Synthesis of Azepino[4,5-b]indole Analogues via 7-endo-Selective Cyclization of Isocyanoacetates and Indole-1,2-alkynylaldehydes: An Approach towards the Chromoazepinone Core

Abstract

Synthesis of azepino[4,5-b]indole analogues via copper-catalyzed 7-endo-selective heteroannulation is reported. This strategy involves the Knoevenagel condensation of indole-1,2-alkynylaldehydes and isocyanoacetates, followed by copper-catalyzed 7-endo-selective annulation gives the product. This approach is applied towards the synthesis of the chromoazepinone core.

Key words

azepino[4,5-b]indole - 7-endo cyclization - copper catalysis - indole-1,2-alkynylaldehyde - isocyanoacetate - chromoazepinone

• References and Notes

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• 12 General Procedure for the Synthesis of Azepino[4,5-b]indole Derivatives 3a–h and 7 An oven-dried 10 mL round-bottomed flask equipped with a Teflon-coated magnetic stirring bar was charged with 1-methyl-3-(phenylethynyl)-1H-indole-2-carbaldehyde (1a, 0.05 g, 0.19 mmol) in MeCN (2 mL). Methyl isocyanoacetate (2a, 0.021 g, 0.21 mmol), Cu(OTf)₂ (7 mg, 5 mol%), and DBU (0.43 g, 0.29 mmol) were added, and the mixture was stirred at 90 °C for 6 h. After completion of reaction (TLC), the mixture was cooled to r.t., and the solvent was evaporated under reduced pressure. Water was added, and the crude reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel (20% EtOAc in hexanes) to afford the product 3a (0.05 g) in 72% yield. R_f = 0.32 (hexanes–EtOAc, 1:1); mp 160–162 °C. IR (KBr): 3151, 2936, 2874, 1692, 1648, 1578, 1457 cm^–1. ¹H NMR (500 MHz, TMS, CDCl₃): δ = 8.13–8.10 (m, 2 H), 8.08 (s, 1 H), 8.05–7.98 (m, 1 H), 7.86 (s, 1 H), 7.84–7.82 (m, 2 H), 7.68 (s, 1 H), 7.48–7.30 (m, 6 H), 3.95 (s, 3 H), 3.87 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 163.9, 162.8, 138.4, 137.0, 134.2, 132.3, 129.0, 128.7, 128.4, 126.5, 126.0, 125.5, 123.0, 121.0, 119.5, 118.3, 117.3, 116.8, 109.9, 52.6, 30.4. HRMS (ESI-MS): m/z calcd for C₂₂H₁₈O₃N₂: 359.1396 [M + H]; found: 359.1395.