Regioselective 6-iodination of 5,7-dioxygenated flavones by benzyltrimethylammonium dichloroiodate

Article abstract of DOI:10.1016/j.tetlet.2004.03.038

The iodination of 5,7-dioxygenated flavones with 1equiv of benzyltrimethylammonium dichloroiodate (BTMA·ICl₂) in the system CH₂Cl₂-MeOH-CaCO₃ at room temperature is presented in this note. Flavones with a free p

Full text of DOI:10.1016/j.tetlet.2004.03.038

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3635–3638
Regioselective 6-iodination of 5,7-dioxygenated flavones by
benzyltrimethylammonium dichloroiodate
J ꢀe r o^ me Quintin and Guy Lewin*
Laboratoire de Pharmacognosie, (BIOCIS, UMR 8076 CNRS), Facult ꢀe de Pharmacie, av. J. B. Cl ꢀe ment,
9
2296 Ch ^a tenay-Malabry Cedex, France
Accepted 8 March 2004
Abstract—The iodination of 5,7-dioxygenated flavones with 1 equiv of benzyltrimethylammonium dichloroiodate (BTMAÆICl
the system CH Cl –MeOH–CaCO at room temperature is presented in this note. Flavones with a free phenol group at C5 and an
alkoxy or a peracylglycosyloxy at C7 lead to the 6-iodoflavones with a good regioselectivity (ratio 6-iodination/8-iodination about
).
Ó 2004 Elsevier Ltd. All rights reserved.
2
) in
2
2
3
9
1. Introduction
available, stable, crystallized and easy-handled reagent
known to iodinate phenols under mild conditions.
12
Biflavonoids are a group of naturally occurring com-
pounds endowed with a variety of biological activities
(
antimicrobial, cytotoxic, antiinflammatory and oth-
1;2
ers). Among them, biflavones with units connected via
at least one 6-position include some interesting structures
12
2. General procedure (from Kajigaeshi et al.)
3
such as robustaflavone 1, an inhibitor of hepatitis B
00
replication and 6,6 -biapigenin hexa-
A mixture of flavone (1 equiv), BTMAÆICl (1 equiv) and
4;5
2
virus (HBV)
CaCO
room temperature until completion of the reaction (4–
2 h). The reaction mixture was taken up in water and
extracted at pH 6 with CH Cl or CH Cl –MeOH (for
-hydroxyflavones). Standard work-up of the organic
3 2 2
(7 equiv) in CH Cl –MeOH 5:2 was stirred at
6;7
methylether 2, an antituberculosis agent. In 1998, a
total synthesis of robustaflavone was performed
through, as a key step, a Suzuki coupling of the
6
Compound 4 was prepared from 3 ((a) BBr ; (b) I /TlOAc
1
0
5
2
2
2
2
- iodoapigenin derivative 4 with the 3 -boronate 5.
7
3
2
layer provided a dried residue which was purified by
flash chromatography on silica gel or crystallized
2 2 2 4
in CH Cl , 73%; (c) Me SO ) by exploiting the ortho-
directing capabilities of thallium(I) salts in the iodination
8
of phenols. Until now, this straightforward method re-
(MeOH or EtOH). Characterization and purity of all
iodo compounds followed from MS, homo- and hetero-
nuclear NMR and microanalysis.
mained the only one which provided 6-iodo compounds
in good yield since iodination (and generally electrophilic
substitutions) of 5,7-dioxygenated flavones are known to
2
As iodination by BTMAÆICl requires at least one free
9–11
occur rather at C8.
However, this easy reaction re-
phenol, reactions were performed with 5-hydroxyflav-
ones bearing at C7 various oxygenated groups (hydroxy,
acetoxy, alkoxy, glycosyloxy).
quires TlOAc, a highly toxic reagent, which accounts for
the search of an alternative iodination method. This
paper relates to a new regioselective 6-iodination of 5,7-
dioxygenated flavones by the use of benzyltrimethylam-
2
monium dichloroiodate (BTMAÆICl ), a commercially
2.1. Iodination of 5,7-dihydroxyflavones
Reaction of diosmetin 6 with 1 equiv of BTMAÆICl2
provided according to TLC four compounds including
Keywords: Flavones; Flavonoids; Iodination; Benzyltrimethylammo-
nium dichloroiodate.
the starting flavone. A second equivalent of BTMAÆICl
simplified the mixture, which led mainly to 6,8-di-
2
*
Corresponding author. Tel.: 33-146835593; fax: 33-146835399;
e-mail: guy.lewin@cep.u-psud.fr
iododiosmetin 7 (54% after crystallization from EtOH;
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.038

3636
J. Quintin, G. Lewin / Tetrahedron Letters 45 (2004) 3635–3638
OMe
MeO
MeO
O
O
OH
OH
6
''
HO
3
O
O
6
HO
O
OMe
6
O
OMe
O
'
OH
O
OH
MeO
1
2
OMe
OMe
MeO
R
O
MeO
O
3'
B
O
6
O
OMe O
OMe O
3
4
R = H
R = I
5
þ
EIMS m=z 552 M ; mp 249–251 °C). Similarly, acacetin
confirmed by methylation by phase-transfer catalysis of
5
þ
8
afforded 6,8-diodoacacetin 9 (EIMS m=z 536 M ; mp
253–255 °C). It is noteworthy that the free phenol group
at the 3 -position in 6 does not lead to iodination of the
15 into 6-iodo-trimethylapigenin 4 (mp 204–205 °C; lit.
13
mp 202–204 °C for 6-iodo-trimethylapigenin, lit. mp
238 °C for 8-iodo-trimethylapigenin). Lastly, starting
from 7-benzyldiosmetin 16 or 7,3 -dibenzyldiosmetin 17
0
0
B ring.
allowed isolation after crystallization (77%) and identi-
fication (as for 13) of the corresponding 6-iodo deriva-
þ
2
.2. Iodination of 7-acetoxyflavones
tives, 18 (EIMS m=z 516 M ; mp 236–238 °C) and 19
þ
(
EIMS m=z 606 M ; mp 197–198 °C). As a result of
0
As compounds 6 and 8, 7,3 -diacetyldiosmetin 10 was
not iodinated in a regioselective manner since reaction
with 1 equiv of BTMAÆICl gave according to TLC a
this good regioselectivity, we decided to compare
BTMAÆICl to other iodinating reagents, ICl and
N-iodosuccinimide. Both reagents were used with 12
under same conditions as BTMAÆICl , but iodination
with ICl was also performed in AcOH (usual solvent for
2
2
mixture of compounds including unreacted 10. As
0
2
expected, 5,7,3 -triacetyldiosmetin 11 with no more free
phenol did not provide any compound under the same
conditions.
14
this reagent). In any case, reactions resulted mainly in
0
0
a mixture of 7,3 -dimethyl-6-iododiosmetin 13 and 7,3 -
dimethyl-8-iododiosmetin 20, but in various ratios.
When the reactions were carried out in the system
2
.3. Iodination of 5-hydroxy-7-alkoxyflavones
CH
product but the best regioselectivity was observed with
BTMAÆICl , 4.6
with ICl and 1.9 with NIS). On the other hand, ICl/
AcOH provided by a slight majority (ratio 13/20 ¼ 0.9)
the compound 20, which could be purified by TLC then
crystallized (mp 267–270 °C) and identified to the 8-iodo
regioisomer (a significant Overhauser effect was
observed between the phenol proton and H6).
2 2 3
Cl –MeOH–CaCO , 13 was always the main
0
When the reaction was accomplished with 7,3 -di-
methyldiosmetin 12, BTMAÆICl (1 equiv) gave quanti-
2
(ratios 13/20 ¼ 10 with BTMAÆICl
2
2
tatively a mixture of two products in a 91/9 ratio [easily
1
inferred from H NMR spectrum by comparing inte-
gration of signals of the phenol proton at 13.7 (major)
and 12.85 ppm (minor)]. The compounds had very close
R
major one was isolated in good yield (73%) as pure 7,3 -
f
in TLC (silica gel, CH
2
Cl
2
–MeOH 99.5:0.5) but the
0
dimethyl-6-iododiosmetin 13 by crystallization from
þ
MeOH (EIMS m=z 454 M ; mp 227–230 °C). The iodo
substitution at the 6-position was proved by compara-
2.4. Iodination of 5-hydroxy-7-peracetylglycosyloxyflav-
ones
tive NMR experiments (NOESY and HMBC) on 12 and
1
3. This conclusion was based on: (a) the loss for 13 of
Our study was then extended to the iodination of 5,7-
dihydroxyflavones glycosylated at the 7 phenol group.
Choice of rhoifolin (apigenin 7-neohesperidoside) 21 and
diosmin (diosmetin 7-rutinoside) 22 was explained by
their easy semisynthetic access from naringin and hes-
peridin, two readily available Citrus flavanone glyco-
sides. Furthermore their glycosyl chains are different,
which can have an influence on the regioselectivity.
the Overhauser effect observed between the phenol
proton and H6 for 12; (b) the strong shielding by the
iodine of the signal of C6 at 69.5 ppm for 13 (97.8 ppm
0
for 12), In the same manner, iodination of 7,4 -dime-
0
15
thylapigenin 14 afforded 7,4 -dimethyl-6-iodo-apigenin
5
1
2
5 in the same good yield (mp 227–229 °C; lit. mp 227–
28 °C). The 6-iodo substitution was unambiguously

J. Quintin, G. Lewin / Tetrahedron Letters 45 (2004) 3635–3638
3637
Iodination was not undertaken with 21 and 22 them-
selves because of their insolubility in CH Cl –MeOH.
Therefore they were first converted to their respective
-hydroxy-heptaacetyl derivatives 23 and 24 by a two-
steps sequence (a) Ac O–pyridine, rt, 48 h; (b) TFA, rt,
C7, that is, a general pattern of substitutions available
from many natural flavones. By comparison with ICl
2
2
and NIS, BTMAÆICl
owing to reaction conditions (CH Cl –MeOH–CaCO
3
2
allows a better regioselectivity
5
2
2
2
vs AcOH) but also to the reagent itself. Consequently,
BTMAÆICl appears to carry out regioselective 6-iodin-
16
6
h; quantitative yield). Treatment of rhoifoline deriv-
2
ative 23 with BTMAÆICl led to the amorphous com-
pound 25 in 96% yield. Compound 25 was homogeneous
1
ation as well as the I /TlOAc system without handling of
a strongly toxic reagent.
2
2
in TLC (silica gel, CH
2
Cl
spectrum displayed a splitting of some characteristic
2
–MeOH 98:2) but its H NMR
0
0
signals (CH
3
of rhamnose, H2 ,6 , phenol group) in a
8:12 ratio. Once more, the NMR comparative study of
3 and 25 fully agreed with a 6-iodo substitution for the
8
2
Acknowledgement
major component of 25. Finally, the observation in the
ESI mass spectrum of 25 of a single peak at m=z 1021
[MþNa] confirmed 25 to be the 6-iodo/8-iodo mixture.
In the same way, 5-hydroxy-heptaacetyldiosmin 24 fur-
The authors are grateful to J.-C. Jullian for NMR
measurements.
þ
nished 26, the amorphous mixture 90/10 of the 6-iodo/
þ
8
-iodo derivatives (ESIMS m=z 1051 [MþNa] ).
References and notes
2
In conclusion, BTMAÆICl proved to be an excellent
1
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dioxygenated flavones and so to provide key interme-
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at C5 and an alkoxy or a peracylglycosyloxy chain at
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3