Synthesis, characterization, molecular structure, and computational studies on 4(1H)-pyran-4-one and its derivatives

Article abstract of DOI:10.1016/j.molstruc.2021.131077

4(1H)-Pyridone-based compounds have shown promise as potent bioactive inhibitors against a broad range of diseases, particularly malaria. Our interest in 4(1H)-pyridones initiated the design and synthesis of a series of 4(1H)-pyridone derivatives, with th

Full text of DOI:10.1016/j.molstruc.2021.131077

Journal of Molecular Structure 1245 (2021) 131077
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, characterization, molecular structure, and computational
studies on 4(1H)-pyran-4-one and its derivatives
Oluwatosin Yemisi Audua, Jessica Joostea, Frederick P. Malana, Olayinka O. Ajanib,
Natasha Octobera,∗
a Department of Chemistry, University of Pretoria, Lynnwood Road, Hatfield, Pretoria, 0002, South Africa
b Department of Chemistry, College of Science and Technology, Covenant University, PMB 1023, Nigeria
a r t i c l e i n f o
a b s t r a c t
Article history:
4(1H)-Pyridone-based compounds have shown promise as potent bioactive inhibitors against a broad
range of diseases, particularly malaria. Our interest in 4(1H)-pyridones initiated the design and synthesis
of a series of 4(1H)-pyridone derivatives, with the hope of finding new antimalarial leads. The synthesis
of 4(1H)-pyran-4-one analogues (4(1H)-pyridone intermediates was successfully achieved using palladium
catalyzed Suzuki-Miyaura coupling reactions. The synthesized 4(1H)-pyran-4-ones were unambiguously
confirmed by TGA, 13 C, 1H NMR, and IR spectroscopic analysis. Further comprehensive insights to ratio-
nalize the outcome of several reactions were deduced by means of single crystal X-ray diffraction, which
was used to determine the single crystal structures of compounds 4 and 5. Compounds 5, 9 and 9a-e
were successfully synthesized in moderate to excellent yields, apart from compound 9e which gave a
very low yield. NMR and XRD analysis of the by-product of compound 9e showed that the boronic acid
substituents reacted with each other in a side-reaction reminiscent to aryl boronic acid homo coupling
or Ullmann coupling reactions. Complimentary DFT analysis of the pyranone and pyridone compounds
provided insight into the substituent effect of the pyranone compounds with regards to the stability and
lack of reactivity to form the corresponding pyridone compounds.
Received 12 April 2021
Revised 21 June 2021
Accepted 7 July 2021
Available online 11 July 2021
Keywords:
Computational
Synthesis
Molecular
Characterization
Coupling
4(1H)-pyran-4-one
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
ment [9]. Literature studies particularly highlight the pharmaceu-
tical properties of 2- and -4 pyrone scaffolds as anticancer, [8,10]
Pyrones are important class of unsaturated oxygenated six-
membered heterocycles that contains a pyran ring, incorporating
a ketone functionality at positions 2 or 4 of the pyran ring, (Fig. 1)
[1].
antimalarial, [11] antimicrobial, [12,13] antidiabetics [14,15] anti-
Alzheimer agents [7], (Fig. 2).
To further explore the medicinal potential and to take advan-
tage of the versatile handle offered by the pyrone scaffold, a de-
fined series of 4(1H)-pyran-4-one-based derivatives were designed
and synthesized. Thus, synthesis of the series of the 2,6-dimethyl-
3-(4-substituted-phenyl)-4H-pyran-4-one, 9a-e (Fig. 3) were suc-
cessfully achieved, when aromatic substituents were linked to-
gether via palladium catalyzed Suzuki-Miyaura [16] coupling and
was further investigated. [17]
Pyrones are used as key intermediates in organic synthesis,
owing to the presence of the conjugated dienes and ester moi-
eties, which promote further derivatization to afford highly struc-
turally diverse compound libraries [2–5]. Thus, pyrones are es-
sential building blocks, employed in the preparation of biolog-
ical active heterocyclic compounds, which amongst others in-
clude; 4(1H)-pyridone, α-chymotrypsin, coumarins, pheromones,
and solano-pyrones [6–8]. Also, pyrones and derivatives thereof are
major composite of natural products and their notable less toxic
nature, make them valuable candidates for further drug develop-
2. Results and discussion
The synthetic pathway in Scheme 1 was employed to pre-
pare the precursor, 3-(4-bromophenyl)-2,6-dimethyl-4H-pyran-4-
one
4 [2,16,17]. Synthesis of the methyl aryl ketone, 1-(4-
∗
bromophenyl)propan-2-one 3, was achieved via reductive methy-
Corresponding author.
E-mail address: natasha.october@up.ac.za (N. October).
lation of 4-bromophenylacetic acid in good yield (72 %), using 1-
https://doi.org/10.1016/j.molstruc.2021.131077
0022-2860/© 2021 Elsevier B.V. All rights reserved.

O.Y. Audu, J. Jooste, F.P. Malan et al.
Journal of Molecular Structure 1245 (2021) 131077
with torsion angles of C3-C4-C7-C8 = 49.1(5)° (4), C3-C4-C7-C8 = -
67.9(11)° (5), and C3-C2-C17-C18 = 119.7(8)° (5). Molecules in the
structure of 4 packs in three dimensions as a ribbon with the pyri-
done moieties of adjacent molecules linking by weak intramolecu-
lar forces, and then overlays with the arene rings to other adjacent
molecules (Figure S1, SI). A similar pattern is also seen with the
packing of molecules in the structure of 5, except that adjacent
molecules is connected via the weak intramolecular forces from
adjacent arene rings on either side of each molecule (Figure S2,
SI). No other mentionable hydrogen bonding or pi-pi stacking in-
teractions were observed in either of the structures of 4 or 5. Typ-
ical bond distances and angles are observed in 4 and 5 compares
well with each other as well as with other closely related struc-
tures [18].
Fig. 1. Structures of 2-pyrone (I) and 4-pyrone (II)
methylimidazole as the catalyst. Compound 3 was confirmed with
1H NMR, which revealed the disappearance of the signal related
to the acetic acid OH group, as well as formation of the methyl
substituent, which resonate upfield as 3H at 2.14 ppm. Thus, the
cyclization of 1-(4-bromophenyl) propan-2-one 3 with acetic an-
hydride in the presence of Eaton’s reagent, [(PO2)2O] [CH3SO2OH],
resulted in the formation of 3-(4-bromophenyl)-2,6-dimethyl-4H-
pyran-4-one 4 in a moderate yield (48 %). The formation of 4 was
further established by means of 1H NMR and single-crystal X-ray
diffractometry (SCXRD). Cyclization of 3 leading to the formation
of 4 was confirmed with the appearance of a vinylic proton, which
resonate downfield as a singlet at 6.22 ppm while two sharp sin-
glets of the two –CH3 groups on position 2 and 6 on the 4(1H)-
pyranone ring were seen upfield at 2.15 and 2.28 ppm respectively.
Interestingly, extensive analysis of the crystalline products in the
product mixture leading to the isolation and identification of com-
pound 4 allowed for the identification of compound 5, which was
identified by means of SCXRD. The detection of this compound
could further explain the observed low yield of 4 by the relative
increased reactivity of 4.
Subsequently, using two different types of boronic acids,
bis(pinacolato)diboron
7
and 7ꢀ (Scheme 2) and 2-substituted
phenylboronic acids, compounds 8a-f, were used to prepare ana-
logues of 4H-pyran-4-one via Suzuki-Miyaura coupling reactions
using 10 mol% of either PdCl2(dppf) or PdCl2(PPh3)2 as catalyst.
In the reaction forming 8a, 4-bromostilbene was coupled with
bis(pinacolato)diboron 7, using PdCl2(dppf) as catalyst along with
potassium acetate, to give the compound 4,4,5,5-tetramethyl-2-
(4-phenethylphenyl)-1,3,2-dioxaborolane 8a in moderate yield (62
%). The 1H NMR of 8a revealed 12 protons of the four –CH3
groups with a sharp intense singlet seen upfield at 1.28 ppm. Com-
pound 4 in turn coupled with compound 8a in the presence of
PdCl2(PPh3)2 (10 mol%) and potassium carbonate to give the com-
ꢀ
ꢀ
pound 2,6-dimethyl-3-{4 -[(1E)-2-phenylethenyl]-[1,1 -biphenyl]-4-
yl}-4H-pyran-4-one 9a in a moderate yield (39 %). The 1H NMR
spectrum of 9a displayed additional four aromatic proton signals,
namely 7.24, 7.26, 7.58, and 7.60 ppm, which shifted downfield,
confirming the formation of compound 9a.
Following the success of the reaction producing compound 9a
from 8a, the series of compounds 2-substituted phenylboronic
acids 8b-f were also employed as coupling partners in the Suzuki-
Miyaura reaction with compound 4 in the presence of PdCl2(PPh3)2
(10 mol%) and K2CO3 to give moderate to good yields of the corre-
sponding adducts 9b-e (39 – 75 %) (Scheme 2).
Single crystals of 4 and 5 suitable for X-ray diffraction were
grown from saturated Hexane:Ethyl acetate(3:1) solutions (Fig. 4).
Crystals of 4 crystallized in the monoclinic P21/c space group with
Z = 4, whereas crystals of 5 crystallized in the orthorhombic space
group P212121 also with Z = 4. A slight bend of the 4-BrPh group
connected to the pyridone ring structure in 4 is seen with a O14-
C3-C4-C7 torsion angle of -5.1(5)° (Tables S1 and S2, SI). The cor-
responding angle in 5 is a near-linear 2.0(12)° with the remain-
ing 4-BrPh group only slightly twisted (O14-C3-C2-C17 = -7.0(12)°).
Each of the arene groups twist with respect to the pyridine ring
The series of compounds 9a-e were successfully synthesized,
however although 9f was synthesized, the yield was not deter-
mined due to its decomposition on standing, which led to the for-
mation of undesired crystallized products. Upon closer inspection
Fig. 2. Structures of some pyrones that displayed biological activities [8], [11],[13],[15],[7].
2

O.Y. Audu, J. Jooste, F.P. Malan et al.
Journal of Molecular Structure 1245 (2021) 131077
Fig. 3. Series of synthesized 2,6-dimethyl-3-(4-substitutedphenyl)-4H-pyran-4-ones, 9a-e
Fig. 4. Crystal structures of Compounds 4 and 5
spectively. The result of the 13C NMR of 9c presented twenty-one
carbon atoms with 15 peaks, with the δC value ranging from 178.5
ppm to 18.7 ppm. A carbonyl carbon substituent on the position
4 of the 4H-pyran-4-one is seen at 178.5 ppm while other twelve
carbon atoms are aromatic carbons, displayed around 164.8 ppm
to 113.8 ppm and the remaining two carbon atoms are ascribed to
two –CH3 groups at the position 2 and 6 of the 4H-pyran-4-one
ring, seen at 18.7 and 19.8 ppm respectively.
of the product mixture of 9d and the decomposed product 9f, a
single crystal picked from each mixture, analyzed using SCXRD, re-
vealed the presence of a corresponding by-product of compound
9d and crystalline product 9f (9d’ and 9f’ respectively, Figures
S3 and S4, SI). This may resulted from the homocoupling of the
boronic acid substituents which has been observed before in re-
lated Suzuki-Miyaura or Ullmann coupling reactions [19]. The for-
mation of these by-products may be suppressed or even avoided
in the case where the aryl boronic acid is added portion wise to
the reaction mixture, or should the use of a protected boronic acid
be possible, be used to avoid homocoupling. Using compound 9c
as a spectroscopy study, 9c displayed 18 protons in its 1H NMR
spectrum. Four aromatic protons were seen as multiplets between
7.62-7.50 ppm: two aromatic protons were observed at 7.5-7.4 ppm
while the remaining two aromatic protons were noticed at 7.3-7.2
ppm. The two alkene (H-C=C-H) protons were observed as a sin-
glet at 7.16 ppm. A singlet proton of a vinyl of the 4H-pyran-4-one
ring was also observed downfield at 6.26 ppm while the remain-
ing two –CH3 protons at the position 2 and 6 of the 4H-pyran-
4-one ring were observed downfield TMS at 2.3 and 2.2 ppm, re-
Attempts to synthesize the targeted 4(1H)-pyridone moieties
10a-e unfortunately was unsuccessful. The unsuccessful synthesis
of the target compounds 10a-e could be due to the initial introduc-
tion of electron donating group in the substituted phenylboronic
acids 8a-f, which led to reduction in the reactivity of the pyrone
ring. This alternatively could have also led to unfavourable SN2 nu-
cleophilic substitution of amino group on position 1 of the 4(1H)-
pyran-4-one ring. Steric hindrance present in the 4(1H)-pyran-4-
one ring structure may also been a contributing factor towards the
unsuccess of the final aminolation reaction, which could in turn
resulted in an increase in the activation energy required for the
reaction to proceed, and ultimately lowered the overall observed
3

O.Y. Audu, J. Jooste, F.P. Malan et al.
Journal of Molecular Structure 1245 (2021) 131077
10c (theoretical) were selected as representative examples and are
shown in Fig. 6. In general, the HOMOs of compounds 9a-e are
distributed mainly over the biphenyl group (at the site where C-C
coupling took place). In the case of aliphatic linkers (e.g. 9a), elec-
tron diffusion via resonance is inhibited, whereas the compounds
containing unsaturated linkers (e.g. 9c), electron diffusion to in-
clude the remainder of arene groups is present. The LUMOs of
both examples are comparable with one another, where the LU-
MOs are delocalized mainly over the biphenyl groups as well as
the pyranone ring structure (Fig. 6. As part of the general Baeyer
pyridine synthesis mechanism, [23] it is accepted that the first step
toward pyridone formation would be the nucleophilic attack of the
ammonia molecule at a partially electron-poor carbon atom adja-
cent to the oxygen atom (Scheme 3). In this particular case, elec-
tron transfer between both the ether-like oxygen (in the pyranone
ring), and the carbonyl oxygen is important to help form an an-
ionic oxygen intermediate specie in the pyranone ring moiety. In
general, the LUMO of the reactant, and the HOMO of the corre-
sponding product molecule should correlate in the sense that elec-
tron transfer could be visualized. Collectively, the reactivity (re-
duction/oxidation) of the series of compounds of 9 is suggested to
lie within the biphenyl moiety, and only slightly populated within
the pyrone ring system (containing the oxygen-containing func-
tional groups) where electron transfer is anticipated. It is there-
fore interesting to note that the corresponding HOMO of the prod-
uct molecules (series of compounds 10) is again only slightly pop-
ulated on either of the two oxygen atoms and more so on the
biphenyl moiety. Collectively this may hint towards the lack of re-
activity of the series of compounds of 9 with nucleophiles such as
NH3 to form the corresponding compounds 10. The interpretation
and conclusion with regards to reactivity does not change after in-
clusion of the implicit solvent model (EtOH), in an attempt to more
closely mimic the reaction conditions. For example, upon full opti-
mization of compound 9a (including the implicit solvent model of
EtOH), the HOMO and LUMO is practically indistinguishable from
9a (gas phase optimized).
Fig. 5. Thermogravimetric Analysis (TGA) of Selected Compounds 4, 9a, 9b and 9e.
rate of reaction [20]. The intermediates 9a-e could not be consid-
ered for antimalarial testing, since the presence of the NH group
in corresponding compounds 10a-e have demonstrated imperative
for antimalarial activity.
As a result of to lack of reactivity displayed by the 4(1H)-pyran-
4-ones and since the conversion of 4-pyrones to 4-pyridones re-
quires high temperatures, the thermal properties of 4H-pyran-4-
ones 4, 9a, 9b, and 9e were analyzed using the thermogravimetric
analysis (TGA,Fig. 5) [21]. The TGA displayed a high rate of thermal
decomposition and instability of these compounds, even at tem-
perature of 37 °C, 73 °C, and 104 °C respectively, lower than the
temperature (140 oC) [22] at which the reaction would have taken
place using ammonium hydroxide (NH4OH) as the reactant [22].
Compound 4 (precursor to compounds 9a-e) was observed to be
quite stable as compared to 9a, 9b, and 9e as seen in Fig. 5.
The energy gap (ꢀE, energy difference between the HOMO and
LUMO) of each compound may directly be compared to provide
information on their respective molecular reactivity and stability.
A molecule with a small energy gap is therefore considered to
be more polarizable, softer, more reactive and kinetically less sta-
ble. The energy gap (ꢀE), ionization potential (I), electron affinity
(A), electronegativity (χ), chemical potential (μ), chemical hard-
ness (η), chemical softness (S), and electrophilicity index (ω) of
compounds 9ae and 10a-e are included in Table 1. From the data it
is apparent that the energy gap of the pyranone-based compounds
(9a-e) generally is slightly larger than the energy gap of the cor-
responding pyridone compounds (10a-e), suggesting higher stabil-
ity and hence lowered reactivity. Inclusion of solvent effect (EtOH
as implicit solvent model) further increases both ꢀE and the ion-
ization potential slightly by ca. 0.02 and 0.1 eV respectively, sug-
gesting lower reactivity compared to the corresponding isolated
molecule in the gas state. Comparing the effect of the functional
groups in 9a-e, the energy gap varies between 3.91 and 5.17 eV,
where the C2H2-linked (ethene bridge) functional groups (9c and
9e) are the least stable (3.91 and 3.94 eV, respectively), and the
C2H4-linked (ethylene bridge) functional groups (9a and 9b) are
the most stable (4.55 and 5.17 eV, respectively). This trend is also
reflected in their corresponding electron affinity (A), chemical soft-
ness (S) and electrophilicity indices (ω), where compounds having
the lowest electron affinity would be the compounds most likely
to act as Lewis acids in the reactions converting pyranones to pyri-
dones. The remainder of the computed reactivity descriptors com-
pare relatively well among the two series of compounds (9a-e and
10a-e) as well as functional-group related compounds between the
two series of compounds.
2.1. DFT analysis
In order to gain more insight into the substituent effect(s) of
the boron-containing compounds on the (by-)product formation,
as well as the lack of reactivity of compounds 9a-e to form 10a-
e, a Density Functional Theory (DFT) computation study was per-
formed. In general, input structures were obtained from the crys-
tallographic information files (CIFs) for the relevant compounds (or
derivations thereof) and were further optimized in the gas phase
until conversion with zero imaginary frequencies. Considering the
C-C coupled compounds 9a-e, their corresponding frontier molec-
ular orbitals and associated properties may be analyzed to help
explain the difference in stability, as well as their lack of reac-
tivity with NH4OH to form the corresponding compounds 10a-
e. The highest occupied molecular orbital (HOMO) may be visu-
alized as providing the source of electrons in an oxidizing reac-
tion and therefore be correlated to the ionization potential of the
compound. In contrast, the lowest unoccupied molecular orbital
(LUMO) may, in turn, be visualized as the electron sink in a re-
duction reaction and hence be correlated to the electron affinity
of the compound. The HOMOs and LUMOs of compounds 9a and
corresponding 10a (theoretical), as well as 9c and corresponding
4

O.Y. Audu, J. Jooste, F.P. Malan et al.
Journal of Molecular Structure 1245 (2021) 131077
3
˚
Fig. 6. B3LYP functional DFT calculated HOMOs and LUMOs of the indicated neutral compounds from this study. A contour of 0.03 e/A was used for the MO plots.
Scheme 1. Synthesis of compounds 3-5. Reagents and conditions: (i) 1-Methylimidazole, rt, N2, 15 h; (ii) Eaton’s reagent, 95°C, 2 h.
Table 1
Molecular parameters and reactivity descriptors of compounds 9a-f and 10a-f.
Parameter
Compound
9a
9b
9c
9d
9e
9f
10a
10b
10c
10d
10e
10f
Energy gapa (ꢀE) (eV)
4.55
5.84
1.29
-3.56
3.56
4.55
0.22
1.39
5.17
6.23
1.06
-3.64
3.64
5.17
0.19
1.28
3.91
5.63
1.72
-3.68
3.68
3.91
0.26
1.73
4.42
5.82
1.41
-3.61
3.61
4.42
0.23
1.48
3.94
5.67
1.73
-3.70
3.70
3.94
0.25
1.74
4.08
5.63
1.55
-3.59
3.59
4.08
0.25
1.58
4.44
5.60
1.16
-3.38
3.38
4.44
0.23
1.28
5.09
5.78
0.69
-3.23
3.23
5.09
0.20
1.03
3.95
5.46
1.51
-3.49
3.49
3.95
0.25
1.54
4.37
5.68
1.31
-3.50
3.50
4.37
0.23
1.40
3.88
5.46
1.58
-3.52
3.52
3.88
0.26
1.60
4.05
5.46
1.41
-3.44
3.44
4.05
0.25
1.46
Ionization potentialb (I) (eV)
Electron affinityc (A) (eV)
Chemical potentiald (μ) (eV)
Electronegativitye (χ) (eV)
Chemical hardnessf (η) (eV)
Chemical softnessg (S) (eV)
Electrophilicity indexh (ω) (eV)
a
b
c
d
e
f
g
h
ꢀE = EHOMO - ELUMO
.
I = -EHOMO
.
A = -ELUMO
.
μ = -(I + A)/2. χ = -μ. η = I - A. S = 1/η. ω = μ2/2η.
5

O.Y. Audu, J. Jooste, F.P. Malan et al.
Journal of Molecular Structure 1245 (2021) 131077
Scheme 2. Synthesis of targets 9a-f via boronic acids and 10a-e via ammonium hydroxide. Reagents and conditions: (i) PdCl2(PPh3)2, K2CO3, distilled H2O, 80 °C, 3 h; (ii)
NH4OH, EtOH, 150 °C, 50 h. In the case of 9a the dioxaborolane 8a is reacted instead of the boronic acid.
Scheme 3. Nucleophillic substitution mechanism for the conversion of 4-pyrone to 4-pyridone
3. Conclusion
4. Experimental
In conclusion, new derivatives of 2,6-dimethyl-4H-pyran-4-one
compounds 5 and 9a-e was successfully synthesized using pal-
ladium catalyzed Suzuki-Miyaura coupling reactions. Single crys-
tal structures of compounds 4 and 5 were determined using X-
ray diffraction and revealed their unique identities upon which
the side reactions were identified. Compounds 5 and 9a-e were
successfully synthesized with moderate to good yields apart from
compound 9f which yield was not determined due to its decom-
position. SCXRD analysis of the by-products of the reactions form-
ing compound 9d (9d’) and decomposed material 9f (9f’) showed
that the homocoupling of boronic acids remain to be one of the
major side-reactions occurring that lower the yield of the main
products. DFT analysis showed that electron density in the HOMO
of compounds 9a-e is mainly distributed over the substituted R-
groups (resulting biphenyl moiety after C-C coupling) and hence,
suggests a lack of reactivity via either of the oxygen-atoms in the
pyranone ring. TGA analysis confirmed the high rate of instability
and thermal decomposition of the selected 2,6-dimethyl-4H-pyran-
4-one compounds 9a, 9b, and 9e, and as result we were unable to
synthesize the target compounds 10a-e.
All reagents used for the purpose of this research were pur-
chased commercially from Sigma-Aldrich Chemicals (South Africa).
All solvents were purchased from Merck Chemicals South Africa.
Solvents such as DMF used were dried accordingly before usage.
DMF was distilled under nitrogen into 4A molecular sieve beads
from calcium hydride at 60 °C and kept overnight. During solvent
extraction, organic fractions collected were dried using anhydrous
magnesium sulfate MgSO4 or sodium sulfate Na2SO4 respectively.
Solvents were evaporated under reduced pressure, using IKRV 10
Rotary evaporator. Merck silica gel (0.063-0.200 mm) was used for
Column chromatography, while Thin Layer Chromatography TLC,
was done using Merck 60 F254 pre-coated silica gel plates and
were further visualized under ultraviolet light at 254 nm. Melting
points were determined with the aid of Gallenkamp melting point,
in an open capillary tube and are uncorrected. The 1H NMR and
13C NMR spectra were collected on a Bruker Avance 400 (at 400.21
MHz for 1H and 100.64 MHz for 13C) spectrometer by the means
of CDCl3, CH3OD or DMSO-d6, depending on the solubility of each
compound. The chemical shifts were reported in part per million
ppm relative to tetremethylsilane, (TMS) as an internal standard.
6

O.Y. Audu, J. Jooste, F.P. Malan et al.
Journal of Molecular Structure 1245 (2021) 131077
4.1. Procedure for the synthesis of 1-(4-bromophenyl)propan-2-one 3
135.1, 129.6(2C), 128.7(2C), 127.8(2C), 126.6(2C), 125.8, 83.8(2C),
24.9(4C).
A solution of 4-bromophenolacetic acid (10.01 g, 46.83 mmol,
1.0 eq.) in acetic anhydride anhydride (21.5 mL, 227.87 mmol, 4.9
eq.) was stirred and purged at room temperature for 10 min un-
der inert conditions. To the mixture was added 1-methylimidazole
(1.80ml, 22.73 mmol, 0.49 eq.) which initiated the reaction. The
mixture stirred for 16 hours at ambient temperature. The reaction
was quenched by the addition of distilled water (30ml) to the reac-
tion flask after which TLC indicated complete conversion of start-
ing materials into product. The mixture was extracted with ethy-
lacetate (200 mL), and washed with saturated NaHCO3 (3 × 100
ml). The organic layer was dried (Mg2SO4), evaporated to dryness
in vacuo to afford crude product that was purified via flash column
chromatography, eluting with Hex:EtAOc (8:2). The combined frac-
tions were evaporated to dryness to obtain 3 as a canary yellow
solid, in excellent yields.
4.3. General procedure for the synthesis of
2,6-dimethyl-3-phenyl-4(1H)-pyran-4-one derivatives 9a-f
(1H)3-(4-Bromophenyl)-2,6-dimethyl-4(1H)-pyran-4-one 4 (200
mg, 1.0 eq.), PdCl2(PPh3)2 (0.1 eq.), K2CO3 (3.0 eq.) were added
in succession to
a solution of either 4,4,5,5-tetramethyl-2-(4-
styrylphenyl)-1,3,2-dioxaborolane 8a or substituted boronic acids
8b-f (1.3 eq.) in a 1,4-dioxane-water mixture (6 mL, 2:1) under ni-
trogen gas and stirred at room temperature. The reaction mixture
was refluxed (80 °C) for 3 h, after which TLC indicated the reac-
tants had converted to products. The mixture was cooled to ambi-
ent temperature, filtered and concentrated in vacuo. The resulting
residue was taken up in ethyl acetate (20 mL) and washed with
water (20 mL). The organic layer separated, and the aqueous layer
was extracted with ethyl acetate (50 mL). The combined organic
fractions were dried (MgSO4) and concentrated in vacuo to afford
compounds and the product was purified using prepatory TLC with
DCM: Hexane (7:3, v:v) to afford 9a-e in average to good yields as
white to yellow solids.
Yield: 7.15 g, 72.19 % MP:247-249 °C; FT-IR: νmax (neat)/cm−1
3085, 2962, 2843, 2808, 2726, 2666, 2509, 1671, 1578, 1421,
3
1272, 751. 1H NMR (300 MHz, DMSO-d6) δH 7.49 (d, JHH = 8.4,
3
3
3JHBr = 6.0 Hz, 2H, ArH), 7.14 (d, JHH = 8.4, JHBr = 5.5 Hz, 2H,
ArH), 3.78 (s, 2H, CH2), 2.14 (s, 3H, CH3) 13C NMR (101 MHz, CDCl3)
δC 178.2, 164.8, 162.6, 131.9, 131.6, 125.7, 122.1, 113.8, 19.8, 18.6.
Synthesis of 3-(4-bromophenyl)-2,6-dimethyl-4H-pyran-4-
one, 4: Eaton’s reagent (22.86 mL, 145.5mmol, 4.41 eq.) was added
to acetic anhydride (11.1 mL, 116.4 mmol, 5.98 eq.) in a 2-neck
round bottom flask at room temperature. The mixture was allowed
stir before being heated to 95 ᵒC under argon. To this solution was
added 4-bromophenylacetone (7.0 g, 32,9 mmol, 1 eq.) drop-wise
and the reacting mixture refluxed for 2 hrs, after which TLC
indicated complete consumption of starting materials. The reacting
mixture was allowed to cool to room temperature, poured into
an ice-water bath (50 mL) and extracted with toluene (5 × 250
mL), washed with saturated NaHCO3 (2 × 300 mL). The organic
layer was dried (Mg2SO4) and concentrated in vacuo to afford the
crude product as a brown solid that was purified by flash column
chromatography, eluting with Hex:EtOAc (3:1). Yield: 4.36 g, 47.5
%; MP: 105.9-110.4 °C; FT-IR: νmax (neat)/cm−1 3062, 3034, 2922,
2853,1658, 1610, 1395, 1234, 1068, 967, 838. 1H NMR (400 MHz,
4(1H)4-((E)-1,2-Diphenylethene2,6-dimethyl-3-phenyl-4(1H)-
pyran-4-one, 9a: Compound 8a (as opposed to the boronic acids)
was employed. Yield, 0.010 g, 39%; MP, 260.9 - 262.0°C; FT-IR:
νmax (neat)/cm−1 2952, 2921, 2855, 1700, 1319. 1H NMR (400
MHz, CDCl3) δH 7.61 – 7.56 (m, 2H, ArH), 7.55 – 7.51 (m, 4H,
3
3
ArH), 7.47 (d, JHH = 7.2 Hz, 2H, ArH), 7.30 (t, JHH = 7.6 Hz,
2H, ArH), 7.27 – 7.20 (m, 3H, ArH), 7.09 (s, 2H, H-C=C-H) 6.17 (s,
1H, -C=C-H), 2.23 (s, 3H, CH3), 2.18 (s, 3H, CH3). 13C NMR (101
MHz, CDCl3) δC 178.6 164.7, 162.7, 140.1, 140.0, 137.3, 136.5, 131.7,
130.6, 128.8, 128.7(2C), 128.2, 127.7, 127.4(2C), 126.9(2C), 126.9,
126.6(2C), 22.7, 18.8.
2,6-dimethyl-3-(4-phenethenylphenyl)-4H-pyran-4-one, 9b:
Compound 8b was employed. Yield, 0.13 g, 59 %; MP, 185.3 - 186.8
ᵒC; FT-IR: νmax (neat)/cm−1 3035, 2923, 2853, 1659, 1608, 1407;
1H NMR (400 MHz, CDCl3) δH 7.46 (dd, JHH = 6.4, JHH = 4.0 Hz,
3
3
3
3
1H), 7.18 (m, 5H, ArH), 7.05 (dd, JHH = 14.4, JHH = 8.0 Hz, 3H,
ArH) 6.16 (s, 1H, C=CH), 2.86 (s, 4H, H2C-CH2), 2.22 (s, 3H, CH3),
2.11(s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 178.8, 164.6, 162.7,
141.8, 141.4, 131.9, 131.6, 130.1(2C), 128.5(2C), 128.4(2C), 128.4(2C),
125.9, 113.7, 37.8, 29.7, 19.9, 18.7.
3
3
CDCl3) δH 7.55 (dd, JHH = 11.2, JHBr = 6.4 Hz 2H, ArH), 7.12 (dd,
3
3JHH = 10.8, JHBr = 6.0 Hz 2H, ArH), 6.21 (s, 1H, C=CH), 2.30 (s,
3H, CH3), 2.19 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δC 178.2,
164.8, 162.6, 131.9 (2C), 131.6 (2C), 131.5, 125.7, 122.1, 113.8, 19.8,
18.6.
2,6-dimethyl-3-(4-styrylphenyl)-4H-pyran-4-one, 9c: Com-
pound 8c was employed. Yield, 0.127 g, 55 %; MP: 185.3 - 186.8
ᵒC; FT-IR: νmax (neat)/cm-1 3036, 2922, 2852, 1658, 1608, 1402.
3
4.2. Procedure for the synthesis of
1H NMR (400 MHz, CDCl3) δH 7.57 (dd, JHH = 12.8, 7.7 Hz, 4H,
3
4,4,5,5-tetramethyl-2-(4-styrylphenyl)-1,3,2-dioxaborolane 8a
ArH), 7.39 (t, JHH = 7.6 Hz, 1H, ArH), 7.33 – 7.22 (m, 3H, ArH),
7.15 (s, 2H, HC=CH), 6.26 (s, 1H, C=CH), 2.32 (s, 3H, CH3), 2.24 (s,
3H, CH3). 13C NMR (101 MHz, CDCl3) δC 178.5, 164.6, 162.6, 137.2,
136.9, 131.8, 130.5(2C), 129.0, 128.7(2C), 128.3, 127.7, 126.7(2C),
126.5(2C), 126.3, 113.8, 19.8, 18.7.
A solution of 4-bromostilbene (518.5 mg, 2.00 mmol, 1 eq.) in
dry 1,4-dioxane under an inert atmosphere was stirred at ambi-
ent temperature and charged with bis(pinacolate)diboron (661 mg,
2.60 mmol, 1.3 eq.), PdCl2(dppf) (163.2 mg, 0.2 mmol, 0.1 eq.),
and KOAc (589.1 mg, 6.00 mmol, 3 eq.) in succession. The reac-
tion mixture was heated at 120 °C for 5 h, after which TLC in-
dicated complete conversion of starting materials into products.
The solution was cooled to room temperature, diluted with EtOAc
and filtered through celite. The filtrate was washed with water
(2 × 200 mL) and brine (2 × 200 mL), dried (MgSO4) and evap-
orated under reduced pressure and the crude product was purified
via column chromatography with Hex:EtOAc (9:1) to afford 8a as a
white powder. Yield: 0.382 g, 62.4 %; MP: 116-120°C; FT-IR: νmax
(neat)/cm−1 2978, 2973, 2923, 2854, 1602, 1354, 1142, 963, 858. 1H
2,6-dimethyl-3-[4-(naphthalen-2-yl)phenyl]-4H-pyran-4-one,
9d: Compound 8d was employed. Yield, 0.44 g, 75.4%; MP: 260.9
- 262.0°C. FT-IR: νmax (neat)/cm−1 3042, 2922, 2852, 1657, 1605,
3
3
1406δH 7.98 (s, 1H, ArH), 7.81 (dt, JHH = 9.0, JHH = 5.2 Hz,
3
3H, ArH), 7.69 (d, JHH = 8.3 Hz, 3H, ArH), 7.47 – 7.36 (m, 2H,
3
ArH), 7.28 (d, JHH = 8.3 Hz, 2H, ArH), 6.16 (s, 1H, C=CH), 2.21 (s,
3H, CH3), 2.17 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δC 178.6,
164.6,162.7, 140.6, 138.2, 133.7, 132.7, 131.7, 130.7(2C), 128.5, 128.2,
127.7, 127.4(2C), 126.30(2C), 125.9, 125.8, 125.6, 113.8, 19.8, 18.8.
3-{4-[(1E)-2-(4-fluorophenyl)ethenyl]phenyl}2,6-dimethyl-
4H-pyran-4-one, 9e: Compound 8e was employed. Yield, 0.52 g,
54.7%; MP: 175.1 - 175.9; FT-IR: νmax (neat)/cm-1 3040, 2923,
2852, 1650, 1604, 1402; 1H NMR (300 MHz, CDCl3) δH 7.60 –
3
NMR (400 MHz, CDCl3) δH 7.72 (d, JHH = 8.1 Hz, 2H, ArH), 7.48
3
– 7.41 (m, 4H, ArH), 7.29 (t, JHH,HH = 8.0 Hz, 2H, ArH), 7.19 (m,
3
3
3
3
1H, ArH), 7.07(dd, JHH =28.4, JHH = 16.4 Hz, 2H, HC=CH), 1.28 (s,
12H,CH3 × 4).13C NMR (75 MHz, CDCl3) δC 140.0(2C), 137.2(2C),
7.45 (m, 4H, ArH), 7.29 – 7.23 (dd, JHH =11.2, JHH = 5.2 Hz, 2H,
HC=CH), 7.13 – 7.03 (m, 4H, ArH), 6.23 (s, 1H, C=CH), 2.31 (s, 3H,
7

O.Y. Audu, J. Jooste, F.P. Malan et al.
Journal of Molecular Structure 1245 (2021) 131077
CH3), 2.24 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) δC 178.5, 164.6,
163.9, 162.6, 160.7, 136.7, 133.5, 133.4, 131.9, 130.5, 128.1, 127.9,
127.8, 126.4, 126.3, 115.8, 115.5, 113.8, 113.8, 19.7, 18.7.
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Oluwatosin Yemisi Audu: Conceptualization, methodology, in-
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Declaration of Competing Interest
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8

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Journal of Molecular Structure 1245 (2021) 131077
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9