Rh-catalyzed asymmetric hydrogenation of racemic aldimines via dynamic kinetic resolution

Article abstract of DOI:10.1016/j.tet.2016.07.046

Catalyzed by a rhodium complex of P-stereogenic diphosphine ligand trichickenfootphos (TCFP), asymmetric hydrogenation of racemic aldimines via dynamic kinetic resolution has been realized for the preparation of chiral arylglycines with good yields and enantioselectivities.

Full text of DOI:10.1016/j.tet.2016.07.046

Accepted Manuscript
Rh-catalyzed asymmetric hydrogenation of racemic aldimines via dynamic kinetic
resolution
Dongyang Fan, Jian Lu, Yang Liu, Zhenfeng Zhang, Yangang Liu, Wanbin Zhang
PII:
S0040-4020(16)30696-2
10.1016/j.tet.2016.07.046
TET 27942
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 May 2016
Revised Date: 13 July 2016
Accepted Date: 15 July 2016
Please cite this article as: Fan D, Lu J, Liu Y, Zhang Z, Liu Y, Zhang W, Rh-catalyzed asymmetric
hydrogenation of racemic aldimines via dynamic kinetic resolution, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.07.046.
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Graphical Abstract
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Rh-Catalyzed Asymmetric Hydrogenation of
Racemic Aldimines via Dynamic Kinetic
Resolution
Leave this area blank for abstract info.
Dongyang Fana,†, Jian Lub,†, Yang Liua, Zhenfeng Zhanga,*, Yangang Liua and Wanbin Zhanga,b,*
aSchool of Pharmacy and bSchool of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800
Dongchuan Road, Shanghai 200240, P. R. China.
+
Ar
Ar
P
P
TCFP-Rh, H2
-
Rh
BF4
N
HN
Dynamic Kinetic Resolution
Ar'
COOR
Ar'
COOR
Me
TCFP-Rh

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Rh-Catalyzed Asymmetric Hydrogenation of Racemic Aldimines via Dynamic
Kinetic Resolution
Dongyang Fana,†, Jian Lub,†, Yang Liua, Zhenfeng Zhanga,*, Yangang Liua and Wanbin Zhanga,b,*
a School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
b School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Catalyzed by a rhodium complex of P-stereogenic diphosphine ligand trichickenfootphos
(TCFP), asymmetric hydrogenation of racemic aldimines via dynamic kinetic resolution has
been realized for the preparation of chiral arylglycines with good yields and enantioselectivities.
2009 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
Asymmetric hydrogenation
Dynamic kinetic resolution
Chiral arylglycines
Racemic aldimines
Rhodium complex
1. Introduction
As the key building blocks of important pharmaceuticals and
bioactive compounds such as clopidogrel, prasugrel, vicagrel and
aprepitant, the asymmetric synthesis of chiral arylglycines has
attracted much attention.1 Various methodologies have already
been developed, such as those relying on hydrolysis or
esterification via (dynamic) kinetic resolution,2 the addition of
aldimines with aryl or carbonyl reagents,3 N-H insertion4 and the
reduction of ketimines.5 However, a practical method which can
be utilized in industry is still highly desired. Recently,
asymmetric hydrogenation, a practical technology for large scale
production,6 has garnered considerable interest for the synthesis
of chiral arylglycines.7 However, the commonly utilized aryl-acyl
ketimines require separation of the Z/E isomers and have the
problem of low activity. It is envisaged that the asymmetric
hydrogenation of racemic aldimines via dynamic kinetic
resolution (DKR) can overcome these drawbacks.8 Previously,
racemic ketones and aldehydes have been studied in asymmetric
Figure 1. Substrates used in asymmetric hydrogenation via
dynamic kinetic resolution.
2. Results and discussion
In contrast to previously reported racemic aldimines bearing a
chiral center at the C-side of the C=N bond, a new type of
substrates with a chiral center at the N-side of the C=N bond have
been studied in this paper (Figure 1). Initially, a model substrate
of methyl (E)-2-(benzylideneamino)-2-phenylacetate (1A), which
can be simply synthesized from methyl 2-amino-2-phenylacetate
and benzaldehyde, was tested in the hydrogenation (Table 1).
Several commonly used transition metal catalysts such as
BiphPHOX-Ir,12 TsDPEN-Ru, BINAP-Rh were screened with the
Rh catalyst giving the best result (entries 1-4). Further screening
of other ligands led to the use of a P-stereogenic diphosphine
ligand trichickenfootphos (TCFP)13 which gave the reduced
product 2A in 44% conversion and 57% ee with the recovered
hydrogenation via dynamic kinetic resolution.9
A similar
transformation of cyclic ketimines has also been mentioned as a
key mechanistic step involved in the asymmetric hydrogenation
of certain enamines and related precursors.10 To the best of our
knowledge, the dynamic kinetic resolution of aldimines has only
been reported using a transfer hydrogenation strategy11 and no
methodologies concerning hydrogenation have been developed
(Figure 1).
Corresponding author. Tel & Fax: +86-021-54743265, e-mail:
wanbin@sjtu.edu.cn (W. Zhang), zhenfeng@sjtu.edu.cn (Z. Zhang).
† D. Fan and J. Lu contributed equally.

2
Tetrahedron
15
TCFP-Rh
dioxane
DCM
15
29
5
76
78
57
83
70
93
14
29
4
imine 1A being obtained with 41% ee (entries 5-7). The solvent
ACCEPTED MANUSCRIPT
16
17
TCFP-Rh
TCFP-Rh
effect showed that the more bulky (or less polar) protic alcohols
gave higher enantioselectivity but lower activity (entries 7-10).
Another linear alcohol n-BuOH provided a similar result to that
of using EtOH (entry 11). The highest conversion of 63% was
obtained using the more polar solvent 2,2,2-trifluoroethanol (TFE)
with an acceptable enantioselectivity (61% for product and 22%
for recovered starting material) (entry 12). Other less polar
solvents gave similar enantioselectivities with lower activities
(entries 13-17). It is worth noting that obvious racemization of
the starting material was only found when the solvent TFE was
used because the ee value of recovered 1A does not obey the rule
of kinetic resolution.14 To balance the enantioselectivity and
activity, the mixed solvent system, hydrogen pressure and
temperature were optimized to give more suitable conditions.
Increasing the ratio of iPrOH/TFE from 1/2 to 2/1 increased ee
but led to a decrease in conversion (entries 18-20). Further
reducing the hydrogen pressure and reaction temperature showed
a similar trend (entries 21-23). Finally, optimized reaction
conditions consisted of TCFP-Rh as catalyst and conducting the
reaction in a mixed solvent system of iPrOH/TFE (2/1), 10 atm
hydrogen pressure and room temperature (entry 21). The absolute
configuration of major enantiomer was assigned by comparison
of the HPLC spectra with that of compound 2A which was
synthesized from the natural (S)-phenylglycine and benzyl
bromide.
toluene
iPrOH/TFE
18
19
TCFP-Rh
TCFP-Rh
TCFP-Rh
TCFP-Rh
TCFP-Rh
TCFP-Rh
62
59
56
47
40
37
63
70
72
75
80
83
20
34
34
47
50
57
59
65
69
59
48
46
(1/2)
iPrOH/TFE
(1/1)
iPrOH/TFE
20
(2/1)
iPrOH/TFE
21e
22f
23g
(2/1)
iPrOH/TFE
(2/1)
iPrOH/TFE
(2/1)
a Conditions: 1A (0.1 mmol), catalyst (1 mol %), H2 (20 atm), solvent (2 mL),
rt (20-25 °C), 24 h. b The conversions and recoveries were calculated from 1H
NMR spectra. c The ee values were determined by HPLC using chiral column.
d 3 h. e H2 (10 atm). f H2 (5 atm). g 0 °C.
For the previously reported dynamic kinetic resolution of
imines with a chiral center on the C-side of the C=N bond,
racemization occurred through an intermediate of enamine under
simple acidic conditions.10,11 However, in our case with a chiral
center on the N-side, addition of acetic acid resulted in a
complete conversion to the product in racemic form. Use of a
basic additive in a neutral solvent also failed without any
conversion. Considering the different racemic pattern for the
above mentioned two imines, we turned our attention to the
racemization of the starting material by changing the substituents
of Ar and R groups (Table 2). A by-product of 3 was detected in
about 10% conversion for most of the entries.15 Dramatic
differences can be seen in the hydrogenation of both Me- and
MeO-substituted imines (entries 2-10). 2-MeO-substituted imines
provided the reduced product in 65% conversion and 67% ee
with the recovered imine being obtained with 2% ee (entry 9).
The substrate bearing an electron-withdrawing F atom at the 2-
position was reduced to the product in 71% conversion and 58%
ee. However, 87% ee was detected for the recovered starting
material which means that almost no dynamic kinetic effect was
observed (entry 11). The more bulky substituents Cl and Br at the
2-position prevented any product obtaining (entries 12-13). Other
substrates with different Ar groups such as 1-naphthyl, 2-thienyl
and 2-furyl showed comparatively worse result than that of a 2-
methoxyphenyl substituted species (entries 14-16 vs 9).
Increasing the loading of catalyst to 2 mol % promoted the
conversion (entry 17). Changing the R group to more bulky alkyl
groups had no obvious effect on the reaction (entries 18-20).
Extending the reaction time to 48 h resulted in a complete
transformation of 1a. The desired product 2a was obtained in 82%
conversion and a satisfactory ee of 60% (entry 21).
Table 1. Conditions optimizationa
2A
1A
entry
catalyst
solvent
conversion
[%]b
ee
recovery
ee
[%]c
[%]b
[%]c
BiphPHOX-
Ir
1
2
MeOH
MeOH
MeOH
7
14
0
92
0
-
TsDPEN-
Ru
Table 2. Screening of Ar and R groupsa
100
31
0
TsDPEN-
Ru
3d
11
69
6
4
5
BINAP-Rh
Duphos-Rh
BenzP*-Rh
TCFP-Rh
TCFP-Rh
TCFP-Rh
TCFP-Rh
TCFP-Rh
TCFP-Rh
TCFP-Rh
TCFP-Rh
MeOH
MeOH
MeOH
MeOH
EtOH
15
10
4
19
0
84
88
96
50
78
81
88
75
31
76
91
3
0
6
17
57
70
80
84
70
61
71
76
0
2
1
7
44
16
15
6
41
17
14
5
entry
Ar
R
conversion
[%]b
ee
recovery
[%]b
ee
8
[%]c
[%]c
9
iPrOH
tBuOH
nBuOH
TFE
1
2
3
4
5
C6H5
Me
Me
Me
Me
Me
47
34
48
39
28
75
79
71
84
77
47
60
40
46
58
59
35
12
41
5
10
11
12
13
14
4-MeC6H4
3-MeC6H4
2-MeC6H4
2,4-Me2C6H3
17
63
22
6
20
22
21
7
EtOAc
THF

6
7
2,6-Me2C6H3
4-OMeC6H4
3-OMeC6H4
2-OMeC6H4
2,4-(OMe)2C6H3
2-FC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
0
-
100
-
A substrate replacing COOMe group with Me group was
ACCEPTED MANUSCRIPT
15
48
65
15
71
0
39
78
67
20
58
-
63
40
24
37
23
85
81
30
40
37
7
7
61
2
tested to give the reduced product and recovered starting material
both in racemic form. This result signifies that the carbonyl
group is probably involved in the transition state during the
reaction. In addition, the N-benzyl aryl-acyl imines 4, which were
reported as stable compounds,16 were not detected during our
8
9
10
11
12
13
14
15
16
17d
18d
19d
20d
21d,e
5
87
-
reactions.
A deuteration experiment of substrate 1c was
2-ClC6H4
performed using D2 under the same reaction conditions.
Compared to the hydrogenated product, almost no change for the
CH signal (δ = 4.34, s, 1H) is observed, whereas the CH2 peak (δ
= 3.72, dd, 2H) was replaced by a single CHD peak (δ = 3.78, s,
1H). Based on the above results, a mechanism has been proposed
for the dynamic kinetic resolution of racemic aldimines bearing a
chiral center at the N-side of the C=N bond (Scheme 1). As
described in the literature which also ruled out the mechanism via
intermediate 4,17 it can be proposed that the substrates are
racemized via an unstable intermediate 5 with the aid of an acidic
medium. One of the enantiomers is reduced at a faster rate to give
the main product in the favored configuration.18
2-BrC6H4
0
-
-
1-naphthyl
2-thienyl
59
52
53
77
72
78
75
82
45
67
70
67
65
66
65
60
67
18
55
11
5
2-furyl
2-OMeC6H4
2-OMeC6H4
2-OMeC6H4
2-OMeC6H4
2-OMeC6H4
10
5
iPr
13
-
tBu
Me
8
0
-
a
Conditions: 1 (0.1 mmol), TCFP-Rh (1 mol %), H2 (10 atm), iPrOH/TFE =
2/1 (2 mL), rt (20-25 °C), 24 h. The conversions and recoveries were
calculated from H NMR spectra. The ee values were determined by HPLC
using chiral column. d TCFP-Rh (2 mol %). e 48 h.
b
1
c
With the optimized conditions in hand, the substrate scope of
the hydrogenation reaction was investigated (Table 3). The
substrates 1b-e with electron-donating methyl substituents
showed improved results compared to 1a (entries 1-5). Substrates
1f and 1g possessing methoxy groups showed a slightly decrease
in enantioselectivity, while a dimethoxy substituted substrate, 1h,
gave higher enantioselectivity (entries 6-8). A similar substrate 1i
bearing 3,4-(OCH2O) substituent also gave the same level of
enantioselectivity (entry 9). Substrate 1j bearing a 4-substituted
phenyl group was converted to its related product with slightly
reduced enantioselectivity (entry 10). A low enantioselectivity
was obtained for substrate 1k bearing a 2-naphthyl substituent
(entry 11). For the substrates 1l-n bearing fluoro substituents, the
enantioselectivity decreased according to the position of the
fluoro substituent (entries 12-14).
Scheme 1. Proposed mechanism.
3. Conclusions
In summary, asymmetric hydrogenation of racemic aldimines
via dynamic kinetic resolution was realized for the first time.
After careful screening and optimization, a series of chiral
arylglycines were synthesized with good yields and
enantioselectivities.
Table 3. Substrate scopea
4. Experimetal section
All air sensitive reactions were performed in dried glassware
under an atmosphere of dry nitrogen, and the workup was carried
out in air, unless otherwise noted. Solvents were dried and
distilled by standard procedures. Commercially available
reagents were used without further purification. Column
chromatography was performed using 100-200 mesh silica gel.
1H NMR (400 MHz) and 13C NMR (101 MHz) spectra were
recorded on a Varian MERCURY plus-400 spectrometer. HRMS
was performed on a Waters Micromass Q-TOF Premier Mass
Spectrometer at the Instrumental Analysis Center of Shanghai
Jiao Tong University. The ee values were determined by HPLC
using Daicel Chiralpak columns. Melting points were measured
with SGW X-4 micro melting point apparatus. IR was measured
with PerkinElmer Spectrum 100 FT-IR Spectrometer. Optical
rotations were measured on a Rudolph Research Analytical
Autopol VI automatic polarimeter using a 50 mm path-length cell
at 589 nm.
entry
1
1
1a
1b
1c
1d
1e
1f
Ar'
C6H5
yield [%]b
79
ee [%]c
60
2
4-MeC6H4
3-MeC6H4
2-MeC6H4
2,4-Me2C6H3
4-OMeC6H4
3-OMeC6H4
3,4-(OMe)2C6H3
3,4-(OCH2O)C6H3
4-PhC6H4
77
61
3
67
62
4
76
69
5
72
67
6
69
58
7
1g
1h
1i
83
55
8
79
66
9
70
56
10
11
12
13
14
1j
82
57
1k
1l
2-naphthyl
4-FC6H4
83
37
79
55
1m
1n
3-FC6H4
77
36
4.1. General procedure for the synthesis of substrates
2-FC6H4
53
19
a
Conditions: 1 (0.2 mmol), TCFP-Rh (2 mol %), H2 (10 atm), iPrOH/TFE =
Substrate 1a were synthesized from commercially available
racemic phenylglycine methyl ester, while other substrates 1b-j
were synthesized from related acetophenone derivatives
according to the reported procedures.19
b
c
2/1 (2 mL), rt (20-25 °C), 24 h. Isolated yields. The ee values were
determined by HPLC using chiral column.

4
Tetrahedron
A mixture of acetophenone derivative (30 mmol) and
110.86, 76.90, 55.46, 52.40, 21.15; IR (KBr): ν 3005, 2950,
ACCEPTED MANUSCRIPT
selenium dioxide (5.0 g, 45 mmol) in pyridine (15 mL) was
stirred at 110 °C under nitrogen atmosphere overnight. After
cooling to room temperature, 4 Å molecular sieves (1.8 g) and
methanol (20 mL) were added and the mixture was stirred for
additional 10 min. Then thionyl chloride (11.3 mL, 150 mmol)
was added dropwise over 1 h in an ice-water bath and stirred at
room temperature for 12 h. Perchloric acid (12 mL, 150 mmol) in
acetonitrile (240 mL) and deionized water (24 mL) (1:20:2 in
volume ratio) were added into the flask, and the mixture was
stirred for at least 0.5 h. Excess acid was neutralized by saturated
sodium bicarbonate, then the mixture was filtrated. After
removing the organic solvent by evaporation, the aqueous phase
was extracted with ethyl acetate. The combined organic extracts
were washed with brine, dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuum. The crude product
was purified by flash chromatography (silica gel, petrol
ether/ethyl acetate = 10/1) to obtain arylglyoxylate.19a
1747, 1488, 1248, 1161, 751 cm-1; HRMS (ESI): m/z calculated
for C18H20NO3+ [M+H]+ 298.1438, found 298.1435.
4.1.3
Methyl
(E)-2-((2-methoxybenzylidene)amino)-2-(m-
tolyl)acetate (1c). White solid, mp 57–59 °C; 1H NMR (400
MHz, CDCl3): δ 8.80 (s, 1H), 8.14 (d, J = 6.9 Hz, 1H), 7.40 (t, J
= 7.2 Hz, 1H), 7.37–7.28 (m, 2H), 7.28–7.23 (m, 1H), 7.11 (d, J
= 7.3 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H),
5.16 (s, 1H), 3.85 (s, 3H), 3.74 (s, 3H), 2.36 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ 171.91, 159.74, 158.97, 138.40, 138.29,
132.51, 128.73, 128.47, 128.32, 127.91, 124.77, 124.10, 120.71,
110.84, 77.23, 55.45, 52.45, 21.45; IR (KBr): ν 3004, 2950, 2840,
1909, 757 cm-1; HRMS (ESI): m/z calculated for C18H20NO3
+
[M+H]+ 298.1438, found 298.1438.
4.1.4.
Methyl
(E)-2-((2-methoxybenzylidene)amino)-2-(o-
tolyl)acetate (1d). White solid, mp 48–49 °C; 1H NMR (400
MHz, CDCl3): δ 8.79 (s, 1H), 8.12 (dd, J = 7.7, 1.6 Hz, 1H),
7.64–7.57 (m, 1H), 7.42–7.36 (m, 1H), 7.25–7.15 (m, 3H), 6.98
(t, J = 7.5 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.39 (s, 1H), 3.84 (s,
3H), 3.73 (s, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3): δ
171.87, 159.76, 159.02, 137.12, 135.91, 132.49, 130.58, 128.54,
127.87, 127.78, 126.29, 124.28, 120.75, 110.92, 74.05, 55.48,
52.41, 19.69; IR (KBr): ν 3648, 3005, 2360, 1747, 1260, 750 cm-
A mixture of above obtained arylglyoxylate (20 mmol),
anhydrous sodium acetate (2.0 g, 24 mmol), hydroxylamine
hydrochloride (2.2 g, 32 mmol) and methanol (70 mL) was
heated to 60 °C for 3 h. After evaporating the organic solvent
under vacuum, ethyl acetate was added to the resulting residue
and the mixture was washed with water. The organic layer was
then washed with brine, dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuum to afford oxime. To a
solution of oxime (20 mmol) and formic acid (24 mL) in
methanol (40 mL) and water (24 mL) at 0 °C was added Zn dust
(3.8 g, 60 mmol) portion-wise over 1 h. The suspension was
stirred for 3 h at 0 °C and an additional 4 h at room temperature.
The mixture was filtered through celite and washed with
methanol. The filtrate was concentrated and the resulting residue
was purified by flash chromatography (silica gel,
1
+
;
HRMS (ESI): m/z calculated for C18H20NO3 [M+H]+
298.1438, found 298.1439.
4.1.5. Methyl
(E)-2-(2,4-dimethylphenyl)-2-((2-
methoxybenzylidene)amino)acetate (1e). White solid, mp 60–61
1
°C; H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.11 (d, J = 7.7
Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.09–
6.92 (m, 3H), 6.88 (d, J = 8.4 Hz, 1H), 5.36 (s, 1H), 3.84 (s, 3H),
3.73 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 172.04, 159.55, 158.96, 137.39, 135.71, 134.15,
132.37, 131.38, 128.46, 127.89, 126.96, 124.33, 120.71, 110.86,
73.80, 55.46, 52.36, 21.03, 19.58; IR (KBr): ν 3689, 2360, 1747,
1488, 1249, 752 cm-1; HRMS (ESI): m/z calculated for
C19H22NO3+ [M+H]+ 312.1594, found 312.1589.
dichloromethane/methanol
= 10/1) to afford the racemic
arylglycine ester.19b
The above obtained arylglycine ester (10 mmol) and
anhydrous magnesium sulfate (1.2 g) were stirred together in
dichloromethane (50 mL) at room temperature for 20 min. Then
the aldehyde (10 mmol) and triethylamine (8 mL) were added
sequentially and dropwise. After stirred for 12 h at the same
temperature, the resulting mixture was filtered and the organic
solvent was evaporated in vacuum. The residue was dissolved in
ethyl acetate (20 mL) and water (20 mL), and the separated
aqueous layer was extracted with ether (2 × 20 mL). The
combined organic extracts were washed with brine, dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuum.
The residue was purified by flash chromatography (silica gel,
petrol ether/triethylamine = 50/1 to 20/1) to afford the substrate
for hydrogenation as a white solid.19c
4.1.6.
Methyl
(E)-2-((2-methoxybenzylidene)amino)-2-(4-
methoxyphenyl)acetate (1f). White solid, mp 61–63 °C; 1H NMR
(400 MHz, CDCl3): δ 8.77 (s, 1H), 8.11 (d, J = 6.7 Hz, 1H),
7.46–7.34 (m, 3H), 6.97 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 8.7 Hz,
3H), 5.14 (s, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.72 (s, 3H); 13C
NMR (101 MHz, CDCl3): δ 172.01, 159.51, 159.30, 158.99,
132.44, 130.75, 128.89, 127.88, 124.20, 120.72, 113.98, 110.88,
76.45, 55.46, 55.25, 52.35; IR (KBr): ν 3649, 3005, 1744, 1508,
1259, 750 cm-1; HRMS (ESI): m/z calculated for C18H20NO4
+
[M+H]+ 314.1387, found 314.1387.
4.1.7.
Methyl
(E)-2-((2-methoxybenzylidene)amino)-2-(3-
methoxyphenyl)acetate (1g). White solid, mp 60–61 °C; 1H NMR
(400 MHz, CDCl3): δ 8.80 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.40
(t, J = 7.7 Hz, 1H), 7.32–7.27 (m, 1H), 7.15–7.06 (m, 2H), 6.99
(t, J = 7.5 Hz, 1H), 6.92–6.81 (m, 2H), 5.17 (s, 1H), 3.85 (s, 3H),
3.82 (s, 3H), 3.74 (s, 3H); 13C NMR (101 MHz, CDCl3): δ
171.67, 159.89, 159.75, 159.04, 140.01, 132.55, 129.52, 127.90,
124.14, 120.73, 120.08, 113.62, 113.26, 110.91, 77.03, 55.47,
55.25, 52.42; IR (KBr): ν 3003, 2950, 1744, 1600, 1541, 1249,
4.1.1.
Methyl
(E)-2-((2-methoxybenzylidene)amino)-2-
1
phenylacetate (1a). White solid, mp 77–79 °C; H NMR (400
MHz, CDCl3): δ 8.81 (s, 1H), 8.14 (d, J = 7.7 Hz, 1H), 7.53 (d, J
= 7.7 Hz, 2H), 7.43–7.33 (m, 3H), 7.33–7.27 (m, 1H), 6.99 (t, J =
7.5 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.20 (s, 1H), 3.85 (s, 3H),
3.74 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 171.76, 159.81,
159.03, 138.57, 132.55, 128.58, 127.94, 127.91, 127.77, 124.14,
120.74, 110.91, 77.14, 55.47, 52.42; IR (KBr): ν 3029, 2950,
1600, 1257, 1161, 1025, 757 cm-1; HRMS (ESI): m/z calculated
for C17H18NO3+ [M+H]+ 284.1281, found 284.1281.
1161, 758 cm-1; HRMS (ESI): m/z calculated for C18H20NO4
+
[M+H]+ 314,1387, found 314.1388.
4.1.8.
Methyl
(E)-2-(3,4-dimethoxyphenyl)-2-((2-
4.1.2.
Methyl
(E)-2-((2-methoxybenzylidene)amino)-2-(p-
methoxybenzylidene)amino)acetate (1h). White solid, mp 81–83
oC; 1H NMR (400 MHz, CDCl3): δ 8.79 (s, 1H), 8.13 (dd, J = 7.7,
1.6 Hz, 1H), 7.43–7.37 (m, 1H), 7.10 (d, J = 1.8 Hz, 1H), 7.06–
6.96 (m, 2H), 6.92–6.83 (m, 2H), 5.14 (s, 1H), 3.91 (s, 3H), 3.87
(s, 3H), 3.85 (s, 3H), 3.74 (s, 3H); 13C NMR (101 MHz, CDCl3):
δ 171.95, 159.66, 158.99, 149.03, 148.78, 132.52, 131.09,
tolyl)acetate (1b). White solid, mp 63–65 °C; 1H NMR (400
MHz, CDCl3): δ 8.79 (s, 1H), 8.12 (d, J = 7.7 Hz, 1H), 7.46–7.32
(m, 3H), 7.17 (d, J = 7.9 Hz, 2H), 6.98 (t, J = 7.6 Hz, 1H), 6.89
(d, J = 8.3 Hz, 1H), 5.17 (s, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 2.34
(s, 3H); 13C NMR (101 MHz, CDCl3): δ 171.95, 159.63, 158.98,
137.66, 135.62, 132.46, 129.28, 127.91, 127.63, 124.19, 120.72,

127.83, 124.13, 120.71, 120.09, 111.03, 110.89, 110.79, 76.69,
(s, 3H), 3.75 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 171.00 (s),
161.29 (s), 160.92 (s), 159.08 (s), 158.84 (s), 132.73 (s), 129.61
55.93, 55.87, 55.45, 52.41; IR (KBr): ν 3002, A29C51C, 2E83P8T, 1E74D3, MANUSCRIPT
1514, 1261, 1026, 758 cm-1; HRMS (ESI): m/z calculated for
C19H22NO5+ [M+H]+ 344,1492, found 344.1487.
(s), 129.57 (s), 129.48 (s), 129.40 (s), 127.78 (s), 125.95 (s),
125.81 (s), 124.36 (s), 124.32 (s), 123.96 (s), 120.70 (s), 115.39
(s), 115.17 (s), 110.92 (s), 69.78 (s), 55.47 (s), 52.63 (s).; IR
(KBr): ν 2952, 2360, 1748, 1653, 1395, 690 cm-1; HRMS (ESI):
4.1.9
Methyl
(E)-2-(benzo[d][1,3]dioxol-5-yl)-2-((2-
+
m/z calculated for C17H17FNO3 [M+H]+ 302.1187, found
methoxybenzylidene)amino)acetate (1i). White solid, mp 60–61
1
°C; H NMR (400 MHz, CDCl3): δ 8.78 (s, 1H), 8.12 (d, J = 7.5
302.1186.
Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.08 (s, 1H), 6.97 (dd, J = 18.3,
8.2 Hz, 2H), 6.89 (d, J = 8.5 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H),
5.95 (s, 2H), 5.10 (s, 1H), 3.85 (s, 3H), 3.74 (s, 3H).13C NMR
(101 MHz, CDCl3): δ 171.82, 159.71, 158.97, 147.79, 147.29,
132.57, 132.36, 127.84, 124.01, 121.10, 120.73, 110.85, 108.32,
108.20, 101.08, 76.68, 55.45, 52.47; IR (KBr): ν 2951, 2894,
1909, 1039, 728 cm-1; HRMS (ESI): m/z calculated for
C18H18NO5+ [M+H]+ 328.1179, found 328.1179.
4.2. General procedure for the asymmetric hydrogenation
Substrate 1 (0.2 mmol) and [Rh((S)-TCFP)(cod)]BF4 (2 mol
%) were charged in an autoclave. And the system was evacuated
and filled with hydrogen. After repeating this operation 3 times,
degassed iPrOH/TFE (2/1, 2 mL) was added and the hydrogen
pressure was adjusted to 10 atm. After vigorous stirring at room
temperature for 48 h, the reaction mixture was evaporated under
reduced pressure. After purification by flash chromatography
(silica gel, petra ether/ethyl acetate = 5/1), the yield was
calculated and the ee value was determined by HPLC using chiral
column.
4.1.10.
Methyl
(E)-2-([1,1'-biphenyl]-4-yl)-2-((2-
methoxybenzylidene)amino)acetate (1j). White solid, mp 85–86
1
°C; H NMR (400 MHz, CDCl3): δ 8.84 (s, 1H), 8.16 (dd, J =
7.7, 1.7 Hz, 1H), 7.63–7.54 (m, 6H), 7.46–7.38 (m, 3H), 7.34 (t,
J = 7.4 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.3 Hz,
1H), 5.24 (s, 1H), 3.86 (s, 3H), 3.77 (s, 3H); 13C NMR (101
MHz, CDCl3): δ 171.76, 159.93, 159.04, 140.87, 140.77, 137.58,
132.57, 128.73, 128.18, 127.92, 127.35, 127.30, 127.11, 124.13,
120.77, 110.90, 76.89, 55.48, 52.51; IR (KBr): ν 3675, 3587,
2949, 1717, 1600, 1465, 757 cm-1; HRMS (ESI): m/z calculated
for C23H22NO3+ [M+H]+ 360.1594, found 360.1598.
4.2.1. Methyl 2-((2-methoxybenzyl)amino)-2-phenylacetate (2a).
1
Colorless oil, 47.7 mg, 79% yield, 60% ee; H NMR (400 MHz,
CDCl3): δ 7.40 (d, J = 7.1 Hz, 2H), 7.36–7.17 (m, 5H), 6.89 (t, J
= 7.3 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 4.37 (s, 1H), 3.79 (s,
3H), 3.74 (dd, J = 54.8, 13.2 Hz, 2H), 3.61 (s, 3H); 13C NMR
(101 MHz, CDCl3): δ 173.40, 157.76, 138.33, 129.98, 128.62,
128.46, 128.05, 127.79, 127.57, 120.41, 110.29, 64.61, 55.24,
52.16, 46.93; IR (KBr): ν 3029, 2951, 1737, 1493, 1243, 1028,
4.1.11.
Methyl
(E)-2-((2-methoxybenzylidene)amino)-2-
(naphthalen-2-yl)acetate (lk). White solid, mp 91–92 °C; 1H
NMR (400 MHz, CDCl3): δ 8.87 (s, 1H), 8.18 (d, J = 6.1 Hz,
1H), 7.97 (s, 1H), 7.88–7.80 (m, 3H), 7.68 (d, J = 8.4 Hz, 1H),
7.51–7.37 (m, 3H), 7.01 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.4 Hz,
1H), 5.37 (s, 1H), 3.85 (s, 3H), 3.75 (s, 3H); 13C NMR (101
MHz, CDCl3): δ 171.79, 160.05, 159.04, 136.03, 133.34, 133.05,
132.59, 128.31, 128.09, 127.94, 127.65, 126.75, 126.13, 126.07,
125.65, 124.15, 120.76, 110.90, 77.23, 55.46, 52.50; IR (KBr): ν
3735, 3005, 2950, 2840, 1745, 1507, 1249, 751 cm-1; HRMS
755 cm-1; HRMS (ESI): m/z calculated for C17H20NO3 [M+H]+
+
286.1438, found 286.1436; HPLC conditions: DAICEL
Chiralpak OD column, Hexane/i-PrOH = 95/5, 220 nm, 1.0
mL/min, 25 °C, tmajor = 14.6 min, tminor = 9.4 min; [α]20 = -43 (c
D
0.52, DCM).
4.2.2. Methyl 2-((2-methoxybenzyl)amino)-2-(p-tolyl)acetate (2b).
1
Colorless oil, 48.6 mg, 77% yield, 61% ee; H NMR (400 MHz,
CDCl3): δ 7.29 (d, J = 8.0 Hz, 2H), 7.25–7.18 (m, 2H), 7.14 (d, J
= 7.9 Hz, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H),
4.34 (s, 1H), 3.79 (s, 3H), 3.73 (dd, J = 54.7, 13.5 Hz, 2H), 3.61
(s, 3H), 2.33 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 173.54,
157.76, 137.76, 135.31, 129.99, 129.33, 128.42, 127.68, 127.62,
120.39, 110.26, 64.30, 55.24, 52.14, 46.86, 21.18; IR (KBr): ν
3003, 2950, 1736, 1541, 1464, 1243, 1029, 754 cm-1; HRMS
(ESI): m/z calculated for C21H20NO3 [M+H]+ 334.1438, found
+
334.1433.
4.1.12.
Methyl
(E)-2-(4-fluorophenyl)-2-((2-
methoxybenzylidene)amino)acetate (1l). White solid, mp 52–53
1
°C; H NMR (400 MHz, CDCl3): δ 8.80 (s, 1H), 8.12 (d, J = 7.7
+
Hz, 1H), 7.57–7.46 (m, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7.10–6.94
(m, 3H), 6.90 (d, J = 8.4 Hz, 1H), 5.17 (s, 1H), 3.86 (s, 3H), 3.74
(s, 3H); 13C NMR (101 MHz, CDCl3): δ 171.57, 163.66, 161.21,
159.94, 159.05, 134.38, 134.35, 132.64, 129.45, 129.37, 127.83,
124.02, 120.76, 115.51, 115.30, 110.93, 76.29, 55.47, 52.47; IR
(KBr): ν 3649, 2952, 1747, 1508, 1248, 757 cm-1; HRMS (ESI):
(ESI): m/z calculated for C18H22NO3 [M+H]+ 300.1594, found
300.1602; HPLC conditions: DAICEL Chiralpak OJ column,
Hexane/i-PrOH = 95/5, 220 nm, 1.0 mL/min, 25 °C, tmajor = 19.1
min, tminor = 22.8 min; [α]20D = -48 (c 0.43, DCM).
4.2.3 Methyl 2-((2-methoxybenzyl)amino)-2-(m-tolyl)acetate (2c).
1
+
m/z calculated for C17H17FNO3 [M+H]+ 302.1187, found
Colorless oil, 40.2 mg, 67% yield, 62% ee; H NMR (400 MHz,
CDCl3): δ 7.26–7.15 (m, 5H), 7.10 (d, J = 7.1 Hz, 1H), 6.89 (t, J
= 7.4 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 4.33 (s, 1H), 3.81 (s,
3H), 3.72 (dd, J = 64.0, 12.0 Hz, 2H), 3.63 (s, 3H), 2.34 (s,
3H).13C NMR (101 MHz, CDCl3): δ 173.46, 157.69, 138.28,
138.10, 129.97, 128.80, 128.44, 128.40, 128.29, 127.49, 124.82,
120.33, 110.17, 64.52, 55.20, 52.16, 46.93, 21.42.; IR (KBr): ν
3003, 2951, 2837, 1734, 1363, 754 cm-1; HRMS (ESI): m/z
302.1180.
4.1.13
Methyl
(E-)-2-(3-fluorophenyl)-2-((2-
methoxybenzylidene)amino)acetate (1m). White solid, mp 66–67
1
°C; H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H), 8.14 (d, J = 7.5
Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.38–7.27 (m, 3H), 7.05–6.96
(m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 5.18 (s, 1H), 3.86 (s, 3H), 3.75
(s, 3H). 13C NMR (101 MHz, CDCl3): δ 171.25, 164.04, 161.59,
160.31, 159.05, 140.90, 140.83, 132.77, 130.02, 129.94, 127.83,
123.86, 123.33, 120.76, 114.96, 114.75, 110.91, 76.50, 55.45,
52.60; IR (KBr): ν 2952, 2360, 1748, 1395, 783 cm-1; HRMS
calculated for C18H22NO3 [M+H]+ 300.1594, found 300.1593;
+
HPLC conditions: DAICEL Chiralpak OD column, Hexane/i-
PrOH = 95/5, 220 nm, 1.0 mL/min, 25 °C, tmajor = 13.6 min, tminor
= 9.0 min; [α]20D = -40 (c 0.44, DCM).
(ESI): m/z calculated for C17H17FNO3 [M+H]+ 302.1187, found
+
4.2.4. Methyl 2-((2-methoxybenzyl)amino)-2-(o-tolyl)acetate (2d).
302.1188.
1
Colorless oil, 48.3 mg, 76% yield, 69% ee; H NMR (400 MHz,
4.1.14
Methyl
(E)-2-(2-fluorophenyl)-2-((2-
CDCl3): δ 7.29 (d, J = 8.0 Hz, 2H), 7.25–7.18 (m, 2H), 7.14 (d, J
= 7.9 Hz, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H),
4.34 (s, 1H), 3.79 (s, 3H), 3.73 (dd, J = 54.7, 13.5 Hz, 2H), 3.61
(s, 3H), 2.33 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 173.76,
157.80, 136.82, 136.69, 130.70, 130.12, 128.49, 127.82, 127.68,
methoxybenzylidene)amino)acetate (1n). White solid, mp 94–95
1
°C; H NMR (400 MHz, CDCl3): δ 8.82 (s, 1H), 8.14 (d, J = 7.5
Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 10.2 Hz, 3H), 7.01
(d, J = 7.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 1H), 5.18 (s, 1H), 3.86

6
Tetrahedron
ACCEPTED MANUSCRIPT
127.02, 126.29, 120.42, 110.28, 60.75, 55.23, 52.08, 47.06,
3.82 (s, 3H), 3.73 (dd, J = 48.0, 13.5 Hz, 2H), 3.64 (s, 3H). 13C
19.28; IR (KBr): ν 3019, 2951, 1736, 1493, 1464, 1243, 1029,
NMR (101 MHz, CDCl3): δ 173.31, 157.68, 147.86, 147.35,
132.04, 129.96, 128.42, 127.40, 121.38, 120.33, 110.19, 108.19,
107.95, 101.08, 64.10, 55.20, 52.20, 46.72; IR (KBr): ν 2360,
1801, 1698, 1260, 1029, 803 cm-1; HRMS (ESI): m/z calculated
754 cm-1; HRMS (ESI): m/z calculated for C18H22NO3 [M+H]+
+
300.1594, found 300.1594; HPLC conditions: DAICEL
Chiralpak OD column, Hexane/i-PrOH = 95/5, 220 nm, 1.0
mL/min, 25 °C, tmajor = 11.8 min, tminor = 8.5 min; [α]20 = -38 (c
for C18H20NO5 [M+H]+ 330.1336, found 330.1337; HPLC
+
D
0.57, DCM).
conditions: DAICEL Chiralpak OD column, Hexane/i-PrOH =
90/10, 220 nm, 1.0 mL/min, 25 °C, tmajor = 15.2 min, tminor = 11.7
min; [α]20D = -40 (c 0.46, DCM).
4.2.5.
Methyl
2-(2,4-dimethylphenyl)-2-((2-
methoxybenzyl)amino)acetate (2e). Colorless oil, 48.4 mg, 72%
yield, 67% ee; 1H NMR (400 MHz, CDCl3): δ 7.28–7.13 (m, 3H),
7.02–6.94 (m, 2H), 6.88 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 8.2 Hz,
1H), 4.54 (s, 1H), 3.79 (s, 3H), 3.74(dd, J = 34.0, 13.2 Hz, 2H)
3.63 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 173.85, 157.75, 137.38, 136.57, 133.65, 131.45,
130.06, 128.38, 127.72, 126.95, 126.93, 120.35, 110.20, 60.47,
55.19, 52.01, 46.94, 21.00, 19.13; IR (KBr): ν 3003, 2950, 1735,
1491, 1243, 755 cm-1; HRMS (ESI): m/z calculated for
4.2.10.
Methyl
2-([1,1'-biphenyl]-4-yl)-2-((2-
methoxybenzyl)amino)acetate (2j). Colorless oil, 61.1 mg, 82%
yield, 57% ee; 1H NMR (400 MHz, CDCl3): δ 7.63–7.56 (m, 4H),
7.50 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3
Hz, 1H), 7.25 (dd, J = 10.2, 5.7 Hz, 2H), 6.93 (t, J = 7.4 Hz, 1H),
6.87 (d, J = 8.0 Hz, 1H), 4.45 (s, 1H), 3.83 (s, 3H), 3.80 (dd, J =
55.1, 13.5 Hz, 2H), 3.67 (s, 3H); 13C NMR (101 MHz, CDCl3): δ
173.39, 157.78, 140.97, 140.75, 137.35, 130.03, 128.81, 128.50,
128.22, 127.56, 127.38, 127.12, 120.44, 110.30, 64.32, 55.27,
52.26, 46.99; IR (KBr): ν 3029, 2950, 2836, 1464, 1490, 1029,
+
C19H24NO3 [M+H]+ 314.1751, found 314.1751; HPLC
conditions: DAICEL Chiralpak OD column, Hexane/i-PrOH =
95/5, 220 nm, 1.0 mL/min, 25 °C, tmajor = 10.9 min, tminor = 7.7
min; [α]20D = -45 (c 0.71, DCM).
757, 699 cm-1; HRMS (ESI): m/z calculated for C23H24NO3
+
[M+H]+ 362.1751, found 362.1755; HPLC conditions: DAICEL
Chiralpak OJ column, Hexane/i-PrOH = 75/25, 220 nm, 1.0
mL/min, 25 °C, tmajor = 14.6 min, tminor = 27.5 min; [α]20D = -55 (c
0.70, DCM).
4.2.6.
Methyl
2-((2-methoxybenzyl)amino)-2-(4-
methoxyphenyl)acetate (2f). Colorless oil, 46.2 mg, 69% yield,
58% ee; 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 8.3 Hz, 2H),
7.25–7.16 (m, 2H), 6.95–6.83 (m, 4H), 4.33 (s, 1H), 3.82 (s, 3H),
3.80 (s, 3H), 3.73 (dd, J = 53.6, 13.4 Hz, 2H), 3.64 (s, 3H); 13C
NMR (101 MHz, CDCl3): δ 173.57, 159.34, 157.70, 130.36,
129.93, 128.85, 128.34, 127.59, 120.33, 113.95, 110.20, 63.88,
55.23, 55.20, 52.07, 46.77; IR (KBr): ν 3335, 3001, 2931, 1736,
1587, 1247, 757 cm-1; HRMS (ESI): m/z calculated for
4.2.11. Methyl 2-((2-methoxybenzyl)amino)-2-(naphthalen-2-
yl)acetate (2k). Colorless oil, 58.6 mg, 83% yield, 37% ee; H
1
NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.84–7.76 (m, 3H), 7.53
(d, J = 8.5 Hz, 1H), 7.49–7.40 (m, 2H), 7.26–7.17 (m, 2H), 6.89
(t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.55 (s, 1H), 3.77
(dd, J = 61.9, 13.5 Hz, 2H), 3.76 (s, 3H), 3.60 (s, 3H); 13C NMR
(101 MHz, CDCl3): δ 173.30, 157.77, 135.69, 133.32, 133.18,
130.01, 128.46, 128.38, 128.00, 127.67, 127.53, 127.01, 126.16,
126.07, 125.52, 120.40, 110.28, 64.65, 55.23, 52.21, 46.87; IR
(KBr): ν 2951, 1541, 1507, 1464, 1244, 1028, 754 cm-1; HRMS
+
C18H22NO4 [M+H]+ 316.1543, found 316.1548; HPLC
conditions: DAICEL Chiralpak OD column, Hexane/i-PrOH =
90/10, 220 nm, 1.0 mL/min, 25 °C, tmajor = 13.6 min, tminor = 10.2
min; [α]20D = -40 (c 0.21, DCM).
(ESI): m/z calculated for C21H22NO3 [M+H]+ 336.1594, found
+
4.2.7.
Methyl
2-((2-methoxybenzyl)amino)-2-(3-
336.1598; HPLC conditions: DAICEL Chiralpak OD column,
Hexane/i-PrOH = 95/5, 220 nm, 1.0 mL/min, 25 °C, tmajor = 18.6
min, tminor = 14.0 min; [α]20D = -36 (c 0.53, DCM).
methoxyphenyl)acetate (2g). Colorless oil, 55.4 mg, 83% yield,
55% ee; 1H NMR (400 MHz, CDCl3): δ 7.32–7.17 (m, 3H), 7.02–
6.97 (m, 2H), 6.91 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.1 Hz, 2H),
4.37 (s, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.75(dd, J= 56.8, 13.4 Hz,
2H), 3.64 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 173.26,
159.84, 157.75, 139.80, 130.00, 129.57, 128.46, 127.52, 120.38,
120.20, 113.70, 113.13, 110.27, 64.53, 55.25, 55.23, 52.19,
46.89; IR (KBr): ν 3002, 2951, 1736, 1587, 1199, 1047, 755 cm-
4.2.12
Methyl
2-(4-fluorophenyl)-2-((2-
methoxybenzyl)amino)acetate (2l). Colorless oil, 50.4 mg, 79%
yield, 55% ee; 1H NMR (400 MHz, CDCl3): δ 7.42–7.35 (m, 2H),
7.23 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.02 (t, J = 8.6
Hz, 2H), 6.94–6.82 (m, 2H), 4.36 (s, 1H), 3.80 (s, 3H), 3.73 (dd,
J = 62.7, 13.5 Hz, 2H), 3.62 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 173.18, 163.7, 161.25, 157.71, 134.06, 136.03, 129.93,
129.44, 129.36, 128.48, 127.36, 120.37, 115.52, 115.30, 110.27,
63.75, 55.20, 52.18, 46.84; IR (KBr): ν 3004, 2952, 1740, 1540,
1493, 1243, 1029, 755 cm-1; HRMS (ESI): m/z calculated for
1
+
;
HRMS (ESI): m/z calculated for C18H22NO4 [M+H]+
316.1543, found 316.1543; HPLC conditions: DAICEL
Chiralpak OJ column, Hexane/i-PrOH = 90/10, 220 nm, 1.0
mL/min, 25 °C, tmajor = 21.1 min, tminor = 25.7 min; [α]20D = -29 (c
0.43, DCM).
C17H18FNO3 [M+H]+ 304.1343, found 304.1344; HPLC
conditions: DAICEL Chiralpak OJ column, Hexane/i-PrOH =
95/5, 220 nm, 1.0 mL/min, 25 °C, tmajor = 18.7 min, tminor = 20.1
min; [α]20D = -36 (c 0.51, DCM).
+
4.2.8.
Methyl
2-(3,4-dimethoxyphenyl)-2-((2-
methoxybenzyl)amino)acetate (2h). Colorless oil, 56.7 mg, 79%
1
yield, 66% ee; H NMR (400 MHz, CDCl3): δ 7.19 (m, 2H),
6.97–6.78 (m, 5H), 4.30 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.79
(s, 3H), 3.72 (dd, J = 54.8, 13.5 Hz, 2H), 3.62 (s, 3H).; 13C NMR
(101 MHz, CDCl3): δ 173.45, 157.72, 149.11, 148.81, 130.73,
129.98, 128.40, 127.51, 120.31, 120.27, 110.99, 110.49, 110.23,
64.15, 55.90, 55.86, 55.21, 52.12, 46.79; IR (KBr): ν 3001, 2952,
2836, 1736, 1514, 1242, 1028, 757 cm-1; HRMS (ESI): m/z
4.2.13
Methyl
2-(3-fluorophenyl)-2-((2-
methoxybenzyl)amino)acetate (2m). Colorless oil, 46.8 mg, 77%
yield, 36% ee; 1H NMR (400 MHz, CDCl3): δ 7.35–7.22 (m, 2H),
7.22–7.13 (m, 3H), 7.04–6.96 (m, 1H), 6.94–6.84 (m, 2H), 4.37
(s, 1H), 3.83 (s, 3H), 3.73 (dd, J = 72.0, 16.0 Hz, 2H) 3.64 (s,
3H). 13C NMR (101 MHz, CDCl3): δ 172.83, 164.13, 161.68,
157.68, 140.76, 140,69, 130.02, 129.97, 129.94, 128.54, 127.21,
123.48, 123.45, 120.36, 115.05, 114.84, 114.79, 114.57, 110.21,
63.99, 63.97, 55.19, 52.32, 46.88.; IR (KBr): ν 2360, 1749, 1362,
1260, 1029, 750 cm-1; HRMS (ESI): m/z calculated for
+
calculated for C19H24NO5 [M+H]+ 346.1649, found 346.1646;
HPLC conditions: DAICEL Chiralpak OJ column, Hexane/i-
PrOH = 80/20, 220 nm, 1.0 mL/min, 25 °C, tmajor = 17.3 min,
tminor = 22.1 min; [α]20D = -31 (c 0.47, DCM)
+
C17H18FNO3 [M+H]+ 304.1343, found 304.1345; HPLC
conditions: DAICEL Chiralpak OD column, Hexane/i-PrOH =
95/5, 220 nm, 1.0 mL/min, 25 °C, tmajor = 13.0 min, tminor = 9.0
min; [α]20D = -12 (c 0.35, DCM).
4.2.9
Methyl
2-(benzo[d][1,3]dioxol-5-yl)-2-((2-
methoxybenzyl)amino)acetate (2i). Colorless oil, 46.1 mg, 70%
yield, 56% ee; 1H NMR (400 MHz, CDCl3): δ 7.26–7.17 (m, 2H),
6.94–6.82 (m, 4H), 6.79–6.75 (m, 1H), 5.95 (s, 2H), 4.28 (s, 1H),

R. W.; Kobayashi, Y.; Kennedy-Smith, J. J.; Toste, F. D. Chem. Eur. J.
2010, 16, 9555.
4.2.14
Methyl
2-(2-fluorophenyl)-2-((2-
ACCEPTED MANUSCRIPT
methoxybenzyl)amino)acetate (2n). Colorless oil, 32.2 mg, 53%
yield, 19% ee; 1H NMR (400 MHz, CDCl3): δ 7.43 (td, J = 7.5,
1.6 Hz, 1H), 7.29–7.16 (m, 3H), 7.12 (td, J = 7.5, 1.0 Hz, 1H),
7.08–7.00 (m, 1H), 6.92–6.79 (m, 2H), 4.70 (s, 1H), 3.80 (s, 3H),
3.74 (dd, J = 56.0, 12.0 Hz, 2H), 3.63 (s, 3H). 13C NMR (101
MHz, CDCl3): δ 172.73, 162.07, 159.61, 157.68, 129.97, 129.56,
129.48, 128.96, 128.92, 128.48, 127.30, 125.73, 125.59, 124.33,
124.29, 120.41, 120.37, 115.68, 115.46, 110.16, 57.58, 57.55,
55.17, 52.33, 46.98; IR (KBr): ν 3004, 2952, 1740, 1363, 1030,
755 cm-1; HRMS (ESI): m/z calculated for C17H18FNO3+ [M+H]+
304.1343, found 304.1342; HPLC conditions: DAICEL
Chiralpak OD column, Hexane/i-PrOH = 95/5, 220 nm, 1.0
6. For representative reviews: (a) Handbook of Homogeneous
Hydrogenation; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH:
Weinheim, Germany, 2007; (b) Phosphorus Ligands in Asymmetric
Catalysis; Börner, A. Ed.; Wiley-VCH: Weinheim, Germany, 2008; (c)
Asymmetric Catalysis on Industrial Scale, 2nd Ed.; Blaser, H.-U.,
Federsel, H.-J., Eds.; Wiley-VCH: Weinheim, Germany, 2010; (d) Xie,
J.-H.; Zhu, S.-F., Zhou, Q.-L. Chem. Rev. 2011, 111, 1713; (e) Xie, J.-
H.; Zhou, Q.-L. Huaxue Xuebao 2012, 70, 1427.
7. Selected papers: (a) Kadyrov, R.; Riermeier, T. H.; Dingerdissen, U.;
Tararov, V.; Börner, A. J. Org. Chem. 2003, 68, 4067; (b) Shang, G.;
Yang, Q.; Zhang, X. Angew. Chem. Int. Ed. 2006, 45, 6360; (c) Wang,
Y.-Q.; Lu, S.-M.; Zhou, Y.-G. J. Org. Chem. 2007, 72, 3729; (d)
Yoshikawa, N.; Tan, L.; McWilliams, J. C.; Ramasamy, D.; Sheppard,
R. Org. Lett. 2010, 12, 276; (e) Chen, Q.-A.; Chen, M.-W.; Yu, C.-B.;
Shi, L.; Wang, D.-S.; Yang, Y.; Zhou, Y.-G. J. Am. Chem. Soc. 2011,
133, 16432; (f) Lu, L.-Q.; Li, Y.; Junge, K.; Beller, M. J. Am. Chem.
Soc. 2015, 137, 2763.
mL/min, 25 °C, tmajor = 13.0 min, tminor = 9.7 min; [α]20 = -27 (c
0.22, DCM).
D
Supplementary Data
8. For recent reviews of dynamic kinetic resolution: (a) Pellissier, H.
Tetrahedron 2008, 64, 1563; (b) Pellissier, H. Adv. Synth. Catal. 2011,
353, 659; (c) Pellissier, H. Tetrahedron 2011, 67, 3769. (d) Rachwalski,
M.; Vermue, N.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2013, 42, 9268.
9. Selected papers concerning racemic ketones: (a) Noyori, R.; Ikeda, T.;
Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.;
Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc.
1989, 111, 9134; (b) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am.
Chem. Soc. 1993, 115, 144; (c) Makino, K.; Goto, T.; Hiroki, Y.;
Hamada, Y. Angew. Chem. Int. Ed. 2004, 43, 882; (d) Makino, K.;
Hiroki, Y.; Hamada, Y. J. Am. Chem. Soc. 2005, 127, 5784; (e) Liu, S.;
Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem. Int. Ed. 2007, 46,
7506; (f) Xie, J.-H.; Liu, S.; Kong, W.-L.; Bai, W.-J.; Wang, X.-C.;
Wang, L.-X.; Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 4222; (g) Liu,
C.; Xie, J.-H.; Li, Y.-L.; Chen, J.-Q.; Zhou, Q.-L. Angew. Chem. Int. Ed.
2013, 52, 593; Papers concerning racemic aldehydes: (h) Xie, J.-H.;
Zhou, Z.-T.; Kong, W.-L.; Zhou, Q.-L. J. Am. Chem. Soc. 2007, 129,
1868; (i) Li, X.; List, B. Chem. Commun. 2007, 1739; (j) Zhou, Z.-T.;
Xie, J.-H.; Zhou, Q.-L. Adv. Synth. Catal. 2009, 351, 363.
Supplementary data (copies of NMR and HPLC spectra)
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2016.XX.XXX.
Acknowledgments
This work was partially supported by the National Natural
Science Foundation of China (No. 21572131) and Science and
Technology Commission of Shanghai Municipality (No.
14XD1402300 and 15Z111220016). We thank the Instrumental
Analysis Center of Shanghai Jiao Tong University (SJTU) for
characterization.
References
10. (a) Wang, D.-S.; Chen, Q.-A.; Li, W.; Yu, C.-B.; Zhou, Y.-G.; Zhang, X.
J. Am. Chem. Soc. 2010, 132, 8909; (b) Duan, Y.; Chen, M.-W.; Ye, Z.-
S.; Wang, D.-S.; Chen, Q.-A.; Zhou, Y.-G. Chem. Eur. J. 2011, 17,
7193; (c) Wang, D.-S.; Tang, J.; Zhou, Y.-G.; Chen, M.-W.; Yu, C.-B.;
Duan, Y.; Jiang, G.-F. Chem. Sci. 2011, 2, 803; (d) Duan, Y.; Chen, M.-
W.; Chen, Q.-A.; Yu, C.-B.; Zhou, Y.-G. Org. Biomol. Chem. 2012, 10,
1235; (e) Yu, C.-B.; Gao, K.; Chen, Q.-A.; Chen, M.-W.; Zhou, Y.-G.
Tetrahedron Lett. 2012, 53, 2560; (f) Yu, C.-B.; Zhou, Y.-G. Angew.
Chem. Int. Ed. 2013, 52, 13365; (g) Li, C.; Chen, J.; Fu, G.; Liu, D.; Liu,
Y.; Zhang, W. Tetrahedron 2013, 69, 6839; (h) Duan, Y.; Li, L.; Chen,
M.-W.; Yu, C.-B.; Fan, H.-J.; Zhou, Y.-G. J. Am. Chem. Soc. 2014, 136,
7688.
1. (a) Kolla, N.; Elati, C. R.; Arunagiri, M.; Gangula, S.; Vankawala, P. J.;
Anjaneyulu, Y.; Bhattacharya, A.; Venkatraman, S.; Mathad, V. T. Org.
Proc. Res. Dev. 2007, 11, 455; (b) Guercio, G.; Bacchi, S.; Goodyear,
M.; Carangio, A.; Tinazzi, F.; Curti, S. Org. Proc. Res. Dev. 2008, 12,
1188; (c) Savage, S. A.; Waltermire, R. E.; Campagna, S.; Bordawekar,
S.; Toma, J. D. R. Org. Proc. Res. Dev. 2009, 13, 510; (d) van der
Meijden, M. W.; Leeman, M.; Gelens, E.; Noorduin, W. L.; Meekes, H.;
van Enckevort, W. J. P.; Kaptein, B.; Vlieg, E.; Kellogg, R. M. Org.
Proc. Res. Dev. 2009, 13, 1195; (e) Cherian, J.; Choi, I.; Nayyar, A.;
Manjunatha, U. H.; Mukherjee, T.; Lee, Y. S.; Boshoff, H. I.; Singh, R.;
Ha, Y. H.; Goodwin, M.; Lakshminarayana, S. B.; Niyomrattanakit, P.;
Jiricek, J.; Ravindran, S.; Dick, T.; Keller, T. H.; Dartois, V.; Barry, III,
C. E. J. Med. Chem. 2011, 54, 5639; (f) Shan, J.; Zhang, B.; Zhu, Y.;
Jiao, B.; Zheng, W.; Qi, X.; Gong, Y.; Yuan, F.; Lv, F.; Sun, H. J. Med.
Chem. 2012, 55, 3342; (g) Wilmink, P.; Rougeot, C.; Wurst, K.;
Sanselme, M.; van der Meijden, M.; Saletra, W.; Coquerel, G.; Kellogg,
R. M. Org. Proc. Res. Dev. 2015, 19, 302.
2. (a) Wang, M.-X.; Lin, S.-J. J. Org. Chem. 2002, 67, 6542; (b) Hang, J.;
Li, H.; Deng, L. Org. Lett. 2002, 4, 3321; (c) Arosio, D.; Caligiuri, A.;
D'Arrigo, P.; Pedrocchi-Fantoni, G.; Rossi, C.; Saraceno, C.; Servi, S.;
Tessaro, D. Adv. Synth. Catal. 2007, 349, 1345; (d) Lu, G.; Birman, V.
B. Org. Lett. 2011, 13, 356.
3. (a) Beenen, M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006,
128, 6304; (b) Reingruber, R.; Baumann, T.; Dahmen, S.; Bräse, S. Adv.
Synth. Catal. 2009, 351, 1019; (c) Seayad, A. M.; Ramalingam, B.;
Yoshinaga, K.; Nagata, T.; Chai, C. L. L. Org. Lett. 2010, 12, 264; (d)
Pérez-Fuertes, Y.; Taylor, J. E.; Tickell, D. A.; Mahon, M. F.; Bull, S.
D.; James, T. D. J. Org. Chem. 2011, 76, 6038; (e) Chen, J.; Lu, X.; Lou,
W.; Ye, Y.; Jiang, H.; Zeng, W. J. Am. Chem. Soc. 2012, 77, 8541.
4. (a) Bachmann, S.; Fielenbach, D.; Jørgensen, K. A. Org. Biomol. Chem.
2004, 2, 3044; (b) Lee, E. C.; Fu, G. C. J. Am. Chem. Soc. 2007, 129,
12066; (c) Xu, B.; Zhu, S.-F.; Xie, X.-L.; Shen, J.-J.; Zhou, Q.-L.
Angew. Chem. Int. Ed. 2011, 50, 11483; (d) Zhu, S.-F.; Xu, B.; Wang,
G.-P.; Zhou, Q.-L. J. Org. Chem. 2012, 134, 436.
11. Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem. Soc. 2006, 128,
13074.
12. (a) Tian, F.; Yao, D.; Liu, Y.; Xie, F.; Zhang, W. Adv. Synth. Catal.
2010, 352, 1841; (b) Liu, Y.; Yao, D.; Li, K.; Tian, F.; Xie, F.; Zhang,
W. Tetrahedron 2011, 67, 8445; (c) Liu, Y.; Zhang, W. Angew. Chem.
Int. Ed. 2013, 52, 2203; (d) Liu, Y.; Gridnev, I. D.; Zhang, W. Angew.
Chem. Int. Ed. 2014, 53, 1901.
13. (a) Hoge, G.; Wu, H.-P.; Kissel, W. S.; Pflum, D. A.; Greene, D. J.; Bao,
J. J. Am. Chem. Soc. 2004, 126, 5966; (b) Gridnev, I. D.; Imamoto, T.;
Hoge, G.; Kouchi, M.; Takahashi, H. J. Am. Chem. Soc. 2008, 130,
2560; (c) Zhang, Z.; Hu, Q.; Wang, Y.; Chen, J.; Zhang, W. Org. Lett.
2015, 17, 5380.
14. Vedejs, E.; Jure, M. Angew. Chem. Int. Ed. 2005, 44, 3974.
15. A control experiment of converting the product 2 to by-product 3 in the
same hydrogenative conditions was failed, so it was presumed that
compound 3 was probably produced from hydrolysis of substrate 1.
16. (a) Guizzetti, S.; Benaglia, M.; Rossi, S. Org. Lett. 2009, 11, 2928; (b)
Abed, H. B.; van Brandt, S. F. A.; Vega, J. A.; Gijsen, H. J. M.
Tetrahedron Lett. 2015, 56, 4028.
5. (a) Nolin, K. A.; Ahn, R. W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
12462; (b) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew.
Chem. Int. Ed. 2006, 45, 6751; (c) Kang, Q.; Zhao, Z.-A.; You, S.-L.
Adv. Synth. Catal. 2007, 349, 1657; (d) Malkov, A. V.; Vranková, K.;
Stončius, S.; Kočovský, P. J. Org. Chem. 2009, 74, 5839; (e) Zhu, C.;
Akiyama, T. Adv. Synth. Catal. 2010, 352, 1846; (f) Nolin, K. A.; Ahn,
17. Clark, J. C.; Phillipps, G. H.; Steer, M. R. J. Chem. Soc., Perkin Trans.
1 1976, 475.
18. Fabrello, A.; Bachelier, A.; Urrutigoïty, M.; Kalck, P. Coord. Chem.
Rev. 2010, 254, 273.
19. (a) Zhuang, J.; Wang, C.; Xie, F.; Zhang, W. Tetrahedron 2009, 65,
9797; (b) Schoenfeld, R. C.; Bourdet, D. L.; Brameld, K. A.; Chin, E.;

8
Tetrahedron
de Vicente, J.; Fung, A.; Harris, S. F.; Lee, E. K.; Le Pogam, S.;
ACCEPTED MANUSCRIPT
Leveque, V.; Li, J.; Lui, A. S.-T.; Najera, I.; Rajyaguru, S.; Sangi, M.;
Steiner, S.; Talamas, F. X.; Taygerly, J. P.; Zhao, J. J. Med. Chem. 2013,
56, 8163; (c) Griffiths-Jones, C. M.; Knight, D. W. Tetrahedron 2010,
66, 4150.