Copper-catalyzed regioselective C-H sulfonylation of 8-aminoquinolines

Article abstract of DOI:10.1021/acs.joc.5b02509

Copper(I)-catalyzed 5-sulfonation of quinolines via bidentate-chelation assistance has been developed. The reaction is compatible with a wide range of quinoline substrates and arylsulfonyl chlorides. Experimental and theoretical (DFT) investigation implicated that a single-electron-transfer process is involved in this sulfonylation transformation.

Full text of DOI:10.1021/acs.joc.5b02509

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Article
Copper-Catalyzed Regioselective C-H Sulfonylation of 8-Aminoquinolines
Jun Wei, Jingxing Jiang, Xinsheng Xiao, Dongen Lin,
Yuanfu Deng, Zhuofeng Ke, Huanfeng Jiang, and Wei Zeng
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Jan 2016
Downloaded from http://pubs.acs.org on January 8, 2016
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The Journal of Organic Chemistry
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Copper-Catalyzed Regioselective C-H Sulfonylation of 8-
Aminoquinolines
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Jun Wei,† Jingxing Jiang,‡ Xinsheng Xiao,† Dongen Lin*,† Yuanfu Deng, † Zhuofeng Ke*,‡ Huanfeng
Jiang, † and Wei Zeng*†
†School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China
‡ MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yatꢀ
sen University, Guangzhou 510275, China
ABSTRACT: Copper(I) ‒ catalyzed 5ꢀsulfonation of quinolines via bidentateꢀchelation assistance has been developed. The reaction is
compatible with a wide range of quinoline substrates and arylsulfonyl chlorides. Experimental and theoretical (DFT) investigation impliꢀ
cated that a singleꢀelectronꢀtransfer process is involved in this sulfonylation transformation.
Ar
H
H
H
O S
2
CuBr (10 mol %)
K CO (2.0 equiv)
2
3
1
1
+
ArSO Cl
2
R
R
o
DCE, 100 C, Ar, 12h
N
H
N
H
HN
O
HN
O
2
2
R
R
1
R
R
= alkyl, aryl, halogens, alknyl etc.
= alkyl and aryl
30 examples
good to excellent yields
2
INTRODUCTION
Transition metalꢀcatalyzed siteꢀselective functionalization of unactive CꢀH bonds is emerging as an attractive methodology for the rapid
construction of complex organic molecules. 1 In the past decades,
σꢀchelationꢀassisted cyclometalation strategy has been well established
for achieving orthoꢀselective CꢀH functionalization. 2 Recent progress in transition metalꢀcatalyzed metaꢀselective aryl CꢀH functionalizaꢀ
tion has also been accomplished. In this regards, Yu, Ackermann, and Dong et al. successively developed efficient metaꢀaryl CꢀH activaꢀ
tion strategies to regioselectively construct CꢀC bonds employing a concealed directing group (DG), 3 orthoꢀmetalationꢀtriggered ArSE, 4 a
6
coordinating Uꢀshaped template, 5 and others. However, transition metalꢀcatalyzed carbonꢀheteroatom bond formingꢀreactions through
paraꢀselective aryl CꢀH functionalization which is farther away from the directing group, remains highly sought. 7
Aryl sulfones are commonly encountered in natural products, biologicallyꢀactive molecules and material chemistry. 8 For example, sulꢀ
fonylꢀsubstituted quinoline derivatives belong to a kind of potent 5ꢀHT6 receptor antagonist for the treatment of CNs disorders. 9 Traditionꢀ
al crossꢀcouplings of arylhalides, 10 arylboronic acids, 11 arylstannanes 12 and arylzinc reagents 13 etc. with sulfonyl partners are widespreadꢀ
ly used to prepare arylsulfone compounds. Although regioselectivity in these crossꢀcoupling reactions is not an issue, the tedious prior
chemical transformations are required to obtain the prefunctionalized aryl partners. Therefore, much recent effort has been switched to the
direct transition metalꢀcatalyzed sulfonation of aryl CꢀH bonds. In this context, Dong reported Pd(II)ꢀcatalyzed orthoꢀselective aryl CꢀH
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bond activation/crossꢀcoupling with arylsulfonyl chlorides to produce sulfones employing monoꢀdentate 2ꢀpyridyl group as directing
3
4
14
groups (Scheme 1a). Interestingly, Frost further found changing the metal catalyst from Pd(II) to Ru(II) in the sulfonation of 2ꢀ
5
6
phenylpyridines led to the formation of metaꢀsubstituted products, in which Ru‒Caryl σꢀbond played an important role in controlling the
7
8
9
metaꢀselectivity (Scheme 1b).4a The aboveꢀmentioned remarkable switch in regioselectivity implies that bidentateꢀchelationꢀassisted cyꢀ
clometalation could also possibly induce an unusual remote CarylꢀH bond functionalization via novel mechanistic pathways. In this comꢀ
munication, we described a direct approach for copperꢀcatalyzed 5ꢀsulfonation of quinolines based on the unique paraꢀdirected features of
bidentateꢀchelation assistance (Scheme 1c). 15
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12
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Scheme 1. Ligand-Directed Regioselective Sulfonation of
Arenes
a) Pd(II)-catalyzed ortho-Caryl-H sulfonation of 2-phenylpyridines
R1
R1
R2
O
O
N
N
S
Pd(II) (10 mol %)
base, solvent, 120 o
O2
S
Cl
R3
+
H
C
R2
R3
b) Ru(II)-catalyzed meta-Caryl-H sulfonation of 2-phenylpyridines
R1
R2
R1
R2
O
O
N
N
S
Ru(II) (10 mol %)
base, solvent, 120 o
Cl
R3
+
H
H
H
C
R3
S
O2
c) This work: Copper-catalyzed para-Caryl-H sulfonation of quinolines
Ar
H
H
H
H
H O2S
ArSO2Cl
R
R
R
Cu(I) catalyst (10 mol %)
N
H
N
H
N
H
DG
[Cu] DG
DG
RESULTS AND DISCUSSION
In the first experiment demonstrating the feasibility of chelationꢀinduced 5ꢀsulfonation of quinolines, we began to explore the effect of
various copper catalysts on the crossꢀcoupling of 8ꢀpropionamido quinoline (1a) with pꢀtoluenesulfonyl chloride (2a) in the presence of
o
Na2CO3 (2.0 equiv) in CH3CN under air condition at 100 C for 12 h (Table 1, entries 1ꢀ7). As desired, all the investigated copper salts
such as CuCl2, Cu(OAc)2 and CuCl etc. showed less to good catalytic activity for the sulfonation of quinoline 1a at the 5ꢀposition, and
CuBr proved to be the optimal catalyst which could bring us 35% yield of 8ꢀpropionamido ꢀ5ꢀ(4ꢀtosyl)ꢀquinoline (3a) (compare entries 1ꢀ6
with 7). Subsequently, we continued to evaluate various bases and solvents for further improving the sulfonation conversion of 1a. Among
them, employing K2CO3 as base could significantly increase yield of 3a from 35% to 49% (compare entries 7ꢀ11 with 12). Moreover, a
slightly improvement of the reaction (74% yield of 3a) was also achieved by employing 1, 2ꢀdichloroethane (DCE) as solvent (entries 12ꢀ
18 vs 19). It should be noted that decreasing or increasing the reaction temperature could not further improve the reaction yield (entries 20ꢀ
21 vs 19). Finally, considering that oxygen possibly deactivate the Cu(I) catalysts by oxidizing Cu(I) to Cu(II), we performed the transforꢀ
mation in Ar atmosphere and obtained the best yield of 3a (79% yield, entries 19 and 23 vs 22). However, this reaction could not occur in
the absence of copper catalysts or K2CO3(entries 24 and 25).
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Table 1. Optimization of the Cu(I)-Catalyzed Regioselective Sul-
onation of Quinolines a
Ts
5
6
7
8
copper catalyst (10 mol %)
base (2.0 equiv)
N
O
+
N
TsCl
NH
solvent, 100 oC, 12h
HN
3a
O
Et
1a
2a
Et
copper
catalyst
CuBr2
CuCl2
9
entry
base
solvent
yield (%) b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
28
29
30
31
32
33
34
35
36
37
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60
1
2
3
4
5
6
7
8
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaOAc
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
11
15
19
27
25
35
27
20
30
5
49
trace
62
0
0
0
67
74
56 c
71 d
79 e
28 f
0 e
0 e
Cu(OAc)2
CuCN
CuCl
CuI
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
‒
9
NaHCO3 CH3CN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Cs2CO3
Li2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
‒
CH3CN
CH3CN
CH3CN
toluene
ethyl acetate
DMSO
DMF
1, 4ꢀdioxane
THF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CuBr
a Unless otherwise noted, all the reactions were carried out using
quinoline 1a (0.10 mmol) with pꢀtoluene sulfonyl chrolide 2a (0.15
mmol) in solvent (1.0 mL) under air atꢀmosphere at 100 oC for 12 h
in a sealed reaction tube, folꢀlowed by flash chromatography on
SiO2; b Isolated yield. cThe reaction temperature is 80 oC. dThe reacꢀ
tion temperature is 120 C; eUnder Ar atmosphere; f Under oxygen
o
atmosphere.
To adapt the copperꢀcatalyzed sulfonation conditions to more complex substrates, we investigated the scope of the current procedure by
testing various sulfonyl chlorides in the reaction with 8ꢀpropionamido quinoline (1a). As shown in Table 2, the reactivity of arylsulfonyl
chlorides (2) was partly dependent on the electronic and structural properties of substituted aryl groups. Para, meta or orthoꢀsubstitution of
aryl rings with electronꢀdonating group (Me, MeO) or electronꢀwithdrawing halogen substituents did not significantly affect the sulfonaꢀ
tion conversion and produced good to excellent yield of 3aꢀ3h (Table 2, entries 1ꢀ8, 62ꢀ83% yields). In contrast, the strong electronꢀ
withdrawing nitro or trifluomethyl groupꢀcontaining sulfonyl chlorides (2i and 2j) afforded moderate yield of the arylsulfones 3i and 3j
(Table 2, entries 9ꢀ10, 52ꢀ54% yields).
Table 2. Substrate Scope a
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Ar
H
SO
2
CuBr (10 mol %)
K CO (2.0 equiv)
2
3
+
ArSO Cl
2
o
N
DCE, 100 C, Ar, 12h
N
HN
O
5
HN
O
2
1a
3
Et
6
Et
7
8
9
entry
quinoline (1a)
sulfonyl chloride (2)
product (3), yield b
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1
2
3
4
5
6
7
8
2a: Ar = 4ꢀMeꢀPh
2b: Ar = Ph
3a: Ar = 4ꢀMeꢀPh, 78%
3b: Ar = Ph, 81%
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2c: Ar = 3ꢀMeꢀPh
2d: Ar = 2ꢀMeꢀPh
2e: Ar = 4ꢀMeOꢀPh
2f: Ar = 4ꢀClꢀPh
2g: Ar = 4ꢀBrꢀPh
2h: Ar = 2ꢀNapthyl
2i: Ar = 4ꢀCF3ꢀPh
2j: Ar = 4ꢀNO2ꢀPh
3c: Ar = 3ꢀMeꢀPh, 68%
3d: Ar = 2ꢀMeꢀPh, 62%
3e: Ar = 4ꢀMeOꢀPh, 83%
3f: Ar = 4ꢀClꢀPh, 72%
3g: Ar = 4ꢀBrꢀPh, 77%
3h:Ar= 2ꢀNapthyl, 75%
3i: Ar = 4ꢀCF3ꢀPh, 54%
3j: Ar = 4ꢀNO2ꢀPh, 52%
9
10
a All the reactions were carried out using quinolines 1 (0.10 mmol) with sulfonyl chrolides 2
o
(0.15 mmol) in DCE (1.0 mL) under Ar atmosphere at 100 C for 12 h in a sealed reaction
tube, followed by flash chromatography on SiO2; b Isolated yield.
Subsequently, the scope of the procedure with regard to various quinoline coupling partners was further evaluated with pꢀ
toluenesulfonyl chloride (2a) as the sulfonating reagent (Table 3 and Table 4). Overall, the reaction tolerated a broad range of substituted
quinolines to provide the corresponding 5ꢀarylsulfonyl quinolines with good conversions. Remarkably, the reaction worked well for aliꢀ
phatic amido or arylamidoꢀsubstituted quinolines under our standard conditions and produced the corresponding sulfonation products in
66% ‒ 80% yields, regardless of whether sterically hindered alkyl groups, electronꢀdeficient or electronꢀrich phenyl groups were introꢀ
duced into the amido moieties (Table 3, entries 1ꢀ10; Table 4, entries 1ꢀ2). It is worth noting that alkylaminoꢀsubstituted quinolines are
also suitable substrates for this transformation and provided around 80% yield of the sulfonation product 3v and 3w, but for the phenylaꢀ
minoꢀsubstituted quinoline 1l, no reaction took place and starting material was recovered (Table 4, entry 1 ). Importantly, it still revealed
that the reaction efficiency was maintained irrespective of the type of substitutes and substituted position in quinoline rings (Table 4). For
examples, 2ꢀmethyl, 2ꢀchloro, 2ꢀphenyl, 4ꢀmethoxyl, 6ꢀchloro or 6ꢀmethylꢀsubstituted quinoline substrates all allowed for this sulfonation
and afforded the desired 5ꢀarylsulfonyl quinolines in good yields (Table 4, entries 2ꢀ4 , 70ꢀ77% yields). In addition, this reaction protocol
could still smoothly convert 2ꢀthienylsulfonyl chloride (2k) and 2ꢀalknylꢀsubstituted quinoline (1u) to the corresponding 5ꢀ(2ꢀ
thienylsulfonyl)ꢀ quinoline 33c and 2ꢀalknylꢀ5ꢀarylsulfonyl quinoline 33d in good yields, respectively (Table 4, entries 4ꢀ5), but alkylꢀ
sulfonyl chlorides were not allowed for this transformation. 16 Finally, the structure of the product 3b was already unambiguously assigned
by its single crystal Xꢀray analysis (see SI for more details), and this compound (3b) could be further hydrolyzed to provide free (NꢀH) 8ꢀ
aminoꢀ5ꢀphenylsulfonylꢀquinoline 3b-1 in 93% yield.
Table 3. Substrate Scope a
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2
H
Ts
3
4
5
6
CuBr (10 mol %)
K CO (2.0 equiv)
2
3
N
N
+
TsCl
o
DCE, 100 C, Ar, 12h
HN
O
HN
O
2
2
1
2a
3
R
R
7
8
9
entry
quinoline (1)
sulfonyl
(2a)
2a
2a
2a
2a
2a
2a
chloride product (3), yield b
10
11
12
13
14
15
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22
23
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60
1
2
3
4
5
6
1b, R2 = Me
1c, R2 = nPr
1d, R2 = iPr
1e, R2 = sBu
1f, R2 = tBu
1g, R2 = ClCH2
3k, R2 = Me, 71%
3l, R2 = nPr, 66%
3m, R2 = iPr, 68%
3n, R2 = sBu, 71%
3o, R2 = tBu, 68%
3p, R2 = ClCH2, 70%
Ts
N
N
HN
O
HN
O
R2
R2
TsCl
2a
2a
2a
2a
1
3
7
8
9
10
1h: R2 = 4ꢀH
3q: R2 = 4ꢀH, 70%
3r: R2 = 4ꢀMeO, 80%
3s: R2 = 4ꢀBr, 76%
3t: R2 = 4ꢀNO2, 75%
1i: R2 = 4ꢀMeO
1j: R2 = 4ꢀBr
1k: R2 = 4ꢀNO2
2a
a All the reactions were carried out using quinolines 1 (0.10 mmol) with sulfonyl chrolides 2
(0.15 mmol) in DCE (1.0 mL) under Ar atmosphere at 100 oC for 12 h in a sealed reaction tube,
followed by flash chromatography on SiO2; b Isolated yield.
Table 4. Substrate Scope a
Ar
H
SO
X
2
CuBr (10 mol %)
K CO (2.0 equiv)
1
R
1
2
3
R
ArSO Cl
2
+
o
N
DCE, 100 C, Ar, 12h
N
X
2
R
2
2
1
3
R
entry
quinoline (1)
sulfonyl chloride (2)
product (3), yield b
Ts
N
N
HN
R2
HN
R2
TsCl
2a
2a
2a
2a
1
1
3
1l, R2 = Ph
1m, R2 = Bn
1n, R2 = Me
3u, R2 = Ph, 0%
3v, R2 = Bn, 79%
3w, R2 = Me, 80%
Ts
R1
1
R
N
N
HN
O
HN
O
TsCl
2a
2a
2a
2a
Me
Me
2
1
3
1o, R1 = 2ꢀMe
1p, R1 = 6ꢀMe
1q, R1 = 2ꢀCl
1r, R1 = 6ꢀCl
3x, R1 = 2ꢀMe, 77%
3y, R1 = 6ꢀMe, 77%
3z, R1 = 2ꢀCl, 75%
33a, R1 = 6ꢀCl, 70%
2a
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2
3
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S
O
O
O
N
O
N
S
HN
O
5
HN
O
S
SO Cl
2
Me
Me
6
7
3
33b, 74%
1s
2k
S
8
SO2
9
Ph
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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47
48
49
50
51
52
53
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60
Ph
N
HN
O
HN
O
S
SO Cl
2
Me
Me
4
5
33c, 70%
1t
2k
Ts
N
N
Ph
HN
O
Ph
HN
O
TsCl
2a
Me
Me
33d,73%
1u
a All the reactions were carried out using quinolines 1 (0.10 mmol) with sulfonyl chrolides 2
(0.15 mmol) in DCE (1.0 mL) under Ar atmosphere at 100 oC for 12 h in a sealed reaction tube,
followed by flash chromatography on SiO2; b Isolated yield.
We then conducted several controlled reactions to further investigate the primary mechanism of the present transformation. The sulfonaꢀ
tion of Nꢀnaphthalenꢀ1ꢀylꢀpropionamide (1v) and NꢀmethylꢀNꢀquinolinꢀ8ꢀylꢀpropionamide (1w) with pꢀtoluenesulfonyl chloride (2a) was
1
performed under our standard conditions, respectively, and no any sulfonation products were monitored by the H NMR and GCꢀMS
methods (Scheme 2aꢀ2b). These results obviously implied the quinoline nitrogen and amide nitrogen played a key role in the chelationꢀ
directed sulfonation process. Moreover, 8ꢀamidoquinoline (1x) which bears two methyl group in 5ꢀ and 6ꢀpositions was not allowed for
this reaction (Scheme 2c). Subsequently, using radical scavenger reagent TEMPO (2.0 equiv), the desired sulfonation reaction was comꢀ
pletely suppressed, and also no sulfonation product 3a was formed, the starting material 1a was recovered in almost 100% yield (Scheme
2d); On the other hand, when radical trapper 1,1ꢀdiphenylethylene 4a was subjected to the standard reaction system, the 5ꢀsulfonation of
quinoline 1a was suppressed to some degree, and the main product was the 1ꢀ(2,2ꢀdiphenylꢀethenesulfonyl)ꢀ4ꢀmethylꢀbenzene (33h, 72%
yield, Scheme 2e). In addition, independent reactions of 1a and dꢀ1a exhibited nearly identical time courses (Figure S11), and no KIE is
observed for this reaction (Scheme 2f, KIE ~ 1,). On the basis of these results, we may conclude that a free radicalꢀmediated process was
most likely involved in our reaction system.
Scheme 2. Several Controlled Experiments about This Transformation
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CuBr (10 mol %)
K2CO3 (2.0 equiv)
Ts
TsCl
+
(a)
ClCH2CH2Cl, 100 o
Ar, 12 h
C
HN
O
HN
O
Et
5
6
7
8
Et
33e (not observed)
1v (1.0 equiv)
2a (1.5 equiv)
Ts
CuBr (10 mol %)
K2CO3 (2.0 equiv)
+
TsCl
N
(b)
ClCH2CH2Cl, 100 o
Ar, 12 h
C
N
9
N
O
Me
N
O
Me
10
11
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Et
Et
33f (not observed)
2a (1.5 equiv)
1w (1.0 equiv)
Me
Me
Me
CuBr (10 mol %)
K2CO3 (2.0 equiv)
Me
+
(c)
TsCl
ClCH2CH2Cl, 100 o
Ar, 12 h
C
N
Ts
O
N
HN
HN
O
2a (1.5 equiv)
1x (1.0 equiv)
33g (not observed)
Ts
CuBr (10 mol %)
K2CO3 (2.0 equiv)
N
(d)
+
TsCl
ClCH2CH2Cl, 100 o
TEMPO (2.0 equiv)
Ar, 12 h
C
N
HN
O
HN
O
Et
Et
0% yield
3a
1a (1.0 equiv)
2a (1.5 equiv)
Ts
CuBr (10 mol %)
K2CO3 (2.0 equiv)
Ph
Ph
Ph
N
+
TsCl
+
(e)
+
Ts
N
ClCH2CH2Cl, 100 o
Ar, 12 h
C
HN
O
Ph
HN
O
Et
Et
33h (72% yield)
4a (3.0 eq)
2a (1.5 equiv)
1a (1.0 equiv)
(8 % yield)
3a
H
D
Ts
Ts
TsCl (1.5 equiv)
92% D
CuBr (10 mol %)
K2CO3 (2.0 equiv)
(f)
or
or
N
H
O
N
D
N
D
O
N
H
ClCH2CH2Cl, 100 o
Ar, 12 h
KIE = 1.01
C
HN
HN
O
HN
HN
O
Et
Et
Et
Et
d-1a (1.0 equiv)
1a (1.0 equiv)
3a
d-3a
Taking these controlled experimental results into account, and in combination with the DFT calculations based on the regioselective sulꢀ
fonation of quinoline 1a with TsCl 2a (for the detailed DFT calculations, see SI), we proposed a plausible reaction mechanism for this
novel transformation (Scheme 3). Starting from a Cu(I)ꢀquinoline complex A, there may exit two pathways to generate the radical intermeꢀ
diate D via the intermolecular single electron transfer (SET) and the intramolecular SET. The intermolecular SET from A to TsCl produces
a Cu(II) intermediate B and an arylsulfonyl radical, while the intramolecular SET within A forms a Cu(II) anion radical C. This anion radiꢀ
cal C is clearly demonstrated by DFT, in which the d9 Cu(II) center bears spin density of 0.77, and the heterocyclic anion radical residues
1.23 spin density (Figure 1). This intramolecular SET process is uphill by 14.6 kcal/mol. Instead, the intermolecular SET to arylsulfonyl
radical 17 is more preferred (downhill by 26.4 kcal/mol). The subsequent radical addition of Ts• to B leads to a Cu(II) radical species D.
DFT calculation revealed a spin density of 0.85 for d9 Cu(II) center and 1.05 for heterocyclic radical, respectively (Figure 1). Then the
deprotonation of D generates a Cu(II) anion radical E, which is further downhill by 21.4 kcal/mol. Both as Cu(II) anion radicals, species E
has similar spin density distribution to C (Figure 1), however, species E is more stable than C along the reaction pathway, which should
be attributed to the stabilization of anion by the arylsulfonyl group. Then an SET process transfer one electron from heterocyclic anion to
Cu(II) center, yielding the Cu(I) species F, and finally the catalytic cycle will be regenerated by the release of product 3a.
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Scheme 3. The Proposed Mechanism for the Copper-
Catalyzed Sulfonylation of Quinolines (ꢀG/ꢀH are given in
kcal/mol; carbonate and counterions are omitted for clarity).
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spin densities
spin densities
spin densities
Cu(CO32-): 0.77
Cu(CO32-): 0.85
Cu(CO32-): 0.78
heterocycle: 1.23
heterocycle: 1.05
heterocycle: 1.18
Ts
H
Ts
N
N
N
CuII
N
O
CuII
N
O
CuII
N
O
Et
Et
Et
C
D
E
Figure 1. The electronic structures of radical intermediates C, D and E.
With the understanding of reaction mechanism, we further studied the regioselectivity of sulfonylation. The radical addition of sulfonyl
radical to quinoline occurs at B ꢀ D. The resonance structures of B are depicted at Figure 2, from which we can see that 5- and 7-positions
are more favored for radical addition. NBO charge also suggests that 5- (−0.211) and 7-positions(−0.229) are more negative than 6ꢀ
position. Actually, a 6ꢀsulfonyl substituted species was not able to locate during optimization, which automatically collapses to B and radiꢀ
cal Ts• (Figure S12). The optimized 5- and 7ꢀside radical addition transition states are shown in Figure 2. The 5-sulfonylation transition
state TS-p is more stable than the 7ꢀsulfonylation transition state TS-o, indicating the para-regioselectivity in the sulfonylation of quinꢀ
olones.
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Figure 2. The Regioselectivity of copperꢀcatalyzed regioselective
sulfonylation of quinolones (Data in purple is NBO charge).
In summary, we have reported a highly regioselective copper(I)ꢀcatalyzed 5ꢀsulfonation of 8ꢀamino quinoline derivatives via bidentateꢀ
chelation assistance. This method provides a useful tool for the rapid construction of 5ꢀarylsulfonyl substituted quinolines. Moreover, we
have also presented a detailed mechanism for this transformation based on DFT calculations, in which a SETꢀbased CꢀH sulfonation was
proposed. Further applications to other heteroarene systems are currently underway in our laboratory.
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all experiments were performed under argon atmosphere. Solvents were treated with 4 Å
molecular sieves or sodium and distilled prior to use. Flash chromatography was performed on silica gel (40~63 mm) by standard techꢀ
nique. 1H and 13C NMR spectra were recorded on a 400 MHz NMR spectrometer (400 MHz for 1 H and 100 MHz for 13 C). Splitting patꢀ
terns are designated as singlet (s), doublet (d), triplet (t), quartet (q). Splitting patterns that could not be interpreted or easily visualized are
designated as multiple (m). Low resolution mass spectra were recorded using HPLC Mass Spectrometer. High resolution exact mass measꢀ
urements (HRꢀMS) were performed on a TOF spectrometer. Infrared spectra (IR) were reported as wavelength numbers (cmꢀ1). Infrared
spectra were recorded by preparing a KBr pellet containing the title compound. Crystal data were obtained by employing graphite monoꢀ
chromated Mo ꢀ Kα radiation (λ = 1.54178 Å) at 293 (2) K and operating in the φꢀω scan mode. The structure was solved by direct methꢀ
ods SHELXSꢀ97. Quinoline substrates including Nꢀ(quinolinꢀ8ꢀyl)propionamide (1a), 18 Nꢀ(quinolinꢀ8ꢀyl)acetamide (1b), 18 Nꢀ(quinolinꢀ8ꢀ
19
19
19
yl)butyramide (1c), Nꢀ(quinolinꢀ8ꢀyl)isobutyramide (1d), 3ꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)butanamide (1e), Nꢀ(quinolinꢀ8ꢀyl)pivalamide
(1f), 18 2ꢀchloroꢀNꢀ(quinolinꢀ8ꢀyl)acetamide (1g), 20 Nꢀ(quinolinꢀ8ꢀyl)benzamide (1h), 21 4ꢀmethoxyꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1i), 21 4ꢀ
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22
bromoꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1j), 4ꢀnitroꢀNꢀ(quinolinꢀ8ꢀyl)benzamide (1k), Nꢀ(2ꢀmethylquinolinꢀ8ꢀyl)acetamide (1o), Nꢀ(6ꢀ
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22
22
methylquinolinꢀ8ꢀyl)acetamide (1p),
Nꢀ(2ꢀchloroquinolinꢀ8ꢀyl)acetamide (1q),
Nꢀ(6ꢀchloroquinolinꢀ8ꢀyl)acetamide (1r),
Nꢀ
23
24
24
phenylquinolinꢀ8ꢀamine (1l), Nꢀbenzylquinolinꢀ8ꢀamine (1m),
Nꢀmethylquinolinꢀ8ꢀamine (1n), Nꢀ(naphthalenꢀ1ꢀyl)propionamide
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(1v), 25 NꢀmethylꢀNꢀ(quinolinꢀ8ꢀyl)propionamide (1w), 26 and 8ꢀaminoꢀ5,7ꢀdideuteroquinoline (D-1),
reported procedure. All the arylsulfonyl substrates are commercially available.
Procedures for the Preparation of Quinoline Substrates (1s, 1t, 1u and 1x)
were prepared using the previous
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General procedure for the synthesis of 1s, 1t and 1x
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9
To a solution of the corresponding 8ꢀamidoquinoline (0.9 mmol, 1.0 equiv) in CHCl3 (2 mL) was added dropwise the solution of
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CH3COCl (0.9 mmol, 1.0 equiv) in CHCl3 (1.0 mL) at 0℃, and the resulting solution was stirred for 3 h at room temperature. After the
solvent was removed under vacuum, the corresponding resulting residue was then added to 5 mL of saturated aqueous sodium bicarbonate
solution and extracted with CH2Cl2 (3 × 10 mL). The corresponding combined organic layers were dried over Na2SO4 and concentrated.
The resulting crude product was purified by flash column chromatography using 25% to 50％ (v/v) ethyl acetate in petroleum ether as
eluent to afford the desired quinoline substrates (1s, 1t, 1x).
N-(4-Methoxyquinolin-8-yl)acetamide (1s): white solid; m.p. = 119 ꢀ 120 °C; 173 mg, 89% yield. 1H NMR (400 MHz, CDCl3) δ 9.77
(s, 1H), 8.73 (d, J = 7.6 Hz, 1H), 8.59 (d, J = 5.1 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 8.1 Hz, 1H), 6.73 (d, J = 5.1 Hz, 1H), 4.01
(s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.7, 162.6, 149.1, 139.1, 134.2, 126.2, 120.9, 116.8, 115.5, 100.7, 55.8, 25.1; IR
(KBr): 3347, 2922, 1680, 1529, 1071, 676 cmꢀ1; HRMS (ESI) calcd for [M + Na]+ : C12H12N2NaO2 : 239.0791, found : 239.0798.
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N-(2-Phenylquinolin-8-yl)acetamide (1t): yellow liquid; 213 mg, 87% yield. H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 8.72 (d, J =
7.3 Hz, 1H), 8.03 (dd, J = 14.5, 8.0 Hz, 3H), 7.74 (d, J = 8.5 Hz, 1H), 7.55 ꢀ7.44 (m, 3H), 7.43 ꢀ 7.34 (m, 2H), 2.29 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 168.6, 154.9, 138.9, 137.7, 137.1, 134.5, 129.6, 128.9, 127.4, 127.1, 126.7, 121.2, 119.1, 116.6, 25.2; IR (KBr): 3352,
2920, 1735, 1528, 1171, 762 cmꢀ1; HRMS (ESI) calcd for [M + H]+ : C17H15N2O : 263.1179, found : 263.1181.
N-(5,6-Dimethylquinolin-8-yl)acetamide (1x): brown solid; m.p. = 80.2 – 80.3 ℃; 177 mg, 92% yield. 1H NMR (400 MHz, CDCl3) δ
9.68 (s, 1H), 8.65 (s, 1H), 8.54 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.38 – 7.31 (m, 1H), 2.41 (s, 6H), 2.30 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 168.6, 146.4, 137.3, 134.6, 132.3, 132.0, 127.1, 125.0, 121.0, 119.4, 25.1, 21.0, 13.6. IR (KBr): 3444, 2962, 1760, 1442, 1380,
776 cm ꢀ1. HRMS (ESI) calcd for [M + H]+ : C13H15N2O : 215.1179, found : 215.1188
N-[2-(Phenylethynyl)quinolin-8-yl]acetamide (1u):
Step 1 29: Et3N (3 mmol, 1.5 equiv) in MeCN (4 mL) was added to the solution of 2ꢀchloroꢀ8ꢀnitroquinoline (2 mmol, 1.0 equiv), termiꢀ
nal alkyne (2.2 mmol, 1.1 equiv), PdCl2(PPh3)2 (1 mol %) and CuI (3 mol %). The mixture was then refluxed under Ar atmosphere for 16 h
at 110℃. After the solvent was removed under vacuum, and 1 mL of H2O was added, then the resulting residue was extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated. The resulted residue was further purified by flash
column chromatography using 20％(v/v) ethyl acetate in petroleum ether as eluent to afford 8ꢀnitroꢀ2ꢀphenylethynylꢀquinoline (1u-1) as a
brown oil (493 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.3 Hz, 1H), 7.99 (t, J = 8.1 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.65 ꢀ
7.52 (m, 3H), 7.48 ꢀ 7.32 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 147.7, 146.0, 139.6, 136.1, 132.4, 131.7, 129.6, 128.5, 127.7, 126.3,
125.6, 124.3, 121.7, 92.2, 89.1; IR (KBr): 3467, 2921, 2209, 1636, 1145, 756 cmꢀ1; HRMS (ESI) calcd for [M + H]+ : C17H11N2O2 :
275.0815, found : 275.0818.
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Step 2: Fe (18 mmol, 10.0 equiv) and NH4Cl (21.6 mmol, 12.0 equiv) was added to the solution of 1u-1 (1.8 mmol, 1.0 equiv) in
CH3CH2OH : H2O (2:1), and the mixture was refluxed for 2 h at 100℃. Then 2 mL of saturated aqueous sodium bicarbonate solution was
added, and then corresponding was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over Na2SO4 and
concerted in vacuum, the resulting crude products were purified by flash chromatography on silical gel using 25％ (v/v) ethyl acetate in
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petroleum ether as eluent to afford 2ꢀphenylethynylꢀquinolinꢀ8ꢀylamine (1u-2) as a brown oil (246 mg, 56%). 1H NMR (400 MHz, CDCl3)
δ 7.97 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 2.5 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 1.7 Hz, 3H), 7.29 (t, J = 7.9 Hz, 1H), 7.06 (d, J =
8.1 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 5.06 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 143.9, 140.4, 138.4, 136.0, 132.2, 129.1, 128.5, 128.3,
127.8, 124.6, 122.4, 115.6, 110.5, 89.9, 89.2; IR (KBr): 3472, 2921, 2209, 1599, 1155, 752 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ :
C17H13N2 : 245.1073, found : 245.1073.
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Step 3: The solution of CH3COCl(1 mmol, 1.0 equiv) in CHCl3 (1 mL) was added dropwise to a solution of 1u-2 (1 mmol, 1.0 equiv) in
CHCl3 (2 mL) at 0℃, and the resulting solution was stirred for 3 h at room temperature. After the solvent was removed under vacuum, 5
mL of saturated aqueous sodium bicarbonate solution was added to the corresponding resulting residue, and the corresponding mixture was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuum. The resulting crude
product was purified by flash column chromatography using 25％ (v/v) ethyl acetate in petroleum ether as eluent to afford 1u as a white
solid.
N-[2-(Phenylethynyl)quinolin-8-yl]acetamide (1u): white solid; m.p. = 102 ꢀ 103℃; 286 mg, 89% yield. 1H NMR (400 MHz, CDCl3)
δ 9.70 (s, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.71 ꢀ 7.63 (m, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H),
7.42 (dd, J = 14.0, 6.6 Hz, 4H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 141.4, 138.2, 136.4, 134.2, 132.2, 129.4, 128.5, 128.1,
126.8, 124.9, 121.9, 121.2, 117.0, 90.3, 89.3, 25.2; IR (KBr) : 3467, 2920, 2190, 1632, 1240, 678 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ :
C19H15N2O : 287.1179, found : 287.1182.
General procedure for the synthesis of the compound 3aꢀ3z, 33a, 33b, 33c and 33d
The reaction mixture of Nꢀ(quinolinꢀ8ꢀyl) carboxamide 1 (0.1 mmol, 1.0 equiv), arylsulfonyl chlorides 2 (0.15 mmol, 1.5 equiv), K2CO3
(0.2 mmol, 2 equiv) and CuBr (0.01 mmol, 10 mol %) in 1.0 mL of DCE in a tube was stirred under Ar atmosphere at 100 °C for 12 h,
and the reaction progress was monitored by TLC method. After the starting materials disappeared, the corresponding reaction mixture was
then cooled down to room temperature and 1.0 mL of H2O was added, and then extracted with CH2Cl2 (3×10 mL). The corresponding
combined organic layers were dried over Na2SO4 and concentrated under vacuum, the resulting crude products were purified by flash
chromatography on silical gel using 25％(v/v) ethyl acetate in petroleum ether as eluent to afford the desired 3.
1
N-(5-Tosylquinolin-8-yl)propionamide (3a): yellow solid; m.p. = 153 ꢀ 154℃; 27.6 mg, 78% yield. H NMR (400 MHz, CDCl3) δ
10.01 (s, 1H), 9.03 (d, J = 8.6 Hz, 1H), 8.84 (d, J = 8.4 Hz, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H),
7.57 ꢀ 7.50 (m, 1H), 7.25 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 148.6, 144.2, 139.8, 139.0,
137.9, 133.4, 131.9, 129.9, 129.1, 127.3, 124.2, 123.3, 114.0, 25.2, 21.5; IR (KBr) : 3416, 3132, 1648, 1400, 1148, 621 cmꢀ1; HRMS (ESI)
calcd for [M + H]+ : C19H19N2O3S : 355.1111, found : 355.1114.
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N-[5-(Phenylsulfonyl)quinolin-8-yl]propionamide (3b): yellow solid; m.p. = 195.5 ꢀ 195.7℃; 27.5 mg, 81% yield. 1H NMR (400 MHz,
CDCl3) δ 10.07 (s, 1H), 9.04 (d, J = 8.6 Hz, 1H), 8.90 (d, J = 8.3 Hz, 1H), 8.82 (s, 1H), 8.53 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 7.4 Hz, 2H),
7.54 (dd, J = 12.4, 6.0 Hz, 2H), 7.48 (t, J = 7.2 Hz, 2H), 2.64 (q, J = 7.3 Hz, 2H), 1.34 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.9, 148.6, 141.9, 140.1, 137.9, 133.3, 133.1, 132.3, 129.3, 128.5, 127.1, 124.2, 123.3, 114.0, 31.3, 9.5; IR (KBr) : 3483, 3129, 1694,
1313, 1147, 723 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C18H17N2O3S : 341.0954, found : 341.0960.
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N-[5-(m-Tolylsulfonyl)quinolin-8-yl]propionamide (3c): yellow solid; m.p. = 198 ꢀ 198.7℃; 24 mg, 68% yield. H NMR (400 MHz,
CDCl3) δ 10.05 (s, 1H), 9.03 (d, J = 8.5 Hz, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 8.4 Hz, 1H), 7.75 (d, J =
7.2 Hz, 1H), 7.70 (s, 1H), 7.55 (dd, J = 8.5, 4.0 Hz, 1H), 7.38 ꢀ 7.30 (m, 2H), 2.62 (q, J = 7.4 Hz, 2H), 2.36 (s, 3H), 1.33 (t, J = 7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 172.9, 148.6, 141.8, 140.0, 139.6, 138.0, 134.0, 133.4, 132.2, 129.1, 128.6, 127.5, 124.3, 123.3, 114.0,
31.3, 21.4, 9.5; IR (KBr) :3412, 3129, 1700, 1316, 1145, 699 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C19H19N2O3S : 355.1111, found :
355.1117.
N-[5-(o-Tolylsulfonyl)quinolin-8-yl]propionamide (3d): yellow solid; m.p. = 179.7 ꢀ 180.6℃; 21.9 mg, 62% yield. 1H NMR (400
MHz, CDCl3) δ 10.08 (s, 1H), 8.90 (d, J = 8.3 Hz, 1H), 8.82 (dd, J = 9.8, 6.2 Hz, 2H), 8.48 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H),
7.50 (dd, J = 8.5, 4.0 Hz, 1H), 7.47 ꢀ 7.34 (m, 2H), 7.19 (d, J = 7.0 Hz, 1H), 2.64 (dd, J = 14.7, 7.2 Hz, 2H), 2.41 (s, 3H), 1.34 (t, J = 7.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.0, 148.6, 139.9, 139.6, 138.0, 137.9, 133.6, 133.2, 133.0, 132.7, 128.9, 128.1, 126.5, 124.2,
123.2, 113.6, 31.3, 20.1, 9.5; IR (KBr): 3321, 3062, 1697, 1315, 1149, 702 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C19H19N2O3S :
355.1111, found : 355.1112.
N-{5-[(4-Methoxyphenyl)sulfonyl]quinolin-8-yl}propionamide (3e): yellow solid; m.p. = 186.2℃; 30.7 mg, 83% yield. 1H NMR
(400 MHz, CDCl3) δ 10.03 (s, 1H), 9.04 (d, J = 8.6 Hz, 1H), 8.86 (d, J = 8.4 Hz, 1H), 8.80 (d, J = 3.1 Hz, 1H), 8.45 (d, J = 8.4 Hz, 1H),
7.86 (d, J = 8.7 Hz, 2H), 7.54 (dd, J = 8.7, 4.1 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 3.80 (s, 3H), 2.62 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.5 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 172.9, 163.3, 148.6, 139.7, 138.0, 133.4, 133.4, 131.7, 129.5, 129.4, 124.1, 123.2, 114.5, 114.0, 55.6,
31.3, 9.5; IR (KBr): 3411, 3129, 1700, 1315, 1144, 699 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C19H19N2O4S: 371.1060, found :
371.1063.
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N-{5-[(4-Chlorophenyl)sulfonyl]quinolin-8-yl}propionamide (3f): yellow solid; m.p. = 162.3 ꢀ 162.9℃; 27 mg, 72% yield. H NMR
(400 MHz, CDCl3) δ 10.06 (s, 1H), 8.99 (d, J = 8.7 Hz, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.83 (d, J = 2.8 Hz, 1H), 8.50 (d, J = 8.4 Hz, 1H),
7.86 (d, J = 8.4 Hz, 2H), 7.57 (dd, J = 8.6, 4.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 2.63 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.5 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 173.0, 148.7, 140.5, 140.3, 139.8, 138.0, 133.1, 132.5, 129.6, 128.6, 128.0, 124.2, 123.5, 114.0, 31.3, 9.5; IR
(KBr) : 3442, 3133, 1670, 1314, 1140, 703 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C18H16ClN2O3S: 375.0565, found : 375.0567.
N-{5-[(4-Bromophenyl)sulfonyl]quinolin-8-yl}propionamide (3g): yellow solid; m.p. = 167.6 ꢀ 167.7℃; 32 mg, 77% yield. 1H NMR
(400 MHz, CDCl3) δ 10.05 (s, 1H), 8.98 (d, J = 8.6 Hz, 1H), 8.88 (d, J = 8.4 Hz, 1H), 8.82 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H),
7.78 (d, J = 8.3 Hz, 2H), 7.57 (dd, J = 16.1, 6.3 Hz, 3H), 2.63 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
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173.0, 148.7, 141.1, 140.3, 138.0, 133.1, 132.6, 132.5, 128.7, 128.3, 127.9, 124.1, 123.5, 114.0, 31.3, 9.5; IR (KBr): 3405, 3089, 1699,
1313, 1142, 686 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C18H16BrN2O3S: 419.0060, found : 419.0059.
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N-[5-(Naphthalen-2-ylsulfonyl)quinolin-8-yl]propionamide (3h): yellow solid; m.p. = 160.4℃; 29.2 mg, 75% yield. 1H NMR (400
MHz, CDCl3) δ 10.01 (s, 1H), 9.07 (d, J = 8.7 Hz, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.74 (s, 1H), 8.65 ꢀ 8.46 (m, 2H), 7.93 (d, J = 5.9 Hz, 1H),
7.79 (dd, J = 26.7, 8.6 Hz, 3H), 7.55 (s, 2H), 7.49 (dd, J = 8.2, 3.7 Hz, 1H), 2.61 (q, J = 7.4 Hz, 2H), 1.31 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 173.0, 148.6, 140.1, 138.8, 137.9, 134.9, 133.2, 132.4, 132.1, 129.7, 129.3, 129.2, 128.4, 127.9, 127.7, 124.2, 123.4,
122.3, 114.0, 31.3, 9.5; IR (KBr): 3414, 3113, 1699, 1314, 1146, 682 cmꢀ1; HRMS (ESI) calcd for [M + H]+ : C22H19N2O3S: 391.1111,
found : 391.1116.
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N-{5-[4-(Trifluoromethyl)phenyl)sulfonyl]quinolin-8-yl}propionamide (3i): yellow solid; m.p. = 196.4 ꢀ 197.1℃; 22 mg, 54% yield.
1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 9.01 (d, J = 8.6 Hz, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.85 (d, J = 2.7 Hz, 1H), 8.56 (d, J = 8.4
Hz, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.59 (dd, J = 8.6, 4.1 Hz, 1H), 2.65 (q, J = 7.5 Hz, 2H), 1.35 (t, J = 7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 173.0, 148.8, 145.6, 140.6, 138.0, 133.0, 132.9, 127.7, 127.2, 126.5, 126.5, 126.4, 126.4, 124.3, 123.6,
114.0, 31.3, 9.4; IR (KBr) : 3409, 3126, 1756, 1318, 1139, 706 cmꢀ1; HRMS (ESI) calcd for [M + H]+ : C19H16F3N2O3S: 409.0828, found :
409.0833.
N-[5-(4-Nitrophenyl)sulfonyl)quinolin-8-yl]propionamide (3j): yellow solid; m.p. = 204.6 ꢀ 205℃; 20 mg, 52% yield. 1H NMR (400
MHz, CDCl3) δ 10.10 (s, 1H), 9.01 (d, J = 8.6 Hz, 1H), 8.96 (d, J = 8.5 Hz, 1H), 8.88 (s, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.32 (d, J = 7.3 Hz,
2H), 8.13 (d, J = 7.5 Hz, 2H), 7.64 ꢀ 7.58 (m, 1H), 2.70 ꢀ 2.61 (m, 2H), 1.35 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.0,
150.2, 148.9, 147.8, 140.9, 138.0, 133.4, 132.8, 128.4, 126.6, 124.5, 124.3, 123.7, 114.1, 31.3, 9.4; IR (KBr): 3412, 3115, 1623, 1318,
1146, 618 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C18H16N3O5S: 386.0805, found : 386.0804.
N-(5-Tosylquinolin-8-yl)acetamide (3k): yellow solid; m.p. = 175.1 ꢀ 175.4℃; 24 mg, 71% yield. 1H NMR (400 MHz, CDCl3) δ 10.01
(s, 1H), 9.03 (d, J = 8.6 Hz, 1H), 8.84 (d, J = 8.4 Hz, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.57
ꢀ 7.50 (m, 1H), 7.25 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 148.6, 144.2, 139.8, 139.0, 137.9,
133.4, 131.9, 129.9, 129.1, 127.3, 124.2, 123.3, 114.0, 25.2, 21.5; IR (KBr) : 3340, 3118, 1698, 1314, 1146, 685 cm ꢀ1; HRMS (ESI) calcd
for [M + H]+ : C18H17N2O3S: 341.0954, found : 341.0955.
N-(5-Tosylquinolin-8-yl)butyramide (3l): yellow solid; m.p. = 150.2 ꢀ 150.3℃; 24.3 mg, 66% yield. 1H NMR (400 MHz, CDCl3) δ
10.03 (s, 1H), 9.04 (d, J = 8.7 Hz, 1H), 8.88 (d, J = 8.4 Hz, 1H), 8.81 (d, J = 2.1 Hz, 1H), 8.49 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 7.7 Hz, 2H),
7.54 (dd, J = 8.3, 3.7 Hz, 1H), 7.25 (d, J = 7.8 Hz, 2H), 2.56 (t, J = 7.3 Hz, 2H), 2.36 (s, 3H), 1.85 (dd, J = 14.7, 7.3 Hz, 2H), 1.05 (t, J =
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2, 148.6, 144.1, 139.9, 139.1, 138.0, 133.4, 132.0, 129.9, 129.0, 127.3, 124.2, 123.2,
114.0, 40.1, 21.5, 18.9, 13.7; IR (KBr) : 3337, 2923, 1697, 1315, 1146, 688 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C20H21N2O3S:
369.1267, found : 369.1271.
N-(5-Tosylquinolin-8-yl)isobutyramide (3m): yellow solid; m.p. = 186.4 ꢀ 187℃; 25 mg, 68% yield. 1H NMR (400 MHz, CDCl3) δ
10.13 (s, 1H), 9.04 (d, J = 8.7 Hz, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.82 (d, J = 3.6 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 7.8 Hz, 2H),
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7.55 (dd, J = 8.6, 4.0 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 2.78 (dt, J = 13.7, 6.8 Hz, 1H), 2.36 (s, 3H), 1.35 (d, J = 6.8 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 176.2, 148.6, 144.1, 140.0, 139.1, 138.2, 133.5, 132.1, 129.9, 129.0, 127.2, 124.2, 123.2, 114.1, 37.2, 21.5, 19.5; IR
(KBr) : 3442, 3136, 1667, 1333, 1149, 674 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C20H21N2O3S: 369.1267, found : 369.1279.
3-Methyl-N-(5-tosylquinolin-8-yl)butanamide (3n): yellow oil; 27.1 mg, 71% yield. 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 9.04
(d, J = 8.7 Hz, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.81 (d, J = 4.0 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.54 (dd, J = 8.6,
4.0 Hz, 1H), 7.25 (d, J = 7.9 Hz, 2H), 2.45 (d, J = 7.1 Hz, 2H), 2.35 (s, 3H), 2.29 (dd, J = 13.3, 6.7 Hz, 1H), 1.06 (d, J = 6.5 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 171.7, 148.6, 144.1, 139.8, 139.1, 138.0, 133.4, 132.0, 129.9, 129.0, 127.3, 124.2, 123.2, 114.1, 47.5, 26.2,
22.5, 21.5; IR (KBr) : 3342, 3130, 1695, 1315, 1145, 684 cmꢀ1; HRMS (ESI) calcd for [M + H]+ : C21H23N2O3S: 383.1424, found :
383.1426.
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N-(5-Tosylquinolin-8-yl)pivalamide (3o): yellow solid; m.p. = 179.2 ꢀ 179.4℃; 26 mg, 68% yield. 1H NMR (400 MHz, CDCl3) δ 10.50
(s, 1H), 9.04 (d, J = 8.7 Hz, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.84 (d, J = 3.4 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 7.7 Hz, 2H), 7.56
(dd, J = 8.5, 3.9 Hz, 1H), 7.25 (d, J = 7.8 Hz, 2H), 2.34 (s, 3H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 177.7, 148.7, 144.1, 140.1,
139.1, 138.5, 133.4, 132.0, 129.9, 128.9, 127.9, 127.2, 124.2, 123.3, 113.9, 40.6, 27.6, 21.5; IR (KBr) : 3340, 3123, 1681, 1311, 1145, 690
cmꢀ1; HRMS (ESI) calcd for [M + H]+ : C21H23N2O3S: 383.1424, found : 383.1427.
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2-Chloro-N-(5-tosylquinolin-8-yl)acetamide (3p): yellow solid; m.p. = 165.3 ꢀ 165.6℃; 26.2 mg, 70% yield. H NMR (400 MHz,
CDCl3) δ 11.09 (s, 1H), 9.05 (d, J = 8.7 Hz, 1H), 8.89 ꢀ 8.80 (m, 2H), 8.48 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.56 (dd, J = 8.5,
4.0 Hz, 1H), 7.26 (d, J = 7.5 Hz, 2H), 4.32 (s, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.0, 149.1, 144.3, 138.8, 138.8, 138.5,
133.4, 131.6, 130.5, 129.9, 127.3, 124.2, 123.4, 114.4, 43.3, 21.5; IR (KBr) : 3355, 3052, 1685, 1325, 1175, 682 cmꢀ1; HRMS (ESI) calcd
for [M + H]+ : C18H16ClN2O3S: 375.0565, found : 375.0568.
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N-(5-Tosylquinolin-8-yl)benzamide (3q): yellow solid; m.p. = 168.1 ꢀ 168.6℃; 28.1 mg, 70% yield. H NMR (400 MHz, CDCl3) δ
10.96 (s, 1H), 9.05 (dd, J = 16.7, 8.5 Hz, 2H), 8.86 (d, J = 2.5 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 7.1 Hz, 2H), 7.84 (d, J = 8.1
Hz, 2H), 7.58 (dd, J = 14.9, 6.9 Hz, 4H), 7.26 (d, J = 7.7 Hz, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 148.8, 144.2, 139.9,
139.0, 138.5, 134.3, 133.5, 132.5, 132.0, 129.9, 129.4, 129.0, 127.4, 127.3, 124.3, 123.4, 114.2, 21.5; IR (KBr) : 3442, 3118, 1698, 1314,
1147, 686 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C23H19N2O3S: 403.1111, found : 403.1114.
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4-Methoxy-N-(5-tosylquinolin-8-yl)benzamide (3r): yellow solid; m.p. = 186.9 ꢀ 187.1℃; 34.6 mg, 80% yield. H NMR (400 MHz,
CDCl3) δ 10.89 (s, 1H), 9.07 (d, J = 8.7 Hz, 1H), 9.01 (d, J = 8.4 Hz, 1H), 8.87 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.3 Hz, 2H),
7.84 (d, J = 7.8 Hz, 2H), 7.57 (dd, J = 8.4, 3.8 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 3.89 (s, 3H), 2.36 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 165.1, 163.0, 148.7, 144.1, 140.2, 139.1, 138.4, 133.5, 132.1, 129.9, 129.4, 129.0, 127.3, 126.5, 124.3, 123.3,
114.2, 114.0, 55.5, 21.5; IR (KBr) : 3442, 3128, 1676, 1315, 1145, 684 cmꢀ1; HRMS (ESI) calcd for [M + H]+ : C24H21N2O4S: 433.1217,
found : 433.1213.
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4-Bromo-N-(5-tosylquinolin-8-yl)benzamide (3s): yellow solid; m.p. = 185.9 ꢀ 186.2℃; 36.5 mg, 76% yield. H NMR (400 MHz,
CDCl3) δ 10.91 (s, 1H), 9.08 (d, J = 8.7 Hz, 1H), 8.99 (d, J = 8.3 Hz, 1H), 8.87 (s, 1H), 8.54 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 7.6 Hz, 2H),
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7.83 (d, J = 7.6 Hz, 2H), 7.69 (d, J = 7.6 Hz, 2H), 7.58 (dd, J = 8.0, 3.8 Hz, 1H), 7.27 (d, J = 6.9 Hz, 2H), 2.36 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 164.7, 148.8, 144.2, 139.6, 139.0, 138.4, 133.6, 133.2, 132.2, 132.0, 129.9, 129.7, 129.0, 127.3, 124.3, 123.4, 114.4, 21.5;
IR (KBr) : 3442, 3131, 1681, 1318, 1145, 682 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C23H18BrN2O3S: 481.0216, found : 481.0211.
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4-Nitro-N-(5-tosylquinolin-8-yl)benzamide (3t): yellow solid; m.p. = 169.5 ꢀ 169.7 ℃; 33.5 mg, 75% yield. H NMR (400 MHz,
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8.1 Hz, 2H), 8.23 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 7.9 Hz, 2H), 7.61 (dd, J = 8.5, 4.0 Hz, 1H), 7.28 (d, J = 8.3 Hz, 2H), 2.37 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 163.5, 150.1, 149.0, 144.4, 139.8, 139.1, 138.8, 138.4, 133.8, 131.8, 130.5, 130.0, 128.6, 127.4, 124.3, 124.2,
123.5, 114.7, 21.5; IR (KBr) :3442, 3125, 1691, 1316, 1146, 684 cm ꢀ1; HRMS (ESI) calcd for [M + Na]+ : C23H17N3NaO5S: 470.0781,
found : 470.0787.
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N-Benzyl-5-tosylquinolin-8-amine (3v): yellow solid; m.p. = 161.1 ꢀ 161.3℃; 30.6 mg, 79% yield. 1H NMR (400 MHz, CDCl3) δ 8.55
(d, J = 2.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.57 (t, J = 6.8 Hz, 3H), 7.38 (t, J = 7.7 Hz, 1H), 7.29 (dd, J = 8.2,
4.0 Hz, 1H), 7.14 (dd, J = 17.0, 7.7 Hz, 7H), 5.21 (s, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.4, 145.1, 142.7, 137.3, 137.3,
136.2, 135.4, 134.2, 129.3, 128.9, 128.7, 128.6, 128.1, 128.0, 127.3, 126.1, 121.0, 54.8, 21.5; IR (KBr) : 3442, 3137, 1667, 1400, 1153,
678 cmꢀ1; HRMS (ESI) calcd for [M + H]+ : C23H21N2O2S: 389.1318, found : 389.1315.
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N-Methyl-5-tosylquinolin-8-amine (3w): yellow oil; 25.9 mg, 80% yield. H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.14 (d, J = 8.2
Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.0 Hz, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.37 ꢀ 7.31 (m, 1H), 7.19 (d, J
= 7.6 Hz, 2H), 3.50 (s, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.7, 145.3, 142.9, 138.5, 136.4, 136.1, 131.3, 129.5, 129.0,
128.5, 128.0, 126.2, 121.2, 39.3, 21.5; IR (KBr) : 3341, 3115, 1696, 1315, 1149, 685 cm ꢀ1; HRMS (ESI) calcd for [M + H]+
C17H17N2O2S: 313.1005, found : 313.1013.
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N-(2-Methyl-5-tosylquinolin-8-yl)acetamide (3x): yellow solid; m.p. = 193.3 ꢀ 193.6℃; 27.3 mg, 77% yield. 1H NMR (400 MHz,
CDCl3) δ 10.04 (s, 1H), 8.89 (d, J = 8.8 Hz, 1H), 8.80 (d, J = 8.3 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.39 (d, J =
8.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 2H), 2.71 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.1, 158.0, 144.0, 139.2,
137.4, 133.3, 130.8, 129.8, 129.0, 127.2, 124.1, 122.3, 114.0, 25.2, 25.0, 21.5; IR (KBr) : 3442, 3129, 1695, 1306, 1147, 695 cm ꢀ1; HRMS
(ESI) calcd for [M + H]+ : C19H19N2O3S: 355.1111, found : 355.1110.
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N-(6-Methyl-5-tosylquinolin-8-yl)acetamide (3y)：yellow solid; m.p. = 197.4 ꢀ 198.2℃; 27.3 mg, 77% yield. H NMR (400 MHz,
CDCl3) δ 10.01 (s, 1H), 9.53 (dd, J = 9.0, 1.4 Hz, 1H), 8.74 (dd, J = 4.1, 1.3 Hz, 1H), 8.68 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.51 (dd, J =
9.0, 4.1 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 2.90 (s, 3H), 2.36 (d, J = 1.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 169.2, 147.5, 143.9, 143.8,
140.6, 138.8, 136.8, 134.0, 129.7, 126.4, 126.1, 126.1, 123.0, 120.1, 25.2, 24.0, 21.5; IR (KBr) : 3316, 2922, 2853, 1695, 1297, 679 cmꢀ1;
HRMS (ESI) calcd for [M + H]+ : C19H19N2O3S: 355.1111, found : 355.1113.
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N-(2-Chloro-5-tosylquinolin-8-yl)acetamide (3z): yellow solid; m.p. = 223.1 ꢀ 224℃; 28.0 mg, 75% yield. H NMR (400 MHz,
CDCl3) δ 9.59 (s, 1H), 9.03 (d, J = 9.0 Hz, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.44 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 9.0
Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 2.38 (s, 3H), 2.37 (s, 3H); 13C NMR (100MHz, CDCl3) δ 169.2, 150.2, 144.4, 138.9, 138.7, 137.8, 136.4,
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131.9, 130.0, 129.6, 127.3, 124.6, 122.9, 115.5, 25.3, 21.5; IR (KBr) :3362, 2923, 2854, 1701, 1322, 691 cmꢀ1; HRMS (ESI) calcd for [M +
H]+ : C18H16ClN2O3S: 375.0565, found : 375.0561.
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N-(6-Chloro-5-tosylquinolin-8-yl)acetamide (33a): yellow solid; m.p. = 229 ꢀ 230℃; 26.2 mg, 70% yield. H NMR (400 MHz,
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CDCl3) δ 10.04 (s, 1H), 9.92 (d, J = 9.0 Hz, 1H), 8.82 (d, J = 4.3 Hz, 2H), 7.83 (d, J = 7.9 Hz, 2H), 7.65 (dd, J = 8.9, 3.9 Hz, 1H), 7.27 (d,
J = 6.7 Hz, 2H), 2.39 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.1, 148.2, 144.3, 139.5, 139.4, 138.1, 136.4, 134.2, 129.5,
127.4, 127.2, 126.3, 123.8, 118.7, 25.2, 21.6; IR (KBr) : 3389, 2921, 1704, 1307, 1150, 678 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ :
C18H16ClN2O3S: 375.0565, found : 375.0568.
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N-[4-Methoxy-5-(thiophen-2-ylsulfonyl)quinolin-8-yl]acetamide (33b): yellow solid; m.p. = 233.3 ꢀ 233.6 ℃; 25.7 mg, 74% yield.
1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 8.80 (d, J = 8.4 Hz, 1H), 8.64 (d, J = 4.4 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 7.56 (s, 2H), 7.06
(s, 1H), 6.90 (d, J = 4.3 Hz, 1H), 3.88 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2, 162.1, 149.6, 145.3, 140.0, 139.6, 133.0,
131.3, 131.0, 129.9, 127.0, 118.1, 114.0, 104.2, 55.5, 25.2; IR (KBr) : 3469, 3105, 2920, 1683, 1313, 671 cm ꢀ1; HRMS (ESI) calcd for [M
+ H]+ : C16H15N2O4S2: 363.0468, found : 363.0478.
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N-[2-Phenyl-5-(thiophen-2-ylsulfonyl)quinolin-8-yl]acetamide (33c): yellow solid; m.p. = 206.6 ꢀ 207.3℃; 28.5 mg, 70% yield. H
NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 9.27 (d, J = 9.0 Hz, 1H), 8.86 (d, J = 8.4 Hz, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.14 ꢀ 8.01 (m, 3H),
7.74 (d, J = 3.1 Hz, 1H), 7.61 ꢀ 7.52 (m, 4H), 7.05 (t, J = 4.2 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.0, 155.9, 143.9,
139.2, 135.3, 134.9, 134.2, 133.4, 133.0, 129.2, 129.0, 127.7, 127.5, 127.2, 126.8, 121.3, 119.4, 116.7, 25.2; IR (KBr) : 3502, 3106, 2919,
1633, 1335, 690 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C21H17N2O3S2: 409.0675, found : 409.0678.
N-[2-(Phenylethynyl)-5-tosylquinolin-8-yl]acetamide (33d): yellow solid; m.p. = 210.7 ꢀ 210.9℃; 32.1 mg, 73% yield. 1H NMR (400
MHz, CDCl3) δ 9.95 (s, 1H), 9.05 (d, J = 8.9 Hz, 1H), 8.91 (d, J = 8.4 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.72 (d, J
= 9.0 Hz, 1H), 7.67 (d, J = 7.7 Hz, 2H), 7.45 (t, J = 6.5 Hz, 3H), 7.30 (s, 2H), 2.43 (s, 3H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
169.3, 144.3, 142.1, 139.3, 138.9, 138.0, 133.5, 132.2, 129.9, 129.7, 129.2, 128.6, 127.3, 126.6, 123.1, 121.5, 114.7, 91.8, 88.4, 25.4, 21.5;
IR (KBr) : 3469, 3105, 2236, 1728, 1303, 733 cm ꢀ1; HRMS (ESI) calcd for [M + H]+ : C26H21N2O3S: 441.1267, found : 441.1268.
5-(Phenylsulfonyl)quinolin-8-amine ( 3b-1 ): To a solution of 3b (0.1 mmol) in 2 mL of EtOH and H2O(v/v= 3 : 1), 0.5 mL of hydroꢀ
chloric acid (1 M) was added. The mixture was refluxed for 5 h, and then 5mL of saturated aqueous sodium bicarbonate solution and
10mL of ethyl acetate were added. The corresponding organic layer was separated and concentrated under reduced pressure. The resulting
crude product was purified by flash chromatography on silica gel using 50％(v/v) ethyl acetate in petroleum ether as eluent to afford the
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product 3b-1 as white solid. M.p. = 159 – 160 ℃; 26 mg, 93% yield. H NMR (400 MHz, CDCl3) δ 8.88 (dd, J = 8.7, 1.5 Hz, 1H), 8.70
(dd, J = 4.1, 1.4 Hz, 1H), 8.32 (d, J = 8.3 Hz, 1H), 7.94 – 7.86 (m, 2H), 7.49 – 7.40 (m, 4H), 6.88 (d, J = 8.4 Hz, 1H), 5.73 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 150.1, 147.6, 143.1, 137.3, 133.1, 132.7, 132.6, 129.1, 126.8, 125.5, 123.3, 120.9, 106.5. IR (KBr): 3500, 3015,
1622, 1588, 1153, 776 cm ꢀ1. HRMS (ESI) calcd for [M + H]+ : C15H13N2O2S, 285.0692, found : 285.0691.
Procedure for the synthesis of the isotopically-labeled substrate D-1a
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The mixture of propionic acid (2 mmol, 1.0 equiv.) and SOCl2 (3 mmol, 1.5 equiv.) was stirred in CHCl3 (2.0 mL) at 80 oC for 2 h under
Ar atmosphere in a sealed reaction tube. After cooling down to room temperature, Et3N (2 mmol, 1.0 equiv.) and 8ꢀaminoꢀ5,7ꢀ
dideuteroquinoline (D-1) (2 mmol, 1.0 equiv.) were added to the reaction mixture. Then the corresponding mixture was stirred at 25℃ for
3 h. The mixture was cooled down to room temperature and 5 mL of saturated aqueous sodium bicarbonate solution was added, then the
mixture was extracted with CH2Cl2 (3 × 10 mL). After the combined organic layers were dried over Na2SO4, the resulting crude product
was purified by flash chromatography on silical gel using 25％ (v/v) ethyl acetate in petroleum ether as eluent to afford the deuterated
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propionamide (D-1a) as a yellow liquid (360 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 8.78 (d, J = 3.0 Hz, 1H), 8.13 (d, J =
8.1 Hz, 1H), 7.52 (s, 1H), 7.48 (s, 0.10H), 7.46 (s, 0.08H), 7.46 ꢀ 7.39 (m, 1H), 2.59 (q, J = 7.5 Hz, 2H), 1.34 (t, J = 7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.5, 148.1, 138.4, 136.3, 134.5, 127.9, 127.2, 121.5, 121.3, 116.4, 31.2, 9.8; IR (KBr): 3302, 3100, 2962, 1680,
1450, 1375 cmꢀ1. HRMS (ESI) calcd for [M + H]+ : C12H11N2OD2: 203.1148, found : 203.1146.
Mechanistic Studies for Copper-Catalyzed Regioselective C-H Sulfonylation of 8-Aminoquinolines
Trapping of the possible radical intermediates for this reaction
The mixture of Nꢀ(quinolinꢀ8ꢀyl)propionamide 1a (0.1 mmol, 1.0 equiv), arylsulfonyl chlorides 2a (0.15 mmol, 1.5 equiv) , K2CO3 (0.2
mmol, 2 equiv) , CuBr (0.01 mmol, 10 mol %) and 1,1ꢀdiphenylethylene 4a (0.3 mmol, 3.0 equiv) was stirred in DCE (1.0 mL) at 100 oC
for 12 h under Ar atmosphere in a sealed reaction tube. After the corresponding reaction mixture was then cooled down to room temperaꢀ
ture, and 1.0 mL of H2O was added, and then extracted with CH2Cl2 (3 × 10 mL). The corresponding combined organic layers were dried
over Na2SO4 and concentrated under vacuum, the resulting crude products were purified by flash chromatography on silical gel using 50％
(v/v) ethyl acetate in petroleum ether as eluent to afford the compounds 3a (8% yield) and 33h 30 (72% yield).
1-(2,2-Diphenyl-ethenesulfonyl)-4-methyl-benzene (33h) 30 : brown solid; m.p. = 94 – 95 ℃; 24 mg, 72% yield; 1H NMR (400 MHz,
CDCl3) δ 7.47 (d, J = 8.3 Hz, 2H), 7.39 – 7.33 (m, 2H), 7.29 (ddd, J = 7.0, 5.3, 1.3 Hz, 4H), 7.19 (dd, J = 5.3, 3.4 Hz, 2H), 7.14 (d, J = 8.1
Hz, 2H), 7.12 – 7.06 (m, 2H), 6.99 (s, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.7, 143.8, 139.3, 138.7, 135.6, 130.2, 129.8,
129.3, 129.0, 128.8, 128.6, 128.2, 127.8, 127.7, 21.6; IR (KBr): 3011, 2980, 1625, 1428, 1138, 810 cmꢀ1. MS (ESI): m/z = 333.85 [M+].
Kinetic isotope effect experiments 31
Parallel Individual Reactions of 1a and Dꢀ1a: Nꢀ(quinolinꢀ8ꢀyl)propionamide 1a (0.1 mmol, 1.0 equiv) or the isotopicallyꢀlabeled subꢀ
strate D-1a (0.1 mmol, 1.0 equiv), arylsulfonyl chlorides 2a (0.15 mmol, 1.5 equiv) , K2CO3 (0.2 mmol, 2 equiv) and CuBr (0.01 mmol, 10
mol %) were dissolved in 2.5 mL of DCE in a tube, and then the tube was sealed under Ar and heated at 100 °C in an oil bath. Then aliꢀ
quots (0.5 mL) were taken at 2 h intervals after the reaction was performed for 3 h. Each aliquot was removed the solvent under reduced
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pressure and analyzed by H NMR. The H NMR raw data of the reactions of 1a and D-1a was displayed in SI (see SI, Figure S5 and
Figure S10). Comparison of the reaction progress indicated that the corresponding KIE value is 1.01 (see SI, Figure S11).
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Computational Details. All calculations were performed with the Gaussian 09 program.32 DFT calculations using the M06ꢀL funcꢀ
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tional were used to locate all the stationary points involved. The 6ꢀ31G(d,p) basis set is applied for all nonꢀmetal elements and the
SDD pseudopotential 36 is used for Cu and K, which denotes as basis set 1 (BS1). Frequency calculations at the same level have been carꢀ
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ried out to confirm each stationary point to be either a minimum or a transition state. In order to confirm the connection of each transition
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state to its corresponding reactant and product, intrinsic reaction coordinate (IRC) calculation were performed. Based on the optimized
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structures at BS1, we calculated the solvated single point energies at a larger basis set BS2 (the SDD for K, the SDD pseudopotential with
outer p functions and a set of fꢀpolarization functions for Cu, and the 6ꢀ311++G (2d,2p) for the other atoms) to further refine the energetꢀ
ics. Both structure optimizations and single point calculations were carried out with integral equation formalism polarizable continuum
medium (IEFꢀPCM) model.38 The parameters for 1,2ꢀdichloroethane (DCE, ε = 10.36) are used corresponding to the experimental condiꢀ
tions. The radii from the UFF force field with an explicit hydrogen radius were used in these calculations. The solvation free energies were
obtained at the M06ꢀL/BS2/IEFꢀPCM//M06ꢀL/BS1/IEFꢀPCM level of theory.
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ASSOCIATED CONTENT
Supporting Information
NMR spectra, single crystal data of 3b and computational data. This material is available free of charge via the internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: denlin@scut.edu.cn
*Eꢀmail: kezhf3@mail.sysu.edu.cn
*Eꢀmail: zengwei@scut.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the NSFC (No. 21372085 and 21203256) and the GNSF (No. 10351064101000000 and 2015A030306027) for financial
support.
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