Microwave-assisted solid-phase synthesis of a 1,2-disubstituted benzimidazole library by using a phosphonium linker

Article abstract of DOI:10.1002/jhet.1619

An efficient and rapid microwave-assisted solid-phase method for the synthesis of 5-methyl-1,2-disubstituted benzimidazoles derivatives has been developed. The phosphonium linker, obtained by reaction between polymer-supported triphenylphosphine and 4-fluoro-3-nitrobenzyl iodide, underwent aromatic substitution with primary amines, followed by one-pot reaction with aldehydes in the presence of SnCl₂·2H ₂O, yielded the benzimidazole system under microwave irradiation. The final products were released from the resin with NaOH under microwave irradiation and were obtained in high purity and good overall yield.

Full text of DOI:10.1002/jhet.1619

Month 2013 Microwave-Assisted Solid-Phase Synthesis of a 1,2-Disubstituted Benzimidazole
Library by Using a Phosphonium Linker
a
a
b
a
*
Natalia Ríos, Cecilia Chavarría, Carmen Gil, and Williams Porcal
aGrupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad
de la República, Iguá 4225, Montevideo 11400, Uruguay
bInstituto de Química Médica (CSIC), Juan de la Cierva 3, Madrid 28006, Spain
*
E-mail: wporcal@fq.edu.uy
Received November 29, 2011
DOI 10.1002/jhet.1619
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
An efficient and rapid microwave-assisted solid-phase method for the synthesis of 5-methyl-1,2-disubstituted
benzimidazoles derivatives has been developed. The phosphonium linker, obtained by reaction between
polymer-supported triphenylphosphine and 4-fluoro-3-nitrobenzyl iodide, underwent aromatic substitution with
primary amines, followed by one-pot reaction with aldehydes in the presence of SnCl2Á2H2O, yielded the
benzimidazole system under microwave irradiation. The final products were released from the resin with NaOH
under microwave irradiation and were obtained in high purity and good overall yield.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
microwave-assisted organic synthesis and solid-phase
organic synthesis methodology, because a facile and versa-
tile preparation of substituted benzimidazoles is highly
desirable [14]. In the last years, the application of
a traceless phosphonium linker during the synthesis of
2-alkylthiobenzimidazoles has been demonstrated [15].
The phosphonium salt formation on a polymer-supported
triphenylphosphine (PS-TPP) has recently been exploited
for the solid phase synthesis of different molecules with
different reaction conditions [16,17]. We have also devel-
oped a small library of benzofuroxan and benzofurozan
derivatives employing PS-TPP as reagent [18]. In this
context, our group is interested on the development of
rapid synthesis of azaheterocyclic molecules with neuro-
protective and antiprotozoan activity by exploring the
possibility to obtain benzimidazole libraries by MASS
methodology. Synthetic approaches to 1,2-disubstituted
benzimidazoles from o-halonitroaromatics have been de-
scribed; however, this procedure requires a multistep pro-
cess resulting in compromised yields and purity [19,20].
Here, we describe a MASS route using an o-fluronitroaro-
matic phosphonium linker for the preparation of benz-
imidazole libraries by exploiting the presence of two
sites of chemical diversity in the molecule.
Solid-phase organic synthesis and microwave-assisted
organic synthesis are powerful techniques for rapid gener-
ation of structurally diverse molecules for drug discovery
[1,2]. The combination of microwave with solid support,
microwave-assisted solid-phase synthesis (MASS), offers
several advantages over conventional techniques [3]. In
fact, in recent years, MASS has emerged as a powerful
synthetic tool because not only ensures greater purity of
the products but also results in improved yields mainly
because of a decrease formation of side products. The use
of MASS in modern organic synthesis has received special
attention during the synthesis of heterocyclic compounds
because of their broad range of pharmacological activities
[4–6]. Benzimidazole is an important heterocyclic system
with many applications in the field of therapeutics.
Benzimidazole and its derivatives present wide ranges of
biological activities, such as anticancer, [7] antiviral, [8]
antiprotozoan, [9] histamine-H3 antagonist, [10] and, more
recently found, as neuroimaging tracers [11,12]. In this
context, it has been reported that there is a selective inter-
action between two well-known benzimidazole deriva-
tives, the antihistamine astemizole and the proton pump
inhibitor lansoprazole, and anomalous aggregates of tau
protein; therefore, both derivates have been proposed as
potential positron emission tomography radiopharmaceuti-
cal for in vivo early detection of Alzheimer’s disease
(Figure 1) [13]. As a result, an increasing number of substi-
tuted benzimidazoles have been prepared by using both
RESULTS AND DISCUSSION
The synthesis of the benzimidazole derivatives started
with the preparation of the 4-fluoro-3-nitrobenzyl iodide
© 2013 HeteroCorporation

N. Ríos, C. Chavarría, C. Gil, and W. Porcal
Vol 000
FTIR spectroscopy monitoring by the disappearance of
characteristic nitro group absorbance and presence of
characteristic NH vibrations at 3356 and 1665 cmÀ1. A
comparison between yields obtained with conventional
procedure and microwave heating is shown in Table 1.
Both primary amines studied performed better with
decreased reaction times when using microwave heating
than using conventional condition without heating
(room temperature, 24 h). The use of this condition with
phenethylamine in DMF resulted in the corresponding
immobilized o-nitroaniline 5a in moderate yields after
cleavage with NaOH (10%) in MeOH at room temperature
for 4 h (entry 1, Table 1). Excellent and quantitative yields
were obtained to o-nitroaniline 5a when o-fluronitroaro-
matic 4 and phenethylamine (3.6 equiv) were irradiated in
a closed vessel after 10 and 15 min at 120ꢀC, respectively
(entries 2 and 3, Table 1). Substitution of the halogen in
4 by n-butylamine gave the corresponding o-nitroaniline
5b with greater than 90 and 75% of purity and yield,
respectively, as judged by 1H NMR analysis of the cleaved
compound (entries 6–8, Table 1). Moreover, similar yields
were obtained using both amines when microwave heating
(100 or 200 W) was performed during resin cleavage
(entries 4, 7, and 8, Table 1). Microwave irradiation also
allowed for a faster conversion.
On the other hand, a recent report describe the genera-
tion of 2-substituted benzimidazoles directly from 2-nitroa-
nilines by an in situ reduction and cyclization using
microwave procedure [25]. In this regard, a previous
work demonstrate that the benzimidazole system can be
efficiently prepared from a support-bound o-nitroaniline
(SynPhaseTM Lanterns) using a “one-pot” reduction–
cyclization method, with DMF in the presence of
SnCl2Á2H2O at 60ꢀC for 3 h [26]. On the basis of these
results, we considered a MASS for the preparation of the
benzimidazole skeleton using o-nitroaniline phosphonium
salt 5 as starting material. During the course of our studies,
we initially optimized a microwave-based procedure for
the formation of 5-methyl-1-phenethyl benzimidazole 7a
(Table 2). The conversion of o-nitroaniline 5a to supported
benzimidazoles 6a is a two-step process. In the first step,
the aniline reacts with DMF presumably via formylation
process followed by reduction of the nitro group using
SnCl2.2H2O and ring closure. The use of SnCl2.2H2O in
great excess (30 equiv.) in DMF for 24 h produced only a
small amount of the desired benzimidazole 7a (after NaOH
.
Figure 1. Drugs structures based on the benzimidazole scaffold.
3 from 4-fluorobenzaldehyde 1 (Scheme 1) [21]. After
nitration reaction and subsequent NaBH4 reduction of alde-
hyde group, the resulting benzylic alcohol 2 was converted
into iodide 3 using PS-TPP-iodine complex in dry dichlor-
omethane with 45% yield after 48 h at room temperature
[22]. The product was isolated after filtration of the poly-
mer-supported phosphine oxide and subsequent aqueous
work-up of the filtrate yield a pure compound after chro-
matographic purification. With the aim to decrease the
reaction times, the iodination of alcohol 2 was optimized
by using microwave irradiation. The reactions were carried
out in a multimode reactor microwave [23,24]. Similar
yield was obtained for 3 when alcohol 2 and PS-TPP-
iodine complex (1.3 equiv) were irradiated in a closed
vessel at 60–70ꢀC (Scheme 1). Under this condition, the
reaction time is drastically reduced to 20 min. In order to
prepare the o-fluronitrobenzene phosphonium salt 4,
benzyl iodide 3 (1.5 equiv) was immobilized on standard
PS-TPP resin (3 mmol/g) by irradiating the pre-swollen
resin either with DMF or N-methylpyrrolidone (NMP) at
150ꢀC for 5 min (Scheme 2). Under these conditions, com-
plete conversion was achieved as judged by on-bead FTIR
monitoring, which result in the appearance of new bands at
1537, 1492, and 1348 cmÀ1 all corresponding to the
stretching vibration of the CAr–NO2 bond, and bands
1181 and 1111 cmÀ1 corresponding to CAr–F bond. On
the other hand, according to the weight increase and
nitrogen analysis, the loading was estimated to be in
1.45–1.55 mmol (90–95%) phosphonium salt per gram
support. We also have performed this transformation under
conventional conditions (room temperature, 48 h) leading
to identical results.
Nucleophilic aromatic displacement (SNAr) of the
activated fluoride 4 with commercially available amines
provided the immobilized o-nitroaniline 5 (Scheme 2).
Progress of aromatic substitution was followed by on-bead
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Microwave-Assisted Solid-Phase Synthesis of a 1,2-Disubstituted
Benzimidazole Library by Using a Phosphonium Linker
Scheme 2
Table 1
Microwave-assisted synthesis of supported ortho-nitroanilines 5.
Entry
R1-NH2
Solvent
Conditions
Cleavage
Product (yield, %)a
1
2
3
4
5
6
7
8
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
DMF
DMF
DMF
DMF
NMP
NMP
NMP
NMP
RT, 24 h
NaOH, RT, 4 h
NaOH, RT, 4 h
NaOH, RT, 4 h
NaOH, 100 W (Tmax = 85 C), 5 min
NaOH, 100 W, 5 min
NaOH, RT, 4 h
NaOH, 100 W, 5 min
NaOH, 200 W (Tmax = 120 C), 5 min
5a (38)
5a (90)
5a (99)
5a (75)
5a (50)
5b (80)
5b (75)
5b (80)
mW, 120 C, 10 min
mW, 120 C, 15 min
mW, 120 C, 10 min
mW, 70 C, 20 min
mW, 70 C, 20 min
mW, 70 C, 20 min
mW, 70 C, 20 min
aYields are based on the weight of purified product and relative to the initial loading of the resin (3.0 mmol/g).
Table 2
Synthesis of 5-methyl-1-phenethyl benzimidazole 7a using supported ortho-nitroanilines 5a under microwave conditions.
Entry
Reagents
Conditions
Yielda (%)
1
2
3
4
5
SnCl2.2H2O (30 equiv)
SnCl2.2H2O (10 equiv)
SnCl2.2H2O (10 equiv)
SnCl2.2H2O (10 equiv), HCO2H (5 equiv)
SnCl2.2H2O (10 equiv), HCOH (2 equiv)
RT, 24 h
60 C, 3 h
200 W (Tmax = 150 C), 10 min
200 W (Tmax = 105 C), 10 min
200 W (Tmax = 115 C), 10 min
2
15
35
18
47
aYields are based on the weight of purified product and relative to the initial loading of the resin (3.0 mmol/g).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Ríos, C. Chavarría, C. Gil, and W. Porcal
Vol 000
cleavage) along with other products that were not character-
ized (entry 1, Table 2). Optimized microwave heating during
the synthesis of 7a resulted in a significantly improved yield
compared with thermal conditions (35% vs 15%, entries
2 and 3, Table 2). Finally, because the condensation/cycliza-
tion with carboxylic acids and aldehydes during the
formation of benzimidazoles is well known, formic acid
and p-formaldehyde were used in order to improve the yield
of 7a (entries 4 and 5, Table 2). Our best result was a 47%
yield when “one-pot” reduction–cyclization was performed
with p-formaldehyde (2 equiv) under microwave irradiation
(200W, Tmax = 115ꢀC) for 10 min (entry 5, Table 2).
linker, obtained by reaction between PS-TPP and 4-fluoro-3-
nitrobenzyl iodide, underwent aromatic substitution with
primary amines, followed by one-pot reaction, reduction of
the nitro group with tin(II) chloride, and oxidative cyclization
of the ortho-diaminoaromatic intermediates with aldehydes un-
der microwave irradiation. The final products were released
from the resin in a short time using 10% NaOH in MeOH
under microwave heating to leave a methyl group at the attach-
ment point and were obtained in moderate overall yield.
EXPERIMENTAL
To illustrate the versatility of this chemistry, a library of 16
benzimidazoles (7b–p) was prepared (Table 3). Two amines
and eight aldehydes were employed to introduce diversity.
In all cases, pure 1,2-disubtituted benzimidazoles were
obtained (in an overall manner) in moderate to good yields
(between 20 and 57%) after the chromatographic purification.
Triphenylphosphine resin (100–200 mesh, 1% cross-linked;
loading of 3.0 mmol/g) was purchased from Novabiochem
(Darmstadt, Germany). All solvents were distilled prior to use.
Analytical TLC was performed on silica gel 60F-254 plates and
visualized with UV light (254 nm) and/or p-anisaldehyde in acidic
ethanolic solution. Column chromatography was performed using
silica gel (Scientific Adsorbents Incorporated, 63–200 mm). Melt-
ing points were determined with an electrothermal melting point
apparatus (Electrothermal 9100, Melting Point Apparatus,
Thermo Fisher Scientific, USA) and are uncorrected. Proton
NMR spectra were recorded on a Bruker DPX-400 spectrometer
(Bruker Corporation, Billerica, MA). The chemical shifts values
are expressed in parts per million relative to tetramethylsilane
CONCLUSIONS
In summary, we have developed an efficient and rapid solid-
phase microwave assisted approach for the synthesis of 1,2-di-
substituted benzimidazole derivatives. The phosphonium
Table 3
5-Methyl-1,2-disubstituted benzimidazolesm.
Compound
R1
R2
Yielda (%)
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
(CH2)4CH3
2-Furyl
p-F-Ph
50
51
33
30
46
30
57
42
19
21
30
19
27
35
20
p-Br-Ph
p-N(Me)2-Ph
p-NHCOMe-Ph
m-p-O,O(CH2)-Ph
Hb
(CH2)4CH3
2-Furyl
p-F-Ph
p-Br-Ph
p-N(Me)2-Ph
p-NHCOMe-Ph
m-p-O,O(CH2)-Ph
aYields are based on the weight of purified product and relative to the initial loading of the resin (3.0 mmol/g).
bDMF was used as solvent.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Microwave-Assisted Solid-Phase Synthesis of a 1,2-Disubstituted
Benzimidazole Library by Using a Phosphonium Linker
1628, 1523, and 1111 cmÀ1. Cleavage: A suspension of resin
5 (400 mg) in a freshly prepared solution of 10% NaOH in
MeOH (4 mL) was irradiated in a sealed tube operated at power
100 W for 5 min (Tmax = 85ꢀC). The resin was washed with
dichloromethane (DCM), the washes were combined, diluted with
DCM and water, and neutralized with HCl. The organic layer was
dried over Na2SO4, filtered, and concentrated to give the crude
product. After work-up, the residue was purified by column
chromatography (SiO2, petroleum ether : EtOAc (7:3)). N-
phenethyl-4-methyl-2-nitroaniline (5a). Orange oil. 1H NMR
(CDCl3) d (ppm): 2.28 (s, 3H), 3.02 (t, J = 6.8 Hz, 2H), 3.56
(m, 2H), 6.79 (d, J = 8.8 Hz, 1H), 7.26–7.29 (m, 5H), 7.34 (d,
J = 8.0 Hz, 1H), 7.99 (s, 1H), 8.00 (bs, 1H). ESI–MS, m/z: 257
(M+ + H). Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N,
10.93. Found: C, 70.01; H, 5.89; N, 11.35. N-buthyl-4-methyl-
2-nitroaniline (5b). Yellow oil. 1H NMR (CDCl3) d (ppm):
0.97 (t, J = 7.6 Hz, 3H), 1.43 (m, 2H), 1.67 (m, 2H), 2.26 (s,
3H), 3.21 (m, 2H), 6.76 (d, J = 8.8 Hz, 1H), 7.25 (dd,
J = 2.0 Hz, J = 8.8 Hz, 1H), 7.97 (d, J = 1.2 Hz, 1H). ESI–MS,
m/z: 209 (M+ + H). Anal. Calcd for C11H16N2O2: C, 76.44; H,
7.74; N, 13.45. Found: C, 76.05; H, 7.50; N, 13.80.
as internal standard. Mass spectra were determined either
on an MSD 5973 Hewlett–Packard or LC/MSD-Series 100
Hewlett–Packard spectrometers (Agilent Technologies, Madrid,
Spain) using EI or ESI, respectively. Infrared spectra were
recorded on a PerkinElmer 1310 infrared spectrophotometer (Per-
kinElmer, USA) (the frequencies are expressed in cmÀ1). Struc-
1
tural assignments are based on H, COSY, HMBC, HMQC, and
MS spectroscopies. Microanalyses were performed in Fisons
EA 1108 CHNS-O elemental analyzer (Fisons, Waltham, MA)
and were within 0.4% of the calculated compositions. Microwave
experiments: reactions in sealed vessels were conducted in com-
mercial microwave systems, multimode cavity WX-4000 from,
PreeKem Scientific Instruments Co., Ltd. Products (Shanghai,
China), with a microwave power delivery system ranging from
100 to 1000 W. Experiments were carried out in closed 60 mL
reactors made of Teflon. The temperature was monitored via fiber
optic contact thermometer protected in a Teflon-coated gain
inserted directly into the reaction mixture. The vessel contents
were stirred by means of an adjustable rotating magnetic plate lo-
cated below the floor of the microwave cavity. Temperature, pres-
sure, and power profiles were monitored using commercially
available softwares provided by the manufacturers.
General procedure for the preparation and cleavage of
resin-bound benzimidazoles (6). A Teflon tube was charged
sequentially with resin-bound o-nitroaniline 5 (650 mg), NMP
(8 mL), SnCl2.2H2O (10 equiv), and the corresponding aldehyde
(2 equiv). The reactor tube was sealed with Teflon septum and
placed inside the cavity of the microwave reactor, operated at
power 200 W for 10 min (Tmax = 160–200ꢀC). After cooling at
room temperature, the suspension was filtered and washed three
times with H2O (15 mL), MeOH (15 mL), DCM (15 mL), and
diethyl ether (15 mL). The resin 6 was finally dried in vacuÀo at
25ꢀC for 24 h. Resin-bound benzimidazoles, FTIR (neat, cm 1):
(6a) 1177 and 1114; (6b) 1180 and 1112; (6c) 1175 and 1111;
(6d) 1180 and 1114; (6e) 1177 and 1111; (6f) 1175 and 1115;
(6g) 3300, 1680, 1530, 1260, 1180, and 1111; (6h) 1177, 1110,
and 1032; (6i) 1179 and 1115; (6j) 1179 and 1114; (6k) 1181 and
1113; (6l) 1180 and 1111; (6m) 1177 and 1115; (6n) 1177 and
1110; (6o) 3400, 1670, 1523, 1259, 1179, and 1113; (6p) 1469,
1179, and 1113. Cleavage: A suspension of corresponding resin
6a–p (200–500 mg) in a freshly prepared solution of 10% NaOH
in MeOH (2–5 mL) was irradiated in a sealed tube operated at
power 100 W for 5 min (Tmax = 75–85ꢀC). The resin was washed
with DCM, the washes were combined, diluted with DCM
and water, and neutralized with HCl. The organic layer was
dried over Na2SO4, filtered, and concentrated to give the crude
product. After work-up, the residue was purified by column
chromatography (SiO2, mixtures of petroleum ether : EtOAc).
5-Methyl-1-phenethyl-1H-benzimidazole (7a). Reddish oil; 1H
NMR (CDCl3) d (ppm): 2.51 (s, 3H), 3.13 (t, J = 7.2 Hz, 2H),
4.38 (t, J = 7.2 Hz, 2H), 7.03–7.05 (m, 2H), 7.14 (dd, J = 1.2 Hz,
J = 8.4Hz, 1H), 7.25–7.28 (m, 3H), 7.29 (d, J = 8.4 Hz, 1H), 7.57
(s, 1H), 7.61 (s, 1H). 13C NMR (CDCl3): d 22.0, 36.4, 47.5,
109.5, 120.2, 124.5, 127.2, 128.5, 131.2, 138.1, 143.5. EI–MS, m/z
(abundance, %): 236 (M+, 80), 145 (100), 118 (13), 91 (23). Anal.
Calcd for C16H16N2: C, 81.32; H, 6.82; N, 11.85. Found: C, 80.95;
H, 6.50; N, 11.60.
4-fluro-3-nitrobenzyl iodide (3). To a suspension of PS-TPP
(1.3 mmol) in anhydrous dichloromethane (12 mL) at room
temperature was added imidazole (88 mg, 1.3 mmol) and iodine
(33 0mg, 1.3 mmol) and stirred for approximately 5 min. The alcohol
(170 mg, 1.0 mmol) was then added to the reaction mixture and
irradiated in a sealed tube at 60–70ꢀC for 20 min (Power
max = 300 W). After cooling at room temperature, the reaction
mixture was filtered and washed with dichloromethane. The filtrate
was then sequentially washed with aqueous thiosulfate solution (5%)
and water, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography (SiO2,
petroleum ether : EtOAc (7:3)), afforded 3 (0.12 g, 42%) as an orange
1
oil. H NMR (CDCl3) d (ppm): 4.46 (s, 2H), 7.24 (dd, J=7.98 Hz,
J= 8.62 Hz, 1H), 7.65 (m, 1H), 8.08 (dd, J=2.37Hz, J=6.87Hz,
1H). ESI–MS, m/z: 282 (M+ +H). Anal. Calcd for C7H5FINO2: C,
29.92; H, 1.79; N, 4.98. Found: C, 30.23; H, 2.09; N, 5.35.
General procedure for the preparation of resin-bound
o-fluronitrobenzene phosphonium salt (4). Triphenylphosphine
resin (1.5g, 4.4 mmol/g) was placed in a 60mL Teflon reactor
and swelled with dry DMF or NMP (15mL) for 10min. The
resin was then treated with benzyl iodide 3 (6.75mmol, 1.5 equiv)
and irradiated in a sealed tube at 160ꢀC for 5 min (Power
max = 300W). After cooling at room temperature, the suspension
was filtered and washed three times with DMF (15mL),
dichloromethane (DCM) (15 mL), and diethyl ether (15 mL). The
resin 4 was finally dried in vacuo at 25ꢀC for 24h. FTIR (neat):
1537, 1492, 1348, and 1181cmÀ1.
General procedure for the preparation and cleavage of
resin-bound o-nitroaniline (5).
A Teflon tube was charged
sequentially with resin-bound phosphonium salt 4 (1.3 g), DMF
or NMP (15 mL), and the corresponding amine (3.6 equiv). The
test tube was then sealed with Teflon septum and heated 20 min
at 70ꢀC for butylamine and 10 min at 150ꢀC for phenethylamine
by microwave irradiation. The vial was cooled, and the crude
reaction mixture was filtered and washed three times with DMF
(15 mL), dichloromethane (15 mL), and diethyl ether (15 mL).
The resin 5 was finally dried in vacuo at 25ꢀC for 24 h. Resin-
bound o-nitroaniline (5a). FTIR (neat): 3356, 1665, 1492, and
1092 cmÀ1. Resin-bound o-nitroaniline (5b). FTIR (neat): 3379,
5-Methyl-2-pentyl-1-phenethyl-1H-benzimidazole (7b). Yellow
oil; 1H NMR (CDCl3) d (ppm): 0.92 (t, J= 6.8 Hz, 3H), 1.31 (m, 4H),
1.69 (m, 2H), 2.42 (t, J= 7.6 Hz, 2H), 2.50 (s, 3H), 3.09 (t,J=6.8Hz,
2H), 4.28 (t, J= 7.2 Hz, 2H), 7.01–7.03 (m, 2H), 7.08 (dd, J=1.2Hz,
J = 8.0Hz, 1H), 7.25–7.31 (m, 3H), 7.21 (d, J = 8.0 Hz, 1H), 7.55
Journal of Heterocyclic Chemistry
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N. Ríos, C. Chavarría, C. Gil, and W. Porcal
Vol 000
(d, J = 0.8 Hz, 1H). 13C NMR (CDCl3): d 14.1, 21.0, 22.2, 27.5,
32.1, 36.42, 45.5, 109.3, 120.3, 123.2, 128.0, 129.1, 132.2, 138.3,
156.4. ESI–MS, m/z: 306.1 (M+ + H). Anal. Calcd for C21H26N2:
C, 82.31; H, 8.55; N, 9.14. Found: C, 81.98; H, 8.10; N, 9.40.
2-(Furan-2-yl)-5-methyl-1-phenethyl-1H-benzimidazole (7c).
Brown oil; 1H NMR (CDCl3) d (ppm): 2.51 (s, 3H), 3.13
(t, J = 7.6 Hz, 2H), 4.65 (t, J = 7.6 Hz, 2H), 6.60 (dd, J = 2.0 Hz,
J = 3.6 Hz, 1H), 7.10–7.13 (m, 2H), 7.16–7.20 (m, 3H), 7.22–7.32
(m, 3H), 7.59 (s, 1H), 7.63 (dd, J = 0.8 Hz, J = 1.6 Hz, 1H). 13C
NMR (CDCl3): d 22.4, 37.4, 47.2, 100.3, 111.7, 112.5, 120.1,
128.5, 129.6, 133.5, 139.0, 144.3, 145.3. ESI–MS, m/z: 303.2
(M+ + H). Anal. Calcd for C16H18N2O: C, 75.56; H, 7.13;
N,11.01. Found: C, 75.915; H, 7.40; N, 11.35.
2-(4-Fluorophenyl)-5-methyl-1-phenethyl-1H-benzimidazole
(7d). Yellow oil; 1H NMR (CDCl3) d (ppm): 2.54 (s, 3H), 3.07
(t, J = 7.2 Hz, 2H), 4.50 (t, J = 7.2 Hz, 2H), 6.77 (d, J = 6.4 Hz,
2H), 7.11–7.14 (m, 3H), 7.16–7.20 (m, 2H), 7.30–7.33 (m, 2H),
7.25 (d, J = 8.0Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H). 13C
NMR (CDCl3): d 22.1, 36.1, 46.2, 110.1, 117.1, 118.2, 125.2,
128.1, 129.4, 131.1, 132.3, 133.1, 151.2, 163.5. ESI–MS, m/z:
331.0 (M+ + H). Anal. Calcd for C22H19FN2: C, 79.97; H, 5.80;
N, 5.75. Found: C, 79.64; H, 5.43; N, 5.37.
2-(4-Bromophenyl)-5-methyl-1-phenethyl-1H-benzimidazole
(7e). Yellow solid; mp 88–89 C, 1H NMR (CDCl3) d (ppm): 2.55
(s, 3H), 3.06 (t, J = 7.2 Hz, 2H), 4.41 (t, J = 7.2 Hz, 2H), 6.86–6.88
(m, 2H), 7.18–7.25 (m, 3H), 7.23 (d, J = 8.4 Hz, 2H), 7.36
(d, J = 8.0Hz, 1H), 7.53 (d, J = 8.4Hz, 2H), 7.63 (s, 1H). 13C
NMR (CDCl3): d 21.6, 36.3, 47.1, 110.3, 120.2, 124.2, 129.1,
131.2, 132.4, 134.0, 137.2, 144.1, 153.7. ESI–MS, m/z: 391.2
(M+ + H). Anal. Calcd for C22H19BrN2: C, 67.53; H, 4.89; N,
7.16. Found: C, 67.82; H, 5.19; N, 7.43.
2-(4-N,N-Dimethylaminophenyl)-5-methyl-1-phenethyl-1H-
benzimidazole (7f). Yellow oil; 1H NMR (CDCl3) d (ppm): 2.52
(s, 3H), 3.06 (s, 6H), 3.12 (t, J = 8.0 Hz, 2H), 4.44 (t, J = 8.0 Hz,
2H), 6.75 (d, J = 9.2 Hz, 2H), 7.05 (m, 2H), 7.25 (m, 3H), 7.13
(dd, J = 0.8 Hz, J = 8.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.47
(d, J = 8.8 Hz, 2H), 7.65 (s, 1H). 13C NMR (CDCl3): d 22.1,
36.1, 40.3, 46.7, 109.3, 112.3, 118.5, 123.2, 120.2, 124.2,
128.2, 129.5, 130.4, 134.0, 137.1, 154.3. EI–MS, m/z
(abundance, %): 355 (M+, 100), 264 (93), 220 (17), 145 (13).
Anal. Calcd for C24H25N3: C, 81.09; H, 7.09; N, 11.82. Found:
C, 81.36; H, 7.42; N, 11.67.
1-Buthyl-5-methyl-1-H-benzimidazole (7i). Reddish oil; 1H NMR
(CDCl3) d (ppm): 0.94 (t, J = 7.6 Hz, 3H), 1.33 (m, 2H), 1.84 (m,
2H), 2.50 (s, 3H), 4.13 (t, J = 7.2 Hz, 2H), 7.12 (d, J = 8.0 Hz,
1H), 7.31 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.84 (s, 1H). 13C
NMR (CDCl3): d 17.1, 20.0, 22.0, 33.4, 45.5, 109.2, 120.1,
123.1, 124.5, 132.1, 133.4, 143.2. ESI–MS, m/z: 189.2
(M+ + H). Anal. Calcd for C12H16N2: C, 76.55; H, 8.57; N,
14.88. Found: C, 76.15; H, 8.86; N, 14.40.
1-Buthyl-5-methyl-2-pentyl-1H-benzimidazole (7j). Reddish
oil; 1H NMR (CDCl3) d (ppm): 0.97 (t, J = 7.4 Hz, 3H), 0.99
(t, J = 7.2 Hz, 3H), 1.36–1.47 (m, 6H), 1.87 (m, 2H), 2.48 (s,
3H), 2.86 (t, J = 8.0 Hz, 2H), 4.08 (t, J = 7.2 Hz, 2H), 7.08
(dd, J = 1.2 Hz, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.56
(s, 1H). 13C NMR (CDCl3): d 14.3, 21.2, 23.1, 28.3, 32.4, 32.6,
43.5, 109.2, 119.5, 124.2, 125.2, 132.5, 133.7, 155.1. EI–MS,
m/z(abundance, %): 258 (M+, 46), 215 (66), 187 (88), 160
(100%); 146 (76%). Anal. Calcd for C17H26N2: C, 79.02; H,
10.14; N, 10.84. Found: C, 79.38; H, 10.45; N, 11.25.
1-Buthyl-2-(furan-2-yl)-5-methyl-1H-benzimidazole (7k).
1
Reddish oil; H NMR (CDCl3) d (ppm): 0.94 (t, J = 7.2Hz, 3H),
1.37 (m, 2H), 1.83 (m, 2H), 2.50 (s, 3H), 4.45 (t, J = 7.2Hz, 2H),
6.62 (dd, J = 2.0 Hz, J = 3.6 Hz, 1H), 7.13 (dd, J = 1.2Hz,
J = 8.4 Hz, 1H), 7.27 (d, J = 8.4Hz, 1H), 7.29 (m, 1H), 7.60
(s, 1H), 7.64 (dd, J = 0.8 Hz, J = 1.6 Hz, 1H). 13C NMR (CDCl3):
d 14.1, 20.3, 22.5, 32.2, 45.4, 109.2, 112.5, 113.2, 119.6, 124.3,
133.2, 134.6, 142.3, 143.8, 146.1. EI–MS, m/z (abundance, %):
254 (M+, 100), 211 (73), 197 (13). Anal. Calcd for C20H18N2O:
C, 79.44; H, 6.00; N,9.26. Found: C, 79.85; H, 6.31; N, 9.56.
1-Buthyl-2-(4-fluorophenyl)-5-methyl-1H-benzimidazole
(7l). Yellow solid; mp 59–61C, 1H NMR (CDCl3) d (ppm): 0.89
(t, J = 7.2 Hz, 3H), 1.25 (m, 2H), 1.77 (m, 2H), 2.52 (s, 3H), 4.18
(t, J= 7.6 Hz, 2H), 7.14 (dd, J=1.2Hz, J=8.4Hz, 1H), 7.21 (t,
J=8.8Hz, 2H), 7.30 (d, J= 8.4 Hz, 1H), 7.61 (s, 1H), 7.69 (m, 2H).
13C NMR (CDCl3): d 13.7, 20.1, 22.2, 32.5, 44.7, 110.4, 116.5,
120.2, 123.2, 124.5, 128.3, 132.2, 133.6, 134.6, 153.4, 162.1.
ESI–MS, m/z: 283.3 (M+ + H). Anal. Calcd for C18H19FN2: C,
76.57; H, 6.78; N, 9.92. Found: C, 76.28; H, 6.47; N, 9.62.
2-(4-Bromophenyl)-1-buthyl-5-methyl-1H-benzimidazole
1
(7m). Yellowish solid; mp 89–91C, H NMR (CDCl3) d (ppm):
0.87 (t, J = 7.6 Hz, 3H), 1.24 (m, 2H), 1.76 (m, 2H), 2.52 (s, 3H),
4.21 (t, J = 7.6 Hz, 2H), 7.18 (dd, J = 1.2 Hz, J = 8.4 Hz, 1H), 7.32
(d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.65 (s, 1H), 7.68
(d, J = 8.8 Hz, 2H). 13C NMR (CDCl3): d 14.2, 20.6, 22.5, 32.1,
44.2, 110.1, 120.5, 125.7, 126.5, 129.3, 130.0, 132.3, 133.2,
142.7, 153.0. EI–MS, m/z (abundance, %): 342 (M+, 87%), 313
(12), 301 (16), 220 (100%). Anal. Calcd for C18H19BrN2: C,
62.98; H, 5.58; N, 8.16. Found: C, 62.64; H, 5.22; N, 8.51.
1-Buthyl-2-(4-N,N-dimethylaminophenyl)-5-methyl-1H-
benzimidazole (7n). Brown solid; mp 95–96C, 1H NMR (CDCl3)
d (ppm): 0.92 (t, J = 7.2 Hz, 3H), 1.31 (m, 2H), 1.82 (m, 2H), 2.51
(s, 3H), 3.06 (s, 6H), 4.20 (t, J = 7.6 Hz, 2H), 6.87 (d, J = 9.2 Hz,
2H), 7.09 (dd, J = 0.8 Hz, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H),
7.59 (s, 1H), 7.61 (d, J = 9.2 Hz, 2H). 13C NMR (CDCl3): d 14.0,
20.1, 22.2, 32.6, 40.4, 45.4, 110.4, 112.6, 118.3, 119.6, 124.5,
130.1, 132.3, 134.2, 135.4, 151.2, 154.1. ESI–MS, m/z: 308.2
(M+ + H). Anal. Calcd for C20H25N3: C, 78.14; H, 8.20; N, 13.67.
Found: C, 78.44; H, 8.53; N, 13.99.
2-(4-Acetamidophenyl)-5-methyl-1-phenethyl-1H-benzimidazole
1
(7g). Brown oil; H NMR (CDCl3) d (ppm): 2.17 (s, 3H), 2.53
(s, 3H), 3.06 (t, J= 7.2 Hz, 2H), 4.40 (t, J=7.6Hz, 2H), 6.90
(m, 2H), 7.16–7.21 (m, 3H), 7.29 (d, J= 8.4 Hz, 2H), 7.34
(d, J= 8.0 Hz, 1H), 7.53 (d, J=8.4Hz, 2H), 7.60 (s, 1H). 13C NMR
(CDCl3): d 22.5, 24.4, 36.5, 46.4, 110.3, 120.3, 126.5, 128.5,
129.3, 136.4, 138.1, 142.2, 153.2, 169.6. EI–MS, m/z (abundance,
%): 369 (M+, 92), 278 (100), 236 (57). Anal. Calcd for C24H23N3O:
C, 78.02; H, 6.27; N, 11.37. Found: C, 78.43; H, 6.49; N, 11.70.
2-(3,4-Methylendioxophenyl)-5-methyl-1-phenethyl-1H-
benzimidazole (7h). Cream solid; mp 129–130 C, 1H NMR
(CDCl3) d (ppm): 2.54 (s, 3H), 3.07 (t, J = 7.2 Hz, 2H), 4.42
(t, J = 7.2 Hz, 2H), 6.06 (s, 2H), 6.86 (d, J = 6.0 Hz, 1H), 6.88
(s, 1H), 6.92–6.95 (m, 3H), 7.15 (dd, J = 1.2 Hz, J = 8.4 Hz, 1H),
7.16–7.24 (m, 3H), 7.33 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H). 13C
NMR (CDCl3): d 22.2, 36.5, 47.4, 102.5, 108.1, 109.2, 110.6,
120.1, 122.2, 123.3, 124.5, 128.5, 129.6, 132.1, 133.5, 139.2,
148.5, 149.1, 153.5. ESI–MS, m/z: 357.1 (M+ + H). Anal. Calcd
for C23H20N2O2: C, 77.51; H, 5.66; N, 7.86. Found: C, 77.30; H,
5.98; N, 8.21.
2-(4-Acetamidophenyl)-1-buthyl-5-methyl-1H-benzimidazole
(7o). Yellow solid; mp 93–95C, 1H NMR (CDCl3) d (ppm): 0.90
(t, J = 7.2 Hz, 3H), 1.35 (m, 2H), 1.79 (m, 2H), 2.27 (s, 3H), 2.53 (s,
3H), 4.22 (t, J = 7.4 Hz, 2H), 7.23 (dd, J = 1.2 Hz, J = 8.4 Hz, 1H),
7.37 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.62 (s, 1H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Microwave-Assisted Solid-Phase Synthesis of a 1,2-Disubstituted
Benzimidazole Library by Using a Phosphonium Linker
7.77 (d, J = 8.4 Hz, 2H), 9.47 (s, 1H). 13C NMR (CDCl3): d 14.4,
20.6, 22.8, 24.2, 33.1, 44.9, 110.6, 118.4, 120.7, 122.6, 124.3,
130.1, 132.7, 133.6, 134.2, 140.1, 153.4, 170.2. EI–MS, m/z
(abundance, %): 321 (M+, 100%), 292 (18), 278 (35), 236 (27%).
Anal. Calcd for C20H23N3O: C, 74.74; H, 7.21; N, 13.07. Found:
C, 74.31; H, 7.67; N, 13.32.
1-Buthy-2-(3,4-methylendioxophenyl)-5-methyl-1H-
benzimidazole (7p). Cream solid; mp 77–79C, 1H NMR (CDCl3)
d (ppm): 0.88 (t, J = 7.6 Hz, 3H), 1.25 (m, 2H), 1.76 (m, 2H), 2.51
(s, 3H), 4.21 (t, J = 7.6 Hz, 2H), 6.08 (s, 2H), 6.95 (d, J = 8.0 Hz,
1H), 7.14 (dd, J = 0.8 Hz, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.23
(dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.63
(s, 1H). 13C NMR (CDCl3): d 13.5, 19.8, 22.1, 30.6, 46.3,
102.6, 109.4, 110.2, 111.7, 116.3, 126.1, 126.4, 128.1, 128.5,
130.0, 137.5, 149.1, 149.7, 150.9. EI–MS, m/z (abundance, %):
308 (M+, 100%), 279 (72), 252 (30), 235 (43%). Anal. Calcd
for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 74.39;
H, 6.86; N, 9.22.
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Acknowledgments. This work was supported by the CSIC-UdelaR.
We thank CSIC-UdelaR and PEDECIBA for scholarship to NR
and CC.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet