A chiral thioureido acid as an effective additive for enantioselective organocatalytic Michael additions of nitroolefins

Article abstract of DOI:10.1039/b804541k

A novel and effective organocatalytic system consisting of pyrrolidinyl-thioimidazole and a chiral thioureido acid efficiently catalyzed the asymmetric Michael addition reactions of ketones to nitroolefins to afford the adducts with high diastereoselectivities (up to 99: 1) and excellent enantioselectivities (up to 99% ee). The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b804541k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A chiral thioureido acid as an effective additive for enantioselective
organocatalytic Michael additions of nitroolefins†
Dan-Qian Xu, Hua-Dong Yue, Shu-Ping Luo, Ai-Bao Xia, Shuai Zhang and Zhen-Yuan Xu*
Received 17th March 2008, Accepted 22nd April 2008
First published as an Advance Article on the web 16th May 2008
DOI: 10.1039/b804541k
A novel and effective organocatalytic system consisting of
pyrrolidinyl-thioimidazole and a chiral thioureido acid effi-
ciently catalyzed the asymmetric Michael addition reactions
of ketones to nitroolefins to afford the adducts with high
diastereoselectivities (up to 99 : 1) and excellent enantioselec-
tivities (up to 99% ee).
The organocatalytic asymmetric Michael addition reaction of
ketones to nitroolefins is widely recognized as one of the most
important carbon–carbon bond-forming reactions in organic
synthesis. Following the development of L-proline as an efficient
and powerful catalyst,1 impressive progress has been made in
the development of efficient organocatalysts for the asymmetric
Michael reaction. With the growing attention focused on the
importance of the pyrrolidine motif in the activation of the
carbonyl group in the enamine intermediate, a series of pyrrolidine
derivatives was synthesized and successfully applied to asymmetric
Michael addition reactions.2 The introduction of acid additives
has been shown to be usually necessary for high activities of
the pyrrolidine-derived catalysts. A variety of Brønsted acids,
such as PhCOOH,3 AcOH,4 pTsOH,5 salicylic acid,6 TFA,7 n-
butyric acid8 and 2,4-dinitrobenzenesulfonic acid,9 have been
applied to Michael reactions, thereby enhancing the yields of
Fig. 1 Chiral pyrrolidinyl-thioimidazole and thioureido acids.
the adducts. However, these additives are mostly achiral and
have their limitations in improving the enantiopurities of the
products. Very recently, a new concept, asymmetric counteranion-
directed catalysis (ACDC), has been introduced as an efficient
strategy for enantioselective transformations.10 In ACDC, chiral
counteranions can help to conduct asymmetric catalytic reactions
that proceed through cationic intermediates. Despite impressive
progress in the use of this strategy in enantioselective reactions,
there is further need for high-performance chiral additives.
In our previous work, we showed that pyrrolidinyl-
thioimidazole 1 could efficiently catalyze the asymmetric Michael
addition reactions of ketones to nitroolefins in the presence
of inorganic or organic acids.6b,11 Herein, we present further
improvements in this organocatalytic system, which uses a series
of novel chiral thioureido acids 2 as additives (Fig. 1). On the basis
of the ACDC strategy, we envisioned that these acids could not
only activate the catalyst, but also enhance the enantioselectivities
of these Michael reactions by asymmetric inducement.
Thioureido acids 2 were easily prepared from isothiocyanates
3 and amino acids 4 by treatment with NaOH in THF–H2O and
subsequent adjustment of the pH with aqueous HCl (Scheme 1).
Scheme 1 Synthesis of the chiral thioureido acids 2.
The direct asymmetric Michael addition of cyclohexanone to
trans-b-nitrostyrene in CHCl3 at room temperature was examined
in the presence of 5 mol% of organocatalyst 1 with a series of
chiral thioureido acids 2. The results are summarized in Table 1.
The asymmetric Michael addition of cyclohexanone 5 to trans-
b-nitrostyrene 6 was catalyzed by 1 without the additive to afford
product 7 in 55% yield and 71% ee (entry 1). With the addition of
hydrobromic acid, catalyst 1 promoted the addition with improved
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Tech-
nology, Zhejiang University of Technology, Hangzhou, 310014, China.
E-mail: greenchem@zjut.edu.cn; Fax: +86-571-88320066; Tel: +86-571-
88320066
† Electronic supplementary information (ESI) available: Experimental
procedures and NMR spectra of the catalysts and the additives. See DOI:
10.1039/b804541k
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Table 1 Organocatalyzed asymmetric Michael addition of cyclohexanone to trans-b-nitrostyrenea
Entry
Additive
Time/days
Yieldb (%)
drc syn/anti
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
—
HBr
PhCOOH
2a
2b
2c
2d
2e
2f
8
8
6
4
4
2
4
3
4
4
4
4
4
55
50
90
85
80
96
92
93
91
94
90
90
88
90 : 10
88 : 12
83 : 17
92 : 8
90 : 10
95 : 5
89 : 11
98 : 2
98 : 2
97 : 3
93 : 7
95 : 5
94 : 6
71
82
78
77
71
97
86
93
87
86
80
87
83
2g
2h
2i
2j
a All reactions were conducted in CHCl3 (5 mL) using 5 (1 mmol) and 6 (0.5 mmol) in the presence of 5 mol% of the catalysts. b Determined by GC with
n-butyl 4-hydroxybenzoate as an internal standard. c Determined by GC–MS. d Determined by chiral HPLC analysis with CD detector (Daicel Chiralpak
AS-H, hexane–i-PrOH = 90 : 10).
enantioselectivity of 82% ee, but the resulting reaction yield was
only 50% (entry 2). The use of benzoic acid, in place of an
inorganic acid, accelerated the reaction and enhanced the yield
(90%), but decreased the ee value to 78% (entry 3). Similar results
were obtained when the additive was replaced with non-chiral
thioureido acids 2a and 2b (entries 4 and 5). Gratifyingly, the
chiral thioureido acid additives 2c–j exhibited excellent activities
and the adducts were afforded with high yields (up to 96%) and
high enantioselectivities (up to 97% ee) (entries 6–13). These results
indicated that chiral thioureido acids 2 could act in a dual role,
not only activating the catalyst 1 (presumably by providing the
acidic proton), but also inducing chiralityby hydrogen bonding.
More excitingly, the additives 2c, 2e, 2g and 2i, all having an (R)-
configuration (entries 6, 8, 10 and 12), showed better efficiency
than (S)-thioureido acids 2d, 2f, 2h and 2j (entries 7, 9, 11 and
13), which further illuminates the synergistic effects of the chiral
thioureido acids.
The effects of solvents on the reaction of cyclohexanone with
trans-b-nitrostyrene were also studied. As shown in Table 2, in
polar solvents, the catalyst system 1+2c exhibited poor activity and
the products were obtained with moderate enantioselectivities (71–
90%) (entries 1–8). This indicated that polar solvents may interact
Table 2 Effects of solvents on the reaction of cyclohexanone with trans-b-nitrostyrenea
Entry
Solvent
Time/days
Yieldb (%)
drc syn/anti
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
DMSO
DMF
CH3OH
Isopropanol
n-Butanol
CH2Cl2
CHCl3
ClCH2CH2Cl
Ethyl ether
8
8
8
3
3
3
2
2
3
8
8
0.5
1.5
1
83
80
92
95
94
95
96
96
92 : 8
91 : 9
92 : 8
90 : 10
98 : 2
93 : 7
95 : 5
93 : 7
98 : 2
97 : 3
90 : 10
97 : 3
98 : 2
98 : 2
71
86
69
86
90
85
97
90
90
99
99
98
95
94
96
73
92
Dioxane
Isopropyl ether
Cyclohexane–n-butanol (4 : 1)
Cyclohexane–CHCl3 (4 : 1)
Cyclohexane–i-propanol (4 : 1)
97 (94e)
95
96
a All reactions were conducted using 6 (1 mmol) and 7 (0.5 mmol) in the presence of 5 mol% of catalyst 1 and additive 2c. b Determined by GC with
n-butyl 4-hydroxybenzoate as an internal standard. c Determined by GC–MS. d Determined by chiral HPLC analysis with CD detector (Daicel Chiralpak
AS-H, hexane–i-PrOH = 90 : 10). e Isolated yield.
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Table 3 Michael addition reactions of ketones to nitroolefinsa
Product
Entry
R3, R4
Ar
Yieldb (%)
drc syn/anti
eed( %)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
H, i-Pr
CH3, H
CH3, i-Pr
CH3, Et
-(CH2)3-
-(CH2)5-
p-MeOC6H4
m-MeOC6H4
p-MeC6H4
o-BrC6H4
o-NO2C6H4
p-CF3C6H4
2-Naphthyl
2-Furanyl
2-Thienyl
Ph
Ph
Ph
Ph
Ph
93 (88e)
96 (92e)
94 (90e)
93
92
85
92
95
94
90
96 : 4
95 : 5
98 : 2
94 : 6
96 : 4
94 : 6
85 : 15
94 : 6
93 : 7
79 : 21
—
99
99
90
92
86
87
89
87
95
70
64
71
74
87
40
78
59
97
95
90
91
67
—
89 : 11
—
Ph
Ph
Ph
Ph
40
—
-CH2CH2SCH2-
-CH2CH2OCH2-
-CH2CH(t-Bu)CH2-
90 (86e)
92 (87e)
95 (90e)
97 : 3
95 : 5
90 : 10
a All reactions were conducted in cyclohexane (4 mL) and n-butanol (1 mL) using ketones (1 mmol) and nitroolefins (0.5 mmol) in the presence of 5 mol%
of catalyst 1+2c. b Determined by GC with n-butyl 4-hydroxybenzoate as an internal standard. c Determined by GC–MS. d Determined by chiral HPLC
analysis with CD detector (Daicel Chiralpak AS-H, hexane–i-PrOH = 90 : 10). e Isolated yields.
with 2c through hydrogen bonding to weaken the activation
ability of 2c towards the reaction. Although the enantiopurities
of the products increased to 99% ee in dioxane and isopropyl
ether, the reaction times and yields were disappointing (entries 10
and 11). This was probably due to the difficulties in dissolution
of the polar catalyst system 1+2c in such nonpolar solvents.
Therefore, the use of mixed solvents was examined (entries 12,
13 and 14). In cyclohexane–n-butanol, the results were improved
and the reactants were rapidly converted to the desired product
with excellent yield (97%), high diastereoselectivity (97 : 3) and
enantioselectivity (98% ee).
Having established these optimized conditions, reactions with
a variety of ketones and nitroolefins were explored, and the
results are summarized in Table 3. First, different nitroolefins
were probed and the reactions reached completion, affording good
yields of up to 96%. Nitroolefins bearing electron-donating aryl
groups afforded the desired adducts with higher selectivities (dr
up to 98 : 2, ee up to 99%) (entries 1–3) than those bearing
electron-withdrawing aryl groups (entries 4–7). Furthermore, 2-
(2-nitrovinyl)furan and 2-(2-nitrovinyl)thiophene also worked well
in the reaction and gave the corresponding products with high
selectivities in excellent yields (entries 8 and 9). Moreover, the
asymmetric additions of the aliphatic aldehydes and ketones
to trans-b-nitrostyrene were examined (entries 10–18). In the
presence of the catalyst system 1+2c, isovaleraldehyde was effi-
ciently converted to the desired adduct in 90% yield and 70%
enantioselectivity (entry 10). The use of the aliphatic ketones in
the reaction with trans-b-nitrostyrene gave similar results (entries
11–13). Cyclopentanone (entry 14) and cycloheptanone (entry
15) were less active as substrates, providing yields of 67% and
40%, and enantioselectivities of 87% and 40% ee, respectively. At
the same time, tetrahydrothiopyran-4-one and tetrahydropyran-
4-one reacted smoothly with trans-b-nitrostyrene to provide the
products in excellent yields, and with high diastereoselectivities
and moderate enantioselectivities (entries 16 and 17). 4-tert-
Butylcyclohexanone was also a suitable substrate in a Michael
addition reaction with trans-b-nitrostyrene and led to the product
in excellent yield of 95% with an ee value of 97% (entry 18).
To account for the high performance of the Michael addition
reactions using the designed catalyst system, an enamine activation
model combined synergistically with the effect of ACDC is
proposed as shown in Fig. 2 using cyclohexanone and trans-b-
nitrostyrene as an example. When the stable ionic pair is formed,
the carboxyl group and two N–H bonds of the (R)-thioureido
acids are oriented in the same direction. The thiourea moiety
then activates the nitro group of the nitroolefin through hydrogen
bonding, enhancing the electrophilicity of the nitroolefin, while
the pyrrolidine activates the ketone by forming an enamine
intermediate. The enamine is favored to attack the nitroolefin from
Fig. 2 Possible transition state model.
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the re-face, affording the desired adduct. The observed solvent
dependency of the reaction enantioselectivities may be due to the
stability of the ion pair allowing the counteranion to influence the
chiral environment of the transition state.
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In summary, a new organocatalytic system composed of a
pyrrolidinyl-thioimidazole catalyst and a chiral thioureido acid
additive has been designed and applied successfully to a series of
asymmetric Michael addition reactions. A large range of Michael
adducts was obtained with excellent yields and high selectivities
using various ketone and nitroolefin substrates, which suggests
that this novel organocatalytic system may find wide application
in the asymmetric Michael reactions of nitroolefins. Further
investigations of the applications of this organocatalytic system
in other asymmetric reactions are in progress.
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The authors acknowledge the National Natural Science Founda-
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The Royal Society of Chemistry 2008
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