Polymer-supported chiral sulfonamide catalyzed one-pot reduction of β-keto nitriles: A practical synthesis of (R)-fluoxetine and (R)-duloxetine

Article abstract of DOI:10.1016/j.tetasy.2005.04.002

Enantioselective reduction of β-keto nitriles to optically active 1,3-amino alcohols has been carried out in one step using an excess of borane-dimethyl sulfide complex as a reductant and a polymer-supported chiral sulfonamide as a catalyst with moderate to high enantioselectivity. The facile and enantioselective method to prepare optically active 1,3-amino alcohols to be converted into 3-aryloxy-3-arylpropylamine-type antidepressant drugs (R)-fluoxetine, and (R)-duloxetine is also reported.

Full text of DOI:10.1016/j.tetasy.2005.04.002

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1873–1879
Polymer-supported chiral sulfonamide catalyzed one-pot
reduction of b-keto nitriles: a practical synthesis
of (R)-fluoxetine and (R)-duloxetine
Guangyin Wang, Xingshun Liu and Gang Zhao*
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 FengLin Lu, Shanghai 200032, China
Received 9 March 2005; accepted 7 April 2005
Abstract—Enantioselective reduction of b-keto nitriles to optically active 1,3-amino alcohols has been carried out in one step using
an excess of borane–dimethyl sulfide complex as a reductant and a polymer-supported chiral sulfonamide as a catalyst with
moderate to high enantioselectivity. The facile and enantioselective method to prepare optically active 1,3-amino alcohols to be
converted into 3-aryloxy-3-arylpropylamine-type antidepressant drugs (R)-fluoxetine, and (R)-duloxetine is also reported.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ing,5 asymmetric reduction,6 microbial reductions and
enzymatic or chemical resolutions7 had been reported.
The structure of 3-aryloxy-3-aryl propyl-amine exits in
many antidepressants, such as fluoxetine,1 tomoxetine,2
nisoxetine, and duloxetine3 (Fig. 1). Fluoxetine, tomoxe-
tine, and nisoxetine are amongst the most important
pharmaceuticals for the treatment of psychiatric disor-
ders and metabolic problems,4 while duloxetine is a dual
inhibitor of serotonin and norepinephrine re-uptake and
has a better pharmacological profile as an antidepres-
sant drug.3 The enantioselective synthesis of the individ-
ual enantiomers is necessary because their (S)- or (R)-
isomers probably display different pharmacological
potencies. This has led to many groups developing
different methods of preparing enantiomerically pure
building blocks for these compounds, in which enantio-
selective epoxidation followed by stereoselective open-
Over the past decade, several groups have reported the
preparation and application of polymer-supported cata-
lysts derived from chiral amino alcohols for enantio-
selective reduction.8 Several years ago, we developed a
new class of polymer-supported sulfonamides and
applied them to the enantioselective reduction of func-
tional ketones, such as b-keto sulfones and a-keto esters
via BH3ÆMe2S or NaBH4/Me3SiCl.9 In these studies, we
found that the reducing systems could provide an effi-
cient methodology for the synthesis of optically active
secondary alcohols. In continuation of our recent stud-
ies, we found that b-keto nitriles could be reduced to
optically active 1,3-amino alcohols in one step using an
excess of borane–dimethyl sulfide complex as a reductant
CF3
Me
O
MeO
O
O
O
NHMe
NHMe
NHMe
S
NHMe
Fluoxetine
Tomoxetine
Nisoxetine
Duloxetine
Figure 1.
*
Corresponding author. Fax: +86 21 641 66128; e-mail: zhaog@mail.sioc.ac.cn
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.04.002

1874
G. Wang et al. / Tetrahedron: Asymmetry 16 (2005) 1873–1879
and a polymer-supported chiral sulfonamide as a cata-
lyst. The use of b-keto nitriles and the high enantioselec-
tivity of the reaction, a direct and enantioselective
method to prepare 3-aryloxy-3-arylpropylamine-type
antidepressant drugs, have been explored. Herein, we re-
port this reaction and its application in the synthesis of
(R)-fluoxetine and (R)-duloxetine.
ciency. In our previous work,9 NaBH4/Me3SiCl could
replace BH3ÆMe2S as the reducing agent to give the same
corresponding product with 89% ee under the same con-
ditions, which BH3ÆMe2S gave 96% ee.
To extend this synthetic procedure to the preparation of
1,3-amino alcohols, we investigated the reaction of a
variety of b-keto nitriles (Table 2). The reductions afford-
ed the corresponding 1,3-amino alcohols in moderate
to good yields. It is noteworthy that aromatic b-keto
nitriles 2a–g were reduced in good enantioselectivities
(85–96% ee). To gain further insight into the effect of
the electron density of the aromatic ring, a series of
b-keto nitriles 2a–g bearing different substituents at the
para position on the phenyl group were studied. The
results show that the electron density of the aromatic
ring has little effect on the enantioselectivity (Table 2,
entries 1–7). When the substituent was at the meta
position, the asymmetric reduction of the b-keto nitrile
2d afforded a slightly lower enantioselectivity when
compared with its para substituted analogues (Table 2,
entry 4). For aliphatic b-keto nitriles 2i and 2j, both
chemical yield and enantiomeric excess were lowered
compared with those obtained from aromatic analogues
(Table 2, entries 9 and 10). A higher enantioselectivity
was obtained when the reaction occurred at the most
hindered carbonyl group (Table 2, entry 10).
2. Results and discussion
All the b-keto nitriles were prepared according to the lit-
erature10 (Scheme 1).
To achieve the best enantioselectivity, the effect of the
amount of catalyst was examined first, using the reduc-
tion of 2a as a model reaction (Table 1). From these re-
sults, the fact that the ee increased when increasing the
amount of catalyst 1 was obvious. When the catalyst
was increased to 30 mol %, the ee of the product was
up to 96%, which is as high as the results of the reduc-
tion of other types of functional ketones we had previ-
ously reported. Although the C/S ratio was increased
to 40 mol %, the ee did not increase simultaneously
but in fact decreased slightly. Although the optimal
C/S ratio is relatively high when compared with our previ-
ous report, the catalyst could be recovered almost quanti-
tatively by simple filtration when the reaction was
complete, after washing with hot water and methanol,
and could be reused without any decline of catalysis effi-
The absolute configuration of 3a was confirmed by the
comparison of the specific rotation with the literature
value6e and is consistent with results we had obtained
in the reduction of other functional ketones, such as b-
keto sulfones.9c Although the absolute configurations
of the corresponding 1,3-amino alcohols 3b–g and 3i–j
could not be assigned, in view of the same reaction
mechanism, we assume the absolute configurations to
be the same with 3a.
O
O
NaH, MeCN
CN
R
OEt
Toluene, reflux
R
2a-j
Scheme 1.
Table 2. Asymmetric reduction of b-keto nitrilesa
AcCl (or BzCl)
NaHCO3 (aq.)
CH2Cl2, rt
1 (30 mol%)
Table 1. The effect of the dosage of catalyst on the asymmetric
reactiona
O
H
OH
H
OH
BH3 Me2S
CN
R
NH2
R
R
NHCOR
R = Me, Ph
4a-j
THF, reflux
O
H
OH
2a-j
3a-j
cat. 1 (30 mol%)
BH3·Me2S
CN
b-Keto 1,2-Amino Yield Ee Config.d
nitriles alcohols
(%)b (%)c
NH2
Entry
R
THF, reflux
1
Ph
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
76
74
79
74
74
67
56
77
43
49
96
93
94
88
94
90
95
85
64
77
R
O
S
e
e
e
e
e
e
2
p-F-C6H4
p-Cl-C6H4
m-Cl-C6H4
p-Br-C6H4
p-Me-C6H4
—
—
—
—
—
—
R
N
3
O
4
HO
cat. 1
Ph
5
Ph
6
Entry
C/S (mol%)
Yield (%)b
Ee (%)c
7
p-MeO-C6H4 2g
Thiophen-2-yl 2h
3g
3h
3i
1
2
3
4
5
15
20
25
30
40
74
78
77
76
76
68
84
90
96
93
8
e
9
10
n-Bu
t-Bu
2i
2j
—
—
e
3j
a Experiments were performed at a 1 mmol scale.
b Isolated yield after column purification.
c Analytical samples were converted to their amide 4a–j; Determined
a Experiments were performed at
a
1 mmol scale; molar ratio:
BH3ÆMe2S/cat.1/b-keto nitrile = 3:0.3:1.
by chiral HPLC.
b Isolated yield after column purification.
d The absolute configurations were determined by the comparison of
the reported specific rotations or predicted by the mechanism of the
reaction.
c Determined by chiral HPLC with a Chiralcel OB column after the
product was converted to its acetamide.

G. Wang et al. / Tetrahedron: Asymmetry 16 (2005) 1873–1879
1875
20
½aꢀ ¼ þ117 (c 1.0, MeOH)}. The physical and spectro-
erature data.7k
The 1,3-amino alcohol 3a was envisaged as a key build-
ing block from which (R)-fluoxetine or related analogues
could be synthesized (Scheme 2). The synthesis of inter-
mediate 3a starts from b-keto nitrile 2a, a readily avail-
able starting material as illustrated in Scheme 1. The
reaction proceeded smoothly with the use of borane–
dimethyl sulfide as the reducing agent, catalyzed by
D
scopic data of 10 are also in full agreement with the lit-
3. Conclusion
polymer-supported chiral sulfonamide 1, providing the
In summary, the results reported herein offer a practical
and highly enantioselective methodology for the synthe-
sis of optically active 1,3-amino alcohol. Due to the
efficiency and high enantioselectivity observed, this
method represents a very useful alternative to previously
reported procedures. Finally, we applied this method to
the enantioselective synthesis of antidepressant drugs
(R)-fluoxetine and (R)-duloxetine.
20
D
1,3-amino alcohol 3a in 76% yield having ½aꢀ ¼ þ40.5
25
D
(c 1.4, CHCl3) {lit.6e ½aꢀ ¼ þ40.5 (c 1.0, CHCl3)}. This
key intermediate could then be used without purification
in the next reaction with ethylchloroformate in aq NaH-
CO3 to give carbamate 5, which on subsequent reduc-
tion with lithium aluminum hydride furnished methyl
20
D
amine 6 having ½aꢀ ¼ þ35.1 (c 0.75, CHCl3) {lit.7j
30
½aꢀ ¼ þ37.1 (c 1.0, CHCl3)}. The arylation of 6 was
D
then carried out by nucleophilic aromatic substitution
employing NaH as a base and 4-chlorobenzotrifluoxe-
tine as an electrophile in DMSO to afford (R)-fluoxetine
4. Experimental
20
7 in 92% yield. ½aꢀ ¼ þ3.8 (c 0.9, CHCl3) {lit.7j
General: All reactions were carried out under a dry Ar
atmosphere. THF was freshly distilled over sodium/ben-
zophenone before use. a-Keto nitriles were prepared
according to the reported procedures and further puri-
fied by silica gel column. All NMR spectra were re-
corded in CDCl3 as the solvent unless otherwise stated.
D
20
D
scopic data of 7 are in agreement with the literature
½aꢀ ¼ þ4.1 (c 1.0, CH3Cl)}. The physical and spectro-
data.7j
Similarly, with the procedure described above in the syn-
thesis of (R)-fluoxetine, (R)-duloxetine (R)-10 was syn-
20
D
thesized (Scheme 3). ½aꢀ ¼ þ113 (c 0.9, MeOH) {lit.7k
4.1. General procedure for the asymmetric reduction of
a-keto nitriles
O
Cat. 1 (0.3 mmol) was added to a 50 mL three-necked
flask, at which point was added 10 mL of THF and
1.6 mL of BH3ÆMe2S (2 M in THF). The suspension
was heated under reflux and stirred for 0.5 h. Then, a
THF (8 mL) solution of b-keto nitrile (1 mmol) was
added at a rate of 3 mL/h by a syringe pump. After
the addition was completed, the mixture was treated
with 10 mL of methanol and filtered. The polymeric cat-
alyst was washed several times with hot water, EtOAc,
and methanol. The resulting solution was evaporated
and purified by silica gel chromatography employing
NH4OH–CH3OH–EtOAc (1:10:90) to give correspond-
ing 1,3-amino alcohol.
OH
O
CN
a, b
c
N
H
OC2H5
2a
OH
6
5
CF3
O
d
NHMe
NHMe
Fluoxetine 7
Scheme 2. Reagents and conditions: (a) BH3ÆMe2S, 1 (30 mol %),
THF, reflux; (b) ClCO2Et, NaHCO3 (aq), CH2Cl2, rt, 2 h, 63% (two
steps); (c) LiAlH4, THF, reflux, 2 h, 93%; (d) NaH, DMSO, 55 °C,
30 min, then 4-chlorobenzotrifluoride, 80–90 °C, 1 h, 92%.
4.1.1. (R)-3-Amino-1-phenyl-propan-1-ol 3a. Colorless
20
D
oil, 74% yield, ½aꢀ ¼ 40.5 (c 1.40, CHCl3) {lit.6e
20
D
½aꢀ ¼ 40.5 (c 1.0, CHCl3)}; 1H NMR (300 MHz,
CDCl3): d 7.40–7.23 (m, 5H), 4.93 (dd, J = 3.3 Hz,
8.5Hz, 1H), 3.05 (br, 3H), 2.97–2.89 (m, 2H), 1.90–
1.69 (m, 2H); IR (film): 3355, 3029, 2940, 1878, 1574,
O
OH
O
CN
S
S
a, b
c
N
H
OC2H5
1492, 1452, 1323, 1062 cmꢁ1
.
2h
8
4.1.2. 3-Amino-1-(4-flurophenyl)-propan-1-ol 3b. White
20
D
solid, 76% yield, ½aꢀ ¼ þ27.6 (c 1.59, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.32 (dd, J = 5.4 Hz, 8.3
Hz, 2H), 7.00 (t, J = 8.8 Hz, 2H), 4.88 (dd, J = 3.2 Hz,
7.7 Hz, 1H), 3.13 (br, 3H), 3.07–3.00 (m, 1H), 2.94–
2.85 (m, 1H), 1.84–1.63 (m, 2H); 19F NMR (300 MHz,
CDCl3): d ꢁ116.6; IR (KBr): 3291, 2937, 2873, 1604,
O
OH
d
S
S
NHCH3
NHCH3
(R)-9
(R)-10
1509, 1326, 1221, 1516, 1069 cmꢁ1
.
13C NMR
(75 MHz, CDCl3): d 163.75(d, JC–F = 242.7Hz), 140.85
(d, JC–F = 2.8 Hz), 127.11, (d, JC–F = 7.8 Hz), 114.86
(d, JC–F = 21.2 Hz), 74.42, 40.25, 39.84. EIMS (m/z, rela-
tive intensity): 169 (M+, 5.27), 152 (M+ꢁNH3, 100), 151
Scheme 3. Reagents and conditions: (a) BH3ÆMe2S, 1 (30 mol%), THF,
reflux; (b) ClCO2Et, NaHCO3 (aq), CH2Cl2, rt, 2 h, 67% (two steps);
(c) LiAlH4, THF, reflux, 2 h, 93%; (d) NaH, DMSO, rt, 30 min, then 1-
fluoro-naphthalene, 45–50 °C, 1 h, 88%.

1876
G. Wang et al. / Tetrahedron: Asymmetry 16 (2005) 1873–1879
(M+ꢁH2O, 90.37), 125 (37.10), 123 (76.81), 122 (90.69),
97 (69.23), 96 (30.72), 95 (43.31), 71 (33.31), 75 (26.64),
45 (76.12), 44 (58.80); HRMS Calcd for C9H13FNO:
170.0981. Found: 170.0976.
6.94–6.98 (m, 2H), 5.21 (dd, J = 3.2 Hz, 8.6 Hz, 1H),
3.10–2.93 (m, 5H), 2.03–1.81 (m, 2H); IR (film): 3281,
2936, 2871, 1578, 1482, 1361, 1037, 853 cmꢁ1
.
4.1.9. 1-Amino-heptan-3-ol 3i. Colorless oil, 54% yield,
20
D
4.1.3. 3-Amino-1-(4-chlorophenyl)-propan-1-ol 3c. Col-
½aꢀ ¼ ꢁ15.2 (c 0.96, CHCl3); 1H NMR (300 MHz,
20
D
1
orless oil, 79% yield, ½aꢀ ¼ þ31.7 (c 0.92, CHCl3); H
CDCl3): d 3.87–3.77 (m, 1H), 3.19–3.12 (m, 1H), 2.89–
2.81 (m, 1H), 2.58 (br, 3H), 1.66–1.30 (m, 8H), 0.91 (t,
J = 7.7 Hz, 3H). IR (film): 3360, 2956, 2931, 2860,
NMR (300 MHz, CDCl3): d 7.30 (m, 4H), 4.91 (dd,
J = 3.2 Hz, 7.8 Hz, 1H), 3.30 (br, 3H), 3.09–3.05 (m,
1H), 2.9–2.89 (m, 1H), 1.86–1.62 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 114.03, 132.89, 128.70, 127.39,
74.98, 40.69, 39.89; IR (film): 3359, 3289, 2934, 2871,
1594, 1467, 1378, 1338, 1129, 1047 cmꢁ1
.
4.1.10. 1-Amino-4,4-dimethyl-petan-3-ol 3j. Colorless
20
D
1594, 1490, 1406, 1333, 1089, 1014 cmꢁ1
.
oil, 49% yield, ½aꢀ ¼ ꢁ10.8 (c 1.72, CHCl3); H NMR
1
(300 MHz, CDCl3): d 3.45 (dd, J = 1.5 Hz, 10.7 Hz,
1H), 3.16 (br, 1H), 2.80 (m, 4H), 1.66–1.59 (m, 1H),
1.44–1.31 (m, 1H), 0.9 (s, 9H); IR (film): 3362, 3292,
4.1.4. 3-Amino-1-(3-chlorophenyl)-propan-1-ol 3d. Col-
20
D
1
orless oil, 79% yield, ½aꢀ ¼ þ32.2 (c 1.22, CHCl3); H
NMR (300 MHz, CDCl3): d 7.38 (s, 1H), 7.28–7.21
(m, 3H), 4.90 (dd, J = 3.2 Hz, 7.5 Hz, 1H), 3.24 (br,
3H), 3.11–3.04 (m, 1H), 2.97–2.88 (m, 1H), 1.88–1.63
(m, 2H); 13C NMR (75 MHz, CDCl3): d 146.99,
133.78, 129.16, 126.66, 125.50, 123.44, 74.44, 40.06,
39.08; IR (film): 3358, 3171, 2937, 2871, 1596, 1573,
1475, 1430, 1321, 1200, 1073 cmꢁ1; EIMS (m/z, relative
intensity): 187 (2.49), 185 (M+, 7.57), 168 (M+ꢁNH3,
22.67), 167 (M+ꢁH2O, 10.54), 138 (52.66), 133 (70.45),
113 (21.87), 103 (28.75), 77 (100), 75 (25.00), 45
(52.70), 44 (52.58); HRMS Calcd for C9H13ClNO:
186.0686. Found: 186.0680.
2954, 2869, 1596, 1479, 1391, 1363, 1077, 1011 cmꢁ1
.
4.2. Acylation of the reduction products 3a–j to form 4a–j
To determine the ee of the reduction products on
HPLC, all the 1,3-amino alcohols were converted to
their acetamides 4a–h or benzamides 4i–j under Schotten
Baumann conditions with saturated sodium bicarbonate
and methylene chloride. The products were purified
through silica gel column chromatography (NH4OH/
CH3OH/EtOAc 1:10:90).
4.2.1. N-(3-Hydroxy-3-phenylpropyl)-acetamide 4a.
20
D
4.1.5. 3-Amino-1-(4-bromophenyl)-propan-1-ol 3e. Col-
orless oil, 74% yield, ½aꢀ ¼ þ23.8 (c 1.81, CHCl3); H
White solid, 90% yield, ½aꢀ ¼ þ22.2 (c 1.67, CHCl3),
20
D
1
1
96% ee, H NMR (300 MHz, CDCl3): d 7.36–7.27 (m,
5H), 6.10 (br, 1H), 4.72 (m, 1H), 3.74–3.62 (m, 1H),
3.57 (br, 1H), 3.27–3.17 (m, 1H), 1.98 (s, 3H), 1.90–
1.84 (m, 2H). IR (KBr): 3296, 3086, 3031, 2930, 2875,
NMR (300 MHz, CDCl3): d 7.45 (d, J = 8.3 Hz, 2H),
7.24 (d, J = 8.4 Hz, 2H), 4.90 (dd, J = 2.9 Hz, 8.7Hz,
1H), 3.24 (br, 3H), 3.12–3.04 (m, 1H), 2.98–2.90 (m,
1H), 1.86–1.62 (m, 2H); 13C NMR (300 MHz, CDCl3):
d 144.18, 131.29, 127.40, 120.64, 74.83, 40.42, 39.44.
IR (film): 3356, 3172, 2937, 2936, 2869, 1590, 1475,
1486, 1400, 1071, 1010 cmꢁ1; EIMS (m/z, relative inten-
sity): 231 (3.73), 229 (M+, 3.79), 212 (M+ꢁNH3, 14.15),
211 (M+ꢁH2O, 5.79), 185 (28.06), 133 (100), 85 (40.64),
83 (61.29), 77 (77.90), 51 (27.38), 47 (25.26), 45 (56.39);
HRMS Calcd for C9H13NOCl: 252.0000. Found:
251.9994.
1651, 1557, 1453, 1369, 1298, 1106, 1064, 998 cmꢁ1
.
4.2.2. N-[3-(4-Fluorophenyl)-3-hydroxy-propyl]-acetam-
ide 4b. Colorless oil, 64% yield, ½aꢀ ¼ þ16.0 (CHCl3,
20
D
1
c 0.93), 93% ee, H NMR (300 MHz, CDCl3): d 7.34–
7.28 (m, 2H), 7.05–6.98 (m, 2H), 6.23 (br, 1H), 4.70
(m, 1H), 4.00 (br, 1H), 3.70–3.61 (m, 1H) 3.23–3.12
(m, 1H), 2.00 (s, 3H), 1.84–1.77 (m, 2H). 13C NMR
(75 MHz, CDCl3): d 169.19, 125.10, 124.99, 113.12,
112.84, 68.74, 36.93, 34.54, 20.97. 19F NMR
(300 MHz, CDCl3): d ꢁ115.8. IR (film): 3305, 3095,
2938, 2878, 1894, 1651, 1597, 1557, 1510, 1435, 1370,
1295, 1222, 1157, 1083, 1014, 837 cmꢁ1. EIMS (m/z,
abundance): 211 (M+, 1.36), 86 (64.28), 84 (100), 73
(11.98), 49 (17.96), 47 (19.35). HRMS Calcd for
C11H14NO2FNa+: 234.0906. Found: 234.0901.
4.1.6. 3-Amino-1-p-tolyl-propan-1-ol 3f. Colorless oil,
20
D
62% yield, ½aꢀ ¼ þ24.4 (c 1.59, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.26 (d, J = 8.0 Hz, 2H), 7.14 (d,
J = 7.9 Hz, 2H), 4.90 (dd, J = 3.6 Hz, 8.6 Hz, 1H),
3.09–3.01 (m, 4H), 2.96–2.87 (m, 1H), 2.33 (s, 3H),
1.88–1.68 (m, 2H); IR (film): 3356, 3289, 2922, 2866,
1584, 1513, 1456, 1332, 1068 cmꢁ1
.
4.2.3. N-[3-(4-Chlorophenyl)-3-hydroxy-propyl]-acetam-
20
D
4.1.7. 3-Amino-1-(4-methoxyphenyl)-1-ol 3g. White
ide 4c. White solid, 61% yield, ½aꢀ ¼ þ9.1 (c 0.425,
20
D
1
solid, 57% yield, ½aꢀ ¼ þ25.2 (c 1.53, CHCl3); 1H
CHCl3), 94% ee, H NMR (300 MHz, CDCl3): d 7.33–
7.29 (m, 4H), 6.53 (br, 1H), 4.65 (dd, J = 4.2 Hz,
8.8 Hz, 1H), 3.66–3.55 (m, 1H) 3.24–3.15 (m, 1H), 1.98
(s, 3H), 1.84–1.73 (m, 2H). 13C NMR (75 MHz, CDCl3):
d 171.22, 142.36, 132.53, 128.13, 126.68, 70.47, 38.60,
36.34, 22.75. IR (film): 3300, 3097, 2934, 2877, 1904,
1651, 1556, 1491, 1435, 1369, 1294, 1090, 1014,
826 cmꢁ1. ESIMS for C11H15NO2+: 227.95. Anal. Calcd
for C11H14NO2Cl: C, 58.03; H, 6.20; N, 6.15. Found: C,
57.86; H, 6.15; N, 6.08.
NMR (300 MHz, CDCl3): d 7.30 (d, J = 8.1 Hz, 2H),
6.88 (d, J = 8.7 Hz, 2H), 4.90 (dd, J = 3.5 Hz, 8.3 Hz,
1H), 3.80 (s, 3H), 3.13–3.06 (m, 1H), 2.90–2.70 (m, 1H),
2.77 (br, 3H), 1.88–1.68 (m, 2H); IR (film): 3356, 2935,
2836, 1611, 1585, 1513, 1302, 1246, 1175, 1033 cmꢁ1
.
4.1.8. (R)-3-Amino-1-thiophen-2-yl-propan-1-ol 3h. Col-
26
D
orless oil, 77% yield, ½aꢀ ¼ þ8.7 (c 0.85, CHCl3);
1H NMR (300 MHz, CDCl3): d 7.21–7.27 (m, 1H),

G. Wang et al. / Tetrahedron: Asymmetry 16 (2005) 1873–1879
1877
4.2.4. N-[3-(3-Chloro-phenyl)-3-hydroxy-propyl]-acetam-
124.70, 123.65, 67.96, 39.30, 36.94, 23.46. IR (film):
3304, 3102, 2931, 2874, 1651, 1557, 1435, 1370, 1295,
1078 cmꢁ1. EIMS (m/z, abundance): 199 (M+, 9.8),
140 (22.3), 87 (26.2), 73 (30.8), 43 (100.0). HRMS Calcd
for C9H13NO2SNa+: 222.05647. Found: 222.05592.
20
ide 4d. Colorless oil, 71% yield, ½aꢀ ¼ þ11.1 (c 2.48,
D
CHCl3), 88% ee, 1H NMR (300 MHz, 300 MHz,): d
7.33 (s, 1H), 7.24–7.17 (m, 3H), 6.64 (br, 1H), 4.63 (m,
2H), 3.63–3.49 (m, 1H) 3.22–3.12 (m, 1H), 1.94 (s,
3H), 1.83–1.71 (m, 2H). 13C NMR (75 MHz, CDCl3):
d 171.55, 146.33, 134.11, 129.61, 127.27, 125.75,
123.74, 70.78, 38.76, 36.57, 22.96. IR (film):3300, 3094,
2940, 2877, 1894, 1651, 1598, 1556, 1433, 1369, 1297,
1196, 1076, 999 cmꢁ1. EIMS (m/z, abundance): 229
(4.61), 227 (M+, 12.77), 87 (70.27), 77 (48.96), 73
(100), 72 (50.89), 44 (36.41), 43 (74.81). HRMS Calcd
for C11H14NO2ClNa+: 250.0611. Found: 250.0605.
4.2.9. N-(3-Hydroxy-heptyl)benzamide 4i. White solid,
20
D
87% yield, ½aꢀ ¼ þ1.6 (c 1.825, CHCl3), 1H NMR
(300 MHz, CDCl3): d 7.79–7.76 (m, 2H), 3.72–3.69 (m,
1H), 3.19 (br, 1H), 1.75–1.31 (m, 8H), 0.89 (t,
J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): d
167.77, 133.82, 131.00, 128.05, 126.48, 69.48, 37.02,
36.70, 36.12, 27.50, 22.24, 13.58. IR (KBr): 3332, 3065,
3031, 2931, 2860, 1641, 1578, 1544, 1489, 1450, 1377,
1311, 1199, 1132, 1100, 1075, 1027, 969 cmꢁ1. EIMS
(m/z, abundance): 235 (M+, 0.23), 217 (3.63), 178
(10.82), 148 (12.98), 134 (20.81), 122 (21.50), 105 (100),
77 (35.6). Anal. Calcd for C14H21NO2: C, 71.46; H,
8.99; N, 5.95. Found: C, 71.11; H, 8.96; N, 5.80.
4.2.5. N-[3-(3-Bromo-phenyl)-3-hydroxyl-propyl]-acetam-
20
D
ide 4e. White solid, 50% yield, ½aꢀ ¼ þ12.1 (c 1.88,
1
CHCl3), 94% ee, H NMR (300 MHz, CDCl3): d 7.46–
7.44 (m, 2H), 7.27 (m, 2H), 3.71–3.59 (m, 1H) 3.22–
3.11 (m, 1H), 1.99 (s, 3H), 1.84–1.71 (m, 2H). 13C
NMR (300 MHz, CDCl3): d 170.94, 142.66, 130.90,
126.84, 120.48, 70.28, 38.51, 36.13, 22.61. IR (KBr):
3304, 3094, 2940, 2873, 1651, 1552, 1487, 1437, 1401,
1369, 1293, 1071, 1010, 821 cmꢁ1. EIMS (m/z, abun-
dance): 273 (64.31), 271 (78.87), 185 (100), 183 (59.28),
87 (48.44), 77 (23.20), 73 (50.74), 43 (27.91). HRMS
Calcd for C11H14NO2 Br+: 272.0286. Found: 272.0281.
4.2.10.
N-(3-Hydroxy-4,4-dimethyl-pentyl)-benzamide
23
4j. White solid, 87% yield, ½aꢀ ¼ þ1.3 (c 1.07, CHCl3).
D
1H NMR (300 MHz, CDCl3): d 7.80–7.76 (m, 2H),
7.50–7.43 (m, 3H), 4.0–3.88 (m, 1H), 3.39–3.28 (m,
2H), 2.78 (br, 1H), 1.84–1.78 (m, 1H), 1.58–1.49 (m,
1H), 0.92 (s, 9H). 13C NMR (75 MHz, CDCl3): d
169.96, 136.33, 133.32, 130.43, 128.86, 40.37, 36.72,
32.67, 27.65. IR (KBr): 3261, 2947, 1636, 1577, 1546,
1078, 948 cmꢁ1. EIMS (m/z, abundance): 235 (M+,
0.20), 178 (32.17), 105 (100), 77 (35.8). Anal. Calcd for
C14H21NO2: C,71.46; H, 8.99; N, 5.95. Found: C,
71.18; H, 8.99; N, 5.80.
4.2.6. N-(3-Hydroxyl-3-p-tolyl-propyl)-acetamide 4f.
20
Colorless oil, 35% yield, ½aꢀ ¼ 12.4 (c 1.71, CHCl3),
D
90% ee, 1H NMR (300 MHz, CDCl3): d 7.18 (d,
J = 7.9 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.33 (br,
1H), 4.62 (m, 1H), 4.16 (br, 1H), 357–3.46 (m, 1H),
3.19–3.09 (m, 1H), 2.30 (s, 3H), 1.83–1.75 (m, 2H). 13C
NMR (75 MHz, CDCl3): d 171.02, 141.23, 137.10,
129.12, 125.59, 72.01, 38.75, 36.96, 23.16, 21.06. IR
(film): 3302, 3095, 3022, 2925, 2872, 1654, 1555, 1515,
1438, 1369, 1297, 1075, 818 cmꢁ1. EIMS (m/z, abun-
dance): 207 (1091), 189 (0.89), 135 (20.47), 133 (22.25),
119 (20.24), 93 (25.11), 91 (47.33), 87 (100), 77 (26.54),
73 (58.03), 72 (48.87), 43 (60.98). HRMS Calcd for
C11H17NO2Na+: 230.1157. Found: 230.1152.
When 4i and 4j were not separated on HPLC, they were
converted to their acetate 4i–a and 4j–a with acetyl
chloride and DMAP. The products were purified
through silica gel column chromatography (n-Hexane/
EtOAc 10:1).
4.2.11. 1-Benzamidoheptan-3-yl acetate 4i–a. Colorless
18
D
oil, 90% yield, ½aꢀ ¼ þ64.4 (c 0.8075, CHCl3), 64%
1
ee, H NMR (300 MHz, CDCl3): d 7.84–7.80 (m, 2H),
7.46–7.43 (m, 3H), 6.98 (br, 1H), 4.96 (m, 1H), 3.89–
3.78 (m, 1H), 3.09–2.98 (m, 1H), 2.11 (s, 3H), 1.98–
1.28 (m, 8H), 0.89 (t, J = 4.2 Hz, 3H). 13C NMR
(75 MHz, CDCl3): d 172.28, 167.59, 134.84, 131.68,
128.85, 127.25, 72.59, 36.29, 34.57, 30.01, 27.93, 22.77,
21.51, 14.25. IR (film): 3331, 2957, 2933, 1736, 1642,
1541, 1242, 1022 cmꢁ1. ESIMS (m/z, abundance):
278.2 (M+1+, 100), 279.2 (20). HRMS Calcd for
C16H23NO3Na+: 300.1576. Found: 300.1570.
4.2.7. N-[3-Hydroxyl-2-(4-methoxy-phenyl-propyl)-acet-
20
D
amide 4g. Colorless oil, 82% yield, ½aꢀ ¼ þ16.4 (c
1
0.995, CHCl3), 94% ee, H NMR (300 MHz, CDCl3):
d 7.25 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H),
6.42 (br, 1H), 4.65 (t, J = 6.3 Hz, 1H), 3.85 (br, 1H),
3.79 (s, 3H), 3.62–3.52 (m, 1H), 3.22–3.15 (m, 1H),
1.95 (s, 3H), 1.85–1.79 (m, 2H). 13C NMR (75 MHz,
CDCl3): d 170.53, 158.38, 135.74, 126.34, 113.27,
71.14, 54.73, 38.19, 36.42, 22.67. IR (film): 3303, 3094,
2936, 2837, 1652, 1553, 1513, 1442, 1369, 1301, 1248,
1176, 1074, 1034, 832 cmꢁ1. ESIMS(m/z, abundance):
223. Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N,
6.2. Found: C, 64.17; H, 7.60; N, 6.04.
4.2.12. 1-Benzamido-4,4-dimethylpentan-3-yl acetate
18
D
4j–a. Colorless oil, 92% yield, ½aꢀ ¼ þ96.9 (c 1.00,
1
CHCl3), 64% ee, H NMR (300 MHz, CDCl3): d 7.87–
7.83 (m, 2H), 7.50–7.41 (m, 3H), 7.10 (br, 1H), 4.75
(dd, J = 2.1 Hz, 11.0 Hz, 1H), 4.00–3.89 (m, 1H), 2.94–
282 (m, 1H), 2.12 (s, 3H), 2.02–1.92 (m, 1H), 1.69–
1.58 (m, 1H), 0.8 (s, 9H). 13C NMR (75 MHz, CDCl3):
d 172.82, 167.46, 134.88, 131.69, 128.91, 127.30, 79.17,
36.48, 34.61, 29.53, 26.24, 21.37. IR (film): 3331, 2957,
2933, 1736, 1642, 1541, 1242, 1022 cmꢁ1. EIMS (m/z,
abundance): 277 (M+, 5.58), 217 (18.54), 178 (19.34),
4.2.8. N-(3-Hydroxy-3-thiophen-2-yl-propyl)-acetamide
23
D
4h. Colorless oil, 50% yield, ½aꢀ ¼ ꢁ4.8 (c 1.30,
1
CHCl3), 85% ee, H NMR (300 MHz, CDCl3): d 7.21–
7.19 (m, 1H), 6.95–6.92 (m, 2H), 6.64 (br, 1H), 4.92
(dd, J = 4.6 Hz, 8.6 Hz, 1H), 4.68 (br, 1H), 3.64–3.52
(m, 1H), 3.26–3.16 (m, 1H), 1.98–1.89 (m, 5H). 13C
NMR (75 MHz, CDCl3): d 171.98, 148.48, 127.02,

1878
G. Wang et al. / Tetrahedron: Asymmetry 16 (2005) 1873–1879
160 (18.01), 105 (100), 77 (24.16). HRMS Calcd for
C16H24NO3+: 278.1757. Found: 278.1751.
CDCl3): d 8.36–8.33 (m, 1H), 7.78–7.75 (m, 1H), 7.49–
7.18 (m, 5H), 6.92–6.83 (m, 3H), 5.77 (dd, J = 5.2 Hz,
7.7 Hz, 1H), 2.82 (t, J = 7.6 Hz, 2H), 2.51–2.42 (m,
1H), 2.42 (s, 3H), 2.28–2.16 (m, 1H); IR (film): 3317,
3052, 2946, 2845, 2794, 1595, 1578, 1462, 1397, 1264,
4.3. (R)-(3-Hydroxy-3-phenylpropyl)carbamic acid ethyl
ester 5
1094 cmꢁ1
.
To a solution of 3a which was prepared from 0.7 g of 2a
and not purified in 10 mL dichloromethane, 15 mL of
saturated aqueous NaHCO3 was added. Ethyl chloro-
formate (0.4 mL) in 15 mL dichloromethane was added
to the mixture dropwise. Colorless oil, 63% yield,
Acknowledgements
Financial support by the Major State of Basic
Research Development Program (No. G2000048007),
the National Natural Science Foundation of China,
QT Program, and Shanghai Natural Science Council is
gratefully acknowledged.
20
30
½aꢀ ¼ 21.4 (c 1.65, CHCl3) {lit.7j ½aꢀ ¼ 24.1 (c 1.0,
D
D
CHCl3)}; 1H NMR (300 MHz, CDCl3): d 7.34–7.24
(m, 5H), 5.23 (br, 1H), 4.76–4.70 (m, 1H), 4.08 (q,
J = 7.0 Hz, 2H), 3.45–3.17 (m, 3H), 1.89–1.82 (m, 2H),
1.23 (t, J = 7.0 Hz, 3H); IR (film): 3342, 2980, 2934,
1697, 1529, 1453, 1264, 1142, 1038 cmꢁ1
.
References
4.4. (R)-3-Methylamino-1-phenylpropane-1-ol 6
1. (a) Molloy, B. B.; Schmiegel, K. K. Ger. Pat. 2,500,110;
US Patent 4,314,081; (b) Florey, K. In Analytical Profiles
of Drug Substances; Academic: San Diego, 1990; Vol. 19,
pp 193–219 and references cited therein; (c) Klieser, E.;
Lehmann, E.; Heinrich, K. Pharmacopsychiatry 1995, 28,
14; (d) Wong, D. T.; Bymaster, F. P.; Engleman, E. A.
Life Sci. 1995, 57, 411; (e) Robertson, D. W.; Jones, N. D.;
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Chem. 1988, 31, 185; (f) Robertson, D. W.; Krushinski, J.
H.; Fuller, R. W.; Leander, J. D. J. Med. Chem. 1988, 31,
1412.
20
Colorless oil, 93% yield, ½aꢀ ¼ þ35.1 (c 0.75, CHCl3).
D
30
D
{lit.7j ½aꢀ ¼ þ37.1 (c 1.0, CHCl3)}; 1H NMR
(300 MHz, CDCl3): d 7.39–7.24 (m, 5H), 4.94 (dd,
J = 3.3 Hz, 8.7 Hz, 1H), 3.58 (br, 2H), 2.94–2.80 (m,
2H), 2.44 (s, 3H), 1.92–1.70 (m, 2H); IR (film): 3308,
3061, 3028, 2938, 2852, 2799, 1492, 1452, 1200, 1109,
1064, 1027, 751 cmꢁ1
.
4.5. (R)-Fluoxetine (7)
2. (a) Foster, B. J.; Lavangnino, E. R. EP 52,492; GB
2,087,883; JP 82,114,555; (b) Zerbe, R. L.; Rowe, H.;
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Labonte, A.; Jones, B.; Mercier, P.; Belanger, M. C.
Psychopharmacol. Bull. 1985, 21, 73.
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Eur. Pat. Appl. EP 273, 658, 1988; Robertson, D. W.;
Wong, D. T.; Krushinski, J. H., Jr. Chem. Abstr. 1988,
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26.
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H.; Fuller, R. W.; Leander, J. D. J. Med. Chem. 1988, 31,
1412.
20
Colorless oil, 92% yield, ½aꢀ ¼ þ3.8 (c 0.90, CHCl3)
D
20
D
1
{lit.7j½aꢀ ¼ 4.1 (c 1.0, CHCl3)}, H NMR (300 MHz,
CDCl3): d 7.42 (d, J = 9.0 Hz, 2H), 7.35–7.26 (m, 5H),
6.90 (d, J = 9.0 Hz, 2H), 5.30 (m, 1H), 2.75 (t, J = 7.0
Hz, 2H), 2.44 (s, 3H), 2.24–2.15 (m, 2H), 2.02–1.97 (m,
19
1H), 1.64 (br, 1H);
F NMR (300 MHz, CDCl3): d
ꢁ61.946; IR (film): 2946, 2848, 2796, 1615, 1517, 1329,
1251, 1178, 1162, 1111, 1068, 1009, 836 cmꢁ1
.
4.6. (R)-(3-Hydroxy-3-thiophen-2-yl-propyl)carbamic
acid ethyl ester 8
22
D
Colorless oil, 67% yield, ½aꢀ ¼ ꢁ2.0 (c 1.28, CHCl3); 1H
NMR (300MHz, CDCl3): d 7.24–7.22 (m, 1H), 6.96–
6.95 (m, 1H), 5.17(br, 1H), 5.02–4.97 (m, 1H), 4.10 (q,
J = 7.2 Hz, 2H), 3.68 (br, 1H), 3.54–3.45 (m, 1H),
3.29–3.19 (m, 1H), 2.04–1.95 (m, 2H), 1.23 (t,
J = 7.2 Hz, 3H); IR (film): 3407, 3338, 3104, 2980,
2937, 1701, 1535, 1268, 1038 cmꢁ1
.
4.7. (R)-3-Methylamino-1-thiophen-2-yl-propan-1-ol 9
24
Colorless oil, 89% yield, ½aꢀ ¼ þ13.3 (c 1.05, MeOH)
5. (a) Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 53, 4081;
(b) Mitchell, D.; Koenig, T. Synth. Commun. 1995, 25,
1231.
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30, 5207; (b) Sakuraba, S.; Achiwa, K. Synlett 1991, 689;
(c) Devocelle, M.; Agbossou, F.; Mortreux, A. Synlett
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2002, 43, 4425.
D
34
D
{lit.7k ½aꢀ ¼ þ13.9 (c 2.4, MeOH)}; 1H NMR
(300 MHz, CDCl3): d 7.20 (m, 1H), 6.98–6.91 (m, 1H),
5.18 (m, 1H), 3.58 (br, 2H), 2.99–2.81 (m, 2H), 2.43 (s,
3H), 2.02–1.84 (m, 1H); IR (film): 3302, 3103, 2939,
2853, 2793, 1473, 1315, 1074, 1038 cmꢁ1
.
4.8. (R)-Duloxetine 10
20
Colorless oil, ½aꢀ ¼ þ113 (c 0.9, MeOH) {lit.7k
7. (a) Quiros, M.; Rebolledo, F.; Liz, R.; Gotor, V. Tetra-
hedron: Asymmetry 1997, 8, 3035; (b) Bracher, F.; Litz, T.
D
20
D
½aꢀ ¼ þ117 (c 1.0, MeOH)}; 1H NMR (300 MHz,

G. Wang et al. / Tetrahedron: Asymmetry 16 (2005) 1873–1879
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