864
O. Torre et al. / Tetrahedron: Asymmetry 17 (2006) 860–866
(50 mL) for 12 h. The reaction mixture was cooled to room
temperature and the white solid was collected by filtration
washing with EtOH (25 mL) and Et2O (25 mL). The solid
was recrystallized in a mixture MeOH/H2O (10:1) affording
The reaction was stopped by adding H2O (2 mL) and the
solution extracted with EtOAc (3 · 2 mL). The organic
phases were combined, dried over Na2SO4 and evaporated
under reduced pressure. The crude was purified by flash
chromatography (90% EtOAc/MeOH) affording 72.5 mg
of 6 as a white solid (57% isolated yield). Rf (90%
EtOAc/MeOH): 0.25; mp: 128–129 ꢁC; IR (KBr) m 3268,
1
3.37 g of 3 as a crystalline solid (68% isolated yield). H
NMR (D2O/K2CO3, 300 MHz): 7.45–7.36 (m, 5H, Ar),
3
4.32 (t, 1H, H3, JHH = 7.35 Hz), 2.70–2.57 (m, 2H, H2).
1
3225, 2360, 1639, 1559, 1372, 1265, 1073, 1033 cmꢀ1; H
4.3. 3-Amino-3-phenylpropan-1-ol 4
NMR (CDCl3, 300 MHz): 7.39–7.26 (m, 5H, Ar), 6.04
(br s, 1H, NH), 5.24–5.16 (m, 1H, H3), 3.66–3.59 (m, 2H,
H1), 3.44 (br s, 1H, OH), 2.24–2.00 (m, 4H, 1H2+3H9),
1.90–1.79 (m, 1H, 1H2); 13C NMR (CDCl3, 75.5 MHz):
A solution of 3 (923 mg, 5.6 mmol) in dry THF (20 mL)
was cooled to 0 ꢁC and LiAlH4 (636 mg, 16.8 mmol) added
in small portions. The reaction mixture was refluxed for 2 h
following the disappearance of the starting material by
TLC analysis. The reaction mixture was cooled to 0 ꢁC,
and the hydride excess destroyed adding H2O dropwise.
The grey mixture was extracted in EtOAc (3 · 20 mL)
and the organic phases were combined, dried over Na2SO4
and evaporated under reduced pressure. The crude was
purified by flash chromatography (100% MeOH) isolating
650 mg of 4 as a white solid (77% isolated yield). Rf
(100% MeOH): 0.15; mp: 76–77 ꢁC; IR (KBr) m 3387,
0
170.6 (C@O), 141.2 (C4), 128.8 (2C, C5+C5 ), 127.7 (C7),
0
126.6 (2C, C6+C6 ), 58.7 (C1), 50.6 (C3), 38.5 (C2), 23.2
(C9); MS (APCI+, m/z): 194 [(M+H)+, 100%]; Anal. Calcd
for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.4;
H, 7.9; N, 7.2.
4.6. Benzyl-(3-hydroxy-1-phenylpropyl)carbamate 7
To a solution of 4 (249 mg, 1.5 mmol) in H2O (1.5 mL) was
added Na2CO3 (126 mg, 1.5 mmol) and the mixture was
cooled to 0 ꢁC. Over the mixture was added benzyl chloro-
formate (211 lL, 1.5 mmol) and the reaction was stirred at
room temperature for 16 h, following the progress of the
reaction by TLC analysis (100% MeOH). The reaction
crude was extracted with CHCl3 (3 · 10 mL) and the or-
ganic phases were combined, dried over Na2SO4 and evap-
orated under reduce pressure. The residue was purified by
flash chromatography affording 383 mg of a white solid
(90% isolated yield). Rf (60% EtOAc/hexane): 0.33; mp:
44–45 ꢁC; IR (KBr) m 3322, 2952, 1694, 1538, 1258,
3348, 3281, 2940, 1578, 1457, 1052 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz): 7.37–7.22 (m, 5H, Ar), 4.11 (t, 1H,
3
3
H3, JHH = 5.59 Hz,), 3.78 (t, 2H, H1, JHH = 5.39 Hz),
2.77 (br s, 3H, NH2 and OH), 1.92–1.85 (m, 2H, H2); 13C
NMR (CDCl3, 75.5 MHz): 146.0 (C4), 128.5 (2C,
0
0
C5+C5 ), 127.0 (C7), 125.6 (2C, C6+C6 ), 61.7 (C1), 56.0
(C3), 39.6 (C2); MS (ESI+, m/z): 152 [(M+H)+, 100%],
174 [(M+Na)+, 9%]; Anal. Calcd for C9H13NO: C, 71.49;
H, 8.67; N, 9.26. Found: C, 71.3; H, 8.6; N, 9.3.
4.4. 3-(Acetylamino)-3-phenylpropyl acetate 5
1055 cmꢀ1
;
1H NMR (CDCl3, 300 MHz): 7.34–7.26 (m,
3
10H, Ar), 5.84 (br d, 1H, NH, JHH = 7.89 Hz), system
AB (dA 5.12 dB 5.06, 2H, H4, JAB = 19.55 Hz), 4.95 (m,
To a solution of 6 (57 mg, 0.4 mmol) in dry CH2Cl2
(0.6 mL) under a nitrogen atmosphere, was added pyridine
(81 lL, 1.0 mmol). The mixture was cooled to 0 ꢁC and
acetyl chloride added dropwise (114 lL, 1.6 mmol). The
reaction mixture was stirred at room temperature for 2 h
and then the solvent evaporated under reduced pressure.
The crude was purified by flash chromatography (90%
EtOAc/MeOH) affording 81 mg of 5 as a white solid
(87% isolated yield). Rf (90% EtOAc/MeOH): 0.37; mp:
90–91 ꢁC; IR (KBr) m 3311, 3060, 3029, 2972, 2923, 2839,
2
1H, H3), 3.74–3.68 (m, 2H, H1), 3.32 (br s, 1H, OH),
2.08–2.01 (m, 1H, H2), 1.91–1.83 (m, 1H, H2); 13C NMR
(CDCl3, 75.5 MHz): 156.3 (C@O), 141.6, 136.1, 128.5,
128.3, 127.9, 127.9, 127.2, 126.1 (12C, Ar), 66.7 (C4), 58.8
(C1), 52.4 (C3), 38.6 (C2); MS (ESI+, m/z): 286 [(M+H)+,
13%], 308 [(M+Na)+, 100%]; Anal. Calcd for
C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.6;
H, 6.7; N, 4.9.
1732, 1650, 1547, 1426, 1370, 1242, 756, 703 cmꢀ1 1H
;
NMR (CDCl3, 300 MHz): 7.32–7.22 (m, 5H, Ar), 6.57
4.7. 3-[[(Benzyloxy)carbonyl]amino]-3-phenylpropyl
acetate 8
3
(br d, 1H, NH, JHH = 3.95 Hz), 5.07 (dd, 1H, H5,
3
3JHH = 15.32 Hz, JHH = 7.61 Hz), 4.10–3.93 (m, 2H,
H3), 2.12–2.01 (m, 2H, H4), 2.00 (s, 3H, CH3), 1.94 (s,
Same procedure than 5, except for using 7 instead of 6 as
the starting material. Rf (50% EtOAc/hexane): 0.57; mp:
47–49 ꢁC; IR (KBr) m 3418, 2978, 1694, 1556, 1238,
3H, CH3); 13C NMR (CDCl3, 75.5 MHz): 170.9 (C@O),
0
169.4 (C@O), 141.3 (C8), 128.6 (2C, C9+C9 ), 127.4 (C11),
126.3 (2C, C10+C10 ), 61.3 (C3), 50.5 (C5), 34.6 (C4), 23.1
1045 cmꢀ1
;
1H NMR (CDCl33, 300 MHz): 7.41–7.29 (m,
0
(CH3), 20.7 (CH3); MS (ESI+, m/z): 236 [(M+H)+, 13%];
Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95.
Found: C, 66.3; H, 7.3; N, 5.9.
10H, Ar), 5.28 (d, 1H, NH, JHH = 8.1 Hz), system AB
(dA 5.14 dB 5.10, 2H, H5, /2JAB/ = 20.19 Hz), 4.91 (m,
1H, H4), 4.19–4.03 (m, 2H, H2), 2.18–2.09 (m, 2H, H3),
2.06 (s, 3H, H1); 13C NMR (CDCl3, 75.5 MHz): 170.8
(C@O), 155.5 (C@O), 136.2, 128.7, 128.7, 128.7, 128.4,
128.0, 127.6, 126.2 (12C, Ar), 66.8 (C5), 61.2 (C2), 52.7
(C4), 35.2 (C3), 20.8 (C1); MS (ESI+, m/z): 328 [(M+H)+,
6%], 350 [(M+Na)+, 100%]; Anal. Calcd for C19H21-
NO4: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.8; H, 6.5;
N, 4.3.
4.5. N-(3-Hydroxy-1-phenylpropyl)acetamide 6
To a solution of 4 (100 mg, 0.66 mmol) in a mixture of
THF (1)/H2O (1) (0.66 mL) was added NaHCO3
(166 mg, 1.98 mmol) and Ac2O (63 lL, 0.66 mmol). The
mixture was stirred at room temperature during 22 h.