One-Pot Synthesis of 2,4-Diacyl Thiophenes from α-Oxo Ketene Dithioacetals and Propargylic Alcohols

Article abstract of DOI:10.1021/acs.joc.0c01093

Although thiophenes having various functionalities are the basic structural units in numerous bioactive compounds and optoelectronic materials, synthetic routes to acylated thiophenes from aliphatic sulfur-containing starting materials are still rare. In particular, there have been no reports concerning the straightforward synthesis of 2,4-diacylthiophenes from alkynes. Herein, we describe a highly efficient and metal-free three-step one-pot synthetic approach to tetrasubstituted 2,4-diacylthiophenes from propargylic alcohols and α-oxo ketene dithioacetals. This research features a relay catalysis system that integrates Br?nsted acid-catalyzed propargylation, molecular iodine-mediated electrophilic cyclization, and visible light-induced deiodinative oxygenation. The 2,4-diacylthiophenes serving as the key starting materials are readily synthesized, enabling facile construction of analogues of related biologically active compounds and the modular assembly of tetrasubstituted thienothiophenes.

Full text of DOI:10.1021/acs.joc.0c01093

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Article
One-Pot Synthesis of 2,4-Diacyl Thiophenes from #-
Oxo Ketene Dithioacetals and Propargylic Alcohols
xue jian, Li-Gang Bai, Liang Zhang, Yue Zhou, Xiao-
Long Lin, Neng-Jie Mou, Dong-Rong Xiao, and Qun-Li Luo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01093 • Publication Date (Web): 13 Jul 2020
Downloaded from pubs.acs.org on July 13, 2020
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One-Pot Synthesis of 2,4-Diacyl Thiophenes from α‑Oxo Ketene Dithioacetals and
Propargylic Alcohols
a
a, †
a
a
a
a
Jian Xue, Li-Gang Bai, Liang Zhang, Yue Zhou, Xiao-Long Lin, Neng-Jie Mou, Dong-Rong
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a
, a, b
Xiao, and Qun-Li Luo*
a
College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.
qlluo@swu.edu.cn
b
Key Laboratory of Applied Chemistry of Chongqing Municipality, Southwest University, Chongqing
400715, China.
†
New address: College of Chemistry and Molecular Sciences, Wuhan University, 430072 Wuhan,
China.
Table of Contents:
Abstract: Although thiophenes having various functionalities are the basic structural units in
numerous bioactive compounds and optoelectronic materials, synthetic routes to acylated thiophenes
from aliphatic sulfur-containing starting materials are still rare. In particular, there have been no
reports concerning the straightforward synthesis of 2,4-diacylthiophenes from alkynes. Herein, we
describe a highly efficient and metal-free three-step one-pot synthetic approach to tetrasubstituted
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2,4-diacylthiophenes from propargylic alcohols and α-oxo ketene dithioacetals. This research features
a relay catalysis system that integrates Brønsted acid-catalyzed propargylation, molecular
iodine-mediated electrophilic cyclization and visible light-induced deiodinative oxygenation. The
2,4-diacylthiophenes serving as the key starting materials are readily synthesized, enabling facile
construction of analogues of related biologically active compounds and the modular assembly of
tetrasubstituted thienothiophenes.
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Introduction
There are ongoing efforts to simplify synthetic methodologies for the construction of functional
organic molecules, as well as to optimize reaction conditions, improve substrate accessibility and
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enhance atom and step economies. Both relay catalysis and sequential transformations are useful
2
approaches to these goals. Relay catalysis, especially multiple relay catalysis, delivers a range of
3
products that would not be accessible with the use of a single catalyst. Sequential transformations,
which are known to chemists under the term “one-pot reactions” and consist of domino reactions and
consecutive reactions, are able to produce the maximum possible structural complexity using a
4
minimum number of pots. A successful sequential transformation will generate the desired organic
compounds in good yields from simple starting materials in few steps and with a significant reduction
in the amount of undesired by-products. Domino reactions (also described as tandem or cascade
reactions) are an especially efficient type of sequential transformation that have frequently been
reported to have significant usefulness.4b Comparatively, consecutive reactions have not been as
helpful as domino reactions, because the intermediate structures in such series are often stable and
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isolatable, such that subsequent reactions may not proceed in the absence of additional promoters.
Therefore, the examples of consecutive reactions combined with multiple relay catalysis have drawn
increasing interest, as a result of the challenges associated with the minimal compatibility of the
reagents and catalysts for specific reaction conditions.5
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Fig. 1 Selected examples of bioactive molecules containing 2,4-diacyl thiophene scaffold.
Thiophene rings are found in numerous organic compounds, including natural products, bioactive
substances, optoelectronic materials and synthetic intermediates.6, 7 Thiophene derivatives are also
widely used as conductive organic materials due to their structural rigidity and electronic properties.8
As a result, there have been many attempts to develop reliable, high yield processes for synthesizing
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functionalized thiophenes. Thiophenes that are acylated at the 2- and 4-positions are especially
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important structural motifs in numerous bioactive molecules (Figure 1). The traditional approach to
obtaining 2-acylthiophenes relies on late-stage modification via the Friedel-Crafts acylation of
thiophenes using specific Lewis acid promotors combined with acyl anhydrides or acid chlorides,
which often provides poor atom economy and/or deleterious environmental effects.11 However, the
synthesis of 2-acylthiophenes has received little attention and, to the best of our knowledge, there
have been no reports to date concerning the straightforward synthesis of 2,4-diacylthiophenes from
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alkynes.12
The intramolecular electrophilic cyclization of alkynes possessing a nucleophile in proximity to the
carbon‒carbon triple bond has proven to be a particularly efficient strategy for constructing
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functionalized heterocyclic rings (Scheme 1a). Based on this approach, a number of methodologies
for synthesizing fused five-membered heterocycles bearing 3-iodo substituents through the
iodocyclization of o-alkynylized anilines, aromatic ethers and thioethers have been developed.9a, 14
Similarly, aliphatic acetylenic analogues have been successfully employed to synthesize substituted
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five-membered N- and O-heterocycles. However, there has been very limited success with regard to
the production of thiophene counterparts using this methodology. 16
Scheme 1. Syntheses of substituted heterocycles via iodocyclization. (a) Traditional strategies; (b)
idea of this work; and (c) feature of this work.
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Theoretically, stoichiometric iodine reagents are necessary in the iodocyclization step. Moreover,
the iodocyclization products frequently need to be further converted into other functional targeted
molecules via deiodinative transformations. Within a two-step operation comprising iodocyclization
followed by deiodinative transformation, potentially toxic halide waste products are generated
twice.15h We therefore envisioned that a catalytic iodocyclization/deiodinative transformation would
greatly reduce the amount of iodine reagent required and thus limit the production of halide waste.
This would be significantly beneficial in terms of atom economy and environmental impact (Scheme
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1b). Herein, we describe a reliable one-pot catalytic protocol for the direct assembly of 2,4-diacyl
thiophenes from propargyl alcohols and -oxo ketene dithioacetals through relay catalysis, using
trifluoroacetic acid (TFA), molecular iodine and visible light (Scheme 1c).
Results and discussion
α-Oxo ketene dithioacetals are versatile sulfur-containing reagents that have been widely used as
1,3-bis-electrophilic three-carbon synthons and two-carbon fragments equivalent to polarized
alkenes.17, 18 Recently, we reported that α-oxo ketene dithioacetals exhibit unique behavior as
C,O-bis-nucleophilic two-carbon synthons.19 These compounds could also serve as
C,S-bis-nucleophiles in specific cascade annulations in conjunction with appropriate
18
bis-electrophiles. Thus, we examined the acid-catalyzed sequential propargylation/iodocyclization of
α-oxo ketene dithioacetal 2a using propargylic alcohol 1a (for details of the reaction optimization
process, see Table S1).20
The general feasibility of the propargylation/iodocyclization of α-oxo ketene dithioacetals was
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assessed by examining the reactions of substrates 2, having a variety of substituents, with a series of
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propargyl alcohols 1 under the optimized conditions. Propargyl alcohols containing different R and
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R substituents were initially investigated through reactions with 2a (Table 1). The substituents at the
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para- or meta-positions on the α-phenyl moiety in propargyl alcohols 1a−1k were found to have
insignificant effects on reactivity, and the majority of the alcohols gave very good yields (3a−3k).
Table 1. Scope of propargyl alcohols for the propargylation/iodocyclization.a
a
Conditions: 1 (0.36 mmol), 2a (0.3 mmol), TFA (0.06 mmol), and CH
3
CN (1 mL) at 50 °C for 2 h, then I (0.3
2
mmol) was added and further reacted for 2 h. Isolated yields are given. TFA: trifluoroacetic acid.
In contrast, the presence of ortho-substituents resulted in lower yields owing to the effects of steric
hindrance (3l−3n vs 3a−3k). A series of α-fused aryl or heteroaryl-derived propargyl alcohols was
also evaluated. Those compounds having aryl groups with electron-donating substituents were
determined to give better results than those with electron-withdrawing groups, because the former
provided a conjugation effect in conjunction with the α-aryl moiety that stabilized the propargyl
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carbocation (3o, 3p, 3s, 3r vs 3q−3r). Trials in which the distal group on the alkyne moiety in the
propargyl alcohol was an alkyl-substituted aryl, such as 4-methylphenyl or 2-methylphenyl, gave the
desired products in very good yields (3u−3v), while the 4-methoxyphenyl and
4-bromophenyl-substituted counterparts only led to moderate yields (3w−3x). These results imply that
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the conjugation effect of R in these propargyl alcohols had a negative effect on the reaction. The
yields obtained from propargyl alcohols bearing a distal alkyl or hydrogen of alkyne moiety were
slightly inferior to those obtained from reactants with a distal phenyl group (3y−3z vs 3b, 3aa vs 3a).
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The use of α-oxoketene dithioacetals containing different R and R substituents was subsequently
investigated based on reactions with 1a (Table 2). A bis(benzylthio)-substituted dithioacetal gave the
product in lower yield than the other compounds (3ae vs 3a−3ad) due to the relatively low stability of
α-oxoketene dithioacetals containing the benzylthio group in the presence of iodine. In contrast,
α-oxoketene dithioacetals with small α-alkyl groups were superior to those with bulky groups (3a vs
3af−3ag) because of the effects of steric hindrance. The yields from α-oxoketene dithioacetals
containing α-aryl groups were slightly inferior to those produced from analogues containing α-alkyl
moieties (3ah−3ao vs 3a−3ad). This result is attributed to decreased polarization of the
carbon−carbon double bond in the α-oxoketene dithioacetal because of the conjugation effect. This, in
turn, reduced the nucleophilicity of the α-aryl α-oxoketene dithioacetals relative to the α-alkyl
counterparts. X-ray single-crystal analysis established that the iodo carbon-carbon double bond in 3ad
had the E configuration (see the Supporting Information).20, 21 The stereochemistry of each of the
other compounds in series 3 was assigned by comparison with that of 3ad.
Table 2. Scope of ketene dithioacetals for the propargylation/iodocyclization.a
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a
Conditions: 1a (0.36 mmol), 2 (0.3 mmol), TFA (0.06 mmol), and CH
3
CN (1 mL) at 50 °C for 2 h, then I (0.3
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mmol) was added and further reacted for 2 h. Isolated yields are given. PMP: para-methoxyphenyl. TFA:
trifluoroacetic acid.
When a solution of 3a in deuterated chloroform was allowed to stand in contact with air for several
days, the compound partially converted into the deiodinatively oxygenated product, whereas the same
compound in its pure state was stable in air. We therefore suspected that the deiodinative oxygenation
was triggered by exposure to visible light. Under optimal conditions (Table S2),20 this same
photoinduced reaction proceeded rapidly in conjunction with exposure to a 30 W household compact
2
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fluorescent lamp, using ethyl acetate as the solvent in an ambient atmosphere. As shown in Table 3,
all the specimens underwent the deiodinative oxygenation smoothly to give the desired diacyl
thiophenes 4 in mostly good to excellent yields. There were only two exceptions (4aa, 4ae) for which
the isolated yields were lower than 75%, because of either the instability of formyl toward aerobic
oxidations (4aa) or the instability of the benzylthio group in the presence of the iodine species formed
in situ (Table 2, 3ae).
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Table 3. Reaction scope for the deiodinative oxygenations.a
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a
Conditions: 3 (0.2 mmol), EtOAc (2 mL), 30 W CFL, RT for 2 h. Isolated yields are given. The reaction vessel was
b
general heavy-wall glass flask. 0.15 mmol of 3aa was used. CFL: household compact fluorescent lamp that was a
white household light bulb. PMP: para-methoxyphenyl.
After the optimized conditions for the propargylation, iodocyclization and photoinduced
deiodinative oxygenation were established, we focused on developing a sequential relay catalysis to
20
enable the efficient synthesis of 2,4-diacylthiophenes through a one-pot operation (Table S3). It was
found to be necessary to dilute the reaction mixtures in the second stage and to prolong the radiation
time to 15‒20 h because these mixtures became darker during the propargylation step, thereby
blocking light transmission. The addition of a small amount of silica gel (such as typically used for
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column chromatography) proved to be an efficient solution for preliminary decolorization. Under
optimal conditions, the relay catalysis was accomplished very successfully and some representative
results are summarized in Table 4. The isolated yields reached 62%–74%, which correspond to
average yields of 85%–90.5% for each step of the three-step consecutive reaction process. This
one-pot synthesis technique completely avoids the need to isolate and purify any intermediate
products or to provide a stoichiometric amount of any additive, thereby reducing the time, resources
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and energy requirements.
Table 4. One-pot synthesis of substituted 2,4-diacylthiophenes.a
a
o
Conditions: 1 (0.36 mmol), 2 (0.3 mmol), TFA (0.06 mmol), and CH CN (1 mL), at 50 C for 2h. EtOAc (10 mL),
3
I
2
(0.18 mmol) and 350 mg of silica gel (200−300 mesh) were then added, and the reaction flask was magnetically
stirred and irradiated with a 30 W CFL at RT for 15‒20 h (typically, 15 h). The reaction vessel and light source were
same as that shown in Table 3. Isolated yields are given. PMP: para-methoxyphenyl.
Gram-scale preparations of 3 and 4 were found to be feasible. Scaling the synthesis of 3a by as
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much as 20-fold and that of 4a by 15-fold had no obvious effect on the reaction efficiency, further
attesting to the robust nature of this process (Scheme 2a).
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Scheme 2. Scale-up Syntheses and Transformations. (a) Scale-up syntheses of 3a and 4a; (b)
late-stage functionalizations of 3ad and 4ad; and (c) modular syntheses of tetrasubstituted
thieno[2,3-b]thiophenes.
The late-stage transformations of 3ad and 4ad were further explored (Scheme 2b). The Suzuki
coupling of 3ad with phenylboronic acid readily gave the tetrasubstituted dihydrothiophene derivative
5a bearing an exocyclic double bond, while base-catalyzed deiodinative hydrolysis of 3ad delivered
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the tetrasubstituted thiophen-2-yl carbinol 5b in good yield. The highly efficient oxidation of 4ad with
m-chloroperbenzoic acid (m-CPBA) furnished sulfone containing the
-acyl-5-aroyl-2-(methylsulfonyl)thiophene scaffold that exactly maps onto the key substructure of
GLP-1 receptor agonist 6a.10a
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Notably, the modular synthesis of tetrasubstituted thieno[2,3-b]thiophenes was particularly
convenient when using 4 as precursors (Scheme 2c). Thieno[2,3-b]thiophenes are useful building
blocks for the construction of organic semiconductors possessing different conjugation lengths.6d
Although the synthesis of thieno[2,3-b]thiophene and its derivatives has been previously achieved
using several different protocols,6, 23 these frequently suffer from one or more disadvantages, such as
tedious multistep syntheses, harsh conditions, relatively low total yields and product mixtures
containing symmetric substituents or lack of functional groups. The present protocol provides a facile
modular synthetic approach to diverse functionalized thieno[2,3-b]thiophenes bearing four different
substituents in a four-step two-pot operation under mild conditions.
Conclusion
In conclusion, we have established a versatile protocol for the synthesis of structurally diverse
2,4-diacylthiophenes through relay catalysis combining chemo- and photo-catalysis. This method
provides a facile approach to structures of interest to researchers in the life sciences and materials
sciences, using inexpensive reagents and easily accessible precursors together with a minimum
number of pots. Under visible light irradiation, a sub-stoichiometric amount of I efficiently realized
2
the cascade iodocyclization/deiodinative transformation of alkyne thioether intermediates for the first
time. The reactions were demonstrated to be extremely reliable and to give high yields while enabling
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the synthesis to proceed in either a stepwise or consecutive manner under mild conditions. The
products of iodocyclization could be converted to functionalized tetrasubstituted dihydrothiophene
and thiophene derivatives. Our strategy of consecutive reactions permits the facile modular synthesis
of diversely functionalized thieno[2,3-b]thiophenes, and thus opens up avenues for the development
of synthetic methodologies for heterocycles from simple precursors via relay catalysis.
Experimental Section
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General methods
Unless otherwise noted, commercially available reagents were used as received. Propargylic
alcohols 1a−1z and α-oxo ketene dithioacetals 2a−2o were prepared according to literature procedures.
19, 24, 25
All solvents for chromatographic separations were distilled before use. Solvents for the
water-free reactions were dried with standard procedures and stored with Schlenk flasks over
molecular sieves. Column chromatography was carried out with 200−300 mesh silica gel. Thin-layer
chromatography (TLC) was performed on glass-backed silica plates. UV light, I , and solutions of 2,
2
4-dinitrophenylhydrazine were used to visualize products. Concentrating a solution under reduced
pressure refers to distillation using a rotary evaporator attached to a vacuum pump (3 – 10 mmHg).
1
13
Products obtained as solids or high boiling oils were dried under vacuum (1 – 3 mmHg). H and C
NMR spectra were recorded on a 600 MHz NMR spectrometer at 293 K and the chemical shifts (δ)
were internally referenced by the residual solvent signals relative to tetramethylsilane (CDCl at 7.26
3
1
13
ppm for H, and at 77.00 ppm for C). Data are reported as (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, b = broad; coupling constant(s) in Hz; integration). The yields in the text refer
to isolated yields of compounds.
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General procedure for the synthesis of 3
To the solutuion of 1 (0.36 mmol) and 2 (0.3 mmol) in CH
3
CN (1 mL) was added trifluoroacetic
acid (5 μL, 0.06 mmol) with stirring. The reaction mixture was continually stirred at 50 °C in an oil
bath until 1 was consumed as indicated by TLC (ca. 2 h). Iodine (76 mg, 0.3 mmol) was added. The
solution was stirred at 50 °C in the oil bath until the intermediate was consumed as indicated by TLC
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(
ca. 2 h). The mixture was cooled to RT, diluted with a saturated aqueous solution of sodium
thiosulfate (5 mL), and extracted with ethyl acetate (3 × 5 mL). The combined organic layer was
washed with water and brine, dried over Na SO , filtered, and concentrated under reduced pressure.
2
4
The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl
acetate as eluent) to give the desired product 3.
(E)-1-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)e
than-1-one (3a). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (20/1, v/v) gave 3a (142 mg, 93%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.43 (d, J =
8
3
1
.6 Hz, 2H), 7.28 – 7.24 (m, 2H), 7.23 – 7.19 (m, 3H), 6.80 (d, J = 8.6 Hz, 2H), 5.10 (s, 1H), 3.73 (s,
1
3
1
H), 2.80 (d, J = 7.4 Hz, 2H), 2.00 (s, 3H), 1.23 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.3,
3
59.1, 156.3, 143.3, 142.8, 130.9 (CH×2 ), 130.0 (CH×2 ), 128.9 (CH×2 ), 128.6 (CH×2 ), 128.5
+
(CH×2 ), 113.9 (CH×2 ), 64.8, 55.2, 29.5, 28.2, 14.3. HRMS (ESI) m/z: [M + H] calcd for
C
22
H22IO
2
2
S 509.0100; found 509.0094.
(E)-1-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-phenyl-4,5-dihydrothiophen-3-yl)ethan-1-one
(3b). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (20/1,
1
v/v) gave 3b (119 mg, 83%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.60 (d, J = 7.2 Hz, 2H),
7
2
1
6
.34 (t, J = 6.6 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 7.28 (m, 4H), 5.23 (s, 1H), 2.88 (q, J = 7.4 Hz, 2H),
13
1
.08 (s, 3H), 1.31 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.1, 156.6, 143.3, 142.6,
3
38.8, 129.7, 129.0 (CH×2 ), 128.9, 128.64 (CH×2 ), 128.55 (CH×2 ), 128.5 (CH×2 ), 127.7, 87.4,
+
5.5, 29.6, 28.3, 14.3. HRMS (ESI) m/z: [M + H] calcd for C21
H
20IOS 478.9995; found 478.9996.
2
(E)-1-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(p-tolyl)-4,5-dihydrothiophen-3-yl)ethan-1-one
(3c). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (20/1,
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v/v) gave 3c (130 mg, 88%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.48 (d, J = 7.9 Hz, 2H),
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
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2
3
3
3
3
3
3
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7
.35 – 7.31 (m, 2H), 7.28 (dd, J = 12.3, 7.1 Hz, 3H), 7.15 (d, J = 7.7 Hz, 2H), 5.19 (s, 1H), 2.88 (q, J
1
3
1
=
7.4 Hz, 2H), 2.34 (s, 3H), 2.07 (s, 3H), 1.31 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ
3
1
1
4
91.2, 156.4, 143.3, 142.8, 137.4, 135.8, 129.7, 129.2, 128.9 (CH×2 ), 128.8 (CH×2 ), 128.60 (CH×2 ),
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+
28.55 (CH×2 ), 87.2, 65.2, 29.5, 28.2, 21.2, 14.3. HRMS (ESI) m/z: [M + H] calcd for C22
H22IOS
2
93.0151; found 493.0139.
(E)-1-(4-(4-ethylphenyl)-2-(ethylthio)-5-(iodo(phenyl)methylene)-4,5-dihydrothiophen-3-yl)etha
n-1-one (3d). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate
1
(20/1, v/v) gave 3d (137 mg, 90%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.50 (d, J = 8.0 Hz,
2
7
H), 7.34 – 7.27 (m, 5H), 7.17 (d, J = 8.0 Hz, 2H), 5.20 (s, 1H), 2.87 (d, J = 7.4 Hz, 2H), 2.64 (d, J =
13
1
.6 Hz, 2H), 2.07 (s, 3H), 1.30 (t, J = 7.4 Hz, 3H), 1.24 (t, J = 7.6 Hz, 3H). C{ H} NMR (151 MHz,
) δ 191.3, 156.5, 143.6, 143.3, 142.8, 135.9, 129.7, 128.9 (CH×2 ), 128.8 (CH×2 ), 128.61
CH×2 ), 128.57 (CH×2 ), 128.0, 87.3, 65.2, 29.5, 28.5, 28.2, 15.3, 14.3. HRMS (ESI) m/z: [M + H]+
calcd for C23 507.0308; found 507.0312.
CDCl
3
(
H24IOS
2
(E)-1-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-isopropylphenyl)-4,5-dihydrothiophen-3-yl)
ethan-1-one (3e). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (20/1, v/v) gave 3e (139 mg, 89%) as a white solid, mp 118−120 °C. H NMR (600 MHz,
CDCl ) δ 7.50 (d, J = 7.9 Hz, 2H), 7.32 (m, 5H), 7.19 (d, J = 7.8 Hz, 2H), 5.20 (s, 1H), 2.91 – 2.85 (m,
3
13
1
3H), 2.07 (s, 3H), 1.30 (dd, J = 10.2, 4.5 Hz, 3H), 1.26 (s, 3H), 1.25 (s, 3H). C{ H} NMR (151 MHz,
CDCl
3
) δ 191.3, 156.5, 148.2, 143.2, 142.8, 136.0, 129.6, 128.9 (CH×4 ), 128.8 (CH×2 ), 128.6
+
(CH×2 ), 126.6 (CH×2 ), 87.4, 65.2, 33.8, 29.6, 28.2, 23.9, 14.3. HRMS (ESI) m/z: [M + H] calcd for
C
24
H26IOS
2
521.0464; found 521.0459.
(E)-1-(4-(4-(tert-butyl)phenyl)-2-(ethylthio)-5-(iodo(phenyl)methylene)-4,5-dihydrothiophen-3-y
l)ethan-1-one (3f). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (20/1, v/v) gave 3f (149 mg, 93%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.49 (s, 2H),
7.34 (d, J = 8.4 Hz, 3H), 7.32 (s, 2H), 7.31 – 7.27 (m, 2H), 5.21 (s, 1H), 2.87 (q, J = 7.4 Hz, 2H), 2.07
13
1
(s, 3H), 1.31 (d, J = 6.5 Hz, 12H). C{ H} NMR (151 MHz, CDCl ) δ 191.3, 150.5, 143.2, 142.7,
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35.6, 129.7 (CH×2 ), 128.8 (CH×2 ), 128.61 (CH×2 ), 128.58 (CH×2 ), 128.4 (CH×2 ), 125.4 (CH×2 ),
+
7.4, 65.1, 34.6, 31.3 (CH
3
×2 ), 29.6, 28.2, 14.4. HRMS (ESI) m/z: [M + H] calcd for C25
H28IOS
2
35.0621; found 535.0624.
(E)-1-(2-(ethylthio)-4-(4-fluorophenyl)-5-(iodo(phenyl)methylene)-4,5-dihydrothiophen-3-yl)eth
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an-1-one (3g). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (40/1, v/v) gave 3g (124 mg, 83%) as a white solid, mp 130−132 °C. H NMR (600 MHz,
CDCl
Hz, 2H), 5.22 (s, 1H), 2.88 (q, J = 7.3 Hz, 2H), 2.09 (s, 3H), 1.31 (t, J = 7.4 Hz, 3H). C{ H} NMR
151 MHz, CDCl
) δ 190.9, 162.2 (d, 1JCF = 246 Hz), 156.6, 143.1, 142.2, 134.7 (d, 4JCF = 2.9 Hz),
30.5 (d, 3JCF = 8.0 Hz), 129.7, 129.0, 128.7 (CH×2 ), 128.5 (CH×2 ), 115.5 (d, 2JCF = 21.4 Hz), 87.7,
3
) δ 7.57 (dd, J = 7.8, 5.4 Hz, 2H), 7.34 (t, J = 7.2 Hz, 2H), 7.30 – 7.27 (m, 3H), 7.03 (t, J = 8.4
13
1
(
3
1
6
+
4.7, 29.7, 28.4, 14.4. HRMS (ESI) m/z: [M + H] calcd for C21
H
19FIOS 496.9901; found 496.9891.
2
(E)-1-(4-(4-chlorophenyl)-2-(ethylthio)-5-(iodo(phenyl)methylene)-4,5-dihydrothiophen-3-yl)eth
an-1-one (3h). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (40/1, v/v) gave 3h (120 mg, 78%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.54 (d, J =
8.1 Hz, 2H), 7.31 (m, 7H), 5.22 (s, 1H), 2.89 (dd, J = 14.7, 7.3 Hz, 2H), 2.10 (s, 3H), 1.32 (t, J = 7.4
1
3
1
Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 190.8, 156.7, 143.1, 142.0, 137.4, 133.5, 130.2, 129.5,
3
129.0 (CH×2 ), 128.8 (CH×2 ), 128.7 (CH×2), 128.4 (CH×2 ), 87.8, 64.8, 29.7, 28.4, 14.3. HRMS
+
(ESI) m/z: [M + H] calcd for C21
H
19ClIOS 512.9605; found 512.9611.
2
(E)-1-(4-(4-bromophenyl)-2-(ethylthio)-5-(iodo(phenyl)methylene)-4,5-dihydrothiophen-3-yl)eth
an-1-one (3i). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (40/1, v/v) gave 3i (134 mg, 80%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.48 (s, 4H),
7
1
1
1
.35 (dd, J = 9.9, 4.5 Hz, 2H), 7.31 – 7.28 (m, 3H), 5.21 (s, 1H), 2.89 (q, J = 7.4 Hz, 2H), 2.10 (s, 3H),
1
3
1
.31 (t, J = 7.5 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 190.8, 156.8, 143.1, 141.9, 137.9, 131.7,
3
30.6, 129.5 (CH×2 ), 129.0 (CH×2 ), 128.7 (CH×2 ), 128.4 (CH×2 ), 121.6, 87.9, 64.9, 29.7, 28.4,
+
4.3. HRMS (ESI) m/z: [M + H] calcd for C21
H
19BrIOS 556.9100; found 556.9117.
2
(E)-1-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(3-methoxyphenyl)-4,5-dihydrothiophen-3-yl)e
than-1-one (3j). Purification by flash column chromatography eluting with petroleum ether/ethyl
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acetate (20/1, v/v) gave 3j (140 mg, 92%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.32 (s, 2H),
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
2
1
8
.30 (d, J = 7.5 Hz, 4H), 7.19 (d, J = 12.6 Hz, 2H), 6.87 – 6.82 (m, 1H), 5.20 (s, 1H), 3.83 (s, 3H),
1
3
1
.87 (d, J = 7.4 Hz, 2H), 2.10 (s, 3H), 1.31 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.2, 159.7,
3
56.9, 143.2, 142.5, 140.2, 129.5, 129.3, 128.9 (CH×2 ), 128.6 (CH×2 ), 128.5, 121.4, 115.2, 112.6,
0
1
2
3
4
5
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7
8
9
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1
2
3
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9
0
1
2
3
4
5
6
7
8
9
0
+
7.5, 65.3, 55.3, 29.6, 28.3, 14.3. HRMS (ESI-TOF) calcd for C22
H22IO
2
S
2
[M + H] : 509.0100;
found 509.0104.
(E)-1-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(m-tolyl)-4,5-dihydrothiophen-3-yl)ethan-1-one
(3k). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (20/1,
1
v/v) gave 3k (127 mg, 86%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.33 (d, J = 7.7 Hz, 1H),
7
1
.30 (s, 1H), 7.28 – 7.24 (m, 2H), 7.24 – 7.18 (m, 3H), 7.15 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 7.4 Hz,
13
1
H), 5.11 (s, 1H), 2.81 (d, J = 7.4 Hz, 2H), 2.30 (s, 3H), 2.00 (s, 3H), 1.23 (t, J = 7.4 Hz, 3H). C{ H}
) δ 190.3, 155.6, 142.3, 141.7, 137.6, 137.2, 128.5 (CH×2 ), 128.4 (CH×2 ),
27.9, 127.6, 127.53, 127.50, 127.3, 125.2, 86.3, 64.4, 28.5, 27.2, 20.6, 13.3. HRMS (ESI) m/z: [M +
NMR (151 MHz, CDCl
3
1
+
H] calcd for C22
H
22IOS 493.0151; found 493.0151.
2
(E)-1-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(2-methoxyphenyl)-4,5-dihydrothiophen-3-yl)e
than-1-one (3l). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (20/1, v/v) gave 3l (85 mg, 56%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.53 (dd, J =
7.6, 1.2 Hz, 1H), 7.38 – 7.35 (m, 2H), 7.34 – 7.29 (m, 4H), 6.99 (s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 5.74
1
3
1
(
s, 1H), 3.95 (s, 3H), 2.87 (d, J = 7.4 Hz, 2H), 2.10 (s, 3H), 1.32 (t, J = 7.4 Hz, 3H). C{ H} NMR
151 MHz, CDCl ) δ 192.1, 156.2, 156.0, 144.9, 144.5, 129.5, 129.0, 128.70, 128.67, 128.43, 128.36,
28.0, 127.5, 121.34, 121.27, 110.8, 84.5, 57.7, 55.4, 28.7, 28.0, 14.2. HRMS (ESI) m/z: [M + H]+
(
3
1
calcd for C22
H22IO
2
2
S 509.0100; found 509.0100.
(E)-1-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(o-tolyl)-4,5-dihydrothiophen-3-yl)ethan-1-one
(3m). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (20/1,
1
v/v) gave 3m (108 mg, 73%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.57 – 7.53 (m, 1H),
7
.36 – 7.32 (m, 2H), 7.28 (dd, J = 16.0, 7.3 Hz, 3H), 7.19 – 7.13 (m, 3H), 5.43 (s, 1H), 2.87 (q, J = 7.4
13
1
Hz, 2H), 2.73 (s, 3H), 2.14 (s, 3H), 1.30 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.6,
3
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2
2
2
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3
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53.4, 144.20, 144.15, 138.2, 136.7, 132.0, 130.9, 129.5, 128.79, 128.76, 128.6, 128.3, 127.7, 127.5,
+
26.3, 84.8, 61.9, 30.3, 28.5, 20.9, 14.5. HRMS (ESI) m/z: [M + H] calcd for C22
H
22IOS 493.0151;
2
found 493.0152.
E)-1-(4-(2-chlorophenyl)-2-(ethylthio)-5-(iodo(phenyl)methylene)-4,5-dihydrothiophen-3-yl)eth
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
an-1-one (3n). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (40/1, v/v) gave 3n (78 mg, 51%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.56 – 7.53
(m, 1H), 7.31 – 7.27 (m, 2H), 7.23 – 7.16 (m, 6H), 5.60 (s, 1H), 2.78 (d, J = 7.4 Hz, 2H), 2.09 (s, 3H),
13
1
1
1
1
.22 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.7, 144.1, 143.9, 137.7, 133.8, 130.4,
3
29.9, 129.0, 128.9 (CH×2 ), 128.8 (CH×2 ), 128.2 (CH×2 ), 127.8 (CH×2 ), 85.5, 60.5, 29.7, 28.2,
+
4.2. HRMS (ESI) m/z: [M + H] calcd for C21
H
19ClIOS 512.9605; found 512.9604.
2
(E)-1-(4-(benzo[d][1,3]dioxol-5-yl)-2-(ethylthio)-5-(iodo(phenyl)methylene)-4,5-dihydrothiophen
-3-yl)ethan-1-one (3o). Purification by flash column chromatography eluting with petroleum
1
ether/ethyl acetate (20/1, v/v) gave 3o (149 mg, 95%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ
7.39 – 7.34 (m, 2H), 7.32 (d, J = 7.8 Hz, 3H), 7.12 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 1.2 Hz, 1H), 6.80
(d, J = 8.0 Hz, 1H), 6.03 – 5.97 (m, 2H), 5.17 (s, 1H), 2.89 (d, J = 7.4 Hz, 2H), 2.13 (s, 3H), 1.33 (t, J
1
3
1
= 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.2, 156.6, 147.8, 147.1, 144.7, 143.2, 142.9,
3
132.3, 129.5, 128.9, 128.7, 128.5, 122.9, 108.8, 108.0, 101.2, 95.7, 87.6, 65.1, 29.6, 28.3, 14.3.
+
HRMS (ESI) m/z: [M + H] calcd for C22
H20IO
3
2
S 522.9893; found 522.9894.
(E)-1-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(naphthalen-1-yl)-4,5-dihydrothiophen-3-yl)eth
an-1-one (3p). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (20/1, v/v) gave 3p (130 mg, 82%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 8.64 (d, J =
8
.2 Hz, 1H), 7.85 (dd, J = 7.1, 2.4 Hz, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.48 (dd,
J = 10.4, 4.9 Hz, 2H), 7.34 – 7.30 (m, 2H), 7.30 – 7.26 (m, 3H), 6.07 (s, 1H), 2.91 (q, J = 7.4 Hz, 2H),
1
3
1
2
1
1
5
.00 (s, 3H), 1.32 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.7, 144.0, 133.7, 131.3,
3
29.0 (CH×2 ), 128.8 (CH×2 ), 128.72 (CH×2 ), 128.68 (CH×2 ), 128.3 (CH×2 ), 127.1 (CH×2 ), 125.9,
+
25.8, 125.7, 125.5, 86.2, 60.4, 30.4, 28.4, 14.4. HRMS (ESI) m/z: [M + H] calcd for C25
29.0151; found 529.0146.
H22IOS
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(E)-1-(4-(3,5-difluorophenyl)-2-(ethylthio)-5-(iodo(phenyl)methylene)-4,5-dihydrothiophen-3-yl)
4
5
6
7
8
9
1
1
1
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1
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2
2
2
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6
ethan-1-one (3q). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (40/1, v/v) gave 3q (100 mg, 65%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.30 – 7.27
(t, J = 7.2 Hz, 2H), 7.25 – 7.21 (m, 3H), 7.08 (dd, J = 7.8, 1.8 Hz, 2H), 6.68 (tt, J = 8.7, 2.4 Hz, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
5
1
1
2
.17 (s, 1H), 2.83 (q, J = 7.4 Hz, 2H), 2.08 (s, 3H), 1.25 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ
3
90.6, 163.0 (dd, JCF = 249, 12.6 Hz), 157.3, 142.9, 142.6 (t, 3JCF = 8.3 Hz), 141.1, 129.2, 129.1,
28.7 (CH×2), 128.4 (CH×2), 111.8 (dd, JCF = 20.6, 5.2 Hz), 103.3 (t, 2JCF = 25.4 Hz), 88.7, 64.9,
+
9.9, 28.6, 14.3. HRMS (ESI) m/z: [M + H] calcd for C21
H
18
F
2
IOS 514.9806; found 514.9818.
2
(E)-1-(4-(2,4-dichlorophenyl)-2-(ethylthio)-5-(iodo(phenyl)methylene)-4,5-dihydrothiophen-3-yl)
ethan-1-one (3r). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (40/1, v/v) gave 3r (76 mg, 46%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.56 (d, J =
8
5
.5 Hz, 1H), 7.40 (d, J = 1.4 Hz, 1H), 7.36 (t, J = 7.3 Hz, 2H), 7.30 (t, J = 8.7 Hz, 3H), 7.26 (s, 1H),
1
3
1
.62 (s, 1H), 2.86 (q, J = 7.3 Hz, 2H), 2.17 (s, 3H), 1.30 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz,
CDCl
3
) δ 191.3, 143.9, 143.2, 136.3, 134.5, 134.0, 131.3, 129.6, 129.3, 129.0 (CH×2 ), 128.8 (CH×2 ),
+
128.2 (CH×2 ), 100.0, 86.1, 60.3, 29.9, 28.4, 14.3. HRMS (ESI) m/z: [M + H] calcd for
C
21
H18Cl
2
IOS 546.9215; found 546.9221.
2
(E)-1-(2-(ethylthio)-4-(furan-2-yl)-5-(iodo(phenyl)methylene)-4,5-dihydrothiophen-3-yl)ethan-1-
one (3s). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate
1
(
20/1, v/v) gave 3s (124 mg, 88%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.40 (s, 1H), 7.35
(br.s, 4H), 7.32 – 7.29 (br.s, 1H), 6.41 (br.s, J = 2.8 Hz, 1H), 6.37 (s, 1H), 5.42 (s, 1H), 2.85 (d, J = 7.4
1
3
1
Hz, 2H), 2.21 (s, 3H), 1.28 (s, 3H). C{ H} NMR (151 MHz, CDCl
3
) δ 191.0, 158.5, 151.3, 142.9,
142.1, 139.9, 129.0, 128.7 (CH×2 ), 128.5 (CH×2 ), 125.2, 110.5, 108.3, 88.5, 59.8, 29.1, 28.2, 14.2.
+
HRMS (ESI) m/z: [M + H] calcd for C19
H18IO
2
S
2
468.9787; found 468.9796.
(E)-1-(5-(ethylthio)-2-(iodo(phenyl)methylene)-2,3-dihydro-[3,3'-bithiophen]-4-yl)ethan-1-one
(3t). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (20/1,
1
v/v) gave 3t (132 mg, 91%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.46 (d, J = 1.6 Hz, 1H),
7.33 (d, J = 7.4 Hz, 2H), 7.31 – 7.27 (m, 4H), 7.26 (s, 1H), 5.41 (s, 1H), 2.90 – 2.83 (m, 2H), 2.13 (s,
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2
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2
2
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5
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5
5
5
5
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6
1
3
1
3
H), 1.30 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.1, 156.7, 142.9, 141.6, 138.7, 129.0
3
(
CH×2 ), 128.6 (CH×2 ), 128.5 (CH×2 ), 127.1, 125.8, 123.6, 87.8, 61.3, 29.4, 28.3, 14.4. HRMS (ESI)
+
m/z: [M + H] calcd for C19
H
18IOS 484.9559; found 484.9555.
3
(
E)-1-(2-(ethylthio)-5-(iodo(p-tolyl)methylene)-4-phenyl-4,5-dihydrothiophen-3-yl)ethan-1-one
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
3u). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (20/1,
1
v/v) gave 3u (126 mg, 85%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.52 (d, J = 7.2 Hz, 2H),
7
2
.27 (d, J = 7.6 Hz, 2H), 7.22 (s, 1H), 7.12 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 5.14 (s, 1H),
13
1
.82 (q, J = 7.4 Hz, 2H), 2.28 (s, 3H), 2.00 (s, 3H), 1.24 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz,
CDCl
3
) δ 191.2, 157.0, 145.3, 142.0, 141.2, 140.4, 139.7, 139.0, 138.8, 131.0, 129.4, 129.3, 128.9,
+
1
28.5, 128.4, 127.7, 87.9, 65.4, 29.5, 28.2, 21.3, 14.3. HRMS (ESI) m/z: [M + H] calcd for
C
22
H
22IOS 493.0151; found 493.0164.
2
(
E)-1-(2-(ethylthio)-5-(iodo(o-tolyl)methylene)-4-phenyl-4,5-dihydrothiophen-3-yl)ethan-1-one
(
3v). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (20/1,
v/v) gave 3v (121 mg, 82%) as a yellow oil. NMR spectra demonstrated there were two rotamers
present in a ratio of about 1:1. 1H NMR (600 MHz, CDCl
) δ 7.58 (d, J = 7.2 Hz, 2H), 7.54 (d, J =
3
7.1 Hz, 2H), 7.38–7.27 (m, 6H), 7.24–7.18 (m, 5H), 7.16–7.12 (m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 5.18
(s, 1H), 5.15 (s, 1H), 2.90 – 2.80 (m, 4H), 2.30 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 1.93 (s, 3H), 1.295
13
1
(t, J = 7.4 Hz, 3H), 1.293 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl
3
) δ 191.3, 191.2, 156.7,
1
56.4, 143.4, 143.2, 142.2, 142.0, 139.1, 138.8, 136.1, 134.9, 130.9, 130.8, 129.9, 129.7, 129.2, 129.1
(
CH×2), 129.0, 128.9, 128.5, 128.4, 127.73, 127.68, 127.65, 126.52, 126.51, 85.9, 85.3, 64.3, 64.0,
+
2
4
9.49, 29.47, 28.33, 28.30, 19.5, 18.5, 14.3, 14.2. HRMS (ESI) m/z: [M + H] calcd for C22
93.0151; found 493.0155.
H22IOS
2
(
E)-1-(2-(ethylthio)-5-(iodo(4-methoxyphenyl)methylene)-4-phenyl-4,5-dihydrothiophen-3-yl)eth
an-1-one (3w). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (20/1, v/v) gave 3w (99 mg, 65%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.59 (d, J =
7
8
.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 6.84 (d, J =
.6 Hz, 2H), 5.20 (s, 1H), 3.81 (s, 3H), 2.89 (q, J = 7.4 Hz, 2H), 2.07 (s, 3H), 1.32 (t, J = 7.4 Hz, 3H).
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C{ H} NMR (151 MHz, CDCl
3
) δ 191.2, 159.8, 156.9, 141.8, 138.9, 135.8, 130.0, 129.5 (CH×2 ),
1
28.9 (CH×2 ), 128.5 (CH×2 ), 127.7, 113.9 (CH×2 ), 87.8, 65.3, 55.3, 29.5, 28.2, 14.3. HRMS (ESI)
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
m/z: [M + H] calcd for C22
H
22IO
2
S 509.0100; found 509.0108.
2
(
E)-1-(5-((4-bromophenyl)iodomethylene)-2-(ethylthio)-4-phenyl-4,5-dihydrothiophen-3-yl)etha
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
n-1-one (3x). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate
1
(
20/1, v/v) gave 3x (114 mg, 68%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.50 (d, J = 7.3 Hz,
2
2
H), 7.39 (d, J = 8.4 Hz, 2H), 7.27 (t, J = 7.4 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 8.4 Hz,
13
1
H), 5.13 (s, 1H), 2.82 (q, J = 7.4 Hz, 2H), 2.00 (s, 3H), 1.25 (t, J = 7.4 Hz, 3H). C{ H} NMR (151
MHz, CDCl
3
) δ 190.1, 155.3, 142.4, 141.1, 137.5, 130.9, 129.1, 128.6 (CH×2 ), 127.9 (CH×2 ), 127.6
+
(
CH×2 ), 126.8 (CH×2 ), 122.0, 84.5, 64.5, 28.6, 27.3, 13.4. HRMS (ESI) m/z: [M + H] calcd for
C
21
H19BrIOS
2
556.9100; found 556.9114.
(
E)-1-(5-(cyclopropyliodomethylene)-2-(ethylthio)-4-phenyl-4,5-dihydrothiophen-3-yl)ethan-1-o
ne (3y). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (20/1,
1
v/v) gave 3y (96 mg, 75%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.40 (d, J = 7.3 Hz, 2H),
7.21 (t, J = 7.3 Hz, 2H), 7.17 (dd, J = 6.5, 1.8 Hz, 1H), 4.99 (s, 1H), 3.04 – 2.94 (m, 2H), 1.96 (d, J =
1.9 Hz, 3H), 1.39 – 1.33 (m, 4H), 0.82 (ddd, J = 13.3, 7.2, 4.7 Hz, 2H), 0.68 (dd, J = 4.8, 3.1 Hz, 1H),
1
3
1
0.56 (d, J = 5.0 Hz, 1H). C{ H} NMR (151 MHz, CDCl
128.4, 127.5, 97.6, 64.8, 29.5, 28.7, 22.5, 19.9, 14.5, 11.9, 11.3, 10.9. HRMS (ESI) m/z: [M + H]+
calcd for C18 442.9995; found 443.0007.
E)-1-(2-(ethylthio)-5-(1-iodopentylidene)-4-phenyl-4,5-dihydrothiophen-3-yl)ethan-1-one (3z).
3
) δ 191.3, 156.0, 140.1, 138.9, 129.5, 129.0,
H
20IOS
2
(
Purification by flash column chromatography eluting with petroleum ether/ethyl acetate (20/1, v/v)
1
gave 3z (95 mg, 69%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.52 (d, J = 7.2 Hz, 2H), 7.31 (s,
2
3
H), 7.29 – 7.26 (m, 1H), 5.05 (s, 1H), 3.10 – 3.01 (m, 2H), 2.50 (dd, J = 10.2, 7.5 Hz, 2H), 2.07 (s,
H), 1.57 – 1.46 (m, 2H), 1.45 (t, J = 7.4 Hz, 3H), 1.33 – 1.26 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).
1
3
1
C{ H} NMR (151 MHz, CDCl
3
) δ 191.3, 139.0, 138.5, 129.6, 128.9, 128.3, 127.5, 95.3, 64.7, 43.9,
+
3
4
6.4, 30.8, 29.5, 28.5, 21.7, 21.4, 16.6, 14.5, 13.9. HRMS (ESI) m/z: [M + H] calcd for C19
59.0308; found 459.0303.
H24IOS
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(
E)-1-(2-(ethylthio)-5-(iodomethylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)ethan-1-o
ne (3aa). Purification by flash column chromatography eluting with petroleum ether/ethyl acetate
1
(20/1, v/v) gave 3aa (92 mg, 71%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.40 (d, J = 8.6 Hz,
2
2
1
H), 6.84 (d, J = 8.6 Hz, 2H), 6.21 (d, J = 1.5 Hz, 1H), 5.01 (d, J = 1.4 Hz, 1H), 3.79 (s, 3H), 3.03 –
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
.94 (m, 2H), 2.02 (s, 3H), 1.41 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.3, 159.1,
3
57.1, 145.7, 130.2, 129.9 (CH×2 ), 129.4, 113.9 (CH×2 ), 68.0, 61.9, 55.2, 29.3, 28.6, 28.6, 14.5.
+
HRMS (ESI) m/z: [M + H] calcd for C16
H18IO
2
2
S 432.9787; found 432.9786.
(E)-1-(2-(hexylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)e
than-1-one (3ab). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (20/1, v/v) gave 3ab (146 mg, 86%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.51 (d, J
=
8.5 Hz, 2H), 7.35 – 7.32 (m, 2H), 7.31 – 7.27 (m, 3H), 6.87 (d, J = 8.6 Hz, 2H), 5.17 (s, 1H), 3.80 (s,
3
H), 2.84 (d, J = 7.4 Hz, 2H), 2.07 (s, 3H), 1.64 (s, 2H), 1.37 (s, 2H), 1.26 (br.s, 4H), 0.86 (t, J = 6.9
1
3
1
Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.3, 159.0, 143.2, 142.8, 131.0, 130.0, 129.7 (CH×2 ),
3
128.9 (CH×2 ), 128.62 (CH×2 ), 128.56 (CH×2 ), 113.9 (CH×2 ), 87.3, 64.8, 55.2, 34.1, 31.2, 29.5,
+
29.2, 28.3, 22.4, 14.0. HRMS (ESI) m/z: [M + H] calcd for C26
H30IO
2
2
S 565.0726; found 565.0715.
(E)-1-(2-(butylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)e
than-1-one (3ac). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (20/1, v/v) gave 3ac (142 mg, 88%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.51 (d, J =
8
1
.6 Hz, 2H), 7.35 – 7.31 (m, 2H), 7.29 (dd, J = 11.8, 7.1 Hz, 3H), 6.88 (d, J = 8.6 Hz, 2H), 5.18 (s,
H), 3.81 (s, 3H), 2.85 (t, J = 7.4 Hz, 2H), 2.08 (s, 3H), 1.63 (s, 2H), 1.41 (d, J = 7.4 Hz, 2H), 0.89 (t,
1
3
1
J = 7.3 Hz, 3H). C{ H} NMR (151 MHz, CDCl
3
) δ 191.3, 159.0, 156.6, 143.2, 142.8, 131.0, 130.0,
1
2
29.7, 128.9 (CH×2 ), 128.61 (CH×2 ), 128.56 (CH×2 ), 113.9 (CH×2 ), 87.2, 64.8, 55.2, 33.7, 31.2,
+
9.5, 21.8, 13.5. HRMS (ESI) m/z: [M + H] calcd for C24
H26IO
2
2
S 537.0413; found 537.0420.
(E)-1-(5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-2-(methylthio)-4,5-dihydrothiophen-3-yl
)ethan-1-one (3ad). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (20/1, v/v) gave 3ad (111 mg, 75%) as a yellow solid, mp 120−122 °C. H NMR (600 MHz,
CDCl
3
) δ 7.51 (d, J = 8.6 Hz, 2H), 7.36 – 7.32 (m, 2H), 7.31 – 7.27 (m, 3H), 6.88 (d, J = 8.6 Hz, 2H),
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5
.18 (s, 1H), 3.81 (s, 3H), 2.38 (s, 3H), 2.05 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.3, 159.1,
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
43.2, 42.7, 130.8 (CH×2 ), 130.0 (CH×2 ), 128.9 (CH×2 ), 128.7 (CH×2 ), 128.5 (CH×2 ), 113.9
+
(CH×2 ), 87.5, 65.0, 55.3, 29.3, 17.0. HRMS (ESI) m/z: [M + H] calcd for C21
H
19
O
3
2
S 383.0770;
found 383.0777.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(E)-1-(2-(benzylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)
ethan-1-one (3ae). Purification by flash column chromatography eluting with petroleum ether/ethyl
1
acetate (20/1, v/v) gave 3ae (99 mg, 58%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.42 (d, J =
8.6 Hz, 2H), 7.27 (d, J = 6.9 Hz, 2H), 7.23 – 7.21 (m, 6H), 7.18 (s, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.09
13
1
(s, 1H), 4.02 (s, 2H), 3.74 (s, 3H), 1.98 (s, 3H). C{ H} NMR (151 MHz, CDCl
3
) δ 190.3, 158.1,
1
1
54.5, 142.2, 141.8, 134.4, 129.7, 129.0 (CH×2 ), 129.0 (CH×2 ), 128.2 (CH×2 ), 127.9 (CH×2 ),
27.7 (CH×2 ), 127.6, 127.5 (CH×2 ), 126.8, 112.9 (CH×2 ), 86.4, 63.5, 54.2, 37.7, 28.3. HRMS (ESI)
+
m/z: [M + H] calcd for C27
H24IO
2
2
S 571.0250; found 571.0257.
Ethyl(E)-4-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-
3-yl)-4-oxobutanoate (3af). Purification by flash column chromatography eluting with petroleum
1
ether/ethyl acetate (20/1, v/v) gave 3af (120 mg, 67%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ
7.45 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 6.8 Hz, 2H), 7.22 (d, J = 7.2 Hz, 3H), 6.81 (d, J = 8.6 Hz, 2H),
5.17 (s, 1H), 4.02 (d, J = 7.1 Hz, 2H), 3.74 (s, 3H), 2.81 (d, J = 7.5 Hz, 3H), 2.51 (s, 1H), 2.33 (dt, J =
1
3
1
20.7, 6.1 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H). C{ H} NMR (151 MHz, CDCl
3
)
δ 191.3, 173.0, 159.1, 143.3, 142.8, 130.8 (CH×2 ), 130.0 (CH×2 ), 128.9 (CH×2 ), 128.64 (CH×2 ),
128.55 (CH×2 ), 114.0 (CH×2 ), 87.3, 64.1, 60.5, 55.2, 36.1, 28.2, 28.1, 14.2, 14.2. HRMS (ESI) m/z:
+
[
M + H] calcd for C26
H28IO
4
2
S 595.0468; found 595.0458.
(E)-1-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)p
ent-4-en-1-one (3ag). Purification by flash column chromatography eluting with petroleum
1
ether/ethyl acetate (20/1, v/v) gave 3ag (130 mg, 79%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ
7
5
.51 (d, J = 8.3 Hz, 2H), 7.35 – 7.31 (m, 2H), 7.29 (d, J = 7.4 Hz, 3H), 6.87 (d, J = 8.3 Hz, 2H),
.77 – 5.67 (br.s, 1H), 5.21 (s, 1H), 4.96 – 4.86 (m, 2H), 3.81 (s, 3H), 2.87 (d, J = 7.3 Hz, 2H), 2.55
13
1
(m, 7.6 Hz, 1H), 2.28 (s, 2H), 2.20 – 2.09 (m, 1H), 1.30 (t, J = 7.3 Hz, 3H). C{ H} NMR (151 MHz,
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2
2
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2
2
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CDCl
3
) δ 192.8, 159.1, 156.4, 143.2, 142.8, 137.6, 130.9, 130.0, 129.2, 128.9, 128.6 (CH×2 ), 128.5
(CH×2 ), 114.8 (CH×2 ), 113.9 (CH×2 ), 87.2, 64.3, 55.2, 40.4, 28.2, 27.7, 14.2. HRMS (ESI) m/z: [M
+
+
H] calcd for C25
H26IO
2
2
S 549.0413; found 549.0404.
(E)-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)(4-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
nitrophenyl)methanone (3ah). Purification by flash column chromatography eluting with petroleum
1
ether/ethyl acetate (20/1, v/v) gave 3ah (157 mg, 85%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ
8.20 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.39 – 7.29 (m, 5H), 7.11 (d, J = 8.5 Hz, 2H), 6.73
(d, J = 8.6 Hz, 2H), 5.33 (s, 1H), 3.76 (s, 3H), 2.86 (dd, J = 7.4, 2.4 Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H).
13
1
C{ H} NMR (151 MHz, CDCl ) δ 188.0, 158.9, 158.6, 157.2, 155.4, 149.0, 146.0, 143.2, 142.0,
3
1
6
6
31.1, 129.5, 129.0, 128.7 (CH×2 ), 128.4 (CH×2 ), 128.2 (CH×2 ), 123.6, 113.9 (CH×2 ), 100.0, 88.0,
+
5.5, 55.2, 28.8, 14.4. HRMS (ESI) m/z: [M + H] calcd for C27
16.0106.
H23INO
4
2
S 616.0108; found
(E)-(4-chlorophenyl)(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrot
hiophen-3-yl)methanone (3ai). Purification by flash column chromatography eluting with petroleum
1
ether/ethyl acetate (20/1, v/v) gave 3ai (120 mg, 66%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ
7.30 (s, 3H), 7.29 – 7.26 (m, 4H), 7.25 (s, 2H), 7.11 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.6 Hz, 2H), 5.36
1
3
1
(s, 1H), 3.68 (s, 3H), 2.77 – 2.66 (m, 2H), 1.16 (s, 3H). C{ H} NMR (151 MHz, CDCl
3
) δ 189.2,
158.8, 152.0, 143.4, 142.8, 138.3, 137.8, 132.2, 131.5, 130.5, 129.4, 128.9, 128.7 (CH×2 ), 128.6
(
[
(
CH×2 ), 128.5, 123.0, 113.9 (CH×2 ), 113.2 (CH×2 ), 87.3, 66.4, 55.2, 28.7, 14.7. HRMS (ESI) m/z:
+
M + H] calcd for C27
H23ClIO
2
2
S 604.9867; found 604.9863.
E)-(4-bromophenyl)(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrot
hiophen-3-yl)methanone (3aj). Purification by flash column chromatography eluting with petroleum
1
ether/ethyl acetate (20/1, v/v) gave 3aj (131 mg, 67%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ
7.42 (d, J = 8.3 Hz, 2H), 7.31 – 7.27 (m, 4H), 7.22 (s, 2H), 7.20 (s, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.68
13
1
(
d, J = 8.6 Hz, 2H), 5.35 (s, 1H), 3.68 (s, 3H), 2.72 (m, 2H), 1.16 (s, 3H). C{ H} NMR (151 MHz,
CDCl ) δ 189.3, 158.8, 143.4, 142.6, 138.8, 131.6 (CH×2 ), 131.4 (CH×2 ), 129.5 (CH×2 ), 129.4
CH×2 ), 128.9 (CH×2 ), 128.7 (CH×2 ), 128.5 (CH×2 ), 126.2, 113.9 (CH×2 ), 87.3, 66.3, 55.2, 28.7,
3
(
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3
+
1
4.7. HRMS (ESI) m/z: [M + H] calcd for C27
H23BrIO
2
S
2
648.9362; found 648.9355.
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
E)-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)(ph
enyl)methanone (3ak). Purification by flash column chromatography eluting with petroleum
1
ether/ethyl acetate (20/1, v/v) gave 3ak (130 mg, 76%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.38 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 7.5 Hz, 2H), 7.32 – 7.25 (m, 6H), 7.22 (t, J = 6.9 Hz, 1H), 7.09 (d,
J = 8.5 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H), 5.40 (s, 1H), 3.67 (s, 3H), 2.78 – 2.64 (m, 2H), 1.15 (t, J =
13
1
7
1
.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 190.5, 158.7, 150.4, 143.5, 142.9, 140.1, 132.7,
3
31.6, 131.5, 129.5 (CH×2 ), 128.8 (CH×2 ), 128.7 (CH×2 ), 128.5 (CH×2 ), 128.3 (CH×2 ), 127.9,
+
1
13.8 (CH×2 ), 87.0, 66.5, 55.2, 28.6, 14.7. HRMS (ESI) m/z: [M + H] calcd for C27
2 2
H24IO S
5
71.0257; found 571.0251.
(E)-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)(4-
methoxyphenyl)methanone (3al). Purification by flash column chromatography eluting with
1
petroleum ether/ethyl acetate (20/1, v/v) gave 3al (133 mg, 74%) as a yellow oil. H NMR (600 MHz,
CDCl
3
) δ 7.43 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 7.2 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 7.21 (dd, J = 15.5,
6.9 Hz, 3H), 6.78 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H), 5.44 (s, 1H), 3.76 (s, 3H), 3.67 (s, 3H),
1
3
1
2.66 (m, 2H), 1.12 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 189.7, 162.9, 158.7, 143.6, 143.1,
3
132.1 (CH×2 ), 131.6 (CH×2 ), 130.9 (CH×2 ), 129.3 (CH×2 ), 128.7 (CH×2 ), 128.6 (CH×2 ), 128.5
+
(CH×2 ), 113.9, 113.6 (CH×2 ), 86.7, 67.1, 55.4, 55.1, 28.6, 14.9. HRMS (ESI) m/z: [M + H] calcd
for C28
H26IO
3
S
2
601.0363; found 601.0373.
(E)-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)(p-t
olyl)methanone (3am). Purification by flash column chromatography eluting with petroleum
1
ether/ethyl acetate (20/1, v/v) gave 3am (128 mg, 73%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ
7
.33 – 7.28 (m, 6H), 7.22 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 6.67
(d, J = 8.6 Hz, 2H), 5.43 (s, 1H), 3.67 (s, 3H), 2.73 – 2.62 (m, 2H), 2.30 (s, 3H), 1.13 (t, J = 7.4 Hz,
1
3
1
3
1
H). C{ H} NMR (151 MHz, CDCl ) δ 190.4, 158.7, 143.6, 143.2, 142.5, 137.1, 131.6 (CH×2 ),
3
29.4 (CH×2 ), 129.0 (CH×2 ), 128.8 (CH×2 ), 128.6 (CH×2 ), 128.5 (CH×2 ), 128.4 (CH×2 ), 113.9
+
(CH×2 ), 86.8, 66.8, 55.1, 28.6, 21.7, 14.8. HRMS (ESI) m/z: [M + H] calcd for C28
H26IO
S
2 2
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5
85.0413; found 585.0423.
(E)-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)(m-
tolyl)methanone (3an). Purification by flash column chromatography eluting with petroleum
1
ether/ethyl acetate (20/1, v/v) gave 3an (126 mg, 72%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7.30 (m, 4H), 7.23 (d, J = 6.9 Hz, 1H), 7.18 (d, J = 9.6 Hz, 2H), 7.16 – 7.13 (m, 2H), 7.11 (d, J = 8.6
Hz, 2H), 6.67 (d, J = 8.6 Hz, 2H), 5.39 (s, 1H), 3.68 (s, 3H), 2.77 – 2.64 (m, 2H), 2.27 (s, 3H), 1.15 (t,
13
1
J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl
3
) δ 190.7, 158.7, 143.0, 139.9, 138.0, 132.3, 131.6,
129.5 (CH×2 ), 128.8 (CH×2 ), 128.6 (CH×2 ), 128.53 (CH×2 ), 128.51 (CH×2 ), 128.1 (CH×2 ), 125.2,
+
1
13.8 (CH×2 ), 86.9, 66.6, 55.2, 28.6, 21.3, 14.7. HRMS (ESI) m/z: [M + H] calcd for C28
85.0413; found 585.0389.
E)-(2-(ethylthio)-5-(iodo(phenyl)methylene)-4-(4-methoxyphenyl)-4,5-dihydrothiophen-3-yl)(o-t
H
26IO
S
2 2
5
(
olyl)methanone (3ao). Purification by flash column chromatography eluting with petroleum
1
ether/ethyl acetate (20/1, v/v) gave 3ao (128 mg, 73%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ
7.30 – 7.25 (m, 4H), 7.24 – 7.19 (m, 2H), 7.11 (t, J = 7.4 Hz, 1H), 7.00 (dd, J = 13.6, 7.5 Hz, 2H),
6.91 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 8.6 Hz, 2H), 5.09 (s, 1H), 3.69 (s, 3H), 2.78 (m, 2H), 1.77 (s,
1
3
1
3H), 1.20 (s, 3H). C{ H} NMR (151 MHz, CDCl ) δ 191.2, 158.7, 143.4, 142.7, 140.8, 135.8, 131.6,
3
130.9, 130.5, 129.8, 129.4 (CH×2 ), 128.9 (CH×2 ), 128.7 (CH×2 ), 128.5 (CH×2 ), 126.1, 125.4,
+
113.5 (CH×2 ), 87.2, 65.7, 55.2, 28.4, 18.6, 14.4. HRMS (ESI) m/z: [M + H] calcd for C28
H
26IO
S
2 2
585.0413; found 585.0402.
General procedure for the synthesis of 4
The solution of compound 3 (0.2 mmol) in EtOAc (2 mL) was continually stirred at RT with the
irradiation of 30 W household compact fluorescent lamp (CFL) until 3 was consumed as indicated by
TLC (ca. 2 h). It was then diluted with a saturated aqueous solution of sodium thiosulfate (5 mL) and
extracted with ethyl acetate (3 × 5 mL). The combined organic layer was washed with water and brine,
dried over Na
2
SO , filtered, and concentrated under reduced pressure. The crude product was purified
4
by column chromatography on silica gel (petroleum ether/ethyl acetate as eluent) to give the desired
product 4.
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Page 27 of 54
The Journal of Organic Chemistry
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1-(5-benzoyl-2-(ethylthio)-4-(4-methoxyphenyl)thiophen-3-yl)ethan-1-one (4a). Purification by
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flash column chromatography eluting with petroleum ether/ethyl acetate (20/1, v/v) gave 4a (66 mg,
1
8
3%) as a white solid, mp 82−84 °C. H NMR (600 MHz, CDCl
3
) δ 7.38 (d, J = 7.1 Hz, 2H), 7.23 (t,
J = 7.4 Hz, 1H), 7.08 (t, J = 7.8 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 8.6 Hz, 2H), 3.65 (s,
0
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0
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H), 3.03 (q, J = 7.4 Hz, 2H), 1.76 (s, 3H), 1.40 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl )
3
δ 196.8, 189.3, 159.7, 145.8, 139.1, 137.8, 135.8, 131.9, 131.1 (CH×2 ), 129.1 (CH×2 ), 127.8
+
(
CH×2 ), 127.1 (CH×2 ), 113.7 (CH×2 ), 55.2, 30.4, 29.9, 13.6. HRMS (ESI) m/z: [M + H] calcd for
C
22
H
21
3
O S
2
397.0927; found 397.0924.
1-(5-benzoyl-2-(ethylthio)-4-phenylthiophen-3-yl)ethan-1-one (4b). Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (20/1, v/v) gave 4b (61 mg, 83%) as a
1
white solid, mp 116−118 °C. H NMR (600 MHz, CDCl
3
) δ 7.46 (d, J = 7.3 Hz, 2H), 7.29 (t, J = 7.4
1
3
1
Hz, 1H), 7.18 – 7.11 (m, 7H), 3.15 – 3.07 (m, 2H), 1.79 (s, 3H), 1.48 (t, J = 7.4 Hz, 3H). C{ H}
NMR (151 MHz, CDCl ) δ 196.6, 189.2, 154.1, 145.9, 138.9, 137.7, 136.1, 135.0, 132.0, 129.8
3
(CH×2 ), 129.1 (CH×2 ), 128.4 (CH×2 ), 128.2 (CH×2 ), 127.8, 30.4, 30.0, 13.6. HRMS (ESI) m/z: [M
+
+ H] calcd for C21
H
19
O
2
S 367.0821; found 367.0830.
2
1-(5-benzoyl-2-(ethylthio)-4-(p-tolyl)thiophen-3-yl)ethan-1-one (4c). Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (20/1, v/v) gave 4c (61 mg, 80%) as a
1
white solid, mp 102−104 °C. H NMR (600 MHz, CDCl
3
) δ 7.46 (d, J = 7.8 Hz, 2H), 7.30 (s, 1H),
7
2
1
.14 (t, J = 7.6 Hz, 2H), 7.00 (d, J = 7.9 Hz, 2H), 6.94 (d, J = 7.7 Hz, 2H), 3.10 (d, J = 7.4 Hz, 2H),
1
3
1
.24 (s, 3H), 1.82 (s, 3H), 1.47 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 196.7, 189.2,
3
53.7, 146.2, 139.1, 138.3, 137.9, 135.9, 132.0, 131.7 (CH×2 ), 129.7 (CH×2 ), 129.1 (CH×2 ), 128.9
+
(
CH×2 ), 127.7, 30.4, 30.0, 21.1, 13.6. HRMS (ESI) m/z: [M + H] calcd for C22
H
21
O
2
S 381.0977;
2
found 381.0977.
1-(5-benzoyl-4-(4-ethylphenyl)-2-(ethylthio)thiophen-3-yl)ethan-1-one (4d). Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate (20/1, v/v) gave 4d (62 mg, 78%)
1
as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.34 (d, J = 7.2 Hz, 2H), 7.19 (d, J = 3.5 Hz, 1H), 7.04
(t, J = 7.7 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 7.9 Hz, 2H), 3.04 (d, J = 7.4 Hz, 2H), 2.45 (d,
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The Journal of Organic Chemistry
Page 28 of 54
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J = 7.6 Hz, 2H), 1.74 (s, 3H), 1.40 (t, J = 7.4 Hz, 3H), 1.04 (d, J = 7.6 Hz, 3H). C{ H} NMR (151
MHz, CDCl ) δ 195.7, 188.3, 145.3, 143.7, 137.9, 136.8, 135.1, 131.1 (CH×2 ), 130.7 (CH×2 ), 128.8
CH×2 ), 128.0 (CH×2 ), 126.7 (CH×2 ), 126.6, 29.4, 28.9, 27.6, 14.4, 12.6. HRMS (ESI) m/z: [M +
3
(
+
H] calcd for C23
H
23
O S
2 2
395.1134; found 395.1131.
0
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0
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-(5-benzoyl-2-(ethylthio)-4-(4-isopropylphenyl)thiophen-3-yl)ethan-1-one (4e). Purification by
flash column chromatography eluting with petroleum ether/ethyl acetate (20/1, v/v) gave 4e (67 mg,
1
8
2
1
1
2%) as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.37 (d, J = 7.3 Hz, 2H), 7.23 (s, 1H), 7.08 (s,
H), 6.99 (d, J = 7.8 Hz, 2H), 6.94 (d, J = 7.7 Hz, 2H), 3.12 (d, J = 7.4 Hz, 2H), 2.81 – 2.73 (m, 1H),
13
1
.81 (s, 3H), 1.48 (s, 3H), 1.13 (d, J = 6.8 Hz, 6H). C{ H} NMR (151 MHz, CDCl ) δ 196.7, 189.5,
3
54.4, 149.3, 146.3, 138.9, 137.8, 136.3, 132.2, 131.6 (CH×2 ), 129.9 (CH×2 ), 129.0 (CH×2 ), 127.6
+
(
CH×2 ), 126.2 (CH×2 ), 33.8, 30.4, 29.9, 23.7, 13.6. HRMS (ESI) m/z: [M + H] calcd for
C
24
H
25
2
O S
2
409.1290; found 409.1290.
1
-(5-benzoyl-4-(4-(tert-butyl)phenyl)-2-(ethylthio)thiophen-3-yl)ethan-1-one (4f). Purification by
flash column chromatography eluting with petroleum ether/ethyl acetate (20/1, v/v) gave 4f (68 mg,
1
80%) as a white solid, mp 120−122 °C. H NMR (600 MHz, CDCl
3
) δ 7.35 (s, 2H), 7.21 (d, J = 7.4
Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 7.06 (s, 2H), 6.99 (d, J = 8.2 Hz, 2H), 3.12 (d, J = 7.4 Hz, 2H), 1.82
13
1
(s, 3H), 1.48 (t, J = 7.4 Hz, 3H), 1.20 (s, 9H). C{ H} NMR (151 MHz, CDCl ) δ 196.7, 189.5, 154.3,
3
151.6, 146.2, 138.9, 137.8, 136.4, 131.8 (CH×2 ), 131.5 (CH×2 ), 129.7 (CH×2 ), 128.9 (CH×2 ),
+
1
27.6 (CH×2 ), 125.0 (CH×2 ), 34.5, 31.1, 30.4, 29.9, 13.6. HRMS (ESI) m/z: [M + H] calcd for
C
25
H
27
2
O S
2
423.1447; found 423.1442.
1
-(5-benzoyl-2-(ethylthio)-4-(4-fluorophenyl)thiophen-3-yl)ethan-1-one (4g). Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate (40/1, v/v) gave 4g (69 mg, 90%)
1
as a white solid, mp 110−112 °C. H NMR (600 MHz, CDCl
3
) δ 7.46 (d, J = 7.7 Hz, 2H), 7.35 (t, J =
7
.7 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H), 7.10 (dd, J = 8.4, 5.4 Hz, 2H), 6.86 (t, J = 8.4 Hz 2H), 3.11 (d, J
1
3
1
=
7.4 Hz, 2H), 1.83 (s, 3H), 1.48 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 196.3, 188.9,
3
1
1
62.7 (d, 1JCF = 249 Hz), 154.2, 144.7, 138.9, 137.7, 136.2, 132.2, 131.5 (d, 3JCF = 8.2 Hz, CH×2 ),
31.0 (d, 4JCF = 3.6 Hz), 129.1 (CH×2 ), 127.9 (CH×2 ), 115.3 (d, 2JCF = 21.7 Hz, CH×2 ), 30.5, 30.0,
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The Journal of Organic Chemistry
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+
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3.6. HRMS (ESI) m/z: [M + H] calcd for C21
H18FO
2
S
2
385.0727; found 385.0728.
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-(5-benzoyl-4-(4-chlorophenyl)-2-(ethylthio)thiophen-3-yl)ethan-1-one (4h). Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate (40/1, v/v) gave 4h (71 mg, 89%)
1
as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.40 (d, J = 7.3 Hz, 2H), 7.30 (d, J = 7.4 Hz, 1H), 7.13
0
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0
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(t, J = 7.7 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 3.03 (q, J = 7.4 Hz, 2H), 1.78 (s,
1
3
1
3
1
2
1
H), 1.40 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 195.1, 187.7, 153.2, 143.6, 137.8,
3
36.8, 135.2, 133.7, 132.5, 131.2 (CH×2 ), 130.0 (CH×2 ), 128.1 (CH×2 ), 127.4 (CH×2 ), 127.0, 29.6,
+
9.1, 12.5. HRMS (ESI) m/z: [M + H] calcd for C21
H18ClO
2
2
S 401.0431; found 401.0436.
-(5-benzoyl-4-(4-bromophenyl)-2-(ethylthio)thiophen-3-yl)ethan-1-one (4i). Purification by flash
column chromatography eluting with petroleum ether/ethyl acetate (40/1, v/v) gave 4i (77 mg, 87%)
1
as a yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.47 (d, J = 7.8 Hz, 2H), 7.39 (t, J = 7.0 Hz, 1H), 7.30
(d, J = 8.1 Hz, 2H), 7.21 (t, J = 7.4 Hz, 2H), 7.01 (d, J = 8.1 Hz, 2H), 3.10 (d, J = 7.4 Hz, 2H), 1.86 (s,
1
3
1
3H), 1.47 (t, J = 7.4 Hz, 3H). C{ H} NMR (151 MHz, CDCl ) δ 196.1, 188.7, 154.2, 144.6, 138.8,
3
137.8, 136.2, 134.0, 132.2, 131.4 (CH×2 ), 131.3 (CH×2 ), 129.1 (CH×2 ), 128.0 (CH×2 ), 122.9, 30.6,
+
30.1, 13.6. HRMS (ESI) m/z: [M + H] calcd for C21
H18BrO
2
2
S 444.9926; found 444.9929.
1-(5-benzoyl-2-(ethylthio)-4-(3-methoxyphenyl)thiophen-3-yl)ethan-1-one (4j). Purification by
flash column chromatography eluting with petroleum ether/ethyl acetate (20/1, v/v) gave 4j (64 mg,
1
81%) as a white solid, mp 80−82 °C. H NMR (600 MHz, CDCl
3
) δ 7.48 (d, J = 7.3 Hz, 2H), 7.32 (t,
J = 7.4 Hz, 1H), 7.17 (t, J = 7.7 Hz, 2H), 7.09 (t, J = 7.9 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.71 (dd, J
=
8.3, 1.9 Hz, 1H), 6.64 (s, 1H), 3.67 (s, 3H), 3.13 (d, J = 7.4 Hz, 2H), 1.86 (s, 3H), 1.50 (s, 3H).
1
3
1
C{ H} NMR (151 MHz, CDCl
3
) δ 196.6, 189.2, 159.3, 154.1, 145.7, 138.8, 137.8, 136.2, 131.9,
129.3 (CH×2 ), 128.9 (CH×2 ), 127.7 (CH×2 ), 122.4, 115.4, 114.4, 55.2, 30.3, 30.0, 13.6. HRMS (ESI)
+
m/z: [M + H] calcd for C22
H
21
O
3
S 397.0927; found 397.0924.
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1-(5-benzoyl-2-(ethylthio)-4-(m-tolyl)thiophen-3-yl)ethan-1-one (4k). Purification by flash column
chromatography eluting with petroleum ether/ethyl acetate (20/1, v/v) gave 4k (62 mg, 82%) as a
1
yellow oil. H NMR (600 MHz, CDCl
3
) δ 7.36 (d, J = 7.4 Hz, 2H), 7.21 (t, J = 5.7 Hz, 1H), 7.05 (t, J
=
7.7 Hz, 2H), 6.96 (t, J = 7.6 Hz, 1H), 6.86 (t, J = 8.7 Hz, 2H), 6.81 (s, 1H), 3.04 (q, J = 7.4 Hz, 2H),
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