Highly diastereo- and enantioselective Michael addition of 3-substituted benzofuran-2(3H)-ones to 4-oxo-enoates catalyzed by lanthanide(iii) complexes

Article abstract of DOI:10.1039/c4cc01499e

An efficient lanthanide(iii)-catalyzed diastereo- and enantioselective Michael addition of 3-substituted benzofuran-2(3H)-ones to 4-oxo-enoates was developed. The desired adducts with contiguous quaternary-tertiary stereocenters were obtained in up to 99%

Full text of DOI:10.1039/c4cc01499e

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Highly diastereo- and enantioselective Michael
addition of 3-substituted benzofuran-2(3H)-ones
to 4-oxo-enoates catalyzed by lanthanide(III)
complexes†
Cite this: Chem. Commun., 2014,
50, 4918
Received 27th February 2014,
Accepted 23rd March 2014
Zhen Wang, Qian Yao, Tengfei Kang, Juhua Feng, Xiaohua Liu, Lili Lin and
Xiaoming Feng*
DOI: 10.1039/c4cc01499e
www.rsc.org/chemcomm
An efficient lanthanide(III)-catalyzed diastereo- and enantioselective
Michael addition of 3-substituted benzofuran-2(3H)-ones to 4-oxo-
enoates was developed. The desired adducts with contiguous
quaternary–tertiary stereocenters were obtained in up to 99% yield
with up to 495/5 dr and 98% ee.
Chiral 3,3-disubstituted benzofuran-2(3H)-ones bearing a quaternary
stereogenic center at the C3 position are extremely important
building blocks1 in organic synthesis due to their biological
activities.2 For their construction,3 the Michael reactions of
3-substituted benzofuran-2(3H)-ones with various electrophiles
are very efficient methods.4 Since the pioneering work by Luo
et al. and Melchiorre in 2010,5 several such Michael reactions
have been realized using chiral thioureas or amines as organo-
catalysts.6 However, 4-oxo-enoates7 have not yet been investigated as
Michael acceptors in such reactions, which can afford optical
benzofuranones with contiguous quaternary–tertiary stereocenters.8
What’s more, searching for new efficient catalytic systems to
construct optical benzofuranone derivatives with both high
diastereo- and enantiomeric excesses5,6a are still desirable. Herein,
we present an efficient lanthanide(III)-catalyzed diastereo- and
enantioselective Michael addition reaction of 3-substituted
benzofuran-2(3H)-ones to 4-oxo-enoates. The corresponding benzo-
furanones featuring all-carbon or thioatom-substituted quaternary
stereocenters at the C3 position were obtained in high yields with
excellent diastereo- and enantiomeric excesses.
Fig. 1 Chiral ligands used in this study.
methyl group at the ortho position of the aniline, could achieve
higher diastereo- and enantioselectivities (Table 1, entry 2 vs.
entry 1). However, upon further increasing the steric hindrance
of the amide moiety led to poor results (Table 1, entry 2 vs.
Table 1 Optimization of the reaction conditionsa
Entry
Ligand
R4 (2)
Yieldb (%)
drc
83/17
89/11
90/10
eec (%)
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Me (2b)
Bn (2c)
iPr (2d)
tBu (2e)
tBu (2e)
tBu (2e)
93 (3a)
92 (3a)
94 (3a)
90 (3a)
90 (3a)
85 (3a)
98 (3a)
94 (3b)
96 (3c)
98 (3d)
97 (3e)
96 (3e)
97 (3e)
87
90
87
60
68
60
91
90
93
94
96
92
86
84/16
91/9
Initially, we examined various N,N0-dioxides9 (Fig. 1) complexed
with Sc(OTf)3 to catalyze the model reaction of 3-phenylbenzofuran-
2(3H)-one 1a with ethyl (E)-4-oxo-4-phenylbutenoate 2a in C2H5OH.
It was found that the substituent at the amide moiety of the N,N0-
dioxide ligands affected the selectivity of the reaction apparently
(Table 1, entries 1–4). Compared with ligand L1, ligand L2 having a
89/11
7d
8d
9d
10d
11d
12f
13g
88/12e
78/22e
86/14e
93/7e
495/5e
495/5e
495/5e
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China.
E-mail: xmfeng@scu.edu.cn; Fax: +86 28 85418249; Tel: +86 28 85418249
† Electronic supplementary information (ESI) available: Additional experimental
and spectroscopic data. CCDC 983289. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4cc01499e
a
Unless otherwise noted, reactions were carried out with 1a (0.1 mmol)
and 2a–e (0.11 mmol) in 1.0 mL EtOH with 5 mol% catalyst loading
b
(metal : ligand = 1 : 1.2) and 20 mg 4 Å MS in air at 10 1C for 3 h. Isolated
c
d
yield. Determined by HPLC. Reaction was performed at 0 1C for 5 h.
e
f
Determined by 1H NMR of the crude products. With 2 mol% catalyst
g
at 23 1C for 8 h. With 0.5 mol% catalyst at 23 1C for 12 h.
4918 | Chem. Commun., 2014, 50, 4918--4920
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entries 3 and 4). As for the chiral backbone moiety, L-pipecolic acid
derived ligand L2 was superior to both L-proline derived L5 and
L-ramipril acid derived L6 (Table 1, entry 2 vs. entries 5 and 6).
N,N0-Dioxide L7 derived from 2,4,6-trimethylaniline could give
higher yield (98%) with 88/12 dr and 91% ee (Table 1, entry 7).
Encouraged by the initial results, we next investigated the effect of
ester groups of 4-oxo-4-arylbutenoates. As presented in Table 1,
the more sterically hindered were the ester groups, the better
were the diastereo- and enantioselectivities (Table 1, entries 7–11).
To our delight, when (E)-tert-butyl 4-oxo-4-phenylbutenoate 2e was
employed, the product 3e was obtained in 97% yield, with 495/5 dr
and 96% ee (Table 1, entry 11). When the catalyst loading was
reduced to 2 or 0.5 mol%, the diastereoselectivity was maintained,
but the enantioselectivity was decreased (Table 1, entries 12 and 13).
Under the optimal reaction conditions (Table 1, entry 11), the
scope of the 4-oxo-enoates was examined. As summarized in
Table 2, regardless of the electronic properties or steric hindrance
of the substituents on the aromatic ring, the corresponding
products were obtained in excellent yields with high diastereo-
and enantiomeric excesses (Table 2, entries 1–9, 12–17). In
addition, heteroaromatic, aliphatic and fused ring substrates
were also well tolerated (Table 2, entries 10–11, 15–17). Further-
more, as 4-oxo-2,5-dienoate, the substrate 2v with a cinnamyl
group also gave good diastereo- and enantioselectivities
(Scheme 1). The absolute configuration of 3n was determined
by X-ray crystallography to be (2R,30R) (Table 2, entry 10).10
Then, the scope of benzofuran-2(3H)-ones was also examined.
As shown in Table 3, a wide spectrum of 3-aryl benzofuran-2(3H)-
ones bearing an electron-donating or an electron-withdrawing
Scheme 1 Michael reactions of 4-oxo-2,5-dienoate 2v.
Table 3 Substrate scope for benzofuran-2(3H)-onesa
a
b
Please see the ESI for details. Determined by 1H NMR of the crude
c
d
e
products. Isolated yield. Determined by HPLC. The reaction was
carried out on a 2.5 mmol scale with 2 mol% catalyst in 10.0 mL EtOH.
Table 2 Substrate scope for 4-oxo-enoatesa
substituted aryl group could achieve excellent diastereo- and
enantioselectivities (up to 495/5 dr, 98% ee). The benzyl substituted
benzofuran-2(3H)-one 1h also reacted well, generating the desired
product 3ad in high yield and with excellent diastereo- and enantio-
selectivities. Notably, by treatment of 2.5 mmol of starting material
with 2 mol% catalyst, the optically active benzofuran-2(3H)-one 3z
was still obtained with excellent results (1.12 g, 98% yield, 495/5 dr,
and 94% ee).
Entry R3
R4
Prod. drb
Yieldc (%) eed (%)
1
2
3
4
5
6
Ph
iPr
iPr
iPr
iPr
iPr
iPr
3d
3f
3g
3h
3i
93/7
93/7
92/8
94/6
93/7
98
98
97
98
98
98
96
94
92
96
96
97
96
97
96
93
98 f
96
89
95
97
97
97
97
2-FC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-ClC6H4
To further extend the application of this protocol,11 3-(phenylthio)-
benzofuran-2(3H)-one 1i was tested. However, only moderate results
(4a; 96% yield, 69/31 dr, and 51% ee) were obtained using the present
catalyst system, which is probably due to the interaction between
thioatom and the scandium catalyst. Pleasingly, excellent
results could be achieved (Table 4; up to 95% yield, 495/5 dr,
and 97% ee) by employing a complex of Y(OTf)3 with more
sterically hindered ligand L8 and acidic chloroform as a solvent
(see the ESI† for details). This is the first example of asymmetric
construction of chiral 3,3-disubstituted benzofuran-2(3H)-ones
bearing a thioatom-substituted quaternary stereocenter at the C3
position.
3j
3k
3l
94/6
495/5
89/11 98
7
8
3,4-Cl2C6H3 iPr
4-MeC6H4
4-MeOC6H4
2-Thienyl
2-Naphthyl
2-MeOC6H4
4-MeOC6H4
4-BrC6H4
2-Furyl
2-Naphthyl
Cyclohexyl
iPr
iPr
iPr
iPr
tBu 3p
tBu 3q
tBu 3r
tBu 3s
tBu 3t
tBu 3u
9e
10
11
12e
13e
14
15
16
17
3m
3n
3o
91/9
94/6
93/7
95
97
98
90/10 98
495/5
98
99
97
95
85
495/5
495/5
495/5
495/5
a
Unless otherwise noted, reactions were carried out with 1a (0.1 mmol) and
2 (0.11 mmol) in 1.0 mL EtOH with 5 mol% catalyst loading and 20 mg 4 Å
MS in air at 0 1C for 5–20 h (see the ESI for details). b Determined by
1H NMR of the crude products. c Isolated yield. d Determined by HPLC.
e Reaction was performed at 25 1C. f The absolute configuration was
determined to be (2R,30R) by X-ray crystallographic analysis.
Based on the absolute configuration of the product 3n and our
previous reports on N,N0-dioxide–lanthanide complexes,9 a possible
working model was proposed to explain the origin of the asymmetric
induction of the Sc(III)-complex-catalyzed reaction (Scheme 2).
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4 Substrate scope for Michael reactions of 3-(phenylthio)
¨
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R. Boese, Tetrahedron, 2002, 58, 279; (c) B. Sontag, M. Ru¨th,
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a
b
c
Please see the ESI for details. Isolated yield. Determined by
3 For a recent review, see: (a) Y. Li, X. Li and J.-P. Cheng, Adv. Synth.
Catal., DOI: 10.1002/adsc.201301038. For selected examples of other
strategies, such as asymmetric Black rearrangement, amination,
allylation etc., see: (b) I. D. Hills and G. C. Fu, Angew. Chem., Int.
Ed., 2003, 42, 3921; (c) S. A. Shaw, P. Aleman, J. Christy, J. W. Kampf,
P. Va and E. Vedejs, J. Am. Chem. Soc., 2006, 128, 925; (d) C.-L. Zhu,
F.-G. Zhang, W. Meng, J. Nie, D. Cahard and J.-A. Ma, Angew. Chem.,
Int. Ed., 2011, 50, 5869; (e) K. Ohmatsu, M. Ito, T. Kunieda and
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F. Xie and W. B. Zhang, Chem. Commun., 2014, 50, 1227.
1H NMR of the crude products. Determined by HPLC. Using L7-
Sc(OTf)3 as a catalyst in EtOH.
d
e
4 For books and recent reviews of Michael reaction, see:
(a) E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Comprehensive
Asymmetric Catalysis, Springer, New York, 1999; (b) M. P. Sibi and
S. Manyem, Tetrahedron, 2000, 56, 8033; (c) R. Ballini, G. Bosica,
D. Fiorini, A. Palmieri and M. Petrini, Chem. Rev., 2005, 105, 933.
5 (a) X. Li, Z. Xi, S. Luo and J.-P. Cheng, Adv. Synth. Catal., 2010,
352, 1097; (b) F. Pesciaioli, X. Tian, G. Bencivenni, G. Bartoli and
P. Melchiorre, Synlett, 2010, 1704.
Scheme 2 Proposed transition state model and the X-ray crystallo-
graphic structure of 3n.
In this transition state, the oxygens of N,N0-dioxides and amide
oxygens coordinated to Sc(III) in a tetradentate manner.
Benzofuran-2(3H)-one 1a coordinated to the Sc(III) via oxygen
to form the enolate 1a0. Meanwhile, 4-oxo-enoate was attached
to Sc(III) at the favorable equatorial position.12 As a result, the
Si face of benzofuranolate 1a0 preferred to attack the Si face of
4-oxo-enoate 2n to afford the desired Michael adduct 3n with a
(2R,30R)-configuration.
6 (a) X. Li, S. S. Hu, Z. G. Xi, L. Zhang, S. Luo and J.-P. Cheng, J. Org.
´
Chem., 2010, 75, 8697; (b) C. Cassani, X. Tian, E. C. Escudero-Adan
and P. Melchiorre, Chem. Commun., 2011, 47, 233; (c) X. Li, X. Xue,
C. Liu, B. Wang, B. Tan, J. L. Jin, Y. Y. Zhang, N. Dong and
J.-P. Cheng, Org. Biomol. Chem., 2012, 10, 413; (d) X. Li, Y. Y.
Zhang, X. Xue, J. L. Jin, B. Tan, C. Liu, N. Dong and J.-P. Cheng,
Eur. J. Org. Chem., 2012, 1774; (e) J. H. Chen, Y. P. Cai and G. Zhao,
Adv. Synth. Catal., 2014, 356, 359.
In summary, we have developed a highly diastereo- and
enantioselective Michael reaction of 3-substituted benzofuran-
2(3H)-ones with 4-oxo-enoates promoted by 0.5–5 mol% N,N0-
dioxide–lanthanide complexes. The protocol not only delivers a
wide variety of enantiopure 3,3-disubstituted benzofuran-2(3H)-
ones with excellent diastereo- and enantioselectivities (up to
495/5 dr, 98% ee), but also successfully constructs optical
benzofuran-2(3H)-ones bearing thioatom-substituted quatern-
ary stereocenters for the first time. Further application of the
current method is currently underway.
7 For selected examples, see: (a) Z. Jiang, Y. Yang, Y. Pan, Y. Zhao,
H. Liu and C.-H. Tan, Chem. – Eur. J., 2009, 15, 4925; (b) H. Lu,
X. Wang, C. Yao, J. Zhang, H. Wu and W.-J. Xiao, Chem. Commun.,
2009, 4251; (c) Z. Wang, D. H. Chen, Z. G. Yang, S. Bai, X. H. Liu,
L. L. Lin and X. M. Feng, Chem. – Eur. J., 2010, 16, 10130.
8 For selected reviews, see: (a) J. Christoffers and A. Baro, Adv. Synth.
´
Catal., 2005, 347, 1473; (b) D. J. Ramon and M. Yus, Curr. Org.
Chem., 2004, 8, 149; (c) J. Christoffers and A. Baro, Angew. Chem., Int.
Ed., 2003, 42, 1688.
9 For our own work in this field, see: (a) X. H. Liu, L. L. Lin and
X. M. Feng, Acc. Chem. Res., 2011, 44, 574; (b) L. Zhou, X. H. Liu, J. Ji,
Y. H. Zhang, X. L. Hu, L. L. Lin and X. M. Feng, J. Am. Chem. Soc.,
2012, 134, 17023; (c) K. Shen, X. H. Liu, G. Wang, L. L. Lin and
X. M. Feng, Angew. Chem., Int. Ed., 2011, 50, 4684; (d) Y. F. Cai,
X. H. Liu, Y. H. Hui, J. Jiang, W. T. Wang, W. L. Chen, L. L. Lin and
X. M. Feng, Angew. Chem., Int. Ed., 2010, 49, 6160.
We appreciate the National Natural Science Foundation of China
(Nos. 21321061 and 21290182), and the Basic Research Program of
China (973 Program: 2011CB808600) for financial support.
10 CCDC 983289 (3n).
11 The current catalytic system was not efficient for the reaction with
chalcone. Only 9% yield, 86/14 dr, 69% ee was obtained when 1b
reacted with chalcone (see the ESI† for details).
Notes and references
1 For selected examples of nature products: (a) N. Lindquist, 12 T. C. Wabnitz, J.-Q. Yu and J. B. Spencer, Chem. – Eur. J., 2004,
W. Fenical, G. D. Van Duyne and J. Clardy, J. Am. Chem. Soc., 10, 484.
4920 | Chem. Commun., 2014, 50, 4918--4920
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