Iodolactonization of 3-Alkynylthiophene-2-Carboxylic and 3-Alkynylpicolinic Acids for the Synthesis of Fused Heterocycles

Article abstract of DOI:10.1002/ejoc.202000468

The iodolactonization of 3-alkynylthiophene-2-carboxylic acids and 3-alkynylpicolinic acids has been investigated. Using I₂ as the iodine source and NaHCO₃ as the base in MeCN, the process took place smoothly to afford thienopyranone

Full text of DOI:10.1002/ejoc.202000468

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Iodolactonization of 3-Alkynylthiophene-2-Carboxylic and 3-
Alkynylpicolinic Acids for the Synthesis of Fused Heterocycles
Authors: Raffaella Mancuso, Mariangela Novello, Patrizio Russo,
Antonio Palumbo Piccionello, and Bartolo Gabriele
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000468
Link to VoR: https://doi.org/10.1002/ejoc.202000468
01/2020

10.1002/ejoc.202000468
European Journal of Organic Chemistry
FULL PAPER
Iodolactonization of 3-Alkynylthiophene-2-Carboxylic and
3-Alkynylpicolinic Acids for the Synthesis of Fused Heterocycles
Raffaella Mancuso,*[a] Mariangela Novello,[a] Patrizio Russo,[a] Antonio Palumbo Piccionello,[b] and
Bartolo Gabriele*[a]
[a]
Dr. R. Mancuso, M. Novello, P. Russo, Prof. Dr. B. Gabriele
Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical Technologies
University of Calabria
Via Pietro Bucci 12/C, 87036 Arcavacata di Rende (CS), Italy
E-mail: raffaella.mancuso@unical.it (R. M.), bartolo.gabriele@unical.it (B. G.).
URL: https://www.unical.it/portale/strutture/dipartimenti_240/ctc/didattica/homedid/docenti/ricercatori/mancusor/ (R.M.)
URL: https://www.unical.it/portale/strutture/dipartimenti_240/ctc/didattica/homedid/docenti/ordinari/gabriele/# (B.G.)
Prof. Dr. A. Palumbo Piccionello,
[b]
Department of Biological, Chemical and Pharmaceutical Science and Technology-STEBICEF
University of Palermo
Viale delle Scienze Ed.17, Palermo 90128, Italy
Supporting information for this article is given via a link at the end of the document.
Abstract: The iodolactonization of 3-alkynylthiophene-2-carboxylic
acids and 3-alkynylpicolinic acids has been investigated. Using I2 as
the iodine source and NaHCO3 as the base in MeCN, the process
protocol for the direct synthesis of important iodinated fused
heterocyclic derivatives.[3]
took
place
smoothly
to
afford
thienopyranones
and
pyranopyridinones, respectively, from 6-endo-dig cyclization. The
method also worked nicely for the transformation of 2-
(phenylethynyl)thiophene-3-carboxylic
acid
and
3-
(phenylethynyl)isonicotinic acid into 7-iodo-6-phenyl-4H-thieno[3,2-
c]pyran-4-one and 4-iodo-3-phenyl-1H-pyrano[4,3-c]pyridin-1-one,
respectively. Although with some 3-alkynylpicolinic acids the process
led to a mixture of the 6-endo-dig and 5-exo-dig products, it could be
still made selective toward the pyranopyridinone compound working
in 1-ethyl-3-methylimidazolium ethyl sulfate as the solvent. On the
other hand, the exclusive formation of the 5-exo-dig product was
observed in N-ethyl-N-methylmorpholinium dicyanamide starting
from 3-(3,3-dimethylbut-1-yn-1-yl)picolinic acid. Some representative
iodinated thienopyridinone products were successfully used as
substrates for Pd-catalyzed Suzuki and Sonogashira reactions.
Scheme 1. Iodocyclization of acetylenic substrates leading to iodine-
containing heterocycles, carried out with molecular iodine as the iodinating
agent and a base (B). Both endo- and exo-dig cyclization modes are possible.
Results and Discussion
The 3-alkynylthiophene-2-carboxylic
acids
1
and 3-
Introduction
alkynylpicolinic acids 3 used as substrates in this work were
prepared by Sonogashira coupling of the corresponding methyl
3-halothiophene-2-carboxylates and methyl 3-bromopicolinate
(commercially available) with terminal alkynes followed by
hydrolysis, as depicted in Schemes S1 and S2 (Supporting
Information) and detailed in the Experimental Section.
To assess the reactivity 3-alkynylthiophene-2-carboxylic
acids under iodocyclization conditions, we used 3-
(phenylethynyl)thiophene-2-carboxylic acid 1a as initial substrate.
The first experiment was carried out with 1.5 equiv of I2 and
NaHCO3 in MeCN at room temperature. After 8 h, analysis of the
reaction mixture evidenced a substrate conversion of 75% and
the formation of a single product, which was isolated and
identified as 4-Iodo-5-phenyl-7H-thieno[2,3-c]pyran-7-one 2a
(yield: 56%, Table 1, entry 1). Substrate conversion was
quantitative using 2 equiv of iodine and the base, either after 8 h
at rt or after 3 h at 40 °C, with a 2a yield of 65% (Table 1, entry
2) and 75% (Table 1, entry 3) respectively.
Iodocyclization of acetylenic substrates bearing a suitably placed
nucleophilic group is a powerful method for the direct synthesis
of a variety of iodine-containing heterocyclic derivatives.[1] The
process usually occurs using molecular iodine as iodinating
agent in the presence of a base to buffer the hydrogen iodide
that is formally eliminated in the process, as shown in Scheme 1.
The intermediate formation of an iodonium species is generally
accepted as the key mechanistic step, which is then followed by
either exo- or endo-cyclization (Scheme 1). The resulting
products bearing an iodovinyl moiety can be further conveniently
decorated by cross-coupling reactions to afford more complex
heterocyclic motifs.
We recently studied the iodolactonization of simple 2-
alkynylbenzoic acids to give either isobenzofuranones or
isochromenones, depending on reaction conditions.[2] Here, we
report an extension of this kind of reactivity to the use of 3-
alkynylthiophene-2-carboxylic acids
acids 3 aimed at developing a simple and convenient new
1 and 3-alkynylpicolinic
The
reaction
could
also
be
performed
1
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10.1002/ejoc.202000468
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Table 1. Synthesis of 4-Iodo-7H-thieno[2,3-c]pyran-7-ones 2 by Regioselective Iodolactonization of 3-Alkynylthiophene-2-Carboxylic Acids 1.[a]
Entry
1
T [°C]
Time [h]
8
2
Yield of 2 [%][b]
1[c]
25
56[d]
2
1a
1a
1a
1a
25
40
60
60
40
8
3
2a
2a
2a
2a
65
75
80
70
70
3
4[e]
5[f]
6
15
15
2
7
40
2
73
8
40
3
70
9
40
3
74
2
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10.1002/ejoc.202000468
European Journal of Organic Chemistry
FULL PAPER
10
40
3
91
11
40
2
61[g]
12
13
1g
25
25
3
5
2g
68[h]
73
14
15
16
25
40
40
5
5
5
65
75
96
[a] Unless otherwise noted, all reactions were carried using 2 equiv of I2 and 2 equiv of NaHCO3 in MeCN as the solvent (0.05 mmol of 1 per mL of MeCN) with a
substrate scale of 0.25 mmol. Products yields were even higher when representative experiments were carried out in a larger scale (2.2 mol of 1; see the
Experimental Section for details). [b] Isolated yield, based on starting material 1. [c] The reaction was carried out with 1.5 equiv of I2 and 1.5 equiv of NaHCO3. [d]
Substrate conversion was 75% (determined by isolation of unreacted 1a). [e] The reaction was carried out in 1-ethyl-3-methylimidazolium ethyl sulfate
(EmimEtSO4) as the solvent (0.2 mmol of 1a per mL of solvent) in the absence of NaHCO3. [f] The reaction was carried out in N-ethyl-N-methylmorpholinium
dicyanamide [Mor1,2N(CN)2] as the solvent (0.2 mmol of 1a per mL of solvent) in the absence of NaHCO3. [g] The reaction also led to the formation of 5-butyl-7H-
thieno[2,3-c]pyran-7-one 5 in 17% yield. [h] The reaction also led to the formation of 5 in 10% yield.
in the absence of NaHCO3 in a basic ionic liquid (IL) as the
solvent (such as 1-ethyl-3-methylimidazolium ethyl sulfate
(EmimEtSO4) or N-ethyl-N-methylmorpholinium dicyanamide
(Mor1,2N(CN)2), even though the substrate conversion rate was
slower, so the process was carried out at 60 °C for 15 h (Table 1,
entries 4 and 5). The regiochemical output of the process,
however, did not change, as 2a was still formed exclusively.
Considering the presence of the carboxylic group in the
substrate, it is most likely that the cyclization takes place after
substrate deprotonation by the base, as shown in Scheme 2.
Scheme 2. Proposed Mechanism for the Regioselective 6-endo-dig
Iodolactonization of 3-(Phenylethynyl)thiophene-2-carboxylic acid 1a to 4-Iodo-
5-phenyl-7H-thieno[2,3-c]pyran-7-one
2a.
3
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10.1002/ejoc.202000468
European Journal of Organic Chemistry
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Table 2. Decoration of the Thienopyridinone core of 2 by the Sonogashira[a] and Suzuki[b] Cross-couplings Reactions.
[a] Sonogashira reactions were carried out with an alkyne:2 molar ratio = 2.2 in the presence of catalytic amounts of PdCl2(PPh3)2 (10 mol%) and CuI (6 mol%) in
iPr2NH as the solvent (0.1 mmol of 2 per mL of solvent) at 70 °C for 24 h. [b] Suzuki reactions were carried out with a boronic acid:2 molar ratio = 1.2 in the
presence of catalytic amounts of Pd(PPh3)4 (1 mol%) and Cs2CO3 (1.4 equiv) in DMF as the solvent (0.035 mmol of 2 per mL of DMF) at 80 °C for 24 h.
The method was then extended to other 3-alkynylthiophene-
2-carboxylic acids, bearing different aryl and alkyl groups on the
triple bond (Table 1, entries 6-16). Substrates bearing a p-tolyl
(1b), p-methoxyphenyl (1c), or m-chlorophenyl group on the
triple bond behaved similarly to 1a and, under the same
conditions as those of entry 3, led to the corresponding
iodothienopyranones 2b-d in good yields (70-73%, respectively)
after 2-3 h reaction time (Table 1, entries 6-8). A heteroaryl grup,
such as 3-thienyl (1e), as well as an alkenyl group, like 1-
cyclohexenyl (1f), were also well tolerated, and the
corresponding iodothienopyranone products 2e and 2f were
formed in 74% and 91% yields, respectively (Table 1, entries 9
and 10). The reaction of 3-(hex-1-yn-1-yl)thiophene-2-carboxylic
acid 1g, substituted with a butyl group, was less chemoselective,
demonstrated by the results obtained with substrates 1j and 1k,
which were converted into the corresponding
iodothienopyranones in good to excellent yields (75% and 96%,
respectively, Table 1, entries 15 and 16).[4]
We also tested the reactivity of 2-(phenylethynyl)thiophene-
3-carboxylic acid 6, with the positions of the alkynyl and the
carboxylic groups inverted with respect to substrates 1. As can
be seen from Scheme 3, the idocyclization of this substrate was
also regioselective, and led to the 6-endo-dig product (7-iodo-6-
phenyl-4H-thieno[3,2-c]pyran-4-one 7) in 65% yield.
and led to
a
mixture of iodothienopyranone 2g and
thienopyranone 5 (from a simple cycloisomerization process) in
61% and 17% yields, respectively (Table 1, entry 11). A more
selective reaction toward 2g, however, could be achieved by
carrying out the process a room temperature for 3 h (yields of 2g
and 5 were 68% and 10%, respectively, Table 1, entry 12). 3-(4-
Phenylbut-1-yn-1-yl)thiophene-2-carboxylic acid 1h was slightly
less reactive, as its conversion reached 100% after 5 h at rt, but
the corresponding iodothienopyranone 2h was formed
exclusively in 73% yield (Table 1, entry 13). The method worked
nicely even with sterically hindered 3-(3,3-dimethylbut-1-yn-1-
yl)thiophene-2-carboxylic acid 1i, bering a tert-butyl group on the
triple bond, which was converted after 5 h into 5-(tert-butyl)-4-
iodo-7H-thieno[2,3-c]pyran-7-one 2i with a reasonable yield of
65% (Table 1, entry 14). The presence of a methyl group close
to the triple bond did not hinder the iodocyclization process, as
Scheme 3. Iodolactonization of 2-(Phenylethynyl)thiophene-3-carboxylic Acid
6 Leading to 7-Iodo-6-phenyl-4H-thieno[3,2-c]pyran-4-one 7.
To expand the synthetic potentiality of the newly prepared
iodothienopyranones 2, we carried out some paradigmatic
cross-coupling reactions, such as the Sonogashira and the
Suzuki reactions. The results obtained are summarized in Table
2. As can be seen from Table 2, fair to good yields of the
corresponding
products
were
obtained
with
all
iodothienopyranones tested, using different terminal alkynes or
arylboronic acids as the coupling partners.
4
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10.1002/ejoc.202000468
European Journal of Organic Chemistry
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Table 3. Iodolactonization of 3-Alkynylpicolinic Acids 3 under Different Conditions[a]
Entry
3
Conditions[a]
A
Products (Yield %)[b]
1
2
3
4
3a
3a
B
C
C
4a (59%)
4a (70%)
5
C
6
C
7
8
3d
D
C
4d (63%)
9
3e
3e
D
E
4e (40%)
21 (16%)
10
21 (58%)
[a] Conditions: A: The reaction was carried using 2 equiv of I2 and 2 equiv of NaHCO3 at 25 °C in MeCN as the solvent (0.05 mmol
of 3 per mL of MeCN) for 1 h with a substrate scale of 0.35 mmol. Products yields were even higher when representative
experiments were carried out in a larger scale (2.2 mol of 3; see the Experimental Section for details).; B: Same conditions as A,
but at 40 °C; C: Same conditions as A, but using 3 equiv of I2 and 3 equiv of NaHCO3; D: The reaction was carried out with 1.5
equiv of I2 in EmimEtSO4 as the solvent (0.2 mmol of 3 per mL of solvent) at 50 °C 3 h in the absence of NaHCO3; E: Same
conditions as D, but with Mor1,2N(CN)2 as the solvent. [b] Isolated yield, based on starting 3.
5
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10.1002/ejoc.202000468
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The iodolactonization of 3-alkynylpicolinic acids 3 was also Conclusion
studied (Table 3).[5] 3-(Phenylethynyl)picolinic acid 3a was
initially allowed to react with 2 equiv of I2 and 2 equiv of NaHCO3
at 25 °C in MeCN. Substrate conversion was quantitative
already after 1 h, with selective formation of 5-iodo-6-phenyl-8H-
pyrano[3,4-b]pyridin-8-one 4a (from 6-endo-dig cyclization) in
60% yield (formation of heavy products, that are,
chromatographically immobile materials, accounted for the
difference between 1a conversion and 4a yield) This relatively
low selectivity was probably due to the basic nature of the
pyridinic ring, which may interact with iodine.[6] This result did not
improve by rising the temperature at 40 °C (Table 3, entry 2).
However, the use of 3 equiv of both I2 and the base raised the
yield to 70% (Table 3, entry 3). Under these latter conditions,
other 3-alkynylpicolinic acids 3b and 3c (bearing a p-tolyl or a
phenethyl group on the triple bond) behaved similarly, and gave
the corresponding iodopyranopyrimidinones 4b and 4c in 66%
and 65% yields, respectively (Table 3, entries 4 and 5). On the
other hand, the reaction of 3-[(3-chlorophenyl)ethynyl]picolinic
acid 3d led to a mixture of the 6-endo-dig product [6-(3-
chlorophenyl)-5-iodo-8H-pyrano[3,4-b]pyridin-8-one, 4d] and the
In conclusion, we have reported that iodocyclization of 3-
alkynylthiophene-2-carboxylic acids
1 and 3-alkynylpicolinic
acids 3 takes place under mild reaction conditions (25-40 °C) in
MeCN as the solvent using 2-3 equiv of I2 as the iodine source
and NaHCO3 as the base. With 3-alkynylthiophene-2-carboxylic
acids, the process is completely regioselective, and affords the
6-endo-dig cyclization products (4-iodo-7H-thieno[2,3-c]pyran-7-
ones 2) in fair to excellent yields (65-96%). In a similar manner,
3-alkynylpicolinic acids 3 are selectively converted into and 5-
iodo-8H-pyrano[3,4-b]pyridin-8-ones 4 in 50-70% yields. With
some picolinic substrates, however, the reaction also leads to
not
negligible
amounts
of
the
5-exo-dig
product
[iodomethylene]furo[3,4-b]pyridin-7(5H)-one derivative], but the
process can still be made selective toward either the
pyranopyridinone or the furopyridinone product working in an
appropriate basic ionic liquid [EmimEtSO4 or Mor1,2N(CN)2] as
the solvent in the absence of NaHCO3. Some representative
iodinated thienopyridinone products were successfully used as
substrates for Pd-catalyzed cross-coupling reactions.
5-exo-dig
product
[(E)-5-[(3-
chlorophenyl)iodomethylene]furo[3,4-b]pyridin-7(5H)-one, 20] in
50% and 16% yields, respectively (Table 3, entry 6) This is
probably due to the steric effect exerted by the meta-
chlorophenyl group, which tends to make the 5-exo-dig process
Experimental Section
General Experimental Methods. Solvent and chemicals were reagent
leading to 20 competitive with the 6-endo-dig route leading to 4d. grade and were used without further purification. All reactions were
analyzed by TLC on silica gel 60 F254 and by GLC using capillary
columns with polymethylsilicone + 5% phenylsilicone as the stationary
phase. Column chromatography was performed on silica gel 60 (70-230
mesh) or neutral alumina (90-170). Evaporation refers to the removal of
solvent under reduced pressure. Melting points are uncorrected. 1H NMR
and 13CNMR spectra were recorded at 25 °C on a 300 Spectrometer in
CDCl3 and DMSO-d6 with Me4Si as internal standard. Chemical shifts ()
and coupling constants (J) are given in ppm and in Hz, respectively. IR
spectra were taken with an FT-IR spectrometer. Mass spectra were
obtained using a GC-MS apparatus at 70 eV ionization voltage (normal
resolution) and by electrospray ionization mass spectrometry (ESI-MS)
However, the process could be made regioselective toward 4d
using EmimEtSO4 as the solvent at 50 °C for 3 h in the absence
of NaHCO3, as shown in Table 3, entry 7. A similar effect of this
IL on the regiochemical output of the iodolactonization reaction
was observed with simple 2-alkynybenzoic acids, and was
confirmed by DFT calculations.[2] A mixture of regioisomeric 4e
and 21 was also obtained in MeCN starting from 3-(3,3-
dimethylbut-1-yn-1-yl)picolinic acid 3e, bearing a bulky tert-butyl
group on the triple bond (Table 3, entry 8), thus confirming the
steric effect exerted by the substituent on the triple bond on the
regiochemical output of the process. Interestingly, while a
mixture was still obtained in EmimEtSO4 (Table 3, entry 9), the
exclusive formation of the 5-exo-dig product 21 was observed in
Mor1,2N(CN)2 (58% yield, Table 3, entry 10), which is in line with
the effect of this IL on iodocyclization regioselectivity previously
observed with 2-alkynylbenzoic acids.[2]
(high resolution) with
a UHD accurate-mass Q-TOF spectrometer
equipped with a Dual AJS ESI source working in positive mode, and
were recorded in the 150–1000 m/z range. The LC-MS experimental
conditions were as follows: N2 was employed as desolvation gas at
300°C and a flow rate of 9 L/min. The nebulizer was set to 45 psig. The
Sheat gas temperature was set at 350°C and a flow of 12 L/min. A
potential of 3.5 kV was used on the capillary for positive ion mode. The
fragmentor was set to 175 V.
The synthetic versatility of the process was further
demonstrated by the reaction of 3-(phenylethynyl)isonicotinic
acid 22 (isomeric with respect to 3a) which, under the usual
conditions, was smoothly converted into 4-iodo-3-phenyl-1H-
pyrano[4,3-c]pyridin-1-one 23 in 70% yield (Scheme 4).
Preparation of Substrates. 3-Alkynylthiophene-2-carboxylic acids 1a-k,
2-(phenylethynyl)thiophene-3-carboxylic acid 6, 3-alkynylpicolinic acids
3a-e and 3-(phenylethynyl)isonicotinic acid 22 were prepared by
Sonogashira coupling of the corresponding methyl 3-halothiophene-2-
carboxylate, methyl 2-bromothiophene-3-carboxylate, methyl 3-
bromopicolinate, and methyl 3-bromoisonicotinate with terminal alkynes
to give methyl alkynylthiophene carboxylates, followed by hydrolysis
(Schemes S1 and S2, Supporting Information), as described below.
1st Step: Sonogashira Coupling of Methyl Halothiophene
Carboxylates
with
Terminal
Alkynes
to
Give
Methyl
Alkynylthiophene
Carboxylates.
Methyl
3-bromothiophene-2-
carboxylate, methyl 3-iodo-4-methylthiophene-2-carboxylate, and methyl
2-bromothiophene-3-carboxylate were commercially available. A solution
of the methyl halothiophene carboxylate (4.5 mmol; 3-bromothiophene-2-
carboxylate, 1.00 g; methyl 3-iodo-4-methylthiophene-2-carboxylate, 1.27
g; 2-bromothiophene-3-carboxylate, 1.00 g), PdCl2(PPh3)2 (325.0 mg,
0.46 mmol), CuI (54.0 mg, 0.28 mmol), and the terminal alkyne
Scheme 4. Iodolactonization of 3-(Phenylethynyl)isonicotinic acid 22 Leading
to 4-Iodo-3-phenyl-1H-pyrano[4,3-c]pyridin-1-one 23.
6
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10.1002/ejoc.202000468
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(phenylacetylene, 1.01 g; 1-ethynyl-4-methylbenzene, 1.15 g; 1-ethynyl-
4-methoxybenzene, 1.31 g; 1-chloro-3-ethynylbenzene, 1.35 g; 3-
ethynylthiophene, 1.07 g; 1-ethynylcyclohexene, 1.05 g; 1-hexyne, 0.81
g; but-3-yn-1-ylbenzene, 1.29 g; 3,3-dimethyl-1-butyne, 0.81 g) (9.91
mmol) in anhydrous diisopropylamine (45 mL) was allowed to stir under
nitrogen at 70 °C (oil bath) for 15 h. After cooling to room temperature,
AcOEt (100 mL) was added, and the mixture was washed with water (3 ×
100 mL). The organic layer was washed with a saturated solution of
NH4Cl (1x100 mL) and then water until neutral pH. After drying over
Na2SO4, the solvent was evaporated, and the residue was purified by
column chromatography on silica gel using hexane-AcOEt (9:1) as eluent.
205 (43), 177 (16), 145 (85); HRMS-ESI (m/z): [(M+H)+] cald for
C12H9O2S2+: 249.0038; found: 249.0039.
Methyl 3-(cyclohex-1-en-1-ylethynyl)thiophene-2-carboxylate. Yield: 0.84
1
g, 76% based on methyl 3-bromothiophene-2-carboxylate. Yellow oil. H
NMR (CDCl3, 300 MHz): δ = 7.41 (d, J = 5.1, 1 H), 7.09 (d, J = 5.1, 1 H),
6.35-6.26 (m, 1 H), 3.89 (s, 3 H), 2.30-2.21 (m 4 H), 2.31-2.11 (m, 2 H),
1,74-1.55 (m, 4 H); 13CNMR (CDCl3, 75 MHz): δ = 161.9, 136.7, 132.5,
132.1, 130.3, 128.1, 120.6, 97.5, 81.5, 52.1, 28.9, 25.9, 22.3, 21.5; IR
(film): ν = 2203 (w), 1724 (s), 1697 (s), 1524 (m), 1435 (m), 1384 (m),
1231 (s), 1099 (m), 1076 (m), 922 (w), 775 (m) cm−1; GC-MS (EI, 70 eV):
m/z = 246 (M+, 100), 231 (30), 203 (28), 187 (32), 171 (23), 147 (25), 115
(43); HRMS-ESI (m/z): [(M+H)+] cald for C14H15O2S+: 247.0787; found:
247.0785.
Methyl 3-(phenylethynyl)thiophene-2-carboxylate. Yield: 827.5 mg, 76%
based on methyl 3-bromothiophene-2-carboxylate. Brown solid, mp = 70-
1
72 °C. H NMR (CDCl3, 300 MHz): δ = 7.63-7.54 (m, 2 H), 7.48-7.43 (m,
1 H), 7.39-7.31 (m, 3 H), 7.22-7.17 (m, 1 H), 3.93 (s, 3 H); 13CNMR
(CDCl3, 75 MHz): δ = 161.8, 133.4, 132.1, 131.8, 130.5, 128.8, 128.4,
127.4, 122.9, 95.3, 84.0, 52.2; IR (KBr): ν = 2210 (w), 1717 (s), 1697 (s),
Methyl 3-(hex-1-yn-1-yl)thiophene-2-carboxylate. Yield: 0.91 g, 91%
based on methyl 3-bromothiophene-2-carboxylate). Yellow oil. 1H NMR
(CDCl3, 300 MHz): δ = 7.40 (d, J = 6.9, 1 H), 7.08 (d, J = 5.1, 1 H), 3.89
(s, 3 H), 2.49 (t, J = 6.9, 2 H), 1.70-1.42 (m, 4 H), 0.95 (t, J = 7.2, 3 H);
13CNMR (CDCl3, 75 MHz): δ = 162.0, 132.54, 132.50, 130.2, 128.4, 97.3,
75.2, 52.0, 30.6, 22.0, 19.5, 13.7; IR (film): ν = 2234 (w), 1724 (s), 1701
(s), 1524 (m), 1439 (m), 1377 (m), 1273 (m), 1227 (m), 1080 (m), 775
(m) cm−1; GC-MS (EI, 70 eV): m/z = 222 (M+, 10), 180 (100), 165 (30),
137 (35); HRMS-ESI (m/z): [(M+H)+] cald for C12H15O2S+: 223.0787;
found: 223.0785. The spectroscopic data agreed with those reported.[8]
1439 (m), 1238 (s), 1099 (m), 1076 (m), 772 (m), 756 (m), 691 (w) cm−1
;
GC-MS (EI, 70 eV): m/z = 242 (M+, 100), 227 (73), 211 (35), 199 (27),
171 (18), 139 (99); HRMS-ESI (m/z): [(M+H)+] cald for C14H11O2S+:
243.0463; found: 243.0467. The spectroscopic data agreed with those
reported.[7]
Methyl 3-(p-tolylethynyl)thiophene-2-carboxylate. Yield: 875.5 mg, 76%
based on methyl 3-bromothiophene-2-carboxylate. Yellow solid, mp = 72-
1
73 °C. H NMR (CDCl3, 300 MHz): δ = 7.51-7.43 (m, 3 H), 7.21-7.13 (m,
Methyl 3-(4-phenylbut-1-yn-1-yl)thiophene-2-carboxylate. Yield: 1.17 g,
96% based on methyl 3-bromothiophene-2-carboxylate. Yellow oil. 1H
NMR (CDCl3, 300 MHz): δ = 7.39 (d, J = 5.1, 1 H), 7.33-7.25 (m, 5 H),
7.04 (d, J = 5.1, 1 H), 3.87 (s, 3 H), 2.97 (t, J = 7.5, 2 H), 2.81-2.73 (m, 2
H); 13CNMR (CDCl3, 75 MHz): δ = 161.9, 140.6, 132.5, 130.3, 128.5,
128.4, 128.2, 126.3, 96.3, 75.8, 52.1, 34.9, 22.0; IR (film): ν = 2234 (w),
1717 (s), 1697 (s), 1524 (m), 1435 (m), 1269 (m), 1223 (s), 1080 (m),
775 (m), 698 (m) cm−1; GC-MS (EI, 70 eV): m/z = 270 (M+, 5), 269 (15),
238 (38), 149 (13), 91 (100)); HRMS-ESI (m/z): [(M+H)+] cald for
C16H15O2S+: 271.0787; found: 271.0788. Spectroscopic data were in
good agreement with those reported.[9]
3 H), 3.93 (s, 3 H), 2.37 (s, 3 H); 13CNMR (CDCl3, 75 MHz): δ= 161.9,
139.0, 133.0, 132.1, 131.7, 130.5, 129.2, 127.6, 119.8, 95.6, 83.4, 52.2,
21.6; IR (KBr): ν = 2210 (w), 1717 (s), 1697 (s), 1531 (m), 1435 (m),
1238 (s), 1099 (m), 1076 (m), 818 (m), 775 (m) cm−1; GC-MS (EI, 70 eV):
m/z = 256 (M+, 100), 241 (78), 225 (27), 213 (28), 197 (6), 185 (11), 169
(8), 139 (7), 112 (10), 98 (8); HRMS-ESI (m/z): [(M+H)+] cald for
C15H13O2S+: 257.0631; found: 257.0623. The spectroscopic data agreed
with those reported.[8]
Methyl 3-((4-methoxyphenyl)ethynyl)thiophene-2-carboxylate. Yield: 1.14
g, 94% based on methyl 3-bromothiophene-2-carboxylate. Light yellow
1
solid, mp = 96-98 °C. H NMR (CDCl3, 300 MHz): δ = 7.52 (d, J = 8.7, 2
Methyl 3-(3,3-dimethylbut-1-yn-1-yl)thiophene-2-carboxylate. Yield: 0.76
g, 76% based on methyl 3-bromothiophene-2-carboxylate. Yellow oil. H
1
H), 7.45 (d, J = 5.1, 1 H), 7.18 (d, J = 5.1, 1 H), 6.89 (d, J = 8.7, 2H), 3.93
(s, 3 H), 3.82 (s, 3 H); 13CNMR (CDCl3, 75 MHz): δ = 162.0, 160.0, 133.4,
132.6, 132.0, 130.4, 127.9, 115.0, 114.0, 95.6, 82.9, 55.3, 52.2; IR (KBr):
ν= 2207 (w), 1713 (s), 1697 (s), 1605 (m), 1531 (s), 1439 (m), 1298 (m),
1238 (s), 1076 (m), 1030 (m), 833 (m), 775 (m) cm−1; GC-MS (EI, 70 eV):
m/z = 272 (M+, 100), 257 (70), 241 (12), 229 (16), 201 (11), 169 (18);
HRMS-ESI (m/z): [(M+H)+] cald for C15H13O3S+: 273.0571; found:
273.0571. The spectroscopic data agreed with those reported.[8]
NMR (CDCl3, 300 MHz): δ = 7.39 (d, J = 5.1, 1 H), 7.06 (d, J = 5.1, 1 H),
3.89 (s, 3 H), 1.35 (s, 9 H); 13CNMR (CDCl3, 75 MHz): δ = 162.0, 132.8,
132.3, 130.2, 128.2, 105.0, 73.8, 51.9, 30.8, 28.3; IR (film): ν = 2222 (m),
1724 (s), 1701 (s), 1524 (m), 1439 (m), 1377 (m), 1242 (s), 1076 (m),
871 (w), 775 (m) cm−1; GC-MS (EI, 70 eV): m/z = 222 (M+, 30), 207 (100),
175 (68), 163 (94), 148 (55), 147 (60); HRMS-ESI (m/z): [(M+H)+] cald for
C12H15O2S+: 223.0787; found: 223.0787.
Methyl 3-((3-chlorophenyl)ethynyl)thiophene-2-carboxylate. Yield: 1.20 g,
97% based on methyl 3-bromothiophene-2-carboxylate. Yellow solid, mp
= 93-94 °C. 1H NMR (CDCl3, 300 MHz): δ = 7.59-7.55 (m, 1H), 7.50-7.44
(m, 2 H), 7.36-7.25 (m, 2 H), 7.23-7.18 (m, 1 H), 3.93 (s, 3 H); 13CNMR
(CDCl3, 75 MHz): δ = 161.7, 134.2, 133.8, 132.0, 131.6, 130.6, 130.0,
129.6, 129.0, 126.9, 124.6, 93.6, 85.0, 52.3; IR (KBr): ν = 1709 (s), 1593
(w), 1435 (m), 1304 (w), 1234 (m), 1076 (m), 941 (m), 772 (s) cm−1; GC-
MS (EI, 70 eV): m/z = 278 [(M+2)+, 41), 276 (M+, 100), 263 (24), 261 (62),
247 (16), 245 (40), 226 (28), 175 (15), 173 (46); HRMS-ESI (m/z):
[(M+H)+] cald for C14H10ClO2S+: 277.0084; found: 277.0083.
Methyl 4-methyl-3-(phenylethynyl)thiophene-2-carboxylate. Yield: 0.82 g,
71% based on methyl 3-Iodo-4-methylthiophene-2-carboxylate. Yellow
solid, mp = 62.2-63.5 °C.1H NMR (CDCl3, 300 MHz): δ = 7.64-7.56 (m, 2
H), 7.39-7.32 (m, 3 H), 7.16-7.12 (m, 1 H), 3.92 (s, 3 H), 2.36 (s, 3 H);
13CNMR (CDCl3, 75 MHz): δ = 162.0, 141.3, 133.0, 131.8, 128.7, 128.44,
128.38, 126.4, 123.1, 97.9, 83.6, 52.1, 15.2; IR (KBr): ν = 2210 (w), 1717
(s), 1701 (s), 1454 (m), 1373 (m), 1296 (m), 1227 (s), 1123 (m), 756 (m),
691 (w) cm−1; GC-MS (EI, 70 eV): m/z = 256 (M+, 100), 241 (78), 225
(39), 213 (22), 197 (13), 152 (25); HRMS-ESI (m/z): [(M+H)+] cald for
C15H13O2S+: 257.0631; found: 257.0633.
Methyl 3-(thiophen-3-ylethynyl)thiophene-2-carboxylate. Yield: 0.94 g,
84% based on methyl 3-bromothiophene-2-carboxylate). Yellow solid, mp
= 102-103 °C. 1H NMR (CDCl3, 300 MHz): δ = 7.63-7.59 (m, 1 H), 7.56 (d,
J = 5.1, 1 H), 7.33-7.29 (m, 1 H), 7.27-7.22 (m, 1 H), 7.19 (d, J = 5.1, 1
H), 3.92 (s, 3 H); 13CNMR (CDCl3, 75 MHz): δ = 161.8, 133.1, 132.1,
130.5, 130.0, 129.6, 127.4, 125.5, 121.9, 90.5, 83.5, 52.2; IR (KBr): ν =
2210 (vw), 1701 (s), 1539 (w), 1435 (m), 1281 (m), 1238 (m), 1076 (w),
787 (s) cm−1; GC-MS (EI, 70 eV): m/z = 248 (M+, 100), 233 (71), 217 (30),
Methyl 4-methyl-3-(4-phenylbut-1-yn-1-yl)thiophene-2-carboxylate. Yield:
1.16 g, 91% based on methyl 3-Iodo-4-methylthiophene-2-carboxylate.
1
Yellow oil. H NMR (CDCl3, 300 MHz): δ = 7.33-7.19 (m, 5 H), 7.07-7.03
(m, 1 H), 3.85 (s, 3 H), 2.98 (distorted t, J =7.2, 2 H), 2.84 (distorted t, J
=7.2, 2 H), 2.15 (s, 3 H); 13CNMR (CDCl3, 75 MHz): δ = 162.1, 141.6,
140.5, 132.3, 129.2, 128.5, 128.4, 126.3, 126.1, 98.8, 75.4, 52.0, 35.0,
22.0, 15.1; IR (film): ν = 2230 (w), 1717 (s), 1694 (m), 1454 (m), 1369 (m),
1273 (s), 1200 (s), 1146 (m), 1080 (m), 1018 (w), 779 (m), 698 (m) cm−1
GC-MS (EI, 70 eV): m/z = 284 (M+, 6), 283 (12), 252 (78), 237 (17), 225
;
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000468
European Journal of Organic Chemistry
FULL PAPER
(17), 193 (31), 169 (30), 163 (22), 91 (100); HRMS-ESI (m/z): [(M+H)+]
(CDCl3, 300 MHz): δ = 8.66 (dd, J = 4.6, 1.6, 1 H), 7.97 (dd, J = 7.9, 1.6,
1 H), 7.61-7.51 (m, 1 H), 7.51-7.40 (m, 2 H), 7.40-7.28 (m, 2 H), 4.05 (s,
3 H); 13CNMR (CDCl3, 75 MHz): δ = 164.9, 149.1, 148.3, 141.6, 134.3,
131.6, 130.0, 129.7, 129.3, 125.5, 124.2, 120.5, 95.7, 86.3, 53.0; IR
(KBr): ν = 2222 (vw), 1721 (s), 1474 (m), 1420 (m), 1304 (s), 1088 (s),
887 (m), 810 (w), 787 (w), 702 (m), 679 (m) cm−1; GC-MS (EI, 70 eV):
cald for C17H17O2S+: 285.0943; found: 285.0946.
Methyl 2-(phenylethynyl)thiophene-3-carboxylate. Yield: 0.93 g, 85%
based on methyl 2-bromothiophene-3-carboxylate. Yellow oil. 1H NMR
(CDCl3, 300 MHz): δ = 7.61-7.54 (m, 2 H), 7.44 (d, J = 5.4, 1 H), 7.40-
7.32 (m, 3 H), 7.19 (d, J = 5.4, 1 H), 3.91 (s, 3 H, OMe); 13CNMR (CDCl3,
75 MHz): δ = 162.8, 134.1, 131.7, 129.6, 129.0, 128.9, 128.4, 125.8,
122.6, 99.1, 81.8, 51.8; IR (film): ν = 2207 (w), 1713 (s), 1524 (w), 1435
(m), 1300 (m), 1242 (s), 1153 (m), 999 (w), 756 (w) cm−1; GC-MS (EI, 70
eV): m/z = 242 (M+, 93), 227 (57), 211 (30), 199 (21), 171 (13), 139
(100); HRMS-ESI (m/z): [(M+H)+] cald for C14H11O2S+: 243.0474; found:
243.0472.
m/z = 273 [(M+2)+, 35), 271 (M+, 94), 213 (100), 177 (46), 150 (30);
+
HRMS-ESI (m/z): [(M+H)+] cald for C15H11NO2
: 272.0473; found:
272.0474.
Methyl 3-(3,3-dimethylbut-1-yn-yl)picolinate. Yield: 0.90 g, 89% based on
methyl 3-bromopicolinate. Brown oil. 1H NMR (CDCl3, 300 MHz): δ =
8.57 (dd, J = 4.7, 1.7, 1 H), 7.82 (dd, J = 7.9, 1.7, 1 H), 7.37 (dd, J = 7.9,
4.7, 1 H), 4.00 (s, 3 H), 1.35 (s, 9 H); 13CNMR (CDCl3, 75 MHz): δ =
165.5, 149.8, 147.4, 141.4, 125.1, 121.2, 106.9, 75.1, 52.6, 30.6, 28.3; IR
(film): ν = 2241 (w), 1740 (s), 1450 (m), 1420 (w), 1308 (m), 1292 (m),
1196 (m), 1134 (m), 1096 (m), 810 (m) cm−1; GC-MS (EI, 70 eV): m/z =
217 (M+, 34), 202 (87), 187 (37), 186 (21), 158 (100), 142 (47), 130 (23),
115 (31); HRMS-ESI (m/z): [(M+H)+] cald for C13H16NO2+: 218.1176;
found: 218.1169.
1st Step: Sonogashira Coupling of Methyl 3-bromopicolinate and
Methyl 3-bromoisonicotinate with Terminal Alkynes to Give Methyl
3-Alkynylpicolinate and Methyl 3-(Phenylethynyl)isonicotinate.
Methyl 3-bromopicolinate and methyl 3-bromoisonicotinate were
commercially available. A solution of methyl 3-bromopicolinate (4.65
mmol; 1.00 g), or methyl 3-bromoisonicotinate (4.65 mmol; 1.00 g),
PdCl2(PPh3)2 (327.0 mg, 0.46 mmol), CuI (53.0 mg, 0.28 mmol), the
terminal alkyne (phenylacetylene, 1.05 g; 1-ethynyl-4-methylbenzene,
1.20 g; 1-hexyne, 0.84 g; but-3-yn-1-ylbenzene, 1.34 g; 1-chloro-3-
ethynylbenzene, 1.40 g; 3,3-dimethyl-1-butyne, 0.85 g) (10.3 mmol) in
anhydrous diisopropylamine (23 mL) was allowed to stir under nitrogen
for at 70 °C (oil bath) for 15 h. After cooling, AcOEt (50mL) was added,
and the mixture was washed with water (3 × 60 mL). The organic layer
was washed with a saturated solution of NH4Cl (1x80 mL) and then with
water until neutral pH. After drying over Na2SO4, the solvent was
evaporated, and the residue was purified by column chromatography on
silica gel using hexane-AcOEt (9:1) as eluent.
Methyl 3-(phenylethynyl)isonicotinate. Yield: 1.07 g, 97% based on
methyl 3-bromoisonicotinate. Brown solid, mp= 50-51 °C. 1H NMR
(CDCl3, 300 MHz): δ = 8.91 (s, br, 1 H), 8.70-8.75 (m, 1 H), 7.78 (d, J =
4.8, 1 H), 7.65-7.51 (m, 2 H), 7.45-7.30 (m, 3 H), 4.00 (s, 3 H); 13CNMR
(CDCl3, 75 MHz): δ = 165.2, 154.5, 148.5, 138.3, 131.9, 129.1, 128.5,
123.1, 122.5, 119.4, 97.4, 85.0, 52.8; IR (KBr): ν= 2218 (w), 1740 (s),
1493 (m), 1435 (m), 1396 (w), 1276 (m), 1099 (m), 964 (w), 756 (m), 671
(m) cm−1; GC-MS (EI, 70 eV): m/z = 237 (M+, 100), 222 (41), 206 (11),
194 (23), 178 (15), 166 (21), 151 (29); HRMS-ESI (m/z): [(M+H)+] cald for
C15H12NO2+: 238.0862; found: 238.0867.
Methyl 3-(phenylethynyl)picolinate. Yield: 0.97 g, 88% based on methyl
3-bromopicolinate. Brown solid, mp = 66-68 °C. 1H NMR (CDCl3, 300
MHz): δ = 8.63 (d, J = 3.7, 1 H), 7.96 (dd, J = 7.9, 1.1, 1 H), 7.64-7.55 (m,
2 H), 7.43 (dd, J = 7.9, 4.7, 1 H), 7.41-7.31 (m, 3 H), 4.04 (s, 3 H);
13CNMR (CDCl3, 75 MHz): δ = 165.0, 149.1, 148.0, 141.5, 31.8, 129.1,
128.5, 125.4, 122.5, 120.9, 97.3, 85.2, 52.9; IR (KBr): ν = 2218 (w), 1732
(s), 1493 (m), 1443 (m), 1296 (s), 1207 (m), 1134 (m), 1088 (m), 760 (m),
691 (m) cm−1; GC-MS (EI, 70 eV): m/z = 237 (M+, 87), 222 (20), 179
(100), 178 (67), 177 (29), 166 (35), 151 (55); HRMS-ESI (m/z): [(M+H)+]
cald for C15H12NO2+: 238.0862; found: 238.0872. The spectroscopic data
agreed with those reported.[10]
2nd Step: Hydrolysis of Methyl Alkynylthiophene Carboxylates to
Give Alkynylthiophene carboxylic acids 1a-1k and 6. A stirred
solution of the methyl alkynylthiophene carboxylate [2.5 mmol; methyl 3-
(phenylethynyl)thiophene-2-carboxylate,
tolylethynyl)thiophene-2-carboxylate,
610
645
mg;
mg;
methyl
methyl
3-(p-
3-((4-
methoxyphenyl)ethynyl)thiophene-2-carboxylate, 680 mg; methyl 3-((3-
chlorophenyl)ethynyl)thiophene-2-carboxylate, 693 mg; methyl 3-
(thiophen-3-ylethynyl)thiophene-2-carboxylate, 626 mg; methyl 3-
(cyclohex-1-en-1-ylethynyl)thiophene-2-carboxylate, 621 mg; methyl 3-
(hex-1-yn-1-yl)thiophene-2-carboxylate, 558 mg; methyl 3-(4-phenylbut-
1-yn-1-yl)thiophene-2-carboxylate, 670 mg; methyl 3-(3,3-dimethylbut-1-
yn-1-yl)thiophene-2-carboxylate,
555
mg;
methyl
4-methyl-3-
(phenylethynyl)thiophene-2-carboxylate, 643 mg; methyl 4-methyl-3-(4-
phenylbut-1-yn-1-yl)thiophene-2-carboxylate, 705 mg; methyl 2-
(phenylethynyl)thiophene-3-carboxylate, 608 mg] and 1 N NaOH (14.0
mL) in THF (3.0 mL) was heated at 50 °C for 15 h. After cooling to room
temperature, the mixture was washed with Et2O (3 × 15 mL), further
cooled with the aid of an ice bath, and neutralized with 1 N HCl. The
resulting mixture was extracted at room temperature with CH2Cl2 (3 × 50
mL), and the collected organic layers were dried over Na2SO4. Filtration
and evaporation of the solvent (at 20 °C, under vacuum) afforded the
crude alkynylthiophene carboxylic acids, which were further purified by
crystallization with Et2O/hexane.
Methyl 3-(p-tolylethynyl)picolinate. Yield: 1.05 g, 90% based on methyl 3-
bromopicolinate. Brown solid, mp= 79-81 °C. 1H NMR (CDCl3, 300 MHz):
δ = 8.63 (d, J = 3.4, 1 H), 7.96 (dd, J = 7.9, 1.5, 1 H), 7.52-7.38 (m, 3 H),
7.17 (d, J = 7.9, 2 H), 4.04 (s, 3 H), 2.38 (s, 3 H, Me); 13CNMR (CDCl3,
75 MHz): δ = 165.1, 149.0, 147.8, 141.4, 139.4, 131.8, 129.2, 125.4,
121.1, 119.5, 97.7, 84.7, 52.9, 21.6; IR (KBr): ν = 2218 (m), 1732 (s),
1512 (w), 1447 (m), 1296 (m), 1207 (w), 1134 (w), 1084 (m), 964 (w),
818 (s), cm−1; GC-MS (EI, 70 eV): m/z = 251 (M+, 100), 236 (30), 208
(19), 194 (15), 193 (54), 180 (22); HRMS-ESI (m/z): [(M+H)+] cald for
C16H14NO2+: 252.1019; found: 252.1025.
Methyl 3-(4-phenylbut-1-yn-yl)picolinate. Yield: 1.07 g, 87% based on
methyl 3-bromopicolinate. Brown oil. 1H NMR (CDCl3, 300 MHz): δ =
8.58 (dd, J = 4.5, 1.1, 1 H), 7.78 (dd, J = 7.9, 1.1, 1 H), 7.40-7.19 (m, 6
H), 3.98 (s, 3 H), 2.97 (m, 2 H), 2.79 (m, 2 H); 13CNMR (CDCl3, 75 MHz):
δ = 165.3, 149.3, 147.5, 141.9, 140.4, 128.5, 128.4, 126.4, 125.3, 121.3,
98.4, 76.7, 52.8, 34.7, 22.0; IR (film): ν = 2234 (w), 1732 (s), 1454 (m),
1420 (w), 1300 (s), 1204 (m), 1134 (m), 1099 (m), 702 (w) cm−1; GC-MS
(EI, 70 eV): m/z = 265 (M+, 14), 264 (41), 250 (17), 232 (29), 206 (31),
204 (34), 116 (15), 91 (100); HRMS-ESI (m/z): [(M+H)+] cald for
C17H16NO2+: 266.1176; found: 266.1174.
3-(Phenylethynyl)thiophene-2-carboxylic acid (1a). Yield: 515 mg, 90%
based on methyl 3-(phenylethynyl)thiophene-2-carboxylate. Light yellow
1
solid, mp = 146-147 °C. H NMR (DMSO-d6, 300 MHz): δ = 7.92 (d, J =
5.1, 1 H), 7.61-7.51 (m, 2 H), 7.51-7.41 (m, 3 H), 7.36 (d, J = 5.1, 1 H);
13CNMR (DMSO-d6, 75 MHz): δ= 161.8, 135.0, 132.0, 131.9, 131.3,
129.0, 128.7, 125.7, 122.3, 94.1, 84.4; IR (KBr): ν = 2210 (vw), 1744 (s),
1678 (m), 1423 (m), 1258 (w), 918 (m), 775 (m), 752 (s), 691 (m) cm−1
;
HRMS-ESI (m/z): [(M-H)-] cald for C13H7O2S-: 227.0172; found: 227.0172.
The spectroscopic data agreed with those reported.[7]
3-(p-Tolylethynyl)thiophene-2-carboxylic acid (1b). Yield: 502 mg, 83%
based on methyl 3-(p-tolylethynyl)thiophene-2-carboxylate. White solid,
Methyl 3-((3-chlorophenyl)ethynyl)picolinate. Yield: 1.07 g, 85% based on
methyl 3-bromopicolinate. Brown solid, mp= 70.2-71.0 °C. 1H NMR
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000468
European Journal of Organic Chemistry
FULL PAPER
mp = 162-164 °C. 1H NMR (CDCl3, 300 MHz): δ = 10.93 (s, br, 1 H), 7.55
(d, J = 5.1, 1 H), 7.48 (d, J = 8.0, 2 H), 7.23 (d, J = 5.1, 1 H), 7.13 (d, J =
7.8, 2 H), 2.36 (s, 3 H); 13CNMR (CDCl3, 75 MHz): δ= 167.0, 139.1, 132.5,
132.4, 132.0, 131.8, 129.2, 128.9, 119.7, 96.8, 83.3, 21.6; IR (KBr): ν=
2210 (vw), 1682 (s), 1659 (s), 1447 (m), 1423 (m), 1300 (m), 1261 (m),
1103 (w), 914 (m), 818 (m), 775 (w) cm−1; HRMS-ESI (m/z): [(M-H)-] cald
for C14H9O2S-: 241.0328; found: 241.0330.
carboxylate. White solid, mp = 120-123 °C. 1H NMR (CDCl3, 300 MHz): δ
= 11.50 (s, br, 1 H), 7.49 (d, J = 5.1, 1 H), 7.09 (d, J = 5.1, 1 H), 1.35 (s, 9
H); 13CNMR (CDCl3, 75 MHz): δ= 166.9, 132.5, 132.4, 131.7, 129.4,
106.5, 73.7, 30.6, 28.4; IR (KBr): ν= 2222 (w), 1678 (s), 1524 (w), 1427
(m), 1292 (m), 1258 (m), 872 (w), 779 (w) cm−1; HRMS-ESI (m/z): [(M-H)-
] cald for C11H11O2S-: 207.0485; found: 207.0486.
4-Methyl-3-(phenylethynyl)thiophene-2-carboxylic acid (1j). Yield: 523 mg,
86% based on methyl 4-methyl-3-(phenylethynyl)thiophene-2-carboxylate.
Yellow solid, mp = 168-170 °C. 1H NMR (DMSO-d6, 300 MHz): δ = 13.26
(s br, 1H, OH), 7.63-7.51 (m, 3 H), 7.51-7.41 (m, 3 H), 2.31 (s, 3 H);
13CNMR (DMSO-d6, 300 MHz): δ= 162.0, 140.4, 134.9, 131.2, 128.9,
128.7, 127.2, 126.5, 122.3, 96.7, 83.9, 14.8; IR (KBr): ν= 2214 (vw), 1651
3-((4-Methoxyphenyl)ethynyl)thiophene-2-carboxylic acid (1c). Yield: 475
mg, 74% based on methyl 3-((4-methoxyphenyl)ethynyl)thiophene-2-
carboxylate. White solid, mp = 175-177 °C. 1H NMR (DMSO-d6, 300
MHz): δ = 7.90 (d, J = 5.1, 1 H), 7.49 (d, J = 8.6, 2 H), 7.31 (d, J = 5.1, 1
H), 7.00 (d, J = 8.6, 2 H), 3.81 (s, 3 H); 13CNMR (DMSO-d6, 75 MHz): δ=
162.0, 159.7, 134.3, 132.9, 131.9, 131.8, 126.1, 114.4, 114.2, 94.6, 83.3,
55.2; IR (KBr): ν= 2207 (vw), 1674 (s), 1647 (s), 1450 (s), 1288 (m), 1146
(w), 1226 (m), 833 (s) cm−1; HRMS-ESI (m/z): [(M-H)-] cald for C14H9O3S-
: 257.0277; found: 257.0278.
(s), 1458 (m), 1304 (m), 1242 (w), 1034 (w), 918 (m), 756 (m) cm−1
;
HRMS-ESI (m/z): [(M+H)+] cald for C14H10 O2S+: 243.0474; found:
243.0480.
4-Methyl-3-(4-phenylbut-1-yn-1-yl)thiophene-2-carboxylic acid (1k). Yield:
585 mg, 87% based on methyl 4-methyl-3-(4-phenylbut-1-yn-1-
yl)thiophene-2-carboxylate. Yellow solid, mp = 108-110 °C. 1H NMR
(DMSO-d6, 300 MHz): δ = 7.52-7.45 (m, 1 H), 7.37-7.25 (m, 4 H), 7.25-
7.15 (m, 1 H), 2.95-2.74 (m, 4 H), 2.06 (s, 3 H); 13CNMR (DMSO-d6, 300
MHz): δ= 162.1, 141.3, 140.3, 133.6, 128.5, 128.1, 127.7, 126.9, 126.1,
98.5, 75.5, 34.1, 21.1, 14.7; IR (KBr): ν= 2230 (w), 1682 (s), 1651 (s),
1543 (w), 1458 (m), 1288 (m), 1211 (w), 1072 (w), 926 (w), 864 (w), 787
(m), 733 (m), cm−1; HRMS-ESI (m/z): [(M+H)+] cald for C16H15O2S+:
271.0787; found: 271.0792.
3-((3-Chlorophenyl)ethynyl)thiophene-2-carboxylic acid (1d). Yield: 363
mg, 55% based on methyl 3-((3-chlorophenyl)ethynyl)thiophene-2-
carboxylate. Yellow solid, mp = 150-151 °C.1H NMR (DMSO-d6, 300
MHz): 7.93 (d, J = 5.1, 1 H), 7.63-7.57 (m, 1 H), 7.57-7.45 (m, 3 H), 7.36
(d, J = 5.1, 1 H), 3.86 (s, br, 1 H); 13CNMR (DMSO-d6, 300 MHz): δ=
162.4, 136.2, 133.8, 132.54, 132.45, 131.1, 130.4, 129.6, 125.5, 124.7,
92.9, 86.1; IR (KBr): ν= 2214 (vw), 1682 (s), 1667 (s), 1520 (w), 1435 (s),
1304 (s), 1273 (s), 995 (w), 880 (w), 772 (s) cm−1; HRMS-ESI (m/z):
[(M+H)+] cald for C13H8ClO2S+: 262.9928; found: 262.9929.
3-(Thiophen-3-ylethynyl)thiophene-2-carboxylic acid (1e). Yield: 563 mg,
96% based on methyl 3-(thiophen-3-ylethynyl)thiophene-2-carboxylate.
Yellow solid, mp = 133-136 °C. 1H NMR (DMSO-d6, 300 MHz): δ = 7.94-
7.84 (m, 2 H), 7.71-7.63 (m, 1 H), 7.32 (d, J = 5.0, 1 H), 7.26 (d, J = 4.4,
1 H); 13CNMR (DMSO-d6, 75 MHz): δ= 161.9, 134.6, 132.0, 131.9, 130.2,
129.4, 127.0, 125.7, 121.1, 89.8, 83.7; IR (KBr): ν= 2210 (w), 1667 (s),
1504 (m), 1427 (m), 1296 (m), 999 (m), 845 (w), 779 (s) cm−1; HRMS-ESI
(m/z): [(M+H)+] cald for C11H7O2S2+: 234.9882; found: 234.9889.
2-(Phenylethynyl)thiophene-3-carboxylic acid (6). Yield: 560 mg, 98%
based on Methyl 2-(phenylethynyl)thiophene-3-carboxylate. Yellow solid,
mp = 122.5-125.2 °C. 1H NMR (DMSO-d6, 300 MHz): δ = 8.30 (s, 1 H),
7.66 (d, J = 5.3, 1 H), 7.61-7.51 (m, 2 H), 7.51-7.40 (m, 4 H); 13CNMR
(DMSO-d6, 75 MHz): δ= 162.9, 135.6, ,131.2, 129.3, 129.0, 128.8, 127.8,
127.4, 121.8, 98.0, 82.0; IR (KBr): ν= 2199 (vw), 1667 (s), 1528 (m),
1443 (m), 1304 (s), 1258 (m), 1165 (w), 1072 (w), 926 (s), 756 (s), 733
(s) cm−1; HRMS-ESI (m/z): [(M+H)+] cald for C13H9O2S+: 229.0318;
found: 229.0318.
3-(Cyclohex-1-en-1-ylethynyl)thiophene-2-carboxylic acid (1f). Yield: 520
mg, 90% based on methyl 3-(cyclohex-1-en-1-ylethynyl)thiophene-2-
carboxylate. Yellow solid, mp = 110-113°C. 1H NMR (CDCl3, 300 MHz): δ
= 11.38 (s, br, 1 H), 7.51 (d, J = 5.1, 1 H), 7.13 (d, J = 5.1, 1 H), 6.35-
6.25 (m, 1 H), 2.31-2.09 (m, 4 H), 1.75-1.55 (m, 4 H); 13CNMR (CDCl3,
75 MHz): δ= 166.9, 137.1, 132.4, 132.0, 131.8, 129.2, 120.6, 98.6, 81.3,
28.8, 25.9, 22.3, 21.4; IR (KBr): ν= 2203 (w), 1678 (s), 1524 (m), 1431
(m), 1288 (m), 1246 (w), 1107 (w), 981 (w), 779 (w) cm−1; HRMS-ESI
(m/z): [(M+H)+] cald for C13H11O2S+: 231.0485; found: 231.0484.
2nd Step: Hydrolysis of Methyl 3-Alkynylpicolinate and Methyl 3-
Phenylisonicotinate to Give 3-Alkynylpicolinic Acids 3a-f and of 3-
(Phenylethynyl)isonicotinic Acid 22. To a stirred solution of the methyl
3-alkynylpicolinate [4.0 mmol; methyl 3-(phenylethynyl)picolinate, 958
mg; methyl 3-(p-tolylethynyl)picolinate, 1.00 g; methyl 3-(4-phenylbut-1-
yn-yl)picolinate, 1.05 g; methyl 3-((3-chlorophenyl)ethynyl)picolinate, 1.08
g; methyl 3-(3,3-dimethylbut-1-ynyl)picolinate, 875 mg] or methyl 3-
(phenylethynyl)isonicotinate (4.0 mmol, 960 mg) in MeOH (26.5 mL) was
added a solution of KOH (3.3 N in H2O, 6 mL) at 0°C with stirring. After
stirring at 0 °C for 15 min, the mixture was allowed to warm up to room
temperature and then stirred for additional 2 h. The solution was then
cooled with the aid of an ice bath, and neutralized with 1 N HCl until
pH=3. The resulting mixture was extracted with AcOEt (3 × 50 mL), and
the collected organic layers were dried over Na2SO4. Filtration and
evaporation of the solvent (at 20 °C, under vacuum) afforded the crude
products, which were further purified by crystallization with Et2O/hexane.
3-(Hex-1-yn-1-yl)thiophene-2-carboxylic acid (1g). Yield: 260 mg, 50%
1
based on methyl 3-(hex-1-yn-1-yl)thiophene-2-carboxylate. Yellow oil. H
NMR (CDCl3, 300 MHz): δ = 11.72 (s, br, 1 H), 7.53-7.46 (m, 1 H), 7.14-
7.07 (m, 2 H), 2.49 (t, J = 6.8, 2 H), 1.73-1.44 (m, 4 H), 0.96 (t, J = 7.2, 3
H); 13CMR (CDCl3, 75 MHz): δ= 167.0, 132.8, 132.0, 131.8, 129.7, 98.6,
75.1, 30.5, 22.0, 19.5, 13.6; IR (film): ν= 2230 (vw), 1717 (s), 1624 (m),
1524 (w), 1427 (m), 1211 (w), 1099 (w), 999 (w) cm−1; HRMS-ESI (m/z):
[(M-H)-] cald for C11H11O2S-: 207.0485; found: 207.0482.
3-(Phenylethynyl)picolinic acid (3a). Yield: 850 mg, 95% based on methyl
3-(phenylethynyl)picolinate. Yellow solid, mp = 110-112 °C. 1H NMR
(DMSO-d6, 300 MHz): δ = 8.65 (dd, J = 6.0, 1.4, 1 H), 8.13 (dd, J = 7.9,
1.4, 1 H), 7.66-7.53 (m, 3 H), 7.53-7.43 (m, 3 H); 13CNMR (DMSO-d6, 75
MHz): δ = 166.4, 151.8, 148.2, 140.7, 131.3, 129.3, 128.8, 125.2, 121.8,
117.6, 95.5, 85.2; IR (KBr): ν = 2218 (w), 1748 (s), 1639 (m), 1493 (m),
1431 (m), 1072 (m), 930 (w), 841 (w), 760 (s), 691 (m) cm−1; HRMS-ESI
(m/z): [(M+H)+] cald for C14H10NO2+: 224.0706; found: 224.0703. The
spectroscopic data agreed with those reported.[10]
3-(4-Phenylbut-1-yn-1-yl)thiophene-2-carboxylic acid (1h). Yield: 560 mg,
87% based on methyl 3-(4-phenylbut-1-yn-1-yl)thiophene-2-carboxylate.
White solid, mp = 84-86 °C. 1H NMR (CDCl3, 300 MHz): δ = 11.26 (s, br,
1 H), 7.47 (d, J = 5.1, 1 H), 7.35-7.18 (m, 5 H), 7.06 (d, J = 5.1, 1 H), 2.94
(t, J = 7.3, 2 H), 2.75 (t, J = 7.3, 2 H); 13CNMR (CDCl3, 75 MHz): δ=
166.8, 140.4, 132.9, 131.8, 129.4, 129.3, 128.5, 128.4, 126.4, 97.6, 75.7,
34.7, 22.0; IR (KBr): ν= 2230 (w), 1678 (s), 1524 (m), 1427 (m), 1281 (s),
1234 (w), 779 (w), 667 (w) cm−1; HRMS-ESI (m/z): [(M-H)-] cald for
C15H11O2S-: 255.0485; found: 255.0490.
3-(p-Tolylethynyl)picolinic acid (3b). Yield: 856 mg, 90% based on Methyl
3-(p-tolylethynyl)picolinate. Brown solid, mp = 108-110 °C. 1H NMR
(DMSO-d6, 300 MHz): δ = 8.64 (s, br, 1 H), 8.16-8.04 (m, 1 H), 7.67-7.55
3-(3,3-Dimethylbut-1-yn-1-yl)thiophene-2-carboxylic acid (1i). Yield: 421
mg, 81% based on methyl 3-(3,3-dimethylbut-1-yn-1-yl)thiophene-2-
9
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10.1002/ejoc.202000468
European Journal of Organic Chemistry
FULL PAPER
(m, 1 H), 7.52-7.39 (m, 2 H), 7.35-7.20 (m, 2 H), 2.36 (s, 3 H); 13CNMR
(DMSO-d6, 75 MHz): δ = 167.0, 152.2, 148.5, 141.1, 139.7, 131.8, 129.9,
125.7, 119.3, 118.3, 96.3, 85.2, 21.5; IR (KBr): ν = 2222 (w), 1744 (s),
4-Iodo-5-phenyl-7H-thieno[2,3-c]pyran-7-one (2a). Yield: 66 mg, starting
from 57 mg of 1a (75%) (Table 1, entry 3). White solid, mp = 149-150 °C.
1H NMR (CDCl3, 300 MHz): δ = 7.87 (d, J = 5.2, 1 H), 7.76-7.68 (m, 2 H),
7.51-7.43 (m, 3 H), 7.40 (d, J = 5.2, 1 H); 13CNMR (CDCl3, 75 MHz): δ =
157.6, 156.3, 150.1, 135.7, 133.9, 130.3, 130.1, 129.9, 128.1, 121.5,
67.4; IR (KBr): ν = 1717 (s), 1493 (w), 999 (w), 899 (w), 764 (m), 691 (w)
cm−1; GC-MS (EI, 70 eV): m/z = 354 (M+, 100), 326 (32), 227 (10), 199
(49), 171 (46), 77 (56); HRMS-ESI (m/z): [(M+H)+] cald for C13H8IO2S+:
354.9284; found: 354.9276. The spectroscopic data agreed with those
reported.[11]
1636 (m), 1512 (m), 1335 (m), 1312 (s), 1204 (w), 810 (s), 687 (m) cm−1
;
+
HRMS-ESI (m/z): [(M+H)+] cald for C15H11NO2
: 238.0862; found:
238.0870.
3-(4-Phenylbut-1-yn-1-yl)picolinic acid (3c). Yield: 954 mg, 95% based on
1
methyl 3-(4-phenylbut-1-yn-yl)picolinate. Brown solid, mp = 83-84 °C. H
NMR (DMSO-d6, 300 MHz): δ = 8.52 (m, 1 H), 7.85 (m, 1 H), 7.48 (s, br,
1 H), 7.40-7.11 (m, 6 H), 2.95-2.62 (m, 4 H); 13CNMR (DMSO-d6, 75
MHz): δ = 166.9, 152.9, 147.4, 140.6, 140.3, 128.5, 128.2, 126.2, 124.7,
117.7, 96.9, 77.1, 34.0, 21.2; IR (KBr): ν = 2222 (w), 1736 (s), 1497 (m),
1450 (m), 1427 (m), 1327 (s), 1242 (w), 1103 (w), 810 (s), 748 (m), 694
(m) cm−1; HRMS-ESI (m/z): [(M+H)+] cald for C13H14NO2+: 252.1019;
found: 252.1020.
4-Iodo-5-(p-tolyl)-7H-thieno[2,3-c]pyran-7-one (2b). Yield: 64 mg, starting
from 61 mg of 1b (70%) (Table 1, entry 6). White solid, mp = 153-155 °C.
1H NMR (CDCl3, 300 MHz): δ = 7.85 (d, J = 5.2, 1 H), 7.64 (d, J = 7.9, 2
H), 7.40 (d, J = 5.1, 1 H), 7.27 (d, J = 7.9, 2 H), 2.43 (s, 3 H, Me);
13CNMR (CDCl3, 75 MHz): δ = 157.7, 156.6, 150.2, 140.7, 135.5, 131.0,
130.1, 129.8, 128.8, 121.4, 67.0, 21.5; IR (KBr): ν = 1724 (s), 1578 (w),
1504 (m), 1427 (w), 1007 (m), 903 (w), 768 (m) cm−1; GC-MS (EI, 70 eV):
m/z = 368 (M+, 100), 340 (39), 241 (12), 213 (48), 185 (24); HRMS-ESI
(m/z): [(M+H)+] cald for C14H10IO2S+: 368.9441; found: 368.9438.
3-((3-Chlorophenyl)ethynyl)picolinic acid (3d). Yield: 966 mg, 94% based
on methyl 3-((3-chlorophenyl)ethynyl)picolinate. Brown solid, mp = 120-
121 °C. 1H NMR (DMSO-d6, 300 MHz): δ = 8.71-8.62 (m, 1 H), 8.14 (d, J
= 7.33, 1 H), 7.70-7.42 (m, 5 H); 13CNMR (DMSO-d6, 75 MHz): δ =166.3,
151.8, 148.5, 140.9, 133.4, 130.8, 130.7, 130.0, 129.4, 125.3, 123.8,
117.3, 93.9, 86.7; IR (KBr): ν= 2222 (vw), 1736 (s), 1474 (m), 1335 (s),
1108 (s), 810 (m), 779 (m), 679 (s) cm−1; HRMS-ESI (m/z): [(M+H)+] cald
for C14H9ClNO2+: 258.0363; found: 258.0368.
4-Iodo-5-(4-methoxyphenyl)-7H-thieno[2,3-c]pyran-7-one (2c). Yield: 70
mg, starting from 65 mg of 1c (73%) (Table 1, entry 7). White solid, mp =
1
166-167 °C. H NMR (CDCl3, 300 MHz): δ = 7.85 (d, J = 5.2, 1 H), 7.71
(d, J = 8.8, 2 H), 7.39 (d, J = 5.2, 1 H), 6.97 (d, J = 8.8, 2 H), 3.87 (s, 3
H); 13CNMR (CDCl3, 75 MHz): δ = 161.0, 157.8, 156.3, 150.4, 135.5,
131.5, 130.1, 126.2, 121.2, 113.5, 66.6, 55.4; IR (KBr): ν = 1717 (s),
1504 (m), 1258 (m), 1177 (w), 829 (m), 764 (m) cm−1; GC-MS (EI, 70
eV): m/z = 384 (M+, 100), 356 (38), 341 (10), 313 (18), 257 (10), 229
(32); HRMS-ESI (m/z): [(M+H)+] cald for C14H10IO3S+: 384.9317; found:
384.9385.
3-(3,3-Dimethylbut-1-yn-1-yl)picolinic acid (3e). Yield: 750 mg, 92%
based on methyl 3-(3,3-dimethylbut-1-yn-yl)picolinate. Yellow solid, mp =
97-99 °C. 1H NMR (DMSO-d6, 300 MHz): δ = 8.53 (d, J = 3.4, 1 H), 7.88
(d, J = 6.9, 1 H), 7.56-7.42 (m, 1 H), 1.29 (s, 9 H); 13CNMR (DMSO-d6, 75
MHz): δ = 166.7, 152.6, 147.4, 140.2, 124.8, 117.8, 105.1, 74.9, 30.2,
27.8; IR (KBr): ν = 2253 (w), 1697 (s), 1450 (m), 1381 (w), 1273 (m),
1196 (m), 1142 (m), 926 (m), 810 (s) cm−1; HRMS-ESI (m/z): [(M+H)+]
cald for C12H14NO2+: 204.1019; found: 204.1015.
5-(3-Chlorophenyl)-4-Iodo-7H-thieno[2,3-c]pyran-7-one (2d). Yield: 68
mg, starting from 66 mg of 1d (70%) (Table 1, entry 8). White solid, mp =
181-182 °C. 1H NMR (DMSO-d6, 300 MHz): δ = 8.41-8.35 (m, 1 H), 7.82-
7.76 (m, 1 H), 7.72-7.65 (m, 1 H), 7.65-7.54 (m, 2 H), 7.49-7.43 (m, 1 H);
13CNMR (DMSO-d6, 75 MHz): δ = 156.7, 154.0, 150.0, 138.1, 135.9,
132.7, 130.2, 130.0, 129.8, 129.4, 128.5, 121.0, 69.9; IR (KBr): ν = 1713
(s), 1574 (m), 1080 (w), 1011 (m), 918 (m), 764 (m) cm−1; GC-MS (EI, 70
eV): m/z = 390 [(M+2)+, 38], 388 (M+, 100), 360 (25), 325 (47), 261 (13),
233 (31), 205 (36); HRMS-ESI (m/z): [(M+H)+] cald for C13H7ClIO2S+:
388.8894; found: 388.8910.
3-(Phenylethynyl)isonicotinic acid (22). Yield: 848 mg, 95% based on
1
methyl 3-(phenylethynyl)isonicotinate. Brown solid, mp = 120-123 °C. H
NMR (DMSO-d6, 300 MHz): δ = 8.93 (s, br, 1 H), 8.79-8.65 (m, 1 H),
7.90-7.78 (m, 1 H), 7.71-7.35 (m, 5 H); 13CNMR (DMSO-d6, 75 MHz): δ =
165.9, 153.6, 149.2, 140.1, 131.4, 129.3, 128.8, 122.8, 121.9, 117.6,
96.0, 85.4; IR (KBr): ν= 2222 (w), 1736 (s), 1489 (w), 1281 (s), 1219 (s),
1065 (m), 795 (m), 718 (m) cm−1; HRMS-ESI (m/z): [(M+H)+] cald for
C14H10NO2+: 224.0706; found: 224.0710.
4-Iodo-5-(thiophen-3-yl)-7H-thieno[2,3-c]pyran-7-one (2e). Yield: 67 mg,
starting from 59 mg of 1e (74%) (Table 1, entry 9). White solid, mp =127-
128 °C. 1H NMR (CDCl3, 300 MHz): δ = 8.08 (dd, J = 3.0, 1.3, 1 H), 7.84
(d, J = 5.2, 1 H), 7.68 (distorted dd, J = 5.0, 1.3, 1 H), 7.43-7.33 (m, 2 H);
13CNMR (CDCl3, 75 MHz): δ = 157.2, 151.9, 150.3, 135.5, 134.1, 130.3,
129.2, 128.3, 125.4, 121.2, 66.2; IR (KBr): ν = 1721 (s), 1574 (m), 1501
(w), 1076 (w), 999 (m), 768 (m) cm−1; GC-MS (EI, 70 eV): m/z = 360 (M+,
100), 332 (29), 233 (12), 205 (57), 177 (43); HRMS-ESI (m/z): [(M+H)+]
cald for C11H6IO2S2+: 360.8848; found: 360.8841.
Preparation of Ionic Liquids. 1-Ethyl-3-methylimidazolium ethyl sulfate
(EmimEtSO4),
and
N-ethyl-N-methylmorpholinium
dicyanamide
[Mor1,2N(CN)2] were prepared according to literature procedures.[2]
General Procedure for the Iodolactonization of 3-Alkynylthiophene-
2-Carboxylic Acids 1a-k and 2-(Phenylethynyl)thiophene-3-
carboxylic Acid 6 in MeCN for the Synthesis of 4-Iodo-7H-thieno[2,3-
c]pyran-7-ones 2a-k and 7-Iodo-6-phenyl-4H-thieno[3,2-c]pyran-4-
one 7, Respectively (Table 1 and Scheme 3). To a solution of 1 (0.25
mmol) (1a, 57 mg; 1b, 61 mg; 1c, 65 mg; 1d, 66 mg; 1e, 59 mg; 1f, 58.0
mg; 1g, 52 mg; 1h, 64 mg; 1i, 52 mg; 1j, 61 mg; 1k, 68 mg) or 6 (0.25
mmol, 56 mg) in MeCN (5 mL) were added NaHCO3 (42 mg, 0.5 mmol)
and I2 (127 mg, 0.5 mmol) in this order under nitrogen. The mixture was
allowed to stir at 40 °C for 2 h (1b,c) or 3h (1a, 1d-f, 6) or at 25°C for 3h
(1g) or 5 h(1h-k). Saturated aqueous Na2S2O3 (7 mL) was then added,
and the mixture was allowed to stir for 10 min. The phases were
separated, and the aqueous phase was extracted with Et2O (3 × 10 mL).
The collected organic layers were dried over Na2SO4. After filtration and
evaporation of the solvent, products 2a−k and 7 were purified by column
chromatography on silica gel using 99:1 hexane−AcOEt as the eluent.
5-(Cyclohex-1-en-1-yl)-4-Iodo-7H-thieno[2,3-c]pyran-7-one (2f). Yield: 81
mg, starting from 58 mg of 1f (91%) (Table 1, entry 10). Yellow solid, mp
= 103-104 °C. 1H NMR (CDCl3, 300 MHz): δ = 7.83 (d, J = 5.2, 1 H), 7.32
(d, J = 5.2, 1 H), 6.27-6.19 (m, 1 H), 2.38-2.28 (m, 2 H), 2.28-2.17 (m, 2
H), 1.83-1.64 (m, 4 H); 13CNMR (CDCl3, 75 MHz): δ = 158.8, 157.9,
150.1, 135.5, 135.4, 132.5, 130.0, 121.0, 66.0, 26.5, 25.1, 22.2, 21.5; IR
(KBr): ν = 1728 (s), 1574 (m), 1427 (m), 1034 (m), 995 (w), 772 (m) cm−1
;
GC-MS (EI, 70 eV): m/z = 358 (M+, 100), 329 (16), 304 (32), 277 (6), 231
(32), 203 (36); HRMS-ESI (m/z): [(M+H)+] cald for C13H12IO2S+:
358.9597; found: 358.9583.
5-Butyl-4-Iodo-7H-thieno[2,3-c]pyran-7-one (2g). Yield: 57 mg, starting
1
from 52 mg of 1g (68%) (Table 1, entry 12). Yellow oil. H NMR (CDCl3,
300 MHz): δ = 7.82 (d, J = 5.2, 1 H), 7.26 (d, J = 5.2, 1 H), 2.87 (t, J = 7.7,
2 H), 1.78-1.64 (m, 2 H), 1.51-1.38 (m, 2 H), 0.96 (t, J = 7.3, 3 H);
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000468
European Journal of Organic Chemistry
FULL PAPER
13CNMR (CDCl3, 75 MHz): δ = 160.1, 158.2, 149.7, 135.7, 129.1, 120.7,
67.6, 35.7, 29.5, 22.2, 13.8; IR (film): ν = 1724 (s), 1585 (m), 1427 (m),
1099 (w), 999 (m), 772 (m) cm−1; GC-MS (EI, 70 eV): m/z = 334 (M+, 74),
291 (12), 263 (18), 165 (100), 137 (97); HRMS-ESI (m/z): [(M+H)+] cald
for C11H12IO2S+: 339.9597; found: 334.9627. The spectroscopic data
agreed with those reported.[11]
(100), 95 (28); HRMS-ESI (m/z): [(M+H)+] cald for C11H13O2S+: 209.0631;
found: 209.0624. The spectroscopic data agreed with those reported.[11]
Typical Procedure for the Iodolactonization of 3-Alkynylthiophene-
2-Carboxylic Acids 1 in MeCN in larger scale. To a solution of 1 (2.2
mmol; 1a, 502 mg; 1b, 533 mg; 1e, 515 mg) in MeCN (44 mL) were
added NaHCO3 (370 mg, 4.4 mmol) and I2 (1.12 g, 4.4 mmol) in this
order under nitrogen. The mixture was allowed to stir at 40 °C for 2 h (1b)
or 3 h (1a and 1e). Saturated aqueous Na2S2O3 (50 mL) was then added,
and the mixture was allowed to stir for 10 min. The phases were
separated, and the aqueous phase was extracted with Et2O (3 × 80 mL).
The collected organic layers were dried over Na2SO4. After filtration and
4-Iodo-5-phenethyl-7H-thieno[2,3-c]pyran-7-one (2h). Yield: 70 mg,
starting from 64 mg of 1h (73%) (Table 1, entry 13). Yellow solid, mp =
82-84 °C. 1H NMR (CDCl3, 300 MHz): δ = 7.82 (d, J = 5.2, 1 H), 7.33-
7.17 (m, 6 H), 3.19-3.10 (m, 2 H), 3.07-2.98 (m, 2 H); 13CNMR (CDCl3,
75 MHz): δ = 158.6, 157.9, 149.5, 139.8, 135.7, 129.1, 128.6, 128.4,
126.5, 120.9, 68.2, 38.0, 33.5; IR (KBr): ν = 1726 (s), 1589 (m), 1426 (m),
1099 (w), 769 (m), 699 (w) cm−1; GC-MS (EI, 70 eV): m/z = 382 (M+, 13),
291 (3), 255 (10), 227 (3), 136 (5), 91 (100); HRMS-ESI (m/z): [(M+H)+]
cald for C15H12IO2S+: 382.9597; found: 382.9577.
evaporation of the solvent, products
2 were purified by column
chromatography on silica gel using 99:1 hexane−AcOEt as the eluent to
give 4-iodo-5-phenyl-7H-thieno[2,3-c]pyran-7-one (2a; 723 mg, 93%); 4-
iodo-5-(p-tolyl)-7H-thieno[2,3-c]pyran-7-one (2b; 730 mg, 90%); 4-iodo-5-
(thiophen-3-yl)-7H-thieno[2,3-c]pyran-7-one (2e; 704 mg, 89%).
5-(tert-Butyl)-4-Iodo-7H-thieno[2,3-c]pyran-7-one (2i). Yield: 54 mg,
starting from 52 mg of 1i (65%) (Table 1, entry 14). Yellow solid, mp =
50-51 °C. H NMR (CDCl3, 300 MHz): δ = 7.80 (d, J = 5.2, 1 H), 7.43 (d,
J = 5.2, 1 H), 1.58 (s, 9 H); 13CNMR (CDCl3, 75 MHz): δ = 163.8, 157.4,
151.5, 134.7, 130.4, 120.5, 64.6, 38.7, 29.0; IR (KBr): ν = 1728 (s), 1551
(m), 1504 (w), 1427 (m), 1092 (m), 1042 (m), 1003 (m), 937 (w), 845 (w),
768 (m) cm−1; GC-MS (EI, 70 eV): m/z = 334 (M+, 100), 319 (25), 291
(18), 277 (38), 249 (19), 207 (58), 192 (16), 165 (56), 164 (57); HRMS-
ESI (m/z): [(M+H)+] cald for C11H12IO2S+: 334.9597; found: 334.9589.
General Procedure for the Iodolactonization of 3-Alkynylpicolinic
Acids 3a-e and of 3-(Phenylethynyl)isonicotinic acid 22 in MeCN for
the Synthesis of 5-iodo-8H-pyrano[3,4-b]pyridin-8-ones 4a-e and of
4-Iodo-3-phenyl-1H-pyrano[4,3-c]pyridin-1-one 23, Respectively
(Table 3 and Scheme 4). To a solution of 3 (0.35 mmol) (3a, 78 mg; 3b,
83 mg; 3c, 88 mg; 3d, 90 mg; 3e, 72 mg) or 22 (0.35 mmol, 79 mg) in
MeCN (7 mL) were added NaHCO3 (88 mg, 1.05 mmol) and I2 (267 mg,
1.05 mmol) in this order under nitrogen. The mixture was allowed to stir
at 25 °C for 1 h. Saturated aqueous Na2S2O3 (10 mL) was then added,
and the mixture was allowed to stir for 10 min. The phases were
separated, and the aqueous phase was extracted with Et2O (3 × 15 mL).
The collected organic layers were dried over Na2SO4. After filtration and
evaporation of the solvent, products 4a−e and 23 were purified by
column chromatography on silica gel using 99:1 hexane−AcOEt as the
eluent.
1
4-Iodo-3-methyl-5-phenyl-7H-thieno[2,3-c]pyran-7-one (2j). Yield: 69 mg,
starting from 61 mg of 1j (75%) (Table 1, entry 15). White solid, mp =
163-164 °C. 1H NMR (CDCl3, 300 MHz): δ = 7.64-7.57 (m, 2 H), 7.56-
7.52 (m, 1 H), 7.50-7.44 (m, 3 H), 2.67 (s, 3 H); 13CNMR (CDCl3, 75
MHz): δ= 158.0, 156.4, 144.5, 137.2, 135.3, 134.7, 130.1, 130.0, 128.2,
124.9, 66.3, 19.4; IR (KBr): ν = 1713 (s), 1443 (w), 1381 (w), 1072 (m),
1003 (w), 764 (m), 694 (s) cm−1; GC-MS (EI, 70 eV): m/z = 368 (M+, 100),
340 (39), 241 (12), 213 (41), 185 (25), 184 (21); HRMS-ESI (m/z):
[(M+H)+] cald for C14H10IO2S+: 368.9441; found: 368.9436.
5-Iodo-6-phenyl-8H-pyrano[3,4-b]pyridin-8-one (4a). Yield: 86 mg,
starting from 78 mg of 3a (70%) (Table 3, entry 3). Yellow solid, mp =
1
204-206 °C. H NMR (CDCl3, 300 MHz): δ = 8.57 (d, J = 3.1, 1 H), 8.26
(d, J = 6.0, 1 H), 7.81-7.66 (m, 3 H), 7.56-7.41 (m, 3 H); 13CNMR (CDCl3,
75 MHz): δ = 159.2, 155.7, 151.5, 139.8, 136.9, 135.9, 134.2, 130.6,
129.9, 129.6, 128.2, 73.8; IR (KBr): ν = 1740 (s), 1269 (w), 1180 (w),
1072 (m), 945 (m), 806 (w), 756 (w), 702 (m) cm−1; GC-MS (EI, 70 eV):
m/z = 349 (M+, 100), 321 (51), 222 (10), 194 (36), 166 (76), 139 (33), 105
4-Iodo-3-methyl-5-phenethyl-7H-thieno[2,3-c]pyran-7-one (2k). Yield: 95
mg, starting from 68 mg of 1k (96%) (Table 1, entry 16). Yellow solid, mp
= 84-86 °C. 1H NMR (CDCl3, 300 MHz): δ = 7.50-7.45 (m, 1 H), 7.36-7.19
(m, 5 H), 3.30-3.17 (m, 2 H), 3.08-2.97 (m, 2 H), 2.62 (s, 3 H, Me);
13CNMR (CDCl3, 75 MHz): δ = 158.4, 157.9, 144.2, 140.0, 136.6, 134.7,
128.6, 128.4, 126.5, 124.1, 66.8, 39.0, 33.4, 19.2; IR (KBr): ν = 1728 (s),
1574 (m), 1450 (m), 1389 (w), 1026 (m), 748 (m), 702 (w) cm−1; GC-MS
(EI, 70 eV): m/z = 396 (M+, 36), 305 (14), 277 (12), 269 (6), 241 (5), 150
(8), 91 (100); HRMS-ESI (m/z): [(M+H)+] cald for C16H14IO2S+: 396.9754;
found: 396.9751.
+
(31), 77 (41); HRMS-ESI (m/z): [(M+H)+] cald for C14H9INO2 : 349.9672;
found: 349.9676. The spectroscopic data agreed with those reported.[11]
5-Iodo-6-(p-tolyl)-8H-pyrano[3,4-b]pyridin-8-one (4b). Yield: 84 mg,
starting from 83 mg of 3b (66%) (Table 3, entry 4). Yellow solid, mp =
1
204-206 °C. H NMR (CDCl3, 300 MHz): δ = 8.85 (d, J = 4.0, 1 H), 8.25
(d, J = 8.2, 1 H), 7.75 (dd, J = 8.2, 4.0, 1 H), 7.63 (d, J = 7.8, 2 H), 7.28 (d,
J = 7.8, 2 H), 2.44 (s, 3 H); 13CNMR (CDCl3, 75 MHz): δ = 159.4, 155.8,
151.4, 141.0, 139.8, 136.8, 136.0, 131.4, 129.9, 129.6, 128.8, 73.4, 21.6;
IR (KBr): ν = 1751 (s), 1508 (m), 1454 (w), 1180 (w), 1069 (m), 945 (m),
810 (m), 756 (m) cm−1; GC-MS (EI, 70 eV): m/z = 363 (M+, 89), 335 (100),
236 (13), 208 (62), 180 (74), 179 (13), 152 (32); HRMS-ESI (m/z):
[(M+H)+] cald for C15H11INO2+: 363.9829; found: 363.9828.
7-Iodo-6-phenyl-4H-thieno[3,2-c]pyran-4-one (7). Yield: 58 mg, starting
from 56 mg of 6 (65%) (Scheme 3). White solid, mp = 124-126 °C. 1H
NMR (CDCl3, 300 MHz): δ = 7.88 (d, J = 5.4, 1 H), 7.79-7.72 (m, 2 H),
7.51-7.44 (m, 3 H), 7.43 (d, J = 5.4, 1 H); 13CNMR (CDCl3, 75 MHz): δ =
157.8, 155.6, 133.4, 130.5, 129.8, 128.2, 127.2, 126.0, 122.6, 63.9; IR
(KBr): ν = 1728 (s), 1562 (w), 1489 (w), 1053 (m), 976 (m), 895 (w), 772
(m), 698 (m) cm−1; GC-MS (EI, 70 eV): m/z = 354 (M+, 100), 326 (24),
227 (7), 199 (42), 171 (33), 77 (49); HRMS-ESI (m/z): [(M+H)+] cald for
C13H8IO2S+: 354.9284; found: 354.9283. The spectroscopic data agreed
with those reported.[12]
5-Iodo-6-phenethyl-8H-pyrano[3,4-b]pyridin-8-one (4c). Yield: 86 mg,
starting from 88 mg of 3c (65%) (Table 3, entry 5). Yellow solid, mp =
101-105 °C. 1H NMR (DMSO-d6, 300 MHz): δ = 8.79 (d, J = 4.2, 1 H),
8.09 (d, J = 8.2, 1 H), 7.87 (dd, J = 8.2, 4.2, 1 H), 7.35-7.14 (m, 5 H),
3.23-3.07 (m, 2 H), 3.04-2.89 (m, 2 H); 13CNMR (DMSO-d6, 75 MHz): δ =
158.4, 157.1, 150.8, 139.8, 138.4, 136.2, 135.1, 130.0, 128.4, 128.2,
126.2, 75.3, 32.4; IR (KBr): ν = 1748 (s), 1582 (m), 1454 (m), 1308 (w),
5-Butyl-7H-thieno[2,3-c]pyran-7-one (5). Yield: 5 mg, starting from 52 mg
1
of 1g (10%) (Table 1, entry 12). Yellow oil. H NMR (CDCl3, 300 MHz): δ
= 7.80 (d, J = 5.1, 1 H), 7.12 (d, J = 5.1, 1 H), 6.45 (s, 1 H), 2.56 (t, J =
7.6, 2 H), 1.69 (quint, J = 7.5, 2 H), 1.39 (hexuplet, J = 7.5, 2 H), 0.94 (t,
J = 7.3, 3 H); 13CNMR (CDCl3, 75 MHz): δ = 161.0, 159.2, 147.6, 136.5,
124.2, 122.1, 100.5, 33.2, 29.2, 22.1, 13.8; IR (film): ν = 1717 (s), 1628
(m), 1524 (w), 1439 (m), 1099 (w), 999 (m), 837 (w), 772 (m) cm−1; GC-
MS (EI, 70 eV): m/z = 208 (M+, 27), 166 (24), 151 (13), 137 (19), 124
1084 (m), 988 (w), 752 (m) cm−1; GC-MS (EI, 70 eV): m/z = 377 (M+, 10),
+
250 (5), 91 (100); HRMS-ESI (m/z): [(M+H)+] cald for C16H13INO2
:
377.9985; found: 377.9996.
11
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000468
European Journal of Organic Chemistry
FULL PAPER
6-(3-Chlorophenyl)-5-iodo-8H-pyrano[3,4-b]pyridin-8-one (4d). Yield: 67
mg, starting from 90 mg of 3d (50%) (Table 3, entry 6). Grey solid, mp =
231-233 °C. 1H NMR (DMSO-d6, 300 MHz): δ = 8.91-8.82 (m, 1 H), 8.26
(d, J = 9.0, 1 H), 8.00-7.91 (m, 1 H), 7.78 (s, br, 1 H), 7.72-7.55 (m, 3 H);
13CNMR (DMSO-d6, 75 MHz): δ = 158.2, 153.2, 151.4, 139.4, 136.8,
135.2, 132.7, 130.2, 130.1, 129.4, 128.5, 76.2; IR (KBr): ν = 1744 (s),
1586 (w), 1474 (w), 1408 (w), 1180 (m), 1072 (m), 953 (m) cm−1; GC-MS
(EI, 70 eV): m/z = 383 (M+, 100), 355 (42), 320 (13), 228 (15), 200 (60),
(24); HRMS-ESI (m/z): [(M+H)+] cald for C14H8ClINO2+: 383.9283; found:
383.9272.
Typical
procedure
for
the
Iodolactonization
of
3-[(3-
Chlorophenyl)ethynyl]picolinic Acid 3d in EmimEtSO4 for the
Synthesis of 6-(3-Chlorophenyl)-5-iodo-8H-pyrano[3,4-b]pyridin-8-
one 4d (Table 3, Entry 7). In a Schlenk flask containing EmimEtSO4 (2
mL) was added, under nitrogen, 3-((3-chlorophenyl)ethynyl)picolinic acid
3d (0.40 mmol; 103 mg). To the solution of the substrate in the IL, was
added, under nitrogen, I2 (152 mg, 0.6 mmol), and the resulting mixture
was heated with stirring at 50 °C (oil bath) for 3 h. After cooling, the
product was extracted with diethyl ether (3 mL, followed by 6 × 4 mL).
The collected ethereal phases were concentrated. After evaporation of
the solvent, product 6-(3-chlorophenyl)-5-iodo-8H-pyrano[3,4-b]pyridin-8-
one 4d was purified by column chromatography on silica gel using 95:5
hexane–AcOEt as the eluent (yield: 97 mg, 63%).
6-(tert-Butyl)-5-iodo-8H-pyrano[3,4-b]pyridin-8-one (4e). Yield: 61 mg,
starting from 72 mg of 3e (53%) (Table 3, entry 8). Brown solid, mp =
120-122 °C. 1H NMR (CDCl3, 300 MHz): δ = 8.87 (s, br, 1 H), 8.35 (d, J =
6.0, 1 H), 7.70 (s, br, 1 H), 1.63 (s, 9 H); 13CNMR (CDCl3, 75 MHz): δ =
163.3, 159.2, 151.3, 139.5, 136.62, 136.59, 129.3, 71.3, 39.2, 29.0; IR
(KBr): ν = 1755 (s), 1574 (m), 1454 (w), 1265 (w), 1076 (m), 960 (m)
Typical procedure for the Iodolactonization of 3-(3,3-Dimethylbut-1-
yn-1-yl)picolinic Acid 3e in Mor1,2N(CN)2 for the Synthesis of (E)-5-
(1-Iodo-2,2-dimethylpropylidene)furo[3,4-b]pyridin-7(5H)-one
21
cm−1; GC-MS (EI, 70 eV): m/z = 329 (M+, 83), 244 (20), 202 (72), 174
(Table 3, Entry 10). In a Schlenk flask containing Mor1,2N(CN)2 (2 mL)
was added, under nitrogen, 3-(3,3-dimethylbut-1-yn-1-yl)picolinic acid 3e
(0.40 mmol; 81 mg). To the solution of the substrate in the IL, was added,
under nitrogen, I2 (151 mg, 0.6 mmol), and the resulting mixture was
heated with stirring at 50 °C (oil bath) for 3 h. After cooling, the product
was extracted with diethyl ether (3 mL, followed by 6 × 4 mL). The
collected ethereal phases were concentrated. After evaporation of the
solvent, product (E)-5-(1-Iodo-2,2-dimethylpropylidene)furo[3,4-b]pyridin-
7(5H)-one 21 was purified by column chromatography on silica gel using
95:5 hexane–AcOEt as the eluent (yield: 76 mg, 58%).
+
(30), 160 (100); HRMS-ESI (m/z): [(M+H)+] cald for C12H13INO2
:
329.9985; found: 329.9989.
4-Iodo-3-phenyl-1H-pyrano[4,3-c]pyridin-1-one (23). Yield: 85 mg,
starting from 79 mg of 22 (70%) (Scheme 4). Brown solid, mp = 178.3-
180.1 °C. 1H NMR (CDCl3, 300 MHz): δ = 9.15 (s, br, 1 H), 8.95-8.85 (m,
1 H), 8.02-7.93 (m, 1 H), 7.25-7.63 (m, 2 H), 7.63-7.48 (m, 3 H); 13CNMR
(CDCl3, 75 MHz): δ = 160.3, 155.9, 153.7, 150.2, 135.1, 131.7, 130.8,
130.2, 128.7, 126.7, 120.6, 72.9; IR (KBr): ν = 1748 (s), 1408 (w), 1238
(m), 1076 (m), 1003 (w), 853 (w), 752 (m) cm−1; GC-MS (EI, 70 eV): m/z
= 349 (M+, 100), 321 (46), 222 (36), 194 (48), 166 (68), 139 (70), 105
General Procedure for the Sonogashira Coupling Between 4-Iodo-
7H-thieno[2,3-c]pyran-7-ones 2 and Terminal Alkynes (Table 2). A
solution of 4-iodo-7H-thieno[2,3-c]pyran-7-one (0.3 mmol; 2a, 106 mg; 2b,
110 mg; 2e, 108 mg; 2g, 100 mg; 2j, 110 mg), PdCl2(PPh3)2 (21 mg, 0.03
mmol), CuI (4 mg, 0.018 mmol), the terminal alkyne (0.66 mmol;
phenylacetylene, 68 mg; 1-ethynyl-4-methylbenzene, 77 mg; 3-
ethynylthiophene, 71 mg; 1-hexyne, 54 mg; but-3-yn-1-ylbenzene, 86
mg) in anhydrous diisopropylamine (3 mL) was allowed to stir under
nitrogen at 70 °C (oil bath) for 24 h. After cooling to room temperature,
AcOEt (8 mL) was added, and the mixture was washed with water (3 ×
10 mL). The organic layer was washed with a saturated solution of NH4Cl
(1x10 mL) and then water until pH=7. After drying over Na2SO4, the
solvent was evaporated, and the residue was purified by column
chromatography on silica gel using hexane-AcOEt (9:1) as eluent.
+
(50), 77 (84); HRMS-ESI (m/z): [(M+H)+] cald for C14H9INO2 : 349.9672;
found: 349.9695.
(E)-5-((3-chlorophenyl)iodomethylene)furo[3,4-b]pyridin-7(5H)-one (20).
Yield: 22 mg, starting from 90 mg of 3d (16%) (Table 3, entry 6). Yellow
solid, mp = 205-207 °C. 1H NMR (CDCl3, 300 MHz): δ = 9.26 (d, J = 8.2,
1 H), 8.98 (d, J = 4.4, 1 H), 7.74 (dd, J = 7.7, 4.3, 1 H), 7.54 (s, br, 1 H),
7.50-7.40 (m, 1 H), 7.40-7.30 (m, 1 H); 13CNMR (CDCl3, 75 MHz): δ =
162.9, 153.6, 144.5, 142.6, 140.7, 134.1, 133.7, 132.9, 130.1, 129.5,
128.3, 127.4, 81.1; IR (KBr): ν = 1778 (s), 1408 (w), 1107 (m), 1007 (s),
868 (w), 764 (m) cm−1; GC-MS (EI, 70 eV): m/z = 283 (M+, 15), 256 (100),
228 (25), 200 (41), 165 (21); HRMS-ESI (m/z): [(M+H)+] cald for
C14H8ClINO2+: 383.9283; found: 383.9298.
5-Phenyl-4-(phenylethynyl)-7H-thieno[2,3-c]pyran-7-one (8). Yield: 87 mg,
starting from 106 mg of 2a (88%). Yellow solid, mp = 105.8-108.0 °C. H
(E)-5-(1-Iodo-2,2-dimethylpropylidene)furo[3,4-b]pyridin-7(5H)-one (21).
Yield: 29 mg, starting from 72 mg of 3e (25%) (Table 3, entry 8). Yellow
solid, mp = 135-136 °C. H NMR (CDCl3, 300 MHz): δ = 9.41-9.26 (m, 1
H), 8.95-8.80 (m, 1 H), 7.67-7.56 (m, 1 H), 1.52 (s, 9 H); 13CNMR (CDCl3,
75 MHz): δ = 163.0, 152.6, 144.1, 141.1, 135.1, 133.8, 126.9, 106.3, 41.0,
32.4; IR (KBr): ν = 1790 (s), 1474 (m), 1404 (w), 1099 (w), 1015 (m), 818
(w) cm−1; GC-MS (EI, 70 eV): m/z = 329 (M+, 37), 273 (44), 202 (100),
187 (48), 159 (19), 130 (33); HRMS-ESI (m/z): [(M+H)+] cald for
C12H13INO2+: 329.9985; found: 329.9995.
1
1
NMR (CDCl3, 300 MHz): δ = 8.27-8.18 (m, 2 H), 7.89 (d, J = 5.1, 1 H),
7.57-5.43 (m, 6 H), 7.42-7.34 (m, 3 H); 13CNMR (CDCl3, 75 MHz): δ =
158.5, 156.9, 148.3, 136.8, 131.8, 131.3, 130.6, 128.9, 128.6, 128.4,
128.3, 125.3, 122.5, 121.9, 98.3, 96.6, 82.8; IR (KBr): ν = 2210 (vw),
1732 (s), 1489 (m), 1447 (m), 1096 (w), 999 (m), 941 (w), 756 (m), cm−1
;
GC-MS (EI, 70 eV): m/z = 328 (M+, 100), 299 (13), 271 (57), 239 (14);
HRMS-ESI (m/z): [(M+H)+] cald for C21H13O2S+: 329.0631; found:
329.0641. The spectroscopic data agreed with those reported.[13]
Typical Iodolactonization Procedure of 3-(Phenylethynyl)picolinic
5-(p-Tolyl)-4-(p-tolylethynyl)-7H-thieno[2,3-c]pyran-7-one (9). Yield: 80
mg, starting from 110 mg of 2b (75%). Yellow solid, mp = 164-166.0 °C.
1H NMR (CDCl3, 300 MHz): δ = 8.13 (d, J = 8.2, 2 H), 7.84 (d, J = 5.1, 1
H), 7.49 (d, J = 5.1, 1 H), 7.37 (distorted d, J = 8.0, 2 H), 8.27 (d, J = 8.2,
2 H), 7.16 (distorted d, J = 8.0, 2 H), 2.41 (s, 3 H), 2.37 (s, 3 H); 13CNMR
(CDCl3, 75 MHz): δ = 158.4, 157.0, 148.6, 140.9, 139.1, 136.6, 131.2,
129.3, 129.1, 129.0, 128.2, 125.3, 121.5, 119.6, 97.8, 96.9, 82.4, 21.6,
21.5; IR (KBr): ν= 2214 (vw), 1728 (s), 1504 (m), 1096 (w), 1072 (w),
1011 (m), 945 (w), 779 (m) cm−1; GC-MS (EI, 70 eV): m/z = 356 (M+,
100), 341 (28), 313 (19), 285 (17); HRMS-ESI (m/z): [(M+H)+] cald for
C23H17O2S+: 357.0944; found: 357.0964. The spectroscopic data agreed
with those reported.[13]
acid in MeCN in Larger Scale. To
a
solution of 3-
(phenylethynyl)picolinic acid 3a (2.2 mmol, 490 mg) in MeCN (44 mL)
were added NaHCO3 (6.6 mmol, 555 mg) and I2 (1.67 g, 6.6 mmol) in this
order under nitrogen. The mixture was allowed to stir at 25 °C for 1 h.
Saturated aqueous Na2S2O3 (50 mL) was then added, and the mixture
was allowed to stir for 10 min. The phases were separated, and the
aqueous phase was extracted with Et2O (3 × 80 mL). The collected
organic layers were dried over Na2SO4. After filtration and evaporation of
the solvent, product 5-iodo-6-phenyl-8H-pyrano[3,4-b]pyridin-8-one 4a
was purified by column chromatography on silica gel using 99:1
hexane−AcOEt as the eluent (yield: 576 mg, 75%).
12
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000468
European Journal of Organic Chemistry
FULL PAPER
4-(Hex-1-yn-1-yl)-5-(p-tolyl)-7H-thieno[2,3-c]pyran-7-one (10). Yield: 62
mg, starting from 110 mg of 2b (64%). Yellow solid, mp = 85-86 °C. H
(KBr): ν = 1721 (s), 1489 (m), 1443 (w), 1427 (w), 1080 (m), 1026 (m),
779 (m), 694 (m) cm−1; GC-MS (EI, 70 eV): m/z = 304 (M+, 100), 276 (21),
227 (50), 215 (10), 199 (15), 171 (19), 105 (66), 77 (59); HRMS-ESI
(m/z): [(M+H)+] cald for C19H13O2S+: 305.0631; found: 305.0626. The
spectroscopic data agreed with those reported.[14]
1
NMR (CDCl3, 300 MHz): δ = 8.09 (d, J = 7.3, 2 H), 7.82 (d, J = 4.2, 1 H),
7.10 (d, J = 4.2, 1 H), 7.25 (d, J = 7.3, 2 H), 2.49 (t, J = 6.3, 2 H), 2.41 (s,
3 H), 1.70-1.55 (m, 2 H), 1.55-1.40 (m, 2 H), 0.96 (t, J = 6.6, 3 H);
13CNMR (CDCl3, 75 MHz): δ =158.1, 157.2, 149.3, 140.6, 136.4, 129.2,
128.9, 128.1, 125.4, 121.5, 98.3, 73.9, 30.5, 22.1, 21.5, 19.5, 13.6; IR
(KBr): ν = 2226 (vw), 1732 (s), 1504 (m), 1435 (m), 1084 (m), 999 (m),
822 (w), 772 (m). cm−1; GC-MS (EI, 70 eV): m/z = 322 (M+, 100), 293
(32), 280 (65), 265 (20), 251 (40), 208 (28), 119 (44), 91 (61); HRMS-ESI
(m/z): [(M+H)+] cald for C20H19O2S+: 323.1100; found: 323.1114.
4-(Furan-3-yl)-5-phenyl-7H-thieno[2,3-c]pyran-7-one (15). Yield: 56 mg,
1
starting from 106 mg of 2a (63%). White solid, mp = 181.8-184.5 °C. H
NMR (CDCl3, 300 MHz): δ = 7.82 (distorted d, J = 5.2, 1 H), 7.55-7.41 (m,
3 H), 7.41-7.21 (m, 4 H), 7.15 (distorted d, J = 5.2, 1 H), 6.32 (s, br, 1 H);
13CNMR (CDCl3, 75 MHz): δ = 158.0, 154.1, 149.3, 143.7, 141.4, 136.5,
132.4, 129.5, 129.2, 128.1, 125.0, 122.8, 118.8, 112.0, 106.9; IR (KBr): ν
= 1713 (s), 1435 (w), 1157 (w), 1011 (m), 872 (w), 772 (m), 702 (m)
cm−1; GC-MS (EI, 70 eV): m/z = 294 (M+, 100), 266 (41), 237 (57), 208
(35), 165 (30), 105 (31), 77 (58); HRMS-ESI (m/z): [(M+H)+] cald for
C17H11O3S+: 295.0423; found: 295.0426.
5-(Thiophen-3-yl)-4-(thiophen-3-ylethynyl)-7H-thieno[2,3-c]pyran-7-one
(11). Yield: 75 mg, starting from 108 mg of 2e (74%). Yellow solid, mp
=110-112 °C. 1H NMR (CDCl3, 300 MHz): δ = 8.39-8.31 (m, 1 H), 8.00
(dd, J = 5.1, 1.2, 1 H), 7.85 (d, J = 5.1, 1 H), 7.64-7.53 (m, 1 H), 7.46 (d,
J = 5.1, 1 H), 7.43-7.32 (m, 2 H), 7.29-7.17 (m, 1 H); 13CNMR (CDCl3, 75
MHz): δ = 156.6, 154.4, 148.4, 136.7, 133.5, 129.5, 129.4, 127.8, 126.9,
126.0, 125.8, 125.2, 121.5, 121.3, 96.7, 93.2, 82.5; IR (KBr): ν = 2214
(vw), 1721 (s), 1582 (m), 1520 (m), 1080 (m), 1003 (w), 972 (w), 778 (m)
cm−1; GC-MS (EI, 70 eV): m/z = 340 (M+, 100), 311 (13), 283 (54), 251
(17); HRMS-ESI (m/z): [(M+H)+] cald for C17H9O2S3+: 340.9759; found:
340.9756.
4,5-di-p-Tolyl-7H-thieno[2,3-c]pyran-7-one (16). Yield: 60 mg, starting
from 110 mg of 2b (60%). White solid, mp =152-154 °C. 1H NMR (CDCl3,
300 MHz): δ = 7.74 (d, J = 5.1, 1 H), 7.33-7.07 (m, 6 H), 7.02 (d, J = 8.0,
2 H,), 6.95 (d, J = 5.1, 1 H), 2.40 (s, 3 H), 2.29 (s, 3 H); 13CNMR (CDCl3,
75 MHz): δ = 158.3, 153.4, 149.9, 139.3, 137.9, 136.0, 132.0, 130.1,
129.8, 129.6, 129.2, 128.7, 125.2, 122.5, 115.3, 21.3; IR (KBr): ν = 1721
(s), 1504 (m), 1427 (w), 1080 (w), 1018 (m), 826 (m), 756 (m) cm−1; GC-
MS (EI, 70 eV): m/z = 332 (M+, 100), 304 (36), 289 (8), 261 (11), 241 (34),
213 (11), 119 (50), 91 (37); HRMS-ESI (m/z): [(M+H)+] cald for
C21H17O2S+: 333.0944; found: 333.0948.
5-Butyl-4-(hex-1-yn-1-yl)-7H-thieno[2,3-c]pyran-7-one (12). Yield: 73 mg,
starting from 100 mg of 2g (84%). Yellow oil. 1H NMR (CDCl3, 300 MHz):
δ = 7.82 (d, J = 5.2, 1 H), 7.30 (d, J = 5.2, 1 H), 2.80 (t, J = 7.5, 2 H), 2.49
(t, J = 6.9, 2 H), 1.80-1.35 (m, 8 H), 1.03-0.91 (m, 6 H); 13CNMR (CDCl3,
75 MHz): δ = 164.3, 157.9, 148.3, 136.5, 124.6, 121.2, 99.5, 97.2, 72.5,
31.8, 30.8, 29.5, 22.2, 22.0, 19.3, 13.8, 13.6; IR (film): ν = 2230 (vw),
4,5-Di(thiophen-3-yl)-7H-thieno[2,3-c]pyran-7-one (17). Yield: 73 mg,
starting from 109 mg of 2e (77%). White solid, mp = 195-197 °C. 1H NMR
(CDCl3, 300 MHz): δ = 7.76 (d, J = 5.2, 1 H), 7.51 (distorted dd, J = 4.9,
2.9, 1 H), 7.43 (distorted dd, J = 2.9, 1.2, 1 H), 7.32 (distorted dd, J = 2.9,
1.2, 1 H), 7.15 (distorted dd, J = 5.2, 2.9, 1 H), 7.04 (dd, J = 5.2, 1.2, 1 H),
6.91 (d, J = 5.2, 1 H), 7.81 (dd, J = 5.2, 1.2, 1 H); 13CNMR (CDCl3, 75
MHz): δ = 157.7, 149.8, 149.7, 136.4, 134.4, 133.5, 128.8, 127.2, 126.9,
125.3, 125.0, 121.9, 109.7; IR (KBr): ν = 1713 (s), 1597 (w), 1504 (w),
1165 (w), 1011 (m), 772 (s), 648 (m) cm−1; GC-MS (EI, 70 eV): m/z = 316
(M+, 100), 288 (70), 259 (45), 227 (37), 111 (47); HRMS-ESI (m/z):
[(M+H)+] cald for C15H9O2S3+: 316.9759; found: 316.9782.
1736 (s), 1597 (m), 1520 (w), 1435 (m), 1096 (w), 995 (m), 779 (m) cm−1
;
GC-MS (EI, 70 eV): m/z = 288 (M+, 80), 259 (53), 245 (100), 203 (43),
189 (29), 161 (16), 147 (16), 115 (14), 89 (12); HRMS-ESI (m/z):
[(M+H)+] cald for C17H29O2S+: 289.1257; found: 289.1295. The
spectroscopic data agreed with those reported.[13]
3-Methyl-5-phenyl-4-(4-phenylbut-1-yn-1-yl)-7H-thieno[2,3-c]pyran-7-one
(13). Yield: 73 mg, starting from 110 mg of 2j (66%). Yellow solid, mp =
103.2-106.9 °C. 1H NMR (CDCl3, 300 MHz): δ = 8.00-7.92 (m, 2 H), 7.47-
7.33 (m, 4 H), 7.33-7.13 (m, 5 H), 2.87 (dist t, J = 7.3, 2 H), 2.71 (t, J =
7.3, 2 H), 2.51 (s, 3 H, Me); 13CNMR (CDCl3, 75 MHz): δ = 159.0, 157.5,
144.8, 140.2, 136.3, 133.2, 132.2, 130.0, 128.9, 128.5, 128.3, 127.9,
126.5, 123.6, 100.0, 97.3, 75.0, 34.2, 21.7, 16.5; IR (KBr): ν = 2220 (vw),
1728 (s), 1582 (w), 1489 (m), 1450 (m), 1396 (w), 1072 (m), 995 (m), 748
(m), 694 (m) cm−1; GC-MS (EI, 70 eV): m/z = 370 (M+, 100), 279 (97),
251 (58), 234 (7), 221 (27), 208 (25), 105 (37), 91 (22); HRMS-ESI (m/z):
[(M+H)+] cald for C24H19O2S+: 371.1100; found: 371.1126.
5-Butyl-4-phenyl-7H-thieno[2,3-c]pyran-7-one (18). Yield: 72 mg, starting
from 101 mg of 2g (85%). Yellow oil. 1H NMR (CDCl3, 300 MHz): δ =
7.72 (d, J = 5.2, 1 H), 7.54-7.38 (m, 3 H), 7.35-7.25 (m, 2 H), 6.78 (d, J =
5.2, 1 H), 2.48 (t, J = 7.6, 2 H), 1.67 (quintuplet, J = 7.6, 2 H), 1.29
(hexuplet, J = 7.6, 2 H), 0.83 (t, J = 7.3, 3 H); 13CNMR (CDCl3, 75 MHz):
δ = 158.8, 157.7, 149.2, 136.1, 134.6, 129.9, 128.9, 128.2, 124.7, 121.8,
115.6, 30.5, 30.0, 22.2, 13.7 ; IR (film): ν = 1728 (s), 1620 (w), 1520 (m),
1427 (m), 1096 (w), 1011 (m), 779 (m), 702 (m) cm−1; GC-MS (EI, 70
eV): m/z = 284 (M+, 100), 241 (20), 227 (81), 213 (37), 200 (42), 171
(28); HRMS-ESI (m/z): [(M+H)+] cald for C17H16O2S+: 285.0944; found:
285.0995.
General Procedure for the Suzuki Coupling Between 4-Iodo-7H-
thieno[2,3-c]pyran-7-ones 2 and Arylboronic Acids (Table 2). A
solution of the 4-iodo-7H-thieno[2,3-c]pyran-7-one 2 (0.3 mmol; 2a, 107
mg; 2b, 110 mg; 2e, 109 mg; 2g, 101 mg; 2j, 110 mg), boronic acid (0.36
mmol; phenylboronic acid, 44 mg; furan-3-ylboronic acid, 40 mg; p-
tolylboronic acid; 49 mg; thiophen-3-ylboronic acid, 46 mg), Pd(PPh3)4
(0.03 mmol, 35 mg), and Cs2CO3 (0.42 mmol; 136 mg) in anhydrous
DMF (8.6 mL) was allowed to stir under nitrogen at 80 °C (oil bath) for 24
h. After cooling to room temperature, AcOEt (10 mL) and a saturated
solution of NH4Cl (10 mL) were added. The organic layer was washed
with a saturated solution of NH4Cl (3x10 mL) and then with brine (1X10
mL). After drying over Na2SO4, the solvent was evaporated, and the
residue was purified by column chromatography on silica gel using
hexane-AcOEt (9:1) as eluent.
3-Methyl-5-phenyl-4-(p-tolyl)-7H-thieno[2,3-c]pyran-7-one (19). Yield: 63
1
mg, starting from 111 mg of 2j (63%). White solid, mp = 162-164 °C. H
NMR (CDCl3, 300 MHz): δ = 7.38-7.37 (m, 1 H), 7.35-7.29 (m, 2 H), 7.23-
7.12 (m, 7 H), 2.38 (s, 3 H), 1.62 (s, 3 H); 13CNMR (CDCl3, 75 MHz): δ =
158.8, 153.1, 146.1, 138.1, 136.2, 133.4, 132.9, 131.1, 129.29, 129.27,
128.7, 127.8, 124.1, 116.6, 21.4, 16.6; IR (KBr): ν = 1728 (s), 1512 (w),
1489 (w), 1450 (m), 1072 (m), 1003 (w), 756 (m), 694 (w) cm−1; GC-MS
(EI, 70 eV): m/z = 332 (M+, 100), 255 (69), 227 (23), 207 (16), 105 (72),
77 (39); HRMS-ESI (m/z): [(M+H)+] cald for C21H17O2S+: 333.0944;
found: 333.0948.
4,5-Diphenyl-7H-thieno[2,3-c]pyran-7-one (14). Yield: 64 mg, starting
from 107 mg of 2a (70%). White solid, mp = 182-184 °C. 1H NMR (CDCl3,
300 MHz): δ = 7.76 (d, J = 4.7, 1 H), 7.46-7.17 (m, 10 H), 6.96 (d, J = 4.7,
1 H); 13CNMR (CDCl3, 75 MHz): δ = 158.2, 153.4, 149.5, 136.3, 134.8,
132.3, 130.3, 129.3, 129.2, 129.1, 128.2, 128.0, 125.2, 122.8, 115.9; IR
Keywords: alkynylcarboxylic acids • fused heterocycles •
iodolactonization • iodothienopyranones •
iodothienopyrimidinones •
13
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10.1002/ejoc.202000468
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[1]
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Experimental Section for details).
Reactions were typically carried out with a substrate scale of 0.35 mmol.
Products yields were even higher when representative experiments
were carried out in a larger scale (2.2 mol of 3), for example, the yield
of 4a was 75% (see the Experimental Section for details).
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14
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FULL PAPER
Entry for the Table of Contents
High value added iodinated fused heterocycles from simple substrates: Iodothienopyranones and iodopyranopyrimidinones are
obtained under mild reaction conditions (25-40 °C, 2-3 equiv of I2 and NaHCO3 in MeCN) by iodolactonization of readily available 3-
alkynylthiophene-2-carboxylic and 3-alkynylpicolinic acids, respectively.
KEY TOPIC: FUSED HETEROCYCLES
15
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