Sulfonium ylide formation and subsequent C[sbnd]S bond cleavage of aromatic isopropyl sulfide catalyzed by hemin in aqueous solvent

Article abstract of DOI:10.1016/j.tet.2019.04.035

Heme is an abundant and widely existed cofactor for a variety of metalloenzymes, whose broader use is generally impeded by its high instability and poor solubility. Here we report an environment-benign and efficient strategy for the sulfonium ylide formation and subsequent C[sbnd]S bond cleavage of aromatic isopropyl sulfides, which was catalyzed by hemin in assistance of Triton X-100. This aqueous catalytic system exhibited good functional group tolerance to a variety of sulfides and diazo esters. And the reaction mechanism was preliminarily proposed on the basis of designed reactions. Furthermore, the cleavage of C[sbnd]S bond followed by introducing a functional ester group to aromatic sulfides, may potentially be employed for the late stage functionalization (LSF) of organosulfur drug in the future.

Full text of DOI:10.1016/j.tet.2019.04.035

Accepted Manuscript
Sulfonium ylide formation and subsequent C S bond cleavage of aromatic isopropyl
sulfide catalyzed by hemin in aqueous solvent
Xiaojing Yan, Chang Li, Xiaofei Xu, Quan He, Xiaoyong Zhao, Yuanjiang Pan
PII:
S0040-4020(19)30447-8
https://doi.org/10.1016/j.tet.2019.04.035
TET 30280
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 February 2019
Revised Date: 9 April 2019
Accepted Date: 13 April 2019
Please cite this article as: Yan X, Li C, Xu X, He Q, Zhao X, Pan Y, Sulfonium ylide formation and
subsequent C S bond cleavage of aromatic isopropyl sulfide catalyzed by hemin in aqueous solvent,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.04.035.
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Sulfonium ylide formation and subsequent
C-S bond cleavage of aromatic isopropyl
sulfide catalyzed by hemin in aqueous
solvent
Leave this area blank for abstract info.
Xiaojing Yan,a Chang Li, b, * Xiaofei Xu,a Quan He,a Xiaoyong Zhaoa and Yuanjiang Pan a, *
a.Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang. Peoples Republic of China.
b.College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang,
Peoples Republic of China.

1
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Tetrahedron
journal homepage: www.elsevier.com
Sulfonium ylide formation and subsequent C-S bond cleavage of aromatic isopropyl
sulfide catalyzed by hemin in aqueous solvent
Xiaojing Yana, Chang Li b, *, Xiaofei Xua, Quan Hea, Xiaoyong Zhaoa and Yuanjiang Pan a, *
a Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang. Peoples Republic of China. E-mail: panyuanjiang@zju.edu.cn;
b College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, Peoples Republic of China. E-mail:
lichang@zju.edu.cn.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Heme is an abundant and widely existed cofactor for a variety of metalloenzymes, whose
broader use is generally impeded by its high instability and poor solubility. Here we report an
environment-benign and efficient strategy for the sulfonium ylide formation and subsequent C-S
bond cleavage of aromatic isopropyl sulfides, which was catalyzed by hemin in assistance of
Triton X-100. This aqueous catalytic system exhibited good functional group tolerance to a
variety of sulfides and diazo esters. And the reaction mechanism was preliminarily proposed on
the basis of designed reactions. Furthermore, the cleavage of C-S bond followed by introducing
a functional ester group to aromatic sulfides, may potentially be employed for the late stage
functionalization (LSF) of organosulfur drug in the future.
Available online
Keywords:
Hemin
Sulfonium ylide
C-S bond cleavage
Aqueous catalytic system
Diazo ester
2009 Elsevier Ltd. All rights reserved
.
Late stage functionalization
functionalization of C–H bonds.26 Very recently, Che et. al.
reported several cobalt (II) porphyrins catalyzed intramolecular
cyclopropanation/ring opening cascade reaction, intramolecular
Buchner reaction and arene cyclopropanation, affording
corresponding nitrogen-containing polycyclic products in good
yields.27-29 Simple iron-porphyrin based catalysts and the reaction
with diazoalkanes have also been achieved by Carreira30 and
other groups.31, 32 However, as the most easily available form of
porphyrin, only few catalytic reactions employing hemin itself as
catalyst have been reported,33, 34 in some degree owing to its high
instability and poor solubility in both organic and aqueous
solvent.35-37 In recent years, our group have developed some
green catalytic strategies38, 39 based on hemin for transformation
of diazo esters, especially for the formation of sulfonium ylide.40-
1. Introduction
The Late stage functionalization (LSF), which aims to
generate ameliorative drug analogs without resorting to de novo
synthesis, has received great attention lately.1-5 However,
molecules bearing C-S bonds are rarely applied in LSF, which is
possibly due to the difficulty in breaking the C-S bonds and
introducing another group subsequently. The C-S bond cleavage
is crucial to synthetic chemistry and petroleum industry.
Although C–S bond cleavage reactions mediated by third row
transition metals have been reported6-8. Most applied C-S bond
cleavage cannot be easily achieved, requiring expensive catalysts,
harsh reaction conditions, and organic solvents as reported
(Scheme 1a).9-15 Thus, it is of great importance to develop mild
and green methods16 for the cleavage of C-S bond and subsequent
formation of new C-S bond, which may also contribute to the
LSF of organosulfur drug leads
45
For instance, [2, 3]-sigmatropic rearrangements (Scheme 1c)46
and Sommelet-Hauser rearrangements39 were successfully carried
out with hemin as the catalyst in aqueous system. As our
continuous interest in green catalysis of hemin and sulfonium
ylide formation, herein, a concise and efficient method was
developed for the sulfonium ylide formation and subsequent C-S
bond cleavage of aromatic isopropyl sulfide (Scheme 1d). This
reaction was catalyzed by hemin and conducted in water with
assistance of a surfactant Triton X-100.
On the other hand, a great endeavor has been devoted to the
modification and application of porphyrin or metallo-porphyrin
enzymes in the past decade. For instance, a series of heme-based
engineered metalloproteins were developed for the catalysis with
excellent conversion and selectivity by Arnold group17-21 and
Fasan group22-25. Among them, the diazo compound-based
reactions were intensively studied. Fasan group reported the
myoglobin variant catalyzed S-H insertion of diazo esters with
remarkable conversions (Scheme 1b).22 Hartwig prepared
modified myoglobins by replacing the iron in Fe-porphyrin IX
(Fe-PIX) proteins with abiological, noble metals to catalyze the

2
Tetrahedron
ACCEPTED MANUSCRIPT
with
sodium
laurylsulfonate
(SDS)
and
sodium
dodecylbenzenesulfate (SDBS), with the yield of 3a reached as
high as 89%. This result is in accordance with the reported works
that Triton X-100 can inhibit the aggregation of hemin in
aqueous solution47 and further improve its catalytic capacity.48 In
addition, one similar result that appropriate amount of Triton X-
100 obviously increase conversation was obtained in one of our
previous studies.46 Thus, Triton X-100 was chosen as the additive
in this reaction. Several other reaction parameters were
optimized, including the amount of hemin (Table 1, entries5-7),
reaction time (Table 1, entries 7-10), molar ratio of 2a/1a (Table
1, entries 10-13) and the amount of Triton X-100 (Table 1,
entries 13-16). Finally, the optimized reaction condition was as
follows, 5 mol% hemin and 20 mol% Triton X-100 shaken at 40
ꢀ for 4 days (Table 1, entry 10). Considering the cleavage of C-
S bond cannot be easily achieved in transition metal catalyzed
reactions conducted in organic solvent at high temperature 9-15, it
is worth mentioning that the reaction time is acceptable for diazo
compound involved reactions conducted in aqueous solvent at
low temperature (40 ꢀ) compared with previous studies.38, 46, 49,
50 The optimized reaction yield was 98%. No desired product was
observed when Cu (II) protoporphyrin IX (Table 1, entry 17) or
iron salt FeCl3·6H2O (Table 1, entry 18) was used as catalyst in
the reaction. This indicated that both porphyrin structure and iron
center were crucial for the reaction. Moreover, control
experiments showed that the reaction didn’t proceed well in the
absence of hemin or Triton X-100 (Table S1, entries 1-5). During
the whole course of the experiments, only tiny amounts of the
dimerization of EDA were observed in the context of excess
EDA, which was added without drop wise.
Scheme 1 Strategies involving C-S bond transformation
2. Results and discussion
Table 1 Optimization of reaction conditionsa
2a
/1a
Catalyst
(mol %)
Time
(d)
Additive
(mol %)
Yieldb
(%)
Entry
1
2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.5
1.0
2.0
1.2
1.2
1.2
hemin (10)
hemin (10)
hemin (10)
hemin (10)
hemin (10)
hemin (1)
hemin (5)
hemin (5)
hemin (5)
hemin (5)
hemin (5)
hemin (5)
hemin (5)
hemin (5)
hemin (5)
hemin (5)
5
5
5
5
5
5
5
2
3
4
4
4
4
4
4
4
\
8
β-CD (20)
17
42
58
89
70
96
57
80
98
33
80
98
36
71
98
3
SDBS (20)
4
SDS (20)
5
Triton X-100 (20)
Triton X-100(20)
Triton X-100(20)
Triton X-100 (20)
Triton X-100 (20)
Triton X-100 (20)
Triton X-100 (20)
Triton X-100 (20)
Triton X-100 (20)
Triton X-100 (5)
Triton X-100 (10)
Triton X-100 (30)
6
Using the optimized reaction conditions,
a variety of
7
substituted isopropyl sulfides were employed in the hemin-
catalyzed sulfonium ylide formation and subsequent C-S bond
cleavage reaction with EDA. The results are summarized in
Table 2. It is demonstrated that the catalytic system has good
8
9
10
11
12
13
14
15
16
functional
group
tolerance
to
halogenated
phenylisopropylsulfides (3b-3g), as well as trifluoromethyl(3h),
ester (3i-3j), methoxyl(3k-3l) and alkylphenylisopropylsulfides
(3m-3p). In most cases, the para-, ortho- and meta-chlorophenyl
isopropyl sulfides performed well, furnishing the corresponding
phenylthioacetate in comparable yields (49%-58%) with no
obvious position effects, while 3f is more popular for the
reaction. In general, both electron-withdrawing groups (3b-3j)
and electron-donating groups (3k-3p) on the aryl ring of the
initial thioether substrates were well tolerated, even though the
substitution in the substrate could bring down the yield. In
addition, 2-(isopropylthio) naphthalene (3q) was readily
converted to the corresponding thioacetate in moderate yield
(43%). What’s more, substrates containing N- or S- heterocycles
such as 2-(isopropylthio)pyridine (3r), 2-(isopropylthio)-6-
methylpyridine(3s) and 2-(isopropylthio)thiophene (3t), which
are poisonous to rhodium or other metal-based catalysts in most
organic reactions,51 could also be converted to the corresponding
products in good yields(60%-68%). Subsequently, gram scale
synthesis of 3a and 3p were realized.
Cu(II)protoporp
hyrinIX(5)
4
4
17
18
1.2
1.2
Triton X-100 (20)
Triton X-100 (20)
0
0
FeCl3·6H2O(5)
aReactions were carried out with 3 mL of H2O at 40 ꢀ in a thermo shaker.
bYields were determined by 1H NMR analysis of the crude reaction mixtures.
In the initial study, 0.5 mmol phenyl isopropyl sulfide (1a)
and 0.6 mmol ethyl diazo acetate (EDA, 2a) were employed as
substrates to optimize the reaction conditions (Table 1). Upon
treatment of 1a and 2a in 3 mL water at 40 ꢀ for 5 days with 10
mol% hemin as the catalyst, the desired product, ethyl 2-
(phenylthio) acetate (3a), was observed in 8% yield, which was
determined by 1H NMR (Table 1, entry 1). Inspired by our
previous studies38, 20 mol% β-cyclodextrin (β-CD) was added to
the catalytic system. However, the yield of 3a was only slightly
raised to 17% (Table 1, entry 2). Several commercially available
surfactants were screened for their ability in improvement of the
catalytic effect in this reaction (Table 1, entries 3-5). Among
them, Triton X-100 showed superior capacity in comparation
As an extension of this catalytic system, several reactants with
tertiary carbon involved alkyl groups as R2 groups were designed
and their reactivities were investigated under the optimized
conditions (Table 3). The results showed that 3-
pentylphenylsulfide (1u), cyclohexylphenylsulfide (1v) and
cyclopentylphenyl sulphide (1w) all generate product 3a.
However, the yields were all not as good as 1a, which might due
to the steric hinderance of the formed sulfonium ylide.

3
Some other thioethers were also investigated. The results are
ACCEPTED MANUSCRIPT
also shown in Table 3, no desired products were observed when
methylphenyl sulfide (1x), ethyl (1y), vinyl (1z), tert-butyl (1aa)
and halomethyl (1ad-1ae) phenyl sulfides were employed as
Table 3 Investigation of diverse substituted sulfidesa,b
substrates.
The
similar
result
was
observed
for
phenylethanethioate (1ah). Meanwhile, diphenylsulfide (1ab)
and diphenylmethyl phenyl sulfide (1ac) were also found to be
incompatible, which may due to the large steric hindrance.
Considering no desired reactions for (1af) and (1ag), we
supposed that the aliphatic thioethers might be inapplicable to
this catalytic system.
1u 24 (20)
1v 43 (37)
1w 74 (68)
Incompatible:
Table 2 Investigation of diverse substituted sulfidesa, b
1y
1aa
1ae
1x
1z
1ab
1ad
1ac
1ag
1ah
1af
3a 98% (89%)
3b 49% (42%)
3e 54% (43%)
3c 58% (50%)
3f 98% (84%)
aReactions were carried out with 3 mL of H2O at 40 ꢀ for 4 d in a thermo
(873 mg)
b
1
shaker; Yields were determined by H NMR analysis of the crude reaction
mixtures. Values in the parentheses are isolated yields.
3d 51% (44%)
Table 4 Investigation of various diazo esters a
3g 72% (63%)
3j 81% (70%)
3m 58% (50%)
3h 52% (42%)
3k 34% (28%)
3i 74% (67%)
3l 40% (35%)
Entry
Diazo ester
Product
Yieldb (%)
R3= H, R4= tBu
1
77 (58)
2u
R3= H, R4= Bn
2v
3u
3v
2
3
45 (33)
61 (50)
3n 44% (39%)
3q 43% (39%)
3t 68% (62%)
3o 50% (41%)
3r 60% (52%)
R3= H, R4= C6H11
2w
3w
3x
3p 78% (68%)
R3= H, R4= C5H9
(953 mg)
4
5
53 (42)
80 (64)
2x
R3= H, R4= C10H15
2y
3s 69% (58%)
aReactions were carried out with 3 mL of H2O at 40 ꢀ for 4 d in a thermo
3y
b
1
shaker; Yields were determined by H NMR analysis of the crude reaction
mixtures. Values in the parentheses are isolated yields and products obtained.
R3= Bn, R4= Et
/
4
0
Furthermore, the reaction scope of α-diazo esters was
investigated. As shown in Table 4, tert-butyl (2u), benzyl (2v),
cyclohexyl (2w), cyclopentyl (2x), and adamantine-2-yl (2y)
diazoacetate can react smoothly with sulfide, leading to the
corresponding products in moderate to good yields (45%-80%).
No reaction was detected when 2z was employed, indicating that
α-substitutions on the carbenoid moiety may be not tolerated.
Several other diazo esters which are not compatible in the
reaction system are listed in the supporting information (Table S2,
2b-2e)
2z
aReactions were carried out with 3 mL of H2O at 40 ꢀ for 4 d in a thermo
b
1
shaker; Yields were determined by H NMR analysis of the crude reaction
mixtures. Values in the parentheses are isolated yields.
Even though some of the α-arylthio carbonyl compounds
could be obtained from nucleophilic substitution of α-bromo-
acetates with thiols and other ways, However, most of those
methods must be conducted either in organic solvent with harsh

4
Tetrahedron
ACCEPTED MANUSCRIPT
condition52-55, or with expensive transition metal catalysts.56
4. Experimental Section
What’s more, the present work consists of two parts, cleavage of
non-activated C-S bond and synthesis of α-arylthio carbonyl
compounds, which is different from Fasan’s work(scheme 1b)
and other work that only provide access to α-arylthio carbonyl
compounds.57 To our best knowledge, there is no aqueous C-S
bond cleavage reaction reported yet (for reference 8, CHCl3 is
added).
4.1. General information
All reagents were purchased at the highest commercial quality
and used without further purification. NMR spectra were
recorded at 400 MHz and 100 MHz with Bruker ARX-400
instrument or 600MHz and 150 MHz with Bruker Avance DMX-
500 instrument. High resolution mass spectra (HRMS) were
recorded on a Shimadzu LC/MS IT-TOF and a Waters
Micromass GCT instrument. All reactions were monitored by
TCL with silica gel-coated plates. For chromatography, 100-200
mesh silica gel (Qingdao, China) was employed.
In order to dug deeper into the mechanism of the reaction, (2,
3-dihydro-1H-inden-1-yl) (phenyl) sulfide (1ai) was designed to
react with EDA under the standard reaction conditions. As shown
in Scheme 2, the compound 1-indanol (4a) instead of 1-indone58
was confirmed as the main byproduct with 3a, 4a in 46% and
33% yield respectively. It could be inferred that the cleaved
fragment of aromatic isopropyl sulfide was further attacked by
water to form the alcohol product, which is isopropanol in most
cases aforementioned.
4.2. General procedures
Sulfide (0.5 mmol) was added into 3 mL of aqueous solution
of 25.0 ꢀmol hemin and 0.1 mmol Triton X-100, followed by
adding 0.6 mmol diazo ester in one portion. The reaction vial was
then placed in a constant temperature shaker and left to shake at
220 rpm under 40 ꢀ. After 4 days, the mixture was extracted
twice with EtOAc (2 mL×2). The organic layer was further
washed with brine and then dried with Na2SO4. Then the organic
solvent was removed in vacuum and hemin was removed by a
short silica gel column, and eluted by petroleum ether to give the
corresponding product. For gram scale synthesis 1a and 1p were
employed with 5 mmol, 6.25 mmol respectively.
Scheme 2 Reaction between (2, 3-dihydro-1H-inden-1-yl) (phenyl) sulfide
(1ai) and EDA
4.3. Characterization of products
4.3.1. Ethy 2-(phenylthio) acetate (3a)
Based on the reported literatures and the observation of
hydrolysed product 4a, the proposed mechanism is depicted in
Colorless oil; 873 mg; 89%yield; 1H NMR (400 MHz, CDCl3)
δ 7.44-7.38 (m, 2H), 7.34-7.27 (t, J = 7.5 Hz, 2H), 7.25-7.20 (t, J
= 7.3 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.64 (s, 2H), 1.22 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.9, 135.1, 130.1,
129.2, 127.1, 61.7, 36.9, 14.2. HRMS (ESI) calcd. for (M+H)+
(C10H13O2S)+: 197.0631, found: 197.0629.
Scheme 3. Initially, hemin reacts with the diazo ester (1) to
60
generate hemin carbene intermediate (2),59,
which has
electrophilic character and can react with sulfide, giving rise to
sulfonium ylide (3). 43, 46, 61 Then, the desired product from the
cleavage of C-S bond and subsequent formation of new C-S bond
is formed. At the same time, the attack of H2O to sulfonium ylide
led to the formation of isopropanol as byproduct.
4.3.2. Ethyl 2-(4-chlorophenylthio) acetate (3b)
Colorless oil; 48.4 mg; 42%yield; 1H NMR (400 MHz, CDCl3)
δ 7.32 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 4.13 (q, J =
7.1 Hz, 2H), 3.58 (s, 2H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 169.4, 133.5, 133.1, 131.4, 129.1, 61.6, 36.8,
14.1. HRMS (EI) calcd. for (M)+ (C10H11ClO2S)+: 230.0168,
found: 230.0170.
4.3.3. Ethyl 2-(3-chlorophenylthio) acetate (3c)
Colorless oil; 57.6 mg; 50%yield; 1H NMR (400 MHz, CDCl3)
δ 7.43-7.40 (m, 1H), 7.32-7.28 (m, 1H), 7.27-7.19 (m, 2H), 4.21
(q, J = 7.1 Hz, 2H), 3.67 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 169.4, 137.3, 134.8, 130.1, 129.2,
127.6, 127.0, 61.8, 36.3, 14.2. HRMS (ESI) calcd. for (M+Na)+
(C10H11ClO2SNa)+: 253.0060, found: 253.0044.
Scheme 3 The proposed reaction mechanism
3. Conclusions
4.3.4. Ethyl 2-(2-chlorophenylthio) acetate (3d)
In summary ꢁ we developed an aqueous hemin-catalyzed
reaction between diazo esters and aromatic isopropyl sulfides,
which involved the sulfonium ylide formation and subsequent C-
S bond cleavage. With the assistance of Triton X-100, the
reaction is efficient under mild and eco-friendly conditions. The
wide substrates scope and concise reaction conditions may
contribute to a biocompatible green catalytic system for the LSF
of organosulfur drug leads in the future. This study may also
expand the range of carbene-mediated transformations via heme-
based catalysts.
Colorless oil; 50.8 mg; 44%yield; 1H NMR (400 MHz,
CDCl3) δ 7.42-7.34 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.12 (m,
1H), 4.16 (q, J = 7.1 Hz, 2H), 3.67 (s, 2H), 1.22 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 169.3, 134.3, 129.9, 127.8,
127.4, 61.8, 35.3, 14.2. HRMS (ESI) calcd. for (M+H)+
(C10H12ClO2S)+: 231.0241, found: 231.0230.
4.3.5. Ethyl 2-(4-fluorophenylthio) acetate (3e)
Colorless oil; 46.0 mg; 43%yield; 1H NMR (400 MHz,
CDCl3) δ 7.30-7.21 (m, 1H), 7.19-7.07 (m, 2H), 6.91 (td, J = 8.4,
2.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.65 (s, 2H), 1.24 (t, J = 7.1
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.4, 164.1, 161.6,

5
137.6, 130.4, 124.8, 116.3, 116.0, 113.9, 113.7, 61.8, 36.2, 14.2.
4.3.13. Ethyl 2-[(2, 4-dimethyl) phenylthio] acetate (3m)
ACCEPTED MANUSCRIPT
HRMS (ESI) calcd. for (M+H)+ (C10H12FO2S)+: 215.0537, found:
215.0545.
Colorless oil; 56.0 mg; 50%yield; 1H NMR (400 MHz, CDCl3)
δ 7.29 (d, J = 7.9 Hz, 1H), 7.02 (s, 1H), 6.97 (d, J = 7.9 Hz, 1H),
4.14 (q, J = 7.1 Hz, 2H), 3.55 (s, 2H), 2.40 (s, 3H), 2.29 (s, 3H),
1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.9,
139.1, 137.4, 131.2, 130.3, 127.4, 61.5, 36.7, 21.0, 20.5, 14.2.
HRMS (ESI) calcd. for (M+H)+ (C12H17O2S)+: 225.0944, found:
225.0939.
4.3.6. Ethyl 2-(3-fluorophenylthio) acetate (3f)
Colorless oil; 90.0 mg; 84%yield; 1H NMR (400 MHz,
CDCl3) δ 7.29-7.24 (m, 1H), 7.19-7.08 (m, 2H), 6.95-6.87 (m,
1H), 4.19 (q, J = 7.1 Hz, 2H), 3.66 (s, 2H), 1.24 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 169.5, 130.5, 124.9, 116.3,
116.1, 113.9, 113.7, 61.9, 36.3, 14.2. HRMS (EI) calcd. for (M)+
(C10H11FO2S)+: 214.0464, found: 214.0465.
4.3.14. Ethyl 2-[4-(1-methylethyl) phenylthio] acetate (3n)
Colorless oil; 46.2 mg; 39%yield; 1H NMR (400 MHz, CDCl3)
δ 7.38-7.33 (m, 2H), 7.19-7.13 (m, 2H), 4.15 (q, J = 7.1 Hz, 2H),
3.59 (s, 2H), 2.88 (hept, J = 6.9 Hz, 1H), 1.25-1.19 (m, 9H). 13C
NMR (100 MHz, CDCl3) δ 167.0, 148.3, 131.6, 131.0, 127.3,
61.5, 37.4, 33.8, 24.0, 14.2. HRMS (ESI) calcd. for (M+H)+
(C13H19O2S)+: 239.1100, found: 239.1088.
4.3.7. Ethyl 2-(4-bromophenylthio) acetate (3g)
Colorless oil; 86.6 mg; 63%yield; 1H NMR (400 MHz,
CDCl3) δ 7.45-7.39 (m, 2H), 7.30-7.23 (m, 2H), 4.16 (q, J = 7.1
Hz, 2H), 3.61 (s, 2H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 169.6, 134.3, 132.2, 131.7, 121.2, 61.8, 36.8,
14.2 .HRMS (EI) calcd. for (M)+ (C10H11BrO2S)+: 273.9663,
found: 273.9656.
4.3.15. Ethyl 2-[4-(1, 1-dimethylethyl) phenylthio] acetate (3o)
Colorless oil; 51.8 mg; 41%yield; 1H NMR (400 MHz,
CDCl3) δ 7.39-7.30 (m, 4H), 4.16 (q, J = 7.1 Hz, 2H), 3.60 (s,
2H), 1.30 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 169.9, 150.5, 131.4, 130.5, 126.2, 61.5, 37.2, 34.6,
31.3, 14.2. HRMS (ESI) calcd. for (M+H)+ (C14H21O2S)+:
253.1257, found: 253.1246.
4.3.8. Ethyl 2-(4-Trifluoromethylphenylthio) acetate (3h)
Colorless oil; 55.6 mg; 42%yield; 1H NMR (400 MHz,
CDCl3) δ 7.53 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 4.19
(q, J = 7.1 Hz, 2H), 3.70 (s, 2H), 1.24 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 169.3, 140.3, 128.2, 125.9, 62.0,
35.4, 14.2. HRMS (ESI) calcd. for (M+Na)+ (C11H11F3O2SNa)+:
287.0324, found: 287.0315.
4.3.16. Ethyl 2-(4-ethylphenylthio) acetate (3p)
Colorless oil; 953 mg; 68%yield; 1H NMR (400 MHz, CDCl3)
δ 7.38-7.33 (m, 2H), 7.13 (d, J = 8.2 Hz, 2H), 4.15 (q, J = 7.1 Hz,
2H), 3.58 (s, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz,
6H). 13C NMR (100 MHz, CDCl3) δ 169.9, 143.7, 131.5, 131.0,
128.7, 61.5, 37.4, 28.5, 15.5, 14.1. HRMS (ESI) calcd. for
(M+H)+ (C12H17O2S)+: 225.0944, found: 225.0936.
4.3.9. 4-(Ethoxycarbonylmethylsulfanyl) benzoic acid ethyl ester
(3i)
Colorless oil; 89.8 mg; 67%yield; 1H NMR (400 MHz, CDCl3)
δ 7.98 – 7.91 (m, 2H), 7.39 – 7.33 (m, 2H), 4.35 (q, J = 7.1 Hz,
2H), 4.19 (q, J = 7.1 Hz, 2H), 3.71 (s, 2H), 1.38 (t, J = 7.1 Hz,
3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
169.26, 166.27, 141.98, 130.17, 128.22, 127.29, 62.00, 61.13,
35.23, 14.46, 14.23. HRMS (ESI) calcd. for (M-H)- (C13H15O4S)-:
267.0697, found: 267.0705.
4.3.17. Ethyl 2-(2-naphthalenylthio) acetate (3q)
Yellow oil; 48.0 mg; 39%yield; 1H NMR (400 MHz, CDCl3) δ
7.87 (s, 1H), 7.81-7.75 (m, 3H), 7.53-7.42 (m, 3H), 4.18 (q, J =
7.1 Hz, 2H), 3.75 (s, 2H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 169.7, 133.7, 132.5, 132.1, 128.6, 128.1, 127.6,
127.3, 126.6, 126.1, 61.6, 36.6, 14.1. HRMS (ESI) calcd. for
(M+H)+ (C14H15O2S)+: 247.0787, found: 247.0767.
4.3.10. Isopropyl 4-((2-ethoxy-2-oxoethyl) thio) benzoate (3j)
Colorless oil; 98.8 mg; 70%yield; 1H NMR (400 MHz,
CDCl3) δ 7.94 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 5.23
(hept, J = 6.3 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.71 (s, 2H), 1.35
(d, J = 6.3 Hz, 6H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 169.26, 165.74, 141.77, 130.15, 128.68, 127.33, 68.55,
61.98, 35.29, 22.07, 14.23. HRMS (ESI) calcd. for (M-H)-
(C14H17O4S)-: 281.0853, found: 281.0892.
4.3.18. Ethyl 2-(2-pyridinylthio) acetate (3r)
Colorless oil; 51.2 mg; 52%yield; 1H NMR (400 MHz,
CDCl3) δ 8.37 (d, J = 4.1 Hz, 1H), 7.47 (td, J = 7.7, 1.7 Hz, 1H),
7.21 (d, J = 8.7 Hz, 1H), 7.00-6.96 (m, 1H), 4.18 (q, J = 7.1 Hz,
2H), 3.96 (s, 2H), 1.24 (t, J = 7.1 Hz, 3H).13C NMR (100 MHz,
CDCl3) δ 169.8, 156.9, 149.4, 136.2, 122.1, 119.9, 61.6, 32.4,
14.2. HRMS (ESI) calcd. for (M+H)+ (C9H12NO2S)+: 198.0583,
found: 198.0576.
4.3.11. Ethyl 2-(4-methoxyphenylthio) acetate (3k)
Colorless oil; 31.6 mg; 28%yield; 1H NMR (400 MHz,
CDCl3) δ 7.37 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 8.9 Hz, 1H), 6.94-
6.82 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.61 (s, 2H),
1.18 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.9,
158.0, 131.7, 128.8, 121.1, 110.7, 61.4, 55.8, 35.1, 14.2. HRMS
(ESI) calcd. for (M+H)+ (C11H15O3S)+: 227.0736, found:
227.0726.
4.3.19. Ethyl 2-((6-methylpyridin-2-yl) thio) acetate (3s)
Yellow oil; 61.2 mg; 58%yield; 1H NMR (400 MHz, CDCl3) δ
7.36 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.82 (d, J = 7.5
Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.93 (s, 2H), 2.44 (s, 3H), 1.26
(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.06,
158.42, 155.94, 136.45, 119.23, 118.88, 61.52, 32.63, 24.36,
14.28.HRMS (ESI) calcd. for (M+H)+ (C10H14NO2S)+: 212.0745,
found: 212.0746.
4.3.12. Ethyl 2-(3-methoxyphenylthio) acetate (3l)
Colorless oil; 39.6 mg; 35%yield;1H NMR (400 MHz, CDCl3)
δ 7.19 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.2 Hz, 2H), 6.76-6.70 (m,
1H), 4.16 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 3.63 (s, 2H), 1.22 (t, J
= 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.7, 159.9,
136.4, 129.9, 121.7, 114.9, 112.7, 61.6, 55.3, 36.5, 14.1. HRMS
(ESI) calcd. for (M+H)+ (C11H15O3S)+: 227.0736, found:
227.0723.
4.3.20. Ethyl 2-(2-thienylthio) acetate (3t)
Colorless oil; 62.8 mg; 62%yield; 1H NMR (400 MHz,
CDCl3) δ 7.39 (dd, J = 5.4, 1.2 Hz, 1H), 7.22-7.21 (m, 1H), 6.99-
6.97 (m, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.49 (s, 2H), 1.24 (t, J =

6
Tetrahedron
ACCEPTED MANUSCRIPT
7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.5, 135.3,
Supplementary data to this article can be found.
130.7, 127.7, 61.7, 41.1, 14.3. HRMS (ESI) calcd. for (M+H)+
(C8H11O2S2)+: 203.0195, found: 203.0203.
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Appendix A. Supplementary data

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