New data on the alkylation of cyclic thioureas with α-halocarboxylic acids and their esters. 1. Alkylation of ethylene thiourea

Article abstract of DOI:10.1007/s10593-006-0075-5

The detailed scheme of reactions, occurring on interacting ethylene thiourea with chloroacetic acid and its esters, has been supplemented with a series of new reactions. The whole spectrum of products formed on interaction of ethylene thiourea with 2-bromobutyric acid has been obtained. 2006 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0075-5

Chemistry of Heterocyclic Compounds, Vol. 42, No. 2, 2006
NEW DATA ON THE ALKYLATION OF
CYCLIC THIOUREAS WITH α-HALO-
CARBOXYLIC ACIDS AND THEIR ESTERS.
1. ALKYLATION OF ETHYLENE THIOUREA
P. M. Kushakova, S. M. Ramsh, and A. V. Garabadgiu
The detailed scheme of reactions, occurring on interacting ethylene thiourea with chloroacetic acid and
its esters, has been supplemented with a series of new reactions. The whole spectrum of products formed
on interaction of ethylene thiourea with 2-bromobutyric acid has been obtained.
Keywords: ethylene thiourea (2-imidazolidinethione), interaction with 2-bromobutyric acid, interaction
with chloroacetic acid and its esters.
The alkylation products of cyclic thioureas with α-halocarboxylic acids and their esters are of interest as
substances with possible biological activity due to affinity towards NO synthase [1] and GABA receptors [2].
Although the considered reactions of individual representatives of this series of compounds have been studied in
some detail, their synthetic possibilities are far from being exhausted. In addition there has been no systematic
consideration of the character of the conversions as a function of the size of the heterocycle of cyclic thioureas.
The present work is the first step on the route of such consideration and suggests a continuation to examples of
six- and seven-membered cyclic thioureas.
Alkylation of the five-membered cyclic thiourea, ethylene thiourea (2-imidazolidinethione, 1), with
α-halocarboxylic acids and their esters has been studied in [3-10], most thoroughly in [3]. We have added to the
data obtained in these studies, pertaining to chloroacetic acid and its esters, with a series of new reactions, and
also have obtained all the possible products formed on interacting ethylene thiourea (1) with 2-bromobutyric
acid, an alkylating agent not used previously.
None of the mentioned studies reported the preparation of [(4,5-dihydro-2-imidazolyl)thio]acetic acid
hydrochloride (2a) in one step, directly by the interaction of compound 1 with chloroacetic acid. Only a two-step
procedure for obtaining this compound was proposed. First the corresponding free base, the zwitter-ion [(4,5-
dihydroimidazol-3-ium-2-yl)thio]acetate (3a) (pathway a), was obtained by the action of chloroacetic acid on
compound 1 in the presence of sodium acetate in boiling ethanol. Compound 3a was then converted into the
desired hydrochloride 2a (pathway b) [3]. Attempts to alkylate compound 1 with chloroacetic acid under the
"usual" conditions, i.e. in boiling ethanol or water, gave not the expected amino acid hydrochloride 2a but the
hydrochloride of 3-(2-aminoethyl)-2,4-thiazolidinedione (4a) (pathway c) [3]. We succeeded in developing a
one-step method of obtaining compound 2a by the interaction of compound 1 with chloroacetic acid in
anhydrous acetone at room temperature (pathway d).
__________________________________________________________________________________________
St Petersburg State Technological Institute (Technical University), Saint Petersburg 198013, Russia;
e-mail: gsramsh@mail.wplus.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 250-255,
February, 2006. Original article submitted December 29, 2003.
0009-3122/06/4202-0221©2006 Springer Science+Business Media, Inc.
221

The preparation of ethyl [(4,5-dihydro-2-imidazolyl)thio]acetate hydrochloride (5) by the interaction of
compound 1 with ethyl chloroacetate on boiling in ethanol (pathway e) or pyridine was described in [3]. The use
of anhydrous solvent was obviously linked with the fear of the possible formation of thiazolidinedione 4a in
place of the desired compound 5 by hydrolysis of the C=N double bond in the product of cyclization of
compound 5, the hydrochloride of 5,6-dihydroimidazo[2,1-b][1,3]thiazol-3(2H)-one (6a).
We have established that such a precaution is excessive, since ester derivative 5 may be obtained not
only by the method indicated but also on boiling compound 1 with ethyl chloroacetate in 96% ethanol
(pathway f), and the transformation of compound 5 into thiazolidinedione 4a expected in the latter case does not
occur. Ester derivative 5 may also be obtained by maintaining the reactants mentioned in anhydrous acetone at
room temperature (pathway g). However to obtain the butyl analog of compound 5 by treating ethylene thiourea
1 with butyl chloroacetate in boiling alcohol was unsuccessful, only thiazolidinedione 4a was isolated from the
reaction mixture (pathway h).
"Discrepant" results on the alkylation of compound 1 with chloroacetic acid and its esters in boiling
ethanol may be explained in the following way. Probably compound 1 is alkylated by chloroacetic acid more
rapidly than by its esters, i.e. amino acid 2a is formed more rapidly than ester derivative 5. Compound 2a, in
turn, is cyclized into bicyclic compound 6a more rapidly than compound 5. The resulting bicyclic compound 6a
is subject to hydrolysis to thiazolidinedione 4a. As a result, at the same time in the reaction, substrate 1 interacts
with chloroacetic acid and "succeeds" in being transformed into thiazolidinedione 4a, and with ethyl
chloroacetate gives only ester derivative 5. The ease of cyclization of amino acid 2a compared with its ester 5
may be caused not only by structural factors but also by the higher acidity of the medium generated by amino
acid 2a, since such cyclizations are usually catalyzed by acids. The different course of the reaction in the case of
the acid and its ethyl ester may also be linked with the different solubility of the monocyclic derivatives 2a and 5
in the reaction medium. Amino acid hydrochloride 2a is possibly more soluble in ethanol than the hydrochloride
of its ester 5. As a result the first succeeds in being cyclized in solution to be precipitated from it, and the second
does not.
It is possible that on alkylation of ethylene thiourea 1 with butyl chloroacetate the reaction mixture is
additionally acidified due to the relative ease of hydrolysis of the ester group in the alkylating agent and/or the
intermediately formed butyl analog of compound 5 [11]. Compound 2a formed in this or any procedure is
relatively rapidly cyclized into bicyclic compound 6a (more rapidly than the hypothetical butyl analog of
compound 5), which in turn is hydrolyzed to thiazolidinedione 4a. Additional acidification of the reaction
mixture (as a result of hydrolysis) favors the acid-catalyzed cyclization.
Previously, only one preparative method was known for obtaining the bicyclic compound 6a, viz. by
boiling zwitter-ion 3a in aqueous methanolic HCl (pathway i) [3]. This compound is also obtained on heating
compound 1 with chloroacetic acid in glacial acetic acid. However this method may not be considered as
preparative since a significant amount of thiazolidinedione 4a is formed in addition to the desired compound [9].
We have developed simple and efficient methods for obtaining 5,6-dihydroimidazo[2,1-b][1,3]thiazol-3(2H)-one
hydrochloride (6a) by heating amino acid hydrochloride 2a or its ethyl ester hydrochloride 5 without solvent at
100°C (pathways j and k respectively). We have also found one further method for obtaining bicyclic compound
6a, by boiling ester derivative 5 in 96% ethanol in the presence of a catalytic amount of HCl (1-2 drops
hydrochloric acid) (pathway l). On adding a larger amount of the same acid (1-2 ml) only thiazolidinedione 4a,
the product of hydrolysis of compound 6a, may be isolated from the reaction mixture (pathway m). Two further
methods are known for obtaining thiazolidinedione 4a, from compound 1 and chloroacetyl chloride in acetone,
and also by extended treatment of zwitter-ion 3a with saturated ethanolic HCl solution [4].
All the possible products of interaction of ethylene thiourea 1 with 2-bromobutyric acid were
successfully obtained by the procedures given in [3]. These were zwitter-ionic 2-[(4,5-dihydroimidazol-3-ium-2-
yl)thio]butyrate (3b), 2-[(4,5-dihydro-2-imidazolyl)thio]butyric acid hydrochloride (2b), 2-ethyl-5,6-
dihydroimidazo[2,1-b][1,3]thiazol-3(2H)-one
hydrochloride
(6b),
and
3-(2-aminoethyl)-5-ethyl-2,4-
222

223

thiazolidinedione hydrobromide (4b) (pathways n-q respectively). It should be noted that the methyl analog of
the bicyclic compound 6b was not successfully obtained in the reaction of compound 1 with ethyl
α-bromopropionate according to the authors of [10].
EXPERIMENTAL
1
The H NMR spectra were obtained in DMSO-d6 on a Bruker DPX-300 (300 MHz) spectrometer,
chemical shifts were determined relative to the signal of the solvent. The chemical shifts for multiplet signals are
given for their geometric centers. TLC was carried out on Silufol UV-254 plates, eluting with butyl acetate–
ethanol–chloroform, 1:10:100. Anhydrous acetone was prepared by the procedure of [12].
2-Imidazolidinethione (1) was obtained by the method of [13]; mp 197-198°C (lit.198°C [10]).
1H NMR spectrum, δ, ppm: 4.0 (4H, 4-, 5-CH2); 10.4 (2H, s, N(1)H, N(3)H).
[(4,5-Dihydroimidazol-3-ium-2-yl)thio]acetate (3a) was obtained by the action of chloroacetic acid on
compound 1 in ethanol in the presence of sodium acetate as described in [3] (pathway a); mp 181-184°C (lit.
183°C [3]). 1H NMR spectrum, δ, ppm: 3.6 (4H, 4-, 5-CH2); 4.0 (2H, s, SCH2); 11.2 (2H, s, N(1)H, N(3)H).
2-[(4,5-Dihydroimidazol-3-ium-2-yl)thio]butyrate (3b) was obtained analogously to compound 3a
(pathway n). Compound 1 (1.02 g, 10 mmol) was dissolved in ethanol (20 ml) with stirring and moderate
heating. 2-Bromobutyric acid (2.50 g, 1.6 ml, 15 mmol) and sodium acetate (1.0 g, 12 mmol) were added to the
obtained solution and stirring was continued for 2.5 h. The solvent was removed in vacuum, and the resulting
1
residue was twice recrystallized from 20% ethanol. Yield 0.90 g (48%); mp 135-137°C. H NMR spectrum,
δ, ppm (J, Hz): 1.1 (3H, t, J = 8, CHCH2CH3); 2.0 (2H, m, CHCH2CH3); 3.6 (4H, NCH2); 4.0 (1H, t, J = 7,
CHCH2CH3); 11.2 (2H, s, N(1)H, N(3)H). Found. %: C 44.66; H 6.48; N 14.86. C7H12N2O2S. Calculated, %:
C 44.66; H 6.43; N 14.88.
[(4,5-Dihydro-2-imidazolyl)thio]acetic Acid Hydrochloride (2a). A (pathway d). Chloroacetic acid
(1.42 g, 15 mmol) was added with vigorous stirring to compound 1 (1.02 g, 10 mmol) in anhydrous acetone
(20 ml) and the reaction mixture was left at ~20°C for 8 h. The resulting solid was filtered off, and washed with
anhydrous acetone. Yield 1.17 g (59%); mp 128-129°C (lit. mp 129°C [3]). 1H NMR spectrum, δ, ppm: 4.0 (4H,
4-, 5-CH2); 4.4 (2H, s, SCH2); 8.2 (2H, s, N(1)H, N(3)H).
B. Compound 2a was obtained by the action of aqueous HCl in ether on compound 3a as described in
[3] (pathway b); mp 128-129°C.
2-[(4,5-Dihydro-2-imidazolyl)thio]butyric Acid Hydrochloride (2b) was obtained analogously to
compound 2a by procedure B (pathway o). Conc. HCl (1 ml) was added dropwise with vigorous stirring to a
suspension of compound 3b (0.56 g, 3.0 mmol) in ether (25 ml) at ~20°C. As a result of the reaction a colorless
oil formed on the bottom of the flask, and crystallized after adding ethanol (25 ml). The resulting solid was
1
recrystallized from 20% ethanol. Yield 0.40 g (59%); mp 112-114°C. H NMR spectrum, δ, ppm (J, Hz): 1.2
(3H, t, J = 8, CHCH2CH3); 2.0 (2H, m, CHCH2CH3); 4.0 (4H, 4-, 5-CH2); 4.4 (1H, t, J = 7, CHCH2CH3); 8.2
(2H, s, N(1)H, N(3)H). Found, %: C 37.45; H 5.83; N 12.40. C7H12N2O2S·HCl. Calculated, %: C 37.41; H 5.83;
N 12.47.
Ethyl [(4,5-Dihydro-2-imidazolyl)thio]acetate Hydrochloride (5). A. Compound 5 was obtained by
the action of ethyl chloroacetate on compound 1 in absolute ethanol as described in [3] (pathway e));
1
mp 143-144°C (lit. 144°C [3]). H NMR spectrum, δ, ppm (J, Hz): 1.3 (3H, t, J = 7, CH2CH3); 3.9 (4H, 4-,
5-CH2); 4.2 (2H, q, J = 7, CH2CH3); 4.4 (2H, s, SCH2); 11.0 (2H, s, N(1)H, N(3)H).
B (pathway f). Compound 1 (2.04 g, 20 mmol) was dissolved by heating in ethanol (15 ml). Ethyl
chloroacetate (3.67 g, 3.17 ml, 30 mmol) was added to the obtained solution, and the reaction mixture boiled for
2 h. The solvent was removed in vacuum, and the residue recrystallized from acetonitrile. Yield 3.10 g (69%);
mp 142-144°C.
224

C (pathway g). Ethyl chloroacetate (1.84 g, 1.6 ml, 15 mmol) was added with vigorous stirring to
compound 1 (1.02 g, 10 mmol) in anhydrous acetone (20 ml) and the mixture left at ~20°C for 10 h. The
resulting solid was filtered off, washed with anhydrous acetone, and recrystallized from acetonitrile. Yield 0.77 g
(34%); mp 143-144°C.
3-(2-Aminoethyl)-2,4-thiazolidinedione Hydrochloride (4a). A. Compound 4a was obtained as
described in [3] by the action of chloroacetic acid on compound 1 in water (pathway c); mp 225-227°C (lit.
1
mp 227°C [3]). H NMR spectrum, δ, ppm (J, Hz): 3.0 (2H, t, J = 6, N(3)CH2CH2); 3.8 (2H, t, J = 6,
N(3)CH2CH2); 4.1 (2H, s, 5-CH2); 8.9 (3H, s, NH3).
B (pathway c). This method was mentioned in [3] but no description was given. Compound 1 (1.02 g, 10
mmol) in 96% ethanol (5 ml) was heated until complete solution of the substrate. A solution of chloroacetic acid
(1.04 g, 11 mmol) in 96% ethanol (5 ml) was added to the obtained solution, and the mixture was boiled for 1 h.
The solvent was removed in vacuum, and the residue recrystallized from ethanol. Yield 0.84 g (43%);
mp 224-225°C.
C (pathway h). Compound 1 (1.02 g, 10 mmol) in 96% ethanol (10 ml) was heated until the substance
had completely dissolved. Butyl chloroacetate (1.70 g, 1.54 ml, 11 mmol) was added to the obtained solution,
and the reaction mixture was boiled for 3 h. The solvent was removed in vacuum, the oily residue was treated
with heptane, and the resulting solid was recrystallized from ethanol. Yield 0.19 g (10%); mp 225-227°C.
D (pathway m). Compound 5 (0.90 g, 4.0 mmol) was dissolved in 96% ethanol (20 ml) by heating.
Conc. HCl (1 ml) was added dropwise to the obtained solution, and the reaction mixture boiled for 3 h. The
solvent was removed in vacuum, and the residue recrystallized from ethanol. Yield 0.47 g (60%);
mp 224-226°C.
3-(2-Aminoethyl)-5-ethyl-2,4-thiazolidinedione Hydrobromide (4b) (pathway q). Compound 1
(1.12 g, 11 mmol) in water (20 ml) was heated until complete solution of the substrate. 2-Bromobutyric acid
(2.39 g, 1.60 ml, 14 mmol) was added to the obtained solution, and the reaction mixture boiled for 12 h. The
solvent was removed in vacuum, the oily residue was treated with ethyl acetate, and the resulting solid was
1
recrystallized from ethanol. Yield 2.48 g (84%); mp 178-179°C. H NMR spectrum, δ, ppm (J, Hz): 1.0 (3H, t,
J = 8, 5-CH2CH3); 1.9 (1H, m, 5-CHAHBCH3); 2.1 (1H, m, 5-CHAHBCH3); 3.0 (2H, t, J = 5, N(3)CH2CH2); 3.8
(2H, t, J = 5, N(3)CH2CH2); 4.4 (1H, m, H-5); 8.2 (3H, s, NH3). Found, %: C 31.27; H 4.91; N 10.36.
C7H12N2O2S·HBr. Calculated, %: C 31.24; H 4.87; N 10.41.
5,6-Dihydroimidazo[2,1-b][1,3]thiazol-3(2H)-one (6a). A. Compound 6a was obtained by the action of
1
HCl on zwitter-ion 3a as described in [3] (pathway i); mp 205-206°C (lit. 206°C [3]). H NMR spectrum,
δ, ppm: 4.4 (2H, 5-CH2); 4.5 (2H, 6-CH2); 4.8 (2H, s, 2-CH2); 10.5 (1H, s, NH).
B (pathway j). A weighted portion of compound 2a (0.20 g, 1.0 mmol) was heated in vacuum at 100°C
for 6 h. Yield 0.18 g (100%); mp 204-206°C.
C (pathway k). A weighted portion of compound 5 (0.22 g, 1.0 mmol) was heated in vacuum at 100°C
for 6 h. Yield 0.18 g (100%); mp 204-205°C.
D (pathway l). Compound 5 (0.90 g, 4.0 mmol) was dissolved in 96% ethanol (20 ml) by heating.
Conc. HCl (2 drops) was added to the obtained solution, and the reaction mixture was boiled for 3 h. The solvent
was removed in vacuum, and the residue was crystallized from 2-propanol–ethanol, 1:1. Yield 0.43 g (60%); mp
205-206°C.
2-Ethyl-5,6-dihydroimidazo[2,1-b][1,3]thiazol-3(2H)-one (6b) (pathway p). Compound 3b (0.56 g,
3.0 mmol) was dissolved in 50% methanol (2 ml) by heating. Conc. HCl (2.5 ml) was added dropwise to the
obtained solution, and the reaction mixture boiled for 10 min. The solvent was removed at atmospheric pressure,
1
and the residue recrystallized from isopropyl alcohol. Yield 0.25 g (40%); mp 198-201°C. H NMR spectrum,
δ, ppm (J, Hz): 1.2 (3H, t, J = 8, CH2CH3); 2.0 (1H, m, 2-CHAHBCH3); 2.1 (1H, m, 2-CHAHBCH3); 4.2 (2H,
5-CH2); 4.6 (2H, 6-CH2); 4.8 (1H, t, J = 7, 2-CH); 12.4 (1H, s, NH). Found, %: C 40.68; H 5.36; N 13.57.
C7H10N2OS·HCl. Calculated, %: C 40.68; H 5.36; N 13.55.
225

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