Synthesis and structure of dithiocarbamates derived from ephedrine alkaloids

Article abstract of DOI:10.1007/s11176-005-0381-0

Products of the reactions of l-ephedrine and d-pseudoephedrine with saturated and unsaturated alkyl halides and carbon disulfide in the presence of triethylamine were obtained. Methyl N-l-ephedrinodithiocarbamate was studied by X-ray diffraction. 2005 Ple

Full text of DOI:10.1007/s11176-005-0381-0

Russian Journal of General Chemistry, Vol. 75, No. 7, 2005, pp. 1139 1141. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 7, 2005,
pp. 1202 1205.
Original Russian Text Copyright
2005 by D. Turdybekov, Isabaeva, K. Turdybekov, Nurkenov, Ibraev, Gazaliev.
Synthesis and Structure of Dithiocarbamates
Derived from Ephedrine Alkaloids
D. M. Turdybekov*, M. B. Isabaeva**, K. M. Turdybekov*,
O. A. Nurkenov**, M. K. Ibraev**, and A. M. Gazaliev**
* Institute of Phytochemistry, Ministry of Science and Education of Kazakhstan, Karaganda, Kazakhstan
** Institute of Organic Synthesis and Coal Chemistry of Kazakhstan, Karaganda, Kazakhstan
Received March 12, 2003
Abstract Products of the reactions of l-ephedrine and d-pseudoephedrine with saturated and unsaturated
alkyl halides and carbon disulfide in the presence of triethylamine were obtained. Methyl N-l-ephedrinodithio-
carbamate was studied by X-ray diffraction.
Derivatives of dithiocarbamic acids exhibit a broad- l-ephedrino(d-pseudoephedrino)dithiocarbamates
spectrum physiologic activity [1]. They were found to
act as fungicides, herbicides, insecticides, acaricides,
zoocides, nematocides, growth regulators, bactericides,
etc. Such dithiocarbamic acid derivatives as Carba-
thion, Cineb, Vegadex and Cyram, have found prac-
tical application in agriculture as pesticides.
III XII. The synthesis involved one stage, namely,
reaction of l-ephedin or d-pseudoephedrine with
carbon disulfide and organic halide in chloroform in
the presence of triethylamine. The reaction involves
intermediate formation of triethylammonium N-l-
ephedrino(d-pseudoephedrino)dithiocarbamate (I or
II, respectively) whose alkylation with alkyl halides
provides final products III XII.
Proceeding with search for biologically active
compounds among alkaloids, we have synthesized N-
C6H5
CH3
OH
N
CH
CH
OH
OH
C6H5
CH3
C6H5
S
CH
CH
CH
CH
+
C
S
SR
NH(C2H5)3
C
N
NH
CH3
OH
S
CH3
CS2, (C2H5)3N
CH3
III, V, VII, IX, XI
CH3
OH
RX
I
C6H5
C6H5
C6H5
OH
CH
CH
CH
CH
+
CH
CH
S
NH(C2H5)3
S
C
NH
CH3
C
N
S
CH3
CH3
N
SR
CH3
CH3
CH3
II
IV, VI, VIII, X, XII
R = CH3 (III, IV), C2H5 (V, VI), C3H7 (VII, VIII), CH2=CHCH2 (IX, X), CH CCH2 (XI, XII).
The IR spectra of compounds III XII have an
absorption band at 1240 1205 cm , characteristic of
(C10N1C8C7), and
(HO1C7C8) torsion angles
1
(Table 2) that characterize the molecular conformation
of ephedrine and its derivatives are 19.7 , 68.2 ,
86.2 , and 164.5 , respectively. All torsion angles,
except for , are close to the corresponding angles in
the C=S group, as well as absorption bands at 1635
1
1625 (VI, XI) and 2120 2100 cm (VII, XII),
assignable to C=C and C C vibrations.
ephedine hydrochloride (XIII) [3] ( 21.4 ,
170.0 , and 175.0 ) and ephedine thiocyanate
(XIV) [4] ( 23.6 , 62.2 , 161.9 , and
70.5 ,
Bond lengths and angles in molecule III are close
to normal [2]. The (C6C1C7O1), (O1C7C8N1),
1070-3632/05/7507-1139 2005 Pleiades Publishing, Inc.

1140
TURDYBEKOV et al.
Table 1. Yields, physicochemical constants, and elemental analyses of dithiocarbamates III XII
Found, %
Calculated, %
a
Comp. no. Yield, % mp,
C
n2D0
Rf
Formula
C
N
C
N
III
IV
V
VI
VII
VIII
IX
X
75
68
66
71
68
67
82
65
80
67
96 97
94 95
0.63
0.81
0.84
0.85
0.83
0.82
0.83
0.75
0.78
0.80
56.16
56.29
57.46
57.39
59.28
59.32
59.25
59.78
60.11
60.05
5.05
5.35
5.10
5.15
4.90
4.93
4.55
4.83
5.00
5.04
C12H17NOS2
C12H17NOS2
C13H19NOS2
C13H19NOS2
C14H21NOS2
C14H21NOS2
C14H19NOS2
C14H19NOS2
C14H17NOS2
C14H17NOS2
56.47
56.47
57.99
57.99
59.36
59.36
59.79
59.79
60.21
60.21
5.49
5.49
5.20
5.20
4.95
4.95
4.98
4.98
5.02
5.02
1.6041
1.6090
172 173
169 170
1.6061
1.6010
1.6012
1.6023
XI
XII
a
Eluent benzene acetone, 1:1.
161 ). The specified value of the angle in structure
III relates to such conformation along the C8 N1
bond, that favors strong nonbonded repulsion of the
methyl groups at C8 and N1 (C9 C10 distance 2.887 ).
Table 2. Torsion angles in structure III
Angle
, deg
Angle
, deg
C6C1C2C3
C7C1C2C3
C1C2C3C4
C2C3C4C5
C3C4C5C6
C4C5C6C1
C2C1C6C5
C7C1C6C5
C6C1C7O1
C2C1C7O1
C6C1C7C8
C2C1C7C8
C11N1C8C9
0.8(5)
179.1(3)
1.1(5)
C10N1C8C9
C11N1C8C7
C10N1C8C7
O1C7C8N1
C1C7C8N1
O1C7C8C9
C1C7C8C9
C10N1C11S2
C8N1C11S2
C10N1C11S1
C8N1C11S1
C12S1C11N1
C12S1C11S2
39.6(3)
90.4(3)
86.2(3)
68.2(2)
167.8(2)
56.9(3)
67.2(3)
4.3(4)
179.12(2)
174.9(2)
1.6(3)
178.1(3)
2.6(3)
O1
C10
N1
C9
1.1(6)
0.9(6)
0.6(5)
0.6(5)
S2
C6
C8
C5
C7
179.4(3)
19.7(4)
160.4(3)
101.5(3)
78.4(3)
143.8(3)
C11
C1
C4
S1
C2
C3
C12
Fig. 1. Molecular structure of methyl N-l-ephedrinodi-
thiocarbamate (III).
Actually, according to quantum-chemical calcula-
tions, three conformations along the C8 N1 bond are
possible ( 90 , 135 , and 295 , Fig. 2). The last
minimum is global and corresponds to anti orientation
of the C9H3 and C10H3 groups. The stabilization of
the energetically less favored conformer of molecule
III in crystal is explained by the formation of an
intermolecular H bond O1 S (x, y, z) [O1 S2 ( x,
242140
242150
242160
242170
242180
242190
1.5 + y, z)] (O S 3.243 , H S 2.34
,
OHS
161.5 ). The hydrogen bond stabilizes this conforma-
tion and form endless tapes along the 21 axis [0, 0, y]
(Fig. 3).
0
40 80 120 160 200 240 280 320 360
, deg
EXPERIEMNTAL
The IR spectra were obtained on a UR-20 instru-
ment in KBr. The melting point was measured on
a Boetius hot stage.
Fig. 2. Dependence of the total energy of molecule III
8
1
on coordinate along the C
N bond.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 7 2005

SYNTHESIS AND STRUCTURE OF DITHIOCARBAMATES
104, for hydrogen atoms 103) in structure III in cell fractions
1141
Table 3. Atomic coordinates (
Atom
x
y
z
Atom
x
y
z
S1
1633(1)
5101(1)
5517(3)
4837(3)
2370(3)
511(4)
743(4)
150(5)
1659(5)
9476(1)
11347(1)
4688(4)
8782(4)
4215(4)
4427(5)
3319(6)
1957(6)
1744(6)
3628(1)
4442(1)
2723(2)
2908(2)
2027(2)
2142(2)
1565(3)
877(3)
C6
2923(4)
3729(3)
3831(3)
4650(4)
6839(4)
4017(4)
953(7)
2850(5)
5466(4)
7470(4)
7452(5)
8849(6)
9823(4)
11110(8)
363(11)
1331(2)
2655(2)
2175(2)
1104(2)
2891(3)
3610(2)
4605(4)
316(5)
S2
C7
O1
N1
C1
C2
C3
C4
C5
C8
C9
C10
C11
C12
HO1
565(8)
761(3)
X-ray diffraction experiment. The unit cell
parameters and the intensities of 1712 unique reflec-
tions were measured on a Bruker-P4 (MoK radiation,
cally by the rider model. The calculations included
1659 reflections with I > 2 (I). Absorption correction
was performed using the -curves. The final diver-
gence factors were R 0.042 and RW 0.117. The struc-
ture was solved and refined by the SHELXS-97 and
SHELXL-97. The atomic coordinates are listed in
Table 3. The conformational calculations for methyl
N-l-ephedrinodithiocarbamate (III) were performed
using the MOPAC-7 program with full geometry
graphite monochromator, /2 scanning 2
Monoclinic crystals, a 3630(7), b 7.0084(7), c
12.8127(12)
93.620(8) , V 659.85(11) 3, dcalc
56 ).
;
3
1.285 g cm , Z 2, C12H17NOS2, space group P21. The
structure was solved by the direct method and refined
by full-matrix least squares in the anisotropic ap-
proximation for non-hydrogen atoms. Hydrogen atoms, optimization.
except for the OH hydrogen, were located geometri-
Methyl N-l-ephedrinodithiocarbamate (III).
To a solution of 1 g of l-l-ephedrine and 0.61 g of
triethylamine in 10 ml of chloroform, we added drop-
wise with stirring and cooling (0 5 C) to 0.45 g of
carbon disulfide, after which 0.61 g of triethylamine
and, with causion, 0.85 g of methyl iodide. The reac-
tion mixture was stirred for 30 min at room tempera-
ture and then washed twice with water and dried with
K2CO3. The solvent was removed, and the residue
was passed through a column of silica gel, eluent
benzene, to obtain 2.3 g (75%) of compound III, mp
96 97 C.
b
Thioesters IV XII were prepared in a similar way.
REFERENCES
1. Mel’nikov, N.N., Pestitsidy. Khimiya, tekhnologiya i
prime-nenie (Pesticides: Chemistry, Technology,
Application), Moscow: Khimiya, 1987, p. 712.
2. Allen, F.H., Kennard, O., Watson, D.G., Bramer, L.,
Orpon, A.G., and Taylor, R., J. Chem. Soc., Perkin
Trans. 2, 1987, no. 3, p. 1356.
a
0
c
3. Berlin, R., Acta Crystallogr., 1971, vol. 27, no. 1,
p. 381.
4. Turdybekov, K.M., Fazylov, S.D., Kasenov, R.Z.,
Gazaliev, A.M., and Struchkov, Yu.T., Zh. Obshch.
Khim., 1994, vol. 64, no. 3, p. 503.
Fig. 3. Crystal packing of molecules III.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 7 2005