Synthetic analogs of natural flavolignans. XIV. Synthesis and transformations of 2′-substituted chalcones and chalconepoxides

Article abstract of DOI:10.1023/A:1017638107159

2 ′-Substituted chalcones and chalconepoxides have been synthesized. Their reactions with BF₃ etherate and hydrazine hydrate were studied.

Full text of DOI:10.1023/A:1017638107159

Chemistry of Natural Compounds, Vol. 37, No. 1, 2001
SYNTHETIC ANALOGS OF NATURAL FLAVOLIGNANS.
XIV. SYNTHESIS AND TRANSFORMATIONS OF 2
-
SUBSTITUTED CHALCONES AND CHALCONEPOXIDES
A. Aitmambetov,1 V. P. Khilya,2
M. Allaniyazova,1 and A. Mamutova1
UDC 547.814.5
2 -Substituted chalcones and chalconepoxides have been synthesized. Their reactions with BF etherate and
3
hydrazine hydrate were studied.
Key words: chalcones, chalconepoxides, isoflavones, synthesis.
Isoflavones are isomeric with flavones and originate biosynthetically from a single precursor, diphenylpropane.
Isoflavones and their heterocyclic analogs are interesting as physiologically active compounds with various applications.
Numerous methods for synthesizing isoflavones are known. Starting compounds are usually 2-hydroxydeoxybenzoins
or 2 -hydroxychalcones.
House et al. [1] studied in detail the BF ·etherate-catalyzed isomerization of chalconepoxides into formyldeoxybenzoins.
3
This method was used first by Bhrara et al. [2] and then by other groups [3-5] to synthesize isoflavones from 2 -substituted
chalconepoxides. Isomerizations catalyzed by conc. HCl or BF ·etherate are considered to be the best ones for synthesizing
3
isoflavones because these reactions are facile and give good yields.
Various methods can be used to show that substituted 2 -benzyloxychalconepoxides are converted by conc. HCl or
BF ·etherate into not only isoflavones but also 3-hydroxyflavonones, depending on the nature of the substituents [2, 6, 7].
3
Therefore, it seemed interesting to study the reaction of 2 -substituted chalconepoxides with BF ·etherate. The starting
3
2 -substituted chalcones are easily prepared via alkaline condensation of 2-substituted acetophenones with the corresponding
hetarylaldehydes [8].
The chalconepoxides needed for this rearrangement are usually prepared by oxidation of 2 -substituted chalcones with
hydrogen peroxide in alkaline medium.
The reaction of chalcones 2a and -e and 3a, -c, and -d with hydrogen peroxide in alkaline medium gives epoxides 4a
and -e and 5a, -c, and -d in good yields.
OR
R
1
R
1
OR
R
R
OR
R
1
O
1
O
-
-
H
HO
H O /HO
2 2
+
Het
C
Het
Het
R
2
R
2
Het
H
2
R
2
O
H
O
O
O
O
4a, e, 5a, c, d
6a, d
1e, 2a, e, 3a, c, d
1e: R = CH OCH , R = OCH OCH , R = H, Het = A
2
3
1
2
3
2
R
OR
H
1
2, 4, 7e: R = CH OCH , R = OCH OCH , R = H, Het = B
2
3
1
2
3
2
3, 5, 6, 8a: R = OCH C H , R = R =H, Het =C
2
6
5
1
2
OH
Het
R
2
c: R=OCH C H , R = OCH , R = H, Het = C
2
6
5
1
3
2
N
N
d: R = OCH C H , R = H, R = F, Het = C
2
6
5
1
2
Het:
A = 6-chloro-1,3-denzodioxan-8-yl
B = 1,4-benzodioxan-6-yl
H
C = 1,5-benzodioxepan-7-yl
7a, e, 8a, c
1) Natural Sciences Institute Complex (KIEN), Karakalpak Division, Academy of Sciences of the Republic of
Uzbekistan, Nukus, 742000, pr. Berdakha, 41; 2) Taras Shevchenko Kiev University, Kiev, Ukraine. Translated from Khimiya
Prirodnykh Soedinenii, No. 1, pp. 23-25, January-February, 2001. Original article submitted January 23, 2001.
0009-3130/01/3701-0025$25.00 ©2001 Plenum Publishing Corporation
25

TABLE 1. Properties of 1-8
Compound
Yield, %
mp, C
Crystallization solvent
1c
2a
3a
3c
3d
4a
5a
5c
5d
6a
6d
7a
7e
8a
8c
40
90
90
73
86
82
87
73
91
49
64
50
27
67
63
110-112
111-112
117-118
90-91
EtOH
EtOH
EtOH
EtOH
122-123
120-121
101-102
88-90
EtOH
EtOH
EtOAc
EtOH
151-152
185-186
193-194
170-171
136-137
149-150
206-207
EtOAc
EtOAc
EtOAc
C6H6
C6H6/hexane
C6H6
C6H6
TABLE 2. Proton Chemical Shifts in PMR Spectra of 2 -Substituted Chalcones
PMR spectrum, , ppm, J/Hz
phenol protons
Compound
heterocycle protons
C6H5-
COCH=CH H-5 or H-7 and H-8 or
CH2-4, s or
R1-3
R2-4
R3-5
H-6
CH2-2, s
-CH2O-2
dd (15-16)
H-6
H-8
H-9
O(CH2)nO
1e
2a
3.50
5.25
5.42
(5.6);
7.70
5.16
7.35
5.13;
7.34
5.12;
7.35
6.83 d
(1.5)
3.50
5.29
6.78 dd
7.69 d
(8.0)
7.52; 7.82
6.96
7.43
-
5.21
-
4.87
(8.0; 1.5)
7.0-8.0 m 7.0-8.0 m 7.0-8.0 m 8.09 d
(11.5)
7.66; 7.93 7.20 m 7.20 m
(6.6; 8.3)
7.20 m
4.48
3a
3c
3d
7.5-6.9 m 7.5-6.9 m 7.5-6.9 m
7.70
7.28; 7.56 7.5-6.9 m 7.5-6.9 m 6.86 d
(8.0)
-
-
-
4.24 t
2.21 q
4.234 t
2.2 q
6.50 d
3.86
6.57 dd
(9.0; 2.5)
-
7.85
(9.0)
7.23; 7.53
6.86
7.05
6.86 m
6.8-7.4 m 6.8-7.4 m
6.8-7.4 m 7.13; 7.56 6.8-7.4 m 6.8-7.4 m 6.8-7.4 m
4.24 t
2.22 q
Chalcones 1, 2, and 3 are yellow or orange crystalline compounds that are very soluble in organic solvents and have
quite high melting points. Epoxides 4 and 5, in contrast with the starting chalcones 1, 2, and 3, are colorless crystalline
compounds.
The PMR spectra of 1, 2, and 3 exhibit signals characteristic of olefinic protons, the chemical shifts of which lie at 7.0-
8.0 ppm. The spin—spin coupling constants (SSCC, J = 15.8-16.1 Hz) indicate that the chalcones have the trans configuration
(Table 2).
The PMR spectra of 4 and 5 have signals characteristic of methine protons in the oxirane ring as doublets with small
SSCC (J = 1.76-1.83 Hz). One of the signals is located at 4.24-4.26 ppm; the other, at 4.30-4.35 ppm (Table 3).
Rearrangement of 5a and -d by BF ·etherate gives 1,5-benzodioxepane analogs of isoflavone 6a and -d in good yields.
3
The PMR spectra of isoflavones 6a and -d contain signals at weak field for protons H-2 and H-5 of the chromone ring.
These protons are deshielded by the oxygen atoms of the pyrone ring.
26

TABLE 3. Proton Chemical Shifts in PMR Spectra of 2 -Substituted Chalconepoxides
PMR spectrum, , ppm, J/Hz
phenol protons
Compound
heterocycle protons
C6H5-
epoxy
group
CH2-2, CH2-4, s
O(CH2)nOn
R1-3
R2-4
R3-5
H-6
H-5, H-6, H-7, H-8, H-9
-CH2O·2
4a
5a
5.27; 7.56
5.01; 7.23
7.33
6.95
7.4-7.8 7.4-7.8
8.12
7.78
4.64; 4.11
4.40; 3.92
(1.95)
7.05 (H-5, H-7, H-8)
6.87(d, 1H, J = 2.0, H-6);
6.73(dd, 1H, J = 8.0; 2.0, H-8);
6.88(d, 1H, J = 8.0, H-9)
4.43
7.46
3.81
7.20
7.02
6.53
-
4.17 t, 2.17 q
5c
5d
4.98; 7.23
4.99; 7.24
6.49
7.20
7.89
8.30
4.43; 3.89
(1.95)
6.86(d, 1H, J = 1.95, H-6);
6.72(dd, 1H, J = 8.30; 1.95, H-8);
6.87(d, 1H, J = 8.3, H-9)
4.17 t, 2.17 q
4.17 t, 2.17 q
4.48; 3.91
(1.95)
6.84(d, 1H, J = 2.0, H-6);
6.73(dd, 1H, J = 8.0; 2.0, H-8);
6.88(d, 1H, J = 8.0, H-9)
TABLE 4. Proton Chemical Shifts in PMR Spectra of 4-Hydroxypyrazolines in CDCl3
PMR spectrum, , ppm, J/Hz
phenol protons
pyrazoline protons
heterocycle protons
(H-7)-6
Compound
OR-2
H-3
R2-4
R3-5
H-6
N-H, OH-4, d H-4, dd
H-5, d
4.61
(H-9)-8
O(CH2)nO
(H-10)-9
7a
7e
5.12 s; 6.8-7.3 m 6.8-7.3 m 6.8-7.3 m 7.92 d
7.34 m (9.29)
4.92 k 6.7-6.9 m 5.20 s 6.7-6.9 m 7.82 d
5.94
6.71
3.16
5.05
6.8-7.3 m
6.7-6.9 m
4.23 s
4.27 s
(5.37) (5.37; 3.42) (5.37; 3.42)
3.20
(3.4)
4.27
3.97
(2.2)
(7);
3.47 s
(9.28)
(3.4; 2.2)
3.20 s
8a
8c
5.12 s; 6.8-7.3 m 6.8-7.3 m 6.8-7.3 m 7.97 dd
5.93
5.83
3.20
(3.4)
3.12
5.10
(5.3; 3.4)
5.0
4.62
(5.3)
4.58
6.8-7.3 m
6.89
4.18t
2.17 q
4.18 t
(5.86);
2.16 q
(5.86)
7.35 m
5.09 s;
7.33 m
(9.2; 3.0)
7.83 d
6.54 d
(2.5)
3.80 s 6.59 dd
(2.28; 2.5) (9.28)
(3.42) (5.37; 3.42)
(5.37)
The reaction of 2 -substituted chalconepoxides 4 and 5 with hydrazine hydrate involves opening of the oxirane ring
and formation of a pyrazoline ring. Thus, brief heating of 4a and -e and 5a and -c with hydrazine hydrate forms the 4-
hydroxypyrazoline ring of 7a and -e and 8a and -c. The structures of 7a and -e and 8a and -c are consistent with their PMR
spectra (Table 4).
Thus, transformation of chalconepoxides into isoflavones by a Lewis acid makes possible broader application of
epoxides. Chalconepoxides are readily converted to various types of flavonoids and other heterocyclic compounds.
EXPERIMENTAL
The course of the reactions and the purity of the products were monitored by TLC on Silufol UV-254 plates using
benzene—ethanol (9:1). PMR spectra of 1-8 were measured in CDCl on a WP-100 SY Bruker spectrometer.
3
27

2 -Substituted Chalcones (1e, 2a and -e, 3a, -c, -d). A hot solution of 2-benzyloxyacetophenone or 2,4-
dimethoxymethoxyacetophenone (20 mmol) in alcohol was treated with the corresponding hetarylaldehyde (20 mmol) and
NaOH solution (50%, 4.7 mL). The reaction mixture was held at room temperature for 20-40 h. The precipitate was suspended
in water. The solution was acidified with acetic acid until it was neutral. The solid was filtered off and crystallized from
alcohol.
1-(2,4-Dimethoxymethoxyphenyl)-3-(hetaryl)-2,3-epoxypropan-1-ones (4a and -e), 1-(2-Benzyloxyphenyl)-3-(1,5-
benzodioxepan-7-yl)-2,3-epoxypropan-1-ones (5a, -c, and -d). A solution of (2a or -e or 3a, -c, or -d) (6 mmol) in an
acetone—methanol (15:4) mixture (80-100 mL) was treated with H O solution (30%, 30 mL) and NaOH solution (2 N, 30 mL).
2
2
After the color disappeared (12 h), the reaction mixture was diluted with water. The precipitate was filtered off and crystallized
from a suitable solvent.
3-(1,5-Benzodioxepan-7-yl)-chromone (6a). A solution of 5a (10 mmol) in absolute benzene (150 mL) was treated
with BF ·etherate (2 mL) and boiled for 25-30 h. The completion of the reaction was determined by TLC. The solution was
3
washed with water. The benzene was evaporated under vacuum from a water aspirator. The precipitate was crystallized from
ethylacetate. PMR spectrum (CDCl , , ppm, J/Hz): chromone ring: 7.99 (1H, s, H-2), 8.31 (1H, dd, J = 8.3, 0.98, H-5), 7.42
3
(1H, t, d, J = 8.3, 0.98, H-6), 7.68 (1H, t, d, J = 8.3, 0.98, H-7), 7.46 (1H, dd, J = 8.3, 0.98, H-8); benzodioxepane ring: 4.26
(4H, t, J = 5.87, CH -2 and CH -4), 2.21 (2H, q, J = 5.87, CH -3), 7.21 (1H, d, J = 2, H-6), 7.15 (1H, dd, J = 7.8, 2.0, H-8), 7.02
2
2
2
(1H, d, J = 7.8, H-9).
3-(1,5-Benzodioxepan-7-yl)-6-fluorochromone 6d was prepared analogously to 6a. PMR spectrum (CDCl , , ppm,
3
J/Hz): 7.99 (1H, s, H-2), 7.93 (1H, dd, J = 9.16, 2.93, H-5), 7.43 (2H, m, H-7,8); benzodioxepane ring 4.24 (4H, t, J = 5.8, CH -
2
2 and CH -4), 2.21 (2H, q, J = 5.8, CH -3), 7.99 (1H, d, J = 2.0, H-6), 7.15 (1H, dd, J = 8.43, 2.0, H-8), 7.01 (1H, dd, J = 8.43,
2
2
0.7, H-9).
3-(2-Substituted phenyl)-4-hydroxy-5-hetaryl Pyrazolines 7a and -e and 8a and -c. A solution of the corresponding
epoxide of chalcones 4a and -e and 5a and -c (4 mmol) in ethanol (50 mL) was treated with hydrazine hydrate (80%, 0.4 mL)
and boiled for 0.5-5 h. The precipitate was filtered off and crystallized from benzene.
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2.
3.
4.
5.
6.
7.
8.
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