Acylation of dithiocarbamates derived from l-ephedrine and d-pseudoephedrine

Article abstract of DOI:10.1134/S107036320607022X

The acylation of dithiocarbamates derived from l-ephedrine and d-pseudoephedrine gives, depending on the structure of the acylating agent, acyl derivatives of the dithiocarbamates or their cyclic decomposition products, viz. oxazolidinethiones. Pleiades P

Full text of DOI:10.1134/S107036320607022X

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 7, pp. 1134 1137.
Pleiades Publishing, Inc., 2006.
Original Russian Text O.A. Nurkenov, M.K. Ibraev, D.M. Turdybekov, A.M. Gazaliev, Sh.T. Ibysheva, K.M.Turdybekov, M.B. Isabaeva, 2006, published
in Zhurnal Obshchei Khimii, 2006, Vol. 76, No. 7, pp. 1183 1186.
Acylation of Dithiocarbamates Derived
from l-Ephedrine and d-Pseudoephedrine
O. A. Nurkenova, M. K. Ibraeva, D. M. Turdybekovb,
A. M. Gazalieva, Sh. T. Ibyshevaa, K. M. Turdybekovb, and M. B. Isabaevaa
a Institute of Organic Chemistry and Coal Chemistry of Kazakhstan,
ul. Alihanova 1, Karaganda, 100000 Kazakhstan
e-mail: mkibr@yandex.ru
b Institute of Phytochemistry, Ministry of Science and Education of Kazakhstan, Karaganda, Kazakhstan
Received June 15, 2005
Abstract The acylation of dithiocarbamates derived from l-ephedrine and d-pseudoephedrine gives,
depending on the structure of the acylating agent, acyl derivatives of the dithiocarbamates or their cyclic
decomposition products, viz. oxazolidinethiones.
DOI: 10.1134/S107036320607022X
The reactions of l-ephedrine (I) and d-pseudo-
ephedrine (II) with -haloketones yield morpholine
derivatives [1, 2, 6].
(II) with -bromobenzoyl chloride give rise to ex-
pected acyl derivatives III and IV (route a). The
acylation with benzoyl chloride or pyromucic acid
chloride provide, instead of the corresponding acyl
derivatives, a heterocyclization (route b) product 3,4-
dimethyl-5-phenyl-1,3-oxazolidine-2-thione (V) as a
mixture of two stereoisomers: l-ephedrine derivative
4S,5R-V and d-pseudoephedrine derivative 4S,5S-V.
To study the steric and electronic effects on the
heterocyclization of ephedrine alkaloids, we per-
formed acylation of their derived dithiocarbamates. It
was shown that the reactions of dithiocarbamates
derived from l-ephedrine (I) and d-pseudoephedrine
OH
C6H5
CH3
OH
C6H5
CH3
+
CS2, (C2H5)3N
S
S
(C2H5)3NH
C
NH
CH3
NH
CH3
I, II
O
OH
C6H5
CH3
S C
o-BrC6H4C(O)Cl
a
C
NH
Br
CH3
O
III, IV
(C2H5)3N HCl
C6H5
H3C
RC(O)Cl
S + R(S)OH
b
N
CH3
V
l (I, III), d (II, IV); R = C6H5, 2-furyl.
1134

ACYLATION OF DITHIOCARBAMATES
1135
Oxazolidinethione V is probably formed via acyl
derivative A, i.e. the first step of the reaction is di-
thiocarbamate acylation. The reactive electron-de-
ficient thiocarbonyl group makes possible cyclization
of the alkaloid via intramolecular nucleophilic attack
of the hydroxy group on the carbonyl carbon atom to
form the final reaction product (route b).
The high electronic deficit on the thiocarbonyl
carbon is associated (along with the electron-acceptor
effect of the thionic sulfur) with a strong electron-
acceptor effect of the acyl carbonyl group. As a result,
the negatively charged hydroxyl oxygen and the
positively charged thiocarbonyl carbon attract each
other. Simultaneously, mutual repulsion of the neigh-
boring positively charged carbon and sulfur arises. As
a result, the C S bond in compounds A (R = C6H5,
2-furyl) gets longer and weaker, thus creating one
more prerequisite for this bond cleavage and forma-
tion of a cyclic product.
The intramolecular cyclization involving the carbon
atom at the double bond occurs more effectively if the
molecular structure, apart from electronic, better meets
the steric demand of the transition state [7]. These
demand is better met when R = C6H5 and 2-furyl.
H
+
V
RC(S)OH
..
+
A
Mechanistically, this reaction has much in common
with the formation of isothiocyanates from dithiocar-
bamates derived from primary amines, which, too,
involves intermediate formation of an acyl derivative
with subsequent C S bond and thiobenzoic acid
cleavage [8].
The steric structure of compound V was established
by X-ray diffraction analysis (see figure). The bond
lengths and bond angles are close to normal values
[9] (see table). Unlike molecules in which the oxa-
zolidine ring assumes the chair and envelope con-
formations, the oxazolidine ring in molecule V is
planar within 0.017 , on account of the -conjuga-
tion with the lone electron pairs of the oxygen and
nitrogen atoms and the C2=S1 bond. The C4 atom
deviates from the ring plane by 0.015 . The
methyl group on C4 and the phenyl group on C5 are
axial (the C7C4N3C2 and C13C8C5C4 angles are 121.1
and 88.25 , respectively). The methyl group on N3
In o-bromobenzoyl derivatives III and IV, the elec-
tron-acceptor effect of the carbonyl carbon is most
likely attenuated by its conjugation with the bromo-
phenyl group. The effect of the carbonyl group on the
thio ester sulfur is much weaker, and, as a result,
compounds III and IV remain stable and undergo no
cyclization in the reaction conditions.
The structure and composition of the synthesized
compounds were proved by elemental analysis and
1H NMR and IR spectroscopy.
C10
C9
O1
S1
C11
1
The H NMR spectrum of compound V contains a
multiplet of aromatic protons at 7.29 7.43 ppm. The
doublet at 5.88 ppm relates to the CHO proton. The
CH3N methyl protons appear as a strong singlet at
3.14 ppm. The quartet at 4.08 4.44 ppm belongs to
the CHN group. The alkaloid CH3C protons appear as
a doublet at 0.80 ppm (J 7.2 Hz).
C13
C8
C2
C5
C4
C7
N3
C6
The IR spectrum of compound V lacks character-
istic OH absorption bands. The spectra of compounds
1
III and IV shows a broad band at 3261 3083 cm
(OH), as well as a strong band at 1609 1587 cm
1
Molecular structure of (4S,5R)-3,4-dimethyl-5-phenyl-
(C=O).
1,3-oxazolidine-2-thione.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 7 2006

1136
NURKENOV et al.
Bond lengths (d) and bond angles ( ) in 4S,5R-V
metrically. Absorption correction by the curves was
applied. Weight parameter 0.0655. Final divergence
factors R 0.0477 and RW 0.1132. The structure solu-
tion and refinement were performed using the
SHELXS-97 program.
Bond
S1 C2
d,
Angle
, deg
1.663(4)
1.339(5)
1.452(6)
1.299(5)
1.450(6)
1.480(6)
1.505(7)
1.551(7)
1.505(6)
1.386(6)
1.390(6)
1.389(7)
1.371(7)
1.367(7)
1.378(7)
C2O1C5
N3C2O1
N3C2S1
109.9(3)
110.8(4)
128.4(4)
120.7(3)
124.2(4)
114.7(4)
120.9(4)
111.2(4)
98.7(4)
115.9(4)
109.6(4)
105.7(3)
118.8(4)
119.0(4)
122.2(4)
118.8(5)
120.3(5)
119.9(5)
120.0(5)
120.9(5)
119.9(5)
O1 C2
O1 C5
C2 N3
N3 C6
N3 C4
C4 C7
C4 C5
C5 C8
C8 C9
C8 C13
C9 C10
C10 C11
C11 C12
C12 C13
S-[N-[(1S,2R)-2-Hydroxy-1-methyl-2-phenyl-
ethyl]-N-methylamino]carbonothioyl o-bromoben-
zenecarbothioate (III). To a solution of 1.5 g of l-
ephedrine and 0.91 g of triethylamine in 10 ml of
chloroform, 0.55 g of hydrogen sulfide was added
dropwise with stirring and cooling ( 5 to 0 C). Tri-
ethylamine, 0.91 g, and 1.05 g of o-bromobenzoyl
bromide were then added. The reaction mixture was
stirred for 0.5 h at room temperature and then washed
with two portions of water and dried with potash. The
solvent was removed, and the residue was passed
through a column of silica gel, eluent benzene. Yield
of compound III 82%, mp 167 168 C. Found, %:
C 51.00; H 4.31; N 3.33. C18H18BrNO2S2. Calculated,
%: C 50.94; H 4.28; N 3.30.
O1C2S1
C2N3C6
C2N3C4
C6N3C4
N3C4C7
N3C4C5
C7C4C5
O1C5C8
O1C5C4
C8C5C4
C9C8C13
C9C8C5
C13C8C5
C8C9C10
C11C10C9
C12C11C10
C11C12C13
C12C13C8
S-[N-[(1S,2S)-2-Hydroxy-1-methyl-2-phenyl-
ethyl]-N-methylamino]carbonothioyl o-bromoben-
zenecarbothioate (III) was prepared similarly to
compound III, yield 85%, mp 49 50 C. Found, %:
C 51.09; H 4.33; N 3.35. C18H18BrNO2S2. Calculated,
%: C 50.94; H 4.28; N 3.30.
and the S2 atom are equatorial (the C5C4N3C6 and
C4N3C2S1 angles are 173.54 and 178.8 , respec-
tively). A flattened oxazolidine ring is also character-
istic of 4,4-dimethyloxazolidine-2-thione [10].
(4S,5R)-3,4-Dimethyl-5-phenyl-1,3-oxazolidine-
2-thione (4S,5R-V) was prepared in a similar way,
yield 84%, mp 60 61 C. Found, %: C 63.70; H 6.29;
N 6.78. C11H13NOS. Calculated, %: C 63.73; H 6.32;
N 6.76.
EXPERIMENTAL
(4S,5S)-3,4-Dimethyl-5-phenyl-1,3-oxazolidine-
2-thione (4S,5S-V) was prepared in a similar way,
yield 81%, mp 125 126 C. Found, %: C 63.69; H
6.38; N 6.71. C11H13NOS. Calculated, %: C 63.73;
H 6.32; N 6.76.
The IR spectra were measured on a UR-20 instru-
ment in KBr. The H NMR spectra were taken on a
Varian MERCURY 300 instrument (300 MHz) in
CD3Cl, internal reference HMDS. The melting points
were measured on a Boetius hot stage.
1
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pound V. The unit cell parameters and the intensities
of 1162 unique reflections of compound V were
measured at 20 C on a Bruker-P4 automatic four-
circle diffractometer (graphite monochromator,
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3
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ACYLATION OF DITHIOCARBAMATES
1137
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