Cu(II)/Ag(I)-Catalyzed Cascade Reaction of Sulfonylhydrazone with Anthranils: Synthesis of 2-Aryl-3-sulfonyl Substituted Quinoline Derivatives

Article abstract of DOI:10.1021/acs.orglett.8b00525

In this paper, a Cu(II)/Ag(I)-catalyzed cascade reaction of anthranils with sulfonylhydrazone to construct 2-phenyl-3-sulfonyl disubstituted quinoline derivatives under mild conditions was studied. The mechanism study indicated that this reaction involves radical addition, and new C-C, C-N, and C-S bonds were constructed in one step.

Full text of DOI:10.1021/acs.orglett.8b00525

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cu(II)/Ag(I)-Catalyzed Cascade Reaction of Sulfonylhydrazone with
Anthranils: Synthesis of 2‑Aryl-3-sulfonyl Substituted Quinoline
Derivatives
Fei Wang, Pei Xu, Shun-Yi Wang,* and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science &
Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, China
S
* Supporting Information
ABSTRACT: In this paper, a Cu(II)/Ag(I)-catalyzed cascade reaction of
anthranils with sulfonylhydrazone to construct 2-phenyl-3-sulfonyl disubstituted
quinoline derivatives under mild conditions was studied. The mechanism study
indicated that this reaction involves radical addition, and new C−C, C−N, and C−
S bonds were constructed in one step.
uinoline derivatives are one of the most important
Hydrazone derivatives are a class of important organic
intermediates for the construction of complex molesulces.9 In
the past few years, great progress has been made in the reaction
of hydrazones catalyzed by transition metals, including the
insertion reaction of X−H (X = C, Si, N, O, etc.),10
cyclization,11 1,2-migration,12 and so on. In recent years, the
reaction of p-toluenesulfonyl hydrazone under the action of a
copper catalyst has also become a hot topic. The reaction
generally proceeds through two processes (sulfonyl free
radical13 or sulfonyl anion14) (Figure1, eq 2). In view of the
unique reaction characteristics of anthranil and p-toluenesul-
fonyl hydrazone, herein, we describe a Cu(II)/Ag(I)-catalyzed
cascade reaction of anthranils with sulfonylhydrazone to
construct 2-phenyl-3-sulfonyl disubstituted quinoline deriva-
tives under mild conditions (Figure 1, eq 3).
Initially, we attempted the reaction of anthranil 1a, p-
toluenesulfonyl hydrazine 2a, copper acetate (15 mol %), and
AgOTf (10 mol %) in DCE at 110 °C for 12 h. Gratifyingly, the
reaction proceeded smoothly to give the 2-phenyl-3-sulfonyl
substituted quinoline 3a in 46% isolated yield (Table 1, entry
1). The reaction failed to afford 3a without a copper catalyst
(Table 1, entry 2). Other copper catalysts, such as Cu(NO3)2
and CuCl, resulted in 3a in 30% and 40% yields, respectively
(Table 1, entries 3 and 4). Then, we studied the effects of the
silver additives such as AgNO3, Ag2CO3, and AgSbF6, which
afforded 3a in 37−43% yields (Table 1, entries 6−8). The
reaction failed to afford 3a without a silver additive (Table 1,
entry 5). We also examined the amount of AgOTf. Increasing
or decreasing the amount of AgOTf did not have a significant
effect on the yield of 3a (Table 1, entries 9−10). In order to
improve the yields of 3a, other ligands such as PPh3 and Xphos
were added to the reaction system. Unfortunately, no better
results were obtained (Table 1, entries 11−12). We screened
the solvents such as were investigated, of which no better result
was obtained. We also screened several solvents and found that
Q heterocyclic compounds, widely found in natural
products, drug-related molecules, and functional materials.1
Functionalized quinoline plays an important role in antimalaria,
inflammation treatment, antiasthma, antibacterial, and anti-
allergy.2 In recent years, the synthesis of quinoline has been
greatly developed. However, most of the existing methods
require highly functionalized starting materials promoted by
expensive transition metals, and the reaction conditions are
mostly harsh.3,4 The methods for the synthesis of 2,3-
disubstituted quinoline with potential activities are still rare.
Therefore, it is more desirable to develop a green and efficient
protocol to prepare 2,3-disubstituted quinolone under mild
conditions.
In recent years, anthranil has been widely used for its unique
electronic properties as a multifunctional synthesis intermedi-
ate. Various transition metal catalyzed reactions of anthranil
with new C−C and C−N bond formations to construct indole,5
quinoline,6 pyrazole,7 pyrrole,8 and other nitrogen-containing
heterocyclic compounds have been well studied (Figure1, eq
1). For example, Prof. Li’s, Jiao’s, and other research groups
have reported the rhodium-catalyzed reactions of anthranil
applied to the synthesis of quinoline derivatives.6b−g
Received: February 13, 2018
Figure 1. Reactions of anthranil and tosylhydrazone.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00525
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of the Reaction Conditions
Scheme 1. Substrate Scope
b
entry
Cu (mol %)
Ag (mol %)
solvent
yield (%)
1
2
Cu(OAc)2 (15)
−
Cu(NO)2 (15)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
−
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
dioxane
DMF
xylene
DCE
DCE
46
n.r.
30
40
trace
37
43
40
44
47
46
46
38
35
20
n.r
46
46
3
4
CuCl (15)
5
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
Cu(OAc)2 (15)
6
AgNO3 (10)
Ag2CO3 (10)
AgSbF6 (10)
AgOTf (20)
AgOTf (30)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
AgOTf (10)
7
8
9
10
c
11
d
12
13
14
15
16
e
17
f
18
a
Reaction conditions: 1a (0.6 mmol), 2a (0.3 mmol), copper catalyst,
b
c
solvent (3 mL), Ag.additive. 110 °C, 12 h. Isolated yields. PPh3 (0.03
d
mmol) was used as ligand. Xphos (0.03 mmol) was used as as ligand.
e
f
a
Under N2 atmosphere. Under Ar atmosphere.
Reaction conditions: anthranils 1a (0.6 mmol), substituted
sulfonylhydrazone 2 (0.3 mmol), Cu(OAc)2 (0.045 mmol), AgOTf
b
(0.03 mol) in DCE (3 mL), 110 °C. Isolated yields.
acetonitrile (MeCN), 1,4-dioxane, and DMF did not give better
results (Table 1, entries 13−16). The reaction in xylene even
failed to afford 3a. The reaction under s nitrogen or an argon
atmosphere had no effects on the yield of 3a (Table 1, entries
17−18). Therefore, the optimized reaction conditions are the
following: anthranil 1 (2.0 equiv), p-toluenesulfonyl hydrazine
2 (1.0 equiv), Cu(OAc)2 (15 mol %), and AgOTf (10 mol %)
in 3 mL of DCE at 110 °C.
corresponding intermediate’s inability to further react with
benzisoxazole.
Next, we examined the reactions of 1a with sulfonohy-
drazides bearing different substituents on the sulfonylbenzene
ring (Scheme 2). It was found that the reaction of N′-(1-
a b
,
Scheme 2. Substrate Scope
With the optimum conditions in hand, we first studied the
scope of p-toluenesulfonylhydrazones bearing different aro-
matic rings (Scheme 1). It was found that there is a slight
increase in the reaction yields when the substrates’ benzene ring
bears electron-donating groups. The target products 3b−d were
obtained in 49−66% yields. The reaction of 1a with para tert-
butyl substituted N′-(1-(4-(tert-butyl)phenyl)ethylidene)-4-
methylbenzenesulfonohydrazide 2e furnished the desired
product 3e in 53% yield. The reaction of 1a with para-phenyl
p-toluenesulfonylhydrazone 2f could lead to the desired
product 3f in 46% yields. When p-toluenesulfonylhydrazones
bearing electron-withdrawing groups were applied to the
reactions, similar yields were observed. The ester and sulfone
substituted p-toluenesulfonylhydrazone 2h and 2i resulted in
the desired products 3h and 3i in 46% and 48% yields,
respectively. The reactions of β-naphthalene and α-naphthalene
functionalized p-toluenesulfonylhydrazones afforded the de-
sired products 3l and 3m in 60% and 47% yields, respectively.
Unfortunately, the reactions of heterocycle-functionalized p-
toluenesulfonylhydrazones 2n−p failed to give the desired
products 3n−p. When the N′-(3,3-dimethylbutan-2-ylidene)-4-
methylbenzenesulfonohydrazide 2r was subjected to the
reaction with 1a, it was found that N′-(3,3-dimethylbutan-2-
ylidene)-4-methyl-N-tosylbenzenesulfonohydrazide 3r′ was
observed in 37% yield instead of quinoline product 3r. This
may be due to the lower reactivity of alkylhydrazone 2r and the
a
Reaction conditions: anthranils 1 (0.6 mmol), substituted sulfonylhy-
drazone 2 (0.3 mmol), Cu(OAc)2 (0.045 mmol), AgOTf (0.03 mmol)
in DCE (3 mL), 110 °C. Isolated yields.
b
phenylethylidene)benzenesulfonohydrazide with 1a gave the
desired product 4a in 42% yield. Weak electron-withdrawing
groups, such as CN and Br substituted sulfonohydrazides 2c
and 2d, could also lead to the desired products 4b and 4c in
51% and 47 yields, respectively. The reaction of N′-(1-
phenylethylidene)pyridine-4-sulfonohydrazide 2e could also
gave the desired product 4d in 27% yield after 48 h.
B
DOI: 10.1021/acs.orglett.8b00525
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Organic Letters
Letter
Then, we investigated the reaction scope of benzo[c]-
isoxazoles under the optimized reaction conditions (Scheme 2).
The reaction of [1,3]dioxolo[4′,5′:4,5]benzo[1,2-c]isoxazole 1b
with 2a furnished the desried product 4e in 45% yield. The
reactions of 5-methoxybenzo[c]isoxazole and 6-methoxybenzo-
[c]isoxazole afforded the desired products 4f and 4g in 40% and
60% yields, respectively. When 6-bromobenzo[c]isoxazole was
subjected to the reaction with 2c, 4h could be obtained in 47%
yield.
Scheme 5. First, p-toluenesulfonyl hydrazone 2a reacts with
zwitterion 1a′ generated from anthranil 1a to give (1-
Scheme 5. Plausible Reaction Mechanism
To demonstrate the application of our method in organic
synthesis, we tried the scale-up reaction of benzo[c]isoxazole 1a
with 4-methyl-N′-(1-(p-tolyl)ethylidene)benzenesulfono-
hydrazide 2d under the standard reaction conditions. To our
delight, the desired product 3d could be obtained in 55% yield
(Scheme 3).
Scheme 3. Scale-up Reaction of 1a and 2d
diazoethyl)benzene A and sulfonyl radical. Cu(II) attacks A
to furnish copper carbene B with release of N2. 1a coordinates
to B to afford C. Following carbene migratory insertion of C, D
is formed. Then, the ring opening of D via N−O bond cleavage
generates intermediates E and its corresponding tautomer F.
AgOTf promoted cyclization of F can give the side product 3a′.
The sulfonyl radical reacts with F to lead to G. AgOTf
promoted cyclization of G affords the main product 3a.
In summary, we developed a Cu(II)/Ag(I)-catalyzed domino
reaction of p-toluenesulfonylhydrazone with anthranils to
construct 2,3-disubstituted quinoline derivatives in one step
via free-radical cyclization. New C−C, C−N, and C−S bonds
were established in this reaction, which provided a practical
method for the preparation of 2,3-disubstituted quinolines.
In order to further understand the reaction mechanism, we
conducted a series of control experiments (Scheme 4). When 1
Scheme 4. Control Experiments
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.8b00525.
equiv of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) was
added to the reaction system of 1a with 2d, the yield of 3d
reduced to only 16%. At the same time, the decomposed
product 1a′ and quinoline product 5a were isolated in 24% and
33% yields, respectively (Scheme 4, eq 1). When 1 equiv of
another radical scavenger (1,1-diphenylethylene) was added to
the reaction system of 1a with 2d, it was found that the desired
product 3d was obtained in 35% yield with the detection of
radical trapped product 3d′ by LC-MS (Scheme 4, eq 2). These
results indicated that the reaction involves a Ts radical process.
Next, we attempted the control experiment of 1a and 2i with 6a
under the optimized conditions. It was found that only 3i was
obtained in 48% yield without the formation of 3a (Scheme 4,
eq 3). A further control experiment of 6a with p-toluene-
sulfonylhydrazide as the source of Ts radical failed to give 3a
(Scheme 4, eq 4). These results meant that the Ts radical has
been involved in the reaction before the formation of the
quinoline skeleton.
Detailed experimental procedures and characterization
datum (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: shunyi@suda.edu.cn.
*E-mail: shunjun@suda.edu.cn.
ORCID
Shun-Yi Wang: 0000-0002-8985-8753
Shun-Jun Ji: 0000-0002-4299-3528
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21772137, 21672157, 21372174), the
Major Basic Research Project of the Natural Science
Foundation of the Jiangsu Higher Education Institutions (No.
Based on the above experimental results and the literature
reports,15 we proposed a plausible reaction mechanism in
C
DOI: 10.1021/acs.orglett.8b00525
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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