Efficient synthesis of isoflavone analogues via a Suzuki coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2005.03.143

Analogues of 3-aryl-8-isobutyl-5,6,7-trihydroxy-2-methyl-4H-chromen-4-one were synthesized with high yields via the Suzuki coupling reaction of 3-iodo-8-isobutyl-5,6,7-trimethoxy-2-methyl-4H-chromen-4-one with different aryl boronic acids.

Full text of DOI:10.1016/j.tetlet.2005.03.143

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3707–3709
Efficient synthesis of isoflavone analogues via a Suzuki
coupling reaction
Ke Ding and Shaomeng Wang*
Departments of Internal Medicine and Medicinal Chemistry, University of Michigan Comprehensive Cancer Center,
University of Michigan, 1500 East Medical Center Dr., Ann Arbor, MI 48109-0934, USA
Received 5 March 2005; revised 16 March 2005; accepted 21 March 2005
Available online 8 April 2005
Abstract—Analogues of 3-aryl-8-isobutyl-5,6,7-trihydroxy-2-methyl-4H-chromen-4-one were synthesized with high yields via the
Suzuki coupling reaction of 3-iodo-8-isobutyl-5,6,7-trimethoxy-2-methyl-4H-chromen-4-one with different aryl boronic acids.
Ó 2005 Elsevier Ltd. All rights reserved.
Isoflavones (3-aryl-chromen-4-ones) (3) represent a
large class of natural products and exhibit remarkably
diverse biological properties. They are found in many
plants and are especially abundant in legumes (Faba-
ceae), such as soya, lentils, chick pea, fenugreek, clovers,
and alfalfa. Compounds with isoflavone as the core
structure have been shown to possess antioxidant,1,2
antitumor,3,4 anticataracts,5 antiinflammatory,6 and
antifertility7 activity. Some isoflavones are well-known
tyrosine kinase inhibitors8 and studies also show that
isoflavones bind to G-protein coupled receptors, includ-
ing serotonin, dopamine, d-opiate, and benzodiazepine
receptors.9
Our synthetic route is shown in Scheme 1. Efficient syn-
thetic methods have been reported to obtain 3-halide-
chromen-4-ones 113 and coupling of 1 with different
boronic acids 2 via Suzuki reaction may afford 3-aryl-
isoflavones 3.
First, 3-iodo-8-isobutyl-5,6,7-trimethoxy-2-methyl-4H-
chromen-4-one was prepared in six steps (Scheme 2).
Using 3,4,5-trimethoxy-phenol 4 as the starting mate-
rial, 5 was obtained by a Friedel–Crafts reaction. With
aluminum chloride as the catalyst, the yield was quite
low (10–20%), and there were other unidentified byprod-
ucts, possibly caused by the removal of the methoxyl
groups in 4 by aluminum chloride. We therefore used
a somewhat weaker Lewis acid–boron trifluoride diethyl
etherate as the catalyst, which gave a satisfactory yield
(80%). The next step was reduction of the carbonyl
group in compound 5 to a methylene group. Surpris-
ingly we found that it was difficult to obtain 6 by hydro-
genation of 5, which might be attributed to the
formation of an intramolecular hydrogen bond between
the carbonyl group and the hydroxyl group in 5. In-
stead, compound 6 was generated in an excellent yield
With their remarkably rich biological activities and
excellent pharmacological properties, isoflavone-based
compounds have been the target of a great deal of re-
search into their synthesis. Almost all of the published
synthetic methods used the cyclization of 2-hydroxyaryl
alkyl ketones under acidic or basic conditions as the key
step.10–12 Although these methods can produce isoflav-
ones individually in good yield, they are not efficient
for synthesis of a series of isoflavones with different
substituted groups at the 3-position. Here, we described
a synthetic method that can be used to obtain a series of
3-aryl isoflavones efficiently via a Suzuki reaction by
using 3-iodo-8-isobutyl-5,6,7-trimethoxy-2-methyl-4H-
chromen-4-one as the general intermediate.
O
O
O
O
3
I
3
Ar
OH
OH
Pd(0) or Pd(2)
R2
R2
2
Ar
B
+
2
R1
R1
8
8
3
1
2
Keywords: Isoflavone; Synthesis; Suzuki coupling reaction.
*
Scheme 1. General synthetic route of 3-aryl-8-isobutyl-5,6,7-trihy-
droxy-2-methyl-4H-chromen-4-ones.
Corresponding author. Tel.: +1 734 615 0362x734; fax: +1 734 647
9647; e-mail: shaomeng@umich.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.143

3708
K. Ding, S. Wang / Tetrahedron Letters 46 (2005) 3707–3709
OMe
Ac
OMe O
OMe
OMe
Iso-butyric
chloride
Acetyl
chloride
BF3-Et2O
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
Et3SiH,
CF3COOH
BF3-Et2O
OH
OH
OH
OH 80%
87%
>90%
7
5
6
4
OMe O
O
O
OMe O
O
OMe O
I2,
Ac2O,
Na2CO3,
MeO
MeO
MeO
MeO
I
MeO
MeO
CF3COOAg
CH3CO2Na
H2O, reflux
76%
57%
~95%
O
8
9
10
Scheme 2. Synthesis of 3-iodo-8-isobutyl-5,6,7-trimethoxy-2-methyl-4H-chromen-4-one.
(>90%) by treating 5 with triethylsilane in trifluoroacetic
acid, followed by another Friedel–Crafts reaction to
generate compound 7 in 87% yield. Using a known pro-
cedure,14 compound 8 was obtained. The acetyl group in
3-position in 8 could be removed easily in basic condi-
tion to generate 9 in a yield of 57%. The moderate yield
of deacylation was due to the generation of a by-prod-
uct. Compound 9 was treated with I2 in the presence
of CF3CO2Ag as the catalyst to obtain compound 10
in almost quantitative yield.
ladium(II)–CH2Cl2 (Pd(dpf)2Cl2–CH2Cl2) was used as
the catalyst, the yield was improved to 85% and this cat-
alyst was therefore used for further exploration (Table
1). We treated compound 10 with different aromatic
boronic acids and obtained 3-aryl-8-isobutyl-5,6,7-trihy-
droxy-2-methyl-4H-chromen-4-one in excellent yield in
most cases (Table 1). The low yield of 11: might be
due to some impurity in 4-benzenesulfonyl-phenyl boro-
nic acid, which was prepared in our laboratory. Finally,
treatment of 12 with BBr3 at ꢀ78 °C and slowly raising
the reaction to room temperature generated analogues
of 3-aryl-8-isobutyl-5,6,7-trihydroxy-2-methyl-4H-chro-
men-4-one (12) in satisfied yield.15
With 3-iodo-8-isobutyl-5,6,7-trimethoxy-2-methyl-4H-
chromen-4-one 10 in hand, we explored the Suzuki cou-
pling reaction of 10 with different boronic acids. Treat-
ment of compound 11 with benzeneboronic acid using
Pd(Ph3P)4 as the catalyst gave 11a in a 60% yield.
When [1,10-bis(diphenylphosphino)ferrocene]dichloropal-
In summary, an efficient method was developed to syn-
thesize a library of isoflavones 3-aryl-4H-chromen-4-
ones with different substituents at the 3-position.
Table 1. Synthesis of 3-aryl-8-isobutyl-5,6,7-trihydroxy-2-methyl-4H-chromen-4-ones via Suzuki reaction
ArB(OH)2,
Pd2(dpf)2Cl2-CH2Cl2,
Na2CO3
OMe O
O
OH
O
O
OMe O
O
MeO
MeO
Ar
HO
HO
Ar
MeO
MeO
I
BBr3
12
11
10
Entry
ArB(OH)2
Compound 11a (%)
Compound 12b (%)
a
b
c
d
e
f
Ar = phenyl
2-Naphthyl
4-Cl-phenyl
85
87
85
89
79
75
87
50
75
43
73
73
76
68c
4-MeO-phenyl
4-PhO-phenyl
4-CO2H-phenyl
4-Phenyl-phenyl
80
65d
71
h
i
4-Benzenesulfonyl-phenyl
6-EtO-2-naphthyl
2-Thianaphenyl
75
j
65e
75
k
a Reported yields are for pure isolated products after chromatography.
b Yields after chromatography and recrystallization.
c Yield for 5,6,7-trihydroxy-3-(4-hydroxy-phenyl)-2-methyl-chromen-4-one.
d Compound 11f was reacted with aniline to get the amide and then N-phenyl-4-(5,6,7-trihydroxy-2-methyl-4-oxo-4H-chromen-3-yl)-benzamide was
obtained by deprotection.
e 5,6,7-Trihydroxy-3-(6-hydroxy-naphthalen-2-yl)-8-isobutyl-2-methyl-chromen-4-one was obtained.

K. Ding, S. Wang / Tetrahedron Letters 46 (2005) 3707–3709
3709
Roth, B. L. Psychopharmacology 2002, 162, 193–
202.
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