Manipulating a Multicomponent Reaction: A Straightforward Approach to Chromenopyrazole Hybrid Scaffolds

Article abstract of DOI:10.1055/s-0036-1589013

An easy access to hybrid bioactive molecules, such as the chromenopyrazoles, is described based on the three-component reactions of 3-formylchromones, arylhydrazines, and acetylenedicarboxylates. By manipulating the reaction, four different scaffolds can

Full text of DOI:10.1055/s-0036-1589013

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–N
paper
A
en
P. M. Kasapidou et al.
Paper
Synthesis
Manipulating a Multicomponent Reaction: A Straightforward
Approach to Chromenopyrazole Hybrid Scaffolds
R3
Paraskevi M. Kasapidoua,b
Tryfon Zarganes-Tzitzikasa,c
Constantinos A. Tsoleridisa
Julia Stephanidou-Stephanatoua
Constantinos G. Neochoritis*a,c
AcOH,
MW, 130 °C, 10 min
R2
R1
O
R1, R3 = H, Cl, Me
R2 = H, Me
O
NHNH2
N
R2
R1
O
N
R
4 = Me, Et
Zwitterion
O
CO2R4
O
a Laboratory of Organic Chemistry, Department of
Chemistry, Aristotle University of Thessaloniki,
Thessaloniki 54124, Macedonia, Greece
b Medway School of Pharmacy, Universities of
Greenwich and Kent at Medway, Chatham Maritime,
Kent, ME4 4TB, UK
c Department of Pharmacy, University of Groningen,
Deusinglaan 1, 9700 AD Groningen, The Netherlands
k.neochoritis@rug.nl
+
53–76% yield, 19 examples
O
R3
O
R2
R1
Yb(OTf)3, toluene,
reflux 5 h
R4O2C
CO2R4
N
R3
N
Schiff base
R
1 = Me, Cl
O
R4O2C
R2 = H, Me
CO2R4
R
3 = H, Me, Cl
R4 = Me, Et
53–66% yield, 4 examples
Dedicated to Prof. C. A. Tsoleridis on the occasion of his
67th birthday
Received: 29.01.2017
Accepted after revision: 28.03.2017
Published online: 09.05.2017
covery with various biophysical screening systems,10–16 or
other types of synthetic approaches e.g. multicomponent
reaction (MCR) chemistry.17–23 In the same direction, we
currently know that a few structural subunits of a certain
bioactive molecule may be more relevant to a specific phar-
macologic activity, governing the main interactions with a
receptor. Therefore, some molecular scaffolds may have
pharmacophoric characteristics for a certain type of recep-
tor and not for others. These types of scaffolds are called
privileged and the privileged scaffold concept is commonly
used in medicinal chemistry, either alone or as a combined
strategy, mixing other molecular design techniques such as
bioisosterism.24,25 Combining two privileged structures in
one chemical entity leading to hybrid molecules, also
known as designed multiple ligands, for a specific biological
target is an emerging approach in drug discovery that could
generate a lead compound being more effective than its in-
dividual components. Furthermore, a hybrid molecule can
independently act at two distinct pharmacological target
structures in an overall synergistic manner and conse-
quently is designed in order to maintain its individual com-
ponents at these two targets. Due to the complexity of cer-
tain diseases, such as neurodegenerative disorders that are
not effectively targeted by one highly selective ligand, the
hybrid approach would have inherent advantages.26–29
Chromenopyrazoles, as a characteristic example of a hy-
brid molecule combing both a chromone30 and a pyrazole
ring,25,31 exhibit a wide range of biological and pharmaco-
logical activities. Recently, they gained attention as Δ9-tet-
rahydrocannabinoid analogues (Figure 1, compounds 1 and
2) with non-psychoactive CB1 and CB2 receptor selectivity,
exhibiting in vivo activity in a model of multiple sclerosis32
DOI: 10.1055/s-0036-1589013; Art ID: ss-2017-z0057-op
Abstract An easy access to hybrid bioactive molecules, such as the
chromenopyrazoles, is described based on the three-component reac-
tions of 3-formylchromones, arylhydrazines, and acetylenedicarboxyl-
ates. By manipulating the reaction, four different scaffolds can be de-
rived in an easy, versatile, and robust fashion. To underscore the
potential, generality, and diversity that can be generated, representa-
tive libraries of each scaffold were synthesized. Moreover, a compre-
hensive NMR analysis with full assignment of all 1H and 13C NMR chemi-
cal shifts has been performed.
Key words 3-formylchromones, multicomponent reactions, chrom-
enopyrazoles, microwave irradiation, hybrid molecules, zwitterions
The use of combinatorial chemistry techniques and
robotized screening, the so-called high throughput synthe-
sis and high throughput screening (HTS), has greatly influ-
enced both the design of new chemical libraries for bio-
assays and the level of research conducted in industrial
laboratories. However during recent years, more scientists
have applied HTS to the identification of chemical probes
and drug leads for an expanding number of biological tar-
gets and because of this the limitations and pitfalls of HTS
technologies are becoming obvious. Inflation-adjusted in-
dustrial R&D costs per novel drug have increased nearly
100-fold between 1950 and 2010 and drugs are more likely
to fail in clinical development today than in the 1970s.1–6
The quality of the libraries in terms of diversity and com-
plexity seems to be a major issue, thus alternative, comple-
mentary techniques have been applied, for example ad-
vanced in silico approaches,7–9 fragment-based ligand dis-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

B
P. M. Kasapidou et al.
Paper
Synthesis
Cl
R3
O
O
O
R2
R1
O
O
N
N
R2
OH
N
N
O
N
R1
N
N
OH
N
O
1
2
3
4
anti-inflammatory, anticancer,
multi-ion detectors
antibacterial, antifungal
selective CB1 cannabinoid agonists
O
O
N
N
OH
D9-THC
Edaravone®
Figure 1 Recent examples of chromenopyrazole scaffolds with enhanced biological activity
and having peripheral antinociceptive properties in a rat
model.33 The chromenopyrazole-based conjugates 3, which
bear the bioactive phenyl-4H-pyrazol-3-one moiety (Edara-
vone, brand name: Radicut)34 were identified as anti-
inflammatory molecules (inhibition of COX-2, COX-1, and
5-LOX),35 anticancer agents on 60 different cell lines36 and
multi-ion detectors.37 Finally, compounds 4 demonstrated
in vitro antibacterial and antifungal activities.38 There are
few synthetic approaches towards chromenylpyrazole scaf-
folds, but they are limited in scope, availability of starting
materials, and difficulty in parallel producing libraries for
screening. Some syntheses are based on chromone phenyl-
hydrazones in a three-step sequence39 or a four-component
reaction involving nitroketene N,S-acetals.40 Chromenopyr-
azolines were synthesized from chromonyl chalcones either
by 1,3-dipolar cycloaddition with diazomethane41,42 or by
refluxing with hydrazines.43–46
In addition, direct condensation of 3-formylchromones
with 1-phenyl-1H-pyrazol-5(4H)-ones towards the desired
Knoevenagel adduct was also employed for the synthesis of
chromenopyrazolinones.47,48 Recently, a three-component
reaction catalyzed by Lewis acid was described involving
differently substituted aromatic aldehydes, ethyl acetoace-
tate, and phenylhydrazine yielded pyrazolone derivatives.49
Overall we could comment that the diversification oppor-
tunities in the above-mentioned synthetic approaches are
relatively low, since most of the structural modifications of
the scaffolds occurred at the chromene ring. We believe
that a cheap, scalable, and one-pot, diverse parallel ap-
proach to chromenopyrazoles could be of high interest and
a valuable tool for constructing vast libraries as screening
decks.
constructing the chromenopyrazole and chromenopyra-
zolinone scaffolds, we envisioned providing an easy access
to these hybrid molecules. A versatile and robust procedure
with as many as possible diversity in order to build decks
for screening would be our goal.
For this reason, we designed a multicomponent reaction
that is based on the zwitterionic intermediates of a hydra-
zine derivative and an acetylenedicarboxylate molecule re-
acting with an aldehyde,58–61 in our case the 3-formylchro-
mone. This reaction could serve our purpose; cheap and
E
R2
R1
O
N
N
E
O
X
R1
R2
O
5
N
O
E
DEAD
PPh3
E
6
DMAD
R2
R1
O
N
DMAD
R4NHNH2
O
this work
O
DMAD
N
O
S
DMAD
R3NC
X
S
R1
R2
N
O
E
R2
R1
O
E
7
O
NHR3
O
X = CHO
E = CO2R3
E
Due to our long experience and extensive studies of em-
ploying amphiphilic species on the 3-formyl-50–55 (Scheme
1, compounds 5–8) or 3-cyanochromone56,57 and taking
into account the general concepts existing in literature of
E
8
Scheme 1 Studies on the 3-formylchromone derivatives of our group
based on the generation of amphiphilic species
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

C
P. M. Kasapidou et al.
Paper
Synthesis
Cl
Cl
CO2Me
NHNH2
CO2Me
O
O
O
N
R2
R1
O
O
O
N
N
or
N
11a
N
O
+
Cl
Cl
conditions
CO2Me
CO2Me
O
HN
Cl
R3
pathway A
(Z)-12a (61%)
10a,b
9a,b
a: R3 = Cl
b: R3 = Me
a: R1 = Cl, R2 = H
b: R1 = Me, R2 = H
(Z)-13a (59%)
AcONa
EtOH, r.t.
O
CO2Me
O
N
N
N
N
or
O
O
O
CO2Me
11a
O
H
MeO2C
MeO2C
H
CO2Me
N
CO2Me
N
+
15b (49%)
conditions
pathway B
H
16b (53%)
OH
14b (65%)
N
N
O
17b (43%)
Scheme 2 Strategy and optimization of the 3-component reaction of 3-formylchromones, arylhydrazines, and acetylenedicarboxylates leading to the
scaffolds 12, 13, 15, and 16
easily available starting materials that give adducts with at
least four points of diversification incorporating both the
chromene and pyrazole core.
We started our investigation on the multicomponent re-
action of the 6-chloro-3-formylchromone (9a) with p-chlo-
rophenylhydrazine (10a) and dimethyl acetylenedicarbox-
ylate (DMAD, 11a) in 1:1:1 ratio (Scheme 2). After quite
some optimization, we performed this reaction in acetic ac-
id60,62 under microwave irradiation (130 °C, 10 min) afford-
ing, to our delight, the chromenopyrazole hybrid (Ζ)-12a in
61% yield. As it was expected, compound 12a was derived
from the intermediate zwitterion of the hydrazine and
DMAD (mechanism on Scheme 5, intermediate A). It is
worth mentioning, when a different ratio of the reagents
R3
R2
R1
O
O
O
N
AcOH, MW
N
130 °C, 10 min
1:1:1 ratio
CO2R4
NHNH2
CO2R4
R2
R1
O
(Z)-12a–g (53–76%)
R3
O
+
+
CO2R4
R3
O
R2
R1
O
O
9a–d
10a–c
11a,b
N
AcOH, MW
N
a: R1 = Cl, R2 = H
b: R1 = Me, R2 = H
c: R1 = H, R2 = H
d: R1 = Cl, R2 = Me
a: R3 = Cl,
b: R3 = Me
c: R3 = H
a: R4 = Me
b: R4 = Et
120 °C, 5 min
1:2:1 ratio
CO2R4
N
HN
R3
(Z)-13a–l (40–82%)
Scheme 3 Three-component reaction of 3-formylchromones, arylhydrazines, and acetylenedicarboxylates leading to the scaffolds 12 and 13
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

D
P. M. Kasapidou et al.
Paper
Synthesis
pathway A
Cl
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
Cl
Cl
Cl
CO2Et
CO2Et
CO2Me
CO2Me
H
H
H
H
12a, 61%
12b, 60%
12c, 64%
12d, 75%
O
O
O
O
H
O
N
O
O
O
O
N
N
N
N
N
Cl
Cl
CO2Et
H
CO2Et
CO2Et
H
12e, 65%
12f, 53%
12g, 76%
Cl
Cl
O
O
N
O
O
O
O
O
N
O
N
N
N
N
N
N
N
N
N
Cl
CO2Me
CO2Me
CO2Me
CO2Me
N
HN
HN
Cl
HN
HN
Cl
13a, 59%
13b, 82%
13c, 81%
13d, 44%
Cl
O
O
O
N
O
N
N
N
O
O
O
O
N
N
N
N
Cl
N
N
CO2Me
CO2Et
N
HN
HN
CO2Me
CO2Me
N
HN
HN
13h, 60%
13g, 77%
Cl
13e, 58%
13f, 40%
O
O
O
O
O
N
O
N
N
N
O
N
N
N
O
N
N
N
N
Cl
CO2Me
CO2Et
N
CO2Me
CO2Et
HN
HN
HN
HN
13i, 45%
13j, 53%
13k, 69%
13l, 62%
Figure 2 Library synthesis of the scaffolds 12 and 13 demonstrating the diversity of the reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

E
P. M. Kasapidou et al.
Paper
Synthesis
was used, 9a/10a/11a in 1:2:1 ratio with similar experi-
mental conditions (120 °C, 5 min), then an additional mole-
cule of hydrazine was added to the initial chromenopyra-
zole derivative 12a on the chromene ring (4-oxo), yielding
the compound (Ζ)-13a in 59% yield (Scheme 2 and Scheme
3). These kinds of reactions on the carbonyl group of the
chromone are not commonly reported in literature, since
the 3-formylchromene ring is quite prone to ring opening.60
These hybrid molecules, 12 and 13, offer many possibilities
for building libraries since they can be highly diversified
and easily obtained (pathway A). Next, we investigated the
potential outcome of the reaction if a different pathway is
followed (pathway B) rather than through a zwitterionic in-
termediate. To ensure this, we firstly obtained hydrazone
14b from the reaction of 6-methyl-3-formylchromone (9b)
with p-methylphenylhydrazine (10b).36 This time, we
wanted to build the targeted hybrid compound by forming
the pyrazole core utilizing the C=N bond.39,64–66 Thus, com-
pound 14b was reacted with DMAD in order to isolate the
corresponding cycloadduct. Indeed, the reaction proceeded
smoothly and after microwave irradiation at 120 °C for only
5 minutes, we were able to isolate the [3+2] cycloadduct
15b in 49% yield along with compound 17b. In the latter,
DMAD is not being incorporated whereas the chromone
ring adopts an open form.63,67–69 In addition, we were also
interested in obtaining directly the aromatic pyrazoles;
Therefore we treated, according to literature,70 the hydra-
zone 14b with DMAD in refluxing toluene in the presence
of Yb(OTf)3 (50 mol%) affording the desired derivative 16b
in 53% yield along again with compound 17b.
figuration (see structure assignments section). In addition
it seems that the substituents on the chromene ring or on
the hydrazine do not play a significant role in the yield of
the reaction.
Next, starting from the hydrazones 14a–d (obtained in
60–75% yield)39,71 following the pathway B depending on
the optimized conditions, we built a representative library
of the chromenopyrazolines 15a–d (relatively stereochem-
istry depicted, the cis other isomer formed by approximate-
ly 10%, see structure assignments section) and chromeno-
pyrazoles 16a–d in moderate to good yields (Scheme 4 and
Figure 3).
It is worth mentioning that treatment of 15a–d with
Yb(OTf)3 in refluxing toluene for 5 hours or in MW (90 °C,
20 min) did not afford the corresponding aromatic com-
pounds 16a–d.
The plausible mechanism of the derivatives 12 is depict-
ed in Scheme 5. It includes the formation of the zwitterion
A which through the formation of the intermediate C, at-
tacks the 3-formylchromone leading to the chromenopyra-
zoles 12. Further reaction with an additional arylhydrazine
molecule, afforded the imine derivative 13. Compounds 15
and 16 are formed after a [3+2] cycloaddition,64 whereas
the mechanism of compounds 17 includes the addition of
one molecule of hydrazine and subsequent opening of the
chromone ring.
The assigned molecular structures of the new com-
pounds 12, 13 and 15 were based on rigorous spectroscopic
analysis including NMR (1H, 13C, COSY, NOESY, HETCOR, and
COLOC), MS, and elemental analysis data. In Figure 4 the
COLOC correlations of protons with carbons via 2J and 3J
coupling for compounds 12g, 13k, and 15a are depicted.
To underscore the potential and generality of our three-
component reaction, we built easily a representative library
with various substituted 3-formylchromones, phenylhydra-
zines, and acetylenedicarboxylates based on the pathway A
(Figure 2). We synthesized both the two scaffolds 12 and 13
in moderate to good yields, using both electron-donating as
well as -withdrawing substituents. The preferred stereo-
chemistry of both compounds 12a–g and 13a–l is (Z)-con-
1
Concerning the identification of compound 12g, in H
NMR the aromatic hydrogens of the chromone ring ap-
peared at δ = 8.23 (s, 1 H) and 7.43 (s, 1 H) whereas the cor-
responding carbons resonate at δ = 126.4 and 120.5. Τhe
two quaternary carbons at positions 6′ and 7′ οf the chro-
mone ring absorb at δ = 133.4 and 144.3 respectively, while
R2
O
R2
R1
OH
AcOH, MW
N
+
N
R3
N
R3
120 °C, 5 min
R1
N
O
R4O2C
O
H
17a–d (37–53%)
H
CO2R4
CO2R4
R2
R1
O
O
R3
15a–d (40–49%)
+
N
N
H
CO2R4
14a–d (60-75%)
11a,b
R2
R1
O
Yb(OTf)3
a: R4 = Me
b: R4 = Et
a: R1 = Me, R2 = H, R3 = Cl
b: R1 = Me, R2 = H, R3 = Me
c: R1 = Cl, R2 = H, R3 = Me
d: R1 = Cl, R2 = Me, R3 = H
+
17a–d (24–32%)
N
R3
toluene, reflux 5 h
N
O
R4O2C
CO2R4
16a–d (53–66%)
Scheme 4 Reaction of arylhydrazones and acetylenedicarboxylates leading to the scaffolds 15 and 16
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

F
P. M. Kasapidou et al.
Paper
Synthesis
pathway B
O
O
O
O
N
N
N
N
Cl
Cl
Cl
N
N
N
N
O
O
O
O
H
MeO2C
H
MeO2C
H
H
MeO2C
MeO2C
H
H
CO2Me
H
CO2Me
H
CO2Me
CO2Me
15a, 42%
15b, 49%
15c, 43%
15d, 40%
O
O
O
O
N
N
N
N
N
N
N
N
O
O
EtO2C
O
O
EtO2C
MeO2C
CO2Et
MeO2C
CO2Et
CO2Me
CO2Me
16a, 58%
16b, 53%
16c, 66%
16d, 57%
Figure 3 Library synthesis of the scaffolds 15 and 16 along with the ‘open-form’ chromones 17
H
H
8
O1
H
O
H
8'
5'
8a' O1'
8a
7'
6'
2
3
H3C
Cl
H3C
Cl
H
O
O
2'
3'
7
H
O
9
H
6 H
H3C
6
H3C
4a
4
4a'
4'
O
5
CH3
CO2CH2CH3
3 CO2CH2CH3
N
4'
4
H
N
CO2CH3
O
N
H
3'
H
HN
H
HN
O
H
5
O
N
N
N
5'
N
O
O
H
N
N
N
H
H
H
H
1''
1''
H
H
6''
2''
3''
6''
2''
H3C
H3C
5''
5''
H
3''
H
4''
H3C4''
CH3
H
12g
12g
13k
13k
H
H
8
H
O
H
O
8a
H
H
2
7
6
3''
N
N
3'
4''Cl
Cl
H C
3
4a
1''
H3C
O4
N
5
N
4'
5'
O
H
H
H
H
CO2CH36''
H3CO2C
H3CO2C
H
H
CO2CH3
15a
15a
Figure 4 HMBC correlations between hydrogens and carbons via 2JC-H and 3JC-H couplings for the compounds 12g, 13k, and 15a, respectively
the C-3′ and C-4a′ give signals at δ = 118.9 and 123.0. Τhe H-
2′ absorbs at δ = 10.6, giving a single peak and the corre-
sponding carbon at δ = 164.2. The C-8a′ (next to oxygen)
resonates at δ = 154.3 and the hydrogen of the double bond
at position 6 shows signal at δ = 9.12 with its carbon at δ =
142.6. Ιn the five-membered ring, the carbonyl carbon at
position 5 absorbs at δ = 162.6 and the C-4 and C-3 at δ =
124.0 and 141.1, respectively. The H-2′′, H-3′′, and H-4′′ give
signals at δ = 7.92, 7.44, and 7.28, respectively with their
carbons resonating at δ = 120.54, 129.0, and 126.5. The C-1′′
absorbs at δ = 137.6. From the 2D spectra is concluded that
the hydrogen at δ = 10.6 corresponds to position 2′, as has
HMBC correlations with the C-3′, C-8a′, C-6, and the car-
bonyl carbon of the chromone ring. The hydrogen at δ =
9.12 belongs to the double bond at position 6 as it is cor-
related with the C-4, C-3, C-3′, C-2′, C-5, and C-4′.
The configuration of the double bond is concluded from
the coupling of the hydrogen at δ = 9.12 with the carbons at
δ = 162.6 (3JC-H = 10.8 Hz) and 141.1 (3JC-H = 6.6 Hz), i.e. large
coupling is trans configuration, while the small coupling is
cis configuration (see the Supporting Information for more
details).
For compound 13k, the aromatic hydrogens of the chro-
mone ring absorb at δ = 6.90 (s, 1 H), 7.14 (d, J = 8.3 Hz, 1 H),
and 6.87 (d, J = 8.3 Hz, 1 H) whereas the corresponding car-
bons resonate at δ = 131.9, 132.4, and 116.5. Τhe C-6 ab-
sorbs at δ = 128.7 and the methyl group as substituent at δ
= 20.3. The C-3 and C-4a absorb at δ = 119.3 and 114.2 re-
spectively. The H-2 absorbs at δ = 9.65 giving a single peak
with its carbon at δ = 145.0. Τhe C-4 resonates at δ = 147.7
and the C-4′, C-3′ and C-5′ absorb at δ = 118.3, 139.9 and
162.5, respectively. Τhe H-9 absorbs at δ = 8.38 and the cor-
responding carbon resonates at δ = 142.3. The H-2′′ and H-
3′′ give signals at δ = 7.29 and 7.11 respectively, while their
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

G
P. M. Kasapidou et al.
Paper
Synthesis
O
H
O
O
OR
CO2R
+
R
H
R
O
N
O
N
Ph
H
Ph
H
Ph
N
Ar-NH-NH2
RO2C
N
N
RO2C
N
H
B
RO2C
H
H
CO2R
H
A
O
O
R'
O
R'
OH
R'
O
O
N
O
O
O
O
H
Ph
O
N
Ph
N
– H2O
H+
N
RO2C
Ph
N
N
RO2C
RO2C
H
12
C
Scheme 5 Plausible mechanism of the derivatives 12a–g
carbons absorb at δ = 123.7 and 129.32. Τhe C-1′′′ and C-4′′′
absorb at δ = 137.3 and 137.7. From the 2D spectra is con-
cluded that the hydrogen at δ = 8.38 corresponding to posi-
tion 9, shows HMBC correlation with the C-2, C-4, C-3′, C-4′,
and C-5′. The hydrogen at δ = 9.65 has HMBC correlation
with C-3 and C-4 (see the Supporting Information for more
details). Finally, concerning compound 15a the aromatic
hydrogens of the chromone ring give signals at δ = 7.41 (d,
J = 8.5 Hz, 1 H), 7.51 (dd, J = 8.5, 1.8 Hz, 1 H), and 8.01 (d, J =
1.8 Hz, 1 H), and the corresponding carbons absorb at δ =
118.0, 135.3, and 125.4, respectively. The C-3, C-4a, and C-6
resonate at 116.6, 123.7, and 135.9, respectively. The H-2
absorbs at δ = 8.64 giving a single peak and the correspond-
ing carbon absorbs at δ = 154.4.
The C-8a (adjacent to oxygen) resonates at δ = 154.4. In
the five-membered ring, the H-5′ and H-4′ absorb at δ =
5.06 and 5.21 with the carbons at δ = 64.7 and 56.7, respec-
tively. The C-3′ and the carbonyls of the ester groups on C-5′
and C-4′ give signals at δ = 140.3, 169.7, and 169.2, respec-
tively. The H-2′′ and H-3′′ absorb at δ = 7.01 and 7.23 with
their carbons to resonate at δ = 114.4 and 129.1. Carbons at
positions 1′′ and 4′′ absorb at δ = 142.2 and 125.3. From the
2D spectra is concluded that the hydrogen at δ = 8.64 corre-
sponds to the hydrogen at C-2 as shows a large coupling (J =
200 Hz) which is characteristic for a hydrogen at this posi-
tion. It is worth mentioning that the other isomer formed
by approximately 10%, with the ester group in cis position,
the hydrogens absorb at δ = 5.03 and 5.39 with J = 13 Hz,
while the corresponding methoxy groups absorb at δ = 3.68
and 3.72 (see the Supporting Information for more details).
In conclusion, in the present work we described a thor-
ough study of the 3-component reaction of 3-formylchro-
mones with arylhydrazines and acetylenedicarboxylates.
Following the different pathways (pathway A or B) of the
reaction, we built a representative library of four scaffolds
that possess two privileged structures. These chromenopy-
razole derivatives could be used against various biological
targets (e.g., CB1 and CB2 receptors, COX-1,2 and 5-LOX).
Furthermore, we demonstrated the different routes that an
MCR can follow and how these in our case can be accessed
by the formation of the zwitterion ion or not. Finally, a
1
thorough NMR analysis with full assignment of all H and
13C NMR chemical shifts has been unambiguously achieved
which will be useful for the interpretation of similar scaf-
folds.
Melting points were measured on a Kofler hot stage. Column chroma-
tography was carried out using Merck silica gel. TLC was performed
using precoated silica gel glass plates 0.25 mm containing fluorescent
indicator UV254 purchased from Macherey-Nagel using petroleum
ether (bp 60–80 °C)/EtOAc (3:1). NMR spectra were recorded at r.t. ei-
ther on an Αgilent 500 spectrometer (for 1H at 500 MHz and for 13C at
125 MHz) or a Bruker AM 300 spectrometer at 300 MHz for 1H and 75
MHz for 13C, respectively, using CDCl3 as solvent relative to TMS as in-
1
ternal standard for H and relative to TMS (δ = 0.00) or to CDCl3 (δ =
77.05) for 13C NMR spectra. Second order 1H spectra in the aromatic
region, where it was possible, were analyzed by simulation (simula-
tion program SpinWorks version 2.5). LR-MS (EI+ were recorded on a
6890N LC/MS system (Agilent Technology). Structural assignments of
the derived compounds were established by analysis of their MS and
NMR spectra (1H, 13C, DEPT, H-H COSY, H-H NOESY, HETCOR, and
COLOC). Microwave irradiation was completed using
Initiator 2.0 microwave oven.
a Biotage
Reaction of 3-Formylchromones/Arylhydrazines/Acetylenedicar-
boxylates (Ratio 1:1:1); General Procedure
In a microwave reaction vial (0.5–2.0 mL), the acetylenedicarboxylate
11a,b (0.5 mmol), phenylhydrazine or its HCl salt 10a–c (0.5 mmol),
and AcOH (1.0 mL) were mixed and then stirred at r.t. for 1 min. Then,
the 3-formylchromone 9a–d (0.5 mmol) was added to the mixture
and it was irradiated in a microwave oven at 130 °C for 10 min. The
progress of the reaction was monitored by TLC. The solvent was re-
moved under vacuum and the resulting residue was subjected to col-
umn chromatography (silica gel, petroleum ether/EtOAc, 5:1–3:1) to
afford 12a–g.
Methyl (Z)-4-[(6-Chloro-4-oxo-4H-chromen-3-yl)methylene]-1-
(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate
(12a)
Yellow solid; yield: 63 mg (61%); mp 225–227 °C.
FT-IR (KBr): 3453, 3069, 2360, 1740, 1686 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

H
P. M. Kasapidou et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 4.04 (s, 3 H, OCH3), 7.42 (d, J = 8.5 Hz, 2
H, 2′′-H, 6′′-Η), 7.54 (d, J = 8.8 Hz, 1 H, 7′-Η), 7.70 (d, J = 8.8 Hz, 1 H, 8′-
Η), 7.90 (d, J = 8.5 Hz, 2 H, 3′′-H, 5′′-Η), 8.27 (s, 1 H, 5′-Η), 9.14 (s, 1 H,
6-Η), 10.62 (s, 1 H, 2′-Η).
13C NMR (125 MHz, CDCl3): δ = 52.9 (OCH3), 118.8 (C-3′), 120.4 (C-8′),
121.4 (C-2′′, C-6′′), 123.7 (C-4a′), 124.8 (C-4), 126.2 (C-7′), 129.1 (C-3′′,
C-5′′), 131.9 (C-4′′), 132.8 (C-6′), 135.0 (C-5′), 136.0 (C-1′′), 140.8 (C-
3), 143.0 (C-6), 154.3 (C-8a′), 160.7 (3-C=O), 162.3 (C-5), 164.3 (C-2′),
173.9 (C=O).
1H NMR (500 MHz, CDCl3): δ = 1.49 (t, J = 7.2 Hz, 3 H, CH3), 4.51 (q, J =
7.2 Hz, 2 H, CH2), 7.26 (d, J = 7.4 Hz, 1 H, 7′-Η), 7.44 (t, J = 7.5 Hz, 2 H,
3′′-H, 5′′-Η), 7.51 (d, J = 7.4 Hz, 1 H, 8′-Η), 7.69 (dd, J = 7.5, 2.4 Hz, 1 H,
4′′-Η), 7.91 (d, J = 7.5 Hz, 2 H, 2′′-H, 6′′-Η), 8.25 (d, J = 2.4 Hz, 1 H, 5′-
Η), 9.10 (s, 1 H, 6-Η), 10.63 (s, 1 H, 2′-Η).
13C NMR (125 MHz, CDCl3): δ = 14.3 (CH3), 62.1 (CH2), 118.9 (C-3′),
120.4 (C-8′), 120.5 (C-2′′, C-6′′), 124.2 (C-4a′),124.9 (C-4), 126.2 (C-7′),
126.6 (C-4′′), 129.0 (C-3′′, C-5′′), 132.7 (C-6′), 134.9 (C-5′), 137.6 (C-
1′′), 141.0 (C-3), 142.2 (C-6), 154.4 (C-8a′), 160.4 (3-C=O), 162.5 (C-5),
164.1 (C-2′), 174.0 (C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 444/446 [4, (M + H)+], 484/486 [85, (M
+ CH3CN)+].
LC-MS (ESI, 1.65 eV): m/z (%) = 423/425 [4, (M + H)+], 520/522 [100,
(M + Na + MeOH + CH3CN)+].
Anal. Calcd for C21H12Cl2N2O5: C, 56.91; H, 2.73; N, 6.32; Cl, 16.00.
Found: C, 56.90; H, 2.67; N, 6.31; Cl, 15.54.
Anal. Calcd for C22H15ClN2O5: C, 62.49; H, 3.58; N, 6.36; Cl, 8.38.
Found: C, 62.42; H, 3.12; N, 6.18; Cl, 8.37.
Methyl (Z)-4-[(6-Chloro-4-oxo-4H-chromen-3-yl)methylene]-5-
oxo-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate (12b)
Ethyl (Z)-4-[(6-Methyl-4-oxo-4H-chromen-3-yl)methylene]-5-oxo-
1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate (12e)
Yellow solid; yield: 62 mg (60%); mp 225–227 °C.
Yellow solid; yield: 61 mg (65%); mp 198–200 °C.
FT-IR (KBr): 3446, 3078, 2362, 1722, 1697 cm–1
.
FT-IR (KBr): 3442, 3060, 2359, 1714, 1652 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.03 (s, 3 H, OCH3), 7.29 (d, J = 7.4 Hz, 1
H, 6′-Η), 7.45 (t, J = 7.5 Hz, 2 H, 3′′-H, 5′′-Η), 7.52 (d, J = 7.4 Hz, 1 H, 7′-
Η), 7.69 (dd, J = 7.5 Hz, 1 H, 4′′-Η), 7.89 (d, J = 7.5 Hz, 2 H, 2′′-H, 6′′-Η),
8.25 (s, 1 H, 5′-Η), 9.11 (s, 1 H, 6-Η), 10.64 (s, 1 H, 2′-Η).
13C NMR (125 MHz, CDCl3): δ = 52.8 (ΟCH3), 118.8 (C-3′), 120.4 (C-8′),
120.5 (C-2′′, C-6′′), 123.8 (C-4a′), 124.7 (C-4), 126.1 (C-7′), 126.6 (C-
4′′), 129.0 (C-3′′, C-5′′), 132.7 (C-6′), 134.9 (C-5′), 137.3 (C-1′′), 140.4
(C-3), 142.4 (C-6), 154.2 (C-8a′), 160.7 (3-C=O), 162.4 (C-5), 164.3 (C-
2′), 173.9 (C=O).
1H NMR (500 MHz, CDCl3): δ = 1.50 (t, J = 7.2 Hz, 3 H, CH3), 2.48 (s, 3
H, 7-CH3), 4.52 (q, J = 7.2 Hz, 2 H, CH2),7.27 (d, J = 8.2 Hz, 1 H, 8′-Η),
7.44 (d, J = 7.5 Hz, 2 H, 3′′-H, 5′′-Η), 7.45 (d, J = 7.5 Hz, 1 H, 4′′-Η), 7.54
(d, J = 8.2 Hz, 1 H, 7′-Η), 7.92 (d, J = 7.5 Hz, 2 H, 2′′-H, 6′′-Η), 8.08 (s, 1
H, 5′-Η), 9.18 (s, 1 H, 6-Η), 10.67 (s, 1 H, 2′-Η).
13C NMR (125 MHz, CDCl3): δ = 14.3 (CH3), 21.1 (7-CH3), 62.1 (CH2),
118.5 (C-8′), 118.8 (C-3′), 120.5 (C-2′′, C-6′′), 123.3 (C-4a′), 123.5 (C-
4), 126.1 (C-4′′), 126.4 (C-7′), 128.9 (C-3′′, C-5′′), 135.9 (C-5′), 136.8 (C-
6′), 137.5 (C-1′′), 141.0 (C-3), 143.3 (C-6), 154.2 (C-8a′), 160.4 (3-C=O),
162.6 (C-5), 164.5 (C-2′), 175.1 (C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 409/411 [4, (M + H)+], 504/506 [100,
(M + Na + MeOH + CH3CN)+].
LC-MS (ESI, 1.65 eV): m/z (%) = 403 [3, (M + H)+], 498 [100, (M + Na +
Anal. Calcd for C21H13ClN2O5: C, 61.70; H, 3.21; N, 6.85; Cl, 8.67.
Found: C, 61.60; H, 3.19; N, 6.79; Cl, 8.50.
MeOH + MeCN)+].
Anal. Calcd for C23H18N2O5: C, 68.65; H, 4.51; N, 6.96. Found: C, 68.42;
H, 4.42; N, 6.78.
Ethyl (Z)-5-Oxo-4-[(4-oxo-4H-chromen-3-yl)methylene]-1-phe-
nyl-4,5-dihydro-1H-pyrazole-3-carboxylate (12c)
Ethyl (Z)-4-[(6-Chloro-4-oxo-4H-chromen-3-yl)methylene]-5-oxo-
1-(p-tolyl)-4,5-dihydro-1H-pyrazole-3-carboxylate (12f)
Yellow solid; yield: 55 mg (64%); mp 196–198 °C.
FT-IR (KBr): 3440, 3071, 2361, 1731, 1690 cm–1
.
Yellow solid; yield: 55 mg (53%); mp 197–199 °C.
1H NMR (500 MHz, CDCl3): δ = 1.49 (t, J = 7.2 Hz, 3 H, CH3), 4.51 (q, J =
7.2 Hz, 2 H, CH2), 7.30 (d, J = 7.2 Hz, 1 H, 4′-H), 7.43 (ddd, J = 8.1, 6.8,
0.9 Hz, 1 H, 6′-Η), 7.46 (t, J = 8.7 Hz, 2 H, 3′′-H, 5′′-Η), 7.52 (d, J = 6.8
Hz, 1 H, 8′-Η), 7.74 (ddd, J = 8.1, 6.8, 0.9 Hz, 1 H, 7′-Η), 7.93 (d, J = 7.5
Hz, 2 H, 2′′-H, 6′′-Η), 8.31 (dd, J = 8.1, 0.9 Hz, 1 Η, 5′-Η), 9.17 (s, 1 H, 6-
Η), 10.66 (s, 1 H, 2′-Η).
13C NMR (125 MHz, CDCl3): δ = 13.9 (CH3), 61.7 (CH2), 118.7 (C-8′),
119.0 (C-3′), 120.5 (C-2′′, C-6′′), 123.8 (C-4a′), 124.0 (C-1), 126.5 (C-
5′), 126.6 (C-6′), 126.8 (C-4′′), 129.0 (C-3′′, C-5′′), 134.7 (C-7′), 137.6
(C-1′′), 141.3 (C-2), 143.0 (C-6), 156.1 (C-8a′), 160.5 (3-C=O), 162.7 (C-
5), 164.4 (C-2′), 175.1 (C=O).
FT-IR (KBr): 3453, 3069, 2360, 1740, 1686 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.49 (t, J = 7.2 Hz, 3 H, CH3), 2.37 (s, 3
H, 4′′-CH3), 4.51 (q, J = 7.2 Hz, 2 H, CH2), 7.24 (d, J = 8.2 Hz, 2 H, 2′′-H,
6′′-Η), 7.52 (d, J = 8.9 Hz, 1 H, 7′-Η), 7.68 (d, J = 8.9 Hz, 1 H, 8′-Η), 7.76
(d, J = 8.2 Hz, 2 H, 3′′-H, 5′′-Η), 8.25 (s, 1 H, 5′-Η), 9.11 (s, 1 H, 6-Η),
10.67 (s, 1 H, 2′-Η).
13C NMR (125 MHz, CDCl3): δ = 14.3 (CH3), 21.1 (4′′-CH3), 62.1 (CH2),
118.8 (C-3′), 120.4 (C-8′), 120.5 (C-2′′, C-6′′), 124.1 (C-4a′), 124.8 (C-
1′), 126.1 (C-7′), 129.5 (C-3′′, C-5′′), 132.6 (C-6′), 134.8 (C-5′), 134.9 (C-
4′′), 136.5 (C-1′′), 140.6 (C-3), 142.2 (C-6), 154.3 (C-8a′), 160.4 (3-
C=O), 162.4 (C-5), 164.2 (C-2′), 174.0 (C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 389 [6, (M + H)+], 484 [85, (M + Na +
MeOH + CH3CN)+].
LC-MS (ESI, 1.65 eV): m/z (%) = 437/439 [5, (M + H)+], 532/534 [100,
(M + Na + MeOH + CH3CN)+].
Anal. Calcd for C22H16N2O5: C, 68.04; H, 4.15; N, 7.21. Found: C, 68.02;
H, 4.12; N, 7.18.
Anal. Calcd for C23H17ClN2O5: C, 63.24; H, 3.92; N, 6.41; Cl, 8.12.
Found: C, 63.12; H, 3.42; N, 6.28; Cl, 7.89.
Ethyl (Z)-4-[(6-Chloro-4-oxo-4H-chromen-3-yl)methylene]-5-oxo-
1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate (12d)
Ethyl (Z)-4-[(6-Chloro-7-methyl-4-oxo-4H-chromen-3-yl)methy-
lene]-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylate
(12g)
Yellow solid; yield: 78 mg (75%); mp 195–197 °C.
FT-IR (KBr): 3448, 3062, 1716, 1686 cm–1
.
Yellow solid; yield: 84 mg (76%); mp 196–198 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

I
P. M. Kasapidou et al.
Paper
Synthesis
FT-IR (KBr): 3447, 3059, 2361, 1716, 1693 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 52.3 (OCH3), 114.6 (C-4a), 117.0 (C-8),
119.4 (C-4), 119.5 (C-3′), 120.5 (C-2′′, C-6′′), 121.2 (C-7), 124.1 (C-2′′′,
C-6′′′), 126.2 (C-5), 128.3 (C-6), 128.92 (C-3′′, C-5′′), 128.98 (C-3′′′, C-
5′′′), 132.0 (C-4′′), 132.3 (C-4′′′), 137.8 (C-1′′), 138.9 (C-1′′′),139.9 (C-
3), 141.2 (C-9), 145.3 (C-2), 146.0 (C-4′), 154.0 (C-8a), 161.3 (3-C=O),
162.5 (5-C=O).
1H NMR (500 MHz, CDCl3): δ = 1.49 (t, J = 7.2 Hz, 3 H, CH3), 2.53 (s, 3
H, 7′-CH3), 4.51 (q, J = 7.2 Hz, 2 H, CH2), 7.28 (t, J = 7.5 Hz, 1 H, 4′′-H),
7.43 (s, 1 H, 8′-H), 7.44 (t, J = 7.5 Hz, 2 H, 3′′-H, 5′′-H), 7.92 (d, J = 7.5
Hz, 2 H, 2′′-H, 6′′-H), 8.23 (s, 1 H, 5′-H), 9.12 (s, 1 H, H-6), 10.6 (s, 1 H,
2′-H).
13C NMR (125 MHz, CDCl3): δ = 14.3 (CH3), 20.9 (7′-CH3), 62.1 (CH2),
118.9 (C-3′), 120.51 (C-8′), 120.54 (C-2′′, C-6′′), 123.0 (C-4a′), 124.0
(C-4), 126.4 (C-5′), 126.5 (C-4′′), 129.0 (C-3′′, C-5′′), 133.4 (C-6′), 137.6
(C-1′′), 141.1 (C-3), 142.6 (C-6), 144.3 (C-7′), 154.3 (C-8a′), 160.4 (3-
C=O), 162.6 (C-5), 164.2 (C-2′), 173.9 (C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 465 [100, (M + H)+].
Anal. Calcd for C27H20N4O4: C, 69.82; H, 4.34; N, 12.07. Found: C,
67.04; H, 3.92; N, 11.67.
Methyl (Z)-4-{[(Z)-6-Methyl-4-(2-phenylhydrazono)-4H-chromen-
3-yl]methylene}-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-
3-carboxylate (13c)
LC-MS (ESI, 1.65 eV): m/z (%) = 437/439 [4,(M + H)+], 532/534 [100, (M
+ Na + MeOH + CH3CN)+].
Yellow solid; yield: 88 mg (81%); mp 235–237 °C.
Anal. Calcd for C23H17ClN2O5: C, 63.24; H, 3.92; N, 6.41; Cl, 8.12.
Found: C, 63.12; H, 3.42; N, 6.28; Cl, 8.08.
FT-IR (KBr): 3422, 1719, 1629 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.28 (s, 3 H, CH3), 3.74 (s, 3 H, OCH3),
6.83 (d, J = 8.3 Hz, 1 H, 8-Η), 6.88 (d, J = 8.3 Hz, 1 H, 5-Η), 7.18 (d, J =
8.3 Hz, 1 H, 7-Η), 7.25 (m, 1 H, 4′′-Η), 7.28 (m, 1 H, 4′′′-Η), 7.29 (m, 2
H, 3′′-H, 5′′-Η), 7.34 (m, 2 H, 2′′′-H, 6′′′-Η), 7.42 (m, 2 H, 3′′′-H, 5′′′-H),
7.97 (d, J = 9.6 Hz, 2 H, 2′′-H, 6′′-Η), 8.25 (s, 1 H, 9-Η), 9.45 (s, 1 H, 2-
Η).
13C NMR (125 MHz, CDCl3): δ = 20.3 (6-CH3), 52.2 (OCH3), 114.3 (C-
4a), 117.0 (C-8), 119.2 (C-4), 119.5 (C-3′), 120.6 (C-2′′, C-6′′), 124.1 (C-
2′′′, C-6′′′), 126.1 (C-4′′), 128.2 (C-4′′′), 128.93 (C-3′′, C-5′′), 129.01 (C-
3′′′, C-5′′′), 130.3 (C-6), 132.0 (C-5), 132.9 (C-7),137.8 (C-1′′), 138.1 (C-
1′′′), 139.6 (C-3), 141.5 (C-9), 145.5 (C-2), 146.5 (C-4′), 152.0 (C-8a),
161.3 (3-C=O), 162.5 (5-C=Ο).
Reaction of 3-Formylchromones/Arylhydrazines/Acetylene-
dicarboxylates (Ratio 1:2:1); General Procedure
In a microwave reaction vial (0.5–2.0 mL), the acetylenedicarboxylate
11a,b (0.5 mmol), phenylhydrazine or its HCl salt 10a–c (1.0 mmol),
and AcOH (1.0 mL) were mixed and then stirred at r.t. for 1 min. Then,
the 3-formylchromone 9a–d (0.5 mmol) was added to the mixture
and it was irradiated in a microwave oven at 120 °C for 5 min. The
progress of the reaction was monitored by TLC. The solvent was re-
moved under vacuum and the resulting residue was subjected to col-
umn chromatography (silica gel, petroleum ether/EtOAc, 5:1–3:1) to
afford 13a–l.
LC-MS (ESI, 1.65 eV): m/z (%) = 479 [100, (M + H)+], 517 [4, (M + K)+].
Methyl (Z)-4-({(Z)-6-Chloro-4-[2-(4-chlorophenyl)hydrazono]-4H-
chromen-3-yl}methylene)-1-(4-chlorophenyl)-5-oxo-4,5-dihydro-
1H-pyrazole-3-carboxylate (13a)
Anal. Calcd for C28H22N4O4: C, 70.28; H, 4.63; N, 11.71. Found: C,
69.04; H, 4.52; N, 11.67.
Yellow solid; yield: 71 mg (59%); mp 250–252 °C.
Methyl (Z)-1-(4-Chlorophenyl)-4-({(Z)-4-[2-(4-chlorophenyl)-
hydrazono]-6-methyl-4H-chromen-3-yl}methylene)-5-oxo-4,5-
dihydro-1H-pyrazole-3-carboxylate (13d)
FT-IR (KBr): 3368, 1716, 1701 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.88 (s, 3 H, OCH3), 6.95 (d, J = 8.5 Hz, 1
H, 8-Η), 7.15 (d, J = 8.5 Hz, 1 H, 7-Η), 7.30–7.37 (m, 6 H), 7.41 (s, 1 H,
5-Η), 7.98 (d, J = 8.1 Hz, 2 H, 2′′-H, 6′′-Η), 8.35 (s, 1 H, 9-Η), 9.66 (s, 1
H, 2-Η).
13C NMR (125 MHz, CDCl3): δ = 52.2 (OCH3), 115.4 (C-4a′), 118.0 (C-8),
119.0 (C-4), 119.3 (C-3′), 121.1 (C-2′′, C-6′′), 124.1 (C-6), 124.8 (C-2′′′,
C-6′′′), 128.7 (C-3′′, C-5′′), 129.0 (C-3′′′, C-5′′′), 130.8 (C-5), 131.0 (C-
4′′), 132.0 (C-7′), 133.5 (C-1′′), 136.3 (C-4′′′), 137.9 (C-1′′′), 140.5 (C-3),
141.6 (C-9), 145.2 (C-2), 146.0 (C-4′), 154.3 (C-8a), 160.8 (2-C=O),
162.1 (5-C=O).
Yellow solid; yield: 62 mg (44%); mp 235–238 °C.
FT-IR (KBr): 3358, 1693, 1604 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.29 (s, 3 H, 6-CH3), 3.74 (s, 3 H, OCH3),
6.84 (d, J = 8.2 Hz, 1 H, 8-Η), 6.88 (s, 1 H, 5-Η), 7.16 (d, J = 8.1 Hz, 2 H),
7.17 (d, J = 8.2 Hz, 1 H, 7-Η), 7.24 (d, J = 8.1 Hz, 2 H), 7.33 (d, J = 8.1 Hz,
2 H), 7.86 (d, J = 8.1 Hz, 2 H), 8.25 (s, 1 H, 9-Η), 9.45 (s, 1 H, 2-Η).
13C NMR (125 MHz, CDCl3): δ = 20.4 (6-CH3), 52.3 (OCH3), 113.9 (C-
4a), 117.3 (C-8), 119.1 (C-4), 119.7 (C-3′), 121.1 (C-2′′, C-6′′), 124.9 (C-
2′′′, C-6′′′), 128.9 (C-3′′, C-5′′), 129.1 (C-3′′′, C-5′′′), 130.6 (C-6), 131.2
(C-4′′),131.8 (C-5), 133.2 (C-7), 134.0 (C-1′′), 136.3 (C-4′′′), 137.3 (C-
1′′′), 140.1 (C-3), 141.8 (C-9), 145.1 (C-2), 146.5 (C-4′), 152.0 (C-8a),
161.1 (3-C=O), 162.1 (5-C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 568/570 [5, (M + H)+], 622/624 [90, (M
+ Na + MeOH)+].
Anal. Calcd for C27H17Cl3N4O4: C, 57.11; H, 3.02; N, 9.87; Cl, 18.73.
Found: C, 57.04; H, 2.92; N, 9.67; Cl, 18.43.
LC-MS (ESI, 1.65 eV): m/z (%) = 548/550 [100, (M + H)+], 560/562 [5,
(M + Na)+].
Methyl (Z)-5-Oxo-1-phenyl-4-{[(Z)-4-(2-phenylhydrazono)-4H-
chromen-3-yl]methylene}-4,5-dihydro-1H-pyrazole-3-carboxyl-
ate (13b)
Anal. Calcd for C28H20Cl2N4O4: C, 61.44; H, 3.68; N, 10.24; Cl, 12.95.
Found: C, 61.04; H, 3.52; N, 10.47; Cl, 12.76.
Yellow solid; yield: 71 mg (82%); mp 215–217 °C.
Methyl (Z)-5-Oxo-1-(p-tolyl)-4-({(Z)-4-[2-(p-tolyl)hydrazono]-4H-
chromen-3-yl}methylene)-4,5-dihydro-1H-pyrazole-3-carboxyl-
ate (13e)
FT-IR (KBr): 3417, 1720, 1691 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.80 (s, 3 H, OCH3), 6.94 (d, J = 8.2 Hz, 1
H, 8-Η), 7.02 (t, J = 7.5 Hz, 1 H, 7′-Η), 7.12 (d, J = 8.2 Hz, 1 H), 7.21–7.24
(m, 5 H),7.38 (d, J = 8.2 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 3 H),7.93 (d, J = 7.5
Hz, 2 H, 2′′-H, 6′′-Η), 8.34 (s, 1 H, 9-Η), 9.63 (s, 1 H, 2-Η).
Yellow solid; yield: 72 mg (58%); mp 254–256 °C.
FT-IR (KBr): 3408, 1701, 1690 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

J
P. M. Kasapidou et al.
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Synthesis
1H NMR (500 MHz, CDCl3): δ = 2.29 (s, 3 H, CH3), 2.37 (s, 3 H, CH3),
3.77 (s, 3 H, OCH3), 6.95 (d, J = 8.2 Hz, 1 H, 5-H), 7.00 (t, J = 7.5 Hz, 1 H,
8-H), 7.06 (d, J = 8.3 Hz, 2 H, 2′′′-H, 6′′′-H), 7.14 (d, J = 8.2 Hz, 1 H, 6-H),
7.2 (d, 8.3 Hz, 2 H, 3′′′-H, 5′′′-H), 7.26 (d, J = 8.3 Hz, 2 H, 3′′-H, 5′′-H),
7.40 (t, J = 8.2 Hz, 1 H, 7-H), 7.80 (d, J = 8.3 Hz, 2 H, 2′′-H, 6′′-H), 8.29
(s, 1 H, 9-H), 9.59 (s, 1 H, 2-Η).
13C NMR (125 MHz, CDCl3): δ = 21.07 (CH3), 21.1 (CH3), 52.2 (OCH3),
114.8 (C-4a), 117.1 (C-8), 119.4 (C-4), 119.5 (C-3′), 120.3 (C-2′′, C-6′′),
121.0 (C-7), 123.8 (C-2′′′, C-6′′′), 129.4 (C-3′′, C-5′′), 129.5 (C-3′′′, C-
5′′′), 131.7 (C-6), 132.1 (C-5), 135.3 (C-4′′), 135.8 (C-1′′), 136.6 (C-4′′′),
138.2 (C-1′′′), 139.5 (C-3), 141.0 (C-9), 145.0 (C-2), 145.2 (C-4′), 154.2
(C-8a), 161.3 (3-C=O), 162.4 (5-C=O).
Ethyl (Z)-5-Oxo-1-phenyl-4-{[(Z)-4-(2-phenylhydrazono)-4H-
chromen-3-yl]methylene}-4,5-dihydro-1H-pyrazole-3-carboxyl-
ate (13h)
Yellow solid; yield: 65 mg (60%); mp 218–220 °C.
FT-IR (KBr): 3425, 1720, 1697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.17 (t, J = 7.5 Hz, 3 H, CH3), 4.24 (q, J =
7.5 Hz, 2 H, OCH2), 6.92 (d, J = 8.1 Hz, 1 H, 5′-H), 6.97 (t, J = 7.5 Hz, 1
H), 7.09 (d, J = 7.5 Hz, 1 H), 7.26–7.32 (m, 6 H), 7.34 (t, J = 7.7 Hz, 1 H),
7.41 (t, J = 7.8 Hz, 2 H), 7.93 (d, J = 8.0 Hz, 2 H), 8.28 (s, 1 H, 9-Η), 9.65
(s, 1 H, 2′-Η).
13C NMR (125 MHz, CDCl3): δ = 13.9 (CH3), 61.8 (OCH2), 114.6 (C-4a),
116.9 (C-8), 119.4 (C-3′), 120.5 (C-2′′, C-6′′), 120.8 (C-4), 124.2 (C-2′′′,
C-6′′′), 126.1 (C-4′′), 128.2 (C-4′′′), 128.8 (C-3′′, C-5′′), 128.9 (C-3′′′, C-
5′′′), 128.91 (C-1′′), 131.8 (C-7),131.9 (C-6), 132.1 (C-5), 137.7 (C-1′′′),
138.9 (C-3), 141.3 (C-9), 145.1 (C-2), 146.1 (C-4′), 154.3 (C-8a), 161.1
(3-C=O), 162.4 (5-C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 493 [100, (M + H)+], 531[5, (M + K)+].
Anal. Calcd for C29H24N4O4: C, 70.72; H, 4.91; N, 11.38. Found: C,
70.04; H, 4.52; N, 11.17.
Methyl (Z)-1-(4-Chlorophenyl)-4-({(Z)-4-[2-(4-chlorophenyl)hy-
drazono]-4H-chromen-3-yl}methylene)-5-oxo-4,5-dihydro-1H-
pyrazole-3-carboxylate (13f)
LC-MS (ESI, 1.65 eV): m/z (%) = 479 [100, (M + H)+], 501 [5, (M + Na)+].
Anal. Calcd for C28H22N4O4: C, 70.28; H, 4.63; N, 11.71. Found: C,
69.04; H, 4.02; N, 10.97.
Yellow solid; yield: 57 mg (40%); mp 242–244 °C.
FT-IR (KBr): 3411, 1719, 1694 cm–1
.
Ethyl (Z)-4-({(Z)-6-Methyl-4-[2-(p-tolyl)hydrazono]-4H-chromen-
3-yl}methylene)-5-oxo-1-(p-tolyl)-4,5-dihydro-1H-pyrazole-3-car-
boxylate (13i)
1H NMR (500 MHz, CDCl3): δ = 3.84 (s, 3 H, OCH3), 6.95 (d, J = 8.1 Hz, 1
H, 5-H), 7.08 (t, J = 7.4 Hz, 1 H), 7.15 (d, J = 7.4 Hz, 1 H), 7.25–7.28 (m,
4 H), 7.40 (d, J = 8.3 Hz, 2 H), 7.44 (t, J = 7.4 Hz, 1 H),7.94 (d, J = 8.3 Hz,
2 H, 2′′-H, 6′′-Η), 8.36 (s, 1 H, 9-H), 9.63 (s, 1 H, 2-H).
13C NMR (125 MHz, CDCl3): δ = 51.7 (ΟCH3), 113.5 (C-4a), 116.2 (C-8),
117.8, (C-7), 118.9 (C-4), 119.2 (C-3′), 120.6 (C-2′′, C-6′′), 124.5 (C-3′′,
C-5′′), 128.3 (C-2′′′, C-6′′′), 128.37 (C-3′′′, C-5′′′), 130.3 (C-6), 131.4 (C-
4′′), 131.7 (C-5), 132.6 (C-1′′), 136.5 (C-4′′′), 137.7 (C-1′′′), 139.7 (C-3),
141.3 (C-9), 144.8 (C-2),147.3 (C-4′), 155.1 (C-8a), 160.5 (3-C=O),
161.8 (5-C=O).
Yellow solid; yield: 55 mg (45%); mp 238–240 °C.
FT-IR (KBr): 3429, 1736, 1688 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.20 (t, J = 7.5 Hz, 3 H, CH3), 2.27 (s, 3
H, CH3), 2.31 (s, 3 H, CH3), 2.36 (s, 3 H, CH3), 4.28 (q, J = 7.5 Hz, 2 H,
CH2), 6.84 (d, J = 8.1 Hz, 1 H, 5-H), 6.90 (s, 1 H), 7.10 (d, J = 8.1 Hz, 1 H),
7.55–7.19 (m, 3 H), 7.21 (d, 2 H), 7.23 (s, 1 H), 7.80 (d, J = 8.3 Hz, 2 H),
8.26 (s, 1 H, 9-H), 9.64 (s, 1 H, 2-H).
13C NMR (125 MHz, CDCl3): δ = 13.9 (CH3), 20.4 (CH3), 21.09 (CH3),
21.1 (CH3), 61.5 (CH2), 114.4 (C-4a), 116.5 (C-8), 116.8 (C-4), 119.5 (C-
3′), 120.5 (C-2′′, C-6′′), 123.7 (C-6), 129.4 (C-3′′, C-5′′), 129.5 (C-3′′′, C-
5′′′), 130.5 (C-9), 132.1 (C-7), 132.8 (C-2′′′, C-6′′′), 135.4 (C-4′′), 135.8
(C-1′′), 136.6 (C-4′′′), 138.2 (C-1′′′), 140.1 (C-3), 140.9 (C-9), 145.2 (C-
2), 145.6 (C-4′), 151.7 (C-8a), 160.9 (3-C=O), 162.5 (5-C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 534/536 [100, (M + H)+], 556/558 [4,
(M + Na)+].
Anal. Calcd for C27H18Cl2N4O4: C, 60.80; H, 3.41; N, 10.50; Cl, 13.29.
Found: C, 60.04; H, 3.22; N, 10.17; Cl, 12.79.
Methyl (Z)-4-{[(Z)-6-Chloro-7-methyl-4-(2-phenylhydrazono)-4H-
chromen-3-yl]methylene}-5-oxo-1-phenyl-4,5-dihydro-1H-pyra-
zole-3-carboxylate (13g)
LC-MS (ESI, 1.65 eV): m/z (%) = 521 [100, (M + H)+], 559 [5, (M + K)+].
Anal. Calcd for C31H28N4O4: C, 71.52; H, 5.43; N, 10.71. Found: C,
70.14; H, 4.92; N, 10.37.
Yellow solid; yield: 85 mg (77%); mp 268–270 °C.
FT-IR (KBr): 3430, 1720, 1690 cm–1
.
Ethyl (Z)-4-{[(Z)-6-Methyl-4-(2-phenylhydrazono)-4H-chromen-
3-yl]methylene}-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazole-3-car-
boxylate (13j)
1H NMR (500 MHz, CDCl3): δ = 2.37 (s, 3 H, 7-CH3), 3.89 (s, 3 H, OCH3),
6.81 (s, 1 H, 5-H), 7.05 (s, 1 H), 7.24 (t, 1 H), 7.37 (m, 4 H), 7.47 (m, 3
H), 7.93 (d, J = 7.7 Hz, 2 H), 8.41 (s, 1 H, 9-Η), 9.67 (s, 1 H, 2-Η).
Yellow solid; yield: 57 mg (53%); mp 238–240 °C.
13C NMR (125 MHz, CDCl3): δ = 19.9 (7-CH3), 52.1 (OCH3), 118.4 (C-
4a), 118.7 (C-4), 119.0 (C-3′), 120.5 (C-2′′, C-6′′), 122.9 (C-1′′), 124.0
(C-2′′′, C-6′′′), 124.5 (C-4′′′), 126.1 (C-8), 128.15 (C-1′′′), 128.68 (C-3′′,
C-5′′), 128.72 (C-3′′′, C-5′′′), 131.2 (C-7), 137.5 (C-6), 138.9 (C-5),
139.95 (C-4′′), 140.0 (C-3), 141.8 (C-9), 145.0 (C-2), 146.2 (C-4′), 153.9
(C-8a), 161.3 (3-C=O), 162.4 (5-C=O).
FT-IR (KBr): 3428, 1723, 1692 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.22 (t, 3 H, CH3), 2.27 (s, 3 H, CH3),
4.28 (q, J = 10 Hz, 2 H, OCH2), 6.83 (d, J = 10 Hz, 1 H), 6.90 (s, 1 H), 7.30
(m, 5 H), 7.33 (d, J = 10 Hz, 1 H), 7.44–7.45 (m, 2 H), 7.95 (d, J = 7.7 Hz,
2 H), 8.31 (s, 1 H, 9-Η), 9.68 (s, 1 H, 2-Η).
13C NMR (125 MHz, CDCl3): δ = 14.0 (CH3), 20.4 (6-CH3), 61.5 (OCH2),
114.4 (C-4a), 116.7 (C-8), 118.3 (C-4), 119.8 (C-3′), 120.5 (C-2′′, C-6′′),
124.0 (C-2′′′, C-6′′′), 125.9 (C-4′′′), 126.1 (C-1′′), 128.1 (C-4′′), 128.8 (C-
3′′, C-5′′), 128.9 (C-3′′′, C-5′′′),130.5 (C-5), 132.1 (C-7), 132.8 (C-6),
137.9 (C-1′′′), 138.9 (C-3), 140.4 (C-4′), 141.1 (C-9), 145.3 (C-2), 151.8
(C-8a), 160.1 (3-C=O), 162.3 (5-C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 513/515 [100,(M + H)+], 551/553 [4,(M
+ K)+].
Anal. Calcd for C28H21ClN4O4: C, 65.56; H, 4.13; N, 10.92; Cl, 6.91.
Found: C, 65.04; H, 4.02; N, 10.17; Cl, 5.79.
LC-MS (ESI, 1.65 eV): m/z (%) = 493 [100, (M + H)+], 531[3, (M + K)+].
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

K
P. M. Kasapidou et al.
Paper
Synthesis
Anal. Calcd for C29H24N4O4: C, 70.72; H, 4.91; N, 11.38. Found: C,
70.24; H, 4.52; N, 11.07.
Dimethyl (4R,5S)-1-(4-Chlorophenyl)-3-(6-methyl-4-oxo-4H-
chromen-3-yl)-4,5-dihydro-1H-pyrazole-4,5-dicarboxylate (15a)
Yellow solid; yield: 57 mg (42%); mp 180–182 °C.
Methyl (Z)-4-({(Z)-6-Methyl-4-[2-(p-tolyl)hydrazono]-4H-
chromen-3-yl}methylene)-5-oxo-1-(p-tolyl)-4,5-dihydro-1H-pyra-
zole-3-carboxylate (13k)
FT-IR (KBr): 1742, 1651 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.47 (s, 3 H, 6-CH3), 3.73 (s, 3 H, OCH3),
3.78 (s, 3 H, OCH3), 5.06 (d, J = 5.2 Hz, 1 H, 5′-Η), 5.21 (d, J = 5.2 Hz, 1
H, 4′-Η), 7.01 (d, J = 8.5 Hz, 2 H, 2′′-H, 6′′-Η), 7.23 (d, J = 8.5 Hz, 2 H, 3′′-
H, 5′′-Η), 7.41 (d, J = 8.5 Hz, 1 H, 8-Η), 7.51 (dd, J = 8.5, 1.8 Hz, 1 H, 7-
Η), 8.01 (d, J = 1.8 Hz, 1 H, 5-Η), 8.64 (s, 1 H, 2-Η).
13C NMR (125 MHz, CDCl3): δ = 21.0 (6-CH3), 53.07 (OCH3), 53.11
(OCH3), 56.7 (C-4′), 64.7 (C-5′), 114.4 (C-2′′, C-6′′), 116.6 (C-3′), 118.0
(C-8), 123.7 (C-4a), 125.3 (C-4′′), 125.4 (C-5′), 129.1 (C-3′′, C-5′′),
135.3 (C-7), 135.9 (C-6), 140.3 (C-3), 142.2 (C-1′′), 154.4 (C-8a), 154.4
(C-2), 169.2 (CO2Me), 169.7 (CO2Me), 175.7 (C=O).
Yellow solid; yield: 74 mg (69%); mp 248–250 °C.
FT-IR (KBr): 3385, 1747, 1717, 1687 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.27 (s, 3 H, 6-CH3), 2.32 (s, 3 H, 4′′′-
CH3), 2.37 (s, 3 H, 4′′-CH3), 3.82 (s, 3 H, OCH3), 6.87 (d, J = 8.3 Hz, 1 H,
H-8), 6.90 (s, 1 H, H-5), 7.11 (d, J = 8.2 Hz, 2 H, 3′′′-H, 5′′′-H), 7.14 (d, J =
8.3 Hz, 1 H, H-7), 7.24 (d, J = 8.3 Hz, 2 H, 3′′-H, 5′′-H), 7.29 (d, J = 8.2
Hz, 2 H, 2′′′-H, 6′′′-H), 7.82 (d, J = 8.3 Hz, 2 H, 2′′-H, 6′′-H), 8.38 (s, 1 H,
H-9), 9.65 (s, 1 H, H-2).
13C NMR (125 MHz, CDCl3): δ = 20.3 (6-CH3), 21.01 (4′′′-CH3), 21.04
(4′′-CH3), 52.0 (OCH3), 114.2 (C-4a), 116.5 (C-8), 118.3 (C-4′), 119.3
(C-3), 120.5 (C-2′′, C-6′′), 123.7 (C-2′′′, C-6′′′), 128.7 (C-6), 129.3 (C-3′′,
C-5′′), 129.32 (C-3′′′, C-5′′′), 131.9 (C-5), 132.4 (C-7), 135.4 (C-4′′),
135.7 (C-1′′), 137.3 (C-1′′′), 137.7 (C-4′′′), 139.9 (C-3′), 142.3 (C-9),
145.0 (C-2), 147.7 (C-4), 153.3 (C-8a), 160.9 (3-C=O), 162.3 (5-C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 455/457 [100, (M + H)+].
Anal. Calcd for C23H19ClN2O6: C, 60.73; H, 4.21; N, 6.16; Cl, 7.79.
Found: C, 65.84; H, 4.02; N, 10.07; Cl, 6.71.
Dimethyl (4R,5S)-3-(6-Methyl-4-oxo-4H-chromen-3-yl)-1-
(p-tolyl)-4,5-dihydro-1H-pyrazole-4,5-dicarboxylate (15b)
LC-MS (ESI, 1.65 eV): m/z (%) = 507 [100, (M + H)+], 529 [80, (M +
Yellow solid; yield: 64 mg (49%); mp 185–187 °C.
Na)+], 561 [10, (M + Na + MeOH)+].
FT-IR (KBr): 1731, 1645 cm–1
.
Anal. Calcd for C30H26N4O4: C, 71.12; H, 5.17; N, 11.08. Found: C,
70.84; H, 5.02; N, 11.07.
1H NMR (500 MHz, CDCl3): δ = 2.29 (s, 3 H, 4′′-CH3), 2.46 (s, 3 H, 6-
CH3), 3.72 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 5.05 (d, J = 5.3 Hz, 1 H, 5-
Η), 5.17 (d, J = 5.3 Hz, 1 H, 4-Η), 6.99 (d, J = 8.3 Hz, 2 H, 2′′-H, 6′′-Η),
7.09 (d, J = 8.3 Hz, 2 H, 3′′-H, 5′′-Η), 7.41 (d, J = 8.6 Hz, 1 H, 8-Η), 7.50
(dd, J = 8.6, 2.0 Hz, 1 H, 7-Η), 8.01 (s, 1 H, 5-Η), 8.65 (s, 1 H, 2-Η).
13C NMR (125 MHz, CDCl3): δ = 20.6 (4′′-CH3), 21.05 (6-CH3), 53.0
(OCH3), 53.03 (OCH3), 56.6 (C-4′), 65.2 (C-5′), 113.3 (C-2′′, C-6′′), 116.9
(C-3′), 118.0 (C-8), 123.7 (C-4a), 124.3 (C-4′′), 125.4 (C-5), 129.8 (C-3′′,
C-5′′), 135.2 (C-7), 135.7 (C-6), 139.1 (C-3), 141.5 (C-1′′), 154.2 (C-8a),
154.4 (C-2), 169.5 (CO2Me), 170.1 (CO2Me), 175.7 (C=O).
Methyl (Z)-4-({(Z)-6-Chloro-4-[2-(p-tolyl)hydrazono]-4H-
chromen-3-yl}methylene)-5-oxo-1-(p-tolyl)-4,5-dihydro-1H-pyra-
zole-3-carboxylate (13l)
Yellow solid; yield: 64 mg (62%); mp 258–260 °C.
FT-IR (KBr): 3371, 1716, 1697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.37 (s, 3 H, 4′′-CH3), 2.40 (s, 3 H, 4′′′-
CH3), 3.86 (s, 3 H, OCH3), 6.98 (d, J = 8.2 Hz, 1 H, 8-Η), 7.12 (d, J = 8.2
Hz, 1 H, 7-Η), 7.16 (d, J = 8.3 Hz, 2 H, 3′′′-H, 5′′′-H), 7.25–7.34 (m, 4 H),
7.43 (s, 1 H, 5-Η), 7.84 (d, J = 8.3 Hz, 2 H, 2′′-H, 6′′-Η), 8.35 (s, 1 H, 9-
Η), 9.68 (s, 1 H, 2-Η).
13C NMR (125 MHz, CDCl3): δ = 20.73 (4′′-CH3), 20.78 (4′′′-CH3), 52.0
(OCH3), 115.7 (C-4a), 117.6 (C-8), 118.5 (C-4), 118.9 (C-3′), 120.1 (C-
2′′, C-6′′), 123.5 (C-2′′′, C-6′′′), 123.6 (C-6), 129.0 (C-3′′, C-5′′), 129.1 (C-
3′′′, C-5′′′), 130.7 (C-5), 131.3 (C-7), 135.0 (C-4′′), 135.3 (C-1′′), 136.6
(C-4′′′), 137.7, (C-1′′′), 139.9 (C-3), 141.0 (C-9), 144.7 (C-2), 145.6 (C-
4′), 154.3 (C-8a), 160.9 (3-C=O), 162.1 (5-C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 435 [100, (M + H)+].
Anal. Calcd for C24H22N2O6: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.24;
H, 5.02; N, 6.37.
Dimethyl (4R,5S)-3-(6-Chloro-4-oxo-4H-chromen-3-yl)-1-
(p-tolyl)-4,5-dihydro-1H-pyrazole-4,5-dicarboxylate (15c)
Yellow solid; yield: 59 mg (43%); mp 179–181 °C.
FT-IR (KBr): 1735, 1654 cm–1
.
LC-MS (ESI, 1.65 eV): m/z (%) = 527 [100, (M + H)+], 581 [5, (M + Na +
1H NMR (500 MHz, CDCl3): δ = 2.28 (s, 3 H, 4′′-CH3), 3.72 (s, 3 H,
OCH3), 3.77 (s, 3 H, OCH3), 5.05 (d, J = 5.3 Hz, 1 H, 5′-Η), 5.17 (d, J = 5.3
Hz, 1 H, 4′-Η), 7.00 (d, J = 8.5 Hz, 2 H, 2′′-H, 6′′-Η), 7.09 (d, J = 8.5 Hz, 2
H, 3′′-H, 5′′-Η), 7.42 (dd, J = 7.9, 7.2 Hz, 1 H, 7-Η), 7.50 (d, J = 8.4 Hz, 1
H, 8-Η), 7.69 (ddd, J = 8.4, 7.2, 1.7 Hz, 1 H, 6-Η), 8.24 (dd, J = 7.9, 1.7
Hz, 1 H, 5-Η).
13C NMR (125 MHz, CDCl3): δ = 20.5 (4′′-CH3), 52.9 (OCH3), 53.07
(OCH3), 56.7 (C-4′), 65.5 (C-5′), 113.6 (C-2′′, C-6′′), 117.4 (C-3′), 118.1
(C-4a), 118.3 (C-8),124.4 (C-4′′), 125.6 (C-5), 126.3 (C-6), 129.8 (C-3′′,
C-5′′), 133.8 (C-7),139.3 (C-3), 141.7 (C-1′′), 154.5 (C-2),156.2 (C-8a),
169.4 (CO2Me), 170.1 (CO2Me), 175.7 (C=O).
MeOH)+].
Anal. Calcd for C29H23ClN4O4: C, 66.10; H, 4.40; N, 10.63; Cl, 6.73.
Found: C, 65.84; H, 4.02; N, 10.07; Cl, 6.70.
Reaction of Arylhydrazones with Acetylenedicarboxylates in Ace-
tic Acid; General Procedure
In a microwave reaction vial (0.5–2.0 mL), the acetylenedicarboxylate
11a,b (1.5 mmol), arylhydrazones 14a–d (0.3 mmol), and AcOH (1.0
mL) were mixed and then the mixture was irradiated in a microwave
oven at 120 °C for 5 min. The progress of the reaction was monitored
by TLC. The solvent was removed under vacuum and the resulting
residue was subjected to column chromatography (silica gel, petro-
leum ether/EtOAc, 5:1–3:1) to afford 15.
LC-MS (ESI, 1.65 eV): m/z (%) = 455 [100, (M + H)+].
Anal. Calcd for C23H19ClN2O6: C, 60.73; H, 4.21; N, 6.16; Cl, 7.79.
Found: C, 60.85; H, 4.30; N, 6.17; Cl, 6.99.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

L
P. M. Kasapidou et al.
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Synthesis
Dimethyl (4R,5S)-3-(6-Chloro-7-methyl-4-oxo-4H-chromen-3-yl)-
1-phenyl-4,5-dihydro-1H-pyrazole-4,5-dicarboxylate (15d)
13C NMR (125 MHz, CDCl3): δ = 20.98 (CH3), 21.2 (CH3), 50.8 (OCH3),
52.4 (OCH3), 116.2 (C-3′), 117.6 (C-8), 117.9 (C-4′), 123.8 (C-4a), 124.3
(C-2′′, C-6′′), 124.6 (C-5′), 125.7 (C-4′′), 129.8 (C-3′′, C-5′′), 135.1 (C-7),
135.5 (C-6), 136.5 (C-5), 139.3 (C-3), 144.3 (C-1′′), 154.4 (C-2), 154.6
(C-8a), 160.6 (CO2Me), 162.7 (CO2Me), 175.3 (C=O).
Yellow solid; yield: 54 mg (40%); mp 181–183 °C.
FT-IR (KBr): 1746, 1650 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.51 (s, 3 H, 7-CH3), 3.73 (s, 3 H, OCH3),
3.78 (s, 3 H, OCH3), 5.08 (d, J = 5.3 Hz, 1 H, 5′-Η), 5.16 (d, J = 5.3 Hz, 1
H, 4′-Η), 6.91 (t, J = 7.3 Hz, 1 H, 4′′-Η), 7.08 (d, J = 7.9 Hz, 2 H, 2′′-H, 6′′-
Η), 7.28 (t, J = 7.9 Hz, 2 H, 3′′-H, 5′′-Η), 7.40 (s, 1 H, 8-Η), 8.16 (s, 1 H,
5-Η), 8.61 (s, 1 H, 2-Η).
LC-MS (ESI, 1.65 eV): m/z (%) = 433 [100, (M + H)+].
Anal. Calcd for C24H20N2O6: C, 66.66; H, 4.66; N, 6.48. Found: C, 66.61;
H, 4.58; N, 6.37.
Dimethyl 3-(4-Oxo-4H-chromen-3-yl)-1-(p-tolyl)-1H-pyrazole-
4,5-dicarboxylate (16c)
13C NMR (125 MHz, CDCl3): δ = 21.0 (7-CH3), 53.0 (OCH3), 53.03
(OCH3), 56.3 (C-4′), 64.9 (C-5′), 113.1 (C-2′′, C-6′′), 117.0 (C-3′), 120.1
(C-8), 120.6 (C-4′′), 123.1 (C-4a), 125.7 (C-5), 129.2 (C-3′′, C-5′′), 132.5
(C-6), 139.01 (C-1′′), 143.2 (C-3), 143.5 (C-7), 154.2 (C-2), 154.3 (C-
8a), 169.3 (CO2Me), 169.8 (CO2Me), 174.5 (C=O).
Yellow solid; yield: 42 mg (66%); mp 177–179 °C.
FT-IR (KBr): 1654, 1714, 1735 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3), 3.78 (s, 3 H, OCH3),
3.85 (s, 3 H, OCH3), 7.26 (m, 2 H, 2′′-H, 6′′-H), 7.38 (d, J = 8.4 Hz, 2 H,
3′′-H, 5′′-H), 7.43 (dd, J = 7.95–7.14 Hz, 1 H), 7.49 (d, 8.43 Hz, 1 H),
7.69 (ddd, J = 8.43, 7.14, 1.7 Hz, 1 H),), 8.24 (s, 1 H, 2-H), 8.29 (dd, J =
7.95, 1.7 Hz, 1 H, 5-H).
LC-MS (ESI, 1.65 eV): m/z (%) = 455/457 [(M + H)+], 477/479 [(M +
Na)+].
Anal. Calcd for C23H19ClN2O6: C, 60.73; H, 4.21; N, 6.16; Cl, 7.79.
Found: C, 60.64; H, 4.02; N, 6.07; Cl, 7.55.
13C NMR (125 MHz, CDCl3): δ = 21.2 (CH3), 50.7 (OCH3), 52.3 (OCH3),
116.4 (C-3′), 118.0 (C-8), 118.2 (C-4′), 124.4 (C-4a), 124.5 (C-2′′, C-6′′),
125.5 (C-5′), 126.4 (C-4′′), 129.8 (C-3′′, C-5′′), 133.8 (C-7), 136.5 (C-5),
136.7 (C-6), 139.3 (C-3), 144.3 (C-1′′), 154.5 (C-2), 156.4 (C-8a), 160.6
(CO2Me), 162.7 (CO2Me), 175.2 (C=O).
Reaction of Arylhydrazones with Acetylenedicarboxylates in Tolu-
ene; General Procedure
To a stirred solution of the arylhydrazone 14a–d (0.2 mmol) in tolu-
ene (10 mL), acetylenedicarboxylate 11a,b (0.2 mmol) and catalytic
amount of Yb(OTf)3 (0.1 mmol) were added. The mixture was re-
fluxed for 5 h monitoring by TLC. The solvent was removed under
vacuum and the solid was subjected to column chromatography (sili-
ca gel, petroleum ether/EtOAc 5:1–3:1).
LC-MS (ESI, 1.65 eV): m/z (%) = 419 [100, (M + H)+].
Anal. Calcd for C23H18N2O6: C, 66.02; H, 4.34; N, 6.70. Found: C, 66.01;
H, 4.28; N, 6.47.
Diethyl 3-(4-Oxo-4H-chromen-3-yl)-1-(p-tolyl)-1H-pyrazole-4,5-
dicarboxylate (16d)
Diethyl 3-(6-Methyl-4-oxo-4H-chromen-3-yl)-1-(p-tolyl)-1H-pyra-
zole-4,5-dicarboxylate (16a)
Yellow solid; yield: 37 mg (57%); mp 165–167 °C.
Yellow solid; yield: 47 mg (58%); mp 169–172 °C.
FT-IR (KBr): 1651, 1717, 1732 cm–1
.
FT-IR (KBr): 1649, 1716, 1736 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.18 (t, J = 7.1 Hz, 3 H, CH3), 1.23 (t, J =
7.1 Hz, 3 H, CH3), 2.41 (s, 3 H, CH3), 4.25 (q, J = 7.1 Hz, 2 H, CH2), 4.30
(q, J = 7.1 Hz, 2 H, CH2), 7.28 (d, J = 7.1 Hz, 2 H, 2′′-H, 6′′-H), 7.39 (d, J =
7.1 Hz, 2 H, 3′′-H, 5′′-H), 7.43 (d, J = 8.5 Hz, 1 H, 7-H), 7.50 (d, J = 8.5
Hz, 1 H, 8-H), 7.70 (ddd, J = 8.5, 7.1, 2.0 Hz, 1 H, 6-H), 8.23 (s, 1 H, 2-
H), 8.30 (dd, J = 8.5, 2.0 Hz, 1 H, 5-H).
13C NMR (125 MHz, CDCl3): δ = 13.8 (CH3), 13.9 (CH3), 21.2 (CH3), 60.9
(OCH2), 62.4 (OCH2), 116.1 (C-3′), 118.0 (C-8), 118.1 (C-4′), 124.2 (C-
4a), 124.3 (C-2′′, C-6′′), 125.4 (C-5′), 126.3 (C-7), 129.7 (C-3′′, C-5′′),
133.7 (C-6), 136.5 (C-5), 137.1 (C-4′′), 139.2 (C-3), 144.2 (C-1′′), 154.4
(C-8a), 156.3 (C-2), 160.2 (CO2Et), 162.1 (CO2Et), 175.2 (C=O).
1H NMR (500 MHz, CDCl3): δ = 1.20 (t, J = 7.1 Hz, 3 H, CH3), 1.24 (t, J =
7.1 Hz, 3 H, CH3), 2.44 (s, 3 H, OCH3), 2.49 (s, 3 H, OCH3), 4.26 (q, J = 7.1
Hz, 2 H, CH2), 4.32 (q, J = 7.1 Hz, 2 H, CH2), 7.28 (d, J = 8.1 Hz, 2 H, 2′′-
H, 6′′-H), 7.40 (d, J = 8.5 Hz, 2 H, 3′′-H, 5′′-H), 7.51 (dd, J = 8.5, 2.0 Hz, 1
H, 8-H), 7.70 (t, 1 H, 7-H), 8.07 (s, 1 H, 5-H), 8.20 (s, 1 H, 2-H).
13C NMR (125 MHz, CDCl3): δ = 13.8 (CH3), 13.9 (CH3), 20.9 (CH3), 21.2
(CH3), 60.8 (OCH2), 62.4 (OCH2), 116.1 (C-3′), 117.8 (C-8), 117.9 (C-4′),
123.9 (C-4a), 124.3 (C-2′′, C-6′′), 125.6 (C-5′), 129.7 (C-3′′, C-5′′), 135.0
(C-7), 135.4 (C-6), 136.6 (C-5), 137.1 (C-4′′), 139.2 (C-3), 144.4 (C-1′′),
154.3 (C-8a), 154.6 (C-2), 160.2 (CO2Et), 162.1 (CO2Et), 175.3 (C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 461 [100, (M + H)+].
LC-MS (ESI, 1.65 eV): m/z (%) = 447 [100, (M + H)+].
Anal. Calcd for C26H24N2O6: C, 67.82; H, 5.25; N, 6.08. Found: C, 67.61;
H, 5.18; N, 6.04.
Anal. Calcd for C25H22N2O6: C, 67.26; H, 4.97; N, 6.27. Found: C, 67.11;
H, 4.88; N, 6.07.
Dimethyl 3-(6-Methyl-4-oxo-4H-chromen-3-yl)-1-(p-tolyl)-1H-
pyrazole-4,5-dicarboxylate (16b)
[1-(4-Chlorophenyl)-1H-pyrazol-4-yl](2-hydroxy-5-methyl-
phenyl)methanone (17a)
Yellow solid; yield: 34 mg (53%); mp 174–176 °C.
Yellow solid; yield: 46 mg (49%); mp 115–117 °C.
FT-IR (KBr): 1620, 1715, 1732 cm–1
.
FT-IR (KBr): 1629, 3436 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3), 2.46 (s, 3 H, CH3),
3.75 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 7.26 (d, J = 7.5 Hz, 2 H, 2′′-H,
6′′-H), 7.38 (d, J = 7.5 Hz, 2 H, 3′′-H, 5′′-H), 7.39 (d, J = 8.6 Hz, 1 H, 7-H),
7.49 (d, J = 8.6 Hz, 1 H, 8-H), 8.08 (d, J = 2.1 Hz, 1 H, 5-H), 8.22 (s, 1 H,
2-H).
1H NMR (500 MHz, CDCl3): δ = 2.33 (s, 3 H), 6.96 (d, J = 5.6 Hz, 1 H),
7.33 (d, 6.2 Hz, 1 H), 7.47 (d, J = 5.6 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 2 H),
8.15 (s, 1 H), 8.43 (s, 1 H), 11.74 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.0 (CH3), 114.4, 118.4, 119.8, 123.8,
125.3, 128.2, 129.8, 130.9, 133.6, 137.2, 137.8, 142.5, 158.1, 191.9
(C=O).
LC-MS (ESI, 1.65 eV): m/z (%) = 313 [100, (M + H)+].
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

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P. M. Kasapidou et al.
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Synthesis
Anal. Calcd for C17H13ClN2O6: C, 65.29; H, 4.19; N, 8.96; Cl, 11.34.
Found: C, 65.11; H, 4.18; N, 8.04; Cl, 10.32.
(4) Macarron, R.; Banks, M. N.; Bojanic, D.; Burns, D. J.; Cirovic, D.
A.; Garyantes, T.; Green, D. V. S.; Hertzberg, R. P.; Janzen, W. P.;
Paslay, J. W.; Schopfer, U.; Sittampalam, G. S. Nat. Rev. Drug Dis-
covery 2011, 10, 188.
(2-Hydroxy-5-methylphenyl)[1-(p-tolyl)-1H-pyrazol-4-yl]metha-
(5) Brown, D. G.; Boström, J. J. Med. Chem. 2016, 59, 4443.
(6) Scannell, J. W.; Bosley, J. PLoS One 2016, 11, 1.
(7) Ekins, S.; Mestres, J.; Testa, B. Br. J. Pharmacol. 2007, 152, 9.
(8) Brown, N. In Silico Medicinal Chemistry: Computational Methods
to Support Drug Design; Royal Society of Chemistry: Cambridge,
2016.
(9) Schneider, P.; Schneider, G. J. Med. Chem. 2016, 59, 4077.
(10) Wu, B.; Zhang, Z.; Noberini, R.; Barile, E.; Giulianotti, M.; Pinilla,
C.; Houghten, R. A.; Pasquale, E. B.; Pellecchia, M. Chem. Biol.
2013, 20, 19.
none (17b)
Yellow solid; yield: 40 mg (43%); mp 117–119 °C.
FT-IR (KBr): 1621, 3425 cm–1
1H NMR (500 MHz, CDCl3): δ = 2.34 (s, 3 H), 2.41 (s, 3 H), 5.35 (s, 1 H),
5.42 (s, 1 H), 7.02 (s, 1 H), 7.36 (d, J = 8.5 Hz, 2 H), 7.40 (d, J = 8.5 Hz, 2
H), 7.43 (d, J = 8.5 Hz, 1 H), 7.50 (dd, J = 8.5, 1.8 Hz, 1 H), 8.15 (s, 1 H),
11.43 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.3, 21.4, 114.2, 114.6, 117.1, 119.2,
126.8, 129.4, 129.8, 129.9, 131.3, 134.7, 135.9, 142.1, 158.7, 191.2.
LC-MS (ESI, 1.65 eV): m/z (%) = 293 [100, (M + H)+].
.
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321.
Anal. Calcd for C18H16N2O6: C, 73.95; H, 5.52; N, 9.58. Found: C, 73.81;
H, 5.46; N, 9.04.
(12) Ohnmacht, S. A.; Neidle, S. Bioorg. Med. Chem. Lett. 2014, 24,
2602.
(13) Larsson, A.; Jansson, A.; Åberg, A.; Nordlund, P. Curr. Opin. Chem.
Biol. 2011, 15, 482.
(2-Hydroxyphenyl)[1-(p-tolyl)-1H-pyrazol-4-yl]methanone (17c)
(14) Tiefenbrunn, T.; Forli, S.; Happer, M.; Gonzalez, A.; Tsai, Y.;
Soltis, M.; Elder, J. H.; Olson, A. J.; Stout, C. D. Chem. Biol. Drug
Des. 2014, 83, 141.
(15) Mashalidis, E. H.; Śledź, P.; Lang, S.; Abell, C. Nat. Protoc. 2013, 8,
2309.
Yellow solid; yield: 32 mg (37%); mp 122–124 °C.
FT-IR (KBr): 1632, 3438 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.33 (s, 3 H), 5.82 (s, 1 H), 6.97 (s, 1 H),
7.20 (t, J = 7.5 Hz, 2 H), 7.42 (d, J = 7.5 Hz, 2 H), 7.5 (d, J = 8.5 Hz, 1 H),
7.72 (d, J = 7.5 Hz, 2 H), 8.15 (d, J = 8.5 Hz, 1 H), 11.76 (s, 1 H).
(16) Rodrigues, T.; Reker, D.; Kunze, J.; Schneider, P.; Schneider, G.
Angew. Chem. Int. Ed. 2015, 54, 10516.
13C NMR (125 MHz, CDCl3): δ = 21.3 (CH3), 114.2, 116.1, 119.2, 124.5,
(17) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(18) Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
(19) Alvim, H. G. O.; da Silva Junior, E. N.; Neto, B. A. D. RSC Adv. 2014,
4, 54282.
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1189.
124.6, 129.3, 129.7, 132.4, 134.2, 135.9, 136.5, 142.1, 162.1, 192.3.
LC-MS (ESI, 1.65 eV): m/z (%) = 279 [100, (M + H)+].
Anal. Calcd for C17H14N2O6: C, 73.37; H, 5.07; N, 10.07. Found: C,
73.11; H, 5.06; N, 10.04.
(5-Chloro-2-hydroxy-4-methylphenyl)(1-phenyl-1H-pyrazol-4-
yl)methanone (17d)
(21) Hulme, C.; Ayaz, M.; Martinez-Ariza, G.; Medda, F.; Shaw, A. In
Small Molecule Medicinal Chemistry: Strategies and Technologies;
Czechtizky, W.; Hamley, P., Eds.; John Wiley: Hoboken, 2015,
145.
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Eds.; Wiley-VCH: Weinheim, 2005, 311.
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2007, 7, 1108.
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Society of Chemistry: Cambridge, 2016.
Yellow solid; yield: 58 mg (53%); mp 121–123 °C.
FT-IR (KBr): 1625, 3434 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.41 (s, 3 H), 6.96 (s, 1 H), 7.26 (t, J = 7.5
Hz, 1 H), 7.42 (s, 1 H), 7.45 (d, J = 7.5 Hz, 2 H), 7.93 (d, J = 7.5 Hz, 2 H),
8.16 (s, 1 H), 8.43 (s, 1 H), 11.84 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.3 (CH3), 113.5, 114.6, 119.4, 119.6,
124.5, 126.2, 129.4, 129.6, 133.7, 139.4, 141.6, 145.8, 161.2, 190.6
(C=O).
(26) Cavalli, A.; Bolognesi, M. L.; Minarini, A.; Rosini, M.; Tumiatti, V.;
Recanatini, M.; Melchiorre, C. J. Med. Chem. 2008, 51, 347.
(27) Messer, W. S. Curr. Pharm. Des. 2004, 10, 2015.
(28) Zhan, P.; Liu, X. Curr. Pharm. Des. 2009, 15, 1893.
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(30) Keri, R. S.; Budagumpi, S.; Pai, R. K.; Balakrishna, R. G. Eur. J.
Med. Chem. 2014, 78, 340.
LC-MS (ESI, 1.65 eV): m/z (%) = 313 [(M + H)+].
Anal. Calcd for C17H13ClN2O6: C, 65.29; H, 4.19; N, 8.96; Cl, 11.34.
Found: C, 65.11; H, 4.18; N, 8.84; Cl, 11.29.
Supporting Information
(31) Schmidt, A.; Dreger, A. Curr. Org. Chem. 2011, 15, 1423.
(32) Morales, P.; Gómez-Cañas, M.; Navarro, G.; Hurst, D. P.; Carrillo-
Salinas, F. J.; Lagartera, L.; Pazos, R.; Goya, P.; Reggio, P. H.;
Guaza, C.; Franco, R.; Fernández-Ruiz, J.; Jagerovic, N. J. Med.
Chem. 2016, 59, 6753.
(33) Cumella, J.; Hernádez-Folgado, L.; Girón, R.; Sánchez, E.;
Morales, P.; Hurst, D. P.; Gómez-Cañas, M.; Gómez-Ruiz, M.;
Pinto, D. C. G. A.; Goya, P.; Reggio, P. H.; Martin, M. I.;
Fernández-Ruiz, J.; Silva, A. M. S.; Jagerovic, N. ChemMedChem
2012, 7, 452.
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589013.
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