Catalytic One-Pot Double Asymmetric Cascade Reaction: Synthesis of Chlorinated Oxindoles and Geminal Diamines

Article abstract of DOI:10.1021/acscatal.8b05019

A multicomponent catalytic double asymmetric cascade reaction for obtaining chlorinated oxindoles and C-N aminals simultaneously is described. A calcium VAPOL phosphate complex was shown to catalyze two enantiocontrolled multicomponent reactions utilizing

Full text of DOI:10.1021/acscatal.8b05019

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Letter
Catalytic One-Pot Double Asymmetric Cascade Reaction:
Synthesis of Chlorinated Oxindoles and geminal Diamines
Xiantao Fang, Zihang Deng, Wen-Hua Zheng, and Jon C Antilla
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Catalytic One-Pot Double Asymmetric Cascade Reaction:
Synthesis of Chlorinated Oxindoles and geminal Diamines
Xiantao Fang,† Zihang Deng,† Wenhua Zheng,‡ and Jon C. Antilla*†
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†Institute for Molecular Design and Synthesis, School of Pharmaceutical Science and Technology, Health Science Platform,
Tianjin University, Tianjin 300072, P. R. China
‡School of Chemistry and Chemical Engineering, Nanjing University, Jiangsu 210023, P. R. China
ABSTRACT: A multicomponent catalytic double asymmetric cascade reaction (DACR) for obtaining chlorinated oxindoles and C-
N aminals simultaneously has been described. A calcium VAPOL phosphate complex was shown to catalyzed two
enantiocontrolled multicomponent reactions utilizing 3-aryloxindoles, N-Boc imines and N-chlorophthalimide, which afforded two
structurally complex and diverse chiral products with high levels of stereocontrol in one-pot. This transformation is facile and has a
high degree of both step and atom economy.
KEYWORDS: Multicomponent reactions; Phosphoric acid; Chiral metal phosphate; Enantioselective synthesis; Cascade
reactions
It is widely known that substitution at the 3-position of
oxindoles results in a stereogenic center that is found in a high
number of pharmaceutically active compounds and natural
products.1 Additionally, chiral geminal diamines are also
important structural motifs found in important biologically
active compounds of interest.2 We have achieved the
preparation of both of these diverse chiral structures with high
enantiocontrol using a new and unique process whereby one
chiral catalyst achieves what we term as a double asymmetric
cascade reaction (DACR).
In the past decades, multicomponent reactions (MCRs)3
have been developed by a number of conceptually interesting
and noteworthy approaches. Asymmetric multicomponent
reactions (AMCRs), in particular the catalytic enantioselective
MCRs, are a versatile and powerful strategy4 for complex
bond construction in organic and medicinal chemistry. These
reactions often feature excellent step and atom economy,
require simple operations, and are often employed in the
enantioselective synthesis of natural products and potentially
biologically active compounds.5
reaction, one of the reactants is partitioned to react with each
of the other two reactants (Scheme 1). However, one could
envision other possible ways a DACR could occur.
Recently, the synergy of chiral phosphoric acids and
efficient transition metal catalysts in enantiocontrolled
reactions have allowed for more diverse synthetic
tranformations to occur in a single reaction pot.6-10 AMCRs
have been used effectively in synthesis, due to their bond-
forming efficiency, and excellent stereoselectivity, along with
the potential to quickly assemble complex products.10,11
Although there are many advantages for AMCRs, the
controlled enantioselective cascade of two different reactions
by only one catalyst in one pot is still one of the remaining
unmet challenges. In addition to the catalyst, various other
factors must be taken into consideration for asymmetric
cascade reactions, such as solvent, substrates and
intermediates.12 Moreover, it is obviously much more difficult
to control the enantioselectivity when the substrates combine
in domino reactions because of the different catalytic
mechanisms. Therefore, the development of a catalytic
enantioselective MCR to access more than one optically pure
chiral product from simple starting materials with a single
catalyst is highly challenging and potentially desirable.
A double asymmetric cascade reaction or DACR will be
defined herein as the reaction of at least two or more reactants
in a single reaction vessel where two different and distinct
enantiocontrolled reactions are catalyzed by a single chiral
catalyst.
We envisioned that we could possible match two
independent enantiocontrolled reactions first discovered in our
laboratory with each other by utilizing the same chiral
catalyst.13 In the first reaction we knew our previously
discovered chlorinations of 3-aryl oxindoles using NCS as the
chlorine source was robust and highly selective using Ca[PA]2
metal complexes.13b In the second reaction we thought the
addition of imides to activated imines previously known to be
catalyzed by chiral PA’s could occur from the NCS byproduct
(imide anion).13a In light of the fact that some reactions before
Ishihara’s 2010 discovery that metal-phosphates could be the
true catalysts for early reactions assumed to be chiral PA’s,13c
we theorized that the imide additions could be occurring with
Scheme 1. General scheme for a double asymmetric
cascade reaction with three reagents (DACR).
C2
<
>
C1
>
DACR
*
>> C1
*
>> C2
A
B
A
B
>
A DACR can conceivably produce at least two new chiral
compounds utilizing all of the reactants. In one iteration of this
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ACS Catalysis
a chiral Ca-phosphate catalyst. Matching these two reactions
Page 2 of 6
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with a single catalyst was the basis of our initial investigations
(Scheme 2).
Table 1. Optimization of reaction conditionsa
3
4
5
6
7
8
9
Ph
Ph
O
NHBoc
N
NBoc
Cl
O
PA
Ca[
]
2
Scheme 2. The double asymmetric cascade reaction
(DACR).
O
Cl
N
R
O
solvent, rt
N
N
R
O
O
CO2Me
CO2Me
O
O
3a-b
4a
5a
1a
2a
O
N
O
Previous work
O
N
O
Boc
HN
Ar
O
O
Boc
Cl
3a
Cl
PA
N
(5 mol%)
3b
a)
N
HN
Ar
ether, rt, 24h
O
O
O
O
O
Ph
Ph
O
O
O
O
Ph
Ph
b
b
up to 99% ee
P
P
4a
5a
Yield (%)
/ee (%)c
Yield (%)
/ee (%)c
Cl
source
OH
entry
1
Additive
Solvent
Ca
2
10
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Ar
Cl
Ar
O
[PA]
Ca
2 (2.5 mol%)
O
R'
b)
O
-
-
R'
iPrOH
3a
99/90
Cl
N
N
N
PA (S)-VAPOL
iPrOAc, rt, 30 min
Ca[PA]2
-
-
-
-
ether
3a
3b
3b
O
99/86
99/88
99/85
OH
R''
2
3
4
O
O
O
R''
up to 99% ee
88/87
72/80
ether
THF
This work
Ar
Cl
Ar
O
NHBoc
N
NBoc
Cl
O
-
-
-
-
81/66
79/64
63/41
3b
3b
3b
3b
5
6
7
8
toluene
DCM
99/53
99/44
99/49
[PA
Ca
]
2 (2.5 mol%)
R1
4 Å MS, ether, rt, 24h
O
N
R1
O
N
R3
R3
N
O
O
O
O
O
O
EtOAc
CH3CN
R2
R2
E
B
C
A
D
up to 99% yield
up to 91% yield
74/58
85/79
92/91
86/88
99/32
99/93
99/96
99/92
99% ee
95% ee
3b
3b
4Å MS
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iPrOH
A + B + C D* + E*
4Å MS
10
ether
3b
3b
3Å MS
5Å MS
11
12
ether
ether
99/91
99/91
95/94
90/87
90/85
After some development we found that N-Moc-protected 3-
phenyloxindole 1a, tert-butyl (E)-(4-methoxybenzylidene)
carbamate 2a, and readily available N-chlorosuccinimide
(NCS) 3a were good substrates. By using catalytic amounts
(2.5 mol %) of calcium VAPOL phosphate complex Ca[PA]2
and iPrOH as the solvent (Table 1, entry 1), it was determined
to that these were the best conditions for a DACR. The data
obtained from these experiments are shown in Table 1. It was
determined that by using NCS as the chlorine source in iPrOH,
the proposed reaction allowed for asymmetric chlorination
product formation but unfortunately did not produce the
aminal product. DACR was also not possible when the
reaction was run in ether (Table 1, entry 2). Then, N-
chlorophthalimide was chosen as an alternate chlorinating
agent. To our delight, it enabled the desired DACR to proceed.
13d
14e
ether
ether
3b
3b
4Å MS
4Å MS
78/82
aUnless otherwise specified, all reactions were carried out with
oxindole 1a (0.05 mmol), N-Boc-imine 2a (0.10 mmol), chlorine
source 3 (0.055 mmol), 40 mg 4Å MS and the catalyst (2.5 mol %) in
b
c
solvent (1.0 mL) at rt for 24h. Isolated yield. The ee values were
d
determined by chiral HPLC analysis. Catalyst loading (2.0 mol %).
eEquivalent ratio of 1a/2a/3b = 1:1:1.
Having found the optimal conditions the Ca[PA]2-catalyzed
DACR was evaluated with N-Moc/Boc-protected oxindoles 1.
The results are summarized in Scheme 3. Substrate generality
for the oxindole core arene ring were first examined by the
reaction with 2a and 3b. Complete conversion of chlorination
products were observed in all cases, and the corresponding
enantioenriched aminal products were all well tolerated. The
electronic nature of the arene substituent on the C-3 and that
of the oxindole core were evaluated. It was found that R1
group can be an electron-donating or -withdrawing group and
still give the products in excellent yields (99%) and up to 86 -
93% ee values, respectively (Scheme 3, 4a-4c, 4k-4l).
Substitutions at the C-3 arene can be both electron rich or poor
for the reactions to be well tolerated, and the desired product
4d, 4e, 4i and 4j was formed in high yield (99%), and with
high enantioselectivities of 88%, 96%, 99% and 91%,
respectively. Notably, substrate 4i allowed for a complete
conversion and excellent enantioselectivity (99% yield, >99%
ee) under the same reaction conditions, and when the electron-
withdrawing substituents in 3-alkyloxindoles 2d and 2j were
used, the corresponding chlorinated products 4d and 4j were
found in high yields, but with lower ee’s than the substrates
with electron-donating groups 4e and 4i (Scheme 3, 4d-4e, 4i-
4j). Substrates 2f and 2g, bearing the substituent groups at the
oxindole core arene ring and at the C-3 arene simultaneously,
also gave the corresponding products 4f and 4g, respectively,
with good enantioselectivities. These seemed to have no
obvious effect on the ee with only a slightly lower
enantioselectivity (91% and 92%). The absolute
configurations of compounds 4a - 4r were found to be “(S)”
Ether was shown to provide conditions for
a higher
enantioselectivity (Table 1, entries 3-8). We also compared
molecular sieves of different pore size and the ee was further
improved to 96% and 91% with 4Å MS as an additive (Table
1, entry 10). The satisfactory yield and enantioselectivity for
4a and 5a were obtained in ether at room temperature.
We next intended to explore whether the catalyst loading
could be reduced. It was found that lowering the catalyst
amounts significantly gave poor results; when 2.0 mol %
catalyst was used a longer reaction time and lower ee was
obtained (Table 1, entry 13). Therefore, the subsequent
reactions used 2.5 mol % catalyst. In order to better realize the
green and step economy, we evaluated the optimal
stoichiometry of the three starting materials. Interestingly,
when the amounts of the three-substrate ratios were change to
1a/2a/3b = 1:1:1 (Table 1, entry 14), the yield and
enantioselective of 5a were sharply lower. Therefore, two
equivalents of tert-butyl imine were used to ensure an efficient
and selective reaction.14
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by comparison of the observed optical rotation values and
respectively. Both the electron-donating (5m-5o) and electron-
withdrawing substituents (5q-5r) and no substituent (5p) on
the arene ring were equally efficient using the reaction
conditions. To our delight, Electron donating groups in the
ortho (Scheme 4, 5o), the meta (Scheme 4, 5m), or the para
(Scheme 4, 5n) position were good substrates for the reaction,
and the products were found in good yields (87%-90%) and ee
values, 87% - 89% respectively (Scheme 4, 5m - 5o). In
addition, electron-withdrawing groups (Scheme 4, 5q - 5r) in
the para-position of the substrate gave excellent results. The
absolute configurations of 5a-5r were determined to be “(R)”
by comparing the observed optical rotation values and HPLC
spectrum to that reported in the literature.[13a, 2b]
HPLC spectrum to the reported literature values.13b, 15
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3
4
5
6
7
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Scheme 3. Variation of N-Moc/Boc oxindole substrate for
the Ca[PA]2 catalyzed DACRa
Ar
Ar
NHBoc
O
NBoc
Cl
O
[PA]
Ca
2 (2.5 mol%)
R1
N
O
R1
O
Cl
N
N
N
4 Å MS, ether, rt
O
O
O
O
O
O
O
O
R2
R2
4a-l
5a-l
1a-l
2a
3b
9
NHBoc
N
Ph
O
NHBoc
N
10
11
12
13
14
15
16
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Cl
Ph
O
Cl
O
O
N
O
O
N
CO2Me
O
O
O
O
CO2Me
4b
5b
4a
5a
99% yield, 93% ee
84% yield, 90% ee
99% yield, 96% ee
93% yield, 91% ee
Scheme 4. Variation of N-Boc imine substrate for the
Ca[PA]2 catalyzed DACRa
F
Ph
Ph
NHBoc
NBoc
O
Cl
O
NHBoc
O
[PA]
2 (2.5 mol%)
NHBoc
O
Ca
Ph
Cl
N
O
O
Cl
N
O
Cl
O
R3
R3
N
O
N
O
N
N
4 Å MS, ether, rt
O
CO2Me
CO2Me
O
O
O
N
N
CO2Me
CO2Me
4m-r
5m-r
1a
2m-s
3b
4d
5d
4c
5c
99% yield, 88% ee
90% yield, 90% ee
99% yield, 90% ee
85% yield, 92% ee
NHBoc
NHBoc
N
O
O
Ph
Cl
Ph
Cl
N
O
O
NHBoc
O
NHBoc
O
N
N
O
O
O
CO2Me
CO2Me
4m
Cl
O
O
Cl
O
N
O
N
O
4a
5a
5m
N
O
N
99% yield, 96% ee
93% yield, 91% ee
99% yield, 90% ee
90% yield, 89% ee
CO2Me
CO2Me
5e
4f
5f
4e
99% yield, 96% ee
88% yield, 92% ee
99% yield, 91% ee
88% yield, 90% ee
NHBoc
O
NHBoc
O
Ph
Cl
Ph
Cl
N
O
F
N
O
O
O
N
N
CO2Me
CO2Me
NHBoc
O
NHBoc
O
Ph
Cl
Cl
O
4o
5o
4n
5n
N
O
N
O
O
99% yield, 91% ee
87% yield, 87% ee
99% yield, 96% ee
89% yield, 90% ee
O
O
N
N
CO2Me
Boc
4h
5h
4g
5g
NHBoc
O
NHBoc
O
99% yield, 92% ee
91% yield, 92% ee
99% yield, 92% ee
88% yield, 90% ee
Ph
Cl
Ph
Cl
N
O
N
O
O
O
F
N
N
F
CO2Me
CO2Me
NHBoc
O
NHBoc
4q
5q
O
4p
5p
N
O
Cl
O
Cl
O
N
90% yield, 93% ee
99% yield, 93% ee
99% yield, 93% ee
89% yield, 88% ee
O
N
O
N
O
Boc
Boc
4i
5i
4j
5j
NHBoc
O
Ph
Cl
99% yield, >99% ee
91% yield, 95% ee
99% yield, 91% ee
90% yield, 94% ee
N
O
O
N
Cl
NHBoc
O
NHBoc
O
CO2Me
Ph
Cl
Ph
Cl
O
F
N
O
N
O
4r
5r
O
O
O
O
N
N
99% yield, 92% ee
88% yield, 88% ee
Boc
Boc
5k
4k
4l
5l
92% yield, 94% ee
99% yield, 90% ee
aReaction condition: all reactions were carried out with oxindole 1a
(0.05 mmol), N-Boc imine 2m-r (0.10 mmol), chlorine source 3b
(0.055 mmol), 40 mg 4Å MS and the catalyst (2.5 mol%) in ether (1.0
88% yield, 92% ee
99% yield, 86% ee
aReaction condition: all reactions were carried out with oxindole 1a-h
(0.05 mmol), N-Boc imine 2a (0.10 mmol), chlorine source 3b (0.055
mmol), 40 mg 4Å MS and the catalyst (2.5 mol%) in ether (1.0 mL) at
b
c
mL) at rt for 24h. Isolated yield. The ee values were determined by
chiral HPLC analysis.
b
c
rt for 24h. Isolated yield. The ee values were determined by chiral
HPLC analysis.
Due to insights in our previous studies with the individual
reactions in this cascade, we believe the chiral chiral calcium
phosphate complex binds to activate both the nucleophile and
the electrophiles in each case, and the proposed reaction
pathway and transition state is shown in Figure 1. Initially, the
centralized chelation sphere of calcium and the carbonyl
oxygen’s of the Moc group (1a) and chlorine source (3b),
increase the Brønsted basicity of the chiral phosphate and this
allows for the oxindole tautomer to also be activated. These
interactions together with the hydrogen-bonding interactions
of the oxindole tautomer O-H group and the P=O group of the
catalyst can give a rationale for the stereoselectivity of the
The reaction scope of imine substrates was next examined in
Scheme 4. The reactions progressed well and gave products 4
and 5 in good yield and moderate to good ee using the general
conditions already established. The chlorination products were
available directly and in high yield along with excellent
selectivity in all cases, and enantioenriched aminal products
were all tolerated well. There appeared to be a good reaction
scope with respect to aryl substituted imines for the DACR. A
series of aryl-substituted imines were synthesized and
performed for the double asymmetric cascade reaction,
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reaction. The imide anion from the chloride source provides
Page 4 of 6
other possible cases where DACR can occur is currently
underway.
1
2
3
4
5
6
7
8
for the subsequent asymmetric aminal formation again via the
catalysis of Ca[PA]2, to provide 5a. The reaction progress was
monitored by the removal of aliquots that were subsequently
analysed by 1H NMR. This analysis showed that the
chlorination product was built-up significantly before the
presumably slower N-H phthalimide addition to the imine was
observed. In consideration of this transition state, the Lewis
acidic Ca[PA]2 could activate the imine via mono-activation
(TS II). The chiral environment created by the Ca[PA]2
backbone and the bulk of the ligand, thus providing the
experimentally observed enantioenriched products (S)-4a and
(R)-5a.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
All detailed experimental procedures, characterizations, NMR and
HPLC spectra are contained in the Supporting Information.
9
AUTHOR INFORMATION
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Corresponding Author
*E-mail: jantilla@tju.edu.cn
Ph
ACKNOWLEDGMENT
1a
O
N
We acknowledge National 1000 Talent Plan of China and Tianjin
City for support, as well at Tianjin University for start-up funding.
O
O
Ph
O
OH
O
P
O
N
O
O
REFERENCES
O
P
O
O
O
O
O
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N
Cl
O
3b
O
Ph
Cl
Cl
O
O
N
O
N
H
O
O
N
O
O
O
O
4a
O
TS I
P
O
O
O
P
O
O
O
NH
O
Boc
N
O
O
P
O
O
O
O
H
O
P
O
O
2a
O
O
H-N
O
Boc
N
NH
O
Boc
O
TS II
O
N
P
O
O
O
O
O
P
O
O
O
5a
Figure 1. Possible mechanism for the DACR.
In conclusion, by using chiral calcium VAPOL phosphate
catalyst, we establish what we believe is the first firm case for
a DACR for the highly enantioselective preparation of both
chlorinated 3-aryloxindoles and geminal diamines. This
cascade reaction efficiency is conducted with mild conditions
at room temperature, and with a relatively low catalyst loading
(2.5 mol%). This DACR requires only readily available
starting materials, has good functional group tolerance, and the
atom-economy is excellent. In addition, our insight might
allow for the future development of other asymmetric
multicomponent/cascade type reactions. Further work into
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