Modified coumarins. 25. N-acyl cytisine derivatives containing a coumarin fragment

Article abstract of DOI:10.1007/s10600-007-0053-x

New modified cytisine derivatives were prepared by acylation with coumarin-3-acetic acids. Springer Science+Business Media, Inc. 2007.

Full text of DOI:10.1007/s10600-007-0053-x

Chemistry of Natural Compounds, Vol. 43, No. 1, 2007
MODIFIED COUMARINS. 25. -ACYL CYTISINE DERIVATIVES
N
CONTAINING A COUMARIN FRAGMENT
I. V. Nagorichna,1 A. S. Ogorodniichuk,1 M. M. Garazd,1
V. I. Vinogradova,2 and V. P. Khilya3
UDC 547.814.5
New modified cytisine derivatives were prepared by acylation with coumarin-3-acetic acids.
Key words: cytisine, coumarins, acylation, activated esters.
Addition of a natural alkaloid fragment to organic molecules leads in most instances to the appearance of new
pharmacological properties in the synthesized compounds. Research on the chemical modification of cytisine is interesting
because of the broad spectrum of its biological activity. In continuation of our work on modification of the cytisine structure
by introducing the benzopyran structure into it [1, 2], herein we report the preparation of new -acyl cytisine derivatives
N
containing the widely distributed coumarin fragment.
Methyl estersofcoumarin-3-aceticacid(1-5)that wererequiredfor furthertransformationswerepreparedbyPechmann
condensation of polyphenols (resorcinol, 2-methylresorcinol, 4-chlororesorcinol, phloroglucinol, and orcinol) with
dimethylacetylsuccinate in the presence of dry HCl as a condensing agent at 0°C [3]. Alklyation of 1-5 under Williamson
reaction conditions by dimethylsulfate formed methoxy derivatives 6-10. Saponification of 1-10 by NaOH solution (1 M) in
aqueous propan-2-ol with subsequent acidolysis synthesized the corresponding coumarin-3-acetic acids 11-20.
R
1
R
1
R
1
R
2
7'
O
O
1. NaOH
2. HCl
R
2
O
O
R
2
O
O
1. SuOH, DIC
3'
R
3
4'
5'
NH
R
3
R
3
R
4
Me
11
2.
N
9
R
4
Me COOH
R
4
Me COOMe
O
N
10
8
13
O
N
O
1 - 10
11 - 20
21 - 30
5
3
1, 6, 11, 16, 21, 26: R1 = R3 = R4 = H; 2, 7, 12, 17, 22, 27: R1 = Me, R3 = R4 = H; 1 - 4, 11 - 14, 21 - 24: R2 = OH;
3, 8, 13, 18, 23, 28: R1 = R4 = H, R3 = Cl; 4, 14, 24: R1 = R3 = H, R4 = OH; 9, 19, 29: R1 = R3 = H, R4 = OMe;
5, 15, 25: R1 = R3 = H, R2 = Me, R4 = OH; 6 - 9, 16 - 19, 26 - 29: R2 = OMe; 10, 20, 30: R1 = R3 = H, R2 = Me, R4 = OMe
The method of activated esters [4] that is widely used in peptide synthesis was used for -acylation of the secondary
N
N atom of cytisine. The carboxylic acid was activated using typically highly reactive -hydroxysuccinimide ester [5].
N
Activated esters were prepared by reacting the corresponding acids 11-20 and -hydroxysuccinimide (SuOH) in
N
absolute dioxane using diisopropylcarbodiimide (DIC) as a condensing agent. The resulting activated esters were condensed
with cytisine in dioxane at room temperature to form in high yields (62-91%) -acyl cytisine derivatives 21-30, which contain
N
coumarin moieties.
1) Institute of Bioorganic and Petroleum Chemistry, National Academy of Sciences, Ukraine, 02094, Ukraine, Kiev,
ul. Murmanskaya, 1, e-mail: gmm@i.com.ua; 2) S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of
Sciences of the Republic of Uzbekistan, 700170, Tashkent, fax (99871) 120 64 75; 3) Taras Shevchenko Kiev National
University, 01033, Ukraine, Kiev, ul. Valdimirskaya, 64. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 10-13,
January-February, 2007. Original article submitted September 25, 2006.
0009-3130/07/4301-0010 ©2007 Springer Science+Business Media, Inc.
10

The PMR spectra of 21-30 contained signals characteristic of both cytisine and benzopyran-2-one. All prepared
compounds exhibited a doubled set of proton signals in the PMR spectra. Obviously rotation about the N–C bond was hindered
as a result of the formation of amide conjugation in invertomers that could be viewed as Z- and E-isomers. Amide conjugation
in the synthesized compounds was confirmed by variable temperature experiments. Heating the products to 100°C caused
coalescence of signals in the PMR spectrum as a result of free rotation of substituents about the N–C bond.
EXPERIMENTAL
The course of reactions and the purity of products were monitored by TLC on Merck 60 F254 plates with elution by
CHCl :CH OH (9:1 and 19:1). Melting points were determined on a Kofler block. PMR spectra were recorded on Varian
3
3
VXR-300 and Varian Mercury 400 spectrometers at 300 and 400 MHz, respectively, relative to TMS (internal standard).
Elemental analyses of all compounds agreed with those calculated.
Hydroxycoumarins 1 and 2 were prepared as before [3]. We used pharmacopeic cytisine isolated from Thermopsis
lanceolata.
Methyl-2-(6-chloro-7-hydroxy-4-methyl-2-oxochromen-3-yl)acetate (3).
A
cooled (0°C) solution of
4-chlororesorcinol (14.46 g, 0.1 mol) and dimethylacetylsuccinate (16.2 mL, 0.1 mol) in absolute methanol (50 mL) was stirred
vigorously with cooling. A stream of dry HCl was passed through for 3 h. The mixture was stirred until thick, left overnight
at room temperature, and poured intoicewater (500 mL). The resulting precipitate was filteredoffandcrystallizedfrom aqueous
methanol, yield 65%, mp 240-241°C, C H ClO .
13 11
5
PMR spectrum (300 MHz, DMSO-d , δ, ppm): 2.34 (3H, s, Me-4′), 3.62 (2H, s, CH -2), 3.64 (3H, s, COOMe), 6.87
6
2
(1H, s, H-8′), 7.73 (1H, s, H-5′), 11.17 (1H, s, OH-7′).
Methyl-(5,7-dihydroxy-4-methyl-2-oxochromen-3-yl)acetate (4) was prepared analogously to 3 starting with
phloroglucinol dihydrate (16.21 g, 0.1 mol) and dimethylacetylsuccinate (18.82 g, 0.1 mol), yield 86%, mp 259-260°C,
C H O .
13 12
6
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.49 (3H, s, Me-4′), 3.60 (2H, s, CH -3′), 3.61 (3H, s, COOMe),
6
2
6.18 (1H, d, J = 2.0, H-6′), 6.29 (1H, d, J = 2.0, H-8′), 10.29 and 10.57 (2H, two s, OH-5′ and OH-7′).
Methyl-(5-hydroxy-4,7-dimethyl-2-oxochromen-3-yl)acetate (5)waspreparedanalogouslyto3startingwith orcinol
monohydrate (14.2 g, 0.1 mol) and dimethylacetylsuccinate (18.82 g, 0.1 mol), yield 73%, mp 233-234°C, C H O .
14 14
5
PMRspectrum (300 MHz, DMSO-d , δ, ppm): 2.29 (3H, s, Me-7 ), 2.54 (3H, s, Me-4′), 3.61 (2H, s, CH -3′), 3.63 (3H,
6
2
s, COOMe), 6.56 (2H, s, H-6′, H-8′), 10.38 (1H, s, OH-5′).
General Method of Synthesizing Methoxycoumarins 6-10. A hot solution of 1-5 (10 mmol) in absolute acetone
(50 mL) was treated with freshly calcined potash (4.14 g, 30 mmol), stirred vigorously and heated (50-56°C), and treated with
dimethylsulfate (1.1 mL, 11 mmol) [for 4, potash (5.52 g, 40 mmol) and dimethylsulfate (2.2 mL, 22 mmol)]. The mixture was
heated for 2-4 h and vigorously stirred (course of reaction monitored by TLC). After the reaction was complete, the mixture
was cooled, poured into icewater (500 mL), and acidified to pH 5-6. The resulting precipitate was filtered off and crystallized
from methanol.
Methyl-(7-methoxy-4-methyl-2-oxochromen-3-yl)acetate (6). Yield 89%, mp 136-137°C, lit. [6] mp 122°C,
C H O .
14 14
5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.37 (3H, s, Me-4′), 3.65 (5H, s, CH -3′, COOMe), 3.86 (3H, s,
6
2
MeO-7′), 6.87 (1H, dd, J = 2.4, 8.7, H-6′), 6.93 (1H, d, J = 2.4, H-8′), 7.68 (1H, d, J = 8.7, H-5′).
Methyl-(7-methoxy-4,8-dimethyl-2-oxochromen-3-yl)acetate (7). Yield 92%, mp 153-154°C, C H O .
15 16
5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.20 (3H, s, Me-8′), 2.37 (3H, s, Me-4′), 3.63 (5H, s, CH -3′,
6
2
COOMe), 3.91 (3H, s, MeO-7′), 7.01 (1H, d, J = 9.0, H-6′), 7.62 (1H, d, J = 9.0, H-5′).
Methyl-(6-chloro-7-methoxy-4-methyl-2-oxochromen-3-yl)acetate (8). Yield 87%, mp 162-163°C, C H ClO .
14 13
5
PMR spectrum (400 MHz, DMSO-d , δ, ppm): 2.36 (3H, s, Me-4′), 3.63 (2H, s, CH -3′), 3.67 (3H, s, COOMe), 3.95
6
2
(3H, s, MeO-7′), 7.18 (1H, s, H-6′), 7.83 (1H, s, H-5′).
Methyl-(5,7-dimethoxy-4-methyl-2-oxochromen-3-yl)acetate (9). Yield 79%, mp 149-150°C, C H O .
15 16
6
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.46 (3H, s Me-4′), 3.62 (3H, s, COOMe), 3.64 (2H, s, CH -3′),
6
2
3.85 and 3.87 (6H, two s, MeO-5′, MeO-7′), 6.51 (1H, d, J = 2.4, H-8′), 6.58 (1H, d, J = 2.4, H-6′).
11

Methyl-(5-methoxy-4,7-dimethyl-2-oxochromen-3-yl)acetate (10). Yield 86%, mp 173-174°C, C H O .
15 16
5
PMR spectrum (300 MHz, DMSO-d , δ, ppm): 2.38 (3H, s, Me-7′), 2.49 (3H, s, Me-4′), 3.63 (5H, s, CH -3′, COOMe),
6
2
3.88 (3H, s, MeO-5′), 6.73 (2H, s, H-6′, H-8′).
General Method for Synthesizing Acids 11-20. A solution or suspension of ester 1-10 (5 mmol) in propan-2-ol
(10 mL) was treated with NaOH solution (20 mL, 20 mmol, 1 M). The mixture was heated and stirred for 0.5-1 h (course of
reaction monitored by TLC). After the reaction was complete the mixture was cooled, poured into icewater (100 mL), and
acidified to pH 5-6. The resulting precipitate was filtered and crystallized from aqueous propan-2-ol.
(7-Hydroxy-4-methyl-2-oxochromen-3-yl)acetic Acid(11). Yield72%, mp268-269°C, lit. [6]mp265 C, [7, 8]265-
268, [9] 268, C H O .
12 10
5
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.33 (3H, s, Me-4′), 3.51 (2H, s, CH -3′), 6.66 (1H, d, J = 1.8,
6
2
H-8′), 6.76 (1H, dd, J = 1.8, 9.0, H-6′), 7.57 (1H, d, J = 9.0, H-5′), 10.29 (1H, s, OH-7′), 12.26 (1H, br.s, COOH).
(7-Hydroxy-4,8-dimethyl-2-oxochromen-3-yl)acetic Acid (12). Yield 83%, mp 255-256°C, C H O .
13 12
5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.18 (3H, s, Me-8′), 2.31 (3H, s, Me-4′), 3.52 (2H, s, CH -3′),
6
2
6.83 (1H, d, J = 9.0, H-6′), 7.40 (1H, d, J = 9.0, H-5′), 10.16 (1H, s, OH-7′), 12.25 (1H, br.s, COOH).
(6-Chloro-7-hydroxy-4-methyl-2-oxochromen-3-yl)acetic Acid (13). Yield 83%, mp 265-266°C, lit. [7] mp 263°C,
C H ClO .
12
9
5
PMR spectrum (400 MHz, DMSO-d , δ, ppm): 2.34 (3H, s, Me-4′), 3.56 (2H, s, CH -3′), 6.89 (1H, s, H-6′), 7.79 (1H,
6
2
s, H-5′), 10.15 (1H, s, OH-7′), 12.10 (1H, br.s, COOH).
(5,7-Dihydroxy-4-methyl-2-oxochromen-3-yl)acetic Acid (14). Yield 78%, mp 271-272°C, lit. [10] mp 264°C, [11]
285, C H O .
12 10
6
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.47 (3H, s, Me-4′), 3.60 (2H, s, CH -3′), 6.15 (1H, d, J = 2.0,
6
2
H-6′), 6.27 (1H, d, J = 2.0, H-8′), 10.29 and 10.57 (2H, two s, OH-5′ and OH-7′), 11.50 (1H, br.s, COOH).
(5-Hydroxy-4,7-dimethyl-2-oxochromen-3-yl)acetic Acid (15). Yield 82%, mp 259°C, lit. [7] mp 270°C, [10] 271,
C H O .
13 12
5
PMR spectrum (400 MHz, DMSO-d , δ, ppm): 2.27 (3H, s, Me-7′), 2.52 (3H, s, Me-4′), 3.55 (2H, s, CH -3′), 6.59 and
6
2
6.62 (2H, two s, H-6′, H-8′), 10.45 (1H, s, OH-5′), 12.30 (1H, br.s, COOH).
(7-Methoxy-4-methyl-2-oxochromen-3-yl)acetic Acid (16). Yield 78%, mp 208-209°C, lit. [8] mp 196-197°C, [6]
198°C, [12] 199°C, C H O .
13 12
5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.36 (3H, s, Me-4′), 3.54 (2H, s, CH -3′), 3.85 (3H, s, MeO-7′),
6
2
6.92 (2H, m, H-6′, H-8′), 7.71 (1H, d, J = 8.7, H-5′), 12.30 (1H, br.s, COOH).
(7-Methoxy-4,8-dimethyl-2-oxochromen-3-yl)acetic Acid (17). Yield 84%, mp 247-248°C, C H O .
14 14
5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.18 (3H, s, Me-8′), 2.34 (3H, s, Me-4′), 3.54 (2H, s, CH -3′),
6
2
3.89 (3H, s, MeO-7′), 6.95 (1H, d, J = 9.0, H-6′), 7.56 (1H, d, J = 9.0, H-5′), 12.31 (1H, br.s, COOH).
(6-Chloro-7-methoxy-4-methyl-2-oxochromen-3-yl)acetic Acid (18). Yield 89%, mp 236-237°C, C H ClO .
13 11
5
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 2.36 (3H, s, Me-4′), 3.59 (2H, s, CH -3′), 3.95 (3H, s, MeO-7′),
6
2
7.21 (1H, s, H-6′), 7.86 (1H, s, H-5′), 12.40 (1H, br.s, COOH).
(5,7-Dimethoxy-4-methyl-2-oxochromen-3-yl)acetic Acid (19). Yield 73%, mp228-229°C, lit. [10] mp 218-220°C,
C H O .
14 14
6
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.46 (3H, s, Me-4′), 3.51 (2H, s, CH -3′), 3.83 and 3.89 (6H, two
6
2
s, MeO-5′, MeO-7′), 6.41 (1H, d, J = 2.4, H-8′), 6.49 (1H, d, J = 2.4, H-6′), 12.24 (1H, br.s, COOH).
(5-Methoxy-4,7-dimethyl-2-oxochromen-3-yl)acetic Acid (20). Yield 89%, mp 221-222°C, lit. [10] mp 225°C,
C H O .
14 14
5
PMR spectrum (400 MHz, DMSO-d , δ, ppm): 2.37 (3H, s, Me-7′), 2.47 (3H, s, Me-4′), 3.57 (2H, s, CH -3′), 3.87 (3H,
6
2
s, MeO-5′), 6.78 and 6.80 (2H, two s, H-6′, H-8′), 12.40 (1H, br.s, COOH).
General Method for N-Acylation of Cytisine. A solution of 11-20 (3 mmol) and N-hydroxysuccinimide (0.38 g,
3.3 mmol) in absolute dioxane (20 mL) was stirred vigorously and treated with diisopropylcarbodiimide (0.52 mL, 3.3 mmol).
The mixture was stirred for 2 h (course of reaction monitored by TLC). The resulting activated ester was treated with cytisine
(0.63 g, 3.3 mmol) and stirred vigorously for 4-6 h (course of reaction monitored by TLC). When the reaction was complete
the mixture was diluted with water (200 mL) and acidified to pH 5-6. The resulting solid was filtered off and crystallized from
propan-2-ol.
12

N-[(7-Hydroxy-4-methyl-2-oxochromen-3-yl)acetyl]cytisine (21). Yield 91%, mp >350°C (dec.), C H N O .
23 22
2 5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.86 and 1.96 (3H, two s, CH -4′), 1.95-2.05 (2H, m, CH -8),
6
3
2
2.70-2.90 (2H, m, H-7, H-9), 3.40-3.75 (4H, m, CH -3′, CH -11α, CH -13α), 3.44 and 3.79 (2H, twod, J = 15.6, CH -10), 4.04-
2
2
2
2
4.58 (2H, CH -11β, CH -13β), 6.08 and 6.18 (2H, two d, J = 8.1, H-5, H-3), 6.61 (1H, d, J = 2.1, H-8′), 6.72 (1H, dd, J = 2.1,
2
2
9.0, H-6 ), 7.24 (1H, t, J = 8.1, H-4), 7.47 (1H, d, J = 9.0, H-5 ), 10.24 (1H, br.s, OH-7 ).
N-[(7-Hydroxy-4,8-dimethyl-2-oxochromen-3-yl)acetyl]cytisine (22). Yield 83%, mp 309-310.5°C, C H N O .
24 24
2 5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.84 and 1.94 (3H, two s, CH -4′), 1.95-2.05 (2H, m, CH -8),
6
3
2
2.15 (3H, s, CH -8′), 2.70-2.90 (2H, m, H-7, H-9), 3.35-3.70 (4H, m, CH -3′, CH -11α, CH -13α), 3.44 and 3.79 (2H, two d,
3
2
2
2
J = 15.6, CH -10), 4.00-4.58 (2H, CH -11β, CH -13β), 6.08 and 6.18 (2H, two m, H-5, H-3), 6.79 (1H, d, J = 8.4, H-6′), 7.20-
2
2
2
7.35 (2H, m, H-4, H-5′), 10.11 (1H, br.s, OH-7′).
N-[(6-Chloro-7-hydroxy-4-methyl-2-oxochromen-3-yl)acetyl]cytisine (23). Yield 87%, mp >355°C (dec.),
C H ClN O .
23 21
2 5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.85 and 1.96 (3H, two s, CH -4′), 1.95-2.05 (2H, m, CH -8),
6
3
2
2.82-2.95 (2H, m, H-7, H-9), 3.36-3.71 (4H, m, CH -3′, CH -11α, CH -13α), 3.42 and 3.79 (2H, twod, J = 15.6, CH -10), 4.00-
2
2
2
2
4.60 (2H, CH -11β, CH -13β), 6.08 and 6.18 (2H, two d, J = 6.9, H-5, H-3), 6.82 (1H, s, H-8′), 7.27 (1H, t, J = 6.9, H-4), 7.61
2
2
(1H, s, H-5′), 11.13 (1H, br.s, OH-7′).
N-[(5,7-Dihydroxy-4-methyl-2-oxochromen-3-yl)acetyl]cytisine (24). Yield62%, mp>350°C(dec.), C H N O .
23 22
2 6
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.95-2.05 (2H, m, CH -8), 1.96 and 2.04 (3H, two s, CH -4′),
6
2
3
2.80-2.92 (2H, m, H-7, H-9), 3.34-3.72 (4H, m, CH -3′, CH -11α, CH -13α), 3.43 and 3.76 (2H, twod, J = 15.6, CH -10), 4.05-
2
2
2
2
4.58 (2H, CH -11β, CH -13β), 6.07 and 6.20 (4H, two m, H-5, H-3, H-6′, H-8′), 7.24 (1H, m, H-4), 10.00 and 10.35 (2H, two
2
2
br.s, OH-5′, OH-7′).
N-[(5-Hydroxy-4,7-dimethyl-2-oxochromen-3-yl)acetyl]cytisine (25). Yield 71%, mp 320-322°C, C H N O .
24 24
2 5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.95-2.05 (2H, m, CH -8), 2.01 and 2.13 (3H, two s, CH -4′),
6
2
3
2.27 (3H, s, CH -7′), 2.80-2.95 (2H, m, H-7, H-9), 3.35-3.75 (4H, m, CH -3′, CH -11α, CH -13α), 3.45 and 3.80 (2H, two d,
3
2
2
2
J = 15.6, CH -10), 4.05-4.60 (2H, CH -11β, CH -13β), 6.08 and 6.20 (2H, two d, J = 6.6, H-5, H-3), 6.52 (2H, br.s, H-6′, H-8′),
2
2
2
7.26 (1H, m, H-4), 10.27 (1H, br.s, OH-5′).
N-[(7-Methoxy-4-methyl-2-oxochromen-3-yl)acetyl]cytisine (26). Yield 85%, mp 348-349°C, C H N O .
24 24
2 5
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.88 and 1.99 (3H, two s, CH -4′), 1.95-2.05 (2H, m, CH -8),
6
3
2
2.60-2.95 (2H, m, H-7, H-9), 3.35-3.75 (4H, m, CH -3′, CH -11α, CH -13α), 3.45 and 3.78 (2H, two d, J = 15.6, CH -10), 3.83
2
2
2
2
(3H, s, OCH -7′), 4.04-4.58 (2H, CH -11β, CH -13β), 6.08 and 6.22 (2H, two d, J = 6.6, H-5, H-3), 6.91 (2H, m, H-6′, H-8′),
3
2
2
7.24 (1H, m, H-4), 7.63 (1H, m, H-5′).
N-[(7-Methoxy-4,8-dimethyl-2-oxochromen-3-yl)acetyl]cytisine (27). Yield 89%, mp 325-326°C, C H N O .
25 26
2 5
PMR spectrum (400 MHz, DMSO-d , δ, ppm, J/Hz): 1.87 and 1.98 (3H, two s, CH -4′), 1.95-2.05 (2H, m, CH -8),
6
3
2
2.15 (3H, s, CH -8′), 2.82-2.99 (2H, m, H-7, H-9), 3.35-3.70 (4H, m, CH -3′, CH -11α, CH -13α), 3.44 and 3.79 (2H, two d,
3
2
2
2
J = 15.6, CH -10), 3.88 (3H, s, OCH -7′), 4.00-4.58 (2H, CH -11β, CH -13β), 6.10 and 6.22 (2H, d, J = 6.4, H-5, H-3), 7.01
2
3
2
2
(1H, d, J = 8.8, H-6′), 7.29 (1H, m, H-4), 7.58 (1H, m, H-5′).
N-[(6-Chloro-7-methoxy-4-methyl-2-oxochromen-3-yl)acetyl]cytisine (28). Yield 83%, mp 301.5-303°C,
C H ClN O .
24 23
2 5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.88 and 1.98 (3H, two s, CH -4′), 1.95-2.05 (2H, m, CH -8),
6
3
2
2.85-2.95 (2H, m, H-7, H-9), 3.36-3.71 (4H, m, CH -3′, CH -11α, CH -13α), 3.45 and 3.79 (2H, twod, J = 15.6, CH -10), 3.93
2
2
2
2
(3H, s, OCH -7′), 4.00-4.60 (2H, CH -11β, CH -13β), 6.08 and 6.20 (2H, two d, J = 6.6, H-5, H-3), 7.11 (1H, s, H-8′), 7.27
3
2
2
(1H, t, H-4), 7.68 (1H, s, H-5′).
N-[(5,7-Dimethoxy-4-methyl-2-oxochromen-3-yl)acetyl]cytisine (29). Yield 81%, mp 318-319°C, C H N O .
25 26
2 6
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.96 and 2.07 (3H, two s, CH -4′), 1.95-2.05 (2H, m, CH -8),
6
3
2
2.80-2.95 (2H, m, H-7, H-9), 3.35-3.75 (4H, m, CH -3′, CH -11α, CH -13α), 3.45 and 3.75 (2H, two d, J = 15.6, CH -10), 3.82
2
2
2
2
and 3.84 (6H, two s, OCH -5′, OCH -7′), 4.03-4.58 (2H, CH -11β, CH -13β), 6.08 and 6.18 (2H, two d, J = 6.6, H-5, H-3), 6.41
3
3
2
2
and 6.45 (2H, two d, J = 2.1, H-6′, H-8′), 7.25 (1H, m, H-4).
N-[(5-Methoxy-4,7-dimethyl-2-oxochromen-3-yl)acetyl]cytisine (30). Yield 76%, mp 337-338°C, C H N O .
25 26
2 5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.97 and 2.09 (3H, two s, CH -4′), 1.95-2.05 (2H, m, CH -8),
6
3
2
2.35 (3H, s, CH -7′), 2.80-2.95 (2H, m, H-7, H-9), 3.35-3.75 (4H, m, CH -3′, CH -11α, CH -13α), 3.45 and 3.80 (2H, two d,
3
2
2
2
13

J = 15.6, CH -10), 3.85 (3H, s, OCH -7′), 4.05-4.60 (2H, CH -11β, CH -13β), 6.11 and 6.25 (2H, two d, J = 6.6, H-5, H-3),
2
3
2
2
6.75 and 6.81 (2H, two s, H-6′, H-8′), 7.32 (1H, m, H-4).
ACKNOWLEDGMENT
We thank OAO Eximed (Ukraine, Kiev) for help with this work.
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