Hydrogen-bond-driven electrophilic activation for selectivity control: Scope and limitations of fluorous alcohol-promoted selective formation of 1,2-disubstituted benzimidazoles and mechanistic insight for rationale of selectivity

Article abstract of DOI:10.1021/jo301793z

Hydrogen-bond-driven electrophilic activation for selectivity control during competitive formation of 1,2-disubstituted and 2-substituted benzimidazoles from o-phenylenediamine and aldehydes is reported. The fluorous alcohols trifluoroethanol and hexafluoro-2-propanol efficiently promote the cyclocondensation of o-phenylenediamine with aldehydes to afford selectively the 1,2-disubstituted benzimidazoles at rt in short times. A mechanistic insight is invoked by NMR, mass spectrometry, and chemical studies to rationalize the selectivity. The ability of the fluorous alcohols in promoting the reaction and controlling the selectivity can be envisaged from their better hydrogen bond donor (HBD) abilities compared to that of the other organic solvents as well as of water. Due to the better HBD values, the fluorous alcohols efficiently promote the initial bisimine formation by electrophilic activation of the aldehyde carbonyl. Subsequently the hydrogen-bond-mediated activation of the in situ-formed bisimine triggers the rearrangement via 1,3-hydride shift to form the 1,2-disubstituted benzimidazoles.

Full text of DOI:10.1021/jo301793z

Article
pubs.acs.org/joc
Hydrogen-Bond-Driven Electrophilic Activation for Selectivity
Control: Scope and Limitations of Fluorous Alcohol-Promoted
Selective Formation of 1,2-Disubstituted Benzimidazoles and
Mechanistic Insight for Rationale of Selectivity
Rajesh Chebolu, Damodara N. Kommi, Dinesh Kumar, Narendra Bollineni, and Asit K. Chakraborti*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar
160 062, Punjab, India
S
* Supporting Information
ABSTRACT: Hydrogen-bond-driven electrophilic activation
for selectivity control during competitive formation of 1,2-
disubstituted and 2-substituted benzimidazoles from o-phenyl-
enediamine and aldehydes is reported. The fluorous alcohols
trifluoroethanol and hexafluoro-2-propanol efficiently promote
the cyclocondensation of o-phenylenediamine with aldehydes
to afford selectively the 1,2-disubstituted benzimidazoles at rt
in short times. A mechanistic insight is invoked by NMR, mass
spectrometry, and chemical studies to rationalize the selectivity. The ability of the fluorous alcohols in promoting the reaction
and controlling the selectivity can be envisaged from their better hydrogen bond donor (HBD) abilities compared to that of the
other organic solvents as well as of water. Due to the better HBD values, the fluorous alcohols efficiently promote the initial
bisimine formation by electrophilic activation of the aldehyde carbonyl. Subsequently the hydrogen-bond-mediated activation of
the in situ-formed bisimine triggers the rearrangement via 1,3-hydride shift to form the 1,2-disubstituted benzimidazoles.
starting materials. Thus, a direct one-pot cyclocondensation of
o-phenylenediamine with aldehydes (route H) appears to be a
straightforward approach.
INTRODUCTION
■
The broad range of biological activities of compounds with the
1,2-disubstituted benzimidazole moiety1 make them highly
sought as synthetic targets. This has generated interest to
develop synthetic methods that follow diverse strategies
(Scheme 1). The reported procedures for the construction of
the 1,2-disubstituted benzimidazole scaffold may be classified
under three broad categories: oxidative cyclocondensation, C-1
or N-2 alkylation/arylation of the preformed N-2 substituted or
C-1 substituted benzimidazole, respectively, and transition
metal-catalyzed inter/intramolecular N-arylation. The cyclo-
condensation involves the treatment of (i) N-alkyl-N-acyl-o-
phenylenediamine (route A),1g,2 or (ii) N-alkyl-o-phenylenedi-
amine with aldehyde1g,3 (route B). The C-1 or N-2 alkylation/
arylation procedures involve (i) N-alkylation of 2-substituted
benzimidazole,1b,d,i (route C) or (ii) Suzuki coupling of aryl
boronic acids with 1-iodo-2-alkylbenzimidazoles4 (route D).
The transition metal-catalyzed N-arylation routes are (i)
copper-catalyzed amidation of o-halo N-alkylated anilines
followed by cyclodehydration of the N-alkyl-N-acyl o-phenyl-
enediamine5 intermediate (route E), (ii) copper/palladium-
catalyzed amination of o-halo N-acylated anilines followed by
cyclodehydration of the N-alkyl-N-acyl o-phenylenediamine6
intermediate (route F), and (iii) palladium-catalyzed intra-
molecular aryl-amination of (o-bromo/iodophenyl)amidines7
or bis(trifluoroacetoxy)iodobenzene-mediated intramolecular
cyclization of N-alkyl-N′-arylamidines8 (route G). These routes
require metal catalysts and special efforts to prepare the desired
The selectivity control9 often becomes the synthetic
bottleneck and is an important conceptual advancement in
organic synthesis. Such a situation has high potential to occur
during the direct cyclocondensation of o-phenylenediamines
with aldehydes, as it poses a selectivity problem due to
competitive formation of the 1,2-disubstituted and the 2-
substituted benzimidazoles (Scheme 2).
Although the condensation of o-phenylenediamine with
aldehydes (route H) is performed under varied catalytic
assistance10 to construct the benzimidazole scaffold, the critical
issue of selectivity control due to the competitive formation of
1,2-disubstituted and 2-substituted benzimidazoles is inad-
equately addressed. We describe herein an efficient metal/
Lewis acid-free protocol for selective formation of the 1,2-
disubstituted benzimidazoles.
RESULTS AND DISCUSSION
■
We realized that the best examples of selectivity control are
demonstrated by Nature’s way to synthesize organic molecules.
Anticipating that the strong Lewis/Bronstead acid catalysts
̈
used for electrophilic activation of the aldehyde carbonyl might
cause a lack of selectivity, we opted for Nature’s synthetic tools
Received: August 24, 2012
Published: October 16, 2012
© 2012 American Chemical Society
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Scheme 1. Synthetic Strategies for 1,2-Disubstituted Benzimidazoles
respect to 1a) is sufficient. The best operational condition is the
treatment of 1a with 2a (2 equiv) in the presence of TFE/
HFIP (3 equiv) at rt. However, the reactions are completed in
shorter time (10 and 5 min, in 3 molar equiv of TFE and HFIP,
respectively) at ∼80 °C with complete selectivity in favor of 3a.
The superiority of TFE/HFIP was clearly established both in
terms of the product yields as well as the selectivity by
comparing the results obtained for the reaction of 1a with 2a
with those obtained using a few reported catalysts (Table 3).
The general applicability of selective 1,2-disubstituted
benzimidazole formation is demonstrated by the reaction of
1a with various aldehydes (Table 4). Although the HFIP-
promoted reactions take shorter time, TFE was chosen due to
its ease of availability and low cost. Excellent results were
obtained in short times (20−60 min) at rt. The reaction
condition is compatible with various sensitive functional groups
(entries 13−16). For substrates with an ortho substituent
(entry 4) or bearing a strong electron-withdrawing group
(entry 11), lack of selectivity was observed and the 2-
substituted benzimidazole was the major product but the
selectivity is directed toward 1,2-disubstituted benzimidazole at
higher temperatures (∼80 °C).
Scheme 2. The Issue of Selectivity in the Formation of the
1,2-Disubstituted and 2-Substituted Benzimidazoles during
the Condensation of o-Phenylenediamine with Aldehydes
of noncovalent interactions. Noncovalent synthesis is Nature’s
strategy to construct molecular architecture with a high
precision of selectivity that is required for various biological
functions and is the central theme of drug−receptor
interaction.11 The hydrogen bond (H-B) is the backbone of
noncovalent synthesis12 and is a frequently adopted synthetic
tool by organic chemists.13 Therefore, we resorted to a milder
hydrogen-bond-driven14 electrophilic activation strategy.
In a model study, o-phenylenediamine (1a) was treated with
benzaldehyde (2a) in different solvents with varying hydrogen
bond donor (HBD) ability in the absence of metal/Lewis acid
catalyst (Table 1).
Poor conversion with competitive formation of 3a and 4a
took place under neat conditions and in solvents with poor
HBD (α) values15 (entries 2−11, Table 1). Moderate results
(total yields of 3a and 4a) were obtained in water and other
protic polar solvents [such as alcohols and polyhydric alcohols
(glycerol,16 PEGs)] (entries 12−19, Table 1) with competitive
formation of 4a. Delightfully, we observed complete selectivity
toward 3a in excellent yields in trifluoroethanol (TFE) and
hexafluoro-2-propanol (HFIP), as these have the highest α
values, 1.51 and 1.96, respectively.15
The effect of various reaction parameters (temperature, time,
molar equivalents of 1a and 2a, and amounts of TFE/HFIP)
were assessed (Table 2). A decrease in selectivity was observed
by lowering the reaction temperature to 0 °C to −40 °C with
competitive formation of 4a. The use of equimolar amounts of
1a and 2a also afforded 3a as the major product and indicated
the ability of TFE/HFIP to drive the selectivity toward 3a
although there is a general trend for competitive formation of
4a at lower temperature. Most significantly, the TFE/HFIP is
not required in large quantities and only 3 molar equiv (with
To rationalize the role of TFE/HFIP on selectivity control,
we set forth to understand the mechanistic course of the
reaction. Two distinctly different pathways have been proposed
(Scheme 3): (i) bisimine-rearrangement (path a)10a,d,e,g,l,m,o,q,r
and (ii) monoimine-cyclocondensation−aminal/immonium-
rearrangement (path b),10l,17 reflecting inconsistent views
without any distinct experimental evidence.
The TFE-promoted reaction of 1a with PhCDO (2 equiv)
afforded 2-phenyl-1-α-d2-methylphenyl-1H-benzimidazole (5)
(Figure 1). Although this observation justifies the proposal of a
1,3-hydride shift (Scheme 3), it remains inconclusive whether
the rearrangement takes place via intermediate III10o,q (path a)
or V/VI (path b).
Path b10l,17 seems unlikely, as no ion peak corresponding to
aminal V (condensation of IV with the aldehyde) or immonium
ion VI was detected (LCMS) during the progress of the
reaction of 1a with 2a (2 equiv). The formation of 3a via 4a is
also ruled out, as no detectable amount of 3a was formed by
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a
Table 1. Selectivity of Formation of 3a and 4a during the Reaction of 1a with 2a under Metal/Catalyst-Free Conditions
b
yield (%)
entry
solvent
neat
3a
4a
1
15
14
19
32
20
22
14
15
18
25
30
25
35
40
32
35
20
30
35
94
95
10
12
15
20
10
15
27
12
19
10
15
21
25
27
25
30
15
20
20
0
2
hexane
heptane
PhMe
3
4
5
1,4-dioxane
THF
6
7
DCE
8
DCM
9
CH3CN
DMF
10
11
12
13
14
15
16
17
18
19
20
21
MeNO2
Water
MeOH
EtOH
iPrOH
tBuOH
glycerol
PEG (2000)
PEG (400)
TFE
HFIP
0
a
b
1a (0.10 g, 1 mmol) was treated with 2a (0.21 g, 2 mmol, 2 equiv) in various solvents (1 mL) at rt for 1 h. Isolated yields of 3a and 4a after
purification.
treatment of the preformed 4a with 2a or benzyl alcohol in the
presence of TFE or HFIP. Further exclusive formation of 3a
observed in comparable yields during the TFE-promoted
reaction of 1a with 2a (2 equiv) under ambient temperature
and nitrogen atmospheres also indicates that the 1,2-
disubstituted benzimidazole formation does not proceed
through imidazoline intermediate IV.17b Hence, we planned
for various spectrometric studies to detect the intermediates
involved during the progress of the reaction.
285 and 289 which correspond to the ion peak of 3a and the
reduced product of the bisimine (bisreductive diamination of
2a with 1a), respectively. After purification (flash chromatog-
raphy), N,N′-dibenzyl-1,2-phenylenediamine (6) was obtained
(spectral data) and provided, for the first time, crucial evidence
that the reaction proceeds via path a.
In the 1H NMR spectrum, sample aliquots withdrawn after 5,
15, and 30 min of the reaction of 1a (1 mmol) with 2a (2
mmol) in MeOH (1 mL) at rt exhibited two singlets at δ 8.54
and 8.45 (Figure 2) corresponding to the bis- and monoimines,
respectively. This justified the lack of selectivity observed in
MeOH.
Mass spectrometric (+p ESI-MS) studies were performed
during the TFE (3 mmol)-promoted reaction of 1a (1 mmol)
with 2a (2 mmol) at rt. A sample aliquot from the reaction after
5 and 15 min exhibited ion peaks at m/z 285, which could be
due to the bisimine or 3a. The tandem mass (ms2) of the ion
with m/z 285 gave daughter ions at m/z 207 and 91 that are
also obtained from the ms2 of the authentic sample of 3a. Thus,
the mass study remains inconclusive with respect to the
intermediacy of the bisimine (path a).
Therefore, the selectivity control for the formation of 1,2-
disubstituted benzimidazole resides on the feasilibility of the
formation of the bisimine under the prescribed set of
experimental condition(s). The better HBD values of TFE
and HFIP15 enable them to act as effective electrophilic
activating agents for bisimine formation and for promoting the
subsequent mechanistic events (intramolecular nucleophilic
attack followed by a 1,3-hydride shift) toward the selective
formation of the 1,2-disubstituted imidazoles. The better HBD
value of HFIP compared to that of TFE makes HFIP a better
promoter as reflected by the shorter reaction time.
The formation of bisimine II is crucial and the determining
factor for 1,2-disubstituted benzimidazole formation (hence
directing/controlling the 1,2-disubstituted vs 2-substituted
benzimidazole selectivity) as demonstrated by the reaction of
1a with 2-methoxybenzaldehyde (2 equiv) that resulted in the
formation of the 2-substituted benzimidazole as the major
1
Next we performed time-dependent H NMR experiments
during the progress of the TFE-promoted reaction of 1a (1
mmol) with 2a (2 mmol) at rt for a sample aliquot withdrawn
after 5, 15, and 30 min. A singlet at δ 8.55 was observed in the
samples at 5 and 15 min reaction time with decreasing intensity
and disappeared in the sample at 30 min reaction (Figure 2).
To find out whether this was due to the monoimine or
bisimine, the reaction of 1a (1 mmol) with 2a (2 mmol) in the
presence of TFE (3 mmol) at rt was treated with NaBH4 (3
equiv) after 5 min and stirred at rt for 1 h (Scheme 4). The
LCMS of the crude reaction mixture exhibited ion peaks at m/z
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bisimine formation with another molecule of 4-nitrobenzalde-
hyde, it undergoes intramolecular nucleophilic attack on the
CN of the monoimine, leading to the formation of the
imidazoline intermediate and finally to the 2-substituted
benzimidazole. However, selective formation of the 1,2-
disubstituted benzimidazole took place under heating, as this
assisted the bisimine formation. Thus, it was anticipated that an
increase in nucleophilicity of the amino group would induce the
formation of the bisimine with 4-nitrobenzaldehyde and hence
the corresponding 1,2-disubstituted benzimidazole. The for-
mation of the 1,2-disubstituted benzimidazole, albeit in low
(18%) yield, from the reaction of 3,4-dimethyl-o-phenylenedi-
amine (1 mmol) with 4-nitrobenzaldehyde (2 mmol) at rt
supported this hypothesis.
Table 2. Effect of Various Reaction Parameters on the
Selectivity of Formation of 3a and 4a during the
a
Condensation of 1a and 2a
c
yield (%)
amount of temp
time
(min)
b
entry equiv
solvent
solvent
(°C)
3a
94
4a
1
2
2
2
2
2
2
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
TFE
1 mL
rt
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
30
20
10
30
20
10
10
5
0
0
2
HFIP
TFE
1 mL
rt
95
78
89
88
89
40
44
36
41
35
41
94
94
85
76
95
87
83
94
85
65
95
95
80
95
95
trace
70
90
95
80
85
3
1 mL
−40
−40
0
20
10
10
10
7
4
HFIP
TFE
1 mL
5
1 mL
6
HFIP
TFE
1 mL
0
7
1 mL
rt
8
HFIP
TFE
1 mL
rt
5
The specific role of TFE/HFIP through hydrogen-bond-
driven electrophilic activation in promoting the tandem
bisimine formation−rearrangement process for selective
formation of the 1,2-disubstituted benzimidazoles is depicted
in Scheme 5.
9
1 mL
−40
−40
0
27
16
17
16
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
HFIP
TFE
1 mL
1 mL
HFIP
TFE
1 mL
0
5 mmol
3 mmol
2 mmol
1 mmol
3 mmol
2 mmol
1 mmol
3 mmol
3 mmol
3 mmol
3 mmol
3 mmol
3 mmol
3 mmol
3 mmol
3 mmol
3 mmol
2 mmol
2 mmol
1 mmol
1 mmol
rt
TFE
rt
0
CONCLUSIONS
TFE
rt
0
■
TFE
rt
0
Hydrogen-bond-driven electrophilic activation for selectivity
control is demonstrated for competitive formation of 1,2-
disubstituted and 2-substituted benzimidazole during reaction
of o-phenylenediamine with aldehydes at rt under metal/Lewis
acid-free conditions. The fluorous alcohols trifluoroethanol and
hexafluoro-2-propanol promote the condensation of o-phenyl-
enediamine with 2 mol equiv of aldehydes to selectively form
the 1,2-disubstituted benzimidazoles. The broad substrate
scope with demonstrated chemoselectivity, metal/catalyst-free
protocol, excellent yields, and room temperature reaction
condition mark a few advantages. The mechanistic investigation
through various spectroscopic and chemical (by first-time
identification/isolation of the crucial intermediates) studies
rationalize the origin of selectivity control and derives the
influence of various factors (e.g., nature of the promoter, steric
and electronic factors of the reactants) on the observed
selectivity. The specific role of the fluorous alcohols in
promoting the reaction has been envisaged through hydro-
gen-bond-driven electrophilic activation of the aldehyde in the
initial bisimine formation stage and the subsequent rearrange-
ment of the in situ-formed bisimine through a 1,3-hydride shift.
The better HBD values of TFE and HFIP compared to other
solvents justifies their superiority over other solvents in
promoting the reaction and controlling the selectivity.
HFIP
HFIP
HFIP
TFE
rt
0
rt
0
rt
0
rt
0
TFE
rt
0
TFE
rt
0
HFIP
HFIP
HFIP
TFE
rt
0
rt
0
rt
0
80
80
rt
0
HFIP
glycerol
glycerol
TFE
0
60
60
10
5
trace
30
5
90
80
80
80
80
HFIP
TFE
0
10
5
15
10
HFIP
a
1a (0.107 g, 1 mmol) was treated with 2a (with varying molar equiv
with respect to 1a) in TFE/HFIP (except for entries 28 and 29) under
b
various conditions. Molar equivalent of 2a used with respect to 1a.
c
Isolated yields of 3a and 4a after purification.
product at rt (Table 4, entry 4, footnotes d and e). To
demonstrate that in this case the bisimine formation does not
occur, the reaction mixture of 2-methoxybenzaldehyde (2
mmol), 1a (1 mmol), and TFE (3 mmol) at rt was treated with
NaBH4. The formation of N1-(2-methoxybenzyl)benzene-1,2-
diamine (7) (Scheme 4) proved that the lack of formation of
the expected 1,2-disubstituted benzimidazole is due to the
feasibilty of only monoimine formation. Similar implication of
the steric factor in suppressing the bisimine formation (and
hence directing the selectivity toward the 2-substituted
benzimidazole) was also observed with pivaldehyde (sterically
hindered aliphatic aldehyde) that gave the 2-substituted
benzimidazole in 92% yield during the reaction with 1a in
the presence of TFE (3 equiv) at rt for 1 h (Table 4, entry 28).
In the case of electron-deficient aldehyde (Table 4, entry 11,
footnote g) due to the highly electrophilic character of the
aldehyde carbonyl, a rapid formation of the monoimine takes
place, and before the second amino group of 1a is involved in
EXPERIMENTAL SECTION
■
General. The glassware to be used in reactions was thoroughly
washed and dried in an oven, and the experiments were carried out
with required precautions. Chemicals and all solvents were
1
commercially available and used without further purification. The H
and 13C NMR spectra were recorded on a 400 MHz NMR
spectrometer in CDCl3 with residual undeuterated solvent (CHCl3:
7.26/77.0) using TMS as an internal standard. Chemical shifts (δ) are
given in ppm, and J values are given in hertz. The 13C NMR spectra
were fully decoupled and were referenced to the middle peak of the
solvent CDCl3 at 77.00 ppm. Splitting patterns were designated as
follows: s, singlet; bs, broad singlet; d, doublet; dd, doublet of doublet;
t, triplet; m, multiplet. Mass spectra were recorded under APCI mode
of ionization. Infrared (IR) spectra were recorded in the range 4000−
600 cm−1 either as neat for liquid or KBr pellets for solid samples.
Purity of the compounds were checked on the silica gel GF-254 under
UV at 254 nm. Melting points were measured using melting point
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Table 3. Selectivity in the Formation of 3a and 4a during the Reaction of 1a with 2a in the Presence of Various Reported
a
Catalysts
de
,
yield (%)
b
c
f
entry
catalyst(mol %)
equiv (1a:2a)
time (h)
3a
4a
3a
lit. ref
1
none
none
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:2
1:2
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:2
5
12
25
21
75
22
58
20
68
22
65
20
48
15
68
18
71
24
62
23
60
22
68
65
88
25
66
22
60
25
64
20
76
16
20
32
18
29
27
35
26
25
22
30
25
35
21
28
25
32
28
26
31
32
15
30
10
32
23
26
28
32
26
28
15
−
−
−
90
−
−
2
5
g
g
3
montmorilonite K-10 (10)
montmorilonite K-10 (10)
H2SO4−SiO2 (10)
H2SO4−SiO2 (10)
L-proline (10)
10 min
10 min
1.5
10b
10b
10c
10c
10e
10e
10d
10d
10g
10g
10h
10h
10i
10i
10l
10l
10n
10n
10o
10o
10p
10p
10q
10q
17
4
5
−
75
−
6
1.5
7
5
8
L-proline (10)
5
95
9
oxalic acid (10)
35 min
35 min
10 min
10 min
20 min
20 min
3
−
97
−
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
23
24
25
26
27
28
29
30
oxalic acid (10)
Fe(ClO4)3 (10)
Fe(ClO4)3 (10)
90/10
glyoxalic acid (75)
glyoxalic acid (75)
[Hmim][TFA] (10)
[Hmim][TFA] (10)
SiO2/ZnCl2 (25)
SiO2/ZnCl2 (25)
Amberlite-IR-20 (0.1 g)
Amberlite-IR-20 (0.1 g)
Me3SiCl (50)
−
95
−
3
86
20 min
20 min
1.45
1.45
5
−
72
−
95
−
87
−
−
−
Me3SiCl (50)
5
h
HOAc (3 mmol)
30 min
30 min
22 min
22 min
10 min
10 min
45
h
HOAc (10 mL)
SDS (10)
SDS (10)
98
Mg(HSO4)2 (30)
Mg(HSO4)2 (30)
Mg(HSO4)2 (30)
Mg(HSO4)2 (30)
−
90
−
17
17
45
92
17
i
[Hbim][BF4] (75)
5
−
88
17b
17b
i
[Hbim][BF4] (75)
5
a
b
1a (2.5 mmol) was treated with 2a in the presence of the catalyst (except for entries 1 and 2) under reported conditions. Molar equivalent of the
c
d
catalyst used with respect to 1a. Molar equivalent of 2a used with respect to 1a. The isolated yield of 3a and 4a after column chromatographic
e
purification obtained in performing the reaction under the present investigation. The products were characterized by NMR (1H and 13C) and MS
f
g
h
(APCI). Yield of 3a as reported in the cited literature except for entry 14. A 10% w/w of the catalyst was used. The reaction was performed using
1 mmol of 1a at rt. The reaction was carried out at 60 °C under N2.
i
apparatus and were uncorrected. Evaporation of solvents was
performed at reduced pressure, using a rotary vacuum evaporator.
Typical Experimental Procedure for the Synthesis of 1-
Benzyl-2-phenyl-1H-benzimidazole 3a. A mixture of 1a (0.10 g, 1
mmol), 2a (0.21 g, 2 mmol, 2 equiv), and TFE (0.30 g, 3 mmol, 217
μL) was stirred magnetically at rt for 30 min (complete consumption
of 1, TLC). The mixture was dissolved in EtOAc (3 mL), adsorbed on
silica gel (0.5 g, 230−400 mesh), and concentrated under rotary
vacuum evaporation. The resultant solid mass was charged onto a flash
chromatography column and eluted with hexane−EtOAc (85:15) to
afford 3a (0.27 g, 95%) (entry 1, Table 4). White solid; mp = 130−
132 °C; IR (KBr) νmax = 3012, 2952, 1601, 1508, 1465, 1264, 1172,
1101, 1065 cm−1; 1H NMR (CDCl3, 400 MHz, TMS) δ: 7.87 (d, J = 8
Hz, 1H), 7.70−7.68 (m, 2H), 7.47−7.44 (m, 3H), 7.33−7.29 (m, 4H),
7.24−7.21 (m, 2H), 7.12−7.09 (m, 2H), 5.46 (s, 2H). 13C NMR
(CDCl3, 75 MHz, TMS) δ: 154.2, 143.2, 136.4, 136.1, 130.1, 129.9,
129.3, 129.1, 128.7, 127.8, 126.0, 123.0, 122.7, 120.0, 110.5, 48.4. MS
(APCI) m/z: 285.1 (M + H)+.10e Unless otherwise mentioned, all
reactions for generalization study under Table 4 were performed using
1 mmol of 1a and 2 mmol of the respective aldehyde.
tert-Butyl-1H-benzimidazole (Entry 28, Table 4). A mixture of 1a
(108 mg, 1 mmol), pivalaldehyde (172 mg, 2 mmol, 2 equiv), and TFE
(300 mg, 3 mmol, 217 μL) was stirred magnetically at rt for 60 min
(complete consumption of 1, TLC). The mixture was dissolved in
EtOAc (3 mL), adsorbed on silica gel (0.5 g, 230−400 mesh), and
concentrated under rotary vacuum evaporation. The resultant solid
mass was charged onto a flash chromatography column and eluted
with hexane−EtOAc (80:20) to afford 2-tert-butyl-1H-benzimidazole
(0.16 g, 92%). White solid; mp = 320−322 °C; IR (KBr) ν max = 3345,
1
2885, 1612, 1442, 1370, 1352, 1390, 1285, 1081 cm−1; H NMR
(DMSO, 400 MHz, TMS) δ: 7.53−7.52 (m, 1H), 7.41−7.39 (m, 1H),
7.14−7.07 (m, 2H), 1.39 (s, 9H). MS (APCI) m/z: 175.2 (M + H)+.18
Investigation on the Progress of the Reaction for an Insight
on the Mechanistic Course of the Reaction. Evidence for a 1,3-
Hydride Shift through a Bisimine Intermediate. TFE-Promoted
Reaction of 1a with Benzaldehyde-α-d1. A mixture of 1a (0.54 g,
0.5 mmol), benzaldehyde-α-d1 (0.10 g, 1 mmol, 2 equiv), and TFE
(0.15 g, 109 μL, 1.5 mmol) was stirred magnetically at rt for 30 min
(complete consumption of 1, TLC). The mixture was dissolved in
EtOAc (3 mL), adsorbed on silica gel (0.5 g, 230−400 mesh), and
concentrated under rotary vacuum evaporation. The resultant solid
mass was charged onto a flash chromatography column and eluted
with hexane−EtOAc (85:15) to afford 2-phenyl-1-α-d2-methylphenyl-
Effect of Steric Hindrance on Selectivity of Formation of 1,2-
Disubstituted and 2-Substituted Benzimidazoles: Reaction of
Pivalaldehyde with 1a in the Presence of Trifluoroethanol. 2-
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Table 4. TFE-Promoted Selective 1,2-Disubstituted
Benzimidazole Formation during the Reaction of 1 with
Various Aldehydes at rt under Metal/Catalyst-Free
Scheme 3. Mechanism for Formation of 1,2-Disubstituted
Benzimidazole
a
Conditions
1
1H-benzimidazole (5) (0.13 g, 91%); H NMR (400 MHz, 25 °C,
CDCl3): δ = 7.90−7.87 (m, 1H), 7.92−7.69 (m, 2 H), 7.49 − 7.45 (m,
3 H), 7.37−7.31 (m, 4 H), 7.26−7.21 (m, 2 H), 7.14 − 7.11 (m, 2 H);
MS (APCI) m/z: 287.2 (M + H)+.10o
Evidence for the Intermediacy of Bisimine during the TFE-
Promoted 1,2-Disubstituted Benzimidazole Formation. For-
mation of N1,N2-Dibenzylbenzene-1,2-diamine during the in
Situ Reduction (with NaBH4) of the Presumably Formed
Bisimine during the Synthesis of the 1,2-Disubstituted
Benzimidazole from 1a with 2a. A mixture of 1a (0.10 g, 1
mmol), 2a (0.21 g, 2 mmol, 2 equiv), and TFE (0.30 g, 3 mmol, 217
μL) was stirred magnetically at rt. After 5 min, NaBH4 (3 mmol, 3
equiv) was added and the resultant mixture was stirred for further 30
min. The mixture was dissolved in EtOAc (3 mL), adsorbed on silica
gel (0.5 g, 230−400 mesh), and concentrated under rotary vacuum
evaporation. The resultant solid mass was charged onto a flash
chromatography column and eluted with hexane−EtOAc (85:15) to
afford N1,N2-dibenzylbenzene-1,2-diamine (6) (0.3 g, 10%). Low
melting solid; IR (KBr) νmax = 3441, 2979, 1610, 1455, 1326, 1265,
1
1165 cm−1; H NMR (CDCl3, 400 MHz, TMS) δ: 7.39−7.35 (m,
4H), 7.34−7.32 (m, 4H), 7.29−7.27 (m, 2H), 6.80−6.78 (m, 2H),
6.72−6.70 (m, 2H), 4.31 (s, 4H), 3.64 (brs, 2H); MS (EI) m/z: 289.2
(M + H)+.19
Evidence for the Intermediacy of Monoimine during the
Reaction of 1a with Sterically Hindered Aldehyde Leading to
the Formation of the 2-Substituted Benzimidazole. Formation
of N1-(2-Methoxybenzyl)benzene-1,2-diamine during the in
Situ Reduction (with NaBH4) of the Presumably Formed
Monoimine during the Reaction of 1a with 2-Methoxybenzal-
dehyde That Led to the Formation of the 2-Substituted
Benzimidazole. A mixture of 1a (0.10 g, 1 mmol), 2-
methoxybenzaldehyde (0.27 g, 1 mmol, 1 equiv), and TFE (0.30 g,
3 mmol, 217 μL) was stirred magnetically at rt. After 5 min, NaBH4 (3
mmol, 3 equiv) was added and the resultant mixture was stirred for a
further 30 min. The mixture was dissolved in EtOAc (3 mL), adsorbed
on silica gel (0.5 g, 230−400 mesh), and concentrated under rotary
vacuum evaporation. The resultant solid mass was charged onto a flash
chromatography column and eluted with hexane−EtOAc (80:20) to
afford N1-(2-methoxybenzyl)benzene-1,2-diamine (7) (0.35 g, 15%).
Light orange color oil; IR (KBr) νmax = 3449, 2989, 2858, 1609, 1455,
1259, 1139, 1074 cm−1; 1H NMR (CDCl3, 400 MHz, TMS) δ: 7.29−
7.25 (m, 2H), 7.02−6.89 (m, 2H), 6.86−6.79 (m, 1H), 6.78−6.67 (m,
3H), 4.31 (s, 2H), 3.86 (s, 3H), 3.58 (brs, 2H); 13C NMR (CDCl3,
100 MHz, TMS) δ: 157.5, 137.8, 134.7, 129.2, 128.4, 127.4, 120.6,
120.6, 118.9, 116.3, 112.6, 110.3, 55.4, 43.9. MS (EI) m/z: 228.3 (M +
H)+. Anal. Calcd For C14H16N2O: C, 73.66; H, 7.06; N, 12.27; O,
7.01%. Found: C, 73.69; H, 7.08; N, 12.29%.
a
1a (0.107 g, 1 mmol) was treated with the aldehyde (0.21 g, 2 mmol,
b
2 equiv) in the presence of TFE (3 mmol) at rt. Isolated yield of the
1,2-disubstituted benzimidazole after purification. Reaction was
performed at 80 °C. 1,2-disubstituted and 2-substituted benzimida-
zoles were formed in 20% and 75% yields, respectively, at rt after 20
min. 1,2-disubstituted and 2-substituted benzimidazoles were formed
in 10% and 85% yields, respectively, at rt after 20 min in the presence
of HFIP (3 mmol). Reaction was performed at 80 °C and the 2-
substituted benzimidazole was isolated in 20% yield in addition to the
c
d
1-(4-Methylbenzyl)-2-(4-methylphenyl)-1H-benzimidazole
e
(Table 4, Entry 2). White solid (0.29 g, 95%); mp = 129−130 °C; IR
1
(KBr) ν
= 2959, 1618, 1605, 1402, 1252, 1128, 1098 cm−1; H
max
f
NMR (CDCl3, 400 MHz, TMS) δ: 7.85 (d, J = 8 Hz, 1H), 7.59 (d, J =
7.7 Hz, 2H), 7.31−7.18 (m, 5H), 7.13 (d, J = 7.7 Hz, 2H), 7.99 (d, J =
7.7 Hz, 2H), 5.40 (s, 2H), 2.40 (s, 3H), 2.33 (s, 3H). MS (APCI) m/z:
313.4 (M + H)+.10e
g
1,2-disubstituted benzimidazole. 2-aryl benzimidazole was formed in
93% yield at rt. Yield of 2-substituted benzimidazole.
h
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1
Figure 1. Evidence of a 1,3-hydride shift through the bisimine during TFE-promoted 1,2-disubstituted benzimidazole formation: (a) H NMR
spectrum of an authentic sample of 3 obtained from the reaction of 1a (1 mmol) with 2a (2 mmol) in TFE (3 mmol) at rt; (b) 1H NMR spectrum
of the product obtained from the reaction of 1a (1 mmol) with PhCDO (2 mmol) in TFE (3 mmol) at rt.
Scheme 5. Hydrogen-Bond-Driven Electrophilic Activation
by Fluorous Alcohols for Selective Formation of 1,2-
Disubstituted Benzimidazoles
Figure 2. Time-dependent NMR study (δ 8.2−10.2) for reaction of 1a
(1 mmol) with 2a (2 mmol) in TFE (3 mmol) and MeOH (1 mL):
(a) 2a; (b) reaction mixture in TFE after 5 min; (c) reaction mixture
in TFE after 30 min; (d) reaction mixture in MeOH after 5 min; (e)
reaction mixture in MeOH after 30 min.
1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-1H-benzimida-
zole (Table 4, Entry 3). White solid (0.33 g, 96%); mp = 130−131
°C; IR (KBr) νmax = 3005, 2895, 1601, 4586, 1238, 1211, 1177, 1050
cm−1; 1H NMR (CDCl3, 400 MHz, TMS) δ: 7.68 (d, J = 8.6 Hz, 3H),
7.44 (d, J = 8.5 Hz, 1H), 7.25−7.19 (m, 2H), 7.09 (d, J = 8.6 Hz, 2H),
6.94 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.49 (s, 2H), 3.83
(s, 3H), 3.68 (s, 3H); MS (APCI) m/z: 345.1 (M + H)+.10e
1-(2-Methoxybenzyl)-2-(2-methoxyphenyl)-1H-benzimida-
1H), 7.46−7.42 (m, 1H), 7.29−7.28 (m, 2H), 7.18−7.14 (m, 1H),
7.09 (d, J = 11.25 Hz, 1H), 4.11 (s, 3H); MS (EI) m/z: 225.4 (M +
zole (Table 4, Entry 4, Footnote c). Off-white solid (0.29 g, 85%);
20
max
H)+.
mp = 150−152 °C; IR (KBr) ν
= 3015, 2985, 1612, 1476, 1432,
1
1395, 1285, 1172, 1098; H NMR (DMSO, 400 MHz, TMS) δ: 7.86
(d, J = 7.76 Hz, 1H), 7.69 (d, J = 7.96 Hz, 2H), 7.31 (t, J = 6.96 Hz,
1H), 7.26−7.22 (m, 1H), 7.20−7.19 (m, 3H), 7.11 (d, J = 8.04 Hz,
2H), 7.06 (d, J = 7.88 Hz, 2H), 5.44 (s, 2H), 2.32 (s, 3H), 2.29 (s,
4-[1-{4-(Dimethylamino)benzyl}-1H-benzimidazol-2-yl]-N,N-
dimethylaniline (Table 4, Entry 5). White solid (0.35 g, 95%); mp
= 254−255 °C; IR (KBr) νmax = 2953, 2895, 1612, 1462, 1422, 1238,
1126 cm−1; 1H NMR (CDCl3, 400 MHz, TMS) δ: 7.82 (d, J = 7.3 Hz,
1H), 7.63 (d, J = 7.7 Hz, 1H), 7.26−7.19 (m, 3H), 7.02 (d, J = 7.4 Hz,
2H), 6.73 (d, J = 7.6 Hz, 2H), 6.68 (d, J = 7.5 Hz, 2H), 5.37 (s, 2H),
3.01 (s, 6H), 2.93 (s, 6H). MS (APCI) m/z: 371.4 (M + H)+.10e
1-(4-Chlorobenzyl)-2-(4-chlorophenyl)-1H-benzimidazole
(Table 4, Entry 6). White solid (0.32 g, 92%); mp = 136−137 °C; IR
(KBr) νmax = 2995, 2856, 1605, 1483, 1354, 1221, 1250, 1162, cm−1;
1H NMR (CDCl3, 400 MHz, TMS) δ: 7.89−7.87 (m, 1H), 7.60 (td, J
10n
3H); MS (EI) m/z: 345.4 (M + H)+.
2-(2-Methoxyphenyl)-1H-benzimidazole (Table 4, Entry 4,
Footnotes d and e). Off-white solid (0.168 g, 75% and 0.19 g, 85%,
for footnotes d and e, respectively); mp = 176−177 °C; IR (KBr) ν max
= 3435, 3028, 1601, 1582, 1485, 1432, 1394, 1280, 1182, 1165, 1095;
1H NMR (DMSO, 400 MHz, TMS) δ: 10.63 (brs, 1H), 8.60 (dd, J =
1.74 and 7.79 Hz, 1H), 7.82 (d, J = 6.65 Hz, 1H), 7.51 (d, J = 6.50 Hz,
Scheme 4. Trapping of the Presumably Involved Monoimine/Bisimine Intermediate during the Formation of 2-Substituted and
1,2-Disubstituted Benzimidazoles, Respectively, through Conversion to the Corresponding Reductive Amination Products by
Treatment with NaBH4
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= 8.6 and 2 Hz, 2H), 7.45 (td, J = 8.6 and 2.4 Hz, 2 H), 7.37−7.26 (m,
5H), 7.21 (d, J = 7.9 Hz, 1H), 7.05−7.02(m, 2H), 5.41 (s, 2H); MS
(APCI) m/z: 354.2 (M + H)+.10e
4-[1-(4-Acetoxybenzyl)-1H-benzimidazol-2-yl]phenyl Ace-
tate (Table 4, Entry 14). White solid (0.43 g, 90%); mp = 154−
155 °C; IR (KBr) ν
= 3028, 2990, 2862, 1756, 1748, 1608, 1520,
max
1
1320, 1250, 1168, 1060 cm−1; H NMR (CDCl3, 400 MHz, TMS) δ:
7.86 (d, J = 7.96 Hz, 1H), 7.71−7.67 (m, 2H), 7.34−7.30 (m, 1H),
7.27−7.23 (m, 1H), 7.21−7.18 (m, 3H), 7.12−7.10 (m, 2H), 7.07−
7.05 (m, 2H), 5.44 (s, 2H), 2.32 (s, 3H), 2.29 (s, 3H). 13C NMR
(CDCl3, 100 MHz, TMS) δ: 169.4, 169.1, 153.2, 151.9, 150.2, 143.1,
136.0, 133.7, 130.4, 127.5, 126.9, 123.3, 122.9, 122.3, 122.1, 120.0,
110.5, 47.9, 21.2, 21.1. MS (EI) m/z: 402.3 (M + H)+. Anal. Calcd For
C24H20N2O 4: C, 71.99; H, 5.03; N, 7.00; O, 15.98%. Found: C, 72.00;
H, 5.05; N, 7.03%.
1-(4-Bromobenzyl)-2-(4-bromophenyl)-1H-benzimidazole
(Table 4, Entry 7). White solid (0.40 g, 93%); mp = 139−141 °C; IR
1
(KBr) νmax = 3021, 2899, 1610, 1595, 1350, 1245, 1052 cm−1; H
NMR (CDCl3, 400 MHz, TMS) δ: 7.87 (d, J = 8.4 Hz, 1H), 7.60 (d, J
= 7.8 Hz, 2H), 7.52 (d, J = 7.2 Hz, 2H), 7.47 (d, J = 7.5 Hz, 2H),
7.34−7.29 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.5 Hz, 2H),
5.38 (s, 2H). MS (APCI) m/z: 440.2 (M + H)+.10o
4-[1-(4-Hydroxybenzyl)-1H-benzimidazol-2-yl]phenol (Table
4, Entry 8). Off-white solid (0.29 g, 93%); mp = 183−185 °C; IR
1
(KBr) νmax = 3450, 3022, 2895, 1618, 1355, 1242 cm−1; H NMR
1-[4-(tert-Butoxycarbonyloxy)benzyl]-2-[4-(tert-butoxy-
carbonyloxy)phenyl]-1H-benzimidazole (Table 4, Entry 15).
White solid (0.49 g, 95%); mp = 135−136 °C; IR (KBr) ν max = 3030,
2986, 2868, 1760, 1754, 1610, 1516, 1254, 1166, 1054 cm−1; 1H NMR
(CDCl3, 400 MHz, TMS) δ: 7.89 (d, J = 8 Hz, 1H), 7.69 (d, J = 8 Hz,
2H), 7.32−7.25 (m, 4H), 7.20−7.15 (m, 3H), 7.10 (d, J = 8.2 Hz,
2H), 5.43 (s, 2H), 1.56 (s, 9H), 1.55 (s, 9H). 13C NMR (CDCl3, 100
MHz, TMS) δ: 153.2, 152.5, 151.7, 151.3, 135.8, 133.5, 131.5, 130.4,
127.1, 126.9, 123.4, 123.0, 122.0, 121.7, 120.9, 119.9, 110.5, 84.0, 83.8,
47.9, 27.7. MS (EI) m/z: 516.3 (M + H)+. Anal. Calcd For
C30H32N2O6: C, 69.75; H, 6.24; N, 5.42; O, 18.58%. Found: C, 69.78;
H, 6.26; N, 5.43%.
(DMSO, 400 MHz, TMS) δ: 7.64 (d, J = 6.72 Hz, 1H), 7.55 (d, J =
7.92 Hz, 2H), 7.40 (d, J = 6.72 Hz, 1H), 7.18 (s, 2H), 6.89 (d, J = 7.96
Hz, 2H), 6.81 (d, J = 7.76 Hz, 2H), 6.64 (d, J = 7.76 Hz, 2H), 5.40 (s,
2H). MS (EI) m/z: 318.2 (M + H)+.10n
1-[4-(Trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-
1H-benzimidazole (Table 4, Entry 9). White solid (0.38 g, 90%);
mp = 146−147 °C; IR (KBr) νmax = 3019, 2956, 1605, 1586, 1256,
1
1109, 1056 cm−1; H NMR (CDCl3, 400 MHz, TMS) δ: 7.91 (d, J =
7.9 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.62
(d, J = 8.2 Hz, 2H), 7.38 (dt, J = 8.1 and 1.1 Hz, 1H), 7.30 (dt, J = 8.1
and 1.1 Hz, 1H), 7.23−7.20 (m, 3H), 5.52 (s, 2H). MS (APCI) m/z:
421.2 (M + H)+.21
4-[1-(4-Cyanobenzyl)-1H-benzimidazol-2-yl]benzonitrile
(Table 4, Entry 10). White solid (0.31 g, 92%); mp = 136−137 °C;
IR (KBr) νm1ax =3031, 2965, 2866, 2229, 2221, 1610, 1485, 1365, 1254,
1165 cm−1; H NMR (DMSO, 400 MHz, TMS) δ: 7.64 (d, J = 6.72
Hz, 1H), 7.55 (d, J = 7.92 Hz, 2H), 7.40 (d, J = 6.72 Hz, 1H), 7.18 (s,
2H), 6.89 (d, J = 7.96 Hz, 2H), 6.81 (d, J = 7.76 Hz, 2H), 6.64 (d, J =
7.76 Hz, 2H), 5.40 (s, 2H). MS (EI) m/z: 318.2 (M + H)+.10f
1-(4-Nitrobenzyl)-2-(4-nitrophenyl)-1H-benzimidazole
(Table 4, Entry 11, Footnote f). Yellow solid (0.18 g, 75%); mp =
1-[4-(tert-Butyldimethylsilyloxy)benzyl]-2-[4-(tert-
butyldimethylsilyloxy)phenyl]-1H-benzimidazole (Table 4,
Entry 16). Colorless liquid (0.51 g, 95%); IR (KBr) νmax = 3035,
1
2986, 2862, 1615, 1450, 1338, 1268, 1186 cm−1; H NMR (CDCl3,
400 MHz, TMS) δ: 7.83 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H),
7.30−7.21 (m, 3H), 6.96 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 8.1 Hz, 2H),
6.78 (d, J = 7.9 Hz, 2H), 5.37 (s, 2H), 0.99 (s, 9H), 0.96 (s, 9H), 0.22
(s, 6H), 0.18 (s, 6H). 13C NMR (CDCl3, 100 MHz, TMS) δ: 157.3,
155.2, 154.2, 143.1, 136.1, 130.7, 129.1, 127.3, 123.1, 122.7, 122.5,
120.5, 120.4, 119.7, 110.4, 48.0, 25.6, 18.25, 18.2, −4.39, −4.43. MS
(EI) m/z: 545.2 (M + H)+. Anal. Calcd For C32H44N2O2Si2: C, 70.54;
H, 8.14; N, 5.14; O, 5.87; Si, 10.31%. Found: C, 70.58; H, 8.17; N,
5.17%.
1-(3,5-Dimethoxybenzyl)-2-(3,5-dimethoxyphenyl)-1H-ben-
zimidazole (Table 4, Entry 17). Semisolid (0.92 g, 91%); IR (KBr)
νmax = 3042, 2985, 2796, 1745, 1704, 1642, 1498, 1255, 1096 cm−1; 1H
NMR (CDCl3, 400 MHz, TMS) δ: 7.87 (d, J = 7.7 Hz, 1H), 7.27−
7.39 (m, 3H), 6.85 (d, J = 2.2 Hz, 2H), 6.38−6.56 (m, 2H), 6.28 (d, J
= 1.6 Hz, 2H), 5.40 (s, 2H), 3.78 (s, 6H), 3.69 (s, 3H); 13C NMR
(CDCl3, 100 MHz, TMS) δ: 161.4, 160.9, 154.0, 142.7, 139.0, 136.2,
131.4, 125.3, 122.9, 119.8, 110.5. 107.0, 104.4, 104.1, 102.8, 99.2, 55.3,
48.4.; MS (APCI) m/z: 405.2 (M + H)+; HRMS (ESI) m/z calcd for
C24H24N2O4Na+ [M + Na+], 427.1628; Found 427.1625.
302−304 °C; IR (KBr) ν
= 2985, 2853, 1610, 1526, 1450, 1375,
max
1230, 1141, 1052 cm−1; 1H NMR (DMSO, 400 MHz, TMS) δ: 8.42−
8.32 (m, 4H), 8.26 (d, J = 8.48 Hz, 2H), 8.13 (d, J = 7.92 Hz, 1H),
7.36−7.23 (m, 2H), 7.02 (t, J = 7.56 Hz, 1H), 6.75 (d, J = 7.88 Hz,
1H), 6.57 (t, J = 7.48 Hz, 1H), 5.41 (s, 2H); MS (APCI) m/z: 375.2
(M + H)+.10n
2-(4-Nitrophenyl)-1H-benzoimidazole (Table 4, Entry 11,
Footnote g). Yellow solid; mp = 328−329 °C; IR (KBr) νmax = 2985,
1
2853, 1610, 1526, 1450, 1375, 1230, 1141, 1052 cm−1; H NMR
(DMSO, 400 MHz, TMS) δ: 8.53 (brs, 1H), 8.30 (s, 2H), 8.03 (d, J =
3.2 Hz, 2H), 7.33−7.22 (m, 4H). MS (APCI) m/z: 240.4 (M + H)+.10f
1-[4-(Benzyloxy)benzyl)-2-(4-(benzyloxy)phenyl]-1H-benzi-
midazole (Table 4, Entry 12). White solid (0.46 g, 93%); mp =
127−128 °C; IR (KBr) ν
= 3034, 2985, 2859, 1612, 1515, 1450,
max
1325, 1256, 1176, 1028 cm−1; H NMR (CDCl3, 400 MHz, TMS) δ:
7.83 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.44−7.27 (m,
11H), 7.22−7.20 (m, 2H), 7.05−7.01 (m, 4H), 6.92 (d, J = 8.3 Hz,
2H), 5.38 (s, 2H), 5.11 (s, 2H), 5.03 (s, 2H). 13C NMR (CDCl3, 100
MHz, TMS) δ: 160.1, 158.3, 154.1, 143.1, 136.7, 136.5, 136.1, 130.7,
128.74, 128.67, 128.6, 128.1, 128.0, 127.5, 127.2, 122.8, 122.7, 122.5,
119.7, 115.3, 115.1, 110.4, 70.1, 47.9. MS (APCI) m/z: 497.5 (M +
H)+; Anal. Calcd For C34H28N2O2: C, 82.23; H, 5.68; N, 5.64%.
Found: C, 82.25; H, 5.67; N, 5.66%.
1
1-(3,4-Dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)-1H-ben-
zimidazole (Table 4, Entry 18). White solid (0.93 g, 92%); mp =
142−144 °C; IR (KBr) ν
= 3196, 2940, 2785, 1750, 1710, 1650,
max
1496, 1265, 1045 cm−1; H NMR (CDCl3, 400 MHz, TMS) δ: 7.86
(d, J = 8 Hz, 1H), 7.29−7.21 (m, 5H), 6.92−6.93 (m, 1H), 6.81 (d, J =
4.9 Hz, 1H), 6.65 (d, J = 9.8 Hz, 2H), 5.40 (s, 2H), 3.97 (s, 3H), 3.86
(s, 3H), 3.77 (s, 6H); 13C NMR (CDCl3, 100 MHz, TMS) δ: 154.1,
150.4, 149.5, 149.0, 148.5, 143.0, 136.3, 129.0, 126.0, 124.3, 222.9,
122.6, 122.5, 121.8, 119.7, 118.0, 112.3, 111.5, 110.9, 110.3, 108.9,
108.8, 55.9, 48.1. MS (APCI) m/z: 405.6 (M + H)+. HRMS (ESI) m/z
1
4-[1-(4-(Benzoyloxy)benzyl)-1H-benzimidazol-2-yl]phenyl
Benzoate (Table 4, Entry 13). White solid (0.48 g, 92%); mp =
calcd for C24H24N O4Na+ [M + Na+], 427.1628; Found 427.1629.
2
2-Ethoxy-3-((2-(3-ethoxy-4-hydroxyphenyl)-1H-benzo[d]-
164−166 °C; IR (KBr) ν
= 3025, 2980, 2848, 1603, 1509, 1338,
max
1245, 1196, 1068 cm−1; 1H NMR (DMSO, 400 MHz, TMS) δ: 8.23−
8.18 (m, 5H), 8.10 (d, J = 8.64 Hz, 1H), 7.88 (d, J = 7.84 Hz, 1H),
7.79−7.76 (m, 2H), 7.70−7.62 (m, 3H), 7.54−7.49 (m, 4H), 7.37−
7.31 (m, 3H), 7.28−7.23 (m, 3H), 5.51 (s, 2H); MS (EI) m/z: 525.3
[M + H+]. 13C NMR (CDCl3, 100 MHz, TMS) δ: 165.1, 164.9, 153.4,
152.3, 150.5, 143.0, 136.0, 133.8, 133.7, 130.5, 130.3, 130.2, 129.3,
129.2, 128.7, 128.6, 127.9, 127.6, 127.1, 123.4, 123.0, 122.5, 122.3,
120.0, 110.6, 48.0; MS (EI) m/ z: 517.5 (M + H)+. Anal. Calcd For
C34H24N2O4: C, 77.85; H, 4.61; N, 5.34; O, 12.20%. Found: 77.86; H,
4.63; N, 5.35%.
imidazol-1-yl)methyl)phenol (Table 4, Entry 19). White solid
(0.91 g, 90%); mp = 200−201 °C; IR (KBr) ν
= 3162, 2948,
max
1
27866, 1748, 1721, 1623, 1472, 1258, 1006 cm−1; H NMR (CDCl3 ,
400 MHz, TMS) δ: 9.56 (s, 1H, OH), 8.96 (s, 1H, OH), 7.65−7.67
(m, 1H), 7.46−7.49 (m, 1H), 7.17−7.23 (m, 4H), 6.92 (d, J = 8.0 Hz,
1H), 6.62−6.67 (m, 2H), 6.36−6.38 (m, 1H), 5.42 (s, 2H), 3.91−3.96
(m, 2H), 3.81−3.86 (m, 2H), 1.22−1.30 (m, 6H); 13C NMR (CDCl3,
100 MHz, TMS) δ: 154.0, 148.9, 147.2, 147.1, 146.6, 142.9, 136.4,
128.3, 122.7, 122.5, 122.3, 121.5, 119.3, 119.0, 116.1, 116.0, 114.5,
112.2, 111.3, 64.2, 47.7, 15.1. MS (APCI) m/z: 405.5 (M + H)+;
10165
dx.doi.org/10.1021/jo301793z | J. Org. Chem. 2012, 77, 10158−10167

The Journal of Organic Chemistry
Article
HRMS (ESI) m/z calcd for C24H24N O4Na+ [M + Na+], 427.1628;
Found 427.1625,
AUTHOR INFORMATION
Corresponding Author
*Tel: 91-(0)-172 2214683; fax: 91-(0)-172 2214692; e-mail:
akchakraborti@niper.ac.in; akchakraborti@rediffmail.com.
2
■
2-(Pyridin-2-yl)-1-(pyridin-2-ylmethyl)-1H-benzimidazole
(Table 4, Entry 20). White solid (0.26 g, 93%); mp = 129−130 °C;
IR (KBr) νmax = 3026, 2985, 2856, 1620, 1595, 1463, 1445, 1389,
1
1285, 1046 cm−1; H NMR (CDCl3 , 400 MHz, TMS) δ: 8.60−8.57
Notes
(m, 2H), 8.49−8.46 (m, 1H), 7.88−7.82 (m, 2 H), 7.49 (dt, J = 7.7
and 1.8 Hz, 1H), 7.38−7.36 (m, 1H), 7.33−7.24 (m, 3H), 7.16−7.13
(m, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.30 (s, 2H); MS (APCI) m/z:
287.3 (M + H)+.10e
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for Senior Research Fellowship (R.C. and
D.N.K.) and Research Associateship (D.K.) from CSIR, New
Delhi, India.
2-(Furan-2-yl)-1-(furan-2-ylmethyl)-1H-benzimidazole
(Table 4, Entry 21). White solid (0.25 g, 93%); mp = 94−95 °C ; IR
(KBr) νmax = 3091, 2895, 1605, 1514, 1450, 1375, 1106, 1056 cm−1;
1H NMR (CDCl3 , 400 MHz, TMS) δ: 7.79−7.77 (m, 1H), 7.65 (s,
1H), 7.51−7.49 (m, 1H), 7.33−7.29 (m, 3H), 7.21 (d, J = 3.4 Hz,
1H), 7.61(t, J = 1.7 Hz, 1H), 6.28−6.23 (m, 2H), 5.64 (s, 2H); MS
(APCI) m/z: 265.3 (M + H)+.10e
REFERENCES
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2-(Thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-benzimida-
zole (Table 4, Entry 22). White solid (0.27 g, 92%); mp = 146−147
°C; IR (KBr) νmax = 3024, 2884, 1615, 1525, 1425, 1362, 1282, 1161,
1
1052 cm−1; H NMR (CDCl3, 400 MHz, TMS) δ: 7.84−7.82 (m,
1H), 7.52 (dd, J = 5.1 and 1.0 Hz, 1H), 7.47 (dd, J = 3.7 and 1 Hz,
1H), 7.38−7.36 (m, 1H), 7.33−7.28 (m, 2H), 7.24 (dd, J = 5.2 and 1.2
Hz, 1H), 7.15−7.13 (m, 1H), 6.95−6.93 (m, 1H), 6.87−6.86 (m, 1H),
5.71 (s, 2H); MS (APCI) m/z: 297.2 (M + H)+.10o
1-((1H-Indol-3-yl)methyl)-2-(1H-indol-3-yl)-1H-benzimida-
zole (Table 4, Entry 23). Brown solid (0.32 g, 89%); mp = 254−256
°C; IR (KBr) νmax = 3025, 2956, 1610, 1590, 1356, 1255, 1101, 1058
cm−1; 1 H NMR (DMSO, 400 MHz, TMS) δ: 11.66 (s, 1H), 11.00 (s,
1H), 8.31 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.67 (d, J = 7.1 Hz, 1H),
7.54 (d, J = 7.1 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.1 Hz,
1H), 7.26−7.13 (m, 5H), 7.03−7.01 (m, 2H), 6.83 (d, J = 7.4 Hz,
1H), 5.82 (s, 2H); MS (APCI) m/z: 363.2 (M + H)+.10f
Satog, T. Bioorg. Med. Chem. 2000, 8, 373. (f) Antibacterial: Goker,
̈
H.; Kus,
̧ C.; Boykin, D. W.; Yildiz, S.; Altanlar, N. Bioorg. Med. Chem.
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Hwu, J. R.; Singha, R.; Hong, S. C.; Chang, Y. H.; Das, A. R.; Vliegen,
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2-(Naphthalen-2-yl)-1-(naphthalen-2-ylmethyl)-1H-benzimi-
dazole (Table 4, Entry 24). White solid (0.35 g, 92%); mp = 124−
126 °C; IR (KBr) ν
= 3055, 2899, 1602 1438, 1370, 1324, 1252,
max
1145 cm−1; 1H NMR (CDCl3 , 400 MHz, TMS) δ: 8.20 (S, 1H), 7.94
(d, J = 8 Hz, 1H), 7.91−7.83 (m, 5H), 7.75−7.70 (m, 2H), 7.57 (s,
1H), 7.55−7.46 (m, 4H), 7.37−7.23 (m, 4H), 5.67 (s, 2H); MS
(APCI) m/z: 385.3 (M + H)+.10g
1-Cinnamyl-2-styryl-1H-benzimidazole (Table 4, Entry 25).
Light red color oil (0.30 g, 90%); 1H NMR (CDCl3, 400 MHz, TMS)
δ: 8.00 (d, J = 15.8 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 7.3
Hz, 2H), 7.39−7.20 (m, 11H), 7.09 (d, J = 15.8 Hz, 1H), 6.44−6.31
(m, 2H), 5.03 (d, J = 4.7 Hz, 2H); MS (EI) m/z: 336.2 (M + H)+.21
2-Cyclohexyl-1-(cyclohexylmethyl)-1H-benzimidazole
(Table 4, Entry 23). White solid (0.27 g, 91%); mp = 91−92 °C; IR
̌ ́
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1
(KBr) νmax = 3011, 2956, 1611, 1445, 1325, 1228, 1156 cm−1; H
NMR (CDCl3 , 400 MHz, TMS) δ: 7.76−7.71 (m, 1H), 7.31−7.27
(m, 1H), 7.23−7.18 (m, 2H), 3.91 (d, J = 7.4 Hz, 2H), 2.81−2.77 (m,
1H), 1.94−1.62 (m, 13H), 1.43−1.38 (m, 3H), 1.19−1.15 (m, 3H),
1.09−1.03 (m, 2H); MS (APCI) m/z: 297.4 (M + H)+.10j
1-Butyl-2-propyl-1H-benzimidazole (Table 4, Entry 27).
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̀
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White solid (0.19 g, 89%); mp = 128−130 °C; IR (KBr) ν
=
max
3035, 2868, 1610, 1518, 1416, 1259, 1186, 1065 cm−1; 1H NMR
(CDCl3 , 400 MHz, TMS) δ: 7.75−7.71 (m, 1H), 7.33−7.29 (m, 1H),
7.26−7.22 (m, 2H), 4.10 (t, J = 7.48 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H),
1.99−1.90 (m, 2H), 1.83−1.75 (m, 2H), 1.46−1.36 (m, 2H), 1.08 (t, J
= 7.4 Hz, 3H), 0.98 (t, J = 7.3 Hz, 3H). MS (EI) m/z: 217.2 (M +
10l
H)+.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of spectra for all compounds.. This material is available
free of charge via the Internet at http://pubs.acs.org.
10166
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Article
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̃
affords 3a and 4a in 20% and 15% yields, respectively, at rt. The use of
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10167
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