Highly Selective Pd-Catalyzed Direct C-F Bond Arylation of Polyfluoroarenes

Article abstract of DOI:10.1021/acs.orglett.8b00692

A directing-group-free palladium-catalyzed direct arylation of simple polyfluoroarenes with arylboronic acids through selective C-F bond activation is described. The combination of Pd(OAc)₂ with BrettPhos was identified as an efficient catalytic system to promote the reaction with high regioselectivity and broad substrate scope. Preliminary mechanistic studies reveal that the oxidative addition of Pd to the C-F bond is involved in the catalytic cycle.

Full text of DOI:10.1021/acs.orglett.8b00692

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Selective Pd-Catalyzed Direct C−F Bond Arylation of
Polyfluoroarenes
Zhi-Ji Luo, Hai-Yang Zhao, and Xingang Zhang*
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A directing-group-free palladium-catalyzed direct arylation of simple polyfluoroarenes with arylboronic acids
through selective C−F bond activation is described. The combination of Pd(OAc)2 with BrettPhos was identified as an efficient
catalytic system to promote the reaction with high regioselectivity and broad substrate scope. Preliminary mechanistic studies
reveal that the oxidative addition of Pd to the C−F bond is involved in the catalytic cycle.
ver the past decades, substantial endeavors have been
witnessed in developing efficient strategies and methods
To overcome these limitations, a suitable catalytic system
that can selectively activate the C−F bond with broad substrate
scope is the key. Considering that, usually, the activities of the
C−F bonds of fluoroarenes depend on the electronic nature of
the carbon that is fluorine attached,3d,5b,9 we envisioned that if a
suitable transition-metal complex with significant nucleophilic
character could facilitate the nucleophilic oxidative addition to
the C−F bond10 it would be feasible to selectively activate the
C−F bonds based on the electrophilicities of the carbon atoms.
Herein, we describe a highly selective C−F bond activation
through palladium-catalyzed cross-coupling of simple and
readily available polyfluoroarenes with arylboronic acids. The
employment of the Pd(OAc)2/BrettPhos catalytic system in
this method features several advantages: (1) high efficiency and
broad substrate scope, including inactive trifluoroarenes; (2)
high regioselectivity without influence by N-containing hetero-
cycle-based directing groups; (3) high functional group
tolerance, even toward nucleophile sensitive ketone; and (4)
synthetic simplicity and convenience without requirement of
directing group and handling moisture-sensitive reagents.
According to the hypothesis, we began our studies on the
palladium-catalyzed cross coupling of pentafluorobenzene 1a
with air-stable phenylboronic acid 2a (Scheme 1). After a
survey of a series of reaction parameters, such as phosphane
ligand, solvent, base, and palladium source, the combination of
electron-rich and bulky ligand BrettPhos (5 mol %) with
Pd(OAc)2 (2.5 mol %) in the presence of Cs2CO3 (2.0 equiv)
in toluene at 120 °C achieved the arylated product 3a in 90%
yield, along with small of amount of regioisomer 3a′ (4% yield;
for details, see the Supporting Information, SI).
O
to access fluorinated compounds due to their prominent
applications in life and materials sciences.1 However, in contrast
to direct introduction of fluorine atom(s) into organic
molecules,2 the transition-metal-catalyzed C−F bond activation
to prepare fluorinated compounds has received less attention
because of the robustness of the C−F bond and the lack of an
efficient catalytic system to discriminate the reactivity of
different C−F bonds.3
As an alternative to the conventional methods, the transition-
metal-catalyzed C−F bond activation not only can prepare
some fluorinated compounds that other methods are hard to
access, but also provides fundamental understandings of C−F
bond activation. Although important progress has been
achieved in the field recently, most of them focus on
hydrodefluorination reactions.4 To date, the formation of C−
C bond through transition-metal-catalyzed selective C−F bond
activation remains a synthetic challenge.5 An effective approach
to facilitate C−F bond activation with high ortho-selectivity is to
employ a directing group.6 However, the intrinsic drawback of
this approach by requirement of multiple steps to install the
directing group into the substrates restricts its widespread
synthetic applications. From the point of view of synthetic
simplicity and efficiency, the use of simple and readily available
fluorinated substrates for selective C−F bond activation would
be more straightforward. In this regard, the regioselective
nickel7 or palladium-catalyzed8 cross-couplings of simple
polyfluoroarenes with arylmetals (Ar−M, M = B, Si, Mg, and
Zn) have been developed. However, these methods either are
limited to active substrates perfluoroarenes7c,e−g or suffer from
low functional group compatibility and use of moisture-
sensitive arylmetals.7a,b,d,8b
Received: February 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In addition to demonstrating the generality of this catalytic
system, perfluoroarenes and other polyfluoroarenes bearing 5−
3 fluorine atoms were also examined (Scheme 3). Mono-
Scheme 1. Palladium-Catalyzed Cross-Coupling of
Pentafluorobenzene 1a with Phenylboronic Acid 2a
Scheme 3. Palladium-Catalyzed Cross-Coupling of
a
Fluoroarenes 1 with Arylboronic Acids 2
To ascertain the substrate scope of this method, reactions of
pentafluorobenzene with a series of arylboronic acids were
examined (Scheme 2). Generally, moderate to good yields of 3
Scheme 2. Palladium-Catalyzed Cross-Coupling of
a
Pentafluorobenzene 1a with Arylboronic Acids 2
a
Reaction conditions (unless otherwise specified): 1 (0.3 mmol, 1.0
equiv), 2 (0.6 mmol, 2.0 equiv), 120 °C, 12 h. All reported yields are
b
isolated yields. 1 (0.3 mmol, 1.0 equiv), 2 (1.2 mmol, 4.0 equiv).
arylation of perfluorobenzene and perfluorotoluene proceeded
efficiently with observation of a small amount of diarylated
products (4a and 4b). Other polyfluoroarenes were also
competent coupling partners and exclusively furnished
corresponding monoarylated products 4 with high regioselec-
tivity. Importantly, many versatile functional groups, including
nucleophile-sensitive moieties such as ketone, ester, and other
groups such as cyano, nitro, and N-containing heteroaryl, were
viable in the cross-coupling, in sharp contrast with previous
approaches using arylmagnesiums as coupling partners, in
which ketone and ester were incompatible with the reaction
conditions (4c−e,i−k).7a,b
a
Reaction conditions (unless otherwise specified): 1a (0.3 mmol, 1.0
equiv), 2 (0.6 mmol, 2.0 equiv), 120 °C, 12 h. All reported yields are
isolated yields. Reactions run at 140 °C.
b
Notably, for all of the tested polyfluoroarenes, the
regioselectivity of arylation of the C−F bond is consistent
with the SNAr-type reactions of polyfluoroarenes in which
fluorine located at the ortho and meta positions to the site of
nucleophilic attack benefits the substitution, but para fluorine
shows a negative effect.9 For example, perfluoronitrobenzene
provided the corresponding arylated product exclusively at the
ortho position to the nitro group (4e).10 This finding was also
observed by employing 1,2,3,5-tetrafluoro-4-nitrobenzene and
1,2,3-trifluoro-4-nitrobenzene as the model substrates 4i and 4j,
where only ortho-monoarylated products were observed.10
Remarkably, the regioselectivity did not interfere with the N-
containing heteroaryl-substituted polyfluoroarene previously
demonstrated to be good substrates for highly ortho-selective
C−F bond activation.6,14 The current palladium catalytic
process exclusively provided para-arylated product without
influence by the quinonlinyl group (4g), probably due to the
steric effect of bulky ligand BrettPhos, which prevents the
with high para-selectivity (regioisomers 3′ <5% yield) were
obtained. Arylboronic acids bearing electron-rich and electron-
deficient substituents all underwent the reaction smoothly. The
sterically hindered substrates, such as o-phenyl-substituted
phenylboronic acid and 1-naphthylboronic acid, did not
interfere with the cross-coupling (3d and 3e). Most remarkably,
some important structures used for the synthesis of organic
optoelectronic materials, such as carbazole, triphenylamine,
fluorene, and dibenzo[b,d]thiophene, were also applicable to
the reaction (3l−o).12 Since the C−H bonds of tetrafluoroar-
ene can functionalize as a useful functional group for the
downstream transformations,13 these new resulting fluorinated
building blocks would provide good opportunities for
applications in the synthesis of advanced functional materials.
Furthermore, vinylboronic acid was also amenable to the
reaction and provided corresponding product 3p in moderate
yield.
B
DOI: 10.1021/acs.orglett.8b00692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
chelation of [Pd] to the N-atom of quinonlinyl group, leading
to para-selectivity. This para-selectivity was also observed when
perfluoropyridine was examined (4f). It should be mentioned
that the inert substrate 1,2,3,4-tetrafluorobenzene also under-
went the current reaction smoothly with excellent regioselec-
tivity (4h). The sole formation of 4h indicates that a SNAr-type
process may have occurred in the oxidative addition of Pd to
the C−F bond. Other polyfluoroarenes bearing three fluorine
atoms were also applicable to the reaction and provided the
corresponding monoarylated products with high efficiency and
excellent regioselectivity (4k and 4l). It was also possible for
diarylation of fluoroarenes. As shown in 4m and 4n, the use of
4.0 equiv of arylboronic acids could furnish the diarylated
polyfluoroarenes efficiently. However, the hexafluorobenzene
yielded a mixture of di- and monoarylation of fluoroarenes.
To demonstrate the synthetic efficiency, high regioselectivity,
and utility of current process further, the sequential C−F bond
activation of polyfluoroarenes was conducted. Gram-scale
synthesis of 4o proceeded efficiently, which in turn underwent
sequential C−F bond activation with another arylboronic acid
to provide diarylated fluoroarene with high regioselectivity
(Scheme 4, eq 1). However, it is hard to prepare such a kind of
Scheme 5. Mechanistic Studies and X-ray Crystal Structure
of Palladium Complex 11
The structure of complex 11 was further confirmed by its
single-crystal X-ray diffraction study (Scheme 5) in which the
palladium center coordinates not only with the phosphorus
atom but also with the triisopropylphenyl ring of BrettPhos,
which is similar to Buchwald’s report.11,17 This finding clearly
demonstrates that the oxidative addition of a palladium
complex to the C−F bond indeed occurred during the reaction
process. Furthermore, a stoichiometric reaction of 11 with
phenylboronic acid also produced arylated product 4o
efficiently (63% yield) (SI). The use of palladium complex
11 as a precatalyst could also promote the reaction and led to
product 4o in good yield (85%) (SI). Thus, these results
demonstrate that the palladium complex formed in the
oxidative addition of Pd to the C−F bond is the key
intermediate in the catalytic cycle.
Scheme 4. Sequential C−F Bond Activation of
Polyfluoroarenes and Synthesis of Liquid Crystal Molecule
On the basis of these results and previous reports,18
a
plausible reaction mechanism is proposed (Scheme 6). The
Scheme 6. Proposed Reaction Mechanism
compound through conventional methods. This strategy can
also be applied in sequential functionalization of pyridyl-
substituted pentafluoroarene 1q (Scheme 4, eq 2). Reaction of
1q with arylboronic acid exclusively provided para-arylated
product 4p with high efficiency. Subsequently, with the aid of
pyridyl as a directing group, 4p could be readily boroylated
through our previously developed method,14b thus featuring the
excellent regioselectivity of this reaction. The utility of current
process can also be highlighted by the rapid synthesis of liquid
crystal molecule 1015 on a gram scale from trifluoroarene 1m
(Scheme 4, eq 3). In light of the importance of polyfluoroar-
enes in pharmaceuticals, agrochemicals, and functional
materials,1c,16 this transformation provides a facile route for
applications of simple polyfluoroarenes in life and materials
sciences.
reaction is initiated by the oxidative addition of electron-rich
Pd(0) to the C−F bond to generate palladium complex B.
Subsequently, transmetalation of C with arylboronic acid
followed by reductive elimination delivers the arylated
polyfluoroarene and regenerate the Pd(0) (A) simultaneously.
The role of BrettPhos is probably to generate a more electron-
rich and bulky Pd(0) center to facilitate the nucleophilic
oxidative addition, which may be the reason for the high
regioselectivity of the current reaction. On the other hand, it
has been demonstrated that the strong coordination of the
fourth ligand to palladium can suppress the transmetalation in
the palladium-catalyzed C−F bond activation reaction.8b
However, the use of BrettPhos in the current reaction can
circumvent this issue and enable the formation of B as a key
intermediate, thus facilitating the following steps to provide the
arylated polyfluoroarene with high efficiency.
To gain some mechanistic insight into the current process, a
stoichiometric reaction of Pd(CH2SiMe3)2(cod) with methyl
pentafluorobenzoate 1p in the presence of BrettPhos in toluene
at 40 °C was performed, providing the palladium complex
(C6F4CO2Me)Pd(BrettPhos)F 11 in 62% yield (Scheme 5).
C
DOI: 10.1021/acs.orglett.8b00692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4) For reviews, see: (a) Meier, G.; Braun, T. Angew. Chem., Int. Ed.
2009, 48, 1546. (b) Clot, E.; Eisenstein, O.; Jasim, N.; Macgregor, S.
A.; McGrady, J. E.; Perutz, R. N. Acc. Chem. Res. 2011, 44, 333. For
selected examples, see: (c) Aizenberg, M.; Milstein, D. Science 1994,
265, 359. (d) Schaub, T.; Fischer, P.; Steffen, A.; Braun, T.; Radius, U.;
Mix, A. J. Am. Chem. Soc. 2008, 130, 9304. (e) Lv, H.; Zhan, J.-H.; Cai,
Y.-B.; Yu, Y.; Wang, B.; Zhang, J.-L. J. Am. Chem. Soc. 2012, 134,
16216. (f) Senaweera, S. M.; Singh, A.; Weaver, J. D. J. Am. Chem. Soc.
2014, 136, 3002.
(5) For reviews, see: (a) Sun, A. D.; Love, J. A. Dalton Trans. 2010,
39, 10362. (b) Weaver, J.; Senaweera, S. Tetrahedron 2014, 70, 7413.
For selected papers, see: (c) Haufe, G.; Suzuki, S.; Yasui, H.; Terada,
C.; Kitayama, T.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2012,
51, 12275. (d) Senaweera, S.; Weaver, J. D. J. Am. Chem. Soc. 2016,
138, 2520. (e) Zheng, T.; Li, J.; Zhang, S.; Xue, B.; Sun, H.; Li, X.;
Fuhr, O.; Fenske, D. Organometallics 2016, 35, 3538. For pioneering
work for C−F bond activation via β-fluorine elimination, see:
(f) Fuchibe, K.; Morikawa, T.; Shigeno, K.; Fujita, T.; Ichikawa, J.
Org. Lett. 2015, 17, 1126. (g) Ichitsuka, T.; Fujita, T.; Ichikawa, J. ACS
Catal. 2015, 5, 5947.
In conclusion, we have developed an efficient method of
highly selective palladium-catalyzed arylation of simple and
readily available polyfluoroarenes through C−F bond activa-
tion. The reaction allows a variety of arylboronic acids and
polyfluoroarenes including inert trifluoroarenes. Because of its
high efficiency, broad substrate scope, synthetic simplicity, and
high regioselectivity without influence by N-containing hetero-
cycle-based directing groups, this protocol paves a new way for
applications of polyfluoroarenes in organic synthesis and related
chemistry. Preliminary mechanistic studies reveal that the high
regioselectivity of the current reaction may be ascribed to the
electron-rich palladium complex Pd(0)BrettPhos, which
facilitates the oxidative addition of the Pd center to the C−F
bond.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00692.
(6) (a) Sun, A. D.; Love, J. A. Org. Lett. 2011, 13, 2750. (b) Sun, A.
D.; Leung, K.; Restivo, A. D.; LaBerge, N. A.; Takasaki, H.; Love, J. A.
Chem. - Eur. J. 2014, 20, 3162. (c) Tobisu, M.; Xu, T.; Shimasaki, T.;
Chatani, N. J. Am. Chem. Soc. 2011, 133, 19505. (d) Xiong, Y.; Wu, J.;
Xiao, S.; Xiao, J.; Cao, S. J. Org. Chem. 2013, 78, 4599. (e) Yu, D.; Lu,
L.; Shen, Q. Org. Lett. 2013, 15, 940.
Detailed experimental procedures, and characterization
data for new compounds (PDF)
(7) (a) Yoshikai, N.; Mashima, H.; Nakamura, E. J. Am. Chem. Soc.
2005, 127, 17978. (b) Saeki, T.; Takashima, Y.; Tamao, K. Synlett
2005, 11, 1771. (c) Schaub, T.; Backes, M.; Radius, U. J. Am. Chem.
Soc. 2006, 128, 15964. (d) Nakamura, Y.; Yoshikai, N.; Ilies, L.;
Nakamura, E. Org. Lett. 2012, 14, 3316. (e) Ohashi, M.; Saijo, H.;
Shibata, M.; Ogoshi, S. Eur. J. Org. Chem. 2013, 2013, 443. (f) Saijo,
H.; Sakaguchi, H.; Ohashi, M.; Ogoshi, S. Organometallics 2014, 33,
3669. (g) Zhou, J.; Berthel, J. H. J.; Kuntze-Fechner, M. W.; Friedrich,
A.; Marder, T. B.; Radius, U. J. Org. Chem. 2016, 81, 5789.
(8) (a) Macgregor, S. A.; Roe, D. C.; Marshall, W. J.; Bloch, K. M.;
Bakhmutov, V. I.; Grushin, V. V. J. Am. Chem. Soc. 2005, 127, 15304.
(b) Ohashi, M.; Doi, R.; Ogoshi, S. Chem. - Eur. J. 2014, 20, 2040. See
also ref 7b.
(9) (a) Brooke, G. M. J. Fluorine Chem. 1997, 86, 1. (b) Chambers, R.
D.; Martin, P. A.; Sandford, G.; Williams, D. L. H. J. Fluorine Chem.
2008, 129, 998.
(10) Cargill, M. R.; Sandford, G.; Tadeusiak, A. J.; Yufit, D. S.;
Howard, J. A. K.; Kilickiran, P.; Nelles, G. J. Org. Chem. 2010, 75,
5860.
Accession Codes
CCDC 1815966 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xgzhang@mail.sioc.ac.cn.
ORCID
Xingang Zhang: 0000-0002-4406-6533
Notes
The authors declare no competing financial interest.
(11) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552.
(12) Po, R.; Bianchi, G.; Carbonera, C.; Pellegrino, A. Macromolecules
2015, 48, 453.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21425208, 21790362, and
21421002), the National Basic Research Program of China
(973 Program) (No. 2015CB931900), the Strategic Priority
Research Program of the Chinese Academy of Sciences (No.
XDB20000000), and the SIOC.
(13) (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 8754. (b) Do, H.-Q.; Daugulis, O. J. Am. Chem.
Soc. 2008, 130, 1128. (c) He, C.-Y.; Fan, S.; Zhang, X. J. Am. Chem.
Soc. 2010, 132, 12850. (d) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min,
Q.-Q.; Yang, J.; Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132, 4506.
(14) (a) Chen, Z.; He, C.-Y.; Yin, Z.; Chen, L.; He, Y.; Zhang, X.
Angew. Chem., Int. Ed. 2013, 52, 5813. (b) Guo, W.-H.; Min, Q.-Q.;
Gu, J.-W.; Zhang, X. Angew. Chem., Int. Ed. 2015, 54, 9075.
(15) Guo, J.; Hua, R.; Sui, Y.; Cao, J. Tetrahedron Lett. 2014, 55,
1557.
(16) For selected recent reviews, see: (a) Meyer, E. A.; Castellano, R.
K.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42, 1210. (b) Murphy, A.
R.; Frechet, J. M. J. Chem. Rev. 2007, 107, 1066. (c) Babudri, F.;
Farinola, G. M.; Naso, F.; Ragni, R. Chem. Commun. 2007, 1003.
(17) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
(18) (a) Widdowson, D. A.; Wilhelm, R. Chem. Commun. 1999,
2211. (b) Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1696. See
also ref 10.
REFERENCES
■
(1) For selected reviews, see: (a) Hiyama, T.; Organofluorine
Compounds, Chemistry and Applications; Springer-Verlag: Berlin,
2000. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320. (c) Muller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881.
(2) (a) Campbell, M. G.; Ritter, T. Chem. Rev. 2015, 115, 612.
(b) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475.
(3) (a) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Chem. Rev.
1994, 94, 373. (b) Braun, T.; Perutz, R. N. Chem. Commun. 2002,
2749. (c) Jones, W. D. Dalton Trans. 2003, 3991. (d) Amii, H.;
Uneyama, K. Chem. Rev. 2009, 109, 2119. (e) Ahrens, T.; Kohlmann,
J.; Ahrens, M.; Braun, T. Chem. Rev. 2015, 115, 931. (f) Eisenstein, O.;
Milani, J.; Perutz, R. N. Chem. Rev. 2017, 117, 8710.
̈
D
DOI: 10.1021/acs.orglett.8b00692
Org. Lett. XXXX, XXX, XXX−XXX