PAPER
Synthesis of 2-Benzazepines
603
2-(4-Methoxybenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine
(1a); Typical Procedure
13C NMR (CDCl3): = 14.0, 22.6, 25.0, 27.2, 29.7, 36.2, 53.4, 59.1,
59.5, 125.8, 127.1, 128.7, 129.7, 139.4, 142.9.
Compound 6 (0.2 g, 0.72 mmol) was dissolved in THF (10 mL) un-
der argon in a round bottom flask containing a stirring bar, and
cooled to 0 °C in an ice-water bath. After 10 min, 4-methoxylphe-
nylmagnesium bromide (0.8 mL, 1.0 M, 0.86 mmol) was added
dropwise. The reaction mixture was stirred at 0 °C for 2 h. This was
then warmed up to r.t. and stirred for an additional 10 h. The reac-
tion was quenched with H2O (10 mL), the organic layer was sepa-
rated and washed with 2 M NaOH solution. The aqueous layer was
back-extracted with CH2Cl2. The combined organic layers were
dried (MgSO4), and concentrated to give a yellow solid. The prod-
uct was purified by column chromatography on silica gel using 30%
Et2O in pentane as eluent; micro-needles (Et2O–pentane); yield:
70%; mp 83–85 °C.
Anal. Calcd for C15H23N: C, 82.89; H, 10.67; N, 6.44. Found: C,
83.20; H, 11.08; N, 6.76.
2-(4-Methylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (1f)
Yellow oil; yield: 78%.
1H NMR (CDCl3): = 1.75 (quintet, 2 H, J = 5.1 Hz), 2.34 (s, 2 H),
2.91(t, 2 H, J = 5.4 Hz), 3.10 (t, 2 H, J = 5.1 Hz), 3.49 (s, 2 H), 3.87
(s, 2 H), 6.95 (d, 1 H, J = 6.9 Hz), 7.05–7.20 (m, 7 H).
13C NMR (CDCl3): = 21.1, 25.2, 29.7, 36.1, 57.5, 58.7, 59.2,
125.8, 127.1, 128.7, 128.8, 128.9, 130.0, 136.1, 136.4, 139.4,
143.1.
Anal. Calcd. for C18H21N: C, 86.01; H, 8.42; N, 5.57. Found: C,
86.13; H, 8.37; N, 5.89.
1H NMR (CDCl3): = 1.75 (quintet, 2 H, J = 5.0 Hz), 2.92 (t, 2 H,
J = 5.1 Hz), 3.10 (t, 2 H, J = 5.1 Hz), 3.46 (s, 2 H), 3.81 (s, 3 H),
3.86 (s, 2 H), 6.85 (d, 2 H, J = 8.7 Hz), 6.95 (d, 1 H, J = 7.2 Hz),
7.00–7.26 (m, 5 H).
Diethyl 1,3,4,5-Tetrahydro-2H-2-benzazepin-2-ylmethylphos-
phonate (2)
13C NMR (CDCl3): = 25.2, 36.2, 55.2, 57.1, 58.7, 59.1, 113.5,
125.8, 127.1, 128.8, 130.0, 130.1, 131.3, 139.4, 143.1, 158.5.
To a solution of 6 (0.1 g, 0.36 mmol) in THF (5 mL), cooled to 0 °C
in ice-water bath, was added ZnBr2 (0.08 g, 0.36 mmol, oven dried)
followed by triethyl phosphite (0.07 mL, 0.4 mmol). The mixture
was stirred overnight, quenched with H2O, extracted with CH2Cl2,
and the organic layer was washed with aq 2 M NaOH (2 15 mL),
and dried (MgSO4). Removal of the solvent gave 0.12 g of oil which
was purified using 5% MeOH in CHCl3 as eluent; colorless oil;
yield: 90 mg, 87%.
1H NMR (CDCl3): = 1.32 (t, 6 H, J = 7.2 Hz), 1.64–1.74 (m, 2 H),
2.72 (d, 2 H, J = 10.5 Hz), 2.90 (t, 2 H, J = 5.1 Hz), 3.27 (t, 2 H,
J = 5.1 Hz), 4.06 (s, 2 H), 4.06–4.20 (m, 4 H), 7.02–7.20 (m, 4 H).
Anal. Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C,
80.43; H, 7.70; N, 5.07.
2-(4-Chlorobenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (1b)
White needles (EtOAc–hexane); yield: 47%; mp 97–99 °C.
1H NMR (CDCl3): = 1.81 (quintet, 2 H, J = 5.0 Hz), 2.98 (t, 2 H,
J = 5.0 Hz), 3.17 (t, 2 H, J = 5.0 Hz,), 3.54 (s, 2 H), 3.90 (s, 2 H),
6.96 (d, 1 H, J = 7.2 Hz), 7.10–7.24 (m, 2 H), 7.25–7.36 (m, 5 H).
13C NMR (CDCl3): = 25.2, 36.1, 57.0, 58.9, 59.1, 125.8, 127.2,
128.3, 128.8, 129.9, 130.2, 132.5, 137.9, 139.2, 143.0.
13C NMR (CDCl3): = 16.5 (d, J = 5.7 Hz), 24.4, 36.1, 47.5 (d,
J = 167.2 Hz), 60.2 (d, J = 9.2 Hz), 60.4 (d, J = 8.0 Hz), 62.0 (d,
J = 6.9 Hz), 125.9, 127.4, 129.0, 130.4, 138.4, 143.0.
Anal. Calcd for C17H18ClN: C, 75.13; H, 6.68; N, 5.15. Found: C,
75.32; H, 7.09; N, 5.05.
Anal. Calcd. for C15H24NO3P: C, 60.59; H, 8.14; N, 4.71. Found: C,
60.16; H, 8.51; N, 5.07.
2-(3-Phenylprop-2-ynyl)-2,3,4,5-tetrahydro-1H-2-benzazepine
(1c)
2-Methyl-2,3,4,5-tetrahydro-1H-2-benzazepine Borane Com-
plex (3)
Yellow oil; yield: 43%.
1H NMR (CDCl3): = 1.80 (quintet, 2 H, J = 5.0 Hz), 2.91 (t, 2 H,
J = 5.0 Hz), 3.20 (t, 2 H, J = 5.0 Hz), 3.52 (s, 2 H), 3.98 (s, 2 H),
7.08–7.22 (m, 4 H), 7.27–7.34 (m, 3 H), 7.40–7.50 (m, 2 H).
13C NMR (CDCl3): = 26.3, 35.6, 45.8, 58.9, 59.7, 84.7, 85.5,
123.3, 126.1, 127.4, 128.0, 128.2, 128.8, 129.8, 131.7, 138.7, 142.8.
To a solution of 6 (0.28 g, 1 mmol) in THF (20 mL) was added
NaBH4 (0.15 g, 4 mmol) and stirred at r.t. for 4 h. The solvent was
evaporated, the residue was dissolved in CH2Cl2, and washed with
2 M NaOH solution. The organic layer was dried (MgSO4) and con-
centrated to give yellow solid, which was purified by column chro-
matography on silica gel using 20% EtOAc in hexane; yellow
prisms (EtOAc–hexane); yield: 83%; mp 67.6–68.8 °C.
Anal. Calcd for C19H19N: N, 5.36. Found: N, 5.67.
1H NMR (CDCl3): = 1.10–2.10 (m, 5 H), 2.32 (s, 3 H), 2.78–3.10
(m, 2 H), 3.15–3.40 (m, 2 H), 4.00 (d, 1 H, J = 14.7 Hz), 4.36 (d, 1
H, J = 14.4 Hz), 7.15–7.30 (m, 4 H).
13C NMR (CDCl3): = 23.7, 34.3, 45.2, 65.5, 65.9, 126.8, 128.9,
129.1, 131.6, 132.9, 142.4.
HRMS-FAB: Calcd for C19H20N (M + 1): 262.1596; Found:
262.1601.
2-Propyl-2,3,4,5-tetrahydro-1H-2-benzazepine (1d)
Yellow oil; yield: 71%.
1H NMR (CDCl3): = 0.85 (t, 3 H, J = 7.2 Hz), 1.45–1.57 (m, 2 H),
1.72 (quintet, 2 H, J = 5.1 Hz), 2.28–2.33 (m, 2 H), 2.89 (t, 2 H,
J = 5.4 Hz), 3.12 (t, 2 H, J = 5.4 Hz), 3.89 (s, 2 H), 7.12 (br s, 4 H).
Anal. Calcd. for C11H18BN: C, 74.46; H, 10.36; N, 8.00. Found: C,
75.56; H, 10.22; N, 7.95.
13C NMR (CDCl3): = 11.9, 20.6, 25.0, 36.2, 55.3, 59.0, 59.4,
125.9, 127.1, 128.8, 129.7, 139.3, 142.9.
3-(1H-1,2,3-Benzotriazol-1-yl)-2-(3-phenylpropyl)-1-isoindoli-
none (8)
3-Phenyl-1-propylamine (0.3 g, 2.2 mmol), BtH (0.28 g, 2.4 mmol),
phthalaldehydic acid (0.34 g, 2.2 mmol) and p-toluenesulfonic acid
monohydrate (0.04 g, 0.24 mmol) were dissolved in toluene (50
mL) and refluxed using a Dean–Stark apparatus. After 24 h, the re-
action mixture was cooled. After evaporating the solvent, the resi-
due was dissolved in CH2Cl2 and washed with aq 2 M NaOH and
brine. The organic layer was dried (Na2SO4), and concentrated to
give a yellow oil, which was purified by column chromatography on
Anal. Calcd for C13H19N: C, 82.48; H, 10.12; N, 7.40. Found: C,
82.61; H, 10.45; N, 7.65.
2-Pentyl-2,3,4,5-tetrahydro-1H-2-benzazepine (1e)
Brown oil; yield: 69%.
1H NMR (CDCl3): = 0.87 (t, 3 H, J = 7.2 Hz), 1.18–1.34 (m, 4 H),
1.46–1.58 (m, 2 H), 1.71–1.79 (m, 2 H,), 2.36–2.42 (m, 2 H), 2.90
(t, 2 H, J = 6.0 Hz), 3.15 (t, 2 H, J = 5.4 Hz), 3.95 (s, 2 H), 7.13 (br
s, 4 H).
Synthesis 2002, No. 5, 601–604 ISSN 0039-7881 © Thieme Stuttgart · New York