Chiral amine thiourea-promoted enantioselective michael addition reactions of 3-substituted benzofuran-2(3 H)-ones to maleimides

Article abstract of DOI:10.1021/jo101832e

A highly diastereo- and enantioselective Michael addition reaction with respect to prochiral 3-substituted benzofuran-2(3H)-ones and maleimides by a chiral bifunctional thiourea-tertiary amine catalyst was investigated. The corresponding adducts, containi

Full text of DOI:10.1021/jo101832e

pubs.acs.org/joc
quaternary-tertiary stereocenters is still one of the most
Chiral Amine Thiourea-Promoted Enantioselective
Michael Addition Reactions of 3-Substituted
Benzofuran-2(3H)-ones to Maleimides
difficult challenges in asymmetric catalysis,2 in which the
whole catalysis is a tandem conjugate addition-protonation
process with simultaneous control of two stereocenters.
Over the past 10 years, significant efforts have been directed
toward to the development of asymmetrically synthetic method-
ology for this challenging area.3,4 In a particularly valuable
context, conjugate addition of 3-substituted oxindoles to ap-
propriate electrophiles promoted by organocatalysts provides
a very straightforward approach to access oxindole-type deriv-
atives bearing two adjacent quaternary-tertiary stereocenters,4
whose structural motifs are ubiquitous in a wide range of
biologically and pharmaceutically active natural alkaloids.5
However, the 3-substituted benzofuran-2(3H)-ones, whose
structures are very similar to the 3-substituted oxindoles, have
been rarely considered as nuclephiles in asymmetric catalysis. It
should be pointed out that the conjugate addition products
by such a process use 3-substituted benzofuran-2(3H)-ones
as nucleophiles, which have quarternary chiral centers at
the C3-position of benzofuran-2(3H)-ones, would serve as
key structural motifs that are ubiquitous in a number of
biologically active heterocyclic compounds (Figure 1), such
as radulifolin,6 3-hydroxycacalolide,7 daphnodorins A-F,8
Xin Li,*,† Shenshen Hu,‡ Zhiguo Xi,† Long Zhang,‡
Sanzhong Luo,*,‡ and Jin-Pei Cheng*,†
†Department of Chemistry and State Key Laboratory of
Elemento-organic Chemistry, Nankai University,
Tianjin 300071, China, and ‡Beijing National Laboratory for
Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, China
xin_li@nankai.edu.cn; luosz@iccas.ac.cn; chengjp@most.cn
Received September 22, 2010
(2) For adjacent quaternary-tertiary stereocenters, see: (a) Bella, M.;
Gasperi, T. Synthesis 2009, 1583. (b) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu,
X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105.
(c) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5363. (d) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204.
(3) For selected examples of related stereoselective construction of vicinal
quaternary-tertiary carbon centers, see: (a) Trost, B. M.; Zhang, Y.
A highly diastereo- and enantioselective Michael addition
reaction with respect to prochiral 3-substituted benzofuran-
2(3H)-ones and maleimides by a chiral bifunctional
thiourea-tertiary amine catalyst was investigated. The
corresponding adducts, containing a quaternary center at
the C3-position of the benzofuran-2(3H)-one as well as a
vicinal tertiary center, were generally obtained in high
yields (up to 99%) with very good diastereo- (up to >20:1 dr)
and enantioselectivities (up to 97% ee).
Chem. Eur. J. 2010, 16, 296. (b) Wu, F.; Hong, R.; Khan, J.; Liu, X.;
;
Deng, L. Angew. Chem., Int. Ed. 2006, 45, 4301. (c) Wu, F.; Li, H.; Hong, R.;
Deng, L. Angew. Chem., Int. Ed. 2006, 45, 947. (d) Lalonde, M. P.; Chen, Y.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366. (e) Poulsen, T. B.;
Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2005, 44, 2896. (f) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.;
MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482.
(4) (a)Zhou,F.;Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381. For
selected examples of catalytic asymmetric synthesis of oxindoles with quaternary
carbon stereocenters, see: (b) Ding, M.; Zhou, F.; Qian, Z. -Q.; Zhou, J. Org.
Biomol. Chem. 2010, 8, 2912. (c) Kato, Y.; Furutachi, M.; Chen, Z.; Mitsunuma,
H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9168. (d) He,
R. J.; Shirakawa, S.; Maruoka, K. J. Am. Chem. Soc. 2009, 131, 16620. (e) Bui,
T.; Syed, S.; Barbas, C. F., III. J. Am. Chem. Soc. 2009, 131, 8758. (f) Galzerano,
P.; Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.;
Bartoli, G.; Melchiorre, P. Chem. Eur. J. 2009, 15, 7846. (g) Cheng, L.; Liu,
;
L.; Jia, H.; Wang, D.; Chen, Y. -J. J. Org. Chem. 2009, 74, 4650.
(5) For reviews, see: (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003,
103, 2945. (b) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36.
(c) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748.
Other selected examples: (d) Zhang, X.; Smith, C. D. Mol. Pharmacol. 1996,
49, 228. (e) Malinakova, H. C.; Liebeskind, L. S. Org. Lett. 2000, 2, 4083.
(f) Wearing, X. Z.; Cook, J. M. Org. Lett. 2002, 4, 4237. (g) Albrecht, B. K.;
Williams, R. M. Org. Lett. 2003, 5, 197. (h) Abadi, A. H.; Abou-Seri, S. M.;
Abdel-Rahman, D. E.; Klein, C.; Lozach, O.; Meijer, L. Eur. J. Med. Chem.
2006, 41, 296. (i) Reisman, S. E.; Ready, J. M.; Weiss, M. M.; Hasuoka, A.;
Hirata, M.; Tamaki, K.; Ovaska, T. V.; Smith, C. J.; Wood, J. L. J. Am.
Chem. Soc. 2008, 130, 2087.
Asymmetric conjugate addition reactions with carbon
nucleophiles, which is one of the most powerful and versatile
processes for the formation of C-C bonds in organic synthe-
sis, have been successfully used in creating molecular com-
plexity with high stereocontrol.1 As a result, a wide variety of
compounds that can serve as electrophiles and nucleophiles
and, consequently, a diverse array of products can be gener-
ated with versatile structures by rational design. Despite
many notable advances in this arena, an efficient and stereo-
selective conjugate addition reaction that generates adjacent
(6) Ramı0rez, M. L. G.; Trejo, A.; Navarro, V.; Bye, R.; Linares, E.;
Delgado, G. J. Nat. Prod. 2001, 64, 432.
(7) Inman, W. D.; Luo, J.; Jolad, S. D.; King, S. R.; Cooper, R. J. Nat.
Prod. 1999, 62, 1088.
(1) For recent reviews of organocatalyzed conjugate addition reactions,
see: (a) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178.
(b) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.;
Feringa, B. L. Chem. Rev. 2008, 108, 2824. (c) Alexakis, A.; Backvall,
J. E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008, 108, 2796.
(d) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (e) Almasi, D.; Alonso,
D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299. (f) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
(8) (a) Baba, K.; Takeuchi, K.; Doi, M.; Inoue, M.; Kozawa, M. Chem.
Pharm. Bull 1986, 34, 1540. (b) Baba, K.; Takeuchi, K.; Doi, M.; Kozawa, M.
Tennen Yuki Kagobutsu Toronkai Koen Yoshihu 1987, 29, 668. (c) Takai, S.;
Sakaguchi, M.; Jin, D.; Baba, K.; Miyazaki, M. Life Sciences 1999, 64, 1889.
(d) Sakuma, S.; Fujimoto, Y.; Tsunomon, M.; Tagano, S.; Nishida, H.;
Baba, K.; Fujita, T. Prostaglandins, Leukotrienes Essent. Fatty Acids 1998,
58, 143.
DOI: 10.1021/jo101832e
r
Published on Web 11/24/2010
J. Org. Chem. 2010, 75, 8697–8700 8697
2010 American Chemical Society

Li et al.
JOCNote
TABLE 1. Optimization of Reaction Conditionsa
FIGURE 1. Benzofuran-2(3H)-one-type natural products with
quarternary chiral centers at the C3-positions.
entry
cat.
solvent
time (h)
yieldb (%)
drc
ndf
1.5:1
3:1
7:1
5:1
5:1
5:1
9:1
eed (%)
ndf
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4a
4b
4c
4d
4e
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CHCl3
DCE
benzene
xylene
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24
2
2
2
2
2
2
2
2
2
2
2
2
nre
75
90
99
92
99
85
99
98
95
96
95
90
97
96
93
98
macrophyllols A and B,9 licoagrodin,10 erysenegalensein J,11
and hopeahainol A.12 In this context, organocatalysis for the
synthesis of chiral 3,3-disubstituted benzofuran-2(3H)-ones
has been scarcely studied.13,14 Discovering electrophiles to
react with prochiral 3-substituted benzofuran-2(3H)-ones
for the synthesis of diversely structured 3,3-disubstituted
benzofuran-2(3H)-ones should be a direct and valuable
strategy and is strongly desired.
Very recently, we reported the first asymmetric Michael
addition reaction of 3-substituted benzofuran-2(3H)-ones,
in which a chiral bifunctional thiourea-catalyzed addition
of 3-substituted benzofuran-2(3H)-ones with chalcones was
conducted.13 Owing to the synthetic importance of chiral 3,3-
disubstituted benzofuran-2(3H)-ones derivatives, and based on
our continuing interest in the construction of potentially
bioactive compounds by asymmetric catalysis,15 herein we
disclose an asymmetric conjugate addition of 3-substituted
benzofuran-2(3H)-ones and maleimides16 promoted by a bi-
functional tertiary-amine thiourea catalyst to give a new range
of 3,30-disubstituted benzofuran-2(3H)-one derivatives bear-
ing vicinal quaternary-tertiary carbon centers in high yields
and with very good diastereo- and enantioselectivities.
We initiated our study by investigating the Michael addi-
tion reaction of benzofuran-2(3H)-one 1a to maleimide 2a
71
81
78
66
-67
83
72
80
78
82
64
87
90
94
96
4f
4g
4d
4d
4d
4d
4d
4d
4dg
4dh
4di
4dj
4:1
6:1
7:1
8:1
4:1
8
15:1
19:1
>20:1
>20:1
24
48
48
aThe reaction was carried out on a 0.1 mmol scale in 400 μL of solvent
at 25 °C, and the molar ratio of 1a/2a is 1/2. bIsolated yield. cDetermined
1
d
e
f
by H NMR. Determined by chiral HPLC. No reaction. Not deter-
mined. gThe reaction was carried out under the general conditions at
-20 °C. hThe reaction was carried out under the general conditions at
i
-40 °C. The reaction was carried out under the general conditions at
-80 °C. jThe reaction was carried out under the general conditions with
4 A molecular sieves at -80 °C.
(Table 1). A brief survey of the single hydrogen-bonding cata-
lyst failed, providing none of the desired addition product
when used with a catalytic amount of thiourea 4a17 (Table 1,
entry 1). We postulated that bifunctional tertiary-amine
hydrogen-bonding compounds would serve as mild catalysts
for the activation of both the benzofuran-2(3H)-one and
maleimide, thereby promoting the reaction. Indeed, the use
of 4b18 provided the desired addition product 3a in 75% yield
in toluene after 2 h reaction time (Table 1, entry 2).
(9) Su, B. -N.; Takaishi, Y.; Tori, M.; Takaoka, S.; Honda, G.; Itoh, M.;
Takeda, Y.; Kodzhimatov, O. K.; Ashurmetov, O. Org. Lett. 2000, 2, 493.
(10) Li, W.; Asada, Y.; Yoshikawa, T. Phytochemistry 2000, 55, 447.
(11) Wandji, J. S.; Awanchiri, S.; Fomum, Z. T.; Tillequin, F.; Daniwicz,
S. M. Phytochemistry 1995, 38, 1309.
(12) For the isolation of hopeahainol A, see: (a) Ge, H. M.; Zhu, C. H.;
Shi, D. H.; Zhang, L. D.; Xie, D. Q.; Yang, J.; Ng, S. W.; Tan, R. X. Chem.
;
Encouraged by these preliminary results, we explored the
use of available chiral bifunctional hydrogen-bonding cata-
lysts. Five widely used bifunctional tertiary-amine thioureas
or urea catalysts 4c-g19,20 (Figure 2) with different scaffolds
were screened in the model reaction at 25 °C. To our delight,
most of the catalysts exhibited high catalytic activities, and
the Michael products were isolated with good to excellent
Eur. J. 2008, 14, 376. (b) Pe0rez-Fons, L.; Garzo0 n, M. T.; Micol, V. J. Agric.
Food Chem. 2010, 58, 161. (c) Pertino, M. W.; Theoduloz, C.; Rodrı0guez,
J. A.; Lazo, V. J. Nat. Prod. 2010, 73, 639. For the synthesis and biological
evaluation of hopeahainol A, see: (d) Nicolaou, K. C.; Wu, T. R.; Kang, Q.;
Chen, D. Y. -K. Angew. Chem., Int. Ed. 2009, 48, 3440. (e) Nicolaou, K. C.;
Kang, Q.; Wu, T. R.; Lim, C. S.; Chen, D. Y.-K. J. Am. Chem. Soc. 2010, 132,
7540.
(13) Li, X.; Xi, Z.; Luo, S.; Cheng, J.-P. Adv. Synth. Catal. 2010, 352,
1097.
(14) Cassani, C.; Tian, X.; Escudero-Adan, E. C.; Melchiorre, P. Chem.
Commun. 2010, DOI: 10.1039/c0cc01957g.
(15) (a) Li, X.; Deng, H.; Zhang, B.; Li, J.; Zhang, L.; Luo, S.; Cheng,
(17) Li, X.; Deng, H.; Luo, S.; Cheng, J.-P. Eur. J. Org. Chem. 2008, 4350.
(18) Buck, J.; Ide, W.; Baltzly., R. J. Am. Chem. Soc. 1942, 64, 2233.
(19) For recent reviews of thiourea and urea catalysis, see: (a) Schreiner,
P. R. Chem. Soc. Rev. 2003, 32, 289. (b) Akiyama, T.; Itoh, J.; Fuchibe, K.
J.-P. Chem. Eur. J. 2010, 16, 450. (b) Li, X.; Zhang, B.; Xi, Z.; Luo, S.;
;
Cheng, J.-P. Adv. Synth. Catal. 2010, 352, 416. (c) Li, X.; Xi, Z.; Luo, S.;
Cheng, J.-P. Org. Biomol. Chem. 2010, 8, 77 and ref 13.
Adv. Synth. Catal. 2006, 348, 999. (c) Connon, S. J. Chem. Eur. J. 2006, 12,
;
(16) For recent study of maleimides as electrophiles in asymmetric
catalysis, see: (a) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Cun, L.-F.; Zhang,
X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 2896. (b) Yu, F.; Sun, X.; Jin, Z.;
Wen, S.; Liang, X.; Ye, J. Chem. Commun. 2010, 46, 4589. (c) Xue, F.; Liu, L.;
5418. (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
(e) Takemoto, Y.; Miyabe, H. Chimia 2007, 61, 269. (f) Yu, W.; Wang, W.
Chem. Asian. J. 2008, 3, 516. (g) Miyabe, H.; Takemoto, Y. Bull. Chem. Soc.
Jpn. 2008, 81, 785. (h) Connon, S. J. Synlett 2009, 354 and references cited
therein. For the seminal paper, see: (i) Sigman, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 1998, 120, 4901.
Zhang, S.; Duan, W.; Wang, W. Chem. Eur. J. 2010, 16, 7979. (d) Alba,
;
A.-N. R.; Valero, G.; Calbet, T.; Bardia, M. F.; Moyano, A.; Rios, R. Chem.
;
Eur. J. 2010, 16, 9884. (e) Jiang, Z.; Pan, Y.; Zhao, Y.; Ma, T.; Lee, R.; Yang, Y.;
Huang, K.-W.; Wong, M. W.; Tan, C.-H. Angew.Chem., Int. Ed. 2009, 48, 3627.
(f) Jiang, Z.; Ye, W.; Yang, Y.; Tan, C. -H. Adv. Synth. Catal. 2008, 350, 2345.
(g) Ye, W.; Jiang, Z.; Zhao, Y.; Goh, S. L. M.; Leow, D.; Soh, Y.-T.; Tan, C.-H.
Adv. Synth. Catal. 2007, 349, 2454. (h) Zu, L.; Xie, H.; Li, H.; Wang, J.; Jiang,
W.; Wang, W. Adv. Synth. Catal. 2007, 349, 1882. (i) Bartoli, G.; Bosco, M.;
Carlone, A.; Cavalli, A.; Locatelli, M.; Mazzanti, A.; Ricci, P.; Sambri, L.;
Melchiorre, P. Angew. Chem., Int. Ed. 2006, 45, 4966.
(20) For a leading example of catalyst 4c, see ref 15a,15b. For a leading
example of catalyst 4d, see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am.
Chem. Soc. 2003, 125, 12672. For a leading example of catalyst 4e, see:
(b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.-N.; Takemoto, Y. J. Am. Chem.
Soc. 2005, 127, 119. For a leading example of catalyst 4f, see: (c) Vakulya, B.;
ꢀ
ꢀ
Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967. For a leading example
of catalyst 4g, see: (d) Liu, T.-Y.; Long, J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.; Ding,
L.-S.; Chen, Y.-C. Org. Biomol. Chem. 2006, 4, 2097.
8698 J. Org. Chem. Vol. 75, No. 24, 2010

Li et al.
JOCNote
SCHEME 1. Results of Michael Addition Reactions of Five
Different Substituted Benzofuran-2(3H)-ones and Maleimide 2a
FIGURE 2. Bifunctional tertiary amine thioureas and urea catalysts.
TABLE 2. Substrate Scopea
SCHEME 2. Results of Michael Addition Reactions of
3-Methyl-Substituted Benzofuran-2(3H)-one with 2a and 1a
with 2-Cyclopenten-1-one
entry
substrate: R =
time (h) yieldb (%)
drc
eed(%)
1
2
3
4
5
6
7
8
2a: Ph
24
48
48
48
48
24
24
24
24
24
48
48
48
48
3a: 98
3b: 91
3c: 95
3d: 96
3e: 93
3f: 98
3g: 99
3h: 99
3i: 98
3j: 94
3k: 88
3l: 92
3m: 97
3n: 95
>20:1
16:1
96
93
95
92
93
94
94
92
95
91
74
91
97
95
2b: 4-MeOPh
2c: 4-MePh
2d: 4-t-BuPh
2e: 4-FPh
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
15:1
6:1
7:1
15:1
16:1
2f: 4-ClPh
or electron-donating substituents (Table 2, entries 1-11). In
most cases, the corresponding products were obtained in
high yields (91-99%), with moderate to very good diastereo-
selectivities (15:1 f 20:1dr) and very good enantioselectiv-
ities (91-96% ee). However, the yield and stereoselectivity
of the reaction are sensitive to the substitution position of the
aryl group. Lower reactivity and selectivity were obtained
when N-2,4,6-triMePh-substituted maleimide 2k was selected
as the Michael acceptor (Table 2, entry 11). As a result, the
corresponding conjugate addition product 3k was obtained
in 88% yield with 6:1 dr and 74% ee.
2g: 3-ClPh
2h: 4-BrPh
2i: 3-BrPh
2j: 3-Cl(4-Me)Ph
2k: 2,4,6-triMePh
2l: Bn
9
10
11e
12e
13e
14e
2m: cyclohexyl
2n: octanyl
aThe reaction was carried out on a 0.1 mmol scale in 400 μL of CH2Cl2
with 4 A molecular sieves at -80 °C, and the molar ratio of 1a/2 is 1/2.
bIsolated yield. cDetermined by 1H NMR. dDetermined by chiral HPLC.
eThe reaction was carried out on the optimized conditions at -40 °C.
Furthermore, three N-alkyl-substituted maleimides were
also examined as electrophiles in the current Michael addition
strategy (Table 2, entries 12-14). We found that the N-alkyl-
substituted maleimides 2l-n proved to be less reactive and
required a higher reaction temperature. After further optimi-
zation, -40 °C was used to desired the reaction rate. How-
ever, the stereoselectivities were still satisfied, in which the
desired conjugate products 3l-n were obtained with 92-97%
yield, 7:1-16:1 dr, and 91-97% ee (Table 2, entries 12-14).
We also explored the influence of Michael donor. A number
of benzofuran-2(3H)-ones, which have different substitution
patterns and positions, were reacted with maleimide 2a under
the optimized conditions, and the results are shown in
Scheme 1. To our delight, the desired Michael products 3o-s
were similarly obtained with high yields (94-98%), moderate
to very good diastereoselectivities (8:1f20:1 dr), and very
good enantioselectivities (93-97% ee).
To further expand the substrate scope, reactions of 3-methyl
benzofuran-2(3H)-one as nuclephile to react with 2a and 2-
cyclopenten-1-one as electrophile to react with 1a were also
attempted in this study (Scheme 2). To our delight, both reac-
tions proceeded smoothly and provided the desired products
in good yields with good selectivities (90% yield, >20:1 dr
and 73% ee for 3t; 87% yield, 6:1 dr and 83% ee for 3u).
yields (85-99%) and moderate stereoselectivities (3:1-7:1 dr
and 66-81% ee, Table 1, entries 2-6). Among the five bifunc-
tional hydrogen-bonding catalysts examined, Takemoto
catalyst 4d was found to give the optimal stereoselectivity
(Table 1, entry 4, 99% yield, 7:1 dr and 81% ee).
The reaction was then optimized by screening solvent,
temperature, and additive in the presence of 10 mol % of 4d.
As illustrated in Table 1, dichloromethane (CH2Cl2) gave the
best result among a range of screened solvents (Table 1,
entries 4 and 8-13). Further improvement could be achieved
by lowering the reaction temperature (Table 1, entries 14-16).
Addition of 4 A molecular sieves to the reaction mixture
slightly increased both the diastereoselectivity and enantio-
selectivity (Table 1, entry 17). Collectively, the best results
with respect to yield and stereoselectivity were obtained by
performing the reaction at -80 °C in CH2Cl2 in the presence
of 4 A molecular sieves. Under these conditions, the reaction
provided the desired product with 98% yield in >20:1 dr and
96% ee (Table 1, entry 17).
With these conditions decided, we then turned our attention
toward the scope of the reaction as summarized in Table 2.
The reactions were shown to work well with a number of N-aryl-
substituted maleimides bearing either electron-withdrawing
J. Org. Chem. Vol. 75, No. 24, 2010 8699

Li et al.
JOCNote
tertiary-amine thiourea organocatalyst. The reaction scope
is substantial, and a number of aryl- or alkylmaleimides and
3-substituted benzofuran-2(3H)-ones could be successfully
applied to give multifunctional chiral benzofuran-2(3H)-
ones compounds bearing an adjacent all carbon-substituted
quaternary stereocenter and a tertiary stereocenter with very
good enantioselectivities. Our current work is actively under-
way to utilize versatile benzofuran-2(3H)-ones as nucleo-
philes with chiral organocatalysts for asymmetric catalysis.
FIGURE 3. Proposed transition state.
Experimental Section
SCHEME 3. Reaction Carried out on a Large Scale
General Experimental Michael Reaction Procedure. To a
stirred solution of 3-phenylbenzofuran-2(3H)-one (0.1 mmol)
and maleimide (2.0 equiv) with 40 mg of 4 A molecular sieves
in 400 μL of dry CH2Cl2 was added amine thiourea catalyst
(0.1 equiv) at -80 °C After the reaction was completed, the reac-
tion solution was concentrated in vacuo and the crude was puri-
fied by flash chromatography to afford the product.
Compound 3a. The Michael product was synthesized accord-
ing to the general procedure as a white solid in 98% overall yield:
[R]25D -103.5 (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.45-7.16 (14H, m), 4.32-4.27 (1H, m), 3.06-2.97 (1H, m),
2.50-2.42 (1H, m); 13C NMR (CDCl3, 75 MHz) δ 175.8, 174.1,
173.3, 153.5, 135.8, 131.4, 130.6, 129.2, 129.1, 128.8, 128.5, 127.0,
126.3, 125.4, 125.1, 111.7, 56.2, 46.3, 32.2 ppm; IR (KBr) ν 1716,
1620, 1597, 1499, 1186, 696 cm-1; HRMS (EIþ) calcd for
C24H17NO4 383.1158, found 383.1161. The enantiomeric excess
was determined by HPLC with an AD-H column at 210 nm
(2-propanol/hexane=3:7), 1.0 mL/min; tR=15.2 min (major),
22.8 min (minor).
We obtained the X-ray crystal structure of product 3h
(Figure S1, Supporting Information),21 which proved the
absolute configuration for 3h. The absolute configurations
of other products can therefore be determined by analogy.
A bifunctional catalytic mode in accordance with previous
studies was proposed to account for the observed stereo-
selectivities (Figure 3).
To investigate the synthetic potential of current Michael
strategy, 3-phenylbenzofuran-2(3H)-one 1a (5 mmol, 1.05 g)
and maleimide 2a (10 mmol, 1.73 g) were reacted under the
optimal conditions, and the corresponding product was
obtained without any loss of yield (1.89 g, 99% yield) or
selectivity (>20:1 dr and 96% ee, Scheme 3).
Acknowledgment. This work was supported by the Natural
Science Foundation (Grant Nos. 20721062, 20702052, and
20902091) and MOST (2009ZX09501-018 and 2010CB833301).
X.L. thanks the China Postdoctoral Science Foundation
for support and the reviewers for helpful suggestions on this
work.
In summary, we have presented a highly diastereoselective
and enantioselective Michael addition reaction of 3-substituted
benzofuran-2(3H)-ones to maleimides by simple bifunctional
(21) CCDC 787619 contains the supplementary crystallographic data for
compound 3h. This data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www. ccdc.cam.ac.uk/data_request/cif.
For details of the crystallographic data of 3h, see Table S1 in the Supporting
Information.
Supporting Information Available: Experimental details,
analytical data for all new compounds, and X-ray crystallography
of 3h. This material is available free of charge via the Internet at
http://pubs.acs.org.
8700 J. Org. Chem. Vol. 75, No. 24, 2010