Synthesis and antioxidative activity of N,N-Diethylthiocarbamate-containing 1,2-Aminopropanethiols

Article abstract of DOI:10.1134/S107042720912012X

Method for synthesis of S-(1,2-epithiopropyl)-N,N-diethylthiocarbamate, which is a key compound for production of various aryl-substituted 1,2-aminopropanethiols, was developed. The antioxidative activity of the compounds synthesized was studied. Pleiades

Full text of DOI:10.1134/S107042720912012X

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2009, Vol. 82, No. 12, pp. 2151–2155. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.T. Guseinova, I.A. Rzaeva, K.I. Alieva, I.A. Aliev, M.A. Allakhverdiev, 2009, published in Zhurnal Prikladnoi Khimii, 2009,
Vol. 82, No. 12, pp. 2008–2013.
ORGANIC SYNTHESIS AND INDUSTRIAL
ORGANIC CHEMISTRY
Synthesis and Antioxidative Activity
of N,N-Diethylthiocarbamate-containing 1,2-Aminopropanethiols
A. T. Guseinova, I. A. Rzaeva, K. I. Alieva, I. A. Aliev, and M. A. Allakhverdiev
Baku State University, Baku, Republic of Azerbaijan
Received July 30, 2008
Abstract—Method for synthesis of S-(1,2-epithiopropyl)-N,N-diethylthiocarbamate, which is a key compound
for production of various aryl-substituted 1,2-aminopropanethiols, was developed. The antioxidative activity of
the compounds synthesized was studied.
DOI: 10.1134/S107042720912012X
It is known [1, 2] that, similarly to thiocarbamide
and thiocyanates of alkali metals [3], salts of thio- and
dithiophosphoric acids are convenient thioepoxydizing
agents and are successfully and widely used to convert
oxiranes to thiiranes. However, as noted in the
monograph [4], the applicability limits of the method
developed in [1, 2] have not been determined so far. In
view of the aforesaid, the reaction of the sodium
diethyldithiocarbamate with 1,2-epoxy-3-chloropropane
was studied. It was found that the sodium diethyldi-
thiocarbamate can also serve as a thioepoxydizing
agent for synthesis of thiiranes [5]. For this purpose,
the reaction of 1,2-epoxy-3-chloropropane with anhyd-
rous sodium diethyldithiocarbamate in a solution in
benzene under mild conditions (60°C) was studied and
thiirane I was synthesized in a 50–60% yield:
S
Cl
S
N−C
N−C
(1)
Na
+
O
S
−NaCl
O
O
It should be noted that, in the reaction of 1,2-epoxy-
3-chloropropane with undehydrated sodium diethyldi-
thiocarbamate, the yield of thiirane decreases to 30%,
because the molecule of sodium diethyldi-thiocar-
bamate contains three molecules of crystallization
water. The mechanism of the reaction in which thiirane
I is formed somewhat resembles that suggested by
C. Calvenor [6]. Presumably, 1,2-epoxypropyl group
first undergoes a nucleophilic substitution to give the
corresponding oxirane, which is then converted via
intramolecular cyclization to a bicyclic oxathiolane.
Further, there occurs a Smiles rearrangement and, in
the end, closure of the three-membered ring yields S-
(2,3-epithiopropyl)-N,N-diethylthiocarbamate (I):
(C2H5)2NCSCH2CH−CH2
CH2−CHCH2Cl + (C2H5)2NCSNa
−NaCl
O
O
S
S
S−CH2
S−CH2
+
−
O−
(C2H5)2N−CH CH
O−
(C2H5)2N−C
S−CH2
CH
S−CH2
S−CH2
S−CH2
(C2H5)2N−C
(C2H5)2NCSCH2CH−CH2
O−
(C2H5)2N−C
CH
CH
CH2−S−
O−
− S−CH2
O
S
2151

2152
GUSEINOVA et al.
It is known that 1,2-amino thiols are of key
(3) these compounds become increasingly important in
technology as effective components in polymerization
processes, improve the radiation hardness of polymers,
suppress oxidation and corrosion, and possess
complexing properties.
practical importance among products of thiirane
transformations in reactions with various nucleophilic
reagents (amines, alcohols, etc.), which proceed via
opening of the thiirane ring. This is due to the
following factors: (1) among amino thiols, only the
aminoethanethiol moiety contains coenzyme A, which
plays an important part in the vital activity of
organisms; (2) aminothiols and their derivatives are
physiologically active compounds exhibiting radiopro-
tective, hypotensive, muscle relaxant, and ganglion-
blocking capacities and find wide use in medicine; and
In view of the aforesaid, the goal of this study was
to synthesize and examine diethylcarbamate-substituted
1,2-aminopropanethiols II–XI produced by reactions
of S-(2,3-epithiopropyl)-N,N-diethylthiocarbamates with
various ring-substituted aromatic amines:
(C2H5)2NCSCH2CH−CH2 + H2NC6H4R
(C2H5)2NCSCH2CHCH2NHC6H4R,
O
S
S
SH
II−XI
R = H (II), 2-CH3 (III), 3-CH3 (IV), 4-CH3 (V), 2-CH3O (VI) 3-CH3O (VII), 4-CH3O (VIII), 2-Cl (IX), 3-Cl (X), 4-Cl (XI).
Therefore, the reaction of the thiirane I under study
with various substituted aromatic amines was performed
in a sealed ampule at a thiirane : amine ratio of 1 : 2.
Systematic studies in synthesis of 1,2-
aminopropanethiols and analysis of their antioxidative
properties have shown [6–8] that the yield of the target
product increases if the reaction is performed with an
excess of an amine, which serves as a solvent in this
case. When the reaction is carried out in air, the
amount of by-products increases via oxidation of 1,2-
aminopropanethiols and polymerization of thiiranes.
All these undesirable factors lead to a pronounced
decrease in the yield of the target product.
The reactivity of the 1,2-aminopropanethiols syn-
thesized is due to the presence of two reaction centers,
which may be involved in reactions both separately
and together, depending on the nature of the reagents
used. In this context, it is of interest to study the reac-
tion of 1,2-aminopropanethiol II with bifunctional rea-
gents, namely, with α-chloroacetic acid and its ethyl ester:
S
ClCH2COOH
C
CH2
C
(C2H5)2NCSHCH2H
H2C
S
N
O
C6H5
(C2H5)2NCSCH2CHCH2NHC6H5
XII
(C2H5)2NCSCH2CHCH2NHC6H5
S
SH
ClCH2COOC2H5
S
SHCH2COOC2H5
XIII
It was found that the intramolecular lactonization of
the primary product formed in the interaction of 1,2-
aminopropanethiol (II) with chloroacetic acid yields
tetrahydro-1,4-thiazin-3-one (XII). A similar reaction
with chloroacetic acid ethyl ester proceeds to give an
acyclic product, aminothioester XIII.
1,2-Aminopropanethiols II–XI are colorless fluids
with a characteristic odor. Upon prolonged storage, the
fluids turn yellow. They are well soluble in all organic
solvents, but insoluble in water. The physicochemical
constants of the compounds are listed in Table 1.
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SYNTHESIS AND ANTIOXIDATIVE ACTIVITY
2153
Table 1. Yield, constants, and elemental analysis data for the compounds synthesized
Calculated/Found, %
Comp. Yield,
bp, °С
(р, mm Hg)
nD20
Formula
Rf
no.
%
C
H
N
S
66
63
70
72
71
55
69
72
75
81
76
60
75
108
1.5402
С8H15NOS2
46.83/46.71 7.32/7.17 6.83/6.65 31.22/31.08 0.49
I
119–120 (0.7) 1.5555
137–138 (0.1) 1.6935
138–139 (0.1) 1.6912
140–141 (0.1) 1.6945
155–156 (0.1) 1.6959
161–162 (0.1) 1.6917
160–161 (0.1) 1.6890
C14H22N2OS2 56.38/56.25 7.38/7.20 9.40/9.22 21.48/21.32 0.57
C15H24N2OS2 57.69/57.56 7.69/7.58 8.97/8.19 20.51/20.35 0.68
C15H24N2OS2 57.69/57.56 7.69/7.54 8.97/8.41 20.51/20.34 0.47
C15H24N2OS2 57.69/57.52 7.69/7.57 8.97/8.41 20.51/20.37 0.55
C15H24N2O2S2 54.88/54.72 7.32/7.15 8.54/8.37 19.51/19.32 0.63
C15H24N2O2S2 54.88/54.71 7.32/7.14 8.54/8.38 19.51/19.35 0.72
C15H24N2O2S2 54.88/54.69 7.32/7.18 8.54/8.39 19.51/19.34 0.58
II
III
IV
V
VI
VII
VIII
IX
X
162–163 (0.1) 1.6975 C14H21ClN2OS2 50.53/50.39 6.32/6.17 8.42/8.26 19.25/19.09 0.53
160–161 (0.1) 1.6956 C14H21ClN2OS2 50.53/50.38 6.32/6.19 8.42/8.24 19.25/19.09 0.65
172–173 (0.1) 1.5967 C14H21ClN2OS2 50.53/50.37 6.32/6.17 8.42/8.23 19.25/19.08 0.42
XI
XII
XIII
188–189 (0.1) 1.5415
175–176 (0.1) 1.5729
C16H22N2O2S2 56.80/56.67 6.51/6.38 8.28/8.14 18.94/18.74 0.63
C18H28N2O3S2 56.25/56.10 7.29/7.18 7.29/7.17 16.67/16.53 0.46
1
The purity of 1,2-aminopropanethiols I–XIII was
In the H NMR spectra of 1,2-aminopropanethiols
II–XI, three protons of the methyl bound to the
aromatic ring [compounds III–V] appear as a doublet
at 2.1–2.2 ppm. Protons of the methoxy group in
compounds VI–VIII appear in a weaker field at 3.6–
3.7 ppm. Protons of the SH and NH groups and those
of the CHCH2 moiety appear as a multiplet at 2.9–
3.7 ppm in all the spectra. Nonequivalent protons of
the benzene ring appear as an unresolved group of
multiplets at 6.0–7.27 ppm.
confirmed by thin-layer chromatography and elemental
1
analysis, and their structure, by IR and H NMR
spectroscopies.
The IR spectrum of thiirane I contains a
characteristic absorption band at around 675 cm–1,
related to the thiirane ring; to stretching vibrations of
the C=O bond corresponds the band at 1650 cm–1.
The IR spectra of the 1,2-aminopropanethiols II–XI
show a characteristic absorption band in the range
3330–3350 cm–1, which corresponds to stretching
vibrations of the NH group of secondary amines.
Stretching vibrations of the group appear as a weak
band at 3540–3545 cm–1. All the spectra contain strong
absorption bands at 1440–1465, 1500–1510, and
1590–1600 cm–1, characteristic of stretching vibrations
of the C=C bond in the benzene ring.
To elucidate the mechanism of the antioxidative
effect of 1,2-aminopropanethiols II, III, VI, and IX,
the activity of these compounds was studied in model
reactions in which the oxidation of cumene is inhibited
by cumyl peroxide radicals. The oxidation of cumene
was initiated with azobisisobutyronitrile (AIBN) at 60°C
in the presence of these compounds.
As can be seen in Table 2, 1,2-aminopropanethiols
II, III, VI, and IX containing a substituted phenyl-
amine moiety hinder the initiated oxidation of cumene.
It is known that thiols do not exhibit any antioxidative
activity by themselves. Only when a molecule
combines ArNH and SH groups, a high antioxidative
activity is manifested.
1
In the H NMR spectrum of thiirane I, protons of
two methyl groups of the (C2H5 )2N moiety appear as a
triplet at 1.10–1.45 ppm. Protons of the CH2 group,
bound to the sulfur atom in the three-membered ring,
appear as two doublets at 2.45 and 2.60 ppm. In a
weak field at 3.60–4.75 ppm appear as a multiplet
superimposed signals of a proton of the methine group,
protons of the CH2 group bound to the C(O)S group,
and two methylene groups at the nitrogen atom.
The duration τ of the induction period was used to
calculate the stoichiometric coefficient equal to the
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2154
GUSEINOVA et al.
Table 2. Kinetic parameters of the reaction of 1,2-amino-
propanethiols II, III, VI, and IX with cumene peroxide
radicals (60°C, [AIBN] = 2×10–2 M, Wi = 2×10–7 M) and
cumene hydroperoxide
[ROOH]0 − [ROOH]∞
ν =
,
[In]0
where [ROOH]0 and [ROOH]∞ are, respectively, the
initial and final concentrations of CHP; [In]0, initial
concentration of an inhibitor; and k, rate constant of
the catalytic factor ν.
k7×
10–4
M–1 s–1
k
Comp.
no.
R
f
ν
C6H5
1.70
2.15
2.17
1.05
1.67
1.85
2.00
0.85
8.12 18900
3.95 21400
4.12 23000
2.15 10500
II
Thus, the compounds under study are oxidation
inhibitors of combined action: they catalytically
decompose hydroperoxides to give molecular products
and thereby terminate oxidation chains in a reaction
with peroxide radicals.
C6H4CH3-2
C6H4OCH3-2
C6H4Cl-2
III
VI
IX
EXPERIMENTAL
number of oxidation chains terminated on a molecule
of an inhibitor and its conversion products.
The IR spectra were measured with a Specord75-IR
spectrophotometer, and 1H NMR spectra, with a
Bruker-300 MHz instrument.
It can be seen in Table 2 that the stoichiometric coef-
ficient varies from 1.05 to 2.17 for 1,2-amino-
propanethiols. The inhibition rate constant k7 varies
from 0.85×10–4 to 2.0×10–4 M–1 s–1.
The reaction was monitored by means of thin-layer
chromatography on Silufol-254 plates. Hexane and
ethanol taken in a 1 : 5 ratio served as the eluent. Only
a single spot was present on a chromatogram
developed with an iodine vapor.
Introduction of electron-donor substituents into the
molecule of 1,2-aminopropanethiols III and VI makes
higher their inhibiting activity (f = 2.17, k7 = 2.00×10–4).
However,
introduction
of
electron-acceptor
S-(2,3-Epithiopropyl)-N,N-diethylthiocarbamate
(I). A three-necked flask equipped with a mechanical
stirrer, reflux, thermometer, and dropping funnel was
charged with 17.1 g (0.11 mol) of dry sodium
diethyldithiocarbamate in 50 ml of benzene and 9.3 g
(0.1 mol) of 1,2-epoxy-3-chloropropane was added
dropwise under vigorous stirring, with the temperature
of the reaction mixture increasing to 50°C. Then the
temperature of the reaction mixture was raised to 60°C
and it was agitated at this temperature for 3 h. The
resulting precipitate was filtered off and benzene was
evaporated. The reaction product was subjected to
vacuum distillation to give 12 g (60%) of compound I,
bp 105°C (0.7 mm Hg), nD20 1.5402, n420 1.1271. Found,
%: C 46.71, H 7.17, N 6.65, S 31.08. C8H15NOS2.
Calculated, %: C 46.83, H 7.32, N 6.83, S 31.22.
substituents (Cl) impairs the inhibiting activity (f =
1.05, k7 = 0.85×10–4 ).
At f ≥ 1, inhibitors commonly terminate a single
oxidation chain. Because the molecule of 1,2-amino-
propanethiols contains a sulfhydryl group, f somewhat
exceeds unity.
The reaction of 1,2-aminopropanethiols II, III, VI,
and IX with cumene hydroperoxide (CHP) was carried
out in the atmosphere of nitrogen at 110°C. It was
found that all the compounds under study actively
decompose CHP. It was shown that one molecules of
1,2-aminopropanethiols can decompose up to several
tens of thousands of CHP molecules. The values of the
parameters characterizing the catalytic decomposition
of CHP under the action of compounds I, III, VI, and
IX under study are listed in Table 2. It can be seen that
the catalytic factor ν is the largest for 1,2-amino-
propanethiol VI, which contains an ortho-anisidine
moiety in its molecule (k = 4.12, ν = 2.3 104). In this
case, electron-donor substituents also make larger the
catalytic factor; by contrast, electronegative sub-
stituents (Cl) make it smaller.
S-(1-Diethylcarbamato)-3-N-phenylamino-2-pro-
panethiol (II). A 9.32-g portion of aniline and 10.3 g
(0.05 mol) of S-(2,3-epithiopropyl)-N,N-diethylthio-
carbamate (I) were heated in a sealed ampule on a
boiling water bath for 6 h. Then the reaction mixture
was cooled and the ampule was opened. First the
excess amount of aniline and then the target reaction
product were subjected to vacuum distillation to give
9.5 g of compound II, bp 119–120°C (0.1 mm Hg),
nD20 1.5555, Rf 0.72. Found, % : C 56.25, H 7.20, N
The value of the catalytic factor ν characterizing the
number of CHP molecules decomposing a single
inhibitor molecule was calculated using the formula
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SYNTHESIS AND ANTIOXIDATIVE ACTIVITY
2155
9.24, S 21.32. C14H22N2OS2 . Calculated, % : C 56.38,
H 7.38, N 9.40, S 21.48.
give 17 g (75%) of compound XIII, bp 175–176°C
(0.1 mm Hg), nD20 1.5729, Rf 0.46. Found, % : C 56.10,
H 7.18, N 7.17, S 16.53. C18H28N2O3S2. Calculated C
56.25, H 7.29, N 7.29, S 16.67.
Diethylcarbamate-substituted 1,2-aminopropanethiols
III–XI, whose physicochemical constants are listed in
Table 1, were synthesized similarly.
CONCLUSIONS
6-Diethylaminocarbamatothiomethyl-4-N-phe-
nyltetrahydro-1,4-thiazin-3-one (XII). A three-necked
flask equipped with a mechanical stirrer, thermometer,
and dropping funnel was charged with 15 g (0.05 mol)
of S-(1-diethylcarbamato)-3-N-phenylamino-2-propa-
nethiol (II), 2 g (0.05 mol) of caustic soda, and 10 ml
of water. Then 0.05 mol of a sodium salts of
chloroacetic acid (4.73 g ClCH2COOH + 2 g NaOH +
10 g H2O) was added dropwise under vigorous agita-
tion. After that the reaction mixture was acidified with
hydrochloric acid and extracted with ether. The extract
was dried over calcined sodium sulfate. The solvent
was evaporated and the residue was subjected to
vacuum distillation to give 10.3 g (60%) of compound
XII, bp 188–189°C (0.1 mm Hg), nD20 1.5415, Rf 0.63.
Found, % : C 56.67, H 6.38, N 8.14, S 18.74.
C16H22N2O2S2. Calculated, % : C 56.80, H 6.51, N
8.28, S 18.94.
(1) Diethylcarbamate-substituted 1,2-aminopropane-
thiols with various ring-substituted aromatic amines
were synthesized from S-(1,2-epithiopropyl)-N,N-
diethylthiocarbamate and their properties were studied.
(2) Fundamental aspects of the influence exerted by
substituents in the molecule of 1,2-aminopropanethiols
on their reactivity as inhibitors in elementary reactions
of inhibition of cumene oxidation were revealed.
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