Development and Application of Pyridinium 1,4-Zwitterionic Thiolates: Synthesis of Polysubstituted Thiophenes

Article abstract of DOI:10.1002/ejoc.202000165

Pyridinium 1,4-zwitterionic thiolates as a class of sulfur-containing synthons were applied to a [3+2] cascade cyclization reaction with activated alkynes, affording a library of polysubstituted thiophenes with excellent regioselectivities, especially those bearing various fluorine-containing groups. The freshly disclosed pyridinium 1,4-zwitterionic thiolates decorated with acyl or trifluoromethyl groups exhibited powerful potential in the synthesis of polysubstituted thiophenes. Of particular note is that pyridinium A4 could introduce sulfur and CF₃ groups to target products simultaneously.

Full text of DOI:10.1002/ejoc.202000165

DOI: 10.1002/ejoc.202000165
Full Paper
Sulfur Chemistry
Development and Application of Pyridinium 1,4-Zwitterionic
Thiolates: Synthesis of Polysubstituted Thiophenes
Bin Cheng,*[a,b] Xiaoguang Duan,[b][‡] Yuntong Li,[b][‡] Xinping Zhang,[a,b] Hui Li,[a,b]
Fufang Wu,[d] Yun Li,[b] Taimin Wang,*[a] and Hongbin Zhai*[a,b,c]
Abstract: Pyridinium 1,4-zwitterionic thiolates as a class of freshly disclosed pyridinium 1,4-zwitterionic thiolates decorated
sulfur-containing synthons were applied to a [3+2] cascade cy- with acyl or trifluoromethyl groups exhibited powerful potential
clization reaction with activated alkynes, affording a library of in the synthesis of polysubstituted thiophenes. Of particular
polysubstituted thiophenes with excellent regioselectivities, es- note is that pyridinium A4 could introduce sulfur and CF3
pecially those bearing various fluorine-containing groups. The groups to target products simultaneously.
Introduction
kind of novel pyridinium 1,4-zwitterionic thiolates
A
(Scheme 1), which could be readily prepared from a three-com-
ponent reaction of dialkyl acetylene dicarboxylates, elemental
sulfur, and pyridine.[7] The solid organosulfur compounds are
air-stable, odorless, easy- to- handle, and readily available. Aliza-
deh had proposed these thiolates were the key intermediates in
the synthesis of tetraalkyl 2,3,4,5-thiophenetetracarboxylate,[12]
but this kind of pyridinium 1,4-zwitterionic thiolates have not
yet been recognized as useful and versatile synthons ever since
their emergence, to the best of our knowledge. In this context,
intrigued by their unique structures, we envisaged that the re-
active intermediates could be used to prepare sulfur-containing
Organosulfur compounds occupy a significant place in organic
chemistry because they serve diverse functions in many aspects
of human life in an array of existing forms.[1] Among them,
thiophenes, one class of sulfur-containing five-membered
heterocycles, widely spread in pharmaceuticals, bioactive mole-
cules,[2] and functional materials.[3] Furthermore, they are
often used as vital organic synthetic intermediates in organic
chemistry and material chemistry.[4] Thus, a great number of
methods have been harnessed to construct this unique hetero-
cycle.[5] However, there are limited approaches to the synthesis
of polysubstituted thiophenes and many of them involve metal
catalysts, malodorous starting materials, and/or harsh reaction
conditions. In addition, metal pollution in the products is always
a conundrum, especially for pharmaceutical and material chem-
istry. Moreover, incorporating multifarious fluorine-containing
groups (e.g., SCF3, CF3) into thiophenes with the same protocol
is scare and fascinating.[6,10,11] Thus, the development of versa-
tile and general to access polysubstituted, thiophenes and
fluorine-containing ones in particular under metal-free and cat-
alyst-free conditions is highly desired.
Recently, we carried out a program to comprehensively ex-
plore and understand the properties and reactivities of one
[a] Institute of Marine Biomedicine, Shenzhen Polytechnic,
Shenzhen 518055, China
E-mail: chengbin@szpt.edu.cn, wangtm@szpt.edu.cn
[b] State Key Laboratory of Applied Organic Chemistry, College of Chemistry
and Chemical Engineering, Lanzhou University,
Lanzhou 730000, China
[c] State Key Laboratory of Chemical Oncogenomics, Shenzhen Engineering
Laboratory of Nano Drug Slow-Release, Peking University Shenzhen
Graduate School,
Shenzhen 518055, China
E-mail: zhaihb@pkusz.edu.cn
[d] School of Chemistry and Materials Engineering, Fuyang Normal University,
Fuyang 236037, China
[‡] Those authors contributed equally to this work
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000165.
Scheme 1. Reaction modes of pyridinium 1,4-zwitterionic thiolates and this
work.
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heterocycles via two reaction modes: [5+m, path a], with pyrid-
ine as a reactive moiety, and [3+m, path b], with pyridine as a
leaving group (Scheme 1). Preliminary results indicated that this
kind of pyridinium 1,4-zwitterionic thiolates as three-atom com-
ponents could react with 1,2-diaza-1,3-dienes derived from
α-halo hydrazones in situ to afford 2,5-dihydro-1,4,5-thiadi-
azepines via path b in a cascade fashion.[8] To exploit more
interesting reaction modes of these thiolates and develop new
analogs of A, we successfully prepared pyridinium 1,4-zwitter-
ionic thiolates A1-A4 decorated with alkoxyl carbonyl, acyl or
trifluoromethyl groups and applied them to a [3+2] cascade
cyclization reaction with activated alkynes, delivering a library
of polysubstituted, especially various fluorine-containing thio-
phenes (Scheme 1). Meanwhile, we found that the X group at
the 4-position of pyridine could be used as a modulator to tune
the reaction speed.
Table 1. Optimization of the reaction conditions.[a]
Entry
1
1/2a
Solvent
Time [h]
Yield [%]
1[b]
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1b
1c
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.2:1
1.8:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
DCM
DCE
DCE
DCE
DCE
50
11.5
1
1.5
1
2.5
1
2
2
2
2
2
76
76
29
60
81
75
74
71
68
70
71
45
51
22
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
DCE
DCE
EtOAc
(CH3)2CO
THF
PhMe
DMF
Results and Discussion
We began our study using 1a and 2a as the model substrates
to acquire the optimal reaction conditions. When 1a and 2a
were simply mixed and stirred in DCM in air at room tempera-
ture and without any additives, a spontaneous cascade cycliza-
tion reaction occurred, but it proceeded very sluggishly. Subse-
quently, when the reaction temperature was elevated to 45 °C,
tetrasubstituted thiophene 3 was obtained in 76 % yield with
excellent regioselectivity after two days (Table 1, entry 1). The
regioselectivity was established by analogy with 27 (vide in-
fra).[9] When the solvent was switched to DCE and accordingly
the temperature was elevated to 85 °C, the reaction was accel-
erated remarkably, offering a maintained yield (entry 2). Next,
we studied the reaction behaviors of pyridiniums with distinct
X groups at the 4-position of pyridine moiety (entries 3–5).
Pyridinium 1b bearing a N,N-dimethylamino group offered 3 in
only a low yield of 29 %, while pyridinium 1c containing a
methyl group gave a moderate yield of 60 %. To our delight,
pyridinium 1d bearing a methoxyl group exhibited the best
reactivity and furnished the highest yield of 81 % within only
1 h. Then, we adjusted the ratio of reactants, but no better
results were obtained. In addition, we also examined a series of
common solvents including ethyl acetate, acetone, toluene, and
so on (entries 8–14). All of them could support the reaction,
but only moderate yields were delivered. Water as a green sol-
vent could not be compatible with this cyclization reaction and
only a trace amount of 3 was detected, probably owing to the
very poor solubility of 1d in water. Thus, the optimal reaction
conditions (1d:2a = 1.5:1, DCE, 85 °C, entry 5) were determined.
CH3CN
MeOH
2
2
[a] Reaction conditions: 1, 2a (0.3 mmol), solvent (3 mL), 85 °C, in air. Isolated
yield. [b] 45 °C was adopted instead.
2-furyl) alkynes were also well-tolerated, providing the corre-
sponding thiophenes (9 and 10) in good yields. Steric hin-
drance impacted on the cyclization efficiency. For example, tert-
butyl ester substrate delivered thiophene 11 in only 73 % yield.
N-methyl-4-oxo-N,4-diphenylbut-2-ynamide was also compati-
ble with this cascade cyclization reaction, affording 12 and 13
in 88 % and 95 % yields, respectively. Pyridiniums decorated
with ethyl esters performed better than those with methyl es-
ters (e.g., 3 vs. 4 and 12 vs. 13). The diethoxyacetal substrate
reacted as well and furnished 14 in a yield of 80 %. For 1,4-
diketone alkynes, the diaryl ketone gave a better performance
than dialkyl ketone (15 vs. 16). As for 1,3-diyne substrate, the
cyclization product 17 was gained in a moderate yield of 59 %,
wherein only one alkynyl group got involved in the cyclization
reaction while another one remained intact. These results indi-
cated that the EWG4 of the reaction partner 2 should be a suit-
able functional group, while thienyl group was not the right
choice. Then, 1,4-diester alkynes were examined, only moderate
yields of thiophenes (18 and 19) were obtained. To further de-
velop the chemistry of pyridinium 1,4-zwitterionic thiolates, we
successfully prepared two new pyridinium 1,4-zwitterionic
thiolates (1f and 1g), which had not been described in the liter-
With the optimal reaction conditions in hand, we turned our ature previously. It is worthy to note that the formation of pyr-
attention to examining the generality and scope of this cascade idinium 1g features excellent regioselectivity. The reactions of
cyclization reaction (Scheme 2). For pyridinium 1,4-zwitterionic pyridinium 1f with 4-oxo-4-phenylbut-2-ynoate and 1,4-diket-
thiolates 1d and 1e, an array of asymmetric internal alkynes one alkyne finished the thiophenes 20 and 21 in 68 % and
were first investigated. For methyl 4-oxo-4-phenylbut-2-ynoate, 55 % yields, respectively. It should be mentioned that for the
substituents on the phenyl group had little influence on the synthesis of 15 from pyridinium 1f, only 40 % yield could be
efficiency of the cyclization reaction (3–8) as strong electron- afforded compared with the route from pyridinium 1e. Pyridin-
donating and electron-withdrawing groups induced slightly ium 1g was also applicable to this transformation and it could
lower yields (7 and 8). Heteroaryl-substituted (e.g., 2-thienyl and react with N-methyl-4-oxo-N,4-diphenylbut-2-ynamide to afford
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thiophene 22 in a yield of 53 %. The regioselectivities for the
As we know that incorporating of fluorine-containing groups
formation pyridinium 1g and thiophenes (3–14, 17, 20 and 22) into bioactive molecules has been developed as an important
were established by analogy with 27 (vide infra).[9] Despite the tool to alter their lipophilicity, bioavailability, and metabolic
above success, some failed substrates should be mentioned. 4- ability.[10] On the other hand, fluorine-bearing thiophenes were
Methoxy-4-oxobut-2-ynoic acid, N1,N4-dimethyl-N1,N4-diphenyl- usually synthesized from preconstructed thiophenes via fluorin-
but-2-ynediamide, and methyl but-2-ynoate did not react with ated reactions with the aid of metal catalysts.[11] Thus far, there
pyridinium 1d. The results gained from methyl but-2-ynoate have been no unified approaches that could access multifarious
and 17 indicated that the EWG4 of the reaction partner 2 fluorine-containing thiophenes under metal-free and catalyst-
should be a suitable electron-withdrawing group, while aryl or free conditions, to the best of our knowledge. Thus, we exam-
alkyl groups were not the right choices. Moreover, 3-chloro-1- ined the reaction between ethyl 4,4,4-trifluorobut-2-ynoate and
phenylprop-2-yn-1-one gave only a trace amount of the desired pyridinium 1e. Delightfully, a moderate yield of triethyl 5-(tri-
thiophene along with other unidentified side-products.
fluoromethyl)thiophene-2,3,4-tricarboxylate (23) was success-
fully obtained with a CF3 group installed at the 5-position
(Scheme 3). Likewise, thiophenes bearing CF2 (24), CF (25) or
SCF3 (26) groups were also obtained from the corresponding
alkynes in 61 % to 92 % yields. To our satisfaction, ethyl 4,4,4-
trifluorobut-2-ynoate could also be transformed into pyridinium
1h using Bazgir's method,[7] which was a CF3-containing organ-
osulfur compound and of great potential to incorporate sulfur
and CF3 group into organic molecules simultaneously. With 1h
in hand, we investigated its reactions with various internal alk-
ynes comprising ester, amide, acetal, or ketone moieties. The
cyclization reactions of them proceeded smoothly, affording
thiophenes (27–30) with a CF3 group installing at the different
position compared with 23. The regioselectivity of 27 was con-
firmed by X-ray diffraction analysis and that of other thiophenes
were established by analogy with 27.[9]
Scheme 2. [3+2] cascade cyclization reaction of internal alkynes. Reaction
Scheme 3. [3+2] cascade cyclization reaction of internal alkynes. Reaction
conditions: 1 (1.5 equiv.), 2 (0.3 mmol), DCE (3 mL), 85 °C, in air. Isolated yield.
conditions: 1 (1.5 equiv.), 2 (0.3 mmol), DCE (3 mL), 85 °C, in air. Isolated yield.
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With the success in the synthesis of tetrasubstituted thio- and 44 vs. 45). In addition, trisubstituted thiophene 46 contain-
phenes (3–30), we wondered if this facile protocol could be ing a CF3 group was obtained as well in 72 % yield. Propiolic
extended to accessing trisubstituted thiophenes using terminal acid and its amide derivatives (e.g., 1-(piperidin-1-yl)prop-2-yn-
alkynes as the reactants. Gratifyingly, when 1-phenylprop-2-yn- 1-one) failed to react with pyridinium 1d as no reactions were
1-one was adopted as the substrate, trisubstituted thiophene detected.
31 was obtained in 81 % yield and the structure of 31 was
unambiguously assigned by X-ray structural analysis
(Scheme 4).[9] Then, the electrophilic and steric effects of the
substituents on the benzoyl groups (32–38) were investigated.
Strong electron-donating and electron-withdrawing substitu-
ents (e.g., 32 and 34) resulted in slightly attenuated yields and
bulky substituents (36 and 37) sharply cut down the yields. The
fused aryl (e.g., 1-naphthyl) and heteroaryl (e.g., 2-furyl and 2-
thienyl) group-substituted terminal alkynes were also well-toler-
ated and gave high yields of the desired thiophenes (39–41).
Terminal alkyne with alkylacyl group furnished 42 only in a
moderate yield of 53 %. Naphthalen-2-ylmethyl propiolate ex-
hibited lower reactivity compared with acyl substrates and an
inferior yield of 25 % (43) could be obtained with prolonged
time. The diester pyridiniums (1d and 1e) performed better
than diketone substrate 1f and gave higher yields (31 vs. 45
To further demonstrate the utility of this synthetic protocol,
a series of derivatization reactions were conducted (Scheme 5).
The condensation reaction of 29 and 30 with hydrazine hydrate
afforded 47 and 48 bearing a thieno[2,3-d]pyridazine fused sys-
tem. The sulfurization of 30 with Lawesson reagent afforded
thieno[3,4-b]thiophene 49 in 94 % yield. Deprotection of the
acetal group of 29 under acidic conditions could afford a new
tetrasubstituted thiophene 50 with an aldehyde function. In
addition, curiously the ester group of 29 could be selectively
reduced to hydroxylmethyl group with DIBAL-H in the presence
of ketone function, probably owing to the bulky steric hin-
drance. After hydrolysis, tetrasubstituted thiophene 51 deco-
rated with a hydroxylmethyl and an aldehyde motif was ob-
tained in 47 % total yield for two steps.
Scheme 5. Further transformations of thiophenes decorated with CF3.
Based on the previous reports,[12] we proposed a possible
mechanism for the [3+2] cascade cyclization reaction
(Scheme 6). The cascade process is initiated by an S-Michael
addition of thiolates to the more electron-deficient end of acti-
vated alkynes followed by a C-Michael addition, the first step
of which dominates the regioselectivities of final products. Then
a retro-Michael addition results in extrusion of 4-MeO-Py from
the system affording the desired thiophenes.
Scheme 4. [3+2] cascade cyclization reaction of terminal alkynes. Reaction
conditions: 1 (1.5 equiv.), 2 (0.3 mmol), DCE (3 mL), 85 °C, in air. Isolated yield.
Scheme 6. Proposed mechanism for [3+2] cascade cyclization reaction.
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idinium 1,4-zwitterionic thiolate (0.45 mmol, 1.5 equiv.), then the
reaction mixture was stirred at 85 °C. After completion as monitored
by TLC, the mixture was concentrated and the residue was directly
subjected to silica gel column chromatography to afford the desired
Conclusions
In summary, pyridinium 1,4-zwitterionic thiolates (A1–A4) have
been developed to react with a series of activated alkynes, de-
livering a library of polysubstituted thiophenes, especially those thiophene.
bearing precious fluorine-containing groups. The freshly dis-
Procedures for the Synthesis of Thiophene Derivatives (47–51)
closed pyridiniums A2–A4 could be powerful and potential syn-
thons to incorporate sulfur atom into organic molecules in the
future. Of particular note is that pyridinium A4 could introduce
sulfur and trifluoromethyl group to target products simultane-
ously. The other performances and reaction modes of pyridin-
ium 1,4-zwitterionic thiolates will be described in due course.
For the Synthesis of 47: To a solution of 29 (26 mg, 0.060 mmol,
1.0 equiv.) in CHCl3 (1 mL) was added TsOH (10 mg, 0.060 mmol,
1.0 equiv.), then the reaction mixture was stirred at room tempera-
ture. After completion as monitored by TLC, the solvent was re-
moved and the residue was redissolved in EtOH (1 mL). To this
solution were added NH2NH2·H2O (80 %, 0.5 mL) and TFA
(0.3 equiv.), then the reaction mixture was heated at 80 °C. After
completion as monitored by TLC, the mixture was concentrated and
the residue was directly subjected to silica gel column chromatogra-
phy (PE/EtOAc = 8:1) to afford the desired product 47 (17 mg, 81 %
yield for 2 steps).
Experimental Section
General Information: All isolated compounds were characterized
on Varian 300, Bruker 400 and JEOL 400 MHz spectrometers in the
CDCl3, (CD3)2CO, or (CD3)2SO. Chemical shifts are reported as δ val-
For the Synthesis of 48: To a solution of 30 (26 mg, 0.060 mmol,
1.0 equiv.) in EtOH (1 mL) were added NH2NH2·H2O (80 %, 0.4 mL)
and TFA (cat.), then the reaction mixture was heated at 80 °C. After
completion as monitored by TLC, the mixture was concentrated and
the residue was directly subjected to silica gel column chromatogra-
phy (PE/EtOAc = 8:1) to afford the desired product 48 (25 mg, 96 %
yield).
1
ues relative to internal chloroform (δ = 7.26 for H NMR and 77.00
for 13C NMR), acetone (δ = 2.05 for 1H NMR and 29.84 for 13C NMR),
and dimethyl sulfoxide (δ = 2.50 for 1H NMR and 39.52 for 13C NMR).
9F NMR chemical shifts were determined as δ values relative to
external standard PhCF3 at –63.00. High-resolution mass spectra
(HRMS) were obtained on a 4G mass spectrometer by using electro-
spray ionization (ESI) analyzed by quadrupole time-of-flight (QTof).
All melting points were measured with the samples after column
chromatography and uncorrected. Column chromatography was
performed on silica gel. Anhydrous THF, PhMe were distilled from
sodium benzophenone ketyl under Ar. All other solvents and rea-
gents were used as obtained from commercial sources without
further purification.
For the Synthesis of 49: To a solution of 30 (34 mg, 0.080 mmol,
1.0 equiv.) in DCM (4 mL) was added Lawesson reagent (48 mg,
0.12 mmol, 1.5 equiv.), then the reaction mixture was heated at
45 °C. After completion as monitored by TLC, the mixture was con-
centrated and the residue was directly subjected to silica gel col-
umn chromatography (PE/EtOAc = 10:1) to afford the desired prod-
uct 49 (32 mg, 94 % yield).
General Procedure for the Preparation of Alkynes: Methyl 4-oxo-
4-phenylbut-2-ynoate (S1, i.e., 2a), methyl 4-oxo-4-(p-tolyl)but-2-
ynoate (S3), methyl 4-(4-methoxyphenyl)-4-oxobut-2-ynoate (S4),
methyl 4-oxo-4-(thiophen-2-yl)but-2-ynoate (S6), methyl 4-(furan-2-
yl)-4-oxobut-2-ynoate (S7), tert-butyl 4-oxo-4-phenylbut-2-ynoate
(S8), and N-methyl-4-oxo-N,4-diphenylbut-2-ynamide (S9) were
prepared according to the literature.[13] 4-(4-Bromophenyl)-4-oxo-
but-2-ynoate (S2) and methyl 4-(4-nitrophenyl)-4-oxobut-2-ynoate
(S5) were prepared according to the literature.[14] 4,4-Diethoxy-1-
phenylbut-2-yn-1-one (S10) was prepared according to the litera-
ture.[15] 4-diphenylbut-2-yne-1,4-dione (S11) and hexacos-13-yne-
12,15-dione (S12) were prepared according to the literature.[16] 1,6-
Diphenylhexa-2,4-diyne-1,6-dione (S13) was prepared according to
the literature.[17] Diisopropyl but-2-ynedioate (S14) was prepared
according to the literature.[18] Ethyl 4-(4-bromophenyl)-4,4-difluoro-
but-2-ynoate (S15) was prepared according to the literature.[19] 1-
(4-Bromophenyl)-4-fluoropent-2-yn-1-one (S16) was prepared ac-
cording to the literature.[20] 1-Phenyl-3-((trifluoromethyl)thio)prop-
2-yn-1-one (S17) was prepared according to the literature.[21] All
the terminal alkynes were prepared according to the literature[22]
besides 1-naphthalen-2-ylmethyl propiolate (S18) and 1-(piperidin-
1-yl)prop-2-yn-1-one (S19). 1-Naphthalen-2-ylmethyl propiolate
(S18) was prepared according to the literature.[23] 1-(Piperidin-1-
yl)prop-2-yn-1-one (S19) was prepared according to the litera-
ture.[24]
For the Synthesis of 50: To a solution of 29 (70 mg, 0.16 mmol,
1.0 equiv.) in CHCl3 (1 mL) was added TFA (0.3 equiv.), then the
reaction mixture was stirred at room temperature. After completion
as monitored by TLC, the solvent was removed and the residue was
directly subjected to silica gel column chromatography (PE/EtOAc =
15:1) to afford the desired product 50 (52 mg, 90 % yield).
For the Synthesis of 51: To a solution of 29 (46 mg, 0.11 mmol,
1.0 equiv.) in THF (10 mL) at –78 °C was added DIBAL-H (1.65 mL,
1
M in hexane, 1.65 mmol, 15 equiv.), then the reaction mixture was
stirred at the same temperature. After completion as monitored by
TLC, the mixture was quenched with saturated aqueous potassium
sodium tartrate solution. Then, the mixture was extracted with
DCM. The combined organic phases were concentrated and the
residue was redissolved in CHCl3 (5 mL). To this solution was added
TFA (cat.), then the reaction mixture was stirred at room tempera-
ture. After completion as monitored by TLC, the solvent was re-
moved and the residue was directly subjected to silica gel column
chromatography (PE/EtOAc = 5:1) to afford the desired product 51
(16 mg, 47 % yield for 2 steps).
Characterization Data of Products: Trimethyl 4-Benzoylthio-
phene-2,3,5-tricarboxylate. Compound 3 (88 mg, Y = 81 %, Rf =
0.2 (PE/EA = 6:1)) was isolated as a light yellow oil. 1H NMR
(400 MHz, CDCl3) δ = 7.79 (d, J = 7.3 Hz, 2H), 7.60 (t, J = 7.4 Hz,
1H), 7.46 (t, J = 7.7 Hz, 2H), 3.95 (s, 3H), 3.69 (s, 3H), 3.68 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ = 190.8, 162.3, 160.4, 160.2, 145.4 137.9,
136.6, 136.4, 133.8, 133.7, 129.0, 128.6, 53.3, 52.9, 52.8; HRMS (ESI) m/z:
[M + H]+ calcd. for C17H15O7S 363.0533, found 363.0547.
General Procedure for the Preparation of Pyridinium 1,4-Zwit-
terionic Thiolates: Pyridinium 1,4-zwitterionic thiolates (1a–h)
were prepared according to the literature.[7]
General Experimental Procedure for Thiophenes 3–46: To a solu-
2,3-Diethyl 5-Methyl 4-Benzoylthiophene-2,3,5-tricarboxylate:
tion of alkyne (0.3 mmol, 1.0 equiv.) in DCE (3 mL) was added pyr- Compound 4 (105 mg, Y = 90 %, Rf = 0.4 (PE/EA = 6:1)) was isolated
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1
as a light yellow solid; m.p. 110–111 °C. H NMR (300 MHz, CDCl3) 136.9, 134.6, 119.3, 112.6, 62.5, 62.1, 52.9, 13.9, 13.5; HRMS (ESI) m/z:
δ = 7.80 (d, J = 7.5 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.7 Hz,
2H), 4.40 (q, J = 7.1 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.69 (s, 3H),
1.39 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ = 190.8, 161.7, 160.3, 160.0, 145.4, 138.6, 136.5, 133.6,
133.4, 129.0, 128.5, 62.6, 62.0, 52.8, 13.9, 13.4, (1C missing); HRMS
(ESI) m/z: [M + H]+ calcd. for C19H19O7S 391.0846, found 391.0859.
[M + H]+ calcd. for C17H17O8S 381.0639, found 381.0649.
5-(tert-Butyl) 2,3-Diethyl 4-Benzoylthiophene-2,3,5-tricarboxyl-
ate: Compound 11 (95 mg, Y = 73 %, Rf = 0.5 (PE/EA = 4:1)) was
isolated as a colorless oil. 1H NMR (400 MHz, (CD3)2CO) δ = 7.72–
7.70 (m, 2H), 7.56–7.51 (m, 1H), 7.43–7.40 (m, 2H), 4.25 (q, J = 7.1 Hz,
2H), 3.98 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H), 1.12 (s, 9H), 0.92
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, (CD3)2CO) δ = 190.9, 162.6,
160.7, 159.9, 144.7, 138.1 (2C), 137.8, 137.5, 134.6, 130.1, 129.5, 84.9,
63.2, 62.5, 27.7, 14.3, 13.9; HRMS (ESI) m/z: [M + Na]+ calcd. for
C22H24O7SNa 455.1135, found 455.1150.
2,3-Diethyl 5-Methyl 4-(4-Bromobenzoyl)thiophene-2,3,5-tri-
carboxylate: Compound 5 (121 mg, Y = 86 %, Rf = 0.4 (PE/EA =
5:1))was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3) δ =
7.67 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 4.40 (q, J = 7.1 Hz,
2H), 4.16 (q, J = 7.1 Hz, 2H), 3.71 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.09
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 189.9, 161.5, 160.2,
159.9, 145.0, 138.9, 136.2, 135.5, 133.3, 131.9, 130.4, 128.9, 62.6, 62.1,
52.9, 13.9, 13.5; HRMS (ESI) m/z: [M + H]+ calcd. for C19H18BrO7S
468.9951, found 468.9970.
Dimethyl
4-Benzoyl-5-(methyl(phenyl)carbamoyl)thiophene-
2,3-dicarboxylate: Compound 12 (116 mg, Y = 88 %, Rf = 0.1 (PE/
EA = 6:1)) was isolated as a pale brown oil. 1H NMR (300 MHz,
CDCl3) δ = 7.65 (d, J = 7.3 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.42 (t,
J = 7.6 Hz, 2H), 7.34–7.21 (m, 3H), 7.18–7.05 (m, 2H), 3.81 (s, 3H),
3.44 (s, 3H), 3.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ = 189.9, 162.8,
160.8, 160.2, 142.4, 142.2, 142.1, 136.4, 136.3, 133.8, 133.2, 129.6,
129.0, 128.2, 128.1, 127.0, 52.8, 52.4, 38.1; HRMS (ESI) m/z: [M + H]+
calcd. for C23H20NO6S 438.1006, found 438.1018.
2,3-Diethyl 5-Methyl 4-(4-Methylbenzoyl)thiophene-2,3,5-tri-
carboxylate: Compound 6 (106 mg, Y = 88 %, Rf = 0.3 (PE/EA =
5:1)) was isolated as a white solid; m.p. 114–115 °C. 1H NMR
(400 MHz, CDCl3) δ = 7.69 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 7.9 Hz,
2H), 4.40 (q, J = 7.1 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 3.69 (s, 3H),
2.40 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ = 190.3, 161.7, 160.3, 160.1, 145.7, 144.6, 138.4,
136.6, 134.2, 133.3, 129.2 (2C), 62.5, 62.0, 52.7, 21.7, 13.9, 13.4; HRMS
(ESI) m/z: [M + H]+ calcd. for C20H21O7S 405.1003, found 405.1014.
Diethyl 4-Benzoyl-5-(methyl(phenyl)carbamoyl)thiophene-2,3-
dicarboxylate: Compound 13 (133 mg, Y = 95 %, Rf = 0.4 (PE/EA =
2:1)) was isolated as a light brown oil. 1H NMR (300 MHz, CDCl3)
δ = 7.72–7.63 (m, 2H), 7.58–7.53 (m, 1H), 7.45–7.39 (m, 2H), 7.32–
7.23 (m, 3H), 4.28 (q, J = 7.1 Hz, 2H), 3.89 (q, J = 7.0 Hz, 2H), 3.29
(s, 3H), 1.29 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ = 190.1, 162.4, 160.9, 160.0, 142.4, 142.3, 141.8,
136.5, 136.1, 134.5, 133.2, 129.6, 129.1, 128.2, 128.0, 127.1, 62.1, 61.7,
38.2, 13.8, 13.2; HRMS (ESI) m/z: [M + H]+ calcd. for C25H24NO6S
466.1319, found 466.1331.
2,3-Diethyl 5-Methyl 4-(4-Methoxybenzoyl)thiophene-2,3,5-tri-
carboxylate: Compound 7 (105 mg, Y = 83 %, Rf = 0.25 (PE/EA =
3:1)) was isolated as a yellow solid; m.p. 85.2–86.1 °C. 1H NMR
(300 MHz, CDCl3) δ = 7.77 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 9.0 Hz,
2H), 4.40 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H),
3.71 (s, 3H), 1.38 (d, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ = 189.2, 164.0, 161.8, 160.3, 160.0, 145.7, 138.1,
136.6, 133.2, 131.4, 129.7, 113.8, 62.5, 61.9, 55.4, 52.7, 13.9, 13.4;
HRMS (ESI) m/z: [M + H]+ calcd. for C20H21O8S 421.0952, found
421.0965.
Diethyl 4-Benzoyl-5-(diethoxymethyl)thiophene-2,3-dicarbox-
ylate: Compound 14 (104 mg, Y = 80 %, Rf = 0.5 (PE/EA = 5:1)) was
isolated as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ = 7.82–
7.76 (m, 2H), 7.62–7.54 (m, 1H), 7.47–7.42 (m, 2H), 5.68 (s, 1H), 4.35
(d, J = 7.1 Hz, 2H), 4.00 (q, J = 7.2 Hz, 2H), 3.62–3.53 (m, 2H), 3.50–
3.39 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.11–1.03 (m, 9H); 13C NMR
(75 MHz, CDCl3) δ = 191.2, 162.9, 160.5, 149.1, 137.8, 137.5, 137.1,
133.4, 132.4, 129.1, 128.4, 96.8, 62.1, 61.8, 61.7, 14.6, 14.0, 13.4;
HRMS (ESI) m/z: [M + Na]+ calcd. for C22H26O7SNa 457.1291, found
457.1309.
2,3-Diethyl 5-Methyl 4-(4-Nitrobenzoyl)thiophene-2,3,5-tricarb-
oxylate: Compound 8 (106 mg, Y = 81 %, Rf = 0.25 (PE/EA = 4:1))
was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 8.30
(d, J = 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 4.43 (q, J = 7.1 Hz, 2H),
4.18 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H), 1.12 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 189.5, 161.4, 160.1,
159.9, 150.4, 144.6, 141.1, 139.7, 136.0, 133.3, 129.8, 123.8, 62.8, 62.3,
53.0, 13.9, 13.5; HRMS (ESI) m/z: [M + H]+ calcd. for C19H18NO9S
436.0697, found 436.0711.
Diethyl 4,5-Dibenzoylthiophene-2,3-dicarboxylate: Compound
15 (130 mg, Y = 99 %, Rf = 0.4 (PE/EA = 5:1)) was isolated as a
brown oil. 1H NMR (300 MHz, CDCl3) δ = 7.56–7.45 (m, 6H), 7.34–
7.26 (m, 4H), 4.42 (q, J = 7.1 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 1.39
(t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ = 190.2, 186.9, 162.6, 159.8, 144.2, 143.5, 138.5, 137.0, 136.8, 136.1,
133.4, 133.3, 128.9, 128.7, 128.4, 128.3, 62.4, 62.1, 13.9, 13.5; HRMS
(ESI) m/z: [M + H]+ calcd. for C24H21O6S 437.1053, found 437.1067.
2,3-Diethyl 5-Methyl 4-(Thiophene-2-carbonyl)thiophene-2,3,5-
tricarboxylate: Compound 9 (100 mg, Y = 84 %, Rf = 0.2 (PE/EA =
4:1)) was isolated as a colorless oil. 1H NMR (300 MHz, CDCl3) δ =
7.74 (dd, J = 4.9, 1.1 Hz, 1H), 7.39 (dd, J = 3.8, 1.2 Hz, 1H), 7.10 (dd,
J = 4.9, 3.9 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 4.18 (q, J = 7.1 Hz, 2H),
3.75 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ = 182.4, 161.7, 160.2, 159.9, 144.4, 143.7, 138.2,
136.5, 135.1, 134.6, 133.8, 128.1, 62.6, 62.1, 52.9, 13.9, 13.4; HRMS
(ESI) m/z: [M + H]+ calcd. for C17H17O7S2 397.0410, found 397.0424.
Diethyl 4,5-Didodecanoylthiophene-2,3-dicarboxylate: Com-
pound 16 (73 mg, Y = 41 %, Rf = 0.7 (PE/EA = 4:1)) was isolated as
1
a brown oil. H NMR (400 MHz, CDCl3) δ = 4.41–4.36 (m, 2H), 4.36–
4.30 (m, 2H), 2.81 (t, J = 7.3 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 1.79–
1.70 (m, 4H), 1.40–1.26 (m, 38H), 0.88 (t, J = 6.8 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ = 201.4, 192.1, 162.5, 160.1, 146.8, 140.0, 136.6
(2C), 62.6, 62.3, 43.4, 41.1, 31.9 (2C), 29.6 (3C), 29.5, 29.4 (2C), 29.3
(2C), 29.0 (2C), 24.2, 23.3, 22.7, 14.1, 14.0, 13.8, (4C missing); HRMS
(ESI) m/z: [M + H]+ calcd. for C34H57O6S 593.3870, found 593.3894.
2,3-Diethyl 5-Methyl 4-(Furan-2-carbonyl)thiophene-2,3,5-tri-
carboxylate: Compound 10 (91 mg, Y = 80 %, Rf = 0.3 (PE/EA =
3:1)) was isolated as a colorless oil. 1H NMR (300 MHz, CDCl3) δ =
7.62 (d, J = 1.2 Hz, 1H), 7.13 (d, J = 3.5 Hz, 1H), 6.57 (dd, J = 3.6,
1.7 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.76 (s,
3H), 1.38 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ = 177.5, 161.8, 160.3, 159.9, 152.5, 147.3, 143.4, 137.8,
Diethyl 4-Benzoyl-5-(3-oxo-3-phenylprop-1-yn-1-yl)thiophene-
2,3-dicarboxylate: Compound 17 (81 mg, Y = 59 %, Rf = 0.4 (PE/
EA = 5:1)) was isolated as a brown red oil. 1H NMR (400 MHz, CDCl3)
δ = 7.95–7.93 (m, 2H), 7.88–7.86 (m, 2H), 7.61–7.55 (m, 2H), 7.51 (t,
Eur. J. Org. Chem. 0000, 0–0
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Full Paper
J = 7.6 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 4.50 (q, J = 7.2 Hz, 2H), 4.41
(q, J = 7.1 Hz, 2H), 1.42 (t, J = 6.4 Hz, 3H), 1.39 (t, J = 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ = 186.8, 176.7, 162.8, 159.6, 149.2,
142.0, 136.3 (2C), 135.1, 134.2, 134.1, 129.9, 129.5, 128.7, 128.5,
121.2, 92.9, 82.3, 62.8, 62.7, 14.0, (1C missing); HRMS (ESI) m/z:
[M + H]+ calcd. for C26H21O6S 461.1053, found 461.1067.
13.8, 13.5; 19F NMR (376 MHz, CDCl3) δ = –76.9; HRMS (ESI) m/z:
[M + H]+ calcd. for C20H20BrF2O6S 505.0127, found 505.0146.
Diethyl 4-(4-Bromobenzoyl)-5-(1-fluoroethyl)thiophene-2,3-di-
carboxylate: Compound 25 (126 mg, Y = 92 %, Rf = 0.5 (PE/EA =
5:1)) was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3) δ =
7.69–7.56 (m, 4H), 5.90 (dq, J = 46.4, 6.4 Hz, 1H), 4.37 (q, J = 7.2 Hz,
2H), 3.96–3.92 (m, 2H), 1.70 (dd, J = 23.6, 6.4 Hz, 3H), 1.37 (t, J =
7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ =
189.8, 162.7, 160.1, 152.2 (d, J = 21.7 Hz), 137.2, 136.5 (d, J = 4.7 Hz),
135.8, 132.3 (d, J = 2.1 Hz), 131.9, 130.7, 129.0, 85.5 (d, J = 167.8 Hz),
62.2, 62.0, 23.6 (d, J = 24.7 Hz), 14.0, 13.5; 19F NMR (376 MHz, CDCl3)
δ = –157.6; HRMS (ESI) m/z: [M + H]+ calcd. for C19H19BrFO5S
457.0115, found 457.0134.
2,3-Diethyl 4,5-Dimethyl Thiophene-2,3,4,5-tetracarboxylate:
Compound 18 (42 mg, Y = 41 %, Rf = 0.2 (PE/EA = 4:1)) was isolated
1
as a colorless oil. H NMR (400 MHz, CDCl3) δ = 4.41–4.34 (m, 4H),
3.92 (s, 6H), 1.39–1.34 (m, 6H); 13C NMR (100 MHz, CDCl3) δ = 162.9,
162.3, 160.4, 159.8, 137.0, 136.9, 136.6, 135.6, 62.5, 62.3, 53.1, 53.0,
14.0, 13.9; HRMS (ESI) m/z: [M + H]+ calcd. for C14H17O8S 345.0639,
found 345.0651.
2,3-Diisopropyl 4,5-Dimethyl Thiophene-2,3,4,5-tetracarboxyl-
ate: Compound 19 (57 mg, Y = 51 %, Rf = 0.4 (PE/EA = 5:1)) was
isolated as a neon yellow oil. 1H NMR (300 MHz, CDCl3) δ = 5.27–
5.19 (m, 2H), 3.91 (s, 6H), 1.36 (d, J = 6.3 Hz, 12H); 13C NMR
(100 MHz, CDCl3) δ = 162.9, 161.8, 160.3, 159.3, 137.2, 136.8 (2C),
135.4, 70.7, 70.2, 53.1, 52.9, 21.6, 21.5; HRMS (ESI) m/z: [M + H]+
calcd. for C16H21O8S 373.0952, found 373.0967.
Diethyl
4-Benzoyl-5-((trifluoromethyl)thio)thiophene-2,3-di-
carboxylate: Compound 26 (79 mg, Y = 61 %, Rf = 0.6 (PE/EA =
5:1)) was isolated as a light yellow oil. 1H NMR (400 MHz, CDCl3)
δ = 7.77–7.75 (m, 2H), 7.64–7.60 (m, 1H), 7.47 (t, J = 7.7 Hz, 2H),
4.40 (q, J = 7.1 Hz, 2H), 4.00 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz,
3H), 1.05 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 189.4,
161.9, 159.4, 148.7, 139.5, 137.3, 136.4, 134.0, 129.5, 128.7, 127.7 (q,
J = 310.1 Hz), 126.8 (q, J = 2.5 Hz), 62.6, 62.2, 14.0, 13.4; 19F NMR
(376 MHz, CDCl3) δ = –42.8; HRMS (ESI) m/z: [M + H]+ calcd. for
C18H16F3O5S2 433.0386, found 433.0399.
Methyl 3,4,5-Tribenzoylthiophene-2-carboxylate: Compound 20
(93 mg, Y = 68 %, Rf = 0.3 (PE/EA = 6:1)) was isolated as a yellow
oil. 1H NMR (300 MHz, CDCl3) δ = 7.84 (d, J = 7.2 Hz, 2H), 7.59–7.50
(m, 3H), 7.48–7.34 (m, 6H), 7.31–7.24 (m, 2H), 7.18 (t, J = 7.7 Hz, 2H),
3.68 (s, 3H); 13C NMR (75 MHz, CDCl3) δ = 191.1, 190.2, 187.0, 160.4,
146.6, 145.6, 144.0, 137.2, 136.9, 136.7, 134.3, 133.6, 133.4, 133.2,
129.0, 128.9, 128.8, 128.4, 128.2, 52.8, (1C missing); HRMS (ESI) m/z:
[M + H]+ calcd. for C27H19O5S 455.0948, found 455.0963.
5-Ethyl 2-Methyl 3-Benzoyl-4-(trifluoromethyl)thiophene-2,5-
dicarboxylate: Compound 27 (99 mg, Y = 85 %, Rf = 0.45 (PE/EA =
5:1)) was isolated as a white solid; m.p. 120.6–122.3 °C. 1H NMR
(400 MHz, CDCl3) δ = 7.78 (d, J = 7.3 Hz, 2H), 7.63–7.58 (m, 1H),
7.47 (t, J = 7.7 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 3.73 (s, 3H), 1.41 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 190.1, 159.9, 158.9,
145.0 (q, J = 2.3 Hz), 139.7 (q, J = 2.7 Hz), 136.2, 134.0, 133.6, 131.8
(q, J = 36.6 Hz), 128.9, 128.8, 120.2 (q, J = 272.0 Hz), 63.0, 53.0, 13.9;
19F NMR (376 MHz, CDCl3) δ = –55.0; HRMS (ESI) m/z: [M + H]+
calcd. for C17H14F3O5S 387.0509, found 387.0527.
Thiophene-2,3,4,5-tetrayltetrakis(phenylmethanone):
Com-
pound 21 (82 mg, Y = 55 %, Rf = 0.2 (PE/EA = 5:1)) was isolated as
1
a wine red oil. H NMR (400 MHz, (CD3)2CO) δ = 7.81 (d, J = 7.3 Hz
4H), 7.73 (d, J = 7.3 Hz, 4H), 7.62 (t, J = 7.5 Hz, 2H), 7.52–7.47 (m,
2H), 7.43 (t, J = 7.8 Hz, 4H), 7.32 (t, J = 7.8 Hz, 4H); 13C NMR (75 MHz,
(CD3)2CO) δ = 191.2, 187.7, 146.4, 145.0, 138.3, 138.1, 134.5, 134.2,
130.0, 129.7, 129.5, 129.2; HRMS (ESI) m/z: [M + H]+ calcd. for
C32H21O4S 501.1155, found 501.1174.
Ethyl
4-Benzoyl-5-(methyl(phenyl)carbamoyl)-3-(trifluoro-
methyl)thiophene-2-carboxylate: Compound 28 (116 mg, Y =
84 %, Rf = 0.2 (PE/EA = 5:1)) was isolated as a yellow solid; m.p.
139.6–140.7 °C. 1H NMR (400 MHz, CDCl3) δ = 7.80–7.77 (m, 2H),
7.58–7.56 (m, 1H), 7.49–7.43 (m, 2H), 7.42–7.38 (m, 3H), 7.29–7.23
(m, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.31 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ = 191.0, 160.3, 159.3, 144.5, 142.4,
138.4, 137.4 (q, J = 3.0 Hz), 136.9, 133.4, 130.3 (q, J = 36.4 Hz), 130.1,
128.9, 128.5, 127.9, 127.3, 120.4 (q, J = 272.0 Hz), 62.6, 38.7, 13.7;
19F NMR (376 MHz, CDCl3) δ = –54.4; HRMS (ESI) m/z: [M + H]+
calcd. for C23H19F3NO4S 462.0981, found 462.0999.
Methyl 2,4-Dibenzoyl-5-(methyl(phenyl)carbamoyl)thiophene-
3-carboxylate: Compound 22 (77 mg, Y = 53 %, Rf = 0.1 (PE/EA =
4:1)) was isolated as a brown oil. 1H NMR (400 MHz, CDCl3) δ = 7.77
(d, J = 7.3 Hz, 2H), 7.69 (d, J = 7.3 Hz, 2H), 7.59–7.52 (m, 2H), 7.47–
7.39 (m, 4H), 7.37–7.30 (m, 3H), 7.27–7.24 (m, 2H), 3.34 (s, 3H), 3.11
(s, 3H); 13C NMR (100 MHz, CDCl3) δ = 191.5, 188.1, 161.3, 160.6,
147.2, 144.7, 142.4, 137.7, 137.0, 136.7, 133.8, 133.1, 131.8, 129.9,
129.0, 128.7, 128.6, 128.4, 127.9, 51.8, 38.5, (1C missing); HRMS (ESI)
m/z: [M + H]+ calcd. for C28H22NO5S 484.1213, found 484.1229.
Ethyl
4-Benzoyl-5-(diethoxymethyl)-3-(trifluoromethyl)thio-
phene-2-carboxylate: Compound 29 (70 mg, Y = 54 %, Rf = 0.5
(PE/EA = 5:1)) was isolated as a brown yellow oil. 1H NMR (400 MHz,
(CD3)2CO) δ = 7.86–7.84 (m, 2H), 7.71–7.67 (m, 1H), 7.56 (t, J =
7.7 Hz, 2H), 5.62 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.58–3.43 (m, 4H),
1.38 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz,
(CD3)2CO) δ = 191.2, 160.0, 148.2, 138.4 (q, J = 2.3 Hz), 137.8, 135.5
(q, J = 3.0 Hz), 134.8, 131.8 (q, J = 35.7 Hz), 130.0, 129.7, 121.9 (q,
J = 270.9 Hz), 97.6, 63.1, 62.8, 14.9, 14.3; 19F NMR (376 MHz,
(CD3)2CO) δ = –54.7; HRMS (ESI) m/z: [M + Na]+ calcd. for
C20H21F3O5SNa 453.0954, found 453.0966.
Triethyl
5-(Trifluoromethyl)thiophene-2,3,4-tricarboxylate:
Compound 23 (49 mg, Y = 44 %, Rf = 0.55 (PE/EA = 6:1)) was iso-
lated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 4.40–4.27 (m,
6H), 1.34–1.27 (m, 9H); 13C NMR (100 MHz, CDCl3) δ = 163.3, 159.6,
159.3, 140.9, 138.6 (q, J = 39.1 Hz), 132.1, 132.0 (q, J = 2.5 Hz), 120.6
(q, J = 270.2 Hz), 62.6, 62.4, 62.3, 14.0, 13.9, 13.7; 19F NMR (376 MHz,
CDCl3) δ = –55.3; HRMS (ESI) m/z: [M + H]+ calcd. for C14H16F3O6S
369.0614, found 369.0626.
Triethyl 5-((4-Bromophenyl)difluoromethyl)thiophene-2,3,4-tri-
carboxylate: Compound 24 (115 mg, Y = 76 %, Rf = 0.4 (PE/EA =
5:1)) was isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 7.56
Ethyl 4,5-Dibenzoyl-3-(trifluoromethyl)thiophene-2-carboxyl-
(d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 4.45–4.34 (m, 4H), 4.09 ate: Compound 30 (107 mg, Y = 82 %, Rf = 0.45 (PE/EA = 5:1)) was
(q, J = 7.1 Hz, 2H), 1.43–1.34 (m, 6H), 1.10 (t, J = 7.1 Hz, 3H); 13C isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 7.75–7.72 (m,
NMR (100 MHz, CDCl3) δ = 163.6, 160.0, 159.6, 146.9 (t, J = 33.0 Hz), 4H), 7.60–7.53 (m, 2H), 7.44–7.39 (m, 4H), 4.44 (q, J = 7.1 Hz, 2H),
140.7, 134.7 (t, J = 27.1 Hz), 131.6, 131.4, 130.8 (t, J = 3.8 Hz), 127.5 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 190.4, 186.0,
(t, J = 5.0 Hz), 125.1, 117.8 (t, J = 240.8 Hz), 62.3, 62.2, 61.7, 14.0,
159.1, 145.0 (q, J = 2.2 Hz), 141.0, 139.3 (q, J = 2.8 Hz), 136.6, 136.5,
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133.7 (2C), 132.1 (q, J = 36.5 Hz), 129.2, 128.8, 128.6, 121.0 (q, J =
7.90 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.65–7.63 (m, 2H),
272.1 Hz), 63.1, 13.8, (1C missing); 19F NMR (376 MHz, CDCl3) δ = 7.51–7.46 (m, 2H), 7.44–7.42 (m, 1H), 3.95 (s, 3H), 3.93 (s, 3H); 13C
–54.7; HRMS (ESI) m/z: [M + H]+ calcd. for C22H16F3O4S 433.0716, NMR (100 MHz, CDCl3) δ = 187.9, 165.0, 160.5, 145.7, 139.9, 139.7,
found 433.0729.
139.5, 137.4, 135.6, 132.3, 130.0, 128.9, 128.3, 127.1 (2C), 53.0, 52.8;
HRMS (ESI) m/z: [M + H]+ calcd. for C21H17O5S 381.0791, found
381.0804.
Dimethyl 4-Benzoylthiophene-2,3-dicarboxylate: Compound 31
(74 mg, Y = 81 %, Rf = 0.3 (PE/EA = 5:1)) was isolated as a yellow
oil. 1H NMR (300 MHz, CDCl3) δ = 7.93 (s, 1H), 7.84–7.77 (m, 2H),
7.64–7.57 (m, 1H), 7.52–7.45 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ = 188.3, 165.0, 160.5, 139.8, 139.7, 137.7,
137.0, 133.0, 132.3, 129.3, 128.5, 53.0, 52.8; HRMS (ESI) m/z: [M +
Na]+ calcd. for C15H12O5SNa 327.0298, found 327.0308.
Dimethyl 4-(1-Naphthoyl)thiophene-2,3-dicarboxylate: Com-
pound 39 (78 mg, Y = 74 %, Rf = 0.2 (PE/EA = 5:1)) was isolated as
1
an orange red solid; m.p. 130.2–131.1 °C. H NMR (400 MHz, CDCl3)
δ = 8.13–8.10 (m, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.82–7.79 (m, 1H),
7.68 (s, 1H), 7.57 (dd, J = 7.1, 1.3 Hz, 1H), 7.45–7.43 (m, 2H), 7.40 (t,
J = 8.3, 1H), 3.84 (s, 3H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ =
189.6, 165.2, 160.6, 141.5, 139.5, 139.2, 135.0, 133.6, 132.2 (2C),
130.4, 128.3, 128.1, 127.6, 126.7, 125.3, 124.1, 53.1, 52.9; HRMS (ESI)
m/z: [M + H]+ calcd. for C19H15O5S 355.0635, found 355.0648.
Dimethyl
4-(4-Methoxybenzoyl)thiophene-2,3-dicarboxylate:
Compound 32 (73 mg, Y = 73 %, Rf = 0.4 (PE/EA = 2:1)) was isolated
as a white solid; m.p. 127.6–128.2 °C. 1H NMR (400 MHz, CDCl3) δ =
7.89 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.92 (s,
3H), 3.91 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 187.0,
165.0, 163.6, 160.6, 140.3, 139.8, 136.5, 132.2, 131.8, 129.6, 113.8,
55.4, 52.9, 52.8; HRMS (ESI) m/z: [M + H]+ calcd. for C16H15O6S
335.0584, found 335.0596.
Dimethyl
4-(Furan-2-carbonyl)thiophene-2,3-dicarboxylate:
Compound 40 (61 mg, Y = 69 %, Rf = 0.4 (PE/EA = 2:1)) was isolated
as a yellow solid; m.p. 104.5–105.5 °C. 1H NMR (400 MHz, CDCl3) δ =
8.59 (s, 1H), 7.69 (dd, J = 1.7, 0.8 Hz, 1H), 7.37 (dd, J = 3.7, 0.8 Hz,
1H), 6.62 (dd, J = 3.7, 1.7 Hz, 1H), 4.00 (s, 3H), 3.91 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ = 173.4, 165.3, 160.6, 152.2, 146.9, 140.1, 138.2,
137.8, 131.5, 120.0, 112.7, 53.0, 52.8; HRMS (ESI) m/z: [M + Na]+
calcd. for C13H10O6SNa 317.0090, found 317.0103.
Dimethyl
4-(4-Methylbenzoyl)thiophene-2,3-dicarboxylate:
Compound 33 (77 mg, Y = 80 %, Rf = 0.2 (PE/EA = 5:1)) was isolated
as a colorless oil. 1H NMR (300 MHz, CDCl3) δ = 7.90 (s, 1H), 7.72 (d,
J = 7.8 Hz, 2H), 7.29 (d, J = 7.5 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 2.43
(s, 3H); 13C NMR (75 MHz, CDCl3) δ = 188.0, 165.0, 160.6, 144.0,
140.1, 139.8, 137.2, 134.4, 132.2, 129.6, 129.2, 53.0, 52.8, 21.6; HRMS
(ESI) m/z: [M + H]+ calcd. for C16H15O5S 319.0635, found 319.0647.
Dimethyl 4-(Thiophene-2-carbonyl)thiophene-2,3-dicarboxyl-
ate: Compound 41 (66 mg, Y = 71 %, Rf = 0.4 (PE/EA = 5:1)) was
1
isolated as a brown oil. H NMR (400 MHz, CDCl3) δ = 8.04 (s, 1H),
7.68–7.64 (m, 2H), 7.09 (dd, J = 5.2, 4.0 Hz, 1H), 3.87 (s, 3H), 3.83 (s,
3H); 13C NMR (100 MHz, CDCl3) δ = 179.6, 164.8, 160.5, 142.5, 139.7,
139.5, 136.0, 134.7, 134.2, 132.4, 128.1, 53.0, 52.8; HRMS (ESI) m/z:
[M + H]+ calcd. for C13H11O5S2 311.0042, found 311.0052.
Dimethyl 4-(4-Nitrobenzoyl)thiophene-2,3-dicarboxylate: Com-
pound 34 (65 mg, Y = 62 %, Rf = 0.5 (PE/EA = 2:1)) was isolated as
a yellow solid; m.p. 154.5–155.2 °C. 1H NMR (300 MHz, CDCl3) δ =
8.35 (d, J = 8.3 Hz, 2H), 7.97 (d, J = 7.5 Hz, 2H), 7.96 (s, 1H), 3.94 (s,
3H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 186.6, 164.6, 160.3,
150.1, 142.0, 139.4, 138.8, 138.4, 133.0, 130.2, 123.7, 53.1, 53.0; HRMS
(ESI) m/z: [M + Na]+ calcd. for C15H11NO7SNa 372.0148, found
372.0158.
Dimethyl 4-Dodecanoylthiophene-2,3-dicarboxylate: Com-
pound 42 (61 mg, Y = 53 %, Rf = 0.4 (PE/EA = 5:1)) was isolated as
1
a brown oil. H NMR (300 MHz, CDCl3) δ = 8.13 (s, 1H), 4.00 (s, 3H),
3.89 (s, 3H), 2.84 (t, J = 7.4 Hz, 2H), 1.71–1.67 (m, 2H), 1.40–1.15 (m,
16H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 193.2,
165.1, 160.2, 140.4, 138.8, 136.2, 132.1, 62.0, 61.9, 39.3, 31.8, 29.5,
29.3 (2C), 29.2, 29.1, 23.8, 22.6, 14.0, 13.8; HRMS (ESI) m/z: [M + H]+
calcd. for C20H31O5S 383.1887, found 383.1901.
Dimethyl
4-(4-Fluorobenzoyl)thiophene-2,3-dicarboxylate:
Compound 35 (74 mg, Y = 76 %, Rf = 0.15 (PE/EA = 5:1)) was iso-
lated as a brown yellow solid; m.p. 105.2–106.3 °C. 1H NMR
(400 MHz, CDCl3) δ = 7.92 (s, 1H), 7.88–7.84 (m, 2H), 7.18 (t, J =
8.6 Hz, 2H), 3.94 (s, 3H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ =
186.9, 165.6 (d, J = 253.7 Hz), 164.9, 160.5, 139.7, 139.6, 137.2, 133.3
(d, J = 3.0 Hz), 132.6, 132.1 (d, J = 9.2 Hz), 115.8 (d, J = 21.8 Hz),
53.0, 52.9; 19F NMR (376 MHz, CDCl3) δ = –104.7; HRMS (ESI) m/z:
[M + Na]+ calcd. for C15H11FO5SNa 345.0203, found 345.0214.
2,3-Dimethyl 4-(Naphthalen-2-ylmethyl) Thiophene-2,3,4-tri-
carboxylate: Compound 43 (29 mg, Y = 25 %, Rf = 0.25 (PE/EA =
5:1)) was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3) δ =
8.28 (s, 1H), 7.88–7.84 (m, 4H), 7.52–7.47 (m, 3H), 5.44 (s, 2H), 3.88
(s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 165.2, 160.6 (2C),
139.5, 138.2, 133.2, 133.1, 132.4, 131.8, 131.6, 128.5, 128.0, 127.7
(2C), 126.4 (2C), 126.0, 67.5, 53.0, 52.8; HRMS (ESI) m/z: [M + Na]+
calcd. for C20H16O6SNa 407.0560, found 407.0573.
Dimethyl 4-(2,6-Dichlorobenzoyl)thiophene-2,3-dicarboxylate:
Compound 36 (60 mg, Y = 53 %, Rf = 0.1 (PE/EA = 4:1)) was isolated
as a brown oil. 1H NMR (300 MHz, CDCl3) δ = 7.80 (s, 1H), 7.39–7.35
(m, 3H), 3.99 (s, 3H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ = 184.5,
164.8, 160.4, 140.0, 139.0, 138.5, 136.7, 132.6, 132.0, 131.3, 128.2,
53.2, 52.9; HRMS (ESI) m/z: [M + H]+ calcd. for C15H11Cl2O5S
372.9699, found 372.9715.
Diethyl 4-Benzoylthiophene-2,3-dicarboxylate: Compound 44
(81 mg, Y = 81 %, Rf = 0.45 (PE/EA = 4:1)) was isolated as a yellow
oil. 1H NMR (400 MHz, CDCl3) δ = 7.91 (s, 1H), 7.81 (d, J = 6.8 Hz,
2H), 7.59 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 4.42–4.35 (m,
4H), 1.37 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ = 188.4,
164.5, 160.2, 139.9, 139.7, 137.5, 137.2, 132.9, 129.3, 128.5, 62.1, 62.0,
14.0, 13.8, (1C missing); HRMS (ESI) m/z: [M + H]+ calcd. for
C17H17O5S 333.0791, found 333.0804.
Diethyl 4-(2-Bromobenzoyl)thiophene-2,3-dicarboxylate: Com-
pound 37 (73 mg, Y = 63 %, Rf = 0.4 (PE/EA = 2:1) was isolated as
1
a yellow oil). H NMR (300 MHz, CDCl3) δ = 7.77 (s, 1H), 7.64 (d, J =
7.4 Hz, 1H), 7.42–7.36 (m, 3H), 3.97 (s, 3H), 3.91 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ = 187.8, 165.0, 160.5, 140.2, 139.5, 139.4, 138.8,
133.4, 131.9, 129.1, 127.3, 119.5, 53.2, 52.9, (1C missing); HRMS (ESI)
m/z: [M + H]+ calcd. for C15H12BrO5S 382.9583, found 382.9598.
Thiophene-2,3,4-triyltris(phenylmethanone): Compound 45
(56 mg, Y = 47 %, Rf = 0.15 (PE/EA = 5:1)) was isolated as a brown
1
red oil. H NMR (400 MHz, (CD3)2CO) δ = 8.45 (s, 1H), 7.90–7.86 (m,
2H), 7.80–7.72 (m, 4H), 7.69–7.63 (m, 1H), 7.63–7.58 (m, 1H), 7.55–
7.49 (m, 3H), 7.47–7.42 (m, 2H), 7.40–7.36 (m, 2H); 13C NMR
(100 MHz, (CD3)2CO) δ = 192.0, 189.5, 187.9, 147.5, 142.8, 141.9,
138.7, 138.6, 138.1, 134.0 (2C), 133.7, 130.4, 129.9, 129.6, 129.5,
Dimethyl 4-([1,1′-Biphenyl]-4-carbonyl)thiophene-2,3-dicarbox-
ylate: Compound 38 (98 mg, Y = 86 %, Rf = 0.2 (PE/EA = 4:1)) was
isolated as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 7.96 (s, 1H),
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129.4, 129.2, (1C missing); HRMS (ESI) m/z: [M + H]+ calcd. for
C25H17O3S 397.0893, found 397.0910.
Characterization Data of Substrates S2–3, S5, S7–9, S12, S20,
and S21: Methyl 4-(4-Bromophenyl)-4-oxobut-2 ynoate. Com-
pound S2 (Rf = 0.55 (PE/EA = 6:1)) was isolated as a white solid;
Ethyl
4-Benzoyl-3-(trifluoromethyl)thiophene-2-carboxylate:
1
m.p. 39.5–40.4 °C. H NMR (300 MHz, CDCl3) δ = 7.92 (d, J = 8.4 Hz,
Compound 46 (71 mg, Y = 72 %, Rf = 0.5 (PE/EA = 4:1)) was isolated
as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 7.84–7.79 (m, 2H),
7.65–7.59 (m, 2H), 7.48 (t, J = 7.8 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H),
1.41 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ = 190.1, 159.7,
141.3 (q, J = 2.2 Hz), 136.8 (q, J = 3.0 Hz), 136.5, 134.0, 131.6 (q, J =
36.5 Hz), 131.0, 129.8, 128.7, 120.8 (q, J = 271.4 Hz), 62.6, 13.9; 19F
NMR (376 MHz, CDCl3) δ = –55.6; HRMS (ESI) m/z: [M + H]+ calcd.
for C15H18F3O3S 329.0454, found 329.0467.
2H), 7.62 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ=174.8,152.3,134.2,132.2,130.9,130.7,80.3,79.4,53.4;HRMS(ESI)m/z:
[M + H]+ calcd. for C11H8BrO3 266.9651, found 266.9664.
Methyl 4-Oxo-4-(p-tolyl)but-2-ynoate: Compound S3 (Rf = 0.5
(PE/EA = 6:1)) was isolated as a white solid; m.p. 46.0–47.5 °C. 1H
NMR (300 MHz, CDCl3) δ = 7.99 (d, J = 8.1 Hz, 2H), 7.30 (d, J =
7.8 Hz, 2H), 3.89 (s, 3H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ =
175.4, 152.6, 146.5, 133.2, 129.7, 129.5, 80.1, 79.6, 53.3, 21.8; HRMS
(ESI) m/z: [M + H]+ calcd. for C12H11O3 203.0703, found 203.0711.
Ethyl
4-Phenyl-3-(trifluoromethyl)thieno[2,3-d]pyridazine-2-
carboxylate: Compound 47 (17 mg, Y = 81 % for 2 steps, Rf = 0.2
(PE/EA = 2:1)) was isolated as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ = 9.69 (s, 1H), 7.66–7.57 (m, 2H), 7.57–7.47 (m, 3H), 4.49
(q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ = 160.5, 157.9, 144.2, 143.3 (q, J = 3.6 Hz), 139.0, 137.9 (q, J =
2.9 Hz), 130.7, 129.5, 128.8, 128.2, 126.4 (q, J = 37.2 Hz), 120.2 (q,
J = 271.6 Hz), 63.8, 13.8; 19F NMR (376 MHz, CDCl3) δ = –52.8; HRMS
Methyl 4-(4-Nitrophenyl)-4-oxobut-2-ynoate: Compound S5 (Rf =
0.5 (PE/EA = 6:1)) was isolated as a white solid; m.p. 68.8–69.6 °C.
1H NMR (400 MHz, CDCl3) δ = 8.34 (d, J = 8.9 Hz, 2H), 8.26 (d, J =
8.8 Hz, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 174.3, 152.2,
151.4, 139.4, 130.7, 124.1, 81.6, 78.9, 53.7; HRMS (ESI) m/z: [M + H]+
calcd. for C11H8NO5 234.0397, found 234.0401.
(ESI) m/z: [M + H]+ calcd. for C16H12F3N2O2S 353.0566, found Methyl 4-(Furan-2-yl)-4-oxobut-2-ynoate: Compound S7 (Rf = 0.4
1
353.0583.
(PE/EA = 6:1)) was isolated as an orange red oil. H NMR (300 MHz,
CDCl3) δ = 7.76 (dd, J = 1.7, 0.7 Hz, 1H), 7.47 (dd, J = 3.9, 0.9 Hz,
1H), 6.66 (dd, J = 3.7, 1.7 Hz, 1H), 3.89 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ = 162.0, 152.3, 152.0, 149.2, 122.8, 113.1, 78.9, 78.4, 53.3;
HRMS (ESI) m/z: [M + H]+ calcd. for C9H7O4 179.0339, found
179.0346.
Ethyl 4,7-Diphenyl-3-(trifluoromethyl)thieno[2,3-d]pyridazine-
2-carboxylate: Compound 48 (25 mg, Y = 96 %, Rf = 0.4 (PE/EA =
4:1)) was isolated as a yellow oil. 1H NMR (300 MHz, CDCl3) δ =
8.10–8.06 (m, 2H), 7.69–7.65 (m, 2H), 7.64–7.60 (m, 3H), 7.56–7.51
(m, 3H), 4.47 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ = 160.6, 156.3, 154.0, 143.7 (q, J = 3.8 Hz), 138.2,
138.0 (q, J = 2.0 Hz), 135.4, 131.7, 130.8, 129.4, 129.3, 129.0, 128.5,
128.2, 126.9 (q, J = 37.2 Hz), 120.1 (q, J = 271.6 Hz), 63.7, 13.9; 19F
NMR (376 MHz, CDCl3) δ = –52.5; HRMS (ESI) m/z: [M + H]+ calcd.
for C22H16F3N2O2S 429.0879, found 429.0891.
tert-Butyl 4-Oxo-4-phenylbut-2-ynoate: Compound S8 (Rf = 0.6
(PE/EA = 6:1)) was isolated as a yellow oil. 1H NMR (300 MHz, CDCl3)
δ = 8.14–8.07 (m, 2H), 7.71–7.61 (m, 1H), 7.56–7.45 (m, 2H), 1.56 (s,
9H); 13C NMR (75 MHz, CDCl3) δ = 176.3, 151.0, 135.5, 134.9, 129.6,
128.7, 85.3, 81.7, 77.8, 27.8; HRMS (ESI) m/z: [M + H]+ calcd. for
C14H15O3 231.1016, found 231.1024.
Ethyl 4,6-Diphenyl-3-(trifluoromethyl)thieno[3,4-b]thiophene-
2-carboxylate: Compound 49 (32 mg, Y = 94 %, Rf = 0.75 (PE/EA =
4:1)) was isolated as a yellow solid; m.p. 113–114 °C. 1H NMR
(400 MHz, CDCl3) δ = 7.66–7.64 (m, 2H), 7.50–7.41 (m, 7H), 7.34 (t,
J = 7.5 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ = 161.5, 142.0 (q, J = 4.0 Hz), 137.9, 135.6,
133.4, 132.4, 129.9, 129.6, 129.3, 128.6, 128.1, 127.8, 125.8, 122.0 (q,
J = 37.2 Hz), 121.0 (q, J = 270.8 Hz), 62.8, 13.9, (1C missing); 19F
N-Methyl-4-oxo-N,4-diphenylbut-2-ynamide: Compound S9 (Rf =
0.15 (PE/EA = 6:1)) was isolated as a yellow solid. 1H NMR (400 MHz,
CDCl3) δ = 7.71–7.67 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.51–7.34 (m,
7H), 3.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 176.2, 152.0, 141.8,
135.6, 134.6, 129.6, 129.4, 128.6, 128.5, 127.2, 84.9, 82.1, 36.6; HRMS
(ESI) m/z: [M + H]+ calcd. for C17H14NO2 246.1019, found 246.1030.
Hexacos-13-yne-12,15-dione: Compound S12 (Rf = 0.7 (PE/EA =
NMR (376 MHz, CDCl3) δ = –54.7; HRMS (ESI) m/z: [M + H]+ calcd. 30:1)) was isolated as a colorless liquid. 1H NMR (400 MHz, CDCl3)
for C22H16F3O2S2 433.0538, found 433.0553.
δ = 2.57 (t, J = 7.4 Hz, 4H), 1.73–1.54 (m, 4H), 1.33–1.12 (m, 32H),
0.82 (t, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ = 186.2, 84.1,
45.1, 31.8, 29.5 (2C), 29.3, 29.2 (2C), 28.8, 23.4, 22.6, 14.0; HRMS (ESI)
m/z: [M + H]+ calcd. for C26H47O2 391.3571, found 391.3563.
Ethyl 4-Benzoyl-5-formyl-3-(trifluoromethyl)thiophene-2-carb-
oxylate: Compound 50 (52 mg, Y = 90 %, Rf = 0.45 (PE/EA = 4:1))
was isolated as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 9.68
(s, 1H), 7.82–7.80 (m, 2H), 7.70–7.66 (m, 1H), 7.54–7.50 (m, 2H), 4.47
(q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ = 189.3, 181.2, 158.9, 146.2 (q, J = 2.3 Hz), 143.0, 141.7 (q, J =
2.9 Hz), 136.3, 134.9, 132.1 (q, J = 36.6 Hz), 129.6, 129.1, 120.2 (q,
J = 272.0 Hz), 63.3, 13.9; 19F NMR (376 MHz, CDCl3) δ = –54.9; HRMS
(ESI) m/z: [M + Na]+ calcd. for C16H11F3O4SNa 379.0222, found
379.0239.
1-(2,6-Dichlorophenyl)prop-2-yn-1-one: Compound S20 (Rf = 0.5
(PE/EA = 6:1)) was isolated as a yellow oil. 1H NMR (300 MHz, CDCl3)
δ = 7.36–7.31 (m, 3H), 3.56 (s, 1H); 13C NMR (100 MHz, CDCl3) δ =
176.2, 137.2, 131.4, 131.2, 128.3, 82.9, 81.0; HRMS (ESI) m/z: [M +
H]+ calcd. for C9H5Cl2O 198.9712, found 198.9720.
Tetradec-1-yn-3-one: Compound S21 (Rf = 0.7 (PE/EA = 6:1)) was
1
isolated as a colorless liquid. H NMR (300 MHz, CDCl3) δ = 3.21 (s,
1H), 2.58 (t, J = 7.4 Hz, 2H), 1.73–1.59 (m, 2H), 1.36–1.19 (m, 16H),
0.88 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 187.3, 81.3,
78.2, 45.3, 31.8, 29.5, 29.3, 29.2 (2C), 28.8, 23.6, 22.6, 14.0, (1C miss-
ing); HRMS (ESI) m/z: [M + Na]+ calcd. for C14H24ONa 231.1719,
found 231.1728.
3-Benzoyl-5-(hydroxymethyl)-4-(trifluoromethyl)thiophene-2-car-
baldehyde: 51 (16 mg, Y = 47 % for 2 steps, Rf = 0.1 (PE/EA = 4:1))
was isolated as a faint yellow oil. 1H NMR (400 MHz, CDCl3) δ = 9.57
(s, 1H), 7.82 (d, J = 7.7 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.51 (t, J =
7.7 Hz, 2H), 5.09 (s, 2H), 3.26 (s, 1H); 13C NMR (100 MHz, CDCl3) δ =
190.7, 181.1, 159.8 (q, J = 3.0 Hz), 146.0 (q, J = 2.3 Hz), 139.2, 136.5,
134.9, 129.8, 129.0, 124.5 (q, J = 35.5 Hz), 121.9 (q, J = 271.2 Hz),
59.4 (q, J = 3.0 Hz); 19F NMR (376 MHz, CDCl3) δ = –55.5; HRMS (ESI)
m/z: [M + H]+ calcd. for C14H10F3O3S 315.0297, found 315.0311.
Characterization Data of Pyridinium 1,4-Zwitterionic Thiolates
1b, 1d–h: 3-(4-(Dimethylamino)pyridin-1-ium-1-yl)-1,4-dimeth-
oxy-1,4-dioxobut-2-ene-2-thiolate. Compound 1b was isolated as
1
a yellow solid, m.p. > 200 °C. H NMR (400 MHz, (CD3)2SO) δ = 7.95
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CCDC 1887126 (for 27), and 1887127 (for 31) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
a) J.-P. Bégué, D. Bonnet-Delpon, A. Perez-Luna, Bioorganic and Medicinal
Chemistry of Fluorine; Wiley-VCH: Hoboken, 2008; b) I. Ojima, (Ed.)
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(d, J = 7.2 Hz, 2H), 6.96 (d, J = 7.6 Hz, 2H), 3.66 (s, 3H), 3.51 (s, 3H),
3.20 (s, 6H); 13C NMR (100 MHz, (CD3)2SO) δ = 177.9, 169.6, 161.5,
155.9, 145.6, 122.7, 107.2, 51.8, 51.3, 39.9; HRMS (ESI) m/z: [M + H]+
calcd. for C13H17N2O4S 297.0904, found 297.0900.
[2]
1,4-Dimethoxy-3-(4-methoxypyridin-1-ium-1-yl)-1,4-dioxobut-
2-ene-2-thiolate: Compound 1d was isolated as a yellow solid, m.p.
161–162 °C. 1H NMR (400 MHz, (CD3)2SO) δ = 8.62 (d, J = 7.6 Hz,
2H), 7.57 (d, J = 7.6 Hz, 2H), 4.12 (s, 3H), 3.70 (s, 3H), 3.54 (s, 3H);
13C NMR (100 MHz, (CD3)2SO) δ = 178.1, 170.8, 169.3, 160.7, 150.0,
123.6, 113.1, 58.1, 52.0, 51.5; HRMS (ESI) m/z: [M + H]+ calcd. for
[3]
[4]
[5]
C12H14NO5S 284.0587, found 284.0584.
1,4-Diethoxy-3-(4-methoxypyridin-1-ium-1-yl)-1,4-dioxobut-2-
ene-2-thiolate: Compound 1e was isolated as a yellow solid, m.p.
144–145 °C. 1H NMR (400 MHz, (CD3)2SO) δ = 8.62 (d, J = 6.8 Hz,
2H), 7.56 (d, J = 7.2 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 4.12 (s, 3H),
4.03 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1.10 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, (CD3)2SO) δ = 177.9, 170.6, 168.7, 160.3,
150.1, 123.8, 113.0, 60.6, 60.0, 58.1, 14.3, 14.0; HRMS (ESI) m/z: [M +
H]+ calcd. for C14H18NO5S 312.0900, found 312.0897.
3-(4-Methoxypyridin-1-ium-1-yl)-1,4-dioxo-1,4-diphenylbut-2-
ene-2-thiolate: Compound 1f was isolated as a yellow solid, m.p.
175–176 °C. 1H NMR (400 MHz, (CD3)2SO) δ = 8.92 (d, J = 7.2 Hz,
2H), 7.98–7.86 (m, 2H), 7.59–7.50 (m, 3H), 7.44 (t, J = 7.2 Hz, 2H),
7.31–7.25 (m, 1H), 7.25–7.20 (m, 2H), 7.20–7.12 (m, 2H), 4.07 (s, 3H);
13C NMR (100 MHz, (CD3)2SO) δ = 191.2, 191.1, 181.6, 170.6, 150.2,
139.1, 135.8, 135.4, 132.0, 130.1, 129.1, 128.0, 128.0, 127.2, 112.9,
58.1; HRMS (ESI) m/z: [M + H]+ calcd. for C22H18NO3S 376.1002,
found 376.1000.
4-Methoxy-3-(4-methoxypyridin-1-ium-1-yl)-1,4-dioxo-1-phen-
ylbut-2-ene-2-thiolate: Compound 1g is a yellow solid, m.p. 169–
170 °C. 1H NMR (400 MHz, (CD3)2SO) δ = 8.83 (d, J = 3.6 Hz, 2H),
8.00–7.92 (m, 2H), 7.66–7.60 (m, 2H), 7.58–7.52 (m, 1H), 7.50–7.44
(m, 2H), 4.14 (s, 3H), 3.39 (s, 3H); 13C NMR (100 MHz, (CD3)2SO) δ =
191.0, 185.9, 170.7, 160.8, 150.1, 135.6, 132.2, 129.2, 128.2, 123.9,
113.0, 58.1, 51.10; HRMS (ESI) m/z: [M + H]+ calcd. for C17H16NO4S
330.0795, found 330.0791.
1-Ethoxy-4,4,4-trifluoro-3-(4-methoxypyridin-1-ium-1-yl)-1-
oxobut-2-ene-2-thiolate: Compound 1h was isolated as a yellow
solid, m.p. 121–122 °C. 1H NMR (400 MHz, (CD3)2SO) δ = 8.70 (d, J =
7.2 Hz, 2H), 7.63 (d, J = 7.2 Hz, 2H), 4.20–4.10 (m, 5H), 1.22 (t, J =
7.2 Hz, 2H); 13C NMR (100 MHz, (CD3)2SO) δ = 171.8, 168.6, 167.5,
150.8, 122.6 (q, J = 267.3 Hz), 116.8 (q, J = 35.8 Hz), 114.1, 60.9,
58.4, 14.0; HRMS (ESI) m/z: [M + H]+ calcd. for C12H13F3NO3S
308.0563, found 308.0560.
[6]
[7]
[8]
[9]
Acknowledgments
[10]
We thank NSFC (21971092, 21901014, 21602029, 21472072, and
21672017), Program for Changjiang Scholars and Innovative Re-
search Team in University (PCSIRT: IRT_15R28), and FRFCU
(lzujbky-2019-50, lzujbky-2017-90) for financial support. We
thank Dr. Hanwei Hu for assistance in polishing the manuscript.
[11]
Keywords: Thiophenes · Sulfur-containing synthons ·
Cascade cyclization reactions · Activated alkynes ·
Pyridinium 1,4-zwitterionic thiolates
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Received: February 5, 2020
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Sulfur Chemistry
B. Cheng,* X. Duan, Y. Li,
X. Zhang, H. Li, F. Wu, Y. Li,
T. Wang,* H. Zhai* .......................... 1–12
Development and Application of
Pyridinium 1,4-Zwitterionic Thiol-
ates: Synthesis of Polysubstituted
Thiophenes
Pyridinium 1,4-zwitterionic thiolates as affording a library of polysubstituted
a class of sulfur-containing synthons thiophenes with excellent regioselec-
were applied to a [3+2] cascade cycli- tivities, especially those bearing multi-
zation reaction with activated alkynes, farious fluorine-containing groups.
DOI: 10.1002/ejoc.202000165
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