Diphenylprolinol silyl ether-derived thioureas as highly efficient catalysts for the asymmetric Michael addition of aldehydes to nitroalkenes

Article abstract of DOI:10.1016/j.tetlet.2015.04.119

Abstract This Letter described the synthesis of the first diarylprolinol silyl ether-derived bifunctional thiourea organocatalysts. The catalysts were applied to the asymmetric Michael addition of aldehydes to nitroalkenes to give the desired adducts in good yields (up to 99%) with excellent enantioselectivities (up to 99% ee) and excellent diastereoselectivities (up to 99:1). The spatial placement of C-4 substituent is of importance to the reaction activity and stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2015.04.119

Accepted Manuscript
Diphenylprolinol silyl ether-derived thioureas as highly efficient catalysts for
the asymmetric Michael addition of aldehydes to nitroalkenes
Chunyan He, Xiaochen Ren, Yingle Feng, Yonghai Chai, Shengyong Zhang,
Weiping Chen
PII:
S0040-4039(15)00776-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.04.119
TETL 46259
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 March 2015
27 April 2015
29 April 2015
Please cite this article as: He, C., Ren, X., Feng, Y., Chai, Y., Zhang, S., Chen, W., Diphenylprolinol silyl ether-
derived thioureas as highly efficient catalysts for the asymmetric Michael addition of aldehydes to nitroalkenes,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.04.119
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Graphical Abstract
Diphenylprolinol silyl ether-derived thioureas as
highly efficient catalysts for the asymmetric Michael
addition of aldehydes to nitroalkenes
Leave this area blank for abstract info.
Chunyan Hea, Xiaochen Rena, Yingle Fenga, Yonghai Chai,a, *
Shengyong Zhanga, b and Weiping Chenb, *

1
Tetrahedron Letters
journal homepage: www.els evier.com
Diphenylprolinol silyl ether-derived thioureas as highly efficient catalysts for the
asymmetric Michael addition of aldehydes to nitroalkenes
Chunyan Hea, Xiaochen Rena, Yingle Fenga, Yonghai Chaia, ∗, Shengyong Zhanga, b and Weiping Chenb, *
a Key Laboratory of Applied Surface and Colloid Chemistry, School of Chemistry and Chemical Engineering Shaanxi Normal University, Xi’an, Shaanxi 710062,
P.R. China
b Department of Medical Chemistry, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi, 710032, P.R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
This paper described the synthesis of the first diarylprolinol silyl ether-derived bifunctional
thiourea organoatalysts. The catalysts were applied to the asymmetric Michael addition of
aldehydes to nitroalkenes to give the desired adducts in good yields (up to 99%) with excellent
enantioselectivities (up to 99%ee) and excellent diastereoselectivities (up to 99:1). The spatial
placement of C-4 substituent is of importance to the reaction activity and stereoselectivity.
Received in revised form
Accepted
Available online
2015 Elsevier Ltd. All rights reserved.
Keywords:
Diphenylprolinol silyl ether
Thiourea
Michael addition
Nitroalkenes
Aldehydes
A central part of the organic chemistry is the formation of C-C
bonds. Among the C-C bond forming reactions, the Michael
addition reaction1 is one of the powerful reactions to generate
new C-C bonds and stereocenters. In particular, the enamine-
mediated asymmetric Michael addition2 has been developed as an
efficient strategy for the construction of new C-C bonds due to
the easy availability of chiral amine catalysts3. Since
diarylprolinol silyl ethers were reported as organocatalysts by
Jørgensen and Hayashi independently in 20054, those catalysts
have been proved to be efficient and versatile organocatalysts
with high enantioselectivity5. However, the diarylprolinol silyl
ethers do not always produce satisfactory results in terms of
reaction reactivity, diastereoselectivity and enantioselectivity.
Thus, to develop more efficient diarylprolinol silyl ether-based
organocatalysts are highly desirable.
been reported so far in spite of the great importance of thiourea
moiety in organocatalytic bifunctional system8, 9
.
Studies show that the introduction of a substituent at C-4
position of the pyrrolidine enhances the catalytic performance of
Our initial study began with the syntheses of the two diphenyl
silyl ether-derived thioureas 1 and 2 (Fig 1). Starting from
commercially available trans-4-hydroxy-L-proline, catalysts 1
and 2 were prepared in 8 steps in 19% and 13% overall yield,
respectively (see SI).
6
diarylprolinol silyl ethers . The Jørgensen group7 reported that
the catalytic reactivity of the diphenylprolinol silyl ether was
increased for the reaction of p-quinonemethide with
hydrocinnamaldehyde catalyzed by the catalyst without the
erosion of reaction enantioselectivity when an achrial thiourea
was added as H-bonding donor. Inspired by these discoveries, we
envisioned that high efficient catalysts based on the
diarylprolinol silyl ether might be developed by introducing a
thiourea moiety at the C-4 position (Fig 1). To our best
With the organocatalysts 1 and 2 in hand, the Michael addition
of valeraldehyde to trans-β-nitrostyrene was selected as a model
reaction to examine the performance of the new catalysts. The
reaction conditions were optimized and the results were
summarized in Table 1.
knowledge, no thiourea-based diaryprolinol silyl ethers have
———
∗Corresponding author. Tel.: 029-81530783; fax: 029-81530783; e-mail: ychai@snnu.edu.cn (Yonghai Chai)
e-mail: wpchen@fmmu.edu.cn (Weiping Chen)

2
Tetrahedron
room temperature (entry 12). The difference between catalyst 1
Table 1 Optimization: Screening of catalysts and
reaction conditions a
and 2 is the C-4 configuration at pyrrolidine ring, which reveals
that the spatial placement of the thiourea moiety has an important
effect on the diastereoselectivity and enantioselectivity of the
Michael addition. The cis-arrangement of the C-4 and C-2
substitutents at pyrrolidine ring favors the enantioselectivity, but
disfavors the diastereoselectivity of the Michael addition.
Entry
Cat.
(mol%)
1(20)
1(20)
1(20)
1(20)
1(20)
1(20)
1(20)
1(20)
1(20)
1(20)
1(20)
2(20)
2(20)
2(20)
2(20)
Solvent
additive
Yied
(%) b
88
dr. c
ee.
(%)d
79
84
71
nd
Besides the substituent’s influence on the reaction reactivity,
diastereoselectivity and enantioselectivity, the concentration also
has of a great importance on the reaction results. When the
reaction concentration was changed from 0.125 mol/L to 0.25
mol/L in the presence of catalyst 1, the reaction yield and
enantioselectivity decreased from 88% to 57% and from 79% to
68% (entry 11). Similar phenomenon was also observed with
catalyst 2 when the reaction concentration increased (entry 13).
1
2
Hexane
Toluene
CH2Cl2
TBME
Ether
—
—
83/17
88/12
88/12
nd
66
3
—
49
4
—
trace
trace
87
Considering acidic additives are often favorable to the
enamine formation between a aldehyde or ketone and a
secondary amine, the acidic additive thereby may affect the yield
and the selectivity of the Michael addition reaction catalyzed by
2 due to the formation of an enamine intermediate during the
catalytic process. Several different acidic additives were
investigated in this reaction. As indicated in Table 1, the increase
of the reaction enantioselectivity was observed no matter which
acidic additive was employed (entries 14-19). In particular,
PhCOOH showed excellent yield (99%), enantioselectivity
(93%) and diasteroselectivity (77/23) (entry 18). Interestingly,
even though the enantioselectivity increased for all acidic
additives, the yield did not have the same tendency. Thus,
PhCOOH was chosen as additive due to the good results obtained
for asymmetric Michael reaction of nitroalkenes to aldehydes.
5
—
nd
nd
6
THF
—
65/35
70/30
71/29
75/15
80/20
80/20
76/24
76/24
76/24
80/20
78
15
48
45
47
68
87
81
89
92
7
EtOH
—
26
8
MeOH
DMF
—
22
9
—
23
10
11e
12
13e
14
15
CH3CN
Hexane
Hexane
Hexane
Hexane
Hexane
—
28
—
57
—
93
Given that the catalyst loading is also a significant factor for
catalytic reactions, the catalyst loading was also investigated and
the results were shown in table 1 (entry 18 and entries 20-22), the
reaction enantioselectivity increased with the decrease of catalyst
loading, however, the reaction yield decreased. The highest
enantioselectivity (97%, entry 22) was achieved when 5% mol of
catalyst was used, but the yield decreased dramatically. 15% of
catalyst loading provided satisfactory 93% of yield along with
95% of enantioselectivity and 80/20 of diastereoselectivity (entry
20).
—
92
TFA
p-NO2-
C6H4COOH
TsOH
AcOH
PhCOOH
4ǺMS
PhCOOH
PhCOOH
PhCOOH
77
89
16
17
18
19
20
21
22
2(20)
2(20)
2(20)
2(20)
2(15)
2(10)
2(5)
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
Hexane
22
92
99
88
93
83
47
84/16
77/23
77/23
76/24
80/20
83/17
84/16
96
87
93
87
95
96
97
With the optimized condition in hand, we studied the substrate
scope of the Michael addition reaction. Different alphatic
aldehydes reacted with a serial of trans-arylnitrolakenes bearing
electro-donating or electro-drawing groups to form the Michael
reaction adducts with excellent enantioselectivities and yields
(Table 2, entries 1-19). Nevertheless, the reaction gave a
moderate to high diastereoselectivities (63/37 to 86/14). Linear
and branched aldehydes proceeded smoothly with nitroalkenes.
Compared to linear aldehydes, the branched one has lower
reaction activity but higher diastereoselectivity (entries 1-6),
presumably due to the difficulty in forming the nucleophile of
enamine. Electro- drawing groups on the aryl ring will increase
the electrophilicity of nitroalkenes. As expected, the aldehyde
reacted with nitroalkenes bearing electro-drawing groups (entries
7-15) in faster reaction rate in comparison with the one bearing
electro-donating groups (entries 16-18). The higher electro-
drawing ability (entry 2) or the more electro-drawing groups
(entry 15) aromatic ring has, the faster rate the reaction has, and
vice versa. The position of the substituent on the aryl ring had a
slight influence on the yield, enantioselectivity and
diastereoselectivity of the Michael addition, but there is no
general rule for this kind of influence. It is worthy to note that the
Michael addition of valeraldehyde to 4-bromophenyl nitroalkene
(entry 14) afforded the adduct 5n in almost quantitative yield
a. Unless specified, reactions were conducted on a 0.125 mmol scale with
nitroalkene and valeraldehyde (1.25 mmol) in solvent (1 mL) in the catalyst
at room temperature for 3 days. b. Isolated yield. c. Determined by 1H
NMR spectroscopy. d. Determined by chiral HPLC analysis. e.
Concentration was 0.25 mol/L.
As indicated in Table 1, the Michael addition proceeded
smoothly in the non-polar solvents in the presence of catalyst 1
(entries 1-3), while the polar solvents (entries 4-10) gave much
lower yield except THF (entry 6). Among those non-polar
solvents, hexane was chosen as reaction solvent for further study
due to the best catalytic activity with a slight compromise of
enantioselectivity and diastereoselectivity (entries 1-3).
Compared to catalyst 1, catalyst 2 gave better yield and higher
enantioselectivity but lower diastereoselectivity in hexane at

3
along with extremely high diastereoselectivity (99/1) and
enantioselectivity (99%). In addition, the addition of aldehyde to
heteroarylnitroalkenes also worked well (entry 19).
(entry 2 vs. 3), which reveals that thiourea group might
accelerate the Michael addition. However, when the thiourea
moiety was incorporated into the C-4 position of the pyrrolidine,
the reaction rate of the Michael addition decreased. The reason
for the lower reaction activity is not certain at this stage and
further work is ongoing to disclose the truth and to expand the
new catalyst to other valuable transformations.
Table 2 Catalytic asymmetric Michael reactions of various
aldehydes to nitroalkenes a
Table 3 Effects of different catalysts on the asymmetric
Michael reactions of carbonyl compounds to
nitroalkenes a
Entry
R1, R2
Adduct Time Yield
dr. c
ee.
(%)d
92
93
95
96
93
90
86
97
90
89
92
89
89
99
91
88
90
89
90
5
5a
5b
5c
5d
5e
5f
(d)
3
(%)b
87
99
93
70
97
90
98
95
99
86
83
97
93
99
94
97
95
97
99
1
2
CH3, C6H5
71/29
75/25
80/20
86/14
77/23
78/22
73/27
67/33
85/15
75/25
63/37
81/19
70/30
99/1
C2H5, C6H5
3
3
C3H7, C6H5
3
4
i-C3H7, C6H5
4
Entry
R1, R3
Catalyst Adduct Time Yield dr. c
ee.
(%)d
5
C7H15, C6H5
3
5
(h) (%)b
6
C9H19, C6H5
3
1
2
3
4
5
6
C3H7,H
C3H7,H
C3H7,H
-(CH2)4-
-(CH2)4-
-(CH2)4-
2
6
5c
5c
5c
5t
5t
5t
72
93
95
95
10
24
24
80/20 95
7
C3H7, 2-FC6H4
C3H7, 4-FC6H4
C3H7, 2-ClC6H4
C3H7, 3-ClC6H4
C3H7, 4-ClC6H4
C3H7, 2-BrC6H4
C3H7, 3-BrC6H4
C3H7, 4-BrC6H4
C3H7,2,4-2ClC6H3
C3H7,4-MeC6H4
C3H7,3-MeOC6H4
C3H7,4-MeOC6H4
C3H7, 2-furyl
5g
5h
5i
2
20
16
77/23
96
8
3
6+7
2
76/24 96
78/22 70
77/23 18
75/25 76
9
2.5
2
168
168
168
10
11
12
13
14
15
16
17
18
19
5j
6
5k
5l
3
6+7
2
a. Unless specified, reactions conducted on a 0.125 mmol scale nitroolefin
in hexane (1 mL) with valeraldehyde/cyclohexanone (1.25 mmol) in the
catalyst (15 mol%) and PhCOOH (20 mol%) at room temperature. b. Isolated
yield. c. Determined by 1H NMR spectroscopy. d. Determined by chiral
HPLC analysis.
5m
5n
5o
5p
5q
5r
5s
2.5
3
1.5
4
74/26
71/29
77/23
71/29
70/30
In summary, we have synthesized new diarylprolinol silyl
ether-derived bifunctional thiourea organocatalysts. The catalysts
were applied to the asymmetric Michael addition of aldehydes
and nitroalkenes to give adducts in excellent yield and enantio-
selectivity. In particular, the addition of valeraldehyde to 4-
bromophenyl nitroalkene quantitatively provided the addition
adduct in almost one single isomer. The spatial placement of the
catalyst C-4 substituent on the pyrrolidine ring has great
influence on the reaction activity, diastereoselectivity and
enantioselectivity.
4
4
3
a. Unless specified, reactions conducted on a 0.125 mmol scale nitroolefin
in hexane (1 mL) with aldehyde (1.25 mmol) in the catalyst 2 (15 mol%)
and PhCOOH (20 mol%) at room temperature. b. Isolated yield. c.
Determined by 1H NMR spectroscopy. d. Determined by chiral HPLC
analysis.
Acknowledgments
This work was supported by National Natural Science
Foundation of China (21172262, 21272271), Special Funds from
Shaanxi Normal University (999565) and the Fundamental
Research Funds for the Central Universities (No. GK200902005).
All of the financial supports are gratefully acknowledged.
Comparative study was taken on the asymmetric Michael
addition of carbonyl compounds to trans-β-nitrostyrene in the
presence of catalyst 2, diphenylprolinol silyl ether 6 with or
without the addition of an achiral thiourea 7 (Table 3). For
valeraldehyde, the diastereoselectivity and enantioselectivity of
catalyst 2 is similar to that of catalyst 6 with or without the
addition of thiourea 7, although the activity is lower (Table 3,
entries 1-3). Surprisingly, for cyclohexanone, the enantio-
selectivity of catalyst 2 is much higher than that of 6 without the
addition of thiourea 7 (entry 4 vs. 5), and comparable with that of
the catalyst 6 with the addition of thiourea 7 (entry 4 vs. 5). With
the addition of thiourea 7, the reaction rate slightly increased
Supplementary Material
Supplementary data associated with this article can be found in
the online version at

4
Tetrahedron
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