Reaction of natural isoflavonoids and their analogs with hydroxylamine

Article abstract of DOI:10.1007/s10600-007-0149-3

Recyclization of the chromone ring in several natural isoflavonoids and their analogs by reaction with hydroxylamine was studied. It has been found that the most suitable base for carrying out the reaction is N-methylmorpholine. Several derivatives of 4-a

Full text of DOI:10.1007/s10600-007-0149-3

Chemistry of Natural Compounds, Vol. 43, No. 4, 2007
REACTION OF NATURAL ISOFLAVONOIDS AND THEIR
ANALOGS WITH HYDROXYLAMINE
S. P. Bondarenko,1 M. S. Frasinyuk,2 and V. P. Khilya1
UDC 547.814.5
Recyclization of the chromone ring in several natural isoflavonoids and their analogs by reaction with
hydroxylamine was studied. It has been found that the most suitable base for carrying out the reaction
is N-methylmorpholine. Several derivatives of 4-aryl-5-(2-hydroxyphenyl)isoxazole were synthesized.
Key words: isoflavonoids, isoxazole derivatives, recyclization, hydroxylamine, -methylmorpholine.
N
In continuation of research on the reactivity of analogs of natural isoflavonoids (cladrin 1a and formononetin 1b), we
studied their reaction with hydroxylamine.
HO
O
HO
O
O
OMe
OMe
O
OMe
1a
1b
It isknown that theproductsfrom reaction ofchromones, flavones, andisoflavoneswith hydroxylaminewerepreviously
described as oximes [1-3]. Recently it has been shown that products from opening of the chromone ring (mono- and dioximes
of ketones and regioisomeric isoxazoles) can be formed in this reaction in addition to oximes [4-6].
The reaction of 3-hetarylchromones with hydroxylamine hydrochloride in pyridine is known to produce derivatives
of regioisomeric 4-hetaryl-5-(2-hydroxyphenyl)isoxazoles and 4-hetaryl-3-(2-hydroxyphenyl)isoxazoles [7-10] although
2-methylisoflavones form only one product, derivatives of 4-hetaryl-5-(2-hydroxyphenyl)isoxazole; those unsubstituted in the
2-position, a mixture of isomeric isoxazoles.
O
O
O
O
R
Het(Ar)
Het(Ar)
R
R
+
Het(Ar)
O
O
O
O
N
N
O
H
H
In contrast with 3-hetarylchromoneswith a -containingsubstituent, thereaction with hydroxylamineofbenzodioxole,
N
benzodioxane, and benzodioxepane analogs of isoflavones proceeds much slower and is acompanied by formation of mixtures
of recyclization products [11, 12].
Natural isoflavonoids are most often encountered in hydroxylated, methoxylated, or glycosylated forms. The presence
in them of several electron-donating groups affects fundamentally the reactivity. Therefore, it seemed interesting to study the
reaction of analogs of natural isoflavones with hydroxylamine.
Thus, we selected formononetin, cladrin, and their analogs [13-17] and derivatives of 2′-methoxyisoflavone [18,
19] containing methyl or trifluoromethyl in the 2-position or 2-unsubstituted isoflavones. The starting 7-alkoxy- and
1)TarasShevchenkoKievNational University, 01033, Ukraine, Kiev, ul. Vladimirskaya, 64; 2) InstituteofBioorganic
and Petroleum Chemistry, National Academy of Sciences of Ukraine, 02094, Ukraine, Kiev, ul. Murmanskaya, 1, e-mail:
mfras@i.kiev.ua. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 332-336, July-August, 2007. Original article
submitted February 8, 2007.
0009-3130/07/4304-0402 ©2007 Springer Science+Business Media, Inc.
402

7-benzyloxyisoflavones were synthesized from the corresponding 7-hydroxyisoflavones byalkylation in acetone in the presence
of potash [20].
As expected, reaction of 2-methylisoflavones with hydroxylamine hydrochloride in pyridine formed exclusively
derivatives of 4-aryl-5-(2-hydroxyphenyl)-3-methylchromones (17a-c, 18b, and 19b). In contrast with 3-hetarylchromones,
recyclization of 2-methylisoflavones containing electron-donating methoxyls in ring B occurred in 2-5 h.
R O
2
O
R
1
R
5
O
R
4
R
3
5 - 11
NH OH
2
R
5
R
5
R
5
R
R
R
R
4
4
4
R O
2
R O
2
R O
2
R
3
R
3
3
Me
17a - c, 18b, 19b
6a - c 7b 8b: 9a,b, 10a,b, 11b:
CF
3
OH
12a - c, 13b, 14b, 15c, 16c
1a - c 2b 3b 4c 5c:
O
OH
O
OH
O
N
N
N
20a,b, 21a,b, 22b
,
,
,
,
R1 = H;
,
,
R1 = Me;
R1 = CF3
1a - c 6a - c 9a b 12a - c 17a - c 20a,b:
2b, 7b, 10a,b, 13b, 18b, 21a,b:
R2 = Me
,
,
, ,
,
,
R2 = H;
3b, 14b:
5c, 16c:
4c, 8b, 11b, 15c, 19b, 22b:
R2 = Et;
R2 = CH2C(Me)=CH2
1a, 6a, 9a, 10a, 12a, 17a, 20a, 21a:
R2 = CH2C6H4F-4;
R3 = H, R4 = R5 = OMe
1c, 4 - 6c, 12c, 15 - 17c:
1 - 3b, 6 - 14b, 17 - 22b:
R3 = R5 = H, R4 = OMe;
R3 = OMe, R4 = R5 = H
Substituted 3-trifluoromethylisoxazoles (20a and b, 21a and b, and 22b) were synthesized under analogous conditions.
The reactions were complete in this instance after 1-2 h.
The new isoxazole derivatives (17a-c, 18b, 19b, 20a and b, 21a and b, and 22b) do not give the characteristic color
with alcoholic iron chloride. This is due to peculiarities of their structures and is explained by the inability to form a chelate
involving the phenol hydroxyl and the isoxazole N atom. The structures of these compounds were confirmed by PMR
spectroscopy. The 2-hydroxyl resonates at 9.60-10.10 ppm in DMSO-d and indicates that there is no intramolecular bond
6
between the phenol hydroxyl and the isoxazole N atom.
Considering the structures of the recyclization products of 2-substituted isoflvaones by hydroxylamine hydrochloride,
it can be assumed that nucleophilic attack occured at C-2 of the chromone ring. Evidence for this was the different reaction rates
for the 2-trifluoromethyl- and 2-methylisoflavones.
For the 2-unsubstituted isoflavones (1a-c, 2b, 3b, 4c, and 5c), hydroxylamine in pyridine formed a mixture of two
isomeric isoxazoles. This was due to nucleophilic attack at C-2 and C-4 of the chromone ring.
Therefore, our task was to find recyclization conditions for formononetin, cladrin, and their derivatives by
hydroxylamine under which the reaction would be regioselective.
Because different bases can substantially affect the nucleophilicity of hydroxylamine hydrochloride, addition of them
to the reaction mixture can change the direction of the nucleophilic attack. Taking this into account, we recyclized the
chromone ring in the presence of tertiary amines (triethylamine, N-methylmorpholine, DBU), potash, and potassium acetate
in various solvents commonly used to synthesize oximes (pyridine, propan-2-ol, ethanol).
As it turned out, reaction of 2-unsubstituted isoflavones with hydroxylamine hydrochloride in ethanol in the presence
of N-methylmorpholine formed exclusively 4-aryl-5-(2-hydroxyphenyl)isoxazoles (12a-c, 13b, 14b, 15c, and 16c). Use of
N-methylmorpholine as the base causes hydroxylamine to attack selectively at the 2-position of the chromone ring and enables
one of the isomeric isoxazoles of the natural isoflavones and their analogs to be produced preparatively.
403

The synthesized isoxazoles (12a-c, 13b, 14b, 15c, and 16c) had typically less chromatographic mobility in
toluene:ethanol (9:1) than their regioisomers and the starting isoflavones (1a-c, 2b, 3b, 4c, and 5c). This provided a qualitative
analysis of the reaction mixtures.
The action of base on 4-hetaryl-5-(2-hydroxyphenyl)isoxazoles is known to form 2-amino-3-hetarylchromone
derivatives [21]. In order to confirm the proposed recyclization pathway of the chromone ring by hydroxylamine and the
structures of the synthesized substituted isoxazoles, we studied their reaction with base using 12c as an example. Thus, 12c was
converted by NaOH solution (4 N) into 2-aminoisoflavone (23), the structure of which was confirmed by PMR spectroscopy.
The PMR spectrum of 23 exhibited a 2H singlet for an amino group at 6.44 ppm and a resonance for H-5 of the chromone ring
at 7.73 ppm, in contrast with that at 7.01 ppm for the starting isoxazole.
RO
RO
O
NH
2
−
−
RO
OH
OH
Het(Ar)
Het(Ar)
Ar(Het)
OH
O
O
OH
N
N
O
Thus, conversion of substituted isoxazole 12c into 23 further proves that hydroxylamine attacks in the presence of
N-methylmorpholine at the C-2 position of the chromone ring and forms 4-aryl-5-(2-hydroxyphenyl)isoxazole derivatives.
We studied the reactivity of the synthesized 5-(2-hydroxyphenyl)isoxazoles by alkylating and acylating the phenol
hydroxyl of 12c. This formed 2-chlorobenzyl and furyl derivatives 24 and 25, respectively. Their structures were confirmed
by PMR spectroscopy and elemental analysis.
Thus, the natural isoflavones cladrin and formononetin and their analogs were used as examples to study the reaction
of isoflavones with hydroxylamine. We found the conditions for a regioselective reaction that enabled substituted 4-aryl-5-(2-
hydroxyphenyl)isoxazoles to be preparatively produced. They can be synthesized only by this route.
EXPERIMENTAL
The course of reactions and the purity of products were monitored by TLC on Sorbfil UV-254 (Russia) and Merck
(Germany) plates with elution by CHCl :CH OH (19:1 and 9:1) or toluene:ethanol (9:1). PMR spectra in DMSO-d were
3
3
6
measured on a VXR-300 (Varian, 300 MHz) instrument relative to TMS (internal standard) on the δ-scale. Elemental analyses
of all compounds agreed with those calculated.
General Method for Synthesizing 7-Alkoxyisoflavones 2b, 3b, 4c, 5c, 7b, 8b, 10a and b, and 11b. A hot solution
of the appropriate 7-hydroxyisoflavone (1a-c, 6a-c, 9b and c, 10 mmol) in absolute acetone (30 mL) was treated with freshly
calcined potash (2.1 g, 15 mmol), stirred, boiled, and treated with the appropriate alkylhalide (12 mmol). The reaction mixture
was stored for 1-4 h (end ofreaction determined byTLC) and poured intoacidified icewater (100 mL). The resulting precipitate
was filtered off and crystallized from a suitable solvent.
3-(2-Methoxyphenyl)-7-[(4-fluorobenzyl)oxy]-4H-chromen-4-one (5c). C H FO , yield 89%, mp 190-192°C
23 17
4
(propan-2-ol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 3.72 (3H, s, OMe-2′), 5.26 (2H, s, ArCH O-7), 7.00, 7.09, 7.26, 7.38,
6
2
3
4
3
7.57 (9H, 5m, H-8, H-3′, H-4′, H-5′, H-6′, FC H ), 7.15 (1H, dd, J = 8.0, J = 2.0, H-6), 8.00 (1H, d, J = 8.0, H-5), 8.26 (1H,
6
4
s, H-2).
7-Methoxy-3-(3,4-dimethoxyphenyl)-2-trifluoromethyl-4H-chromen-4-one (10a). C H F O , yield76%, mp184-
19 15 3
5
185°C (ethanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 3.66, 3.78, 3.81 (9H, 3s, OMe-7, OMe-3′, OMe-4′), 6.82 (1H, dd,
6
3
4
4
3
3
4
J = 8.0, J = 2.0, H-6), 6.91 (1H, d, J = 2.0, H-8), 7.03 (1H, d, J = 8.0, H-5′), 7.28 (1H, dd, J = 8.0, J = 2.0, H-6′), 7.54 (1H,
d, J = 2.0, H-2 ), 8.06 (1H, d, J = 8.0, H-5).
4
3
7-[(2-Methylprop-2-enyl)oxy]-3-(4-methoxyphenyl)-2-(trifluoromethyl)-4H-chromen-4-one (11b). C21H17F3O4,
yield 68%, mp 88-89°C (ethanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 1.80, 4.70, 5.02, 5.11 [3H, s, 2H, s, 2H, 2s,
6
3
3
4
MeC(=CH )CH O-7], 3.81 (3H, s, OMe-4′), 7.00 (2H, d, J = 8.0, H-3′, H-5′), 7.18 (1H, dd, J = 8.0, J = 2.0, H-6), 7.20 (2H,
d, J = 8.0, H-2′, H-6′), 7.29 (1H, d, J = 2.0, H-8), 7.99 (1H, d, J = 8.0, H-5).
2
2
3
4
3
General Method for Synthesizing 5-(2-Hydroxyphenyl)isoxazoles 12a-c, 13b, 14b, 15c, and 16c. A solution of the
appropriate isoflavone (1a-c, 2b, 3b, 4c, and 5c, 5 mmol) in ethanol (25 mL) was treated with hydroxylamine hydrochloride
404

(0.7 g, 10 mmol) and N-methylmorpholine (1 mL). The reaction mixture was boiled for 6-8 h (end of reaction determined by
TLC) and poured into water (100 mL) acidified with dilute HCl until the pH was 6. The resulting precipitate was filtered off
and crystallized from methanol.
4-[4-(3,4-Dimethoxyphenyl)isoxazol-5-yl]benzene-1,3-diol(12a). C H NO , yield63%, mp205-207°C(methanol).
17 15
5
3
4
PMR spectrum (DMSO-d , δ, ppm, J/Hz): 3.61, 3.73 (6H, 2s, OMe-4′ and OMe-4′), 6.34 (1H, dd, J = 8.0, J = 2.0, H-6), 6.45
(1H, d, J = 2.0, H-2), 7.09 (1H, d, J = 8.0, H-5), 6.88-6.98 (3H, m, H-2′, H-5′, and H-6′), 8.69 (1H, s, isoxazole H-3), 9.82
(2H, 2s, OH-1 and OH-3).
6
4
3
4-[4-(4-Methoxyphenyl)isoxazol-5-yl]benzene-1,3-diol (12b). C H NO , yield 80%, mp 125°C (methanol). PMR
16 13
4
3
4
4
spectrum (DMSO-d , δ, ppm, J/Hz): 3.73 (3H, s, OMe-4′), 6.33 (1H, dd, J = 8.0, J = 2.0, H-6), 6.42 (1H, d, J = 2.0, H-2),
6.90 (2H, d, J = 8.0, H-3′, H-5′), 7.06 (1H, d, J = 8.0, H-5), 7.30 (2H, d, J = 8.0, H-2′, H-6′), 8.90 (1H, s, isoxazole H-3), 9.79
(2H, s, OH-1 and OH-5).
6
3
3
3
4-[4-(2-Methoxyphenyl)isoxazol-5-yl]benzene-1,3-diol (12c). C H NO , yield 54%, mp 196-198°C (methanol).
16 13
4
3
4
4
PMR spectrum (DMSO-d , δ, ppm, J/Hz): 3.70 (3H, s, OMe-2′), 6.27 (1H, dd, J = 8.0, J = 2.0, H-6), 6.37 (1H, d, J = 2.0,
H-2), 7.01 (1H, d, J = 8.0, H-5), 6.85, 7.03, 7.09, 7.26 (4H, 4m, H-3′, H-4′, H-5′, and H-6′), 8.69 (1H, s, isoxazole H-3), 9.70,
6
3
9.72 (2H, 2s, OH-1 and OH-3).
5-Methoxy-2-[4-(4-methoxyphenyl)isoxazol-5-yl]phenol (13b). C H NO , yield 85%, mp 130°C (methanol).
17 15
4
PMR spectrum (DMSO-d , δ, ppm, J/Hz): 3.72, 3.76 (6H, 2s, OMe-5, and OMe-4′), 6.52 (2H, 2m, H-4 and H-6), 6.90 (2H, d,
6
3
3
3
J = 8.0, H-3′, H-5′), 7.20 (1H, d, J = 8.0, H-3), 7.29 (2H, d, J = 8.0, H-2′, H-6′), 8.93 (1H, s, isoxazole H-3), 10.03 (1H, s,
OH-1).
2-[4-(4-Methoxyphenyl)isoxazol-5-yl]5-ethoxyphenol (14b). C H NO , yield 56%, mp 140-142°C (methanol).
18 17
4
3
PMR spectrum (DMSO-d , δ, ppm, J/Hz): 1.34, 4.02 (3H, t, 2H, q, OEt-5), 3.73 (3H, s, OMe-4′), 6.49 (1H, dd, J = 8.0,
J = 2.0, H-4), 6.50 (1H, d, J = 2.0, H-6), 6.90 (2H, d, J = 8.0, H-3′, H-5′), 7.17 (1H, d, J = 8.0, H-3), 7.30 (2H, d, J = 8.0,
6
4
4
3
3
3
H-2′, H-6′), 8.92 (1H, s, isoxazole H-3), 9.79 (1H, s, OH-1).
5-[(2-Methylprop-2-enyl)oxy]-2-[4-(2-methoxyphenyl)isoxazol-5-yl]phenol (15c). C H NO , yield55%, mp122-
20 19
4
124°C (methanol). PMRspectrum (DMSO-d , δ, ppm, J/Hz): 1.76, 4.44, 4.96, 5.05 [3H, s, 2H, s, 2H, 2s, MeC(=CH )CH O-5],
6
2
2
3
4
4
3
3.68 (3H, s, OMe-2′), 6.46 (1H, dd, J = 8.0, J = 2.0, H-4), 6.47 (1H, d, J = 2.0, H-6), 7.11 (1H, d, J = 8.0, H-3), 6.86, 7.06,
7.08, 7.27 (4H, 4m, H-3′, H-4′, H-5′, and H-6′), 8.79 (1H, s, isoxazole H-3), 9.91 (1H, s, OH-1).
2-[4-(2-Methoxyphenyl)isoxazol-5-yl]-5-[(4-fluorobenzyl)oxy]phenol (16c). C H FNO , yield60%, mp159-161°C
23 18
4
(methanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 5.06 (4H, m, 2H, s, ArCH O-5), 3.68 (3H, s, OMe-2′), 6.51 (1H, d,
6
2
4
3
4
3
J = 2.0, H-6), 6.53 (1H, dd, J = 8.0, J = 2.0, H-4), 7.21 (1H, d, J = 8.0, H-3), 6.82-7.54 (8H, 4m), 8.72 (1H, s, isoxazole H-3),
9.96 (1H, s, OH-1).
General Method for Synthesizing 5-(2-Hydroxyphenyl)isoxazoles 17a-c, 18b, 19b, 20a and b, 21a and b, and 22b.
A solution of the appropriate isoflavone (6a-c, 7b, 8b, 9a and b, 10a and b, and 11b, 5 mmol) in dry pyridine (10 mL) was
treated with hydroxylamine hydrochloride (0.7 g, 10 mmol), heated at 80-90°C for 1-5 h (end of reaction determined by TLC),
and poured into water (100 mL) acidified with dilute HCl until the pH was 6. The resulting precipitate was filtered off and
crystallized from methanol.
4-[3-Methyl-4-(3,4-dimethoxyphenyl)isoxazol-5-yl]benzene-1,3-diol (17a). C H NO , yield73%, mp102-104°C
18 17
5
(methanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 2.27 (3H, s, isoxazole Me-3), 3.62, 3.74 (6H, 2s, OMe-3′ and OMe-4′),
6
3
4
4
3
4
4
6.25 (1H, dd, J = 8.0, J = 2.0, H-6), 6.36 (1H, d, J = 2.0, H-2), 6.78 (1H, dd, J = 8.0, J = 2.0, H-6′), 6.83 (1H, d, J = 2.0,
H-2′), 6.92 (1H, d, J = 8.0, H-5′), 6.96 (1H, d, J = 8.0, H-5), 9.66 (2H, 2s, OH-1 and OH-3).
3
3
4-[3-Methyl-4-(4-methoxyphenyl(isoxazol-5-yl]benzene-1,3-diol (17b). C H NO , yield 66%, mp 178-180°C
17 15
4
(methanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 2.23 (3H, s, isoxazole Me-3), 3.74 (3H, s, OMe-4′), 6.23 (1H, dd,
6
3
4
4
3
3
J = 8.0, J = 2.0, H-6), 6.34 (1H, d, J = 2.0, H-2), 6.90 (2H, d, J = 8.0, H-3′, H-5′), 6.95 (2H, d, J = 8.0, H-3′, H-5′), 7.16
(2H, d, J = 8.0, H-2′, H-6′), 9.63, 9.67 (2H, 2s, OH-1 and OH-3).
3
4-[3-Methyl-4-(2-methoxyphenyl)isoxazol-5-yl]benzene-1,3-diol (17c). C H NO , yield 68%, mp 204-205°C
17 15
4
(methanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 2.08 (3H, s, isoxazole Me-3), 3.69 (3H, s, OMe-2′), 6.17 (1H, dd,
6
3
4
4
3
J = 8.0, J = 2.0, H-6), 6.31 (1H, d, J = 2.0, H-2), 7.05 (1H, d, J = 8.0, H-5), 6.86, 6.88, 7.02, 7.30 (4H, 4m, H-3′, H-4′, H-5′,
and H-6′), 9.60 (2H, 2s, OH-1 and OH-3).
5-Methoxy-2-[3-methyl-(4-methoxyphenyl)isoxazol-5-yl]phenol (18b). C H NO , yield87%, mp80°C(methanol).
18 17
4
PMR spectrum (DMSO-d , δ, ppm, J/Hz): 2.24 (3H, s, isoxazole Me-3), 3.72, 3.74 (6H, 2s, OMe-5 and OMe-4′), 6.42 (1H, dd,
6
405

3
3
4
4
3
3
J = 8.0, J = 2.0, H-4), 6.44 (1H, d, J = 2.0, H-6), 6.91 (2H, d, J = 8.0, H-3′, H-5′), 7.08 (1H, d, J = 8.0, H-3), 7.16 (2H, d,
J = 8.0, H-2′, H-6′), 9.87 (1H, s, OH-1).
2-[3-Methyl-4-(4-methoxyphenyl)isoxazol-5-yl]-5-[(2-methylprop-2-enyl)oxy]phenol (19b). C H NO , yield75%,
21 21
4
mp 126-128°C (methanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 1.74, 4.40, 4.94, 5.02 [3H, s, 2H, s, 2H, 2s,
6
3
4
MeC(=CH )CH O-5], 2.23 (3H, s, isoxazole Me-3), 3.72 (3H, s, OMe-4′), 6.42 (1H, dd, J = 8.0, J = 2.0, H-4), 6.43 (1H, d,
J = 2.0, H-6), 6.90 (2H, d, J = 8.0, H-3′, H-5′), 7.05 (1H, d, J = 8.0, H-3), 7.15 (2H, d, J = 8.0, H-2′, H-6′), 9.92 (1H, s,
OH-1).
2
2
4
3
3
3
4-[4-(3,4-Dimethoxyphenyl)-3-(trifluoromethyl)isoxazol-5-yl]benzene-1,3-diol (20a). C H F NO , yield 77%,
18 14 3
5
mp 206-208 C (methanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 3.63, 3.75 (6H, 2s, OMe-3′ and OMe-4′), 6.26 (1H, dd,
6
3
4
4
3
4
4
J = 8.0, J = 2.0, H-6), 6.39 (1H, d, J = 2.0, H-2), 6.80 (1H, dd, J = 8.0, J = 2.0, H-6′), 6.86 (1H, d, J = 2.0, H-2′), 6.97 (1H,
d, J = 8.0, H-5′), 7.03 (1H, d, J = 8.0, H-5), 9.93 (2H, 2s, OH-1 and OH-3).
3
3
4-[4-(4-Methoxyphenyl)-3-(trifluoromethyl)isoxazol-5-yl]benzene-1,3-diol (20b). C H F NO , yield 81%, mp
17 12 3
4
3
4
170-172°C (methanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 3.76 (3H, s, OMe-4′), 6.25 (1H, dd, J = 8.0, J = 2.0, H-6),
6.36 (1H, d, J = 2.0, H-2). 6.95 (2H, d, J = 8.0, H-3′, H-5′), 7.00 (2H, d, J = 8.0, H-3′, H-5′), 7.19 (2H, d, J = 8.0, H-2′,
H-6′), 9.88, 9.94 (2H, 2s, OH-1 and OH-3).
6
4
3
3
3
5-Methoxy-2-[4-(3,4-dimethoxyphenyl)-3-(trifluoromethyl)isoxazol-5-yl]phenol (21a). C H F NO , yield 64%,
19 16 3
5
mp 159-161°C (methanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 3.64, 3.72, 3.75 (9H, 3s, OMe-5, OMe-3′, and OMe-4′),
6
3
4
4
3
4
4
6.45 (1H, dd, J = 8.0, J = 2.0, H-4), 6.47 (1H, d, J = 2.0, H-6), 6.80 (1H, dd, J = 8.0, J = 2.0, H-6′), 6.87 (1H, d, J = 2.0,
H-2′), 6.97 (1H, d, J = 8.0, H-5), 7.17 (1H, d, J = 8.0, H-5 ), 10.17 (2H, 2s, OH-1 and OH-3).
3
3
5-Methoxy-2-[4-(4-methoxyphenyl)-3-(trifluoromethyl)isoxazol-5-yl]phenol (21b). C H F NO , yield 76%,
18 14 3
4
mp 106-108°C (methanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 3.73, 3.76 (6H, 2s, OMe-5 and OMe-4′), 6.45 (1H, dd,
6
3
4
4
3
3
J = 8.0, J = 2.0, H-4), 6.48 (1H, d, J = 2.0, H-6), 6.96 (2H, d, J = 8.0, H-3′, H-5′), 7.15 (1H, d, J = 8.0, H-3), 7.20 (2H, d,
J = 8.0, H-2′, H-6′), 10.18 (1H, s, OH-1).
3
5-[(2-Methylprop-2-enyl)oxy]-2-[4-(4-methoxyphenyl)-3-(trifluoromethyl)isoxazol-5-yl]phenol (22b).
C H F NO , yield 58%, mp 104-105°C (methanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 1.75, 4.44, 4.96, 5.04 [3H,
21 18 3
4
6
3
4
4
s, 2H, s, 2H, 2s, MeC(=CH )CH O-5], 3.77 (3H, s, OMe-4′), 6.45 (1H, dd, J = 8.0, J = 2.0, H-4), 6.48 (1H, d, J = 2.0, H-6),
2
2
3
3
3
6.96 (2H, d, J = 8.0, H-3′, H-5′), 7.15 (1H, d, J = 8.0, H-3), 7.20 (2H, d, J = 8.0, H-2′, H-6′), 10.18 (1H, s, OH-1).
2-Amino-7-hydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one (23). A solution of 12c (1.4 g, 5 mmol) in ethanol
(30 mL) was treated with NaOH solution (2.5 mL, 10 mmol, 4 N), boiled for 5 h, diluted with water (50 mL), and neutralized
until the pH was 7 with dilute HCl. The resulting precipitate was filtered off and crystallized from ethanol. C H NO , yield
16 13
4
43%, mp 264-266°C (ethanol). PMR spectrum (DMSO-d , δ, ppm, J/Hz): 3.72 (3H, s, OMe-2′), 6.44 (2H, s, NH -2), 6.64 (1H,
6
2
4
3
4
3
d, J = 2.0, H-8), 6.73 (1H, dd, J = 8.0, J = 2.0, H-6), 7.73 (1H, d, J = 8.0, H-5), 6.94, 6.99, 7.11, 7.28 (4H, 4m, H-3′, H-4′,
H-5′, and H-6′), 10.19 (1H, s, OH-7).
3-Methyl-5-{4-methoxy-2-[(2-chlorobenzyl)oxy]phenyl}-4-(4-methoxyphenyl)isoxazole (24). Ahot solutionof12c
(1.4 g, 5 mmol) in absolute acetone (30 mL) was treated with freshlycalcined potash (1.05 g, 7.5 mmol), stirred, boiled, treated
with 2-chlorobenzylchloride (0.7 mL, 5.5 mmol), stored for 2 h, and poured into acidified icewater (100 mL). The resulting
precipitate was filtered off and crystallized from ethanol. C H ClNO , yield 82%, mp 125-127°C (ethanol). PMR spectrum
25 22
4
3
(DMSO-d , δ, ppm, J/Hz): 2.45 (3H, s, isoxazole Me-3), 3.74, 3.78 (6H, 2s, OMe-4 and OMe-4′), 6.64 (1H, dd, J = 8.0,
J = 2.0, H-5), 6.68 (1H, d, J = 2.0, H-3), 6.85 (2H, d, J = 8.0, H-3′, H-5′), 7.04-7.46 (7H, m).
6
4
4
3
5-Methoxy-2-[4-(4-methoxyphenyl)-3-methylisoxazol-5-yl]phenyl-2-furate (25). A solution of12c (1.4 g, 5mmol)
in dry pyridine (10 mL) was treated with 2-furylchloride (0.54 mL, 5.5 mmol), stored at room temperature for 36 h (end of
reaction determined by TLC), and poured into acidified icewater (100 mL). The resulting precipitate was filtered off, washed
with water, and crystallized from ethanol. C H NO , yield 75%, mp 96-97°C (ethanol). PMR spectrum (DMSO-d , δ, ppm,
23 19
6
6
3
4
J/Hz): 2.18 (3H, s, isoxazole Me-3), 3.77, 3.81 (6H, 2s, OMe-4 and OMe-4′), 6.94 (1H, dd, J = 8.0, J = 2.0, H-4), 7.94 (1H,
d, J = 2.0, H-6), 6.90 (2H, d, J = 8.0, H-3′, H-5′), 7.11 (2H, d, J = 8.0, H-2′, H-6′), 7.30 (1H, d, J = 8.0, H-3); furyl protons:
6.75 (1H, dd, J = 3.6, J = 1.7, H-4), 7.27 (1H, dd, J = 3.6, J = 0.9, H-3), 8.05 (1H, dd, J = 1.7, J = 0.9, H-5).
4
3
3
3
3
3
3
4
3
4
406

REFERENCES
1.
2.
3
P. Venturella and A. Bellino, Ann. Chim., 58, No. 2, 145 (1968).
M. W. Moon and J. C. Sharp, Ger. Pat. No. 2,513,652, Oct. 9, 1975; Chem. Abstr., 84, 30890s (1976).
W. Basinski and Z. Jerzmanowska, Rocz. Chem., 48, 989 (1974).
4.
W. Basinski and Z. Jerzmanowska, Pol. J. Chem., 53, 229 (1979).
5.
6.
7.
8.
V. Szabo, J. Borda, and L. Losonczi, Magy. Kem. Foly., 83, No. 6, 278 (1977).
L. G. Grishko, I. P. Kupchevskaya, and V. P. Khilya, Dokl. Akad. Nauk Ukr. SSR, Ser. B, 6, 518 (1978).
I. P. Kupchevskaya and V. P. Khilya, Dokl. Akad. Nauk Ukr. SSR, Ser. B, 2, 119 (1979).
V. P. Khilya, V. F. Vakulenko, and I. P. Kupchevskaya, Khim. Geterotsikl. Soedin., 1, 25 (1979).
V. P. Khilya, L. G. Grishko, and T. L. Davidkova, Khim. Geterotsikl. Soedin., 7, 892 (1980).
V. P. Khilya, I. P. Kupchevskaya, I. L. Kazakov, and T. M. Tkachuk, Khim. Geterotsikl. Soedin., 3, 321 (1982).
V. P. Khilya, A. Aitmambetov, and G. M. Golubushina, Khim. Prir. Soedin., 633 (1994).
M. Sree Rama Murthy and E. Venkata Rao, Indian J. Chem., Sect. B, 24, No. 7, 667 (1985).
A. Pelter and S. Foot, Synthesis, 5, 326 (1976).
A. Levai, J. Chem. Res. Synop., 5, 163 (1992).
V. G. Pivovarenko, V. P. Khilya, and S. A. Vasil ev, Khim. Prir. Soedin., 639 (1989).
A. S. Kukla and T. R. Seshadri, Indian J. Chem., 1, 343 (1963).
S. P. Bondarenko, M. S. Frasinyuk, and V. P. Khilya, Khim. Prir. Soedin., 273 (2003).
A. Levai, W. Adam, R. T. Fell, R. Gessner, T. Patonay, A. Simon, and G. Toth, Tetrahedron, 54, 13105 (1998).
M. S. Frasinyuk, S. P. Bondarenko, and V. P. Khilya, Khim. Prir. Soedin., 117 (2006).
S. P. Bondarenko, M. S. Frasinyuk, and V. P. Khilya, Khim. Prir. Soedin., 277 (2003).
A. L. Kazakov, V. P. Khilya, V. V. Mezheretskii, and D. Litkei, Natural and Modified Isoflavonoids [in Russian],
Izd. RGU, Rostov-on-Don (1985).
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
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