4-aminothioureaprolinal dithioacetal as a catalyst for highly enantioselective michael additions of ketones and aldehydes to nitroolefins

Article abstract of DOI:10.1002/ejoc.201001211

4-Aminothioureaprolinal dithioacetal 4a is a highly efficient catalyst for the asymmetric Michael addition of ketones and aldehydes to nitroolefins requiring only 3 mol-% catalyst loading. The reactions proceeded smoothly and gave syn selective adducts with excellent yields (up to 98a% yield), diastereoselectivity (up to >99:1adr), and enantioselectivity (up to 99a%aee) under solvent free conditions at room temperature. This extremely simple and practical procedure increases the attractiveness of this reaction. 4-Aminothioureaprolinal dithioacetal 4a is a highly efficient catalyst for asymmetric Michael additions of ketones and aldehydes to nitroolefins. Using only 3 mol-% catalyst loading, reactions proceededsmoothly and gave syn selective adducts in excellent yields with excellent diastereoselectivity and enantioselectivity under solvent-free conditions at room temperature.

Full text of DOI:10.1002/ejoc.201001211

FULL PAPER
DOI: 10.1002/ejoc.201001211
4-Aminothioureaprolinal Dithioacetal as a Catalyst for Highly Enantioselective
Michael Additions of Ketones and Aldehydes to Nitroolefins
Yong-Ming Chuan,[a] Li-Yang Yin,[b] Yan-Mei Zhang,[b] and Yun-Gui Peng*[a,b]
Keywords: Asymmetric catalysis / Michael addition / Enantioselectivity / Organocatalysis / Hydrogen bonds / Sulfur
4-Aminothioureaprolinal dithioacetal 4a is a highly efficient
catalyst for the asymmetric Michael addition of ketones and
aldehydes to nitroolefins requiring only 3 mol-% catalyst
loading. The reactions proceeded smoothly and gave syn se-
lective adducts with excellent yields (up to 98% yield), dia-
stereoselectivity (up to Ͼ99:1dr), and enantioselectivity (up
to 99%ee) under solvent free conditions at room tempera-
ture. This extremely simple and practical procedure in-
creases the attractiveness of this reaction.
water[3j,4a–4d,5a,5b,6b–6d,8d] or under solvent-free condi-
tions,[3g,5e,6i–6m,7] although such successes are very limited.
Despite such advances, it remains a challenge to identify
highly efficient organocatalysts that proceed smoothly un-
der moderate reaction conditions and in the absence of or-
ganic solvents.
Introduction
The Michael addition reaction is one of the most impor-
tant C–C bond-forming reactions in organic synthesis.[1]
The development of organocatalysts for asymmetric
Michael reactions of carbonyl compounds with nitroal-
kenes is an attractive area of research.[2] Since the pioneer-
ing work of List,[3a] considerable effort has been focused on
the development of organocatalytic asymmetric versions of
the reaction and great advances have been made re-
cently.[3–8] Consequently, a variety of asymmetric organoca-
talysts have been documented for the Michael addition of
ketones or aldehydes to nitroolefins. Pyrrolidine-based or-
ganocatalysts bearing bulky groups,[4] H-bonding function-
alities,[5] salt moieties,[6] or a phosphane oxide[7] function-
ality at the 2-position of the pyrrolidine ring have been
identified as good catalysts. Thus, chiral pyrrolidine is gen-
erally considered as a “privileged” framework for asymmet-
ric catalysis. Among the reported organocatalysts, some
have shown very high efficiency, requiring only 0.5–3 mol-
% catalyst loading when aldehydes were used as sub-
strates.[3i,4a,4e,6a] In cases of less reactive donors such as
ketones high catalyst loadings (5–30 mol-%) are required to
effect the desired transformation in reasonable time frames
and with good enantioselectivity; this is a major drawback
of chiral organocatalysts. Other drawbacks include the
requirements of low temperature and the use of organic sol-
vents, which are incompatible with green chemistry. It is
noteworthy that good results have been achieved in
Interested in developing an efficient chiral organocata-
lytic system to achieve high yielding and enantioselective
Michael additions, we previously developed pyrrolidine-
based silyl ether 1 and homodiphenylproline methyl ether
2[4i,4j] in which enantioselectivity was controlled primarily
by steric interactions. High levels of both enantioselectivity
(73–98%ee) and diastereoselectivity (99:1dr) were achieved
with catalyst loadings of 20 mol-% for 1 and 5 mol-% for 2
in hexane (Figure 1). Catalyst 2 has shown better catalytic
efficiency than catalyst 1 but its complicated synthesis has
encumbered its further development and use. Subsequently,
on the basis of the results obtained with 1, we introduced
an H-bond donor group into the 4-position of the pyrrol-
idine ring. Tuning of the H-bond donating ability localized
at the 4-position by changing the electronic and steric envi-
ronment through pyrrolidine modification led to the discov-
ery of 3a and 3b.[8c] Catalyst 3b was found to be superior
(reaction yields Ͼ99%) to 3a (76% yield) in terms of its
catalytic reactivity, but similar to 3a in terms of asymmetric
[a] Chengdu Institute of Organic Chemistry, Chinese Academy of
Sciences (CAS),
Chengdu, 610041, P. R. China
[b] School of Chemistry and Chemical Engineering, Southwest
University,
Chongqing, 400715, P. R. China
Fax: +86-23-6825-3157
E-mail: pyg@swu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001211.
Figure 1. Previously reported pyrrolidine-based organocatalysts by
our group.
578
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 578–583

Enantioselective Michael Additions of Ketones and Aldehydes to Nitroolefines
induction. Michael additions of ketones to nitroolefins cat- nating ability of the sulfonamide group in 4b relative to that
alyzed by 3b (5 mol-%) proceed with excellent yields of the dual H-bond donating thiourea in 4a may be respon-
(Ͼ99%) and stereoselectivities (99:1dr, 99%ee). However, sible for both the lower yield and the lower enantio-
this approach is limited by the requirement of high catalyst selectivity of reactions using 4b (Table 1, Entries 5 and 6).
loadings (5 mol-%), low temperatures, and the need for or- Predicated on these data, the thiourea appears to be far
ganic solvent.
superior to the sulfonamide in terms of reactivity and abil-
On the basis of our experience with 3a and 3b, we envi- ity to exert stereocontrol in this catalytic system. This is
sioned that both the catalytic efficiency and the stereoselec- contrasted with our previous reports looking at the use of
tivity could be further enhanced by adjusting the size of the catalysts 3a and 3b in hexane.[8c] Consequently, these data
group at the stereogenic pyrrolidine 2-position (i.e., the all indicated that the catalytic performance of 4a was supe-
-CH2OTBDPS group). Accordingly, we designed and syn- rior to that of catalysts 1–3 and 4b.
thesized catalysts 4a and 4b (Figure 2). The dithioacetal
Table 1. The effect of catalysts and conditions on the asymmetric
prolinals have shown better catalytic efficiency than catalyst
Michael addition reactions of cyclohexanone and nitrostyrene.[a]
1, and thus the size and/or the shape of bis(4-methylphen-
ylthio)methyl was deemed more suitable than -OTBDPS in
terms of retaining activity and exerting stereocontrol during
Michael addition.[4h] Therefore, we believed that catalysts
4a and 4b with H-bond donors at the 4-position of the di-
thioacetalprolinal pyrrolidine ring would possess high cata-
lytic efficiency; this would translate to lower catalyst con-
centrations necessary for highly efficient and stereocon-
trolled reactions. Herein, we demonstrate the effectiveness
of catalysts 4a and 4b in catalyzing Michael addition reac-
tions of ketones and aldehydes to nitroolefins.
Entry Catalyst
Solvent
Yield[b]
dr[c]
ee[d]
1
2
1
DCM
DCM
DCM
DCM
DCM
DCM
hexane
CHCl3
DCE
toluene
DMF
H2O
neat
neat
16
70
92
94
94
75
96
82
91
92
trace
92
96
97
98:2
97:2
94:6
97:3
98:2
97:3
99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
–
87
95
90
88
97
90
95
96
97
96
–
2
3
4
5
6
7
8
9
3a
3b
4a
4b
4a
4a
4a
4a
4a
4a
4a
4a
4a
10
11
12
13[e]
14
15[f]
99:1
Ͼ99:1
99:1
97
98
98
98
Figure 2. Designed and synthesized novel bifunctional organocata-
lysts.
neat
95
99:1
[a] Unless specified, all reactions were carried out with cyclohexa-
none (1.25 mmol, 5 equiv.) and nitrostyrene (0.25 mmol, 1 equiv.)
in the presence of the catalyst (0.0125 mmol, 5 mol-%) and
PhCO2H (5 mol-%) as additive in the solvent (1 mL) at room tem-
perature (25 °C). [b] Isolated yield. [c] Determined by 1H NMR
spectroscopy. [d] Determined by chiral HPLC analysis. [e] With
6 mmol of cyclohexanone. [f] With 3 mol-% of catalyst 4a was used.
Results and Discussion
We first examined novel catalysts 4a and 4b in a model
reaction, the conjugate addition of cyclohexanone (5a) and
β-nitrostyrene (6a), which was conducted in dichlorometh-
ane at room temperature. We also compared the results of
these reactions with those of reactions using catalysts 1–3,
previously reported by our group. As shown in Table 1,
these catalysts showed differing activities and gave the cor-
responding products 7a with a range of diastereoselectivity
and enantioselectivity (Table 1, Entries 1–6). Catalysts 1
and 2 displayed lower catalytic efficiency, attributable most
likely to the absence of any H-bond donating group at the
4-position of pyrrolidine. The use of catalysts 2 and 4a af-
forded the Michael product with excellent stereoselectivities
(Table 1, Entries 2 and 5), although the use of catalyst 2
Figure 3. Proposed transition-state model of the 4a-catalyzed
Michael addition reaction.
In order to refine and optimize the high reactivity and
gave a slightly lower yield. In comparison to 4a, both cata- enantioselectivity of catalyst 4a, various reaction conditions
lysts 3a and 3b gave almost the same yields but with slightly were examined. A series of solvents were screened in the
lower enantioselectivity (Table 1, Entries 3–5). This obser- presence of benzoic acid (5 mol-%) and catalyst 4a (5 mol-
vation may be attributable to the less effective steric interac- %) at room temperature (Table 1, Entries 4 and 7–13). In
tion of the -OTBDPS group with one face of the transient nonpolar or less polar solvents, desired Michael product 7a
enamine than is possible with the bulkier bis(4-methylphen- was obtained in good yield and with excellent stereocontrol
ylthio)methyl moiety (Figure 3). The impaired H-bond do- (Table 1, Entries 4 and 7–10). However, the reaction pro-
Eur. J. Org. Chem. 2011, 578–583
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
579

Y.-M. Chuan, L.-Y. Yin, Y.-M. Zhang, Y.-G. Peng
FULL PAPER
ceeded sluggishly in polar solvents such as DMF, and only selectivity was not significantly influenced by the difference
trace amounts of product were observed (Table 1, En- in substitution pattern (Table 2, Entries 6–8). The excellent
try 11). To our delight, excellent yields and stereoselectivi- enantioselectivity (93–95%ee) observed for reactions in-
ties (92% yield, 99:1dr, and 97%ee) could be obtained volving heteroaryl substrates (Table 2, Entries 16 and 17)
when the reaction was carried out in water (Table 1, En- indicated that they also are good Michael acceptors for cy-
try 12). The best result was achieved under neat conditions clohexanone.
(96% yield, Ͼ99:1dr, 98%ee; Table 1, Entry 13). We then
Other carbonyl compounds, including aldehydes and cy-
examined the influence of catalyst loading on the reaction. clic or acyclic ketones, were also examined in 4a-catalyzed
Remarkably, the use of only 3 mol-% catalyst with 5 mol-% Michael additions with 6a. The reactions gave the corre-
benzoic acid as an additive in 5 equiv. of cyclohexanone sponding products (Table 3, Entries 1–7) in moderate to
afforded the desired product in outstanding yield with ex-
Table 3. Asymmetric Michael additions of ketones and nitrostyrene
cellent diastereoselectivity and enantioselectivity (95%
yield, 99:1dr, 98%ee; Table 1, Entry 15). To the best of our
catalyzed by 4a.[a]
knowledge reports using such a low catalyst loading for
Michael additions of cyclic ketones to nitrostyrene are ex-
ceedingly rare.
With optimized conditions in hand, a variety of nitro-
styrenes bearing different substitutions were investigated,
and the results are summarized in Table 2. Generally, nitro-
styrenes bearing both electron-withdrawing (Table 2, En-
tries 2–10) and electron-donating (Table 2, Entries 11–15)
aryl groups and heterocyclic groups (Table 2, Entries 16 and
17) gave the desired products in good yields (84–98% yield)
with excellent selectivities (up to Ͼ99:1dr and up to
99%ee). The position of substitution for β-nitrostyrenes in
some substrates had a slight influence on the yield. For ex-
ample, when the brominated position of nitrostyrene was
changed from ortho to meta and para, the yield decreased
from 94 to 90 and 86%, respectively, although the enantio-
Table 2. Asymmetric Michael addition reactions of cyclohexanone
and nitroolefins catalyzed by 4a.[a]
dr[c]
syn/anti
Entry
Ar
Time [h] Yield[b] [%]
ee[d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph
2-FPh
4-FPh
2-ClPh
4-ClPh
2-BrPh
3-BrPh
4-BrPh
4-NO2Ph
2,4-Cl2Ph
4-MePh
2-MeOPh
4-MeOPh
1-naphthyl
2-naphthyl
2-furyl
24
24
48
27
48
24
48
72
48
72
24
21
48
60
60
22
46
95
97
92
92
94
94
90
86
89
86
92
97
98
86
90
84
85
99:1
99:1
Ͼ99:1
99:1
99:1
99:1
98:2
99:1
98:2
99:1
99:1
98:2
98:2
99:1
98:2
98:2
97:3
98
99
98
97
98
98
98
98
97
98
99
91
96
97
95
93
95
[a] Unless otherwise specified, reactions were carried out with
ketone (1.25 mmol, 5 equiv.) and nitrostyrene (0.25 mmol, 1 equiv.)
in the presence of catalyst 4a (5 mol-%) and benzoic acid (5 mol-
%) as additive under neat conditions at room temperature (25 °C).
[b] Isolated yield. [c] Determined by 1H NMR spectroscopy. [d] De-
termined by chiral HPLC analysis. [e] With 1 mL of dichlorometh-
ane as solvent. [f] With ketone (5 mmol, 20 equiv.), catalyst 4a
(20 mol-%), and benzoic acid (10 mol-%). [g] With acetone
(5 mmol, 20 equiv.) and benzoic acid (10 mol-%). [h] With ketone
(5 mmol, 20 equiv.), catalyst 4a (10 mol-%), and benzoic acid
(10 mol-%). [i] With isovaleraldehyde (2.5 mmol, 10 equiv.), catalyst
4a (10 mol-%), and benzoic acid (10 mol-%).
2-thienyl
[a] All reactions were carried out with cyclohexanone (1.25 mmol,
5 equiv.) and nitrostyrene (0.25 mmol, 1 equiv.) in the presence of
the catalyst (0.0075 mmol, 3 mol-%) and PhCO2H (5 mol-%) as ad-
ditive in the absence of solvent at room temperature (25 °C).
[b] Isolated yield. [c] Determined by 1H NMR spectroscopy. [d] De-
termined by chiral HPLC analysis.
580
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 578–583

Enantioselective Michael Additions of Ketones and Aldehydes to Nitroolefines
good yields (72–97% yield) and with moderate to excellent the catalyst, only 3 mol-% catalyst loading was sufficient for
enantioselectivity (55–98%ee). The analogues of cyclohex- good yields (up to 98% yield) and excellent stereoselectivi-
anone, such as 1,4-cyclohexanedione monoethylene acetal ties (up to Ͼ98%dr and 99%ee) under solvent-free condi-
and tetrahydro-4H-thiopyran-4-one, displayed good reac- tions at room temperature. This catalytic system is universal
tivity, and their use afforded the corresponding products in and is amenable to an exceptionally broad range of sub-
high yields and with good stereoselectivities (Table 3, En- strates including ketones (cyclic/acyclic), aldehydes, and a
tries 1 and 2). The ring size of cyclic ketones was found variety of nitroolefins.
to strongly impact the reaction rate. Cycloheptanone was
minimally reactive although the inclusion of 4a led to a
Experimental Section
moderate yield with good stereoselectivity of the α-substi-
tuted product (Table 3, Entry 3). Acyclic symmetric
ketones, such as acetone and 3-pentanone, were also found
to be effective Michael donors. Reaction of acetone with 6a
proceeded with excellent yield (97%) and moderate enantio-
General: Reactions requiring anhydrous conditions were performed
under a positive pressure of nitrogen by using oven-dried glassware
(110 °C). All organic layers obtained from extractions were dried
with anhydrous sodium sulfate. THF was distilled from sodium
selectivity (55%ee; Table 3, Entry 4). The use of 3-pentan- benzophenone ketyl, and dichloromethane was distilled from cal-
cium hydride prior to use. Petroleum ether and ethyl acetate for
flash column chromatography were distilled before use. All reac-
tions were monitored by TLC with silica gel coated plates. Flash
column chromatography was performed on silica gel H (10–40 μ).
1H NMR and 13C NMR spectra were recorded with a Bruker Av-
ance 300 spectrometer. HPLC analysis was performed with a
Waters 1525 HPLC with 2487 UV detector. ChiralPak columns
were purchased from Daicel Chemical Industries, Ltd. Optical rota-
tions were measured with a Perkin–Elmer-341 Polarimeter at λ =
589 nm by using a 1-mL cell with a 1-dm path length at room
one, one of the most challenging ketones, afforded excellent
diastereoselectivity (Ͼ99:1dr) and enantioselectivity
(97%ee) despite requiring a high catalyst loading and long
reaction time (Table 3, Entry 6). To the best of our knowl-
edge, only two reports thus far have examined the analo-
gous transformation of 3-pentanone to give syn[3c] or anti[3g]
products with Ͼ80%dr and Ͼ95%ee.
When using unsymmetrical ketone substrates such as 2-
butanone, the reaction took place at the more substituted
site, presumably because the enamine intermediates were temperature.
formed under thermodynamic control. Good enantio-
Synthesis of Catalyst 4a and 4b: The syntheses of catalysts 1, 2, 3a,
and 3b have been reported previously.[4i,4j,8c] Intermediate 8, formed
selectivity (syn 84%ee, anti 90%ee) and good yield (84%
yield) were achieved with moderate diastereoselectivity
en route to catalysts 4a and 4b, was prepared from (2S,4R)-4-hy-
(Table 3, Entry 5). Aldehydes were also found to be compat- droxyproline. For experimental details and data see the Supporting
Information.
ible with catalyst 4a as evidenced by the reaction of isova-
leraldehyde to nitrostyrene. This Michael addition pro-
ceeded smoothly, leading to the desired product in 85%
1-{(3R,5S)-5-[bis(p-tolylthio)methyl]pyrrolidin-3-yl}-3-[3,5-bis(tri-
fluoromethyl)phenyl]thiourea (4a): 1-Isothiocyanato-3,5-bis(trifluo-
yield with good stereoselectivities (98:2dr, 83%ee; Table 3, romethyl)benzene (0.623 g, 2.3 mmol) was added to a solution of 8
(0.519 g, 1.17 mmol) in THF (5 mL) at room temperature. The mix-
ture was stirred for 3 h and then purified by silica gel column
chromatography to give compound 9 (0.676 g, 81% yield). Tri-
fluoroacetic acid (1 mL) was added to a solution of compound 9
in dichloromethane (4 mL) at 0 °C, and the mixture was stirred
further for 6 h. The reaction mixture was concentrated to remove
the excess amount of trifluoroacetic acid. The residue was dissolved
in water, and the pH of the solution was adjusted to 8 with aqueous
NH3. The resulting aqueous solution was extracted with dichloro-
methane, and the combined organic layer was dried (Na2SO4) and
Entry 7).
The stereochemistry of major product 7a was determined
to be (2S,3R) by comparison of its optical rotation with the
value reported in the literature.[3g,6d] The absolute stereo-
chemical result can be explained by an acyclic synclinal
transition state, as proposed by Seebach and Golinski.[9] As
shown in Figure 3, we propose that pyrrolidine-based thio-
urea 4a serves as a bifunctional catalyst. The pyrrolidine
reacts with carbonyl compounds to form an enamine,
whereas the thiourea moiety activates the nitroolefin concentrated. The residue was purified by flash column chromatog-
raphy to give 4a (0.469 g, 83% yield) as a yellowish foam. 1H NMR
(300 MHz, CDCl3): δ = 2.10–2.18 (m, 2 H, CH2 pyrrolidine), 2.30–
2.32 (s, 6 H, CH3), 3.00–3.02 (m, 2 H, CH2 pyrrolidine), 3.31–3.37
towards nucleophilic attack by establishing a dual H-bond-
ing network. We envision that the transient enamine attacks
the nitroolefin from the Re face to afford the syn product;
this process is consistent with the data generated and may
help to inform future applications of 4a and related cata-
lysts.
Conclusions
In conclusion, we have designed and synthesized novel
chiral pyrrolidine-based thiourea and sulfonamide bifunc-
tional organocatalysts and have successfully applied these
catalysts to the asymmetric Michael addition reactions of
ketones and aldehydes to nitroolefins. When 4a was used as
Eur. J. Org. Chem. 2011, 578–583
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
581

Y.-M. Chuan, L.-Y. Yin, Y.-M. Zhang, Y.-G. Peng
FULL PAPER
(m, 1 H, CH pyrrolidine), 3.63–3.65 (m, 1 H, CH pyrrolidine),
4.21–4.23 (m, 1 H, CH), 4.75 (br., 1 H, NH), 7.06–7.32 (m, 8 H,
CH phenyl), 7.62 (s, 1 H, CH phenyl), 7.91 (s, 2 H, CH phenyl)
ppm. 13C NMR (75 MHz, CDCl3): δ = 21.0, 36.4, 51.4, 55.5, 60.0,
65.8, 117.5, 118.4, 118.5, 121.1, 123.4, 124.7, 128.3, 129.1, 129.3,
1.75 (m, 4 H, CH2 hexanone), 2.04–2.10 (m, 1 H, CH2 hexanone),
2.38–2.47 (m, 2 H, CH2, hexanone), 2.68 (m, 1 H, CH hexanone),
3.72–3.80 (dt, J = 9.9, 4.5 Hz, 1 H, CH), 4.53–4.66 (dd, J = 12.3,
10 Hz, 1 H, CH2), 4.91–4.97 (dd, J = 12.4, 4.5 Hz, 1 H, CH2), 7.15–
7.17 (d, J = 6.9 Hz, 2 H, CH phenyl), 7.23–7.34 (m, 3 H, CH
129.9, 131.9, 132.3, 132.8, 132.9, 133.4, 133.5, 138.7, 140.1, phenyl) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.0, 28.5, 33.1,
179.8 ppm.
42.7, 43.9, 52.5, 78.8, 127.7, 128.1, 128.9, 137.7, 211.9 ppm. HPLC
(Chiralpak AS-H, 254 nm, 0.5 mL/min, hexane/iPrOH = 80:20): tR
= 22.8 (major), 17.2 (minor) min; 98%ee.
N-{(3R,5S)-5-[Bis(p-tolylthio)methyl]pyrrolidin-3-yl}-1,1,1-trifluoro-
methanesulfonamide (4b): (CF3SO2)2O (0.25 mL, 1.48 mmol) was
added dropwise to the mixture of compound
8 (0.519 g,
Supporting Information (see footnote on the first page of this arti-
1.17 mmol), NEt3 (0.25 mL, 1.8 mmol), and DMAP (0.05 g,
0.4 mmol) in freshly distilled DCM (20 mL) at –76 °C. After ad-
dition, the mixture was stirred for 30 min and then poured into
saturated aqueous sodium hydrogen carbonate. The phases were
separated, and the aqueous phase was extracted with CH2Cl2. The
combined organic phase was washed with 1 n HCl and brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
silica gel column chromatography to give compound 10 (0.565 g,
84% yield). Trifluoroacetic acid (1.1 mL, 15 equiv.) was added to
the solution of product 10 (0.565 g) in dichloromethane at 0 °C,
and the mixture was stirred at room temperature overnight. After
workup, the residue was purified by silica gel column chromatog-
raphy to afford catalyst 4b (0.427 g, 94% yield) as a yellowish foam.
1H NMR (300 MHz, CDCl3): δ = 1.82–2.30 (m, 2 H, CH2 pyrrol-
idine), 2.32–2.33 (s, 6 H, CH3), 2.85–2.89 (d, J = 12 Hz, 1 H, CH
pyrrolidine), 3.20–3.25 (m, 1 H, CH pyrrolidine), 3.38–3.45 (m, 1
H, CH), 4.19–4.24 (m, 2 H, CH2 pyrrolidine), 5.75 (br., 1 H, NH),
7.09–7.14 (m, 4 H, CH phenyl), 7.25–7.34 (m, 4 H, CH phenyl)
ppm. 13C NMR (75 MHz, CDCl3): δ = 21.1, 37.5, 52.6, 55.2, 59.3,
65.3, 117.7, 122.0, 129.2, 129.3, 130.0, 130.0, 133.3, 133.5, 138.7,
138.7 ppm.
cle): Full experimental procedures and catalyst synthesis.
Acknowledgments
This work supported by the Natural Science Foundation of China
(NSFC-20872120), the Program for New Century Excellent Talents
in University (NCET-06–0772), the Municipal Science Foundation
of Chongqing City (CSTC-2009BB5110), and the Fundamental
Research Funds for the Central Universities.
[1] P. Perlmutter, “Conjugate Addition Reactions” in Organic Syn-
thesis, Pergamon, Oxford, 1992.
[2] a) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 43,
5138–5175; b) J. Seayad, B. List, Org. Biomol. Chem. 2005, 3,
719–724; c) A. Berkessel, H. Groger, Asymmetric Organocata-
lysis: From Biomimetic Concepts to Applications in Asymmetric
Synthesis, Wiley-VCH, Weinheim, Germany, 2005; d) S. B. Tso-
goeva, Eur. J. Org. Chem. 2007, 11, 1701–1716; e) S. J. Connon,
Chem. Commun. 2008, 2499–2510; f) J. L. Vicario, D. Badía, L.
Carrillo, Synthesis 2007, 14, 2065–2092; g) D. Almasi, D. A.
Alonso, C. Nájera, Tetrahedron: Asymmetry 2007, 18, 299–365;
h) H. Pellissier, Tetrahedron 2007, 63, 9267–9331.
¸
[3] a) B. List, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3, 2423–
2425; b) S. B. Tsogoeva, S.-W. Wei, Chem. Commun. 2006,
1451–1453; c) H.-B. Huang, E. N. Jacobsen, J. Am. Chem. Soc.
2006, 128, 7170–7171; d) M. P. Lalonde, Y.-G. Chen, E. N. Ja-
cobsen, Angew. Chem. Int. Ed. 2006, 45, 6366–6370; e) Y.-M.
Xu, A. Córdova, Chem. Commun. 2006, 460–462; f) Y.-M. Xu,
W.-B. Zou, H. Sundén, I. Ibrahem, A. Córdova, Adv. Synth.
Catal. 2006, 348, 418–424; g) S. H. McCooey, S. J. Connon,
Org. Lett. 2007, 9, 599–602; h) K. Liu, H.-F. Cui, J. Nie, K.-Y.
Dong, X.-J. Li, J.-A. Ma, Org. Lett. 2007, 9, 923–925; i) M.
Wiesner, J. D. Revell, H. Wennemers, Angew. Chem. Int. Ed.
2008, 47, 1871–1874; j) Z.-G. Yang, J. Liu, X.-H. Liu, Z. Wang,
X.-M. Feng, Z.-S. Su, C.-W. Hu, Adv. Synth. Catal. 2008, 350,
2001–2006; k) Y. Xiong, Y.-H. Wen, F. Wang, B. Gao, X.-H.
Liu, X. Huang, X.-M. Feng, Adv. Synth. Catal. 2007, 349,
2156–2166; l) L. Peng, X.-Y. Xu, L.-L. Wang, J. Huang, J.-F.
Bai, Q.-C. Huang, L.-X. Wang, Eur. J. Org. Chem. 2010, 1849–
1853; m) T.-X. He, Q. Gu, X.-Y. Wu, Tetrahedron 2010, 66,
3195–3198; n) B.-L. Li, Y.-F. Wang, S.-P. Luo, A.-G. Zhong,
Z.-B. Li, X.-H. Du, D.-Q. Xu, Eur. J. Org. Chem. 2010, 656–
662; o) M. Laars, K. Ausmees, M. Uudsemaa, T. Tamm, T.
Kanger, M. Lopp, J. Org. Chem. 2009, 74, 3772–3775; p) X.-
J. Zhang, S.-P. Liu, X.-M. Li, M. Yan, A. S. C. Chan, Chem.
Commun. 2009, 833–835; q) J. Liu, Z.-G. Yang, X.-H. Liu, Z.
Wang, Y.-L. Liu, S. Bai, L.-L. Lin, X.-M. Feng, Org. Biomol.
Chem. 2009, 7, 4120–4127.
Representative Procedure for the Michael Addition of Ketones to Ni-
troolefins: Catalyst 4a (4.6 mg, 0.0075 mmol), benzoic acid (1.5 mg,
0.0125 mmol), and cyclohexanone (0.13 mL, 1.25 mmol) were
mixed at room temperature (25 °C). After stirring for 10 min, ni-
troolefin 6a (37.3 mg, 0.25 mmol) was added. The resulting mixture
was gently stirred at room temperature for the given time and then
directly diluted with ethyl acetate (20 mL) and washed with satu-
rated NaHCO3 and NaCl solutions. The organic layer was dried
(Na2SO4) and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (ethyl acetate/
petroleum ether) to afford Michael adduct product 7a (58 mg, 95%
yield) as a white solid. The relative configurations of the products
(syn or anti) were determined by comparison of the 1H NMR spec-
troscopic data with those reported in the literature. The absolute
configurations of each product were determined either by compari-
son of optical rotation values with those reported in the literature
or by comparison of HPLC retention times. Spectral data for com-
pounds are in agreement with literature reports.
[4] For selected examples of using bulky groups to control stereo-
chemistry, see: a) S.-L. Zhu, S.-Y. Yu, D.-W. Ma, Angew. Chem.
Int. Ed. 2008, 47, 545–548; b) J.-B. Wu, B.-K. Ni, A. D. Head-
ley, Org. Lett. 2009, 11, 3354–3356; c) E. Alza, X. C. Cambeiro,
C. Jimeno, M. A. Pericàs, Org. Lett. 2007, 9, 3717–3720; d) S.-
E. Syu, T.-T. Kao, W.-W. Lin, Tetrahedron 2010, 66, 891–897;
e) Y.-G. Chi, L. Guo, N. A. Kopf, S. H. Gellman, J. Am. Chem.
Soc. 2008, 130, 5608–5609; f) Y. Hayashi, H. Gotoh, T. Haya-
shi, M. Shoji, Angew. Chem. Int. Ed. 2005, 44, 4212–4215; g)
(S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanone (7a): 1H NMR
(300 MHz, CDCl3): δ = 1.21–1.58 (m, 1 H, CH2 hexanone), 1.62–
582
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 578–583

Enantioselective Michael Additions of Ketones and Aldehydes to Nitroolefines
S. Mossé, M. Laars, K. Kriis, T. Kanger, A. Alexakis, Org.
Lett. 2006, 8, 2559–2562; h) T. Mandal, C.-G. Zhao, Tetrahe-
dron Lett. 2007, 48, 5803–5806; i) F.-Y. Liu, S.-W. Wang, N.
Wang, Y.-G. Peng, Synlett 2007, 15, 2415–2419; j) S.-W. Wang,
J. Chen, G.-H. Chen, Y.-G. Peng, Synlett 2009, 9, 1457–1462;
k) E. Alza, M. A. Pericàs, Adv. Synth. Catal. 2009, 351, 3051–
3056.
Zhang, S. Liu, H. Xu, J.-P. Cheng, Angew. Chem. Int. Ed. 2006,
45, 3093–3097; f) S.-Z. Luo, H. Xu, X.-L. Mi, J.-Y. Li, X.-X.
Zheng, J.-P. Cheng, J. Org. Chem. 2006, 71, 9244–9247; g) L.-Y.
Wu, Z.-Y. Yan, Y.-X. Xie, Y.-N. Niu, Y.-M. Liang, Tetrahedron:
Asymmetry 2007, 18, 2086–2090; h) W.-H. Wang, X.-B. Wang,
K. Kodama, T. Hirose, G.-Y. Zhang, Tetrahedron 2010, 66,
4970–4976; i) P.-H. Li, L. Wang, Y.-C. Zhang, G.-W. Wang,
Tetrahedron 2008, 64, 7633–7638; j) B.-K. Ni, Q.-Y. Zhang, K.
Dhungana, A. D. Headley, Org. Lett. 2009, 11, 1037–1040; k)
P.-H. Li, L. Wang, M. Wang, Y.-C. Zhang, Eur. J. Org. Chem.
2008, 1157–1160; l) B.-K. Ni, Q.-Y. Zhang, A. D. Headley, Tet-
rahedron Lett. 2008, 49, 1249–1252; m) G.-H. Lv, R.-Z. Jin,
W.-P. Mai, L.-X. Gao, Tetrahedron: Asymmetry 2008, 19, 2568–
2572; n) D.-Z. Xu, S. Shi, Y.-M. Wang, Eur. J. Org. Chem.
2009, 4848–4853; o) S. V. Pansare, K. Pandya, J. Am. Chem.
Soc. 2006, 128, 9624–9625.
[5] For selected examples of proline derivatives containing H-
bonding moieties to control stereochemistry, see: a) L.-S. Zu,
J. Wang, H. Li, W. Wang, Org. Lett. 2006, 8, 3077–3079; b) Y.-
J. Cao, Y.-Y. Lai, X. Wang, Y.-J. Li, W.-J. Xiao, Tetrahedron
Lett. 2007, 48, 21–24; c) A. J. A. Cobb, D. A. Longbottom,
D. M. Shaw, S. V. Ley, Chem. Commun. 2004, 1808–1809; d)
C. E. T. Mitchell, A. J. A. Cobb, S. V. Ley, Synlett 2005, 4, 611–
614; e) C.-L. Cao, M.-C. Ye, X.-L. Sun, Y. Tang, Org. Lett.
2006, 8, 2901–2904; f) J. Wang, H. Li, B.-S. Lou, L.-S. Zu, H.
Guo, W. Wang, Chem. Eur. J. 2006, 12, 4321–4332; g) H. J.
Martin, B. List, Synlett 2003, 1901–1902; h) J.-R. Chen, Y.-J.
Cao, Y.-Q. Zou, F. Tan, L. Fu, X.-Y. Zhu, W.-J. Xiao, Org.
Biomol. Chem. 2010, 8, 1275–1279; i) D.-F. Lu, Y.-F. Gong, W.-
Z. Wang, Adv. Synth. Catal. 2010, 352, 644–650; j) J.-R. Chen,
Y.-Y. Lai, H.-H. Lu, X.-F. Wang, W.-J. Xiao, Tetrahedron 2009,
65, 9238–9243; k) A.-D. Lu, R.-H. Wu, Y.-M. Wang, Z.-H.
Zhou, G.-P. Wu, J.-X. Fang, C.-C. Tang, Eur. J. Org. Chem.
2010, 2057–2061; l) S. V. Pansare, R. L. Kirby, Tetrahedron
2009, 65, 4557–4561; m) L.-Q. Gu, G. Zhao, Adv. Synth. Catal.
2007, 349, 1629–1632.
[7]
[8]
B. Tan, X.-F. Zeng, Y.-P. Lu, P.-J. Chua, G.-F. Zhong, Org.
Lett. 2009, 11, 1927–1930.
To control stereochemistry by using H-bonding and bulky
groups, see: a) C. Palomo, S. Vera, A. Mielgo, E. Gómez-
Bengoa, Angew. Chem. Int. Ed. 2006, 45, 5984–5987; b) D. Al-
mas¸i, D. A. Alonso, C. Nájera, Tetrahedron: Asymmetry 2006,
17, 2064–2068; c) C. Wang, C. Yu, C.-L. Liu, Y.-G. Peng, Tetra-
hedron Lett. 2009, 50, 2363–2366; d) Y.-M. Chuan, G.-H.
Chen, Y.-G. Peng, Tetrahedron Lett. 2009, 50, 3054–3058; e)
R. J. Reddy, H.-H. Kuan, T.-Y. Chou, K.-M. Chen, Chem. Eur.
J. 2009, 15, 9294–9298; f) Y.-F. Ting, C.-L. Chang, R. J. Reddy,
D. R. Magar, K.-M. Chen, Chem. Eur. J. 2010, 16, 7030–7038;
g) J.-F. Bai, X.-Y. Xu, Q.-C. Huang, L. Peng, L.-X. Wang, Tet-
rahedron Lett. 2010, 51, 2803–2805.
[6] For selected examples of using salts to control stereochemistry,
see: a) Z.-L. Zheng, B. L. Perkins, B.-K. Ni, J. Am. Chem. Soc.
2010, 132, 50–51; b) N. Mase, K. Watanabe, H. Yoda, K. Tak-
abe, F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006, 128,
4966–4967; c) S.-Z. Luo, X.-L. Mi, S. Liu, H. Xu, J.-P. Cheng,
Chem. Commun. 2006, 3687–3689; d) Vishnumaya, V. K. Singh,
Org. Lett. 2007, 9, 1117–1119; e) S.-Z. Luo, X.-L. Mi, L.
[9] D. Seebach, J. Golinski, Helv. Chim. Acta 1981, 64, 1413–1423.
Received: August 27, 2010
Published Online: November 30, 2010
Eur. J. Org. Chem. 2011, 578–583
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
583