A simple proline-based organocatalyst for the enantioselective reduction of imines using trichlorosilane as a reductant

Article abstract of DOI:10.1016/j.tet.2012.03.035

A simple and inexpensive proline-based organocatalyst was developed for the reduction of imines using trichlorosilane as a reductant. The reduction of N-aryl imines in the presence of 10 mol % of N-pivaloyl-l-proline anilide was carried out to give the co

Full text of DOI:10.1016/j.tet.2012.03.035

Tetrahedron 68 (2012) 3893e3898
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A simple proline-based organocatalyst for the enantioselective reduction
of imines using trichlorosilane as a reductant
*
Takuya Kanemitsu, Atsushi Umehara, Rieko Haneji, Kazuhiro Nagata, Takashi Itoh
School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and inexpensive proline-based organocatalyst was developed for the reduction of imines using
Received 14 January 2012
Received in revised form 9 March 2012
Accepted 9 March 2012
trichlorosilane as a reductant. The reduction of N-aryl imines in the presence of 10 mol % of N-pivaloyl-L-
proline anilide was carried out to give the corresponding amines in excellent yields (up to 99%) with high
enantioselectivities (up to 93% ee).
Available online 15 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Organocatalysis
Reduction
Lewis bases
Amines
1. Introduction
organocatalytic approaches, N-formyl9 and N-picolinoyl10 groups
have been considered to be suitable substituents of chiral amino
The enantioselective synthesis of amines is one of the most
important steps in stereo-controlled syntheses of natural and
pharmaceutical products.1 Several synthetic methodologies have
been disclosed for the synthesis of chiral amines.2 One of them is
the catalytic reduction of imines or enamines, and the common
asymmetric method is hydrogenation using a transition metal
catalyst.3,4 Metal-catalyzed reactions, however, often require high
pressures and/or high temperatures. In addition, it is difficult in
some cases to separate the metal reagents from the resulting
amines, which are good ligands for metals. Thus, organocatalysis
has offered an attractive alternative for the reduction of nitrogen-
containing compounds. In this context, reduction of imines using
a trichlorosilane activated with Lewis-basic organocatalyst has
been developed.5 Matsumura and co-workers have accomplished
acid-based organocatalysts for the reduction. However, other sub-
stituents on the amine position of amino acid-based catalysts
have been significantly less evaluated.7b,11 We predicted that
N-substituted prolines, in addition to N-formyl and N-picolinoyl
derivatives, would be able to catalyze the reduction with tri-
chlorosilane. Herein, we report a simple proline derivative that has
a high ability to promote the asymmetric reduction of imines with
trichlorosilane.
2. Results and discussion
To initiate our study, we screened various L-proline derivatives
(Fig. 1) as catalysts for the reduction. The imine 1a was adopted as
the substrate for the reduction with trichlorosilane in the presence
the first N-formyl-L-proline anilide catalyzed reduction of imines
I: R = H
with trichlorosilane to afford enantiomerically enriched amines
with moderate optical yields.6 A few years later, Kocovsky and co-
workers have developed N-formyl- -valine derivatives as chiral
II: R = Cbz
ꢀ
ꢁ
III: R = Fmoc
IV: R = Boc
H
N
L
Lewis-basic organocatalysts for improvement of enantioselectivity
in the reduction.7 Furthermore, Sun and co-workers have presented
a S-chiral catalyst, which promoted the reduction of imines with
trichlorosilane in high yield and enantioselectivity.8 Among the
N
R
V: R = Troc
O
VI: R = Ac
VII: R = Bz
VIII: R = Piv
IX: R = trichloroacetyl
X: R = formyl
Fig. 1. Structure of L-proline-based catalysts.
* Corresponding author. Tel.: þ81 3 3784 8184; fax: þ81 3 3784 5982; e-mail
address: itoh-t@pharm.showa-u.ac.jp (T. Itoh).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.035

3894
T. Kanemitsu et al. / Tetrahedron 68 (2012) 3893e3898
of a proline-based catalyst. Addition of
L
-proline anilides IeX to the
substrate was interfered with toluene, which resulted in low ac-
tivity. Zhang reported that toluene afforded inferior reactivity and
enantioselectivity in the case of N-picolinoyl catalysts.10b,e In Et2O,
the reaction hardly proceeded (Table 2, entry 3). Using THF as the
solvent resulted in high yields, but poor enantioselectivities (Table
2, entry 4). Zhang has suggested that THF can coordinate with tri-
chlorosilane.10b In the case of DMF, the reaction gave a racemic
product in good yields (Table 2, entry 6). Under this condition,
trichlorosilane was activated by the excess amount of DMF as
reported by Kobayashi.12 When the reaction was performed in
CH3CN, CH3Cl, ClCH2CH2Cl or CH2Cl2, the enantioselectivities were
significantly improved (Table 2, entries 7e10). The best enantio-
selectivity of 88% ee was achieved when CH2Cl2 was used.
reaction accelerated the reaction rate considerably in every case.
The enantiomeric excess of the purified amine 2a was measured by
chiral HPLC and the absolute configuration was determined by
comparison with specific rotation values reported in the literature.7
The results are gathered in Table 1.
Table 1
Catalyst screening for the reduction of imine 1a
HSiCl3 (1.5 equiv)
catalyst (10 mol%)
HN
N
∗
CH2Cl2
rt, 16 h
1a
2a
Table 2
Optimization studies on the reduction of 1a
Entrya
Catalyst
Yieldb [%]
eec [%]
Config.
H
N
1
2
3
4
5
6
7
8
9
I
II
58
62
62
75
33
72
72
74
57
75
61
80
78
72
70
79
78
88
84
43
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
N
O
III
IV
V
VI
VII
VIII
IX
X
O
VIII (10 mol%)
HSiCl3 (1.5 equiv)
HN
N
Solvent
Temp.
Time
2a
1a
10
a
The reactions were performed using 0.25 mmol of imine 1a and 0.375 mmol of
Entrya
Solvent
Temp
Time [h]
Yieldb [%]
eec [%]
trichlorosilane with 0.025 mmol of catalyst.
b
1
2
3
4
5
6
7
8
Toluene
Benzene
Et2O
THF
DMSO
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
21
21
21
22
22
21
16
16
21
16
24
48
96
11
19
NRd
88
14
74
82
43
27
74
96
93
89
4
12
d
7
1
0
81
66
81
88
92
92
92
Isolated yields.
Determined by chiral HPLC.
c
We first attempted to use L-proline with a free amine group as
a catalyst for the reduction. Treatment of imine 1a with tri-
chlorosilane in the presence of 10 mol % of proline anilide I in
CH2Cl2 at room temperature gave the corresponding aryl amine 2a
in moderate yield (58%) with moderate enantioselectivity (61% ee)
(Table 1, entry 1).
Then, the effects of an N-substituent were examined. Catalysts II
and III, which are N-substituted with Cbz and Fmoc groups, re-
spectively, afforded the product 2a in moderate yields with good
enantioselectivities (Table 1, entries 2 and 3). Catalysts V and IX
gave low yields, indicating that strong electron-withdrawing
groups, such as Troc and trichloroacetyl groups, decrease the
product yields (Table 1, entries 5 and 9). Boc, acetyl, and benzoyl
CH3CN
CH3Cl
9
ClCH2CH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
11
12
13
0
ꢀC
ꢁ20 ꢀC
ꢁ40 ꢀC
a
The reactions were performed using 0.25 mmol of imine 1a and 0.375 mmol of
trichlorosilane with 0.025 mmol of catalyst VIII.
b
Isolated yields.
Determined by chiral HPLC.
No reaction.
c
d
groups substituted -proline IV, VI, and VII afforded high yields
L
Thus, we further investigated the reaction temperature using
CH2Cl2 as the solvent. An increase in yield (96%) and enantiose-
lectivity (92% ee) was observed when the reaction temperature was
decreased to 0 ꢀC (Table 2, entry 11). Further decrease in the re-
action temperature, however, led to a decrease in yields without
decreasing the enantioselectivities (Table 2, entries 12 and 13).
With the optimal reaction condition in hand, we then examined
a variety of imines 1aeh to investigate the generality of catalyst VIII
in the asymmetric reduction. The substituent effects in the re-
duction of N-aryl imines with trichlorosilane has been reported by
other groups.7e10 To demonstrate the effect of catalyst VIII, we
examined the reduction with ordinary N-aryl imines. The results
are summarized in Table 3. The reduction of imines 1 (0.25 mmol)
with trichlorosilane (0.375 mmol) was carried out in CH2Cl2
(0.5 mL) using catalyst VIII (0.025 mmol) at 0 ꢀC for 24 h. It was
found that all results of the reactions using imines 1aeh obtained
the corresponding amines 2aeh with satisfactory yields and
enantioselectivities. When the reduction of imines 1b and 1f,
having electron-withdrawing groups, were carried out, the yields
and enantioselectivities were slightly lower (Table 3, entries 2 and
6) than those of 1a. In the case of substrates 1cee, the reactions
gave good to excellent yields (84e99%) with high enantioselectiv-
ities (90e93% ee) (Table 3, entries 3e5). The resultant amines 2cee
with high enantioselectivities (Table 1, entries 4, 6, and 7). To our
surprise, the reaction using VIII, which has a sterically hindered
pivaloyl group, proceeded smoothly to give the desired reductive
product 2a in good yield (74%) with high enantioselectivity (88% ee)
(Table 1, entry 8). In comparison, Matsumura’s N-formyl catalyst X
gave high yield, but poor enantioselectivity (Table 1, entry 10). This
result was in agreement with the literature data.6 Moreover, an
intriguing aspect is that the N-formyl catalyst X gave the (R)-con-
figured amine, whereas IeIX gave the (S)-enantiomer. These results
suggested that the reaction mechanism for the N-formyl catalyst X
are dramatically different from that of N-bulky group catalysts.
However, further evidence is required to clarify the difference.
To further improve the enantioselectivity, we focused our at-
tention on reaction conditions using N-pivaloyl- -proline VIII as the
L
catalyst. The optimization studies are summarized in Table 2. We
first investigated the reduction of imine 1a in various solvents. A
survey of solvents revealed that the reaction media had a signifi-
cant effect on the rate of the reduction process. Reactions carried
out in toluene, benzene, and DMSO gave poor yields and enantio-
selectivities (Table 2, entries 1, 2, and 5). Although N-formyl cata-
lysts afforded good reactivity in toluene in the previous reports,7,9
catalyst VIII obtained poor results in our reaction system. We
presume that the areneearene interaction of the catalyst with

T. Kanemitsu et al. / Tetrahedron 68 (2012) 3893e3898
3895
Table 3
proline anilide, which is easily prepared from
L
-proline. This method
Reduction of imines 1aeh with trichlorosilane catalyzed by VIII
provides access to optically active amines in high yields. We are
currently applying this methodology toward the preparation of
a variety of amines containing chiral building blocks.
H
N
N
O
O
4. Experimental section
4.1. General information
VIII (10 mol%)
HSiCl3 (1.5 equiv)
R3
R3
R2
N
HN
CH2Cl2
R1 R2
1a-h
∗
R1
All materials were purchased from commercial suppliers and
used without further purification. Progress of the reaction was
monitored by thin layer chromatography (TLC) performed on
Merck Art. 5715 Kieselgel 60 plate with F254/0.25 mm thickness.
Visualization was accomplished with UV light and cerium sulfate-
ammonium molybdate solution followed by heating. Column
chromatography was performed using forced flow of the indicated
solvent on basic silica gel NH-DM1020 (Fuji Silysia Chemical Ltd).
1H and 13C NMR spectra were recorded with JEOL JNM AL-400 in-
strument (400 MHz for 1H and 100 MHz for 13C) in deuterated
2a-h
24 h
Entrya R1
R2
R3
Product Yieldb eec
[%]
[%]
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
C6H5
4-BrC6H4
4-CH3OC6H4
2,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2 2e
2a
2b
2c
2d
96
81
99
87
84
78
95
90
92
86
93
91
90
84
92
92
4-NO2C6H4 CH3
4-BrC6H4
C6H5
4-CH3OC6H4
4-CH3OC6H4
2f
2g
2h
¼0.0 ppm in 1H NMR spectra)
CH3
solvent, using tetramethylsilane (
d
CH2CH3 4-CH3OC6H4
and CDCl3
(d
¼77.0 ppm in 13C NMR spectra) as internal standards.
a
1H data are reported as follows: chemical shift (
d in parts per mil-
The reactions were performed using 0.25 mmol of imine 1 and 0.375 mmol of
trichlorosilane with 0.025 mmol of catalyst VIII.
lion), multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
dd¼doublet of doublets, m¼multiplet) and coupling constant (J in
hertz). Optical rotations were measured on a JASCO P1020 polar-
imeter operating at the sodium D line at room temperature. Con-
centration is given in g/100 mL. The HPLC analyses were performed
b
Isolated yields.
Determined by chiral HPLC.
c
could be deprotected in oxidative conditions to form free ami-
nes.4c,9g,h Using 1g gave amine 2g in high yield (95%) and enan-
tioselectivity (92% ee) (Table 3, entry 7). Furthermore, high yield
(90%) and enantioselectivity (92% ee) were achieved with 1h as the
imine substrate (Table 3, entry 8). In the case of imines 1a, 1c, and
1h, catalyst VIII exhibited comparable enantioselectivity with
valine-derived catalyst by Malkov and Kocovsky or N-picolinoy-
laminoalcohol catalyst by Zhang.10b Using electron-withdrawing
group substituted imine, such as 1b, 1f, and 1g, catalyst VIII
obtained slightly lower selectivity with compared to S-chiral cata-
lyst by Sun.8 To present more detailed comparison, however, fur-
ther investigation with much broader substrate is required.
To provide an explanation to the observed stereoselectivity,
a plausible transition state model is proposed in Fig. 2. Malkov and
with Shimadzu equipment (254
l absorbance Detector) using
Daicel Chemical Industries Ltd. CHIRALCEL OD column with hex-
ane/isopropyl alcohol or hexane/ethyl alcohol solvent systems
(composition and flow rate as indicated). HPLC methods were
calibrated with the corresponding racemic mixtures. High-
resolution mass spectra (HRMS) were measured with JEOL JMS-
MS700V using p-nitrobenzyl alcohol as a matrix. The known
compounds have been identified by comparison of spectral data
with those reported. The absolute configurations of the optically
active compounds were determined on the basis of the measured
optical rotation compared with literature values.
ꢀ
ꢁ9k
ꢀ
ꢁ
Kocovsky have shown the transition state for the reduction of imines
with valine-derived catalyst.7a We proposed a transition state model
with our catalyst VIII in a similar way. The Lewis base VIII could
coordinate with trichlorosilane, thereby activating the reducing
agent in a synergistic manner. In addition, the catalyst could interact
with the substrate imine 1a to promote the asymmetric reduction.
The reaction was accelerated presumably through coordination
between the silicon atom and oxygen of the amide group and a hy-
drogen bond between the imine nitrogen and anilide hydrogen.
Consequently, the proposed interactions could result in the attack
from the Re face of the imine to give the opticallyactive amine (S)-2a.
4.2. Synthesis of L-proline-based catalyst
4.2.1. (S)-Benzyl 2-(phenylcarbamoyl)pyrrolidine-1-carboxylate
(II). To a solution of Cbz- -proline (4.0 g, 16.1 mmol) and aniline
(1465 L, 16.1 mmol) in CH2Cl2 (20 mL) was added 1-ethyl-3-(3-
L
m
dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 3230 mg,
16.9 mmol). The mixture was stirred at room temperature for 30 min.
The reaction mixture was then added to H2O and extracted with
CH2Cl2 (3ꢂ). The combined organic phases were washed with H2O,
dried over MgSO4, and concentrated in vacuo. The residue was
crystallized from CH2Cl2/hexane to give II (4944 mg, 95%) as white
crystals; mp 145e146 ꢀC; ½a D22
ꢃ
ꢁ123.6 (c 0.94, CHCl3); 1H NMR
Re-face attack
(400 MHz, CDCl3)
d
7.43e7.24 (m, 9H), 7.06 (t, J¼7.3 Hz, 1H), 5.22 (d,
J¼2.4 Hz, 1H), 5.16 (d, J¼2.7 Hz,1H), 4.47 (d, J¼5.1 Hz,1H), 3.53e3.52
(m, 2H), 2.48 (s, 1H), 2.06e1.90 (m, 3H); 13C NMR (100 MHz, CDCl3)
H
N
Cl
Cl
N
HN
d
169.5,158.2,136.4,128.9,128.6,128.2,128.0,124.8,124.2,120.0, 67.7,
H
O
61.4, 47.3, 28.0, 24.5; HR-FABMS calcd for C19H21N2O3 [MþH]þ
Si
325.1552, found 325.1547.
O
H
N
Cl
(S)-2a
4.2.2. (S)-N-Phenylpyrrolidine-2-carboxamide (I).13 A suspension of
II (520 mg, 1.6 mmol) and 10% Pd/C (85 mg) in MeOH (10 mL) was
stirred at room temperature under hydrogen atmosphere. After
20 h, the reaction mixture was filtered through a pad of Celite. The
filtrate was concentrated in vacuo. The residue was crystallized
from Et2O/hexane to give I (303 mg, 99%) as white crystals; mp
Fig. 2. Proposed transition state for the formation of 2a.
3. Conclusions
In conclusion, we have developed a highly enantioselective re-
duction of N-aryl imines with trichlorosilane catalyzed by N-pivaloyl
79e80 ꢀC; ½a 2D2
ꢃ
ꢁ71.1 (c 0.90, CHCl3); 1H NMR (400 MHz, CDCl3)
d
9.74 (s, 1H), 7.60 (d, J¼7.6 Hz, 2H), 7.32 (t, J¼7.3 Hz, 2H), 7.08

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T. Kanemitsu et al. / Tetrahedron 68 (2012) 3893e3898
(t, J¼7.3 Hz, 1H), 3.86 (dd, J¼5.4, 9.0 Hz, 1H), 3.08 (dt, J¼6.6, 10.2 Hz,
1H), 2.98 (dt, J¼6.3, 10.2 Hz, 1H), 2.26e2.17 (m, 2H), 2.08e2.00 (m,
128.8, 123.8, 119.6, 60.4, 48.5, 26.5, 25.1, 22.5; HR-FABMS calcd for
C
13H17N2O2 [MþH]þ 233.1290, found 233.1295.
1H), 1.83e1.68 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 173.3, 137.8,
128.9, 123.9, 119.2, 61.0, 47.3, 30.7, 26.3; HR-FABMS calcd for
4.2.7. (S)-1-Benzoyl-2-(phenylcarbamoyl)pyrrolidine (VII). To a so-
lution of I (227 mg, 1.19 mmol) in pyridine (2 mL) was added
C11H15N2O [MþH]þ 191.1184, found 191.1181.
benzoyl chloride (280 m
L, 2.41 mmol) at 0 ꢀC. The mixture was then
4.2.3. (S)-9H-Fluorenylmethyl 2-(phenylcarbamoyl)pyrrolidine-1-
warmed to room temperature and stirred for 1 h. The reaction
mixture was then added to H2O and extracted with CH2Cl2 (3ꢂ).
The combined organic phases were washed with H2O, dried over
MgSO4, and concentrated in vacuo. The residue was crystallized
from CH2Cl2/hexane to give VII (213 mg, 61%) as white crystals; mp
carboxylate (III). To
a
solution of Fmoc-
L-proline (500 mg,
1.48 mmol) and aniline (135
m
L, 1.48 mmol) in CH2Cl2 (5 mL) was
added EDCI (312 mg, 1.63 mmol). The mixture was stirred at room
temperature for 1 h. The reaction mixture was then added to H2O
and extracted with CH2Cl2 (3ꢂ). The combined organic phases were
washed with H2O, dried over MgSO4, and concentrated in vacuo.
The residue was crystallized from CH2Cl2/hexane to give III
198e200 ꢀC; ½a 2D3
ꢃ
ꢁ187.8 (c 0.69, CHCl3); 1H NMR (400 MHz, CDCl3)
d
9.57 (s,1H), 7.57e7.52 (m, 4H), 7.52e7.40 (m, 3H), 7.28 (t, J¼7.6 Hz,
2H), 7.06 (t, J¼7.3 Hz, 1H), 5.00 (dd, J¼5.1, 8.0 Hz, 1H), 3.61e3.48 (m,
(604 mg, 99%) as white crystals; mp 124e125 ꢀC; ½a D23
ꢁ94.2 (c 1.07,
ꢃ
2H), 2.68e2.62 (m, 1H), 2.17e2.01 (m, 2H), 1.92e1.82 (m, 1H); 13C
CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.83e6.96 (m, 13H), 4.52e4.43
NMR (100 MHz, CDCl3) d 171.8, 168.7, 138.2, 135.9, 130.4, 128.8,
(m, 3H), 4.25 (s, 1H), 3.57e3.43 (m, 2H), 2.55 (s, 1H), 2.08e1.84 (m,
128.4, 127.1, 124.0, 119.8, 60.7, 50.6, 26.4, 25.4; HR-FABMS calcd for
3H); 13C NMR (100 MHz, CDCl3)
d
172.0, 153.3, 143.6, 141.3, 138.0,
C18H19N2O2 [MþH]þ 295.1447, found 295.1461.
128.9, 127.8, 127.10, 127.07, 124.9, 124.1, 120.0, 67.9, 60.9, 47.2, 30.7,
27.3, 24.2.
4.2.8. (S)-1-Pivaloyl-2-(phenylcarbamoyl)pyrrolidine (VIII). To a so-
lution of I (200 mg, 1.05 mmol) in pyridine (2 mL) was added
4.2.4. (S)-tert-Butyl 2-(phenylcarbamoyl)pyrrolidine-1-carboxylate
pivalic anhydride (430 m
L, 2.11 mmol) at 0 ꢀC. The mixture was
(IV).14 To a solution of Boc-
L-proline (1.0 g, 4.7 mmol) and aniline
then warmed to room temperature and stirred for 1 h. The re-
action mixture was then added to H2O and extracted with CH2Cl2
(3ꢂ). The combined organic phases were washed with H2O, dried
over MgSO4, and concentrated in vacuo. The residue was crystal-
lized from CH2Cl2/hexane to give VIII (185 mg, 64%) as white
(425
mL, 4.7 mmol) in CH2Cl2 (10 mL) was added EDCI (983 mg,
5.1 mmol). The mixture was stirred at room temperature for
30 min. The reaction mixture was then added to H2O and extracted
with CH2Cl2 (3ꢂ). The combined organic phases were washed with
H2O, dried over MgSO4, and concentrated in vacuo. The residue was
crystallized from CH2Cl2/hexane to give IV (1240 mg, 92%) as white
crystals; mp 176e177 ꢀC; ½a D23
ꢃ
ꢁ124.0 (c 0.67, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
9.31 (s, 1H), 7.49 (d, J¼7.8 Hz, 2H), 7.26 (t,
crystals; mp 187e188 ꢀC; ½a D22
ꢃ
ꢁ140.9 (c 0.86, CHCl3); 1H NMR
J¼7.5 Hz, 2H), 7.04 (t, J¼7.6 Hz, 1H), 4.84 (dd, J¼2.9, 8.0 Hz, 1H),
3.79e3.67 (m, 2H), 2.46e2.39 (m, 1H), 2.25e2.14 (m, 1H),
2.03e1.94 (m, 1H), 1.90e1.81 (m, 1H), 1.30 (s, 9H); 13C NMR
(400 MHz, CDCl3)
d
7.50 (d, J¼8.0 Hz, 2H), 7.28 (t, J¼7.8 Hz, 2H), 7.06
(t, J¼7.3 Hz, 1H), 4.41 (d, J¼3.9 Hz, 1H), 3.44 (s, 2H), 2.45 (s, 1H),
2.01e1.87 (m, 3H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
170.0,
(100 MHz, CDCl3) d 178.6, 169.8, 138.3, 128.8, 123.8, 119.7, 62.4,
156.1, 138.3, 128.9, 124.1, 119.8, 80.9, 61.2, 47.3, 29.7, 28.5, 24.5; HR-
48.4, 39.3, 27.6, 25.92, 25.88; HR-FABMS calcd for C16H23N2O2
FABMS calcd for C16H23N2O3 [MþH]þ 291.1709, found 291.1710.
[MþH]þ 275.1760, found 275.1751.
4.2.5. (S)-2,2,2-Trichloroethyl 2-(phenylcarbamoyl)pyrrolidine-1-
4.2.9. (S)-1-(2,2,2-Trichloroacetyl)-2-(phenylcarbamoyl)pyrrolidine
carboxylate (V). To a solution of I (216 mg, 1.14 mmol) in pyridine
(IX). To a solution of I (205 mg, 1.08 mmol) in pyridine (2 mL) was
(2 mL) was added 2,2,2-trichloroethyl chloroformate (310
mL,
added trichloroacetyl chloride (240 m
L, 2.15 mmol) at 0 ꢀC. The
2.25 mmol) at 0 ꢀC. The mixture was then warmed to room tem-
perature and stirred for 3 h. The reaction mixture was then added
to H2O and extracted with CH2Cl2 (3ꢂ). The combined organic
phases were washed with H2O, dried over MgSO4, and concen-
trated in vacuo. The residue was crystallized from CH2Cl2/hexane to
mixture was then warmed to room temperature and stirred for
1 h. The reaction mixture was then added to H2O and extracted
with CH2Cl2 (3ꢂ). The combined organic phases were washed
with H2O, dried over MgSO4, and concentrated in vacuo. The
residue was crystallized from CH2Cl2/hexane to give IX (335 mg,
give V (283 mg, 68%) as white crystals; mp 151e152 ꢀC; ½a D23
ꢃ
ꢁ103.3
93%) as white crystals; mp 165e166 ꢀC; ½a D23
ꢁ67.8 (c 0.73, CHCl3);
ꢃ
(c 0.85, CHCl3); 1H NMR (400 MHz, CDCl3)
d
8.71 (s, 1H), 7.48 (d,
1H NMR (400 MHz, CDCl3)
d
8.41 (s, 1H), 7.49 (d, J¼7.6 Hz, 2H), 7.26
J¼7.6 Hz, 2H), 7.29 (t, J¼7.6 Hz, 2H), 7.08 (t, J¼7.6 Hz, 1H), 4.80 (s,
(t, J¼7.4 Hz, 2H), 7.07 (t, J¼7.6 Hz, 1H), 4.73 (s, 1H), 4.16e4.10 (m,
1H), 4.01e3.95 (m, 1H), 2.42e2.35 (m, 1H), 2.32e2.24 (m, 1H),
2.17e2.09 (m, 1H), 2.08e1.99 (m, 1H); 13C NMR (100 MHz, CDCl3)
2H), 4.52e4.50 (m, 1H), 3.66e3.59 (m, 2H), 2.51 (s, 1H), 2.13e1.95
(m, 3H); 13C NMR (100 MHz, CDCl3)
d 168.8, 157.0, 137.9, 129.0,
124.4, 120.0, 95.5, 75.4, 61.6, 47.5, 28.1, 24.4; HR-FABMS calcd for
d 168.3, 160.5, 137.6, 128.9, 124.4, 119.9, 92.9, 64.1, 50.4, 27.5, 25.8;
C14H16Cl3N2O3 [MþH]þ 365.0227, found 365.0273.
HR-FABMS calcd for C13H14Cl3N2O2 [MþH]þ 335.0121, found
335.0129.
4.2.6. (S)-1-Acetyl-2-(phenylcarbamoyl)pyrrolidine (VI). To a solu-
tion of I (260 mg, 1.37 mmol) in pyridine (2 mL) was added acetic
4.2.10. (S)-1-Formyl-2-(phenylcarbamoyl)pyrrolidine
(X).15 To
anhydride (260
mL, 2.75 mmol). The mixture was stirred at room
a mixture of I (135 mg, 0.71 mmol) and formic acid (1.0 mL,
temperature for 1 h. The reaction mixture was then concentrated in
vacuo. The reaction mixture was then added to H2O and extracted
with CH2Cl2 (3ꢂ). The combined organic phases were washed with
H2O, dried over MgSO4, and concentrated in vacuo. The residue was
crystallized from CH2Cl2/hexane to give VI (270 mg, 85%) as white
26.5 mmol) was added acetic anhydride (0.45 mL, 4.8 mmol) at
0
ꢀC. The mixture was stirred at 0 ꢀC for 10 min, then warmed to
room temperature and stirred for 1 h. The reaction mixture was
then concentrated in vacuo. The residue was purified by column
chromatography on silica gel with CH2Cl2/MeOH (95:5) to give
the desired product X (109 mg, 70%) as white crystals; mp
crystals; mp 175e176 ꢀC; ½a D22
ꢃ
ꢁ209.3 (c 0.93, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
9.71 (s, 1H), 7.53 (dd, J¼1.0, 8.5 Hz, 2H), 7.28 (t,
154e155 ꢀC; ½a 2D3
ꢃ
ꢁ296.7 (c 0.09, CHCl3); 1H NMR (400 MHz,
J¼8.3 Hz, 2H), 7.08 (dt, J¼1.0, 7.3 Hz, 1H), 4.79 (d, J¼7.6 Hz, 1H), 3.57
(dt, J¼2.2, 8.3 Hz, 1H), 3.45 (dt, J¼7.1, 16.8 Hz, 1H), 2.61 (dd, J¼6.6,
12.4 Hz, 1H), 2.23e2.10 (m, 1H), 2.15 (s, 3H), 2.08e1.97 (m, 1H),
CDCl3)
d
9.39 (s, 1H), 8.36 (s, 1H), 7.52 (dd, J¼1.0, 8.5 Hz, 2H), 7.30
(t, J¼7.6 Hz, 2H), 7.07 (tt, J¼1.0, 7.6 Hz, 1H), 4.71 (dd, J¼3.4, 7.8 Hz,
1H), 3.67e3.54 (m, 2H), 2.72e2.65 (m, 1H), 2.16e2.08 (m, 1H),
1.88e1.78 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
171.8, 168.7, 138.3,
2.07e1.90 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 167.9, 162.9,

T. Kanemitsu et al. / Tetrahedron 68 (2012) 3893e3898
3897
138.1, 128.9, 124.1, 119.8, 58.8, 47.1, 26.1, 24.2; HR-FABMS calcd for
CDCl3) d 171.3, 155.7, 144.8, 138.3, 130.2, 128.4, 127.5, 120.2, 114.3,
55.5, 23.2, 12.8.
C12H15N2O2 [MþH]þ 219.1134, found 219.1132.
4.3. General procedure for synthesis of imines
4.4. General procedure for reduction of imines
To a mixture of ketone (10 mmol) and amine (12 mmol) in
toluene (25 mL) was added molecular sieves 4 A (5 g) and
Imine 1 (0.25 mmol) and catalyst VIII (6.9 mg, 0.025 mmol)
ꢂ
were dissolved in dry CH2Cl2 (0.5 mL) under an argon atmosphere
p-toluenesulfonic acid monohydrate (950 mg, 5 mmol) at room
temperature. The suspension was warmed to 100 ꢀC and stirred
for 12 h. The reaction mixture was then filtered through a pad of
Celite. The filtrate was concentrated in vacuo. The residue was
purified by column chromatography on basic silica gel with
hexane/ethyl acetate (90:10) as an eluent to give the desired
product 1.
and cooled to 0 ꢀC. To the solution, trichlorosilane (38
mL,
0.375 mmol) was added and the mixture stirred at 0 ꢀC. After 24 h,
saturated NaHCO3 was added and extracted with CH2Cl2 (3ꢂ). The
combined organic phases were washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography on basic silica gel with hexane/ethyl ac-
etate as an eluent to give the desired product 2. The ee value of the
reduction product 2 was determined by chiral-phase HPLC analysis.
4.3.1. N-(1-Phenylethylidene)aniline (1a).4b,c,11 Yield 66% as yellow
crystals; mp 39e41 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.99e7.95 (m,
4.4.1. (S)-N-Phenyl-1-phenylethylamine (2a).4b,c,11,17,18 Yield 96% as
2H), 7.48e7.42 (m, 3H), 7.37e7.25 (m, 2H), 7.09 (t, J¼7.3 Hz, 1H),
a yellow syrup; ½a D18
ꢃ
þ4.5 (c 1.0, CHCl3, 92% ee); lit.4c ꢁ4.5 (c 1.05,
6.80 (dd, J¼1.0, 7.3 Hz, 2H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3)
CHCl3, 87% ee, major isomer R); 1H NMR (400 MHz, CDCl3)
d
165.5, 151.7, 139.5, 130.4, 128.9, 128.3, 127.1, 123.2, 119.4, 17.4.
d 7.36e7.27 (m, 4H), 7.22e7.18 (m, 1H), 7.10e7.05 (m, 2H), 6.63 (t,
J¼7.3 Hz,1H), 6.49 (d, J¼7.8 Hz, 2H), 4.45 (q, J¼6.8Hz,1H), 4.00 (s,1H),
4.3.2. N-(1-Phenylethylidene)-4-bromoaniline (1b).4b,16 Yield 30% as
yellow crystals; mp 69e71 ꢀC; 1H NMR (400 MHz, CDCl3)
1.48 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 146.1, 144.6, 131.7,
128.7, 127.0, 125.7, 144.9, 108.8, 53.5, 24.9; HPLC (Daicel CHRALCEL
d
7.97e7.94 (m, 2H), 7.47e7.45 (m, 5H), 6.70e6.66 (m, 2H), 2.23 (s,
OD, hexane/iPrOH¼9/1, flow rate 1.0 mL/min,
¼254 nm): major
l
3H); 13C NMR (100 MHz, CDCl3)
128.4, 127.2, 121.2, 116.1, 17.4.
d
166.2, 150.6, 139.1, 132.0, 130.7,
isomer (S isomer): tR¼6.0 min; minor isomer (R isomer): tR¼7.5 min;
HR-FABMS calcd for C14H15N [M]þ 197.1204, found 197.1214.
4.3.3. N-(1-Phenylethylidene)-4-methoxyaniline (1c).4b,c,11,16 Yield
72% as yellow crystals; mp 87e88 ꢀC; 1H NMR (400 MHz, CDCl3)
4 . 4 . 2 . ( ꢁ) - N - ( 4 - B r o m o p h e n yl ) - 1 - p h e n yl e t h y l a m i n e
(2b).4b,17,18 Yield 81% as white crystals; mp 65e68 ꢀC; ½a 1D8
ꢁ15.0 (c
ꢃ
d
7.97e7.95 (m, 2H), 7.46e7.43 (m, 3H), 6.92e6.90 (m, 2H),
6.77e6.74 (m, 2H), 3.82 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz,
CDCl3) 165.7, 155.9, 144.8, 139.7, 130.3, 128.3, 127.1, 120.7, 114.2,
55.5, 17.3.
0.7, CHCl3, 86% ee); lit.17 þ7.6 (c 0.53, CHCl3, 97% ee, absolute con-
figuration not determined but assumed to be R isomer in analogy
with other compounds prepared); 1H NMR (400 MHz, CDCl3)
d
d
7.33e7.30 (m, 3H), 7.24e7.21 (m,1H), 7.16e7.12 (m, 2H), 6.38e6.35
(m, 2H), 4.42 (q, J¼6.6 Hz, 1H), 4.06 (s, 1H), 1.50 (d, J¼6.6 Hz, 3H);
13C NMR (100 MHz, CDCl3)
146.1, 144.6, 131.7, 128.7, 127.0, 125.7,
4.3.4. N-(1-Phenylethylidene)-2,4-dimethoxyaniline (1d). Yield 47%
as a colorless syrup; 1H NMR (400 MHz, CDCl3)
7.99e7.97 (m, 2H),
d
d
144.9, 108.8, 53.5, 24.9; HPLC (Daicel CHRALCEL OD,
7.44e7.40 (m, 3H), 6.69 (d, J¼8.5 Hz,1H), 6.54 (d, J¼2.7 Hz, 1H), 6.50
hexane/iPrOH¼9/1, flow rate 1.0 mL/min,
¼254 nm): minor iso-
l
(dd, J¼2.7, 8.5 Hz,1H), 3.80 (s, 3H), 3.75 (s, 6H), 2.17 (s, 3H); 13C NMR
mer: tR¼6.7 min; major isomer: tR¼8.0 min; HR-FABMS calcd for
(100 MHz, CDCl3)
d
167.3, 156.9, 149.9, 139.7, 134.0, 130.2, 128.2,
C14H14BrN [M]þ 275.0310, found 275.0309.
127.2, 120.8, 104.2, 99.6, 55.6, 55.4, 17.6.
4. 4 . 3. ( S ) - N - ( 4 - M e t h ox y p h e nyl) - 1 - p h e nyl e t hyl a min e
4.3.5. N-(1-Phenylethylidene)-3,4,5-trimethoxyaniline (1e).4c Yield
38% as yellow crystals; mp 83e85 ꢀC; 1H NMR (400 MHz, CDCl3)
(2c).4b,c,11,17,18 Yield 99% as a yellow syrup; ½a 1D8
ꢁ4.0 (c 0.7, CHCl3,
ꢃ
93% ee); lit.11 ꢁ5.6 (c 0.54, CHCl3, 87% ee, major isomer S); 1H NMR
d
7.98e7.96 (m, 2H), 7.48e7.43 (m, 3H), 6.04 (s, 2H), 3.85
(s, 3H), 3.84 (s, 6H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3)
166.1, 153.6, 147.9, 139.2, 133.8, 130.6, 128.4, 127.1, 96.6, 61.0,
(400 MHz, CDCl3) d 7.37e7.35 (m, 4H), 7.32e7.19 (m, 1H), 6.71e6.67
(m, 2H), 6.49e6.45 (m, 2H), 4.41 (q, J¼6.8 Hz,1H), 3.69 (s, 3H),1.49 (d,
d
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 151.9, 145.5, 141.5, 128.6,
126.8,125.9,114.7,114.5, 55.7, 54.3, 25.1; HPLC (Daicel CHRALCEL OD,
56.1, 17.5.
hexane/iPrOH¼9/1, flow rate 1.0 mL/min,
¼254 nm): minor isomer
l
4.3.6. N-(1-(4-Nitrophenyl)ethylidene)-4-methoxyaniline
(R isomer): tR¼6.7 min; major isomer (S isomer): tR¼7.2 min; HR-
(1f).11 Yield 80% as yellow crystals; mp 95e97 ꢀC; 1H NMR
FABMS calcd for C15H17NO [M]þ 227.1310, found 227.1304.
(400 MHz, CDCl3)
6.96e6.92 (m, 2H), 6.81e6.77 (m, 2H), 3.83 (s, 3H), 2.33 (s, 3H); 13C
NMR (100 MHz, CDCl3) 163.6, 156.5, 148.8, 145.2, 143.7, 128.1,
d 8.31e8.27 (m, 2H), 8.15e8.12 (m, 2H),
4.4.4. (þ)-N-(2,4-Dimethoxyphenyl)-1-phenylethylamine
d
(2d). Yield 87% as yellow crystals; mp 51e54 ꢀC; ½a D18
þ11.8 (c 0.9,
ꢃ
123.5, 120.8, 114.3, 55.5, 17.5.
CHCl3, 91% ee); 1H NMR (400 MHz, CDCl3)
d 7.37e7.30 (m, 4H),
7.24e7.18 (m, 1H), 6.43 (d, J¼1.5 Hz, 1H), 6.23 (m, 2H), 4.40 (q,
4.3.7. N-(1-(4-Bromophenyl)ethylidene)-4-methoxyaniline
J¼6.8 Hz, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 1.52 (d, J¼6.8 Hz, 3H); 13C
(1g). Yield 57% as yellow crystals; mp 110e112 ꢀC; 1H NMR
NMR (100 MHz, CDCl3) d 151.6,147.6,145.7,131.6,128.5, 126.7, 125.8,
(400 MHz, CDCl3)
(m, 2H), 6.76e6.72 (m, 2H), 3.81 (s, 3H), 2.22 (s, 3H); 13C NMR
(100 MHz, CDCl3) 164.5, 156.1, 144.3, 138.5, 131.4, 128.7, 124.9,
120.7, 114.2, 55.4, 17.1.
d
7.85e7.80 (m, 2H), 7.57e7.34 (m, 2H), 6.92e6.89
111.2, 103.6, 99.0, 55.7, 55.5, 53.9, 25.2; HPLC (Daicel CHRALCEL OD,
hexane/iPrOH¼9/1, flow rate 1.0 mL/min,
¼254 nm): minor iso-
l
d
mer: tR¼5.4 min; major isomer: tR¼6.2 min; HR-FABMS calcd for
C16H19NO2 [M]þ 257.1416, found 257.1416.
4.3.8. N-(1-Phenylpropylidene)-4-methoxyaniline (1h).11 Yield 63%
as a colorless syrup; 1H NMR (400 MHz, CDCl3)
7.92e7.89 (m, 2H),
7.46e7.43 (m, 3H), 6.93e6.89 (m, 2H), 6.76e6.72 (m, 2H), 3.82 (s,
3H), 2.68 (q, J¼7.6 Hz, 2H),1.08 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz,
4.4.5. (þ)-N-(3,4,5-Trimethoxyphenyl)-1-phenylethylamine
d
(2e).4c Yield 84% as a yellow syrup; ½a 1D8
þ18.5 (c 0.8, CHCl3, 90%
ꢃ
ee); lit.4c ꢁ21.0 (c 1.09, CHCl3, 99% ee, absolute configuration was
not determined); 1H NMR (400 MHz, CDCl3)
d 7.39e7.31 (m, 4H),

3898
T. Kanemitsu et al. / Tetrahedron 68 (2012) 3893e3898
3029e3069; (c) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.;
Studer, M. Adv. Synth. Catal. 2003, 345, 103e151; (d) Nugent, T. C.; El-Shazly, M.
Adv. Synth. Catal. 2010, 352, 753e819; (e) Nugent, T. C. Chiral Amine Synthesis:
Methods, Developments and Applications; Wiley-VCH: Weinheim, Germany,
2010; (f) Kocovsky, P.; Malkov, A. V. Chiral Lewis Bases as Catalysts In Enan-
tioselective Organocatalysis: Reactions and Experimental Procedures; Dalko, P. I.,
Ed.; Wiley-VCH: Weinheim, Germany, 2007; p 255.
7.25e7.21 (m, 1H), 5.76 (s, 2H), 4.43 (q, J¼6.6 Hz, 1H), 3.71 (s, 3H),
3.68 (s, 6H), 1.52 (d, J¼6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
153.7, 145.3, 143.9, 128.7, 128.3, 127.0, 125.8, 91.0, 61.0, 55.7, 54.2,
ꢀ
ꢁ
24.9; HPLC (Daicel CHRALCEL OD, hexane/EtOH¼9/1, flow rate
0.5 mL/min,
l
¼254 nm): minor isomer: tR¼22.5 min; major isomer:
tR¼24.1 min; HR-FABMS calcd for C17H22NO3 [MþH]þ 288.1600,
3. For recent reviews of metal-catalyzed hydrogenation of imine, see: (a) Fleury-
ꢁ
ꢁ
Bregeot, N.; de la Fuente, V.; Castillon, S.; Claver, C. ChemCatChem 2010, 2,
1346e1371; (b) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev. 2011, 111, 1713e1760.
4. For recent examples of transition-metal catalyzed reduction of imine, see: (a)
Li, W.; Hou, G.; Chang, M.; Zhang, X. Adv. Synth. Catal. 2009, 351, 3123e3127; (b)
Han, Z.; Wang, Z.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2009, 48,
found 288.1610.
4.4.6. (S)-N-(4-Methoxyphenyl)-1-(4-nitrophenyl)ethylamine
(2f).11,17,18 Yield 78% as yellow crystals; mp 65e68 ꢀC; ½a 1D8
ꢁ27.9 (c
ꢃ
0.9, CHCl3, 84% ee); lit.11 ꢁ25.9 (c 0.54, CHCl3, 86% ee, major isomer
ꢀ ꢁ
5345e5349; (c) Mrsic, N.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. J. Am.
Chem. Soc. 2009, 131, 8358e8359; (d) Steinhuebel, D.; Sun, Y.; Matsumura, K.;
Sayo, N.; Saito, T. J. Am. Chem. Soc. 2009, 131, 11316e11317; (e) Geng, H.; Zhang,
W.; Chen, J.; Hou, G.; Zhou, L.; Zou, Y.; Wu, W.; Zhang, X. Angew. Chem., Int. Ed.
2009, 48, 6052e6054; (f) Baeza, A.; Pfaltz, A. Chem.dEur. J. 2010, 16,
4003e4009; (g) Lyubimov, S. E.; Rastorguev, E. A.; Petrovskii, P. V.; Kelbysheva,
E. S.; Loim, N. M.; Davankov, V. A. Tetrahedron Lett. 2011, 52, 1395e1397; (h)
S); 1H NMR (400 MHz, CDCl3)
d 8.19e8.16 (m, 2H), 7.56e7.52 (m,
2H), 6.71e6.67 (m, 2H), 6.42e6.38 (m, 2H), 4.50 (q, J¼6.8 Hz, 1H),
3.69 (s, 3H), 1.52 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
153.4, 152.3, 147.0, 140.7, 126.7, 124.0, 114.8, 114.5, 55.7, 54.0, 25.0;
HPLC (Daicel CHRALCEL OD, hexane/iPrOH¼9/1, flow rate 1.0 mL/
ꢀ ꢁ
Mrsic, N.; Panella, L.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. Tetrahedron:
Asymmetry 2011, 22, 36e39; (i) Zhao, Y.; Huang, H.; Shao, J.; Xia, C. Tetrahedron:
Asymmetry 2011, 22, 769e774; (j) Zhou, S.; Fleischer, S.; Junge, K.; Beller, M.
Angew. Chem., Int. Ed. 2011, 50, 5120e5124; (k) Perron, Q.; Alexakis, A. Tetra-
min,
l¼254 nm): minor isomer (R isomer): tR¼19.7 min; major
isomer (S isomer): tR¼23.2 min; HR-FABMS calcd for C15H16N2O3
[M]þ 272.1161, found 272.1176.
ꢁ
hedron: Asymmetry 2008, 19, 1871e1874; (l) Mrsic, N.; Panella, L.; IJpeij, E. G.;
Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. ChemCatChem 2011, 3, 1139e1142;
(m) Trifonova, A.; Diesen, J. S.; Andersson, P. G. Chem.dEur. J. 2006, 12,
2318e2328.
5. (a) Orito, Y.; Nakajima, M. Synthesis 2006, 1391e1401; (b) Guizzetti, S.; Benaglia,
M. Eur. J. Org. Chem. 2010, 5529e5541.
4.4.7. (ꢁ)-N-(4-Methoxyphenyl)-1-(4-bromophenyl)ethylamine
a 18
(2g).18 Yield 95% as a yellow syrup; ½ ꢃD ꢁ22.7 (c 1.0, CHCl3, 92% ee);
1H NMR (400 MHz, CDCl3)
d 7.44e7.41 (m, 2H), 7.25e7.22 (m, 2H),
6. Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.; Maki, T.; Matsumura, Y.
Tetrahedron Lett. 2001, 42, 2525e2527.
6.71e6.67 (m, 2H), 6.45e6.41 (m, 2H), 4.35 (q, J¼6.8 Hz, 1H), 3.67 (s,
3H),1.46 (d, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 152.0,144.6,
ꢀ
ꢁ
7. (a) Malkov, A. V.; Mariani, A.; MacDougall, K. N.; Kocovsky, P. Org. Lett. 2004, 6,
ꢀ
141.1, 131.7, 127.7, 120.4, 114.7, 114.5, 55.7, 53.8, 25.1; HPLC (Daicel
2253e2256; (b) Malkov, A. V.; Stoncius, S.; MacDougall, K. N.; Mariani, A.;
McGeoch, G. D.; Kocovsky, P. Tetrahedron 2006, 62, 264e284.
CHRALCEL OD, hexane/iPrOH¼9/1, flow rate 1.0 mL/min,
l¼254 nm):
ꢀ
ꢁ
8. (a) Pei, D.; Wang, Z.; Wei, S.; Zhang, Y.; Sun, J. Org. Lett. 2006, 8, 5913e5915; (b)
Pei, D.; Zhang, Y.; Wei, S.; Wang, M.; Sun, J. Adv. Synth. Catal. 2008, 350,
619e623; (c) Wang, C.; Wu, X.; Zhou, L.; Sun, J. Chem.dEur. J. 2008, 14,
8789e8792; (d) Wu, X.; Li, Y.; Wang, C.; Zhou, L.; Lu, X.; Sun, J. Chem.dEur. J.
2011, 17, 2846e2848.
9. For examples of chiral N-formyl catalysts, see Refs. 6 and 7 and the following:
(a) Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett. 2006, 8,
999e1001; (b) Wang, Z.; Cheng, M.; Wu, P.; Wei, S.; Sun, J. Org. Lett. 2006, 8,
3045e3048; (c) Zhou, L.; Wang, Z.; Wei, S.; Sun, J. Chem. Commun. 2007,
minor isomer: tR¼8.4 min; major isomer: tR¼9.9 min; HR-FABMS
calcd for C15H17BrNO [MþH]þ 306.0494, found 306.0498.
4.4.8. (ꢁ)-N-(4-Methoxyphenyl)-1-phenylpropylamine
(2h).11,18 Yield 90%asayellowsyrup;½a 1D7
ꢁ25.2 (c1.2, CHCl3, 92%ee);
ꢃ
lit.11 ꢁ26.9 (c 1.0, CHCl3, 84% ee, absolute configuration was not de-
termined); 1H NMR (400 MHz, CDCl3)
d 7.34e7.19 (m, 5H), 6.69e6.65
ꢀ
ꢀ
ꢁ
2977e2979; (d) Malkov, A. V.; Figlus, M.; Stoncius, S.; Kocovsky, P. J. Org. Chem.
(m, 2H), 6.49e6.45 (m, 2H), 4.14 (t, J¼6.5 Hz, 1H), 3.68 (s, 3H),
ꢀ
ꢀ
ꢁ
2007, 72, 1315e1325; (e) Malkov, A. V.; Stoncius, S.; Kocovsky, P. Angew. Chem.,
Int. Ed. 2007, 46, 3722e3724; (f) Baudequin, C.; Chaturvedi, D.; Tsogoeva, S. B.
Eur. J. Org. Chem. 2007, 2623e2629; (g) Wu, P.; Wang, Z.; Cheng, M.; Zhou, L.;
1.89e1.72 (m, 2H), 0.94 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
151.8,144.1,141.7,128.4,126.8,126.5,114.7,114.5, 60.6, 55.7, 31.6,10.8;
ꢀ
Sun, J. Tetrahedron 2008, 64, 11304e11312; (h) Malkov, A. V.; Stoncius, S.;
HPLC (Daicel CHRALCEL OD, hexane/iPrOH¼9/1, flow rate 0.5 mL/min,
ꢀ
ꢁ
Vrankov$, K.; Arndt, M.; Kocovsky, P. Chem.dEur. J. 2008, 14, 8082e8085; (i)
Zhang, Z.; Rooshenas, P.; Hausmann, H.; Schreiner, P. R. Synthesis 2009,
1531e1544; (j) Malkov, A. V.; Figlus, M.; Cooke, G.; Caldwell, S. T.; Rabani, G.;
Prestly, M. R.; Kocovsky, P. Org. Biomol. Chem. 2009, 7, 1878e1883; (k) Malkov,
A. V.; Vrankov$, K.; Stoncius, S.; Kocovsky, P. J. Org. Chem. 2009, 74, 5839e5849;
l
¼254 nm): minor isomer: tR¼11.5 min; major isomer: tR¼12.3 min;
HR-FABMS calcd for C16H19NO [M]þ 241.1467, found 241.1456.
ꢀ
ꢁ
ꢀ
ꢀ
ꢁ
ꢀ
ꢁ
(l) Malkov, A. V.; Figlus, M.; Prestly, M. R.; Rabani, G.; Cooke, G.; Kocovsky, P.
Acknowledgements
Chem.dEur. J. 2009, 15, 9651e9654; (m) Malkov, A. V.; Vrankov$, K.; Sigerson,
ꢀ
ꢀ
ꢁ
R. C.; Stoncius, S.; Kocovsky, P. Tetrahedron 2009, 65, 9481e9486; (n) Figlus, M.;
This work was supported in part by a Grant for the High-Tech
Research Center Project from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
ꢀ
ꢁ
Caldwell, S. T.; Walas, D.; Yesilbag, G.; Cooke, G.; Kocovsky, P.; Malkov, A. V.;
Sanyal, A. Org. Biomol. Chem. 2010, 8, 137e141.
10. For examples of chiral N-picolinoyl catalysts, see: (a) Onomura, O.; Kouchi, Y.;
Iwasaki, F.; Matsumura, Y. Tetrahedron Lett. 2006, 47, 3751e3754; (b) Zheng, H.;
Deng, J.; Lin, W.; Zhang, X. Tetrahedron Lett. 2007, 48, 7934e7937; (c) Guizzetti,
S.; Benaglia, M.; Cozzi, F.; Annunziata, R. Tetrahedron 2009, 65, 6354e6363; (d)
Guizzetti, S.; Benaglia, M.; Celentano, G. Eur. J. Org. Chem. 2009, 3683e3687; (e)
Xue, Z.-Y.; Jiang, Y.; Peng, X.-Z.; Yuan, W.-C.; Zhang, X.-M. Adv. Synth. Catal.
2010, 352, 2123e2136.
11. Gautier, F.-M.; Jones, S.; Martin, S. J. Org. Biomol. Chem. 2009, 7, 229e231.
12. Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407e408.
13. Moorthy, J. N.; Saha, S. Eur. J. Org. Chem. 2009, 739e748.
14. Doherty, S.; Knight, J. G.; McRae, A.; Harrington, R. W.; Clegg, W. Eur. J. Org.
Chem. 2008, 1759e1766.
Supplementary data
1H and 13C NMR spectra for reduction products, and HPLC
chromatograms for all results in Table 3. Supplementary data re-
lated to this article can be found online at doi:10.1016/
j.tet.2012.03.035.
15. Wen, Y.; Xiong, Y.; Chang, L.; Huang, J.; Liu, X.; Feng, X. J. Org. Chem. 2007, 72,
7715e7719.
16. Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C. Chem.dEur. J. 2004, 10,
References and notes
ꢁ
494e507.
1. Cho, B. T. Tetrahedron 2006, 62, 7621e7643.
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18. Li, C.; Villa-Marcos, B.; Xiao, J. J. Am. Chem. Soc. 2009, 131, 6967e6969.
2. For recent reviews of synthesis of chiral amines, see: (a) Kobayashi, S.; Ishitani,
H. Chem. Rev. 1999, 99, 1069e1094; (b) Tang, W.; Zhang, X. Chem. Rev. 2003, 103,