Dimerization of heteroaromatic N-oxides under metal-free conditions

Article abstract of DOI:10.1039/c4ra02820a

A novel procedure for the dimerization of heteroaromatic N-oxides under transition-metal-free conditions has been developed. The protocol is effective and convenient. The biheteroaromatic mono N-oxides products were obtained in up to 93% yield.

Full text of DOI:10.1039/c4ra02820a

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Dimerization of heteroaromatic N-oxides under
metal-free conditions†
Cite this: RSC Adv., 2014, 4, 26244
*
*
Hui Wang, Yu Pei, Jie Bai, Jinli Zhang, Yangjie Wu and Xiuling Cui
Received 31st March 2014
Accepted 5th June 2014
DOI: 10.1039/c4ra02820a
www.rsc.org/advances
A novel procedure for the dimerization of heteroaromatic N-oxides The desired product 2a was isolated in 56% yield (entry 1).
under transition-metal-free conditions has been developed. The Encouraged by this result, we further optimized the reaction
protocol is effective and convenient. The biheteroaromatic mono conditions. Surprisingly, 87% yield could be obtained in the
N-oxides products were obtained in up to 93% yield.
absence of Pd(OAc)2 (entry 2). We found that reducing reaction
time was benecial for the reaction, as the yield of 2a was
improved to 91% (entry 3). For this process, examination of the
amount of tBuOLi indicated that 1.5 equiv. of tBuOLi was
optimal (entries 3–6). Base screening disclosed that tBuOLi was
superior to others (entries 4, 7–11). Investigation of different
solvents showed that toluene was the best suitable solvent
(entries 4, 12–17). Furthermore, decreasing the temperature of
the reaction brought a signicant decrease in the yields (entries
18–20). Finally, the optimal conditions for the dimerization
were identied to be tBuOLi (1.5 equiv.) as the base and toluene
Biheteroaromatic N-oxides have found wide application as
structure motifs in pharmaceuticals, functional materials and
organic synthesis as ligands.1 Conventional strategies to build
such a structure typically involve multistep reaction sequences,2
or transition-metal-catalyzed coupling-reactions of a heteroaryl
halide or pseudohalide with a heteroaryl organometallic
reagent3 (Scheme 1, path a). These approaches always require
harsh reaction conditions, or transition metals, most of which
are expensive and non environmentally benign. The removal of
harmful transition-metal contamination is oen costly and
difficult in pharmaceuticals.4 Therefore an environmentally
benign and practical access to construct biheteroarmatic
N-oxide compounds is highly desired. Recently, the dimeriza-
tion of quinoline N-oxide was achieved under organocatalytic
reaction conditions by Kondo group.5 However, an organo-
silicon additive is required and the biquinoline N-oxide is
obtained in lower yield. Then, they developed a similar proce-
dure using onium amide bases in situ generated.6 To the best of
our knowledge, one-pot protocol to synthesize biquinoline
N-oxide under transition metals and catalysts free conditions
has not been reported so far. Herein, we disclosed an efficient,
simple method to construct the biheteroaromatic mono
N-oxides under metal-free conditions (Scheme 1, path b).
At the outset of the study, we chose quinoline N-oxide (1a) as
a model substrate to screen the reaction parameters (Table 1).
Firstly, the reaction was carried out in the presence of 10 mol%
Pd(OAc)2 and 2.0 equiv. of tBuOLi in toluene at 120 ꢀC for 20 h.
ꢀ
as the solvent at 120 C for 3 hours.
Having established the optimal reaction conditions in hand,
we investigated the generality and scope of substrates for this
transition-metal-free transformation. The results in Table 2
demonstrated that this reaction had a good functional group
tolerance. The reaction of quinoline N-oxide and its derivatives
with moderate electron-withdrawing group, such as Br and Cl,
readily proceeded smoothly and provided the desired products
in 75–93% yields (2a–2e). When Br group at 3-position of
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. E-mail: cuixl@zzu.edu
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral data for all products. See DOI: 10.1039/c4ra02820a
Scheme 1 Dimerization of heteroaromatic N-oxides through different
methods.
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Table 1 Optimization of reaction conditionsa
Table 2 Substrate scope for the dimerization of heteroaromatic N-
oxides using tBuOLi as the basea,b
Entry
Catalyst
Bases (equiv.)
Solvents
Yieldb (%)
1c
2c
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18e
19f
20g
Pd(OAc)2 (10%)
tBuOLi (2.0)
tBuOLi (2.0)
tBuOLi (2.0)
tBuOLi (1.5)
tBuOLi (2.5)
tBuOLi (1.0)
tBuONa (1.5)
K2CO3 (1.5)
K3PO4 (1.5)
Cs2CO3 (1.5)
DBU (1.5)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
56
87
91
93
93
81
58
0
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
0
0
0
tBuOLi (1.5)
tBuOLi (1.5)
tBuOLi (1.5)
tBuOLi (1.5)
tBuOLi (1.5)
tBuOLi (1.5)
tBuOLi (1.5)
tBuOLi (1.5)
tBuOLi (1.5)
ndd
0
THF
DMF
40
0
CH3CN
Dioxane
DCE
Toluene
Toluene
Toluene
72
Trace
81
75
72
a
Reaction conditions: 1 (0.5 mmol), solvent (2.5 mL), 3 h, 120 ꢀC.
b
Isolated yields. c 130 ꢀC.
a
Reaction conditions: 1a (0.5 mmol), solvent (2.5 mL), 3 h at 120 ꢀC.
b
Isolated yields. c 20 h. d nd is not detected. e 110 ꢀC. f 100 ꢀC. g 90 ꢀC.
quinoline N-oxide was also well tolerated and the product was
obtained in 75% yield (2e), indicating that this reaction was not
sensitive signicantly to steric hindrance in the substrate.
Electron-rich substrates, such as methyl, methoxyl groups
substituted on the aromatic rings, provide the dimerization
products in moderate yields (2f and 2g). However, when the
pyridine rings were substituted by methyl or methoxyl groups,
the dimerization products were obtained in 49%, 28% and 34%
yields, respectively (2h–2j). Good yield was afforded when the
reaction system was applied to quinoxaline N-oxide (2k). In
addition, pyridine N-oxide derivatives were also shown to be
possible substrates and gave the desired products in moderate
to good yields (2l–2n).
Scheme 2 Controlled experiment.
The controlled experiment was carried out to see if the
dimerization was achieved via a nucleophilic addition-elimi-
nation process5–7 (Scheme 2). When benzoxazole was employed
in the reaction, the corresponding products 2a and 2o could be
given in 40% and 41% (based on 1a) yields, respectively, which
suggested that benzoxazole carbanion was generated by the aid
of base and served as an external nucleophile.
Scheme 3 Proposed reaction mechanism.
N-oxide. (iii) The nal product 2a was generated with concom-
itant release of the LiOH.
In conclusion, a mild and efficient method for the dimer-
ization of heteroaromatic N-oxides under metal-free conditions
has been developed. A broad range of 2,20-biheteroaromatic
mono N-oxides were obtained in up to 93% yield. Further efforts
on the reaction mechanism will be studied in the future
research.
A possible mechanism for this dimerization of quinoline
N-oxide was proposed and described as follows (Scheme 3): (i)
deprotonation of quinoline N-oxide in situ-generated carbanion
t
A rstly by BuOLi. (ii) Subsequently, the intermediate B was
formed by attacking at the a-position of another quinoline
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Acknowledgements
This work was supported by the NSF of China (21102133,
21172200) and the NSF of Henan (082300423201). The authors
declare no competing nancial interest.
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