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

Synthesis, Structure, and Biological Activity of Cinnamoyl-Containing Cytisine

and Anabasine Alkaloids Derivatives

O. A. Nurkenov^a*, Zh. S. Nurmaganbetov^{a, b}, T. M. Seilkhanov^c, S. D. Fazylov^a, Zh. B. Satpayeva^a, K. M. Turdybekov^d, S. A. Talipov^e, and R. B. Seydakhmetova^f

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

d E.A. Buketov Karaganda State University, Karaganda, Kazakhstan

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 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 [6, 7]. The interaction of cytisine with cinnamoyl chloride 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.

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

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 75 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 confi rmed by the data of IR spectroscopy, NMR spectroscopy [¹Н, ¹³С, COSY (¹H–¹H), and HMQC (¹H–¹³C)], and X-ray diffrac- tion analysis (for N-cynnamoylanabasine 1). IR spectra of compounds 1 and 2 contained the absorption band of the amide carbonyl at 1648 and 1643 cm^–1, respectively. The

1Н NMR data suggested the presence of several rotamers (with respect to the N–СО и СО –СН=СН–С₆Н₅ bonds) 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.

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Let us consider the ¹Н NMR spectrum of compound 1 in more detail. It contained the signals of piperidine ring as multiplets at 1.30–1.42 (1Н, Н^11ax), 1.54–1.57 (2H, Н^11eq,10ax), 2.36–2.46 (1H, Н^12ax), and 3.43–3.46 (1H, Н^9ax) ppm and broadened singlets at 1.79 (1H, H^10eq), 2.87 (1H, H^12eq), 4.22 (1H, H^9eq), and 5.87 (1H, Н⁷) ppm. The unsaturated aliphatic protons Н¹⁵ and Н¹⁶ were manifested as a multiplet at 7.56–7.69 ppm. The aromatic phenyl and pyridine protons resonated as multiplets at 7.30–7.34 (5H, Н5,18,19,21,22), 7.56–7.69 (2H, Н^4,20), and 8.44–8.47 (2H, Н^2,6) ppm.

13С NMR spectrum of compound 1 contained the signals of the piperidine ring atoms at 19.72 (С¹¹), 26.19 (С¹⁰), 27.61 (С¹²), 48.23 (С⁹), and 49.84 (С⁷) ppm. The at- oms of the phenyl and pyridine fragments were observed at 124.13 (С⁵), 128.58 (С³), 128.80 (С²⁰), 129.23 (С^19,21), 130.05 (С^18,22), 134.92 (С⁴), 135.68 (С¹⁷), 148.28 (С⁶), and 148.65 (С²) ppm. The signals at 118.83 and 142.68 ppm were assigned to the carbon atoms at the double bond:

С¹⁵ and С¹⁶, respectively. A weak-fi eld signal at 166.27 ppm was assigned to the carbonyl group carbon (С¹³).

The structure of compound 1 was further confi rmed by means of two-dimensional ¹H–¹³C 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:

Н¹¹/С¹¹ (1.56, 20.37), Н¹⁰/С¹⁰ (1.60, 26.65), Н¹²/С¹² (2.34, 28.02), Н⁹/С⁹ (4.24, 42.78), Н⁷/С⁷ (5.90, 50.36), Н⁵/С⁵ (7.31, 124.58), Н18,19,20,21,22/С18,19,20,21,22 (7.28, 129.33),

Spatial structure of N-cymmanoylanabasine 1 was 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 confi rmed 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 of N⁷-methylanabasine [13].

At the same time, the conformation of the piperidine ring in compound 1 was close to the ideal chair [ΔС_S⁹ = 1.1° and ΔС₂^7,8 = 1.1° (max)], whereas it was somewhat distorted in compound 3 due to the presence of a bulkier substituent [ΔС_S⁸ = 2.7° (max) и ΔС₂^8,9 = 2.8° (max)]. The N⁷ atom in the molecule of compound 3 took pyramidal confi guration (sum of bond angles 328.2°).

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- tion was observed in compound 1 as well (the H⁸···H¹⁴ contact 1.88 Å, sum of the van der Waals radii being N

NH

N O

NH

ClCHC=HC

NCHC=HC

N

O

O

10 9 11

12 8 7

3

2 1

4 5 6

13 15 16 17 22 21

20 18 19

1

N O

NCHC=HC O

17 18 19

20 22 21 12 14 15 16

14

11 15a 13 6 7

89 1 10 2 4 3

16a 5

2 Scheme 1.

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to conjugation of the p-orbitals of the С¹³=С and С¹³=О¹ double bonds. Moreover, the conjugation of the C¹³=О¹ double bond and the lone-electron pair of the N⁷ atom was observed (mesomeric effect). The latter interaction led to the change in the pyramidal confi guration of the N⁷ atom into the planar-trigonal one (sun of bond angles 359.8°), and the piperidine ring conformation was sig- nifi cantly distorted [ΔС_S⁹ = 3.9° (max) and ΔС₂^8,9 = 4.1°

(max)]. It should be noted that the O¹, C¹³, N⁷, C⁸, C¹², C¹⁴, and C¹⁵ atoms in compound 1 were located almost in the same plane (±0.02 Å) due to the π-conjugation and mesomeric effect.

1Нand 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 downfi eld shift of the signals of compound 2 in comparison with derivative 1. For example, the Н¹⁵ and Н¹⁶ olefi nic protons of the cinnamoyl moiety appeared at 6.49–6.75 and 7.16–

7.64 ppm, respectively, in the spectrum of compound 2, whereas the spectrum of compound 1 contained those signals at 7.56–7.69 ppm. The same effect was observed for the С¹³ carbonyl atoms: they were assigned to the signals at 166.27 ppm (compound 1) and 165.65 ppm (compound 2).

Fig. 1. Correlations in the HMQC spectrum of compound 1. Fig. 2. General view of compound 1 molecule in the crystal.

N

N N NH

8 7 6

9

10 11 18 19 20

23 22

21 2 1

4 5 12 17 16 13 15

14

3

N O

N

7 17 15 16

18

10 9 11 13 12

14

N_{2 1} NH

4 5 19 20 21 24 22

23 3

3

6

8

4

NH₂NH₂·H₂O EtOH, tq

1, 2

Scheme 2.

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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.

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).

Compounds 5 and 6 were white crystalline solids exhibit- ing moderate solubility in organic solvents. Structure and purity of compounds 5 and 6 were confi rmed by means of IR and ¹Н NMR spectroscopy as well as thin-layer chro- matography. IR spectra of compounds 5 and 6 contained an absorption band at 1465 and 1550 cm^–1, characteristic of the C=S group. Absorption bands of the amide group were observed at 1691 and 1689 cm^–1. IR spectrum of compound

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).

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.

In summary, we prepared novel N-cinnamoyl and pyrazole derivatives of anabasine and cytisine and in- Scheme 3.

N

NH

N O

NH

S=C=NCHC=HC

NCNHCHC=HC

N

10 9 11

12 8 7

3 2 4 1

5 6

20 21 22

23 25 24

5

N O

NCNHCHC=HC

14 2 12 10 11

13 5 4 6 8 7

16 9

6

O

S

O

14

17 15 16 18 19

S

O

15

3 19

17 18 20 21 22 23 24

25 27 26 13

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Compound S. aureus B. subtilis E. coli С. Аlbicans

1 18±0.2 14±0.2 20±0.1 20±0.2

2 12 ±0.2 – 16 ±0.1 14±0.1

3 17±0.1 13±0.2 18±0.2 20±0.1

4 14±0.1 – 13±0.2 –

5 – – 11±0.1 13±0.2

6 – – 12±0.2 –

Gentamycin 24 ± 0.1 21± 0.1 26± 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

Compound с, μg/mL Number of alive larva, run

LD₅₀, μg/mL

1 2 3

1 1 9 9 9 62.18

10 7 6 8

100 4 4 5

2 1 10 8 9 –

10 9 7 7

100 4 5 5

3 1 9 8 8 59.36

10 6 6 7

100 4 4 5

4 1 10 8 8 –

10 6 7 7

100 6 4 4

5 1 10 10 10 –

10 10 9 9

100 8 8 7

6 1 9 9 9 –

10 8 7 8

100 8 7 8

DMSO 1 10 10 10 930.27

10 10 9 9

100 8 8 9

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EXPERIMENTAL

1Н and ¹³С NMR spectra were recorded using a JNN- ECA Jeol 400 spectrometer (399.78 and 100.53 MHz, respectively) in DMSO-d₆. The reaction progress and 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 : 4); development in iodine vapor]. The products were isolated via recrystallization or column chromatography on alumina. The solvents were purifi ed and dried via conventional procedures [22].

X-ray diffraction analysis. Unit cell parameters and intensity of 2745 refl ections (2148 of them being inde- pendent, R_int = 0.0285) were measured using an Xcalibur Ruby diffractometer (Oxford Diffraction) (CuK_α, graphite monochromator, ω-scanning, 5.60° ≤ θ ≤ 76.05°) at 293 K.

Crystals of compound 1 were monoclinic, C₁₉H₂₀N₂O, unit cell parameters: a = 8.213(1) Å, b = 9.895(1) Å, c = 10.4238(9) Å, β = 106.03(1)^o, V = 814.3(2) ų, Z = 2, space group P2₁, d_calc = 1.192 g/cm³, μ = 0.582 mm^–1. The raw data processing (including account- ing for absorbance) was performed using CrysAlisPro software [23]. The structure was solved via direct method.

The positions of non-hydrogen atoms were refi ned via full-matrix least squares method under anisotropic ap- proximation. The hydrogen atoms were placed in the geometry-calculated positions and refi ned under isotropic approximation with fi xed position and heat parameters (the rider model). Confi guration of the molecule was cor- related with the known absolute confi guration of anaba- sine hydrochloride and hydroiodite [14]. The calculations used 1229 independent refl ections with I ≥ 2σ(I), refi ning 200 parameters. Final divergence factors: R₁ = 0.0535, wR₂ = 0.1051 [over refl ections with I ≥ 2σ(I)], R₁ = 0.1020, wR₂ = 0.1347 (over all refl ections), GooF = 1.015. Re- sidual electron density peaks: Δρ = 0.101 and –0.100 е/ų. The structure was solved and refi ned using SHELXS [24]

and SHELXL-2018.3 [25] software. The X-ray diffraction data were deposited at the Cambridge Crystallographic Data Centre (CCDC 1905735).

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 150 mL of benzene. The reaction mixture was stirred during 3 h at room temperature until the precipitate for-

was purifi ed by chromatography on alumina (eluents:

benzene or 100 : 1 benzene–ethyl acetate). Yield 3.9 g (75%), white crystals, mp 96–98°С. ¹Н NMR spectrum, δ, ppm (J, Hz): 1.30–1.42 m (1Н, H^11ax), 1.54–1.57 (2H, H^11eq,10ax), 1.79 br. s (1Н, Н^10eq), 2.36–2.46 m (1Н, Н^12ax), 2.87 br. s (1Н, Н^12eq), 3.43-3.46 m (1Н, Н^9ax), 4.22 br. s (1Н, Н^9eq), 5.87 br. s (1Н, Н⁷), 7.30–7.34 m (5Н, Н5,18,19,21,22), 7.56–7.69 m (4Н, Н^4,15,16,20), 8.4–8.47 m (2Н, Н^2,6). ¹³С NMR spectrum, δ_C, ppm: 19.72 (С¹¹), 26.19 (С¹⁰), 27.61 (С¹²), 48.23 (С⁹), 49.84 (С⁷), 118.83 (С¹⁵), 124.13 (С⁵), 128.58 (С³), 128.80 (С²⁰), 129.23 (С^19,23), 130.05 (С^18,22), 134.92 (С⁴), 135.68 (С¹⁷), 142.68 (С¹⁶), 148.28 (С⁶), 148.65 (С²), 166.7 (С¹³).

N-Cinnamoylcytisine (2) was prepared similarly 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.

1Н NMR spectrum, δ, ppm (J, Hz): 1.86–1.97 m (2Н, Н^8,8), 2.44 br. s (1Н, Н⁹), 2.90–3.40 m (3Н. Н7,11ax,13ax), 3.63–3.97 m (2Н, Н^10ax,10eq), 4.24–4.65 m (2Н, Н^11eq,13eq), 6.14 d (2Н, Н^3,5, ³J = 6.1), 6.49–6.75 m (1Н, Н¹⁵), 7.16–7.64 m (7Н, Н^4,15,18–22). ¹³С NMR spectrum, δ_C, ppm: 25.95 (С⁸), 27.86 (С⁹), 35.13 (С⁷), 49.05 (С¹⁰), 51.31 (С¹¹), 53.04 (С¹³), 105.29 (С⁵), 116.40 (С³), 128.85 (С¹⁵), 129.24 (С18,19,21,22), 129.99 (С²⁰), 135.55 (С⁴), 139.09 (С¹⁶), 141.32 (С¹⁷), 150.47 (С⁶), 162.66 (С²), 165.65 (С¹⁴). ¹H–¹³C HMQC NMR spectrum, ppm:

Н⁸/С⁸ 1.96/26.60, Н⁹/С⁹ 2.44/28.48, Н⁷/С⁷ 3.13/35.65, Н^10ax/С^10ax 3.59/49.56, Н^10ax/С^10ax 3.98/49.58, Н⁵/С⁵ 6.14/105.76, Н³/С³ 6.12/116.82, Н18,19,21,22/С18,19,21,22

7.37/129.52).

3-[1-(5-Phenyl-4,5-dihydro-1H-pyrazol-3-yl)- 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 residue was dissolved in 300 mL of СHCl₃, washed with water (3×60 mL), and dried over MgSO₄. The solvent was evaporated under reduced pressure, and the residue was purifi ed by chromatography on alumina (eluents: benzene and 100 : 1 benzene–chloroform). Yield 2.1 g (87%), yellow-green oil. ¹Н NMR spectrum, δ, ppm: 1.31–1.52 m (1Н, Н^9ax), 1.53–1.61 m (3Н, Н8ах,10ах,9eq), 1.70–1.88 m (1Н, Н^8eq), 2.18–2.40 m (1Н, Н^10eq), 2.76–2.84 m (2Н, Н^4ах,7ах), 2.96–2.98 m (1Н, Н^7eq), 3.58–3.65 m

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8.40–8.50 m (2Н, Н ). С NMR spectrum, δ_C, ppm:

19.43 (С⁹), 25.93 (С⁸), 26.96 (С¹⁰), 42.12 (С¹¹), 42.14 (С⁴), 49.01 (С⁷), 70.49 (С⁵), 126.29 (С^14–16), 127.58 (С^15,21), 128.61 (С13,17,19,23), 134.60 (С13,17,22,23), 141.20 (С¹⁸), 141.22 (С¹²), 148.61 (С^19,21). ¹H–¹H COSY NMR spectrum, ppm: Н^4ах/Н⁵ 2.76/5.16 and 5.16/2.75, Н^13,17/ Н^14,16 7.34/7.16 and 7.16/7.34, Н^21,23/Н²² 8.39/7.34 and 7.34/8.39. ¹H–¹³C HMQC NMR spectrum, ppm: Н^4ах/С⁴ 2.75/42.19, Н^4eq/С⁴ 3.64/42.19, Н⁵/С⁵ 5.20/70.38, Н^8ax/С⁸ 1.53/25.86, Н^8eq/С⁸ 1.73/25.86, Н^9ax/С⁹ 1.37/ 19.54, Н^9eq/ С⁹ 1.61/19.54, Н^10eq/С¹⁰ 2.25/26.85, Н¹¹/С¹¹ 3.58/42.12, Н²²/С²² 7.34/134.83.

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, mp 123–125°С. ¹Н NMR spectrum, δ, ppm: 1.87–1.99 m (2Н, Н¹⁸), 2.25–3.33 m (6Н, Н^4,7,8,16), 3.58–4.63 m (5Н, Н^5,9,17), 6.11–6.20 m (2Н, Н^12,14), 6.97–7.64 m (7Н, Н^1,13,20–24). ¹³С NMR spectrum, δ_С, ppm: 25.80 (С¹⁸), 27.52 (С⁸), 33.76 (С¹⁶), 34.79 (С⁴), 48.75 (С⁹), 49.18 (С⁷), 51.21 (С¹⁷), 52.82 (С⁵), 105.27 (С¹⁴), 116.31 (С¹²), 126.32 (С²²), 128.51 (С^21,23), 129.25 (С^20,24), 139.30 (С¹³), 141.62 (С¹⁹), 150.19 (С¹⁵), 162.64 (С³), 170.85 (С¹¹). ¹H–¹³C NMR spectrum HMQC, ppm: Н¹⁸/С¹⁸ 1.88/26.44, Н⁸/С⁸ 2.44/28.40, Н¹⁶/С¹⁶ 2.52/34.62, Н⁷/ С⁷ 2.74/48.79, Н⁴/С⁴ 3.10/34.89, Н⁵/С⁵ 4.22/53.55, Н¹⁷/ С¹⁷ 4.43/51.92, Н⁹/С⁹ 4.53/48.45, Н¹⁴/С¹⁴ 6.15/105.77, Н¹²/С¹² 6.21/117.00, Н^21,23/С^21,23 7.09/129.08, Н²²/ С²² 7.12/126.67, Н^20,24/С^20,24 7.32/129.32, Н¹³/С¹³ 7.28/139.80.

3-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; fi ne precipitate was fi ltered off, washed with small amount of diethyl ether, and recrystallized from isopropanol. Yield 2.82 g (80.4%), white powder, mp 150–151°С. ¹Н NMR spectrum, δ, ppm (J, Hz): 0.99–1.00 m (1Н, Н^10ax), 1.31–1.34 m (1Н, Н^11ax), 1.44–1.65 m (2Н, Н^10eq,11eq), 1.88–2.00 m (1Н, Н^12ах), 2.52–2.55 m (1Н, Н^12eq), 3.00–3.05 m (1Н, Н^9ax), 3.73–3.87 m (1Н, Н^9eq), 6.72 br. s (1Н, Н⁷), 6.87 d (1Н, Н¹⁸, ³J = 16.0), 7.39 br. s (4Н, Н^5,22–24), 7.58 d (2Н, Н^21,25, ³J = 6.4),

7.65 d (1Н, Н , J = 15.6), 7.86 br. s (1Н, Н ), 8.47 d (1Н, Н⁶, ³J = 4.1), 8.66 br. s (1Н, Н²), 10.85 br. s (1Н, Н¹⁵). ¹³С NMR spectrum, δ_С, ppm: 18.99 (С¹¹), 26.02 (С¹⁰), 27.49 (С¹²), 48.27 (С⁹), 59.00 (С⁷), 120.80 (С¹⁸), 124.11 (С⁵), 128.49 (С^21,25), 129.60 (С^22,24), 130.83 (С²³), 133.35 (С²⁰), 134.89 (С⁴), 134.93 (С³), 143.27 (С¹⁹), 148.52 (С²), 148.65 (С⁶), 162.64 (С¹⁶), 181.61 (С¹³). ¹H–¹³C NMR spectrum HMQC, ppm: Н^10ax/С¹⁰ 1.00/26.67, Н^11ax/С¹¹ 1.28/19.67, Н^11eq/С¹¹ 1.55/19.70, Н^10eq/С¹⁰ 1.55/26.80, Н^12ax/С¹² 1.90/28.20, Н^12eq/С¹² 2.57/28.11, Н^9ax/С⁹ 3.03/48.86, Н^9eq/С⁹ 3.91/48.87, Н⁷/ С⁷ 6.74/59.48, Н¹⁸/С¹⁸ 6.90/121.09, Н⁵/С⁵ 7.39/124.50, Н^22–24/С^22–24 7.40/130.11, Н^21,25/С^21,25 7.58/128.91, Н⁴/ С⁴ 7.87/135.37, Н¹⁹/С¹⁹ 7.68/143.50, Н⁶/С⁶ 8.47/148.93, Н²/С² 8.54/148.93.

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 2.32 g (61.3%), white crystals, mp 177–178°С (ben- zene). ¹Н NMR spectrum, δ, ppm (J, Hz): 1.84–1.87 m (1Н, Н³), 2.47 br. s (1Н, Н^13ax), 2.65 br. s (1Н, Н^13eq), 3.12 br. s (1Н, Н¹¹), 3.28 br. s (1Н, Н^2ax), 3.36–3.38 m (1Н, Н^2eq), 3.57–3.61 m (1Н, Н^12ax), 3.79–3.88 m (1Н, Н^4ax), 3.98–4.01 m (1Н, Н^12eq), 4.22–4.25 m (1Н, Н^4eq), 6.08–6.10 m (1Н, Н⁹), 6.18–6.20 m (1Н, Н⁷), 6.68–6.79 m (1Н, Н²⁰), 7.32–7.53 m (7Н, Н^8,21,23–26), 10.53 br.

s (1Н, Н¹⁷). ¹³С NMR spectrum, δ_С, ppm: 25.31 (С³), 28.90 (С¹³), 35.47 (С¹¹), 48.41 (С⁴), 55.45 (С²), 58.68 (С¹²), 105.08 (С⁹), 116.95 (С⁷), 120.86 (С²⁰), 128.43 (С^23,27), 128.85 (С^24,26), 129.57 (С²⁵), 130.79 (С²²), 139.36 (С⁸), 142.85 (С²¹), 149.42 (С¹⁰), 161.97 (С⁶), 162.70 (С¹⁸), 180.65 (С¹⁴). ¹H–¹³C HMQC NMR spec- trum, ppm: Н³/С³ 1.87/25.98, Н^13ax/С¹³ 2.47/29.50, Н^13eq/ С¹³ 2.66/29.50, Н¹¹/С¹¹ 3.12/36.12, Н²/С² 3.36/56.72, Н^12ax/С¹² 3.53/59.30, Н^4ax/С⁴ 3.84/49.34, Н^12eq/С¹² 3.98/57.98, Н^4eq/С⁴ 4.24/49.34, Н⁹/С⁹ 6.09/105.49, Н⁷/ С⁷ 6.20/117.26, Н²⁰/С²⁰ 6.74/121.45, Н⁸/С⁸ 7.26/139.76, Н^23–27/С^23–27 7.32/129.27, Н²¹/С²¹ 7.52/142.

FUNDING

This study was fi nancially supported by the Committee for Science, Ministry of Education and Science of Kazakhstan (PTsF no. BR05236438-OT-18).

CONFLICT OF INTEREST No confl ict of interest was declared by the authors.

Buketov

University

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Buketov

University