Catalytic Enantioselective Synthesis of 4-Amino-5-aryltetrahydro-1H-benzo[c]azepines by an Aminoarylation Reaction

Abstract

A one-pot asymmetric aminoarylation reaction has been executed for the synthesis of trans-4-amino-5-aryltetrahydrobenzo[c]azepines with excellent diastereo- and enantioselectivity (dr > 99: 1; ee ≤97%). The reaction progresses through aziridination of prochiral N-tosyl-N-cinnamylbenzylamines, followed by an intramolecular 7-endo-tet Friedel–Crafts cyclization of the tethered aziridines generated in situ, where the combination of Cu(OTf)₂ as a catalyst and PhINNs as a nitrene source was found to be effective. A chiral indenyl bis(oxazoline) was shown to be an efficient ligand for the catalytic enantioselective version of this one-pot transformation. This 7-endo-tet cyclization is contrary to the Baldwin cyclization rules.

Key words

tetrahydrobenzazepines - asymmetric catalysis - aminoarylation - aziridines - Friedel–Crafts reaction - endo-tet cyclization

Publication History

Received: 26 May 2022

Accepted after revision: 28 July 2022

Accepted Manuscript online:
28 July 2022

Article published online:
23 September 2022

• References and Notes

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• 13 4-Amino-5-aryltetrahydro-2-benzazepines 3b–j; General Procedure A two-necked, 25 mL, round-bottomed flask was charged with the Box ligand (1R,2S)-L6 (0.011 g, 0.03 mmol, 0.12 equiv) and Cu(OTf)₂ (0.009 g, 0.025 mmol, 0.1 equiv). Anhyd CH₂Cl₂ (1.2 mL) was added by syringe, and the resulting mixture was stirred for 30 min at rt. To this solution were added substrate 1 (0.467 g, 1.23 mmol, 5.0 equiv) in CH₂Cl₂ (1.2 mL), PhINNs (0.1 g, 0.24 mmol, 1.0 equiv), and powered 4Å MS (0.2 g) and the mixture stirred at rt under argon. As soon as all the nitrenoid reagents were dissolved, additional Cu(OTf)₂ (0.007 g, 0.01 mmol, 0.1 equiv) was added to the reaction medium, which was then stirred at 35 °C under argon. The reaction, which was completed within 1 h, was quenched by dilution with EtOAc (10 mL). The mixture was then filtered through a short plug of silica gel that was washed with additional EtOAc (10 mL). The filtrate was concentrated by rotary evaporation under reduced pressure to give a crude mass that was purified by flash column chromatography (silica gel, EtOAc–hexane). N-{(4S,5R)-5-Phenyl-2-tosyl-2,3,4,5-tetrahydro-1H-2-benzazepin-4-yl}-4-nitrobenzenesulfonamide (3b) White solid; yield: 91% (96% ee); mp 164–166 °C; [α]_D ²⁸ −137 (c 0.30, CH₂Cl₂). HPLC [Daicel Chiralpak IA-3, hexane–EtOAc (60:40), 1.0 mL/min, λ = 254 nm]: t _major = 6.1 min, t _minor = 7.2 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.12 (d, J = 9.2 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 2 H), 7.52 (d, J = 8.8 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.27–7.25 (m, 3 H), 7.19–7.17 (m, 3 H), 7.10 (d, J = 6.8 Hz, 4 H), 5.03 (d, J = 9.2 Hz, 1 H), 4.99–4.96 (m, 1 H), 4.34 (d, J = 9.2 Hz, 1 H), 3.86 (d, J = 10.8 Hz, 1 H), 3.24 (dd, J = 10.0, 2.0 Hz, 1 H), 3.18–3.14 (m, 1 H), 2.49 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 150.0, 144.6, 143.8, 140.5, 139.5, 132.9, 129.9, 128.9, 128.6, 128.5, 128.4, 128.3, 128.2, 127.7, 127.4, 127.1, 124.2, 62.9, 62.2, 53.8, 49.4, 21.6. DEPT-135 NMR (100 MHz, CDCl₃): δ = 130.4, 129.4, 129.2, 129.1, 129.0, 128.7, 128.6, 128.1, 127.9, 127.5, 124.6, 63.3, 62.7, 54.2, 49.9, 22.0. ESI-MS: m/z [M + Na]⁺ calcd for C₂₉H₂₇N₃NaO₆S₂: 600.1239; found: 600.1238.