Pd-catalyzed direct cross-coupling of electron-deficient polyfluoroarenes with heteroaromatic tosylates

Article abstract of DOI:10.1021/ol201706t

We report a Pd-catalyzed direct cross-coupling of electron-deficient polyfluoroarenes with heteroaromatic tosylates. The notable features of this reaction are its high reaction efficiency, excellent chemoselectivity, operational simplicity, and mild react

Full text of DOI:10.1021/ol201706t

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4374–4377
Pd-Catalyzed Direct Cross-Coupling of
Electron-Deficient Polyfluoroarenes with
Heteroaromatic Tosylates
Shilu Fan, Jie Yang, and Xingang Zhang*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
xgzhang@mail.sioc.ac.cn
Received June 24, 2011
ABSTRACT
We report a Pd-catalyzed direct cross-coupling of electron-deficient polyfluoroarenes with heteroaromatic tosylates. The notable features of this
reaction are its high reaction efficiency, excellent chemoselectivity, operational simplicity, and mild reaction conditions. We have applied this
protocol to prepare the semiconducting materials in a highly efficient manner.
Heterobiaryl structures are omnipresent in a wide range
of biologically active compounds, natural products, and
functional materials. Among them, azines (e.g., pyridine,
quinoline) and diazines (e.g., quinoxaline, quinazoline)
bearing an aromatic ring adjacent to a nitrogen atom
constitute a distinct class of structural motif owing to their
importance in medicinal chemistry and material sciences.1
Hence, it is of great synthetic interest to develop efficient
reactions to access them. The most common method used
to prepare such a class of heterobiaryls is the transition-
metal-catalyzed cross-coupling of a metalated arene/het-
eroarene with a halogenated heteroarene/arene.2 How-
ever, this traditional process suffers from intrinsic
limitations in terms of step economy and the stability
and availability of azine/diazine organometallics.2a,b In
addition, many Pd-catalyzed reactions do not work well
with 2-halopyridine analogues, owing to the easy forma-
tion of a stable dimeric Pd-complex that effectively
removes the Pd from the catalytic cycle.3 In this regard,
Pd-catalyzed direct arylation of an azine N-oxide4 or N-
iminopyridinium ylide5 with aryl halides has recently been
developed. Additionally, the direct coupling of azines to
aryl halides or aryl metals, which represents a better
(3) Bozell, I. J.; Vogt, C. E.; Gozum, J. J. Org. Chem. 1991, 56, 2584.
(4) For Pd-catalyzed direct arylation of pyridine N-oxide, see: (a)
Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2006,
127, 18020. (b) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006,
45, 7781. (c) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 15185. (d) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem.
Soc. 2008, 130, 9254. (e) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.;
Bertrand-Laperle, M.; Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond,
N.; Lecavallier, M.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291.
(f) Ackermann, L.; Fenner, S. Chem. Commun. 2011, 47, 430.
(5) Larivee, A.; Mousseau, J. J.; Charette, A. B. J. Am. Chem. Soc.
2008, 130, 52.
(1) For selected reviews, see: (a) Torborga, C.; Bellera, M. Adv.
Synth. Catal. 2009, 351, 3027. (b) Hill, M. D.; Movassaghi, M.
Chem.;Eur. J. 2008, 14, 6836. (c) Thomas, S. W., III; Joly, G. D.;
Swager, T. M. Chem. Rev. 2007, 107, 1339. (d) Fairlamb, I. J. S. Chem.
Soc. Rev. 2007, 36, 1036. (e) Pozharski, A. F.; Soldartenko, A. T.;
Katritsky, A. Heterocylces in Life and Society; Wiley: New York, 1997.
(2) For selected examples, see: (a) Littke, A. F.; Dai, C.; Fu, G. C. J.
Am. Chem. Soc. 2000, 122, 4020. (b) Molander, G. A.; Biolatto, B. J.
Org. Chem. 2003, 68, 4302 and references therein. (c) Hodgson, P. B.;
Salingue, F. H. Tetrahedron Lett. 2004, 45, 685.
(6) For a carboxy-directed palladium-catalyzed arylation of pyridine
using aryl halides, see: (a) Wasa, M.; Worrell, B. T.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2010, 49, 1275. For a rhodium-catalyzed direct arylation
of pyridine using aryl halides, see:(b) Berman, A. M.; Lewis, J. C.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14926. For
nickel-catalyzed direct arylation of pyridine using arylzincs, see:(c)
Tobisu, M.; Hyodo, I.; Chatani, N. J. Am. Chem. Soc. 2009, 131,
12070. (d) For a radical arylation of azines with aryl boron acids, see:
Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.;
Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 13194.
r
10.1021/ol201706t
Published on Web 07/20/2011
2011 American Chemical Society

reaction efficiency, has also been accomplished using
different transition-metal catalysts.6 From the point of
view of synthetic convenience, the direct heteroarylation
of ArÀH using heteroaromatic tosylates would be an
attractive alternative, because the heterocyclic alcohols,
such as quinoxalinols, quinolinols, and pyridinols, are
readily available and inexpensive, the corresponding het-
eroaromatic tosylates are chemically stable, highly crystal-
line, and easily prepared. However, the construction of
such arylated azine or diazine structures through the
present strategy (e.g., direct heteroarylation of polyfluor-
oarenes using heteroaromatic tosylates) has never been
reported, despite important progress that has been
achieved on the cross-couplings of aryl metals with hetero-
aromatic sulfonates7 or phosphonium salts.8 Conse-
quently, developing new methods to access this valuable
heterobiaryl moiety for widespread synthetic applications
are still highly desirable.
Scheme 1. Pd-Catalyzed Direct Cross-Coupling of
Polyfluoroarenes with Heteroaromatic Tosylates
We began this study by choosing electron-deficient
pentafluorobenzene 1a and 2-quinaxolinyl tosylate 2a
as model substrates (eq 1). Compound 2a was prepared
from commercially available quinoxalin-2-ol with tosyl
chloride.
It has been demonstrated that the installation of a
polyfluoroaryl group ortho to a nitrogen atom of azines
or diazines can make the heterobiaryl based electronic and
optoelectronic materials possess several advantages with
respect to their nonfluorinated counterparts, such as en-
hanced photoluminescence efficiency, minimized self-
quenching behavior, and lowered HOMO and LUMO
energy levels.9 However, the preparation of these poly-
fluoroarylated azines or diazines requires prefunctiona-
lized polyfluoroarenes and several synthetic steps.10
Therefore, developing highly efficient methods by using
simple polyfluoroarenes to directly construct this key
structural motif is a topic of immense importance in
organic synthesis.11 Recently, an important example of a
copper-catalyzed cross-coupling of pentafluorobenzene
with 2-pyridyl halides was reported.11c,d However, the
reaction was restricted by harsh reaction conditions
(120À150 °C) and the availability of pyridyl halides. Here-
in, we describe a Pd-catalyzed direct cross-coupling of
electron-deficient polyfluoroarenes with heteroaromatic
tosylates under mild reaction conditions. This approach
provides a concise and convenient protocol for the pre-
paration of a wide range of polyfluoroarylated azine/
diazine structures with high efficiency (Scheme 1).
Initially, the use of Pd(OAc)2 (10 mol %), PPh3 (20mol%),
and Cs2CO3 (1.2 equiv) in toluene at 120 °C failed to
afford desired product 3a. After a survey of reaction
parameters, we found that the catalytic activity was highly
sensitive to the components of the catalyst system (see
Table S1 in the Supporting Information). The Buchwald
Cy-JohnPhos ligand L, P(biphenyl-2-yl)Cy2, and K3PO4
were the best choice. Other ligands, such as SPhos, XPhos,
DavePhos, RuPhos, tricyclohexylphosphine, and biden-
tate ligand, dppe, were less effective. The absence of a
phosphine ligand led to no 3a, indicating the pivotal role of
a phosphine ligand in the catalytic cycle. The reaction
temperature also had an impact on the reaction
efficiency,12 and a 72% NMR yield of 3a was afforded
when the reaction temperature decreased to 80 °C with
the use of Pd(OAc)2 (10 mol %), P(biphenyl-2-yl)Cy2
(20 mol %), and K3PO4 (1.2 equiv) in dioxane. Interest-
ingly, when the Pd(OAc)2 loading was decreased to 5 mol %,
an alcoholic solvent, tBuOH,13 was found to be the
optimum reaction medium. Further optimization revealed
that the optimal isolated yield (73%) was achieved by use
of3 mol % of Pd(TFA)2 and 6 mol % of L with 1.2 equiv of
1-adamantanecarboxylic acid (AdOH) as an additive at
90 °C.14,15
(7) For examples, see: (a) Bhayana, B.; Fors, B. P.; Buchwald, S. L.
Org. Lett. 2009, 11, 3954. (b) Gogsig, T. M.; Lindhardt, A. T.; Skrydstrup,
T. Org. Lett. 2009, 11, 4886.
(8) Kang, F.-A.; Sui, Z.; Murray, W. V. J. Am. Chem. Soc. 2008, 130,
11300.
(9) Babudri, F.; Farinola, G. M.; Naso, F.; Ragni, R. Chem. Com-
mun. 2007, 1003.
Under the optimum reaction conditions, a variety of
pentafluorophenylated azine and diazine structures were
obtained with high efficiency (Table 1).
(12) Decreasing the reaction temperature is beneficial to the reaction;
for details, see Supporting Information Table S1.
(13) BuOH is often used as a (co)solvent in cross-coupling reactions
of aryl tosylates; see: (a) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J.
Am. Chem. Soc. 2003, 125, 11818. (b) So, C. M.; Lau, C. P.; Kwong,
F. Y. Angew. Chem., Int. Ed. 2008, 47, 8059 and ref 7a.
(10) For selected examples, see: (a) Chen, J.; Cammers-Goodwin, A.
Tetrahedron Lett. 2003, 44, 1503. (b) Hamilton, C. W.; Laitar, D. S.;
Sadighi, J. P. Chem. Commun. 2004, 1628. (c) Yamamoto, Y.; Kinpara,
K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J.
Am. Chem. Soc. 2005, 127, 605. (d) Dash, J.; Reissig, H.-U. Chem.;Eur.
J. 2009, 15, 6811.
t
(14) Using 5 mol% Pd(OAc)2 and 1.2 equiv of AdOH furnished the
reaction in a slightly lower yield (60% isolated yield). PivOH can also be
used as an additive but is less effective.
(15) It has been demonstrated that phosphine-ligated arylpalladium
carboxylates LPd(Ar)(OCOR) were typically proposed to react with
arenes to form biarylpalladium complexes through a concerted metala-
tionÀdeprotonation (CMD) pathway. The role of AdOH or PivOH was
proposed to function as a proton shuttle during the aryl CÀH cleavage
step. See: Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
(11) For recent examples for transition-metal-catalyzed direct aryla-
tion of polyfluroroarenes with arylhalides, see: (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) Rene,
O.; Fagnou, K. Org. Lett. 2010, 12, 2116. For oxidative cross-coupling of
polyfluoroarenes with electron-rich heteroarenes, see:(f) He, C.-Y.; Fan, S.;
Zhang, X. J. Am. Chem. Soc. 2010, 132, 12850.
Org. Lett., Vol. 13, No. 16, 2011
4375

Table 1. Pd-Catalyzed Direct Cross-Coupling of Pentafluoro-
benzene with Various Heteroaromatic Tosylatesa
Table 2. Pd-Catalyzed Direct Cross-Coupling of Fluoroarenes
with Various Heteroaromatic Tosylatesa
a Reaction conditions (unless otherwise specified): 1a (2.0 equiv), 2
(0.3 mmol, 1.0 equiv), Pd(TFA)2 (5 mol %), P(biphenyl-2-yl)Cy2 L (10
mol %), K3PO4 (1.2 equiv), and AdOH (1.2 equiv) in tBuOH (1.5 mL) at
90 °C for 12 h. b Using 3 mol % of Pd(TFA)2 and 6 mol % of L.
c Reaction run at 80 °C for 36 h.
a Reaction conditions (unless otherwise specified): 1 (3.0 equiv), 2
(0.3 mmol, 1.0 equiv), K3PO4 (1.2 equiv), and AdOH (1.2 equiv) in
tBuOH (1.5 mL) at 90 °C for 12 h. L, P(biphenyl-2-yl)Cy2. b Reaction
run at 80 °C for 36 h. c Using 1.2 equiv of 1. d Using 10 mol % of
Pd(TFA)2 and 20 mol % of L.
Substrates of 2-quinaxolinyl tosylates bearing an elec-
tron-donating group furnished the reaction smoothly in
good yields with only utilization of 3 mol % Pd-catalyst
(entries 3bÀd). While for electron-withdrawing group
substituted 2-quinaxolinyl tosylates, lower yields were
afforded (entries 3eÀf). This can be addressed by increas-
ing the loading of Pd(TFA)2 to 5 mol % (entry 3f).
4-Quinazolinyl tosylates did not interfere with the cou-
pling, and good to excellent yields were obtained (entries
3gÀi). Azines are also suitable substrates for the reaction
(entries 3jÀm). Importantly, although product 3e was
obtained in a reasonable yield, it revealed a good chemos-
electivity at 2-quinaxolinyl tosylate over aryl chloride, thus
providing a good opportunity for further transformations
by utilizing traditional techniques (entry 3e).
To further probe the applicability of this methodology,
couplings of various fluoroarenes 1 bearing three or four
fluorines with heteroaromatic tosylates were also tested
(Table 2).
To our delight, fluoroarenes 1 containing more than
one reaction site provided good yields of monoazine- or
diazine-substituted products without observation of
bis(heteroaryl)fluoroarenes (entries 3nÀp). However, due
to the poor reactivity of 1,3,5-trifluorobenzene,16 only a
27% yield of 3y was afforded (entry 3y). The nature of the
substituents on the fluoroaromatic ring did not influence
the reaction efficiency, and both electron-rich and -poor
groups furnished the reaction in good yields (entries 3qÀt).
We were pleased to observe that polyfluoropyridine was
viable for the direct heteroarylation, forming bishetero-
cycles 3u and 3v in good yields (entries 3uÀv). Benzylated
fluoroarene is also a suitable substrate and provided 3w in
a reasonable yield (entry 3w). Notably, an R,β-unsaturated
ester is compatible with the catalytic system with no
formation of a Heck reaction byproduct, thus demonstrat-
ing the utility of this protocol in the synthesis of highly
functionalized heteroarylpolyfluoroarenes (entry 3x).
The importance of this protocol can also be featured by
the rapid access of semiconducting materials through
sequential CÀH bond and CÀO bond activation from
simple and inexpensive starting materials. As shown in
Scheme 2, chemoselective functionalization of inexpensive
quinoline-2,4-diyl bis(tosylate) 4 under the standard reac-
tion conditions afforded monofluoroarylated quinoline-4-
yl tosylate 5. The resulting compound 5 was subsequently
(16) (a) Hyla-Kryspin, I.; Grimme, S.; Buker, H. H.; Nibbering,
N. M. M.; Cottet, F.; Schlosser, M. Chem.;Eur. J. 2005, 11, 1251. (b)
Schlosser, M.; Marzi, E. Chem.;Eur. J. 2005, 11, 3449.
(17) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.;
Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132, 4506.
4376
Org. Lett., Vol. 13, No. 16, 2011

polyfluorophenylquinoline derivative 718 in a highly effi-
cient manner. A 2-g-scale synthesis of 8 was alsoperformed
in good yield (62%), thus indicating the good reliablility of
the process (Scheme 2). Similarly, phenylation of 8 pro-
vided a semiconducting compound 918 efficiently. These
transformations demonstrated thatcompounds 5and 8 are
very useful and can be used as versatile building blocks to
access a wide range of functional materials through the
present strategy.
Scheme 2. Synthesis of Semiconducting Polyfluorophenylqui-
nolines 7 and 9 through Chemoselective Functionalization of
Quinoline-2,4-diyl Bis(tosylate) 4
In conclusion, we have developed a straightforward and
convenient method for Pd-catalyzed direct heteroarylation
of electron-deficient polyfluoroarenes. The reaction makes
direct use of a simple polyfluoroarenes and readily avail-
able and inexpensive heteroaromatic tosylates without the
requirement of several synthetic steps to prepare cross-
coupling partners. Application of the method leads to the
semiconducting materials in a highly efficient manner.
Because of the high reaction efficiency, excellent chemos-
electivity, and the ease of conducting such reactions, this
protocol provides a useful and facile access to polyfluor-
oaryl azine and diazine structures of interest in functional
materials of electronic devices. Further studies to expand
the substrate scope and their applications are now in
progress.
Acknowledgment. The NSFC (Nos. 20902100, 2083-
2008), the Shanghai Rising-Star Program (09QA140-
6900), and SIOC are greatly acknowledged for funding
this work.
treated with phenylboronic acid in the presence of a Pd-
catalyst,13a followed by the oxidative olefination via se-
quential CÀH activation,17 to give a semiconducting
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org
(18) Stefopoulos, A. A.; Kourkouli, S. N.; Economopoulos, S.;
Ravani, F.; Andreopoulou, A.; Papagelis, K.; Siokou, A.; Kallitsis,
J. K. Macromolecules 2010, 43, 4827.
Org. Lett., Vol. 13, No. 16, 2011
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