Synthesis of New Pyrrolobenzazepines via Pictet-Spengler Cyclization

Abstract

A new six-step divergent strategy was developed allowing access to pyrrolobenzazepine structures from pyrrole. This strategy was based on a regioselective Friedel-Crafts acylation followed by a Pictet-Spengler cyclization.

Key words

azepine - pyrrole - fused-ring systems - Pictet-Spengler reaction

References and Notes

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18

The X-ray crystal structure has been filed with the Cambridge Crystallographic Centre with deposition number CCDC 640594.

19

General Procedure for Preparation of Compounds 10-13 To a stirred 1 M solution of amine 6, 7, 8, or 9 in anhyd toluene was added the para-substituted benzaldehyde derivative (1.1 equiv), under argon atmosphere (in the case of amines 8 and 9, 4 equiv of MgSO₄ were added). The mixture was heated at reflux until total conversion of the amine into the intermediary imine (followed by ^¹H NMR). Then, the mixture was cooled to r.t. to add TFA (5 or 10 equiv). The resulting mixture was left at specified temperature (r.t. or 70 ˚C) until completion of the reaction. Residual TFA was neutralized at 0 ˚C with an aq sat. NaHCO₃ solution. The reaction mixture was extracted with CH₂Cl₂. The combined organic layers were successively washed with H₂O and brine, dried over MgSO₄, filtered, and solvents removed under reduced pressure. The crude product was purified by flash chromatography.
Analytical Data of Compound 11a Pale yellow solid obtained in 98% yield after flash chromatography (cyclohexane-EtOAc, 9:1). ^¹H NMR (300 MHz, CDCl₃): δ = 2.33 (s, 3 H), 3.63 (d, J = 16.2 Hz, 1 H), 3.73 (br s, 1 H), 4.14 (d, 16.2 Hz, 1 H), 6.06 (m, 1 H), 6.08 (dd, J = 1.3, 7.3 Hz, 1 H), 6.28 (d, J = 3.4 Hz, 1 H), 6.73 (d, J = 8.3 Hz, 2 H), 6.85 (m, 2 H), 6.97 (d, J = 8.3 Hz, 2 H), 7.04 (d, J = 8.3 Hz, 2 H), 7.11 (dd, J = 1.3, 7.1 Hz, 1 H), 7.15 (d, J = 8.3 Hz, 2 H), 7.30 (d, J = 3.4 Hz, 1 H). HRMS: m/z = 439.5326.

24

General Procedure for Preparation of Compounds 14-17 A mixture of the azepine 10a-e, 11a-e, 12a-e, or 13a-e (1 equiv) and TBAF 1 M solution in THF (10 equiv) was heated at 70 ˚C for 10 h. The mixture was washed with H₂O. The aqueous phase was extracted with CH₂Cl₂. The combined organic layers were dried over MgSO₄, filtered, and solvents removed under reduced pressure. The crude product was purified by flash chromatography.
Analytical Data of Compound 15a Yellow solid obtained in 88% yield after flash chromatography (heptane-EtOAc, 8:2). ^¹H NMR (300 MHz, CDCl₃): δ = 3.75 (s, 2 H), 6.21 (t, J = 2.6 Hz, 1 H), 6.93 (t, J = 2.6 Hz, 1 H), 7.2 (dd, J = 1.7, 6.6 Hz, 1 H), 7.22 (td, J = 1.7, 6.6 Hz, 1 H), 7.29 (td, J = 1.7, 6.6 Hz, 1 H), 7.48 (dd, J = 1.7, 7.2 Hz, 1 H), 7.76 (d, J = 8.3 Hz, 2 H), 8.0 (d, J = 8.3 Hz, 2 H), 8.24 (br s, 1 H). ^¹³C NMR (300 MHz, CDCl₃): δ = 32.6, 108.7, 114.1, 118.9, 123.3, 123.5, 126.9, 127.8, 128.2, 128.7, 130.5, 132.0, 132.8, 133.4, 144.2, 147.0, 155.0. HRMS: m/z = 437.5148.