New simple primary amine-thiourea organocatalysts and their application in asymmetric conjugate addition

Article abstract of DOI:10.1016/j.tetlet.2014.05.006

A kind of simple primary amine-thiourea organocatalysts was developed. And their application in asymmetric conjugate addition of ketone to nitroalkene was investigated. In the presence of the new primary amine-thiourea, the conjugate addition of ketone to

Full text of DOI:10.1016/j.tetlet.2014.05.006

Accepted Manuscript
New simple primary amine-thiourea organocatalysts and their application in
asymmetric conjugate addition
Lu Yu, Pengfei Li
PII:
S0040-4039(14)00782-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.006
TETL 44596
Reference:
Tetrahedron Letters
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29 April 2014
5 May 2014
Please cite this article as: Yu, L., Li, P., New simple primary amine-thiourea organocatalysts and their application
in asymmetric conjugate addition, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.006
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New simple primary amine-thiourea
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asymmetric conjugate addition
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Lu Yua, Pengfei Lia,b*

1
Tetrahedron Letters
journal homepage: www.els evier.com
New simple primary amine-thiourea organocatalysts and their application in
asymmetric conjugate addition
Lu Yua, Pengfei Lia,b ∗
a Department of Chemistry, South University of Science and Technology of China, 1088 Xueyuan Blvd., Nanshan District, Shenzhen, Guangdong, 518055, PR
China
b State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom,
Kowloon, Hong Kong, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
A kind of simple primary amine-thiourea organocatalysts was developed. And their application
in asymmetric conjugate addition of ketone to nitroalkene was investigated. In the presence of
the new primary amine-thiourea, the conjugate addition of ketone to nitroalkene proceeded
smoothly to afford the 1,4-adducts in high yields with good enantioselectivities.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Conjugate addition
Primary amine
thiourea
nitroalkene
Asymmetric organocatalysis has emerged as an alternative
and/or complementary approach to currently developed
organometallic and enzymatic catalysis, which offers an efficient
access to highly enantioenriched natural products, chiral drugs,
building-blocks, and interesting molecules.1 Since pioneering
examples from Jacobsen,2 Schreiner3 and Takemoto,4 employing
thiourea derivatives as catalyst has become a subject of
considerable interest in asymmetric organocatalysis.5
Therefore, we have a high motivation to develop a simple amine-
thiourea as organocatalyst to affect the reaction with excellent
efficiency and asymmetric induction.
Available backbone:
i) stereo-hindrance effect for high stereoselectivity;
ii) Acting as base or H-bonding acceptor when
tertiary amine group exists.
We have successfully developed a new type of multifunctional
organocatalysts consisting of 1,2-diaminocyclohexane and 9-
amino(9-deoxy)epicinchona alkaloid for the enantioselective
Michael addition of α,β-unsaturated ketone.6 This type of primary
amine-thioureas provides multifunctional groups: a primary
amine activating and arranging α,β-unsaturated ketone via
iminium ion, and tertiary amine and thiourea helping to active
and arrange the nucleophile via hydrogen bond. These functional
groups exhibit synergistic cooperation and affect organic reaction,
which was confirmed by the results with excellent yields and
enantioselectivities.
S
∗
∗
N
H
N
H
NH2
active carbonyl via
iminium or enamine
H-bonding for activation of
nucleophiles / electrophiles
Scheme 1. General structure of new primary amine-thiourea
Here, we describe new primary amine-thiourea
a
organocatalyst consisting of chiral 1,2-diaminocyclohexane and
available achiral backbone (Scheme 1). The primary amine is
expected to activate carbonyl compound (enone, enal, ketone,
aldehyde, et al.) via iminium ion or enamine formed in situ. And
the hydrogen of thiourea is expected to activate nucleophile /
electrophile via hydrogen bonding. The available backbone
provides sterically hindered interaction and helps to construct a
chiral pocket. When a tertiary amine group exists on available
As a result of the demonstrated potential of thiourea as
attractive organocatalyst, many research groups focus their
interest on developing new thiourea as organocatalyst and its
application in the useful asymmetric transformation. However,
most of these amine-thioureas contain three or more than three
stereocenters, which caused some difficulties in terms of optical
purity and yield in the preparations of these complex structures.7
———
∗ Corresponding author. Tel.: +86-755-88018319; fax: +86-755-88018304; e-mail: li.pf@sustc.edu.cn or flyli1980@gmail.com

2
Tetrahedron Letters
backbone, it can act as base to activate nucleophile or act as
hydrogen acceptor to activate nucleophile / electrophile.
by 3-aminopyridine derived the primary amine-thiourea II (Table
1, entry 6). Using the primary amine-thiourea III afforded 1,4-
adduct with similar yield and ee value (Table 1, entry 7). To our
delight, up to 73% ee and 11% yield were obtained in the
presence of the primary amine-thiourea IV derived from 9H-
fluoren-9-amine, which indicated that the new simple primary
amine-thiourea was effective for the conjugate addition of ketone
to nitroalkene (Table 1, entry 8). In contrast, the primary amine-
thiourea V catalyzed conjugate addition of acetone to β-
nitrostyrene furnished adduct in 45% yield with 65% ee under the
same conditions (Table 1, entry 9). The primary amine-thiourea
VI was found to hardly catalyze the conjugate addition and yield
trace of the desired product (Table 1, entry 10).
Based on our design of the primary amine-thiourea
organocatalyst,
a series of primary amine-thioureas are
synthesized (Scheme 2). Compared with our former developed
primary amine-thiourea organocatalyst,6 the complex chiral
cinchona alkaloid skeleton was replaced with simple achiral
available backbones, such as pyridine ring (organocatalysts Ia-d,
II), isoquinoline ring (organocatalyst Ie), 1H-benzoimidazole
ring (organocatalyst III), 9H-fluorene ring (organocatalyst IV)
and et al. There is a tertiary amine group on each of pyridine ring
and isoquinoline ring, which can act as base and/or hydrogen
bonding acceptor as well as providing stereo-hindrance effect.
The 1H-benzoimidazole ring in catalyst III contains two nitrogen
atoms, which may offer the stronger basicity and hydrogen
bonding interaction. The 9H-fluorene ring in catalyst IV has a
bigger bulk, which could be better to shield a face of the
intermediate formed from substrates and catalyst to construct
chiral environment. For comparison, the reported efficient
organocatalysts V and VI were also prepared.
Table 1. Identification of the organocatalyst a
O
organocatalyst
O2N
NO2
+
Ph
Ph
3aa
O
toluene, RT, 24 h
2a
1a
Entry
Organocatalyst
Yield (%)b
ee (%)c
4
1
Ia
Ib
Ic
21
27
14
16
18
29
31
11
45
trace
S
S
R
N
2
1
N
H
N
H
N
H
N
H
N
3
6
II
NH2
NH2
NH2
4
Id
Ie
-16
16
Ia R = H;
S
S
HN
5
Ib R = 3-Me;
Ic R = 5-Me;
Id R = 6-Me;
6
II
60
N
N
H
N
H
III
7
III
IV
V
53
8
73
S
N
9
65
10
VI
N.D.d
N
H
N
a Unless noted, the reaction was carried out as following: The mixture of 1a
(0.5 mmol), 2a (2.5 mmol) and organocatalyst (15 mol%) was stirred in
toluene (0.5 mL) for 24 h.
N
H
N
H
NH2
H
NH2
IV
Ie
CF3
b Isolated yield.
S
S
c Determined by chiral HPLC analysis (Chiralpak AS-H, n-hexane/2-propanol
= 70/30).
N
N
N
H
N
H
CF3
d N.D. = Not determined.
VI
H
NH2
H
V
NH2
Scheme 2. Structures of new primary amine-thioureas
With the promising organocatalyst IV in hand, optimization of
reaction conditions was then investigated. An overview of the
representative results is summarized in Table 2.
To evaluate the catalytic potential of the new primary-thiourea
organocatalysts, the enantioselective conjugate addition of ketone
to nitroalkene is chosen as a test reaction. The conjugate addition
of ketone to nitroalkene offers an efficient access to γ-nitroketone,
which is a valuable and diversified building block in organic
synthesis and medicinal chemistry.8-12 As a result, much effort
has been devoted to the development of more efficient catalytic
systems for this important transformation.13
After careful screening of solvent, it was found that reaction
media affected the conjugate addition severely, especially in
terms of reaction rate. The conjugate addition proceeded hardly
in CH2Cl2, MeCN, THF, Et2O, t-BuOMe, respectively (Table 2,
entries 2-6). The reaction in EtOAc furnished 3aa in 8% yield
with 60% ee (Table 2, entry 7). Using 1,2-dimethoxyethane as
solvent resulted in 25% yield and 60% ee (Table 2, entry 8). 1,4-
Dioxane was found to be more suitable for this transformation to
afford 3aa in 36% yield with 71% ee (Table 2, entry 9).
Initial experiments were performed with the reaction between
β-nitrostyrene 1a and acetone 2a in toluene to identify the most
active organocatalyst. And the results were listed in Table 1. It
was confirmed that the new primary amine-thiourea could
successfully catalyze the conjugate addition of acetone to β-
nitrostyrene. The primary amine-thioureas containing pyridine
ring furnished adducts with quite different enantioselectivities.
Both the size and position of substituent on pyridine ring affected
the asymmetric induction obviously (Table 1, entries 1-4).
Replacing pyridine ring with isoquinoline ring resulted in a slight
higher ee value (Table 1, entry 5). An essential enhancement of
enantioselectivity was achieved when the reaction was catalyzed
A survey of additives revealed that they play an important role
in governing reaction yields and have a small effect on the
enantioselectivities. Remarkable enhancements of yield were
achieved when different acidic additive was added to the reaction
system, respectively. In the presence of catalyst IV combined
with benzoic acid, adduct 3aa was obtained in 80% yield with
75% ee (Table 2, entry 10). Notably, IV/4-methylbenzoic acid
catalytic system furnished adduct 3aa in up to 86% yield with

3
75% ee (Table 2, entry 12). The use of 2-methoxybenzoic acid as
additive also afforded satisfactory results, 85% yield and 72% ee
(Table 2, entry 13). Both 2-nitrobenzoic acid and 4-nitrobenzoic
acid were found to affect the yield slightly (Table 2, entries 16-
17). The chiral acidic additives were also investigated and
moderate yields were obtained (Table 2, entries 20-21). It should
be noted that all the probed acidic additives affected asymmetric
induction slightly and the ee values vibrated around the level of
75%.
the aromatic ring with a small effect on the yield and
asymmetric induction of the conjugate addition (Table 3, entries
2-16). Particularly, the heteroaromatic nitroalkene (1q) could
also be successfully employed under these reaction conditions to
afford addust 3qa in 72% yield with 77% ee (Table 3, entry 17).
The conjugate addition between β-nitrostyrene (1a) and
acetophenone (2b) was also surveyed and adduct 3ab with about
90% ee was obtained in 16% yield (Table 3, entry 18).
Table 3. Scope of the conjugate addition a
Table 2. Optimization of reaction conditions a
O
R
IV, 4-methylbenzoic aicd
O2N
NO2
+
O
Ar
IV, Additive
O2N
1,4-dioxane, RT, 24 h
Ar
3
O
NO2
R
+
Ph
2
1
Ph
3aa
O
Solvent, RT, 24 h
2a
1a
Entry
1
Ar
R
Adduct
3aa
3ba
3ca
3da
3ea
3fa
Yield (%)b
86
ee (%)c
75
Entry
1
Solvent
Additive
Yield (%)b
11
ee (%)c
73
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
toluene
-
2
2-FPh
80
73
2
CH2Cl2
-
trace
trace
trace
trace
trace
8
N.D.d
N.D.
N.D.
N.D.
N.D.
60
3
2-ClPh
57
74
3
MeCN
-
4
2-NO2Ph
2-MeOPh
74
61
4
THF
-
5
38
80
5
Et2O
-
6
2,3-(MeO)2Ph
3-BrPh
70
73
6
t-BuOMe
EtOAc
-
7
3ga
3ha
3ia
60
67
7
-
8
3-NO2Ph
3-MePh
3-MeOPh
4-FPh
51
63
8
(CH2OMe)2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
-
25
60
9
54
70
9
-
36
71
10
11
12
13
14
15
16
17
18
3ja
57
72
10
11
12
13
14
15
16
17
18
19
20
21
PhCO2H
80
75
3ka
3la
56
74
2-MePhCO2H
77
74
4-ClPh
76
71
4-MePhCO2H
86
75
4-BrPh
3ma
3na
3oa
3pa
3qa
3ab
64
71
2-MeOPhCO2H
4-MeOPhCO2H
4-FPhCO2H
85
72
4-CF3Ph
4-MePh
4-MeOPh
2-thienyl
Ph
58
67
81
73
68
77
67
76
59
78
2-NO2PhCO2H
4-NO2PhCO2H
1-naphthoic acid
2-naphthoic acid
(R)-PhCH(OH)CO2H
L-N-Boc-tyrosine
35
79
72
77
34
77
16
90
64
76
a Unless noted, the reaction was carried out as following: The mixture of 1
(0.5 mmol), 2 (2.5 mmol), IV (15 mol%) and 4-methylbenzoic acid (15 mol%)
was stirred in 1,4-dioxane (0.5 mL) for 24 h.
68
78
52
77
b Isolated yield.
58
75
c Determined by chiral HPLC analysis (see Supporting Information).
a Unless noted, the reaction was carried out as following: The mixture of 1a
(0.5 mmol), 2a (2.5 mmol), IV (15 mol%) and additive (15 mol%) was stirred
in the solvent (0.5 mL) for 24 h.
The absolute configuration of IV-catalytic conjugate addition
adduct 5-nitro-4-phenylpentan-2-one was S, which was
determined by comparison of the chiral HPLC analysis method
according to the literature.7
b Isolated yield.
c Determined by chiral HPLC analysis (Chiralpak AS-H, n-hexane/2-propanol
= 70/30).
d N.D. = Not determined.
In conclusion, we have developed a new simple primary
amine-thiourea derived from chiral 1,2-diaminocyclohexane and
achiral available backbone. And we have successfully extended
the new organocatalyst to catalyze asymmetric conjugate
addition of ketone to nitroalkene with good to high yields and
asymmetric induction. Further efforts on the application of the
primary amine-thiourea organocatalyst to other valuable
transformation are under active investigation.
To further test the effectiveness of the IV/4-methylbenzoic
acid system, the conjugate additions of acetone to a series of
nitroalkenes were examined (Table 3). In the presence of primary
amine-thiourea IV together with 4-methylbenzoic acid, adducts 3
were isolated in moderate to good yield with 61-78% ee from the
reactions between nitroalkenes and acetone. One exception was
2-methoxynitrostyrene, which was found to react slowly with
acetone to afford adduct 3ea in 38% yield with 80% ee (Table 3,
entry 5). Both electron-withdrawing (F, Cl, Br, NO2, CF3) and
eletron-donating substituents (Me, MeO) can be introduced on
Acknowledgments
We gratefully thank the Startup Fund from South University
of Science and Technology of China (SUSTC) and National

4
Tetrahedron Letters
13. For reviews on conjugate addition of nitroalkene, see: (a) Berner,
Natural Science Foundation of China (NSFC 21302089) for
financial support.
O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877-
1894; (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701-1716; (c)
Sulzer-Mossé, S.; Alexakis, A. Chem. Commun. 2007, 3123-3135;
(d) Zhang, Y.; Wang, W. Catal. Sci. Technol. 2012, 2, 42-53.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://
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