Nickel-catalyzed selective defluorination to generate partially fluorinated biaryls

Article abstract of DOI:10.1021/ol200860t

A Ni-catalyzed, chemoselective cross-coupling reaction of polyfluoroarenes under mild reaction conditions is reported. A variety of fluorine-containing biaryls are synthesized in good-to-excellent yields. A wide range of substitution patterns and functional groups are tolerated.

Full text of DOI:10.1021/ol200860t

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2750–2753
Nickel-Catalyzed Selective Defluorination
to Generate Partially Fluorinated Biaryls
Alex D. Sun and Jennifer A. Love*
Department of Chemistry, 2036 Main Mall, University of British Columbia, Vancouver,
British Columbia V6T 1Z1, Canada
jenlove@chem.ubc.ca
Received April 2, 2011
ABSTRACT
A Ni-catalyzed, chemoselective cross-coupling reaction of polyfluoroarenes under mild reaction conditions is reported. A variety of fluorine-
containing biaryls are synthesized in good-to-excellent yields. A wide range of substitution patterns and functional groups are tolerated.
Aryl fluorides are important components of many bio-
logically active molecules, including pharmaceuticals and
agrochemicals.1 Becauseno naturalsourceofarylfluorides
has been identified, fluoroaromatic building blocks must
be generated through synthesis.2 The substitution patterns
present in commercially available sources remain quite
limited, which in turn limits the structural and functional
diversity of drugs that can be readily constructed. Thus, a
considerable need exists for the development of efficient,
versatile methods of generating functionalized fluoroaro-
matic building blocks.
One approach is to fluorinate functionalized arenes.2,3
Traditional methods rely on hazardous electrophilic fluor-
inating reagents and often exhibit low selectivity. Direct
arylation of fluoroaromatics has been achieved, but the
yields and selectivity are often low and diarylation is
sometimes observed.4 Reactions of diazonium salts with
fluoride ions have been reported, but these suffer from the
need to generate highly reactive intermediates. Suitably
activated aryl halides can undergo halogen exchange reac-
tions, although the scope remains limited. Recently, metal-
catalyzed replacement of halides, boronic acids and stan-
nanes with fluoride has emerged as a powerful strategy for
fluoroarene synthesis.5 However, these processes have yet
to be used to generate functionalized polyfluorinated
arenes, which are found in a number of top-selling drugs,
including Januvia and Diflucan.
An alternative approach is to selectively functionalize
polyfluoroaromatics via cross-coupling reactions.6,7 Poly-
fluorinated arenes are typically more readily available and
cheaper than their mixed halo counterparts. Toward this
goal, our group has developed Pt(II)-catalyzed cross-
coupling reactions of polyfluoroaryl imines, including
methylation with zinc reagents8 and methoxylation with
silicon reagents.9 A wide range of mono- and polyfluoroaryl
(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.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(d) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071.
(5) (a) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed.
2008, 47, 5993. (b) Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2008, 130,
10060. (c) Furuya, T.; Strom, A. E.; Ritter, T. J. Am. Chem. Soc. 2009,
131, 1662. (d) Furuya, T.; Benitez, D.; Tkatchouk, E.; Strom, A. E.;
Tang, P.; Goddard, W. A., III; Ritter, T. J. Am. Chem. Soc. 2010, 132,
3793. (e) Tang, P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 132,
12150. (f) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 7134. (g) Ball, N. D.; Sanford, M. S. J. Am. Chem. Soc. 2009,
131, 3796. (h) Grushin, V. V.; Marshall, W. J. Organometallics 2007, 26,
4997. (i) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcia-
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
(6) Sun, A. D.; Love, J. A. Dalton Trans 2010, 39, 10362.
(2) Furuya, T.; Klein, J. E. M. N.; Ritter, T. Synthesis 2010, 11, 1804.
(3) Simizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214.
(4) (a) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 8754. (b) Lafrance, M.; Shore, D.; Fagnou, K.
Org. Lett. 2006, 8, 5097. (c) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 1128. (d) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am.
Chem. Soc. 2008, 130, 15185. (e) Nakao, Y.; Kashihara, N.; Kanyiva,
K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 16170. (f) Zhang, X.;
Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.; Jiang, Z.-X. J. Am.
Chem. Soc. 2010, 132, 4506. (g) Li, H.; Liu, J.; Sun, C.-L.; Li, B.-J.; Shi,
Z.-J. Org. Lett. 2011, 13, 276.
(7) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
r
10.1021/ol200860t
Published on Web 04/21/2011
2011 American Chemical Society

imines can be generated. Potentially reactive functional
groups are well-tolerated, and the reactions typically pro-
ceed with high yields and high selectivity for the fluorine
adjacent to the imine directing group.
suppress catalysis, aryl coupling reagents can be used and a
relatively unactivated polyfluoroarene can undergo effi-
cient cross-coupling to yield the corresponding biaryl
product.13 Encouraged by this result, we were now poised
to explore the scope in more detail.
Despite these promising developments, these reactions
have a number of limitations. A hydrogen in an ortho
position results in CÀH activation, which precludes cross-
coupling. At least three electron-withdrawing groups in
addition to the imine are required to render the substrate
sufficiently reactive toward CÀF activation, which is typi-
cally rate-limiting. Finally, the reaction has been principally
limited to methylation and methoxylation. These limits
need to be addressed for this strategy to be widely applic-
able. In particular, we sought to explore the use of Ni(0)
catalysts for selective defluorination/cross-coupling with
broad scope. We report herein a Ni(0)-catalyzed protocol
that overcomes all of the limitations of the Pt(II) system.
A number of groups have made important contributions
in the field of Ni-catalyzed cross-coupling of mono- and
polyfluoroarenes,10 although the scope and functional
group tolerance remains limited. We anticipated that the
use of a suitable directing group, particularly one that can
be easily modified, would permit a considerable extension
of substrate scope without compromising synthetic utility.
Boronic acids were chosen as the coupling partner because
they are readily available and offer great functional group
diversity.
Our first task was to explore the transmetalation re-
agent. In addition to organoboronic acids, organoboronic
ester and trifluoroborate salt both proved viable in the
reaction without compromising the yield (Table 1). In
particular, the use of trifluoroborate salt precludes the
need for added base (entry 3). Given the availability and
ease of use organoboronic acids, we sought to use these
reagents for further exploration.
Table 1. Exploration of Organoboron Sources
Our study began with the Ni-catalyzed reaction of a 2,4-
difluoroaryl imine. This substrate was selected for initial
study, as it was unsuccessful in Pt-catalyzed cross-coupling
reactions. This substrate undergoes efficient cross-cou-
pling with 4-methoxylbenzeneboronic acid in THF in the
presence of 10 mol % Ni(COD)2, 20 mol % PPh3 and 3.0
equiv of K2CO3.11,12 The reaction resulted in exclusive
functionalization of the ortho fluorine to generate the
desired biaryl products in nearly quantitative conversion.
The corresponding aldehyde was obtained in 85% yield
after hydrolysis and column chromatography. This result
demonstrated that the use of Ni(0) overcomes all of the
limitations of the Pt system: an ortho CÀH bond does not
a A: 24 h, 3.0 equiv K2CO3. B: 48 h. No base added. b Isolated yield.
We next examined the scope of arylboronic acids. As
shown in Table 2, a wide variety of arylboronic acids are
compatible with the reaction conditions, providing the
desired products in good-to-excellent yields after hydro-
lysis and isolation. Both electron-donating and electron-
withdrawing are well-tolerated. An unprotected hydroxyl
group does not diminish the yield (entry 4), although use of
an ortho-substituted methoxyl group (entry 3) appears to
suppress reactivity, presumably due to sterics. Of particu-
lar significance is that all of these products are 1,2,4-
trisubstituted arenes, which is one of the most common
motifs in pharmaceuticals aryl rings.14 Moreover, fluoro-
and trifluoromethyl groups (entries 5À7) can be incorpo-
rated as a means to generate more highly fluorinated
building blocks.
(8) (a) Wang, T.; Alfonso, B. J.; Love, J. A. Org. Lett. 2007, 9, 5629.
(b) Wang, T.; Love, J. A. Organometallics 2008, 27, 3290. (c) Buckley,
H. L.; Sun, A. D.; Love, J. A. Organometallics 2009, 28, 6622. (d) Sun,
A. D.; Love, J. A. J. Fluorine Chem. 2010, 131, 1237.
(9) Buckley, H. L.; Wang, T.; Tran, O.; Love, J. A. Organometallics
2009, 28, 2356.
(10) (a) Kiso, Y.; Tamao, K.; Kumada, M. J. Organomet. Chem.
1973, 50, C12. (b) Braun, T.; Parsons, S.; Perutz, R.; Voith, M.
Organometallics 1999, 18, 2254. (b) Braun, T.; Izundu, J.; Steffen, A.;
Neumann, B.; Stammler, H.-G. Dalton Trans. 2006, 5118. (d) Steffen,
A.; Sladek, M. I.; Braun, T.; Neumann, B.; Stammler, H.-G. Organo-
metallics 2005, 24, 4057. (e) Yoshikai, N.; Mashima, H.; Nakamura, E.
J. Am. Chem. Soc. 2005, 127, 17978. (f) Schaub, T.; Backes, M.; Radius,
U. J. Am. Chem. Soc. 2006, 128, 15964. (g) Schaub, T.; Fischer, P.;
Steffen, A.; Braun, T.; Radius, U.; Mix, A. J. Am. Chem. Soc. 2008, 130,
9304. (h) Saeki, T.; Takashima, Y.; Tamao, K. Synlett 2005, 1771.
(i) Ackermann, L.; Wechsler, C.; Kapdi, A.; Althammer, A. Synlett
2010, 294.
(13) Stoichiometric and catalytic CÀH activation in fluoroarenes
have been reported recently: (a) Johnson, S. A.; Huff, C. A.; Mustafa, F.;
Saliba, M. J. Am. Chem. Soc. 2008, 130, 17278. (b) Johnson, S. A.;
Taylor, E. T.; Cruise, S. J. Organometallics 2009, 28, 3842. (c) Doster,
M. E.; Hatnean, J. A.; Jeftic, T.; Modi, S.; Johnson, S. A. J. Am. Chem.
Soc. 2010, 132, 11923. (d) Hatnean, J. A.; Beck, R.; Borrelli, J. D.;
Johnson, S. A. Organometallics 2010, 29, 6077. (e) Johnson, S. A.; Mroz,
N. M.; Valdizon, R.; Murray, S. Organometallics 2011, 30, 441.
(f) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253. (g) Nakao,
Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008,
130, 16170. (h) Kanyiva, K. S.; Kashihara, N.; Nakao, Y.; Hiyama, T.
Dalton Trans. 2010, 39, 10483.
(11) Importantly, no reaction occurred in the absence of Ni, phos-
phine or base. Likewise, the corresponding 2,4-difluoroaryl aldehyde did
not undergo cross-coupling.
(12) Other phosphines were investigated but did not provide superior
yields. Given the low cost and ease of handing, PPh3 was used for the rest
of the study. Details are provided in the Supporting Information.
(14) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337.
Org. Lett., Vol. 13, No. 10, 2011
2751

Table 2. Arylboronic Acid Scope and Limitation
Table 3. Scopes and Limitations of Polyfluoroaryl Imines
a Isolated yield.
Having established the feasibility of this process, we
then explored imines that would generate fluorinated
building blocks after cross-coupling (Table 3). A broad
range of substitution patterns are well-tolerated, with one
exception (entry 3). One substrate with two ortho CÀF
bonds underwent monosubstition (entry 7). It is note-
worthy that the product of this reaction has the same
difluoro substitution pattern as the substrate in entry 3.
Thus, it thus appears this substitution pattern is not
tolerated for CÀF activation. We are currently investi-
gating the cause of this phenomenon. In contrast, two
other substrates, both with at least one additional fluor-
ine substituent, underwent efficient diarylation (entries 8
and 9). The monoarylated product was not detected even
at incomplete conversion, suggesting that the second
arylation is competitive with or faster than the initial
arylation reaction. This reactivity is complementary to
that observed with Pt(II) catalysts, in which monosub-
stitution occurs peferentially.
a Ar = 4-methoxylphenyl. b A: 1.5 equiv boronic acid, 24 h, C: 3.0
equiv boronic acid, 48 h. c Isolated yield.
In summary, we have found that Ni(COD)2/PPh3 cata-
lyzes the cross-coupling of polyfluoroarenes to generate
functionalized fluorinated building blocks under mild
conditions. This work addresses the key limitations of
our previously reported Pt-catalyzed aryl fluoride cross-
coupling reactions and provides access to a broad range of
fluorinated biaryl molecules. In general, the reactions are
high yielding, and the process is tolerant of electron-
donating, electron-withdrawing and protic functional
goups. Arylboronic acids and ester and trifluoroborate
salts provide comparable yields. Mechanistic analysis of
this reaction is currently underway, as is the development
of tandem functionalization reactions.
2752
Org. Lett., Vol. 13, No. 10, 2011

Acknowledgment. We thank the following for support
of this research: University of British Columbia, NSERC
(Discovery Grant, Collaborative Research and Develop-
ment Grant, Research Tools and Instrumentation Grant),
AstraZeneca Canada (2008 Award in Chemistry to
J.A.L.), the Canada Foundation for Innovation (New
Opportunities Grant) and the British Columbia Knowl-
edge Development Fund.
Supporting Information Available. Complete experimen-
tal details for all 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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