Chemoenzymatic asymmetric synthesis of fluoxetine, atomoxetine, nisoxetine, and duloxetine

Article abstract of DOI:10.1016/j.tetasy.2013.06.003

The asymmetric synthesis of two well-known anti-depressant drugs, fluoxetine and duloxetine has been accomplished in a chemoenzymatic manner. The main highlight of the synthesis is the enantioselective cyanohydrin formation by a plant (R)-HNL (hydroxynitrile lyase). The enantiopure cyanohydrins are then synthetically manipulated into the above two drug molecules and two of their structural analogues, atomoxetine and nisoxetine.

Full text of DOI:10.1016/j.tetasy.2013.06.003

Tetrahedron: Asymmetry 24 (2013) 913–918
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chemoenzymatic asymmetric synthesis of fluoxetine, atomoxetine,
nisoxetine, and duloxetine
⇑
Rohan Kalyan Rej, Tapas Das, Suman Hazra, Samik Nanda
Department of chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric synthesis of two well-known anti-depressant drugs, fluoxetine and duloxetine has been
accomplished in a chemoenzymatic manner. The main highlight of the synthesis is the enantioselective
cyanohydrin formation by a plant (R)-HNL (hydroxynitrile lyase). The enantiopure cyanohydrins are then
synthetically manipulated into the above two drug molecules and two of their structural analogues, ato-
moxetine and nisoxetine.
Received 9 May 2013
Accepted 14 June 2013
Available online 12 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
name Cymbalta, Ariclaim, Duzela, Yentreve, and a few others) be-
longs to the SNRI class and was manufactured and marketed by
Selective serotonin re-uptake inhibitors or serotonin-specific
reuptake inhibitor (SSRIs) are a class of organic molecules gener-
ally used as antidepressants for the treatment of several depression
related disorders. They are believed to enhance the extracellular le-
vel of serotonin (the well-known neurotransmitter) by inhibiting
its reuptake in the presynaptic cell.1 Serotonin–norepinephrine
reuptake inhibitors (SNRIs) are another class of organic molecules
used mainly in the treatment of major depression. In principle,
SNRIs are able to increase the level of two neurotransmitters (sero-
tonin and norepinephrine) in the brain which are known to play an
important role in mood related phenomenon.2 Fluoxetine (known
as Prozac, Saraferm, Fomtex as brand names) belongs to the SSRI
class and is a very well-known antidepressant developed by Eli-
Lilly in 1987. Fluoxetine was a blockbuster drug during the early
1990s and its estimated annual sales reached US$350 million with-
in a year, as the drug was off patented in 2001 several generic ver-
sions came into the market. Duloxetine (sold under the brand
Eli-Lilly and used mainly in the treatment of major depression
and general anxiety disorder (GAD). Atomoxetine is another drug
that belongs to the norepinephrine reuptake inhibitor (NRI or
NERI) class and acts as a reuptake inhibitor of norepinephrine.3 It
blocks the action of norepinephrine transporter receptor and hence
leads to enhanced concentration of that neurotransmitter in adren-
ergic neurotransmission. Atomoxetine was manufactured by Eli-
Lilly and sold under the brand name Strattera worldwide and is ap-
proved for the treatment of ADHD (attention deficit hyperactivity
disorder).4 Nisoxetine, which is structurally similar to fluoxetine
and atomoxetine was first synthesized by Eli-Lilly in 1970; it also
belongs to the NRI class, and while it was not marketed, it was used
widely in biochemical experiments as a selective NRI agent.
All of the aforementioned molecules have a common structural
unit, N-methyl-3-aryloxy-3-aryl-proylamine (Fig. 1) hence a com-
mon intermediate would be effective for accessing all of these mol-
ecules in an efficient way. Numerous synthetic reports exist in the
R
O
F3C
O
O
NHMe
NHMe
NHMe
S
(R)-fluoxetine 1
(R)-duloxetine 2
R = Me, (R)-atomoxetine 3
R = OMe, (R)-nisoxetine 4
Figure 1. Structure of the (R)-enantiomer of fluoxetine, duloxetine, atomoxetine, and nisoxetine.
⇑
Corresponding author. Tel.: +91 3222283328.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.06.003

914
R. K. Rej et al. / Tetrahedron: Asymmetry 24 (2013) 913–918
literature describing the asymmetric synthesis of all of the four
molecules.5
from the corresponding c,d-unsaturated aldehydes with excellent
enantioselection.8b We have also synthesized some novel enantio-
pure aromatic cyanohydrins from the respective aromatic alde-
hydes.8c At this point we thought that it would be appropriate to
use the new enzyme ParsHNL for the asymmetric biocatalytic syn-
thesis of a few enantiopure cyanohydrins which can be syntheti-
cally manipulated to drug molecules such as fluoxetine,
atomoxetine, nisoxetine, and duloxetine.
2. Results and discussion
To the best of our knowledge enantiopure cyanohydrins have
not been used as chiral intermediates for the synthesis of the above
molecules. Although fluoxetine was sold as a racemic compound, it
was later shown that the (R)-enantiomer is the so-called ‘Improved
Chemical Entity’ version of the drug.6 Herein we report the asym-
metric synthesis of the (R)-enantiomer of all of these four mole-
cules from enantiopure cyanohydrins. The retrosynthetic analysis
is presented below (Scheme 1). One of the most promising and
interesting way to synthesize enantiomerically pure cyanohydrins
is the HNL catalyzed addition of a cyanide source to the respective
carbonyl compounds.7 HNLs are now widely used as efficient bio-
catalysts for the asymmetric synthesis of various cyanohydrins.
The resulting cyanohydrins are versatile intermediates for a broad
variety of chiral synthons. The reaction is extremely important,
since it allows the synthesis of enantiomerically pure compounds
from prochiral substrates in a quantitative yield.
We have started our synthesis from commercially available
benzaldehyde. An asymmetric hydrocyanation reaction with Prunus
armeniaca hydroxynitrile lyase (ParsHNL) and HCN in DIPE (diiso-
propyl ether) solvent afforded the corresponding (R)-cyanohydrin
[(R)-mandelonitrile] in 92% yield (er = 98%). The enzymatic hydrocy-
anation with hydroxynitrile lyase is a well documented strategy for
the asymmetric synthesis of cyanohydrins, and we have explored
the methodology extensively by using an (R)-HNL (hydroxynitrile
lyase from Prunus armeniaca) from Himalayan apricot (Shakarpara
cultivar). The reaction is very efficient in terms of chemical
yield and excellent enantioselection is obtained in the product
cyanohydrin. (R)-Mandelonitrile serves as a chiral intermediate for
the synthesis of fluoxetine, atomoxetine, and nisoxetine.
R
F3C
OH
O
O
NHMe
NHMe
NHMe
(S)-3-(methylamino)-1-phenylpropan-1-ol 5
R = Me, (R)-atomoxetine 3
R = OMe, (R)-nisoxetine 4
(R)-fluoxetine 1
OP
OH
CHO
ParsHNL
CN
(R)-mandelonitrile
OH
OH
ParsHNL
CHO
CN
O
NHMe
S
S
S
NHMe
S
(S)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol 6
(R)-duloxetine 2
Scheme 1. Retrosynthetic analysis of fluoxetine, atomoxetine, nisoxetine, and duloxetine by enzymatic hydrocyanation.
We envisioned that (S)-3-(methylamino)-1-phenylpropan-1-ol
2-Thiophene-carboxaldehyde was subjected to an asymmetric
hydrocyanation reaction by employing similar reaction conditions
as stated above. The respective enantiopure cyanohydrin was ob-
tained in 88% yield with excellent enantioselection (er = 97%). In
general, we followed the modified method developed by Griengl
et al.9for the HNL catalyzed hydrocynation reaction (see Section 4
for details).
With the enantiopure cyanohydrins in hand, we then proceeded
further for the total synthesis of the target molecules. (R)-Mandel-
onitrile was protected as its TBS (tert-butyldimethyl silyl) ether by
treatment with imidazole and TBS–Cl at 25 °C to afford the pro-
tected cyanohydrin 7 in 88% yield. Compound 7 was not purified
further, and so the crude mixture of 7 was subjected to DIBAL-H
treatment at ꢀ78 °C for 2 h, which yielded the corresponding alde-
hyde 8 in almost quantitative yield. The aldehyde after usual work-
up (no chromatographic separation is needed) was subjected to
one carbon Wittig olefination with Ph3P@CH2 to afford olefin 9 in
5 could act as a common intermediate for the synthesis of the
(R)-enantiomer of fluoxetine 1, atomoxetine 3, and nisoxetine 4
by Mitsunobu inversion with the required phenols. In the case of
duloxetine 2, the Mitsunobu reaction of 1-naphthol with (S)-3-
(methylamino)-1-(thiophen-2-yl)propan-1-ol 6 would lead to the
target molecule. The intermediates 5 and 6 were planned to be
synthesized from the respective cyanohydrins by straightforward
synthetic manipulation. The enantiopure cyanohydrins were ac-
cessed from their respective aldehydes by an HNL route developed
earlier in our group. Recently we have found a new (R)-HNL from
white apricot (shakarpara cultivar, found in the Himalayan region
of Nepal and India; Prunus armeniaca). The new enzyme (ParsHNL)
exhibits excellent enantioselectivity during the preparation of sev-
eral cyanohydrins from aliphatic and aromatic carbonyl com-
pounds.8 By employing this newly found HNL we have
synthesized several enantiopure d,e-unsaturated cyanohydrins

R. K. Rej et al. / Tetrahedron: Asymmetry 24 (2013) 913–918
915
82% yield. Compound 9 upon hydroboration with BH3 SMe2
3. Conclusion
afforded the corresponding alcohol 10 in 86% yield (no chro-
matographic separation was needed). Alcohol 10 was then
treated with methanesulfonyl chloride (Ms-Cl) and Et3N to fur-
nish the respective mesylate 11 in 90% yield (no chromato-
graphic separation is needed). Mesylate 11 upon treatment
with an aq. solution of 40% MeNH2 in refluxing THF afforded
the corresponding amine 12 in 78% yield. Desilylation (TBS
deprotection) of compound 12 was achieved by treatment
with TBAF/THF to afford aminoalcohol 5 in 88% yield (no chro-
matographic separation was needed). Mitsunobu reaction10 of 5
with 4-trifluromethyl phenol, 2-methyl phenol, and 2-methoxy
phenol afforded fluoxetine 1 (overall yield = 23%), atomoxetine
3 (overall yield = 24.7%), and nisoxetine 4 (overall yield = 23.5%),
respectively, (Scheme 2). For the synthesis of (R)-duloxetine, a
similar reaction sequence was applied starting from (S)-2-
In conclusion, we have reported an efficient and general syn-
thetic strategy for the enantiopure synthesis of a few important
antidepressant drug molecules. The main highlight of our synthesis
is the enzymatic formation of enantiopure cyanohydrins from their
respective aldehydes by a plant HNL (ParsHNL). The enantiopure
cyanohydrins were then synthetically manipulated to the target
molecules. It is also noteworthy that out of the nine synthetic steps
employed, we have used chromatographic purification methods in
only three steps. As a result, the synthesis is cost effective and
green also, as chromatographic separation in some steps is
avoided.
4. Experimental
4.1. General
hydroxy-2-(thiophen-2-yl)acetonitrile. By following
a similar
strategy, we obtained compound 6 in good yield. The Mitsunobu
reaction of compound 6 with 1-naphthol afforded the target
molecule (R)-duloxetine (overall yield = 21% from compound
13).
Unless otherwise stated, materials were obtained from com-
mercial suppliers and used without further purification. Benzalde-
hyde and thiophene-2-carbaldehyde were freshly distilled or
OTBS
CHO
OH
OTBS
CN
CHO
c
a
b
CN
8
7
(R)-mandelonitrile
d
OTBS
OTBS
OTBS
e
f
OMs
OH
10
11
9
g
R
OTBS
OH
O
h
i
NHMe
NHMe
NHMe
12
5
R = 4-CF3, fluoxetine 1
R = 2-Me, atomoxetine 3
R = 2-OMe, nisoxetine 4
OP
OTBS
CHO
OTBS
e
CHO
a
c
d
CN
S
S
S
S
16
15
13; P = H
14
b
; P = TBS
OTBS
OH
h
i
OR
NHMe
O
6
S
S
17; R = H
f
NHMe
18; R = Ms
S
g
19; R = NHMe
(R)-duloxetine 2
Scheme 2. Reagents and conditions: (a) HCN in iPr2O, ParsHNL, citrate buffer (pH 4.0), 92% (90% for 13); (b) imidazole, TBS–Cl, rt, 88% (92% for 14); (c) DIBAL-H, ꢀ78 °C; (d)
LHMDS, Ph3P+MeIꢀ, 0 °C, 82% (75% for 16); (e) BH3 SMe2, 0 °C, H2O2, NaOH, 86% (84% for 17); (f) MeSO2Cl, Et3N, DMAP, 90% (88% for 18); (g) MeNH2 (40% aq), THF, 78% (72% for
19); (h) TBAF, THF, 88% (90% for 6); (i) Ph3P, DIAD, THF, Ar-OH.

916
R. K. Rej et al. / Tetrahedron: Asymmetry 24 (2013) 913–918
washed with an aq NaHCO3 solution in order to minimize the
amount of free acid, which is supposed to inhibit HNL activity.
The enzymatic hydrocyanation reactions were performed in well
ventilated fume hoods with proper glassware, handware (gloves),
and using a mask if necessary. Any excess HCN remaining after
the reaction was destroyed cautiously by treatment with an excess
of bleach solution and disposed of in a proper way. Reactions were
monitored by TLC, carried out on 0.25 mm silica gel plates (Merck)
with UV light, ethanolic anisaldehyde, and phosphomolybdic acid/
heat as developing agents. Silica gel 100–200 mesh was used for
column chromatography. Yields refer to chromatographically and
spectroscopically homogeneous materials unless otherwise stated.
NMR spectra were recorded on 200 MHz spectrometer at 25 °C in
CDCl3 using TMS as the internal standard. Chemical shifts are
shown in d. 13C NMR spectra were recorded with a complete pro-
ton decoupling environment. The chemical shift value is listed as
dH and dC for 1H and 13C, respectively. Chiral HPLC was performed
using chiral OJ-H column (0.46 ꢁ 25 cm, Daicel industries) with
Shimadzu Prominence 20AT and UV–vis detector (254 nm). Eluting
solvent used was different ratios of hexane and 2-propanol.
ꢀ45 °C, and the mixture was warmed up to 0 °C. After stirring for
1 h at this temperature, the reaction mixture was poured into a
mixture of ether and saturated aqueous ammonium chloride solu-
tion and extracted with ether. The organic layer was washed with
brine and dried over MgSO4. It was then concentrated in a rotary
evaporator which yielded the corresponding aldehyde 8 in almost
quantitative yield, which was used in the next step without any
further purification.
½
a 2D8
ꢂ
¼ ꢀ19:5 (c 0.6, CHCl3). 1H NMR
(200 MHz, CDCl3): 9.54 (d, J = 2 Hz, 1H), 7.42–7.30 (m, 5H), 5.04
(d, J = 2.2 Hz, 1H), 0.97 (s, 9H), 0.15 (s, 3H), 0.07 (s, 3H). 13C NMR
(50 MHz, CDCl3): 199.6, 136.7, 128.8, 128.5, 126.5, 80.1, 25.9,
18.4, ꢀ4.6.
4.6. ((S)-1-Phenylallyloxy)(tert-butyl)dimethylsilane 9
To a suspension of methyltriphenylphosphonium iodide (1.5 g,
3.74 mmol) in dry THF was added LiHMDS (3.4 ml) at 0 °C. The yel-
low mixture was stirred at 0 °C for 15 min. A solution of the alde-
hyde 8 (800 mg, 3.23 mmol) in 10 ml of THF was added to the
reaction mixture. The yellow suspension was then stirred at room
temperature for a further 1 h. After completion of the reaction, as
indicated by TLC analysis, the reaction was quenched with water
and the layers were separated. The organic layer was extracted
with 50 ml of ether, washed with brine, and dried over MgSO4.
The solvent was removed in vacuo and the crude residue was puri-
fied by flash column chromatography to afford compound 9
4.2. (R)-2-Hydroxy-2-phenylacetonitrile
To a solution of benzaldehyde (1.06 g, 1.0 mol) in DIPE (60 ml),
a solution of ParsHNL (300 IU/10 mmol of aldehyde, approximately
10 ml of crude enzyme solution) was added and the resulting mix-
ture was stirred vigorously until an emulsion was formed. The pH
of the enzyme solution was previously adjusted to 4.0 with 10% cit-
ric acid solution. Freshly prepared HCN in DIPE (2 equiv) was
added to it, and the temperature of the solution was kept at
10 °C. After completion of the reaction, it was extracted thoroughly
with ether several times and the organic layer was dried over
MgSO4. Evaporation of the solvent yielded the crude cyanohydrin
in 92% yield. The (R)-mandelonitrile obtained provides comparable
spectroscopic and optical data with those reported in the
literature.11
(EtOAc/hexane = 1:20) in 82% yield. ½a D28
¼ ꢀ31:4 (c 0.9, CHCl3).
ꢂ
1H NMR (200 MHz, CDCl3): 7.47–7.29 (m, 5H), 6.13–5.96 (m, 1H),
5.44–5.14 (m, 3H), 1.04 (s, 9H), 0.21 (s, 3H), 0.12 (s, 3H). 13C
NMR (50 MHz, CDCl3): 143.9, 141.9, 128.4, 127.2, 126.2, 113.5,
76.1, 26.1, 18.5, ꢀ4.4, ꢀ4.5. HRMS (ESI) for C15H24NaOSi [M+Na]+,
calcd 271.1494, found: 271.1490.
4.7. (S)-3-(tert-Butyldimethylsilylyloxy)-3-phenylpropan-1-ol
10
To a cooled (0 °C), stirred solution of 9 (635 mg, 2.56 mmol) in
THF (8 ml) was added BH3 SMe2 (1.4 ml, 2.8 mmol). The mixture
was stirred for an additional 2 h and then quenched with EtOAC
(30 ml) followed by the addition of 1 M aqueous NaOH (4.6 ml)
and 30% H2O2 (4.6 ml) at 0 °C dropwise. The mixture was stirred
vigorously for 3.5 h. It was then extracted with EtOAc and washed
with brine. The organic solvent was dried (MgSO4), and concen-
trated to provide the crude alcohol 10 in 86% yield, which was
4.3. Preparation of HCN in DIPE
At first, NaCN (10 g) and citric acid (0.1 g) were dissolved in
water (100 ml). The solution was cooled in an ice/water bath and
extracted with DIPE (50 ml), while acidifying with 33% HCl until
pH 5.5. The water layer, which contained a suspension of NaCl,
was extracted twice with DIPE (25 ml). The combined DIPE layers
were stored in a dark bottle. The above procedure must be per-
formed in a well ventilated fume hood with proper glassware
and handware (gloves).
used in the next step without further purification. ½a D28
¼ ꢀ16:8
ꢂ
(c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3): 7.27–7.25 (m, 5H),
4.93–4.87 (m, 1H), 3.75–3.65 (m, 2H), 1.93–1.84 (m, 2H), 0.85
(s, 9H), 0.01 (s, 3H), ꢀ0.19 (s, 3H). 13C NMR (50 MHz, CDCl3):
144.6, 128.3, 127.3, 125.9, 74.5, 60.3, 42.3, 25.9, 18.2, ꢀ4.5,
ꢀ5.0. HRMS (ESI) for C15H26NaO2Si [M+Na]+, calcd 289.1600,
found: 289.1606.
4.4. (R)-2-(tert-Butyldimethylsilyloxy)-2-phenylacetonitrile 7
(R)-Mandelonitrile (500 mg, 3.75 mmol) was taken in anhy-
drous DCM (15 ml) and cooled to 0 °C. Imidazole (281 mg,
4.13 mmol) and DMAP (catalytic) were then added to the reaction
mixture followed by the addition of TBS–Cl (620 mg, 4.13 mmol).
The reaction mixture was then allowed to warm at room temper-
ature for 6 h, after which water was added to it and the organic
layer was diluted with DCM, washed with brine and dried over
MgSO4. Evaporation afforded the TBS-protected compound in 88%
yield. The TBS protected cyanohydrin is used in the next step with-
out further purification.
4.8. (S)-3-(tert-Butyldimethylsilyloxy)-3-phenylpropyl
methanesulfonate 11
To a cooled (0 °C), stirred solution of 10 (681 mg, 2.56 mmol) in
DCM (8 ml) were added Et3N (391
ll, 2.81 mmol) and methanesul-
fonyl chloride (218 l, 2.81 mmol) and the reaction mixture was
l
stirred at room temperature for 2 h. The reaction was then stopped
by adding 5 ml of saturated NH4Cl. The water phase was extracted
with DCM twice. The combined extracts were dried and evapo-
rated to furnish the respective mesylate 11 in 90% yield.
4.5. (R)-2-(tert-Butyldimethylsilyloxy)-2-phenylacetaldehyde 8
½
a 2D8
ꢂ
¼ ꢀ22:5 (c 1.6, CHCl3). 1H NMR (200 MHz, CDCl3): 7.22–7.20
The crude TBS protected cyanohydrin (815 mg, 3.3 mmol) was
taken in 10 ml of dry DCM under an argon atmosphere. To this
solution was added DIBAL-H (1 M in DCM, 3.3 ml), dropwise at
(m, 5H), 4.74 (t, J = 6.4 Hz, 1H), 4.31–4.26 (m, 1H), 4.15–4.08 (m,
1H), 2.86 (s, 3H), 2.00–1.93 (m, 2H), 0.80 (s, 9H), ꢀ0.03 (s, 3H),
ꢀ0.26 (s, 3H). 13C NMR (50 MHz, CDCl3): 144.1, 128.3, 127.5,

R. K. Rej et al. / Tetrahedron: Asymmetry 24 (2013) 913–918
917
125.8, 71.0, 66.9, 40.1, 37.3, 25.8, 22.6, 18.1, 14.4, ꢀ4.6, ꢀ5.1. HRMS
1H), 5.25 (dd, J1 = 4.4 Hz, J2 = 8.4 Hz, 1H), 2.78–2.74 (m, 2H), 2.42
(s, 3H), 2.31 (s, 3H), 2.20–2.17 (m, 1H), 2.05–2.02 (m, 1H). 13C
NMR (100 MHz, CDCl3): 142.2, 130.8, 129.0, 128.8, 128.5, 127.6,
126.7, 125.9, 125.8, 120.4, 112.9, 78.1, 48.7, 39.0, 36.7, 16.8. HRMS
(ESI) for C17H21NNaO [M+Na]+, calcd 278.1521, found: 278.1526.
(ESI) for C16H28NaO4SSi [M+Na]+, calcd 367.1375, found: 367.1381.
4.9. (S)-3-(tert-Butyldimethylsilyloxy)-N-methyl-3-
phenylpropan-1-amine 12
A solution of (S)-3-(tert-butyldimethylsilyloxy)-3-phenylpropyl
methanesulfonate 11 (450 mg, 1.30 mmol) and methylamine
(9 ml, 40% in water) in THF (9 ml) was heated at 65 °C for 3 h. After
cooling, the solution was diluted with ether, washed with satu-
rated aqueous sodium bicarbonate and brine, and dried over anhy-
drous potassium carbonate. After concentration, a pale yellow oil
was obtained. The residue was then purified by flash chromatogra-
phy (CH2Cl2/MeOH/NH4OH, 90:5:1) to afford the desired product
4.14. (R)-3-(2-Methoxyphenoxy)-N-methyl-3-phenylpropan-1-
amine 2 (nisoxetine)
½
a 2D8
ꢂ
¼ þ36:2 (c 1.0, CHCl3). Lit. ½a D28
ꢂ
¼ þ35:0 (c 1.0, CHCl3).5o 1
H
NMR (400 MHz, CDCl3): 7.36–7.26 (m, 5H), 6.88–6.87 (m, 2H),
6.70–6.68 (m, 1H), 6.62–6.60 (m, 1H), 5.19 (dd, J1 = 4 Hz,
J2 = 8.4 Hz), 3.97 (s, 3H), 2.96–2.89 (m, 2H), 2.53 (s, 3H), 2.36–
2.29 (m, 1H), 2.10–2.03 (m, 1H). 13C NMR (100 MHz, CDCl3):
149.7, 147.1, 141.2, 128.6, 127.7, 125.8, 121.7, 120.7, 116.1, 81.1,
55.9, 48.2, 36.9, 35.1, 11.7. HRMS (ESI) for C17H21NNaO2 [M+Na]+,
calcd 294.1470, found: 294.1474.
in 78% yield. ½a 2D8
ꢂ
¼ ꢀ19:2 (c 0.6, CHCl3). 1H NMR (200 MHz, CDCl3)
7.27–7.26 (m, 5H), 4.77 (t, J = 5.8 Hz, 1H), 2.75 (t, J = 7.2 Hz, 2H),
2.44 (s, 3H), 2.00–1.96 (m, 2H), 0.87 (s, 9H), 0.01 (s, 3H), ꢀ0.16
(s, 3H). 13C NMR (50 MHz, CDCl3): 144.9, 128.1, 127.1, 125.7,
73.4, 47.7, 39.5, 35.3, 25.8, 18.1, ꢀ4.6, ꢀ5.0. HRMS (ESI) for C16H29-
NNaOSi [M+Na]+, calcd 302.1916, found: 302.1921.
4.15. (S)-2-Hydroxy-2-(thiophen-2-yl)acetonitrile 13
½
a 2D8
ꢂ
¼ þ42:2 (c 1.6, CHCl3). 1H NMR (200 MHz, CDCl3): 7.33–
4.10. (S)-3-(Methylamino)-1-phenylpropan-1-ol 5
7.30 (m, 1H), 7.20–7.15 (m, 1H), 6.94 (dd, J1 = 3.8 Hz, J2 = 5.0 Hz,
1H), 5.74 (d, J = 5.8 Hz, 1H). 13C NMR (50 MHz, CDCl3): 136.9,
127.3, 126.9, 126.8, 118.4, 58.8.
Compound 12 (279 mg, 1.0 mmol) was taken in dry THF (3 ml)
after which TBAF (1 M in THF, 1.2 ml) was added to it, and the reac-
tion mixture was stirred for 3 h at room temperature, after which
THF was evaporated, and water (1 ml) was added to it. The reaction
mixture was extracted with EtOAc (10 ml), washed with NaHCO3
and brine, then dried by using CaCO3 and concentrated to afford
the desired product 5 in 88% yield, which was subsequently used
4.16. (S)-2-(tert-Butyldimethylsilyloxy)-2-(thiophen-2-
yl)acetonitrile 14
½
a 2D8
ꢂ
¼ þ55:8 (c 0.8, CHCl3). 1H NMR (200 MHz, CDCl3):
7.35 (dd, J1 = 1.2 Hz, J2 = 5.0 Hz, 1H), 7.18 (dd, J1 = 1 Hz,
J2 = 2.4 Hz, 1H), 7.00 (dd, J1 = 3.6 Hz, J2 = 5.0 Hz, 1H), 5.77 (s, 1H),
0.96 (s, 9H), 0.24 (s, 3H), 0.19 (s, 3H). 13C NMR (50 MHz, CDCl3):
140.0, 127.0, 126.9, 125.9, 118.4, 60.2, 25.5, 18.2, ꢀ5.0, ꢀ5.1. HRMS
in the next step without further purification. ½a D28
¼ ꢀ36:5 (c 1.0,
ꢂ
CHCl3). 1H NMR (200 MHz, CDCl3): 7.36–7.20 (m, 5H), 4.84 (dd,
J1 = 4.0 Hz, J2 = 7.8 Hz, 1H), 4.02 (br s, 2H, –NH and –OH), 2.80–
2.73 (m, 2H), 2.36 (s, 3H), 1.84–1.72 (m, 2H). 13C NMR (50 MHz,
CDCl3): 145.2, 128.2, 126.9, 125.6, 74.8, 50.0, 37.0, 35.9. HRMS
(ESI) for C10H15NNaO [M+Na]+, calcd 188.1051, found: 188.1056.
(ESI) for
276.0850.
C
12H19NNaOSSi [M+Na]+, calcd 276.0854, found:
4.17. (S)-2-(tert-Butyldimethylsilyloxy)-2-(thiophen-2-
4.11. Mitsunobu procedure
yl)acetaldehyde 15
Triphenylphosphine (100 mg, 0.4 mmol), and diethyl azodicar-
½
a 2D8
ꢂ
¼ þ13:5 (c 0.3, CHCl3). 1H NMR (200 MHz, CDCl3): 9.52 (d,
boxylate (63
l
l, 0.4 mmol) were added to a solution of 5 (66 mg,
J = 2.2 Hz, 1H), 7.34–7.31 (m, 1H), 7.04–7.02 (m, 2H), 5.22 (d,
J = 2 Hz, 1H), 0.95 (s, 9H), 0.13 (s, 3H), 0.08 (s, 3H). 13C NMR
(50 MHz, CDCl3): 197.7, 140.4, 127.5, 126.3, 125.0, 76.6, 25.9,
0.4 mmol) and the properly substituted phenols (0.4 mmol) in
THF (2 ml). The mixture was stirred at room temperature over-
night until the reaction was completed (TLC). Next, the THF was re-
moved in vacuo and the residue was extract with EtOAc (3 ꢁ 5 ml).
The combined organic fractions were concentrated, and the residue
was purified by flash chromatography (CH2Cl2/MeOH/NH4OH,
97:2:1) to afford the desired product in 60–70% yield.
18.5, ꢀ4.7. HRMS (ESI) for
C
12H20NaO2SSi [M+Na]+, calcd
276.0854, found: 276.0850.
4.18. 2-((S)-1-(tert-Butyldimethylsilyloxy)allyl)thiophene 16
½
a 2D8
ꢂ
¼ þ40:6 (c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3): 7.26–
4.12. (R)-3-(4-(Trifluoromethyl)phenoxy)-N-methyl-3-
phenylpropan-1-amine 1 (fluoxetine)
7.22 (m, 1H), 7.00–6.91 (m, 2H), 6.14–5.97 (m, 1H), 5.47–5.40
(m, 1H), 5.34–5.30 (m, 1H), 5.22–5.15 (m, 1H), 0.99 (s, 9H), 0.15
(s, 3H), 0.12 (s, 3H); 13C NMR (50 MHz, CDCl3): 148.7, 140.9,
126.5, 124.5, 123.1, 114.3, 72.4, 25.9, 18.4, ꢀ4.5, ꢀ4.8.
HRMS (ESI) for C13H22NaOSSi [M+Na]+, calcd 277.1058, found:
277.1052.
½
a 2D8
ꢂ
¼ þ3:2 (c 1.0, CHCl3). Lit. ½a D28
ꢂ
¼ þ3:8 (c 0.9, CHCl3).5f 1H
NMR (400 MHz, CDCl3): 7.38–7.20 (m, 7H), 6.85–6.81 (m, 2H),
5.32 (dd, J1 = 4.4 Hz, J2 = 8.2 Hz, 1H), 2.84–2.81 (m, 2H), 2.47 (s,
3H), 2.29–2.19 (m, 2H). 13C NMR (100 MHz, CDCl3): 160.3, 140.5,
128.7, 128.3, 127.9, 126.7, 126.6, 125.7, 115.7, 78.2, 47.7, 35.7,
35.6. HRMS (ESI) for C17H18F3NNaO [M+Na]+, calcd 332.1238,
found: 332.1232.
4.19. (S)-3-(tert-Butyldimethylsilylyloxy)-3-(thiophen-2-
yl)propan-1-ol 17
½
a 2D8
ꢂ
¼ þ22:4 (c 0.5, CHCl3). 1H NMR (200 MHz, CDCl3):
4.13. (R)-3-(o-Tolyloxy)-N-methyl-3-phenylpropan-1-amine 3
(atomoxetine)
7.21–7.18 (m, 1H), 6.97–6.89 (m, 2H), 5.23 (t, J = 5.8 Hz, 1H),
3.86–3.64 (m, 2H), 2.30 (br, s), 2.08–1.99 (m, 2H), 0.91 (s, 9H),
0.09 (s, 3H), ꢀ0.05 (s, 3H). 13C NMR (50 MHz, CDCl3): 149.1,
126.5, 124.1, 123.1, 115.1, 70.3, 60.1, 43.0, 25.9, 18.2, ꢀ4.7, ꢀ4.9.
HRMS (ESI) for C13H24NaO2SSi [M+Na]+, calcd 295.1164, found:
295.1157.
½
a 2D8
ꢂ
¼ ꢀ35:0 (c 1.0, CHCl3). Lit. ½a D28
ꢂ
¼ ꢀ44:0 (c 1.0, MeOH).5t 1
H
NMR (400 MHz, CDCl3): 7.36–7.22 (m, 5H), 7.11 (d, J = 7.2 Hz, 1H),
6.95 (t, J = 7.6 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 8.4 Hz,

918
R. K. Rej et al. / Tetrahedron: Asymmetry 24 (2013) 913–918
4.20. (S)-3-(4-Methoxybenzyloxy)-3-(thiophen-2-yl)propylmeth-
anesulfonate 18
authors (R.R. and S.H.) are thankful to CSIR (New Delhi, India) for
a senior research fellowship.
½
a 2D8
ꢂ
¼ þ16:75 (c 1.1, CHCl3). 1H NMR (200 MHz, CDCl3): 7.23–
References
7.19 (m, 1H), 6.94–6.92 (m, 2H), 5.13 (dd, J1 = 5.4 Hz, J2 = 7.2 Hz,
1H), 4.43–4.07 (m, 2H), 2.98 (s, 3H), 2.25–2.16 (m, 2H), 0.89 (s,
9H), 0.09 (s, 3H), ꢀ0.07 (s, 3H). 13C NMR (50 MHz, CDCl3): 148.5,
126.5, 124.5, 123.5, 67.4, 66.8, 40.5, 37.4, 25.8, 18.2. HRMS (ESI)
for C14H26NaO4S2Si [M+Na]+, calcd 373.0939, found: 373.0944.
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(m, 2H), 2.42 (s, 3H), 2.06–1.90 (m, 2H), 0.89 (s, 9H), 0.06 (s, 3H),
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4.22. (S)-3-(Methylamino)-1-(thiophen-2-yl)propan-1-ol 6
½
a 2D8
ꢂ
¼ þ13:2 (c 1.2, CHCl3). 1H NMR (200 MHz, CDCl3): 7.20–
7.18 (m, 1H), 6.97–6.93 (m, 2H), 5.17 (dd, J1 = 4 Hz, J2 = 7.6 Hz,
1H), 2.95–2.86 (m, 2H), 2.43 (s, 3H), 2.00–1.90 (m, 2H). 13C NMR
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194.0610.
4.23. (R)-N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)
propan-1-amine 2 (duloxetine)
½
a 2D8
ꢂ
¼ ꢀ109:5 (c 1.2, CHCl3). Lit. ½a D21
ꢂ
¼ ꢀ114:3 (c 1.0, MeOH).5b
1H NMR (400 MHz, CDCl3): 8.34–8.32 (m, 1H), 7.80–7.77 (m, 1H),
7.52–7.49 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.29–7.27 (m, 1H),
7.25–7.21 (m, 1H), 7.20–7.09 (m, 1H), 6.92 (dd, J1 = 3.6 Hz,
J2 = 5.2 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.86 (dd, J1 = 5.2 Hz,
J2 = 7.6 Hz, 1H), 3.27–3.20 (m, 2H), 2.64–2.61 (m, 1H), 2.54 (s,
3H), 2.47–2.41 (m, 1H). 13C NMR (100 MHz CDCl3): 153.1, 144.9,
134.3, 127.2, 126.3, 126.1, 125.8, 125.5, 125.0, 124.5, 121.9,
120.3, 106.7, 74.5, 48.0, 38.7, 36.3. HRMS (ESI) for C18H19NNaOS
[M+Na]+, calcd 320.1085, found: 320.1081.
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Acknowledgments
We are thankful to DBT (New Delhi, India; Grant no. BT/
PR13830/PID/06/568/2010) for financial support. Two of the