Tetrahedron Letters
Palladium-catalyzed highly regioselective oxidative homocoupling
of 1,2,3-triazole N-oxides
b,
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Xiangjun Peng a, Panpan Huang b, Lili Jiang b, Jiayi Zhu b, , Liangxian Liu
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a School of Pharmaceutical Science, Gannan Medical University, Ganzhou, Jiangxi 341000, PR China
b Department of Chemistry and Chemical Engineering, Gannan Normal University, Ganzhou, Jiangxi 341000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and highly regioselective palladium-catalyzed direct C–H homocoupling of 1,2,3-triazole
N-oxides was developed in the presence of silver carbonate and 1,10-phenanthroline. This protocol
provides a straightforward and operationally simple route for the preparation of bis(1,2,3-triazole)3,30-
dioxides in good to excellent yields.
Received 24 June 2016
Revised 4 October 2016
Accepted 9 October 2016
Available online 15 October 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
1,2,3-Triazole N-oxide
Homocoupling
Biheteroaryl N-oxide
Introduction
the past years, the direct dehydrogenative coupling through the
cleavage of two C–H bonds for the synthesis of biheteroaryls has
1,2,3-Triazoles are important heterocycles,1 which are widely
used in pharmaceuticals and agrochemicals. 1,2,3-Triazoles have
been shown to exhibit a wide spectrum of biological activities,2
such as antibacterial, herbicidal, fungicidal, antiallergic, and anti-
HIV properties. For example, 4-aryl-1H-1,2,3-triazoles have been
used as human methionine aminopeptidase (hMetAP2) and indo-
leamine 2,3-dioxygenase (IDO) inhibitors, and are expected to
become medicines to treat cancers, AIDS, Alzheimer’s disease, tris-
timania, cataracts, and some other serious diseases.3 In addition,
1,2,3-triazoles have attracted increasing attention as an important
class of heterocycles with numerous applications in materials and
synthetical chemistry.4,5 Since 2005, the pyridine, azine, diazine,
azole, 1,2,3-triazole, and other heterocyclic N-oxides have been
introduced as easily available and stable substrates for direct
cross-coupling reactions by Fagnou6 and other groups.7 Recently,
our group has developed efficient direct C5-amination, thiolation,
and arylation of 1,2,3-triazole N-oxides.8
attracted considerable attention in modern organic synthesis due
to its synthetic efficiency and atom economy.10 Although those ele-
gant reactions have been developed, there is still an intrinsic need
to develop biheterocycle N-oxides. Herein, we report an efficient
palladium-catalyzed highly regioselective oxidative homocoupling
of 1,2,3-triazole N-oxides to construct bitriazole N-oxides. To our
knowledge, the metal-catalyzed oxidative homocoupling of two
N-oxide C–H bonds to form biheteroaryl N-oxides still remained
elusive.5b
To begin our investigation, 2-phenyl-2H-1,2,3-triazole 1-oxide
(1a) was selected as a model system to screen the optimal condi-
tions, and the results are summarized in Table 1. First, with the
combination of Pd(OAc)2 (5 mol%), Ag2CO3 (1 equiv), PPh3
(0.2 equiv), and K3PO4 (1 equiv) in DMF at 100 °C for 24 h, the
desired homocoupling product 2a was obtained in 36% isolated
yield (Table 1, entry 5). Other transition metal catalysts, such as
Cu(OAc)2, FeCl3, AgNO3, and NiSO4, showed inferior or no reactivi-
ties (Table 1, entries 1–4). Among the examination of palladium
catalysts, other palladium catalysts, including PdCl2, Pd(PPh3)4,
and Pd/C, were inferior to Pd(OAc)2 (Table 1, entries 5–8). No
desired product was observed in a control experiment without
the addition of Pd catalyst (Table 1, entry 9). Among the oxidants
we tested, Ag2CO3 was shown to be the most effective one, while
other oxidants such as AgOAc, AgNO3, AgBF4, and AgNO2 proved
to be less effective (Table 1, entries 10–13). Subsequently, different
bases were examined, including Na2CO3, Cs2CO3, LiOH, and t-BuOK.
Linked biheterocycles are important as fine chemicals and con-
stitute an important class of heterocycles with numerous applica-
tions for various biologically active compounds and functional
materials.9 Considering their importance, developing efficient syn-
thetic methods for the formation of carbon–carbon bonds to pre-
pare biheteroaryls is a worthwhile task in organic synthesis. Over
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0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.