New 2-pyrone-based hydrazones: Synthesis, spectral characterisation, UV–visible study and evaluation of the antiradicalar activity

Article abstract of DOI:10.1080/00397911.2016.1276602

The synthesis of new 2-pyrone-based hydrazones has been prepared by the coupling of 6-methyl-2H-furo[3,2-c]pyran-3,4-dione with diazonium salts, obtained by diazotization of aniline derivatives. The structure of all compounds was established by spectrosco

Full text of DOI:10.1080/00397911.2016.1276602

New 2-Pyrone-Based Hydrazones: Synthesis, spectral Characterisation, UV-visible
Study and Evaluation of the Antiradicalar Activity
Djamila Oukacha-Hikem1,2, Malika Makhloufi-Chebli1,2, Anissa Amar3,4, Houria
Bouherrou2, Yahia Rachedi2, Hacène Meghezzi4, Artur M. S. Silva5,, Maamar Hamdi2
1Laboratoire de Physique et Chimie des Matériaux LPCM, Faculté des Sciences,
Université Mouloud Mammeri, Tizi-Ouzou, Algeria, 2Laboratoire de Chimie Organique
Appliquée (Groupe Hétérocycles), Faculté de Chimie, Université des Sciences et de la
Technologie Houari Boumediène, Alger, Algeria, 3Département de Chimie, Université
Mouloud Mammeri, Tizi-Ouzou, Algeria, 4Laboratoire de Thermodynamique et
Modélisation Moléculaire, Faculté de Chimie, Université des Sciences et de la
Technologie Houari Boumediène, Alger, Algeria, 5QOPNA, Department of Chemistry,
University of Aveiro, Aveiro, Portugal
Abstract
The synthesis of new 2-pyrone-based hydrazones have been prepared by the coupling of
6-methyl-2H-furo[3,2-c]pyran-3,4-dione with diazonium salts, obtained by diazotization
of aniline derivatives. The structure of all compounds was established by spectroscopic
methods and the structure of the more stable conformer was theoretically confirmed by
potential energy profile analysis. The prepared 2-pyrone-based hydrazones dyes were
acetylated and both groups of compounds showed moderate to good radical scavenging
activity (DPPH).
Graphical Abstract:
1

KEYWORDS: Pyran-2-ones, Diazonium salts, Hydrazones, Theoretical calculations,
Antiradicalar activity
1. INTRODUCTION
Hydrazones and their derivatives constitute a versatile class of compounds in organic
chemistry and they are characterized by the presence of –NH–N=CH– group in their
molecules [1-2]. These compounds have interesting biological properties, such as anti-
inflammatory, analgesic, anticonvulsant, antituberculosis, antitumor, anti-HIV and
antimicrobial activity [3-6]. Hydrazones are also important compounds for drug design,
as possible ligands for metal complexes, organocatalysis, and also for the syntheses of
heterocyclic compounds [7-9]. Due to these important potential applicatiions, hydrazones
have been under study for a long time, but much of their basic chemistry remains
unexplored. On the other hand, the presence of heterocyclic rings in many synthetic
hydrazones plays a main role in their pharmacological properties [8].
2-Pyrones demonstrate a whole spectrum of biological properties, such as antibiotic,
antifungal, cytotoxic, neurotoxic, and phytotoxic activities. Simple change in the
substitution pattern on the 2-pyrone ring often leads to compounds possessing new
biological activity. Indeed, some of the 4-alkyl/aryl/alkenyl/hydroxy-substituted-6-
methyl-2-pyrones show remarkable biological effects, such as antimicrobial activity,
human chronic myelogenous leukemia, and human ovarian carcinoma inhibitory
properties [10-20].
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The afore mentioned biological activities of hydrazone and 2-pyrone derivatives led us to
prepare some dyads by the coupling of 6-methyl-2H-furo[3,2-c]pyran-3,4-dione with
diazonium salts and to evaluate their radical scavenging activity (DPPH radical).
2. RESULTS AND DISCUSSION
6-Methyl-4H-furo[3,2-c]pyran-3,4(2H)-dione 3 is obtained by the reaction of 3-(2-
bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one 2 with aliphatic amines [21]. The
required α-haloketone 2 is easily obtained via the selective α-monobromination of
dehydroacetic acid (DHAA) 1 in 70% yield according to a known procedure (Scheme 1)
[21, 22].
The coupling of diazonium salts, obtained by diazotization of aniline derivatives in
presence of sodium nitrite and concentrated hydrochloric acid, with pyran-3,4-dione 3 in
the presence of sodium acetate gives (E)-6-methyl-2-(2-phenylhydrazono)-4H-furo[3,2-
c]pyran-3,4(2H)-diones 4a,b in moderate to good yields (51-60%) (Scheme 2).The
structure of these dyes may exist in four possible tautomeric forms, namely hydrazone-
anti T1, hydrazone-synT2, azo-keto T3 and azo-enol T4 (Scheme 3).
The 1H NMR spectra of pyran-3,4(2H)-diones 4a,b showed the presence of singlet signal
at 11.2 ppm, which fits with a strongly deshielded chelated NH or OH proton. As so, it
can be suggested that these dyes exist as the hydrazone T1 or azo-enol T4 forms.
However the former hydrazone T1 form is amply confirmed using HSQC and HMBC
3

correlations (NH C-1’ and C-2’,6’). The referred intramolecular hydrogen bond
implies that pyran-3,4(2H)-diones 4a,b present a (E)-configuration.
Determination of energy barriers of the hydrazone form to internal rotation has been
made possible by quantum chemical methods. Contributions from steric and electrostatic
attractive and repulsive interactions become important in determining the rotational
barrier and equilibrium conformation when the molecule is substituted with various
groups.
Conformational analysis of the obtained product 4a was carried out at the PBE1PBE [23]
level combined with the LANL2DZ [24] basis set, using Gaussian 09 [25] program, in
order to determine the most stable isomer. Note that the nature of the different isomers
relative to the N-N bond was confirmed by the frequencies calculation of the normal
modes of vibration. The most stable structure is determined by rotating the phenyl group
along N-N bond using the dihedral angle C-N-N-C; the more stable structure belongs to
the minimum in the potential energy surface. The initial value of the dihedral angle C-N-
N-C was set to 180° and for every 1° the energies of the isomers are determined. The
obtained potential energy surface is presented in Figure 1. In addition, the (E)- and (Z)-
isomers/N-N bond of the hydrazone form of pyran-3,4(2H)-diones 4a,b with the relative
energy are shown in Figure 2. The (E)-isomer (A) with a C-N-N-C dihedral angle equal
to 180° is found to be more favoured relatively to the (Z)-isomer (B) with C-N-N-C of 0°
by 15.67 kcal/mol. It is worth noting that for (E)-isomer, an intramolecular hydrogen
bond exists between respectively carbonyl group of the furanone and NH of the
4

hydrazone moiety, which is responsible for the higher stability of this structure. The
distance between atoms O···H‒ N equals 1.95Å, which supports stabilizing of the
investigated compounds in the form of the (E)-isomer relative to the N-N bond. Indeed,
NBO analysis (Natural Bond Orbital) [26] indicate a significant hydrogen bond type
interaction between LP(O) and ϭ *(N–H), with a stabilization energy E2 of 8.61 kcal/mol.
In the other hand, steric repulsion effects between the phenyl ring and the rest of the
molecule destabilize the (Z)-isomer compared to the (E)-one.
In addition, (E)/(Z)-isomerism of the C=N bond of 4a have been analysed using the same
level of theory considering the most stable (E)-isomer relative to the N-N bond (A). A
recent study of Maiorova et al. [9] on similar compounds have shown that these types of
isomerism are related and depend substantially on the structural fragments in the
hydrazone molecule, namely in the introduction of additional substituents containing
heteroatoms and double bonds capable of participating in the formation of intramolecular
hydrogen bonds. The PBE1PBE/LANL2DZ results indicate that the (E)-isomer/C=N
bond (A’) is slightly less stable than the (Z)-isomer/C=N bond (A) (Figure 2) by 4.06
kcal/mol. These results show the importance of the intramolecular hydrogen bond in the
stability of these compounds.
The UV-vis absorption spectra of azo dyes 4a,b were recorded immediately after product
dissolution in various solvents at a concentration of 10−6 M in the range 260-600 nm. The
absorption maxima of these azo compounds in various organic solvents are given in
Table 1 and also presented in Figure 3 and 4 respectively.
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The absorption spectra of 4a, showed an intense absorption maxima in DMSO, which
mean that the latter is present in only one tautomeric form. In toluene, chloroform,
methanol acetonitrile and acetic acid, they exhibit two absorption maxima; indicate the
presence of two tautomeric forms. For the compound 4b only one absorption wavelength
was observed in all the solvents. Except in the chloroform, two wavelengths were
observed. As shown in Table 1, the electronic absorption spectra of the two studied
compounds in different polar aprotic solvents did not significantly change. Strong
evidence that this dyes exist in equilibrium is provided by the two absorption maxima and
isobestic points in the visible spectra of (Figure 3). This equilibrium may exist between
tautomeric forms.
NH-function of the pyran-3,4(2H)-diones 4a,b has been acetylated with acetic anhydride
leading to the formation of N-acetyl-hydrazones 5a,b (Scheme 2). The structure of these
acetyl derivatives is confirmed by IR, 1H and 13C NMR, and mass spectra and in an
indirect way confirms the structure of the starting materials 4a,b.
2.4 Antiradicalar Activity
The 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) is a stable free radical, which has
been widely accepted as a tool for estimating the free radical scavenging activities of
potential antioxidants [27, 28]. The lower IC50 value indicates a stronger ability of the
tested compound to act as a DPPH scavenger while the higher IC50 value indicates a
lower scavenging activity of the scavengers. On electron or hydrogen reception the
6

purple colour of DPPH radical fades or disappears due to its conversion to 2,2-diphenyl-
1-picrylhydrazine resulting in decrease in absorbance at λ 517 nm. The more decrease the
absorption in the presence of scavengers the more effective is its radical scavenging
activity. Herein the antiradicalar activity of compounds 1-5 was expressed as IC50 (Figure
5). The IC50 values vary between 38.91 and 24.09 μg/mL for compounds 1-5 while
butylhydroxytoluene (BHT, positive control) presented a value of 10.46 μg/mL. After the
acylation of NH group in 4a,b the scavenging activity of 5a,b increased. This seems
indicate that the radical scavenging activity of compounds 5a,b is due to an electron
donating mechanism and not an hydrogen donating mechanism since there no hydrogen
atoms to be given [29].
3. CONCLUSION
New 2-pyrone-based hydrazones 4a,b have been prepared by the coupling of 6-methyl-
2H-furo[3,2-c]pyran-3,4-dione with diazonium salts and then acetylated with acetic
anhydride giving the acetyl-2-pyrone-based dyes 5a,b. The structure of the more stable
isomer of the 2-pyrone-based hydrazone 4a was confirmed theoretically using the
PBE1PBE/LANL2DZ level of theory. The calculated potential energy profile indicates
the stability of the hydrazone (E)-isomer by 15.67 kcal/mol over the (Z)-one. The
obtained results showed the importance of the intramolecular hydrogen bond in the
stability of these compounds. The acetyl-2-pyrone-based hydrzones 5a,b presented good
DPPH radical scavenging activity.
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4. EXPERIMENTAL
4.1. Materials And Method
Melting points were determined on a Stuart scientific SPM3 apparatus fitted with a
microscope and are uncorrected. 1H and 13C NMR spectra were recorded in CDCl3 or
DMSO-d6 solutions on a Bruker Avance 300 (300.13 MHz for 1H and 75.47 MHz for
13C) spectrometer. Chemical shifts are reported in ppm ( ) using tetramethylsilane (TMS)
as internal reference and coupling constants (J) are given in Hz. 13C assignments were
made using gradient selected heteronuclear single quantum coherence (gHSQC) and
gradient selected heteronuclear multiple quantum coherence (gHMBC) (delays for one
bond and long-range JC/H couplings were optimized for 145 and 7 Hz, respectively)
experiments. Positive-ion electrospray ionization (ESI) mass spectra were acquired using
a QTOF 2 instrument [diluting 1 µL of the sample chloroform solution ( 10-5M) in 200
µL of 0.1% trifluoroacetic acid/methanol solution. Nitrogen was used as nebulizer gas
and argon as collision gas. The needle voltage was set at 3000 V, with the ion source at
80°C and desolvation temperature at 150°C. Cone voltage was 35 V]. Infrared spectra
(KBr) were determined as KBr pellets of the solids on a Magna- IR 550 series II Nicolet
apparatus. UV spectra were recorded on Cary 50 Scan UV–vis spectrometer in
acetonitrile solutions.
4.2. Synthesis Of (E)-6-Methyl-2-(2-Phenylhydrazono)-4H-Furo[3,2-C]Pyran-
3,4(2H)-Diones 4a,B.
The appropriate aromatic amine (5 mmol) was dissolved in HCl (20 mL, 10%) and
cooled in an ice-salt bath to 0−5°C. The mixture was then added in portions to a cold
8

solution of NaNO2 (345 mg, 5 mmol) in water (20 mL) and stirred for 30 min. This
diazonium salt solution was added to a vigorously stirring solution of 6-methyl-4H-
furo[3,2-c]pyran-3,4(2H)-dione 3 (830 mg, 5 mmol) in sodium acetate (4.1 g, 50 mmol)
and water (20 mL). The reaction mixture stirred for 4 h. The coloured products obtained
were filtered, washed with water, dried and then recrystallized from ethanol.
(E)-6-Methyl-2-(2-phenylhydrazono)-4H-furo[3,2-c]pyran-3,4(2H)-dione 4a: Brown
powder (0.81 g, 60%). mp 135°C; IR: ( ) 3100, 3350, 2980, 1750, 1640, 1574, 1515,
1425, 1350, 750 cm-1; 1H NMR (DMSO-d6): 2.29 (s, 3H, 6-CH3), 6.74 (s, 1H, H-7),
7.50-7.53 (m, 3H, H-2’,4’,6’), 7.21-7.24 (m, 2H, H-3’,5’), 11.15 (s, 1H, NH); 13C NMR
(DMSO-d6): 21.1 (6-CH3), 95.8 (C-7), 101.2 (C-3a), 115.8 (C-2’,6’), 120.1 (C-4’),
129.6 (C-3’,5’), 141.7 (C-1’), 155.2 (C-6), 171.9 (C-2), 174.7 (C-4), 184.9 (C-7a), 190.1
(C-3); ESI+-MS: m/z 293 [(M+Na)+, 100], 271 [(M+H)+, 12]. Anal. Calcd. For
C14H10N2O4: C 62.2; H 3.7; N 10.4. Found: C 62.3; H 3.6; N 10.5%.
4.3. Synthesis Of (E)-N'-(6-Methyl-3,4-Dioxo-4H-Furo[3,2-C]Pyran-2(3H)-Ylidene)-
N-Phenylacetohydrazides 5a,B.
A solution of the appropriate (E)-6-methyl-2-(2-phenylhydrazono)-4H-furo[3,2-c]pyran-
3,4(2H)-dione 4a,b (5 mmol) and pyridine (0.01 mL) in acetic anhydride (20 mL) was
refluxed with stirring, for 30 min. After cooling at room temperature, the obtained solid
was filtered and recrystallized from ethanol.
9

(E)-N'-(6-Methyl-3,4-dioxo-4H-furo[3,2-c]pyran-2(3H)-ylidene)-N-phenylacetohydrazide
5a: Brown powder (0.57 g, 37%); mp 178°C; IR: ( ) 2982, 1750, 1640, 1572, 1425,
1368, 750 cm-1; 1H NMR (DMSO-d6): 2.29 (s, 3H, 6-CH3), 2.32 (s, 3H, COCH3), 6.74
(s, 1H, H-7), 7.61-7.64 (m, 3H, H-2’,4’,6’), 7.72-7.78 (m, 2H, H-3’,5’); 13C NMR
(DMSO-d6): 20.6 (6-CH3), 21.1 (COCH3), 95.8 (C-7), 101.2 (C-3a), 120.8 (C-2’,6’),
124.5 (C-4’), 129.6 (C-3’,5’), 138.5 (C-1’), 155.2 (C-6), 168.8 (N-C=O), 171.9 (C-2),
174.7 (C-4), 187.4 (C-7a), 190.1 (C-3); ESI+-MS: m/z 335 [(M+Na)+, 45], 313 [(M+H)+,
100]. Anal. Calcd. For C16H12N2O5: C 61.5; H 3.9; N 8.9. Found: C 61.4; H 3.7; N 8.8%.
ACKNOWLEDGMENTS
Thanks are due to University of Aveiro, FCT/MEC for the financial support to the
QOPNA research Unit (FCT UID/QUI/00062/2013), through national funds and where
applicable co-financed by the FEDER, within the PT2020 Partnership Agreement, and
also to the Portuguese NMR Network. We thank Cristina Barros and Hilário Tavares
(Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal) for
performing the mass and NMR spectra.
Supporting Information: Full experimental detail, 1H and 13C NMR spectra, evaluation
of the free-radical-scavenging activity by using 1,1-diphenyl-2-picryl-hydrazyl radical.
This material can be found via the “Supplementary Content” section of this article’s
webpage.
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Table 1. Influence of solvent on λmax of dyes 4a,b.
Dye
λmax/nm
DMSO ACN
Ethyl
Acetic Methanol
Chloroform Toluene
acetate acid
307
303
351
438
306
352
442
310
348
463
307
346
442
307
351
444
364
360
463
316
460
4a
4b
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Scheme 1. Synthesis of 6-methyl-4H-furo[3,2-c]pyran-3,4(2H)-dione 3.
15

Scheme 2. Synthesis and acetylation of (E)-6-methyl-2-(2-phenylhydrazono)-4H-
furo[3,2-c] pyran-3,4(2H)-diones 4a,b.
16

Scheme 3. Possible tautomeric forms of (E)-6-methyl-2-(2-phenylhydrazono)-4H-
furo[3,2-c]pyran-3,4(2H)-diones 4a,b.
17

Figure 1. PBE1PBE/LANL2DZ calculated potential energy profile of 4a.
18

Figure 2. The (E)/(Z)-isomers of 4a with the relative energies
19

Figure 3. Absorption spectra of dye 4a in various solvents.
20

Figure 4. Absorption spectra of dye 4b in various solvents
21

Figure 5. The DPPH radical scavenging activity (IC50 μg/mL) of compounds 1, 3, 4a,b
and 5a,b.
22