An Example of Regioselective Fischer Indole Annulation

Abstract

Bicyclo[n.4.0]alkan-3-ones (n = 3, 4, 5) with a trans bridge-head configuration give linear annulated tetrahydro­carbazole derivatives in Fischer indole synthesis. The structure of two tetrahydro­carbazoles was confirmed by X-ray crystal analysis. The hexa­hydroindanone derivative with a cis bridge-head configuration gives, contrastingly, the angular annulation product under the same reaction conditions.

carbazole derivatives - indole derivatives - heterocycles - regioselectivity - annulation

References and Notes

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11

Ethyl 6,6a,7,8,9,10-Hexahydro-5 H -cyclopenta[ b ]carb-azole-9a-carboxylate ( 2a); Typical Procedure A mixture of ketone 1a (191 mg, 0.908 mmol), glacial AcOH (2.3 mL), TFA (0.80 mL), and PhNHNH₂ (260 mg, 2.40 mmol) was stirred for 16 h at 100 °C in a tightly closed reaction vial. The mixture was added to ice-H₂O (ca. 20 g) and the resulting emulsion was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried (MgSO₄) and the solvent was evaporated. The residue was chromatographed twice (SiO₂; hexanes-EtOAc, 5:1, R _f 0.36) to furnish carbazole derivative 2a (210 mg, 0.881 mmol, 97%) as light yellow crystals, mp 175-177 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.07 (t, J = 7.1 Hz, 3 H), 1.68-1.74 (m, 1 H), 1.83-1.90 (m, 2 H), 1.93-2.00 (m, 2 H), 2.17-2.23 (m, 2 H), 2.51 (dt, J = 15.1, 2.0 Hz, 1 H), 2.85 (ddd, J = 15.7, 5.7, 1.2 Hz, 1 H), 3.09 (br t, J = 13.7 Hz, 1 H), 3.59 (d, J = 15.0 Hz, 1 H), 3.88-3.93 (m, 1 H), 3.95-4.03 (m, 1 H), 7.06 (td, J = 7.4, 1.1 Hz, 1 H), 7.10 (td, J = 7.4, 1.2 Hz, 1 H), 7.25 (dd, J = 6.0, 1.1 Hz, 1 H), 7.46 (br d, J = 7.5 Hz, 1 H), 7.70 (br s, 1 H, NH). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 175.59 (C), 136.40 (C), 134.88 (C), 127.50 (C), 120.95 (CH), 118.99 (CH), 117.72 (CH), 110.37 (CH), 110.02 (C), 59.84 (CH₂), 53.72 (C), 46.11 (CH), 36.73 (CH₂), 31.90 (CH₂), 28.01 (CH₂), 26.06 (CH₂), 22.59 (CH₂), 14.02 (CH₃). MS (EI, 70 eV), m/z (%) = 283 (100) [M⁺]. Anal. calcd for C₁₈H₂₁NO₂ (283.37): C, 76.30; H, 7.47; N, 4.94. Found: C, 76.09; H, 7.53; N, 4.83.

12

CCDC-286970 (2c) and CCDC-286971 (2a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; E-mail: [e-mail]].

13

Ethyl 2,3,4,5,6,10c-Hexahydro-1 H -cyclopenta[ c ]carb-azole-3a-carboxylate ( 4) Yellow oil; R _f 0.30 (SiO₂; hexanes-EtOAc, 5:1). ¹H NMR (500 MHz, CDCl₃): δ = 7.67 (br s, 1 H, NH), 7.50 (br d, J = 7.5 Hz, 1 H), 7.26 (br d, J = 7.5 Hz, 1 H), 7.10 (td, J = 7.1, 1.1 Hz, 1 H), 7.07 (td, J = 7.2, 1.1 Hz, 1 H), 4.11-4.19 (m, 1 H), 4.04-4.11 (m, 1 H), 3.76 (t, J = 8.3 Hz, 1 H), 2.78-2.88 (m, 1 H), 2.67 (dt, J = 16.4, 4.9 Hz, 1 H), 2.39-2.46 (m, 1 H), 2.29 (dt, J = 13.2, 4.8 Hz, 1 H), 2.17 (ddd, J = 12.6, 8.8, 6.0 Hz, 1 H), 1.86-1.96 (m, 1 H), 1.77-1.86 (m, 2 H), 1.61-1.77 (m, 2 H), 1.22 (t, J = 7.1 Hz, 3 H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 177.66 (C), 136.02 (C), 132.69 (C), 127.47 (C), 120.91 (CH), 118.92 (CH), 118.22 (CH), 112.16 (C), 110.53 (CH), 60.52 (CH₂), 52.26 (C), 40.17 (CH), 36.86 (CH₂), 33.04 (CH₂), 29.45 (CH₂), 24.82 (CH₂), 20.75 (CH₂), 14.15 (CH₃). HRMS (EI, 70 eV): m/z calcd for C₁₈H₂₁NO₂ [M⁺], 283.1572; found: 283.1574

14 Preparation of 3a by hydrogenation: Dauben WG. McFarland JW. Rogan JB. J. Org. Chem.  1961,  26:  297 

Preparation of 1b by hydrogenation:

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15b de la Puente ML. Ley SV. Simmonds MSJ. Blaney WM. J. Chem. Soc., Perkin Trans. 1  1996,  1523 

16 Preparation of 1a-c by radical cyclization: Clive DLJ. Postema MHD. J. Chem. Soc., Chem. Commun.  1993,  429