Copper(ii)-catalyzed enantioselective hydrosilylation of halo-substituted alkyl aryl and heteroaryl ketones: Asymmetric synthesis of (R)-fluoxetine and (S)-duloxetine

Article abstract of DOI:10.1039/c3ob42214c

A set of reaction conditions has been established to facilitate the non-precious copper-catalyzed enantioselective hydrosilylation of a number of structurally diverse β-, γ- or ε-halo-substituted alkyl aryl ketones and α-, β- or γ-halo-substituted alkyl heteroaryl ketones under air to afford a broad spectrum of halo alcohols in high yields and good to excellent enantioselectivities (up to 99% ee). The developed procedure has been successfully applied to the asymmetric synthesis of antidepressant drugs (R)-fluoxetine and (S)-duloxetine, which highlighted its synthetic utility.

Full text of DOI:10.1039/c3ob42214c

Organic &
Biomolecular Chemistry
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PAPER
Copper(II)-catalyzed enantioselective
hydrosilylation of halo-substituted alkyl aryl and
heteroaryl ketones: asymmetric synthesis of
(R)-fluoxetine and (S)-duloxetine†
Cite this: Org. Biomol. Chem., 2014,
12, 1009
Ji-Ning Zhou, Qiang Fang, Yi-Hu Hu, Li-Yao Yang, Fei-Fei Wu, Lin-Jie Xie, Jing Wu*
and Shijun Li*
A set of reaction conditions has been established to facilitate the non-precious copper-catalyzed
enantioselective hydrosilylation of a number of structurally diverse β-, γ- or ε-halo-substituted alkyl aryl
ketones and α-, β- or γ-halo-substituted alkyl heteroaryl ketones under air to afford a broad spectrum of
halo alcohols in high yields and good to excellent enantioselectivities (up to 99% ee). The developed pro-
cedure has been successfully applied to the asymmetric synthesis of antidepressant drugs (R)-fluoxetine
and (S)-duloxetine, which highlighted its synthetic utility.
Received 8th November 2013,
Accepted 3rd December 2013
DOI: 10.1039/c3ob42214c
www.rsc.org/obc
alcohols is perhaps among the most attractive, and various
strategies have been developed accordingly. In 1987, Corey and
Introduction
Enantiomerically enriched halo alcohols constitute ubiquitous co-workers reported the enantioselective borane reduction of
building blocks for the construction of a variety of structurally α-chloroacetophenone catalyzed by chiral oxazaborolidines to
versatile compounds, such as chiral diols, amino alcohols, produce (S)-2-chlorophenylethanol with up to 97% ee.4a Fol-
epoxides and azido alcohols (Scheme 1), owing to the versati- lowing this significant lead, several catalyst systems for the
lity conferred by the existence of the halogen that can readily enantioselective hydroboration of halo ketones have been
behave as a good leaving group. Also, many biologically active established.4b–e Additionally, some chiral transition metal cata-
pharmaceuticals or agricultural chemicals have been per- lysts, especially those based on rhodium,5 ruthenium,5c,6 and
mitted to be prepared in optically pure form by employing iridium,5c,7 have been exploited and exhibited good to
corresponding chiral halo alcohols as the precursors.1,2 For
instance, enantiomerically active γ-halo alcohols can serve as
key intermediates in the preparation of (R)-fluoxetine 12a,b or
(S)-duloxetine 2,2c,d which are important pharmaceuticals for
the treatment of psychiatric disorders, such as depression,
anxiety, and alcoholism, as well as certain metabolic problems.
(R)-Ibutilide 3 is a potent class III antiarrhythmic agent, the
synthesis of which demands a non-racemic δ-halo alcohol
intermediate.3 Therefore, the development of efficient, econo-
mical and practical methodologies for the preparation of
structurally diverse chiral halo alcohols has been an appealing
objective in organic synthesis for many years.
From both academic and technical points of view, the cata-
lytic asymmetric reduction of halo-substituted ketones as a
straightforward approach towards single enantiomer halo
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou 310036, China. E-mail: jingwubc@hznu.edu.cn,
l_shijun@hznu.edu.cn; Fax: (+86)-571-2886-8023
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Representative examples of biologically active compounds
c3ob42214c
derived from chiral halo alcohols.
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excellent enantioselectivities for the asymmetric transfer
hydrogenation of various prochiral α-halo-acetophenone
derivatives. Efficient chiral catalysts for the hydrogenation of
halo ketones are relatively scarce.8,9 Noteworthy is the elegant
report in 2007 by Noyori et al. on the η6-arene/TsDPEN-Ru(II)
catalysts, which allowed for the enantioselective hydrogenation
of a series of α-chloro alkyl aryl ketones to chlorohydrins of
excellent enantiopurities.9 With the exception of the need for
using noble metal catalysts, the aforementioned studies
mainly focused on the stereoselective reduction of α-halo-
substituted alkyl aryl ketones, while β-, γ-, and other halo
ketonic substrates were seldom involved.
Table 1 Effects of copper salts and chiral ligands on the copper-cata-
lyzed asymmetric hydrosilylation of 5a in aira
In the past decade, by using stoichiometric amounts of
silane as hydride donors, copper-mediated asymmetric
reduction of ketones as a desirable tool, leading to a broad
range of chiral alcohols, has attracted growing interest, owing
to the usage of economically appealing transition metals, the
mild reaction conditions, and the operational simplicity.10,11
Nonetheless, the application of chiral inexpensive metal cata-
lysts in the stereoselective hydrosilylation process for the syn-
thesis of halo alcohols has been relatively unexplored.12 In
2006, Lipshutz et al. described the use of the (DTBM-
SEGPHOS)CuH13 catalyst for effecting the asymmetric hydro-
silylation of β-chloropropiophenone in 92% ee at −78 °C.12c
Recently, we have established an effective Cu(II)/dipyridyl-
phosphine (Table 1, P-Phos 4a or Xyl-P-Phos 4c)14/PhSiH3 or
PMHS (polymethylhydrosiloxane) system, which was docu- 17e
mented to be highly selective (ee up to 99.9%) yet reactive
(substrate to ligand ratio up to 100 000) for the catalytic
enantioselective hydrosilylation of a diverse assortment of
simple ketones15 as well as 1,4-reduction of β-dehydroamino
acid esters16 under an ambient atmosphere and mild con-
ditions. Herein, we wish to report our endeavors in the appli-
cation of this catalyst system to the hydrosilylation of a wide
range of halo-substituted alkyl aryl and heteroaryl ketones.
The reactions proceeded smoothly in air and a broad spectrum
of halo alcohols bearing high degrees of enantiopurity became
accessible. Furthermore, the developed hydrosilylation
methodology has been successfully applied as the key step to
the enantioselective synthesis of two frequently used anti-
depressants, (R)-fluoxetine 1 2b and (S)-duloxetine 2.2c,d
Entry
Copper salt
Ligand
Convb (%)
eec (%)
1
2
3
4
5
6
7
8
CuF2
CuI
CuCl
CuCl2
CuCl2·2H2O
CuBr2
Cu(TC)
CuCl + NaBArF
[CuF(PPh3)3]·2EtOH
Cu(OTf)2
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4a
(S)-4b
(S)-4c
(S)-4a
(S)-4c
98
<5
<5
<5
<5
13
>99
99
95
<5
<5
99
>99
99
88
n.d.d
n.d.
n.d.
n.d.
n.d.
73
85
34
n.d.
n.d.
80
92
88
89
96
9
10
11
12
13
14
15
16e
Cu(acac)2
Cu(OCOCF3)2·XH2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
99
99 f
99g
99
a Reaction conditions: 51 mg substrate, substrate concentration =
0.1–0.3 M in toluene at 25 °C. b The conversions were determined by
NMR and GC analysis. c The ee values were determined by chiral HPLC
analysis. The absolute configuration was determined by comparing the
retention times with known data (see the ESI). d n.d. = not determined.
e The reaction was carried out at −20 °C. Reaction time = 48 h. f The
isolated yield was 94%. g The isolated yield was 96%.
the reaction rate largely relied on the choice of halogen in
copper salts. Thus, except for the use of CuF2, all other copper(I)
or copper(II) halides such as CuI, CuCl, CuCl2, CuCl2·2H2O
and CuBr2 exhibited disappointing reactivities under otherwise
identical conditions (<5% conversion, entries 2–6). With
respect to the other investigated copper sources, including
Cu(TC), CuF(PPh3)3·2EtOH, Cu(OTf)2 and Cu(acac)2, either
poor activities or low to moderate ees were observed. Although
promising outcomes were achieved as well by utilizing CuBArF
or Cu(OCOCF3)2·XH2O, Cu(OAc)2·H2O (entry 13, >99% conv.
and 92% ee) appeared to be the most preferable choice
because of its substantially low cost and ease of handling. On
the other hand, both (S)-Tol-P-Phos ((S)-4b) and (S)-Xyl-P-Phos
((S)-4c) gave comparative levels of activity and asymmetric
induction with those of the P-Phos ligand (entries 14 and 15
vs. entry 13). Further examination demonstrated that full con-
version and up to 99% ee were realized at −20 °C in the pres-
ence of (S)-4c as the chiral ligand simply by prolonging the
reaction time to 48 hours (entry 17) and 96% ee was obtained
by applying (S)-4a (entry 16).
Results and discussion
To initiate our studies, we selected 3-chloro-1-phenylpropan-
1-one 5a as the model substrate and subjected it to a premixed
solution of 3 mol% of CuF2, 1 mol% of (S)-4a and 1.2 equi-
valent of hydride resource PhSiH3 in toluene. As shown in
entry 1 of Table 1, the reaction was completed in air at room
temperature after 4 hours to afford (S)-6a quantitatively in 88%
ee. Next, multifarious Cu(I) or Cu(II) salts were investigated as
catalyst precursors in detail (entries 2–13) under a given set of
reaction conditions and the results indicated that the extent of
conversions or ee values varied considerably as a function
of the counter-ion. Consistent with the previous findings,11c,f
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Scheme 3 Cu(II)-catalyzed asymmetric hydrosilylation of ε-halo-substi-
tuted alkyl aryl ketones 7a–7d in air.
Scheme 2 Cu(II)-catalyzed asymmetric hydrosilylation of β- or γ halo-
substituted alkyl aryl ketones 5b–5g in air.
With the optimized conditions in hand, we turned our
attention to evaluating the efficiency of the present catalyst
system for the asymmetric reduction of a range of other β- or γ
halo-substituted alkyl aryl ketones 5b–5g under an air atmos-
phere. Gratifyingly, as illustrated in Scheme 2, the complete
hydrosilylation of most substrates to the corresponding γ-, or
δ-substituted halo alcohols 6b–6g with good to excellent enan-
tiopurities (84–99% ees) was realized in the presence of (S)-4a
or (S)-4c as the chiral ligand within 48 h at −20 °C (76–96%
yield). The stereoselectivities of the reaction were affected by
the positioning of the substituents on the arene ring of
ketones. Transformations of substrates with either electron-
withdrawing or electron-donating para-substituents (5b, 5c,
Scheme 4 Cu(II)-catalyzed asymmetric hydrosilylation of halo-substi-
tuted alkyl heteroaryl ketones 9a–9c in air.
5e–5g) proceeded well to furnish the desired alcohols (6b, 6c, commercial manufacture of pharmaceuticals,1,2c,d,4c the cataly-
tic asymmetric synthesis of halo-substituted alkyl hetero-
6e–6g) of 92–96% enantioselectivities in high isolated yields.
In contrast, the presence of an ortho-substituent (5d) resulted aromatic alcohols has received scant attention and hence
in the diminution in enantioselectivities (84–85% ee), possibly remained a challenge. Given the good performance of the
present catalyst system in the hydrosilylation of a broad assort-
due to the bulky group at the ortho-position, which blocked
the approach of the carbonyl group to the copper hydride.
ment of β-, γ- and ε-halo alkyl aromatic ketones, we were there-
To access a wide range of halo-substituted alkyl aryl alco- fore interested in the examination of its general applicability
in the stereoselective reduction of halo-substituted alkyl
hols of high optical purity, we turned to the reactions of
several ε-chloro-substituted alkyl aryl ketones 7a–7d. As the heteroaryl ketones under an air atmosphere and a given set of
findings in Scheme 3 indicated, the distance between a halo conditions, and the representative results are summarized
in Scheme 4. To our delight, the chiral dipyridylphosphine
substituent and a carbonyl group did not show a pronounced
influence on the outcome of the reactions. Substrates posses- ligated Cu-H behaved as an efficacious catalyst, rendering high
sing a meta- or para-substituted electron-rich or electron- isolated yields (85–97%) and excellent ee values (94–96%) for
the reduction of 2-thienyl alkyl ketones with α-, β- or γ-halo
air atmosphere to give the desired products neatly in consist- substituent (9a–9c).
deficient arene group all underwent facile reduction under an
ently high ee values (92–95%, 7b–7d). Whereas the halo ketone
substrate bearing an ortho-substituted phenyl group (7a) was
With a practical and economical catalytic method for the
highly asymmetric preparation of structurally diverse halo-
converted to the corresponding alcohol product of moderate substituted alcohols available, we turned to applying this
enantiomeric purity (76% or 78% ee).
methodology to the enantioselective synthesis of significant
antidepressant drugs (R)-fluoxetine (1) and (S)-duloxetine (2).
Despite the wide utility of enantioenriched halo-substituted
alkyl heteroaryl alcohols and their derivatives in the As the procedure outlined in Scheme 5 indicated, asymmetric
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Cu(OAc)2·H2O and optically pure dipyridylphosphine ligand
(S)-4 along with the stoichiometric hydride donor PhSiH3
under an air atmosphere. The excellent enantioselectivities
and the satisfactory yields observed in these reactions,
accompanied by the commercial availability and stability of
the ligands and reagents, the mild reaction conditions, as well
as the wide substrate scope, make this procedure economical,
practical and versatile. In particular, the practical viability of
the developed process was evinced by the efficient transform-
ation of enantiomerically enriched halo-substituent alcohol
products to the significant antidepressant drugs (R)-fluoxetine
and (S)-duloxetine.
Experimental section
General
1H NMR and 13C NMR spectra were recorded in CDCl3 on a
Bruker advance spectrophotometer (400 or 500 MHz) at room
temperature. Chemical shifts (δ) are given in ppm and are
referenced to residual solvent peaks. HRMS spectra were
recorded at the UCSB mass spectrometry facility using a Micro-
mass VG 70e magnetic sector by the ESI standard methods.
Low resolution mass spectra were obtained using an Agilent
Technologies 5975C. IR absorption spectra (FT = diffuse reflec-
tance spectroscopy) were recorded for samples loaded as neat
films on KBr plates using a Bruker TENSOR27 and only note-
worthy absorptions (in cm−1) are listed. Conversions were
determined by 1H NMR and gas chromatographic analyses
(Capillary GC, INNOWAX column, 30 m × 0.25 mm, carrier gas,
N2). Enantiomeric excess of the asymmetric hydrosilylation
products was determined by chiral HPLC. Gas chromato-
graphic analyses were conducted using a Fuli 9790 with an FID
detector. HPLC analyses were performed using an Agilent 1200
with a UV detector. Optical rotations were measured using a
Perkin-Elmer Model 341 polarimeter in a 10 cm cell. Optically
pure P-Phos (4a) and Xyl-P-Phos (4c) were purchased from
commercial sources. (S)-Tol-P-Phos (4b) was prepared accord-
ing to a previously reported procedure.17 Substrates were
prepared and characterized according to the literature pro-
cedures.18,19 All solvents were purified and dried according to
standard methods prior to use. Copper salts, phenylsilane,
and some ketone substrates were purchased from Aldrich, Alfa
Aesar or Acros Organics and used as received without further
purification unless otherwise stated.
Scheme 5 Asymmetric synthesis of (R)-fluoxetine
xetine 2.
1 and (S)-dulo-
hydrosilylation of ketones 5a and 9b under the aforemen-
tioned optimized conditions proceeded uneventfully in air to
furnish the corresponding chloro-substituted alcohols (R)-6a
and (S)-10b with 97% and 95% ee, respectively. Then, reaction
of enantioenriched (R)-6a or (S)-10b and saturated sodium
iodide in acetone at reflux for 16 h cleanly provided iodo
alcohol (R)-11 or (S)-12 (>99% yield). Next, the mixture of iodo
alcohol product (R)-11 or (S)-12 and 40% aqueous methyl-
amine in THF was stirred at room temperature for 12 h to
afford amine intermediates (R)-13 (98% yield) or (S)-14 (80%
yield) after work-up steps. Finally, (R)-13 or (S)-14 reacted with
sodium hydride in N,N-dimethylacetamide (DMA) at 70 °C for
0.5–1 h followed by the treatment of p-chlorobenzotrifluoride
or 1-fluoronaphthalene to form target chiral product (R)-fluo-
xetine 1 (84% yield) or (S)-duloxetine 2 (62% yield).
Conclusion
General procedure for the catalytic asymmetric hydrosilylation
reaction in air (Table 1, entry 16, 3-chloro-1-phenylpropan-
1-one, 5a)15b
In summary, the copper-catalyzed asymmetric hydrosilylation
of a diverse range of β-, γ- or ε-halo-substituted alkyl aryl
ketones and α-, β- or γ-halo substituted alkyl heteroaryl Cu(OAc)2·H2O (1.8 mg, 9.0 × 10−3 mmol) and (S)-P-Phos (4a,
ketones was realized with good to excellent enantioselectivities 1.9 mg, 3.0 × 10−3 mmol) were weighed under air and placed
(up to 99%), leading to a vast array of optically active halo-sub- in a 25 mL round-bottomed flask equipped with a magnetic
stituted alcohols, which are important building blocks for the stirring bar. Toluene (1.0 mL) was added and the mixture was
synthesis of numerous biologically active and structurally stirred at room temperature for 20 min. To the solution, phe-
interesting compounds. The present catalyst system was nylsilane (44.9 µL, 3.6 × 10−1 mmol) in toluene (0.5 mL) was
formed in situ from catalytic amounts of copper source added and the mixture was cooled to −20 °C. A solution of
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3-chloro-1-phenylpropan-1-one (5a, 50.6 mg, 0.3 mmol) in chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel OD-H
toluene (0.5 mL) was added under vigorous stirring, and the column (eluent, 2-propanol–hexane 2 : 98; flow rate: 1.0 mL
flask was stoppered. The reaction was monitored by TLC. min−1; detection: 254 nm light); tR (major) = 20.39 min;
Upon completion, the reaction mixture was treated with 10% tR (minor) = 24.89 min. [α]2D0 = –13.3 (c = 1.0 in CHCl3).
HCl (2.0 mL) and the organic product was extracted with ether
(−)-3-Chloro-1-(2,4-dimethylphenyl)propan-1-ol (6d).22 1H
(3 × 3 mL). The combined extract was washed with water, dried NMR (400 MHz, CDCl3): δ 1.94 (br, 1H), 2.02–2.12 (m, 2H),
with anhydrous sodium sulfate, filtered through a plug of 2.30 (s, 6H), 3.59–3.64 (m, 1H), 3.77–3.82 (m, 1H), 5.12–5.15
silica gel and concentrated in vacuo to give the crude product. (m, 1H), 6.96–7.34 (m, 4H). 13C NMR (100 MHz, CDCl3): δ
The conversion and the enantiomeric excess of the product 18.83, 20.96, 40.50, 42.09, 67.37, 125.03, 127.05, 131.31,
(S)-3-chloro-1-phenylpropan-1-ol (6a) were determined by 134.36, 137.15, 138.95. IR (thin film): νmax (cm−1) = 3392, 2955,
NMR, GC (Capillary GC, INNOWAX column, 30 m × 0.25 mm, 2925, 2855, 1615, 1594, 1456, 1283, 1134, 1052, 821, 738, 698.
carrier gas, N2) and chiral HPLC (25 cm × 4.6 mm Chiralcel MS (EI, m/z, relative intensity): 163 ([M − Cl]+, 3), 91 (100),
OD column) analysis to be 99% and 96%, respectively. The 77 (37), 41 (11).
pure product was isolated (48 mg, 94% yield) by column
The conversion was determined by capillary GC with a 30 m
chromatography (ethyl acetate–petroleum ether = 1 : 10).
× 0.25 mm INNOWAX column; 180 °C; isothermal; tR (5d) =
(S)-3-Chloro-1-phenylpropan-1-ol (6a).15b 1H NMR (400 MHz, 3.52 min; tR (6d) = 23.97 min. The ee value was determined by
CDCl3): δ 1.99 (br, 1H), 2.09–2.28 (m, 2H), 3.54–3.60 (m, 1H), chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel AD
3.72–3.78 (m, 1H), 4.93–4.97 (m, 1H), 7.28–7.39 (m, 5H). 13C column (eluent, 2-propanol–hexane 2 : 98; flow rate: 1.0 mL
NMR (100 MHz, CDCl3): δ 41.43, 41.79, 71.33, 125.81, 127.97, min−1; detection: 254 nm light); tR (major) = 19.28 min;
128.71, 143.70. IR (thin film): νmax (cm−1) = 3391, 2955, 2925, tR (minor) = 15.93 min. [α]D20 = –40.5 (c = 1.0 in CHCl3).
2854, 1493, 1455, 1377, 1285, 1135, 1055, 763, 700. MS (EI,
m/z, relative intensity): 172 (M+, 1), 170 (M+, 3), 107 (100), CDCl3): δ 1.77–1.93 (m, 5H), 2.34 (s, 3H), 3.53–3.55 (m, 2H),
91 (5), 63 (4), 51 (9), 39 (4).
4.65–4.67 (m, 1H), 7.15–7.36 (m, 4H). 13C NMR (100 MHz,
(−)-4-Chloro-1-p-tolylbutan-1-ol (6e).23 1H NMR (400 MHz,
The conversion was determined by capillary GC with a 30 m CDCl3): δ 21.14, 29.02, 36.12, 45.02, 73.79, 125.79, 129.27,
× 0.25 mm INNOWAX column; 180 °C; isothermal; tR (5a) = 137.50, 141.36. IR (thin film): νmax (cm−1) = 3371, 2955, 2924,
2.62 min; tR (6a) = 13.28 min. The ee value was determined by 2853, 1431, 1378, 1135, 818, 741, 699. MS (EI, m/z, relative
chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel OD intensity): 163 ([M − Cl]+, 15), 149 (1), 91 (100), 77 (23), 41 (8).
column (eluent, 2-propanol–hexane 2 : 98; flow rate: 1.0 mL
min−1; detection: 254 nm light); tR (R) = 19.6 min; tR (S) = × 0.25 mm INNOWAX column; 180 °C; isothermal; tR (5e) =
24.2 min. 4.85 min; tR (6e) = 3.34 min. The ee value was determined by
The conversion was determined by capillary GC with a 30 m
(−)-3-Chloro-1-(4-chlorophenyl)propan-1-ol (6b).20 1H NMR chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel OD-H
(400 MHz, CDCl3): δ 2.00–2.24 (m, 3H), 3.51–3.57 (m, 1H), column (eluent, 2-propanol–hexane 2 : 98; flow rate: 1.0 mL
3.71–3.77 (m, 1H), 4.94 (m, 1H), 7.26–7.35 (m, 4H). 13C NMR min−1; detection: 254 nm light); tR (major) = 22.34 min;
(100 MHz, CDCl3): δ 41.43, 41.54, 70.67, 127.17, 128.81, tR (minor) = 28.14 min. [α]2D0 = –34.2 (c = 1.0 in CHCl3).
133.59, 142.20. IR (thin film): νmax (cm−1) = 3385, 2962, 2925,
(−)-4-Chloro-1-(4-fluorophenyl)butan-1-ol (6f).24 1H NMR
1596, 1491, 1430, 1136, 1091, 1055, 925, 827, 736, 699. MS (EI, (400 MHz, CDCl3): δ 1.77–1.92 (m, 5H), 3.54–3.56 (m, 2H),
m/z, relative intensity): 206 (M+, 4), 204 (M+, 6), 169 (1), 167 (1), 4.69–4.70 (m, 1H), 7.02–7.06 (m, 2H), 7.30–7.36 (m, 2H). 13C
141 (100), 133 (1), 77 (49), 63 (5), 51 (8).
NMR (100 MHz, CDCl3): δ 28.87, 36.27, 44.91, 73.29, 115.42 (d,
The conversion was determined by capillary GC with a 30 m JC,F = 21.3 Hz), 127.45 (d, JC,F = 7.9 Hz), 140.06 (d, JC,F = 2.8
× 0.25 mm INNOWAX column; 200 °C; isothermal; tR (5b) = Hz), 162.34 (d, JC,F = 244.1 Hz). IR (thin film): νmax (cm−1) =
2.99 min; tR (6b) = 18.63 min. The ee value was determined by 3386, 2957, 2926, 1605, 1510, 1445, 1223, 1157, 1067, 837, 726,
chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel OD-H 651. MS (EI, m/z, relative intensity): 165 ([M − Cl]+, 2), 125
column (eluent, 2-propanol–hexane 2 : 98; flow rate: 1.0 mL (100), 109 (8), 97 (42), 77 (14), 63 (2), 63 (6), 41 (6).
min−1; detection: 254 nm light); tR (major) = 18.39 min;
tR (minor) = 22.72 min. [α]2D0 = –15.6 (c = 1.0 in CHCl3).
The conversion was determined by capillary GC with a 30 m
× 0.25 mm INNOWAX column; 180 °C; isothermal; tR (5f) =
(−)-1-(4-Bromophenyl)-3-chloropropan-1-ol (6c).21 1H NMR 9.84 min; tR (6f) = 2.73 min. The ee value was determined by
(400 MHz, CDCl3): δ 2.00–2.23 (m, 3H), 3.51–3.57 (m, 1H), chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel OD-H
3.70–3.77 (m, 1H), 4.91–4.94 (m, 1H), 7.23–7.50 (m, 4H). 13C column (eluent, 2-propanol–hexane 2 : 98; flow rate: 1.0 mL
NMR (100 MHz, CDCl3): δ 41.36, 41.57, 70.66, 121.69, 127.53, min−1; detection: 254 nm light); tR (major) = 18.72 min;
131.77, 142.72. IR (thin film): νmax (cm−1) = 3386, 2959, 2924, tR (minor) = 21.30 min. [α]D20 = –39.8 (c = 1.0 in CHCl3).
1592, 1486, 1407, 1287, 1104, 1070, 927, 823, 729, 663. MS (EI,
m/z, relative intensity): 250 (M+, 8), 248 (M+, 6), 217 (1), 215 (3), (400 MHz, CDCl3): δ 1.78–1.93 (m, 5H), 3.55–3.59 (m, 2H),
185 (100), 157 (17), 105 (6), 91 (5), 77 (57), 63 (7), 51 (12).
4.70–4.72 (m, 1H), 7.28–7.34 (m, 4H). 13C NMR (100 MHz,
(−)-4-Chloro-1-(4-chlorophenyl)butan-1-ol (6g).25 1H NMR
The conversion was determined by capillary GC with a 30 m CDCl3): δ 28.75, 36.19, 44.85, 73.21, 127.18, 128.70, 133.38,
× 0.25 mm INNOWAX column; 180 °C; isothermal; tR (5c) = 142.78. IR (thin film): νmax (cm−1) = 3396, 2956, 2925, 2870,
7.00 min; tR (6c) = 25.32 min. The ee value was determined by 1596, 1491, 1445, 1297, 1136, 1090, 1014, 830, 728, 699, 649.
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MS (EI, m/z, relative intensity): 183 ([M − Cl]+, 14), 181 ([M − determined by chiral HPLC analysis with a 25 cm × 4.6 mm
Cl]+, 42), 147 (100), 139 (98), 125 (11), 115 (23), 105 (23), Daicel Chiralcel OB-H column (eluent, 2-propanol–hexane
77 (24), 63 (10), 51 (11).
5 : 95; flow rate: 1.0 mL min−1; detection: 254 nm light);
The conversion was determined by capillary GC with a 30 m tR (major) = 14.4 min; tR (minor) = 18.26 min. [α]2D0 = –16.8
× 0.25 mm INNOWAX column; 200 °C; isothermal; tR (5g) = (c = 1.0 in CHCl3).
4.11 min; tR (6g) = 3.40 min. The ee value was determined by
(−)-6-Chloro-1-(4-methoxyphenyl)hexan-1-ol (8d).27 1H NMR
chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel OD-H (400 MHz, CDCl3): δ 1.43–1.47 (m, 4H), 1.72–1.82 (m, 5H),
column (eluent, 2-propanol–hexane 2 : 98; flow rate: 1.0 mL 3.49–3.53 (m, 2H), 3.80 (s, 3H), 4.60–4.63 (m, 1H), 6.87–6.89
min−1; detection: 254 nm light); tR (major) = 19.66 min; tR (m, 2H), 7.25–7.27 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
(minor) = 23.71 min. [α]2D0 = –34.3 (c = 1.0 in CHCl3).
25.18, 26.77, 32.52, 38.73, 45.07, 55.31, 74.09, 113.84, 127.14,
(−)-6-Chloro-1-o-tolylhexan-1-ol (8a). 1H NMR (400 MHz, 136.90, 159.03. IR (thin film): νmax (cm−1) = 3392, 2935, 2859,
CDCl3): δ 1.37–1.53 (m, 4H), 1.67–1.84 (m, 5H), 2.34 (s, 3H), 1612, 1585, 1512, 1443, 1247, 1175, 1035, 832, 731, 649. MS
3.50–3.53 (m, 2H), 4.90–4.94 (m, 1H), 7.12–7.46 (m, 4H). 13C (EI, m/z, relative intensity): 207 ([M − Cl]+, 6), 147 (100), 121
NMR (100 MHz, CDCl3): δ 19.08, 25.31, 26.81, 32.54, 37.84, (34), 91 (43), 77 (13), 41 (12).
45.04, 70.53, 125.08, 126.30, 127.19, 130.40, 134.39, 142.88. IR
The conversion was determined by capillary GC with a 30 m
(thin film): νmax (cm−1) = 3385, 2936, 2860, 1488, 1461, 1379, × 0.25 mm INNOWAX column; 220 °C; isothermal; tR (7d) =
1181, 758, 728, 650. MS (EI, m/z, relative intensity): 228 (M+, 23.48 min; tR (8d) = 8.98 min. The ee value was determined by
0.7), 226 (M+, 2), 121 (100), 105 (5), 77 (12), 51 (1), 41 (5). chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel AD-H
HRMS (ESI) Calcd for C13H19ClNaO 249.1019; Found 249.1012 column (eluent, 2-propanol–hexane 5 : 95; flow rate: 1.0 mL
[M + Na]+.
The conversion was determined by capillary GC with a 30 m (minor) = 25.98 min. [α]2D0 = –53.5 (c = 1.0 in CHCl3).
× 0.25 mm INNOWAX column; 220 °C; isothermal; tR (7a) = (−)-2-Bromo-1-(thiophen-2-yl)ethanol
(10a).28 1H
min−1; detection: 254 nm light); tR (major) = 28.50 min; tR
NMR
6.85 min; tR (8a) = 11.80 min. The ee value was determined by (400 MHz, CDCl3): δ 2.88 (br, 1H), 3.60–3.70 (m, 2H), 5.14–5.17
chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel OD-H (m, 1H), 6.98–7.30 (m, 3H). 13C NMR (100 MHz, CDCl3):
column (eluent, 2-propanol–hexane 2 : 98; flow rate: 1.0 mL δ 39.47, 70.00, 124.73, 125.39, 126.95, 143.78. IR (thin film):
min−1; detection: 254 nm light); tR (major) = 17.92 min; tR νmax (cm−1) = 3406, 2958, 2925, 2854, 1437, 1419, 1378, 1219,
(minor) = 20.49 min. [α]2D0 = –45.8 (c = 1.0 in CHCl3).
1065, 850, 703, 657. MS (EI, m/z, relative intensity): 208 (M+, 5),
(−)-6-Chloro-1-(3-methoxyphenyl)hexan-1-ol (8b).26 1H NMR 206 (M+, 5), 126 (2), 113 (100), 85 (37), 45 (14).
(400 MHz, CDCl3): δ 1.45 (m, 4H), 1.67–1.79 (m, 4H), 1.97 (br,
The conversion was determined by capillary GC with a 30 m
1H), 3.49–3.52 (m, 2H), 3.80 (s, 3H), 4.63 (m, 1H), 6.80–7.27 × 0.25 mm INNOWAX column; 180 °C; isothermal; tR (9a) =
(m, 4H). 13C NMR (100 MHz, CDCl3): δ 25.09, 26.77, 32.52, 8.98 min; tR (10a) = 15.13 min. The ee value was determined by
38.80, 45.03, 55.24, 74.41, 111.40, 112.96, 118.20, 129.50, chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel OJ-H
146.53, 159.78. IR (thin film): νmax (cm−1) = 3407, 2936, 2859, column (eluent, 2-propanol–hexane 5 : 95; flow rate: 1.0 mL
1601, 1586, 1487, 1456, 1316, 1156, 1045, 877, 785, 746, 700, min−1; detection: 254 nm light); tR (major) = 27.63 min; tR
649. MS (EI, m/z, relative intensity): 244 (M+, 11), 242 (M+, 4), (minor) = 35.83 min. [α]D20 = –32.3 (c = 1.0 in CHCl3).
137 (100), 121 (5), 109 (78), 77 (20), 41 (7).
(S)-3-Chloro-1-(thiophen-2-yl)propan-1-ol (10b).29 1H NMR
The conversion was determined by capillary GC with a 30 m (400 MHz, CDCl3): δ 2.16–2.36 (m, 3H), 3.55–3.60 (m, 1H),
× 0.25 mm INNOWAX column; 200 °C; isothermal; tR (7b) = 3.71–3.77 (m, 1H), 5.19–5.21 (m, 1H), 6.97–7.28 (m, 3H).
16.92 min; tR (8b) = 25.22 min. The ee value was determined 13C NMR (100 MHz, CDCl3): δ 41.43, 41.46, 67.15, 124.13,
by chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel OB-H 124.99, 126.80, 147.42. IR (thin film): νmax (cm−1) = 3399, 2955,
column (eluent, 2-propanol–hexane 5 : 95; flow rate: 1.0 mL 2925, 2854, 1458, 1377, 1307, 1135, 1063, 852, 699, 649. MS
min−1; detection: 254 nm light); tR (major) = 31.10 min; (EI, m/z, relative intensity): 179 (M+, 0.7), 177 (M+, 3), 163 (1),
tR (minor) = 39.12 min. [α]2D0 = –15.4 (c = 1.0 in CHCl3).
91 (100), 85 (8), 77 (98), 45 (86).
(−)-1-(3-Bromophenyl)-6-chlorohexan-1-ol (8c).27 1H NMR
The conversion was determined by capillary GC with a 30 m
(400 MHz, CDCl3): δ 1.29–1.48 (m, 4H), 1.67–1.81 (m, 4H), 1.90 × 0.25 mm INNOWAX column; 180 °C; isothermal; tR (9b) =
(br, 1H), 3.50–3.53 (m, 2H), 4.65–4.68 (m, 1H), 7.19–7.25 (m, 3.69 min; tR (10b) = 16.43 min. The ee value was determined
2H), 7.39–7.53 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 25.0, by chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel
26.7, 32.5, 38.9, 45.0, 73.8, 122.6, 124.5, 129.0, 130.1, 130.6, OD-H column (eluent, 2-propanol–hexane 2 : 98; flow rate:
147.1. IR (thin film): νmax (cm−1) = 3405, 2930, 2862, 1600, 1.0 mL min−1; detection: 254 nm light); tR (S) = 28.23 min;
1582, 1455, 1322, 1045, 876, 780, 750, 649. MS (EI, m/z, relative tR (R) = 32.22 min. [α]2D0 = –32.3 (c = 1.0 in CHCl3).
intensity): 292 (M+, 19), 290 (M+, 15), 257 ([M − Cl]+, 1), 255 (−)-4-Chloro-1-(thiophen-2-yl)butan-1-ol (10c).23 1H NMR
([M − Cl]+, 1), 187 (100), 185 (100), 159 (55), 157 (62), 77 (100), (400 MHz, CDCl3): δ 1.82–2.03 (m, 4H), 2.13 (br, 1H), 3.56–3.61
41 (40).
(m, 2H), 4.94–4.96 (m, 1H), 6.96–7.27 (m, 3H). 13C NMR
The conversion was determined by capillary GC with a 30 m (100 MHz, CDCl3): δ 28.92, 36.44, 44.87, 69.70, 123.92, 124.82,
× 0.25 mm J & W Scientific INNOWAX column; 230 °C; isother- 126.76, 148.23. IR (thin film): νmax (cm−1) = 3414, 3051, 2956,
mal; tR (7c) = 14.48 min; tR (8c) = 4.01 min. The ee value was 2925, 2869, 1665, 1443, 1431, 1311, 1134, 1069, 853, 786, 699,
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650. MS (EI, m/z, relative intensity): 154 ([M − Cl]+, 94), 111 Procedure for the synthesis of (S)-duloxetine (2)2c,e
(100), 97 (34), 84 (20), 58 (6).
The conversion was determined by capillary GC with a
30 m × 0.25 mm INNOWAX column; 180 °C; isothermal; tR (9c)
The nonracemic alcohol (S)-10b was furnished via the copper-
catalyzed asymmetric hydrosilylation of 9b (524 mg, 3.0 mmol)
under the aforementioned conditions in 80% yield (423 mg)
and 95% ee. Then, a mixture of (S)-3-chloro-1-(thiophen-2-yl)-
= 15.54 min; tR (10c) = 4.67 min. The ee value was determined
by chiral HPLC analysis with a 25 cm × 4.6 mm Chiralcel
propan-1-ol (423 mg, 2.4 mmol) and NaI in saturated acetone
OD-H column (eluent, 2-propanol–hexane 2 : 98; flow rate:
solution (50 mL), protected from light, was refluxed for 16 h.
1.0 mL min−1
; detection: 254 nm light); tR (major) =
The reaction mixture was filtered to remove the precipitated
NaCl and concentrated in vacuo. The residue was dissolved in
water (30 mL) and extracted with Et2O (3 × 20 mL). The com-
bined extract was washed with sat NaCl, dried with MgSO4 to
yield (S)-12 (642 mg, >99% yield) as a yellow oil. GC purity was
100%, hence (S)-12 was used without further purification.
A solution of (S)-12 (642 mg, 2.4 mmol) in THF (15 mL) was
mixed with methylamine (40% aqueous, 2.0 mL, 24 mmol).
The mixture was stirred at room temperature under a N2
atmosphere for 12 h. After the reaction mixture was treated
with 5 mol L−1 NaOH (2 mL) and then concentrated in vacuo,
water (15 mL) was added, and the mixture was extracted with
Et2O (3 × 20 mL). The combined extracts were washed with
saturated brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by flash chromatography (CH2Cl2–
MeOH–NH4OH, 40 : 10 : 1) to yield (S)-14 in 80% yield
(328.8 mg).
To NaH (456 mg, 19 mmol) suspended in pentane (6 mL)
and dimethylacetamide (8 mL), was added a solution of (S)-14
(328.8 mg, 1.9 mmol) in dimethylacetamide (8 mL), and the
mixture was heated to 60–70 °C for 1 h. When the solution
became clear, 1-fluoronaphthalene (277.7 mg, 1.9 mmol) was
added. The temperature was raised to 90 °C, and the reaction
was stirred for an additional 48 h. The mixture was poured
into water (40 mL), and extracted with Et2O (3 × 20 mL). The
extract was washed with saturated brine, dried with Na2SO4,
and concentrated under reduced pressure. The residue was
purified by flash chromatography (CH2Cl2–MeOH–NH4OH,
100 : 10 : 1) to afford (S)-duloxetine (350 mg) in 62% yield.
(S)-Duloxetine (2).2c,e 1H NMR (400 MHz, CDCl3): δ 1.75 (br,
1H), 2.20–2.24 (m, 1H), 2.42 (s, 3H), 2.44–2.48 (m, 1H),
2.80–2.84 (m, 2H), 5.76–5.79 (m, 1H), 6.84–7.05 (m, 3H),
7.19–7.49 (m, 5H), 7.76–7.78 (m, 1H), 8.34–8.36 (m, 1H). 13C
NMR (100 MHz, CDCl3): δ 36.58, 39.00, 48.34, 74.74, 106.98,
120.64, 122.17, 124.62, 124.77, 125.31, 125.78, 126.11, 126.38,
126.63, 127.54, 134.58, 145.21, 153.34. IR (thin film): νmax
(cm−1) = 3052, 2927, 2846, 2793, 1595, 1578, 1462, 1397, 1236,
1177, 1064, 791, 771, 731. MS (EI, m/z, relative intensity): 297
(M+, 1), 144 (94), 115 (100), 89 (14), 72 (9), 28 (8). [α]2D0 = +73.3
(c = 0.4, CH3OH). Literature data: [α]2D2 = +75 (c = 1.0, CH3OH).
40.84 min; tR (minor) = 62.85 min. [α]2D0 = –21.4 (c = 1.0 in
CHCl3).
Procedure for the synthesis of (R)-fluoxetine (1)2b
The nonracemic alcohol (R)-6a was furnished via the copper-
catalyzed asymmetric hydrosilylation of 5a (505.9 mg,
3.0 mmol) under the aforementioned conditions in 94% yield
(481 mg) and 97% ee. Then, a solution of (R)-3-chloro-1-
phenyl-1-propanol (481 mg, 2.8 mmol) in 50 mL of acetone
that had been saturated with sodium iodide was refluxed for
16 h. The acetone was removed under reduced pressure.
Product isolation (water, ether, water, brine, Na2SO4) provided
nearly homogeneous product (R)-11 (738.7 mg, >99% yield)
as a light red oil that was used without further purification.
An analytical sample was prepared by recrystallization
from hexane–ether to provide white crystals with mp
55–56 °C.
A solution of (R)-3-iodo-1-phenyl-1-propanol (738.7 mg,
2.8 mmol) and methylamine (2.2 mL of a 40% solution in
water, 28 mmol) in 15 mL of THF was stirred at room tempera-
ture for 12 h. The solvent was removed under reduced pressure
and then brine and 2 mL of 2 N sodium hydroxide was added.
Product isolation (ether, brine, Na2SO4) provided homo-
geneous
453.3 mg, 98% yield) as an oil.
mixture of (R)-3-(methylamino)-1-phenyl-1-propanol
(R)-3-(methylamino)-1-phenyl-1-propanol
((R)-13,
A
(453.3 mg, 2.7 mmol) and sodium hydride (677 mg of a 60%
dispersion in oil, 28.2 mmol; oil removed with hexane) in
15 mL of dimethylacetamide was heated to 70 °C for 0.5 h.
p-Fluorobenzotrifluoride (487.5 mg, 2.7 mmol) was added and
the reaction was heated at 93 °C for 2.5 h. After the mixture
cooled to room temperature, product isolation (water, ether,
water, brine, Na2SO4) and flash chromatography [silica
gel, methanol/methylene chloride/ammonium hydroxide
(10/100/l)] provided homogeneous (R)-fluoxetine as an oil
(634.7 mg, 84% yield).
(R)-Fluoxetine (1).2b 1H NMR (400 MHz, CDCl3): δ 2.00–2.04
(m, 1H), 2.18–2.23 (m, 1H), 2.44 (s, 3H), 2.73–2.77 (m, 2H),
5.29–5.32 (m, 1H), 6.89–7.44 (m, 9H). 13C NMR (100 MHz,
CDCl3): δ 36.34, 38.57, 48.15, 78.56, 115.74, 125.76, 126.69,
126.73, 126.81, 127.86, 128.81, 140.95, 160.48. IR (thin film):
Acknowledgements
νmax (cm−1) = 3032, 2927, 2852, 2797, 1615, 1517, 1454, 1328, We thank the National Natural Science Foundation of China
1251, 1112, 1068, 1009, 835, 756, 701, 637. MS (EI, m/z, relative (21172049, 91127010, 21032003, 21072039), the Program for
intensity): 309 (M+, 2), 251 (1), 162 (9), 145 (6), 104 (12), Changjiang Scholars and Innovative Research Team in
44 (100). [α]2D0 = −14.7 (c = 1.0 in CHCl3), Literature data: Chinese University (IRT 1231), the Zhejiang Provincial Natural
[α]2D3 = –13.8 (c = 1.0, CHCl3).
Science Foundation of China (LZ13B030001), the Public
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Welfare Technology and Application Program of Zhejiang Pro-
vince (2010C31042) and the Special Funds for Key Innovation
Team of Zhejiang Province (2010R50017) for generous finan-
cial support of this research.
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