An environmentally benign synthesis of aurones and flavones from 2′-acetoxychalcones using n-tetrabutylammonium tribromide

Article abstract of DOI:10.1016/S0040-4039(01)01938-4

A wide variety of aurones (3a-f) can be prepared exclusively from 2′-acetoxychalcones (1a-f) in high yields in two steps, by bromination using n-tetrabutylammonium tribromide (TBATB) in the presence of CaCO₃ in CH₂Cl₂-MeOH (5:2) at 0-5°C followed by cyclization of the brominated products 2a-f on treating with 0.2 M ethanolic KOH solution at 0-5°C, respectively. In contrast various flavone derivatives 6a-f can be obtained exclusively from compounds 1a-f in fairly good yields, by brominating with the same reagent in CH₂Cl₂, followed by dehydrobromination and finally cyclization on treating with 0.1 M NaOMe solution.

Full text of DOI:10.1016/S0040-4039(01)01938-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8907–8909
An environmentally benign synthesis of aurones and flavones
from 2%-acetoxychalcones using n-tetrabutylammonium
tribromide†,‡
Gopal Bose,a Ejabul Mondal,a Abu T. Khana,* and Manob J. Bordoloib
aDepartment of Chemistry, Indian Institute of Technology, Guwahati 781 039, India
bNatural Products Chemistry Division, Regional Research Laboratory, Jorhat 785 006, India
Received 28 August 2001; revised 5 October 2001; accepted 12 October 2001
Abstract—A wide variety of aurones (3a–f) can be prepared exclusively from 2%-acetoxychalcones (1a–f) in high yields in two steps,
by bromination using n-tetrabutylammonium tribromide (TBATB) in the presence of CaCO3 in CH2Cl2–MeOH (5:2) at 0–5°C
followed by cyclization of the brominated products 2a–f on treating with 0.2 M ethanolic KOH solution at 0–5°C, respectively.
In contrast various flavone derivatives 6a–f can be obtained exclusively from compounds 1a–f in fairly good yields, by
brominating with the same reagent in CH2Cl2, followed by dehydrobromination and finally cyclization on treating with 0.1 M
NaOMe solution. © 2001 Elsevier Science Ltd. All rights reserved.
Both aurones1 [2-benzylidenebenzofuran-3(2H)-ones]
and flavones,2 which are structurally isomeric com-
pounds, are widely distributed in nature. They play
significant roles for the pigmentation of the flowers3 in
which they occur. On the other hand, flavones are well
known in the literature due to their wide range of
biological activities.4 Among the various flavones, ring-
A hydroxylated flavones in particular are of current
interest due to their biological activities including inhi-
bition of retroviral-reverse transcriptases,5 protein–
tyrosine kinases6 and serine/threonine kinases.7 They
also possess anticancer8 and chemo preventative activi-
ties.9 Therefore, the synthesis of these compounds are
still of interest largely on account of their biological
activities.
flavones.11 One of the methods which was originated by
Kostanecki, based on cyclization of 2%-hydroxychalcone
dibromides in aqueous alkali, is a useful route12 for the
synthesis of naturally occurring flavones. However, this
procedure has certain disadvantages in that some of
these dibromides give significant quantities of unwanted
product aurones under certain conditions and some-
times fail to provide ring-A substituted flavones. There-
fore, Donnelly and co-workers have investigated
thoroughly the cyclization of 2%-acetoxychalcone
dibromides13 or a-bromo-2%-hydroxychalcones14 to find
out the probable reasons for failure. They have come to
the conclusion that the formation of flavones is usually
favored at low base concentrations as well as if there is
no substituent at the position 3% and 6% or at any of the
two positions of ring-A. Later on, Main et al. also
studied15 the cyclization of 2%-hydroxy-6%-methoxychal-
cone epoxide to find out whether the cyclization occurs
preferentially either at the a or b position of the
epoxide and came to similar conclusions that the
cyclization takes place at the a-position preferably if
there is a substituent on ring-A particularly at the 6%
position, which gives ultimately aurone hydrate. Unfor-
tunately, it is not possible to access aurones exclusively
by the above methods irrespective of the substitution
pattern. The other problems which are associated with
the preparation of 2%-hydroxychalcone dibromides
include the use of molecular bromine which is haz-
ardous, difficult to handle and which gives relatively
low yields of the brominated products. It is also neces-
The aurones are usually prepared from benzofuran-
3(2H)-one, by acid- or base-catalyzed condensation
with an appropriate aldehyde.10 Similarly, there are a
large number of methods available for the synthesis of
Keywords: 2%-acetoxychalcones; bromination; n-tetrabutylammonium
tribromide; aurones; flavones.
* Corresponding author. Fax: +91-361-690 762; e-mail: atk@
iitg.ernet.in
† This paper is dedicated to my Ph.D. supervisor, Professor K. C.
Majumdar, University of Kalyani, Kalyani, West Bengal for his
constant encouragement.
‡
Part of this work was presented at the 17th International Congress
of Heterocyclic Chemistry at Vienna, Austria, August 1–6, 1999.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01938-4

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G. Bose et al. / Tetrahedron Letters 42 (2001) 8907–8909
sary to maintain a stoichiometric ratio of reactants
whilst carrying out the reaction. Therefore, what is
needed is a methodology that is environmentally
benign, clean, efficient and yet unambiguous.
compounds 1b–f afforded 2b–f in 75–85% yields, on
bromination under identical conditions.
Aurones are obtained from compounds 2a–f on treat-
ment with 0.2 M KOH solution in EtOH (Table 1). All
1
Very recently, we disclosed that organic ammonium
tribromides are useful reagents in organic synthesis.16
From the unique behavior and properties of these
reagents, we have conceived that they can be utilized
for the selective synthesis of aurones and flavones
depending upon the bromination steps. In this commu-
nication, we wish to report a very simple and practical
synthesis of various aurones and flavones. Bromination
of 2%-acetoxychalcone 1a with n-tetrabutylammonium
tribromide (TBATB, 1.2 equiv.) in the presence of
CaCO3 in a CH2Cl2–MeOH (5:2) mixture provided
compound 2a in 80 % yield (Scheme 1). Similarly, the
these compounds were fully characterized by H NMR,
13C NMR and elemental analyses.17 The compounds
1a–f on bromination with the same reagent in CH2Cl2
gave the brominated products 4a–f in good yields.
Various flavones (6a–f) were obtained in good yields
from the brominated products 4a–f by dehydrobromi-
nation followed by cyclization on treatment with 0.1 M
sodium methoxide solution (Table 1). All the products
were characterized by usual spectroscopic techniques.18
The formation of the cyclized product aurones 3a–f or
flavones 6a–f can be explained as follows. The forma-
R3
R2
R2
R2
R1
R4
R1
R3
R4
R1
R3
R4
TBATB (1.2 equiv.)
0.2 M KOH
R6
R6
OAc
OAc
EtOH-H2O (4:1)
R6
O
CH2Cl2-MeOH (5:2)
MeO
A
H
0-5°C
CaCO3, 0-5°C
Br
R5
O
R5
O
O
R5
3a-f
2a-f
1a-f
TBATB (1.1 equiv.)
CH2Cl2, 0-5°C
R2
R2
R2
R1
R3
R4
R1
R3
R4
R1
R3
R4
K2CO3 or Et3N
rt.
0.1 M NaOMe
MeOH, 0-5°C
R6
R6
R6
O
OAc
Br
OAc
CH2Cl2,
Br
Br
R5
O
R5
O
R5
O
4a-f
5a-f
6a-f
a: R1 = R2 = R4 = H, R3 = R5 = R6 = OMe
b: R1 = R2 = R4 = H, R3 = OBn, R5 = R6 = OMe
c: R1 = R3 = R5 = R6 = OMe, R2 = R4 = H
d: R1 = H, R2 = R3 = R4 = R5 = R6 = OMe
e: R1 = R4= H, R2 = R3= R5 = R6 = OMe
f: R1 = R2 = R4 = R5 = R6 = H, R3 = OMe
Scheme 1.
Table 1. Percentage yields of products
Entry
Product 2
% Yield
Aurone 3
% Yield
Dibromo
product (4)
% Yield
a-Bromo
chalcone (5)
% Yield
Flavone (6)
% Yield
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
80
75
85
84
76
80
3a
3b
3c
3d
3e
3f
85
91
87
95
86
87
4a
4b
4c
4d
4e
4f
70
78
75
80
80
75
5a
5b
5c
5d
5e
5f
80
90
83
85
88
80
6a
6b
6c
6d
6e
6f
78
70
88
74
65
60

G. Bose et al. / Tetrahedron Letters 42 (2001) 8907–8909
8909
tion of aurone is favored because Br is a better leaving
group in comparison to OMe, so the cyclization takes
place exclusively at the a-position. In contrast the for-
mation of the flavones from compounds 5a–f takes
place via Michael type reactions.
8. Hirano, T.; Oka, K.; Akiba, M. Res. Commun. Chem.
Path. Pharmacol. 1989, 64, 69.
9. Cassady, J. M.; Baird, W. H.; Chang, C.-J. J. Nat. Prod.
1990, 53, 22.
10. King, T. J.; Hastings, J. S.; Heller, H. G. J. Chem. Soc.,
Perkin 1 1975, 1475 and references cited therein.
11. (a) Nagarathnam, D.; Cushman, M. J. Org. Chem. 1991,
56, 4884; (b) Litkei, G.; Gulacsi, K.; Antus, S.; Blasko,
G. Liebigs Ann. 1995, 1, 1711 and references cited therein.
12. Emilewicz, T.; Kostanecki, S. Ber. Dtsch. Chem. Ges.
1898, 31, 696.
In conclusion, we have accomplished the synthesis of
ring-A hydroxylated naturally occurring flavone deriva-
tives such as the methyl ether of apigenin (6a), norarto-
carpetin (6c), tricetin (6d), luteolin (6e) and the
naturally occurring aurone derivative aureusidin (3e).
We have also demonstrated the synthesis of aurones
and flavones exclusively by tuning the bromination
step. Other organic ammonium tribromides can also be
used for the bromination reactions, which are under
investigation.
13. Donnelly, J. A.; Doran, H. J.; Murphy, J. J. Tetrahedron
1973, 29, 1037.
14. Donnelly, J. A.; Doran, H. J. Tetrahedron 1975, 31, 1565,
1791 and references cited therein.
15. Adams, C. J.; Main, L. Tetrahedron 1991, 47, 4979.
16. Mondal, E.; Bose, G.; Khan, A. T. Synlett 2001, 785.
17. Spectroscopic data of 2a: crystalline solid, mp: 122–
123°C, 1H NMR (300 MHz, CDCl3) l 2.29 (s, 3H,
COCH3), 3.17 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.83
(s, 3H, -OCH3), 3.86 (s, 3H, -OCH3), 4.65 (d, 1H J=9.6
Hz, CHOMe), 5.01 (d, 1H, J=9.6 Hz, COCHBr), 6.29
(s, 1H, ArH), 6.38 (s, 1H, ArH), 6.90 (d, 2H, J=8.2 Hz,
ArH), 7.31 (d, 2H, J=8.2 Hz, ArH). 13C NMR (75 MHz,
CDCl3) l 193.02, 169.21, 163.14, 159.96, 159.78, 151.24,
130.22, 129.35 (2C), 114.83, 113.60 (2C), 101.37, 96.77,
84.16, 57.42, 56.16, 55.69, 55.24, 54.33, 20.91. Anal. calcd
for C21H23BrO7: C, 53.97; H, 4.96. Found C, 53.43, H,
4.92.
Acknowledgements
The authors acknowledge the financial support from
the Council of Scientific and Industrial Research, New
Delhi [Grant No. 01(1541)/98/EMR- II to A.T.K].
E.M. and G.B. are thankful to CSIR for research
fellowships. The authors are grateful to the Director,
I.I.T. Guwahati for providing general facilities for this
work and thankful to Professor M. K. Chaudhuri for
the reagent. We are also grateful to the referee for his
valuable suggestion and thankful to Dr. M. J. Bordoloi
Spectroscopic data of 3a: Yellow crystalline solid, mp:
1
167–168°C, H NMR (300 MHz, CDCl3) l 3.84 (s, 3H,
1
for recording H and 13C NMR spectra.
OCH3), 3.89 (s, 3H, OCH3), 3.94 (s, 3H, -OCH3), 6.15 (d,
1H, J=1.6 Hz, ArH), 6.36 (d, 1H, J=1.6 Hz, ArH), 6.73
(s, 1H, ꢀCHPh), 6.94 (d, 2H, J=8.7 Hz, ArH), 7.80 (d,
2H, J=8.7 Hz, ArH). 13C NMR (75 MHz, CDCl3): l
180.53, 168.84, 168.71, 160.62, 159.41, 146.84, 132.84
(2C), 125.90, 125.39, 114.37 (2C), 110.90, 93.97, 89.24,
56.18, 56.02, 55.32. Anal. calcd for C18H16O5: C, 69.22;
H, 5.16. Found C, 68.99; H, 4.98.
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18. Spectroscopic data of 5a: gummy liquid, 1H NMR (250
MHz, CDCl3) l 2.10 (s, 3H, COCH3), 3.74 (s, 3H,
OCH3), 3.81 (s, 3H, OCH3), 3.82 (s, 3H, -OCH3), 6.31 (d,
1H, J=2.1 Hz, ArH), 6.38 (d, 1H, J=2.1 Hz, ArH), 6.92
(d, 2H, J=9.0 Hz, ArH), 7.72 (s, 1H, ꢀCHPh), 7.89 (d,
2H, J=9.0 Hz, ArH). 13C NMR (62.5 MHz, CDCl3): l
187.67, 168.74, 162.07, 161.57, 158.64, 149.47, 143.66,
132.91 (2C), 126.17, 122.38, 114.12, 113.87 (2C), 100.26,
96.69, 56.05, 55.62, 55.34, 20.68. Anal. calcd for
C20H19BrO6: C, 55.18; H, 4.40. Found C, 55.03; H, 4.32.
Spectroscopic data of 6a: crystalline solid, mp: 155–156°C
1
(lit. 156–157°C), H NMR (250 MHz, CDCl3) l 3.82 (s,
3H, OCH3), 3.85 (s, 3H, OCH3), 3.89 (s, 3H, -OCH3),
6.30 (d, 1H, J=2.3 Hz), 6.50 (d, 1H, J=2.3 Hz, ArH),
6.57 (s, 1H, ꢀCH-), 6.93 (d, 1H, J=9.0 Hz, ArH) 7.75 (d,
2H, J=9.0 Hz, ArH). 13C NMR (75 MHz, CDCl3): l
177.46, 163.95, 162.06, 160.79, 159.74, 130.00, 127.54
(2C), 123.63, 114.27 (2C), 108.94, 107.29, 96.06, 92.78,
56.29, 55.66, 55.36. Anal. calcd for C18H16O5: C, 69.22;
H, 5.16. Found C, 68.99; H, 4.98.
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Pratt, D. E. J. Nat. Prod. 1989, 52, 982.
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