New method for the synthesis of 4-aryl-3,4-dihydro-2H-benzo[g]chromene-2,5,10-triones

Article abstract of DOI:10.1080/00397911.2019.1646286

We report herein a new method for the synthesis of 4-aryl-3,4-dihydro-2H-benzo[g]chromene-2,5,10-triones 4 that proceeds in good yields (74–86%) and mild reaction conditions between readily available 2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]chrom

Full text of DOI:10.1080/00397911.2019.1646286

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
New method for the synthesis of 4-aryl-3,4-
dihydro-2H-benzo[g]chromene-2,5,10-triones
Emna Choura, Marwa Ncir, Emna Maalej, José Marco-Contelles, Lhassane
Ismaili & Fakher Chabchoub
To cite this article: Emna Choura, Marwa Ncir, Emna Maalej, José Marco-Contelles, Lhassane
Ismaili & Fakher Chabchoub (2019): New method for the synthesis of 4-aryl-3,4-dihydro-2H-
benzo[g]chromene-2,5,10-triones, Synthetic Communications
To link to this article: https://doi.org/10.1080/00397911.2019.1646286
View supplementary material
Published online: 30 Jul 2019.
Submit your article to this journal
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1646286
New method for the synthesis of 4-aryl-3,4-dihydro-2H-
benzo[g]chromene-2,5,10-triones
a
b
a,c
d
ꢀ
Emna Choura , Marwa Ncir , Emna Maalej , Jose Marco-Contelles , Lhassane
Ismailie , and Fakher Chabchouba
a
ꢀ
ꢀ ꢀ
ꢁ
ꢀ
Laboratoire de Chimie Appliquee: Heterocycles, Corps Gras et Polymeres, Faculte des Sciences de Sfax,
b
ꢀ
Universite de Sfax, Sfax, Tunisia; Laboratory of Animal Ecophysiology, Sciences Faculty of Sfax,
University of Sfax, Sfax, Tunisia; Laboratoire Materiaux, Traitement et Analyse (LMTA), Institut National
de Recherche et d’Analyse Physico-chimique Technopole, Ariana, Tunisia; Laboratory of Medicinal
Chemistry (IQOG, CSIC), Madrid, Spain; Laboratoire de Chimie Organique et Therapeutique,
Neurosciences Integratives et Cliniques EA 481, Universite Bourgogne Franche-Comte, UFR Sante,
Besanc¸on, France
c
ꢀ
d
e
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ABSTRACT
ARTICLE HISTORY
Received 26 April 2019
We report herein a new method for the synthesis of 4-aryl-3,4-dihy-
dro-2H-benzo[g]chromene-2,5,10-triones 4 that proceeds in good
yields (74–86%) and mild reaction conditions between readily avail-
able 2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene-3-
carbonitriles 1, and formic acid (88%), at reflux for 6 h. In addition,
we have also studied the antioxidant activities using DPPH and total
TAC methods.
KEYWORDS
2-Amino-4-aryl-5,10-dioxo-
5,10-dihydro-4H-benzo[g]-
chromene-3-carbonitriles;
antioxidant activity; 4-aryl-
3,4-dihydro-2H-benzo[g]-
chromene-2,5,10-triones;
88% formic acid
GRAPHICAL ABSTRACT
O
Ar
O
Ar
88% HCO2H
reflux, 6 h
CN
O
NH2
O
O
O
O
1
4
Ar: C6H5 (74%), 4-CH3C6H4 (82%), 3-OCH3C6H4 (74%),
4-ClC6H4 (86%), 2-ClC6H4 (81%), 2,4-Cl2C6H3 (80%),
4-OCH3C6H4 (80%)
Introduction
The benzo[g]chromene-2,5,10-trione is a privileged heterocyclic ring system that has
attracted the interest of several laboratories in the context of the preparation of a-lapa-
chone analogs, giving rise consequently to a number of synthetic methods for the prep-
aration of 4-aryl-3,4-dihydro-2H-benzo[g]chromene-2,5,10-triones(4). Most of these
ꢀ
ꢀ ꢀ
CONTACT Fakher Chabchoub
fakher.chabchoub@yahoo.fr
Laboratoire de Chimie Appliquee: Heterocycles, Corps
ꢁ
ꢀ
ꢀ
Gras et Polymeres, Faculte des Sciences de Sfax, Universite de Sfax, Sfax, Tunisia; Lhassane Ismaili
ꢀ ꢀ
Laboratoire de Chimie Organique et Therapeutique, Neurosciences Integratives et
lhassane.ismaili@univ-fcomte.fr
ꢀ
ꢀ
ꢀ
Cliniques EA 481, Universite. Bourgogne Franche-Comte, UFR Sante, Besanc¸on, France.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
E. CHOURA ET AL.
O
O
Ar
O
Ar
O
O
O
Ar
88% HCO2H
reflux, 6 h
CN
O
CN
CO2H
O
O
NH2
O
O
3
2
1a-g
X
a Ar: C6H5 (74%)
X
O
O
Ar
b Ar: 4-CH3C6H4 (82%)
c Ar: 3-OCH3C6H4 (74%)
d Ar: 4-ClC6H4 (86%)
e Ar: 2-ClC6H4 (81%)
f Ar: 2,4-Cl2C6H3 (80%)
g Ar: 4-OCH3C6H4 (80%)
3
4
O
O
O
O
O
O
CN
4a-g
NH
O
O
O
N
O
5a
6a
Scheme 1. Synthesis of 4-aryl-3,4-dihydro-2H-benzo[g]chromene-2,5,10-triones 4a–g.
approaches are based on multicomponent reactions of the appropriate starting materials,
differing only in the experimental reaction conditions.[1–5]
We report herein a new synthetic method for the preparation of 4-aryl-3,4-dihydro-
2H-benzo[g]chromene-2,5,10-triones (4) obtained by the serendipitous reaction of read-
ily available 2-amino-5,10-dioxo-4-phenyl-5,10-dihydro-4H-benzo[g]chromene-3 carbon-
itriles 1[6] with 88% formic acid (Scheme 1). All compounds 4a–g obtained showed
antioxidant propriety.
Results and discussion
In our current research projects targeted to the synthesis of biologically active fused
pyrimidines,[7] we reacted 2-amino-5,10-dioxo-4-phenyl-5,10-dihydro-4H-benzo[g]chro-
mene-3-carbonitrile (1a) with formic acid, at reflux, with the expectation to obtain 5-
phenyl-3,5-dihydro-4H-benzo[6,7] chromeno[2,3-d]pyrimidine-4,6,11-trione (5a) or 2,5,
10-trioxo-4-phenyl-3,4,5,10-tetrahydro-2H-benzo[g]chromene-3-carbonitrile (6a), as described
by El-Agrody.[8]
Thus, the reaction of compound 1awith 88% formic acid cleanly gave a single prod-
uct in 74% yield, whose exact molecular weight (304.07356; HRMS spectrum), molecular
formula (C19H12O4) resulting from the elemental analysis, and bands at 1792, 1683,
1661 cmꢀ1 in the IR spectrum, led us to conclude that we have not obtained the pre-
sumed compounds 5a or 6a, but 4-phenyl-3,4-dihydro-2H-benzo[g]chromene-2,5,10-tri-
1
one (4a) (Scheme 1). In fact, in the H NMR spectrum of the new compound, in
addition to the expected aromatic protons, we observed signals at d 4.97 (1H),
3.60–3.54 (1H), and 3.27–3.22 (1H), with coupling constants for a typical AMX system,
in good agreement for the proposed structure for compound 4a (see Supplementary
Data). In the 13C NMR spectrum, two signals were observed at d 36.7 and 36.2 corre-
sponding to C4 and C3, respectively, according to the 13C NMR-DEPT experiment. In
summary, the new product 4a would be presumably the result of the acid hydrolysis of

R
SYNTHETIC COMMUNICATIONSV
3
Table 1. % Inhibition radical scavenging activity and IC50 for compounds 4a–g.
Concentrations (mg/mL)
Compounds
62.5
125
250
500
1000
IC50 (lg/mL)
4a
4b
4c
4d
4e
4f
48.00 1.01
45.01 0.65
52.85 0.15
46.00 0.37
45.06 0.22
36.26 0.11
20.26 0.20
89.33 0.25
55.71 1.26
51.14 1.21
58 0.45
50.66 0.58
49.21 0.31
44.06 0.63
34.4 0.25
92.4 0.35
59.57 1.66
54.28 1.26
60.50 0.55
53.35 0.63
51.75 0.47
49.57 0.70
48.26 0.35
93.06 0.60
64.85 2.17
59 1.51
70.00 3.68
61.71 2.47
61.57 1.74
62.85 1.66
55.35 1.08
55.71 1.22
54.71 1.55
96.4 1.56
65.55 0.45
77.50 0.78
59.51 0.52
74.43 0.75
80.52 0.71
230.50 0.84
280.20 0.54
42.45 0.28
61.5 1.13
56.28 0.86
53.35 0.95
51.14 0.80
51.2 0.55
93.33 1.08
4g
VitC
Results are expressed as mean of triplicates standard deviation.
the b-enaminonitrile motif present in precursor of type 1a, leading to intermediate 2a,
whose acid hydrolysis to yield compound 3a followed by decarboxylation would result
in the final lactone 4a. This unexpected transformation prompted us to analyze the
scope and generality of the process. Then, precursors 1b–g[6] were prepared, and sub-
mitted to reaction with formic acid (88%) to give compounds 4b–g in good yields,
whose spectroscopic and analytical values (Supplementary Data) confirmed
their structures.
Antioxidant activity
Few studies have been dedicated to investigate the antioxidant activity of benzochro-
mene derivatives. For this reason we decided to evaluate the antioxidant power of the
compounds synthesizedhere[9–12] against 2,20-diphenyl-1-picrylhydrazyl (DPPH) and
measure their total antioxidant capacity (TAC).
DPPH radical-scavenging activity
The radical scavenging activity of compounds 4a–g, determined by using the free
stable radical DPPH are shown in Table 1, was comparable to the standard values
of ascorbic acid (VITC) (30 min: ascorbic acid IC50¼ 42.45 lg/mL). As shown, low
IC50 values indicate high antioxidant activity. Compounds 4f and 4g demonstrated
moderate antioxidant activity with IC50 values of 240.5 and 280.2 mg/mL, respect-
ively. Among the synthesized compounds, the best antioxidant activity was
observed for compounds 4c and 4a with IC50 value of 59.51 and 65.55 mg/mL,
respectively.
Determination of total antioxidant capacity. Results of the TAC are expressed as lg
equivalents per mL of ascorbic acid (Figure 1), with TAC values in the
180.46–629.34 lg/mL range. The TAC assay describes the possibility of the tested
compound to reduce Mo(VI) to Mo(V), the most potent compound being 4b and
the less powerful agent 4f. The decreasing order in the activity was:
4 b > 4d > 4c > 4a > 4e > 4g > 4f.

4
E. CHOURA ET AL.
Figure 1. TAC of benzochromenes 4a–g. Results are mean values SD from at least three
experiments.
Conclusions
To sum up, a new method for the synthesis of 4-aryl-3,4-dihydro-2H-benzo[g]chro-
mene-2,5,10-triones 4a–g has been discovered, that proceeds in good yields, and mild
conditions, from readily available 2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]-
chromene-3-carbonitriles 1, an unexpected result in view of the previously reported
transformations.[7,8,13,14] Presumably the “quinone” motif in compounds of type 1
makes the critical difference, directing the reactivity via a totally different path.
Experimental part
Melting points were measured on an Electrothermal apparatus. Progress of the reactions
was monitored with thin-layer chromatography (TLC) using aluminum sheets with silica
gel 60 F254 from Merck. Spectra infrared (IR) were recorded on a Perkin-Elmer Paragon
1
FT-IR spectrometer covering field 400–4000cmꢀ1. The spectra of H NMR and 13C
NMR were recorded in solution in CDCl3 or in dimethylsulfoxide (DMSO-d6) on a
Bruker spectrometer (1H at 400 MHz and 13C at 100 MHz). The chemical shifts are
expressed in parts per million (ppm) using tetramethylsilane (TMS) as internal reference.
The multiplicities of the signals are indicated by the following abbreviations: s, singlet; d,
doublet; t, triplet; q, quadruplet; and m, multiplet, and coupling constants are expressed
in hertz. Elemental analysis was performed on Flash EA 1112 ThermoFinnigan (Thermo
scientific, Waltham, MA). High-resolution mass spectrawereobtained at Center Commun
ꢀ
de Spectrometrie de Masse (Lyon, France) on a BrukermicrOTOF-Q II spectrometer
(BrukerDaltonics) in positive electrosprayionization-time of flight.
General procedure synthesis of compounds (4a–g)
In a typical experiment, a solution of 2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4H-ben-
zo[g]chromene-3-carbonitriles (1) (0.001 mol) and formic acid (3 mL, 88%, Aldrich) was

R
SYNTHETIC COMMUNICATIONSV
5
heated under reflux for 6 h. The solid product formed by cooling was filtered, washed
with cold diethyl ether, and dried. Following this protocol, it was possible to synthesize
4-aryl-3,4-dihydro-benzo[g]chromene-2,5,10-triones 4a–g with good yields. All new
compounds showed good analytical and spectroscopic (see Supplementary Material)
agreement with those described in the literature (4a[5], 4b[1], 4c[3], 4d–f[1], 4g[3]).
Antioxidant assays
DPPH radical scavenging activity assay
The antioxidant activity of benzochromene derivatives 4a–g was determined in terms of
hydrogen donating or radical scavenging ability, using the stable radical 1.1-diphenyl-2-
picrylhydrazyl (DPPH), according to method of Kirby and Schmidt.[15] Briefly, 1 mL of
various concentrations (0.06–1.0 mg/mL) of each compound in methanol was mixed
with 1.0 mL of 0.004% methanol solution of the free DPPHꢁ followed by 30 min incuba-
tion at ambient temperature. The absorbance of the resulting solution was recorded
against control at 517 nm using UV spectrophotometer (Thermo electron corporation
USA). The control sample was prepared similarly without test and reference com-
pounds. Ascorbic acid was used as standard antioxidant. The radical scavenging activity
of the tested compounds, expressed as percentage inhibition of DPPH, was calculated
according to the following equation:
ð Þ
Scavenging effect % ¼ ½ðA0 ꢀ A1Þ=A0ꢂ ꢃ 100;
where A0 is the absorbance of the control reaction, and A1 is the absorbance of the test
compound. Percent inhibition after 30 min, was plotted against concentration, and the
equation for the line was used to obtain IC50 value. All determinations were carried out
in triplicate. A lower IC50 value indicates greater antioxidant activity.
Total antioxidant capacity
Total antioxidant capacities of the molecules was determined spectrophotometrically
through phosphomolybdenum method of Prieto et al.[16] This assay is based on the
reduction of MO (VI) to MO (V) by the sample and the subsequent formation of a
green phosphate/MO (V) complex at acidic pH. An aliquot of 0.1 mL of ethanolic sam-
ple solution was mixed with 1 mL of the reagent solution (0.6 M sulfuric acid, 28 mM
sodium phosphate and 4 mM ammonium molybdate). The tubes were capped and incu-
bated in boiling water bath at 95 ꢄC for 90 min. After incubation, the samples were
cooled to room temperature, and the absorbance of the test sample was measured at
695 nm against a blank. Ascorbic acid was used as a reference standard and the TAC
was expressed as micrograms equivalents per mL of ascorbic acid.
1
Supplementary data (experimental details, characterization data, and copies of H and
13C NMR) associated with this article can be found in the online version.
ORCID
Lhassane Ismaili
http://orcid.org/0000-0002-6013-3150

6
E. CHOURA ET AL.
References
[1] Wei, P.; Zhang, X.; Tu, S.; Yan, S.; Ying, H.; Ouyang, P. Bioorg. Med. Chem. Lett. 2009,
19, 828–830. DOI: 10.1016/j.bmcl.2008.12.006.
[2] Khurana, J. M.; Vij, K. Tetrahedron Lett. 2011, 52, 3666–3669. DOI: 10.1016/j.tetlet.2011.
05.032.
[3] Mofakham, H.; Ghadari, R.; Shaabani, A.; Pedarpour, M.; Ghasemi, S. J. Iran. Chem. Soc.
2013, 10, 307–317. DOI: 10.1007/s13738-012-0160-x.
[4] Vajargahy, M. P.; Dabiri, M.; Bazgir, A. J. Iran. Chem. Soc. 2017, 14, 1899–1907. DOI:
10.1007/s13738-017-1129-6.
[5] Yetra, S. R.; Roy, T.; Bhunia, A.; Porwal, D.; Biju, A. T. J. Org. Chem. 2014, 79,
4245–4251. DOI: 10.1021/jo500693h.
[6] Chioua, M.; Serrano, E.; Dgachi, Y.; Martin, H.; Jun, D.; Janockova, J.; Sepsova, V.;
Soukup, O.; Moraleda, I.; Chabchoub, F.; et al. J. Chem. Select. 2018, 3, 461–466. DOI: 10.
1002/slct.201702781.
[7] Cherif, O.; Masmoudi, F.; Allouche, F.; Chabchoub, F.; Trigui, M. Heterocyclic Commun.
2015, 21, 191–194.
[8] Srivastava, S.; Batra, S.; Bhaduri, A. P. Indian J. Chem. 1996, 35B, 602–604.
[9] Shanthi, G.; Perumal, P. T.; Rao, U.; Sehgal, P. K. Indian J. Chem. 2009, 48B, 1319–1323.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
[10] Mladenovic, M.; Mihailovic, M.; Bogojevic, D.; Matic, S.; Niciforovic, N.; Mihailovic, V.;
ꢀ
ꢀ
Vukovic, N.; Sukdolak, S.; Solujic, S. IJMS. 2011, 12, 2822–2841. DOI: 10.3390/
ijms12052822.
[11] Sivaguru, P.; Sandhiya, R.; Adhiyaman, M.; Lalitha, A. Tetrahedron Lett. 2016, 57,
2496–2501. DOI: 10.1016/j.tetlet.2016.04.097.
[12] Abozeid, M. A.; El-Kholany, M. R.; AbdelRahman, A. H.; El-Desoky, E. S. I. Int. J. Org.
Chem. 2018, 5, 1–11.
[13] El-Agrody, A. M.; Emam, H. A.; El-Hakim, M. H.; El-Latif, M. S. A.; Fakery, A. H. J.
Chem. Res. 1997, 9, 320–321. DOI: 10.1039/a608348j.
[14] Bedair, A. H.; Emam, H. A.; El-Hady, N. A.; Ahmed, K. A. R.; El-Agrody, A. M. Farmaco
2001, 56, 965–973. DOI: 10.1016/S0014-827X(01)01168-5.
[15] Kirby, A. J.; Schmidt, R. J. J. Ethnopharmacol. 1997, 56, 103–108. DOI: 10.1016/S0378-
8741(97)01510-9.
[16] Prieto, P.; Pineda, M.; Aguilar, M. Anal. Biochem. 1999, 269, 337–341. DOI: 10.1006/abio.
1999.4019.