Synthesis of Azepino[4,5-b]indolones by an Intramolecular Cyclization of ­Unsaturated Tryptamides

Dedicated to Prof. H. Ila, an outstanding organic chemist from India, on the occasion of her 70th birthday

Abstract

A facile general route for the synthesis of azepino[4,5-b]indolones is presented. The strategy involves a Brønsted acid assisted intramolecular cyclization of unsaturated tryptamides. The methodology developed has been applied to the synthesis of the ABCD tetracyclic core of the natural product tronocarpine.

Key words

alkaloids - azepino[4,5-b]indolone - tronocarpine - tryptamide - ethyl lactate

• References and Notes

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• 16 Representative Procedure for the Preparation of Azepino[4,5-b]indolones: To a solution of hydroxy tryptamide 11b (33 mg, 0.10 mmol) in anhyd benzene (1 mL) under nitrogen atmosphere was added (+)-CSA (46 mg, 0.2 mmol). The resulting mixture was heated to 80 °C and was stirred at that temperature for 2 h. After completion of reaction (as indicated by TLC), the reaction mixture was cooled to r.t. and quenched by the addition of sat. NaHCO₃ solution to a pH value of ca. 9 and was then extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhyd Na₂SO₄. The crude residue obtained after filtration and evaporation of the solvent was purified by silica gel column chromatography using petroleum ether–EtOAc (4:1) as eluent to afford azepino[4,5-b]indolone 12b (22 mg, 71%) as a pale yellow solid. Recrystallization of 12b from petroleum ether–EtOH solvent system (9:1) gave crystals suitable for X-ray diffraction analysis; mp 168–170 °C; [α]_D ²⁴ –26.3 (c, 0.35, CHCl₃), corresponding to 20% ee as determined by chiral HPLC analysis [CHIRACEL OD-H, isopropanol–hexane (5:95), flow rate = 1.0 mL/min, t _R (major) = 12.11 min, t _R (minor) = 28.76 min]. IR (KBr): 3387, 2919, 1625, 1464, 1233 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.95 (br s, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.19 (t, J = 7.2 Hz, 1 H), 7.11 (t, J = 7.2 Hz, 1 H), 5.87 (ddt, J = 17.2, 9.2, 5.6 Hz, 1 H), 5.72 (dd, J = 15.6, 1.6 Hz, 1 H), 5.27 (dq, J = 15.6, 6.4 Hz, 1 H), 5.21 (dd, J = 16.0, 1.2 Hz, 1 H), 5.19 (d, J = 9.2 Hz, 1 H), 4.28 (dd, J = 15.2, 5.6 Hz, 1 H), 4.02–4.15 (m, 2 H), 3.41 (dt, J = 15.2, 4.0 Hz, 1 H), 2.88–3.05 (m, 2 H), 2.57 (sext, J = 7.2 Hz, 1 H), 1.92 (sext, J = 7.2 Hz, 1 H), 1.67 (d, J = 6.4 Hz, 3 H), 0.97 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.7, 135.1, 134.8, 133.7, 131.8, 128.3, 125.6, 121.9, 119.2, 117.9, 116.9, 112.6, 110.5, 55.4, 52.0, 45.8, 31.9, 24.7, 17.6, 10.7. HRMS: m/z [M + Na] calcd for C₂₀H₂₄N₂O: 331.1786; found: 331.1786.
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• 18 For an ORTEP diagram of 12b, see the Supporting Information. The crystal structure data have been deposited with the Cambridge Crystallographic Data Centre (CCDC No. 1000488). The data can be accessed free of charge from CCDC at: www.ccdc.cam.ac.uk/data_request/cif.
• 19 The experimental procedures for the preparation of compounds 11c–m are described in the Supporting Information.
• 20 The structure of E-isomer was elucidated by single crystal X-ray diffraction analysis. For an ORTEP diagram, see the Supporting Information. The crystal structure data have been deposited with the Cambridge Crystallographic Data Centre (CCDC No. 980704).
• 21 The crystal structure data have been deposited with the Cambridge Crystallographic Data Centre (CCDC No. 995842).
• 22 For an ORTEP diagram of 18, see the Supporting Information. The crystal structure data have been deposited with the Cambridge Crystallographic Data Centre (CCDC No. 980703).

For approaches towards the pentacyclic and tetracyclic cores of tronocarpine, see:
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• 23c Also see ref. 13a.
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