PdCl2(dppf)-catalyzed in situ coupling of 2-hydroxypyridines with aryl boronic acids mediated by PyBroP and the one-pot chemo- and regioselective construction of two distinct aryl-aryl bonds

Article abstract of DOI:10.1039/c1cc15753a

We present a PdCl₂(dppf)-catalyzed synthesis of 2-arylated pyridine derivatives via the in situ coupling of 2-OH pyridines and boronic acids mediated by PyBroP. In addition, the highly chemo- and regioselective construction of two different aryl-aryl bonds via a one-pot operation has also been demonstrated by the orthogonal use of this method with the Ni-catalyzed Suzuki-Miyaura coupling of phenols.

Full text of DOI:10.1039/c1cc15753a

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COMMUNICATION
PdCl2(dppf)-catalyzed in situ coupling of 2-hydroxypyridines with aryl
boronic acids mediated by PyBroP and the one-pot chemo- and
regioselective construction of two distinct aryl–aryl bondsw
Shui-Ming Li,a Jie Huang,a Guo-Jun Chena and Fu-She Han*ab
Received 17th September 2011, Accepted 16th October 2011
DOI: 10.1039/c1cc15753a
We present a PdCl2(dppf)-catalyzed synthesis of 2-arylated
pyridine derivatives via the in situ coupling of 2-OH pyridines
and boronic acids mediated by PyBroP. In addition, the highly
chemo- and regioselective construction of two different aryl–aryl
bonds via a one-pot operation has also been demonstrated by the
orthogonal use of this method with the Ni-catalyzed Suzuki–
Miyaura coupling of phenols.
Herein, we present a general and efficient synthesis of
2-arylated pyridines through the PdCl2(dppf)-catalyzed
in situ coupling of 2-OH pyridines with aryl boronic acids.
Most importantly, we demonstrated that the orthogonal use of
this method with the Ni-catalyzed in situ Suzuki–Miyaura
coupling of common phenols8f provides an efficient pathway
for the highly chemo- and regioselective construction of two
distinct aryl–aryl bonds via a one-pot procedure.
For the in situ activation of 2-OH pyridines, PyBroP (bromo-
tripyrrolidinophosphonium hexafluorophosphate) was selected
as the most suitable activator. Since first introduced by Kang
et al. for in situ activation of phenolic C–O bonds,8a–c this
activator displayed a broader generality and functional group
tolerance than other reagents.9–11 Surprisingly, when 2-OH
pyridine 1 was employed to couple with 4-methoxyphenyl
boronic acid 2a (Table 1), only poor yield was obtained either
under Kang’s conditions using PdCl2(PPh3)2 as the catalyst,8a
or under our conditions using NiCl2(dppp) as the catalyst8f
(entries 1 and 2). The results are in stark contrast to those of
The 2-arylated pyridine derivatives are valuable structural
motifs in a wide spectrum of fields. They are core motifs in
numerous bioactive compounds.1 More significantly, they can
coordinate with a wide range of transition as well as rare earth
metal ions, giving rise to the generation of not only interesting
metallo-supramolecular architectures, but also distinctive
magnetic, optoelectrical, and catalytic properties.2 So far, the
transition-metal-catalyzed couplings such as Suzuki,3 Stille,4
and Negishi reactions5 have been frequently studied, and a few
promising catalyst systems for coupling 2-halogen pyridines
and arylboronic compounds have been developed.6 More
recently, the direct C–H arylation of pyridine derivatives, such
as the pyridinium N-oxide or N-imino ylide, with aryl halides
has stood for a renowned methodology for the synthesis of
arylated pyridines.7
Table 1 Optimization of the reaction conditionsa
As a latent substrate for the synthesis of 2-arylated pyridines,
2-OH pyridine derivatives can be promising coupling partners
because they are commercially available, inexpensive, and
stable. Furthermore, the reaction occurs regiospecifically at
the OH position, avoiding the generation of regioisomers as
seen in direct C–H functionalization of pyridinium ylides.7b,d
Unfortunately, the coupling of 2-OH pyridines has been less
considered. Owing to the recent advances in transition-metal-
catalyzed cross-coupling of phenolic compounds via the in situ
C–O activation strategy,8–11 as well as our constant interest in
the synthesis and functional development of heteroarenes,12 we
initiated an investigation into the synthesis of 2-arylpyridines
from 2-OH pyridines.
Entry Cat./mol%
Base
Ligand/mol% Yieldb (%)
c
1
PdCl2(PPh3)2 (5) Na2CO3
—
—
Traced
18
37
43
53
57
56
74
93
2
3
NiCl2(dppp) (5)
Pd(OAc)2 (5)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
K2CO3
K3PO4
K2CO3
K3PO4
PCy3 (10)
PCy3 (10)
PCy3 (10)
PCy3 (10)
PCy3 (10)
PCy3 (10)
—
4
5
PdCl2(cod) (5)
Pd(acac)2 (5)
6
7
8
9
10
11
12
Pd(PPh3)4 (5)
PdCl2(dppf) (5)
PdCl2(dppf) (5)
PdCl2(dppf) (5)
PdCl2(dppf) (5)
PdCl2(dppf) (2)
PdCl2(dppf) (2)
—
—
90
26
—
16
a
a Changchun Institute of Applied Chemistry, Chinese Academy of
Sciences, 5625 Renmin Street, Changchun 130022, Jilin, China.
E-mail: fshan@ciac.jl.cn; Tel: +86-431-8526-2936
Reaction conditions: 2-OH pyridine 1 (47.5 mg, 1.0 equiv.), PyBroP
(350 mg, 1.5 equiv.), Et3N (3.0 equiv.), and inorganic base (3.0 equiv.)
in dioxane (3.0 mL) at 100 1C for 3 h; then catalyst, 2a (152 mg,
b State Key Laboratory of Fine Chemicals, Dalian 116024, China
w Electronic supplementary information (ESI) available: Experimental
procedures, UV-vis titration, characterization data, and 1H- and
13C-NMR spectra. See DOI: 10.1039/c1cc15753a
b
2.0 equiv.), and 5% H2O (v/v) at 100 1C for 16–24 h. Isolated yields.
c
d
No external ligands were used. Three trials under conditions
identical to those in ref. 8a.
c
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3- and 4-OH pyridines which underwent smooth coupling with
various aryl boronic acids in the presence of the Ni catalyst.8f,13
An insight into the reasons for using UV-vis titration suggests
that the low activity of these catalysts is due most possibly to the
coordination effect between the metal ions and intermediate A,
leading to formation of a stable six-membered chelate B (eqn (1),
see ESIw for detailed discussion).
NH2, and OH, neutral Me and H, as well as electron-deficient
ester, cyano, ketone, aldehyde, and chloride groups were
examined. The results showed that each type of boronic acid
displays good compatibility to the reaction conditions to give
the coupled products 3a–k or 5a–k in high to excellent yields,
although a somewhat diminished yield was obtained for 3c, 3k,
and 5b. In addition, high yields for 3e and 5e imply that a
sterically encumbered substrate is tolerated.
More interestingly, heterobiaryls 3l–q and 5l–q, particularly the
highly valuable 2,20-bis-heteroaryls 3n–q and 5n–5q, could be
obtained in good to excellent yields. These results are noteworthy
because synthesis of bisheteroaryls via the traditional coupling of a
2-heteroaryl halide and 2-heterocyclic boronic acid is considerably
challenging.3,6 Finally, the coupling efficiency of the delocalized
1- and 2-naphthylboronic acids (i.e., weak nucleophilic) was
examined. While the reaction of 2-OH pyridine was somewhat
reluctant (3r and s), 2-OH quinoline underwent smooth coupling
to afford 5r and 5s in excellent yields.
ð1Þ
Thus, our attention was shifted to examine other catalyst
systems bearing bulk or electron-rich ligands because such
catalysts are assumed to exhibit a decreased coordination
ability with the intermediate A because of the steric or
electronic effect of the ligated ligands. An extensive survey of
various catalysts (entries 3–10) revealed that PdCl2(dppf) is a
competent catalyst, affording the coupled product 3a in 93%
yield (entry 9). The optimized conditions are PyBroP (1.5 equiv.),
K2CO3 (3.0 equiv.), and Et3N (3.0 equiv.) at 100 1C for 3 h in
dioxane (3 mL); then the reaction vessel was recharged in situ
with boronic acid 2a (2.0 equiv.), PdCl2(dppf) (5 mol%), 5%
H2O (v/v), and heated at 100 1C for 16 h. In good agreement
with our assumption, only negligible coordination between
PdCl2(dppf) and the phosphonium salt A was observed as
confirmed by UV-vis titration (ESIw).
Owing to the distinctive catalytic property of PdCl2(dppf)
on 2-OH pyridine and NiCl2(dppp) on common phenols,8f it is
anticipated that the orthogonal use of the two catalyst systems
would provide a straightforward pathway for the installation
of two different aryl–aryl bonds in a chemoselective manner
controlled by the catalysts. To demonstrate this assumption, a
mixture of 2-OH quinoline 4 and 1-naphthanol 6a in a 1 : 1
molar ratio was first activated by PyBroP (Table 3). Subse-
quently, boronic acid 2a and PdCl2(dppf) were added. The
reaction mixture was stirred at 100 1C for 4 h. Then, the
reaction vessel was recharged with boronic acid 2f and
NiCl2(dppp), and was further heated for an additional 20 h.
The results showed that in such a complex one-pot operation,
the first added boronic acid 2a was coupled chemoselectively
with quinoline 4 to afford the biaryl 5a, and the secondly
added boronic acid 2f was coupled efficiently with phenol 6a to
give 7a in excellent yield, respectively. No crossover products
generated from the coupling of 4 with 2f, or 6a with 2a were
isolated. Such a highly chemoselective coupling was firmly
confirmed by reversing the feeding sequence of boronic acids
2a and 2f. Namely, when 2f was added prior to 2a, the
corresponding coupled products 5f and 7b were obtained
exclusively in 96% and 77% yields, respectively. The generality
of the catalyst controlled highly chemoselective coupling was
Having established the optimized conditions, the coupling
efficiency of 2-OH pyridine 1 and 2-OH quinoline 4 was then
examined, respectively, by varying the boronic acids (Table 2).
A range of boronic acids decorated by electron-rich OMe,
Table 2 Cross-coupling of 2-OH pyridine 1 and 2-OH quinoline 4,
respectively, with various boronic acids 2a
Table 3 One-pot construction of two distinct biaryls from two
intermolecular phenolic OHsa
a
Reaction conditions: 2-OH quinoline 4 (0.5 mmol), phenol 6a
(0.5 mmol), PyBroP (1.5 mmol), Et3N (3.0 mmol), and K3PO4
(4.0 mmol) in dioxane (6 mL) at 100 1C for 3 h; then PdCl2(dppf)
(10 mol% relative to 4), and 2a (0.75 mmol) at 100 1C for 4 h; then
NiCl2(dppp) (20 mol% relative to 6a), and 2f (1.0 mmol) at 100 1C for
a
Reaction conditions: 1 or 4 (0.5 mmol, 1.0 equiv.), PyBroP (1.5 equiv.),
b
c
20 h. Isolated yield. Yield was determined by 1H-NMR due to the
contamination by a small amount of inseparable by-product derived
from the homocoupling of 2f.
Et3N (3.0 equiv.), and K2CO3 (3.0 equiv.) in dioxane (3 mL) at 100 1C for
3 h; then PdCl2(dppf) (5 mol%), boronic acid (1.0 mmol, 2.0 equiv.), and
5% H2O (v/v) at 100 1C for 2–16 h; isolated yields.
c
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Table 4 One-pot construction of two distinct aryl–aryl bonds from
two intramolecular phenolic OHsa
the methods toward the synthesis of some newly designed
pyridine-containing organic modules as well as their potential
applications in functional materials are currently underway.
Financial support from Hundred Talent Program and Academy-
Locality Cooperation Program of CAS, and State Key Laboratory
of Fine Chemicals (KF1008) is acknowledged.
Notes and references
1 (a) G. Jones, in Comprehensive Heterocyclic Chemistry II, ed.
A. R. Katrizky, C. W. Rees, E. F. V. Scriven and A. McKillop,
Pergamon, Oxford, 1996, vol. 5, p. 167; (b) R. Capdeville,
E. Buchdunger, J. Zimmermann and A. Matter, Nat. Rev. Drug
Discovery, 2002, 1, 493.
2 For reviews, see: (a) E. C. Constable, Chem. Soc. Rev., 2007,
36, 246; (b) M. W. Cooke and G. S. Hanan, Chem. Soc. Rev., 2007,
36, 1466; (c) L.-M. Xu, B.-J. Li, Z. Yang and Z.-J. Shi, Chem. Soc.
a
Reaction conditions: 8a or 8b (0.5 mmol), PyBroP (1.5 mmol), Et3N
(3.0 mmol), and K3PO4 (4.0 mmol) in dioxane (6 mL) at 100 1C for 4 h;
then PdCl2(dppf) (10 mol%) and 2f (0.6 mmol) at 100 1C for 4 h; then
NiCl2(dppp) (20 mol%) and 2a (1.0 mmol) at 100 1C for 20 h; average
isolated yields of two runs. 20 mol% of PdCl2(dppf) and 30 mol% of
NiCl2(dppp) were used.
b
Rev., 2010, 39, 712; (d) A. Wild, A. Winter, F. Schlutter and
¨
further demonstrated by varying the structures of boronic
acids, 2-OH pyridines, and phenols (see Table S1, ESIw).
Next, we tried the installation of two different aryl–aryl
bonds from two intramolecular OHs. This is more challenging
compared with the two intermolecular OHs as exemplified
above owing to the interference of the two intramolecular
OHs, and thereby leads to not only chemoselective but also
regioselective concerns. To our delight, we found that by employing
a similar procedure as shown in Table 3, the one-pot formation of
two intramolecular aryl–aryl bonds could be achieved both in
high chemo- and regioselectivities (Table 4). Namely, when
2,4-dihydroxyquinoline 8a or 2,4-dihydroxypridine 8b was
employed to couple with two different boronic acids 2f and 2a,
the first added boronic acid 2f was coupled chemo- and regio-
selectively at the C-2 position of 8a or 8b in the presence of
PdCl2(dppf), and the secondly added boronic acid 2a was coupled
at the C-4 position in the presence of NiCl2(dppp), producing 9a
and 9b in fairly good yields. The structure of 9a was clearly
exemplified by single X-ray analysis (Fig. S4, ESIw).14
U. S. Schubert, Chem. Soc. Rev., 2011, 40, 1459.
3 (a) R. P. Roques, D. Florentin and M. Callanquin, J. Heterocycl.
Chem., 1975, 12, 195; (b) H. G. Kuivila and K. V. Nahabedian,
J. Am. Chem. Soc., 1961, 83, 2159.
4 (a) U. Lehmann, O. Henze and A. D. Schluter, Chem.–Eur. J., 1999,
¨
5, 854; (b) M. Heller and U. S. Schubert, J. Org. Chem., 2002, 67, 8269;
(c) D. Cuperly, P. Gros and Y. Fort, J. Org. Chem., 2002, 67, 238.
5 J. C. Loren and J. S. Siegel, Angew. Chem., Int. Ed., 2001, 40, 754.
6 (a) A. F. Littke, C. Dai and G. C. Fu, J. Am. Chem. Soc., 2000,
122, 4020; (b) G. A. Molander and B. Biolatto, J. Org. Chem.,
2003, 68, 4302; (c) B. Bhayana, B. P. Fors and S. L. Buchwald,
Org. Lett., 2009, 11, 3954; (d) T. Kinzel, Y. Zhang and
S. L. Buchwald, J. Am. Chem. Soc., 2010, 132, 14073.
7 For 2-arylation, see: (a) L.-C. Campeau, S. Rousseaux and
K. Fagnou, J. Am. Chem. Soc., 2005, 127, 18020; (b) A. Larivee,
´
J. J. Mousseau and A. B. Charette, J. Am. Chem. Soc., 2008,
130, 52; (c) S. H. Cho, S. J. Hwang and S. Chang, J. Am. Chem.
Soc., 2008, 130, 9254; (d) A. M. Berman, J. C. Lewis,
R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc., 2008,
130, 14926; (e) L.-C. Campeau, D. R. Stuart, J. P. Leclerc,
M. Bertrand-Laperle, E. Villemure, H. Y. Sun, S. Lasserre,
N. Guimond, M. Lecavallier and K. Fagnou, J. Am. Chem. Soc.,
2009, 131, 3291; (f) M. Tobisu, I. Hyodo and N. Chatani, J. Am.
Chem. Soc., 2009, 131, 12070; (g) S. Duric and C. C. Tzschucke,
Org. Lett., 2011, 13, 2310.
8 For in situ activation with phosphonium salt, see: (a) F.-A. Kang,
Z. Sui and W. V. Murray, J. Am. Chem. Soc., 2008, 130, 11300;
(b) F.-A. Kang, Z. Sui and W. V. Murray, Eur. J. Org. Chem.,
2009, 461; (c) F.-A. Kang, J. C. Lanter, C. Cai, Z. Sui and
W. V. Murray, Chem. Commun., 2010, 46, 1347; (d) C. Shi and
C. C. Aldrich, Org. Lett., 2010, 12, 2286; (e) V. P. Mehta,
S. G. Modha and E. V. Van der Eycken, J. Org. Chem., 2010,
75, 976; (f) G.-J. Chen, J. Huang, L.-X. Gao and F.-S. Han,
Chem.–Eur. J., 2011, 17, 4038.
9 For in situ activation with the Grignard reagent, see: D.-G. Yu,
B.-J. Li, S.-F. Zheng, B.-T. Guan, B.-Q. Wang and Z.-J. Shi,
Angew. Chem., Int. Ed., 2010, 49, 4566.
10 For in situ activation with tosylate, see: L. Ackermann and
M. Mulzer, Org. Lett., 2008, 10, 5043.
11 In situ activation with pivalate ester was also reported. However,
the generality remains to be determined since only limited examples
were presented, see: K. W. Quasdorf, X. Tian and N. K. Garg,
J. Am. Chem. Soc., 2008, 130, 14422.
12 (a) F.-Q. Yuan, L.-X. Gao and F.-S. Han, Chem. Commun., 2011,
47, 5289; (b) F.-S. Han, M. Higuchi and D. G. Kurth, J. Am.
Chem. Soc., 2008, 130, 2073.
It is noteworthy that the new protocol accomplished the
construction of two different aryl groups at the 2,4-position
of 2,4-OH pyridines via a one-pot procedure. However, in
principle, a six-step sequence is required if traditional methods
are employed.
In summary, we have developed an efficient and straight-
forward pathway for the diverse synthesis of 2-arylated pyridine
derivatives via the one-pot cross-coupling of 2-OH pyridine
derivatives and boronic acids. More importantly, we have
established a catalyst-controlled highly chemo- and regio-
selective protocol for the construction of two different aryl–aryl
bonds via a one-pot procedure. The results would be of great
interest because, of the concepts used to improve the synthetic
efficiency in modern organic chemistry, the combination of
multi-step synthesis into a one-pot operation and/or achieving
the reaction with high selectivity (e.g., chemo-, regio-, and
enantioselectivity) has been recognized as the especially effective
way for atom-efficient and environmentally benign synthesis.
Consequently, these methods should find practical applications
in pharmaceuticals, functional materials, catalysts, and coordina-
tion and supramolecular chemistry owing to the unique property
of 2-arylated pyridines in these areas. Studies on application of
13 K. W. Quasdorf, A. Antoft-Finch, P. Liu, A. L. Silberstein,
A. Komaromi, T. Blackburn, S. D. Ramgren, K. N. Houk,
V. Snieckus and N. K. Garg, J. Am. Chem. Soc., 2011, 133, 6352;
and references therein.
14 CCDC 834931 contains the supplementary crystallographic data of
compound 9a.
c
12842 Chem. Commun., 2011, 47, 12840–12842
This journal is The Royal Society of Chemistry 2011