Synthesis of 3-(5-methylthiophen-2-yl)coumarins and their photochromic dihetarylethene derivatives

Article abstract of DOI:10.1002/jhet.931

Novel unsymmetrical di(thienyl)maleic acid anhydride, including coumarin moiety, has been designed and synthesized. Its photochromism study and fatigue resistance estimation are reported. Microwave-assisted procedure has been successfully used for synthesis of 3-(5-methylthiophen-2-yl)coumarins.

Full text of DOI:10.1002/jhet.931

July 2013
Synthesis of 3-(5-Methylthiophen-2-yl)coumarins and Their
Photochromic Dihetarylethene Derivatives
891
Andrei Y. Bochkov,a Mikhail M. Krayushkin,b Vladimir N. Yarovenko,b
c
d
a
*
Valery A. Barachevsky, Irina P. Beletskaya, and Valery F. Traven
aDepartment of Organic Chemistry, Mendeleev University of Chemical Technology, Moscow 125047, Russia
bLaboratory of Heterocyclic Compounds, Zelinsky Institute of Organic Chemistry Russian Academy of Sciences,
Moscow 119991, Russia
cLaboratory of Photochromic Systems, Photochemistry Center Russian Academy of Sciences, Moscow 119421, Russia
dLaboratory of Physicochemical Problems, Frumkin Institute of Physical Chemistry Russian Academy of Sciences,
Moscow 119071, Russia
*
E-mail: traven@muctr.ru
Received September 16, 2010
DOI 10.1002/jhet.931
View this article online 2 July 2013 at wileyonlinelibrary.com.
Novel unsymmetrical di(thienyl)maleic acid anhydride, including coumarin moiety, has been designed
and synthesized. Its photochromism study and fatigue resistance estimation are reported. Microwave-assisted
procedure has been successfully used for synthesis of 3-(5-methylthiophen-2-yl)coumarins.
J. Heterocyclic Chem., 50, 891 (2013).
INTRODUCTION
the compound 2, and several examples of Suzuki cross-cou-
pling of 3-halocoumarins and arylboron derivatives have been
reported [4]. Another method of synthesis of 3-arylcoumarins
involves Knoevenagel condensation of arylacetic acid deriva-
tives and o-hydroxycarbonyl compounds. Condensation of
arylacetyl chlorides with salicylaldehydes was reported in ace-
tone/K2CO3 [5a] and using phase-transfer conditions (K2CO3
aq./benzene; Ref. 5b or K2CO3 aq./DCM (dichloromethane);
Refs. 5c and 5d). Arylacetic acids may be condensed with
salicylaldehydes or 2-hydroxyacetophenones in acetic an-
hydride in the presence of bases (acetates or triethylamine)
to give 3-arylcoumarins [5e,f]. Carboxyl-activating reagents
have also been successfully used for synthesis of various
3-arylcoumarins from arylacetic acids: dicyclohexylcarbodiimide
[5g], carbonyldiimidazole [5h], phenyldichlorophosphate
[5i], and Mukaiyama reagent (2-chloro-1-methylpyridinium
iodode; ref. 5j]. Arylacetates [5k–m] and arylacetonitriles
[5n,o] afford 3-arylcoumarins upon condensation with
o-hydroxycarbonyl compounds in basic conditions.
High photochromic performance (fatigue resistance and
thermal irreversibility) of dithienylethenes is well known.
Synthesis, properties, and applications of dithienylethenes
were extensively reviewed in last decade [1].
Dithienylethene photoswitching unit makes possible
photomodulation of various properties of the material,
namely color, fluorescence, refractive index, optical rota-
tion, and so forth. Fluorescent switches based on
dithienylethenes are of high interest for their applications
in optical memory devices [1b]. In continuation of our study
of photochromic dihetarylethenes with photomodulated
fluorescence, incorporating coumarin moiety [2], we aimed
to synthesize a dithienylethene, bearing a coumarin frag-
ment as a substitute in thiophene ring. We proposed that
coumarin-substituted 3,4-bis(thienyl)furan-2,5-dione would
combine high photochromic performance (thermal stability
of cyclic form and high fatigue resistance) and intense fluo-
rescence of open form, because 3-arylcoumarins exhibit
high fluorescence quantum yields [3]. We have developed
a synthetic route to dithienylethene 1, including a coumarin
moiety. Retrosynthetic analysis of 1 leads to a key interme-
diate—earlier unreported 3-(5-methyl-2-thienyl)coumarin 2.
This compound, in turn, is available via two synthetic
approaches, widely used for synthesis of analogous
3-substituted coumarins (Scheme 1).
RESULTS AND DISCUSSION
3-Bromocoumarin 4 was synthesized via two-step
procedure, including bromination of coumarin to give
3,4-dibromocoumarin [6] and subsequent HBr elimination [7].
5-Methyl-2-thienylboronic acid 3 was prepared by
standard procedure through directed metallation of
2-methylthiophene with n-butyllithium followed by addition
of tri(isopropyl)borate (Scheme 2).
Suzuki–Miyaura coupling of 5-methyl-2-thienylboronic
acid 3 and 3-bromocoumarin 4 is one of the evident routes to
© 2013 HeteroCorporation

892
A. Y. Bochkov, M. M. Krayushkin, V. N. Yarovenko, V. A. Barachevsky,
I. P. Beletskaya, and V. F. Traven
Vol 50
Scheme 1
Suzuki coupling of 3-bromocoumarin 4 and 5-methyl-2-
7-(diethylamino)-3-(5-methyl-2-thienyl)coumarin from
7-(diethylamino)-3-bromocoumarin and borate 7. The
strongly electron-donating diethylamino-substituent is likely
to complicate oxidative addition step and thus slowing
cross-coupling reaction. We considered Knoevenagel con-
densation to be more convenient and versatile for variation
of substituents in coumarin's benzene ring of 3-arylcoumarins,
as many substituted salicylaldehydes are commercially
available.
thienylboronic acid 3 gave poor yields of 2, although various
solvents (dioxane and acetonitrile), bases (Na2CO3, K3PO4,
and CsF), and catalysts (Pd(PPh3)4 and Pd(dppf)Cl2) have
been tested. TLC (thin layer chromatography) control of
reactions showed rapid consumption of 3 (0.5–1 h), whereas
4 was still present in reaction mixture. Further, we performed
optimization of cross-coupling reaction parameters using
pinacolate ester 7 (Scheme 3 and Table 1).
Highest yields of 3-(5-methyl-2-thienyl)coumarin 2
were obtained using Pd(dppf)Cl2 as a catalyst and CsF as
a base in polar aprotic solvent (CH3CN or DMF (N,N-
dimethylformamide); Table 1, entries 7–9).
7-Diethylaminocoumarins exhibit strong bathochromic
shift and higher quantum yields in comparison
with unsubstituted analogs [3], therefore, synthesis of
7-diethylamino-substituted analog of 1 would be of high
interest for this work. To our disappointment, the above-
optimized procedure was inappropriate for synthesis of
To this time, no convenient procedure for preparation of
5-methyl-2-thienylacetic acid 8 or its esters has been
reported in the literature.
The most common method for synthesis of arylacetic
acids is Willgerodt–Kindler reaction starting from corre-
sponding methylketones via intermediate thiomorfolides
[8]. In standard reaction conditions, reported to be success-
ful for synthesis of some thienylacetic acids [9], unsatisfac-
tory yield of thiomorfolide 10 (21%) was obtained by us.
Use of microwave-irradiation [10] and addition of catalytic
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis of 3-(5-Methylthiophen-2-yl)coumarins and Their Photochromic
Dihetarylethene Derivatives
July 2013
893
Scheme 3
amounts of TsOH [11] gave only slight yield increase to
29% (Scheme 4, route 1).
not detected, if lower amount of aluminum chloride was
added. This may be due to complexation of AlCl3 (1 equiv.)
with coumarin ester functionality. Ketoester 14 was isolated
in excellent yield (95%). NOE (nuclear Overhauser effect)
correlation of thiophene proton and 4-coumarin proton con-
firms the regioselectivity of acylation. Further, reduction of
14 using Et3SiH/TFA gave thienylacetate 15 in 86% yield
and corresponding 2-hydroxyacetate byproduct 15a in
10% yield. Alkaline hydrolysis of 15 provided arylacetic
acid 16 in 75% yield, which was then transformed into cor-
responding chloride 17 by treatment with SOCl2.
Triethylamine-promoted condensation of arylacetic acid
chloride 17 and arylglyoxalic acid 20 according to the
reported procedure [14] gave desired photochrome 1.
Acylation of 7-(diethylamino)-3-(5-methyl-2-thienyl)
coumarin 13 in the same reaction conditions as for
synthesis of 14 gave complex mixture of unidentified
products, and therefore, we could not isolate the desired
2-oxoacetate.
Dithienylethene 1 shows photochromism in solution
(Scheme 7). UV-irradiation of 1 leads to photocyclization,
as judged by appearance of strong absorption band at
610 nm. It is noteworthy that spectrum does not show
any significant changes in UV-region during irradiation
(Fig. 1). Visible light irradiation of cyclic form leads to
recovery of open form absorption.
Dithienylethene 1 shows relatively high photostability.
The photochromic cycle may be performed for many times
without significant decrease of optical density in cyclic
form absorption maximum. After 50 cycles of photo-
chromic transformation (in the presence of air) its
photostationary optical density at 612 nm makes up 95%
Reduction of corresponding 2-oxoacetate with
triethylsilane in trifluoroacetic acid [12] turned out to be
a more convenient approach to 12. Ethyl 2-oxo-2-(5-
methyl-2-thienyl)acetate 11 was obtained via Friedel–
Crafts acylation of 2-methylthiophene by ethyl oxalyl chlo-
ride similar to reported procedure [13]. Further reduction
with Et3SiH/TFA (trifluoroacetic acid) was clear and com-
pleted in 2 h at 0°C affording ethyl 5-methyl-2-
thienylacetate 12 in 85% yield (Scheme 4, route 2).
First, synthesis of 2 was attempted using standard
reaction conditions for 3-arylcoumarins preparation:
salicylaldehyde and 12 were refluxed in ethanol for 16 h
[5k]. However, these conditions did not provide full
conversion of 12. The reaction may be very slow because
of the electron-donating character of thiophene ring. To
improve yield of 2 and shorten the reaction time, we
decided to perform this condensation using microwave-
irradiation and solvent-free conditions. This procedure
gave high yields of desired 3-(5-methyl-2-thienyl)couma-
rins: 73% for 2 and 84% for 13. However, some limitations
of this method were observed: 2-hydroxyacetophenone did
not give even traces of 4-methyl-substituted analog of 2
under the same reaction conditions (Scheme 5).
3-(5-Methyl-2-thienyl)coumarin 2 was transformed to
the goal compound 1 via five-step pathway (Scheme 6).
We have chosen the same acylation–reduction approach
for preparation of 15, as we used for preparation of 12.
Friedel–Crafts acylation of 3-(5-methyl-2-thienyl)couma-
rin 2 with ethyl oxalyl chloride requires addition of at least
3 equiv. of aluminum chloride. Acylation product 14 was
Table 1
Optimization of Suzuki–Miyaura coupling conditions.
No.
Catalyst
Solvent
Base
Additive
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Dioxane
Dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
CsF (3 equiv.)
Na2CO3 (2.5 equiv.)
Na2CO3 (2.5 equiv.)
CsF (5 equiv.)
K3PO4 (3 equiv.)
Na2CO3 (2.5 equiv.)
CsF (5 equiv.)
–
H2O
H2O
–
Bu4NBr
H2O
–
10
6
6
48
9
6
6
3
3
34
Traces
36
21
15
55
80
75
84
Na2CO3 (5 equiv.)
CsF (5 equiv.)
H2O
–
DMF
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

894
A. Y. Bochkov, M. M. Krayushkin, V. N. Yarovenko, V. A. Barachevsky,
I. P. Beletskaya, and V. F. Traven
Vol 50
Scheme 4
from initial value (Fig. 2). Both oxidation and photochem-
ical byproduct formation may be responsible for observed
photodegradation. Dithienylethenes nonsubstituted at 4-
and 4′-positions of thiophene rings are favorable to form
tetracyclic nonphotochromic byproduct, isomeric to closed
form, thus loosing photochromic performance [15]. Cyclic
form of 1 is dark stable. No any significant decrease of
optical density in cyclic form absorption maxima was
observed during eight days-long storage (darkness, 20°C)
of irradiated to reach photostationary state solution.
Photoisomerization of 1 is not accompanied by changes
in fluorescence spectra. This may be due to fluorescence
maxima of open form (441 nm) lies nearby to isobestic
point (457 nm; Fig. 3) and cross-section with absorption
band of cyclic form is not significant.
procedure has been developed for synthesis of 3-(5-
methylthiophen-2-yl)coumarins.
EXPERIMENTAL
2-(2,5-Dimethylthiophen-3-yl)-2-oxoacetic acid (20) was
prepared from 2,5-dimethylthiophene according to previously
reported procedure [16].
General procedures.
All reagents purchased were used
without purification, as received. DCM and dichloroethane were
distilled over P4O10, and THF (tetrahydrofuran) was distilled over
LiAlH4. Column chromatography was carried out using Merck
Kieselgel 60 H silicagel. Analytical thin layer chromatography
was carried out using aluminum-backed plates coated with Merck
Kieselgel 60 F254 that were visualized under UV light (at 254 or
363 nm). 1H NMR spectra were recorded on Bruker AC-200
operating at 200 MHz, and 13C NMR spectra were recorded on
Bruker Avance II 300 at 75 MHz. Chemical shifts are reported
downfield from TMS (tetramethylsilane) (δ = 0) as internal
reference. Abbreviations for multiplicities are as follows: s,
singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m,
multiplet. EI (electron ionisation) mass-spectra were recorded on
Kratos MS-30. Absorption spectrometry was performed using a
CARY UV 50 (Varian) spectrophotometer. Fluorescence
measurements were conducted using a CARY ECLIPSE (Varian)
spectrofluorimeter. Absorption and fluorescence spectra were
CONCLUSIONS
In summary, we have designed and synthesized new
photochromic dithienylethene, containing fluorescent
coumarin moiety in conjugation with photochromic system.
Coumarin-containing dithienylethene shows long-wave-
length absorption of cyclic form, good fatigue resistance,
and thermal irreversibility. Convenient microwave-assisted
Scheme 5
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis of 3-(5-Methylthiophen-2-yl)coumarins and Their Photochromic
Dihetarylethene Derivatives
July 2013
895
Scheme 6
recorded in toluene solution (4 × 10−5M) in 1-cm length quartz
cuvette. Irradiation of solutions during photochemical studies was
performed using Hamamatsu LC-4 mercury–xenon lamp
(Hamamatsu photonics), equipped with composite glass light
filters. Toluene used for spectroscopy experiments was
spectrophotometric grade. Microwave-assisted reactions were
performed in a household microwave oven Rolsen MS1770SA.
Tri(isopropyl)borate [17]. The mixture of boric acid (0.15
mol, 9 g), 2-propanol (40 mL), and benzene (40 mL) were boiled
for 18 h in a distillation setup with a Vigreux column (50 cm). The
azeotrope mixture of water/2-propanol/benzene was distilled off at
65°C. During the reaction time, a mixture of 2-propanol/benzene
(v/v 1:1) was added several times to maintain the reaction mixture
volume. After completion of esterification, solvents were
evaporated in vacuo, and residue was distilled at atmospheric
pressure to give the title compound as colorless liquid. Yield 13.5
g (48%). B.p. 134–140°C (Lit. b.p. 138–139°C; Ref. 18).
temperature did not exceed 0°C. The resulting solution was
stirred for 1 h at −5°C, followed by cooling down to −78°C, and
quenching with tri(isopropyl)borate (40 mmol, 7.52 g), which
was added in one portion. The resulting mixture was allowed to
warm up to room temperature (RT) and left overnight. The
reaction mixture was poured into water, and 10% aqueous HCl
(20 mL) was added. After stirring for 5 h at RT, the reaction
mixture was extracted with diethyl ether (2× 50 mL). The
combined organic layers were dried (Na2SO4) and evaporated,
and the residue was consequently washed with cold water and
1
hexane. White powder. Yield 86%. M.p. 161–164°C. H NMR
(CDCl3), δ, ppm: 2.61 (s, 3H), 6.96 (d, 1H, J = 2.9 Hz), 7.82
(d, 1H, J = 3.4 Hz).
4,4,5,5-Tetramethyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxo-
borolane (7).
5-Methylthiophen-2-ylboronic acid 3 (17.5
mmol, 2.49 g) and pinacol monohydrate (18.4 mmol, 2.5 g)
were dissolved in anhydrous THF (50 mL) and stirred at RT for
24 h. The solvent was evaporated in vacuo, and resulting
residue was chromatographed on silica gel column (eluent—
petr. ether/ethylacetate, 3:1) to give title compound. Yield
3.64 g (92%), orange oil.
5-Methylthiophen-2-ylboronic acid (3).
To a stirred
solution of 2-methylthiophene 6 (30 mmol, 2.94 g) in anhydrous
THF (50 mL) at −5°C, solution of n-BuLi was slowly added via
syringe (2.5M in hexane, 35 mmol, 14 mL) in such a rate that
Scheme 7
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

896
A. Y. Bochkov, M. M. Krayushkin, V. N. Yarovenko, V. A. Barachevsky,
I. P. Beletskaya, and V. F. Traven
Vol 50
Figure 3. UV/vis absorption (line 1) and fluorescence spectra (line 2) of
open form and absorption spectrum of cyclic form (line 3) of 1.
Figure 1. UV/vis absorption spectra of 1 in toluene before (line 1) and af-
ter UV-irradiation (365 nm) for 1, 2, 4, 8, and 16 s (lines 2-6,
respectively).
(16.2 mmol, 3.2 g) in TFA (16 mL) at 0°C, triethylsilane (38.8
mmol, 4.5 g) was added. Stirring was continued for 3 h, and
reaction mixture was quenched with water, neutralized by
addition of saturated aqueous NaHCO3 solution, and extracted
with ethylacetate. The solvent was evaporated in vacuo, and
resulting residue was chromatographed on silica gel column
(eluent—petr. ether/ethylacetate, 10:1) to give title compound.
Ethyl 2-(5-methylthiophen-2-yl)-2-oxoacetate (11). To a
stirred suspension of AlCl3 (16.5 mmol, 2.20 g) in DCM (15 mL)
at −5°C, ethyl oxalyl chloride (15 mmol, 2.06 g) was added, and
stirring continued for 20 min until clear solution formed. A
solution of 2-methylthiophene 6 (15 mmol, 1.47 g) in DCM
(5 mL) was added dropwise. Stirring was continued for 30 min,
and reaction mixture was poured into ice/water, followed by
extraction with DCM (2× 50 mL). The combined organic
layers were dried (Na2SO4) and filtered through a pad of
silica gel to remove tarry impurities. The solvent was evaporated
in vacuo, and resulting residue was chromatographed on silica
gel column (eluent—petr. ether/ethylacetate, 10:1) to give title
compound.
1
Yield 2.44 g (82%), colorless oil. H NMR (CDCl3), δ, ppm:
1.29 (t, 3H, J = 7.1), 2.46 (s, 3H), 3.75 (s, 2H), 4.19 (q, 2H, J =
7.1 Hz), 6.61 (s, 1H), 6.71 (s, 1H). MS, m/z (%): 184 (100)
[M]+. Found, %: C 58.78; H 6.48. C9H12O2S. Calculated, %: C
58.67; H 6.56.
3-(5-Methylthiophen-2-yl)-2H-chromene-2-one (2). Method A:
Suzuki–Miyaura coupling. To acetonitrile (15 mL) solution of 3-
bromocoumarin 4 (225 mg, 1 mmol) and 4,4,5,5-tetramethyl-2-
(5-methylthiophen-2-yl)-1,3,2-dioxoborolane 7 (240 mg, 1.1
mmol), Pd(dppf)Cl2·CH2Cl2 (33 mg, 0.04 mmol) and CsF
(750 mg, 5 mmol) were added. The reaction mixture was
stirred at reflux for 3 h, cooled, and poured into water.
Precipitate thus formed was filtered off and purified by column
chromatography (eluent—petr. ether/ethylacetate, 10:1) to give
title compound. Yield 192 mg (80%).
1
Yield 1.81 g (61%). Yellow oil. H NMR (CDCl3), δ, ppm:
1.43 (t, 3H, J = 7.1 Hz), 2.59 (s, 3H), 4.23 (q, 2H, J = 7.1 Hz),
6.90 (d, 1H, J = 3.8 Hz), 7.96 (d, 1H, J = 3.9 Hz). MS, m/z
(%): 198 (100) [M]+. Found, %: C 54.80; H 4.95. C9H10O3S. Cal-
culated, %: C 54.53; H 5.08.
Ethyl 2-(5-methylthiophen-2-yl)acetate (12). To a stirred
solution of ethyl 2-(5-methylthiophen-2-yl)-2-oxoacetate 11
Method B:. Knoevenagel condensation. Ethyl 2-(5-
methylthiophen-2-yl)acetate 12 (3 mmol, 552 mg), salicyl
aldehyde (3 mmol, 366 mg), and piperidine (3 mmol, 255 mg)
were mixed together in a glass tube with a thermoresistant
screw-cap and well shaked. The tube was placed into a
microwave oven and irradiated for 30 min at 350 W. After
cooling, the reaction mixture was dissolved in DCM and
washed with aqueous HCl. Organic layer was evaporated in
vacuo, and the residue was purified by column chromatography
(eluent—petr. ether/ethylacetate, 10:1) to give title compound.
Yield 486 mg (67%).
Yellow crystals, m.p. 152−154°C (petr. ether/ethanol). 1H
NMR (CDCl3), δ, ppm: 2.54 (s, 3H), 6.79 (d, 1H, J = 3.4 Hz),
7.30−7.54 (m, 4H), 7.64 (d, 1H, J = 3.7 Hz), 7.90 (s, 1H). 13C
NMR (CDCl3), δ, ppm: 15.3, 116.2, 119.5, 121.7, 124.5, 126.0,
127.4, 127.5, 130.7, 133.6, 134.2, 142.5, 152.4, 159.3. MS, m/z
(%): 242(88) [M]+, 214(100), 184(26), 174(33), 151(20), 127
(32). Found, %: C 69.21; H 4.30. C14H10O2S. Calculated, %: C
69.40; H 4.16.
Figure 2. Reversibility of photochromic transformations of 1 in toluene
solution.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis of 3-(5-Methylthiophen-2-yl)coumarins and Their Photochromic
Dihetarylethene Derivatives
July 2013
897
(m, 4H), 7.60 (s, 1H), 7.95 (s, 1H). 13C NMR (DMSO-d6), δ,
ppm: 12.6, 13.6, 60.5, 67.0, 115.5, 118.9, 120.6, 124.2, 126.0,
127.4, 130.5, 131.0, 134.2, 135.7, 138.6, 151.8, 158.7, 172.0.
2-(2-Methyl-5-(2-oxo-2H-chromene-3-yl)thiophene-3-yl)acetic
acid (16). A suspension of ester 15 in 10% water/ethanol (1:1)
solution of KOH (40 mL) was vigorously stirred at 50°C for 4 h.
The reaction mixture was diluted with water (100 mL), washed
with ethylacetate, and treated with concentrated HCl to give a
yellow precipitate, which was filtered off and dried.
7-(N,N-Diethylamino)-3-(5-methylthiophen-2-yl)-2H-chromene-
2-one (13). The title compound was prepared by microwave-assisted
procedure similar to the synthesis of 2 using ethyl 2-(5-
methylthiophen-2-yl)acetate 12 (3 mmol, 552 mg), 4-
diethylaminosalicylaldehyde (3 mmol, 579 mg) and piperidine
(3 mmol, 255 mg). The reaction mixture was chromatographed
directly after cooling without acid washing (eluent—DCM).
Yield 788 mg (84%), orange crystals, m.p. 158−159°C (etha-
1
nol). H NMR (CDCl3), δ, ppm: 1.23 (t, 6H, J = 7.0 Hz), 2.52
Yield 75%, yellow crystals, m.p. 275−276°C. 1H NMR
(DMSO-d6), δ, ppm: 2.38 (s, 3H), 3.54 (s, 2H), 7.39−7.45 (m,
2H), 7.57−7.62 (m, 1H), 7.67 (s, 1H), 7.79 (d, 1H, J = 7.5 Hz),
8.46 (s, 1H), 12.35 (br. s, 1H). 13C NMR (DMSO-d6), δ, ppm:
12.7, 33.6, 115.8, 119.4, 124.8, 128.3, 129.2, 130.4, 131.2,
131.3, 134.9, 138.0, 146.6, 151.9, 158.8, 171.9. MS, m/z (%):
300(60) [M]+, 255(100) [M−COOH]+, 241(36), 227(27), 165
(34). Found, %: C 63.82; H 4.35. C16H12O4S. Calculated, %: C
63.99; H 4.03.
3-(2,5-Dimethylthiophen-3-yl)-4-(2-methyl-5-(2-oxo-2H-
chromen-3-yl)thiophen-3-yl)furan-2,5-dione (1). Thionyl
chloride (0.4 mL) was added to a suspension of acid 16 (0.4
mmol, 120 mg) in DCM (40 mL), and the mixture was refluxed
for 3 h. The resulting clear solution was evaporated in vacuo to
give crude acid chloride 17. The acid chloride was dissolved in
DCM (40 mL), and 2,5-dimethyl-3-thienylglyoxalic acid 20
(0.4 mmol, 74 mg) was added. To the stirred above solution
triethylamine (0.84 mmol, 85 mg, in 5 mL of DCM) was
added dropwise at 0°C (ice bath), treated with concentrated
HCl (3 mL), and extracted with DCM. Organic Stirring was
continued for 2 h, and then, the reaction mixture was poured into
water (50 mL), layer was evaporated in vacuo, and the residue
was purified by column chromatography (eluent—DCM) to give
title compound.
(s, 2H), 3.43 (q, 4H, J = 7.0 Hz), 6.54 (s, 1H), 6.74 (d, 1H, J =
3.1 Hz), 6.61 (d, 1H, J = 8.8 Hz), 7.31 (d, 1H, J = 8.8 Hz),
7.47 (d, 1H, J = 3.5 Hz), 7.79 (s, 1H). 13C NMR (CDCl3), δ,
ppm: 12.44, 15.21, 44.8, 97.1, 108.8, 109.2, 115.1, 125.1,
125.5, 128.6, 135.0, 135.8, 140.2, 150.2, 155.3, 160.4. MS, m/z
(%): 313(100) [M]+, 298(75) [M−CH3]+. Found, %: C 69.13; H
6.06. C18H19NO2S. Calculated, %: C 68.98; H 6.11.
Ethyl 2-(2-methyl-5-(2-oxo-2H-chromen-3-yl)thiophen-3-
yl)-2-oxoacetate (14). To a solution of 3-(5-methylthiophen-2-
yl)-2H-chromene-2-one 2 (2 mmol, 480 mg) and ethyl oxalyl
chloride (2.1 mmol, 289 mg) in DCM (40 mL) at −5°C, AlCl3
(6.2 mmol, 828 mg) was added portionwise upon 20 min. The
stirring was continued for 2 h, and the mixture was poured onto
crushed ice. The reaction mixture was extracted with DCM (2×
50 mL), combined organic layers were dried over MgSO4, and
filtered through a silica gel pad to remove tarry impurities.
Solvent was removed in vacuo to give pure desired product.
Yield 650 mg (95%), yellow crystals, m.p. 118−120°C (petr.
1
ether/acetone). H NMR (CDCl3), δ, ppm: 1.46 (t, 3H, J = 7.1
Hz), 2.82 (s, 3H), 4.46 (q, 2H, J = 7.1 Hz), 7.32−7.40 (m, 2H),
7.53−7.59 (m, 2H), 8.04 (s, 1H), 8.14 (s, 1H). 13C NMR (CDCl3),
δ, ppm: 14.0, 16.0, 62.3, 116.4, 119.0, 120.5, 124.8, 127.9, 128.0,
131.6, 133.9, 134.1, 135.6, 152.7, 156.1, 159.4, 163.5, 180.2.
MS, m/z (%): 342(30) [M]+, 269(100), 197(19), 151(53). Found,
%: C 63.04; H 4.19. C18H14O5S. Calculated, %: C 63.15; H 4.12.
Reduction of ethyl 2-(2-methyl-5-(2-oxo-2H-chromene-3-
yl)-thiophene-3-yl)-2-oxoacetate. To a solution of ethyl 2-
(2-methyl-5-(2-oxo-2H-chromene-3-yl)-3-thienyl)-2-oxoacetate
14 (2 mmol, 684 mg) in TFA (4 mL) at 0°C triethylsilane
(4.7 mmol, 550 mg) was added dropwise with stirring. Stirring
was continued for 3 h, the cooling bath was then removed, and
solution left overnight at RT. The reaction mixture was
quenched with water and extracted with DCM. Organic layer
was washed with saturated aqueous NaHCO3, solvent was
removed in vacuo, and the residue was chromatographed on
silica gel column. The desired product 15 was eluted by DCM.
Subsequent elution with petr. ether/ethyl acetate (1:1) gave
2-oxyester 15a.
Ethyl 2-(2-methyl-5-(2-oxo-2H-chromene-3-yl)thiophene-3-
yl)acetate (15). Yield 86%, greenish-yellow crystals, m.p. 201
−202°C (ethanol). 1H NMR (CDCl3), δ, ppm: 1.28 (t, 3H, J = 7.9
Hz), 2.46 (s, 3H), 3.58 (s, 2H), 4.19 (q, 2H, J = 6.8 Hz), 7.28
−7.38 (m, 2H), 7.48−7.56 (m, 2H), 7.65 (s, 1H), 7.93 (s, 1H).
13C NMR (DMSO-d6), δ, ppm: 12.8, 14.1, 33.3, 60.3, 115.8,
119.3, 120.3, 124.7, 128.3, 129.0, 130.5, 130.6, 131.2, 134.9,
138.3, 151.9, 158.8, 170.4. MS, m/z (%): 328(100) [M]+, 254
(78). Found, %: C 66.00; H 4.74. C18H16O4S. Calculated, %: C
65.84; H 4.91.
Yield 29 mg (16%), dark orange crystals, m.p. 181−183°C. 1H
NMR (CDCl3), δ, ppm: 2.01 (s, 3H), 2.06 (s, 3H), 2.45 (s, 3H),
6.78 (s, 1H), 7.31−7.41 (m, 2H), 7.53−7.61 (m, 2H), 7.75 (s,
1H), 8.03 (s, 1H). MS, m/z (%): 448(100) [M]+. Found, %: C
64.04; H 3.83. C24H16O5S2. Calculated, %: C 64.27; H 3.60.
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1
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