Palladium-catalyzed oxidative CH/CH cross-coupling of pyridine N-oxides with five-membered heterocycles

Article abstract of DOI:10.1039/c4cc04129a

Using Ag₂CO₃ as an additive, we developed the Pd-catalyzed intermolecular C-H/C-H cross-coupling of pyridine N-oxides with five-membered heterocycles such as 1-benzyl-1,2,3-triazoles, thiophens and furans. This protocol provides an e

Full text of DOI:10.1039/c4cc04129a

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Palladium-catalyzed oxidative CH/CH
cross-coupling of pyridine N-oxides with
five-membered heterocycles†
Wei Liu,ab Xin Yu,ab Yahui Liab and Chunxiang Kuang*ab
Cite this: Chem. Commun., 2014,
50, 9291
Received 29th May 2014,
Accepted 20th June 2014
DOI: 10.1039/c4cc04129a
www.rsc.org/chemcomm
Using Ag2CO3 as an additive, we developed the Pd-catalyzed inter- biological activities.9 However, the metal-catalyzed oxidative cross-
molecular C–H/C–H cross-coupling of pyridine N-oxides with five- coupling of two heteroaryl C–H bonds to form 1-benzyl-5-pyridinyl-
membered heterocycles such as 1-benzyl-1,2,3-triazoles, thiophens 1,2,3-triazole molecules remains a challenge. Moreover, only a few
and furans. This protocol provides an efficient and regioselective investigations on two heteroaryl C–H bonds forming 2-pyridinyl-
approach for the synthesis of unsymmetrical biheteroaryl molecules. thiophen(furan) have been reported to date; however, the substrates
pyridine N-oxides are limited only to 2-substituted pyridine N-oxides
A heteroaryl–heteroaryl structural motif is frequently featured and quinoline N-oxides.10 Additionally, direct arylation of the
at the core of many natural products, pharmaceuticals, and 3-substituted pyridine N-oxides and isoquinoline N-oxide confronted
electronic materials.1 Carbon–carbon biheteroaryl linkages the problem of regiochemistry because of a competition between C2
are generally considered to be formed through the C–C bond and C6 positions.7j With a continuing interest in C–H/C–H cross-
cross-coupling between a heteroarylhalide and a heteroaryl coupling of heterocyclic N-oxides,11 we continued our efforts to
organometallic reagent.2 However, the preactivation of hetero- expand the application and understanding of the metal-catalyzed
aromatic carbon fragments with metal-containing functionalities cross-coupling between pyridine N-oxides and heterocycles. Herein,
and halides could involve several synthetic steps. Moreover, several we illustrate an efficient and site-selective CH/CH cross-coupling
important types of heteroaryl organometallic compounds have of pyridine N-oxides with 1-benzyl-1,2,3-triazole, thiophen and
proven to be inadequately stable to participate in cross-coupling furan derivatives.
reactions.3–5 For example, the instability and difficult synthesis
We initially used the conditions similar to that reported10a,b
of 2-pyridyl organometallics severely limit their applications.6 for the oxidative CH/CH cross-coupling reaction of pyridine
To solve this drawback, pyridine N-oxides have been introduced N-oxide (1a) and 1-(p-methoxylbenzyl)-1,2,3-triazoles (2a); how-
as widely available and bench-stable substrates for direct cross- ever, the desired product (3a) was obtained in a low yield of 15%
coupling reactions.7
(Table 1, entry 1). From the tests using different oxidants, we
At present, C–H/C–H oxidative cross-coupling between two found that the corresponding products were obtained by the
(hetero)arenes is regarded as one of the most attractive strate- incomplete ionization of silver salts (Ag2CO3, Ag2O, and AgOAc).
gies for building biheteroaryl linkages without the need for the In addition, the oxidant Ag2CO3 was more effective than AgOAc,
tedious prefunctionalization of starting materials.8 However, Ag2O, Ag2SO4, AgNO3, Cu(OAc)2ÁH2O, and FeCl3 (Table 1, entries
this type of C–H/C–H cross-coupling for the unsymmetrical 2 to 7), respectively. It was found that 2,6-lutidine gave a higher
construction of ‘‘heteroaryl–heteroaryl’’ scaffolds has rarely yield than pyridine and 1,10-phenanthroline as ligands (Table 1,
been studied because of the daunting complexity in the inver- entries 7 to 9). Moreover, we found that the addition of DMSO
sion of reactivity and selectivity.8 To the best of our knowledge, with dioxane resulted in the highest yield of 83% (Table 1,
a few methods have been reported for the synthesis of the entry 10) in comparison with other solvents, such as DMSO,
structure of 2-pyridinyl-1,2,3-triazoles because of their various DMF, and NMP (entries 10 to 15, respectively), even when the
reaction was performed at 160 1C (Table 1, entry 16). The optimal
yield can be achieved by using 5 mol% of Pd(OAc)2, Ag2CO3
(2 equiv.), and 30 mol% of 2,6-lutidine and the desired product
(3a) formed with complete regioselectivity (Table 1, entry 10).
Moreover, no homocoupling product 2a was observed.
a Department of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092,
China. E-mail: kuangcx@tongji.edu.cn; Tel: +86-21-6598319
b Key Laboratory of Yangtze River Water Environment, Ministry of Education,
Siping Road 1239, Shanghai 200092, China
With the optimized conditions (Table 1, entry 10) in hand,
we then tested the protocol for the cross-coupling of other
† Electronic supplementary information (ESI) available: Characterization data,
and 1H and 13C NMR spectra. See DOI: 10.1039/c4cc04129a
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Table 1 Influence of reaction conditions on the reaction of 1a with 2aa
pyridine N-oxides and 1-benzyl-1,2,3-triazoles (Table 2). As outlined,
a wide range of various substituted pyridine N-oxides, thereby
allowing a linkage of 2-methyl (3b), 3-methyl (3c and 3l), 4-methyl
(3d), 4-methoxyl (3e), 4-benzyloxyl (3j), 3-fluoro (3f), gave the desired
products in good yields. Furthermore, the above heteroarylation also
proceeded with other biologically important heteroarene cores, such
as isoquinoline N-oxide, which only occurred at the C3 position
giving a yield of 73% (3g). No desired cross-coupling product was
obtained when 4-nitropyridine and quinoline N-oxides were used
as coupling partners. Notably, groups at the N-1 position of the
triazole ring bearing p-methoxylbenzyl (3a to 3d), p-tolylbenzyl
(3i), m-tolyl-benzyl (3e to 3h), o-tolylbenzyl (3j and 3k) and
p-fluorobenzyl (3l) can also be used for this reaction. Moreover,
no reaction occurred under the same conditions if 1-phenyl-
1,2,3-triazole reacted with pyridine N-oxide (1a).
Oxidant
(2 equiv.)
Yield of
Entry
Ligand
Solvent
3ac (%)
1
2
3
Cu(OAc)2
FeCl3
Ag2O
Pyridine
Pyridine
Pyridine
Dioxane
Dioxane
Dioxane
15
Trace
55
4
5
6
7
8
9
10
11
12
13
14
15
16
Ag2SO4
AgNO3
AgOAc
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Pyridine
Pyridine
Pyridine
Pyridine
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
5% DMSO/dioxane
10% DMSO/dioxane
20% DMSO/dioxane
DMSO
Trace
Trace
46
53
45
Phen
2,6-Lutidine
2,6-Lutidine
2,6-Lutidine
2,6-Lutidine
2,6-Lutidine
2,6-Lutidine
2,6-Lutidine
2,6-Lutidine
66
Using the above conditions, we also found that the cross-
coupling reaction occurred when using thiophens and furans
83 (65)b
51
43
36
43
47
DMF
NMP
NMP
Table 3 Scope of CH/CH cross-coupling of pyridine N-oxides with
thiophens or furansa,b
Trace
a
Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), Pd(OAc)2
(0.025 mmol), ligand (0.15 mmol) and oxidant (1.0 mmol) in 3 mL of
b
c
solvent at 120 1C for 16 h. No 2,6-lutidine was added. Isolated yields.
Table 2 Scope of CH/CH cross-coupling of pyridine N-oxides with
1,2,3-trazolesa,b
a
a
Reaction conditions:
1
(0.5 mmol),
2
(0.55 mmol), Pd(OAc)2
Reaction conditions: 1 (0.5 mmol), 2 (0.55 mmol), Pd(OAc)2
(0.025 mmol), Ag2CO3 (1 mmol), and 2,6-lutidine (0.15 mmol) in 5% (0.025 mmol), Ag2CO3 (1 mmol), and 2,6-lutidine (0.15 mmol) in 5%
b
b
DMSO/1,4-dioxane (3 mL) at 120 1C for 16 h. Isolated yields.
DMSO/1,4-dioxane (3 mL) at 120 1C for 16 h. Isolated yields.
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instead of 1-benzyl-1,2,3-triazoles as substrates. Then we explored
the scope of the cross-coupling reactions of pyridine N-oxides with
thiophens and furans (Table 3). Diverse decorated products 4a–4q
formed in moderate to good yields, and regioisomeric products
were not observed. Notably, product 4, which originates from
the reaction of 3-substituted pyridine N-oxide with an electron-
withdrawing group (4f) and 4-substituted pyridine N-oxides with
an electron-donating group (4e, 4i to 4l), was obtained in high
yields. Furthermore, thiophen and furan derivatives, including
2-methylthiophen, 2-methylfuran, 2-ethylfuran, benzothiophen,
and benzofuran can also be used for this reaction. The desired
cross-coupling product was not obtained when 2-methylpyridine
and 4-nitropyridine N-oxide were used as coupling partners.
Surprisingly, the above heteroarylation also proceeded well with
isoquinoline N-oxides (4p and 4q), but the reaction only occurred
at the C1 position of isoquinoline N-oxide in good yields. Notably,
the desired product was not observed under the above conditions
when quinoline N-oxide was used as a substrate.
Scheme 3 Deoxygenation for biheterocyclic N-oxide.
the cross-coupling reaction of pyridine N-oxide.11a,12 Moreover, the
results from the above experiments demonstrated that, relative to
thiophens, this catalytic system inverted its high compatibility and
reactivity in the cross-coupling reaction of 1-benzyl-1,2,3-triazole as
substrates. Further studies are needed to understand the mechanism
of the different position cross-coupling of isoquinoline N-oxide with
five-membered heterocycles.
Lastly, heterocyclic N-oxide 3k was easily reduced by PBr3 to
generate the corresponding biheterocycle 6a, indicating that
the cross-coupling reaction is practical for the preparation of
biheteroaryl molecules (Scheme 3). Additionally, in contrast to
the reported protocol for direct arylation7j of the 3-substituted
pyridine N-oxides and isoquinoline N-oxide, our catalytic system
offers complete regioselectivity.
Interestingly, under the same catalytic conditions, the cross-
coupling between 2-substituted 1,2,3-triazole N-oxides and
2-methylthiophen gave product (5a) in a moderate yield of
65% (Scheme 1).
To gain insight into the reaction mechanism, the H/D
exchange control experiments for five-membered heterocycles
2c and 2h were performed. As shown in Scheme 2, moderate
and high deuterium incorporations were observed, respectively.
Moreover, no deuterium incorporation occurred when pyridine
N-oxide (1a) was applied to the above system (Scheme 2). The results
indicated that the five-membered heterocycles undergo a substitution
reaction in the presence of the Pd-catalyst to generate a palladium
intermediate. We proposed that the cross-coupling reaction proceeds
through a plausible catalytic cycle similar to the typical mechanism of
In summary, a highly efficient and regioselective oxidative
cross-coupling of pyridine N-oxides with five-membered hetero-
cycles through a two-fold C–H activation has been developed. More-
over, this catalytic system shows good compatibility with numerous
synthetically relevant functional groups. We hope that this protocol
may provide insights into the synthesis of unsymmetrical bihetero-
aryl molecules in materials and medical chemistry.
We thank the Natural Science Foundation of China
(No. 21272174), the Key Projects of Shanghai in Biomedicine
(No. 08431902700), and the Scientific Research Foundation of
the State Education Ministry for Returned Overseas Chinese
Scholars for the support of this research.
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Scheme 1 C–H/C–H oxidative cross-coupling between 1,2,3-triazole
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