Synthesis of flavonoid derivatives of cytisine. 4. Synthesis of 3-aryl-7-[2-(cytisin-12-yl)ethoxy]coumarins

Article abstract of DOI:10.1007/s10600-014-0975-z

The possibility of using the alkaloid cytisine to synthesize N ¹²-cytisinylethoxy 3-arylcoumarin derivatives was studied. A series of substituted 3-aryl-7-(N ¹²-cytisinylethoxy)coumarins with the coumarin and cytisine moieties connected by a linker were synthesized.

Full text of DOI:10.1007/s10600-014-0975-z

Chemistry of Natural Compounds, Vol. 50, No. 3, July, 2014 [Russian original No. 3, May–June, 2014]
SYNTHESIS OF FLAVONOID DERIVATIVES OF CYTISINE. 4. SYNTHESIS
OF 3-ARYL-7-[2-(CYTISIN-12-YL)ETHOXY]COUMARINS
1,2*
4
2
3
S. P. Bondarenko,
E. V. Podobii, M. S. Frasinyuk,
1
V. I. Vinogradova, and V. P. Khilya
12
The possibility of using the alkaloid cytisine to synthesize N -cytisinylethoxy 3-arylcoumarin derivatives
12
was studied. A series of substituted 3-aryl-7-(N -cytisinylethoxy)coumarins with the coumarin and cytisine
moieties connected by a linker were synthesized.
Keywords: cytisine, coumarin, 2-(cytisine-12-yl)ethanol, alkylation.
Neuronal nicotinic acetylcholine receptors (nAChR) are interesting to many researchers because they are involved in
complicated processes such as trainability, motivation, memory, attention, pain sensitivity, etc. Namely these functions are
significantly impaired with aging and several neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s, schizophrenia). At
present, nAChR are considered an interesting target for development of new drugs to treat CNS dysfunctions [1–3].
Cytisine exhibits high affinity for many nAChR subtypes, especially ꢀ ꢁ and ꢀ . However, its low lipophilicity
4
2
3
hinders penetration through the blood–brain barrier (BBB) [2–5]. Therefore, a series of cytisine derivatives substituted in the
12
N
[6–12] and other positions [4, 5] were recently synthesized in order to discover new nAChR agonists or antagonists.
12
Biological tests found that adding a substituent in the N -position decreased slightly the affinity for nAChR but allowed
compounds with higher selectivity for the central ꢀ ꢁ -subtype than for the ꢀ -subtype receptors to be prepared [11].
Furthermore, the analgesic, antiarrhythmic [13, 14], and antihypertensive activity [9] of N -substituted cytisine derivatives
stimulated interest in developing new compounds of this series.
4
2
3
12
In our opinion, flavonoid cytisine derivatives are interesting as the combination of two pharmacophores in a single
molecule with increased lipophilicity. This could enhance the passage of these compounds through the BBB. We synthesized
previously various derivatives containing flavonoid and cytisine moieties connected by one or two methylenes in the
8-position or on O-7 of the chromone ring [15–17]. We chose 3-aryl-7-hydroxycoumarins for cytisine modification because
they are a flavonoid subclass of biosynthetic origin. It was interesting to study the possibility of using this alkaloid to synthesize
3''
derivatives containing coumarin and cytisine moieties connected by a linker.
O
N
5''
Br
8''
9''
11''
7''
13''
N12''
HO
O
O
O
O
R
O
R
R
2
R
R
2
a
b
O
O
O
1
R
1
1
R
R
6
3
2
3
4
R
1
4'
3
1a-e
2a-e
3a-e
a: R = R = R = H; b: R = H, R = R = OMe, c: R = R = H, R = Cl
1
2
3
1
2
3
1
2
3
d: R = Me, R = R = OMe, e: R = Me, R = H, R = Cl
1
2
3
1
2
3
a. BrCH CH Br, K CO , DMF; b. cytisine, i-Pr NEt, EtOH
2
2
2
3
2
1) Taras Shevchenko Kiev National University, 01601, Ukraine, Kiev, Ul. Vladimirskaya, 64, e-mail:
svitlana.bondarenko@ukr.net; 2) National University of Food Technologies, 01601, Ukraine, Kiev, Ul. Vladimirskaya, 68;
3) Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 02094, Ukraine, Kiev, Ul.
Murmanskaya, 1; 4) S. Yu. Yunusov Institute of the Chemistry of Plant Substances, 100170, Uzbekistan, Tashkent. Translated
from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2014, pp. 364–366. Original article submitted February 6, 2014.
©
420
0009-3130/14/5003-0420 2014 Springer Science+Business Media New York

Starting substituted 3-aryl-7-hydroxycoumarins 1a–e were obtained under Perkin reaction conditions via condensation
of substituted phenylacetic acids with 2,4-dihydroxybenzaldehyde or 2,4-dihydroxyacetophenone in acetic anhydride in the
presence of KOAc as the base with subsequent deacylation of the 7-acetoxy derivatives [18].
Alkylation of 1a–e by an excess of dibromoethane in DMF in the presence of potash synthesized their corresponding
7-bromoethoxy derivatives 2a–e.
12
The synthesis of 3-aryl-7-(N -cytisinylethoxy)coumarins 3a–e was studied using the reaction of cytisine with 2a–e
in the presence of base. Cytisine was alkylated by 2a–e, like for 7-(2-bromoethoxy)isoflavones [15], in high yield if the
reaction was performed in EtOH in the presence of di-isopropylethylamine and produced 3a–e. The product yields decreased
if NEt or N-methylmorpholine was used as the HBr acceptor because of quaternization of these bases. Alkylation of cytisine
3
in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) formed coumarin vinyl ethers that complicated isolation and
purification of the target compounds.
12
Thus, we synthesized a series of substituted 3-aryl-7-(N -cytisinylethoxy)coumarins containing coumarin and cytisine
pharmacophores connected by a linker.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on Sorbfil UV-254 (Russia) and Merck
(Germany) plates using toluene–EtOH (9:1, 95:5) as eluent. PMR spectra were measured in CDCl or DMSO-d with TMS
3
6
internal standard on the ꢂ-scale on a VXR-300 instrument (Varian, 300 MHz). Elemental analyses of all compounds agreed
with those calculated. Starting 1a–e were prepared as before [18].
General Method for Synthesizing 3-Aryl-7-(2-bromoethoxy)coumarins 2a–e. A solution of 1a–e (10 mmol) in
DMF (20 mL) was treated with potash (25 mmol) and dibromoethane (50 mmol), stirred at 75–80°C for 3–5 h (end of reaction
determined by TLC), and filtered to remove potash. The DMF was evaporated in vacuo. The residue was crystallized from
i-PrOH–DMF.
1
7-(2-Bromoethoxy)-3-phenyl-2H-chromen-2-one (2a). Yield 65%, C H BrO , mp 150–151ꢃC. Í NMR spectrum
17 13
3
3
3
(300 MHz, DMSO-d ꢄ ꢅꢂ, ppm, J/Hz): 3.86 (2Í, t, J = 5.0, OÑÍ CH Br), 4.46 (2Í, t, J = 5.0, OÑÍ CH Br), 7.02 (1Í, dd,
6
2
2
2
2
3
4
4
J = 8.7, J = 2.4, Í-6), 7.07 (1Í, d, J = 2.4, Í-8), 7.36–7.50 (3Í, m, H-3ꢆ, 4ꢆ, 5ꢆ), 7.68–7.76 (3H, m, H-5, 2ꢆ, 6ꢆ), 8.21 (1Í, s,
Í-4).
7-(2-Bromoethoxy)-3-(3,4-dimethoxyphenyl)-2H-chromen-2-one (2b). Yield 68%, C H BrO , mp 135–136ꢃC.
19 17
5
1
Í NMR spectrum (300 MHz, DMSO-d ꢄ ꢅꢂ, ppm, J/Hz): 3.81 (6Í, s, 3ꢆ, 4ꢆ-ÎÌå), 3.84–3.91 (2Í, m, OÑÍ CH Br), 4.42–
6
2
2
3
4.52 (2Í, m, OÑÍ CH Br), 6.98–7.10 (3Í, m, Í-6, 8, 5ꢆ), 7.23–7.37 (2Í, m, Í-2ꢆ, 6ꢆ), 7.69 (1Í, d, J = 8.9, Í-5), 8.19 (1H,
2
2
s, Í-4).
7-(2-Bromoethoxy)-3-(4-chlorophenyl)-2H-chromen-2-one (2c). Yield 63%, C H BrClO , mp 165–166ꢃC.
17 12
3
1
3
3
Í NMR spectrum (300 MHz, DMSO-d ꢄ ꢅꢂ, ppm, J/Hz): 3.85 (2Í, t, J = 5.2, OÑÍ CH Br), 4.47 (2Í, t, J = 5.2, OÑÍ CH Br),
6
2
2
2
2
3
4
4
3
3
7.02 (1Í, dd, J = 8.7, J = 2.4, Í-6), 7.08 (1Í, d, J = 2.4, Í-8), 7.52 (2Í, d, J = 8.6, Í-3ꢆ, 5ꢆ), 7.71 (1Í, d, J = 8.7, Í-5), 7.76
3
(2Í, d, J = 8.6, Í-2ꢆ, 6ꢆ), 8.26 (1H, s, Í-4).
7-(2-Bromoethoxy)-3-(3,4-dimethoxyphenyl)-4-methyl-2H-chromen-2-one (2d). Yield 65%, C H BrO , mp 157–
20 19
5
1
158ꢃC. Í NMR spectrum (300 MHz, DMSO-d ꢄ ꢅꢂ, ppm, J/Hz):2.26 (3H, s, 4-CH ), 3.75, 3.80 (3H each,s, 3ꢆ, 4ꢆ-ÎÌå), 3.86 (2Í,
6
3
3
3
3
4
4
t, J = 5.0, OÑÍ CH Br), 4.47 (2Í, t, J = 5.0, OÑÍ CH Br), 6.83 (1Í, dd, J = 8.1, J = 2.0, Í-6), 6.91 (1Í, d, J = 2.0,
Í-8), 6.98–7.08 (3Í, m, Í-2ꢆ, 5ꢆ, 6ꢆ), 7.75 (1Í, d, J = 8.1, Í-5).
2
2
2
2
3
7-(2-Bromoethoxy)-4-methyl-3-(4-chlorophenyl)-2H-chromen-2-one (2e). Yield 61%, C H BrClO , mp 137–
18 14
3
1
3
138ꢃC. Í NMR spectrum (300 MHz, CDCl ꢄ ꢅꢂ, ppm, J/Hz): 2.24 (3H, s, 4-CH ), 3.86 (2Í, t, J = 5.2, OÑÍ CH Br), 4.47
3
3
2
2
3
3
3
(2Í, t, J = 5.2, OÑÍ CH Br), 7.0–7.08 (2Í, m, Í-6, 8), 7.35 (2Í, d, J = 8.2, Í-3ꢆ, 5ꢆ), 7.51 (2Í, d, J = 8.2, Í-2ꢆ, 6ꢆ), 7.78 (1Í,
2
2
3
d, J = 8.7, Í-5).
12
General Method for Synthesizing 3-Aryl-7-(N -cytisinylethoxy)coumarins 3a–e. A solution of the appropriate
2a–e (2 mmol) in EtOH (30 mL) was treated with cytisine (2.4 mmol) and di-isopropylethylamine (3 mmol), refluxed for
14–18 h (end of reaction determined by TLC), cooled, and diluted with H O. The resulting precipitate was filtered off and
2
crystallized from EtOH–H O.
2
421

(1S,5R)-3-{2-[(2-Oxo-3-phenyl-2H-chromen-7-yl)oxy]ethyl}-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-
1
a][1,5]diazocin-8-one (3a). Yield 74%, C H N O , mp 164–165ꢃC. Í NMR spectrum (300 MHz, DMSO-d ꢄ ꢅꢂ, ppm,
28 26
2
4
6
J/Hz): cytisine protons: 1.65–1.85 (2Í, m, ÑÍ -8ꢆꢆ), 2.32–2.48 (3Í, m, Í-9ꢆꢆ, 11ꢆꢆa, 13ꢆꢆa), 2.85–2.94, 2.97–3.07 (1H, 2H, 2m,
2
3
4
3
4
Í-7ꢆꢆ, 11ꢆꢆb, 13ꢆꢆb), 3.65–3.85 (2Í, m, ÑÍ -10ꢆꢆ), 6.06 (1Í, dd, J = 7.0, J = 1.4, H-5ꢆꢆ), 6.18 (1Í, dd, J = 9.0, J = 1.4, H-3ꢆꢆ),
7.29 (1Í, dd, J = 9.0, J = 7.0, H-4ꢆꢆ); coumarin protons: 2.60–2.73 (2Í, m, NCH ÑÍ O-7), 4.00–4.14 (2Í, m,
NÑÍ CH O-7), 6.87 (1Í, dd, J = 8.4, J = 2.4, Í-6), 6.95 (1Í, d, J = 2.4, Í-8), 7.36–7.50 (3Í, m, H-3ꢆ, 4ꢆ, 5ꢆ), 7.71 (1Í, d,
J = 8.4, Í-5), 7.68–7.75 (2Í, m, H-2ꢆ, 6ꢆ), 8.18 (1H, s, Í-4).
2
3
3
2
2
3
4
4
2
2
3
(1S,5R)-3-(2-{[3-(3,4-Dimethoxyphenyl)-2-oxo-2H-chromen-7-yl]oxy}ethyl)-1,2,3,4,5,6-hexahydro-8H-1,5-
1
methanopyrido[1,2-a][1,5]diazocin-8-one (3b). Yield 70%, C H N O , mp 87–88ꢃC. Í NMR spectrum (300 MHz,
30 30
2 6
DMSO-d ꢄ ꢅꢂ, ppm, J/Hz): cytisine protons: 1.66–1.85 (2Í, m, ÑÍ -8ꢆꢆ), 2.32–2.47 (3Í, m, Í-9ꢆꢆ, 11ꢆꢆa, 13ꢆꢆa), 2.84–2.92,
6
2
3
4
2.95–3.07 (1H, 2H, 2m, Í-7ꢆꢆ, 11ꢆꢆb, 13ꢆꢆb), 3.66–3.85 (8Í, m, ÑÍ -10ꢆꢆ, 3ꢆ, 4ꢆ-OCH ), 6.06 (1Í, dd, J = 7.0, J = 1.2, H-5ꢆꢆ),
6.18 (1Í, dd, J = 9.0, J = 1.2, H-3ꢆꢆ), 7.25–7.37 (3Í, m, H-4ꢆꢆ, 2ꢆ, 6ꢆ); coumarin protons: 2.60–2.73 (2Í, m, N-CH ÑÍ O-7),
3.99–4.12 (2Í, m, NÑÍ CH O-7), 6.86 (1Í, dd, J = 8.3, J = 2.0, Í-6), 6.94 (1Í, d, J = 2.0, Í-8), 6.98–7.06 (1H, d, J = 7.6,
H-5ꢆ), 7.62 (1Í, d, J = 8.3, Í-5), 8.15 (1H, s, Í-4).
2
3
3
4
2
2
3
4
4
3
2
2
3
(1S,5R)-3-(2-{[2-Oxo-3-(4-chlorophenyl)-2H-chromen-7-yl]oxy}ethyl)-1,2,3,4,5,6-hexahydro-8H-1,5-
1
methanopyrido[1,2-a][1,5]diazocin-8-one (3c). Yield 77%, C H ClN O , mp 176–177ꢃC. Í NMR spectrum (300 MHz,
28 25
2 4
DMSO-d ꢄ ꢅꢂ, ppm, J/Hz): cytisine protons: 1.65–1.86 (2Í, m, ÑÍ -8ꢆꢆ), 2.29–2.47 (3Í, m, Í-9ꢆꢆ, 11ꢆꢆa, 13ꢆꢆa), 2.85–2.93,
6
2
3
4
2.96–3.06 (1H, 2H, 2m, Í-7ꢆꢆ, 11ꢆꢆb, 13ꢆꢆb), 3.66–3.83 (2Í, m, ÑÍ -10ꢆꢆ), 6.05 (1Í, dd, J = 7.0, J = 1.4, H-5ꢆꢆ), 6.17 (1Í, dd,
2
3
4
3
3
J = 9.0, J = 1.4, H-3ꢆꢆ), 7.29 (1Í, dd, J = 9.0, J = 7.0, H-4ꢆꢆ); coumarin protons: 2.59–2.76 (2Í, m, NCH ÑÍ O-7), 4.00–
2
2
3
4
4
3
4.15 (2Í, m, NÑÍ CH O-7), 6.87 (1Í, dd, J = 8.6, J = 2.4, Í-6), 6.95 (1Í, d, J = 2.4, Í-8), 7.51 (2Í, d, J = 8.6, H-3ꢆ, 5ꢆ),
7.64 (1Í, d, J = 8.6, Í-5), 7.75 (2Í, d, J = 8.6, H-2ꢆ, 6ꢆ), 8.23 (1H, s, Í-4).
2
2
3
3
(1S,5R)-3-(2-{[3-(3,4-Dimethoxyphenyl)-4-methyl-2-oxo-2H-chromen-7-yl]oxy}ethyl)-1,2,3,4,5,6-hexahydro-8H-
1
1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (3d). Yield 79%, C H N O , mp 103–104ꢃC. Í NMR spectrum
31 32
2 6
(300 MHz, DMSO-d ꢄ ꢅꢂ, ppm, J/Hz): cytisine protons: 1.69–1.86 (2Í, m, ÑÍ -8ꢆꢆ), 2.30–2.47 (3Í, m, Í-9ꢆꢆ, 11ꢆꢆa, 13ꢆꢆa),
6
2
3
2.82–2.92, 2.95–3.09 (1H, 2H, 2m, Í-7ꢆꢆ, 11ꢆꢆb, 13ꢆꢆb), 3.63–3.86 (8Í, m, ÑÍ -10ꢆꢆ, 3ꢆ, 4ꢆ-OCH ), 6.07 (1Í, dd, J = 7.0,
J = 1.5, H-5ꢆꢆ), 6.20 (1Í, dd, J = 9.0, J = 1.5, H-3ꢆꢆ), 7.30 (1Í, dd, J = 9.0, J = 7.0, H-4ꢆꢆ); coumarin protons: 2.25 (3H, s,
4-CH ), 2.62–2.74 (2Í, m, NCH ÑÍ O-7), 4.00–4.19 (2Í, m, NÑÍ CH O-7), 6.79–7.04 (5Í, m, Í-6, 8, 2ꢆ, 5ꢆ, 6ꢆ), 7.70 (1Í,
2
3
4
3
4
3
3
3
2
2
2
2
3
d, J = 8.4, Í-5).
(1S,5R)-3-(2-{[4-Methyl-2-oxo-3-(4-chlorophenyl)-2H-chromen-7-yl]oxy}ethyl)-1,2,3,4,5,6-hexahydro-8H-1,5-
1
methanopyrido[1,2-a][1,5]diazocin-8-one (3e). Yield 70%, C H ClN O , mp 99–100ꢃC. Í NMR spectrum (300 MHz,
29 27
2 4
DMSO-d ꢄ ꢅꢂ, ppm, J/Hz): cytisine protons: 1.65–1.84 (2Í, m, ÑÍ -8ꢆꢆ), 2.30–2.44 (3Í, m, Í-9ꢆꢆ, 11ꢆꢆa, 13ꢆꢆa), 2.85–2.92,
6
2
3
4
2.96–3.07 (1Í, 2H, 2m, Í-7ꢆꢆ, 11ꢆꢆb, 13ꢆꢆb), 3.65–3.81 (2Í, m, ÑÍ -10ꢆꢆ), 6.06 (1Í, dd, J = 7.0, J = 1.4, H-5ꢆꢆ), 6.18 (1Í, dd,
2
3
4
3
3
J = 9.0, J = 1.4, H-3ꢆꢆ), 7.30 (1Í, dd, J = 9.0, J = 7.0, H-4ꢆꢆ); coumarin protons: 2.23 (3H, s, 4-CH ), 2.61–2.74 (2Í, m,
3
3
4
4
NCH ÑÍ O-7), 4.02–4.14 (2Í, m, NÑÍ CH O-7), 6.89 (1Í, dd, J = 8.4, J = 2.4, Í-6), 6.95 (1Í, d, J = 2.4, Í-8), 7.35 (2Í,
2
2
2
2
3
3
3
d, J = 8.6, Í-3ꢆ, 5ꢆ), 7.52 (2Í, d, J = 8.6, Í-2ꢆ, 6ꢆ), 7.72 (1Í, d, J = 8.4, Í-5).
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