Dehydrogenative etherification homocoupling of heterocyclic N-oxides

Article abstract of DOI:10.1016/j.tetlet.2018.03.071

A novel approach was developed for the dehydrogenative etherification homocoupling of heterocyclic N-oxides in the presence of silver oxide and PyBroP. Various substrates were well tolerated and the desired products were obtained in moderate to good yields. Generally, this reaction features excellent functional group compatibility, broad substrate scope and good regioselectivity.

Full text of DOI:10.1016/j.tetlet.2018.03.071

Accepted Manuscript
Dehydrogenative etherification homocoupling of heterocyclic N-oxides
Dong Zhang, Kai Qiao, Xin Yuan, Mingwei Zheng, Zheng Fang, Li Wan, Kai
Guo
PII:
S0040-4039(18)30400-3
https://doi.org/10.1016/j.tetlet.2018.03.071
TETL 49840
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
13 February 2018
20 March 2018
23 March 2018
Please cite this article as: Zhang, D., Qiao, K., Yuan, X., Zheng, M., Fang, Z., Wan, L., Guo, K., Dehydrogenative
etherification homocoupling of heterocyclic N-oxides, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.03.071
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Dehydrogenative etherification
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homocoupling of heterocyclic N-oxides
Dong Zhang, Kai Qiao, Xin Yuan, Mingwei Zheng, Zheng Fang, Li Wan and Kai Guo

3
Tetrahedron Letters
journal homepage: www.elsevier.com
Dehydrogenative etherification homocoupling of heterocyclic N-oxides
a, b, 
Dong Zhang a , Kai Qiao a, Xin Yuan a, Mingwei Zheng a, Zheng Fang a, Li Wan a, b, , and Kai Guo
a College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University 30 Puzhu South Road, Nanjing211816, P. R. China
b
State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech University 30 Puzhu South Road, Nanjing 211816, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
A novel approach was developed for the dehydrogenative etherification homocoupling of
heterocyclic N-oxides in the presence of silver oxide and PyBroP. Various substrates were well
tolerated and the desired products were obtained in moderate to good yields. Generally, this
reaction features excellent functional group compatibility, broad substrate scope and good
regioselectivity.
Available online
Keywords:
regioselective
homocoupling
quinoline
PyBroP
O-tethered
Quinoline heterocycles are ubiquitous core structures in
medicinal chemistry, the agrochemical industry, and materials
science.1 As an important class of N-heterocycle, the direct
functionalization of quinolines has attracted extensive attention
from synthetic chemists,2 and in recent years, there have been
many attempts regarding their direct functionalization. Various
modifications have been reported at the C2-position of
quinolines, such as halogenation, amination, alkylation, arylation,
alkenylation, cyanation, and acylation.3 Among quinoline
derivatives, the homodimers of electron-deficient N-heterocycles
are important and useful compounds. They are widely used in
light-emitting materials,4 for marking biomacromolecules in
bioanalysis,5 as ligands in transition metal catalyzed synthesis,6
and as substructures in a wide variety of biologically active
compounds.7 Remarkably,
(1-pyrrolidinyl) phosphonium hexafluorophosphate)12 is utilised
as a nucleophile to activate the homocoupling reaction.
Figure 1. Structures related to O-tethered dimeric quinolines.
similar structures to
O-tethered dimeric quinolines (Fig. 1).8 Malathi,9 Małgorzata,10
and Zhao11 have reported the synthesis of O-tethered dimeric
quinolines using quinolin-2 (1 H)-ones as precursors, but which
suffers from relatively low yields, requires multiple steps, and
utilises strong bases (Scheme 1). Additionally, there are few
literature reports regarding the direct synthesis of homodimers of
electron- deficient N-heterocycles via homocoupling of the
corresponding N-heterocycles. Herein, we report the reaction of
quinoline N-oxides with silver oxide in acetonitrile to afford the
corresponding homodimers which are connected by an ether
bond at the C2 position. The phosphonium salt PyBroP (bromotri
Scheme 1. Synthesis of O-tethered dimeric quinolines.
Initially, quinoline N-oxide 1a was chosen as a model
substrate for optimization of the reaction parameters due to its
———
 Corresponding author. Tel.: +86 25 5813 9926; fax: +86 25 5813 9935; e-mail: liwan126@126.com
 Corresponding author. Tel.: +86 25 5813 9926; fax: +86 25 5813 9935; e-mail: guok@njtech.edu.cn

2
Tetrahedron
widespread use in C–H functionalization reactions (Table 1).
To our delight, excellent conversion of 1a was achieved in the
reaction utilising PyBroP (3 equiv.), potassium carbonate (2
equiv.) and acetonitrile at 25 oC for 12 h under an air atmosphere.
The corresponding dimeric product 2a was isolated in 38% yield
(Entry 1). To improve the yield of the quinoline homodimer,
different additives were examined. Silver oxide was
demonstrated as a favorable additive, compared to potassium
carbonate, sodium carbonate, cesium carbonate and silver
carbonate, affording the desired product 2a in 80% yield (Entry
5). A number of solvents such as DCE, CH2Cl2, THF, CHCl3 and
DMF were examined, however none could match the efficiency
of CH3CN (Entries 14-18). Temperatures lower or higher than 50
oC resulted in reduced yields of 2a (Entries 7 and 13). Finally,
different amounts of PyBroP and silver oxide were examined for
the formation of 2a; the optimal loading was determined as
PyBroP (2 equiv.) and silver oxide (1 equiv.) (Entries 8-12).
Table 1. Reaction Conditions Optimization.a
Yield
PyBroP Additive
(equiv.) (equiv.)
Temp
(oC)
Entry
Solvent
2a
(%)b
1
2
3
4
5
6
7
8
3
3
3
3
3
2
2
2
3
3
2
1
2
2
2
2
2
2
K2CO3 (2)
Cs2CO3 (2)
Na2CO3 (2)
Ag2CO3 (2)
Ag2O (2)
Ag2O (2)
Ag2O (1)
Ag2O (1)
Ag2O (2)
Ag2O (1)
Ag2O (0.5)
Ag2O (1)
Ag2O (1)
Ag2O (1)
Ag2O (1)
Ag2O (1)
Ag2O (1)
Ag2O (1)
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
25 oC
50 oC
50 oC
50 oC
50 oC
50 oC
70 oC
50 oC
50 oC
50 oC
50 oC
50 oC
CH3CN 38
CH3CN 48
CH3CN 51
CH3CN 61
CH3CN 80
CH3CN 78
CH3CN 77
CH3CN 86
CH3CN 86
CH3CN 86
CH3CN 69
CH3CN 72
CH3CN 83
CH2Cl2 51
9
10
11
12
13
14
15
16
17
18
aReagents conditions: quinoline N-oxide (0.2 mmol), PyBroP (0.4
mmol), Ag2O (0.2 mmol), CH3CN (2.0 mL), under air in a sealed
tube, 12 h.
bIsolated yield.
DCE
THF
46
56
37
24
Halogenated substrates also exhibited high reactivity,
affording the desired products (2i–n) in good to excellent yields,
which were slightly higher than those obtained with the methyl-
substituted substrates. Moreover, this methodology was effective
at converting benzoquinoline and N-oxides of 2-phenylpyridine
to their dimerized derivatives, 2r and 2s, respectively. A number
of strongly electron withdrawing group (CN, NO2, CHO)
substituted quinoline N-oxides were also examined.
Disappointingly, these substrates afforded the corresponding
dimers in trace yields. Meanwhile in order to investigate the
compatibility of this protocol with other N-heterocycles,
isoquinoline N-oxides were also subjected to the optimized
reaction conditions. Unfortunately, this reaction only afforded the
corresponding dimer in trace yield. This discrepancy suggested
that further work is required to generalize the reaction conditions.
CHCl3
DMF
aReagents and conditions: quinoline N-oxide (0.2 mmol),
PyBroP, Ag2O, solvent (2.0 mL), under air in a sealed tube, 12 h.
bIsolated yield.
With the optimized reaction conditions in hand, we then
explored the scope of quinoline N-oxides amenable to the
synthesis of O-tethered dimeric quinolones (Table 2). A series of
quinoline N-oxides reacted smoothly to afford a diverse array of
O-tethered dimeric quinoline (2b−n, 2r, 2s) in modest to high
yields. Methyl-substituted quinoline N-oxides gave the desired
dimeric quinolines in moderate to good yields (2b–f). The
presence of an electron-donating methyl group at the 4-position
resulted in a slightly decreased yield of the dimeric quinoline 2c.
Methoxy and ethoxy-substituted quinoline N-oxides underwent
dimerization in 88% (2g) and 62% (2h) yield, respectively.
After successful exploration of the dimerization of
heterocyclic N-oxides, we turned our attention to the potential
application of these dimeric compounds in organic synthesis. The
ether linkage of 2a is susceptible to cleavage; heating at reflux
with 40% hydrobromic acid for 4 h, resulted in the formation of
2-bromoquinoline 3.13 Subsequent Suzuki cross-coupling reaction
of 2-bromoquinoline with mesitylboronic acid afforded
Table 2. Substrate scope.a

3
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Scheme 2. Potential application of the dimeric quinolines in organic
synthesis.
Scheme 3. Control experiment.
In order to shed light on the mechanism, a control experiment
was carried out with the radical inhibitor TEMPO (Scheme 3).
The addition of TEMPO (2 equiv.) did not suppress the
5.
formation of 2a, suggesting that a radical reaction is not involved.
A possible mechanism for this reaction is shown in Scheme 4.
In the first step, under the activation of PyBroP, compound A is
obtained from 1a as reported by Wang and co-workers.15
Nucleophilic attack of Ag2O at the C2-position of the quinoline
affords compound B, which with the assistance of the bromide
anion furnishes intermediate C. Next, intermediate C reacts as a
nucleophile with compound A. Finally, upon the precipitation of
silver ions, the desired product 2a was obtained in high yield.
6.
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Scheme 4. Proposed mechanism.
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6578.
In summary, we report a practical and mild method for the
synthesis of O-tethered dimeric quinolines. The dimerization is
operationally simple and exhibits a wide substrate scope,
especially using substrates which contain electron donating
groups.
Acknowledgments
This study was supported by the National Key Research and
Development Program of China (2016YFB0301501), the
National Natural Science Foundation of China (21502090，
21522604 and 21776130), Natural Science Foundation of Jiangsu
Province (BK20150942 and BK20150031).
15. Wang, D.; Zhao, J.; Wang, Y.; Hu, J.; Li, L.; Miao, L.; Feng, H.;
Yu, P. Asian J. Org. Chem., 2016, 5, 1442−1446.
References and notes

4
Tetrahedron
Highlights:



Regioselective homocoupling of quinolines
via electrophilically activated was
developed.
Eighteen examples of O-tethered dimeric
quinolines were synthesized in good to
excellent yields.
The homodimers of electron-deficient N-
heterocycles are important and useful
compounds.