A facile synthesis of novel benzofuranyl benzimidazole derivatives

Article abstract of DOI:10.1002/jhet.1739

In this article, we report a facile route for the synthesis of novel benzofuranyl benzimidazole derivatives. The methodology involves the Sonagashira reaction of 2-(3-iodo-4-methoxyphenyl)-1H-benzimidazole (3) with variety of terminal alkynes to have novel benzimidazole alkynyl derivatives followed by iodo-cyclisation to give novel iodo benzofuranyl benzimidazole derivatives. The resulting iodo benzofuranyl benzimidazoles were functionalized further via palladium mediated carbon-carbon bond formation for molecular diversity generating novel heterocyclic compounds.

Full text of DOI:10.1002/jhet.1739

September 2014 A Facile Synthesis of Novel Benzofuranyl Benzimidazole Derivatives
1491
a
c
d
Venugopal Soodamani,a,b and Divyesh Patel, and Devanna Nayakanti, and Ramanatham Josyula
*
aJanus Research Laboratories, Hyderabad 500072, India
bChemistry Division, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad
500085, India
cOil Technological Research Institute, Jawaharlal Nehru Technological University, Anantpur 515001, India
dAstrazeneca India Pvt. Limited, Bangalore 5600024, India
*
E-mail: venugopal.soodamani@gmail.com
Received January 20, 2012
DOI 10.1002/jhet.1739
Published online 17 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
In this article, we report a facile route for the synthesis of novel benzofuranyl benzimidazole derivatives.
The methodology involves the Sonagashira reaction of 2-(3-iodo-4-methoxyphenyl)-1H-benzimidazole (3)
with variety of terminal alkynes to have novel benzimidazole alkynyl derivatives followed by iodo-cyclisation
to give novel iodo benzofuranyl benzimidazole derivatives. The resulting iodo benzofuranyl benzimidazoles
were functionalized further via palladium mediated carbon–carbon bond formation for molecular diversity
generating novel heterocyclic compounds.
J. Heterocyclic Chem., 51, 1491 (2014).
INTRODUCTION
evaluated for the synthesis of these novel benzofuranyl
benzimidazole derivatives.
In the recent past, synthesis of polyheterocycles [1] has
evolved as a major area of research because of diverse
and potential biological activity of the series. Especially
in the polyheterocycle arena, benzimidazole-based polyhe-
terocycles have evolved as a fascinating target for medici-
nal chemistry, as these heterocycles show a wide range of
interesting biological properties, for example, benzimida-
zoquinazolines [2], benzimidazo isoquinoline [3], and
benzimidazo[2,1-a]isoindolones [4] were reported as anti-
tumor agents. Benzimidazo[2,1-b]quinazolines are potent
immune suppressors [5]; benzimidazo[2,1-b]benzo[f]iso-
quinoline ring system [6] is present in pharmacologically
active compounds. Isoindolo[2,1-a]benzimidazolones [7]
are also known to be sedatives and tranquilizers.
Among the various benzimidazole heterocycles, benzo-
furanyl benzimidazole heterocycles have attracted great
deal of attention because of hybrid structure of benzofuran
and benzimidazole. Individually, benzofuran and benz-
imidazole heterocycles are known for their broad spectrum
of biological activities [8]. So, the combination of these
two heterocycles is envisaged to have synergistic effect
and be a more biologically potent.
RESULTS AND DISCUSSION
The key iodo benzimidazole (3) required for our study
was prepared according to the similar process reported in
the literature [9]. Condensation of o-phenylene diamine
(1) with sodium metabisulfite adduct of the appropriate
benzaldehyde in DMF solvent yielded the corresponding
iodo benzimidazole (3) (Scheme 1).
For the Sonagashira reaction [10] of (3) with terminal
alkyne, many different conditions were explored (Table 1).
Among the various conditions pursued, we were able to
see medium to significant amount of dimerization of
terminal alkyne upon using CuI catalyst, whereas in the
CuI free reaction condition, the dimerization product is
reduced considerably. PdCl2(PPh3)2 in triethyl amine as a
base and solvent was found to be the optimum condition
regarding better yield and negligible side product for the
Sonagashira coupling. We chose to use this condition for
synthesis of different derivatives. All the benzimidazole
alkynyl derivatives (4a–4i) were obtained in good to
excellent yield, and they all are very well characterized
(Scheme 2; Table 2).
Herein, we report a facile route for the synthesis of
novel benzofuranyl benzimidazole derivatives. This
methodology gives extensive scope in terms of synthe-
sizing a variety of novel polyheterocyclic compounds. To
the best of our knowledge, this methodology has not been
After completing the synthesis of benzimidazole alkynyl
derivative (4a–4i), iodo-cyclisation [11] was carried out. In
general, iodo-cyclisation is an efficient reaction and
© 2014 HeteroCorporation

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V. Soodamani, D. Patel, D. Nayakanti, and R. Josyula
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Scheme 1. Reagent and conditions: (a) sodium metabisulfite, ethanol, RT, DMF, 100ꢀC.
Table 1
Screening of optimized condition for Sonagashira reaction.a
Entry
Catalyst
Pd/C:PPh3:CuI (1:4:2)
Pd/C:PPh3:CuI (1:4:2)
Pd/C:PPh3:CuI (1:4:2)
Pd/C:PPh3:CuI (1:4:2)
PdCl2(PPh3)2 (0.1 equiv)
Pd/C:PPh3 (1:4)
Base (equiv)
Solvent
Solvent yieldb (%)
1
2
3
4
5
6
7
2-Amino ethanol (3.0)
Triethyl amine (3.0)
Triethyl amine (3.0)
Triethyl amine (3.0)
Triethyl amine (15)
Triethyl amine (15)
Triethyl amine (3.0)
Water
Water
60
65
70
70
80
—
75
Dimethoxy ethane
Ethanol
—
—
PdCl2(PPh3)2:CuI (0.1 equiv:0.06 equiv)
THF
aAll reactions were carried out by using 3 (1.0 equiv), phenyl acetylene (1.5 equiv), catalyst, and base at 80ꢀC.
bYields refer to isolated pure products characterized by IR, NMR, and HRMS.
Scheme 2. Reagent and conditions: (a) terminal alkyne, PdCI2(PPh3)2, TEA, 80ꢀC.
proceeds under mild reaction conditions and exhibits
broad scope in terms of molecular diversity. The intramolec-
ular iodo-cyclisation of alkyne (4a) was examined using
(1) iodine in dichloromethane at 30ꢀC, (2) iodine/K2CO3 in
acetonitrile at 30ꢀC, (3) ICl in dichloromethane. There was
no product formation in condition (1) and condition (2). In
fact, starting material is found to be intact. However,
condition (3) gave complete conversion of starting material
to required product (Scheme 3).
We chose to use this condition for our different
derivative synthesis (5a and 5b), and they are well charac-
terized by NMR and mass (Table 3).
After the synthesis of novel iodo benzofuranyl benzimid-
azole derivatives (5a–5b), we planned to explore the reactivity
of iodo group towards the palladium catalyzed carbon–carbon
bond formation to yield diversified benzofuranyl benzimid-
azole derivatives. On this front, Heck, Sonagashira, and
Suzuki coupling reactions were carried out (Scheme 4).
The details are given in Table 4.
benzimidazole alkynyl derivatives have been synthesized,
and biological evaluation of these molecules are under
progress, which will be reported in due course of time.
EXPERIMENTAL
All solvents and reagents were purchased from the suppli-
ers and used without further purification. Thin layer chroma-
tography was performed on Merck precoated Silica gel
60F254 plates, visualizing with ultraviolet light or iodine
spray. Flash chromatography was performed on silica gel
(60–120 mesh) using n-heptane, ethyl acetate. 1H and 13C
NMR spectra were recorded in DMSO-d6 /CDCl3/MeOH-d4
using 500/400 MHz, on a Bruker/Varian FT NMR. The chem-
ical shifts were reported in d ppm relative to TMS. Spin
multiplicities are given as s (singlet), d (doublet), t (triplet),
dd (doublet of doublet),
m (multiplet), and b (broad).
Coupling constants (J) are given in hertz. Infrared spectra
were recorded on an FTIR spectrometer. HRMS was deter-
mined using waters Q-Tof premier micro mass apparatus.
Melting points were determined using a scientific open capil-
lary melting point apparatus and are uncorrected. Chromato-
graphic purity by HPLC (Waters-Empower software) using
area normalization method and the condition is as follows.
Column: XBridge C18, 5 mm (4.6*150 mm), mobile phase
A: 10 mM ammonium acetate in water, Mobile Phase B: ace-
tonitrile, gradient (T/%B) = 0/10, 3/10, 35/90, 40/90, 42/10,
48/10, 52/10. Flow 1.0 mL/min; UV 235 nm.
CONCLUSION
In conclusion, we have developed a simple and efficient
route for the synthesis of novel benzofuranyl-benzimidazole
derivatives. As a part of these studies, a number of novel
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A Facile Synthesis of Novel Benzofuranyl Benzimidazole Derivatives
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Table 2
Synthesis of 2-(3-alkynyl-4-methoxy phenyl)-1H-benzimidazole.a
Entry
a
Alkyne
Product (4)
Time (h)
2
Yieldb (%)
80
b
c
d
e
2
1.5
2
82
83
80
3
85
(Continued)
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V. Soodamani, D. Patel, D. Nayakanti, and R. Josyula
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Table 2
(Continued)
Entry
Alkyne
Product (4)
Time (h)
3
Yieldb (%)
81
f
g
3
83
h
4
80
i
4
78
aAll reactions were carried out by using 3 (1.0 equiv), terminal alkyne (1.5 equiv), catalyst, (10 mol%) and triethyl amine (15 equiv) at 80ꢀC.
bYields refer to isolated pure products characterized by IR, NMR, and HRMS.
Compound 3: Off-white solid; mp 215–217ꢀC; IR (KBr, v): 3500,
1601, 1435, 1261, 1047, 743 cmÀ1; 1H NMR (CDCl3, 400 MHz): d
8.64 (d, J= 2.0 Hz, 1H, Ar-H), 8.20 (dd, J=2.0Hz, J=8.8Hz, 1H,
Ar-H), 7.60 (dd, J=3.2Hz, J= 6.0 Hz, 2H, Ar-H), 7.22 (dd,
J=3.2Hz, J=6.0 Hz, 2H, Ar-H), 6.95 (d, J= 8.8 Hz, 1H, Ar-H),
3.97 (s, 3H, OCH3); 13C NMR (DMSO-d6, 125 MHz): d 159.5,
150.3, 137.3, 128.6, 128.5, 124.9, 122.6, 114.9, 112.2, 86.9, 57.1;
HRMS (m/z): calculated for C14H12IN2O (M+H)+ 351.0671, found
351.0670; HPLC Purity: 99.5%; HPLC retention time: 19.87 min.
General procedure for the preparation of alkynyl
2-(3-Iodo-4-methoxyphenyl)-1H-benzimidazole (3).
To a
solution of 3-iodo-4-methoxy benzaldehyde (2) (20 g, 0.0763 mol)
in ethanol (200 mL) was added a solution of sodium metabisulfite
(8.14 g, 0.0428 mol) in 10mL of water at room temperature. The
reaction mass was stirred at room temperature for 30min and then
kept in the refrigerator for 4 h. The precipitated solid was
filtered and dried at 50ꢀC (26.5g; yield = 95%). This salt (26g,
0.075mol) was added to a solution of o-phenylene diamine
(1) (7.67g, 0.075 mol) in 50 mL of DMF at room temperature;
the reaction mass was heated to 100ꢀC for 4 h. After
completion of starting material, the reaction mass was cooled to
room temperature and poured in to water, precipitated solid was
filtered and dried at 50ꢀC to offered title compound (22.4g;
yield = 90.0%).
benzimidazole (4a–4i).
To a mixture of iodo benzimidazole
(3) (0.5 g, 1.43mmol) in TEA (2.2 g, 22mmol) was added PdCl2
(PPh3)2 (0.1004 g, 0.143 mmol) followed by alkyne (1.5equiv) at
room temperature under nitrogen atmosphere; this reaction
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Scheme 3. Reagent and conditions: (a) iodine monochloride, DCM, RT.
Table 3
Synthesis of 2-(3-iodo-2-subsituted-1-benzofuran-5-yl)-1H-benzimidazole.a
Entry
a
Starting material
Product (5)
Time (h)
0.5
Yieldb (%)
85
b
1
80
aAll reactions were carried out by using 4 (1.0 equiv), iodine monochloride (1.5 equiv), dichloro methane solvent (10 volume) at RT.
bYields refer to isolated pure products characterized by IR, NMR, and HRMS.
Scheme 4. Reagent and conditions: (a) alkene, tetra-butyl ammonium chloride, sodium carbonate, palladium acetate. DMF, 85ꢀC, (b) terminal alkyne,
PdCI2(PPh3)2, triethyl amine 80ꢀC, (c) aryl boronic acid, Na2CO3, Toluene:IPA (2:1), Pd(PPh3)4, 100ꢀC.
mixture was stirred at 80ꢀC for the time mentioned in Table 2. After
completion of reaction, as monitored by TLC, cooled the
reaction mass to room temperature and poured into water (50 mL)
and extracted with ethyl acetate (3Â 25mL). The organic layers
were collected, combined, and washed with water, dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography using
n-heptane-EtOAc mixture to give the desired product.
2-[4-Methoxy-3-(phenyl ethynyl)phenyl]-1H-benzimidazole
(4a).
Off-white solid; mp 312–314ꢀC; IR (KBr, v): 3444,
1607, 1284, 1022, 742 cmÀ1 1H NMR (DMSO-d6, 500 MHz):
d 12.96 (s, 1H, NH), 8.29 (d, J = 2.0 Hz, 1H, Ar-H), 8.20
(dd, J = 2.0 Hz, J = 8.5 Hz, 1H, Ar-H), 7.45–7.58 (m, 7H, Ar-H),
7.2–7.31 (m, 3H, Ar-H), 3.95 (s, 3H, OCH3); 13C NMR
(DMSO-d6, 125 MHz): d 161.2, 150.9, 144.1, 135.4, 131.8,
131.4, 129.3, 129.2, 123.1, 122.9, 122.2, 119.0, 112.5, 112.2,
;
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V. Soodamani, D. Patel, D. Nayakanti, and R. Josyula
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Table 4
Heck, Sonagashira, and Suzuki coupling reaction of 5a.
Entry
Starting material
Product (6)
Time (h)
6
Yielda (%)
a
b
c
d
82
80
83
83
7
4
4
e
8
83
aYields refer to isolated pure products characterized by IR, NMR, and HRMS.
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111.7, 93.9, 85.9, 56.6. HRMS (m/z): calculated for C22H17N2O
(M + H)+ 325.1592, found 325.1601; HPLC Purity: 99.2%;
HPLC retention time: 23.66 min.
50.1; HRMS (m/z) calculated for C17H15N2O2 (M + H)+
279.1363, found 279.1396; HPLC Purity: 99.0%; HPLC
retention time: 14.43 min.
2-{4-Methoxy-3-[(4-methylphenyl)
ethynyl]phenyl}-1H-
4-[5-(1H-Benzimidazol-2-yl)-2-methoxyphenyl]buty-3-yn-1-
benzimidazole (4b). Off-white solid; mp 231–234ꢀC; IR
(KBr, v): 3434, 1606, 1431, 1276, 1022, 820, 747 cmÀ1; 1H NMR
(DMSO-d6, 500 MHz): d 12.88 (s, 1H, NH), 8.27 (d, J = 2.0 Hz,
1H, Ar-H), 8.19 (dd, J = 2.0 Hz, J = 8.5 Hz, 1H, Ar-H), 7.63
(d,J = 7.5Hz , 1H, Ar-H), 7.51 (d, J = 7.0 Hz, 1H, Ar-H), 7.46
(d,J = 8.0Hz, 2H, Ar-H), 7.26–7.30 (m, 3H, Ar-H), 7.18–7.21
(m,2H, Ar-H), 3.94 (s, 3H, OCH3), 2.35 (s, 3H, CH3); 13C NMR
(DMSO-d6, 125MHz): d 161.1, 150.9, 144.1, 139.1, 135.4,
131.7, 131.4, 129.9, 128.9, 123.1, 122.9, 122.2, 119.9, 119.0,
112.4, 111.7, 94.1, 85.3, 56.6, 21.5; HRMS (m/z): calculated for
C23H19N2O (M+ H)+ 339.1821, found 339.1804; HPLC Purity:
99.3%; HPLC retention time: 25.14min.
ol (4g). Off-white solid; mp 219–221ꢀC; IR (KBr, v): 3444,
1
1608, 1284, 1046, 743 cmÀ1; H NMR (CH3OH-d4, 500 MHz):
d 7.6–8.10 (m, 4H, Ar-H), 7.25 (dd, 2H, Ar-H, J = 3.0 Hz,
J = 6.0 Hz), 7.17 (d, 1H, Ar-H, J = 9.0 Hz), 3.95 (s, 3H, OCH3),
3.78 (t, 2H, OCH2, J = 7.0 Hz), 2.70 (t, 2H, CH2, J = 7.0 Hz);
13C NMR (DMSO-d6, 125 MHz): d 161.2, 151.0, 131.6, 128.2,
122.9, 122.4, 113.1, 112.2, 93.35, 77.4, 60.3, 56.3, 24.0;
HRMS (m/z): calculated for C18H17N2O2 (M + H)+ 293.1542,
found 293.1573; HPLC Purity: 99.2%; HPLC retention time:
14.65 min.
2-[4-Methoxy-3-(pent-1-yn-1-yl)phenyl]-1H-benzimidazole
(4h).
Off-white solid; mp 174–176ꢀC; IR (KBr, v): 3435,
1
2-{4-Methoxy-3-[(4-nitrophenyl)ethynyl]phenyl}-1H-benzimi-
1607, 1269, 1024, 745cmÀ1; H NMR (CH3OH-d4, 500MHz):
d 7.59À8.09 (m, 4H, Ar-H), 7.25 (dd, J = 3.0 Hz, J = 6.0 Hz,
2H, Ar-H), 7.16 (d, J = 8.5 Hz, 1H, Ar-H), 3.95 (s, 3H, OCH3),
2.46 (t, J = 7.0 Hz, 2H, –CH2), 1.67 (m, 2H, –CH2,), 1.11
(t, J = 7.0 Hz, 3H, –CH3); 13C NMR (DMSO-d6 125 MHz):
d 161.2, 131.4, 128.1, 122.9, 122.1, 113.2, 112.2, 95.4, 77.1,
56.3, 22.2, 21.3, 13.8. HRMS (m/z): calculated for C19H19N2O
(M+ H)+ 291.1749, found 291.1734; HPLC Purity: 99.4%;
HPLC retention time: 22.1 min.
dazole (4c). Pale yellow solid; mp 244–246ꢀC; IR (KBr, v):
3359, 2203, 1510, 1343, 855, 748 cmÀ1; H NMR (DMSO-d6,
1
500 MHz): d 12.91 (s, 1H, NH), 8.24–8.35 (m, 4H, Ar-H),
7.83 (d, J = 8.5 Hz, 2H, Ar-H), 7.64 (d, J = 7.5 Hz, 1H, Ar-H),
7.51 (d, J = 7.5 Hz, 1H, Ar-H), 7.18–7.35 (m, 3H, Ar-H), 3.97
(s, 3H, OCH3); 13C NMR (DMSO-d6, 125 MHz): d 161.4,
150.7, 147.3, 132.9, 131.8, 130.0, 129.7, 124.5, 123.2, 122.9,
122.2, 119.1, 112.6, 111.2, 92.2, 91.0, 56.7; HRMS (m/z):
calculated for C22H16N3O3 (M + H)+ 370.1556, found
370.1537; HPLC Purity: 99.5%; HPLC retention time:
23.68 min.
2-(3-Hex-1-yn-1-yl)-4-methoxyphenyl]-1H-benzimidazole
(4i).
3445,2958, 1445, 1271, 1023, 746 cmÀ1
Off-white solid; mp 199–201ꢀC; IR (KBr, v):
;
1H NMR (DMSO-d6,
4-{[5-(1H-Benzimidazol-2-yl)-2-methoxyphenyl]ethynyl}
500 MHz): d 12.84 (s, 1H, NH), 7.49–8.13 (m, 4H, Ar-H), 7.18–
7.21 (m, 3H, Ar-H), 3.94 (s, 3H, OCH3), 2.46–2.51 (m, 2H,
CH2), 1.43–1.57 (m, 4H, CH2ÀCH2), 0.93 (t, J = 7 Hz , 3H, CH3);
13C NMR (DMSO-d6, 125 MHz): d 161.2, 151.1, 144.1, 135.4,
131.4, 128.1, 122.9, 122.8, 122.1, 118.9, 113.2, 112.2, 111.6,
95.5, 76.9, 56.3, 30.8, 21.9, 19.0, 13.9; HRMS (m/z) calculated
for C20H21N2O (M+ H)+ 305.1905, found 305.1922; HPLC
Purity: 99.4%; HPLC retention time: 23.9 min.
aniline (4d). Pale-brown solid; mp 186–188ꢀC; IR (KBr, v):
1
3374, 2204, 1622, 1517, 1279, 744 cmÀ1; H NMR (CH3OH-
d4, 500 MHz): d 8.16 (d, J = 2.0 Hz, 1H, Ar-H), 8.05 (dd,
J = 2.0 Hz, J = 9.0 Hz, 1H, Ar-H), 7.59–7.65 (m, 2H, Ar-H),
7.25–7.29 (m, 4H, Ar-H), 7.19 (d, J = 9.0 Hz, 1H, Ar-H), 6.70
(d, J = 8.5 Hz, 2H, Ar-H), 4.66 (s, 2H, NH2), 3.99 (s, 3H,
OCH3); 13C NMR (DMSO-d6, 125 MHz): d 160.8, 151.1,
149.9, 144.1, 135.4, 132.9, 130.9, 128.1, 122.9, 122.8, 122.1,
119.0, 114.2, 113.4, 112.2, 111.6, 108.8, 95.9, 83.0, 56.4;
HRMS (m/z): calculated for C22H18N3O (M + H)+ 340.1774,
found 340.1765 HPLC Purity: 99.2%; HPLC retention time:
19.3 min.
General procedure for the preparation of compound
5a/5b.
To a solution of 4a/4b (1.54 mmol) in DCM (5mL)
was added iodine mono chloride (2.3 mmol) at room temperature.
The reaction mass was stirred under nitrogen atmosphere, and the
progress of the reaction was monitored by TLC. After completion
of starting material, reaction mass was poured in to water
(50 mL) and product extracted with ethyl acetate (3*100 mL).
The organic layers were collected, combined, dried over
anhydrous sodium sulfate and concentrated to have the desired
product.
Methyl 2{[5-(1H-benzimidazol-2-yl)-2-methoxyphenyl]
ethynyl} benzoate (4e). Off-white solid; mp 138–141ꢀC; IR
(KBr, v): 3445, 1714, 1433, 1276, 747 cmÀ1
;
1H NMR
(DMSO-d6, 500 MHz): d 12.92 (s, 1H, NH), 8.29 (d, 1H, Ar-H,
J = 2.0 Hz), 8.21 (dd, 1H, Ar-H, J = 2.0 Hz, J = 8.5 Hz), 7.93
(d, 1H, Ar-H, J= 8.0 Hz), 7.72 (d, 1H, Ar-H, J= 7.5 Hz), 7.64–7.68
(m, 2H, Ar-H), 7.51–7.56 (m, 2H, Ar-H), 7.2–7.32 (m, 3H, Ar-H,),
3.96 (s, 3H, COOCH3), 3.91 (s, 3H, OCH3); 13C NMR (DMSO-d6,
125 MHz): d 166.7, 161.3, 150.9, 134.3, 132.7, 132.2, 131.6, 130.5,
129.4, 129.2, 123.1, 122.8, 122.2, 119.0, 112.5, 112.4, 111.7,
92.5, 90.5, 56.6, 52.8; HRMS (m/z): calculated for C24H19N2O3
(M+ H)+ 383.1563, found 383.1751; HPLC Purity: 99.1%; HPLC
retention time: 22.8 min.
2-(3-Iodo-2-phenyl-1-benzofuran-5-yl)-1H-benzimidazole
(5a).
Off-white solid; mp 207–209ꢀC; IR (KBr, v): 3391,
1632, 1457, 1054, 746 cmÀ1
;
1H NMR (DMSO-d6, 500MHz):
d 12.97 (s, 1H, NH), 8.38 (d, J = 1.5Hz, 1H, Ar-H), 8.27 (dd,
J = 1.5Hz, J = 8.5 Hz, 1H, Ar-H), 8.10–8.17 (m, 2H, Ar-H),
7.95–8.01(m,1H, Ar-H,), 7.76–7.79 (m, 2H, Ar-H), 7.54–7.63
(m, 3H, Ar-H), 7.42–7.47 (m, 2H, Ar-H); 13C NMR (DMSO-
d6, 125 MHz): d 155.7. 154.8. 150.2, 135.0, 133.7, 130.5,
129.5, 129.3, 127.7, 125.9, 125.1, 122.1, 121.8, 114.8, 113.1,
63.9; HRMS (m/z): calculated for C21H14IN2O (M + H)+
437.0239, found 437.0226; HPLC Purity: 99.7%; HPLC
retention time: 26.9min.
3-[5-(1H-Benzimidazol-2-yl)-2-methoxyphenyl]prop-2-yn-
1-ol (4f). Off-white solid; mp 186–188ꢀC; IR (KBr, v): 3434,
1
1449, 1270, 1017, 733cmÀ1; H NMR (DMSO-d6, 500 MHz): d
12.86 (s, 1H, NH), 8.15–8.18 (m, 2H, Ar-H), 7.49-7.63 (m, 2H,
Ar-H), 7.16–7.25 (m, 3H, Ar-H), 5.44 (t, J = 6.0Hz, 1H, OH),
4.36 (d, 2H, CH2, J = 6.0 Hz), 3.93 (s, 3H, OCH3); 13C NMR
(DMSO-d6, 125MHz): d 161.2, 150.9, 144.1, 135.4, 129.2,
122.9, 122.8, 122.1, 119.0, 112.4, 111.6, 94.5, 80.1, 56.4,
2-[3-Iodo-2-(4-methylphenyl)-1-benzofuran-5-yl]-1H-benzimi-
dazole (5b). Off-white solid; mp 219–221ꢀC; IR (KBr, v): 3435,
;
1627, 1440, 1274, 1061, 745 cmÀ1 1H NMR (DMSO-d6,
500 MHz): d 13.12 (s, 1H, NH), 8.25–8.28 (m, 2H, Ar-H), 8.05
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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V. Soodamani, D. Patel, D. Nayakanti, and R. Josyula
Vol 51
(d, J = 8.0 Hz, 2H, Ar-H), 7.22–7.82 (m, 7H, Ar-H,), 2.40 (s, 3H,
CH3); 13C NMR (DMSO-d6, 125MHz): d 154.7, 154.3, 151.6,
140.2, 133.4, 129.9, 127.6, 126.8, 126.6, 125.1, 120.1, 112.4,
63.1, 21.5; HRMS (m/z): calculated for C22H16IN2O (M+ H)+
451.0606, found 451.0601; HPLC Purity: 99.5%; HPLC retention
time: 28.7min.
500 MHz): d 13.12 (s, 1H, NH), 8.27–8.56 (m, 4H, Ar-H), 8.15
(d, J = 7.5 Hz, 1H, Ar-H), 7.45–7.95 (m, 10H, Ar-H), 7.22–
7.23 (m, 2H, Ar-H); 13C NMR (DMSO-d6, 125 MHz): d 157.2,
154.8, 154.2, 151.6, 131.9, 130.6, 130.3, 130.0, 129.8, 129.7,
129.6, 129.5, 129.4, 129.3, 127.7, 126.8. 126.7, 126.1, 125.4,
125.3, 122.7, 122.4, 120.2, 118.4, 112.7, 112.5, 99.1, 97.8,
80.5 HRMS (m/z): calculated for C29H19N2O (M + H)+
411.1920, found 411.1917; HPLC Purity: 99.5%; HPLC
retention time: 25.14 min.
General procedure for Heck coupling (6a–6b).
To a
solution of 5a (0.5 g, 1.15 mmol) in dimethyl formamide
(10 mL) was added appropriate alkene (4.6 mmol), sodium
carbonate (0.37 g, 3.45 mmol), tetra-butyl ammonium chloride
(0.32 g, 1.15 mmol) followed by Palladium acetate (0.12 mmol)
at room temperature under nitrogen atmosphere. The reaction
mass was heated at 85ꢀC for 6–7 h; after completion of starting
material as indicated by TLC, the reaction mass was cooled to
room temperature, and water (50 mL) was added into the
reaction mass and extracted with ethyl acetate (3 Â 50 mL). The
organic layers were collected and washed with water and brine.
The ethyl acetate extract was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was purified
by column chromatography using n-heptane-EtOAc to give the
desired product.
2-{3[(4-Methylphenyl)ethynyl]-2-phenyl-1-benzofuran-5-yl}-
1H-benzimidazole (6d). Off-white solid; mp 258–261ꢀC; IR
(KBr): 3437, 1438, 1272, 813, 745, 686 cmÀ1 1H NMR
;
(DMSO-d6, 500 MHz): d 13.1 (s, 1H, NH), 8.29–8.55 (m,
4H, Ar-H), 7.87 (d, J = 8.5 Hz, 1H, Ar-H), 7.51–7.69 (m, 7H,
Ar-H), 7.23–7.34 (m, 4H, Ar-H), 2.38 (s, 3H, CH3); 13C
NMR (DMSO-d6, 125 MHz): d 157.0, 154.2, 151.6, 139.7,
131.9, 130.6, 130.0, 129.7, 129.4, 129.3, 126.8, 126.1, 125.4,
119.4, 118.4, 112.7, 99.3, 98.1, 79.9, 21.6; HRMS (m/z):
calculated for C30H21N2O (M + H)+ 425.2076, found
425.2085; HPLC Purity: 99.3%; HPLC retention time:
32.8 min.
Methyl-3-[5-(1H-benzimidazol-2-yl)-2-phenyl-1-benzofuran-
General procedure for Suzuki coupling (6e).
To a
3yl]prop-2-enoate (6a).
(KBr, v): 3445, 1716, 1654, 1432, 1172, 748 cmÀ1
Off-white solid; mp 173–176ꢀC; IR
solution of 5a (0.5 g, 1.15 mmol) in Toluene:IPA (2:1) solvent
mixture (10 mL) was added 2.0 M of sodium carbonate (3 eq),
followed by boronic acid (0.27 g, 1.73 mmol) and Pd(PPh3)4
(0.133, 0.115 mmol) at room temperature. The reaction mixture
was heated to 100ꢀC and stirred at this temperature for 8 h; after
completion of starting material confirmed by TLC, cool the
reaction mass to room temperature and add water (50 mL)
product extracted with ethyl acetate (3 Â 50 mL). The organic
layers were collected, combined, and subjected to water
followed by brine washings; the organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography using
n-heptane-EtOAc to give the desired product.
;
1H NMR
(CDCl3, 500 MHz): d 10.55 (s, 1H, NH), 8.50 (s, 1H, Ar-H), 8.16
(d, J = 8.5Hz, 1H, Ar-H), 7.74–8.05 (m, 5H, Ar-H), 7.61
(d, J = 9.0 Hz, 1H, Ar-H), 7.51–7.56 (m, 3H, Ar-H), 7.30–7.32
(m, 2H, Ar-H), 6.75 (d, J= 16.0 Hz, 1H, CH═CH), 3.84 (s, 3H,
OCH3); 13C NMR (DMSO-d6, 125MHz): d 167.4, 162.9, 158.9,
155.1, 151.7, 135.5, 135.1, 131.0, 129.8, 129.0, 128.9, 126.9,
126.8, 125.3, 123.1, 122.3, 119.6, 119.2, 112.9, 112.7, 111.8, 52.2;
HRMS (m/z): calculated for C25H19N2O3 (M + H)+ 395.2658, found
395.2636. HPLC Purity: 99.3%; HPLC retention time: 25.85 min.
Ethyl-3-[5-(1H-benzimidazol-2-yl)-2-phenyl-1-benzofuran-
3yl]prop-2-enoate (6b). Off-white solid; mp 89–91ꢀC; IR (KBr,
v): 3444, 1632, 1441, 1179, 745 cmÀ1 1H NMR (DMSO-d6,
;
2-[3-(4-Chlorophenyl)-2-phenyl-1-benzofuran-5-yl]-1H-
benzimidazolete (6e).
Off-white solid; mp 308–311ꢀC; IR
500 MHz): d 13.14 (s, 1H, NH), 8.72 (s, 1H, CH), 8.34
(d, J= 8.0 Hz, 1H, Ar-H), 7.61–7.88 (m, 9H, Ar-H), 7.24
(d, J= 8.0 Hz, 2H, Ar-H), 6.93 (d, J= 16 Hz, 1H, CH═CH), 4.25
(d, J= 6.5 Hz, 2H, CH2), 1.30 (t, J= 6.5 Hz, 3H, CH3); 13C NMR
(DMSO-d6, 125 MHz): d 166.9, 158.9, 155.1, 151.7, 144.2, 135.5,
135.0, 130.9, 129.8, 129.0, 128.9, 126.9, 126.7, 125.3, 123.1,
122.2, 119.8, 119.3, 112.9, 112.7, 111.8, 60.8, 14.7; HRMS (m/z):
calculated for C26H21N2O3 (M + H)+ 409.1956, found 409.1958;
HPLC Purity: 99.7%; HPLC retention time: 27.37 min.
(KBr): 3445, 1434, 1267, 1088, 743 cmÀ1; H NMR (DMSO-d6,
500 MHz): d 12.97 (s, 1H, NH), 7.86–8.27 (m, 3H, Ar-H),
7.52–7.67 (m, 8H, Ar-H), 7.20–7.46 (m, 5H, Ar-H); 13CNMR
(DMSO-d6, 125 MHz): d 154.6, 151.8, 133.4, 131.9, 130.9,
130.3, 129.9, 129.8, 129.7, 129.4, 127.2, 126.3, 124.6, 118.2,
116.7, 112.4; HRMS (m/z): Calcd for C27H18ClN2O (M + H)+
421.1440, found 421.1409.
1
General procedure for Sonagashira coupling (6c–6d). To a
mixture of 5a (0.5g, 1.15 mmol) in TEA (3 mL) was added PdCl2
(PPh3)2 (0.08g 0.115 mmol) followed by alkyne (1.725mmol) at
room temperature under nitrogen atmosphere; this reaction
mixture was stirred at 80ꢀC for 4 h. After completion of starting
material as confirmed by TLC, the reaction mass was cooled to
room temperature and diluted with water (50 mL).The product
was extracted with ethyl acetate (3 Â 50mL). The organic layers
were collected, combined, and subjected to water followed by
brine washings. The organic layer was dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue
was purified by column chromatography using n-heptane-EtOAc
to give the desired product.
Acknowledgment. We are thankful to Janus Research Laboratories,
Hyderabad for providing the laboratory support.
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1
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A Facile Synthesis of Novel Benzofuranyl Benzimidazole Derivatives
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