Comparative studies on conventional and microwave assisted synthesis of benzimidazole and their 2-substituted derivative with the effect of salt form of reactant

Article abstract of DOI:10.1248/cpb.55.115

Benzimidazole and their derivative were reported to have wide biological activities and were synthesized by using different solvents and ring closing agents. The present work deals with the comparative synthesis of 2-alkyl and aryl substituted benzimidazole derivative in the presence of polyphosphoric acid through microwave and conventional methods and also studied the effect of salt form of reactant for completion of the reaction. The 2-substituted aryl and alkyl benzimidazole derivative were synthesized via microwave and was observed to be more beneficial, in respect of yield (increases up to 10 to 50%) and time (96 to 98% was reduced) than conventional method of synthesis. This study was concluded that the salt form of reactant (o-phenylenediamine dihydrochloride) gave reduced colour impurities, homogenous mixing and reduced time for completion of reaction.

Full text of DOI:10.1248/cpb.55.115

January 2007
Notes
Chem. Pharm. Bull. 55(1) 115—117 (2007)
115
Comparative Studies on Conventional and Microwave Assisted Synthesis
of Benzimidazole and Their 2-Substituted Derivative with the Effect of
Salt Form of Reactant
a
Raghvendra DUBEY and Narayana Subbiah HARI NARAYANA MOORTHY*,b
a Ujjain Institute of Pharmaceutical Sciences; Ujjain, Madhya Pradesh, India: and b School of Pharmaceutical Sciences,
Rajiv Gandhi Technical University; Airport Bypass Road, Gandhi Nagar, Bhopal–462036, Madhya Pradesh, India.
Received July 3, 2006; accepted September 30, 2006
Benzimidazole and their derivative were reported to have wide biological activities and were synthesized by
using different solvents and ring closing agents. The present work deals with the comparative synthesis of 2-alkyl
and aryl substituted benzimidazole derivative in the presence of polyphosphoric acid through microwave and
conventional methods and also studied the effect of salt form of reactant for completion of the reaction. The
2-substituted aryl and alkyl benzimidazole derivative were synthesized via microwave and was observed to be
more beneficial, in respect of yield (increases up to 10 to 50%) and time (96 to 98% was reduced) than conven-
tional method of synthesis. This study was concluded that the salt form of reactant (o-phenylenediamine dihy-
drochloride) gave reduced colour impurities, homogenous mixing and reduced time for completion of reaction.
Key word benzimidazole; microwave assisted synthesis; conventional synthesis; o-phenylenediamine dihydrochloride
In the rapidly developing environment, every process tures reveals benzimidazole can be synthesized convention-
needs automation to increase productivity, quality and safety ally in the presence of ring closing agent (solvents) e.g. ploy
with reduced manpower and time. Microwave is found to be phosphoric acid)24,25) through microwave and conventional
an important tool, which fulfills these criteria.1,2)
method and studied the effect of salt form of reactant for
In mid of 1980’s, microwave irradiation was first applied completion of the reaction (Chart 1).
towards synthetic chemistry. In 1986, first microwave-
Chemistry In the conversion of conventional method to
assisted synthesis paper was published by Gedye and microwave assisted synthesis, the sample was started heating
Giguere/Majetich.3)
at minimum percentage for minimum duration, because the
Microwave assisted organic synthesis (MAOS) is superior actual duration in which reaction will complete was not
in many ways to traditional heating.4—6) The benefits of mi- known.
crowave assisted synthesis, including speed, increased yield
Conventional synthesis of alkyl and aryl benzimidazoles
and clear chemistry have provided the momentum for many was done by standard procedure.12,13,24) Microwave assisted
chemists to switch from traditional heating method to mi- synthesis of this compound was done by using the starting
crowave assisted chemistry. Now, microwave has become a material as its salt form (o-phenylenediamine was converted
new era in the field of synthetic chemistry.7,8)
into o-phenylenediamine dihydrochloride).
Number of conventional reactions, including basic reac-
The development of method was started with addition of
tions and name reactions were converted into microwave-as- reagents in the dried Erlenmeyer flask and the mixture was
sisted synthesis such as alkylation, condensation, substitution homogenized thoroughly, the flask was capped with small
reaction, etc.9—11) Among the reactions, cyclization reaction funnel and the hole of funnel was plugged with cotton. The
is a reaction resulting synthesis of various heterocyclic com- reaction mixture was kept in microwave cavity (applicator)
pounds. Through cyclization reaction, various substituted for heating, at minimum percentage (20%) for minimum
benzimidazole derivatives were synthesized in the presence time duration (10 s). After completion of heating, reaction
of various solvents and ring closing agents such as dry ben- mixture was taken out of cavity. A TLC of the reaction mix-
zene, xylene, p-tolune sulfonic acid, mercaptoacetic acid, ture and the starting compound were run in suitable solvent
toluene, ethanol and polyphosphoric acid (ring closing system. Each time, the sample was taken by, removing the
agents).12,13)
cotton from the hole of funnel and dipping the capillaries in a
Benzimidazoles are five membered benzoheterocyclic reaction mixture. After development of TLC, the progress of
compounds containing two heteroatoms. Both heteroatoms reaction was known. According to that the rate of heating
are nitrogen (N), which are present at non-adjacent position. was increased, on completion of reaction, a constant TLC
Benzimidazoles (aryl and alkyl substituted) have wide vari- spot was observed. From this, the time duration and heating
ety of reported activities especially, antimicrobial, antitumor, percentage in which reaction got complete was observed.
antiviral, antifungal, antioxidant, antiulcer, antiamoebic, anti-
histaminic, anthelmintic and antihypertensive activity.14—20)
From 1996, various substituted benzimidazole derivatives
are synthesized through microwave heating, in the presence
of different solvents and catalytic agents.21—23)
In the present investigation, we performed a study on com-
parative synthesis of 2-alkyl and aryl substituted benzimida-
Chart 1
zole derivative in the presence of polyphosphoric acid (litera-
∗ To whom correspondence should be addressed. e-mail: nshnm06@yahoo.co.in
© 2007 Pharmaceutical Society of Japan

116
Vol. 55, No. 1
Experimental
ized with ice-cold 10% aqueous sodium carbonate solution. Solid product
Material and Methods All the chemicals and solvents used for this obtained was collected, dried at room temperature and recrystallized with
work were obtained from E-Merck Ltd., Mumbai and S.D. Fine Chem. Ltd., aqueous methanol. (Conventionally synthesized by reported method.)24)
Mumbai. LG-health wave microwave system (MG-607APR, 230 V—50 Hz) Colour: Light yellow crystalline (small crystal size), (0.461 g, 84.83 %). 1H-
was used and the output of microwave power is mentioned as percent inten- NMR (acetone-d6) d: 7.70—7.21 (4H, m), 7.48—7.32 (5H, m), 5.0 (1H, s).
sity i.e. (20%, 40%, 60%, 100%). Melting points of the synthesized com-
pounds were determined in open capillary tubes and were uncorrected. IR
absorption spectra were recorded on Jasco FT/IR-470 Plus, KBr diffuse re-
IR (KBr) cmꢀ1: 3071, 1602, 1583, 1558, 1507, 1455, 1324, 1180, 1698. m/z:
194 (Mꢁ), Anal. Calcd for C13H10N2: C, 80.39; H, 5.19; N, 14.42. Found: C,
80.10; H, 5.29; N, 14.51.
1
flectance, H-NMR spectra were recorded on the JEOL GSX-400, 60 MHz
Synthesis of 2-(4-Aminophenyl)benzimidazole Half gram (0.0028
spectrometer in acetone and TMS (tetramethylsilane) as an internal stan- mol) of o-phenylenediamine dihydrochloride (prepared as per the reported
dard. The 1H chemical shifts were reported as parts per million (ppm) down- literature),24) 0.387 g (0.0028 mol) of p-amino benzoic acid (PABA) and
1
field from TMS (Me4Si). H-NMR and IR spectra were consistent with the 6.99 g poly phosphoric acid (PPA) were added and mixed homogeneously.
assigned structures. The elemental analysis (CHN analysis) was done on a The mixture was heated trice at 20% for 1 min 40 s; each time mixture was
CHN rapid analyzer. Purity of the compounds was checked by thin layer removed and stirred for few moments. The mixture was then cooled upto
chromatography (TLC).
room temperature and neutralized with ice-cold 10% aqueous sodium car-
Synthesis of Benzimidazole Half gram (0.0046 mol) of o-phenylenedi- bonate. The obtained solid product was collected, dried at room temperature
amine and 0.32 g (3 ml, 0.062 mol) of 90% formic acid was added in Erlen-
and recrystallized with aqueous methanol. (Conventionally synthesized by
meyer flask and the reaction mixture was homogeneously mixed. The mix- reported method.)24) Colour: Yellowish white, crystalline (large needle
1
ture was heated at 20% for 80 s, the flask was then removed, cooled (up to shape) product was obtained. (0.5606 g, 94.80%). H-NMR (acetone-d6) d:
room temperature) and 10% sodium hydroxide solution was added slowly, 7.70—7.26 (4H, m), 7.23 (2H, d), 6.7—6.6 (2H, d), 5.0 (1H, s), 4.0 (2H, s).
with constant stirring, until the mixture was just alkaline to litmus. The IR (KBr) cmꢀ1: 3010, 1600, 1573, 1440, 1311, 1680, 1174, 3461, 3386. m/z:
crude benzimidazole was filtered off and washed thrice with ice-cold water 209 (Mꢁ). Anal. Calcd for C13H11N3: C, 74.62; H, 5.30; N, 20.08. Found: C,
and dried. To decolorize, the crude product obtained was dissolved in boil- 74.31; H, 5.46; N, 20.30.
ing water, 0.2 g of decolorizing carbon was added and digested for 10 min
Synthesis of 2-(4-Chlorophenyl)benzimidazole Half gram (0.002 mol)
then filtered rapidly at 10 °C. The product was filtered off, washed with cold of o-phenylenediamine dihydrochloride (prepared as per the reported litera-
water and dried at 100 °C. Recrystallized the product with methanol and
ture),24) 0.442 g (0.0028 mol) of p-chlorobenzoic acid and 6.99 g poly phos-
phoric acid (PPA) were added and mixed homogeneously. The mixture was
weighed. (Conventionally synthesized by reported method.)20) Colour: Dusty
1
white, crystalline product obtained (yield 0.501 g, 91.75%). H-NMR (ace- heated trice at 20% for 90 s; each time the mixture was removed and stirred
tone-d6) d: 8.23 (1H, d), 7.70—7.21 (4H, m), 5.0 (1H, d). IR (KBr) cmꢀ1
:
for little moment. Then the mixture was cooled upto room temperature and
neutralized with ice-cold 10% aqueous sodium carbonate solution. Solid
3061, 1601, 1587, 1495, 1457, 1692, 1346, 1161. m/z: 118 (Mꢁ). Anal.
Calcd for C7H6N2: C, 71.17; H, 5.12; N, 23.71. Found: C, 70.95; H, 5.45; N, product obtained was collected and dried at room temperature and recrystal-
23.84.
Synthesis of Methyl Benzimidazole Half gram (0.0028 mol) of
lized with aqueous methanol. (Conventionally synthesized by reported
method.)21) Colour: White crystalline (small size crystal), (0.5724 g 88.63
o-phenylenediamine dihydrochloride (prepared as per the reported litera- %), 1H-NMR (acetone-d6) d: 8.03—7.54 (4H, m), 7.42—7.33 (2H, d), 7.2—
ture),24) 3 ml of water and 0.5087 g (0.5 ml, 0.0085 mol) of acetic acid was 7.0 (2H, d), 5.0 (1H, s). IR (KBr) cmꢀ1: 3094, 1590, 1574, 1508, 1456,
added in Erlenmeyer flask and the mixture was heated at 20% for 80 s. The 1682, 1130, 1177, 760, 712. m/z: 228 (Mꢁ), Anal. Calcd for C13H9ClN2: C,
mixture was cooled (upto room temperature) and neutralized with concen- 68.28; H, 3.97; N, 12.25. Found: C, 68.48; H, 3.65; N, 12.55.
trated ammonia solution. Crude methyl benzimidazole was filtered off,
washed thrice with ice-cold water and dried, decolorized the crude product
Results and Discussion
as earlier procedure, recrystallized with ethanol and weighed. (Convention-
ally synthesized by reported method.)20) Colour: Pale yellowish (0.332 g,
89.01%). 1H-NMR (acetone-d6) d: 7.70—7.21 (4H, m), 5.0 (1H, s), 2.4 (3H,
s). IR (KBr) cmꢀ1: 3028, 1591, 1504, 1457, 1634, 1320, 1155. m/z: 133
(Mꢁ). Anal. Calcd for C8H8N2: C, 72.70; H, 6.10; N, 21.20. Found: C,72.71;
H, 6.50; N, 20.84.
Synthesis of Phenyl Benzimidazole Half gram (0.0028 mol) of o-
phenylenediamine dihydrochloride (prepared as per the reported litera-
ture),24) 0.344 g (0.0028 mol) of benzoic acid and 6.99 g poly phosphoric
acid (PPA) were added and mixed homogeneously. Mixture was heated trice
at 20% for 1 min 30 s; each time the mixture was removed and stirred for
few moments. Mixture was then cooled upto room temperature and neutral-
Benzimidazole and its 2-alkyl and aryl substituted deriva-
tives were synthesized by conventional and microwave as-
sisted methods. The synthesized compounds and their
physicochemical properties are given in Tables 1 and 2. The
structures of the synthesized compounds were confirmed by
NMR, IR, Mass and elemental analysis. The results obtained
from the spectroscopy confirm the structure of the synthe-
sized compounds. The comparative data of the synthesized
compounds are provided in Table 2. The reaction time for the
Table 1. Reactants and Solvents Used for Synthesis of Benzimidazole Derivatives by Conventional and Microwave Assisted Synthesis Method
S. No
R1
R2
Reactant I
Reactant II
Formic acid
A
Compound
Benzimidazole
Molecular formula
1
2
H
H
CH3
o-Phenylenediamine
o-Phenylenediamine
dihydrochloride
—
Water
C7H6N2 (118.14)
C8H8N2 (132.16)
H·HCl
Acetic acid
2-Methyl benzimidazole
3
4
5
Ha)
o-Phenylenediamine
Benzoic acid
PPA
PPA
PPA
2-Phenyl benzimidazole
C13H10N2 (194.23)
C13H11N3 (209.25)
H·HCl
o-Phenylenediamine
dihydrochloride
Ha)
o-Phenylenediamine
2-(4-Aminophenyl)
benzimidazole
p-Amino benzoic acid
p-Chloro benzoic acid
H·HCl
o-Phenylenediamine
dihydrochloride
Ha)
o-Phenylenediamine
2-(4-Chlorophenyl)
benzimidazole
C13H9ClN2 (228.68)
H·HCl
o-Phenylenediamine
dihydrochloride
a) Conventional method.

January 2007
117
Table 2. Comparative Physicochemical Data of Conventional and Microwave Assisted Synthesized Compounds
Conventional synthesis
Compound
Microwave assisted synthesis
RTa)
% Yield
mp °C (reported)
Rf value
RT
% Yield
91.75%
mp (°C)
172 °C
Rf value
Benzimidazole
2 h
80.22%
171—172 °C
(171 °C)
0.575b)
1 min 20 s
0.609b)
0.468c)
0.276c)
2-(Methyl)benzimidazole
2-(Phenyl)benzimidazole
45 min
4 h
47.90%
33.58%
177—180 °C
(179 °C)
0.469c)
0.272c)
1 min 20 s
4 min 30 s
89.01%
84.83%
179 °C
238 °C
238 °C
(238 °C)
—
—
—
—
0.250c)
8 mind)
5 min
82.44%d)
94.80%
—
—
0.265c)
2-(Amino phenyl)benzimidazole
2-(Chloro phenyl)benzimidazole
4 h
56.55%
248 °C
(246 °C)
—
246 °C
—
—
—
0.304c)
8 mind) 40 s
4 min 30 s
94.23%d)
88.63%
—
—
0.297c)
4 h
43.37%
240—242 °C
(241 °C)
—
242 °C
—
—
—
6 mind) 30 s
87.84%d)
—
—
a) Reaction time, b) ethyl acetate : n-hexane 7 : 3, c) ethyl acetate : n-hexane : water 7 : 2 : 1, d) reaction time and percentage yield of compounds synthesized from o-phenylene-
diamine in microwave method.
3) Gedye R., Smith F., Westaway K., Ali H., Baldisera L., Laberge L.,
Rousell J., Tetrahedron Lett., 27, 279—282 (1986).
4) Johansson H., Am. Lab., 33, 28—32 (2001).
synthesis of benzimidazole derivatives by conventional
method was 45 min to 4 h in comparison with the microwave
heating (1—5 min), which reduced the time duration many
5) Bradley D., Modern Drug Discovery, 4, 32—36 (2001).
fold. Approximately 96 to 98% was decreased reaction time
and the yield obtained was increased by 10 to 50%. Use of
reactant and their salt form were observed to have effect on
yield and time of reaction, shown in Table 2. The salt form of
the reactant reduced the reaction time approximately 30—
50% than o-phenylenediamine itself in microwave assisted
method. This may be due to interfacial polarization. As heat-
ing is very important for reactant to crossover the activation
barrier and perform the reaction, microwave have made easy
to do so.
6) Larhed M., Hallberg A., Drug Discovery Today, 6, 406—416 (2001).
7) Wathey B., Tierney J., Lidrom P., Westman J., Drug Discovery Today,
7, 373—380 (2002).
8) Dzieraba C. D., Combs A. P., Annu. Rep. Med. Chem., 37, 247—256
(2002).
9) Abramovitch R. A., Shi Q., Bogdal D., Synth. Commun., 25, 1—8
(1995).
10) Kim J. K., Kwon P. S., Kwon T. W., Chung S. K., Lee J. W., Synth.
Commun., 26, 535—542 (1996).
11) Arevela R. K., Leadbeater N. E., J. Org. Chem., 68, 9122—9125
(2003).
12) Crawford K. R., Bur S. K., Straub C. S., Padwa A., Org. Lett., 5,
3337—3340 (2003).
13) Lednicer D., Mitscher L. A., “The Organic Chemistry of Drug Synthe-
sis,” A Wiley-Interscience publication, New York, 1999.
14) Afaf H., El-Masry H. H., Fammy S. H., Ali A., Molecule, 5, 1429—
1438 (2000).
15) White A. W., Curtin N. J., Eastman B. W., Golding B. T., Hostomsky
Z., Kyle S., Li J., Maegley K., Skalitzky D. J., Webber S. E., Yu X. H.,
Griffin R. J., Bioorg. Med. Chem. Lett., 14, 2433—2437 (2004).
16) Garuti L., Roberti M., Gentilomi G., I1 Farmaco, 55, 35—39 (2000).
17) Maxwell W. A., Brody G., Appl. Microbial., 21, 944—945 (1971).
18) Givens D. M., Dyksta C. C., Brock K. V., Stringfellow D. A., Kumar
A., Stephens C. E., Goker H., Boykin D. W., Antimicrob. Agents
Chemother., 47, 2223—2236 (2003).
19) Sondhi S. M., Nagar A., Sahu R., Mahesh V. K., Shukla R., Patnaik G.
K., Synthesis, 1994, 1175—1180 (1994).
20) Kaliszan R., Foksh D. B., Nasal A., Petrusewicz J., Radwaanska A.,
Saczewski F., Kuzmier K. W., Pol. J. Pharmacol. Pharm., 39, 419—
431 (1987).
21) Song L. Q., Tan G. Z., Xu X. L., Hecheng Huaxue, 9, 175—176
(2001).
22) Shieh W. C., Dell S., Repic O., Org. Lett., 3, 4279—4281 (2001).
23) Khajiavi M. S., Rad-Maghadam K., Hazarkhani H., Syn. Commun., 29,
2617—2624 (1999).
24) Furniss B. S., Hannaford A. J., Smith P. W. G., Tatchell A. R., “Vogel’s
Textbook of Practical Organic Chemistry,” 5th ed., ELBS Publication,
U.K., 1989.
Conclusion
From the study it was concluded that synthesis of benzimi-
dazole and their 2-substituted derivative from microwave has
reduced the reaction time from 96 to 98% and increase the
yield near about 10 to 50%. The study also showed some re-
markable inferences while the use of salt form of reactant (o-
phenylenediamine dihydrochloride).
In the final product, no color impurities of o-phenylenedi-
amine was observed.
The salt form of reactant allowed the homogeneous mixing
of reaction mixture, while in o-phenylenediamine the mixing
require continuous stirring which cause sticking of reactant
on stirr.
The reaction completion time was reduced.
This study also concluded that the developed procedure
for synthesis of compound benzimidazole derivatives
through microwave is simple, increased purity and yields of
product, ease of work up, simplicity and overall safety com-
pared with reported conventional method.
References
25) Shi D. F., Bradshaw T. D., Wrigley S., McCall C. J., Lelieveld P., Ficht-
ner I., Stevens M. F. G., J. Med. Chem., 39, 3375—3384 (1996).
1) Adam D., Nature (London), 421, 571—572 (2003).
2) Blackwell H. E., Org. Biomol. Chem., 1, 1251—1255 (2003).