A versatile method for the synthesis of benzimidazoles from o-nitroanilines and aldehydes in one step via a reductive cyclization

Article abstract of DOI:10.1055/s-2004-834926

A highly efficient and versatile method for the synthesis of benzimidazoles was achieved in one step via the Na₂S₂O₄ reduction of o-nitroanilines in the presence of aldehydes. Heating a solution of o-nitroaniline (Ic) and an aldehyde in EtOH or another appropriate solvent, in the presence of aqueous or solid Na₂S₂O₄, provided facile access to a series of 2-substituted N-H benzimidazoles 5a-m containing a wide range of functional groups not always compatible with the existing synthetic methods. This methodology has also been applied to the regioselective synthesis of N-alkyl and N-aryl benzimidazoles 6a-f via the cyclization of the corresponding N-substituted nitroanilines 13a-e, respectively. In addition, the method was applied successfully to the synthesis of other imidazole containing heterocyclic ring systems such as 1H-imidazo[4,5-b]pyridines 14a,b and 1H-imidazo[4,5-f]quinoline 15.

Full text of DOI:10.1055/s-2004-834926

PAPER
47
A Versatile Method for the Synthesis of Benzimidazoles from o-Nitroanilines
and Aldehydes in One Step via a Reductive Cyclization
B
enzimidazoles in
o
One Step
f
ro
n
m
o
-Nitroan
g
ilines and
A
l
a
s
i Yang,*1 Demosthenes Fokas,* Jingzhou Li, Libing Yu, Carmen M. Baldino
Department of Chemistry, ArQule Inc, 19 Presidential Way, Woburn, MA 01801, USA
Fax +1(781)3766019; E-mail: dfokas@arqule.com
Received 26 April 2004; revised 5 June 2004
lactones requires the use of strong mineral acids such as
Abstract: A highly efficient and versatile method for the synthesis
of benzimidazoles was achieved in one step via the Na2S2O4 reduc-
tion of o-nitroanilines in the presence of aldehydes. Heating a solu-
tion of o-nitroaniline (1c) and an aldehyde in EtOH or another
hydrochloric acid, sulfuric acid, hot glacial acetic acid or
polyphosphoric acid under very high temperatures, condi-
tions not fully compatible with a broad range of functional
appropriate solvent, in the presence of aqueous or solid Na2S2O4, groups and desirable substrates. Aromatic esters require
provided facile access to a series of 2-substituted N-H benzimida-
temperatures of up to 250–300 °C, thus rendering the syn-
thesis of 2-aryl benzimidazoles almost impractical.4 How-
zoles 5a–m containing a wide range of functional groups not always
compatible with the existing synthetic methods. This methodology
ever, the reaction of aromatic esters with arylenediamines
has also been applied to the regioselective synthesis of N-alkyl and
N-aryl benzimidazoles 6a–f via the cyclization of the corresponding
N-substituted nitroanilines 13a–e, respectively. In addition, the
under Weinreb conditions could provide access to 2-aryl
benzimidazoles.5 From the acid anhydrides of monobasic
acids, only acetic anhydride has been practically used in
the preparation of 2-methyl benzimidazoles. Cyclic anhy-
drides of dibasic acids have also been utilized in the syn-
thesis of benzimidazoles, although high temperatures and
strong acids are usually required to convert the intermedi-
ate N-(o-aminopheny)-imide into the desired benzimida-
method was applied successfully to the synthesis of other imidazole
containing heterocyclic ring systems such as 1H-imidazo[4,5-b]py-
ridines 14a,b and 1H-imidazo[4,5-f]quinoline 15.
Key words: benzimidazoles, reductive cyclization, sodium
dithionite, imidazopyridines, imidazoquinolines
zole.6 In addition,
a
mixture of regio-isomeric
benzimidazoles could result from the reaction of non-
symmetric anhydrides and arylenediamines.
Benzimidazole containing structures have been well doc-
umented to exhibit a wide range of biological properties.
This class of molecules has found commercial applica-
tions in several therapeutic areas such as anti-ulcerative,
anti-hypertensive, antiviral, antifungal, anti-tumor, and
antihistaminic agents as well as antihelminthic agents in
veterinarian medicine.2 Medicinal chemists consider
these heterocycles privileged structures. Indeed, the de-
velopment of new synthetic methods, which could render
accessible chemistry space currently not attainable by ex-
isting methods, would be of considerable importance to
the chemistry community.
Also, the reaction of diamine 1a with amides7 and nitriles8
at 200–250 °C, in the presence of HCl could afford 2-sub-
stituted benzimidazoles with the general structure 5 via
the cyclization of intermediate amidine 3a (Scheme 1,
route b). Alternatively, the reaction of diamine 1a with an
imidate could afford benzimidazole 5 as well, upon for-
mation and subsequent cyclization of amidine 3a under
milder conditions.9 Although the imidate route could pro-
vide access to a diverse set of 2-substituted benzimid-
azoles starting from several commercially available
aliphatic and aromatic nitriles, the hydroscopic nature of
the intermediate imidates might be of concern, particular-
ly in a high throughput set-up. The palladium catalyzed
intramolecular N-arylation reaction of o-bromophenyl-
amidine precursors of type 3b, resulting from the assisted
POCl3 condensation of bromoaniline 1b and an amide,
has been recently developed providing entry to N-substi-
tuted benzimidazoles with general structure 6.10 Despite
the somewhat harsh conditions required to generate the in-
termediate amidine precursors, this method successfully
addresses the regioselective synthesis of N-substituted
benzimidazoles which currently constitutes a limitation of
many other approaches.
The most popular synthetic approaches generally involve
the condensation of an arylenediamine with a carbonyl
equivalent (Scheme 1).3 For example, the reaction of
arylenediamine 1a with a carboxylic acid or acid chloride
results in intermediate amide 2. The latter in turn could
undergo a cyclodehydration reaction under strong acidic
or alternatively under harsh dehydrating conditions, often
at elevated temperatures, in order to afford benzimidazole
5 (Scheme 1, route a). Similarly, esters, lactones and an-
hydrides could generate benzimidazoles via the cycliza-
tion of amide 2, although their scope might be limited
given the rather harsh reaction conditions required and the
poor diversity profile of the final products. For instance,
the reaction of arylenediamines with aliphatic esters and
Aldehydes and, to a lesser extent, ketones can also afford
benzimidazoles when they are condensed with arylenedi-
amines (Scheme 1, route c). Although the reaction of ke-
tones with arylenediamine 1a in the presence of HCl at
250–300 °C can yield benzimidazole 5 by the aromatiza-
SYNTHESIS 2005, No. 1, pp 0047–0056
x
x
.
x
x
.2
0
0
4
Advanced online publication: 24.11.2004
DOI: 10.1055/s-2004-834926; Art ID: M02904SS
© Georg Thieme Verlag Stuttgart · New York

48
D. Yang et al.
PAPER
(R2CO)2O
R2CO2R'
R2CO2H
R2COCl
R2
O
NH
NH2
R1
route a
Cyclization
Cyclization
2
R2(C=NH)OMe
R2CONHR3
R2CN
R2
NHR3
H
N
NH2
N
N
R2
R1
R2
R1
R1
R1
route b
N
N
X
X
R3
3a X = NH2, R3 = H
3b X = Br
1a X = NH2
1b X = Br
1c X = NO2
6
5
Reductive
Cyclization
route d
Oxidation
Elimination
R2
R3
H
N
R2
R3
R2
N
O
R1
R1
route c
N
Z
NO2
7
4a Z = H
4b Z = H, R3 = H
Scheme 1 Common strategies for the synthesis of benzimidazoles
tion of intermediate benzimidazoline 4a, their use has preparation and isolation of the corresponding N-ben-
been rather limited.3a,11 Furthermore, since aromatization zylidene-2-nitroanilines prior to subjecting them to cy-
of benzimidazoline 4a occurs via the elimination of an clization conditions. Herein, we report the results of our
alkyl group, a mixture of benzimidazoles could result studies describing the development of a versatile method
from non-symmetric ketones. Alternatively, aldehydes for the synthesis of benzimidazoles in one step, whereby
have been used more extensively in the preparation of 2- benzimidazoles were directly derived from o-nitroanilines
substituted benzimidazoles according to Weidenhagen’s and aldehydes, via a reductive cyclization without the
method.12 For example, condensation of diamine 1a with need for the preparation or isolation of any intermediate
an aldehyde, followed by oxidation of the intermediate agents.
benzimidazoline 4b could afford benzimidazole 5 as well.
While the oxidation can proceed spontaneously by dispro-
portionation, this can lead to the occurrence of side prod-
The synthesis of benzimidazoles from aldehydes and o-ni-
troanilines via the in situ reduction of o-nitroanilines was
thought to constitute an appealing method, as our premise,
ucts. Oxidative methods usually require heating in
with the potential of becoming amenable to high through-
nitrobenzene or DMF at elevated temperatures, as well as
put solution phase parallel synthesis, should the appropri-
the use of metal ions, iodine, organic oxidants or inorgan-
ate reducing agent be utilized. Although a few methods
describing the synthesis of benzimidazoles from o-nitro-
ic sulfites under heating.13 However, one mild set of oxi-
dation conditions utilizing oxone® has been recently
anilines and aldehydes via a transition metal-catalyzed re-
described for the synthesis of N-substituted and N-H
ductive cyclization have been reported in the literature,
benzimidazoles.14
their scope has been proven to be rather limited.19 For in-
A method which could be a viable alternative to the wide- stance, the synthesis of 2-alkyl benzimidazoles has been
ly used arylenediamine based synthetic methods, although reported on the surface of a ZnO or TiO2 semiconductor,
not studied in depth to date according to our knowledge, through a reductive cyclization pathway, during the pho-
employs the reductive cyclization of N-benzylidene-2-ni- tolysis of a primary alcohol solution of a nitroaniline.19a
troanilines 7 (R2 = Ar), prepared from o-nitroaniline (1c) An oxidation-reduction mechanism is postulated where
and benzaldehydes (Scheme 1, route d). Triethylphos- the alcohol is photocatalytically oxidized to the aldehyde,
phite,15 triruthenium dodecacarbonyl16 in the presence of followed by condensation with o-nitroaniline (1c) to form
carbon monoxide, and recently, phenylmagnesium the corresponding imine 7 (Scheme 2). Subsequent four-
chloride17 have been successfully utilized as the reducing electron reduction of the nitro group, which results in hy-
agents for this transformation. The reaction presumably droxylamine 8, followed by cyclization to benzimidazo-
proceeds via an in situ aryl nitro reduction, followed by an line 4c and consequent dehydration, could account for the
intramolecular cyclization,18 to afford benzimidazole 5 formation of benzimidazole 5. Although this method leads
(R2 = Ar). Even though this strategy could obviate the to the exclusive formation of 2-alkyl benzimidazoles in
preparation and isolation of the intermediate arylenedi- high yield, it is limited only to the preparation of 2-methyl
amines, especially those that are known to be water-solu- and 2-ethyl benzimidazoles. When a primary alcohol larg-
ble or prone to air-oxidation, it would still require the er than EtOH or PrOH was used as the solvent during the
Synthesis 2005, No. 1, 47–56 © Thieme Stuttgart · New York

PAPER
Benzimidazoles in One Step from o-Nitroanilines and Aldehydes
49
photolysis of a nitroaniline, the reaction was found to pro- Our initial results showed that when a solution of a nitro-
ceed very slowly. Furthermore, this methodology fails to aniline (1 equiv) and an aldehyde (1 equiv) in EtOH was
address the synthesis of 2-aryl benzimidazoles and is not treated with 3 equivalents of a freshly prepared23 aqueous
suitable for high throughput synthesis.
solution of Na2S2O4 at 70 °C for 5 hours, the desired benz-
imidazoles with general structure 5 were formed in a
straightforward manner (Table 1). The products were eas-
ily isolated in good yields and high purities by filtration,
after cooling and neutralizing the reaction mixture with
aqueous ammonia, or by silica gel flash chromatography
when the products did not readily precipitate. The chem-
istry worked well with both aliphatic (entries 1 and 2) and
aromatic aldehydes (entries 3–13), including heterocyclic
aldehydes (entries 4–6). Substituted o-nitroanilines also
performed well, under these reaction conditions, provid-
ing selective reduction of the nitro group in the presence
of a number of other substituents (entries 7–13). The reac-
tion afforded reproducible yields on scales ranging from
200 mmol, typical of high throughput synthesis, to multi-
gram scale, as was illustrated through the synthesis of the
benzimidazole 5l (entry 12) on a 25 g scale.
By application of the same strategy (Scheme 2), a mix-
ture of monosubstituted and 1,2-disubstituted benzimida-
zoles 5 (R1 = H, R2 = Ar) and 11 (R1 = H, R2 = Ar)
respectively, has been synthesized from o-nitroaniline and
benzaldehydes, in the presence of Zn metal and 2-bromo-
2-nitropropane in MeOH–CH2Cl2 at room temperature.19b
Based on GC/MS data, it was proposed that entry to benz-
imidazole 5 might involve the intermediacy of primary
amine 9, the six-electron reduction product of nitroimine
7, and subsequently the oxidation of the Weidenhagen
benzimidazoline 4b. Alternatively, access to the disubsti-
tuted benzimidazole 11 was rationalized via the cycliza-
tion of intermediate diimine 10,20 the condensation
product of primary amine 9 with another aldehyde mole-
cule. The difficulty in controlling the formation of the un-
desired 1,2-disubstituted benzimidazoles coupled with the
absence of data supporting the use of aliphatic aldehydes Similarly, N-substituted benzimidazoles with the general
has rendered this reducing system less attractive for fur- structure 6 were efficiently synthesized in one pot from
ther investigation.
the corresponding N-substituted nitroanilines 13 through
the application of this methodology, as shown in Table 2.
The requisite N-alkyl nitroanilines 13a,b were prepared in
situ by heating a mixture of the corresponding 1-fluoro-2-
nitrobenzene 12 and a primary amine in DMSO at 80 °C.
Subsequent treatment of the DMSO solution of the result-
ing N-alkyl nitroaniline with a solution of an aldehyde in
EtOH and solid24 Na2S2O4 at 80 °C for 5 hours afforded
the N-alkyl benzimidazoles 6a–6c in good yields. Unlike
the N-alkylation of non-symmetric benzimidazoles,
which usually results in a mixture of regioisomers, appli-
cation of this methodology to substituted N-alkyl nitro-
anilines led to the regioselective formation of N-alkylated
non-symmetric benzimidazoles (entries 2 and 3).
We surmised that if disubstituted benzimidazole 11 result-
ed from the formation and cyclization of diimine 10, then
the reduction of hydroxylamine21 intermediate 8 to 9
should compete with its cyclization to benzimidazoline
4c, the precursor of 5. Therefore, by controlling the reduc-
tion of nitroimine 7 to hydroxylamine 8 through the ap-
propriate choice of a reducing system, the generation of
benzimidazole 5 would be favored thermodynamically
via the dehydration of intermediate benzimidazoline 4c.
Sodium dithionite (Na2S2O4), a very inexpensive and effi-
cient reducing reagent which acts as a single electron
transfer donor, has been reported to reduce aryl nitro
groups to aryl amines via hydroxylamines by a six-elec-
tron mechanism.22 This observation coupled with the mild N-Aryl nitroanilines 13c–13e, prepared similarly by the
reaction conditions of the method and a demonstrated tol- reaction of the corresponding 1-fluoro-2-nitrobenzene
erance for other functional groups such as halogens, alde- with an aniline in DMSO at 100 °C, also underwent a
hydes, ketones, nitriles and olefins, rendered Na2S2O4 a smooth cyclization under the same conditions, ultimately
prime candidate for our studies.
allowing access to N-aryl benzimidazoles 6d–6f (entries
4–6).10,25
H
N
R2
NH2
N
R2
OH
N
R2CHO
4e-
4H+
R2
R1
R1
R1
R1
N
NO2
NO2
N
H
-H2O
-H2O
OH
1c
7
8
4c
H
N
R2
R1
2H+
2e-
N
5
H
N
Oxidation
N
R2
R2
N
R2
N
N
R2CHO
-H2O
R2
R2
R1
R1
R1
R1
N
H
N
NH2
R2
4b
9
10
11
Scheme 2 Benzimidazoles from o-nitroanilines and aldehydes via an in situ nitro reduction
Synthesis 2005, No. 1, 47–56 © Thieme Stuttgart · New York

50
D. Yang et al.
PAPER
Table 1 Synthesis of N-H Benzimidazoles
cases in order to drive the reaction to completion. Also,
selection of an appropriate solvent was critical in order to
dissolve the starting o-nitroarylamine. For instance, DMF
and DMSO were used as solvents for the synthesis of imi-
dazopyridines (entries 1 and 2) and imidazoquinoline (en-
try 3), respectively. This indicates that the reaction works
in solvents other than EtOH, which constitutes a signifi-
cant advantage when compared to other methods, given
that it is particularly when EtOH is used as the solvent that
solubility problems are encountered with polar substrates.
Generally, the synthesis of imidazopyridines relies on the
preparation of a 2,3-diaminopyridine precursor followed
by condensation of the diamine with a carboxylic acid or
its equivalent under extensive heating.26 These approach-
es are often inefficient and lack regiocontrol. Imidazo-
quinolines could also be obtained by the Doebner–von
Miller quinoline synthesis method which involves the
condensation of 5-aminobenzimidazoles and a,b-unsatur-
ated carbonyl compounds or b-ketoesters, followed by a
thermal cyclization step at high temperatures.27 They
could also be synthesized by the condensation of quino-
line 5,6-diamines with acids or alternatively with alde-
hydes. In the latter, a mixture of mono- and disubstituted
imidazoquinolines is usually observed.28 On the contrary,
our method does not require the synthesis and isolation of
the starting diaminopyridines or aminobenzimidazoles,
intermediates which sometimes might be difficult to iso-
late from aqueous media and might be prone to air oxida-
tion depending on the ring substitution. Furthermore, our
approach does not require excessively high temperatures,
as is usually the case in the Doebner–von Miller quinoline
synthesis.
R2CHO
NH2
H
N
Na2S2O4
R1
R1
R2
EtOH, 70 °C, 5 h
N
NO2
1c
5
Entry R1
R2
Product
Yield (%)a
91
1
H
5a
2
3
H
H
CH3CH2-
5b
5c
80
93
4
5
H
H
5d
5e
95
96
N
N
H
6
H
5f
68
N
H
7
8
7-OHb
5g
5h
5i
80
74
90
80
89
88
MeO
MeO
MeO
MeO
MeO
5-CNb
9
5-CO2Hb
b
10
11
12
5-NH2
5j
5-OHb
5-Clb
5k
5l
In order to test our initial hypothesis postulating a rather
controlled aryl nitro reduction during the reductive cy-
clization step and in order to explain the observed reaction
outcome, we attempted some comparison experiments
with two other reducing reagents which have been widely
used in the aryl nitro group reduction (Table 4).
OMe
Cl
13
5-COPhb
5m
95
a Isolated yields. All compounds produced satisfactory 1H NMR, 13
NMR and mass spectra.
C
For example, when the reaction between o-nitroaniline
and 4-methoxybenzaldehyde was tried under hydrogeno-
lysis conditions (Pd/HCO2H) or with SnCl2,29 a mixture of
monosubstituted and 1,2-disubstituted benzimidazoles
was formed with the disubstituted analog as the major
component (entries 1 and 2). On the contrary, when the
same reaction was subjected to the Na2S2O4 conditions,
the desired monosubstituted benzimidazole was generated
as the sole product in high yield (entry 3). The presence of
a catalytic amount (0.1 equiv) of methyl viologen chlo-
ride, an electron transfer catalyst utilized in the aryl nitro
reduction,22,30 did not alter the reaction outcome. Further-
more, the monosubstituted benzimidazole was maintained
as the only product. Exclusive formation of the monosub-
stituted benzimidazole was also observed even when 6
b Benzimidazole numbering.
The mild reaction conditions involved in this method al-
lows for the use of reagents, which previously failed to
generate the desired products. For example, aldehydes
such as pyrrole-2-carboxaldehyde, 2-methoxybenzalde-
hyde and 4-dimethylaminobenzaldehyde, which failed to
yield the desired benzimidazole under a recently reported
mild oxidation method,14 were successfully incorporated
using our approach. These results clearly demonstrate the
mildness and the versatility of this method, which allows
for a wide range of functional groups and substrates to be
employed, affording otherwise problematic structures.
This methodology could be extended successfully to the equivalents of Na2S2O4 were utilized with or without
synthesis of other imidazole containing heterocyclic ring methyl viologen chloride. Only a trace amount of the dis-
systems such as 1H-imidazo-[4,5-b]pyridines 14a, 14b ubstituted benzimidazole could be detected by LC/MS in
and 1H-imidazo-[4,5-f]quinoline 15 (Table 3). Slightly all cases.
longer reaction times (12–24 h) were necessary for these
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Benzimidazoles in One Step from o-Nitroanilines and Aldehydes
51
Table 2 Regioselective Synthesis of N-Alkyl and N-Aryl Benzimidazoles
H
R2
R3CHO
F
N
R2NH2
Na2S2O4
N
N
R2
NO2
R1
R1
R1
R3
NO2
DMSO, 100 °C
DMSO-EtOH, 80 °C
12
13
6
Entry
1
o-Nitroanilinea
Aldehyde
Product (Yield, %)b
H
N
Et
N
OHC
N
Et
N
N
NO2
6a (88)
13a
2
3
N
H
N
OHC
NO2
F3C
N
N
N
13b
F3C
6b (83)
H
N
OHC
NO2
F3C
N
N
13b
F3C
6c (85)
4
5
H
N
Cl
Cl
OHC
OHC
N
N
NO2
F3C
13c
F3C
6d (90)
H
N
N
OMe
NO2
N
N
N
OMe
13d
13e
6e (91)
6
H
N
OMe
N
OHC
OMe
N
NO2
OMe
N
N
OMe
6f (85)
a Not isolated. Prepared in situ and used directly in the reductive cyclization step.
b Isolated yields. All compounds produced satisfactory 1H NMR, 13C NMR and mass spectra.
However, we found the reaction to be pH dependent. might be required to catalyze the formation of nitroimine
When the reaction was conducted at a basic pH = 8–10, by intermediate 7, thus facilitating the nitro reduction.31
adding 3 equivalents K2CO3, presumably to prevent the
decomposition of Na2S2O4, only a small amount of the
monosubstituted benzimidazole was produced in the same
Should the reaction first involve the intermediacy of o-
phenylenediamine rather than any other intermediate
originating from its precursor o-nitroaniline, its cycliza-
period of time, with no consumption of the starting 4-
tion with 4-methoxybenzaldehyde would presumably al-
methoxybenzaldehyde. This suggests that a slightly acidic
low the exclusive formation of the monosubstituted
pH = 4–6, as is the case with our optimum conditions,
benzimidazole as well. However, a mixture of monosub-
stituted and 1,2-disubstituted benzimidazoles was ob-
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D. Yang et al.
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Table 3 Entry to Imidazopyridines and Imidazoquinolines
Entry
1
o-Nitroarylamine
Aldehyde
Product (Yield, %)a
NO2
H
N
OHC
OMe
OMe
N
NH2
N
N
14a (85)
2
3
Me
Me
H
OHC
OHC
F
NO2
NH2
N
F
N
N
N
14b (89)
OMe
H
N
N
NH2
NO2
N
OMe
N
15 (76)
a Isolated yields. All compounds produced satisfactory 1H NMR, 13C NMR and mass spectra.
ed to assess whether Na2S2O4 by itself or its decomposi-
tion by-products would accelerate the formation of the
monosubstituted benzimidazole via a rapid oxidation of
the intermediate benzimidazoline 4b. A mixture of mono-
and disubstituted benzimidazoles in a 2:1 ratio was ob-
served (entry 6).
Table 4 Comparison Studies with Other Reducing Reagents
N
OMe
N
H
CHO
X
A
B
Conditions
NH2
EtOH, 70 °C
N
N
OMe
Although we were not able to detect any of the putative
hydroxylamine or N-hydroxy benzimidazoline intermedi-
ates during the reductive cyclization of o-nitroaniline and
4-methoxybenzaldehyde, by carefully monitoring the re-
action by LC/MS, the absence of any disubstituted benz-
imidazole in conjunction with the exclusive formation of
the monosubstituted benzimidazole indicates that the cy-
clization step might involve the intermediacy of hydroxyl-
amine 8. This could be the outcome of a controlled
reduction of the nitroimine 7 to hydroxylamine 8 with
Na2S2O4 as the reducing agent.
1 equiv
1 equiv
OMe
Entry
X
Conditions
A
B
Yield (%)a Yield (%)a
1
2
3
4
5
6
NO2
NO2
NO2
NH2
NH2
NH2
10 equiv HCO2H/Pd
6 equiv SnCl2
3 equiv Na2S2O4
-
13
7
25
30
–
90
13
–
25
40
20
In summary, we have found an efficient and versatile
method for the preparation of a series of benzimidazoles
as well of other imidazole containing ring systems, in one
step, by the reduction of o-nitroarylamines in the presence
of aldehydes. This method addresses successfully and uni-
formly not only the synthesis of N-H benzimidazoles, but
the regioselective synthesis of N-alkyl and N-aryl-benz-
imidazoles as well, under one set of conditions. The reac-
tion is readily applicable not only to high throughput
solution phase parallel synthesis,33 but also to large scale
synthesis. Application of this methodology towards the
synthesis of other heterocyclic ring systems is currently
under investigation and will be communicated in due
course.
3 equiv NaHSO3
3 equiv Na2S2O4
40
a Isolated yields.
served after heating o-phenylenediamine with 4-
methoxybenzaldehyde in EtOH at 70 °C (entry 4). The as-
sumption that sodium bisulfite (NaHSO3), the by-product
of the Na2S2O4 aryl nitro reduction, could account for the
exclusive formation of the monosubstituted benzimida-
zole by promoting the condensation of the resulting di-
amine with the aldehyde bisulfite adduct, was also put to
the test.32 When the bisulfite adduct of 4-methoxybenzal-
dehyde was treated with o-phenylenediamine in EtOH at
70 °C, the disubstituted benzimidazole was isolated as the
sole product, presumably via the cyclization of an inter-
mediate diimine 10 (entry 5). Also treating o-phenylene-
diamine with 4-methoxybenzaldehyde, in the presence of
3 equivalents of Na2S2O4 in EtOH at 70 °C, was conduct-
1H NMR spectra were recorded on a 300 MHz Varian FT spectro-
meter. 13C NMR spectra were recorded on a 300 MHz Varian FT
(75.4 MHz) spectrometer. Low resolution mass spectra were re-
corded on a Waters ZQ mass spectrometer with electrospray ioniza-
tion (ESI). HRMS were recorded on a Micromass LCT mass
spectrometer with ESI. TLC was carried out on EM Science pre-
coated silica gel 60F 254 plates. Flash column chromatography was
Synthesis 2005, No. 1, 47–56 © Thieme Stuttgart · New York

PAPER
Benzimidazoles in One Step from o-Nitroanilines and Aldehydes
53
performed with EM Science silica gel 60 (230–400 mesh). All re-
agents were purchased from Aldrich and used without further puri-
fication.
Compound 5f
It was prepared according to method A. Registry Number 3878-23-
7. Spectral data were consistent with those reported in the litera-
ture.37
Method A
This procedure was used for the synthesis of most of the compounds
listed in Table 1. A solution of o-nitroaniline (1.0 mmol) and alde-
hyde (1.0 mmol) in EtOH (4 mL) was treated with 1 M aq Na2S2O4
(3.0 mmol, 3 mL). After heating the reaction mixture at 70 °C for 5
h, it was cooled to r.t. and treated dropwise with 5 N aq NH4OH (2
mL). A precipitate was immediately formed which was then fil-
tered, washed with water (2 × 15 mL) and dried under reduced pres-
sure to afford the desired product in satisfactory purity (95% by
HPLC: UV 254 nm, ELSD). Precipitated compounds with lower
purity were further purified by flash chromatography on silica gel.
2-(4-Methoxyphenyl)-1H-benzimidazol-7-ol (5g)
It was prepared according to method A and isolated as a beige solid
by flash chromatography on silica gel with EtOAc–hexanes (3:1) as
the eluent.
1H NMR (300 MHz, DMSO-d6): d = 9.8 (br s, 1 H), 8.1 (d, J = 8.8
Hz, 2 H), 7.05 (d, J = 9.2 Hz, 2 H), 6.95 (q, J = 9.2, 8.4 Hz, 2 H),
6.55 (dd, J = 1.3, 7.5 Hz, 1 H), 3.83 (s, 3 H).
13C NMR (75 MHz, CD3OD): d = 161.66, 151.04, 146.52, 139.73,
129.01, 128.25, 123.46, 121.95, 114.26, 107.19, 105.10, 54.73.
HRMS: m/z [M + H] calcd for C14H13N2O2: 241.0977; found:
241.0984.
Method B
This procedure utilized the addition of solid sodium dithionite. A
mixture of o-nitroaniline (1.0 mmol) and aldehyde (1.0 mmol) in
EtOH (4 mL) was treated with solid Na2S2O4 (3.0 mmol) and was
then heated at 80 °C for 12 h. After removal of the solvent under re-
duced pressure, the resulting residue was partitioned between
EtOAc (20 mL) and aq NH4OH (2 N, 5 mL). The organic layer was
isolated and the remaining aqueous layer was washed with EtOAc
(2 × 20 mL). The combined organic layer was dried over Na2SO4
and concentrated under reduced pressure. The resulting crude prod-
uct was then purified by flash chromatography on silica gel.
Compound 5h
It was prepared according to method A. Registry Number 167959-
14-0. Spectral data were consistent with those reported in the liter-
ature.38
Compound 5i
It was prepared according to method A. Registry Number 174422-
17-4. Spectral data were consistent with those reported in the liter-
ature.39
2-(4-Methoxyphenyl)-1H-benzimidazol-5-amine (5j)27a
It was prepared according to method B and isolated as a brown solid
by flash chromatography on silica gel with EtOAc as the eluent.
Registry Number 40655-15-0.
1H NMR (300 MHz, CDCl3): d = 7.95 (d, J = 8.4 Hz, 2 H), 7.40 (d,
J = 8.4 Hz, 1 H), 6.90 (d, J = 8.7 Hz, 2 H), 6.78 (s, 1 H), 6.62 (dd,
J = 1.2, 8.1 Hz, 1 H), 3.80 (s, 3 H).
Method C
This procedure was used for the one-pot synthesis of N-alkyl and N-
aryl benzimidazoles from the corresponding 1-fluoro-2-nitroben-
zenes. A solution of 1-fluoro-2-nitrobenzene (1.0 mmol) and amine
(1.0 mmol) in DMSO (1 mL) was heated at 100 °C for 10 h. After
cooling to r.t., addition of aldehyde (1.0 mmol) in EtOH (4 mL) and
solid Na2S2O4 (3.0 mmol) followed, and the reaction mixture was
heated at 80 °C for 12 h. The crude reaction mixture was then con-
centrated and treated dropwise with 5 N NH4OH (2 mL), resulting
in the formation of a precipitate which was then filtered, washed
with water (2 × 15 mL) and dried under reduced pressure to afford
the desired product in satisfactory purity (95% by HPLC: UV 254
nm, ELSD). Precipitated compounds with lower purity were further
purified by flash chromatography on silica gel.
13C NMR (75 MHz, CDCl3): d = 161.01, 151.42, 142.79, 139.05,
134.56, 128.14, 122.84, 116.73, 114.60, 112.83, 99.13, 55.53.
HRMS: m/z [M + H] calcd for C14H14N3O: 240.1137; found:
240.1142.
2-(4-Methoxyphenyl)-1H-benzimidazol-5-ol (5k)
It was prepared according to method B and isolated as a white solid
by flash chromatography on silica gel with EtOAc–hexanes (3:1) as
the eluent.
1H NMR (300 MHz, CD3OD): d = 7.95 (d, J = 8.8 Hz, 2 H), 7.40 (d,
J = 8.8 Hz, 1 H), 7.05 (d, J = 8.3 Hz, 2 H), 6.95 (s, 1 H), 6.78 (d,
J = 8.3 Hz, 1 H), 3.83 (s, 3 H).
Compound 5a
It was prepared according to method A. Registry Number 36947-
70-3. Spectral data were consistent with those reported in the liter-
ature.34
Compound 5b
13C NMR (75 MHz, CD3OD): d = 161.59, 154.02, 151.50, 138.67,
133.31, 127.90, 121.99, 115.28, 114.30, 112.22, 98.77, 54.72.
It was prepared according to method B. Registry Number 1848-84-
6. Spectral data were consistent with those reported in the litera-
ture.19a
HRMS: m/z [M + H] calcd for C14H13N2O2: 241.0977; found:
241.0980.
Compound 5c
It was prepared according to method A. Registry Number 716-79-
0. Spectral data were consistent with those reported in the litera-
ture.35
5-Chloro-2-(2-methoxyphenyl)-1H-benzimidazole (5l)
It was prepared according to method A and isolated as a beige solid.
Registry Number 133688-90-1. A large-scale synthesis was carried
out as follows:
A solution of 4-chloro-2-nitroaniline (25 g, 0.144 mol) and o-anis-
aldehyde (19.7 g, 0.144 mol) in EtOH (400 mL) was treated with 1
M aq Na2S2O4 (0.432 mol, 432 mL) at r.t. After heating the reaction
mixture at 70 °C for 5 h, it was cooled to r.t. and treated dropwise
with 10 N aq NH4OH (140 mL). A precipitate was immediately
formed which was then filtered, washed with water and dried under
reduced pressure to afford pure product (32.7 g, 88%); 95% by
HPLC: UV 254 nm, ELSD) as a beige solid.
Compound 5d
It was prepared according to method A. Registry Number 1137-67-
3. Spectral data were consistent with those reported in the litera-
ture.36
Compound 5e
It was prepared according to method A. Registry Number 166670-
56-0. Spectral data were consistent with those reported in the liter-
ature.5
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54
D. Yang et al.
PAPER
1H NMR (300 MHz, CD3OD): d = 7.66–7.50 (m, 4 H), 7.42 (t, J =
7.9 Hz, 1 H), 7.22 (dd, J = 1.7, 8.3 Hz, 1 H), 7.05 (m, 1 H), 3.87 (s,
3 H).
13C NMR (75 MHz, DMSO-d6): d = 159.10, 137.73, 135.27,
129.74, 129.19, 127.55, 126.15, 123.45, 121.91, 114.19, 112.28,
79.95, 46.67, 35.06, 11.37, 7.69.
13C NMR (75 MHz, CD3OD): d = 160.50, 153.35, 139.88, 137.47,
130.54, 130.05, 128.23, 123.12, 118.86, 116.40, 115.59, 114.53,
111.79, 54.69.
HRMS: m/z [M + H] calcd for C19H18F3N2: 331.1422; found:
331.1430.
1-(3-Chlorophenyl)-2-(3-methylphenyl)-5-(trifluoromethyl)-
1H-benzimidazole (6d)
HRMS: m/z [M + H] calcd for C14H12ClN2O: 259.0638; found:
259.0638.
It was prepared according to method C and isolated as a yellow sol-
id.
1H NMR (300 MHz, CDCl3): d = 8.19 (s, 1 H), 7.59 (dd, J = 1.8, 8.8
Hz, 1 H), 7.45 (d, J = 8.8 Hz, 1 H), 7.40–7.15 (m, 7 H), 7.05 (m, 1
H), 2.20 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 154.87, 142.76, 137.99, 137.56,
137.13, 135.48, 130.90, 130.88, 130.86, 130.37, 129.20, 128.99,
126.86, 126.17, 125.95, 125.74, 125.03, 120.70, 118.16, 110.94,
20.25.
[2-(2-Chlorophenyl)-1H-benzimidazol-5-yl](phenyl)metha-
none (5m)
It was prepared according to method B and isolated as a white solid
by flash chromatography on silica gel with EtOAc–hexanes (1:1) as
the eluent.
1H NMR (300 MHz, CDCl3): d = 8.32 (m, 1 H), 8.12 (s, 1 H), 7.82
(m, 3 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.60 (m, 1 H), 7.48 (m, 3 H),
7.40 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 196.98, 151.75, 138.44, 132.87,
132.48, 132.36, 131.70, 131.64, 130.99, 130.24, 128.46, 128.12,
127.83, 125.69.
HRMS: m/z [M + H] calcd for C21H15ClF3N2: 387.0876; found:
387.0877.
4-[2-(4-Methoxyphenyl)-1H-benzimidazol-1-yl]-N,N-dimethyl-
aniline (6e)
It was prepared according to method C and isolated as a violet solid.
HRMS: m/z [M + H] calcd for C20H14ClN2O: 333.0794; found:
333.0788.
4-(1-Ethyl-1H-benzimidazol-2-yl)-N,N-dimethylaniline (6a)
It was prepared according to method A and isolated as a brown solid
by flash chromatography on silica gel with EtOAc–hexanes (2:1) as
the eluent.
1H NMR (300 MHz, DMSO-d6): d = 7.70 (d, J = 7.0 Hz, 1 H), 7.51
(d, J = 8.8 Hz, 2 H), 7.20 (m, 4 H), 7.05 (d, J = 8.4 Hz, 1 H), 6.91
(d, J = 8.8 Hz, 2 H), 6.80 (d, J = 8.8 Hz, 2 H), 3.75 (s, 3 H), 2.96 (s,
6 H).
1H NMR (300 MHz, CDCl3): d = 7.80 (m, 1 H), 7.60 (d, J = 8.8 Hz,
2 H), 7.38 (m, 1 H), 7.25 (m, 2 H), 6.80 (d, J = 8.8 Hz, 2 H), 4.25
(q, J = 7.0 Hz, 2 H), 3.00 (s, 6 H), 1.45 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 160.73, 152.60, 150.71,
143.10, 138.52, 131.08, 128.71, 125.30, 123.29, 123.09, 122.90,
119.54, 114.48, 113.27, 111.02, 55.90, 40.62.
13C NMR (75 MHz, CDCl3): d = 154.49, 151.38, 143.40, 135.76,
130.42, 122.26, 119.61, 117.76, 112.04, 109.86, 40.45, 39.85,
15.48.
HRMS: m/z [M + H] calcd for C22H22N3O: 344.1763; found:
344.1772.
2-(4-Methoxyphenyl)-1-(6-methoxypyridin-3-yl)-1H-benzimi-
dazole (6f)
It was prepared according to method C and isolated as a violet solid.
HRMS: m/z [M + H] calcd for C17H20N3: 266.1657; found:
266.1655.
1-(2-Phenylethyl)-2-pyridin-2-yl-5-(trifluoromethyl)-1H-benz-
imidazole (6b)
It was prepared according to method C and isolated as a yellow solid
by flash chromatography on silica gel with EtAOc–hexanes (1:6) as
the eluent.
1H NMR (300 MHz, CDCl3): d = 8.72 (d, J = 4.8 Hz, 1 H), 8.28 (d,
J = 7.9 Hz, 1 H), 8.11 (s, 1 H), 7.81 (ddd, J = 1.7, 7.9 Hz, 1 H), 7.52
(dd, J = 1.3 7.8 Hz, 1 H), 7.42 (d, J = 8.8 Hz, 1 H), 7.37 (m, 1 H),
7.22 (m, 3 H), 7.10 (m, 2 H), 5.05 (t, J = 7.5 Hz, 2 H), 3.18 (t, J =
7.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 152.02, 150.20, 148.88, 142.18,
138.52, 138.19, 137.17, 128.98, 128.80, 126.98, 125.46, 125.10,
124.39, 123.27, 120.25, 118.05, 110.66, 47.45, 36.71.
1H NMR (300 MHz, CDCl3): d = 8.20 (s, 1 H), 7.86 (d, J = 7.9 Hz,
1 H), 7.50 (m, 3 H), 7.40–7.12 (m, 3 H), 6.85 (m, 3 H), 4.00 (s, 3 H),
3.80 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 163.86, 160.91, 152.83, 145.67,
143.11, 137.97, 137.58, 131.17, 127.82, 123.49, 123.34, 122.04,
119.90, 114.22, 112.18, 110.20, 55.51, 54.21.
HRMS: m/z [M + H] calcd for C20H18N3O2: 332.1399; found
332.1395.
Compound 14a
It was prepared according to method A. Registry Number 63581-
47-5. Spectral data were consistent with those reported in the liter-
ature.40
HRMS: m/z [M + H] calcd for C21H17F3N3: 368.1374; found:
368.1375.
2-(4-Fluorophenyl)-7-methyl-1H-imidazo[4,5-b]pyridine (14b)
It was prepared according to method A and isolated as a yellow sol-
id by flash chromatography on silica gel with EtOAc–hexanes (2:1)
as the eluent.
1H NMR (300 MHz, DMSO-d6): d = 8.30 (m, 2 H), 8.17 (d, J = 5.3
Hz, 1 H) 7.42 (m, 2 H), 7.05 (d, J = 4.8 Hz, 1 H), 2.60 (s, 3 H).
2-Cyclopropyl-1-(2-phenylethyl)-5-(trifluoromethyl)-1H-benz-
imidazole (6c)
It was prepared according to method C and isolated as a yellow solid
by flash chromatography on silica gel with EtOAc–hexanes (1:6) as
the eluent.
1H NMR (300 MHz, CD3OD): d = 8.02 (s, 1 H), 7.98 (d, J = 8.8 Hz,
1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.21 (m, 3 H), 7.05 (m, 2 H), 4.90 (t,
J = 6.6 Hz, 2 H), 3.30 (t, J = 6.6 Hz, 2 H), 2.21 (m, 1 H), 1.40 (m, 2
H), 1.25 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 165.28, 162.81, 144.37,
129.79, 129.70, 127.04, 127.01, 119.63, 116.75, 116.53, 16.78.
HRMS: m/z [M + H] calcd for C13H11FN3: 228.0937; found:
228.0948.
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Benzimidazoles in One Step from o-Nitroanilines and Aldehydes
55
2-(4-Methoxyphenyl)-1H-imidazo[4,5-f]quinoline (15)28b
It was prepared according to method A. Registry Number 93201-
92-4.
1H NMR (300 MHz, CD3OD): d = 8.81 (br s, 1 H), 8.68 (dd, J = 1.8,
4.4 Hz, 1 H), 7.95 (d, J = 8.8 Hz, 2 H), 7.83 (d, J = 9.2 Hz, 1 H),
7.75 (d, J = 9.2 Hz, 1 H), 7.48 (dd, J = 4.4, 8.3 Hz, 1 H), 6.97 (d,
J = 9.2 Hz, 2 H), 3.78 (s, 3 H).
products by cyclization of these diimines at 350 °C: Ochoa,
C.; Rodriguez, J. J. Heterocycl. Chem. 1997, 34, 1053.
(21) For reduction of nitro groups to hydroxylamines, see:
(a) Rondestvedt, C. S.; Johnson, T. A. Synthesis 1977, 850.
(b) Yanada, K.; Yamaguchi, H.; Meguri, H.; Uchida, S. J.
Chem. Soc., Chem. Commun. 1986, 1655. (c) Feuer, H.;
Bartlett, R. S.; Vincent, B. F.; Anderson, R. S. J. Org. Chem.
1965, 30, 2880.
13C NMR (75 MHz, CD3OD): d = 161.56, 152.08, 147.47, 145.10,
130.63, 128.02, 123.05, 122.06, 120.95, 114.25, 54.67.
(22) Park, K. K.; Oh, C. H.; Joung, W. K. Tetrahedron Lett. 1993,
34, 7445.
(23) Old solutions were ineffective. A fresh solution of sodium
dithionite was used each time as it gradually decomposes in
water.
HRMS: m/z [M + H] calcd for C17H14N3O: 276.1137; found:
276.1136.
(24) Reaction with solid sodium dithionite was found to work as
well as an aqueous solution of the reagent. However, better
results were obtained in some cases utilizing solid sodium
dithionite rather than an aqueous solution.
(25) For other approaches to N-aryl benzimidazoles, see:
(a) Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. J.
Org. Chem. 1995, 60, 5678. (b) Kobayashi, M.; Uneyama,
K. J. Org. Chem. 1996, 61, 3902. (c) Katritzky, A. R.;
Yang, B.; Abonia, R.; Insuasty, B. J. Chem. Res., Synop.
1996, 540. (d) Alberti, A.; Carloni, P.; Greci, L.; Stipa, P.;
Andruzzi, R.; Marrosu, G.; Trazza, A. J. Chem. Soc., Perkin
Trans. 2 1991, 1019.
References
(1) Current address: Donglai Yang, SSCI, Inc., 3065 Kent
Avenue, West Lafayette, IN 47906, USA. E-mail:
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T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893.
(b) Brain, C. T.; Steer, J. T. J. Org. Chem. 2003, 68, 6814.
(11) Elderfield, R. C.; Kreysa, F. J. J. Am. Chem. Soc. 1948, 70,
44.
(12) Weidenhagen, R. Ber. 1936, 69B, 2263.
(13) For oxidative methods, see ref. 14 and references cited
therein.
(14) Beaulieu, P. L.; Haché, B.; von Moos, E. Synthesis 2003,
1683.
(15) Cadogan, J. I. G.; Marshall, R.; Smith, D. M.; Todd, M. J. J.
Chem. Soc. C 1970, 2441.
(16) Tolari, S.; Cenini, S.; Crotti, C.; Gianella, E. J. Mol. Catal.
(26) For a synthesis of imidazopyridines from the ureas of 2,3-
diaminopyridines, see: Senanayake, C. H.; Fredenburgh, L.
E.; Reamer, R. A.; Liu, J.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J. Tetrahedron Lett. 1994, 35, 5775; and
references therein for other approaches.
(27) (a) Ogretir, C.; Kaniskan, N. Turk. J. Chem. 1992, 16, 189.
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J.; Hatton, C. J.; Kohls, R. E. J. Med. Chem. 1978, 21, 298.
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B: Org. Chem. Incl. Med. Chem. 1984, 23, 673. (b) Reddy,
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(29) (a) For a similar one-pot conversion of nitroaniline and
aldehydes to benzimidazoles, in solid phase, using SnCl2 as
the reducing agent, see: Wu, Z.; Rea, P.; Wickham, G.
Tetrahedron Lett. 2000, 41, 9871. (b) Disubstituted
benzimidazoles were also formed as by-products.
(30) For a chemoselective reduction of aromatic nitro groups
with samarium(0) and 1,1-dioctyl-4,4¢-bipyridinium
dibromide, see: Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001,
66, 919.
(31) We observed that the presence of the aldehyde had a
dramatic effect on the reduction of the starting o-nitroaniline
as shown in Scheme 3.
Imine formation could facilitate the aryl nitro group
reduction because of electronic effects. Indeed, the fact that
the corresponding benzimidazole (rather than the arylene
diamine) is captured in high yield as the end product could
indicate that the thermodynamically formed benzimidazole
might be the one driving the nitro reduction.
1994, 87, 203.
(17) Dohle, W.; Staubitz, A.; Knochel, P. Chem.–Eur. J. 2003, 9,
5323.
(18) Cyclization might invoke a nitrene or N-O nitrenoid
intermediate resulting from the deoxygenation of the nitro
group. For more information, see: (a) Sundberg, R. J. J.
Org. Chem. 1965, 30, 3604. (b) Sundberg, R. J.; Yamazaki,
T. J. Org. Chem. 1967, 32, 290. (c) Ref. 17
(19) (a) Wang, H.; Partch, R. E.; Li, Y. J. Org. Chem. 1997, 62,
5222. (b) Kim, B. H.; Han, R.; Han, T. H.; Jun, Y. M.; Baik,
W.; Lee, B. M. Heterocycles 2002, 57, 5. (c) Watanabe, Y.;
Suzuki, N.; Tsuji, Y. Bull. Chem. Soc. Jpn. 1982, 55, 2445.
(20) Diimines of this type were observed as side products in a
recent benzimidazole synthesis. For more information, see
ref. 14. 2,3-Diarylquinoxalines were obtained as by-
NH2
NO2
NH2
NH2
3 equiv Na2S2O4
EtOH, 70 °C
+
SM
O
O
2 : 1
(determined by HPLC and NMR)
NH2
NO2
N
1.0 equiv RCHO
OMe
N
3 equiv Na2S2O4
EtOH, 70 °C
H
O
O
90% (isolated yield)
Scheme 3
Synthesis 2005, No. 1, 47–56 © Thieme Stuttgart · New York

56
D. Yang et al.
PAPER
(32) (a) Ridley, H. F.; Spickett, R. G. W.; Timmis, G. M. J.
Heterocycl. Chem. 1965, 2, 453. (b) Jonas, R.; Klockow,
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Med. Chem. 1993, 28, 129.
(35) Abdelhamid, A. O.; Párkányi, C.; Rashid, S. M. K.; Lloyd,
W. D. J. Heterocycl. Chem. 1988, 25, 403.
(36) Jung, M. H.; Park, J. M.; Lee, I.-Y. C.; Ahn, M. J.
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(33) This method has been routinely applied in our AMAPTM
(Automated Molecular Assembly Plant) for the high
throughput solution phase synthesis of benzimidazole
containing structures. More details will be communicated in
due course.
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Synthesis 2005, No. 1, 47–56 © Thieme Stuttgart · New York