Enantioselective Synthesis of (S)-Γ-Amino Alcohols by Ru/Rh/Ir Catalyzed Asymmetric Transfer Hydrogenation (ATH) with Tunable Chiral Tetraaza Ligands in Water

Article abstract of DOI:10.1007/s10562-018-2641-8

Abstract: (R/S)-γ-Amino alcohols are the key intermediates for the preparation of Fluoxetine, Atomoxetine, Nisoxetine and Duloxetine. In this paper, we describe an effective method to obtain (S)-γ-amino alcohols by Ru/Rh/Ir catalyzed asymmetric transfer h

Full text of DOI:10.1007/s10562-018-2641-8

Catalysis Letters
https://doi.org/10.1007/s10562-018-2641-8
Enantioselective Synthesis of (S)-γ-Amino Alcohols by Ru/Rh/Ir
Catalyzed Asymmetric Transfer Hydrogenation (ATH) with Tunable
Chiral Tetraaza Ligands in Water
Jianxiang Chen1 · Tian Zhang1 · Xungao Liu1 · Liang Shen1
Received: 13 September 2018 / Accepted: 8 December 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
(R/S)-γ-Amino alcohols are the key intermediates for the preparation of Fluoxetine, Atomoxetine, Nisoxetine and Duloxetine.
In this paper, we describe an effective method to obtain (S)-γ-amino alcohols by Ru/Rh/Ir catalyzed asymmetric transfer
hydrogenation with tunable chiral tetraaza ligands (L1–L5) in HCOONa/H2O system. The asymmetric reduction of acetophe-
none with [Ru(p-cymene)Cl2]2/L1 was utilized as the model ATH reaction to achieve the optimum reaction conditions. The
best results were obtained by [RhCp*Cl2]2/L5 affording the corresponding (S)-γ-amino alcohol with a good 97% conversion
and an excellent>99% ee in the reduction of 3-(N-methyl, N-carbethoxy)-1-phenylpropan-1-one. The influence of electronic
and steric effects of the substituents in the ligands on the catalytic activities was also discussed.
Graphical Abstract
(S)-γ-Amino alcohols were prepared via asymmetric transfer hydrogenation of β-amino ketones catalyzed by Ru/Rh/Ir com-
plexes in situ with tunable chiral tetraaza ligands in HCOONa/H2O system. A moderate to excellent conversion (~99%) and
enantioselectivity (~99%) were obtained with varied electronic and steric effects of the substituents on ligands and substrates.
Keywords Tetraaza ligand · Asymmetric transfer hydrogenation · β-Amino ketones · γ-Amino alcohols · HCOONa
1 Introduction
Fluoxetine, atomoxetine and duloxetine are the efficient ser-
otonin (5-HT), norepinephrine (NE) and serotonin-norepi-
nephrine re-uptake inhibitor, respectively. They are generally
used as antidepressants for the treatment of several depres-
sion related disorders [1, 2]. Enantiomerically pure (R/S)-
γ-amino alcohols, the key chiral precursor of these xetine’s
* Liang Shen
shenliang@hznu.edu.cn
1
College of Material Chemistry and Chemical Engineering,
Hangzhou Normal University, Hangzhou 311121,
People’s Republic of China
Vol.:(0123456789)
1 3

J. Chen et al.
API, are obtained in the industrial production by chemical or
enzymatic kinetic resolution [3, 4]. From the view of green
chemistry, this approach has the disadvantage of low utiliza-
tion rate of atom and serious environmental pollution.
Asymmetric transfer hydrogenation (ATH) have been
developed to prepare the chiral secondary alcohols in excel-
lent enantioselectivity and good yield by the reduction of
simple or functionalized ketones with chiral Ru/Rh/Ir cata-
lysts [5–8]. The ATH of β-amino ketones by Ru/Rh com-
plexes with chiral monotosylated 1,2-diamines or amino
alcohols, introduced by Noyori, is the efficient method to
obtain the chiral γ-amino alcohol with mild reaction condi-
tion and operational simplicity [6, 9–11]. A highly enan-
tioselective synthesis of (R)-N-Boc-N-methyl-3-hydroxy-
3-phenyl-propylamine, a precursor of (R)-Fluoxetine, was
achieved via ATH of 3-(N-Boc, N-methyl)-1-phenylpropan-
1-one with combination of [RhCp*Cl2]2 and a chiral amino
alcohol ligand [12]. (S)-N-methyl-3-hydroxy-3-(2-thienyl)
propylamine, a precursor of (S)-Duloxetine, was reported to
be accomplished by aza-Michael addition-ATH of 1-(thio-
phen-2-yl)prop-2-enone and methylamine catalyzed by
(S,S)-TsDPEN-Ru in HCOONa system with 92% yield and
99% ee [13]. Inspired by Noyori’ (S,S)-TsDPEN-Ru, our
group had developed some air-stable bis(sulfonyl) tetraaza
ligands derived from (1S, 2S)-diphenylethylenediamine and
paid attention to their catalytic activity in the [Ru(p-cymene)
Cl2]2-Catalyzed ATH of aromatic ketones [14–17]. In this
work, we report the ATH of β-amino ketones catalyzed
by Ru/Rh/Ir complexes in situ with tunable chiral tetraaza
ligands (L1–L5) in HCOONa/H2O system, giving the cor-
responding optically active γ-amino alcohols in moderate to
excellent conversion and enantioselectivity.
were carried out under nitrogen atmosphere using oven-
dried glassware in oil bath.
The 1H NMR and 13C NMR spectra were recorded on a
500 MHz Bruker spectrometer. Mass spectra were measured
with Agilent (Santa Clara, CA, USA) 5979 spectrometer.
LC-MS was measured with Agilent (Santa Clara, CA, USA)
Infinity 1290 LC and 6530 Accurate-Mass Q-TOF MS. Chi-
ral GC analysis was carried out using Agilent GC 7890A
with CP-Chiralsil-Dex-CB Chiral column (Santa Clara, CA,
USA).
2.2 Synthesis of the Ligands
L1–L5 were prepared as per the procedure reported in
our previous work [16]. The synthetic route in outlined in
Scheme 1.
2.2.1 (S,S,S,S)-N,N-Bis(1,2-Diphenylethylenediamino)-1,3
-Benzenedisulfonyl Amine L1
Light yellow powder, [α]D20: +88.4°(c 0.1, CHCl3). H
1
NMR (500 MHz, DMSO-d6): δ (ppm) 3.38 (br singlet, 6H),
3.99-4.00 (d, J=7.5 Hz, 2H), 4.31–4.33 (d, J=7.5 Hz, 2H),
6.87–6.92 (m, 10H), 7.08–7.09 (m, 10H), 7.19 (m, 1H),
7.28–7.30 (dd, J=1.5 Hz, 8.0 Hz, 2H), 7.70 (singlet, 1H).
13C NMR (125 MHz, DMSO-d6): δ (ppm) 60.22(CHNH),
64.23(CHNH), 124.71, 127.31, 127.82, 127.98, 128.09,
128.14, 128.29, 128.58, 129.50, 138.41, 140.72, 140.09,
141.09. HRMS (ESI) calcd for C34H35N4O4S2 [M + H]+
627.2100, found 627.2088.
2.2.2 (S,S,S,S)-N,N-Bis(1,2-Bis(4′-Methyloxybenzene)
Ethylenediamino)-1,3-Benzenedisulfonyl Amine L2
2 Experimental
Bright yellow powder, [α]D20: -109° (c 0.1, CHCl3). H
1
NMR (500 MHz, DMSO-d6): δ (ppm) 3.58 (s, 6H), 3.648 (s,
6H), 3.98-4.00 (d, J=8.0 Hz, 2H), 4.28–4.29 (d, J=8.0 Hz,
2H), 6.43–6.45 (d, J=8.5 Hz, 4H), 6.65–6.67 (d, J=9.0 Hz,
4H), 6.75–6.77 (d, J=8.5 Hz, 4H), 7.01–7.02 (d, J=9.0 Hz,
4H), 7.04–7.07 (t, J=8.0 Hz, 1H), 7.29–7.30 (d, J=1.5 Hz,
1H), 7.31–7.32 (d, J=2.0 Hz, 1H), 7.66 (s, 1H). 13C NMR
(125 MHz, DMSO-d6): δ (ppm) 55.21(OCH3), 55.32(OCH3),
59.85(CHNH), 64.26(CHNH), 113.41, 113.58, 124.82,
128.91, 129.06, 129.40, 131.00, 133.25, 142.01, 158.25,
158.56. HRMS (ESI) calcd for C38H43N4O8S2 [M + H]+
747.2522, found 747.2480.
2.1 General
Unless otherwise stated, commercial reagents and sol-
vents were used as received without further purification.
2-Acetylthiophene and 3-(dimethylamino)-1-phenylpro-
pan-1-one were obtained from Zhejiang Liaoyuan Phar-
maceutical Co., Ltd. (1S,2S)-1,2-diphenylethylenediamine
and (1R,2R)-1,2-bis-(2-hydroxyphenyl)-1,2-diaminoethane
were purchased from Sigma-Aldrich (Steinem, Germany).
1,3-Benzenedisulfonyl chloride and trifluoroacetic anhydride
were purchased from TCI (Shanghai, China). Methylamine
hydrochloride, N-methylbenzylamine, 2′-methyloxybenza-
ldehyde, 4′-methyloxybenzaldehyde, 4′-nitrobenzaldehyde
and 4′-trifluoromethylbenzaldehyde were obtained from
J&K chemicals (Shanghai, China). [Ru(η6-p-cymene)Cl2]2,
[RhCp*Cl2]2 and [IrCp*Cl2]2 were purchased from Alfa
Aesar (Ward Hill, Massachusetts, UK). All ATH reactions
2.2.3 (S,S,S,S)-N,N-Bis(1,2-Bis(2′-Methyloxybenzene)
Ethylenediamino)-1,3-Benzenedisulfonyl Amine L3
Yellow powder, [α]D20: +125° (c 0.1, CHCl3). H NMR
1
(500 MHz, CDCl3): δ (ppm) 3.42 (s, 6H), 3.55 (s, 6H),
1 3

Enantioselective Synthesis of (S)-γ-Amino Alcohols by Ru/Rh/Ir Catalyzed Asymmetric…
Scheme 1 Synthesis of ligands L1–L5
4.81 (s, 2H), 5.10 (s, 2H), 6.27–6.28 (d, J = 8.0 Hz,
2H), 6.40–6.43 (d, J = 7.5 Hz, 2H), 6.71–6.80 (m, 7H),
6.91–6.95 (t, J = 7.5 Hz, 8.0 Hz, 2H), 7.10–7.14 (td,
J = 1.0 Hz, 8.0 Hz, 2H), 7.19–7.21 (dd, J= 1.5 Hz, 8.0 Hz,
2H), 7.30 (s, 2H), 7.43 (s, 1H). 13C NMR (125 MHz,
CDCl3): δ (ppm) 55.37(CHNH), 55.91(CHNH),
110.22, 111.29, 119.87, 120.30, 129.10, 129.34, 129.56,
130.44, 140.80, 155.82, 156.84. HRMS (ESI) calcd for
C38H43N4O8S2 [M + H]+ 747.2522, found 747.2480.
2.2.4 (S,S,S,S)-N,N-Bis(1,2-Bis(4′-Nitrobenzene)
Ethylenediamino)-1,3-Benzenedisulfonylnyl Amine
L4
Brownish red powder, [α]D20: − 107° (c 0.1, CHCl3).
1H NMR (500 MHz, CDCl3): δ (ppm) 4.20 (s, 4H),
6.80–6.83 (t, J = 7.5 Hz, 1H), 6.93–6.95 (d, J = 8.0 Hz,
1H), 6.97–6.99 (d, J=7.5 Hz, 1H), 7.19–7.22 (t, J=7.0 Hz,
8.0 Hz, 1H), 7.41–7.43 (d, J = 8.5 Hz, 8H), 8.13–8.15 (d,
J=8.5 Hz, 8H). 13C NMR (125 MHz, DMSO-d6): δ (ppm)
1 3

J. Chen et al.
45.99(CHNH), 82.89, 89.18, 123.77, 123.85, 123.90,
124.17, 128.90, 128.93, 129.39, 129.67. HRMS (ESI) calcd
for C34H31N8O12S2 [M+H]+ 807.1503, found 807.1454.
yield) was formed, which was filtered off, washed with
cooled acetone (3×10 mL), and dried in air.
I (1.737 g, 6 mmol) or III (1.773 g, 6 mmol), NaHCO3
(1.2629 g, 15 mmol), KI (0.0499 g, 0.3 mmol), and ethyl
chloroacetate (0.9609 g, 9 mmol) were mixed in dichlo-
romethane (20 mL). The mixture was heated to reflux at
50 °C. After completion of the reaction tracing by TLC,
the solvent was removed under reduced pressure. The crude
product was purified by column chromatogram on silica
using ethyl acetate/petroleum ether (1:4) as the eluent (Rf =
0.29). Product II and IV were obtained as pale yellow oily
liquid (II: 0.79 g, 56%; IV (0.74 g, 51%).
2.2.5 (S,S,S,S)-N,N-Bis(1,2-Bis(4′-Trifluoromethylbenzene)
Ethylenediamino)-1,3-Benzenedisulfo-nyl Amine L5
Pinkish purple solid, [α]D20: − 95.6° (c 0.1, CHCl3). H
1
NMR (500 MHz, CDCl3): δ (ppm) 4.20–4.21 (d, J=4.5 Hz,
2H), 4.49–4.50 (d, J=5.0 Hz, 2H), 6.80–6.83 (t, J=7.5 Hz,
8.0 Hz, 1H), 7.29–7.31 (d, J = 8.0 Hz, 4H), 7.35–7.37 (d,
J = 8.0 Hz, 4H), 7.37–7.39 d, J = 8.5 Hz, (4H), 7.44–7.46
(d, J=8.5 Hz, 4H), 7.54–7.55 (d, J=8.0 Hz, 3H), 7.95 (s,
1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 59.69(CF3),
61.64(CHNH), 62.74(CHNH), 125.29, 125.32, 125.51,
125.58, 125.62, 126.70, 126.96, 137.31, 129.46, 129.56,
129.96, 130.21, 140.85, 142.57, 144.512, 147.04. HRMS
(ESI) calcd for C38H31F12N4O4S2 [M+H]+ 899.1595, found
899.1587.
II: 1H NMR (500 MHz, CDCl3): δ(ppm) 1.25 (t,
J = 6.5 Hz, 3H), 2.96 (s, 3H), 3.25 (m, 2H), 3.68 (t,
J=7.5 Hz, 2H), 4.13 (t, J=4.5 Hz, 2.5 Hz, 2H), 7.45–7.48
(m, 2H), 7.55–7.58 (m, 1H), 7.98–7.97 (m, 2H).
IV: 1H NMR (500 MHz, CDCl3): δ(ppm) 1.22–1.26 (m,
3H), 2.83 (s, 3H), 4.09–4.13 (m, 2H), 4.15–4.20 (m, 2H),
4.46 (s, 2H), 7.24–7.73 (m, 3H).
3-(N-Methyl, N-trifluoroacetyl)amino-1-(thiophen-2-yl)
propan-1-one (VI) was synthesized according to the reported
method [20] as a yellow crystalline solid.
2.3 Synthesis of the Substrates
3-(N-Carbethoxy, N-methyl)-1-phenylpropan-1-one (II) and
3-(N-carbethoxy, N-methyl)-1-(thiophen-2-yl)propan-1-one
(IV) were prepared by a modified literature procedure [18,
19] with improved yield (Scheme 2)
VI: Mp: 44–45 °C. 1H NMR (500 MHz, CDCl3): δ (ppm)
3.06 (s, 3H), 3.28 (t, 2H), 3.82–3.89 (t, J = 6.5 Hz, 2H),
7.13–7.18 (m, 1H), 7.66–7.77 (m, 2H).
N-Benzylmethylamine (9.09 g, 75 mmol), paraformalde-
hyde (2.26 g, 75 mmol), and 37% HCl (2 mL) were added
to isopropanol (16 mL). The mixture was heated to reflux
at 78 °C till the full dissolution of paraformaldehyde. Ace-
tophenone (6.6 g, 60 mmol) or 2-Acetylthiophene (7.56 g,
60 mmol) was added to the reaction mixture with stirring,
and the mixture was refluxed for a further 8 h. After the
removal of the solvent, 20 mL of acetone was added. White
crystalline powder I (11.5 g, 58% yield) or III (9.8 g, 52%
2.4 General Procedure for the Asymmetric Transfer
Hydrogenation in Water
The metal precursor [Ru(η6-p-cymene)Cl2]2, [Cp*RhCl2]2
or [Cp*IrCl2]2 (0.005 mmol) and the ligands L1–L5
(0.011 mmol) were mixed in degassed water (2 mL) and
stirred at 28 °C for 1 h, subsequently, anhydrous sodium for-
mate (0.6801 g, 10 mmol) and the substrate (1.0 mmol) were
added. If applicable, cetyl trimethylammonium bromide
Scheme 2 Synthesis of the substrates
1 3

Enantioselective Synthesis of (S)-γ-Amino Alcohols by Ru/Rh/Ir Catalyzed Asymmetric…
Table 1 ATH reaction of acetophenone
(CTMAB, 0.0365 g, 0.1 mmol) was added. At 28 °C, 40 °C
or 60 °C the mixture was heated for another 11 h. The sus-
pension was extracted with dichloromethane (3×5 mL). The
organic layers were combined, dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure, and then
passed through a short silica gel column. The enantiomeric
excess (ee) was measured by Chiral GC analysis along with
the conversion.
OH
O
[Ru(p-cymene)Cl2]2, Ligand L1
S/C 100:1, HCOONa, H2O
Entrya
S/M/L/base
T/°C
T/h
Conv.b (%)
ee (%)
1
2
3
4
5
6
7
8
100:1:1.1:100
100:1:1.1:500
100:1:1.1:1000 28
100:1:1.1:1500 28
100:1:1.1:2000 28
100:1:1.1:100
100:1:1.1:500
100:1:1.1:1000 40
100:1:1.1:1500 40
100:1:1.1:2000 40
28
28
11
11
11
11
11
11
11
11
11
11
11
11
4
6
8
11
13
11
11
24
58
71
96
75
52
75
86
95
98
76
98
48
61
72
>99
98
98
98
95(S)
94(S)
96(S)
93(S)
94(S)
93(S)
93(S)
93(S)
93(S)
92(S)
85(S)
90(S)
90(S)
90(S)
90(S)
90(S)
90(S)
89(S)
90(S)
3 Results and Discussion
Tetraaza ligands L2–L5 were designed to explore the elec-
tronic and steric effects on the catalytic activity by introduc-
ing either an electron donating or an electron withdrawing
substituent at 2- or 4-position of the phenyl rings.
40
40
The asymmetric reduction of acetophenone catalyzed by
[Ru(p-cymene)Cl2]2 complexed with L1 in situ was utilized
as the model ATH reaction to gain the optimum reaction
conditions in HCOONa/H2O system. Screening was carried
out for the base amount, reaction temperature and reaction
time. The results were reported in Table 1.
9
10
11
12
13
14
15
16
17
18
19
100:1:1.1:100
100:1:1.1:500
60
60
100:1:1.1:1000 60
100:1:1.1:1000 60
100:1:1.1:1000 60
100:1:1.1:1000 60
100:1:1.1:1000 60
100:1:1.1:1500 60
100:1:1.1:2000 60
The reaction temperature had an important effect on
conversion and ee value. By comparing the data of the
same base amount and reaction time at 28, 40 and 60 °C
in Table 1, the conversion increased significantly, but the
ee value decreased slowly as the reaction temperature
increased. The conversion and ee value of the reduction reac-
tion at 60 °C under different reaction time were determined,
respectively. As shown in Fig. 1a, the highest conversion was
more than 99% at 11 h. However, the ee value was compara-
tively stable with the extending of reaction time. The influ-
ence of HCOONa amount on catalysis activities was also
investigated when the reduction reaction was performed. As
shown in Fig. 1b, the conversion increased obviously, and
S/M/L/base: mole proportion of substrate, metal, ligand and base
aReaction conditions: acetophenone: 1.0×10−3 mol; ligand:
1.1×10−5 mol; [Ru(p-cymene)Cl2]2: 5.0×10−6 mol; HCOONa:
1–20 mmol; water: 2 cm3; temperature: 28, 40 and 60 °C; reaction
time: 4, 6, 8, 11 and 13 h; nitrogen protection
bConversion and ee were determined by chiral GC (CP-Chiralsil-Dex-
CB Chiral column)
Fig. 1 a The effect of reaction time on conversion and ee value (temperature of 60 °C, HCOONa of 10 mmol). b The effect of HCOONa on
catalysis activities (reaction time of 11 h)
1 3

J. Chen et al.
Table 2 ATH reaction of 3-(N,N-dimethyl)amino-1-phenylpropan-1-one and 3-(N-carbethoxy, N-methyl) amino-1-phenylpropan-1-one
O
OH
*
metal precursor, ligands L1-L5
S/C 100:1, HCOONa, H2O
N R
Me
N R
Me
1
2
R= Me
R= COOEt
Entrya
Sub.
Metal precursor
Ligand
CTMAB
(mg)
Conv.b(%)
ee (%)
(Reduction by-pro-
ductc)
1
2
3
4
5
6
7
8
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
[Ru(p-cymene)Cl2]2
L1
L1
L2
L3
L4
L5
L1
L2
L3
L4
L5
L1
L2
L3
L4
L5
L1
L2
L3
L4
L5
–
–
–
–
–
–
36.5
36.5
36.5
36.5
36.5
36.5
36.5
36.5
36.5
36.5
36.5
36.5
36.5
36.5
36.5
0.0(71)
93
80
61
16
81
99
>99
95
80
95
55
98
96
97
97
68
94
N(N)
82(S)
79(S)
83(S)
47(R)
87(S)
92(S)
93(S)
90(S)
40(R)
94(S)
>99(S)
90(S)
90(S)
59(R)
>99(S)
98(S)
96(S)
89(S)
27(R)
96(S)
9
10
11
12
13
14
15
16
17
18
19
20
21
[RhCp*Cl2]2
[IrCp*Cl2]2
90
88
88
“–”: no surfactant; “N”: no detected
aReaction conditions: substrate: 1.0×10−3 mol; ligand: 1.1×10−5 mol; catalyst: 5.0×10−6 mol; HCOONa: 1.0×10−2 mol; water: 2 cm3; tem-
perature 60 °C; reaction time 11 h; nitrogen protection
bConversion and ee were determined by chiral GC (CP-Chiralsil-Dex-CB Chiral column)
cReduction by-product: 1-phenylpropan-1-ol
ee value declined gently on the whole when the amount of
HCOONa increased from 1 to 20 mmol.
As shown surprisingly on entry 1 in Table 2, the reduc-
tion reaction did not afford the expected 3-(N,N-dimethyl)
amino-1-phenylpropan-1-ol, but instead 1-phenylpropanol,
the deamination by-product, was available with the con-
version of 71% when the substrate was 3-(N,N-dimethyl)
amino-1-phenylpropan-1-one. Due to the strong alkalinity
of N atom of substrate resulting from two electron-donating
groups of methyl, the N atom was apt to coordinate with
Ru(II), resulting in the activation of C–N bond. It may ben-
efit the side reaction of deamination. Similar results was
found in Qu’s experiments when the ATH reduction was exe-
cuted under formic acid/triethylamine system [22]. In order
to avoiding the side reaction, carbethoxy or trifluoroacetyl,
After preliminary optimization, it was established that
60 °C of reaction temperature, 10 mmol of HCOONa and
11 h of reaction time were the optimum reaction conditions
taking both conversion and ee value into account.
Comparing entries 2–6 with entries 7–11 in Table 2 when
[Ru(p-cymene)Cl2]2 was used as the catalysis precursor,
cetyl tri methyl ammonium bromide (CTMAB), a surfactant,
was significantly helpful for both conversion and ee value
[21]. Therefore, this surfactant was applied in the ATH of
β-amino ketones in HCOONa/H2O system.
1 3

Enantioselective Synthesis of (S)-γ-Amino Alcohols by Ru/Rh/Ir Catalyzed Asymmetric…
Table 3 ATH reaction of 3-(N-carbethoxy, N-methyl)amino-1-(thiophen-2-yl)propan-1-one and 3-(N-methyl, N-trifluoroacetyl)amino-1-
(thiophen-2-yl)propan-1-one
O
OH
*
S
S
Metal precursor, ligands L1-L5
N
R
N
Me
R
S/C 100:1, HCOONa, H2O
Me
1
2
R = COOEt
R = COCF3
Entrya
Sub.
Metal precursor
Ligand
Conv. b(%)
ee (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1
[Ru(p-cymene)Cl2]2
L1
L2
L3
L4
L5
L1
L2
L3
L4
L5
L1
L2
L3
L4
L5
L1
L2
L3
L4
L5
92
91
85
71
95
92
93
88
67
94
42
51
22
26
56
80
78
12
54
78
74(S)
81(S)
76(S)
40(R)
84(S)
76(S)
81(S)
80(S)
59(S)
87(S)
81(S)
47(S)
40(S)
81(R)
57(S)
56(S)
48(S)
32(S)
56(R)
56(S)
9
10
11
12
13
14
15
16
17
18
19
20
[RhCp*Cl2]2
[IrCp*Cl2]2
aReaction conditions: substrate: 1.0×10−3 mol; ligand: 1.1×10−5 mol; catalyst: 5.0×10−6 mol; HCOONa: 1.0×10−2 mol; water: 2 cm3; sur-
factant: 36.5 mg; temperature 60 °C; reaction time 11 h
bConversion and ee were determined by chiral GC (CP-Chiralsil-Dex-CB Chiral column)
Fig. 2 The proposed six-mem-
bered metal–ligand-substrate
transition state (M: Rh or Ir)
an electron-withdrawing group, was introduced to the N
atom of two β-amino ketones as described in Sect. 2.3.
Comparing to ligand L2 and L3 carrying an electron-
donating group on the phenyl, the ligand L5 bearing a strong
electron-withdrawing group displayed higher catalytic
enantioselectivity (94–99% (S)-enantiomer), but did not
exhibit advantage on conversion when the substrate is
3-(N-carbethoxy, N-methyl)amino-1-phenylpropan-1-one
(entries 8, 9 and 11; entries 13, 14 and 16; entries 18, 19
and 21 in Table 2). The same trend was also observed
1 3

J. Chen et al.
when substrates are 3-(N-carbethoxy, N-methyl)amino-1-
(thiophen-2-yl)propan-1-one and 3-(N-methyl, N-trifluoro-
acetyl)amino-1-(thiophen-2-yl)propan-1-one (entries 2, 3
and 5; entries 7, 8 and 10; entries 12, 13 and 15; entries 17,
18 and 20 in Table 3). We had proposed a six-membered
metal–ligand substrate transition state (TS) in the previ-
ous work based on the experimental results and Noyori’s
calculated mechanism [9] when mixing 1:1 ratio of Ru to
ligand L1 in water at 60 °C [16]. The component of [(Cp*)
ClRhL1RhCl(Cp*)] was confirmed by elemental analysis of
the isolated precatalyst when 1:1 ratio of [Cp*RhCl2]2 to L1
was mixed in HCOONa/H2O at 60 °C with the same reaction
conditions as in transfer hydrogenation. It was reasonable to
presume the similar double metals TS as indicated in Fig. 2
when [Cp*RhCl2]2 or [Cp*IrCl2]2 was the precursor under
the same reaction conditions. The electron withdrawing
effect may promote the formation of six-membered hydro-
gen bonds ring in TS via increasing the nucleophilicity of
ligands to Ru/Rh/Ir. However, the electron donating effect
restrains the stability of the six-membered metal–ligand
substrate TS [9, 23–25]. Moreover, comparing to L2, L3
with steric hindrance effect besides electron-donating effect
exerted a more negative influence on conversion and enan-
tioselectivity (entries 8 and 9, entries 13 and 14, entries 18
and 19 in Table 2; entries 2 and 3, entries 7 and 8, entries 17
and 18 in Table 3).
Rh/Ir precursor complexing with tunable chiral tetraaza
ligands in an environmentally friendly medium with a
moderate to excellent conversions and enantioselectivities.
A good 97% conversion and an excellent > 99% ee value
of (S)-3-(N-methyl, N-carbethoxy)amino-1-phenylpropan-
1-ol were obtained by [RhCp*Cl2]2/L5 under the optimal
reaction conditions. This makes it particularly attractive
for the practical synthesis of antidepressants through a
sequential de-esterification and etherification reaction.
The influence of electronic and steric effects of the sub-
stituents in the ligands on the catalytic activities was pre-
liminary explored. The experiment results reveal that the
electron withdrawing effect strengthens the enantioselec-
tivity by way of consolidating the sixed-membered transi-
tion state but the electron donating effect and steric effect
discourage the catalytic activity of the ligands.
Acknowledgements We are grateful to the Zhejiang Provincial Natural
Science Foundation of China (LY16B010003) and the Education Office
of Zhejiang Province (Y200907718) for financial Support.
Compliance with Ethical Standards
Conflict of interest The authors declare no conflict of interest.
References
When (S,S,S,S)-tetraaza ligand and p-cymene or penta-
methylcyclopentadiene (Cp*) were used as ancillaries, two
(R)-configured metal centers were obtained, in which two N
atoms of tetraaza ligand chelated one metal independently.
The transfer hydrogenation via this (R)-configured TS with
S conformation of carbonyl carbon atom, resulting perhaps
from the attractive CH/π interaction between p-cymene or
pentamethylcyclopentadiene of the Ru/Rh/Ir complexes and
the aryl substituent in the substrate, afforded (S)-enantiomer.
Astonishingly, a reversion of enantioselectivity was
observed when nitro was imported in para-position (L4)
(entries 10, 15, 20 in Table 2 and entries 4, 9, 14,19 in
Table 3). (R)-enantiomer was found to be the predominant
product. The reversion phenomenon was also found in our
previous work when nitro-tetraaza ligand was applied in
the ATH reduction of simple or functionalized ketones
[16]. It is speculated that the delocalized π-bond of nitro
causes this distinctness of enantioselectivity by dragging
strongly the hydrogen attached upon the prochiral carbon.
1. Dugan SE, Fuller MA (2004) Duloxetine: a dual reuptake inhibi-
tor. Ann Pharmacother 38:2078–2082
2. Fournier JC, DeRubeis RJ, Hollon SD, Sona Dimidjian S, Amster-
dam JD, Shelton RC, Fawcett J (2010) Antidepressant drug effects
and depress severity. J Am Med Assoc 303:47–53
3. Sakai K, Sakurai R, Yuzawa A, Kobayashi Y, Saigo K (2003)
Resolution of 3-(methylamino)-1-(2-thienyl)propan-1-ol, a new
key intermediate for duloxetine, with (S)-mandelic acid. Tetrahe-
dron: Asymmetry 14:1631–1636
4. Liu HL, Hoff BH, Anthonsen T (2000) Chemo-enzymatic synthe-
sis of the antidepressant duloxetine and its enantiomer. Chirality
12:26–29
5. Fujii A, Hashiguchi S, Uematsu N, Ikariya T, Noyori R (1996)
Ruthenium(II)-catalyzed asymmetric transfer hydrogenation of
ketones using a formic acid—triethylamine mixture. J Am Chem
Soc 118:2521–2522
6. Noyori R, Hashiguchi S (1997) Asymmetric transfer hydrogena-
tion catalyzed by chiral ruthenium complexes. Acc Chem Res
30:97–102
7. Noyori R, Yamakawa M, Hashiguchi S (2001) Metal–ligand
bifunctional catalysis: a nonclassical mechanism for asymmetric
hydrogen transfer between alcohols and carbonyl compounds. J
Org Chem 66:7931–7944
8. Hashiguchi S, Fujii A, Takehara J, Ikariya T, Noyori R (1995)
Asymmetric transfer hydrogenation of aromatic ketones cata-
lyzed by chiral ruthenium(II) complexes. J Am Chem Soc
117:7562–7563
4 Conclusions
9. Hamada T, Torii T, Izawa K, Noyori R, Ikariya T (2002) Prac-
tical synthesis of optically active styrene oxides via reductive
transformation of 2-chloroacetophenones with chiral rhodium
catalysts. Org Lett 4:4373–4376
On the basis of our efforts in asymmetric transfer hydro-
genation, we report herein the asymmetric synthesis of
(S)-γ-amino alcohols via ATH reduction catalyzed by Ru/
1 3

Enantioselective Synthesis of (S)-γ-Amino Alcohols by Ru/Rh/Ir Catalyzed Asymmetric…
10. He SZ, Li XM, Dai J, Yan M (2008) Synthesis of antidepressant
duloxetine via asymmetric transfer hydrogenation. Chin Chem
Lett 19:23–25
19. Li AJ, Liu DZ, Zhou XQ, Yin CX, Cao H Process for preparing
of duloxetine and its isomer. CN 101012219 2007-08-08
20. Barbara M, Rok Z, Michel SM, Miha S, Jaroslav T Process for
preparation of duloxetine via asymmetric transfer hydrogenation
of β-ketoamines. WO 2010003942 A2 2010-01-14
11. Cortez NA, Aguirre G, Parra-Hake M, Somanathan R (2013) Syn-
thesis of (R)-tembamide and (R)-aegeline via asymmetric transfer
hydrogenation in water. Tetrahedron: Asymmetry 24:1297–1302
12. Buitrago E, Lundberg H, Andersson H, Ryberg P, Adolfsson H
(2012) High throughput screening of a catalyst library for the
asymmetric transfer hydrogenation of heteroaromatic ketones:
formal syntheses of (R)-fluoxetine and (S)-duloxetine. Chem-
CatChem 4:2082–2089
21. Yamakawa M, Ito H, Noyori R (2000) The metal-ligand bifunc-
tional catalysis: a theoretical study on the ruthenium(II)-catalyzed
hydrogen transfer between alcohols and carbonyl compounds. J
Am Chem Soc 122:1466–1478
22. Zhao JF, Dou HJ, Zhou YH, Qu JP (2011) Asymmetric transfer
hydrogenation of β-amino ketone catalyzed by (S,S)-TsDPEN-Ru
complex and its application in the synthesis of duloxetine. Chem
J Chin Univ 32:2331–2334
13. Wu L, Jin RH, Li L, Hu XY, Cheng TY, Liu GH (2017) A michael
addition–asymmetric transfer hydrogenation one-pot enantioselec-
tive tandem process for syntheses of chiral γ-secondary amino
alcohols. Org Lett 19:3047–3050
23. Cortez NA, Rodrıguez-Apodaca R, Aguirre G, Parra-Hake
M, Cole T, Somanathan R (2006) New C2-symmetric
bis(sulfonamide)-cyclohexane1,2-diamine-RhCp* complex and
its application in the asymmetric transfer hydrogenation (ATH)
of ketones in water. Tetrahedron Lett 47:8515–8518
14. Hong YL, Tan HJ, Qiu J, Shen L (2012) New C2-symmetric chi-
ral tetraaza ligands and their application for [Ru(p-cymene)Cl2]2-
catalyzed asymmetric transfer hydrogenation. Synth React Inorg
Met-Org Nano-Met Chem 42:502–506
24. Cortez NA, Aguirre G, Parra-Hake M, Somanathan R (2009) New
heterogenized C2-symmetric bis(sulfonamide)-cyclohexane1,2-
diamine-RhIIICp* complexes and their application in the asym-
metric transfer hydrogenation (ATH) of ketones in water. Tetra-
hedron Lett 50:2228–2231
15. Liu XG, Zhang T, Hu YY, Shen L (2013) Synthesis and crystal
structure of (S,S,S,S)-N,N’-bis[N-(P-toluenesulfonamido)-1,2-di-
phenylethyl]ethylenediamine. Crystallogr Rep 58:1091–1095
16. Liu XG, Zhang T, Hu YY, Shen L (2014) Asymmetric trans-
fer hydrogenation of aromatic ketones catalyzed by new chiral
C2-symmetric bis(sulfonyl) tetraaza ligands complexed with
[Ru(η6-p-cymene)Cl2]2 in water. Catal Lett 144:1289–1295
17. Yu HQ, Liu XG, Shen L (2015) Synthesis and structure of
C2-symmetric chiral tetraaza liangds and asymmetric trans-
fer hydrogenation of acetophenone. J Hangzhou Norm Univ
14:378–384
25. Soni R, Cheung FK, Clarkson GC, Martins JED, Grahamb MA,
Wills M (2011) The importance of the N–H bond in Ru/TsDPEN
complexes for asymmetric transfer hydrogenation of ketones and
imines. Org Biomol Chem 9:3290–3294
Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
18. Kenny JA, Palmer MJ, Wills M (1999) Asymmetric transfer
hydrogenation of α-amino and α-alkoxy substituted ketones. Synth
Lett 10:1615–1617
1 3