Synthesis of Flavonoid Derivatives of Cytisine. 3. Synthesis of 7-[2-(Cytisin-12-yl)ethoxy]isoflavones

Article abstract of DOI:10.1007/s10600-013-0441-3

The possibility of using the alkaloid cytisine to synthesize N ₁₂-cytisinylethoxy derivatives of isoflavonoids and their analogs was studied. A series of substituted 7-(N₁₂-cytisinylethoxy)isoflavones containing chromone and cytisine fragments connected through a linker were synthesized.

Full text of DOI:10.1007/s10600-013-0441-3

Chemistry of Natural Compounds, Vol. 48, No. 6, January, 2013 [Russian original No. 6, November–December, 2012]
SYNTHESIS OF FLAVONOID DERIVATIVES OF CYTISINE.
3. SYNTHESIS OF 7-[2-(CYTISIN-12-YL)ETHOXY]ISOFLAVONES
1
2*
S. P. Bondarenko, M. S. Frasinyuk,
UDC 547.814.5
3
4
V. I. Vinogradova, and V. P. Khilya
12
The possibility of using the alkaloid cytisine to synthesize N -cytisinylethoxy derivatives of isoflavonoids
12
and their analogs was studied. A series of substituted 7-(N -cytisinylethoxy)isoflavones containing chromone
and cytisine fragments connected through a linker were synthesized.
Keywords: alkaloid, cytisine, isoflavone, 7-[2-(cytisin-12-yl)ethoxy]isoflavone, alkylation.
Biologically active compounds of plant origin that are presently known are extremely varied. Nevertheless, the
development of methods for synthesizing and modifying natural compounds is becoming more and more critical.
Compounds containing a benzopyrone ring bound through a linker to a secondary amine attracted our interest. These
were derivatives containing ꢀ-(N,N-dialkylamino)alkyl substituents on phenol hydroxyls. It was shown that these compounds
exhibit antibacterial, antifungal [1], and antihypertensive activity [2, 3] and inhibit monoamine oxidases A and B [4].
Furthermore, N-containing analogs of ipriflavone exhibit antiosteoporosis action [5, 6].
It is well known that the reaction of hydroxyflavones with ꢀ-(N,N-dialkylamino)alkylhalides [7–9], amines with
ꢀ-haloalkoxyflavonoids [6, 10–15], and amines with glycidyl phenyl ethers [2, 3] are often used to synthesize
ꢀ-(N,N-dialkylamino)alkoxy derivatives of flavonoids.
12
The goal of the present work was to study the possibility of using the alkaloid cytisine to synthesize N -cytisinylethoxy
derivatives of natural isoflavones and their analogs.
7-Hydroxyisoflavones 1a–c were prepared by Vilsmeier–Haack formylation of the corresponding
2,4-dihydroxydeoxybenzoins in the presence of BF ·Et O by the previously published methods [16, 17]. 2-Methyl-7-
3
2
hydroxyisoflavones 1d and 1e were synthesized by the reaction of 2,4-dihydroxydeoxybenzoins with acetic anhydride and
subsequent deacylation of the resulting 7-acetoxy derivatives [17]. Alkylation of 7-hydroxyisoflavones 1a–e with an excess
of dibromoethane in DMF in the presence of potash synthesized their 7-bromoethoxy derivatives 2a–e.
We studied the reaction of cytisine with 7-(2-bromoethoxy)isoflavones 2a–e in the presence of base in order to
12
synthesize 7-(N -cytisinylethoxy)isoflavones. As it turned out, alkylation of cytisine by 7-(2-bromoethoxy)isoflavones
2a–e occurred in high yield if the reaction was carried out in EtOH in the presence of diisopropylethylamine to give
12
7-(N -cytisinylethoxy)isoflavones 3a–e containing chromone and cytisine fragments. Use of Et N or N-methylmorpholine
3
as HBr acceptors led in certain instances to quaternization and a reduction of the yield of the final products. Use of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) caused formation of vinyl ethers of the isoflavones as side products. This hindered
isolation and purification of the final cytisine derivatives.
The structures of synthesized 2a–e and 3a–e were confirmed by PMR spectral data.
Thus, the method developed by us opened new possibilities for using the alkaloid cytisine to synthesize
N -cytisinylethoxy derivatives of natural isoflavonoids and their analogs.
12
1) National University of Food Technology, 01601, Ukraine, Kiev, Ul. Vladimirskaya, 68; 2) Institute of Bioorganic
Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 02094, Ukraine, Kiev, Ul. Murmanskaya, 1, e-mail:
mfras@i.kiev.ua; 3) S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of
Uzbekistan, Tashkent; 4) Taras Shevchenko Kiev National University, 01601, Ukraine, Kiev, Ul. Vladimirskaya, 64. Translated
from Khimiya Prirodnykh Soedinenii, No. 6, November–December, 2012, pp. 859–861. Original article submitted May 26,
2012.
©
970
0009-3130/13/4806-0970 2013 Springer Science+Business Media New York

O
N6''
1''
7''
9''
10''
NH
Br
13''
N12''
N
R
3
R
3
R
3
HO
O
R
1
O
O
O
R
1
O
O
O
R
1
1
a
b
6
4
O
O
R
2
R
2
4'
R
2
1a - e
2a - e
3a - e
a: R = R = R = H; b: R = R = H, R = OMe; c: R = H, R = OMe, R = Me
1
2
3
1
3
2
1
2
3
d: R = Me, R = R = H; e: R = Me, R = OMe, R = H
1
2
3
1
2
3
a. BrCH CH Br, K CO , DMF; b. i-Pr NEt, EtOH
2
2
2
3
2
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Sorbfil UV-254 (Russia) and Merck
(Germany) plates. The eluents were toluene:EtOH mixtures (9:1, 95:5). PMR spectra were measured in CDCl or DMSO-d
3
6
relative to TMS (internal standard) on a VXR-300 instrument (Varian, 300 MHz). Analyses of all compounds agreed with
those calculated. Data for starting isoflavones 1a–e corresponded with those published earlier [16–19].
General Method for Preparing 7-(2-Bromoethoxy)isoflavones 2a–e. A solution of 1a–e (10 mmol) in DMF
(20 mL) was treated with potash (25 mmol) and dibromoethane (50 mmol) and stirred at 75–80°C for 2–5 h (end of reaction
determined by TLC). The inorganic precipitate was filtered off. The DMF was evaporated in vacuo. The solid was crystallized
from i-PrOH:DMF.
7-(2-Bromoethoxy)-3-phenyl-4H-chromen-4-one (2a). Yield 61%, C H BrO , mp 202–204°C. PMR spectrum
17 13
3
3
4
(300 MHz, DMSO-d , ꢁ, ppm, J/Hz): 3.84–3.91 (2H, m, CH Br), 4.46–4.55 (2H, m, CH O-7), 7.13 (1H, dd, J = 8.9, J = 2.5,
H-6), 7.23 (1H, d, J = 2.5, H-8), 7.35-7.63 (5H, m, Ph-3), 8.06 (1H, d, J = 8.9, H-5), 8.48 (1H, s, H-2).
6
2
2
4
3
7-(2-Bromoethoxy)-3-(4-methoxyphenyl)-4H-chromen-4-one (2b). Yield 58%, C H BrO , mp 178–180°C.
18 15
4
PMR spectrum (300 MHz, DMSO-d , ꢁ, ppm, J/Hz): 3.79 (3H, s, 4ꢂ-OMe), 3.84–3.91 (2H, m, CH Br), 4.47–4.54 (2H, m,
6
2
3
3
4
4
CH O-7), 7.0 (2H, d, J = 9.0, H-3ꢂ, H-5ꢂ), 7.12 (1H, dd, J = 8.9, J = 2.5, H-6), 7.21 (1H, d, J = 2.5, H-8), 7.53 (2H, d,
J = 9.0, H-2ꢂ, H-6ꢂ), 8.05 (1H, d, J = 8.9, H-5), 8.43 (1H, s, H-2).
2
3
3
7-(2-Bromoethoxy)-8-methyl-3-(4-methoxyphenyl)-4H-chromen-4-one (2c). Yield 60%, C H BrO , mp 129–
19 17
4
131°C. PMR spectrum (300 MHz, DMSO-d , ꢁ, ppm, J/Hz): 2.31 (3H, s, CH -8), 3.79 (3H, s, 4ꢂ-OMe), 3.84–3.91 (2H, m,
6
3
3
3
3
CH Br), 4.46–4.54 (2H, m, CH O-7), 6.99 (2H, d, J = 8.9, H-3ꢂ, H-5ꢂ), 7.22 (1H, d, J = 9.2, H-6), 7.53 (2H, d, J = 8.9,
H-2ꢂ, H-6ꢂ), 7.98 (1H, d, J = 9.2, H-5), 8.45 (1H, s, H-2).
2
2
3
7-(2-Bromoethoxy)-2-methyl-3-phenyl-4H-chromen-4-one (2d). Yield 57%, C H BrO , mp 134–136°C. PMR
18 15
3
spectrum (300 MHz, DMSO-d , ꢁ, ppm, J/Hz): 2.26 (3H, s, CH -2), 3.82–3.90 (2H, m, CH Br), 4.45–4.54 (2H, m, CH O-7),
6
3
2
2
3
4
4
3
7.08 (1H, dd, J = 8.9, J = 2.5, H-6), 7.17 (1H, d, J = 2.5, H-8), 7.25–7.48 (5H, m, Ph-3), 7.96 (1H, d, J = 8.9, H-5).
7-(2-Bromoethoxy)-2-methyl-3-(4-methoxyphenyl)-4H-chromen-4-one (2e). Yield 64%, C H BrO , mp 165–
19 17
4
167°C. PMR spectrum (300 MHz, CDCl , ꢁ, ppm, J/Hz): 2.30 (3H, s, CH -2), 3.64–3.74 (2H, m, CH Br), 3.84 (3H, s,
3
3
2
4
3
4ꢂ-OMe), 4.33–4.43 (2H, m, CH O-7), 6.84 (1H, d, J = 2.3, H-8), 6.92–7.0 (3H, m, H-6, H-3ꢂ, H-5ꢂ), 7.20 (2H, d, J = 8.7,
2
3
H-2ꢂ, H-6ꢂ), 8.14 (1H, d, J = 8.6, H-5).
12
General Method for Preparing 7-(N -Cytisinylethoxy)isoflavones 3a–e. A solution of the appropriate
7-(2-bromoethoxy)isoflavone 2a–e (2 mmol) in EtOH (30 mL) was treated with cytisine (2.4 mmol) and diisopropylethylamine
(3 mmol), refluxed for 4–8 h (end of reaction determined by TLC), cooled, and diluted with H O. The resulting precipitate
2
was filtered off and crystallized from EtOH:H O.
2
(1R,5S)-3-{2-[(4-Oxo-3-phenyl-4H-chromen-7-yl)oxy]ethyl}-1,2,3,4,5,6-hexahydro-8H-1,5-methanepyrido[1,2-
a][1,5]diazocin-8-one (3a). Yield 71%, C H N O , mp 195–196°C. PMR spectrum (300 MHz, DMSO-d , ꢁ, ppm, J/Hz):
28 26
2
4
6
971

cytisine protons: 1.63–1.86 (2H, m, CH -8), 2.32–2.55 (3H, m, H-9, H-11a, H-13a), 2.83–3.08 (3H, m, H-7, H-11b, H-13b),
2
3
3
3
3
3.63–3.87 (2H, m, CH -10), 6.05 (1H, d, J = 6.8, H-5), 6.18 (1H, d, J = 8.9, H-3), 7.28 (1H, dd, J = 6.8, J = 8.9, H-4);
isoflavone protons: 2.62–2.74 (2H, m, 7-OCH ꢃCH ), 4.01–4.19 (2H, m, 7-OCH ), 6.96 (1H, dd, J = 8.9, J – 2.5, H-6), 7.07
(1H, d, J = 2.5, H-8), 7.34–7.64 (5H, m, Ph-3), 7.99 (1H, d, J = 8.9, H-5), 8.35 (1H, s, H-2).
2
3
4
2
2
2
4
3
(1R,5S)-3-(2-{[3-(4-Methoxyphenyl)-4-oxo-4H-chromen-7-yl]oxy}ethyl)-1,2,3,4,5,6-hexahydro-8H-1,5-
methanepyrido[1,2-a][1,5]diazocin-8-one (3b). Yield 74%, C H N O , mp 85–86°C. PMR spectrum (300 MHz,
29 28
2 5
DMSO-d , ꢁ, ppm, J/Hz): cytisine protons: 1.65–1.85 (2H, m, CH -8), 2.33–2.49 (3H, m, H-9, H-11a, H-13a), 2.86–3.06 (3H,
6
2
3
4
3
4
m, H-7, H-11b, H-13b), 3.64–3.84 (2H, m, CH -10), 6.06 (1H, dd, J = 7.0, J = 1.2, H-5), 6.18 (1H, dd, J = 9.0, J = 1.2,
H-3), 7.29 (1H, dd, J = 7.0, J = 9.0, H-4); isoflavone protons: 2.63–2.71 (2H, m, 7-OCH ꢃCH ), 3.79 (3H, s, 4ꢂ-OCH ),
4.04–4.17 (2H, m, 7-OCH ), 6.93–7.04 (3H, m, H-6, H-3ꢂ, H-5ꢂ), 7.08 (1H, d, J = 2.5, H-8), 7.53 (2H, d, J = 8.9, H-2ꢂ, H-6ꢂ),
7.99 (1H, d, J = 8.9, H-5), 8.40 (1H, s, H-2).
2
3
3
2
2
3
4
3
2
3
(1R,5S)-3-(2-{[8-Methyl-3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl]oxy}ethyl)-1,2,3,4,5,6-hexahydro-8H-1,5-
methanepyrido[1,2-a][1,5]diazocin-8-one Hydrochloride (3c). Yield 75%, C H N O ·HCl, mp 196–198°C. PMR spectrum
30 30
2 5
(300 MHz, DMSO-d , ꢁ, ppm, J/Hz): cytisine protons: 1.84–2.10 (2H, m, CH -8), 2.75–2.83 (1H, m, H-7), 3.36–3.76, 3.82–
6
2
3
3
4.14 (9H, 2m, CH -8, H-9, CH -11, CH -13, 7-OCH ꢃCH ), 6.38 (1H, d, J = 6.5, H-5), 6.46 (1H, d, J = 9.3, H-3), 7.47 (1H,
dd, J = 6.5, J = 9.3, H-4); isoflavone protons: 2.29 (3H, s, 8-CH ), 3.80 (3H, s, 4ꢂ-OCH ), 4.48–4.68 (2H, m, 7-OCH ), 7.00
(2H, d, J = 9.0, H-3ꢂ, H-5ꢂ), 7.23 (1H, d, J = 8.9, H-6), 7.54 (2H, d, J = 9.0, H-2ꢂ, H-6ꢂ), 7.99 (1H, d, J = 8.9, H-5), 8.49 (1H,
s, H-2).
2
2
2
2
2
3
3
3
3
2
3
3
3
3
(1R,5S)-3-{2-[(2-Methyl-4-oxo-3-phenyl-4H-chromen-7-yl)oxy]ethyl}-1,2,3,4,5,6-hexahydro-8H-1,5-
methanepyrido[1,2-a][1,5]diazocin-8-one (3d). Yield 72%, C H N O , mp 86–88°C. PMR spectrum (300 MHz,
29 28
2 4
DMSO-d , ꢁ, ppm, J/Hz): cytisine protons: 1.64–1.87 (2H, m, CH -8), 2.33–2.48 (3H, m, H-9, H-11a, H-13a), 2.84–3.07 (3H,
6
2
3
4
3
4
m, H-7, H-11b, H-13b), 3.64–3.86 (2H, m, CH -10), 6.05 (1H, dd, J = 7.0, J = 1.2, H-5), 6.18 (1H, dd, J = 8.9, J = 1.2,
2
H-3); isoflavone protons: 2.45 (3H, s, 2-CH ) 2.64–2.72 (2H, m, 7-OCH ꢃCH ), 4.03–4.16 (2H, m, 7-OCH ), 6.92 (1H, dd,
3
2
2
2
3
4
4
3
J = 8.7, J = 2.4, H-6), 7.06 (1H, d, J = 2.4, H-8), 7.24–7.48 (6H, m, Ph-3, cytisine H-4), 7.89 (1H, d, J = 8.7, H-5).
(1R,5S)-3-(2-{[2-Methyl-3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl]oxy}ethyl)-1,2,3,4,5,6-hexahydro-8H-1,5-
methanepyrido[1,2-a][1,5]diazocin-8-one (3e). Yield 76%, C H N O , mp 155–157°C. PMR spectrum (300 MHz,
30 30
2 5
DMSO-d , ꢁ, ppm, J/Hz): cytisine protons: 1.65–1.85 (2H, m, CH -8), 2.34–2.49 (3H, m, H-9, H-11a, H-13a), 2.85–3.08 (3H,
6
2
3
4
3
4
m, H-7, H-11b, H-13b), 3.65–3.89 (2H, m, CH -10), 6.05 (1H, dd, J = 7.0, J = 1.2, H-5), 6.19 (1H, dd, J = 9.0, J = 1.2,
H-3), 7.29 (1H, dd, J = 7.0, J = 9.0, H-4); isoflavone protons: 2.56 (3H, s, 2-CH ), 2.63–2.73 (2H, m, 7-OCH ꢃCH ), 3.80
(3H, s, 4ꢂ-OCH ), 4.03–4.16 (2H, m, 7-OCH ), 6.91 (1H, dd, J = 8.9, J = 2.4, H-6), 6.98 (2H, d, J = 8.7, H-3ꢂ, H-5ꢂ), 7.04
(1H, d, J = 2.4, H-8), 7.20 (2H, d, J = 8.7, H-2ꢂ, H-6ꢂ), 7.88 (1H, d, J = 8.9, H-5).
2
3
3
3
2
2
3
4
3
3
2
4
3
3
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