Copper-catalyzed oxidative trifluoromethylation of terminal alkenes using nucleophilic CF3SiMe3: Efficient C(sp3)-CF 3 bond formation

Article abstract of DOI:10.1021/ol300639a

An efficient C(sp³)-CF₃ bond-forming reaction via Cu-catalyzed oxidative trifluoromethylation of terminal alkenes has been developed, which proceeds under mild conditions using readily available, less expensive CF₃SiMe₃ as the source of the CF₃ group. This method allows access to a variety of trifluoromethylated allylic compounds.

Full text of DOI:10.1021/ol300639a

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2106–2109
Copper-Catalyzed Oxidative
Trifluoromethylation of Terminal Alkenes
Using Nucleophilic CF3SiMe3: Efficient
C(sp3)ꢀCF3 Bond Formation
Lingling Chu† and Feng-Ling Qing*,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China, and College of
Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North
Renmin Lu, Shanghai 201620, China
flq@mail.sioc.ac.cn
Received March 13, 2012
ABSTRACT
An efficient C(sp3)ꢀCF3 bond-forming reaction via Cu-catalyzed oxidative trifluoromethylation of terminal alkenes has been developed, which
proceeds under mild conditions using readily available, less expensive CF3SiMe3 as the source of the CF3 group. This method allows access to a
variety of trifluoromethylated allylic compounds.
Development of new methods for the incorporation of
the trifluoromethyl group (CF3) into diverse organic mole-
cules is of great importance due to the useful properties
that the trifluoromethyl group imparts on organic mole-
cules such as excellent metabolic stability and high
lipophilicity.1,2 Accordingly, a variety of processes for
the incorporation of the CF3 group into diverse organic
molecules has been developed.2 Transition-metal-
mediated carbonꢀCF3 bond formation reactions have
emerged as powerful synthetic tools in this area.2ꢀ5 For
example, Pd-3 orCu-based4 protocols have been developed
(3) For recent examples, see: (a) Grushin, V. V.; Marshall, W. J.
J. Am. Chem. Soc. 2006, 128, 12644. (b) Ball, N. D.; Kampf, J. W.; Sanford,
M. S. J. Am. Chem. Soc. 2010, 132, 2878. (c) Cho, E. J.; Senecal, T. D.;
Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science 2010, 328,
1679. (d) Cho, E. J.; Buchwald, S. L. Org. Lett. 2011, 13, 6552. (e) Ball,
N. D.; Gary, J. B.; Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133,
7577. (f) Mu, X.; Wu, T.; Wang, H.; Guo, Y.; Liu, G. J. Am. Chem. Soc.
2012, 134, 878. For FeCl2 catalyst: (g) Parsons, A. T.; Senecal., T. D.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2012, 51, 2947.
(4) For recent examples, see: (a) Dubinina, G. G.; Furutachi, H.;
Vicic, D. A. J. Am. Chem. Soc. 2008, 130, 8600. (b) Oishi, M.; Kondo, H.;
Amii, H. Chem. Commun. 2009, 1909. (c) Chu, L.; Qing, F.-L. Org. Lett.
2010, 12, 5060. (d) Senecal, T. D.; Parsons, A. T.; Buchwald, S. L. J. Org.
Chem. 2011, 76, 1174. (e) Kondo, H.; Oishi, M.; Fujikawa, K.; Amii, H.
Adv. Synth. Catal. 2011, 353, 1247. (f) Zhang, C.-P.; Wang, Z.-L.; Chen,
Q.-Y.; Zhang, C.-T.; Gu, Y.-C.; Xiao, J.-C. Angew. Chem., Int. Ed. 2011,
50, 1896. (g) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2011, 50, 3793. (h) Knauber, T.; Arikan, F.;
Roschenthaler, G.-V.; Gooβen, L. J. Chem.;Eur. J. 2011, 17, 2689. (i)
Liu, T.; Shen, Q. Org. Lett. 2011, 13, 2342. (j) Xu, J.; Luo, D.-F.; Xiao,
B.; Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L. Chem. Commun. 2011, 47,
4300. (k) Zhang, C.-P.; Cai, J.; Zhou, C. -B.; Wang, X.-P.; Zheng, X.;
Gu, Y.-C.; Xiao, J.-C. Chem. Commun. 2011, 47, 9516. (l) Tomashenko,
O. A.; Escudero-Adan, E. C.; Belmonte, M. M.; Grushin, V. V. Angew.
Chem., Int. Ed. 2011, 50, 7655. (m) Hafner, A.; Brase, S. Adv. Synth.
Catal. 2011, 353, 3044. (n) Weng, Z.; Lee, R.; Jia, W.; Yuan, Y.; Wang,
W.; Feng, X.; Huang, K.-W. Organometallics 2011, 30, 3229. (o) Popov,
I.; Lindeman, S.; Daugulis, O. J. Am. Chem. Soc. 2011, 133, 9286. (p)
Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchholz, J.; Grushin,
V. V. J. Am. Chem. Soc. 2011, 133, 20901.
† Shanghai Institute of Organic Chemistry.
‡ Donghua University.
(1) For selected reviews, see: (a) Kirsch, P. Modern Fluoroorganic
Chemistry; Wiley-VCH: Weinheim, 2004. (b) Uneyama, K. Organofluorine
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Ed. 2010, 49, 9322. (c) Roy, S.; Gregg, B. T.; Gribble, G. W.; Le, V.-D.;
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r
10.1021/ol300639a
Published on Web 04/12/2012
2012 American Chemical Society

for the trifluoromethylation of halides,3b,c,4a,4b,4eꢀ4h,4lꢀ4p
boronic acids,4c,d,iꢀk and sulfonates,3c allowing efficient
access to a diverse array of trifluoromethylated analogues.
Recent advances in direct CꢀH trifluoromethylation pro-
tocols are particularly attractive due to obviating the need
for prefunctionalization of the substrates.5 Using a
nucleophilic, electrophilic, or radical-based trifluoro-
methylating reagent, it is now possible to install the
trifluoromethyl group in place of CꢀH bonds of arenes
and heteroarenes.5 While construction of C(sp2)ꢀCF3
bonds via direct trifluoromethylation of C(sp2)ꢀH
bonds has been achieved with high efficiency, the ana-
logous transformation to form C(sp)ꢀCF3 and C(sp3)ꢀ
CF3 was less explored.
Very recently, the groups of Buchwald,6a Liu,6b and
Wang6c have independently reported Cu-catalyzed trifluoro-
methylation of olefins to construct allylic CꢀCF3
bonds using electrophilic trifluoromethylating reagents
(Togni’s reagent and Umemoto’s reagent). These methods
not only provide a straightforward and efficient route
to allylic trifluoromethylated products that were pre-
viously prepared from Pd-catalyzed or Cu-mediated
trifluoromethylation of ‘prefunctionalized’ starting
materials such as allylstannanes or allylic halides7 but
also represent rare examples of C(sp3)ꢀCF3 bond for-
mation through C(sp3)ꢀH activation (Scheme 1). How-
ever, these methods are limited by the high cost of the
electrophilic trifluoromethylating reagents.
In 2010, our group demonstrated the first example of
Cu-mediated oxidative trifluoromethylation of terminal
alkynes using a nucleophilic trifluoromethylating reagent
(CF3SiMe3).8 This is the first example of C(sp)ꢀCF3 bond
formation via transition-metal-mediated CꢀH oxidative
trifluoromethylation. Later, the Cu-mediated oxidative
trifluoromethylation protocol was successfully employed
in the direct trifluoromethylation of boronic acids4c and
even CꢀH bonds of heteroaromatics.5i Particularly, pre-
liminary mechanistic studies have successfully enabled this
oxidative transformation in a catalytic fashion.5i,9 Herein,
we describe Cu-catalyzed direct allylic CꢀH oxidative
trifluoromethylation of terminal alkenes with nucleophilic
CF3SiMe3 (RuppertꢀPrakash reagent).10 In comparison
with the trifluoromethylation of olefins using electrophilic
trifluoromethylating reagents,6 our new method employed
readily available and less expensive CF3SiMe3 as the
trifluoromethylating reagent.11
Table 1. Optimization of Cu-Catalyzed Oxidative Trifluoro-
methylation of 4-Phenyl-1-butene 1a with CF3SiMe3
a
copper
ligand
solvent
[0.3 M]
yield of 2a
entry
(30 mol %)
(30 mol %)
(%)b
Scheme 1. Direct Trifluoromethylation of Alkenes
1
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuOAc
CuTc
CuTc
/
phen
phen
phen
phen
phen
phen
phen
phen
/
DCE
24 þ 24 (4a)c
2
DMF
DMSO
NMP
DME
CH3CN
NMP
NMP
NMP
NMP
52
3
50
4
57
5
complex
6
58 þ 11 (4a)c
7
12
8
80
9
10
82
/
12 þ 51 (3a)c
a Reaction conditions: 1a (0.3 mmol), copper catalyst (0.09 mmol),
ligand (0.09 mmol), CF3SiMe3 (1.2 mmol), K2CO3 (1.2 mmol), PhI-
(OAc)2 (0.6 mmol), solvent (1 mL), 80 °C, 24 h, under N2 atmosphere.
b Yield was determined by 19F NMR analysis using fluorobenzene as an
internal standard. c Detected by GC-MS and 19F NMR.
(5) For recent examples for trifluoromethylation of CꢀH bonds of
(hetero)arenes, see: (a) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 3648. (b) Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem.;
Eur. J. 2011, 17, 6039. (c) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett.
2011, 13, 5464. (d) Loy, R. N.; Sanford, M. S. Org. Lett. 2011, 13, 2548.
(e) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.;
Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
14441. (f) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224. (g)
Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012,
51, 536. (h) Liu, T.; Shao, X.; Wu, Y.; Shen, Q. Angew. Chem., Int. Ed.
2012, 51, 540. (i) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 1298.
(j) Mejia, E.; Togni, A. ACS Catal. 2012, 2, 521. (k) Iqbal, N.; Choi, S.;
Ko, E.; Cho, E. J. Tetrahedron Lett. 2012, 53, 2005. (l) Hafner, A.; Brase,
S. Angew. Chem., Int. Ed. 2012DOI: 10.1002/anie.201107414.
(6) (a) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011,
50, 9120. (b) Xu, J.; Fu, Y.; Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.; Liu, Z.-J.;
Gong, T.-J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 15300. (c) Wang, X.;
Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011,
133, 16410.
Based on the previous reports of Cu-based oxidative
trifluoromethylations,4c,5i,8,9 we first examined the ability
of various oxidants to mediate the trifluoromethylation of
4-phenyl-1-butene 1a using CF3SiMe3 in the presence of
base and catalytic copper salts. After some initial experi-
ments, we found PhI(OAc)2 to be a promising oxidant for
the transformation, providing the desired linear allylic
(8) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2010, 132, 7262.
(9) Jiang, X.; Chu, L.; Qing, F.-L. J. Org. Chem. 2012, 77, 1251.
(10) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
(11) Current prices for these reagents (Sigma-Aldrich in China) are
$74,106.6/mol (Umemoto’s reagent), $81,440.3/mol (Togni’s reagent),
and $3,535.9/mol (CF3SiMe3).
(7) (a) Matsubara, S.; Mitani, M.; Utimoto, K. Tetrahedron Lett.
1987, 28, 5857. (b) Su, D.-B.; Duan, J.-X.; Chen, Q.-Y. Tetrahedron Lett.
1991, 32, 7689. (c) Chen, Q.-Y.; Duan, J.-X. J. Chem. Soc., Chem.
Commun. 1993, 1389. (d) Duan, J.-X.; Su, D.-B.; Chen, Q.-Y. J. Fluorine
Chem. 1993, 61, 279. (e) Kim, J.; Shreeve, J. M. Org. Biomol. Chem. 2004,
2, 2728.
Org. Lett., Vol. 14, No. 8, 2012
2107

trifluoromethylated product 2a in 24% yield as well as
other side products (Table 1, entry 1). No product was
observed in the presence of other oxidants such as 1,4-
benzoquinone (BQ), Ag(I) salts, K2S2O8, Selectfluor, and
even PhI(OCOCF3) (see Supporting Information, Table S1).
To suppress the formation of the further chlorinated side
product 4a which might be derived from the solvent (1,2-
dichloroethane), various solvents containing no chloro
were subsequently evaluated. As summarized in Table 1,
reactions in polar and aprotic solvents such as DMF,
DMSO, or NMP occurred in moderate yields, while reac-
tion in DME was found to be sluggish (entries 1ꢀ6). NMP
was found to be optimal. Although a comparable yield of
the desired product 2a was obtained in the case of CH3CN
as the solvent, the formation of side product 4a compli-
cated the reaction (entry 6). This result further suggested
that the formation of 4a might be derived from the copper
catalyst with a chloride counterion (CuCl). To improve the
yield, we further screened the catalysts and found that
(thiophene-2-carbonyloxy)copper (CuTc) dramatically in-
creased the yield of the desired product 2ato80% (entry 8).
It should be noted that the yield of 2awas slightly increased
without ligand 1,10-phenanthroline (phen) (entry 9). The
oxidative trifluoromethylation of 1a proceeded smoothly
in the absence of a copper catalyst, but it was surprising
that the major product was side product 3a in 51% yield
and the desired product 2a was formed in only 12% yield
(entry 10). Apparently, the copper catalyst plays a pivotal
role in the formation of trifluoromethylated allylic
compounds.
Scheme 3. Trifluoromethylation of Substrates Containing
Epoxide or Bromo
moderatetogoodyields (Scheme2). Terminalalkenessuch
as those derived from 3-hydroxyflavone (2k), 4-methylum-
belliferone (2l), and estrone (2m) also underwent the
transformation, producing the corresponding allylic tri-
fluoromethylation products in moderate to good yields. A
range of functional groups, including esters (2dꢀ2g, 2l),
amides (2h, 2i), nitro (2j), ketone (2k, 2m), and heteroaro-
matic rings (2g), were tolerated in this transforma-
tion. Bromo on the arene ring was tolerated in the reaction
(2f), providing a platform for further functionalization,
whereas an alkyl bromide was found to be an unsuitable
substrate because of the competitive nucleophilic substitu-
tion of the alkyl bromide by (thiophene-2-carbonyloxy)-
copper (CuTc) (Scheme 3, eq 1). Terminal peroxide
was found to be unstable under the oxidative conditions
(Scheme 3, eq 2), and the formation of a complex mixture
of the desired product and other unidentified products was
observed. In most cases, the E/Z selectivity was moderate,
with a ratio range of 6:1ꢀ17:1 for the substrates evaluated
(Scheme 2).
Scheme 2. Scope of Cu-Catalyzed Oxidative Trifluoromethyla-
tion of Terminal Alkenes with CF3SiMe3
a
Scheme 4. Trapping Experiments
The direct oxidative trifluoromethylation of terminal
alkenes with CF3SiMe3 in the presence of PhI(OAc)2 was
not expected to proceed through an equivalent of Togni’s
eletrophilic trifluoromethylating reagent, in situ generated
PhI(CF3)(OAc) based on the following experimental re-
sults. All attempts to synthesize the acyclic trifluoromethyl
hypervalent iodides failed due to the instability of the
resulting trifluoromethylated compounds.12 19F NMR
analysis of the reaction mixture showed that no related
peak of PhI(CF3)(OAc) (Togni’s reagent resonates from
δ = ꢀ30 to ꢀ40 ppm) was observed under the reaction
a Reaction conditions: 1a (1.2 mmol), CuTc (0.36 mmol), CF3SiMe3
(4.8 mmol), K2CO3 (4.8 mmol), PhI(OAc)2 (2.4 mmol), NMP (4 mL),
80 °C, 24 h, under N2 atmosphere, isolated yield, the E/Z ratio in
parentheses was determined by 19F NMR spectroscopy.
With the optimized reaction conditions in hand, we next
examined the scope of the Cu-catalyzed oxidative trifluoro-
methylation process and found that a variety of terminal
alkenes can be transformed into the desired products in
€
(12) Eisenberger, P. Thesis, Eidgenossische Technische Hochschule
€
ETH Zurich (Zurich), 17371, 2007.
2108
Org. Lett., Vol. 14, No. 8, 2012

conditions of entries 1ꢀ10 of Table 1. Buchwald6a and
Wang6c found that the Cu catalyst was necessary for the
trifluoromethylation of olefins with Togni’s reagent,
whereas oxidation of terminal alkene 1a using CF3SiMe3
and PhI(OAc)2 in the absence of a Cu catalyst provided
trifluoromethylated products 2a in 12% yield and 4a in
51% yield (Table 1, entry 10). Additionally, no detectable
amounts of the TEMPOꢀCF3 trapped product was ob-
served in the reaction mixture of CF3SiMe3, PhI(OAc)2,
and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a
well-known radical scavenger, in the presence or absence
of CuTc (Scheme 4, eq 1). But the TEMPOꢀCF3 trapped
product was formed in 44% yield from treatment of
TEMPO with Togni’s reagent and stoichiometric CuCl.6c
Before mechanism consideration, inhibition experi-
ments were conducted. Addition of 2,6-di-tert-butyl-4-
methyl-phenol (BHT) or TEMPO to the reaction mixture
led to a complete inhibition of the desired transformation
under either the Cu-catalyzed or metal-free conditions
(Scheme 4, eq 2). These experimental results showed that
our present oxidative trifluoromethylation reaction in-
volves radical intermediates. However, neither an allyl-
TEMPO adduct nor a TEMPOꢀCF3 adduct was detected,
precluding the involvement of the allylic radical or the
trifluoromethyl radical in this process (Scheme 4). These
experimental results prompted us to consider that a single
electron transfer mechanism was operating in these oxida-
tive trifluoromethylation reactions (Scheme 5), as this
mechanism was proposed for hypervalent iodine-induced
functionalization of arenes.13 In the presence of a Cu
catalyst and PhI(OAc)2, the terminal alkene 1 might be
oxidized to a radical cation intermediate A via single
electron transfer,14 and subsequent nucleophilic attack of
the radical cation A by the CF3 anion would give rise to a
radical intermediate B. Intermediate B could be then
oxidized to form cation intermediate C. Finally, deproto-
nation of C would give the desired product 2. This pro-
posed mechanistic pathway was further supported by the
formation of side products 3a and 4a under the specific
reaction conditions (Table 1); compound 3a might be
formed by radical intermediate B via H-abstraction, and
either chloro-abstraction by B or nucleophilic attack of
cation C by a chloride anion would give compound 4a.
However, the exact role of the Cu catalyst in the reaction is
stillunclear. The12% yield of thedesiredproductand51%
yield of 3a were observed under metal-free conditions
using the PhI(OAc)2 oxidant alone (Table 1, entry 10),
indicating that the Cu catalyst might play an important
role in the selectivity of the oxidative trifluoromethylation.
Scheme 5. Proposed Mechanism
In summary, an efficient copper-catalyzed oxidative
trifluoromethylation of terminal alkenes using CF3SiMe3
as the trifluoromethylating reagent has been developed.
This method allows a general, direct approach to construct
allylic trifluoromethylated compounds containing numer-
ous functional groups, providing a complementary meth-
od to the analogous allylic trifluoromethylations using
Togni’s reagent or Umemoto’s reagent. Ongoing studies
will focus on probing the mechanism and expanding the
scope of this transformation.
Acknowledgment. National Natural Science Founda-
tion of China (21072028, 20832008) and National Basic
Research Program of China (2012CB21600) are gratefully
acknowledged for funding this work.
(13) (a) Dohi, T.; Ito, M.; Morimoto, K.; Iwata, M.; Kita, Y. Angew.
Chem., Int. Ed. 2008, 47, 1301. (b) Dohi, T.; Ito, M.; Yamaoka, N.;
Morimoto, K.; Fujioka, H.; Kita, Y. Angew. Chem., Int. Ed. 2010, 49,
3334. (c) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133,
5996. (d) Kantak, A. A.; Potavathri, S.; Barham, R. A.; Romano, K. M.;
DeBoef, B. J. Am. Chem. Soc. 2011, 133, 19960.
Supporting Information Available. Detailed experimen-
tal procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) (a) Moeller, K. D. Synlett 2009, 8, 1208. (b) Xu, H.-C.; Moeller,
K. D. Org. Lett. 2010, 12, 1720.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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