Pyrrolidinyl-sulfamide derivatives as a new class of bifunctional organocatalysts for direct asymmetric Michael addition of cyclohexanone to nitroalkenes

Article abstract of DOI:10.1039/c1ob05442b

A series of chiral pyrrolidinyl-sulfamide derivatives have been identified as efficient bifunctional organocatalysts for the direct Michael addition of cyclohexanone to a wide range of nitroalkenes. The desired Michael adducts were obtained in high chemical yields and excellent stereoselectivities (up to 99/1 dr and 95% ee). The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05442b

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PAPER
Pyrrolidinyl-sulfamide derivatives as a new class of bifunctional
organocatalysts for direct asymmetric Michael addition of cyclohexanone
to nitroalkenes†
Jia-Rong Chen,* Liang Fu, You-Quan Zou, Ning-Jie Chang, Jian Rong and Wen-Jing Xiao*
Received 21st March 2011, Accepted 28th April 2011
DOI: 10.1039/c1ob05442b
A series of chiral pyrrolidinyl-sulfamide derivatives have been identified as efficient bifunctional
organocatalysts for the direct Michael addition of cyclohexanone to a wide range of nitroalkenes. The
desired Michael adducts were obtained in high chemical yields and excellent stereoselectivities (up to
99/1 dr and 95% ee).
donor catalysts for the conjugate addition of 1,3-dicarbonyl
Introduction
compounds to nitroalkenes.15 Inspired by these advances, we
Recently, organocatalytic asymmetric catalysis has been identified
envisaged that the introduction of new H-bonding donors to the
as one of the most powerful and economical approaches to a
chiral amine scaffold would probably lead to a new class of efficient
variety of enantiomerically enriched compounds that are widely
bifunctional organocatalysts for the asymmetric Michael addition.
used in drug discovery and chemical synthesis.1–3 In this scenario,
The key point for this research was to identify new bifunctional
great research efforts have been directed toward the design of
organocatalysts, that are significantly more active than those pre-
environmentally friendly, highly efficient, and selective organocat-
viously reported, with minimal perturbation of the overall parent
alysts. As a result, a great number of chiral amine derivatives have
catalyst structure. To reach this goal, we evaluated structural
modifications of secondary amine-thiourea I, a catalyst that we16
been developed for a wide range of asymmetric transformations,
and Tang12j have previously developed for asymmetric Michael
additions of cyclohexanone to nitroalkenes. We envisioned that
the sulfamide motif, which is a structural relative of (thio)urea,
could possibly be introduced to the chiral amine to serve as a
versatile core activation unit for bifunctional catalysis (Fig. 1).17
The sulfamides, such as II, are expected to provided stronger
acidity of N–H bonds than the corresponding (thio)urea. Notably,
Yan et al. recently developed a series of primary amine-sulfamide
catalysts and successfully applied them to the conjugate addition
of aldehydes to nitroalkenes by combination with base additives.18
As a part of our interest in developing novel and structurally
different bifunctional chiral amine organocatalysts,19 we herein
disclose the synthesis of unprecedented pyrrolidinyl-sulfamide
catalysts 1–4 and their application to the highly enantioselective
direct Michael addition of cyclohexanone to nitroalkenes.
especially for the enantioselective functionalization of the carbonyl
compounds.4–8 Of these reactions, the organocatalytic asymmetric
Michael addition reactions9 of ketones/aldehydes to nitroalkenes
have received much attention because the corresponding adducts,
g-nitrocarbonyl compounds, are synthetically versatile.10 Stimu-
lated by the seminal works of List11a and Barbas,11b,c many efficient
and highly selective catalytic systems have been developed for
this reaction.11–14 Elegant catalysts include Wang’s pyrrolidine
sulfonamides12h and thiourea-dehydroabietic amine,13k Barbas’
diamines,12i Tang’s thiourea-secondary amines,12j Tsogoeva’s13g,h
and Jacobsen’s primary amine-thioureas,13i Takemoto’s thiourea-
tertiary amine,13l and Chen’s pyrrolidinyl-camphor derivatives.13t
Among them, those chiral amines based on the thiourea and urea
cores dominate the field.14 Essential to the overwhelming success
of thiourea-based catalysts is their capability to form two or more
H-bonds with a reaction component. Such H-bonding interactions
not only further activate the reactant but also direct it to a well-
defined orientation, required for asymmetric induction. Quite
recently, the Rawal group firstly developed the (-)-cinchonine-
derived squaramide derivatives as highly effective H-bonding
Results and discussion
To access the utility of representative sulfamides for asymmetric
catalysis (Fig. 1), several differently substituted chiral pyrrolidinyl-
sulfamide derivatives were synthesized by the modification of
known procedures.18,20 As highlighted in Scheme 1, the preparation
of pyrrolidinyl-sulfamides 1a–1c and 2 with benzyl groups was
based on path A. Stirring catechol sulfate 5 with an amine 6 in
CH2Cl2 with Et3N as the base promoted the first substitution
reaction. Repeating such a process with the (S)-2-amino-1-N-Boc-
pyrrolidine 821 in refluxing DCE gave rise to the disubstituted
Key Laboratory of Pesticide & Chemical Biology, Ministry of Edu-
cation, College of Chemistry, Central China Normal University, 152
Luoyu Road, Wuhan, Hubei, 430079, China. E-mail: jiarongchen2003@
yahoo.com.cn, wxiao@mail.ccnu.edu.cn; Fax: +86 27 67862041
† Electronic supplementary information (ESI) available: Experimental
details, characterization of all catalysts, NMR spectra, and HPLC spectra
of Michael addition products. See DOI: 10.1039/c1ob05442b
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Table 1 Solvent screening for the asymmetric Michael addition of
cyclohexanone 13 to trans-b-nitrostyrene 14aa
Entry
Solvent
t/h
Yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
n-Hexane
Toluene
CHCl3
CH2Cl2
DCE
Et2O
DMF
CH3CN
Dioxane
THF
MeOH
EtOH
6
22
22
22
22
22
22
46
46
46
22
22
94
90
91
92
92
90
85
33
31
92/8
92/8
93/7
93/7
92/8
94/6
95/5
91/9
93/7
95/5
—
84
84
86
85
83
85
86
80
80
82
—
—
9
10
11
12
43
< 5
< 5
Fig. 1 A new class of pyrrolidinyl-sulfamide catalysts.
—
a Reactions were carried out with cyclohexanone 13 (3.0 mmol), trans-
b-nitrostyrene 14a (0.3 mmol) and 10 mol% catalyst 1a and 10 mol%
PhCO2H in the solvent (0.6 mL) indicated. DCE = 1,2-dichloroethane.
b Isolated yield for both diastereomers. c Syn/anti ratio was determined by
1H NMR. d ee of syn diastereomer, determined by chiral HPLC analysis.
sulfamide 9. Removing the Boc protecting group from nitrogen
with TFA/CH2Cl2 afforded the target catalysts 1a–1c and 2
smoothly. The other pyrrolidinyl-sulfamides 3 and 4 bearing
aromatic substitution or cyclohexyl group on the nitrogen were
also efficiently prepared by a slight change of the substitution
sequence (path B). Moreover, the structures of the catalysts 1–4
were fully characterized (see the ESI†). Notably, these catalysts
could be easily prepared on gram scales.
With success in synthesizing the above mentioned organocata-
lysts, we chose the Michael addition of cyclohexanone to trans-
b-nitrostyrene 14a as the benchmark reaction for examining the
catalytic performance of these catalysts (Table 1). To our delight,
pyrrolidinyl-sulfamide 1a could indeed efficiently catalyze the
Michael reaction with PhCO2H as the acidic additive under our
previous conditions,16 giving the corresponding adduct in 94%
yield with 92/8 dr and 84% ee (Table 1, entry 1). Encouraged by
these preliminary results, we examined the effects of additional
solvents on the reaction with 1a as the catalyst. It was found that
the reaction could be performed in a variety of commonly used
solvents, such as toluene, CHCl3, CH2Cl2, DCE, Et2O, and DMF,
and consistently excellent yields and high stereoselectivities were
obtained. The use of CH3CN, dioxane, and THF as the reaction
media gave the desired adduct 15a in moderate yield but with
good diastereoselectivity and enantioselectivity (Table 1, entries
8–10). In accordance with our previous observation,19b only trace
amounts of the Michael adducts were formed in protonic polar
solvents, such as MeOH and EtOH (Table 1, entries 11 and 12).
Thus, in terms of the reaction efficiency and stereoselectivity, we
chose n-hexane as the reaction medium for further optimizations.
As can be seen from the results summarized in Table 2, the
catalytic activities and the stereoselectivities of 1b–4 (Fig. 1) were
significantly influenced by a subtle change in the sulfamide moiety.
An elegant alignment of the steric and electronic properties of
the catalyst would determine the reaction efficiency. Among the
nine pyrrolidinyl-sulfamide catalysts examined, catalysts 3a and
3b were found to give optimal results (Table 1, entries 5 and 6,
95/5 dr, 88% and 89% ee, respectively). Further screenings of other
reaction parameters demonstrated that a substantial improvement
of the dr and ee to 97/3 and 92% was achieved when the reacti◦on
was carried out in a mixture of n-hexane and CH2Cl2 at -10 C
(Table 1, entry 14). Note that the reaction proceeded well even
with 5 mol% of catalyst 3a without loss of stereoselectivity albeit
with a somewhat prolonged reaction time (Table 2, entry 13).
Interestingly, the reaction proceeded much more slowly but with
comparable dr and ee values in the absence of PhCO2H (Table 2,
entry 15 vs. 5).
Scheme 1 Synthesis of a series of novel pyrrolidinyl-sulfamide catalysts 1–4.
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Table 2 Catalyst screening for the asymmetric Michael addition of
cyclohexanone 13 to trans-b-nitrostyrene 14aa
Table 3 Asymmetric Michael addition reaction between 13 and 14
catalyzed by catalyst 3aa
Entry
Nitroolefin, Ar
t/h
Yield (%)b
drc
ee (%)d
Entry
Catalyst
t/h
Yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
Ph (14a)
4-NO2-Ph (14b)
4-F-Ph (14c)
4-Br-Ph (14d)
2-Br-Ph (14e)
4-Cl-Ph (14f)
25
41
45
27
15
30
11
22
48
15
27
58
44
25
72
89
90
89
93
85
95
94
89
91
96
96
95
94
94
< 5
97/3
98/2
98/2
97/3
99/1
97/3
97/3
99/1
96/4
97/3
93/7
92/8
98/2
92/8
—
92
94
93
93
93
93
93
95
88
89
85
79
91
83
—
1
2
3
4
5
6
7
8
1a
1b
1c
2
3a
3b
3c
3d
4
3a
3b
3a
3a
3a
3a
6
6
7
7
4
4
5
13
20
12
12
12
46
25
36
94
92
97
92
94
95
95
92
90
96
94
85
84
89
38
92/8
92/8
93/7
95/5
95/5
95/5
95/5
94/6
94/6
96/4
96/4
97/3
97/3
97/3
94/6
84
81
85
88
88
89
87
88
87
90
89
90
91
92
88
2-Cl-Ph (14g)
2,4-Cl2-Ph (14h)
4-Me-Ph (14i)
2-MeO-Ph (14j)
3,4-MeO2-Ph (14k)
4-MeO-Ph (14l)
1-naphthyl (14m)
2-furyl (14n)
9
9
10
11e
12
13
14
15
10e
11e
12f
13f,g
14f,h
15i
cyclohexyl (14o)
a Unless otherwise noted, the reactions were carried out with 0.3 mmol of
14, 3.0 mmol of cyclohexanone 13 in 0.6 mL of n-hexane/CH2Cl2 (2 : 1,
v/v) in the presence of 10 mol% of catalyst 3a and 10 mol% of PhCO2H
for the indicated time. b Isolated yield for both diastereomers. c Syn/anti
ratio was determined by 1H NMR. d ee of syn diastereomer, determined by
chiral HPLC analysis. e Performed at room temperature.
a Unless otherwise noted, reactions were carried out with 0.3 mmol of
trans-b-nitrostyrene 14a, 3.0 mmol of cyclohexanone 13 in 0.6 mL of n-
hexane in the presence of 10 mol% of catalyst and 10 mol% of PhCO2H.
b Isolated yield for both diastereomers. c Syn/anti ratio was determined by
1H NMR. d ee of◦syn diastereomer, dete◦rmined by chiral HPLC analysis.
e Performed at 0 C. f Performed at -10 C. g With 5 mol% of catalyst 3a.
h A mixture of n-hexane/CH2Cl2 (2 : 1, v/v) was used. i Without PhCO2H.
oping highlyenantioselective organocatalyzed Michael addition of
aldehydes and ketones to nitrodienes. Whereas, the development
of efficient organocatalysts for the Michael addition of ketones
to nitrodienes is still challenging but desirable. Therefore, we
preliminarily examined the feasibility of utilizing nitrodiene 18 as
the Michael acceptor with 3a as the catalyst (eqn (2)). Gratifyingly,
the Michael addition proceeded smoothly under the above optimal
conditions and afforded the corresponding product 19 in a yield
of 91% with 96/4 dr and 90% ee. In addition, the use of acylic
acetone 16 was amenable to the reaction, although the yield and
enantioselectivity needs further improvement (eqn (3)).
Having identified the optimal catalyst and conditions, we set out
to explore the substrate scope with some representative aromatic
nitroolefins as highlighted in Table 3. The parent system worked
well. A variety of electron-withdrawing and electron-donating
groups at the 4- or 2-positions of the aromatic ring of the
nitroolefins were also well tolerated, leading to the formation of
Michael adducts 15b–k in high yields with excellent diastereo-
(93/7–99/1 dr) and enantioselectivities (85–95% ee) (Table 3,
entries 2–11). In the case of 4-methoxyl substituted nitroolefin 14l,
however, only 79% ee was obtained but still with high diastereose-
lectivity (92/8 dr, Table 3, entry 12). A fused aromatic nitroolefin,
such as 14m, was also successfully employed in this transformation
and high yield, dr (98/2), and ee (91%) were obtained. Moreover,
heteroaromatic nitroolefin 14n was a viable substrate (Table 3,
entry 14). Unfortunately, the alkyl substituted nitroolefin 14o
proved very sluggish, and no product was observed even after
3 days (Table 3, entry 15). Further structural modification of the
catalyst to improve the catalytic activity for alkyl nitroolefins is
currently underway in our laboratory.
(2)
To further investigate the scope of the new catalyst 3a for
Michael addition, the acylic acetone 16 was also examined as
the donor. The desired product 17 was obtained in 61% isolated
yield but with only 7% ee (eqn (1)).
(3)
Based on the observed stereochemical outcomes, we pro-
posed a possible transition state for this asymmetric Michael
addition (Fig. 2). Mechanistically, the in situ formed enamine
intermediate between cyclohexanone 13 and catalyst 3a adopts
the E-conformation. The sulfamide moiety provides H-bonding
interactions with the nitro group, thereby directing the Re face of
trans-b-nitrostyrene to be attacked by the Re face of the enamine
to give the corresponding preferred syn Michael adduct 15a.
(1)
In sharp contrast to the wide utility of trans-b-nitrostyrenes
in the conjugate addition, the nitrodienes have been less used as
Michael acceptors and little progress has been made.22 Recently,
Alexakis,22a,b Wu,22d and Ma22f independently succeeded in devel-
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Catalyst 1b. 1H NMR (400 MHz, DMSO-d6, TMS): d 1.30–
1.39 (m, 1H), 1.57–1.69 (m, 2H), 1.72–1.81 (m, 1H), 2.74–2.85
(m, 4H), 3.11–3.18 (m, 1H), 4.02 (s, 2H), 7.35–7.41 (m, 4H); 13C
NMR (100 MHz, DMSO-d6): d 24.5, 28.7, 45.0, 45.5, 46.5, 57.3,
128.1, 129.5, 131.5, 137.6; HRMS (EI): calcd for C12H18ClN3O2S
(M+H)+ 304.0887, found 304.0879; [a]2D0.5 = +18.5 (c = 1.0,
CH3CN).
Fig. 2 Proposed transition state.
Catalyst 1c. 1H NMR (400 MHz, DMSO-d6, TMS): d 1.23–
1.34 (m, 1H), 1.53–1.63 (m, 2H), 1.67–1.76 (m, 1H), 2.28 (s, 3H),
2.67–2.78 (m, 4H), 3.04–3.11 (m, 1H), 3.97 (s, 2H), 7.13 (d, J =
8.0 Hz, 2H), 7.22 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, DMSO-
d6): d 20.7, 24.9, 28.9, 45.6, 45.7, 47.2, 57.2, 127.7, 128.7, 135.4,
136.0; HRMS (EI): calcd for C13H21N3O2S (M+H)+ 284.1433,
found 284.1416; [a]2D0.7 = +22.4 (c = 1.0, CHCl3).
Conclusions
In conclusion, we have designed and synthesized a new class of
chiral pyrrolidinyl-sulfamide derivatives starting from inexpensive
proline and amines, which proved to be excellent catalysts for the
Michael addition of cyclohexanone to nitroolefins. The reactions
proceeded with high yields (85–96%), excellent diastereo- and
enantioselectivities (up to 99/1 dr and 95% ee). The modular
nature of the synthesis means that a wide range of other
chiral amine-sulfamide bifunctional organocatalysts, tuned with
regard to the hydrogen-bonding donors as well as the chiral
environment, should be readily accessible. Further investigation
of these catalysts in other enantioselective transformations and
the development of related modified catalysts are ongoing in our
laboratory.
Catalyst 2. 1H NMR (400 MHz, DMSO-d6, TMS): d 1.10–
1.19 (m, 1H), 1.44–1.57 (m, 2H), 1.60–1.68 (m, 1H), 2.54–2.65
(m, 2H), 2.76–2.82 (m, 1H), 2.97–3.01 (m, 1H), 3.04–3.11 (m,
1H), 4.58 (s, 2H), 4.96 (brs, 3H), 7.33–7.37 (m, 1H), 7.42–7.51
(m, 3H), 7.74 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 8.07
(d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d 25.0,
28.6, 44.9, 45.6, 46.7, 57.7, 123.4, 125.2, 125.8, 126.3, 126.6, 128.5,
131.1, 132.4, 133.5; HRMS (EI): calcd for C16H21N3O2S (M+H)+
320.1433, found 320.1422; [a]2D0.9 = +14.8 (c = 1.0, CHCl3).
Experimental section
Catalyst 3a. 1H NMR (400 MHz, DMSO-d6, TMS): d 1.19–
1.27 (m, 1H), 1.51–1.66 (m, 3H), 2.67–2.81 (m, 4H), 3.02–3.08 (m,
1H), 6.17 (brs, 2H), 6.98 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 8.0 Hz,
2H), 7.26 (t, J = 7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6):
d 24.7, 28.7, 45.5, 47.0, 56.9, 118.0, 122.2, 128.9, 139.1; HRMS
(EI): calcd for C11H17N3O2S (M+H)+ 256.1120, found 256.1096;
[a]2D0.7 = +41.5 (c = 1.0, CH3CN).
General information
Unless otherwise noted, materials were purchased from com-
mercial suppliers and used without further purification.
Dichloromethane and 1,2-dichloroethane were freshly distilled
from calcium hydride. Toluene, n-hexanes, ethyl ether and tetrahy-
drofuran (THF) were distilled from sodium/benzophenone. Re-
actions were monitored by thin layer chromatography (TLC), and
column chromatography purifications were performed using 200–
300 mesh silica gel and 200–300 mesh basic aluminum oxide.
1H NMR spectra were recorded on 400 MHz or 600 MHz
spectrophotometer. Solvent for NMR is CDCl3 or DMSO-d6
unless otherwise noted. Chemical shifts are reported in delta
(d) units in parts per million (ppm) relative to the singlet
(0 ppm) for tetramethylsilane (TMS). Data are reported as follows:
chemical shift, multiplicity (s = single, d = doublet, t = triplet,
q = quartet, br = broad, m = multiplet), coupling constants (Hz)
and integration. 13C NMR spectra were recorded on 100 MHz
or 150 MHz. Chemical shifts are reported in ppm relative to the
central line of the heptet at 77.0 ppm for CDCl3 or 39.5 ppm for
DMSO-d6. The ee value determination was carried out using chiral
high-performance liquid chromatography (HPLC) with Daicel
Chiracel AD-H, OD-H and AS-H column and the dr values
were determined by 1H NMR. Organocatalysts 1–4 were prepared
according to the modified literature procedure18–20 from proline-
derived amine21 and commercially available amines.
Catalyst 3b. 1H NMR (400 MHz, DMSO-d6, TMS): d 1.21–
1.29 (m, 1H), 1.49–1.68 (m, 3H), 2.23 (s, 3H), 2.68–2.72 (m,
2H), 2.73–2.80 (m, 2H), 3.02–3.08 (m, 1H), 7.06 (t, J = 9.6 Hz,
4H); 13C NMR (100 MHz, DMSO-d6): d 20.3, 24.7, 28.7, 45.5,
46.9, 57.0, 118.5, 129.3, 131.3, 136.5; HRMS (EI): calcd for
C12H19N3O2S (M+H)+ 270.1276, found 270.1253; [a]2D1.0 = +45.7
(c = 1.0, CH3CN).
Catalyst 3c. 1H NMR (400 MHz, CDCl3, TMS): d 1.28–1.36
(m, 1H), 1.61–1.83 (m, 3H), 2.24 (s, 6H), 2.81–2.85 (m, 2H), 2.96
(dd, J = 8.0, 13.6 Hz, 1H), 3.15 (dd, J = 4.4, 13.2 Hz, 1H), 3.24–
3.31 (m, 1H), 5.69 (brs, 3H), 6.70 (s, 1H), 6.79 (s, 2H); 13C NMR
(100 MHz, CDCl3): d 21.2, 25.3, 28.7, 45.9, 46.7, 57.8, 117.3,
125.4, 137.9, 138.8; HRMS (EI): calcd for C13H21N3O2S (M+H)+
284.1433, found 284.1419; [a]2D0.8 = +40.3 (c = 1.0, CH3CN).
Catalyst 3d. 1H NMR (400 MHz, DMSO-d6, TMS): d 1.22–
1.29 (m, 1H), 1.51–1.68 (m, 3H), 2.69–2.73 (m, 2H), 2.75–2.82
(m, 2H), 3.04–3.10 (m, 1H), 5.69 (brs, 3H), 7.15 (d, J = 8.8 Hz,
2H, 7.32 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6):
d 24.7, 28.7, 45.5, 46.8, 57.0, 119.5, 125.8, 128.7, 138.5; HRMS
(EI): calcd for C11H16ClN3O2S (M+H)+ 290.0730, found 290.0731;
[a]2D1.0 = +46.1 (c = 1.0, CH3CN).
Catalyst 1a. 1H NMR (400 MHz, DMSO-d6, TMS): d 1.26–
1.35 (m, 1H), 1.53–1.65 (m, 2H), 1.68–1.76 (m, 1H), 2.67–2.78
(m, 4H), 2.31 (s, 1H), 3.04–3.11 (m, 1H), 4.02 (s, 2H), 7.25–7.34
(m, 5H); 13C NMR (100 MHz, DMSO-d6): d 24.7, 28.9, 45.7,
45.8, 47.2, 57.2, 127.0, 127.7, 128.2, 138.5; HRMS (EI): calcd for
C12H19N3O2S (M+H)+ 270.1276, found 270.1258; [a]1D9.4 = +24.9
(c = 1.0, CHCl3).
Catalyst 4. 1H NMR (400 MHz, DMSO-d6, TMS): d 1.05–
1.22 (m, 5H), 1.30–1.37 (m, 1H), 1.50–1.85 (m, 8H), 2.69–2.80
(m, 4H), 2.95 (s, 1H), 3.06–3.12 (m, 1H), 6.89 (brs, 1H), 2.95
(s, 1H), 3.06–3.12 (m, 1H), 6.89 (brs, 1H); 13C NMR (100 MHz,
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DMSO-d6): d 24.7, 24.8, 25.1, 28.9, 33.4, 33.5, 45.7, 47.3, 51.6,
57.2; HRMS (EI): calcd for C11H23N3O2S (M+H)+ 262.1589, found
262.1576; [a]D20.8 = +25.9 (c = 1.0, CHCl3).
l = 210 nm, 20 ◦C); tR (minor) = 13.5 min; tR (major) = 22.0 min,
syn/anti = 97/3, syn: ee = 93%; 1H NMR (400 MHz, CDCl3, TMS):
d 1.16–1.26 (m, 1H), 1.53–1.79 (m, 4H), 2.05–2.11 (m, 1H), 2.32–
2.47 (m, 2H), 2.61–2.68 (m, 1H), 3.72–3.78 (m, 1H), 4.59 (dd, J =
10.4, 12.4 Hz, 1H), 4.94 (dd, J = 4.4, 12.8 Hz, 1H), 7.06 (d, J =
8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 24.9, 28.3, 33.0, 42.6, 43.2, 52.1, 78.4, 121.5, 129.8, 131.9, 136.7,
211.4.
Representative procedure for the asymmetric Michael reaction of
nitroolefin 14a with cyclohexanone 13 (Table 3, entry 1)
The organocatalyst 3a (7.7 mg, 0.03 mmol), PhCO2H (3.7 mg, 0.03
mmol) and cyclohexanone 13 (0.32 mL, 3.0 mmol) were stirred in
0.6 mL of n-hexane/CH2Cl2 (2 : 1, v/v) for 20 min at -10 ◦C. The
trans-b-styrene 14a (45.0 mg, 0.3 mmol) was then added and
the reaction mixture was stirred for 25 h. After the complete
consumption of 14a (as monitored by TLC), the reaction mixture
was concentrated under reduced pressure, and the residue was
purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate (4 : 1 to 2 : 1)) to give the corresponding pure
Michael product 13a (110.0 mg, 89%) as a white solid. Relative
and absolute configurations of the products were determined by
comparison of 1H NMR, 13C NMR spectra and HPLC data
with the known literature. Compounds 15a–o, 17, 19, and 20 are
known.12,19,22
2-(1-(2-Bromophenyl)-2-nitroethyl)cyclohexanone (15e), (Table
3, entry 5). 85% yield; the ee was determined by HPLC (Chiral-
pak AD column, hexane/i-PrOH 85 : 15, flow rate 1.0 mL min-1,
l = 210 nm, 20 ◦C); tR (minor) = 8.9 min; tR (major) = 14.5 min,
syn/anti = 99/1, syn: ee = 93%; 1H NMR (400 MHz, CDCl3, TMS):
d 1.33–1.41 (m, 1H), 1.53–1.83 (m, 4H), 2.06–2.12 (m, 1H), 2.31–
2.48 (m, 2H), 2.88 (s, 1H), 4.32 (d, J = 8.0 Hz, 1H), 4.89 (d, J =
5.6 Hz, 2H), 7.10–7.14 (m, 1H), 7.21–7.23 (m, 1H), 7.27–7.31 (m,
1H), 7.57 (dd, J = 1.2, 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
25.1, 28.4, 32.8, 42.7, 52.0, 77.3, 125.2, 127.9, 128.9., 133.5, 137.1,
211.5.
2-(1-(4-Chlorophenyl)-2-nitroethyl)cyclohexanone (15f), (Table
3, entry 6). 95% yield; the ee was determined by HPLC (Chiral-
pak AD column, hexane/i-PrOH 90 : 10, flow rate 1.0 mL min-1,
l = 210 nm, 20 ◦C); tR (minor) = 12.6 min; tR (major) = 19.1 min,
syn/anti = 97/3, syn: ee = 93%; 1H NMR (400 MHz, CDCl3, TMS):
d 1.16–1.26 (m, 1H), 1.49–1.79 (m, 4H), 2.05–2.10 (m, 1H), 2.31–
2.47 (m, 2H), 2.61–2.68 (m, 1H), 3.73–3.79 (m, 1H), 4.57 (dd, J =
10.4, 12.4 Hz, 1H), 4.95 (dd, J = 4.4, 12.8 Hz, 1H), 7.12 (d, J =
8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 24.9, 28.3, 33.0, 42.6, 43.2, 52.1, 78.4, 128.9, 129.4, 133.3, 136.1,
211.5.
2-(2-Nitro-1-phenylethyl)cyclohexanone (15a), (Table 3, entry 1).
89% yield; the ee was determined by HPLC (Chiralpak AS colu◦mn,
hexane/i-PrOH 75 : 25, flow rate 1.0 mL min-1, l = 210 nm, 20 C);
tR (minor) = 9.3 min; tR (major) = 13.6 min. syn/anti = 97/3, syn:
1
ee = 92%; H NMR (400 MHz, CDCl3, TMS): d 1.17–1.27 (m,
1H), 1.50–1.79 (m, 4H), 2.03–2.11 (m, 1H), 2.34–2.41 (m, 1H),
2.44–2.49 (m, 1H), 2.65–2.71 (m, 1H), 3.71–3.79 (m, 1H), 4.62
(dd, J = 10.0, 12.8 Hz, 1H), 4.94 (dd, J = 4.4, 12.4 Hz, 1H), 7.15–
7.17 (m, 2H), 7.23–7.27 (m, 1H), 7.29–7.33 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 24.9, 28.4, 33.1, 42.6, 43.8, 52.3, 78.8, 127.6,
128.0, 128.8, 137.6, 211.9.
2-(1-(2-Chlorophenyl)-2-nitroethyl)cyclohexanone (15g), (Table
3, entry 7). 94% yield; the ee was determined by HPLC (Chi-
ralpak AD column, hexane/i-PrOH 95 : 5, flow rate 1.0 mL min-1,
l = 210 nm, 20 ◦C); tR (minor) = 14.2 min; tR (major) = 26.0 min,
syn/anti = 97/3, syn: ee = 93%; 1H NMR (400 MHz, CDCl3, TMS):
d 1.28–1.37 (m, 1H), 1.57–1.87 (m, 4H), 2.06–2.11 (m, 1H), 2.31–
2.48 (m, 2H), 2.86–2.92 (m, 1H), 4.28–4.34 (m, 1H), 4.84–4.94 (m,
2H), 7.18–7.24 (m, 3H), 7.37 (dd, J = 0.8, 7.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 25.1, 28.4, 32.8, 40.7, 42.6, 51.5, 77.1, 127.2,
128.7, 129.2, 130.1, 134.3, 135.3, 211.6.
2-(2-Nitro-1-(4-nitrophenyl)ethyl)cyclohexanone (15b), (Table 3,
entry 2). 90% yield; the ee was determined by HPLC (Chiralpak
AD column, hexane/i-PrOH 75 : 25, flow rate 1.0 mL min-1, l =
254 nm, 20 ◦C); tR (minor) = 13.0 min; tR (major) = 28.4 min,
1
syn/anti = 98/2, syn: ee = 94%; H NMR (600 MHz, CDCl3,
TMS): d 1.24–1.30 (m, 1H), 1.57–1.71 (m, 4H), 1.81–1.84 (m,
1H), 2.11–2.13 (m, 1H), 2.36–2.42 (m, 1H), 2.48–2.50 (m, 1H),
2.70–2.75 (m, 1H), 3.91–3.95 (m, 1H), 4.70 (dd, J = 10.8, 12.6 Hz,
1H), 5.00 (dd, J = 4.2, 13.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 8.20
(d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 24.9, 28.1,
33.0, 42.5, 43.6, 52.0, 77.9, 123.9, 129.2, 145.5, 147.2, 210.8.
2-(1-(2,4-Dichlorophenyl)-2-nitroethyl)cyclohexanone
(15h),
(Table 3, entry 8). 89% yield; the ee was determined by HPLC
(Chiralpak AD column, hexane/i-PrOH 90 : 10, flow rate
1.0 mL min-1, l = 210 nm, 20 ◦C); tR (minor) = 9.9 min; tR
2-(1-(4-Fluorophenyl)-2-nitroethyl)cyclohexanone (15c), (Table
3, entry 3). 89% yield; the ee was determined by HPLC (Chi-
ralpak OD column, hexane/i-PrOH 95 : 5, flow rate 1.0 mL min-1,
l = 210 nm, 20 ◦C); tR (minor) = 19.1 min; tR (major) = 21.2 min,
syn/anti = 98/2, syn: ee = 93%; 1H NMR (400 MHz, CDCl3, TMS):
d 1.16–1.26 (m, 1H), 1.54–1.86 (m, 4H), 2.05–2.11 (m, 1H), 2.31–
2.47 (m, 2H), 2.62–2.69 (m, 1H), 3.74–3.80 (m, 1H), 4.58 (dd, J =
10.0, 12.8 Hz, 1H), 4.95 (dd, J = 4.8, 12.4 Hz, 1H), 7.01 (t, J =
8.8 Hz, 2H), 7.14–7.17 (m, 2H); 13C NMR (100 MHz, CDCl3): d
24.9, 28.3, 33.0, 42.6, 43.1, 52.3, 78.7, 115.6, 115.8, 129.6, 129.7,
133.3, 133.4, 160.7, 163.1, 211.6.
1
(major) = 14.5 min, syn/anti = 99/1, syn: ee = 95%; H NMR
(400 MHz, CDCl3, TMS): d 1.29–1.38 (m, 1H), 1.57–1.83 (m,
4H), 2.08–2.13 (m, 1H), 2.32–2.48 (m, 2H), 2.82–2.89 (m, 1H),
4.23–4.29 (m, 1H), 4.82–4.93 (m, 2H), 7.18–7.25 (m, 2H), 7.40 (t,
J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 25.3, 28.5, 33.0,
40.5, 42.8, 51.6, 77.4, 127.7, 130.1, 134.0, 134.2, 135.3, 211.4.
2-(2-Nitro-1-p-tolylethyl)cyclohexanone (15i), (Table 3, entry 9).
91% yield; the ee was determined by HPLC (Chiralpak AS colu◦mn,
hexane/i-PrOH 90 : 10, flow rate 0.8 mL min-1; l = 210 nm, 20 C).
tR (minor) = 15.4 min; tR (major) = 27.0 min, syn/anti = 96/4, syn:
2-(1-(4-Bromophenyl)-2-nitroethyl)cyclohexanone (15d), (Table
3, entry 4). 93% yield; the ee was determined by HPLC (Chiral-
pak AD column, hexane/i-PrOH 90 : 10, flow rate 1.0 mL min-1,
1
ee = 88%; H NMR (600 MHz, CDCl3, TMS): d 1.19–1.26 (m,
1H), 1.53–1.59 (m, 1H), 1.64–1.79 (m, 3H), 2.05–2.09 (m, 1H),
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2.31 (s, 3H), 2.35–2.40 (m, 1H), 2.45–2.48 (m, 1H), 2.64–2.68 (m,
1H), 3.69–3.73 (m, 1H), 4.60 (dd, J = 10.2, 12.0 Hz, 1H), 4.92 (dd,
J = 4.8, 12.6 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 7.8 Hz,
2H); 13C NMR (100 MHz, CDCl3): d 20.9, 24.8, 28.4, 33.1, 42.6,
43.4, 52.3, 78.9, 127.8, 129.4, 134.4, 137.2, 212.0.
210 nm, 20 ◦C); tR (major) = 10.9 min; tR (minor) = 13.1 min,
syn/anti = 92/8, syn: ee = 83%; H NMR (400 MHz, CDCl3,
1
TMS): d 1.15–1.25 (m, 1H), 1.50–1.59 (m, 2H), 1.64–1.77 (m,
2H), 1.98–2.05 (m, 1H), 2.25–2.38 (m, 2H), 2.64–2.71 (m, 1H),
3.86–3.92 (m, 1H), 4.58 (dd, J = 9.6, 12.4 Hz, 1H), 4.71 (dd, J =
4.4, 12.8 Hz, 1H), 6.10 (d, J = 3.2 Hz, 1H), 6.20 (dd, J = 1.6, 3.2 Hz,
1H), 7.27 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
24.9, 28.0, 32.3, 37.3, 42.4, 50.9, 76.5, 108.7, 110.1, 142.1, 150.8,
210.8.
2-(1-(2-Methoxyphenyl)-2-nitroethyl)cyclohexanone
(15j),
(Table 3, entry 10). 96% yield; the ee was determined by
HPLC (Chiralpak AS column, hexane/i-PrOH 90 : 10, flow rate
1.0 mL min-1, l = 210 nm, 20 ◦C); tR (minor) = 15.6 min; tR
1
5-Nitro-4-phenylpentan-2-one (17), (eqn (1)). 61% yield; the ee
was determined by HPLC (Chiralpak AS column, hexane/i-PrOH
(major) = 18.1 min, syn/anti = 97/3, syn: ee = 89%; H NMR
(400 MHz, CDCl3, TMS): d 1.14–1.24 (m, 1H), 1.54–1.68 (m,
3H), 1.71–1.77 (m, 1H), 2.04–2.08 (m, 1H), 2.34–2.47 (m, 2H),
2.94–3.01 (m, 1H), 3.83 (s, 3H), 3.92–3.98 (m, 1H), 4.79–4.87 (m,
2H), 6.87 (t, J = 7.6 Hz, 2H), 7.08 (t, J = 6.0 Hz, 1H), 7.21–7.27
(m, 2H); 13C NMR (100 MHz, CDCl3): d 25.0, 28.4, 33.1, 41.2,
42.6, 50.3, 55.2, 77.3, 110.8, 120.7, 125.1, 128.7, 130.8, 157.4,
212.5.
◦
75 : 25, flow rate 1.0 mL min-1, l = 256 nm, 20 C). tR (minor) =
1
15.2 min; tR (major) = 20.2 min, ee = 7%. H NMR (400 MHz,
CDCl3, TMS): d 2.12 (s, 3H), 2.91 (d, J = 4.0 Hz, 2H), 3.97–4.04
(m, 1H), 4.59 (dd, J = 8.0, 12.0 Hz, 1H), 4.69 (dd, J = 8.0, 12.0 Hz,
1H), 7.21–7.23 (m, 2H), 7.28–7.35 (m, 3H); 13C NMR (100 MHz,
CDCl3): d 30.3, 38.9, 46.0, 79.3, 127.3, 127.8, 128.9, 138.7, 205.4.
(E)-2-(1-Nitro-4-phenylbut-3-en-2-yl)cyclohexanone (19), (eqn
(2)). 91% yield; the ee was determined by HPLC (Chiralpak
AS column, hexane/i-PrOH 85 : 15, flow rate 1.0 mL min-1, l =
254 nm, 20 ◦C). tR (minor) = 11.5 min; tR (major) = 18.9 min,
2-(1-(3,4-dimethoxyphenyl)-2-nitroethyl)cyclohexanone (15k),
(Table 3, entry 11). 96% yield; the ee was determined by
HPLC (Chiralpak AS column, hexane/i-PrOH 70 : 30, flow rate
1.0 mL min-1, l = 210 nm, 20 ◦C); tR (minor) = 13.7 min; tR
1
syn/anti = 96/4, syn: ee = 90%. H NMR (400 MHz, CDCl3,
1
(major) = 27.1 min, syn/anti = 93/7, syn: ee = 85%; H NMR
TMS): d 1.37–1.47 (m, 1H), 1.59–1.71 (m, 2H), 1.83–1.89 (m,
1H), 2.03–2.17 (m, 2H), 2.29–2.45 (m, 2H), 2.48–2.55 (m, 1H),
3.30–3.38 (m, 1H), 4.53 (dd, J = 8.8, 12.0 Hz, 1H), 4.66 (dd, J =
4.8, 12.0 Hz, 1H), 6.00 (dd, J = 9.6, 15.6 Hz, 1H), 6.47 (d, J =
15.6 Hz, 1H), 7.20–7.24 (m, 1H), 7.25–7.34 (m, 4H); 13C NMR
(100 MHz, CDCl3): d 24.9, 27.9, 32.4, 41.7, 42.5, 51.4, 77.9, 125.5,
126.3, 127.7, 128.4, 134.2, 136.1, 211.1.
(400 MHz, CDCl3, TMS): d 1.19–1.29 (m, 1H), 1.55–1.80 (m,
4H), 2.04–2.09 (m, 1H), 2.31–2.47 (m, 2H), 2.62–2.68 (m, 1H),
3.67–3.73 (m, 1H), 3.85 (s, 3H), 3.86 (s, 3H), 4.60 (dd, J = 10.4,
12.4 Hz, 1H), 4.92 (dd, J = 4.4, 12.4 Hz, 1H), 6.68–6.72 (m, 2H),
6.81 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 24.8,
28.3, 32.9, 42.5, 43.4, 52.4, 55.6, 55.7, 78.8, 111.1, 111.2, 119.9,
129.9, 148.1, 148.8, 211.9.
4-Nitromethyl-6-phenylhex-5-en-2-one (20), (eqn (3)). 33%
yield; the ee was determined by HPLC (Chirapak AS column,
hexane/i-PrOH 80 : 20, 254 nm, 20 ◦C). tR (minor) = 20.6 min; tR
(major) = 22.5 min, ee = 14%. 1H NMR (400 MHz, CDCl3, TMS):
d 2.18 (s, 3H), 2.74 (d, J = 4.0 Hz, 2H), 3.48–3.57 (m, 1H), 4.51
(dd, J = 8.0, 12.0 Hz, 1H), 4.59 (dd, J = 8.0, 12.0 Hz, 1H), 6.07 (q,
2-(1-(4-Methoxyphenyl)-2-nitroethyl)cyclohexanone
(15l),
(Table 3, entry 12). 95% yield; the ee was determined by
HPLC (Chiralpak AD column, hexane/i-PrOH 75 : 25, flow rate
0.7 mL min-1, l = 210 nm, 20 ◦C); tR (minor) = 11.3 min; tR
1
(major) = 13.6 min, syn/anti = 92/8, syn: ee = 79%; H NMR
(400 MHz, CDCl3, TMS): d 1.16–1.28 (m, 1H), 1.50–1.78 (m,
4H), 2.03–2.09 (m, 1H), 2.33–2.47 (m, 2H), 2.61–2.67 (m, 1H),
3.68–3.74 (m, 1H), 3.76 (s, 3H), 4.56 (dd, J = 10.4, 12.0 Hz, 1H),
4.92 (dd, J = 4.8, 12.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 7.08 (d,
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d 24.8, 28.4, 33.0,
42.6, 43.0, 52.4, 55.0, 78.9, 114.1, 129.0, 129.3, 158.8, 212.0.
J = 8.0 Hz, 1H), 6.53 (d, J = 16.0 Hz, 1H), 7.23–7.34 (m, 5H); 13
C
NMR (100 MHz, CDCl3): d 30.4, 36.9, 44.8, 78.5, 126.1, 126.3,
127.9, 128.5, 133.3, 136.0, 205.6.
Acknowledgements
We are grateful to the National Natural Science Foundation
of China (NO. 21002036 and 21072069), the Natural Science
Foundation of the Hubei Province (NO. 2010CDB04006) and the
Program for Changjiang Scholars and Innovative Research Team
in University (IRT0953) for support of this research.
2-(1-(Naphthalen-1-yl)-2-nitroethyl)cyclohexanone
(15m),
(Table 3, entry 13). 94% yield; the ee was determined by
HPLC (Chiralpak AS column, hexane/i-PrOH 50 : 50, flow rate
0.7 mL min-1, l = 254 nm, 20 ◦C); tR (minor) = 11.7 min; tR
1
(major) = 16.8 min, syn/anti = 98/2, syn: ee = 91%; H NMR
(400 MHz, CDCl3, TMS): d 1.14–1.24 (m, 1H), 1.38–1.47 (m,
1H), 1.54–1.62 (m, 3H), 1.98–2.03 (m, 1H), 2.30–2.33 (m, 1H),
2.43–2.46 (m, 1H), 2.80 (s, 1H), 4.77 (s, 1H), 4.86 (t, J = 12.0 Hz,
1H), 5.06 (dd, J = 3.6, 12.8 Hz, 1H), 7.34–7.48 (m, 4H), 7.74 (d,
J = 8.4 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 5.6 Hz, 1H);
13C NMR (100 MHz, CDCl3): d 25.0, 28.5, 33.1, 36.5, 42.7, 53.6,
78.5, 122.6, 123.4, 125.2, 125.7, 126.4, 127.9, 128.8, 132.3, 133.7,
134.5, 212.2.
Notes and references
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AD column, hexane/i-PrOH 90 : 10, flow rate 1.0 mL min-1, l =
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