Sulfonylation of quinoline N-oxides with aryl sulfonyl chlorides via copper-catalyzed C-H bonds activation

Article abstract of DOI:10.1021/ol400178k

An efficient and concise one-pot protocol to synthesize sulfonylated quinoline N-oxides via copper-catalyzed C-H bond activation has been developed. Commercially available and less expensive aryl sulfonyl chlorides were used as the sulfonylation reagents. Various 2-aryl sulfonyl quinolines were obtained in up to 91% yields in chemo- and regioselective manners.

Full text of DOI:10.1021/ol400178k

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1270–1273
Sulfonylation of Quinoline N‑Oxides
with Aryl Sulfonyl Chlorides via
Copper-Catalyzed CÀH Bonds Activation
Zhiyong Wu,† Hongyu Song,† Xiuling Cui,*,†,‡ Chao Pi,† Weiwei Du,† and Yangjie Wu*,†
Department of Chemistry, Henan Key Laboratory of Chemical Biology and
Organic Chemistry, Key Laboratory of Applied Chemistry of Henan Universities,
Zhengzhou University, Zhengzhou, 450052, P. R. China, and School of Biomedical
Sciences, Engineenring Research Center of Molecular Medicine of Chinese Education
Ministry, Xiamen Key Laboratory of Ocean and Gene Drugs, Institute of Molecular
Medicine of Huaqiao University, Fujian, Xiamen, 361021, P. R. China
cuixl@zzu.edu.cn; wyj@zzu.edu.cn
Received January 25, 2013
ABSTRACT
An efficient and concise one-pot protocol to synthesize sulfonylated quinoline N-oxides via copper-catalyzed CÀH bond activation has been
developed. Commercially available and less expensive aryl sulfonyl chlorides were used as the sulfonylation reagents. Various 2-aryl sulfonyl
quinolines were obtained in up to 91% yields in chemo- and regioselective manners.
The heterocyclic aromatic sulfone skeleton has proven
to be a useful building block in organic synthesis,
medicinal chemistry, and natural products.1 It exists
widely in pharmaceutical molecules, such as enzyme
inhibitors2 and biological activity antagonists,3 which
are exemplified in Figure 1. Compound a was found to
be a novel potent and highly selective HIV-1 non-
nucleoside reverse transcriptase inhibitor.4 Compounds
b and c are potent and selective serotonin 5-HT6 receptor
(5-HT6R) antagonists.5
Figure 1. Examples illustrating the importance of heterocyclic
aromatic sulfone.
† Zhengzhou University.
‡ Institute of Molecular Medicine of Huaqiao University.
(1) (a) Otzen, T.; Wempe, E. G.; Kunz, B.; Bartels, R.; Lehwark-
The wide usefulness of compounds containing this
skeleton has resulted in the development of synthetic
methodologies to construct them. The conventional
methods have typically involved a nucleophile substitu-
tion reaction of halide with thiol, followed by oxidation of
the corresponding sulfide.6 Recently, a “one step” proto-
col was explored from the cross-coupling of sulfinate salts
with halides catalyzed by metal7 or tetrabutylammonium
chloride.8 However, some halogenated heterocyclic aro-
matic compounds are not commercially available and are
problematic to prepare. Therefore, a rapid, efficient, and
€
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r
10.1021/ol400178k
Published on Web 03/05/2013
2013 American Chemical Society

practical access to heteroaromatic sulfone compounds is
highly desired from a synthetic practicality viewpoint.
Recently, significant progress has been made in transition-
metal-catalyzed CÀH bond functionalization.9 Sub-
stantial growth in carbonÀheteroatom bond formation
based on the transition-metal-catalyzed CÀH bond acti-
vation has been observed.10 Nevertheless the development
of effective CÀS bond formation reactions is still under-
developed compared to CÀN11 and CÀO12 bond forma-
tion. Until very recently, several representative examples
were reported by Doi and Dong involving intra- and
intermolecular reactions to generate the CÀS bond.13
Quinoline N-oxides are widely present in biologically
active compounds,14 and they are important intermediates
for the syntheses of substituted quinoline as motifs in
biologically active compounds.15 Moreover, N-oxide
could serve as a directing group and allow CÀH function-
alization to occur at the 2-position.16 In our continuing
effort to develop versatile CÀX (X = C, O, S, N) bond
formations based on metal-catalyzed CÀH activation of
quinoline N-oxides,17 we embarked on the development of
CÀS bond formation. Herein, we disclose a highly prac-
tical procedure to build 2-aryl sulfonyl quinolines in one
step from quinoline N-oxides with aryl sulfonyl chloride
catalyzed by a cheap metal, copper.
We initiated our investigation on the model reaction of
quinoline N-oxides with p-tolylsulfonyl chloride to opti-
mize the critical reaction parameters (Table 1). To our
delight, the direct C2-sulfonylation took place in the pres-
ence of Pd(OAc)2 (10 mol %) and K2CO3 (2 equiv) in
toluene under air, affording compound 3a in 47% yield
(entry 1, Table 1). Compound 3a was identified by 1D and
2D NMR spectra. Inspired by this result, various catalysts,
such as PdCl2, Pd(PhCN)2Cl2, Pd(PPh3)2Cl2, Pd(TFA)2,
CuI, CuCl, and CuBr, werescreened(entries1À8, Table1).
10 mol % CuI provided product 3a in the highest yield
(73%, entry 8, Table 1). A 41% yield was obtained in the
absence of catalyst (entry 9, Table 1). It was found that
the solvent played a crucial role in this transformation.
Among the solvents examined (toluene, dioxane,
C2H5OH, NMP, DMAc, CH3CN, DME, DCE, DMA,
and DMF, entries 10À18, Table 1), DCE was the best,
affording 3a in 91% yield (entry 18, Table 1). The base also
played an important role in the reaction. No product was
detected in the absence of any base (entry 26, Table 1).
K2CO3 was superior to other bases, such as Na2CO3,
NaHCO3, KHCO3, Cs2CO3, CsF, KOAc, and Et3N
(entry 18 vs entries 19À25, Table 1). The yield decreased
to 79% when the catalyst loading was reduced to 5 mol %
from 10 mol % (entry 27, Table 1). After surveying a
variety of catalysts, bases, solvents, and catalyst loadings,
we found that the combination of 10 mol % of CuI and
2 equiv of K2CO3 in DCE at 100 °C for 24 h served as the
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Org. Lett., Vol. 15, No. 6, 2013
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optimal conditions for this transformation. These results
indicated that this transformation was facile and practical,
as it did not require the use of strong bases, an expensive
catalyst, and the rigorous exclusion of air.
product 3p was obtained in 88% yield (Scheme 1). No
products were afforded when N-oxides derived from pyr-
azine, pyrimidine, 1-methyl-imidazole, pyridine, and their
derivatives were utilized as the substrate.
Table 1. Direct 2-Sulfonylation of Quinoline N-Oxide with
p-Tolylsulfonyl Chloridea
entry
catalyst
base
solvent
yield (%)b
1
Pd(OAc)2
PdCl2
Pd(PPh3)2Cl2
Pd(PhCN)2Cl2
Pd(TFA)2
CuCl
CuBr
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KHCO3
Na2CO3
NaHCO3
Cs2CO3
CsF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DMF
47
2
60
3
55
4
61
5
N.R.
72
6
7
62
8
73
9
À
41
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
CuI
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
91
CuI
CuI
NMP
CuI
DMAc
CH3CN
DMA
CuI
CuI
CuI
DME
CuI
C2H5OH
DCE
CuI
Figure 2. Copper-catalyzed sulfonylation of quinoline N-oxides.
Reaction conditions: 1(0.2 mmol), 2(0.8mmol), CuI(10mmol%),
K2CO3 (0.4 mmol), DCE (3 mL), under air, 100 °C, 24 h, sealed
tube. Isolated yields.
CuI
DCE
23
CuI
DCE
58
CuI
DCE
31
CuI
DCE
81
CuI
DCE
<5
CuI
KOAc
DCE
38
CuI
Et3N
DCE
<5
CuI
À
DCE
N.R.
79c
Scheme 1. Copper-Catalyzed Sulfonylation of Isoquinoline
N-Oxide
CuI
K2CO3
DCE
a Reaction conditions: 1a (0.2mmol), 2a (0.8 mmol), catalyst (10 mol %)
and base (2 equiv), solvent (3 mL), under air, 100 °C, 24 h, sealed tube.
b Isolated yields. c Catalyst (5 mol %).
With the optimized reaction conditions in hand, the
scope of substrates was examined. The results were sum-
marized in Figure 2. A series of functional groups on the
phenyl ring of sulfonyl chlorides were tested. Both the
electron-donating and -withdrawing groups were compat-
ible. The products were isolated in 61À91% moderate to
excellent yields (3aÀ3i, Figure 2). Generally, the reaction
efficiencywas slightly sensitivetothe electronic property of
the sulfonyl chlorides. Electron-donating compared to
electron-withdrawing groups gave slightly higher yields.
The quinoline N-oxide derivatives with electron-donating
methyl groups at the 4- and 6-positions smoothly under-
went sulfonylation at the 2-position with arenesulfonyl
chlorides (3jÀ3o, Figure 2). This catalytic system was also
applied to isoquinoline N-oxide. However, C4-substituted
A plausible reaction mechanism was outlined according
to the literature and reaction results in Scheme 2. First, the
CuI electrophilic attack at the 2-carbon of the quinoline
N-oxides afforded intermediate A.18 The following oxida-
tive addition of arene sulfonyl chloride to the intermediate
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€
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2008, 130, 11244.
1272
Org. Lett., Vol. 15, No. 6, 2013

the intermediate C provided the target product as well as
CuCl. Then CuCl underwent an anion exchange process
and regenerated the CuI to finish the catalytic cycle.
In conclusion, an efficient approach for the direct
C2-sulfonylationofquinolineN-oxides hasbeen developed
based on a copper-catalyzed CÀH bond activation. This
novel method provides easy access to sulfonylated hetero-
cyclic compounds using commercially available, inexpen-
sive aryl sulfonyl chlorides as the sulfonylation reagents
and cheap copper as the catalyst.
Scheme 2. Plausible Reaction Mechanism
Acknowledgment. ThisworkwassupportedbytheNSF
of China (20972139, 21172200) and the NSF of Henan
(082300423201). Dedicated to Professor Irina Petrovna
Beletskaya for her contribution to metal-catalyzed reactions.
Supporting Information Available. Typical experimen-
tal procedure and characterization for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
A formed the Cu(III) intermediate B.19 Then, the inter-
mediate B produced intermediate C with coordination of
the copper atom with the oxygen atom of N-oxide. Finally,
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
1273