Synthetic analogs of natural flavolignans. XV. Isomerization of 2′-hydroxychalcones into flavanones using triethylamine

Article abstract of DOI:10.1023/A:1014454923089

A simple and effective method for preparing synthetic analogs of natural flavanones via isomerization of 2′-hydroxychalcones with triethylamine was proposed.

Full text of DOI:10.1023/A:1014454923089

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Chemistry of Natural Compounds, Vol. 37, No. 5, 2001
SYNTHETIC ANALOGS OF NATURAL FLAVOLIGNANS.
XV. ISOMERIZATION OF 2
-HYDROXYCHALCONES
INTO FLAVANONES USING TRIETHYLAMINE
A. Aitmambetov,1 D. Dalimov,2 and A. Kubzheterova1
UDC 547.814.5
A simple and effective method for preparing synthetic analogs of natural flavanones via isomerization of 2 -
hydroxychalcones with triethylamine was proposed.
Key words: flavanone, method, triethylamine, isomerization.
Flavanones are a large group of flavonoids, the structures of which are based on the unstable dihydro-γ-pyrone ring.
They convert to the corresponding chalcones in the presence of base.
Flavanones contain one assymetric C atom (C-2). They are usually found in plants as the levorotary isomers.
Flavanones are known to possess hepato-protective, anti-edemic, anti-inflammatory, estrogenic, and other types of activity [1-3].
Flavanones are prepared via isomerization of chalcones in acidic or alkaline medium. The conditions that shift the
equilibrium toward flavanone formation cannot be predicted.
Known methods for isomerizing 2 -hydroxychalcones into the corresponding flavanones utilize dilute alkali or hot
ethanolic solution of sulphuric or phosphoric acid. Methanolic HCl, sodium acetate, and amberlyst ion-exchange resin [4, 5]
are also often used for these conversions. Sometimes, pyridine and glacial acetic acid are used [6].
Boiling 2-hydroxy-3 -iodo-4,4 ,6 -trimethoxychalcone in the presence of nickel chloride, zinc powder, and KI produces
the flavone and traces of 5-hydroxy-7,4 -dimethoxyflavanone [7].
R
4
R
3
OH R
R
R
4
O
R
2
R
3
R
2
R
1
R
1
O
O
2a - y
1a - y
a: R = R = R = R = R =H
n: R = CH , R = R = H, R = R = OCH O, X = Cl
3 1 2 3 4 2
1
2
3
4
b: R = CH , R = R = R = R = H
o: R = CH , R = R = H, R = R = OCH , X = Br
3 1 2 3 4 2
1
3
2
3
4
c: R = OCH , R= R = R = R = H
p: R = OCH , R = R = H, R = R = OCH O, X = COOH
1
3
2
3
4
3 1 2 3 4 2
d: R = Cl, R = R = R = R = H
q: R = R = CH , R = H, R = R = OCH O, X = COOH
2 3 1 3 4 2
1
2
3
4
e: R = F, R = R = R = R =H
r: R = CH , R = R = H, R = R = OCH CH O
3 1 2 3 4 2 2
1
2
3
4
f: R= R = R = R =H, R = OCH
s: R = OCH , R = R = H, R = R = OCH CH O
1
2
3
4
3
3 1 2 3 4 2 2
g: R = CH , R = OCH , R = R = R =H
t: R = R = CH , R = H, R = R = OCH CH O
2 3 1 3 4 2 2
1
3
4
3
2
3
u: R = Cl, R = R = H, R = R = OCH CH O
1
2
3
4
2
2
h: R = OCH , R = OCH , R = R = R =H
1
3
4
3
2
3
v: R = CH , R = R = H, R = R = O(CH ) O
3
1
2
3
4
2 3
i: R =R = R = H, R - R = -OCH O-
1
2
3
4
2
w: R = OCH , R = R , R = R = O(CH ) O
3
1
2
3
4
2 3
j: R = R = R = H, R - R = -OCH CH O-
1
2
3
4
2
2
x: R = R = CH , R = H, R = R = O(CH ) O
2 3
2
3
1
3
4
k: R = R = R = H, R - R = -O(CH ) O-
2 5
1
2
3
4
y: R = Cl, R = R = H, R = R = O(CH ) O
1
2
3
4
2 3
l: R = CH , R = R = H, R - R = -OCH CH O-
1
3
2
3
4
2
2
m: R = OCH , R = R = H, R - R = -O(CH ) O-
1
3
2
3
4
2 3
1) Karakalpak Institute of Natural Sciences, Karakalpak Division of Academy of Sciences of the Republic of
Uzbekistan, Nukus; 2) A. S. Sadykov Institute of Bioorganic Chemistry, Academy of Sciences of the Republic of Uzbekistan,
Tashkent. Translated from Khimiya Prirodnykh Soedinenii, No. 5, pp. 359-360, September-October, 2001. Original article
submitted March 30, 2001.
0009-3130/01/3705-0421$25.00 ©2001 Plenum Publishing Corporation
421

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TABLE 1. Properties of 2a-y
Compound
Yield, %
mp, C
Empirical formula
Solvent for crystallization
2a
2b
2c
2d
2e
2f
47.6
48.2
75.2
78.5
72.1
58.8
69.4
80.2
85.2
73.3
60.5
62.3
84.9
76-78
104-105
97-98
C15H12O2
C16H14O2
C16H14O3
C15H11ClO2
C15H11FO2
C16H14O3
C17H16O3
C17H16O4
C16H12O4
C17H14O4
C18H16O4
C18H16O4
C19H18O5
C18H15O4
C8H15O4
EtOH
EtOH
EtOH
96-97
EtOH
76-77
EtOH
94-95
EtOH
2g
2h
2i
109-110
158-159
127-128
108-109
94-96
EtOH
MeOH
MeOH
EtOH
2j
2k
2l
MeOH
EtOH
76-78
2m
87-89
EtOH
MeOH
EtOH
2n
2o
38.0
46.9
180-181
149-151
2p
2q
2r
2s
41.5
36.4
31.2
40.0
28.9
36.5
31.8
42.1
37.8
45.4
226-227
226-227
76-78
C19H16O7
C20H18O6
C18H16O4
C18H16O5
C19H18O4
C17H14O4
C19H18O4
C19H18O5
C20H20O4
C18H16 Cl O4
iso-PrOH
iso-PrOH/(CH3)2CO
EtOH
116-117
113-115
116-118
92-94
EtOH
2t
MeOH
MeOH
EtOAc/C7H14
EtOH
2u
2v
2w
2x
2y
87-89
142-144
83-85
MeOH
EtOH
A simple method for isomerizing 2 -hydroxychalcones that uses silica gel in the presence of conc. H SO ,
2
4
ethylenediamine, and hydroxylamine hydrochloride has been described [8].
Condensation of 2-hydroxyacetophenones with certain aromatic or heteroaldehydes forms the target chalcones and
sometimes flavanones [9-14].
We proposed an effective method for isomerizing 2 -hydroxychalcones into the corresponding flavanones by boiling
with triethylamine.
The ease of isomerizing chalcones into flavanones as a function of the position and nature of the substituents on the
A and B rings has been noted (Table 1).
We now present the proposed mechanism for cyclization of chalcones into flavanones in alcohol in the presence of
triethylamine.
Apparently release of a proton from the 2 -hydroxyl, which is accelerated by substituents in the 5 -position of the
chalcone and the presence of a catalyst, and its subsequent attack on the chalcone α-C atom occur simultaneously. Further
attack of the phenoxide oxygen on the positively charged β-C atom of the chalcone results in flavanone formation. The course
of the reaction is monitored using TLC.
Isomerization of chalcones using triethylamine showed that mainly flavanones are formed. However, we were unable
to prove this in some instances owing to the difficulty of separating the chalcone—flavanone mixtures, which are isolated as
oils. In such instances, column chromatography over silica gel (benzene eluent) was effective for separating the mixtures. We
were able to isolate some flavanones (2c, -d, -e, and -g-m) in high yields by fractional crystallization from the appropriate
solvents.
422

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H
:O: :N-(C H )
-
O :N-(C H )
2
5 3
2
5 3
R'
O
O
H
H
+
R
R
R'
R
R'
O
O
The structures of the synthesized flavanones were confirmed by elemental analyses, TLC, and melting points of
mixtures. The properties of the synthesized flavanones are listed in Table 1.
EXPERIMENTAL
The purity of the synthesized compounds was monitored by TLC on Silufol UV-254 plates using benzene—ethanol
(9:1). Analyses of all compounds corresponded to those calculated.
Synthesis of Flavanones 2a-y. A solution of the appropriate 2 -hydroxychalcone (2 mmole) and triethylamine
(0.28 mL, 2 mmole) in alcohol (25 mL) was boiled for 2-3 h. The reaction mixture was poured into cold water containing HCl
(1 mL, 10%). The resulting precipitate was filtered off, washed with water, and crystallized from a suitable solvent. If TLC
indicated the presence of chalcone and flavanone in the reaction products, the mixture was separated using fractional
crystallization or column chromatography over silica gel with benzene eluent.
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