An efficient and facile synthesis of functionalized flavones from flavanones

Article abstract of DOI:10.1007/s13738-019-01801-4

A mild and efficient scheme for the synthesis of 3-substituted functionalized flavones was developed. The reaction of flavanone and glyoxylic acid in ethanol in the presence of the catalytic amount of sulphuric acid at reflux temperature for 2–3?h yielded

Full text of DOI:10.1007/s13738-019-01801-4

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01801-4
ORIGINAL PAPER
An efcient and facile synthesis of functionalized favones
from favanones
Dasharath Kondhare1 · Anjaneyulu Kasa1 · Balaji Totawar2 · Venkat Bhadke3 · Harshad Lade4
Received: 27 January 2019 / Accepted: 20 October 2019
© Iranian Chemical Society 2019
Abstract
A mild and efcient scheme for the synthesis of 3-substituted functionalized favones was developed. The reaction of fa-
vanone and glyoxylic acid in ethanol in the presence of the catalytic amount of sulphuric acid at refux temperature for 2–3 h
yielded good to excellent functionalized favones. As per present scenario for the synthesis of diferent substituted favones,
this method represents mild reaction conditions, low-cost catalyst, broad substrate scope along with high yields, which makes
it more credible and handy synthetic strategy.
Keywords C-3-substituted favone · Facile synthesis · Claisen–Schmidt condensation · Functional group interconversion
Introduction
position is alkylated or oxygenated to get the comprehen-
sive new spectrum of favones for various pharmacological
activities (Fig. 2) [14, 15].
Flavonoids represent the class of natural products which are
widely present in diversifed fruits and vegetables [1, 2].
Flavonoids seized the attraction of chemists worldwide as
its varied derivatives exhibit an array of pharmacological
activities. The most promising pharmacological activities
include antibacterial [3], antifungal [4], antimalarial [5],
anticancer [6] antioxidant [7], antidiabetic [8], anti-HIV [9],
anti-tubercular [10], anti-infammatory [11], immune-stim-
ulatory [12], and wound healing [13] as shown in (Fig. 1).
The literature search suggests that in the basic com-
mon natural favonoids, the C-3 position is unsubstituted
and because of this several reports concluded that the C-3
There are several synthetic approaches have been devel-
oped over the last decade [16–19]. However, the direct func-
tionalization of earlier reported or favonoid from natural
sources has been less studied [20, 21]. The synthesis of
these functionalized C-3 favones ring system has special
importance as numerous favonoids could be extracted in
gram scale from their natural sources. This might give quick
access to libraries of diverse favonoid scafolds in the feld
of organic chemistry. For the functionalization goal, lim-
ited methods for the alkylation at C-3 position are avail-
able [22, 23]. Earlier, Detty and McGarry [24, 25] showed
a direct alkylation at C-3 via lithiation with lithium diiso-
propylamide (LDA). Additionally, there are some reports
which proved the establishment of an alkyl substituent at C-3
could be accomplished through a palladium-mediated cross-
coupling process using 3-halofavones basic building block
[26–28]. Furthermore, numerous strategies are available in
the literature for the efcient and novel substitution at the
3-position of favones [29, 30]. To date, for the functionali-
zation at the C-3 position of favanone, frst hydroxyl group
need to convert into a good leaving group such as trifate or
halogen in palladium-mediated reactions. However, to per-
form this reaction, use strong basic conditions and expensive
transition metal complexes are required [31–33].
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-019-01801-4) contains
supplementary material, which is available to authorized users.
* Harshad Lade
harshadlade@gmail.com
1
School of Chemical Sciences, Swami Ramanand Teerth
Marathwada University, Nanded, MS 431606, India
2
Gramin Science (Vocational) College, Vishnupuri, Nanded,
MS 431606, India
3
Unisynaxis Laboratories Private Limited, IDA Mallapur,
Hyderabad 500076, India
By considering all these observations, we pondered if the
favanone ring frame (1) could be selectively functionalized
4
Department of Environmental Engineering, Konkuk
University, Seoul 05029, Korea
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Fig. 1 Pharmacologically active favanones
at C-3 position using a milder addition process to get the
corresponding favones (Scheme 1). In this context, we
explore a metal-free alternative approach for the construc-
tion of the favone ring framework with functionalization at
the C3 position.
visualized under UV light or iodine chamber. Silica gel
(100–200 mesh) (Merck, Darmstadt, Germany) was used
for the column chromatography separations. The melting
points (mp) were determined by the open capillary method
and reported uncorrected. The spectra were collected on
EOL GS-400 model FT-NMR spectrometer (400 MHz for
1H and 100 MHz for 13C NMR spectra) in DMSO-d6 and
CDCl3. Chemical shift values were reported in parts per
million (ppm) on the delta (δ) scale using tetramethylsilane
(TMS) as the internal standard, and coupling constants were
expressed in hertz. Infrared (IR) spectra were recorded at
room temperature on Nicolet iS 10 spectrometer(Thermo
Fisher Scientifc, Waltham, MA, USA) using KBr pellets in
the range of 4000–500 cm−1. The mass spectral data were
Experimental
All chemicals were purchased from Merck (Darmstadt,
Germany) and Sigma-Aldrich (St. Louis, MO, USA) and
used without further purifcation. Reactions during synthe-
sis were monitored by thin-layer chromatography (TLC)
on precoated silica gel 60F254 (mesh), and spots were
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Journal of the Iranian Chemical Society
Fig. 2 Leading examples of C3
favanoids
Scheme 1 Synthesis of 3-sub-
stituted favone derivatives
obtained using Agilent Technologies 6530 Accurate-Mass
Q-TOF LC/MS mass spectrometer. Elemental CHN analysis
was performed on a Perkin-Elmer Model 240B automatic
analyser.
Synthesis of 3‑substituted favones
A mixture of glyoxylic acid 2 (1.0 mmol) and favanone [38]
1(a–t) (1.0 mmol) in ethanol (2 mL) was prepared at room
temperature, and concentrated sulphuric acid (0.1 mol%)
was added. The reaction mixture was slowly heated to refux
for 2–3 h. After the starting material completion as moni-
tored by TLC, the solvent was removed under reduced pres-
sure. The resulted residue was dissolved in CH2Cl2 (20 mL)
followed by an ice-water wash to remove the residual acid
stresses. Then, the aqueous layer was washed with CH2Cl2
(2* 20 mL) and the combined organic layer with brine solu-
tion (30 mL) followed by concentration under reduced pres-
sure to aford a crude product. This was then purifed by
silica column chromatography with an eluent of hexane/
ethyl acetate (9:1) to get 3-substituted favones 3a–t (Fig. 3).
Fig. 3 General numbering of favone
Ethyl 2‑(4‑oxo‑2‑phenyl‑4H‑chromen‑3‑yl)acetate (3a)
White powder, mp. 102–103 °C. IR (neat) Vmax/cm−1 698,
711, 765, 940, 963, 1033, 1123, 1170, 1193, 1333, 1390,
1
1464, 1574, 1635, 1731, 2904, 2968, 2981, 3444. H
NMR (400 MHz, CDCl3): δ 1.25–1.30 (3H, t) 3.56 (2H,
s), 4.16–4.23 (2H, q), 7.39–7.55 (5H, m), 7.69–7.71 (3H,
m), 8.23–8.26 (1H, dd,J=1.70, 8.12). 13C NMR (100 MHz,
CDCl3): δ 14.1, 32.1, 60.9, 115.9, 117.9, 122.6, 124.3,
125.0, 125.9, 128.6, 130.6, 132.7, 133.6, 156.2, 163.2,
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Journal of the Iranian Chemical Society
171.2, 177.8. EI MS: m/z (rel. abund.%) M+1: 309 (100)
263 (35). Anal. Calcd. for C19Hl6O4 (308.33): C, 74.01; H,
5.23. Found: C, 74.06; H, 5.20%.
Ethyl 2‑(2‑(4‑bromophenyl)‑4‑oxo‑4H‑chromen‑3‑yl)
acetate (3e)
Yellow solid, mp. 241–242 °C. IR (KBr) Vmax/cm−1 678,
750, 758, 973, 1140, 1152, 1172, 1191, 1370, 1435, 1460,
1572, 1628, 1731, 2849, 2945, 2995, 3070. 1H NMR (CDCl3,
400 MHz): δ 1.26–1.32 (3H, t), 3.53 (2H, s), 4.18–4.25 (2H,
q), 7.05 (2H, d), 7.35 (2H, dd, J=8.4, 1.6 Hz), 7.55 (1H, td,
J = 8.4, 1.6 Hz), 7.56 (2H, dd, J= 8.4, 2.0 Hz), 7.95 (1H,
dd, J=8.0, 2.0 Hz). 13C NMR (CDCl3, 100 MHz): δ 14.1,
32.0, 61.1, 116.2, 117.8, 122.5, 125.1, 125.5, 126.2, 130.3,
131.6, 132.1, 132.3, 134.1, 156.1, 162.4, 171.2, 177.6. EI
MS: m/z (rel. abund.%)=M+1: 388.01 (97.3). Anal. Calcd.
for C19H15BrO4 (386.02):C, 58.93; H, 3.90 Found: C, 58.95;
H, 3.88%.
Ethyl 2‑(2‑(4‑chlorophenyl)‑4‑oxo‑4H‑chromen‑3‑yl)acetate
(3b)
Off-white solid, mp. 213–216 °C. IR (neat) Vmax/cm−1
693, 713, 748, 950, 1133, 1140, 1168, 1195, 1350, 1387,
1465, 1575, 1645, 1740, 2910, 2975, 2985, 3445. 1H NMR
(400 MHz, CDCl3): δ 1.26–1.31 (3H, t) 3.53 (2H, s),
4.16–4.23 (2H, q) 7.40–7.52 (4H, m) 7.61–7.72 (3H, m),
8.22–8.25 (dd, 1H, J = 1.51, 7.93) 13C NMR (100 MHz,
CDCl3): δ 13.9, 33.6, 61.3, 117.2, 118.0, 121.3, 125.6,
126.0, 127.9, 128.6, 133.5, 134.1, 136.4, 155.2, 165.2,
175.2, 178.8. EI MS: m/z (rel. abund.%) M+1: 344.06 (33),
343.07 (20.9), 345.07 (6.8), 344.07 (2.9) Anal. Calcd. for
C19H15ClO4 (342.07): C, 66.58; H, 4.41 Found: C, 66.55;
H, 4.45%.
Ethyl 2‑(2‑(4‑nitrophenyl)‑4‑oxo‑4H‑chromen‑3‑yl)acetate
(3f)
Yellow solid, mp. 303–304 °C. IR (KBr) Vmax/cm−1 676,
756, 763, 970, 1143, 1155, 1168, 1193, 1371, 1438, 1464,
1575, 1630, 1733, 2842, 2946, 2989, 3075. 1H NMR (CDCl3,
400 MHz): δ 1.23–1.26 (3H, t), 3.48 (2H, s), 4.17–4.26 (2H,
q), 7.10 (2H, m), 7.48 (1H, td, J=8.4, 1.6 Hz), 7.65 (2H, dd,
J=8.4, 2.0 Hz), 7.92 (1H, dd, J=8.0, 2.0 Hz), 8.31 (2H, dd,
J=8.8, 2.0 Hz). 13C NMR (CDCl3, 100 MHz): δ 14.2, 32.3,
61.2, 116.7, 116.5, 123.5, 124.8, 126.5, 127.2, 129.3, 130.8,
132.7, 133.4, 135.2, 157.3, 165.4, 173.2, 176.1. EI MS: m/z
(rel. abund.%)=M+1: 354.09. Anal. Calcd. for C19H15NO6
(353.09):C, 64.59; H, 4.28; N, 3.96 Found: C, 64.55; H,
4.33; N, 3.97%.
Ethyl 2‑(4‑oxo‑2‑p‑tolyl‑4H‑chromen‑3‑yl)acetate (3c)
Pale yellow solid, mp. 197–199 °C. IR (KBr) Vmax/cm−1
690, 715, 751, 953, 1131, 1143, 1171, 1193, 1356, 1390,
1471, 1581, 1635, 1730, 2923, 2985, 2995, 3451. 1H NMR
(CDCl3) δ 1.27 (3H, t), 2.42 (3H, s), 3.57 (2H, s), 4.18
(2H, q), 7.02–7.05 (m, 2H), 7.25 (2H, d, J=7.81 Hz), 7.35
(2H, d, J=7.81 Hz), 7.52 (1H, m), 7.90 (1H, dd, J=8.08,
1.76 Hz). 13C NMR (CDCl3, 100 MHz): δ 14.1, 32.3, 21.4,
59.6, 113.1, 112.4, 116.9, 123.6, 125.2, 126.9, 127.3, 131.4,
135.2, 157.4, 162.1, 165.1, 173.5, 176.9. EI MS: m/z (rel.
abund.%) = M+1: 322.12 (100.0), 323.12 (21.8), 324.13
(2.3). Anal. Calcd. for C20H18O4 (322.12): C, 74.52; H, 5.63;
Found: C, 74.65; H, 5.57%.
Ethyl 2‑(2‑(4‑fuorophenyl)‑4‑oxo‑4H‑chromen‑3‑yl)acetate
(3g)
Off-white solid, mp. 176–177 °C. IR (KBr) Vmax/cm−1
695, 724, 735, 945, 1148, 1153, 1178, 1204, 1335, 1390,
1471, 1565, 1655, 1745, 2925, 2995, 3048, 3455. 1H NMR
(CDCl3, 400 MHz): δ 1.20–1.23 (3H, t), 3.45 (2H, s),
4.18–4.25 (2H, q), 7.11 (4H, m), 7.45 (2H, m), 7.55 (1H,
td, J=8.4, 1.6 Hz), 7.97 (1H, dd, J=8.0, 2.0 Hz).13C NMR
(CDCl3, 100 MHz): δ 14.4, 32.6, 61.4, 116.3, 117.6, 124.6,
125.4, 125.2, 126.9, 130.1, 131.2, 132.3, 133.1, 134.5,
158.7, 164.7, 172.3, 176.7. EI MS: m/z (rel. abund.%)=M+1:
327.10. Anal. Calcd. for C19H15FO4 (326.10): C, 69.93; H,
4.63 Found: C, 69.90; H, 4.65%.
Ethyl 2‑(2‑(4‑methoxyphenyl)‑4‑oxo‑4H‑chromen‑3‑yl)
acetate (3d)
Pale yellow solid, mp. 219–221 °C. IR (KBr) Vmax/cm−1
675, 725, 748, 963, 1138, 1145, 1170, 1189, 1367, 1432,
1458, 1567, 1623, 1720, 2848, 2935, 2985, 3068. 1H NMR
(CDCl3, 400 MHz): δ 1.28 (t, 3H), 3.58 (s, 2H), 3.86 (s,
3H), 4.21 (q, 2H), 7.02 (d, 2H, J = 9.0), 7.43 (m, 2H,
J=7.4), 7.65 (m, 3H), 8.23 (m, 3H, J=1.6, 7.8). 13C NMR
(CDCl3, 100 MHz): δ 13.9, 33.4, 56.3, 62.3, 115.1, 116.2,
119.1, 124.1, 125.8, 127.0, 128.9, 132.3, 135.6, 157.2,
160.1, 162.5, 172.5, 176.8 EI MS: m/z (rel. abund.%)=M+:
338.12 (100.0), 339.12 (22.0), 340.12 (3.3). Anal. Calcd.
for C20H18O5 (338.12): C, 70.99; H, 5.36; Found: C, 70.94;
H, 5.38%.
Ethyl 2‑(2‑(2‑methoxyphenyl)‑4‑oxo‑4H‑chromen‑3‑yl)
acetate (3h)
Pale yellow solid, mp. 147–148 °C. IR (KBr) Vmax/cm−1 676,
728, 743, 965, 1140, 1142, 1177, 1199, 1376, 1438, 1463,
1572, 1630, 1731, 2850, 2923, 2967, 2995, 3038. 1H NMR
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Journal of the Iranian Chemical Society
(CDCl3, 400 MHz): δ 1.27–133 (3H, t), 3.58 (2H, s), 3.81
(3H, s), 4.18–4.30 (2H, q), 7.01–7.04 (1H, d, J= 8.3 Hz),
7.06–7.08 (3H, m), 7.33–7.36 (1H, m), 7.47–7.53 (1H,
m), 7.62 (1H, dd, J = 0.8, 7.5 Hz), 7.92 (1H, dd, J = 1.36,
7.8 Hz). 13C NMR (CDCl3, 100 MHz): δ 14.2, 32.1, 57.3,
65.1, 114.1, 115.2, 118.2, 120.1, 123.2, 126.3, 127.3, 128.0,
133.3, 134.6, 154.3, 156.2, 161.3, 162.4, 173.3, 175.8. EI
MS: m/z (rel. abund.%) = M+1: 339.12. Anal. Calcd. for
C20H18O5 (338.12): C, 70.99; H, 5.36 Found: C, 70.96; H,
5.38%.
13C NMR (CDCl3, 100 MHz): δ 14.1, 28.4, 59.5, 116.2,
117.5, 118.1, 123.1, 123.9, 126.9, 127.9, 129.1, 131.9,
132.7, 133.6, 135.5, 155.9, 166.6, 173.4, 176.7. EI MS: m/z
(rel. abund.%)=M+1: 343.07. Anal. Calcd. for C19H15ClO4
(342.07): C, 66.58; H, 4.41 Found: C, 66.60; H, 4.39%.
Ethyl 2‑(2‑(3‑methoxyphenyl)‑4‑oxo‑4H‑chromen‑3‑yl)
acetate (3l)
Yellow solid, mp. 127–129 °C. IR (KBr) Vmax/cm−1 675,
730, 745, 970, 1138, 1145, 1176, 1210, 1335, 1367, 1428,
1453, 1562, 1603, 1670, 1735, 2867, 2920, 2962, 2990,
Ethyl 2‑(2‑(2‑fuorophenyl)‑4‑oxo‑4H‑chromen‑3‑yl)acetate
(3i)
1
3018. H NMR (400 MHz, CDCl3): δ 1.22–1.25 (3H, t),
3.48 (2H, s), 3.84 (3H, s), 4.11–4.13 (2H, q), 6.87–6.91 (1H,
m), 7.01–7.01 (4H, m), 7.35 (1H, t, J=8.4 Hz), 7.47–7.51
(1H, m), 7.93 (1H, dd, J=8.24, 1.64 Hz). 13C NMR (CDCl3,
100 MHz): δ 14.3, 32.5, 56.5, 65.8, 114.7, 115.8, 117.9,
120.6, 124.1, 126.8, 127.7, 127.9, 132.1, 133.5, 153.8, 155.7,
164.5, 165.6, 173.1, 175.8. EI MS: m/z (rel. abund.%)=M+1:
339.12. Anal. Calcd. for C20H18O5 (338.12): C, 70.99; H,
5.36 Found: C, 70.96; H, 5.38%.
Colourless gummy solid, IR (KBr) Vmax/cm−1 675, 715,
745, 958, 1168, 1176, 1189, 1214, 1352, 1408, 1468, 1562,
1
1652, 1743, 2921, 2996, 3058, 3415. H NMR (CDCl3,
400 MHz): δ 1.23–1.26 (3H, t), 3.47 (2H, s), 4.07–4.13 (2H,
q), 7.02–7.13 (3H, m), 7.22–7.25 (1H, m), 7.34–7.39 (1H,
m), 7.49–7.53 (1H, m), 7.64–7.72 (1H, m), 7.96 (1H, dd,
J=8.56, 1.0 Hz). 13C NMR (CDCl3, 100 MHz): δ 14.5, 29.6,
58.3, 115.1, 116.4, 117.6, 123.6, 126.2, 126.8, 127.6, 130.6,
131.5, 132.8, 133.2, 135.5, 158.7, 164.7, 172.3, 176.7. EI
MS: m/z (rel. abund.%) = M+1: 327.10. Anal. Calcd. for
C19H15FO4 (326.10): C, 69.93; H, 4.63 Found: C, 69.89;
H, 4.64%.
Ethyl 2‑(2‑(3‑nitrophenyl)‑4‑oxo‑4H‑chromen‑3‑yl)acetate
(3m)
Pale yellow solid, mp. 182–184 °C. IR (KBr) Vmax/cm−1
670, 757, 771, 975, 1135, 1145, 1190, 1235, 1360, 1462,
1474, 1575, 1640, 1732, 2848, 2918, 2989 3170.1H NMR
(400 MHz, CDCl3): δ 1.28–1.31 (3H, t) 3.54 (2H, s),
4.20–4.24 (2H, q) 7.44–7.47 (1H, t) 7.50–7.52 (2H, m),
7.67–7.73 (1H, d, J=8.99), 7.71–7.75 (2H, m), 8.04–8.05
(1H, d, J = 7.99), 8.25–8.27 (dd, 1H, J = 2.00, 7.99),
8.40–8.45 (1H, d, J=7.99), 8.58 (1H, s). 13C NMR (CDCl3,
100 MHz): δ 14.6, 28.5, 62.4, 116.2, 118.9, 120.9, 123.2,
124.8, 126.3, 127.5, 127.8, 128.2, 131.9, 134.5, 148.7,
163.5, 164.6, 170.1, 176.6. EI MS: m/z (rel. abund.%)=M+1:
354.09. Anal. Calcd. for C19H15NO6 (353.09): C, 64.59; H,
4.28; N, 3.96 Found: C, 64.55; H, 4.30; N, 3.95%.
Ethyl 2‑(2‑(2‑nitrophenyl)‑4‑oxo‑4H‑chromen‑3‑yl)acetate
(3j)
Pale yellow solid, mp. 177–179 °C. IR (KBr) Vmax/cm−1
678, 761, 773, 976, 1145, 1159, 1172, 1215, 1375, 1442,
1465, 1578, 1637, 1738, 2846, 2950, 2995, 3070. 1H NMR
(CDCl3, 400 MHz): δ 1.20–1.24 (3H, t), 3.51 (2H, s),
4.04–4.06 (2H, q), 6.09 (1H, dd, J= 13.12, 2.6 Hz), 7.03
(1H, d, J=8.0 Hz), 7.06–7.13 (1H, m), 7.48–7.56 (1H, m),
7.76 (1H, m), 7.97 (1H, dd, J = 7.8, 1.6 Hz), 8.03 (1H, d,
J = 8.20 Hz), 8.08 (1H, dd, J = 8.20, 1.0 Hz). 13C NMR
(CDCl3, 100 MHz): δ 14.4, 31.1, 58.5, 115.2, 116.7, 118.7,
123.9, 124.6, 126.1, 127.8 130.1, 130.9, 132.7, 133.5, 135.7,
156.9, 166.7, 172.4, 175.7. EI MS: m/z (rel. abund.%)=M+1:
354.09. Anal. Calcd. for C19H15NO6 (353.09): C, 64.59; H,
4.28; N, 3.96 Found: C, 64.62; H, 4.25; N, 4.01%.
Ethyl 2‑(2‑(2,4‑dichlorophenyl)‑4‑oxo‑4H‑chromen‑3‑yl)
acetate (3n)
Of-white solid, mp. 134–136 °C. IR (KBr) Vmax/cm−1675,
741, 761, 860, 970, 1047, 1118, 1251, 1323, 1465, 1575,
1685, 1948, 2862, 2975, 3130, 3325. 1H NMR (400 MHz,
CDCl3): δ 1.21–1.24 (3H, t) 3.36 (2H, s), 4.10–4.14 (2H,
q), 7.39–7.7.45 (3H, m) 7.50–7.52 (1H, d, m, J=7.99), 7.57
Ethyl 2‑(2‑(2‑chlorophenyl)‑4‑oxo‑4H‑chromen‑3‑yl)acetate
(3k)
Off-white solid, mp. 164–166 °C. IR (KBr) Vmax/cm−1
(1H, s), 7.67–7.71 (1H, t), 8.24–8.26 (1H, d, J=7.99). 13
C
695, 715, 750, 958, 1125, 1145, 1172, 1190, 1355, 1390,
NMR (100 MHz, CDCl3) δ 14.4, 27.8, 58.9, 117.4, 121.4,
121.7, 127.2, 127.6, 128.8, 130.5, 133.1, 133.8, 134.7, 135.7,
160.4, 162.3, 170.3, 176.1. EI MS: m/z (rel. abund.%)=M+1:
377.03. Anal. Calcd. for C19H14Cl2O4 (376.03): C, 60.50; H,
3.74 Found: C, 60.56; H, 3.71%.
1
1470, 1584, 1655, 1748, 2920, 2978, 2992, 3450. H
NMR (400 MHz, CDCl3): δ 1.20–1.24 (3H, t) 3.49 (2H,
s), 4.08–4.15 (2H, q) 7.38–7.7.49 (4H, m) 7.51–7.57 (2H,
m), 7.67–7.73 (1H, m), 8.25–8.28 (7.54, dd, 1H, J=1.51).
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Journal of the Iranian Chemical Society
Ethyl 2‑(2‑(2,4‑dimethylphenyl)‑4‑oxo‑4H‑chromen‑3‑yl)
acetate (3o)
1560, 1608, 1635, 1708, 1750, 2830, 2945, 3094. 1H NMR
(CDCl3, 400 MHz): δ 1.23 (t, 3H), 3.40 (s, 2H), 3.79 (s,
3H), 3.88 (s, 3H), 4.12 (q, 2H), 6.58 (m, 2H), 7.41 (m, 3H),
7.65 (m, 1H, J = 1.6, 7.7), 8.25 (m, 1H, J = 1.6, 7.8). 13C
NMR (CDCl3, 100 MHz): δ 14.4, 29.1, 55.4, 60.3, 98.7,
104.8, 115.5, 117.7, 117.9, 123.0, 124.3, 125.6, 131.2,
133.3, 156.6, 158.2, 161.3, 162.9, 171.1, 177.8. EI MS: m/z
(rel. abund.%) = M+1: 369.13. Anal. Calcd. for C21H20O6
(368.13): C, 68.47; H, 5.47 Found: C, 68.45; H, 5.48%.
Pale yellow solid, mp. 207–209 °C. IR (KBr) Vmax/cm−1:
668, 757, 781, 865, 967, 1147, 1255, 1322, 1475, 1525,
1630, 1690, 1835, 1925, 2873, 2895, 2963, 3135, 3349.
1H NMR (400 MHz, CDCl3): δ 1.19–1.22 (3H, t), 2.33
(6H, s), 3.42 (2H, s), 4.09–4.12 (2H, q), 7.03–7.06 (2H,
m), 7.11–7.13 (2H, d), 7.18–7.20 (1H, m), 7.24 (1H, d,
J = 7.81 Hz), 7.48 (1H, m). 13C NMR (100 MHz, CDCl3)
δ 14.8, 18.7, 20.8, 27.2, 59.9, 115.9, 119.7, 120.2, 123.6,
125.6, 126.8, 127.8, 131.3, 133.1, 134.6, 136.7, 137.3,
161.5 163.3, 171.3, 177.1. EI MS: m/z (rel. abund.%)=M+1:
337.14. Anal. Calcd. for C21H20O4 (336.14): C, 74.98; H,
5.99 Found: C, 74.95; H, 6.00%.
Ethyl 2‑(4‑oxo‑2‑(3,4,5‑trimethoxyphenyl)‑4H‑chromen‑3
‑yl)acetate (3s) [37]
Of-white solid, mp. 122–124 °C. IR (KBr) Vmax/cm−1: 672,
735, 742, 855, 945, 1030, 1047, 1153, 1180, 1268, 1374,
1423, 1442, 1538, 1608, 1685, 1728, 1750, 2831, 2935,
1
Ethyl 2‑(2‑(3,4‑dimethylphenyl)‑4‑oxo‑4H‑chromen‑3‑yl)
acetate (3p)
3005, 3109. H NMR (CDCl3, 400 MHz): δ 1.26 (t, 3H),
3.59 (s, 2H), 3.90 (s, 6H), 3.93 (s, 3H), 4.20 (q, 2H), 6.93
(s, 2H), 7.45 (m, 2H), 7.69 (m, 1H, J=1.8, 7.7), 8.24 (m,
1H, J=1.5, 7.8). 13C NMR (CDCl3, 100 MHz): δ 14.3, 28.3,
56.2, 60.3, 61.3, 105.1, 115.7, 117.9, 125.2, 125.8, 127.4,
132.6, 134.6, 138.3, 153.7, 159.0, 161.4, 170.9, 176.7. EI
MS: m/z (rel. abund.%) = M+1: 399.14. Anal. Calcd. for
C22H22O7, (398.14): C, 66.32; H, 5.57 Found: C, 66.35; H,
5.55%.
Pale yellow solid, mp. 136–138 °C. IR (KBr) Vmax/cm−1:
671, 755, 775, 855, 957, 1137, 1215, 1352, 1480, 1535,
1628, 1685, 1850, 1930, 2872, 2965, 3125, 3350. 1H NMR
(400 MHz, CDCl3): δ 1.23–1.26 (3H, t), 2.38 (6H, s), 3.45
(2H, s), 4.13–4.15 (2H, q), 7.03–7.10 (2H, m), 7.11–7.13
(2H, d), 7.20 (1H, s), 7.42–7.45 (1H, m), 7.80–7.85 (1H,
dd, J=8.65, 1.76 Hz). 13C NMR (100 MHz, CDCl3) δ 14.5,
18.7, 19.8, 27.8, 61.2, 116.9, 120.9, 122.3, 123.6, 125.6,
126.8, 127.8, 132.3, 133.1, 134.6, 136.7, 137.9, 159.5 160.7,
170.3, 176.1. EI MS: m/z (rel. abund.%) = M+1: 337.14.
Anal. Calcd. for C21H20O4 (336.14): C, 74.98; H, 5.99
Found: C, 74.95; H, 6.00%.
Ethyl 2‑(2‑(naphthalen‑2‑yl)‑4‑oxo‑4H‑chromen‑3‑yl)
acetate (3t)
Off-white solid, mp. 163–165 °C. IR (KBr) Vmax/cm−1
:
648, 765, 878, 948, 1087, 1147, 1268, 1289, 1370, 1403,
1482, 1540, 1638, 1689, 1738, 2848, 2939, 3075, 3149. 1H
NMR (400 MHz, CDCl3): δ 1.22–1.27 (3H, t) 3.35 (2H,
s), 4.15–4.18 (2H, q) 7.05 (m, 2H), 7.07–7.10 (m, 2H),
7.55–7.60 (m, 4H), 7.90–7.95 (m, 3H). 13C NMR (100 MHz,
CDCl3): δ 14.3, 28.1, 61.9, 115.9, 121.9, 122.6, 123.8, 124.3,
125.0, 125.9, 128.6, 130.6, 132.7, 133.1, 134.9, 135.8,
158.4, 160.6, 170.3, 176.7. EI MS: m/z (rel. abund.%)=M+1:
359.12. Anal. Calcd. for C23H18O4 (358.12): C, 77.08; H,
5.06 Found: C, 77.05; H, 5.07%.
Ethyl 2‑(2‑(2,5‑dimethoxyphenyl)‑4‑oxo‑4H‑chromen‑3‑yl)
acetate (3q)
Yellow solid, mp. 214, 216 °C. IR (KBr) Vmax/cm−1: 673,
764, 785, 868, 982, 1037, 1190, 1263, 1374, 1468, 1560,
1623, 1690, 1965, 2865, 2938, 3125. 1H NMR (400 MHz,
CDCl3): δ 1.26–1.29 (3H, t), 2.39 (6H, s) 3.55 (2H, s),
4.17–4.22 (2H, q) 7.17 (1H, s) 7.24 (2H, s), 7.40–7.43 (1H,
t), 7.47–7.49 (1H, d, J=7.99), 7.66–7.69 (1H, t), 8.24–8.25
(1H, d, J=7.99). 13C NMR (100 MHz, CDCl3) δ 14.4, 27.3,
54.7, 55.2, 60.4, 110.7, 111.5, 115.2, 115.7, 118.7, 122.3,
123.8, 127.6, 128.7, 133.4, 148.3, 152.7, 159.5 160.7, 170.3,
176.1. EI MS: m/z (rel. abund.%) = M+1: 369.13. Anal.
Calcd. for C21H20O6 (368.13): C, 68.47; H, 5.47 Found: C,
68.45; H, 5.48%.
Results and discussion
To introduce active ester functionality at the 3-positions of
the favones using favanone as a precursor, conventional
Claisen–Schmidt condensation chemistry was used for fa-
vones preparation. The initial optimization was performed
using a model reaction of favanone and glyoxalic acid with
a catalytic amount of sulphuric acid in ethanol at room tem-
perature. The reaction was too slow and took more than
7 h to get the poorly yielded product. However, TLC sub-
stantiated clean product formation with unreacted starting
Ethyl 2‑(2‑(3,5‑dimethoxyphenyl)‑4‑oxo‑4H‑chromen‑3‑yl)
acetate (3r) [37]
Pale yellow solid, mp. 103–105 °C. IR (KBr) Vmax/cm−1:
675, 760, 765, 850, 962, 1047, 1183, 1265, 1379, 1420,
1 3

Journal of the Iranian Chemical Society
material without any side-product formation. To promote
the reaction further, heat energy was provided. When the
reaction was performed at a refuxed temperature, complete
conversion of favanone to favones was observed on TLC.
With this optimized condition, the scope of substituted
aryl rings was investigated. For this reaction to proceed,
a catalytic amount of sulphuric acid is required. However,
with optimized results in our hands, this reaction proved
an easy and reliable addition of ester at 3-position, and the
plausible mechanism of reaction pathway is demonstrated
in Fig. 4. The formation of C-3-substituted favones from
favanone and glyoxalic acid is proposed via acid-catalysed
Claisen–Schmidt condensation. A plausible mechanistic pro-
posal could involve initially protonation of favanone leading
to the formation of enol-type intermediate (I); later interme-
diate (II) was formed through resonance stabilization. Here
we assume that the intermediate II attacks on the carbonyl
carbon of glyoxalic acid which results into formation of
intermediate III. Subsequently, dehydration gave interme-
diate IV. To render stability, the intermediate IV converted to
V. With this idea in mind, we proposed that the intermediate
VI was formed through proton exchange. Now the electro-
philicity of VI has been increased. The compound VI on
nucleophilic addition gave intermediate VII. Followed by
deprotonation, an unstable intermediate VIII was formed
which on dehydration results into fnal C-3 functionalized
favones.
Here we developed an excellent strategy for the direct
ester functionality at 3-position of favone which comes
from favanones under mild reaction conditions, having
an inexpensive catalyst, broad substrate scope along with
high yields. Hence, we believe that this methodology will
Fig. 4 A plausible mechanism
based on the Claisen–Schmidt
condensation for the synthesis
of 3-substituted favones
1 3

Journal of the Iranian Chemical Society
Table 1 Synthesis of novel
Entry
R1
R-2
R3
R4
R5
Time (h)
Yield (%)
3-substituted favones derivative
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
OMe
F
H
H
H
H
H
H
H
H
H
H
H
OMe
NO2
H
H
Me
H
H
Cl
Me
OMe
Br
NO2
F
H
H
H
H
H
H
Cl
Me
Me
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2
97
95
98
93
90
91
90
92
90
85
85
80
80
83
92
85
80
85
88
90
1.5
2.5
1.5
2
1.5
1.5
2
2
1.5
2
2.5
1.5
2
1.5
2
3j
3k
3l
NO2
Cl
H
3m
3n
3o
3p
3q
3r
3s
3t
H
Cl
Me
H
OMe
H
OMe
OMe
OMe
2
OMe
OMe
2.5
2.5
2.5
H
Naphthyl favanone
be more compliant over conventional methods. Stille and
Heck’s reactions were often applied for the introduction of
varied substituents in the 3-positions, whereas Sonogashira
and Suzuki reactions were only applied in the 8-position
[34–37].
the reactivity. Thus, the process which omits strong basic
conditions, cessation of expensive transition metal com-
plexes, and pre-functionalized starting material will be a
more benefcial and straightforward synthetic strategy for the
preparation of exclusively useful favone derivatives. There-
fore, in this work, structural modifcations on the C ring of
favanones 1a–1t, leading to compounds 3a–3t, respectively,
were reported.
The Stille reaction is widely used to introduce either
an allyl or benzyl substituents. The allyl substituent can
be functionalized through various reactions, for instance,
hydroxylation followed by further oxidation to an aldehyde
or a carboxylic acid. The Heck reaction, which is widely
applied to introduce an α,β-unsaturated ester functionality,
can be modifed by additional reactions. The similar advan-
tage of our protocol is that this reaction gives directly a ver-
satile ester functional group at 3-positions of favones which
will be easily converted to another functional group that will
help to develop further useful building blocks for favonoids
chemistry (Table 1).
Conclusions
A simple synthetic strategy for 3-functionalized favones
was developed starting from a variety of favanone. This
approach allows the introduction of diferent substituents
or functionalities at the 3-positions of favones using FGI
strategy. Results show that the choice of a substituent on aryl
rings does not infuence the reactivity at the other positions
of the favones ring system. Hence, these protocols would
be a good inclusion to the environmentally benign methods
reported for the said category of favonoids synthesis.
The scope of this acid-catalysed Claisen–Schmidt reac-
tion was examined under optimized conditions. In all the
tested case, the desired C-3 functionalization reaction pro-
ceeded smoothly. In general, the reaction performed on vari-
ous para-, ortho-, meta- as well as disubstituted favanones
(1a–t), thus giving the corresponding C-3 functionalized
flavones (3a–t) with 80–97% yields. Various valuable
functional groups at various positions on favanone ring
were tolerated, such as trimethoxy, chloro, furo, bromo,
methyl, nitro, dichloro, dimethyl, and naphthyl (Table 1).
These results indicate that the electron-withdrawing or
electron-donating properties in the aryl rings do not afect
Acknowledgements This research was supported by the KU Research
Professor Program of Konkuk University.
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