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

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

Accepted author version posted online: 10

Apr 2017.

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Date: 25 April 2017, At: 19:00

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,¹Shuyun Liu,¹Shaohua Zhu,¹Wenzhu Bi,¹Xiaolan Chen,^1,*and Yufen Zhao^1,2

1

College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450001,

China

²Department 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-HT₆receptor

selective antagonists for the treatment of Alzheimer's disease^3b. 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 sulfides⁴or 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 CCl₄in 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 CDCl₃at 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

(v_{petroleum ether}: v_{ethyl 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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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

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Table 1. Optimization of the reaction conditions^a

Entry

H-phosphonate (eq.)

H-P(O)(OR)₂, R =

CH₃CH₂(2)

CH₃(2)

Solv.

Base (eq.)

Temp.

(°C)

70

30

50

90

70

Time

(h)

4

Yield

(%)^b

8

Ratio

3a : 4a^c

2 : 3

1 : 3

2 : 5

1 : 3

--

1

CH₃CN

DMSO

DMF

KOH (4)

K₂CO₃(4)

NEt₃(4)

HN(Et)₂(4)

Na₂CO₃(4)

KOH (1)

KOH (2)

KOH (6)

KOH (4)

2

8

15

3

12

16

20

24

28

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)

trace^d

23

--

2 : 3

1 : 5

1 : 4

1 : 1

--

47

62

34

37

53

NR^d

trace^d

32

--

DCE

1 : 4

--

Toluene

Dioxane

THF

11

trace^d

46

1 : 5

1 : 4

CCl₄

23

^aReaction 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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^bisolated yields.

^cdetected by ¹H NMR.

^ddetected by thin layer chromatography (TLC).

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Table 2. Scope of the 3/4-sulfonylated quinoline derivatives^a,b,c

^aReaction 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. ^bisolated yields. ^cratio 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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Article Doi

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

DOI: 10.1080/10426507.2017.1315422

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Article abstract of DOI:10.1080/10426507.2017.1315422

Full text of DOI:10.1080/10426507.2017.1315422

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