Chiral calcium VAPOL phosphate mediated asymmetric chlorination and Michael reactions of 3-substituted oxindoles

Article abstract of DOI:10.1021/ja109824x

We disclose a novel high yielding and highly enantioselective chiral calcium VAPOL phosphate-catalyzed chlorination of 3-substituted oxindoles with N-chlorosuccinimide (NCS). The reaction conditions are also shown to be effective for the catalytic enantio

Full text of DOI:10.1021/ja109824x

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pubs.acs.org/JACS
Chiral Calcium VAPOL Phosphate Mediated Asymmetric Chlorination
and Michael Reactions of 3-Substituted Oxindoles
Wenhua Zheng, Zuhui Zhang, Matthew J. Kaplan, and Jon C. Antilla*
Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States
S Supporting Information
b
Table 1. Catalyst Optimization for the Asymmetric Chlor-
ination of 3-Phenyloxindole 1aa
ABSTRACT: We disclose a novel high yielding and highly
enantioselective chiral calcium VAPOL phosphate-catalyzed
chlorination of 3-substituted oxindoles with N-chlorosuccini-
mide (NCS). The reaction conditions are also shown to be
effective for the catalytic enantioselective Michael addition of
3-aryloxindoles to methyl vinyl ketone.
xindoles bearing a tetrasubstituted chiral carbon center at
the 3-position are important structural motifs found in
O
alkaloid natural products and pharmaceuticals.1 For this reason,
methods for the stereoselective synthesis of chiral 3,30-disubsti-
tuted oxindoles are of considerable interest.1-3 Chiral oxindoles
containing a heteroatom at the 3-position have found applications
in medicinal chemistry.4-6 Catalytic enantioselective methods
for the synthesis of biologically important chiral 3-heteroatom
substituted oxindoles such as 3-fluorooxindoles,4 3-hydroxylo-
xindoles,3a,5 and 3-aminooxindoles3b,6 have been recently reported.
In spite of these advancements, methods detailing the efficient
enantioselective synthesis of 3-chlorooxindoles, which are poten-
tially important in medicinal chemistry, are unavailable.7-9
Despite the fact that numerous important pharmaceutical
agents contain chiral centers with chloro-substitution,10 there has
been little corresponding progress in asymmetric chlorination.
The examples of highly enantioselective chlorination are rare
and often limited to 1,3-dicarbonyl compounds, such as β-keto
esters11 and aliphatic aldehydes.12 Thus, the development of novel
asymmetric chlorinations involving other substrate classes is of
considerable importance.
yield
(%)b
ee
(%)c
entry
catalyst
solvent
1d
2
_
toluene
toluene
DCM
<20
99
99
99
99
99
99
99
99
99
99
99
99
99
99
-
51
48
50
60
80
90
0
PA1 purified on silica gel
PA1 purified on silica gel
PA1 purified on silica gel
PA1 purified on silica gel
PA1 purified on silica gel
PA1 purified on silica gel
PA1 washed with HCI
Na[P1]
3
4
EtOAc
5
benzene
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
6
7e
8e,f
9e
10e
11e
12e
13e
14e
15g
6
K[P1]
0
Mg[P1]2
37
91
86
9
Ca[P1]2
Sr[P1]2
Group 2 alkaline earth metals, such as calcium, strontium, and
barium, are abundant, inexpensive, and relatively nontoxic, but
their use in organic synthesis is fairly limited.13 Applications of
these metals as catalysts in asymmetric transformations is even
more scarce.14 Herein, we describe a novel enantioselective chlor-
ination of oxindoles with N-chlorosuccinimide (NCS) catalyzed by
a chiral calcium VAPOL phosphate to afford the product in quan-
titative yield with high enantioselectivity. Furthermore, we demon-
strate that the methodology can be effectively extended to the
catalytic enantioselective Michael addition of oxindoles to methyl
vinyl ketone.
As part of our ongoing program toward the development
of new chiral phosphoric acid catalyzed asymmetric reactions,15
we theorized that chiral phosphoric acids could activate NCS via
protonation of the imide carbonyl. Following an initial screen-
ing of chiral phosphoric acids (purified by silica gel column
Ba[P1]2
Ca[P1]2
94
a Reaction conditions: 1a (1.0 equiv), NCS (1.2 equiv), 5 mol % catalyst
(based on VAPOL phosphate), with solvent indicated 0.10 M.
b Isolated yield. c Enantiomeric excess determined by chiral HPLC
analysis. d Reaction time of 24 h. e Reaction performed at 0.050 M.
f Reaction time of 3 h. g NCS was added as a 0.12 M solution in i-PrOAc.
chromatography),16 we found VAPOL phosphoric acid (PA1)
to be the best catalyst in terms of enantioselectivity. PA1 also
demonstrated the ability to dramatically accelerate the reaction
(Table 1, entry 2 vs entry 1). Solvent screening showed isopropyl
acetate to be the most suitable solvent, allowing for 80% ee of 2 in
Received: November 1, 2010
Published: February 22, 2011
r
2011 American Chemical Society
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|

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Table 2. Substrate Scope for the Ca[P1]2 Catalyzed Asym-
metric Chlorinationa
Table 3. Asymmetric Michael Reaction of Oxindoles and
Methyl Vinyl Ketone Catalyzed by Ca[P1]2
a
a Reaction conditions: 1 (1.0 equiv), methyl vinyl ketone (3.0 equiv),
and 2.5 mol % catalyst at 0 °C. Yields reported are isolated. Enantiomeric
excess was determined by chiral HPLC analysis. The (R)-VAPOL
derived salt was used in each example.
The enantioselectivity could be further increased to 94% through
the slow addition of NCS.18
aReaction conditions: 1 (1.0 equiv), Ca[P1]2 (2.5 mol %), and NCS (1.2
equiv) are added as a 0.12 M solution in i-PrOAc over 20 min. The (S)-
VAPOL derived salt was used in each example. b Reaction time
of 80 min.
With the optimized conditions in hand, we turned our focus to
the substrate scope and generality of the reaction. The introduc-
tion of electron-donating and -withdrawing groups on both the
oxindole core and the 3-aryl group provided for products with
excellent enantioselectivity with 30 min reaction times. The
enantioselectivity of products bearing electron-donating groups
was found to be slightly lower than that of products bearing
electron-withdrawing groups (Table 2, 2b vs 2c and 2e vs 2f).
High yield and modest enantioselectivity can be obtained even
with an alkyl substituent at the 3-position of the oxindole. With a
3-methyl substituted oxindole as a substrate, the reaction affords
the product with 98% yield and 62% ee (Table 2, 2k), although a
longer reaction time is required. Variation of the carbamate
protecting group afforded the product with high enantioselec-
tivity (Table 2, 2l), while lower ee or complete loss of reactivity
was observed with other protecting groups on nitrogen.19
Although a detailed mechanism has yet to be elucidated, we
propose a transition state (Figure 1) that highlights the bifunc-
tional nature of the chiral calcium VAPOL phosphate in the
activation of both the nucleophile and the electrophile.14,17
Chelation of the carbonyl oxygens of the BOC group and the
NCS to calcium creates a more compact reaction sphere. The
increased Brønsted basicity of the chiral phosphate further
activates the oxindole tautomer. Hydrogen bonding interactions
between the oxindole tautomer and NCS coupled with the
above-mentioned interactions could allow for the high enantio-
control observed.
Figure 1. Proposed transition state for the asymmetric chlorination of
oxindole 1a.
just 1 h (Table 1, entries 2-6). When the concentration was
decreased to 0.05 M, the ee increased to 90% (Table 1, entry 7).
Surprisingly, PA1 washed with 6 N HCl led to the formation
of a racemic product (Table 1, entry 8). Comparison of this result
to a recent report by Ishihara and co-workers,17 documenting the
presence of chiral phosphate salts in the absence of a final HCl
wash of the chiral phosphoric acid/salt mixture obtained by silica
gel purification, led us to investigate different chiral VAPOL
phosphate salts (Table 1, entries 9-14). Sodium and K derived
VAPOL phosphates afforded a racemic product (Table 1, entries
9 and 10). Magnesium, calcium, and strontium derived VAPOL
phosphates allowed for the chlorination product with dramati-
cally increased enantioselectivity (Table 1, entries 11-14). To
our delight, the calcium derived VAPOL phosphate salt mediated
conditions provided yield the product with 99% yield and 91% ee.
Based on the proposed transition state, we envisioned this
newly developed chlorination protocol could be applied to
other reaction systems. Methyl vinyl ketone (MVK) is an
exemplary electrophile for Michael additions.3e,20 Application of
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Journal of the American Chemical Society
COMMUNICATION
our chlorination protocol to MVK afforded products bearing a
quaternary carbon center with both high yield and high enantios-
electivity (Table 3).21
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In conclusion, we have developed a facile method for the
highly efficient enantioselective chlorination of oxindoles cata-
lyzed by a novel chiral calcium VAPOL phosphate salt. This
method provides access to 3-chloro-oxindole products with high
enantioselectivity. The aforementioned VAPOL phosphate salt
was also found to be a highly effective promoter for the Michael
reaction of 3-aryloxindoles with methyl vinyl ketone. Mechan-
istic investigations and extension of the asymmetric chlorination
protocol to additional reaction systems are currently underway in
our laboratory and will be reported in due course.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org
’ AUTHOR INFORMATION
Corresponding Author
jantilla@usf.edu
’ ACKNOWLEDGMENT
We thank the National Institutes of Health (NIH GM-082935)
and the National Science Foundation CAREER Program (NSF-
0847108) for financial support.
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(16) For details on our initial catalyst/solvent screening, please see
the Supporting Information.
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