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

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

• 1a Pindur U. Heterocycles  1988,  27:  1253 
• 1b Abbiati G. Canevari V. Facoetti D. Rossi E. Eur. J. Org. Chem.  2007,  517 
• 1c Chen CB. Wang XF. Cao YJ. Cheng H. Xiao WJ. J. Org. Chem.  2009,  74:  3532 
• 1d Jones SB. Simmons B. MacMillan DWC. J. Am. Chem. Soc.  2009,  131:  13606 
• 1e Wang XF. Chen JR. Cao YJ. Cheng HG. Xiao WJ. Org. Lett.  2010,  12:  1140 
• 2a Gioia C. Hauville A. Bernardi L. Fini F. Ricci A. Angew. Chem. Int. Ed.  2008,  47:  9236 
• 2b Gioia C. Bernardi L. Ricci A. Synthesis  2009,  161 
• 2c Bergonzini G. Gramigna L. Mazzati A. Fochi M. Bernardi L. Ricci A. Chem. Commun.  2010,  327 
• 2d Zheng C. Lu Y. Zhang J. Chen X. Chai Z. Ma W. Zhao G. Chem. Eur. J.  2010,  16:  5853 
• 3a McNulty J. Das P. Eur. J. Org. Chem.  2009,  4031 
• 3b McNulty J. Das P. McLeod D. Chem. Eur. J.  2010,  16:  6756 
• 3c Related (E)-3-(2′-arylethenyl)-1(H)-indole analogues have recently been discovered that arrest mitosis at the metaphase-anaphase transition. See: Tcherniuk S. Skoufias DA. Labriere C. Rath O. Gueritte F. Guillou C. Kozielski F. Angew. Chem. Int. Ed.  2010,  49:  8228 
• 3d The first reported synthesis of (E)-3-(2′-arylethenyl)-1(H)-indole derivatives employed an alternative Wittig-type procedure. See: De Silva SO. Snieckus V. Can. J. Chem.  1974,  52:  1294 
• 4 Noland WE. Xia GM. Gee KR. Konkel MJ. Wahlstrom MJ. Condoluci JJ. Rieger DL. Tetrahedron  1996,  52:  4555 
• 5a Ziegler F. Spitzner EB. Wilkins CK. J. Org. Chem.  1971,  36:  1759 
• 5b Harrison CA. Leinweber R. Moody CJ. Williams JMJ. J. Chem. Soc., Perkin Trans. 1  1995,  1127 
• 5c Cheng KF. Kong YC. Chan TY. J. Chem. Soc., Chem. Commun.  1985,  48 
• 6a Steyn PS. Vleggaar R. Fortschr. Chem. Org. Naturst.  1985,  48:  1 
• 6b Sings H. Singh S. In The Alkaloids   Vol. 60:  Cordell GA. Academic Press; San Diego: 2003.  p.51-163  
• 6c Smith AB. Mewshaw R. J. Am. Chem. Soc.  1985,  107:  1769 
• 7 Chan WL. Ho DD. Lau CP. Wat KH. Kong YC. Cheng KF. Wong TT. Chan TY. Eur. J. Med. Chem.  1991,  26:  387 
• 8 Achenbach H. Biemann K. J. Am. Chem. Soc.  1965,  87:  4944 
• 9 Smith AB. Davulcu AH. Cho YS. Ohmoto K. Kurti L. Ishiyama H. J. Org. Chem.  2007,  72:  4596 
• 10 Roll DM. Barbieri LR. Bigelis R. McDonald LA. Arias DA. Chang LP. Singh MP. Luckman SW. Berrodin TJ. Yudt MR. J. Nat. Prod.  2009,  72:  1944 
• 11 Oishi S. Watanabe T. Sawada J. Asai A. Ohno H. Fujii N. J. Med. Chem.  2010,  53:  5054 
• 12 Pearson WH. Pure Appl. Chem.  2002,  74:  1339 
• 13a Voituriez A. Panossian A. Fleury-Bregeot N. Retailleau P. Marinetti A. J. Am. Chem. Soc.  2008,  130:  14030 
• 13b Trost BM. Seoane P. Mignani S. Acemoglu M. J. Am. Chem. Soc.  1989,  111:  7487 
• 13c Trost BM. Angew. Chem. Int. Ed.  1986,  25:  1 
• 13d Kauffmann T. Angew. Chem. Int. Ed.  1974,  13:  627 

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.