Modified coumarins. 22. Synthesis of N-coumarinyloxyacetyl derivatives of cytisine

Article abstract of DOI:10.1007/s10600-006-0061-2

N-Acetyl derivatives of cytisine modified by coumarins were synthesized. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10600-006-0061-2

Chemistry of Natural Compounds, Vol. 42, No. 2, 2006
MODIFIED COUMARINS. 22. SYNTHESIS OF
N-COUMARINYLOXYACETYL DERIVATIVES
OF CYTISINE
I. P. Dubovik,1 M. M. Garazd,1
V. I. Vinogradova,2 and V. P. Khilya3
UDC 547.814.5
N
-Acetyl derivatives of cytisine modified by coumarins were synthesized.
Key words: cytisine, coumarins, acylation, activated esters.
Adding a natural alkaloidal fragment to organic molecules leads in most instances to the appearance of new biological
properties. Cytisine possesses potent pharmacological activity[1, 2]. On the other hand, coumarins form a group ofstructurally
varied natural bioregulators of plant origin that are based on the benzopyran-2-one skeleton [3]. Depending on the structure,
natural coumarins and their synthetic analogs possess a wide spectrum of biological activity [4]. We synthesized a series of
cytisine derivatives that contain the coumarin moiety, a heterocycle that is widely distributed in nature.
Hydroxycoumarins 1-8 that were required for further transformations were prepared by Pechmann condensation of
polyphenols (resorcinol, 2-methylresorcinol, orcine) and ethyl-2-oxocyclopentanecarboxylate or ethyl-2-
oxocyclohexanecarboxylate in the presence of conc. H SO [5, 6].
2
4
Alkylation of 1-8 in acetone in the presence of potash by ethylchloroacetate produced ethyl esters 9-16, saponification
of which by NaOH in aqueous propan-2-ol with subsequent acidolysis gave the corresponding acids 17-24.
Cytisine was modified by two methods. The first method of cytisine -acylation was based on the method of activated
N
esters that is widely applied in peptide synthesis [7]. We used the highly reactive -hydroxysuccinimide ester to activate the
N
carboxylic function [8]. Activated esters were prepared by reacting corresponding acids 17-24 and -hydroxysuccinimide
N
(SuOH) in absolute dioxane using diisopropylcarbodiimide (DIC) as the condensing agent. Condensation of the resulting esters
with cytisine in dioxane at room temperature formed in high yields the -acyl cytisine derivatives 25-32, which contain
N
coumarin moieties.
The second method was based on activation of the carboxylic function of coumarinyloxyacetic acids using
, -carbonyldiimidazole (CDI) [9, 10]. Reaction of acids 17-24 and CDI in absolute DMF formed -acylimidazoles, which
N N
N
were converted in high yields and smoothly by cytisine to the corresponding -acyl cytisine derivatives 25-32.
N
Analysis of PMR spectra revealed that a doubled set of signals was found for all prepared compounds. Obviously
formation of amide bonds in such systems produces invertomers with hindered rotation around the N–C bond that can be
considered to be - and -isomers. The presence of amide conjugation was confirmed by temperature experiments. Thus,
Z
E
heating samples of the prepared compounds to 100°C caused signals in the PMR spectrum to coalesce because of free rotation
of the substituents around the N–C bond.
1) Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kiev, ul.
Murmanskaya, 1, e-mail: gmm@i.com.ua; 2) S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of
Sciencesofthe Republic ofUzbekistan, Tashkent, fax (99871) 1206475;3)TarasShevchenkoKievNationalUniversity, 01033,
Ukraine, Kiev, ul. Vladimirskaya, 64. Translatedfrom KhimiyaPrirodnykh Soedinenii, No. 2, pp. 110-113, March-April, 2006.
Original article submitted December 15, 2005.
0009-3130/06/4202-0133 ©2006 Springer Science+Business Media, Inc.
133

O
R
R
1. NaOH
2. HCl
O
HO
O
O
O
O
EtO
ClCH COOEt
2
R
1
R
1
K CO
2
3
(
CH )n
2
(
CH )n
2
1 - 6
9 - 14
O
O
R
R
O
O
O
O
O
N
O
HO
A or B
N
R
1
R
1
(
CH )n
O
(
CH )n
2
2
17 - 22
25 - 30
Method A: 1. SuOH, DIC; 2. Cytisine
Method B: 1. CDI; 2. Cytisine
1, 9, 17, 25: R = R = H, n = 1; 2, 10, 18, 26: R = Me, R = H, n = 1; 3, 11, 19, 27: R = H, R = Cl, n = 1;
1
1
1
4, 12, 20, 28: R = R = H, n = 2; 5, 13, 21, 29: R = Me, R = H, n = 2; 6, 14, 22, 30: R = H, R = Cl, n = 2
1
1
1
Me
O
O
Me
O
O
1. NaOH
2. HCl
O
Me
O
O
O
ClCH COOEt
2
K CO
2
3
OH
7, 8
(
CH )n
2
O
(
O
CH )n
2
(
CH )n
2
HO
EtO
15, 16
23, 24
Me
O
O
A or B
O
O
(
CH )n
2
N
N
Method A: 1. SuOH, DIC; 2. Cytisine
Method B: 1. CDI; 2. Cytisine
O
31, 32
7, 15, 23, 31: n = 1; 8, 16, 24, 32: n = 2
EXPERIMENTAL
The course of reactions and purity of compounds 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 a Varian
3
3
VXR-300 spectrometer at 300 MHz relative toTMS (internal standard). Elemental analyses ofall compounds agreed with those
1 8
12
20
calculated. Hydroxycoumarins - were synthesized as before [5, 6]; and , by the literature method [11]. Pharmacopoeic
cytisine isolated from Thermopsis alterniflora was used.
Ethylcoumarinyloxyacetates 9-16.
1 8
A hot solution of - (10 mmol) in absolute acetone (50 mL) was treated with
freshly calcined potash (4.14 g, 30 mmol), stirred vigorously, heated (50-56°C), treated with ethylchloroacetate (1.2 mL,
11 mmol), and stirred vigorouslyfor 2-4 h (course of reaction monitored byTLC). After the reaction was complete, the mixture
was cooled, transferred into icewater (500 mL), and acidified to pH 5-6. The resulting precipitate was filtered off and
crystallized from propan-2-ol (75%).
Ethyl[(4-oxo-1,2,3,4-tetrahydrocyclopenta[ ]chromen-7-yl)oxy]acetate (9).
c
Yield86%, C H O , mp148-149°C.
16 16 5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.26 (3H, t, J = 7.2, CH -2′), 2.14 (2H, m, CH -2), 2.76 (2H, m,
6
3
2
CH -1), 3.06 (2H, m, CH -3), 4.17 (2H, q, J = 7.2, CH -1′), 4.87 (2H, s, CH O-7), 6.88 (1H, dd, J = 2.4, 8.7, H-8), 6.97 (1H,
2
2
2
2
d, J = 2.4, H-6), 7.49 (1H, d, J = 8.7, H-9).
Ethyl[(6-methyl-4-oxo-1,2,3,4-tetrahydrocyclopenta[ ]chromen-7-yl)oxy]acetate (10).
c
Yield 91%, C H O ,
17 18 5
mp 169-170°C.
134

PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.26 (3H, t, J = 7.2, CH -2′), 2.10 (2H, m, CH -2), 2.26 (3H, s,
6
3
2
CH -6), 2.74 (2H, m, CH -1), 3.04 (2H, m, CH -3), 4.17 (2H, q, J = 7.2, CH -1′), 4.97 (2H, s, CH O-7), 6.98 (1H, d, J = 8.7,
3
2
2
2
2
H-8), 7.39 (1H, d, J = 8.7, H-9).
Ethyl[(8-chloro-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yl)oxy]acetate (11). Yield 89%, C H ClO ,
16 15
5
mp 181-182°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.26 (3H, t, J = 7.2, CH -2′), 2.14 (2H, m, CH -2), 2.76 (2H, m,
6
3
2
CH -1), 3.05 (2H, m, CH -3), 4.19 (2H, q, J = 7.2, CH -1′), 4.98 (2H, s, CH O-7), 7.17 (1H, s, H-6), 7.62 (1H, s, H-9).
2
2
2
2
Ethyl[(4-methyl-6-oxo-7,8,9,10-tetrahydrobenzo[c]chromen-3-yl)oxy]acetate (13). Yield 83%, C H O ,
18 20
5
mp 158-159°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.26 (3H, t, J = 7.2, CH -2′), 1.77 (4H, m, CH -8, CH -9), 2.26
6
3
2
2
(3H, s, CH -4), 2.41 (2H, m, CH -10), 2.74 (2H, m, CH -7), 4.18 (2H, q, J = 7.2, CH -1′), 4.87 (2H, s, CH O-7), 6.86 (1H, d,
3
2
2
2
2
J = 8.7, H-2), 7.44 (1H, d, J = 8.7, H-1).
Ethyl[(2-chloro-6-oxo-7,8,9,10-tetrahydrobenzo[c]chromen-3-yl)oxy]acetate (14). Yield 86%, C H ClO ,
17 17
5
mp 183-184°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.23 (3H, t, J = 7.2, CH -2′), 1.72 (4H, m, CH -8, CH -9), 2.40
6
3
2
2
(2H, m, CH -10), 2.75 (2H, m, CH -7), 4.18 (2H, q, J = 7.2, CH -1′), 5.04 (2H, s, CH O-3), 7.17 (1H, s, H-4), 7.75 (1H, s, H-1).
2
2
2
2
Ethyl[(7-methyl-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-9-yl)oxy]acetate (15). Yield 85%, C H O ,
17 18
5
mp 166-167°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.25 (3H, t, J = 7.2, CH -2′), 2.04 (2H, m, CH -2), 2.35 (3H, s,
6
3
2
CH -7), 2.67 (2H, m, CH -1), 3.24 (2H, m, CH -3), 4.18 (2H, q, J = 7.2, CH -1′), 4.89 (2H, s, CH O-9), 6.74 (1H, s, H-8), 6.84
3
2
2
2
2
(1H, s, H-6).
Ethyl[(3-methyl-6-oxo-7,8,9,10-tetrahydrobenzo[c]chromen-1-yl)oxy]acetate (16). Yield 79%, C H O ,
18 20
5
mp 151-152°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.28 (3H, t, J = 7.2, CH -2′), 1.70 (4H, m, CH -8, CH -9), 2.34
6
3
2
2
(3H, s, CH -3), 2.42 (2H, m, CH -10), 3.14 (2H, m, CH -7), 4.18 (2H, q, J = 7.2, CH -1′), 4.83 (2H, s, CH O-1), 6.67 (2H, s,
3
2
2
2
2
H-2), 6.74 (2H, s, H-4).
Coumarinyloxyacetic Acids 17-24. A solution or suspension of ester 9-16 (5 mmol) in propan-2-ol (10 mL) was
treated with NaOH solution (1 M, 20 mL, 20 mmol) and heated with stirring for 0.5-1 h (course of reaction monitored by TLC).
After the reaction was complete, the mixture was cooled, transferred into icewater (100 mL) and acidified to pH 5-6. The
resulting precipitate was filtered off and crystallized from aqueous propan-2-ol.
[(4-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yl)oxy]acetic Acid(17). Yield86%, C H O , mp206-207°C.
14 12
5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.13 (2H, m, CH -2), 2.74 (2H, m, CH -1), 3.06 (2H, m, CH -3),
6
2
2
2
4.87 (2H, s, CH O-7), 6.88 (1H, dd, J = 2.4, 8.7, H-8), 6.97 (1H, d, J = 2.4, H-6), 7.48 (1H, d, J = 8.7, H-9), 12.45 (1H, br.s,
2
COOH).
[(6-Methyl-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yl)oxy]acetic Acid (18). Yield 88%, C H O ,
15 14
5
mp 228-229°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.11 (2H, m, CH -2), 2.25 (3H, s, CH -6), 2.74 (2H, m, CH -1),
6
2
3
2
3.04 (2H, m, CH -3), 4.84 (2H, s, CH O-7), 6.94 (1H, d, J = 8.7, H-8), 7.38 (1H, d, J = 8.7, H-9), 12.18 (1H, br.s, COOH).
2
2
[(8-Chloro-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yl)oxy]acetic Acid (19). Yield 92%, C H ClO ,
14 11
5
mp 213-214°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.13 (2H, m, CH -2), 2.75 (2H, m, CH -1), 3.05 (2H, m, CH -3),
6
2
2
2
4.89 (2H, s, CH O-7), 7.12 (1H, s, H-6), 7.62 (1H, s, H-9), 12.05 (1H, br.s, COOH).
2
[(4-Methyl-6-oxo-7,8,9,10-tetrahydrobenzo[c]chromen-3-yl)oxy]acetic Acid (21). Yield 86%, C H O ,
16 16
5
mp 223-224°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.75 (4H, m, CH -8, CH -9), 2.25 (3H, s, CH -4), 2.41 (2H, m,
6
2
2
3
CH -10), 2.76 (2H, m, CH -7), 4.82 (2H, s, CH O-7), 6.84 (1H, d, J = 8.7, H-2), 7.44 (1H, d, J = 8.7, H-1), 12.54 (1H, br.s,
2
2
2
COOH).
[(2-Chloro-6-oxo-7,8,9,10-tetrahydrobenzo[c]chromen-3-yl)oxy]acetic Acid (22). Yield 88%, C H ClO ,
15 13
5
mp 231-232°C.
135

PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.74 (4H, m, CH -8, CH -9), 2.41 (2H, m, CH -10), 2.74 (2H,
6
2
2
2
m, CH -7), 4.93 (2H, s, CH O-3), 7.08 (1H, s, H-4), 7.71 (1H, s, H-1), 12.20 (1H, br.s, COOH).
2
2
[(7-Methyl-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-9-yl)oxy]acetic Acid (23). Yield 84%, C H O ,
15 14
5
mp 227-228°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 2.04 (2H, m, CH -2), 2.35 (3H, s, CH -7), 2.67 (2H, m, CH -1),
6
2
3
2
3.30 (2H, m, CH -3), 4.78 (2H, s, CH O-9), 6.72 (1H, s, H-8), 6.83 (1H, s, H-6), 13.04 (1H, br.s, COOH).
2
2
[(3-Methyl-6-oxo-7,8,9,10-tetrahydrobenzo[c]chromen-1-yl)oxy]acetic Acid(24). Yield86%, C H O , mp214-
16 16
5
215°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.67 (4H, m, CH -8, CH -9), 2.33 (3H, s, CH -3), 2.40 (2H, m,
6
2
2
3
CH -10), 3.12 (2H, m, CH -7), 4.79 (2H, s, CH O-1), 6.71 (2H, s, H-2), 6.78 (2H, s, H-4), 12.42 (1H, br.s, COOH).
2
2
2
General Method of Cytisine N-Acylation. Method A. A solution of 17-24 (3 mmol) and N-hydroxysuccinimide
(0.38 g, 3.3 mmol) in absolute dioxane (20 mL) was stirred vigorously, treated with DIC (0.52 mL, 3.3 mmol), and stirred for
2 h (course of reaction monitored by TLC). The resulting activated ester was treated with cytisine (0.63 g, 3.3 mmol). The
mixture was stirred vigorously for 4-6 h (course of reaction monitored by TLC). After the reaction was complete the
mixture was diluted with water (200 mL) and acidified to pH 5-6. The resulting precipitate was filtered offand crystallized from
propan-2-ol.
Method B. A solution of 17-24 (3 mmol) in absolute DMF (5 mL) was treated with CDI (0.54 g, 3.3 mmol), stirred
vigorously at room temperature for 2 h, and treated with cytisine (0.63 g, 3.3 mmol). The mixture was stirred vigorously at
room temperature for 4-6 h. After the reaction was complete the mixture was diluted with water (100 mL) and acidified to
pH 5-6. The resulting precipitate was filtered off and crystallized from propan-2-ol.
N-[([-Oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yl]oxy)acetyl]cytisine (25). Yield 82%, C H N O ,
25 24
2 5
mp 255.5-257°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.90-2.08 (2H, m, CH -8), 2.10-2.18 (2H, m, CH -2′), 2.54 (1H,
6
2
2
m, H-9), 2.75 (2H, m, CH -1′), 2.90 (1H, m, H-11 ), 3.04 (2H, m, CH -3′), 3.14 (1H, m, H-7), 3.35 and 3.44 (1H, 2d, J = 13.2,
2
ax
2
H-13 ), 3.60-3.70 (1H, m, H-10 ), 3.83-4.02 (2H, m, H-10 , H-13 ), 4.43 and 4.62 (1H, 2d, J = 13.2, H-11 ), 4.22 (2d,
ax
ax
eq
eq
eq
J = 13.2), 4.65 (dd, J = 6.3, 13.2) and 4.89 (2H, d, J = 13.2, COCH O-7 ), 6.11 and 6.25 (1H, 2d, J = 6.3, H-5), 6.21 (1H, d,
2
J = 6.3, H-3), 6.52 and 6.76 (1H, 2dd, J = 2.4, 8.7, H-8′), 6.73 and 6.88 (1H, d, J = 2.4, H-6′), 7.20-7.30 (1H, m, H-4), 7.35 and
7.38 (1H, 2d, J = 8.7, H-9′).
N-[([6-Methyl-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yl]oxy)acetyl]cytisine (26).
C H N O , mp 254-255°C.
Yield 89%,
26 26
2 5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.90-2.08 (2H, m, CH -8), 2.11 (2H, m, CH -2′), 2.16 and 2.18
6
2
2
(3H, 2s, CH -6′), 2.54 (1H, m, H-9), 2.73 (2H, m, CH -1′), 2.90 (1H, m, H-11 ), 3.03 (2H, m, CH -3′), 3.18 (1H, m, H-7), 3.34
3
2
ax
2
and 3.48 (1H, 2d, J = 13.2, H-13 ), 3.60-3.70 (1H, m, H-10 ), 3.80-4.05 (2H, m, H-10 , H-13 ), 4.25 and 4.47 (1H, 2d,
ax
ax
eq
eq
J = 13.2, H-11 ), 4.26 (2d, J = 13.2), 4.82 (dd, J = 6.3, 13.2) and 5.09 (2H, d, J = 13.2, COCH O-7′), 6.10-6.50 (3H, m, H-3,
eq
2
H-5, H-8′), 7.18-7.40 (2H, m, H-4, H-9′).
N-[([8-Chloro-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-7-yl]oxy)acetyl]cytisine (27).
C H ClN O , mp 256.5-258°C.
Yield 78%,
25 23
2 5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.90-2.08 (2H, m, CH -8), 2.13 (2H, m, CH -2′), 2.54 (1H, m,
6
2
2
H-9), 2.76 (2H, m, CH -1′), 2.91 (1H, m, H-11 ), 3.04 (2H, m, CH -3′), 3.18 (1H, m, H-7), 3.35 and 3.49 (1H, 2d, J = 13.2,
2
ax
2
H-13 ), 3.60-3.70 (1H, m, H-10 ), 3.80-4.02 (2H, m, H-10 , H-13 ), 4.33 and 4.52 (1H, 2d, J = 13.2, H-11 ), 4.20 (2d,
ax
ax
eq
eq
eq
J = 13.2), 4.82 (dd, J = 6.3, 13.2) and 5.04 (2H, d, J = 13.2, COCH O-7′), 6.08-6.25 (2H, m, H-3, H-5), 6.78 and 6.92 (1H, 2s,
2
H-6′), 7.20-7.35 (1H, m, H-4), 7.56 (1H, s, H-9′).
N-[([6-Oxo-7,8,9,10-tetrahydrobenzo[c]chromen-3-yl]oxy)acetyl]cytisine (28). Yield84%, C H N O , mp157-
26 26
2 5
159°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.70-1.85 (4H, m, CH -8′, CH -9′), 1.90-2.08 (2H, m, CH -8),
6
2
2
2
2.41 (2H, m, CH -10′), 2.54 (1H, m, H-9), 2.75 (2H, m, CH -7′), 2.90 (1H, m, H-11 ), 3.18 (1H, m, H-7), 3.32 and 3.47 (1H,
2
2
ax
2d, J = 13.2, H-13 ), 3.62-3.71 (1H, m, H-10 ), 3.80-4.02 (2H, m, H-10 , H-13 ), 4.36 and 4.52 (1H, 2d, J = 13.2, H-11 ),
ax
ax
eq
eq
eq
4.21 (2d, J = 13.2), 4.67 (dd, J = 6.3, 13.2) and 4.91 (2H, d, J = 13.2, COCH O-3′), 6.10 and 6.28 (1H, 2d, J = 6.3, H-5), 6.22
2
(1H, d, J = 6.3, H-3), 6.47 and 6.76 (1H, 2dd, J = 2.4, 8.7, H-2′), 6.67 and 6.81 (1H, d, J = 2.4, H-4′), 7.24-7.36 (1H, m, H-4),
7.43 and 7.48 (1H, 2d, J = 8.7, H-9′).
136

N-[([4-Methyl-6-oxo-7,8,9,10-tetrahydrobenzo[c]chromen-3-yl]oxy)acetyl]cytisine (29). Yield83%,C H N O ,
27 28
2 5
mp 219-220.5°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.70-1.85 (4H, m, CH -8′, CH -9′), 1.90-2.08 (2H, m, CH -8),
6
2
2
2
2.17 and 2.20 (3H, 2s, CH -4′), 2.41 (2h, m, CH -10′), 2.54 (1H, m, H-9), 2.74 (2H, m, CH -7′), 2.89 (1H, m, H-11 ), 3.18
3
2
2
ax
(1H, m, H-7), 3.35 and 3.47 (1H, 2d, J = 13.2, H-13 ), 3.65-3.76 (1H, m, H-10 ), 3.80-4.09 (2H, m, H-10 , H-13 ), 4.35
ax
ax
eq
eq
and 4.51 (1H, 2d, J = 13.2, H-11 ), 4.26 (2d, J = 13.2), 4.72 (dd, J = 6.3, 13.2) and 5.03 (2H, d, J = 13.2, COCH O-3′), 6.05-
eq
2
6.41 (3H, m, H-3, H-5, H-8′), 7.22-7.32 (2H, m, H-4, H-9′).
N-[([2-Chloro-6-oxo-7,8,9,10-tetrahydrobenzo[c]chromen-3-yl]oxy)acetyl]cytisine (30).
C H ClN O , mp 275.5-277°C.
Yield 84%,
26 25
2 5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.68-1.85 (4H, m, CH -8′, CH -9′), 1.90-2.08 (2H, m, CH -8),
6
2
2
2
2.41 (2H, m, CH -10′), 2.54 (1H, m, H-9), 2.73 (2H, m, CH -7′), 2.91 (1H, m, H-11 ), 3.18 (1H, m, H-7), 3.38 and 3.47 (1H,
2
2
ax
2d, J = 13.2, H-13 ), 3.65-3.76 (1H, m, H-10 ), 3.82-3.99 (2H, m, H-10 , H-13 ), 4.35 and 4.51 (1H, 2d, J = 13.2, H-11 ),
ax
ax
eq
eq
eq
4.26 (2d, J = 13.2), 4.72 (dd, J = 6.3, 13.2) and 5.01 (2H, d, J = 13.2, COCH O-3′), 6.08-6.26 (3H, m, H-3, H-5), 6.72 and 6.85
2
(1H, 2s, H-6′), 7.22-7.36 (2H, m, H-4), 7.61 (1H, s, H-9′).
N-[([7-Methyl-4-oxo-1,2,3,4-tetrahydrocyclopenta[c]chromen-9-yl]oxy)acetyl]cytisine (31).
C H N O , mp 207-209°C.
Yield 78%,
26 26
2 5
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.90-2.08 (4H, m, CH -8, CH -2′), 2.31 (3H, br.s, CH -7′), 2.54
6
2
2
3
(1H, m, H-9), 2.65 (2H, m, CH -1′), 2.90 (1H, m, H-11 ), 3.20 (3H, m, H-7, CH -3′), 3.34 and 3.48 (1H, 2d, J = 13.2, H-13 ),
2
ax
2
ax
3.60-3.70 (1H, m, H-10 ), 3.80-4.05 (2H, m, H-10 , H-13 ), 4.31 and 4.48 (1H, 2d, J = 13.2, H-11 ), 4.18 (2d, J = 13.2),
ax
eq
eq
eq
4.77 (dd, J = 6.3, 13.2) and 4.98 (2H, d, J = 13.2, COCH O-9′), 6.11-6.22 (2H, m, H-3, H-5), 6.26 and 6.50 (1H, 2d, H-8′), 6.79
2
(1H, s, H-6′), 7.26-7.35 (1H, m, H-4).
N-[([3-Methyl-6-oxo-7,8,9,10-tetrahydrobenzo[c]chromen-1-yl]oxy)acetyl]cytisine (32). Yield74%, C H N O ,
27 28
2 5
mp 148-150°C.
PMR spectrum (300 MHz, DMSO-d , δ, ppm, J/Hz): 1.60-1.80 (4H, m, CH -8′, CH -9′), 1.90-2.05 (2H, m, CH -8),
6
2
2
2
2.28 and 2.30 (3H, 2s, CH -3′), 2.39 (2H, m, CH -10′), 2.54 (1H, m, H-9), 2.90-3.15 (3H, m, H-11 , CH -7′), 3.20 (1H, m,
3
2
ax
2
H-7), 3.34 and 3.46 (1H, 2d, J = 13.2, H-13 ), 3.60-3.72 (1H, m, H-10 ), 3.80-4.05 (2H, m, H-10 , H-13 ), 4.35 and 4.53
ax
ax
eq
eq
(1H, 2d, J = 13.2, H-11 ), 4.18 (d, J = 13.2), 4.73 (dd, J = 6.3, 13.2) and 4.96 (2H, d, J = 13.2, COCH O-1′), 6.08-6.18 (2H,
eq
2
m, H-3, H-5), 6.19 and 6.41 (1H, 2s, H-2′), 6.66 (1H, s, H-4′), 7.22-7.31 (1H, m, H-4).
ACKNOWLEDGMENT
We thank OAO "Eximed" (Kiev, Ukraine) for assistance in performing this work.
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