Synthesis and some conversions of N-substituted benzimidazole-2-sulfonic acids

Article abstract of DOI:10.1007/s10593-006-0112-4

A series of N-substituted benzimidazole-2-sulfonic acids was synthesized in good yield by the N-alkylation of benzimidazole-2-sulfonic acids by alkylation with simple and functionalized alkylating agents under mild conditions. The corresponding N-substitu

Full text of DOI:10.1007/s10593-006-0112-4

Chemistry of Heterocyclic Compounds, Vol. 42, No. 4, 2006
SYNTHESIS AND SOME CONVERSIONS OF
N-SUBSTITUTED BENZIMIDAZOLE-2-SULFONIC ACIDS
L. N. Divaeva, T. A. Kuzmenko, A. S. Morkovnik, and V. N. Komissarov
A series of N-substituted benzimidazole-2-sulfonic acids was synthesized in good yield by the
N-alkylation of benzimidazole-2-sulfonic acids by alkylation with simple and functionalized alkylating
agents under mild conditions. The corresponding N-substituted benzimidazolones and also primary,
secondary, and tertiary amines were obtained by the action on the obtained compounds of alkali,
ammonia, ammonium acetate, and amines.
Keywords: 2-aminobenzimidazoles, benzimidazolones, benzimidazole-2-sulfonic acids, N-alkylation,
nucleophilic substitution.
The sulfonyl group in benzimidazole-2-sulfonic acids is a good nucleophile, consequently these
compounds provoke considerable interest as intermediates in the synthesis of various, including practically
significant, derivatives of benzimidazole, in particular 2-amino and 2-alkoxy benzimidazoles, and
benzimidazolones [1-5]. Until now, however, only certain representatives of N-substituted benzimidazole-2-
sulfonic acids have been described. They were synthesized in two stages from 1-alkyl or 1-benzyl
benzimidazoles. On thiolating these compounds under forcing conditions (220-250°C) 1-substituted 1,3-dihydro-
2H-benzimidazole-2-thiones are formed, which are then oxidized to the corresponding sulfonic acids with
KMnO4, H2O2, or sodium percarbonate [1, 2, 6-8]. It is evident that in one of these stages, when labile N-
substituents are present in the molecule, their thermal or oxidative destruction is possible.
To overcome the limitations mentioned we have developed a method of alkylating N-unsubstituted
benzimidazole-2-sulfonic acids 1a,k with simple or functionalized alkylating reagents. This process takes place
under mild conditions (50-70°C), in good yield in water, alcohol, or aqueous-alcoholic medium in the presence
of 2 equiv. alkali. Somewhat unexpectedly the sulfonic acids are alkylated approximately as readily as the
benzimidazole itself [9], although the electron-withdrawing sulfonyl group must significantly reduce the electron
density on the nitrogen atom and thereby aid a reduction of its reactivity. This is probably connected with the
fact that under the reaction conditions the sulfonyl group is in the less electron-withdrawing anionic form. The
synthetic usefulness of N-substituted sulfonic acids 2a-k was demonstrated by us in the example of their
reactions with alkali, ammonia, and amines, which lead to the corresponding 1-substituted benzimidazolones
3c,d,i,k and 2-aminobenzimidazoles of types 4-6, including those with ω-dialkylaminoalkyl or β-aryloxyethyl
groups.
__________________________________________________________________________________________
Research Institute of Physical and Organic Chemistry, Rostov State University, Rostov-on-Don 344090,
Russia; e-mail: asmork2@ipoc.rsu.ru. Translated from Khimiya Geterotsiklicheskikh, No. 4, pp. 528-534.
Original article submitted June 16, 2004.
0009-3122/06/4204-0463©2006 Springer Science+Business Media, Inc.
463

H
R
R
R
R
N
N
N
SO3H
O
N
R1
H
1a,k
–
3c,d,i,k
1
1
.
.
OH
R X(R X HCl)
R
R
N
N
R1
SO3H
2a–k
R3
R2
NH3
(MeCOONH4)
HN
R = H
R = H
OH
N
NH2
R3
R2
N
N
R1
N
NH2
N
R1
4a,b,d,g–i
6d,h
OH
R
R
N
N
N
H
R1
5d–f,h,k
1-5 a-i R = H, k R = Me; 2-6 a R1 = Me, b R1 = Et, c R1 = Bn, d, k R1 = PhO(CH2)2,
e R1 = p-ClC6H4O(CH2)2, f R1 = p-MeC6H4O(CH2)2, g R1 = Et2N(CH2)2,
h R1 = β-piperidinoethyl, i R1 = β-morpholinoethyl, j R1 = Me2N(CH2)2,
6 d R2,R3 = (CH2)2O(CH2)2, h R2,R3 = (CH2)4
Reaction with ammonia and low-boiling amines is usually carried out in an autoclave [3]. We found
however that to obtain primary 2-aminobenzimidazoles it was far more convenient to use ammonium acetate as
the reactant. This enables nucleophilic substitution of an amino group to be carried out with practically the same
yield but at atmospheric pressure. In the same manner 2-amino-1-(β-phenoxyethyl)benzimidazole (4d) in
particular was obtained, the synthesis of which by amination of 1-(β-phenoxyethyl)-2-benzimidazole with
sodium amide according to Chichibabin was previously unsuccessfully effected due to destruction of the N-
substituent [13].
It is interesting to note that benzimidazole-2-sulfonic acid interacts with ammonium formate in a
completely different way. In this case in place of the formation of amino derivatives reduction of the sulfonic
acid group is observed combined with desulfurization [15].
1-(ω-Dialkylaminoalkyl)benzimidazole-2-sulfonic acids 2g-k, in difference to the other 1-substituted
sulfonic acids synthesized by us, dissolve readily in water. Consequently their preparation and subsequent
replacement of the sulfonic acid group was carried out as a one-pot process. The exception was
1-(β-piperidinoethyl)benzimidazole-2-sulfonic acid (2h) which precipitated from the reaction mixture as the
poorly soluble potassium salt.
464

TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C*
Yield, %*2
С
H
N
2b
2c
2d
2e
2f
C9H10N2O3S
C14H12N2O3S
C15H14N2O4S
C15H13ClN2O4S
C16H16N2O4S
C17H18N2O4S
C14H12N2O
47.32
47.78
58.01
58.32
56.37
56.59
51.34
51.07
57.73
57.82
58.64
58.94
75.21
74.98
70.62
70.85
63.64
63.14
72.37
72.32
71.12
71.13
66.13
66.02
68.04
68.67
61.67
61.54
69.03
69.43
52.77
53.19
4.21
4.46
3.98
4.20
4.41
4.43
4.24
3.71
4.58
4.85
4.93
5.24
5.43
5.39
5.94
5.55
6.78
6.93
6.65
6.43
6.35
5.97
8.27
8.31
6.45
6.44
5.57
5.47
6.86
6.80
7.03
7.25
12.07
12.38
9.51
9.72
9.15
8.80
8.31
7.94
8.57
8.43
7.87
8.09
12.51
12.49
11.17
11.02
17.33
16.99
10.13
9.92
16.38
16.59
25.96
25.66
14.67
14.13
13.00
12.66
13.77
13.49
15.07
15.51
315-316
263-265
281-284
270-273
238-241
258-261
194-196 [10]
132-134
126-127
196-197
167-168
150 [13]
198-199
194-195
225-226
195-197
182-183
119-120
254-255
87
80
59
81
59
80
60
72
34
72
83
50
86
75
63
65
72
69
67
2k
3c
3d
3i
C15H14N2O2
C13H17N3O2
C17H18N2O2
C15H15N3O
3k
4d
4j
C12H18N4
5d
5e
5f
C17H19N3O
C17H18ClN3O2
C18H21N3O2
C16H24N4O·2HCl
C19H23N3O2
C19H21N3O2
C18H26N4·2HCl
5h
5k
6d
6h
69.88
70.13
70.55
70.57
58.56
58.22
7.01
7.12
6.77
6.55
7.87
7.60
13.01
12.91
13.17
12.99
15.44
15.09
_______
* Compounds 2b, 4b were recrystallized from water, 2c from aqueous
alcohol, 2d,e,f,k, 3c,k, 4j, 5d,f,l, 6d,h from ethanol, 3d from iso-octane, 3i
from CCl4, 4d, 5e from 2-propanol, and 5h from MeCN.
*2 Yield of compound 2g was 67% and 2j 50% (according to the yield of
amino derivative in the reaction with ammonia) and of compounds 2h 78
and 2i 70% (according to the yield of the potassium salt of the sulfonic
acid).
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian XL 300 (300 MHz) instrument in a mode internally
2
stabilized by the polar resonance of the H line of the deuterated solvent. The physicochemical and spectral
characteristics of the synthesized compounds are given in Tables 1 and 2.
465

TABLE 2. 1H NMR Spectra of the Synthesized Compounds
Com-
pound
Chemical shifts, δ, ppm (J, Hz)*
1
2
2d
4.51 (2H, t, J = 4.9, CH2); 5.12 (2H, t, J = 4.9, CH2); 6.78 (2H, d, J = 8.3,
о-H Ph); 6.85 (1H, t, J = 7.4, p-H Ph); 7.18 (2H, t, J = 7.8, m-HPh); 7.60 (2H, m, H-5,6);
7.75 (1H, d, J = 8.0, H-4 or H-7); 8.05 (1H, d, J = 7.7, H-7 or H-4)
2e
4.51 (2H, t, J = 5.0, CH2); 5.12 (2H, t, J = 5.0, CH2); 6.81 (2H, d, J = 8.9,
o-HPh); 7.16 (2H, d, J = 8.5, m-HAr); 7.54-7.67 (2H, m, H-5,6); 7.75 (1H, d, J = 7.20,
H-7 or H-4); 8.04 (1H, d, J = 7.7, H-4 or H-7)
2k
2.42 (3H, s, CH3); 2.45 (3H, s, CH3); 4.50 (2H, t, J = 4.9, CH2); 5.04 (2H, t, J = 4.9, CH2);
6.79 (2H, d, J = 8.3, o-HPh); 6.87 (1H, t, J = 7.5, p-НPh); 7.20 (2Н, t, J = 7.9, m-НPh);
7.47 (1H, s, H-4); 7.73 (1H, s, H-7 or H-4)
3d
3i
4.30 (4H, s, CH2CH2); 6.86 (2H, d, J = 8.0, o-H Ph); 6.93 (1H, t, J = 7.5, p-HPh);
7.05-7.17 (3H, m, HAr.); 7.20-7.29 (3H, m, HAr.); 9.06 (1H, br. s, NH)
2.54 (4Н, t, J = 4.9, NCH2); 2.64 (2Н, t, J = 7.5, NCH2); 3.63 (4Н, t, J = 5.3, 2ОСН2);
3.99 (2Н, t, J = 7.5, NCH2); 6.99-7.11 (4Н, m, HAr); 8.91 (1H, s, NH) [14]
3k
4d
2.27 (3Н, s, CH3); 2.31 (3H, s, CH3); 4.26 (4H, s, CH2CH2); 6.8-7.1 (5H, m, HAr);
7.23-7.28 (2H, m, HAr); 8.83 (1H, s, NH)
4.30 (2Н, t, J = 4.8, CH2); 4.37 (2Н, t, J = 4.8, CH2); 5.05 (2H, br. s, NH2);
6.84 (2H, d, J = 8.4, о-НPh); 6.97 (1Н, t, J = 7.9, p-НPh); 7.05-7.30 (5H, m, HAr);
7.44 (1Н, d, J = 7.5, Н-4 or H-7)
5d
5e
5f
3.47 (2H, q, JCH2–NH = JCH2–CH2 = 5.4, CH2NH); 3.66 (2H, t, JCH2–NH = 5.5, CH2OH);
4.20 (2H, t, J = 5.2, CH2); 4.37 (2H, t, J = 5.2, CH2); 4.90 (1H, br. s, NH);
6.57 (1H, t, J = 6.0, p-HPh); 6.83-6.96 (5H, m, HAr); 7.12-7.25 (4H, m, HAr)
3.45 (2H, q, JCH2–NH = JCH2–CH2 = 5.3, CH2NH); 3.64 (2H, t, JCH2–NH = 5.3, CH2OH);
4.19 (2H, t, J = 5.4, CH2); 4.35 (2H, t, J = 5.4, CH2); 4.88 (1H, br. s, OH);
6.55 (1H, t, J = 5.4, NH); 6.81-6.94 (4H, m, HPh + H-5,6); 7.10-7.21 (4H, m, HPh + H-4,7)
2.23 (3H, s, CH3); 3.46 (2H, q, JCH2–NH = JCH2–CH2 = 5.3, CH2NH); 3.64 (2H, t,
JCH2–NH = 5.3, CH2OH); 4.15 (2H, t, J = 5.5, CH2); 4.34 (2H, t, J = 5.5, CH2);
4.90 (1H, br. s, OH); 6.55 (1H, t, J = 5.3, NH); 6.74 (2H, d, J = 8.6, o-HAr);
6.8-6.9 (2H, m, H-5,6); 6.99 (2H, d, J = 8.2, m-HAr); 7.10-7.17 (2H, m, H-4,7)
5h*2
1.40-2.15 (6H, m, 3-,4-,5-CH2, piperidyl); 3.20 (2H, br. m, CH2);
3.44 (2H, br. t, J ~ 7.0, CH2); 3.52 (1H, br. s, NH); 3.58 (2H, br. q, J ~ 5.0, NHCH2);
3.73 (2H, t, J = 5.0, CH2OH); 4.89 (2H, t, J = 8.0, N(1)CH2); 7.19-7.35 (2H, m, H-5,6);
7.41 (2H, d, J = 7.3, H-4 or H-7); 7.96 (1H, d, J = 7.2, H-7 or H-4);
9.94 (1H, br. t, J ~ 5.0, NH); 11.77 (1H, br. s, NH); 13.44 (1H, br. s, NH)
5k
2.25 (3H, s) and 2.27 (3H, s) – 5-CH3 and 6-CH3, 3.44 (2H, q, J1 = 5.1; J2 = 5.1, NHCH2);
3.64 (2H, t, J = 5.1, CH2OH); 4.18 (2H, t, J = 5.4, CH2); 4.30 (2H, t, J = 5.4, CH2);
5.06 (1H, br. s, NH); 6.44 (1H, t, J = 5.7, p-НPh); 6.87 (2H, d, J = 8.0, о-HPh);
6.90 (1H, s) and 6.93 (1H, s) – H-4,7); 7.22 (2Н, t, J = 8.0, m-НPh)
6d
3.36 (4Н, t, J = 4.7, CH2NCH2); 3.87 (4H, t, J = 4.7, CH2OCH2);
4.37 (2H, t, J = 5.5, CH2); 4.46 (2H, t, J = 5.5, CH2); 6.83 (2H, d. t, J1 = 7.8; J2 = 1.0,
o-HPh); 6.97 (1H, tt, J = 7.4, J = 0.8, p-HPh); 7.15-7.32 (4H, m, H-5,6 + m-НPh);
7.32-7.41 (1H, m, H-4 or H-7); 7.61-7.69 (1Н, m, H-7 or H-4)
6h*2
1.42-2.23 (6H, m, 3CH2); 2.11 (4H, br. t, J ~ 6.5, NCH2CH2CH2, pyrrolidyl);
3.05 (2H, br. m, CH2); 3.44 (2H, br. m, CH2); 3.52-3.69 (2Н, br. m, CH2);
3.94 (4H, br. t, J ~ 6.5, CH2NCH2, pyrrolidyl); 4.93 (2Н, br. t, J ~ 6, CH2);
7.22-7.34 (2H, m, HAr); 7.50-7.59 (1Н, m, HAr); 7.81-7.91 (1Н, m, HAr)
_______
* The 1H NMR spectra of compounds 2d,e,k, 5d-f,h,k, and 6h were taken in
DMSO-d6, and of the remainder in deuterochloroform.
*2 Dihydrochloride.
1-Methyl- and 1-Ethylbenzimidazole-2-sulfonic Acids 2a,b. The appropriate dialkyl sulfate (13 mmol)
was added with stirring to a solution of sulfonic acid 1a (1.98 g, 10 mmol) and KOH (1.34 g, 20 mmol) in water
(15 ml), and the mixture stirred for 4 h at 50°C. After cooling, the reaction mixture was acidified with conc. HCl
to pH 4-5. The solid N-substituted sulfonic acid which separated was filtered off, washed with water and with
acetone, and dried.
466

Compound 2a had mp 329-331°C (recrystallized from water) [2], yield 98%.
1-Benzylbenzimidazole-2-sulfonic Acid (2c) was obtained analogously from sulfonic acid 1a and
benzyl chloride in aqueous alcohol (2:1) at 60-70°C during 5-6 h.
1-(β-Aryloxyethyl)benzimidazole-2-sulfonic Acids 2d-f,k were synthesized from sulfonic acids 1a,k
and the appropriate β-aryloxyethyl bromides in alcohol at 70°C during 3 h. The reaction products were isolated
as for sulfonic acids 2a,b.
1-(ω-Dialkylaminoalkyl)benzimidazole-2-sulfonic Acids 2g-j. A solution of sulfonic acid 1a (1.98 g,
10 mmol), KOH (2.1 g, 32 mmol), and the appropriate ω-aminoalkyl chloride hydrochloride (12 mmol) in water
(10 ml) was stirred for 4 h at 60-70°C. In the case of sulfonic acids 2g,i,j the reaction mixture was cooled,
washed with benzene (10 ml) to remove the excess of alkylating agent, acidified to pH 4-5 with conc. HCl, and
used in this form for subsequent conversions.
In the case of 1-(β-piperidinoethyl)-substituted sulfonic acid 2h the poorly soluble potassium salt was
precipitated from the reaction mixture on cooling, and was filtered off, washed with acetone, and dried.
1-Substituted Benzimidazolones 3c,d,i,k. A solution of the appropriate 1-substituted sulfonic acid
(10 mmol) and KOH (4 g, 60 mmol) in water (10 ml) was boiled for 4-5 h, cooled, and acidified with acetic acid
to pH 6. After 10 h the solid benzimidazolone was filtered off, washed with a small volume of cold water, and
dried. In the case of compounds 3d,k the reaction products were dissolved in chloroform, and chromatographed
on a column of Al2O3 (20 x 70 mm) in chloroform, before recrystallization.
1-Alkyl(β-phenoxyethyl)-2-aminobenzimidazoles 4a,b,d. A mixture of the appropriate sulfonic acid
(10 mmol) and ammonium acetate (3.9 g, 50 mmol) in water (2 ml) was boiled for 3 h. On cooling the mixture
was made alkaline with 20% NaOH solution, the precipitated solid amine was filtered off, and washed with
water. Compound 4a had mp 201-202°C [9], 64% yield; 4b mp 155-156°C [11], 98% yield.
2-Amino-1-(ω-dialkylaminoalkyl)benzimidazoles 4g-j. An aqueous solution of 1-(ω-dialkylamino-
alkyl)benzimidazole-2-sulfonic acid 2g,i,j, obtained from unsubstituted acid 1a (20 mmol), or a solution
obtained by acidifying with HCl a suspension of sulfonic acid 2h potassium salt (20 mmol) in water (25 ml), was
saturated with ammonia, and then heated in an autoclave for 2 h at 140-160°C. After cooling, the solid amine
4h,i was filtered off, and washed with water.
In the case of amine 4g a viscous oil was isolated from the reaction mixture and crystallized by treatment
with hot octane (10 ml). Compound 4g had mp 134-135°C (recrystallized from octane) [9], yield was 61%, 4h
mp 176°C [12], yield 61%, 4i mp 190-191°C [12], yield 70%. Mixing tests of compounds 4g-i with known
samples melted with no depression of melting point.
Amine 4j was extracted from the reaction mixture with chloroform (3 × 15 ml) and was then isolated in
the usual way.
2-(β-Hydroxyethylamino)benzimidazoles 5d-f,h,k. A mixture of the 1-substituted sulfonic acid
(5 mmol) and monoethanolamine (3 g, 50 mmol) was heated for 1 h at 150-160°C. After cooling, the mixture
was treated with water (5 ml) and the separated solid amine was filtered off.
In the case of amino alcohol 5h the sulfonic acid 2h was previously obtained from its potassium salt by
treatment with conc. HCl to pH 1, and evaporated to dryness on a water bath. After carrying out the reaction
aminoalcohol 5h was extracted with chloroform (2 x 20 ml), and purified by chromatography on a column of
Al2O3 (20 × 40 mm), eluting with chloroform. The compound was identified as the dihydrochloride, which was
obtained by treatment of an acetone solution of the base with gaseous HCl.
Tertiary Amines 6d,h. A solution of benzimidazole-2-sulfonic acid 2d (5 mmol) in morpholine (5 ml)
was boiled for 3 h, cooled, water (10 ml) was added, and the solid amine 6d was filtered off. With pyrrolidine
the reaction was carried out at 150-160°C in a sealed ampul. After cooling, and treating with water, compound
6h was extracted with chloroform, the solvent was distilled, and the oily amine was converted into the
dihydrochloride by the method described above
467

The work was carried out with the financial support of the Russian Fund for Fundamental Investigations
and administered by the Rostov region (grant No. 04-03-96804).
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