A novel route to synthesis of flavones from salicylaldehyde and acetophenone derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.02.108

Convenient, facile, and alternate synthesis of medicinally important flavones is reported. The 2-hydroxychalcones derived from condensation between acetophenones and salicylaldehyde, underwent oxidative cyclization on heating in the presence of catalytic iodine, generating diversified flavones under solvent-free conditions. Eleven compounds have been synthesized in good to excellent yields and their mechanism of formation is described.

Full text of DOI:10.1016/j.tetlet.2012.02.108

Tetrahedron Letters 53 (2012) 2355–2359
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel route to synthesis of flavones from salicylaldehyde and
acetophenone derivatives q
⇑
Koneni V. Sashidhara , Manoj Kumar, Abdhesh Kumar
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, (CSIR–CDRI), Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Convenient, facile, and alternate synthesis of medicinally important flavones is reported. The 2-hydroxy-
chalcones derived from condensation between acetophenones and salicylaldehyde, underwent oxidative
cyclization on heating in the presence of catalytic iodine, generating diversified flavones under solvent-
free conditions. Eleven compounds have been synthesized in good to excellent yields and their mecha-
nism of formation is described.
Received 19 January 2012
Revised 23 February 2012
Accepted 26 February 2012
Available online 5 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Synthesis
Salicylaldehyde
Chalcones
Iodine
Flavones
Flavonoids, one of the important group of plant secondary
metabolites,1 are well known for having a wide range of pharmaco-
logical activities such as anti-cancer,2 anti-inflammatory,3
anti-osteoporotic,4 anti-diabetic,5 and metal chelating activities.6
Because of their broad range of significant biological activities, this
family of molecules has been extensively investigated and more
than 4000 chemically unique flavonoids have been isolated from
plants. Figure 1 shows the representative chemical structures of
some naturally occurring bioactive flavone derivatives.15–18 As a
result, this important ring system continues to hold a charm for
chemist worldwide.
attractive alternative to synthesize chromones,9 however, in some
situations, this reaction produces a mixture of six-membered chr-
omones and five-membered aurones. Thus, the classical methods
possess a number of drawbacks, such as, moderate yields, moder-
ate purity of products, and poor reaction selectivity.
Intrigued by the above observations and our earlier work on
biologically active alpha-chromones,10 we herein, wish to report
Traditionally, flavones have been prepared by the Baker–
Venkatraman–rearrangement which involves the conversion of
2-hydroxyacetophenones into benzoyl esters, followed by rear-
rangement in base into 1,3-diphenylpropane 1,3-diones, which
upon cyclization under acidic conditions furnishes flavones.7 On
the other hand, 2-hydroxychalcone, synthesized from 2-hydroxy-
acetophenone and benzaldehyde under Claisen–Schmidt condi-
tions can undergo oxidative cyclization to furnish flavones ring
system (Scheme 1).8 These reactions suffer from the use of strong
bases, acids, and particularly 2-hydroxychalcone synthesized from
2-hydroxyacetophenone and benzaldehyde, utilize long reaction
time and low yields. Furthermore, the palladium catalyzed carbon-
ylation of o-iodophenols with terminal alkynes has become an
q
Part IX in the series, ‘Studies on Novel Synthetic Methodologies.’
⇑
Corresponding author. Tel.: +91 9919317940; fax: +91 522 2628493.
E-mail addresses: kv_sashidhara@cdri.res.in, sashidhar123@gmail.com (K.V.
Sashidhara).
Figure 1. Naturally occuring flavones with potent biological activities.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.108

2356
K. V. Sashidhara et al. / Tetrahedron Letters 53 (2012) 2355–2359
Scheme 1. Our protocol for synthesis of flavones using salicylaldehyde as a key substrate.
Scheme 2. Reagents and conditions: (a) 10% aq. KOH, ethanol, reflux, 2.5 h. (b) l2, 110–130 °C, 1.5 h.
Table 1
Table 2
Optimization of reaction conditions for the synthesis of flavones 3b
Optimization of reaction solventsb
Entry
Product
Solvent
Yielda (%)
1
2
3
4
5
6
7
3b
3b
3b
3b
3b
3b
3b
1,4-Dioxane
Acetonitrile
Ethanol
Methanol
THF
56
0
33
12
15
20
74
DMSO
Neat
Entry
Product
Catalyst
Time (h)
Yielda (%)
a
Isolated yield.
All reactions were run up to 1.5 h.
1
2
3
4
5
6
7
8
3b
3b
3b
3b
3b
3b
3b
3b
AlCl3
ZnCl2
BF3ÁOEt2
SnCl2Á2H2O
HgCl2
FeCl3
SnCl4
Iodine
2.5
3.0
3.0
2.0
3.0
3.0
3.0
1.5
28
10
0
54
5
5
0
74
b
SnCl4, HgCl2, and Iodine) using chalcone 2b as the starting sub-
strate. It is quite apparent from Table 1 that among various Lewis
acid catalysts screened, only iodine afforded the finest results with
respect to the reaction time and yield. It was also found that the
use of 10 mol % of iodine gave the best results, whereas, other Le-
wis acids completed the reaction in moderate yield or resulted in
multiple products. Notably, the reaction was conducted under sol-
vent-free conditions. Initially, the reaction was attempted with dif-
ferent solvents but the yields were found to be better in the
absence of any solvent as shown in Table 2 (entry 8).
With these findings, to test the generality of this synthetic
route, a variety of substituted acetophenones (with both electron
withdrawing and electron donating) were reacted with salicylalde-
hydes under the conditions described above to give the corre-
sponding final flavone derivatives in very satisfactory yields.
These results are summarized in Table 3.
On the basis of the experimental results, a plausible mechanism
for the formation of flavones 3b from the 2-hydroxychalcone 2b
via iodine mediated oxidative cyclization is presented in Scheme 3.
The mechanism involves the following steps: Isomerization (the
possibility of thermally induced trans- cis chalcone isomerization
cannot be ruled out) of the initial adduct, trans-3-(2-hydroxy-
phenyl)-1-(4-methylphenyl)prop-2-en-1-one to cis isomer13
a
Isolated yield.
our finding on solvent-free synthesis of flavones using molecular
iodine as catalyst. In our methodology 2-hydroxychalcones were
synthesized using easily accessible starting materials, salicylalde-
hyde, and acetophenones (Scheme 1) which furnished respective
chalcones (2a–k) in good to excellent yields.11
Our synthetic approach was initiated with the synthesis of var-
ious intermediate chalcones (2a–k) which was achieved through
Claisen–Schmidt condensation between salicylaldehyde and aceto-
phenone in a mixture of 10% KOH(aq) and ethanol under refluxing
condition for 2–2.5 h (Scheme 2). These chalcones were then oxi-
datively cyclized in the presence of iodine to furnish the flavone
derivatives (3a–k) in good yields.12 All the compounds were char-
acterized using 1H NMR, 13C NMR, 2D NMR, and mass spectrome-
try. The purity of these compounds was ascertained by TLC and
spectral analysis.
Initially, we have proceeded to a preliminary study of a catalytic
evaluation of Lewis acids (BF3ÁOEt2, SnCl2Á2H2O, Bi(NO2)3, AlCl3,

K. V. Sashidhara et al. / Tetrahedron Letters 53 (2012) 2355–2359
2357
Table 3
Synthesis of flavones (3a–k)
Entry
1
Substrate (1)
Substrate (2)
Product
Reaction time (h)
Yielda (%)
OH
OH
OH
O
O
O
CHO
CHO
CHO
O
1.5
72
74
O
O
3a
2
3
1.5
1.4
O
O
3b
OMe
76
78
OMe
O
O
3c
OH
OH
O
OMe
OMe
CHO
CHO
4
5
1.4
1.5
OMe
OMe
OMe
O
O
O
3d
OMe
OMe
OMe
72
MeO
O
OMe
O
O
3e
OH
OH
OH
F
CHO
CHO
CHO
6
7
8
2.0
2.0
2.5
68
70
F
O
O
3f
O
Cl
Cl
O
O
O
3g
Br
66
Br
O
3h
(continued on next page)

2358
K. V. Sashidhara et al. / Tetrahedron Letters 53 (2012) 2355–2359
Table 3 (continued)
Entry
Substrate (1)
Substrate (2)
Product
Reaction time (h)
Yielda (%)
OH
O
O
O
O
S
CHO
O
O
S
9
2.4
62
O
O
3i
3j
OH
CHO
10
2.4
2.5
65
60
O
OH
CHO
O
11
Br
Br
O
3k
Reagents and conditions: (a) 10% aq. KOH, ethanol, reflux, 2.5 h. (b) I2, 110–130 °C, 1.5 h.
a
Isolated yield.
Scheme 3. Plausible mechanism of reaction.
followed by intramolecular cyclization results in its hemiacetal
species (i), which gets converted to more reactive flavylium ion
(ii).14 Furthermore, water molecules attack on the more reactive
3-position of (ii) to form adduct (iii), that on oxidation in the pres-
ence of iodine yields flavones (3a). To the best of our knowledge,
this is the first report for the synthesis of flavones from chalcones,
whereas the oxygen which forms the ether is introduced as salicyl-
aldehyde, while previously reported procedure involves the oxy-
gen derived from 2-hydroxyacetophenone.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.108.
References and notes
1. Verma, A. K.; Partap, R. Nat. Prod. Rep. 2010, 27, 1571–1593.
2. Liu, H. L.; Jiang, W. B.; Xie, M. X. Recent Pat. Anti-Cancer Drug Discov. 2010, 5,
152–164.
In conclusion, we have demonstrated here a simple, efficient,
and alternate route for the synthesis of flavones utilizing molecular
iodine as a catalyst for the first time. This methodology involves
the use of salicylaldehydes instead of 2-hydroxyacetophenone, in
which formation of chalcone is quite easier with high yields. The
advantages of this method comprise good substrate generality,
the use of inexpensive reagents/ and catalyst and experimental
operational ease. Additionally, our protocol is environmental
friendly and devoid of organic solvents and metal catalysts.
3. Manthey, J. A.; Grohmann, K.; Montanari, A.; Ash, K.; Manthey, C. L. J. Nat. Prod.
1999, 62, 441–444.
4. Maurya, R.; Rawat, P.; Sharan, K.; Siddiqui, J. A.; Swarnkar, G.; Mishra, G.;
Manickavasagam, K.; Arya, R.; Chattopadhyay, N. World Pat. 110003, 2009.
5. Kunimasa, K.; Kuranuki, S.; Matsuura, N.; Iwasaki, N.; Ikeda, M.; Ito, A.; Sashida,
Y.; Mimaki, Y.; Yano, M.; Sato, M.; Igarashi, Y.; Oikawa, T. Bioorg. Med. Chem.
Lett. 2009, 19, 2062–2064.
6. Gao, X. In Seabuckthorn (Hippophae L.) Biochemistry and Pharmacology; Singh,
Virendra, Ed.; Daya Publishing House: Delhi, 2006; Vol. 2, pp 390–401.
7. (a) Baker, W. J. Chem. Soc. 1933, 1381; (b) Mahal, H. S.; Venkataraman, K. J.
Chem. Soc. 1934, 1767.
8. (a) Zhiyun, D.; Kun, Z.; Huifen, N.; Huaqiang, Z.; Jian, W. Org. Biomol. Chem.
2011, 9, 6930–6933; (b) Franco, C.; Rossella, F.; Adriana, B.; Paola, C.; Daniela,
S.; Francesca, R.; Matilde, Y.; Francisco, O.; Francesco, O.; Stefano, A.; Roberto,
C.; Rosella, F.; Luisa, S. M. Bioorg. Med. Chem. 2010, 18, 1273–1279; (c) Naseem,
Ahmed.; Hasrat, Ali.; Johan, E. vanL. Tetrahedron Lett. 2005, 46, 253–256; (d)
Hemanth, K. K.; Paramasivan, P. T. Tetrahedron 2007, 63, 9531–9535.
9. (a) Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765–1768; (b) Awuah, E.; Capretta, A.
Org. Lett. 2009, 11, 3210–3213; (c) Barnard, C. F. J. Organometallics 2008, 27,
5402–5422; (d) Liang, B.; Huang, M.; You, Z.; Xiong, Z.; Lu, K.; Fathi, R.; Chen, J.;
Yang, Z. J. Org. Chem. 2005, 70, 6097–6100; (e) Yang, Q.; Alper, H. J. Org. Chem.
Acknowledgments
Instrumentation facilities from SAIF, CDRI are gratefully
acknowledged. M.K. and A.K. are thankful to CSIR, New Delhi, India
for financial support. This is CSIR–CDRI communication number
8208.

K. V. Sashidhara et al. / Tetrahedron Letters 53 (2012) 2355–2359
2359
2010, 75, 948–950; (f) Ciattini, P. G.; Morera, E.; Ortar, G.; Rossi, S. S.
Tetrahedron 1991, 47, 6449–6456.
a calcium chloride guard tube. The mixture was stirred at 100–110 °C
temperature for 1.5 h. After completion of the reaction (TLC monitoring), the
mixture was treated with aq. Na2S2O3 solution (5%, 10 mL) and the product
was extracted with chloroform (3 Â 20 mL). The combined organic layers were
dried with anhydrous sodium sulphate, concentrated in vacuo and purified by
column chromatography (100–200 mesh) (ethyl acetate:hexane) to afford the
pure compound 3b. White solid; yield: 74%; mp 109–110 °C; 1H NMR (CDCl3,
300 MHz): 8.22 (dd, J = 7.9, 1.5 Hz, 1H), 8.25 (d, J = 8.2 Hz, 2H), 7.72–7.67 (m,
1H), 7.56 (d, J = 8.1 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 6.80
(s, 1H), 2.44 (s, 3H); 13C NMR (CDCl3, 75 MHz): 178.6, 163.8, 156.4, 142.4,
133.8, 129.9, 129.1, 126.4, 125.8, 125.3, 124.2, 118.2, 107.1, 21.7; ESI-MS (m/z):
237 (M+H)+.
10. (a) Sashidhara, K. V.; Kumar, A.; Kumar, M.; Singh, S.; Jain, M.; Dikshit, M.
Bioorg. Med. Chem. Lett. 2011, 21, 7034–7040; (b) Sashidhara, K. V.; Kumar, M.;
Modukuri, R. K.; Srivastava, A.; Puri, A. Bioorg. Med. Chem. Lett. 2011, 21, 6709–
6713; (c) Sashidhara, K. V.; Kumar, A.; Chatterjee, M.; Rao, K. B.; Singh, S.;
Verma, A. K.; Palit, G. Bioorg. Med. Chem. Lett. 2011, 21, 1937–1941; (d)
Sashidhara, K. V.; Kumar, A.; Kumar, M.; Sonkar, R.; Bhatia, G.; Khanna, A. K.
Bioorg. Med. Chem. Lett. 2010, 20, 4248–4251; (e) Sashidhara, K. V.; Rosaiah, J.
N.; Kumar, A.; Bhatia, G.; Khanna, A. K. Bioorg. Med. Chem. Lett. 2010, 20, 3065–
3069; (f) Sashidhara, K. V.; Kumar, A.; Kumar, M.; Srivastava, A.; Puri, A. Bioorg.
Med. Chem. Lett. 2010, 20, 6504–6507; (g) Sashidhara, K. V.; Kumar, A.; Kumar,
M.; Sarkar, J.; Sinha, S. Bioorg. Med. Chem. Lett. 2010, 20, 7205–7211; (h)
Sashidhara, K. V.; Rosaiah, J. N.; Kumar; Gara, R. K.; Nayak, L. V.; Srivastava, K.;
Bid, H. K.; Konwar, R. . Bioorg. Med. Chem. Lett. 2010, 20, 7127–7131; (i)
Sashidhara, K. V.; Kumar, A.; Agarwal, S.; Kumar, M.; Kumar, B.; Sridhar, B. Adv.
Syn. Catal. (in press, accepted manuscript).
13. (a) Gomes, R.; Parola, A. J.; Bastkowski, F.; Polkowska, J.; Klärner, F. G. J. Am.
Chem. Soc. 2009, 131, 8922–8938; (b) Roque, A.; Lodeiro, C.; Pina, F.; Maestri,
M.; Dumas, S.; Passaniti, P.; Balzani, V. J. Am. Chem. Soc. 2003, 125, 987–994.
14. Fichtner, C.; Remennikov, G.; Mayr, H. Eur. J. Org. Chem. 2001, 4451–4456.
15. Gabrielska, J.; Soczyn´ ska-Kordala, M.; Przestalski, S. J. Agric Food Chem. 2005,
53, 76–83.
16. Martens, S.; Mithofer, A. Phytochemistry 2005, 66, 2399–2407.
17. Halliwell, B.; Aeshbach, R.; Loliger, J.; Aruoma, O. I. Food Chem. Toxicol. 1995, 33,
601–617.
11. Mazimba, O.; Masesane, I. B.; Majinda, R. R. Tetrahedron Lett. 2011, 52, 6716–
6718.
12. Representative Synthesis of 2-p-tolyl-4H-chromen-4-one (3b): A mixture (E)-3-
(2-hydroxyphenyl)-1-p-tolylprop-2-en-1-one 2b (0.4 mmol and I2 (10 mol %)
were charged in a 10 mL round bottom flask fitted with a reflux condenser and
18. Ammar, N. M.; El-Diwany, A. I. J. Islamic Acad. Sci. 1988, 1, 72–73.