Copper-catalyzed C5-regioselective C-H sulfonylation of 8-aminoquinoline amides with aryl sulfonyl chlorides

Article abstract of DOI:10.1016/j.tetlet.2016.04.011

Copper-catalyzed C-H sulfonylation of 8-aminoquinoline scaffolds in the unusual C5 position was developed. The protocol using inexpensive CuI as the catalyst and commercially available aryl sulfonyl chlorides as the sulfonylation reagents, shows broad substrate scope, producing moderate to good yield of sulfone. The developed method was conveniently applied to synthesize a potential fluorinated PET radioligand of 5-HT₆ serotoninergic receptor. Moreover, mechanistic studies revealed that the reactions underwent a radical process.

Full text of DOI:10.1016/j.tetlet.2016.04.011

Accepted Manuscript
Copper-catalyzed C5-regioselective C−H sulfonylation of 8-aminoquinoline
amides with aryl sulfonyl chlorides
Jun-Ming Li, Jiang Weng, Gui Lu, Albert S.C. Chan
PII:
S0040-4039(16)30360-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.011
TETL 47511
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 January 2016
4 April 2016
6 April 2016
Please cite this article as: Li, J-M., Weng, J., Lu, G., Chan, A.S.C., Copper-catalyzed C5-regioselective C−H
sulfonylation of 8-aminoquinoline amides with aryl sulfonyl chlorides, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.04.011
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Tetrahedron Letters
Copper-catalyzed C5-regioselective C−H sulfonylation of 8-aminoquinoline
amides with aryl sulfonyl chlorides
Jun-Ming Lia, Jiang Wenga,*, Gui Lua,b, and Albert S. C. Chana
a Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People’s Republic of China
b Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, People’s Republic of China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Copper-catalyzed C-H sulfonylation of 8-aminoquinoline scaffolds in the unusual C5 position
was developed. The protocol using inexpensive CuI as the catalyst and commercially available
aryl sulfonyl chlorides as the sulfonylation reagents, shows broad substrate scope, producing
moderate to good yield of sulfone. The developed method was conveniently applied to
synthesize a potential fluorinated PET radioligand of 5-HT6 serotoninergic receptor. Moreover,
mechanistic studies revealed that the reactions underwent a radical process.
Available online
Keywords:
Copper
2016 Elsevier Ltd. All rights reserved.
Quinoline
Regioselectivity
Radical reactions
C-H activation
The quinoline skeleton is one of the most important aromatic heterocycles1 present in various natural products2 and
pharmaceuticals.3 Quinolines can also be employed as ligands4 and directing groups5 in organic synthesis, as well as fluorescence
probes in analytical chemistry.6 Thus, considerable efforts have been directed toward the formation and modification of quinoline-
based scaffolds.7
Quinoline rings are often constructed via annulation of anilines and carbonyl compounds by using a variety of classic named
reactions (e.g., Friedländer, Combes, Skraup, Gould−Jacobs, Conrad−Limpach, Doebner−Miller, and Povarov syntheses).8
Nevertheless, these methods usually require harsh acidic or basic conditions and prohibit adequate diversity and substitutes in the
quinoline ring system. By contrast, the functionalization of preformed quinoline scaffold is more straightforward for the rapid
preparation of diversely substituted quinolines. However, for the electron-deficient property of quinoline ring and the interaction of
sp2-hybridized nitrogen atoms with electrophiles or Lewis acids, direct functionalization of quinolines presents a significant
challenge.9
In the past decade, significant progress has been made in transition-metal-catalyzed C−H bond functionalization.10 In contrast to
the widely studied C−H functionalization on the phenyl rings, C−H functionalization on the quinoline ring systems remains
underdeveloped.11 Most examples of site-selective C−H functionalization of quinolines focus on the transformation in the C2,12
C4,13 and C814 positions. However,
efficient approaches toward the C5-functionalization of quinolines are rarely reported.15 Stahl et al. recently reported the first C5
chlorination of 8-aminoquinoline amides via Cu-catalyzed single-electron-transfer mechanism.15a Zeng,15b Yin,15c and Zhang15d
subsequently reported the allylation, chlorination, and chacogenation of 8-aminoquinoline amides in the C5 position, respectively.
Heterocyclic aromatic sulfones are ubiquitous structural motifs found in numerous biologically active natural products,
pharmaceuticals and functional materials.16 Direct C−H bond sulfonylation has recently been obtained under transition-metal
catalysis or metal-free conditions.17 No direct method for the sulfonylation of quinolines was available in C5 position via C−H
functionalization before this study was conducted. The conventional method for synthesis of quinoline sulfones requires a multi-
step operation, involving the de novo synthesis of halogenated quinoline and cross-coupling of the halide with thiol, followed by
oxidation to the corresponding sulfone.16a During our study, Wei15e et al. reported a CuCl-catalyzed direct C5−H bond sulfonylation
of 8-aminoquinoline amides with arylsulfonyl chloride. Shortly thereafter, Wu15f et al. reported the similar reactions in air by using
CuI as the catalyst, and the substrate scope was expanded to cyclic aliphatic sulfonic chlorides. However, the detailed mechanism of
this sulfonylation remains unclear. Two different mechanisms, organometallic and radical processes were proposed in the
———
 Corresponding author. Tel.: 86-20-39943048; fax: 86-20-39943048; e-mail: lugui@mail.sysu.edu.cn (G. Lu) or wengj2@mail.sysu.edu.cn (J.
Weng)

3
aforementioned study. In the current study, we presented our independent work, with particular focus on the mechanism and
practical application of this methodology.18
Initially, the sulfonylation of N-(quinolin-8-yl)benzamide (1a) with p-tolysulfonyl chloride (2a) was chosen as the model
reaction for the optimization of the reaction parameters (Table 1). The reaction gave the desired C5-sulfonylated product 3aa in
42% yield by using Cu(OAc)2·H2O (20 mol%) as the catalyst in the presence of Ag2CO3 (0.5 equiv.) and Na2CO3 (2.0 equiv.) in 1,4-
dioxane for 46 h under air (entry 1). The structure of 3aa was unequivocally confirmed by X-ray diffraction. No product was
detected in the absence of a copper catalyst (entry 2). Without adding Ag2CO3, the yield of the product decreased to 30% while 15%
C5-chlorinated byproduct was generated (entry 3). Various copper catalysts, such as CuBr2, Cu(OTf)2, CuBr, and CuI were screened
to catalyze this transformation, in which CuI gave the best result (entries 4-7). Subsequent base screening showed that K2CO3 was
superior to other bases, such as Na2CO3 and Cs2CO3, affording 3aa in 61% yield (entry 9 vs entries 7-8). Among the solvents
(dioxane, DMSO, DMF, DCE and MeCN) screened, dioxane was the best choice (entries 9-13). Increasing the loading of Ag2CO3 to
1.0 equiv. gave 3aa in 69% yield with significantly short reaction time (entry 14). Reducing the loading of CuI to 10 mol% resulted
in an increased yield of 3aa (72% yield, entry 16), and further lowering the loading of CuI to 5 mol% led to a decreased yield and
longer reaction time (entry 15). When the amount of p-TsCl was reduced from 3.0 equiv. to 1.0 equiv., the yield dropped to 53%
(entry 17). Interestingly, replacement of the arylsulfonyl source with p-MePhSO2Na can also give the product 3aa in 45% yield
(entry 18).
Table 1
Optimization of the reaction conditionsa
Entry
Catalyst
Base
Solvent
T
(h)
46
-
46
46
48
46
46
46
46
-
Yield
(%)
42
N.R.
30
30
20
35
55
15
61
N.R.
N.R.
47
50
69
61
72
.
1
Cu(OAc)2 H2O
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMSO
DMF
2
-
3b
4
Cu(OAc)2 H2O
.
CuBr2
Cu(OTf)2
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
5
6
7
8
9
10
11
12
13
14c
15c
16c
17c,f
18c,g
-
DCE
MeCN
46
46
12
17
12
12
24
CuI
dioxane
dioxane
dioxane
dioxane
dioxane
CuId
CuIe
CuIe
CuIe
53
45
a
Unless otherwise specified, the reactions were carried out in a sealed tube in the presence of 1a (0.1 mmol), 2a (0.3 mmol), catalyst (20 mol%), Ag2CO3
(0.05 mmol), base (0.2 mmol), and solvent (1 mL) at 110 °C under air; isolated yields.
b Without Ag2CO3.
c 0.1 mmol Ag2CO3.
d 5 mol% CuI.
e 10 mol% CuI.
f 1.0 equiv. of TsCl.
g p-MePhSO2Na was used instead of TsCl.
With the optimal reaction conditions in hand, we evaluated the scope of the reaction with respect to the sulfonyl component
(Table 2). The results showed that various aryl sulfonyl chlorides bearing electron-withdrawing, -neutral or -donating groups in the
benzene ring readily participate in this selective sulfonylation reaction. Substrates with electron-donating methyl groups in the para-,
meta- and ortho-positions were compatible under these reaction conditions, with the yields being 72%, 65% and 32%, respectively
(3aa−3ac). The relatively lower yield of the ortho-substituted product may be a steric effect. Benzene sulfonyl chloride afforded the
corresponding sulfone in 79% yield (3ad). The arylsulfonyl chloride with electron-donating groups such as 4-OMePh and 4-tBuPh,
provided the desired products in 53% and 77% yields, respectively (3ae-3af). Electron-withdrawing substituted sulfonyl chlorides
were also suitable substrates. When trifluoromethyl and fluoro groups were substituted in the p-position, 75% or 74% yields were
obtained, respectively (3ag-3ah). Notably, 4-bromophenylsulfonyl chloride gave the highest yield of 91% (3ai). These halogen-
substituted products are useful intermediates, owing to their ability to undergo further transformations via transition-metal catalyzed
coupling reactions (see Scheme 1). In addition, 2-naphthylsulfonyl chloride was also tolerated, affording 3aj in 59% yield.
However, the use of aliphatic methanesulfonyl chloride resulted in no conversion in this system (3ak).

4
Table 2
Investigation on the scope of arylsulfonyl chloridesa
a
Reaction conditions: 1a (0.1 mmol), 2 (0.3 mmol), CuI (0.01 mmol), Ag2CO3 (0.1 mmol), K2CO3 (0.2 mmol), 1,4-dioxane (1.0 mL), 110 °C under air;
isolated yields.
A variety of 8-aminoquinoline amides were subsequently investigated to evaluate the generality of the current reaction (Table
3). The substrates bearing electron-donating groups such as 4-OMe, 2-Me, 3-Me, and 4-Me on the benzamides reacted smoothly
with 4-bromobenzenesulfonyl chloride 2i and afforded the corresponding sulfones in good yields (3bi-3ei). 1-Naphthoic acid amide
was also a suitable substrate, affording 3fi in 84% yield. The highly electron-deficient 4-nitroaromatic amide could also generate
product 3gi in 51% yield. Moreover, aliphatic acid amides, such as phenylacetic amide and acetamide were also tolerated, affording
the corresponding products 3hi and 3ii in moderate yields. Unfortunately, attempts to utilize acrylamide failed to afford the
corresponding product 3ji. The reactions of 4-bromobenzamide with arylsulfonyl chloride provided both mono- and bis-
sulfonylated products in 58% and 24% yields, respectively (3ki and 3ki'). Reducing the loading of arylsulfonyl chloride to 1.5 equiv.
cause the yield of C5-substituted product 3ki to increase to 65%. Similarly, 2-thiophenecarboxylic acid amide was also converted to
both mono- and bis-sulfonylated products in 53% and 12% yields, respectively (3li-3li').
Based on the above results, we explored the applications of this sulfonylation protocol (Scheme 1). This C5-sulfonylation of 1a
with 2a was successfully scaled up to gram-scale under the same reaction conditions, and 3aa was obtained in 74% yield. 3aa was
then transformed to the corresponding amine 4 under basic conditions (Scheme 1a). As previously mentioned, the bromo-substituted
sulfone 3ai was allowed for further modification via palladium-catalyzed Suzuki cross-coupling reactions (Scheme 1b).
Table 3
Investigation on the scope of aromatic amidesa

5
a Reaction conditions: 1 (0.1 mmol), 2i (0.3 mmol), CuI (0.01 mmol), Ag2CO3 (0.1 mmol), K2CO3 (0.2 mmol), 1,4-dioxane (1.0 mL), 110 °C, under air, 10 h;
isolated yields.
b 0.15 mmol aryl sulfonyl chloride was used.
Scheme 1 Synthetic applications
The synthetic utility of this method was further demonstrated by the efficient synthesis of 8, a potential fluorinated PET
radioligand of 5-HT6 serotoninergic receptor. 8 was initially prepared from 8-chloroquinoline in 4 steps, and the sulfone group was
introduced using a two-step strategy, including the coupling of thiol with iodoquinoline and the oxidation of the resulting sulfide.16a
By applying our new method, sulfone 3ag can be prepared directly from 1a and 4-fluorobenzenesulfonyl chloride 2g. After
deprotection, bromination and subsequent coupling with N-methylpiperazine, 8 was obtained in 31% overall yield (Scheme 2).
Scheme 2 Synthesis of 8

6
A number of control experiments were conducted under the optimized conditions to gain a mechanistic insight into these
copper-catalyzed sulfonylation reactions (Scheme 3). Amino quinoline 9 and dimethylamino quinoline 10 failed to give the
corresponding sulfones (Scheme 3a). Meanwhile, no sulfonylated product was detected in the reactions of N-naphthylamide 11 and
2i (Scheme 3a). N-Methyl-protected amide 12 cannot give rise to the desired sulfone (Scheme 3a). These results of the investigation
on the scope of quinolines indicate that chelation of copper with N,N′-bidentate 8-aminoquinoline plays an important role in
promoting the reaction. The reaction was inhibited when the radical scavenger TEMPO or BHT was added, and the yield was
sharply decreased to trace or 33% (Scheme 3b). Meanwhile, the reaction of TsCl with BHT gave product 13 in 45% yield,
suggesting that p-tolylsulfonyl radical was formed and could be captured by BHT under the reaction condition (Scheme 3c).
Scheme 3 Control experiments
Moreover, kinetic isotope effect (KIE) experiments were performed to gain further mechanistic insight.17 No KIEs were observed
from both intermolecular competition (kH/D = 1.03) and two parallel reactions (kH/D = 1.04) (Scheme 3d and 3e), indicating that the
cleavage of aromatic C−H bond is not the rate-determining step.
On the basis of the aforementioned experimental results and the literatures,15a,15d,18 a radical process probably occurred in the
reaction course. A proposed mechanism is depicted in Scheme 4. CuII is first oxidized to CuIIX2 (X = Cl or I) by Ag2CO3.19 N-
(Quinolin-8-yl)benzamide 1a chelates with CuIIX2 to form complex A, and then the radical complex B is formed through the
intermolecular SET between the electron-rich imidoquinoline moieties and the highly oxidative CuIIX2. Meanwhile, the p-
tolylsulfonyl radical is generated.20 The transfer of the p-tolylsulfonyl radical to B produces the imino−CuII complex C. Complex D
is then provided under a deprotonation process of C. Complex D undergoes elimination to afford product 3aa, and CuIIX2 is
regenerated for the catalytic cycle.

7
Scheme 4 Proposed mechanism of Cu-catalyzed C–H sulfonylation
Conclusion
In summary, we developed an efficient reaction of copper-catalyzed C5-regioselective C−H sulfonylation of quinolineamide
scaffolds using commercially available arylsulfonyl chlorides. The developed method was conveniently applied to synthesize a
potential fluorinated PET radioligand 8. Our insight into mechanistic studies suggested that sulfonylation of the quinoline ring
undergo a radical process. Further studies focusing on the applications of this selective sulfonylation are currently underway.
Acknowledgments
The authors thank the National High-tech R&D Program of China (No. 2013AA092903), the National Natural Science
Foundation of China (No. 21502240), Guangdong Natural Science Foundation (Nos. S2013040012409 and 2015A030313130) for
financial support.
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9
Scheme 1 Synthetic applications
Scheme 2 Synthesis of 8

10
Scheme 3 Control experiments
Scheme 4 Proposed mechanism of Cu-catalyzed C–H sulfonylation

11
Table 1
Optimization of the reaction conditionsa
Entry
Catalyst
Base
Solvent
T
(h)
46
-
46
46
48
46
46
46
46
-
Yield
(%)
42
N.R.
30
30
20
35
55
15
61
N.R.
N.R.
47
50
69
61
72
.
1
Cu(OAc)2 H2O
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMSO
DMF
2
-
3b
4
Cu(OAc)2 H2O
.
CuBr2
Cu(OTf)2
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
5
6
7
8
9
10
11
12
13
14c
15c
16c
17c,f
-
DCE
MeCN
46
46
12
17
12
12
24
CuI
dioxane
dioxane
dioxane
dioxane
dioxane
CuId
CuIe
CuIe
CuIe
53
45
18c,g
a
Unless otherwise specified, the reactions were carried out in a sealed tube in the presence of 1a (0.1 mmol), 2a (0.3 mmol), catalyst (20 mol%), Ag2CO3
(0.05 mmol), base (0.2 mmol), and solvent (1 mL) at 110 °C under air; isolated yields.
b Without Ag2CO3.
c 0.1 mmol Ag2CO3.
d 5 mol% CuI.
e 10 mol% CuI.
f 1.0 equiv. of TsCl.
g p-MePhSO2Na was used instead of TsCl.

12
Table 2
Investigation on the scope of arylsulfonyl chloridesa
a
Reaction conditions: 1a (0.1 mmol), 2 (0.3 mmol), CuI (0.01 mmol), Ag2CO3 (0.1 mmol), K2CO3 (0.2 mmol), 1,4-dioxane (1.0 mL), 110 °C under air;
isolated yields.

13
Table 3
Investigation on the scope of aromatic amidesa
a Reaction conditions: 1 (0.1 mmol), 2i (0.3 mmol), CuI (0.01 mmol), Ag2CO3 (0.1 mmol), K2CO3 (0.2 mmol), 1,4-dioxane (1.0 mL), 110 °C, under air, 10 h;
isolated yields.
b 0.15 mmol aryl sulfonyl chloride was used.

14
Graphical Abstract
Copper-catalyzed C5-regioselective C−H
sulfonylation of 8-aminoquinoline amides
with aryl sulfonyl chlorides
Leave this area blank for abstract info.
Jun-Ming Li, Jiang Weng, Gui Lu and Albert S. C. Chan

15
Highlights

A
copper-catalyzed C-H sulfonylation of 8-
aminoquinoline on unusual C5 position was
developed.



The protocol showed broad substrates scope, giving
the sulfones in good to excellent yields.
With this method as the key step, a potential
fluorinated PET radioligand was synthesized.
Possible mechanism reveals that the reaction might
undergo a radical process.