Synthesis of novel carbohydrate-based valine-derived formamide organocatalysts by CuAAC click chemistry and their application in asymmetric reduction of imines with trichlorosilane

Article abstract of DOI:10.1016/j.tetasy.2014.10.003

Novel organocatalysts combining carbohydrate and N-formyl-l-valine derivatives were prepared by Cu^II-catalyzed diazo transfer and Cu^I-catalyzed azide-alkyne 1,3-dipolar cycloaddition CuAAC click chemistry. It was found that the carbohydrate-based valine-derived formamide organocatalyst had high catalytic activity for the asymmetric reduction of imines with trichlorosilane. The reduction can proceed at room temperature in toluene in high yield (up to 98%) and with excellent enantioselectivity (up to 94%). 'CuAAC' click chemistry is a bridge to link N-formyl-l-valine derived organocatalysts with carbohydrates.

Full text of DOI:10.1016/j.tetasy.2014.10.003

Tetrahedron: Asymmetry 25 (2014) 1450–1455
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of novel carbohydrate-based valine-derived formamide
organocatalysts by CuAAC click chemistry and their application in
asymmetric reduction of imines with trichlorosilane
⇑
Xin Ge, Chao Qian , Xinzhi Chen
Key Laboratory of Biomass Chemical Engineering of Ministry of Education, Department of Chemical and Biological Engineering, 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:
Received 10 August 2014
Accepted 2 October 2014
Novel organocatalysts combining carbohydrate and N-formyl-L-valine derivatives were prepared by
II
I
Cu -catalyzed diazo transfer and Cu -catalyzed azide–alkyne 1,3-dipolar cycloaddition CuAAC click
chemistry’. It was found that the carbohydrate-based valine-derived formamide organocatalyst had high
catalytic activity for the asymmetric reduction of imines with trichlorosilane. The reduction can proceed
at room temperature in toluene in high yield (up to 98%) and with excellent enantioselectivity (up to
94%). ‘CuAAC’ click chemistry is a bridge to link N-formyl-
L-valine derived organocatalysts with
carbohydrates.
Ó 2014 Elsevier Ltd. All rights reserved.
9
1
. Introduction
Chiral amines are key building blocks for the pharmaceutical and
pipecolinic acid derived, piperazine-2-carboxylic acid derived10
1
1
and S-chiral catalysts to reduce imines with high enantioselectiv-
ity. In spite of these significant developments of Lewis-basic
organocatalysts, the design and synthesis of organocatalysts mainly
depend on the chiral scaffolds of natural compounds. Thus, it is
challenging and important to develop more natural, efficient
organocatalysts.
Carbohydrates have been developed as organocatalysts for
application in asymmetric organic synthesis. In 2007, D-glucosa-
mine-derived bifunctional urea schiff base organocatalysts were
first reported to catalyze enantioselective Strecker and Mannich
fine chemistry industry, and are mainly prepared by the enantiose-
lective reduction of prochiral imines.1 In addition to transition
metal-catalyzed and biocatalytic reduction, organocatalytic
reduction has received much attention as a relatively easy
operation and environmentally friendly method. The Lewis-basic
organocatalytic reduction with trichlorosilane is an emerging
organocatalytic methodology and complementary to Bronsted acid
organocatalyzed-biomimetic reduction with Hantzsch esters. In
1
2
1
3
2
001, N-formyl-
L-proline anilide as a Lewis-basic organocatalyst
reactions.
Subsequently, carbohydrate-derived bifunctional
was first reported to catalyze the reduction of imines with trichlo-
rosilane with moderate enantioselectivity.2 Some highly effective
Lewis-basic organocatalysts were subsequently developed to cata-
lyze the reduction of imines with trichlorosilane. In addition to
primary amine-thiourea catalysts showed high enantioselectivity
for Michael additions of aromatic ketones with nitroolefins. In
14
our preliminary work, we developed carbohydrate-derived amino
1
5
16
alcohols
and novel carbohydrate-derived prolinamides
to
N-formyl-
catalysts were also developed such as N-picolinoyl-
-proline derived C2-symmetric chiral tetraamide, N-formyl
L
-proline anilide,2 some other
L
-proline-derived organo-
catalyze asymmetric aldol reactions. Recently, we described
carbohydrate-derived pyridinecarboxylic organocatalysts for the
enantioselective reduction of imines with trichlorosilane in high
yield (up to 93%) and with moderate enantioselectivity (up to
3
L
-pyrrolidine,
4
L
5
6
proline fatty amide, and N-substitutedprolines. N-Formyl-L-valine
1
7
derived Lewis-basic organocatalysts were found to significantly
improve the enantioselectivity.7 N-Picolinoyl chiral amino acid-
based organocatalysts were also considered to be highly effective
organocatalysts for the reduction of imines.3 Sun et al. developed
75%).
As part of our continued interests in carbohydrates as new
1
5–18
organocatalysts,
drate and N-formyl-
novel organocatalysts combining carbohy-
-valine derivatives made by copper-catalyzed
,8
L
azide–alkyne cycloaddition CuAAC click chemistry are developed
herein to catalyze the enantioselective reductions of imines with
trichlorosilane.
⇑
Corresponding author. Tel./fax: +86 571 87951615.
E-mail address: qianchao@zju.edu.cn (C. Qian).
http://dx.doi.org/10.1016/j.tetasy.2014.10.003
957-4166/Ó 2014 Elsevier Ltd. All rights reserved.
0

X. Ge et al. / Tetrahedron: Asymmetry 25 (2014) 1450–1455
1451
Table 1
2
2
. Results and discussion
.1. Synthesis of carbohydrate-derived organocatalysts 9
a
Asymmetric reduction of imine 10a
Ph
N
Ph
SiHCl3
HN
*
N-Formyl-L-valine derived alkynes 5 were obtained by a three
catalyst
Ph
Ph
step reaction from N-BOC-valine, which had been reported in the
literature. Carbohydrate-based valine-derived formamide organ-
ocatalysts 9 were synthesized by Cu -catalyzed diazo transfer and
Cu -catalyzed azide–alkyne 1,3-dipolar cycloaddition CuAAC click
1
9
11a
10a
II
Temp (°C) Yield (%) eec (%) (config)d
b
I
Entry Catalyst (mol %) Solvent
chemistry. Imidazole-1-sulfonyl azide was employed to transfer a
1
2
3
4
5
6
7
8
9a (10)
9b (10)
9b (10)
9b (10)
9b (10)
9b (10)
9b (10)
9b (10)
Toluene
Toluene
rt 94
rt 95
rt 93
rt 91
rt 87
73 (S)
88 (S)
61 (S)
43 (S)
12 (S)
89 (S)
92 (S)
91 (S)
diazo moiety onto the
D
-glucosamine hydrochloride catalyzed by
Cu , to give 2-azido-2-deoxy-3,4,6-tri-O-acetyl- ,b- -glucopyr-
anosylacetate 8 via acetylation. N-Formyl- -valine derived alkynes
could be linked with azidoglucopyranosylacetate with good
yield. The carbohydrate-based valine-derived formamide organo-
catalysts 9 were in a 3:7 ratio of - and b-isomers (Scheme 1).
II
CH
CHCl
CH CN
Cl
2 2
a
D
3
L
3
5
Toluene
Toluene
Toluene
0
87
À20 73
e
À20 92
a
a
3
The reactions were carried out with catalyst 9b and 1.5 equiv of SiHCl on a
0
.5 mmol scale in 2.0 mL of solvent for 24 h.
2
.2. Catalytic activities of carbohydrate-derived organocatalysts
b
Isolated yield based on the imine.
Determined by chiral HPLC.
The absolute configuration was determined by comparison of the specific
in asymmetric reductions of imines with trichlorosilane
c
d
10
With the aforementioned organocatalysts in hand, we next
evaluated their catalytic activities in the enantioselective reduction
of imines with trichlorosilane. The asymmetric reduction of imine
rotation with that of the literature value.
e
This reaction was carried out for 48 h.
1
0a with trichlorosilane was selected as a model reaction. Initially,
these new catalysts were screened in toluene and the results are
shown in Table 1.
trile. We found that toluene was the best solvent and afforded the
product in 95% yield and with 88% ee. We further investigated the
reaction temperature effect using toluene as the solvent (Table 1,
entries 2, 6–8). Lowering the reaction temperature led to an
increased ee. However, the increase of ee value was not obvious.
When the reaction temperature decreased from room temperature
to À20 °C, the ee value only increased from 88% to 91%. Based on
the above results, we selected room temperature as the optimal
temperature for this reaction.
In the presence of 10 mol % catalyst 9a, the asymmetric
reduction of imine 10a with trichlorosilane proceeded smoothly
at room temperature. The desired product was obtained in
excellent yield and with moderate ee value (Table 1, entry 1).
Organocatalyst 9b showed higher catalytic activity than organocat-
alyst 9a, with the ee value for the (S)-enantiomer being improved
to 88% (Table 1, entry 2). The optimization of reaction conditions
was next focused on the solvent (Table 1, entries 2–5). The reaction
was carried out in chloroform and dichloromethane, it gave mod-
erate ee values. The ee value of the reduction was poor in acetoni-
Having established the optimal reaction conditions, we next
explored the substrate scope of the asymmetric reduction. In order
to investigate the generality of catalyst 9b, we examined the asym-
R
R
O
O
O
O
O
O
R
R
OH
OH
R
NH2
CH3I,NaH
THF
O
H
3
N
H
R
NH
O
N
1. CF COOH,rt, 1h
3
O
N
HN
O
O
N
DCC, DMAP
2. HCO2H, Ac2O, rt, 12h
O
O
O
5
4
5a: R=H
1
2
5
b: R=Me
O
S
AcO
N
HO
HO
HO
HO
O
N
N3
K2CO3,CuSO4
O
O
Ac O, pyridine
AcO
AcO
OAc
O
2
OH
OH
MeOH
N3
HO
N3
HO
NH2..HCl
8
7
6
H
AcO
AcO
O
O
N
H
N
OAc
5
R
CuI, DIPEA,DMF
AcO
N
O
N
O
N
R
9
9
a, R=H
9
b, R=Me
Scheme 1. Synthesis of carbohydrate-derived organocatalysts 9.

1
452
X. Ge et al. / Tetrahedron: Asymmetry 25 (2014) 1450–1455
metric reduction of some ordinary N-aryl imines with trichlorosi-
lane under the optimal reaction conditions. The results are summa-
rized in Table 2. As the substrate of the model reaction, imine 10a
could be reduced in 95% yield and with 88% ee (Table 2, entry 1).
For aromatic N-Ph imines 10b–10e, the desired products 11b–
Ph
Ph
N
catalyst 9b (10 mol%)
HN
Ph
SiHCl3, toluene, r.t.
Ph
*
1
0a
11a
1
1e were obtained with satisfactory yields and enantioselectivities.
100
When the aromatic N-Ph imines with electron-withdrawing
groups 10b–10d were reduced, the yields increased (97–98%,
entries 2–4, Table 2) with excellent enantioselectivities (92–94%).
Imines 10e with an electron-donating group led to a yield and ee
that were lower than those of 10a (Table 2, entry 5). Phenyl N-aryl
imines were somewhat different from the aromatic N-Ph imines,
and only afforded the 34-86% ee values (Table 2, entries 6–11). In
the case of imine 10h, phenyl N-aryl imines with electron-with-
drawing groups 10f, 10g, and 10i could be reduced in high yields
yield
ee
8
0
60
4
2
0
0
0
1
2
3
4
5
Figure 1. Recycling and reuse of catalyst 9ba,b,c. aThe reactions were carried out
(
92–96%) and with moderate enantioselectivities (83–86% ee val-
3
with 10 mol % catalyst 9a and 1.5 equiv of SiHCl on a 0.5 mmol scale in 2.0 mL of
ues). On the other hand, the yields and enantioselectivities of phe-
nyl N-aryl imines with electron-donating groups 10j–10k were not
satisfactory with 69–84% yields and only 34–53% ee (Table 2,
entries 10–11). Overall, for organocatalyst 9b, the catalytic effect
of imines with electron-withdrawing groups was better than that
of imines with electron-donating groups. For valine-derived organ-
ocatalysts, arene–arene interactions between the catalyst and sub-
strate have a great influence on the catalytic activity.7a As N-alkyl
acetophenone ketimines, ketimine 10l was different from 10a
and gave nearly racemic products (Table 2, entries 12). For ali-
phatic imines, good yields and low enantioselectivities were
obtained (Table 2, entries 14 and 15). It is noteworthy that 10m
could also be reduced in good yield and with moderate enantiose-
lectivity (Table 2, entries 13).
toluene for 24 h. bIsolated yield based on the imine. Determined by chiral HPLC.
c
catalyze the reduction. Generally, the catalyst recycling had a
slight loss of activity. Therefore, the catalyst used in every new
cycle was less than the previous one, which in turn led to a slight
decrease in the yield and enantioselectivity. After five cycles, a
marginal effect of the reactivity and selectivity was observed, indi-
cating that organocatalyst 9b could be reused. Thus it is possible
that N-formyl-
carbohydrates by CuAAC.
L-valine derived organocatalysts can be linked with
3
. Conclusion
In order to determine whether organocatalyst 9b could be
recovered and reused, we carried out a recycling test of 9b to cat-
alyze the asymmetric reduction of imine 10a with trichlorosilane
In conclusion, we have described a novel carbohydrate-based
valine-derived formamide organocatalyst and its application in
the asymmetric reduction of imines with trichlorosilane. The car-
bohydrate-based valine-derived formamide organocatalyst can
promote the asymmetric reduction of imines with trichlorosilane
in high yield (up to 98%) and with excellent enantioselectivity
(Fig. 1). When the reaction was completed, organocatalyst 9b
was recovered by separation from the product. By using column
chromatography on silica gel with a petroleum ether/ethyl acetate
mixture (99:1), the crude product eluted the pure amine and con-
tinued elution with pure ethyl acetate, then released the organo-
catalyst. The recovered organocatalyst was directly reused to
(
up to 94%). The organocatalyst can be reused by a relatively
undemanding recovery process. Thus, CuAAC click chemistry is a
potential method to link N-formyl- -valine derived organocatalysts
L
with carbohydrates such as chitosan, polysaccharides, and so on.
Further investigations into the application of valine-derived form-
amide organocatalyst immobilization in asymmetric reduction of
imines with trichlorosilane are currently underway.
Table 2
Asymmetric reduction of imine 10 with catalyst 9ba
R2
R3
R2
R3
HN
N
catalyst 9b (10 mol%)
4
4
. Experimental
SiHCl , toluene, r.t.
3
R1
R1
*
.1. General
1
1
1
0
Entry
Imine
R1
R2
R3
Yieldb (%)
eec (%)
Nuclear magnetic resonance (NMR) spectra were measured at
1
13
1
2
3
4
5
6
7
8
9
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
C
6
H
5
C
C
C
C
C
6
6
6
6
6
H
H
H
H
H
5
5
5
5
5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
95
97
97
98
72
96
96
85
92
84
69
56
89
85
95
88
92
94
93
67
84
83
76
86
53
34
5
400 MHz ( H) or at 100 MHz ( C) on a Bruker Avance DRX-400
spectrometer. Enantiomeric excesses (% ee) were determined by
HPLC (Agilent 1100) analysis using Chiral OD column. All reactions
were monitored by analytical thin-layer chromatography (TLC)
from Merck with detection by spraying with 5% (w/v) phosphomo-
lybdic acid in ethanol and subsequent heating or UV. All reagents
and solvents were of general reagent grade unless otherwise sta-
ted. All reactions were carried out in predried glassware (150 °C,
5 h) cooled under vacuum.
4-FC
4-ClC
4-NO
4-CH
C
C
C
C
C
C
C
C
6 4
H
6
H
4
2
C
6
H
4
3 6
C H
4
6
H
6
H
6
H
6
H
6
H
6
H
6
H
6
H
5
5
5
5
5
5
5
5
6 4
4-FC H
4-ClC
3-ClC
3-BrC
4-CH
2-CH
C
C
C
C
6
H
H
4
6
4
6
H
4
1
1
1
1
1
1
0
1
2
3
4
5
3
C
6
H
H
4
4
3
C
6
6
H
6
H
6
H
6
H
4
5
5
5
CH
2
79
28
21
4
.2. General procedure for the synthesis of compound 5
c-C
3-Me-i-Bu
6
H
11
Me
Me
To a solution of N-BOC-valine 1 (217 mg, 1 mmol) and iodo-
a
The reactions were carried out with 10 mol % catalyst 9b and 1.5 equiv of SiHCl
3
methane (1.42 g, 10 mmol) in anhydrous tetrahydrofuran (THF,
20 mL) was added neat sodium hydride (240 mg, 10 mmol). The
reaction mixture was stirred at room temperature for 24 h. The
on a 0.5 mmol scale in 2.0 mL of toluene for 24 h.
b
Isolated yield based on the imine.
Determined by chiral HPLC.
c

X. Ge et al. / Tetrahedron: Asymmetry 25 (2014) 1450–1455
1453
mixture was then quenched with water (30 mL). The reaction mix-
ture was extracted with ethyl acetate (EtOAc, 2 Â 15 mL) and the
aqueous solution was acidified to pH 3, after which it was
extracted with EtOAc (3 Â 20 mL). The combined organic phase
under reduced pressure to give a crude product, which was purified
by column chromatography on silica gel, eluting with 2:1 PE/EtOAc
solvent mixture, to give pure product 9. Compound 9a (pale yellow
1
oil, yield 91%) H NMR (400 MHz, CDCl
3
) d 8.23 (s, 1H), 8.09 (s, 1H),
was dried over anhydrous Na
2
SO
4
and evaporated to afford the
7.56 (s, 1H), 7.43–7.35 (m, 2H), 6.89–6.75 (m, 2H), 6.29 (d, J = 3.5 Hz,
0.3H), 6.13 (t, J = 7.8 Hz, 0.8H), 5.87 (dd, J = 11.3, 9.3 Hz, 0.4H), 5.79–
5.64 (m, 0.8H), 5.26–5.12 (m, 2H), 5.12–5.06 (m, 2H), 4.63–4.54 (m,
1H), 4.35–4.28 (m, 2H), 4.03–3.97(m, 1H), 2.94 (s, 3H), 2.45–2.27(m,
1H), 2.07–1.94 (m, 12H), 0.96 (d, J = 6.5 Hz, 3H), 0.83 (d, J = 6.1 Hz,
corresponding N-methylated product 2 (thick colorless oil, 99%
1
yield. H NMR (400 MHz, CDCl
3
) d 10.04 (s, 1H), 4.49–3.93 (m,
1
H), 2.87 (s, 3H), 2.23 (dd, J = 16.3, 9.9 Hz, 1H), 1.47 (s, 9H), 1.03
(
d, J = 6.5 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H).
1
3
To a stirred solution of amine 3 (175 mg, 1 mmol) in CH
2
Cl
2
3
3H). C NMR (100 MHz, CDCl ) d 169.52, 169.13, 168.60, 168.07,
(
100 mL) were added 2 (231 mg, 1 mmol), dicyclohexylcarbodiim-
167.05, 166.00, 162.97, 153.73, 143.46, 130.57, 121.99, 120.57,
114.15, 90.58, 71.93, 71.05, 68.05, 67.04, 61.71, 61.24, 60.35,
ide (DCC, 226 mg, 1.1 mmol), and 4-dimethylaminopyridine (DMAP,
2 mg, 0.1 mmol). The reaction mixture was stirred at room temper-
1
30.62, 24.36, 19.87, 19.67, 19.53, 19.45, 19.14, 18.50, 17.53. Com-
1
ature for 24 h. The organic phase was filtered and evaporated under
reduced pressure to give a crude product, which was purified by
column chromatography through silica gel, eluting with a 5:1
EtOAc/petroleum ether (PE) solvent mixture, to give pure product
4
pound 9b (pale yellow oil, yield 92%) H NMR (400 MHz, CDCl
3
) d
8.07 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.11 (d, J = 9.4 Hz, 2H), 6.33
(d, J = 3.5 Hz, 0.3H), 6.12 (d, J = 8.7 Hz, 0.7H), 5.92 (dd, J = 11.2,
9.4 Hz, 0.4H), 5.80–5.67 (m, 0.7H), 5.28–5.03 (m, 2H), 4.92–4.77
(m, 2H), 4.63 (dd, J = 10.5, 8.9 Hz, 1H), 4.37–4.26 (m, 2H), 4.06–
3.94 (m, 1H), 2.93 (s, 3H), 2.46–2.35 (m, 1H), 2.15 (s, 6H), 2.09–
1
(yellow oil, 44% yield). Compound 4a H NMR (400 MHz, CDCl
3
)
d 8.31 (br s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H),
.66 (d, J = 2.2 Hz, 2H), 4.12 (d, J = 7.1 Hz, 1H), 2.84 (s, 3H), 2.51 (t,
J = 2.4 Hz, 1H), 2.43–2.27 (m, 1H), 1.48 (s, 9H), 1.02 (d, J = 6.4 Hz,
4
1.89 (m, 12H), 0.98 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H). 13
C
3
NMR (100 MHz, CDCl ) d 169.52, 168.89, 168.62, 168.10, 167.06,
3
1
5
H), 0.91 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl
3
) d 168.60,
166.10, 163.00, 151.00, 143.80, 132.63, 130.49, 121.92, 119.42,
90.64, 89.04, 71.92, 71.11, 68.05, 67.77, 67.09, 62.11, 61.25, 60.36,
30.60, 24.28, 19.87, 19.67, 19.54, 19.52, 19.24, 18.51, 17.54, 15.42.
57.42, 154.07, 132.14, 121.27, 115.36, 80.65, 78.55, 75.53, 65.97,
1
6.14, 30.53, 28.38, 26.00, 19.85, 18.60. Compound 4b H NMR
(
3
400 MHz, CDCl ) d 8.19 (br, 1H), 7.18 (s, 2H), 4.46 (d, J = 2.2 Hz,
2
2
0
1
5
H), 4.12 (d, J = 7.1 Hz, 1H), 2.83 (s, 3H), 2.50 (t, J = 2.4 Hz, 1H),
4.4. General experimental procedure for the asymmetric reduction
of imines with trichlorosilane catalyzed by an organocat alyst
.44–2.33 (m, 1H), 2.29 (s, 6H), 1.47 (s, 9H), 1.01 (d, J = 6.4 Hz, 3H),
.91 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl
) d 168.69,
3
57.41, 151.63, 134.12, 131.78, 120.11, 80.64, 79.26, 75.03, 65.99,
9.90, 30.44, 28.38, 25.98, 19.85, 18.58, 16.63.
Compound 4 (388 mg, 1 mmol) was dissolved in trifluoroacetic
To a stirred solution of imine 10 (0.5 mmol) and organocatalyst
(0.05 mmol) in toluene (2 mL) was added trichlorosilane (0.15 ml,
1.5 mmol) at room temperature and the reaction mixture was
acid (2.0 mL) at room temperature. After 1 h the reaction mixture
was evaporated in vacuo, the residue was dissolved in formic acid
stirred at room temperature for 24 h. Next, saturated NaHCO
3
(2 ml) was added and extracted with ethyl acetate (3 * 10 ml).
The combined organic phases were washed with brine, and dried
(
0.75 mL), and the resulting solution was cooled to 0 °C. Acetic anhy-
dride (2 mL) was added dropwise and the mixture was stirred at
room temperature overnight. The organic phase was evaporated
under reduced pressure. Purification using column chromatography
4
over anhydrous MgSO . Afterward the organic phase was
evaporated under reduced pressure to give the crude product,
which was purified by column chromatography through silica
gel, eluting with 1:99 EtOAc/PE solvent mixture, to give pure prod-
uct 11. The ee value of the reduction product was determined by
HPLC on a chiral column (Daicel, Chiralpak, OD).
on silica gel, eluting with a 2:1 PE/EtOAc mixture afforded product 5.
1
Compound 5a (yellow oil, 76% yield), H NMR (400 MHz, CDCl
3
) d
8
2
2
1
.41 (s, 1H), 8.14 (s, 1H), 7.48 (d, J = 9.1 Hz, 2H), 6.92 (d, J = 9.0 Hz,
H), 4.66 (d, J = 2.4 Hz, 2H), 4.43 (d, J = 11.2 Hz, 1H), 3.02 (s, 3H),
.51 (t, J = 2.4 Hz, 1H), 2.48–2.41 (m, 1H), 2.09 (d, J = 6.3 Hz, 2H),
.04 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz,
2
,17
4.4.1. (S)-N-Phenyl-1-phenylethylamine 11a
1
3
Yellow oil, 95% yield. H NMR (400 MHz, CDCl ) d 7.32–7.18 (m,
CDCl
3
) d 167.03, 163.99, 154.29, 131.78, 121.50, 115.34, 78.51,
4H), 7.14 (t, J = 7.1 Hz, 1H), 7.01 (t, J = 7.6 Hz, 2H), 6.56 (t, J = 7.2 Hz,
7
5.57, 69.07, 56.13, 31.65, 25.43, 19.52, 18.57. Compound 5b (yellow
1H), 6.43 (d, J = 7.6 Hz, 2H), 4.41 (q, J = 6.6 Hz, 1H), 3.92 (br, 1H),
1.43 (d, J = 6.7 Hz, 3H). C NMR (100 MHz, CDCl ) d 146.26, 144.20,
3
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 = 8.81 min, tminor = 10.21 min, ee: 88%.
1
13
oil, 75% yield), H NMR (400 MHz, CDCl
7
2
3
) d 8.40 (s, 1H), 8.14 (s, 1H),
.21 (s, 2H), 4.47–4.41 (m, 3H), 3.02 (s, 3H), 2.50 (t, J = 2.2 Hz, 1H),
.47–2.38 (m, 1H), 2.28 (s, 6H), 1.04 (d, J = 6.4 Hz, 3H), 0.91 (d,
1
3
J = 6.6 Hz, 3H).
3
C NMR (100 MHz, CDCl ) d 167.18, 163.97,
1
2
51.84, 133.77, 131.79, 120.38, 79.23, 75.08, 62.97, 59.89, 31.61,
5.44, 19.50, 18.59, 16.63.
4.4.2. (S)-N-Phenyl-N-[1-(4-fluorophenyl)ethyl]amine 11b21
1
Yellow oil, 97% yield. H NMR (400 MHz, CDCl
3
) d 7.35–7.24
4
.3. General procedure for the synthesis of compound 9
(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 (br, 1H), 1.46 (d, J = 6.7 Hz, 3H). C NMR (100 MHz, CDCl ) d
3
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 = 7.304 min, tminor = 8.064 min,
ee: 92%.
1
3
Product 8 was prepared by a diazo transfer reaction of
1
8c,20
D
-glucosamine hydrochloride 6 as reported in the literature.
A
solution of 8 (0.25 mmol) and CuI (5.0 mg, 0.0255 mmol, 0.1 equiv)
in degassed DMF (5 mL) was stirred under nitrogen. The appropriate
alkyne 5 (0.30 mmol, 1.2 equiv) was then added, following by the
addition of N,N-diisopropylethylamine (DIPEA, 0.25 mmol,
3
2.0 mg, 1.0 equiv). The solution was stirred at 100 °C under nitro-
gen, and the reaction was reacted for 12 h. The mixture was cooled
to room temperature and then diluted with EtOAc (80 mL). The
organic layer was washed with hydrochloric acid (5%, 10 mL Â 2),
4.4.3. (S)-N-Phenyl-N-[1-(4-chlorophenyl)ethyl]amine 11c21
1
3
Yellow oil, 97% yield. H NMR (400 MHz, CDCl ) 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 (br, 1H), 1.45 (d, J = 6.7 Hz, 3H). 13
NMR (100 MHz, CDCl ) d 147.03, 143.90, 132.45, 129.23, 128.87,
NaHCO
anhydrous Na
3
(5%, 10 mL Â 2), and brine (20 mL Â 1), and then dried over
C
2
SO
4
. The organic phase was filtered and evaporated
3

1
454
X. Ge et al. / Tetrahedron: Asymmetry 25 (2014) 1450–1455
1
27.35, 117.61, 113.43, 53.06, 25.14. HPLC analysis: Chiralcel
(m, 2H), 4.35 (q, J = 6.7 Hz, 1H), 3.77 (br, 1H), 2.09 (s, 3H), 1.39
1
3
OD-H (Hexane/i-PrOH = 95/5, 1.0 mL/min, 254 nm, 25 °C): tmajor
7
=
(d, J = 6.7 Hz, 3H). C NMR (100 MHz, CDCl
128.54, 127.55, 125.73, 125.27, 124.80, 112.38, 52.61, 23.98,
9.30. HPLC analysis: Chiralcel OD-H (Hexane/i-PrOH = 99/1,
3
) d 144.37, 143.97,
.795 min, tminor = 8.939 min, ee: 94%.
1
1
0
1.0 mL/min, 254 nm, 25 °C): tminor = 9.004 min, tmajor = 9.678 min,
ee: 53%.
4
.4.4. (S)-N-Phenyl-N-[1-(4-nitrophenyl)ethyl]amine 11d
1
Yellow oil, 98% yield. H NMR (400 MHz, CDCl
3
) d 8.14–7.95 (m,
2
H), 7.46 (d, J = 8.7 Hz, 2H), 7.01 (dd, J = 8.5, 7.4 Hz, 2H), 6.61 (d,
2
2
4
.4.11. (S)-2-Methyl-N-(1-phenylethyl)aniline 11k
J = 7.3 Hz, 1H), 6.47–6.20 (m, 2H), 4.48 (q, J = 6.8 Hz, 1H), 4.02 (br,
1
H), 1.46 (d, J = 6.8 Hz, 3H). 1 C NMR (100 MHz, CDCl
1
3
3
Yellow oil, 69% yield. H NMR (400 MHz, CDCl ) d 7.27
1
3
) d 153.21,
47.08, 146.55, 129.26, 126.73, 124.09, 117.99, 113.32, 53.33, 24.94.
(
3
dd, J = 8.2, 1.2 Hz, 2H), 7.24–7.18 (m, 2H), 7.12 (ddd, J = 12.1, 6.4,
.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),
.75 (br, 1H), 2.13 (s, 3H), 1.46 (d, J = 6.7 Hz, 3H). 13C NMR
100 MHz, CDCl ) 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,
HPLC analysis: Chiralcel OD-H (Hexane/i-PrOH = 85/15, 1.0 mL/min,
254 nm, 25 °C): tmajor = 15.38 min, tminor = 17.349 min, ee: 93%.
3
(
(
1
1
1
0
3
4
.4.5. (S)-N-phenyl-N-[1-(4-methylphenyl)ethyl]amine 11e
Yellow oil, 72% yield. 1H NMR (400 MHz, CDCl
) 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
3
1
5
3
6.57. HPLC analysis: Chiralcel OD-H (Hexane/i-PrOH = 99/1,
.0 mL/min, 254 nm, 25 °C): tmajor = 5.837 min, tminor = 8.211 min,
.51–6.44 (m, 2H), 4.42 (q, J = 6.7 Hz, 1H), 3.95 (br, 1H), 2.28 (s,
ee: 34%.
H), 1.45 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl
3
) d 146.26,
41.14, 135.27, 128.13 (d, J = 23.1 Hz), 124.69, 116.09, 112.24,
2.05, 23.92, 19.99. HPLC analysis: Chiralcel OD-H (Hexane/i-
7b
4
.4.12. (S)-N-Benzyl-1-phenylethanamine 11l
1
Yellow oil, 56% yield. H NMR (400 MHz, CDCl
3
) d 7.42–7.21
PrOH = 99/1, 1.0 mL/min, 254 nm, 25 °C):
tmajor = 6.806 min,
(
(
1
m, 10H), 4.57 (d, J = 9.0 Hz, 1H), 3.81–3.62 (m, 2H), 2.00
tminor = 7.236 min, ee: 67%.
13
d, J = 1.2 Hz, 3H). C NMR (100 MHz, CDCl
28.57, 128.40, 127.31, 127.09, 127.04, 60.04, 51.43, 16.43. HPLC
analysis: Chiralcel OD-H (Hexane/i-PrOH = 99/1, 1.0 mL/min,
3
) d 143.61, 140.53,
4
.4.6. (S)-4-Fluoro-N-(1-phenylethyl)aniline 11f22
1
Yellow oil, 96% yield. H NMR (400 MHz, CDCl
3
) d 7.28–7.19 (m,
2
54 nm, 25 °C): tminor = 6.142 min, tmajor = 7.357 min, ee: 5%.
4
4
H), 7.17–7.10 (m, 1H), 6.76–6.65 (m, 2H), 6.39–6.27 (m, 2H),
.36–4.27 (m, 1H), 3.83 (br, 1H), 1.41 (d, J = 6.7 Hz, 3H). 13C NMR
8
a
4
.4.13. (S)-N-(1-Phenylpropyl)aniline 11m
1
(
100 MHz, CDCl
3
) d 154.63 (d, J = 234.7 Hz), 144.01, 142.59,
Yellow oil, 89% yield. H NMR (400 MHz, CDCl
m, 10H), 4.57 (d, J = 9.0 Hz, 1H), 3.81–3.62 (m, 2H), 2.00 (d,
3
) d 7.42–7.21
1
27.64, 125.92, 124.78, 114.46 (d, J = 22.2 Hz), 113.06 (d,
(
1
3
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 = 8.956 -
min, tmajor = 9.419 min, ee: 84%.
J = 1.2 Hz, 3H).
1
3
C NMR (100 MHz, CDCl ) d 146.48, 142.88,
28.03, 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 = 8.572 min, tminor = 10.207 min, ee:
a
4
.4.7. (S)-4-Chloro-N-(1-phenylethyl)aniline 11g9
7
9%.
1
Yellow oil, 96% yield. H NMR (400 MHz, CDCl
3
) d 7.28–7.19 (m,
1
1b
4
(
(
H), 7.19–7.11 (m, 1H), 6.99–6.88 (m, 2H), 6.39–6.29 (m, 2H), 4.35
4
.4.14. (S)-N-(1-Cyclohexylethyl)aniline 11n
q, J = 6.7 Hz, 1H), 4.01 (br, 1H), 1.42 (d, J = 6.7 Hz, 3H). 1 C NMR
3
1
Yellow oil, 85% yield. H NMR (400 MHz, CDCl
3
) d 7.06
100 MHz, CDCl
26.03, 124.77, 120.96, 113.50, 52.70, 23.86. HPLC analysis:
Chiralcel OD-H (Hexane/i-PrOH = 95/5, 1.0 mL/min, 254 nm,
3
) d 144.57, 143.53, 127.79 (d, J = 19.7 Hz).
(
t, J = 7.7 Hz, 2H), 6.55 (t, J = 7.3 Hz, 1H), 6.47 (d, J = 8.3 Hz, 2H),
1
3
5
3
1
2
1
.38 (s, 1H), 3.30–3.09 (m, 1H), 1.67 (ddd, J = 45.0, 27.7, 14.1 Hz,
H), 1.44–1.30 (m, 1H), 1.28–1.06 (m, 3H), 1.02 (d, J = 6.5 Hz,
1
3
2
5 °C): tminor = 7.440 min, tmajor = 8.252 min, ee: 83%.
3
H), 1.00–0.86 (m, 2H). C NMR (100 MHz, CDCl ) d 148.03,
29.31, 116.56, 113.01, 53.03, 43.05, 29.84, 28.48, 26.71, 26.56,
6.42, 17.48. HPLC analysis: Chiralcel OD-H (Hexane/i-PrOH = 99/
, 1.0 mL/min, 254 nm, 25 °C): tminor = 5.059 min, tmajor = 5.232
4
.4.8. (S)-3-Chloro-N-(1-phenylethyl)aniline 11h17
1
Yellow oil, 85% yield. H NMR (400 MHz, CDCl
3
) d 7.28–7.19 (m,
4
1
0
3
1
H), 7.18–7.10 (m, 1H), 6.88 (t, J = 8.0 Hz, 1H), 6.51 (ddd, J = 7.9,
.9, 0.8 Hz, 1H), 6.40 (t, J = 2.1 Hz, 1H), 6.27 (ddd, J = 8.2, 2.3,
.8 Hz, 1H), 4.36 (q, J = 6.7 Hz, 1H), 4.04 (br, 1H), 1.41 (d, J = 6.7 Hz,
3
) d 148.41, 144.57, 134.83, 130.13,
28.80, 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,
54 nm, 25 °C): tmajor = 7.645 min, tminor = 9.277 min, ee: 76%.
min, ee: 28%.
1
1b
4
.4.15. (S)-N-(3-Methylbutan-2-yl)aniline 11o
1
3
1
H). C NMR (100 MHz, CDCl
Yellow oil, 95% yield. H NMR (400 MHz, CDCl
J = 11.7, 4.1 Hz, 1H), 6.56 (td, J = 7.3, 0.8 Hz, 1H), 6.52–6.46
m, 1H), 3.38 (s, 1H), 3.26 (dt, J = 11.8, 6.0 Hz, 1H), 1.75 (tt,
J = 13.4, 6.5 Hz, 1H), 1.02 (d, J = 6.4 Hz, 1H), 0.89 (d, J = 6.9 Hz,
3
) d 7.07 (dd,
(
2
1
3
1
1
1
1
H), 0.83 (d, J = 6.8 Hz, 1H).
3
C NMR (100 MHz, CDCl ) d
4
.4.9. (S)-3-Bromo-N-(1-phenylethyl)aniline 11i17
47.89, 129.29, 116.66, 113.10, 53.47, 32.28, 19.21, 17.54,
6.61. HPLC analysis: Chiralcel OD-H (Hexane/i-PrOH = 99/1,
.0 mL/min, 254 nm, 25 °C): tminor = 4.796 min, tmajor = 5.097 min,
1
Yellow oil, 92% yield. H NMR (400 MHz, CDCl
3
) d 7.29–7.19 (m,
4
6
4
H), 7.19–7.10 (m, 1H), 6.83 (t, J = 8.0 Hz, 1H), 6.65 (dddd, J = 8.3,
.4, 2.5, 1.3 Hz, 1H), 6.58 (t, J = 2.1 Hz, 1H), 6.34–6.27 (m, 1H),
.43–4.28 (m, 1H), 4.04 (br, 1H), 1.42 (t, J = 5.9 Hz, 3H). 1 C NMR
ee: 21%.
3
(
100 MHz, CDCl
3
) d 147.43, 143.40, 129.34, 127.71, 126.06, 124.72,
1
22.01, 119.01, 114.97, 110.79, 52.28, 23.76. HPLC analysis: Chiral-
Acknowledgements
cel OD-H (Hexane/i-PrOH = 95/5, 1.0 mL/min, 254 nm, 25 °C):
major = 8.303 min, tminor = 10.118 min, ee: 86%.
t
The authors are grateful for financial support from the Natural
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)-4-Methyl-N-(1-phenylethyl)aniline 11j17
Yellow oil, 84% yield. 1H NMR (400 MHz, CDCl
) 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
3
(

X. Ge et al. / Tetrahedron: Asymmetry 25 (2014) 1450–1455
1455
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c) Wang, Z. Y.; Wang, C.; Zhou, L.; Sun, J. Org. Biomol. Chem. 2013, 11, 787.
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