Angewandte
Chemie
DOI: 10.1002/anie.201305075
Trifluoromethylthiolation
Enantioselective Electrophilic Trifluoromethylthiolation of b-Keto-
esters: A Case of Reactivity and Selectivity Bias for Organocatalysis**
Xueqiang Wang, Tao Yang, Xiaolin Cheng, and Qilong Shen*
The incorporation of an SCF3 group into small molecules is of
great interest to the pharmaceutical and agrochemical
industries,[1] because the high lipophilicity and high elec-
tron-withdrawing character of the SCF3 group may have
beneficial effects on the pharmacokinetics of drug mole-
cules.[2] Thus, the development of efficient methods for the
introduction of a SCF3 group into organic compounds has
recently become a subject of intense study[3] and tremendous
progress has been achieved in the transition-metal-catalyzed
trifluoromethylthiolation of aryl, alkenyl, or alkynyl sub-
strates under mild conditions.[4] In particular, there has been
a growing interest in the stereoselective introduction of SCF3
groups to generate chiral centers.[5] While there is a growing
number of methods for the catalytic enantioselective trifluor-
omethylation,[6] to the best of our knowledge, the analogous
catalytic asymmetric direct trifluoromethylthiolation has
never been reported.
We recently reported the preparation of an electrophilic
trifluoromethylthiolated hypervalent iodine reagent (1),
which is stable in the most common solvents even at 808C.[7]
This reagent is remarkably reactive and allows the trifluoro-
methylthiolation of a variety of nucleophiles, such as aryl or
vinyl boronic acids, alkynes, aldehydes, and amides, under
mild conditions. More specifically, reactions of b-ketoesters
with compound 1 gave the corresponding trifluoromethylth-
iolated products in excellent yields when N,N-dimethylami-
nopyridine (DMAP) was used as the base. We wondered if it
is possible to influence the stereoselectivity of the reaction by
employing a chiral organic Lewis base. Herein, we report the
asymmetric trifluoromethylthiolation reaction of b-ketoesters
with good to excellent enantioselectivity in the presence of
a quinine or quinine-based phase-transfer catalyst.
We initially chose the reaction of indanone-derived b-
ketoester 2a–c with reagent 1 to optimize the reaction
conditions. We used quinine as the base because of the ability
of cinchona alkaloids to function as effective organic chiral
Lewis bases and nucleophilic catalysts.[8,9] The reaction of b-
ketoester 2a with reagent 1 in THF was complete after 12 h at
room temperature in the presence of 20 mol% of quinine,
affording the trifluoromethylthiolated product in 90% yield
with 42% ee (Table 1, entry 1). The reaction proceeded much
more slowly for more hindered b-ketoesters 2b or 2c
(Table 1, entries 2 and 3). However, to our delight, the
enantioselectivity of the trifluoromethylthiolation increased
significantly to 90% ee when b-ketoester 2c was employed
(Table 1, entry 3). The reactions of b-ketoester 2c with
reagent 1 in other ethers, such as diethyl ether, dioxane,
DME, or diglyme, occurred with similar enantioselectivity,
but the reaction in diethyl ether was faster than those in other
solvents (Table 1, entries 4–7). Reactions in more polar
solvents, such as CH3CN and acetone, or a less polar solvent,
such as CH2Cl2, generated the corresponding products with
slightly lower enantioselectivity (Table 1, entries 8–10). Inter-
estingly, when CHCl3 or toluene were used as the solvent, the
enantioselectivity of the reaction was increased to 92% ee
(Table 1, entries 11 and 12). As reactions in toluene were
faster than those in CHCl3, we further optimized the reaction
conditions using toluene as the solvent. We found that
reaction in toluene was complete after 36 h at 408C, giving
the desired product in 90% yield with 92% ee (Table 1,
entry 13). Other cinchona alkaloids, such as cinchonidine
(3b), hydroquinine (3c), quinidine (3d), cinchonine (3e), and
hydroquinidine (3 f), were then tested under the optimized
conditions, but the reactions in the presence of these bases
generally occurred with lower enantioselectivity (Table 1,
entries 14–18). The hydroxy group of quinine is important for
the high reactivity of the catalyst. The use of ester derivative
3g or thiourea derivative 3h as the catalyst led to the
complete shutdown of the reaction (Table 1, entries 19 and
20).
[*] X. Q. Wang,[+] T. Yang,[+] Prof. Dr. Q. Shen
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P.R. China)
E-mail: shenql@sioc.ac.cn
The optimized reaction conditions summarized in entry 13
in Table 1 were used to study the scope of the quinine-
catalyzed asymmetric trifluoromethylthiolation of a variety of
b-ketoesters (Table 2). In general, indanone-derived b-
ketoesters generated the corresponding products in high
yields with excellent enantioselectivities (86–94% ee),
regardless of the nature and position of the substituents on
the b-ketoester derivatives (Table 2, 4a–k). Reactions of
substrates with electron-withdrawing groups occurred with
similar enantioselectivity to those of substrates with electron-
donating groups (Table 2, 4c–e vs. 4g–k). The size of the ester
group has a huge influence on the enantioselectivity of the
Dr. X. Cheng
Center for Molecular Biophysics, Oak Ridge National Laboratory
1 Bethel Valley Rd, Oak Ridge, TN 37831 (USA)
[+] These authors contributed equally to this work.
[**] The authors gratefully acknowledge financial support from the
National Basic Research Program of China (2012CB821600), the
Key Program of Natural Science Foundation of China (21032006),
the National Natural Science Foundation of China (21172245/
21172244/B020304), the Shanghai Pujiang Program (11J1412200),
and SIOC.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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