Organocatalytic enantioselective Michael addition of thioacetic acid to enones

Article abstract of DOI:10.1016/j.tetlet.2006.02.140

An enantioselective, organocatalytic Michael addition reaction of thioacetic acid with enones has been developed. The process, catalyzed by a chiral bifunctional amine thiourea, furnishes products in excellent yields with up to 63% ee.

Full text of DOI:10.1016/j.tetlet.2006.02.140

Tetrahedron Letters 47 (2006) 3145–3148
Organocatalytic enantioselective Michael addition
of thioacetic acid to enones
Hao Li, Liansuo Zu, Jian Wang and Wei Wang*
Department of Chemistry, University of New Mexico, Albuquerque, NM 87131-0001, USA
Received 6 February 2006; revised 18 February 2006; accepted 23 February 2006
Available online 10 March 2006
Abstract—An enantioselective, organocatalytic Michael addition reaction of thioacetic acid with enones has been developed. The
process, catalyzed by a chiral bifunctional amine thiourea, furnishes products in excellent yields with up to 63% ee.
Ó 2006 Elsevier Ltd. All rights reserved.
The preparation of sulfur-containing molecules has long
been a mainstay of organic synthesis as a result of their
broad application to organic and medicinal chemistry.1
Conjugate addition of sulfur-centered nucleophiles to
a,b-unsaturated carbonyls serves as a powerful synthetic
method in this area of sulfur chemistry.2–5 While an
asymmetric version of this Michael addition process
would furnish enantiomerically enriched adducts, to
date reports of this reaction are sparse.4,5 A great deal
of effort has been directed toward the use of strong
nucleophilic thiols as a Michael donor.4,5 However,
the employment of weakly nucleophilic thioacid
(RCOSH) for the Michael addition reaction has not
been explored. From a synthetic perspective, the result-
ing thioester can be readily transformed into versatile
SH group under various, mild reaction conditions.6
Along this line, recently, we have disclosed an organo-
catalytic enantioselective approach for the Michael
addition of thioacetic acid to b-nitrostyrenes in high
yields (91–98%) with up to 70% ee.7 In our continuing
effort in the area, we wish to describe the results of an
investigation which has led to the development of an
efficient method for carrying out enantioselective
Michael addition reactions of thioacetic acid with
a,b-unsaturated ketones by using a bifunctional amine
thiourea.
lyst I,11,12 chiral binaphthyl-derived amine thiourea
II,13 developed in our laboratory, a quinine-based thio-
urea III,14 and cinchona alkaloids quinine IV, quinidine
V, and quinine-OH VI.15 These catalysts can provide
two site activations of substrates (Fig. 1). Subsequently,
such synergistic activation by two functionalities on the
catalyst can lead to specific control of the transition
state structure, thus resulting in products with good
yields and high stereocontrol.16 To test their catalytic
ability to promote asymmetric Michael addition, a reac-
tion between trans-chalcone 1a and thioacetic acid 2 in
the presence of 10 mol % catalyst in Et2O at rt was
carried out. Examination of the results of the studies
reveals that the organocatalyzed processes proceeded
smoothly (3–4 h) in high yields (P90%), but the enantio-
selectivities varied significantly (Table 1). Among the
organocatalysts probed, catalyst I displayed the highest
enantioselectivity (58% ee, Table 1, entry 1). No or
lower ee was observed for other organocatalysts (entries
2–6). Utilization of thiobenzoic acid (2b) as a Michael
donor resulted in longer time (12 h), lower yield (41%)
and poorer 33% ee (Table 1, entry 7).
A survey of solvents revealed that the reaction media had
a significant effect on this process. For example, the reac-
tion carried out in Et2O and THF gave highest enantio-
selectivities (58%, 58%, respectively, Table 2, entries 1
and 3). Lower enantioselectivities were observed when
other solvents were used in the processes (Table 2, entries
4–9). By lowering the temperature to 0 °C for reaction in
Et2O, interestingly the enantioselectivity was decreased
to 44% ee (Table 2, entry 2). Thus, Et2O was selected
as the reaction medium for reactions to probe the scope
of the asymmetric processes at room temperature.
In the exploratory investigation, we surveyed six bifunc-
tional organocatalysts8–10 including Takemoto’s cata-
Keywords: Amine thiourea; Asymmetric organocatalysis; Enones;
Michael addition reaction; Thioacetic acid.
*
Corresponding author. Tel.: +1 505 277 0756; fax.: +1 505 277
2609; e-mail: wwang@unm.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.140

3146
H. Li et al. / Tetrahedron Letters 47 (2006) 3145–3148
Table 2. Effect of solvents on the asymmetric Michael addition
reactionsa
CF3
S
N
H
H
F3C
N
N
N
H
N
O
H
Catalyst I
(10 mol%)
AcS
Ph
O
S
N
+
CF3
AcSH
N
Ph
Ph
Ph
II
solvent, rt
I
CF3
1a
2a
3a
H
Entry
Solvent
t (h)
Yieldb (%)
eec (%)
CF3
H
H
N
N
1
2d
3
4
5
6
7
8
9
Et2O
Et2O
THF
Toluene
CH2Cl2
CHCl3
CH3CN
Dioxane
Benzene
3
8
4
4
4
4
4
4
4
95
93
93
90
92
92
91
92
90
58
44
58
27
43
47
35
38
24
H
N
H
H
H
S
OH
IV
H3CO
H3CO
CF3
III
N
N
H
H
N
N
H
H
HO
H
OH
H
a See footnote a in Table 1.
HO
H3CO
b Isolated yield after chromatographic purification.
c Determined by chiral HPLC analysis (Chiralpak AS-H).
V
VI
N
d The reaction was run at 0 °C.
N
O
Bifunctional
Ar
O
organocatalysts
*
RCOSH
+
Ar
R
RCOS
R
to heterocyclic systems (e.g., thiophene, entry 10) with
55% ee. When trans-4-phenyl-3-buten-2-one was used
as Michael acceptor, the reaction occurred in high yield
(93%) with lower ee (15%) (entry 11). Interestingly, no
ee was observed for enone containing aliphatic substitu-
ents at both ends (entry 12). In a controlled study, in the
absence of catalyst I, the reaction proceeded much slower
with lower yield (24 h, 75% yield) (Table 3, entry 3). This
indicates that the catalyst can facilitate the process. The
absolute configuration of 3g was determined by X-ray
crystallography to be R (Fig. 2).17
S
chiral
scaffold
N
H
N
H
O
HN
S
R
Ar
R
O
Figure 1. Organocatalysts for asymmetric Michael addition reactions.
To demonstrate the generality of direct Michael reac-
tions catalyzed by thiourea I, reactions of a variety of
enones 1 with thioacetic acid 2 in Et2O at rt were
explored (Table 3). All processes took place smoothly
to give products in excellent yields (>95%) with moderate
ee (33–65% ee, entries 1–2 and 4–10). Relatively low ee
values were observed for the chalcones containing elec-
tron-withdrawing groups (Table 3, entries 2 and 4–6).
However, the chalcones containing neutral or electron-
donating groups gave products with higher enantioselec-
tivities (entries 1 and 7–9). The reaction is also applicable
In conclusion, we have developed a catalytic variant of
the asymmetric Michael addition reactions between
chalcones and thioacetic acid. The reactions are cata-
lyzed by bifunctional amine thiourea I, affording syn-
thetically useful thioesters in excellent yields with
moderate enantioselectivities. The full scope and the fur-
ther improvement of enantioselectivity of the process
and its application in the synthesis of biologically active
molecules are under investigation.
Table 1. Asymmetric Michael addition of thioacid (2) to trans-chalcone (1a) catalyzed by organocatalystsa
Organocatalyst
(10 mol%)
O
RCOS
Ph
O
+
RCOSH
Ph
Ph
Ph
Et2O, rt
1a
2a: R = CH3
2b: R = Ph
3
Entry
Catalyst
R
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
I
Me
Me
Me
Me
Me
Me
Ph
3
4
4
4
4
95
90
91
92
91
92
41
58
0
26
12
0
II
III
Quinine IV
Quinidine V
Hydroquinine VI
4
12
8
33
I
a Unless otherwise specified, the reaction was carried out using 1a (0.1 mmol) and 2 (0.2 mmol) in the presence of 10 mol % catalyst in 0.5 mL of
solvent at room temperature.
b Isolated yields after chromatographic purification.
c Determined by chiral HPLC analysis (Chiralpak AS-H).

H. Li et al. / Tetrahedron Letters 47 (2006) 3145–3148
Table 3. Catalytic asymmetric Michael addition of thioacetic acid to chalconesa
3147
Catalyst I
(10 mol%)
O
SAc
O
AcSH
+
R1
R2
R1
R2
Et2O, rt
1
2a
3
Entry
1
Product
SAc O
t (h)
Yieldb (%)
95
eec (%)
3
58
3a
Cl
Cl
SAc O
2
3
97
75
51
0
3b
SAc O
3d
24
SAc O
4
5
3
3
100
97
33
37
3c
F
F
SAc O
3d
Cl
SAc O
6
7
8
3
3
3
96
97
97
48
50
53
3e
Cl
SAc O
3f
OMe
SAc O
3g
SAc O
3h
MeO
HO
9
24
3
95
97
65
55
SAc O
S
10
3i
S
SAc O
11
12
10
12
93
90
15
0
3j
SAc O
n-Bu
3k
a See footnote a in Table 1 and Supplementary data.
b Isolated yield after chromatographic purification.
c Determined by chiral HPLC analysis (Chiralpak AS-H).
d The reaction was run without catalyst I.

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H. Li et al. / Tetrahedron Letters 47 (2006) 3145–3148
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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.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.02.140.
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