Microwave Assisted Synthesis of Trifluoro Substituted 2-Aminobenzimidazole Derivatives via Iodoacetic Acid Mediated One-pot Condensation

Article abstract of DOI:10.1002/jhet.2841

Microwave-assisted efficient one-pot syntheses of trifluoro substituted 2-aminobenzimidazole derivative were synthesized using iodoacetic acid mediated cyclodesulfurization of thioureas. This method eliminates need to handle preformed substituted thioureas, requires lesser reaction time and temperature, is facile, and also gives higher yields of the target molecules.

Full text of DOI:10.1002/jhet.2841

Month 2017
Microwave Assisted Synthesis of Trifluoro Substituted
2-Aminobenzimidazole Derivatives via Iodoacetic Acid Mediated
One-pot Condensation
*
R. Sriram, R. Sapthagiri, L. Ilavarasan, and A. Ravi
PG & Research Department of Chemistry, Government Arts College, Thiruvalluvar University, Tiruvannamalai, 606603
Vellore, Tamil Nadu, India
*
E-mail: draravigac@gmail.com
Additional Supporting Information may be found in the online version of this article.
Received September 6, 2016
DOI 10.1002/jhet.2841
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Microwave-assisted efficient one-pot syntheses of trifluoro substituted 2-aminobenzimidazole derivative
were synthesized using iodoacetic acid mediated cyclodesulfurization of thioureas. This method eliminates
need to handle preformed substituted thioureas, requires lesser reaction time and temperature, is facile,
and also gives higher yields of the target molecules.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
We recognized that this microwave assisted one-pot
process could be considerably simplified by iodoaceicacid
as a cyclodesulfurization agent, ethanol solvent, and less
reaction time to provide desired product with high yields.
The aminobenzimidazole derivatives are important
numerous categories of therapeutic agent such as
antibacterial, antioxidant [1], antimicrobial, antifungal and
anti-mycobacterial [2–4], anticancer [5], etc. Various
substitutions around the benzimidazole nucleus that have
provided a wide biological activities were reported. Most of
the literature have reported about 4-substituted benzene-1,2-
diamine, which was used for the synthesis of benzimidazole
derivatives carried out in multiple steps [6]. To address the
importance of this nucleus, we have synthesized 3-substituted
benzene-1,2-diamine in novel N-(2,3-diaminobenzyl)methane
sulfonamide. 2-Aminobenzimidazoles derivatives are
interesting heterocycles that are found in natural products
as well as drugs and a number of biologically active
molecules [7]. A number of methods for the preparation
of 2-aminobenzimidazole have been reported [8,9]. Also
this motif was synthesized by Buchwald Hartwig C―N
bond formation [10] and intramolecular copper-catalyzed
arylation [11]. The preparation of 2-aminobenzimidazole
derivatives involves the cyclodesulfurization of a pre-
formed thiourea. The reported desulfurization agents were
mercury(II)oxide [12], mercury(II)chloride [13], copper(I)
chloride [14], methyl iodide [15], tosyl chloride [16],
dicyclohexyl carbodiimide [17], PhI(OAc)2 [18], and
polymer supported carbodiimide [19]. The reported
method frequently requires harsh condition, heating, and
long reaction time. Furthermore, formation of urea side
product can pose significant challenges during purification
and make halogenated solvents environmentally unsafe.
RESULTS AND DISCUSSION
In Scheme 1, synthesis of compound 7 involved six
steps. The first step was 3-methyl-1, 2-diamine was
protected using thionyl chloride, pyridine as a solvent at
room temperature; it gave good yields of intermediate 2.
Then, bromination was carried out by using NBS and UV
light to afford intermediate 3; the same was treated with
potassium carbonate, di-Boc amine, and THF at reflux
condition to give intermediate 4. The intermediate 4 was
BOC deprotected using HCl in 1,4-dioxane; the
intermediate 5 was further sulphonated using TEA and
methyl sulphonyl chloride to get intermediate 6 and
further treated with Raney-nickel under H2 atmosphere to
give deprotection of diamine intermediate 7 with good
yields.
In Scheme 2, methyl 3-amino-3-(3-(trifluoromethyl)
phenyl)propanoate 10 were synthesized from compound
8. Compound 8 was condensed with malonic acid, and
ammoniumformate provides compound 9. It reacts with
thionylchloride and methanol to afford compound 10 as
good yield.
In Scheme 3, the compounds 11a–11c were synthesized
from compounds 10a – 10c using sodium bicarbonate and
thiophosgene at room temperature to provide good yield.
© 2017 Wiley Periodicals, Inc.

R. Sriram, R. Sapthagiri, L. Ilavarasan, and A. Ravi
Vol 000
Scheme 1. Synthesis of N-(2,3-diaminobenzyl)methanesulfonamide.
Cyclodesulfurization proposed mechanism.
involves long reaction time and significant challenges
during purification of the products. Initially, our targeted
work was done in normal labouratory conditions using
magnetic bar with heating various temperatures, but it
gives less yields and more than 2-h reaction time. So, we
have developed the method microwave-assisted one-pot
synthesis using iodoacetic acid as a cyclodesulfurization
agent and optimized the reaction condition (Table 2)
using different solvents and temperature. In this present
investigation we observed that in ethanol and 2 eq of
iodoacetic acid to provide desired product at 60°C,
30 min with high yields. Similarly, in Table 3, a variety
of synthesized 2-aminobenzimidazole derivatives were
denoted.
EXPERIMENTAL SECTION
Methods and materials.
The chemicals used are 3-
methylbenzene-1,2-diamine,1-(3-(trifluoromethyl)phenyl)
ethanamine, NBS, methane sulphonyl chloride, iodoacetic
acid, and thionyl chloride purchased from Avra
chemicals. Raney nickel was purchased from Aldrich. All
commercially available chemicals and solvents were used
without further purification. TLC experiments were
performed on alumina-backed silica gel 60 F254 plates
In Scheme 4, novel 2-amino benzimidazole derivatives
12a–12f were synthesized from the condensation between
compound 7a–b and 11a–11c in the presence of
iodoaceticacid. Most of the researcher have synthesized
2-aminobenzimidazole derivatives by using hazardous
catalyst like mercury(II)oxide, mercury(II)chloride,
copper(I)chloride, DCC, EDC (Table 1) etc., which
Scheme 2. Synthesis of methyl 3-amino-3-(3-(trifluoromethyl)phenyl)propanoate.
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Trifluoro substituted 2-Aminobenzimidazole Derivatives
Scheme 3. Synthesis of isothiocyanate compounds.
300-W maximum power. The machine was used in the
standard configuration as delivered, including proprietary
software. The reaction were carried in a 100-mL glass
vials sealed with an aluminium/Teflon crimp top, which
can be exposed to a maximum temperature of 250°C and
20 bar internal pressure. The temperature was measured
with an IR sensor on the outer surface of the process vail.
After the irradiation period, the reaction vessel was cooled
rapidly (60–120 s) to room temperature by gas jet cooling.
Merck. Homogeneity of the compound was monitored by
TLC, visualized by UV-light and KMnO4.
Synthesis. Preparation of intermediate 2.
3-Methyl
All 1H and 13C NMR spectra were recorded on a Bruker
AV (400, 300, 100 MHz) NMR spectrometer. Chemical
shifts were reported in ppm (δ) with reference to the
benzene-1, 2-diamine 1 (25 g, 0.2046 mol) was dissolved
in 250 mL of pyridine under nitrogen atmosphere, and
1
internal standard TMS. In H NMR spectra, CDCl3 and
Table 2
DMSO-d6 were used as solvents. The signals were
designated as follows: s, singlet; d, doublet; t, triplet; m,
multiplet; dd, doublet of doublet. Mass spectra have been
recorded on SHIMADZU spectrometer using chemical
ionization technique. Elemental analyses were carried out
on an automatic flash EA 1112 series, CHN analyzer
(thermo).
Optimization condition for iodoacetic acid mediated cyclodesulfurization.
Entry Solvent Temp (°C) Equiv
Time (min)a Yield (%)a
1.
2.
3.
4.
5.
6.
7.
8.
9.
DMA
DMF
THF
100
100
70
65
70
70
90
60
60
1
60
30
30
60
30
30
30
30
60
53
64
69
55
65
40
75
91
60
1.5
2.5
2
2
2
1.5
2
1
THF
ACN
DMSO
EtOH
EtOH
EtOH
Microwave irradiation experiments.
All microwave
irradiation experiments were carried out in a dedicated
BIOTAGE microwave apparatus. Operating at
a
frequency of 2.45 GHz with continuous irradiation power
from 0 to 300 W utilizing the standard absorbance level of
aThe isolated yield.
Scheme 4. Synthesis of 2-aminobenzimidazole derivatives.
Table 1
Reported one-pot cyclodesulfurization condition.
Entry
Reagent
Condition
Yield (%)
1.
2.
3.
4.
5.
6.
HgO, S (cat)
CuCl
DCC
EDC
Ph(OAc)2, Et3N
BOP, DBU
EtOH, reflux
4:1 PhMe/ACN, ref
THF, 70°C
THF, 70°C
Acetonitrile, RT
Acetonitrile, RT
53
35
68
63
60
90
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R. Sriram, R. Sapthagiri, L. Ilavarasan, and A. Ravi
Vol 000
Table 3
Synthesized 2-aminobenzimidazoles.
Entry
1.
Reactant
Reactant 1
Product
Yield (%)
7a
7a
79
2.
3.
86
7a
78
4.
5.
91
76
6.
80
then the reaction mixture was cooled to 0°C. SOCl2
(44.5 mL, 0.6138 mol) were added dropwise, and the
reaction mixture was gradually allowed RT and stirred
for 1 h. The reaction was monitored by TLC which
indicates the absence of int-1. The reaction mixture was
quenched with 1.5 N HCl solution and extracted with
ethyl acetate (2 × 100 mL). The combined organic layer
was washed 1.5 N HCl (100 mL), water(100 mL),
and brine (100 mL), solution. The organic layer was
dried over anhydrous sodium sulphate, filtered, and
concentrated under vacuum to afford the crude product as
a pale brown oil 2 (22 g, 71.6%). The crude was taken as
(100.6 MHz, DMSO-d6) (δppm): 19.81, 122.72, 127.46,
129.43, 130.24, 153.51, 154.62. Mass (m/z): Calculated
M.W: 150.2, Observed M.W: 151.2 (M + 1), Analytical
calculated for C7H6N2S; C, 55.97; H, 4.03; N, 18.65
found; C, 55.73; H, 3.98; N, 18.25.
Preparation of intermediate 3. To a stirred solution of
Int-2 (22 g, 0.1464 mol) in 250 mL of CCl4, which was
cooled to 0°C. To the reaction mixture NBS (28.6 g,
0.1464 mol) were added portion wise over a period of
30 min. The reaction mixture was refluxed and irradiated
with UV light and stirred for 16 h. The reaction was
monitored by TLC which shows the completion of Int-2.
The reaction mixture was brought to RT, filtered through
celite bed. Filtrate was concentrated to obtain crude product.
The crude was purified by column chromatography (silica
1
such for next step without further purification. H NMR
(400 MHz, CDCl3/TMS int) (δppm): 2.35(s,3H, –CH3),
7.62–7.63(1 m, 1H), 8.01(d, 2H, J = 9.3 Hz),13C NMR
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Trifluoro substituted 2-Aminobenzimidazole Derivatives
gel 60–120 mesh) using hexane/ethyl acetate as eluent (90:10)
to get pure desired product as off-white solid 3 (25 g,
74.16%).1H NMR (400 MHz, CDCl3/TMS int)(δppm):
4.65(s,2H), 7.62–7.64(m, 1H), 8.01(d, 2H, J = 9.2 Hz), 13C
NMR (100.6 MHz, DMSO-d6): δ = 31.26, 121.71, 127.43,
129.44, 129.92, 153.52, 154.59. Mass (m/z): Calculated M.
W: 227.30, Observed M.W: 229.3 (M + 2), Analytical
calculated for C7H5BrN2S; C, 36.70; H, 2.20; N, 12.23
found; C, 36.76; H, 2.92; N, 12.84.
at RT for 16 h. The reaction was monitored by TLC,
which shows the consumption of starting material. The
reaction mixture was quenched with water (100 mL) and
extracted with DCM (2 × 100 mL). The combined
organic layer was washed with water (100 mL) and brine
solution(100 mL) and dried over anhydrous sodium
sulphate, filtered, and concentrated under vacuum to
afford crude product as brown solid. The crude product
obtained was purified by column chromatography (silica
gel 60–120 mesh) using hexane/ethyl acetate (90:10) as
eluent to get pure desired product as brown solid 6
Preparation of intermediate 4. To a stirred solution of
Int-3 (24 g, 0.1047 mol) in 250 mL of DCM, TEA
(29.2 mL, 0.2095 mol) was added. The reaction mixture
was cooled to 0°C. To the reaction mixture N-DiBoc
Amine (34.1 g, 0.1571 mol) were added dropwise. The
reaction mixture was stirred at RT for 16 h. The reaction
was monitored by TLC which shows the completion of
Int-3. The reaction mixture was diluted with water
(100 mL) and DCM (200 mL); the layers were separated.
The organic layer washed with saturated brine (100 mL)
solution, dried over anhydrous sodium sulphate, filtered,
and concentrated under vacuum to afford the crude
1
(28.1 g, 84.4%). H NMR (400 MHz, DMSO-d6/TMS
int)(δppm): 2.8(s, 3H), 3.9(s,2H), 5.1(broad s,1H),
6.36.6.4(m,2H), 6.51(d,1H J = 8 Hz). 13C NMR
(100.6 MHz, DMSO-d6): δ = 39.3, 41.42, 115.74,
118.24, 119.73, 122.36, 137.63, 139.06. Mass (m/z):
Calculated M.W: 243.31, Observed M.W: 243.2 (M),
Analytical calculated for C8H9N3O2S2; C, 39.49; H,3.73;
N, 17.27 found; C, 39.53; H, 3.6.2; N, 17.42.
Preparation of intermediate 7. To a stirred solution of
Int-6 (10 g, 0.0411 mol) in methanol (150 mL), the
reaction mixture was degassed with nitrogen for 15 min.
Then the activated raney nickel (10%) was added, and
the resulting reaction mixture was allowed to stir at RT
for 16 h under hydrogen atmosphere. The reaction was
monitored by TLC, which shows the completion of
reaction. The reaction mixture was filtered through celite
bed and washed with methanol (100 mL), and filtrate was
concentrated under reduced pressure to yield as off-
white solid 7 (5.3 g, 60.2%).1H NMR (400 MHz, DMSO6/
TMS int)(δppm): 2.86(s, 3H), 3.9(s,2H),4.3(boad s, 2H)),
4.5(brod s, 2H) 6.32–6.42(m,2H) 6.51(d,1H J = 8 Hz)
7.27(broad s,IH).13C NMR (100.6 MHz, DMSO-d6):
δ = 44.41, 114.75, 117.24, 118.73, 121.36, 133.09,
135.67. Mass (m/z): Calculated M.W: 215.2, Observed M.
W: 215.2 (M), Analytical calculated for C8H13N3O2S; C,
44.63; H, 6.09; N, 19.5 found; C,44.61; H, 6.14; N, 19.71.
1
product as pale brown solid 4 (29 g, 75.9%). H NMR
(400 MHz, CDCl3/TMSint)(δppm): 1.51(m,18H), 4.97
(s,2H), 7.56–7.59(m, 1H), 7.8(s, 1H,) 7.96(d, 1H,
J = 9.2 Hz), 13C NMR (100.6 MHz, DMSO-d6):
δ = 29.17, 38.6, 121.71, 127.44, 129.43, 130.26, 153.52,
154.6. Mass (m/z): Calculated M.W: 365.45, Observed
M.W: 365(M), Analytical calculated for C17H23N3O4S;
C, 55.87; H, 6.34; N, 11.50 found; C, 55.67; H,6.24;
N, 11.63.
Preparation of intermediate 5. To a stirred solution of
Int-4 (28 g, 0.0766 mol) in 150 mL of 1,4-dioxane,
which was cooled to 0°C. To the reaction mixture,
dioxane in HCl (5 M solution 150 mL) were added
dropwise. The resulting reaction mixture was allowed to
stir at RT 16 h. The reaction was monitored by TLC,
which indicates the completion of reaction. The reaction
mixture was concentrated under reduced pressure to
afford crude product. The crude product obtained was
stirred with MTBE and filtered to afford off white solid 5
Synthesis of 3-amino-3-(3-(trifluoromethyl)phenyl)propanoic
acid 9. 3-(Trifluoromethyl)benzaldehyde (5 g, 0.0286 mol)
was dissolved in ethanol (50 mL). To the reaction mixture,
malonic acid (2.98 g, 0.0286 mmol) and ammonium
formate (5.43 g, 0.08615 mol, 5 equ.) were added. The
reaction mixture was refluxed for 16 h. The reaction was
monitored by TLC (chloroform-methanol; 7:3) which
indicates the formation of new spot. Ethanol was distilled
off. The residue was quenched with 1.5 N HCl to adjust
(pH = 2–3). The reaction mixture was extracted with ethyl
acetate (2 × 50 mL). The combined organic layer was
washed with brine solution and dried over anhydrous
sodium sulphate, filtered, and concentrated in vacuum to
afford crude product 9 as a white solid with the yield (4.8 g,
71.8%). 1H NMR (300 MHz, CDCl3/TMS int)(δppm):
2.3–2.47(2H,dd), 4.41–4.44(1H,m), 7.56(1H, d, J = 5.7 Hz),
7.62(1H, m), 7.74(1H, d, J = 5.7 Hz), 7.8(1H, s).
(8.75 g, 69%).1H NMR (400 MHz, CDCl3/TMS
)
int
(δppm): 1.78 (broad s, 2H), 4.09(s, 2H), 7.56–7.66(m,
1H), 7.88(s,1H), 7.97(d,1H, J = 8.0 Hz). 13C NMR
(100.6 MHz, DMSO-d6): δ = 38.62, 66.81, 121.71,
127.44, 130.2, 130.3, 153.52, 154.90. Mass (m/z):
Calculated M.W: 165.2, Observed M.W: 166.2(M + 1),
Analytical calculated for C7H7N3S; C, 50.89; H, 4.27; N,
25.43 found; C, 501.20; H,4.38; N, 25.94.
Preparation of intermediate 6. To a stirred solution of
Int-5 (8.7 g, 0.0256 mol) in DCM (150 mL) under
nitrogen atmosphere, the reaction mixture was cooled to
0°C. TEA (50.9 g, 0.1579mols) were added followed by
methanesulfonyl chloride (9 g, 0.0789mols) added
dropwise. Then, the reaction mixture was allowed to stir
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R. Sriram, R. Sapthagiri, L. Ilavarasan, and A. Ravi
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Synthesis of methyl 3-amino-3-(3-(trifluoromethyl)phenyl)
propanoate 10.
was purified by column chromatography (silica gel
60–120 mesh) using chloroform:methanol as eluent
3-Amino-3-(3-(trifluoromethyl)phenyl)
propanoic acid (4.0 g, 0.01715 mol) was dissolved in
methanol (40 mL). The reaction mixture was cooled to
0°C; SOCl2 (6.1 g, 0.5146 mol, 3 eq) was added
dropwise, and the resulting reaction mixture was refluxed
(90:10) to get pure desired product 12a–12c (~82%).
Synthesis of N-((2-(1-(3-(trifluoromethyl)phenyl)ethylamino)
-1H–benzo[d]
imidazol-4-yl)methyl)methanesulfonamide
12a. The title compound was synthesized from 7a and
11a according to a above general procedure B to get pure
desired product as 12a an off-white solid (0.15 g, 79%).
1H NMR (300 MHz, CDCl3/TMS int)(δppm): 1.50(d, 3H,
J = 6.9 Hz), 2.75(s, 3H), 4.33(broad s, 2H), 5.06 (m, 1H),
6.84–6.83(d, 1H, J = 5.7 Hz), 6.92(d, 1H, J = 6.9 Hz),
7.03(d,1H, J = 7.5 Hz, Ar-H), 7.315–7.575(m, 2H),
7.53(d, 1H, J = 9 Hz), 7.57(s, 1H), 7.74(s, 1H), 7.81
(s, 1H), 10.94 (s, 1H), 13C NMR (100.6 MHz, DMSO-
d6): δ = 23.8, 40.5, 42.5, 51.7, 59.0, 72.0, 106.3, 113.6,
120.3, 122.8, 123.4, 123.8, 126.1, 129.2, 129.5, 130.7,
147.7, 155.1. Mass (m/z): Calculated M.W: 412.43,
Observed M.W: 413.0 (M + 1). Analytical calculated for
C18H19F3N4O2S; C, 52.42; H,4.64; N, 13.58 found; C,
for
3 h. The reaction was monitored by TLC
(chloroform-methanol; 7:3), which indicates the absence
of starting materials. Methanol was distilled off. The
residue obtained was cooled to 0°C and quenched with
10% sodium bicarbonate. The reaction mixture was
extracted with ethyl acetate (2 × 50 mL). The combined
organic layer washed with brine solution and dried over
anhydrous sodium sulphate, filtered, and concentrated
under vacuum to yield crude product found to be low
melting solid which solidifies at room temperature
1
overnight (3.9 g, 92.8%). H NMR (300 MHz, CDCl3/
TMS int)(δppm): 3.11–3.18(2H, dd), 3.6(3H,s), 5.32–
5.4(1H,m), 7.70(1H, d,
J = 5.7 Hz), 7.73(1H,d,
52.51; H, 4.66; N, 13.64.
Synthesis of N-((2-(3-(trifluoromethyl)benzylamino)-1H–
benzo[d]imidazol-4-yl)methyl)methanesulfonamide 12b. The
J = 5.7 Hz), 7.80–7.88(1H,m), 8.0(1H,s), 9.4(2H, broad s).
General procedure A: preparation of compounds
11a–11c.
Compounds 10a–10c (0.01585 mol, 1 eq)
title compound was synthesized from 7a and 11b
according to above general procedure B to get pure
desired product as 12b a light brown solid (0.17 g, 86%).
1H NMR (400 MHz, DMSO-d6/TMS int)(δppm):
2.89(s,3H), 3.89(s, 3H), 4.33( s, 2H), 7.24(d, 2H,
J = 8 Hz), 7.42–7.43(m, 2H), 7.58–7.67(m, 3H), 7.87(d,
2H, J = 7.2 Hz), 7.9(s, 1H), 13C NMR (100.6 MHz,
DMSO-d6): δ = 42.3, 50.41, 118.60, 120.39, 122.77,
122.79, 123.48, 123.78, 123.84, 126.13, 129.21, 129.53,
130.84, 131.89, 147.71, 155.12. Mass (m/z): Calculated
M.W: 398.4, Observed M.W: 397.2 (M-1). Analytical
calculated for C17H17F3N4O2S; C, 51.25; H,4.30; N,
was dissolved in 30 mL of dichloromethane. To this
reaction mixture, 9 mL of 10% sodium bicarbonate was
added followed by thiophosgene (0.04757 mol, 3 eq)
added dropwise at 0°C and stirred for 3 h at room
temperature. The reaction was monitored by TLC
(hexane-ethyl acetate 7:3) which indicates the absence of
starting materials. The reaction mixture was diluted with
water and then extracted with DCM (2 × 50 mL). The
combined organic layer was washed with brine solution
(50 mL) and dried over anhydrous sodium sulphate and
filtered, concentrated in rota vapor to afford crude
product as a light brown oil of compounds 11a–11c
yields 84%. The crude was taken for the next step
without purification.
14.06 found; C, 51.28; H, 4.36; N, 14.14.
Synthesis of methyl 3-(4-(methylsulfonamidomethyl)-
1H–benzo[d]imidazol-2-ylamino)-3-(3-(trifluoromethyl)phenyl)
General procedure B: preparation of compounds (12a–
propanoate 12c.
The title compound was synthesized
12f).
The compound 7a–b (0.0139 mmol, 1 eq), in
from 7a and 11c according to above general procedure
B to get pure desired product as 12a an off-white
solid (0.22 g, 78%). 1H NMR (400 MHz, DMSO-d6/
TMS int)(δppm): 2.70(s,3H), 3.13–3.21(m, 2H), 3.6(s,
3H), 4.1(s, 2H), 5.38–5.44(m, 1H), 7.24(d, 1H,
J = 8.0 Hz), 67.26–7.28(m, 2H), 7.29–7.43(m, 3H),
7.64–7.83(m, 3H), 8.01(s, 1H).13C NMR (100.6 MHz,
anhydrous ethanol (10 mL) and compound 11a–c
(0.0139 mmol, 1 eq) were added in a 10-mL glass vial
equipped with a small magnetic stirring bar. To this was
added iodoacetic acid (0.0278 mmol, 2 eq), and the vial
was tightly sealed with an aliminium/teflon crimp top.
The reaction mixture was then irradiated for the time and
temperature indicated in Table 2, using an irradiation
power of 100 W. After completion of the reaction, the
vial was cooled to RT by gas jet cooling before it was
opened. The reaction was monitored by TLC, which
shows the completion of reaction. The reaction mixture
was diluted with water (10 mL) and then extracted with
DCM (3 × 30 mL). The combined organic layer was
washed with brine solution (50 mL) and dried over
anhydrous sodium sulphate, filtered, and concentrated
under vacuum to afford crude product. The crude obtained
DMSO-d6):
δ = 42.5, 53.2, 53.7, 111.9, 123.21,
123.78, 123.81, 123.83, 125.3, 125.4, 125.9, 128.9,
129.3, 129.6, 129.9, 130.2, 130.3, 131.2, 141.5, 149.7.
Mass (m/z): Calculated M.W: 470.2, Observed M.W:
473.4 (M
+
2). Analytical calculated for
C20H21F3N4O4S; C, 51.06; H,4.50; N, 11.91 found; C,
51.21; H, 4.48; N, 12.12.
Synthesis of N-(1-(3-(trifluoromethyl)phenyl)ethyl)-1H–
benzo[d]imidazol-2-amine 12d.
synthesized from 7b and 11a according to above
The title compound was
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Trifluoro substituted 2-Aminobenzimidazole Derivatives
general procedure B to get pure desired product as 12d as
off-white solid (0.16 g, 91%).1H NMR (300 MHz,
CDCl3/TMS int)(δppm): 1.4(3H,d), 5.10(1H, broad s),
6.8(2H,d, j = 5.7 Hz), 6.91(1H,d, J = 3.9 Hz),7.41(1H,s),
7.52–7.57(2H,m), 7.57(1H,s), 7.7(1H,m), 7.9(1H,s),
10.9(1H,broad s). 13C NMR (100.6 MHz, DMSO-d6): δ
=, 51.7, 59.0, 72.0, 114.4, 118.6, 123.4, 126.1,129.2,
130.7, 147.7, 155.1. Mass (m/z): Calculated M.W: 305.3,
Observed M.W: 306.2 (M + 1), Analytical calculated for
C16H14F3N3; C, 62.95; H, 4.62; N, 13.76 found; C,
information for development of clinically viable
molecules like mebendazole, astemizole etc.,
REFERENCES AND NOTES
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2002, 25, 250.
62.98; H, 4.68; N, 13.70.
Synthesis of N-(3-(trifluoromethyl)benzyl)-1H–benzo[d]
imidazol-2-amine 12e.
synthesized from 7b and 11b according to above general
procedure B to get pure desired product as 12e as light
The title compound was
[4] Hayes, M. E.; Wallace, G. A.; Grongsaard, P.; Bischoff, A.;
George, D. M.; Miao, w.; McPherson, M. J.; Stoffel, R. H.; Green, D. W.;
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[5] Abdel-Mohsen, H. T.; Ragab, F. A. F.; Ramla, M. M.;
El Dewani, H. I. Eur J Med Chem 2010, 445, 2336.
1
brown semi solid. (0.2 g, 76%). H NMR (400 MHz,
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C.; Wu, X.; Zong, X.; Chen, J.; Ji, M. Bioorg Med Chem 2015, 23, 657;
(b) Gill, C.; Jadhav, G.; Shaikh, M.; Kale, R.; Ghawalkar, A.; Nagagoje,
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Wald, S. A.; Senanyake, C. H. Tetrahedron Lett 1997, 38, 5607; (b)
Hong, Y.; Senanyake, C. H.; Xiang, T. J.; Vandenbossche, C. P.;
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CDCl3/TMS int)(δppm): 4.9(2H,s), 7.24(1H,d, J = 8 Hz),
7.41–7.43(2H,d, J = 7.6 Hz), 7.52–7.67(2H,m), 7.85 (1H,
d, J = 7.6 Hz) 7.9(1H,s), 8.6(1H,s), 13.7(1H,broad s). 13C
NMR (100.6 MHz, DMSO-d6): δ = 45.9, 112.1, 118.3,
122.8, 123.7, 125.0, 126.4, 129.2, 129.8, 130.5, 132.2,
139.3, 150.5 Mass (m/z): Calculated M.W: 291.0,
Observed M.W: 292.0 (M + 1). Analytical calculated for
C15H12F3N3; C, 61.85; H, 4.15; N, 14.45. Found; C,
61.72; H, 4.18; N, 14.42.
Synthesis of methyl 3-(1H–benzo[d]imidazol-2-ylamino)-
3-(3 (trifluoromethyl)phenyl)propanoate 12f.
The title
compound was synthesized from 7b and 11c
according to above general procedure B to get pure
desired product as 12f as brown solid (0.16 g, 80%).
1H NMR (400 MHz, CDCl3/TMS int)(δppm): 3.11–
3.18(2H,dd), 3.6(3H,s), 5.3–5.4 (1H,m), 7.24 (2H,d,
J = 8.0 Hz), 7.27(2H,d, J = 7.6 Hz), 7.32–7.74(2H,
m,), 7.65(1H,d, J = 7.6 Hz), 7.74 (1H,m) 7.9(1H,s),
9.5(1H,d), 12.8(1H, broad s). 13C NMR (100.6 MHz,
DMSO-d6): δ =52,2, 53.7, 111.9, 123.2. 125.2, 125.3,
125.9, 128.6, 129.3, 131.2, 141.5, 149.7, 117.8,
129.6,129.9, 130.1. Mass (m/z): Calculated M.W:
291.0, Observed M.W: 292.0 (M + 1). Analytical
calculated for C18H16F3N3O2; C, 59.50; H, 4.44; N,
11.57; found, C, 59.45; H, 4.41; N, 11.49.
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74, 5618.
CONCLUSIONS
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A microwave enhanced fast and efficient one-pot
synthesis of 2-aminobenzimidazole derivatives has been
developed. The method avoids isolation of thioureas and
handling of mercaptons. In this present work, iodoacetic
acid is used as a cyclodesulfurization agent. The
microwave irradiation drammatically decreases reaction
time from hour to minutes. The result shows that new
2-aminobenzimidazole derivatives will be further explored
in this field for research, drug designer, and medicinal
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chemist for
a comprehensive and target oriented
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet