Synthesis, reactions and DFT calculations of novel bis(chalcones) linked to a thienothiophene core through an oxyphenyl bridge

Article abstract of DOI:10.1039/c5ra27322f

A synthesis of novel isomeric bis(chalcones) based-thienothiophene and study of their synthetic utilities as building blocks for novel bis(dihydroisoxazoles), bis(dihydropyrazoles) and bis(dihydropyrimidines) each linked to a thienothiophene core through an oxyphenyl bridge is reported. Density functional theory (DFT) calculations at the B3LYP/6-31G level of theory have been carried out to investigate the equilibrium geometry of the novel isomeric chalcones 7 and 10. Moreover, total energy, energy of the HOMO and LUMO and Mullikan atomic charges were calculated. In addition, the dipole moment and orientation of the two π-isoelectronic chalcones 7 and 10 have been measured and their interactions with hydrazine hydrate to form dihydropyrazoles have been studied.

Full text of DOI:10.1039/c5ra27322f

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Synthesis, reactions and DFT calculations of novel bis(chalcones) linked to a
thienothiophene core through an oxyphenyl bridge
Osama M. Sayed, H. Moustafa, Ahmed E. M. Mekky, Ahmad M. Farag and Ahmad
H. M. Elwahy∗
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
E-mail: aelwahy@hotmail.com
Abstract: A synthesis of novel isomeric bis(chalcones) based-thienothiophene and
study of their synthetic utilities as building blocks for novel bis(dihydroisoxazes),
bis(dihydropyrazoles) and bis(dihydropyrimidines) each linked to a thienothiophene
core through an oxyphenyl bridge is reported. Density functional theory (DFT)
calculations at the B3LYP/6-31G level of theory have been carried out to investigate
the equilibrium geometry of the novel isomeric chalcones 7 and 10. Moreover, total
energy, energy of HOMO and LUMO and Mullikan atomic charges were calculated.
In addition, dipole moment and orientation of the two π-isoelectronic chalcones 7 and
10 have been performed and their interactions with hydrazine hydrate to form
dihydropyrazoles have been studied.
1. Introduction
Chalcones are very interesting molecules due to their diverse applications in
different fields. They display a wide range of pharmacological properties, including
antimutagenic and antitumor-promoting activities, antibacterial, anti-inflammatory,
antiulcerative, and hepatoprotective activities.1 They are also useful in materials
science fields such as nonlinear optics,2 optical limiting,3 Langmuir films, and
photoinitiated polymerization.4 Chalcones are also useful intermediates for the
synthesis of five-, six- and seven-membered heterocyclic compounds.5
Heterocyclic compounds containing the pyrazole unit have a broad spectrum of
biological activities, such as monoamine oxidase inhibitor,6 anticonvulsant,7
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antibacterial,8 hypotensive,9 antipyretic10 and anti-inflammatory11 activity. Moreover,
the pyrazole nucleus represent the core unit in a variety of drugs (Figure 1) such as
celecobix (Celebrex) I, sildenafil (Viagra) II, and rimonabant (Acomplia) III.12
Figure 1. Some drugs incorporating pyrazole ring
Cl
O
CF3
N
HN
O
N
N
N
O
S
HN
O
N
N
N
N
N
O
N
H2NO2S
Cl
Cl
I
II
Viagra
III
Rimonabant
Celebrex
In addition, isoxazoles are reported to show potent anti-tuberculosis,13 antimicrobial14
and anti-inflammatory activities.15
The literature survey indicated also that compounds encompassing pyrimidines
nucleus exhibited a wide range of pharmacological activities including antifungal,16
anti-inflammatory,17
antihypertensive,18 antiviral,19 antidiabetic,20 antioxidant,21
anticancer activities.22 During the last two decades several pyrimidine derivatives IV-
VII (Figure 2) have been reported as antibacterial drugs.23, 24
Figure 2. Some pyrimidine derivatives as antibacterial drugs
OCH3
N
NH2
H3CO
H3CO
Cl
NH2
N
N
NH2
O
NH2
NH2
OCH3
N
N
H2N
OCH3
H3C
NH2
H3CO
OCH3
N
NH2
Br
IV
V
VI
Trimethoprim
VII
Pyrimethamine
Brodiprim
Iclaprim
In addition, considerable attention has been focused on thienothiophenes due to
their interesting biological activities. They have been tested as potential antitumor,
2

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antiviral, antibiotic and antiglaucoma drugs or as inhibitors of platelet aggregation.25
Thienothiophenes are also of potential interest as π-electron donors and have potential
applications in a wide variety of optical and electronic systems.26
Furthermore, attention has been increasingly paid in recent years to the
synthesis of bis-heterocyclic for their numerous applications as electrical materials,27
chelating agents, and metal ligands.28 They also exhibit various biological activities
including antibacterial, fungicidal, tuberculostatic, and plant growth regulative
properties.29 Moreover, compounds including bis-heterocyclic moieties were
encountered in many bioactive natural product and recent reports showed that among
libraries of derivatized heterocycles, the most active library compounds had a bis-
heterocyclic structure.30 Some bis-heterocycles VIII and IX (Figure 3) exemplified by
LU 79553 and WMC-26, both showing high effectiveness against tumor xenografts in
vivo.31
Figure 3. Some bis-heterocycles with anti-tumor activity
O
O
N
NH
N
O
HN
O
N
H
N
NH
N
N
O
O
N
N
VIII
LU-79553
IX
WMC-26
The estimation of relative energies of molecules is very important both in theoretical
studies and in the investigation of their chemical reactivity as well as to understand the
possible interactions of reactants. Theoretical calculation can give an insight into some
of these issues since it can determine the structure of the molecules, the active sites,
and atomic level description of interaction mechanisms on the intermediate formation
involved in a given reaction.32-35 Recently, because of their high accuracy theoretical
calculations have also significantly contributed to drug discovery and design.36-38
In connection with these findings, we report herein on the synthesis of some
novel bis(chalcones) and studied their synthetic utility as versatile synthons for the
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synthesis
of
novel
bis(dihydroisoxazes),
bis(dihydropyrazoles)
and
bis(dihydropyrimidines) each linked to a thienothiophene core through an oxyphenyl
bridge. DFT calculations have also been carried out to investigate the equilibrium
geometry of the synthesized chalcones as well as their interaction with binucleophilic
reagents.
2. Results and Discussion
2.1. Synthesis
Very recently, we reported the synthesis of ethyl 3,4-bis(bromomethyl)-5-
(ethyloxycarbonyl)thieno[2,3-b]thiophene-2-carboxylate 139 and studied its use as a
key intermediatefor the synthesis of the novel bis(acetophenone) 4 as well as the novel
bis(aldehyde) 5. The latter compounds can be prepared by the reaction of 1 with p-
hydroxyacetophenone 2 or p-hydroxybenzaldehyde 3, respectively, in basic media40
(Scheme 1).
Scheme 1. Synthesis of bis(acetophenone) 4 and bis(aldehyde) 5
O
O
Me
Me
O
Me
HO
2
O
O
i) KOH/EtOH
EtOOC
COOEt
ii) DMF, reflux 10 min
S
S
Br
EtOOC
Br
COOEt
4
O
H
O
H
O
H
S
S
1
HO
O
O
3
i) KOH/EtOH
EtOOC
COOEt
ii) DMF, reflux 10 min
S
S
5
The synthetic utility of 4 and 5 as precursors for novel bis(chalcones) were thus
investigated. A classical method for synthesis of chalcones is claisen-schmidt
4

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condensation in which the appropriate aldehyde reacted with the corresponding
acetophenone in the presence of aqueous alkaline bases41,42 under conventional
heating, microwave irradiation or ultrasound irradiation.43
Accordingly, we studied the synthesis of the bis(chalcone) 7 by Claisen–
Schmidt condensation reaction of the bis(acetyl) compound 4 with benzaldehyde 6 in
basic solution. Unfortunately, we were not be able to isolate a pure sample of the
corresponding bis(chalcone) 7 neither by stirring at room temperature nor by heating
at reflux and the reaction gave instead a mixture of products that cannot be handled.
The bis(chalcone) 7 can be prepared by another strategy, in which the chalcone
844 was prepared separately by the reaction of p-hydroxyacetophenone 2 with
benzaldehyde 6 in the presence of 20% alcoholic KOH solution. Reaction of the
potassium salt of 4-benzoylvinylphenol 8 (obtained upon treatment of 8 with ethanolic
KOH) with dibromo compound 1 in boiling DMF afforded 7 in 82% yield (Scheme 2).
Scheme 2. Synthesis of bis(chalcone) 7
Similarly, the bis(chalcone) 10 was prepared firstly by preparation of chalcone
1145 from the reaction of p-hydroxybenzaldehyde 3 and acetophenone 9 in presence of
20% alcoholic KOH solution.This was then treated with dibromo compound 1 in the
presence of anhydrous KOH in refluxing DMF to give 10 in 75% yield (Scheme 3).
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It is noteworthy to mention that the direct synthesis of the bis(chalcone) 10 by
treatment of the bis(formyl) compound 5 with acetophenon 9 under basic conditions
was also unsuccessful.
Scheme 3. Synthesis of bis(chalcone) 10
Presence of α,β-unsaturated keto function makes chalcone very prone to
undergo reactions with bidentate nucleophiles to give five-, six- and seven-membered
heterocyclic compounds. This property of chalcone was exploited in the present work
to generate pyrazole, isoxazole, and pyrimidine rings linked on 3,4-positions of a
thienothiophene core through an oxyphenyl spacer. Thus, condensation of 7 with each
of hydrazine hydrate 12 and semicarbazide 13 in refluxing acetic acid afforded the
corresponding bis(4,5-dihydropyrazoles) 15 and 16 in 88 and 85% yields, respectively.
Furtheremore, reaction of bis(chalcone) 7 with thiosemicarbazide 14 in refluxing
acetic acid afforded directly bis(3-aryl-4,5-dihydro-1H-pyrazole-1-thiocarboxamide)
17 in 80% yield (Scheme 4).
Bis(chalcone) 7 was further reacted with hydroxylamine hydrochloride 22 in
alkaline medium to yield the corresponding isoxazoline derivative 23 in 68% yield
(Scheme 4).
Moreover, cyclocondensation of 7 with urea 18 and thiourea 19 in refluxing
ethanolic KOH solution gave bis(dihydroarylpyrimidin-2(1H)-one) 20 in 70% yield.
and pyrimidin-2(1H)-thione 21 in a 72% yield, respectively (Scheme 4).
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Scheme 4. Reaction of bis(chalcone) 7 with different binucleophilic reagents
Ph
Ph
R
R
N
N
N
N
O
O
15 R = COCH3
16 R = CONH2
17
R = CSNH2
O
H3CH2CO
O
OCH2CH3
S
15 -17
S
12 R = H
13 R = CONH2
14
R = CSNH2
NH2NHR
AcOH reflux 8 h
12 -14
H
H
O
Ph
Ph
O
O
O
O
O
S
S
H3CH2CO
X
OCH2CH3
7
KOH /50 ml EtOH 95%
CH3COOH/CH3COONa
reflux 8 h
NH2-OH HCl
1,4-Dioxan
refiux 8 h
H2N
NH2
X = O
22
18
19 X = S
Ph
Ph
Ph
Ph
N
N
O
N
O
N
HX
XH
N
N
O
O
O
O
O
O
O
OCH2CH3
O
S
S
H3CH2CO
S
S
H3CH2CO
OCH2CH3
23
20 X = O
21 X = S
On the other hand, the cyclizations of bis(chalcone) 10 with hydrazine hydrate
12 or semicarbazide 13, respectively, in refluxing acetic acid did not lead to the
formation of pure samples of the corresponding bis(pyrazolines) 24 and 25. The NMR
spectra of the reaction products indicated the presence of characteristic signals for
both of the target bis(dihydropyrazoles) as well as those of the precursors
bis(chalcones). Repeated attempts to isolate pure samples of 24 and 25 by carrying out
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the reaction under a variety of conditions (varied temperatures, reaction time, etc.)
were also unsuccessful.
The bis(dihydropyrazole) 24 was successfully prepared by another strategy, in
which the dihydropyrazole 2646 was prepared separately by the condensation of
chalcone 8 with hydrazine hydrate 12 in refluxing acetic acid. Subsequent reaction of
26 with 3,4-dibromo compound 1 in basic medium afforded 24 in 65% yield (Scheme
5).
Similarly, the bis(dihydropyrazole) 25 can also prepared in 72% yield firstly by
reaction of chalcone 8 with semicarbazide 13 in refluxing acetic acid to give
dihydropyrazole 27 in 60% yield followed by reaction with dibromo compound 1.
Scheme 5. Synthesis of bis(dihydropyrazoles) 24 and 25
Ph
Ph
O
O
Ph
Ph
N
N
N
N
H
H
R
R
24 R = COCH3
25 R = CONH2
12 R = H
13 R = CONH2
NH2NHR
O
O
O
O
O
O
O
H3CH2CO
O
AcOH/reflux 8h
S
S
H3CH2CO
OCH2CH3
S
S
OCH2CH3
10
Br
Br
O
O
S
S
H3CH2CO
OCH2C
H3
1
i) KOH/EtOH
ii) DMF, reflux 10 min
R
N
N
H
O
12 R = H
13 R = CONH2
Ph
NH2NHR
HO
HO
8
26 R = COCH3
27 R = CONH2
AcOH/reflux 8h
2.2. Spectroscopy
The chemical structures of the synthesized compounds were established by
spectroscopic data (FTIR, 1H NMR and 13C NMR) and elemental analyses.
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The IR spectrum of bis-chalcones 7 and 10 reveal the presence of a strong bands at
υ1657 and 1658 cm-1, respectively, assignable for the α, β-unsaturated C═O group.
1H NMR spectra of compounds 7 and 10 exhibit each of the olefinic protons as a
doublet signal at δ = 7.47–7.55 and 7.61–7.80 regions with a mutual coupling constant
value J = 15.2 Hz. The large J value clearly reveals the trans geometry for the
chalcones. All other protons were seen at the expected chemical shifts and integral
values (c.f. experimental part).The carbonyl carbon of the chalcones 7 and 10 appears
at δ 187.60 and 189.34 ppm in their 13C NMR spectrum.
The IR spectra of dihydropyrazoles 16, 17 and 25 reveal the presence of amino
stretching vibration bands at υ 3423-3396 cm-1. In addition, dihydropyrazoles 16 and
25 exhibit amidic carbonyl stretching vibration (at υ 1670–1664 cm-1).
1H NMR spectra of dihydropyrazoles 15-17, 24 and 25 exhibit three signal sets
each appears as a mutiplet assignable for nonmagnetically equivalent pyrazoline H2C-
4 (at δ 2.88-4.18, 3.64-4.30) coupled with each other and in turn with the vicinal
methine proton HC-5 (at δ 5.38–6.25).
The IR spectrum of compound 20 showed an absorption band at (υ 3428 cm-1)
corresponding to the OH stretching frequency. On the other hand, the IR spectrum of
compound 21 exhibited an absorption band at (υ 1448 cm-1) corresponding to the C=S
stretching frequency.
1H NMR spectral features of dihydropyrimidines 20 and 21 are closely similar
to those of 15-17 exhibiting non-magnetically equivalent methylene H2C-5 as
multiplet signals at δ 4.15-4.18 and 4.26-4.29 beside the multiplet dihydropyrimidine
HC-6 at δ 6.22-6.26 ppm.
Moreover, compounds 15-17, 20, 21, 23 and 25 also featured the methylene
ether linkage OCH2 as multiplet or two separate doublets signals at δ 4.89–5.94
regions although their precursors 7 and 10 exhibit singlet signals for these protons at δ
= 5.67 and 5.70 ppm, respectively. This suggests the generation of asymmetric centre
(in the dihydropyrazole, dihydrooxazole and dihydropyrimidine rings) and it is close
enough to this CH2 group to effect such spliting. Evidence from the 13C NMR data for
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compound 16 indicate that it exists entirely as one stable conformer. On the other
hand, the two methylene ether linkage OCH2 resonance appears exceptionally as a
singlet signal at δ = 5.57 in compound 24.
2.3. Molecular orbital calculations
DFT calculation at the B3LYP level of theory and 6-31G as a basis set can be
used to explain why bis(chalcone) 7 reacted with hydrazine hydrate 12, as
representative example of binucleophilic reagents, to yield the corresponding
bis(dihydropyrazole) 15 (88%). On the other hand, the cyclization of bis(chalcone) 10
with hydrazine hydrate did not lead to formation of pure sample of the corresponding
bis(dihydropyrazole) 24. Also, DFT calculation was employed to study the stability of
the bis(dihydropyrazoles) 15 and 24.
Bis(chalcones) 7 and 10 are π–isoelctronic molecules, both have
thionothiophene core and oxyphenyl bridge, but they differ in the arrangement of the
enone moiety (CH=CH-C=O) with respect to the oxyphenyl bridge. In case of
bis(chalcone) 7 the C=O group is attached directly to the oxyphenyl bridge while for
bis(chalcone) 10, the C=C moiety is directly attached to the oxyphenyl bridge.
The optimized geometries (bond lengths, bond angles and dihedral angles) as
well as ground state energies (total energy ET, energy of highest occupied MO EHOMO
,
energy of lowest unoccupied MO ELUMO, energy gap Eg, dipole moment µ, and net
charge on eneone moiety) of 7 and 10 using B3LYP/6-31G are presented in Tables 1-3
and Figures 4 and 5.
From the results of Tables 1-3 and Figures 4 and 5, the following conclusions were
infered:-
1- The optimized bond length of C=C in phenyl ring falls in the range from
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1.393 to 1.428 Å which are in good agreement with the experimental data
1.411 Å 43, for C=O bonds the optimized length obtained by B3LYP/6-31G is
slightly shorter than the experimental value 1.229 Å.43
2- The bond angles for DFT/6-31G reported in Table 1 and 2 are slightly better
than the HF-method compared to experimental results.
From the analysis of bond lengths and bond angles (paragraphs 1 and 2), we
notice such differences between calculated and measured values. These
discrepancies can be explained by the fact that the calculations assume an isolated
molecule, where the intermolecular columbic interactions with the neighboring
molecules are absent.
3- For both chalcones 7 and 10, the two compounds are non-planar, where both
the oxyphenyl bridges are out of the molecular plane of thienothiophene core.
4- For chalcone 7, the two oxyphenyl bridges are out of the molecular plane of
thienothiophene core by 26.6o (C27 O28 C29 C34) and 178.0o (C19 O20 C21
C26), respectively, which allow the interaction with the appropriate
binucleophilic reagents to afford the corresponding target molecule, compound
15 (88%).
5- For chalcone 10, the two oxyphenyl bridges are out of the molecular plane of
thienothiophene core by 2o (C19 O20 C21 C22) and -32.7o (C27 O28 C29
C34), respectively, which may allow the interaction of chalcone moiety in one
side only, and this should not lead to isolation of pure sample of 24.
6- For chalcone 7, the frame work at which the addition occurs are (C29 O60 C61
C62) and (C49 O50 C51 C52). The active centers for electrophilic attack are
C59, C62, C49, and C52. The above two moieties are out of the molecular
plane of oxyphenyl by 27.6o and 93.1o, respectively, [Tables 1-3 and Figures 4
and 5].
7- For chalcone 10, where no products obtained, the frame work moieties are
(C59 O60 C61 C62) and (C49 O50 C51 C52). Two moieties are out of the
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molecular pla ne of oxyphenyl by 24.9o and 134.9o, respectively [Tables 1-3,
Figures 4 and 5].
From the above results (3-7), it is clear that as the eneone moiety (CH=CH-C=O)
comes close to the molecular plane of the oxyphenyl moiety the addition process
occurs and pure sample of the corresponding target products could be isolated as
in chalcone 7. On the other hand, as the two enone moieties go far from the
molecular plane of the oxyphenyl moiety, by increasing its dihedral angles, no
pure products would be expected from the addition reaction as in case of chalcone
10.
8- The two π–isoelctronic structures 7 and 10 are of nearly the same order of
stability, even though chalcone 10 seems a little bit more stable than chalcone
7 by 0.27 eV (≈ 6 kcal).
9- From the calculations of the energy gap, Eg, which measure the chemical
activity, chalcone 10 was found to be more reactive than chalcone 7 by 5.3
kcal.
10- The polarity or charge separation over the molecule, which is measured by
the dipole moment µ, showed that µ of chalcone 10 ˃ µ of chalcone 7 by 3.5
D.
From the above results (8-10), one can conclude that although the total energy
(ET) of chalcone 7 is less than that of 10 by a factor of 6 kcal together with the
fact that polarity as well as reactivity of compound 10 are more than that of 7,
experimental results showed that chalcone 7 reacted easily with hydrazine hydrate
to give the corresponding cyclic product 15 while compound 10 cannot do that,
this may confirm that the geometry of the enone moiety is the most effective
factor in the formation of pure sample of 15 or 24.
11- As outlined in Scheme 5, compound 24 can be obtained using alternative
pathway. DFT calculations at the same level of theory B3LYP/6-31G for both
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π-isoelectronic structures 15 and 24 were performed. The geometry and
ground state energies of both structures are presented in Table 4 and Figure 6.
The results of DFT calculations predicted that structure 15 is more stable than
structure 24 by only ≈ 24 kcal. It is also found that the structure 15 is more
chemically active than structures 24 by only ≈ 3 kcal This implies that the
two structures have almost the same order of stability, reactivity and both can
chemically exist.
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Table 1. Optimized bond length Å, bond angle degrees, and dihedral angle
degrees of compound 7 using B3LYP/6-31G:-
Parameters of
Bond Lengths
O20-C21
Parameters of
Bond Angles
< C19 O20 C21
Å
Degrees
117.0
122.8
120.4
32.3
1.374
1.487
1.236
1.481
1.346
1.090
1.096
1.380
1.498
1.226
1.492
1.338
1.095
1.096
C24-C49
C49-O50
C49-C51
C51-C52
C51-H77
C51-H78
O28-C29
C32-C59
C59-O60
C59-C51
C61-C62
C61-H85
C62-H84
< C25 C24 C49
< C24 C49 O50
< O50 C49 C51
< C49 C51 H77
117.1
117.1
115.3
117.5
121.2
115.0
119.8
24.1
< C51 C52 H78
< O28 C29 C30
< C35 C59 C61
< C32 C59 O60
< C59 C91 H85
< C61 C62 H84
< C23 C24 C49 O50
< O50 C49 C51 C52
< C25 C24 C49 C51
< C19 C20 C21 C26
<C33 C32 C59 C61
< C32 C59 C61 C62
-168.6
27.6
2.4
93.1
103.8
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Table 2. Optimized bond length Å, bond angle degrees, and dihedral angle degrees of
compound 10 using B3LYP/6-31G:-
Parameters of
Bond Lengths
O20-C21
Parameters of
Bond Angles
Å
Degrees
115.3
126.2
121.3
121.1
114.9
124.9
121.4
27.3
1.384 ˂ C24 C49 H88
1.464 ˂ C24 C49 C50
1.094 ˂ C49 C50 H87
1.341 ˂ C50 C51 O75
1.091 ˂ C32 C58 H89
1.484 ˂ C32 C58 C59
1.234 ˂ C58 C59 H90
1.502 ˂ C58 C59 C60
1.398 ˂ C59 C60 O81
1.474 ˂ O20 C21 C22 H67
1.095 ˂ C25 C24 C49 C50
1.335 ˂ C23 C24 C49 C50
1.092 ˂ C24 C49 C50 C51
1.496 ˂ C28 C29 C34 C33
1.231 ˂ C31 C32 C58 C59
1.491 ˂ C32 C58 C59 C60
˂ C58 C59 C60 O81
C24-C49
C49-H88
C49-C50
C50-H87
C50-C51
C51-O75
C51-C52
O28-C29
C32-C58
C58-H89
C58-C59
C59-H90
C59-C60
C60-O81
C60-C61
26.4
-1.0
19.8
-161.3
179.0
175.0
134.9
170.8
24.9
˂ H90 C58 C60 O81
-84.2
175.2
˂ C60 C59 C58 CH89
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Table 3. Ground state properties and net charges on active centers of 7 and 10 using
B3LYP/6-31G:
Compound 7
-3079.890
Compound 10
ET (au)
3079.920
EHOMO (au)
ELOMO (au)
Eg (eV)
-0.2193
0.2111
-0.0725
-0.0727
3.99
3.76
7.167
µ (D)
3.654
C49 0.384 C59
0.294
C49 0.0944 C58 0.0606
O50 -0.478 O60 -0.384 C50 -0.0691 C59 -0.0137
Net
Charges
C51 -0.067 C61
C52 0.093 C62
0.0005 C51 0.398
C60 0.364
0.045 O75 -0.0483 O81 -0.443
Eg= ELOMO - EHOMO
Table 4. Energetics of the ground state of 7 and 10 using B3LYP/6-31G
Chalcone 7
-3150.363
-0.1836
-0.0698
3.09
Chalcone 10
-3150.325
-0.1923
-0.0742
3.21
ET (au)
EHOMO (au)
ELOMO (au)
Eg (eV)
µ (D)
2.722
4.372
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Figure 4. The optimized geometry, numbering system, the vector of the dipole
moment and moiety of addation of 7 using B3LYP/6-31G.
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Figure 5. The optimized geometry, numbering system, the vector of the dipole
moment and the moiety of addition of 10 using B3LYP/6-31G.
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Figure 6. The optimized geometry, numbering system and the vector of the dipole
moment of 15 and 24 using B3LYP/6-31G.
15
24
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3. Conclusions
We developed a straightforward strategy for the synthesis of some novel
bis(chalcones) and highlighted the significance of this class of compounds as versatile
synthons
for
novel
bis(dihydroisoxazes),
bis(dihydropyrazoles)
and
bis(dihydropyrimidines) via simple reactions. Due to the mild reaction conditions,
good yields as well as easily accessible starting material we think that the synthetic
approaches
discussed
here
should
provide
access
for
novel
bis(functionalized)heterocycles.
The new synthesized compounds are interesting both in their own right as unusual
molecules as well as for their promising pharmacological and biological activities.
This forecast depends on a large volume of research papers and review articles which
reported the use of chalcones and bis-heterocycles as potent and efficient drugs for the
treatment of several dreadful diseases. Full characterization of these compounds is
reported.
DFT calculations at B3LYP/6-31G predicted that the dihedral angles of (eneone)
moiety of both π-isoelectronic structures 7 and 10 are mainly responsible for the
addition reaction. The presence of both enone moieties of 7 near the molecular plane
of the oxyphenyl bridge enables the nuclephile to attack the electrophillic centers
leading to the formation of the target molecules. However, in chalcone 10 the two
eneone moieties are far from the molecular plane of the oxyphenyl bridge and hence
no pure samples of the corresponding bis(azoles) could be isolated. Also, DFT
calculations predicted that the products 15 and 24 are of the same order of stability and
reactivity and experimentally exists.
4. Expermintal
4.1. General
Melting points were determined in open glass capillaries with a Gallenkamp
apparatus and were not corrected. The infrared spectra were recorded in potassium
bromide disks on a PyeUnicam SP 3-300 and Shimadzu FTIR 8101 PC infrared
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1
spectrophotometer. The H and 13C NMR spectra were determined on a Varian
Mercury VX 300 NMR spectrometer using TMS as an internal standard and DMSO-d6
as a solvent. Mass spectra were measured on a GCMS-QP1000 EX spectrometer at 70
eV. Elemental analyses were carried out at the Microanalytical Center of Cairo
University, Giza, Egypt.
4.2. Synthesis of bis(chalcone) compounds 7, 10
General Procedure: To a solution of each of 1-(4-hydroxyphenyl)-3-phenylprop-2-en-
1-one 8 or 3-(4-hydroxyphenyl)-1-phenylprop-2-en-1-one 11 (10 mmol) in ethanol (10
mL), KOH (0.56 g, 10 mmol) was added. The reaction mixture was stirred at room
temperature for 10 min. The solvent was removed in vacuo and the remaining
materials were dissolved in DMF (15 ml) and the appropriate dibromides 5 (5 mmol)
was added. The reaction mixture was refluxed for 5 min during which potassium
chloride was separated. The solvent was then removed in vacuo and the remaining
materials were washed with water and purified by crystallization from acetic acid to
give bis(chalcones) 7 and 10 as off-white crystals.
4.2.1.
Diethy
3,4-bis((4-(3-phenylacryloyl)phenoxy)methyl)thieno[2,3-
o
b]thiophene-2,5-dicarboxylate (7): Yield (82%), mp. 230-232 C; IR (cm-1): 1715,
1657 (2 CO); 1H NMR (DMSO-d6): δ 1.28 (t, 6H, CH2CH3, J = 6 Hz), 4.34 (q, 4H,
CH2CH3,J = 6 Hz), 5.70 (s, 4H, OCH2), 6.95 (d, 4H, ArH, J = 9 Hz), 7.37-7.78 (m,
14H, ArH and CH=CH-), 7.93 (d, 4H, ArH, J = 9 Hz);13CNMR (DMSO-d6): δ14.45,
61.42, 62.24, 114.68, 122.154, 127.50, 128.64, 129.16, 129,47, 130.77, 131.08,
135.76, 136.19, 143.50, 145.85, 146.22, 161.51, 161.98, 187.60; MS: m/z 756 (M+,
1.25%); C44H36O8S2: Anal. Calcd: C, 69.82; H, 4.79; S, 8.47. Found: C, 69.70; H,
4.50; S, 8.50%.
4.2.2. Diethyl 3,4-bis((4-(3-oxo-3-phenylprop-1-enyl)phenoxy)methyl)thieno[2,3-
o
b]thiophene-2,5-dicarboxylate (10): Yield (75%), mp. 160-162 C; IR (cm-1): 1712,
1658 (2 CO); 1H NMR (DMSO-d6): δ 1.27 (t, 6H, CH2CH3, J = 6 Hz), 4.34 (q, 4H,
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CH2CH3, J = 6 Hz), 5.67 (s, 4H, OCH2), 6.93 (d, 4H, ArH, J = 9 Hz), 7.46-7.71 (m,
13
14H, ArH, -CH=CH-), 8.02 (d, 4H, ArH, J = 9 Hz); CNMR (DMSO-d6): δ14.43,
61.26, 62.22, 115.25, 120.11, 128.14, 128.80, 129.09, 131.13, 132.08, 133.44, 135.21,
136.31, 144.29, 145.80, 146.23, 160.20, 161.72, 189.34; MS: m/z 756 (M+, 1.48%);
C44H36O8S2: Anal. Calcd: C, 69.82; H, 4.79; S, 8.47. Found: C, 69.73; H, 4.85; S,
8.41%.
4.3. Synthesis of bis(pyrazole) derivatives 15-17
General procedure: To a solution of the appropriate bis(chalcone) 7 (0.01 mol) in
acetic acid (20 mL), hydrazine hydrate (12), semicarbazide (13) or thiosemicarbazide
(14) (0.02 mol) was added. The reaction mixture was heated under reflux for 5 h (in
case of compounds 15 and 16) and 8 h (in case of compound 17). The reaction mixture
was then cooled and poured onto crushed ice. The solid residues were collected by
filtration and recrystallized from the proper solvent to give the corresponding
bis(pyrazole) derivatives 15-17 as off-white crystals.
4.3.1. Diethyl3,4-bis((4-(1-acetyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenoxy)
methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (15): methanol, yield (88%), mp.
o
1
131-133 C; IR (cm-1): 1710, 1663 (2 CO); H NMR (DMSO-d6): δ 1.28 (t, 6H,
CH2CH3, J = 6 Hz), 2.25 (s, 3H, CH3CO), 2.26 (s, 3H, CH3CO), 3.01-3.07 (m, 2H,
pyrazole-4-CH), 3.64-3.73 (m, 2H, pyrazole-4-CH), 4.33 (q, 4H, CH2CH3, J = 6 Hz),
5.43-5.47 (m, 2H, pyrazole-5-CH), 5.64-5.68 (m, 4H, OCH2), 6.93 (d, 4H, ArH, J =
13
7.5), 7.13-7.33 (m, 10H, ArH), 7.57 (d, 4H, ArH, J = 7.5); C NMR (DMSO-d6):
δ14.38, 22.11, 42.52, 59.82, 61.21, 62.28, 115.07, 124.41, 127.95, 128.63 129.11,
131.03, 135.20, 136.52, 142.91, 145.79, 146.15, 154.26, 159.79, 161.73, 167.59; MS:
m/z 868 (M+, 1.77%); C48H44N4O8S2: Anal. Calcd: C, 66.34; H, 5.10; N, 6.45; S, 7.38.
Found: C, 66.29; H, 5.01; N, 6.56; S, 7.31%.
4.3.2. Diethyl 3,4-bis((4-(1-carbamoyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)
phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (16): acetic acid, yield
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o
1
(85%), mp. 333-335 C; IR (cm-1): 3423 (br) (NH2), 1709, 1663 (2 CO); H NMR
(DMSO-d6): δ 1.28 (t, 6H, CH2CH3, J = 6 Hz), 4.15-4.30 (m, 4H, pyrazole-4-CH),
4.35 (q, 4H, CH2CH3, J = 6 Hz), 4.98 (d, 2H, OCH2, J = 9.9 Hz ), 5.65 (m, 4H, NH2),
5.91 (d, 2H, OCH2, J = 9.9 Hz), 6.23-6.25 (m, 2H, pyrazole-5-CH), 6.96 (d, 4H, ArH,
J = 8.4), 7.21-7.36 (m, 10H, ArH), 7.78 (d, 4H, ArH, J = 8.4); 13C NMR (DMSO-d6): δ
14.38, 42.21, 50.28, 61.28, 62.21, 117.20, 127.11, 127.47, 128.85, 129.07, 129.89,
132.75, 135.45, 135.78, 142.60, 145.62, 146.82, 154.17, 161.53, 162.01; MS: m/z 870
(M+, 0.23%); C46H42N6O8S2: Anal. Calcd: C, 63.43; H, 4.86; N, 9.65; S, 7.36. Found:
C, 63.50; H, 4.75; N, 9.58; S, 7.30 %.
4.3.3. Diethyl 3,4-bis((4-(1-carbamothioyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)
phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (17): acetic acid, yield
o
(80%), mp. 325-327 C; IR (cm-1): 3437 (br) (NH2), 1710, 1664 (2 CO); 1H NMR
(DMSO-d6): δ 1.28 (t, 6H, CH2CH3, J = 6 Hz), 4.14-4.27 (m, 4H, pyrazole H-4), 4.33
(q, 4H, CH2CH3, J = 6 Hz), 4.98 (d, 2H, OCH2, J = 10.2 Hz ), 5.67 (m, 4H, NH2), 5.90
(d, 2H, OCH2, J = 10.2 Hz), 6.22-6.25 (m, 2H, pyrazole-5-CH), 6.96 (d, 4H, ArH, J =
7.9 Hz), 7.21-7.34 (m, 10H, ArH), 7.78 (d, 4H, ArH, J = 7.9); MS: m/z 902 (M+,
0.31%); C46H42N6O6S4: Anal. Calcd: C, 61.18; H, 4.69; N, 9.31; S, 14.20. Found: C,
61.25; H, 4.60; N, 9.21; S, 14.27 %.
4.4. Synthesis of bis(oxazole) compound 23
General procedure: To a solution of the appropriate bis(chalcone) compound 7 (0.01
mol) in acetic acid (20 mL), hydroxyl amine hydrochloride 22 (0.02 mol) and sodium
acetate (0.02 mol) were added. The reaction mixture was heated under reflux for 6 h.
The solid obtained upon cooling was collected by filtration and recrystallized from
acetic acid to give 23 as off-white crystals.
4.4.1. Diethyl 3,4-bis((4-(5-phenyl-4,5-dihydroisoxazol-3-yl)phenoxy)methyl)
o
thieno[2,3-b]thiophene-2,5-dicarboxylate (23): Yield (68%), mp. 336-338 C; IR
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(cm-1): 1709 (CO) 1H NMR (DMSO-d6): δ 1.28 (t, 6H, CH2CH3, J = 7.2 Hz), 4.15 (d,
2H, isoxazole-4-CH, J = 6.9 Hz), 4.15-4.28 (m, 4H, isoxazole-4-CH), 4.33 (q, 4H,
CH2CH3, J = 6.9 Hz), 4.98 (d, 2H, OCH2, J = 10.2 Hz), 5.90 (d, 2H, OCH2, J = 10.2
Hz), 6.23-6.25 (m, 2H, isoxazole-5-CH), 6.96 (d, 4H, ArH, J = 8.7 Hz), 7.21-7.35 (m,
10H, ArH), 7.78 (d, 4H, ArH, J = 8.7 Hz); MS: m/z 786(M+, 0.31%); C44H38N2O8S2:
Anal. Calcd: C, 67.16; H, 4.87; N, 3.56; S, 8.15. Found: C, 67.27; H, 4.80; N, 3.50; S,
8.20 %.
4.5. Synthesis of bis(dihydropyrimidin) dreviatives 20, 21
General procedure: To a solution of the bis(chalcone) 7 (0.01 mol) in DMF (3 mL),
urea 18 or thiourea 19 (0.02 mol) and potassium hydroxide (0.02 mol) in ethanol (25
ml) were added. The reaction mixture was heated under reflux for 6 h. The reaction
mixture was then cooled and poured onto crushed ice acidified with few drops of conc.
HCl. The solid residue was collected by filtration and recrystallized from acetic acid to
give the corresponding bis(dihydropyrimidine) derivatives 20 and 21 as off-white
crystals.
4.5.1. Diethyl 3,4-bis((4-(2-hydroxy-6-phenyl-5,6-dihydropyrimidin-4-yl)phenoxy)
methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (20): acetic acid, yield (70%), mp.
o
1
272-274 C; IR (cm-1): 3428 (br) (OH), 1709 (CO); H NMR (DMSO-d6): δ 1.28 (t,
6H, CH2CH3, J = 6.9 Hz), 4.14-4.29 (m, 4H, prymidin-5-CH), 4.33 (q, 4H, CH2CH3, J
= 6.9 Hz), 4.94-4.99 (m, 2H, OCH2), 5.89-5.94 (m, 2H, OCH2), 6.22-6.25 (m, 2H,
prymidin-6-CH), 6.96 (d, 4H, ArH, J = 8.7), 7.19-7.26 (m, 10H, ArH), 7.78 (d, 4H,
ArH, J = 8.7 Hz); MS: m/z 840 (M+, 0.22%); C46H40N4O8S2: Anal. Calcd: C, 65.70; H,
4.79; N, 6.66; S, 7.63. Found: C, 61.30; H, 4.55; N, 9.30; S, 14.30 %.
4.5.2.
Diethyl
3,4-bis((4-(2-mercapto-6-phenyl-5,6-dihydropyrimidin-4-yl)
phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (21): acetic acid,Yield
o
(72%), mp. 320-325 C; IR (cm-1): 1701 (CO), 1448 (C=S); 1H NMR (DMSO-d6): δ
1.28 (t, 6H, CH2CH3, J = 6.9 Hz), 4.15-4.29 (m, 4H, pyrimidin-5-CH), 4.33 (q, 4H,
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CH2CH3, J = 6.9 Hz), 4.98 (d, 2H, OCH2, J = 10.2 Hz ), 5.90 (d, 2H, OCH2, J = 10.2
Hz), 6.22-6.26 (m, 2H, pyrimidin-6-CH), 6.96 (d, 4H, ArH, J = 7.9 Hz), 7.20-7.76 (m,
10H, ArH), 7.78 (d, 4H, ArH, J = 9 Hz); 13C NMR (DMSO-d6): δ 14.4, 40.62, 50.09,
61.37, 62.20, 114.72, 122.20, 127.54, 128.99, 129.25, 129.79, 130.77, 131.0, 135.18,
142.56, 143.46, 161.75, 162.05, 163.44, 187.62; MS: m/z 873 (M+, 0.57%);
C46H40N4O6S4: Anal. Calcd: C, 63.28; H, 4.62; N, 6.42; S, 14.69. Found: C, 61.30; H,
4.65; N, 9.40; S, 14.6. %.
4.6. Synthesis of bis(pyrazole) derivatives 24, 25
General procedure: To a solution of each of 1-(5-(4-hydroxyphenyl)-3-phenyl-4,5-
dihydro-1H-pyrazol-1-yl)ethan-1-one 26 or 5-(4-hydroxyphenyl)-3-phenyl-4,5-
dihydro-1H-pyrazole-1-carboxamide 27 (10 mmol) in ethanol (10 mL), KOH (0.56 g,
10 mmol) was added. The reaction mixture was stirred at room temperature for 10
min. The solvent was removed in vacuo and the remaining material was dissolved in
DMF (15 ml) and the dibromo compound 1 (5 mmol) was then added. The reaction
mixture was refluxed for 5 min. during which potassium chloride was separated. The
solvent was then removed in vacuo and the remaining materials were washed with
water and purified by crystallization from the proper solvent to give bis(pyrazole)
derivatives 24 and 25 as off-white crystals.
4.6.1. Diethyl 3,4-bis((4-(1-acetyl-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl)phenoxy)
methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (24): benzene, yield (65%), mp.
o
1
130-133 C; IR (cm-1): 1711, 1664 (2 CO); H NMR (DMSO-d6): δ 1.24 (t, 6H,
CH2CH3, J = 9.6 Hz), 2.27 (s, 6H, CH3CO), 3.24-3.28 (m, 2H, pyrazole-4-CH), 3.66-
3.84 (m, 2H, pyrazole-4-CH), 4.30 (q, 4H, CH2CH3, J = 9.6 Hz), 5.38-5.50 (m, 2H,
pyrazole-5-CH), 5.57 (s, 4H, OCH2), 6.77 (d, 4H, ArH, J = 7.8), 7.00-7.78 (m, 12H,
ArH); MS: m/z 869 (M+, 0.77%); C48H44N4O8S2: Anal. Calcd: C, 66.34; H, 5.10; N,
6.45; S, 7.38. Found: C, 66.29; H, 5.20; N, 6.40; S, 7.31 %.
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4.6.2. Diethyl 3,4-bis((4-(1-carbamoyl-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl)
phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (25): ethanol, yield
(72%), mp. 192-195oC; IR (cm-1): 3476, 3396 (NH2), 1700, 1675 (2 CO); 1H NMR
(DMSO-d6): δ 1.27 (t, 6H, CH2CH3, J = 6.9 Hz), 2.88-3.04 (m, 2H,pyrazole-4-CH),
3.64-3.88 (m, 2H, pyrazole-4-CH), 4.31 (q, 4H, CH2CH3, J = 6.9 Hz), 5.24-5.38 (m,
2H, pyrazole-5-CH), 5.24-5.40 (m, 4H, OCH2), 6.44 (s, 4H, NH2),6.76-7.80 (m, 18H,
ArH); MS: m/z 871 (M+, 0.52%); C46H42N6O8S2: Anal. Calcd: C, 63.43; H, 4.86; N,
9.65; S, 7.36. Found: C, 63.51; H, 4.92; N, 9.57; S, 7.30 %.
4.7. Synthesis of pyrazolen compound 27
General procedure: To a solution of chalcone 8 (0.01 mol) in acetic acid (20 mL),
semicarbazide 13 (0.01 mol) was added. The reaction mixture was heated under reflux
for 6 h. The solid obtained upon cooling was collected by filtration and recrystallized
from ethanol to give pyrazole derivative 27 as colorless crystals.
4.7.1.
5-(4-Hydroxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide
o
(27): ethanol, yield (82%), mp. 270-275 C; IR (cm-1): 3400-3255 (br) (OH, NH2),
1
1663 (CO); H NMR (DMSO-d6): 3.30 (dd, 1H, pyrazole-4-CH, J = 5.1, 17.7 Hz),
3.75 (dd, 1H, pyrazole-4-CH, J = 12, 17.6 Hz), 5.31 (dd, 2H, pyrazole-5-CH, J = 4.8,
11.7 Hz), 6.42 (s, 2H, NH2), 6.68-7.79 (m, 9H, ArH), 9.27 (s, 1H, OH); MS: m/z 281
(M+, 2.23%); C16H15N3O2: Anal. Calcd: C, 68.31; H, 5.37; N, 14.94; Found: C, 68.35;
H, 5.41; N, 15.1 %.
4.8. Computational method
Calculations have been performed using Khon-Sham᾿s DFT method subjected to
the gradient-corrected hybrid density functional B3LYP.48 This function is a
combination of the Becke᾿s three parameters non-local exchange potential with the
non-local correlation functional of Lee et al.49 For each structure, a full geometry
optimization was performed using this function
and the 6-311G bases set50 as
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implemented by Gaussian 09 package.51 All geometries were visualized either using
GaussView 5.0.952 or chemcraft 1.653 software packages. No symmetry constrains
were applied during the geometry optimization. Subsequently, to locate stationary
point and validate the optimized structures as true minimums, the vibrational spectrum
was determined to confirm that no imaginary frequency exists.
Acknowledgements
Professor A. H. M. Elwahy gratefully acknowledge the Alexander von Humboldt
Foundation for a research fellowship.
References and notes
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