A highly efficient and environmentally benign synthesis of 6,8-dibromoflavones, 8-bromoflavones, 5,7-dibromoaurones and 7-bromoaurones

Article abstract of DOI:10.1016/j.tetlet.2005.05.102

Various ring substituted 6,8-dibromoflavones (3a-e) as well as 8-bromoflavones (3f-j) can be synthesized easily from the corresponding 2′-hydroxychalcones (1a-j) in good yields and in two steps under environmentally benign reaction conditions. This can be

Full text of DOI:10.1016/j.tetlet.2005.05.102

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4937–4940
A highly efficient and environmentally benign
synthesis of 6,8-dibromoflavones, 8-bromoflavones,
5,7-dibromoaurones and 7-bromoauronesq
Abu T. Khan* and Papori Goswami
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
Received 8 February 2005; revised 16 May 2005; accepted 25 May 2005
Available online 13 June 2005
This work is dedicated to my teacher Professor K. Dey on the occasion of his 65th birthday
Abstract—Various ring substituted 6,8-dibromoflavones (3a–e) as well as 8-bromoflavones (3f–j) can be synthesized easily from the
corresponding 20-hydroxychalcones (1a–j) in good yields and in two steps under environmentally benign reaction conditions. This
can be achieved by bromination with concomitant cyclization by using a combination of vanadium pentoxide, hydrogen peroxide
and ammonium bromide in dichloromethane-water at 0–5 ꢀC, followed by dehydrobromination of the brominated products 2a–j
using 0.2 M ethanolic KOH solution at ice-bath temperature. On the other hand, various 5,7-dibromoaurones and 7-bromoaurone
derivatives 6a–c can be obtained, exclusively, from the corresponding 20-acetoxychalcones (4a–c) in good yields and in two steps by
tuning the reaction conditions.
ꢁ 2005 Elsevier Ltd. All rights reserved.
Aurones1 [2-benzylidenebenzofuran-3(2H)-ones] and
flavones2 [2-phenylchromones] are structurally isomeric
compounds, which are widely distributed in Nature.
Among them, flavones are well known in the literature
due to their wide range of biological activities,3 such
as anti-oxidant, anti-inflammatory, anti-viral,4 anti-
cancer5 and chemo preventative activities.6 Recently
Medina et al. reported7 that some flavonoids possess
anxiolytic activity and low sedative or myorelaxant
effects. They have also noted that some brominated
flavones, particularly 6-bromoflavone and 6-bromo-30-
nitroflavone, showed activities close to or higher than
that of diazepam. Some 8-bromoflavone derivatives,
namely 8-bromo-5,7,40-trimethoxyflavone (3g) might
be useful synthetic precursors for the synthesis of bio-
logically active natural products such as vitexin8 and
aciculatin.9 The synthesis of compound 3g was first re-
ported by Wheeler and Hutchins10 from the correspond-
ing 20-hydroxy-4,40,60-trimethoxychalcone by bromin-
ation using molecular bromine followed by cyclization
under basic conditions. Later on, Chen and his group re-
ported11 the synthesis of compound 3g in a sequence
that used selenium dioxide oxidation. Later, Donnelly
et al.12 also synthesized 3g along with 7-bromo-aurone
derivative 6c in the ratio 8:5 by cyclization of 20-hydro-
xy-4,40,60-trimethoxychalcone dibromide using ethan-
olic KOH solution. They concluded that a substituent
either at the 40- or 60-position on the A-ring did not
favour the exclusive formation of the flavone. The synthe-
sis of brominated flavones from 20-hydroxychalcone can
be accomplished using molecular bromine followed by
cyclization with a base or from 2-hydroxy-4,6-dimeth-
oxyacetophenone in three subsequent steps. Both proce-
dures have drawbacks since both molecular bromine
and selenium dioxide are harmful chemicals. At the
same time, molecular bromine is difficult to handle
and provides relatively low yields of the brominated
products. Therefore, a methodology that is environmen-
tally benign, clean, efficient and yet unambiguous is still
required.
Keywords: 20-Acetoxychalcones; 20-Hydroxychalcones; Bromination;
Vanadium pentoxide; Hydrogen peroxide; Ammonium bromide;
8-Bromoflavones; 6,8-Dibromoflavones; 7-Bromoaurones; 5,7-Di-
bromoaurones.
q Part of this work was presented at the conference ÔChemistry Biology
Interface: Synergistic New FrontiersÕ, New Delhi, India, November
21–26, 2004.
Taking a cue from the discovery of vanadium bromo-
peroxidase (VBrPO),13 a vanadium enzyme, which cata-
lyzes bromination of marine natural products as well as
*
Corresponding author. Tel.: +913612582305; fax: +913612690
762; e-mail: atk@postmark.net
0040-4039/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.102

4938
A. T. Khan, P. Goswami / Tetrahedron Letters 46 (2005) 4937–4940
the earlier results reported by Clague and Butler14 and
others,15 we have observed that vanadium pentoxide,
hydrogen peroxide and tetrabutylammonium bromide
are a good combination for generating reactive bromo-
nium ions.16 Moreover, the promoter (V2O5) and the oxi-
dant (H2O2) are environmentally acceptable reagents. By
changing the source of bromide ion, we have recently
demonstrated various valuable organic transforma-
tions.17 In this letter, we report a very simple, efficient
and environmentally benign synthesis of various 6,8-di-
bromoflavones and 8-bromoflavones starting from 20-
hydroxychalcones as shown in Scheme 1 as well as
5,7-dibromoaurones and 7-bromoaurone derivatives
from 20-acetoxychalcones as shown in Scheme 2.
6,8-dibromoflavone derivatives 3c–e in good yields
(Table 1).
Interestingly, when 20-hydroxychalcone 1f was added to
the above combination, it provided the 3,8-dibromo-5,7-
dimethoxyflavanone (2f), which was readily converted
to the 8-bromochrysin derivative 3f in an 80% yield.
From this observation, it is clear that bromination at
position 6 is difficult due to the presence of two methoxy
groups at the 40- and 60-positions on ring-A. Likewise,
various 8-bromoflavones 3g–j were synthesized from
the corresponding 20-hydroxychalcones (1g–j) in good
yields as shown in Table 2.
Next, we were interested in the synthesis of bromo-
aurone derivatives and found that 20-acetoxychalcones
(4a–c) in the above reaction media gave 5a–c, which
were converted into the 5,7-dibromoaurones 6a–b and
7-bromoaurone 6c on treatment with 0.2 M KOH solu-
tion. The yields of the products are shown in Table 3.
All the products were characterized by the usual spectro-
scopic techniques.19
For our investigation, various substituted chalcones
were prepared by the literature procedures.18 When 20-
hydroxychalcone (1a) was added to a solution of vana-
dium pentoxide, hydrogen peroxide and ammonium
bromide, it gave 3,6,8-tribromo-40,7-dimethoxyflava-
none (2a) in 81% yield. Compound 2a was then con-
verted to the corresponding 6,8-dibromoflavone 3a in
84% yield on treatment with ethanolic 0.2 M KOH solu-
tion. Similarly, the chalcone 1b was transformed to the
6,8-dibromo-40-benzyl-7-methoxyflavone (3b). Likewise,
chalcones 1c–e were converted to the corresponding
In conclusion, we have accomplished the synthesis
of various 6,8-dibromoflavones, 8-bromoflavones,
5,7-dibromoaurones and 7-bromoaurone from the
6
6
6
R
R
R
R
R
5
5
4
5
4
R
R
R
X
X
R
1
1
1
OH
O
R
O
O
O
O
R
R
4
0.2 M KOH
EtOH-H O (4:1) / rt
R
R
R
V O / H O / NH Br
2
5
2
2
4
A
3
3
3
o
R
CH Cl / 0-5
C
2
2
2
Y
Y
Br
2
2
2
R
R
1a-j
2a-e: X = Y = Br
2f-j: X = Br, Y = H
3a-e: X = Y = Br
3f-j: X = Br, Y = H
1a: R1 = R5 = OMe, R2 = R3 = R4 = R6 = H
1f: R1 = R2 = OMe, R3 = R4 = R5 = R6 = H
1b: R1 = OMe, R5 = OBn, R2 = R3 = R4 = R6 = H 1g: R1 = R2 = R5 = OMe, R3 = R4 = R6 = H
1c: R1 = R3 = R5 = OMe, R2 = R4 = R6 = H
1d: R1 = R4 = R5 = OMe, R2 = R3 = R6 = H
1e: R1 = R4 = R5 = R6 = OMe, R2 = R3 = H
1h: R1 = R2 = OMe, R5 = OBn, R3 = R4 = R6 = H
1i: R1 = R2 = R3 = R5 = OMe, R4 = R6 = H
1j: R1 = R2 = R4 = R5 = R6 = OMe, R3 = H
Scheme 1.
5
R
O
4
3
R
5
5
R
R
X
X
R
1
1
MeO
OR
1
OR
R
R
4
4
R
O
V O / H O / NH Br
0.2 M KOH
2
5
2
2
4
R
R
H
A
3
3
EtOH-H O (4:1) / rt
2
R
R
o
MeOH-CH Cl / 0-5
C
Y
Br
2
2
Y
2
2
R
O
R
O
2
R
R = Ac
5a-b: X = Y = Br
5c: X = Br, Y = H
6a-b: X = Y = Br
6c: X = Br, Y = H
4a-c
4a: R1 = R3 = R5 = OMe, R2 = R4 = H
4b: R1 = R4 = R5 = OMe, R2 = R3 = H
4c: R1 = R2 = R5 = OMe, R3 = R4 = H
Scheme 2.

A. T. Khan, P. Goswami / Tetrahedron Letters 46 (2005) 4937–4940
4939
Table 1. Percentage yields of products
Entry
3,6,8-Tribromoflavanone 2
% Yield
6,8-Dibromoflavone 3
% Yield
Mp/ꢀC
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
81
65
75
79
73
3a
3b
3c
3d
3e
84
98
88
94
92
220
205
209
180
188
Table 2. Percentage yields of products
Entry
3,8-Dibromoflavanone 2
% Yield
Mp/ꢀC
8-Bromoflavone 3
% Yield
Mp/ꢀC
1f
2f
2g
2h
2i
77
85
69
88
74
230
210
165
191
180
3f
3g
3h
3i
80
93
92
94
70
254 [lit. 25311
]
]
1g
1h
1i
238 [lit. 23611
193
217
220
1j2j
3e
Table 3. Percentage yields of products 5 and 6
6. Cassady, J. M.; Baird, W. H.; Chang, C.-J. J. Nat. Prod.
1990, 53, 22.
7. Medina, J. H.; Vioila, H.; Wolfman, C.; Marder, M.;
Wasowski, C.; Calvo, D.; Paladini, A. C. Neurochem. Res.
1997, 22, 419.
8. Frick, W.; Schmidt Liebigs Ann. Chem. 1989, 565.
9. Carte, B. K.; Carr, S.; DeBrosse, C.; Hemling, M. E.;
MacKenzie, L.; Offen, P.; Berry, D. E. Tetrahedron 1991,
47, 1815.
Entry Compound
(5)
% Compound
Yield (6)
%
Yield
Mp/ꢀC
4a
4b
4c
5a
5b
5c
70
75
83
6a
6b
6c
85
28121
83
206
253 [lit. 25210
]
10. Hutchins, W. A.; Wheeler, T. S. J. Chem. Soc. 1939, 91 .
11. Chang, C. T.; Chen, T. S.; Chen, F. C. J. Org. Chem. 1961,
26, 3142.
12. Donnelly, D. J.; Donnelly, J. A.; Philbin, E. M. Tetra-
hedron 1972, 28, 53.
corresponding 20-hydroxychalcones without involving
molecular bromine. We have also demonstrated the syn-
thesis of bromoaurones and bromoflavones exclusively,
by tuning the bromination step.
13. Butler, A.; Walker, J. V. Chem. Rev. 1993, 93, 1937.
14. Clague, M. J.; Butler, A. J. Am. Chem. Soc. 1995, 117,
3475.
15. Conte, V.; DiFuria, F.; Moro, S. Tetrahedron Lett. 1994,
35, 7429.
Acknowledgements
The authors acknowledge financial support from
the Council of Scientific and Industrial Research, New
Delhi [Grant No. 01(1541)/98/EMR-II to A.T.K]. P.G.
is thankful to the CSIR for her Research Associateship.
The authors are also grateful to the Director, I.I.T.
Guwahati, for providing general facilities for this work.
We are also grateful to the referee for valuable sugges-
tions and comments.
16. Bora, U.; Bose, G.; Chaudhuri, M. K.; Dhar, S. S.;
Gopinath, R.; Khan, A. T.; Patel, B. K. Org. Lett. 2000, 2,
247.
17. (a) Mondal, E.; Bose, G.; Sahu, P. R.; Khan, A. T. Chem.
Lett. 2001, 1158; (b) Mondal, E.; Sahu, P. R.; Bose, G.;
Khan, A. T. J. Chem. Soc., Perkin Trans. 1 2002, 1026; (c)
Bujar Barua, P. M.; Sahu, P. R.; Mondal, E.; Bose, G.;
Khan, A. T. Synlett 2002, 81 .
18. Vogel’s Textbook of Practical Organic Chemistry; Furniss,
B. S., Hannaford, A. J., Smith, P. W. G., Tatchell, A. R.,
Eds.; ELBS: Singapore, 1996, pp 1032–1035.
19. General procedure: A mixture of vanadium pentoxide
(0.6 mmol, 110 mg) and aq 30% hydrogen peroxide
(0.035 mmol, 4 mL) was stirred for 25–30 min at 0 ꢀC
until the colour changed from light orange to deep red.
Then, ammonium bromide (2.24 mmol, 219 mg) was
added and the reaction mixture was stirred for another
10 min. Subsequently, 20-hydroxychalone (0.14 mmol) in
dichloromethane (5 mL) was added. The reaction mixture
was then stirred for a further 3.5 h at 0 ꢀC. After
completion of the reaction as monitored by TLC, it was
extracted with dichloromethane (25 mL · 2) and the
combined organic layer was washed with saturated sodium
metabisulfite solution (2 mL). Finally, it was washed with
water and dried over anhydrous sodium sulfate. Evapo-
ration of the solvent provided the crude residue, which
was purified by column chromatography. The compound
was eluted with a mixture of hexane–ethyl acetate (3:7)
and the desired product was obtained either as a gummy
liquid or solid.
References and notes
1. Geissman, T. A.; Harborne, J. B. J. Am. Chem. Soc. 1956,
78, 832.
2. Brouillard, R.; Dangles, O. In The Flavonoids: Advances in
Research Since 1986; Harborne, J. B., Ed.; Chapman and
Hall: London, 1993, p 565.
3. (a) Welton, A. F.; Tobias, L. D.; Fiedler-Nagy, C.;
Anderson, W.; Hope, W.; Meyers, K.; Coffey, J. W. In
Plant Flavonoids in Biology and Medicine; Cody, V.,
Middleton, E., Jr., Harborne, J. B., Eds.; Alan R. Liss
Inc.: New York, 1986, p 231; (b) Selway, J. W. T. In Plant
Flavonoids in Biology and Medicine; Cody, V., Middleton,
E., Jr., Harborne, J. B., Eds.; Alan R. Liss Inc.: New
York, 1986, p 521.
4. Zanoli, P.; Avallone, R.; Baraldi, M. Fitoterapia 2000, 71,
S117.
5. Hirano, T.; Oka, K.; Akiba, M. Res. Commun. Chem.
Pathol. Pharacol. 1989, 64, 69.

4940
A. T. Khan, P. Goswami / Tetrahedron Letters 46 (2005) 4937–4940
Procedure for dehydrobromination: To a stirred solution of
(2C), 157.83, 160.03, 162.35, 162.73, 181.70. Mass: m/z 472
(M+). Anal. Calcd for C18H16Br2O5: C, 45.79; H, 3.42.
Found: C, 45.54, H, 3.39.
bromoflavanone 2 (0.10 mmol) in ethanol (5 mL) was
added aqueous KOH (0.2 M, 0.5 mL) solution dropwise at
room temperature. During addition of KOH solution, the
reaction mixture turned yellow in colour. The reaction was
complete within 25–30 min as monitored by TLC and was
extracted with dichloromethane (25 mL · 2). The organic
layer was washed with water and dried over anhydrous
sodium sulfate. Evaporation of the solvent and purifica-
tion of the residue by silica gel column chromatography,
[ethyl acetate–hexane (2:3)] gave the desired product,
which was further recrystallized from methanol.
8-Bromo-40,5,7-trimethoxyflavone (3g): Mp: 238 ꢀC [lit.12
mp 236 ꢀC], IR: 1634 (C@O) cmꢀ1. UV (CHCl3): 325,
268 nm. 1H NMR (400 MHz, CDCl3): d 3.89 (s, 3H,
OCH3), 4.02 (s, 3H, OCH3), 4.04 (s, 3H, –OCH3), 6.46 (s,
1H, ArH), 6.63 (s, 1H, H-3), 7.02 (d, 2H, J = 9.2 Hz,
ArH), 7.96 (d, 2H, J = 9.2 Hz, ArH). Mass: m/z 392 (M+).
Anal. Calcd for C18H15BrO5: C, 55.26; H, 3.86. Found: C,
55.05; H, 3.80.
2-Bromo-1-(2-acetoxy-3-bromo-4,6-dimethoxyphenyl)-3-
methoxy-3-(4-methoxyphenyl)-prop–1-one (5c): Mp: 216
ꢀC; 1H NMR (400 MHz, CDCl3): 2.37 (s, 3H, COCH3)
3.19 (s, 3H, CHOCH3), 3.83 (s, 3H, OCH3), 3.89 (s, 3H,
OCH3), 3.93 (s, 3H, OCH3), 4.60 (d, 1H, J = 10.0 Hz, H-
2), 4.97 (d, 1H, J = 10.0 Hz, H-3), 6.52 (s, 1H, ArH), 6.90
(d, 2H, J = 8.8 Hz, ArH), 7.29 (d, 2H, J = 8.4 Hz, ArH).
13C NMR (100 MHz, MeOH-d4): d 21.05, 54.48, 55.57,
56.93, 57.17, 57.66, 84.20, 94.59, 99.67, 113.86 (2C),
114.83, 129.43 (2C), 129.94, 148.48, 158.99, 159.68,
159.86, 167.65, 193.02 (C@O). Anal. Calcd for
C21H22Br2O7: C, 46.18, H, 4.06. Found: C, 46.01; H, 4.00.
7-Bromo-40,4,6-trimethoxyaurone (6c): Mp: 253 ꢀC; UV
Spectroscopic data of 3,6,8-tribromo-40,7-dimethoxyflava-
none (2a): Gummy liquid, IR (neat): 1701 (C@O) cmꢀ1. 1H
NMR (400 MHz, CDCl3): d 3.79 (s, 3H, OCH3), 3.84 (s,
3H, OCH3), 4.89 (d, 1H, J = 6.0 Hz, H-2), 5.73 (d, 1H,
J = 6.0 Hz, H-3), 6.89 (d, 2H, J = 8.8 Hz, ArH), 7.27 (d,
2H, J = 9.2 Hz, ArH), 7.97 (s, 1H, ArH). Anal. Calcd for
C17H13Br3O4: C, 39.19; H, 2.51. Found: C, 39.01; H, 2.56.
6,8-Dibromo-40,7-dimethoxyflavone (3a): Mp: 220 ꢀC, IR
1
(KBr): 1650 (C@O) cmꢀ1. H NMR (400 MHz, CDCl3) d
3.90 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 6.70 (s, 1H, H-3),
7.04 (d, 2H, J = 8.8 Hz, ArH), 7.94 (d, 2H, J = 9.2 Hz,
ArH), 8.08 (s, 1H, ArH). Anal. Calcd for C17H12Br2O4: C,
46.40; H, 2.75. Found: C, 46.21; H, 2.68.
1
(CHCl3): 399, 329, 250 nm. H NMR (400 MHz, CDCl3):
3,8-Dibromo-40,5,7-trimethoxyflavanone (2g): Mp: 211 ꢀC;
d 3.86 (s, 3H, OCH3), 4.01(s, 3H, OCH 3), 4.02 (s, 3H,
OCH3), 6.18 (s, 1H, ArH), 6.79 (s, 1H, H-3), 6.98 (d, 2H,
J = 8.8 Hz, ArH), 7.89 (d, 2H, J = 8.9 Hz, ArH). 13C
NMR(100 MHz, CDCl3): d 55.44, 56.57, 56.96, 85.44,
90.69, 106.62, 112.22, 114.51 (2C), 125.01, 132.27 (2C),
146.41, 158.78, 160.90, 163.94, 164.35, 180.34 (C@O).
Anal. Calcd for C18H15BrO5: C, 55.26, H, 3.86. Found: C,
55.38; H, 3.92.
IR: 1685 (C@O) cmꢀ1 1H NMR (400 MHz, CDCl3): d
.
3.78 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.98 (s, 3H,
OCH3), 4.84 (d, 1H, J = 4.8 Hz, H-3), 5.72 (d, 1H,
J = 5.2 Hz, H-2), 6.16 (s, 1H, ArH), 6.85 (d, 2H,
J = 8.4 Hz, ArH), 7.27 (d, 2H, J = 8.4 Hz, ArH). 13C
NMR (100 MHz, MeOH-d4): d 50.98, 55.63, 56.72, 57.07,
82.95, 90.44, 91.52, 104.69, 114.46 (2C), 127.70, 128.22