Chincona alkaloid-catalyzed enantioselective trifluoromethylthiolation of oxindoles

Article abstract of DOI:10.1002/cjoc.201400392

An organocatalytic asymmetric trifluoromethylthiolation of 3-aryl or 3-alkyloxindoles employing a trifluoromethyl-substituted thioperoxide as the electrophilic trifluoromethylthiolating reagent was described. Reactions occurred in good to excellent enanti

Full text of DOI:10.1002/cjoc.201400392

COMMUNICATION
DOI: 10.1002/cjoc.201400392
Chincona Alkaloid-Catalyzed Enantioselective
Trifluoromethylthiolation of Oxindoles†
Tao Yang, Qilong Shen,* and Long Lu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
An organocatalytic asymmetric trifluoromethylthiolation of 3-aryl or 3-alkyloxindoles employing a trifluoro-
methyl-substituted thioperoxide as the electrophilic trifluoromethylthiolating reagent was described. Reactions oc-
curred in good to excellent enantioselectivities to generate oxindoles with a SCF3-substituted quaternary chiral cen-
ter.
Keywords organocatalytic, fluorine, trifluoromethylthio, asymmetric, oxindole
Introduction
methods for the preparation of optically pure trifluoro-
methylthiolated oxindoles will be highly beneficial to
the drug development. During the preparation of this
manuscript, Rueping, Liu and Tan independently re-
ported two asymmetric trifluoromethylthiolation of
3-aryloxindoles using cinchona alkaloid catalyst and
electrophilic trifluoromethylthiolating reagents.[8a-8b]
However, no asymmetric trifluoromethylthiolation of
3-alkyloxindoles was described in both methods. Herein,
we demonstrated an organo-catalytic enantioselective
trifluoromethylthiolation of both 3-aryl and 3-alkyl-
oxindoles using trifluoromethyl-substituted thioperoxide
as the electrophilic trifluoromethylthiolating reagent.
The trifluoromethylthio group (CF3S － ) with a
Hansch value of 1.44 is considered as one of the most
lipophilic groups.[1] It is generally recognized that in-
corporation of the trifluoromethylthio group into drug
molecules will enhance their transmembrane permeation
ability and consequently, improve the drug’s pharma-
cological properties and efficiency.[2] As a result, con-
siderable efforts have been devoted to the development
of efficient methods for the introduction of the tri-
fluoromethylthio group into organic molecules.[3] In the
last few years, several elegant methods have emerged
by either employing transition metal catalyst[4] or using
electrophilic trifluoromethylthiolating reagents.[5] These
methods showed advantages over the classic methods
that typically conduct under harsh conditions and re-
quire the pre-formation of thiols or their derivatives.
In contrast with these significant achievements for
the formation of C－SCF3 bond, the corresponding
transformations that enantioselectively introduce the
trifluoromethylthio group into organic compounds are
still scare.[6] Shen and Rueping independently reported
the first cinchona alkaloid-catalyzed asymmetric tri-
fluoromethylthiolation of cyclic β-ketoesters.[6a-6b] Gade
and coworkers reported a copper-catalyzed asymmetric
trifluoromethylthiolation of cyclic β-ketoesters using the
trifluoromethylated thioperoxide reagent.[6c] Thus, de-
velopment of new highly enantioselective trifluoro-
methylthiolating methods remains largely unexplored.
Oxindole is among one of the privileged structural
motifs in biological systems and biologically active nat-
ural products.[7] Development of new asymmetric
Results and Discussion
We initially explored the reaction of N-Boc pro-
tected-3-phenyloxindole and trifluoromethyl-substituted
thioperoxide using quinine[9] as the catalyst in different
solvent to optimise the reaction conditions. It was found
that when diethyl ether was used as the solvent, the re-
action of N-Boc protected-3-phenyloxindole with re-
agent 2 occurred to 97% conversion with 78% ee (Table
1, entry 3). Reaction in THF occurred slightly slowly
and in slightly lower enantioselectivity, while reaction
in dioxane resulted in much lower enantioselectivity
(27% ee) (Table 1, entries 1, 2). Reactions in other sol-
vents such as CH2Cl2 or CHCl3 or toluene generated the
corresponding products with slightly lower enantiose-
lectivity (Table 1, entries 4－6). Several other commer-
cially available cinchona alkaloid catalysts were further
evaluated. However, those catalysts displayed less effi-
cienct enantioselectivity than those of quinine (Table 1,
*
E-mail: lulong@mail.sioc.ac.cn, shenql@mail.sioc.ac.cn; Tel.: 0086-021-54925197
Received June 15, 2014; accepted July 18, 2014; published online August 25, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400392 or from the author.
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai on the occasion of their 90th birthdays.
†
678
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 678—680

Chincona Alkaloid-Catalyzed Enantioselective Trifluoromethylthiolation of Oxindoles
entries 7－10). Switching the protecting group from Boc
to a more hindered CO2Ad did not have a significant
effect on the enantioselectivity (Table 1, entry 11). To
our delight, when N-Boc protected 3-methyloxindole
was used as the substrate, an excellent enantioselectivity
was obtained (97% ee) (Table 1, entry 12). Interestingly,
when N-(trifluoromethylthio)phthalimide was used as
the electrophilic trifluoromethylthiolating reagent under
otherwise identical conditions, the reaction occurred to
85% yield with a 33% ee (Table 1, entry 13).
ity (Table 2, 3n－3p).
Table 2 Scope of quinine-catalyzed enantioselective trifluoro-
methylthiolation of oxindolesa-c
R1
R1
SCF3
Me
20 mol% Quinine
R3
O
R3
O
Ar
O SCF3
Et2O, 35 o
C
N
R2
N
R2
Me
Ar = 2-iodophenyl
36−60 h
1
2
3
F
Table 1 Optimization of the reaction conditions for cinchona-
alkoloid-catalyzed asymmetric trifluoromethylthiolation of oxi-
dolesa
SCF3
O
SCF3
O
SCF3
O
F
N
N
Boc
N
Boc
Boc
R1
R1
3a: 44 h, 92% , 85% ee
3b: 48 h, 95%, 85% ee
3c: 44 h, 95%, 77% ee
Me
Me
SCF3
O
conditions
F
MeO
Ar
O SCF3
+
O
N
R2
N
R2
SCF3
O
SCF3
SCF3
O
Ar = 2-iodophenyl
F
1
2
3
O
N
CO2Ad
N
N
Boc
Boc
Entry R1/R2
Catalyst
quinine
quinine
quinine
quinine
quinine
quinine
quinidine
Solvent Temp./℃ Time/h Yieldb/% eec/%
3d: 44 h, 95%, 73% ee
3e: 48 h, 93%, 87% ee
3f: 60 h, 94%, 80% ee
1
2
3
4
5
6
7
8
9
Ph/Boc
THF 40
dioxane 40
Et2O 40
CH2Cl2 40
CHCl3 40
toluene 40
Et2O 40
36
36
36
36
36
36
36
36
36
36
60
36
36
73
83
97
89
93
87
62
91
87
10
94
99
85
63
Me
Me Me
SCF3
SCF3
Me
Ph/Boc
Ph/Boc
Ph/Boc
Ph/Boc
Ph/Boc
Ph/Boc
Ph/Boc
Ph/Boc
27
SCF3
MeO
R
78
O
O
O
N
N
N
58
Me
Boc
Boc
Boc
68
3g: R = H, 36 h, 99%, 97% ee 3i: 36 h, 94%, 96% ee
3h: R = Me, 36 h, 99%, 98% ee
3j: 36 h, 95%, 98% ee
78
Me
Me
SCF3
O
SCF3
O
−20
48
Me
SCF3
O
F
hydroquinine Et2O 40
hydroquinidine Et2O 40
N
N
N
−63
−42
80
Boc
Boc
Boc
CF3
F
10 Ph/Boc
cinchonine
Et2O 40
Et2O 40
Et2O 35
Et2O 35
3k: 36 h, 92%, 95% ee
3l: 36 h, 99%, 98% ee
3m: 36 h, 95%, 96% ee
11 Ph/CO2Ad quinine
12 Me/Boc quinine
13 Me/Boc quinine
Bn
Et
Pent
SCF3
SCF3
SCF3
97
33d
O
O
O
N
N
N
Boc
Boc
Boc
a Reaction conditions: 1 (1.0 equiv.), 2 (1.2 equiv.), catalyst (20
mol%), in 0.2 mol/L solution of solvent at 35－40 ℃ for 36－
60 h. b Yields were determined by 19F NMR spectroscopy in the
presence of an internal standard. c Determined by chiral HPLC
analysis. d N-(Trifluoromethylthio) phthalimide was used as the
electrophilic trifluoromethylthiolating reagent.
3n: 36 h, 98%, 97% ee
3o: 48 h, 92%, 96% ee
3p: 36 h, 92%, 99% ee
a Reaction conditions: 1 (0.4 mmol), 2 (0.48 mmol), quinine (20
mol%), in 0.2 mol/L solution of Et2O at 35 ℃ for 36－60 h.
b Isolated yields. c ee values were determined by HPLC analysis
on a chiral stationary phase.
With optimized conditions in hand, we evaluated the
scope of this enantioselective trifluoromethylthiolation
with various 3-aryl and 3-alkyl oxindoles. In general,
reactions of 3-aryl-oxindoles generated the correspond-
ing products in lower enantioselectivities than those of
3-alkyloxindoles. Reactions of 3-aryloxindoles gener-
ated the corresponding trifluoromethylthiolated products
in 73% － 87% ee, while reactions of the 3-alkyl-
oxindoles formed the products in 95%－99% ee. In ad-
dition, reactions of 3-alkylindoles with electron-donat-
ing or withdrawing groups at different position of in-
doles occurred in excellent enantioselectivities (95%－
99% ee, Table 2, 3g－3p). Not only 3-methyloxindoles
but also 3-ethyl, benzyl and pentyloxidoles generated
the corresponding products in excellent enantioselectiv-
The absolute configuration (S) of the stereogenic
center in compound 3 was determined by X-ray crystal-
lographic analysis of a single crystal of compound 3l
(Figure 1). The configurations of the other products
were assigned on the assumption of a uniform mecha-
nistic pathway.
Conclusions
In summary, we have developed an organocatalytic
asymmetric trifluoromethylthiolation of oxindoles. A
series of optically active oxindoles bearing a SCF3-sub-
stituted quaternary stereogenic center were obtained in
excellent yields with good to excellent enantioselectivi-
ties. Further development of relevant catalytic system is
Chin. J. Chem. 2014, 32, 678—680
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
679

Yang, Shen & Lu
COMMUNICATION
[4] Selected methods for the introduction of trifluoromethylthio group
via transition metal catalysts: (a) Chen, Q.-Y.; Duan, J.-X. Chem.
Commun. 1993, 918; (b) Adams, D. J.; Clark, J. H. J. Org. Chem.
2000, 65, 1456; (c) Teverovskiy, G.; Surry, D. S.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2011, 50, 7312; (d) Zhang, C.-P.; Vicic, D. A.
J. Am. Chem. Soc. 2012, 134, 183; (e) Chen, C.; Chu, L.-L.; Qing,
F.-L. J. Am. Chem. Soc. 2012, 134, 12454; (f) Chen, C.; Xie, Y.; Chu,
L.-L.; Wang, R.-W.; Zhang, X.-G.; Qing, F.-L. Angew. Chem., Int. Ed.
2012, 51, 2492; (g) Zhang, C.-P.; Vicic, D. A. Chem. Asian J. 2012,
7, 1756; (h) Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc.
2012, 134, 18237; (i) Xu, C.-F.; Shen, Q. Org. Lett. 2014, 16, 2046;
(j) Weng, Z.; He, W.; Chen, C.; Lee, R.; Dan, D.; Lai, Z.; Kong, D.;
Yuan, Y.; Huang, K.-W. Angew. Chem., Int. Ed. 2013, 52, 1548; (k)
Wang, K.-P.; Yun, S. Y.; Mamidipalli, P.; Lee, D. Chem. Sci. 2013, 4,
3205; (l) Zhai, L.; Li, Y.; Yin, J.; Jin, K.; Zhang, R.; Fu, X.; Duan, C.
Tetrahedron 2013, 69, 10262; (m) Rueping, M.; Tolstoluzhsky, N.;
Nikolaienko, P. Chem. Eur. J. 2013, 19, 14043; (n) Danoun, G.;
Bayarmagnai, B.; Grünberg, M. F.; Gooßen, L. J. Chem. Sci. 2014, 5,
1312; (o) Hu, M.-Y.; Rong, J.; Miao, W.-J.; Ni, C.-F.; Han, Y.-X.; Hu,
J.-B. Org. Lett. 2014, 16, 2030; (p) Wang, X.; Zhou, Y. J.; Ji, G.-J.;
Wu, G.-J.; Li, M.; Zhang, Y.; Wang, J.-B. Eur. J. Org. Chem. 2014,
3093; (q) Tan, J.-W.; Zhang, G.-T.; Ou, Y.-L.; Yuan, Y.-F.; Weng,
Z.-Q. Chin. J. Chem. 2013, 31, 921.
Figure 1 ORTEP view of trifluoromethylthiolated compound 3l.
Thermal ellipsoids are set at 50% probability.
[5] Selected methods for the introduction of trifluoromethylthio group
via electrophilic trifluoromethylthiolating reagents: (a) Yagupolskii,
L. M.; Kondratenko, N. V.; Timofeeva, G. N. J. Org. Chem. USSR
1984, 20, 103; (b) Munavalli, S.; Rohrbaugh, D. K.; Rossman, D. I.;
Berg, F. J.; Wagner, G. W.; Durst, H. D. Synth. Commun. 2000, 30,
2847; (c) Ferry, A.; Billard, T.; Langlois, B. R.; Bacque, E. J. Org.
Chem. 2008, 73, 9362; (d) Ferry, A.; Billard, T.; Langlois, B. R.;
Bacque, E. Angew. Chem., Int. Ed. 2009, 48, 8551; (e) Ferry, A.;
Billard, T.; Bacque, E.; Langlois, B. R. J. Fluorine Chem. 2012, 134,
160; (f) Shao, X.-X.; Wang, X.-Q.; Yang, T.; Lu, L.; Shen, Q. Angew.
Chem., Int. Ed. 2013, 52, 3457; (g) Vinogradova, E. V.; Müller, P.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2014, 53, 3125; (h) Pluta, R.;
Nikolaienko, P.; Rueping, M. Angew. Chem., Int. Ed. 2014, 53, 1650;
(i) Kang, K.; Xu, C.-F.; Shen, Q. Org. Chem. Front. 2014, 1, 294; (j)
Yang, Y.; Jang, X.-L.; Qing, F.-L. J. Org. Chem. 2012, 77, 7538; (k)
Yang, Y.-D.; Azuma, A.; Tokunaga, E.; Yamasaki, M.; Shiro, M.;
Shitaba, N. J. Am. Chem. Soc. 2013, 135, 8782.
in progress in our laboratory and will be reported in due
course.
Acknowledgement
The authors gratefully acknowledge the financial
support from National Basic Research Program of
China (2012CB821600), the Key Program of Natural
Science Foundation of China (21032006), National
Natural Science Foundation of China (21172245/
21172244/21372247) and 100-talent program of SIOC.
References
[6] (a) Wang, X.-Q.; Yang, T.; Cheng, X.-L.; Shen, Q. Angew. Chem.,
Int. Ed. 2013, 52, 12860; (b) Bootwicha, T.; Liu, X.; Pluta, R.; Ato-
diresei, I.; Rueping, M. Angew. Chem., Int. Ed. 2013, 52, 12856; (c)
Deng, Q.-H.; Rettenmeier, C.; Wadepohl, H.; Gade, L. H. Chem. Eur.
J. 2014, 20, 93.
[1] (a) Leo, A.; Hansch, C.; Elkins, D. Chem. Rev. 1971, 71, 525; (b)
Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
[2] (a) Filler, R. Biomedical Aspests of Fluorine Chemistry, Kodansha,
Tokyo, 1982; (b) Yagupolskii, L. M.; Ilchenko, A. Y.; Kondratenko,
N. V. Russ. Chem. Rev. 1974, 43, 32.
[7] Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945.
[8] (a) Rueping, M.; Liu, X.; Bootwicha, T.; Pluta, R.; Merkens, C.
Chem. Commun. 2014, 50, 2508; (b) Zhu, X.-L.; Xu, J.-H.; Cheng,
D.-J.; Zhao, L.-J.; Liu, X.-Y.; Tan, B. Org. Lett. 2014, 16, 2192.
[9] (a) Li, H.-M.; Chen, Y.-G.; Deng, L. in Priviliged Chiral Ligands
and Catalysts, Eds: Zhou, Q.-L., Wiley-VCH, Weinheim, Germany,
2011; (b) Tian, S.-K.; Chen, Y.-G.; Hang, J.-F.; Tang, L.; Mcdaid, P.;
Deng, L. Acc. Chem. Res. 2004, 37, 621; (c) France, S.; Weatherwax,
A.; Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004, 37, 592; (d)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 45, 5138; (e)
Kacprzak, K.; Gawroñski, J. Synthesis 2001, 961.
[3] (a) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105, 827;
(b) Mantear, B.; Pazenok, S.; Vors, J.-P.; Leroux, F. R. J. Fluorine
Chem. 2010, 131, 140; (c) Boiko, V. N. Beilstein J. Org. Chem. 2010,
6, 880; (d) Manteau, B.; Pazenok, S.; Vor, J.-P.; Leroux, F. R. J.
Fluorine Chem. 2010, 131, 140; (e) Landelle, G.; Panossian, A.;
Pazenok, S.; Vors, J.-P.; Leroux, F. R. Beilstein J. Org. Chem. 2013,
9, 2476; (f) Tlili, A.; Billard, T. Angew. Chem., Int. Ed. 2013, 52,
6818; (g) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int.
Ed. 2013, 52, 8214; (h) He, W.-M.; Weng, Z.-Q. Prog. Chem. 2013,
25, 1071; (i) Toulgoat, F.; Alazet, S.; Billard, T. Eur. J. Org. Chem.
2014, 2415.
(Pan, B.)
680
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 678—680