Asymmetric hydrogenation of β-amino ketones with the bimetallic complex RuPHOX-Ru as the chiral catalyst

Article abstract of DOI:10.1039/c3ob40135a

Asymmetric hydrogenations of a series of β-amino ketones were carried out with a bimetallic complex (RuPHOX-Ru) as the chiral catalyst. Almost all the reactions (performed in a mixed solvent system of toluene and H₂O in the presence of KOH) gave quantitative conversions into their respective products with up to 99.9% ee. The RuPHOX-Ru catalyst is stable to both moisture and air. The procedure has the benefits of being inexpensive, environmentally friendly and highly efficient. Under a relatively low catalyst loading (TON = 2000), key intermediates of fluoxetine, tomoxetine and nisoxetine could be obtained in quantitative yield and in up to 99.9% ee. This methodology represents a promising alternative to the synthesis of the aforementioned drugs and their analogues. This journal is The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40135a

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Asymmetric hydrogenation of β-amino ketones with
the bimetallic complex RuPHOX-Ru as the chiral
catalyst†
Cite this: Org. Biomol. Chem., 2013, 11,
3855
Jiahao Wang,a Delong Liu,*a Yangang Liua and Wanbin Zhang*a,b
Asymmetric hydrogenations of a series of β-amino ketones were carried out with a bimetallic complex
(RuPHOX-Ru) as the chiral catalyst. Almost all the reactions (performed in a mixed solvent system of
toluene and H2O in the presence of KOH) gave quantitative conversions into their respective products
with up to 99.9% ee. The RuPHOX-Ru catalyst is stable to both moisture and air. The procedure has the
benefits of being inexpensive, environmentally friendly and highly efficient. Under a relatively low catalyst
loading (TON = 2000), key intermediates of fluoxetine, tomoxetine and nisoxetine could be obtained in
quantitative yield and in up to 99.9% ee. This methodology represents a promising alternative to the syn-
thesis of the aforementioned drugs and their analogues.
Received 22nd January 2013,
Accepted 11th April 2013
DOI: 10.1039/c3ob40135a
www.rsc.org/obc
1. Introduction
Fluoxetine, tomoxetine and nisoxetine are amongst the most
important norepinephrine reuptake inhibiting antidepressants
for the treatment of psychiatric disorders (Fig. 1).1 Their asym-
metric synthesis has received significant interest in recent
years because both enantiomers of the aforementioned drugs
show different curative effects.2 Chiral γ-amino alcohol, (R)-3-
methylamino-1-phenylpropan-1-ol, is the key building block
for the synthesis of these molecules.
Fig. 1 The structure of fluoxetine, tomoxetine and nisoxetine.
There are three common different pathways which can be
used to prepare γ-amino alcohols: (1) utilising a chiral alcohol
containing a facile leaving group (OMs, OTs, Cl, Br, etc.) at the
γ-position, which can be replaced by an amine substituent
(Scheme 1, Pathway 1);3 (2) using a chiral ethylene oxide in
place of a chiral alcohol (Scheme 1, Pathway 2);4 and (3) the
asymmetric hydrogenation of the corresponding β-amino
ketones using a chiral metal-based catalyst (Scheme 1, Pathway 3).
The initial study on the asymmetric hydrogenation of
β-amino ketones was performed by Achiwa. Up to 90.8% ee
was obtained by using a (2S,4S)-MCPPM-Rh complex for the
synthesis of 3-(N-benzyl-N-methylamino)propiophenone
hydrochloride.5 Noyori subsequently applied a chiral RuCl2-
(diphosphine)(1,2-diamine) complex to the reaction and
Scheme 1 The common different pathways to γ-amino alcohols.
obtained 97.5% ee and 96% yield for N,N-dimethyl-3-phenyl-
propanone6 and 92.0% ee and 100% yield for 3-dimethyl-
amino-1-(2-thienyl)-1-propanone.7 Ding8 and Huang9 achieved
the above utilizing ruthenium catalysts containing chiral di-
amines and achiral diphosphanes, with products being
obtained in up to 99% yield and not more than 98% ee. Zhang
prepared (S)-2-methyl-α-[2-(methylamino)ethyl]benzenemetha-
nol in 92% yield and 99% ee utilizing a Rh-duanphos-cata-
lyzed hydrogenation reaction of functionalized CvO.10
aSchool of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, P. R. China. E-mail: wanbin@sjtu.edu.cn; Fax: +86-21-5474-3265;
Tel: +86-21-5474-3265
bSchool of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, P. R. China
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob40135a
Recently, Zhang developed
a
Ru-catalyzed asymmetric
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Table 1 The effect of the solvent on the reactiona
hydrogenation of β-ketoenamines to synthesize chiral γ-amino
alcohols in up to 99% ee.11 The above examples utilize high H2
pressures, high temperatures and/or unstable catalyst systems,
or provide somewhat low enantioselectivities, hampering their
applicability to industrial processes. The efficient synthesis of
β-amino ketones thus remains a challenge and is worthy of
further investigation.
Entry
Solvent
Conv.b (%)
eec (%) (Config.d)
Recently, our group has focused on the development of
novel planar chiral metallocenyl ligands and their applicability
to different types of asymmetric syntheses.12 Among them, C2-
symmetric metallocenyl planar P,N-ligands 1 (RuPHOX) have
shown promising catalytic activity in many asymmetric reac-
tions, most likely due to their dual reaction sites and large
steric hindrance.12e,f,h,n Ligand 1b especially has proven to be
the most efficient ligand in the Ru-catalyzed asymmetric
hydrogenation of simple ketones (Fig. 2).12n Herein we wish to
disclose the asymmetric hydrogenation of β-amino ketones
with a bimetallic RuPHOX-Ru complex 2 pre-prepared from 1b
and Ru(II)(PPh3)3Cl2 as the chiral catalyst (Fig. 2).
1
2
3
4
5
MeOH
83.1
25.3
95.2
96.0
70.4
90.3 (R)
69.4 (R)
73.4 (R)
90.7 (R)
62.9 (R)
Toluene
Toluene + MeOHe
Toluene + H2Oe
MeOH + H2Oe
a Reactions were conducted with β-amino ketone (0.4 mmol) in a
solvent (4 mL) using 2 (0.25 mol%) as a catalyst in the presence of
K2CO3 (10 mol%) under an H2 atmosphere (20 bar) at 25 °C for 12 h.
b Determined by 1H NMR. c Determined by HPLC using a Chiralcel
OD-H column. d The absolute configuration of the product was
assigned through the comparison of the sign of specific rotations with
the literature data.5f e The mixed solvent was composed of 3 mL MeOH
(or toluene) and 1 mL H2O (or MeOH).
MeOH and toluene were used as solvents because they are
very cheap and are frequently used in industry. Thus, asym-
metric hydrogenation of 3-(benzyl(methyl)amino)-1-phenylpro-
panone (3a) was performed under 20 bar H2 pressure at 25 °C
with K2CO3 as a base.
2. Results and discussion
Initially, complex 2 was prepared via a simple procedure. As
shown in Scheme 2, treatment of ligand 1b and Ru(II)
(PPh3)3Cl2 in toluene at 90 °C provided complex 2 in 97%
yield. This dark green solid is inert to both moisture and air,
and could be preserved in air for more than one year without a
decrease in catalytic activity. Asymmetric catalysis using
readily prepared 2 or that prepared in situ from lb and Ru(II)-
(PPh3)3Cl2 performed similarly. Thus 2 could be used directly
in subsequent reactions with the aim to facilitate the reaction
procedure.
However, as shown in Table 1, poor conversions to products
and only moderate to good enantioselectivities were obtained
when using only MeOH or toluene as the solvent (entries 1
and 2). When a mixed solvent system of toluene (3 mL) and
MeOH (1 mL) were used, the reaction yield increased but with
low enantioselectivity (entry 3). We believed that increasing the
solubility of the K2CO3 could promote the reaction. H2O was
added to both MeOH and toluene. To our delight, the product
was obtained in 96.0% yield and 90.7% ee in a system of
toluene and H2O (entry 4). However, a system of methanol and
H2O afforded low reaction activity and enantioselectivity (entry
5). According to the catalytic behavior described above, a
solvent system of toluene and water was used for the hydrogen-
ation reactions.
The effect of base on the reaction was then examined
(Table 2). Inorganic bases were used because of their inexpen-
siveness and availability. Weak inorganic bases such as
Na2CO3 and K2CO3 gave only middling results (entries 1 and
2). LiOH provided excellent enantioselectivity but low conver-
sions (entry 3). Strong bases such as NaOH and KOH were
used and found to greatly benefit the hydrogenation process.
Reactions proceeded in quantitative yields and excellent
enantioselectivities (99.9% ee, entries 4 and 5). Further reac-
tions were thus performed with KOH as a base in the presence
of 2, using a mixed solvent system of toluene and H2O at
25 °C.
Fig. 2 RuPHOX 1 and its Ru-complex 2.
With the optimal reaction conditions in hand, the applica-
bility of our catalytic system to a number of substrates was
explored. Hydrogenation of a series of β-amino ketones pro-
ceeded with excellent yields and enantioselectivities (Table 3).
Scheme 2 The synthesis of RuPHOX-Ru 2.
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Table 2 The effect of the base on the reactiona
groups (such as Me and Cl) on the aromatic ring resulted in
low reaction activity (less than 50% conversion). A substrate
with a phenyl group at the para position also occurred
with quantitative conversions to the product with 99.2% ee
(entry 11).
Replacement of the phenyl backbone by a naphthalene ring
or a furan ring had little effect on the catalytic behavior
(entries 12 and 13). Additionally, the frequently used N,N-
dimethyl β-amino ketone was also subjected to the catalytic
system (entry 14).
Entry
Base
Conv.b (%)
eec (%) (Config.d)
1
2
3
4
5
K2CO3
Na2CO3
LiOH
NaOH
KOH
96.0
87.2
22.4
100
90.7 (R)
83.8 (R)
99.9 (R)
99.9 (R)
99.9 (R)
According to Wilkinson’s catalytic cycle13 and the reaction
results above, the mechanism of our reaction can be proposed
(Fig. 3). Initially, 2 reacts with a H2 molecule in the presence of
KOH to give Ru species. The carbonyl group of the β-amino
ketone coordinates to the Ru, resulting in the release of PPh3.
The hydride is then transferred to the carbon atom of the car-
bonyl group. Another H2 molecule is subsequently activated in
the manner mentioned above via an alkoxyl anion instead of
the KOH base. The hydrogenated product is then released and
the catalyst is regenerated.
100
a Reactions were conducted with β-amino ketone (0.4 mmol) in toluene
(3 mL)/H2O (1 mL) using 2 (0.25 mol%) as a catalyst in the presence of
a base (10 mol%) under an H2 atmosphere (20 bar) at 25 °C for 12 h.
b Determined by 1H NMR. c Determined by HPLC using a Chiralcel
OD-H column. d The absolute configuration of the product was
assigned through the comparison of the sign of specific rotations with
the literature data.5f
At first, β-amino ketones containing an electron-donating
To examine the applicability of the catalyst system to an
group (such as methyl and methoxyl substituents) at the industrial process, the hydrogenation of 3a was tested with a
meta and para positions were examined, and excellent cata- relatively low catalyst loading (TON = 2000). To our delight, the
lytic results were obtained (entries 2–5). Substrates with reaction proceeded smoothly with quantitative conversion of
electron-withdrawing groups such as F, Cl, Br, etc. were also the substrate and 99.9% ee. The corresponding alcohol 4a can
amenable to the catalytic system (entries 6–10). Strong elec- be further extrapolated to several antidepressants, fluoxetine,
tron-withdrawing groups resulted in low reaction activity in tomoxetine and nisoxetine, according to the reported method
addition to requiring lengthy reaction times. However, (Scheme 3).2 The present catalytic system shows potential for
excellent enantioselectivities were obtained with these sub- synthesis of several norepinephrine reuptake inhibiting
strates (entries 8 and 9). Unfortunately, ortho substituted antidepressants.
Table 3 The exploration of a series of β-amino ketonesa
Entry
Sub.
Ar
R
TON
T (h)
Pro.
Conv.b (%)
eec (%) (Config.d)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
C6H5
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
400
400
400
200
200
200
200
100
200
200
200
200
200
200
12
12
12
12
12
12
12
36
24
12
12
12
12
12
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
100
100
100
100
100
100
100
100
100
100
100
100
100
100
99.9 (R)
99.9 (R)
99.6 (R)
99.9 (R)
99.9 (R)
99.3 (R)
99.9 (R)
99.9 (R)
99.3 (R)
97.3 (R)
99.2 (R)
99.9 (R)
98.7 (R)
99.6 (S)
3-MeOC6H4
4-MeOC6H4
3-MeC6H4
4-MeC6H4
3-ClC6H4
4-ClC6H4
3,4-diClC6H3
4-FC6H4
4-BrC6H4
4-PhC6H4
2-Naphthyl
2-Furan
9
10
11
12
13
14
Ph
a Reactions were conducted with β-amino ketone (0.4 mmol) in toluene (3 mL)/H2O (1 mL) using 2 (0.25 mol%) as a catalyst in the presence of
KOH (10 mol%) under an H2 atmosphere (20 bar) at 25 °C for a certain time. b Determined by 1H NMR. c Determined by HPLC using a Chiralcel
OD-H or IC-3 column. d The absolute configuration of the product was assigned through the comparison of the sign of specific rotations with the
literature data.5f
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400 spectrometer with TMS as an internal standard. The
enantioselectivity was measured by high performance liquid
chromatography (HPLC) using a Daicel Chiralcel OD-H or IC-3
column with hexane–2-propyl alcohol as the eluent and 0.1%
Et3N as the additive. Column chromatography was performed
using 100–200 mesh silica gel. All commercially available sub-
strates were used as received. β-Amino ketones were prepared
through Mannich reaction according to literature procedures.8
General procedure for the synthesis of catalyst 2
A
solution of ligand 1b (69.5 mg) and Ru(II)(PPh3)3Cl2
(156.8 mg) in toluene (20 mL) was heated to 90 °C for 5 h. The
solvent was removed and the residue was purified by flash
column silica-gel chromatography (PE–EA = 5/1) to give the
catalyst 2 (96.8% yield) as a dark green solid. mp. 210–211 °C.
[α]2D5 18.5° (c = 0.2, CHCl3). 1H NMR (CDCl3, 400 MHz):
δ 7.66–6.75 (m, 50H), 5.60–5.50 (m, 2H), 5.43 (s, 2H), 4.93
(t, J = 9.2 Hz, 2H), 4.66 (t, J = 8.4 Hz, 2H), 4.45 (s, 2H), 4.4 (t, J =
8.8 Hz, 2H), 0.8 (s, 18H); 13C NMR (100 MHz, CDCl3): δ 166.9,
138.1, 137.6, 135.5, 135.4, 135.3, 134.9, 134.6, 133.9, 133.8,
133.1, 133.0, 131.3, 130.7, 130.2, 129.5, 129.2, 128.7, 127.7,
127.6, 127.4, 127.3, 127.2, 127.1, 93.2, 86.9, 86.2, 85.8, 81.9,
77.8, 77.6, 77.3, 77.2, 76.9, 75.8, 75.7, 69.6, 39.8, 33.4, 32.1,
29.9, 27.6; 31P NMR (CDCl3, 162 MHz): δ 68.76, 43.58.
Fig. 3 The possible asymmetric hydrogenation mechanism.
General procedure for the asymmetric hydrogenation of
β-amino ketones
2 (0.25 mol%) and β-amino ketone (0.4 mmol) were dissolved
in a degassed solution of toluene (3 mL) under a nitrogen
atmosphere. KOH (10 mol%) was added to degassed H2O
(1 mL) and both solutions were mixed in a glove box under a
nitrogen atmosphere. The reaction began when the solution
was transferred to an autoclave in the presence of H2 (20 bar).
After several hours, the reaction mixture was concentrated
under reduced pressure. The percentage conversion of the
Scheme 3 The asymmetric synthesis of tomoxetine.
1
product was determined by H NMR of the crude residue. The
mixture was purified by flash chromatography with ethyl
acetate–petrol ether (1 : 1) to give pure product 4 for the deter-
mination of the ee using a Daicel Chiralcel OD-H or IC-3
column with hexane–2-propyl alcohol as the eluent and 0.1%
Et3N as the additive.
3. Conclusions
In conclusion, asymmetric hydrogenations of a series of
β-amino ketones were performed using a stable bimetallic
chiral catalyst, RuPHOX-Ru complex 2. Almost all the examples
gave quantitative yields of products with up to 99.9% ee. The
procedure has the advantages of being inexpensive, environ-
mentally beneficial, and highly efficient (even under relatively
low catalyst loadings (TON = 2000)).
(R)-3-(Benzyl(methyl)amino)-1-phenylpropan-1-ol (4a).14 As
a pale yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.50–7.20
(m, 10H), 4.91 (dd, J = 8.0, 4.0 Hz, 1H), 3.65 (d, J = 12.8 Hz,
1H), 3.48 (d, J = 12.8 Hz, 1H), 3.87–2.76 (m, 1H), 2.64–2.55 (m,
1H), 2.27 (s, 3H), 1.95–1.82 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 145.4, 138.0, 129.6, 128.8, 128.5, 127.7, 127.2, 125.8,
75.6, 62.9, 56.6, 41.9, 35.9; [α]2D2 20.572° (c = 1.0, methanol).
HPLC conditions: the enantiomeric excess was determined by
HPLC (Chiralcel OD-H), Hex–i-PrOH 95 : 5, UV 200 nm, 0.8 mL
4. Experimental section
General information
All reactions were performed under a nitrogen atmosphere, min−1, tR = 14.52 min (major) and tR = 13.17 min (minor).
and workups were carried out in air. Toluene, MeOH, EtOH (R)-3-(Benzyl(methyl)amino)-1-(3-methoxyphenyl)propan-1-ol
and i-PrOH were distilled over dehydrating reagents. Commer- (4b). As a colorless liquid. 1H NMR (400 MHz, CDCl3):
cially available reagents were used without further purification. δ 7.60–7.20 (m, 6H), 7.01–6.88 (m, 2H), 6.84–6.72 (m, 1H), 4.89
1H NMR (400 MHz), 13C NMR (100 MHz) and 31P NMR (dd, J = 7.6, 3.6 Hz, 1H), 3.81 (s, 3H), 3.65 (d, J = 12.8 Hz, 1H),
(162 MHz) spectra were recorded on a Varian MERCURY plus- 3.48 (d, J = 12.4 Hz, 1H), 2.88–2.76 (m, 1H), 2.65–2.53 (m, 1H),
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2.26 (s, 3H), 1.98–1.76 (m, 2H); 13C NMR (100 MHz, CDCl3): 12.8 Hz, 1H), 3.47 (d, J = 12.8 Hz, 1H), 2.85–2.76 (m, 1H),
δ 159.8, 146.9, 137.9, 135.9, 129.4, 128.7, 127.7, 118.1, 112.7, 2.62–2.54 (m, 1H), 2.27 (s, 3H), 1.87–1.76 (m, 2H); 13C NMR
111.2, 75.9, 63.0, 56.8, 55.4, 41.9, 34.7; [α]2D2 20.373° (c = 1.0, (100 MHz, CDCl3): δ 143.7, 137.8, 132.6, 129.5, 128.8, 128.5,
methanol). HPLC conditions: the enantiomeric excess was 127.7, 127.2, 75.4, 63.1, 56.5, 42.1, 34.6; [α]2D2 19.374° (c = 1.0,
determined by HPLC (Chiralcel OD-H), Hex–i-PrOH 95 : 5, UV methanol). HPLC conditions: the enantiomeric excess was
200 nm, 1.0 mL min−1, tR = 19.25 min (major) and tR
15.44 min (minor).
=
determined by HPLC (Chiralcel OD-H), Hex–i-PrOH 95 : 5, UV
210 nm, 0.6 mL min−1, tR = 21.47 min (major) and tR
=
(R)-3-(Benzyl(methyl)amino)-1-(4-methoxyphenyl)propan-1-ol 16.09 min (minor).
(4c). As a colorless liquid. 1H NMR (400 MHz, CDCl3):
(R)-3-(Benzyl(methyl)amino)-1-(3,4-dichlorophenyl)propan-1-ol
δ 7.45–7.20 (m, 7H), 6.93–6.84 (m, 2H), 4.86 (dd, J = 8.4, (4h). As a pale yellow liquid. 1H NMR (400 MHz, CDCl3):
2.8 Hz, 1H), 3.79 (s, 3H), 3.65 (d, J = 12.8 Hz, 1H), 3.47 (d, J = δ 7.49–7.45 (m, 1H), 7.42–7.24 (m, 6H), 7.18–7.10 (m, 1H), 4.84
12.8 Hz, 1H), 2.87–2.75 (m, 1H), 2.63–2.54 (m, 1H), 2.27 (s, (t, J = 6.0 Hz, 1H), 3.64 (d, J = 12.8 Hz, 1H), 3.47 (d, J = 12.4 Hz,
3H), 1.95–1.76 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 158.8, 1H), 2.87–2.76 (m, 1H), 2.63–2.53 (m, 1H), 2.27 (s, 3H),
138.0, 137.5, 129.5, 128.7, 127.6, 126.9, 113.8, 75.6, 63.0, 56.7, 1.87–1.75 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 145.6, 137.7,
55.5, 42.0, 34.9; [α]2D2 46.538° (c = 1.0, methanol). HPLC con- 132.5, 130.7, 130.3, 129.5, 128.8, 127.9, 127.8, 125.2, 74.9, 63.0,
ditions: the enantiomeric excess was determined by HPLC 56.5, 42.0, 34.4; [α]2D2 19.973° (c = 1.0, methanol). HPLC con-
(Chiralcel OD-H), Hex–i-PrOH 95 : 5, UV 200 nm, 1.0 mL ditions: the enantiomeric excess was determined by HPLC
min−1, tR = 19.38 min (major) and tR = 14.84 min (minor).
(R)-3-(Benzyl(methyl)amino)-1-(m-tolyl)propan-1-ol (4d). As min−1, tR = 13.56 min (major) and tR = 10.39 min (minor).
a pale yellow liquid. 1H NMR (400 MHz, CDCl3): δ 8.00–7.00
(R)-3-(Benzyl(methyl)amino)-1-(4-fluorophenyl)propan-1-ol
(Chiralcel OD-H), Hex–i-PrOH 95 : 5, UV 200 nm, 1.0 mL
(m, 9H), 4.88 (dd, J = 8.4, 2.8 Hz, 1H), 3.66 (d, J = 12.8 Hz, 1H), (4i).15 As a pale yellow liquid. 1H NMR (400 MHz, CDCl3):
3.49 (d, J = 12.8 Hz, 1H), 2.89–2.76 (m, 1H), 2.66–2.55 (m, 1H), δ 7.45–7.20 (m, 7H), 7.04–6.94 (m, 2H), 4.88 (dd, J = 8.0, 3.6
2.35 (s, 3H), 2.28 (s, 3H), 1.99–1.78 (m, 2H); 13C NMR Hz, 1H), 3.65 (d, J = 12.8 Hz, 1H), 3.48 (d, J = 12.8 Hz, 1H),
(100 MHz, CDCl3): δ 145.1, 138.0, 137.9, 129.5, 128.8, 128.3, 2.87–2.76 (m, 1H), 2.66–2.54 (m, 1H), 2.28 (s, 3H), 1.94–1.74
127.9, 127.7, 126.5, 122.9, 76.0, 63.0, 56.9, 42.0, 34.7, 21.7; (m, 2H); 13C NMR (100 MHz, CDCl3): δ 129.5, 128.8, 127.7,
[α]2D2 21.571° (c = 0.5, methanol). HRMS (ESI-TOF) Calcd for 127.4, 127.3, 115.3, 115.0, 75.5, 63.1, 56.6, 42.1, 34.8, 29.9;
C18H24NO [M + H]+ 270.1858, Found: 270.1862. HPLC con- [α]2D2 23.221° (c = 1.0, methanol). HPLC conditions: the enan-
ditions: the enantiomeric excess was determined by HPLC tiomeric excess was determined by HPLC (Chiralcel OD-H),
(Chiralcel OD-H), Hex–i-PrOH 95 : 5, UV 200 nm, 0.8 mL Hex–i-PrOH 95 : 5, UV 200 nm, 0.8 mL min−1, tR = 14.26 min
min−1, tR = 13.51 min (major) and tR = 12.05 min (minor).
(R)-3-(Benzyl(methyl)amino)-1-(p-tolyl)propan-1-ol (4e).15 As
(major) and tR = 11.12 min (minor).
(R)-3-(Benzyl(methyl)amino)-1-(4-bromophenyl)propan-1-ol
a pale yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.40–7.26 (4j). As a pale yellow liquid. 1H NMR (400 MHz, CDCl3):
(m, 7H), 7.20–7.14 (m, 2H), 4.90 (dd, J = 8.0, 3.6 Hz, 1H), 3.66 δ 7.70–7.15 (m, 9H), 4.85 (t, J = 5.6 Hz, 1H), 3.63 (d, J =
(d, J = 12.8 Hz, 1H), 3.49 (d, J = 12.8 Hz, 1H), 2.87–2.78 (m, 12.8 Hz, 1H), 3.48 (d, J = 12.8 Hz, 1H), 2.86–2.75 (m, 1H),
1H), 2.66–2.56 (m, 1H), 2.35 (s, 3H), 2.27 (s, 3H), 1.97–1.81 (m, 2.64–2.53 (m, 1H), 2.27 (s, 3H), 1.92–1.80 (m, 2H); 13C NMR
2H); 13C NMR (100 MHz, CDCl3): δ 140.8, 137.2, 131.5, 130.1, (100 MHz, CDCl3): δ 144.3, 137.8, 131.5, 129.5, 128.8, 127.7,
129.4, 129.2, 128.8, 125.8, 70.7, 53.4, 39.6, 33.5, 21.3; 127.6, 120.8, 75.4, 63.0, 56.5, 42.1, 34.6; [α]2D2 1.398° (c = 1.0,
[α]2D2 26.621° (c = 1.0, methanol). HPLC conditions: the enan- methanol); HRMS (ESI-TOF) Calcd for C17H21BrNO [M + H]+
tiomeric excess was determined by HPLC (Chiralcel OD-H), 334.0807, Found: 334.0808; HPLC conditions: the enantio-
Hex–i-PrOH 95 : 5, UV 200 nm, 0.8 mL min−1, tR = 14.19 min meric excess was determined by HPLC (Chiralcel OD-H), Hex–
(major) and tR = 11.07 min (minor).
i-PrOH 90 : 10, UV 200 nm, 0.6 mL min−1, tR = 14.94 min
(R)-3-(Benzyl(methyl)amino)-1-(3-chlorophenyl)propan-1-ol (major) and tR = 12.41 min (minor).
(4f). As a pale yellow liquid. 1H NMR (400 MHz, CDCl3):
(R)-1-([1,1′-Biphenyl]-4-yl)-3-(benzyl(methyl)amino)propan-1-ol
δ 7.80–7.15 (m, 9H), 4.87 (dd, J = 7.6, 4.8 Hz, 1H), 3.64 (d, J = (4k). As a pale yellow liquid. 1H NMR (400 MHz, CDCl3):
13.2 Hz, 1H), 3.48 (d, J = 12.4 Hz, 1H), 2.87–2.75 (m, 1H), δ 7.61–7.26 (m, 14H), 4.96 (dd, J = 4.0 Hz, 1H), 3.66 (d, J =
2.64–2.52 (m, 1H), 2.27 (s, 3H), 1.95–1.69 (m, 2H); 13C NMR 13.2 Hz, 1H), 3.50 (d, J = 13.2 Hz, 1H), 2.90–2.78 (m, 1H),
(100 MHz, CDCl3): δ 147.5, 137.8, 134.4, 129.7, 129.5, 128.8, 2.68–2.57 (m, 1H), 2.28 (s, 3H), 2.01–1.84 (m, 2H); 13C NMR
127.7, 127.2, 126.1, 123.9, 75.3, 62.9, 56.6, 42.0, 34.6; (100 MHz, CDCl3): δ 144.3, 141.3, 140.0, 137.9, 129.5, 128.9,
[α]2D2 13.182° (c = 0.5, methanol). HRMS (ESI-TOF) Calcd for 128.8, 75.8, 63.1, 56.7, 42.0, 34.6, 30.0; [α]2D2 28.961° (c = 1.0,
C17H21ClNO [M + H]+ 290.1312, Found: 290.1317; HPLC con- methanol); HRMS (ESI-TOF) Calcd for C23H26NO [M + H]+
ditions: the enantiomeric excess was determined by HPLC 332.2014, Found: 332.2042; HPLC conditions: the enantio-
(Chiralcel OD-H), Hex–i-PrOH 95 : 5, UV 200 nm, 1.0 mL meric excess was determined by HPLC (Chiralcel IC-3), Hex–
min−1, tR = 12.08 min (major) and tR = 9.18 min (minor).
i-PrOH 90 : 10, UV 230 nm, 0.8 mL min−1, tR = 31.48 min
(R)-3-(Benzyl(methyl)amino)-1-(4-chlorophenyl)propan-1-ol (major) and tR = 16.94 min (minor).
(4g).16 As a pale yellow liquid. 1H NMR (400 MHz, CDCl3):
(R)-3-(Benzyl(methyl)amino)-1-(naphthalen-2-yl)propan-1-ol
δ 7.41–7.24 (m, 9H), 4.87 (t, J = 5.2 Hz, 1H), 3.64 (d, J = (4l).17 As a pale yellow liquid. 1H NMR (400 MHz, CDCl3):
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δ 7.80–7.50 (m, 5H), 7.35–7.10 (m, 9H), 4.90 (dd, J = 8.0,
4.4 Hz, 1H), 3.45 (d, J = 12.8 Hz, 1H), 3.30 (d, J = 12.8 Hz, 1H),
2.90–2.78 (m, 1H), 2.66–2.57 (m, 1H), 2.10 (s, 3H), 2.07–1.91
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 142.8, 139.1, 138.1,
133.7, 133.1, 129.5, 128.9, 128.3, 128.2 127.9, 127.8, 126.2,
125.8, 124.5, 124.3, 75.9, 63.0, 56.7, 42.0, 34.8, 25.6;
[α]2D2 19.574° (c = 2.0, methanol). HPLC conditions: the enan-
tiomeric excess was determined by HPLC (Chiralcel OD-H),
Hex–i-PrOH 95 : 5, UV 200 nm, 1.0 mL min−1, tR = 24.65 min
(major) and tR = 17.84 min (minor).
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(R)-(Benzyl(methyl)amino)-1-(furan-2-yl)propan-1-ol (4m).
As a pale yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.40–7.20
(m, 6H), 6.30 (dd, J = 3.2, 2.0 Hz,1H), 6.20 (m, 1H), 4.91 (dd,
J = 8.0, 3.2 Hz, 1H), 3.61 (d, J = 12.4 Hz, 1H), 3.48 (d, J =
11.2 Hz, 1H), 2.82–2.70 (m, 1H), 2.69–2.60 (m, 1H), 2.25 (s,
3H), 2.16–1.90 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 157.4,
141.7, 137.9, 129.4, 128.7, 127.6, 110.3, 105.5, 69.9, 62.9, 56.2,
41.9, 30.9; [α]2D2 2.796° (c = 1.0, methanol); HRMS (ESI-TOF)
Calcd for C15H20NO2 [M + H]+ 246.1494, Found: 246.1480;
HPLC conditions: the enantiomeric excess was determined by
HPLC (Chiralcel OD-H), Hex–i-PrOH 95 : 5, UV 200 nm, 0.5 mL
min−1, tR = 20.74 min (major) and tR = 18.38 min (minor).
(S)-3-(Dimethylamino)-1-phenylpropan-1-ol (4n).18 As a color-
less liquid. 1H NMR (400 MHz, CDCl3), δ 7.45–7.20 (m, 5H),
4.93 (dd, J = 8.0, 4.0 Hz, 1H), 2.70–2.60 (m, 1H), 2.52–2.43 (m,
1H), 2.30 (s, 6H), 1.89–1.74 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 145.7, 128.0, 126.7, 125.7, 73.2, 57.0, 53.7, 44.9, 35.9;
[α]2D2 −33.641° (c = 1.0, methanol). HPLC conditions: the
enantiomeric excess was determined by HPLC (Chiralcel
OD-H), Hex–i-PrOH 95 : 5, UV 254 nm, 1.0 mL min−1, tR
8.61 min (major) and tR = 12.49 min (minor).
=
Acknowledgements
This work was partly supported by the National Nature Science
Foundation of China (No. 21172143, 21172145 and 21232004),
Science and Technology Commission of Shanghai Municipal-
ity (No. 09JC1407800), Nippon Chemical Industrial Co. Ltd
and the Instrumental Analysis Center of Shanghai Jiao Tong
University. We thank Prof. Tsuneo Imamoto and Dr Masashi
Sugiya for helpful discussions.
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