N-bromosuccinimide mediated decarboxylative sulfonylation of β-keto acids with sodium sulfinates toward β-keto sulfones: Evaluation of human carboxylesterase 1 activity

Article abstract of DOI:10.1016/j.tet.2018.08.024

A N-bromosuccinimide (NBS) mediated decarboxylative sulfonylation of β-keto acids with sodium sulfinates is developed. The transformation exhibits a broad substrate scope and good functional group tolerance. Preliminary mechanistic studies showed that this reaction is likely to proceed through a nucleophilic substitution of β-keto acid with sulfonyl bromide pathway. All synthesized β-keto sulfones were evaluated the inhibitory effect against human carboxylesterase 1 (CES1). This investigation offers an expedient strategy for efficient synthesis of β-keto sulfones that are widely present in biologically active natural products and pharmaceutical agents.

Full text of DOI:10.1016/j.tet.2018.08.024

Accepted Manuscript
N-Bromosuccinimide mediated decarboxylative sulfonylation of β-keto acids with
sodium sulfinates toward β-keto sulfones: Evaluation of human carboxylesterase 1
activity
Fuzhong Han, Bobo Su, Peifang Song, Yaqiao Wang, Lina Jia, Shanshan Xun,
Minggang Hu, Liwei Zou
PII:
S0040-4020(18)30988-8
10.1016/j.tet.2018.08.024
TET 29744
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 June 2018
Revised Date: 14 August 2018
Accepted Date: 17 August 2018
Please cite this article as: Han F, Su B, Song P, Wang Y, Jia L, Xun S, Hu M, Zou L, N-
Bromosuccinimide mediated decarboxylative sulfonylation of β-keto acids with sodium sulfinates toward
β-keto sulfones: Evaluation of human carboxylesterase 1 activity, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.08.024.
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N-Bromosuccinimide mediated
decarboxylative sulfonylation of β-keto acids
with sodium sulfinates toward β-keto
sulfones: evaluation of human
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carboxylesterase 1 activity
Fuzhong Hana,  , Bobo Sua , Peifang Songb , Yaqiao Wangb , Lina Jiaa , Shanshan Xuna , Minggang Hua and
Liwei Zoub, 
aCollege of Chemistry and Chemical Engineering, Qiqihar University, Qiqihar 161006, China
bInstitute of Interdisciplinary Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai
201203, China

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Tetrahedron
journal homepage: www.elsevier.com
N-Bromosuccinimide mediated decarboxylative sulfonylation of β-keto acids with
sodium sulfinates toward β-keto sulfones: evaluation of human carboxylesterase 1
activity
Fuzhong Hana,  , Bobo Sua , Peifang Songb , Yaqiao Wangb , Lina Jiaa , Shanshan Xuna , Minggang Hua
and Liwei Zoub, 
aCollege of Chemistry and Chemical Engineering, Qiqihar University, Qiqihar 161006, China
bInstitute of Interdisciplinary Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A N-bromosuccinimide (NBS) mediated decarboxylative sulfonylation of β-keto acids with
sodium sulfinates is developed. The transformation exhibits a broad substrate scope and good
functional group tolerance. Preliminary mechanistic studies showed that this reaction is likely to
proceed through a nucleophilic substitution of β-keto acid with sulfonyl bromide pathway. All
synthesized β-keto sulfones were evaluated the inhibitory effect against human carboxylesterase
1 (CES1). This investigation offers an expedient strategy for efficient synthesis of β-keto
sulfones that are widely present in biologically active natural products and pharmaceutical
agents.
Available online
Keywords:
β-Keto sulfones
N-Bromosuccinimide
Mechanistic study
Carboxylesterase
Inhibitor
2009 Elsevier Ltd. All rights reserved.
1. Introduction
The decarboxylative reaction of β-keto acids and its
subsequent functionalization have been an attractive topic in
Sulfones not only belong to key structural motifs distributed in
biologically active molecules and functional materials but also
act as versatile precursors for organic chemistry.1 Among those,
β-keto sulfones are prominent in medicinal chemistry owing to
their remarkable pharmaceutical properties, i.e., antagonists of
bacterial quorum sensing in Vibrio harveyi 1a,2 and inhibitors of
LpxC 1b and MMP 1c (Fig. 1)3. They also play a crucial role in
synthetic applications for natural products and various important
structural components such as disubstituted acetylenes,4 allenes,
vinylsulfones,5 ketones,6 polyfunctionalized 4H-pyrans,7 and
optically active β-hydroxysulfones.8 Recognizing the great
importance of β-keto sulfones, the formation of Csp3-SO2R bond
has been of intensive research area. Recently, many efforts have
been achieved in the development of efficient synthetic processes
for these scaffolds.9 However, most of them require transition-
metal catalysts, expensive reagents, relatively complicated or
harsh reaction conditions, and have limited substrate scopes.
Therefore, the development of new strategies for the synthesis of
β-keto sulfones is highly desirable, which continue to be a
challenging issue.
organic synthesis and play a crucial role in fine chemicals,
material science, and medicinal chemistry.10 A large array of β-
keto acids transformation systems for carbon-carbon and carbon-
hetero bond forming reactions have been well established in the
past decades.11 Despite these notable achievements, however,
little progress has been made in the development of a carbon-
sulfur version for this important reaction. In light of the literature
precedence2-11 and continuation of our work on the utility of β-
keto acids for carbon-carbon and carbon-hetero bond forming
reactions,12 we thought it would be of interest to develop a
method by a decarboxylative sulfonylation of β-keto acids using
sodium sulfinates (easily prepared, bench-top stable, non-odorous
solids). Herein, we report a one-pot chemoselective synthesis of
β-keto sulfones via decarboxylative coupling of β-keto acids with
sodium sulfinates through
a N-bromosuccinimide (NBS)-
promoted pathway. In addition, all synthetic β-keto sulfones
compounds have been screened for inhibitory effects against
human carboxylesterase 1 (CES1) using D-Luciferin methyl ester
(DME) as specific optical substrate.13 Primary structure-activity
relationships (SAR) analysis of all tested β-keto sulfones
compounds provide insights into the fine relationships linking
———
 Corresponding author. Tel.: +86-452-273-8215; fax: ++86-452-273-8215; e-mail: hfzgood1982@163.com
 Corresponding author. Tel.: +86-215-132-3182; e-mail: chemzlw@shutcm.edu.cn

2
Tetrahedron
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With the optimal conditions in hands, we examined the
between the inhibitory effects on CES1 and the substituent-
substrate scope with respect to β-keto acids (Scheme 1). β-Keto
acids with both the electron-donating groups (4-OMe), electron-
neutral (4-H, 4-Me, 3-Me), and halogenated (4-F, 4-Cl) on the
aromatic ring were smoothly converted to the corresponding
products 4a-4f in excellent yields (80-88%). Moreover, reactions
with ortho-substituted substrate also gave the corresponding β-
keto sulfone 4g in high yield (83%), indicating the tolerance of
steric hindrance. Gratifyingly, 2-Naphthylphenone-derived β-
keto acid was also viable substrate, and the isolation of 4h in
83% yield, whereas heteroaryl-substituted β-keto acid furnished
the desired product 4i with 78% yield. Notably, aliphatic
substituted β-keto acids displayed lower reactivity under the
standard reaction conditions.
properties of these compounds. Guided by these SARs, we
design and synthesize a novel β-keto sulfone compound leading
to a dramatically increase of the inhibitory effects against CES1.
Next, we explored the scope of sodium sulfinates under the
optimal reaction conditions, as shown in Scheme 1. It was found
that a range of sodium benzenesulfinates bearing various
electrondonating, electronwithdrawing, and halogen substituents
at the para position of the arene ring were effectively coupled
with 2a and furnished the desired product (4n-4r) in 68-81%
isolated yields. In addition, 2-naphthyl substituted sulfinic acid
sodium also proved to be a suitable substrate, delivering the
desired product 4t in 73% yield. In addition to aromatic sodium
sulfinates, less reactive sodium methanesulfinate was tolerated in
this transformation, affording product 4s in good yield.
Fig.1 Bioactive molecules having β-keto sulfone core.
2. Results and discussion
2.1. Optimization of Reaction Conditions
We commenced the initial condition-screening experiments by
utilizing benzoylacetic acid 2a and sodium sulfinate 3a as the
model substrates (Table 1). To our delight, the desired β-keto
sulfone product 4a was obtained in a 28% yield by using N-
bromosuccinimide (NBS, 1.5 equiv.) at room temperature in
CH2Cl2 for 24 h under air (Table 1, entry 1). To promote the yield
of 4a, further studies surveyed a series of bases (Table 1, entries
2-7). The switching of base from K2CO3 to various other bases
proves K3PO4 as the optimum base, where the yield of 4a could
be increased to 88% (Table 1, entry 6). Further screening of
solvents revealed that CH2Cl2 is superior to H2O, CH3CN, THF ,
MeOH and DMF (Table 1, entries 8-12).
Table 1. Optimization and screening of the reaction
conditionsa
Entry
Base
Solvent
Yield (%) b
1
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
H2O
28
64
51
52
43
88
82
18
67
57
55
47
2
K2CO3
Et3N
3
4
iPr2NEt
KOH
5
6
K3PO4
Na3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
7
8
9
CH3CN
THF
10
11
12
CH3OH
DMF
a General reaction conditions: 2a (0.75 mmol), 3a (0.5 mmol) and base (0.75
mmol) in solvent (3 mL) at room temperature for 24 h.
b The yields indicated are the isolated yields by column purification.
Scheme 1. Reaction conditions: 2 (0.75 mmol), 3 (0.5 mmol) and K3PO4
(0.75 mmol) in 3 mL CH2Cl2 at room temperature for 24 h. The yields
indicated are the isolated yields by column purification.
2.2. Substrate scope

2.3. Mechanistic studies
plays key roles in endobiotic homeostasis and xenobiotic
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metabolism.14 Recent studies have revealed that the activities of
CES1 are markedly elevated in obese individuals and patients
with type 2 diabetes, and the treatment of CES1 inhibitors
displayed multiple beneficial effects in both lipid and glucose
homeostasis in genetic and diet-induced mouse models of obesity,
insulin resistance and type 2 diabetes.15 Because of the enzymatic
cleaving of triglyceride stores in hepatocytes, CES1 has been
recognized as a therapeutic target for hypertriglyceridaemia.16
Unfortunately, only one CES1 inhibitor termed GR148672X is in
We further carried out a series of control experiments to gain
insight into the reaction mechanism (Scheme 2). Firstly, radical
inhibition experiment was performed (Scheme 2a). When radical
inhibitor 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
employed in the standard reaction, the reaction was not obviously
inhibited. The results indicated that the reaction presumably did
not undergo a radical pathway. Secondly, using acetophenone 5
and 2-bromoacetophenone 6 under the optimized reaction
conditions did not furnish the expected product (Scheme 2b and
2c). This result suggested that the β-keto acid is essential for the
reaction to proceed efficiently. Treatment of sodium sulfinate 3a
with 1.5 equiv of NBS at room temperature gave benzenesulfonyl
bromide 7 in 60% yield (Scheme 2d). The compound 7 further
reacted with benzoylacetic acid 2a to afford β-keto sulfone
product 4a in 79% yield (Scheme 2e). These results partially
implied that this transformation probably proceeded through a
sulfonyl bromide intermediate pathway.
preclinical
development
for
the
treatment
of
hypertriglyceridaemia and no CES1 modulators have been
approved as medicines to date.17 It is highly desirable to find
CES1 inhibitors for potential remedy of the related diseases.18
Thus, a further survey was carried out to evaluate the inhibitory
effect against CES1 of these novel β-keto sulfones using D-
Luciferin methyl ester (DME) as specific optical substrate for
CES1. As shown in Table 2, we firstly focused our attention on
the variation of the benzoyl moiety of β-keto sulfones (4a-4g).
Substitution with a 4-chlorine on the benzoyl unit of the β-keto
sulfone showed good inhibitory effect against CES1 with IC50
value of 6.11 µM (4d), but the benzoyl unit with other substitutes
(methyl, methoxyl, fluorine) at 4-position displayed poor
inhibition toward CES1. The β-keto sulfone (4h) with 2-
naphthoyl unit afforded increased inhibitory effect against CES1
compared with compound 4d, while the variation of the benzoyl
group with 2-thienoyl group (4i) and alkanoyl group (4j-m)
finally resulted in a loss of potency. Further characterizations of
compounds 4n-t with the variation of sulfonyl unit demonstrated
that compound 4r with the 4-methoxyl substitute in sulfonyl unit
is more beneficial for compound inhibitory property toward
CES1. Primary SAR analysis of all tested β-keto sulfones
compounds provide insights into the fine relationships linking
between the inhibitory effects on CES1 and the substituent-
properties of these compounds. 2-naphthoyl and 4-methoxyl
sulfonyl moiety were beneficial for β-keto sulfones inhibitory
property toward CES1, led to the increase of the inhibitory effect
on CES1.
Table 2 The inhibition potency of β-keto sulfones towards
CES1. a
Scheme 2. Control experiments.
Compound
4a
IC50 (µM)
Compound
IC50 (µM)
＞100
On the basis of these experiments and literature precedents, a
plausible mechanism for the β-keto sulfone synthesis process is
proposed in Scheme 3. β-keto acid 2a reacts with K3PO4 to give
the enolate intermediate A. The nucleophilic attack of the enolate
intermediate A onto benzenesulfonyl bromide 7 generates β-keto
sulfone product 4a followed by subsequent decarboxylation.
62.10±10.61
4l
4b
4c
4m
4n
＞100
＞100
＞100
36.95±5.41
4d
4e
6.11±1.18
4o
4p
＞100
＞100
＞100
4f
4q
4r
41.42±3.75
21.54±1.61
＞100
＞100
4g
4h
4i
3.74±0.47
4s
4t
＞100
27.55±4.33
＞100
4j
4u
1.61±0.33
3.72±0.94
＞100
＞100
4k
bavachininb
Scheme 3. Proposed mechanism.
a All data presented are averages of at least three separate experiments.
b Bavachinin, a positive inhibitor against CES1.
2.4. Evaluation of inhibitory activities against CES1
Following the establishment of these β-keto sulfones and
considering the pharmacophore characters of the β-keto sulfone,
a further investigation was carried out to evaluate whether these
novel compounds possess potential biological activities as
expected. Human carboxylesterase 1 (CES1), one of the most
important serine hydrolases distributed in liver and adipocytes,
Guided by these SARs results, we next design and synthesize
a novel β-keto sulfone compound 4u that may exhibit more
potent inhibitory effect on CES1. The synthetic route is
described in Scheme 4. Gratifyingly, 2-naphthylphenone-
derived β-keto acid 2h was reacted with sodium 4-methoxyl

4
Tetrahedron
4.2. General Procedure for the decarboxylative sulfonylation
benzenesulfinate 3f to harvest the target product 4u in 86%
ACCEPTED MANUSCRIPT
reaction.
yield. The novel β-keto sulfone compound 4u showed unusually
potent inhibitory activity against CES1 with much lower IC50
value of 1.61 µM (Scheme 4 and Fig. S1).
A 25 mL Schlenk tube was charged with β-keto acids 2 (0.75
mmol), sodium sulfinates 3 (0.5 mmol), NBS (0.75 mmol),
K3PO4 (0.75 mmol) and CH2Cl2 (3 mL). The mixture was stirred
at room temperature for 24 h. After completion of the reaction,
the solvent was evaporated under reduced pressure, and the
resulting residue was purified by flash column chromatography
on silica gel to provide the desired product.
4.2.1 1-phenyl-2-(phenylsulfonyl)ethan-1-one (4a).9d
White solid; yield: 114.5 mg, 88%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.2 2-(phenylsulfonyl)-1-(p-tolyl)ethan-1-one (4b). 9d
Scheme 4. Synthesis of compound 4u.
White solid; yield: 116.6 mg, 85%; eluent composition
petroleum ether/ethyl acetate = 4:1.
3. Conclusion
In summary, the transient directing strategy was successfully
utilized in the decarboxylative sulfonylation of β-keto acids with
sodium sulfinates. This synthetic protocol featured by mild reaction
conditions and good functional group compatibility. Preliminary
mechanistic studies showed that this reaction is likely to proceed
through a nucleophilic substitution of β-keto acid with sulfonyl
bromide pathway. All synthesized β-keto sulfones were evaluated the
inhibitory effect against CES1. The SAR analysis revealed that 2-
naphthoyl moiety and 4-methoxyl sulfonyl moiety of β-keto sulfones
are very essential for CES1 inhibition. In addition, we design and
synthesize a novel β-keto sulfone 4u, which demonstrated potent
inhibitory activity against CES1. Detailed mechanism for the β-keto
sulfones synthesis process and other biological activity studies for
the β-keto sulfones are currently ongoing in our laboratory..
4.2.3 1-(4-methoxyphenyl)-2-(phenylsulfonyl)ethan-1-one (4c). 9d
White solid; yield: 124.8 mg, 86%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.4 1-(4-chlorophenyl)-2-(phenylsulfonyl)ethan-1-one (4d). 9d
White solid; yield: 119.4 mg, 81%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.5 1-(4-fluorophenyl)-2-(phenylsulfonyl)ethan-1-one (4e). 9d
White solid; yield: 111.3 mg, 80%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.6 2-(phenylsulfonyl)-1-(m-tolyl)ethan-1-one (4f). 9d
4. Experimental section
White solid; yield: 119.3 mg, 87%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.1. General Information
4.2.7 2-(phenylsulfonyl)-1-(o-tolyl)ethan-1-one (4g). 9d
All reactions were carried out under air. Flash chromatography
was performed on silica gel 60 (40-63μm, 60Å). Thin layer
chromatography (TLC) was performed on glass plates coated
with silica gel 60 with F254 indicator. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on a Bruker 600
MHz spectrometer. Chemical shifts for protons are reported in
parts per million downfield from tetramethylsilane and are
referenced to residual protium in the NMR solvent (CHCl3 = δ
7.28). Carbon nuclear magnetic resonance (13C NMR) spectra
recorded on a Bruker 600 operating at 150 MHz. Chemical shifts
for carbon are reported in parts per million downfield from
tetramethylsilane and are referenced to the carbon resonances of
the solvent (CDCl3 = δ 77.07). Data are represented as follows:
chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t
= triplet, q = quartet, m = multiplet), coupling constants in Hertz
(Hz), integration. Electrospray ionization high-resolution mass
spectra (ESI-HRMS) were recorded on a Bruke P-SIMS-Gly FT-
ICR mass spectrometer. Starting materials: β-keto acids11c and
sodium sulfinates9k were prepared according to literature
procedures. Commercial available chemicals were purchased
from Sigma-Aldrich and used without further purification.
Bavachinin was purchased from purchased from Chengdu Pufei
De Biotech Co., Ltd. (Chengdu, Sichuan, China). Stock solutions
of β-keto sulfones were prepared in DMSO and stored at 4°C
until use. Phosphate buffer (100 mM, pH 6.5) was prepared by
using Millipore water and stored at 4°C until use. Human liver
microsomes (HLMs) were obtained from Celsis (Shanghai,
China). The specific probes DME was synthesized in our lab as
described previously.13 The Luciferin Detection Reagent (LDR)
was obtained from Promega Corporation (USA).
White solid; yield: 113.8 mg, 83%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.8 1-(naphthalen-2-yl)-2-(phenylsulfonyl)ethan-1-one (4h). 9d
White solid; yield: 128.8 mg, 83%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.9 2-(phenylsulfonyl)-1-(thiophen-2-yl)ethan-1-one (4i). 9e
White solid; yield: 103.9 mg, 78%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.10 1-(phenylsulfonyl)propan-2-one (4j). 9e
White solid; yield: 74.3 mg, 75%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.11 1-cyclopropyl-2-(phenylsulfonyl)ethan-1-one (4k).
White solid; yield: 72.9 mg, 65%; eluent composition
petroleum ether/ethyl acetate = 4:1; m.p. = 54.2-55.2 oC; H
1
NMR (600 MHz, CDCl3) δ 7.91 (d, J = 7.3 Hz, 2H), 7.68 (t, J =
7.5 Hz, 1H), 7.57 (t, J = 7.9 Hz, 2H), 4.29 (s, 2H), 2.29-2.26 (m,
1H), 1.10-1.04 (m, 4H); 13C NMR (151 MHz, CDCl3) δ 197.8,
138.2, 133.7, 128.7, 127.8, 67.6, 21.5, 12.8; HRMS calc. for
[M+H]+ C11H13O3S: 225.0585, found, 225.0575.
4.2.12 3-methyl-1-(phenylsulfonyl)butan-2-one (4l).
White solid; yield: 79.2 mg, 70%; eluent composition
petroleum ether/ethyl acetate = 4:1; m.p. = 68.3-69.2 oC; H
1

NMR (600 MHz, CDCl3) δ 7.91 (dd, J = 8.4, 1.2 Hz, 2H), 7.71-
concentration), and each inhibitor. After 10 min pre-incubation at
37 °C, the reaction was started by the addition of DME (3μM,
near the Km value of DME in HLM, final concentration), with the
final concentration of DMSO at 1% (v/v, without loss of the
catalytic activity). After incubation at 37 °C for 10 min in a
shaking bath, LDR (equal volume of incubation mixture, 50 μL)
was added to terminate the reaction. The mixture was then taken
for luminescence measurements by a Synergy H1 Multi-Mode
Reader (Biotek, USA). The luminescent product of D-Luciferin
(the hydrolytic metabolite of DME) was quantified with the
excitation wavelength of 600 nm, while the emission wavelength
was 662 nm. The gain value was set at 60. The residual activities
of CES1 were calculated with the following formula: the residual
activity (%) = (the florescence intensity in the presence of
inhibitor)/the florescence intensity in negative control (without
any inhibitor) × 100%. All assays were conducted in triplicate,
and the data were shown as mean ± SD.
ACCEPTED MANUSCRIPT
7.68 (m, 1H), 7.60-7.58 (m, 2H), 4.25 (s, 2H), 2.94-2.89 (m, 1H),
1.11 (d, J = 6.9 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 201.3,
138.3, 133.7, 128.7, 127.8, 64.1, 41.4, 17.0; HRMS calc. for
[M+Na]+ C11H14NaO3S: 249.0561, found, 249.0551.
4.2.13 3, 3-dimethyl-1-(phenylsulfonyl)butan-2-one (4m).
White solid; yield: 91.3 mg, 76%; eluent composition
1
petroleum ether/ethyl acetate = 4:1; m.p. = 77.6-78.9 oC; H
NMR (600 MHz, CDCl3) δ 7.97-7.96 (m, 2H), 7.70-7.67 (m,
1H), 7.60-7.58 (m, 2H), 4.34 (s, 2H), 1.13 (s, 9H); 13C NMR (151
MHz, CDCl3) δ 202.7, 138.9, 133.4, 128.5, 128.1, 60.2, 44.7,
25.0; HRMS calc. for [M+H]+ C12H17O3S: 241.0898, found,
241.0889.
4.2.14 1-phenyl-2-tosylethan-1-one (4n). 9d
White solid; yield: 111.1 mg, 81%; eluent composition
petroleum ether/ethyl acetate = 4:1.
Acknowledgments
4.2.15 2-((4-chlorophenyl)sulfonyl)-1-phenylethan-1-one (4o). 9d
We are grateful for financial support from the Heilongjiang
Province Science Foundation for Youths (no. QC2016015), the
National Natural Science Foundation of China (no. 21602219),
the Fundamental Research Funds in Heilongjiang Provincial
Universities (no. 135209222) and the Innovative Research
Program for Graduates of Qiqihar University (no. YJSCX2017-
024X).
White solid; yield: 113.5 mg, 77%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.16 2-((4-fluorophenyl)sulfonyl)-1-phenylethan-1-one (4p). 9d
White solid; yield: 96.0 mg, 69%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.17 2-((4-bromophenyl)sulfonyl)-1-phenylethan-1-one (4q). 9d
References and notes
White solid; yield: 115.3 mg, 68%; eluent composition
petroleum ether/ethyl acetate = 4:1.
1. (a) Trost B. M., Comprehensive Organic Chemistry, Pergamon
Press, Oxford, 1991; (b) Alba, A. N. R.; Companyo, X.; Rios, R.
Chem. Soc. Rev. 2010, 39, 2018.
2. Peng, H.; Cheng, Y.; Ni, N.; Li, M.; Choudhary, G.; Chou, H. T.;
Lu, C. D.; Tai, P. C.; Wang, B. ChemMedChem 2009, 4, 1457.
3. (a) Montgomery, J. I.; Brown, M. F.; Reilly, U.; Price, L. M.;
Abramite, J. A.; Arcari, J.; Barham, R.; Che, Y.; Chen, J. M.;
Chung, S. W.; Collantes, E. M.; Desbonnet, C.; Doroski, M.;
Doty, J.; Engtrakul, J. J.; Harris, T. M.; Huband, M.; Knafels, J.
D.; Leach, K. L.; Liu, S.; Marfat, A.; McAllister, L.; McElroy, E.;
Menard, C. A.; MittonFry, M.; Mullins, L.; Noe, M. C.;
O’Donnell, J.; Oliver, R.; Penzien, J.; Plummer, M.;
Shanmugasundaram, V.; Thoma, C.; Tomaras, A. P.; Uccello, D.
P.; Vaz, A.; Wishka, D. G. J. Med. Chem. 2012, 55, 1662; (b)
Aranapakam, V.; Grosu, G. T.; Davis, J. M.; Hu, B.; Ellingboe, J.;
Baker, J. L.; Skotnicki, J. S.; Zask, A.; DiJoseph, J. F.; Sung, A.;
Sharr, M. A.; Killar, L. M.; Walter, T.; Jin, G.; Cowling, R. J.
Med. Chem. 2003, 46, 2361.
4. (a) Bartlett, P. A.; Green, F. R., III; Rose, E. H. J. Am. Chem. Soc.
1978, 100, 4852; (b) Mandai, T.; Yanagi, T.; Araki, K.; Morisaki,
Y.; Kawada, M.; Otera, J. J. Am. Chem. Soc. 1984, 106, 3670.
5. Sengupta, S.; Sarma, D. S.; Mondal, S. Tetrahedron: Asymmetry
1998, 9, 2311.
6. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1964, 86,
1639; (b) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T.
R. Tetrahedron Lett. 1976, 27, 3477.
4.2.18 2-((4-methoxyphenyl)sulfonyl)-1-phenylethan-1-one (4r).
9d
White solid; yield: 103.1 mg, 71%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.19 2-(methylsulfonyl)-1-phenylethan-1-one (4s). 9k
White solid; yield: 69.4 mg, 70%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.20 2-(naphthalen-2-ylsulfonyl)-1-phenylethan-1-one (4t).9k
White solid; yield: 113.3 mg, 73%; eluent composition
petroleum ether/ethyl acetate = 4:1.
4.2.21 2-((4-methoxyphenyl)sulfonyl)-1-(naphthalen-2-yl)ethan-
1-one (4u).
White solid; yield: 146.4 mg, 86%; eluent composition
o
1
petroleum ether/ethyl acetate = 4:1; m.p. = 158.6-161.0 C; H
1
NMR (600 MHz, CDCl3) δ H NMR (600 MHz, CDCl3) δ 8.45
7. (a) Marco, J. L.; Fernandez, I.; Khiar, N.; Fernandez, P.; Romero,
A. J. Org. Chem. 1995, 60, 6678; (b) Marco, J. L. J. Org. Chem.
1997, 62, 6575.
(s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.93-7.87 (m, 2H), 7.81 (d, J =
8.9 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H),
6.96 (d, J = 8.9 Hz, 2H), 4.84 (s, 2H), 3.83 (s, 3H); 13C NMR
(151 MHz, CDCl3) δ 188.2, 164.2, 136.0, 133.2, 132.3, 132.2,
130.9, 130.2, 130.0, 129.4, 128.8, 127.8, 127.1, 124.0, 114.4,
64.0, 55.7; HRMS calc. for [M+H]+ C19H17O4S: 341.0848, found,
341.0840.
8. (a) Svatos, A.; Hunkova, Z.; Kren, V.; Hoskovec, M.; Sÿaman, D.;
Valterova, I.; Vrkoc, J.; Koutek, B. Tetrahedron: Asymmetry
1996, 7, 1285; (b) Bertus, P.; Phansavath, P.; Ratovelomanana-
Vidal, V.; Genet, J.-P.; Touati, A. R.; Homri, T.; Hassine, B. B.
Tetrahedron: Asymmetry 1999, 10, 1369; (c) Gotor, V.;
Rebolledo, F.; Liz, R. Tetrahedron: Asymmetry 2001, 12, 513.
9. For selected examples, see: (a) Suryakiran, N.; Reddy, T. S.;
Ashalatha, K.; Lakshman, M.; Venkateswarlu Y. Tetrahedron
Lett. 2006, 47, 3853; (b) Kumar, D.; Sundaree, S.; Raoa, V. S.;
Varma, R. S. Tetrahedron Lett. 2006, 47, 4197; (c) Singh, A. K.;
Chawla, R.; Yadav, L. D. S. Tetrahedron Lett. 2014, 55, 2845; (d)
Wei, W.; Liu, C. L.; Yang, D. S.; Wen, J. W.; You, J. M.; Suo,Y.
R.; Wang, H. Chem. Commun. 2013, 49, 10239; (e) Rawat, V. S.;
Reddy, P. L. M.; Sreedhar, B. RSC Adv. 2014, 4, 5165; (f) Lu, Q.
Q.; Chen, J. Y.; Liu, C.; Huang, Z. Y.; Peng, P.; Wang, H. M.; Lei
4.3 General procedure for inhibition assays of CES1-mediated
DME hydrolysis.
The inhibitory effects against human carboxylesterase 1
(CES1) were investigated using D-Luciferin methyl ester (DME)
as the probe substrate,13 while bavachinin were used as positive
control.19 In brief, the incubation mixture with a total volume of
100 μL was consisted of PBS (pH 6.5), HLM (10 μg/mL, final

6
Tetrahedron
ACCEPTED MANUSCRIPT
A. W. RSC Adv. 2015, 5, 24494; (g) Lu, Q. Q.; Zhang, J.; Peng,
W.; Hu, X.-P. Adv. Synth. Catal. 2017, 359, 146; (c) Han, F. Z.;
P.; Zhang, G. H.; Huang, Z. L.; Yi, H.; Miller, J. T.; Lei, A. W.
Jia, L. N. Beilstein J. Org. Chem. 2017, 13, 1425.
13. Wang, D. D.; Jin, Q.; Zou, L. W.; Hou, J.; Lv, X.; Lei, W.; Cheng,
H. L.; Ge, G. B.; Yang, L. Chem Commun 2016, 52, 3183.
14. (a) Sanghani, S. P.; Sanghani, P. C.; Schiel, M. A.; Bosron, W. F.
Protein and peptide letters 2009, 16, 1207; (b) Ross, M. K.; Crow,
J. A. J Biochem Mol Toxic 2007, 21, 187.
15. (a) Dominguez, E.; Galmozzi, A.; Chang, J. W.; Hsu, K. L.;
Pawlak, J.; Li, W. W.; Godio, C.; Thomas, J.; Partida, D.; Niessen,
S.; O'Brien, P. E.; Russell, A. P.; Watt, M. J.; Nomura, D. K.;
Cravatt, B. F.; Saez, E. Nature chemical biology 2014, 10, 113; (b)
Lian, J. H.; Nelson, R.; Lehner, R. Protein & cell 2018, 9, 178; (c)
Quiroga, A. D.; Li, L.; Trotzmuller, M.; Nelson, R.; Proctor, S. D.;
Kofeler, H.; Lehner, R. Hepatology 2012, 56, 2188.
Chem. Sci. 2015, 6, 4851; (h) Handa, S.; Fennewald, J. C.;
Lipshutz, B. H. Angew. Chem., Int. Ed. 2014, 53, 3432; (i) Lu, Q.
Q.; Zhang, J.; Zhao, G. L.; Qi, Y.; Wang, H. M.; Lei, A. W. J. Am.
Chem. Soc. 2013, 135, 11481; (j) Liu, C. R.; Ding, L. H.; Guo, G.;
Liu, W. W. Eur. J. Org. Chem. 2016, 910; (k) Tang, X. D.;
Huang, L. B.; Xu, Y. L.; Yang, J. D.; Wu, W. Q.; Jiang, H. F.
Angew. Chem., Int. Ed. 2014, 53, 4205; (l) Yadav, V. K.;
Srivastava, V. P.; Yadav, L. D. S. Synlett 2016, 27, 427; (m)
Wang, H. H.; Wang, G. Y.; Lu, Q. Q.; Chiang, C. W.; Pan Peng,
Zhou, J. F.; Lei, A. W. Chem. Eur. J. 2016, 22, 14489; (n) Yu, J.
Y.; Mao, R. Y.; Wang, Q. Y.; Wu, J. Org. Chem. Front., 2017, 4,
617; (o) Chen, W. T.; Liu, X. Y.; Chen, E.; Chen, B. H.; Shao, J.
A.; Yu, Y. P. Org. Chem. Front., 2017, 4, 1162; (p) Xiong Y. S.;
Weng J.; Lu G. Adv. Synth. Catal. 2018, 360, doi:
10.1002/adsc.201701209; (q) Jiang, H.; Cheng, Y. Y.; Zhang,Y.;
Yu, S. Y. Eur. J. Org. Chem. 2013, 5485.
16. (a) Gilham, D.; Ho, S.; Rasouli, M.; Martres, P.; Vance, D. E.;
Lehner, R. Faseb Journal 2003, 17, 1685; (b) Wei, E.; Ben Ali,
Y.; Lyon, J.; Wang, H.; Nelson, R.; Dolinsky, V. W.; Dyck, J. R.;
Mitchell, G.; Korbutt, G. S.; Lehner, R. Cell metabolism 2010, 11,
183.
10. For selected reviews, see: (a) Nakamura, S. Org. Bioml. Chem.
2014, 12, 394; (b) Wang, Z. L. Adv. Synth. Catal. 2013, 355,
2745.
17. Bachovchin, D. A.; Cravatt, B. F. Nature reviews. Drug discovery
2012, 11, 52.
11. For selected examples on the decarboxylative reaction of
ketoacids, see: (a) Wei, A. J.; Nie, J.; Zheng, Y.; Ma, J. A. J. Org.
Chem. 2015, 80, 3766; (b) Nakamura, S.; Sano, M.; Toda, A.;
Nakane, D.; Masuda, H. Chem. Eur. J. 2015, 21, 3929; (c) Xiong,
H. Y.; Yang, Z. Y.; Chen, Z.; Zeng, J. L.; Nie, J.; Ma, J. A. Chem.
Eur. J. 2014, 20, 8325; (d) Zhang, H. X.; Nie, J.; Cai, H.; Ma, J.
A. Org. Lett. 2014, 16, 2542; (e) Yuan, H. N.; Wang, S.; Nie, J.;
Meng, W.; Yao, Q. W.; Ma, J. A. Angew. Chem. Int. Ed. 2013, 52,
3869; (f) Chen, Y.; Tian, S. K. Chinese J. Chem. 2013, 31, 37; (g)
Zhong, F. R.; Yao, W. J.; Dou, X. W.; Lu, Y. X. Org. Lett. 2012,
14, 4018; (h) Yang, C. F.; Shen, C.; Wang, J. Y.; Tian, S. K. Org.
Lett. 2012, 14, 3092; (i) Evans, D. A.; Seidel, D. J. Am. Chem.
Soc. 2007, 129, 11583; (j) Chen, S. J.; Lua, G. P.; Cai, C. Chem.
Commun. 2015, 51, 11512; (k) Tang, X. D.; Li, S.; Guo, R.; Nie,
J.; Ma, J. A. Org. Lett. 2015, 17, 1389; (l) Saadi, J.; Wenneemers,
H. Nat. Chem. 2016, 8, 276; (m) Lai, B. N.; Qiu, J. F.; Zhang, H.
X.; Nie, J.; Ma, J. A. Org. Lett. 2016, 18, 520; (n) Li, C.; Grugel,
C. P.; Breit, B. Chem. Commun. 2016, 52, 5840; (o) Guo, Y. L.;
Li, Y. H.; Chang, H. H.; Kuo, T. S.; Han, J. L. RSC Adv. 2016, 6,
74683; (p) Cruz, F. A.; Chen, Z.; Kurtoic, S. I.; Dong, V. M.
Chem. Commun. 2016, 52, 5836.
18. (a) Zou, L. W.; Dou, T. Y.; Wang, P.; Lei, W.; Weng, Z. M.; Hou,
J.; Wang, D. D.; Fan, Y. M.; Zhang, W. D.; Ge, G. B.; Yang, L.
Front Pharmacol 2017, 8, 435; (b) Wang, D. D.; Zou, L. W.; Jin,
Q.; Hou, J.; Ge, G. B.; Yang, L. Fitoterapia 2017, 117, 84; (c)
Zou, L. W.; Jin, Q.; Wang, D. D.; Qian, Q. K.; Hao, D. C.; Ge, G.
B.; Yang, L. Current medicinal chemistry 2018, 25, 1627.
19. Sun, D. X.; Ge, G. B.; Dong, P. P.; Cao, Y. F.; Fu, Z. W.; Ran, R.
X.; Wu, X.; Zhang, Y. Y.; Hua, H. M.; Zhao, Z. Y.; Fang, Z. Z.
Xenobiotica 2016, 46, 503.
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12. (a) Han, F. Z. ; Zhang, X.; Hu, M.; Jia, L. Org. Biomol. Chem.
2015, 13, 11466. (b) Han, F. Z.; Su, B.-B.; Jia, L. N.; Wang, P.