Synthesis of analogs of natural 2′-methoxyisoflavones

Article abstract of DOI:10.1007/s10600-006-0063-0

2-(Un)substituted-2′-methoxy-7-hydroxyisoflavones were synthesized. They were derivatized at the phenol hydroxyl using alkylation and acylation reactions and Mannich base formation. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10600-006-0063-0

Chemistry of Natural Compounds, Vol. 42, No. 2, 2006
SYNTHESIS OF ANALOGS OF NATURAL 2 -METHOXYISOFLAVONES
′
M. S. Frasinyuk,1 S. P. Bondarenko,2 and V. P. Khilya2
UDC 547.814.5
′
2-(Un)substituted-2 -methoxy-7-hydroxyisoflavones were synthesized. They were derivatized at the phenol
hydroxyl using alkylation and acylation reactions and Mannich base formation.
Key words:
isoflavonoids, alkylation, acylation, aminomethylation.
Flavonoids as a class are some of the most widely distributed compounds of plant origin. Representatives of them are
present in practically all plant species [1]. Flavonoids are most frequently found as hydroxylated, methoxylated, and
glycosylated derivatives. We reported previously on the isolation from plant material of the natural isoflavones teralin
(7,4′-dihydroxy-2′-methoxyisoflavone) [2], milldurone (6,7,2′-trimethoxy-4′,5′-methylenedioxyisoflavone) [3], and irisolone
(7,8,2′-trimethoxy-4′,5′-methylenedioxyisoflavone) [4]. Irilin C (5,2′-dimethoxy-6,7-methylenedioxyisoflavone) was recently
isolated from
, which is used in Mongolian folk medicine [5]; 2′- -methyllabronisoflavone (2′-methoxy-5,7-
O
Iris bungei
dihydroxy-6-methylisoflavone), from
, which exhibits high antifungicidal activity [6].
Mirabilis jalapa
In continuation of research on the synthesis of natural alkoxyisoflavones (formononetin, orobol, biochanin A,
pseudobaptigenin, cladrin) and their analogs [7-10] and considering the high and varied biological activityof these compounds,
it was interesting to prepare analogs of natural 2′-methoxyisoflavones and their derivatives.
1
The starting compound for constructing the chromone nucleus was 2,4-dihydroxy-2′-methoxydeoxybenzoin ( ) [11,
12], which was dictated by its availability and the preparative capabilities of converting it to isoflavones.
Me
O
O
R
1
Me
O
O
Me
H C
2
O
MeO
6, 7
O
Cl
O
MeO
8
O
R
1
HO
O
O
R
1
O
O
MeO
O
MeO
Me
Me
2 - 5
9, 10
Me
Me
O
Me
O
O
R
O
O
O
O
O
R
1
O
R
4
R
2
O
MeO
3
11 - 16
17
MeO
2, 6, 9, 11, 15: R = H; 3, 7, 10, 13, 16: R = Me; 4, 12, 14: R = CF ; 5: R = COOEt
1
1
1
3
11, 12: R = R = Me, R = H; 13, 14: R = R = H, R = OMe; 15, 16: R = H, R = R = Me
2
4
3
2
3
4
2
3
4
1) Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 02094, Ukraine,
Kiev, ul. Murmanskaya, 1, e-mail: mfras@i.kiev.ua; 2) Taras Shevchenko Kiev National University, 01033, Ukraine, Kiev, ul.
Vladimirskaya, 64. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 117-121, March-April, 2006. Original article
submitted November 7, 2005.
0009-3130/06/4202-0142 ©2006 Springer Science+Business Media, Inc.
142

2-Unsubstituted isoflavone 2 was synthesized byformylation of 2-hydroxydeoxybenzoin using Vilsmeier reagent with
subsequent heterocyclization [12, 13]. Its 2-methyl derivative 3 was synthesized by the literature method [11].
Acid (chloro)anhydrides were used as acylating agents toprepare 2-substituted isoflavones 4 and 5 under Kostanetsky-
Robinson conditions.
New derivatives of 7-hydroxyisoflavones 2-5 were prepared and their reactivities were investigated using reactions at
the phenol hydroxyl and aminomethylation.
Natural isoflavones are frequentlyethersofhydroxyisoflavones(e.g., maximaisoflavonesAandB, xanthocercine, etc.).
Therefore, considering the high and varied biological activity of natural isoflavonoids, the synthesis of alkoxy derivatives is
especially interesting because the introduction of new pharmacophores into analogs of natural isoflavones can cause new
valuable pharmacological properties to appear. For this reason we investigated the reaction of the prepared isoflavones with
various alkylating reagents such as haloalkenes, compounds containing heterocyclic fragments (4-chloromethylcoumarins and
8-chloromethyl-6-chlorobenzo-1,3-dioxane), and chloroacetic ester with a steroid fragment.
We prepared 7-dimethylallyloxy-(6 and 7) and 7-methylallyloxyisoflavones (8) because allyl derivatives ofisoflavones
that are methoxylated on the B ring are insecticides [14].
Substituted 4-chloromethylcoumarins were used as the alkylating reagents to prepare analogs of natural
bisbenzopyrones 11-16. In this instance longer heating ofthe reaction mixture with an excess of alkylating reagent was required
to complete the alkylation. This was due to the low stability of substituted 4-chloromethylcoumarins in alkaline media. Under
these conditions they are known to rearrange into the corresponding substituted 3-benzofuranacetic acids [15].
Acylation of 7-hydroxyisoflavones proceeded readily in pyridine at room temperature. The acylating reagents were
acid chlorides of substituted 3-benzofurancarboxylic and cyclopropane- and cyclohexanecaboxylic acids.
Compounds of the urethane type (21-23) were prepared for the first time as analogs of 2′-methoxyisoflavone using
acylating reactions of N,N-disubstituted carbamoyl chlorides. Esters of methanesulfonic acid, isoflavones 28 and 29, were
synthesized using methanesulfonyl chloride.
R
8
R
6
O
O
O
R
1
R
5
O
O
R
1
N
O
O
R
1
R
7
O
O
O
R O
9
O
MeO
O
MeO
O
MeO
24 - 27
21 - 23
18 - 20
X
N
O
O
O
R
1
O
O
R
1
Me
S
HO
O
2 - 5
O
MeO
MeO
28, 29
30 - 35
23, 24, 28, 31 - 34: R = H; 18, 25, 26, 35:R = Me; 19 - 22, 30:R = CF ; 27, 29:R = COOEt;18: R = Me
1
1
1
3
1
5
19: R = cyclopropyl; 20: R = cyclohexyl; 21: R R = (CH ) O(CH ) ; 22: R = R = Ph; 23: R = R = Et
2 2 2 2
5
5
6
7
6
7
6
7
24, 25:R = Me, R = Ac; 26, 27:R = Ph, R = Et; 30: X = bond;31: X = CH ; 32: X = CHMe
8
9
8
9
2
33: X = N(CH ) OH; 34, 35:X = NCH
2 2
3
Preparation of Mannich bases 30-35 is a variation of C-alkylation of the chromone nucleus. Aminomethyl derivatives
of 7-hydroxyisoflavones were synthesized using aminals of secondaryamines. Using an equivalent amount of aminal produced
a chromone ring aminomethylated at the 8-position.
143

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 :CH OH (95:5 and 9:1). PMR spectra were measured on a VXR-300 (Varian,
3
3
300 MHz) instrument in DMSO-d (Mannich bases in CDCl ) relative to TMS (internal standard) on the δ-scale. Analytical
6
3
data for all compounds agreed with those calculated.
Synthesis of 2-Trifluoromethyl- and 2-Ethoxycarbonylisoflavones (4, 5). A cooled (0°C) solution of 1 (2.42 g,
10 mmol) in absolute pyridine (10 mL) was treated dropwise with trifluoroacetic anhydride or ethyloxalylchloride (20 mmol),
left at room temperature for 1 d, and poured into icewater (100 mL) containing HCl (1 N, 1-3 mL). The precipitate was filtered
off and crystallized from CH OH.
3
7-Hydroxy-3-(2-methoxyphenyl)-2-trifluoromethyl-4H-chromen-4-one (4). C H F O , yield 78%, mp247-249°C
17 11 3
4
4
(CH OH). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.70 (3H, s, OMe-2′), 6.96 (1H, d, H-8, J = 2.1), 7.00 (1H,
m, H-5′), 7.02 (1H, dd, J = 8.8, J = 2.1, H-6), 7.09 (1H, m, H-3′), 7.15 (1H, m, H-6′), 7.42 (1H, m, H-4′), 7.92 (1H, d,
3
6
3
4
3
J = 8.8, H-5), 11.13 (1H, s, HO-7).
Ethyl 7-hydroxy-3-(2-methoxyphenyl)-4-oxo-4H-chromen-2-carboxylate (5). C H O , yield76%, mp 99-101°C
19 16
6
3
3
(CH OH). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.91 (3H, t, J = 7.2), 4.06 (2H, q, J = 7.2) CH CH COO-2,
3
6
3
2
4
3
4
3.66 (3H, s, OMe-2′), 6.90 (1H, d, J = 2.0, H-8), 6.97 (1H, m, H-5′), 6.98 (1H, dd, J = 8.8, J = 2.0, H-6), 7.04 (1H, m, H-3′),
3
7.12 (1H, m, H-6′), 7.36 (1H, m, H-4′), 7.92 (1H, d, J = 8.8, H-5), 11.03 (1H, s, HO-7).
General Method for Preparing7-Alkyloxyisoflavones(6-17). A hot solution ofthe appropriate 7-hydroxyisoflavone
(2-4, 10 mmol) in absolute acetone (30 mL) was treated with fershly calcined potash (2.1 g, 15 mmol), stirred, boiled, treated
with the appropriate alkylhalide (12 mmol), left for 1-4 h (completion of reaction determined byTLC), and poured intoacidified
icewater (100 mL). The resulting precipitate was filtered off and crystallized from a suitable solvent.
3-(2-Methoxyphenyl)-7-[3-methylbut-2-enyl)oxy]-4H-chromen-4-one (6). C H O , yield 84%, mp 135-136°C
21 20
4
(ethanol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.72 (3H, s, OMe-2′), 6.99 (1H, m, H-5′), 7.07 (1H, dd,
6
3
4
4
J = 8.8, J = 2.4, H-6), 7.08 (1H, m, H-3′), 7.16 (1H, d, J = 2.4, H-8), 7.24 (1H, m, H-6′), 7.38 (1H, m, H-4′), 7.97 (1H, d,
J = 8.8, H-5), 8.25 (1H, s, H-2); alkyl-substituent protons 1.76 (6H, s, 2CH ), 5.48 (1H, d, J = 6.8, CH), 4.69 (2H, d, J = 6.8,
3
3
3
3
CH O).
2
3-(2-Methoxyphenyl)-2-methyl-7-[(3-methylbut-2-enyl)oxy]-4H-chromen-4-one (7). C H O , yield78%, mp91-
22 22
4
92°C (ethanol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.14 (3H, s, CH -2), 3.71 (3H, s, OMe-2′), 6.99 (1H, m,
6
3
3
4
4
H-5′), 7.02 (1H, dd, J = 8.8, J = 2.4, H-6), 7.08 (1H, m, H-6′), 7.13 (1H, d, J = 2.4, H-8), 7.14 (1H, m, H-3′), 7.37 (1H, m,
H-4′), 7.89 (1H, d, J = 8.8, H-5); alkyl-substituent protons 1.75 (6H, s, 2CH ), 5.48 (1H, d, J = 7.2, CH), 4.68 (2H, d, J = 7.2,
3
3
3
3
CH O).
2
3-(2-Methoxyphenyl)-7-[(2-methylprop-2-enyl)oxy]-4H-chromen-4-one (8). C H O , yield75%, mp117-119°C
20 17
4
(CH OH). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.71 (3H, s, OMe-2′), 6.99 (1H, m, H-5′), 7.08 (1H, m, H-3′),
3
6
3
4
4
3
7.11 (1H, dd, J = 8.8, J = 2.4, H-6), 7.17 (1H, d, J = 2.4, H-8), 7.23 (1H, m, H-6′), 7.38 (1H, m, H-4′), 7.99 (1H, d, J = 8.8,
H-5), 8.26 (1H, s, H-2); alkyl-substituent protons 1.80 (3H, m, CH ), 5.11, 5.01 (2H, m, =CH ), 4.66 (2H, m, CH O).
3
2
2
7-[(6-Chloro-4H-1,3-benzodioxan-8-yl)methoxy]-3-(2-methoxyphenyl)-4H-chromen-4-one (9). C H ClO , yield
25 19
6
69%, mp 259-260°C (ethanol:DMF). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.73 (3H, s, OMe-2′), 7.00 (1H, m,
6
4
3
4
H-5′), 7.09 (1H, m, H-3′), 7.16 (1H, m, H-6′), 7.23 (1H, d, J = 2.0, H-8), 7.24 (1H, dd, J = 8.8, J = 2.0, H-6), 7.39 (1H, m,
H-4′), 8.01 (1H, d, J = 8,8, H-5), 8.27 (1H, s, H-2); alkyl-substituent protons 5.19 (2H, s, OCH O), 4.93 (2H, s, OCH -Ar),
3
2
2
4
7.43, 7.28 (2H, 2d, J = 2.0, H-6, H-8), 5.36 (2H, s, CH O).
2
7-[(6-Chloro-4H-1,3-benzodioxan-8-yl)methoxy]-2-methyl-3-(2-methoxyphenyl)-4H-chromen-4-one (10).
C H ClO , yield 69%, mp 252-253°C (ethanol:DMF). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.15 (3H, s,
26 21
6
6
3
4
CH -2), 3.72 (3H, s, OMe-2′), 7.01 (1H, m, H-5′), 7.09 (1H, m, H-3′), 7.12 (1H, dd, J = 8.8, J - 2.0, H-6), 7.15 (1H, m, H-6′),
3
4
3
7.23 (1H, d, J = 2.0, H-8), 7.39 (1H, m, H-4′), 7.93 (1H, d, J = 8,8, H-5); alkyl substituent protons 5.19 (2H, s, OCH O), 4.93
(2H, s, OCH -Ar), 7.42, 7.14 (2H, 2d, J = 2.0, H-6, H-8), 5.36 (2H, s, CH O).
2
4
2
2
4-({[3-(2-Methoxyphenyl)-4-oxo-4H-chromen-7-yl]oxy}methyl)-5,7-dimethyl-2H-chromen-2-one (11). C H O ,
28 22
6
yield 65%, mp 246-247°C (propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.73 (3H, s, OMe-2′), 7.00 (1H,
6
4
3
m, H-5′), 7.09 (1H, m, H-3′), 7.25 (1H, m, H-6′), 7.29 (1H, dd, J = 8.8, J = 2.0, H-6), 7.38 (1H, m, H-4′), 7.39 (1H, d,
144

4
3
J = 2.0, H-8), 8.06 (1H, d, J = 8,8, H-6), 8.30 (1H, s, H-2); alkyl substituent protons 2.37 (3H, s, CH -7), 2.72 (3H, s, CH -5),
3
3
4
4
5.70 (2H, s, CH -4), 6.59 (1H, s, H-3), 7.07 (1H, d, J = 2.0, H-8), 7.15 (1H, d, J = 2.0, H-6).
2
4-({[3-(2-Methoxyphenyl)-4-oxo-2-(trifluoromethyl)-4H-chromen-7-yl]oxy}methyl)-5,7-dimethyl-2H-chromen-
2-one (12). C H F O , yield 60%, mp 187-188°C (propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.71
29 21 3
6
6
3
4
(3H, s, OMe-2′), 7.03 (1H, m, H-5′), 7.11 (1H, m, H-3′), 7.19 (1H, m, H-6′), 7.38 (1H, dd, J = 8.8, J = 2.0, H-6), 7.44 (1H,
m, H-4′), 7.56 (1H, d, J = 2.0, H-8), 8.05 (1H, d, J = 8,8, H-5); alkyl substituent protons 2.38 (3H, s, CH -7), 2.74 (3H, s,
CH -5), 5.77 (2H, s, CH -4), 6.54 (1H, s, H-3), 7.09 (1H, d, J = 2.0, H-8), 7.16 (1H, d, J = 2.0, H-6).
4
3
3
4
4
3
2
7-Methoxy-4-({[3-(2-methoxyphenyl)-2-methyl-4-oxo-4H-chromen-7-yl]oxy}methyl)-2H-chromen-2-one (13).
C H O , yield 59%, mp 224-226°C (ethanol). PMRspectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.16 (3H, s, CH -2), 3.72
28 22
7
6
3
3
4
(3H, s, OMe-2′), 7.02 (1H, m, H-5′), 7.10 (1H, m, H-3′), 7.15 (1H, m, H-6′), 7.27 (1H, dd, J = 8.8, J = 2.0, H-6), 7.39 (1H,
m, H-4′), 7.49 (1H, d, J = 2.0, H-8), 7.97 (1H, d, J = 8.8, H-5); alkyl substituent protons 3.89 (3H, s, CH O-7), 5.56 (2H, s,
4
3
3
3
3
4
4
CH -4), 6.48 (1H, s, H-3), 7.03 (1H, dd, J = 8,8, J = 2.4, H-6), 7.07 (1H, d, J = 2.4, H-8), 7.87 (1H, d, J = 8.8, H-5).
2
7-Methoxy-4-({[3-(2-methoxyphenyl)-4-oxo-2-(trifluoromethyl)-4H-chromen-7-yl]oxy}methyl)-2H-chromen-2-one
(14). C H F O , yield 69%, mp 235-236°C (propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.72 (3H,
28 19 3
7
6
3
4
s, OMe-2′), 7.03 (1H, m, H-5′), 7.12 (1H, m, H-3′), 7.19 (1H, m, H-6′), 7.39 (1H, dd, J = 8.8, J = 2.0, H-6), 7.45 (1H, m,
H-4′), 7.70 (1H, d, J = 2.0, H-8), 8.03 (1H, d, J = 8.8, H-5); alkyl substituent protons 3.89 (3H, s, CH O-7), 5.60 (2H, s,
CH -4), 6.50 (1H, s, H-3), 7.03 (1H, dd, J = 8.8, J = 2.0, H-6), 7.05 (1H, d, J = 2.0, H-8), 7.88 (1H, d, J = 8.8, H-5).
4
3
3
3
3
4
4
2
4-({[3-(2-Methoxyphenyl)-4-oxo-4H-chromen-7-yl]oxy}methyl)-6,7-dimethyl-2H-chromen-2-one(15). C H O ,
28 22
6
yield 74%, mp 275-277°C (ethanol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.73 (3H, s, OMe-2′), 7.01 (1H, m,
6
3
4
4
H-5′), 7.10 (1H, m, H-3′), 7.26 (1H, m, H-6′), 7.33 (1H, dd, J = 8.8, J = 2.0, H-6), 7.40 (1H, m, H-4′), 7.59 (1H, d, J = 2.0,
H-8), 8.06 (1H, d, J = 8.8, H-5), 8.31 (1H, s, H-2); alkyl substituent protons 2.23, 2.35 (6H, 2s, CH -6, CH -7), 5.56 (2H, s,
3
3
3
CH -4), 6.58 (1H, s, H-3), 7.28 (1H, s, H-8), 7.70 (1H, s, H-5).
2
4-({[3-(2-Methoxyphenyl)-2-methyl-4-oxo-4H-chromen-7-yl]oxy}methyl)-6,7-dimethyl-2H-chromen-2-one (16).
C H O , yield 70%, mp 283-284°C (ethanol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.16 (3H, s, CH -2), 3.72
29 24
6
6
3
3
4
(3H, s, OMe-2′), 7.02 (1H, m, H-5′), 7.10 (1H, m, H-3′), 7.15 (1H, m, H-6′), 7.29 (1H, dd, J = 8.8, J = 2.0, H-6), 7.39 (1H,
m, H-4′), 7.51 (1H, d, J = 2.0, H-8), 7.97 (1H, d, J = 8.8, H-5); alkyl substituent protons 2.33, 2.35 (6H, 2s, CH -6, CH -7),
4
3
3
3
5.55 (2H, s, CH -4), 6.57 (1H, s, H-3), 7.28 (1H, s, H-8), 7.73 (1H, s, H-5).
2
Cholest-5-en-3-yl-{[3-(2-methoxyphenyl)-4-oxo-4H-chromen-7-yl]oxy}acetate (17). C H O , yield59%, mp156-
45 58
6
4
157°C (propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.81 (3H, s, OMe-2′), 6.85 (1H, d, J = 2.0, H-8),
6.99 (1H, m, H-3′), 7.03 (1H, dd, J = 8.8, J = 2.0, H-6), 7.04 (1H, m, H-5′), 7.32 (1H, m, H-6′), 7.38 (1H, m, H-4′), 7.92 (1H,
6
3
4
3
s, H-2), 8.23 (1H, d, J = 8.8, H-5); cholestene protons 0.59-5.47; 4.71 (2H, s, CH O-7).
2
General Methodfor Preparing7-Acyloxyisoflavones(18-29). Asolution oftheapproprate7-hydroxyisoflavone(2-5,
10 mmol) in the minimal amount of absolute pyridine was treated with the acid chloride (12 mmol). The reaction mixture was
left for 1 d at room temperature and poured into icewater. The resulting precipitate was filtered off and crystallized from a
suitable solvent.
3-(2-Methoxyphenyl)-2-methyl-4-oxo-4H-chromen-7-yl-acetate (18). C H O , yield79%, mp113-114°C(propan-
19 16
6
2-ol). PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 2.23 (3H, s, CH -2), 2.36 (3H, s, CH COO-7), 3.77 (3H, s, OMe-2′),
3
3
3
3
4
4
6.98 (1H, m, H-3′), 7.03 (1H, m, H-5′), 7.11 (1H, dd, J = 8.8, J = 2.4, H-6), 7.17 (1H, m, H-6′), 7.26 (1H, d, J = 2.4, H-8),
3
7.37 (1H, m, H-4′), 8.24 (1H, d, J = 8.8, H-5).
3-(2-Methoxyphenyl)-4-oxo-2-trifluoromethyl-4H-chromen-7-yl-cyclopropanecarboxylate (19). C H F O , yield
21 15 3
5
87%, mp 145-146°C (CH OH). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.71 (3H, s, OMe-2′), 7.03 (1H, m, H-5′),
3
6
3
4
4
7.12 (1H, m, H-3′), 7.20 (1H, m, H-6′), 7.42 (1H, dd, J = 8.8, J = 2.1, H-6), 7.44 (1H, m, H-4′), 7.76 (1H, d, J = 2.1, H-8),
8.12 (1H, d, J = 8.8, H-5); acyl protons 1.12 (4H, m, 2CH ), 1.90 (1H, m, CH).
3
2
3-(2-Methoxyphenyl)-4-oxo-2-trifluoromethyl-4H-chromen-7-yl-cyclohexanecarboxylate (20). C H F O , yield
24 21 3
5
78%, mp 106-107°C (CH OH). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.71 (3H, s, OMe-2′), 7.03 (1H, m, H-5′),
3
6
3
4
4
7.12 (1H, m, H-3′), 7.20 (1H, m, H-6′), 7.38 (1H, dd, J = 8.8, J = 2.1, H-6), 7.45 (1H, m, H-4′), 7.73 (1H, d, J = 2.1, H-8),
8.13 (1H, d, J = 8.8, H-5); acyl protons 1.17-2.76 (10H, m, 5CH ), 2.61 (1H, m, CH).
3
2
3-(2-Methoxyphenyl)-4-oxo-2-trifluoromethyl-4H-chromen-7-yl-morpholine-4-carboxylate (21). C H F NO ,
22 18 3
6
yield 87%, mp 138-139°C (propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.71 (3H, s, OMe-2′), 7.03 (1H,
6
145

3
4
m, H-5′), 7.12 (1H, m, H-3′), 7.20 (1H, m, H-6′), 7.43 (1H, dd, J = 8.8, J = 2.1, H-6), 7.45 (1H, m, H-4′), 7.73 (1H, d,
4
3
J = 2.1, H-8), 8.11 (1H, d, J = 8.8, H-5); morpholine protons 3.43-3.73 (8H, m, 4CH ).
2
3-(2-Methoxyphenyl)-4-oxo-2-trifluoromethyl-4H-chromen-7-yl-diphenylcarbamate (22). C H F NO , yield
30 20 3
5
76%, mp 189-190°C (propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.70 (3H, s, OMe-2′), 7.03 (1H, m,
6
3
4
4
H-5′), 7.11 (1H, m, H-3′), 7.20 (1H, m, H-6′), 7.29 (1H, dd, J = 8.8, J = 2.1, H-6), 7.45 (1H, m, H-4′), 7.87 (1H, d, J = 2.1,
3
H-8), 8.10 (1H, d, J = 8.8, H-5); acyl protons 7.30-7.61 (10H, m, 2Ph).
3-(2-Methoxyphenyl)-4-oxo-4H-chromen-7-yl-diethylcarbamate (23). C H NO , yield 72%, mp 104-105°C
21 21
5
(propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.72 (3H, s, OMe-2′), 7.00 (1H, m, H-5′), 7.09 (1H, m,
6
3
4
4
H-3′), 7.25 (1H, m, H-6′), 7.29 (1H, dd, J = 8.8, J = 2.0, H-6), 7.39 (1H, m, H-4′), 7.53 (1H, d, J = 2.0, H-8), 8.09 (1H, d,
J = 8.8, H-5), 8.34 (1H, s, H-2); acyl protons 1.22, 1.14 (6H, 2t, J = 7.6, 2CH ), 3.33, 3.43 (4H, 2q, J = 7.6, 2CH ).
3
3
3
3
2
3-(2-Methoxyphenyl)-4-oxo-4H-chromen-7-yl-5-(acetyloxy)-2-methyl-1-benzofuran-3-carboxylate (24). C H O ,
28 20
8
yield 69%, mp 151-153°C (DMF:propan-2-ol). PMRspectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.82 (3H, s, OMe-2′), 7.00
6
3
4
(1H, m, H-3′), 7.04 (1H, m, H-5′), 7.32 (1H, dd, J = 8.8, J = 2.0, H-6), 7.35 (1H, m, H-6′), 7.39 (1H, m, H-4′), 7.46 (1H, d,
J = 2.0, H-8), 8.00 (1H, s, H-2), 8.34 (1H, d, J = 8.8, H-5); benzofuran protons 2.34 (3H, s, CH COO-5), 2.87 (3H, s, CH -2),
7.07 (1H, dd, J = 8.8, J = 2.0, H-6), 7.49 (1H, d, J = 8.8, H-7), 7.73 (1H, d, J = 2.0, H-4).
4
3
3
3
3
4
3
4
3-(2-Methoxyphenyl)-2-methyl-4-oxo-4H-chromen-7-yl-5-(acetyloxy)-2-methyl-1-benzofuran-3-carboxylate (25).
C H O , yield 76%, mp 219-220°C (DMF:propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.25 (3H, s,
29 22
8
6
3
4
CH -2), 3.79 (3H, s, OMe-2′), 7.00 (1H, m, H-3′), 7.05 (1H, m, H-5′), 7.20 (1H, m, H-6′), 7.27 (1H, dd, J = 8.8, J = 2.0, H-6),
3
4
3
7.38 (1H, m, H-4′), 7.42 (1H, d, J = 2.0, H-8), 8.31 (1H, d, J = 8.8, H-5); benzofuran protons 2.34 (3H, s, CH COO-5), 2.87
(3H, s, CH -2), 7.07 (1H, dd, J = 8.8, J = 2.0, H-6), 7.49 (1H, d, J = 8.8, H-7), 7.73 (1H, d, J = 2.0, H-4).
3
3
4
3
4
3
3-(2-Methoxyphenyl)-2-methyl-4-oxo-4H-chromen-7-yl-5-ethoxy-2-phenyl-1-benzofuran-3-carboxylate (26).
C H O , yield 57%, mp 152-154°C (DMF:propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.19 (3H, s,
34 26
7
6
CH -2), 3.73 (3H, s, OMe-2′), 7.03 (1H, m, H-5′), 7.12 (1H, m, H-3′), 7.18 (1H, m, H-6′), 7.41 (1H, m, H-4′), 7.46 (1H, dd,
3
3
4
4
3
3
J = 8.8, J = 2.0, H-6), 7.55 (1H, d, J = 2.0, H-8), 8.10 (1H, d, J = 8.8, H-5); benzofuran protons 1.38 (3H, t, J = 6.8), 4.12
(2H, q, J = 6.8) CH CH O-5, 7.09 (1H, dd, J = 8.8, J = 2.0, H-6), 7.54-8.10 (5H, m, Ph-2), 7.71 (1H, d, J = 8.8, H-7), 7.76
(1H, d, J = 2.0, H-4).
3
3
4
3
3
2
4
Ethyl7-{[(5-ethoxy-2-phenyl-1-benzofuran-3-yl)carbonyl]oxy}-3-(2-methoxyphenyl)-4-oxo-4H-chromen-2-
carboxylate (27). C H O , yield 79%, mp 182-184°C (DMF:propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm,
36 28
9
6
3
3
J/Hz): 0.94 [(3H, t, J = 7.2), 4.09 (2H, q, J = 7.2) CH CH COO-2], 3.69 (3H, s, OMe-2′), 7.00 (1H, m, H-5′), 7.07 (1H, m,
H-3′), 7.19 (1H, m, H-6′), 7.40 (1H, m, H-4′), 7.53 (1H, dd, J = 8.8, J = 2.0, H-6), 7.54 (1H, d, J = 2.0, H-8), 8.15 (1H, d,
J = 8.8, H-5); benzofuran protons 1.38 [(3H, t, J = 6.8), 4.11 (2H, q, J = 6.8) CH CH O-5], 7.08 (1H, dd, J = 8.8, J = 2.0,
H-6), 7.54-8.11 (5H, m, Ph-2), 7.70 (1H, d, J = 8.8, H-7), 7.89 (1H, d, J = 2.0, H-4).
3-(2-Methoxyphenyl)-4-oxo-4H-chromen-7-yl-methanesulfonate (28). C H O S, yield 87%, mp 161-163°C
3
2
3
4
4
3
3
3
3
4
3
2
3
4
17 14
6
(propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 3.52 (3H, s, CH SO O-7), 3.72 (3H, s, OMe-2′), 7.01 (1H,
6
3
2
3
4
m, H-5′), 7.09 (1H, m, H-3′), 7.26 (1H, m, H-6′), 7.40 (1H, m, H-4′), 7.49 (1H, dd, J = 8.8, J = 2.4, H-6), 7.77 (1H, d,
J = 2.4, H-8), 8.20 (1H, d, J = 8.8, H-5), 8.40 (1H, s, H-2).
4
3
Ethyl 3-(2-methoxyphenyl)-7-[(methylsulfonyl)oxy]-4-oxo-4H-chromen-2-carboxylate (29). C H O S,yield80%,
20 18
8
3
3
mp 157-159°C (propan-2-ol). PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 0.94 (3H, t, J = 7.2), 4.09 (2H, q, J = 7.2)
6
CH CH COO-2, 3.53 (3H, s, CH SO O-7), 3.67 (3H, s, OMe-2′), 7.00 (1H, m, H-5′), 7.06 (1H, m, H-3′), 7.16 (1H, m, H-6′),
3
2
3
2
3
4
4
3
7.39 (1H, m, H-4′), 7.52 (1H, dd, J = 8.8, J = 2.4, H-6), 7.85 (1H, d, J = 2.4, H-8), 8.18 (1H, d, J = 8.8, H-5).
General Method for Preparing of 8-Dialkylaminomethylisoflavones (30-35). A boiling solution of the appropriate
isoflavone (2-4, 10 mmol) in absolute dioxane (20 mL) was treated with the aminal (15 mmol), boiled for 1 h (completion of
reaction determined by TLC), cooled, and evaporated in vacuo. The solid was crystallized from a suitable solvent.
7-Hydroxy-3-(2-methoxyphenyl)-8-(pyrrolidin-1-yl-methyl)-2-trifluoromethyl-4H-chromen-4-one (30).
C H F NO , yield 89%, mp 150-151°C (toluene:hexane). PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 3.76 (3H, s,
22 20 3
4
3
3
OMe-2′), 4.18 (2H, s, CH -8), 6.90 (1H, d, J = 8.8, H-6), 6.96 (1H, m, H-3′), 7.00 (1H, m, H-5′), 7.12 (1H, m, H-6′), 7.39 (1H,
m, H-4′), 8.03 (1H, d, J = 8.8, H-5), 11.13 (1H, s, HO-7); amine protons 1.94 (4H, m, 2CH ), 2.80 (4H, m, 2NCH ).
2
3
2
2
7-Hydroxy-3-(2-methoxyphenyl)-8-(piperidin-1-ylmethyl)-4H-chromen-4-one (31). C H NO , yield 79%,
22 23
4
mp 132-134°C (ethylacetate:hexane). PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 3.79 (3H, s, OMe-2′), 3.99 (2H, s,
3
146

3
CH -8), 6.86 (1H, d, J = 8.8, H-6), 6.98 (1H, m, H-3′), 7.01 (1H, m, H-5′), 7.31 (1H, m, H-6′), 7.35 (1H, m, H-4′), 7.87 (1H,
2
3
s, H-2), 8.09 (1H, d, J = 8.8, H-5); amine protons 1.28-3.31 (10H, m, 5CH ).
2
7-Hydroxy-3-(2-methoxyphenyl)-8-[(4-methylpiperidin-1-yl)methyl)]-4H-chromen-4-one (32). C H NO , yield
23 25
4
75%, mp 177-179°C (toluene:hexane). PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 3.80 (3H, s, OMe-2′), 4.00 (2H, s,
3
3
CH -8), 6.86 (1H, d, J = 8.8, H-6), 6.98 (1H, m, H-3′), 7.00 (1H, m, H-5′), 7.31 (1H, m, H-6′), 7.36 (1H, m, H-4′), 7.87 (1H,
s, H-2), 8.09 (1H, d, J = 8.8, H-5); amine protons 0.97 (3H, m, 4-CH ), 1.23-3.16 (9H, m).
2
3
3
7-Hydroxy-8-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-3-(2-methoxyphenyl)-4H-chromen-4-one (33).
C H N O , yield 80%, mp 140-142°C (propan-2-ol). PMRspectrum (300 MHz, CDCl , δ, ppm, J/Hz): 3.80 (3H, s, OMe-2′),
23 26
2 5
3
3
4.05 (2H, s, CH -8), 6.88 (1H, d, J = 8.8, H-6), 6.98 (1H, m, H-3′), 7.01 (1H, m, H-5′), 7.31 (1H, m, H-6′), 7.36 (1H, m, H-4′),
7.89 (1H, s, H-2), 8.12 (1H, d, J = 8.8, H-5); amine protons 2.61, 3.65 (4H, 2m, 4-NCH CH O), 2.09-3.22 (8H, m, 4CH ).
2
3
2
2
2
7-Hydroxy-3-(2-methoxyphenyl)-8-[(4-methylpiperazin-1-yl)methyl]-4H-chromen-4-one (34). C H N O , yield
22 34
2 4
76%, mp 164-165°C (propan-2-ol:hexane). PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 3.81 (3H, s, OMe-2′), 4.04 (2H,
3
3
s, CH -8), 6.88 (1H, d, J = 8.8, H-6), 6.99 (1H, m, H-3′), 7.02 (1H, m, H-5′), 7.32 (1H, m, H-6′), 7.37 (1H, m, H-4′), 7.89 (1H,
s, H-2), 8.12 (1H, d, J = 8.8, H-5); amine protons 2.34 (3H, s, 4-NCH ), 1.95-3.28 (8H, m, 4CH ).
2
3
3
2
7-Hydroxy-3-(2-methoxyphenyl)-2-methyl-8-[(4-methylpiperazin-1-yl)methyl]-4H-chromen-4-one (35).
C H N O , yield 68%, mp 186-188°C (propan-2-ol:hexane). PMR spectrum (300 MHz, CDCl , δ, ppm, J/Hz): 2.21 (3H,
23 24
2 4
3
3
s, CH -2), 3.78 (3H, s, OMe-2′), 4.04 (2H, s, CH -8), 6.84 (1H, d, J = 8.8, H-6), 6.98 (1H, m, H-3′), 7.02 (1H, m, H-5′), 7.16
3
2
3
(1H, m, H-6′), 7.35 (1H, m, H-4′), 8.05 (1H, d, J = 8.8, H-5); amine protons 2.35 (3H, s, 4-NCH ), 2.00-3.24 (8H, m, 4CH ).
3
2
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