Opianic acid in the synthesis of benzimidazole derivatives

Article abstract of DOI:10.1007/s10600-017-1923-5

Heating an equimolar mixture of opianic acid and o-phenylenediamine in MeOH or EtOH produced 2-(2-carboxy-3,4-dimethoxyphenyl)benzimidazole, which was readily dehydrated in refluxing acetic or propionic anhydride to 11H-1,2-dimethoxyisoindolo[2,3-a]benzim

Full text of DOI:10.1007/s10600-017-1923-5

DOI 10.1007/s10600-017-1923-5
Chemistry of Natural Compounds, Vol. 53, No. 1, January, 2017
OPIANIC ACID IN THE SYNTHESIS OF BENZIMIDAZOLE
DERIVATIVES
1
1*
1
G. S. Borodkin, L. Yu. Ukhin, L. V. Belousova,
2
1
E. N. Shepelenko, and A. V. Alekseenko
Heating an equimolar mixture of opianic acid and o-phenylenediamine in MeOH or EtOH produced
2-(2-carboxy-3,4-dimethoxyphenyl)benzimidazole, which was readily dehydrated in refluxing acetic or
propionic anhydride to 11H-1,2-dimethoxyisoindolo[2,3-a]benzimidazol-11-one. Analogous reactions were
carried out with 4,5-dichloro-o-phenylenediamine.
Keywords: opianic acid, o-phenylenediamine, 4,5-dichloro-o-phenylenediamine, benzimidazole derivatives.
Benzimidazole derivatives are lead compounds in medicinal chemistry [1]. Incorporation of natural biologically
active compounds into the synthesis of benzimidazole derivatives causes interesting variations in their properties.
Prolonged refluxing of an equimolar mixture of tautomeric o-formylbenzoic acid and o-phenylenediamine in EtOH
or MeOH was reported to form 2-(2-carboxyphenyl)benzimidazole [2, 3].
Natural opianic acid (o-formyl-2,6-dimethoxybenzoic acid) is also tautomeric and, as a rule, undergoes reactions
characteristic of o-formylbenzoic acid. One example of this was published [4]. As it turned out, its reaction with
o-phenylenediamine was no exception. Prolonged refluxing of an equimolar mixture of the reagents in MeOH or EtOH
formed 2-(2-carboxy-3,4-dimethoxyphenyl)benzimidazole (5a). Scheme 1 illustrates a possible reaction mechanism. We
hypothesized that the reaction began with formation of aminophthalide 3a, like for anilines [5]. Then, 3a recyclized into
benzimidazoline 4a, which was oxidized by atmospheric O into 5a.
2
Compound 5a was also included in a series of benzimidazole derivatives [6] that were prepared with catalysis by
Cu-containing plant oxidases, i.e., laccases [7] (according to Chemical Abstracts Service, this is the only reference to this
product). However, spectral and physical characteristics of this compound were not given in the paper.
OMe
OMe
O
MeO
MeO
COOH
CHO
X
X
NH
NH
2
2
a
O
+
H
OH
1
2a, b
O
3''
OMe
OMe O
O
H
HO
OMe
3'
3
2''
1'
MeO
H
N
3a
7a
MeO
X
X
5
N
X
X
OH
H
X
X
H N
2
O
OMe
1
4''
N
-2H
N
H
5'
7
H
H
N
H
5a, b
3a, b
4a, b
X = H (a), Cl (b)
a. MeOH or EtOH, reflux for 3 h
Scheme 1
1) Research Institute of Physical and Organic Chemistry, Southern Federal University, 194/2 Prosp. Stachki,
Rostov-on-Don, 344090, Russian Federation, fax: (863) 243 47 00, e-mail: may@ipoc.sfedu.ru; 2) Southern Scientific Center,
Russian Academy of Sciences, 41 Chekhov St., Rostov-on-Don, 344006, Russian Federation; e-mail: dubon@ipoc.sfedu.ru.
Translated from Khimiya Prirodnykh Soedinenii, No. 1, January–February, 2017, pp. 99–101. Original article submitted
April 28, 2016.
©
118
0009-3130/17/5301-0118 2017 Springer Science+Business Media New York

An analogous previously undescribed compound 5b was obtained from the reaction of opianic acid with 4,5-dichloro-
1,2-phenylenediamine. In contrast with 5a, where a precipitate separated after refluxing for 2.5 h, the precipitate in this
reaction appeared in the first few minutes. However, the IR spectrum showed that it consisted mainly of phthalide 3b, which
converted with subsequent prolonged refluxing into benzimidazole derivative 5b. This confirmed the proposed mechanism.
In this instance, the reaction should be conducted in EtOH because refluxing in MeOH did not convert phthalide 3b into 5b.
Compounds 5a and 5b were readily dehydrated by refluxing acetic or propionic anhydrides into the previously also unknown
11H-1,2-dimethoxyisoindolo[2,3-a]benzimidazol-11-one 6a and 11a-1,2-dimethoxyisoindolo[2,3-a]-7,8-dichlorobenzimidazol-
11-one 6b, respectively (Scheme 2).
O
OMe
1
9
10
N
11a
X
X
OMe
9a
a
11
5a, b
3
4b
4a
7
5a
N
5
6a, b
X = H (a), Cl (b)
a. Ac O or (EtCO) O, ꢄ, -H O
2
2
Scheme22
The proposed structures were confirmed by complete assignment of resonances in their NMR spectra, for which two-
13
dimensional COSY pulse sequences were used for PMR spectra; HSQC and HMBC, for C NMR spectra; and HMBC, for
15
N NMR spectra. The agreement of the chemical shifts (CS) for C(4)H/C(7)H and C(5)H/C(6)H in 5a and C(4)H/C(7)H in
5b could be explained by migration of the amine proton between the N atoms (N-1 and N-3) as a result of fast intermolecular
exchange with H O in the solvent (DMSO-d ). This would make the benzimidazole moieties in 5a and 5b symmetric.
2
6
Compounds 5a and 5b, which combined a benzimidazole moiety and a 2-carboxy-3,4-dimethoxyphenyl group, were
interesting as potential biologically active compounds, like dimethoxyisoindolonobenzimidazole derivatives 6a and 6b. Our
results from testing using the PASS Internet program supported this. According to the tests, 5a and 5b could act as inhibitors
of various enzyme-catalyzed biochemical redox processes; 6a and 6b would highly probably manifest sedative properties.
EXPERIMENTAL
13
15
IR spectra were recorded on a Varian Excalibur 3100 FTIR instrument. PMR, C NMR, and N NMR spectra were
recorded on an Avance-600 spectrometer (Bruker). Mass spectra were obtained on a Shimadzu GCMS-QP 2010 SE GC-MS
with direct sample introduction into the ion source (EI, 70 eV). Elemental analyses of all compounds agreed with those
calculated.
2-(2-Carboxy-3,4-dimethoxyphenyl)benzimidazole (5a). A mixture of opianic acid (0.93 g, 5 mmol),
o-phenylenediamine (0.54 g, 5 mmol), MeOH (15 mL), and AcOH (2 drops) was refluxed for 3.5 h. A precipitate began to
form after 2.5 h. The mixture was cooled. The precipitate was filtered off, rinsed with MeOH, and dried to afford a colorless
compound. Yield 0.27 g (18%). The filtrate was refluxed another 2 h and left for 1 d. More compound (0.2 g) with the same
IR spectrum was isolated for a total yield of 0.47 g (31%). The compound was insoluble in refluxing MeCN, MeNO , and
2
–1
i-PrOH; soluble with heating in DMF and propylenecarbonate; mp 240–242°C (propylenecarbonate). IR spectrum (ꢀ, cm ):
1
3100 br. (OH, NH), 1692 (C=O), 1629, 1595, 1570 (Ar), 1279 (Ñ-O-CH ). H NMR spectrum (600 MHz, DMSO-d , ꢁ, ppm,
3
6
J/Hz): 3.80 (3Í, s, ÑÍ -4ꢂꢂ), 3.92 (3Í, s, 3ꢂꢂ-OCH ), 7.19 (2Í, m, Í-5, 6), 7.28 (1Í, d, J = 8.5, Í-6ꢂ), 7.55 (2H, m, Í-4, 7),
3
3
6ꢂ5ꢂ
13
7.68 (1Í, d, J
= 8.5, H-5ꢂ). C NMR spectrum (150 MHz, DMSO-d , ꢁ, ppm): 56.03 (s, Ñ-3ꢂꢂ), 60.97 (s, Ñ-4ꢂꢂ), 113.01
5ꢂ6ꢂ
6
(s, Ñ-6ꢂ), 114.93 (s, Ñ-4), 114.97 (s, Ñ-7), 119.63 (s, Ñ-2ꢂ), 121.84 (s, Ñ-5), 121.84 (s, Ñ-6), 124.30 (s, Ñ-5ꢂ), 130.49 (s, Ñ-1ꢂ),
139.20 (s, Ñ-3à), 139.20 (s, Ñ-7à), 145.39 (s, Ñ-4ꢂ), 149.85 (s, Ñ-2), 153.53 (s, Ñ-3ꢂ), 167.47 (s, Ñ-2ꢂꢂ). Mass spectrum
+
(EI, 70 eV), m/z (I , %): 298 (M , 40), 280 (82), 265 (20), 254 (100), 252 (55).
rel
2-(2-Carboxy-3,4-dimethoxyphenyl)-5,6-dichlorobenzimidazole (5b). Opianic acid (0.11 g, 0.5 mmol) in EtOH
(5 mL) was heated until dissolved, treated with 4,5-dichloro-o-phenylenediamine (0.1 g, 0.55 mmol) and AcOH (2 drops), and
ꢃ
refluxed for 3h. A small amount of crystalline precipitate consisting mainly of phthalide 3b according to the IR spectrum
formed almost immediately. The mixture was cooled in ice. The precipitate was filtered off, rinsed with cold EtOH and
petroleum ether, and dried to afford a slightly cream-colored compound, mp 251–253°C, yield 0.062 g (28%). IR spectrum
______
–1
*IR spectrum (ꢀ, cm ): 3470 (NH), 3373 (NH , as), 3308 (NH , s), 1736 (C=O), 1034 (C-O-C, as), 855 (C-O-C, s).
2
2
119

–1
1
(ꢀ, cm ): 3200 br. (OH, NH), 1692 (C=O), 1625, 1593, 1574 (Ar). H NMR spectrum (600 MHz, DMSO-d , ꢁ, ppm, J/Hz):
6
3.80 (3Í, s, ÑÍ -4ꢂꢂ), 3.93 (3Í, s, 3ꢂꢂ-OMe), 7.30 (1Í, d, J = 8.6, Í-6ꢂ), 7.67 (1Í, d, J = 8.6, Í-5ꢂ), 7.77 (2Í, s, Í-4, 7), 12.98
3
13
(2Í, s, ÎÍ, NH). C NMR spectrum (150 MHz, DMSO-d , ꢁ, ppm): 55.79 (s, Ñ-3ꢂꢂ), 60.45 (s, Ñ-4ꢂꢂ), 113.15 (s, Ñ-6ꢂ), 115.61
6
(s, Ñ-4), 115.61 (s, Ñ-7), 119.00 (s, Ñ-2ꢂ), 123.92 (s, Ñ-5), 123.92 (s, Ñ-6), 124.20 (s, Ñ-5ꢂ), 130.16 (s, Ñ-1ꢂ), 138.42 (s, Ñ-3à),
138.42 (s, Ñ-7à), 145.53 (s, Ñ-4ꢂ), 152.18 (s, Ñ-2), 153.64 (s, Ñ-3ꢂ), 166.24 (s, Ñ-2ꢂꢂ). Mass spectrum (EI, 70 eV), m/z (I , %):
rel
+
366 (M , 47), 368 (36), 348 (34), 322 (45), 321 (87), 276 (100).
11H-1,2-Dimethoxyisoindolo[2,1-a]benzimidazol-11-one (6a). Compound 5a (0.3 g, 1 mmol) was refluxed in
Ac O (1.5 mL) until dissolved (~5 min), cooled, treated with i-PrOH (3 mL), washed with petroleum ether, and dried to afford
2
–1
yellow crystals, mp 150–152°C (i-PrOH), yield 0.23 g (82%). IR spectrum (ꢀ, cm ): 1755 (C=O), 1628, 1562, 1494 (Ar),
1269, 1245 (Ñ-O-CH ). H NMR spectrum (600 MHz, CDCl , ꢁ, ppm, J/Hz): 3.92 (3H, s, 2-OMe), 4.16 (3H, s, CH O-1), 7.03
1
3
3
3
(1Í, d, J = 8.0, Í-3), 7.25 (1Í, t, J = 7.7, Í-7), 7.28 (1Í, t, J = 7.7, Í-8), 7.49 (1Í, d, J = 8.0, Í-4), 7.64 (1Í, d, J = 7.7, Í-4),
13
7.75 (1Í, d, J = 7.7, Í-9). C NMR spectrum (150 MHz, CDCl , ꢁ, ppm): 56.47 (s, Ñ-2ꢂ), 62.45 (s, Ñ-1ꢂ), 112.45 (s, Ñ-9),
3
116.74 (s, Ñ-3), 117.91 (s, Ñ-4), 120.76 (s, Ñ-6), 124.34 (s, Ñ-4à), 123.92 (s, Ñ-6), 124.81 (s, Ñ-7), 125.21 (s, Ñ-11à), 125.70
15
(s, Ñ-8), 129.94 (s, Ñ-9à), 149.23 (s, Ñ-5à), 149.88 (s, Ñ-1), 155.90 (s, Ñ-4b), 156.07 (s, Ñ-2), 159.01 (s, C-11). N NMR
spectrum (60 MHz,ꢅCDCl , ꢁ, ppm): 185.90 (s, N-10), 243.50 (s, N-5). Mass spectrum (EI, 70 eV), m/z (I , %): 280
3
rel
+
(M , 100), 265 (27), 237 (40), 235 (15), 207 (12).
11H-1,2-Dimethoxyisoindolo[2,1-a]-7,8-dichlorobenzimidazol-11-one (6b). Compound 5b (30 mg, 0.08 mmol)
was refluxed in Ac O (2 mL) until dissolved (~2–3 min), and cooled. The whole mixture crystallized and was treated with
2
i-PrOH (3 mL) and cooled in ice. The precipitate was filtered off, washed with i-PrOH and petroleum ether, and dried to afford
–1
yellow crystals, mp 233–235°C (i-PrOH), yield 24 mg (80%). IR spectrum (ꢀ, cm ): 1741 (CO), 1626, 1556, 1493 (arom),
1
1255 (Ñ-O-CH ). H NMR spectrum (600 MHz, CDCl , ꢁ, ppm, J/Hz): 3.97 (3Í, s, ÑÍ Î-2), 4.18 (3Í, s, ÑÍ Î-1), 7.10
3
3
3
3
13
(1Í, d, J = 8.1, Í-3), 7.54 (1Í, d, J = 8.1, Í-4), 7.74 (1Í, s, Í-6), 7.89 (1Í, s, Í-9). C NMR spectrum (150 MHz, CDCl ,
3
ꢁ, ppm): 56.62 (s, Ñ-2ꢂ), 62.56 (s, Ñ-1ꢂ), 113.87 (s, Ñ-9), 117.08 (s, Ñ-3), 118.51 (s, Ñ-4), 121.99 (s, Ñ-6), 123.70 (s, Ñ-4à),
124.77 (s, Ñ-11à), 128.88 (s, Ñ-7), 128.99 (s, Ñ-9à), 129.77 (s, Ñ-8), 148.59 (s, Ñ-5à), 150.32 (s, Ñ-1), 156.60 (s, Ñ-2), 157.41
15
(s, Ñ-4b), 158.52 (s, C-11). N NMR spectrum (60 MHz, CDCl , ꢁ, ppm): 182.80 (s, N-10), 239.50 (s, N-5). Mass spectrum
3
+
(EI, 70 eV), m/z (I , %): 348 (M , 100), 350 (63), 333 (14), 321 (15), 319 (24).
rel
ACKNOWLEDGMENT
Spectral studies used equipment at the Molecular Spectroscopy CCU, SFU. The work was supported financially by
the RF Ministry of Education and Science (project part of a state task for scientific activity of SFU, topic No. 4.967.2014/K).
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