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N-Phthaloyl-(S)-phenylalanine was obtained following the methodology described by: Casimir JR.
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7b 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]
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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.
14
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).
15
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).
16 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.
17 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.
18 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 Ueq 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: deposit@ccdc.cam.sc.uk).
19
Sheldrick GM.
SHELXS-97, Program for Crystal Structure Solution
University of Göttingen;
Göttingen, Germany:
1997.
20
Sheldrick GM.
SHELXL-97, Program for Crystal Structure Refinement
University of Göttingen;
Göttingen, Germany:
1997.
