (d, J = 7.5 Hz, 1 H, trans), 6.93 (dd, J = 7.6, 1.5 Hz, 1 H, cis), 6.89–6.84 (m, 2 H, trans), 6.82–6.78 (m, 2 H, cis), 6.67 (d, J = 1.9 Hz, 1 H, cis), 6.25–6.16 (m, 2 H, trans), 6.08 (ddd, J = 16.9, 10.1, 8.9 Hz, 1 H, cis), 5.53 (dd, J = 10.1, 1.2 Hz, 1 H, trans), 5.42 (d, J = 16.9 Hz, 1 H, trans), 5.30–5.25 (m, 2 H, trans and cis), 5.16 (d, J = 10.1 Hz, 1 H, cis), 5.02 (d, J = 1.9 Hz, 1 H, cis), 4.33 (d, J = 10.3 Hz, 2 H, trans and cis), 2.40 (s, 3 H, cis), 2.39 (s, 3 H, trans) ppm. 13C NMR (126 MHz, CDCl3): δ (one C Ar cis ‘missing’ due to overlap) = 146.4 (trans), 146.1 (trans), 146.0 (cis), 145.9 (cis), 140.9 (trans), 140.1 (cis), 136.4 (cis), 135.8 (trans), 134.1 (cis), 133.4 (trans), 133.0 (trans), 132.2 (cis), 130.52 (trans), 130.46 (cis), 130.3 (cis), 129.5 (trans), 129.4 (cis), 129.1 (trans), 128.6 (cis), 127.1 (cis), 127.0 (trans), 126.1 (trans), 124.4 (trans), 124.3 (trans), 123.8 (trans), 122.50 (cis), 122.47 (cis), 122.3 (trans), 120.7 (cis), 118.2 (trans), 118.1 (cis), 117.10 (trans), 117.06 (cis), 114.8 (trans), 114.4 (cis), 107.9 (cis), 107.6 (trans), 100.3 (trans), 98.6 (cis), 80.6 (trans), 77.4 (cis), 52.6 (cis), 50.0 (trans), 21.82 (cis), 21.80 (trans) ppm. IR (ATR): ν = 3376, 2920, 2851, 2231, 1608, 1557, 1479, 1362, 1168, 1086, 954, 808, 732, 590, 548 cm–1. HRMS (ESI): m/z calcd for C25H19N4O4S [M − H] 471.11325; found: 471.11352. (±)-(5aR,10bR,11R)-9-Bromo-10b-nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3am) White solid (15.8 mg, 63% yield, dr 94:6). 1H NMR (400 MHz, CDCl3): δ = 7.59–7.56 (m, 3 H), 7.41–7.37 (m, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.16 (app. t, J = 7.6 Hz, 1 H), 6.96 (d, J = 7.5 Hz, 1 H), 6.88–6.82 (m, 2 H), 6.21 (dt, J = 16.9, 10.1 Hz, 1 H), 6.11 (d, J = 2.5 Hz, 1 H), 5.47 (d, J = 10.1 Hz, 1 H), 5.36 (d, J = 17.0 Hz, 1 H), 5.16 (d, J = 2.5 Hz, 1 H), 4.31 (d, J = 10.0 Hz, 1 H), 2.37 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 145.6, 142.2, 141.2, 134.8, 133.3, 131.5, 130.3, 130.0, 129.0, 127.1, 126.2, 125.6, 124.0, 123.5, 121.9, 116.9, 116.8, 116.2, 100.6, 80.3, 50.1, 21.8 ppm. IR (ATR): ν = 3381, 3094, 2918, 1551, 1466, 1355, 1165, 1008, 818, 747, 662, 584, 530 cm–1. HRMS (ESI): m/z calcd for C24H21BrN3O4S [M + H]+: 526.0431; found: 526.0449. (±)-(5aR, 10bR)-9-Chloro-10b-nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3an) White solid (7.9 mg, 42% yield, dr 92:8). 1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.4 Hz, 2 H), 7.44 (dd, J = 5.5, 3.2 Hz, 2 H), 7.24 (d, J = 2.2 Hz, 1 H), 7.22 (d, J = 7.9 Hz, 2 H), 7.16 (app. t, J = 7.7 Hz, 1 H), 6.96 (d, J = 7.5 Hz, 1 H), 6.88–6.82 (m, 2 H), 6.22 (dt, J = 17.0, 10.1 Hz, 1 H), 6.12 (d, J = 2.5 Hz, 1 H), 5.47 (dd, J = 10.2, 1.3 Hz, 1 H), 5.37 (d, J = 17.1 Hz, 1 H), 5.15 (s, 1 H), 4.31 (d, J = 9.8 Hz, 1 H), 2.37 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 145.6, 141.7, 141.2, 133.3, 132.0, 130.3, 130.0, 129.6, 129.0, 128.6, 127.1, 126.1, 125.2, 124.0, 123.5, 121.9, 116.9, 115.9, 100.7, 80.3, 50.1, 21.8 ppm. IR (ATR): ν = 3378, 2954, 2853, 1554, 1469, 1357, 1251, 1167, 1086, 1008, 798, 751, 661, 588, 533 cm–1. HRMS (ESI): m/z calcd for C24H21ClN3O4S [M + H]+: 482.0936; found: 482.0953. (±)-(5aR,10bR)-9-10b-Dinitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3ao) White solid (13.2 mg, 56% yield, dr 91:9). 1H NMR (400 MHz, CDCl3): δ = 8.36 (d, J = 2.3 Hz, 1 H), 8.19 (dd, J = 9.1, 2.4 Hz, 1 H), 7.62 (d, J = 8.3 Hz, 2 H), 7.57 (d, J = 9.1 Hz, 1 H), 7.29–7.25 (m, 2 H), 7.17 (app. t, J = 7.6 Hz, 1 H), 6.97 (d, J = 7.6 Hz, 1 H), 6.90–6.84 (m, 2 H), 6.31–6.22 (m, 2 H), 5.57 (d, J = 10.1 Hz, 1 H), 5.45 (d, J = 16.9 Hz, 1 H), 5.27 (d, J = 2.4 Hz, 1 H), 4.38 (d, J = 10.2 Hz, 1 H), 2.38 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 148.0, 146.3, 144.0, 140.9, 133.4, 130.6, 129.3, 129.2, 127.9, 127.0, 126.1, 125.0, 124.5, 124.3, 123.9, 122.4, 117.1, 114.0, 100.1, 81.2, 49.9, 21.8 ppm. IR (ATR): ν = 3379, 2919, 2850, 1596, 1556, 1518, 1340, 1086, 996, 955, 905, 728, 660, 580 cm–1. HRMS (ESI): m/z calcd for C24H19N4O6S [M – H]: 491.10308; found: 491.10335. (±)-(5aR,10bR)-9-Methyl-10b-nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3ap) White solid (13.9 mg, 80% yield, dr 93:7). 1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.25 (d, J = 5.6 Hz, 1 H), 7.19 (d, J = 8.1 Hz, 2 H), 7.15–7.08 (m, 2 H), 6.95 (d, J = 7.5 Hz, 1 H), 6.86 (dd, J = 7.8, 1.2 Hz, 1 H), 6.81 (td, J = 7.5, 1.2 Hz, 1 H), 6.24 (dt, J = 17.0, 10.0 Hz, 1 H), 6.11 (d, J = 2.5 Hz, 1 H), 5.40 (dd, J = 10.1, 1.4 Hz, 1 H), 5.32 (d, J = 17.0, 1 H), 5.13 (d, J = 2.6 Hz, 1 H), 4.33 (d, J = 9.8 Hz, 1 H), 2.35 (s, 3 H), 2.28 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 145.2, 141.5, 140.8, 134.1, 133.5, 132.7, 130.8, 130.1, 128.74, 128.67, 127.2, 126.2, 124.4, 123.9, 122.6, 121.6, 116.7, 114.7, 101.3, 80.0, 50.2, 21.7, 21.2 ppm. IR (ATR): ν = 3377, 2918, 2861, 1552, 1482, 1354, 1250, 1167, 1008, 810, 755, 732, 660, 579, 528 cm–1. HRMS (ESI): m/z calcd for C25H24N3O4S [M + H]+: 462.14820; found: 462.14663. (±)-(5aR,10bR)-8-Chloro-10b-nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3aq) White solid (19.2 mg, 84% yield, dr 94:6). 1H NMR (400 MHz, CDCl3): δ = 7.60 (d, J = 8.4 Hz, 2 H), 7.52 (d, J = 1.9 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 2 H), 7.16 (app. t, J = 7.7 Hz, 1 H), 7.00 (dd, J = 8.3, 1.9 Hz, 1 H), 6.94 (d, J = 7.4 Hz, 1 H), 6.87 (dd, J = 7.9, 1.1 Hz, 1 H), 6.84 (td, J = 7.5, 1.2 Hz, 1 H), 6.21 (dt, J = 16.9, 10.1 Hz, 1 H), 6.12 (d, J = 2.5 Hz, 1 H), 5.45 (dd, J = 10.2, 1.3 Hz, 1 H), 5.36 (dd. J = 16.9, 0.9 Hz, 1 H), 5.17 (d, J = 2.4 Hz, 1 H), 4.32 (d, J = 9.9 Hz, 1 H), 2.37 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 145.7, 144.1, 141.2, 138.1, 133.5, 130.4, 130.2, 129.5, 128.9, 127.1, 126.0, 124.5, 124.2, 123.4, 122.1, 121.9, 116.9, 115.0, 100.7, 80.5, 50.1, 21.8 ppm. IR (ATR): ν = 3358, 2324, 1597, 1549, 1478, 1422, 1355, 1167, 1081, 964, 934, 863, 794, 751, 665, 587 cm–1. HRMS (ESI): m/z calcd for C24H21ClN3O4S [M + H]+: 482.09358; found: 482.09333. CCDC 1960944-1960945 contains the supplementary crystallographic data for compounds 3aq and 3as. (±)-Methyl (5aR,10bR)-10b-Nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline-10-carboxylate (3ar) White solid (19.7 mg, 81% yield, dr 72:28). 1H NMR (500 MHz, CDCl3): δ = 8.03 (dd, J = 8.2, 1.1 Hz, 1 H, cis), 7.71 (dd, J = 7.8, 1.1 Hz, 1 H, cis), 7.68–7.62 (m, 5 H, 3 H trans and 2 H cis), 7.51 (app. t, J = 8.0 Hz, 1 H, cis), 7.29 (app. t, J = 8.0 Hz, 1 H, trans), 7.27–7.16 (m, 7 H, 3 H trans and 4 H cis), 7.11–7.06 (m, 2 H, trans), 6.96 (app. t, J = 7.5 Hz, 1 H, cis), 6.85 (d, J = 7.8 Hz, 1 H, cis), 6.80–6.77 (m, 2 H, trans), 6.46 (d, J = 1.8 Hz, 1 H, trans), 6.27–6.19 (m, 1 H, trans), 5.52 (dt, J = 16.9, 9.9 Hz, 1 H, cis), 5.46 (d, J = 3.1 Hz, 1 H, cis), 5.38 (d, J = 8.9 Hz, 1 H, trans), 5.19 (dd, J = 17.0, 1.4 Hz, 1 H, trans), 5.09 (dd, J = 10.0, 1.5 Hz, 1 H, trans), 4.98 (d, J = 1.9 Hz, 1 H, trans), 4.89 (d, J = 3.2 Hz, 1 H, cis), 4.85–4.82 (m, 2 H, cis), 4.66 (dd, J = 10.0, 1.5 Hz, 1 H, cis), 3.98 (s, 3 H, trans), 3.85 (s, 3 H, cis), 2.36 (s, 3 H, trans), 2.35 (s, 3 H, cis) ppm. 13C NMR (126 MHz, CDCl3): δ = 167.8 (trans), 165.8 (cis), 145.6 (cis), 145.5 (trans), 144.7 (cis), 143.7 (trans), 140.7 (trans), 139.8 (cis), 134.9 (min), 134.0 (trans), 133.8 (trans), 133.2 (cis), 132.8 (trans), 131.88 (cis), 131.85 (trans), 130.22 (trans), 130.16 (cis), 129.1 (cis), 128.8 (trans), 128.7 (trans), 128.6 (cis), 128.4 (cis), 127.9 (cis), 127.6 (min), 127.3 (trans), 127.1 (cis), 126.8 (cis), 125.8 (trans), 124.1 (trans), 123.1 (trans), 122.3 (cis), 121.9 (trans), 119.7 (trans), 119.6 (cis), 116.9 (cis), 116.7 (trans), 116.44 (trans, 116.38 (cis), 101.2 (trans), 99.6 (cis), 81.0 (cis), 77.2 (trans), 53.0 (trans), 52.6 (cis), 50.6 (trans), 47.9 (cis), 21.80 (cis), 21.76 (trans) ppm. IR (ATR): ν = 3367, 2953, 2923, 1725, 1554, 1352, 1165, 754, 659, 575, 540 cm–1. HRMS (ESI): m/z calcd for C26H24N3O6S [M + H]+: 506.13803; found: 506.13808. (±)-(5aR, 10bR, 11R)-7-Chloro-10b-nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3as) White solid (18.4 mg, 80% yield, dr >98:2); mp 216–219 °C. 1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 8.4 Hz, 2 H), 7.40 (dd, J = 7.8, 1.2 Hz, 1 H), 7.29 (dd, J = 8.0, 1.2 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 2 H), 7.10 (app. t, J = 7.8 Hz, 1 H), 7.04 (app. t, J = 7.9 Hz, 1 H), 6.85 (d, J = 7.5 Hz, 1 H), 6.80 (dd, J = 7.9, 1.1 Hz, 1 H), 6.75 (td, J = 7.5, 1.2 Hz, 1 H), 6.51 (d, J = 2.4 Hz, 1 H), 6.18 (dt, J = 16.9, 10.1 Hz, 1 H), 5.39 (dd, J = 10.2, 1.3 Hz, 1 H), 5.31 (d, J = 17.0 Hz, 1 H), 4.84 (d, J = 2.3 Hz, 1 H), 4.27 (d, J = 9.9 Hz, 1 H), 2.41 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 145.3, 141.0, 140.6, 134.5, 133.8, 130.0, 129.9, 129.7, 128.9, 127.5, 126.7, 126.5, 125.8, 124.5, 123.4, 123.3, 121.5, 116.1, 99.6, 80.9, 51.0, 21.8 ppm. IR (ATR): ν = 3414, 3381, 1728, 1485, 1363, 1172, 1089, 919, 771, 738, 683, 660, 572, 524 cm–1. HRMS (ESI): m/z calcd for C24H21ClN3O4S [M + H]+: 482.09358; found: 482.09334. CCDC 1960944 and 1960945 contain the supplementary crystallographic data for compounds 3aq and 3as. (±)-(5aR,10bR,11R)-7-Chloro-1-fluoro-10b-nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3bs) White solid (16.8 mg, 80% yield, dr 94:6). 1H NMR (500 MHz, CDCl3): δ = 7.79 (d, J = 8.1 Hz, 2 H), 7.58 (dd, J = 7.6, 1.2 Hz, 1 H), 7.33 (dd, J = 8.1, 1.1 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 2 H), 7.15–7.09 (m, 2 H), 6.95 (d, J = 3.9 Hz, 1 H), 6.61 (dd, J = 8.0 Hz, 1 H), 6.57 (app. t, J = 8.7 Hz, 1 H), 5.52 (dt, J = 17.4, 9.3 Hz, 1 H), 5.41 (d, J = 3.5 Hz, 1 H), 4.93 (d, J = 16.9 Hz, 1 H), 4.88 (d, J = 10.0 Hz, 1 H), 4.75 (d, J = 8.6 Hz, 1 H), 2.43 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 160.3 (d, J = 246.5 Hz), 144.7, 142.1 (d, J = 6.8 Hz), 139.4, 137.0, 134.2, 130.5, 129.9, 129.8, 129.2, 127.5, 126.1, 124.3, 121.8, 120.2, 111.2 (d, J = 3.1 Hz), 108.7 (d, J = 19.7 Hz), 107.5 (d, J = 21.6 Hz), 95.0, 77.3, 46.1 (d, J = 2.4 Hz), 21.8 ppm. IR (ATR): ν = 3381, 3070, 3040, 1619, 1500, 1434, 1286, 1174, 1088, 909, 782, 676, 570, 519 cm–1. HRMS (ESI): m/z calcd for C24H20ClFN3O4S [M + H]+: 500.0842; found: 500.0938. (±)-(5aR,10bR,11R)-3,7-Dichloro-10b-nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3cs) White solid (19.0 mg, 94% yield, dr >98:2); mp 198–200 °C. 1H NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 8.2 Hz, 2 H), 7.39 (d, J = 7.8 Hz, 1 H), 7.33 (dd, J = 8.0, 1.2 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 2 H), 7.06 (app. t, J = 7.9 Hz, 1 H), 6.80–6.71 (m, 3 H), 6.51 (d, J = 2.3 Hz, 1 H), 6.12 (dt, J = 16.9, 10.0 Hz, 1 H), 5.40 (dd, J = 10.2, 1.2 Hz, 1 H), 5.31 (d, J = 16.9 Hz, 1 H), 4.88 (d, J = 2.7 Hz, 1 H), 4.22 (d, J = 9.9 Hz, 1 H), 2.41 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ (one CHAr trans ‘missing’ due to overlap) = 145.4, 142.1, 140.5, 134.49, 134.46, 134.1, 130.0, 129.38, 129.35, 127.5, 127.0, 126.7, 124.6, 123.8, 121.6, 121.3, 116.0, 99.2, 80.4, 50.5, 21.8 ppm. IR (ATR): ν = 3408, 3387, 2256, 1549, 1360, 1170, 1086, 910, 814, 773, 729, 671, 576 cm–1. HRMS (ESI): m/z calcd for C24H18Cl2N3O4S [M – H]: 514.0401; found: 514.0392. (±)-(5aR,10bR)-7-Chloro-4-methyl-10b-nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3ds) White solid (12.8 mg, 59% yield, dr >98:2); mp 219–222 °C. 1H NMR (500 MHz, CDCl3): δ = 7.42 (d, J = 8.4 Hz, 2 H), 7.38 (dd, J = 7.8, 1.2 Hz, 1 H), 7.28–7.26 (m, 1 H), 7.18 (d, J = 8.0 Hz, 2 H), 7.03 (app. t, J = 7.9 Hz, 1 H), 6.98 (d, J = 7.3 Hz, 1 H), 6.70–6.64 (m, 2 H), 6.51 (d, J = 2.4 Hz, 1 H), 6.19 (dt, J = 16.9, 10.1 Hz, 1 H), 5.39 (dd, J = 10.2, 1.3 Hz, 1 H), 5.32 (d, J = 16.8 Hz, 1 H), 4.87 (d, J = 2.5 Hz, 1 H), 4.26 (d, J = 10.0 Hz, 1 H), 2.40 (s, 3 H), 2.26 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 145.3, 140.6, 139.3, 134.3, 133.7, 130.1, 130.02, 129.98, 129.7, 127.5, 126.8, 126.5, 124.5, 124.0, 123.44, 123.43, 123.3, 121.0, 99.9, 81.3, 51.1, 21.8, 16.7 ppm. IR (ATR): ν = 3397, 3352, 2926, 2852, 1598, 1551, 1464, 1339, 1150, 942, 747, 538, 508 cm–1. HRMS (ESI): m/z calcd for C25H23ClN3O4S [M + H]+: 496.10923; found: 496.10931. (±)-(5aR,10bR)-7-Chloro-3,4-dimethyl-10b-nitro-6-tosyl-11-vinyl-5a,6,10b,11-tetrahydro-5H-indolo[2,3-b]quinoline (3es) Beige solid (10.1 mg, 49% yield, dr >98:2); mp 227–228 °C. 1H NMR (400 MHz, CDCl3): δ = 7.42 (d, J = 8.4 Hz, 2 H), 7.38 (dd, J = 7.8, 1.2 Hz, 1 H), 7.27 (d, J = 8.7 Hz, 1 H), 7.17 (d, J = 8.2 Hz, 2 H), 7.02 (app. t, J = 7.9 Hz, 1 H), 6.60–6.55 (m, 2 H), 6.51 (d, J = 2.5 Hz, 1 H), 6.18 (dt, J = 16.9, 10.2 Hz, 1 H), 5.38 (dd, J = 10.2, 1.4 Hz, 1 H), 5.31 (d, J = 16.9 Hz, 1 H), 4.96 (d, J = 2.6 Hz, 1 H), 4.23 (d, J = 10.0 Hz, 1 H), 2.40 (s, 3 H), 2.21 (s, 3 H), 2.16 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 145.3, 140.5, 139.0, 137.0, 134.2, 133.7, 130.1, 130.0, 129.6, 127.5, 126.9, 126.4, 124.3, 123.2, 122.7, 122.61, 122.57, 121.3, 100.0, 81.4, 51.1, 21.8, 20.6, 12.6 ppm. IR (ATR): ν = 3418, 3367, 1725, 1553, 1364, 1170, 943, 811, 672, 577, 536 cm–1. HRMS (ESI): m/z calcd for C26H24ClN3O4S [M + H]+: 510.12488; found: 510.12469. Procedure for the Reduction of Nitro Group to Amine (4)8a To a solution of cycloadduct 3aq (28.0 mg, 0.06 mmol, 1.00 equiv) and TMSCl (0.16 mL, 1.24 mmol, 20.00 equiv) dissolved in MeOH (2 mL) was added Zinc powder (88.3 mg, 1.35 mmol, 22.00 equiv) portionwise at 0 °C. The solution was left to stir at 0 °C for 30 min, before the suspension was filtered and washed with MeOH (3×) and dichloromethane (3×). The filtrate was then washed with sat. aq. NaHCO3 and the aqueous layer extracted with dichloromethane (3×). The combined organic layers were dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via trituration with diethyl ether to give the amine 4 as a white solid in 58% yield (15.3 mg, >98:2 dr). (±)-(5aR,10bR,11R)-8-Chloro-6-tosyl-11-vinyl-5,5a,6,11-tetrahydro-10bH-indolo[2,3-b]quinolin-10b-amine (4) Mp 188–190 °C. 1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.3 Hz, 2 H), 7.38 (d, J = 1.9 Hz, 1 H), 7.26 (d, J = 8.2 Hz, 2 H), 7.11 (app. t, J = 7.6 Hz, 1 H), 7.07 (d, J = 8.1 Hz, 1 H), 6.95–6.88 (m, 2 H), 6.88–6.75 (m, 2 H), 6.09 (dt, J = 16.9, 10.0 Hz, 1 H), 5.35 (d, J = 1.8 Hz, 1 H), 5.31–5.26 (m, 2 H), 5.17 (d, J = 2.9 Hz, 1 H), 3.44 (d, J = 9.8 Hz, 1 H), 2.38 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 144.9, 142.4, 141.6, 135.0, 134.4, 133.6, 132.3, 130.1, 128.1, 127.4, 126.4, 126.2, 125.9, 123.9, 121.2, 120.9, 116.3, 114.4, 85.6, 66.1, 52.3, 21.7 ppm. IR (ATR): ν = 3550, 3372, 3304, 3080, 3032, 1596, 1478, 1347, 1164, 961, 757, 662, 578, 538 cm–1. HRMS (ESI): m/z calcd for C24H20ClN2O2S [M + H – NH3]+: 435.0929; found: 495.0934.