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4.3.4. (S)-N-Benzyl-N-(3-methoxybenzyl)-2-acetyloxy-2-
phenylethanamide (1d). According to the procedure (B)
from (S)-acetyl mandelic acid (0.20 g, 1.03 mmol) in
CH2Cl2 (10 mL) and DMF (two drops), oxalyl chloride
(0.09 mL, 1.03 mmol), 3-methoxybenzylmethylamine
(0.195 g, 0.86 mmol) and N-ethyldiisopropylamine
(0.44 mL, 2.58 mmol) in CH2Cl2 (20 mL). The crude
product was purified by flash chromatography (SiO2/eluent:
cyclohexane/ethyl acetate: 80/20) to give compound 1d as a
yellow oil in 64% yield. [a]2D0¼þ28.8 (c 0.250, CHCl3).
Compound 1d was obtained as a mixture of two rotamers
which interconvert via rotation about the amide N–CO
formate (0.480 g, 7.6 mmol) and 10% Pd/C (0.30 g). After
stirring for 4 h at room temperature, the solution was filtered
through a plug of celite and evaporated in vacuo affording 1f
as a yellow solid in 93% yield. 1H NMR (300 MHz, CDCl3)
d 7.77–7.62 (1H, m), 7.52–7.33 (4H, m), 7.08 (1H, t, J¼
7.5 Hz), 6.97 (1H, d, J¼6.9 Hz), 6.63–6.57 (2H, m),
6.17(1H, s), 4.52 (2H, s), 2.80 (3H, s), 2.18 (3H, s). 13C
NMR (60 MHz, CDCl3) d 170.84, 168.56, 146.31, 133.62,
131.97, 131.03, 129.60, 129.23, 128.94, 118.83, 116.96,
115.52, 73.82, 49.25, 33.52, 21.01. Anal. calcd for
C18H20N2O3: C, 69.21; H, 6.45; N, 8.97. Found: C, 69.26;
H, 6.36; N, 8.64.
1
bond (ratio 1/1). H NMR (300 MHz, CDCl3) d 7.59–7.09
(11H, m), 6.84–6.59 (3H, m), 6.21 (0.5H, s), 6.19 (0.5H, s),
5.09–4.84 (1H, m), 4.59–4.42 (1H, m), 4.25–4.09 (2H, m),
3.79 (1.5H, s), 3.74 (1.5H, s), 2.21 (3H, s). 13C NMR
(60 MHz, CDCl3) d 171.01, 170.94, 168.54, 168.48, 160.33,
160.02, 138.35, 137.15, 136.81, 135.46, 133.95, 133.91,
129.97, 129.67, 129.26, 129.19, 128.99, 128.93, 128.86,
128.69, 128.36, 127.95, 127.81, 127.56, 127.53, 127.16,
120.58, 119.39, 114.01, 113.80, 112.85, 111.98, 74.25,
55.46, 55.30, 49.31, 48.22, 48.05, 20.96. IR (neat) 3030,
1667, 1235, 1049, 752 cm21. Anal. calcd for C25H25NO4:
C, 74.42; H, 6.25; N, 3.56. Found: C, 74.15; H, 6.31; N,
3.47. The optical purity was determined by HPLC analysis
using a Chiracel OD column (250£4.6 mm; 10 mm).
Chromatographic conditions: injection: 20 mL (0.5 mg of
1d in 10 mL of hexane). Eluent: heptane/2-propanol: 90/10.
Flow rate: 1 mL/min. Pressure: 400 psi. Temperature:
208C. UV detection: l¼230 nm. Retention time: 10.3 min
[(S)-enantiomer] and 8.8 min [(R)-enantiomer]. ee.97%
(S).
4.3.7. (S)-N-Methyl-N-(2-acetamidobenzyl)-2-acetyloxy-
2-phenylethanamide (1g). To a solution of 1f (0.201 g,
0.64 mmol) and triethylamine (0.25 mL, 1.78 mmol) in
CH2Cl2 (15 mL) was added acetyl chloride (0.13 mL,
1.83 mmol) at 08C. The resulting solution was stirred at
room temperature for 4 h. After addition of water (15 mL)
and phases separation, the resulting aqueous layer was
extracted with CH2Cl2 (2£15 mL). The combined organic
phases were dried (MgSO4) and evaporated under vacuum.
The crude product was purified by chromatography (SiO2:
cyclohexane/ethylacetate: 60:40) to afford 1g in 90% yield.
[a]2D0¼þ0.73 (c 2.89, CHCl3). 1H NMR (300 MHz, CDCl3)
d 9.28 (1H, s), 8.40 (1H, d, J¼9 Hz), 7.43–7.27 (6H, m),
7.12 (1H, d, J¼9 Hz), 7.00 (1H, t, J¼6 Hz), 6.13 (1H, s),
4.75 (1H, d, J¼12 Hz), 4.30 (1H, d, J¼12 Hz), 2.81 (3H, s),
2.21 (3H, s), 2.19 (2H, s). 13C NMR (60 MHz, CDCl3) d
170.64, 169.48, 169.35, 137.67, 132.93, 131.43, 129.64,
129.57, 129.18, 128.26, 123.74, 123.09, 121.71, 73.38,
49.34, 33.86, 24.49, 20.69. IR (neat) 3276, 1643, 1235,
759 cm21. Anal. calcd for C20H22N2O4: C, 67.78; H, 6.26;
N, 7.90. Found: C, 67.90; H, 6.31; N, 7.65. The optical
purity was determined by HPLC analysis using a Chiracel
OD column (250£4.6 mm; 10 mm). Chromatographic
conditions: injection: 20 mL (0.5 mg of 1g in 10 mL of
hexane). Eluent: heptane/2-propanol: 85/15. Flow rate:
1 mL/min. Pressure: 400 psi. Temperature: 208C. UV detec-
tion: l¼230 nm. Retention time: 28.8 min [(S)-enantiomer]
and 21.5 min [(R)-enantiomer]. ee.97% (S).
4.3.5. (S)-N-[(S)-1-Phenylethyl]-N-(3-methoxybenzyl)-2-
acetyloxy-2-phenylethanamide (1e). According to the
procedure (B) from (S)-acetyl mandelic acid (0.20 g,
1.03 mmol) in CH2Cl2 (10 mL) and DMF (two drops),
oxalyl chloride (0.09 mL, 1.03 mmol), (S)-N-(3-methoxy-
benzylamine)-1-phenylethylamine (0.207 g, 0.86 mmol)
and N-ethyldiisopropylamine (0.44 mL, 2.58 mmol) in
CH2Cl2 (20 mL). The crude product was purified by flash
chromatography (SiO2/eluent: cyclohexane/ethyl acetate:
80/20) to give compound 1e as a yellow oil in 64% yield.
Compound 1e was obtained as a mixture of two rotamers
which interconvert via rotation about the amide N–CO
4.4. Friedel–Crafts type cyclization of 1
4.4.1. (S)-N-Methyl-8-bromo-4-phenyl-1,4-dihydroiso-
quinolin-3-one (5a). Procedure (C). To a solution of 1a
(276 mg, 0.73 mmol) in CH2Cl2 (1 mL) pre-cooled to
2158C was slowly added H2SO4 (1 mL). The solution
was stirred at this temperature for 4 h. The reaction mixture
was poured on ice–water and neutralized with sodium
carbonate. The aqueous solution was extracted with CH2Cl2
(3£20 mL). The combined organic phases were dried
(MgSO4) and evaporated under vacuum. The crude product
was purified by flash chromatography (SiO2/eluent: cyclo-
hexane/ethyl acetate: 70:30) to give 5a as a white solid in
70% yield and 90% ee (S). [a]2D0¼þ61.49 (c 1.7, CHCl3). 1H
NMR (300 MHz, CDCl3) d 7.52 (1H, d, J¼7.5 Hz), 7.28–
7.05 (7H, m), 4.84 (1H, s), 4.53 (2H, s), 3.11 (3H, s). 13C
NMR (60 MHz, CDCl3) d 169.26, 139.20, 137.91, 131.17,
130.95, 129.48, 128.9, 128.0, 127.97, 127.45, 121.22, 53.20,
52.33, 35.09. IR (neat) 3028, 2926, 1631, 1441, 1256,
716 cm21. Anal. calcd for C16H14BrNO: C, 60.78; H, 4.46;
N, 4.43. Found: C, 59.72; H, 4.75; N, 4.43. The optical
1
bond (ratio 7/3). H NMR (300 MHz, CDCl3) d 7.50–6.98
(10H, m), 6.80–6.40 (4H, m), 6.10 (1H, q, J¼7.5 Hz), 5.84
(1H, s), 4.72 (0.3H, d, J¼11.8 Hz), 4.14 (0.7H, d, J¼
18.2 Hz), 4.87 (0.7H, d, J¼18.2 Hz), 3.75 (2H, s), 3.68–
3.57 (1.3H, m), 2.13 (1H, s), 2.07 (2H, s), 1.34 (2H, d, J¼
8.6 Hz), 0.98 (1H, d, J¼8.6 Hz). 13C NMR (60 MHz,
CDCl3) d 170.58, 170.08, 169.05, 168.15, 160.35, 159.55,
140.75, 140.20, 139.70, 139.20, 134.46, 133.66, 129.80,
129.70, 129.63, 129.31, 129.16, 129.09, 128.97, 128.91,
128.51, 127.99, 127.54, 127.48, 127.20, 119.37, 118.59,
113.67, 112.79, 112.11, 111.51, 75.32, 74.37, 55.43, 55.30,
54.98, 52.61, 46.51, 46.38, 20.93, 17.46, 17.18. Anal. calcd
for C26H27NO4: C, 74.80; H, 6.52; N, 3.35. Found: C, 74.76;
H, 6.30; N, 3.23.
4.3.6. (S)-N-Methyl-N-(2-aminobenzyl)-2-acetyloxy-2-
phenylethanamide (1f). To a solution of 1b (0.260 g,
0.76 mmol) in CH2Cl2 (15 mL) was added ammonium