Cinchona-based squaramide-catalysed cascade aza-Michael-Michael addition: Enantioselective construction of functionalized spirooxindole tetrahydroquinolines

Article abstract of DOI:10.1039/c3cc44930k

An efficient enantioselective cascade aza-Michael-Michael addition reaction catalysed by a chiral bifunctional tertiary amine-squaramide catalyst has been developed. This cascade reaction proceeded well under mild conditions, furnishing highly functionalized spirooxindole tetrahydroquinolines with three contiguous stereocenters in excellent yields with excellent diastereoselectivities (>25:1 dr) and high enantioselectivities (up to 94% ee). The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc44930k

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Cinchona-based squaramide-catalysed cascade aza-Michael/Michael
addition: enantioselective construction of functionalized spirooxindole
tetrahydroquinolines †
Wen Yang and Da-Ming Du*
5
Received (in XXX, XXX) Xth XXXXXX 2013, Accepted Xth XXXXX 2013
DOI: 10.1039/c000000x
An efficient enantioselective cascade aza-Michael/Michael
OMe
addition reaction catalysed by a chiral bifunctional tertiary
amine-squaramide catalyst has been developed. This cascade
OMe
O
O
N
O
O
O
H
O
N
H
Ar
Ar
N
H
N
H
Ar
N
H
N
H
10 reaction proceeded well under mild conditions, furnishing
highly functionalized spirooxindole tetrahydroquinolines with
three contiguous stereocenters in excellent yields with
excellent diastereoselectivities (> 25:1 dr) and high
enantioselectivities (up to 94% ee).
N
N
H
N
H
N
N
V: Ar = 3,5-(CF3)2C6H3
I: Ar = 3,5-(CF3)2C6H3
II: Ar = 4-CF3C6H4
III: Ar = 3,5-(CF3)2C6H3
IV: Ar = 4-CF3C6H4
O
O
O
O
N
N
H
H
H
NH HN
N
N
N
Ar
H
N
N
H
Ar
H
H
MeO
OMe
MeO
S
N
15 Spirocyclic oxindole cores are a class of important structural
motifs frequently found in many nature products, biologically
synthetic molecules, and even pharmaceutical candidates.1 Due to
their well defined three-dimensional structures and diverse
biological activities, spirocyclic oxindoles have been proven to be
20 fascinating synthetic targets and intriguing drug research subjects.
In recent years, great efforts have been devoted to this area, and
numerous effective methods for the enantioselective synthesis of
spirocyclic oxindoles with various carbocycles, or heterocycles
have been established.2 However, to the best of our knowledge,
25 there is only one report on the synthesis of tetrahydroquinoline-
fused spirooxindoles in the methodology.3 Yuan and co-workers
N
N
N
VI: Ar = 3,5-(CF3)2C6H3
VIII: Ar = 3,5-(CF3)2C6H3
VII
Fig. 1 Screened organocatalysts
of new drugs. As powerful tool in organic
a
chemistry,organocatalytic cascade reaction is one of the main
50 strategies for the enantioselective synthesis of spirooxindoles in
previous reports.5 For our persistent study on organocatalytic
reactions with squaramides,6,7 herein, we would like to document
an efficient squaramide-catalysed enantioselective cascade aza-
Michael/Michael addition of 2-tosylaminoenones and 3-
55 ylidenoxindoles for the construction of highly functionalized
spirooxindole tetrahydroquinolines containing three contiguous
stereocenters.
disclosed
an
efficient
FeCl3-catalysed
stereoselective
intramolecular tandem 1,5-hydride transfer/ring closure reaction,
providing spirooxindole tetrahydroquinolines in high yields with
30 good to excellent diastereoselectivities. And the catalytic
enantioselective version using a chiral phosphoric acid with a
preliminary result was reported. Tetrahydroquinolines are
featured in many natural products and medically synthetic
molecules, exhibiting a wide spectrum of significant biological
35 activities.4 So the development of efficient approaches for the
enantioselective synthesis of spirooxindole tetrahydroquinolines
with two privileged motifs integated together is valuable for the
structural diversity of spirooxindoles, as well as for the discovery
Initially, we explored the viability of the cascade process with
2-tosylaminochalcone 1a and 3-ylidenoxindole 2a as the model
60 substrates. In the presence of 5 mol% quinine-based squaramide
catalyst I, the model reaction was carried out in CH2Cl2 at room
temperature. To our delight, the cascade aza-Michael/Michael
addition reaction proceeded well to furnish the desired adduct
3aa in excellent yield with almost complete diastereoselectivity
65 and high enantioselectivity (> 25:1 dr, 88% ee). With the
promising result, a brief survey of organocatalysts (Fig. 1) was
performed. The results are shown in Table 1. Squaramide II with
4-CF3 on the aromatic ring gave identical stereoselectivity but a
little lower yield (entry 2). When squaramides III and IV derived
70 from quinidine were employed, the opposite enantiomers of 3aa
were obtained with lower enantioselectivities (80% ee and 81%
ee, respectively) (entries 3 and 4). We then turned our attention to
40 School of Chemical Engineering and Environment, Beijing Institute of
Technology, Beijing 100081, People’s Republic of China.
*Corresponding author, Tel: 86-10-68914985; E-mail: dudm@bit.edu.cn
† Electronic Supplementary Information (ESI) available: [Experimental
procedures, Characteristion data and HPLC chromatographs]. See
45 DOI: 10.1039/c000000x/
squaramide catalysts
V and VI derived from (1S,2S)-
cyclohexane-1,2-diamine, but inferior results were achieved
75 (entries 5 and 6). C2-symmetric quinine-derived squaramides VII
was also screened, and only moderate enantioselectivity was
This journal is © The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 00–00 | 1

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Page 2 of 3
Table 2 Scope of asymmetric cascade aza-Michael/Michael reactionsa
observed (entry 7). In contrast to squaramide I, quinine-based
thiourea VIII displayed lower enantioselectivity and reactivity
(entry 8). Therefore, squaramide I was identified as the best
catalyst.
O
Ts View Article Online
R2
N
DOI: 10.1039/C3CC44930K
O
R2OC
R3
COR1
R3
5 mol% I
R1
+
O
O
N
5
ClCH2CH2Cl
r.t., 12-24 h
N
Ac
Table 1 Screening of organocatalystsa
NHTs
1a-g
Ac
3aa-ah
2a-h
45
O
Ts
N
Yieldb
Ph
O
PhOC
Entry
R1
R2
R3
Product
drc eed (%)
(%)
COPh
5 mol% I-X
Ph
+
O
O
CH2Cl2, r.t., 24 h
N
N
1
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
99
99
99
99
99
95
79
97
97
99
94
96
85
99
99
99
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
90
88
88
90
94
92
5
NHTs
Ac
3aa
Ac
4-ClC6H4
4-BrC6H4
4-MeC6H4
2a
1a
3
H
Entry
Catalyst
Yieldb (%)
drc
eed (%)
4
H
1
2
3
4
5
6
7
8
99
93
92
90
90
78
86
86
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
> 25:1
88
88
80e
81e
38
69
49
63
I
II
III
IV
V
VI
VII
VIII
5
4-MeOC6H4
2-MeOC6H4
tBu
H
6
7e
H
H
8
C6H5
4-ClC6H4
4-BrC6H4
4-MeC6H4
H
91
91
89
89
85
86
76
89
90
9
C6H5
H
10
11
12
13
14
15
16
C6H5
H
C6H5
4-MeOC6H4
Me
H
a
Reactions were carried out with 1a (0.11 mmol) and 2a (0.1 mmol) in
C6H5
H
CH2Cl2 (0.5 mL). Isolated yield. Determined by 1H NMR analysis.
b
c
d Determined by chiral HPLC analysis. e Opposite enantiomer.
C6H5
tBu
H
C6H5
C6H5
F
C6H5
C6H5
Cl
OMe
With the optimal catalyst in hand, we investigated reaction
C6H5
C6H5
3aj
10 parameters involving solvent, temperature, and catalyst loading
for the optimal conditions. The results are presented in Table S1
(see ESI†). Variation of the solvents had an effect on the catalytic
process. The solvent evaluation showed that chlorinated solvents
were suited for the reaction and dichloroethane was the best
a
Reactions were carried out with 1 (0.11 mmol) and 2 (0.1 mmol) in
ClCH2CH2Cl (0.5 mL). Isolated yield. Determined by 1H NMR
b
c
d
e
analysis.
Determined by chiral HPLC analysis.
Reaction was
performed at 30 oC for 60 h.
15 reaction medium The solvents toluene and THF gave only 50 desired adduct with good enantioselectivity (79% ee). For
relatively higher reactivity, the reaction was performed at −10 oC,
moderate yields, and the use of THF and MeCN resulted in a
descrease on the enantioselectivity. Disappointingly, lowering the
reaction temperature led to no enhanced enantioselectivity. The
catalyst loading was screened and had a very limited impact on
and an increase on the enantioselectivity was observed (84% ee).
As expected, substrate with higher reactivity is more sensitive for
improving enantioselectivity by lowering the temperature. Under
20 the enantioselectivity. Considering the enantoselectivity, yield 55 the new conditions, 3-ylidenoxidoles 2l and 2m also gave
and reaction time, an amount of 5 mol% catalyst loading was still
a appropriate choice.
comparable good results. N-Boc protected 3-yildenoxidole 2n
afforded moderate enantioselectivity, and 3-yildenoxidole
without N-protecting group displayed very low reactivity. It
appears that N-protecting group is crucial for enantioselectivity
60 and reactivity. The absolute configuration of 3aa was
unambiguously established to be (2’R,3’S,4’S) by X-ray analysis
(Fig. 2),8 and those of other adducts were assigned by analogy.
The substrate scope of the enantioselective squaramide-
catalysed cascade aza-Michael/Michael addition was explored
25 under the optimized reaction conditions. The results are
summarized in Table 2. A range of different substituted 2-
tosylaminochalcones 1a−f and 3-ylidenoxindoles 2a−j were
examined. In most of cases, the reactions proceeded well,
providing the corresponding oxindole tetrahydroquinolines 3 in
30 excellent yields with almost complete diastereoselectivities (>
25:1 dr) and high enantioselectivities (up to 94% ee) (entries 1−6,
8−16). The results demonstrate that the electronic nature and
position of the substituents on the aromatic rings have a limited
impact on the cascade process. But there are limitations in the
35 substrate scope. 2-Tosylaminoenone 1g derived from aliphatic
enone exhibited lower reactivity and gave a near racemic adduct
(entry 7). No reaction occurred for 2-tosylaminoenoate (R1 =
OEt). As shown in Scheme 1, the substrate scope was further
investigated. The 3-ylidenoxidoles 2k−m were also suitable
40 substrates. The reaction of 2-tosylaminochalcone 1a and
yilidenoxidole 2k was complete within 6 hours to afford the
Ts
EtO2C
N
O
EtO2C
R3
R3
COPh
5 mol% I
Ph
+
O
O
ClCH2CH2Cl
-10 oC, 48 h
N
Ac
NHTs
1a
N
Ac
3ak-am
2k-m
3ak: R3 = H
3al: R3 = Cl
97% yield, > 25:1 dr, 84% ee
99% yield, > 25:1 dr, 78% ee
3am: R3 = OMe 98% yield, > 25:1 dr, 84% ee
O
Ts
N
Ph
O
PhOC
COPh
Ph
5 mol% I
O
+
O
ClCH2CH2Cl
r.t., 16 h
N
Boc
N
NHTs
Boc
3an
99% yield, > 25:1 dr, 53% ee
1a
2n
Scheme 1 Further investigation of substrate scope.
2
| Chem. Commun., 2013, 49, 00–00
This journal is © The Royal Society of Chemistry 2013

Page 3 of 3
ChemComm
2
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50
55
Fig. 2 X-ray crystal structure of 3aa.
On the basis of the absolute configuration of 3aa, a possible
transition state model was proposed for the cascade process (Fig.
3). In the transition state A, quinine-based squaramide I works in
a dual activation model. 3-Yilidenoxindole 2a is oriented and
activated by the squaramide moiety through multiple hydrogen
bonding, while 2-tosylaminochalcone 1a is deprotonated by the
basic nitrogen atom of the quinine moiety. The intermolecular
10 aza-Michael addition occurs by the Re face attack to afford the R-
configured intermediate. Subsequently, in the transition state B,
the intermediate could undergo intramolecular Michael addition
through the Si face attack, leading to the formation of the
(2’R,3’S,4’S)-configured 3aa.
5
60
65
3
4
Y.-Y. Han, W.-Y. Han, X. Hou, X.-M. Zhang and W.-C. Yuan, Org.
Lett., 2012, 14, 4054.
(a) A. R. Katritzky, S. Rachwal and B. Rachwal, Tetrahedron, 1996,
52, 15031; (b) V. Sridharan, P. A. Suryavanshi and J. C. Menendez,
Chem. Rev. 2011, 111, 7157.5
70
15
N
CF3
O
O
Ts
O
5
For reviews of organocatalytic cascade reactions, see: (a) D. Enders,
C. Grondal and M. R. Huttl, Angew. Chem., Int. Ed., 2007, 46, 1570;
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N. Alba, X. Companyo, M. Viciano and R. Rios, Curr. Org. Chem.,
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237.
N
OMe
H
F3C
O
N
N
Ph
75
Ts
PhOC
N
COPh
Ts
H
H
N
O
PhOC
H
NAc
N
O
N
PhOC
Ac
3aa
O
O
N
Ph
80
6
For reviews of squaramides, see: (a) R. I. Storer, C. Aciro and L. H.
Jones, Chem. Soc. Rev., 2011, 40, 2330; (b) J. Alemán, A. Parra and
H. Jiang and K. A. Jørgensen, Chem. Eur. J., 2011, 17, 6890. For
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Malerich and V. H. Rawal, Angew. Chem., Int. Ed., 2010, 49, 153;
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C.-J. Wang, Adv. Synth. Catal., 2013, 355, 327.
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and D.-M. Du, Adv. Synth. Catal., 2011, 353, 1241; (c) W. Yang
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Yang and D.-M. Du, Adv. Synth. Catal., 2013, 355, 1137.
A
B
Re face attack
Intermolecular aza-Michael addition
Si face attack
Intramolecular Michael addition
85
Fig. 3 Proposed transition state model.
In summary, we have disclosed an efficient squaramide-
20 catalysed enantioselective aza-Michel/Michael addition reaction
of 2-tosylaminoenones to 3-ylidenoxindoles. The corresponding
cascade double Michael adducts were obtained in excellent yields
with excellent diastereoselectivities (> 25:1 dr) and high
enantioselectivities (up to 94% ee) under mild reaction conditions.
25 This cascade process provides a straightforward approach to the
construction of highly functionalized tetrahydroquinoline-fused
spirooxindole derivatives with three contiguous stereocenters
from simple starting materials. Further studies on organocatalytic
cascade reactions are ongoing in our laboratory.
We are grateful for financial support from the National
Natural Science Foundation of China (Grant no. 21272024), the
Science and Technology Innovation Program of Beijing Institute
of Technology (Grant No. 2011CX01008) and the Development
Program for Distinguished Young and Middle-aged Teachers of
90
95
7
100
105
110
30
35 Beijing Institute of Technology.
8. CCDC-948179 contains the supplementary crystallographic data in
this paper. This data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk
/data_request /cif.
Notes and references
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40
This journal is © The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 00–00 | 3