Synthesis of dithiocarbamine derivatives on the matrix of cytisine, anabasine and d-pseudoephedrine alkaloids. Crystalline structure of N-cytisine dithiocarbamate ammonium salt

Article abstract of DOI:10.1134/S1070363209080234

On the matrix of physiologically active alkaloids such as cytisine, anabasine, and d-pseudoephedrine the simplest alkaloid dithiocarbamates ammonium salts were synthesized by reaction with carbon disulfide in solution of ammonia in alcohol. Spatial struct

Full text of DOI:10.1134/S1070363209080234

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 8, pp. 1716–1719. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © I.V. Kulakov, O.A. Nurkenov, A.A. Ainabayev, D.M. Turdybekov, K.M. Turdybekov, 2009, published in Zhurnal Obshchei Khimii,
2009, Vol. 79, No. 8, pp. 1356–1359.
Synthesis of Dithiocarbamine Derivatives on the Matrix
of Cytisine, Anabasine and d-Pseudoephedrine Alkaloids.
Crystalline Structure
of N-Cytisine Dithiocarbamate Ammonium Salt
I. V. Kulakova, O. A. Nurkenova, A. A. Ainabayeva,
D. M. Turdybekovb, and K. M. Turdybekovb
a Institute of Organic Synthesis and Coal Chemistry of Republic of Kazakhstan,
ul. Alikhanova 1, Karaganda, 100008 Kazakhstan
e-mail: kulakov_iv@mail.ru
b
Phytochemistry Scientific Production Centre, Karaganda, Kazakhstan
Received November 13, 2008
Abstract—On the matrix of physiologically active alkaloids such as cytisine, anabasine, and d-
pseudoephedrine the simplest alkaloid dithiocarbamates ammonium salts were synthesized by reaction with
carbon disulfide in solution of ammonia in alcohol. Spatial structure of ammonium N-cytisine dithiocarbamate
crystal hydrate was proved with X-ray diffraction analysis.
DOI: 10.1134/S1070363209080234
Among the wide class of sulfur-containing
compounds an important role belongs to the acids
dithiocarbamine derivatives. Interest in these com-
pounds is caused by their great usability [1]. Acids
dithiocarbamine derivatives possess antifungal,
antibacterial, insecticide, fungicide and other practical
important properties [2–5].
ephedrine alkaloids was reported earlier [6].
To continue the work on the synthesis of new
dithiocarbamine derivatives on the basis of cytisine,
anabasine, and d-pseudoephdrine alkaloids, we
obtained the alkaloid dithiocarbamates simple am-
monium salts. Dithiocarbamine derivatives I–III were
produced by reaction of alkaloids with carbon disulfide
in ethanol saturated with ammonia.
Synthesis of dithiocarbamates on the matrix of
S
NH3
+
_
NH + CS2
C
N
NH4
S
_
I III
7
9
5
4
3
OH
CH
6
8
3
N
8
2
1
5
2
=
(I),
(II), C6H5
9
CH3
(III).
CH
HN
N
N
6
1
4
N CH3
7
N
O
The target products yields are 60–70%. Compounds
I–III synthesized are crystalline substances soluble in
polar solvents. Composition and structure of I–III was
proved by elemental analysis and 1Н NMR
spectroscopy. Compound I forms crystal hydrate with
three water molecules.
Aiming to confirm spatial structure and also to
continue studying cytisine stereochemistry, we
performed X-ray diffraction analysis of the obtained
salt: ammonium N-cytisine dithiocarbamate crystalline
hydrate I. General view of compound I is shown in
Fig. 1.
1716

SYNTHESIS OF DITHIOCARBAMINE DERIVATIVES
1717
O3w
N1'
O1w
S2
C3
C4
C11
C5
C13
C6
C7
C2
N12
C10
S1
C1
N1
C8
O1
C9
O2w
Fig. 1. Structure of ammonium N-cytisinodithiocarbamate crystallohydrate molecule I.
Bond lengths and bond angles in cytisine frame are
close to the standard (Tables 1–3) [7] except for bond
angles at N12 atom. Thus, in N-methylcytisine and N-
cyanomethylcytisine molecules studied earlier [8, 9]
coordination of the atom N12 is pyramidal (sum of
bond angles is 335.7°, 334.0°), whereas in the
molecule I coordination is planar-trigonal (sum of
bond angles is 359.3°), same as in acrylic acid N-
cytisinylamide molecule (sum of bond angles is 360°).
Distinction in the nitrogen atom coordination in the N-
methylcytisine and N-cyanomethylcytisine on the one
hand, and in compound I and acrylic acid N-
Тable 1. Bond lengths (d, Å) for molecule I
Тable 2. Bond angles (ω, grad) for structure I
Bond
d, Å
Bond
d, Å
Angle
ω, deg
Angle
ω, deg
C6N1C2
C6N1C10
C2N1C10
O1C2C3
O1C2N1
C3C2N1
C4C3C2
C3C4C5
C6C5C4
C5C6N1
C5C6C7
N1C6C7
C6C7C8
C6C7C13
121.9(14)
124.5(13)
113.4(14)
123.5(17)
119.8(16)
116.7(19)
121.5(18)
121.4(18)
120.1(18)
118.2(15)
126.0(16)
115.7(14)
115.1(14)
110.7(14)
C8C7C13
C9C8C7
112.0(15)
103.5(14)
114.3(14)
109.6(15)
111.0(14)
112.7(13)
107.9(13)
123.1(15)
122.5(16)
113.9(14)
106.4(13)
119.7(14)
120.2(15)
120.1(10)
S1–C14
1.69(2)
C6–C7
1.45(2)
S2–C14
O1–C2
N1–C6
1.72(18)
1.28(2)
1.39(2)
C7–C8
C7–C13
C8–C9
1.51(2)
1.58(2)
1.51(3)
C8C9C11
C8C9C10
C11C9C10
N1C10C9
N12C11C9
C14N12C13
C14N12C11
C13N12C11
N12C13C7
N12C14S1
N12C14S2
S1C14S2
N1–C2
N1–C10
C2–C3
C3–C4
1.41(2)
1.49(2)
1.38(3)
1.32(3)
C9–C11
C9–C10
C11–N12
N12–C14
1.55(2)
1.56(2)
1.51(2)
1.35(2)
C4–C5
C5–C6
1.40(3)
1.35(2)
N12–C13
1.46(2)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 8 2009

1718
KULAKOV et al.
Тable 3. Torsion angles (τ, grad) for molecule I
distribution between molecules in the crystal
arrangement (Fig. 2).
Angle
τ, deg
Angle
τ, deg
C6N1C2O1
C10N1C2O1
C6N1C2C3
179.7(1)
3(2)
C13C7C8C9
C7C8C9C11
C7C8C9C10
C6N1C10C9
C2N1C10C9
C8C9C10N1
C11C9C10N1
C8C9C11N12
C10C9C11N12
C9C11N12C14
C9C11N12C13
C14N12C13C7
C11N12C13C7
C6C7C13N12
C8C7C13N12
C13N12C14S1
C11N12C14S1
C13N12C14S2
C11N12C14S2
62.6(2)
–60.0(2)
65.3(2)
8(2)
Dihydropyridine ring in the structure I is planar
within ±0.005Å accuracy, carbonyl atom О1 lies
practically in this plane (divergence from this plane is
0.06Å). Tetrahydropyridine ring N1C5C6C7C8C9 takes
the conformation of distorted sofa with the bridgehead
С7 atom withdrawn from the mean plane of the other
ring atoms by 0.76 Å. Piperidine ring takes the dis-
torted chair conformation.
–2(3)
C10N1C2C3 –179.5(2)
O1C2C3C4
N1C2C3C4
C2C3C4C5
C3C4C5C6
C4C5C6N1
C4C5C6C7
C2N1C6C5
C10N1C6C5
C2N1C6C7
C10N1C6C7
C5C6C7C8
N1C6C7C8
C5C6C7C13
N1C6C7C13
C6C7C8C9
–178.2(2)
4(3)
–175.1(1)
–39.8(2)
87.5(2)
56.7(2)
–67.9(2)
133.0(1)
–55.6(2)
–130.2(1)
58.4(2)
66.4(2)
–63.5(2)
–172.7(1)
–2(2)
–3(4)
Thus, by reaction of cytisine, anabasine and d-
pseudoephedrine with carbon disulfide the new
alkaloid ammonium salts were first synthesized and
characterized. Structure and composition of the
thiocarbamate derivatives were confirmed with
1(3)
1(3)
–177.6(2)
0(2)
1
elemental analysis, X-ray diffraction and Н NMR
176.7(2)
178.7(1)
–4(2)
spectroscopy data.
EXPERIMENTAL
1
The Н NMR spectra were registered on a Bruker
–147.0(2)
34(2)
DRX500 device (500 МHz) in DMSO–d6 relative to
internal ТМS. Melting points were determined on a
Boetius device. Reaction progress and purity of
compounds obtained were monitored by TLC on
Sorbfil plates, eluent benzene-acetone, 1:1, detecting
agent was iodine vapor.
85(2)
–93.9(2)
–65.0(2)
8(2)
178.2(1)
cytisinylamide on the other hand, is caused by
mesomeric effect, i.e. electron density delocalization
of S1 and N12 atoms occurs. The latter leads to the
increase of bond angles at the nitrogen atom, to
lengthening of S=О (C=O) bond and to shortening of
C–N bond relative to the standard values.
Single crystal X-ray diffraction analysis. The unit
cell parameters and intensities of 2564 reflections were
measured on a Bruker P4 automatic four-circle diffrac-
tometer (λMoKα radiation, graphite monochromator).
The crystals are monoclinic, а 24.20(3), b 9.047(1), c
7.454(1) Å, β 102.26(9)o, V 1595(4)Å3, Z 4
(C15H20N2OS), dcalc1.401 g сm–3, space group C2.
The presence of ammonium ion in the structure I
out the field of electronegative charge of dithio-
carbamate fragment is explained by the overall charge
In the calculation we used 1499 independent
reflections with I > 2σ. The structure was solved by the
N1'
O3w
O1w
O2w
O1w
O3w
O2w
N1'
N1'
O3w
O3w
O1w
O1w
O2w
N1'
Fig. 2. Molecule I crystal arrangement.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 8 2009

SYNTHESIS OF DITHIOCARBAMINE DERIVATIVES
1719
1
direct method and refined by the least-squares method
in the full-matrix anisotropic approximation for non-
hydrogen atoms. All the H atoms are geometrically
placed by the rider type, except the hydroxyl hydrogen
atoms at the О1 and О2 atoms, which were refined in
the anisotropic approximation. The final values of the
divergence factors are R 0.1316 and wR2 0.3364. All
the calculations were performed using the SHELX-97
program package.
disulfide. Yield 0.71 g (69.3%), mp 167–168оС. Н
NMR spectrum, δ, ppm: 0.98 d (3Н, СН3–СН, J
5.1 Hz), 2.85 s (3Н, N–CH3), 3.55 m (1Н, СНN), 4.75
d (1Н, СНО, J 3.5 Hz), 7.28 m (5Н, НAr). Found, %: C
50.68; H 6.54; N 10.31; S 25.13. C11H18N2OS2.
Calculated, %: C 51.13; H 7.02; N 10.84; S 24.82.
REFERENCES
1. Byr’ko, V.M., Ditiokarbamaty (Dithiocarbamates),
N-Cytisinodithiocarbamate ammonium salt
crystalline hydrate (I). 95% ethanol was saturated
with ammonia for 3 h. To this solution was added 1 g
(0.005 mol) of cytisine and then 0.4 g (0.005 mol) of
carbon disulfide was added at gentle cooling (10°С).
Further the reaction mixture was stirred at room
Moscow: Nauka, 1984, p. 342.
2. Mel’nikov, N.N., Proizvodnye tio- i ditiokarbaminovykh
kislot (Thio- and Dithiocarbamine Acids Derivatives),
Moscow: Khimiya, 1960, p. 195.
3. Mel’nikov, N.N., Uspekhi
v
oblasti izucheniya
pesticidov (Pesticides Study Advances), Moscow:
Khimiya, 1962, p. 137.
temperature for
7 h. Then the solvent was removed
and the residue was recrystallized from ethanol. Yield
1.03 g (73.6%), mp 169–170°С. 1Н NMR spectrum, δ ,
ppm: 2.00 m (2Н, Н5), 2.54 br.s (1Н, Н6), 3.35 br.s
(1Н, Н4), 3.50 m (2Н, Н8), 3.60 m (2Н, Н7), 4.20 m
(2Н, Н9), 6.15 d [1Н, Н3, J(Н3Н2) 6.85 Hz], 6.25 d
[1Н, Н1, J(Н1Н2) 9.0 Hz], 7.35 d.d [1Н, Н2, J(Н2Н3)
6.85 Hz]. Found, %: C 50.29; H 5.87; N 14.25; S
22.91. C12H17N3OS2 (anhydrous salt). Calculated, %: C
50.85; H 6.05; N 14.83; S 22.63.
4. Mel’nikov, N.N., Pesticidy. Khimiya, tekhnologiya i
primenenie (Pesticides. Chemisty, Technology, and
Applicaition), Moscow: Khimiya, 1987, p. 712.
5. Korablev, M.V., Proizvodnye ditiokarbaminovykh
kislot. Khimiya, toksikologiya, farmakologiya
i
klinicheskoye primeneniye (Dithiocarbamine Acids
Derivatives. Chemistry, Toxicology, Pharmacology, and
Clinical Use), Minsk: Belarus’, 1971, p. 152.
6. Turdybekov, D.M., Isabayeva, M.B., Turdybekov, K.М.,
Nurkenov, О.А., Ibrayev, М.K., and Gazaliev, А.М.,
Zh. Obshch. Khim., 2005, vol. 75, no. 7, p. 1202.
N-Anabasinodithiocarbamate ammonium salt
(II) was prepared similarly from 1 g (0.006 mol) of
anabasine and 0.45 g (0.006 mol) of carbon disulfide.
7. Allen, F.H., Kennard, O., Watson, D.G., Brammer, L.,
Orpen, A.G., and Taylor, R., J. Chem. Soc. Perkin
Trans. 2, 1987, p. 19.
1
Yield 0.95 g (62.1%), 175–176оС. Н NMR spectrum,
δ, ppm: 1.37–2.05 m (6Н, Н6, Н7, Н8), 2.60 m (2Н,
Н9), 3.04 t (1Н, Н5), 7.47 d.d (1Н, Н2), 8.0 d (1Н, Н3),
8.50 s (1Н, Н4), 8.71 d [1Н, Н1, J(Н1Н2) 5.0 Hz].
Found, %: C 52.14; H 6.94; N 16.81; S 25.50.
C11H17N3S2. Calculated, %: C 51.73; H 6.71; N 16.45;
S 25.11.
8. Freer, A.A., Robins, D.J., and Sheldrake, G.N., Acta
Cryst., 1987, vol. 43, p. 1119.
9. Nurkenov, О.А., Gazaliev, А.М., Shalbayeva, А.B.,
Turdybekov, K.М., Zhurinov, М.Zh., and Aubakiro-
va, А., Zh. Obshch. Khim., 1999, vol. 69, no. 4, p. 675.
10. Turdybekov, D.M., Ibrayev, М.K., Fazylov, S.D.,
Turdybekov, K.М., Gazaliev, А.М., Zhurinov, M.Zh.,
Kudaibergenova, S.Zh., Zh.Org. Khim., 2004, vol. 73,
no. 5, p. 752.
N-D-Pseudoephedrinodithiocarbamate ammonium
salt (III) was prepared similarly from 0.66 g (0.004 mol)
of d-pseudoephedrine and 0.3 g (0.004 mol) of carbon
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 8 2009