Copper(I)-Catalyzed Sulfonylation of 8-Aminoquinoline Amides with Sulfonyl Chlorides in Air

Article abstract of DOI:10.1021/acs.orglett.5b03114

A simple and mild protocol for copper(I)-mediated sulfonylation of 8-aminoquinoline amides with sulfonyl chlorides was developed, affording desired products in moderate to good yields. This reaction proceeds in air and features excellent substrate tolerance, especially for aliphatic sulfonyl chlorides.

Full text of DOI:10.1021/acs.orglett.5b03114

Letter
pubs.acs.org/OrgLett
Copper(I)-Catalyzed Sulfonylation of 8‑Aminoquinoline Amides with
Sulfonyl Chlorides in Air
Huijie Qiao,† Suyan Sun,† Fan Yang,*,† Yu Zhu,† Weiguo Zhu,† Yaxi Dong,† Yusheng Wu,*,‡
Xiangtao Kong,§ Ling Jiang,§ and Yangjie Wu*,†
†The College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key
Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, People’s Republic of China
‡Tetranov Biopharm, LLC., 75 Daxue Road, Zhengzhou, 450052, People’s Republic of China
§State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457
Zhongshan Road, Dalian 116023, Liaoning, People’s Republic of China
S
* Supporting Information
ABSTRACT: A simple and mild protocol for copper(I)-mediated
sulfonylation of 8-aminoquinoline amides with sulfonyl chlorides was
developed, affording desired products in moderate to good yields. This
reaction proceeds in air and features excellent substrate tolerance,
especially for aliphatic sulfonyl chlorides.
Scheme 1. Direct Sulfonylation of C−H Bond
ulfones have been extensively proven to possess a variety of
Sbioactivities, such as anticancer, anti-HIV, and antibacterial
activities.1 Among them, heterocyclic aromatic sulfones have
aroused great interest due to their wide application in organic
synthesis, pharmaceutical chemistry, biological chemistry, and
material sciences.2 The most conventional synthetic routes to
sulfones are the oxidation of sulfides and Friedel−Crafts
sulfonylation.3 However, these classic methods usually involve
harsh reaction conditions (e.g., strong oxidants, strong acids) or
are limited by the electronic effect. To cope with the above-
mentioned limitation and satisfy the increasing synthetic
demands of sulfones, developing new synthetic methodologies
of these compounds is urgent and challenging.
During the past decades, transition-metal-catalyzed C−H
functionalization has become a facile and robust tool in organic
synthesis, and a series of transformations from C−H to C−C
and C−heteroatom bonds have been demonstrated.4−6
Particularly, sulfonylation of the C−H bond has been realized
under transition metal catalysis (e.g., palladium,7 copper,8 and
ruthenium9) or even transition-metal-free conditions10
(Scheme 1a). Just recently, the Wei group reported a copper-
catalyzed direct C−H bond sulfonylation of aminoquinolines
with arylsulfonyl chlorides, and sulfonylation took place
exclusively at the C5−H position of the quinoline ring
(Scheme 1b).8d However, this reaction proceeded under an
argon atmosphere and could not tolerate aliphatic sulfonyl
chlorides. Our research interest is to demonstrate a simple and
mild sulfonylation at the C5−H position of 8-aminoquinoline
amides and a broader substrate scope such as aromatic and
aliphatic sulfonyl chlorides. To this end, we envisioned
developing a green reaction pattern for this C5−H
sulfonylation of 8-aminoquinoline amides with sulfonyl
chlorides, possibly in a different single electron transfer process
(Scheme 1c).
Initially, the sulfonylation of N-(quinolin-8-yl)benzamide
(1a) with p-tolysulfonyl chloride (2a) (2.0 equiv) was chosen
as a model reaction for optimization of the reaction parameters,
and the results are displayed in Table 1. After the catalytic
activity of various copper salts was checked, CuI (20 mol %) as
a catalyst gave the desired product 3aa in 80% yield in the
presence of K2CO3 (2.0 equiv) under air for 24 h (Table 1,
entry 3). However, CuCl, CuBr, CuSCN, and CuBF4 showed
lower catalytic activity (Table 1, entries 1−2, 4−5) as well as
other copper(II) species (e.g., Cu(OAc)2, CuCl2, CuBr2,
Cu(CF3SO3)2, and CuO) (<30%; see Supporting Information
(SI)). The reaction did not occur at all under the copper-
Received: October 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03114
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Letter
a
Table 1. Screening of Reaction Conditions
Scheme 2. Substrate Scope of Sulfonyl Chlorides
b
entry
catalyst
base
solvent
yield (%)
1
2
3
4
5
6
CuCl
CuBr
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
tBuOLi
−
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DCE
26
DCE
22
DCE
80
CuSCN
CuBF4
−
DCE
45
DCE
21
group could lead to the coupling products in slightly higher
yields. For example, when arylsulfonyl chlorides possessed
electron-donating groups (e.g., Me and Bu), the target
DCE
trace
72
c
7
CuI
DCE
t
8
CuI
DCE
22
9
CuI
DCE
70
products were obtained in 80%, 75%, and 76% yields,
respectively (3aa−3ac). Electron-neutral arylsulfonyl chlorides
such as benzenesulfonyl chloride and naphthalenesulfonyl
chloride could also afford the desired products in 78% and
73% yield, respectively (3ad and 3ae). Substrates with electron-
withdrawing groups (e.g., F, Cl, Br, CF3, and NO2) provided
the corresponding products in a 35%−68% yield range (3af−
3aj). To our delight, the heterocyclic sulfonyl chloride could
also produce the desired products in a moderate yield (3ak).
Note that the reaction could tolerate the aliphatic sulfonyl
chloride, generating the product in 60% yield (3al).
10
11
12
13
14
15
CuI
DCE
51
CuI
DCE
trace
56
CuI
toluene
CH3CN
dioxane
tBuOH
DCE
CuI
24
CuI
49
CuI
32
d
16
CuI
56
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), copper catalyst
(20 mol %), base (0.4 mmol), solvent (1 mL) at 100 °C under air for
24 h. Isolated yield. Copper catalyst (10 mol %). At 90 °C.
b
c
d
Then, the scope of 8-aminoquinoline amides was explored
under the standard reaction conditions (Scheme 3). The
catalyst-free conditions, and reducing the catalyst loading
resulted in a decreased yield of the desired product (entries 6
and 7). Among the bases examined, including K2CO3, Na2CO3,
Scheme 3. Substrate Scope of 8-Aminoquinoline Amides
t
Cs2CO3, and BuOLi, K2CO3 was the best choice (entry 3 vs
entries 8−10); other bases (e.g., K3PO4, NaHCO3, KHCO3,
t
KF, and BuOK) generated the desired product in even lower
yields (see SI); no desired product was observed in the absence
of the base (entry 11). The results show that K2CO3 play a
central role, and the lower efficacy of other bases may be
influenced by their basicity and solubility in the solvent.11
Then, other solvents such as toluene, CH3CN, dioxane, and
tBuOH were also examined, and it was found that none of them
could match the efficacy of DCE (entry 3 vs entries 12−15).
Finally, the yield of 3aa dropped to 56% when the oil bath
temperature was altered from 100 to 90 °C (entry 16). The
molecular structure of 3aa was unambiguously confirmed by
single crystal X-ray diffraction study.
With the optimized reaction conditions in hand, we explored
the applicability of the present sulfonylation protocol and
examined a series of sulfonyl chlorides (Scheme 2). The results
demonstrate that arylsulfonyl chlorides bearing electron-
donating, -neutral, or -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 (3aa−
3aj). Comparatively, substrates containing an electron-donating
B
DOI: 10.1021/acs.orglett.5b03114
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Letter
electronic effect was not obvious on the benzene ring of
benzamides, and the desired products were afforded in
moderate to good yields (3ba−3ea). Remarkably, the
heterocyclic amide could afford the sulfonylated product in
good yield (3fa). However, aliphatic amides could generate the
products in relatively lower yields (3ga and 3ha). Moreover,
cyclopropanesulfonyl chloride could also react with a fluoro-
substituted 8-aminoquinoline derivative, affording the desired
product in a moderate yield of 68% (3dl). In addition, the
substrates bearing Me and MeO groups on the quinoline ring
could afford the desired products in 81% and 64% yields,
respectively (3ia and 3ja). The slight decrease of the yield of
3ja might be attributed to the influence of the steric hindrance
of the 6-MeO group.
However, when the quinoline ring was changed into
quinoline N-oxide, no desired product (3ka) was observed,
but 1a and 3aa were obtained as byproducts in 88% and 7%
yields, respectively (Scheme 4a). If the C5−H position was
blocked by a Cl group (1la), the reaction did not occur at all,
which was unlike the report of the Wei group (Scheme 4b).8d
Scheme 6. Plausible Mechanism
decomposition of C provides the desired product 3aa, along
with the regeneration of the active copper(I) species to fulfill
the catalytic cycle.
In order to demonstrate that the reaction occurs at the C5
position, we calculated the theoretical data of some carbon
atoms (C2, C4, C5, C7) on the quinoline ring of the chelated
intermediate A (Scheme 7). The natural charges of the C2, C4,
Scheme 7. Natural Charge Distribution and pz Orbital
Occupancy of the C2, C4, C5, and C7 Atoms in the
Structure A
Scheme 4. Two Examples of Other Type of Substituted
Quinoline Ring
C5, and C7 atoms are predicted to be 0.080, −0.144, −0.259,
and −0.290, respectively. However, the natural charges include
contributions from all valence electrons. Considering that the
direction of the pz orbital is in accordance with the π orbital of
the quinolone ring, the pz orbital occupancy would be more
effective to assess the reactivity of a specific atom. Among the
four carbon atoms, C5 has the largest pz orbital occupancies,
implying that C5 may be the most likely electrophilic reactive
site.13
Further studies were performed to obtain insight into the
mechanism (Scheme 5). Performing the reaction under a
Scheme 5. Control Experiments
In conclusion, we have developed a copper-catalyzed direct
sulfonylation of 8-aminoquinoline amides with sulfonyl
chlorides, providing a facile and convenient route to C5−H
sulfonylated 8-aminoquinoline amides. This reaction features a
mild catalytic system and good tolerance of substrates including
aliphatic sulfonyl chlorides. Moreover, a different single
electron transfer mechanism is outlined on the basis of our
experimental results and theoretical data of some carbon atoms.
Finally, we indicate that oxygen has no obvious effect on this
reaction and isolation from air or oxygen is not necessary in this
reaction.
nitrogen or oxygen atmosphere instead of air resulted in similar
yields of 3aa, which showed that oxygen might have no effect
on this sulfonylation and an oxidant might be not essential for
this system. The addition of radical inhibitor 2,6-diisopropyl-4-
methylphenol (BHT) resulted in inhibition of the reaction,
indicating that the reaction might involve radical steps. Wei’s
mechanism which includes Cu(I) and Cu(III) species may be
correct. However, our reaction system is different from Wei’s.
Our experiment results indicate our reaction system proceeds
via the radical process, so a single electron transfer mechanism
is proposed.
Though the detailed mechanism of this sulfonylation remains
unclear, a tentative mechanism is proposed on the basis of the
previous reports8,12 and the above-mentioned results (Scheme
6). First, in the presence of a base, the coordination of 1a with
CuI affords the chelated intermediate A. On the other hand, the
homolytic cleavage of 2a releases a p-tolylsulfonyl radical B and
a chloro radical via a single electron transfer process. Then, the
addition of the radical B to the intermediate A occurs at the C5
position to form an intermediate radical C. Finally,
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.5b03114.
Experimental details, characterizations, and NMR spectra
of all products (PDF)
X-ray data for 3aa (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yangf@zzu.edu.cn.
C
DOI: 10.1021/acs.orglett.5b03114
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Lu, Y.; Dai, H. X.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132, 12203.
(m) Shen, C.; Zhang, P. F.; Sun, Q.; Bai, S. Q.; Hor, T. S. A.; Liu, X. G.
Chem. Soc. Rev. 2015, 44, 291.
*E-mail: wyj@zzu.edu.cn.
*E-mail: yusheng.wu@tetranovglobal.com.
Notes
́
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21102134, 21172200) for financial support.
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