Organocatalytic stereoselective conjugate addition of 3-substituted oxindoles with in situ generated ortho-quinone methides

Article abstract of DOI:10.1016/j.tetlet.2018.03.069

A novel method for the stereoselective conjugate addition of 3-substituted oxindoles to in situ generated o-QMs was described. This process was catalyzed efficiently by a cinchonidine-derived squaramide catalyst in oil-water phase, furnishing the corresponding 3,3-disubsituted oxindole derivatives in moderate to high yields (up to 98%) with high stereoselectivities (up to 95% ee, 15.4:1 dr). The utility of this reaction was also investigated by the gram-scale synthesis and derivatization of one of the products.

Full text of DOI:10.1016/j.tetlet.2018.03.069

Accepted Manuscript
Organocatalytic Stereoselective Conjugate Addition of 3-Substituted Oxindoles
with In Situ Generated ortho-Quinone Methides
Weihong Liang, Wenhao Yin, Tingzhong Wang, Fayang G. Qiu, Junling Zhao
PII:
S0040-4039(18)30397-6
https://doi.org/10.1016/j.tetlet.2018.03.069
TETL 49838
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
9 February 2018
20 March 2018
23 March 2018
Please cite this article as: Liang, W., Yin, W., Wang, T., Qiu, F.G., Zhao, J., Organocatalytic Stereoselective
Conjugate Addition of 3-Substituted Oxindoles with In Situ Generated ortho-Quinone Methides, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.03.069
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Organocatalytic Stereoselective Conjugate Addition of 3-Substituted Oxindoles with In Situ
Generated ortho-Quinone Methides
Weihong Liang,a Wenhao Yin,a Tingzhong Wang,c Fayang G. Qiu*,a,c and Junling Zhao*,b
a Guangzhou Institute of Biomedicine and Health, University of Chinese Academy of Sciences, 190
Kaiyuan Avenue, The Science Park of Guangzhou, Guangdong 510530, China
b School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
c Launch-Pharma Technologies, Ltd., 188 Kaiyuan Avenue, Building D, 5th Floor, The Science Park of
Guangzhou, Guangdong 510530, China
*Corresponding authors: qiu_fayang@gibh.ac.cn; Tel.: +86 20 32015230; Fax: +862032015230;
zhaojling3@mail.sysu.edu.cn.; Tel.: +86 20 32015230; Fax: +862032015230.
1

Abstract
A novel method for the stereoselective conjugate addition of 3-substituted oxindoles to in situ
generated o-QMs was described. This process was catalyzed efficiently by a cinchonidine-derived
squaramide catalyst in oil-water phase, furnishing the corresponding 3,3-disubsituted oxindole
derivatives in moderate to high yields (up to 98%) with high stereoselectivities (up to 95% ee, 15.4:1
dr ). The utility of this reaction was also investigated by the gram-scale synthesis and derivatization of
one of the products.
Key words: Organocatalysis; conjugate addition; enantioselective; 3-substituted oxindoles; o-QMs.
2

Introduction
The optically active 3,3-disubstituted oxindoles are commonly found in many alkaloid natural
products and biologically relevant compounds.1 Consequently, considerable efforts have been devoted
to the stereoselective synthesis of this important structure core, and many elegant methods have been
developed. Taking advantage of the high nucleophilic activity of the C3-position, the catalytic
asymmetric nucleophilic reactions of 3-substituted oxindoles with suitable electrophilic reagents have
become common practices for the enantioselective syntheses of 3,3-disubstituted oxindoles. Different
types of organic transformations have been successfully applied in this strategy, for example, the
aldol/Mannich reaction,2 halogenation,3 amination/hydroxylation/sulfenylation,4 conjugate addition,5
and alkylation/arylation.6 Even with these advancement, the application of new electrophiles which
enables the formation of structurally diversified 3,3-disubstituted oxindoles is still highly desirable.
Scheme 1. Organocatalytic asymmetric conjugate addition of 3-substituted oxindoles with quinone
methides (QMs).
Ortho-Quinone methides (o-QMs) are active intermediates both in many biological processes7 as
well as chemical transformations,8 and have recently been used as electrophiles in asymmetric catalysis.
3

Because of their unique chemical property, o-QMs were successfully used in the enantioselective
cycloaddition reactions or conjugate additions.9 However, the application of o-QMs in asymmetric
synthesis is still less developed mainly due to the reactive and unstable nature of these species. The use
of in situ generated o-QMs from their stable precursors provides an effective solution for this tricky
problem.10 In this regard, Zhou et al developed a novel method by using 2-(arylsulfonyl)alkyl phenols
as precursors, which produced o-QMs under mild brønsted basic conditions, for their cyclization
reaction with sulfur ylides.11 Recently, a variety of nucleophiles have been successfully applied for the
organocatalytic asymmetric reactions with in situ generated o-QMs using this strategy. For example,
activated methylenes,12 sulfur nucleophiles,13 2-naphthols,14 butenolides,15 and azlactones.16 As a class
of well-known nucleophiles, 3-substituted oxindoles have been used for the asymmetric 1,6-conjugate
addition with p-QMs,17 however, the application of o-QMs in this transformation is still elusive. Very
recently, Shi et al reported an example of enantioselective [4+1] cyclization of o-QMs with
3-chlorooxindoles for the synthesis of 2,3-dihydrobenzofuran derivatives (Scheme 1).18 As our
continuing research interest in the application of 3-oxindole derivatives in organocatalysis,19 we herein
present our recently research progress in the asymmetric conjugate addition of 3-oxindoles with in situ
generated o-QMs.
Results and discussion
To start our investigation, the reaction of N-Boc-3-phenyloxindole 1a and 2-[phenyl(tosyl)methyl]-
phenol 2a was chosen as a model reaction. Various cinchona alkaloids derived bifunctional catalysts
were screened with K2CO3 as base in CH2Cl2/H2O (1:1 v/v) at room temperature. The results are
summarized in Table 1. Generally, the expected adduct 3aa was formed smoothly under these
conditions but with poor stereoselectivity (Table 1, entries 1-7). Inspired by Xu’s most recent discovery
4

on the bifunctional squaramide catalyzed conjugate addition of in situ generated o-QMs,13b,14 we
Table 1. Optimization of the reaction conditions.a
entry
catalyst
solvent
base
time (h)
yield
drc
ee(%)c
2
(%)b
1
CH2Cl2 / H2O
CH2Cl2 / H2O
CH2Cl2 / H2O
CH2Cl2 / H2O
CH2Cl2 / H2O
CH2Cl2 / H2O
CH2Cl2 / H2O
CH2Cl2 /H2O
CH2Cl2 /H2O
CH2Cl2 /H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CHCl3/H2O
DCE/H2O
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Na2CO3
NaHCO3
KHCO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
14 h
14 h
14 h
11 h
14 h
14 h
14 h
3
1.8:1
1:1.5
1:3.3
1:3.4
1:2.8
1:3.3
1:7.3
11.5:1
11.0:1
15.7:1
5.0:1
5.9:1
20.7:1
17.5:1
4.2:1
5.9:1
6.8:1
8.6:1
8.6:1
14d
50
60d
58d
67
13
23
91
95
94
84
89
91
92
88
89
93
92
94
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
C1
C2
C3
C4
C5
C6
C7
C3
C4
C5
C4
C4
C4
C4
C4
C4
C4
C4
C4
3aa, 43
3aa, 76
3aa, 78
3aa, 71
3aa, 86
3aa, 73
3aa, 85
3ab, 71
3ab, 77
3ab, 67
3ab, 41
3ab, 46
3ab, 20
3ab, 27
3ab, 69
3ab, 70
3ab, 83
3ab, 73
3ab, 79
2
3
4
5
6
7
8
9
3
10
11
12
13
14
15
16
17
18
19
3
3
3
3
3
3
3
3
PhCl/H2O
3
toluene/H2O
3
a Unless otherwise specified, all reactions were conducted with 1a (0.1 mmol), 2 (1.2 equiv., 0.12 mmol), and catalyst (0.01 mmol, 10
mol %), inorganic base (2.4 equiv.) in 1 mL of CH2Cl2 and 1 mL of H2O at room temperature for 3 h. b Isolated yield. c Diastereomeric
ratio and enantiomeric excess was determined by HPLC on a chiral stationary phase and the enantiomeric excess of the major products
are given. d Product with opposite configuration.
envisaged that the introduction of a methoxyl group at the ortho position of the phenol hydroxyl
functionality might improve the stereocontrol of this transformation too. Experimental results indicated
that this was the case. The efficiency of the reaction was significantly improved with the use of 2b as
an electrophile (shorter reaction time with high stereoselectivity). Cinchonidine-derived squaramide C4
5

proved to be the best catalyst to give the corresponding product 3ab in 77% yield with 95% ee and
11.0:1 dr (Table 1, entry 9). With the optimal catalyst determined, we then studied the effect of base on
this reaction. The results indicated that this reaction was significantly influenced by the basicity of the
base used. Stronger base give lower stereoselectivity and weaker base produced lower yields with high
stereocontrol maintained. For example, the use of Cs2CO3 gave 3ab in 69% yield with 88% ee and
4.2:1 dr (Table 1, entry 15), while a 91% ee and 20.7:1 dr with only 20% yield was obtained when
NaHCO3 was tested (Table 1, entry 13). An examination of the organic solvent failed to further
improve the efficiency of the reaction and CH2Cl2 remains the best choice.
Table 2. Substrate scope with respect to 3-substituted oxindoles.a
6

a Unless otherwise noted, all reactions were conducted with 1 (0.1 mmol), 2 (1.2 equiv., 0.12 mmol), and C4 (0.01 mmol, 10
mol%), K2CO3 (2.4 equiv.) in 1 mL of CH2Cl2 and 1 mL of H2O at room temperature for 3 h. Yields of isolated products are
given. The diastereomeric ratio and enantiomeric excesses were determined by HPLC analysis using a chiral stationary phase. b
NaHCO3 (2.4 equiv.) was used as base, reaction time: 65 h.
With these optimal reaction conditions in hand, we subsequently investigated the substrate scope with
7

respect to 3-substituted oxindoles 1a-r (Table 2). In general, this reaction worked well with various
N-Boc-3-aryl oxindoles, both electron-donating and electron-withdrawing substituents on the 3-aryl
ring or the oxindole benzene ring were well tolerated, affording the corresponding adducts in moderate
to high yields (35-98%) with high stereoselectivities (87-95% ee, 3.5:1-15.4:1 dr). However, 3-benzyl
substrate 1r gave product 3rb in relatively lower stereoselectivities (80% ee, 1.6:1 dr). The absolute
configuration of the two chiral centers in compound 3db were determined as (S, S) by X-ray
crystallographic analysis, and those of other adducts were assigned on the assumption of a uniform
mechanistic pathway.20
Table 3. Substrate scope with respect to in situ generated o-QMs.a
a Unless otherwise noted, all reactions were conducted with 1 (0.1 mmol), 2 (1.2 equiv., 0.12 mmol), and C4 (0.01 mmol, 10
mol%), K2CO3 (2.4 equiv.) in 1 mL of CH2Cl2 and 1 mL of H2O at room temperature for 3 h. Yields of isolated products are
given. The diastereomeric ratio and enantiomeric excesses were determined by HPLC analysis using a chiral stationary phase. b
Performed at 4 oC, reaction time: 11 h.
Further examination of the substrate scope of this organocatalytic asymmetric conjugate addition
was focused on the 2-[aryl(tosyl)methyl]phenol 2 (Table 3). Removal of the methoxyl group at the
8

ortho-position of hydroxyl group led to a decreased stereocontrol. For example, the use of
2-[phenyl(tosyl)methyl]phenol (2a) gave product 3aa in 79% ee and 2.3:1 dr. The stereoselectivity of
his reaction was slightly affected by the electronic nature of the substituents on the para position of the
aryl ring. The presence of an electron-donating group resulted in relatively lower stereoselectivity
(3ad). On the contrary, substrates with electron-withdrawing groups often furnish the corresponding
products with high stereoselectivities. Unfortunately, the stereo outcome of this reaction was sluggish
with the use of heteroaromatic substrate such as 2j, affording 3aj in 73% yield but with only 16% ee
and 2.8:1 dr.
Scheme 2. 1) Gram-scale synthesis of 3ab. 2) Derivatization of 3ab.
In order to show the synthetic utility of this methodology, the gram-scale synthesis of 3ab and a
representative derivatization were performed (Scheme 2). When the reaction was scaled up to 3.6 mmol
of 1a and 4.3 mmol of 2b, 1.2g of product 3ab was obtained with the high stereoselectivity retained.
Compound 3ab was readily reduced to a hemiacetal 4. Catalyzed by (DL)-camphorsulfonic acid, 4
underwent a cyclization process to give a tetrahydrobenzo[7,8]chromeno[2,3-b]indole derivative 5 in
56% overall yield with 94% ee and > 20:1 dr.
9

Scheme 3. Proposed mechanism of this reaction.
Based on the stereochemistry of the product described above and previous literature reports on
conjugate addition of 3-substituted oxindoles, a plausible transition state was proposed as depicted in
Scheme 3. Firstly, Reaction of 2b with a base produces intermediate A and the bifunctional catalyst C4
activates intermediate A by double hydrogen-bonding interactions of squaramide moiety to the
carbonyl group and the methoxyl group at the 6 position,14 while substrate 1a is deprotonated by the
tertiary amine of the catalyst to form intermediate B. It can be seen that the Re face of intermediate A is
more open to react with the Re face of the enolate species to generate product 3ab, which is consistent
with the experimental results.
Conclusions
In conclusion, we have developed a highly stereoselective organocatalytic conjugate addition
reaction of 3-substituted oxindoles with in situ generated o-QMs using 2-[aryl(tosyl)methyl]phenol as
precursors. This protocol was efficient with a wide range of substrates, affording the corresponding
3,3-disubstituted oxindoles in moderate to high yields with high stereoselectivities. The scale-up
reaction and derivatization of one of the products were also performed.
Acknowledgement
We are grateful to the National Natural Science Foundation of China for the financial support of this
work (Grant Nos.21372221, 21772199 and 21572228) and the Open Fund of the Key Laboratory of
10

Functional Molecular Engineering of Guangdong Province (2016kf01), South China University of
Technology. Prof. Jinsong Liu and Dr. Yongzhi Lu at the Guangzhou Institutes of Biomedicine and
Health, Chinese Academy of Sciences are gratefully acknowledged for X-ray structure determination.
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Graphical abstract
15

Highlights



Conjugate addition of 3-substituted oxindoles to in situ generated o-QMs.
A cinchonidine-derived squaramide was used as catalyst for this transformation.
A series of optically active 3,3-disubstituted oxindoles were obtained with high efficiency.
16