Synthesis, Structure, and Biological Activity of Cinnamoyl-Containing Cytisine and Anabasine Alkaloids Derivatives

Article abstract of DOI:10.1134/S1070363219100098

The reactions of the cytisine and anabasine alkaloids with cinnamic acid chloride have been studied, and hydrazinolysis of the resulting N-cinnamoylcytisine and N-cinnamoylanabazine has been carried out. The reaction of cinnamoyl isothiocyanate with alkal

Full text of DOI:10.1134/S1070363219100098

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 10, pp. 2044–2051. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 10, pp. 1550–1559.
Synthesis, Structure, and Biological Activity
of Cinnamoyl-Containing Cytisine
and Anabasine Alkaloids Derivatives
a
a, b
c
a
O. A. Nurkenov *, Zh. S. Nurmaganbetov , T. M. Seilkhanov , S. D. Fazylov ,
a
d
e
f
Zh. B. Satpayeva , K. M. Turdybekov , S. A. Talipov , and R. B. Seydakhmetova
a
Institute of Organic Synthesis and Coal Chemistry of the Republic of Kazakhstan,
ul. Alikhanova 1, Karaganda, 100008 Kazakhstan
*
e-mail: nurkenov_oral@mail.ru
b
Karaganda State Medical University, Karaganda, Kazakhstan
c
Sh. Ualikhanov Kokshetau State University, Kokshetau, Kazakhstan
E.A. Buketov Karaganda State University, Karaganda, Kazakhstan
d
e
A.S. Sadykov Institute of Bioorganic Chemistry, Academy of Sciences of the Republic of Uzbekistan, Tashkent, Uzbekistan
f
International Research and Production Holding “Phytochemistry”, Karaganda, Kazakhstan
Received April 5, 2019; revised April 5, 2019; accepted April 12, 2019
Abstract―The reactions of the cytisine and anabasine alkaloids with cinnamic acid chloride have been studied, and
hydrazinolysis of the resulting N-cinnamoylcytisine and N-cinnamoylanabazine has been carried out. The reaction
of cinnamoyl isothiocyanate with alkaloids has afforded the corresponding thiourea derivatives.Antimicrobial and
cytotoxic activity of cinnamoyl-containing derivatives of these alkaloids has been evaluated.
Keywords: cytisine, anabasine, N-cinnamoylcytisine, N-cinnamoylanabasine, cinnamoyl chloride
DOI: 10.1134/S1070363219100098
The interest to the study of chemical transformations
formed N-cymmanoylcytisine and N-cynnamoylanaba-
sine.Acylation of the alkaloids was performed in benzene
in the presence of triethylamine at room temperature.
The interaction occurred smoothly and afformed the
derivatives of anabasine (1) and cytisine (2) with yield
of alkaloids cytisine and anabasine has been inspired
by wide range of biological activity of their derivatives.
Many derivatives of cytisine and anabasine bearing dif-
ferent substituents at the nitrogen atom [1–3] including
the acryloyl groups [4] have been prepared. It has been
shown that the substitution of the N–H hydrogen atom
with an acyl group results in the decrease in toxicity and
appearance of other peculiar biological properties [5].
Many cinnamoyl derivatives have been recommended as
drugs for the treatment or prevention of arterial and/or
venous thrombosis, acute coronary syndrome, restenosis,
stable pectoris, cardiac rhythm disturbance, myocar-
dial infarction, hypertensia, heart failure, and apoplexy
7
5 and 95%, respectively (Scheme 1). The synthesized
compounds 1 and 2 were white crystalline compounds
readily soluble in organic solvents.
The structure of compounds 1 and 2 was confirmed by
1
13
the data of IR spectroscopy, NMR spectroscopy [ Н, С,
1
1
1
13
COSY( H– H), and HMQC ( H– C)], and X-ray diffrac-
tion analysis (for N-cynnamoylanabasine 1). IR spectra of
compounds 1 and 2 contained the absorption band of the
–1
amide carbonyl at 1648 and 1643 cm , respectively. The
Н NMR data suggested the presence of several rotamers
1
[
6, 7]. The interaction of cytisine with cinnamoyl chloride
(
with respect to the N–СО и СО– СН=СН–С Н bonds)
6 5
in toluene has been reported [8]; the product has been
obtained in low yield (45%). The preparation of a similar
derivative of anabasine has not been reported.
in solutions of N-cynnamoylanabasine 1 and N-cynnam-
oylcytisine 2. Since the rotation barriers were low, they
could result either to the appearance of the spectra signals
assignable to several conformers or to the lines broadening.
In certain cases, that did not allow unambiguous assignment
of the signals.
To extend the range of reactions on cytisine and anaba-
sine N-acylation, we investigated their interaction with
cinnamoyl chloride and further transformations of the
2
044

SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF CINNAMOYL-CONTAINING CYTISINE 2045
Scheme 1.
1
0
9
22 21
18 19
1
3
15
16
1
7
8
7
1
1
NꢀCꢀHC=HC
20
O 14
1
2
3
2
ClꢀCꢀHC=HC
N 1
N
4
H
O
5
6
N
O
1
1
8 19
NH
13
1
2 14 15
NꢀCꢀHC=HC
16
5
17
7
6
20
4
N
8
9
O
15a
22 21
3
2
N
11
1
1
0
O 16a
2
1
Let us consider the Н NMR spectrum of compound 1
Spatial structure of N-cymmanoylanabasine 1 was
in more detail. It contained the signals of piperidine ring
as multiplets at 1.30–1.42 (1Н, Н ), 1.54–1.57 (2H,
elucidated by means of X-ray diffraction analysis. General
view of the molecule is shown in Fig. 2. Bond lengths
and bond angles in the compound 1 were close to usual
ones [11]. As is seen from Fig. 2, the pyridine ring in
the molecule of compound 1 was in axial orientation
with respect to the piperidine one. The X-ray diffraction
analysis data for anabasine hydroiodite [12] have shown
that anabasine cation takes a single conformation: the
piperidine cycle in the chair conformation with equatorial
orientation of the pyridine ring. This has been confirmed
by means of molecular mechanics simulation. The sub-
stitution of the N–H hydrogen of the piperidine ring with
bulkier methyl group has not changed the conformation
11ax
1
1eq,10ax
12ax
Н
), 2.36–2.46 (1H, Н ), and 3.43–3.46 (1H,
9ax
10eq
Н ) ppm and broadened singlets at 1.79 (1H, H ),
9eq
7
2
.87 (1H, H12eq), 4.22 (1H, H ), and 5.87 (1H, Н )
15
16
ppm. The unsaturated aliphatic protons Н and Н were
manifested as a multiplet at 7.56–7.69 ppm. The aromatic
phenyl and pyridine protons resonated as multiplets at
.30–7.34 (5H, Н
.44–8.47 (2H, Н ) ppm.
5
,18,19,21,22
4,20
7
8
), 7.56–7.69 (2H, Н ), and
2
,6
1
3
С NMR spectrum of compound 1 contained the
11
signals of the piperidine ring atoms at 19.72 (С ), 26.19
10
12
9
7
(
С ), 27.61 (С ), 48.23 (С ), and 49.84 (С ) ppm. The at-
7
of N -methylanabasine [13].
oms of the phenyl and pyridine fragments were observed
5
3
20
19,21
at 124.13 (С ), 128.58 (С ), 128.80 (С ), 129.23 (С
),
At the same time, the conformation of the piperidine
1
1
30.05 (С1 ), 134.92 (С ), 135.68 (С ), 148.28 (С ), and
8,22
4
17
6
ring in compound 1 was close to the ideal chair [ΔС =
9
S
2
7,8
48.65 (С ) ppm. The signals at 118.83 and 142.68 ppm
1.1° and ΔС2 = 1.1° (max)], whereas it was somewhat
were assigned to the carbon atoms at the double bond:
distorted in compound 3 due to the presence of a bulkier
15
16
8
8,9
С and С , respectively. A weak-field signal at 166.27
substituent [ΔС = 2.7° (max) иΔС = 2.8° (max)]. The
S 2
1
3
7
ppm was assigned to the carbonyl group carbon (С ).
N atom in the molecule of compound 3 took pyramidal
configuration (sum of bond angles 328.2°).
The structure of compound 1 was further confirmed
1
13
by means of two-dimensional H– C HMQC NMR
spectroscopy revealing the heteronuclear spin-spin inter-
actions. The observed correlations are shown in Fig. 1.
Heteronuclear interactions of the protons with the adja-
cent carbon atoms were revealed for the following atoms:
The unusual orientation of the pyridine ring with
respect to the piperidine one revealed in compound 1
has been earlier observed in the structure of anabasino-
N-ethylthiocarbamide and has been ascribed to the steric
hindrance between the ethylaminothiocarbonyl group and
the pyridine ring [14]. Fairly strong van der Waals interac-
1
1
11
10 10
12 12
Н /С (1.56, 20.37), Н /С (1.60, 26.65), Н /С (2.34,
9
9
7
7
5
5
8
14
2
(
8.02), Н /С (4.24, 42.78), Н /С (5.90, 50.36), Н /С
tion was observed in compound 1 as well (the H ···H
contact 1.88 Å, sum of the van der Waals radii being
1
8,19,20,21,22 18,19,20,21,22
7.31, 124.58), Н
/С
(7.28, 129.33),
1
5
15
4
4
16 16
7
13
Н /С (7.60, 119.22), Н /С (7.55, 135.27), Н /С
2.32 Å [15]). However, the rotation about the N –C
bond did not lead to more favorable conformation, due
2
,6 2,6
(
7.56, 143.13), and Н /С (8.45, 148.86).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

2046
NURKENOV et al.
Fig. 1. Correlations in the HMQC spectrum of compound 1.
Fig. 2. General view of compound 1 molecule in the crystal.
1
3
13
1
1
1Н and 13С chemical shifts of the cinnamoyl frag-
ments bound to the anabasine and cytisine moieties were
similar. Slight predominance of the mesomeric effect of
the cytisine fragment led to small downfield shift of the
signals of compound 2 in comparison with derivative
to conjugation of the p-orbitals of the С =С and С =О
1
3
double bonds. Moreover, the conjugation of the C =О
7
double bond and the lone-electron pair of the N atom
was observed (mesomeric effect). The latter interaction
led to the change in the pyramidal configuration of the
N atom into the planar-trigonal one (sun of bond angles
59.8°), and the piperidine ring conformation was sig-
nificantly distorted [ΔС = 3.9° (max) and ΔС = 4.1°
max)]. It should be noted that the O , C , N , C , C ,
C , and C atoms in compound 1 were located almost
in the same plane (±0.02 Å) due to the π-conjugation and
mesomeric effect.
1
5
16
1
. For example, the Н and Н olefinic protons of the
cinnamoyl moiety appeared at 6.49–6.75 and 7.16–
.64 ppm, respectively, in the spectrum of compound 2,
7
3
7
9
8,9
S
2
whereas the spectrum of compound 1 contained those
1
13
7
8
12
(
signals at 7.56–7.69 ppm. The same effect was observed
14
15
13
for the С carbonyl atoms: they were assigned to the
signals at 166.27 ppm (compound 1) and 165.65 ppm
(compound 2).
Scheme 2.
N 2 1 NH
7
3
17
5
6
4
12
8
9
16
N
1
9
1
3 15
18
20
N
11
1
0
1
4
2
1
2
3
NH ꢀNH ·H O
22
2
2
2
1
, 2
3
EtOH, tq
N2 1 NH
1
8
7
20
3
5
1
4
4
19
1
6
1
5
N6
21
1
3
1
2
2
2
4
1
2
11
N
7
1
0
8
23
9
O
4
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF CINNAMOYL-CONTAINING CYTISINE 2047
Scheme 3.
1
S
4
1
0
9
21 22
25 24
1
5
16
18 19
2
0
1
1
8
7
NꢀCꢀNHꢀCꢀHC=HC
23
13
O 17
1
2
2
3
N 1
4
S=C=NꢀCꢀHC=HC
N
5
6
H
5
O
N
O
1
S
5
NH
23 24
1
2
17
18
20 21
9
22
1
1
1
0
NꢀCꢀNHꢀCꢀHC=HC
25
N
8
1
3
14
2
7 26
7
6
N
2
O 19
3
5
4
O 16
6
Cyclocondensation of hydrazines with α,β-unsaturated
ketones is an important synthetic route to 1,2-azoles. Cer-
tain derivatives of pyrazoles can serve as analgesics and
inhibitors of platelet aggregation [16] and exhibit strong
antibacterial [17] or anaesthetic [18] effect.
and 6 contained the typical signals of the fragments in their
suggested structures.
To reveal the biological activity of the prepared al-
kaloids derivatives, we performed primary screening of
antimicrobial (Table 1) and cytotoxic (Table 2) effects of
compounds 1–6 (Table 1). The antimicrobial activity with
respect to Gram-positive (Staphylococus aureus, Bacillus
subtilis) and Gram-negative (Escherichia coli) strains as
well as Candida ablicans yeast fungus was assessed by
diffusion in agar. The reference drugs were Gentamycin
for the bacteria and Nystatin for C. ablicans. Antimicro-
bial activity of compounds 1–6 was determined from
the diameter of the growth suppression zones; each ex-
periment was performed in triplicate [19]. The cytotoxic
activity was determined during the in vitro cultivation
of the Artemia salina (Leach) larva [20, 21] (Table 2).
Further investigation of synthesis and biological activity
of the obtained N-cinnamoyl derivatives 1 and 2 involved
their interaction with hydrazine hydrate (Scheme 2). It
was found that the interaction of compounds 1 and 2 with
hydrazine hydrate in ethanol resulted in the formation of
the respective pyrazole derivatives 3 and 4, likely due
to intramolecular cyclocondensation of the hydrazones.
To extend the capacity of cytisine and anabasine
functionalization, it was interesting to obtain their novel
acyl derivatives via the interaction with cinnamoyl iso-
thiocyanate. The latter was synthesized via the reaction
between cinnamoyl chloride with potassium thiocyanate
in acetone at heating. The prepared cinnamoyl isothio-
cyanate reacted with anabasine and cytisine to afford the
respective derivatives 5 and 6 (Scheme 3).
The performed primary screening revealed moder-
ate antimicrobial activity of compounds 1 and 3 against
Gram-positive Staphylococcus aureus, Gram-negative
Escheriсhia coli, and Сandida albicans yeast fungus.
Compound 2 revealed moderate antibacterial activity
against the Gram-negative Escheriсhia coli strain. Com-
pounds 4–6 revealed weak antimicrobial activity against
the tested strains. Compounds 1 and 3 revealed moderate
cytotoxicity against Artemia salina (Leach) larva.
Compounds 5 and 6 were white crystalline solids exhibit-
ing moderate solubility in organic solvents. Structure and
purity of compounds 5 and 6 were confirmed by means of
1
IR and Н NMR spectroscopy as well as thin-layer chro-
matography. IR spectra of compounds 5 and 6 contained an
–1
absorption band at 1465 and 1550 cm , characteristic of
the C=S group. Absorption bands of the amide group were
In summary, we prepared novel N-cinnamoyl and
pyrazole derivatives of anabasine and cytisine and in-
vestigated their further chemical transformations into
potentially biologically active compounds.
–1
observed at 1691 and 1689 cm . IR spectrum of compound
contained a strong band of the cytisine amide group
6
–1 1
(N–C=O) at 1648 cm . Н NMR spectra of compounds 5
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

2048
NURKENOV et al.
Table 1. Antimicrobial activity of compounds 1–6а
Compound
S. aureus
18±0.2
12 ±0.2
17±0.1
14±0.1
–
B. subtilis
E. coli
20±0.1
16 ±0.1
18±0.2
13±0.2
11±0.1
12±0.2
26± 0.1
–
С. Аlbicans
20±0.2
14±0.1
20±0.1
–
1
14±0.2
2
–
3
13±0.2
4
–
5
–
13±0.2
–
6
–
–
21± 0.1
–
Gentamycin
24 ± 0.1
–
–
Nystatin
21 ± 0.2
a
“
–“ denotes the absence of the growth suppression zone. Diameter of the growth suppression zone less than 10 mm or its absence was
considered no antibacterial activity, diameter of the growth suppression zone of 10–15 mm was considered weak activity, diameter of the
growth suppression zone of 15–20 mm was considered moderate activity, diameter of the growth suppression zone more than 20 mm was
considered pronounced activity.
Table 2. Cytotoxicity of compounds 1–6
Number of alive larva, run
Compound
с, μg/mL
LD , μg/mL
50
1
9
2
9
3
9
1
1
62.18
1
0
7
6
8
1
1
1
1
1
1
1
00
1
4
4
5
2
10
9
8
9
–
1
0
00
1
7
7
4
5
5
3
9
8
8
59.36
1
0
00
1
6
6
7
4
4
5
4
10
6
8
8
–
1
0
00
1
7
7
6
4
4
5
6
10
10
8
10
9
10
9
–
–
1
0
00
1
8
7
9
9
9
1
0
00
1
8
7
8
8
7
8
DMSO
10
10
8
10
9
10
9
930.27
1
0
00
8
9
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF CINNAMOYL-CONTAINING CYTISINE 2049
EXPERIMENTAL
Н and С NMR spectra were recorded using a JNN-
was purified by chromatography on alumina (eluents:
benzene or 100 : 1 benzene–ethyl acetate). Yield 3.9 g
1
13
1
(
75%), white crystals, mp 96–98°С. Н NMR spectrum,
ECA Jeol 400 spectrometer (399.78 and 100.53 MHz,
δ, ppm (J, Hz): 1.30–1.42 m (1Н, H11ax), 1.54–1.57
respectively) in DMSO-d . The reaction progress and
6
11eq,10ax
10eq
(
Н
4
2H, H
), 1.79 br. s (1Н, Н ), 2.36–2.46 m (1Н,
), 2.87 br. s (1Н, Н ), 3.43-3.46 m (1Н, Н ),
purity of the products were monitored by thin-layer
chromatography on Silufol UV-254 plates [isopropa-
nol–ammonia–water (7 : 2 : 1) or ethanol–chloroform
1
2ax
12eq
9ax
9
eq
7
.22 br. s (1Н, Н ), 5.87 br. s (1Н, Н ), 7.30–7.34 m
(
5Н, Н5
,18,19,21,22
), 7.56–7.69 m (4Н, Н4,15,16,20), 8.4–8.47
(
1 : 4); development in iodine vapor]. The products were
2
,6 13
11
m (2Н, Н ). С NMR spectrum, δ , ppm: 19.72 (С ),
C
isolated via recrystallization or column chromatography
on alumina. The solvents were purified and dried via
conventional procedures [22].
1
0
12
9
7
2
6.19 (С ), 27.61 (С ), 48.23 (С ), 49.84 (С ), 118.83
С ), 124.13 (С ), 128.58 (С ), 128.80 (С ), 129.23
), 134.92 (С ), 135.68 (С ), 142.68
С ), 148.28 (С ), 148.65 (С ), 166.7 (С ).
1
5
5
3
20
(
(
(
С1 ), 130.05 (С
9,23
18,22
4
17
X-ray diffraction analysis. Unit cell parameters and
intensity of 2745 reflections (2148 of them being inde-
1
6
6
2
13
N-Cinnamoylcytisine (2) was prepared similarly
pendent, R = 0.0285) were measured using an Xcalibur
int
from 1.14 g (0.006 mol) of cytisine, 0.6 g (0.006 mol) of
triethylamine, and 1 g (0.006 моль) of cinnamoyl chlo-
ride. Yield 1.82 g (95%), white powder, mp 132–134°С.
Ruby diffractometer (Oxford Diffraction) (CuK , graphite
α
monochromator, ω-scanning, 5.60° ≤ θ ≤ 76.05°) at 293 K.
Crystals of compound 1 were monoclinic, C H N O,
1
9
20
2
1
Н NMR spectrum, δ, ppm (J, Hz): 1.86–1.97 m (2Н,
unit cell parameters: a = 8.213(1) Å, b = 9.895(1) Å,
8
,8
9
7,11ax,13ax
Н ), 2.44 br. s (1Н, Н ), 2.90–3.40 m (3Н. Н
),
),
o
3
c = 10.4238(9) Å, β = 106.03(1) , V = 814.3(2) Å ,
1
11eq,13eq
3
6
7
.63–3.97 m (2Н, Н 0ax,10eq), 4.24–4.65 m (2Н, Н
3
Z = 2, space group P2 , d
= 1.192 g/cm , μ =
.582 mm . The raw data processing (including account-
1
calc
3
,5
3
15
.14 d (2Н, Н , J = 6.1), 6.49–6.75 m (1Н, Н ),
–1
0
4
,15,18–22
). 13С NMR spectrum, δ ,
.16–7.64 m (7Н, Н
C
ing for absorbance) was performed using CrysAlisPro
software [23]. The structure was solved via direct method.
The positions of non-hydrogen atoms were refined via
full-matrix least squares method under anisotropic ap-
proximation. The hydrogen atoms were placed in the
geometry-calculated positions and refined under isotropic
approximation with fixed position and heat parameters
8
9
7
10
ppm: 25.95 (С ), 27.86 (С ), 35.13 (С ), 49.05 (С ),
5
1
1
13
5
3
1.31 (С ), 53.04 (С ), 105.29 (С ), 116.40 (С ), 128.85
1
5
18,19,21,22
20
4
(
С ), 129.24 (С
), 129.99 (С ), 135.55 (С ),
1
6
17
6
2
1
1
39.09 (С ), 141.32 (С ), 150.47 (С ), 162.66 (С ),
65.65 (С ). H– C HMQC NMR spectrum, ppm:
1
4
1
13
8
8
9
9
7
7
Н /С 1.96/26.60, Н /С 2.44/28.48, Н /С 3.13/35.65,
Н10ax/С10ax 3.59/49.56, Н10ax/С10ax 3.98/49.58, Н /С
6
7
5
5
(
the rider model). Configuration of the molecule was cor-
.14/105.76, Н /С 6.12/116.82, Н18,19,21,22/С
3
3
18,19,21,22
related with the known absolute configuration of anaba-
sine hydrochloride and hydroiodite [14]. The calculations
used 1229 independent reflections with I ≥ 2σ(I), refining
.37/129.52).
3-[1-(5-Phenyl-4,5-dihydro-1H-pyrazol-3-yl)-
2
00 parameters. Final divergence factors: R = 0.0535,
piperidin-2-yl]pyridine (3). 1.9 mL (39 mmol) of
hydrazine hydrate was added dropwise to a solution of
2.33 g (7.9 mol) of compound 1 in 100 mL of ethanol.
The reaction mixture was stirred during 1 h at 25°С and
7 h at 70–75°С, cooled to ambient, and evaporated. The
1
wR = 0.1051 [over reflections with I ≥ 2σ(I)], R = 0.1020,
wR = 0.1347 (over all reflections), GooF = 1.015. Re-
sidual electron density peaks:Δρ = 0.101 and –0.100 е/Å .
The structure was solved and refined using SHELXS [24]
and SHELXL-2018.3 [25] software. The X-ray diffraction
data were deposited at the Cambridge Crystallographic
Data Centre (CCDC 1905735).
2
1
2
3
residue was dissolved in 300 mL of СHCl , washed with
3
water (3×60 mL), and dried over MgSO . The solvent was
4
evaporated under reduced pressure, and the residue was
purified by chromatography on alumina (eluents: benzene
and 100 : 1 benzene–chloroform). Yield 2.1 g (87%),
N-Cinnamoylanabasine (1). 1.81 g (0.018 mol)
of triethylamine and a solution of 3.0 g (0.018 mol) of
cinnamoyl chloride in 50 mL of benzene were added at
stirring to a solution of 3 g (0.018 mol) of anabasine in
1
yellow-green oil. Н NMR spectrum, δ, ppm: 1.31–1.52
9
ax
8ах,10ах,9eq
m (1Н, Н ), 1.53–1.61 m (3Н, Н
), 1.70–1.88
m (1Н, Н8eq), 2.18–2.40 m (1Н, Н ), 2.76–2.84 m
10eq
1
50 mL of benzene. The reaction mixture was stirred
4
ах,7ах
7eq
during 3 h at room temperature until the precipitate for-
mation. Precipitate of triethylammonium chloride was
filtered off, the filtrate was evaporated, and the residue
(2Н, Н
(2Н, H
), 2.96–2.98 m (1Н, Н ), 3.58–3.65 m
4
eq,11
1
5
), 4.58 br. s (1Н, Н ), 5.12–5.21 m (1Н, Н ),
7.18–7.22 m (3Н, Н14–16), 7.25–7.37 m (4Н, Н13,17,22,23),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

2050
NURKENOV et al.
1
9,21 13
19
3
4
8
1
.40–8.50 m (2Н, Н
). С NMR spectrum, δ , ppm:
7.65 d (1Н, Н , J = 15.6), 7.86 br. s (1Н, Н ), 8.47 d
C
9
8
10
11
6
3
2
9.43 (С ), 25.93 (С ), 26.96 (С ), 42.12 (С ), 42.14
(1Н, Н , J = 4.1), 8.66 br. s (1Н, Н ), 10.85 br. s (1Н,
С ), 49.01 (С ), 70.49 (С ), 126.29 (С14–16), 127.58
4
7
5
15 13
11
(
(
(
Н ). С NMR spectrum, δ , ppm: 18.99 (С ), 26.02
С
1
5,21
13,17,19,23
13,17,22,23
С
), 128.61 (С
), 134.60 (С
), 141.20
10
12
9
7
18
(
1
(
(
(
1
С ), 27.49 (С ), 48.27 (С ), 59.00 (С ), 120.80 (С ),
18
12
19,21
1
1
С ), 141.22 (С ), 148.61 (С
). H– H COSY NMR
24.11 (С ), 128.49 (С21,25), 129.60 (С22,24), 130.83
5
spectrum, ppm: Н /Н 2.76/5.16 and 5.16/2.75, Н13,17/
4
ах
5
23
20
4
3
С ), 133.35 (С ), 134.89 (С ), 134.93 (С ), 143.27
Н14,16 7.34/7.16 and 7.16/7.34, Н
21,23
/Н 8.39/7.34 and
22
19
2
6
16
С ), 148.52 (С ), 148.65 (С ), 162.64 (С ), 181.61
1
13
4ах
4
7
2
1
.34/8.39. H– C HMQC NMR spectrum, ppm: Н /С
.75/42.19, Н /С 3.64/42.19, Н /С 5.20/70.38, Н /С
С ). H– C NMR spectrum HMQC, ppm: Н10ax/С10
13
1
13
4eq
4
5
5
8ax
8
.00/26.67, Н11ax/С 1.28/19.67, Н /С 1.55/19.70,
11
11eq 11
8eq
8
9ax
9
9eq
.53/25.86, Н /С 1.73/25.86, Н /С 1.37/ 19.54, Н /
Н10eq/С 1.55/26.80, Н /С 1.90/28.20, Н12eq/С12
10
12ax 12
9
10eq 10
11 11
С 1.61/19.54, Н /С 2.25/26.85, Н /С 3.58/42.12,
9
ax
9
9eq
9
7
2
.57/28.11, Н /С 3.03/48.86, Н /С 3.91/48.87, Н /
22
22
Н /С 7.34/134.83.
7
18 18
5
5
С 6.74/59.48, Н /С 6.90/121.09, Н /С 7.39/124.50,
Н22–24/С22–24 7.40/130.11, Н21,25/С21,25 7.58/128.91, Н4/
С 7.87/135.37, Н /С 7.68/143.50, Н /С 8.47/148.93,
Н /С 8.54/148.93.
3
-(5-Phenyl-4,5-dihydro-1H-pyrazol-3-yl)-3,4,5,6-
tetrahydro-1H-1,5-methanopyrido[1,2-a][1,5]diazo-
cinn-8(2H)-one (4) was prepared similarly from 0.33 g
1 mmol) of compound 2 and 0.50 mL (10 mmol) of
hydrazine hydrate. Yield 0.28 g (85.7%), yellow crystals,
4
19 19
6
6
2
2
(
N-Cytisino-3-carbonothioylphenylacrylamide (6)
was prepared similarly from 1.9 g (0.01 mol) of cytisine
and 2.07 g (0.011 mol) of cinnamoyl thiocyanate. Yield
.32 g (61.3%), white crystals, mp 177–178°С (ben-
zene). Н NMR spectrum, δ, ppm (J, Hz): 1.84–1.87 m
(1Н, Н ), 2.47 br. s (1Н, Н13ax), 2.65 br. s (1Н, Н13eq),
1
mp 123–125°С. Н NMR spectrum, δ, ppm: 1.87–1.99
m (2Н, Н ), 2.25–3.33 m (6Н, Н4,7,8,16), 3.58–4.63 m
18
2
(
Н
2
(
1
(
(
1
5Н, Н5,9,17), 6.11–6.20 m (2Н, Н12,14), 6.97–7.64 m (7Н,
1
1,13,20–24
). 13С NMR spectrum, δ , ppm: 25.80 (С ),
18
С
3
8
16
4
9
7.52 (С ), 33.76 (С ), 34.79 (С ), 48.75 (С ), 49.18
С ), 51.21 (С ), 52.82 (С ), 105.27 (С ), 116.31 (С ),
26.32 (С ), 128.51 (С
С ), 141.62 (С ), 150.19 (С ), 162.64 (С ), 170.85
11
2ax
7
17
5
14
12
3.12 br. s (1Н, Н ), 3.28 br. s (1Н, Н ), 3.36–3.38 m
(1Н, Н ), 3.57–3.61 m (1Н, Н12ax), 3.79–3.88 m (1Н,
2eq
2
2
21,23
20,24
), 129.25 (С
15
), 139.30
13
19
3
Н4ax), 3.98–4.01 m (1Н, Н12eq), 4.22–4.25 m (1Н, Н4eq),
11
1
13
18 18
9
7
С ). H– C NMR spectrum HMQC, ppm: Н /С
6.08–6.10 m (1Н, Н ), 6.18–6.20 m (1Н, Н ), 6.68–6.79
m (1Н, Н ), 7.32–7.53 m (7Н, Н8,21,23–26), 10.53 br.
s (1Н, Н17). 13С NMR spectrum, δ , ppm: 25.31 (С ),
28.90 (С ), 35.47 (С ), 48.41 (С ), 55.45 (С ), 58.68
(С ), 105.08 (С ), 116.95 (С ), 120.86 (С ), 128.43
С23,27), 128.85 (С24,26), 129.57 (С ), 130.79 (С ),
39.36 (С ), 142.85 (С ), 149.42 (С ), 161.97 (С ),
162.70 (С ), 180.65 (С ). H– C HMQC NMR spec-
trum, ppm: Н /С 1.87/25.98, Н /С 2.47/29.50, Н13eq/
8
8
16 16
7
20
.88/26.44, Н /С 2.44/28.40, Н /С 2.52/34.62, Н /
7
4
4
5
5
17
3
С 2.74/48.79, Н /С 3.10/34.89, Н /С 4.22/53.55, Н /
С
17
9
9
14 14
13
11
4
2
С 4.43/51.92, Н /С 4.53/48.45, Н /С 6.15/105.77,
Н /С 6.21/117.00, Н21,23/С21,23 7.09/129.08, Н /
С22 7.12/126.67, Н20,24/С20,24 7.32/129.32, Н /С
.28/139.80.
-Phenyl-N-(anabasinocarbonothioyl)acrylamide
5). A solution of 2.07 g (0.011 mol) of cinnamoyl
thiocyanate in 10 mL of acetone was added dropwise
at vigorous stirring to a solution of 1.62 g (0.01 mol) of
anabasine in 5 mL of acetone. The mixture was stirred
during 1 h at 30°С. The reaction progress was monitored
by TLC. After the reaction was complete, the mixture
was cooled; fine precipitate was filtered off, washed with
small amount of diethyl ether, and recrystallized from
1
2
12
22
12
9
7
20
13
13
25
22
(
1
7
8
21
10
6
1
8
14
1
13
3
3
3
13ax 13
(
1
3
11 11
2
2
С 2.66/29.50, Н /С 3.12/36.12, Н /С 3.36/56.72,
Н12ax/С12 3.53/59.30, Н4ax/С4 3.84/49.34, Н12eq/С12
4eq
4
9
9
7
3
.98/57.98, Н /С 4.24/49.34, Н /С 6.09/105.49, Н /
7
20 20
8
8
С 6.20/117.26, Н /С 6.74/121.45, Н /С 7.26/139.76,
Н23–27/С23–27 7.32/129.27, Н21/С21 7.52/142.
FUNDING
isopropanol. Yield 2.82 g (80.4%), white powder, mp
This study was financially supported by the Committee
1
1
50–151°С. Н NMR spectrum, δ, ppm (J, Hz): 0.99–1.00
for Science, Ministry of Education and Science of Kazakhstan
m (1Н, Н10ax), 1.31–1.34 m (1Н, Н11ax), 1.44–1.65 m
(
PTsF no. BR05236438-OT-18).
0eq,11eq
12ах
(
(
2Н, Н1
), 1.88–2.00 m (1Н, Н ), 2.52–2.55 m
1
2eq
9ax
1Н, Н ), 3.00–3.05 m (1Н, Н ), 3.73–3.87 m (1Н,
CONFLICT OF INTEREST
9eq
7
18 3
Н ), 6.72 br. s (1Н, Н ), 6.87 d (1Н, Н , J = 16.0),
.39 br. s (4Н, Н5,22–24), 7.58 d (2Н, Н21,25, 3J = 6.4),
7
No conflict of interest was declared by the authors.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

SYNTHESIS, STRUCTURE, AND BIOLOGICAL ACTIVITY OF CINNAMOYL-CONTAINING CYTISINE 2051
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019