Sulfonylation of C(sp3)–H bond for synthesis of 2-sulfolmethyl azaarenes catalyzed by TBAI in water

Article abstract of DOI:10.1007/s11164-018-3573-z

A tetrabutylammonium iodide (TBAI)-catalyzed method for synthesis of 2-sulfolmethyl quinolone has been developed. Using water as solvent, a wide range of 2-sulfolmethyl quinolones were obtained in high to excellent yield. In addition, water and TBAI could be reused for five times without significant decrease of the yield of the corresponding product.

Full text of DOI:10.1007/s11164-018-3573-z

Research on Chemical Intermediates
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Sulfonylation of C(sp3)–H bond for synthesis
of 2-sulfolmethyl azaarenes catalyzed by TBAI in water
Dao-Qing Dong1 Xing Gao2 Li-Xia Li1 Shuang-Hong Hao1
Zu-Li Wang1
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Received: 20 March 2018 / Accepted: 24 August 2018
Ó Springer Nature B.V. 2018
Abstract
A tetrabutylammonium iodide (TBAI)-catalyzed method for synthesis of 2-sulfol-
methyl quinolone has been developed. Using water as solvent, a wide range of
2-sulfolmethyl quinolones were obtained in high to excellent yield. In addition,
water and TBAI could be reused for five times without significant decrease of the
yield of the corresponding product.
Keywords Sulfonylation Á TBAI Á Water Á Azaarenes
Introduction
Organosulfones are important intermediates in organic synthesis and have been
widely used in the fields of pharmaceutical chemistry, macromolecular chemistry,
and agrochemicals [1–6]; For example, compound Z1 can be used as a leukotriene
antagonist and inhibitor of leukotriene biosynthesis [7], and Z2 can be used as an
antibacterial agent [8] (Fig. 1). Organosulfones are also important intermediates in
¨
Ramberg–Backlund and Julia–Lythgoe reactions [9–11]. Because of the importance
of organosulfone compounds in various fields, their synthesis has attracted
considerable interest. Traditionally, sulfonyl chlorides were used as sulfonyl
reagent [12, 13], but they are water sensitive and have strong smell. Due to their
advantages including commercial availability, water and air insensitivity, and easy
handling, sulfites have been widely used in sulfonyl reactions in recent years
[14–16]. An iodine-catalyzed direct sulfonylation of pyrazolones with sodium
&
Zu-Li Wang
wangzulichem@163.com; wangzuli09@tsinghua.org.cn
1
2
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University,
Qingdao 266109, People’s Republic of China
School of Chemical and Biological Engineering, Qilu Institute of Technology, Jinan 250200,
People’s Republic of China
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D.-Q. Dong et al.
Fig. 1 Selected organosulfone compounds
sulfinates was developed by Wang and coworkers [17]. In 2017, Liu’s group
presented a method for synthesis of (E)-b-iodo vinylsulfones by reaction of alkynes
with sodium sulfinates at room temperature [18].
Because of their low cost, nontoxicity, ready availability, and ecofriendly
properties, iodine reagents have been widely used as metal-free catalysts to promote
diverse organic transformations in recent decades [19–23]. In presence of iodine
reagents, C–C bond [24–26], C–O bond [27, 28], C–N bond [29–31], and other
reactions [32, 33] have been realized smoothly. In 2015 [34], Deng and coworkers
presented sulfonylation of 2-methylquinolines promoted by KI (1 equiv) and tert-
butyl hydroperoxide (TBHP). As part of our continuing effort to use iodine reagents
[35–38] to mediate organic transformations, we describe herein TBAI-catalyzed
sulfonylation of 2-methylquinolines with sodium sulfinates using water as solvent
(Scheme 1).
Experimental
Nuclear magnetic resonance (NMR) spectra were recorded at 500 MHz for protons
1
using JOEL JNM-ECA spectrometers. H NMR chemical shifts (d) are given in
parts per million (ppm) relative to tetramethylsilane (TMS) (d = 0.0). Chemical
shifts for 13C NMR spectra are reported in ppm from tetramethylsilane with the
solvent as internal standard. Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad
Scheme 1 Sulfonylation of C(sp3)–H bond for synthesis of 2-sulfolmethyl azaarenes
123

Sulfonylation of C(sp3)–H bond for synthesis of…
signal), integration, coupling constant (Hz), and identification. All major chemicals
and solvents were obtained from commercial sources and used without further
purification.
General procedure A sealable reaction tube equipped with a magnetic stirrer bar
was charged with azaarenes (1.0 mmol), sodium benzenesulfinate (2 equiv), TBAI
(0.2 equiv), tert-butyl peroxybenzoate (TBPB, 1 equiv), and water (1 ml). The
reaction was carried out at 100 °C. After completion, the result was diluted with
diethyl ether, washed with water and brine, and dried with Mg2SO4. After solvent
removal under reduced pressure, the residue was purified by column chromatog-
raphy on silica gel to afford the corresponding product.
1
2-((Phenylsulfonyl)methyl)quinoline (3a) Off-white (87 %), H NMR (500 MHz,
CDCl3) d 8.06 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.1 Hz,
1H), 7.62–7.53 (m, 3H), 7.46 (t, J = 9.8 Hz, 3H), 7.30 (t, J = 7.8 Hz, 2H), 4.67 (s,
2H). 13C NMR (126 MHz, CDCl3) d 149.25 (s), 147.80 (s), 138.30 (s), 136.97 (s),
133.82 (s), 129.93 (s), 129.04 (d, J = 17.3 Hz), 128.52 (s), 127.61 (s), 127.28 (d,
J = 19.2 Hz), 122.76 (s), 65.14 (s).
1
2-(((4-Chlorophenyl)sulfonyl)methyl)quinoline (3b) White solid (76 %), H NMR
(500 MHz, CDCl3) d 8.10 (d, J = 8.4 Hz, 1H), 7.86–7.71 (m, 2H), 7.60 (t,
J = 7.6 Hz, 1H), 7.48 (t, J = 10.1 Hz, 4H), 7.28 (d, J = 8.3 Hz, 2H), 4.65 (s, 2H).
13C NMR (126 MHz, CDCl3) d 149.03 (s), 147.83 (s), 140.59 (s), 137.09 (s), 136.71
(s), 130.09 (s), 129.19 (d, J = 15.8 Hz), 127.64 (s), 127.35 (d, J = 1.7 Hz), 122.72
(s), 65.21 (s).
2-(((4-Fluorophenyl)sulfonyl)methyl)quinoline (3c) Brown solid (69 %),1H NMR
(500 MHz, CDCl3) d 8.06 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 9.1 Hz, 2H), 7.56 (dd,
J = 13.5, 7.0 Hz, 3H), 7.52–7.35 (m, 2H), 6.95 (t, J = 8.1 Hz, 2H), 4.64 (s, 2H).
13C NMR (126 MHz, CDCl3) d 166.89 (s), 164.85 (s), 149.16 (s), 147.80 (s), 137.04
(s), 134.24 (d, J = 3.1 Hz), 131.49 (d, J = 9.7 Hz), 130.04 (s), 129.10 (s), 127.64
(s), 127.32 (d, J = 3.9 Hz), 122.73 (s), 116.33 (s), 116.15 (s), 65.29 (s).
2-((Methylsulfonyl)methyl)quinoline (3d) White solid (79 %),1H NMR (500 MHz,
CDCl3) d 8.16 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.1 Hz,
1H), 7.69 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 6.8 Hz, 2H), 4.54 (s, 2H), 2.89 (s, 3H).
13C NMR (126 MHz, CDCl3) d 149.95 (s), 147.97 (s), 137.53 (s), 130.23 (s), 129.17
(s), 127.79 (s), 127.59 (s), 127.42 (s), 122.90 (s), 63.70 (s), 40.09 (s).
1
2-(Tosylmethyl)quinoline (3e) White solid (75 %), H NMR (500 MHz, CDCl3) d
8.16 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.68
(t, J = 7.6 Hz, 1H), 7.56 (t, J = 9.5 Hz, 4H), 7.21 (d, J = 7.7 Hz, 2H), 4.73 (s,
2H), 2.39 (s, 3H). 13C NMR (126 MHz, CDCl3) d 149.40 (s), 147.87 (s), 144.83 (s),
136.87 (s), 135.46 (s), 129.85 (s), 129.62 (s), 129.20 (s), 128.52 (s), 127.61 (s),
127.37 (s), 127.14 (s), 122.75 (s), 65.32 (s), 21.63 (s).
7-Chloro-2-(((4-chlorophenyl)sulfonyl)methyl)quinoline (3f) Yellow solid (88 %),
1H NMR (500 MHz, DMSO) d 8.42 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H),
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D.-Q. Dong et al.
7.82 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.64 (t, J = 8.0 Hz, 3H), 7.57 (d,
J = 8.4 Hz, 1H), 5.11 (s, 2H). 13C NMR (126 MHz, DMSO) d 151.66 (s), 147.91
(s), 139.56 (s), 137.93 (s), 137.38 (s), 135.02 (s), 130.62 (s), 130.42 (s), 129.79 (s),
128.21 (s), 127.58 (s), 126.03 (s), 124.22 (s), 63.75 (s). HRMS: m/z calcd. for
C16H12O2NCl2S [M ? H]?: 351.99603; found: 351.99582.
1
7-Chloro-2-((phenylsulfonyl)methyl)quinoline (3g) White solid (91 %), H NMR
(500 MHz, CDCl3) d 8.04 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.65 (d, J = 8.7 Hz,
1H), 7.59 (d, J = 7.9 Hz, 2H), 7.49 (dd, J = 15.2, 7.9 Hz, 2H), 7.39 (d,
J = 8.7 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 4.63 (s, 2H). 13C NMR (126 MHz,
CDCl3) d 150.44 (s), 148.13 (s), 138.20 (s), 136.72 (s), 135.76 (s), 133.96 (s),
129.05 (s), 128.85 (s), 128.47 (s), 128.22 (d, J = 9.8 Hz), 125.68 (s), 122.96 (s),
65.12 (s).
7-Chloro-2-(tosylmethyl)quinoline (3h) Off-white solid (77 %), 1H NMR
(500 MHz, CDCl3) d 8.16 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.77 (d, J = 8.6 Hz,
1H), 7.59 (dd, J = 14.7, 8.1 Hz, 3H), 7.51 (d, J = 8.7 Hz, 1H), 7.24 (d,
J = 7.7 Hz, 2H), 4.72 (s, 2H), 2.42 (s, 3H). 13C NMR (126 MHz, CDCl3) d
150.63 (s), 148.17 (s), 144.99 (s), 136.66 (s), 135.73 (s), 135.39 (s), 129.68 (s),
128.83 (s), 128.47 (s), 128.23 (d, J = 2.1 Hz), 125.71 (s), 122.97 (s), 65.22 (s),
21.66 (s). HRMS: m/z calcd. for C17H15O2NClS [M ? H]?: 332.05065; found:
332.05045.
7-Chloro-2-(((4-fluorophenyl)sulfonyl)methyl)quinoline (3i) Yellow solid (76 %),
1H NMR (500 MHz, CDCl3) d 8.16 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.76 (d,
J = 8.6 Hz, 1H), 7.73–7.64 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.6 Hz,
1H), 7.11 (t, J = 8.1 Hz, 2H), 4.74 (s, 2H). 13C NMR (126 MHz, CDCl3) d 166.95
(s), 164.91 (s), 150.36 (s), 148.11 (s), 136.84 (s), 135.92 (s), 134.23 (d, J = 3.1 Hz),
131.43 (d, J = 9.7 Hz), 128.87 (s), 128.38 (s), 128.12 (s), 125.68 (s), 122.94 (s),
116.44 (s), 116.26 (s), 65.17 (s). HRMS: m/z calcd. for C16H12O2NClFS [M ? H]?:
336.02558; found: 336.02542.
7-Chloro-2-((methylsulfonyl)methyl)quinoline (3j) White solid (77 %), 1H NMR
(500 MHz, DMSO) d 8.48 (d, J = 8.4 Hz, 1H), 8.15–8.00 (m, 2H), 7.69 (d,
J = 8.6 Hz, 2H), 4.89 (s, 2H), 3.13 (s, 3H). 13C NMR (126 MHz, DMSO) d 152.70
(s), 148.03 (s), 137.57 (s), 135.06 (s), 130.45 (s), 128.14 (s), 127.83 (s), 126.15 (s),
124.36 (s), 62.39 (s), 41.23 (s). HRMS: m/z calcd. for C11H11O2NClS [M ? H]?:
256.01935; found: 256.01920.
2-(((4-chlorophenyl)sulfonyl)methyl)-3-methylquinoxaline (3k) White solid (66 %),
1H NMR (500 MHz, CDCl3) d 7.95 (d, J = 8.3 Hz, 1H), 7.65 (ddd, J = 28.7, 15.9,
7.5 Hz, 3H), 7.53 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.19 (s, 1H), 4.75
(s, 2H), 2.85 (s, 3H). 13C NMR (126 MHz, CDCl3) d 154.16 (s), 144.16 (s), 141.68
(s), 140.91 (s), 140.69 (s), 136.58 (s), 130.81 (s), 130.30 (s), 129.63 (s), 129.39 (s),
128.63 (d, J = 18.9 Hz), 62.13 (s), 23.20 (s). HRMS: m/z calcd. for C16H14O2N2-
ClS [M ? H]?: 333.04590; found: 333.04578.
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Sulfonylation of C(sp3)–H bond for synthesis of…
1
2-Chloro-3-((phenylsulfonyl)methyl)quinoxaline (3l) White solid (65 %), H NMR
(500 MHz, CDCl3) d 7.94 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.80–7.65
(m, 4H), 7.60 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 4.93 (s, 2H). 13C NMR
(126 MHz, CDCl3) d 147.59 (s), 143.50 (s), 141.52 (s), 140.74 (s), 138.68 (s),
134.25 (s), 131.95 (s), 130.81 (s), 129.21 (d, J = 14.6 Hz), 128.69 (s), 128.28 (s),
61.42 (s). HRMS: m/z calcd. for C15H12O2N2ClS [M ? H]?: 319.63025; found:
319.03014.
2-((Phenylsulfonyl)methyl)quinoxaline (3m) Red solid (83 %), 1H NMR
(500 MHz, CDCl3) d 8.81 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.1 Hz,
1H), 7.76–7.60 (m, 4H), 7.54 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.4 Hz, 2H), 4.70 (s,
2H). 13C NMR (126 MHz, CDCl3) d 146.06 (s), 144.59 (s), 142.03 (s), 141.85 (s),
137.96 (s), 134.20 (s), 130.66 (d, J = 17.1 Hz), 129.43–129.17 (m), 128.52 (s),
62.88 (s).
2-Methyl-3-((phenylsulfonyl)methyl)quinoxaline (3n) White solid (65 %), 1H NMR
(500 MHz, CDCl3) d 7.93 (d, J = 8.3 Hz, 1H), 7.71–7.63 (m, 2H), 7.63–7.50 (m,
4H), 7.39 (t, J = 7.5 Hz, 2H), 4.75 (s, 2H), 2.82 (s, 3H). 13C NMR (126 MHz,
CDCl3) d 154.18 (s), 144.36 (s), 141.63 (s), 140.77 (s), 138.18 (s), 134.06 (s),
130.66 (s), 129.44 (s), 129.12 (s), 128.77 (d, J = 14.2 Hz), 128.48 (s), 62.19 (s),
23.15 (s).
2-(((4-Fluorophenyl)sulfonyl)methyl)quinolin-8-ol (3o) Gray solid (65 %), 1H NMR
(500 MHz, CDCl3) d 8.11 (d, J = 8.3 Hz, 1H), 7.57 (dd, J = 6.8, 5.4 Hz, 2H), 7.49
(d, J = 8.3 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.26 (d, J = 8.2 Hz, 1H), 7.13–6.92
(m, 3H), 4.64 (s, 2H). 13C NMR (126 MHz, CDCl3) d 166.99 (s), 164.95 (s), 151.85
(s), 147.02 (s), 137.63 (s), 137.35 (s), 134.11 (d, J = 3.1 Hz), 131.48 (d,
J = 9.7 Hz), 128.65 (s), 127.63 (s), 123.48 (s), 117.77 (s), 116.42 (s), 116.24 (s),
110.71 (s), 64.89 (s). HRMS: m/z calcd. for C16H13O3NFS [M ? H]?: 318.05947;
found: 318.05933.
1
6-Methyl-2-((phenylsulfonyl)methyl)quinoline (3p) Yellow solid (79 %), H NMR
(500 MHz, CDCl3) d 8.08 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.68 (d,
J = 7.7 Hz, 2H), 7.64–7.48 (m, 4H), 7.42 (t, J = 7.5 Hz, 2H), 4.74 (s, 2H), 2.54 (s,
3H). 13C NMR (126 MHz, CDCl3) d 148.21 (s), 146.47 (s), 138.26 (s), 137.22 (s),
136.23 (s), 133.77 (s), 132.22 (s), 128.88 (d, J = 15.9 Hz), 128.55 (s), 127.41 (s),
126.40 (s), 122.73 (s), 65.20 (s), 21.63 (s).
2-((Phenylsulfonyl)methyl)benzo[d]thiazole (3q) Yellow solid (74 %), 1H NMR
(500 MHz, CDCl3) d 7.86 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.72 (d,
J = 7.7 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.49–7.29 (m, 4H), 4.80 (s, 2H). 13C
NMR (126 MHz, CDCl3) d 156.63 (s), 152.66 (s), 137.67 (s), 136.21 (s), 134.36 (s),
129.30 (s), 128.62 (s), 126.49 (s), 126.00 (s), 123.56 (s), 121.71 (s), 60.64 (s).
6-Bromo-2-(((4-fluorophenyl)sulfonyl)methyl)quinoline (3r) Yellow solid (90 %),
1H NMR (500 MHz, CDCl3) d 8.09 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.74 (d,
J = 9.0 Hz, 1H), 7.70–7.56 (m, 4H), 7.08 (t, J = 8.2 Hz, 2H), 4.71 (s, 2H). 13C
NMR (126 MHz, CDCl3) d 166.94 (s), 164.90 (s), 149.67 (s), 146.36 (s), 135.98 (s),
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D.-Q. Dong et al.
134.14 (d, J = 3.1 Hz), 133.55 (s), 131.46 (d, J = 9.7 Hz), 130.84 (s), 129.66 (s),
128.38 (s), 123.59 (s), 121.32 (s), 116.40 (s), 116.22 (s), 65.23 (s). HRMS: m/
z calcd. for C16H12O2NBrFS [M ? H]?: 379.97507; found: 379.97473.
1
6-Bromo-2-(tosylmethyl)quinoline (3s) Yellow solid (74 %), H NMR (500 MHz,
CDCl3) d 8.06 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.73 (s, 2H), 7.57 (dd, J = 16.5,
8.1 Hz, 3H), 7.21 (d, J = 7.7 Hz, 2H), 4.70 (s, 2H), 2.39 (s, 3H). 13C NMR
(126 MHz, CDCl3) d 149.92 (s), 146.39 (s), 144.94 (s), 135.81 (s), 135.36 (s),
133.33 (s), 130.92 (s), 129.65 (d, J = 4.0 Hz), 128.44 (d, J = 9.6 Hz), 123.62 (s),
121.10 (s), 65.22 (s), 21.65 (s). HRMS: m/z calcd. for C17H15O2NBrS [M ? H]?:
376.00014; found: 375.99974.
6-Bromo-2-(((4-chlorophenyl)sulfonyl)methyl)quinoline (3t) Yellow solid (82 %),
1H NMR (500 MHz, CDCl3) d 8.12 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.75 (dd,
J = 19.3, 8.9 Hz, 2H), 7.61 (dd, J = 20.3, 8.0 Hz, 3H), 7.39 (d, J = 8.0 Hz, 2H),
4.76 (s, 2H). 13C NMR (126 MHz, CDCl3) d 149.54 (s), 146.28 (s), 140.73 (s),
136.60 (s), 136.14 (s), 133.66 (s), 130.72 (s), 130.04 (s), 129.68 (s), 129.32 (s),
128.43 (s), 123.66 (s), 121.42 (s), 64.97 (s). HRMS: m/z calcd. for C16H12O2NBrClS
[M ? H]?: 395.94552; found: 395.94516.
1
6-Bromo-2-((phenylsulfonyl)methyl)quinoline (3u) Yellow solid (92 %), H NMR
(500 MHz, CDCl3) d 7.98 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.71–7.54 (m, 4H),
7.49 (t, J = 8.4 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 4.63 (s, 2H). 13C NMR
(126 MHz, CDCl3) d 149.75 (s), 146.39 (s), 138.17 (s), 135.86 (s), 133.91 (s),
133.39 (s), 130.92 (s), 129.63 (s), 129.03 (s), 128.44 (d, J = 13.1 Hz), 123.60 (s),
121.18 (s), 65.17 (s).
6-Fluoro-2-((phenylsulfonyl)methyl)quinoline (3v) Off-white solid (82 %), 1H
NMR (500 MHz, CDCl3) d 8.03 (d, J = 8.4 Hz, 1H), 7.82–7.71 (m, 1H), 7.59 (d,
J = 7.5 Hz, 2H), 7.49 (t, J = 7.1 Hz, 2H), 7.34 (d, J = 7.3 Hz, 4H), 4.64 (s, 2H).
13C NMR (126 MHz, CDCl3) d 161.72 (s), 159.74 (s), 148.62 (d, J = 2.8 Hz),
144.97 (s), 138.24 (s), 136.25 (d, J = 5.5 Hz), 133.87 (s), 131.79 (d, J = 9.2 Hz),
129.01 (s), 128.50 (s), 128.04 (d, J = 10.2 Hz), 123.47 (s), 120.32 (s), 120.12 (s),
110.70 (s), 110.53 (s), 65.08 (s).
2-(((4-Chlorophenyl)sulfonyl)methyl)-6-fluoroquinoline (3w) White solid (82 %),
1H NMR (500 MHz, CDCl3) d 8.06 (d, J = 8.4 Hz, 1H), 7.83–7.70 (m, 1H),
7.62–7.46 (m, 3H), 7.38 (dd, J = 15.6, 8.6 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 4.64
(s, 2H). 13C NMR (126 MHz, CDCl3) d 161.82 (s), 159.83 (s), 148.40 (d,
J = 2.8 Hz), 144.95 (s), 140.67 (s), 136.67 (s), 136.42 (d, J = 5.4 Hz), 131.75 (d,
J = 9.3 Hz), 130.05 (s), 129.30 (s), 128.08 (d, J = 10.2 Hz), 123.44 (s), 120.54 (s),
120.34 (s), 110.75 (s), 110.58 (s), 65.07 (s). HRMS: m/z calcd. for C16H12O2NClFS
[M ? H]?: 336.02558; found: 336.02563.
6-Fluoro-2-(((4-fluorophenyl)sulfonyl)methyl)quinoline (3x) White solid (86 %), 1H
NMR (500 MHz, CDCl3) d 8.13 (d, J = 8.4 Hz, 1H), 7.96–7.76 (m, 1H), 7.75–7.64
(m, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 9.7 Hz, 2H), 7.08 (t, J = 7.9 Hz,
2H), 4.72 (s, 2H). 13C NMR (126 MHz, CDCl3) d 166.92 (s), 164.88 (s), 161.77 (s),
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Sulfonylation of C(sp3)–H bond for synthesis of…
159.78 (s), 148.55 (d, J = 2.8 Hz), 144.92 (s), 136.37 (d, J = 5.4 Hz), 134.21 (d,
J = 3.1 Hz), 131.72 (d, J = 9.3 Hz), 131.46 (d, J = 9.7 Hz), 128.05 (d,
J = 10.2 Hz), 123.46 (s), 120.47 (s), 120.27 (s), 116.38 (s), 116.19 (s), 110.75
(s), 110.57 (s), 65.14 (s). HRMS: m/z calcd. for C16H12O2NF2S [M ? H]?:
320.05513; found: 320.05521.
1
6-Fluoro-2-(tosylmethyl)quinoline (3y) White solid (83 %), H NMR (500 MHz,
CDCl3) d 8.10 (d, J = 8.4 Hz, 1H), 7.98–7.79 (m, 1H), 7.65–7.51 (m, 3H), 7.44 (t,
J = 9.8 Hz, 2H), 7.21 (d, J = 7.7 Hz, 2H), 4.70 (s, 2H), 2.39 (s, 3H). 13C NMR
(126 MHz, CDCl3) d 161.70 (s), 159.71 (s), 148.80 (d, J = 2.8 Hz), 144.95 (d,
J = 12.9 Hz), 136.18 (d, J = 5.5 Hz), 135.44 (s), 131.80 (d, J = 9.2 Hz), 129.64
(s), 128.50 (s), 128.06 (d, J = 10.1 Hz), 123.48 (s), 120.26 (s), 120.05 (s), 110.70
(s), 110.53 (s), 65.17 (s), 21.63 (s). HRMS: m/z calcd. for C17H15O2NFS [M ? H]?:
316.08020; found: 316.08008.
Results and Discussion
At the start of our studies, the reaction of 2-methylquinoline with sodium
benzenesulfinate was used as model reaction under various conditions. The effects
of various oxidants, iodine reagents, and temperature on the yield of the reaction
were investigated; the results are summarized in Table 1. To our delight, the
corresponding product was obtained in 88 % yield when tert-butyl peroxybenzoate
(TBPB) was used as oxidant (Table 1, entry 1) in presence of tetrabutylammonium
iodide (TBAI). Very low yield of product was isolated when the reaction was
performed using K2S2O8 as oxidant (Table 1, entry 4). Other oxidants (Table 1,
entries 2, 3, 6) such as tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide
(DTBP), and oxone were ineffective with no desired product being detected. With
respect to the iodine reagent species, TBAI was found to be optimal. Other iodine
reagents such as NH4I, KI, I2O5, and I2 were inferior compared with TBAI (Table 1,
entries 7–10). We next turned our attention to investigate the effect of the catalyst
loading on the sulfonylation reaction (Table 1, entries 11–13). The yield showed no
significant change when the loading of TBAI was decreased to 0.2 equiv. However,
lower product yield of 61 % was obtained when only 0.1 equiv TBAI was added
(Table 1, entry 13). The effect of temperature on the yield of the reaction was also
examined; the results showed that 100 °C was optimal (Table 1, entries 14, 15).
Therefore, the optimized reaction conditions were TBAI (0.2 equiv) and TBPB
(1 equiv) in water at 100 °C for 10 h.
With the optimized reaction conditions in hand, a variety of alkyl azaarenes and
sodium sulfinates were examined to illustrate the efficiency and scope of the TBAI-
catalyzed sulfonylation reaction of C(sp3)–H bond. Generally speaking, alkyl
azaarenes and derivatives with electron-rich or electron-poor groups on the aryl
rings could readily participate in the reaction, providing the desired product in high
yield. There was no obvious electronic effect in the reaction. Alkyl azaarenes
without substituent could react with various sodium sulfinates and afford the desired
product in moderate to high yield (3a–c). Alkyl azaarenes with substituents such as
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D.-Q. Dong et al.
Table 1 Optimization of reaction conditions
Entry
[I] (equiv)
[O] (1 equiv)
Yield (%)a
1
TBAI (1)
TBAI (1)
TBAI (1)
TBAI (1)
TBAI (1)
NH4I (1)
KI (1)
TBPB
TBHP
DTBP
K2S2O8
Oxone
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
88
2
NR
NR
Trace
NR
44
3
4
6
7
8
Trace
Trace
Trace
87
9
I2O5 (1)
10
11
12
13
14
15
I2(1)
TBAI (0.5)
TBAI (0.2)
TBAI (0.1)
TBAI (0.2)
TBAI (0.2)
87
61
87b
75c
1a (0.5 mmol), 2a (2 equiv), water (1 mL), 100 °C, 10 h
aIsolated yield
bReacted at 110 °C
cReacted at 90 °C
Cl, F, Br, OH, and CH3 on the benzene ring were also well tolerated in the reaction
system, reacting with sodium sulfinates to generate the corresponding product in
yield of 74–95 % (3g, h, k–p, s–y). Furthermore, when 2-methylbenzo[d]thiazole
was subjected to this reaction system, the desired product 3q was obtained in 74 %
isolated yield. Substituted sodium sulfinates with different groups were also
investigated. Sodium sulfinates with electron-donating group (CH3) or electron-
withdrawing group (Cl, F) on the phenyl rings could react with alkylquinoline to
give the desired product in moderate to high yield (3e, f, r). Note that sodium
methanesulfinate also showed high reactivity for this transformation, giving the
desired product 3d, j in yield of 79 % and 77 %, respectively (Table 2).
Although water and TBAI are low cost, from the environmental and economic
points of view, recycling of solvent and TBAI was also investigated using the
reaction between 2-methylquinoline (1a) and sodium benzenesulfinate (2a). After
reaction completion, the product was extracted with diethyl ether, and the water and
TBAI were reused for the next time. To our delight, the recovered solvent and TBAI
could be reused for five times without a significant decrease of the yield of the
corresponding product 3a (Table 3).
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Sulfonylation of C(sp3)–H bond for synthesis of…
Table 2 Substrate scope for sulfonylation of azaarenes
Reaction conditions: 1 (0.5 mmol), 2 (2 equiv), TBAI (0.2 equiv), TBPB (1 equiv), water (1 mL), 100 °C,
10 h. Isolated yield
Table 3 Recovery and reuse of
water and TBAI
Entry
1
2
3
4
5
Yield (%)
87
87
84
82
80
1a (0.5 mmol), 2a (2.0 equiv), TBAI (0.2 equiv), TBPB (1 equiv),
water (1 mL)
To understand the reaction mechanism, a series of control experiments were
conducted, as shown in Scheme 1. When 2 equiv 2,2,6,6-tetramethyl-1-piperidiny-
loxy (TEMPO) was added in the standard reaction conditions, the reaction was
completely suppressed (Scheme 2a). If the reaction was conducted in absence of
sodium benzenesulfinate, no 2-(iodomethyl)quinolone was obtained (Scheme 2b).
These observations indicate that radical species may be involved in the present
transformation.
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D.-Q. Dong et al.
Scheme 2 Control experiments
Scheme 3 A plausible reaction mechanism
Based on previous reports [34, 39–43] and our preliminary results, a possible
mechanism is proposed in Scheme 3. In presence of I2 and TBPB, sulfonyl radical
B can be generated from sodium benzenesulfinate A. 2-Methylquinolone undergoes
isomerization to afford intermediate D. Then, addition reaction between B and
D affords intermediate E. Finally, the desired product F is formed with concomitant
formation of HI (Scheme 3). The generated HI could be reused for the next catalytic
cycle.
Conclusions
An efficient and concise method for sulfonylation of alkylazaarenes was developed.
Using water as solvent and TBAI as catalyst, various desired products were obtained
in high yield. Furthermore, water and TBAI could be reused for five times without a
significant decrease of the yield of the corresponding product. Further investigation
on the reaction mechanism and substrate scope is underway in our laboratory.
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Sulfonylation of C(sp3)–H bond for synthesis of…
Acknowledgements We gratefully acknowledge financial support from the National Natural Science
Foundation of China (21402103, 21772107), China Postdoctoral Science Foundation (150030), and
Research Fund of Qingdao Agricultural University’s Highlevel Person (631303).
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