Aminomethylation of Afromosin, Cladrastin, and Their 2-Methyl Derivatives

Article abstract of DOI:10.1007/s10600-018-2440-x

Aminomethylation of the natural isoflavones afromosin and cladrastin and their 2-methyl derivatives was studied. Several new Mannich bases of 7-hydroxy-6-methoxyisoflavones were synthesized under Mannich reaction conditions using aminals of secondary amin

Full text of DOI:10.1007/s10600-018-2440-x

DOI 10.1007/s10600-018-2440-x
Chemistry of Natural Compounds, Vol. 54, No. 4, July, 2018
AMINOMETHYLATION OF AFROMOSIN, CLADRASTIN,
AND THEIR 2-METHYL DERIVATIVES
1*
2
2
S. P. Bondarenko, G. P. Mrug, K. M. Kondratyuk,
2
and M. S. Frasinyuk
Aminomethylation of the natural isoflavones afromosin and cladrastin and their 2-methyl derivatives was
studied. Several new Mannich bases of 7-hydroxy-6-methoxyisoflavones were synthesized under Mannich
reaction conditions using aminals of secondary amines.
Keywords: isoflavone, afromosin, cladrastin, aminomethylation, Mannich base, aminal.
Mannich bases of isoflavonoids were shown by us earlier to be promising intermediates for designing biologically
active compounds [1, 2].
In continuation of research on aminomethylation of flavonoids, we turned our attention to the natural 6-methoxy-
substituted isoflavones afromosin (also called afrormosin) (1a), which occurs in plants of the family Leguminosae such as
Afromosia elata Harms [3], Wistaria floridunda [4], Amphimas pterocarpoides [5], Myroxylon balsamium L. Harms [6],
Baptisia australis [7], Glycyrrhiza glabra [8], and Hedysarum theinum [9] and cladrastin (1b), which was isolated from
Cladrastis lutea [10], C. platycarpa [11], and Millettia griffoniana [12].
HO
OH
a
R
b
MeO
O
OMe
2a,b
Me
HO
O
O
AcO
MeO
O
Me
HO
O
c
R
R
R
MeO
MeO
O
O
OMe
OMe
OMe
1a,b
3c,d
1c,d
a,c: R = H; b,d: R = OMe
a. POCl , DMF, Et O4BF ; b. Ac O, Et N; c. HCl, EtOH
3
2
3
2
3
The positions of the substituents on flavonoid ring A have a great influence on the direction and regioselectivity of
electrophilic attack under Mannich reaction conditions and on the ability to perform electrophilic substitution. Our research
showed that 5,7-dihydroxyflavonoids act as CH substrates in the Mannich reaction and form the corresponding
6,8-bis(aminomethyl) derivatives [13–16]. The Mannich reaction of 7-hydroxy-5-methoxyisoflavones occurred regioselectively
at the C-8 atom [17] whereas aminomethylation of 7-methoxy-5-hydroxyisoflavones formed a mixture of 6-aminomethyl and
8-aminomethyl derivatives with the C-6 isomer dominating [1]. Mannich reaction of 7-hydroxy-8-methylisoflavones gave the
corresponding 6-aminomethyl derivatives [2].
1) National University of Food Technologies, 68 Vladimirskaya St., Kiev, 01601, Ukraine, e-mail:
svitlana.bondarenko@ukr.net; 2) Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of
Ukraine, 1 Murmanskaya St., Kiev, 02094, Ukraine. Translated from Khimiya Prirodnykh Soedinenii, No. 4, July–August,
2018, pp. 559–563. Original article submitted January 22, 2018.
©
660
0009-3130/18/5404-0660 2018 Springer Science+Business Media, LLC

The natural isoflavones afromosin (1a) and cladrastin (1b) and their 2-methyl derivatives (1c and 1d) were of interest
for studying aminomethylation of a chromone core containing electron-donating hydroxyl and methoxyl groups situated in
a discordant orientation.
The starting compounds for constructing the chromone core were the corresponding 2,4-dihydroxy-5-
methoxydeoxybenzoins 2a and 2b, which were prepared using a Hoesch reaction. Afromosin (1a) has been synthesized via
formylation followed by heterocyclization of 2-hydroxydeoxybenzoin under Gattermann reaction conditions using Zn(CN)
2
and HCl [3] or 1,3,5-triazine and Et O·BF [18]. Also, a one-pot method for synthesizing 1a using the reaction of
2
3
2-hydroxydeoxybenzoin prepared under Friedel–Crafts reaction conditions with DMF and MeSO Cl was reported [19].
2
Cladrastin (1b) was also synthesized via formylation under Gattermann reaction conditions using Zn(CN) and HCl [10].
2
Afromosin (1a) and cladrastin (1b) were synthesized via formylation of the corresponding 2-hydroxydeoxybenzoins
2a and 2b using Vilsmeier reagent (complex of DMF and POCl ) in the presence of Et O4BF followed by heterocyclization.
3
2
3
Reaction of starting 2-hydroxydeoxybenzoins 2a and 2b with an excess of acetic anhydride in the presence of Et N as the base
3
produced 2-methyl-7-acetoxyisoflavones 3c and 3d. The 2-methyl derivatives of afromosin (1c) and cladrastin (1d) were
synthesized via deacylation of 7-acetoxyisoflavones 3c and 3d in acidic solution.
Aminals of secondary amines are the most reactive aminomethylation reagents and were selected for studying features
of Mannich reactions involving 7-hydroxy-6-methoxyisoflavonoids 1a–d because the direction and sequence of
aminomethylation of the isoflavonoid chromone core were practically independent of the aminomethylation reagent [20].
This could enable aminomethyl derivatives at all positions capable of undergoing electrophilic substitution to be obtained.
Thus, 7-hydroxyisoflavones 1a–d reacted with an excess of the aminal in i-PrOH to form the 8-aminomethyl derivatives.
The yields of the target Mannich bases 4b–d, 5a–d, 6a, and 7a–d were slightly reduced as compared with those of
the aminomethyl derivatives of other 7-hydroxyisoflavones because of the discordant orientation of the hydroxyl and methoxyl
in isoflavone ring A. Thus, the yields of Mannich bases of 1a and 1b and their 2-methyl derivatives were 69–90%. Increasing
the amount of aminal or using the higher boiling solvent dioxane did not significantly affect the yields of the 8-aminomethyl
derivatives.
1a - d
a
Me
N
Me
N
N
N
Me
O
R
R
3
HO
O
O
R
1
HO
R
1
HO
O
O
1
R
2
R
R
2
2
MeO
MeO
MeO
O
OMe
OMe
OMe
4b-d
5a-d; 6a
5a-d: R = H, 6a: R = OH
7a-d
3
3
a: R = R = H; b: R = H, R = OMe; c: R = Me, R = H; d: R = Me, R = OMe
1
2
1
2
1
2
1
2
a. Bis(dimethylamino)methane, 1,12-methylenedi(3-R-piperidine) or 1,12-methylenebis(4-methylpiperazine), i-PrOH
The structures of 4b–d, 5a–d, 6a, and 7a–d were confirmed by NMR spectroscopy. PMR spectra of the aminomethyl
derivatives exhibited proton resonances for the isoflavone and amine fragments, lacked a resonance for H-8, and showed a 2H
singlet for the methylene at 3.98–4.07 ppm.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Merck plates (Germany) using
13
CH Cl –MeOH (100:1, 50:1) and EtOAc. PMR and C NMR spectra were measured vs. TMS internal standard on
2
2
the ꢀ-scale on Varian-400 (400 and 100 MHz) and Varian 500 instruments (500 and 125 MHz). GC-MS were recorded using
an Agilent 1100 Series HPLC-MS equipped with an Agilent LC\MSD SL mass-selective diode-array detector and chemical
ionization at atmospheric pressure (APCI). Elemental analyses of all compounds agreed with those calculated.
General Method for Preparing 2-Aryl-1-(2,4-dihydroxy-5-methoxyphenyl)ethanones 2a and 2b. A solution of
arylacetonitrile (10 mmol) and 4-methoxyresorcinol (100 mmol) in Et O4BF (50 mL) was stirred, purged with a stream of dry
2
3
661

HCl for 5–6 h, left overnight, transferred into hot H O (400 mL) containing conc. H SO (10 mL), refluxed for 1.5–2 h, and
2
2
4
cooled. The resulting precipitate was filtered off and crystallized from EtOH.
1-(2,4-Dihydroxy-5-methoxyphenyl)-2-(4-methoxyphenyl)ethanone (2a). C H O , yield 58%, mp 122–124ꢁÑ.
16 16
5
+
1
MS (CI): 289.0 [M + H] (100). Í NMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 3.72, 3.78 (3Í each, s, 5, 4ꢂ-OCH ),
6
3
4.25 (2H, s, ÑH ), 6.34 (1H, s, Í-3), 6.88 (2Í, d, J = 8.1, H-3ꢂ, 5ꢂ), 7.22 (2Í, d, J = 8.1, H-2ꢂ, 6ꢂ), 7.43 (1H, s, Í-6), 10.52 (1H,
2
13
s, 4-ÎÍ), 12.37 (1H, s, 2-ÎÍ). C NMR spectrum (100 MHz, DMSO-d , ꢀ, ppm): 43.6, 55.0, 56.4, 103.3, 110.4, 113.4,
6
113.9, 127.2, 130.6, 141.1, 155.6, 158.0, 159.3, 202.0.
1-(2,4-Dihydroxy-5-methoxyphenyl)-2-(3,4-dimethoxyphenyl)ethanone (2b). C
H O , yield 51%,
17 18 6
+
1
mp 163–165ꢁÑ. MS (CI): 319.0 [M + H] (100). Í NMR spectrum (400 MHz, DMSO-d , ꢀ, ppm): 3.74, 3.75, 3.78 (3Í each,
6
s, 6, 3ꢂ, 4ꢂ-OCH ), 4.16 (2H, s, ÑH ), 6.26 (1H, s, H-3), 6.77–6.85 (2H, m, H-5ꢂ, 6ꢂ), 6.87–6.91 (1H, m, H-2ꢂ), 7.35 (1H, s,
3
2
13
H-6), 10.26 (1H, s, 4-OH), 12.37 (1H, s, 2-OH). C NMR spectrum (125 MHz, CDCl , ꢀ, ppm): 44.1, 55.5, 55.5, 56.4, 103.4,
3
110.5, 111.9, 113.4, 113.4, 121.6, 127.7, 141.1, 147.7, 148.7, 155.6, 159.4, 201.9.
General Method for Preparing 3-Aryl-7-hydroxy-6-methoxy-4H-chromen-4-ones 1a and 1b. A solution of 2a
or 2b (10 mmol) in DMF (15 mL) was stirred, treated dropwise with Et O4BF (3.8 mL, 30 mmol) and then POCl (2.3 mL,
2
3
3
25 mmol) at a rate such that the temperature did not rise above 70–75°C, held for 1 h at 75°C, poured into H O (200 mL), and
2
heated at 90–95°C for 0.5 h. The isoflavone precipitate was filtered off and crystallized from EtOH.
7-Hydroxy-6-methoxy-3-(4-methoxyphenyl)-4H-chromen-4-one (1a). C H O , yield 69%, mp 225–226ꢁÑ.
17 14
5
+
1
MS (CI): 299.1 [M + H] (100%). Í NMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 3.78, 3.87 (3Í each, s,
6
6, 4ꢂ-OCH ), 6.93 (1H, s, Í-8), 6.98 (2Í, d, J = 8.8, H-3ꢂ, 5ꢂ), 7.42 (1H, s, Í-5), 7.51 (2Í, d, J = 8.8, H-2ꢂ, 6ꢂ), 8.31 (1H, s, Í-2).
3
13
C NMR spectrum (100 MHz, DMSO-d , ꢀ, ppm): 55.1, 55.8, 102.8, 104.7, 113.6, 116.2, 122.6, 124.5, 130.1, 147.0, 151.7,
6
152.8, 152.9, 158.9, 174.2.
7-Hydroxy-3-(3,4-dimethoxyphenyl)-6-methoxy-4H-chromen-4-one (1b). C H O , yield 56%, mp 197–198ꢁÑ.
18 16
6
+
1
MS (CI): 329.2 [M + H] (100%). Í NMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 3.78, 3.88 (6Í, 3H, 2s,
6
6, 3ꢂ, 4ꢂ-OCH ), 6.94 (1H, s, Í-8), 7.00 (1Í, d, J = 8.2, H-5ꢂ), 7.13 (1Í, dd, J = 8.2, 2.0, H-6ꢂ), 7.20 (1H, d, J = 2.1, H-2ꢂ), 7.44
3
13
(1H, s, Í-5), 8.36 (1H, s, Í-2), 10.67 (1H, s, 7-ÎÍ). C NMR spectrum (100 MHz, DMSO-d , ꢀ, ppm): 55.5, 55.6, 55.8, 102.8,
6
104.7, 111.5, 112.8, 116.3, 121.1, 122.7, 124.8, 147.0, 148.3, 148.5, 151.7, 152.9, 153.0, 174.2.
General Method for Preparing 3-Aryl-2-methyl-6-methoxy-4-oxo-4H-chromen-7-yl Acetates 3c and 3d.
A mixture of 2a or 2b (10 mmol), acetic anhydride (4.6 mL, 50 mmol), and Et N (5.6 mL, 40 mmol) was heated at 120–130°C
3
for 6–10 h (TLC monitoring), and transferred into cold H O (100 mL) containing HCl (5 mL). The precipitate of isoflavone
2
3c or 3d was filtered off and crystallized from i-PrOH.
2-Methyl-6-methoxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl Acetate (3c). C H O , yield 87%,
20 18
6
+
1
mp 174–175ꢁÑ. MS (CI): 355.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz): 2.31, 2.38 (3H each,
3
s, CH -2, 7-OOCCH ), 3.85, 3.92 (3Í each, s, 6, 4ꢂ-OCH ), 6.98 (2H, d, J = 8.8, H-3ꢂ, 5ꢂ), 7.21 (1H, s, H-8), 7.21 (2H, d,
3
3
3
13
J = 8.8, H-2ꢂ, 6ꢂ), 7.68 (1H, s, H-5). C NMR spectrum (125 MHz, CDCl , ꢀ, ppm): 19.5, 20.6, 55.2, 56.4, 106.6, 112.4, 113.8,
3
121.8, 122.5, 125.1, 131.5, 144.4, 149.1, 150.1, 159.1, 163.3, 168.2, 176.0.
3-(3,4-Dimethoxyphenyl)-6-methoxy-2-methyl-4-oxo-4H-chromen-7-yl Acetate (3d). C H O , yield 78%,
21 20
7
+
1
mp 173–174ꢁÑ. MS (CI): 385.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz): 2.31, 2.37 (3H each,
3
s, CH -2, 7-OOCCH ), 3.88, 3.91, 3.91 (3Í each, s, 6, 3ꢂ, 4ꢂ-OCH ), 6.78–6.83 (2H, m, H-2ꢂ, 6ꢂ), 6.93 (1Í, d, J = 8.6, H-5ꢂ),
3
3
3
13
7.20 (1H, s, Í-8), 7.67 (1H, s, Í-5). C NMR spectrum (125 MHz, CDCl , ꢀ, ppm): 19.6, 20.6, 55.9, 55.9, 56.4, 106.6, 111.2,
3
112.4, 113.7, 121.8, 122.8, 125.6, 144.5, 148.6, 148.8, 149.2, 150.2, 163.5, 168.3, 176.1.
General Method for Preparing 3-Aryl-7-hydroxy-2-methyl-6-methoxy-4H-chromen-4-ones 1c and 1d. A hot
solution of 3c or 3d (10 mmol) in the minimal amount of EtOH was treated with HCl (0.5 mL) and refluxed for 1–2 h (TLC
monitoring). The precipitate of 1c or 1d that formed on cooling was filtered off and rinsed with EtOH.
7-Hydroxy-2-methyl-6-methoxy-3-(4-methoxyphenyl)-4H-chromen-4-one (1c). C H O , yield 78%,
19 18
6
+
1
mp 215–216ꢁÑ. MS (CI): 343.2 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz): 2.29 (3H, s, ÑÍ -2),
3
3
3.84, 3.97 (3Í each, s, 6, 4ꢂ-OCH ), 6.93 (1H, s, Í-8), 6.96 (2H, d, J = 8.6, H-3ꢂ, 5ꢂ), 7.21 (2H, d, J = 8.6, H-2ꢂ, 6ꢂ), 7.56 (1H,
3
13
s, Í-5). C NMR spectrum (100 MHz, CDCl , ꢀ, ppm): 19.6, 55.4, 56.5, 102.6, 104.9, 113.9, 116.7, 122.3, 125.6, 131.7,
3
145.4, 151.3, 152.2, 159.1, 162.8, 176.5.
7-Hydroxy-3-(3,4-dimethoxyphenyl)-2-methyl-6-methohxy-4H-chromen-4-one (1d). C H O , yield 81%,
18 16
5
+
1
mp 179–180ꢁÑ. MS (CI): 313.1 [M + H] (100%). Í NMR spectrum (400 MHz, DMSO-d , ꢀ, ppm, J/Hz): 2.24 (3H, s, ÑÍ -2),
6
3
3.73, 3.79, 3.85 (3Í each, s, 6, 3ꢂ, 4ꢂ-OCH ), 6.78 (1Í, dd, J = 8.2, 2.0, H-6ꢂ), 6.84 (1H, d, J = 2.0, H-2ꢂ), 6.90 (1H, s, Í-8), 6.99
3
662

13
(1H, d, J = 8.2, H-5ꢂ), 7.34 (1H, s, Í-5), 10.59 (1H, s, 7-ÎÍ). C NMR spectrum (100 MHz, DMSO-d , ꢀ, ppm): 19.2, 55.5,
6
55.5, 55.8, 102.6, 104.8, 111.4, 114.4, 115.2, 121.6, 122.8, 125.9, 146.6, 148.1, 148.2, 151.3, 152.7, 162.2, 174.6.
General Method for Preparing Aminomethyl Derivatives 4–7. A hot solution of the appropriate isoflavone 1a–d
(2 mmol) in i-PrOH (20 mL) was treated with the corresponding aminal (2.2 mmol), refluxed for 3–5 h, and cooled
(TLC monitoring). The solvent was evaporated in vacuo. The solid was triturated with Et O, dried, and crystallized from
2
i-PrOH–hexane.
7-Hydroxy-8-[(dimethylaminomethyl)methyl]-3-(3,4-dimethoxyphenyl)-6-methoxy-4H-chromen-4-one (4b).
+
1
C H NO , yield 79%, mp 169–170ꢁÑ. MS (CI): 386.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz):
21 23
6
3
2.46 (6H, s, N(CH ) ), 3.91, 3.93, 3.97 (3Í each, s, 6, 3ꢂ, 4ꢂ-OCH ), 4.02 (2Í, s, ÑÍ -8), 6.93 (1H, d, J = 8.2, H-5ꢂ), 7.04 (1Í,
3 2
3
2
13
dd, J = 8.2, 2.1, H-6ꢂ), 7.25 (1H, d, J = 2.2, H-2ꢂ), 7.59 (1H, s, Í-5), 7.93 (1H, s, Í-2). C NMR spectrum (125 MHz, CDCl , ꢀ, ppm):
3
44.3, 55.1, 55.7, 55.7, 55.9, 103.8, 107.5, 110.9, 112.4, 115.8, 120.7, 123.6, 124.8, 146.8, 148.4, 148.7, 149.7, 151.1, 154.7, 175.3.
7-Hydroxy-8-[(dimethylaminomethyl)methyl]-2-methyl-6-methoxy-3-(4-methoxyphenyl)-4H-chromen-4-one
+
1
(4c). C H NO , yield 81%, mp 108–109ꢁÑ. MS (CI): 370.0 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl ,
21 23
5
3
ꢀ, ppm, J/Hz): 2.30 (3H, s, ÑÍ -2), 2.46 (6H, s, N(CH ) ), 3.85, 3.95 (3Í each, s, 6, 4ꢂ-OCH ), 4.01 (2Í, s, ÑÍ -8), 6.97 (2Í,
3
3 2
3
2
13
d, J = 8.8, H-3ꢂ, 5ꢂ), 7.21 (2Í, d, J = 8.8, H-2ꢂ, 6ꢂ), 7.52 (1H, s, H-5ꢂ). C NMR spectrum (100 MHz, CDCl , ꢀ, ppm): 19.4, 44.6,
3
55.3, 55.5, 56.1, 104.3, 107.5, 113.8, 115.0, 122.2, 125.6, 131.6, 146.6, 149.5, 154.3, 159.0, 161.5, 176.3.
7-Hydroxy-8-[(dimethylaminomethyl)methyl]-3-(3,4-dimethoxyphenyl)-6-methoxy-2-methyl-4H-chromen-4-
+
1
one (4d). C H NO , yield 89%, mp 176–177ꢁÑ. MS (CI): 400.2 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl ,
22 25
6
3
ꢀ, ppm, J/Hz): 2.30 (3H, s), 2.46 (6H, s, N(CH ) ), 3.87 (3H, s), 3.91 (3H, s), 3.95 (3H, s), 4.01 (2Í, s, ÑÍ -8), 6.81 (1Í, dd,
3 2
2
13
J = 8.1, 2.0, H-6ꢂ), 6.83 (1H, d, J = 2.0, H-2ꢂ), 6.93 (1H, d, J = 8.1, H-5ꢂ), 7.52 (1H, s). C NMR spectrum (125 MHz, CDCl ,
3
ꢀ, ppm): 19.5, 44.6, 55.5, 55.9, 56.1, 104.3, 107.6, 111.2, 113.8, 115.1, 122.4, 122.9, 126.1, 146.7, 148.5, 148.7, 149.5, 154.4, 161.7, 176.3.
7-Hydroxy-6-methoxy-3-(4-methoxyphenyl)-8-(piperidin-1-ylmethyl)-4H-chromen-4-one (5a). C H NO ,
23 25
5
+
1
yield 80%, mp 176–177ꢁÑ. MS (CI): 396.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz): 1.37–1.58
3
(2H, m, H-4ꢂꢂ), 1.60–1.73 (4H, m, H-3ꢂꢂ, 5ꢂꢂ), 2.39–2.93 (4H, m, H-2ꢂꢂ, 6ꢂꢂ), 3.79, 3.94 (3Í each, s, 6, 4ꢂ-OCH ), 3.98 (2Í, s,
3
ÑÍ -8), 6.92 (2H, d, J = 8.6, H-3ꢂ, 5ꢂ), 7.46 (2H, d, J = 8.6, H-2ꢂ, 6ꢂ), 7.52 (1H, s, Í-5), 7.83 (1H, s, Í-2), 12.71 (1H, s,
2
13
7-OÍ). C NMR spectrum (125 MHz, CDCl , ꢀ, ppm): 23.7, 25.7, 54.1, 54.9, 55.4, 56.2, 104.0, 107.2, 114.0, 116.0, 124.0,
3
124.7, 130.2, 147.0, 150.2, 151.1, 155.0, 159.5, 175.6.
7-Hydroxy-3-(3,4-dimethoxyphenyl)-6-methoxy-8-(piperidin-1-ylmethyl)-4H-chromen-4-one (5b). C H NO ,
24 27
6
+
1
yield 69%, mp 175–176ꢁÑ. MS (CI): 426.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz): 1.43–1.66
3
(2H, m, H-4ꢂꢂ), 1.64–1.79 (4H, m, H-3ꢂꢂ, 5ꢂꢂ), 2.36–3.08 (4H, m, H-2ꢂꢂ, 6ꢂꢂ), 3.92, 3.93, 3.98 (3Í each, s, 6, 3ꢂ, 4ꢂ-OCH ), 4.03
3
(2Í, s, ÑÍ -8), 6.93 (1H, d, J = 8.4, H-5ꢂ), 7.04 (1Í, dd, J = 8.4, 2.0, H-6ꢂ), 7.26 (1H, d, J = 2.1, H-2ꢂ), 7.57 (1H, s, Í-5), 7.92
2
13
(1H, s, Í-2). C NMR spectrum (100 MHz, CDCl , ꢀ, ppm): 23.6, 25.6, 53.9, 54.8, 55.9, 56.0, 103.8, 107.1, 111.0, 112.5,
3
115.8, 120.8, 123.8, 125.0, 147.0, 148.6, 148.8, 150.0, 151.2, 155.1, 175.5.
7-Hydroxy-2-methyl-6-methoxy-3-(4-methoxyphenyl)-8-(piperidin-1-ylmethyl)-4H-chromen-4-one (5c).
+
1
C H NO , yield 81%, mp 186–187ꢁÑ. MS (CI): 410.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz):
24 27
5
3
1.48–1.65 (2H, m, H-4ꢂꢂ), 1.66–1.81 (4H, m, H-3ꢂꢂ, 5ꢂꢂ), 2.28 (3H, s, ÑÍ -2), 2.53–2.82 (4H, m, H-2ꢂꢂ, 6ꢂꢂ), 3.84, 3.95 (3Í each,
3
13
s, 6, 4ꢂ-OCH ), 4.02 (2Í, s, ÑÍ -8), 6.96 (2H, d, J = 8.6, H-3ꢂ, 5ꢂ), 7.20 (2H, d, J = 8.6, H-2ꢂ, 6ꢂ), 7.49 (1H, s, Í-5). C NMR
3
2
spectrum (100 MHz, CDCl , ꢀ, ppm): 19.3, 23.6, 25.6, 54.0, 54.9, 55.2, 56.0, 104.0, 106.9, 113.7, 114.8, 122.1, 125.6, 131.6,
3
146.5, 149.6, 154.5, 158.9, 161.3, 176.2.
7-Hydroxy-3-(3,4-dimethoxyphenyl)-2-methyl-6-methoxy-8-(piperidin-1-ylmethyl)-4H-chromen-4-one (5d).
+
1
C H NO , yield 75%, mp 203–204ꢁÑ. MS (CI): 440.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz):
25 29
6
3
1.41–1.64 (2H, m, H-4ꢂꢂ), 1.63–1.79 (4H, m, H-3ꢂꢂ, 5ꢂꢂ), 2.30 (3H, s, ÑÍ -2), 2.49–2.90 (4H, m, H-2ꢂꢂ, 6ꢂꢂ), 3.88, 3.92, 3.95 (3Í
3
each, s, 6, 3ꢂ, 4ꢂ-OCH ), 4.03 (2Í, s, ÑÍ -8), 6.81 (1Í, dd, J = 8.1, 1.9, H-6ꢂ), 6.84 (1H, d, J = 1.9, H-2ꢂ), 6.93 (1H, d, J = 8.2, H-5ꢂ),
3
2
13
7.50 (1H, s, H-5). C NMR spectrum (125 MHz, CDCl , ꢀ, ppm): 19.2, 23.5, 25.5, 53.8, 54.7, 55.7, 55.8, 103.7, 106.8, 110.9, 113.6,
3
114.6, 122.1, 122.6, 125.9, 146.4, 148.2, 148.4, 149.5, 154.4, 161.4, 176.0.
7-Hydroxy-8-[(3-hydroxypiperidin-1-yl)methyl]-6-methoxy-3-(4-methoxyphenyl)- 4H-chromen-4-one (6a).
+
1
C H NO , yield 90%, mp 175–176ꢁÑ. MS (CI): 412.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz):
23 25
6
3
1.40–1.74, 1.86–1.98, 2.26–2.53, 2.70–2.84, 2.91–3.03, 3.89–3.95 (2H, 3Í, 2Í, 1Í, 1Í, 1Í, 6m, piperidine), 3.84, 3.97 (3Í
each, s, 6, 4ꢂ-OCH ), 4.06 (2Í, s, ÑÍ -8), 6.97 (2Í, d, J = 8.6, H-3ꢂ, 5ꢂ), 7.50 (2Í, d, J = 8.6, H-2ꢂ, 6ꢂ), 7.58 (1H, s, Í-5), 7.89
3
2
13
(1H, s, Í-2). C NMR spectrum (125 MHz, CDCl , ꢀ, ppm): 22.3, 32.1, 53.0, 54.3, 55.4, 56.2, 60.0, 66.4, 104.2, 107.3,
3
114.0, 116.2, 124.0, 124.6, 130.2, 147.0, 150.1, 151.2, 154.7, 159.5, 175.7.
663

7-Hydroxy-8-[(4-methylpiperazin-1-yl)methyl]-6-methoxy-3-(4-methoxyphenyl)-4H-chromen-4-one (7a).
+
1
C H N O , yield 78%, mp 184–185ꢁÑ. MS (CI): 411.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz):
23 26
2
5
3
2.33 (3H, s, NCH ), 2.40–3.01 (8Í, m, piperazine ring), 3.85, 3.98 (3Í each, s, 6, 4ꢂ-OCH ), 4.07 (2Í, s, ÑÍ -8), 6.97 (2H, d,
3
3
2
13
J = 8.8, H-3ꢂ, 5ꢂ), 7.50 (2H, d, J = 8.8, H-2ꢂ, 6ꢂ), 7.59 (1H, s, H-5), 7.90 (1H, s, Í-2). C NMR spectrum (125 MHz, CDCl , ꢀ, ppm):
3
45.9, 52.6, 53.9, 54.7, 55.3, 56.1, 104.2, 107.2, 113.9, 116.4, 123.9, 124.5, 130.1, 146.8, 149.9, 151.1, 154.0, 159.4, 175.5.
7-Hydroxy-3-(3,4-dimethoxyphenyl)-8-[(4-methylpiperazin-1-yl)methyl]-6-methoxy-4H-chromen-4-one (7b).
+
1
C H N O , yield 80%, mp 198–200ꢁÑ. MS (CI): 441.1 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl , ꢀ, ppm, J/Hz):
24 28
2
6
3
2.33 (3H, s, NCH ), 2.40–3.01 (8Í, m, piperazine ring), 3.91, 3.93, 3.98 (3Í each, s, 6, 3ꢂ, 4ꢂ-OCH ), 4.07 (2Í, s, ÑÍ -8),
3
3
2
6.93 (1H, d, J = 8.2, H-5ꢂ), 7.04 (1Í, dd, J = 8.2, 2.0, H-6ꢂ), 7.25 (1H, d, J = 1.9, H-2ꢂ), 7.59 (1H, s, H-5), 7.94 (1H, s, Í-2).
13
C NMR spectrum (125 MHz, CDCl , ꢀ, ppm): 45.8, 52.6, 53.9, 54.7, 55.9, 56.1, 104.1, 107.2, 111.1, 112.5, 116.3, 120.8,
3
123.9, 124.9, 146.9, 148.6, 148.9, 149.9, 151.3, 154.1, 175.5.
7-Hydroxy-2-methyl-8-[(4-methylpiperazin-1-yl)methyl]-6-methoxy-3-(4-methoxyphenyl)-4H-chromen-4-one
+
1
(7c). C H N O , yield 78%, mp 203–204ꢁÑ. MS (CI): 425.2 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl ,
24 28
2
5
3
ꢀ, ppm, J/Hz): 2.30, 2.33 (3H each, s, ÑÍ -2, NCH ), 2.41–3.20 (8Í, m, piperazine ring), 3.85, 3.96 (3Í each, s, 6, 4ꢂ-OCH ),
3
3
3
13
4.07 (2Í, s, ÑÍ -8), 6.97 (2H, d, J = 8.8, H-3ꢂ, 5ꢂ), 7.21 (2H, d, J = 8.8, H-2ꢂ, 6ꢂ), 7.52 (1H, s, Í-5). C NMR spectrum
2
(100 MHz, CDCl , ꢀ, ppm): 19.3, 45.8, 52.6, 54.0, 54.7, 55.2, 56.0, 104.2, 106.9, 113.7, 115.2, 122.1, 125.5, 131.5, 146.4,
3
149.5, 153.6, 158.9, 161.5, 176.1.
7-Hydroxy-3-(3,4-dimethoxyphenyl)-2-methyl-8-[(4-methylpiperazin-1-yl)methyl]-6-methoxy-4H-chromen-4-
+
1
one (7d). C H N O , yield 72%, mp 194–195ꢁÑ. MS (CI): 455.2 [M + H] (100%). Í NMR spectrum (400 MHz, CDCl ,
25 30
2
6
3
ꢀ, ppm, J/Hz): 2.31, 2.32 (3H, s, ÑÍ -2, NCH ), 2.42–3.04 (8Í, m, piperazine ring), 3.87, 3.91, 3.95 (3Í each, s,
3
3
6, 3ꢂ, 4ꢂ-OCH ), 4.06 (2Í, s, ÑÍ -8), 6.80 (1Í, dd, J = 8.1, 1.9, H-6ꢂ), 6.83 (1H, d, J = 1.9, H-2ꢂ), 6.92 (1H, d, J = 8.1, H-5ꢂ),
3
2
13
7.51 (1H, s, Í-5). C NMR spectrum (125 MHz, CDCl , ꢀ, ppm): 19.3, 45.7, 52.5, 53.8, 54.6, 55.7, 55.9, 104.1, 106.8, 110.9,
3
113.6, 115.0, 122.2, 122.6, 125.8, 146.3, 148.3, 148.5, 149.4, 153.6, 161.5, 176.0.
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