Pd-catalyzed C3-selective arylation of pyridines with phenyl tosylates

Article abstract of DOI:10.1039/c3cc41066h

We have discovered that phenyl tosylates can be used to arylate pyridines at the C3-position using a Pd(OAc)₂-1,10-phenanthroline catalyst system. We also discovered that the reaction of 4-methylpyridine with naphthyl tosylates occurred on the methyl group instead of at the C3-position. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41066h

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Pd-catalyzed C3-selective arylation of pyridines with
phenyl tosylates†
Cite this: Chem. Commun., 2013,
49, 4634
Fenglin Dai, Qingwen Gui, Jidan Liu, Zhiyong Yang, Xiang Chen, Ruqing Guo and
Ze Tan*
Received 7th February 2013,
Accepted 26th March 2013
DOI: 10.1039/c3cc41066h
www.rsc.org/chemcomm
We have discovered that phenyl tosylates can be used to arylate Yu’s group using a catalyst system consisting of Pd(OAc)2 and
pyridines at the C3-position using a Pd(OAc)2–1,10-phenanthroline 1,10-phenanthroline (eqn (1)). They also demonstrated that the same
catalyst system. We also discovered that the reaction of 4-methyl- catalyst system could enable the C3-alkenylation of unsubstituted
pyridine with naphthyl tosylates occurred on the methyl group pyridines as well.16b Inspired by these results, we wonder if phenol
instead of at the C3-position.
esters such as triflates or tosylates could be used in place of aryl
iodides or bromides since, in this way, phenol derivatives could be
used as aryl sources for the synthesis of C3-arylpyridine. Herein we
report that this Pd-catalyzed C3-selective arylation of pyridines could
be indeed extended to phenyl tosylates (eqn (2)).
Recently transition metal-catalyzed arylation of arenes based on the
C–H activation mode has been developed as a valuable tool for the
construction of biaryls.1 Compared with the traditional cross coupling
methods,2 these reactions do not need the usually expensive organo-
metals or metal equivalents; instead a C–H activation process is
involved in the reaction. As a result, the requirements for the starting
materials are less demanding and the overall synthetic efficiency is
considerably higher. In order to achieve selective activation of desired
arene C–H bonds, chemists have used directing groups such as
oximes,3 imines,4 pyridines,5 amides6 as well as carboxylates7 to direct
the reactive site and excellent selectivities have been demonstrated.
While numerous methods have been developed for the arylation of
benzenes and other heterocycles,1,8 transition metal-catalyzed aryla-
tion of pyridines is much underdeveloped.9 This is to be expected due
to the electron-poor nature of the pyridine ring and its tendency to
form a non-productive complex with the transition metal catalyst
center. To overcome these problems, chemists have used masked
pyridines to circumvent these difficulties. For example, pyridine
N-oxides and N-iminopyridium ylides have been used as pyridine
surrogates to allow selective C2-arylations.10 As for the arylation of
unmasked pyridines,11–16 most of the successes have been achieved
with substituted pyridines. For example, C2-selective arylations have
been developed with 2-methyl pyridines11 and C3- and C4-selective
arylations12 have been achieved with perfluoropyridines,13 pyridines
with directing groups and pyridines with a strong electron-
withdrawing group at the C4 position.14,15 On the other hand, the
non-directed C3-arylation of pyridines is rare. In fact, it was until
very recently that the C3-arylation16a of pyridines was reported by
(1)
(2)
Initial experiments started with the reaction of pyridines with
phenyl triflate. When 3 mL of pyridine (1a) was treated with 0.5 mmol
of phenyl triflate and 1.5 mmol of Cs2CO3 in the presence of
Pd(OAc)2 (5 mol%) and 1,10-phenanthroline (15 mol%) at 140 1C
for 48 h, only a trace amount of the desired product, 3-phenylpyr-
idine (3a), was isolated. The major side-product was phenol derived
from the hydrolysis of the starting triflate. Since tosylates17 are much
more stable than the corresponding triflates, we next tested the
coupling between pyridines and phenyl tosylate (2a) under Yu’s
conditions. Much to our delight, the desired 3-phenylpyridine (3a)
could be isolated in 21% yield (ESI,† Table S1, entry 1). Increasing
the amount of Pd-catalyst to 10 mol% increased the yield to 32%
(ESI,† Table S1, entry 2). The yield can be increased to 38% if the
ligand 1,10-phenanthroline was also increased to 30 mol% (ESI,†
Table S1, entry 3). After a series of tests, we found that running the
reaction at 150 1C led to production of the desired 3-phenylpyridine
(3a) in 63% yield (ESI,† Table S1, entry 4). Surprisingly the yield
actually dropped slightly when the catalyst amount was further
increased to 15 mol% (ESI,† Table S1, entry 5). The tests also showed
that running the reaction at 160 1C did not benefit the reaction (ESI,†
Table S1, entry 6). It is important to note that we did not observe any
appreciable amount of 2-phenylpyridine or 4-phenylpyridine in our
crude product mixture, indicating that the C3-selectivity is very
high.18 While the use of PdCl2 instead of Pd(OAc)2 resulted in a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry
and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
E-mail: ztanze@gmail.com; Tel: +86 731 88822400
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and characterization of all products. See DOI: 10.1039/c3cc41066h
c
4634 Chem. Commun., 2013, 49, 4634--4636
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slight drop in terms of product yield, the use of Pd(TFA)2 as a catalyst in synthetically useful yields (Table 1, entries 1–9). Naphthyl tosylates
gave the desired product 3a only in 15% yield (ESI,† Table S1, entries 7 worked satisfactorily too (Table 1, entries 10–14 and 18–20). 3-Methyl,
and 8). Substituting the base Cs2CO3 with K2CO3 or K3PO4 also 3-ethyl substituted pyridines did not give any problem at all though
produced inferior results (ESI,† Table S1, entries 9 and 10) whereas the amount of Pd catalyst and the 1,10-phenanthroline ligand
the use of strong bases such as tBuONa or tBuOK led to disastrous needed to be increased in order to achieve good yields (Table 1,
failures (not shown in ESI,† Table S1). Similar to Yu’s reaction, DMF entries 13–21). On the other hand, attempts to couple 2-methyl
can also be used as a cosolvent in our procedure, but it can only be pyridine with phenyl tosylate did not furnish any of the C3-arylation
used as a minor component (ESI,† Table S1, entries 11 and 12). product, instead it gave an unidentifiable side-product (not shown in
Control experimentsshowedthatthereactiondidnotproceedwithout Table 1). The reaction of 4-methyl substituted pyridine with tosylates
the Pd-catalyst (ESI,† Table S1, entry 13). Finally we decided to set is a completely different story. The reaction of 4-methyl pyridine with
reaction of 0.5 mmol of tosylate with 3 mL of pyridine and 3 equiv. methyl and dimethyl substituted phenyl tosylates proceeded in a
of Cs2CO3 in the presence of 10 mol% of Pd(OAc)2 and 30 mol% of normal fashion to afford the desired C3-phenyl pyridines 3w and 3x
1,10-phenanthroline at 150 1C for 48 h as our standard condition.
in yields of 61% and 53%, respectively (Table 1, entries 22 and 23).
With the optimized conditions in hand, we next set out to explore However, when the phenyl tosylates were replaced by naphthyl
the scope and limitation of this reaction. Using various pyridines and tosylates, their reactions with 4-methyl pyridine did not produce
tosylates as the coupling partners, a variety of C3-aryl substituted the C3-naphthyl substituted pyridines, instead the C–H activation
pyridines were successfully synthesized in 32–67% yield and the occurred on the methyl group to give the diaryl methane products
results are summarized in Table 1. Substituents such as methyl, (Table 2). For example, the reaction of 4-methyl pyridine with
fluoro, tBu, methoxy and trifluoromethyl as well as phenyl groups are 2-naphthyl tosylate gave product 3y in 51% yield while the reaction
well tolerated on the aromatic rings of the tosylates, and the reactions of 4-methyl pyridine with 1-naphthyl tosylate gave 3z in slightly lower
of these tosylates with pyridines afforded the desired products 3b–3j yield. In addition, the coupling of a phenyl substituted 2-naphthyl
Table 1 Pd-catalyzed C3-arylation of pyridines with tosylatesa
Yieldb
(%)
Yieldb
(%)
Yieldb
(%)
Entry Tosylate
1
Product
Entry Tosylate
9
Product
Entry Tosylate
17
Product
55
59
57
60
56c
46c
2
3
10
11
18
19
67
52
47c
4
5
6
7
61
41
46
12
13
14
60
52c
51c
20
21
22
23
49c
53c
61c
53c
32
48
15
16
54c
50c
8
a
Reaction conditions: pyridine (3.0 mL) and 2 (0.5 mmol) were stirred with 3 equiv. of Cs2CO3, Pd(OAc)2 (0.05 mmol) and 1,10-phenanthroline
b
c
(0.15 mmol) at 150 1C in a sealed tube under N2 for 48 h. Isolated yields. Pd(OAc)2 (15 mol%) and ligand (45 mol%) were used.
c
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Table 2 Pd-catalyzed coupling of naphthyl tosylates with 4-methylpyridinea
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a
Reaction conditions: 1b (3.0 mL), tosylate (0.5 mmol), Pd(OAc)2
(15 mol%), ligand (45 mol%), and Cs2CO3 (1.5 mmol) at 150 1C for 48 h.
b
Isolated yields.
Scheme 1 Possible reaction intermediates.
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9 For a recent review on C–H functionalization of pyridines, see:
Y. Nakao, Synthesis, 2011, 3209.
10 For C2 arylation of pyridine N-oxides and N-iminopyridiniums, see:
(a) P. Xi, F. Yang, S. Qin, D. Zhao, J. Lan, G. Gao, C. Hu and J. You, J. Am.
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tosylate with 4-methyl pyridine led to production of the product 3aa
in 59% yield. It should be mentioned that the same type of product
was also observed when we tried to couple 4-methyl pyridine with
1-bromonaphthalene and 2-bromonaphthalene. It is possible that
the large size of the naphthyl ring has made it difficult for the
3-position of the pyridine ring to be activated. Consequently the
reaction took place at the less sterically crowded benzylic position.
On the basis of literature reports,1 we reason that the reaction
starts with the oxidative insertion of the Pd(0) catalyst into the
C–OTs bond to form phenyl–Pd(II) intermediate I. I next reacts with
pyridine either through C–H activation or proton abstraction to
form a diaryl–Pd(II) intermediate II. After reductive elimination, the
desired product is obtained and the Pd(0) catalyst is regenerated.
Alternatively, the reaction may go through a Pd(II)/Pd(IV) catalytic
cycle19 and intermediates such as III and IV may be involved. At
present, the exact mechanism remains to be clarified (Scheme 1).
In summary, we have demonstrated that C3-selective aryla-
tion of pyridines can be accomplished with phenyl tosylates
using Pd(OAc)2–1,10-phenanthroline as the catalyst and Cs2CO3
as the base. The coupling of naphthyl tosylates with 4-methyl
pyridine was found to occur on the methyl group instead of at
the C3 position. Detailed mechanistic investigations are still
ongoing and the results will be reported in due course.
13 For C4 arylation of perfluoropyridines, see: (a) Y. Wei and W. Su,
J. Am. Chem. Soc., 2010, 132, 16377; (b) C.-Y. He, S. Fan and X. Zhang,
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T. K. Woo and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 8754.
14 For Pd(0)-catalyzed C3 arylation of pyridines using directing groups,
This work was supported by grants from the National
Science Foundation of China (No. 21072051), NCET program
(NCET-09-0334) and the Fundamental Research Funds for the
Central Universities, Hunan University.
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c
4636 Chem. Commun., 2013, 49, 4634--4636
This journal is The Royal Society of Chemistry 2013