The highly enantioselective bifunctional organocatalysts for the Michael addition of сyclohexanone to titroolefins

Article abstract of DOI:10.1134/S1070363216060244

A new family of organocatalyst derived from proline has been developed and shown to be an efficient catalyst for asymmetric Michael addition of cyclohexanone to nitroolefins with high diastereo- and enanthio -selectivities. (syn: anti ratio up to 99:1, ee

Full text of DOI:10.1134/S1070363216060244

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 6, pp. 1381–1388. © Pleiades Publishing, Ltd., 2016.
The Highly Enantioselective Bifunctional Organocatalysts1
for the Michael Addition of Сyclohexanone to Тitroolefins
a
a
a
a
b
a*
M. Yang , Y.C. Zhang , J. Q. Zhao , Q. S. Yang , Y. Ma , and X. H. Cao
a
School of Chemical Engineering and Technology, Hebei University of Technology , Tianjin, China
e-mail: nkallwar@126.com
*
b
National Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin ,China
Received October 29, 2015
Abstract—A new family of organocatalyst derived from proline has been developed and shown to be an
efficient catalyst for asymmetric Michael addition of cyclohexanone to nitroolefins with high diastereo- and
enanthio -selectivities. (syn: anti ratio up to 99:1, ee. up to 95%.). The result of computational studies at the
B3LYP/6-31G* level indicate that both the hydrogen bonding and the stereo hindrance play the crucial role in
the activation of the nitro alkene and help to discriminate between the two diastereofacial approaches.
Keywords: asymmetric catalysis, Michael addition, proline, DFT
DOI: 10.1134/S1070363216060244
Organocatalyzed asymmetric carbon-carbon bond-
forming reactions have received recently a great deal
of attention [1]. The Michael reaction is generally
regarded as one of the most efficient and effective
transformations in organic synthesis, and studies
concerning this reaction have played an important role
in the development of modern synthetic organic
chemistry [2, 3]. Particularly, Michael addition
reactions of nitroolefins with aldehydes and ketones
are important methods for the synthesis of
synthetically useful γ-nitrocarbonyl compounds, which
serve as versatile building blocks for the preparation of
complex organic substances. The nitro group in these
substances can be readily converted into a variety of
new functionalities including amines, nitrile oxides,
ketones, and carboxylic acids [4].
investigated [10–27]. Although impressive progress
towards improving stereoselectivity and substrate
generality has been made, development of simple
readily accessible bifunctional systems with improved
catalytic activity remains of interest. In 2007, a series
of 1,2-amino-alcohol-derived prolinamides
1
as
bifunctional catalysts was evaluated for catalyzing the
Michael addition, but showed moderate enantioselec-
tivity (~30–80% ee) [22]. Herein, we report chiral
diamines 2 containing hydroxyl group to catalyze the
Michael addition with high diastereoselectivity and
enantioselectivity (Fig. 1).
Catalysts 2 were prepared in good to excellent
yields from N-Cbz-L-prolinol and the corresponding
commercially available β-amino alcohols through the
reaction sequence shown in Scheme 1.
Barbas and List independently reported the first
organocatalytic addition of ketones to trans-β-nitro-
styrene with proline as a catalyst with good yields but
very low enantioselectivities (0–23% ee) [5, 6]. Recent
investigations have examined the catalysis of the
ketonenitroalkene conjugate addition reaction with
derivatives of chiral diamines [7] , amino acids [8], and
ionic liquids [9], but a significant amount of effort has
been devoted to the modification of the proline motif.
Many organocatalysts derived from proline have been
Firstly, the model Michael reactions of cyclo-hexa-
none with trans-β-nitrostyrene catalyzed by
organocatalyst 2a were examined in various organic
solvents and the observed results are summarized in
Table 1. When 2a catalyzed the reaction without proto-
nic acid in different solvents, no Michael addition
product was obtained (Table 1 entries 1, 5, 9), ho-
wever, a quantitative amount of polymerization pro-
duct was formed quickly in this reaction. Other studies
have indicated that amines behave as initiators of poly-
merization, and Barbas’s group have described that
addition of Brønsted acids can promote the formation
1
The text was submitted by the authors in English.
1
381

1
382
YANG et al.
O
N
H
N
H
N
N
H
R1
R2
HN
HO
HN
HO
H
HN
HN
HO
HO
2b
Fig. 1. Organocatalysts for the Michael addition.
2
c
1
2a
of enamine thus inhibiting the polymerization. There-
fore, several sulfonic and carboxylic acids were surveyed
for their effect on the organocatalyst 2a catalyzed
Michael addition of cyclohexanone to nitrostyrene.
As shown in Table 2, cyclohexanone efficiently
underwent Michael reactions with different aryl-
substituted nitroolefins to give Michael adducts 3a–3h
in high yields with excellent enantio- (91–96% ee) and
diastereoselectivities (syn : anti ratio up to 99 : 1). The
results in Table 3 also show that the nature of the
substituents on the aryl groups only slightly influences
the yields and enatioselectivities. For nitroolefins with
electron-rich groups (methyl and methoxy), the
reaction proceeded smoothly to afford Michael adducts
As indicated in Table 1, the addition of an acid
efficiently improved the reaction. All the acids used
led to the formation of the Michael addition product. In
the presence of an acid the catalyst 2a generally
showed better stereochemical outcome than the
reported catalyst 1 [22]. The highest enantioselectivity
of 92% and high diastereoselectivity of 96:4 were
observed in the presence of 20 mol % TFA for the
reaction catalyzed by 2a in DMSO (Table 1, entry 12).
3
b, 3c in excellent enantio- (95–97% ee) and
diastereoselectivities (syn : anti ratio = 99 : 1)
Table 2, entries 2–3). For nitroolefins with electron-
(
deficient groups, the Michael adducts 3d–3h were also
obtained in high yields (77–86%) with excellent
enantio- (91–95% ee) and diastereoselectivities (syn :
antiratio up to 99 : 1) (Table 2, entries 4–8).
Under the optimized reaction conditions, the chiral
β-amino alcohol derivatives 2b and 2c as catalysts
were also evaluated for the Michael addition. As show
in Table 1, (S)- β-amino alcohol derivate 2b showed
slightly higher enantioselectivity (95% ee, Table 1,
entry 15) than its’ diastereoisomer 2c (93% ee,
Table 1, entry 16) and 2a. These results indicated that
the chirality of the stereogenic center of the side chain
had little effect on the enantioselectivity and diastereo-
selectivity.
To account for the stereochemical outcome of the
Michael reaction, the plausible transition-state model
is proposed in Scheme 2 (Favorable TS). The amine
and hydroxy groups were expected to interact by
double hydrogen bonding with the nitro group of the
electrophile in order to enhance their reactivity as
depicted in the TS.
With the catalyst 2b in hand, the Michael addition
of cyclohexanone to a range of nitro-olefins was
examined. The results are summarized in Table 2.
To gain a more detailed understanding of the origin
of the high enantio- and diastereoselectivity of the
Scheme 1. Synthesis of bifunctional organocatalysts 2.
R
H
N
R
H N *
OH
2
TsCl
Py
OTs
OH
*
N
N
N
Cbz
Cbz
HO
Cbz
H
N
R
*
H /Pd
2
N
H
HO
2
2
: R = H (a), R = Et C* (S) (b), R = Et C* (R) (с).
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THE HIGHLY ENANTIOSELECTIVE BIFUNCTIONAL ORGANOCATALYSTS
1383
Table 1. Model Michael reaction
Table 2. Michael reactions of ketones to nitroolefins
O
O
NO2
O
+
Ar
NO2
NO2
Cat./additive
+
O
Ar
solvent,
NO2
room temperature,
3
2b : TFA = 20 mol %
4
8 h
DMSO,
room temparature,
3
a
Entry
Solvent Additive
4
8 h
Yield, syn : anti ee,
Entry
Ar
Product
%
85
86
74
82
77
86
83
85
Ratio
98:2
97:3
97:3
99:1
94:6
98:2
93:7
95:5
%
95
97
95
96
97
97
93
91
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
MeOH
MeOH
MeOH
MeOH
DMF
–
–
–
–
1
2
3
4
5
6
7
8
Ph
4-Me-Ph
3a
3b
3c
3d
3e
3f
PhCOO
H
43
56
61
–
93 : 7 84
95 : 5 83
98 : 2 79
p-TsOH
TFA
–
4-OMe-Ph
4-Cl-Ph
–
–
DMF
64
72
69
–
98 : 2 90
99 : 1 91
97 : 3 88
2-Cl-Ph
DMF
PhCOO
H
DMF
2,4-Cl-Ph
DMSO
DMSO
DMSO
DMSO
p-TsOH
TFA
–
–
–
4-NO
2-NO
2
-Ph
-Ph
3g
3h
1
1
1
1
1
1
1
0
1
2
3
4
5
6
71
78
86
79
72
85
81
97 : 3 91
98 : 2 90
96 : 4 92
95 : 5 81
93 : 7 83
98 : 2 95
97 : 3 93
2
PhCOO
H
2 2
CH Cl
different transition states, two for each enantiomer
Fig. 2). The two transition states arising from the anti
enamine (TS and TS ) can benefit from hydrogen-
Toluene p-TsOH
(
DMSO
DMSO
TFA
TFA
A
B
bonding activation between the amine NH and the
hydroxyl group presented in the prolinamine, and our
initial hypothesis was that this interaction might
contribute to a lowering in the energy barriers,
resulting in faster reaction rates. Meanwhile, reaction
through syn-enamine conformations would proceed
without the help of hydrogen-bonding activation (TSC
and TSD).
a
1
0 equiv of ketone, 20 mol % catalyst and 20 mol % additive.
Isolated yield. Determined by Chiral HPLC. Determined by
Chiral HPLC.
b
c
d
processes catalyzed by 2, we have computationally
studied the transition states by density functional
theory (DFT) at the B3LYP/6-31G* level. Firstly, the
enamine formation is assumed to be a fast process thus
has no effect on the stereoselectivity of the reaction.
Secondly, the final hydrolysis step to recover the
catalyst is also believed to be a low-energy barrier
step. Therefore, we focused on the study of the
transition states involved in the rate-limiting step the
nucleophilic attack of the enamines. As shown in
Scheme 2, the enamine intermediates can adopt anti
and syn conformations and each of them has two
different transition states existing for the approach of
the nitropropene to the diastereotopical Re and Si faces
of the enamine, resulting in the formation of four
We located the four possible transition states and
found that the lowest in energy (7.6 kcal/mol)
corresponds to TSA, the one that leads to the
experimentally observed syn-(2S,3R) enantiomer.
According to our initial hypothesis, this result shows
that both the amine NH and the hydroxyl group in the
catalyst activate the nitroalkene by the concurrence of
up to three hydrogen bonds, favouring the approach of
the nitro alkene from the Re face of the anti enamine.
The minor enantiomer syn-(2R, 3S) is formed through
a Si approach of the nitro alkene to the anti enamine
(TS ), whose activation energy is 9.1 kcal/mol. As
B
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384
YANG et al.
Scheme 2. The proposed mechanism and transition state.
OH
OH
O
N
NH
NH
O
N
N
+
O
anti-enamine
syn-enamine
−
H O
2
N
N
H
O
O
N
H
H
N
O
OH
N
H
Favorable TS
H
N
H O
2
N
O
HO
O N
NO2
2
expected, the activation barriers of the other two
bonding effect is not the main reason why catalyst 2 is
better than their acid amide analogue 1.
transition states for syn-enamine (TS , TS ) are much
C
D
higher than those of their activated counterparts,
because they cannot form the hydrogen bond. More
detailed parameters are summarized in Table 3.
As shown in Table 3, the Re face arrangement of
the reactant complex has a lower energy (1.8 kcal/mol)
than its si counterpart. This higher energy of RC is
si
3
As shown in Table 3, the reason for the observed
stereoselectivity is understandable in view of the
hydrogen-bonding differences between TS and TS .
more likely due to the stereo hindrance, in which C
4
methylene group is much closer to C methylene group
than in the re counterpart as displayed in Fig. 3. This is
A
B
3
4
In both cases, three hydrogen bonds formed between
the two oxygens of the nitro group and amine NH and
hydroxyl group. We can distinguish a strong hydrogen
evidenced by the corresponding C –H···H–C distance
of 2.0 Å (in RC ) and 2.36 Å (in RC ) as listed in
si
re
Table 3. The similar stereo hindrance effect can be
found in the transition state structures (TS and TS )
3
1
bond (O –H···O , 1.85 Å), and a weak bond
A
3
B
1
2
4
(
N –H···O , 2.65 Å) in TS , we also can find the
displayed in Fig. 3 and Table 3, the C –H···H–C
distance in TS (2.13 Å) is farther than TS (1.99 Å).
A
3
1
1
1
similar intensity bond (O –H···O , 1.84 Å; N –H···O ,
.67 Å) in TS . But the TS shows another strong
hydrogen bond (N –H···O , 2.02 Å) whereas TS
A
B
2
We suggest the difference of stereo hindrance between
TSA and TSB is another important beneficial to
improve the stereo-selectivity. In comparison, the
steric effect is not found in transition states which
B
A
1
1
B
shows relatively weaker bonds with larger distance for
1
2
N –H···O (2.25 Å). However, according to Alonso
group’s report [22], the similar hydrogen-bonding
effect was also found in the structure of transition
states which formed with catalyst 1, so the hydrogen-
4
formed with acid-amide analogue 1 due to their C
carbonyl is a plane group [22]. In summary, these
results of DFT study suggested that the stereo-
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THE HIGHLY ENANTIOSELECTIVE BIFUNCTIONAL ORGANOCATALYSTS
1385
a
Table 3. Activation energies and interatomic distances for the transition states calculated at the B3LYP/6-31G* level
Distances, Å
Energy,
kcal/mol
a
E ,
kJ/mol
State
1
2
3
1
1
1
1
2
3
4
3
4
C –C O –H···O
N –H···O
N –H···O
C ···C
C –H···H–C
Reactant complex
0.0
7.6
–
4.00
2.19
2.01
3.53
2.06
2.03
1.92
1.85
–
2.80
2.02
–
2.43
2.65
–
3.46
3.46
–
2.36
2.13
–
TS
TS
A
C
7.6
11.4
–
11.4
5.8
RCsi
1.99
1.84
–
2.95
2.68
–
2.16
2.25
–
3.24
3.22
–
2.00
1.99
–
TS
TS
B
14.9
21.3
9.1
15.5
D
a
Energies calculated at the B3LYP/6-31G*+ZPVE level.
3
4
hindrance effect (C methylene–C methylene) is the
main reason why the amine-catalysts are better than
their acid amine analogue.
two diastereofacial approaches. The computationally
favored transition state TSA presents the strongest
hydrogen bonds and, in accordance with the experi-
mental results, leads to the observed major syn-(2S,3R)
enantiomer. On the other hand, the preference of the re
reaction path in ketone reactions seems to originate
from the stereo hindrance between the bulky β-amino
alcohol group in the catalyst and an alkyl group in the
enamine intermediate. These results provide valuable
insight into the mechanisms of asymmetric
organocatalysis and might help the design of new and
more efficient organocatalysts.
In summary, a new family of organocatalysts which
can be used to promote asymmetric Michael addition
reactions of cyclohexanone to nitroolefins in high
efficiency has been developed. Computational studies
at the B3LYP/6-31G* level have been conducted on a
model reaction, confirming the initial hypothesis that
hydrogen bonding plays a crucial role in the activation
of the nitro alkene and helping to distinguish between
Reactant complex (Re face) Reactant complex (Si face)
A B C D
TS (anti-Re): 7.6 kcal/mol TS (anti-Si): 9.1 kcal/mol TS (syn-Re): 11.4 kcal/mol TS (syn-Si): 15.5 kcal/mol
Fig. 2. Transition-state geometries and activation energies for the reaction between 4 and 5, calculated at B3LYP/6-31G* level.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016

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386
YANG et al.
RCre
RCsi
TS
A
TS
B
Fig. 3. Stereo hindrance of reactant complexes and transition states.
EXPERIMENTAL
H and C NMR spectra were recorded on a Varian
distillation and the residue was chromatographed to
give corresponding Cbz derivative. The crude product
was dissolved in EtOH (20 mL) and 0.1 g of Pd/C
(10%) was added. The reaction mixture was stirred at
1
13
-
500 instrument. Chemical shifts reported in ppm
down field from Me S as internal standard. Mass
room temperature under H (1 atm) overnight. Pd/C
4
2
spectra were recorded using electrospray ionization
was filtered off and the solution was concentrated in
vacuum. The residue was purified by flash chromato-
grahy on silica gel to give the desired product 2.
(
ESI) on LCQ Advanted MAX Mass instruments.
Optical rotations were tested on a WZZ-3 polarimeter
using 10mL cell with a 1 dm path length and Autopol
II polarimeter using 1 mL cell with a 1 dm path length.
HPLC analysis was performed using ChiralPak AS-H
column.
(
S)-2-(Pyrrolidin-2-ylmethylamino)ethanol (2a).
1
Yield 73.1%, [α] = +13.4° (1.0 MeOH) H NMR
D
spectrum (CDCl ), δ, ppm: 1.24–1.27 m (1H), 1.62–
3
1
2
.69 m (2H), 1.79–1.81 m (1H), 2.44–2.48 m (1H),
.67 m (2H) 2.82–2.83 m (2H), 3.16 m (1H), 3.37 m
Commercial reagents were used without further
purification. Analytical thin layer chromatography was
performed on 0.20 mm silica gel plates and silica gel
1
3
(
3H) 3.49–3.56 m (2H). C NMR spectrum (CDCl ),
3
δC, ppm: 25.82, 29.87, 46.50, 51.91, 54.63, 58.51,
(
200–300 mesh) was used for flash chromatography.
6
1
0.72. Mass spectrum: m/z 145.3158. Calculated: M
45.3147.
Both were purchased from Qingdao Haiyang Chem.
Company, Ltd.
(
S)-2-[(S)-pyrrolidin-2-ylmethylamino]butan-1-
Synthesis of catalyst 2 (general procedure). To a
stirred solution of 5.5g (0.023 mol) Cbz- protected (S)-
prolinol in 20 mL of pyridine a solution of 3.2 g
1
ol (2b). Yield 75.6%, [α] = +17.3° (1.1 MeOH) H
D
NMR spectrum (CDCl ) δ, ppm: 0.87 t (3H, J =
3
7
2
.5 Hz), 1.22–1.44 m (3H), 1.64–1.88 m (3H), 2.48–
(
0.028 mol) TsCl in 20 mL of CH Cl was added
2 2
.61 m (3H), 2.89 t (2H, J = 6.5 Hz), 3.20–3.30 m
dropwise at 0°C. The reaction mixture was allowed to
warm to room temperature and was stirred for further
13
(5H), 3.52–3.55 d.d (1H, J = 4.0 Hz, J = 11.0 Hz) C
1
2
NMR spectrum (CDCl ) δ , ppm: 10.78, 24.47, 25.89,
3
C
1
8 h. The mixture was diluted with 50 mL of water,
2
9.72, 46.46, 51.03, 59.02, 60.72, 63.10. Mass
then the resulted mixture was extracted with CH Cl
2
2
spectrum: m/z 173.4201. Calculated: M 173.4123.
(
3 × 20 mL). The combined organic layers was washed
with 1M HCl solution (2 × 25 mL) and brine (2 ×
0 mL) then dried over anhydrous Na SO and
(R)-2-[(S)-Pyrrolidin-2-ylmethylamino]butan-1-
1
2
ol (2c). Yield 72.4%, [α] = +37.8° (1.0, MeOH) H
2
4
D
concentrated in vacuum to give the Cbz-protected (S)-
prolinol tosylate (7.3 g, 99% yield). Then the tosylate
was dissolved in 10 mL of corresponding β-amino
alcohol. The reaction mixture was stirred at 50°C for
NMR spectrum (CDCl ) δ, ppm: 0.89 t (3H, J =
7.5 Hz), 1.33–1.43 m (3H), 1.66–1.92 m (3H), 2.44–
3
2.60 m (2H), 2.74dd (1H, J = 4.0 Hz, J = 12 Hz), 2.91–
1
2
1
3
2.93 m (2H), 3.22–3.32 m (2H), 3.54–3.62 m (2H). C
2
4 h. The excess amide was removed by vacuum
NMR spectrum (CDCl ) δ , ppm: 10.82, 24.66, 25.89,
3
C
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THE HIGHLY ENANTIOSELECTIVE BIFUNCTIONAL ORGANOCATALYSTS
1387
2
9.69, 46.46, 51.67, 59.32, 61.12, 63.31. Mass
(S)-2-[(R)-1-(2-Chlorophenyl)-2-nitroethyl]-
cyclohexanone (3d). H NMR spectrum (CDCl ), δ,
3
1
spectrum: m/z 173.4148. Calculated: M 173.4123.
ppm: 1.30–1.38 m (1H), 1.59–1.85 m(4H), 2.09–2.14
m (1H), 2.37–2.43 m (1H), 2.47–2.51 m (1H), 2.90–
General experimental procedure for the Michael
addition. To a solution of the amine catalyst
0.1 mmol), p-toluene sulfonic acid monohydrate
0.1 mmol) and the nitroalkene (0.5 mmol) in DMF
2 mL) was added cyclohexanone (5 mmol), and the
2
7
.97 m (1H), 4.27–4.31 m (1H), 4.87–4.94 m (2H),
(
(
(
.20–7.25 m (3H), 7.38–7.39 m (1H). HPLC: t = 20.2
r
min (minor), 27.7 min (major).
solution was stirred at ambient temperature for 24 h
except when noted otherwise. The solution was then
concentrated at ambient temperature under reduced
pressure and the residue was purified by flash column
chromatography on silica gel. Alternatively, ethyl
acetate (10 volumes) was added and the solution was
washed with water, 1 N HCl, dried (Na SO ) and
(
S)-2-[(R)-1-(4-Chlorophenyl)-2-nitroethyl]-
1
cyclohexanone (3e). H NMR spectrum (CDCl ), δ,
ppm: 1.19–1.28 m (1H), 1.57–1.83 m(4H), 2.08–2.13
m (1H), 2.35–2.42 m (1H), 2.46–2.51 m (1H), 2.63–
.68 m (1H), 3.74–3.79 m (1H), 4.59–4.63 m (1H),
.92–4.96 m (1H), 7.11–7.14 m (2H), 7.29–7.32 m
2H). HPLC: t = 21.1 min (minor), 35.1 min (major)
3
2
4
(
2
4
r
concentrated to give the crude product which was
purified by flash chromatography on silica gel.
(
S)-2-[(R)-1-(2,4-Dichlorophenyl)-2-nitroethyl]-
1
cyclohexanone (3f): H NMR spectrum (CDCl ), δ,
ppm: 1.30–1.38 m (1H), 1.60–1.86 m (4H), 2.10–2.15
m (1H), 2.35–2.42 m (1H), 2.46–2.51 m (1H), 2.84–
.92 m (1H), 4.11–4.24 m (1H), 4.86–4.92 m (2H),
.17 d (1H, J = 8.0 Hz), 7.23 d.d (1H, J = 8.0 Hz, J =
The relative configurations of the products (syn-
and anti-) were determined by comparison of HPLC
data with those reported in the literature. The absolute
configurations of the product and the e.e. were
determined by comparison of HPLC retention times
with those reported in the literature. The enantiomeric
excess for products 3a–3g was determined by chiral
HPLC on a Chiralpack AS-H column (UV detection at
3
2
7
2
1
2
.0 Hz), 7.41 d (1H, J = 2.0 Hz). HPLC: t = 16.5 min
minor), 25.1 min (major)
r
(
(
S)-2-[(R)-2-Nitro-1-(2-nitrophenyl)ethyl]-
2
0
38 nm, hexane : 2-propanol = 90 : 10, as eluent,
.7 mL/min).
1
cyclohexanone (3g). H NMR spectrum (CDCl ), δ,
3
ppm: 1.19–1.28 m (1H), 1.57–1.82 m (4H), 2.05–2.11
m (1H), 2.36–2.42 m (1H), 2.46–2.50 m (1H), 2.62–
2.68 m (1H), 3.69–3.74 m (1H), 3.79 s (3H), 4.57–4.61
m (1H), 4.90–4.93 m (1H), 6.84 d (2H, J = 8.5 Hz),
.06 d (2H, J = 8.5 Hz). HPLC: t = 37.4 min (minor),
8.6 min (major).
(
S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanone
1
(
3a). H NMR spectrum (CDCl ), δ, ppm: 1.10–1.23 m
3
(
1H), 1.43–1.73 m(4H), 1.97–2.05 m (1H), 2.26–2.45
m (2H), 2.57–2.66 m (1H), 3.65–3.73 m (1H), 4.56 d.d
1H, J = 12.5, 9.9 Hz), 4.87 d.d (1H, J = 12.5, 4.5 Hz),
7
7
r
(
7
3
.07–7.28 m (5H). HPLC : t = 24.1 min (minor),
4.5 min (major).
r
Computational methods. DFT calculations were
carried out with Gaussian 09 package [28]. The
transition structure were fully optimized by B3LYP
(
S)-2-[(R)-2-Nitro-1-p-tolylethyl]cyclohexanone
1
(
(
(
3b). H NMR spectrum (CDCl ), δ, ppm: 1.20–1.28 m
1H), 1.57–1.81 m (4H), 2.03–2.11 m (1H), 2.32 s
3H), 2.36–2.42 m (1H), 2.46–2.50 m (1H), 2.64–2.70
m (1H), 3.70–3.75 m (1H), 4.59–4.63 m (1H), 4.90–
.94 m (1H), 7.04 d (2H, J = 8.0 Hz), 7.12 d (2H, J =
3
[29–31] method using 6-31G* basis set and have been
confirmed to be a transition state geometry by the
harmonic frequencies calculations at the same level of
theory. The transition state was verified by the
existence of imaginary frequency and the connectivity
between the reactant and transition sate confirmed by
intrinsic reaction coordinate (IRC) calculation [32].
4
8
.0 Hz). HPLC: t = 16.7 min (minor), 29.6 min (major).
r
(
S)-2-[(R)-1-(4-Methoxyphenyl)-2-nitroethyl]-
1
cyclohexanone (3c). H NMR spectrum (CDCl ), δ,
3
ppm: 1.19–1.28 m (1H), 1.57–1.82 m (4H), 2.05–2.11
m (1H), 2.36–2.42 m (1H), 2.46–2.50 m (1H), 2.62–
ACKNOWLEDGMENTS
2
.68 m (1H), 3.69–3.74 m (1H), 3.79 s (3H), 4.57–4.61
This research was supported by National Natural
Science Foundation of China (no. 21306038) and
Natural Science Foundation of Hebei Province
(no. B2013202216).
m (1H), 4.90–4.93 m (1H), 6.84 d (2H, J = 8.5 Hz),
7
6
.06 d (2H, J = 8.5 Hz). HPLC: t = 42.2 min (minor),
r
8.6 min (major).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 6 2016

1
388
YANG et al.
19. Mase, N., Watanabe, K., Yoda, H., Takabe, K., Tanaka, F.,
REFERENCES
and Barbas III, C.F., J. Am. Chem. Soc., 2006, vol. 128,
1
. Dalko, P.I., Angew. Chem. Int. Ed. 2004, vol. 43,
p. 4966. DOI: 10.1021/ja060338e.
p. 5138. DOI: 10.1002/anie.200400650.
. Perlmutter, A., Conjugative Additions in Organic
Synthesis, Oxford: Pergamon Press, 1992.
20. Xu, D.-Q., Wang, L.-P., Luo, S.-P., Wang, Y.-F.,
Zhang, S., and Xu, Z.-Y., Eur. J. Org. Chem., 2008,
p. 1049. DOI: 10.1002/ejoc.200700856.
2
3
2
1. Wang, B-G., Ma, B-C., Wang, Q., and Wang, W., Adv.
Synth. Catal., 2010, vol. 352, p. 2923. DOI: 10.1002/
adsc.201000508.
. Ballini, R., Bosica, G., Fiorini, D., Palmieri, A., and
Petrini, M., Chem. Rev. 2005, vol 105, p. 933. DOI:
1
0.1021/cr040602r.
2
2. Almasi, D., Alonso, D.A., Bengoa, E.G., Nagel, Y., and
Nàjera, C., Eur. J. Org. Chem., 2007, p. 2328. DOI:
10.1002/ejoc.200700031.
4
5
. (a) Ono, N., The Nitro Group in Organic Synthesis New
York: Wiley-VCH, 2001. (b) Berner, O.M., Tedeschi, L.,
and Enders, D., Eur. J. Org. Chem. 2002, p. 1877. DOI:
1
0.1002/1099-0690(200206)2002:12<1877::AID-
23. Zheng, Z., Perkins, B.L., Ni, Bukuo, J. Am. Chem. Soc.,
EJOC1877>3.0.CO;2-U.
. Sakthive, K.I., Notz, W., Bui, T., and Barbas III, C.F.,
2010, vol. 132, p. 50. DOI: 10.1021/ja9093583.
24. Albrecht, L., Jiang, H., and Jørgensen, K.A., Chem. Eur. J.,
J. Am. Chem.Soc. 2001, vol. 123, p. 5260. DOI:
2014, vol. 20, p. 358. DOI: 10.1002/chem.201303982.
1
0.1021/ja010037z.
2
5. Zhang, R., Yin, G., Li, Y., Yan X., and Chen, L. RSC
Adv., 2015, vol. 5, p. 3461. DOI: 10.1039/
C4RA10684A.
6
7
. List, B., Pojarliev, P., and Martin, H.J., Org. Lett. 2001,
vol. 3, p. 2423. DOI: 10.1021/ol015799d.
. (a) Tsogoeva, S.B. and Wei, S. Chem. Commun. 2006,
p. 1451. DOI: 10.1039/B517937H. (b) Huang, H. and
Jacobsen, E.N., J. Am. Chem. Soc. 2006, vol. 128,
p. 7170. DOI: 10.1021/ja0620890.
. Xu, Y. and Cordova, A., Chem. Commun., 2006, p. 460.
DOI: 10.1039/B514783M.
26. Lu, D., Gong, Y., and Wang, W., Adv. Synth. Catal.
2010, vol. 352, p. 644. DOI: 10.1002/adsc.200900687.
2
2
7. Cao, X., Wang, G., Zhang, R., Wei, Y., Wang, W.,
Sun, H., and Chen, L., Org. Biomol. Chem. 2011, vol. 9,
p. 6487. DOI: 10.1039/C1OB05679D.
8
9
8. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E.,
Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V.,
Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M.,
Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J.,
Zheng, G., Sonnenberg, J.L., Hada, M., Ehara, M.,
Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M.,
Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T.,
Montgomery, J.A., Jr., Peralta, J.E., Ogliaro, F.,
Bearpark, M., Heyd, J.J., Brothers, E., Kudin, K.N.,
Staroverov, V.N., Keith, T., Kobayashi, R., Normand, J.,
Raghavachari, K., Rendell, A., Burant, J.C., Iyengar, S.S.,
Tomasi, J., Cossi, M., Rega, N., Millam, J.M., Klene, M.,
Knox, J.E., Cross, J.B., Bakken, V., Adamo, C.,
Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O.,
Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W.,
Martin, R.L., Morokuma, K., Zakrzewski, V.G.,
Voth, G.A., Salvador, P., Dannenberg, J.J., Dapprich, S.,
Daniels, A.D., Farkas, O., Foresman, J.B., Ortiz, J.V.,
Cioslowski, J., and Fox, D.J., Gaussian 09, Revision
D.01, Gaussian, Inc., Wallingford CT, 2013.
. Luo, S., Mi, X., Zhang, L., Liu, S., Xu, H., and Cheng, J.-P.,
Angew. Chem., Int. Ed., 2006, vol. 45, p. 3093. DOI:
1
0.1002/anie.200600048.
1
1
1
1
0. Ishii, T., Fujioka, S., Sekiguchi, Y., and Kotsuki, H.,
J. Am. Chem. Soc., 2004, vol. 126, p. 9558. DOI:
1
0.1021/ja046871g.
1. Mase, N., Thayumanavan, R., Tanaka, F., and
Barbas, III, C.F., Org. Lett., 2004, vol. 6, p. 2527. DOI:
1
0.1021/ol049196o.
2. Andrey, O., Alexakis, A., Tomassini, A., and
Bernardinelli, G., Adv. Synth. Catal., 2004, vol. 346,
p. 1147. DOI: 10.1002/adsc.200404037.
3. Cobb, A.J.A., Longbottom, D.A., Shaw, D.M., and
Ley, S.V., Chem. Commun., 2004, p. 1808. DOI:
1
0.1039/B409646K.
1
1
1
1
4. Reyes, E.,Vicario, J.L., Badia, D., and Carrillo, L., Org.
Lett. 2006,vol. 8,p. 6135. DOI: 10.1021/ol062627d.
5. Cao, C.L., Ye, M.C., Sun, X.L., and Tang, Y., Org.
Lett., 2006, vol. 8, p. 2901. DOI: 10.1021/ol060481c.
29. Becke, A.D., J. Chem. Phys. 1993, vol. 98, p. 1372.
DOI: org/10.1063/1.464304.
30. Becke, A.D., J. Chem. Phys. 1993, vol. 98, p. 5648.
DOI: org/10.1063/1.464913
31. Lee, C., Yang, W., and Parr, R.G., Phys. Rev. B 1988,
6. Wang,W., Wang, J., and Li, H., Angew. Chem. Int. Ed.,
2
005, vol. 44, p. 1369. DOI: 10.1002/anie.200461959.
7. Wang, J., Li, H., Lou, B., Zu, L., Guo, H., and Wang, W.,
Chem.-Eur. J. 2006, vol. 12, p. 4321. DOI: 10.1002/
chem.200600115.
vol. 37, p. 785. DOI: org/10.1103/PhysRevB.37.785.
3
2. Francisco, J.S. and Schlegel, H.B., J. Phys. Chem. 1988,
1
8. Pansare, S.V., and Pandya, K. J. Am. Chem. Soc., 2006,
vol. 88, p. 3736. DOI: org/10.1063/1.453873.
vol. 128, p. 9624. DOI: 10.1021/ja062701n.
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