A novel synthetic approach to pyran-2,4-dione scaffold production: Microwave-assisted dimerization, cyclization, and expeditious regioselective conversion into β-enamino-pyran-2,4-diones

Article abstract of DOI:10.1016/j.tetlet.2020.152660

Here, we report a novel, green, simple, low-cost, and rapid methodology for the high-yield production of pyran-2,4-dione scaffolds under microwave irradiation. Regio- and stereoselective conversions of β-diketone systems into β-enaminones were achieved us

Full text of DOI:10.1016/j.tetlet.2020.152660

Journal Pre-proofs
A novel synthetic approach to pyran-2,4-dione scaffold production: micro‐
wave-assisted dimerization, cyclization, and expeditious regioselective con‐
version into β-enamino-pyran-2,4-diones
Ahmed A.M. Sarhan, Matti Haukka, Assem Barakat, Ahmed T.A. Boraei
PII:
S0040-4039(20)31171-0
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152660
TETL 152660
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Tetrahedron Letters
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13 October 2020
6 November 2020
11 November 2020
Please cite this article as: Sarhan, A.A.M., Haukka, M., Barakat, A., Boraei, A.T.A., A novel synthetic approach
to pyran-2,4-dione scaffold production: microwave-assisted dimerization, cyclization, and expeditious
regioselective conversion into β-enamino-pyran-2,4-diones, Tetrahedron Letters (2020), doi: https://doi.org/
10.1016/j.tetlet.2020.152660
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A novel synthetic approach to pyran-2,4-dione scaffold
production: microwave-assisted dimerization, cyclization,
and expeditious regioselective conversion into β-enamino-
pyran-2,4-diones
Ahmed A. M. Sarhana,*, Matti Haukkab, Assem Barakatc,d,*,ID, Ahmed T. A. Boraeie,*
aChemistry Department, Faculty of Science, Arish University, Al-Arish 45511, Egypt
bDepartment of Chemistry, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, Finland
cChemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh
11451, Saudi Arabia
dChemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia,
Alexandria 21321, Egypt
eChemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
*Corresponding authors
E-mail addresses: ahmed_sarhan252@yahoo.com (A.A.M.S); ambarakat@ksu.edu.sa (A.B.);
ahmed_tawfeek83@yahoo.com, ahmed_boraei@science.suez.edu.eg (A.T.A.B.)
Abstract
Here, we report a novel, green, simple, low-cost, and rapid methodology for the high-yield
production of pyran-2,4-dione scaffolds under microwave irradiation. Regio- and
stereoselective conversions of β-diketone systems into β-enaminones were achieved using 18
primary amines and four amino acid esters. Microwave-assisted further cyclization of 3-(β-
1

substitutedvinyl)-6-phenyl-pyran-2,4-dione into 3-benzoyl-4,7-diphenyl-2H,5H-pyrano[4,3-
b]pyran-2,5-dione via reaction with ethyl benzoyl acetate.
Keywords
pyran-2,4-dione; microwave; β-enaminones; intramolecular cyclization
Introduction
Pyrone nucleus is extensively found in nature.1–3 Molecules containing pyrone ring exhibit a
wide range of pharmaceutical properties such as cytotoxic,4 antitumor,5,6 and antimicrobial
activity.7 4-Hydroxy-2H-pyran-2-one, is a core structure of triacetic lactone and is utilized as
a building block in synthetic chemistry. Another representative example of pyrone class
compounds, kavalactones, possess many biological activities such as antituberculosis, anti-
inflammatory, analgesic, anticonvulsant, antimalarial, local anesthetic, sleep-inducing, and
sedative activities.8–11 Furthermore, pyrone compounds have been reported to have
pharmacological usefulness as selective COX-2 inhibitors12,13 and HIV protease inhibitors.14–
16. As another representative example, photopyrones occur naturally in Photorhabdus
luminescens; they been investigated as signaling molecules in the cell-cell communication
system of this bacterium.17 Many other compounds in nature have the structural feature of a
pyrone scaffold; indeed, Schäberle18 reported a wide range of biologically active metabolites
in a 2016 review.
Several methods have been reported for the synthesis of 2-pyrones which mostly include an
expensive catalyst. For example 2-pyrones could be obtained from: 3-iodoacrylic acid and
terminal acetylenes using PdCl2(PPh3)2 and CuI,19,20 cyclo-isomerization of 3-ethynyl-indole-
2-carboxylic acid in the presence of gold(III) chloride,21 allenyl propiolates and terminal
2

alkynes catalyzed using gold(I) catalyst,22,23 annulation of alkynes by acrylic acid promoted
by ruthenium(II),24 Baylis-Hillman adducts,25 1,2-allenyl ketones and electron-withdrawing
group substituted acetates using a base catalyst,26,27 and aryl-4,4,4-trifluorobutane-1,3-diones,
PCl5, and sodium diethyl malonate.28
Developing a direct method for the simple, efficient, and green construction of
particular heterocyclic motifs that makes use of available materials remains an ongoing
challenge for chemists from both a synthetic and mechanistic perspective. Among the many
available construction strategies,29–37 microwave-assisted synthesis of heterocyles is perhaps
the most promising. Herein, we introduce a novel and simple method for the synthesis of
substituted pyran-2,4-dione and its conversion into β-enamino-pyran-2,4-diones. Importantly,
this method could be applied to any β-ketoester for the production of biologically and
photochemically active motifs.
Results and Discussion
Microwave-assisted synthesis of a substituted pyran-2,4-dione 1 in one step from ethyl
benzoyl acetate is shown in Scheme 1. When the reaction was conducted under microwave
irradiation without a catalyst, the product was obtained with a chemical yield of <5%; when
acetic acid was used as a promoter, the yield improved to 62%. Compound 1 can exist in four
possible prototropic tautomeric forms: 1(A-D) as shown in Scheme 1. The NMR of 1 was
recorded in two deuterated solvents, CDCl3 (nonpolar solvent) and DMSO-d6 (polar solvent),
which revealed that only two tautomeric transformations were present and the structure was
highly dependent on solvent polarity. In CDCl3, the 1H NMR of 1 showed the hydroxy1 group
proton at 15.97 ppm and the ortho- protons of the two phenyl groups at 7.93 and 7.72 ppm,
respectively. In the same solvent, the 13C NMR showed, in addition to the phenyl carbons, six
carbons at 200.31, 180.92, 166.04, 160.20, 99.54, and 98.12 ppm. In DMSO-d6, the 1H NMR
3

did not show the hydroxyl group signal, while the ortho- protons of the two phenyl groups
13
were found together at 7.92–7.87 ppm. The C NMR in the same solvent also displayed, in
addition to the phenyl carbons, six carbons at 193.40, 170.91, 161.83, 161.22, 102.59, and
98.47 ppm. This NMR data suggests that 1 is present solely in the exocyclic ketone (benzoyl)
tautomer A in a nonpolar solvent, whereas the unique exocyclic enol tautomer B is favored in
a polar solvent. In a solid state, the crystal structure shows that compound 1 exists exclusively
in the tautomer A as well as the non-polar solvent (Scheme 1) (CCDC No. 2034810).
Scheme 1: Synthesis and possible tautomeric isomers of substituted pyran-2,4-dione 1.
β-amination of (E)-3-(hydroxy(phenyl)methylene)-6-phenyl-2H-pyran-2,4(3H)-dione
(1) was achieved directly by a reaction with a set of aromatic amines, including aniline, 4-
chloroaniline, 4-bromoaniline, p-phenylenediamine, m-toluidine, o-toluidine, 4-aminophenol,
3-aminophenol, p-anisidine, and o-anisidine, in ethanol to give excellent yields of the
corresponding β-enamino-pyran-2,4-diones 2–11 (Scheme 2).
4

Scheme 2: Reaction of compound 1 with aromatic amines to give the β-enamino-pyran-2,4-
diones 2–11.
In addition, compound 1 was reacted with ammonium acetate and a set of aliphatic amines
including cyclohexylamine, ethanolamine, n-butylamine, allylamine, and benzylamine; in this
reaction, the amination produced the respective β-enamino-pyran-2,4-diones 12–17 (Scheme
3) exclusively, which were present in the E-form that was stabilized by the H-bond with the
pyrandione carbonyl oxygen and amine NH (C4-O … NH).
5

Scheme 3. Reaction of compound 1 with ammonium acetate and aliphatic amines to
give β-enaminopyran-2,4-diones 12–17.
In addition, the reaction of the pyran-2,4-dione 1 with 1,2-diaminoethane and 1,3-
diaminopropane produced the bis(β-enamino-pyran-2,4-diones) 18 and 19 (Scheme 4).
6

Scheme 4. Reaction of compound 1 with diamines to produce the bis(β-enamino-pyran-2,4-
diones) 18 and 19.
In another reaction, (E)-3-(hydroxy(phenyl)methylene)-6-phenyl-2H-pyran-2,4(3H)-
dione (1) was reacted with the amino-acid methyl ester hydrochlorides of glycine, β-alanine,
valine, and leucine in pyridine and stirring overnight to produce a good yields of the β-
enamino-pyran-2,4-diones 20–23 (Scheme 5) of the relative amino-acid methyl esters.
Scheme 5. Reaction of the enol 1 with amino-acid methyl ester hydrochlorides.
7

Finally, microwave irradiation methodology was extended to convert (E)-3-
(hydroxy(phenyl)methylene)-6-phenyl-2H-pyran-2,4(3H)-dione 1 to 3-benzoyl-4,7-diphenyl-
2H,5H-pyrano[4,3-b]pyran-2,5-dione 24 via a reaction with ethyl benzoylacetate in acetic
acid for 15 min. The final product was believed to proceed by condensation followed by a
subsequent intramolecular cyclization (Scheme 6).
Scheme 6. Microwave-assisted condensation and intramolecular cyclization of 3-benzoyl-4,7-
diphenyl-2H,5H-pyrano[4,3-b]pyran-2,5-dione (24).
Conclusion
In conclusion, the method reported here is a simple and green microwave-assisted strategy for
the synthesis of β-substitutedvinyl-pyran-2,4-dione from ethyl benzoylacetate. A direct
regioselective β-amination of the exocyclic enol-pyran-2,4-dione produced excellent yields of
β-enamino-pyran-2,4-diones. Further cyclization of pyran-2,4-dione 1 with another molecule
of ethyl benzoylacetate in microwave produced fused pyrano[4,3-b]pyran-2,5-dione system
24. Importantly, these transformations can produce highly functionalized, substituted,
8

exocyclic pyran-2,4-diones and β-enamino-pyran-2,4-diones from low-cost commercial
substrates.
Supporting Information
The experimental procedure for the synthesis of the target compounds along with copies of 1H
and 13C NMR spectra and x-ray data are supplied as Supporting Information.
Acknowledgments
The authors would like to extend their sincere appreciation to the Researchers Supporting
Project Number (RSP-2020/64), King Saud University, Riyadh, Saudi Arabia.
ORCID
Ahmed A.M. Sarhan: 0000-0002-6486-1761
Matti Haukka: 0000-0002-6744-7208
Assem Barakat: 0000-0002-7885-3201
Ahmed T. A. Boraei: 0000-0003-3832-1275
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Conflicts of Interest
“The authors declare no conflict of interest.”
Highlights
– A novel synthetic approach to pyran-2,4-dione scaffold.
– Microwave-assisted dimerization, and cyclization to afford pyran-2,4-dione.
–
Expeditious regioselective conversion β-diketone systems into β-enamino-pyran-2,4-
diones.
– Cyclization of 3-(β-substitutedvinyl)-6-phenyl-pyran-2,4-dione into 3-benzoyl-4,7-
diphenyl-2H,5H-pyrano[4,3-b]pyran-2,5-dione.
12