Direct arylation for the synthesis of 2-arylquinolines from N-methoxyquinoline-1-ium tetrafluoroborate salts and arylboronic acids

Article abstract of DOI:10.1016/j.tetlet.2018.02.008

A rapid and direct arylation reaction of N-methoxyquinoline-1-ium tetrafluoroborate derivatives and arylboronic acids with high regioselectivety at room temperature was discovered. The reaction shows exceptional functional group tolerance and broad substrate scope regarding both the quinoline derivatives and the arylboronic acids.

Full text of DOI:10.1016/j.tetlet.2018.02.008

Accepted Manuscript
Direct arylation for the synthesis of 2-arylquinolines from N-methoxyquino-
line-1-ium tetrafluoroborate salts and arylboronic acids
Xiaoxiao Ren, Shuaijun Han, Xianying Gao, Jingya Li, Dapeng Zou, Yangjie
Wu, Yusheng Wu
PII:
S0040-4039(18)30165-5
https://doi.org/10.1016/j.tetlet.2018.02.008
TETL 49693
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 December 2017
28 January 2018
2 February 2018
Please cite this article as: Ren, X., Han, S., Gao, X., Li, J., Zou, D., Wu, Y., Wu, Y., Direct arylation for the synthesis
of 2-arylquinolines from N-methoxyquinoline-1-ium tetrafluoroborate salts and arylboronic acids, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.008
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Direct arylation for the synthesis of
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2-arylquinolines from N-methoxyquinoline
1-ium tetrafluoroborate salts and
arylboronic acids
Xiaoxiao Ren, Shuaijun Han, Xianying Gao, Jingya Li, Dapeng Zou, Yangjie Wu, Yusheng Wu

1
Tetrahedron Letters
Direct arylation for the synthesis of 2-arylquinolines from N-methoxyquinoline-1-ium
tetrafluoroborate salts and arylboronic acids
Xiaoxiao Rena, Shuaijun Hana, Xianying Gaoa, Jingya Lib, Dapeng Zoua, Yangjie Wua, Yusheng Wub,c
aThe College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Zhengzhou University, Zhengzhou
450052, PR China
bTetranov Biopharm, LLC. And Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450052, PR China
cTetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A rapid and direct arylation reaction of N-methoxyquinoline-1-ium tetrafluoroborate derivatives
and arylboronic acids with high regioselectivety at room temperature was discovered. The
reaction shows exceptional functional group tolerance and broad substrate scope regarding both
the quinoline derivatives and the arylboronic acids.
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
N-methoxyquinoline-1-ium tetrafluoroborate
Arylation
2-arylquinoline
Introduction
Quinoline and their derivates have been extensively proven to
own a variety of bioactivities, such as antimicrobial, antiviral and
antihypertensive activities.1 Among them, 2-arylquinolines have
aroused great interest and are widely found in bioactive
molecules and drug candidates (Figure 1). 2
Traditional methods for the synthesis of 2-arylquinolines
usually use cross-coupling between arylhalides and
organometallics.3 Recently, the direct coupling of heterocycles
with aryl groups by C-H activity has emerged as an economical
and ecological alternative,4 and a series of methods for the direct
C-H arylation of heterocycles have been developed.5 Among
these, due to the stable and readily available characteristics,
arylboronic acids and their derivatives used as coupling partners
for the direct coupling of heterocycles have aroused wide
attentions.6 In 2010, Baran and co-workers applied a mild silver
catalytic system to achieve the direct C-H arylation of electron
deficient heterocycles with arylboronic acids which afford the
desired regioselective products predominantly at C2- and C4-
positions (Scheme 1a).7 In 2012, Yu’s group reported a novel
iron-mediated direct C-H arylation of quinoline and arylboronic
acids with a ratio of 1.4:1 regioselectivity for the 2- and 4
arylation of quinoline (Scheme 1b).8 Although the poor
Figure 1. Bioactive compounds containing 2-arylquinolines
regioselectivity may limit these methods to more wide
application in organic synthesis, it inspired chemists to explore
other improved systems to solve this challenging works.
Recently, significant improvements have been made for the
direct C-H coupling of heterocyclic N-oxides.9 The utilization of
heterocyclic N-oxides enhanced the reactivity toward
———
* Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327; e-mail: yusheng.wu@tetranovglobal.com, wyj@zzu.edu.cn,
zdp@zzu.edu.cn

2
Tetrahedron Letters
nucleophiles on the C2- and C4-positions,10 thus improve the
decreasing the amount of AgNO3 to 0.1 mmol (32%, entry 2).
Next, obvious increase of the yield of 3aa was found when the
amount of 1a and 2a was adjusted to 3 equiv and 1 equiv (entries
4-5). The Na2S2O8 was slightly better than K2S2O8 and
(NH4)2S2O8 (entries 5-7). The screening of the amount of the
TFA showed that a good yield (75%) of 3aa was obtained when
1 equiv TFA was employed. Increasing or decreasing the amount
of the additive caused the decrease of the yields (entries 8-10).
Finally, the reaction time was optimized as 30 minutes (entries
10-14).
regioselectivity of direct C-H coupling. In 2015, Antonchick and
co-workers developed a transition-metal-free protocol to couple
quinoline N-oxides with arylboronic acid which features a high
regioselectivity on the C2-positions of quinoline N-oxides by
o
using DMSO as solvent at 110 C. Unfortunately, isoquinoline,
pyridine and quinazoline N-oxides were not compatible with the
developed reaction.11 Our group is interested in the development
of novel methods for the synthesis and functionalization of
heterocycles.12 As a part of our ongoing efforts on the
introduction of aryl functional groups into heterocycle molecules,
we herein report a novel and efficient procedure for the direct and
selective synthesis of 2-arylquinoline from arylboronic acids and
the readily prepared N-methoxy-4-methylquinoline-1-ium
tetrafluoroborate salts at room temperature.
With the optimized conditions in hand, we then explored a
range of N-methoxyquinoline-1-ium tetrafluoroborate salts
derivatives for the arylation reaction (Table 2). Both C-2 and C-4
arylation products were detected. To our delight, the C-2
arylation products were formed with high regioselectivity. This
synthetic method was compatible with both electron-donating
and electron-withdrawing groups. The reaction of N-
methoxyquinoline-1-ium tetrafluoroborate salts 1b with
phenylboronic acid 2a gave the coupling product 3ba in 62%
yield. Substrate with an electron-withdrawing group on C4
position, such as cyano gave higher yield (3ea, 86%) than that
with electron-donating one (3ja, 37%). In the case of substrate
with phenyl, 3da were obtained in 65% isolated yield. Especially,
the substrate with -Cl group at the 4-position could readily
converted to the corresponding product in good yield (3ka). The
bromine-substituted substrates were tolerated as well, resulting
the desired products in 63%, 60%, and 67% yields (3fa, 3ga and
3ha), respectively. Importantly, the arylation reactions go
smoothly with substrates derived from isoquinoline and pyridine,
and the desired products 3ia and 3la were obtained in moderate
to good yields.
Scheme 1. Direct 2-arylation of quinoline derivatives with
aryl boronic acids.
Results and Discussion
Table 1. Optimization of the Reaction Conditionsa, b, c
Table 2. Scope of Substratesa,b
Entry
1a
(eq)
2a
(eq)
Oxidant
TFA
(eq)
Time
(h)
Yield
(%)b
1
1
3
3
1
1
1
1
1
1
1
1
1
1
1
1
K2S2O8
-
6
41
32
52
56
64
68
64
75
74
72
75
75
75
75
2c
1
K2S2O8
-
6
3
2
K2S2O8
-
6
4
2.5
3
K2S2O8
-
6
5
K2S2O8
-
6
6
3
Na2S2O8
(NH4)2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
Na2S2O8
-
6
7
3
-
6
8
3
1
1.5
0.5
1
1
1
1
6
9
3
6
10
11
12
13
14
3
6
aReaction conditions: 1a (1.5 mmol), 2a (0.5 mmol), Na2S2O8 (1 eq), AgNO3
(0.15 mmol), DCM:H2O = (1:1, 4 mL) at 25 °C under air.
3
4
3
2
bThe C-2 and C-4 ratio was determined by LC-MS.
3
1
In light of these encouraging results, we further examined the
substrate scope for arylboronic acids. The results are summarized
in Table 3. The results demonstrate that arylboronic acids bearing
electron-donating, electron-neutral, or electron-withdrawing
groups on the benzene ring are all well tolerated in this reaction,
and the desired products can be obtained in moderate to good
yields (3ab-3an). Substrates containing an electron-donating
group gave the coupling products in slightly higher yields. For
example, when benzene ring possessed electron-donating groups
(e.g., -Me and -OMe), the target products were obtained in 54%,
70%, 57%, 62%, 53% and 57% yields, respectively (3ab-3ag). A
slightly decrease of the yields was found from a substrate with 4-
3
0.5
aReaction conditions: 1a (1.5 mmol), 2a (0.5 mmol), oxidant (1 eq ), AgNO3
(0.15 mmol), DCM:H2O = (1:1, 4 mL) at 25 °C under air.
bIsolated yield.
cAgNO3 (0.1 mmol).
Initially, the reaction of N-methoxy-4-methylquinoline-1-ium
tetrafluoroborate salts (1a) with phenylboronic acid (2a) was
chosen as a model reaction for optimization. Performing the
reaction in the presence of AgNO3 (0.15 mmol), oxidant(1 equiv)
at room temperature for 6 h give the desired product 3aa in 41%
yield. (Table 1, entry 1). Dramatic decline was observed by

3
phenyl and 2-naphthyl group under the optimal conditions (3ah,
3ai). Substrates with halogens (-F, -Cl) provided the yields of the
corresponding products in the range of 38-55% (3ak-3ao).
anion was converted to sulfate radical. The radical could induce
the arylboronic acid to produce an aryl radical. It was probably
that this aryl radical reacted with protonated heterocycle to give
the desired product (Scheme 4)14.
Table 3. Scope of Substrates.
Conclusions
aReaction conditions: 1a (1.5 mmol), 2a (0.5 mmol), Na2S2O8 (1 eq), AgNO3
(0.15 mmol), DCM:H2O = (1:1, 4 mL) at 25 °C under air.
In summary, we have described a new and efficient direct
arylation reaction of N-methoxy-4-methylquinoline-1ium
tetrafluoroborate salts and arylboronic acids. The high
regioselective cross-coupling revealed a good functional group
tolerance. In addition, the reaction proceeds quickly with 30
minutes in an ambient temperature under air atmosphere. This
approach provides a simple and mild alternative to prepare a
variety of valuable aryl heterocyclic compound that are very
common in natural products and pharmaceuticals.
Then a comparative experiment was studied, in which the N-
methoxy-4-methylquinoline-1-ium tetrafluoroborate salts was
changed to 4-methyquinoline N-oxide and 4-methyquinoline,
only trace amount of the desired products 3aa and 3 were
detected by LC-MS (Scheme 2).
Based on the previous report13, we attempted to probe the
plausible reaction mechanism for our reaction. A radical
scavenger experiments effect was investigated to study the
mechanism for reaction. When 1 equiv of tetramethylpiperidine
N-oxide (TEMPO) was added to the reaction under the same
conditions, trace amount of product was observed, as shown in
Scheme 3, which indicated that a radical was probably involved
in this transformation. In the presence of silver(I) salts, persulfate
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (21172200, 21702191) for financial support.
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5
Highlights
•Using derect C-H functionalization to prepare 2-
arylquinolines
•The system features good substrates tolerance with
high regioselectivity
•The rapid reaction proceeds under an ambient
temperature under air atmosphere

6
Tetrahedron
Graphical Abstract
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Direct arylation for the synthesis of
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2-arylquinolines from N-methoxyquinoline
1-ium tetrafluoroborate salts and
arylboronic acids
Xiaoxiao Ren, Shuaijun Han, Xianying Gao, Jingya Li, Dapeng Zou, Yangjie Wu, Yusheng Wu