Synthesis of oxygen heterocycles

Article abstract of DOI:10.1016/j.tetlet.2005.12.062

A generalised scheme for the synthesis of flavones, flavonones and chromones involving 3-acyl-γ-pyrone intermediates has been developed. Convenient synthesis of other oxygen heterocycles using similar procedure have been outlined.

Full text of DOI:10.1016/j.tetlet.2005.12.062

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1347–1349
Synthesis of oxygen heterocycles
A. K. Ganguly,* P. K. Mahata and D. Biswas
Stevens Institute of Technology, Hoboken, NJ 07030, USA
Received 10 November 2005; revised 6 December 2005; accepted 7 December 2005
Available online 9 January 2006
Abstract—A generalised scheme for the synthesis of flavones, flavonones and chromones involving 3-acyl-c-pyrone intermediates
has been developed. Convenient synthesis of other oxygen heterocycles using similar procedure have been outlined.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Present work
There has been considerable interest1 in recent years in
the area of flavonoids, which are known to be kinase
inhibitors. They also show activity in apoptosis, which
is implicated in cancer chemotherapy. In addition they
are known to be antioxidants and also show activity
against P-gp 170, a multiple drug resistant gene product.
We therefore decided to explore chemistry in this area
with an idea of making a library of compounds for bio-
logical testing. We decided to synthesise these com-
pounds using Baker–Venkataraman (B–V)2 reaction
and during our study we made an unusual observa-
tion.3a We observed that Baker–Venkataraman reaction
under our experimental condition did not yield the
expected c-pyrones instead we obtained 3-acyl-c-
pyrones.3b
In our present work we have explored this reaction
further thus making it possible to prepare a library of
flavonoids for biological testing. In addition we have
discovered a novel approach for the synthesis of other
oxygen heterocycles.
In Scheme 2 a brief summary is presented of the acid
chlorides used in the above reaction and the products5,6
obtained. It should be noted that excepting in the case
of the 3-substituted acid chlorides wherein a single prod-
uct was isolated in all the other cases both the possible
compounds were obtained. We have already reported
that the treatment of the phenolic 3-acyl-c-pyrones with
aqueous potassium carbonate yield c-pyrones. Thus the
combination of the above reactions will provide a
library of flavonoids for biological testing.
Thus when compounds 1a–d were treated with aliphatic
or aromatic acid chlorides in the presence of 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU) and pyridine they
yielded 3-acyl-c-pyrones. We speculated that the forma-
tion 3-acyl-c-pyrones involved the intermediacy of the
triketones 2 (Scheme 1).
We also explored whether 3-acyl-c-pyrones could be a
source for the preparation of flavonones. Thus we have
reduced 11a with sodium borohydride to the trans-di-
hydro compound 13. The methyl ether 14 obtained from
13 was in turn converted to the oxime 15 by treatment
O
R1
O
O
R3
O
R1
OH
CH3
R1
O
OH
R3
O
Cl
R3
R3
R3
R2
R2
1a R1 = R2 = H; 1b R1 = OH, R2 =H
1c R1 = OCH3, R2 = H; 1d R1 = R2 = OH
O
R2
O
2
3
Scheme 1.
Keywords: Synthesis; Heterocycles.
*
Corresponding author. Tel.: +1 201 216 5540; fax: +1 201 216 8240; e-mail: akganguly1@aol.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.062

1348
A. K. Ganguly et al. / Tetrahedron Letters 47 (2006) 1347–1349
X
H3CO
O
O
H3CO
O
O
H3CO
OH
O
X
5e
5a -c
O
O
O
4a X = H
10 (65%)
4b X = OCH3
Br
5d
Y
X
X
6a X = H, Y = Br (35%)
6b X = Br, Y = H (32%)
7a X = H, Y = OCH3 (33%)
7b X = OCH3, Y = H (29%)
8a X = OCH3, Y = NO2 (38%)
8b X = NO2, Y = OCH3 (40%)
Y
Z
H3CO
O
O
5a X = Br, Y = Z = H
5b X = OCH3, Y = Z = H
5c X = NO2, Y = Z = H
5d X = Y = H, Z = Br
5e X = Z =H, Y = Br
O
Y
O
Cl
9a X = H, Y = Br (40%)
9b X = Br, Y = H (37%)
X
X
HO
O
O
O
HO
O
O
12a X = H
11a X = Y = H
12b X = Br
11b X = H, Y = Br
11c X = Br, Y = H
Y
Scheme 2.
H
H
H
H3CO
Ph
O
N
Ph
H3CO
O
O
Ph
H3CO
O
HO
O
O
Ph
11a
Ph
O
Ph
H
O
O
OH
14 (75%)
15 (45%)
16 (65%)
13 (55%)
Scheme 3.
HO
OH
O
HO
O
O
O
O
HO
O
O
CH3
OH
O
O
18
17 (75%)
21
H
Scheme 4.
H3CO
O
O
H3CO
O
R
R
19a R = C6H5- (45%)
HCHO
RCHO
OH
O
4a
19b R = 2-ClC6H4- (46.5%)
19c R = 3-ClC6H4- (49%)
19d R = 4-ClC6H4- (46%)
O
O
H
20 (35%)
H
O
R
H3CO
O
R
H3CO
R
H
19
4a
O
HO
O
R
O
O
O
HCHO
H
R
R
H
H3CO
O
OH
H3CO
OH
H3CO
O
20
O
O
O
O
O
OH O
H
HO
H
Scheme 5.

A. K. Ganguly et al. / Tetrahedron Letters 47 (2006) 1347–1349
1349
with hydroxylamine hydrochloride/KOH in ethanol.
The oxime 15 was converted to the flavonone 16 by
reacting with nitrous acid (Scheme 3).
(P.K.M.) would like to sincerely thank Stevens Institute
of Technology for the award of a postdoctoral fellow-
ship. We also wish to thank Dr. B. N. Pramanik of SPRI
for providing MS data presented in this letter.
To extend further our synthesis of 3-acyl-c-pyrones we
treated 21 with carbonyl diimidazole and DBU/pyridine
and obtained in good yield the 4-hydroxy coumarin
derivative 17, which has been previously synthesised4
using a multistep procedure. 4-Hydroxy coumarins pos-
sess important biological activity, for example, warfarin
18 is a well known anticoagulant (Scheme 4). As di-
ketones such as 21 are easily synthesised the above reac-
tion could be extended further to make analogues.
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,
573; (d) Lee, Y.; Yeo, H.; Liu, S.-H.; Jiang, Z.; Savizky,
R. M.; Austin, D. J.; Cheng, Y.-C. J. Med. Chem. 2004,
47, 5555–5566; (e) Middleton, E., Jr.; Kandaswami, C.;
Theoharides, T. C. Pharmacol. Rev. 2000, 52, 673–
751.
2. (a) Baker, W. J. Chem. Soc. 1933, 1381; (b) Mahal, H. Si.;
Venkataraman, K. J. Chem. Soc. 1934, 1767.
3. (a) Ganguly, A. K.; Kaur, S.; Mahata, P. K.; Biswas, D.;
Pramanik, B. N.; Chan, T. M. Tetrahedron Lett. 2005, 46,
4119–4121; (b) Cummings, R. T.; DiZio, J. P.; Krafft, G. A.
Tetrahedron Lett. 1988, 29, 69–72.
Interestingly when the diketone 4a was treated with aro-
matic aldehydes it gave 19a–d and on treatment with
formaldehyde it yielded 20. The possible mechanisms
involved in these conversions are summarised in Scheme
5. Using diketones with different substitutions on the phe-
nolic ring and various aromatic and aliphatic aldehydes
we are in the process of making a library of compounds.
4. Veres, K.; Jonas, J.; Horeni, A. In Collection of Czechoslo-
vak Chemical Communications; Karlova University: Prague,
1959; 24, pp 3471–3475.
3. Conclusion
5. 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.
6. All compounds described in this letter were crystalline.
Crystals were obtained from dichloromethane–hexane or
ethylacetate. The melting points of compounds 6a,b, 7a,b,
8a,b, 9a,b, 10, 11a–c, 12a,b, 13–17, 19a–d and 20 were
182–183, 203–204, 158–159, 196–197, 176–177, 196–197,
186–187, 144–146, 166–167, 270–271, 268–269, 287–288,
241–242, 282–283, 220–221, 175–176, 139–140, 62–63, 263–
264, 123–124, 171–172, 112–113, 152–153 and 129–130 °C.
Yields are indicated in the parenthesis.
Using our modified experimental condition of Baker–
Venkataraman reaction we have developed convenient
synthetic procedures, which will allow preparation of
libraries of compound containing flavones, flavanones,
coumarines and other oxygen heterocycles.
Acknowledgements
We wish to thank Schering-Plough Research Institute
for generous financial assistance and one of us