Novel carbohydrate-derived pyridinecarboxylic organocatalysts for the enantioselective reduction of imines with trichlorosilane

Article abstract of DOI:10.1016/j.tetasy.2014.03.015

A new type of carbohydrate-derived pyridinecarboxylic organocatalyst was prepared by fine-tuning a d-glucosamine backbone at the C-2 and C-3 positions. The carbohydrate-derived pyridinecarboxylic organocatalyst was used for the enantioselective reduction of imines with trichlorosilane. The reduction proceeded in high yield (up to 93%) and with moderate enantioselectivity (up to 75%).

Full text of DOI:10.1016/j.tetasy.2014.03.015

Tetrahedron: Asymmetry 25 (2014) 596–601
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Novel carbohydrate-derived pyridinecarboxylic organocatalysts
for the enantioselective reduction of imines with trichlorosilane
a
a,b
Xin Ge a,b, Chao Qian a,b, , Yunbin Chen , Xinzhi Chen
⇑
a Department of Chemical and Biological Engineering, Zhejiang University, PR China
b Key Laboratory of Biomass Chemical Engineering of Ministry of Education, Zhejiang University, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new type of carbohydrate-derived pyridinecarboxylic organocatalyst was prepared by fine-tuning a
Received 15 December 2013
Revised 18 March 2014
Accepted 19 March 2014
D
-glucosamine backbone at the C-2 and C-3 positions. The carbohydrate-derived pyridinecarboxylic
organocatalyst was used for the enantioselective reduction of imines with trichlorosilane. The reduction
proceeded in high yield (up to 93%) and with moderate enantioselectivity (up to 75%).
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
stereodifferentiating groups.8 In 2007, Kunz et al. reported on
D-glucosamine-derived bifunctional urea Schiff base organocata-
The enantioselective reduction of imines is an attractive ap-
proach for preparing chiral amines, which have a wide application
in the pharmaceutical and fine chemical industry.1 In addition to
hydrogenation by the transition metal-catalyzed reduction,1,2 an
organocatalytic approach is a promising alternative method to ob-
tain chiral amine production. A Lewis-basic organocatalytic ap-
proach with trichlorosilane reduction has been developed and
this can complement Bronsted acid organocatalysis based on
biomimetic reduction with a Hantzsch ester.3 Matsumura et al. re-
lysts for enantioselective Streck and Mannich reactions.7b Subse-
quently, Machinami et al. found that aqueous asymmetric aldol
reactions could be catalyzed by enanine-based carbohydrates.7e
Highly enantioselective Michael additions of aromatic ketones
with nitroolefins promoted by carbohydrate-derived bifunctional
primary amine-thiourea catalysts were reported by Ma and Liu.7c
In 2011, our research group described that carbohydrate-derived
amino alcohols can catalyze the asymmetric aldol reaction of ke-
tones with isatins in high yield and with moderate enantioselcetiv-
ity.9 We also reported novel carbohydrate-derived prolinamides to
catalyze asymmeteric aldol reactions in high yield, excellent
enantioselectivity, and diastereoselectivity.10
ported that N-formyl-L L-pyrrol-
-proline anilide3a and N-picolinoyl-
idine4 catalyzed the reduction of imines with trichlorosilane with
moderate enantioselectivity. Later, Malkov and Kocovsky found
that N-formyl-L-valine derived Lewis-basic organocatalysts can
Following our interests in carbohydrates9–11 to develop novel
organocatalysts for asymmeteric reactions, we herein report carbo-
hydrate-derived pyridinecarboxylic organocatalysts for the enan-
tioselective reduction of imines with trichlorosilane.
significantly improve the enantioselectivity.3c N-Formyl and N-
picolinoyl chiral amino acid-based organocatalysts have also been
considered to be important organocatalysts for the reduction of
imines.3a,b,e,f,4,5 Sun et al. developed S-chiral catalysts to reduce
imines with high enantioselectivity.6 Asymmetric organocatalysis
has received much attention as an environmentally friendly ap-
proach for the preparation of enantiomerically pure organic com-
pounds. Thus, the design of new and effective organocatalysts for
asymmetric synthesis is both challenging and important.
2. Results and discussion
Initially, we screened various carbohydrate-derivatives (Fig. 1)
as organocatalysts for the reduction of imines with trichlorosilane.
The results of the catalyst screening and optimizations are shown
in Table 1.
We first attempted to use carbohydrate-derived amino alcohols
1a and 1b as catalysts and obtained moderate yields at room
temperature, but the ee values were low (Table 1, entries 1–2).
Carbohydrate-derived acetamide alcohols 2a and 2b also failed to
catalyze the enantioselective reduction (Table 1, entries 3–4).
Carbohydrate-derived amino alcohols and carbohydrate-derived
acetamide alcohols did not catalyze the enantioselective reduction
Due to the high density of chiral information on the backbone
and a number of functional groups useful for variation and
optimization, carbohydrates have been intensively used in asym-
metric organic synthesis.7 The design and fine-tuning of carbohy-
drate-derived catalysts is facilitated by introducing additional
⇑
Corresponding author. Tel./fax: +86 571 87951615.
E-mail addresses: Qianchao@zju.edu.cn, chemtec@163.com (C. Qian).
http://dx.doi.org/10.1016/j.tetasy.2014.03.015
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

X. Ge et al. / Tetrahedron: Asymmetry 25 (2014) 596–601
597
O
Ph
O
O
O
O
O
OR1
O
Ph
O
Ph
O
OR1
NH2
O
OR1
O
HO
HN
HO
HO
HN
N
1a: R1 = Bn
1b:
1 = Bn
2b: R1 = CH3
2a:
3a: R1 = Bn
3b:
R
R
1 = CH3
R
1 = CH3
O
O
O
O
Ph
O
Ph
O
OBn
O
OR1
O
O
O
O
HN
O
HN
N
N
N
4a: R1 = Bn
5
4b: R1 = CH3
Figure 1. Structures of various carbohydrate-derived organocatalysts evaluated herein.
Table 1
product with 93% yield and with 51% ee (Table 1, entry 9). Thus,
we further investigated the reaction temperature using dichloro-
methane as the solvent. The best yield was obtained at room tem-
perature (Table 1, entry 9). However the best enantioselectivity
was observed when the reaction temperature was decreased to
0 °C (Table 1, entry 13). A further temperature decrease led to a
reduction in yield without any obvious increase in the enantiose-
lectivity (Table 1, entry 14). Based on the above results, we selected
0 °C as the best reaction temperature.
Having established the optimal reaction conditions, the sub-
strate scope for the enantioselective reduction of imines with tri-
chlorosilane was explored further. A range of N-aryl imines were
reduced with SiHCl3 in the presence of 10 mol % catalyst in dichlo-
romethane at 0 °C. The results are summarized in Table 2. It was
found that the results for the reduction of imines 6b–6l were
similar to imine 6a, with satisfactory yields and moderate enanti-
oselectivities being obtained (53–93% yield, 51–75% ee, entries
1–15). Moreover, imines 6m–6o with an ethyl group were found
Asymmetric reduction of ketimine 6aa
Ph
N
Ph
HN
SiHCl3
catalyst
Ph
Ph
*
7a
6a
Entry Catalyst Solvent
Temp (°C) Yieldb (%) eec (%) Configd
1
2
3
4
5
6
7
8
1a
1b
2a
2b
3a
3b
4a
4b
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Benzene
CH3Cl
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
74
63
67
61
0
0
0
0
—
—
—
—
88 ꢀ38
(R)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
73 ꢀ21
74
69
93
13
74
86
89
63
26
23
51
5
43
44
62
65
9
10
11
12
13
14
5
5
5
5
5
ClCH2CH2Cl
CH2Cl2
CH2Cl2
ꢀ20
Table 2
Asymmetric reduction of ketimine 6 with catalyst 5a
a
The reactions were carried out with 10 mol % catalyst and 2.0 equiv of SiHCl3 on
R2
R2
R3
a 0.5 mmol scale in 2.0 mL of solvent for 24 h.
SiHCl3, CH2Cl2, 0oC
N
HN
b
Isolated yield based on the imine.
Determined by chiral HPLC.
The absolute configuration was determined by comparison of the specific
c
R1
R1
R3
10% catalyst 5
d
*
rotation with that in the literature.3e
6
7
Entry
Imine
R1
R2
R3
Yieldb (%)
eec (%)
of imines with trichlorosilane. Thus it was necessary to fine-tune
carbohydrate-derivatives by introducing additional groups. Picoli-
noyl has been considered to be an important group in organocata-
lysts for the reduction of imines.4,5 Carbohydrate-derived pyridine
formamides 3a and 3b, which catalyze enantioselective reductions
and improve yields and ee values for the (R)-enantiomer (Table 1,
entries 5–6), were prepared by introducing a picolinoyl group.
When carbohydrate-derived organocatalysts 4a and 4b were used
for this reduction, the (S)-enantiomer was obtained, affording 26%
ee and 23% ee separately (Table 1, entries 7–8). Encouraged by
these preliminary results, we continued to optimize carbohy-
drate-derivatives and prepared organocatalyst 5, which increased
the ee value for the (S)-enantiomer to 51% (Table 1, entry 9).
We next selected catalyst 5 for further studies, and the optimi-
zation of the reaction conditions was examined. The effect of sol-
vent was first investigated (Table 1, entries 9–12). It was found
that dichloromethane was the best solvent and afforded the
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-FC6H4
4-ClC6H4
4-NO2C6H4
4-CH3C6H4
C6H5
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
89
72
93
67
92
74
72
53
79
76
81
92
86
77
87
62
65
59
51
67
61
57
59
60
67
63
68
71
75
72
4-FC6H4
2-CH3C6H4
4-ClC6H4
4-CH3C6H4
3-ClC6H4
3-BrC6H4
C6H4CH2
C6H5
9
10
11
12
13
14
15
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-ClC6H4
4-CH3C6H4
Et
Et
a
The reactions were carried out with 10 mol % catalyst and 2.0 equiv of SiHCl3 on
a 0.5 mmol scale in 2.0 mL of solvent for 24 h.
b
Isolated yield based on the imine.
Determined by chiral HPLC.
c

598
X. Ge et al. / Tetrahedron: Asymmetry 25 (2014) 596–601
O
O
O
O
O
O
OR
H-bonding
OR
H-bonding
N
O
N
O
H
H
O
Cl
O
N
O
Cl
O
N
Si
Cl
Cl
Si
N
Cl
Cl
H
N
arene-arene
stacking
H
(S)
(R)
Figure 2. A proposed mechanism for the imine reduction catalyzed by 5.
to be good substrates for organocatalyst 5, affording 77–87% yield
and 71–75% ee. When imines with electron-withdrawing groups
were reduced, the yield decreased. The electronic effect on the
enantioselectivity was probed by substitution of the phenyl ring
with electron-donating and electron-withdrawing groups and
was found to be negligible.
We have proposed a mechanism, which is shown in Figure 2. It
can be seen that the enantioselective reduction of imines with tri-
chlorosilane is catalyzed by the carbohydrate-derived pyridine-
carboxylic organocatalyst 5. Organocatalyst 5 could coordinate
with trichlorosilane via the nitrogen atom of the pyridine ring
and the carbonyl oxygen atom. The imine is activated by a hydro-
gen bond of the amide group. Consequently, the proposed arene–
arene interactions between the pyridine of the catalyst and the
benzene ring of the substrate aid the catalyst assembly with the
reaction partners, leading to the (S)-enantiomer, being favoured.
This is similar to the transition state proposed by Zhang et al.5b
4.2.1. Benzyl-4,6-O-benzylidene-2-amino-2-deoxy-a-D-glucopy-
ranoside 1a
White solid. Mp 172.4–173.8 °C. ½a D20
¼ þ59:7 (c 1.05, CHCl3).
ꢁ
1H NMR (400 MHz, CDCl3) d 7.80–6.91 (m, 10H), 5.53 (s, 1H),
4.90 (d, J = 3.6 Hz, 1H), 4.75 (d, J = 11.7 Hz, 1H), 4.52 (d,
J = 11.8 Hz, 1H), 4.24 (dd, J = 10.1, 4.8 Hz, 1H), 3.88 (td, J = 9.9,
4.8 Hz, 1H), 3.83–3.66 (m, 2H), 3.49 (t, J = 9.3 Hz, 1H), 2.81 (dd,
J = 9.7, 3.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 137.86, 137.67,
128.97, 128.42, 128.06, 127.89, 127.76, 126.62, 101.47, 99.58,
82.08, 71.70, 69.33, 68.74, 63.30, 57.06. Anal. Calcd (%) for
C20H23NO5: C, 67.21; H, 6.49; N, 3.92; O, 22.38. Found: C, 67.12;
H, 6.32; N, 3.81.
4.2.2. Methyl-4,6-O-benzylidene-2-amino-2-deoxy-a-D-glucopy-
ranoside 1b
White solid. Mp 166–167 °C; ½a D20
ꢁ
¼ þ103:1 (c 0.905, CHCl3). 1H
NMR (400 MHz, CDCl3) d 7.47–7.41 (m, 2H), 7.41–7.35 (m, 3H),
5.61 (s, 1H), 4.62 (d, J = 3.6 Hz, 1H), 4.18 (dd, J = 9.9, 4.8 Hz, 1H),
3.76 3.56 (m, 3H), 3.48 (t, J = 9.2 Hz, 1H), 3.29 (s, 3H), 2.81 (dd,
J = 9.7, 3.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 142.99, 134.09,
133.24, 131.63, 106.13, 103.97, 87.27, 73.27, 72.63, 67.68, 59.96,
59.35. Anal. Calcd (%) for C14H19NO5: C, 59.78; H, 6.81; N, 4.98;
O, 28.44. Found: C, 59.764; H, 6.75; N, 4.81.
3. Conclusion
In conclusion, we have described a new type of carbohydrate-
derived pyridinecarboxylic organocatalyst for the enantioselective
reduction of imines with trichlorosilane, which were constructed
from commercial D-glucosamine as an inexpensive natural chiral
4.2.3. Benzyl-4,6-O-benzylidene-2-acetylamino-2-deoxy-a-D-
pool starting material. The fine-tuning of carbohydrate-derived
catalysts was carried out by introducing pyridinecarboxylic groups.
We also screened the reaction conditions and proposed a plausible
mechanism.
glucopyranoside 2a
White solid. Mp 189–192 °C; ½a D20
ꢁ
¼ þ56 (c 0.21, MeOH); 1H
NMR (400 MHz, DMSO) d 8.00 (d, J = 8.2 Hz, 1H), 7.49–7.43 (m,
2H), 7.42–7.33 (m, 7H), 7.30 (ddd, J = 8.4, 3.6, 1.8 Hz, 1H), 5.62 (s,
1H), 5.19 (d, J = 5.8 Hz, 1H), 4.80 (d, J = 3.6 Hz, 1H), 4.70 (d,
J = 12.6 Hz, 1H), 4.49 (d, J = 12.6 Hz, 1H), 4.18–4.11 (m, 1H), 3.86
(ddd, J = 10.6, 8.3, 3.7 Hz, 1H), 3.72 (ddd, J = 21.9, 12.6, 7.9 Hz,
3H), 3.51 (t, J = 9.0 Hz, 1H), 1.84 (d, J = 9.8 Hz, 3H). 13C NMR
(100 MHz, DMSO) d 169.93, 138.19 (d, J = 3.3 Hz), 129.34, 128.7,
128.49, 128.07 (d, J = 7.3 Hz), 126.86, 101.34, 97.43, 69.06, 68.48,
67.73, 63.33 54.67, 23.00. Anal. Calcd (%) for C22H25NO6: C,
66.15; H, 6.31; N, 3.51; O, 24.03. Found: C, 66.04; H, 6.15; N, 3.48.
4. Experimental
4.1. General
Melting points were determined on an X4-Data microscopic
melting point apparatus and are uncorrected. Optical rotation val-
ues were measured on a PerkinElmer P241 polarimeter operating
at 589 nm. Nuclear magnetic resonance (NMR) spectra were mea-
sured at 400 MHz (1H) or at 100 MHz (13C) on a Bruker Avance
DRX-400 spectrometer. All reactions were monitored by analytical
thin-layer chromatography (TLC) from Merck with detection by
spraying with 5% (w/v) phosphomolybdic acid in ethanol and sub-
sequent heating or UV. All reagents and solvents were general re-
agent grade unless otherwise stated. All reactions were carried out
in predried glassware (150 °C, 5 h) cooled under vacuum.
4.2.4. Methyl-4,6-O-benzylidene-2-acetylamino-2-deoxy-a-D-
glucopyranoside 2b
White solid. Mp 250–252 °C; ½a D20
ꢁ
¼ þ90 (c 0.11, MeOH); 1H
NMR (400 MHz, DMSO) d 7.90 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 6.6,
3.2 Hz, 2H), 7.41–7.35 (m, 3H), 5.61 (s, 1H), 4.62 (d, J = 3.6 Hz,
1H), 4.18 (dd, J = 9.9, 4.8 Hz, 1H), 3.89–3.80 (m, 1H), 3.74 (t,
J = 10.1 Hz, 1H), 3.69–3.63 (m, 1H), 3.63–3.56 (m, 1H), 3.48 (t,
J = 9.2 Hz, 1H), 3.29 (s, 3H), 1.85 (s, 3H). 13C NMR (100 MHz, DMSO)
d 169.43, 137.74, 128.84, 127.99, 126.37, 100.87, 98.71, 82.01,
68.02, 67.37, 62.43, 54.71, 54.10, 22.57. Anal. Calcd (%) for
4.2. The synthesis of carbohydrate derived organocatalyst 1a–b,
2a–b
C
16H21NO6: C, 59.43; H, 6.55; N, 4.33; O, 29.69 Found: C, 59.67;
The carbohydrate derived organocatalysts 1a–b and 2a–b were
prepared according to the literature.7a,9–11
H, 6.72; N, 4.21.

X. Ge et al. / Tetrahedron: Asymmetry 25 (2014) 596–601
599
4.3. General procedure for the synthesis of carbohydrate derived
organocatalyst 3a–b, 4a–b, 5
1H), 4.82 (t, J = 5.8 Hz, 1H), 4.72 (td, J = 10.2, 3.7 Hz, 1H), 4.28
(dd, J = 10.3, 4.5 Hz, 1H), 4.04–3.89 (m, 2H), 3.80 (t, J = 10.0 Hz,
1H), 3.40 (s, 3H). 13C NMR (100 MHz, CDCl3) d 163.48, 163.44,
148.88, 148.04, 147.38, 146.45, 136.05, 135.93, 135.89, 127.95,
127.14, 125.78, 125.30, 125.15, 124.48, 121.12, 100.51, 98.27,
78.38, 70.60, 67.94, 61.89, 54.45, 51.36. Anal. Calcd (%) for
To a stirred solution of picolinic acid (246 mg, 2.0 mmol) in
CH2Cl2 (20 mL) were added the corresponding carbohydrate
derived organocatalyst (2.0 mmol), carbonyldiiazole (CDI,
356 mg, 2.2 mmol), and 4-dimethylamiopyridine (DMAP, 24 mg,
0.2 mmol) at 0 °C and the reaction mixture was stirred at room
temperature for 24 h. The organic phase was evaporated under re-
duced pressure to give the crude product, which was purified by
column chromatography through silica gel to give a pure product.
C26H25N3O7: C, 63.54; H, 5.13; N, 8.55; O, 22.79. Found: C, 63.26;
H, 5.29; N, 8.41.
4.3.5. Benzyl-4,6-O-benzylidene-3-O-(pyridinecarboxylic)-2-ace-
tylamino-2-deoxy-a-D-glucopyranoside 5
White solid. Yield 87%. Mp 179–181 °C. ½a D20
¼ þ19:2 (c 0.97,
ꢁ
4.3.1. Benzyl-4,6-O-benzylidene-2-picolinamide-2-deoxy-
a
-
D
-
CHCl3). 1H NMR (400 MHz, CDCl3) d 8.72 (d, J = 4.1 Hz, 1H), 8.10
(dd, J = 7.0, 4.9 Hz, 2H), 7.85–7.75 (m, 2H), 7.43–7.24 (m, 10H),
5.67 (t, J = 10.0 Hz, 1H), 5.53 (s, 1H), 4.97 (d, J = 3.6 Hz, 1H), 4.77
(d, J = 11.8 Hz, 1H), 4.56 (dd, J = 16.9, 7.7 Hz, 2H), 4.26 (dd,
J = 10.3, 4.7 Hz, 1H), 4.03 (d, J = 4.7 Hz, 1H), 3.90 (t, J = 9.5 Hz,
1H), 3.80 (t, J = 10.2 Hz, 1H), 1.81 (s, 3H). 13C NMR (100 MHz,
CDCl3) d 170.40, 165.00, 149.88, 147.12, 137.34, 136.83, 136.55,
131.53, 129.54, 129.09, 128.71, 128.41, 128.32, 128.20, 128.07,
127.31, 126.16, 125.64, 121.30, 101.54, 97.33, 79.08, 71.88, 70.24,
68.82, 63.21, 52.37, 23.04. Anal. Calcd (%) for C28H28N2O7: C,
66.66; H, 5.59; N, 5.55; O, 22.20. Found: C, 66.69; H, 5.53; N, 5.51.
glucopyranoside 3a
White solid. Yield 81%. Mp 187.6–188.5 °C. ½a D20
¼ þ40:0 (c 1.08,
ꢁ
CHCl3). 1H NMR (400 MHz, CDCl3) d 8.68–8.56 (m, 1H), 8.49 (d,
J = 9.2 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.86 (td, J = 7.7, 1.7 Hz,
1H), 7.50 (d, J = 1.8 Hz, 2H), 7.46 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H),
7.42–7.33 (m, 4H), 7.33–7.23 (m, 5H), 5.60 (s, 1H), 5.00 (d,
J = 3.9 Hz, 1H), 4.82 (dd, J = 19.0, 9.3 Hz, 1H), 4.59 (d, J = 12.1 Hz,
1H), 4.49–4.37 (m, 1H), 4.28 (dd, J = 10.2, 4.9 Hz, 1H), 4.16 (t,
J = 9.6 Hz, 1H), 3.98 (td, J = 9.9, 4.9 Hz, 1H), 3.81 (t, J = 10.3 Hz,
1H), 3.70 (t, J = 9.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 165.32,
149.27, 148.20, 137.38, 137.11, 136.83, 129.23, 128.50, 128.32,
128.10, 126.36, 122.60, 102.03, 97.33, 82.18, 70.65, 69.94, 68.91,
62.78, 54.15. Anal. Calcd (%) for C26H26N2O6: C, 67.52; H, 5.67; N,
6.06; O, 20.76. Found: C, 67.41; H, 5.59; N, 6.18.
4.4. General experimental procedure for the the enantioselec-
tive reduction of imines with trichlorosilane catalyzed by 5
To a stirred solution of imine 6 (0.5 mmol) and catalyst 5
(25 mg, 0.05 mmol) in dry CH2Cl2 (2 mL) was added the trichloros-
ilane (0.1 ml, 1 mmol) at 0 °C and the reaction mixture was stirred
at 0 °C for 24 h. Saturated NaHCO3 (2 ml) was then added and ex-
tracted with CH2Cl2 (3 ꢂ 5 ml). The combined organic phases were
washed with saturated brine, dried over MgSO4, and concentrated
in vacuo. The crude product was purified by column chromatogra-
phy through silica gel, eluting with a 1:99 ethyl acetate/petroleum
ether solvent mixture to give pure 7. The ee value of the reduction
product was determined by HPLC on a chiral column (Daicel,
Chiralpak, OD-H).
4.3.2. Methyl-4,6-O-benzylidene-2-picolinamide-2-deoxy-a-D-
glucopyranoside 3b
White solid. Yield 74%. Mp 177.8–178.5 °C. ½a D20
¼ þ24:9 (c
ꢁ
0.95, CHCl3). 1H NMR (400 MHz, CDCl3) d 8.60 (d, J = 4.3 Hz, 1H),
8.37 (d, J = 9.0 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.85 (td, J = 7.7,
1.6 Hz, 1H), 7.55–7.32 (m, 5H), 7.26 (s, 1H), 5.60 (s, 1H), 4.83 (d,
J = 3.8 Hz, 1H), 4.43 (td, J = 9.7, 3.8 Hz, 1H), 4.32 (dd, J = 9.8,
4.4 Hz, 1H), 4.10 (t, J = 8.8 Hz, 1H), 3.96–3.77 (m, 2H), 3.68 (t,
J = 9.2 Hz, 1H), 3.46 (s, 3H), 3.04 (d, J = 2.3 Hz, 1H). 13C NMR
(100 MHz, CDCl3)
d 165.42, 148.26, 137.37, 129.22, 128.31,
126.47, 126.36, 122.66, 102.04, 99.09, 82.20, 70.68, 68.95, 62.40,
55.46, 54.20. Anal. Calcd (%) for C20H22N2O6: C, 62.17; H, 5.74; N,
7.25; O, 24.84. Found: C, 62.12; H, 5.69; N, 7.21.
4.4.1. (S)-N-Phenyl-1-phenylethylamine 7a3a,3b,4
Yield 89%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.32–7.18 (m,
4H), 7.14 (t, J = 7.1 Hz, 1H), 7.01 (t, J = 7.6 Hz, 2H), 6.56 (t, J = 7.2 Hz,
1H), 6.43 (d, J = 7.6 Hz, 2H), 4.41 (q, J = 6.6 Hz, 1H), 1.43 (d,
J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 146.26, 144.20,
128.07, 127.60, 125.83, 124.82, 116.21, 112.29, 52.43, 23.98. HPLC
analysis: Chiralcel OD-H (Hexane/i-PrOH = 99/1, 1.0 mL/min,
254 nm, 25 °C): tmajor = 10.193 min, tminor = 11.987 min, ee: 62%.
4.3.3. Benzyl-4,6-O-benzylidene-3-O-(pyridinecarboxylic)-2-pic-
olinamide-2-deoxy-a-D-glucopyranoside 4a
White solid. Yield 91%. Mp 142.1–143.3 °C. ½a D20
¼ þ47:2 (c
ꢁ
1.00, CHCl3). 1H NMR (400 MHz, CDCl3) d 8.73–8.63 (m, 1H),
8.62–8.45 (m, 2H), 8.14–7.95 (m, 2H), 7.76 (dtd, J = 22.9, 7.7,
1.6 Hz, 2H), 7.46–7.35 (m, 6H), 7.35–7.31 (m, 1H), 7.29 (dd,
J = 3.6, 2.5 Hz, 1H), 7.27 (dd, J = 6.5, 2.8 Hz, 2H), 7.25–7.17 (m,
2H), 5.91 (t, J = 10.0 Hz, 1H), 5.68–5.45 (m, 1H), 5.04 (dd, J = 7.0,
3.8 Hz, 1H), 4.87–4.71 (m, 2H), 4.31 (dt, J = 10.3, 5.2 Hz, 1H),
4.21–4.07 (m, 1H), 4.07–3.91 (m, 1H), 3.85 (t, J = 10.2 Hz, 1H). 13C
NMR (100 MHz, CDCl3) d 164.48, 164.43, 149.92, 149.07, 148.34,
147.51, 137.36, 137.09, 136.91, 136.64, 128.98, 128.56, 128.45,
128.29, 128.24, 128.18, 128.17, 128.09, 126.82, 126.32, 126.18,
126.15, 125.53, 122.13, 101.52, 97.39, 79.44, 71.66, 70.05, 68.92,
63.26, 52.36. Anal. Calcd (%) for C32H29N3O7: C, 67.71; H, 5.15; N,
7.40; O, 19.73. Found: C, 67.54; H, 5.21; N, 7.35.
4.4.2. (S)-4-Fluoro-N-(1-phenylethyl)aniline 7b12
Yield 72%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.28–7.19 (m,
4H), 7.17–7.10 (m, 1H), 6.76–6.65 (m, 2H), 6.39–6.27 (m, 2H),
4.36–4.27 (m, 1H), 3.83 (s, 1H), 1.41 (d, J = 6.7 Hz, 3H). 13C NMR
(100 MHz, CDCl3)
d 154.63 (d, J = 234.7 Hz), 144.01, 142.59,
127.64, 125.92, 124.78, 114.46 (d, J = 22.2 Hz), 113.06 (d,
J = 7.3 Hz), 113.02, 53.03, 24.03. HPLC analysis: Chiralcel OD-H
(Hexane/i-PrOH = 99/1, 1.0 mL/min, 254 nm, 25 °C): tminor
11.332 min, tmajor = 12.671 min, ee: 65%.
=
4.4.3. (S)-2-Methyl-N-(1-phenylethyl)aniline 7c13
4.3.4. Methyl-4,6-O-benzylidene-3-O-(pyridinecarboxylic)-2-pic-
Yield 93%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.27 (dd,
J = 8.2, 1.2 Hz, 2H), 7.24–7.18 (m, 2H), 7.12 (ddd, J = 12.1, 6.4,
3.2 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.90–6.81 (m, 1H), 6.51 (td,
J = 7.4, 0.9 Hz, 1H), 6.28 (d, J = 7.9 Hz, 1H), 4.44 (q, J = 6.7 Hz, 1H),
3.75 (s, 1H), 2.13 (s, 3H), 1.46 (d, J = 6.7 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d 144.17 (d, J = 12.5 Hz), 128.92, 127.59, 125.87
(d, J = 15.1 Hz), 124.73, 120.49, 115.79, 109.99, 52.25, 24.20,
olinamide-2-deoxy-a-D-glucopyranoside 4b
White solid. Yield 94%. Mp 197.5–199.2 °C. ½a D20
¼ þ45:0 (c 1.1,
ꢁ
CHCl3). 1H NMR (400 MHz, CDCl3) d 8.62–8.56 (m, 1H), 8.47 (d,
J = 4.2 Hz, 1H), 8.35 (d, J = 10.0 Hz, 1H), 7.95 (dd, J = 16.5, 7.8 Hz,
2H), 7.70–7.60 (m, 2H), 7.38–7.31 (m, 2H), 7.28 (ddd, J = 13.7,
7.4, 5.1 Hz, 2H), 7.25–7.17 (m, 3H), 5.90–5.69 (m, 1H), 5.50 (s,

600
X. Ge et al. / Tetrahedron: Asymmetry 25 (2014) 596–601
16.57. HPLC analysis: Chiralcel OD-H (Hexane/i-PrOH = 99/1,
1.0 mL/min, 254 nm, 25 °C): tmajor = 9.847 min, tminor = 10.467 min,
ee: 59%.
OD-H (Hexane/i-PrOH = 95/5, 1.0 mL/min, 254 nm, 25 °C):
tmajor = 7.499 min, tminor = 8.319 min, ee: 61%.
4.4.11. (S)-N-Phenyl-N-[1-(4-nitrophenyl)ethyl]amine 7k3e
Yield 81%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 8.14–7.95 (m,
2H), 7.46 (d, J = 8.7 Hz, 2H), 7.01 (dd, J = 8.5, 7.4 Hz, 2H), 6.61 (d,
J = 7.3 Hz, 1H), 6.47–6.20 (m, 2H), 4.48 (q, J = 6.8 Hz, 1H), 4.02 (s,
1H), 1.46 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 153.21,
147.08, 146.55, 129.26, 126.73, 124.09, 117.99, 113.32, 53.33,
24.94. HPLC analysis: Chiralcel OD-H (Hexane/i-PrOH = 85/15,
1.0 mL/min, 254 nm, 25 °C): tmajor = 18.570 min, tminor = 22.780 -
min, ee: 63%.
4.4.4. (S)-4-Chloro-N-(1-phenylethyl)aniline 7d3f,6a
Yield 67%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.28–7.19 (m,
4H), 7.19–7.11 (m, 1H), 6.99–6.88 (m, 2H), 6.39–6.29 (m, 2H), 4.35
(q, J = 6.7 Hz, 1H), 4.08 (s, 1H), 1.42 (d, J = 6.7 Hz, 3H). 13C NMR
(100 MHz, CDCl3)
d 144.57, 143.53, 127.79 (d, J = 19.7 Hz).
126.03, 124.77, 120.96, 113.50, 52.70, 23.86. HPLC analysis: Chiral-
cel OD-H (Hexane/i-PrOH = 95/5, 1.0 mL/min, 254 nm, 25 °C):
tminor = 7.563 min, tmajor = 9.026 min, ee: 51%.
4.4.5. (S)-4-Methyl-N-(1-phenylethyl)aniline 7e3f,12
4.4.12. (S)-N-Phenyl-N-[1-(4-methylphenyl)ethyl]amine 7l3e
Yield 92%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.22 (d,
J = 8.1 Hz, 2H), 7.12–7.00 (m, 4H), 6.61 (tt, J = 7.4, 1.0 Hz, 1H),
6.51–6.44 (m, 2H), 4.42 (q, J = 6.7 Hz, 1H), 3.95 (s, 1H), 2.28 (s,
3H), 1.45 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 146.26,
141.14, 135.27, 128.13 (d, J = 23.1 Hz), 124.69, 116.09, 112.24,
52.05, 23.92, 19.99. HPLC analysis: Chiralcel OD-H (Hexane/i-
PrOH = 99/1, 1.0 mL/min, 254 nm, 25 °C): tmajor = 5.330 min,
tminor = 5.861 min, ee: 68%.
Yield 92%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.30–7.16 (m,
4H), 7.15–7.08 (m, 1H), 6.80 (d, J = 8.1 Hz, 2H), 6.37–6.28 (m, 2H),
4.35 (q, J = 6.7 Hz, 1H), 3.77 (s, 1H), 2.09 (s, 3H), 1.39 (d, J = 6.7 Hz,
3H). 13C NMR (100 MHz, CDCl3) d 144.37, 143.97, 128.54, 127.55,
125.73, 125.27, 124.80, 112.38, 52.61, 23.98, 19.30. HPLC analysis:
Chiralcel OD-H (Hexane/i-PrOH = 99/1, 1.0 mL/min, 254 nm,
25 °C): tminor = 20.440 min, tmajor = 22.681 min, ee: 67%.
4.4.6. (S)-3-Chloro-N-(1-phenylethyl)aniline 7f
Yield 74%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.28–7.19 (m,
4H), 7.18–7.10 (m, 1H), 6.88 (t, J = 8.0 Hz, 1H), 6.51 (ddd, J = 7.9, 1.9,
0.8 Hz, 1H), 6.40 (t, J = 2.1 Hz, 1H), 6.27 (ddd, J = 8.2, 2.3, 0.8 Hz, 1H),
4.36 (q, J = 6.7 Hz, 1H), 4.05 (s, 1H), 1.41 (d, J = 6.7 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d 148.41, 144.57, 134.83, 130.13, 128.80, 127.14,
125.81, 117.17, 113.10, 111.52, 53.38, 24.89. HPLC analysis:
Chiralcel OD-H (Hexane/i-PrOH = 95/5, 1.0 mL/min, 254 nm,
25 °C): tmajor = 8.075 min, tminor = 10.059 min, ee: 61%.
4.4.13. (S)-N-Benzyl-1-phenylpropylamine 7m3e
Yield 86%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.42–7.21 (m,
10H), 4.57 (d, J = 9.0 Hz, 1H), 3.81–3.62 (m, 2H), 2.00 (d, J = 1.2 Hz,
3H). 13C NMR (100 MHz, CDCl3) d 146.48, 142.88, 128.03, 127.44,
125.82, 125.44, 116.08, 112.22, 58.67, 30.59, 9.77. HPLC analysis:
Chiralcel OD-H (Hexane/i-PrOH = 99/1, 1.0 mL/min, 254 nm,
25 °C): tmajor = 8.143 min, tminor = 9.720 min, ee: 71%.
4.4.14. (S)-N-phenyl-N-[1-(4-chlorophenyl)propyl]amine 7n3e
Yield 77%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.18 (d,
J = 10.4 Hz, 4H), 7.00 (dd, J = 8.5, 7.4 Hz, 2H), 6.57 (t, J = 7.3 Hz,
1H), 6.40 (dd, J = 8.5, 0.9 Hz, 2H), 4.12 (t, J = 6.7 Hz, 1H), 3.95 (s,
1H), 1.82–1.59 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR
4.4.7. (S)-3-Bromo-N-(1-phenylethyl)aniline 7g
Yield 72%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.29–7.19 (m,
4H), 7.19–7.10 (m, 1H), 6.83 (t, J = 8.0 Hz, 1H), 6.65 (dddd, J = 8.3,
6.4, 2.5, 1.3 Hz, 1H), 6.58 (t, J = 2.1 Hz, 1H), 6.34–6.27 (m, 1H),
4.43–4.28 (m, 1H), 4.04 (s, 1H), 1.42 (t, J = 5.9 Hz, 3H). 13C NMR
(101 MHz, CDCl3)
d 146.19, 141.50, 131.42, 128.10, 127.64,
(100 MHz, CDCl3)
d
147.43, 143.40, 129.34, 127.71, 126.06,
126.83, 116.40, 112.25, 58.15, 30.64, 9.66. HPLC analysis: Chiralcel
OD-H (Hexane/i-PrOH = 99/1, 1.0 mL/min, 254 nm, 25 °C):
tmajor = 9.873 min, tminor = 14.328 min, ee: 75%.
124.72, 122.01, 119.01, 114.97, 110.79, 52.28, 23.76. HPLC analy-
sis: Chiralcel OD-H (Hexane/i-PrOH = 95/5, 1.0 mL/min, 254 nm,
25 °C): tmajor = 8.644 min, tminor = 10.835 min, ee: 57%.
4.4.15. (S)-N-Phenyl-N-[1-(4-methylphenyl)propyl]amine 7o3e
Yield 87%. Yellow oil. 1H NMR (400 MHz, CDCl3) 1H NMR
(400 MHz, CDCl3) d 7.21–7.12 (m, 3H), 7.08–6.96 (m, 3H), 6.55 (d,
J = 7.3 Hz, 1H), 6.44 (dd, J = 8.6, 0.9 Hz, 2H), 4.12 (t, J = 6.7 Hz, 1H),
3.97 (s, 1H), 2.24 (s, 3H), 1.74 (td, J = 14.4, 7.1 Hz, 2H), 0.87 (t,
J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 146.58, 139.86,
135.35, 128.16, 128.04, 125.36, 116.02, 112.21, 58.42, 30.61,
20.04, 9.81. HPLC analysis: Chiralcel OD-H (Hexane/i-PrOH = 99/1,
1.0 mL/min, 254 nm, 25 °C): tmajor = 6.522 min, tminor = 8.431 min,
ee: 72%.
4.4.8. (S)-N-Benzyl-1-phenylethanamine 7h14
Yield 53%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.42–7.21 (m,
10H), 4.57 (d, J = 9.0 Hz, 1H), 3.81–3.62 (m, 2H), 2.00 (d, J = 1.2 Hz,
3H). 13C NMR (100 MHz, CDCl3) d 143.61, 140.53, 128.57, 128.40,
127.31, 127.09, 127.04, 60.04, 51.43, 16.43. HPLC analysis: Chiral-
cel OD-H (Hexane/i-PrOH = 99/1, 1.0 mL/min, 254 nm, 25 °C):
tminor = 6.072 min, tmajor = 7.286 min, ee: 59%.
4.4.9. (S)-N-Phenyl-N-[1-(4-fluorophenyl)ethyl]amine 7i15
Yield 79%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.35–7.24 (m,
2H), 7.08 (t, J = 7.9 Hz, 2H), 7.01–6.90 (m, 2H), 6.64 (t, J = 7.3 Hz,
1H), 6.47 (d, J = 7.9 Hz, 2H), 4.43 (d, J = 6.7 Hz, 1H), 4.01 (s, 1H),
1.46 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3)d 161.82 (d,
J = 244.3 Hz), 147.13, 140.97, 140.94, 129.22,127.41 (d, J = 8.0 Hz),
117.54, 115.50 (d, J = 21.3 Hz), 113.44, 52.98, 25.22. HPLC analysis:
Chiralcel OD-H (Hexane/i-PrOH = 95/5, 1.0 mL/min, 254 nm,
25 °C): tmajor = 12.998 min, tminor = 14.982 min, ee: 60%.
Acknowledgements
The authors are grateful for the financial support from the Nat-
ural Science Foundation of China (21376213), the Research Fund
for the Doctoral Program of Higher Education of China
(20120101110062) and the Low Carbon Fatty Amine Engineering
Research Center of Zhejiang Province (2012E10033).
4.4.10. (S)-N-Phenyl-N-[1-(4-chlorophenyl)ethyl]amine 7j15
Yield 76%. Yellow oil. 1H NMR (400 MHz, CDCl3) d 7.33–7.20 (m,
4H), 7.12–7.00 (m, 2H), 6.64 (t, J = 7.3 Hz, 1H), 6.52–6.36 (m, 2H),
4.42 (q, J = 6.7 Hz, 1H), 4.01 (s, 1H), 1.45 (d, J = 6.7 Hz, 3H). 13C
NMR (100 MHz, CDCl3) d 147.03, 143.90, 132.45, 129.23, 128.87,
127.35, 117.61, 113.43, 53.06, 25.14. HPLC analysis: Chiralcel
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