Synthesis and properties of 3-acyl-γ-pyrones, a novel class of flavones and chromones

Article abstract of DOI:10.1016/j.tetlet.2005.04.010

Using modified Baker-Venkataraman reaction a novel class of 3-acyl flavones and chromones have been synthesised. Reaction mechanism for their formation have been elucidated. The properties of 3-acyl flavonoids indicate them to be precursors for the synthesis of flavones.

Full text of DOI:10.1016/j.tetlet.2005.04.010

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4119–4121
Synthesis and properties of 3-acyl-c-pyrones, a novel class
of flavones and chromones
a,
a
a
a
b
A. K. Ganguly, S. Kaur, P. K. Mahata, D. Biswas, B. N. Pramanik and T. M. Chan
b
*
a
Stevens Institute of Technology, Hoboken, NJ 07030, USA
Schering-Plough Research Institute, Kenilworth, NJ 07033-1300, USA
b
Received 10 March 2005; accepted 1 April 2005
Availableonline19 April 2005
Abstract—Using modified Baker–Venkataraman reaction a novel class of 3-acyl flavones and chromones have been synthesised.
Reaction mechanism for their formation have been elucidated. The properties of 3-acyl flavonoids indicate them to be precursors
for the synthesis of flavones.
Ó 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
verted to esters 2, which undergo rearrangement in the
presence of potassium hydroxide and pyridine to the
diketones 3, which then undergo cyclisation to 4 under
rather harsh conditions for example treatment with
concentrated sulfuric acid or heating with glacial acetic
acid.
Flavonoids area w el l known class of natural products
and have been known for a long time to possess anti-
oxidant properties. Recent reports suggesting their
possible use in cancer chemotherapy involving kinase
1
O
R1
OH
CH
1
O
O
OH
O
O
O
R1
R COCl / Py
R
R
R
R
R1
3
CH3
O
O
1
3
2
4
inhibition or apoptosis attracted our attention and we
decided to investigate whether a library of flavonoids
could be synthesised conveniently for biological testing.
Over a period of years several groups have investigated
and improved upon the experimental conditions of
Baker–Venkataraman reaction amongst which the
3
work of Riva and colleagues attracted our attention.
To achieve this objective we performed solution chemis-
2
In their procedure compounds such as 5 were heated
with acyl chlorides in the presence of 1,8-diazabicyclo
[5.4.0] undec-7-ene (DBU) and pyridine to obtain
compounds of general structures 6.
try following Baker–Venkataraman reaction for the
synthesis of flavonoids. In Baker–Venkataraman reac-
tion substituted 2-hydroxy acetophenones 1 arecon-
O
O
R2
R2
1
R COCl
2
3
R = CH or H; R = esters or olefins;
3
1
R1
R = aliphatic, aromatic or alicyclic groups
OH
O
R3
R3
5
6
Keywords: Synthesis; Heterocycles.
*
Corresponding author. Tel.: +1 201 216 5540; fax: +1 201 216 8240; e-mail: akganguly1@aol.com
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.010

4120
A. K. Ganguly et al. / Tetrahedron Letters 46 (2005) 4119–4121
2. Present work
Compound 9e, C H O Br , shows H at d 6.28 and
22 12 5 2 6
H at d 6.54, which are mutually meta coupled. The
8
As we were interested in synthesising compounds,
which resembled naturally occurring flavonoids we
signal for H3 proton, which appears at d ꢀ 6.64 in
1
3
flavonoids is missing in 9e and the C NMR spectrum
shows the presence of carbonyl groups at d 179.6 and d
191 assigned to C and C , respectively. NMR spectra
0
0
repeated the above work with 2 ,4 -dihydroxy and
0
0
0
2
,4 ,6 -trihydroxy acetophenones and made an unex-
pected observation. In our hands this reaction yielded
-acyl-c-pyrones, which to the best of our knowledge
4
17
of 9e also shows the presence of two exchangeable phe-
nolic hydroxyl groups at d 11.1 and d 12.1 assigned to
the OH groups at 7- and 5-positions, respectively, and
a total of 10 aromatic protons out of which H and H
3
have never been reported in the literature. In this com-
munication wewish to discloseour pr el iminary r es ults
including the properties of 3-acyl-c-pyrones and the
mechanism of their formation. Some comments on
Baker–Venkataraman reaction are also being presented.
We also believe that 3-acyl-c-pyrones are versatile
intermediates for the preparation of substituted flav-
ones.
6
8
5
have already been identified. Compound 9b, C H O
14
1
4
shows H at d 6.2 and H at d 6.4, which aremutually
6
8
1
3
meta coupled. The signal for H is missing and
C
3
NMR spectra shows the presence of two carbonyl
groups at d 202 and d 180 assigned to C13 and C4,
respectively. There are two triplets at d 1.0 and d 1.2
assigned to H15 and H , respectively. The two –CH
12
2
4
Thus when compounds 7a–d were treated with acyl
groups appear as quartets at d 2.6 (H ) and d 2.8
11
chlorides 8a–f in the presence of DBU and pyridine they
yielded 9a–i. In someinstanc es in addition to the3-acyl-
c-pyrones we have noticed the formation of the corre-
sponding phenolic esters.
(H ).
14
Intrigued by the above observation we decided to ex-
plore the mechanism involved in the formation of 3-acyl
9
a R1 = R2 =OH, R3 = CH
3
- (51%)
b R = R = OH, R = CH CH - (48%)
R1
OH
CH3
R1
R3
O
O
O
1
2
3
9
O
3
2
9c R = R = OH, R3 = C H - (55%)
1
2
+
R3
6 5
Cl
R3
1
2
3
9
9
d R = R = OH, R = 3-ClC H - (60.4%)
6 4
R2
O
R2
e R = R = OH, R3 = 3-BrC H - (60%)
1
2
6
4
8a R3 = CH3-
2
7
7
7
7
a R1 = R = OH
9f R1 = R = OH, R3
2
=
3
b R1 = OH, R2 = H
8b R3 = CH CH -
(62%)
3
2
N
1
2
6 5
8c R = C H -
c R = OCH , R = H
d R = R = H
3
9g R1 = OH, R2 = H, R3 = C H - (66.6%)
9h R = R = H, R = C H - (47%)
6 5
9
3
1
2
8d R = 3-ClC H -
6 5
6
6
4
4
f R3
8
=
1
2
3
3
.HCl
8
e R = 3-BrC
H
-
N
1
2
3
i R = OCH , R = H, R = C H (55%)
3 6 5
5
Thestructurse
of 3-acyl-c-pyrones were solved using
flavonoids. Thus we treated 10a with benzoyl chloride in
the presence of DBU and pyridine under identical con-
high resolution mass spectrometry and by the applica-
tion of 2-D NMR spectroscopy. We wish to summarise
the NMR assignments of relevant protons and carbons
with compounds 9e and 9b.
4
dition used for the preparation of 3-acyl flavones and
5
,6
obtained only 11 and not 9g thus establishing that
the 3-acyl flavones were not formed by acylation of
flavones.
Br
1
3
The next question we wished to address was whether
3-acyl flavones were precursors to the formation of
flavones. On heating under reflux with an aqueous
solution of 5% potassium carbonatecompound 9g and
9c yielded 10a (58%) and 10b (53%), respectively.
8
2
3
8
11 12
CH
HO
7
O
1
5
9
HO
O 2
1
1
1
7
20
2
1
6
7
6
3
19
3
1
4
15
6
5
4
O
18
5
10
4
O
13 CH
O
3
2
9e
OH
O
9b
OH
Br
HO
O
Ph
HO
O
O
HO
HO
O
O
R
1
O
9g R = H
c R = OH
1
0a R = H
R
O
9
R
10b R = OH
0a R = H
O
O
O
Ph
HO
OH O
O
OH
O
Ph
R
1
O
R
O
R
O
1
1
3a R = H
1 R = H
12a R = H,
2b R = OH
3b R = OH
1

A. K. Ganguly et al. / Tetrahedron Letters 46 (2005) 4119–4121
4121
Although we have not isolated the triketones 12a and
fellowship. We would also like to thank Schering-
Plough Research Institute for generous financial assis-
tance.
1
1
2b in these conversions, it appears entirely possible that
0a and 10b arosevia 12a and 12b that is the triketones
are converted to the diketones 13a and 13b (which are
similar to the Baker–Venkataraman reaction intermedi-
ates) followed by cyclisation to the flavones 10a and 10b.
However it should be noted that the condition of our
experiment is very different than that used in Baker–
Venkataraman reaction.
References and notes
1. (a) Marchand, L. L. Biomed. Pharmacother. 2002, 56,
296; (b) Sausville, E. A.; Zaharvitz, D.; Gussio, R.
Pharmacol. Ther. 1999, 83, 285; (c) Matsui, J.; Kiyokawa,
N.; Takenouchi, H.; Taguchi, T. Leukemia Res. 2005, 29,
To confirm the above hypothesis we have treated the di-
ketones 14a and 14b with acyl chlorides 8b, 8c and 8e,
respectively in the presence of DBU and pyridine under
5
73.
2
. (a) Baker, W. J. Chem. Soc. 1933, 1381; (b) Mahal, H. Si.;
Venkataraman, K. J. Chem. Soc. 1934, 1767.
. (a) Riva, C.; DeToma, C.; Donadd, L.; Boi, C.; P en nini,
R.; Motta, G.; Leonardi, A. Synthesis 1997, 195, and
references cited therein; (b) Hirao, I.; Yamaguchi, M.;
Hamada, M. Synthesis 1984, 1076.
4
our experimental condition and obtained 9h, 9i, 15a,
3
1
1
5b, 15c and 15d. It should be noted that when 14a or
4b were treated with acyl chloride 8b or 8e weobtained
only one product and their formation perhaps indicates
that the less bulkier carbonyl groups in the triketone
intermediates cyclise with the phenolic hydroxyl group
followed by dehydration to yield the corresponding
4. In a typical experiment an acyl chloride (8.88 mmol)
was added dropwise under N -atmosphere to a solution
2
of hydroxy acetophenone (2.69 mmol) in anhydrous
pyridine. Finally DBU (10.71 mmol) was added dropwise
to the reaction mixture and it was heated at temperature
of 80–90 °C for 6–7 h (monitored by TLC). The reaction
mixture was dissolved in dichloromethane, washed with
ice water, acidified until pH 3–4 using dil HCl, and
finally washed with water again, dried over Na SO
and evaporated under reduced pressure. The crude
product was purified by silica-gel column chromatogra-
phy using hexane–EtOAc (60:40) as eluent. The com-
3
-acyl-c-pyrones. Thus suggesting that the 3-acyl flavo-
noids are formed via the triketones such as 12a and
2b and not through acylation of flavones. Interestingly
1
when the 3-acyl flavone 9i was treated with hydroxyl-
amine it yielded 16. Theformation of 16 perhaps also in-
volves the triketone intermediate 17. The presence of the
hydrogen bonded phenolic hydroxylic group in 16 ruled
out thealt er nativestructure 18 for theisoxazol e.
2
4
R1
OH
R1
O
O
R1
O
O
CH
CH
2 3
O
+
Cl
R2
O
O
O
O
2
-
8
b R = CH
3
CH
2
X
2
-
9h R1 = H, X = H (54%)
15c R1 = H (65%)
15d R = OCH3 (56%)
1
1
4a R1 = H
8c R = C H
6
5
1
1
2
-
15a R = H, X = Br (60%)
1
4b R = OCH3
8e R = 3-BrC H
6
4
1
9i
R
= OCH , X = H (53%)
5b R = OCH , X = Br (62%)
3
1
1
3
MeO
O
MeO
H
O
OH O
Ph
O
Ph
O
MeO
OH
Ph
9
i
Ph
Ph
16
Ph
O
N
O
O
N
1
7
18
3. Conclusion
pound crystallised from hexane–dichloromethane or
ethanol.
5
6
. NMR and high-resolution mass spectra of all the com-
pounds described in this paper were consistent with the
assigned structures. Assignments were further confirmed
using HMBC, HSQC and COSY experiments.
. All compounds described in this paper were crystal-
line. Crystals were obtained from dichloromethane-
hexane or ethanol. The melting points of compounds 9a,
Using a modified Baker–Venkataraman reaction we
have synthesised a novel class of 3-acyl-c-pyrones. The
reaction mechanism for their formation and the proper-
ties of 3-acyl-c-pyrones have been elucidated. 3-Acyl-c-
pyrones have been shown to be the precursors for the
formation of c-pyrones.
9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 10a, 10b, 11, 15a, 15b, 15c,
15d and 16 were 250–251, 144–145, 193–194, 224–225,
215–216, 304–305, 270–271, 121–122, 162–163, 241–
242, 284–285, 151–152, 126–127, 100–102, 64–65, 132–
Acknowledgements
One of us (P.K.M.) would like to thank Stevens Insti-
tuteof T ce hnology for theaward of a postdoctoral
133 and 150–151 °C. Yields were indicated in the
parenthesis.