Novel thiourea-amine bifunctional catalysts for asymmetric conjugate addition of ketones/aldehydes to nitroalkenes: Rational structural combination for high catalytic efficiency

Article abstract of DOI:10.1039/b925962g

A series of thiourea-amine bifunctional catalysts have been developed by a rational combination of prolines with cinchona alkaloids, which are connected by a thiourea motif. The catalyst 3a, prepared from l-proline and cinchonidine, was found to be a high

Full text of DOI:10.1039/b925962g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Novel thiourea-amine bifunctional catalysts for asymmetric conjugate
addition of ketones/aldehydes to nitroalkenes: rational structural combination
for high catalytic efficiency†
Jia-Rong Chen,* Yi-Ju Cao, You-Quan Zou, Fen Tan, Liang Fu, Xiao-Yu Zhu and Wen-Jing Xiao*
Received 9th December 2009, Accepted 12th January 2010
First published as an Advance Article on the web 21st January 2010
DOI: 10.1039/b925962g
A series of thiourea-amine bifunctional catalysts have been
developed by a rational combination of prolines with cin-
chona alkaloids, which are connected by a thiourea motif.
The catalyst 3a, prepared from L-proline and cinchonidine,
was found to be a highly efficient catalyst for the conjugate
addition of ketones/aldehydes to a wide range of nitroalkenes
(up to 98/2 dr and 96% ee). The privileged cinchonidine
backbone and the thiourea motif are essential to the reaction
activity and enantioselectivity.
and enantioselectivities (Scheme 1).15a As a key design element,
the rational coupling of two privileged chiral motifs is critical
to the catalytic performance of 1 and 2. In an effort to extend
this strategy, we recently questioned whether “privileged chiral
catalysts” might be combined to generate a new catalyst system
for enantioselective Michael reactions. Herein, we disclose the
synthesis of unprecedented thiourea-amine bifunctional catalysts
3–6 by rational incorporation of structurally privileged proline
and cinchona alkaloids into one molecule (Fig. 1)17 and the
results of utilizing 3a and 6 in the Michael addition of unmodified
ketones/aldehydes to nitroalkenes.
Over the last decade, organocatalysis has become one of the
most active and attractive research fields in modern organic
chemistry.1,2 In this context, great research efforts have been
directed toward the development of efficient organocatalysts for
asymmetric reactions. As a consequence, a number of chiral
amines have been identified as versatile catalysts for enantioselec-
tive functionalizations of carbonyl compounds.3–7 The asymmetric
direct conjugate addition of ketones/aldehydes to nitroalkenes,
which provides a straightforward approach to optically active and
synthetically versatile g-nitrocarbonyl compounds, has received
extensive attention.8–10 Inspired by the seminal works of List,11b
and Barbas11c,d and co-workers, many elegant catalytic systems
have been developed for the asymmetric Michael addition of
carbonyl compounds to nitroalkenes.11–14 Representative examples
include Wang’s pyrrolidine sulfonamides,12h Barbas’ diamines,12i
Tang’s thiourea-secondary amines,12j Jacobsen’s primary amine-
thioureas,13g Takemoto’s thiourea-tertiary amine,13j and Wang’s
thiourea-dehydroabietic amine.13k Despite remarkable advances
being made, efforts to develop readily available and easily tun-
able organocatalysts for asymmetric Michael addition reactions
continue with the goal of increasing the reaction efficiency and
stereoselectivity.
Scheme 1 Direct aldol reaction of aromatic aldehydes with acetone.
A detailed description of our bifunctional and tunable catalysts
is presented in Scheme 2 with the synthesis of 3a as a representative
example. Treatment of (S)-2-aminomethyl-1-N-Boc-pyrrolidine
(7)18a with carbon disulfide using a known procedure18b gave
the corresponding isothiocyanate 8 in 76% isolated yield. Subse-
quently, the reaction of 8 with the cinchonidine-derived amine 9 in
CH2Cl2 at room temperature afforded the Boc-protected thiourea-
amine 10 in 88% yield,18c which was then deprotected directly with
TFA in CH2Cl2 to give rise to the desired organocatalyst 3a in
55% yield.14a Other thiourea-amine catalysts 3b–6 were synthesized
according to this three-step procedure without incident. The
structures of the catalysts 3–6 were fully characterized (see the
Supporting Information). Notably, these catalysts could be easily
prepared on gram scales. The catalytic performance of these
catalysts were then evaluated in the direct asymmetric conjugate
addition of cyclohexanone 11 to trans-b-nitrostyrene 12a and the
results are summarized in Table 1.
Recently, our group introduced a new and powerful methodol-
ogy, combining two privileged backbones into one, for the catalyst
design, which led to two efficient chiral amines for the direct
aldol reaction between aromatic aldehydes and acyclic ketones.15,16
In the presence of 10 mol% of catalyst 1 or 2, a broad range
of aldehydes reacted efficiently with acetone, affording both
enantiomers of the corresponding aldol adducts in excellent yields
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, 152 Luoyu Road,
Wuhan, Hubei 430079, China. E-mail: jrchen@mails.ccnu.edu.cn, wxiao@
mail.ccnu.edu.cn; Fax: +86 27 67862041; Tel: +86 27 67862041
† Electronic supplementary information (ESI) available: Experimental
details, characterization of all catalysts, NMR spectra, and HPLC spectra
of Michael addition products. See DOI: 10.1039/b925962g
As shown in Table 1, catalysts 1 and 2, which are excellent
catalysts for the direct aldol reaction of acetone with aldehydes,
can also efficiently promote this Michael reaction under our
previous reaction conditions.14a High levels of reaction efficiency
and diastereoselectivities were achieved (up to 96% yield and
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Fig. 1 New class of thiourea-amine bifunctional catalysts.
Table 1 Asymmetric Michael reaction of cyclohexanone 11 with trans-b-
nitrostyrene 12a catalyzed by organocatalysts 1–6a
entry
cat. solvent
t/h
yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1
n-Hexane
4
4
5
96
93
89
82
83
76
82
87
<5
<5
<5
85
80
77
80
88
17
63
<5
82
62
86
50
96/4
95/5
97/3
96/4
96/4
97/3
95/5
97/3
—
34
-16
96
91
91
91
-86
-96
—
—
—
94
90
92
90
92
82
86
—
90
88
91
91
2
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
EtOH
MeOH
i-PrOH
Toluene
xylene
CHCl3
CH2Cl2
DCE
CH3CN
Dioxane
DMSO
Et2O
3a
3b
4a
4b
5
22
12
17
13
10
24
24
24
8
Scheme 2 Synthesis of thiourea-amine bifunctional catalyst 3a.
6
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
96/4 dr), but the enantiomeric excess of the corresponding
Michael adduct was not satisfactory (16–34% ee). In order to
overcome this limitation, we then applied the chiral thiourea-
amines 3–6 to this model reaction. Indeed, the combination of
the proline with cinchona alkaloid plays an important role in the
stereocontrol in this Michael addition. It was found that the chiral
thiourea-amines 3a and 4a, derived from L-proline, cinchonidine
and quinine, displayed slightly higher selectivity and/or efficiency
than their analogues 3b and 4b, respectively (Table 1, entries 3
vs. 4, 5 vs. 6). As expected, when D-proline was incorporated into
the catalyst backbone (catalyst 5), the opposite enantiomer of the
Michael adduct was generated in 82% yield with 95/5 dr and 86%
ee (Table 1, entry 7). Furthermore, the catalyst 6, prepared from
D-proline and cinchonine, induced higher enantioselectivity than
5 did, giving the product with opposite configuration in 87% yield
with 97/3 dr and 96% ee. We then simply examined the effects
of other solvents on the reaction with 3a as the catalyst. The
diastereo- and enantioselectivity/solvent profile showed that the
n-hexane was the ideal reaction medium (Table 1, entries 9–23).
It was documented that the addition of Brønsted acid could
accelerate the formation of the enamine/iminium intermediate in
the aminocatalysis, and thereby increases the reaction efficiency
and selectivity. Accordingly, various Brønsted acids were then
screened to further improve the diastereo- and enantioselectivity
of the reaction. As can be seen from Table 2, the acid additive does
indeed affect the diastereo- and enantioselectivity and reaction
efficiency. For example, in the presence of formic acid, the dr and
ee decreased to 90/10 and 88%, respectively (Table 2, entry 1).
—
—
96/4
93/7
95/5
93/7
95/5
90/10
91/9
—
95/5
93/7
94/6
89/11
8
28
21
8
45
45
24
21
45
8
THF
TBME
neat
8
a Reactions were carried out with cyclohexanone 11 (5.0 mmol), trans-b-
nitrostyrene 12a (0.5 mmol) and 10 mol% catalyst and 10 mol% PhCO2H
in the solvent (1.0 mL) indicated. b Isolated yield for both diastereomers.
c syn/anti Ratio was determined by 1H NMR. d ee of syn diastereomer,
determined by chiral HPLC.
Surprisingly, in the case of p-TsOH, only 52% yield of the Michael
adduct was obtained even after two days albeit with 94/6 dr and
90% ee (Table 2, entry 7). Among the additives examined, PhCO2H
proved to benefit the reaction (Table 2, entry 14). It is worthwhile
noting that the reaction proceeded much more slowly and with
lower dr and ee values in the absence of PhCO2H (Table 2, entry
15 vs. 14).
With the optimal reaction conditions in hand, we next in-
vestigated the scope of the Michael reaction with a variety of
nitroolefins and the results are shown in Table 3. In addition
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Table 2 Effect of the acid additives on the catalytic performance of
catalyst 3aa
Table 3 Asymmetric Michael addition reaction between 11 and 12
catalyzed by catalysts 3a and 6a
entry
nitroolefin Ar
cat.
yield (%)b
drc
ee (%)d
entry
HX
t/h
yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Ph (12a)
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
6
89
75
76
92
85
98
89
89
95
98
95
97
93
87
86
92
80
97
81
90
92
97
91
87
85
87
<5
97/3
93/7
98/2
97/3
94/6
98/2
93/7
97/3
95/5
94/6
95/5
93/7
92/8
97/3
98/2
91/9
94/6
98/2
91/9
97/3
98/2
92/8
94/6
95/5
89/11
85/15
—
96
94
95
94
94
90
94
94
95
92
92
92
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
HCO2H
HOAc
ClCH2CO2H
NCCO2H
TFA
CH3CH2CO2H
p-TsOH
p-MeO-PhCO2H
p-F-PhCO2H
3,5-DNBA
p-CF3-PhCO2H
CH3(CH2)10CO2H
CH3(CH2)14CO2H
PhCO2H
14
12
12
14
14
12
48
12
12
12
12
12
12
5
90
85
91
84
89
81
52
89
97
93
96
87
85
89
17
90/10
94/6
95/5
93/7
94/6
93/7
94/6
93/7
94/6
93/7
94/6
91/9
91/9
97/3
91/9
88
92
91
90
93
92
90
92
91
89
92
90
90
96
83
4-NO2-Ph (12b)
2-NO2-Ph (12c)
4-F-Ph (12d)
4-Br-Ph (12e)
2-Br-Ph (12f)
4-Cl-Ph (12g)
2-Cl-Ph (12h)
2,4-Cl2-Ph (12i)
4-Me-Ph (12j)
2-MeO-Ph (12k)
1-naphthyl (12l)
2-furyl (12m)
Ph (12a)
85
-96
-94
-91
-94
-93
-91
-94
-95
-89
-91
-93
-85
-82
—
2-NO2-Ph (12c)
4-F-Ph (12d)
4-Br-Ph (12e)
2-Br-Ph (12f)
4-Cl-Ph (12g)
2-Cl-Ph (12h)
2,4-Cl2-Ph (12i)
4-Me-Ph (12j)
2-MeO-Ph (12k)
1-naphthyl (12l)
4-MeO-Ph (12n)
2-thienyl (12o)
t-Bu (12p)
6
none
72
6
a Unless otherwise noted, reactions were carried out with 0.5 mmol of trans-
b-nitrostyrene 12a, 5.0 mmol of cyclohexanone 11 in 1.0 mL of n-hexane
in the presence of 10 mol% of catalyst 3a and 10 mol% of co-catalyst HX.
b Isolated yield for both diastereomers. c syn/anti Ratio was determined by
1H NMR. d ee of syn diastereomer, determined by chiral HPLC.
6
6
6
6
6
6
6
6
6
to trans-b-nitrostyrene 12a, various electron-poor and -rich
nitroolefin derivatives with different substitution patterns on
the aromatic ring reacted smoothly with cyclohexanone in the
presence of 10 mol% of 3a with 10 mol% of PhCO2H as the
co-catalyst, giving the corresponding Michael adducts 13a–k in
high yields with excellent diastereo- (up to 98/2 dr) and enantios-
electivities (90–95% ee) (Table 3, entries 2–11). Fused aromatic
nitroolefins, such as 12l, can also be successfully employed in
this transformation and high yield, dr (93/7) and ee (92%) were
obtained. Heteroaromatic nitroolefins, such as 12m and 12o, were
also viable substrates (Table 3, entries 13 and 26). As expected,
the opposite enantiomeric Michael addition product can also
be obtained with high dr and ee values when thiourea-amine
catalyst 6/PhCO2H was employed under the same conditions
(Table 3, entries 14–26). However, aliphatic nitroolefins displayed
much less reactivity in this reaction. For example, the addition
of aliphatic nitroolefin 12p proceeded very slowly and only trace
amount of the product was detected even after 4 days (Table 3,
entry 27).
The synthesis of quaternary stereogenic centers remains a
challenging task in synthetic organic chemistry, and there have
only been a few examples of the use of a,a-disubstituted aldehydes
as Michael donors.19 The Michael addition of a,a-disubstituted
aldehydes to nitroolefin should provide a direct access to nitro
compounds with one all-carbon quaternary center. Therefore, we
primarily examined the feasibility of utilizing isobutyraldehyde 14
as Michael donor with 3a as the catalyst. As shown in eqn (1), the
Michael addition of isobutyraldehyde 14 to trans-b-nitrostyrene
12a proceeded smoothly and the corresponding product was
obtained in 91% yield with 85% ee. Further optimization of the
reaction conditions to improve the enantioselectivity is underway
in our laboratory.
6
3a
a Unless otherwise noted, the reactions were carried out with 0.5 mmol of
12, 5.0 mmol of cyclohexanone 11 in 1.0 mL of n-hexane in the presence of
10 mol% of catalyst 3a or 6 and 10 mol% of PhCO2H for 5–48 h. b Isolated
yield for both diastereomers. c syn/anti Ratio was determined by 1H NMR.
d ee of syn diastereomer, determined by chiral HPLC.
(1)
Based on the observed stereoselectivities, we proposed a
plausible catalytic mode for this asymmetric conjugate addition
(Fig. 2).20 Presumably, the in situ formed enamine interme-
diate between cyclohexanone 11 and catalyst 3a adopts the
E-conformation. Similar to other well-developed diamine–
protonic acid-catalyzed reactions,21 the protonated cinchonidine
moiety of 3a would act as a synergistic Brønsted acid to provide
another hydrogenbondinteractionwiththe nitrogroup besides the
Fig. 2 Proposed intermediate via concerted activation.
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two NH groups of thiourea moiety. Then, the Re face of enamine
intermediate attacks the Re face of trans-b-nitrostyrene to give the
corresponding preferred syn Michael adduct 13a. Nevertheless,
the precise catalytic mechanism needs further investigation.
In conclusion, we have designed a new class of thiourea-amine
bifunctional catalysts by a rational combination of commercially
available and inexpensive proline with cinchona alkaloids. They
have been successfully utilized in the asymmetric conjugate
addition of ketones/aldehydes to nitroalkenes (up to 98% yield),
from which both syn-enantiomers can be obtained in high
stereoselectivity in the presence of catalyst 3a or 6 (up to 98/2 dr
and 96% ee). The present study has further demonstrated that
the coupling of two chiral privileged skeletons, proline and
cinchonidine is a useful strategy to reach high reaction efficiency
and enantioselectivity. The development of modified catalysts with
wider substrate scopes and further application of the current
strategy to the design of other chiral bifunctional organocatalysts
are ongoing in our laboratory.
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Acknowledgements
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We are grateful to the Program for Academic Leader in Wuhan
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dation of China (20672040 and 20872043) for support of this
research.
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