Photoredox-Catalyzed Generation of Sulfamyl Radicals: Sulfonamidation of Enol Silyl Ether with Chlorosulfonamide

Article abstract of DOI:10.1021/acs.joc.9b02062

A novel and practical photoredox-catalyzed generation of sulfamyl radicals followed by radical sulfonamidation of enol silyl ether has been described. Diverse functionalized β-ketosulfonamides were prepared in modest to excellent yields under mild and economic reaction conditions through the present catalytic protocol. Furthermore, the methodology developed provides an efficient and convenient approach to the synthesis of the antiseizure drug Zonisamide.

Full text of DOI:10.1021/acs.joc.9b02062

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Article
Photoredox-Catalyzed Generation of Sulfamyl Radicals:
Sulfonamidation of Enol Silyl Ether with Chlorosulfonamide
Qiyu Luo, Runyu Mao, Yan Zhu, and Yonghui Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02062 • Publication Date (Web): 14 Oct 2019
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Photoredox-Catalyzed Generation of Sulfamyl Radicals:
Sulfonamidation of Enol Silyl Ether with Chlorosulfonamide
Qiyu Luo,‡ Runyu Mao,‡ Yan Zhu and Yonghui Wang*
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Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng
Road, Pudong, Shanghai 201203, China
yonghuiwang@fudan.edu.cn
ABSTRACT: A novel and practical photoredox-catalyzed generation of sulfamyl radicals
followed by radical sulfonamidation of enol silyl ether has been described. Diverse functionalized
β-ketosulfonamides were prepared in modest to excellent yields under mild and economic reaction
conditions through the present catalytic protocol. Furthermore, the methodology developed
provides an efficient and convenient approach to the synthesis of antiseizure drug Zonisamide.
Introduction
Sulfonamide was found to be the most important and valuable functional group in pharmaceutical
and agrochemical industries.1 In 2016, about 15% of the top 100 most prescribed drugs with a
wide range of therapeutic applications such as cancer, cardiovascular, infectious and neurological
diseases contain sulfonamide structure.2 For example, Polmacoxib (A) is a cyclooxygenase-2
(COX-2) inhibitor used to treat osteoarthritis,3 while Zonisamide (B) plays an important role in the
treatment of partial seizures in adults (Figure 1).4 Until now, although the traditional method of
nucleophilic addition of amines to sulfonyl chlorides for synthesizing sulfonamides constitutes a
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large proportion in organic synthesis, it still has several limitations such as poor reaction
selectivity and instability during storage due to the high reactivity of sulfonyl chloride.5 As a
consequence of versatility and importance of sulfonamides, substantial attention was attracted in
recent years to the development of new synthetic methods to prepare sulfonamide containing
molecules. In 2018, Wu group reported a copper-catalyzed aminosulfonylation of aryldiazonium
tetrafluoroborates, DABCO·(SO2)2, and N-chloroamines, affording a wide range of sulfonamides
in moderate to good yields under mild conditions.6 Later a method using calcium triflimide
[Ca(NTf2)2] as a Lewis acid to activate sulfonyl fluorides toward nucleophilic addition with
amines mediating the corresponding sulfonamides in good yields was described by Ball and his
colleagues.7 However, the development of a mild, effective and operationally simple approach to
the synthesis of functionalized sulfonamides is still limited.
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Figure 1. Biologically Active Molecules Containing Sulfonamide Core Structure
Silyl enol ethers are versatile reaction partners for constructing functionalized ketones and their
derivatives in organic synthesis due to its property of reacting rapidly with the electrophilic
carbon-centered radicals.8 In 2011, MacMillan group reported a mild, operationally simple
photoredox-catalyzed approach to the synthesis of α-trifluoromethyl carbonyl compounds from
silyl enol ethers (Scheme 1, a).9 Later a copper-catalyzed oxidative coupling of AIBN and
ketone-derived enoxysilanes to γ-ketonitriles was presented by Huang group (Scheme 1, b).10
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Very recently, Fu group disclosed a pioneering work on photocatalytic decarboxylative alkylations
of silyl enol ethers mediated by triphenylphosphine and sodium iodide (Scheme 1, c).11 Despite
these progress achieved, it is particularly urgent and important to develop new methods to
construct diverse functionalized ketones such as β-ketosulfonamides. Instead of the construction
of S-N bond, installation of the whole aminosulfonyl motif would provide a better accessibility to
complex sulfonamides. To that end, sulfamyl radicals have been considered as the key
intermediates.12 We were intrigued by the possibility whether chlorosulfonamide could serve as a
new radical precursor to react with silyl enol ether generating highly functionalized
β-ketosulfonamides by visible-light-mediated photoredox catalysis which was boomed as a
competitive method for functional-group interconversions.13 Herein, we report a novel and
practical photoredox-catalyzed method for the generation of sulfamyl radicals from
chlorosulfonamide followed by sulfonamidation of enol silyl ether, and demonstrate its application
on efficient synthesis of antiseizure drug Zonisamide.
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Scheme 1. Research Background and Summary of This Work
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Results and Discussion
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To verify the feasibility of our hypothesis, 1-phenyl-1-trimethylsiloxyethylene (1a) and
piperidine-1-sulfonyl chloride (2a) were taken as representative reactants to conduct the
optimization of reaction conditions under a photoredox-catalyzed system. To our delight, the
reaction went smoothly generating the desired β-ketosulfonamide product in 23% yield using
Ru(bpy)3Cl2 as photocatalyst (PC), K2CO3 as base and CH3CN as solvent in blue LED (25 W) at
room temperature (Table 1, entry 1). Further screening of PC revealed that no other PCs were
superior to Ru(bpy)3Cl2 (Table 1, entry 2 and 3). The control experiments found that PC and light
were essential in this photoredox-catalyzed system (Table 1, entry 4 and 5). Further investigation
on ratio of the reactants 1a and 2a indicated that 45% of the product 3a could be obtained when a
ratio of 1a and 2a of 5:1 was applied (Table 1, entry 6-8). Base screening revealed that Et3N was
the best choice by increasing the yield to 67% (Table 1, entry 9). Obviously, the reaction couldn’t
occur in the absence of base (Table 1, entry 10). It is noteworthy that an excellent yield of 90%
(86% isolated yield) was achieved by increasing the loading of PC to 4 mol% (Table 1, entry 11
and 12).
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Table 1. Screening of the Reaction Conditionsa
Ratio
Yield
(%)b
Base
Entry
1
PC (mol%)
(1a : 2a)
Ru(bpy)3Cl2 (2)
K2CO3
K2CO3
2:1
2:1
23
17
2
fac-Ir(ppy)3 (2)
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Eosin Y (2)
-
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
2:1
2:1
2:1
3:1
4:1
5:1
5:1
12
NR
NR
26
5c
6
Ru(bpy)3Cl2 (2)
Ru(bpy)3Cl2 (2)
Ru(bpy)3Cl2 (2)
Ru(bpy)3Cl2 (2)
Ru(bpy)3Cl2 (2)
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67
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Ru(bpy)3Cl2 (2)
Ru(bpy)3Cl2 (3)
Ru(bpy)3Cl2 (4)
-
5:1
5:1
5:1
NR
75
Et3N
Et3N
90(86d)
[a] Reaction conditions: 1a, 2a (0.2 mmol), PC, base (1.0 equiv, 0.2 mmol), CH3CN, blue LED
(25 W), N2, rt, 24 h; [b] HPLC yield; [c] No light; [d] Yield based on 2a.
We then explored the reaction scope with a wide range of silyl enol ethers bearing multiple
functional groups under the optimized reaction conditions as summarized in Table 2. It was
demonstrated that the substrates with different electron-donating groups such as methyl, methoxy,
tert-butyl and phenyl group proceeded smoothly to afford the desired β-ketosulfonamide products
in good yields (Table 2, 3b-3g). In addition, halogen substituents were found to be suitable
candidates in this transformation to produce the corresponding products 3h-3m in 59-96% yields.
Notably the electron-withdrawing substituents such as CF3- (3n), CN- (3o) and COOMe- (3p) on
the para position of the aromatic ring were also compatible in this protocol. Furthermore,
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naphthyl-substituted substrate performed well in 96% yield (Table 2, entry 3q). Interestingly,
heteroaromatic substrates were able to be efficiently converted into the desired
β-ketosulfonamides (Table 2, 3r and 3s). More importantly, a moderate yield was achieved by
using (E)-trimethyl((1-phenylbut-1-en-1-yl)oxy)silane as a substrate in this reaction (Table 2, 3t).
However, for the substrate of trimethyl((2-methyl-1-phenylprop-1-en-1-yl)oxy)silane, the reaction
could hardly occur probably due to steric effect (Table 2, 3u). To our delight, for the less reactive
substrate 3v, the reaction could occur in a satisfactory yield.
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Table 2. Substrate Scope of Various Enol Silyl Ethersa, b
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[a] Reaction conditions: 1 (5.0 equiv, 1.0 mmol), 2a (0.2 mmol), Ru(bpy)3Cl2 (4 mol%, 0.008
mmol), Et3N (1.0 equiv, 0.2 mmol), CH3CN, blue LED (25W), N2, rt, 24 h; [b] Yield based on 2a.
Encouraged by these results, we further probe the reaction generality with respect to different
chlorosulfonamides under the optimized reaction conditions as depicted in Table 3. It was
interesting to learn that unsubstituted chlorosulfonamide could serves as good substrate in this
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process and efficiently formed β-ketosulfonamide 4a which could undergo further
functionalizations in organic synthesis and have applications in pharmaceutical industry. In the
meanwhile, other chlorosulfonamides bearing a mono-substituted group or di-substituted groups
were all converted to the corresponding β-ketosulfonamides smoothly in good to excellent yields
(Table 3, 4b-4g). Interestingly, benzenesulfonyl chloride and ethanesulfonyl chloride (Table 3, 4h
and 4i) were also well tolerated in our photoredox-catalyzed system.
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Table 3. Substrate Scope of Various Sulfonyl Chloridesa, b
[a] Reaction conditions: 1a (5.0 equiv, 1.0 mmol), 2 (0.2 mmol), Ru(bpy)3Cl2 (4 mol%, 0.008
mmol), Et3N (1.0 equiv, 0.2 mmol), CH3CN, blue LED (25W), N2, rt, 24 h; [b] Yield based on 2.
To demonstrate the potential application of our methodology, a gram-scale synthesis was then
performed. 6.0 Mmol of 2a was taken into the model reaction, the corresponding product 3a was
obtained in 78% yield (1.25 g, Scheme 2, d). Next, a one-pot synthetic protocol was attempted by
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using acetophenone as the starting material without purifying the intermediate 1a, but only 17% of
the desired β-ketosulfonamide product 3a was detected by HPLC (Scheme 2, e). Further
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transformations of β-ketosulfonamide were conducted by subjecting 4a into copper-catalyzed
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14
coupling reaction with phenylboronic acid
to provide 5 in 70% yield and nucleophilic
substitution reaction with 1-bromopropane 15 to mediate 6 in 52% yield (Scheme 2, f). To further
demonstrate the utility of the method developed, we have applied it to the preparation of
Zonisamide 16 (Scheme 2, g). Key intermediate 7c could be easily prepared in 71% yield with our
method from intermediate 7b which was derived from commercially available
2'-fluoroacetophenone. Finally, Zonisamide was prepared from β-ketosulfonamide 7c by
sequential hydroxyl amination and cyclization reaction with an overall of 54% yield.
Scheme 2. Functional Group Transformation and Synthetic Application
Gram-scale synthesis:
One-pot synthesis:
Functionalization of β-ketosulfonamide 4a:
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Synthesis of Zonisamide:
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To validate the reaction mechanism, some experiments were designed and carried out. First, the
desired transformation was completely hindered after the introduction of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (Scheme 3, h). Next, reaction with the radical
clock precursor 8a gave the ring-opening product 8 in 29% yield (Scheme 3, i). Last, radical
trapping product was isolated in 49% yield by using 1,1-diphenylethylene under the standard
condition (Scheme 3, j). All these experimental results indicated that a free-radical addition
process was involved in the reaction.
Scheme 3. Mechanistic Study
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In order to understand the quenching cycle of this system, we carried out some luminescence
quenching experiments. It showed that Ru(bpy)3Cl2 luminescence decreased dramatically in the
presence of piperidine-1-sulfonyl chloride (2a), but dropped a little in the presence of
trimethylamine and maintained in the presence of trimethyl[(1-phenylvinyl) oxy] silane (1a)
(Supporting Information, Schemes S1-S3). Also we have determined the quantum yield of the
photoreaction (Φ = 41%).
Based on the present experimental evidence and literature precedent, a plausible mechanism for
the generation of sulfamyl radical followed by sulfonamidation of enol silyl ether was proposed in
Scheme 4. Initially, irradiation of Ru(bpy)3Cl2 with visible light makes it convert into the
excited-state species Ru(bpy)32+*. Immediately single electron transfer (SET) oxidation of
3+
Ru(bpy)32+* by electrophilic chlorosulfonamide generates Ru(bpy)3 and sulfamyl radical D.17
D
subsequently attacks 1-phenyl-1-trimethylsiloxyethylene to produce radical intermediate F. A
2+ 18
second SET oxidation process of F then occurs, generating intermediate G and Ru(bpy)3
.
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Ultimately, eliminating the proton of G in the presence of base gives the desired
β-ketosulfonamide H.
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Scheme 4. Proposed Mechanism
In an attempt to elucidate the reactivity of sulfamyl radical, substituted styrenes with different
electronic properties were subjected to the optimal reaction condition. Only strong
electron-donating group provided the corresponding product (Scheme 5, k), whereas
electron-withdrawing substituent or non-substituted styrenes resulted in no reaction (Scheme 5, l
and m), which indicated the electrophilic character of the sulfamyl radical. Indole was also taken
as a coupling partner in the reaction, but there was no desired product obtained. The electrical
selectivity of sulfamyl radical can guide us to design radical series reactions, and possibly, three
component reactions can be performed.
Scheme 5. Reactivity of Sulfamyl Radical
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Conclusion
In summary, we have developed a novel and practical photoredox-catalyzed generation of
sulfamyl radicals from chlorosulfonamide followed by radical sulfonamidation of enol silyl ethers.
A set of β-ketosulfonamides are synthesized with expanded substrate scope and good functional
group compatibility. Besides, the excellent performance in the synthesis of antiseizure drug
Zonisamide indicates that the transformation is efficient, practical and valuable in organic
synthesis. Further investigation on detailed mechanism and synthetic applications are currently in
progress.
Experimental Section
General Information. All commercially available reagents were used without further purification
unless otherwise stated. Ru(bpy)3Cl2 was purchased from Shanghai Bidepharm. The reactions
were monitored by thin-layer chromatography (TLC) analysis. Silica gel (200−300 mesh) was
used for column chromatography. High-resolution MS (HRMS) was analyzed by a TOF analyzer.
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The ion source is electrospray ionization (ESI). H, 19F NMR spectra were recorded at 400 MHz,
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and 13C NMR spectra was recorded on 600 MHz. Chemical shifts in 1H NMR spectra are reported
in parts per million (ppm) on the δ scale from an internal standard of DMSO-d6 (δ 2.50 ppm). Data
are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, m = multiplet), coupling constant in hertz (Hz), and integration. Chemical shifts of 13C
NMR spectra are reported in ppm from the central peak of DMSO-d6 (δ 39.52 ppm) on the δ scale.
The blue LED was manufactured by Xuzhou Aijia Electronic Technology Co. Ltd.. The power is
25 W, 15 W, 5 W and the wavelength range is from 460 nm to 465 nm. The distance from the
light source to the irradiation vessel is 5 cm. The quantum yield was determined by a FZ-A
irradiatometer, and the luminescence quenching experiment was recorded using a F98
Fluorospectrophotometer.
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General procedure for preparation of silyl enol ethers (GP-1).19 A round-bottom flask
containing a mixture of ketone (1.0 equiv, 10 mmol), sodium iodide (1.2 equiv, 12 mmol) and dry
CH3CN (15 mL) was evacuated and filled with nitrogen three times, stirring for 5 mins at room
temperature. To the resulting solution, triethylamine (1.5 equiv, 15 mmol) and
chlorotrimethylsilane (1.2 equiv, 12 mmol) were added. The reaction mixture was stirred
overnight at room temperature and quenched with a mixture of petroleum ether (25 mL) and
saturated NH4Cl (25 mL) at 0 °C. The organic phase was separated and the aqueous layer was
extracted with petroleum ether (2 × 30 mL). The combined organic fractions were washed with ice
water (25 mL) and saturated NH4Cl (25 mL), and then dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure and the crude product was purified by distillation under
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reduced pressure to deliver silyl enol ethers 1a – 1v.
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General procedure for photoredox-catalyzed sulfamidation of silyl enol ethers (GP-2).
Ru(bpy)3Cl2 (4.0 mol%, 0.008 mmol, 0.004mmol/mL) was added to a dry 10 mL Schlenk tube
with a stirring bar, then air was withdrawn and backfilled with N2 (three times). Dry CH3CN (2
mL), silyl enol ether (5.0 equiv, 1.0 mmol) and sulfamyl chloride (1.0 equiv, 0.2 mmol) were
added under N2. The reaction mixture was stirred under the irradiation of a 25 W blue LED for 24
h at room temperature. After that, the mixture was extracted with ethyl acetate, washed with brine,
dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column
chromatography (petroleum ether / ethyl acetate = 5:1 – 1:1) to provide the product 3a – 3v, 4a –
4i, 7c, 8, 9, 10. Two tubes were set up at the same time.
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Gram-scale synthesis of 3a. Ru(bpy)3Cl2 (4.0 mol%, 0.24 mmol) was added to a dry
round-bottom flask with a stirring bar, then air was withdrawn and backfilled with N2 (three times).
Dry CH3CN (60 mL), 1a (5.0 equiv, 30.0 mmol) and 2a (1.0 equiv, 6.0 mmol) were added under
N2. The reaction mixture was stirred under the irradiation of a 25 W blue LED for 24 h at room
temperature. After that, the mixture was extracted with ethyl acetate, washed with brine, dried
over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography
(petroleum ether / ethyl acetate = 10:1 – 5:1) to provide the product 3a (1.25 g, 78%) as white
solid.
One-pot synthesis of 3a. Crude product of 1a was prepared by GP-1 without reduced pressure
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distillation. Ru(bpy)3Cl2 (4.0 mol%, 0.008 mmol) was added to a dry 10 mL Schlenk tube with a
stirring bar, then air was withdrawn and backfilled with N2 (three times). Dry CH3CN (2.0 mL),
crude 1a (5.0 equiv, 1.0 mmol) and 2a (1.0 equiv, 0.2 mmol) were added under N2. The reaction
mixture was stirred under the irradiation of a 25 W blue LED for 24 h at room temperature. The
yield was determined by HPLC, 17%.
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Procedure for preparation of 2-Oxo-N, 2-diphenylethane-1-sulfonamide (5).14
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round-bottom flask with a stirring bar contained a mixture of 4a (1.0 equiv, 0.4 mmol, 79.6 mg),
Cu(OAc)2 (2.0 equiv, 0.8 mmol, 145.3 mg), phenylboronic acid (3.0 equiv, 1.2 mmol, 146.3 mg),
pyridine (4.0 equiv, 1.6 mmol, 136.2 mg) and CH2Cl2 (4 mL). The reaction mixture was stirred at
room temperature overnight, then extracted with CH2Cl2 (10 ml×2), dried over anhydrous sodium
sulfate, concentrated in vacuo, and purified by column chromatography (petroleum ether / ethyl
acetate = 5:1 – 1:1) to provide the product 5 as white solid.
Procedure for preparation of 2-Oxo-2-phenyl-N-propylethane-1-sulfonamide (6).15
A
round-bottom flask with a stirring bar containing a mixture of 4a (1.0 equiv, 0.4 mmol, 79.6 mg),
1-bromopropane (1.1 equiv, 0.44 mmol, 54.1 mg), K2CO3 (3.0 equiv, 1.2 mmol, 165.6 mg),
acetone (4 mL). The reaction mixture was stirred at 60 ºC in an oil bath, monitored by TLC. After
full conversion, concentrated in vacuo, and purified by column chromatography (petroleum ether /
ethyl acetate = 5:1 – 1:1) to provide the product 6 as white solid.
Procedure for preparation of Benzo [d] isoxazol-3-ylmethanesulfonamide (7).20
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Intermediate 7b was prepared by following GP-1 and 7c was obtained by following GP-2.
A mixture of 7c (1.0 equiv, 0.3 mmol, 65.0 mg), NH2OH·HCl (1.5 equiv, 0.45 mmol, 31.3 mg),
and NaOAc (2.5 equiv, 0.75 mmol, 61.5 mg) in ethanol (1.5 mL) was placed into a 10 mL
round-bottom-flask with a reflux condenser. Then the reaction flask was heated to 95 ºC in an oil
bath and the reaction progress was monitored by TLC. After full conversion, the mixture was
cooled to room temperature and filtered, the solution was concentrated in vacuo without further
purification. Then CH3CN (2 mL) and DBU (4.0 equiv, 1.2 mmol, 182.7 mg) were added to the
crude product, the reaction mixture was refluxed in an oil bath at 85 ºC and monitored by TLC.
After completion of the reaction, the resulting mixture was concentrated in vacuo, and purified by
silica gel chromatography (DCM / MeOH) to provide the final product 7 as white solid and the
total yield was 54%.
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1-Phenyl-2-(piperidin-1-ylsulfonyl) ethan-1-one (3a).21 91.8 mg, yield: 86%, white solid, mp:
106.4 – 107.9 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 7.6 Hz, 2H), 7.70 (t, J = 7.3 Hz,
1H), 7.57 (t, J = 7.7 Hz, 2H), 4.89 (s, 2H), 3.21 – 3.18 (m, 4H), 1.56 – 1.49 (m, 6H); 13C {1H}
NMR (150 MHz, DMSO-d6) δ 189.8, 136.0, 134.1, 129.2, 128.8, 55.9, 46.3, 25.1, 23.1; MS (ESI)
[M+H]+ 268.1.
2-(Piperidin-1-ylsulfonyl)-1-(o-tolyl) ethan-1-one (3b). 74.2 mg, yield: 66%, white solid, mp: 63.8
1
– 65.2 ºC; H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.3 Hz, 1H),
7.39 – 7.33 (m, 2H), 4.81 (s, 2H), 3.15 (s, 4H), 2.42 (s, 3H), 1.49 (s, 6H); 13C {1H} NMR (150
MHz, DMSO-d6) δ 192.7, 138.2, 136.5, 132.3, 131.7, 130.3, 125.8, 58.3, 46.2, 25.1, 23.1, 20.7;
HRMS (ESI-TOF) m/z [M+H]+ calcd for C14H20NO3S 282.1158, found 282.1157.
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2-(Piperidin-1-ylsulfonyl)-1-(m-tolyl) ethan-1-one (3c). 106.8 mg, yield: 95%, white solid, mp:
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72.8 – 75.0 ºC; H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.84 (m, 2H), 7.52 (d, J = 6.6 Hz, 1H),
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7.46 (t, J = 7.6 Hz, 1H), 4.86 (s, 2H), 3.19 (s, 3H), 2.39 – 2.37 (m, 4H), 1.56 – 1.48 (m, 6H); 13C
{1H} NMR (150 MHz, DMSO-d6) δ 189.8, 138.2, 136.0, 134.7, 129.4, 128.6, 126.6, 55.9, 46.2,
25.1, 23.1, 20.8; HRMS (ESI-TOF) m/z [M+H]+ calcd for C14H20NO3S 282.1158, found
282.1157.
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2-(Piperidin-1-ylsulfonyl)-1-(p-tolyl) ethan-1-one (3d). 86.5 mg, yield: 77%, white solid, mp: 73.5
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– 75.3 ºC; H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 6.8 Hz, 2H), 7.38 (d, J = 6.8 Hz, 2H),
4.83 (s, 2H), 3.21 – 3.17 (m, 4H), 2.39 (s, 3H), 1.56 – 1.49 (m, 6H); 13C {1H} NMR (150 MHz,
DMSO-d6) δ 189.2, 144.8, 133.6, 129.4, 129.3, 55.8, 46.3, 25.1, 23.2, 21.2; HRMS (ESI-TOF)
m/z [M+H]+ calcd for C14H20NO3S 282.1158, found 282.1156.
1-(4-Methoxyphenyl)-2-(piperidin-1-ylsulfonyl) ethan-1-one (3e). 102.2 mg, yield: 86%, white
solid, mp: 95.6 – 97.3 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 8.9 Hz, 2H), 7.08 (d, J =
8.9 Hz, 2H), 4.79 (s, 2H), 3.86 (s, 3H), 3.20 – 3.17 (m, 4H), 1.56 – 1.48 (m, 6H); 13C {1H} NMR
(150 MHz, DMSO-d6) δ 187.9, 163.9, 131.8, 129.0, 114.0, 55.8, 55.7, 46.3, 25.1, 23.2; HRMS
(ESI-TOF) m/z [M+H]+ calcd for C14H20NO4S 298.1108, found 298.1106.
1-(4-(Tert-butyl) phenyl)-2-(piperidin-1-ylsulfonyl) ethan-1-one (3f). 105.9 mg, yield: 82%, white
solid, mp: 155.7 – 156.8 ºC; 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 7.2 Hz, 2H), 7.57 (d, J
= 7.2 Hz, 2H), 4.84 (s, 2H), 3.21 – 3.18 (m, 4H), 1.56 – 1.51 (m, 6H), 1.31 (s, 9H); 13C {1H}
NMR (150 MHz, DMSO-d6) δ 189.2, 157.3, 133.5, 129.3, 125. 6, 55.9, 46.2, 34.9, 30.7, 25.1, 23.1;
HRMS (ESI-TOF) m/z [M+H]+ calcd for C17H26NO3S 324.1628, found 324.1629.
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1-([1,1'-Biphenyl]-4-yl)-2-(piperidin-1-ylsulfonyl) ethan-1-one (3g). 113.9 mg, yield: 83%, white
solid, mp: 109.8 – 110.9 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 8.3 Hz, 2H), 7.87 (d, J
= 8.3 Hz, 2H), 7.78 (d, J = 7.5 Hz, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.5 Hz, 1H), 4.92 (s,
2H), 3.23 – 3.21 (m, 4H), 1.58 – 1.50 (m, 6H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 189.3,
145.4, 138.6, 134.8, 123.0, 129.1, 128.6, 127.1, 126.9, 56.0, 46.3, 25.1, 23.1; HRMS (ESI-TOF)
m/z [M+H]+ calcd for C19H22NO3S 344.1315, found 344.1318.
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1-(4-Fluorophenyl)-2-(piperidin-1-ylsulfonyl) ethan-1-one (3h). 109.4 mg, yield: 96%, white solid,
mp: 132.2 – 133.5 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.15 – 8.12 (m, 2H), 7.43 – 7.39 (m, 2H),
4.89 (s, 2H), 3.20 – 3.18 (m, 4H), 1.56 – 1.49 (m, 6H); 13C {1H} NMR (150 MHz, DMSO-d6) δ
188.4, 165.6 (d, J = 255.0 Hz), 132.7, 132.4 (d, J = 9.5 Hz), 132.4, 155.9, 115.9 (d, J = 21.8 Hz),
56.0, 46.3, 25.1, 23.1; 19F {1H} NMR (376 MHz, DMSO-d6) δ -104.41 – -104.38 (m, 1F); HRMS
(ESI-TOF) m/z [M+H]+ calcd for C13H17FNO3S 286.0908, found 286.0907.
1-(4-Chlorophenyl)-2-(piperidin-1-ylsulfonyl) ethan-1-one (3i). 112.0 mg, yield: 93%, white solid,
mp: 148.4 – 150.2 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.7
Hz, 2H), 4.89 (s, 2H), 3.21 – 3.17 (m, 4H), 1.56 – 1.50 (m, 6H); 13C {1H} NMR (150 MHz,
DMSO-d6) δ 188.9, 139.1, 134.6, 131.1, 128.9, 56.1, 46.2, 25.1, 23.1; HRMS (ESI-TOF) m/z
[M+H]+ calcd for C13H17ClNO3S 302.0612, found 302.0611.
1-(4-Bromophenyl)-2-(piperidin-1-ylsulfonyl) ethan-1-one (3j). 120.1 mg, yield: 87%, white solid,
mp: 158.8 – 161.0 ºC; 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4
Hz, 2H), 4.90 (s, 2H), 3.20 – 3.18 (m, 4H), 1.56 – 1.50 (m, 6H); 13C {1H} NMR (150 MHz,
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DMSO-d6) δ 89.1, 134.9, 131.8, 131.2, 128.4, 56.1, 46.2, 25.1, 23.1; HRMS (ESI-TOF) m/z
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[M+H]+ calcd for C13H17BrNO3S 346.0107, found 346.0106.
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1-(2-Fluorophenyl)-2-(piperidin-1-ylsulfonyl) ethan-1-one (3k). 107.2 mg, yield: 94%, white solid,
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mp: 82.7 – 84.1 ºC; H NMR (400 MHz, DMSO-d6) δ 7.93 – 7.90 (m, 1H), 7.73 – 7.71 (m, 1H),
7.40 – 7.36 (m, 2H), 4.79 (s, 2H), 3.19 – 3.16 (m, 4H), 1.56 – 1.49 (m, 6H); 13C {1H} NMR (150
MHz, DMSO-d6) δ 187.4, 160.9 (d, J = 254.4 Hz), 136.0 (d, J = 9.3 Hz), 131.0, 124.8, 117.0 (d, J
= 22.8 Hz), 59.2, 46.2, 25.1, 23.1; 19F {1H} NMR (376 MHz, DMSO-d6) δ -110.63 – -110.57 (m,
1F); HRMS (ESI-TOF) m/z [M+H]+ calcd for C13H17FNO3S 286.0908, found 286.0905.
1-(2,4-Difluorophenyl)-2-(piperidin-1-ylsulfonyl) ethan-1-one (3l). 87.3 mg, yield: 72%, white
solid, mp: 106.4 – 107.6 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.03 (dd, J = 8.4 Hz, 1H), 7.47 (t, J
= 10.3 Hz, 1H), 7.28 (t, J = 8.8 Hz, 1H), 4.78 (s, 2H), 3.19 – 3.17 (m, 4H), 1.56 – 1.50 (m, 6H);
13C {1H} NMR (150 MHz, DMSO-d6) δ 186.2, 165.5 (dd, J = 254.0 Hz, 12.8 Hz), 161.9 (dd, J =
257.7 Hz, 13.2 Hz), 133.4 (d, J = 10.4 Hz), 121.8 (d, J = 10.2 Hz), 112.4 (d, J = 21.6 Hz), 105.4 (t,
J = 26.6 Hz), 59.1, 46.2, 25.1, 23.1; 19F {1H} NMR (376 MHz, DMSO-d6) δ -110.81 – -110.71 (m,
1F), -105.22 – -105.13 (m, 1F); HRMS (ESI-TOF) m/z [M+H]+ calcd for C13H16F2NO3S 304.0813,
found 304.0812.
1-(3,5-Difluorophenyl)-2-(piperidin-1-ylsulfonyl) ethan-1-one (3m). 71.5 mg, yield: 59%, white
solid, mp: 101.4 – 103.4 ºC; 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 6.1 Hz, 2H), 7.67 (t, J
= 8.7 Hz, 1H), 4.96 (s, 2H), 3.21 – 3.18 (m, 4H), 1.56 – 1.50 (m, 6H); 13C {1H} NMR (150 MHz,
DMSO-d6) δ 188.0, 162.4 (dd, J = 246.8 Hz, 12.2 Hz), 138.9 (t, J = 8.0 Hz), 112.4 (d, J = 21.3
Hz), 109.4 (t, J = 25.6 Hz), 56.3, 46.2, 25.1, 23.1; 19F {1H} NMR (376 MHz, DMSO-d6) δ -108.31
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(t, J = 7.5 Hz, 2F); HRMS (ESI-TOF) m/z [M+H]+ calcd for C13H16F2NO3S 304.0813, found
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304.0814.
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2-(Piperidin-1-ylsulfonyl)-1-(4-(trifluoromethyl) phenyl) ethan-1-one (3n). 101.8 mg, yield: 76%,
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white solid, mp: 109.4 – 110.0 ºC; H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.0 Hz, 2H),
7.95 (d, J = 8.0 Hz, 2H), 4.99 (s, 2H), 3.22 – 3.19 (m, 4H), 1.56 – 1.51 (m, 6H); 13C {1H} NMR
(150 MHz, DMSO-d6) δ 189.5, 139.00, 133.2 (q, J = 32.0 Hz), 130.0, 125.7, 123.6 (q, J = 271.0
Hz), 56.4, 46.2, 25.1, 23.1; 19F {1H} NMR (376 MHz, DMSO-d6) δ - 61.72 (s, 3F); HRMS
(ESI-TOF) m/z [M+H]+ calcd for C14H17F3NO3S 336.0876, found 336.0873.
4-(2-(Piperidin-1-ylsulfonyl) acetyl) benzonitrile (3o). 79.4 mg, yield: 68%, white solid, mp: 134.1
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– 137.0 ºC; H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 8.2 Hz, 2H), 8.07 (d, J = 8.2 Hz, 2H),
4.98 (s, 2H), 3.21 – 3.18 (m, 4H), 1.56 – 1.49 (m, 6H); 13C {1H} NMR (150 MHz, DMSO-d6) δ
189.4, 138.9, 132.7, 129.7, 118.0, 115.9, 56.3, 46.2, 25.1, 23.1; HRMS (ESI-TOF) m/z [M+Na]+
calcd for C14H16N2O3SNa 315.0774, found 315.0774.
Methyl 4-(2-(piperidin-1-ylsulfonyl) acetyl) benzoate (3p). 78.0 mg, yield: 60%, white solid, mp:
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92.4 – 94.1 ºC; H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 8.3 Hz, 2H), 8.11 (d, J = 8.3 Hz,
2H), 4.96 (s, 2H), 3.90 (s, 3H), 3.21 – 3.18 (m, 4H), 1.56 – 1.51 (m, 6H); 13C {1H} NMR (150
MHz, DMSO-d6) δ 189.7, 165.4, 139.2, 133.9, 129.4, 129.4, 56.3, 52.6, 46.2, 25.1, 23.1; HRMS
(ESI-TOF) m/z [M+H]+ calcd for C15H20NO5S 326.1057, found 326.1056.
1-(Naphthalen-2-yl)-2-(piperidin-1-ylsulfonyl) ethan-1-one (3q). 121.7 mg, yield: 96%, white
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solid, mp: 109.0 – 111.3 ºC; H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.14 (d, J = 7.8 Hz,
1H), 8.05 – 8.02 (m, 3H), 7.71 – 7.68 (m, 2H), 5.03 (s, 2H), 3.24 – 3.22 (m, 4H), 1.54 – 1.49 (m,
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6H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 189.7, 135.3, 133.3, 132.1, 132.0, 129.8, 129.2,
128.4, 127.7, 127.2, 123.8, 56.0, 46.3, 25.1, 23.1; HRMS (ESI-TOF) m/z [M+H]+ calcd for
C17H20NO3S 318.1158, found 318.1160.
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2-(Piperidin-1-ylsulfonyl)-1-(pyridin-3-yl) ethan-1-one (3r). 61.1 mg, yield: 57%, white solid, mp:
100.3 – 102.1 ºC; 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.85 (d, J = 4.0 Hz, 1H), 8.38 (d,
J = 8.0 Hz, 1H), 7.62 (dd, J = 8.0, 4.0 Hz 1H), 4.98 (s, 2H), 3.21 – 3.19 (m, 4H), 1.56 – 1.51 (m,
6H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 189.4, 154.1, 150.3, 136.5, 131.3, 123.9, 56.4, 46.2,
25.1, 23.1; HRMS (ESI-TOF) m/z [M+H]+ calcd for C12H17N2O3S 269.0954, found 269.0952.
2-(Piperidin-1-ylsulfonyl)-1-(thiophen-2-yl) ethan-1-one (3s). 90.6 mg, yield: 83%, white solid,
mp: 135.4 – 137.5 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 4.0 Hz, 1H), 8.14 (d, J = 4.0
Hz, 1H), 7.31 (t, J = 4.0 Hz, 1H), 4.81(s, 2H), 3.21 – 3.18 (m, 4H), 1.55 – 1.52 (m, 6H); 13C {1H}
NMR (150 MHz, DMSO-d6) δ 182.1, 143.3, 137.1, 136.5, 129.0, 56.6, 46.3, 25.1, 23.1; HRMS
(ESI-TOF) m/z [M+H]+ calcd for C11H16NO3S2 274.0566, found 274.0564.
1-Phenyl-2-(piperidin-1-ylsulfonyl) butan-1-one (3t). 68.4 mg, yield: 58%, white solid, mp: 105.3
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– 107.1 ºC; H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 7.6 Hz, 2H), 7.71 (t, J = 6.9 Hz, 1H),
7.58 (t, J = 6.7 Hz, 2H), 5.49 – 5.46 (m, 1H), 3.15 – 3.13 (m, 4H), 2.20 – 2.12 (m, 1H), 1.99 –
1.92 (m, 1H), 1.43 – 1.40 (m, 6H), 0.83 (t, J = 6.0 Hz, 3H); 13C {1H} NMR (150 MHz, DMSO-d6)
δ 193.1, 137.1, 134.0, 128.8, 66.6, 46.7, 25.5, 23.1, 21.4, 10.9; HRMS (ESI-TOF) m/z [M+H]+
calcd for C15H22NO3S 296.1315, found 296.1315.
2-(Piperidin-1-ylsulfonyl)-2,3-dihydro-1H-inden-1-one (3v). 65.8 mg, yield: 59%, white solid, mp:
1
93.9 – 95.8 ºC; H NMR (400 MHz, DMSO-d6) δ 7.77 – 7.70 (m, 2H), 7.66 (d, J = 7.6 Hz, 1H),
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7.49 (t, J = 7.3 Hz, 1H), 4.68 (dd, J = 8.0, 2.7 Hz, 1H), 3.60 – 3.54 (m, 1H), 3.44 – 3.39 (m, 1H),
3.33 – 3.23 (m, 4H), 1.51 – 1.49 (m, 6H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 195.8, 152.7,
135.8, 135.5, 128.1, 126.9, 123.8, 64.9, 46.6, 29.2, 25.4, 23.2; HRMS (ESI-TOF) m/z [M+H]+
calcd for C14H18NO3S 280.1002, found 280.1004.
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2-Oxo-2-phenylethane-1-sulfonamide (4a). 59.7 mg, yield: 75%, white solid, mp: 152.7 – 154.0
ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 7.9 Hz, 2H), 7.69 (t, J = 7.3 Hz, 1H), 7.56 (t, J
= 7.6 Hz, 2H), 7.17 (s, 2H), 4.81 (s, 2H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 190.0, 135.9,
133.9, 129.2, 128.7, 61.8; HRMS (ESI-TOF) m/z [M-H]— calcd for C8H8NO3S 198.0230, found
198.0230.
N, N-dimethyl-2-oxo-2-phenylethane-1-sulfonamide (4b).22 68.1 mg, yield: 75%, white solid, mp:
81.6 – 82.8 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 7.6 Hz, 2H), 7.71 (t, J = 7.4 Hz, 1H),
7.57 (t, J = 7.6 Hz, 2H), 4.93 (s, 2H), 2.83 (s, 6H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 189.9,
135.9, 134.1, 129.2, 128.8, 54.8, 37.4; MS (ESI) [M+H]+ 228.1.
N, N-diethyl-2-oxo-2-phenylethane-1-sulfonamide (4c).23 87.7 mg, yield: 86%, white solid, mp:
56.6 – 58.4 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 7.2 Hz, 2H), 7.70 (t, J = 7.4 Hz, 1H),
7.56 (t, J = 7.7 Hz, 2H), 4.90 (s, 2H), 3.24 – 3.19 (m, 4H), 1.12 – 1.09 (t, J = 6.0 Hz, 6H); 13C {1H}
NMR (150 MHz, DMSO-d6) δ 189.7, 135.9, 134.0, 129.2, 128.7, 58.2, 42.2, 14.6; MS (ESI)
[M+H]+ 256.2.
N-isopropyl-2-oxo-2-phenylethane-1-sulfonamide (4d). 78.1 mg, yield: 81%, white solid, mp: 81.7
1
– 84.0 ºC; H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 7.9 Hz, 2H), 7.69 (t, J = 7.4 Hz, 1H),
7.56 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 7.1 Hz, 1H), 4.85 (s, 2H), 3.55 – 3.47 (m, 1H), 1.11 (d, J =
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6.5 Hz, 6H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 189.9, 136.0, 133.9, 129.3, 128.7, 59.7, 45.5,
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23.6; HRMS (ESI-TOF) m/z [M+Na]+ calcd for C11H15NO3SNa 264.0665, found 264.0666.
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1-Phenyl-2-(pyrrolidin-1-ylsulfonyl) ethan-1-one (4e).24 82.0 mg, yield: 81%, white solid, mp:
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99.0 – 101.2 ºC; H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 6.9 Hz, 2H), 7.70 (t, J = 6.8 Hz,
1H), 7.57 (t, J = 6.7 Hz, 2H), 4.97 (s, 2H), 3.31 – 3.28 (m, 4H), 1.86 – 1.83 (m, 4H); 13C {1H}
NMR (150 MHz, DMSO-d6) δ 190.1, 136.0, 134.1, 129.3, 128.8, 55.1, 47.8, 25.3; MS (ESI)
[M+H]+ 254.1.
2-((4-Methylpiperazin-1-yl) sulfonyl)-1-phenylethan-1-one (4f). 93.7 mg, yield: 83%, white solid,
mp: 60.4 – 62.1 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 7.5 Hz, 2H), 7.71 (t, J = 7.3 Hz,
1H), 7.57 (t, J = 7.7 Hz, 2H), 4.95 (s, 2H), 3.23 (t, J = 6.1 Hz, 4H), 2.36 (t, J = 6.0 Hz, 4H), 2.19
(s, 3H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 189.7, 135.9, 134.2, 129.2, 128.8, 55.9, 54.0,
45.4, 45.3; HRMS (ESI-TOF) m/z [M+H]+ calcd for C13H19N2O3S 283.1111, found 283.1113.
2-(Morpholinosulfonyl)-1-phenylethan-1-one (4g).25 78.5 mg, yield: 73%, white solid, mp: 135.1 –
137.0 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 7.8 Hz, 2H), 7.71 (t, J = 7.9 Hz, 1H), 7.58
(t, J = 8.1 Hz, 2H), 5.00 (s, 2H), 3.63 (t, J = 6.3 Hz, 4H), 3.23 (t, J = 6.1 Hz, 4H); 13C {1H} NMR
(150 MHz, DMSO-d6) δ 189.7, 135.9, 134.2, 129.2, 128.8, 65.8, 55.7, 45.6; MS (ESI) [M+H]+
270.1.
1-Phenyl-2-(phenylsulfonyl) ethan-1-one (4h).26 86.3 mg, yield: 83%, white solid, mp: 95.8 – 97.1
ºC; 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 7.2 Hz, 2H), 7.91 (t, J = 7.6 Hz, 2H), 7.73 (t, J
= 6.6 Hz, 1H), 7.69 – 7.62 (m, 3H), 7.52 (t, J = 6.8 Hz, 2H), 5.37 (s, 2H); 13C {1H} NMR (150
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MHz, DMSO-d6) δ 189.1, 139.5, 135.7, 134.2, 134.0, 129.2, 129.0, 128.7, 128.0, 62.1; MS (ESI)
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[M+H]+ 260.9.
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2-(Ethylsulfonyl)-1-phenylethan-1-one (4i).27 25.5 mg, yield: 30%, colourless liquid; H NMR
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(400 MHz, DMSO-d6) δ 8.08 (d, J = 7.6 Hz, 2H), 7.71 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.5 Hz, 2H),
5.11 (s, 2H), 3.31 (q, J = 7.3 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H); 13C {1H} NMR (150 MHz,
DMSO-d6) δ 190.2, 136.0, 134.5, 129.3, 129.0, 58.5, 48.2, 6.2; MS (ESI) [M+H]+ 213.0.
2-Oxo-N, 2-diphenylethane-1-sulfonamide (5). 77.0 mg, yield: 70%, white solid, mp: 97.6 – 100.2
ºC; 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.00 (d, J = 7.1 Hz, 2H), 7.68 (t, J = 6.9 Hz,
1H), 7.54 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.0 Hz, 2H), 7.25 (d, J = 7.3 Hz, 2H), 7.12 (t, J = 6.8 Hz,
1H), 4.92 (s, 2H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 189.2, 137.7, 135.8, 134.1, 129.2,
128.7, 124.1, 120.2, 57.8; HRMS (ESI-TOF) m/z [M+H]+ calcd for C14H14NO3S 276.0689, found
276.0688.
2-Oxo-2-phenyl-N-propylethane-1-sulfonamide (6).28 50.1 mg, yield: 52%, white solid, mp: 101.8
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– 103.4 ºC; H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 7.2 Hz, 1H),
7.56 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 5.6 Hz, 1H), 4.86 (s, 2H), 2.97 – 2.92 (m, 2H), 1.48 – 1.43 (m,
2H), 0.85 (t, J = 6.1 Hz, 3H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 188.9, 134.9, 132.9, 128.2,
127.7, 57.6, 43.5, 21.8, 10.1; MS (ESI) m/z [M-H]– 240.2.
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((1-(2-Fluorophenyl) vinyl) oxy) trimethylsilane (7b). 840.0mg, yield: 95%, colorless liquid; H
NMR (400 MHz, DMSO-d6) δ 7.53 (t, J = 8.0 Hz, 1H), 7.38 – 7.35 (m, 1H), 7.22 (t, J = 9.7 Hz,
2H), 4.93 (s, 1H), 4.68 (s, 1H), 0.23 (s, 9H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 159.4 (d, J =
248.1 Hz), 150.0, 130.0 (d, J = 8.6 Hz), 128.5, 124.9 (d, J =11.0 Hz), 124.1, 115.9 (d, J = 23.0 Hz),
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96.8 (d, J = 10.7 Hz), 0.2; 19F {1H} NMR (376 MHz, DMSO-d6) δ -113.39 – -113.33 (m, 1F);
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HRMS (ESI-TOF) m/z [M+H]+ calcd for C11H16FOSi 211.0949, found 211.0944.
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2-(2-Fluorophenyl)-2-oxoethane-1-sulfonamide (7c). 122.4 mg, yield: 71%, white solid, mp:
155.0 – 155.7 ºC; 1H NMR (400 MHz, DMSO-d6) δ 7.90 (t, J = 8.0 Hz, 1H), 7.73 – 7.68 (m, 1H),
7.42 – 7.31 (m, 2H), 7.20 (s, 2H), 4.75 (s, 2H).; 13C {1H} NMR (150 MHz, DMSO-d6) δ 187.7,
161.6 (d, J = 254.4 Hz), 135.9 (d, J = 8.7 Hz), 131.1, 124.8, 116.9 (d, J = 22.7 Hz), 65.1; 19F {1H}
NMR (376 MHz, DMSO-d6) δ -110.48 – -110.42 (m, 1F); HRMS (ESI-TOF) m/z [M-H]— calcd
for C8H7FNO3S 216.0136, found 216.0139.
Benzo [d] isoxazol-3-ylmethanesulfonamide (7).29 52.0 mg, yield: 54%, white solid, mp: 163.9 –
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165.4 ºC; H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H),
7.67 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.28 (s, 2H), 4.85 (s, 2H); 13C {1H} NMR (150
MHz, DMSO-d6) δ 162.8, 150.7, 130.4, 123.8, 123.3, 121.0, 109.6, 50.8; MS (ESI) m/z [M-H]–
211.0.
(E)-1-((5-Chloro-2-phenylpent-2-en-1-yl) sulfonyl) piperidine (8). 37.9 mg, yield: 29%, white
solid, mp: 106.4 – 108.2 ºC; 1H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 7.0 Hz, 2H), 7.35 (t, J
= 6.9 Hz, 2H), 7.28 (t, J = 6.6 Hz, 1H), 6.09 (t, J = 6.7 Hz, 1H), 4.32 (s, 2H), 3.77 (t, J = 6.2 Hz,
2H), 3.03 – 3.00 (m, 4H), 2.77 (q, J = 5.6 Hz, 2H), 1.44 – 1.39 (m, 6H); 13C {1H} NMR (150 MHz,
DMSO-d6) δ 140.9, 132.6, 130.6, 128.3, 127.3, 126.3, 45.9, 44.2, 32.2, 25.1, 23.1; HRMS
(ESI-TOF) m/z [M+Na]+ calcd for C16H22ClNO2SNa 350.0952, found 350.0961.
1-((2,2-Diphenylvinyl) sulfonyl) piperidine (9). 64.1 mg, yield: 49%, white solid, mp: 100.4 –
102.8 ºC; 1H NMR (400 MHz, DMSO-d6) δ 7.43 – 7.38 (m, 6H), 7.30 – 7.28 (m, 2H), 7.22 – 7.20
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(m, 2H), 6.92 (s, 1H), 3.08 – 3.05 (m, 4H), 1.51 – 1.48 (m, 6H); 13C {1H} NMR (150 MHz,
DMSO-d6) δ 153.1, 139.3, 136.7, 129.8, 129.2, 128.6, 128.3, 128.1, 127.7, 122.5, 45.8, 25.0, 23.0;
HRMS (ESI-TOF) m/z [M+H]+ calcd for C19H22NO2S 328.1366, found 328.1366.
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(E)-1-((4-methoxystyryl) sulfonyl) piperidine (10). 64.1 mg, yield: 41%, white solid, mp: 125.9 –
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127.0 ºC; H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 15.4 Hz, 1H),
7.08 (d, J = 15.4 Hz, 1H), 6.99 (d, J = 8.3 Hz, 2H), 3.80 (s, 3H), 3.04 – 3.02 (m, 4H), 1.56 – 1.44
(m, 6H); 13C {1H} NMR (150 MHz, DMSO-d6) δ 161.2, 141.9, 130.4, 125.3, 119.7, 114.3, 55.3,
46.1, 24.8, 23.0; HRMS (ESI-TOF) m/z [M+H]+ calcd for C14H20NO3S 282.1158, found
282.1157.
Associated Content
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
XXX
1
Reaction optimization, Quantum yield measurement, Luminescence quenching experiment, H,
13C and 19F NMR data for all compounds (PDF).
Author Information
Corresponding Author
*E-mail for Y. Wang: yonghuiwang@fudan.edu.cn
Author Contributions
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‡Luo, Q.-Y. and Mao, R.-Y. contributed equally.
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Notes
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The authors declare no competing financial interest.
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Acknowledgments
This work was supported by National Science Foundation of China (Grant Numbers: 81573276;
81874287), Shanghai Bio-pharmaceutical Science and Technology Supporting Plan (Grant
Number: 17431902100; 19431900100), National Science and Technology Major Project Key New
Drug Creation and Manufacturing Program, China (Grant Number: 2018ZX09711002-003-014),
and Fudan-SIMM Joint Research Fund (Grant Number: FU-SIMM20174007).
References
(1) For selected examples, see: (a) Drews, J. Drug Discovery: A Historical Perspective. Science
2000, 287, 1960-1964. (b) Harrak, Y.; Casula, G.; Basset, J.; Rosell, G.; Plescia, S.; Raffa, D.
M.; Cusimano, G.; Pouplana, R.; Pujol, M. D. Synthesis, Anti-Inflammatory Activity, and in
Vitro Antitumor Effect of a Novel Class of Cyclooxygenase Inhibitors: 4-(Aryloyl)phenyl
Methyl Sulfones. J. Med. Chem. 2010, 53, 6560-6571. (c) Mojzych, M.; Karczmarzyk, Z.;
̆
Wysocki, W.; Ceruso, M.; Supuran, C. T.; Krystof, V.; Urbańczyk-Lipkowska, Z.; Kalicki, P.
New Approaches to the Synthesis of Sildenafil Analogues and Their Enzyme Inhibitory
Activity. Bioorg. Med. Chem. 2015, 23, 1421-1429. (d) Ilardi, E. A.; Vitaku, E.; Njardarson, J.
T. Data-Mining for Sulfur and Fluorine: An Evaluation of Pharmaceuticals to Reveal
Opportunities for Drug Design and Discovery. J. Med. Chem. 2014, 57, 2832-2842.
(2) Devendar, P.; Yang, G.-F. Sulfur-Containing Agrochemicals. Top. Curr. Chem. 2017, 375,
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82.
5
6
7
8
9
(3) Kim, H. T.; Cha, H.; Hwang, K. Y. Structural Insight into the Inhibition of Carbonic
Anhydrase by the COX-2-Selective Inhibitor Polmacoxib (CG100649). Biochem. Bioph. Res.
Co. 2016, 478, 1-6.
10
11
12
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15
16
17
18
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23
24
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27
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45
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47
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55
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57
58
59
60
(4) Reimers, A.; Ljung, H. An Evaluation of Zonisamide, Including Its Long-Term Efficacy, for
the Treatment of Focal Epilepsy. Expert Opin. Pharmaco. 2019, 20, 909-915.
(5) Goldberg, F. W.; Kettle, J. G.; Kogej, T.; Perry, M. W. D.; Tomkinson, N. P. Designing
Novel Building Blocks is an Overlooked Strategy to Improve Compound Quality. Drug
Discov. Today 2015, 20, 11-17.
(6) Zhang, F.; Zheng, D.-Q.; Lai, L.-F.; Cheng, J.; Sun, J.-T.; Wu, J. Synthesis of Aromatic
Sulfonamides through a Copper-Catalyzed Coupling of Aryldiazonium Tetrafluoroborates,
DABCO·(SO2)2, and N Chloroamines. Org. Lett. 2018, 20, 1167-1170.
(7) Mukherjee, P.; Woroch, C. P.; Cleary, L.; Rusznak, M.; Franzese, R. W.; Reese, M. R.;
Tucker, J. W.; Humphrey, J. M.; Etuk, S. M.; Kwan, S. C.; Ende, C. W.; Ball, N. D.
Sulfonamide Synthesis via Calcium Triflimide Activation of Sulfonyl Fluorides. Org. Lett.
2018, 20, 3943-3947.
(8) (a) Kong, W.-G.; Yu, C.-J.; An, H.-J.; Song, Q.-L. Photoredox-Catalyzed Decarboxylative
Alkylation of Silyl Enol Ethers to Synthesize Functionalized Aryl Alkyl Ketones. Org. Lett.
2018, 20, 349-352. (b) Yang, H.-B.; Selander, N. Divergent Iron-Catalyzed Coupling of
O-Acyloximes with Silyl Enol Ethers. Chem. Eur. J. 2017, 23, 1779-1783. (c) Zhou, Z.;
Cheng, Q.-Q.; Kürti, L. Aza-Rubottom Oxidation: Synthetic Access to Primary
α-Aminoketones. J. Am. Chem. Soc. 2019, 141, 2242-2246. (d) Cai, S.-H.; Xie, J.-H.; Song,
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