Organocatalytic asymmetric conjugate addition of thioacetic acid to β-nitrostyrenes

Article abstract of DOI:10.1016/j.tetlet.2006.02.036

A method for organocatalytic, enantioselective Michael addition reactions of thioacetic acid with a range of trans-β-nitrostyrenes has been developed. The processes, promoted by the chiral amine thiourea organocatalyst, take place in high yields with up t

Full text of DOI:10.1016/j.tetlet.2006.02.036

Tetrahedron Letters 47 (2006) 2585–2589
Organocatalytic asymmetric conjugate addition of
thioacetic acid to b-nitrostyrenes
Hao Li, Jian Wang, Liansuo Zu and Wei Wang*
Department of Chemistry, MSC03 2060, University of New Mexico, Albuquerque, NM 87131-0001, USA
Received 24 January 2006; revised 5 February 2006; accepted 6 February 2006
Available online 23 February 2006
Abstract—A method for organocatalytic, enantioselective Michael addition reactions of thioacetic acid with a range of trans-b-
nitrostyrenes has been developed. The processes, promoted by the chiral amine thiourea organocatalyst, take place in high yields
with up to 70% ee.
Ó 2006 Elsevier Ltd. All rights reserved.
In recent years, the catalytic asymmetric Michael addi-
tion reactions catalyzed by chiral organocatalysts have
been recognized as an efficient method for enantioselec-
tive carbon–carbon bond formations.1,2 Efficient cata-
lytic asymmetric Michael additions using aldehydes,3
ketones,4 1,3-dicarbonyl compounds,5 nitroalkanes6 or
preformed silyl ethers7 as Michael donors have been
intensively studied. In contrast, a catalytic enantioselec-
tive process using a thiol derivative as a nucleophile has
been much less explored.8 The studies reported to date
have mainly focused on the use of thiols9,10 as a Michael
donor. Generally, harsh reaction conditions are required
for the conversion of the newly formed C–S bond to
more synthetically versatile SH group.11 On the other
hand, the use of a thioacid (RCOSH) as a nucleophile
for the Michael addition reaction is more attractive since
the resulting thioester can be readily transformed into
SH group under various, mild reaction conditions,11
but an organocatalytic enantioselective process has not
yet been developed. In this letter, we wish to disclose
the first organocatalytic asymmetric method for the
Michael addition of thioacetic acid to b-nitrostyrenes
in high yields (91–98%) with up to 70% ee.
OMe
N
OMe
OH
OH
N
N
N
H
N
H
QD I
Q II
OMe
OH
6'
OBn
OH
4'
N
9
9
N
H
N
H
QD-H IV
QD-Bn III
OH
6'
N
H
H
OBn
F3C
N
N
N
9
S
N
H
CF3
VI
Ar
QD-Bn-H V
Bifunctional
organocatalysts
*
NO2
SCOR
NO2
+
RCOSH
S
Ar
chiral
scaffold
N
H
N
H
Bifunctional cinchona alkaloids were the first organo-
catalysts used for promoting asymmetric Michael addi-
tion reactions of thiols. Wynberg et al. have
demonstrated the utility of quinidine (QD I) and quinine
HN
S
O
O
N
Ar
R
O
Figure 1. Bifunctional organocatalyst-promoted asymmetric Michael
addition of thioacids to nitroolefins.
Keywords: Amine thiourea; Asymmetric organocatalysis; Michael
addition reaction; Nitroolefins; Thioacetic acid.
*
(Q II) for asymmetric addition of a thiol to a,b-unsatu-
Corresponding author. Tel.: +1 (505) 277 0756; fax: +1 (505) 277
2609; e-mail: wwang@unm.edu
rated ketones (Fig. 1).10a Almost at the same time,
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.036

2586
H. Li et al. / Tetrahedron Letters 47 (2006) 2585–2589
Mukaiyama and co-workers reported using proline
derivative for a similar purpose.10c Recently, Deng and
co-workers have described an elegant approach for
using the modified forms of these cinchona alkaloids
in the conjugate reactions of thiols to cyclic enones with
significantly improved enantioselectivities.10d These
observations prompted us to investigate the enantio-
selective Michael addition of thioacetic acid to trans-b-
nitrostyrenes. We envisioned that a chiral bifunctional
organocatalyst could activate the weakly nucleophilic
thioacid and the electron deficient trans-b-nitroolefin
simultaneously to facilitate the process, thus forming
addition products enantioselectively with high reaction
efficiency (Fig. 1).
selectivity was observed. The reaction rate was also
significantly reduced presumably as a result of blocking
the 9–OH group. Catalyst QD-H IV with more acidic
phenol group was synthesized and evaluated (Table 1,
entry 5). The reaction proceeded more quickly than that
using QD I probably due to the enhanced H-bonding
interaction of the nitro group of the nitroolefin 1a with
the two OH groups in IV, but a lower ee was achieved as
well. The enantioselectivity of the reaction was im-
proved when the more rigid V was employed (31% ee,
Table 1, entry 6). Based on these studies, we synthesized
bifunctional amine thiourea VI (Table 1, entry 7). Prec-
edent studies have shown that the thiourea group in VI
can afford a strong two-hydrogen bonding interaction
with the nitro group in b-nitrostyrene (Fig. 1).5e,f,12–15
Indeed, the utilization of VI as an organocatalyst
resulted in further improved ee (34%). No enantioselec-
tivity was observed when the more sterically demanding
PhCOSH 2b was used as a Michael donor (Table 1,
entry 8).
To test the working hypothesis, we initially conducted a
model reaction of trans-b-nitrostyrene 1a with thioacetic
acid 2a in toluene in the absence of an organocatalyst.
As expected, the reaction resulted in the desired adduct
3a, but took place slowly (24 h) to afford 3a in a moder-
ate yield (Table 1, entry 1). In contrast, under the same
reaction conditions in the presence of 10 mol % QD I,
the conjugate addition proceeded much faster (15 min)
and gave 3a in a high yield (95%), but gave rise to only
a low enantioselectivity (23% ee) (Table 1, entry 2). A
similar result was obtained using Q II as the catalyst
(Table 1, entry 3).
Having identified the amine thiourea VI as the best cata-
lyst among the organocatalysts tested, optimization of
reaction conditions for the process was carried out next.
First, the effect of solvent on the Michael addition reac-
tions was examined (Table 2, entries 1–7) and it was
found that the use of Et2O as a reaction medium was
superior to others. In this solvent, the highest ee (50%)
at a room temperature reaction was obtained (Table 2,
entry 7). Finally, the effects of reaction temperature
and catalyst loading on the process were determined
(Table 2, entries 8–14). When the reaction temperature
The encouraging results prompted us to carry out more
detailed investigation on the asymmetric version of the
Michael reactions. First, we attempted to identify the
best organocatalyst for the process. Deng and co-work-
ers have demonstrated that increasing the rigidity of
these cinchona alkaloids can improve enantioselectivity
of reactions.10d Accordingly, a benzyl group was intro-
duced at the position 9 in QD I to restrict the rotation
of C40–C9 bond. The resulting organocatalyst QD-Bn
III was tested for the reaction and the results turned
out to be disappointing (Table 1, entry 4). No enantio-
Table 2. Optimization of reaction conditions of the Michael addition
of thioacetic acid to trans-b-nitrostyrene catalyzed by VIa
O
SAc
VI
NO2
+
NO2
Ph
H3C
SH
Ph
R
1a
2a
3a
Entry
Solvent
T (°C)
t (min)
Yield (%)b
ee (%)c
Table 1. Asymmetric Michael addition of thioacid (2) to trans-b-
nitrostyrene (1a) catalyzed by organocatalystsa
1
2
3
4
5
6
7
8
Toluene
CH2Cl2
CH3CN
THF
rt
rt
rt
rt
rt
rt
rt
0
ꢀ15
ꢀ78
ꢀ15
ꢀ15
ꢀ15
ꢀ15
30
60
60
15
15
15
15
15
60
45
45
45
45
45
92
93
92
95
95
94
94
93
91
92
92
93
92
91
34
42
17
21
44
43
50
54
78
73
52
70
63
64
catalyst
10 mol%
O
SCOR
NO2
NO2
+
Ph
R
SH
Ph
toluene, RT
CHCl3
1a
3
EGDMEd
Et2O
R = CH3, 2a
R = Ph, 2b
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Entry
Catalyst
t
Yield (%)b
ee (%)c
9
10
11e
12f
13g
14h
1
2
3
4
5
6
7
8d
None
I
24 h
71
95
94
94
95
93
92
92
0
23
17
0
19
31
34
0
15 min
15 min
1.5 h
5 min
15 min
30 min
1 h
II
III
IV
V
a Unless specified, see footnote a in Table 1 and Supplementary data
for reaction conditions.
VI
VI
b Isolated yield after chromatographic purification.
c Determined by chiral HPLC analysis (Chiralpak AS-H).
d Ethylene glycol dimethyl ether.
e 5 mol % VI used.
a Unless otherwise specified, the reaction was carried out using 1a
(0.20 mmol) and 2a (0.40 mmol) in the presence of 10 mol % of an
organocatalyst in 1.0 mL of toluene at rt for the specified time.
b Isolated yields after chromatographic purification.
c Determined by chiral HPLC analysis (Chiralpak AS-H).
d Compound 2b used as a Michael donor.
f 2 mol % VI used.
g 1 mol % VI used.
h 0.5 mol % VI used.

H. Li et al. / Tetrahedron Letters 47 (2006) 2585–2589
2587
was lowered to ꢀ15 °C, the enantioselectivity was im-
proved up to 78% without affecting the reaction yield
(Table 2, entry 9). Interestingly, a slight drop in enantio-
selectivity (73% ee) was observed at ꢀ78 °C (entry 10).
Remarkably, a catalyst loading as low as 0.5 mol % still
showed considerable catalytic activity at ꢀ15 °C (entry
14). From an operational standpoint, we chose to use
2 mol % VI at ꢀ15 °C in Et2O to evaluate the scope of
the Michael addition reactions. The absolute configura-
tion of 3a prepared under these reaction conditions was
determined by X-ray crystallography to be R (Fig. 2).16
A range of ortho-, meta-, and para-substituted nitroole-
fins were tested for their ability to undergo the reaction
(Table 3). Generally, the reactions proceeded to comple-
tion in less than 2 h in excellent yields (91–98%). Low to
Figure 2. X-ray crystal structure of 3a.
Table 3. Scope of amine thiourea VI promoted the Michael addition reactions of thioacetic acid to nitroolefinsa
O
SAc
VI, 2 mol%
NO2
+
NO2
R
Et2O, -15 o
C
H3C
SH
R
1
2a
3
Entry
1
Product
SAc
t (h)
% Yieldb
93
% eec
70
0.75
NO2
SAc
Ph
NO2
2
3
1.0
0.5
93
95
53
42
SAc
NO2
MeO
SAc
NO2
4
1.5
91
58
O
O
OMe SAc
NO2
5
6
0.5
1.5
98
93
56
53
OMe SAc
NO2
MeO
SAc
NO2
7
8
0.5
0.5
92
94
27
20
Cl
F
SAc
NO2
CF3 SAc
NO2
9
0.5
1
92
92
24
52
SAc
NO2
10
a See footnote a in Table 1 and the Supplementary data.
b Isolated yield after chromatographic purification.
c Determined by chiral HPLC analysis (Chiralpak AS-H).

2588
H. Li et al. / Tetrahedron Letters 47 (2006) 2585–2589
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moderate enantioselectivities (20–70% ee) were
obtained. It was observed that the phenyl rings having
electron-donating substituent groups provided Michael
adducts with higher enantioselectivities (Table 3, entries
1–6) than those possessing electron-withdrawing groups
(entries 7–9). The process was also applicable to ali-
phatic nitroolefin trans-Ph(CH2)2CH@CHNO2 in 92%
yield with 52% ee (entry 10).
In conclusion, we have identified bifunctional chiral
amine thiourea VI as an effective organocatalyst for pro-
moting the Michael addition reactions of thioacetic acid
to nitroolefins. The processes take place in excellent
yields (91–98%) with up to 70% ee under mild reaction
conditions. To our knowledge, this study represents
the first example of using a chiral organocatalyst for cata-
lyzing the 1,4-conjugate addition reactions of a less
reactive thioacid with b-nitrostyrenes. The resulting thio-
ester products can be readily transformed into more
synthetically useful thiols. Further efforts will be direc-
ted toward developing more efficient organocatalysts
to improve the enantioselectivities of the processes and
their applications in synthesis of biologically active mole-
cules will be explored.
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Acknowledgements
The financial support by the Department of Chemistry
and the Research Allocation Committee, University of
New Mexico is gratefully acknowledged. The Bruker
X8 X-ray diffractometer was purchased via an NSF
CRIF:MU award to the University of New Mexico,
CHE-0443580. The expert X-ray crystallographic mea-
surements made by Dr. Eileen N. Duesler are greatly
appreciated. We thank Professor Cary Morrow for his
comments about the manuscript.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.02.036.
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