Solvolysis of 2-amino-2-thiazoline derivatives by aliphatic amino alcohols

Article abstract of DOI:10.1023/A:1022190728686

The opening of the thiazoline ring upon the action of amino alcohols was studied. The effects of the reagent ratio and structures of the heterocycles and amino alcohols on aminolysis were investigated. A new method was developed for the preparative synthesis of a series of N′-(hydroxyalkyl)-2-guanidinoalkanethiols.

Full text of DOI:10.1023/A:1022190728686

Chemistry of Heterocyclic Compounds, Vol. 38, No. 11, 2002
SOLVOLYSIS OF 2-AMINO-2-THIAZOLINE
DERIVATIVES BY ALIPHATIC
AMINO ALCOHOLS
A. A. Mandrugin, V. M. Fedoseev, O. V. Dubovaya, A. A. Rodyunin, and M. N. Semenko
The opening of the thiazoline ring upon the action of amino alcohols was studied. The effects of the
reagent ratio and structures of the heterocycles and amino alcohols on aminolysis were investigated. A
new method was developed for the preparative synthesis of a series of N'-(hydroxyalkyl)-2-
guanidinoalkanethiols.
Keywords: N'-(hydroxyalkyl)-2-guanidinoalkanethiols, 2-amino-2-thiazoline derivatives, solvolysis.
Thousands of compounds have now been synthesized and tested on mammals, some of which have
proved effective radioprotective agents. The most active anti-radiation agents include S,N-containing organic
compounds such as 2(3)-aminoalkanethiols and their amidine derivatives, S-(aminoalkyl)isothioureas and
guanidinoalkanethiols. There have been only
a
few studies of the anti-radiation activity of
guanidinoalkanethiols, mainly due to the difficulty in preparing these compounds [1].
We have already shown that the introduction of a hydroxy group into 2-amino-2-thiazoline and
S-(aminopropyl)isothioureas considerably reduces toxicity with retention of a strong radioprotective effect [2].
The introduction of a hydroxy group into the aminothiol molecule also does not lead to the loss of
radioprotective activity. Thus, 3-amino-4-mercapto-2-butanol displays strong activity in mouse experiments [3].
In light of these results, we started work on the preparative synthesis of N'-(hydroxyalkyl)-2-
guanidinoalkanethiol derivatives.
In previous work [4], we have shown that dihydrothiazine derivatives can be converted to the
corresponding 2(3)-guanidinoalkanethiols in aqueous solution in the presence of ammonia. In the present work,
we studied the solvolysis of 2-amino-2-thiazoline derivatives upon the action of various aliphatic amino
alcohols. The major reaction products are the corresponding N'-(hydroxyalkyl)-2-guanidinoalkanethiols. The
corresponding aminoalkanethiols, their disulfides, and unsubstituted guanidine were found in insignificant
amounts as side products. The products of the hydrolytic decomposition of thiazoline derivatives, namely, the
corresponding ureidoalkanethiols, are lacking.
The effect of the reagent ratio on the reaction product yield was studied in order to select the optimal
conditions for the preparative synthesis of guanidine 5 by the reaction of thiazoline (1) with 3-aminopropanol
(18).
Thus, the yield of guanidine 5 in the reaction of 0.01 mol/l 1 with amino alcohol 18 taken in various mol
amounts was as follows (the concentration of 18 is indicated in parentheses: 35 (0.01), 51 (0.02), 55 (0.03),
59 (0.04), 65 (0.05), and 66% (0.06).
__________________________________________________________________________________________
M. V. Lomonosov Moscow State University, 119899 Moscow, Russia; e-mail:
mandrug@radio.chem.msu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11,
pp. 1566-1572, April 10, 2000.
1382
0009-3122/02/3811-1382$27.00©2002 Plenum Publishing Corporation

R1
R2
R1
R2
NH
NHR3
R1
R2
NH
NHR3
R3NH2
[O]
_
S
N
S
S
+
+
H2N
NH2
H2N
2
1–4
5–17
CS2
R1
R2
_
.
CS2
NH
NHR3
S
+
H2N
Com-
pound
Com-
pound
R1
R2
R3
R1
R2
R3
H
Me
H
H
H
Me
H
H
H
H
Me
Et
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
CH2CH(OH)Me
Et(–CH)CH2OH
Me(–CH)CH2(OH)
Me(–CH)CH2(OH)
(CH2)2OH
Et(–CH)CH2OH
(CH2)2OH
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
(CH2)3OH
(CH2)3OH
(CH2)3OH
(CH2)3OH
(CH2)2OH
H
Me
Et
H
Me
Me
H
Et(–CH)CH2OH
H
Guanidine 5 here and subsequently was isolated from the reaction medium and identified as the
corresponding trithiocarbonate obtained by the reaction of guanidine with carbon disulfide.
A four- or five-fold excess of amino alcohol 18 is required to obtain a suitable yield of guanidine 5.
However, a further increase in the amine concentration does not give a significantly enhanced yield of
guanidine. Furthermore, the yield of the desired compound drops with increasing duration of the reaction.
We have already found that 2(3)-guanidinoalkanethiols in aqueous solution at pH 2.5-9.8 are
converted irreversibly into the corresponding derivatives of dihydrothiazine and thiazoline [5]. Hence, it
appeared that the lack of effect of the reaction time and increase in the concentration of amino alcohol 18 on the
yield of the solvolysis product, guanidine 5, is related to cyclization of guanidine 5 under the aminolysis
conditions.
A more detailed study of the mechanism of the reaction of thiazoline 1 with amino alcohol 18
was required. This study was carried out using thin-layer chromatography and heterocycle 1 labeled with
carbon-14.
We studied the change in the relative concentrations of heterocycle 1 (c0 = 0.01 mol/l) over time in the
reaction of amino alcohol 18 (c0 = 0.02 mol/l) in water at 100°C. Guanidine 5 was found to accumulate during
the course of the reaction and then was consumed in the formation of an additional product,
N'-(3-hydroxypropyl)-2-amino-2-thiazoline (19). This heterocycle was isolated from the reaction medium and
identified. Furthermore, guanidine 5 is partially oxidized over time under the reaction conditions to give
disulfide 22. These results indicated the following reaction mechanism:
1383

k1
_
NH
S
1
HO(CH2)3NH2
+
k–1
18
+
5
H2N
NH(CH2)3OH
k6
k–2
+NH3
k3
+NH3
k4 [O]
k2
–NH3
k–3
+NH3
_
NH
S
S
N
+
NH
S
H2N
NH2
NH(CH2)3OH
20
+
H2N
NH(CH2)3OH
19
2
22
k5
+NH2(CH2)3OH
_
NH
S
+
HO(CH2)3HN
NH(CH2)3OH
21
Analysis of these data taking account of a series of limitations permitted us to simplify this scheme.
Thus, the extent of oxidation of guanidine 5 (step k4) was less than 10%, which could be considered negligible,
under conditions excluding oxygen. Substituted thiazolines such as 19 are known to be more stable under
solvolysis conditions than unsubstituted heterocycles such as 1 [4-6]. Thus, at the reaction onset, reaction
through step k1 is favored over reaction through step k5. The unlikely reactions proceeding through steps k-2, k-3,
and k6 may also be excluded from consideration without major error. This is permissible since the ammonia
concentration in the reaction mixture at the onset is much lower than the concentration of amino alcohol 18.
Thus, if we consider mainly the initial periods of this reaction, the aminolysis may rather correctly be described
by the following simplified scheme:
k1
k2
_
1
+ 19
NH
S
S
N
k–1
–NH3
+
5
H2N
NH(CH2)3OH
NH(CH2)3OH
19
A kinetic study of the aminolysis of thiazoline 1 was carried out to evaluate the cyclization rate
constants for guanidine 5 to give thiazoline 1 (k-1) and substituted thiazoline 19 (k2). For this purpose, a sample
of carbon-14-labelled guanidine 5 was prepared. In order to obtain comparable conditions for the aminolysis of
the heterocycles by amino alcohols, we studied the solvolysis of [14C]-5 in a reaction mixture consisting of
alcohol 18 and N,N-dimethylaminopropanol (23). The first-order rate constants of the parallel reactions given in
Table 1 indicate a preference for cyclization of guanidine 5 under the given conditions to give thiazoline 19. We
should note that the hydrolysis of thiazoline 1 to N-mercaptoethylurea does not proceed under the aminolysis
reaction conditions. Thus, heating an aqueous solution of 23 with thiazoline 1 for 2 h at reflux showed the latter
is stable under these conditions.
1384

TABLE 1. Rate Constants for the Cyclization of Guanidine 5
(c0 = 0.1 mol/l) to Heterocycles 1 and 19 at 100°C in Water
19, mol/l
24, mol/l
k-1·105, s-1
k2·105, s-1
—
0.1
0.2
0.2
6.2±0.8
6.9±1.1
13.1±1.8
13.8±2.2
Comparison of the rate constants for the cyclization of guanidine 5 (k2 and k-1) clearly shows that the
aminolysis should be carried out over the optimal, experimentally determined time period to achieve the
maximum yield of N'-substituted guanidines.
Following the our previous study of ammonolysis reactions [4] and the present kinetic data, we
attempted to find a preparative synthesis for N'-(hydroxyalkyl)-2-guanidinoalkanethiol derivatives. The reaction
of the heterocycles with amino alcohols was carried out at 100°C with a five-fold molar excess of amine without
solvent to select the optimal conditions for obtaining guanidines.
The results of our study of the reactivity of 4- and 5-substituted thiazolines in their reaction with amino
alcohol 18 are given in Table 2.
We found that unsubstituted thiazoline has the greatest reactivity and the greatest yield of the reaction
product is reached 30 min after onset of the reaction. The introduction of a methyl group at C(5) of the
heterocycle somewhat reduces the reactivity of thiazoline 2. However, the reaction time to obtain the maximum
yield is unchanged. The introduction of alkyl substituents at C(4) of the thiazoline ring in 3 and 4 alters the time
for the optimal synthetic procedure for the corresponding guanidine. On the other hand, the times required for
maximum product yields when using heterocycles 3 and 4 are much less than in the reaction with thiazoline 1.
It was of interest to study the effect of the nucleophile structure on the maximum yield of guanidines 5
and 9-13. For this purpose, we studied the reaction of thiazoline 1 with various amino alcohols under
comparable conditions (see Table 3).
TABLE 2. Dependence of the Yield of Trithiocarbonates from Guanidines
5-8 on the Time of Reaction of Thiazolines 1-4 with 18 at 100°C (Mol Ratio
of the Reagents was 1:5)
Yield, %, by t, min
Compound
10
20
30
60
90
80
68
78
66
85
72
63
95
83
55
59
65
57
49
51
55
51
21
5
6
7
8
TABLE 3. Yield of Trithiocarbonates from Guanidines 5 and 9-13 obtained
in the Reaction of Thiazoline 1 with Various Amino Alcohols (Mol Ratio
1:5) at 100°C
Compound
t
opt, min
Yield, %
Compound
11
12
13
t
opt, min
Yield, %
30
45
15
95
92
51
30
30
30
44
61
58
5
9
10
1385

TABLE 4. Yield of Trithiocarbonates from Guanidines 6-8 and 14-17
obtained in the Reaction of Thiazolines 2-4 with Various Amino Alcohols at
100°C (Mole Ratio 1:5, t = 30 min)
Heterocycle
HO(CH2)2NH2
HO(CH2)3NH2
HOCH2CH(NH2)Et
45
66
—
66
63
65
33
51
—
2
3
4
The optimal reaction time depends significantly on the amino alcohol structure. The highest guanidine
yields are obtained in the reaction with amino alcohol 18 and 2-aminoethanol. The lower reactivity of amino
alcohols with the amino group at a secondary carbon atom may be related to steric hindrance.
The aminolysis of substituted thiazolines 2-4 was studied with the most reactive amino alcohols
(Table 4). The highest guanidine yield is observed for unsubstituted thiazoline 1 (Table 3). Substituents
introduced at C(4) and C(5) in heterocycles 2-4 lead to a marked decrease in the yield of the desired product.
Further investigation of the aminolysis of thiazoline derivatives permitted us to select the optimal
conditions for obtaining new N-(hydroxyalkyl)guanidinoalkanethiols and then develop preparative syntheses of
these compounds in high yield.
We should note that the use of the starting heterocycles as salts or bases has no effect on the yield of the
desired products and the reaction conditions. The selection of the heterocycles or their salts was made solely on
the basis of synthetic availability. The preparation of guanidines should be carried out in an inert gas
atmosphere since these compounds are readily oxidized by atmospheric oxygen at 100°C. For identification and
subsequent preparation of various salts, N'-(hydroxyalkyl)guanidinoalkanethiols are conveniently isolated as
trithiocarbonates, which have low solubility in water and are stable upon storage. These products precipitate out
when carbon disulfide is added to the reaction mixture [7]. Then, the trithiocarbonate solution was decomposed
by the action of the required acid [8].
The products of the solvolysis of thiazolines 1-4 were isolated and identified (see Table 5).
Thus, we have studied the opening of the thiazoline ring upon the action of aliphatic amino alcohols.
The effects of the reagent ratio and structures of the heterocycles and amino alcohols on the aminolysis reaction
were studied. These results suggested a new preparative synthesis of a series of new N'-(hydroxyalkyl)-
guanidinoalkanethiols.
EXPERIMENTAL
The mass spectra were taken on a Varian MAT-III mass spectrometer with direct introduction of the
sample into the ionization chamber. The 13C NMR spectra were taken in methanol on a Bruker HX-80
spectrometer at 80 MHz with TMS as the internal standard. The IR spectra were taken on a Perkin–Elmer 457
spectrometer for KBr pellets. The reaction course and purity of the products were monitored by thin-layer
chromatography on Silufol UV-254 plates.
Guanidinoalkanetrithiocarbonates of 5-17. A sample of corresponding hydrobromide salt of
heterocycle 1-4 (0.01 mol) was dissolved in amino alcohol (0.01-0.06 mol). The solution was placed in an
ampule and flushed with argon. The ampule was sealed and heated at the optimal temperature for a given
period. After cooling to 0°C, the ampule was opened. Then, carbon disulfide (2 ml) was added with stirring and
left for 12 h at 0°C. The residue was filtered off and washed with water, 2-propanol, and ether. The
physicochemical and spectral indices of these compounds are given in Table 5.
1386

TABLE 5. Physicochemical Indices of N-Derivatives of 2(3)-Guanidinoalkanethiols
Found, %
13С NMR spectrum, δ, ppm.
——————
Empirical
formula
Compound
Calculated, %
mp, °С
Yield, %
C
H
N
CS3
CN+
СH2O
CH2S
38.44
46.95
45.74
44.34
Other groups
3
C7H15N3OS3
C8H17N3OS3
C8H17N3OS3
C9H19N3OS3
33.01
33.20
5.94
5.93
16.81
16.60
145-147
145-146
142-143
170-172
238.50
238.67
238.71
238.98
155.65
155.77
155.01
155.50
57.93
57.90
57.91
57.93
40.73 (C4H2N); 31.74 (C6H2N);
30.78 (CH2)
95
63
60
66
5·CS2
6·CS2
7·CS2
8·CS2
35.71
6.37
15.64
46.22 (C5H2N); 38.38 (C3H2N)
31.41 (CH2); 16.30 (CH3)
35.95
6.15
15.74
35.62
35.95
6.10
6.37
15.48
15.73
47.38 (CH); 38.37 (CH2N);
31.43 (CH2); 19.74 (CH3)
37.84
6.43
14.53
38.42 (C3H2N); 10.06 (CH3);
52.92 (CH)
38.43
6.76
14.95
9·CS2
C6H13N3OS3
C7H15N3OS3
29.84
30.12
5.10
5.45
17.50
17.57
162-164
155-157
238.87
238.43
156.10
155.60
59.52
57.82
38.70
38.38
48.89 (C5H2N); 40.85 (C3H2N)
92
51
10·CS2
32.41
5.90
16.85
48.89 (C5H2N); 38.33 (C3H2N);
38.38 (CH2S); 31.39 (CH3)
32.20
5.77
16.60
11·CS2
12·CS2
13·CS2
14
C8H17N3OS3
C7H15N3OS3
C8H17N3OS3
C7H15N3OS3
C9H19N3OS3
C7H15N3OS3
C8H17N3OS3
C6H12N2OS
35.54
35.93
5.99
6.37
15.66
15.73
141-143
156-158
148-150
160-163
128-130
167-168
130-132
139-141
238.42
238.53
238.24
238.56
238.46
238.83
238.69
—
155.75
155.72
155.56
156.15
155.90
155.34
155.10
—
62.55
55.66
63.61
59.40
62.70
59.42
63.52
—
39.35
38.36
38.38
46.94
46.80
45.73
45.72
—
40.72 (CH2N); 54.87 (CHN);
44
61
58
66
51
45
33
62
2.71 (CH2); 10.14 (CH3)
33.71
5.42
16.44
35.90 (C6H2N); 28.29 (CH2);
14.30 (CH3)
33.20
5.93
16.60
35.31
35.93
6.21
6.37
15.82
15.73
40.66 (C4H2N); 38.43 (CH2), (CH),
223.73 (CH3)
32.95
5.35
16.75
46.29 (C5H2N); 43.74 (C3H2N);
16.33 (CH3)
33.20
5.93
16.60
15·CS2
16·CS2
17·CS2
19*
38.19
38.43
6.55
6.76
14.41
14.95
54.95 (C5H2N); 46.30 (C3H2N);
23.76 (CH2); 10.10 (CH3)
32.97
5.71
16.70
47.48 (CH); 43.85 (CH2N);
33.20
5.93
16.60
19.76 (CH3)
38.03
38.43
6.10
6.76
14.80
14.95
54.89 (C5H2N); 47.30 (C3H2N);
23.72 (CH2); 10.13 (CH3)
44.80
7.82
17.28
45.00
7.50
17.50
_______
-1
≡
≡
* IR spectrum, ν, cm : 3250 (=NH); 1650, 1620, 1570, 1430 (=C=N–); 1000, 960, 860, 800 ( C–S–C ).

Hydrochlorides 5-17 were obtained as aqueous solutions by decomposition of the corresponding
guanidinoalkanetrithiocarbonates upon adding an equivalent amount of hydrochloric acid at 20°C in an argon
stream required to prevent oxidation of the thiols formed.
The kinetic studies were carried out using thin-layer chromatography (see Table 1). A sample of carbon-
14-labelled guanidine 5 was prepared according to the method of the unlabelled compound. The synthesis of
carbon-14-labelled thiazoline 1 was described in our previous work [4].
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2.
V. G. Vladimirov, I. I. Krasil'nikov, and O. V. Arapov, Radioprotectors: Structure and Function
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A. A. Mandrugin, V. M. Fedoseev, M. N. Semenenko, and S. M. Khomutov, Khim. Geterotsikl. Soedin.,
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A. A. Mandrugin, V. M. Fedoseev, S. M. Khomutov, A. A. Rodyunin, and Yu. A. Leshchev, Khim.
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7.
8.
N. M. Turkevich and B. I. Shvydkii, Ukr. Khim. Zh., 18, 513 (1952).
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1388