Highly enantioselective Michael addition reactions of 3-substituted benzofuran-2(3H)-ones to chalcones catalyzed by a chiral alkyl-substituted thiourea

Article abstract of DOI:10.1002/adsc.201000106

A highly enantioselective Michael addition of 3-substituted benzofuran-2(3H)-ones to chalcones catalyzed by a chiral bifunctional thiourea was developed. Several chiral 3,3′-substituted benzofuran-2(3H)-ones derivatives, bearing adjacent quaternary-tertiary stereocenters, were efficiently synthesized with excellent enantioselectivities.

Full text of DOI:10.1002/adsc.201000106

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DOI: 10.1002/adsc.201000106
Highly Enantioselective Michael Addition Reactions of
3-Substituted Benzofuran-2(3H)-ones to Chalcones Catalyzed
by a Chiral Alkyl-Substituted Thiourea
Xin Li,a Zhiguo Xi,b Sanzhong Luo,a,* and Jin-Pei Chengb,*
a
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and
Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, Peopleꢀs Republic of China
Fax : (+86)-10-6255-4449; e-mail: luosz@iccas.ac.cn
Department of Chemistry and State-key Laboratory of Elementoorganic Chemistry, Nankai University, Tianjin 300071,
b
Peopleꢀs Republic of China
Received: February 9, 2010; Revised: March 29, 2010; Published online: April 26, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000106.
Abstract: A highly enantioselective Michael addi-
tion of 3-substituted benzofuran-2(3H)-ones to
chalcones catalyzed by a chiral bifunctional thiour-
ea was developed. Several chiral 3,3’-substituted
benzofuran-2(3H)-ones derivatives, bearing adja-
cent quaternary-tertiary stereocenters, were effi-
ciently synthesized with excellent enantioselectivi-
ties.
furan-2-ones would serve as potentially key chiral
transformations for the synthesis of these benzofura-
none-containing structures with all-carbon quaternary
centers at the 3-position (Scheme 1). Unfortunately,
this type of reaction, to the best of our knowledge,
has not been reported so far.
Keywords: benzofuran-2(3H)-ones; chiral thiour-
eas; Michael addition; organocatalysis; quaternary-
tertiary stereocenters
Asymmetric conjugate addition reactions with carbon
nucleophiles, which represent one of the most versa-
À
tile C C bond transformations, have been very suc-
cessful in creating molecular complexity with high ste-
reocontrol.[1] Despite many notable advances in this
area, an efficient and stereoselective conjugate addi-
tion reaction that generates adjacent quaternary-terti-
ary stereocenters still poses a formidable challenge in
asymmetric catalysis.[2] One such synthetic challenge
Scheme 1. Synthetic route to benzofuroACTHNUTRGNEUNG[2,3-b]pyran deriva-
tives.
Recently, we have developed a simple alkyl-substi-
is to stereoselectively construct benzofuran-2(3H)- tuted thiourea catalyst via electronic scanning and its
one-type lactones bearing a quaternary stereocenter potential has been successfully demonstrated in the
at the 3-position. This type of structural motif is synthesis of oxindole compounds with all-carbon qua-
widely distributed in a number of bioactive com- ternary centers.[9a,b] In our continuing efforts on the
pounds such as radulifolin,[3a] 3-hydroxycacalolide,[3b] construction of potentially bioactive compounds by
daphnodorins A–F,[4] macrophyllols A and B,[5] licoa- asymmetric catalysis,[9] we were delighted to find that
grodin[6] and erysenegalensein J.[7] Due to their bio- this alkyl-substituted thiourea catalyst is also a very
logical and medicinal activities and unique structural effective catalyst for the Michael addition reaction of
features, these natural products have been of interests 3-substituted benzofuran-2-ones to chalcones. Herein,
in total synthesis.[8] Retrosynthetically, asymmetric we report the first asymmetric Michael addition reac-
conjugate addition reactions of 3-substituted benzo- tions of 3-substituted benzofuran-2(3H)-ones.
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Xin Li et al.
Table 1. Screening of different thiourea catalysts.[a]
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The Michael addition reaction of 3-phenylbenzofur-
an-2(3H)-one 1a to chalcone 2a was selected as our
initial test reaction. Five widely used bifunctional ter-
tiary-amine thioureas/urea 4a–4e with different chiral
scaffolds[10,11] were screened in the model reaction at
208C in toluene. To our delight, all of the catalysts ex-
hibited high catalytic activities and the Michael addi-
tion products were isolated with very good yields
(Table 1, entries 1–5). Although the diastereoselectivi-
ties are generally low (1.3:1–1.1:1), the enantioselec-
tivities are acceptable with 56–92% ee for the major
diastereomers and 38–87% ee for the minor diastereo-
mers. Among the thiourea catalysts examined, the
alkyl-substituted thiourea 4a was found to give the
best enantioselectivity (93% yield, 1.2:1 dr and 92/
87% ee, Table 1, entry 1).
The reaction was next optimized by screening sol-
vent, temperature and additive in the presence of
10 mol% of 4a. It was found that the reaction in the
initially selected solvent toluene gave the best results
(Table 1, entries 1 and 6–11). The addition of 4 ꢂ mo-
lecular sieves to the reaction mixture slightly in-
creased both the yield and stereoselectivity (Table 1,
entry 12). Further improvement could be achieved by
lowering the reaction temperature (Table 1, entry 13).
Collectively, the best results with respect to yield and
enantioselectivity were obtained by performing the
reaction at À208C in toluene in the presence of 4 ꢂ
molecular sieves, affording 3a in 95% yield, 3:2 dr
and 97/94% ee (Table 1, entry 14). Although the dia-
stereoselectivity is rather poor under the conditions
and efforts for further improvements were in vain, it
is worthy of note that the diastereoisomers are easily
separated with excellent enantioselectivity, thus pro-
viding readily two structurally complex and valuable
chiral benzofuran-2(3H)-one-type products.
Under the optimized conditions, the substrate
scope was next explored (Table 2). The reactions
were shown to work well with a range of chalcones
bearing either electron-withdrawing or electron-do-
nating substituents (Table 2, entries 4–17). In all these
cases, the corresponding products were obtained in
high yields (80–99%), with moderate diastereoselec-
tivities (1:1–3:1) and excellent enantioselectivities
(78–98% ee for major diastereomers and 81–95% ee
for minor diastereomers). Two differently substituted
3-arylbenzofuran-2(3H)-ones were also investigated.
Similarly, the desired Michael products were obtained
with good yields and high enantioselectivities for both
diastereomers in spite of low diastereoselectivities
(Table 2, entries 2 and 3).
Entry cat Solvent Time
[h]
Yield[b]
[%]
dr[c] ee[d]
[%]
1
2
3
4
5
6
7
8
4a toluene
4b toluene
4c toluene
4d toluene
4e toluene
4a CH2Cl2
4a CHCl3
4a DCE
4
4
4
4
4
4
4
4
93
94
90
95
86
92
82
81
93
94
65
96
94
95
1.2:1 92/87
1.2:1 83/74
1.2:1 56/38
1.1:1 77/81
1.3:1 78/71
1.6:1 85/86
1.2:1 89/81
1.3:1 83/89
1.2:1 90/85
1.2:1 90/86
9
4a benzene 4
10
11
12
13
14
4a xylene
4a THF
4
4
4
1:1
85/89
4a[e] toluene
1.3:1 93/88
3:2 95/93
3:2 97/94
4a[f] toluene 36
4a[g] toluene 48
[a]
The reaction was carried out on a 0.1 mmol scale in
400 mL solvent at 208C, and the molar ratio of 1a/2a was
1/2.
[b]
[c]
[d]
[e]
[f]
Isolated yield.
Determined by H NMR.
Determined by chiral HPLC.
Reaction at 208C.
1
Reaction at À108C.
[g]
Reaction at À208C.
We obtained the X-ray crystal structures of prod-
ucts 3j and 3p’ (Figure 1),[12] which proved the absolu- studies was proposed to account for the observed ste-
tion configurations for 3 and 3’ as depicted in reoselectivities.[10,11] Accordingly, the formaiton of dia-
Figure 1. The absolute configurations of other prod- stereoisomers 3 and 3’ can be rationalized by consid-
ucts can therefore be determined by analogy. A bi- ering ternary transition states TS-I and TS-II, respec-
functional catalytic mode in accodance with previous tively. The less face-differentiation of enolate in TS-I
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Highly Enantioselective Michael Addition Reactions of 3-Substituted Benzofuran-2(3H)-ones
Table 2. Substrate scope.[a]
Entry
R1
R2
R3
R4
Reaction time [h]
Yield[b] [%]
dr[c] (3:3’)
ee[d] [%] (3/3’)
1
2
3
4
5
6
7
8
H
H
4-Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
48
36
36
84
72
72
48
60
60
60
54
48
48
48
72
48
48
3a (3a’): 95
3b (3b’): 92
3c (3c’): 91
3d (3d’): 80
3e (3e’): 89
3f (3f’): 85
3g (3g’): 93
3h (3h’): 98
3i (3i’): 92
3j (3j’): 91
3k (3k’): 91
3l (3l’): 94
3m (3m’): 99
3n (3n’): 91
3o (3o’): 80
3p (3p’): 95
3q (3q’): 96
3:2
2:1
3:2
1:1
3:2
3:2
1:1
3:2
1:1
1:1
2:1
2:1
2:1
3:2
2:1
3:1
2:1
97/94
97/90
98/96
97/93
94/92
97/95
98/92
98/91
89/84
78/83
96/92
96/81
97/94
97/86
97/94
97/94
98/91
4-CH3O
4-CH3
4-Ph
4-Cl
3-Cl
2-Cl
2-Br
H
H
H
H
H
9
H
H
10
11
12
13
14
15
16
17
4-F
4-Cl
3-Cl
4-Br
4-CF3
4-Br
3-Cl
3-Cl
3-Cl
[a]
The reaction was carried out on a 0.1 mmol scale with 40 mg 4 ꢂ molecular sieves in 400 mL toluene at À208C, and the
molar ratio of 3-arylbenzofuran-2(3H)-ones/chalcones was 1/2.
[b]
[c]
[d]
Isolated yield.
Determined by H NMR or based on isolated yields.
1
Determined by chiral HPLC.
Figure 1. X-ray crystal structures of 3j and 3p’.
and TS-II might be a reason for the low diastereo- methyl vinyl ketone, ethyl vinyl ketone and phenyl
A
vinyl ketone worked well to give the desired products
Some other electrophiles, such as activated terminal in high yields with unfortunately low enantioselectivi-
alkenes and nitrostyrene, were also attempted in this ty (5: 95% yield and 27% ee; 6: 82% yield and 7%
study (Scheme 3). The addition reactions of 3-phenyl- ee; 7: 78% yield and 0% ee).[13] In the reaction of 3-
benzofuran-2(3H)-one to vinyl ketones including phenylbenzofuran-2(3H)-one to phenyl vinyl sulfone,
Adv. Synth. Catal. 2010, 352, 1097 – 1101
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Xin Li et al.
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tion in asymmetric catalysis and synthesis are ongoing
in our laboratory.
Experimental Section
General Experimental Procedure for the Michael
Reaction
To
a
stirred solution of 3-arylbenzofuran-2(3H)-one
(0.1 mmol) and chalcone (2.0 equiv.) with 40 mg 4 ꢂ molec-
ular sieves in dry toluene (400 mL) was added the thiourea
catalyst (0.1 equiv.) at À208C. After the reaction was com-
plete, the reaction solution was concentrated under vacuum
and the crude material was purified by flash chromatogra-
phy to afford the desired product.
Acknowledgements
Scheme 2. Proposed transition states.
The project was supported by the Natural Science Foundation
(NSFC
20632060
and
NSFC
20902091),
MOST
Michael product 8 was obtained after 7 days with
80% yield and 35% ee at 08C in toluene. 2-Chloro-
ACHTUNGTRENNUNGacrylonitrile could also be applied to give Michael
adduct 9 bearing 1,3-non-adjacent stereocenters with
60% ee. In the case of nitrostyrene, although the reac-
tion was very fast, no stereoselectivity was observed
(Scheme 3, product 10).
(2008CB617501, 2009ZX09501-018) and the Chinese Acade-
my of Sciences. We also thank Dr. X. Hao and Dr. T. L.
Liang in ICCAS for X-ray analysis of the single crystals. X.
Li thanks China Postdoctoral Science Foundation for sup-
port.
In conclusion, we have developed a highly enantio-
selective Michael addition reaction of 3-arylbenzofur-
an-2(3H)-ones to chalcones by a simple alkyl-substi-
tuted bifunctional thiourea catalyst. The reactions
work with a broad range of chalcones, giving chiral
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