Pd-catalyzed oxidative CH/CH direct coupling of heterocyclic N-oxides

Article abstract of DOI:10.1021/ol4019776

A highly efficient protocol for C-H/C-H cross-coupling has been found to occur between 2-aryl-1,2,3-triazole N-oxides and pyridine N-oxide derivatives. In addition, two homocoupling reactions of 2-substituted 1,2,3-triazole N-oxides and some pyridine N-oxide derivatives were developed. A possible pathway of C-H/C-H direct coupling is discussed.

Full text of DOI:10.1021/ol4019776

ORGANIC
LETTERS
2013
Vol. 15, No. 18
4682–4685
Pd-Catalyzed Oxidative CH/CH Direct
Coupling of Heterocyclic N‑Oxides
Wei Liu,† Yahui Li,† Yue Wang,† and Chunxiang Kuang*,†,‡
Department of Chemistry, Tongji University, Siping Road 1239, Shanghai, 200092,
P. R. China, and Key Laboratory of Yangtze River Water Environment,
Ministry of Education, Siping Road 1239, Shanghai, 200092, P. R. China
kuangcx@tongji.edu.cn
Received July 14, 2013
ABSTRACT
A highly efficient protocol for CÀH/CÀH cross-coupling has been found to occur between 2-aryl-1,2,3-triazole N-oxides and pyridine N-oxide
derivatives. In addition, two homocoupling reactions of 2-substituted 1,2,3-triazole N-oxides and some pyridine N-oxide derivatives were devel-
oped. A possible pathway of CÀH/CÀH direct coupling is discussed.
Recently, transition-metal-catalyzed CÀH bond activa-
tion for CÀC bond formation has become a powerful tool
for the construction of CÀC bond frameworks.1 Since
2005, pyridine and other heterocyclic N-oxides have been
introduced as easily available and stable substrates for di-
rect cross-coupling reactions by Fagnou and other groups.
The scope of direct cross-coupling partners has broadened
to include various (hetero) arene halides, arene boronic
acid, alkenes, and even simple arenes such as benzene.2
Linked biheterocycles constitute an important class of
heterocycles with numerous applications for various bio-
logically active compounds and functional materials.3
Considering their importance, the synthesis of bihetero-
cycle units through transition-metal-catalyzed CÀH bond
activation has received increased attention. Transition-
metal-catalyzed oxidative CÀH/CÀH cross-coupling be-
tween two (hetero) arenes is one of the most attractive
approaches in forging biheteroaryl linkages, without
the time-consuming and tedious prefunctionalization of
both starting materials.4 However, this type of CÀH/CÀH
cross-coupling for the unsymmetrical construction of
† Tongji University.
‡ Ministry of Education
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r
10.1021/ol4019776
Published on Web 09/10/2013
2013 American Chemical Society

“heteroarylÀheteroaryl” scaffolds with double electron-
deficient rings remains less explored because of a daunting
hindrance in reactivity and selectivity inversion.5 To
our knowledge, a few methods have been reported for
the synthesis of 2-pyridinyl-1,2,3-triazoles because of
their various biological activities.6 However, the metal-
catalyzed oxidative cross-coupling of two heteroaryl CÀH
bondstoform 2-pyridinyl-1,2,3-triazolemoleculesremains
a challenge. Furthermore, we have a continuing interest
in the direct C5-functionalization of 2-substituted 1,2,3-
triazole N-oxides.2n Thus, we propose that the introduc-
tion of the N-oxide moiety can increase the reactivity and
selectivity of the oxidative CÀH/CÀH cross-coupling reac-
tion. Herein, we illustrate an efficient site-selective CH/CH
cross-coupling between 2-aryl-1,2,3-triazole N-oxides and
other heterocyclic N-oxides, several of which are readily
prepared in excellent yields or are commercially available.
The resulting heterocyclic N,N-dioxides were efficiently
reduced to the final products
efficiency. While no desired product was observed without
the oxidant in the reaction system (entry 2), the oxidant
Ag2CO3 was more effective than Cu(OAc)2 H2O, AgOAc,
3
Ag2O, Ag2SO4, and AgNO3 (entries 3 to 7). The reaction
proceeded highly efficiently when the reaction was per-
formed at 120 °C (entries 7 to 9). We found that the use of
1,4-dioxane as solvent gave the highest yield (91%, entry 7)
compared with other solvents, such as DMSO, toluene,
and NMP (entries 10 to 12), even when the reaction was
performed at 150 °C (entry 13). The optimal yield could
be achieved by using 5 mol % of Pd(OAc)2 and Ag2CO3
(2 equiv) in1,4-dioxane, and the desiredproduct3aformed
with complete regioselectivity (entry 7).
With the optimized conditions (Table 1, entry 7), we
then explored the scope of the cross-coupling reaction
(Scheme 1). Similarly, the protocol was also applicable to
various substituted pyridine N-oxides, thereby allowing an
Scheme 1. Substrate Scopea
Our study was instigated by an unexpected observation
during the investigation of the Pd-catalyzed CÀH function-
alization reaction of 2-aryl-1,2,3-triazole N-oxides. During
the tests with different cross-partners, we found that cross-
coupling reactions occurred between 2-aryl-1,2,3-triazole
N-oxides (1a) and pyridine N-oxide (2a) in a low yield of
28% (Table 1, entry 1). The oxidant, temperature, and
solvent were found to play critical roles in the reaction
Table 1. Optimization of Typical Reaction Conditionsa
oxidant
yield of
3a (%)c
entry
(2 equiv)
t (°C)
solvent
1
Cu(OAc)2
none
120
120
120
120
120
120
120
60
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMSO
Toluene
NMP
28
trace
48
13
8
2
3
Ag2O
4
Ag2SO4
AgNO3
AgOAc
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
5
6
61
91
12
56
67
71
48
59
7
8
9b
10
11
12
13
90
120
120
120
150
NMP
a Reaction conditions: 1 (0.5 mmol), 2 (0.55 mmol), Pd(OAc)2 (0.025
mmol), and Ag2CO3 (1 mmol) in 1,4-dioxane (1 mL) at 120 °C for 24 h.
Isolated yields are shown.
a Conditions: 1a (0.5 mmol), 2a (0.55 mmol), Pd(OAc)2 (0.025
mmol), and oxidant (1.25 mmol) in 1 mL of solvent for 24 h. b Run for
48 h. c Isolated yields.
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Org. Lett., Vol. 15, No. 18, 2013
4683

observed when six-membered heterocycle N-oxides were
applied to the above catalytic system instead of 2-substituted
1,2,3-triazole N-oxides.
Table 2. Homocoupling of 2-Aryl-1,2,3-Triazole N-Oxidesa
Considering that pyridine has been extensively used as a
base or an activator in the oxidative CH/CH coupling of
heteroarene N-oxides,2f,n,5a we speculated whether an ad-
ditional introduction of pyridine added into this catalytic
system could assist the CÀH bond activation of hetero-
cyclic N-oxides. As expected, the above reactions with up
to 1 equiv of pyridine added significantly improved cata-
lytic efficiency (Table 2). Surprisingly, 5a and 5b were ob-
tained in low yields when 2-methylpyridine and 3-methyl-
pyridine N-oxides, respectively, were applied to the catalytic
system of Pd(OAc)2, AgCO3, and pyridine, and no reac-
tion occurred when pyridine was free (Scheme 2). No
homocoupling product was observed under the above con-
ditions when pyridine, 4-methylpyridine, 4-nitropyridine,
2-phenylpyridine, quinoline, and isoquinoline N-oxides were
used as substrates.
a Conditions: 1 (0.5 mmol), 2 (0.55 mmol), Pd(OAc)2 (0.025 mmol),
and Ag2CO3 (1 mmol) in 1,4-dioxane (1 mL) at 120 °C for 48 h.
b Pyridine (0.5 mmol) as base.
Further studies were conducted to determine the reac-
tion mechanism. We performed the control experiment
using a 2:1 mixture of 1a and 2a under the standard
conditions. The reaction afforded 3a in 45% yield and
4a in 8% yield. Moreover, no homocoupling product of
pyridine N-oxide was observed when the reaction was
performed in an opposite ratio (Scheme 3). Therefore,
2-substituted 1,2,3-triazole N-oxides might be the pre-
ferred compound to undergo the CÀH substitution of
Pd(OAc)2 for generating the palladium(II) intermediate.
Scheme 2. Homocoupling of Pyridine N-Oxide Substrates
Scheme 3. Control Experiment
unprecedented direct linkage of 4-methyl (3b, 3k, 3q),
3-methyl (3d, 3i, 3p), 4-methoxyl (3c, 3r), 4-phenyl (3e),
and 4-benzyloxyl (3f) groups. Interestingly, the above
heteroarylation also proceeded well with other biologically
important heteroarene cores, such as isoquinoline N-oxide
(3g), which only occurred at the C3 position. No desired
cross-coupling product was obtained when 2-methyl-
pyridine, 2-phenylpyridine, 4-nitropyridine, and quinoline
N-oxides were used as coupling partners. Notably, aryl
groups at the N-2 position of the triazole ring bearing
m-tolyl (3ato3f), 1-naphthyl(3gto3i), 2,4-dichlorophenyl
(3j, 3k), 4-fluorophenyl (3l), 3-chlorophenyl (3m), 4-meth-
oxylphenyl (3n), and the 3-chloro-4-fluorophenyl moiety
(3o to 3r) can also be used for this reaction. Such unsymme-
trical biheterocyclic scaffolds are expected to possess im-
portant applications in medicinal and materials chemistry.
Interestingly, under the same catalytic conditions, the
homocoupling product (4a, 4b) of 2-substituted 1,2,3-
triazole N-oxides formed in low yields, even with the ex-
tension of the reaction time to48h when the other coupling
partners of the six-membered heterocycle N-oxide was free
in the reaction system (Table 2). Notably, no reaction was
Scheme 4. Plausible Catalytic Cycle
(7) (a) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126,
5074. (b) Takahashi, M.; Masui, K.; Sekiguchi, H.; Kobayashi, N.;
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4684
Org. Lett., Vol. 15, No. 18, 2013

needed to understand the mechanism of the homocoupling
of six-membered heterocycle N-oxides in a Pd-catalyzed
CÀH functionalization reaction.
Scheme 5. Deoxygenation for Biheterocyclic N,N-Dioxides
Finally, 3a and 3m were easily reduced by Zn8 or PCl3
2,9
to produce the corresponding biheterocycles, showing that
the new CH/CH cross-coupling reaction is practical for the
preparation of unsymmetrical and symmetrical bihetero-
aryl molecules (Scheme 5).
In summary, for the first time, we have developed a
highly efficient and regioselective oxidative cross-coupling
and homocoupling among 2-substituted 1,2,3-triazole
N-oxides, pyridine N-oxide derivatives, and even isoquino-
line N-oxide through a 2-fold CÀH activation. This pro-
tocol constitutes a rather rare example of synthesis of
unsymmetrical and symmetrical biheterocyclic N,N-diox-
ides and the corresponding biheterocycles. Inaddition, this
protocol shows good compatibility with numerous synthe-
tically relevant functional groups, thus providing a novel
practical tool for the preparation of unsymmetrical and
symmetrical biheterocyclic N,N-dioxides. We hope that
this investigation may have a broader impact on the
synthesis of unsymmetrical and symmetrical biheterocyclic
N,N-dioxides and biheteroaryl molecules in material, med-
ical, and natural product chemistry.
Although more detailed investigations on the reaction
mechanism are currently underway,5a,7 we propose that
the Pd-catalyzed direct coupling proceeds through a plau-
sible catalytic cycle (Scheme 4). In the first step, the above
observations indicated that the abstraction of hydro-
gen from the 2-substituted 1,2,3-triazole N-oxides easily
occursin the reactionsystem. Thus, the 2-substituted1,2,3-
triazole N-oxides would undergo regioselective electrophi-
lic CÀH substitution (SEAr) of Pd (OAc)2 to generate the
palladium(II) intermediate (A). In the second step, bis-
heteroarylpalladium species (B) is formed by CÀH sub-
stitution of the intermediate A with pyridine N-oxide.
Compared with the intermediate B related to the cross-
coupling, the homocoupling intermediate (C) might form
with some difficulty because of its lower relative rate than
that of B. Therefore, when a catalyst, 2-substituted 1,2,3-
triazole N-oxide, and pyridine N-oxide coexist in a reaction
system, B might be the predominant intermediate after the
formation of A. The homocoupling of the 2-substituted
1,2,3-triazole N-oxides proceeded through the formation
of intermediate C when N-oxide 2 was free in the reaction
system. The introduction of pyridine should give more
reaction activity and an increased rate to form intermedi-
ate C. The result demonstrated that the catalytic system
inverted its selectivity in the homocoupling reaction of the
six-membered heterocycle N-oxides. Further studies are
Acknowledgment. The present work was supported by
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. We also thank the Center for Instru-
mental Analysis, Tongji University, China.
Supporting Information Available. Typical experimen-
tal procedures, characterization data, and 1H NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 18, 2013
4685