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Synlett 2011(5): 717-721  
DOI: 10.1055/s-0030-1259688
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Discovery of an Acid-Promoted [3+2] Cyclodimerization of 3-Vinylindoles and the Development of a General Lewis Acid Catalyzed Process

James McNulty*, David McLeod
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4M1, Canada
Fax: +1(905)5222509; e-Mail: jmcnult@mcmaster.ca;
Further Information

Publication History

Received 16 December 2010
Publication Date:
25 February 2011 (online)

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Abstract

A novel proton-catalyzed [3+2]-type cyclodimerization of 3-vinylindoles is reported leading to fused cyclopenta[b]indoles, contrasting to the normal [4+2]-cycloaddition pathway. The development of a general, high yielding version of the reaction catalyzed by zinc bromide in toluene is described.

Key words

cycloaddition - Lewis acid - fused indoles - alkenes

    References and Notes

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14

Typical Procedure for the Lewis Acid Promoted [3+2] Cycloaddition: Into a flame-dried flask containing a magnetic stirring bar was weighed 3-vinyl-2′-(4-methoxy-phenyl)-1H-indole (1c; 60 mg, 0.24 mmol). Anhyd toluene (0.5 mL) was added followed by zinc bromide (6.0 mg, 0.020 mmol). The flask was sealed and placed in an oil bath at 80 ˚C and the reaction mixture was allowed to stir for 24 h after which time the starting material was shown to be consumed by TLC. After removal of toluene, the resulting mixture was chromatographed on silica (20% EtOAc-hexane) to afford 3c (53.4 mg, 89%). Spectral data are provided below for Table  [¹] . All cycloadducts were isolated as glassy solids and, with the exception of 3a, resisted crystallization attempts. Crystals of 3a suitable for X-ray diffraction were deposited on slow evaporation of an EtOAc solution. Crystallographic data were deposited at the Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk) as CCDC 796791.
1-Benzyl-1,2,3,4-tetrahydro-3-(1 H -indol-3-yl)-2-phenylcyclopenta[ b ]indole (3a): yield: 85%; mp 251-253 ˚C (dec.; EtOAc). ¹H NMR (600 MHz, CDCl3): δ = 3.03 (1 H, dd, J = 7.8, 13.8 Hz), 3.28 (1 H, dd, J = 5.4, 13.8 Hz), 3.73 (1 H, m), 3.94 (1 H, m), 4.64 (1 H, d, J = 7.2 Hz), 6.80 (2 H, m), 6.87 (1 H, t, J = 7.2 Hz), 6.92 (1 H, d, J = 7.8 Hz), 6.97 (1 H, t, J = 7.2 Hz), 7.08 (1 H, t, J = 7.8 Hz), 7.14 (1 H, t, J = 7.8 Hz), 7.20 (9 H, m), 7.24 (2 H, m) 7.34 (1 H, d, J = 8.4 Hz), 7.79 (1 H, br s, NH), 7.99 (1 H, br s, NH). ¹³C NMR (150 MHz, CDCl3): δ = 41.4, 46.6, 49.4, 65.0, 107.1, 107.2, 111.2, 111.7, 117.1, 119.6, 119.7, 119.8, 121.0, 122.0, 122.2, 124.9, 128.2, 128.4, 128.5, 130.0, 136.9, 140.5, 141.0, 143.8, 144.6. HRMS (CI): m/z [M]+ calcd for C32H26N2: 438.2096; found: 438.2081.
1-(2-Fluorobenzyl)-2-(2-fluorophenyl)-1,2,3,4-tetrahydro-3-(1 H -indol-3-yl)cyclopenta[ b ]indole (3b): yield: 82%. ¹H NMR (600 MHz, CDCl3): δ = 3.09 (1 H, dd, J = 7.3, 13.8 Hz, CH2), 3.40 (1 H, dd, J = 6.7, 13.8 Hz, CH2), 3.93 (1 H, m), 4.08 (1 H, m), 4.76 (1 H, d, J = 7.4 Hz), 7.05 (15 H, m), 7.25 (1 H, d, J HH = 8.5 Hz), 7.35 (1 H, d, J = 8.2 Hz), 7.80 (1 H, s, NH), 7.96 (1 H, s, NH). ¹³C NMR (150 MHz, CDCl3): δ = 35.0, 44.9, 46.9, 59.7, 111.3, 111.8, 115.2 (J CF = 23 Hz), 115.6 (J CF = 23 Hz), 116.9, 119.3, 119.5, 119.7, 121.0, 121.1, 121.9, 122.3, 123.9, 124.0, 124.8, 126.5, 127.4 (J CF = 16 Hz), 127.9 (J CF = 8 Hz), 128.0 (J CF = 8 Hz), 130.4 (J CF = 4 Hz), 130.9 (J CF = 14 Hz), 131.9 (J CF = 4 Hz), 136.8, 140.9, 143.7, 161.1 (J CF = 245 Hz), 161.6
(J CF = 245 Hz). HRMS (CI): m/z [M]+ calcd for C32H24N2F2: 474.1908; found: 474.1888.
1-(4-Methoxybenzyl)-1,2,3,4-tetrahydro-3-(1 H -indol-3-yl)-2-(4-methoxyphenyl)cyclopenta[ b ]indole (3c): yield: 89%. ¹H NMR (600 MHz, CDCl3): δ = 2.97 (1 H, dd, J = 7.8, 13.8 Hz), 3.29 (1 H, dd, J = 4.8, 13.8 Hz), 3.72 (1 H, t, J = 7.2 Hz), 3.79 (3 H, s), 3.80 (3 H, s), 3.90 (1 H, m), 4.61 (1 H, d, J = 7.2 Hz), 6.75 (3 H, m), 6.83 (4 H, m), 6.96 (1 H, d, J = 7.8 Hz), 7.03 (1 H, t, J = 7.1 Hz), 7.11 (6 H, m), 7.22 (1 H, d, J = 7.8 Hz), 7.31 (1 H, d, J = 8.4 Hz), 7.72 (1 H, s, NH), 7.87 (1 H, s, NH). ¹³C NMR (150 MHz, CDCl3): δ = 39.9, 46.7, 49.4, 55.4, 55.5, 63.7, 111.2, 111.7, 113.8, 113.9, 117.0, 119.5, 119.6, 119.7, 119.9, 120.9, 122.0, 122.2, 125.0, 126.4, 129.2, 130.9, 132.6, 136.6, 136.9, 141.0, 143.8, 158.2, 158.3. HRMS (CI): m/z [M]+ calcd for C34H30N2O2: 498.2307; found: 498.2297.
1-(4-Bromobenzyl)-2-(4-bromophenyl)-1,2,3,4-tetrahydro-3-(1 H -indol-3-yl)cyclopenta[ b ]indole (3d): yield: 91%. ¹H NMR (600 MHz, CDCl3): δ = 3.01 (1 H, dd, J = 6.6, 13.8 Hz), 3.23 (1 H, dd, J = 5.4, 13.8 Hz), 3.65 (1 H, t, J HH = 7.2 Hz), 3.88 (1 H, m), 4.54 (1 H, d, J HH = 7.2 Hz), 6.71 (1 H, d, J HH = 2.4 Hz), 6.78 (1 H, d, J HH = 7.8 Hz), 6.90 (1 H, t, J HH = 7.5 Hz), 7.01 (4 H, m), 7.15 (4 H, m), 7.21 (1 H, d, J HH = 7.8 Hz), 7.29 (2 H, d, J HH = 8.4 Hz), 7.32 (1 H, d, J HH = 8.4 Hz), 7.39 (2 H, d, J HH = 8.4 Hz), 7.69 (1 H, br s, NH), 7.90 (1 H, br s, NH). ¹³C NMR (150 MHz, CDCl3):
δ = 29.9, 46.7, 48.9, 63.7, 111.3, 111.9, 116.4, 119.2, 119.6, 119.8, 120.1, 120.2, 120.4, 121.3, 122.1, 122.4, 129.9, 131.4, 131.7, 131.8, 136.9, 138.8, 141.1, 143.3, 143.6. HRMS (CI): m/z [M]+ calcd for C32H24N2Br2: 594.0306; found: 594.0317.
1,2,3,4-Tetrahydro-3-(1 H -indol-3-yl)-2-(thiophen-2-yl)-1-[(thiophen-2-yl)methyl]cyclopenta[ b ]indole (3e): yield: 77%. ¹H NMR (600 MHz, CDCl3): δ = 3.35 (1 H, dd, J = 6.6, 15.0 Hz), 3.59 (1 H, dd, J = 4.2, 14.4 Hz), 3.94 (1 H, ddd, J HH = 1.9, 4.6, 8.7 Hz), 4.10 (1 H, t, J HH = 8.0 Hz), 4.69 (1 H, d, J HH = 8.4 Hz), 6.78 (1 H, d, J HH = 3.6 Hz), 6.84 (1 H, d, J HH = 3.0 Hz), 6.86 (2 H, m), 6.92 (2 H, m), 6.95 (1 H, d, J HH = 2.4 Hz), 7.07 (1 H, m), 7.12 (4 H, m), 7.19 (1 H, d, J HH = 4.2 Hz), 7.24 (1 H, m), 7.34 (1 H, d, J HH = 8.4 Hz), 7.84 (1 H, s, NH), 8.05 (1 H, s, NH). ¹³C NMR (150 MHz, CDCl3): δ = 33.9, 47.1, 50.3, 58.7, 111.3, 111.8, 115.8, 119.4, 119.6, 119.8, 119.9, 120.0, 121.2, 122.3, 122.6, 123.7, 124.0, 124.8, 125.0, 126.3, 126.6, 127.0, 136.9, 140.7, 142.1, 143.6, 146.9. HRMS (CI): m/z [M]+ calcd for C28H22N2S2: 450.1224; found: 450.1214.