Design of Highly Stable Iminophosphoranes as Recyclable Organocatalysts: Application to Asymmetric Chlorinations of Oxindoles

Article abstract of DOI:10.1021/acs.orglett.5b02323

A new family of tartaric acid derived chiral iminophosphoranes has been developed as highly effective organocatalysts in the asymmetric chlorinations of 3-substituted oxindoles with a high level of enantioselectivity. Importantly, these catalysts are air- and moisture-stable. Recovery of the catalyst after simple chromatographic separation for reuse in the model reaction was achieved; the catalyst can be recycled six times without loss of any enantioselectivity. Several advantages of this catalytic process are high conversion after a very short reaction time at ambient temperature, low catalytic loading, and scale-up to multigram quantities with an excellent enantiomeric excess value of >99%, which meets the enantiomeric purity required for pharmaceutical purposes.

Full text of DOI:10.1021/acs.orglett.5b02323

Letter
pubs.acs.org/OrgLett
Design of Highly Stable Iminophosphoranes as Recyclable
Organocatalysts: Application to Asymmetric Chlorinations of
Oxindoles
Xing Gao,†,‡ Jianwei Han,*,‡ and Limin Wang*,†
†Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Meilong
Road, 130, Shanghai 200237, P. R. China
‡Shanghai−Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: A new family of tartaric acid derived chiral iminophosphoranes has been developed as highly effective
organocatalysts in the asymmetric chlorinations of 3-substituted oxindoles with a high level of enantioselectivity. Importantly,
these catalysts are air- and moisture-stable. Recovery of the catalyst after simple chromatographic separation for reuse in the
model reaction was achieved; the catalyst can be recycled six times without loss of any enantioselectivity. Several advantages of
this catalytic process are high conversion after a very short reaction time at ambient temperature, low catalytic loading, and scale-
up to multigram quantities with an excellent enantiomeric excess value of >99%, which meets the enantiomeric purity required
for pharmaceutical purposes.
ver recent years, chiral Brønsted base catalysis has
emerged as a fast growing branch of asymmetric
transfers to and from the basic site. As such, the chiral
iminophosphoranes would be highly stable and effective for
asymmetric reactions. Herein we wish to report the asymmetric
chlorinations of 3-substituted oxindoles under the catalysis of
these structurally unique organobases to form a carbon−
chlorine bond.11
As shown in Scheme 1, starting from L-(+)-tartaric acid
derived TADDOLs (1, TADDOL = α,α,α′,α′-tetraaryl-1,3-
dioxolane-4,5-dimethanol), TADDAmines 2 was readily
prepared over two steps (azide substitution and reduction
with LiAlH4; see Supporting Information).12 With TADD-
Amines 2 in hand, the construction of P-spirocyclic
iminophosphoranes 3 was achieved by reaction of diamines
with phosphorus pentachloride in good yields of 87−95% after
chromatographic separation. Of note, another corresponding
isomer 3h in a contrasting configuration to 3g was also
prepared from D-(−)-tartaric acid in a similar manner.
O
organocatalysis.1 In this area, various types of single-enantiomer
organobases have been developed for a wide range of catalytic
enantioselective transformations.2 Particularly, phosphorus-
based nonionic bases of Schwesinger’s phosphazenes or
Verkade’s iminophosphoranes attracted much attention.3
A
few early examples of chiral versions of iminophosphoranes
were prepared for metal complexation in catalysis.4 In 2007, the
research group of Ooi pioneered the design and catalytic
applications of P-spiro tetraaminophosphonium salts in
organocatalysis.5 Since then, the application of iminophos-
phoranes as organocatalysts has emerged as a useful tool for the
effective introduction of chirality into target molecules.5−8
Although these catalysts offer good enantiocontrol, there is still
much room for improvement with respect to robustness,
stability in air and moisture, and ease of handling.6,9 Specifically,
to bring organocatalysis into the realm of practically useful
methodologies, the loss of enantioselectivity in scale up, the low
turnover, and difficult catalyst recovery present great challenges
to be overcome from research and industrial points of view.10
In this context, we are interested in designing structurally rigid,
chiral iminophosphoranes with a P-spirocyclic subunit. Within
the structure of (RN−)3PNR′, we hypothesized that
incorporation of a plurality of aryl rings could shield the
basic site of the catalyst from moisture to improve the stability
while maintaining the adequate ability of proton or other atom
At the outset of our studies, the newly designed molecular
structures of both phosphonium salt (HCl salt of 3a) and
iminophosphorane 3a containing one molecule of acetone were
successfully determined by single-crystal X-ray diffraction
analyses. As shown in Figure 1, the symmetric structure of
phosphonium salt (3a·HCl) containing eight phenyl rings is
Received: August 11, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthesis of Chiral Iminophosphoranes 3 from
Tartaric Acids
Table 1. Screening of Reaction Conditions for Asymmetric
Chlorination
a
b
c
entry
catalyst (mol %)
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
3a (10)
3b (10)
3c (10)
3d (10)
3e (10)
3f (10)
3g (10)
3a·HCl (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3g (10)
3g (5)
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
toluene
DCM
MeCN
THF
99
99
99
99
99
99
99
95
99
99
99
99
99
99
99
99
99
99
73
80
86
0
10
20
88
17
70
23
21
35
46
86
98
98
96
−98
d
8
9
10
11
12
13
14
15
dioxane
Et2O
Et2O
e
16
Et2O
e
17
3g (2.5)
3h (5)
Et2O
e
18
Et2O
a
Reaction conditions: 4a (0.1 mmol, 1.0 equiv) and catalyst were
dissolved in solvent (1 mL), and NCS (1.2 equiv) was added in once
into this stirring solution; after stirring for 5 min, the reaction mixture
was purified directly by silica gel column chromatography to yield
Figure 1. Single crystal X-ray structures of HCl salt of 3a and the
complex of 3a with a molecule of acetone.
b
c
product 6a. Isolated yield. Enantiopurity of product was determined
by HPLC analysis using a chiral column with hexane−isopropanol as
d
e
solvent. A premade HCl salt of 3a was used. NCS (1.2 equiv) was
added in portions over 10 min into the stirring solution, followed by
stirring for an additional 5 min.
shown with a central phosphorus(V), and the chloride anion is
located in proximity to two of the N−H protons with an
interaction via double hydrogen bonding (atom distance of H···
Cl was 2.445 Å). Interestingly, a crystallographic analysis of the
acetone complex of iminophosphorane 3a suggests the
activation of the carbonyl group by double hydrogen bonding
of the iminophosphorane. Both structures show that two
diazaphosphacycles are linked through the phosphorus center
to form a spirocycle with an encompassment of polyphenyl
rings, which indicates a promising chiral environment for
asymmetric induction.
With iminophosphoranes 3 in hand, we then investigated
their potential as organocatalysts in the asymmetric chlorina-
tions of 3-substituted oxindoles with N-chlorosuccinimide (5,
NCS) at room temperature.13 Table 1 shows the results from
the optimization of the catalysts 3a−g and various solvents. As
can be seen, the reaction was completed within 5 min and gave
the chlorinated product 3a quantitatively in ethyl acetate as
solvent. Enantiomeric excess values of 0−88% were achieved,
and the catalyst 3g furnished the best ee value of 88% (Table 1,
entries 1−7). When the HCl salt of 3a was used as the catalyst
in this reaction, a slightly lower yield of 95% was obtained, but
the enantioselectivity was greatly compromised (17% ee, Table
1, entry 8). Subsequently, in order to enhance the product ee
value, catalyst 3a was chosen for screening the solvents due to
its easy availability. In comparison, the use of diethyl ether
increases the enantioselectivity to 86% ee (Table 1, entries 9−
14). Pleasingly, optimal catalyst 3g afforded the desired product
in 98% ee with a quantitative yield in diethyl ether as solvent
(entry 15). An attempt to decrease the catalyst loading was
tried; using a 5 mol % catalyst loading did not affect both
productivity and enantiodiscrimination, but a slight decrease of
enantioselectivity was observed in the presence of 2.5 mol %
catalyst (entries 16−17). Moreover, catalyst 3h was evaluated
in the reaction under the optimized conditions, and a 99% yield
with a 98% ee value of the corresponding isomer of 6a was
attained after 15 min (entry 18).
After optimizing the reaction conditions, we started to
investigate the performance of catalyst 3g in asymmetric
chlorinations of 3-phenyl-oxindole on a preparative scale. Thus,
the chlorination of 4a with NCS produced 6a in gram scale
(1.24 g, 4 mmol, 99% yield, 99% ee) in 1 h using 5 mol % of
catalyst (Scheme 2). Given that the chlorination reaction is very
clean, after isolation of desired product 6a with column
chromatography, recovery of the catalyst 3g by simple
chromatographic separation was realized in 98% yield with
polar eluents. Reuse and recycle of the catalyst in the reaction
of 4a with NCS six times on 1.6 mmol scale (500 mg) did not
lose any efficiency or enantioselectivity, which proves the high
stability of these iminophosphoranes. The results as shown in
Scheme 2 suggested that this catalytic process could meet the
main criteria of large-scale applications of organocatalysis
(stability and availability of the catalyst, handling issues,
recycling issues, conversion, and enantioselectivity).10
We further explored the substrate scope of 3-substituted
oxindoles in the chlorination. As summarized in Scheme 3, all
B
DOI: 10.1021/acs.orglett.5b02323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
of tested 3-aryl substituted oxindoles, regardless of electron-
donating or -withdrawing groups on both the oxindole core and
the 3-aryl group, were converted into the corresponding
products 6a−l in high yields with excellent enantioselectivities
(90−99% ee). Several cases gave the desired products with 99%
ee values (Scheme 3, 6a, 6g−h, 6j, and 6l), which compare
favorably with previously reported systems.13 Notably, both
high yields and excellent enantioselectivity can be obtained
even with an alkyl substituent at the 3-position of the oxindole
(Scheme 3, 6m and 6n). With a 3-benzyl substituted oxindole
4m as substrate, the reaction affords the product with 94% yield
and 90% ee after a longer reaction time of 1 h; the catalytic
activity and enantioselectivity in this case are obviously superior
to the results achieved by the cinchona alkaloid catalytic system
in the literature (85% yield with 29% ee).13a In the case of 3-
methyl substituted oxindole (4n), the chlorinated product of
6n was furnished in 97% yield with 90% ee, which are also the
best results to date in comparison to previous reports (98%
yield and 62% ee achieved by using chiral calcium VAPOL
phosphate;13b 91% yield and 22% ee achieved by using
cinchona alkaloid;13a 86% yield and 20% ee by using a
nickel(II) complex with chiral binaphthalenediimine li-
gands13c).
Scheme 2
a
Reaction conditions: 4a (1.0 equiv) and catalyst 3g (5 mol %) were
dissolved in Et2O (0.1 M), and NCS (1.2 equiv) was added in portions
over 45 min into the stirring solution; after stirring for an additional 15
min, the reaction mixture was purified directly by silica gel column
chromatography to yield product 6a. Then, recovery of catalyst was
performed using chromatography with hexane/EtOAc/Et3N (10:1:1)
as polar eluents.
Scheme 3. Scope of Asymmetric Chlorinations of 3-
Substituted Oxindoles with NCS
Intrigued by a very recent report concerning the preparation
of 3-sulfonylated oxindole derivatives,14 we employed chiral N-
Boc protected 3-chlorooxindole 6a as a substrate; the
sulfonylation of 6a with sodium p-toluenesulfinate in the
presence of triethylamine as the base afforded the desired
product 7 in 87% yield with 96% ee in acetonitrile (Scheme
4).14
a
Scheme 4. Sulfonylation of 6a for the Preparation of Chiral
3-Sulfonylated-3-Phenyled Oxindole 7
In conclusion, we have designed and developed a family of
iminophosphoranes as organocatalysts. These iminophosphor-
anes are air- and moisture-stable, which have been applied to
the asymmetric chlorinations of 3-substituted oxindoles. The
desired chlorinated products were obtained in excellent yields
with high levels of enantiomeric excesses (90−99% ee).
Importantly, recovery of the catalyst after simple chromato-
graphic separation for reuse in the model reaction was
achieved; the catalyst can be recycled more than six times
without loss of any enantioselectivity. Several advantages of this
catalytic process are high conversion after a very short reaction
time at ambient temperature, low catalytic loading, and scale-up
to multigram quantities with an excellent enantiomeric excess
value of >99%.
a
All reactions were carried out with 4 (0.1 mmol, 1.0 equiv) and
ASSOCIATED CONTENT
* Supporting Information
(PDF) Crystallographic data in CIF format for the (ZDF). The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b02323.
■
catalyst 3g (0.005 mmol) in Et2O (1 mL) at 25 °C; NCS (0.12 mmol,
S
1.2 equiv) was added in portions over 10 min into the stirring solution.
b
Reaction time was 1 h.
C
DOI: 10.1021/acs.orglett.5b02323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: jianweihan@sioc.ac.cn.
*E-mail: wanglimin@ecust.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is dedicated to Professor Dieter Enders (RWTH
Aachen University). This work was supported by grants from
National Natural Science Foundation of China (NSFC,
21472213, 21202186, 21272199), as well as by the Croucher
Foundation (Hong Kong) in the form of a CAS-Croucher
Foundation Joint Laboratory Grant. We thank Professor Henry
N. C. Wong (The Chinese University of Hong Kong) for
helpful discussions and generous support.
(14) Zuo, J.; Wu, Z.-J.; Zhao, J.-Q.; Zhou, M.-Q.; Xu, X.-Y.; Zhang,
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DOI: 10.1021/acs.orglett.5b02323
Org. Lett. XXXX, XXX, XXX−XXX