Facile synthesis of 2,3-diacetoxyflavanones from 3-aminoflavones

Article abstract of DOI:10.1246/cl.2009.952

3-Aminoflavone reacts with isopentyl nitrite in acetic acid to give 2,3-diacetoxyflavanone in good yield. 3-Aminoflavone, the starting material, is readily available, and this method is a powerful tool for the synthesis of 2,3-dihydroxyflavanone derivativ

Full text of DOI:10.1246/cl.2009.952

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52
Chemistry Letters Vol.38, No.10 (2009)
Facile Synthesis of 2,3-Diacetoxyflavanones from 3-Aminoflavones
ꢀ
Hideyoshi Miyake, Shouko Nishino, and Mitsuru Sasaki
Graduate School of Agricultural Science, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501
(Received July 3, 2009; CL-090626; E-mail: miyakeh@kobe-u.ac.jp)
3
-Aminoflavone reacts with isopentyl nitrite in acetic acid to
MeO
O
OH
give 2,3-diacetoxyflavanone in good yield. 3-Aminoflavone, the
starting material, is readily available, and this method is a pow-
erful tool for the synthesis of 2,3-dihydroxyflavanone deriva-
tives.
O
OH
OAc
OH
O
O
1
2
Scheme 1.
Flavonoids consist one of the largest groups of natural com-
pounds. Many flavones, not only the natural ones but also the ar-
1
tificial ones have very interesting biological activity. In 2003, a
new type of flavonoid, 2,3,5-trihydroxyflavanone (1) (Scheme 1),
was discovered in the ethanol extract of L. polygalifolium subsp.
Table 1. Synthesis of 2,3-diacetoxyflavanone
R3
R4
2
polygalifolium. The derivative of 2,3-dihydroxyflavanone was
synthesized via the epoxidation of flavone by dimethyldioxi-
R2
R1
O
O
3
rane. Bernini et al. reported a new synthesis of 3-acetoxy-2-me-
thoxyflavanones (2), some of which have antifungal activities
NH2
R3
R4
4
3
against Trichoderma koningii et al. The key step in their proce-
AcO
O
R2
R1
dures is the oxidation of flavone by CH3ReO3. However, the ox-
idants used in the above two methods are expensive or difficult to
handle.
ONO
CH COOH
OAc
3
rt. 1 h
O
During our study of the synthetic use of 3-aminoflavone (3),
which is readily prepared from 3-bromoflavone or similar mate-
4
5
Isolated
yield/%
rial by reaction with aqueous NH3, 3-aminoflavone (3) reacts
6
1
2
3
4
Entry
R
R
R
R
Product
cis:trans
with isopentyl nitrite or NaNO2 in acetic acid to give 2,3-di-
acetoxyflavanone (4). 2,3-Diacetoxyflavanone, which is a deriv-
ative of 2,3-dihydroxyflavanone, has a similar structure to the
1
2
3
4
5
6
7
H
H
H
H
H
OMe
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
83
66
83
89
61
98
68
2.1:1
2.1:1
2.5:1
2.2:1
2.1:1
1.3:1
2.4:1
Me
Cl
H
H
H
H
H
Cl
3-acetoxy-2-methoxyflavanone mentioned above. In this paper,
we report on a new synthesis of 2,3-diacetoxyflavanones from
Br
H
3-aminoflavones.
The procedures of this transformation are quite simple.
When isopentyl nitrite is added to an acetic acid solution of 3-
Me
Br
t-Bu
H
H
4g
ꢁ
aminoflavone at 0 C, the reaction proceeds smoothly to give
2
,3-diacetoxyflavanone in good yield. The results are summariz-
ed in Table 1.
When propionic acid was used instead of acetic acid, 2,3-di-
propanoyloxyflavanone was obtained in a 91% yield (Scheme 2).
An aqueous solution of NaNO2 also gave 4 in somewhat lower
yield, and a considerable amount of benzoic acid was obtained
(Scheme 3). The reaction in alcoholic solvent in the presence
of an acid gave unidentified mixtures.
EtCOO
O
O
ONO
NH2
EtCOOH
rt. 1 h
OOCEt
O
O
4h
3
a
91%
The reaction predominantly gave the cis isomer. The ap-
1
cis : trans = 2.5 : 1
proximate diastereomeric ratios, determined by H NMR, are
shown in Table 1. The structure of the diastereomers was de-
Scheme 2.
1
duced as follows. The H NMR chemical shift of the 3-acetoxy
group was influenced by the aromatic ring (B ring). For the trans
isomer, the ring current of the aromatic B ring causes the upfield
shift of the methyl proton of the 3-acetoxy group (Scheme 4).
AcO
O
COOH
Ph
OAc
NaNO /H O
2
2
1
3a
+
Similar results were observed in the H NMR data of the 2-
4
CH COOH
3
methoxy-3-acetoxyflavanones.
A plausible mechanism for this reaction is as follows
rt. 8 h
O
4
a
6
4%
35%
(Scheme 5). The reaction of 3a with isopentyl nitrite gives diazo-
nium salt 5. The conjugate addition of acetic acid proceeds to
Scheme 3.
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.10 (2009)
953
δ 1.85
CH3
CH3
OH
O
CH3
O
O
H
O
O
O
O
O
O
CH3
O
Ph
O
O
O
O
+ Ph
+
O
O
CH3
δ 1.91,1.95
O
O
δ 1.71
O
CH3
O
O
CH3
O
CH3
O
7
8
cis-4a
trans-4a
Scheme 4.
trans-4a
cis-4a
CH3
Scheme 6.
Ph
O O
O
Ph
ONO
AcOH
3a
O
N2+
Ph
O
H
N2+
H
Ph
O
O
O
H
H
O
O
O
5
6
H O
2
5
Ph
H
N2+
N2+
O
O + Ph
OAc
O
O
+
CH3
O
O
H
Ph
O
O H
O
O
7
8
HO
PhCOOH + unidentified products
N2+
Ph
OAc
OAc
O
O
Ph
O
AcOH
+
Scheme 7.
OAc
OAc
O
O
cis-4a
trans-4a
flavonol or 2,3-dihydroxyflavone is not facile. When 3a is treat-
ed with NaOH or amines, unidentified mixtures are obtained.
Further studies on these compounds are under investigation.
The following are typical procedures for the synthesis of
2,3-diacetoxyflavanone. To an acetic acid (1.5 mL) solution of
3a (0.163 g, 0.69 mmol), isopentyl nitrite (0.097 g, 0.87 mmol)
was added at room temperature and stirred for one hour. The
mixture was poured into water (5 mL) and extracted with ethyl
acetate. After the usual workup, the crude product was purified
by column chromatography on silica gel to give 4a (0.191 g,
0.56 mmol) in 83% yield.
Scheme 5.
give 6. The diazonium 6 is presumed to be unstable and readily
decomposes with the generation of N2; the decomposition is ac-
companied with the migration of the acetoxy group to give 7 or
. These cations react with acetic acid to give 4a.
If the cation 7 reacts with acetic acid, the reaction proceeds
with inversion of configuration to give trans-4a (Scheme 6).
However, the reaction proceeds with moderate cis selectivity,
meaning that the mechanism described above does not prevail.
An alternative pathway to cis isomer is as follows. Interaction
of 8 with acetic acid causes a nucleophilic attack from the same
face as the 3-acetoxy group to give cis isomer cis-4a predomi-
nantly.
Plausible reasons why the presence of alcohol lowers the
yield of 4a include the following. Alcohol is more nucleophilic
than acetic acid, and the nucleophilic addition of alcohol to 5
proceeds much faster than that of acetic acid. However, the intra-
8
References
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R. J. Nijveldt, E. Nood, D. E. C. Hoorn, P. G. Boelens, K.
Norren, P. A. M. Leeuwen, Am. J. Clin. Nutr. 2001, 74,
418, and references cited therein.
2
3
4
5
6
K. Mustafa, N. B. Perry, R. T. Weavers, Phytochemistry
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M. Hauteville, M. Chadenson, J. Chopin, Bull. Soc. Chim.
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R. Bernini, E. Mincione, G. Provenzano, G. Farrizi, S.
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þ
molecular replacement of N2 is not as fast as that of the acetoxy
group, and decomposition occurrs to give unidentified mixtures.
In the presence of water, the conjugate addition of water to 5
occurrs, and the following C–C bond cleavage shown in
Scheme 7 gives benzoic acid and unidentified products.
2,3-Diacetoxyflavanone is considered to be a precursor of
flavonol. However, as far as we have studied, the conversion into
Published on the web (Advance View) September 5, 2009; doi:10.1246/cl.2009.952