In situ generation of electrophilic trifluoromethylthio reagents for enantioselective trifluoromethylthiolation of oxindoles

Article abstract of DOI:10.1021/ol5006888

An organocatalytic asymmetric trifluoromethylthiolation reaction via in situ generation of active electrophilic trifluoromethylthio species involving trichloroisocyanuric acid and AgSCF₃ as a practical and easily handled electrophilic SCF₃ source for C_SP ³-SCF₃ bond formation was developed. Reactions with this one-pot version strategy occurred in good yields and excellent stereoselectivities to access enantiopure oxindoles bearing a SCF ₃-substituted quaternary chiral center. The straightforward process described here makes use of simple starting materials and proceeds under mild conditions, which will be useful in medicinal chemistry and diversity-oriented syntheses.

Full text of DOI:10.1021/ol5006888

Letter
pubs.acs.org/OrgLett
In Situ Generation of Electrophilic Trifluoromethylthio Reagents for
Enantioselective Trifluoromethylthiolation of Oxindoles
Xing-Li Zhu,† Jin-Hui Xu,† Dao-Juan Cheng, Li-Jiao Zhao, Xin-Yuan Liu,* and Bin Tan*
Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, P. R. China
S
* Supporting Information
ABSTRACT: An organocatalytic asymmetric trifluorome-
thylthiolation reaction via in situ generation of active
electrophilic trifluoromethylthio species involving trichloroiso-
cyanuric acid and AgSCF3 as a practical and easily handled
electrophilic SCF3 source for CSP3−SCF3 bond formation was
developed. Reactions with this one-pot version strategy
occurred in good yields and excellent stereoselectivities to
access enantiopure oxindoles bearing a SCF3-substituted quaternary chiral center. The straightforward process described here
makes use of simple starting materials and proceeds under mild conditions, which will be useful in medicinal chemistry and
diversity-oriented syntheses.
Scheme 1. General Synthetic Strategies for Direct
Trifluoromethylthiolation Involving Electrophilic SCF3
Reagents
t is well-known that the extremely high lipophilicity and high
Ielectron-withdrawing character of the trifluoromethylthio
(SCF3) group may contribute to an increase in their
transmembrane permeation, thus enhancing their bioavail-
ability.1 Therefore, the introduction of a SCF3 group into small
molecules is of considerable interest for the design and
discovery of bioactive compounds,2 such as JUK 0422, Tiflorex,
and Toltrazuril (Figure 1).
appears to be not so easy to carry out, and its stability seems
limited. N-(Trifluoromethylthio)phthalimide (D) appears to be
the best reagent in terms of accessibility, reactivity, and
enantioselective control.9 Even though these direct trifluor-
omethylthiolation reagents are shelf-stable and safe, a more
critical issue is the fact that these SCF3 reagents must be
prepared in advance. Because of these limitations and negative
aspects, it is still highly desirable to develop a more practical
and easily handled method for the generation of the SCF3
source directly. Our strategy is to generate the electrophilic
SCF3 reagents in situ from simple and readily available starting
materials, which would be trapped by nucleophile to access the
desired SCF3 product with good results (Scheme 1, right). If
this approach is successful, this would be an excellent method
without workup and isolation of SCF3 reagents.
Figure 1. Bioactive compounds bearing an SCF3 group.
Accordingly, the development of efficient methods for the
incorporation of the SCF3 group into organic compounds has
drawn much attention from synthetic research groups.1,2 Apart
from earlier indirect strategies,2c,3,4 a series of nucleophilic
SCF3-transfer reagents have been disclosed and employed for
the direct construction of the trifluoromethylthio moiety into
organic molecules.5 Recently, several elegant transformations
for Csp3−CF3S bond formation have been reported involving
newly developed electrophilic SCF3 reagents (Scheme 1, left).
Shibata and co-workers developed a hypervalent iodonium
ylide reagent (A) via in situ reduction of the trifluorometha-
nesulfonyl group to afford SCF3-substituted products.6
However, atom economy is very low, and metal is necessary
for SCF3-transfer, indicating that organocatalytic transforma-
tion is difficult. Billard and co-workers reported that
trifluoromethanesulfenamide (B) is an effective electrophilic
SCF3 source for the trifluoromethylthiolation of various
substrates.7 Inspired by Togni’s reagent, the Shen group
described a novel trifluoromethylthiolated thioperoxy reagent
(C) with interesting reactivity.8 However, the synthetic process
Oxindole compounds bearing a quaternary stereogenic
center at the 3-position are a prominent substructure in
numerous pharmaceuticals and bioactive compounds.10 In this
context, various synthetic strategies have been devised in recent
years for the asymmetric synthesis of 3,3-disubstituted oxindole
Received: March 5, 2014
Published: April 3, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
derivatives.11 If SCF3 group would be combined with oxindole,
it might result in further advances in the pharmacological
applications. Therefore, an effective approach for the
installation of a SCF3 group into 3-position of oxindoles
bearing a quaternary stereogenic center attracts our attention.
As for the enantioselective catalytic direct trifluoromethylth-
iolation reaction, only a few examples have been developed very
recently by Gade, Shen, and Rueping.12 During the preparation
of this manuscript, Rueping and co-workers reported the first
catalytic asymmetric trifluoromethylthiolation of oxindoles
using cinchona alkaloid catalyst and electrophilic SCF3 reagent
D,13 but the more practical approach is still desirable from the
point of view of step-economy and potential industrial
applications. Herein, we demonstrate an organocatalytic
enantioselective trifluoromethylthiolation of oxindoles via in
situ generation of electrophilic trifluoromethylthio reagents
from trichloroisocyanuric acid (TCCA) and AgSCF3 in the
presence of cinchona alkaloids as organocatalysts.
suggesting that the electrophilic trifluoromethylthio reagents
were able to be in situ generated and trapped by 3-substituted
oxindole (Table 1, entry 1). Considering the pioneering studies
of Barbas14and others by using cinchona alkaloid16,17 bifunc-
tional catalysts efficiently in functionalization of 3-substituted
oxindole substrates, we turned our attention to catalysts II, V,
and VI. The disappointed results (Table 1, entries 2, 5, and 6)
indicated that the bifunctional catalysts with a hydrogen bond
donor part have a negative effect on this transformation. In
great contrast, when the hydroxyl group of quinidine was
protected by a benzoyl group, the enantioselectivity was
improved to moderate (49% ee, entry 3) and the TMS-
protected quinidine did not have any improvement (Table 1,
entry 4). These results possibly demonstrated that the aromatic
interaction plays a crucial role in the control of enantiose-
lectivity. Based on these results and previous reports,14−16 we
postulated the commercially available Sharpless ligands (VII,
VIII, IX, and X) may be suitable catalysts for this attractive
transformation. Indeed, the yield and enantioselectivity of the
reaction increased when catalyst (DHQD)2PYR IX (Table 1,
entry 9) was used. Of the solvents tested, tetrahydrofuran
(THF) proved optimal with respect to catalytic activity and
selectivity (Table 1, entry 12). The best result (78% yield and
90% ee) in terms of selectivity and yield was obtained when the
reaction was conducted at 0 °C (Table 1, entry 16).
We initiated our studies by mixing the commercially available
reagent TCCA and AgSCF3 (3.3 equiv) in dichloromethane.
After the mixture was stirred at 30 °C for 30 min, 1a and
quinidine (I) were added (Table 1). To our delight, the
reaction proceeded smoothly and afforded the desired product
in 50% yield, albeit with poor enantioselectivity (8% ee),
a
Encouraged by these results, we expanded the substrate
scope of the reaction by using a variety of substituted oxindoles
with the in situ generated electrophilic SCF3 reagent under the
optimized reaction conditions. It was discovered that most of
the reactions were performed with good enantioselectivities and
yields (Scheme 2). It was shown that the position and the
Table 1. Screening Results of Reaction Conditions
Scheme 2. Scope of Trifluoromethylthiolation of Different
Aryl Oxindoles
b
c
entry
cat.
solvent
temp (°C)
yield (%)
ee (%)
1
I
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
THF
30
30
30
30
30
30
30
30
30
30
30
30
30
30
10
0
50
33
44
41
27
40
48
38
66
39
67
67
59
76
76
78
8
−17
49
6
2
II
3
III
IV
V
4
5
8
6
VI
VII
VIII
IX
X
−7
−66
58
70
46
83
85
76
40
90
90
7
8
9
10
11
12
13
14
15
16
IX
IX
IX
IX
IX
IX
Et2O
electronic property of the substituents for aromatic rings have a
very limited effect on the stereoselectivity of the process. For
example, various 3-aromatic oxindoles, bearing electron-
donating groups (X = OMe, Me) or electron-withdrawing
groups (X = F, Cl, Br, CF3) on the aryl ring, reacted efficiently
with electrophilic SCF3 reagents to afford the corresponding
products 2a−j in 61−95% yields with 83−95% ee. It is
noteworthy that the substrates containing electron-withdrawing
groups (2f−j) should be carried out at a temperature of −30 °C
for better results.
CH3CN
THF
THF
a
Reaction conditions: TCCA (0.06 mmol) and AgSCF3 (0.2 mmol)
were mixed in solvent (1.0 mL) and stirred for 30 min at 30 °C, and
then a solution of 1a (0.1 mmol) and catalyst (0.01 mmol, 10 mol %)
in solvent (1.0 mL) was added. After 12 h, the mixture was treated
with trifluoroacetic acid (TFA). Isolated yield. Determined by chiral
HPLC analysis.
b
c
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Letter
Further exploration of the substrate scope was focused on the
indolinone moiety (Scheme 3). Various substituents bearing
Scheme 4. Investigation for Reactive Electrophilic SCF3
Species
Scheme 3. Trifluoromethylthiolation of Oxindole with a
Variety of Substituents on Indolinones
crystallographic analysis (Figure 2), and those of other
trifluoromethylthio-containing compounds were assigned on
the assumption of the same mechanism.
Figure 2. X-ray crystal structure of product 2a.
In conclusion, we have developed an asymmetric trifluor-
omethylthiolation reaction via in situ generation of active
electrophilic trifluoromethylthio species involving TCCA and
AgSCF3 as a practical and easily handled electrophilic SCF3
source for CSP3−SCF3 bond formation through organocatalysis.
This practical protocol provided a highly efficient method for
the rapid synthesis of oxindoles bearing a SCF3-substituted
quaternary chiral center with excellent enantioselectivity from
simple and cheap starting materials without workup and
isolation of SCF3 reagents, which provide a particularly
advantageous alternative to the current useful SCF3 reagents.
This convenient and practical strategy should facilitate the
development of a wide range of trifluoromethylthiolation
reactions catalyzed by organic and metal catalysts.
different electronic properties were tolerable, giving the
corresponding products with high yields ranging from 50% to
93% and stereoselectivities (88−95% ee). The presence of Cl,
Br, or F at the indolinone moiety is very important for drug
discovery because halides are very reactive in many transition
metal-catalyzed reactions,17 which offer opportunities for
further modifications at these positions.
Although we are sure the electrophilic SCF3 reagents were
involved in this transformation, the SCF3 intermediate needs to
be further investigated for a better understanding of this
reaction. To gain some insights into the real SCF3 reagents in
current reaction, a series of control experiments were
conducted. Initially, monitoring the reaction of TCCA (0.1
mmol) with AgSCF3 (3.3 equiv) in CD3CN (1 mL) at room
temperature after 30 min by 19F NMR spectroscopy and GC−
MS revealed the formation of F3CS−SCF3 as the only active
species during this process (characterized by the F3CS−SCF3
resonance at δ = −45.7 ppm9a,18). In order to further confirm
F3CS−SCF3 as the active SCF3 reagent, the in situ generated
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedures, analytic date for products,
1
crystal data for 2a (CIF), and copies of H, 13C, and 19F NMR
and HPLC spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
19
F3CS−SCF3 was bubbled with the help of argon gas into
another solution of 1a and catalyst IX in THF at 0 °C. The
desired product was isolated with consistent enantioselectivity
(90% ee), further suggesting F3CS−SCF3 should be one of the
reactive species. To the best of our knowledge, it is the first
time that F3CS−SCF3 has acted as an electrophilic SCF3 source
for CSP3−SCF3 bond formation.20 However, after removal of
the F3CS−SCF3 active reagent and then the treatment of the
resulting residue with 1a and catalyst IX, to our surprise, the
expected product was also obtained with 90% ee, indicating the
existence of other electrophilic SCF3 species under the current
system. The resulting residue was difficult to characterize
because of its insolubility in some organic solvents. Although
we were not able to confirm the active SCF3 intermediate at the
present stage (Scheme 4), this in situ process provides a more
convenient and practical approach for the synthesis of
enantiopure SCF3 substituted compounds. The absolute
configuration of 2a was determined to be (S) by X-ray
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: liuxy3@sustc.edu.cn.
*E-mail: tanb@sustc.edu.cn.
Author Contributions
†X.L.Z. and J.H.X. contributed equally to this work
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful for the financial support from the National
Natural Science Foundation of China (Nos. 21302088,
21302087), Shenzhen special funds for the development of
biomedicine, internet, new energy, and new material industries
(JCYJ20130401144532131, JCYJ20130401144532137), and
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Letter
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