H-phosphonate mediated sulfonylation of 2-substituted quinoline N-oxides: One-pot strategy for the synthesis of 3/4-sulfonylquinoline derivatives

Article abstract of DOI:10.1080/10426507.2017.1315422

series of biologically important 3/4-sulfonylquinoline derivatives was synthesized starting from easily available sodium benzenesulfinates, diethyl H-phosphonate and 2-substituted quinoline N-oxides in onepot under metal-free conditions. H-phosphonate plays a decisive role in activating the C₃-H, C₄-H bonds of the 2-substituted quinoline N-oxides. The isolated 3/4-sulfonylquinolines were characterized by ¹H, ¹³CNMR spectroscopy and HR MS.

Full text of DOI:10.1080/10426507.2017.1315422

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
H-phosphonate mediated sulfonylation of 2-
substituted quinoline N-oxides: one-pot strategy
for the synthesis of 3/4-sulfonylquinoline
derivatives
Huili Ma, Shuyun Liu, Shaohua Zhu, Wenzhu Bi, Xiaolan Chen & Yufen Zhao
To cite this article: Huili Ma, Shuyun Liu, Shaohua Zhu, Wenzhu Bi, Xiaolan Chen & Yufen Zhao
(2017): H-phosphonate mediated sulfonylation of 2-substituted quinoline N-oxides: one-pot strategy
for the synthesis of 3/4-sulfonylquinoline derivatives, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2017.1315422
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1315422
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ACCEPTED MANUSCRIPT
H-phosphonate mediated sulfonylation of 2-substituted quinoline N-oxides: one-pot
strategy for the synthesis of 3/4-sulfonylquinoline derivatives
Huili Ma,1 Shuyun Liu,1 Shaohua Zhu,1 Wenzhu Bi,1 Xiaolan Chen,1,* and Yufen Zhao1,2
1
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450001,
China
2 Department of Chemistry, Xiamen University, Xiamen, 361000, China
Corresponding author. Tel.: +86-371-67767051; Fax: +86-371-67767051; E-mail:
chenxl@zzu.edu.cn
Abstract
A series of biologically important 3/4-sulfonylquinoline derivatives was synthesized starting
from easily available sodium benzenesulfinates, diethyl H-phosphonate and 2-substituted
quinoline N-oxides in one-pot under metal-free conditions. H-phosphonate plays a decisive role
in activating the C3-H, C4-H bonds of the 2-substituted quinoline N-oxides. The isolated
3/4-sulfonylquinolines were characterized by 1H, 13C NMR spectroscopy and HR MS.
Keywords
H-phosphonate; 3/4-sulfonylquinolines; sodium benzenesulfinates; C-H activation.
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Introduction
Aromatic sulfones have drawn great attention not only due to their important role in the
synthesis of agrochemicals and pharmaceuticals as protecting and activating groups1, but also
their prominent drug activities2. Among them, 3/4-sulfonylquinolines can be found in various
drugs as potential antidepressant, anxiolytic, and antipsychotic agents, such as compound a and b,
which produced significant antidepressant activity in FST in mice (Scheme 1)3. Compound a,
SB-742457, developed by GlaxoSmithKline, has reached clinical phase II as 5-HT6 receptor
selective antagonists for the treatment of Alzheimer's disease3b. Compound c, a
quinolinesulfonamide derivative of long-chain arylpiperazines (LCAP) produced
antidepressant-like effect in the forced-swim test in mice (Scheme 1)3a.
As to the synthesis of 3/4-sulfonated quinoline derivatives, common methods, including
oxidation of the corresponding aryl sulfides4 or sulfonylation of arenes5, suffer from obvious
drawbacks, such as foul-smelling starting materials and harsh reaction conditions. Ogura’s group
reported
a
novel
intramolecular
cycloaddition
reaction
of
2-(arylamino)-1-(methylthio)-1-tosylethenes to give the 3-tosyl-2-(tosylmethyl)quinolines with
1.1 equivalent of hydrogen iodide in refluxing toluene (Scheme 2a)6. Wróbel’s group developed
a silane-mediated methodology to synthesize 2-phenyl-4-phenylsulfonylbenzo[h]quinolines,
which was realized by employing synthetic equivalents with the nitroarene and allylic compound
bearing an electron withdrawing substituent (Scheme 2b)7. However, these two methods also
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suffers from obvious drawbacks, such as limited reaction scopes and unavailable starting
materials.
Moreover,
Shimada
et
al.
reported
a
direct
synthesis
of
4-(p-toluenesulfonyl)quinolines from 2-methylquinoline N-oxide with 2 equiv. of sodium
p-toluenesulfininate as a sulfur source, in which another 2 equiv. of p-toluenesulfonyl chloride
(MsCl) was needed as activation reagent (Scheme 2c)8. In 2015, our research group reported a
direct strategy for the construction of 2-sulfonyl quinolines/pyridines in one-pot under metal-free
conditions at room temperature9. In this reaction, H-phosphonate plays an important role in
activating the C2-H bond of the 2-unsubstituted quinoline N-oxides. It is well known that quinine,
a 2-unsubstituted quinoline derivative, easily loses efficacy in the body due to oxidation at its C2
position10. So, in the following research exploration, we utilized the 2-substituted quinoline
N-oxides as starting materials to synthesize the pharmaceutical important 3/4-sulfonated
quinoline derivatives3. Herein, we disclose an efficient sulfonylation strategy for the construction
of 3/4-sulfonated 2-substituted quinoline derivatives in one-pot under metal-free conditions. In
this reaction, the inert C3-H, C4-H bonds of the 2-substituted quinoline N-oxides were activated
by diethyl H-phosphonate. Compared with the above mentioned cycloaddition reactions, this
reaction features mild reaction conditions, easily available starting materials, and a broader
reaction scopes (Scheme 2d).
Results and discussion
We initiated the study by establishing optimal experimental conditions using the model
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reaction of 2-methylquinoline N-oxide (1a) and sodium benzenesulfinate (2a) in the presence of
diethyl H-phosphonate, KOH and CCl4 in CH3CN at 70 °C, as summarized in Table 1. The
influence of the reaction time on the model reaction was firstly investigated (entries 1-7).
A high yield of 3a and 4a was obtained when the reaction time was 24 h (63 %) (entry 6). The
yield of 3/4-sulfonated quinoline ceased to increase with a longer reaction time (entry 7). The
influence of various dialkyl H-phosphonates on the model reaction was then evaluated (entry 6,
8-11). Diethyl H-phosphonate still brought out the best yield (entry 6). The ratio of 3a : 4a in the
above mentioned reaction conditions was maintained approximately 2 : 3. Subsequently, the base
employed in this reaction was investigated (entry 6, 12-15). The results showed that weak bases,
K2CO3, NEt3, HNEt2, Na2CO3, cannot trigger the reaction process. The investigation of the
amount of KOH used in the model reaction showed that 4 equiv. of KOH afforded the satisfied
yield. The influence of temperature on the model reaction showed that low temperature (entry 19)
was favorable for the formation of 4-sulfonated quinoline with a ratio of 3a : 4a = 1 : 5, while a
high temperature (entry 21) was favorable for the formation of 3-sulfonated quinoline with a
ratio of 3a : 4a = 1 : 1. However, the overall yield at these two conditions was unsatisfactory.
Finally, the effect of seven solvents (CH3CN, DMSO, DMF, DCE, Toluene, Dioxane, THF, CCl4)
on the model reaction was then investigated, respectively (entries 6, 22-28). No sulfonated
quinoline was detected when the reaction was performed in DMSO, DMF and dioxane (entries
22, 23, 26). Low yield of sulfonated quinoline was obtained with a ratio of 3a : 4a = 1 : 4-5 in
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DCE, toluene, THF and CCl4 (entries 24, 25, 27, 28). Considering that both the 3-sulfonated
quinoline and the 4-sulfonated quinoline were all pharmaceutical important molecules, we
choose the reaction condition of entry 6 as the optimized reaction to synthesize the sulfonated
quinoline derivatives.
Using the optimal conditions, the substrate scope of 2-substituted quinoline N-oxides and
sodium benzenesulfinates was then examined. The results were summarized in Table 2. Sodium
benzenesulfinates with electron withdrawing group (-Cl) and electron donating group (-CH3)
reacted well with 2-methylquinoline N-oxides giving the sulfonated quinoline in moderate to
good yields (3a/4a-3c/4c, 59-81%). Then sodium benzenesulfinate was used to react with
2-methylquinoline N-oxides with both an electron withdrawing group (6-Br, 6-Cl, 6-F) and an
electron donating group (6-CH3, 6-OCH3). The substituted group on the 2-methylquinoline
N-oxides didn’t show much influence on the overall yield of the reaction (3d/4d-3h/4h, 45-61%).
It was mentioned that when 6-methoxy-2-methylquinoline N-oxides was used, only 4-sulfonated
quinoline (4h) was obtained. This phenomenon was shown again in the next experiments giving
4i and 4j in moderate overall yields (65% and 53%). The reason for the exclusively obtained
4-substituted quinolines may be attributed to the strong electron donating group (-OCH3) on the
6 position and (-N(Et)2) on the 2 position of the quinoline rings. Besides 2-methylquinoline
N-oxide derivatives, 2-(diethylamino)quinoline N-oxide and 2-morpholinoquinoline N-oxide
were also utilized in this reaction system, giving the corresponding sulfonated quinoline
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derivatives in moderate yields (3k/4k-3l/4l, 53%-61%).
A plausible mechanism for the sulfonylated reaction is thus proposed accordingly as indicated
in Scheme 3. Initially, as indicated by Atherton-Todd reaction11, diethyl H-phosphonate (1) can
be transformed to diethyl chlorophosphate (2). Then, 2-methylquinoline N-oxide (1a) reacted
with diethyl chlorophosphate (2), through a nucleophilic addition/elimination process, forming
an instable intermediate 3 and a chloride anion. Through path a, the C3 position of the
intermediate 4 (4 is in resonance with 3) was attacked by the nucleophile sulfonyl anion 2a’ (2a’
is in resonance with 2a) and then initiated a multi-electron rearrangement process to the
3-sulfonated 2-methylquinoline. Through path b, the C4 position of the intermediate 8 (8 is in
resonance with 3) was attacked by the nucleophile sulfonyl anion 2a’ and then initiated a
multi-electron rearrangement process to the 4-sulfonated 2-methylquinoline.
Conclusion
In summary, a direct and efficient synthetic methodology has been developed for the
construction of 3/4-sulfonated 2-substituted quinoline derivatives. With the optimized reaction
conditions, 20 new compounds were obtained in moderate to good yields starting from sodium
benzenesulfinates, diethyl H-phosphonate and 2-substituted quinoline N-oxides in one-pot under
metal-free conditions. Compared with previous synthetic methods, this strategy features mild
reaction conditions, easily available starting materials, and a broader reaction scopes.
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Experimental
All the chemicals were obtained from Tianjin Kermel Chemical Reagent Co., Ltd., and
Shanghai Aladdin Bio-Chem Technology Co., Ltd., and used as received. 1H and 13C NMR
spectra were recorded with a Bruker Avance 400 MHz spectrometer operating at 400.13 and
100.61 MHz, respectively, with 13C NMR spectra being recorded with broad band proton
decoupled. All NMR spectra were recorded in CDCl3 at room temperature (20 ± 3 C). 1H and
13C chemical shifts are quoted in parts per million downfield from TMS. High resolution mass
spectra (HR MS) were obtained with a Waters Micromass Q-Tof Micro instrument using the
ESI technique.
General procedure
Synthesis of 3/4-sulfonylquinoline derivatives
2-methylquinoline N-oxides (0.2 mmol), sodium benzenesulfinates (0.8 mmol), diethyl
H-phosphonate (0.055 g, 0.4 mmol), CCl4 (1.0 mL), and KOH (0.045 g, 0.8 mmol) were mixed
in CH3CN (6 mL) in a 50 mL bottom flask. The reaction mixture was heated at 70 °C for 24 h,
then the mixture was cooled to room temperature, diluted with brine and extracted by CH2Cl2 (3
×10 mL). The combined organic layers were dried over anhydrous Na2SO4. The solvent was
removed in vacuum and the two isomers were obtained by column chromatography on silica gel
(vpetroleum ether : vethyl acetate = 20 : 1).
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2-methyl-3-(phenylsulfonyl)quinoline (3a). Yield 25%. White solid. m.p. 144-146 °C. 1H NMR
(CDCl3, 400 MHz) δ: 9.07 (s, 1H, 4-H), 8.04 (d, J = 8.4 Hz, 1H, 8-H), 7.99 (d, J = 8.0 Hz, 1H,
5-H), 7.93 (m, 2H, 13-H), 7.86 (m, 1H, 15-H), 7.63 (m, 2H, 14-H), 7.54 (m, 2H, 7-H, 6-H), 2.78
13
(s, 3H, 11-H). C NMR (CDCl3, 100 MHz) δ: 155.2 (2-C), 149.2 (9-C), 140.2 (12-C), 139.3
(15-C), 133.6 (4-C), 133.5 (3-C), 132.8 (14-C), 129.3 (10-C), 129.0 (7-C), 128.6 (5-C), 128.0
(13-C), 127.4 (8-C), 125.6 (6-C), 24.2 (11-C). IR(KBr), (cm-1): 1150, 1320 (O=S=O), 1606,
1448 (Ar-H). HR MS Calcd for C16H13NO2S [M+H] +: m/z 284.0745, found 284.0742.
2-methyl-4-(phenylsulfonyl)quinoline (4a). Yield 38%. White solid. m.p. 166-167 °C. 1H NMR
(CDCl3, 400 MHz) δ: 8.55 (d, J = 8.4 Hz, 1H, 5-H), 8.11 (s, 1H, 3-H), 8.08 (d, J = 8.6 Hz, 1H,
8-H), 8.00 (m, 2H, 13-H), 7.72 (m, 1H, 15-H), 7.55 (m, 4H, 6-H, 7-H, 14-H), 2.86 (s, 3H, 11-H).
13C NMR (CDCl3, 100 MHz) δ: 158.8 (2-C), 149.3 (9-C), 144.8 (4-C), 140.4 (12-C), 133.8
(15-C), 130.4 (14-C), 129.8 (7-C), 129.4 (13-C, 8-C), 127.8 (5-C), 124.0 (6-C), 122.3 (10-C),
120.5 (3-C), 25.5 (11-C). IR(KBr), (cm-1): 1146, 1319 (O=S=O), 1607, 1449 (Ar-H). HR MS
Calcd for C16H13NO2S [M+H] +: m/z 284.0745, found 284.0741.
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3-((4-chlorophenyl)sulfonyl)-2-methylquinoline (3b). Yield 21%. White solid. m.p.
153-155 °C. 1H NMR (CDCl3, 400 MHz) δ: 9.08 (s, 1H, 4-H), 8.07(d, J = 8.4 Hz, 1H, 8-H), 8.01
(d, J = 8.0 Hz, 1H, 5-H), 7.89 (m, 3H, 13-H, 6-H), 7.67(m, 1H, 7-H), 7.53(d, J = 8.6 Hz, 2H,
14-H), 2.80(s, 3H, 11-H). 13C NMR (CDCl3, 100 MHz) δ: 155.0 (2-C), 149.2 (9-C), 140.4 (12-C),
139.5 (15-C), 138.7 4-C), 133.1 (3-C), 129.7 (14-C), 129.5 (13-C, 7-C), 129.1 (8-C), 128.7 (5-C),
127.6 (10-C), 125.5 (6-C), 24.3 (11-C). IR(KBr), (cm-1): 1143, 1321 (O=S=O), 1610, 1453
(Ar-H). HR MS Calcd for C16H12ClNO2S [M+H] +: m/z 318.0356, found 318.0351.
4-((4-chlorophenyl)sulfonyl)-2-methylquinoline (4b). Yield 38%. White solid. m.p.
163-165 °C. 1H NMR (CDCl3, 400 MHz) δ: 8.52 (d, J = 8.6 Hz, 1H, 5-H), 8.11(m, 2H, 8-H, 3-H),
7.94(d, J = 8.6 Hz, 2H, 13-H), 7.76(m, 1H, 7-H), 7.60 (m, 1H, 6-H), 7.49 (d, J = 8.6 Hz, 2H,
14-H), 2.88 (s, 3H, 11-H). 13C NMR (CDCl3, 100 MHz) δ: 158.8 (2-C), 149.3 (9-C), 144.4 (4-C),
140.7 (12-C), 138.9 (15-C), 130.5 (7-C), 129.9 (8-C), 129.8 (14-C), 129.3 (13-C), 128.0 (5-C),
123.7 (6-C), 122.4 (10-C), 120.3 (3-C), 25.5 (11-C). IR(KBr), (cm-1): 1145, 1316 (O=S=O),
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1608, 1450 (Ar-H). HR MS calcd for C16H12ClNO2S [M+H] +: m/z 318.0356, found 318.0352.
2-methyl-3-tosylquinoline (3c). Yield 33%. White solid m.p. 126-129 °C. 1H NMR (CDCl3, 400
MHz) δ: 9.07 (s, 1H, 4-H), 8.05 (d, J = 8.4 Hz, 1H, 5-H), 7.99 (d, J = 8.2 Hz, 1H, 8-H), 7.84(m,
3H, 13-H, 6-H), 7.64 (t, 1H, 7-H), 7.33 (d, J = 8.2 Hz, 2H, 14-H), 2.80 (s, 3H, 11-H), 2.43 (s, 3H,
13
16-H). C NMR (CDCl3, 100 MHz) δ: 155.3 (2-C), 149.1 (9-C), 144.7 (15-C), 139.1 (12-C),
137.2 (4-C), 133.8 (3-C), 132.7 (7-C), 129.9 (14-C), 129.0 (8-C), 128.6 (5-C), 128.1 (13-C),
127.4 (6-C), 125.6 (10-C), 24.2 (11-C), 21.6 (16-C). IR(KBr), (cm-1): 1160, 1308 (O=S=O),
1611, 1452 (Ar-H). HR MS calcd for C17H15NO2S [M+H] +: m/z 298.0902, found 298.0900.
1
2-methyl-4-tosylquinoline (4c). Yield 48%. White solid. m.p. 158-160 °C. H NMR (CDCl3,
400 MHz) δ: 8.57 (d, J = 8.6 Hz, 1H, 5-H), 8.09 (s, 1H, 3-H), 8.08 (d, J = 7.2 Hz, 1H, 8-H), 7.88
(d, J = 8.4 Hz, 2H, 13-H), 7.71 (m, 1H, 6-H), 7.56 (m, 1H, 7-H), 7.30 (d, J = 8.2 Hz, 2H, 14-H),
2.84 (s, 3H, 11-H), 2.37 (s, 3H, 16-H). 13C NMR (CDCl3, 100 MHz) δ: 158.7 (2-C), 149.2 (9-C),
145.1(15-C), 145.0 (12-C), 137.4 (4-C), 130.3 (7-C), 130.0 (14-C), 129.7 (8-C), 127.9 (13-C),
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127.7 (5-C), 124.0 (6-C), 122.1 (3-C), 120.5 (10-C), 25.4 (11-C), 21.6 (16-C). IR(KBr), (cm-1):
1155, 1327 (O=S=O), 1603, 1451 (Ar-H). HR MS calcd for C17H15NO2S [M+H] +: m/z 298.0902,
found 298.0897.
6-bromo-2-methyl-3-(phenylsulfonyl)quinoline (3d). Yield 22%. White solid. m.p. 141-143 °C.
1H NMR (CDCl3, 400 MHz) δ: 8.98 (s, 1H, 4-H), 8.16 (s, 1H, 5-H), 7.93 (m, 4H, 7-H, 8-H,
13-H), 7.66 (m, 1H, 15-H), 7.57 (m, 2H, 14-H), 2.79 (s, 3H, 11-H). 13C NMR (CDCl3, 100 MHz)
δ: 155.7 (2-C), 147.7 (9-C), 139.8 (15-C), 138.1 (3-C), 136.1 (4-C), 134.5 (7-C,), 133.8 (5-C),
130.8 (10-C), 130.3 (8-C), 129.4 (13-C), 128.1 (14-C), 24.2 (11-C). IR(KBr), (cm-1): 1147,
1317 (O=S=O), 1609, 1448 (Ar-H). HR MS calcd for C16H12BrNO2S [M+H] +: m/z 361.9850,
found 361.9842.
6-bromo-2-methyl-3-(phenylsulfonyl)quinoline (4d). Yield 39%. White solid. m.p. 155-157 °C.
1H NMR (CDCl3, 400 MHz) δ: 8.76 (d, J = 2.4 Hz, 1H, 5-H), 8.10 (s, 1H, 3-H), 8.01 (d, J = 7.4
Hz, 2H, 13-H), 7.94 (d, J = 9.0 Hz, 1H, 8-H), 7.79 (dd, J = 2.0 Hz, J = 9.2 Hz, 1H, 7-H), 7.63 (m,
1H, 15-H), 7.56 (m, 2H, 14-H), 2.83 (s, 3H, 11-H). 13C NMR (CDCl3, 100 MHz) δ: 159.2 (2-C),
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147.8 (9-C), 144.0 (4-C), 140.0 (12-C), 134.1 (15-C), 134.0 (7-C), 131.3 (8-C), 129.6 (14-C),
127.9 (13-C), 126.4 (5-C), 123.0 (10-C), 122.2 (3-C), 121.6 (6-C), 25.5 (11-C). IR(KBr), (cm-1):
+
1149, 1323 (O=S=O), 1607, 1457 (Ar-H). HR MS calcd for C16H12BrNO2S [M+H] : m/z
361.9850, found 361.9842.
6-chloro-2-methyl-3-(phenylsulfonyl)quinoline (3e). Yield 20%. White solid. m.p. 177-179 °C.
1H NMR (CDCl3, 400 MHz) δ: 8.98 (s, 1H, 4-H), 8.00 (d, J = 9.0 Hz, 1H, 8-H), 7.98 (d, J = 2.2
Hz, 1H, 5-H), 7.94 (d, J = 7.4 Hz, 2H, 13-H), 7.79 (dd, J = 2.4 Hz, J = 9.0 Hz, 1H, 7-H), 7.66 (m,
1H, 15-H), 7.57 (m, 2H, 14-H), 2.79 (s, 3H, 11-H). 13C NMR (CDCl3, 100 MHz) δ: 155.6 (2-C),
147.5 (9-C), 139.8 (12-C), 138.2 (3-C), 134.6 (15-C), 133.8 (4-C), 133.6 (6-C), 133.3 (7-C),
130.3 (8-C), 129.4 (14-C), 128.1 (13-C), 127.5 (10-C), 126.2 (5-C), 24.2 (11-C). IR(KBr),
(cm-1): 1148, 1310 (O=S=O), 1611, 1447 (Ar-H). HR MS calcd for C16H12ClNO2S [M+H] +:
m/z 318.0356, found 318.0349.
6-chloro-2-methyl-4-(phenylsulfonyl)quinoline (4e). Yield 34%. White solid. m.p. 174-175 °C.
1H NMR (CDCl3, 400 MHz) δ: 8.59 (d, J = 2.2 Hz, 1H, 5-H), 8.12 (s, 1H, 3-H), 8.02 (m, 3H,
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13-H, 15-H), 7.68 (dd, J = 2.2 Hz, J = 9.0 Hz, 1H, 7-H), 7.63 (d, J = 7.2 Hz, 1H, 8-H), 7.57 (m,
13
2H, 14-H), 2.86 (s, 3H, 11-H). C NMR (CDCl3, 100 MHz) δ: 159.1 (2-C), 147.6 (9-C), 144.1
(4-C), 140.0 (12-C), 134.1 (15-C), 134.0 (7-C), 131.4 (8-C), 131.3 (10-C), 129.6 (14-C), 127.9
(13-C), 123.11 (5-C), 123.08 (3-C), 121.1 (6-C), 25.4 (11-C). IR(KBr), (cm-1): 1153, 1323
(O=S=O), 1607, 1450 (Ar-H). HR MS calcd for C16H12ClNO2S [M+H] +: m/z 318.0356, found
318.0348.
6-fluoro-2-methyl-3-(phenylsulfonyl)quinoline (3f). Yield 13%. White solid. m.p. 154-156 °C.
1H NMR (CDCl3, 400 MHz) δ: 9.03 (s, 1H, 4-H), 8.07 (m, 1H, 7-H), 7.94 (m, 2H, 5-H, 8-H),
7.64 (m, 3H, 13-H, 15-H), 7.57 (m, 2H, 14-H), 2.79 (s, 3H, 11-H). 13C NMR (CDCl3, 100 MHz)
δ: 139.9 (2-C), 138.6 (9-C), 138.5 (12-C), 134.5 (3-C), 133.7 (15-C), 131.3 (4-C), 131.2 (6-C),
129.4 (13-C), 128.1 (14-C), 123.1 (7-C), 122.8 (8-C), 112.1 (10-C), 111.9 (5-C), 24.1 (11-C).
IR(KBr), (cm-1): 1146, 1315 (O=S=O), 1605, 1447 (Ar-H). HR MS calcd for C16H12FNO2S
[M+H] +: m/z 302.0651, found 302.0644.
6-fluoro-2-methyl-4-(phenylsulfonyl)quinoline (4f). Yield 32%. White solid. m.p. 167-169 °C.
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1H NMR (CDCl3, 400 MHz) δ: 8.23 (dd, J = 2.6 Hz, J = 10.2 Hz, 1H, 7-H), 8.14 (s, 1H, 3-H),
8.10 (m, 1H, 8-H), 8.01 (d, J = 7.6 Hz, 2H, 13-H), 7.63 (m, 1H, 15-H), 7.52 (m, 3H, 5-H, 14-H),
2.86 (s, 3H, 11-H). 13C NMR (CDCl3, 100 MHz) δ: 159.6 (2-C), 158.0 (6-C), 146.4 (9-C), 144.4
(4-C), 144.3 (4-C), 140.0 (12-C), 134.0 (15-C), 132.3 (8-C), 132.2 (8-C), 129.6 (13-C), 127.8
(14-C), 123.1 (10-C), 121.4 (5-C), 121.3 (5-C), 120.8 (7-C), 120.5 (7-C), 108.4 (3-C), 108.1
(3-C), 25.3 (11-C). IR(KBr), (cm-1): 1155, 1328 (O=S=O), 1604, 1445 (Ar-H). HR MS calcd
for C16H12FNO2S [M+H] +: m/z 302.0651, found 302.0647.
1
2,6-dimethyl-3-(phenylsulfonyl)quinoline (3g). Yield 22%. White solid. m.p. 135-137 °C. H
NMR (CDCl3, 400 MHz) δ: 8.99 (s, 1H, 4-H), 7.94 (m, 3H, 8-H, 13-H), 7.75 (s, 1H, 5-H), 7.69
(d, J = 8.6 Hz, 1H, 7-H), 7.62 (m, 1H, 15-H), 7.54 (m, 2H, 14-H), 2.77 (s, 3H, 11-H), 2.58 (s, 3H,
13
16-H). C NMR (CDCl3, 100 MHz) δ: 154.2 (2-C), 147.8 (9-C), 140.3 (4-C), 138.8 (12-C),
137.6 (15-C), 135.1 (13-C), 133.5 (14-C), 133.4 (6-C), 129.3 (7-C), 128.2 (8-C), 128.0 (5-C),
127.7 (10-C), 125.6 (3-C), 24.1 (11-C), 22.7 (16-C). IR(KBr), (cm-1): 1149, 1321 (O=S=O),
1607, 1451 (Ar-H). HR MS calcd for C17H15NO2S [M+H] +: m/z 298.0902, found 298.0897.
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1
2,6-dimethyl-4-(phenylsulfonyl)quinoline (4g). Yield 36%. White solid. m.p. 143-146 °C. H
NMR (CDCl3, 400 MHz) δ: 8.32 (s, 1H, 3-H), 8.06 (s, 1H, 5-H), 8.00 (m, 3H, 8-H, 13-H), 7.56
(m, 4H, 5-H, 14-H, 15-H), 2.84 (s, 3H, 11-H), 2.52 (s, 3H, 16-H). 13C NMR (CDCl3, 100 MHz) δ:
157.6 (2-C), 47.9 (9-C), 143.9 (4-C), 140.5 (12-C), 138.1 (6-C), 133.8 (15-C), 132.6 (8-C), 129.4
(7-C), 129.4 (14-C), 127.8 (13-C), 122.8 (5-C), 122.2 (3-C), 120.5 (10-C), 25.3 (11-C), 22.1
(16-C). IR(KBr), (cm-1): 1161, 1327 (O=S=O), 1601, 1453 (Ar-H). HR MS calcd for
C17H15NO2S [M+H] +: m/z 298.0902, found 298.0898.
6-methoxy-2-methyl-4-(phenylsulfonyl)quinoline (4h). Yield 53%. White solid. m.p.
171-173 °C. 1H NMR (CDCl3, 400 MHz) δ: 8.10 (s, 1H, 3-H), 7.98 (m, 3H, 13-H, 8-H), 7.78 (d,
J = 2.8 Hz, 1H, 5-H) 7.59 (m, 1H, 15-H), 7.51 (m, 2H, 14-H), 7.34 (dd, J = 2.8 Hz, J = 9.2 Hz,
13
1H, 7-H), 3.88 (s, 3H, 11-H), 2.81 (s, 3H, 16-H). C NMR (CDCl3, 100 MHz) δ: 158.5 (2-C),
155.7 (6-C), 145.5 (4-C), 142.9 (9-C), 140.4 (12-C), 133.8 (15-C), 131.1 (8-C), 129.3 (13-C),
127.7 (14-C), 123.1 (7-C), 122.3 (10-C), 121.7 (3-C), 102.0 (5-C), 55.6 (16-C), 25.1 (11-C);
IR(KBr), (cm-1): 1147, 1321 (O=S=O), 1606, 1456 (Ar-H). HR MS calcd for C17H15NO3S
[M+H] +: m/z 314.0851, found 314.0848.
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6-methoxy-2-methyl-4-tosylquinoline (4i). Yield 65%. White solid. m.p. 148-150 °C. 1H NMR
(CDCl3, 400 MHz) δ: 8.07 (s, 1H, 3-H), 7.95 (d, J = 9.2 Hz, 1H, 8-H), 7.87 (d, J = 8.4 Hz, 2H,
13-H), 7.73 (d, J = 2.6 Hz, 1H, 5-H), 7.33 (dd, J = 2.6 Hz, J = 9.2 Hz, 1H, 7-H), 7.29 (d, J = 8.2
Hz, 2H, 14-H), 3.89 (s, 3H, 17-H), 2.80 (s, 3H, 11-H), 2.37 (s, 3H, 16-H). 13C NMR (CDCl3, 100
MHz) δ: 158.4 (2-C), 155.7 (6-C), 145.4 (4-C), 145.0 (9-C), 143.3 (15-C), 137.4 (12-C), 131.0
(8-C), 130.0 (14-C), 127.8 (13-C), 123.0 (10-C), 122.2 (7-C), 121.7 (3-C), 102.1 (5-C), 55.6
(17-C), 25.0 (11-C), 21.6 (16-C). IR(KBr), (cm-1): 1154, 1327 (O=S=O), 1602, 1458 (Ar-H).
HR MS calcd for C18H17NO3S [M+H] +: m/z 328.1007, found 328.1007.
4-((4-chlorophenyl)sulfonyl)-6-methoxy-2-methylquinoline (4j). Yield 53%. White solid. m.p.
1
168-171 °C. H NMR (CDCl3, 400 MHz) δ: 8.07 (s, 1H, 3-H), 7.98 (d, J = 9.2 Hz, 1H, 8-H),
7.92 (d, J = 8.6 Hz, 14-H), 7.755 (d, J = 2.6 Hz, 1H, 5-H), 7.48 (d, J = 8.6 Hz, 2H, 13-H), 7.37
(dd, J = 2.6 Hz, J = 9.2 Hz, 7-H), 3.90 (s, 3H, 17-H), 2.81 (s, 3H, 11-H). 13C NMR (CDCl3, 100
MHz) δ: 158.6 (2-C), 155.7 (6-C), 145.5 (4-C), 142.5 (9-C), 140.6 (15-C), 138.9 (12-C), 131.2
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(8-C), 129.7 (14-C), 129.1 (13-C), 123.1 (10-C), 122.4 (7-C), 121.6 (3-C), 101.9 (5-C), 55.6
(17-C), 25.0 (11-C). IR(KBr), (cm-1): 1148, 1318 (O=S=O), 1609, 1450 (Ar-H). HR MS calcd
for C17H14ClNO3S [M+H] +: m/z 348.0461, found：348.0463.
N,N-diethyl-4-(phenylsulfonyl)quinolin-2-amine (4k). Yield 61%. White solid. m.p.
1
197-200 °C. H NMR (CDCl3, 400 MHz) δ: 8.26 (d, J = 8.4 Hz, 1H, 5-H), 7.99 (d, J = 7.6 Hz,
2H, 13-H), 7.74 (s, 1H, 3-H), 7.70(d, J = 8.6 Hz, 1H, 8-H), 7.57-7.49 (m, 4H, 6-H, 7-H, 14-H),
7.17 (m, 1H, 15-H), 7.72 (m, 4H, CH2-H), 1.29 (m, 6H, CH3-H). 13C NMR (CDCl3, 100 MHz) δ:
154.6 (2-C), 150.0 (9-C), 145.5 (4-C), 140.7 (12-C), 133.6 (15-C), 130.2 (7-C), 129.3 (14-C),
127.6 (13-C), 127.3 (8-C), 123.9 (5-C), 122.7 (6-C), 116.0 (10-C), 110.7 (3-C), 42.8 (CH2-C),
13.2 (CH3-C). IR(KBr), (cm-1): 1153, 1321 (O=S=O), 1607, 1449 (Ar-H). HR MS calcd for
C19H20N2O2S [M+H] +: m/z 341.1324, found 341.1327.
4-(3-(phenylsulfonyl)quinolin-2-yl)morpholine (3l). Yield 20%. White solid. m.p. 173-175 °C.
1H NMR (CDCl3, 400 MHz) δ: 9.11 (s, 1H, 4-H), 7.94 (m, 2H, 14-H), 7.89 (d, J = 7.6 Hz, 2H,
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13-H), 7.80 (m, 1H, 15-H), 7.56 (m, 2H, 5-H, 8-H), 7.46 (m, 2H, 6-H, 7-H), 3.74 (m, 4H, 17-H),
3.17 (m, 4H, 16-H). 13C NMR (CDCl3, 100 MHz) δ: 156.0 (2-C), 149.3 (9-C), 146.0 (4-C), 140.5
(12-C), 133.7 (15-C), 130.5 (7-C), 129.3 (14-C), 127.6 (13-C), 124.1 (5-C), 124.0 (8-C), 117.0
(6-C), 110.9 (3-C), 66.7 (17-C), 45.5 (16-C). IR(KBr), (cm-1): 1160, 1322 (O=S=O), 1610,
1450 (Ar-H). HR MS calcd for C19H18N2O3S [M+H] +: m/z 355.1116, found: 355.1115.
4-(4-(phenylsulfonyl)quinolin-2-yl)morpholine (4l). Yield 41%. White solid. m.p. 214-216 °C.
1H NMR (CDCl3, 400 MHz) δ: 8.27 (d, J = 8.4 Hz, 1H, 5-H), 7.97 (m, 2H, 14-H), 7.88 (s, 1H,
3-H), 7.74 (d, J = 8.4 Hz, 1H 8-H), 7.60-7.49 (m, 4H, 6-H, 7-H, 13-H), 7.25 (d, J = 7.2 Hz, 1H,
13
15-H), 3.88 (m, 4H, 17-H), 3.79 (m, 4H, 16-H). C NMR (CDCl3, 100 MHz) δ: 158.3 (2-C),
148.9 (9-C), 142.9 (4-C), 141.1 (12-C), 133.2 (15-C), 132.6 (7-C), 130.1 (14-C), 129.1 (13-C),
128.6 (8-C), 128.1 (5-C), 128.0 (6-C), 126.6 (10-C), 125.1 (3-C), 66.6 (17-C), 52.2 (16-C);
IR(KBr), (cm-1): 1158, 1323 (O=S=O), 1607, 1458 (Ar-H). HR MS calcd for C19H18N2O3S
[M+H] +: m/z 355.1116, found: 355.1115.
Acknowledgements
Financial support from The National Natural Science Foundation of China (No. 21072178),
Innovation Specialist Projects of Henan Province (No. 114200510023), Technology and Science
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talent Cultivation Project in Zhengzhou City (No. 112PLJRC359).
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References
[1]. Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon Press: Oxford, 1993.
[2]. (a) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C.; Rooney,C. S.; Balani, S. K.; Condra,
J. K.; Emini, E. A.; Goldman, M. E.; Greenlee, W. J.; Kauffman, L. R.; O’Brien, J. A.;
Sardana, V. V.; Schleif, W. A.; Theoharides, A. D.; Anderson, P. A. J. Med. Chem. 1993, 36,
1291-1294. (b) Dol, F.; Schaeffer, P.; Lamarche, I.; Mares, A.; Chatelain, P.; Herbert, J. Eur.
J. Pharmacol. 1995, 280, 135-142. (c) Artico, M.; Silvestri, R.; Massa, S.; Loi, A. G.;
Corrias, S.; Piras, G.; La Colla, P. J. Med. Chem. 1996, 39, 522-530.
[3]. Zajdel, P.; Marciniec, K.; Satala, G.; Wrobel, D.; Pawlowski, M. Eur. J. Med. Chem. 2013,
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Z.; Xu, X; Wang, D. RSC Adv., 2016, 6, 62298-62301. (h) Ge, B.; Wang, D.; Dong, W. Ma,
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Table 1. Optimization of the reaction conditionsa
Entry
H-phosphonate (eq.)
H-P(O)(OR)2, R =
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3 (2)
Solv.
Base (eq.)
Temp.
(°C)
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
30
50
90
70
70
70
70
70
70
70
Time
(h)
4
Yield
(%)b
8
Ratio
3a : 4ac
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
2 : 3
1 : 3
2 : 5
1 : 3
1 : 3
--
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
K2CO3 (4)
NEt3 (4)
HN(Et)2 (4)
Na2CO3 (4)
KOH (1)
KOH (2)
KOH (6)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
KOH (4)
2
8
15
3
12
16
20
24
28
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
21
4
34
5
43
6
63
7
62
8
23
9
(CH3)2CH (2)
Ph (2)
37
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
13
PhCH2 (2)
31
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
CH3CH2 (2)
traced
traced
traced
traced
23
--
--
--
2 : 3
2 : 3
2 : 3
1 : 5
1 : 4
1 : 1
--
47
62
34
37
53
NRd
traced
32
--
DCE
1 : 4
1 : 4
--
Toluene
Dioxane
THF
11
traced
46
1 : 5
1 : 4
CCl4
23
a Reaction conditions: 1a (0.2 mmol), 1b (0.8 mmol), H-phosphonate (0.4 mmol), base (0.8
mmol), CCl4 (1.0 mL) in 6 mL solvent.
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b isolated yields.
c detected by 1H NMR.
d detected by thin layer chromatography (TLC).
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Table 2. Scope of the 3/4-sulfonylated quinoline derivativesa,b,c
a Reaction conditions: 1a (0.2 mmol), 1b (0.8 mmol), diethyl H-phosphonate (0.4 mmol),
KOH (0.8 mmol), CCl4 (1.0 mL) in 6 mL CH3CN. b isolated yields. c ratio based on
isolated yield.
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Scheme 1. Some important 3/4-sulfonylated quinoline derivatives
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Scheme 2. Methodologies for the synthesis of sulfonylated quinoline derivatives
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Scheme 3. Proposed reaction mechanism
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