The palladium-catalyzed trifluoromethylation of vinyl sulfonates

Article abstract of DOI:10.1021/ol202885w

A method for the palladium-catalyzed trifluoromethylation of cyclohexenyl sulfonates has been developed. Various cyclohexenyl triflates and nonaflates underwent trifluoromethylation under mild reaction conditions using a catalyst system composed of Pd(dba

Full text of DOI:10.1021/ol202885w

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6552–6555
The Palladium-Catalyzed
Trifluoromethylation of Vinyl Sulfonates
Eun Jin Cho† and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts
Avenue, Cambridge, Massachusetts 02139, United States
sbuchwal@mit.edu
Received October 26, 2011
ABSTRACT
A method for the palladium-catalyzed trifluoromethylation of cyclohexenyl sulfonates has been developed. Various cyclohexenyl triflates and
nonaflates underwent trifluoromethylation under mild reaction conditions using a catalyst system composed of Pd(dba)2 or [(allyl)PdCl]2 and the
monodentate biaryl phosphine ligand tBuXPhos. The trifluoromethyl anion (CF3ꢀ) or its equivalent for the process was generated in situ from
TMSCF3 in combination with KF or TESCF3 in combination with RbF.
The development of methods for the trifluoromethylation
of organic compounds is of great importance since the
introduction of a trifluoromethyl (CF3) group can dramati-
cally change the physical and biological activities of a mole-
cule. In many instances, inclusion of a CF3 group increases
the metabolic stability, lipophilicity, bioavailability, and
binding selectivity of a pharmaceutical candidate.1 Notably,
many top-selling pharmaceuticals as well as agrochemicals
contain a trifluoromethyl group.1a,c
While a variety of processes for the construction of sp3
carbon-CF3 bonds have been reported (using electrophi-
lic, nucleophilic, and radical-based reagents),2 processes
Figure 1. Construction of sp2 carbon-CF3 bonds.
for the construction of sp2 carbon-CF3 bonds are rarer.
Traditional methods for the formation of benzotrifluorides
require harsh reaction conditions such as the use of HF and
SbF5 at high temperature,3 precluding the use of highly
functionalized substrates. In contrast, cross-coupling
processes can facilitate the construction of sp2 carbon-CF3
bonds under milder reaction conditions, rendering them
more amenable to the late-stage modification of highly
functionalized molecules.4 Toward this end, a variety of
copper5- and palladium6-mediated reactions have recently
been developed [Figure 1, reaction 1]. These transition-
metal-catalyzed trifluoromethylations, however, are mainly
limited to the installation of aryl-CF3 groups.
† Present address: Department of Applied Chemistry, Hanyang University,
55 Hanyangdaehak-ro, Sangnok-gu, ansan, Kyeonggi-do, 426-791, Korea.
€
(1) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (b)
Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (c) Purser, S.; Moore,
P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (d)
Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.;
Wiley-Blackwell: Chichester, 2009.
(2) (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119. (b) Ma, J.-A.;
Cahard, D. J. Fluorine Chem. 2007, 128, 975. (c) Prakash, G. K. S.;
Chacko, S. Curr. Opin. Drug Discovery Dev. 2008, 11, 793. (d) Parsons,
A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9120.
(3) Swarts, F. Bull. Acad. Roy. Belg. 1892, 24, 309.
Trifluoromethylated alkenes are key structural compo-
nents of many biologically active compounds and are
featured in pharmaceuticals and agrochemicals such as
panomifene7 and bifenthrin.8 Despite the importance of these
(4) Recent reviews:(a) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011,
473, 470. (b) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475.
r
10.1021/ol202885w
Published on Web 11/23/2011
2011 American Chemical Society

vinyl-CF3 moieties, processes for their direct installation have
not been well developed [Figure 1, reaction 2]. Typically,
trifluoromethylated alkenes are generated from aldehydes,
ketones, or alkynes via several synthetic manipulations.9
Regarding copper-mediated coupling processes, trifluoro-
methylations of vinylboronic acids were reported recently.
However, the process reported by Chu and Qing5c required
the use of a stoichiometric quantity of copper with sensitive
reagents and the process by Liu and Shen5g produced a
mixture of alkene stereoisomers. Herein, we report the first
palladium-catalyzed process for the trifluoromethylation of
vinyl electrophiles. This method allows the conversion of
cyclohexenyl triflates and nonaflates into trifluoromethylated
alkenes under mild conditions. We found the use of Pd(dba)2
or [(allyl)PdCl]2 as the palladium source in conjunction with
Scheme 1. Ligand Screen for the Trifluoromethylation of Vinyl
Triflate 1aa,b
t
the electron-rich bulky biphenyl based ligand BuXPhos
provided the optimal results.
Our studies of the vinyl trifluoromethylation reaction
began by evaluating various monodentate biaryl phosphine
ligands (Scheme 1). 1-Cyclohexenyl trifluoromethanesulfo-
nate 1a was used as a test substrate with 5 mol % Pd(dba)2
and 10 mol % ligand in dioxane at 110 °C. Trifluoromethyl-
trimethylsilane (Ruppert’s reagent, TMSCF3)10 was used as
the trifluoromethyl anion (CF3ꢀ) source in combination
with KF as an activator. Interestingly, the cyclohexyl-
substituted biaryl phosphine ligand L1 (BrettPhos), which
was found to be the optimal ligand for the palladium-
catalyzed trifluoromethylation of aryl chlorides under similar
conditions,6d was unsuccessful in providing any of the desired
trifluoromethylated alkene 2a. In fact, only catalysts based
on ligands with tert-butyl substitution on phosphorus were
successful in promoting this transformation. In addition, it
a Reaction conditions: 1a (0.3 mmol), Pd(dba)2 (5 mol %), ligand
(10 mol %), TMSCF3 (0.6 mmol), KF (0.6 mmol), dioxane (0.3 mL),
110 °C, 5 h. bThe yield was determined by 19F NMR spectroscopy with
4-fluorotoluene as an internal standard.
was found that catalysts based on ligands lacking substitu-
tion at the 3-position of the upper aromatic ring (L5 and L6)
were the most effective in generating the desired trifluoro-
methylated alkene products. Specifically, the use of ligand L5
(tBuXPhos) provided the best results for this transformation
and was chosen for further study.
We next investigated the substrate scope for the coupling
process using various 4-phenyl-substituted cyclohexenyl
halides and sulfonates with ligand L5 (Table 1). Both vinyl
triflates and nonaflates (ꢀONf = OSO2CF2CF2CF2CF3)
participated in the reaction to give the desired trifluoro-
methylated alkene 2b (entries 4ꢀ12). In contrast, the tri-
fluoromethylation of a vinyl chloride (entry 1) or bromide
(entry 2) did not occur under these conditions.
(5) Some recent examples: (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) Kondo, H.; Oishi, M.; Fujikawa, K.; Amii, H. Adv. Synth. Catal.
2011, 353, 1247. (e) Senecal, T. D.; Parsons, A. T.; Buchwald, S. L. J. Org.
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Chem. 2011, 76, 1174. (f) Knauber, T.; Arikan, F.; Roschenthaler, G.-V.;
Goossen, L. J. Chem.;Eur. J. 2011, 17, 2689. (g) Liu, T.; Shen, Q. Org.
Lett. 2011, 13, 2342. (h) Zhang, C.-P.; Cai, J.; Zhou, C.-B.; Wang, X.-P.;
Zheng, X.; Gu, Y.-C.; Xiao, J.-C. Chem. Commun. 2011, 47, 9516. (i)
Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem.,
The source of the trifluoromethyl anion or its equivalent
was also examined with several combinations of TMSCF3
or TESCF3 (trifluoromethyltriethylsilane) and metal fluor-
ꢀ
Int. Ed. 2011, 50, 3793. (j) Tomashenko, O. A.; Escudero-Adan, E. C.;
Belmonte, M. M.; Grushin, V. V. Angew. Chem., Int. Ed. 2011, 50, 7655. (k)
€
Hafner, A.; Brase, S. Adv. Synth. Catal. 2011, 353, 3044.
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(6) (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) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 3648. (d) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.;
Watson, D. A.; Buchwald, S. L. Science 2010, 328, 1679. (e) Mu, X.;
Chen, S.; Zhen, X.; Liu, G. Chem.;Eur. J. 2011, 17, 6039.
(7) Biological properties: (a) Borvendeg, J.; Hermann, I.; Csuka, O.
Acta Physiol. Hung. 1996, 84, 405. (b) Erdelyi-Toth, V.; Gyergyay, F.;
Szamel, I.; Pap, E.; Kralovanszky, J.; Bojti, E.; Csorgo, M.; Drabant, S.;
ide activators as shown in Table 1. The rate of in situ CF3
generation is crucial, since it decomposes readily to difluor-
ocarbene (F2C:) and fluoride (Fꢀ).11 We found that the
highest yield of product was obtained by using TMSCF3
and KF for triflate electrophiles (entry 4), while the use of
TESCF3 and RbF gave better results for nonaflate electro-
philes (entry 10). Additionally, we found that switching the
palladium source from Pd(dba)2 to [(allyl)PdCl]2 increased
the yield of product for vinyl nonaflate substrates (entry 11).
With the optimized conditions in hand, we investigated
the substrate scope of the vinyl trifluoromethylation
reaction (Scheme 2). TMSCF3 was employed with KF
as the activator for the reactions of vinyl triflates while the
ꢀ
Klebovich, I. Anti-Cancer Drugs 1997, 8, 603. Synthesis: (c) Nemeth, G.;
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Liu, X.; Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2004, 43, 879.
(8) Biological properties: (a) Amweg, E. L.; Weston, D. P.; Ureda, N. M.
Environ. Toxicol. Chem. 2005, 24, 966. Synthesis: (b) Fujita, M.; Hiyama, T.;
Kondo, K. Tetrahedron Lett. 1986, 27, 2139. (c) Shimizu, M.; Hiyama, T.
Angew. Chem., Int. Ed. 2005, 44, 214.
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Org. Lett., Vol. 13, No. 24, 2011
6553

Table 1. Optimization of the Trifluoromethylation of Vinyl
Substratesa,b
Scheme 2. Scope of the Palladium-Catalyzed Trifluoromethy-
lation of Vinyl Triflates and Vinyl Nonaflatesa,b
t
a Reaction conditions: RX (0.2 mmol), Pd(dba)2 (5 mol %), BuX-
Phos (10 mol %), TMSCF3 (0.4 mmol), KF (0.4 mmol), dioxane
(0.2 mL), 110 °C, 5 h. b The given yield was determined by 19F NMR
spectroscopy with 4-fluorotoluene as an internal standard. c 2.5 mol %
[(allyl)PdCl]2 was used as the palladium source.
TESCF3/RbF system was used for reactions of vinyl
nonaflates. Generally, 5 mol % palladium [5% Pd(dba)2
or 2.5% [(allyl)PdCl]2] was used with 10 mol % tBuXPhos
in dioxane at 90 to 110 °C with a reaction time of 3 h. A
variety of six-membered vinyl triflates and vinyl nona-
flates were transformed into trifluoromethylated alkenes
in modest to high yields. Additionally, minor amounts
(1ꢀ5%) of reduced starting materials (vinyl-H) were
usually observed. Several functional groups are tolerated
under the reaction conditions including ketals (2d),
amides (2e), and heteroaromatic rings (2g).12 Conjugated
alkenyl sulfonates such as those derived from 2-tetralone
(2h, 2i), (þ)-nootkatone (2j), and cholesterol (2k) also
underwent the transformation, producing the corre-
sponding trifluoromethylated alkenes in high yield. The
reaction conditions also proved applicable to larger
scale reactions, and trifluoroalkene products 2a and 2b
were prepared on a 5 mmol scale in yields similar to those
reported for the 1 mmol scale reactions. Conversely, we
found that reactions of triflates conducted on a smaller
scale (less than 0.5 mmol) with TMSCF3 and KF gave the
desired products in yields 10ꢀ20% lower than those from
reactions conducted on a larger scale.13
a Reaction conditions: The exact amount of Pd catalyst used for each
substrate is described in the Supporting Information. (A) ROTf
R
(1.0 mmol), 4ꢀ6 mol % Pd(dba)2 or [(allyl)PdCl]2β, 8ꢀ12 mol %
tBuXPhos (Pd/L = 1:2), TMSCF3 (2.0 mmol), KF (2.0 mmol), dioxane
R
(1.0mL),90ꢀ110 °C, 3ꢀ10 h. (B) RONf (1.0 mmol), 4ꢀ6 mol % Pd(dba)2
or [(allyl)PdCl]2β, 8ꢀ12 mol % tBuXPhos (Pd/L = 1:2), TESCF3
(1.5 mmol), RbF (1.5ꢀ2.0 mmol), dioxane (1.0 mL), 90ꢀ110 °C, 3ꢀ
10 h. bThe given yields are isolated yields based on an average of at least two
runs except 2a. The yield of 2a was determined by 19F NMR spectroscopy
using 4-fluorotoluene as an internal standard due to its volatility.
Scheme 3. Trifluoromethylation of 2-Alkyl Substituted Cyclo-
hexenyl Triflatesa,b
While 3- or 4-alkyl substituted cyclohexenyl substrates
work well in this reaction, cyclohexenyl sulfonates with
substitution at the 2-position were less successful sub-
strates. Though several 2-methyl-substituted substrates
did undergo the trifluoromethylation under optimized
conditions, these reactions proceeded slowly (Scheme 3).
or
a Reaction conditions: ROTf (1.0 mmol), 6 mol % PdR
β, 12 mol %
tBuXPhos, TMSCF3 (2.0 mmol), KF (2.0 mmol), dioxane (1.0 mL),
110 °C, 4ꢀ10 h. bThe given yields are determined by 19F NMR spectro-
scopy. cThe given yields are isolated and based on an average of two runs.
(12) Substrates bearing aldehydes, ketones, and unprotected OH or
NH groups are not suitable for this process.
(13) The reason is unclear at the moment. The change of either
concentration or surface area of the reaction did not affect the results.
6554
Org. Lett., Vol. 13, No. 24, 2011

Longer reaction times failed to improve yields signifi-
cantly due to a competing triflate decomposition pathway
under these conditions. Interestingly, we found that a 2,2-
disubstituted triflate was a competent substrate, with
trifluoromethyl alkene 2n produced in 71% yield.
primarily via competitive β-hydride elimination of alkenyl-
Pd oxidative addition complexes. These results indicate
that relatively slow transmetalation compared to β-hydride
elimination likely results in this distribution of products.
We have developed a palladium-catalyzed trifluoro-
methylation of vinyl triflates and nonaflates, providing a
direct method to access trifluoromethylated alkenes from
vinyl electrophiles. A variety of trifluoromethylated cyclo-
hexenes were generated under mild reaction conditions.
Compared to six-membered fluoroalkylsulfonates, the
analogous five-membered substrates demonstrated signif-
icantly reduced reactivity. For example, trifluoromethyla-
tion of cyclopentenyl fluoroalkylsulfonates did not go to
completion even after being subjected to higher tempera-
tures and catalyst loadings. Current efforts seek to develop
suitable conditions for these more challenging substrates.
In the case of reactions of larger cyclic (>7-membered
rings) or acyclic systems, alkyne or allene side products
were observed as the major products. Further investiga-
tions revealed that the formation of alkynes or allenes was
slow and did not go to completion in the absence of a
palladium catalyst, while inthe presence of palladium these
products were obtained in quantitative yields in just 1 h.
These findings suggest that these side processes proceed
Acknowledgment. We thank the National Institutes of
Health (Grant GM46059) for financial support of this work.
We thank Dr. Meredeth A. McGowan (Massachusetts Insti-
tute of Technology) and Dr. Andrew Parsons (Massachusetts
Institute of Technology) for help with this manuscript.
Supporting Information Available. Experimental proce-
dures and spectral data for products. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 24, 2011
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