Unexpected synthesis of novel 2-pyrone derivatives: crystal structures, Hirshfeld surface analysis and computational studies

Article abstract of DOI:10.1080/07391102.2020.1780943

Here we report synthesis of three new compounds namely, 1-acetyl-1H-benzimidazolo-2(3H)-one (I), N-(5-acetyl-6-methyl-2-oxo-2H-pyran-4-yl)-N-(2-acetamidophenyl)acetamide (II) and N-(2-acetamidophenyl)-N-2-oxo-2H-pyran-4-yl)acetamide (III) have been synthe

Full text of DOI:10.1080/07391102.2020.1780943

Journal of Biomolecular Structure and Dynamics
ISSN: 0739-1102 (Print) 1538-0254 (Online) Journal homepage: https://www.tandfonline.com/loi/tbsd20
Unexpected synthesis of novel 2-pyrone
derivatives: crystal structures, Hirshfeld surface
analysis and computational studies
Jihad Sebhaoui, Youness El Bakri, Chin-Hung Lai, Subramani Karthikeyan, El
Hassane Anouar, Joel T. Mague & El Mokhtar Essassi
To cite this article: Jihad Sebhaoui, Youness El Bakri, Chin-Hung Lai, Subramani Karthikeyan, El
Hassane Anouar, Joel T. Mague & El Mokhtar Essassi (2020): Unexpected synthesis of novel 2-
pyrone derivatives: crystal structures, Hirshfeld surface analysis and computational studies, Journal
of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2020.1780943
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JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
https://doi.org/10.1080/07391102.2020.1780943
Unexpected synthesis of novel 2-pyrone derivatives: crystal structures, Hirshfeld
surface analysis and computational studies
Jihad Sebhaouia#, Youness El Bakria,b#, Chin-Hung Laic,d, Subramani Karthikeyane, El Hassane Anouarf, Joel T.
Magueg and El Mokhtar Essassia
a
ꢀ ꢀ
ꢀ
^
ꢀ
Laboratoire de Chimie Organique Heterocyclique, Centre de Recherche des Sciences des Medicaments, Pole de Competences
b
ꢀ
Pharmacochimie, URAC 21, Faculte des Sciences, Mohammed V University Rabat, Rabat, Morocco; South Ural State University, Chelyabinsk,
Russian Federation; Department of Medical Applied Chemistry, Chung Shan Medical University, Taichung, Taiwan; Department of Medical
Education, Chung Shan Medical University Hospital, Taichung, Taiwan; Organic Chemistry Department, Science Faculty, RUDN University,
Moscow, Russian Federation; Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam bin Abdulaziz
c
d
e
f
g
University, Al-Kharj, Saudi Arabia; Department of Chemistry, Tulane University, New Orleans, LA, USA
Communicated by Ramaswamy H. Sarma
ABSTRACT
ARTICLE HISTORY
Received 28 March 2020
Accepted 7 June 2020
Here we report synthesis of three new compounds namely, 1-acetyl-1H-benzimidazolo-2(3H)-one (I),
N-(5-acetyl-6-methyl-2-oxo-2H-pyran-4-yl)-N-(2-acetamidophenyl)acetamide (II) and N-(2-acetamido-
phenyl)-N-2-oxo-2H-pyran-4-yl)acetamide (III) have been synthesized and characterized by single crys-
tal X-ray diffraction. Compounds I and II crystallize in the monoclinic space groups P21/n, and P21/c,
respectively, while III crystallizes in the triclinic space group P-1. The theoretical parameters of I–III
have been calculated through density functional theory (DFT) by using the hybrid functional B3LYP
KEYWORDS
Pyrane; benzimidazole;
crystal structure; DFT
calculations; molecular
docking; molecular
dynamics simulation
ꢀꢀ
and basis set 6-311þþG . These theoretical parameters have been compared with the experimental
ones obtained by XRD. The significant intermolecular interactions arising in crystal packing are ration-
alized by means of the Hirshfeld surface analysis method. The major intermolecular contacts in the
Hirshfeld surfaces of I–III are from H … H contacts. In addition, binding modes of I–III within Tyrosine-
protein kinase JAK2 were investigated using molecular docking and molecular dynamics simula-
tion studies.
1. Introduction
suitable drug candidates against various human diseases is
worth pursuing.
a-pyrones are known for their versatile biological properties.
They have the ability to bind specific protein domains in
diverse biological systems and possess cytotoxic (Sang et al.,
2017), antiviral (Poppe et al., 1997; Thaisrivongs et al., 1996;
Turner et al., 1998), antifungal (Altomare et al., 2000, 2004;
Chattapadhyay & Dureja, 2006; Lohaus & Dittmar, 1981), and
antimicrobial activity (Ronad et al., 2010). Recently, they have
shown efficacy against Leishmania (L.) infantum and
Trypanosoma cruzi (Tempone et al., 2017). Moreover, many
chlorinated 2-pyrone based derivatives were discovered to
be potent anticancer agents (Marrison et al., 2002; Newell
et al., 1998; Perchellet et al., 1997, 2009; Ridley & Khosla,
2007; Woo et al., 2012; Yoon et al., 2012). Tricyclic 2-pyrones
are reported to be effective against Alzheimer’s amyloid tox-
icity (Hong et al., 2009; Maezawa et al., 2006; Rana et al.,
2009). The biological activity of pyrone based molecules in
all of these examples is believed to be due to enzyme inhib-
ition (Altmann & Gertsch, 2007; Fairlamb et al., 2004).
Because of the lactonic structure of a-pyrones, they repre-
sent highly valuable building blocks. Their derivatives are
convenient and progressively used in a variety of organic
syntheses, especially in the synthesis of new types of hetero-
cyclic compounds due to the existence of functional groups
such as conjugated dienes and the ester group, their reactiv-
ity has been reported in the literature (El Abbassi et al.,
1987, 1990).
A wide variety of pyrone moieties have been isolated
from natural sources (Dean, 1963; Sharma et al., 2011; Wilk
et al., 2009), such as the petrocortyne C (Seo et al., 1998),
verticipyrone (Ui et al., 2006), cyercene A (Vardaro et al.,
1991), onchitriols I and II (Rodriguez et al., 1992), the auripyr-
ones A and B (Suenaga et al., 1996).
However, a wide range of synthetic methods for pyrones
is accessible due to the broad range of applications that
motivated organic practitioners to the development of sev-
eral methodologies to access them. In summary, the follow-
Undoubtedly, therefore, the probable scope of a-pyrones as ing are typical approaches for the synthesis of a-pyrone: (1)
ꢀ ꢀ
ꢀ
^
CONTACT Youness El Bakri
yns.elbakri@gmail.com
Laboratoire de Chimie Organique Heterocyclique, Centre de Recherche des Sciences des Medicaments, Pole
ꢀ
ꢀ
de Competences Pharmacochimie, URAC 21, Faculte des Sciences, Mohammed V University Rabat, Rabat, Morocco; Chin-Hung Lai
Medical Applied Chemistry, Chung Shan Medical University, Taichung, Taiwan
chlai125@csmu.edu.tw
Department of
#Both of these authors contributed equally to this paper.
Supplemental data for this article can be accessed online at https://doi.org/10.1080/07391102.2020.1780943.
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
J. SEBHAOUI ET AL.
Scheme 1. Reaction scheme for the synthesis of compounds I, II and III.
1
Pd-catalyzed carbometalation-lactonization of 3-halo-(2Z)- uncorrected. A Bruker 300 MHz NMR instrument recorded H
and 13C NMR spectra at 300 MHz and 75 MHz using TMS as
enoates with alkynes (Larock et al., 1999); (2) lactonization
reaction of various functionalized a,b-unsaturated enones,
which were prepared via numerous methods from diverse
starting materials (Bickel, 1950; Dieter & Fishpaugh, 1983;
Migliorese & Miller, 1974); (3) Pd-catalyzed coupling-lactoni-
zation of 3-halo-(2Z)-enoic acids with 1,2-allenic tins (Rousset
et al., 2000); and (4) cyclization of 3,5-diketocarboxylic acids
(Harris & Harris, 1966).
The majority of the synthetic approaches to 2-pyrones use
expensive catalysts and harmful organic solvents. There is no
methodology developed from a cycle transposition which is
economic in atoms, and few routes answer the current chal-
lenges for the development of a green chemistry. For this
reason, the unexpected reaction of the transformation of a
1,5-benzodiazepine (4-(2-oxopropylidene)-1,5-benzodiazepin-
2-one (c) into substituted 2-pyrone derivatives, appeared
interesting to exploit. Due to our continuing interests on the
biologically active heterocycles (El Bakri, Anouar, et al., 2018;
El Bakri, Lai, et al., 2018; El Bakri et al., 2019; Sebhaoui et al.,
2019), we thus report in this article, an original ring trans-
formation of the seven-membered moiety of the 1,5-benzodi-
azepine (c) that leads to novel substituted a-pyrones and an
an internal standard and CDCl3 as solvent. Mass spectra were
performed on a Perkin–Elmer SCIEX API unit 300. The sam-
ples are ionized by the electrospray technique (ESI).
The solution of 4Z-(2-oxopropylidene)-2,3,4,5-tetrahydro-
1H-1,5-benzodiazepin-2-one
c in acetic anhydride was
refluxed for 3 h. The reaction was monitored by TLC. After
completion of the reaction, the solvent was evaporated
under reduced pressure leading to a black residue, which
provided the three compounds I, II and III respectively after
a column chromatography separation using a polarity 8:2 of
hexane/ethyl acetate. The compounds were identified by
NMR and X-Ray crystallographic techniques.
2.1.1. Synthesis of 1-acetyl-benzimidazol-2(3H)-one (I)
Yield: 15%. Colourless crystal, m.p: 154–156 ꢁC, 1H NMR
(300 MHz, CDCl3) d ppm 2.15 (s, 3 H, CH3) 7.49–7.65 (m, 4 H,
CHAr), 13C NMR (75 MHz, CDCl3) d ppm: 26.60, 129.49, 130.73,
131.59, 135.51, 155.21, 164.69, 169.64, 172.30. HRMS (ESI)
Calculated for C9H8N2O2: [M þ Hþ] ¼ 176.0635, Found:
[M þ Hþ] ¼ 176.0631. Elemental analysis Calculated: C,
acetyl benzimidazolone, along with crystal structures, 61.36%; H, 4.58%; N, 15.90%; O, 18.16%; Found: C, 61.34%; H,
Hirshfeld surface analysis and DFT studies. The pathway for
the synthesis is illustrated in Scheme 1.
4.60%; N, 15.88%; O, 18.14%.
2.1.2. Synthesis of N-acetyl-N-(O-acetamidophenyl)-amino-
6-methyl-pyran-2-one (II)
2. Materials and methods
Yield: 35%. Colourless crystal, m.p: 179–181 ꢁC, 1H NMR
(300 MHz, CDCl3) d ppm: 1.95 (s, 3H, CH3), 2.12 (s, 3H, CH3),
2.14 (s, 3H, CH3), 5.76 (s, 1H, CHpyran), 6.26 (s, 1H, CHpyran),
2.1. Experimental procedure
Melting points were determined on a Buchi B-540 melting
point apparatus using an open-ended capillary tube and are 7.14–8.27 (m, 4H, CHAr). 13C NMR (75 MHz, CDCl3) d ppm:

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
3
2.2.2. Product II
A colourless column-like specimen of compound II, approxi-
mate dimensions 0.10 ꢂ 0.10 ꢂ 0.27 mm3, was used for the
X-ray crystallographic analysis. The X-ray intensity data were
measured on a Bruker Smart APEX system equipped with a
graphite monochromator and a MoKa fine-focus, sealed tube
source (k ¼ 0.71073 Å). A complete data set was processed
using SAINT (Sheldrick, 2015b). The structure (Figure 2) was
solved by direct methods and refined by full-matrix least
squares method on F2 using SHELXT and SHELXL programs
(Sheldrick, 2015a). All the hydrogen atoms were revealed in
the first difference Fourier map and were refined with iso-
tropic displacement parameters.
2.2.3. Product III
A colourless block-like specimen of compound III, approximate
dimensions 0.14ꢂ 0.18ꢂ 0.24mm3, was used for the X-ray crys-
tallographic analysis. The X-ray intensity data were measured
on a Bruker Smart APEX CCD system equipped with a graphite
Figure 1. ORTEP of the molecule I with labeling scheme and 50% probability
ellipsoids. The intramolecular C–HꢄꢄꢄO interaction is shown by a dotted line.
monochromator and
a
MoKa fine-focus sealed tube
(k ¼ 0.71073 Å). A complete data set was processed using SAINT
(Sheldrick, 2015b). The structure (Figure 3) was solved by direct
methods and refined by full-matrix least squares method on F2
using SHELXT and SHELXL programs (Sheldrick, 2015a). All the
hydrogen atoms were revealed in the first difference Fourier
map and were refined with isotropic displacement parameters.
20.29, 24.00, 25.49 (CH3), 99.15, 100.75 (CHpyran), 126.12,
126.58, 129.48, 130.73 (CHAr), 131.59, 135.51, 155.20, 161.91,
164.69, 169.64, 172.30 (Cq). HRMS (ESI) Calculated for
C16H16N2O4: [M þ Hþ] ¼ 300.1105, Found: [M þ Hþ] ¼ 300.1107.
Elemental analysis Calculated: C, 63.99%; H, 5.37%; N, 9.33%;
O, 21.31%; Found: C, 63.97%; H, 5.38%; N, 9.34%; O, 21.33%.
2.3. DFT calculations
2.1.3. Synthesis of 5-acetyl-N-acetyl-N-(O-acetamido-
phenyl)-amino-6-methyl-pyran-2-one (III)
The gas phase structures of the title compounds were opti-
mized by density functional theory. The DFT calculations
were performed by the hybrid functional B3LYP, which is
based on the idea of Becke and considers a mixture of the
exact (HF) and DFT exchange utilizing the B3 functional,
together with the LYP correlation functional (Becke, 1993;
Lee et al., 1988). The B3LYP calculation was done in conjunc-
Yield: 42%. Colourless crystal, m.p: 176–178 ꢁC, 1H NMR
(300 MHz, CDCl3). d ppm: 1.95 (s, 3H, CH3), 2.12 (s, 3H, CH3),
2.14 (s, 3H, CH3), 2.47 (s, 3H, CH3), 5.86 (s, 1H, CHpyran),
7.24–7.50 (m, 4H, CHAr). 13C NMR (75 MHz, CDCl3) d ppm:
20.75, 25.44, 30.02, 31.18 (CH3), 98.31 (CHpyran), 127.13, 127.78,
130.15, 131.54 (CHAr), 133.78, 135.23, 135.41, 160.79, 162.19,
165.35, 172.33, 201.14 (Cq). HRMS (ESI) Calculated for
C18H18N2O5: [M þ Hþ] ¼ 342.1231, Found: [M þ Hþ] ¼ 342.1329.
Elemental analysis Calculated: C, 63.15%; H, 5.30%; N, 8.18%;
O, 23.37%; Found: C, 63.13%; H, 5.29%; N, 8.16%; O, 23.38%.
ꢀꢀ
tion with the basis set 6-311þþG . Among I ꢃ III, there
might be many conformers and a difference in the energies
of these conformers. Therefore, the MMX force field imple-
mented in GMMX, the add-on for the GaussView 6.1.1 pro-
gram, was used to do a conformational search (Dennington
et al., 2016). The most stable conformers for I–III were then
taken as the initial guesses for the B3LYP geometry optimiza-
tions. After obtaining the converged geometry, the harmonic
vibrational frequencies were calculated on the same theoret-
ical level to confirm the number of imaginary frequency is
zero for the stationary point. Both the geometry optimization
and harmonic vibrational frequency analyses of the title com-
pounds were done by the Gaussian 09 program (Frisch
et al., 2009).
2.2. Single crystal X-ray diffraction
2.2.1. Product I
A
single
colourless
crystal
of
dimension
0.27 ꢂ 0.10 ꢂ 0.10 mm3 of the title compound was selected
and X-ray intensity data were collected at 150 K on a Bruker
D8 VENTURE PHOTON 100 CMOS diffractometer equipped
with an X-ray generator operating at 50 kV and 10 mA, using
CuKa radiation of wavelength 1.54178 Å. A hemisphere of
data was processed using SAINT (Sheldrick, 2015b). The
structure (Figure 1) was solved by direct methods and
refined by full-matrix least squares method on F2 using
SHELXT and SHELXL programs (Sheldrick, 2015a). All the
hydrogen atoms were revealed in the first difference Fourier
map and were refined with isotropic displace-
ment parameters.
2.4. Hirshfeld surface calculations
Both the definition of a molecule in a condensed phase
and the recognition of distinct entities in molecular liquids
and crystals are fundamental concepts in chemistry. Based
on Hirshfeld’s partitioning scheme, Spackman et al. in 1997
proposed a method to divide the electron distribution in a

4
J. SEBHAOUI ET AL.
Figure 2. ORTEP of the molecule II with labeling scheme and 50% probability ellipsoids.
Figure 3. Packing of the molecules of I viewed along the c-axis direction with a selection of the intermolecular interactions depicted as in Figure 4.
crystalline phase into molecular fragments (McKinnon et al., utilizing the CrystalExplorer program (Spackman
&
Jayatilaka, 2009).
2004; Spackman & Byrom, 1997; Spackman & Jayatilaka,
2009). Their proposed method partitioned the crystal into
regions where the electron distribution of a sum of spher-
ical atoms for the molecule dominates over the correspond-
ing sum of the crystal. Because it derived from Hirshfeld’s
stockholder partitioning, the molecular surface is named as
the Hirshfeld surface. In this study, the Hirshfeld surface
2.5. Molecular docking and molecular dynamics studies
For compounds I, II and III, 2 D chemical structures were
drawn using CHEMDRAW Pro 12.0 and those chemical struc-
tures were energetically minimized using the conjugate gra-
analysis of the title compounds were performed dient method. The target protein of tyrosine kinase–Janus

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
5
Figure 4. Detail of the intermolecular N–HꢄꢄꢄO and C–HꢄꢄꢄO hydrogen bonding (blue and black dotted lines, respectively) and the p-stacking interactions (orange
and green dotted lines) in I (symmetry codes: (i) ꢅx þ 2, ꢅy þ 1, ꢅz þ 2; (ii) x ꢅ 1/2, ꢅy þ 1/2, z ꢅ 1/2; (iii) ꢅx þ 2, ꢅy þ 1, ꢅz þ 1; (iv) ꢅx þ 1, ꢅy þ 1, ꢅz þ
1).
Scheme 2. The proposed mechanism for the formation of compound I.
kinase 2 (JAK2) (PDB ID: 5AEP) was chosen using the Swiss with a 10 Å3 cubic box from the centre of mass of the protein
€
target prediction server and the protein molecule was pre- (Schrodinger, 2018). A TIP3P water solvation system was used
pared using the protein preparation wizard which is built in a buffer system with charged ions placed isotropically to
€
into the Schrodinger suite 2018-3 version (Gfeller et al., 2013; neutralise the Ewald charge summation of the solvated pro-
€
tein entity. The system was minimized with a maximum itera-
tions of 5000 steps with a gradient convergence threshold of
1.0 kcal molꢅ1Åꢅ1. Once the system was minimized, it was
subjected to Newtonian dynamics of the model system to
evaluate its energy. A series of 2 ps steps was integrated to
record the simulation. A six stage NPT ensemble default relax-
ation process was carried out before performing the molecu-
lar dynamics simulation. In the first stage, a solute-restrained
Brownian dynamics of the ensemble was carried out while
keeping the energy constant using the NVT condition. In the
second stage the Berendsen thermostat was used and the
NVT (canonical) ensemble was allowed to relax with respect
to temperature with velocity resembling of every 1 ps applied
Schrodinger, 2018). Once the initial structure of the protein
molecule was prepared, it was optimized and minimized
using the OPLS 2005 force field using the same protein prep-
aration wizard panel. The active site residues were taken from
the co-crystal site and further subjected to induced fit dock-
ing analysis. From this induced fit docking 20 different poses
were generated for each compound and protein complex
and from that the best binding pose was picked based on
glide energy and number of interacting residues. Once the
docking analysis finished, the best compound–protein com-
plex was taken for molecular dynamics studies. Using
€
DESMOND contained in the Schrodinger 2018-03 version the
protein system was built using a periodic boundary condition

6
J. SEBHAOUI ET AL.
Scheme 3. A plausible mechanism for the formation of compound II.
Scheme 4. A plausible mechanism for the formation of compound III.
to non-hydrogen solute sample. Subsequently, the NVT the formation of the three compounds I, II and III
(Scheme 1). It is worthy to note that they were obtained via
interesting ring-transformations of the seven-membered ring
as depicted in Schemes 2–4.
Studying the mechanism of these transpositions, we
found that the benzodiazepine c might present several react-
ive sites towards acetic anhydride: the amide nitrogen N1,
the amine nitrogen N5, and the a-carbon of the oxopropyli-
dene group at the position 4 of the bicyclic system.
ensemble was changed to an NPT ensemble with
a
Berendsen barostat and the system was kept at 1 atm pres-
sure followed by system equilibration of 1 ns. Then the
ensemble was subjected to a 50 ns molecular dynamics run.
3. Results and discussion
Benzodiazepine c, prepared using the method described in a
previous work (El Abbassi et al., 1989), reacted with acetic
anhydride, at reflux for 3 h. Acetic anhydride was used as
Indeed, when the acetylation affects only the amide nitro-
gen N1, and the amine nitrogen N5 remains intact, there
could be two possibilities for rearrangement: either by the
reagent and solvent at the same time. This reaction allowed attack of N5 on the carbonyl group to form the

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
7
benzimidazole I (Scheme 2), or by oxygen attack of the oxo-
propylidene group to lead to the pyrone II (Scheme 3).
However, when acetylation affects the amide nitrogen N1
along with the a-carbon of the oxopropylidene group, tauto-
meric equilibrium occurs, allowing the oxygen of the oxopro-
pylidene group to attack the amidic carbonyl to furnish
pyrone III.
To understand the course of this reaction, we tried to
carry it out at room temperature in order to isolate the inter-
mediates involved in these rearrangements. It should be
noted that under these conditions, the starting compound
remains unchanged.
3.1. Mechanistic approach
3.1.1. Product I
Table 1. Hydrogen bond geometry of compound I (Åꢁ).
The initial stage was the acetylation of the amide nitrogen
N1 leading to the compound [A] which undergoes a transan-
nular attack involving the amine nitrogen N5 and the car-
bonyl group of the amide function leading to the
intermediate [B]. The latter compound, after the ring open-
ing of the azetane moiety affords the benzimidazole com-
pound [C]. The attack of a water molecule on sp2 carbon
atom of [C] led to intermediate [D] which after elimination
of acetylacetone gave 1-acetyl-benzimidazolone I.
D–HꢄꢄꢄA
D–H
HꢄꢄꢄA
DꢄꢄꢄA
D–HꢄꢄꢄA
N1–H1ꢄꢄꢄO1i
C2–H2ꢄꢄꢄO2
0.909(18)
0.972(16)
0.977(17)
0.977(17)
1.903(18)
2.344(15)
2.864(17)
2.599(18)
2.8066(12)
2.8774(15)
3.4922(16)
3.5335(15)
173.0(16)
113.9(11)
122.9(11)
160.1(13)
C9–H9AꢄꢄꢄCg2ii
C9–H9CꢄꢄꢄO1iii
Symmetry codes: (i) ꢅx þ 2, ꢅy þ 1, ꢅz þ 2; (ii) ꢅx þ 1, ꢅy þ 1, ꢅz þ 1; (iii)
x ꢅ 1/2, ꢅy þ 1/2, z ꢅ 1/2.
Table 2. Hydrogen bond geometry of compound II (Åꢁ).
3.1.2. Product II
D–HꢄꢄꢄA
D–H
HꢄꢄꢄA
DꢄꢄꢄA
D–HꢄꢄꢄA
N1–H1ꢄꢄꢄO4i
0.878(16)
0.969(14)
0.966(15)
0.968(16)
0.984(14)
2.133(17)
2.420(14)
2.475(15)
2.543(16)
2.420(15)
2.9779(14)
3.3769(15)
3.3075(16)
3.3533(18)
3.3290(17)
161.2(13)
169.2(11)
144.2(11)
141.3(12)
153.4(11)
The acetylation of the nitrogen N1 [A] was again the first
step of this transformation The tautomeric form [E] under-
goes an intramolecular cyclization involving the hydroxyl
oxygen atom and the amidic carbonyl group giving the tri-
cyclic intermediate [F] which, after deprotonation and
protonation, leads to the opening of the diazepinic ring and
C6–H6ꢄꢄꢄO2ii
C8–H8BꢄꢄꢄO4i
C16–H16AꢄꢄꢄO2i
C16–H16BꢄꢄꢄO1iii
Symmetry codes: (i) ꢅx þ 1, ꢅy þ 1, ꢅz þ 1; (ii) ꢅx þ 2, ꢅy þ 1, ꢅz þ 1; (iii)
ꢅx þ 1, ꢅy þ 1, ꢅz.
Figure 5. Packing of the molecules II viewed along the b-axis direction. The N–HꢄꢄꢄO and C–HꢄꢄꢄO hydrogen bonds and the p-stacking interaction are shown,
respectively, as blue, black and orange dotted lines.

8
J. SEBHAOUI ET AL.
formation of the intermediate [H] which is the tautomeric
form of the compound [G]. An acetylation of the nitrogen
atom at the 4-position of the pyrone [G], afforded to the for-
mation of the compound II.
3.1.3. Product III
The first step was a double acetylation of the amide nitrogen
N1 [A] as well as the a-carbon of the acetyl group leading to
the intermediate [I]. The corresponding tautomeric form [J]
undergoes an intramolecular cyclization involving the
hydroxyl oxygen atom and the amidic carbonyl group lead-
ing to the tricyclic intermediate [K]. The opening of the dia-
zepine ring gives the compound [L], which the
corresponding tautomeric form [M] undergoes a final acetyl-
ation to furnish pyrone III.
Table 3. Hydrogen bond geometry of compound III (Åꢁ).
D–HꢄꢄꢄA
D–H
HꢄꢄꢄA
DꢄꢄꢄA
D–HꢄꢄꢄA
N1–H1ꢄꢄꢄO5
0.913(14)
0.978(13)
0.982(17)
0.929(19)
2.141(14)
2.401(13)
2.443(17)
2.898(17)
3.0374(12)
3.2994(13)
3.3270(15)
3.7752(13)
167.0(13)
152.5(10)
149.6(12)
158.0(15)
C6–H6ꢄꢄꢄO2i
C18–H18AꢄꢄꢄO1ii
C17–H17CꢄꢄꢄCg(2)iii
Symmetry codes: (i) ꢅx þ 1, ꢅy þ 1, ꢅz þ 1; (ii) ꢅx þ 2, ꢅy þ 1, ꢅz þ 1; (iii)
ꢅx þ 1, ꢅy þ 1, ꢅz.
Figure 6. ORTEP of the molecule III with labeling scheme and 50% probability ellipsoids. The intramolecular N–HꢄꢄꢄO hydrogen bond is shown by a dotted line.
Figure 7. A portion of the chain in III formed by the two sets of pairwise C–HꢄꢄꢄO hydrogen bonds (dotted lines).

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
9
Figure 8. Packing of the molecules III viewed along the b-axis direction with the C–HꢄꢄꢄO hydrogen bonds and the C–Hꢄꢄꢄp(ring) interactions shown, respectively,
as black and orange dotted lines.
associated into chains parallel to the b-axis direction by pair-
wise C16–H16BꢄꢄꢄO1ii hydrogen bonds while pairwise
C6–H6ꢄꢄꢄO2iii hydrogen bonds tie the chains together (Table
2 and Figure 5).
3.2. Description of the crystal structure
3.2.1. Compound I
The bicyclic core is slightly twisted as indicated by the dihe-
dral angle of 1.57(6)ꢁ between the 5- and 6-membered rings.
In addition, the 5-membered ring shows a greater deviation
from planarity (N1 is 0.0060(7) Å from one side of the mean
plane and C6 and C7 are both 0.0047(7) Å from the other).
The rotational orientation of the acetyl substituent appears
partially determined by a C2–H2ꢄꢄꢄO2 hydrogen bond (Figure
1; Table 1). In the crystal, complementary N1–H1ꢄꢄꢄO1i hydro-
gen bonds form dimers from which stepped ribbons of mol-
3.2.3. Compound III
The conformation of the title molecule is partly determined
by the intramolecular N1–H1ꢄꢄꢄO5 hydrogen bond (Table 3;
Figure 6). The dihedral angle between the C1ꢄꢄꢄC6 and O3/
C11ꢄꢄꢄC15 planes is 86.75(3)ꢁ. In the crystal, complementary
C6–H6ꢄꢄꢄO2i hydrogen bonds form dimers which are elabo-
rated into chains parallel to the (110) direction by pairwise
C18–H18AꢄꢄꢄO1ii hydrogen bonds (Table 3; Figure 7). The full
three-dimensional supramolecular structure is generated by
C17–H17Cꢄꢄꢄp(Cg2iii) (Cg2 ¼ centroid of the C1ꢄꢄꢄC6 ring)
interactions which tie the chains together (Table 3; Figures 7
and 8).
ecules are formed by
a
combination of p-stacking
interactions between the 5- and 6-membered rings of adja-
cent molecules on one side (centroidꢄꢄꢄcentroid
¼
3.4591(8) Å, dihedral angle ¼ 1.57(7)ꢁ) and between the 5-
membered ring and the C8 ¼ O2 carbonyl group of the mol-
ecule on the other side (centroidꢄꢄꢄcentroid ¼ 3.248(1) Å,
angle between the CO vector and the ring plane¼ 84.44(8)ꢁ)
(Figures 3 and 4). The latter interaction is reinforced by a
C9–H9Aꢄꢄꢄp(ring)iv interaction (Table 1 where Cg2 is the cen-
troid of the C1ꢄꢄꢄC6 ring). The full three-dimensional structure
is assembled from these ribbons through C9–H9CꢄꢄꢄO1ii
hydrogen bonds (Table 1; Figures 3 and 4).
3.3. DFT results
The gas phase structures of I, II and III were obtained by
DFT–B3LYP optimization and these are depicted in Figure 9.
In general, there is good agreement between the calculated
and experimental geometric parameters although in some
instances the former underestimate differences between the
lengths of similar bonds while in others the opposite is true.
For example, in I, the C7 ¼ O1 (1.2269(14) Å) and C8 ¼ O2
(1.2131(14) Å) bonds differ by almost 10 r but the calculated
values are basically identical. In contrast, in II, the C7 ¼ O1
(1.2185(15) Å) and C13 ¼ O4 (1.2220(14) Å) bonds are equal
3.2.2. Compound II
The dihedral angle between the two 6-membered rings is
82.04(3)ꢁ. In the crystal, complementary N1–H1ꢄꢄꢄO4i hydro-
gen bonds form dimers which are reinforced by C8–H8ꢄꢄꢄO4i
and C16–H16AꢄꢄꢄO2i hydrogen bonds as well as p-stacking
interactions between the pyrone rings (centroidꢄꢄꢄcentroid¼
3.4979(8) Å) (Table 2; Figures 2 and 5). The dimers are within experimental error (D/r ¼ 2.5) but the calculated

10
J. SEBHAOUI ET AL.
Figure 9. The DFT–B3LYP optimized geometries of I, II, and III (bond lengths in Å; carbon in gray, nitrogen in blue, oxygen in red, and hydrogen in white).
values differ by 0.012 Å. As the aforementioned, for I–III, the ones could be seen in Tables S5–S7 in the Supporting
B3LYP-optimized geometries showed some differences with Information (the values in italic were the ones obtained by
respect to the X-ray measured ones. To quantify the differ- the B3LYP optimization).
ence between the calculated geometry and the experimental
The important aspect of the frontier molecular orbital the-
one, the structure comparer built in the ChemCraft program ory is the focus on the highest occupied and lowest unoccu-
was used to gain their root-mean-square deviation (RMSD, pied molecular orbitals (HOMO and LUMO). Instead of
Chemcraft—graphical software for visualization of quantum thinking about the total electron density in a nucleophile,
chemistry computations. https://www.chemcraftprog.com). the localization of the HOMO orbital should be considered
The weighted RMSD was 0.6546, 2.249, 2.955 for I, II, and III, because electrons from this orbital have the most chance to
respectively. A more detailed investigation showed that O participate in the nucleophilic attack, while a site where the
atoms gave the largest RMSD among all kinds of atoms con- lowest unoccupied orbital is localized is a good electrophilic
tained by I, II, and III. A more detailed comparison between site. The frontier molecular orbitals of I–III were further
the B3LYP-optimized geometries and the X-ray measured investigated in this study and the highest occupied

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
11
Figure 10. The frontier orbitals of I, II, and III (the isovalue ¼ 0.02; carbon in gray, nitrogen in blue, oxygen in red, and hydrogen in white).
molecular orbital (HOMO) and lowest unoccupied molecular transparent so the molecular moiety can be visualized in a
similar orientation for all of the structures around which they
were calculated. The 3D dnorm surface can be used to identify
very close intermolecular interactions. The value of dnorm is
negative (positive) when intermolecular contacts are shorter
(longer) than the van der Waals radii. The dnorm value is
mapped onto the Hirshfeld surface by red, white or blue col-
ors. The red regions represent closer contacts with a nega-
tive dnorm value while the blue regions represent longer
contacts with a positive dnorm value. Moreover, the white
orbital (LUMO) are depicted in Figure 10. As shown there, for
I and II, the electronic transition from HOMO to LUMO is
ꢀ
mainly a p!p transition. In contrast, for III, this transition is
mainly an intramolecular charge transfer.
3.4. Hirshfeld surface analyses
The standard resolution molecular Hirshfeld surface (dnorm) of
I–III are depicted in Figure 11. The surface is shown as regions represent contacts equal to the van der Waals

12
J. SEBHAOUI ET AL.
Figure 11. The dnorm Hirshfeld surfaces of I, II, and III (scale for I: –0.6249 ꢃ 1.3681, II: –0.4605 ꢃ 1.2347, and III: –0.2225 ꢃ 1.2619).
separation and have a dnorm value of zero. As depicted in I, II, and III, respectively; while the contribution of HꢄꢄꢄH con-
tacts to the intermolecular interactions were 43.5%, 46.7%,
and 44.3% for I, II, and III, respectively. Although I–III con-
tain nitrogen, no NꢄꢄꢄH hydrogen bonds were found experi-
mentally and from the fingerprint plots, the NꢄꢄꢄH contact
contributions to the intermolecular interactions were 0.3%,
0.4%, and 0.6% for I, II, and III, respectively, so can
be ignored.
Figure 11, the important interactions among the title com-
pounds may be HꢄꢄꢄO hydrogen bonds. To obtain more
detailed information about the intermolecular interactions,
the 2D fingerprint plots for I–III were also investigated in
this study.
The 2D fingerprint plots highlight particular atom pair
contacts and enable the separation of contributions from dif-
ferent interaction types that overlap in the full fingerprint.
Using the standard 0.6–2.6 view with the de and di distance
scales displayed on the graph axes and including the recipro-
cal contacts, we found the most important interaction involv-
ing hydrogen in the title compounds was the HꢄꢄꢄH contact
3.5. Molecular docking and dynamics studies for I, II,
and III
Molecular docking studies can help to understand the bind-
(Figure 12). The contributions of the HꢄꢄꢄO contacts to the ing interaction mechanism of protein/drug complexes
intermolecular interactions were 26.2%, 32.4%, and 36.4% for (Karthikeyan et al., 2019a, 2019b). The target tyrosine-kinase,

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
13
Figure 12. The 2 D fingerprint plot of the title compound (a) full, (b) resolved by the HꢄꢄꢄO contacts, (c) resolved by the HꢄꢄꢄH contacts, (d) resolved by the
HꢄꢄꢄO contacts.
Janus kinase 2 (JAK2), was chosen based on data from the treatment of myeloproliferative disorders. Hence, the molecu-
Swiss target online server. The major function of JAK2 is lar docking studies were carried out between compounds I,
focused in the signal transduction pathways mediated by the II, and III with tyrosine-protein kinase JAK2. The induced fit
cytokines, as well pyrrole inhibitors of JAK2 as possible docking result shows that there is good binding affinity

14
J. SEBHAOUI ET AL.
Figure 13. The ligand interaction diagram of (a) I, (b) II and (c) III in JAK2 complex.
between compounds I, II, and III within the JAK2 enzyme. 50 ns in the protein molecule environment. Root mean
Based on these studies, the glide energies for compounds I, square deviation (RMSD) and root mean square fluctuation
II, and III are –33.03, ꢅ45.81 and –46.03 kcal/mol, respect- (RMSF) values for the protein–ligand complex were obtained
ively. The best binding complexes were chosen based on the to probe the protein molecule conformation and backbone
glide energy and further subjected for interaction analysis as atom deviations during the simulation of the protein–ligand
shown in Figure 13. As depicted in Figure 13, I is forming complex system.
two hydrogen bonds with the hydrophobic LEU932 residue,
Figure 14 shows the RMSD results of I, II and III com-
II shows one hydrogen bonding formation with the same plexes with the JAK2 enzyme. In general, RMSD changes on
residue and III forms one hydrogen bond contact with the the order of 1–3 Å is acceptable for small or globular protein
negatively charged ASP994 residue. Further, a molecular and the RMSD results obtained for these three complexes
dynamics (MD) analysis was carried out for the best docked within JAK2 show that these compounds converged well in
complex to understand the stability of the complex during the JAK2 environment.

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
15
Figure 14. RMSD of compound (a) I, (b) II and (c) III complex with JAK2.
Figure 15 presents the RMSF plot for the Ca and back- 1.0 suggest that possibility of two or more contact and
bone atoms of the JAK2 enzyme complexes with I, II and III which is correlated with docking studies. In the case of com-
with the green color indicating the active site residue con- pound II which is near 1.0 and in compound III the contact
tacts. The protein–ligand contacts are also monitored around 0.3 and also LEU983 contributes 50% of hydropho-
through the simulation and those interactions are shown in bic. Also, Figure S2 and Figure 16 give more detailed infor-
Figure S1, from the values of 0.7 suggest that 70%. mation of the ligand–protein contacts during the 50 ns
Figure S1 cleared that after the MD simulations LEU932 simulation which also confirms the role of LEU932 residue in
were stable contact with compound I 100%, the value over all three complex systems.

16
J. SEBHAOUI ET AL.
Figure 15. The RMSF plot of compound (a) I (b) II and (c) III complex with JAK2.
presence of acetic anhydride. In the present reaction, N-
acetyl-N-(O-acetamidophenyl)-amino-6-methyl-pyran-2-one
II and 5-acetyl-N-acetyl-N-(O-acetamidophenyl)-amino-6-
methyl-pyran-2-one III can be easily obtained and may
present excellent precursors for the synthesis of other
4. Conclusion
In summary, we have found a novel method for 2-pyrone
and a 1-acetylbenzimidazolone synthesis by rearrange-
ment of the diazepine ring of a benzodiazepine in the

JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS
17
Figure 16. The post-MD simulation ligand interaction plot of compound (a) I, (b) II and (c) III complex with JAK2.
heterocycles. The molecular docking results indicate that behaviour than I. Molecular dynamics analysis also indi-
all three molecules have good binding affinity with the cates that all three compounds are stable in the JAK2 sys-
JAK2 enzyme and based on glide energies and active site tem, and that compounds II and III show more stability
residues, compounds II and III show better inhibitory than I.

18
J. SEBHAOUI ET AL.
dynamics simulation and evaluation of the anticorrosion performance
of a new pyrazolotriazole derivative. Journal of Molecular Structure,
1176, 290–297. https://doi.org/10.1016/j.molstruc.2018.08.107
El Bakri, Y., Lai, C.-H., Sebhaoui, J., Ali, A. B., Ramli, Y., Essassi, E. M., &
Mague, J. T. (2018). Synthesis, crystal structure, Hirshfeld surface ana-
lysis, and DFT calculations of new 1-[(1-benzyl-1H-1, 2, 3-triazol-4-yl)
methyl]-6-methoxy-1H-benzimidazol-2 (3H)-one. Chemical Data
Collections, 17–18, 472–482. https://doi.org/10.1016/j.cdc.2018.11.008
Fairlamb, I. J. S., Marrison, L. R., Dickinson, J. M., Lu, F.-J., & Schmidt, J. P.
(2004). 2-Pyrones possessing antimicrobial and cytotoxic activities.
Bioorganic & Medicinal Chemistry, 12(15), 4285–4299. https://doi.org/
10.1016/j.bmc.2004.01.051
Acknowledgements
The authors gratefully acknowledge Mohammed V University (Morocco)
for the facility for this study. We also thank the National Center for
High-Performance Computing (Taiwan) for providing computing time.
Special thanks are also due to the reviewers and the editor for their
helpful suggestions and comments.
Disclosure statement
No potential conflict of interest was reported by the authors.
Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A.,
Cheeseman, J. R., Scalmani, G., Barone, V., Mennucci, B., Petersson,
G. A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H. P., Izmaylov, A. F.,
Bloino, J., Zheng, G., Sonnenberg, J. L., Hada, M., … Fox, D. J. (2009).
Gaussian 09, revision E.01. Gaussian, Inc.
Gfeller, D., Michielin, O., & Zoete, V. (2013). Shaping the interaction land-
scape of bioactive molecules. Bioinformatics (Oxford, England), 29(23),
3073–3079. https://doi.org/10.1093/bioinformatics/btt540
Funding
The support of NSF-MRI Grant #1228232 for the purchase of the diffract-
ometer and Tulane University for support of the Tulane Crystallography
Laboratory are gratefully acknowledged.
Harris, T. M., & Harris, C. M. (1966). Carboxylation of b-dicarbonyl com-
pounds through dicarbanions. Cyclizations to 4-hydroxy-2-pyrones.
The Journal of Organic Chemistry, 31(4), 1032–1035. https://doi.org/10.
1021/jo01342a010
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