Synthesis of novel indole-benzimidazole derivatives

Article abstract of DOI:10.3184/174751916X14737735069962

2-Methylindole-3-acetic acid and its 5-methoxy derivative were prepared from the respective phenylhydrazines and levulinic acid. Indole-3-carboxylic acid was obtained from indole, dimethylformamide and trifluoroacetic acid. These indole carboxylic acids were then condensed with substituted o-phenylenediamines under high temperature conditions in the presence of polyphosphoric acid as a catalyst to give the combined indole-benzimidazoles.

Full text of DOI:10.3184/174751916X14737735069962

588 RESEARCH PAPER
VOL. 40 OCTOBER, 588–590
JOURNAL OF CHEMICAL RESEARCH 2016
Synthesis of novel indole-benzimidazole derivatives
Xinying Wang, Yizhou Liu, Juan Xu, Fanwei Jiang and Congmin Kang*
College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, P.R. China
2-Methylindole-3-acetic acid and its 5-methoxy derivative were prepared from the respective phenylhydrazines and levulinic acid.
Indole-3-carboxylic acid was obtained from indole, dimethylformamide and trifluoroacetic acid. These indole carboxylic acids were then
condensed with substituted o-phenylenediamines under high temperature conditions in the presence of polyphosphoric acid as a catalyst
to give the combined indole-benzimidazoles.
Keywords: 2-methylindole-3-acetic acid, indole-3-carboxylic acid, substituted o-phenylenediamines, indole-benzimidazoles
Results and discussion
Indoles and their derivatives are common heterocyclic
compounds in nature. The indole ring system is an important
structural component of many drugs.1 Indole derivatives are
used as neuroprotective agents affecting oxidative stress,2
potent opioid receptor agonists,3 highly functionalised
pharmacophores4 and potent PPAR-c binding agents with
potential application for the treatment of osteoporosis.5 Drugs
containing an indole ring are used for the treatment of peripheral
neuropathy and neurodegenerative diseases,6 as glucokinase
activators,7 in the cytotoxic antibiotic CC-1065 and prodrugs,8
and as PPAR delta activators for the treatment of cardiovascular
diseases and dyestuffs.9
Benzimidazoles are very useful intermediates/subunits for
the development of molecules of pharmaceutical or biological
interest.10 Substituted benzimidazole derivatives have found
applications in diverse therapeutic areas, including antiulcer,
antihypertensive,11 antiviral, antifungal, anticancer7,12 and
antihistamine drugs.13
We have developed an efficient method for the synthesis of linked
indole-benzimidazole derivatives which involves the combination
of either 2-methylindole-3-acetic acid (2 R = H), its 5-methoxy
derivatives (2 R = OMe) or indole-3-carboxylic acid (6) with
the easily accessible substituted o-phenylenediamines (3) in the
presence of a high boiling point solvent containing polyphosphoric
acid as a catalyst. In the initial experiments 2-methylindole-3-
acetic acid (2 R = H) was synthesised from phenylhydrazine (1
R = H) and levulinic acid and reacted with o-phenylenediamine (3
R = H) in a normal solvent such as ethanol, methanol or DMF but
without success. Only a low yield was obtained when the reaction
was carried out in a solvent with a higher boiling point. However,
when polyphosphoric acid was used as a catalyst in ethylene glycol
as a solvent, compound 4a was obtained in 86% yield. On the basis
of this result, we have synthesised a series of substituted indole-
benzimidazole derivatives (4b–4f, 7a–7c) from compounds 2 and
6 in a single-step process. The results are summarised in Table 1.
NHNH2
COOH
R1
levulinic acid
CH3COOH
N
H
R1
2
1
N
COOH
R2
R1
R2
NH2
NH2
R1
polyphosphoric acid
(CH2OH)2
HN
+
N
N
H
H
2
4
3
Scheme 1
COOH
trifluoroacetic anhydride
DMF
N
N
H
H
6
5
N
R2
COOH
R2
NH2
NH2
polyphosphoric acid
(CH2OH)2
HN
+
N
N
H
H
6
3
7
Scheme 2
* Correspondent. E-mail: cmkang@qust.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2016 589
Table 1 Substituted indole-benzimidazole derivatives
ArH), 7.50 (2H, d, J = 5.0 Hz, ArH), 7.86 (1H, d, J = 7.5 Hz, ArH),
8.03 (1H, d, J = 7.5 Hz, ArH), 11.75 (1H, s, NH), 12.85 (1H, s, NH); IR
(νmax cm−1): 1504, 1580, 1610, 1622, 1638, 1660, 1669, 2874, 3242, 3431;
HRMS m/z 262.1302 (calcd 262.1300 for C17H15N3 [M + H]+).
5-Methyl-2-((2-methyl-1H-indole-3-yl) methyl)-1H-benzimidazole
(4b): Brown solid, yield 87%, m.p. 246–248 °C; 1H NMR (500 MHz,
DMSO-d6), δ 2.31 (3H, s, CH3), 2.43 (3H, s, CH3), 3.84 (2H, s, CH2),
7.05 (1H, t, J = 7.5 Hz, ArH), 7.17 (1H, t, J = 7.5 Hz, ArH), 7.48 (1H, d,
J = 4.5 Hz, ArH), 7.53 (1H, d, J = 4.5 Hz, ArH), 7.60 (2H, d, J = 7.5 Hz,
ArH), 8.13 (1H, s, ArH), 11.76 (1H, s, NH), 12.91 (1H, s, NH); IR (νmax
cm−1): 1505, 1520, 1545, 1610, 1640, 1650, 1672, 2860, 2910, 3371,
3420; HRMS m/z 276.1451 (calcd 276.1456 for C18H17N3 [M + H]+).
Compound R1
R2
Yield (%)
4a
4b
4c
4d
4e
4f
7a
7b
7c
–H
–H
–H
–OCH3
–OCH3
–OCH3
–H
–CH3
–COOCH2CH3
–H
–CH3
–COOCH2CH3
–H
–CH3
86
87
83
78
62
72
79
62
61
–COOCH2CH3
2-((2-Methyl-1H-indole-3-yl)
methyl)-1H-benzimidazole-5-ethyl
formate (4c): Dark brown solid, yield 83%, m.p. 198–201 °C, 1H NMR
(500 MHz, DMSO-d6), δ 1.29 (3H, t, J = 7.5 Hz, CH3), 2.30 (3H, s,
CH3), 3.84 (2H, s, CH2), 4.30 (2H, m, CH2), 7.06 (1H, t, J = 7.5 Hz,
ArH), 7.19 (1H, t, J = 7.5 Hz, ArH), 7.45 (1H, d, J = 8.0 Hz, ArH), 7.56
(1H, d, J = 8.0 Hz, ArH), 7.61 (2H, d, J = 7.5 Hz, ArH), 8.12 (1H, s,
ArH), 11.71 (1H, s, NH), 12.84 (1H, s, NH); IR (νmax cm−1): 1217, 1530,
1539, 1585, 1593, 1606, 1651, 1652, 1780, 2899, 2969, 3296, 3476;
HRMS m/z 334.1509 (calcd 334.1511 for C20H19N3O2 [M + H]+).
2-((5-Methoxy-2-methyl-1H-indole-3-yl) methyl)-1H-benzimidazole
(4d): Sandy brown solid, yield 78%, m.p. 205–206 °C, 1H NMR
(500 MHz, DMSO-d6), δ 2.31 (3H, s, CH3), 3.42 (3H, s, OCH3), 3.82
(2H, s, CH2), 6.90 (1H, d, J = 7.5 Hz, ArH), 7.12 (1H, d, J = 7.5 Hz,
ArH), 7.45 (2H, t, J = 5.0 Hz, ArH), 7.50 (1H, d, J = 5.0 Hz, ArH), 8.12
(1H, s, J = 7.5 Hz, ArH), 8.03 (1H, d, J = 7.5 Hz, ArH), 11.79 (1H, s,
NH), 12.88 (1H, s, NH); IR (νmax cm−1): 1100, 1515, 1540, 1554, 1590,
1620, 1671, 1680, 2840, 2910, 3301, 3395; HRMS m/z 292.1408
(calcd 292.1405 for C18H17N3O [M + H]+).
5-Methyl-2-((5-methoxy-2-methyl-1H-indole-3-yl)methyl)-1H-
benzimidazole (4e): Dark brown solid, yield 62%, m.p. 231–234 °C,
1H NMR (500 MHz, DMSO-d6), δ 2.31 (3H, s, CH3), 2.40 (3H, s, CH3),
3.42 (3H, s, OCH3), 3.82 (2H, s CH2), 7.06 (1H, t, J = 7.5 Hz, ArH),
7.16 (1H, t, J = 7.5 Hz, ArH), 7.51 (1H, d, J = 5.0 Hz, ArH), 7.56 (1H,
d, J = 5.0 Hz, ArH), 7.65 (2H, d, J = 7.5 Hz, ArH), 7.99 (1H, s, ArH),
11.63 (1H, s, NH), 12.78 (1H, s, NH); IR (νmax cm−1): 1110, 1520,
1537, 1560, 1582, 1610, 1670, 1685, 2850, 2905, 2925, 3310, 3290;
HRMS m/z 306.1556 (calcd 306.1562 for C19H19N3O [M + H]+).
2- ((5 - Methox y-2- methyl-1H-indole-3-yl) methyl) -1H-
benzimidazole-5-ethyl formate (4f): Brown solid, yield 72%, m.p.
229–230 °C, 1H NMR (500 MHz, DMSO-d6), δ 1.29 (3H, t, J = 7.5 Hz,
CH3), 2.29 (3H, s, CH3), 3.42 (3H, s, OCH3), 3.85 (2H, s, CH2), 4.28
(2H, m, CH2), 7.01 (1H, t, J = 7.5 Hz, ArH), 7.21 (1H, t, J = 7.5 Hz,
ArH), 7.46 (1H, d, J = 4.0 Hz, ArH), 7.57 (1H, d, J = 4.0 Hz, ArH), 7.70
(2H, d, J = 7.5 Hz, ArH), 8.13 (1H, s, ArH), 11.45 (1H, s, NH), 12.77
(1H, s, NH); IR (νmax cm−1): 1105, 1200, 1515, 1526, 1572, 1600, 1615,
1660, 1675, 1750, 2860, 2900, 2930, 3315, 3340; HRMS m/z 364.1620
(calcd 364.1616 for C21H21N3O3 [M + H]+).
Conclusion
In conclusion, we have synthesised a series of new indole-
benzimidazole derivatives in a two-step process. The method
has the advantages of shorter reaction times, good yields and
easy workup.
Experimental
Reagents were purchased from commercial suppliers and used as
received. TLC analysis was performed using silica gel plates and using
ultraviolet light (254 nm) or vanillin solution for visualisation. Melting
points were taken on an Electrothermal apparatus and are uncorrected.
1H NMR spectra were determined on a 500 MHz Bruker spectrometer.
Mass spectra were determined on a XEVO G2-XS spectrometer.
Infrared spectra were determined on a Bruker EQUINOXX55 infrared
spectrometer.
Preparation of compound 2
Compound 1 (10 mmol) was dissolved in acetic acid (30 mL), and
levulinic acid (15 mmol) was added to the stirred solution which was
then refluxed for 4 h. After cooling to room temperature, the mixture
was poured into water (200 mL) and then the solution was treated with
30% sodium hydroxide to slight acidity (pH = 5–6). The precipitated
solid was filtered off, recrystallised from ethanol and dried in vacuo to
give compound 2.
2-Methylindole-3-acetic acid (2a): Yellow solid, yield 78%, m.p.
200–203 °C (199–200 °C14); 1H NMR (500 MHz, CDCl3), δ 2.31 (3H,
s, CH3), 3.65 (2H, s, CH2), 6.97 (1H, t, J = 7.5 Hz, ArH), 7.12 (1H, t,
J = 7.5 Hz, ArH), 7.23 (1H, d, J = 6.0 Hz, ArH), 7.33 (1H, d, J =6.0 Hz,
ArH), 10.83 (1H, s, COOH), 12.15 (1H, s, NH); IR (νmax cm−1): 1504,
1518, 1565, 1624, 1769, 2935, 3001, 3535; HRMS m/z 190.0824
(calcd 190.0823 for C11H11NO2 [M + H]+).
5-Methoxy-2-methylindole-3-acetic acid (2b): Red brown solid,
yield 74%, m.p. 161–163 °C (161–162 °C15); H NMR (500 MHz,
1
DMSO-d6), δ 2.31 (3H, s, CH3), 3.81 (3H, s, OCH3), 3.70 (2H, s,
CH2), 7.19 (1H, d, J = 7.5 Hz, ArH), 7.23 (1H, d, J = 7.5 Hz, ArH), 7.56
(1H, s, J = 7.5 Hz, ArH), 10.80 (1H, s, COOH), 12.21 (1H, s, NH); IR
(νmax cm−1): 1092, 1581, 1602, 1604, 1671, 1773, 2926, 3072, 3232;
HRMS m/z 220.0923 (calcd 220.0929 for C12H13NO3 [M + H]+).
Preparation of indole-3-carboxylic acid (6)
Indole (2.34 g, 20 mmol) was dissolved in DMF (10 mL) and then
trifluoroacetic anhydride (4.2 mL, 30 mmol) was added dropwise
at 0 °C. After stirring at room temperature for 3 h, water was added
and the resulting pink solid was filtered. The collected solid was
treated with 20% NaOH (40 mL, 0.2 mol) at 50 °C overnight. After
cooling to room temperature, the solution was extracted with
Et2O. The aqueous phase was acidified with concentrated HCl
and the product was obtained by filtration. Compound 6 indole-3-
carboxylic acid was obtained as a light yellow solid, yield 77%, m.p.
Preparation of compound 4
Compound 3 (10 mmol) was dissolved in ethylene glycol (50 mL) and
then compound 2 (10 mmol) and a small amount of polyphosphoric
acid were added to the stirred solution which was then refluxed for
several hours (the reaction was monitored by TLC). On completion of
the reaction, the mixture was poured into ice water. The solution was
treated with 30% sodium hydroxide to slight alkalinity (pH = 9). The
precipitated solid was filtered off, recrystallised from ethanol and
dried in vacuo to give compound 4.
1
194–196 °C (194–196 °C16); H NMR (500 MHz, DMSO-d6), δ 7.12
(2H, t, J = 5.0 Hz, ArH), 7.48 (1H, d, J = 7.5 Hz, ArH), 7.95 (1H, d,
J = 7.5 Hz, ArH), 8.13 (1H, s, ArH), 11.68 (1H, s, COOH), 11.79 (1H,
s, NH); IR (νmax cm−1): 1513, 1554, 1613, 1682, 1776, 3019, 3376;
HRMS m/z 162.0511 (calcd 162.0510 for C9H7NO2 [M + H]+).
2-((2-Methyl-1H-indole-3-yl)
methyl)-1H-benzimidazole
(4a):
Khaki solid, yield 86%, m.p. 215–218 °C; 1H NMR (500 MHz,
DMSO-d6), δ 2.31 (3H, s, CH3), 3.87 (2H, s CH2), 7.01 (1H, t,
J = 7.5 Hz, ArH), 7.16 (1H, t, J = 7.5 Hz, ArH), 7.45 (2H, t, J = 5.0 Hz,
Preparation of compound 7
Compound 3 (10 mmol) was dissolved in ethylene glycol (50 mL) and
then compound 6 (10 mmol) and a small amount of polyphosphoric

590 JOURNAL OF CHEMICAL RESEARCH 2016
acid were added to the stirred solution which was then refluxed for
several hours (the reaction was monitored by TLC). On completion of
the reaction, the mixture was poured into ice water. The solution was
treated with 30% sodium hydroxide to slight alkalinity (pH = 9). The
precipitated solid was filtered, recrystallised from ethanol and dried in
vacuo to give compound 7.
2-(1H-Indole-3-yl)-1H-benzimidazole (7a): Yellow solid, yield 79%,
m.p. 224–226 °C (226–228 °C17), 1H NMR (500 MHz, DMSO-d6),
δ 7.28 (2H, t, J = 7.5 Hz, ArH), 7.34 (2H, t, J = 7.5 Hz, ArH), 7.47
(1H, d, J = 7.5 Hz, ArH), 7.52 (1H, d, J = 7.5 Hz, ArH), 7.81 (2H, d,
J = 4.0 Hz, ArH), 8.03 (1H, s, ArH), 12.41 (1H, s, NH);. IR (νmax (cm−1):
1482, 1500, 1526, 1605, 1617, 3405, 3426;. HRMS m/z 234.0984
(calcd 234.0987 for C15H11N3 [M + H]+).
2-(1H-Indole-3-yl)-5-methyl-1H-benzimidazole (7b): Dark brown
solid, yield 62%, m.p. 215–217 °C (214–216 °C17), 1H NMR (500 MHz,
DMSO-d6), δ 2.38 (3H, s, CH3), 7.12 (1H, d, J = 7.5 Hz, ArH), 7.34 (2H,
t, J = 4.0 Hz, ArH), 7.54 (1H, d, J = 7.5 Hz, ArH), 7.56 (1H, s, ArH),
7.72 (2H, d, J = 4.0 Hz, ArH), 8.12 (1H, s, ArH), 12.46 (1H, s, NH);
IR (νmax cm−1): 1490, 1500, 1580, 1605, 1620, 1670, 1680, 2950, 3300,
3380; HRMS m/z 248.1146 (calcd 248.1143 for C16H13N3 [M + H]+).
2-(1H-Indole-3-yl)-1H-benzimidazole-5-ethyl formate (7c): Dark
brown solid, yield 61%, m.p. 220–221 °C, 1H NMR (500 MHz,
DMSO-d6), δ 1.31 (3H, t, J = 7.5 Hz, CH3), 4.25 (2H, m, CH2), 7.11
(1H, d, J = 7.5 Hz, ArH), 7.34 (2H, t, J = 4.0 Hz, ArH), 7.56 (1H, d,
J = 7.5 Hz, ArH), 7.62 (1H, s, ArH), 7.71 (2H, d, J = 4.0 Hz, ArH), 8.16
(1H, s, ArH), 12.36 (1H, s, NH); IR (νmax cm−1): 1119, 1482, 1486, 1540,
1576, 1670, 1672, 1675, 1736, 2974, 3287, 3412; HRMS m/z 306.1201
(calcd 306.1198 for C18H15N3O2 [M + H]+).
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