Efficient one-pot synthesis of 4-aroyl-2-pyrones: Nucleophilic addition of active methylene groups to 1,2-diaroylacetylenes

Article abstract of DOI:10.1080/00397911.2010.515350

An efficient synthesis of 3,6-disubstituted-4-aroyl-2-pyrones in a single-stepreaction through Michael addition of 1,2-diaroylacetylenes with active methylene compounds in the presence of NaH in dimethylsulfoxide at room temperature is reported. The structures have been confirmed by spectral data analyses. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.515350

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Efficient One-Pot Synthesis of 4-
Aroyl-2-pyrones: Nucleophilic Addition
of Active Methylene Groups to 1,2-
Diaroylacetylenes
Ravi Shankar a , Harsha Shukla a , Uma Sharan Singh a , Vinay Thakur
a & K. Hajela a
a Medicinal and Process Chemistry Division, Central Drug Research
Institute, Lucknow, India
Published online: 29 Jun 2011.
To cite this article: Ravi Shankar , Harsha Shukla , Uma Sharan Singh , Vinay Thakur & K. Hajela
(2011): Efficient One-Pot Synthesis of 4-Aroyl-2-pyrones: Nucleophilic Addition of Active Methylene
Groups to 1,2-Diaroylacetylenes, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:18, 2738-2746
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Synthetic Communications1, 41: 2738–2746, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515350
EFFICIENT ONE-POT SYNTHESIS OF 4-AROYL-2-
PYRONES: NUCLEOPHILIC ADDITION OF ACTIVE
METHYLENE GROUPS TO 1,2-DIAROYLACETYLENES
Ravi Shankar, Harsha Shukla, Uma Sharan Singh,
Vinay Thakur, and K. Hajela
Medicinal and Process Chemistry Division, Central Drug Research Institute,
Lucknow, India
GRAPHICAL ABSTRACT
Abstract An efficient synthesis of 3,6-disubstituted-4-aroyl-2-pyrones in a single-step
reaction through Michael addition of 1,2-diaroylacetylenes with active methylene com-
pounds in the presence of NaH in dimethylsulfoxide at room temperature is reported.
The structures have been confirmed by spectral data analyses.
Keywords 4-Aroyl-2-pyrones; 1,2-diaroylacetylenes; Michael addition
INTRODUCTION
Synthetic compounds as well as simple and complex natural products[1]
possessing a 2-pyrone moiety exhibit an incredibly diverse range of biological
activities such as anticancer,[2] antimicrobial,[3] phytotoxic,[4] and COX-2 inhibitory
activities.[5] In organic synthesis, 2-pyrones find application as dienes in Diels–Alder
reactions[6] and as precursors to many carbocyclic and heterocyclic systems.[7] Very
recently, 4-hydroxy-2-pyrones have been shown to be potent HIV-1 protease
inhibitors,[8] and consequently, the syntheses of 2-pyrones with different substitution
patterns presents an interesting challenge.
A number of methods for the introduction of substituents at different posi-
tions of the 2-pyrone ring have been reported. Most of these methods involve the
Received April 12, 2010.
CDRI Communication No. 7494.
Address correspondence to K. Hajela, Medicinal and Process Chemistry Division, Central Drug
Research Institute, Lucknow 226001, UP, India. E-mail: hajelak@yahoo.com; kanchan_hajela@cdri.res.in
2738

4-AROYL-2-PYRONES
2739
lactonization of 4-alkynoic acids promoted by palladium or by electrophilic
reagents.[9] In many cases, these procedures lead to alkylidene butenolides instead
of pyrones, and when carried out with nonsymmetric alkynes two 2-pyrone regioi-
somers may be obtained.[10] Recently, a potassium carbonate–catalyzed 1,4-addition
of malonic esters to allenic ketones forming 2-pyrones has been reported.[11]
RESULTS AND DISCUSSION
As part of our research on syntheses of new chemical leads with estrogen recep-
tor modulating activities, we felt the need for a 4-aroyl-3,6-disubstituted 2-pyrone
system as a suitable building block that could be modified with desirable substituents
to target molecules. A survey of literature revealed only one reference reporting[12]
Michael addition of mandelic acid enolate to trans-1,2-diaroylethenes and trans-
formation of the resulting intermediate into 4-aroyl-2-pyrones.The process is tedious
and required the formation of cumbersome intermediate 1,3-dioxolan-4-ones. It is
reported in the literature that 3,4,6-triarylpyrone derivatives can be prepared by con-
densation of esters of phenyl acetic acid with 1,3-diaryl propyne-2-ones in the pres-
ence of a base in dimethylsulfoxide (DMSO) at room temperatute.[13] We envisaged
that the same reaction conditions could be applied to condensing diaroylacetylene
with an active methylene compound and found that the reaction between 1,4-
diphenyl-but-2-yne-1,4-dione and diethylmalonate (1:1 equiv) using sodium hydride
in dimethylformamide (DMF) at room temperature proceeded very smoothly, giving
the desired 4-aroyl-2-pyrone in very good yield. In this communication, we describe
this novel one-step reaction for the preparation of 4-aroyl-2-pyrones 3 by nucleophil-
lic addition of 1,2-diaroylacetylenes 1 to active methylene groups 2 (Scheme 1).
The target molecules, 3,6-diaryl-4-aroyl-pyran-2-ones (15–20), were obtained
in moderate to good yields (22–62%) by condensation of 1,2-diaroylacetylenes
(10–12) with 4-substituted-phenylacetic acid esters (13, 14) in the presence of a base
such as sodium hydride at 25 ꢀC. All the reactions were complete in 1 h. Quenching
of the reaction mixture with 20% aqueous HCl mostly precipitated solids (in some
cases, dark-colored viscous liquids were obtained), which were suitably crystallized
or purified by silica gel or basic alumina column chromatography to give the desired
pure compounds in good yields (Scheme 2).
To explore the scope of this cyclization strategy, 1,2-diaroylacetylenes (10–12)
were reacted with different active methylene groups such as diethylmalonate, ethyl-
cyanoacetate, and ethylacetoacetate (21–23) under the same reaction conditions as
described previously. The desired 4-aroyl-2-pyranones (24–32) were obtained in
yields of 80–90% in all cases (Scheme 3).
Scheme 1. Synthesis of 3,6-disubstituted-4-aroyl-2-pyrones.

2740
R. SHANKAR ET AL.
Scheme 2. Synthesis of 3,6-diaryl-4-aroyl-2-pyrones.
Among the bases tested, sodium hydride was found to be the most effective.
Other bases such as potassium carbonate, sodium ethoxide, or potassium t-butoxide
yielded inseparable reaction mixtures from which the desired compounds could be
isolated in very poor yields. Changing the solvent to DMF or 1,4-dioxane prolonged
the reaction times several fold.
A plausible reaction mechanism is shown in Scheme 4. The first step in the
reaction cascade involves the attack of carbanion of the active methylene compound
of 1,2-diaroylacetylene, forming the allene adduct (A), which undergoes intramolecu-
lar cyclization, forming B. Facile elimination of EtOH under acidic conditions gave
Scheme 3. Synthesis of 3-substituted-6-aryl-4-aroyl-2-pyrones.
Scheme 4. A plausible mechanism for the synthesis of 3,6-disubstituted-4-aroyl-2-pyrones.

2741

2742

2743

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R. SHANKAR ET AL.
the desired 4-aroyl-2-pyrones. The yield of pyrones was excellent when electron-
withdrawing groups were present in the nucleophiles.
The order of reactivity was found to be diethylmalonate > ethylcyanoacetate >
ethylacetoacetate > ethyl 4-nitrophenylacetate > ethylphenylacetate. The reaction
was not successful with either diethyl succinate or ethyl-4-methoxyphenylacetate
bearing electron-donating groups. Under the optimized conditions, a number of
compounds with active methylene groups (2a–e) reacted with simple and substituted
1,2-diaroylacetylenes (1a–c) forming 3,6-disubstituted-4-aroyl-2-pyrones (3a–o) in
excellent yields (Table 1).
CONCLUSIONS
We report for the first time a facile, one-step synthesis of 3,6-disubstituted-4-
aroyl-2-pyrones. The reaction is simple, fast, and convenient. Excellent yields of
the products make it attractive for large-scale synthesis of this potentially biologi-
cally active class of molecules.
EXPERIMENTAL
General melting points are uncorrected and were determined in capillary tubes
on a hot-stage apparatus containing silicon oil. Infrared (IR) spectra were recorded
using a Perkin-Elmer RX I Fourier transform (FT)–IR spectrophotometer. 1H NMR
and 13C NMR spectra were recorded on either a 300- or 200-MHz FT spectrometer,
using tetramethylsilane (TMS) as an internal standard (chemical shifts in d values, J
in Hz). The electrospray ionization–mass spectra were recorded through direct flow
injections in a Merck M-8000 liquid chromatography–mass spectroscopy (LCMS)
system. Elemental analyses were performed on a Carlo Erba 1108 microanalyzer
or Elementar’s Vario EL III microanalyzer.
Representative Procedure
A solution of the ethyl phenyl acetate (2a, 164 mg, 1 mmol) was added to a sus-
pension of NaH (60% oil dispersion, 32.8 mg, 1.2 mmol) in dry DMSO (15 ml), and
the reaction mixture was allowed to stir for 30 min. A solution of 1,2-diaroylacety-
lene (1c, 294 mg, 1 mmol) in DMSO was added dropwise, and the mixture was stirred
at room temperature for another 45 min. Within this period, the reaction was found
to be complete as checked by thin-layer chromatography (TLC). It was quenched
with 20% aqueous HCl, and the precipitated solid was filtered, washed with water,
and purified by column chromatography. Finally, crystallization from ethanol gave
3c as a white crystalline solid.
Spectral Data for Selected Compounds
1
Compound 3c. Mp 190–192 ꢀC; HNMR (300 MHz, CDCl3): d 3.85 (s, 3H),
3.90 (s, 3H), 6.65 (s, 1H), 6.83 (d, 2H, J ¼ 8.9 Hz), 6.99 (d, 2H, J ¼ 8.9 Hz), 7.23 (m,
3H), 7.37 (m, 2H), 7.76 (d, 2H, J ¼ 8.9 Hz),7.87 (d, 2H, J ¼ 8.9 Hz). 13C NMR
(75 MHz, CDCl3): d 55.45, 99.63, 114.10, 114.45, 127.44, 128.14, 128.60, 129.21,

4-AROYL-2-PYRONES
2745
129.88, 132.08, 133.61, 134.90, 135.88, 136.84, 139.25, 141.87, 160.06, 164.34, 196.67.
ESI: 413 (Mþ þ 1). HRMS calculated for C26H20O5: 412.1311; measured: 412.1302.
Compound 3d. Mp 172–175 ꢀC; 1H NMR (300 MHz, CDCl3): d 6.67 (s, 1H),
7.54 (m, 5H), 7.57 (m, 1H), 7.92 (m, 4H). 13C NMR (75 MHz, CDCl3): d 98.63,
125.23, 127.80, 127.93, 127.96, 131.27, 133.21, 157.16, 163.28, 191.37. ESI:
302(Mþ þ 1). HRMS calcd. for C19H11NO3: 303.0895; measured: 303.0903.
Compound 3h. Mp 138–140 ꢀC; 1H NMR (300 MHz, CDCl3): d 1.09 (t, 3H),
2.45 (s,6H), 4.10 (q, 2H), 6.61 (s, 1H), 7.31 (d, 2H, J ¼ 8.9 Hz), 7.33 (d, 2H,
J ¼ 8.9 Hz), 7.79 (d, 2H, J ¼ 8.9 Hz), 7.81 (d, 2H, J ¼ 8.9 Hz). 13C NMR (75 MHz,
CDCl3): d 12.27, 20.15, 20.58, 60.65, 98.13, 125.22, 126.06, 128.08, 128.48, 130.59,
142.24, 144.44, 157.56, 191.15. ESI: 377 (Mþ þ 1), 331(Mþ-C2H5OH). HRMS
calculated for C23H20O5: 376.1311; measured: 376.1289.
1
Compound 3j. Mp 135–137 ꢀC; H NMR (300 MHz, CDCl3): d 2.24 (s, 3H),
6.76 (s, 1H), 6.82 (d, 2H, J ¼ 6.7 Hz), 7.05 (d, 2H, J ¼ 6.7 Hz), 7.24 (d, 2H,
J ¼ 6.7 Hz), 7.64 (d, 2H, J ¼ 6.7 Hz). 13C NMR (75 MHz, CDCl3): d 13.12, 105.36,
120.86, 123.70, 127.00, 127.52, 127.76, 128.06, 129.14, 132.32, 135.96, 137.46,
149.46, 158.09, 188.55. ESI: 318 (Mþ þ 1). HRMS calculated for C20H15O4:
319.09703 (Mþ þ 1); measured: 319.09872.
Compound 3n. 1H NMR (300 MHz, CDCl3): 2.36 (s, 3H), 2.43 (s, 3H), 7.04
(s, 1H), 7.15 (d, 2H, J ¼ 8.04), 7.57 (d, 2H, J ¼ 8.58), 7.66 (d, 2H, J ¼ 8.0 Hz), 7.92
(m, 2H), 8.06 (d, 2H, J ¼ 8.07 Hz), 8.21 (d, 2H, J ¼ 8.58 Hz). 13C NMR (75 MHz,
CDCl3) 21.62, 21.75, 96.16, 122.85, 123.72, 128.99, 129.22, 129.44, 129.99, 130.96,
133.74, 141.58, 143.91, 144.62, 145.00, 147.90, 165.75, 194.88. ESI: 426 (Mþ þ 1).
ACKNOWLEDGMENTS
Ravi Shankar is thankful to the Council of Scientific and Industrial Research
for a senior fellowship; Uma Sharan Singh and Harsha Shukla are grateful to the
Ministry of Health and Family Welfare for financial assistance; and all authors
thank Sophisticated Analytical Instrument Facility (SAIF) for spectroscopic analy-
ses of the compounds.
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