An efficient synthesis of some new bisbenzimidazoles via microwave technique

Article abstract of DOI:10.3906/kim-1305-17

2,2′-[1,4 (1,3)-Phenylenedi(methylene)]bis-1H-benzimidazole derivatives were obtained from the reaction of 1,4- or (1,3)-bisiminoester hydrochloride and o-phenylenediamine derivatives under microwave irradiation. Ester and hydrazide derivatives were prepared from a free NH group. This practical method revealed good results for yield, reaction time, and quick isolation of products. TUeBITAK.

Full text of DOI:10.3906/kim-1305-17

Turk J Chem
Turkish Journal of Chemistry
(2014) 38: 423 – 429
¨
http://journals.tubitak.gov.tr/chem/
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c
⃝ TUBITAK
doi:10.3906/kim-1305-17
Research Article
An efficient synthesis of some new bisbenzimidazoles via microwave technique
1,∗
2
2
2
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Bahittin KAHVECI , Nesrin KARAALI , Fatih YILMAZ , Emre MENTES¸E
1Department of Nutrition and Dietetics, Karadeniz Technical University, Trabzon, Turkey
2Department of Chemistry, Recep Tayyip Erdo˘gan University, Rize, Turkey
Received: 09.05.2013
•
Accepted: 22.10.2013
•
Published Online: 14.04.2014
•
Printed: 12.05.2014
Abstract: 2,2’-[1,4 (1,3)-Phenylenedi(methylene)]bis-1H -benzimidazole derivatives were obtained from the reaction of
1,4- or (1,3)-bisiminoester hydrochloride and o-phenylenediamine derivatives under microwave irradiation. Ester and
hydrazide derivatives were prepared from a free NH group. This practical method revealed good results for yield, reaction
time, and quick isolation of products.
Key words: Bisbenzimidazole, bisiminoester hydrochloride, microwave synthesis, hydrazine hydrate
1. Introduction
Benzimidazoles are significant for many areas of chemistry.1 They are contained in agrochemicals, dyestuffs, and
high-temperature polymer products, and they have interesting biological and pharmaceutical activities.2−6 Due
to these facts, there has been significant attention paid to the synthesis of benzimidazole and bisbenzimidazole
compounds in recent years. These kinds of heterocycles have also shown different pharmacological activities
against gram-positive drug-resistant bacteria and some fungi, which are responsible for some infections in acute
systems.7
The classical method for preparation of benzimidazole or bisbenzimidazole derivatives is via condensation
of o-phenylenediamines with carboxylic acids under strong acid (polyphosphoric acid or mineral acid)/high
temperature conditions or with corresponding aldehydes under oxidative conditions.8−10 In recent years, various
efficient synthetic methods have been developed. For example, trifluoromethylaryl ketones, orthoesters, and
1,3-dicarbonyl compounds have been used as an intermediate with 3,3’-diaminobenzidine for the synthesis of
bisbenzimidazoles.9,10 However, many of these methods involve challenges like expensive reagents, harsh reaction
conditions, extended reaction times, occurrence of side products, and low yields. Therefore, there is a need for
an efficient synthetic method that is short and economical for these types of compounds.
2. Experimental
2.1. General
1 H NMR and 13 C NMR spectra were recorded in DMSO-d6 on a Varian Mercury spectrometer using TMS
as an internal reference. The elemental analyses were determined on a Carlo Erba 1106 CHN analyzer; the
measured percentages were in agreement (ꢀ0.2%) with the calculated ones. A monomode CEM-Discover
Microwave apparatus was used in the standard configuration as delivered, including proprietary software. All
∗Correspondence: bahittin@ktu.edu.tr
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experiments were carried out in microwave process vials (35 mL) with temperature controlled by an infrared
detection temperature sensor. It was monitored by a computer and a constant temperature was maintained by
discrete modulation of delivered microwave power. After completion of the reaction, the vial was cooled to 60
◦ C via air jet cooling. All reactions were monitored by TLC using precoated aluminum sheets (silica gel 60 F
2.54, 0.2 mm thickness).
2.2. Synthesis of compounds 3a–3c and 4a–4c
Compounds 1 or 2 (0.014 mol) and corresponding o-phenylenediamine derivative (0.02 mol) in methanol (10
mL) were taken in a closed vessel. The mixture was then irradiated in a microwave at 65 ◦ C for 10 min
(hold time) at 300 W maximum power. After the reaction was complete (monitored by TLC; ethyl acetate
and hexane, 4:1), the mixture was left to cool to room temperature. The precipitate was filtrated, dried, and
recrystallized from ethanol to yield the pure product.
2.2.1. 2,2’-[1,3-Phenylenedi(methylene)]bis-1H -benzimidazole (3a)
Yield: 2.74 g (81%), mp: 291–292 ◦ C (lit.11 290–291 ◦ C). 1 H NMR spectrum (200 MHz, DMSO-d6) δ 3.58 (s,
4H, CH2), 6.40-7.45 (m, 12H, Ar-H); 13 C NMR spectrum (50 MHz, DMSO-d6) δ 41.28 (CH2), 119.23, 121.92,
127.96, 129.09, 129.42, 129.76, 135.67, 137.45 (Ar-C), 157.03 (C=N); Anal. Calcd. for C22 H18 N4 : C, 78.05;
H, 5.32; N, 16.51. Found: C, 78.08; H, 5.36; N, 16.56.
2.2.2. 2,2’-[1,3-Phenylenedi(methylene)]bis-6-methyl-1H -benzimidazole) (3b)
Yield: 2.85 g (78%), mp: 154–155 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 2.38 (s, 6H, CH3), 4.11 (s,
4H, CH2), 6.91-7.36 (m, 10H, Ar-H); 13 C NMR spectrum (100 MHz, DMSO-d6) δ 21.71 (CH3), 35.35 (CH2),
144.46, 115.00, 123.15 (2C), 127.45 (2C), 129.08, 129.60, 130.84, 137.90, 138.37, 139.10 (Ar-C), 153.52 (C=N);
Anal. Calcd. for C24 H22 N4 : C, 78.65; H, 6.06; N, 15.31. Found: C, 78.66; H, 6.05; N, 15.29.
2.2.3. 2,2’-[1,3-Phenylenedi(methylene)]bis-6-nitro-1H -benzimidazole) (3c)
Yield: 3.30 g (77%), mp: 211–212 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 4.24 (s, 4H, CH2), 7.23-7.33
(m, 5H, Ar-H), 7.64 (s, 2H, Ar-H), 8.06 (d, J =8.4 Hz, 2H, Ar-H), 8.38 (s, 1H, Ar-H), 13.01 (s, 2H, NH); 13 C
NMR spectrum (100 MHz, DMSO-d6) δ 35.02 (CH2), 111.35, 118.85, 121.66, 129.38 (2C), 135.50, 136.34,
143.15 (Ar-C), 154.04 (C=N); Anal. Calcd. for C22 H16 N6 O4 : C, 61.70; H, 3.69; N, 19.61. Found: C, 61.68;
H, 3.76; N, 19.62.
2.2.4. 2,2’-[14-Phenylenedi(methylene)]bis-1H -benzimidazole (4a)
Yield: 2.97 g (88%), mp: 360–362 ◦ C (lit.11 >300 ◦ C). 1 H NMR spectrum (400 MHz, DMSO-d6) δ 4.14 (s,
4H, CH2), 7.10-7.46 (m, 12H, Ar-H), 12.21 (s, 2H, NH); 13 C NMR spectrum (100 MHz, DMSO-d6) δ 35.05
(CH2), 111.35, 118.85, 121.66, 129.38 (2C), 135.50, 136.34, 143.15 (Ar-C), 154.04 (C=N); Anal. Calcd. for
C22 H18 N4 : C, 78.05; H, 5.32; N, 16.51. Found: C, 78.08; H, 5.36; N, 16.56.
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2.2.5. 2,2’-[1,4-Phenylenedi(methylene)]bis-6-methyl-1H -benzimidazole) (4b)
Yield: 3.07 g (84%), mp: 283–285 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 2.37 (s, 6H, CH3), 4.11 (s,
4H, CH2), 6.93 (d, J =8.4 Hz, 2H, Ar-H), 7.26-7.35 (m, 8H, Ar-H), 12.13 (s, 2H, NH); 13 C NMR spectrum
(100 MHz, DMSO-d6) δ 21.71 (CH3), 35.05 (CH2), 123.08, 129.32 (4C), 130.77, 136.40 (2C) (Ar-C), 153.67
(C=N); Anal. Calcd. for C24 H22 N4 : C, 78.65; H, 6.06; N, 15.31. Found: C, 78.65; H, 6.06; N, 15.31.
2.2.6. 2,2’-[1,4-Phenylenedi(methylene)]bis-6-nitro-1H -benzimidazole) (4c)
Yield: 3.38 g (79%), mp: 301–303 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 4.24 (s, 4H, CH2), 7.32
(s, 5H, Ar-H), 7.64 (d, J =8.8 Hz, 2H, Ar-H), 8.05 (d, J =8.8 Hz, 2H, Ar-H), 8.38 (s, 1H, Ar-H); 13 C NMR
spectrum (100 MHz, DMSO-d6) δ 35.02 (CH2), 117.85 (2C), 129.69 (4C), 135.75 (2C), 142.73 (2C) (Ar-C),
159.15 (C=N); Anal. Calcd. for C22 H16 N6 O4 : C, 61.70; H, 3.69; N, 19.61. Found: C, 61.68; H, 3.76; N, 19.62.
2.3. Synthesis of compounds 5a–5c and 6a–6c
A solution of compounds 3a–3c or 4a–4c (0.01 mol) in acetone (10 mL) was placed in a closed vessel and dry
K2 CO3 (0.05 mol) was added. The mixture was irradiated in a microwave at 90 ◦ C for 5 min (hold time) with
pressure control. The mixture was then cooled to room temperature and ethyl bromoacetate (0.021 mol) was
added. Again, it was irradiated in a microwave at 90 ◦ C for 10 min (hold time) at 300 W maximum power.
After the reaction was completed (monitored by TLC; ethyl acetate and hexane, 3:1), the mixture was cooled
and taken in a beaker, and the product was precipitated by addition of water. The product was filtrated, dried,
and recrystallized from ethanol.
2.3.1. Diethyl 2,2’-[1,3-phenylenebis(methylene-1H -benzimidazole-2,1-diyl)]diacetate (5a)
Yield: 4.99 g (98%), mp: 181–183 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 1.11 (t, J = 6.8 Hz, 6H,
CH3), 4.01 (q, J = 6.8 Hz, 4H, OCH2), 4.22 (s, 4H, CH2), 5.15 (s, 4H, NCH2), 7.13-7.20 (m, 8H, Ar-H), 7.45
(s, 2H, Ar-H), 7.59 (s, 2H, Ar-H); 13 C NMR spectrum (100 MHz, DMSO-d6) δ 14.35 (CH3), 33.25 (CH2),
44.99 (NCH2), 61.61 (OCH2), 110.54, 119.06, 122.08, 122.47, 127.67, 128.95, 129.87, 136.13, 137.02, 142.55
(Ar-C), 154.09 (C=N), 168.26 (C=O); Anal. Calcd. for C30 H30 N4 O4 : C, 70.59; H, 5.94; N, 16.96. Found: C,
70.57; H, 5.97; N, 16.97.
2.3.2. Diethyl 2,2’-{1,3-phenylenebis[methylene-6-methyl-1H -benzimidazole-2,1-diyl)]} diacetate
(5b)
Yield: 5.00 g (93%), mp: 87–89 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 1.11 (t, J =6.8 Hz, 6H, CH3),
2.40 (s, 6H, CH3), 4.00 (q, J =6.8 Hz, 4H, OCH2), 4.17 (s, 4H, CH2), 5.09 (s, 4H, NCH2), 6.99-7.47 (m, 10H,
Ar-H); 13 C NMR spectrum (100 MHz, DMSO-d6) δ 14.36 (CH3), 21.61, 21.83 (CH3), 33.26 (CH2), 44.88,
45.00 (NCH2), 61.56, 61.59 (OCH2), 110.06, 110.30, 118.67, 118.91, 123.47, 123.73, 127.56, 127.58, 128.91,
129.78, 131.02, 131.75, 134.26, 137.11, 140.69, 142.90 (Ar-C), 153.51, 153.91 (C=N), 168.27, 168.30 (C=O);
Anal. Calcd. for C32 H34 N4 O4 : C, 71.32; H, 6.33; N, 10.42. Found: C, 71.35; H, 6.36; N, 10.40.
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2.3.3. Diethyl 2,2’-{1,3-phenylenebis[methylene-6-nitro-1H -benzimidazole-2,1-diyl)]} diacetate (5c)
Yield: 5.34 g (89%), mp: 179–180 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 1.11 (q, J = 6.8, 6H,
CH3), 4.01 (t, J =6.8 Hz, 4H, OCH2), 4.29 (s, 4H, CH2), 5.29, 5.36 (s, 4H, NCH2), 7.17-7.26 (m, 4H, Ar-H),
7.71-7.78 (m, 2H, Ar-H), 8.11-8.16 (m, 2H, Ar-H), 8.47 (d, J =1.5 Hz, 1H, Ar-H), 8.62 (d, J =1.5 Hz, 1H,
Ar-H); 13 C NMR spectrum (100 MHz, DMSO-d6), δ, ppm: 14.31 (CH3), 33.26 (CH2), 45.44 (NCH2), 61.85
(OCH2), 108.00, 111.36, 115.23, 117.97, 118.32, 119.36, 128.01, 129.15, 130.05, 135.67, 136.31, 140.69, 141.74,
143.09, 143.31, 147.16 (Ar-C), 158.45, 159.85 (C=N), 167.74, 167.91 (C=O); Anal. Calcd. for C30 H28 N6 O8 :
C, 60.05; H, 4.74; N, 14.02. Found: C, 60.00; H, 4.70; N, 13.99.
2.3.4. Diethyl 2,2’-[1,4-phenylenebis(methylene-1H -benzimidazole-2,1-diyl)]diacetate (6a)
Yield: 5.05 g (99%), mp: 345 ◦ C (decomp.). 1 H NMR spectrum (400 MHz, DMSO-d6) δ 1.05 (t, J =5.1
Hz, 6H, CH3), 3.93 (q, J =5.1 Hz, 4H, OCH2), 4.20 (s, 4H, CH2), 5.13 (s, 4H, NCH2), 7.09-7.59 (m, 12H,
Ar-H); 13 C NMR spectrum (100 MHz, DMSO-d6) δ 14.28 (CH3), 33.04 (CH2), 44.93 (NCH2), 61.56 (OCH2),
110.51, 119.51, 121.71, 122.05, 122.43, 129.37 (3C), 135.17, 136.12, 136.33, 142.50 (Ar-C), 154.03 (C=N), 168.22
(C=O); Anal. Calcd. for C30 H30 N4 O4 : C, 70.54; H, 5.99; N, 16.94. Found: C, 70.57; H, 5.97; N, 16.97.
2.3.5. Diethyl 2,2’-{1,4-phenylenebis[methylene(5(6)-methyl-1H -benzimidazole-2,1-diyl)]} diace-
tate (6b)
Yield: 5.17 g (96%), mp: 248–250 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 1.05 (t, J = 6.8 Hz, 6H,
CH3), 2.39 (s, 6H, CH3), 3.52 (q,J = 6.8 Hz, 4H, OCH2), 4.18 (s, 4H, CH2), 5.09 (s, 4H, NCH2), 6.98-7.46
(m, 10H, Ar-H); 13 C NMR spectrum (100 MHz, DMSO-d6) δ 14.27 (CH3), 21.60, 21.81 (CH3), 32.89 (CH2),
44.72, 44.83 (NCH2), 61.55 (OCH2), 110.04, 110.27, 118.64, 118.87, 123.49, 123.74, 129.33 (2C), 131.06, 131.77,
134.22, 135.22, 136.29, 140.68, 142.89 (Ar-C), 153.68, 154.11 (C=N), 168.25, 168.79 (C=O); Anal. Calcd. for
C32 H34 N4 O4 : C, 71.30; H, 6.36; N, 10.45. Found: C, 71.35; H, 6.36; N, 10.40.
2.3.6. Diethyl 2,2’-{1,4-phenylenebis[methylene-6-nitro-1H -benzimidazole-2,1-diyl)]} diacetate (6c)
Yield: 5.46 g (91%), mp: 238–240 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 1.08 (t,J =5.1 Hz, 6H,
CH3), 3.98 (q, J =5.1 Hz, 4H, OCH2), 4.30 (s, 4H, CH2), 5.30 (s, 4H, NCH2), 7.23 (s, 4H, Ar-H), 7.71-7.78
(m, 2H, Ar-H), 8.09-8.16 (m, 2H, Ar-H); 13 C NMR spectrum (100 MHz, DMSO-d6) δ 14.26 (CH3), 32.94,
33.04 (CH2), 45.35, 45.42 (NCH2), 61.84 (OCH2), 108.01, 111.37, 115.22, 118.00, 118.34, 119.35, 129.60,
134.62, 135.65, 140.69, 141.77, 143.09, 143.32, 147.19 (Ar-C), 158.61, 160.01 (C=N), 167.73, 167.90 (C=O);
Anal. Calcd. for C30 H28 N6 O8 : C, 60.02; H, 4.76; N, 14.05. Found: C, 60.00; H, 4.70; N, 13.99.
2.4. Synthesis of compounds 7a–7c and 8a–8c
A solution of compound 5a–5c or 6a–6c (0.01 mol) in n-butanol (10 mL) and hydrazine monohydrate (0.05
mol) was taken in a closed vessel. The mixture was irradiated in a microwave at 120 ◦ C for 10 min (hold time)
at 300 W maximum power. After the reaction was completed (monitored by TLC; ethyl acetate and hexane,
3:1), the mixture was cooled to room temperature and taken in a beaker, and a white solid appeared. This
crude product was filtrated, dried, and washed with ethanol to yield the pure product.
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2.4.1. 2,2’-[1,3-Phenylenebis(methylene-1H -benzimidazole-2,1-diyl)]diacetohydrazide (7a)
Yield: 4.00 g (83%), mp: 235–236 ◦ C. 1 H NMR spectrum (200 MHz, DMSO-d6) δ 3.54 (s, 4H, CH2), 4.22
(s, 4H, NH2), 4.78 (s, 4H, NCH2), 7.15-7.56 (m, 12H, Ar-H), 9.53 (s, 2H, NH); 13 C NMR spectrum (50 MHz,
DMSO-d6) δ 33.60 (CH2), 45.15 (NCH2), 110.69, 119.22, 122.17, 122.49, 127.91, 128.25, 130.38, 136.27, 137.55,
142.87 (Ar-C), 154.76 (C=N), 166.66 (C=O); Anal. Calcd. for C26 H26 N8 O2 : C, 64.75; H, 5.46; N, 23.20.
Found: C, 64.72; H, 5.43; N, 23.22.
2.4.2. 2,2’-{1,3-Phenylenebis[methylene-6-methyl-1H -benzimidazole-2,1-diyl)]} diacetohydrazide
(7b)
Yield 4.34 g (86%), mp: 284–286 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 2.40 (s, 6H, CH3), 3.44
(s, 4H, CH2), 4.21 (s, 4H, NH2), 4.76 (s, 4H, NCH2), 6.98-7.44 (m, 10H, Ar-H), 9.53 (s, 2H, NH); 13 C NMR
spectrum (100 MHz, DMSO-d6) δ 21.63, 21.88 (CH3), 33.39 (CH2), 43.85, 44.98 (NCH2), 110.01, 110.26,
118.60, 118.83, 123.30, 123.52, 127.60, 128.97, 130.08, 130.85, 131.48, 134.21, 136.30, 137.43, 140.75, 142.95
(Ar-C), 153.95, 154.36 (C=N), 166.45, 166.47 (C=O); Anal. Calcd. for C28 H30 N8 O2 : C, 65.80; H, 5.87; N,
21.89. Found: C, 65.86; H, 5.92; N, 21.95.
2.4.3. 2,2’-{1,3-Phenylenebis[methylene-6-nitro-1H -benzimidazole-2,1-diyl)]} diacetohydrazide (7c)
Yield: 4.63 (81%), mp: 290–293 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 4.28 (s, 4H, CH2), 4.35 (s,
4H, NH2), 4.95 (s, 4H, NCH2), 7.19-7.31 (m, 4H, Ar-H), 7.60-7.74 (m, 2H, Ar-H), 8.07-8.17 (m, 2H, Ar-H),
8.44 (d, J =1.5 Hz, 1H, Ar-H), 8.52 (d, J =1.5 Hz, 1H, Ar-H), 9.57 (s, 2H, NH); 13 C NMR spectrum (100
MHz, DMSO-d6) δ 33.41 (CH2), 43.38 (NCH2), 107.78, 111.21, 115.14, 117.83, 118.18, 119.26, 128.04, 129.17,
130.26, 135.62, 136.59, 140.74, 141.76, 142.90, 143.15, 147.24 (Ar-C), 158.84, 160.26 (C=N), 166.38 (C=O);
Anal. Calcd. for C26 H24 N10 O6 : C, 54.50; H, 4.27; N, 24.49. Found: C, 54.54; H, 4.23; N, 24.46.
2.4.4. 2,2’-[1,4-Phenylenebis(methylene-1H -benzimidazole-2,1-diyl)]diacetohydrazide (8a)
Yield: 4.19 g (87%), mp: 305–308 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 3.42 (s, 4H, CH2), 4.23 (s,
4H, NH2), 4.81 (s, 4H, NCH2), 7.15-7.24 (m, 8H, Ar-H), 7.42 (d, J =1.5 Hz, 2H, Ar-H), 7.55 (d, J =1.5 Hz,
2H, Ar-H), 9.51 (2H, s, NH); 13 C NMR spectrum (100 MHz, DMSO-d6) δ 33.03 (CH2), 43.91 (NCH2), 110.45,
118.99, 121.89, 122.01, 122.22, 129.48 (2C), 135.44, 136.07, 142.66 (Ar-C), 154.60 (C=N), 166.38 (C=O); Anal.
Calcd. for C26 H26 N8 O2 : C, 64.79; H, 5.45; N, 23.26. Found: C, 64.72; H, 5.43; N, 23.22.
2.4.5. 2,2’-{1,4-Phenylenebis[methylene-6-methyl-1H -benzimidazole-2,1-diyl)]} diacetohydrazide
(8b)
Yield: 4.28 g (84%), mp: 265–267 ◦ C. 1 H NMR spectrum (200 MHz, DMSO-d6) δ 2.34 (s, 6H, CH3), 3.42
(s, 4H, CH2), 4.17 (s, 4H, NH2), 4.73 (s, 4H, NCH2), 6.93-7.42 (m, 10H, Ar-H), 9.46 (s, 2H, NH); 13 C NMR
spectrum (50 MHz, DMSO-d6) δ 21.86, 22.10 (CH3), 33.25 (CH2), 45.00 (NCH2), 110.23, 110.48, 118.82,
119.028, 123.52, 123.71, 129.64, 131.05, 131.66, 134.40, 135.72, 136.48, 140.98 (Ar-C), 154.28, 154.68 (C=N),
166.67 (C=O); Anal. Calcd. for C28 H30 N8 O2 : C, 65.80; H, 5.87; N, 21.89. Found: C, 65.83; H, 5.91; N, 21.94.
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2.4.6. 2,2’-{1,4-Phenylenebis[methylene-6-nitro-1H -benzimidazole-2,1-diyl)]} diacetohydrazide (8c)
Yield: 4.57 g (80%), mp: 305–306 ◦ C. 1 H NMR spectrum (400 MHz, DMSO-d6) δ 4.22 (s, 4H, CH2), 4.30
(s, 4H, NH2), 4.98 (s, 4H, NCH2), 7.27 (s, 4H, Ar-H), 7.66-7.77 (m, 2H, Ar-H), 8.08-8.17 (m, 2H, Ar-H), 8.46
(d, J =1.5 Hz, 1H, Ar-H), 8.53 (d, 1H, J =1.5 Hz, Ar-H), 9.56 (s, 2H, NH); 13 C NMR spectrum (100 MHz,
DMSO-d6) δ 33.11 (CH2), 45.35 (NCH2), 107.80, 111.23, 115.16, 117.85, 118.18, 119.26, 129.72, 134.82, 135.62,
140.77, 141.80, 142.88, 143.15, 147.29 (Ar-C), 159.00, 160.42 (C=N), 165.83, 165.91 (C=O); Anal. Calcd. for
C26 H24 N10 O6 : C, 54.52; H, 4.25; N, 24.47. Found: C, 54.54; H, 4.23; N, 24.46.
3. Results and discussion
This study reports the synthesis of potential bioactive bisbenzimidazole derivatives starting from iminoester
hydrochlorides and o-phenylenediamine derivatives. The synthetic approach is similar to the conventional
method; however, this approach has not yet been applied to the synthesis of bisbenzimidazoles. Intermediate
N
H C O
5
2
OC
H
5
2
EtOH, Diethylether
NH.HCl
HCl.NH
N
0-5 °C
1, 2
H
H
N
2
MeOH, MW
65 °C, 10 min
N
R
2
R
R
R
R
BrCH2COOC2H5, K2CO3
N
N
N
N
OC2H5
NH
NH
MW, Ac2CO, 90 °C, 10 min
N
N
O
OC2H5
3a-3c, 4a-4c
O
5a-5c, 6a-6c
NH2NH2.H2O, n-Butanol
MW, 120 °C
R
R
1: 1,3-disubstituted iminoester hydrochloride
2: 1,4-disubstituted iminoester hydrochloride
3, 5, 7: 1,3-disubstituted benzimidazole
4, 6, 8: 1,4-disubstituted benzimidazole
a: H, b: -CH3, c: NO2
N
N
NHNH2
N
N
O
NHNH2
O
7a-7c, 8a-8c
Scheme. Synthetic route of target compounds.
428

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KAHVECI et al./Turk J Chem
iminoester hydrochlorides, compounds 1 and 2, were synthesized according to the Pinner method.12 They were
then treated with o-phenylenediamine derivatives to synthesize bisbenzimidazole derivatives (3a–3c and 4a–
4c). The alkylation reaction of bisbenzimidazole compounds with ethyl bromoacetate gave ester derivatives (5a–
5c and 6a–6c). Finally, compounds 5a–5c and 6a–6c were treated with hydrazine monohydrate to synthesize
hydrazide derivatives, which are a good intermediate for preparation of potential bioactive compounds (7a–7c
and 8a–8c) (Scheme).12−16
The chemical shift of the NH proton of bisbenzimidazole derivatives (3a–3c and 4a–4c) in 1 H NMR is
usually around 12.50 ppm. The reaction of bisbenzimidazoles with ethyl bromoacetate in the presence of dry
K2 CO3 in absolute acetone led to the formation of acetate derivatives (5a–5c and 6a–6c). In addition, in 1 H
NMR spectra a signal suggesting the presence of the NH group was not observed and the formation of new N-
CH2 , OCH2 , and –CH3 signals proved the alkylation of bisbenzimidazole derivatives. The ethoxy group is an
easy-leaving group.13−16 The reaction of compounds 5a–5c and 6a–6c with hydrazine monohydrate resulted in
high yields of hydrazide derivatives 7a–c and 8a–c. No signals were shown belonging to –OCH2 CH3 , and new
–NHNH2 signals were formed at about 4.20 ppm (NH2) and 9.50 ppm (NH) in 1 H NMR spectra. Furthermore,
all NH and NH2 signals remained with the addition of D2 O to the DMSO-d6 solution of compounds.
4. Conclusion
This study has described a rapid and efficient protocol for the synthesis of bisbenzimidazole derivatives. Various
o-phenylenediamine derivatives were subjected to reactions with bisiminoester hydrochlorides, providing the
corresponding products in good to excellent yields under microwave heating. This method is an important
alternative for the synthesis of bisbenzimidazole derivatives.
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