Intermolecular Amidation of Quinoline N-Oxides with Arylsulfonamides under Metal-Free Conditions

Article abstract of DOI:10.1021/acs.orglett.7b02922

An efficient method for the synthesis of N-(quinolin-2-yl)sulfonamides is described. The intermolecular amidation of quinoline N-oxides with sulfonamides proceeded smoothly in the presence of PhI(OAc)₂ and PPh₃ to afford N-(quinolin-

Full text of DOI:10.1021/acs.orglett.7b02922

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Intermolecular Amidation of Quinoline N‑Oxides with
Arylsulfonamides under Metal-Free Conditions
Xiaoqiang Yu,† Sana Yang,† Yue Zhang,† Mingju Guo,† Yoshinori Yamamoto,†,‡ and Ming Bao*,†
†State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, P. R. China
‡WPI-AIMR (WPI-Advanced Institute for Materials Research), Tohoku University, Sendai 980-8577, Japan
S
* Supporting Information
ABSTRACT: An efficient method for the synthesis of N-
(quinolin-2-yl)sulfonamides is described. The intermolecular
amidation of quinoline N-oxides with sulfonamides proceeded
smoothly in the presence of PhI(OAc)2 and PPh3 to afford N-
(quinolin-2-yl)sulfonamides in satisfactory to excellent yields.
he N-(quinolin-2-yl)sulfonamide structural motifs have
been frequently found in the frameworks of various
to synthesize 2-aminoquinolines.7 However, the mixture of 2-
aminoquinoline and 4-aminoquinoline is commonly obtained
because of their poor 2,4-regioselectivity in these reactions. In
addition, this type of the nucleophilic addition usually requires
more nucleophilic amides. It is well-known that sulfonamides
are difficult to use as nucleophiles for nucleophilic substitution
reactions due to their poor nucleophilicity.8 Therefore, the
nucleophilic addition of sulfonamides to quinoline N-oxides for
the synthesis of N-(quinolin-2-yl)sulfonamides remains a
challenge.
In the course of our continuing research on the dehydrogen-
ative reaction of amine N-oxide under metal-free conditions,9
the intermolecular amidation of quinoline N-oxides with
sulfonamides has been found to proceed in the presence of
PhI(OAc)2 and PPh3 through 1,3-dipolar [3 + 3]-cycloaddition.
A new type of 1,3-dipolar cycloaddition of quinoline N-oxides
with sulfonamides should provide the following synthetic
advantages: (1) overcome the extremely poor reactivity of
sulfonamides as nucleophiles and (2) realize quinoline N-oxides
as 1,3-dipoles to provide various N-(quinolin-2-yl)sulfonamides
by cycloaddition.
T
pharmacologically active compounds and functional dyes.1,2
Thus, the development of convenient and efficient methods for
the synthesis of N-(quinolin-2-yl)sulfonamides is attracting
considerable attention. Over the past years, two main methods
have been developed for the synthesis of N-(quinolin-2-
yl)sulfonamides. The most common method of synthesizing N-
(quinolin-2-yl)sulfonamides is sulfonylation reactions of 2-
amino-substituted quinolines with arylsulfonyl chlorides,3
namely the Hinsberg reaction (Scheme 1, eq 1).4 The second
Scheme 1. Synthesis of N-(Quinolin-2-yl)sulfonamides
In our initial studies, the intermolecular amidation of
quinoline N-oxide (1a) with 4-methylbenzenesulfonamide
(2a) was selected as a model reaction to optimize the reaction
conditions. Table 1 summarizes the preliminary results.
The reaction of 1a with 2a, PhIO, and PPh3 proceeded
smoothly at 80 °C and produced the desired product 3a with
43% yield (Table 1, entry 1). The use of PhI(OTf)2 and
PhI(OH)OTs as trivalent iodine compounds, instead of PhI
O, afforded the desired product in poor yields (5% and 24%,
respectively; Table 1, entries 2 and 3). The desired reaction
proceeded smoothly with PhI(OAc)2 to yield 97% 3a (Table 1,
entry 4). No reaction was observed in the absence of a trivalent
iodine compound (Table 1, entry 5). The solvents were
screened by using PPh3 as an additive (entries 4, 6−10).
Nonpolar (toluene and 1,2-dichloroethane) and polar (dioxane,
method involves the transition-metal-catalyzed cross-coupling
of sulfonamides with halogenated quinolines (Scheme 1, eq 2).5
Although these methods can be employed to synthesize N-
(quinolin-2-yl)sulfonamides, these methods are limited by
various factors, such as microwave radiation, high temperature,
and the use of organic halides. In transition-metal-catalyzed
reactions, specific ligands or Lewis acids are generally necessary
because the ligating ability of heteroatoms can lead to catalyst
deactivation; the electronic properties of specific ring positions
can be unfavorable for elementary reactions.6
Recently, the nucleophilic addition of amines and amides to
quinoline N-oxides has been considered as a common approach
Received: September 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02922
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Optimization of Reaction Conditions
Table 2. Amidation of Quinoline N-Oxide with
Benzenesulfonamide Derivatives under Metal-Free
a
Conditions
b
entry
iodine
additive
solvent
yield (%)
1
PhIO
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DCE
43
5
2
PhI(OTf)2
3
PhI(OH)OTs
PhI(OAc)2
24
97
0
4
5
6
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
72
64
59
59
84
21
7
8
dioxane
acetone
DMF
9
10
11
CH3CN
a
Reaction conditions: quinoline N-oxide (1a) (1.0 mmol, 145 mg),
sulfonamides 2a (0.5 mmol, 85.0 mg), PhI(OAc)2 (322 mg, 1.0
mmol), PPh3 (262 mg,1.0 mmol), and CH3CN (2.0 mL), 80 °C, 12 h.
b
Isolated yield was provided.
acetone, DMF, and CH3CN) solvents were examined. Among
these solvents, CH3CN was the most effective (entry 4).
However, the reaction of quinoline N-oxide with sulfonamide
was performed in the absence of PPh3 to produce 3a with 21%
yield (Table 1, entry 11).
The reactions of sulfonamides 2a−j with quinoline N-oxide
were performed under optimized conditions. The results are
summarized in Table 2. Good to excellent yields of N-
quinolinesulfonamides 3a−f were obtained from the reactions
of sulfonamides 2a−f (entries 1−6, 70%−97%). A relatively
higher yield of N-(quinolin-2-yl)sulfonamide was synthesized
from a sulfonamide bearing an electron-donating group on the
benzene ring than that from a sulfonamide bearing an electron-
withdrawing group on benzene ring (entries 1 and 4 vs entry
5).
The sulfonamide 2g bearing an −NH2 group on the benzene
ring was also suitable for this reaction to produce 70% N-
(quinolin-2-yl)sulfonamide 3g (entry 7). The sulfonamides 2h
and 2i that contain a halogen atom (Br or Cl) were also
employed successfully to synthesize N-(quinolin-2-yl)-
sulfonamides. The corresponding products 3h and 3i were
obtained in 87% and 93% yields, respectively (entries 8 and 9).
The reaction of 5-bromothiophene-2-sulfonamide (2j) was
evaluated under the same conditions, and N-(quinolin-2-
yl)sulfonamide 3j was formed with 45% yield (entry 10).
Good preliminary results encouraged us to examine the
scope of this reaction for various quinoline N-oxides under the
optimized reaction conditions; the results are summarized in
Table 3. The reaction of quinoline N-oxides 1b−e with
sulfonamide 2a produced 3k−n in satisfactory yields (Table 2,
entries 1−4). The relatively low yield of 3m was attributed to
the steric effect of the 8-methyl group in quinoline N-oxide
substrate (entry 3). Low yield (55%) was also observed in the
reaction of 1f bearing a bromo on quinoline (entry 5).
To extend the scope of this reaction, isoquinoline N-oxide
(1h) and 2-phenylpyridine N-oxide (1g) were employed to
react with 2a under the optimized conditions. The results are
shown in Scheme 2. The reaction of 1h with 2a proceeded
smoothly to produce sulfonamide 3p in 94% yield (Scheme 2,
eq 4). New product 3p was identified by means of its NMR, IR,
a
Reaction conditions: quinoline N-oxide (1a) (1.0 mmol, 145 mg),
sulfonamides 2a−j (0.5 mmol), PhI(OAc)2 (322 mg, 1.0 mmol), PPh3
b
(262 mg, 1.0 mmol), and CH3CN (2.0 mL), 80 °C, 12 h. Isolated
yield was provided.
and HRMS data and X-ray structure (Figure 1).10 A test on 1g
with sulfonamide 2a was also carried out. However, the yield of
sulfonamide 3q was only 19% (Scheme 2, eq 5). This low yield
was not improved when the reaction temperature and time
were increased or large amounts of PhI(OAc)2 and PPh3 were
added.
Control experiments were conducted to gain insights into the
mechanism of this type of amidation reactions. N-(4-
Methylphenylsulfonyl) imino-phenyl-λ3-iodane (A) was synthe-
sized via the reaction of 2a with PhI(OAc)2 with 90% yield to
verify the proposed mechanism of the present method (Scheme
3). Subsequently, the 1,3-dipolar [3 + 3]-cycloaddition reaction
B
DOI: 10.1021/acs.orglett.7b02922
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Letter
of A with quinoline N-oxide and PPh3 was carried out to
produce 3a, Ph3P = O, and PhI in almost the same yield (97%
isolated yield vs 95% isolated yield vs 99% GC yield).
Table 3. Amidation of Quinoline N-Oxide Derivatives with
4-Methylbenzenesulfonamide under Metal-Free Conditions
a
Scheme 4 shows the proposed mechanism for the 1,3-dipolar
[3 + 3]-cycloaddition reaction of quinoline N-oxides with
Scheme 4. Schematic of the Proposed Mechanism
sulfonamides PhI(OAc)2 and PPh3. The reaction of 2a with
PhI(OAc)2 proceeded to produce tolylsulfonyl imino iodo
arene (A).11 After PPh3 was added to A, intermediate B was
generated. The 1,3-dipolar [3 + 3]-cycloaddition reaction of
quinoline N-oxides with intermediate B may have occurred to
generate the six-membered intermediate C; the ring-opening
reaction then proceeded to yield the desired product 3a.
In summary, we developed a new method to synthesize N-
quinolinesulfonamides via 1,3-dipolar [3 + 3]-cycloaddition
reactions by quinoline N-oxides, sulfonamides, PhI(OAc)2, and
PPh3. The new method is applicable to various quinoline N-
oxide substrates and sulfonamides; hence, this methodology
could be used to synthesize organic substances, particularly in
the context of biologically active target molecules and
pharmaceutical research areas. Further investigations are
underway to apply this methodology in organic compound
synthesis.
a
Reaction conditions: quinoline N-oxide derivatives 1b−g (1.0 mmol),
4-methylbenzenesulfonamide (0.5 mmol, 85.0 mg), PhI(OAc)2, (1.0
mmol 322 mg), and PPh3 (1.0 mmol, 262 mg) in CH3CN (2.0 mL) at
80 °C for 12 h. Isolated yield.
b
Scheme 2. Amidation of Isoquinoline N-Oxide and 2-
Phenylpyridine N-Oxide with 4-Methylbenzenesulfonamide
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02922.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mingbao@dlut.edu.cn.
ORCID
Figure 1. X-ray structure of 3p.
Xiaoqiang Yu: 0000-0001-9396-3882
Ming Bao: 0000-0002-5179-3499
Notes
Scheme 3. Control Experiment
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21273026 and 21572028) for their financial
support. This work was also supported by the Fundamental
Research Funds for the Central Universities (DUT15LK37)
C
DOI: 10.1021/acs.orglett.7b02922
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Letter
and the Outstanding Young Scholars Development Growth
Plan of universities in Liaoning Province (LJQ2015027).
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