Synthesis of analogs of natural isoflavonoids containing phloroglucinol

Article abstract of DOI:10.1023/A:1025422502712

Analogs of the natural isoflavonoids biochanin A and orobol were synthesized. Alkylation involving phenolic hydroxyls and the chromone ring was studied.

Full text of DOI:10.1023/A:1025422502712

Chemistry of Natural Compounds, Vol. 39, No. 3, 2003
SYNTHESIS OF ANALOGS OF NATURAL ISOFLAVONOIDS
CONTAINING PHLOROGLUCINOL
S. P. Bondarenko, A. V. Levenets,
M. S. Frasinyuk, and V. P. Khilya
UDC 547.814.5
Analogs of the natural isoflavonoids biochanin A and orobol were synthesized. Alkylation involving phenolic
hydroxyls and the chromone ring was studied.
Key words: Hesch synthesis, isoflavonoids, alkylation, aminomethylation.
Natural isoflavonoids occur as hydroxy-, methoxy-, methylenedioxy-, C-methyl-, and C-prenyl-derivatives. They can
also be condensed with 2,2-dimethylpyrano- or furano-rings [1]. General syntheses of them and their natural distribution have
been described [2].
Our goal was to synthesize and study the reactivity of analogs of the natural isoflavonoids biochanin A (1) and
orobol (2).
1
7
HO
O
HO
O
6'
3
OH
OH
5'
4'
5
OH
O
OH
O
O
3'
Me
1
2
Considering previous results [2], we used 2,4,6-trihydroxydeoxybenzoins 3a-c to synthesize analogs of natural
isoflavones. These are the most convenient starting materials for constructing the chromone system.
Starting ketones 3a-c were prepared by condensation of phloroglucinol with substituted acetonitriles in ether in the
presence of HCl and ZnCl as a catalyst (Houben—Hoesch reaction) [3].
2
We used acylation of an α-methylene by Vilsmeier reagent in addition to acid (chloro)anhydrides to synthesize
2-(un)substituted analogs of 1 and 2. Thus, the proposed [4] modified version that uses methanesulfonylchloride was
successfullyapplied tothe synthesis ofisoflavonoids with "phloroglucinol" replacing the hydroxyls. Various isoflavonoids were
synthesized by this method [5]. Use of this method with 3a-c led to 2-unsubstituted isoflavonoids 4a-c.
In contrast with the synthesis of 2-unsubstituted isoflavones, the use of traditional methods to construct the chromone
ring is not always justified for isoflavones containing methoxys in ring B. Thus, use of acetic anhydride and triethylamine to
synthesize2-methylisoflavones5a-c did not lead tothe desired compounds owing tolowyieldsanddifficultieswith theisolation.
Apparently in this instance the electron-donating groups in ring B of 3a-c have an effect.
Therefore, we propose a different method for synthesizing 2-methylisoflavones 5a-c. We used dimethylacetamide and
methanesulfonylchloride in the presence of BF —etherate as the cyclization reagent.
In contrast with the
3
Kostanetskii—Robinson reaction, the use of this method produced 7-hydroxy-2-methylisoflavones 5a-c in high yields in one
step [6-8].
Taras Shevchenko Kiev University, 252033, Kiev, ul. Vladimirskaya, 64, fax (380) 442 351 273, e-mail:
mfras@i.kiev.ua. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 211-214, May-June, 2003. Original article
submitted June 16, 2003.
0009-3130/03/3903-0271$25.00 ©2003 Plenum Publishing Corporation
271

HO
OH
HO
OH
HO
O
O
CF
3
N
+
R
1
R
3
OH
O
R
OH
OH
R
2
R
R
3
3
1
R
1
R
2
R
2
3a - c
6b, c
Br
HO
O
O
R
4
HO
O
COOEt
O
O
O
R
4
O
OH
O
OH
OH
8c, 9c
R
3
R
3
O
R
R
1
1
R
R
2
2
4, 5a - c
7b, c
R
5
Me
N
N
O
N
Cl
HO
R
4
HO
N
O
O
R
4
O
O
Cl
O
O
O
N
N
OH
OH
O
O
R
3
R
3
R
2
R
2
R
5
10c
12b, c, 13b, 14b
11b, c
Me
3
3
5a:
3
7b 11 4b:
-1 R1 = R2 = H, R3 = OMe;
-
-
R1 = OMe, R2 = R3 = H;
-
,
7c 11c 12c:
,
4a c 8c 11b 12b,c 14b:
,
R1 = H, R2 = R3 = OMe; - ,
12b,c 13b
,
,
,
R4 = H;
5a - c 9c 11c 13b
: R4 = Me;
14b:
R5 = Me
,
,
,
,
: R5 = H;
6a c
7a c
2-Trifluoromethyl- and 2-ethoxycarbonyl isoflavones
trifluoroacetic anhydride or ethoxyallylchloride [9].
We studied the alkylation of the prepared isoflavone analogs
acetonein the presence ofpotash produced 7-benzyloxy-5-hydroxyisoflavones and . Usingan excessofthealkylatingagent
10c
- and - , respectively, can be synthesized by using
4,5a c
- . Reaction with one equivalent of benzylhalide in
8c 9c
produced the bis-alkylated product
.
We also studied the reactivity of isoflavones with substitution of hydroxyls by phloroglucinol in electrophilic-
substitution reactions. The Mannich reaction was selected as an example. On one hand, Mannich bases are biologically active
compounds with a wide spectrum ofactivity. On the other, theyare promising starting compounds for further modification [10].
Introducing a tertiary nitrogen atom produces water-soluble salts for biological investigations. Furthermore, introducing an
amine, analogously to previously described carboxyl [3, 11], makes it possible to test the products in immunological
investigations since they can be incorporated into a polypeptide chain.
It should be noted that it is somewhat difficult to introduce an amine into the chromone fragment. Reactiton of
3-halochromoneswith primaryor secondaryamines does not always proceed smoothly. Sometimesa mixtureofseveral products
forms [12]. The synthesis of 5-aminoflavones is a multistep process [13].
Recalling the previous investigations of aminomethylation of benzopyrones [14], we prepared Mannich bases using
aminals.
According toTLC, reaction of one equivalent of aminomethylating reagent forms a mixture ofseveral products. Using
11 14b c
- .
an excess of bis(dialkylamino)methane led to aminomethylation ofthe 6- and 8-positions ofthe chromone ring togive
-
272

EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Sorbfil UV-254 (Russia) and Merck
(Germany) plates with elution by CHCl :MeOH mixtures (95:5 and 9:1). PMR spectra were measured on VXR-300 and
3
Mercury400 instruments (Varian, 300 and 400 MHz, respectively) in DMSO-d , except for Mannich bases 11-14b-c (CDCl ),
6
3
relative to TMS (internal standard) on the δ scale. Elemental analyses corresponded to those calculated.
Starting ketones 3a-c were prepared as before [3].
General Method for Preparing 4a-c. A solution of the appropriate 3a-c (10 mmol) in DMF (10 mL) was treated with
BF —etherate (40 mmol) and then methanesulfonylchloride (30 mmol) at a rate such that the temperature of the reaction
3
mixture remained below 50°C. The mixture was held at 100°C and stirred for 3-4 h and then poured into cold water (100 mL).
The resulting hydrolyzed precipitate of 4a-c was filtered off and crystallized from MeOH.
5,7-Dihydroxy-3-(2-methoxyphenyl)chromen-4-one (4a), mp 200-201°C (MeOH). PMR spectrum (δ, ppm., J/Hz):
3.74 (3H, s, OMe-2′), 6.24 (1H, d, H-6, J = 2), 6.41 (1H, d, H-8, J = 2), 6.98, 7.09, 7.25, 7.40 (4H, m, 3′,4′,5′,6′), 8.24 (1H,
6,8
8,6
s, H-2), 10.92 (1H, s, OH-7), 12.86 (1H, s, OH-5).
General Method for Preparing 2-Methylisoflavones 5a-c. The synthesis was carried out analogouslytothat for 4a-c
using dimethylacetamide as the solvent and reagent. The reaction mixturewastreatedwith methanesulfonylchloride and heated
at 100°C with stirring for 16-24 h. The resulting crystals were filtered off and crystallized from MeOH.
5,7-Dihydroxy-3-(2-methoxyphenyl)-2-methylchromen-4-one (5a), mp 150-151°C (MeOH). PMR spectrum (δ,
ppm., J/Hz): 2.13 (3H, s, Me-2), 3.73 (3H, s, OMe-2′), 6.20 (1H, d, H-6, J = 2), 6.36 (1H, d, H-8, J = 2), 7.01, 7.10, 7.15,
6,8
8,6
7.39 (4H, m, 3′,4′,5′,6′), 10.83 (1H, s, OH-7), 12.91 (1H, s, OH-5).
5,7-Dihydroxy-3-(4-methoxyphenyl)-2-methylchromen-4-one (5b), mp 175-176°C (MeOH). PMR spectrum (δ,
ppm., J/Hz): 2.24, J/Hz (3H, s, Me-2), 3.80 (3H, s, OMe-4 ), 6.20 (1H, d, H-6, J = 2), 6.35 (1H, d, H-8, J = 2), 6.99 (2H,
6,8
8,6
d, J
= 7, H-3, H-5), 7.22 (2H, d, J
= 7, H-2, H-6), 10.87 (1H, s, OH-7), 12.95 (1H, s, OH-5).
3′,2′
2 ,3
3-(3,4-Dimethoxyphenyl)-5,7-dihydroxy-2-methylchromen-4-one (5c), mp 185-186°C (MeOH). PMR spectrum
(δ, ppm., J/Hz): 2.26 (3H, s, Me-2), 3.74, 3.79 (6H, 2s, OMe-3′, OMe-4′), 6.19 (1H, d, J = 2, H-6), 6.36 (1H, d, H-8,
6,8
J
= 2), 6.81 (1H, dd, J
= 2, J
= 8, H-6′), 6.88 (1H, d, J
= 2, H-2′), 7.02 (1H, d, J
= 8, H-5′), 10.80 (1H, s,
8,6
6 ,2
6 ,5
2 ,6
5 ,6
OH-7), 12.97 (1H, s, OH-5).
General Method for Preparing 6,7a-c. A cooled solution of 3a-c (10 mmol) in the minimal amount of pyridine was
treated with ethoxyallylchloride (40 mmol) or trifluoroacetic anhydride. The reaction mixture was held at 0°C for 2 h, left at
room temperature for 48-72 h, and poured into water (100 mL). The resulting precipitate was filtered off and crystallized from
MeOH.
5,7-Dihydroxy-3-(4-methoxyphenyl)-2-trifluoromethylchromen-4-one (6b), mp 215-216°C (MeOH). PMR
spectrum (δ, ppm., J/Hz): 3.80 (3H, s, OMe-4 ), 6.31 (1H, d, H-6, J = 2), 6.49 (1H, d, H-8, J = 2), 7.02 (2H, d, J = 2,
3 ,2
6,8
8,6
H-3, H-5), 7.22 (2H, d, J
= 7, H-7, H-6), 11.24 (1H, s, OH-7), 12.25 (1H, s, OH-5).
2 ,3
3-(3,4-Dimethoxyphenyl)-5,7-dihydroxy-2-trifluoromethylchromen-4-one (6c), mp 243-244°C (MeOH). PMR
spectrum (δ, ppm., J/Hz): 3.72, 3.80, J/Hz (6H, 2s, OMe-3′, OMe-4′), 6.31 (1H, d, H-6, J = 2), 6.47 (1H, d, H-8, J = 2),
6,8
8,6
6.83 (1H, dd, J
(1H, s, OH-5).
= 2, J
= 8, H-6′), 6.93 (1H, d, J
= 2, H-2′), 7.01 (1H, d, J
= 8, H-5′), 11.23 (1H, s, OH-7), 12.26
6 ,2
6 ,5
2 ,6
5 ,6
Ethyl 3-(3,4-dimethoxyphenyl)-5,7-dihydroxy-4-oxo-4H-chromen-2-carboxylate (7c), mp 230-231°C (MeOH).
PMR spectrum (δ, ppm., J/Hz): 0.97, 4.12 (3H, t, 2H, q, J = 7, CH CH OOC-2), 3.72, 3.79 (6H, 2s, OMe-3′, OMe-4′), 6.28 (1H,
3
2
d, H-6, J = 2), 6.42 (1H, d, H-8, J = 2), 6.80 (1H, dd, J
= 2, J
= 8, H-6′), 6.89 (1H, d, J
= 2, H-2′), 6.98 (1H,
6,8
8,6
6 ,2
6 ,5
2 ,6
d, J
= 8, H-5′), 11.13 (1H, s, OH-7), 12.52 (1H, s, OH-5).
5 ,6
7-(4-Bromobenzyloxy)-5-hydroxyisoflavones 8c and 9c. A hot solution of the appropriate 4c or 5c (10 mmol) in
absolute acetone (15 mL) was treated with freshlycalcined K CO (2.1 g, 15 mmol), stirred and heated to 50-56 C, treated with
2
3
4-bromobenzylbromide (10.5 mmol), left for 4 h (completion of the reaction monitored by TLC), cooled, and poured onto
acidified icewater (100 mL). The precipitate was filtered off and crystallized from MeOH.
7-(4-Bromobenzyloxy)-3-(3,4-dimethoxyphenyl)-5-hydroxychromen-4-one (8c), mp 171-172°C (MeOH). PMR
spectrum (δ, ppm., J/Hz): 3.79 (6H, s, OMe-3′, OMe-4′), 5.23 (2H, s, OCH -7), 6.50 (1H, d, H-6, J = 2), 6.76 (1H, d, H-8,
2
6,8
J
= 2), 7.03 (1H, d, J
= 8, H-5′), 7.12 (1H, dd, J
= 2, J
= 8, H-6′), 7.18 (1H, d, J = 2, H-2′), 7.45, 7.61 (4H,
2 ,6
8,6
5 ,6
6 ,2
6 ,5
2d, J = 8, benzyl protons), 8.49 (1H, s, H-2), 12.95 (1H, s, OH-5).
2,3
273

7-(4-Bromobenzyloxy)-3-(3,4-dimethoxyphenyl)-5-hydroxy-2-methylchromen-4-one (9c), mp169-170°C(MeOH).
PMR spectrum (δ, ppm., J/Hz): 2.28 (3H, s, Me-2), 3.74, 3.79 (6H, 2s, OMe-3′, OMe-4′), 5.23 (2H, s, OCH -7), 6.47 (1H, d,
2
H-6, J = 2), 6.70 (1H, d, H-8, J = 2), 6.83 (1H, dd, J
= 2, J
= 8, H-6′), 6.90 (1H, d, J
= 2, H-2′), 7.00 (1H, d,
6,8
8,6
6 ,2
6 ,5
2 ,6
J
= 8, H-5′), 7.44, 7.61 (4H, 2d, J = 8, benzyl protons), 12.98 (1H, s, OH-5).
2,3
5 ,6
5,7-Bis-(4-chlorobenzyloxy)-3-(3,4-dimethoxyphenyl)chromen-4-one (10c) was synthesized analogously to 8c and
9c using 4-chlorobenzylchloride (25 mmol). mp 182-183°C (MeOH). PMR spectrum (δ, ppm., J/Hz): 3.77 (6H, s, OMe-3′,
OMe-4′), 5.23 (4H, 2s, OCH -7, OCH -5), 6.71 (1H, d, H-6, J = 2), 6.80 (1H, d, H-8, J = 2), 7.00 (1H, d, J = 8, H-5′),
2
2
6,8
8,6
5 ,6
7.05 (1H, dd, J
= 2, J
= 8, H-6′), 7.10 (1H, d, J
= 2, H-2′), 7.50, 7.61 (6H, 2H, 2m, benzyl protons), 8.23 (1H, s, H-2).
6 ,2
6 ,5
2 ,6
General Methodfor Preparing6,8-Bis(dialkylamino)methylisoflavones11-14. Aboilingsolution oftheappropriate
isoflavone 4,5a-c (10 mmol) in absolute dioxane (20 mL) was treated with aminal (25 mmol), boiled for 3-4 h (completion of
the reaction monitored by TLC), and cooled. The dioxane, released amine, and unreacted aminal were evaporated in vacuum.
The solid was crystallized from toluene—hexane.
5,7-Dihydroxy-3-(4-methoxyphenyl)-6,8-bis-(4-methylpiperazin-1-ylmethyl)chromen-4-one(11b), mp183-184°C.
PMR spectrum (δ, ppm., J/Hz): 2.29 (6H, s, 2N–Me), 2.35-2.80 (16H, m, piperazine protons), 3.79 (2H, s, N–CH ), 3.84 (5H,
2
s, N–CH and OMe-4′), 6.99 (2H, d, J
= 8, H-3, H-5), 7.44 (2H, d, J
= 8, H-2, H-6), 7.87 (1H, s, H-2).
2
3 ,2
2 ,3
3-(3,4-Dimethoxyphenyl)-5,7-dihydroxy-2-methyl-6,8-bis-(4-methylpiperazin-1-ylmethyl)chromen-4-one (11c),
mp 165-166°C. PMR spectrum (δ, ppm., J/Hz): 2.30 (9H, s, 2N–Me and Me-2), 2.35-2.80 (16H, m, piperazine protons), 3.80,
3.83 (4H, 2s, 2N–CH ), 3.88, 3.91 (6H, 2s, OMe-3′ and OMe-4′), 6.78 (1H, dd, J
= 2, J
= 8, H-6′), 6.83 (1H, d,
2
6 ,2
6 ,5
J
= 2, H-2′), 6.93 (1H, d, J
= 8, H-5′).
2 ,6
5 ,6
5,7-Dihydroxy-3-(4-methoxyphenyl)-6,8-bis-piperidin-1-ylmethyl-chromen-4-one (12b), mp 139-140°C. PMR
spectrum (δ, ppm., J/Hz): 1.27-1.82 and 2.34-2.83 (12H, m, 8H, m, piperidine protons), 3.73, 3.80 (4H, 2s, 2N–CH ), 3.84 (3H,
2
s, OMe-4′), 6.99 (2H, d, J
= 8, H-3, H-5), 7.45 (2H, d, J
= 8, H-2, H-6), 7.88 (1H, s, H-2).
3 ,2
2 ,3
3-(3,4-Dimethoxyphenyl)-5,7-dihydroxy-6,8-bis-piperidin-1-ylmethyl-chromen-4-one(12c), mp137-138°C. PMR
spectrum (δ, ppm., J/Hz): 1.30-1.74 and 2.36-2.79 (12H, m, 8H, m, piperdine protons), 3.73, 3.80 (4H, 2s, 2N–CH ), 3.92, 3.93
2
(6H, 2s, OMe-3′ and OMe-4′), 6.93 (1H, d, J
H-2′), 7.90 (1H, s, H-2).
= 8, H-5′), 7.04 (1H, dd, J
= 2, J
= 8, H-6′), 7.10 (1H, d, J
= 2,
5 ,6
6 ,2
6 ,5
2 ,6
5,7-Dihydroxy-3-(4-methoxyphenyl)-2-methyl-6,8-bis-piperdin-1-ylmethyl-chromen-4-one (13b), mp113-114°C.
PMR spectrum (δ, ppm., J/Hz): 1.32-1.78 and 2.39-2.75 (12H, m, 8H, m, piperidine protons), 2.29 (3H, s, Me-2), 3.75, 3.78
(4H, 2s, 2N–CH ), 3.84 (3H, s, OMe-4′), 6.99 (2H, d, J
= 8, H-3, H-5), 7.19 (2H, d, J
= 8, H-2, H-6).
2
3 ,2
2 ,3
5,7-Dihydroxy-3-(4-methoxyphenyl)-6,8-bis-(3-methylpiperdin-1-ylmethyl)chromen-4-one(14b), mp142-143°C.
PMR spectrum (δ, ppm., J/Hz): 0.86 (6H, 2Me), 1.47-2.22 and 2.83-3.04 (14H, m, 4H, m, piperdine protons), 3.74, 3.80 (4H,
2s, 2N–CH ), 3.84 (3H, s, OMe-4′), 6.99 (2H, d, J
= 8, H-3, H-5), 7.44 (2H, d, J
= 8, H-2, H-6), 7.87 (1H, s, H-2).
2
3 ,2
2 ,3
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