Remote radical halogenation of aminoquinolines with aqueous hydrogen halide (HX) and oxone

Article abstract of DOI:10.1016/j.tetlet.2018.04.036

Simple and halide-atom economical HX reagents (X = Cl, Br and I) were applied to the remote C–H bond halogenation reaction of 8-aminoquinoline amides. This strategy features a broad substrate scope and good functional group tolerance. A series of C5-halog

Full text of DOI:10.1016/j.tetlet.2018.04.036

Accepted Manuscript
Remote Radical Halogenation of Aminoquinolines with Aqueous Hydrogen
Halide (HX) and Oxone
Li Qiao, Xianting Cao, Kejie Chai, Jiabin Shen, Jun Xu, Pengfei Zhang
PII:
S0040-4039(18)30493-3
https://doi.org/10.1016/j.tetlet.2018.04.036
TETL 49899
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
31 January 2018
6 April 2018
16 April 2018
Please cite this article as: Qiao, L., Cao, X., Chai, K., Shen, J., Xu, J., Zhang, P., Remote Radical Halogenation of
Aminoquinolines with Aqueous Hydrogen Halide (HX) and Oxone, Tetrahedron Letters (2018), doi: https://doi.org/
1
0.1016/j.tetlet.2018.04.036
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Remote Radical Halogenation of Aminoquinolines with Aqueous
Hydrogen Halide (HX) and Oxone
*
Li Qiao, Xianting Cao, Kejie Chai, Jiabin Shen, Jun Xu and Pengfei Zhang
*
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou 310036, China. e-mail: zpf100@163.com.
Tel.: (+)86 -571-28862867; Fax.: (+)86-28862867
Abstract
Simple and halide-atom economical HX reagents (X= Cl, Br and I) were
applied to the remote C-H bond halogenation reaction of 8-aminoquinoline amides.
This strategy features a broad substrate scope and good functional group tolerance. A
series of C5-halogenated 8-aminoquinolines were obtained in moderate to good yields
under mild conditions.
Keywords: 8-Aminoquinolines, Catalyzed-free, C-H functionalization, Halogenation,
Hydrogen Halide (HX)
Introduction
Recently, 8-aminoquinoline derivatives have drawn significant attention
1
due to their unique characteristics in applications towards pharmaceuticals,
2
3
organic
sythesis
and
functional
materials.
Inspired
by
the
transition-metal-catalyzed remote C–H bond chlorination of 8-aminoquinolines
4
by Stahl and co-workers in 2013, strategies for the synthesis of substituted
8
-aminoqunolines have attracted increased attention. Various valuable
5
6
7
8
functional groups including sulfonyl, nitryl, halide, and benzyl, have been
introduced to the phenyl counterparts of quinoline rings.
9
As important precursors for coupling reactions or the preparation of
1
0
organometallic reagents, carbon−halogen bonds have been widely used in
1
1
organic chemistry. Therefore, it is meaningful to develop more efficient,
eco-friendly and atom economical methods to synthesize these halogenated
quinoline scaffolds.

Figure. 1 Construction of C5 halogenated quinolines
Compared with the traditional halogenation of aromatic compounds which
1
2
13
14
suffers from poor site-selectivity, high toxicity and low atom economy,
recent attention has been focused on concise and low-cost oxidative C-H
activation reactions. In our previous work, we reported a highly regioselective
7
b
C-H halogenation of 8-acylaminoquinolines catalyzed by copper(II). However,
the requirement for the usage of hypervalent iodine reagents made the reaction
system unsuitable. To the best of our knowledge, most papers for the synthesis
of halogenated aminoquinolines featured metal halides (MX
the halogen source, such as CuX , LiX, NaX and FeX (X=Cl, Br, I) (Fig. 1, eq.
in which organometallic waste could often not be avoided. Although Xu
and co-workers demonstrated halogenation based on N-halosuccinimide (NXS,
n
) as the catalyst or
n
n
7a-c
1
),
7
d
X=Cl, Br, I) without additional additives or oxidants, the halogen source was
relatively expensive (Fig. 1, eq. 2). Herein, we report a new strategy for the
halogenation of 8-acylaminoquinolines using HX (X= Cl, Br, I) as the halogen
1
5
source and propose a radical mechanism, which differs from the oxidative
7e
halogenation mechanism reported by Li and co-workers.
Results and Discussion
Initially, we chose N-(quinolin-8-yl)benzamide 1a and HCl as model substrates
to investigate the aromatic C-H functionalization reaction (Table 1). The reactivity of
o
various oxidants was first tested in the presence of HCl (1.1 equiv.), at 60 C in water
under
an
air
atmosphere
(Entries
1-6).
The
target
material
N-(5-(chloro)quinolin-8-yl)benzamide 2a was isolated in 55% yield in the presence of
Oxone (Entry 4). The structure of product 2a was confirmed by single X-ray

crystallography (Fig. 2). Simple organic initiators such as hydrogen peroxide (H
2
2
O )
and tert-butyl peroxide (TBHP) showed poor chlorination activity in the
transformation with low yields (Entries 5-6). Organic solvents including DCE, EtOH,
THF, MeCN, and DMF were then added to the reaction system (Entries 7-12), and the
results suggested that H
screening under oxygen or nitrogen atmospheres did not enhance the product yield
Entries 13-14).
2
O/EtOH (3:1, v/v) was the most suitable (89%). Further
(
a
Table 1. Optimization of the chlorination reaction conditions
b
Entry
Yield 2a (%)
Oxidant (equiv.)
Na (2.0 )
K S O (2.0 )
Solvent
1
2
3
4
5
6
7
8
9
2
S
2
O
8
H
2
O
19
23
0
2
2
8
H O
2
2
NH HS O (2.0 )
4
2
8
H O
Oxone (1.0 )
(4.0 )
H
H
2
O
O
55
5
2 2
H O
2
TBHP (4.0 )
Oxone (1.0 )
Oxone (1.0 )
Oxone (1.0 )
Oxone (1.0 )
Oxone (1.0 )
Oxone (1.0 )
Oxone (1.0 )
Oxone (1.0 )
2
H O
0
3:1 H O/DCE
2
NR
89
60
NR
12
63
89
88
3:1 H
2
O/EtOH
3:1 H
2
O/THF
1
1
1
0
1
2
3:1 H O/MeCN
2
3:1 H O/Dioxane
2
3:1 H
3:1 H
3:1 H O/ EtOH
2
O/DMF
c
13
2
O/EtOH
d
14
2
a
b
Reagents and conditions: 1a (0.2 mmol), HCl (1.1 equiv.), oxidant, solvent (2.0 mL), 1 h.
c
d
Isolated yield. Under O
2
. Under N .
2

Figure. 2 X-ray crystal structure of 2a
With the optimum reaction conditions in hand (Table 1, entry 8), the substrate
scope was examined with diversely substituted N-(8-quinolinyl)amides (Scheme 1).
Pleasingly, almost all of the chlorination reactions using aryl, alkyl and heterocyclic
substrates proceeded smoothly under the standard conditions to afford the
corresponding products in moderate to good yields (72-91%). Several functionalized
benzamides containing simple groups, such as methoxy (2b-c), methyl (2d),
trifluoromethyl (2e), fluoro (2f) and chloro (2g) on the phenyl ring were well tolerated
(
83-91% yield). Chlorinated aliphatic amides with cyclohexyl, allyl, or ethyl
substituents were also obtained in high yields (2h-j). It is worth noting that
heterocycle amides with furyl (2k) or pyridyl (2l) substituents and bulky
8
-acylaminoquinolines with naphthyl (2m) or biphenyl (2n) substituents all
performed well in chlorination reaction and provided the desired products in high
yields.

a
Scheme 1. Substrate scope of the quinoline amides. Reagents and conditions: 1 (0.2 mmol),
o
b
HCl (1.1 equiv.), Oxone (1.0 equiv.), H O/EtOH (3:1), 60 C, 1 h. Isolated yield.
2
We subsequently explored the scope of the reaction with diverse
-aminoquinoline scaffolds (Scheme 2). This protocol was examined for methyl
8
groups at the C2, C6 and C7 positions of the quinoline substrates, which gave the
target products 3a-c in 72-80% yield. Similarly, the substrate bearing a methoxyl
group at C6 gave the corresponding product in 72% yield. (3d). However, substrates
containing phenyl, p-methylphenyl and iodine groups at the C3 position of the
pyridine moiety were not tolerated with lower yields (3e-g). The dichlorination of
8
-aminoquinoline amide at the C5 and C7 positions could be achieved in 96% yield
when using double HCl and Oxone (3h).

a
Scheme 2. Substrate scope of the quinoline amide. Reagents and conditions: 1 (0.2 mmol),
o
b
c
HCl (1.1 equiv.), Oxone (1.0 equiv.), H
2
O/EtOH (3:1), 60 C, 1 h. Isolated yield. HCl (2.2
equiv.), Oxone ( 2.0 equiv.).
We found that HBr and HI could also serve as the reactant. Adjusting the
loading of the halide source and oxidant, both brominated and iodinated quinolines at
the C5 position could be obtained in moderate yields (Scheme 3). Clearly, the
reactivity for chlorination of 8-acylaminoquinolines was highest under these reaction
conditions, followed by bromination, then iodination.

a
Scheme 3. Substrate scope for the brominated and iodinated quinoline amide. Reagents and
o
b
conditions: 1 (0.2 mmol), HX (1.2 equiv.), Oxone (1.5 equiv.), H O/EtOH (3:1), 60 C, 1 h.
2
Isolated yield.
To provide insight into the mechanism of the C-H bond halogenation with HX
X= Cl, Br, I), a series of control experiments were performed. First, the structure of
(
2
a was confirmed through hydrolysing 2a under strong alkaline conditions to give
1
5
5
-chloroquinolin-8-amine in 95% yield (Scheme 4, eq 4). Second, the reaction was
supressed when 3.0 equivalents of the radical scavengers TEMPO
2,2,6,6-tetra-methylpiperid-idine-N-oxyl) or BHT (2,6-di-tert-butyl-4-methylphenol)
(
were added, implying that a radical reaction pathway might exist (Scheme 4, eq 5).
Furthermore, structurally similar substrates including N-phenylbenzamide 1aa,
N-(naphthalen-1-yl)benzamide
1ab,
quinolin-8-yl
benzoate
1ac
and
N-methyl-N-(quinolin-8-yl)benzamide 1ad failed to afford the corresponding product
under the standard conditions; these results demonstrate that the quinoline structure
17
and amide group with a free NH unit were required (Scheme 4, eq 6). To evaluate
the function of the amido linkage, 8-aminoquinoline was examined and surprisingly
only the 5,7-dichlorinated product was detected (Scheme 4, eq 7). The poor
site-selective C-H activation and reduced reactivity account for the vital role of the
acyl protecting groups during the reaction.

Scheme 4. Investigation of the mechanism
A radical mechanism was then proposed to explain the C5 halogenation of
-aminoquinoline amides (Scheme 5). Initially, the halogen radical X· and radical
8
cation intermediate A were formed using Oxone. These combined with each other to
form species B which after deprotonation affords the desired product C.
Scheme 5. Plausible mechanism for the halogenation of 8-aminoquinoline amides
Conclusion
In conclusion, we report a highly atom-economical and site-selective protocol
for the radical C-H halogenation of 8-acylaminoquinolines in moderate to good yields.

In this reaction, HX (X= Cl, Br, I) and Oxone were utilised to afford the
halogen-radicals. This new halogenated method avoids the use of metal catalysts and
proceeds with highly efficiency, broad substrate scope and functional group tolerance.
Acknowledgements
Financial support from the Major Scientific and Technological Innovation
Projects of Hangzhou City (No. 20162011A036), and the Natural Science Foundation
of China (No. 21376058) is acknowledged.
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1
. We developed a simple method to synthesizing halogenated 8-aminoquinoline
amides;
2
3
4
. The most halide-atom economical HX were used to afford halogen resources;
. A range of halogenated products were obtained in moderate to good yields;
. The reaction system was carried out in green solvents: water and alcohol.