Synthesis of Substituted 4-Amino-2-benzazepin-3-ones via N-Acyliminium Ion Cyclizations

Abstract

Two versatile syntheses of 1- and 1,2-disubstituted 2-benzazepinones are presented, using N-acyliminium ions as reactive intermediates. The methodology for 1-substitution is based on the synthesis of benzotriazole adducts, which are cyclized upon ­addition of AlCl₃. The simultaneous introduction of 1- and 2-sub­stitions is realized by an N-acylation of an imine.

Key words

4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one template - N-acyliminium ions - Friedel-Crafts alkylation - benzotriazole adducts

References

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  The amides 9 were obtained by converting the phthaloyl-protected amino acid into the acid chloride by treatment with α,α-dichloromethyl methyl ether [2a] followed by the addition of aq NH₃.

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13

General Procedure for the Preparation of Compounds 5 (Entries 1-3).
N-Phthaloyl-(S)-phenylalanine amide 9a (0.5 g, 1.7 mmol), benzotriazole (1 equiv, 0.202 g, 1.7 mmol) and p-TsOH (0.1 equiv, 32 mg, 0.17 mmol) were added to an oven-dried 100-mL flask, and dissolved in dry benzene (15 mL). After addition of the aldehyde (1 equiv, 1.7 mmol) the flask was heated by means of an oil bath (105 °C) and the solution was refluxed over night. After evaporation of the solvent, trituration with Et₂O gave compound 5 (entries 1-3) in quantitative yields.

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General Procedure for the Preparation of Compounds 8 (Entries 1-5).
Benzotriazole adducts 5 (100 mg) were dissolved in dry CH₂Cl₂ (10 mL). Then, 10 equiv of AlCl₃ were added and these mixtures were refluxed over a period varying between 3 h and 5 h. The reaction mixtures were cooled down to r.t. after which H₂O (10 mL) was added. The organic phase was isolated and washed with brine (10 mL). After drying over MgSO₄ the solvent was removed in vacuo. Flash chromatography (15% EtOAc in hexanes) or crystallization (from EtOH) yielded compounds 8 (entries 1-5).

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General Procedure for the Preparation of Compounds 10 (Entries 1-7).
In an oven-dried 25-mL flask, Pht-Phe (150 mg, 0.5 mmol) was dissolved in α,α-dichloromethyl methyl ether (5 mL) and the reaction mixture was stirred at 60 °C (oil bath temperature) over night. After evaporation the residue was re-dissolved in dry benzene (10 mL) and evaporated (2 times). The resulting white solid was dissolved in dry CH₂Cl₂ (5 mL) and cooled down to 0 °C by means of an ice bath. The flask was filled with argon, the imine 7 (1.5 equiv) was added, the reaction mixture was stirred during 45 min at 0 °C after which 1.2 equiv (0.6 mL, 0.60 mmol) of a 1 M solution of SbCl₅ in CH₂Cl₂ was added. Overnight reaction at r.t. was followed by quenching with H₂O (5 mL). Isolation of the organic phase, evaporation and flash chromatography yielded the benzazepinones 10 (entries 1-7).

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Analytical data of N-phthaloyl-(4S)-amino-1-phenyl-1,2,4,5-tetrahydrobenzo[c]azepin-3-one (8, entry 1): white solid, R _f = 0.70 (EtOAc), mp 222-224 °C. MS (ESP⁺): m/z calcd for C₂₄H₁₉N₂O₃: 383.13. Found: 383 [M + H]⁺. HPLC: t _R = 21.2 (min). ¹H NMR (250 MHz, CDCl₃): δ = 2.65 (dd, J = 13.5 Hz, J = 3.0 Hz, 1 H), 3.19 (br s, 1 H), 3.71 (dd, J = 13.0 Hz, J = 12.6 Hz, 1 H), 4.90 (dd, J = 12.5 Hz, J = 3.0 Hz, 1 H), 4.19 (m, 3 H), 4.86 (dd, J = 3.0 Hz, J = 14.0 Hz, 1 H), 5.65 (d, J = 6.5 Hz, 1 H), 7.21-7.40 (m, 9 H), 7.74 (m, 2 H), 7.85 (m, 2 H). ¹³C NMR (63 MHz, CDCl₃): δ = 34.6, 52.7, 123.9, 126.9, 128.0, 128.0, 129.0, 129.7, 130.0, 131.0, 132.9, 134.5, 136.8, 139.3, 141.1, 167.8, 172.0.

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Analytical data of N-phthaloyl[1-phenyl-(4S)-amino-3-oxo-1,2,4,5-tetrahydrobenzo[c]azepin-2-yl]acetic acid ethyl ester) (10, entry 2): white solid, R _f = 0.68 (EtOAc), mp 108-110 °C. MS (ESP⁺): m/z calcd for C₂₈H₂₅N₂O₅: 468.17. Found: 469 [M + H]⁺. HPLC: t _R = 24.1 and 24.3 (min). ¹H NMR (250 MHz, CDCl₃): δ = 1.08 and 1.22 (t, J = 7.1 Hz, 3 H), 2.55 and 3.18 (dd, J = 17.0 Hz, J = 4.0 Hz, 1 H), 4.11 (q, J = 7.1 Hz, 2 H), 3.62 and 4.25 (d, J = 17.0 Hz, 1 H), 4.32 (m, 1 H), 4.91 and 5.12 (d, J = 17.0 Hz, 1 H), 4.85 and 5.32 (dd, J = 12.0 Hz, J = 4.0 Hz, 1 H), 5.65 and 5.70 (s, 1 H), 7.15-7.50 (m, 9 H), 7.68-7.82 (m, 4 H). ¹³C NMR (63 MHz, CDCl₃): δ = 14.2 and 14.6, 33.7 and 34.6, 53.1, 52.3 and 54.0, 61.7 and 61.8, 69.3 and 70.4, 123.8, 126.9, 128.0, 129.0, 129.5, 130.3, 131.9, 134.5, 136.0, 137.5, 139.6, 139.3, 141.5, 169.2, 169.5, 170.1.

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X-ray structure analysis of compounds 8 (entry 1) and 10 (entry 2). Suitable crystals were mounted on glass fibers. Data collections were performed at 295 nm on a Nonius BV MACH diffractometer with graphite monochromated CuKα (λ = 1.54178 Å). Both structures were solved with direct methods using the SHELXS97 [19] and refined with SHELXL97 [20] software. Refinements were performed anisotropically for all non-hydrogen atoms using the full-matrix least-squares method. In general, hydrogen atoms were assigned to idealized positions and were allowed to ride with thermal parameters fixed at 1.2 U_eq of the parent atom. The residual electron densities were of no chemical significance. Accordingly, CCDC-279757 [8 (entry 1)], and CCDC-279758 [10 (entry2)] contain the supplementary crystallographic data for this paper. These data can be obtained free of charge at http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; e-mail: [e-mail]).