Recyclization of benzimidazo[2,1-b]thiazanium salts into 1-(2,3-epithiopropyl)benzimidazol-2-ones under the action of epichlorhydrin

Article abstract of DOI:10.1007/s10593-010-0511-4

It has been shown that the reaction of epichlorhydrin with 3-hydroxybenzimidazo[2,1-b]thiazanium salts leads to recyclization of the thiazanium ring with the formation of substituted 1-(2,3-epithiopropyl) benzimidazol-2-ones in high yield. The proposed method enables the introduction of functional groups unstable in alkaline medium into the structure of thiirane derivatives. 2010 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-010-0511-4

Chemistry of Heterocyclic Compounds, Vol. 46, No. 3, 2010
RECYCLIZATION OF BENZIMIDAZO[2,1-b]THIAZANIUM
SALTS INTO 1-(2,3-EPITHIOPROPYL)BENZIMIDAZOL-2-ONES
UNDER THE ACTION OF EPICHLORHYDRIN
M. A. Orlov1, A. F. Aslanov1, and N. I. Korotkikh1*
It has been shown that the reaction of epichlorhydrin with 3-hydroxybenzimidazo[2,1-b]thiazanium
salts leads to recyclization of the thiazanium ring with the formation of substituted 1-(2,3-
epithiopropyl)benzimidazol-2-ones in high yield. The proposed method enables the introduction of
functional groups unstable in alkaline medium into the structure of thiirane derivatives.
Keywords: 3-hydroxybenzimidazo[2,1-b]thiazanium salts, thiiranes, 1-(2,3-epithiopropyl)benzimidazol-
2-ones, epichlorhydrin, recyclization.
In spite of the fact that the chemistry of thiiranes has attracted the attention of investigators for a long
time [1-4], the number of efficient approaches to the synthesis of their derivatives containing functional groups
is limited [5-7]. An important method of obtaining derivatives of hetarylthiiranes 2 is the recyclization of
3-hydroxy- and 3-halo-substituted thiazanium salts 2 under the action of alkali [8, 9]. Thiirane derivatives of
azolones with alkyl and aralkyl substituents may be obtained by such a method. However, this method is not
suitable for obtaining compounds containing, apart from the thiirane ring, fragments sensitive to the action of
alkalis (esters, amides, ketone groups).
We have established that in the cases when the counter-ion in the condensed thiazanium salts 1 is halide,
heating the salts with an excess of epichlorhydrin leads directly to recyclization into thiirane derivatives –
1-(2,3-epithiopropyl)benzimidazol-2-ones 2 in high yield and without affecting functional groups in position 3
of the ring. Phenacyl, aminocarbonylmethyl, and alkoxycarbonylmethyl were used as functional groups in this
work.
The conversion of compounds 1  2 is caused by the fact that epichlorhydrin is able to bind halide anions
forming the alkoxide anion of glycerin dihalohydrin 1B which is rapidly protonated as a result of the hydroxyl
group of thiazanium salt 1, assisting the irreversible course of recyclization of the latter to thiirane through the
oxidothiazanium zwitterion 2A and its covalent form 2C. The synchronous occurrence of a reaction with addition
of chloride ion to the oxirane with cleavage of proton from the thiazanium salt is also possible. If the OH
_______
* To whom correspondence should be addressed, e-mail: nkorotkikh@ua.fm.
1L. M. Litvinenko Institute of Physical-Organic Chemistry and Coal Chemistry, National Academy of Sciences
of Ukraine, Donetsk 83114, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 440-444, March, 2010. Original
article submitted June 23, 2009.
0009-3122/10/4603-0347©2010 Springer Science+Business Media, Inc.
347

group is protected by acylation then recyclization does not occur, which is caused by the impossibility of
carrying out the stage of forming intermediate 2A. It is interesting that with perchlorate salts of 1, obtained
analogously [9], the reaction also does not proceed due to the low nucleophilicity of this anion.
R
N +
R
+
N
Cl
S
O
S
Cl
X
X
N
N
–
O
–
X
OH
OH
1A
1B
1
–
Cl
OH
2B
R
R
R
+
N
N
N
O
S
S
N
N
N
O
2C
2A
–
S
O
2
1, 2 а R = PhCOCH2, b R = p-BrC6H4COCH2, c R = (piperidino)СОСН2,
d R = (morpholino)СОСН2, e R = MeОСОСН2, f R = EtОСОСН2
1
In the H NMR spectra of thiazanium salts 1a-f the most characteristic signal is that of the OH group
protons in the 5.95-6.15 region and of the methylene group of the substituent in position 1 (6.21-6.31 for
phenacyl derivatives 1a,b and 5.49-5.53 ppm for the aminoalkoxy derivatives 1c-f). The signals of the
propylene fragment were observed in the regions 3.42-3.76 (CH2S), 4.63-4.75 (CHO), and 4.33-4.58 ppm
(CH2N). The characteristic signals of the 2,3-epithiopropyl group of compounds 2a-f are the two multiplets of
the thiirane rings (in the resolved form of two dd in the 2.37-2.51 and 2.46-2.60 ppm regions, caused by the
geminal and vicinal splitting of the small ring protons), the multiplet signals of the CHS (3.14-3.31), and the
multiplets of the CH2N fragment protons (3.88-4.20 ppm).
A new approach has therefore been developed for obtaining azacyclic derivatives of thiiranes containing
functional groups unstable in alkaline medium, which comprises recyclization of benzimidazo-
[2,1-b]-1,3-thiazanium halides 1a-f on heating in epichlorhydrin. The derivatives obtained may be useful in the
search for new biologically active substances, which is confirmed by predictions of the PASS program. Thus it
forecast high activity of thiiranes 2a-f as inhibitors of prolylaminopeptidases and limonene synthetase, as
cardiovascular analeptics, peripheral vasodilotators, antagonists of acetylcholine receptors, nootropic
preparations, anticonvulsants, etc.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian Gemini 200 (200 MHz) instrument in DMSO-d6,
internal standard was TMS. Chromatography in a thin layer of silica gel was carried out on Silufol plates (Czech
Republic), eluent was chloroform–methanol, 10:1, visualization was with iodine vapor.
3-Hydroxy-10-R-benzimidazo[2,1-b]-1,3-thiazanium Salts 1a-f (General Method). A mixture of
3-hydroxybenzimidazo[2,1-b]thiazane (1 g, 5 mmol), alkylating agent (5.5 mmol), and DMF (1 ml) was heated
348

at 150oC for 40 min. For the isolation of compounds 1a,b precipitated after cooling, the solid was filtered off,
washed with DMF, and with acetonitrile, and dried. For the isolation of compounds 1c-f after cooling, ether
(5 ml) was added, the precipitated solid was filtered off, washed with acetonitrile, and dried.
3-Hydroxy-10-phenacylbenzimidazo[2,1-b]-1,3-thiazanium Bromide (1a). Yield 84%; mp 237-238
oC (DMF). Rf 0.09. 1H NMR spectrum, δ, ppm (J, Hz): 3.42 (1H, dd, 3Jcis = 5.0, 2Jgem = 12.4, CH2S); 3.58 (1H, d,
2
2
2Jgem = 12.4, CH2S); 4.33 (1H, d, Jgem = 13.4, NCH2); 4.47 (1H, d, Jgem = 13.4, NCH2); 4.63 (1H, m, CHO);
5.95 (1H, d, J = 3.4, OH); 6.21 (2H, d, J = 6.8, CH2CO); 7.43 (2H, m, CH arom.); 7.52 (2H, m, CH arom.); 7.68
(1H, m, CH arom.); 7.83 (2H, m, CH arom.); 8.05 (2H, m, CH arom.). Found, %: C 53.5; H 4.3; N 6.7.
C18H17BrN2O2S. Calculated, %: C 53.3; H 4.2; N 6.9.
10-(4-Bromophenacyl)-3-hydroxybenzimidazo[2,1-b]-1,3-thiazanium Bromide (1b). Yield 90%; mp
1
3
2
232-233oC (DMF). Rf 0.08. H NMR spectrum, δ, ppm (J, Hz): 3.54 (1H, dd, Jcis = 4.8, Jgem = 12.5, CH2S);
2
2
3
3.69 (1H, d, Jgem = 12.5, CH2S); 4.45 (1H, dd, Jcis = 2.4, Jgem = 13.5, NCH2); 4.58 (1H, dd, Jtrans = 2.7,
2Jgem = 13.5, NCH2); 4.74 (1H, m, CHO); 6.07 (1H, s, OH); 6.31 (2H, dd, J = 6.9, CH2CO); 7.57 (2H, m, CH arom.);
7.92 (2H, d, J = 8.6, CH arom.); 7.94 (2H, m, CH arom.); 8.09 (2H, d, J = 8.6, CH arom.). Found, %: C 44.5;
H 3.4; N 5.9. C18H16Br2N2O2S. Calculated, %: C 44.7; H 3.3; N 5.8.
3-Hydroxy-10-(piperidinocarbonylmethyl)benzimidazo[2,1-b]-1,3-thiazanium Bromide (1c). Yield
1
76%; mp 197-198oC (DMF). Rf 0.07. H NMR spectrum, δ, ppm (J, Hz): 1.39-1.71 (6H, m, CH2 piperidino);
3.41-3.71 (6H, m, CH2S, CH2N piperidino); 4.41 (1H, dd, 3Jcis = 2.4, 2Jgem = 13.4, NCH2); 4.52 (1H, dd, 3Jtrans = 2.6,
2Jgem = 13.4, NCH2); 4.71 (1H, m, CHO); 5.49 (2H, s, CH2CO); 6.15 (1H, s, OH); 7.59 (2H, m, CH arom.); 7.91 (2H,
m, CH arom.). Found, %: C 49.7; H 5.3; N 10.1. C17H22BrN3O2S. Calculated, %: C 49.5; H 5.4; N 10.2.
3-Hydroxy-10-(morpholinocarbonylmethyl)benzimidazo[2,1-b]-1,3-thiazanium Bromide (1d).
1
Yield 75%; mp 237-238oC (DMF). Rf 0.06. H NMR spectrum, δ, ppm (J, Hz): 3.45-3.76 (10H, m, CH2S, CH2
3
2
3
2
morpholino); 4.42 (1H, dd, Jcis = 2.3, Jgem = 13.4, NCH2CH); 4.54 (1H, dd, Jtrans = 2.6, Jgem = 13.4,
NCH2CH); 4.72 (1H, m, CHO); 5.53 (2H, s, CH2CO); 6.11 (1H, s, OH); 7.59 (2H, m, CH arom.); 7.90 (2H, m,
CH arom.). Found, %: C 46.7; H 4.8; N 10.2. C16H20BrN3O3S. Calculated, %: C 46.4; H 4.9; N 10.1.
3-Hydroxy-10-(methoxycarbonylmethyl)benzimidazo[2,1-b]-1,3-thiazanium Iodide (1e). Yield
1
3
2
60%; mp 212-213oC (DMF). Rf 0.08. H NMR spectrum, δ, ppm (J, Hz): 3.58 (1H, dd, Jcis = 4.9, Jgem = 12.4,
2
2
CH2S); 3.72 (1H, d, Jgem = 12.4, CH2S); 3.78 (3H, s, OCH3); 4.42 (1H, d, Jgem = 13.4, NCH2); 4.57 (1H, d,
2Jgem = 13.4, NCH2); 4.75 (1H, m, CHO); 5.51 (2H, d, J = 7.2, CH2CO); 6.07 (1H, s, OH); 7.60 (2H, m, CH arom.);
7.93 (2H, m, CH arom.). Found, %: C 38.6; H 3.8; N 6.8. C13H15IN2O3S. Calculated, %: C 38.4; H 3.7; N 6.9.
10-(Ethoxycarbonylmethyl)-3-hydroxybenzimidazo[2,1-b]-1,3-thiazanium bromide (1f). Yield
1
71%; mp 179-180oC (DMF). Rf 0.09. H NMR spectrum, δ, ppm (J, Hz): 1.26 (3H, t, J = 7.1, CH3); 3.58 (1H,
dd, 3Jcis = 4.8, 2Jgem = 12.5, CH2S); 3.71 (1H, d, 2Jgem = 12.5 CH2S); 4.24 (2H, q, J = 7.1, OCH2); 4.41 (1H, dd,
3Jcis = 2.4, 2Jgem = 13.5, NCH2); 4.55 (1H, dd, 3Jtrans = 2.7, 2Jgem = 13.5, NCH2); 4.75 (1H, m, CHO); 5.49 (2H, d,
J = 8.0, CH2CO); 6.07 (1H, d, J = 3.4, OH); 7.61 (2H, m, CH arom.); 7.95 (2H, m, CH arom.). Found, %:
C 45.3; H 4.5; N 7.6. C14H17BrN2O3S. Calculated, %: C 45.1; H 4.6; N 7.5.
1-R-3-(2,3-Epithiopropyl)benzimidazol-2-ones 2a-f (General Method). The 3-hydroxybenzimidazo-
[2,1-b]thiazanium salt 1a-f was boiled in a 20-fold molar excess of epichlorhydrin until solution and then for an
additional 5 min, cooled, the solid was filtered off, and recrystallized from alcohol. In the cases when the
reaction product was soluble (compounds 2c-f), the epichlorhydrin was evaporated in vacuum, the residue was
dissolved in chloroform, passed through a layer of silica gel, the chloroform was evaporated in vacuum, and the
obtained substance recrystallized from hexane–2-propanol, 10:1.
3-(2,3-Epithiopropyl)-1-phenacylbenzimidazol-2-one (2a). Yield 80%; mp 134-135oC (2-propanol).
Rf 0.72. 1H NMR spectrum, δ, ppm (J, Hz): 2.50 (1H, d, 3Jcis = 5.4, CH2S); 2.59 (1H, d, 3Jtrans = 6.2, CH2S); 3.28
(1H, m, CHS); 4.02 (1H, dd, 3Jtrans = 6.5, 2Jgem = 14.7, NCH2); 4.19 (1H, dd, 3Jcis = 5.6, 2Jgem = 14.7, NCH2); 5.52
349

(2H, s, CH2CO); 7.01-7.14 (3H, m, CH arom.); 7.34 (1H, m, CH arom.); 7.57-7.71 (3H, m, CH arom.); 8.09
(2H, m, CH arom.). Found, %: C 66.9; H 5.1; N 8.5. C18H16N2O2S. Calculated, %: C 66.7; H 5.0; N 8.6.
1-(4-Bromophenacyl)-3-(2,3-epithiopropyl)benzimidazol-2-one (2b). Yield 85%; mp 209-210oC
(2-propanol). Rf 0.65. 1H NMR spectrum, δ, ppm (J, Hz): 2.51 (1H, m, CH2S); 2.60 (1H, d, 3Jtrans = 6.2, CH2S); 3.31
(1H, m, CHS); 4.03 (1H, dd, 3Jtrans = 6.5, 2Jgem = 14.8, NCH2); 4.20 (1H, dd, 3Jcis = 5.6, 2Jgem = 14.8, NCH2); 5.53 (2H,
s, CH2CO); 7.03-7.10 (2H, m, CH arom.); 7.14 (1H, d, J = 7.5, CH arom.); 7.35 (1H, d, J = 7.6, CH arom.); 7.83
(2H, d, J = 8.3, CH arom.); 8.03 (2H, d, J = 8.3, CH arom.). Found, %: C 53.8; H 3.7; N 7.1. C18H15BrN2O2S.
Calculated, %: C 53.6; H 3.8; N 7.0.
3-(2,3-Epithiopropyl)-1-(piperidinocarbonylmethyl)benzimidazol-2-one (2c). Yield 78%; mp
1
157-158oC (hexane–2-propanol, 10:1). Rf 0.64. H NMR spectrum, δ, ppm (J, Hz): 1.39-1.68 (6H, m,
3
CH2 piperidino); 2.48 (1H, m, CH2S); 2.58 (1H, d, Jtrans = 6.2, CH2S); 3.27 (1H, m, CHS); 3.39-3.56 (4H, m,
3
2
3
2
CH2 piperidino); 4.01 (1H, dd, Jtrans = 6.5, Jgem = 14.8, NCH2); 4.16 (1H, dd, Jcis = 5.6, Jgem = 14.8, NCH2);
4.72 (2H, s, CH2CO); 7.03 (3H, m, CH arom.); 7.28 (1H, m, CH arom.). Found, %: C 61.9; H 6.2; N 12.5.
C17H21N3O2S. Calculated, %: C 61.6; H 6.4; N 12.7.
3-(2,3-Epithiopropyl)-1-(morpholinocarbonylmethyl)benzimidazol-2-one (2d). Yield 80%; mp
161-162oC (hexane–2-propanol, 10:1). Rf 0.59. 1H NMR spectrum, δ, ppm (J, Hz): 2.50 (1H, m, CH2S); 2.59 (1H,
3
3
d, Jtrans = 6.2, CH2S); 3.28 (1H, m, CHS); 3.40-3.71 (8H, m, CH2 morpholino); 4.02 (1H, dd, Jtrans = 6.5,
2Jgem = 14.7, NCH2); 4.17 (1H, dd, 3Jcis = 5.6, 2Jgem = 14.7, NCH2); 4.79 (2H, s, CH2CO); 7.06 (3H, m, CH arom.);
7.29 (1H, m, CH arom.). Found, %: C 57.3; H 5.8; N 12.7. C16H19N3O3S. Calculated, %: C 57.6; H 5.7; N 12.6.
3-(2,3-Epithiopropyl)-1-(methoxycarbonylmethyl)benzimidazol-2-one (2e). Yield 85%; mp
1
100-101oC (hexane–2-propanol, 10:1). Rf 0.70. H NMR spectrum, δ, ppm (J, Hz): 2.49 (1H, m, CH2S); 2.57
3
3
2
(1H, d, Jtrans = 6.2, CH2S); 3.26 (1H, m, CHS); 3.68 (3H, s, OCH3); 3.99 (1H, dd, Jtrans = 6.5, Jgem = 14.8,
NCH2); 4.15 (1H, dd, 3Jcis = 5.6, 2Jgem = 14.8, NCH2); 4.75 (2H, s, CH2CO); 7.06 (2H, m, CH arom.); 7.17 (1H,
d, J = 7.2, CH arom.), 7.32 (1H, d, J = 7.0, CH arom.). Found, %: C 56.4; H 5.2; N 10.2. C13H14N2O3S.
Calculated, %: C 56.1; H 5.1; N 10.1.
3-(2,3-Epithiopropyl)-1-(ethoxycarbonylmethyl)benzimidazol-2-one (2f). Yield 75%; mp 127-129oC
(hexane–2-propanol, 10:1). Rf 0.74. 1H NMR spectrum, δ, ppm (J, Hz): 1.08 (3H, t, J = 7.1, CH3); 2.37 (1H, m,
3
3
2
CH2S); 2.46 (1H, d, Jtrans = 6.2, CH2S); 3.14 (1H, m, CHS); 3.88 (1H, dd, Jtrans = 6.5, Jgem = 14.8, NCH2);
4.01-4.07 (3H, m, NCH2, CH2O); 4.61 (2H, s, CH2CO); 6.95 (2H, m, CH arom.); 7.05 (1H, d, J = 7.5,
CH arom.); 7.21 (1H, d, J = 7.0, CH arom.). Found, %: C 57.7; H 5.3; N 9.5. C14H16N2O3S. Calculated, %:
C 57.5; H 5.5; N 9.6.
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