Benzoylthiourea-pyrrolidine as another bifunctional organocatalyst: Highly enantioselective Michael addition of cyclohexanone to nitroolefins

Article abstract of DOI:10.1002/ejoc.201300225

Asymmetric Michael addition of cyclohexanone to nitrostyrenes in the presence of organocatalyst 1 (10 mol-%) and 2,4-dichlorobenzoic acid (10 mol-%) afforded the corresponding synthetically valuable γ-nitroketones in moderate to good yields with high diastereoselectivities (up to >99:1 dr) and high enantioselectivities (up to >99 % ee) under mild conditions. A benzoylthiourea-pyrrolidine catalyst was synthesized and used in the asymmetric Michael addition of ketones to nitroalkenes. The corresponding synthetically valuable γ-nitroketones were obtained in moderate to good yields with high levels of diastereo- and enantioselectivities (up to >99:1 dr and up to >99 % ee). Copyright

Full text of DOI:10.1002/ejoc.201300225

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300225
Benzoylthiourea–Pyrrolidine as Another Bifunctional Organocatalyst: Highly
Enantioselective Michael Addition of Cyclohexanone to Nitroolefins
Shu-rong Ban,*[a][‡] Xi-xia Zhu,[a][‡] Zhi-ping Zhang,[a] Hong-yu Xie,[a] and Qing-shan Li*[a]
Keywords: Organocatalysis / Diastereoselectivity / Enantioselectivity / Michael addition / Nitroalkenes
Asymmetric Michael addition of cyclohexanone to nitrostyr-
enes in the presence of organocatalyst 1 (10 mol-%) and 2,4-
dichlorobenzoic acid (10 mol-%) afforded the corresponding
synthetically valuable γ-nitroketones in moderate to good
yields with high diastereoselectivities (up to Ͼ99:1dr) and
high enantioselectivities (up to Ͼ99%ee) under mild condi-
tions.
increases their H-bond donating ability. Learning from the
concept of bioisosterism in medicinal chemistry, we envis-
aged that the cheaper and generally more available benzoyl
or p-toluenesulfonyl group would be a better choice. Benz-
oylthiourea and sulfonylurea, which are structural relatives
of (thio)urea and expected to provide strong acidity to the
N–H bonds, could possibly be introduced to the chiral
amine to serve as a versatile core activation unit for bifunc-
tional catalysis. Therefore, we designed benzoylthiourea/
sulfonylurea–pyrrolidine-based catalysts and analogues 1–4
(Figure 1) and found that benzoylthiourea–pyrrolidine 1
was excellent for catalyzing the asymmetric Michael ad-
dition of cyclohexanone to nitroolefins. In this paper, we
report the preliminary results.
Introduction
In recent years, organocatalytic asymmetric catalysis has
been identified as one of the most economical and powerful
approaches to access a great variety of enantiomerically en-
riched compounds that are widely used in drug discovery
and chemical synthesis.[1] Advantages of organocatalytic re-
actions, including mild reaction conditions, environmental
benignity, and facile recovery of the catalysts, render some
features of green chemistry to these processes.[2] The strate-
gies for organocatalysis include the formation of temporary
covalent bonds (enamine[3,4] or iminium[5] catalysis), hydro-
gen-bonding interactions (urea or thiourea catalysis),[6]
Brønsted acid–base interactions,[7] and ion-pair interactions
(phase-transfer catalysts).[8] The combination of some of
these strategies may lead to unexpected synergistic effects,
and the success of bifunctional organocatalysts in a wide
array of asymmetric processes provides a good example.[9]
(Thio)urea–pyrrolidine[10] and sulfamide–pyrrolidine[11]
have been reported and were successfully used as bifunc-
tional organocatalysts in asymmetric catalysis. Essential to
these bifunctional 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 that is re-
quired for asymmetric induction.[12] To the best of our
knowledge, the 3,5-bis(trifluoromethyl)phenyl substituent
has been frequently used in thiourea cataly-
sis.[6a,6e,6f,6g,10b,10c] The presence of electron-withdrawing
Figure 1. Bifunctional organocatalysts 1–4.
Results and Discussion
Benzoylthiourea/sulfonylurea–pyrrolidines 1–4 were
groups serves to decrease the pKa of the N–H bonds, which easily prepared from benzoyl isothiocyanate or p-tolu-
enesulfonyl isocyanate and (S)-tert-butyl-2-(aminomethyl)-
pyrrolidine-1-carboxylate or (S)-tert-butyl-2-(hydroxymeth-
yl)pyrrolidine-1-carboxylate in two steps in 26–55% overall
yield (see the Experimental Section).
Initially, various solvents and additives were examined in
the model asymmetric Michael addition of cyclohexanone
to β-nitrostyrene. The results are summarized in Table 1.
The conjugate addition was first examined in different sol-
[a] School of Pharmaceutical Science, Shanxi Medical University,
Taiyuan 030001, People’s Republic of China
Fax: +86-351-4690322
E-mail: shurongban@163.com
qingshanl@yahoo.com
Homepage: www.sxmu.edu.cn
[‡] These two authors contributed equally to this work
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300225.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S.-r. Ban, X.-x. Zhu, Z.-p. Zhang, H.-y. Xie, Q.-s. Li
SHORT COMMUNICATION
vents at 15 °C with benzoic acid as the additive. Among the into proline–sulfonamide organocatalysts that were used to
various organic solvents tested, dichloromethane, toluene, perform Michael additions.[13] Carter and Yang’s work sug-
and no solvent were better in terms of diastereoselectivity gests that in the future we can add appropriate hydrophobic
and enantioselectivity (90, 91, and 93%ee, respectively; groups into the structure of 3 to improve its catalytic effi-
Table 1, entries 1, 2, and 5). If the reaction was performed ciency. In addition, catalysts 2 and 4 were still inactive in
in polar solvents (THF, EtOH, and DMSO), the yield of 7a THF, DMSO, and DMF, as well as under neat conditions.
was very poor (Table 1, entries 3, 4, and 6). Toluene was
Table 2. Screening of the catalysts.[a]
then selected as the solvent to study the influence of the
additive and catalyst. The addition of a carboxylic acid was
found to be an essential factor for this reaction. In the ab-
sence of a carboxylic acid, or in the presence of trifluoro-
acetic acid (TFA), the reaction proceeded slowly (Table 1,
entries 10 and 11). Almost the same level of enantio-
selectivity was observed for substituted benzoic acid as for
unsubstituted benzoic acid (91%ee; Table 1, entry 2), 2-ni-
trobenzoic acid (94%ee; Table 1, entry 7), 4-methylbenzoic
acid (95%ee; Table 1, entry 8), and 2,4-dichlorobenzoic
acid (94%ee; Table 1, entry 9). 2,4-Dichlorobenzoic acid
was the best choice in terms of diastereoselectivity and reac-
tion rate.
Entry Cat. Solvent
Yield [%][b] dr (syn/anti)[c]
ee [%][c]
1
1
2
3
4
2
2
2
2
3
3
3
3
4
4
4
4
toluene
toluene
toluene
toluene
THF
92
0
0
99:1
–
–
94
–
–
–
–
–
–
–
86
–
83
75
–
–
–
2
3
4
0
0
–
–
5
6
7
8
DMSO
DMF
neat
0
0
–
–
0
44
0
–
93:7
–
9
THF
Table 1. Effects of solvents and additives on the reaction of cyclo-
hexanone to nitrostyrene.[a]
10
11
12
13
14
15
16
DMSO
DMF
neat
40
66
0
94:6
95:5
–
THF
DMSO
DMF
neat
0
–
0
0
–
–
–
[a] All reactions were carried out with 5 (100 mg, 1.0 mmol) and
6a (18.7 mg, 0.13 mmol) in the presence of the catalyst (10 mol-%).
[b] Yield of the isolated product after chromatography on silica gel.
[c] Determined by chiral HPLC with a Chiralpak AS-H column
and n-hexane/2-propanol as eluents.
Entry Additive[b]
Solvent
Yield [%][c] dr (syn/anti)[d] ee [%][d]
1
2
BA
BA
CH2Cl2
toluene
THF
MeOH
neat
DMSO
toluene
toluene
toluene
toluene
toluene
95
93
89:11
94:6
97:3
94:6
82:18
94:6
98:2
98:2
99:1
–
90
91
95
93
93
87
94
95
94
–
3
BA
40[e]
20[e]
90
4
BA
5
BA
Under the optimized conditions, a variety of nitroolefins
with different structures were investigated, and the results
are shown in Table 3. Various styrene-type nitroalkenes re-
acted smoothly with cyclohexanone to provide the corre-
sponding adducts in moderate to excellent yields with excel-
lent diastereoselectivities and enantioselectivities (Table 3,
entries 1–9). Excellent diastereoselectivities and enantio-
selectivities were observed regardless of the electronic na-
ture of the aromatic R substituent, although the nature of
the substituent on the benzene ring did exhibit a slight in-
6
BA
20[e]
65[e]
66
7
8
9
10
11
o-NBA
p-MBA
2,4-DCBA
TFA
92
trace[e]
80[d]
none
97:3
93
[a] All reactions were carried out with 5 (100 mg, 1.0 mmol) and
6a (18.7 mg, 0.13 mmol) in the presence of catalyst 1 (10 mol-%).
[b] BA = benzoic acid, o-NBA = 2-nitrobenzoic acid, p-MBA = 4-
methylbenzoic acid, 2,4-DCBA = 2,4-dichlorobenzoic acid, TFA =
trifluoroacetic acid. [c] Yield of the isolated product after
chromatography on silica gel. [d] Determined by chiral HPLC with fluence on the reaction rate and yield. If an electron-donat-
a Chiralpak AS-H column and n-hexane/2-propanol as eluents.
[e] Reaction time = 24 h.
ing substituent was introduced onto the benzene ring, the
reaction proceeded slowly (Table 3, entries 2 and 9). In ad-
dition, thiophenyl- and furyl-containing nitroalkenes as
Chiral catalysts 2–4 were screened by employing these Michael acceptors gave moderate yields but good stereose-
optimized conditions, and the results are summarized in lectivities (Table 3, entries 10 and 11). An aliphatic aldehyde
Table 2. Compounds 2–4, however, proved incapable of cat- nitroalkene also appeared to be a good candidate for this
alyzing this model reaction. The inefficiency of 2–4 may be asymmetric Michael addition reaction (Table 3, entry 12).
due to their poor solubility in toluene (for 3 and 4) and/or
Cyclopentanone, acetophenone, acetone, and isobutyr-
the lower acidity of the protons (for 2 and 4). Catalysts 2– aldehyde were subsequently examined in the 1-catalyzed
4 were then re-examined in other solvents, and the data are Michael addition with nitrostyrene (6a). Unfortunately, as
also listed in Table 2. In THF and DMF, and under neat depicted in Scheme 1, the results were not satisfactory.
conditions, catalyst 3 gave moderate conversions and asym- Acetone and cyclopentanone gave moderate yields and
metric inductions (Table 2, entries 9, 11, and 12). In 2010, stereoselectivities, and no product was obtained for aceto-
Carter and Yang introduced alkylbenzenesulfonyl groups phenone or isobutyraldehyde as the nucleophile.
2
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Benzoylthiourea–Pyrrolidine as Another Bifunctional Organocatalyst
Table 3. Catalytic Michael addition of cyclohexanone to nitroalk-
enes.[a]
Conclusions
In conclusion, we have developed new benzoylthiourea–
pyrrolidine 1 as a novel bifunctional organocatalyst for the
asymmetric Michael addition of ketones to nitroalkenes.
Moderate to excellent diastereoselectivities and enantio-
selectivities were obtained for the addition of cyclohexan-
one to a variety of nitroalkenes under mild conditions. Ap-
plication of this new type of organocatalyst in other asym-
metric reactions is underway in our laboratory.
Entry
R
Time
[h]
Yield
[%][b]
dr
ee
(syn/anti)[c]
[%][c]
1
2
3
4
5
6
7
8
Ph
12
36
12
12
12
12
12
12
72
72
72
72
92
60
80
98
98
90
85
88
trace
65
99:1
98:2
Ͼ99:1
94
93
97
97
98
95
96
96
–
4-MeC6H4
2,4-Cl2C6H3
4-BrC6H4
3-NO2C6H4
2-ClC6H4
4-ClC6H4
4-FC6H4
3,4-(MeO)2C6H3
2-thiophenyl
2-furyl
98:2
97:3
Ͼ99:1
98:2
98:2
–
95:5
92:8
79:21
Experimental Section
General Procedure for the 1-Catalyzed Asymmetric Michael Ad-
dition of Ketones to Nitroalkenes:
A solution of catalyst 1
(0.013 mmol) and cyclohexanone (0.1 mL, 0.1 mmol) in toluene
(0.2 mL) was stirred at room temperature for 30 min. Then, 2,4-
dichloridebenzoic acid (2.5 mg, 0.013 mmol) was added, and the
reaction mixture was stirred for 15 min. To the resulting mixture
was added nitroalkene (0.13 mmol) at 15 °C. After the reaction was
complete (monitored by TLC), the mixture was purified by column
chromatography on silica gel (200–300 mesh, petroleum ether/ethyl
acetate = 10:1) to afford the product.
9
10
11
12
91
89
Ͼ99
56
66
isopropyl
[a] All reactions were carried out with 5 (100 mg, 1.0 mmol) and 6
(0.13 mmol) in the presence of catalyst 1 (10 mol-%). [b] Yield of
the isolated product after chromatography on silica gel. [c] Deter-
mined by chiral HPLC with a Chiralpak AS-H column and n-hex-
ane/2-propanol as eluents.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H NMR and 13C NMR spectra for all key intermediates and final
products.
Acknowledgments
The authors gratefully acknowledge the financial support of the
National Natural Science Foundation of China (NSFC) (grant
number 81172938), the Main Cultivate Object of the Program for
the Top Science and Technology Innovation Teams of Higher
Learning Institutions of Shanxi, and the Science and Technology
Innovation Foundation of Shanxi Medical University.
Scheme 1. Michael addition of ketones and aldehyde to 6a.
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Eur. J. Org. Chem. 0000, 0–0
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SHORT COMMUNICATION
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Received: February 12, 2013
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30225
/KAP1
Date: 16-04-13 16:53:42
Pages: 5
Benzoylthiourea–Pyrrolidine as Another Bifunctional Organocatalyst
Bifunctional Organocatalyst
S.-r. Ban,* X.-x. Zhu, Z.-p. Zhang,
H.-y. Xie, Q.-s. Li* ........................... 1–5
Benzoylthiourea–Pyrrolidine as Another
Bifunctional Organocatalyst: Highly En-
antioselective Michael Addition of Cyclo-
hexanone to Nitroolefins
A benzoylthiourea–pyrrolidine catalyst was
synthesized and used in the asymmetric
Michael addition of ketones to nitroal-
kenes. The corresponding synthetically
valuable γ-nitroketones were obtained in
moderate to good yields with high levels of
diastereo- and enantioselectivities (up to
Ͼ99:1dr and up to Ͼ99%ee).
Keywords: Organocatalysis
/ Diastereo-
selectivity / Enantioselectivity / Michael
addition / Nitroalkenes
Eur. J. Org. Chem. 0000, 0–0
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