Palladium-catalyzed C-H perfluoroalkylation of arenes

Article abstract of DOI:10.1021/ol200628n

A new Pd-catalyzed reaction for the coupling between perfluoroalkyl iodides (R_FI) and simple aromatic substrates is described. The perfluoroalkylated arene products are obtained in good to excellent yields in the presence of a phosphine-ligated Pd catalyst and Cs₂CO₃ as a base. The development, optimization, scope, and preliminary mechanistic studies of these transformations are reported.

Full text of DOI:10.1021/ol200628n

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2548–2551
Palladium-Catalyzed CÀH
Perfluoroalkylation of Arenes
Rebecca N. Loy and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann
Arbor, Michigan 48109, United States
mssanfor@umich.edu
Received March 9, 2011
ABSTRACT
A new Pd-catalyzed reaction for the coupling between perfluoroalkyl iodides (RFI) and simple aromatic substrates is described. The
perfluoroalkylated arene products are obtained in good to excellent yields in the presence of a phosphine-ligated Pd catalyst and Cs2CO3 as
a base. The development, optimization, scope, and preliminary mechanistic studies of these transformations are reported.
The introduction of fluorine-containing functional groups
can drastically change both the biological and physical
properties of organic molecules.1 In particular, trifluoro-
methyl and perfluoroalkyl (RF) substituents are important
structural features of many commercial agrochemicals,
pharmaceuticals, and materials.2 There are numerous meth-
ods for the construction of alkylÀRF bonds.3,4 In contrast,
the generation of arylÀRF linkages (particularly arylÀCF3)
remains synthetically challenging,5À8 particularly via tran-
sition metal catalysis.6b,9À12 Several recent reports have
demonstrated Cu- or Pd-catalyzed reactions for the trifluoro-
methylation of CÀH bonds and/or aryl halides using, for
example, [(S-trifluoromethyl)dibenzothiophene][BF4] (1),10
TESCF3 (2),11 and TMSCF3 (3)12a as CF3 sources. While
these transformations represent very exciting advances, they
are limited by the high cost of the reagents,13 the requirement
for forcing reaction conditions, and/or have a modest sub-
strate scope.9À12
(1) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320.
(2) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
(3) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
(4) For recent reviews, see: (a) Ma, J.-A.; Cahard, D. Chem. Rev.
2004, 104, 6119. (b) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1.
(c) Prakash, G. K. S.; Chacko, S. Curr. Opin. Drug Discovery Dev. 2008,
11, 793. (d) Shibata, N.; Mizuta, S.; Kawai, H. Tetrahedron: Asymmetry
2008, 19, 2633.
(5) Examples of stoichiometric reactions that form of arylÀRF
bonds: (a) Swarts, F. Bull. Acad. R. Belg. 1892, 24, 309. (b) McLoughlin,
V. C. R.; Thrower, J. Tetrahedron 1969, 25, 5921. (c) Matsui, K.; Tobita,
E.; Ando, M.; Kondo, K. Chem. Lett. 1981, 10, 1719. (d) Chu, L.; Qing,
F.-L. Org. Lett. 2010, 12, 5060. (e) 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. (f) Senecal, T. D.; Parsons, A. T.; Buchwald, S. L. J. Org. Chem.
2011, 76, 1174.
(6) For examples of stoichiometric free-radical perfluoroalkylations
of aromatics with perfluoroalkyl halides, see: (a) Cowell, A.; Tamborski,
C. J. Fluorine Chem. 1981, 17, 345. (b) Bravo, A.; Bjørsvik, H.-R.;
Fontana, F.; Liguori, L.; Mele, A.; Minisci, F. J. Org. Chem. 1997, 62,
7128. (c) Huang, X.-T.; Long, Z.-Y.; Chen, Q.-Y. J. Fluorine Chem.
2001, 111, 107. (d) Li, Y.; Li, C.; Yue, W.; Jiang, W.; Kopecek, R.; Qu, J.;
Wang, Z. Org. Lett. 2010, 12, 2374.
(7) Use of electrophilic perfluoroalkylating reagents: (a) Kieltsch, I.;
Eisenberger, P.; Stanek, K.; Togni, A. Chimia 2008, 62, 260. (b)
Umemoto, T. Chem. Rev. 1996, 96, 1757.
(9) For examples of metal-catalyzed free radical perfluoroalkylations
of aromatics, see: (a) Zhou, Q.-L.; Huang, Y.-Z. J. Fluorine Chem. 1989,
43, 385. (b) Huang, X.-T.; Chen, Q.-Y. J. Org. Chem. 2001, 66, 4651. (c)
Kino, T.; Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.;
Tokuhisa, K.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98.
(10) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
3648.
(11) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679.
(12) (a) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.
€
(b) Knauber, T.; Arikan, F.; Roschenthaler, G.; Goossen, L. J. Chem.;
(8) For examples of stoichiometric ArylÀCF3 coupling from discrete
Pd, Ni, and Cu complexes, see: (a) Grushin, V. V.; Marshall, W. J. J. Am.
Chem. Soc. 2006, 128, 4632. (b) Dubinina, G. G.; Furutachi, H.; Vicic,
D. A. J. Am. Chem. Soc. 2008, 130, 8600. (c) Dubinina, G. G.; Brennessel,
W. W.; Miller, J. L.; Vicic, D. A. Organometallics 2008, 27, 3933. (d)
Dubinina, G. G.; Ogikubo, J.; Vicic, D. A. Organometallics 2008, 27, 6233.
(e) Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132,
2878. (f) Ye, Y.; Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem.
Soc. 2010, 132, 14682.
Eur. J. 2011, 17, 2689.
(13) Current prices for these reagents are $23,000/mol (1), $11,700/
mol (2), $2,200/mol (3), $755/mol (CF3I): McReynolds, K. A.; Lewis,
R. S.; Ackerman, L. K. G.; Dubinina, G. G.; Brennessel, W. W.; Vicic,
D. A. J. Fluorine Chem. 2010, 131, 1108.
r
10.1021/ol200628n
Published on Web 04/22/2011
2011 American Chemical Society

We aimed to develop a mild Pd-catalyzed method for the
perfluoroalkylation of simple arenes. In addition, our goal
was to utilize relatively inexpensive perfluoroalkyl iodides as
RF precursors.6,9,14 We report herein that a variety of
aromatic substrates undergo facile perfluoroalkylation with
RFI in the presence of a Pd0 catalyst, a phosphine ligand, and
a base. The development, optimization, scope, site-selectivity,
and mechanism of this transformation are discussed herein.
Initial studies focused on the Pd-catalyzed CÀH perfluoro-
alkylation of benzene with C6F13I (Table 1).6,15 We noted
that aryl iodides can participate in Pd(OAc)2/PCy3-catalyzed
CÀC coupling reactions with simple arenes.16,17 Fagnou and
co-workers have proposed that these transformations pro-
ceed via a Pd0/II mechanism initiated by oxidative addition of
the aryl iodide to Pd0.16 Since perfluoroalkyl iodides are
known to undergo related oxidative addition reactions at Pd0
centers,18 we reasoned that a similar transformation might be
feasible with these substrates. To test this possibility, we first
examined the coupling of C6F13I with benzene under Fag-
nou’s conditions for ArI/arene coupling (10 mol % of Pd-
(OAc)2/20 mol % phosphine and 2 equiv of K2CO3). We
initially selected BrettPhos as our phosphine ligand, since it is
known to facilitate ArylÀCF3 bond-forming reductive elim-
ination from PdII centers.11 We were pleased to find that this
reaction provided 9% yield of the desired CÀH perfluoro-
alkylation product 4 (Table 1, entry 1).19
This effect may be due to the higher solubility of Cs2CO3
compared to other alkali metal carbonates.20 The final
optimized conditions (5 mol % of Pd2dba3, 20 mol % of
BINAP, 2 equiv of Cs2CO3 at 80 °C for 15 h), provided
perfluoroalkylated product 4 in 81% yield (entry 10).
Table 1. Optimization of Perfluoroalkylation Reactiona
entry
phosphine
base
yield (%)b
1
2
20 mol % BrettPhos
20 mol % BrettPhos
20 mol % RuPhos
20 mol % PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
9c,d
38d
13d
24d
47d
23d
57d
2
3
4
5
10 mol % dppf
6
20 mol % PtBu3
10 mol % BINAP
10 mol % BINAP
20 mol % BINAP
20 mol % BINAP
7
8
9
67
10
81
The CÀH perfluoroalkylation reaction was optimized
with respect to Pd precursor, phosphine ligand, and base.
As shown in Table 1, Pd2dba3 provided significantly higher
yield than Pd(OAc)2 (entries 2 and 1, respectively). An
evaluation of different phosphines revealed that BINAP
was the optimal ligand examined, and the combination of
10 mol % of BINAP and 5 mol % of Pd2dba3 provided 57%
yield of 4 under an N2 atmosphere (entry 7). Interestingly,
when the analogous transformation was conducted in air,
only 2% yield of 4 was detected (entry 8). Under these
conditions, 31P NMR spectroscopic analysis showed the
formation of significant quantities of phosphine oxide. Thus,
we reasoned that the use of an excess of BINAP relative to Pd
might provide improved results by maintaining ligated Pd
species throughout the reaction. Indeed, a 2:1 ratio of
BINAP/Pd afforded significantly higher yields, without the
need to exclude O2 (entry 9). Carbonate salts were the best
bases of this reaction, with Cs2CO3 proving optimal (entry 10).
a General conditions: C6F13I (1 equiv), Pd2dba3 (5 mol %), base (2
equiv) in C6H6 at 80 °C for 15 h. b Yields determined by GC analysis.
c Pd(OAc)2 (10 mol %). d Under N2.
The scope of this transformation was evaluated using a
variety of different aromatic substrates (Table 2). A longer
chain perfluoroalkyl iodide (C10F21I) was used to facilitate
isolation of the products. Arenes containing electron-donat-
ing methyl and alkoxy substituents generally reacted to
provide perfluoroalkylated products in good to excellent
yields (entries 2À8). In substrates containing benzylic CÀH
sites, these transformations were highly selective for function-
alization on the aromatic ring. In general, significantly lower
reactivity was observed with aromatic substrates containing
electron withdrawing substituents; however, 1,2-dichloro-
benzene did undergo perfluoroalkylation in modest yield
(entry 10). In addition, N-methylpyrrole afforded the 2-per-
fluoroalkylated product 15 as a single detectable isomer
(entry 11).
(14) Kitazume, T.; Ishikawa, N. Chem. Lett. 1982, 11, 137.
(15) Review on fluoroalkyl radicals: Dolbier, W. R. Chem. Rev. 1996,
96, 1557.
The site selectivity of these transformations was
dictated by the substitution patterns on the aromatic
substrate. All of the 1,2-disubstituted arenes afforded
high selectivity for functionalization at the 4-position.
The 1,3-substituted substrates underwent preferential
functionalization at the 4-position, which is the kineti-
cally preferred site for electrophilic substitution.21 Si-
milarly, naphthalene perfluoroalkylation proceeded
(16) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 581.
(17) For other recent examples of Pd-catalyzed CÀH functionaliza-
tion reactions with aryl or alkyl halides, see: (a) Lafrance, M.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 16496. (b) Chiong, H. A.; Pham, Q. -N.;
Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. (c) Shabashov, D.;
Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965. CÀH Activation:(d)
Yu, J.-Q., Shi, Z., Eds; Topics in Current Chemistry 292; Springer:
Heidelberg, Germany, 2010; pp 1À76.
(18) (a) Rosevear, D. T.; Stone, F. G. A. J. Chem. Soc. A 1968, 164.
(b) Mukhedkar, A. J.; Green, M.; Stone, F. G. A. J. Chem. Soc. A 1969,
3023. (c) Empsall, H. D.; Green, M.; Stone, F. G. A. J. Chem. Soc.,
Dalton Trans. 1972, 96.
(20) Cella, J. A.; Bacon, S. W. J. Org. Chem. 1984, 49, 1122.
(21) (a) Zysman-Colman, E.; Arias, K.; Siegel, J. S. Can. J. Chem.
2009, 87, 440. (b) Braddock, D. C.; Cansell, G.; Hermitage, S. A. Synlett
2004, 461.
(19) Only trace amounts of product were obtained when the palla-
dium, phosphine or both were excluded from the reaction. The yield was
reduced to 7% when base is excluded.
Org. Lett., Vol. 13, No. 10, 2011
2549

catalytic cycle has precedent in the literature for related
systems;8,11,16,17,22 however, step iii is known to be challenging
at most phosphine PdII(Aryl)(CF3) intermediates.8,11,23
Table 2. Substrate Scope of Pd-Catalyzed Perfluoroalkylation
Scheme 1. CÀH Activation Mechanism
An alternative mechanistic possibility would involve Pd/
phosphine/base-promoted generation of free perfluoroalkyl
radicals (RF•) that could react directly with the aromatic
substrates. Such transformations also have precedent in the
literature, but typically occur under quite different reaction
conditions and proceed with different selectivity than the
current transformations.6,9 For example, free radical per-
fluoroalkylation of veratrol via the oxidation of sodium
perfluoroalkanesulfinates with Mn(OAc)2 H2O affords a
3
1:1 ratio of regioisomeric products.24 In contrast, this
Pd-catalyzed reaction affords >20:1 selectivity (Table 2,
entry 2). Caged and/or “Pd-associated” radical interme-
diates are a final mechanistic possibility.
Table 3. Effect of Additives on Pd-Catalyzed Perfluoroalkyla-
tion of Benzene
entry
additive
yield
1
2
3
4
5
6
none (ambient light)
none (dark)
81%
87%
71%
74%
76%
73%
a NMR yields obtained by 19F NMR analysis of the crude reaction
mixtures. b Selectivity determined by 19F NMR analysis of the crude
reacion mixture. c Selectivity determined from isolated product.
10 mol % AIBN
1 equiv BHT
20 mol % hydroquinone
20 mol % 1,4-dinitrobenzene
with modest selectivity for the kinetically preferred
R-position.
Experimental studies showed that the yield of Pd-cata-
lyzed benzene perfluoroalkylation is identical in the pre-
sence and absence of ambient light (Table 3, entries 1 and 2).
Furthermore, the addition of azobisisobutyronitrile
(AIBN) (a radical initiator), butylhydroxytoluene (BHT)
or hydroquinone (radical inhibitors), and 1,4-dinitroben-
zene (an ET scavenger)9b all had negligible impact on the
yield of this reaction (entries 3À6). This latter result is in
particular contrast to Ni0-catalyzed free radical addi-
tions of perfluoroalkyl halides to olefins, which were
dramatically inhibited by 1,4-dinitrobenzene.9b,25
There are several potential mechanisms for these reactions.
One possibility is similar to that proposed by Fagnou for
Pd-catalyzed CÀH arylation with aryl iodides. This mech-
anism would involve: (i) oxidative addition of RFI to Pd0 to
generate PdII intermediate A, (ii) arene activation at Ato form
the diorgano PdII species B, and (iii) CÀC bond-form-
ing reductive elimination to release the product and regene-
rate the Pd0 catalyst (Scheme 1). Notably, each step of this
(22) For examples of Pd0-catalyzed coupling of RFX with alkenes or
Bu3SnÀE (E = ArR2, PR2, SeR), see: (a) Ishihara, T.; Kuroboshi, M.;
Okada, Y. Chem. Lett. 1986, 15, 1895. (b) Matsubara, S.; Mitani, M.;
Utimoto, K. Tetrahedron Lett. 1987, 28, 5857. (c) Urata, H.; Yugari, H.;
Fuchikami, T. Chem. Lett. 1987, 16, 833. (d) Chen, Q.-Y.; Yang, Z.-Y.;
Zhao, C.-X; Qiu, Z.-M. J. Chem. Soc., Perkin Trans. 1 1988, 563. (e)
Rossi, R. A. Tetrahedron Lett. 2006, 47, 3511. (f) Uberman, P. M.;
Lanteri, M. N.; Martın, S. E. Organometallics 2009, 28, 6927.
(23) Grushin, V. V.; Marshall, W. J. J. Am. Chem. 2006, 128, 12644.
(24) Huang, W.-Y.; Xie, Y. Chin. J. Chem. 1990, 536.
(25) For example, the addition of 20 mol % of DNB to the NiCl2/
PPh3-catalyzed reaction of C6F13Cl with 3-(allyloxy)prop-1-ene de-
creased the yield from 90 to 0%. See ref 9b.
2550
Org. Lett., Vol. 13, No. 10, 2011

These preliminary studies suggest against a purely free
radical pathway, and implicate the formation of either caged
radical or organometallic intermediates. Further details of
the mechanism are the subject of ongoing investigations.
The most synthetically valuable perfluoroalkyl group to
introduce is CF3,3 and we have conducted preliminary
studies to establish the viability of arene trifluoromethyla-
tion with the Pd2dba3/BINAP catalyst system. Under our
standard conditions benzene reacts with CF3I to afford
trifluorotoluene (16) in 26% yield as determined by gas
chromatography (eq 1). This result provides promising
precedent for the viability of Pd-catalyzed trifluoromethy-
lation with CF3I. The scope of this trifluoromethylation
reaction is currently under investigation.
In conclusion, this communication describes Pd-cata-
lyzed coupling of perfluoroalkyl iodides with simple are-
nes. Preliminary mechanistic investigations suggest that
the reaction is not proceeding via free perfluoroalkyl radicals.
The optimized conditions for CÀH perfluoroalkylation
were also effective for CÀH trifluoromethylation. Ongoing
studies are focused on probing both the mechanism and
scope of this transformation in more detail.
Acknowledgment. This material is based upon work
supported by the U.S. Department of Energy Office of
Basic Energy Sciences DE-FG02-08ER 15997. We also
thank Amgen for partial support. Dr. Eugenio Alvarado,
the University of Michigan’s chemistry NMR co-director,
is acknowledged for assistance with NMR spectroscopy.
Supporting Information Available. Experimental and
spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 10, 2011
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