Unexpected formation of imidazole-4,5-dicarboxylic acid in the oxidation of 2-substituted benzimidazoles with hydrogen peroxide

Full text of DOI:10.1134/S1070428016100286

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 10, pp. 1528–1530. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © M.A. Brusina, D.N. Nikolaev, S.M. Ramsh, L.B. Piotrovskii, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52,
No. 10, pp. 1533–1535.
SHORT
COMMUNICATIONS
Unexpected Formation of Imidazole-4,5-dicarboxylic Acid
in the Oxidation of 2-Substituted Benzimidazoles
with Hydrogen Peroxide
M. A. Brusinaa, b, D. N. Nikolaeva, S. M. Ramshb,* and L. B. Piotrovskiia
a Institute of Experimental Medicine, Russian Academy of Medical Sciences,
ul. Akad. Pavlova 12, St. Petersburg, 197376 Russia
b St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
*e-mail: sramsh@technolog.edu.ru
Received April 20, 2016
DOI: 10.1134/S1070428016100286
The unique structure of imidazole-4,5-dicarboxylic
acid (4,5-IDC) and its 2-alkyl derivatives, specifically
the presence of six heteroatoms in a single molecule
and the ability to lose one to three protons with forma-
tion of the corresponding anions, gives rise to a variety
of coordination modes in their complexes with tran-
sition metal ions [1–3] and determines the use of
4,5-IDC derivatives in different fields of chemistry
such as catalysis [1] and gas separation and adsorption
[2]. On the other hand, 4,5-IDC derivatives are inter-
esting for pharmacology [4–6]. Amides derived from
4,5-IDC stimulate the central nervous system and
exhibit antiproliferative activity [5], while 2-alkyl-sub-
stituted derivatives are NMDA receptor ligands [6].
and the overall yield is poor, so that it cannot be used
to obtain large amounts of the target products.
An alternative method for the synthesis of 2-alkyl-
imidazole-4,5-dicarboxylic acids is the oxidation of
2-alkylbenzimidazoles with potassium dichromate
[8, 9] or hydrogen peroxide [9–11]. Comparison of dif-
ferent oxidants showed that the use of hydrogen per-
oxide is preferred due to higher yields [9]. However,
acceptable yields were achieved only for unsubstituted
4,5-IDC (72%) and its lower alkyl derivatives (R =
Me, Et, Pr), whereas the yield of 2-pentylimidazole-
4,5-dicarboxylic acid was as poor as 15%.
The goal of the present work was to elucidate the
reason for the sharp reduction of the yield of 2-alkyl-
substituted 4,5-IDCs with increase of the length of the
alkyl chain in the oxidation of 2-alkylbenzimidazoles
1a–1c with hydrogen peroxide according to the proce-
dure described in [9]. Detailed study of the composi-
tion of the reaction mixtures revealed the presence of
a by-product, unsubstituted 4,5-IDC (3). The oxidation
of 2-phenyl-substituted analog 1d was also accom-
panied by formation of 3.
However, despite strong interest in 2-alkyl-substi-
tuted 4,5-IDCs, their synthesis still remains difficult.
Two synthetic approaches to 4,5-IDC derivatives are
known. The first one involves imidazole ring construc-
tion from diaminomaleonitrile, followed by hydrolysis
of imidazoledicarbonitriles [7], and the second is based
on the oxidation of a more complex cyclic system
[8–11]. The first approach ensures preparation of
4,5-IDC derivatives with alkyl radicals of different
lengths, but the procedure includes a number of steps,
Because of very poor solubility of acids 2a–2d in
water and organic solvents, we succeeded in separating
COOH
COOH
COOH
COOH
N
N
N
H2O2, H2SO4, 100–130°C
+
R
R
N
H
N
H
N
H
1a–1d
2a–2d
3
R = Me (a), Et (b), Pr (c), Ph (d).
1528

UNEXPECTED FORMATION OF IMIDAZOLE-4,5-DICARBOXYLIC ACID
1529
the products only by treatment with triethanolamine,
Oxidation of benzimidazoles 1a–1d (general
procedure). A solution of 10.0 mmol of compound 1a–
1d in 14 mL of concentrated sulfuric acid was heated
to 100–105°C, 14 mL (0.26 mol) of 30% aqueous
hydrogen peroxide was added dropwise with stirring,
and the mixture was stirred for 1 h at 130°C. After
cooling, the mixture was poured into water and
adjusted to pH 4, and the precipitate was filtered off.
We thus isolated the following product mixtures:
1.328 g (78%) of 2a and 12 mg (<1%) of 3; 1.039 g
(57%) of 2b and 0.181 g (12%) of 3; 12 mg (<1%) of
2c and 0.478 g (31%) of 3; 0.813 g (35%) of 2d and
0.547 g (35%) of 3.
and acid 3 precipitated from aqueous solution first. It
1
was identified by H and 13C NMR spectra and
1
elemental analysis. In the H NMR spectrum of 3, the
2-H proton characteristically resonated as a singlet at
δ 9.09 ppm, and the 13C NMR spectrum contained
signals at δ 129.2 (C4, C5), 135.9 (C2) and 159.8 ppm
1
(C=O). The IR and H NMR spectra of 3 were
identical to those obtained for a commercial sample of
4,5-IDC (Merck).
The product ratios were determined from the
relative signal intensities in the 1H NMR spectra of the
product mixtures. The fraction of acid 3 increased in
parallel with the length of the alkyl radical on C2. In
the oxidation of 2-methyl-1H-benzimidazole (1a) only
traces of 3 were detected (2a:3 = 99:1), the oxidation
of 2b gave an appreciable amount of 3 (2b:3 = 83:17),
and acid 3 was the major product of the oxidation of 1c
(2c:3 = 2:98). In the reaction with 2-phenyl-1H-benz-
imidazole (1d), the oxidation involved both benzene
rings (2d:3 = 50:50).
Isolation of 1H-imidazole-4,5-dicarboxylic acid
(3). Mixture 2b/3 or 2d/3 was treated with 1 equiv
(1.49 g, 10.0 mmol) of triethanolamine, 70 mL of
water, and 30 mL of ethanol, the mixture was heated to
dissolve the major part of the solid, and the undis-
solved material was filtered off. The filtrate was
evaporated under reduced pressure, the residue was
dissolved in 10 mL of water on heating, the solution
was cooled, and the precipitate was filtered off. Yield
5% (from 2b/3), 20% (from 2d/3); mp 291–293°C
(published data [10]: mp 292–295°C), Rf 0.46. IR
spectrum (KBr), ν, cm–1: 3175 (N–H), 3000–2400
(O–H), 1582 (C=O), 1535, 1466 (C=N). Found, %:
C 38.33; H 2.56; N 17.17. C5H3N2O4. Calculated, %:
C 38.47; H 2.58; N 17.95.
Thus, the reaction of 2-substituted benzimidazoles
with hydrogen peroxide under harsh conditions, apart
from oxidation of the fused benzene ring, involves
oxidative elimination of the 2-substituent. Presumably,
unsubstituted imidazole-4,5-dicarboxylic acid (3) is
formed through hypothetical intermediate imidazole-
2,4,5-tricarboxylic acid which undergoes decarboxyla-
tion in statu nascendi. Although imidazole-2,4,5-tri-
carboxylic acid has not been reported in the literature,
it is known that the oxidation of 2-substituted benz-
imidazoles with readily oxidizable groups on C2 (e.g.,
hydroxymethyl) gives benzimidazole-2-carboxylic
acid which loses CO2 on heating to form benzimid-
azole [12]. It is also known that imidazole-2-carbox-
ylic acid is converted to imidazole above 120°C [13].
1
The H and 13C NMR spectra were recorded on
a Bruker Avance III-400 spectrometer at 400 and
100 MHz, respectively, using DMSO-d6 as solvent.
The IR spectra were recorded on a Shimadzu FTIR
8400S spectrometer. The melting points were meas-
ured on a Franz Kustner Nacht HMK melting point
apparatus. Analytical TLC was performed using
Sorbfil PTSKh-P-A-UF plates (eluent ethanol–25%
aqueous ammonia, 7:3; detection under UV light).
Our results led us to presume that the fused benzene
ring and substituent on C2 are oxidized either concur-
rently or the fused benzene ring is oxidized first and
next follows oxidative elimination of the 2-substituent.
Otherwise, i.e., in the case of initial oxidation of the
2-substituent, acid 3 would be formed as the only
product.
This study was performed in the framework of the
project part of state assignment no. 10.735.2014/K of
the Ministry of Education and Science of the Russian
Federation in the sphere of research activity (project
no. 735).
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