An Efficient Synthetic Access to Substituted Thiazolyl-pyrazolyl-chromene-2-ones from Dehydroacetic Acid and Coumarin Derivatives by a Multicomponent Approach

Article abstract of DOI:10.1002/ejoc.201600173

Two new series of pyran- or coumarin-substituted thiazolyl-pyrazole-chromen-2-one derivatives 10a-10d and 11a-11d were efficiently synthesized under environmentally friendly reaction conditions through a convenient one-pot multicomponent reaction of a heterocyclic bromoacetyl derivative 3 or 4 with thiosemicarbazide and a substituted 3-(acetoacetyl)coumarin derivative 5a-5d in anhydrous ethanol. The reaction proceeds through Hantzsch thiazole and Knorr pyrazole syntheses in refluxing ethanol. The key features of this approach are its operational simplicity, the quick access to the desired products, and the good to excellent yields. The structures of the newly synthesized compounds were established by IR spectroscopy, ¹H, ¹³C, and 2D NMR spectroscopy, and mass spectrometry. Two new series of pyran- or coumarin-substituted (thiazolyl-pyrazole-chromen-2-ones) may be efficiently accessed from bromoacetyl derivatives of dehydroacetic acid or coumarin, thiosemicarbazide, and substituted 3-(acetoacetyl)coumarins by green multicomponent reactions. The newly synthesized structures were established by IR spectroscopy, ¹H, ¹³C, and 2D NMR spectroscopy, and mass spectrometry.

Full text of DOI:10.1002/ejoc.201600173

DOI: 10.1002/ejoc.201600173
Full Paper
Multicomponent Reactions
An Efficient Synthetic Access to Substituted Thiazolyl-pyrazolyl-
chromene-2-ones from Dehydroacetic Acid and Coumarin
Derivatives by a Multicomponent Approach
[
a]
[a]
[a]
[b]
Soumaya Ben Mohamed, Yahia Rachedi* Maamar Hamdi, Franck Le Bideau,
[c]
[b]
Camille Dejean, and Françoise Dumas*
Abstract: Two new series of pyran- or coumarin-substituted tion proceeds through Hantzsch thiazole and Knorr pyrazole
thiazolyl-pyrazole-chromen-2-one derivatives 10a–10d and syntheses in refluxing ethanol. The key features of this ap-
1
1a–11d were efficiently synthesized under environmentally proach are its operational simplicity, the quick access to the
friendly reaction conditions through a convenient one-pot mul- desired products, and the good to excellent yields. The struc-
ticomponent reaction of a heterocyclic bromoacetyl derivative tures of the newly synthesized compounds were established by
1
13
3
or 4 with thiosemicarbazide and a substituted 3-(acetoacet- IR spectroscopy, H, C, and 2D NMR spectroscopy, and mass
yl)coumarin derivative 5a–5d in anhydrous ethanol. The reac- spectrometry.
Introduction
Sulfur–nitrogen-containing heterocyclic compounds, and
specifically thiazoles and their derivatives, represent a medici-
nally and pharmaceutically important class of heterocycles that
are found in a variety of drug molecules, such as sulfathiazole,
ritonavir, and abafungin (Figure 1). They also have a wide range
of biological and pharmacological activities, including anti-
Heterocyclic chemistry has constituted one of the largest areas
of research in organic chemistry, starting with Perkin's mauve
dye. Heterocycles have become key compounds in society's de-
velopment through their contributions to the understanding
of life processes, and their use in the improvement of health
conditions in particular. Indeed, more than 80 % of drugs are
based on heterocyclic molecules. They have also contributed to
industrial development and to the improvement of the quality
of life through their applications as agrochemicals, dyes, fluo-
[
6]
[7,8]
[9]
tuberculosis, anticancer,
and anti-HIV activities; more re-
cently, they have also been found to be of interest for materials
[
10]
science.
When nitrogen and sulfur heteroatoms take the
place of ring carbon atoms, or of a complete ethylene group, in
aromatic carbocycles, this formally results in the corresponding
aromatic heterocycles. The presence of these heteroatoms indu-
ces significant changes in the stereoelectronic properties of
such heterocycles relative to their carbon analogues, in part
because of their unshared electron pairs and different electro-
[
1]
rescent agents, plastics, food additives, cosmetics, and so on.
Genetic information carriers such as DNA and RNA, or oxy-
gen carriers in living organisms, are made of aromatic hetero-
cycles, which therefore play an essential role in biochemical
processes. Heterocycles are present in a wide variety of drugs,
many natural products, biomolecules, and biologically active
compounds, and they are often key structural units in pharma-
[
4]
negativities.
On the other hand, pyrazole and its derivatives, which make
up a class of well-known nitrogen heterocycles, have been re-
ported in the literature to show various therapeutic activi-
[
1–5]
ceuticals and agrochemicals.
[
11,12]
[13]
[14]
ties
microbial,
such as anti-inflammatory, antihypertensive, anti-
[
a] Laboratory of Applied Organic Chemistry, Faculty of Chemistry,
University of Science and Technology Houari Boumediene,
BP 32, El-Alia, 16111 Bab-Ezzouar, Algiers, Algeria
E-mail: yrachedi@usthb.dz
[
15]
[16]
and anticancer[17] activities. Block-
antidiabetic,
buster drugs such as celecoxib and pyrazofurin, among others,
incorporate such a pyrazole ring in their core structure (Fig-
ure 1). In addition, compounds of this class have played a cru-
cial role in the development of heterocyclic chemistry, and they
http://www.lcoa.usthb.dz/
[
b] Laboratoire BioCIS, UMR CNRS 8076,
Chimie des Substances Naturelles, IPSIT and LabEx LERMIT,
CNRS, Université Paris-Saclay,
Université Paris-Sud, Faculté de Pharmacie,
[
18,19]
are also used extensively in organic synthesis.
Pyran-2-one and coumarin derivatives form an exceptional
class of oxygen-containing heterocyclic compounds. They are
useful intermediates for the synthesis of various compounds,
and they play a key role in the medicinal area due to their
5
, rue Jean-Baptiste Clément, 92296 Châtenay-Malabry CEDEX, France
E-mail: francoise.dumas@u-psud.fr
http://www.biocis.u-psud.fr/
[
c] Département de RMN, BioCIS UMR CNRS 8076,
Université Paris-Saclay, Université Paris-Sud,
[
20,21]
structural diversity and their pharmaceutical properties.
5
, rue Jean-Baptiste Clément, 92296 Châtenay-Malabry CEDEX, France
Consequently, the synthesis of compounds containing such
pyran or coumarin heterocycles has attracted considerable at-
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600173.
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Figure 1. Some biologically active drugs containing thiazole, pyrazole, or coumarin moieties.
[
40–43]
tention for years, and several syntheses of these derivatives lactone (TAL)],
as found in bromoacetyl derivative 3, and
[
33]
have been reported. The great interest in these compounds coumarin, as found in bromoacetyl derivative 4. Our current
stems from their physiological and biological activities, as ex- study is aimed towards the development of new routes for the
emplified by their roles as anticoagulants (dicoumarols and synthesis of two new series of thiazolyl-pyrazolyl-chromen-2-
their derivatives, warfarin), spasmolytics, anti-inflammatories, one-containing pyran-2-ones (10a–10d) and coumarins (11a–
[
22–26]
[44]
[45]
and antioxidants (Figure 1).
They have been extensively 11d) through Hantzsch thiazole and Knorr pyrazole MCRs,
investigated for decades, and have been found to exert other
[
27]
valuable biological effects such as antiapoptotic (HA14-1),
[
28,29]
[30]
[31]
anticancer
and antiviral activities;
interesting optical,
photophysical, photochemical, and fluorescent properties have
[
32–34]
also been found.
Multicomponent reactions (MCRs) have emerged as useful
tools for exploring chemical space. They involve domino proc-
esses in which at least three different reactants are directly con-
[
35]
verted into products in a one-pot fashion. Compared to clas-
sical multistep synthesis, MCRs offer higher atom economy and
selectivity, and give easy access to molecular complexity and
diversity while generating fewer by-products. As a result, the
[
36]
importance of MCRs in modern organic chemistry is growing,
and MCRs are being developed for the efficient production of
medicinally relevant scaffolds.
In view of the various activities of pyrans, coumarins, thi-
azoles, and pyrazolones, we have developed a research pro-
gram focussed on the synthesis of new heterocyclic systems
related to chemical transformations of 3-acetyl-4-hydroxy-6-
methyl-2H-pyran-2-one [1; also named dehydroacetic acid
Scheme 1. Strategy for the synthesis of substituted thiazolyl-pyrazolyl-chrom-
ene-2-ones 10a–10d and 11a–11d.
[
37–39]
(
DHA)],
4-hydroxy-6-methyl-2H-pyran-2-one [2; or triacetic
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respectively, involving bromoacetyl heterocycles 3 or 4 com-
bined with coumarins 5a–5d and thiosemicarbazide 6 as a dou-
ble dinucleophilic coupling partner (Scheme 1).
Results and Discussion
One reason behind the continuous research into the design of
synthetic approaches to new heterocyclic systems lies in the
wide use of heterocycles in modern pharmaceuticals. The first
task in this study was to prepare the starting materials, i.e., α-
bromo ketones 3 and 4, and coumarins 5a–5d.
The procedure started from DHA (1), which was converted
into TAL (2) in 65 % yield through deacetylation under acidic
[
46,47]
conditions
(Scheme 2). Compound 2 would then be used
for the synthesis of coumarins 5a–5d (see Scheme 4). Studies
dealing with the bromination of DHA (1) and coumarins are
significant, because the resulting α-bromo ketones are potential
precursors for the synthesis of various heterocyclic compounds.
In this context, 3-(bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-
Scheme 4. Synthesis of 3-(acetoacetyl)coumarin derivatives 5a–5d and a
plausible mechanism for their formation.
The following mechanism supports the formation of com-
2-one (3) and 3-(bromoacetyl)-2H-chromene-2-one (4) were pounds 5a–5d. First, a Knoevenagel condensation of pyranone
synthesized as key starting materials for the preparation of tar- 2 with salicylaldehydes 7a–7d could give the intermediate 3-
get compounds 10 and 11. Thus, bromination of DHA (1) in salicylidenepyrane-2,4-dione (A). This could then undergo an
glacial acetic acid gave the desired bromoacetyl derivative (i.e., intramolecular translactonisation through nucleophilic attack of
[
38]
3
) in 61 % yield (Scheme 2).
the phenol group onto the lactone carbonyl group to give inter-
mediate B. In turn, this could lead to a ring-opening reaction
of the pyranone unit in B, resulting in the formation of 3-
(acetoacetyl)coumarin ꢀ-diketones 5a–5d (Scheme 4). The ꢀ-
diketone moiety in structures 5a–5d undergoes keto/enol tau-
1
tomerism in DMSO solution, as shown by H NMR spectroscopy
(
Scheme 5). The relative proportions of the keto and enol tau-
1
Scheme 2. Synthesis of 4-hydroxy-6-methyl-2H-pyran-2-one (2) and 3-
bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one (3) from DHA (1).
tomers of 5a–5d were easily determined by H NMR spectro-
scopy by integration of the ketone α-methylene signals (be-
(
tween δ = 4.09 and 4.17 ppm in [D ]DMSO) and the enol ethyl-
6
3
-(Bromoacetyl)coumarin 4 was synthesized by a two-stage
ene signals (from δ = 6.84 to 6.92 ppm in [D ]DMSO). The pro-
6
process, viz., Knoevenagel condensation then bromination. The
first stage was carried out by treating salicylaldehyde (7a) with
ethyl acetoacetate (8) in the presence of piperidine to give 3-
acetylcoumarin 9
brominated using bromine in acetic acid to give the corre-
portion of the enol form was in the range 79–83 %. The relative
contributions of the keto and enol tautomers depend on sev-
eral factors, such as the solvent characteristics, temperature,
and ring structure. In general, most ꢀ-diketones exist in solution
at room temperature predominantly in the enol form. The enol
form can exist in different cis- and trans-isomeric forms depend-
ing on the temperature and on the polarity and hydrogen-
[
48]
in 77 % yield. This compound was then
[
49]
sponding bromoacetyl compound (i.e., 4)
Scheme 3).
in 60 % yield
(
[
50]
bonding nature of the solvents. The presence of a trans-enol
[
11,41,50]
form is controversial in the case of ꢀ-diketones.
In con-
trast, the cis-enol form is generally stable, due to the presence
[
41]
of intramolecular hydrogen bonding.
In the case of unsym-
metrical ꢀ-dicarbonyl compounds, two possible enol isomers
E1 and E2 can be formed by the transfer of an enol proton from
[
50,51]
one oxygen atom to the other.
MNDO-PM3 calculations for
Scheme 3. Synthesis of 3-acetylcoumarin (6) and 3-(bromoacetyl)coumarin
7).
(
such enol forms E1 and E2 of compound 5a recently reported
by Makhloufi-Chebli et al. showed that enol form E1 is favored
The second part of the synthesis of the target compounds over its isomer E2. The bonds are highly polarized, and the
involved the preparation of 3-(acetoacetyl)coumarin derivatives atoms bear higher charges in enol form E1 than in enol form
[
32]
5
a–5d by the reaction of TAL (2) with 2-hydroxybenzaldehydes E2.
7a–7d using piperidine in ethanol under microwave irradiation
The structures of coumarins 5a–5d were deduced from spec-
(
Scheme 4). The reaction gave excellent yields after only short troscopic data and high-resolution mass spectra (HRMS), as dis-
reaction times; this means that less energy was wasted in heat- cussed here for the new derivative 5d. The infrared spectrum
ing, which makes the process environmentally friendly.
of 5d showed prominent peaks at ν˜ = 3331 (OH) and 1692 (C=
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1
57.8 ppm for the C=O group of the coumarin nucleus, and
two signals at δ = 174.8 and 197.5 ppm that are assigned to
the carbonyl groups at C-9 and C-11, respectively, of the enol
form of the acetoacetyl moiety. The mass spectrum of 5d
+
showed peaks at m/z (%) = 263.0552 (20) [M + H] and 285.0375
+
(
100) [M + Na] , confirming its molecular formula as C H O .
1
3 10 6
With compounds 5a–5d in hand, we went on to develop a
facile, one-pot method for the synthesis of two new series of
pyran or coumarin-thiazole-pyrazole-coumarin derivatives,
10a–10d and 11a–11d, which incorporate three or four impor-
tant pharmacophores: pyran, coumarin ring, thiazole, and pyr-
azolone heterocycles. According to the strategy shown in
Scheme 1, these series were synthesized by multicomponent
reactions of 3-(bromoacetyl) heterocycles 3 or 4, 3-(aceto-
acetyl)coumarin derivatives 5a–5d, and thiosemicarbazide 6.
Isolation of the products was easily achieved by filtration, fol-
lowed by washing with hot ethanol, then DMSO, and finally by
drying. This process is fairly general, quick, and efficient, and is
does not give any side-products.
The condensation of an equimolar mixture of 3-(bromo-
acetyl)-4-hydroxy-6-methyl-2H-pyran-2-one (3) with thiosemi-
carbazide 6 and 3-(acetoacetyl)coumarin derivatives 5a–5d in
refluxing anhydrous ethanol delivered the first series of substi-
tuted coumarin derivatives 3-{1-[4-(4-hydroxy-6-methyl-2-oxo-
Scheme 5. Keto/enol tautomerism and atom numbering of 3-(acetoacet-
1
yl)coumarins 5a–5d, their H characteristic chemical shifts (10-H), and their
ratios from 1H NMR spectroscopy in DMSO.
–
1
1
O) cm . The H NMR spectrum of compound 5d was consistent
with a mixture of two compounds, which suggests that both
keto and enol forms of the acetoacetyl moiety are present in
DMSO solution. Characteristic singlets at δ = 2.22 and 4.11 ppm
assigned to the protons of the methyl group and to the 10-H
methylene protons, respectively, correspond to the minor diket-
one tautomer (Scheme 5 and Figure 2). Singlet signals at δ =
2
H-pyran-3-yl)thiazol-2-yl]-3-methyl-1H-pyrazol-5-yl}-2H-chrom-
en-2-ones 10a–10d in good yields (73–84 %; Scheme 6). No
regioisomers or intermediates were isolated (see Scheme 8).
2
1
.19 and 6.86 ppm were assigned to the methyl group and the
0-H enol proton of major enol form E1. Doublet signals cen-
tred at δ = 6.86/7.29 and 6.89/7.34 ppm (J = 8.6 Hz) correspond
to the adjacent aromatic protons 5-H and 6-H, respectively. Fur-
ther characteristic singlets appeared for 4-H at δ = 8.66/
8.61 ppm and a broad singlet at δ = 10.17 ppm accounting for
two phenolic hydroxy groups. Finally, the appearance of a
hydroxy proton signal at δ = 16.27 ppm provides evidence for
the predominance of the enol form in the acetoacetyl moiety
with a ratio of 80:20. This high value is a result of stabilization
of the enol by a strong intramolecular hydrogen bond with the
oxygen atom of the ꢀ-carbonyl group.
Scheme 6. One-pot synthesis of substituted thiazolyl-pyrazolyl-coumarin de-
rivatives 10a–10d.
The structures of the products were confirmed by spectro-
1
13
scopic analysis, including IR, H and C NMR, 2D-NMR, and
mass spectral analysis, as described here in detail for a repre-
sentative compound 10b. The molecular formula C H N O S
2
2 15 3 6
for this compound was deduced on the basis of ESI-HRMS data,
which showed a peak at m/z = 472.0579 attributed to [M +
+
Na] . This confirmed the success of the multicomponent syn-
thesis. The IR spectrum of 10b showed prominent peaks due
to lactone (C=O) and imine (C=N) functional groups at ν˜ = 1715
–
1
–1
and 1687 cm , and a broad band centered at ν = 3410 cm
˜
due to the hydroxy groups of the pyran and coumarin rings.
The H NMR spectrum of compound 10b in DMSO showed six
1
1
13
Figure 2. Selected H (top) and C (middle) chemical shifts of 5d tautomers,
and table of the remaining signals in the 1 C NMR spectra.
3
characteristic singlets: of a CH group at δ = 2.31 ppm and of
3
a CH group at δ = 6.56 ppm assigned to the pyrazolone ring;
The 13C NMR spectrum of 5d showed the characteristic of a CH group at δ = 2.16 ppm and of a CH group at δ =
3
peaks at δ = 26.5 ppm for the methyl group, and at δ = 5.87 ppm assigned to the pyrone; the signals of the thiazole
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proton and of the proton at C-4 of the coumarin nucleus ap-
peared at δ = 7.96 and 8.17 ppm, respectively. This last signal
at δ = 8.17 ppm showed 2D-NOESY correlations with the signals
at δ = 7.96 (H-14) and 6.56 (H-10) ppm, indicating that the
thiazole and coumarin heterocycles are not coplanar with the
pyrazole ring.
The 13C NMR spectrum of 10b showed peaks at δ = 13.0 and
19.1 ppm due to the pyrazolone and pyran methyl carbon at-
oms, respectively, and at δ = 144.5 and 158.9 ppm due to C-4
and C-2, respectively, of the coumarin. From the HSQC correla-
tion chart, protons with resonances at δ = 5.87, 6.56, 7.96, and
Scheme 7. One-pot synthesis of coumarin derivatives 11a–11d.
8.17 ppm are linked to the carbon atoms with signals appearing
at δ = 100.5, 112.7, 112.1, and 144.5 ppm, which is typical of
pyran-2-one, pyrazolone, thiazole, and coumarin heterocycles,
respectively (Figure 3a). The long-range connectivities seen in
the methyl group singlet at δ = 2.34 ppm), thus confirming
the presence of the four heterocycles. Moreover, the H NMR
1
the HMBC spectrum (e.g., δH = 6.56 ppm → δ = 13.0, 138.5,
C
spectrum of this compound showed two doublets at δ = 7.06
and 7.33 ppm, which were not related by an H,H-COSY correla-
tion, and which were readily assignable to the two coumarin
protons H-5′ and H-8′. These two protons were found to be
linked to carbon atoms that resonated at δ = 128.3 and
1
1
1
52.4, and 160.2 ppm; δH = 7.96 ppm → δC = 144.5 and
60.2 ppm; δH = 8.17 ppm → δ = 102.2, 111.3, 130.5, 138.5,
C
56.2, and 158.9 ppm) supported the structure of 10b (Fig-
ure 3b). Further support for the presence of a thiazole ring is
provided by the signals at δ = 112.1 (C-14), 144.1 (C-13), and
1
16.0 ppm, respectively.
13C NMR spectroscopic analysis also confirmed the structural
160.2 (C-15) ppm. The spectroscopic data described above are
consistent with those expected for 3-methyl-1,5-diarylpyrazole
[
52,53]
identity, with resonances observed at δ = 111.9 ppm due to the
pyrazolone, δ = 116.9 ppm due to the thiazole, δ = 152.1 ppm
due to the C=N group, and δ = 158.8 and 158.6 ppm due to
the C=O groups. Analysis of the HSQC spectrum allowed the
assignment of all the protonated carbon resonances (Figure 4a);
the connectivities encountered in the HMBC spectrum (e.g.,
structures,
confirmed.
and thus the structure of compound 10b is
δH = 7.82 ppm → δC = 120.3, 144.4, and 158.6 ppm; δH
=
8
.07 ppm → δ = 160.1 ppm; and δ = 8.13 ppm → δ = 138.1,
C
H
C
1
42.3, 144.8, and 158.8 ppm) allowed the assignment of all the
quaternary carbon atoms, and confirmed the structure of com-
pound 11c as 3-{2-[5-(7-hydroxy-2-oxo-2H-chromen-3-yl)-3-
methyl-1H-pyrazol-1-yl]thiazol-4-yl}-2H-chromen-2-one
(Fig-
ure 4b). The molecular ion peaks of compound 11c were found
+
in the mass spectrum at m/z (%) = 469.0732 (19) [M + H] and
4
Figure 3. Selected H/13C NMR chemical shifts (δ [ppm]) (left); HMBC correla-
tions of compound 10b (black arrows), and significant nOe correlations (dou-
ble-ended blue arrows) (right).
1
+
92.0630 (100) [M + Na] , corresponding to the molecular for-
mula C H N O S. All the above spectroscopic data clearly in-
25 15
3 5
dicate the formation of the target product.
Following this successful strategy, a second series of couma-
rin derivatives 11a–11d was prepared by a related route.
Hantzsch cyclocondensation of 3-(bromoacetyl)coumarin 4 and
thiosemicarbazide 6 with a range of differentially substituted
3-(acetoacetyl)coumarins 5a–5d in ethanol under reflux gave
coumarin derivatives 11a–11d in very good yields (75–82 %),
without isolation of any intermediates (Scheme 7).
The structures of these bis(coumarin) derivatives were estab-
lished on the basis of spectroscopic data, as exemplified for
derivative 11c. Infrared spectroscopic analysis of compound
–
1
1
1c showed absorption bands at ν˜ = 1719, 1687, and 1347 cm
due to lactone (C=O), imine (C=N), and (C–S) functional groups,
respectively. The H NMR spectrum of 11c showed singlet sig-
Figure 4. Selected H/13C NMR chemical shifts (δ [ppm]) (left); HMBC correla-
tions (black arrows), and NOESY correlations (red arrows) for compound 11c
(right).
1
1
nals corresponding to the methine protons of two coumarins
(
δ = 8.13 and 7.82 ppm, assigned through their strong NOESY
correlation with signals at δ = 7.22 and 7.06 ppm, respectively),
A plausible mechanism for the formation of derivatives 10a–
a thiazole (δ = 8.07 ppm, without NOESY correlation) and a 10d and 11a–11d is shown in Scheme 8. First, the thiosemi-
pyrazolone (δ = 6.61 ppm, showing a NOESY correlation with carbazide could react with 3-(bromoacetyl) heterocycle 3 or 4
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with successive loss of HBr and water to give a Hantzsch thiaz- Conclusions
[
44,52]
ole product.
Nucleophilic displacement of the bromine
A new, facile, one-pot, multicomponent reaction for the synthe-
sis of substituted 3-{1-[4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-
atom of the bromoacetyl group by the sulfur atom of the thio-
semicarbazide could give an open-chain α-thioketone, which,
after protonation and nucleophilic attack onto the carbonyl
group gives 4-hydroxythiazoline intermediate D. Dehydration
then gives α-hydrazino-thiazole E. A product of type E has been
obtained in high yield from the reaction of bromide 3 with
3
-yl)thiazol-2-yl]-3-methyl-1H-pyrazol-5-yl}coumarins 10a–10d
and 3-{2-[5-(substituted-2-oxo-2H-chromen-3-yl)-3-methyl-1H-
pyrazol-1-yl]thiazol-4-yl}coumarins 11a–11d is presented. This
approach provides various advantages, such as short reaction
times, good yields, no catalyst requirements, high regioselectiv-
ity, and easy workup. It does not involve the use of volatile
organic solvents, which makes it an environmentally friendly
process. These highly functionalized derivatives containing up
to four different types of heterocyclic rings may be beneficially
used in drug research; their biological evaluation is in progress.
Moreover, intermediate α-hydrazonothiazoles or related
α-hydrazono heterocycles are useful building blocks in
[
57]
thiosemicarbazide 6 in ethanol.
Subsequently, condensation
reaction of 2-hydrazino-thiazole derivative E with (aceto-
acetyl)coumarins 5a–5d could result in formation of the Knorr-
[
45,53,54]
pyrazole skeleton,
and give the final products via thi-
azolyl-hydrazono-butanoyl-coumarin derivative F. The reaction
is initiated by protonation of one of the carbonyl groups of the
1,3-diketone to form an imine. Although such a Knorr pyrazole
cyclocondensation is generally known to occur with poor regio-
selectivity, we observed only the 3-methyl-1,5-diarylpyrazoles
[
57–60]
MCRs;
these compounds deserve further study as they
could provide access to greater skeletal diversity.
(
i.e., 10 and 11) through this MCR protocol. Similar highly regio-
selective access to analogous 3-alkyl-1,5-diarylpyrazoles has
previously been described starting from arylhydrazines and ꢀ-
Experimental Section
[
52]
diketones in water under supported acid catalysis,
at 50–
[
45]
6
0 °C for 4–5 h in neutral or basic ethanol,
or under acidic General Remarks: Anhydrous ethanol, ethyl acetoacetate, 2-
[
53]
conditions.
This further supports the proposed mechanism hydroxybenzaldehydes, dehydroacetic acid, and thiosemicarbazide
were purchased from Sigma–Aldrich, and were used without further
starting with formation of the thiazole, because production of
HBr in the first step will favor the high regioselectivity of the
MCR, leading to the exclusive formation of the 1,5-diarylpyr-
azoles 10 and 11. Overall, this three-component domino trans-
formation leads to the generation of one C–S, one C=N, and
two C–N bonds. In this reaction, two heterocyclic ring systems,
thiazole and pyrazole, were developed successively.
purification unless otherwise stated. Melting points were deter-
mined with a Stuart scientific SPM3 apparatus fitted with a micro-
scope. FTIR spectra were recorded as neat solids with a Fourier
Transform Bruker Vector 22 spectrometer. NMR spectra were re-
1
corded with a Bruker Avance 1 spectrometer [400 MHz ( H) and
13
1
1
00 MHz ( C)] or a Bruker AH 300 FT spectrometer [300 MHz ( H)
13
and 75 MHz ( C)]. Chemical shifts are expressed in parts per million
ppm) downfield from the TMS signal. Data are reported as follows:
(
chemical shift [multiplicity (s: singlet, d: doublet, dd: doublet of
doublets, ddd: doublet of doublet of doublets, dt: doublet of trip-
lets, t: triplet, m: multiplet), integration, coupling constants (J) in
Hertz (Hz)]. The numbers of attached proton(s) in the 13C NMR spec-
tra were elucidated using JMOD experiments, and are described as:
(
CH ) methyl, (CH ) methylene, (CH) methine, (C) quaternary carbon
3 2
1
13
atom. Shifts of H and C NMR spectra were calibrated using the
solvent residual isotopic peak as internal reference. Reference peaks
1
13
for the NMR spectra in (CD S) O: δ = 2.50 ( H) and 39.52 ( C) ppm.
3
2
1
3
C NMR assignments were checked using the free CSEARCH Robot
[
61]
Referee online service.
Deviations less than 5 ppm were ob-
served for new compounds. The enol and keto forms are described
as they appear in the spectra as a mixture of Major (M) and/or
minor (m) tautomers. Mass spectra were determined with a Waters
Micromass LCT Premier Q-TOF mass spectrometer coupled with a
Waters Alliance HPLC system. Syntheses under microwave irradia-
tion were carried out with a CEM Discover monomode microwave
apparatus.
Synthesis of 3-Acetyl-2H-chromen-2-one (9) and 3-(Bromo-
acetyl)-2H-chromen-2-one (4): 3-Acetylcoumarin (9) and 3-
(
bromoacetyl)coumarin (4) were prepared as follows: A mixture of
salicylaldehyde (12.212 g, 10.6 mL, 0.1 mol) and ethyl acetoacetate
13.014 g, 12.8 mL, 0.1 mol) was stirred in ethanol (20 mL) in the
(
presence of a catalytic amount of piperidine (5 drops) at room tem-
perature for 30 min. The yellowish solid was collected by filtration,
then washed and recrystallized from ethanol to give 3-acetylcouma-
[48]
rin (9; 14.49 g, 77 %) as fine yellow needles; m.p. 120 °C (ref. m.p.
1
Scheme 8. A plausible mechanism for the formation of 10a–10d and 11a–
119–121 °C). H NMR (300 MHz, [D
6
]DMSO): δ = 2.58 (s, 3 H), 7.37–
11d.
7.45 (m, 2 H), 7.73 (ddd, J = 8.3, 7.3, 1.6 Hz, 1 H), 7.93 (dd, J = 7.7,
Eur. J. Org. Chem. 2016, 2628–2636
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2633
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
.6 Hz, 1 H), 8.63 (s, 1 H) ppm. 13C NMR (75 MHz, [D ]DMSO): 30.5
13
C NMR (75 MHz, [D ]DMSO): δ = 27 (CH3M), 30.39 (CH3m), 56.4
1
6
6
(
(
(
CH ), 116.5 (CH), 118.6 (C), 124.9 (C), 125.3 (CH), 131.2 (CH), 134.9 (CH2m), 100.9 (CH ), 119.0 (C ), 119.2 (C ), 119.5 (C ), 120.2 (CH ),
3 M m M M M
CH), 147.5 (CH), 155.0 (C), 158.8 (C), 195.5 (C) ppm. Coumarin 9 120.5 (CH ), 120.9 (CH ), 124.9 (CH ), 125.1 (CH ), 142.6 (C ), 144.3
M
m
M
m
M
3.764 g, 20 mmol) was dissolved in acetic acid (20 mL), and a solu-
(C ), 146.5 (CH ), 148.3 (C ), 157.3 (C ), 173.1 (C ), 191.8 (C ),
M M m M M m
tion of bromine (3.196 g, 1.03 mL, 20 mmol) in acetic acid (10 mL) 199.0 (C ), 203.3 (C ) ppm. HRMS (ESI): calcd. for C H O [M +
M
m
13 11 5
+
was added dropwise with stirring. The mixture was heated at reflux
for 1 h, then it was cooled, and the crude solid was collected by
filtration. The solid was purified by recrystallization from glacial ace-
H] 247.0606; found 247.0607 (20 %); calcd. for C H NaO [M +
Na] 269.0426; found 269.0426 (100 %).
13 10 5
+
7
,8-Dihydroxy-3-(1-hydroxy-3-oxobut-1-enyl)-2H-chromen-2-
tic acid to give 3-(bromoacetyl)coumarin (4; 3.205 g, 60 %) as a dark
yellow solid; m.p. 160–163 °C (ref.[
49]
m.p. 160–163 °C). 1H NMR
one (5d): Yellow solid (0.905 g, 69 %); m.p. 252 °C. M: enol form
8
0 %, m: keto form 20 %. IR (neat): ν˜ = 3331, 1692, 1612, 1464, 1253,
(
300 MHz, [D ]DMSO): δ = 4.70 (s, 2 H ), 4.90 (s, 2 H ), 7.46 (dd, J =
6 m M
–1 1
1159, 1078, 813 cm . H NMR (300 MHz, [D ]DMSO): δ = 2.19 (s, 3
6
1
7.2, 8.0 Hz, 2 H), 7.72–7.81 (m, 1 H), 7.96–8.00 (m, 1 H), 8.74 (s, 1
7
9
+
+
H
M
, CH
1 H ), 6.89 (s, 1 H
1 H ), 7.34 (d, J = 8.6 Hz, 1 H
(br. s, 2 H, OH), 16.27 (s, 1 H
[D ]DMSO): δ = 26.5 (CH3M), 30.6 (CH3m), 56.5 (CH2m), 100.0 (CH
11.6 (C ), 111.8 (C ), 113.5 (CH ), 113.6 (CH ), 114.1 (C ), 118.0
3
), 2.22 (s, 3 H
), 6.89 (d, J = 8.6 Hz, 1 H
), 8.61 (s, 1 H
, OH) ppm. C NMR (75 MHz,
),
m
, CH
3
), 4.11 (s, 2 H
m
, CH
2
), 6.86 (d, J = 8.6 Hz,
), 7.29 (d, J = 8.6 Hz,
), 8.66 (s, 1 H ), 10.17
H ), 8.83 (s, 1 H ) ppm. HRMS (ESI): calcd. for C H O Br [M + H]
2
2
Na] 288.9476; found 288.9471 (100 %); calcd. for C H O BrNa [M
+
m
M
11
8
3
8
1
M
M
m
66.9657; found 266.9661 (21 %); calcd. for C H O Br [M + H]
68.9636; found 268.9639 (20 %); calcd. for C H O BrNa [M +
1
1 8 3
7
9
M
m
m
M
1
1 7 3
1
3
+
81
M
1
1 7 3
+
6
M
Na] 290.9456; found 290.9451 (99 %).
1
m
M
M
m
M
General Procedure for the Synthesis of 3-Acetoacetylcoumarin
Derivatives 5a–5d: Substituted 2-hydroxybenzaldehydes 7a–7d
(C ), 121.8 (CH ), 122.7 (CH ), 131.7 (C ), 131.8 (C ), 144.2 (C ),
m M m M m M
144.9 (C ), 147.2 (CH ), 149.1 (CH ), 152.7 (C ), 153.2 (C ), 157.8
m M m M m
(5 mmol), TAL (2; 0.630 g, 5 mmol), and piperidine (2 mL) were
(C ), 159.4 (C ), 174.8 (C ), 191.5 (C ), 197.5 (C ), 203.4 (C ) ppm.
M m M m M m
placed into a dry microwave glass flask (80 mL). The mixture was
submitted to microwave irradiation at 300 W for 5–10 min. Then,
the mixture was cooled to room temperature, and the solid material
was collected by filtration and washed with water. The crude prod-
+
HRMS (ESI): calcd. for C H O [M + H] 263.0566; found 263.0552
1
3 11 6
+
(
(
20 %); calcd. for C H NaO [M + Na] 285.0375; found 285.0368
100 %).
13 10 6
uct was purified by recrystallization from ethanol to give pure prod- General Procedure for the Synthesis of Compounds 10a–10d: A
ucts 5a–5d.
mixture of 3-(bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one (3;
.247 g, 1 mmol), thiosemicarbazide (0.091 g, 1 mmol), and 3-
acetoacetyl)coumarin derivative (5a–5d; 1 mmol), in anhydrous
0
(
3
-(1-Hydroxy-3-oxobut-1-enyl)-2H-chromen-2-one (5a): Yellow
[42,55]
solid (0.806 g, 70 %); m.p. 149 °C (ref.
m.p. 148–150 °C). M:
ethanol (10 mL) was heated at reflux for 4 h. The products obtained
were collected by filtration, washed with hot ethanol, dried, then
washed again with DMSO in order to remove all traces of the start-
ing materials.
8
1
0 % enol form, m: 20 % ketone form. IR (neat): ν˜ = 3063, 1729,
–1 1
608, 1584, 1262, 1187, 1010, 818 cm . H NMR (300 MHz,
[D ]DMSO): δ = 2.23 (s, 3 H ), 2.24 (s, 3 H ), 4.17 (s, 2 H ), 6.90 (s,
6 m M m
1
H ), 7.39–7.48 (m, 2 H), 7.74 (ddd, J = 8.7, 7.3, 1.6 Hz, 1 H), 7.96
M
13
(dd, J = 7.8, 1.6 Hz, 1 H), 8.81 (s, 1 H), 16.04 (s, 1 H ) ppm. C NMR
M
3-{1-[4-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)thiazol-2-yl]-
3-methyl-1H-pyrazol-5-yl}-2H-chromen-2-one (10a): Yellow solid
(0.347 g, 80 %); m.p. 262–264 °C. IR (neat): ν˜ = 3410, 1715, 1687,
(75 MHz, [D ]DMSO): δ = 27.0 (CH3M), 30.4 (CH3m), 56.4 (CH2m), 101.0
6
(CH), 116.0 (CH ), 116.0 (CH ), 118.1 (C ), 118.3 (C ), 119.7 (C ),
M
m
m
M
M
1
20.5 (C ), 124.9 (CH ), 125.1 (CH ), 130.3 (CH ), 131.1 (CH ), 134.4
–1 1
m
M
m
M
m
1346 cm . H NMR (300 MHz, [D ]DMSO): δ = 2.16 (s, 3 H, pyrone),
6
(CH ), 134.9 (CH ), 146.1 (CH ), 147.9 (CH ), 153.9 (C), 157.3 (C),
M
m
M
m
2.36 (s, 3 H, pyrazole), 5.90 (s, 1 H, pyrone), 6.71 (s, 1 H, pyrazole),
7.41–7.57 (m, 2 H), 7.73 (t, J = 7.4 Hz, 1 H), 7.83 (d, J = 7.7 Hz, 1 H),
7.98 (s, 1 H, thiazole), 8.45 (s, 1 H, coumarin), 12.47 (s, 1 H, OH) ppm.
+
+
1
2
2
72.9 (C), 199.0 (C) ppm. HRMS (ESI): calcd. for C H O [M + H]
13 11 4
31.0657; found 231.0652 (40 %); calcd. for C H NaO [M + Na]
1
3
10
4
53.0477; found 253.0471 (100 %).
13
C NMR (75 MHz, [D ]DMSO): δ = 13.2 (CH -12), 19.2 (CH -20), 94.1
6
3
3
(
C-16), 100.4 (CH), 112.3 (CH), 113.1 (CH), 116.2 (CH), 117.7 (C), 118.4
(C), 125.0 (CH), 129.1 (CH), 133.1 (CH), 137.5 (C), 143.7 (C), 144.3
CH), 152.3 (C), 153.7 (C), 158.3 (C), 159.9 (C), 161.1 (C), 162.8 (C),
7
-Hydroxy-3-(1-hydroxy-3-oxobut-1-enyl)-2H-chromen-2-one
[42]
(5b): Yellow solid (0.887 g, 72 %); m.p. 214 °C (ref.
m.p. 215 °C).
(
M: enol form, 79 %; m: keto form, 21 %. IR (neat): ν˜ = 3362, 1688,
+
–
1
1
167.5 (C) ppm. HRMS (ESI): calcd. for C22H16N O S [M + H]
4
Na] 456.063; found 456.0638 (100 %).
1
623, 1560, 1284, 1134, 1023, 822 cm
.
H NMR (300 MHz,
3 5
34.0811; found 434.0814 (43 %); calcd. for C H N NaO S [M +
[D ]DMSO): δ = 2.19 (s, 3 H , CH ), 2.21 (s, 3 H , CH ), 4.09 (s, 2 H,
22 15 3 5
6
M
3
m
3
+
CH2m), 6.72 (d, J = 2.1 Hz, 1 H ), 6.82 (d, 1 H , J = 2.2 Hz), 6.84 (s,
M
M
1
H ), 6.85 (s, 1 H ), 7.76 (d, J = 8.6 Hz, 1 H ), 8.65 (s, 1 H ), 8.70
M m M m
7
-Hydroxy-3-{1-[4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)thi-
1
3
(
[
s, 1 H ), 9.91 (s, 1 H, OH), 16.24 (s, 1 H, OH) ppm. C NMR (75 MHz,
D ]DMSO): δ = 26.5 (CH3M), 30.4 (CH3m), 56.5 (CH2m), 100 (CHM),
M
azol-2-yl]-3-methyl-1H-pyrazol-5-yl}2H-chromen-2-one (10b):
Yellow solid (0.328 g, 73 %); m.p. >300 °C. IR (neat): ν˜ = 3410, 1715,
6
1
01.7 (CH ), 101.8 (CH ), 110.7 (C ), 110.8 (C ), 114.3 (C ), 114.4
–1 1
M
m
m
M
m
1687, 1346 cm . H NMR (400 MHz, [D ]DMSO): δ = 2.16 (s, 3 H,
6
(CH ), 114.6 (CH ), 117.6 (C ), 132.2 (CH ), 133 (C ), 146.6 (CH ),
M m M M m M
pyrone), 2.31 (s, 3 H, pyrazole), 5.87 (s, 1 H, pyrone), 6.56 (s, 1 H,
pyrazole), 6.77 (d, J = 1.6 Hz, 1 H, 8-H), 6.85 (dd, J = 8.4, 1.6 Hz, 1
H, 6-H), 7.58 (d, J = 8.4 Hz, 1 H, 5-H), 7.96 (s, 1 H, thiazole), 8.17 (s,
1
1
1
48.4 (CH ), 156.6 (C ), 157.4 (C ), 157.8 (C ), 164.5 (C ), 165 (C ),
M M m M M m
74.9 (C ), 191.3 (C ), 197.4 (C ), 203.3 (C ) ppm. HRMS (ESI): calcd.
M
m
M
m
+
for C H O [M + H] 247.0606; found 247.0609 (22 %); calcd. for
C H NaO [M + Na] 269.0426; found 269.0426 (100 %).
13
1
3 11 5
H, 4-H), 10.60 (s, 1 H, OH), 12.45 (s, 1 H, OH) ppm. C NMR
+
13
10
5
(100 MHz, [D ]DMSO): δ = 13.0 (CH -12), 19.1 (CH -20), 94.4 (C-16),
6 3 3
8
-Hydroxy-3-(1-hydroxy-3-oxobut-1-enyl)-2H-chromen-2-one
100.5 (CH-18), 102.2 (CH-8), 111.3 (C-4a), 112.1 (CH-14), 112.7 (CH-
10), 113.1 (C-3), 113.8 (CH-6), 130.5 (CH-5), 138.5 (C-9), 144.1 (C-15),
[56]
(5c): Yellow solid (0.911 g, 74 %); m.p. 230 °C (ref.
m.p. 235 °C).
M: enol form 83 %, m: keto form 17 %. IR (neat): ν˜ = 3189, 1719, 144.5 (CH-4), 152.4 (C-11), 156.2 (C-8a), 158.9 (CO-2), 160.2 (C-13),
–
1 1
1
[
612, 1470, 1290, 1113, 1077, 816 cm
. H NMR (300 MHz, 161.4 (CO-21), 162.4 (C-7), 162.8 (C-17 and C-19) ppm. HRMS (ESI):
+
D ]DMSO): δ = 2.23 (s, 3 H , CH ), 2.24 (s, 3 H , CH ), 4.17 (s, 2 H,
CH2m), 6.92 (s, 1 H ), 7.19–7.25 (m, 2 HM+m), 7.33–7.42 (m, 1 HM+m), calcd. for C22H15N NaO S [M + Na] 472.0579; found 472.0579
calcd. for C H N O S [M + H] 450.0760; found 450.0760 (19 %);
6
m
3
M
3
22 16 3 6
+
M
3
6
8
.69 (s, 1 H ), 8.76 (s, 1 H ), 10.42 (s, 1 H, OH), 16.04 (s, 1 H) ppm.
(100 %).
m
M
Eur. J. Org. Chem. 2016, 2628–2636
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2634
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
+
8
-Hydroxy-3-{1-[4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)thi- C H N O S [M + H] 470.0811; found 470.0818 (18 %); calcd. for
25 16 3 5
+
azol-2-yl]-3-methyl-1H-pyrazol-5-yl}-2H-chromen-2-one (10c):
C H N NaO S [M + Na] 492.0630; found 492.0642 (100 %).
25 15 3 5
Yellow solid (0.342 g, 76 %); m.p. >300 °C. IR (neat): ν = 3201, 1730,
˜
3
-{2-[5-(8-Hydroxy-2-oxo-2H-chromen-3-yl)-3-methyl-1H-pyr-
–1 1
1
672, 1360 cm . H NMR (300 MHz, [D ]DMSO): δ = 2.17 (s, 3 H,
6
azol-1-yl]-thiazol-4-yl}-2H-chromen-2-one (11c): Yellow solid
pyrone), 2.34 (s, 3 H, pyrazole), 5.94 (s, 1 H, pyrone), 6.70 (s, 1 H,
pyrazole), 7.00–7.35 (m, 3 H), 7.99 (s, 1 H, thiazole), 8.39 (s, 1 H,
coumarin), 10.30 (s, 1 H, OH), 12.45 (s, 1 H, OH) ppm. 13C NMR
(
0.357 g, 76 %); m.p. >300 °C. IR (neat): ν˜ = 3140, 1719, 1687,
–1 1
1
6
4
7
347 cm . H NMR (400 MHz, [D ]DMSO): δ = 2.34 (s, 3 H, CH ),
6
3
.61 (s, 1 H, pyrazole), 7.06 (d, J = 7.4 Hz, 1 H, 5′-H), 7.21–7.25 (m,
H, 5-H, 6-H, 7-H, 6′-H), 7.33 (d, J = 8.1 Hz, 1 H, 8′-H), 7.56 (t, J =
.5 Hz, 1 H, 7′-H), 7.82 (s, 1 H, 4′-H), 8.07 (s, 1 H, thiazole), 8.13 (s, 1
(
75 MHz, [D ]DMSO): δ = 13.2 (CH -12), 19.2 (CH -20), 94.1 (C-16),
6 3 3
1
1
00.5 (CH), 112.2 (CH), 113.1 (CH), 117.5 (C), 119.0 (CH), 119.3 (CH),
19.4 (C), 124.9 (CH), 137.6 (C), 142.4 (C), 143.7 (C), 144.5 (C), 144.7
13
H, 4-H) ppm. C NMR (100 MHz, [D ]DMSO): δ = 13.0 (CH -12),
6
3
(
CH), 152.3 (C), 158.2 (C), 159.9 (C), 161.1 (C), 162.7 (C), 167.6 (C)
111.9 (CH-10), 116.0 (CH-8′), 116.5 (CH-14), 118.9 (C-4′a), 119.1 (CH-
7), 119.2 (CH-5), 119.9 (C-4a), 120.1 (C-3), 120.3 (C-3′), 124.7 (CH-6′),
125.1 (CH-6), 128.3 (CH-5′), 132.1 (CH-7′), 138.1 (C-9), 138.6 (CH-4′),
142.3 (C-8), 143.0 (CH-4), 144.4 (C-15), 144.8 (C-8a), 152.1 (C-11),
+
ppm. HRMS (ESI): calcd. for C H N O S [M + H] 450.0760; found
4
2
2 16 3 6
+
50.0763 (33 %); calcd. for C22H15N NaO S [M + Na] 472.0579;
3 6
found 472.0573 (100 %).
7
,8-Dihydroxy-3-{1-[4-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-
152.7 (C-8′a), 158.6 (C-2′), 158.8 (C-2), 160.1 (C-13) ppm. HRMS (ESI):
+
yl)thiazol-2-yl]-3-methyl-1H-pyrazol-5-yl}-2H-chromen-2-one
calcd. for C H N O S [M + H] 470.0811; found 470.0813 (19 %);
2
5 16 3 5
+
(10d): Yellow solid (0.391 g, 84 %); m.p. >300 °C. IR (neat): ν = 3419,
calcd. for C25H15N NaO S [M + Na] 492.063; found 492.0630
˜
3 5
–1 1
1
719, 1668, 1342 cm . H NMR (300 MHz, [D ]DMSO): δ = 2.14 (s, (100 %).
6
3
H, pyrone), 2.29 (s, 3 H, pyrazole), 5.93 (s, 1 H, pyrone), 6.60 (s, 1
3
-{2-[5-(7,8-Dihydroxy-2-oxo-2H-chromen-3-yl)-3-methyl-1H-
H, pyrazole), 6.88 (d, J = 8.5 Hz, 1 H), 7.14 (d, J = 8.5 Hz, 1 H), 7.93
pyrazol-1-yl]thiazol-4-yl}-2H-chromen-2-one (11d): Yellow solid
(s, 1 H, thiazole), 8.22 (s, 1 H, coumarin), 9.54 (s, 1 H, OH), 10.41 (s,
(
0.388 g, 79 %); m.p. >300 °C. IR (neat): ν˜ = 3348, 1703, 1625,
–1 1
1
3
1
1
H, OH), 12.51 (s, 1 H, OH) ppm. C NMR (75 MHz, [D ]DMSO): δ =
6
1
6
7
1
345 cm . H NMR (400 MHz, [D ]DMSO): δ = 2.35 (s, 3 H, CH ),
6
3
3.7 (CH -12), 19.2 (CH -20), 94.1 (C-16), 100.6 (CH), 111.8 (CH), 112.0
3
3
.62 (s, 1 H, pyrazole), 6.92 (d, J = 8.4 Hz, 1 H), 7.07–7.18 (m, 2 H),
.29 (td, J = 7.7, 0.9 Hz, 1 H), 7.39 (d, J = 8.3 Hz, 1 H), 7.58–7.64 (m,
(
1
(
C), 112.4 (C), 112.8 (CH), 113.1 (CH), 119.8 (CH), 132.0 (C), 138.3 (C),
43.7 (C), 143.9 (C), 145.1 (CH), 150.7 (C), 152.2 (C), 158.6 (C), 160.0
C), 161.1 (C), 162.7 (C), 167.7 (C) ppm. HRMS (ESI): calcd. for
H), 7.86 (s, 1 H, coumarin), 8.09 (s, 1 H, thiazole), 8.10 (s, 1 H,
13
coumarin), 9.49 (s, 1 H, OH), 10.19 (s, 1 H, OH) ppm. C NMR
+
C H N O S [M + H] 466.0709; found 466.0715 (20 %); calcd. for
C H N NaO S [M + Na] 488.0528; found 488.0541 (100 %).
22 16 3 7
(
(
100 MHz, [D ]DMSO): δ = 13.3 (CH ), 111.8 (CH), 111.9 (C), 113.0
CH), 114.8 (C), 116.0 (CH), 116.6 (CH), 118.6 (C), 119.6 (CH), 120.1
6
3
+
22
15
3
7
General Procedure for the Synthesis of Compounds 11a–11d: A
mixture of 3-(bromoacetyl)-2H-chromen-2-one (7; 0.267 g, 1 mmol),
thiosemicarbazide (0.091 g, 1 mmol), and 3-(acetoacetyl)coumarin
derivatives (5a–5d; 1 mmol) in anhydrous ethanol (10 mL) was
heated at reflux for 4 h. The products obtained were collected by
filtration, washed with hot ethanol, dried, then washed again with
DMSO in order to remove all traces of the starting materials.
(C), 124.9 (CH), 128.2 (CH), 132.2 (CH), 132.3 (COH), 138.3 (C), 138.4
(CH), 143.4 (C), 143.7 (CH), 144.0 (C), 150.4 (C), 151.7 (C), 152.4 (C),
158.4 (C), 159.2 (C), 159.8 (C) ppm. HRMS (ESI): calcd. for
+
C H N O S [M + H] 486.0754; found 486.0756 (17 %); calcd. for
2
5 16 3 6
+
C H N NaO S [M + Na] 508.0574; found 508.0579 (100 %).
25
15
3
6
Acknowledgments
3
-{2-[3-Methyl-5-(2-oxo-2H-chromen-3-yl)-1H-pyrazol-1-yl]thi-
The authors thank Karine Leblanc (Faculty of Pharmacy, Châte-
azol-4-yl}-2H-chromen-2-one (11a): Yellow solid (0.372 g, 82 %);
1
m.p. >300 °C. H NMR (300 MHz, [D ]DMSO): δ = 2.36 (s, 3 H), 6.71 nay-Malabry, France) for high-resolution mass spectra and ele-
6
(s, 1 H, pyrazole), 6.79 (dd, J = 7.8, 1.3 Hz, 1 H), 7.30 (td, J = 7.6, mental analyses. The Ministry of Higher Education and Scientific
0
7
7
.9 Hz, 1 H), 7.41 (d, J = 8.3 Hz, 1 H), 7.51 (td, J = 7.6, 1.0 Hz, 1 H),
.58–7.63 (m, 1 H), 7.68 (d, J = 8.1 Hz, 1 H), 7.74 (s, 1 H, thiazole),
.78–7.84 (m, 1 H), 7.87 (dd, J = 7.7, 1.4 Hz, 1 H), 8.13 (s, 1 H,
Research (Algeria), the Centre National de la Recherche Scientif-
ique, and the Ministry of Education, Research, and Technology
(France) are gratefully acknowledged for financial support.
1
3
coumarin), 8.34 (s, 1 H, coumarin) ppm. C NMR (75 MHz,
[
(
D ]DMSO): δ = 13.8 (CH ), 112.5 (CH), 116.6 (CH), 116.8 (CH), 117.3
6
3
CH), 118.9 (C), 119.2 (C), 120.4 (C), 120.6 (C), 125.3 (CH), 125.9 (CH), Keywords: Multicomponent reactions · Nitrogen
1
1
(
28.2 (CH), 129.7 (CH), 132.7 (CH), 133.3 (CH), 138.6 (CH), 139.6 (C), heterocycles · Oxygen heterocycles · Sulfur heterocycles ·
43.1 (CH), 143.3 (C), 152.4 (C), 152.8 (C), 153.8 (C), 155.7 (CS), 157.4
Cyclization · One-pot reactions
+
C), 160.2 (C) ppm. HRMS (ESI): calcd. for C H N O S [M + H]
25 16 3 4
4
54.0862; found 454.0857 (28 %); calcd. for C H N NaO S [M +
25 15 3 4
+
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2636
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim