An Organocatalytic Asymmetric Friedel-Crafts Addition/Fluorination Sequence: Construction of Oxindole-Pyrazolone Conjugates Bearing Vicinal Tetrasubstituted Stereocenters

Article abstract of DOI:10.1021/acs.orglett.5b02470

A highly efficient and practical one-pot sequential process, consisting of an organocatalytic enantioselective Friedel-Crafts-type addition of 4-nonsubstituted pyrazolones to isatin-derived N-Boc ketimines and a subsequent diastereoselective fluorination of the pyrazolone moiety, is developed. This reaction sequence delivers novel oxindole-pyrazolone adducts featuring vicinal tetrasubstituted stereocenters with a 0.5 mol % catalyst loading in high yield with excellent enantio- and diastereocontrol. Notably, chloro, bromo, and thioether functionalities can be readily incorporated, rendering a broad diversity of the product.

Full text of DOI:10.1021/acs.orglett.5b02470

Letter
pubs.acs.org/OrgLett
An Organocatalytic Asymmetric Friedel−Crafts Addition/Fluorination
Sequence: Construction of Oxindole−Pyrazolone Conjugates Bearing
Vicinal Tetrasubstituted Stereocenters
Xiaoze Bao, Baomin Wang,* Longchen Cui, Guodong Zhu, Yuli He, Jingping Qu, and Yuming Song
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian
116024, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient and practical one-pot sequential
process, consisting of an organocatalytic enantioselective Friedel−
Crafts-type addition of 4-nonsubstituted pyrazolones to isatin-
derived N-Boc ketimines and a subsequent diastereoselective
fluorination of the pyrazolone moiety, is developed. This reaction
sequence delivers novel oxindole−pyrazolone adducts featuring
vicinal tetrasubstituted stereocenters with a 0.5 mol % catalyst
loading in high yield with excellent enantio- and diastereocontrol.
Notably, chloro, bromo, and thioether functionalities can be readily incorporated, rendering a broad diversity of the product.
esearch efforts toward the development of novel chemical
structures have always been welcome and encouraged by
leading to a wide variety of enantioenriched 3-amino quaternary
oxindole products.9,10 In this context, noteworthy is that elegant
contributions from the groups of Feng,10a Shao,10b Wenne-
mers,10c and others10d−f realized the assembly of vicinal
tetrasubstituted stereogenic structures. Despite the elegance of
these reports, in general, the simultaneous formation of both
stereocenters in a single-step reaction with a tertiary carbon
nucleophile through the orchestration of a chiral promoter
restricts the variability of the substituents attached to the
quaternary carbon center outside the oxindole ring (Scheme 1).
To address this deficiency and to broaden the diversity of the
stereocenters generated, we envisioned a one-pot stereoselective
sequential transformation involving an organocatalytic enantio-
selective Friedel−Crafts-type addition of pyrazolones to isatin-
derived N-Boc ketimines and a further diastereoselective
functionalization of the pyrazolone moiety (Scheme 1). This
simple one-pot operation takes advantage of the double
nucleophilic reactivity of the 4-nonsubstituted pyrazolone
species and would lead to the construction of a novel
oxindole−pyrazolone conjugate bearing vicinal tetrasubstituted
stereocenters in a highly stereoselective manner. More
interestingly, by varying the electrophile of the second step, a
wide variety of different tetrasubstituted pyrazolone carbon
centers could potentially be achieved, thereby significantly
extending the diversity of the stereodiads. Herein, we document
our research efforts toward the validation of this concept.
R
the medicinal and agrochemical communities, as these endeavors
often hold great potential for the discovery of new drug leads. In
this context, studies based on modifications of privileged
pharmacophores are especially appealing due to the established
biological activities of the parent core structures. Oxindole and
pyrazolone scaffolds represent privileged heterocyclic structures
and pharmacophores found in a variety of biologically active
natural products and medicinal agents (Figure S-1).1,2 Inspired
by the pharmaceutical importance and hence the synthetic value
of these species, recent years have seen intense efforts toward the
construction of enantiomerically enriched chiral 3,3-disubsti-
tuted oxindoles1a−c,3 and 4,4-disubstituted pyrazolones.4
Despite these efforts, however, the construction of vicinal
tetrasubstituted stereocenters incorporated into the oxindo-
le1a−c,5−7 or pyrazolone scaffolds in a highly stereoselective
manner remains a remarkably challenging task, and methods
toward this goal are very rare, mainly due to the inherent
difficulties associated with the assembly of such a sterically
congested structural arrangement. To date, very limited
approaches to oxindoles incorporating fully substituted adjacent
stereogenic centers have been developed starting from 3-
substituted oxindoles6 or isatins.7 In contrast, access to
pyrazolone entities with such a stereodiad is even rarer, with
only one example being reported.8 Hence, when considering the
formidable challenge within this topic coupled with the
significant pharmaceutical relevance of oxindole and pyrazolone
scaffolds, the development of highly efficient, enantio- and
diastereoselective methods leading to the expeditious buildup of
vicinal tetrasubstituted stereocenters featuring oxindole and/or
pyrazolone skeletons is arguably in high demand.
The one-pot reaction sequence of the Friedel−Crafts addition
of pyrazolone 2a to isatin-derived N-Boc ketimine 1a followed by
fluorination with N-fluorobenzenesulfonimide (NFSI) was
selected as a testing system to define the optimal conditions
(Table 1). An initial brief screening of chiral organic base
Very recently, isatin-derived ketimines have risen to
Received: August 27, 2015
prominence owing to their versatile electrophilic reactivity,
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02470
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Organic Letters
Letter
Compared to tartrate-based guanidines G1, G2 and natural
quinine, to our great pleasure, the well-established quinine
thiourea catalyst Q1 exhibited excellent reactivity and perfect
stereocontrol, affording the oxindole−pyrazolone conjugate with
vicinal N- and F-containing quaternary centers in 90 min (30 min
for the first step) with a 95% yield and a more than 99%
enantiomeric excess (entry 4). Notably, an even better reactivity
was observed with quinine squaramide catalyst Q2, which
accomplished the addition step in only 10 min (entry 5). Given
the extremely high reactivity of Q2, reactions with lower catalyst
loadings were investigated. Interestingly, with 2 mol % Q2, still a
very fast reaction was observed, completing the addition step in
20 min without any loss of the yield or stereoselectivity for the
whole transformation (entry 6). Remarkably, further reducing
the loading to 0.5 mol % had no impact on the yield and
stereoselectivity, only with a modest extension of the reaction
time to 1.5 h (entry 7). Particularly noteworthy is that even a very
low catalyst loading of 0.1 mol % could also afford an excellent
result of 92% yield and 97% ee, though a 9-h period was needed
to drive the addition step to completion (entry 8). It should be
stressed that such a low catalyst amount is among the very rare
examples of low-loading organocatalysis.12 In consideration of
the rate and stereoselectivity, 0.5 mol % Q2 was used in the
following studies. In addition, the stoichiometries of pyrazolone
2a, NFSI, and K2CO3 can be reduced without compromising the
outcome (entry 9). A comparison experiment confirmed the
superiority of Q2, as Q1 exhibited lower reactivity and
enantioselectivity under otherwise identical conditions (entry
10 vs 9).
Scheme 1. Strategies to Construct 3-Amino Oxindoles with
Vicinal Tetrasubstituted Stereocenters
a
a
PG = protecting group, EWG = electron-withdrawing group.
a
Table 1. Optimization of Reaction Conditions
With the optimal conditions being identified, the substrate
generality with respect to both the isatin ketimine and
pyrazolone components was evaluated. The results were
summarized in Figure 1, which indicates that a broad spectrum
of isatin N-Boc ketimines and pyrazolones were amenable to the
sequential addition/fluorination process, affording a diverse
array of oxindole−pyrazolone conjugates bearing vicinal N- and
F-containing quaternary centers in uniformly high yields with
perfect stereocontrol. In most cases, essentially enantiopure
products were obtained.
Initially, N-substitution of the oxindole nitrogen was
investigated (Figure 1, 3aa−3da). Interestingly, other than the
benzyl group, methyl and allyl substituents were well
accommodated. In addition, nonprotected free NH on the
oxindole ring was also tolerated (3da), which allows for facile
potential N-substitutions on demand. Next, with N-benzyl
protection, substitution on the benzene ring of the oxindole
frame was evaluated. It was found that both electron-withdrawing
halogen atoms and electron-donating methyl and methoxy
substituents were well accommodated, achieving the same levels
of excellence in efficiency and stereoselectivity (3ea−3ia).
Following the establishment of the broad generality of the
isatin ketimine component, the substrate scope with respect to
the pyrazolone partner was surveyed. Similarly, a broad array of
pyrazolones were demonstrated to be competent substrates,
affording excellent yields and perfect stereoselectivities with high
efficiency (3ab−3am). Specifically, various substituents at the
C3 position of the pyrazolone ring were broadly accommodated,
including alkyl, benzyl, aryl, and heteroaryl groups. Of note is the
tolerance to the cyclopropyl group (3ad), a pharmaceutically
relevant structure motif.13 In addition, the presence of allyl,
chloro, and bromo functional groups in the product molecules
provides useful synthetic handles for further derivatization,
thereby potentially enhancing the structural diversity of the
b
c
d
entry
cat.
x
time
yield (%)
ee (%)
1
2
3
4
5
6
7
8
quinine
G1
10
10
10
10
10
2
41 h
14 h
27 h
95
94
94
95
94
94
93
92
93
94
50
59
G2
23
Q1
30 min
10 min
20 min
1.5 h
9 h
>99
>99
>99
>99
97
Q2
Q2
Q2
0.5
0.1
0.5
0.5
Q2
e
9
Q2
2 h
>99
97
e
10
Q1
9 h
a
Unless otherwise noted, reactions were conducted with 1a (0.1
mmol), cat. (x mol %), 2a (0.12 mmol) in solvent (1.0 mL). After 1a
was consumed, K2CO3 (0.15 mmol) and NFSI (0.15 mmol) were
added, and the mixture was stirred for 1 h at 25 °C. Time for the first
b
c
d
step. Isolated yield. Ee determined by chiral HPLC analysis; dr
e
determined by 1H NMR of the crude reaction mixture. 2a (0.11
mmol), K2CO3 (0.13 mmol), and NFSI (0.13 mmol) were used.
catalysts revealed that both tartrate-derived guanidines11
developed recently by us and cinchona alkaloids can effectively
catalyze the reaction with excellent yields and varying degrees of
enantiocontrol (Table 1, entries 1−3). It is interesting to note
that uniformly high diastereoselectivities of over 20:1 dr were
always observed on forging the fluorine-containing quaternary
center in the fluorination event with NFSI and K2CO3.
B
DOI: 10.1021/acs.orglett.5b02470
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Organic Letters
Letter
Scheme 2. Elucidation of the Stereochemical Course of the
Sequential Process
event is independent of the chiral catalyst, but a pure substrate-
controlled result.15
The stepwise sequential nature of the current process and the
independence of the diastereocontrol on the chiral catalyst make
it possible to vary the electrophiles in the second step, thereby
expanding the diversity of the vicinal tetrasubstituted stereogenic
structures. As proof of concept, the enantioselective Friedel−
Crafts addition of pyrazolone 2a to isatin ketimine 1a was readily
combined with diastereoselective chlorination and bromination
processes by simple N-chloro- and N-bromosuccinimide
(Scheme 3), respectively, with high yield and excellent
Scheme 3. Variability of the Vicinal Tetrasubstituted
Stereocenters
stereoselectivity. Furthermore, the sequential process is also
amenable to the introduction of a thioether structure, as
demonstrated by the capture of the addition product by N-
phenylthiophthalimide, giving the vicinal quaternary-center
product in 93% yield, 14:1 dr, and 94% ee (Scheme 3). Given
the reported reactivity of 4-substituted pyrazolones,4 the
synthetic potential of the current strategy may be considerably
expanded.
Figure 1. Generality of the Friedel−Crafts addition/fluorination
sequence; dr > 20:1 for all cases.
product. Owing to the low catalyst loading of the process, a gram-
scale synthesis of 3aj was readily achieved with maintained
efficiency and stereoselectivity (eq 1), thus highlighting the
practical utility of the current reaction.
In conclusion, a highly efficient and practical one-pot
sequential process, consisting of an organocatalytic enantiose-
lective Friedel−Crafts-type addition of 4-nonsubstituted pyr-
azolones to isatin-derived N-Boc ketimines and a subsequent
diastereoselective functionalization of the pyrazolone moiety, is
developed. This reaction sequence delivers novel oxindole−
pyrazolone adducts featuring vicinal tetrasubstituted stereo-
centers in high yield with excellent enantio- and diastereocontrol.
Additional salient features include a very low catalyst loading of
0.5 mol %, mild reaction conditions, ease of operation, facile
scale-up, and broad substrate scope. Most importantly, the
flexible variability of the electrophiles employed in the second
step coupled with the independence of the diastereocontrol on
the chiral catalyst allows for a broad diversity of the product, as
exemplified by the facile incorporation of fluoro, chloro, bromo,
and thioether functionalities into the product molecules. Studies
directed toward extending the scope of the sequential process
and evaluating the biological activities of the oxindole−
pyrazolone conjugates are currently underway in our laboratory,
and the results will be reported in due course.
The absolute stereochemistry of product 3aj was determined
to be (3S, 4′R) by X-ray crystallographic analysis,14 and those of
other products were assigned by analogy. In order to elucidate
the stereochemical course of the sequential process, a two-pot
experiment was investigated. Thus, upon completion of the
addition of 2a to 1b, the intermediate product 4 was isolated in
95% yield and 99% ee (Scheme 2), which clearly indicates that
the first step is enantioselective. Then, exposure of 4 to NFSI and
K2CO3 in the absence of the chiral catalyst Q2 delivered the final
product 3ba in 92% yield, with 98% ee and over 20:1 dr (Scheme
2). This result firmly demonstrates that the second step is
diastereoselective, and the diastereoselectivity of the fluorination
C
DOI: 10.1021/acs.orglett.5b02470
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Zhou, Z.; Tang, C. Eur. J. Org. Chem. 2013, 2013, 4844. (i) Han, X.; Yao,
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02470.
■
S
(5) (a) Pesciaioli, F.; Righi, P.; Mazzanti, A.; Bartoli, G.; Bencivenni, G.
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Y.; Ooi, T. J. Am. Chem. Soc. 2013, 135, 18706.
Experimental procedures and detailed characterization
data of all new compounds (PDF)
X-ray crystal details for 3aj (CIF)
AUTHOR INFORMATION
Corresponding Author
■
(7) (a) Wang, X.-N.; Zhang, Y.-Y.; Ye, S. Adv. Synth. Catal. 2010, 352,
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*E-mail: bmwang@dlut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21076035, 20972022), the Program for New Century
Excellent Talents in University (NCET-11-0053), and the
Fundamental Research Funds of the Central Universities
(DUT13ZD202, DUT15TD25) for support of this work.
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in the Supporting Information for details.
D
DOI: 10.1021/acs.orglett.5b02470
Org. Lett. XXXX, XXX, XXX−XXX