Synthesis of 1-azolylcytizines [7]

Full text of DOI:10.1007/s10593-007-0109-7

Chemistry of Heterocyclic Compounds, Vol. 43, No. 5, 2007
SYNTHESIS OF 1-AZOLYLCYTIZINES
M. A. Demina, N. P. Belskaia, and V. A. Bakulev
Keywords: amidines, 1,2,3-triazole, cytisine, oxidation.
Heterocyclic derivatives of the natural alkaloid cytisine are of interest for medicinal chemistry as
potential cholinomimetics [1]. We have for the first time synthesized a heterocyclic esembles, containing in the
molecules not only cytisine, but also 1,2,3-triazole and thiazole rings. By the reactions of
arylhydrazonomalonodinitrile 1 with cytisine we obtained 3-substituted cytisine 2, which, on heating in pyridine
in the presence of copper(II) acetate, was oxidized to 3-(1,2,3-triazol-4-yl)cytisine 3.
H
Ar
N
CN
Ar
N
CN
CN
CN
Cyt
N
Cu(OAc)2
N
H2S
N
Ar
N
Cyt
N
H2N
1
3
2
O
N
Br
Ar
CSNH2
Cyt
N
N
Ar
S
N
5
Ar
Ar
N
N
N
Cyt
4
6
N
Ar = 4-Cl–C6H4
Cyt =
N
O
Subsequent modification of the nitrile groups in thioamide and cyclization in ethanol with
bromoacetophenone 5 led to the formation of 5-[thiazol-2-yl(1,2,3-triazol-4-yl]cytisine 6.
1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded with a Bruker
DRX-400 (400 MHz) instrument.
3-Amino-2-(4-chlorophenylhydrazono)-3-(8-oxo-1,5,6,8-tetrahydro-2H,4H-1,5-methanopyrido-
[1,2-a][1,5]diazocin-3-yl)acrylnitrile (2). Arylhydrazone 1 (0.613 g, 3.0 mmol) and cytisine (0.741 g,
3.9 mmol) in EtOH (30 ml) were stirred for 3 h at 60°C. The mixture was cooled and the precipitate was filtered
1
off. Yield 1.11 g (93%), mp 170-171°C. H NMR spectrum, δ, ppm (J, Hz): 2.00 and 2.11 (2H, AB, J =15.0,
CH2); 2.61 (1H, s, CH); 3.24 (1H, s, CH); 3.41 (1H, d, J = 15.0, CH); 3.56 (1H, dd, J = 13.0, J = 12.7, CH);
__________________________________________________________________________________________
Ural State Technical University, 620002 Ekaterinburg, Russia; e-mail: belska@htf.ustu.ru. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, 794-795, May, 2007. Original article submitted December
23, 2006.
0009-3122/07/4305-0671©2007 Springer Science+Business Media, Inc.
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3.69 (1H, dd, J = 15.5, J = 14.3, CH); 4.02 (1H, m, CH); 4.31 (1H, d, J = 13.5, CH); 4.42 (1H, d, J = 15.7, CH),
6.12 (1H, dd, J = 6.5, J = 1.0, CH); 6.21 (1H, dd, J = 9.0, J = 1.0, CH); 7.25 (1H, dd, J = 9.0, J = 6.5, CH);
7.25 and 7.43 (4H, AA'XX', J = 8.8, H Ar); 7.41 (2H, s, NH2). Found, %: C 60.78; H 5.15; Cl 8.98; N 21.40.
C20H21ClN6O. Calculated, %: C 60.53; H 5.33; Cl 8.93; N 21.18.
2-(4-Chlorophenyl)-5-(8-oxo-1,5,6,8-tetrahydro-2H,4H-1,5-methanopyrido[1,2-a][1,5]diazocin-3-yl)-
2H-1,2,3-triazole-4-carbonitrile (3). Compound 2 (0.75 g, 2.0 mmol) and copper(II) acetate (6.6 mmol) in
pyridine (30 ml) were stirred at 60°C for 3 h, added to water, and the precipitate was filtered off. Yield 0.53 g
1
(67%), mp 172-173°C. H NMR spectrum, δ, ppm (J, Hz): 2.04 (2H, s, CH2); 2.66 (1H, s, CH); 3.32 (3H, m,
CH); 3.78 (1H, dd, J = 15.0, J =14.0, CH); 4.1 (3H, m, 3CH); 6.16 (2H, d, J = 7.5, H Ar); 7.27 (1H, dd, J = 7.5,
J = 8.0, CH); 7.51 and 7.87 (4H, AA'XX', J = 8.5, H Ar). Found, %: C 61.33; H 4.16; Cl 9.26; N 21.54.
C20H17ClN6O. Calculated, %: C 61.15; H 4.36; Cl 9.02; N 21.39.
2-(4-Chlorophenyl)-5-(8-oxo-1,5,6,8-tetrahydro-2H,4H-1,5-methanopyrido[1,2-a][1,5]diazocin-3-yl)-
2H-[1,2,3]triazole-4-carbothioamide (4). Hydrogen sulfide was passed through a solution of triazole 3 (0.8 g,
20 mmol) in dry pyridine (10 ml) and TEA (0.8 ml) for 2 h. The mixture was poured into 1 N HCl (50 ml). The
precipitate was filtered off. Yield 0.76 g (89%), mp 144-145°C. 1H NMR spectrum, δ, ppm (J, Hz): 1.96 (2H, s,
CH2); 2.57 (1H, s, CH); 3.10 (3H, m, 3CH); 3.75 (2H, m, 2CH); 4.16 (1H, d, J = 11.3, CH); 4.30 (1H, d,
J = 15.5, CH); 6.10 (1H, d, J = 6.8, CH); 6.19 (1H, d, J = 6.8, CH); 7.27 (1H, dd, J = 7.0, J = 9.0, CH); 7.47 and
7.94 (4H, AA'XX', J = 8.5, H Ar); 9.21 (1H, s, CSNH2); 9.68 (1H, s, CSNH2). Found, %: C 56.35; H 4.56,
Cl 8.54; N 19.49. C20H19ClN6OS. Calculated, %: C 56.27; H 4.49; Cl 8.30; N 19.68.
3-{2-(4-Chlorophenyl)-5-[4-(4-chlorophenyl)thiazol-2-yl]-2H-1,2,3-triazol-4-yl}-1,2,3,4,5,6-hexa-
hydro-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (6). Thioamide
4
(0.086 g, 0.2 mmol) and
bromoacetophenone 5 (0.047 g, 0.2 mmol) in EtOH (20 ml) were boiled for 3 h. The solvent was evaporated and
the residue was recrystallized. Yield 0.088 g (78%), mp 164-165°C (EtOH). 1H NMR spectrum, δ ppm (J, Hz):
2.0 (2H, s, CH2); 2.55 (1H, s, CH); 2.95 (1H, d, J = 11.3, CH); 3.28 (1H, s, CH); 3.32 (1H, d, J =15.5, CH); 3.93
(2H, m, CH); 4.44 (2H, m, CH); 6.20 (1H, d, J = 6.8, CH); 6.34 (1H, d, J = 9.2, CH); 7.29 (1H, dd, J = 9.0,
J = 7.0, 2CH), 8.00 (1H, s, CH), 7.53 and 8.04 (4H, AA'XX', J = 9.0, H Ar); 7.49 and 7.93 (4H, AA'XX', J = 8.8,
H Ar). Found: C 60.12, H 4.06, Cl 12.52, N 15.19. Calculated for C28H22Cl2N6OS, %: C 59.90, H 3.95, Cl 12.63,
N, 14.97.
This work was carried out with the support of the RFFI (grant No.04-03-32926a).
REFERENCE
1.
C. C. Boido, B. Tasso, V. Boido, and F. Sparatore, Il Farmaco, 58, 265 (2003).
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