Preparation of polymer-supported Ru-TsDPEN catalysts and use for enantioselective synthesis of (S)-fluoxetine

Article abstract of DOI:10.1039/b505943g

Polymer-supported chiral ligands 9 and 17 were prepared based on Noyori's (1S,2S)- or (1R,2R)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine. The combination with [RuCl₂(p-cymene)]₂ has been shown to exhibit high activities and enantioselectivities for heterogeneous asymmetric transfer hydrogenation of aromatic ketones (19a-c) with formic acid-triethylamine azeotrope as the hydrogen donor, whereby affording the respective optically active alcohols 20a-c, the key precursors of chiral fluoxetine. As exemplified by ligand 17 for substrate 19c, the catalysts can be recovered and reused in three consecutive runs with no significant decline in enantioselectivity. The procedure avoids the plausible contamination of fluoxetine by the toxic transition metal species. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b505943g

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A R T I C L E
Preparation of polymer-supported Ru-TsDPEN catalysts and use for
enantioselective synthesis of (S)-fluoxetine
Yangzhou Li, Zhiming Li, Feng Li, Quanrui Wang* and Fanggang Tao
Department of Chemistry, Fudan University, 200433, Shanghai, P. R. China.
E-mail: qrwang@fudan.edu.cn
Received 28th April 2005, Accepted 1st June 2005
First published as an Advance Article on the web 20th June 2005
Polymer-supported chiral ligands 9 and 17 were prepared based on Noyori’s (1S,2S)- or (1R,2R)-N-(p-tolylsulfonyl)-
1,2-diphenylethylenediamine. The combination with [RuCl2(p-cymene)]2 has been shown to exhibit high activities and
enantioselectivities for heterogeneous asymmetric transfer hydrogenation of aromatic ketones (19a–c) with formic
acid–triethylamine azeotrope as the hydrogen donor, whereby affording the respective optically active alcohols 20a–c,
the key precursors of chiral fluoxetine. As exemplified by ligand 17 for substrate 19c, the catalysts can be recovered
and reused in three consecutive runs with no significant decline in enantioselectivity. The procedure avoids the
plausible contamination of fluoxetine by the toxic transition metal species.
drimer and silica as the support.11 The reactivity of the Ru-
TsDPEN catalysts seemed to be influenced by the sulfonamide
Introduction
Fluoxetine (ProzacTM, Eli Lilly Co.) and analogues belong to
group, tending to decrease with increasing electron-withdrawing
the first selective serotine (5-HT) reuptake inhibitors (SSRIs),
ability of sulfonamide group.12 Several RSO2-DPEN ligands
and have been widely used in the treatment of anxiety and
for transfer hydrogenation have been reported with R = Ar,
depression that show little effect on noradrernegic or dopamin-
CF3, R2N.13 In an attempt to develop readily accessible and
ergic systems.1 A recent report also revealed that fluoxetine can
hence more appealing catalyst candidates for production of in-
ameliorate primary negative symptoms in chronic schizophrenia
termediates used in the synthesis of fluoxetine, we have prepared
patients who are treated with typical antipsychotics.2 Although
two novel polystyrene-bound chiral Ru-TsDPEN catalysts and
fluoxetine is currently used therapeutically as a racemate, it
tested the efficacy in the heterogeneous asymmetric transfer
has been demonstrated that the two enantiomers have quite
hydrogenation of several functionalized aromatic ketones. The
different bioactivities and rates of metabolism. Thus, whilst
resulting secondary alcohols are useful in the synthesis of
the stereospecificity of the (S)-enantiomer for anti-depressant
optically active fluoxetine.
efficacy has been claimed,3 Lily submitted also an approval
application for (R)-fluoxetine in the US for the treatment of
bulimia in 1995.4 Due to its potential medicinal significance,
Results and discussion
considerable efforts have been devoted to the synthesis of
optically active fluoxetine during the past decade. These syn-
theses relied on the production of the suitable chiral alcohol
intermediates. Representative procedures for this subject include
enzymatic resolution,5 asymmetric reduction of the prochiral
ketones,6 dihydroxylation or Sharpless epoxidation of styrene,7
and carbonyl-ene reaction of benzaldehyde.8
Two polystyrene-supported TsDPEN-derived ligands 9 and
17 were synthesized according to Scheme 1 and Scheme 2,
respectively. As shown in Scheme 1, 4-hydroxybenzenesulfonic
acid sodium salt dihydrate 1 was dehydrated using a Dean
Stark apparatus, which was then allowed to react with ethyl
bromoacetate affording the benzenesulfonic acid sodium salt
2 using K2CO3 as base. Upon treatment with excess thionyl
chloride in the presence of catalytic amount of DMF, the salt
2 was further transformed into the corresponding benzenesul-
fonyl chloride 3. The commercially available (1S,2S)-diamine
4 was then sulfonylated with 3 to provide 5. N-protection of
5 with di-tert-butyl dicarbonate led to the N-Boc derivative
6. Basic saponification of 6 gave the free acid 7, which is
ready to be coupled to a solid support. Immobilization onto
aminomethylated polystyrene (1.07 mmol g−1, DVB 1%) to
provide ligand 8 was readily achieved under the standard
peptide coupling conditions using DCC, pentafluorophenol and
DMAP. Deprotection of the N-Boc group occurred readily with
50% TFA in dichloromethane in 98% yield whereby affording
the ligand 9 with a polystyrene backbone.
Next, we expected to relieve the electron-withdrawing effect
of the sulfamido group by lengthening the linkage. However, the
standard Williamson ether reaction proved to be unsuccessful
using ethyl 3-bromopropionate in place of ethyl bromoacetate.
An alternative way has been devised which is depicted by
Scheme 2. By screening the protecting group, benzyl group
appeared to be more appropriate for protecting the hydroxyl
group of sodium 4-hydroxybenzenesulfonate salt. Conversion
of the sodium salt 10 to the corresponding benzenesulfonyl
chloride 11 occurred with SOCl2 as for 3. TsDPEN-derived
One of the most attractive chemical methods to obtain
optically active secondary alcohols is the asymmetric transfer
hydrogenation of prochiral ketones due to its high enantiose-
lectivity, high product yield, and green chemistry.9 Amongst the
various types of chiral catalysts, Noyori’s (1S,2S)- or (1R,2R)-
N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine (TsDPEN) in
combination with [RuCl2(p-cymene)]2 has been recognized as
the most efficient one giving products with up to 99% ee for
most aromatic ketones including those bearing neighboring
functional groups at the a or b position of the carbonyl group.6i
In recent years, covalent immobilization of chiral catalysts
which allow for feasible recycling of catalyst with low leaching
level of metals have aroused considerable research efforts.10
In comparison to the solution counterparts, using polymer-
supported catalysis can facilitate the catalyst separation from the
reaction mixture, simplify the recovery and recycling of the often
expensive and even toxic catalysts, and eventually be prospective
to meet the need for more environmentally benign chemistry.
However, in view of practical use, the advantages gained by
covalent attachment to a support should be outweighed by the
added complexity associated with synthesizing the appropriately
modified ligands.
A few papers have appeared describing the chiral supported
Ru-TsDPEN complex, including the use of polystyrene, den-
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 1 3 – 2 5 1 8
2 5 1 3
©

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Scheme 1 Preparation of the supported ligand 9. Reagents and conditions: (i) Dean Stark; then BrCH2CO2Et, K2CO3, dibenzo-18-crown-6, acetone,
95%; (ii) SOCl2, DMF (cat.), 71%; (iii) Et3N, CH2Cl2, 55%; (iv) (Boc)2O, DIPEA, CH2Cl2, 98%; (v) NaOH, H2O, 95%; (vi) aminomethylated
polystyrene, DCC, pentafluorophenol, DMAP; (vii) TFA, CH2Cl2.
Table 1 Asymmetric transfer hydrogenation of aromatic ketones
ligand 12 was synthesized by reacting the (1S,2S)-diamine 4
with 11. Consecutive N-Boc protection of the amino group and
deprotection of the benzyl group with hydrogen in the presence
of 10% Pd/C provided the phenol 14, which was etherified with
3-bromopropanoic acid using Cs2CO3 as a base that diminished
the plausible formation of N-alkylated byproduct. Immobiliza-
tion onto the aminomethylated polystyrene and deprotection of
the N-Boc group provided ligand 17 having one more carbon
between the polymer backbone and the binding sites.
19a–ca
Time (h) Conversionb (%) Eec (%)
The ruthenium catalysts Ru-9 and Ru-17 were formed in situ
by mixing the ligands with [RuCl2(p-cymene)]2 giving orange–
red beads for each polymer. The effectiveness of the catalysts
were evaluated in the asymmetric transfer hydrogenation of flu-
oxetine precursors 19a–c. For comparison, the known supported
chiral ligand 18 bearing a para electron-withdrawing carboxyl
group on the benzene ring was also prepared and used in the
reaction. Table 1 shows the results for the ruthenium catalyzed
prochiral ketones using a 5 : 2 formic acid–triethylamine
azeotrope as the hydrogen donor. All reactions were performed
with 1 mol% catalyst in dichloromethane at 35 ◦C. The three cat-
alysts all displayed remarkably high catalytic activity and good
enantioselectivity, affording the corresponding optically active
alcohols. The absolute configuration of the key intermediate was
determined from the sign of rotation of the isolated product.
One notable feature of this asymmetric transfer hydrogen is
the keto-carbonyl group selectivity and the neighboring ester,
amido or cyano groups did not interfere with the reduction. It
can also be seen that the electronic character and the spacer
length between the supporter and the benzene ring has only a
subtle effect on the reduction outcome (entries 1–3 and 7–9).
Entry Ketone Ligand
1
2
3
4
5
6
7
8
9
19a
19a
19a
19b
19b
19b
19c
19c
19c
19c
19c
19c
18
9
17
18
9
24
24
20
22
22
22
22
17
17
97
97
95
85
93
95
97
98
98
95
94
96
91
86
88
95
95
97
93
93
97
17
18
9
17
10
11
12
17 (2nd use) 28
92d
81d
>99
17 (3rd use) 60
12
18
a Ketone : chiral ligand : [Ru] = 100 : 1.2 : 1, ketone = 0.5 mol L−1, acid :
triethylamine azeotrope : CH2Cl2 = 1 : 1. b Isolated yield. c Enantiomeric
excesses were determined by HPLC on a Daciel Chiralcel OD column.
d Based on GC analysis.
However, for N-methyl-3-oxo-3-phenylpropanamide (19b), the
catalyst Ru-17 gave more promising result (entries 4–6).
The best result (97% ee at 98% conversion) was obtained using
2 5 1 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 1 3 – 2 5 1 8

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Scheme 2 Preparation of the supported ligand 17. Reagents and conditions: (i) Dean Stark; then BnBr, K2CO3, dibenzen-18-crown-6, acetone,
99%; (ii) SOCl2, DMF (cat.), 85%; (iii) 4, Et3N, CH2Cl2, 65%; (iv) (Boc)2O, DIPEA, CH2Cl2, 95%; (v) Pd/C, H2, CH3OH, 99%; (vi) Cs2CO3,
3-bromopropionic acid, acetone, 67%; (vii) aminomethylated polystyrene, DCC, pentafluorophenol, DMAP; (viii) TFA, CH2Cl2.
Ru-17 for 2-cyanoacetophenone 19c (entry 9). For comparison,
the homogenous ligand 12 was also used for the reduction of 19c.
Under the similar condition, (S)-2-cyano-1-phenyl-1-ethanol
was obtained in 99% conversion rate and 97% ee (entry 12).
a prolonged time (60 hours) was requested to achieve 81%
conversion (entry 11). Addition of more [RuCl2(p-cymene)]2 to
the polymer supported ligand cannot regenerate the catalytic
activity. The cause of the activity drop is unclear at the
present.
All of the three resulting alcohols (S)-20a–c are appropriate
intermediates for the construction of optically active fluoxetine
according to known procedures.5 Thus, reduction of (S)-20c with
Ru-17 under our asymmetric transfer hydrogenation conditions
afforded 20c. The alcohol 20c was then reduced with BH3·Me2S
in dry THF to provide optically active 3-amino-1-phenyl-1-
propanol (S)-21, which was transformed to the N-methylated
derivative (S)-22 by sequential treatment with methyl chlorofor-
mate and reduction with lithium aluminium hydride. Finally, 4-
chlorobenzontrifluoride was subjected to aromatic nucleophilic
substitution with sodium alkoxide of (S)-22, generated by action
with NaH. By this procedure, (S)-fluoxetine hydrochloride 23
was obtained as a white solid in 75% overall yield for four steps,
and in 97% ee, as well as 98% chemical purity (Scheme 3).
We found that there was no ruthenium contamination of the
product down to the level of detection of the analytical apparatus
(Graphite Furnace Atomic Absorption, less than 0.04 ppm).
After reduction the visual appearance of the polymer is
unchanged with the bead remaining orange to red in color. The
catalyst was easily recovered from the mixture by filtration and
solvent washing under nitrogen. The recycling reactions for the
substrate 19c were attempted with the recovered catalysts Ru-17.
As shown in Table 1 (entry 10), the catalyst can be successfully
reused but with a slight drop in activity and enantioselectivity. A
third use performed well with nearly the same enantioselectivity
as in the second run, but still shows a drop in activity, and
Scheme 3 Synthesis of (S)-fluoxetine. Reagents and conditions: (i) ligand 17, [RuCl2(p-cymene)]2, HCOOH–Et3N, CH2Cl2, 98%; (ii) BH3·Me2S, THF,
92%; (iii) methyl chloroformate, K2CO3, CH2Cl2; then LiAlH4, THF; two steps: 92%; (iv) NaH, 4-chlorobenzotrifluoride, DMSO, then satd. HCl of
Et2O, 90%.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 1 3 – 2 5 1 8
2 5 1 5

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CH), 4.78 (s, 2 H, CH2CO), 6.77 (d, J = 8.7 Hz, 2 H, C6H4),
6.92–7.12 (m, 10 H, 2 × C6H5), 7.33 (d, J = 8.7 Hz, 2 H, C6H4).
Conclusion
This work presents the successful reductive transformation
of three aromatic ketones 19a–c via asymmetric hydrogen
transfer reaction to optically active alcohols, which are suitable
intermediates for the synthesis of fluoxetine, a very important
antidepressant. The real synthesis of (S)-fluoxetine was exempli-
fied by using the product (S)-2-cyano-1-phenyl-1-ethanol (20c)
in 75% overall yield and 97% ee. Immobilization of the chiral
ligand onto polymer bead allows the simple recovery and reuse
of the expensive chiral Ru-catalyst and decreases the potentially
toxic transition metal species contaminating the product, thus
rendering the procedure to be green and practical.
(1S,2S)-N-Boc-Nꢀ-((4-ethoxycarbonyl)methoxybenzenesulfonyl)-
1,2-diphenylethylenediamine (6). A solution of 5 (454 mg,
1.0 mmol), (Boc)2O (262 mg, 1.2 mmol), and DIPEA (258 mg,
2 mmol) in CH2Cl2 (20 mL) was stirred at room temperature
for 4 h. The solution was washed with 5% aq. HCl. The organic
phase was separated, dried over Na2SO4 and concentrated. The
residue was purified by chromatography (CH2Cl2–EtOAc, 1 :
1) to give 6 as a white powder (544 mg, 98%). Mp 131–133 ◦C;
IR (KBr): m 3033, 2934, 1710, 1627, 1593, 1450, 1320 cm−1; dH
(500 MHz, DMSO-d6): 1.21 (t, J = 7.1 Hz, 3 H, CH2CH3), 1.29
(s, 9H, C(CH3)3), 4.20 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.64 (s,
2 H, 2 × CH), 4.71 (s, 2 H, CH2CO), 6.80 (d, J = 8.8 Hz, 2 H,
C6H4), 7.08–7.25 (m, 10 H, 2 × C6H5), 7.35 (d, J = 8.8 Hz, 2H,
C6H4), 8.10 (s, 1 H, NHCO).
Experimental
General
The NMR data were acquired on a Bruker 500 or a Varian
400 spectrometer. 1H and 13C chemical shifts (d) are reported in
ppm relative to TMS as internal standard. Coupling constants
(J) are given in Hz. The reactions were monitored by thin
layer chromatography coated with silica gel. Ee % values were
determined by HPLC on a Daciel Chiralcel OD column.
Absolute configuration was determined by comparison with the
known specific rotation values.
( 1S,2S ) - N - Boc - Nꢀ - (4 - carboxymethoxybenzenesulfonyl ) -
1,2-diphenylethylenediamine (7). A solution of 6 (555 mg,
1.0 mmol) and NaOH (160 mg, 4.0 mmol) in 4 mL of
CH3OH–H2O (1 : 1, v/v) was stirred at reflux for 6 h. The
resulting mixture was diluted with 10 mL H2O and acidified
with citric acid, and then extracted with EtOAc (3 × 15 mL).
The combined organic phases were washed with 10 mL of
brine, dried over MgSO4 and concentrated in vacuo. Flash
chromatography using hexane–EtOAc (1 : 2, v/v) as the eluent
yielded 7 as a colorless crystal (501 mg, 95%). Mp 142–143 ◦C;
IR (KBr): m 3390, 2921, 2851, 1685, 1592, 1316 cm−1; dH
(500 MHz, DMSO-d6): 1.23 (s, 9 H, C(CH3)3), 4.61–4.64 (m,
2H, CH2CO and CH), 4.81 (s, 1 H, CH), 6.67 (d, J = 8.7 Hz, 2
H, C6H4), 7.04–7.18 (m, 10 H, 2 × C6H5), 7.30 (d, J = 8.7 Hz, 2
H, C6H4), 8.05 (s, 1 H, NHCO).
Preparation of ligand 9
Sodium 4-((ethoxycarbonyl)methoxy)benzenesulfonate (2).
4-Hydroxybenzenesulfonic acid sodium salt dihydrate (2.32 g,
0.01 mol) was dehydrated by distillation with benzene and
dissolved in 20 mL of acetone. Ethyl bromoacetate (2.00 g,
0.012 mol), K2CO3 (2.76 g, 0.02 mol) and dibenzo-18-crown-
6 (68 mg, 0.2 mmol) were added, and the mixture was heated at
reflux for 48 h. After cooling to room temperature, the crystals
were collected by filtration, washed with acetone (2 × 60 mL),
and dried under reduced pressure to yield 2 as a white powder
(2.68 g, 95%). Mp > 300 ◦C; IR (KBr): m 3070, 2866, 1730, 1598,
1495, 1451 cm−1.
The polymer-bound ligand 8
A solution of 7 (527 mg, 1.0 mmol), DCC (1.03 g, 5 mmol),
pentafluorophenol (920 mg, 5 mmol), DMAP (cat.) and the
aminomethylated polystyrene (930 mg, 1.07 mmol g−1) in dry
CH2Cl2 (20 mL) was stirred at room temperature for 24 h under
N2. The polymer was filtered, rinsed sequentially with CH2Cl2
and acetone and dried at 50 ◦C in vacuo to yield the product as
pale yellow beads. Elemental analysis Found: N, 2.90 requires
N, 2.91%; IR (KBr): m 3058, 2922, 2850, 1671, 1601, 1492, 1451,
1366 cm−1.
Ethyl (4-chlorosulfonyl)phenoxyacetate (3). To the sodium
salt 2 (2.68 g, 0.095 mol) was added dropwise a solution of DMF
(69 mg, 0.95 mmol) in SOCl2 (15 mL) at 0 ◦C. The resulting
mixture was stirred at 60 ◦C for 2 h. At the end of this time,
the mobile, nearly homogeneous reaction mixture was poured
over 100 g of ice with vigorous stirring. The aqueous layer was
extracted with EtOAc (3 × 50 mL). The organic phases were
combined, washed with 50 mL of ice water, dried over MgSO4,
and concentrated in vacuo. Flash chromatography on silica gel
(EtOAc–hexane, 1 : 9, v/v) provided 3 as a colorless vicious
liquid (1.87 g, 67%). IR (neat): m 3093, 2938, 1720, 1586, 1492,
1368, 1262 cm−1; dH (400 MHz, CDCl3): 1.32 (t, J = 7.1 Hz, 3
H, CH2CH3), 4.30 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.74 (s, 2 H,
CH2CO), 7.06 (d, J = 8.7 Hz, 2 H, C6H4), 7.99 (d, J = 8.7 Hz,
2 H, C6H4).
The polymer-bound ligand 9
The polymer-bound ligand 8 (500 mg) was added in batches
to a solution of TFA–CH2Cl2 (1 : 1, v/v, 10 mL). The mixture
was stirred at room temperature for 40 min. The polymer was
filtrated, rinsed sequentially with CH2Cl2 and CH2Cl2–Et3N (1 :
4, v/v), and dried at 50 ◦C in vacuo to yield the deprotected
ligand 9 as pale yellow beads. Elemental analysis Found: N, 3.04
requires N, 3.13%; IR (KBr): m 3025, 2922, 2851, 1664, 1601,
1493, 1452, 1382 cm−1.
(1S,2S )-N -((4-Ethoxycarbonyl)methoxybenzenesulfonyl)-
1,2-diphenylethylenediamine (5). To a solution of (1S,2S)-
diphenylethylenediamine (212 mg, 1.0 mmol) and Et3N (101 mg,
1.0 mmol) in CH2Cl2 (10 mL) was added dropwise a solution of
3 (279 mg, 1.0 mmol) in CH2Cl2 (20 mL) over 1 h. The mixture
was stirred at room temperature for 4 h, and washed with satd.
aq. NaHCO3 (20 mL). The organic phase was separated and
dried over Na2SO4 and concentrated. The product was purified
by silica gel chromatography (gradient elution: CH2Cl2 to
CH2Cl2–EtOAc–Et3N (1 : 2 : 0.01, v/v/v)) to yield 5 as a white
powder (250 mg, 55%). Mp 121–123 ◦C; IR (KBr): m 3209,
3010, 2880, 1729, 1589, 1453 cm−1; dH (500 MHz, CDCl3): 1.21
(t, J = 7.0 Hz, 3 H, CH2CH3), 3.94 (d, J = 7.5 Hz, 1 H, CH),
4.17 (q, J = 7.0 Hz, 2 H, CH2CH3), 4.29 (d, J = 7.5 Hz, 1 H,
Preparation of ligand 17
Sodium 4-(benzyloxy)benzenesulfonate (10). As described
for the sodium salt 2 using benzyl bromide. The salt 10 was
obtained as a white powder in 99% yield. Mp > 300 ◦C; IR
(KBr): m 3063, 2864, 1599, 1499, 1453, 1241 cm−1.
4-(Benzyloxy)benzenesulfonyl chloride (11). As described for
3. The crude product 11 was purified by chromatography
(CH2Cl2–hexane, 1 : 4, v/v) to yield a white powder in 86% yield.
Mp 102–103 ◦C; IR (KBr): m 3094, 2938, 1587, 1492, 1368, 1262,
1163 cm−1; dH (400 MHz, CDCl3): 5.18 (s, 2 H, CH2), 7.12 (d,
J = 9.2 Hz, 2 H, C6H4), 7.42–7.43 (m, 5 H, C6H5), 7.99 (d, J =
9.2 Hz, 2 H, C6H5).
2 5 1 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 1 3 – 2 5 1 8

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(1S,2S)-N-((4-Benzyloxy)benzenesulfonyl)-1,2-diphenylethyl-
enediamine (12). As described for the ligand 5. The crude
product was purified by chromatography (gradient elution:
from pure CH2Cl2 to CH2Cl2–EtOAc–Et3N (1 : 3 : 0.01, v/v/v)
to provide a white powder in 65% yield. Mp 141–142 ◦C; IR
(KBr): m 3290, 3028, 2988, 1591, 1519, 1450, 1319, 1450, 1390,
1151 cm−1; dH (500 MHz, CDCl3): 4.11 (d, J = 5.1 Hz, 1 H,
CH), 4.36 (d, J = 5.1 Hz, 1 H, CH), 5.05 (s, 2 H, CH2), 6.71 (d,
J = 8.8 Hz, 2 H, C6H4), 6.72–7.16 (m, 10 H, 2 × C6H5), 7.33 (d,
J = 8.8 Hz, 2 H, C6H4), 7.41–7.42 (m, 5 H, C6H5CH2).
for the appropriate period of time (see Table 1) at 35 ◦C. After
completion of the reaction, the suspension was diluted with
CH2Cl2 (20 mL) and filtered immediately. The filtrates were
washed with satd. aq. NaHCO3 and dried over MgSO4. The
volatiles were removed in vacuo and the residue was purified by
chromatography on silica gel using CH2Cl2 as eluent.
The recovered catalyst was washed with CH2Cl2 four times
and reused in the hydrogen transfer reaction by reloading
formic acid–triethylamine azeotrope (1.0 mL) and the ketone
(1.0 mmol).
(1S,2S )-N -Boc-Nꢀ -((4-benzyloxy)benzenesulfonyl)-1,2-
diphenylethylenediamine (13). As described for the ligand 6.
The crude product was purified by chromatography (CH2Cl2–
hexane, 1 : 2, v/v) to yield a white powder (95%). IR (KBr):
m 3031, 2960, 1690, 1590, 1516, 1453, 1319, 1450 cm−1; Mp
145–146 ◦C; dH (500 MHz, CDCl3): 1.47 (s, 9 H, C(CH3)3), 4.55
(m, 1 H, CH), 4.78 (m, 1 H, CH), 5.20 (s, 2 H, CH2), 6.76 (d,
J = 8.8 Hz, 2 H, C6H4), 6.78–7.16 (m, 10 H, 2 × C6H5), 7.34
(s, 1 H, NHCO), 7.38–7.40 (m, 5 H, C6H5CH2), 7.45 (d, J =
8.8 Hz, 2 H, C6H4).
(1S,2S)-N-Boc-Nꢀ -(4-hydroxybenzenesulfonyl)-1,2-diphenyl-
ethylenediamine (14). A solution of 13 (559 mg, 1 mmol) and
10% Pd/C (11 mg, 0.1 mmol) in 20 mL methanol was stirred
at room temperature for 24 h under an atmosphere of H2.
Upon completion of the reaction, the mixture was filtered, and
the cake was washed with methanol. The combined methanol
solution was evaporated in vacuo and the residue was purified by
chromatography using CH2Cl2 as eluent to yield a white powder
(464 mg, 99%). Mp 132 ◦C (dec.); IR (KBr): m 3381, 3033,
2978, 1688, 1590, 1517, 1452, 1319, 1450 cm−1; dH (500 MHz,
DMSO-d6): 1.25 (s, 9 H, C(CH3)3), 4.60 (m, 1 H, CH), 4.79 (m,
1 H, CH), 6.50 (d, J = 8.7 Hz, 2 H, C6H4), 7.02–7.24 (m, 10
H, 2 × C6H5), 7.25 (s, 1 H, NHCO), 7.95 (d, J = 8.7 Hz, 2 H,
C6H4), 10.07 (br, 1 H, OH).
(1S,2S)-N -Boc-Nꢀ -((4-carboxyethoxybenzenesulfonyl)-1,2-
diphenylethylenediamine (15). A solution of 14 (469 mg,
1 mmol), 3-bromopropionic acid (153 mg, 1 mmol) and Cs2CO3
(652 mg, 2 mmol) in 10 mL of acetone was heated at reflux
for 24 h. The volatiles were removed in vacuo and the residue
was triturated with CH2Cl2. The extracts were filtered, dried
over Na2SO4, after evaporation of the solvent under reduced
pressure, a pale yellow foam was obtained which was purified
by chromatography (CH2Cl2–hexane, 1 : 2, v/v) to yield a white
crystal (362 mg, 67%). Mp 161–163 ◦C; IR (KBr): m 3381,
2923, 2852, 1687, 1590, 1454, 1318, 1288 cm−1; dH (500 MHz,
DMSO-d6): 1.27 (s, 9 H, C(CH3)3), 2.67 (t, J = 5.8 Hz, 2 H,
CH2COOH), 4.14 (t, J = 5.8 Hz, 2 H, OCH2), 4.61 (m, 1 H,
CH), 4.79 (m, 1 H, CH), 6.68 (d, J = 8.6 Hz, 2 H, C6H4),
7.07–7.19 (m, 10 H, 2 × C6H5), 7.29 (d, J = 8.6 Hz, 2 H, C6H4),
8.04 (s, 1 H, NHCO), 12.41 (br, 1 H, COOH).
Preparation of (S)-fluoxetine hydrochloride
(S)-2-Cyano-1-phenyl-1-ethanol (20c).
A
solution of
[RuCl2(p-cymene)]2 (90 mg, 0.15 mmol) and the ligand 17
(494 mg, 0.36 mmol) in CH2Cl2 (30 mL) was stirred for 1 h at
room temperature under argon. 2-Cyanoacetophenone (4.35 g,
30.0 mmol) and HCOOH–Et3N azeotrope (30 mL) were added
and then stirred for 18 h at 35 ◦C. After addition of CH2Cl2
(50 mL), the organic phase was separated, washed with satd. aq.
NaHCO3, and dried over MgSO4. The volatiles were removed in
vacuo and the residue purified by chromatography (CH2Cl2) to
yield a colorless vicious liquid (4.33 g, 98%). [a]2D0 −53.2 (c 2.60,
C2H5OH) (lit.,6i [a]D20 −52.5 (c 2.60, C2H5OH)); dH (500 MHz,
CDCl3): 2.54 (br, 1 H, OH), 2.77–2.79 (m, 2 H, CH2CN), 5.07
(t, J = 6.1 Hz, 1 H, CHOH), 7.33–7.57 (m, 5 H, C6H5).
(S)-3-Amino-1-phenyl-1-propanol (21). A solution of borane–
dimethyl sulfide complex (1.76 g, 2.2 mL, 23 mmol) in anhyd
THF (10 mL) was added dropwise to a solution of (S)-20 (4.30 g,
29 mmol) in dry THF (10 mL) at 0 ◦C with stirring under
N2. The mixture was heated at 70 ◦C for 4 h. After cooling
to 0 ◦C 20 mL of water was carefully added to quench the
reaction and extracted with EtOAc (3 × 15 mL). The combined
organic extracts were dried over MgSO4 and concentrated in
vacuo. Purification by chromatography (EtOAc–methanol, 1 : 1)
afforded a white solid (4.03 g, 92%). Mp 53–55 ◦C (lit.6e 56 ◦C);
[a]2D0 −44.1 (c 1, CH3OH) (lit.14 [a]D20 −43.7 (c 1, CH3OH)); dH
(500 MHz, CDCl3): 1.72–1.85 (m, 2 H, CH2NH2), 2.91–3.13 (m,
2 H, CH2CH), 5.01 (dd, J = 3.0, 8.6 Hz, 1 H, CHOH), 7.25–7.57
(m, 5 H, C6H5).
(S)-3-Methylamino-1-phenyl-1-propanol (22). To a solution
of (S)-21 (4.03 g, 27 mmol) and methyl chloroformate (3.00 g,
32 mmol) in CH2Cl2 (15 mL) ◦was added K2CO3 (14.9 g,
108 mmol) in H2O (15 mL) at 0 C with stirring. The mixture
was warmed to room temperature, stirred further for 30 min.
After the reaction, 10 mL of water were added, the mixture
was extracted with CH2Cl2 (2 × 10 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The
residual was dissolved in 10 mL of THF and the resulting
solution was directly used in the next reduction step. Reduction:
To a suspension of LiAlH4 (1.03 g, 27 mmol) in anhyd. THF
(20 mL) was added dropwise a solution of the above formamide
intermediate in 10 mL of THF at 0 ◦C with stirring under
N2. Then the mixture was heated at reflux for 8 h. After
cooling to 0 ◦C, 4 mL of degassed water was carefully added
to quench the reaction. The resulting mixture was filtered off,
and the organic layers were separated, dried over Na2SO4 and
concentrated in vacuo. Purification by flash chromatography on
silica gel chromatography (CH2Cl2–methanol, 1 : 1) yielded 22 as
a colorless vicious liquid (4.10 g, 92%). [a]2D0 −37.5 (c 1, CHCl3)
(lit.6c [a]D20 −38.2 (c 1.07, CHCl3)); dH (500 MHz, CDCl3): 1.83
(m, 2 H, CH2NH), 2.44 (s, 3 H, CH3), 2.87 (m, 2 H, CH2CH),
4.92 (dd, J = 3.0, 8.5 Hz, 1 H, CHOH), 7.31–7.42 (m, 5 H, C6H5).
The polymer-bound ligand 16
16 was prepared as described for the polymer 8. Elemental
analysis Found: N, 2.71 requires N, 2.88%; IR (KBr) 3059, 2923,
2853, 1669, 1602, 1494, 1451, 1367, 1165, 1090 cm−1.
The polymer-bound ligand 17
17 was prepared as described for the polymer 9. Elemental
analysis Found: N, 3.01 requires N, 3.06%; IR (KBr): m 3058,
2924, 2855, 1671, 1601, 1492, 1450, 1369, 1163 cm−1.
General procedure for the asymmetric transfer hydrogenation
A suspension of [RuCl2(p-cymene)]2 (3.1 mg, 0.005 mmol) and
the polymer ligand (0.012 mmol) in CH2Cl2 (1 mL) was stirred
for 1 h at room temperature under an atmosphere of argon. The
appropriate ketone (1.0 mmol) and HCOOH–Et3N azeotrope
(1.0 mL) were sequentially added, and the mixture was stirred
(S)-Fluoxetine hydrochloride (23). 60% NaH (1.19 g,
30 mmol) was added in three batches into a◦solution of (S)-
22 (4.10 g, 25 mmol) in DMSO (20 mL) at 0 C with stirring.
After the mixture was vigorously stirred at 70 ◦C for 30 min, a
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 1 3 – 2 5 1 8
2 5 1 7

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solution of 4-chlorobenzontrifluoride (4.5 g, 25 mmol) in DMSO
Wald and C. H. Senanayaake, Tetrahedron Lett., 2001, 42, 8919;
(i) M. Watanabe, K. Murata and T. Ikariya, J. Org. Chem., 2002, 67,
1712; (j) J. B. Ribeiro, M. D. Ramos, F. R. Neto, S. G. F. Leite and
O. A. C. Antunes, Catal. Commun., 2005, 6, 131.
◦
(5 mL) was added to the mixture and then heated at 90 C for
◦
2 h. The resulting mixture was cooled to 0 C, water (20 mL)
was added carefully and extracted with Et2O (2 × 20 mL).
The Et2O extracts were combined and dried over MgSO4 and
concentrated to about 10 mL. A satd. solution of HCl in Et2O
was added dropwise into the solution to provide (S)-fluoxetine
hydrochloride◦as colorless crystals (7.79 g, 90%). Mp 144–145 ◦C
(lit.8 138–140 C); [a]D20 +13.5 (c 1, CHCl3) (lit.15 [a]D20 +13.9 (c
1.01, CHCl3)); dH (500 MHz, CDCl3): 2.50 (m, 2 H, CH2N+),
2.64 (s, 3 H, CH3), 3.21 (m, 2 H, CH2CH), 5.51 (dd, J = 6.2 Hz,
1 H, CHC6H5), 6.91 (d, J = 8.5 Hz, 2 H, C6H4), 7.21–7.53 (m,
7 H, C6H5+C6H4).
7 R. K. Pandey, R. A. Fernandes and P. Kumar, Tetrahedron Lett.,
2002, 43, 4425.
8 W. H. Miles, E. J. Fialcowitz and E. S. Halstead, Tetrahedron, 2001,
57, 9925.
9 For reviews on asymmetric transfer hydrogenations, see: (a) H.-U.
Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner and M. Studer,
Adv. Synth. Catal., 2003, 345, 103; (b) K. Everaere, A. Mortreux
and J.-F. Carpentier, Adv. Synth. Catal., 2003, 345, 67; (c) C. Saluzzo
and M. Lemaire, Adv. Synth. Catal., 2002, 344, 915; (d) C. Saluzzo,
R. ter Halle, F. Touchard, F. Fache, E. Schulz and M. Lemaire,
J. Organomet. Chem., 2000, 603, 30; (e) M. J. Palmer and M.
Wills, Tetrahedron: Asymmetry, 1999, 10, 2045; (f) R. Noyori and
S. Hashiguchi, Acc. Chem. Res., 1997, 30, 97; (g) G. Zassinovich, G.
Mestroni and S. Gladiali, Chem. Rev., 1992, 92, 1051.
Acknowledgements
10 For reviews see(a) B. C. G. Soderberg, Coord. Chem. Rev., 2002,
224(1–2), 171; (b) B. M. Bhanage and M. Arai, Catal. Rev. Sci. Eng.,
2001, 43, 315; (c) Y. R. de Miguel, J. Chem. Soc., Perkin Trans. 1,
2000, 24, 4213; (d) S. V. Ley, I. R. Baxendale, R. N. Bream, P. S.
Jackson, A. G. Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I.
Storer and S. J. Taylor, J. Chem. Soc., Perkin Trans. 1, 2000, 23, 3815;
(e) G. Jannes and V. Dubois, Eds., Chiral Reactions in Heterogeneous
Catalysis, Plenum Press, New York, 1995.
11 (a) X. Li, W. Chen, W. Hem, F. King and J. Xiao, Tetrahedron Lett.,
2004, 45, 951; (b) P. N. Liu, P. M. Wang and Y. Q. Tu, Org. Lett.,
2004, 6, 169; (c) Y. C. Chen, T. F. Wu, J. G. Deng, H. Liu, J. Zhu,
Y. Z. Jiang, M. C. K. Choi and A. S. C. Chan, J. Org. Chem., 2002,
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M. C. K. Choiband and A. S. C. Chan, Chem. Commun., 2001, 1488;
(e) D. J. Bayston, C. B. Travers and M. E. C. Polywka, Tetrahedron:
Asymmetry, 1998, 9, 2015.
Financial funding from the Municipal Government of Shanghai,
China, through grant no. 03DZ19209 is gratefully acknowl-
edged.
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2 5 1 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 1 3 – 2 5 1 8