Base-promoted cross-dehydrogenative coupling of quinoline N-oxides with 1,3-azoles

Article abstract of DOI:10.1021/acs.orglett.5b00330

An efficient cross-dehydrogenative coupling of quinoline N-oxides and 1,3-azoles has been developed under external oxidant and metal free conditions. The desired products were isolated in good to excellent yields for 26 examples. This methodology provides a practical pathway to biheteroaryls and features high practicality, high efficiency, and environmental friendliness.

Full text of DOI:10.1021/acs.orglett.5b00330

Letter
pubs.acs.org/OrgLett
Base-Promoted Cross-Dehydrogenative Coupling of Quinoline
N‑Oxides with 1,3-Azoles
Xiaopei Chen,† Xiuling Cui,*,†,‡ Fangfang Yang,† and Yangjie Wu*,†
†Department of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied
Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, P. R. China
‡Xiamen Key Laboratory of Ocean and Gene Drugs, School of Biomedical Sciences, Institute of Molecular Medicine of Huaqiao
University & Engineering Research Centre of Molecular Medicine of Chinese Education Ministry, Xiamen, Fujian 361021, P. R.
China
S
* Supporting Information
ABSTRACT: An efficient cross-dehydrogenative coupling of
quinoline N-oxides and 1,3-azoles has been developed under
external oxidant and metal free conditions. The desired
products were isolated in good to excellent yields for 26
examples. This methodology provides a practical pathway to
biheteroaryls and features high practicality, high efficiency, and
environmental friendliness.
iheteroaryls have attracted considerable attention due to
their wide application in organic synthesis, advanced
described a successful copper-mediated intermolecular direct
cross-coupling of two aromatic heterocycles.8 However, some
problems still exist with these procedures, such as (1) the
homocoupling reaction is difficult to avoid and (2) the
requirement of transition metal may contaminate the products,
thereby limiting their application, especially in the pharma-
ceutical industry and in advanced functional materials.
Therefore, the development of simple, efficient, and environ-
mentally benign methods for synthesizing various biheteroaryls
is quite appealing.
On the other hand, the electron-withdrawing effect of N−O
group can activate the ortho C−H bond of heteroaryls, which
results in its easier cleavage.9 Our group succeeded in realizing
the olefination, sulfonylation, alkylation, acetoxylation, phos-
phonation, and amination of quinoline N-oxides, which showed
that N-oxides could serve as a directing group to allow the C−
H functionalization at the 2-position.10 In continuation of our
effort on C2−H functionalization of quinoline, we embark on
development of a simple and practical procedure to synthesize
biheteroaryls via a cross-coupling of quinoline N-oxides and
1,3-azoles under metal-free11 conditions (Scheme 1, path C).
We initiated our investigation on the model reaction of
quinoline N-oxide (1a) with benzoxazole (2a) to optimize
various reaction parameters (Table 1). First, the reaction was
carried out in the presence of CuI. The desired product was not
detected (entry 1), and Pd(OAc)2 gave a trace amount of the
desired product (entry 2). To our delight, the product 3a was
isolated in 40% yield in the absence of any metal catalyst. The
molecular structure of the 2-(2-benzoxazolyl)quinoline (3a)
was confirmed by NMR spectra and single-crystal X-ray
B
functional materials, and pharmaceuticals.1 Enormous efforts
have been devoted to developing efficient methods for building
such a structure. Transition-metal-catalyzed coupling reactions
of heteroaryl halides with heteroaryl boronates or metal
reagents, such as Kumada−Tamao−Corriu, Suzuki−Miyaura,
Negishi, Migita−Kosugi−Stille, and Hiyama reactions, provided
powerful protocols to construct biheteroaryls (Scheme 1, path
Scheme 1. Synthesis of Biheteroaryls via Cross-Coupling
Reaction
A).2 However, the instability of 2-heteroaryl boronates or metal
reagents limited their application. Oxidative coupling, which is
different from the traditional coupling, occurs between two
nucleophiles.3 Recent efforts have been made via metal-
catalyzed direct oxidative cross-dehydrogenative coupling of
two heteroarenes (Scheme 1, path B).4−6 The representative
example developed by You and co-workers involves the cross-
coupling of xanthines with thiophenes or furans uses palladium
salt as a catalyst and Cu salt as an oxidant.7 Miura et al. also
Received: February 1, 2015
Published: March 4, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00330
Org. Lett. 2015, 17, 1445−1448

Organic Letters
Letter
Table 1. Screening the Various Reaction Parameters for the
Scheme 2. Substrate Scope for the Cross-Coupling of
a,b
Cross-Coupling Reaction of Quinoline N-Oxide 1a with
Heteroaromatic N-Oxides with Oxazoles
a
Benzoxazole 2a
b
entry
catalyst
CuI
Pd(OAc)2
base
solvent
yield (%)
f
1
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
tBuOLi
KCO3
toluene
toluene
toluene
CH3CN
DMF
NR
2
trace
40
3
4
40
5
20
6
dioxane
DCE
15
7
trace
75
8
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
9
NR
NR
30
10
11
12
DBU
tBuOK
tBuONa
tBuOLi
tBuOLi
tBuOLi
NR
30
c
13
d
14
21
e
15
70
a
Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), xylene (2.0 mL),
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (10 mol
%), base (0.75 mmol), solvent (2.0 mL), under air, 120 °C, 24 h.
Isolated yields. 80 °C. Room temperature. Under N2. NR = not
b
24 h at 120 °C under air. Isolated yields.
b
c
d
e
f
detected.
albeit in low yields (3k,l). This reaction system was also applied
to isoquinoline N-oxide and quinoxaline N-oxide and gave the
products 3m and 3n in 52% and 24% yields. This reaction
proceeded smoothly with substituted benzo[d]oxazole deriva-
tives (3o and 3p). Similarly, the electron-donating group was
beneficial for the reaction.
diffraction analysis shown in Figure 1 in the Supporting
Information.
Encouraged by this result, we further optimized other
reaction parameters. The solvent was crucial for this reaction.
Moderate or low yields were obtained when this reaction was
carried out in acetonitrile, DMF, dioxane, and DCE (entries 4−
7). A 75% yield was achieved when xylene was used as the
solvent. Among the bases examined (tBuOLi, K2CO3, DBU,
Encouraged by the results obtained with oxazoles, we applied
this catalytic system to benzothiazole. It was found that
benzothiazoles could be employed as suitable substrates in
DMF, giving the corresponding products 4a−j in good to
excellent yields for most cases. The results are summarized in
Scheme 3. When either group substituted in the aromatic ring
or pyridine ring the ideal results could be obtained. The Cl
group substituted on the aromatic ring also provided the
products in 75% yield (4g), which made this reaction
particularly attractive for increasing the molecular complexity
through cross-dehydrogenation coupling reactions. Finally, we
were delighted to find that isoquinoline N-oxide also worked
well and provided the product in 95% yield (4i). Quinoxaline
N-oxide showed low efficiency as a substrate (4j). Other
thiazoles, for example, 4,5-dimethylthiazole, were not beneficial
for this transformation, and no desired product was isolated.
According to the previous reports,12 the cross-dehydrogen-
ative coupling might be achieved via a nucleophilic addition−
elimination process, and then the controlled experiments were
carried out (Scheme 4). When the reaction of quinoline with 2a
was carried out, the desired product 3a was not detected (eq 1).
The mixture of 1:1 3-methylquinoline N-oxide 1i and quinoline
was added to the reaction system consisting 2.0 equiv of 2a
under the optimized reaction conditions. Compound 3i was
obtained in 80% yield. However, 3a was not observed (eq 2),
suggesting N-oxide might play a crucial role in this trans-
formation. In order to examine the reaction pathway, two
parallel reactions were conducted under the standard reaction
tBuOK, BuONa), BuOLi was the best (entry 8 vs entries 9−
12). Decreasing the temperature resulted in a significant
decrease in the yield (entries 13 and 14). A 21% yield of
product was afforded at room temperature. When the reaction
was carried out under nitrogen atmosphere, the desired product
3a was obtained in 70% yield (entry 15), which indicated that
the oxygen in air did not effect this transformation. After
surveying a variety of catalysts, bases, solvents, and temper-
atures, the optimal reaction conditions were assigned as
t
t
t
follows: 2.5 equiv of BuOLi in xylene at 120 °C for 24 h
under air.
With the optimized reaction conditions in hand, the scope of
substrates was examined. The results are summarized in
Scheme 2. The reaction could proceed well with a series of
substituted heteroaryl N-oxides and oxazoles, affording the
corresponding products 3a−s in moderate to good yields.
Quinoline N-oxide with electron-donating groups, such as
methyl or MeO groups substituted in the aromatic rings, readily
proceeded smoothly and provided the desired products in 48−
75% yields (3a−f). Moderate electron-withdrawing groups,
such as Br and Cl, afforded the desired products in 25% and
40% yields, respectively (3g,h). When the pyridine ring was
substituted by methyl, the products were isolated in 89% and
75% yields (3i and 3j). In addition, Br and Cl were tolerated
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DOI: 10.1021/acs.orglett.5b00330
Org. Lett. 2015, 17, 1445−1448

Organic Letters
Letter
Scheme 3. Substrate Scope for the Cross-Coupling of
Heteroaromatic N-Oxides and Benzothiazole
Scheme 5. Proposed Reaction Mechanism
a,b
of heteroaryl N-oxides and 1,3-azoles under air atmosphere and
metal-free conditions has been developed. A broad range of
biheteroaryl products were obtained in up to 95% yield.
Moreover, this metal-free approach was economically beneficial.
The process provides concise access to biheteroaryls, is highly
practical, efficient, atomic economic, and environmentally
friendly, and features a transition-metal catalyst, ligand,
additives, and finally, external oxidant-free conditions.
a
Reaction conditions: 1 (0.3 mmol), benzothiazole (0.6 mmol), DMF
b
(2.0 mL), reacted for 24 h at 120 °C under air. Isolated yields.
Scheme 4. Controlled Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedure, characterization data of the
products, and CIF data of 3a. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: cuixl@zzu.edu.cn.
*E-mail: wyj@zzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the NSF of China (Nos. 21102133
and 21172200) for financial support.
■
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