Highly enantioselective conjugate addition of 1-bromonitroalkanes to α,β-unsaturated ketones catalyzed by 9-amino-9-deoxyepiquinine

Article abstract of DOI:10.1016/j.tet.2009.03.055

Asymmetric conjugate addition of 1-bromonitroalkanes to α,β-unsaturated ketones was studied using chiral primary amines as the catalysts. 9-Amino-9-deoxyepiquinine was found to be highly efficient catalyst for the transformation. 4-Bromo-4-nitroketones we

Full text of DOI:10.1016/j.tet.2009.03.055

Tetrahedron 65 (2009) 4124–4129
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Tetrahedron
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Highly enantioselective conjugate addition of 1-bromonitroalkanes
to a,b-unsaturated ketones catalyzed by 9-amino-9-deoxyepiquinine
*
Li-ting Dong, Rui-jiong Lu, Quan-sheng Du, Jun-min Zhang, Sheng-ping Liu, Yi-ning Xuan, Ming Yan
Industrial Institute of Fine Chemicals and Synthetic Drugs, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric conjugate addition of 1-bromonitroalkanes to
a,b
-unsaturated ketones was studied using
Received 3 February 2009
Received in revised form 19 March 2009
Accepted 20 March 2009
Available online 27 March 2009
chiral primary amines as the catalysts. 9-Amino-9-deoxyepiquinine was found to be highly efficient
catalyst for the transformation. 4-Bromo-4-nitroketones were obtained with excellent enantioselectiv-
ities (97–99% ee) and good yields (61–99%) for a variety of alkyl vinyl ketones. The product could be
further debrominated with Bu3SnH/AIBN to provide chiral 4-nitroketones in good yield and without loss
of the optical purity.
Keywords:
9-Amino-9-deoxyepiquinine
Organocatalysis
Ó 2009 Elsevier Ltd. All rights reserved.
Conjugate addition
1-Bromonitroalkane
a,b-Unsaturated ketone
1. Introduction
aldehydes and ketones is a valuable method to prepare chiral g-
amino aldehydes and ketones,4 which are useful intermediates for
the synthesis of natural products and drugs. Enantioselective ad-
dition of nitroalkanes to chalcones was achieved with chiral bi-
functional thiourea-amine catalysts and other metal-based chiral
catalysts.5 As the useful analogs of nitroalkanes, bromonitroalkanes
provide an additional leaving group for further transformations.
Ley and co-workers reported the addition of bromonitromethane to
In recent years asymmetric organocatalysis has been developed
to be a powerful tool for the synthesis of valuable chiral com-
pounds.1 A large number of asymmetric reactions have been de-
veloped catalyzed by chiral amines, thioureas (or ureas), and other
chiral organic small molecules. Since initiated by MacMillan et al.,
the activation of
a,b-unsaturated aldehydes and ketones toward
conjugate addition by chiral secondary amines has been one of the
most successful strategies in organocatalysis.2 Many kinds of nu-
cleophilic reagents were applied in the transformation, such as
malonates, indoles, aldehydes, ketones, thiols, and peroxides, etc.
Excellent enantioselectivities were achieved catalyzed by proline
and its derivatives, MacMillan’s imidazolidinones, and other chiral
secondary amines. These catalysts uniquely activate the substrates
by formation of the iminium cation and a LUMO lowing mechanism
is well conceptualized. Although chiral secondary amines are
a,b-unsaturated ketones using proline tetrazole as the catalyst. The
reaction provided nitrocyclopropanes in good yields and enantio-
selectivities.6 Recently we7 and the others8 explored the asym-
metric conjugate addition of bromonitroalkanes to a,b-unsaturated
aldehydes catalyzed by prolinol silyl ethers. Excellent enantiose-
lectivities and good yields were obtained in the reactions. However
the method is not applicable for a,b-unsaturated ketones due to the
low reactivity. Very recently, Wang and co-workers reported the
enantioselective conjugate addition of 1-bromonitroalkanes to cy-
clic enones and chalcones catalyzed by chiral primary amines.9 9-
Amino-9-deoxyepiquinine was found to be the efficient catalyst for
the reaction. In the presence of appropriate bases, chiral nitro-
cyclopropanes were obtained with excellent enantioselectivities
and in good yields. However alkyl vinyl ketones, such as oct-3-en-
2-one, were found to be inactive in the reaction. At the same time,
we also explored the asymmetric conjugate addition of 1-bromo-
highly efficient for activation of
show inferior catalytic activities for sterically congested
saturated ketones. Recently chiral primary amines emerged as the
a
,b
-unsaturated aldehydes, they
a,b
-un-
powerful catalysts for activation of
a,b-unsaturated ketones and
a number of successful examples had been reported.3
Nitroalkanes are important synthons in organic synthesis.
Asymmetric conjugate addition of nitroalkanes to a,b-unsaturated
nitroalkanes to
a,b-unsaturated ketones catalyzed by chiral pri-
mary amines. We found that the addition of 1-bromonitroalkanes
to a variety of alkyl vinyl ketones could be achieved using 9-amino-
9-deoxyepiquinine as the catalyst. Chiral bromonitroketones were
* Corresponding author. Tel./fax: þ86 20 39943049.
E-mail address: yanming@mail.sysu.edu.cn (M. Yan).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.055

Li-t. Dong et al. / Tetrahedron 65 (2009) 4124–4129
4125
Table 2
obtained with excellent enantioselectivities and in good yields.
Herein we report the results in detail.
Effects of the additives and solventsa
Br
O2N
O
O
∗
10 mol% 1e
2. Results and discussion
20 mol% additive
+
BrCH2NO2
solvent, rt, 48 h
Initially chiral primary amines (1a–1f) were examined in the
reaction of benzylidene acetone 2a and bromonitromethane 3. The
results are summarized in Table 1. 2-Phenylethylamine 1a provided
the adduct 4a in poor yield and enantioselectivity. 1,2-Diphenyl-
ethane-1,2-diamine 1b gave 4a with good enantioselectivity,
however in low yield. Cyclohexane-1,2-diamine 1c provided the
adduct in better yield and with moderate enantioselectivity.
Binaphthyl diamine 1d was inefficient for the reaction. Further
studies uncovered that chiral primary amines (1e and 1f), derived
from natural cinchona alkaloids, were highly efficient for the re-
action (Table 1, entries 5 and 6).10 9-Amino-9-deoxyepiquinine 1e,
readily available from cheap quinine, provided the adduct 4a with
excellent yield and enantioselectivity. On the other hand, 9-amino-
9-deoxyepicinchonidine 1f gave another enantiomer of 4a with
excellent yield and enantioselectivity.
Benzoic acid was found to be necessary for the reaction, thus
a number of acid additives were further screened and the results
are summarized in Table 2. Brønsted acids, such as benzoic acid,
trifluoroacetic acid (TFA), trifluoromethanesulfonic acid (TfOH), p-
toluenesulfonic acid (p-TSA), and acetic acid, accelerated the re-
action (Table 2, entries 1–5). Benzoic acid was identified as the best
additive considering the excellent enantioselectivity and yield. The
reaction solvents were also screened (Table 2, entries 6–13). Tolu-
ene was the preferential solvent in terms of both enantioselectivity
and chemical yield. In addition the reaction was faster in toluene
and complete conversion was achieved after 10 h as indicated by
TLC analysis. CHCl3 provided similar enantioselectivity and yield
with CH2Cl2. Excellent enantioselectivities were also obtained in
2a
3
4a
Entry
Additive
Solvent
Yieldb/%
drc
eed/%
1
2
3
4
5
6
7
PhCOOH
TFA
TfOH
p-TSA
AcOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Toluene
Toluene
Toluene
THF
95
81
30
44
96
93
95
84
28
51
37
72
37
57:43
57:43
57:43
59:41
57:43
56:44
57:43
56:44
56:44
59:41
56:44
58:42
56:44
99/99
96/97
91/91
96/95
98/98
>99/>99
>99/>99
>99/>99
>99/>99
98/98
99/99
91/91
80/81
8e
9f
10
11
12
13
Et2O
MeOH
DMF
a
The reactions were carried out at room temperature for 48 h with 2a (0.2 mmol),
3 (0.3 mmol), 1e (0.02 mmol), additive (0.04 mmol), and solvent (1 mL).
b
Isolated yield.
Determined by 1H NMR analysis.
c
d
Determined by chiral HPLC analysis.
5 mol % 1a was used.
1 mol % 1a was used.
e
f
THF and Et2O, however with lower chemical yield. More polar
solvents, such as MeOH and DMF gave inferior enantioselectivity. It
is noted that the diastereoselectivities of the reaction were almost
consistent with different additives and solvents. The loading of
catalyst was also investigated (Table 2, entries 8 and 9). While
5 mol % 1e was used, 84% yield was achieved after 48 h. The yield
was decreased to 28% while 1 mol % 1e was used. Although the
chemical yield was significantly affected by the catalyst loading, the
enantioselectivities were still excellent. The fact confirmed that
the background reaction without the catalyst did not occur. In
a comparative experiment, nitromethane was also examined in the
reaction with benzylidene acetone under optimized reaction con-
ditions (10 mol % 1e, 20 mol % PhCOOH, toluene, room tempera-
ture), however no reaction occurred even after 48 h. The result may
Table 1
The reaction of 2a and 3 catalyzed by 1a–1fa
NH2
Ph
Ph
NH2
NH2
NH2
NH2
1a
1b
1c
be ascribed to the stronger acidity of
methane than in nitromethane.
a-proton in bromonitro-
OMe
A variety of
a,b-unsaturated ketones were examined and the
NH2
NH2
N
N
results are summarized in Table 3. Excellent enantioselectivities
and yields were obtained for a number of substituted benzylidene
acetones. Electron-withdrawing groups and electron-donating
groups at the para-position of the phenyl group were well tolerated
(Table 3, entries 2–7). ortho- and meta-Chloro substituted
benzylidene acetones also provided the product with excellent
enantioselectivities and yields (Table 3, entries 8 and 9). 4-Furanyl-
but-3-en-2-one and 4-thiophenyl-but-3-en-2-one were applicable
in the reaction with excellent enantioselectivities and yields,
however longer reaction time was necessary for these substrates
H2N
NH2
N
N
1d
1e
1f
Br
O2N
O
O
10 mol% cat*
20 mol% PhCOOH
CH2Cl2, rt, 48 h
∗
BrCH2NO2
+
2a
3
4a
(Table 3, entries 10 and 11). The reaction of b-propyl-but-3-en-2-
Entry
Catalyst
Yieldb/%
drc
57:43
60:40
55:45
d
eed/%
one gave the product in 89% yield and with 98% enantioselectivity
after extended reaction time (Table 3, entry 12). 1-Phenyl-pent-1-
en-3-one was also suitable substrate for the reaction (Table 3, entry
13). The reaction of chalcone provided the product with excellent
enantioselectivity, but in lower yield (Table 3, entry 14).
1-Bromonitroethane and 1-bromonitropropane were also ex-
amined in the reaction with benzylidene acetone. The corre-
sponding adducts were obtained with excellent enantioselectivities
and in good yields (Scheme 1). The sterically demanding 1-bro-
monitropropane required longer reaction time.
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
11
44
53
d
36/38
94/93
ꢀ76/ꢀ78
d
95
88
57:43
56:44
99/99
ꢀ97/ꢀ98
a
The reactions were carried out at room temperature for 48 h with 2a (0.2 mmol),
3 (0.3 mmol), 1a–1f (0.02 mmol), PhCOOH (0.04 mmol), and CH2Cl2 (1 mL).
b
Isolated yield.
c
Determined by 1H NMR analysis.
d
Determined by chiral HPLC analysis.

4126
Li-t. Dong et al. / Tetrahedron 65 (2009) 4124–4129
Table 3
acetone. The acid additive is supposed to promote this step.
Conjugate addition of 1-bromonitromethane to
a
,
b
-unsaturated ketones catalyzed
Bromonitromethane is deprotonated by tertiary amine group of
1e and the hydrogen bonding between the nitro group and
protonated tertiary amines is formed. The resulting intermediate
II provides a pre-organized structure and controls the enantio-
selectivity of the reaction. The consequent conjugate addition of
bromonitroalkane anion and the tautomerization of the imine
give the intermediate III, which is hydrolyzed to provide the
product and to regenerate catalyst 1e.
by 1ea
Br
10 mol%1e
O2N
O
O
20 mol% PhCOOH
+ BrCH2NO2
R2
R1
∗
R2
toluene, rt
R1
2a-2n
3
4a-4n
Entry
R1
Ph
R2
Time/h
Yieldb/%
drc
eed/%
1
2
3
4
5
6
7
8
Me (2a)
Me (2b)
Me (2c)
Me (2d)
Me (2e)
Me (2f)
Me (2g)
Me (2h)
Me (2i)
Me (2j)
10
10
9
6
6
95
94
95
97
99
89
90
92
97
89
94
89
90
49
57:43
57:43
56:44
57:43
55:45
61:39
52:48
45:55
54:46
51:49
52:48
56:44
58:42
63:37
>99/>99
>99/>99
99/97
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-NO2C6H4
2-ClC6H4
3-ClC6H4
2-Furyl
>99/>99
99/nde
99/99
OMe
6
6
N
nde
98/98
N
NH2
18
12
36
36
96
48
96
NH2
9
>99/nde
>99/>99
>99/>99
98/98
N
1e
10
11
12
13
14
2-Thiophenyl
Me (2k)
Me (2l)
Et (2m)
Ph (2n)
O
n-Pr
Ph
Ph
*
>99/>99
98/98
Ph
*
Me
N
H+
NH+
Me
O2N
O
N
a
The reactions were carried out at room temperature with 2 (0.2 mmol), 3
(0.3 mmol), 1e (0.02 mmol), PhCOOH (0.04 mmol), and toluene (1 mL).
a
Br
Ph
O
O
N
I
H2O
b
Isolated yield.
c
Determined by 1H NMR analysis.
Ph
NH2
b
*
Me
Br
d
d
Determined by chiral HPLC analysis.
Not determined.
H+
e
H2O
N
R
Br
O2N
H
O
N
*
O
O
N
H
R
10 mol% 1e
20 mol% PhCOOH
*
∗
+
BrCHNO2
Br
O
NH+
Me
O
N
toluene, rt
2a
Br
O
NH
Ph
5 (48 h, 83% yield, dr: 75/25, ee%: >99/>99)
6 (96 h, 61% yield, dr: >99/1, ee%: >99)
c
R = Me
R = Et
II
*
Me
Ph
III
Scheme 1. The reaction of 1-bromonitroethane and 1-bromonitropropane with
benzylidene acetone.
Scheme 3. Proposed catalytic mechanism.
The product 4a (>99% ee) was debrominated with Bu3SnH/
AIBN (Scheme 2, equation 1). Compound 7 was obtained with
excellent enantioselectivity (>99% ee) and in good yield. The ab-
solute configuration of 7 was determined as S by comparing the
optical rotation with the reported data.11 Analogically the absolute
configuration of 4a was assigned as S. On the other hand, the
treatment of 4a with various bases, such as Et3N, DIPEA, DBU, and
NMM, did not provide the expected nitrocyclopropane,9 instead
a complicated mixture was observed (Scheme 2, equation 2). The
result was ascribed to the competitive intermolecular aldol re-
action of 4a.
3. Conclusion
In summary, we have developed an efficient asymmetric con-
jugate addition of 1-bromonitroalkanes to -unsaturated ketones
a,b
catalyzed by readily available 9-amino-9-deoxyepiquinine. The
corresponding bromonitroketones were obtained in good yields
and with excellent enantioselectivities for a variety of alkyl vinyl
ketones. The product could be further debrominated with Bu3SnH/
AIBN to provide the chiral 4-nitroketone in good yield and without
loss of the optical purity. Further applications of the products are
currently under investigation.
A catalytic mechanism of the reaction is proposed (Scheme 3).10p
The iminium cation I is generated from 1e and benzylidene
4. Experimental section
4.1. General details
O2N
Br
O2N
O
O
Bu SnH (120 mol%
)
3
AIBN (20 mol% )
1)
2)
All solvents were used as commercial anhydrous grade without
further purification. The flash column chromatography was car-
ried out over silica gel (230–400 mesh), purchased from Qingdao
Haiyang Chemical Co., Ltd. Optical rotations were measured on
a Perkin Elmer digital polarimeter. Melting points were recorded
on an electrothermal digital melting-point apparatus. 1H and 13C
NMR spectra were recorded on a Bruker 400 MHz spectrometer as
solutions in CDCl3. Chemical shifts in 1H NMR spectra are reported
toluene
4a
(S)-7
hv
dr: 57/43
>99% ee
86% yield
>99% ee
O2N
Br
O
NO2
O
base
solvent
4a
in parts per million (ppm, d) downfield from the internal standard
complicated mixture
Scheme 2. Transformations of compound 4a.
Me4Si (TMS,
d
¼0 ppm). Chemical shifts in 13C NMR spectra are
reported relative to the central line of the chloroform signal

Li-t. Dong et al. / Tetrahedron 65 (2009) 4124–4129
4127
(
d
¼77.0 ppm). High resolution mass spectra were obtained with
4.3.3. Compound 4c
the Thermo MAT 95XP mass spectrometer. The low resolution
mass spectra were obtained at the Thermo Trace GC Ultra – DSQ.
Enantiomeric excesses of the products were determined by HPLC
using Daicel Chiralcel AS-H, AD-H, OJ-H, and IC columns and
eluting with n-hexane/i-PrOH. Compound 1e and 1f were pre-
pared according to the reported procedures.12
Major isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼7.15–7.08
(m, 4H), 6.21 (d, J¼8.8 Hz, 1H), 4.14–4.06 (m, 1H), 3.19–3.00 (m, 2H),
2.30 (s, 3H), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3):
133.0, 129.8, 128.0, 83.8, 46.2, 45.5, 30.5, 21.1; IR (thin film)
d¼204.5,138.5,
n
/cmꢀ1
:
3011 (m), 2923 (m), 1719 (s), 1565 (s), 1420 (m), 1355 (s), 787 (m);
HRMS (EI) calcd for C12H14NO3Br [Mþ]: 299.0152, found: 299.0151.
The enantiomeric excess was determined by HPLC with an
AS-H column (n-hexane/i-PrOH¼90/10, ¼220 nm, 1.0 mL/min); tR
l
4.2. Typical experimental procedure for the conjugate
addition of 1-bromonitroalkanes to a,b-unsaturated ketones
(major enantiomer)¼22.7 min, tR (minor enantiomer)¼24.1 min,
99% ee.
Minor isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼7.15–7.08
(m, 4H), 6.31 (d, J¼6.8 Hz, 1H), 4.14–4.06 (m, 1H), 3.19–3.00 (m, 2H),
2.32 (s, 3H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3):
9-Amino-9-deoxyepiquinine 1e (6.5 mg, 0.02 mmol) was dis-
solved in toluene (1 mL). After addition of PhCOOH (4.9 mg,
0.04 mmol), the solution was stirred for 15 min at room tem-
perature. Benzylidene acetone 2a (29.2 mg, 0.2 mmol) was added
and the mixture was stirred for another 15 min. Then 1-bromo-
nitromethane 3 (42 mg, 0.3 mmol) was added in one portion and
the reaction mixture was stirred for 10 h (monitored by TLC). The
reaction solution was diluted with CH2Cl2 (5 mL) and washed
with aqueous saturated NaHCO3 (3 mL). The organic layer was
dried over anhydrous sodium sulfate. After the solvent was
evaporated under vacuum, the residue was purified by flash
column chromatography over silica gel (EtOAc/petroleum ether)
to provide product 4a.
d¼204.5, 138.5,
132.9, 129.7, 128.2, 85.0, 45.7, 45.2, 30.4, 21.1. The enantiomeric
excess was determined by HPLC with an AS-H column (n-hexane/
i-PrOH¼90/10,
l
¼220 nm, 1.0 mL/min); tR (major enantio-
mer)¼20.8 min, tR (minor enantiomer)¼27.9 min, 97% ee.
4.3.4. Compound 4d
Major isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d¼7.33–
7.28 (m, 2H), 7.20–7.15 (m, 2H), 6.23 (d, J¼8.4 Hz, 1H), 4.17–4.08 (m,
1H), 3.20–3.00 (m, 2H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼204.0, 134.6, 134.5, 129.6, 129.2, 83.2, 45.8, 45.3, 30.4; IR (thin
film) n
/cmꢀ1: 2361 (w), 2340 (w), 1700 (s), 1558 (s), 1459 (m), 1356
(m), 721 (w); HRMS (ESI) calcd for C11H11NNaO3ClBr [MþNa]þ:
341.9509, found: 341.9524. The enantiomeric excess was de-
termined by HPLC with an OJ-H column (n-hexane/i-PrOH¼70/30,
4.3. Spectral data of (bromo)nitroketones13
4.3.1. Compound 4a
l
¼220 nm, 0.5 mL/min); tR (major enantiomer)¼24.6 min, tR (mi-
Major isomer: white solid. 1H NMR (400 MHz, CDCl3):
d
¼7.37–
nor enantiomer)¼26.8 min, >99% ee.
7.29 (m, 3H), 7.25–7.21 (m, 2H), 6.25 (d, J¼8.8 Hz, 1H), 4.18–4.11 (m,
Minor isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d¼7.33–
1H), 3.21–3.03 (m, 2H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3):
7.28 (m, 2H), 7.20–7.15 (m, 2H), 6.33 (d, J¼6.8 Hz, 1H), 4.17–4.08 (m,
d
¼204.3, 136.1, 129.0, 128.6, 128.1, 83.6, 46.4, 45.4, 30.4; IR (thin
1H), 3.20–3.00 (m, 2H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3):
film)
n
/cmꢀ1: 2360 (w), 2339 (w), 1715 (s), 1563 (s), 1418 (w), 1357
d
¼204.1, 134.5, 134.4, 129.7, 129.1, 84.6, 45.3, 45.1, 30.2. The enan-
(m), 702 (m); HRMS (EI) calcd for C11H12NO3Br [Mþ]: 284.9995,
found: 284.9993. The enantiomeric excess was determined by HPLC
tiomeric excess was determined by HPLC with an OJ-H column
(n-hexane/i-PrOH¼70/30,
l
¼220 nm, 0.5 mL/min); tR (minor
with an AS-H column (n-hexane/i-PrOH¼75/25,
l
¼220 nm, 0.5 mL/
enantiomer)¼37.4 min, tR (major enantiomer)¼38.3 min, >99% ee.
min); tR (minor enantiomer)¼17.6 min, tR (major enantio-
mer)¼18.4 min, >99% ee.
4.3.5. Compound 4e
Minor isomer: white solid. 1H NMR (400 MHz, CDCl3):
d
¼7.37–
Major isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d¼7.48–
7.29 (m, 3H), 7.25–7.21 (m, 2H), 6.34 (d, J¼7.2 Hz, 1H), 4.18–4.11 (m,
7.44 (m, 2H), 7.14–7.08 (m, 2H), 6.22 (d, J¼7.2 Hz, 1H), 4.16–4.06 (m,
1H), 3.21–3.03 (m, 2H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3):
1H), 3.20–3.00 (m, 2H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼204.4, 135.9, 128.9, 128.3, 128.1, 84.8, 46.0, 45.1, 30.3. The enan-
d
¼204.0, 135.2, 132.2, 129.9, 122.8, 83.1, 45.9, 45.3, 30.4; IR (thin
tiomeric excess was determined by HPLC with an AS-H column (n-
film) n
/cmꢀ1: 2361 (w), 2338 (w), 1718 (s), 1564 (s), 1410 (w), 1356
hexane/i-PrOH¼75/25,
l¼220 nm, 0.5 mL/min); tR (major enan-
(m), 1011 (w); HRMS (EI) calcd for C11H11NO3Br2 [Mþ]: 362.9100,
found: 362.9091. The enantiomeric excess was determined by HPLC
tiomer)¼19.8 min, tR (major enantiomer)¼21.1 min, >99% ee.
with an IC column (n-hexane/i-PrOH¼96/4,
l¼208 nm, 0.8 mL/
4.3.2. Compound 4b
min); tR (minor enantiomer)¼14.7 min, tR (major enantio-
mer)¼16.6 min, 99% ee.
Major isomer: yellow solid. 1H NMR (400 MHz, CDCl3):
d¼7.17–
7.11 (m, 2H), 6.87–6.82 (m, 2H), 6.19 (d, J¼8.8 Hz, 1H), 4.13–4.04 (m,
Minor isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d¼7.48–
1H), 3.76 (s, 3H), 3.17–2.98 (m, 2H), 2.09 (s, 3H); 13C NMR (100 MHz,
7.44 (m, 2H), 7.14–7.08 (m, 2H), 6.33 (d, J¼6.8 Hz, 1H), 4.16–4.06 (m,
CDCl3):
(thin film)
d
¼204.5, 159.6, 129.3, 127.8, 114.5, 83.7, 45.6, 45.2, 30.5; IR
1H), 3.20–3.00 (m, 2H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3):
n
/cmꢀ1: 2361 (w), 2340 (w), 1716 (s), 1560 (s), 1517 (m),
d¼204.0, 135.0, 132.1, 130.1, 122.8, 84.5, 45.4, 45.1, 30.3.
1358 (m), 838 (w); HRMS (EI) calcd for C12H14NO4Br [Mþ]: 315.0101,
found: 315.0094. The enantiomeric excess was determined by HPLC
4.3.6. Compound 4f
with an AS-H column (n-hexane/i-PrOH¼90/10,
l¼220 nm, 1.0 mL/
Major isomer: yellow solid. 1H NMR (400 MHz, CDCl3):
d
¼7.62–
min); tR (major enantiomer)¼25.8 min, tR (minor enantio-
mer)¼28.6 min, >99% ee.
7.58 (m, 2H), 7.40–7.35 (m, 2H), 6.29 (d, J¼8.4 Hz, 1H), 4.32–4.18 (m,
1H), 3.25–3.06 (m, 2H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3):
Minor isomer: yellow solid. 1H NMR (400 MHz, CDCl3):
d¼7.17–
d
¼203.9, 140.3, 130.9 (q, JC–F¼32.6 Hz), 128.8, 126.1 (q, JC–F¼3.7 Hz),
7.11 (m, 2H), 6.87–6.82 (m, 2H), 6.31 (d, J¼6.4 Hz, 1H), 4.13–4.04 (m,
125.1 (d, JC–F¼5.9 Hz), 83.0, 46.2, 45.4, 30.4; IR (thin film)
n
/cmꢀ1
:
1H), 3.77 (s, 3H), 3.17–2.98 (m, 2H), 2.11 (s, 3H); 13C NMR (100 MHz,
2362 (w), 2338 (w), 1716 (s), 1560 (s), 1128 (s), 1115 (s), 850 (m);
HRMS (EI) calcd for C12H11NO3BrF3 [Mþ]: 352.9869, found:
352.9871. The enantiomeric excess was determined by HPLC with
CDCl3):
d
¼204.6, 159.7, 129.5, 127.7, 114.3, 85.3, 55.2, 45.8, 45.3,
30.4. The enantiomeric excess was determined by HPLC with an AS-
H column (n-hexane/i-PrOH¼90/10,
l
¼220 nm, 1.0 mL/min); tR
an OJ-H column (n-hexane/i-PrOH¼99/1, ¼215 nm, 0.8 mL/min);
l
(major enantiomer)¼23.2 min, tR (minor enantiomer)¼39.9 min,
>99% ee.
tR (minor enantiomer)¼71.9 min, tR (major enantiomer)¼86.9 min,
99% ee.

4128
Li-t. Dong et al. / Tetrahedron 65 (2009) 4124–4129
Minor isomer: yellow solid. 1H NMR (400 MHz, CDCl3):
d
¼7.62–
determined by HPLC with an AS-H column (n-hexane/i-PrOH¼90/
10,
7.58 (m, 2H), 7.40–7.35 (m, 2H), 6.37 (d, J¼4.4 Hz, 1H), 4.32–4.18 (m,
l
¼220 nm, 1 mL/min); tR (minor enantiomer)¼15.0 min, tR
1H), 3.25–3.06 (m, 2H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3):
(major enantiomer)¼18.4 min, >99% ee.
d
¼203.9, 140.1, 130.9 (q, JC–F¼32.6 Hz), 129.0, 125.9 (q, JC–F¼3.7 Hz),
Minor isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼7.36–7.33
122.4 (d, JC–F¼6.0 Hz), 84.2, 45.7, 45.2, 30.3. The enantiomeric ex-
(m, 1H), 6.33–6.28 (m, 1H), 6.36 (d, J¼5.6 Hz, 1H), 6.24–6.22 (m, 1H),
cess was determined by HPLC with an OJ-H column (n-hexane/
4.37–4.27 (m,1H), 3.17–2.99 (m, 2H), 2.18 (s, 3H); 13C NMR (100 MHz,
i-PrOH¼99/1,
l
¼215 nm, 0.8 mL/min); tR (minor enantio-
CDCl3):
d
¼204.1, 149.0, 142.9, 110.6, 109.5, 82.6, 42.9, 40.3, 30.2. The
mer)¼78.7 min, tR (major enantiomer)¼93.1 min, 99% ee.
enantiomeric excess was determined by HPLC with an AS-H column
(n-hexane/i-PrOH¼90/10, ¼220 nm, 1 mL/min); tR (major enantio-
l
4.3.7. Compound 4g
mer)¼21.3 min, tR (major enantiomer)¼23.7 min, >99% ee.
Major isomer: white solid. 1H NMR (400 MHz, CDCl3):
d
¼8.23–
8.18 (m, 2H), 7.48–7.42 (m, 2H), 6.30 (d, J¼8.4 Hz,1H), 4.33–4.22 (m,
4.3.11. Compound 4k
1H), 3.28–3.08 (m, 2H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3):
Major isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼7.27–7.24
(m,1H), 6.98–6.92 (m, 2H), 6.31 (d, J¼8.0 Hz,1H), 4.56–4.41 (m,1H),
3.24–3.06 (m, 2H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3):
¼204.2,
137.6, 127.7, 127.2, 126.0, 83.2, 46.4, 41.9, 30.4; IR (thin film)
/cmꢀ1
d
¼203.6, 147.8, 143.5, 129.4, 124.1, 82.5, 46.1, 45.2, 30.3; IR (thin
film)
n
/cmꢀ1: 2361 (w), 2340 (w), 1713 (s), 1562 (s), 1523 (s), 1355
d
(s), 857 (m); HRMS (EI) calcd for C11H11NO3Br [MꢀNO2]þ: 283.9917,
n
:
found: 283.9917.
2360 (w), 2339 (w), 1718 (s), 1565 (s), 1355 (m), 708 (m); HRMS (EI)
calcd for C9H10NO3BrS [Mþ]: 290.9559, found: 290.9565. The en-
antiomeric excess was determined by HPLC with an AS-H column
(n-hexane/i-PrOH¼90/10,
tiomer)¼16.4 min, tR (major enantiomer)¼18.4 min, >99% ee.
Minor isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
Minor isomer: white solid. 1H NMR (400 MHz, CDCl3):
d
¼8.23–
8.18 (m, 2H), 7.48–7.42 (m, 2H), 6.39 (d, J¼6.8 Hz,1H), 4.33–4.22 (m,
1H), 3.28–3.08 (m, 2H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3):
l¼220 nm, 1 mL/min); tR (minor enan-
d¼203.6, 147.9, 143.2, 129.6, 124.0, 83.8, 45.5, 45.1, 30.2.
d
¼7.27–
4.3.8. Compound 4h
7.24 (m,1H), 6.98–6.92 (m, 2H), 6.45 (d, J¼5.6 Hz,1H), 4.56–4.41 (m,
Major isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼7.44–
1H), 3.24–3.06 (m, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3):
7.37 (m, 1H), 7.31–7.21 (m, 3H), 6.54 (d, J¼7.6 Hz, 1H), 4.69–4.60 (m,
d
¼204.3, 138.0, 127.5, 127.0, 125.9, 85.2, 46.6, 41.6, 30.3. The enan-
1H), 3.27–3.13 (m, 2H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3):
tiomeric excess was determined by HPLC with an AS-H column
d
¼204.1, 133.9, 133.7, 130.5, 129.7, 127.3, 82.6, 43.7, 43.0, 30.2; IR
(n-hexane/i-PrOH¼90/10, ¼220 nm, 1 mL/min); tR (major enan-
l
(thin film)
n
/cmꢀ1: 2361 (w), 2340 (w), 1718 (s), 1563 (s), 1439 (m),
tiomer)¼22.5 min, tR (minor enantiomer)¼26.6 min, >99% ee.
1359 (m), 1130 (m); HRMS (EI) calcd for C11H11NO3BrCl [Mþ]:
318.9605, found: 318.9608. The enantiomeric excess was de-
termined by HPLC with an OJ-H column (n-hexane/i-PrOH¼95/5,
4.3.12. Compound 4l
Major isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼6.19 (d,
l
¼215 nm, 0.8 mL/min); tR (minor enantiomer)¼43.7 min, tR (ma-
J¼4.8 Hz, 1H), 2.90–2.76 (m, 2H), 2.63–2.55 (m, 1H), 2.17 (s, 3H),
jor enantiomer)¼52.4 min, 98% ee.
1.50–1.26 (m, 4H), 0.95–0.89 (m, 3H); 13C NMR (100 MHz, CDCl3):
Minor isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼7.44–
d
¼205.7, 85.4, 43.9, 39.6, 32.3, 30.2, 19.7, 13.8; IR (thin film)
n :
/cmꢀ1
7.37 (m, 1H), 7.31–7.21 (m, 3H), 6.42 (d, J¼7.6 Hz, 1H), 4.69–4.60 (m,
2361 (w), 2340 (w), 1718 (s), 1564 (s), 1358 (m); HRMS (ESI) calcd
for C8H14NNaO3Br [MþNa]þ: 274.0055, found: 274.0055. The en-
antiomeric excess was determined by HPLC with an IC column
1H), 3.27–3.13 (m, 2H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼203.9, 134.4, 133.9, 130.5, 129.7, 127.4, 81.5, 43.3, 43.0, 30.1. The
enantiomeric excess was determined by HPLC with an OJ-H column
(n-hexane/i-PrOH¼85/15,
tiomer)¼12.1 min, tR (major enantiomer)¼12.4 min, 98% ee.
Minor isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
l¼208 nm, 0.5 mL/min); tR (minor enan-
(n-hexane/i-PrOH¼95/5, ¼215 nm, 0.8 mL/min); tR (major enan-
l
tiomer)¼39.5 min, tR (minor enantiomer)¼41.8 min, 98% ee.
d
¼6.30 (d,
J¼4.8 Hz, 1H), 2.90–2.76 (m, 2H), 2.63–2.55 (m, 1H), 2.18 (s, 3H),
4.3.9. Compound 4i
1.50–1.26 (m, 4H), 0.95–0.89 (m, 3H); 13C NMR (100 MHz, CDCl3):
Major isomer: yellow solid. 1H NMR (400 MHz, CDCl3):
d
¼7.32–
d
¼205.3, 85.2, 43.7, 39.4, 33.0, 30.2, 20.0, 13.7. The enantiomeric
7.27 (m, 2H), 7.25–7.23 (m, 1H), 7.16–7.10 (m, 1H), 6.23 (d, J¼8.4 Hz,
excess was determined by HPLC with an IC column (n-hexane/
1H), 4.17–4.09 (m, 1H), 3.21–3.02 (m, 2H), 2.14 (s, 3H); 13C NMR
i-PrOH¼85/15,
l
¼208 nm, 0.5 mL/min); tR (minor enantio-
(100 MHz, CDCl3):
83.2, 45.9, 45.3, 30.4; IR (thin film)
d
¼203.9, 138.2, 134.8, 130.3, 128.9, 128.3, 126.5,
mer)¼11.0 min, tR (major enantiomer)¼11.4 min, 98% ee.
n
/cmꢀ1: 2361 (w), 2342 (w),
1709 (s), 1559 (s), 1434 (m), 1352 (s), 784 (m); HRMS (EI) calcd for
C11H11NO3BrCl [Mþ]: 318.9605, found: 318.9617. The enantiomeric
excess was determined by HPLC with an IC column (n-hexane/
4.3.13. Compound 4m
Major isomer: white solid. 1H NMR (400 MHz, CDCl3):
d
¼7.34–
7.82 (m, 2H), 7.25–7.20 (m, 2H), 6.26 (d, J¼8.8 Hz, 1H), 4.20–4.13 (m,
i-PrOH¼75/25,
mer)¼10.2 min, tR (major enantiomer)¼10.8 min, >99% ee.
Minor isomer: yellow solid. 1H NMR (400 MHz, CDCl3):
l
¼208 nm, 0.5 mL/min); tR (minor enantio-
1H), 3.18–3.00 (m, 2H), 2.47–2.25 (m, 2H), 1.01–0.96 (m, 3H); 13C
NMR (100 MHz, CDCl3):
46.5, 44.3, 36.6, 7.5; IR (thin film) n
d
¼207.2, 136.2, 129.1, 128.6, 128.2, 83.7,
d
¼7.32–
/cmꢀ1: 2361 (w), 2339 (w), 1711
7.27 (m, 2H), 7.25–7.23 (m, 1H), 7.16–7.10 (m, 1H), 6.33 (d, J¼7.2 Hz,
(s), 1559 (s), 1354 (m), 756 (w); HRMS (EI) calcd for C12H14NO3Br
[Mþ]: 299.0152, found: 299.0143. The enantiomeric excess was
determined by HPLC with an AD-H column (n-hexane/i-PrOH¼75/
1H), 4.17–4.09 (m, 1H), 3.21–3.02 (m, 2H), 2.14 (s, 3H); 13C NMR
(100 MHz, CDCl3):
84.3, 45.5, 45.0, 30.3.
d
¼204.0, 137.9, 134.7, 130.1, 128.9, 128.5, 126.7,
25,
l
¼208 nm, 0.3 mL/min); tR (major enantiomer)¼16.7 min, tR
(minor enantiomer)¼18.8 min, >99% ee.
4.3.10. Compound 4j
Minor isomer: white solid. 1H NMR (400 MHz, CDCl3):
d
¼7.34–
Major isomer: yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼7.36–
7.82 (m, 2H), 7.25–7.20 (m, 2H), 6.35 (d, J¼7.2 Hz, 1H), 4.20–4.13 (m,
7.33 (m, 1H), 6.33–6.28 (m, 1H), 6.27 (d, J¼7.2 Hz, 1H), 6.24–6.22 (m,
1H), 3.18–3.00 (m, 2H), 2.47–2.25 (m, 2H), 1.01–0.96 (m, 3H); 13C
1H), 4.37–4.27 (m, 1H), 3.17–2.99 (m, 2H), 2.17 (s, 3H); 13C NMR
NMR (100 MHz, CDCl3):
46.1, 43.9, 36.5, 7.5. The enantiomeric excess was determined by
d¼207.2, 136.1, 128.9, 128.3, 128.2, 84.8,
(100 MHz, CDCl3):
d
¼204.0, 148.7, 142.9, 110.8, 109.3, 81.8, 42.9,
40.3, 30.2; IR (thin film)
n
/cmꢀ1: 2361 (w), 2340 (w), 1719 (s), 1566
HPLC with an AD-H column (n-hexane/i-PrOH¼75/25, ¼208 nm,
l
(s), 1355 (s), 744 (m); HRMS (ESI) calcd for C9H11NO4Br [MþH]þ:
0.3 mL/min); tR (major enantiomer)¼17.5 min, tR (minor enantio-
mer)¼18.2 min, >99% ee.
275.9871, found: 275.9873. The enantiomeric excess was

Li-t. Dong et al. / Tetrahedron 65 (2009) 4124–4129
4129
4.3.14. Compound 4n
2339 (w), 1714 (s), 1547 (s), 1361 (m), 758 (m); MS (EI): 161
Major isomer: yellow solid. 1H NMR (400 MHz, CDCl3):
d¼7.95–
[MꢀNO2]þ. The enantiomeric excess was determined by HPLC with
7.89 (m, 2H), 7.60–7.55 (m, 1H), 7.48–7.43 (m, 2H), 7.34–7.28 (m,
an AS-H column (n-hexane/i-PrOH¼75/25,
l¼208 nm, 0.8 mL/
5H), 6.39 (d, J¼8.4 Hz, 1H), 4.42–4.35 (m, 1H), 3.76–3.59 (m, 2H);
min); tR (major enantiomer)¼15.9 min, tR (minor enantio-
mer)¼21.8 min, >99% ee.
13C NMR (100 MHz, CDCl3):
d
¼195.9, 136.5, 136.3, 133.5, 129.0,
128.7, 128.6, 128.3, 128.0, 84.1, 46.8, 40.9; IR (thin film) n :
/cmꢀ1
2349 (w), 2325 (w), 1680 (s), 1561 (s), 1350 (m), 747 (m); HRMS (EI)
calcd for C16H14OBr [MꢀNO2]þ: 301.0223, found: 301.0221. The
enantiomeric excess was determined by HPLC with an AD-H col-
Acknowledgements
We thank National Natural Science Foundation of China (No.
20772160), NCET plan of Ministry of Education of China, Guangz-
hou Bureau of Science and Technology for the financial support of
this study.
umn (n-hexane/i-PrOH¼90/10,
enantiomer)¼13.5 min, tR (minor enantiomer)¼17.5 min, 98% ee.
Minor isomer: yellow solid. 1H NMR (400 MHz, CDCl3):
l¼208 nm, 1 mL/min); tR (major
d¼7.95–
7.89 (m, 2H), 7.60–7.55 (m, 1H), 7.48–7.43 (m, 2H), 7.34–7.28 (m,
5H), 6.49 (J¼6.4 Hz, 1H), 4.42–4.35 (m, 1H), 3.76–3.59 (m, 2H); 13C
Supplementary data
NMR (100 MHz, CDCl3):
128.6, 128.5, 128.0, 85.1, 46.3, 40.5. The enantiomeric excess was
d
¼196.0, 136.4, 136.2, 133.6, 128.9, 128.8,
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.03.055.
determined by HPLC with an AD-H column (n-hexane/i-PrOH¼90/
10,
l
¼208 nm, 1 mL/min); tR (major enantiomer)¼10.9 min, tR
(minor enantiomer)¼14.8 min, 98% ee.
References and notes
4.3.15. Compound 5
1. For the general reviews on asymmetric organocatalysis, see: (a) Tsogoeva, S. B.
Eur. J. Org. Chem. 2007, 1701; (b) Guillena, G.; Najera, C.; Ramon, D. J. Tetrahe-
dron: Asymmetry 2007, 18, 2249; (c) Dalko, P. I. Enantioselective Organocatalysis;
Wiley-VCH: Weinheim, 2007; (d) The special issue devoted to: List, B., Ed.
Asymmetric Organocatalysis. Chem. Rev. 2007, 107, 5413; (e) Yu, X. H.; Wang, W.
Chem. Asian J. 2008, 3, 516.
Major isomer: yellow solid. 1H NMR (400 MHz, CDCl3):
d
¼7.33–
7.29 (m, 3H), 7.23–7.21 (m, 2H), 4.21 (dd, J¼9.2, 4.0 Hz, 1H), 3.32–
3.24 (m, 2H), 2.19 (s, 3H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼204.2, 136.0, 129.2, 128.6, 128.5, 98.7, 51.5, 45.9, 30.3, 29.5; IR
2. For the reviews on the activation of
a,b-unsaturated aldehydes and ketones
(thin film) n
/cmꢀ1: 2360 (w), 2339 (w), 1717 (s), 1553 (s), 1357 (m),
with chiral secondary amines, see: (a) Ouellet, S. G.; Walji, A. M.; Macmillan,
D. W. C. Acc. Chem. Res. 2007, 40, 1327; (b) Mielgo, A.; Palomo, C. Chem. Asian J.
2008, 3, 922; (c) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037; (d) Mac-
millan, D. W. C. Nature 2008, 455, 304.
3. For the reviews of primary amine catalysts, see: (a) Peng, F. Z.; Shako, Z. H.
J. Mol. Catal. A: Chem. 2008, 285, 1; (b) Bartoli, G.; Melchiorre, P. Synlett
2008, 1759; (c) Chen, Y. C. Synlett 2008, 1919; (d) Xu, L. W.; Lu, Y. X. Org.
Biomol. Chem. 2008, 6, 2047.
741 (w); HRMS (EI) calcd for C12H14NO3Br [Mþ]: 299.0152, found:
299.0148. The enantiomeric excess was determined by HPLC with
an IC column (n-hexane/i-PrOH¼90/10, ¼208 nm, 0.8 mL/min); tR
l
(minor enantiomer)¼9.4 min, tR (major enantiomer)¼10.2 min,
>99% ee.
Minor isomer: yellow solid. 1H NMR (400 MHz, CDCl3):
d
¼7.33–
4. (a) Rosini, G.; Ballini, R. Synthesis 1988, 833; (b) Ono, N. The Nitro Group in
Organic Synthesis; Wiley-VCH: New York, NY, 2001; (c) Adams, J. P. J. Chem. Soc.,
Perkin Trans. 1 2002, 2586.
7.29 (m, 3H), 7.23–7.21 (m, 2H), 4.33 (dd, J¼10.0, 3.6 Hz, 1H), 3.19–
3.05 (m, 2H), 2.19 (s, 3H), 2.09 (s, 3H); 13C NMR (100 MHz, CDCl3):
5. (a) Vakulya, B.; Varga, S.; Csa´mpai, A.; Soo´s, T. Org. Lett. 2005, 7, 1967; (b) Va-
d
¼203.8, 135.5, 129.4, 128.7, 128.5, 101.5, 50.4, 46.1, 30.2, 29.1. The
´
kulya, B.; Varga, S.; Soos, T. J. Org. Chem. 2008, 73, 3475; (c) Yamaguchi, M.;
enantiomeric excess was determined by HPLC with an IC column
Shiraishi, T.; Igarashi, Y.; Hirama, M. Tetrahedron Lett. 1994, 35, 8233; (d) Ya-
maguchi, M.; Igarashi, Y.; Reddy, R. S.; Shiraishi, T.; Hirama, M. Tetrahedron
1997, 53, 11223; (e) Keller, E.; Veldman, N.; Spek, A. L.; Feringa, B. L. Tetrahedron:
Asymmetry 1997, 8, 3403; (f) Funabashi, K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai,
H.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 7557.
6. (a) Hansen, H. M.; Longbottom, D. A.; Ley, S. V. Chem. Commun. 2006, 4838; (b)
Wascholowski, V.; Hansen, H. M.; Longbottom, D. A.; Ley, S. V. Synthesis 2008,
1269.
7. Zhang, J. M.; Hu, Z. P.; Dong, L. T.; Xuan, Y. N.; Lou, C. L.; Yan, M. Tetrahedron:
Asymmetry 2009, 20, 355.
8. Vesely, J.; Zhao, G. L.; Bartoszewicz, A.; Co´rdova, A. Tetrahedron Lett. 2008, 49,
4209.
9. Lv, J.; Zhang, J. M.; Lin, Z.; Wang, Y. M. Chem.dEur. J. 2009, 15, 972.
10. For the selected examples of asymmetric catalysis by primary amines derived
from cinchona alkaloids, see: (a) Xie, J. W.; Chen, W.; Li, R.; Zeng, M.; Du, W.;
Yue, L.; Chen, Y. C.; Wu, Y.; Zhu, J.; Deng, J. G. Angew. Chem., Int. Ed. 2007, 46,
389; (b) Xie, J. W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J. G.; Chen, Y. C. Org.
Lett. 2007, 9, 413; (c) Liu, T. Y.; Cui, H. L.; Zhang, Y.; Jiang, K.; Du, W.; He, Z. Q.;
Chen, Y. C. Org. Lett. 2007, 9, 3671; (d) Chen, W.; Du, W.; Duan, Y. Z.; Wu, Y.;
Yang, S. Y.; Chen, Y. C. Angew. Chem., Int. Ed. 2007, 46, 7667; (e) Chen, W.; Du,
W.; Yue, L.; Li, R.; Wu, Y.; Ding, L. S.; Chen, Y. C. Org. Biomol. Chem. 2007, 5, 816;
(f) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org.
Lett. 2007, 9, 1403; (g) Carlone, A.; Bartoli, G.; Bosco, M.; Pesciaioli, F.; Ricci, P.;
Sambri, L.; Melchiorre, P. Eur. J. Org. Chem. 2007, 5492; (h) Ricci, P.; Carlone, A.;
Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49;
(i) Li, X. F.; Cun, L. F.; Lian, C. X.; Zhong, L.; Chen, Y. C.; Liao, J.; Zhu, J.; Deng, J. G.
Org. Biomol. Chem. 2008, 6, 349; (j) Kang, T. R.; Xie, J. W.; Du, W.; Feng, X.; Chen,
Y. C. Org. Biomol. Chem. 2008, 6, 2673; (k) Tan, B.; Chua, P. J.; Li, Y. X.; Zhong, G. F.
Org. Lett. 2008, 10, 2437; (l) Tan, B.; Shi, Z. G.; Chua, P. J.; Zhong, G. F. Org. Lett.
2008, 10, 3425; (m) Tan, B.; Chua, P. J.; Zeng, X. F.; Lu, M.; Zhong, G. F. Org. Lett.
2008, 10, 3489; (n) Wang, X. W.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2008,
130, 6070; (o) Li, X. J.; Liu, Y.; Sun, B. F.; Cindric, B.; Deng, L. J. Am. Chem. Soc.
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11. Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170.
(n-hexane/i-PrOH¼90/10,
l¼208 nm, 0.8 mL/min); tR (minor
enantiomer)¼12.4 min, tR (major enantiomer)¼13.7 min, >99% ee.
4.3.16. Compound 6
20
Yellow oil. [
CDCl3):
a
]
¼þ14.0 (c 1.5, CHCl3); 1H NMR (400 MHz,
D
d
¼7.30–7.27 (m, 3H), 7.25–7.22 (m, 2H), 4.21 (dd, J¼8.4,
6.0 Hz, 1H), 3.24–3.23 (m, 2H), 2.09 (s, 3H), 2.57–2.48 (m, 1H), 2.19–
2.10 (m, 1H), 1.08 (t, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
¼204.4, 136.3, 129.2, 128.5, 111.0, 51.0, 46.6, 35.7, 30.5, 10.1; IR (thin
film) n
/cmꢀ1: 2349 (w), 2339 (w), 1721 (s), 1557 (s), 1418 (w), 1357
(m), 816 (w); HRMS (EI) calcd for C13H16NO3Br [Mþ]: 313.0308,
found: 313.0309. The enantiomeric excess was determined by HPLC
with an IC column (n-hexane/i-PrOH¼75/25, ¼208 nm, 0.5 mL/
l
min); tR (minor enantiomer)¼10.0 min, tR (major enantio-
mer)¼11.1 min, >99% ee.
4.4. Experimental procedure for the debromination of 4a14
Under nitrogen atmosphere, a solution of 4a (57.2 mg, 0.2 mmol,
dr: 57:43, ee: >99%/>99%), Bu3SnH (65 mL, 0.24 mmol), and AIBN
(6.7 mg, 0.04 mmol) in dry toluene (1.5 mL) was sealed in a quartz
tube. The solution was irradiated with a UV lamp for 10 h. The
solvent was removed under vacuum and the residue was purified
by flash column chromatography over silica gel (EtOAc/petroleum
20
ether) to give 7 as a white solid (35.6 mg, 86% yield). [
a
]
¼þ2.0 (c
D
3.0, CHCl3); mp: 118–119 ꢁC; 1H NMR (400 MHz, CDCl3):
d¼7.35–
12. Brunner, H.; Bu¨ gler, J.; Nuber, B. Tetrahedron: Asymmetry 1995, 6, 1699.
13. The diastereoisomers of 4 and 5 are inseparable by column chromatography.
Their 1H NMR and 13C NMR data were obtained by analyzing the NMR spectra
of the mixtures. However, IR and MS spectroscopic data could not be assigned
individually for them.
7.27 (m, 3H), 7.23–7.21 (m, 2H), 6.70 (dd, J¼6.8, 12.4 Hz, 1H), 4.60
(dd, J¼8.0, 12.0 Hz, 1H), 4.05–3.97 (m, 1H), 2.92 (d, J¼6.8 Hz, 2H),
2.12 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼205.4, 138.8, 129.0,
127.9, 127.3, 79.4, 46.1, 39.0, 30.3; IR (thin film)
n
/cmꢀ1: 2360 (w),
14. Blay, G.; Herna´ndez-Olmos, V.; Pedro, J. R. Chem. Commun. 2008, 4840.