Efficient microwave assisted synthesis of some new benzimidazoles containing the mebendazole nucleus

Article abstract of DOI:10.3184/174751913X13603595770952

A simple and practical method has been developed for the synthesis of benzimidazoles containing the biological active mebendazole nucleus. Iminoester hydrochlorides of phenylacetic acids were used as intermediates in the reaction with 3,4-diaminobenzophen

Full text of DOI:10.3184/174751913X13603595770952

168 RESEARCH PAPER
MARCH, 168–170
JOURNAL OF CHEMICAL RESEARCH 2013
Efficient microwave assisted synthesis of some new benzimidazoles
containing the mebendazole nucleus
Emre Menteşe
Department of Chemistry, Art and Science Faculty, RecepTayyip Erdogan University, 53100-Rize, Turkey
A simple and practical method has been developed for the synthesis of benzimidazoles containing the biological
active mebendazole nucleus. Iminoester hydrochlorides of phenylacetic acids were used as intermediates in the reac-
tion with 3,4-diaminobenzophenone under microwave irradiation leading to the products in good yields and in short
reaction times.
Keywords: benzimidazole drug, microwave, iminoester hydrochloride, mebendazole
Benzimidazoles are an important class of biologically active
heterocyclic organic compounds,1 and their synthesis is of con-
siderable interest. Some noteworthy biological effects of benz-
imidazoles include anticancer,2 antihelmintic,3 antimicrobial,4
antihistaminic,5 antitumour,6 anti-inflammatory7 and antiviral8
activities. They are also used in various areas of chemistry and
are important intermediates in organic reactions.9 They can
also act as ligands to transition metals for modeling biological
systems.10
There are many synthetic routes that have been described
for the preparation of benzimidazoles containing mebendazole
nucleus. The most common method for this process is using an
o-phenylenediamine derivative and a carboxylic acid or an aro-
matic aldehyde as intermediate.11,12 Esters, lactones and nitriles
can also produce benzimidazoles.12,13 However, several draw-
backs are associated with these processes such as expensive
reagents, harsh reaction conditions, extended reaction times,
the occurrence of side products, unsatisfactory yields and
complicated experimental procedures14–20. Therefore, there is a
need for a new short and economical synthesis of benzimida-
zoles containing the mebendazole nucleus.
way of synthesising potential bioactive benzimidazoles.
Comparison of the yields and reaction times under microwave
irradiation and the conventional method for compounds 2a–l
are given in Table 1.
The spectra of the new compounds are accordance with their
1
proposed structures. The H NMR spectrum in DMSO-d6
revealed signals at 1.70–2.25, 4.17–4.66 and 11.93–12.79 ppm
(revealed by introducing D2O) assigned to CH3, CH2 and NH
protons, respectively. In the 1H NMR spectra of benzimidazole
derivatives, the NH signals are shown as a broad singlet at
room temperature. The NH signals can be removed by deute-
rium exchange in DMSO-d6 D2O. Aromatic protons of benz-
imidazole compounds are shown as multiplet because of rapid
substitution of the imidazole hydrogen between two nitrogen
atoms. Thus, aromatic protons of compounds 2a–l were
observed at 7.01–8.01 ppm as multiplets. In the 13C NMR
spectra of compounds 2a–l, the signals for the C=N and C=O
atoms appeared between 153.8–161.1 and 194.7–196.4 ppm
respectively. Aromatic carbons of compounds for 2a–l were
observed at 111.9–162.9 ppm. The nuclear spin of fluorine is
½. This means that carbon signals are split into n+1 parts. One-
bond 13C–19F coupling constants are very large, so the carbon
directly bound to the fluorine will appear as a doublet with a
coupling constant of ~250 Hz. Thus, these carbons in 2a–c
were observed at 162.7–165.4 and 157.8–160.5 ppm as
doublet with a coupling constant of ~243 Hz. The carbons
ortho to the fluorine were shown doublets but with much
smaller couplings.
In this study, we have developed a novel and practical
method for the synthesis of benzimidazole derivatives contain-
ing the mebendazole nucleus. This method can provide a
convenient way of synthesising potential bioactive benzimid-
azoles. The structures of new compounds were confirmed by
1H NMR, 13C NMR spectroscopy and elemental analyses. The
synthetic path of the target compounds is shown in Scheme 1.
Results and discussion
Conclusion
In this study of the synthesis of benzimidazoles, we have
shown that iminoester hydrochlorides can be useful intermedi-
ates in the reaction with 3,5-diaminobenzophenone under
microwave irradiation in methanol. These new heterocyclic
compounds (2a–l) were also obtained by using conventional
heating in methanol. Microwave technology has been used to
synthesise benzimidazole derivatives, and important changes
have been seen on the yield and reaction time.20–22 Using this
new method, we obtained products within short reaction times
and in high yields. In addition, the reaction was carried out
under mild conditions. This method can provide a convenient
In conclusion, we have developed a novel and practical method
has been used for the synthesis of benzimidazole derivatives
containing mebendazole nucleus under microwave irradiation.
This method can provide a convenient way of synthesising
potential bioactive benzimidazoles.
Experimental
All the chemicals were supplied by Merck, Aldrich and Fluka.
Iminoester hydrochlorides (1a–l) were prepared according to the
Pinner method.24,25 Melting points were determined on capillary tubes
1
on a Büchi oil-heated melting point apparatus and uncorrected. H
NMR and 13C NMR spectra were performed on the Varian-Mercury
200 MHz spectrometer in DMSO-d6 using TMS as internal. Elemental
Analyses were performed on a Carla Erba 1106 CHN analyser. A
mono-mode CEM-Discover microwave was used to carry out micro-
wave reactions in 30 mL microwave process vials with temperature
control by infrared detection temperature sensor. All reactions were
monitored by TLC using precoated aluminum sheets (silica gel 60 F
2.54 0.2 mm thickness).
Synthesis of 2a–l
Fig. 1 Structure of mebendazole.
Conventional method: A mixture of corresponding iminoester hydro-
chlorides (1a–l) (0.012 mol), HCl (2 mL) and 3,5-diaminobenzophe-
none (0.01 mol) in dry methanol (15 mL) was placed in a round-bottomed
* Correspondent. E-mail: emre.mentese@erdogan.edu.tr

JOURNAL OF CHEMICAL RESEARCH 2013 169
Scheme 1 The synthetic path of the target compounds 2a–l.
Table 1 Comparison of the yields and reaction times under
microwave irradiation and the conventional methods for
compounds 2a–l
7.86–7.01 (m, 12H), 4.23 (s, 2H); 13C NMR (50 MHz, DMSO-d6)
δ 196.4, 161.7 (d, J = 241.3), 157.2, 139.2, 138.8, 133.9, 132.7, 131.5,
131.2, 131.1, 129.1, 124.4, 118.5, 116.2, 115.4 (d, J = 4), 34.7. Anal.
Calcd for C21H15FN2O: C, 76.35; H, 4.58; N, 8.48. Found: C, 76.38; H,
4.55; N, 8.52%.
Compound
No.
MWI
Time/min
Conventional
Phenyl [2-(2-chlorobenzyl)-1H-1,3-benzimidazol-5-yl]methanone
Yield/% Time/min Yield/%
1
(2d): M.p. 198 °C, H NMR (200 MHz, DMSO-d6) δ 12.68 (s, 1H),
7.84–7.29 (m, 12H), 4.35 (s, 2H); 13C NMR (50 MHz, DMSO-d6)
δ 196.4, 155.5, 138.8, 135.84, 134.0, 132.7, 132.3, 131.0, 130.1,
130.0, 129.6, 129.1, 128.1, 124.6, 121.9, 118.8, 114.7, 111.9, 33.6.
Anal. Calcd for C21H15ClN2O: C, 72.73; H, 4.36; N, 8.08. Found: C,
72.75; H, 4.35; N, 8.04%.
2a
2b
2c
2d
2e
2f
2g
2h
2i
10
10
10
10
10
10
10
10
10
10
10
10
84
87
90
85
88
89
83
85
91
80
88
91
90
90
90
90
90
90
90
90
90
90
90
90
75
75
77
78
79
79
77
78
78
75
78
79
Phenyl [2-(3-chlorobenzyl)-1H-1,3-benzimidazol-5-yl]methanone
(2e): M.p. 231 °C, 1H NMR (200 MHz, DMSO-d6) δ 12.01 (bs, 1H),
7.89–7.33 (m, 12H), 4.30 (s, 2H); 13C NMR (50 MHz, DMSO-d6)
δ 196.3, 156.5, 141.7, 139.8, 138.7, 138.3, 133.8, 132.8, 131.6, 131.2,
130.2, 129.5, 129.1, 128.5, 127.6, 124.8, 118.4, 115.1, 34.8. Anal.
Calcd for C21H15ClN2O: C, 72.73; H, 4.36; N, 8.08. Found: C, 72.76;
H, 4.34; N, 8.06%.
2j
2k
2l
Phenyl [2-(4-chlorobenzyl)-1H-1,3-benzimidazol-5-yl]methanone
1
(2f): M.p. 259 °C, H NMR (200 MHz, DMSO-d6) δ 12.71 (s, 1H),
7.99–7.37 (m, 12H), 4.23 (s, 2H); 13C NMR (50 MHz, DMSO-d6)
δ 196.4, 156.9, 141.5, 138.8, 136.7, 132.7, 132.1, 131.5, 131.2, 130.1,
129.2, 129.1, 124.4, 118.7, 115.5, 34.9. Anal. Calcd for C21H15ClN2O:
C, 72.73; H, 4.36; N, 8.08. Found: C, 72.74; H, 4.35; N, 8.10%.
Phenyl [2-(2-bromobenzyl)-1H-1,3-benzimidazol-5-yl]methanone
(2g): M.p. 210 °C, 1H NMR (200 MHz, DMSO-d6) δ 12.66 (bs, 1H),
7.86–7.24 (m, 12H), 4.37 (s, 2H); 13C NMR (50 MHz, DMSO-d6)
δ 196.4, 156.1, 138.8, 137.1, 133.3, 132.7, 132.4, 131.1, 130.2, 129.8,
129.1, 128.7, 124.9, 124.4, 118.4, 115.2, 36.2. Anal. Calcd for
C21H15BrN2O: C, 64.46; H, 3.86; N, 7.16. Found: C, 64.50; H, 3.84; N,
7.18%.
flask. The solution was stirred for 1.5 h at room temperature. After
completion of the reaction (monitored by TLC, ethylacetate:hexane,
3:1), the mixture was poured into water and neutralised with sodium
bicarbonate. The precipitate was collected by filtration and recrystal-
lised from ethanol–water (1:3) to give pure 2a–l.
Microwave method: A mixture of corresponding iminoester hydro-
chlorides (1a–l) (0.012 mol), HCl (2 mL) and 3,5-diaminobenzophe-
none (0.01 mol) in dry methanol (15 mL) was irradiated in closed
vessels with pressure control at 65 °C for 10 min. (hold time) at
300 W maximum power. The above purification methods were used to
give pure products 2a–l.
Phenyl [2-(3-bromobenzyl)-1H-1,3-benzimidazol-5-yl]methanone
Phenyl [2-(2-fluorobenzyl)-1H-1,3-benzimidazol-5-yl]methanone
(2a): M.p. 185 °C, 1H NMR (200 MHz, DMSO-d6) δ 12.09 (bs, 1H),
8.01–7.23 (m, 12H), 4.66 (s, 2H); 13C NMR (50 MHz, DMSO-d6)
δ 194.7, 160.2 (d, J = 244), 153.8, 136.8, 134.0, 133.8, 132.7, 131.8,
131.0, 130.2, 129.6, 128.5, 126.7, 124.9, 120.5 (d, J = 15.4), 116.0,
115.8, 114.7 (d, J = 61.5), 104.2, 26.1. Anal. Calcd for C21H15FN2O:
C, 76.35; H, 4.58; N, 8.48. Found: C, 76.37; H, 4.54; N, 8.50%.
Phenyl [2-(3-fluorobenzyl)-1H-1,3-benzimidazol-5-yl]methanone
1
(2h): M.p. 175 °C, H NMR (200 MHz, DMSO-d6) δ 12.59 (s, 1H),
7.88–7.28 (m, 12H), 4.26 (s, 2H); 13C NMR (50 MHz, DMSO-d6)
δ 196.4, 156.6, 142.7, 140.4, 139.3, 139.2, 138.8, 132.7, 132.3, 131.4,
131.2, 130.3, 130.1, 129.0, 128.7, 124.4, 122.4, 118.6, 155.1, 35.1.
Anal. Calcd for C21H15BrN2O: C, 64.46; H, 3.86; N, 7.16. Found: C,
64.50; H, 3.84; N, 7.18%.
Phenyl [2-(4-bromobenzyl)-1H-1,3-benzimidazol-5-yl]methanone
1
1
(2i): M.p. 189 °C, H NMR (200 MHz, DMSO-d6) δ 12.72 (s, 1H),
(2b): M.p. 248 °C, H NMR (200 MHz, DMSO-d6) δ 12.03 (s, 1H),
7.87–7.29 (m, 12H), 4.26 (s, 2H); 13C NMR (50 MHz, DMSO-d6)
δ 196.4, 156.7, 140.5, 138.8, 132.7, 132.3, 131.4, 131.2, 130.3, 130.2,
129.1, 129.0, 128.8, 124.4, 122.4, 118.7, 155.2, 35.1. Anal. Calcd for
C21H15BrN2O: C, 64.46; H, 3.86; N, 7.16. Found: C, 64.45; H, 3.85; N,
7.14%.
8.01–7.12 (m, 12H), 4.62 (s, 2H); 13C NMR (50 MHz, DMSO-d6)
δ 195.5, 162.9 (d, J = 242.5), 155.2, 137.6, 137.0, 136.9, 134.7, 133.6,
131.8, 131.6, 131.5, 130.4, 130.3, 129.3, 127.5, 126.3, 117.1 (d,
J = 22.3), 115.6, 115.1 (d, J = 61.5), 32.5.Anal. Calcd for C21H15FN2O:
C, 76.35; H, 4.58; N, 8.48. Found: C, 76.36; H, 4.56; N, 8.51%.
Phenyl [2-(4-fluorobenzyl)-1H-1,3-benzimidazol-5-yl]methanone
Phenyl [2-(2-methylbenzyl)-1H-1,3-benzimidazol-5-yl]methanone
1
1
(2j): M.p. 190 °C, H NMR (200 MHz, DMSO-d6) δ 12.61 (s, 1H),
(2c): M.p. 231 °C, H NMR (200 MHz, DMSO-d6) δ 11.93 (s, 1H),

170 JOURNAL OF CHEMICAL RESEARCH 2013
7.86–7.32 (m, 12H), 4.43 (s, 2H) 1.70 (s, 3H); 13C NMR (50 MHz,
DMSO-d6) δ 196.4, 161.1, 143.9, 138.8, 132.7, 131.1, 130.1, 129.3,
129.1, 128.0, 127.4, 124.3, 119.2, 40.0, 21.0. Anal. Calcd for
C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.99; H, 5.53; N,
8.60%.
2
3
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4
5
6
Phenyl [2-(3-methylbenzyl)-1H-1,3-benzimidazol-5-yl]methanone
1
(2k): M.p. 219 °C, H NMR (200 MHz, DMSO-d6) δ 7.88–7.19 (m,
12H), 4.19 (s, 2H) 2.11 (s, 3H); 13C NMR (50 MHz, DMSO-d6)
δ 196.4, 157.4, 142.6, 139.1, 138.8, 138.4, 137.6, 132.7, 131.2, 130.1,
129.2, 129.1, 128.0, 126.6, 124.4, 118.5, 115.1, 35.6, 21.7. Anal.
Calcd for C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.98; H,
5.54; N, 8.61%.
7
8
9
10 M.R. Maurya and N. Bharti, Transit. Met. Chem., 1999, 24, 389.
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Phenyl [2-(4-methylbenzyl)-1H-1,3-benzimidazol-5-yl]methanone
1
(2l): M.p. 188 °C, H NMR (200 MHz, DMSO-d6) δ 12.79 (s, 1H),
7.85–7.15 (m, 12H), 4.17 (s, 2H) 2.25 (s, 3H); 13C NMR (50 MHz,
DMSO-d6) δ 196.4, 157.5, 142.7, 138.8, 134.7, 132.7, 131.1, 130.1,
129.8, 129.4, 129.1, 124.3, 118.3, 115.0, 35.3, 21.3. Anal. Calcd for
C22H18N2O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.94; H, 5.57; N,
8.60%.
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Berlin, 1892.
Received 2 November 2012; accepted 9 January 2013
Paper 1201608 doi: 10.3184/174751913X13603595770952
Published online: 12 March 2013
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