Synthesis of 3-aroylcoumarin-flavone hybrids

Article abstract of DOI:10.2174/157017812800167501

A facile two step synthesis of 3-aroylcoumarin-flavone hybrids was achieved from 7-hydroxyflavone and α- oxoketene dithioacetals. In the first step 7-hydroxyflavone was regioselectively formylated under Duff reaction conditions. Resulting 8-formyl-7-hydro

Full text of DOI:10.2174/157017812800167501

218
Letters in Organic Chemistry, 2012, 9, 218-220
Synthesis of 3-Aroylcoumarin-Flavone Hybrids
Hulluru S.P. Rao* and Venkata S. Tangeti
Department of Chemistry Pondicherry University, Pondicherry-605014, India
Received July 22, 2011: Revised November 04, 2011: Accepted November 04, 2011
Abstract: A facile two step synthesis of 3-aroylcoumarin-flavone hybrids was achieved from 7-hydroxyflavone and ꢀ-
oxoketene dithioacetals. In the first step 7-hydroxyflavone was regioselectively formylated under Duff reaction
conditions. Resulting 8-formyl-7-hydroxy flavones were condensed with ꢀ-oxoketene dithioacetals in the presence of a
catalytic amount of piperidine to furnish 3-aroylcoumarin-flavone hybrids.
Keywords: 7-hydroxyflavone, ꢀ-oxoketene dithioacetal, 8-formyl-7-hydroxy flavones, coumrain-flaovone hybrid, duff
reaction.
INTRODUCTION
piperidine furnished a small combinatorial library of six 3-
aroylcoumarin-flavone hybrids 3a-f in good yield (Scheme
1). Appearance of two singlet signals at about ꢁ 8.8 and 6.9
ppm in the 1H NMR spectra assignable to two olefinic CH of
3-aroylcoumarin-flavone hybrids 3 confirmed formation of
the product. Moreover, the 13C NMR spectra displayed two
lactone carbonyls at about ꢁ 177 and 163 ppm, in addition to
one ꢀ,ꢂ-unsaturated carbonyl carbon at ꢁ 191 ppm.
Both coumarins and flavones are widely distributed
heterocyclic natural products with varied biological activities
[1]. In technological and medicinal fields, coumarins and
flavones, independently, find extensive use [2]. While
coumarins, especially those having electronic push-pull
characteristics, find applications as fluorescent probes and as
triplet sensitizers, flavones, particularly those with several
phenolic hydroxyl groups, are used as antioxidants. In
continuation of our synthetic efforts towards 3-aroyl
coumarins we contemplated the synthesis of 3-aroylco-
umarin-flavone hybrids. Such hybrid molecules represent
both 3-aroylcoumarin and flavones characteristics. Even
though there were scattered reports on simple coumarin-
flavone hybrid systems, no systematic synthesis or spectral
characterization has been reported [3]. Moreover, 3-
aroylcoumarin-flavone hybrids, target molecules of present
study are not known. We have shown recently that ꢀ-
oxoketene dithioacetals 1, the three carbon push-pull sys-
tems, on condensation with 2-hydroxybenzaldehydes furnish
a wide variety of 3-aroylcoumarins [4]. We have now
extended this study by condensation of ꢀ-oxoketene dithio-
acetals 1 with 2-hydroxybenzaldehyde incorporated in a
flavone scaffold eg., 2 to furnish 3-aroylcoumarin-flavone
hybrids 3 (Scheme 1). Synthesis of such heterocyclic entities
holds promise for integrating medicinal and fluorescent
properties.
In conclusion we have described a short and facile two-
step synthesis of 3-aroylcoumarin-flavone hybrids 3 from 7-
hydroxy flavone 4 and ꢀ-oxoketene dithioacetals 1.
EXPERIMENTAL SECTION
General
The progression of all the reactions was monitored by
TLC using hexanes (60-80 °C boiling mixture) / ethyl
acetate mixture as eluent. Column chromatography was
carried on silica gel (100-200 mesh SRL chemicals) using
1
increasing percentage of ethyl acetate in hexanes. H NMR
spectra (400 MHz) and 13C NMR (100MHz) and DEPT
spectra were recorded for (CDCl3 + CCl4) solutions on a
Bruker - 400 spectrometer with tetramethylsilane (TMS) as
internal standard; J-values are in Hz. IR spectra were
recorded as KBr pellets on a Nicolet-6700 spectrometer. UV
spectra were recorded using Hitachi ratio-beam
spectrometer. Melting points were recorded using open-
ended capillary tubes on VEEGO VMP-DS instrument. High
7-Hydroxyflavones 4, prepared from resacetophenone
and aroyl chloride via Baker-Venkataraman rearrangement
[5], were formylated with hexamethylenetetramine and
acetic acid (Duff reaction) [6] to furnish 8-formyl-7-hydroxy
resolution mass spectra were recorded on
a Waters
Micromass Q-TOF micro mass spectrometer using electron
spray ionization mode. Organic solvents were distilled and
dried before use.
flavones
(2-(4-aryl)-7-hydroxy-4-oxo-4H-chromene-8-
carbaldehydes 2a, R2 = H and 2b R2 = Cl) [3b].
Regioselectivity of formylation was ensured from the 1H
NMR spectra which displayed two doublets in the aromatic
region for two 1,2-coupled hydrogens in 2. Condensation of
flavones 2a and 2b, independently, with one mole each of
three ꢀ-oxoketene dithioacetals 1a-c in presence of
General Procedure for Formylation of 7-hydroxyflavone:
7-Hydroxy-4-oxo-2-phenyl-4H-chromene-8-carbaldehyde
2a
A solution of 7-hydroxyflavone (238 mg, 0.001 mol)
dissolved in glacial acetic acid (5 mL), hexamethylen-
etetramine (560 mg, 0.004 mol) was added and the resulting
solution was heated on a water bath for12 h. To the rt cooled
solution 4 mL of 6 N aq HCl was added and then heated on a
*Address correspondence to this author at the Department of Chemistry
Pondicherry University, Pondicherry-605014, India; Tel: +914132654411;
Fax: +914132656230; E-mail: hspr.che@pondiuni.edu.in
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Synthesis of 3-Aroylcoumarin-Flavone Hybrids
Letters in Organic Chemistry, 2012, Vol. 9, No. 3
219
R1
O
O
R2
R2
CHO
O
SMe
SMe
O
O
i
HO
O
+
R1
O
O
3a-f
1a-c
2a-b
1a: R1 = H
1b: R1 = Cl
1c: R1 = Me
2a: R2 = H
2b: R2 = Cl
3a: R1 = R2 = H
3b: R1 = H, R2 = Cl
3c: R1 = Cl, R2 = H
3d: R1 = Cl, R2 = Cl
3e: R1 = Me, R2 = H
3f: R1 = Me, R2 = Cl
Scheme 1. Synthesis of coumarin-flavone hybrids 3 from ꢃ-oxoketene dithioacetals 1 and 8-formyl-7-hydroxyflavones 2.
Reagents and conditions: (i) piperidine, dry THF reflux, 8-32 h, 44-85%.
water bath for a further period of for 30 min. The reaction
mixture was then diluted with water (10 mL) and left
standing for 1 h at 5 C in the refrigerator. The reaction
en-1-one 1a (42 mg, 0.187 mmol) in dry THF and piperidene
(13 mg, 0.187 mmol) in dry THF (1.2 mL) was added drop
wise at rt under a blanket of nitrogen. The reaction mixture
o
°
mixture was extracted with dichloromethane (2 x 10 mL).
Combined organic solution was washed with water (20 mL),
brine (20 mL) and dried over anhydrous Na2SO4. Column
chromatographic purification on silica gel with increasing
amount of ethyl acetate in hexanes provided 2a as a free
flowing solid in 70% yield. Analytical samples were
obtained by recrystallization from chloroform. mp = 181°C;
UV (DCM), 343 nm (log ꢀ = 3.28), 289 nm (log ꢀ = 3.18);
IR (KBr) ꢁ max 3065, 2959, 1642, 1597, 1444, 1405, 1376,
1302, 1215, 1173, 1077, 1026, 860, 770 cm-1; 1H NMR (400
MHz, CDCl3) 10.70 (s, 1H), 8.31 (d, J = 9.2 Hz, 1H), 7.83
(d, J = 8.8 Hz, 2H), 7.57-7.53 (m, 3H), 6.99 (d, J = 8.8, 2H),
6.80 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3) 191.9, 176.4,
167.6, 162.7, 158.1, 134.8, 131.2, 129.4, 126.1, 116.4, 109.0,
108.5 ppm. HRMS (ESI, m/z) C16H10O4 calcd for (M+H)
found 267. 0530 and 267.0523.
was heated at reflux in a pre-heated oil bath (80 C) for 36 h
for completion of reaction (TLC, 20% dicholromethane in
hexanes; Rf = 0.3). The reaction mixture was diluted with
dichloromethane (10 mL) and the organic solution was
washed with water (20 mL) and brine (20 mL) and dried
over anhydrous Na2SO4. Column chromatographic
purification on silica gel with increasing amount of
dichlormethane in hexanes provided 3a as a free flowing
solid in about 68% yield. Analytical samples were obtained
by recrystallization from 5% DCM in hexanes. mp > 240°C;
UV (DCM), 361 nm (log ꢀ = 3.48), 293 nm (log ꢀ = 3.35);
IR (KBr) ꢁ max 3058, 2919, 1731, 1664, 1439, 1379, 1260,
1087, 865, 804 cm-1; 1H NMR (500 MHz, DMSOD6) ꢂ 8.93
(s, 1H), 8.31 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 7.5 Hz, 2H),
7.73 (t, J = 7.5 Hz, 1H), 7.59-7.55 (m, 1H), 7.20 (s, 1H); 13C
NMR (125 MHz, DMSO D6) ꢂ 190.7, 176.3, 163.1, 158.0,
157.9, 153.0, 138.0, 136.2, 134.6, 132.5, 130.2, 130.7, 129.7,
129.6, 127.9, 127.1, 120.0, 115.0, 109.7, 108.1 ppm; HRMS
(ESI, m/z) calcd for C25H14O5 (M+Na) 417.0734 found
417.0725.
2-(4-Chlorophenyl)-7-hydroxy-4-oxo-4H-chromene-8-
carbaldehyde 2b
Yellow color solid; Yield = 65%; mp = 190°C; UV
(DCM) 349 nm (log ꢀ = 3.46), 293 nm (log ꢀ = 4.12); IR
(KBr) ꢁ max 3453, 3078, 1657, 1594, 1412, 1315, 1294, 830
cm-1; 1H NMR (400 MHz, CDCl3) ꢂ 10.72 (s, 1H), 8.35 (d, J
= 8.8 Hz, 1H), 7.79 (d, J = 8.8, 2H), 7.58 (d, J = 8.8 Hz,
2H), 7.04 (d, J = 9.2 Hz, 1H), 6.80 (s, 1H); 13C NMR (100
9-Benzoyl-2-(4-chlorophenyl)pyrano[2,3-f]chromene-4,8-
dione 3b
°
Colorless solid; Yield = 48%; mp = >240 C. UV (DCM)
349 nm (log ꢀ = 3.46), 293 nm (log ꢀ = 4.12); IR (KBr) ꢁ max
MHz, CDCl3)
ꢂ
191.6, 176.1, 167.6, 161.6, 158.0,
3053, 1734, 1657, 1625, 1481, 1438, 1406, 1375, 1256,
1
138.3,134.8, 129.7, 129.6, 127.3, 116.5, 116.3, 108.9, 108.7
ppm; HRMS (ESI, m/z) C16H9ClO4 calcd for (M+Na) found
323.0734 and 323.0729.
1093, 830 cm-1; H NMR (400 MHz, CDCl3) ꢂ 8.67 (s, 1H),
8.47 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.82 (d, J
= 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8 Hz,
2H), 7.45 (d, J = 8.8 Hz, 1H), 6.87 (s, 1H); 13C NMR (100
MHz, CDCl3) ꢂ 192.0, 175.0, 165.0, 159.0, 154.0, 153.0,
145.03, 138.7, 134.1, 132.3, 131.7, 130.9, 129.6, 128.7,
127.9, 127.5, 126.5, 121.6, 114.0, 108.5, 107.9 ppm; HRMS
(ESI, m/z) 451.0349 calcd for C25H13ClO5 (M+Na) found
451.0345.
General Procedure for Synthesis of Coumarin-flavone
Hybrids; 9-Benzoyl-2-phenylpyrano[2,3-f]chromene-4,8-
dione 3a
To stirred solution of 7–hydroxyl-8-formyl flavone 2a
(50 mg, 0.187 mol) and 3,3-bis(methylthio)-1-phenylprop-2-

220 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
Rao and Tangeti
1
9-(4-Chlorobenzoyl)-2-phenylpyrano[2,3-f]chromene-4,8-
dione 3c
1092, 868, 782, 674 cm-1; H NMR (400 MHz, CDCl3) ꢂ
8.65 (s, 1H), 8.46 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.8Hz,
2H), 7.81 (d, J = 8.8Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.45
(d, J = 8.8 Hz, 1H), 7.32 (d, J = 8 Hz, 2H), 6.87 (s, 1H),
2.45(s, 3H) ppm; 13CNMR (100 MHz, CDCl3) ꢂ 190.7,
176.3, 162.3, 158.2, 157.4, 152.9, 145.5, 138.6, 137.9, 133.1,
130.6, 129.8, 129.7, 129.5, 129.3, 127.9, 127.4, 120.2, 114.8,
108.76, 108.73, 21.9 ppm; HRMS (ESI, m/z) 443.0630 calcd
for C26H15ClO5 (M+H) found 443.0625.
Colorless solid; Yield = 53%; mp > 240°C; UV (DCM),
315 nm (log ꢀ = 3.44), 298 nm (log ꢀ = 4.18); IR (KBr) ꢁ max
2927, 1732, 1657, 1613, 1532, 1438, 1375, 1262, 1093, 824
cm-1; 1H NMR (400 MHz, CDCl3) ꢂ 8.78(s, 1H), 8.45 (d, J =
8.9 Hz, 1H), 7.89 (d, J = 8.6 Hz, 2H), 7.85 (d, J = 2.4 Hz,
2H), 7.57 (t, J = 9.9 Hz, 1H), 7.52 (d, J = 4.4 Hz, 2H), 7.50
(d, J = 6.7 Hz, 2H), 7.44 (d, J = 8.8 Hz, 1H), 6.89 (s, 1H)
ppm; 13C NMR (100 MHz, CDCl3) ꢂ 189.8, 177.0, 163.5,
158.4, 154.9, 153.0, 145.5, 139.0, 134.2, 132.2, 131.2, 130.9,
129.4, 129.1, 127.2, 126.2. 120.5, 114.6, 108.7 ppm; HRMS
(ESI, m/z) 429.0530 calcd for C25H13ClO5 (M+H) found
429.2375.
ACKNOWLEDGEMENTS
H.S.P.R thanks UGC, UGC-SAP, CSIR and DST-FIST
for financial assistance. V. S. T. thanks CSIR for fellowship.
We thank IISc, Bangalore for recording MS spectra.
9-(4-Chlorobenzoyl)-2-(4-chlorophenyl)pyrano[2,3-
f]chromene-4,8-dione 3d
CONFLICT OF INTEREST
°
Colorless solid; Yield = 44%; mp 240 C above, UV
(DCM), 335 nm (log ꢀ = 3.44), 298 nm (log ꢀ = 4.18); IR
(KBr) ꢁ max 3071, 1738, 1663, 1625, 1412, 1368, 1262, 1093,
Declared none.
1
861, 830, 780 cm-1; H NMR (400 MHz, CDCl3) ꢂ 8.72 (s,
SUPPLEMENTARY MATERIAL
1H), 8.48 (d, J = 5.2 Hz, 1H), 7.84 (d, J = 4.8Hz, 2H),
7.55(d, J = 4.4 Hz, 2H ), 7.53 (d, J = 8.8 Hz, 2H), 7.48 (d, J
= 8.8 Hz, 2H), 7.46 (d, J = 8 Hz, 1H), 6.87 (s, 1H) ppm; 13C
NMR (100 MHz, CDCl3) ꢂ 191.1, 176.9, 163.4, 158.9,
157.4, 153.6, 149.0, 138.0, 134.1, 132.4, 131.0, 130.7, 130.1,
129.7, 129.5, 127.9, 127.1, 120.3, 114.7, 108.8, 108.5 ppm;
HRMS (ESI, m/z) 484.9959 calcd for C25H12Cl2O5 (M+Na)
found 484.9963.
Supplementary material is available on the publishers
Web site along with the published article.
REFERENCES
[1]
(a) Murry, R. D. H.; Mendez, J.; Brown, S. A. The Natural
Coumarins: Occurrence, Chemistry and Biochemistry, John Wiley
& Sons: New York, 1982. (b) Andersen, M.; Markham, K. R. (Ed)
Flavonoids: Chemistry, Biochemistry and Applications, CRC Press,
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(a) Meuly, W. C. Kirk-Othmer Encyclopedia of Chemical
Technology, New York, 1979, 7, 196-206, 3rd Ed, John Wiley &
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significance of the flavonoids. Pharm. & Ther., 2002, 96, 67-202.
(a) Subba Raju, K. V.;Srimannarayana, G.; Subba Rao, N. V.
Reaction of some substited 2-Allyl Phenols with 2,3 dichloro-5, 6-
Dicyano-1,4-Benzoquinone (DDQ)-a new method for the synthesis
of coumarins Tetrahedron Lett. 1977, 473-476. (b) Rangaswami,
S.; Seshadri, T. R. 7-Hydroxychromene-8-aldehydes and their
conversion into chromono-7, 8-a-pyrones.Proceedings – Ind. Acad.
Sci., Section A 1939, 9A, 7-9. Chemical Abstracts Number 1939
33:29861.
9-(4-Methylbenzoyl)-2-phenylpyrano[2,3-f]chromene-4,8-
dione 3e
Colorless solid; Yield = 85% ; mp > 240°C; UV (DCM)
303.5 nm (log ꢀ = 3.36), 340.5 nm (log ꢀ = 4.18), IR (KBr) ꢁ
[2]
[3]
3071, 2921, 1737, 1661, 1625, 1441, 1380, 1266, 1087,
max
1
867, 832 cm-1; H NMR (400 MHz, CDCl3) ꢂ 8.69 (s, 1H),
8.48 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 9.6 Hz, 2H), 7.83 (d, J
= 8.4 Hz, 2H), 7.59-7.45 (m, 3H), 7.44 (d, J = 9.2 Hz, 1H),
7.31(d, J = 8 Hz, 2H), 6.90 (s, 1H), 2.45 (s, 3H); 13C NMR
(100 MHz, CDCl3) ꢂ 190.8, 176.8, 163.5, 158.4, 157.4,
153.0, 145.2, 138.0, 133.2, 132.2, 130.9, 130.7, 129.8, 129.5,
129.4, 127.8, 126.2, 120.3, 114.6, 108.7, 108.6, 21.90 ppm;
HRMS (ESI, m/z) calcd C26H16O5 for 431.0895 (M+Na)
found 431.0898.
[4]
Rao, H.S.P.; Sivakumar, S. Condensation of ꢃ-Aroylketene
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Wheeler, T. S. Flavone. Org.Syn.1952, 32, 72-76.
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and phenolic compounds, part II: Formation of phenolic aldehydes:
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°
Colorless solid; Yield = 56%; mp > 240 C, UV (DCM),
345 nm (log ꢀ = 3.45), 296 nm (log ꢀ = 4.04); IR (KBr) ꢁ max
3079, 2921, 1737, 1654, 1615, 1440, 1408, 1378, 1265,1182,