Chiral 2-aminobenzimidazole bifunctional organocatalysts: Effect of di-CF3 and TFA on catalytic mechanisms

Article abstract of DOI:10.1016/j.tet.2011.12.021

(S,S)-trans-Cyclohexanediamine-5,7-di-CF₃-benzimidazole (3b) was developed as a new chiral bifunctional organocatalyst and successfully applied to Michael addition of diethyl malonate to nitroolefins (up to 99%, 98% ee) under neutral condition.

Full text of DOI:10.1016/j.tet.2011.12.021

Tetrahedron 68 (2012) 1452e1459
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chiral 2-aminobenzimidazole bifunctional organocatalysts: effect of di-CF3 and
TFA on catalytic mechanisms
,
Myungmo Lee a, Lei Zhang a, Yohan Park b, Hyeung-geun Park a
*
a Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, San 56-1, Sinllim-dong, Kwanak-gu, Seoul 151-742, Republic of Korea
b College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 October 2011
Received in revised form 9 December 2011
Accepted 10 December 2011
Available online 16 December 2011
(S,S)-trans-Cyclohexanediamine-5,7-di-CF3-benzimidazole (3b) was developed as
a new chiral bi-
functional organocatalyst and successfully applied to Michael addition of diethyl malonate to nitroolefins
(up to 99%, 98% ee) under neutral condition. Systematic investigation on the catalytic mechanism re-
vealed that the role of the guanidine moiety and the dimethylamine moiety in catalysts might be re-
versed with respect to Brønsted/Lewis acidic or basic functionalities, depending on the reaction
conditions (neutral or TFA co-catalyst). Generally, di-CF3 group substituted 2-aminobenzimidazole cat-
alysts in neutral condition and non-substituted 2-aminobenzimidazole catalysts in co-catalyst (TFA)
condition give high chemical yield and enantioselectivity.
Keywords:
Chiral 2-aminobenzimidazole
Bifunctional organocatalysis
Asymmetric synthesis
Catalytic mechanism
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
could facilitate the cleavage of phosphate esters to cyclic phosphate
and the corresponding alcohol. Since the 2-aminobenzimidazole
Since the Jacobsen group reported the metal-free Strecker re-
action by using the first thiourea-based chiral ligands as hydrogen
bond donors in 1998,1 thioureas have been extensively developed
as Brønsted/Lewis acid organocatalysts, and successfully applied to
various useful organic reactions thus far.2e8 Especially, chiral amine
conjugated thioureas have been used as chiral bifunctional orga-
nocatalysts capable of simultaneously activating both nucleophiles
and electrophiles in asymmetric reactions due to their Brønsted/
Lewis acidic (thiourea moiety) and basic (chiral amine moiety)
functionalities.9e21
Among the disclosed thiourea-based catalysts, the N-5,7-
bis(trifluoromethyl)phenyl group substituted catalysts, which was
first introduced by the Schreiner group in 2002, have been widely
used as chiral bifunctional catalysts.22 The electron-withdrawing
CF3 group not only increases NeH acidity, which in turn facilitates
a stronger hydrogen bonding interaction, but also contributes to the
conformational rigidity of the catalyst by polarizing the adjacent H
atoms and inducing an intramolecular hydrogen bonding in-
teraction with the sulfur atom in the thioureas (Fig.1).23 In 2005, the
group is conformationally more rigid and can potentially serve as
new Brønsted/Lewis acid catalysts, we recently reported new 2-
aminobenzimidazoles conjugated with cinchona alkaloid (Fig. 2; 1,
2) and successfully applied to enantioselective Michael additions.25
ꢀ
Independently, Alonso and Najera also developed a very efficient
trans-cyclohexanediamine-benzimidazole (3a), which could pro-
mote the conjugate addition of a wide variety of 1,3-dicarbonyl
compounds to nitroolefins.26 Very recently, Takemoto disclosed
quinazoline and benzothiadiazine type bifunctional organocatalysts
having cyclic guanidine skeletons.27 In this article, we report the
synthesisand application of (S,S)-trans-cyclohexanediamine-5,7-di-
CF3-benzimidazole (3b) as a new efficient chiral bifunctional orga-
nocatalysts and also investigated the catalytic mechanism of chiral
2-aminobenzimidazole type bifunctional organocatalysts at differ-
ent reaction conditions.
Takemoto showed briefly that the stereoselectivity depended on
functional groups, substituted on the N-phenyl ring of the thiourea
€
Gobel group reported that the cleavage of RNA could be catalyzed by
tris[2-(benzimidazol-2-ylamino)ethyl]amine under neutral condi-
tions (pH 7.0).24 The guanidine moiety in 2-aminobenzimidazoles
efficiently activated phosphates by hydrogen bonding, which
* Corresponding author. Tel.: þ82 2 880 8264; fax: þ82 2 872 9129; e-mail ad-
dress: hgpk@snu.ac.kr (H.-geun Park).
Fig. 1. Chiral thiourea and benzimidazole bifunctional organocatalysts.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.021

M. Lee et al. / Tetrahedron 68 (2012) 1452e1459
1453
Table 1
Effects of electron-withdrawing di-CF3 group
Entrya
Catalyst
Solvent
T (ꢀC)
Time (h)
Yieldb (%)
eec (%)
Fig. 2. Chiral 2-aminobenzimidazole type bifunctional organocatalysts.
1
2
3
4
5
6
3a
3b
3b
3b
3b
3b
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
0
6
6
6
24
72
96
45
99
97
99
96
87
78(R)
90(R)d
90(R)
93(R)
95(R)
98(R)
moiety.9 Recently, Luo also reported the relationship between the
pKa values and stereoselectivity of thiourea bifunctional catalysts
with the respect to electron-withdrawing functionality.28 Both re-
ports revealed in concord that the di-CF3 group was the best
electron-withdrawing functional group for high enantioselectivity.
Based on the positive effects of the electron-withdrawing group in
the thiourea system, we used the di-CF3 group in the 2-
aminobenzimidazole system (1 and 2), which was very effective
for high enantioselectivity.25 In a continuation of our studies on the
development of new 2-aminobenzimidazole bifunctional organo-
catalysts, we attached the di-CF3 group onto trans-cyclohexanedi-
amine-benzimidazole (3a), which was previously optimized by
ꢁ20
ꢁ40
a
Reactions were carried out with 4a (0.2 mmol), 5 (0.4 mmol), and catalyst 3
(0.02 mmol) in 0.5 mL CH2Cl2 at room temperature.
b
Isolated yield.
c
Determined by chiral HPLC analysis (Chiralpak AD-H, hexane/EtOH 90/10).
Absolute configurations were determined by comparison of the optical rotation
d
of 6a with reported values.
Table 2
Michael addition of diethyl malonate to nitroolefins
ꢀ
Alonso and Najera in the presence of TFA as co-catalyst.
2. Results and discussion
2.1. (S,S)-trans-Cyclohexanediamine-5,7-di-CF3-
benzimidazole catalyst
Entrya
1a
2
3
4
5
6
7
R
Time (h)
Yieldb (%)
eec (%)
C6H5 (4a)
24
40
24
24
24
40
40
24
72
99 (6a)
87 (6b)
96 (6c)
95 (6d)
93 (6e)
90 (6f)
94 (6g)
93 (6h)
82 (6i)
93(R)d
91(R)
91(R)
92(R)
94(R)
93(R)
96(R)
91(R)
90(R)
4-MeC6H5 (4b)
4-ClC6H5 (4c)
4-BrC6H5 (4d)
2-BrC6H5 (4e)
4-MeOC6H5 (4f)
2-MeOC6H5 (4g)
As shown in Scheme 1, catalyst 3b could be prepared from 7b in
two steps, based on our previously reported method.25 The cou-
pling of 7b with (S,S)-trans-cyclohexanediamine under microwave
irradiation at 175 ꢀC, followed by N,N-dimethylation with formal-
dehyde in formic acid afforded (S,S)-trans-cyclohexanediamine-
5,7-di-CF3-benzimidazole (3b).
8
b
-Naphthyl (4h)
9e
n-Hexyl (4i)
a
Reactions were carried out with 4 (0.2 mmol), 5 (0.4 mmol), and catalyst 3b
(0.02 mmol) in CH2Cl2 (0.5 mL) at 0 ꢀC.
b
Isolated yield.
Determined by chiral HPLC analysis.
Absolute configurations were determined by comparison of the optical rotation
c
d
of 6 with reported values.
e
Catalyst 3b (0.04 mmol) was used.
Scheme 1. Preparation of catalysts 3a and 3b.
The catalytic efficiency of 3b along with the reference catalyst 3a
was evaluated by the Michael addition of diethyl malonate to 4a in
dichloromethane at room temperature under neutral condition. As
shown in Table 1, (S,S)-trans-cyclohexanediamine-5,7-di-CF3-
benzimidazole (3b) (entry 2, 99%, 90% ee) showed higher chemical
yield and enantioselectivity, compared to (S,S)-trans-cyclo-
hexanediamine-benzimidazole (3a)(entry 1, 45%, 78%ee). Thelower
catalytic efficiency of 3a, relative to its trifluoromethyl analog 3b,
implies that the trifluoromethyl group clearly played an important
role in both chemical yield and enantioselectivity, which is in
agreement with our previous results.25 Lower temperatures resul-
ted in increased enantioselectivities with longer reaction time up to
98% ee (entries 4e6). Reaction solvent seemed insensitive to enan-
tioselectivity, but slightly higher chemical yield was observed in
CH2Cl2, compared to toluene (entries 2 and 3).
Further investigation into the scope and limitations was per-
formed using various nitroolefins 4bei at 0 ꢀC (entry 3 in Table 1),
which resulted in very high chemical yields (R-6, up to 99%) and
enantioselectivities (R-6, up to 96% ee) were obtained (Table 2).
Notably, the catalyst 3b could be recovered from the reaction
mixture by acid/base extraction in work-up process (93%), and it
could be used without loss of both chemical yield and
stereoselectivity.
2.2. Investigation on reaction mechanisms
ꢀ
As mentioned earlier, Alonso and Najera developed trans-
cyclohexanediamine-benzimidazole (3a) as Brønsted/Lewis acid
bifunctional organocatalysts in 2009.26 It is interesting that they
used stoichiometric amounts of TFA to catalyst 3a as a co-catalyst,
which is in contrast to the usual neutral condition used for case 1,
2, and other thiourea catalysts. So we tried to systematically in-
vestigate the catalytic reaction mechanism of benzimidazole
organocatalysts at different reaction conditions. First, we chose four
of representative chiral 2-aminobenzimidazoles (1a, b, 3a, b) and
their catalytic efficiency was evaluated by the Michael addition of
diethyl malonate to 4a in dichloromethane under neutral condi-
tions or using TFA as a co-catalyst in toluene.
As shown in Table 3, there was quite dramatic variation in
chemical yield and enantioselectivity depending on the reaction
conditions according to the presence of co-catalyst (TFA) and the
electron-withdrawing di-CF3 group in catalyst. Generally, all of the
four catalysts under neutral conditions afforded Michael adduct 6a
in high chemical yield and enantioselectivity within 16 h at room
temperature (entries 1, 4, 6, and 12). In the case of using 10 mol %
TFA in toluene as co-catalyst, non-functionalized catalysts (1a and
3a) gave higher enantioselectivities and comparable chemical

1454
M. Lee et al. / Tetrahedron 68 (2012) 1452e1459
Table 3
Effects of the electron-withdrawing di-CF3 group and co-catalyst (TFA) on the reaction mechanisms
Entrya
1
Catalyst
Additive (mol %)
Solvent
CH2Cl2
Temp (ꢀC)
rt
Time (h)
16
Yieldb (%)
92
eec (%)
d
82(S)e
N
OCH3
N
NH
N
2
3
TFA (10)
TFA (20)
Toluene
Toluene
rt
rt
48
72
97
91(S)
N
H
NRd
d
a
1
N
OCH3
4
5
d
CH2Cl2
rt
rt
6
95
89(S)
F3C
N
NH
N
NRd
d
N
H
TFA (10)
Toluene
72
CF3
1b
6
d
CH2Cl2
rt
16
95
78(R)
N
7
8
9
10
11
TFA (10)
TFA (20)
TFA (10)
TFA (10)
TFA (10)
Toluene
Toluene
Toluene
Toluene
Toluene
rt
rt
0
48
72
72
72
96
95
89(R)
d
NH
N
NRd
32
N
H
94(R)
d
a
3
ꢁ20
Trace
ꢁ40
NRd
d
12
d
CH2Cl2
rt
6
99
90(R)
F3C
N
NRd
99
96
NH
N
13
14
15
16
TFA (10)
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
rt
0
72
24
72
96
d
N
H
d
d
d
93(R)
95(R)
98(R)
F
C
ꢁ20
3
3b
ꢁ40
87
a
Reactions were carried out with 4a (0.2 mmol), 5 (0.4 mmol), catalyst (0.02 mmol), and additive in CH2Cl2 (0.5 mL) at room temperature.
Isolated yield.
Determined by chiral HPLC analysis (Chiralpak AD-H, hexane/EtOH 90/10).
No reaction.
Absolute configurations were determined by comparison of the optical rotation of 6a with reported values.
b
c
d
e
yields with longer reaction time (three times) than those under the
Since the proton abstraction of diethyl malonate was relatively slow
due to the weak basicity of guanidine, compared to dimethylamine,
a longer time would be required to complete the reaction than that
at the neutral condition. The further addition of TFA (20 mol %)
protonate both of the basic moieties (dimethylamine and guani-
dine) in the catalyst, which would result in no reaction. In case of
the di-CF3 substituted catalysts (1b and 3b), the electron-
withdrawing effect of di-CF3 would decrease the basicity of gua-
neutral condition (entries 1, 2, 6, and 7). The TFA co-catalyst clearly
contributed the increase of enantioselectivity. However, no reaction
occurred at higher TFA concentration (20 mol %) (entries 3 and 8).
The di-CF3 functional group on catalyst (1b and 3b) in neutral
condition, could recover the enantioselectivities with faster re-
action time (eight times), compared to those of non-functionalized
catalysts in acid co-catalytic condition (entries, 2, 4, 7, and 12).
Notably, the di-CF3 substituted catalysts, 1b and 3b afforded no
Michael adduct even in the presence of TFA (10 mol %) (entries 5
and 13). Generally, lower temperatures gave increased enantiose-
lectivities with longer reaction time in the presence of 3b under
neutral condition (entries 14e16, 93e98% ee). However, the slow
reaction in the case of 3a under TFA co-catalyst condition resulted
in quite low chemical yields (entry 9, 32%, 0 ꢀC; entry 10, trace,
ꢁ20 ꢀC) or no reaction (entry 11, ꢁ40 ꢀC).
nidine so that it could no longer abstract the a-proton of diethyl
malonate, which would also cause no reaction in the presence of
the co-catalyst TFA (10 mol %).
To confirm that guanidine functions as
a base in non-
substituted 2-aminobenzimidazole, we prepared three of chiral
dimeric benzimidazole catalysts (9e11) and compared their bi-
functional catalytic efficiency in the Michael reaction. As shown in
Table 4, both catalysts 9 and 11, which possess a non-substituted
benzimidazole moiety, afforded the Michael adduct with moder-
These cumulative results led us to hypothesize that following
reaction mechanism occurred when the co-catalyst (TFA) was
added. First of all, TFA protonated the basic dimethylamine moiety
in catalyst, which then activated nitroolefin via hydrogen bonding.
The guanidine moiety of the catalyst would then act as a weak base
ate chemical yields (entries
2 and 4), while the tetra-CF3
substituted catalyst 10 showed no reaction due to the lack of ba-
sicity (entry 3). Notably, catalyst 11 showed some level of enan-
tioselectivity, while no enantioselectivity was observed in the case
of 9. Each non-substituted benzimidazole moiety and di-CF3
substituted benzimidazole moiety of 11 acts as a base and
to abstract the
a-proton of diethyl malonate forming an ion-pair,
which then performed the 1,4-addition to afford Michael adducts.

M. Lee et al. / Tetrahedron 68 (2012) 1452e1459
1455
Table 4
malonate to form an ion-pair located downside to 4a (Fig. 3, B). As
a consequence, the malonate anion can only approach the -carbon
of the nitroolefin from the downside during the 1,4-nucleophilic
addition, affording the R isomer (6a) again. These mechanisms
are all in agreement with the experiment results.
Dimeric benzimidazole catalysts
b
EtO2C
Ph
CO2Et
NO2
O
O
cat. (10 mol%)
NO2
+
Ph
EtO
OEt
CH2Cl2, r.t.
5
6a
4a
3. Conclusion
Entrya
1d
Catalyst
Time (h) Yieldb (%) eec (%)
(S,S)-trans-Cyclohexanediamine-5,7-di-CF3-benzimidazole (3b)
was prepared as an efficient chiral bifunctional organocatalysts by
the incorporation of the electron-withdrawing di-CF3 groups on the
benzimidazole moiety and successfully applied to Michael addi-
tions of diethyl malonate to nitroolefins. The catalytic mechanism
of 2-aminobenzimidazole bifunctional organocatalysts under dif-
ferent reaction conditions was also investigated. Under a neutral
condition, the dimethylamine moiety and guanidine moiety play
Triethylamine
48
15
rac
N
N
NH HN
2
3
88
24
rac
N
H
N
H
9
the role of base to abstract the
a-hydrogen of malonate and
F3C
N
F
3
C
N
Brønsted/Lewis acid to activate nitroolefin, respectively. However,
the dimethylamine moiety, which is protonated under TFA co-
catalyst condition, serves to form hydrogen bonds with nitro-
olefin as a Brønsted/Lewis acid, and the guanidine moiety then
NH HN
72
24
NR
20
d
N
H
N
H
C
F
C
F
3
3
10
functions as a weak base to abstract the a-hydrogen of malonate,
which in turn forms an ion pair between the guanidinium cation
and malonate anion. In short, the role of guanidine moiety and
dimethylamine moiety might be reversed depending on the two
reaction conditions. The positive basic role of 2-
aminobenzimidazoles, compared to thioureas, quinazoline, and
benzothiadiazine, might be applied to design new efficient bi-
functional organocatalysts.
CF3
N
N
4
15(R)e
NH HN
N
H
N
H
CF3
11
a
Reactions were carried out with 4a (0.2 mmol), 5 (0.4 mmol), and catalyst
(0.02 mmol) in CH2Cl2 (0.5 mL) at room temperature.
b
Isolated yield.
c
Determined by chiral HPLC analysis.
Triethylamine (0.2 mmol) was used.
Absolute configurations were determined by comparison of the optical rotation
4. Experimental
4.1. General
d
e
of 6a with reported values.
Microwave experiments were run using CEM Discover S mi-
crowave instrument with external surface temperature sensor. The
flash column chromatography was carried out over silica gel
(230e400 mesh). NMR spectra were measured on 300, 400 MHz
Brønsted/Lewis acid, respectively, which could induce enantio-
selectivity. However, each of two non-substituted benzimidazoles
in 9 could function as either a base or a Brønsted/Lewis acid, which
would result in no enantioselectivity.
Based on these finding, plausible reaction mechanisms under
the two reaction conditions are shown in Fig. 3. In the case of the
electron-withdrawing di-CF3 group substituted catalysts (1b and
3b), the nitro group of substrate 4a forms hydrogen bonds with two
NeH moieties from the catalysts with the assistance of the di-CF3
groups, while the dimethylamine of the (S,S)-trans-cyclohexyldi-
instruments. Chemical shifts (ppm, d) are relative to the solvent
(CDCl3, CD3OD, DMSO-d6). Peaks are identified as singlet (s), dou-
blet (d), triplet (t), quartet (q), and multiplet (m). HRMS spectral
data were measured with FAB positive ion mode. Infrared spectra
were recorded on FT-IR spectrophotometer as neat thin films. Op-
tical rotations were determined using the sodium D line (589 nm).
4.2. Synthesis of catalysts
amine moiety abstracts an
an ion-pair located upside to 4a (Fig. 3, A). As a consequence, the
malonate anion can only approach the -carbon of the nitroolefin
a-proton from diethyl malonate to form
4.2.1. Synthesis of 2-chlorobenzimidazole (7a).
b
from the upside during the 1,4-nucleophilic addition, affording the
R isomer (6a). In the case of the non functional group substitute
catalysts (1a and 3a), the dimethylamine moiety is protonated by
the stoichiometric amount of TFA to catalysts, which forms hy-
drogen bonds with the nitro group of substrate 4a, while the gua-
nidine moiety acts as a base to abstract an
a-proton of diethyl
A
mixture of 3,5-di(trifluoromethyl)aniline (A, 7.40 g,
32.3 mmol) and acetic anhydride (30 mL) was stirred at room
temperature for 3 h. The reaction mixture was evaporated in vacuo
Fig. 3. Proposed mechanism: (A) neutral condition; (B) TFA co-catalyst condition.

1456
M. Lee et al. / Tetrahedron 68 (2012) 1452e1459
to yield acetamide B (8.42 g, 31.1 mmol) as a white solid (96%),
which was used in the next step without further purification. Mp
1638, 1530, 1484, 1432, 1389, 1350, 1277, 1193, 1128, 1079, 984, 887,
761, 732 cmꢁ1. MS FABþ (m/z): [MþH]þ 289.
159.3e159.9 ꢀC. 1H NMR (300 MHz, CDCl3)
d
8.00 (s, 2H), 7.58 (s,
1H), 7.44 (s, 1H), 2.21 (s, 3H) ppm. 13C NMR (125 MHz, CD3OD)
172.92, 142.92, 134.42 (q, J¼32.7 Hz), 128.76 (q, J¼270.1 Hz),
4.2.2. Non-functional group substituted catalysts (8a, 9, and 4a). To
(S,S)-trans-cyclohexanediamine (170.0 mg, 1.5 mmol) was added an
acetonitrile (1.0 mL) and DMF (0.1 mL) solution of 2-
chlorobenzimidazole 7a (152.0 mg, 1.0 mmol) in a microwave vial
(10 mL) with a stir bar. After sealing of reaction vial, followed by
placing to CEM Discover S microwave instrument with surface
temperature sensor, the reaction mixture was heated to 180 ꢀC and
stirred for 50 min. After cooling to room temperature, the reaction
solvent was removed in vacuo. The residue was purified by flash
column chromatography (EtOAc/hexane) to yield 9 (65.9 mg,
0.21 mmol) as a white solid (21%), followed by eluting MeOH in
EtOAc to yield 8a (122.1 mg, 0.53 mmol) as a yellow solid (53%).
d
121.08, 118.30, 24.75 ppm; IR (KBr) 3289, 1680, 1624, 1570, 1470,
1437, 1383, 1274, 1146, 1021, 918, 884, 842, 740, 699, 679 cmꢁ1
;
FABMS m/z: 272 [MþH]þ.
To a solution of acetamide B (8.07 g, 29.7 mmol) in concentrated
sulfuric acid (30 mL) was added 90% nitric acid (4 mL) in dropwise
with stirring at 0 ꢀC. The resulting solution was stirred at room
temperature for 3 h and poured into crushed ice. The mixture was
carefully neutralized with solid NaHCO3 and extracted by EtOAc.
The combined organic extracts were washed with water and brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane/EtOAc)
to yield the nitro derivative C (4.48 g, 14.2 mmol) as white solid
4.2.2.1. (1R,2R)-N1-(1H-Benzo[d]imidazol-2-yl)cyclohexane-1,2-
(47%). Mp 183.5e184.0 ꢀC. 1H NMR (300 MHz, CDCl3)
7.96 (s, 1H), 7.59 (s, 1H), 2.25 (s, 3H) ppm; 13C NMR (125 MHz,
CD3OD)
d
8.89 (s, 1H),
diamine (8a). Analytical data match the literature.26 Mp
231e233 ꢀC. 1H NMR (300 MHz, CD3OD):
d 7.18e7.06 (m, 2H),
d
173.30, 146.03, 135.36 (q, J¼34.0 Hz), 134.54, 130.87,
6.95e6.86 (m, 2H), 3.72e3.58 (m, 1H), 3.09e2.96 (m, 1H),
127.83 (q, J¼271.4 Hz), 126.92 (q, J¼271.7 Hz), 126.56 (q, J¼34.5 Hz),
122.89, 23.91 ppm; IR (KBr) 3240, 1683, 1542, 1452, 1360, 1308,
1275, 1209, 1182, 1129, 900, 876, 826, 672 cmꢁ1; FABMS m/z: 317
[MþH]þ.
2.15e2.05 (m, 2H), 1.81e1.65 (m, 2H), 1.53e1.10 (m, 4H) ppm. 13C
NMR (100 MHz, CD3OD):
d 156.5, 139.1, 122.7, 113.8, 67.3, 57.1, 56.6,
34.1, 32.3, 26.4, 25.8 ppm. FT-IR (neat): 3211, 3011, 2939, 2861, 1631,
1602, 1578, 1468, 1410, 1389, 1271, 1120, 1020, 929, 848, 754 cmꢁ1
.
To a solution of the compound C (4.48 g, 14.2 mmol) in MeOH
(8 mL) was added aqueous 3 N NaOH (50 mL) at room tempera-
ture. The reaction mixture was stirred at 110 ꢀC for 2 h, cooled to
room temperature, and extracted by EtOAc, washed with water
and brine, dried over Na2SO4, purified by silica gel column
chromatography (hexane/EtOAc), which was used in the next
step immediately because compound D is unstable in the air. To
a solution of the aniline D in EtOH (50 mL), was added 10% Pd/C
(0.3 g) under argon atmosphere. Charged in hydrogen and stirred
at room temperature for 2 h, filtered through a short pad of
Celite, concentrated in vacuo. The residue was purified by silica
gel column chromatography (hexane/EtOAc) to yield diamine E
(3.43 g, 14.1 mmol) as a yellow solid (99%). Mp 46.5e47.7 ꢀC. 1H
HRMS FABþ (m/z): [MþH]þ calcd for C13H19N4þ231.1610, found
231.1611. ½a 2D4
ꢁ27.60 (c 0.28, MeOH).
ꢂ
4.2.2.2. (1R,2R)-N1,N2-Bis(1H-benzo[d]imidazol-2-yl)cyclohex-
ane-1,2-diamine (9). Analytical data match the literature.26 Mp
188e190 ꢀC. 1H NMR (300 MHz, CD3OD):
d 7.17e7.09 (m, 4H),
6.96e6.89 (m, 4H), 3.73e6.69 (m, 2H), 2.28e2.17 (m, 2H), 1.86e1.69
(m, 2H), 1.59e1.40 (m, 4H) ppm. FT-IR (neat): 2926, 1634, 1604,
1575, 1469, 1401, 1287, 1263, 1224, 1070, 1033, 1005, 932, 731 cmꢁ1
.
4.2.2.3. (1R,2R)-N1-(1H-Benzo[d]imidazol-2-yl)-N2,N2-dimethyl-
cyclohexane-1,2-diamine (3a). This compound was prepared
according to the literature procedure.26 Compound 8a (390.0 mg,
1.7 mmol) was added to a solution of 80% formic acid (8.0 mL) and
NMR (300 MHz, CD3OD)
CD3OD)
d
7.05 (s, 2H) ppm; 13C NMR (125 MHz,
138.98, 138.42, 130.29 (q, J¼270.0 Hz), 129.97 (q,
d
36% aqueous formaldehyde (295 mL, 3.7 mmol) in round-bottom
J¼268.0 Hz), 120.98 (q, J¼32.7 Hz), 115.95, 114.49, 114.14 (q,
J¼29.9 Hz) ppm; IR (KBr) 3397, 1637, 1509, 1456, 1393, 1345, 1306,
1276, 1236, 1159, 1113, 940, 881, 726, 666 cmꢁ1; FABMS m/z: 245
[MþH]þ.
flask (10 mL) with a stir bar. The reaction mixture was stirred for
16 h at 120 ꢀC. After removal of solvent, the pH of solution was
adjusted to 8 by saturated NaHCO3 solution and 1 N NaOH solution.
After extraction with DCM (20 mLꢃ3), the combined solution was
concentrated in vacuo. The residue purified by flash column chro-
matography (EtOAc/MeOH) and then recrystallized in hexane/DCM
to yield 3a (130.1 mg, 0.50 mmol) as a white solid (30%). Analytical
data match the literature. Mp 232e234 ꢀC. 1H NMR (300 MHz,
To a solution of diamine E (2.4 g, 9.84 mmol) in 50 mL THF, was
added 1,10-carbonylbis-1H-imidazole (1.76 g, 10.85 mmol), the re-
action mixture was stirred at room temperature for 3 h. Solvent was
evaporated out and the residue was purified by silica gel column
chromatography (hexane/EtOAc) to yield urea F (2.43 g, 8.99 mmol)
as a white solid (91%). Mp 227.7e228.5 ꢀC. 1H NMR (300 MHz,
CDCl3): d 7.29e7.21 (m, 2H), 7.21e6.95 (m, 2H), 5.48 (br s, 1H), 3.43
(td, J¼12, 4 Hz, 1H), 2.68e2.58 (m, 1H), 2.32e2.22 (m, 1H), 2.18 (s,
CD3OD)
157.79, 132.80, 130.81 (partly overlapping signal), 130.81 (q,
d
7.52 (s, 1H), 7.48 (s, 1H) ppm; 13C NMR (75 MHz, CD3OD)
6H), 1.87e1.72 (m, 2H), 1.68e1.58 (m, 1H), 1.34e1.04 (m, 4H) ppm.
d
13C NMR (100 MHz, CDCl3):
d 155.8, 138.2, 120.3, 112.3, 111.9, 67.3,
J¼271.5 Hz), 129.98 (q, J¼268.8 Hz), 125.18 (q, J¼33.15 Hz), 116.15
(m), 113.34 (q, J¼34.6 Hz), 110.20 ppm; IR (KBr) 3149, 1700, 1466,
1399, 1322, 1267, 1129, 1016, 895, 882, 761, 703 cmꢁ1; FABMS m/z:
271 [MþH]þ.
54.1, 39.9, 33.3, 25.3, 24.4, 21.2 ppm. FT-IR (neat): 3275, 3056, 2933,
2861, 2828, 2784, 1631, 1599, 1576, 1464, 1364, 1270, 1205, 1145,
1065,1043, 948, 876, 740 cmꢁ1. HRMS FABþ (m/z): [MþH]þ calcd for
C15H23Nþ4 259.1923, found 259.1924. ½a 2D4
ꢁ39.6 (c 1.0, CH2Cl2).
ꢂ
A solution of urea F (2.4 g, 8.89 mmol) in 50 mL POCl3 was
heated to reflux for 15 h. Cooled to room temperature, evaporated
out the solvent, neutralized with saturated NaHCO3, and extracted
by EtOAc, the organic phase was washed with water and brine,
dried over Na2SO4, concentrated, and purified by silica gel column
chromatography (hexane/EtOAc) to give 2-chlorobenzimidazole 7a
(2.01 g, 6.97 mmol) as a white solid (78%). Analytical data match the
4.2.3. Di-CF3 group substituted catalysts (8b, 10, and 3b). (S,S)-
trans-Cyclohexanediamine (170.0 mg, 1.5 mmol) was added to an
acetonitrile solution (1.0 mL) of 5,7-di-(trifluoromethyl) substituted
2-chlorobenzimidazole 7b (288.6 mg,1.0 mmol) in a microwave vial
(10 mL) with a stir bar. After sealing of reaction vial, followed by
placing to CEM Discover S microwave instrument with surface
temperature sensor, the reaction mixture was heated to 175 ꢀC and
stirred for 50 min. After cooling to room temperature, the reaction
solvent was removed in vacuo. The residue was purified by flash
column chromatography (EtOAc/hexane) to yield 10 (116.8 mg,
literature.25 mp 170e171 ꢀC. 1H NMR (300 MHz, CD3OD):
d 7.96 (s,
146.6, 141.7,
1H), 7.79 (s, 1H) ppm. 13C NMR (125 MHz, CD3OD):
d
138.8, 129.4 (q, J¼269.5 Hz), 128.5 (q, J¼269.6 Hz), 127.2 (q,
J¼33.3 Hz), 119.3, 118.8 (m), 118.2 ppm. FT-IR (neat): 3019, 2835,

M. Lee et al. / Tetrahedron 68 (2012) 1452e1459
1457
0.19 mmol) as a white solid (19%), followed by eluting MeOH in
EtOAc to yield 8b (173.7 mg, 0.47 mmol) as a yellow solid (47%).
3059, 2939, 2862, 1631, 1578, 1465, 1387, 1338, 1285, 1240, 1189,
1166, 1121, 1040, 983, 878, 759, 742, 718, 692, 662 cmꢁ1. HRMS FABþ
(m/z): [MþH]þ calcd for C22H21F6N6þ 483.1732, found 483.1727. ½a D24
ꢂ
4.2.3.1. (1R,2R)-N1-(5,7-Bis(trifluoromethyl)-1H-benzo[d]imida-
zol-2-yl)cyclohexane-1,2-diamine (8b). Mp 275e277 ꢀC. 1H NMR
þ115.25 (c 0.36, MeOH).
(300 MHz, CD3OD):
3.11e2.98 (m, 1H), 2.20e2.08 (m, 2H), 1.92e1.79 (m, 2H), 1.60e1.37
(m, 4H) ppm. 13C NMR (100 MHz, DMSO-d6):
158.6, 142.8, 137,
d
7.5 (s, 1H), 7.45 (s, 1H), 3.88e3.75 (m, 1H),
4.3. General procedure for asymmetric Michael addition of
diethyl malonate to
b-nitroolefins
d
124.8 (q, J¼270 Hz), 124 (q, J¼270 Hz), 117.8 (q, J¼32 Hz), 113.5 (q,
J¼4.4 Hz), 112.7 (q, J¼32 Hz), 109.3, 55.2, 53.5, 31.9, 30.4, 24.1,
23.6 ppm. FT-IR (neat): 2939, 2865, 1644, 1622, 1587, 1455, 1339,
Malonate 5 (2 equiv) was added to an anhydrous DCM (0.5 mL)
solution of catalyst (0.1 equiv), additive, and
b-nitroolefin 4
(1 equiv) in a reaction tube (10 mL) under Ar gas at 0 ꢀC. The re-
1284, 1238, 1188, 1166, 1121, 1028, 984, 880, 761, 719, 616 cmꢁ1
.
action solution was stirring for 6e96 h. When TLC analysis in-
dicated complete consumption of b-nitrostyrene, the reaction
solution was concentrated in vacuo and the crude product was
purified by column chromatography (hexane/EtOAc) to give prod-
uct 6.
HRMS FABþ (m/z): [MþH]þ calcd for C15H17F6Nþ4 367.1357, found
367.1362. ½a 2D4
ꢂ
þ19.86 (c 0.5, MeOH).
4.2.3.2. (1R,2R)-N1,N2-Bis(5,7-bis(trifluoromethyl)-1H-benzo[d]
imidazole-2-yl)cyclohexane-1,2-diamine (10). Mp 183e184 ꢀC. 1H
NMR (300 MHz, CD3OD):
2.28e2.17 (m, 2H), 1.92e1.80 (m, 2H), 1.61e1.45 (m, 4H) ppm. 13C
NMR (100 MHz, CD3OD):
d
7.68e7.29 (m, 4H), 3.9 (br s, 2H),
4.3.1. (R)-Diethyl 2-(2-nitro-1-phenylethyl)malonate (6a). Com
pound 4a (30.0 mg, 0.20 mmol) was used and the reaction mixture
was stirred for 24 h, gave 6a (61.4 mg, 0.20 mmol) as a colorless oil
in 99%. Analytical data match the literature.29 1H NMR (300 MHz,
d
160.3, 126.7 (q, J¼270 Hz), 125.9 (q,
J¼270 Hz), 115.8, 59.1, 34.7, 26.7 ppm. FT-IR (neat): 2943, 1644,
1585, 1490, 1454, 1382, 1342, 1284, 1239, 1195, 1121, 1040, 983, 881,
CDCl3): d 7.32e7.19 (m, 5H), 4.93e4.80 (m, 2H), 4.28e4.13 (m, 3H),
761, 719, 664 cmꢁ1
.
HRMS FABþ (m/z): [MþH]þ calcd for
3.99 (q, J¼7.1 Hz, 2H), 3.8 (d, J¼9.3 Hz, 1H), 1.24 (t, J¼7.1 Hz, 3H),
C24H19F12Nþ6 619.1480, found 619.1481. ½a 2D4
ꢂ
þ193.62 (c 0.5, MeOH).
1.02 (t, J¼7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d 167.5,
166.8, 136.2, 128.9, 128.3, 128, 77.6, 62.1, 61.9, 55, 43, 14, 13.7 ppm.
FT-IR (neat): 2983, 1732, 1555, 1456, 1372, 1256, 1178, 1095, 1027,
860, 701 cmꢁ1. HRMS FABþ (m/z): [MþH]þ calcd for C15H20NOþ6
310.1291, found 310.1287. HPLC 93% ee [DIACEL Chiralpak AD-H,
4.2.3.3. (1R,2R)-N1-(5,7-Bis(trifluoromethyl)-1H-benzo[d]imida-
zol-2-yl)-N2,N2-dimethylcyclohexane-1,2-diamine (3b). Compound
8b (198.0 mg, 0.54 mmol) was added to a solution of 80% formic
acid (5.0 mL) and 36% aqueous formaldehyde (99
m
L, 1.2 mmol) in
hexane/ethanol¼90/10, 1.0 ml/min,
l
¼210 nm, retention times:
round-bottom flask (10 mL) with a stir bar. The reaction mixture
was stirred for 16 h at 120 ꢀC. After removal of solvent, the pH of
solution was adjusted to 8 by saturated NaHCO3 solution and 1 N
NaOH solution. After extraction with DCM (20 mLꢃ3), the com-
bined solution was concentrated in vacuo. The residue purified by
flash column chromatography (EtOAc/MeOH) and then recrystal-
lized in hexane/DCM to yield 3b (130.1 mg, 0.33 mmol) as a white
(major) 15.9 min, (minor) 23.4 min]. ½a D20
ꢁ5.2 (c 1.0, CHCl3).
ꢂ
4.3.2. (R)-Diethyl 2-(2-nitro-1-(p-tolyl)ethyl)malonate (6b). Com
pound 4b (32.8 mg, 0.20 mmol) was used and the reaction mixture
was stirred for 40 h, gave 6b (56.4 mg, 0.18 mmol) as a colorless oil
in 87%. Analytical data match the literature.30 1H NMR (300 MHz,
CDCl3): d 7.11e7.04 (m, 4H), 4.91e4.77 (m, 2H), 4.27e4.11 (m, 3H), 4
solid in 61%; mp 239e241 ꢀC. 1H NMR (300 MHz, CDCl3):
d
7.68 (s,
(q, J¼7.1 Hz, 2H), 3.77 (d, J¼9.3 Hz, 1H), 2.28 (s, 3H), 1.24 (t, J¼7.1 Hz,
1H), 7.45 (s, 1H), 5.27 (s, 1H), 3.42e3.35 (m, 1H), 2.47e2.41 (m, 1H),
2.36 (s, 7H), 1.99e1.91 (m, 1H),1.89e1.80 (m, 1H),1.79e1.66 (m,1H),
3H), 1.05 (t, J¼7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d 167.5,
166.9,138.1 ppm,133.1, 129.6, 127.8, 77.8, 62.1, 61.8, 55.1, 42.6, 21, 14,
13.7. FT-IR (neat): 2984, 1733, 1556, 1516, 1444, 1371, 1301, 1256,
1179, 1097, 1028, 860, 819 cmꢁ1. HRMS FABþ (m/z): [MþH]þ calcd
for C16H22NOþ6 324.1447, found 324.1443. HPLC 91% ee [DIACEL
1.40e1.17 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3):
d 159.2, 143.6,
134.9, 124.5 (q, J¼270 Hz), 124 (q, J¼270 Hz), 122.7 (q, J¼32 Hz),
114.5 (q, J¼3.8 Hz), 113.7 (q, J¼3.8 Hz), 112.4 (q, J¼32 Hz), 68.5, 54.5,
39.9, 33.5, 24.7, 34.4, 21.8 ppm. FT-IR (neat): 3290, 2937, 1587, 1453,
1284, 1189, 1120, 982, 877 cmꢁ1. HRMS FABþ (m/z): [MþH]þ calcd
Chiralpak AD-H, hexane/ethanol¼90/10, 1.0 ml/min,
l
¼210 nm,
retention times: (major) 14.0 min, (minor) 18.3 min]. ½a D20
ꢂ
ꢁ4.3 (c
for C17H21F6N4þ 395.1670, found 395.1681. ½a 2D4
ꢂ
þ71.7 (c 0.5, CHCl3).
1.0, CHCl3).
The substituted position of di-CF3 on benzimidazole was assigned
as 5,7-(CF3)2 via 2D-COSY and 2D-NOESY spectroscopic analysis.
4.3.3. (R)-Diethyl
2-(1-(4-chlorophenyl)-2-nitroethyl)malonate
(6c). Compound 4c (36.9 mg, 0.20 mmol) was used to give 6c
(66.5 mg, 0.19 mmol) as a pale yellow solid in 96% (24 h). Analytical
data match the literature.29 Mp 43e47 ꢀC. 1H NMR (300 MHz,
4.2.3.4. (1R,2R)-N1-(1H-Benzo[d]imidazol-2-yl)-N2-(5,7-
bis(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)cyclohexane-1,2-
diamine (11). Di-(trifluoromethyl) substituted 2-chlorobenizimd
azole 7b (78.7 mg, 0.27 mmol) was added to an acetonitrile (1.0 mL)
and DMF (0.1 mL) solution of 8a (69.1 mg, 0.30 mmol) in a micro-
wave vial (10 mL) with a stir bar. After sealing the reaction vial,
followed by placing to CEM Discover S microwave instrument with
surface temperature sensor, the reaction mixture was heated to
185 ꢀC and stirred for 50 min. After cooling to room temperature, the
reaction solvent was removed in vacuo. The residue was purified by
flash column chromatography (EtOAc/hexane), followed by eluting
MeOH in EtOAc to yield 11 (22.0 mg, 0.05 mmol) as a pale yellow
CDCl3):
d
7.22 (dd, J¼16.5, 8.4 Hz, 4H), 4.91e4.76 (m, 2H), 4.25e4.12
(m, 3H), 4.04e3.97 (q, J¼7.1 Hz, 2H), 3.75 (d, J¼9.3 Hz, 1H), 1.24 (t,
J¼7.1 Hz, 3H),1.06 (t, J¼7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d
167.2, 166.6, 134.8, 134.3, 129.4, 129.2, 77.4, 62.3, 62, 54.8, 42.3, 14,
13.8 ppm. FT-IR (neat): 2984, 1733, 1556, 1494, 1444, 1372, 1302,
1255, 1180, 1095, 1015, 834, 718 cmꢁ1. HRMS FABþ (m/z): [MþH]þ
calcd for C15H19ClNOþ6 344.0901, found 344.0913. HPLC 91% ee
[DIACEL Chiralpak AD-H, hexane/ethanol¼90/10, 1.0 ml/min,
l
¼210 nm, retention times: (major) 21.6 min, (minor) 29.2 min].
½
a 2D0
ꢂ
ꢁ5.7 (c 1.0, CHCl3).
solid in 17%. Mp 164e167 ꢀC. 1H NMR (300 MHz, CD3OD):
d 7.58 (s,
1H), 7.42 (s, 1H), 7.14e7.10 (m, 2H), 6.97e6.90 (m, 2H), 3.91e3.69 (m,
2H), 2.98 (s, 2H), 2.85 (s, 2H), 2.30e2.18 (m, 2H), 1.88e1.76 (m, 2H),
4.3.4. (R)-Diethyl 2-(1-(4-bromophenyl)-2-nitroethyl)malonate
(6d). Compound 4d (45.9 mg, 0.20 mmol) was used to give 6d
(74.5 mg, 0.19 mmol) as a pale yellow solid in 95% (24 h). Analytical
data match the literature.30 Mp 57e60 ꢀC. 1H NMR (300 MHz,
1.56e1.45 (m, 4H) ppm. 13C NMR (100 MHz, CD3OD):
d 165.6, 160.5,
156.7, 144.9, 138.5, 126.8 (q, J¼270 Hz), 126 (q, J¼270 Hz), 122.6,
115.7, 114, 113.1, 58.7, 45.5, 37.7, 34.7, 32.4, 26.5 ppm. FT-IR (neat):
CDCl3): d 7.45e7.40 (m, 2H), 7.13e7.08 (m, 2H), 4.91e4.76 (m, 2H),

1458
M. Lee et al. / Tetrahedron 68 (2012) 1452e1459
4.25e4.14 (m, 3H), 4.01 (q, J¼7.1 Hz, 2H), 3.75 (d, J¼9.2 Hz, 1H), 1.24
(t, J¼7.1 Hz, 3H), 1.07 (t, J¼7.1 Hz, 3H) ppm. 13C NMR (100 MHz,
(m/z): [MþNa]þ calcd for C19H21NO6Naþ 382.1267, found 382.1281.
HPLC 91% ee [DIACEL Chiralpak AD-H, hexane/ethanol¼90/10,
CDCl3):
d
167.2, 166.6, 135.3, 132.1, 129.8, 122.5, 62.3, 62.1, 54.7, 42.4,
1.0 ml/min,
l
¼210 nm, retention times: (major) 27.8 min, (minor)
14, 13.8 ppm. FT-IR (neat): 2983, 1733, 1556, 1490, 1444, 1372, 1302,
1255, 1179, 1112, 1074, 1028, 1011, 860, 825, 716 cmꢁ1. HRMS FABþ
(m/z): [MþNa]þ calcd for C15H18BrNO6Naþ 410.0215, found
410.0208. HPLC 92% ee [DIACEL Chiralpak AD-H, hexane/
36.7 min]. ½a 2D0
ꢁ7.9 (c 1.0, CHCl3).
ꢂ
4.3.9. (S)-Diethyl 2-(1-nitrooctan-2-yl)malonate (6i). Compound 4i
(31.4 mg, 0.20 mmol)andcatalyst3b(15.7 mg, 0.04 mmol)wereused
to give 6i (51.8 mg, 0.16 mmol) as a colorless oil in 82% (72 h).1H NMR
ethanol¼90/10, 1.0 ml/min,
l
¼210 nm, retention times: (major)
23.2 min, (minor) 30.2 min]. ½a D20
ꢂ
ꢁ6.3 (c 1.0, CHCl3).
(300 MHz, CDCl3): d 4.72e4.65 (m,1H), 4.55e4.47 (m,1H), 4.24e4.16
(m, 4H), 3.6 (d, J¼5.9 Hz, 1H), 2.90e2.81 (m, 1H), 1.54 (br s, 2H),
4.3.5. (R)-Diethyl
2-(1-(2-bromophenyl)-2-nitroethyl)malonate
1.45e1.41 (m, 2H),1.28e1.24 (m,12H), 0.86 (t, J¼6.4 Hz, 3H) ppm. 13C
(6e). Compound 4e (45.9 mg, 0.20 mmol) was used to give 4e
NMR (100 MHz, CDCl3):d 168,167.8, 77.2, 61.9, 61.8, 52.7, 37, 31.5, 30.1,
(72.3 mg, 0.19 mmol) as a colorless oil in 93% (24 h). Analytical data
28.9, 26.6, 22.5, 14 ppm. FT-IR (neat): 2931, 2859, 1734, 1555, 1466,
1371, 1302, 1177, 1097, 1032, 862 cmꢁ1. HRMS FABþ (m/z): [MþH]þ
calcd for C15H28NOþ6 318.1917, found 318.1911. HPLC 90% ee [DIACEL
match the literature.28 1H NMR (300 MHz, CDCl3):
d 7.59e7.56 (m,
1H), 7.28e7.20 (m, 2H), 7.16e7.10 (m, 1H), 5.13e5.06 (m, 1H),
4.95e4.89 (m, 1H), 4.76e4.69 (m, 1H), 4.23e4.04 (m, 5H), 1.21 (t,
J¼7.1 Hz, 3H), 1.1 (t, J¼7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
Chiralcel OD-H, hexane/isopropanol¼97/3, 1.0 ml/min,
l
¼210 nm,
retention times: (major) 7.9 min, (minor) 5.9 min]. ½a D20
ꢂ
ꢁ1.4 (c 0.6,
d
167.4, 166.8, 133.8, 129.7, 127.9, 106.7, 99.5, 75.7, 62.11, 62.07, 53.3,
CHCl3).
41.5, 13.9, 13.8 ppm. FT-IR (neat): 2983, 1734, 1556, 1473, 1442, 1377,
1302, 1230, 1180, 1096, 1026, 860, 757 cmꢁ1. HRMS FABþ (m/z):
[MþH]þ calcd for C15H19BrNOþ6 388.0396, found 388.0381. HPLC
94% ee [DIACEL Chiralpak AD-H, hexane/ethanol¼90/10, 1.0 ml/
5. Recovery of catalyst 3b
After the addition reaction was completed in neutral condition,
the reaction solution was diluted with ethyl acetate (50 mL) and
washed with water (10 mLꢃ2). The organic layer was extracted
with 5% aqueous-HCl (10 mLꢃ5) and the pH of the combined water
layer was adjusted to 10 by addition of 50% aqueous-KOH at 0 ꢀC.
The water layer was extracted with ethyl acetate (10 mLꢃ5). The
combined ethyl acetate was dried over anhydrous MgSO4, filtered,
and concentrated in vacuo to recover catalyst 3b (93%).
min,
l
¼210 nm, retention times: (major) 8.3 min, (minor)
44.3 min]. ½a 2D0
ꢂ
ꢁ3.9 (c 1.0, CHCl3).
4.3.6. (R)-Diethyl
2-(1-(4-methoxyphenyl)-2-nitroethyl)malona-
te(6f). Compound 4f (36.0 mg, 0.20 mmol) was used to give 6f
(61.4 mg, 0.18 mmol) as a colorless oil in 90% (24 h). Analytical data
match the literature.30 1H NMR (300 MHz, CDCl3):
d 6.97 (dd,
J¼48.2, 8.8 Hz, 4H), 4.89e4.74 (m, 2H), 4.25e4.08 (m, 3H), 3.98 (q,
J¼7.1 Hz, 2H), 3.79e3.70 (m, 4H), 1.24 (t, J¼7.1 Hz, 3H), 1.05 (t,
Acknowledgements
J¼7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d 167.5, 166.9, 159.4,
129.1, 128, 114.3, 77.9, 62.1, 61.8, 55.2, 55.1, 42.3, 14, 13.8 ppm. FT-IR
(neat): 2982, 1733, 1612, 1556, 1515, 1465, 1371, 1301, 1254, 1181,
1117, 1032, 835 cmꢁ1. HRMS FABþ (m/z): [MþNa]þ calcd for
C16H21NO7Naþ 362.1216, found 362.1198. HPLC 93% ee [DIACEL
This work was supported by the Mid-career Researcher Support
Programs of the National Research Foundation of Korea (2009-
0078814) and by the National Research Foundation of Korea Grant
funded by the Korean Government (MEST) (NRF-C1ABA001-2010-
0020428).
Chiralpak AD-H, hexane/ethanol¼90/10, 1.0 ml/min,
l
¼210 nm,
retention times: (major) 25.1 min, (minor) 43.9 min]. ½a D20
ꢂ þ4.9 (c
1.0, CHCl3).
Supplementary data
4.3.7. (R)-Diethyl-2-(1-(2-methoxyphenyl)-2-nitroethyl)malonate
(6g). Compound 4g (36.0 mg, 0.20 mmol) was used to give 6g
(63.8 mg, 0.19 mmol) as a white solid in 94% (24 h). Mp 64e65 ꢀC.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.12.021. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
1H NMR (300 MHz, CDCl3):
d 7.25e7.19 (m, 1H), 7.13e7.10 (m, 1H),
6.86e6.82 (m, 2H), 5.04e4.96 (m, 1H), 4.87e4.81 (m, 1H),
4.39e4.31 (m, 1H), 4.25e4.11 (m, 3H), 3.92 (q, J¼7.1 Hz, 2H), 3.85 (s,
3H), 1.24 (t, J¼7.1 Hz, 3H), 0.98 (t, J¼7.1 Hz, 3H) ppm. 13C NMR
References and notes
(100 MHz, CDCl3):
d 167.9, 167.2, 157.4, 130.9, 129.6, 123.8, 120.8,
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1122, 1027, 861, 757 cmꢁ1. HRMS FABþ (m/z): [MþH]þ calcd for
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ꢂ
ꢁ20.3 (c 1.0,
CHCl3).
4.3.8. (R)-Diethyl
2-(1-(naphthalen-2-yl)-2-nitroethyl)malonate
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€
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1H), 7.47e7.43 (m, 2H), 7.35e7.32 (m, 1H), 4.98 (d, J¼6.6 Hz, 2H), 4.4
(q, J¼7.1 Hz, 1H), 4.26e4.16 (m, 2H), 3.99e3.89 (m, 3H), 1.24 (t,
J¼7.1 Hz, 3H), 0.97 (t, J¼7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
Ed. 2005, 44, 807.
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d
167.5, 166.8, 133.7, 133.2, 133, 128.9, 127.9, 127.6, 127.5, 126.5, 126.4,
125.3, 77.6, 62.2, 61.9, 55.1, 43.1, 14, 13.7 ppm. FT-IR (neat): 2983,
1733, 1555, 1444, 1371, 1259, 1182, 1025, 751, 822 cmꢁ1. HRMS FABþ

M. Lee et al. / Tetrahedron 68 (2012) 1452e1459
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