Convenient synthesis of linear 2H,6H-pyrano[3,2-g] chromenes from natural occurring compound; visnagin

Article abstract of DOI:10.1080/00397911.2019.1671455

A simple and convenient rout for the synthesis of linear 2-imino-2H,6H-pyrano[3,2-g] chromene-6-ones and 2H,6H-pyrano[3,2-g]chromene-2,6-diones has been described starting from natural occurring furochromone; visnagin (1). Ring opening of 1 yielded 6-form

Full text of DOI:10.1080/00397911.2019.1671455

Synthetic Communications
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Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Convenient synthesis of linear 2H,6H-pyrano[3,2-g]
chromenes from natural occurring compound;
visnagin
Anhar Abdel-Aziem, Eslam R. El-Sawy & Gilbert Kirsch
To cite this article: Anhar Abdel-Aziem, Eslam R. El-Sawy & Gilbert Kirsch (2019): Convenient
synthesis of linear 2H,6H-pyrano[3,2-g] chromenes from natural occurring compound; visnagin,
Synthetic Communications, DOI: 10.1080/00397911.2019.1671455
To link to this article: https://doi.org/10.1080/00397911.2019.1671455
Published online: 06 Oct 2019.
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https://doi.org/10.1080/00397911.2019.1671455
Convenient synthesis of linear 2H,6H-pyrano[3,2-g]
chromenes from natural occurring compound; visnagin
a
b,c
c
ꢀ
ꢀ
Anhar Abdel-Aziem , Eslam R. El-Sawy , and Gilbert Kirsch
a
ꢀ
ꢀ
ꢀ
ꢀ
Faculty of Science (Girl’s Branch), Departement of Chemistry, Al-Azhar Universite, Cairo, Egypt;
Chemistry of Natural Compounds Departement, National Research Centre, Dokki-Giza, Egypt;
Laboratoire Lorrain de Chimie Moleculaire (L.2.C.M.), Universite de Lorraine, Lorraine, France
b
c
ꢀ
ABSTRACT
ARTICLE HISTORY
Received 2 September 2019
A simple and convenient rout for the synthesis of linear 2-imino-
2H,6H-pyrano[3,2-g] chromene-6-ones and 2H,6H-pyrano[3,2-g]chro-
mene-2,6-diones has been described starting from natural occurring
furochromone; visnagin (1). Ring opening of 1 yielded 6-formyl-7-
KEYWORDS
Anticancer activity;
chromone; coumarine;
2H,6H-pyrano[3,2-g]chro-
mene; visnagin
hydroxy-5-methoxy-2-methylchromone
(2),
which
underwent
reaction with different acetonitrile derivatives furnished 2-imino-
2H,6H-pyrano[3,2-g] chromene-6-ones (5a–h). Acid hydrolysis of
5a–h led to the formation of 2H,6H- structures pyrano[3,2-g]chro-
mene-2,6-diones (6a–h). Structures of the synthesized compounds
were clarified based on their elemental analyses and spectral data.
The entire target compounds were selected for in vitro anticancer
activity against 60 human cancer cell lines at a single dose (10ꢁ5 M)
by the National Cancer Institute (NCI, Bethesda, USA).
GRAPHICAL ABSTRACT
X
Introduction
It is well known that both chromones and coumarins possess pronounced biological
activity.[1] Chromone and its derivatives are naturally occurring compounds everywhere
exist in the plant kingdom, and therefore, present in representative amounts in the nor-
mal human diet.[2] The chromone and its derivatives possess numerous of biological
activities such as anti-inflammatory,[3] antifungal,[4] antibacterial,[5] antiviral,[6]
ꢀ
Chemistry of Natural Compounds Departement, National
CONTACT Eslam R. El-Sawy
Research Centre, El-Behoos St. 33, Dokki-Giza, Egypt.
eslamelsawy@gmail.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
ꢀ
These authors contributed equally to this work.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
A. ABDEL-AZIEM ET AL.
Scheme 1. Synthesis of 2H,6H-pyrano[3,2-g]chromene derivatives; reagents and conditions: (i) 10%
H2SO4, 10% K2Cr2O7, 70–80 ꢂC; (ii) EtOH, piperidine (2 drops), stirring, 15 min and/or piperidine (2
drops), grinding, 5 min; (iii) 10% HCl, stirring, 1–2 min.
antitumour and anticancer.[7] On the other hand, coumarin the basic molecule of the
simplest natural occurring phenolic substance that possessing fused benzene and
a-pyrone rings.[8] The coumarins occur in a diversity of forms, due to the numerous
substitutions possible in their basic structure, which alter their biological activity.[9]
Coumarins possess anti-inflammatory,[10] antioxidant,[11] hepatoprotective,[12] anti-
viral,[13] antimicrobial[14] and anti-carcinogenic effects.[15] Some coumarins can be
obtained based on chromone derivatives.[16] Starting from 6-formyl-7-hydroxy-5-
methoxy-2-methylchromone a new coumarin derivative, namely 3-acetyl-5-hydroxy-8-
methyl-2,6-dioxo-2H,6H-benzo[l,2-b:5,4-b0]dipyran has been created.[16] We are,
therefore, searching for such heterocyclic systems that combine chromone and coumarin
moieties namely 2H,6H-pyrano[3,2-g]chromene starting from natural occurring furo-
chromone; visnagin to be exploited for further diversification and screened for anti-
cancer activity.
Results and discussion
In this investigation, we report the synthesis of linear 2-imino-2H,6H-pyrano[3,2-
g]chromene-6-ones and 2H,6H-pyrano[3,2-g]chromene-2,6-diones as summed up in
Scheme 1. 6-Formyl-7-hydroxy-5-methoxy-2-methylchromone (2) was used as the start-
ing material, 2 was obtained by potassium dichromate oxidation of the naturally occur-
ring furochromone; visnagin (1).[17]
Kenovenagel condensation of 2 with some prepared nitrile derivatives possessing an
active methylene group 3a-h, namely 3-oxo-3-phenylpropanenitrile (3a),[18] 3-(benzo-furan-
2-yl)-3-oxopropanenitrile
(3b),[19,20]
3-(5-bromobenzofuran-2-yl)-3-oxopropane-nitrile

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Table 1. Linear 2H,6H-pyrano[3,2-g]chromenes 5a–h and 6a–h.
R
5a-h
5a
6a-h
6a
5b
5c
5d
6b
6c
6d
5e
5f
6e
6f
5g
6g
5h
6h
(3c),[21] 3-(1H-indol-3-yl)-3-oxopropanenitrile (3d),[22] 2-(benzo[d]thiazol-2-yl) acetonitrile
(3e),[23] 2-(2-phenylthiazol-4-yl)acetonitrile (3f),[24] 2-(2-(benzo-furan-2-yl) thiazol-4-yl)ace-
tonitrile (3g) and 2-(2-(2-oxo-2H-chromen-3-yl)thiazol-4-yl) acetonitrile (3h),[25] respect-
ively, under stirring in presence of piperidine led to the formation of 3-substituted-2-
imino-5-methoxy-8-methyl-2H,6H-pyrano[3,2-g] chromen-6-one (5a–h) (Table 1).
Compounds 5a–h were also formed when the reaction was carried out in presence of 2

4
A. ABDEL-AZIEM ET AL.
drops of piperidine under grinding for 5 min; which gave products identical in all aspects
(mp, admixed mp) with no difference in their yields.
It was difficult to dissolve most of the target compounds even in DMSO or TFA in
order to elucidate their structures. Accordingly, the target compounds have ascertained
based on their elemental analysis and IR spectra. A few of compounds were elucidated
1
based on their H NMR and ESI (LC-MS) spectra.
Compounds 5a–h were subjected to hydrolysis via their reaction with 10% of hydro-
chloric acid under stirring to furnish 2H,6H-pyrano[3,2-g]chromene-2,6-diones 6a–h
(Scheme 1, Table 1). Most of compounds 6a–h experiences the same behavior as the
first compounds 5a–h, where they’re not dissolved even in DMSO or TFA. Accordingly,
the target compounds were ascertained on the basis of their elemental analysis and IR
spectra. A few of compounds have elucidated based on their 1H NMR and ESI
(LC-MS) spectra.
Evaluation of in vitro anticancer activity
The newly synthesized compounds were selected by the National Cancer Institute,
(NCI, Bethesda, Maryland, USA), to be evaluated in vitro towards a panel of the
approximately 60 human tumors cell lines; derived from the nine different cancer types
including leukemia, breast, ovarian, prostate, non-small cell lung, colon, CNS, melan-
oma and renal cancers at a single concentration of (10ꢁ5 M).[26–28] The results are
summed up in Table S1 (Supporting Information) as growth inhibition percent (GIP)
and delta values. The result indicate that, compounds 5d, 5e, 6e, 6c and 6f showed
mild activity with growth inhibition (GI) of 28.90, 28.98, 27.29, 25.39 and 28.52%,
respectively on the Renal Cancer UO-31; whereas 6b showed moderate activity toward
the same cancer cell with growth inhibition (GI) of 35.7%. Besides, compounds 5d
exerted moderate growth inhibition (GI) activity towards Non-Small Cell Lung Cancer
(HOP-92) by 31.64%. In addition, compound 6e showed moderate growth inhibition
(GI) activity against Melanoma (UACC-62) by 32.28%. The rest of the tested com-
pounds showed little to no effect on the human cancer cells under investigated.
Experimental
All reagents and solvents were of commercial grade. Visnagin 1 has been purchased
from Chemical industries development CID, Giza (Egypt). Melting points were deter-
mined on the digital melting point apparatus (Electro thermal 9100, Electro thermal
Engineering Ltd, serial No. 8694, Rochford, United Kingdom) and were uncorrected.
Elemental analyses were performed on CHNS-O analyzer (Perkin-Elmer, USA) and
were found within 0.4% of the theoretical values.1H and 13C NMR spectra were meas-
ured with a Bruker Avance spectrometer (Bruker, Germany) at 400 and 101 MHz,
respectively, using TMS as the internal standard. Hydrogen coupling patterns are
described as (s) singlet, (d) doublet, (t) triplet, (q) quartet and (m) multiplet. The chem-
ical shifts were defined as parts per million (ppm) relative to the solvent peak. The
mass spectra (ESI) were measured with Liquid Chromatography Mass Spectrometry
(LC-MS) using Multimode Source for 6100 Series Single Quad LC/MS. The reaction

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5
progress was checked by pre-coated TLC Silica gel 0.2 nm F254 nm [Fluka], visualized
under UV lamp 254 and 365 nm.
General procedure for the preparation of 3-substituted-2-imino-5-methoxy-
8-methyl-2H,6H-pyrano[3,2-g]chromen-6-one (5a–h)
Method 1
To a mixture of 2 (0.23 g, 1 mmol) and the appropriate acetonitrile derivatives 3a–h
(1 mmol) in ethanol (5 ml), was added two drops of piperidine under stirring at room
temperature. After 10–15 min, the precipitate that formed was collected by filtration,
then crystallized from N,N-dimethylformamide to obtain pure products.
Method 2
A mixture of 2 (0.23 g, 1 mmol) and the appropriate acetonitrile derivatives 3a–h
(1 mmol) containing two drops of piperidine was ground in a mortar with a pestle at
room temperature for 2–3 min. After 5 min, a drop was taken out of the reaction mix-
ture and dissolved in acetone to follow the progress of the reaction using TLC. After
completion of the reaction, the mixture was transferred by ethanol then filtered off. The
obtained solid was crystallized from N,N-dimethylformamide to obtain pure products.
2-Imino-5-methoxy-8-methyl-3-(2-phenylthiazol-4-yl)-2H, 6 H-pyrano[3,2-g]chro-
men-6-one (5 h)
Dark brown powder; yield 70%; mp 221-3 ꢂC; FT-IR (KBr, v cmꢁ1) 3262 (NH), 1714,
1
1667 (2C ¼ O), 1618 (C ¼ N), 1588 (C ¼ C); H NMR (400 MHz, CDCl3) d: 8.90 (s, 1H,
NH), 8.04 (s, 2H), 7.69 (s, 1H), 7.50 (t, J ¼ 7.6 Hz, 2H), 7.40 (s, 1H), 7.28 (s, 1H), 6.94
(s, 1H), 6.09 (s, 1H), 4.10 (s, 3H, OCH3), 2.37 (s, 3H, CH3); HRMS (ESI): m/z
[M þ Na]þ calcd for C23H16N2O4S (416.45); found: 416.8; Anal Calcd for C23H16N2O4S:
C, 66.34; H, 3.87; N, 6.73; S, 7.70; found: C, 66.30; H, 3.85; N, 6.69; S, 7.61.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by grant from the French Embassy in Egypt (Institut Franc¸ais
ꢀ
ꢀ
d’Egypte) and Universite de Lorraine, Laboratoire Lorrain de Chimie Moleculaire (L.2.C.M.),
Metz, France.
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