Copper-Catalyzed Oxidative Trifunctionalization of Olefins: An Access to Functionalized β-Keto Thiosulfones

Article abstract of DOI:10.1021/acs.joc.8b01161

Aerobic oxidative trifunctionalization of olefins for the synthesis of functionalized β-keto thiosulfones has been described. The transformation proceeds through molecular oxygen activation under copper catalysis and forms the two new C-S bonds in a single operation using mild conditions. A novel Cu-catalyzed sulfonyl radical addition/oxidation/funtionalization relay mechanism was proposed for the discovered reaction.

Full text of DOI:10.1021/acs.joc.8b01161

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Note
Copper-Catalyzed Oxidative Trifunctionalization of
Olefins: An Access to Functionalized #-keto Thiosulfones
Shuai Huang, Nuligonda Thirupathi, Chen-Ho Tung, and Zhenghu Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01161 • Publication Date (Web): 20 Jul 2018
Downloaded from http://pubs.acs.org on July 20, 2018
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CopperꢀCatalyzed Oxidative Trifunctionalization of Olefins:
An Access to Functionalized βꢀketo Thiosulfones
9
Shuai Huang†, Nuligonda Thirupathi†, Chen-Ho Tung† and Zhenghu Xu*†‡
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†Key Lab of Colloid and Interface Chemistry of Ministry of Education,
School of Chemistry and Chemical Engineering, Shandong University, No.
27 South Shanda Road, Jinan, Shandong 250100, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR
China
xuzh@sdu.edu.cn
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O
SO2Ph
CuTc, bpy
PhSO2SR
SR
28 examples
O2 activation
Mild conditions
air, 50 o
C
Alkene trifunctionalization
Broad scope
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Abstract: Aerobic oxidative trifunctionalization of olefins for the synthesis of functionalized
βꢀketo thiosulfones has been described. The transformation proceeds through molecular
oxygen activation under copper catalysis, and forms the two new CꢀS bonds in a single
operation using mild conditions.
A
novel Cuꢀcatalyzed sulfonyl radical
addition/oxidation/funtionalization relay mechanism was proposed for the discovered
reaction.
In past few decades, oxidative difunctionalization of olefins has attracted great
attention,1 as it introduce diverse functional groups through the formation of a carbonyl
group and another new CꢀC or Cꢀhetero atom bonds.2 Consequently, numerous synthetic
efforts have been made in this direction towards the great success. Although significant
progress has been made towards the oxidative difunctionalization of olefins, reactions
towards the trifunctionalization of olefins,3 where the synergistic formation of a carbonyl
group and two new CꢀC or CꢀX bonds has not been explored. The major reason may be
due to the lack of an effective method to realize such challenging transformations.
On the other hand, organo sulphur compounds are ubiquitously found in a large
number of natural products and chiral ligands and have gained a sizable attention due to
the wide range of biological and medicinal properties.4 Among them, substituted βꢀ
thiofunctionalized ketones particularly occupy a pivotal position, since they are not only
found in the structures of bioactive and drug molecules, but also important building
blocks in organic synthesis.5 In this context, numerous synthetic methods towards
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thiofunctionalize ketones have been developed (Scheme 1).6 Typically βꢀ
thiofunctionalized ketones are synthesized from the nucleophillic substitution on αꢀhalo
carbonyl compounds in the presence of thiolates.7 Recently, Zhang reported a [2,3]ꢀ
sigmatropic rearrangement reaction between allyl sulfide and in situ generated carbene
intermediate.6b The Lei group reported an oxygen promoted oxidatve difunctionalizaton
reaction to βꢀketo sulfides and sulfones from vinylphosphates under catalyst free
conditions.6c Although useful, many of the reported methods suffering from severe
drawbacks such as harsh reaction conditions, longer reaction times, limited substrate
scope, low yields and the prefunctionalization of starting materials.8 All the above
approaches can only introduce one sulfur atom adjacent to carbonyl group. Therefore, the
development of new and efficient synthetic methods particularly, that starting from
readily available starting materials to construct a diverse functionalized βꢀthio ketone is
highly desirable. Herein, we report the first copperꢀcatalyzed alkene oxidative
trifunctionalization reaction, which synergistically forms one carbonyl group and two
new CꢀS bonds under mild conditions.
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Scheme 1. Oxidative alkene functionalization reactions.
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Previously, we developed a gold/photoredoxꢀmediated alkene disulfuration reaction by
using electrophilic S ꢀphenyl benzenesulfonothioate.9 Inspired by recent reports on
alkene oxidative functionalization,10 we became curious about the oxidative
functionalization of styrene with benzenesulfonothioate. Initially we choose styrene 1a
and Sꢀbutyl benzenesulfonothioate 2a as model substrates. Pleasingly, the
trifunctionalized product 3a was isolated in 46% yields in the presence of 20 mol % of
copper(I)ꢀthiopheneꢀ2ꢀcarboxylate, together with 20 mol % of bipyridine (bpy) ligand in
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o
MeCN at 80 C under air (Scheme 2). Further, the structure of product 3a was
unambiguously characterized by single Xꢀray analysis.
Scheme 2. Initial formation of the trifunctionalization product.
Encouraged by this initial result we next focused our attention towards the
optimization of the reaction conditions. (Table 1) Various solvents were tested first
(entries 1ꢀ4), the reaction proceeded also very well in other polar solvents such as DMF
and DMSO, and the latter was found as the best solvent, giving the target product in 62%
yield (entry 4). Toluene could not deliver any product. Performing the reaction in CH3CN
also produced the desired product in reasonable yield (entry 1). These data indicated that
the oxygen atom in the final product came from molecular oxygen, but not from the
solvent DMSO. Other commonly used copper catalysts such as Cu(OTf)2,
Cu(CH3CN)4PF6 were also screened and found to be less productive. Other oxidants such
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as H2O2 and 1,4ꢀbenzoquinone under the same conditions provided diminished yields
(entries 8, 9). Lower the temperature to 50 oC and adding 10 equivalents of water slightly
improved the reaction yield to 68% yield (entriey 11). Finally, the product could be
isolated in the highest 75% yield by increasing the loading of the thiolation reagent 2a
(entry 12). When performing the reaction under nitrogen atmosphere, only traces of the
product was observed (entry 13).
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Table 1. Optimization of Reaction Conditionsa
.
a
Reaction conditions: Styrene 1a (0.2 mmol), PhSO2SC4H9 2a (0.4 mmol), catalyst (20mmol%), bpy
(20mmol%) in solvent (1mL), in the air. b H2O2 (0.4 mmol), or Quinone (1,4ꢀBenzoquinone, 0.4 mmol), or
H2O (2mmol). c Isolated yield. d PhSO2SC4H9 (0.6 mmol). e Under N2 atmosphere.
After having the optimizing conditions in hand, we next investigated the scope and
limitation of the method. First, a variety of commercially available styrene derivatives
(1aꢀo) were exposed to standard reaction conditions and the results are presented in
Table 2. A variety of electronically rich, neutral and poor styrenes were well tolerated
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under the standard conditions and afforded the corresponding α functionalized βꢀketo
thioethers (3aꢀq) in moderate to good yields (28ꢀ75%). Various functional groups at the
para position of styrene such as alkyl, fluoro, chloro, bromo, cyano, methoxy, acetoxy,
were well tolerated and produced the corresponding βꢀketo thioethers (3aꢀi) in moderate
to good yields (45ꢀ75%). Methyl styrene 1o and indene 1p also afforded the
corresponding ketones (3o, 3p), albeit in low yields (38 and 43%). Vinylnaphthalene 1o
also produced corresponding βꢀketo thioether (3q) without much complication. However,
Aliphatic alkenes are not suitable for this transformation under this conditions.
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Table 2. Substrate Scope of Alkenes for the Synthesis of βꢀKeto thioethersa
.
aReaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), Copper thiopheneꢀ2ꢀcarboxylate(20 mol%), bpy
o
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(20 mol%), DMSO (1 mL), H2O (36 mg), 50 C, 12h, in the air. Ligand: 1,10ꢀphen instead of bpy;
Reaction time: 24 h; 80 oC.
Then we turned to investigate the scope of the oxidative trifunctionalization reaction
with respective to PhSO2SR. Thus, a variety of Sꢀalkyl benzenesulfonothioates were
reacted with styrene under the optimized conditions and results are summarized in Table
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3. A variety of Sꢀalkyl benzenesulfonothioates 2 were synthesized. As it is evident in
Table 3, Sꢀalkyl benzenesulfonothioates (2bꢀi) were tolerated to standard conditions and
afforded corresponding βꢀketo thioether derivatives (3rꢀy) in good yields (50ꢀ70%). Sꢀ
aryl benzenesulfonothioates (2j, 2k) also produced corresponding βꢀketo sulphides (3z,
3aa) with moderate yields. Unfortunately, Seꢀphenyl benzenesulfonothioate substrate 2l
is less reactive in standard conditions and produced the corresponding βꢀketo sulphides
3ab in lower (37%) yield.
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Table 3. Substrate Scope of PhSO2SR for the Synthesis of βꢀKeto thioethersa
.
a Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), Copper thiopheneꢀ2ꢀcarboxylate (20 mol%), bpy
o
b
(20 mol%), DMSO (1 mL), H2O (36 mg), 50 C, 12h in the air. Ligand: 1,10ꢀphen instead of bpy;
Reaction time: 24 h; 80 oC.
Several control experiments were conducted to explore the mechanism of this reaction.
When radical scavenger was added in the reaction system, no product was formed (eq. 1,
Scheme 3). Since styrenes can be aerobically oxidized to aldehyde and acetophenone, the
reaction of acetophenone 4 under standard reaction was performed and do not lead to any
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products (eq. 2, Scheme 3), which indicated that acetophenone is not a reaction
intermediate. The reaction of βꢀketo sulfone 5 with 2a under standard conditions gave
product 3a in 58% yield (eq. 3, Scheme 3), indicating 5 might be a possible reaction
intermediate. However we couldn't detect or isolate 5 from the reaction mixture, a
possible reason might be that this step is a fast reaction, and indeed the reaction of 5 with
2a could produce sulfenylation product 3a in 92% yield in the presence of base without
copper catalyst under N2 atmosphere (eq. 4, Scheme 3).
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Scheme 3. Control experiments.
Based on these results and literature precedents, a possible reaction mechanism has
been proposed as depicted in Scheme 4. First, Sꢀphenyl benzenesulfonothioate 1 may
react with copper(I) catalyst to produce sulfonyl radical, which could react with styrene
to produce radical intermediate A. Intermediate A produces the peroxy radical B by
activating molecular oxygen in presence of Lꢀ[Cu]SC4H9.1j Fragmentation of peroxy
radical produces the βꢀketo sulfone C, which would then react with the expelled Lꢀ
[CuOH]+ 1h to produce intermediate D. Finally, intermediate D yields the title product via
reductive elimination, and regenerates the copper catalyst.
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Scheme 4. Possible reaction pathways.
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In summary, the first copperꢀcatalyzed trifunctionalization of alkenes via O2 activation
has been developed. The attractive features of the method include, commercial
accessibility and stability of starting materials, experimental simplicity, broad substrate
scope, mild reaction conditions, providing an easy and reliable access to βꢀ
thiofunctionalize ketones in good yields. This strategy can be applied in other oxidative
alkene trifunctionalization reactions.
Experimental Section
General Details. Unless otherwise noted, all the reagents were obtained commercially
and used without further purification and reactions were monitored by TLC. Analytic
grade solvents for the chromatography were used as received. All NMR spectra were
recorded on Brukerꢀ500 MHz spectrometer. HRMS were measured on the QꢀTOF6510
instruments.
Typical Procedure for the Synthesis of Substituted Benzenesulfonothioate (2aꢀ2i). To
a solution of PhSO2Na (40 mmol) in nꢀBuNH2 (40 mL) was added sulfur (42 mmol) at
room temperature and the solution was stirred for 3 h. The reaction mixture was
evaporated under reduced pressure to remove solvent. The residue was washed by Et2O
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and white powder (PhSO2SNa) was obtained. To a solution of PhSO2SNa in EtOH (50
mL) was added nꢀC4H9I (60 mmol). Then the solution was stirred at 45 for 12 h. Upon
completion, water (40 mL) was added to the reaction mixture and the solution was
extracted with CH2Cl2 (30 mL×3). The combined organic layer was dried with anhydrous
Na2SO4 and evaporated under reduced pressure. The residue was purified through column
chromatography afforded the product 2a (silica gel, petroleum ether/ethyl acetate = 30/1).
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Benzenesulfonothioate (2jꢀ2k) were prepared by reported procedure9a
Typical procedure for the synthesis of desired product (3aꢀ3z). To a mixture of
Copper thiopheneꢀ2ꢀcarboxylate (20 mol%), 2,2'ꢀBipyridine (20 mol%) in solvent (1 mL
DMSO + 36 mg water), alkene (0.2 mmol) and thiosulfonylation reagent 2a (0.6 mmol)
were added. The reaction system was stirred at 50oC under air atmosphere for 12 h. Then,
the resulting mixture was evaporated under reduced pressure and purified by flash
chromatography to afford the desired product 3a (silica gel, petroleum ether/ethyl acetate
= 15/1).
Procedure for the synthesis of 1ꢀphenylꢀ2ꢀ(phenylsulfonyl)ethanꢀ1ꢀone (5). To a
solution of PhSO2Na (12 mmol) in EtOH (40 mL) was added 2ꢀbromoacetophenone (10
mmol) at room temperature and the solution was stirred for 12 h. The reaction mixture
was evaporated under reduced pressure to removal of solvent. The residue was purified
through column chromatography afforded the desired product (5).
2-(butylthio)-1-phenyl-2-(phenylsulfonyl)ethan-1-one (3a). White solid (52.0 mg, 75%):
mp 89ꢀ91 oC. 1H NMR (500 MHz, CDCl3) δ 8.00 (dd, J = 8.3, 1.1 Hz, 2H), 7.97ꢀ7.94 (m,
2H), 7.67 (t, J = 6.9 Hz, 1H), 7.62 (t, J = 6.9 Hz, 1H), 7.55 (t, J = 7.0 Hz, 2H), 7.48 (t, J =
7.8 Hz, 2H), 5.57 (s, 1H), 2.90ꢀ2.71 (m, 2H), 1.51 (m, 2H), 1.33 (m, 2H), 0.86 (t, J = 7.4
Hz, 3H).13C NMR (126 MHz, CDCl3) δ 189.1, 136.3, 135.1, 134.3, 134.3, 130.6, 129.0,
128.9, 128.6, 70.8, 32.5, 30.9, 21.8, 13.6. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C18H20O3S2Na 371.0746; Found 371.0733.
2-(butylthio)-2-(phenylsulfonyl)-1-(p-tolyl)ethan-1-one (3b). White solid (51.0 mg, 70%).
1H NMR (500 MHz, CDCl3) δ 7.99 (dd, J = 8.3, 1.1 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H),
7.66 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.31ꢀ7.25 (m, 2H), 5.57 (s, 1H), 2.90ꢀ
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2.70 (m, 2H), 2.42 (s, 3H), 1.51 (m, 2H), 1.34 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).13C NMR
(126 MHz, CDCl3) δ 188.6, 145.6, 136.3, 134.3, 132.5, 130.6, 129.6, 129.2, 128.6, 70.8,
32.4, 30.9, 21.8, 21.8, 13.6. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C19H22O3S2Na
385.0903; Found 385.0900.
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1-(4-(tert-butyl)phenyl)-2-(butylthio)-2-(phenylsulfonyl)ethan-1-one (3c). White solid
1
(61.3 mg, 76%). H NMR (500 MHz, CDCl3) δ 8.04ꢀ7.97 (m, 2H), 7.91 (d, J = 8.5 Hz,
2H), 7.67 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 5.58 (s,
1H), 2.91 – 2.70 (m, 2H), 1.58ꢀ1.45 (m, 2H), 1.38ꢀ1.29 (m, 11H), 0.86 (t, J = 7.4 Hz,
3H).13C NMR (126 MHz, CDCl3) δ 188.6, 158.4, 136.3, 134.3, 132.4, 130.6, 129.1,
128.6, 125.9, 70.7, 35.3, 32.5, 31.0, 30.9, 21.8, 13.6. HRMS (ESIꢀTOF) m/z: [M + Na]+
Calcd for C22H28O3S2Na 427.1372; Found 427.1374.
2-(butylthio)-1-(4-fluorophenyl)-2-(phenylsulfonyl)ethan-1-one (3d). White solid (45.1
1
mg, 62%). H NMR (500 MHz, CDCl3) δ 8.05ꢀ7.96 (m, 4H), 7.68 (t, J = 8.0 Hz, 1H),
7.56 (t, J = 7.8 Hz, 2H), 7.15 (t, J = 8.6 Hz, 2H), 5.54 (s, 1H), 2.89ꢀ2.70 (m, 2H), 1.57ꢀ
1.44 (m, 2H), 1.35ꢀ1.31 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, CDCl3) δ
187.6, 167.4, 165.4, 136.2, 134.4, 132.0, 131.9, 130.5, 128.7, 116.2, 116.1, 71.1, 32.5,
30.8, 21.7, 13.5. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C18H19O3S2FNa 389.0652;
Found 389.0655.
2-(butylthio)-1-(4-chlorophenyl)-2-(phenylsulfonyl)ethan-1-one (3e). White solid (45.7
1
mg, 60%). H NMR (500 MHz, CDCl3) δ 7.98 (dd, J = 8.4, 1.2 Hz, 2H), 7.94ꢀ7.90 (m,
2H), 7.68 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 5.51 (s,
1H), 2.90ꢀ2.69 (m, 2H), 1.54ꢀ1.46 (m, 2H), 1.37ꢀ1.29 (m, 2H), 0.86 (t, J = 7.3 Hz,
3H).13C NMR (126 MHz, CDCl3) δ 188.0, 141.0, 136.1, 134.5, 133.3, 130.5, 130.5,
129.3, 128.7, 71.0, 32.5, 30.8, 21.8, 13.6. HRMS (ESIꢀTOF) m/z: [M + NH4]+ Calcd for
C18H23O3S2ClN 400.0802; Found 400.0803.
1-(4-bromophenyl)-2-(butylthio)-2-(phenylsulfonyl)ethan-1-one (3f). White solid (56.3
mg, 66%). 1H NMR (500 MHz, CDCl3) δ 7.98 (dd, J = 8.3, 1.0 Hz, 2H), 7.84 (d, J = 8.6
Hz, 2H), 7.68 (t, J = 7.5 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.56 (t, J = 7.8 Hz, 2H), 5.51
(s, 1H), 2.90ꢀ2.68 (m, 2H), 1.56ꢀ1.44 (m, 2H), 1.36ꢀ1.30 (m, 2H), 0.86 (t, J = 7.3 Hz,
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3H).13C NMR (126 MHz, CDCl3) δ 188.2, 136.1, 134.5, 133.7, 132.3, 130.6, 129.9,
128.7, 71.0, 32.5, 30.8, 21.8, 13.6. HRMS (ESIꢀTOF) m/z: [M + NH4]+ Calcd for
C18H23O3S2BrN 444.0297; Found 444.0286.
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4-(2-(butylthio)-2-(phenylsulfonyl)acetyl)benzonitrile (3g). White solid (33.9 mg, 45%).
1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 8.5 Hz, 2H), 7.98 (dd, J = 8.4, 1.2 Hz, 2H),
7.79 (d, J = 8.6 Hz, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.58 (t, J = 7.8 Hz, 2H), 5.52 (s, 1H),
2.88ꢀ2.69 (m, 2H), 1.52ꢀ1.47 (m, 2H), 1.35ꢀ1.30 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H).13C
NMR (126 MHz, CDCl3) δ 188.0, 138.0, 136.0, 134.7, 132.7, 130.5, 129.5, 128.8, 117.6,
117.4, 71.2, 32.6, 30.8, 21.7, 13.5. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C19H19NO3S2Na 396.0699; Found 396.0695.
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2-(butylthio)-1-(4-methoxyphenyl)-2-(phenylsulfonyl)ethan-1-one (3h). White solid (54.9
mg, 73%). 1H NMR (500 MHz, CDCl3) δ 7.97 (dd, J = 17.6, 8.2 Hz, 4H), 7.66 (t, J = 7.5
Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 5.54 (s, 1H), 3.87 (s, 3H),
2.89ꢀ2.70 (m, 2H), 1.57ꢀ1.45 (m, 2H), 1.36ꢀ1.31 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).13C
NMR (126 MHz, CDCl3) δ 187.4, 164.6, 136.4, 134.3, 131.6, 130.6, 128.6, 127.9, 114.14,
71.0, 55.7, 32.5, 30.9, 21.8, 13.6. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C19H22O4S2Na 401.0852; Found 401.0846.
4-(2-(butylthio)-2-(phenylsulfonyl)acetyl)phenyl acetate (3i). White solid (55.2 mg, 61%).
1H NMR (500 MHz, CDCl3) δ 8.00 (t, J = 7.6 Hz, 4H), 7.67 (t, J = 7.5 Hz, 1H), 7.55 (t, J
= 7.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 5.56 (d, J = 1.8 Hz, 1H), 2.91ꢀ2.68 (m, 2H), 2.32
(s, 3H), 1.56ꢀ1.45 (m, 2H), 1.36ꢀ1.29 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H).13C NMR (126
MHz, CDCl3) δ 187.9, 168.7, 155.3, 136.3, 134.4, 132.5, 130.8, 130.5, 128.7, 122.1, 70.8,
32.4, 30.8, 21.8, 21.2, 13.8, 13.6. HRMS (ESIꢀTOF) m/z: [M + NH4]+ Calcd for
C20H26O5S2N 424.1247; Found 424.1253.
2-(butylthio)-2-(phenylsulfonyl)-1-(o-tolyl)ethan-1-one (3j). White solid (40.3 mg, 56%).
1H NMR (500 MHz, CDCl3) δ 8.03ꢀ7.98 (m, 2H), 7.74 (d, J = 7.7 Hz, 1H), 7.68 (t, J =
7.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.26 (t, J = 7.3 Hz, 2H),
5.39 (s, 1H), 2.96ꢀ2.75 (m, 2H), 2.42 (s, 3H), 1.53 (ddt, J = 21.1, 14.7, 7.6 Hz, 2H), 1.35
(p, J = 7.5 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 136.5, 134.3,
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132.4, 132.1, 130.6, 128.7, 128.6, 125.9, 72.6, 32.7, 30.9, 21.7, 20.9, 13.5. HRMS (ESIꢀ
TOF) m/z: [M + Na]+ Calcd for C19H22O3S2Na 385.0903; Found 385.0899.
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2-(butylthio)-1-(2-chlorophenyl)-2-(phenylsulfonyl)ethan-1-one (3k). White solid (21.7
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mg, 28%). H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 7.5 Hz, 2H), 7.62 (t, J = 7.4 Hz,
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1H), 7.51 (t, J = 7.7 Hz, 3H), 7.36 (dt, J = 14.3, 7.4 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H),
5.51 (s, 1H), 2.92ꢀ2.64 (m, 2H), 1.44 (ddd, J = 21.9, 14.6, 7.6 Hz, 2H), 1.27 (dq, J = 14.2,
7.2 Hz, 2H), 0.80 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 190.5, 134.4, 133.0,
130.7, 130.5, 128.7, 127.2, 73.2, 32.7, 30.8, 21.7, 13.6. HRMS (ESIꢀTOF) m/z: [M +
Na]+ Calcd for C18H19O3S2ClNa 405.0356; Found 405.0353.
2-(butylthio)-2-(phenylsulfonyl)-1-(m-tolyl)ethan-1-one (3l). White solid (49.2 mg, 68%).
1H NMR (500 MHz, CDCl3) δ 8.03ꢀ7.98 (m, 2H), 7.75 (d, J = 6.8 Hz, 2H), 7.67 (t, J =
7.4 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H),
5.58 (s, 1H), 2.92ꢀ2.71 (m, 2H), 2.41 (s, 3H), 1.57ꢀ1.46 (m, 2H), 1.37ꢀ1.31 (m, 2H), 0.86
(t, J = 7.4 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 189.2, 138.9, 136.3, 135.2, 135.1,
134.3, 130.6, 129.4, 128.8, 128.6, 126.2, 70.6, 32.4, 30.9, 21.8, 21.4, 13.6. HRMS (ESIꢀ
TOF) m/z: [M + NH4]+ Calcd for C19H26O3S2N 380.1349; Found 380.1339.
2-(butylthio)-1-(3-chlorophenyl)-2-(phenylsulfonyl)ethan-1-one (3m). White solid (43.0
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mg, 56%). H NMR (500 MHz, CDCl3) δ 8.02ꢀ7.96 (m, 2H), 7.91 (t, J = 1.8 Hz, 1H),
7.85 (d, J = 7.9 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.58 (dd, J = 14.8, 7.1 Hz, 3H), 7.44 (t,
J = 7.9 Hz, 1H), 5.49 (s, 1H), 2.92ꢀ2.70 (m, 2H), 1.58ꢀ1.46 (m, 2H), 1.39ꢀ1.30 (m, 2H),
0.87 (t, J = 7.3 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 188.0, 136.5, 136.1, 135.3, 134.5,
134.2, 130.6, 130.2, 129.0, 128.7, 127.1, 70.9, 32.5, 30.8, 21.8, 13.6. HRMS (ESIꢀTOF)
m/z: [M + H]+ Calcd for C18H20O3S2Cl 383.0537; Found 383.0525.
1-(3-bromophenyl)-2-(butylthio)-2-(phenylsulfonyl)ethan-1-one (3n). White solid (55.9
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mg, 66%). H NMR (500 MHz, CDCl3) δ 8.06 (t, J = 1.7 Hz, 1H), 7.99 (dd, J = 8.3, 1.1
Hz, 2H), 7.90 (d, J= 7.9 Hz, 1H), 7.76ꢀ7.72 (m, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.57 (t, J =
7.8 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 5.49 (s, 1H), 2.93ꢀ2.69 (m, 2H), 1.55ꢀ1.48 (m, 2H),
1.38ꢀ1.29 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 187.9, 137.1,
136.7, 136.1, 134.5, 131.9, 130.6, 130.4, 128.7, 127.6, 123.2, 70.8, 32.5, 30.8, 21.8, 13.6.
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HRMS (ESIꢀTOF) m/z: [M + NH4]+ Calcd for C18H23O3S2BrN 444.0297; Found
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444.0294.
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2-(butylthio)-1-phenyl-2-(phenylsulfonyl)propan-1-one (3o). White solid (27.3 mg, 38%).
1H NMR (500 MHz, CDCl3) δ 8.13ꢀ8.04 (m, 4H), 7.65 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.8
Hz, 3H), 7.42 (t, J = 7.8 Hz, 2H), 2.74ꢀ2.60 (m, 2H), 1.92 (s, 3H), 1.51ꢀ1.44 (m, 2H),
1.33ꢀ1.28 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 193.8, 136.6,
136.2, 133.9, 132.9, 131.6, 129.3, 128.4, 128.4, 79.6, 31.7, 30.5, 22.0, 21.4, 13.6. HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C19H22O3S2Na 385.0903; Found 385.0899.
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2-(butylthio)-2-(phenylsulfonyl)-2,3-dihydro-1H-inden-1-one (3p). Light gray solid (31.2
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mg, 43%). H NMR (500 MHz, CDCl3) δ 8.07ꢀ8.01 (m, 2H), 7.77 (d, J = 7.7 Hz, 1H),
7.70ꢀ7.61 (m, 2H), 7.56 (t, J = 7.8 Hz, 2H), 7.45ꢀ7.39 (m, 2H), 4.11 (d, J = 18.0 Hz, 1H),
3.25 (d, J = 18.1 Hz, 1H), 2.90ꢀ2.63 (m, 2H), 1.44ꢀ1.38 (m, 2H), 1.34ꢀ1.27 (m, 2H), 0.84
(t, J = 7.3 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 193.5, 149.5, 136.0, 135.6, 134.4,
134.3, 131.3, 128.5, 128.5, 126.2, 125.5, 75.0, 38.1, 30.8, 30.3, 22.0, 13.6. HRMS (ESIꢀ
TOF) m/z: [M + Na]+ Calcd for C19H20O3S2Na 383.0746; Found 383.0747.
2-(butylthio)-1-(naphthalen-2-yl)-2-(phenylsulfonyl)ethan-1-one (3q). White solid (54.8
mg, 69%). 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 8.05ꢀ8.01 (m, 2H), 8.00ꢀ7.94 (m,
2H), 7.90ꢀ7.69 (m, 2H), 7.68ꢀ7.62 (m, 2H), 7.59ꢀ7.54 (m, 3H), 5.75 (s, 1H), 2.95ꢀ2.76 (m,
2H), 1.61ꢀ1.47 (m, 2H), 1.38ꢀ1.32 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz,
CDCl3) δ 189.0, 136.3, 136.0, 134.4, 132.3, 131.4, 130.7, 130.0, 129.4, 128.9, 128.7,
127.8, 127.2, 124.0, 71.0, 32.5, 30.9, 21.8, 13.6. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
for C22H22O3S2Na 421.0903; Found 421.0908.
2-(methylthio)-1-phenyl-2-(phenylsulfonyl)ethan-1-one (3r). White solid (40.7 mg, 67%).
1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 7.9 Hz, 2H), 7.95 (d, J = 7.9 Hz, 2H), 7.68 (t,
J = 7.4 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H),
5.54 (s, 1H), 2.27 (s, 3H).13C NMR (126 MHz, CDCl3) δ 188.5, 136.4, 134.9, 134.4,
130.5, 129.0, 128.9, 128.9, 128.8, 70.6, 15.3. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
for C15H14O3S2Na 329.0277; Found 329.0280.
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1-phenyl-2-(phenylsulfonyl)-2-(propylthio)ethan-1-one (3s). White solid (36.5 mg, 55%).
1H NMR (500 MHz, CDCl3) δ 8.06ꢀ7.90 (m, 4H), 7.68 (t, J = 7.5 Hz, 1H), 7.63 (t, J = 7.4
Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.49 (t, J = 7.8 Hz, 2H), 5.58 (s, 1H), 2.92ꢀ2.65 (m, 2H),
1.64ꢀ1.50 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 189.1, 136.2,
135.0, 134.4, 134.4, 130.6, 129.0, 128.9, 128.7, 70.7, 34.7, 22.3, 13.3. HRMS (ESIꢀTOF)
m/z: [M + NH4]+ Calcd for C17H22O3S2N 352.1036; Found 352.1042.
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2-(octylthio)-1-phenyl-2-(phenylsulfonyl)ethan-1-one (3t). White solid (43.2 mg, 54%):
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mp 49ꢀ50 oC. H NMR (500 MHz, CDCl3) δ 7.98 (dd, J = 22.0, 7.4 Hz, 4H), 7.67 (t, J =
7.5 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.48 (t, J = 7.8 Hz, 2H),
5.59 (s, 1H), 2.90ꢀ2.70 (m, 2H), 1.59ꢀ1.44 (m, 2H), 1.32ꢀ1.18 (m, 10H), 0.86 (t, J = 7.1
Hz, 3H).13C NMR (126 MHz, CDCl3) δ 189.1, 136.3, 135.0, 134.4, 134.3, 130.6, 129.0,
128.9, 128.6, 70.7, 32.8, 31.7, 29.1, 29.0, 28.8, 28.6, 22.6, 14.1. HRMS (ESIꢀTOF) m/z:
[M + NH4]+ Calcd for C22H32O3S2N 422.1818; Found 422.1816.
2-(benzylthio)-1-phenyl-2-(phenylsulfonyl)ethan-1-one (3u). White solid (41.6 mg, 54%).
1H NMR (500 MHz, CDCl3) δ 8.02 (dd, J = 8.3, 1.0 Hz, 2H), 7.67 (t, J = 7.5 Hz, 1H),
7.55 (t, J = 7.8 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.40ꢀ7.33 (m, 7H), 7.26 (dd, J = 11.1,
4.5 Hz, 2H), 5.46 (s, 1H), 4.33 (d, J = 13.0 Hz, 1H), 3.89 (d, J = 13.0 Hz, 1H).13C NMR
(126 MHz, CDCl3) δ 189.1, 136.1, 135.8, 134.7, 134.4, 134.2, 130.9, 130.0, 129.1, 128.8,
128.7, 128.5, 128.0, 68.2, 37.1. HRMS (ESIꢀTOF) m/z: [M + NH4]+ Calcd for
C21H22O3S2N 400.1036; Found 400.1033.
2-(allylthio)-1-phenyl-2-(phenylsulfonyl)ethan-1-one (3v). White solid (42.3 mg, 64%).
1H NMR (500 MHz, CDCl3) δ 7.98ꢀ7.91 (m, 4H), 7.68 (t, J = 7.5 Hz, 1H), 7.62 (t, J = 7.4
Hz, 1H), 7.55 (dd, J = 8.1, 7.6 Hz, 2H), 7.48 (dd, J = 8.2, 7.5 Hz, 2H), 5.78ꢀ5.69 (m, 1H),
5.66 (s, 1H), 5.39ꢀ5.30 (m, 2H), 3.73 (dd, J = 13.4, 9.4 Hz, 1H), 3.29 (dd, J = 13.0, 5.4
Hz, 1H).13C NMR (126 MHz, CDCl3) δ 189.4, 135.9, 135.1, 134.5, 134.4, 132.1, 130.7,
129.2, 128.9, 128.6, 120.6, 68.9, 35.7. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C17H16O3S2Na 355.0433; Found 355.0436.
(E)-2-(but-2-en-1-ylthio)-1-phenyl-2-(phenylsulfonyl)ethan-1-one (3w). White solid (43.3
mg, 60%). 1H NMR (500 MHz, CDCl3) δ 8.01ꢀ7.95 (m, 2H), 7.95ꢀ7.90 (m, 2H), 7.68 (t, J
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= 7.5 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.48 (t, J = 7.8 Hz, 2H),
5.83ꢀ5.76 (m, 1H), 5.65 (s, 1H), 5.41ꢀ5.31 (m, 1H), 3.65 (dd, J = 13.2, 9.5 Hz, 1H), 3.26ꢀ
3.19 (m, 1H), 1.77 (d, J = 6.5 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 189.5, 136.1, 135.2,
134.4, 134.3, 132.2, 130.8, 129.1, 128.9, 128.5, 125.1, 68.9, 35.3, 29.7, 17.8. HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C18H18O3S2Na 369.0590; Found 369.0597.
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2-(butylthio)-1-phenyl-2-tosylethan-1-one (3x). White solid (50.5 mg, 70%). H NMR
(500 MHz, CDCl3) δ 7.96 (d, J = 7.5 Hz, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.61 (t, J = 7.4
Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 5.56 (s, 1H), 2.92ꢀ2.71 (m,
2H), 2.44 (s, 3H), 1.57ꢀ1.46 (m, 2H), 1.39ꢀ1.29 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).13C
NMR (126 MHz, CDCl3) δ 189.2, 145.5, 135.2, 134.2, 133.3, 130.6, 129.3, 129.0, 128.9,
70.8, 32.5, 30.9, 21.8, 13.5. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C19H22O3S2Na
385.0903; Found 385.0907.
2-(butylthio)-2-((4-chlorophenyl)sulfonyl)-1-phenylethan-1-one (3y). White solid (38.4
mg, 50%). 1H NMR (500 MHz, CDCl3) δ 7.99ꢀ7.91 (m, 4H), 7.64 (t, J = 7.4 Hz, 1H),
7.56ꢀ7.47 (m, 4H), 5.60 (s, 1H), 2.94ꢀ2.73 (m, 2H), 1.59ꢀ1.47 (m, 2H), 1.38ꢀ1.30 (m, 2H),
0.87 (t, J = 7.4 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 189.1, 141.3, 134.9, 134.5, 134.5,
132.2, 129.0, 129.0, 128.9, 70.7, 32.6, 30.8, 21.8, 13.6. HRMS (ESIꢀTOF) m/z: [M +
Na]+ Calcd for C18H19O3S2ClNa 405.0356; Found 405.0352.
1-phenyl-2-(phenylsulfonyl)-2-(phenylthio)ethan-1-one (3z). White solid (41.6 mg, 57%).
1H NMR (500 MHz, CDCl3) δ 8.01 (dd, J = 8.3, 1.1 Hz, 2H), 7.88 (dd, J = 8.3, 1.1 Hz,
2H), 7.68 (t, J = 7.5 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.9 Hz, 2H), 7.52ꢀ7.49
(m, 2H), 7.46 (t, J = 7.9 Hz, 2H), 7.37ꢀ7.33 (m, 1H), 7.33ꢀ7.29 (m, 2H), 5.81 (s, 1H).13C
NMR (126 MHz, CDCl3) δ 189.3, 136.3, 135.1, 134.5, 134.4, 133.6, 132.1, 130.8, 129.5,
129.4, 129.3, 128.9, 128.7, 75.6. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C20H16O3S2Na 391.0433; Found 391.0440.
1-phenyl-2-(phenylsulfonyl)-2-(p-tolylthio)ethan-1-one (3aa). White solid (43.4 mg,
57%). 1H NMR (500 MHz, CDCl3) δ 8.02 (dd, J = 8.4, 1.1 Hz, 2H), 7.87 (dd, J = 8.4, 1.1
Hz, 2H), 7.68 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.9 Hz, 2H), 7.46 (t,
J = 7.9 Hz, 2H), 7.37 (s, 2H), 7.11 (d, J = 8.0 Hz, 2H), 5.73 (s, 1H), 2.34 (s, 3H).13C
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NMR (126 MHz, CDCl3) δ 189.3, 140.0, 136.5, 135.2, 134.4, 134.3, 134.1, 130.8, 130.2,
129.2, 128.9, 128.7, 128.4, 75.8, 21.3. HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C21H18O3S2Na 405.0590; Found 405.0599.
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1-phenyl-2-(phenylselanyl)-2-(phenylsulfonyl)ethan-1-one (3ab). Yellowish solid (30.6
mg, 37%). 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 7.4 Hz, 2H), 7.78 (d, J = 7.4 Hz,
2H), 7.65 (t, J = 7.5 Hz, 1H), 7.62 – 7.51 (m, 5H), 7.45 – 7.35 (m, 3H), 7.29 (d, J = 7.6
Hz, 2H), 5.79 (s, 1H).13C NMR (126 MHz, CDCl3) δ 189.4, 137.0, 135.8, 135.0, 134.3,
134.2, 130.6, 129.8, 129.5, 128.9, 128.8, 128.7, 127.7, 68.1. HRMS (ESIꢀTOF) m/z: [M +
Na]+ Calcd for C20H16O3SSeNa 438.9878; Found 438.9888.
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1-phenyl-2-(phenylsulfonyl)ethan-1-one (5). White solid. 1H NMR (500 MHz,
Chloroformꢀd) δ 7.96 – 7.92 (m, 2H), 7.92 – 7.88 (m, 2H), 7.67 (t, J = 7.5 Hz, 1H), 7.63
(t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.49 (t, J = 7.8 Hz, 2H), 4.75 (s, 2H).
Supporting Information
1H and 13C NMR spectra and XRD data (3a). This material is available free of charge via
the Internet at http://pubs.acs.org.
Author Information
Corresponding Author
*Eꢀmail: xuzh@sdu.edu.cn.
Acknowledgements.
We are grateful for financial support from the Natural Science Foundation of China and
Shandong province (no. 21572118 & JQ201505), subject construction funds (104.205.2.5)
and Tang scholar award of Shandong University.
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