Facile syntheses of 3-hydroxyflavones

Article abstract of DOI:10.1021/ol300310e

Modification of the present synthetic methods led to the syntheses of 3-hydroxyflavones in a shorter reaction time, with simple purification and higher yields. Application of the method provided the syntheses of 3HFs having a hydroxyl group on the phenyl ring (ring B) in one step, which is an improvement compared to the four steps, long reaction time, and low yield using the current method available in the literature.

Full text of DOI:10.1021/ol300310e

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1576–1579
Facile Syntheses of 3-Hydroxyflavones
Simay Gunduz,†,‡ Ahmet C. Goren,† and Turan Ozturk*,†,‡
Chemistry Group Laboratories, TUBITAK UME, Gebze, Kocaeli, Turkey, and
Department of Chemistry, Istanbul Technical University, Istanbul, Turkey
ozturktur@itu.edu.tr
Received February 7, 2012
ABSTRACT
Modification of the present synthetic methods led to the syntheses of 3-hydroxyflavones in a shorter reaction time, with simple purification and
higher yields. Application of the method provided the syntheses of 3HFs having a hydroxyl group on the phenyl ring (ring B) in one step, which is
an improvement compared to the four steps, long reaction time, and low yield using the current method available in the literature.
3-Hydroxyflavones (3HFs) 1 (Figure 1) are a unique
class of flavonoids, which are composed of fused phenyl
and pyranyl rings (A- and C-rings) and a phenyl moiety
(ring B) attached to the ring C. They are mainly found in a
wide variety of natural sources and are known to affect
various biological processes, including the development of
cancer, platelet aggregation, detoxification, and inflam-
matory and immune responses.1 Moreover, it has been
indicated that a daily intake of flavonoids from fruits and
vegetables reduces the risk of coronary heart disease.2
Among 3HFs, quercetin3 and kaempferol4 are the most
known natural 3-hydroxyflavones.
Figure 1. 3-Hydroxyflavone.
In addition to their important biological properties,
3HFs are environmentally sensitive (solvatochromic) fluo-
rescent dyes, which make them attractive for researchers
as prospective molecular fluorescent sensors, particularly
for monitoring biomolecular interactions.5 This property
comes from their well separated dual emission bands in
† TUBITAK-UME.
‡ Istanbul Technical University.
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Chopra, K. Drug Chem. Toxicol. 2005, 27, 145–156. (e) Middleton, E.
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r
10.1021/ol300310e
Published on Web 03/08/2012
2012 American Chemical Society

Table 1. Synthesized 3HFa
a Experimental conditions: (i) NaOH (solid), MeOH, reflux; (ii) NaOH (0.5 N), H2O2. While P1ꢀP4 were extracted with EtOAc, P4ꢀP17 were
filtered after the crude product was poured into ice-water (see the Supporting Information for the experimental details).
Org. Lett., Vol. 14, No. 6, 2012
1577

fluorescence spectra, originated from normal (N*) and
phototautomer forms (T*) of an excited state intramole-
cular proton transfer (ESIPT) reaction.6 The ratio of the
intensities of these two bands is strongly sensitive to the
environment of the molecule, including polarity7 and
hydrogen bonding perturbations in proteins,8 micelles,9
and polymers.10 Recently, the ESIPT property of 3HF
enabled thesynthesis of an analogue of 3HF, P10 (Table 1,
entry 10), incorporating thiophene in place of phenyl ring
B, as a material for bulk heterojunction solar cells.11
In our search for the synthesis of new 3HFs, particularly
having a hydroxyl group on ring B, a more efficient
synthetic method was developed with modifications of
the current synthetic methods, which led to the syntheses
of various 3HF derivatives, including 3HFs having a
4-hydroxyl group on ring B. The syntheses were achieved
with higher yields and shorter reaction times and were easy
to isolate with no intermediate and side product such as
chalcone and aurone, respectively (Table 1). One can
realize that, in spite of the importance of 3HFs, there are
limited synthetic methods available in the literature, the
oldest of which is Auwers synthesis.12 As it consists of a
series of reactions, currently, the more modern Algarꢀ
FlynnꢀOyamada (AFO) reaction is widely applied.11,13
However, it is not a very efficient one as well. It involves a
couple of steps such as the preparation of chalcone and its
oxidative cyclization reaction, which results in two pro-
ducts, 3HF and aurone. Moreover, the reaction requires a
long reaction time (such as days or, if lucky, overnight) to
complete, tedious workup, and isolation processes of the
products. The reaction yields are no more than 40%, in
general ∼15ꢀ35%.5h,6b,c,7,14
involves four steps, starting with the reaction of 2-hydro-
xyacetophenone K1 with 4-methoxybenzaldehyde 2, and
the whole synthesis requires 113 h to complete (Figure 2).15
To obtain P1 in one step, we reacted 2-hydroxyacetophe-
none K1 with 4-formylphenylboronic acid A1 (Table 1,
entry 1). Unfortunately all our attempts applying conven-
tional reaction methods did not give any satisfactory re-
sult. On the other hand, when the reaction was performed
in refluxing methanol in the presence of solid sodium
hydroxide for 5 h, followed by in situ oxidative cyclization
with hydrogen peroxide at room temperature, P1 was
obtained in one step with a relatively high yield, 65%, by
simply extracting the crude product, which did not require
any further purification (see Supporting Information for
experimental details). In order to understand if the new
modified reaction condition will be successful with hydro-
xyphenylaldehydes to obtain the 3HFs P1ꢀP4, attempts
were performed with the reactions of 4-hydroxybenzal-
dehde and 2-hydroxy-5-nitrobenzaldehyde A4 with ke-
tones K1ꢀK4. Although all attempts for the syntheses of
flavones P1ꢀP3 failed, P4 was successfully obtained in
moderate yield, 35% (Table 1, entry 4). This could be due
to a greater sensitivity of the para hydroxyl substituted
phenyls to the environment, compared with the ortho
hydroxy substituted one.
Two more 3HFs having a 40-hydroxyphenyl moiety were
synthesized satisfactorily in moderate yields, 44 and 40%,
applying a new reaction condition to 4- formylphenyl-
boronic acid (Table 1, entries 2 and 3). Then, since such a
successful new reaction procedure is now available, we
decided to apply it to the syntheses of a series of 3HFs
P5ꢀP17, reacting the corresponding ketones K5ꢀK17
with aldehydes A5ꢀA17, respectively, which included the
3HF analogue P10 for bulk heterojunction solar cells,
mentioned above.11 (Table 1, entries 5ꢀ17, entry 10,
respectively). New reactions gave the 3HFs in shorter
reaction times (2, 3 h) and with better yields, even reaching
79%. P10 was obtained in 55% yield in 3 h, which was
reported to be synthesized in two steps, overnight, with an
overall yield of 26%.
Concerning the synthesis of 3HF P1, having a hydroxyl
group on ring B, the synthesis available in the literature
(6) (a) Klymchenko, A. S.; Demchenko, A. P. J. Am. Chem. Soc.
2002, 124, 12372–12379. (b) Klymchenko, A.; Ozturk, T.; Pivovarenko,
V.; Demchenko, A. Can. J. Chem. 2001, 79, 358–363. (c) Klymchenko,
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538, 25–28.
(9) Klymchenko, A. S.; Demchenko, A. Langmuir 2002, 18, 5637–
5639.
Fluorescence spectra of the 3HFs displayed two bands,
N* and T*, between 309ꢀ505 and 480ꢀ608 nm, respec-
tively, which are a typical indication of ESIPT reactions of
3HFs (Table 2, see Supporting Information).
Environmental sensitivity (solvatochromic effect) of the
3HFs was demonstrated with the flavone P1, which, upon
(10) Dharia, J. R.; Johnson, K. F.; Schlenoff, J. B. Macromolecules
1994, 27, 5167–5172.
(11) Chen, D.-Y.; Chen, C.-L.; Cheng, Y.-M.; Lai, C.-H.; Yu, J.-Y.;
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Chou, P.-T. ACS Appl. Mater. Interfaces 2010, 2, 1621–1629.
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Jain, N.; Mely, Y. J. Phys. Chem. B 2008, 112, 12050–12055. (b) M’Baye,
G.; Klymchenko, A. S.; Yushchenko, D. A.; Shvadchak, V. V.; Ozturk,
T.; Mely, Y.; Duportail, G. Photochem. Photobiol. Sci. 2007, 6, 71–76. (c)
Klymchenko, A. S.; Pivovarenko, V. G.; Ozturk, T.; Demchenko, A. P.
New J. Chem. 2003, 27, 1336–1343. (d) Klymchenko, A. S.; Pivovarenko,
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Figure 2. Literature synthesis of 3HF, having hydroxyl on ring B.14
(15) Sagrera, G.; Seoane, G. Synthesis 2010, 16, 2776–2786.
Org. Lett., Vol. 14, No. 6, 2012
1578

Table 2. Spectroscopic Data of 3HF Derivativesa
3HF
λabs
λN*
λT*
max
solvent
IN*/IT*
QY
max
max
P1
351
419
536
acetone
CH2Cl2
CH2Cl2
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
acetone
acetone
CH2Cl2
EtOAc
0.076
0.025
0.009
6.03
0.10
0.10
0.13
0.09
0.22
0.07
0.29
0.09
0.18
0.21
0.26
0.17
0.06
0.03
0.20
0.17
0.11
P2
356
346
414
346
317
349
400
343
364
460
448
321
329
355
457
349
420
401
353
420
418
418
488
392
423
393
398
394
502
399
406
410
530
533
496
530
532
525
567
522
548
545
551
532
580
547
551
543
P3
P4
P5
0.04
P6
0.003
0.002
0.446
0.007
0.12
P7
P8
P9
P10
P11
P12
P13
P14
P15
P16
P17
0.017
0.011
0.004
0.68
Figure 3. Fluorescence spectra of 3HF P1 (0.165 mM in THF),
titrated with H2O.
acetone
acetone
acetone
0.014
0.024
0.04
a λabsmax, absorptionmaxima;λN*max and λT*max, fluorescence maxima
of N* and T* bands. Fluorescence quantum yields (QY) were measured
using anthracene in ethanol as a reference.
3HFs having a hydroxyl group on the phenyl ring B. The
reaction does not lead to any side products, and 3HFs can
be isolated from the reaction mixture by simple filtration,
which are pure enough for further use. As the current
methods produce lower yields with various side products,
which make their isolation difficult, the method presented
herein will be useful for the syntheses of wide variety of
3-hydroxyflavones.
Figure 4. Ratiometric change of N*/T* fluorescence band in-
tensities of P1 upon addition of water.
Acknowledgment. We thank Istanbul Technical Uni-
versity for a grant to Simay Gunduz (PhD) and Gokhan
Bilsel of TUBITAK UME for mass measurements.
addition of water, exhibited a ratiometric increase and
decrease of N* and T* bands, respectively (Figure 3). A
linear ratiometric change of the two bands was depicted in
Figure 4.
In conclusion, a rapid and more efficient method than
the methods available in the literature has been developed.
It is applicable to the syntheses of various 3HFs, including
Supporting Information Available. Detailed experi-
mental procedures and compound characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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