Synthetic utility of catalytic Fe(III)/Fe(II) redox cycling towards fused heterocycles: A facile access to substituted benzimidazole, bis-benzimidazole and imidazopyridine derivatives

Article abstract of DOI:10.1055/s-2000-7111

A catalytic Fe(III)/Fe(II) redox cycling approach has been examined and applied towards synthesis of a wide range of benzimidazole, bis-benzimidazole and imidazopyridine derivatives from oxidative coupling of aromatic ortho-diamines with aromatic as well

Full text of DOI:10.1055/s-2000-7111

1380
PAPER
Synthetic Utility of Catalytic Fe(III)/Fe(II) Redox Cycling Towards Fused
Heterocycles: A Facile Access to Substituted Benzimidazole, Bis-
benzimidazole and Imidazopyridine Derivatives
Malvinder P. Singh,* Sanjita Sasmal, Wei Lu, Manashi N. Chatterjee
Department of Chemistry, 110 Science Place, University of Saskatchewan, Saskatoon, Sask. S7N 5C9, Canada
Fax +1(306)9664730; E-mail: singh@sask.usask.ca
Received 31 March 2000; revised 17 May 2000
reactions of aromatic diamines with carboxylic acids,10 or
Abstract: A catalytic Fe(III)/Fe(II) redox cycling approach has
nitriles and equivalent imidate esters,11 using strongly
acidic conditions, and the applications of oxidative cyclo-
dehydrogenation strategies towards initial condensation
been examined and applied towards synthesis of a wide range of
benzimidazole, bis-benzimidazole and imidazopyridine derivatives
from oxidative coupling of aromatic ortho-diamines with aromatic
as well as heterocyclic aldehydes bearing different types of substit- products from diamines and aryl aldehydes using either
high-boiling oxidant/solvent like nitrobenzene12 or very
uents. This versatile and convenient method has further proven to be
strong oxidants.13 However, we determined during our
particularly useful in expeditiously affording a number of novel bis-
benzimidazole class of Hoechst 33258 analogs towards potential
early attempts that such reported procedures for the prep-
development as fluorescent nucleic acid binding probes. Successful
aration of benzimidazole derivatives were not quite versa-
preparation and characterization of a diverse set of thirty different
tile nor compatible with differently substituted starting
materials, and also posed practical difficulties in the form
of laborious reaction workup protocols. For example, the
use of very high temperatures appeared mandatory for the
PPA-mediated condensation reaction for diamine-carbox-
ylate combinations,10b,c and therefore not suitable for the
compounds targeted in our program, whereas the ni-
trobenzene method required extensive removal (vacuum
distillation followed by chromatography) of nitrobenzene
and aniline (the reaction byproduct).12 In addition, the tar-
geted nitroaryl benzimidazole derivatives (vide infra) did
not seem amenable to the use of nitrobenzene under high
temperatures, due to anilino/amino byproduct formation.
Much to our satisfaction, the presently developed Fe(III)-
mediated oxidative cyclization approach, akin to one of
our previous mechanistic studies of cyclocondensation re-
actions of amines with ortho-quinones,14 has proven to be
more versatile and straightforward towards expeditiously
affording a variety of substituted benzimidazole and imi-
dazopyridine derivatives with ease.
compounds is presented here.
Key words: benzimidazoles, bis-benzimidazoles, imidazopy-
ridines, catalytic redox-cycling, fluorescent probes, heterocycles.
Schiff bases
Fused heterocycles such as benzimidazoles, benzox-
azoles, benzothiazoles, and closely related imidazopy-
ridines, are very useful intermediates for the development
of pharmaceutical compounds,1-3 photochromic dyes,4
and also as molecular probes,5 due to their associated flu-
orescence characteristics. For example, the utility of bis-
benzimidazole class of fluorescent dyes, such as Hoechst
33258 (chemical name: 2-(4-hydroxyphenyl)-5-[5-(4-me-
thyl-1-piperazinyl)-1H-benzimidazol-2-yl]-1H-benzimi-
dazole), is well established in molecular genetics and
cytofluorimetry studies,6 owing to the fact that such com-
pounds bind to selected DNA subsequences with high af-
finity and an accompanying large enhancement of the
observed fluorescence quantum yields.7,8 Synthetic inter-
est in surrogate Hoechst 33258-like structures has been
spurred by their potential gene-targeted biological activi-
ty.2,3 As part of a leading initiative aimed at developing
new benzimidazole-derived analogs of Hoechst 33258
and to seek a better understanding of the structure-fluores-
cence relationships for such compounds, we required a
general procedure applicable to various types of substitu-
tion patterns in benzimidazole derivatives.9 In this study
we wish to report the use of a catalytic redox cycling ap-
proach to the synthesis of various benzimidazole deriva-
tives, based on (Fe(III)/Fe(II))-redox-mediated oxidation
of the Schiff’s base intermediates derived from differently
substituted aromatic ortho-diamines and a variety of aro-
matic and heterocyclic aldehydes.
Our development of this method considered the putative
mechanistic scheme (Scheme 1)12,13 for the generation of
benzimidazoles from initial Schiff’s bases (IIa/b) generat-
ed from diamines and aldehydes, that exist in equilibrium
with the cyclic reduced dihydrobenzimidazoles (III), and
we reasoned that the final aromatization step to benzimi-
dazoles could conceivably be mediated with the use of
transition metal ions as the ultimate oxidants that could
possibly be regenerated in situ with molecular O2 or air
exposure, thereby potentially capable of providing high
catalytic turnover numbers. Judging from the literature
survey, we found that the scarcely reported effectiveness
of Cu(II),15 and Fe(III)16 in mediating oxidative aromati-
zation of Schiff’s base intermediates to benzimidazoles
had not been fully capitalized upon for synthetic purposes,
presumably due to the potential for loss in yields of the
benzimidazole products through their strong coordination
From the synthesis standpoint, there are a number of dif-
ferent methods reported for the preparation of 2-arylben-
zimidazole derivatives, such as cyclocondensation
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Synthetic Utility of Catalytic Fe(III)/Fe(II) Redox Cycling Towards Fused Heterocycles
1381
with the transitional metal ions.17 The conceptual aspects aldehydes in stoichiometric amounts, followed by heating
of the synthetic plan, as applied to the preparation of ben- for a period of 1 hour, and treatment with a catalytic
zimidazole derivatives, are outlined in Scheme 1. Shown amount of FeCl3 (0.01 molar equivalent dissolved in
therein are the initial condensation products, the mono MeCN) under constant O2 bubbling conditions. The
Schiff’s bases present in equilibrium with the cyclic re- benzimidazole products usually precipitate out of solution
duced form that is apparently readily aromatized to the as they are formed, when the reactions are carried out
benzimidazole product via two one-electron oxidation in MeCN, and the reactions are typically complete within
steps. These last steps are catalyzed by Fe(III) and the re- 5−8 h.
duced Fe(II) form is then regenerated as part of the redox
In order to test this procedure for preparative scale appli-
cycling schematic with O2 that can be bubbled constantly
cations, a variety of benzaldehydes bearing electron-do-
through the reaction periods.
nating (Table 1, Entries 1−6) and electron-withdrawing
Our initial set of experiments with 4-(4-methylpiperazi- substituents (Entries 7−12) were successfully employed to
nyl)-1,2-phenylenediamine12b-e and either 2-imidazole- prepare the benzimidazole derivatives 4a−f and 5a−f in
carboxaldehyde18 or 2-pyridinecarboxaldehyde using less high yields. Dimethylformamide proved to be better than
than stoichiometric amounts of Fe(III) (0.25 equiv ferric other polar solvents for the reactions with electron-defi-
chloride hydrate), and the success in obtaining the corre- cient aldehydes. Note that the benzimidazole derivatives
sponding benzimidazole derivatives (compounds 6a/7b of type 5a−f from such electron-deficient substrates are
described further in Table 2) in >70% yields, free of iron generally considered to be more difficult to obtain than
contamination after silica gel flash chromatography, pro- those from electron-rich aldehydes,12e presumably due to
vided us with the impetus for developing this method fur- the destabilization of the one-electron oxidized intermedi-
ther as a versatile and convenient one-pot procedure for ates in the aromatization steps (Scheme 1).
the preparation of a variety of benzimidazole derivatives.
In the next steps towards examining the general scope and
That the actual oxidant is Fe(III) and not O2 was con-
versatility of this method, differently substituted diamines
firmed in control experiments where mere bubbling of O2
were also successfully coupled with N-methyl-2-imida-
zolecarboxaldehyde to afford compounds 6a−e (Table 2,
Entries 13−17), with 0.03 equivalent FeCl3 and DMF as
the solvent (Method B), and eventually four additional hy-
through the reaction mixture did not accelerate the reac-
tion and was determined to be insufficient for complete
product formation, until as long as >5 days, as monitored
by TLC and NMR analysis of the reaction aliquots. In
droxymethylbenzimidazole derivatives 7a−d were also
contrast, the addition of a catalytic amount of FeCl3 typi-
obtained starting from 3,4-diaminobenzyl alcohol19 and
cally resulted in completion of reactions in less than 6 h,
heterocyclic aldehydes as shown in Table 2 (Entries 18−
21). The high yields of the benzimidazole products ob-
rendering the procedure valuable for synthetic purposes.
The optimum amounts of FeCl3 required for the reactions
tained in all the above cases clearly attest to the synthetic
were determined from several trial runs and applied to-
utility of this mild approach based upon redox cycling of
wards developing a general protocol for reactions on a
the Fe(III)/Fe(II) couple and high catalytic turnover for
preparative scale. Briefly, this one-pot procedure entails
benzimidazole formation.
initial mixing of the ortho-diamines with the aromatic
Y
Y
NH2
NH2
N
X
X
OHC
+
N
H
oxyradicals
H2O2, H2O
FeII
Y
H
N
C
FeIII
O2
X
IIa
IIb
H
Y
NH2
NH2
H
N
X
+
N
H
Y
X
III
N
C
H
Mechanistic scheme showing intermediate steps involved in the formation of Schiff’s bases from aromatic diamines and aldehydes, and the
role of Fe(III)/Fe(II) redox cycling in mediating oxidative cyclization to benzimidazole derivatives
Scheme 1
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M. P. Singh et al.
PAPER
Table 1 Preparation of benzimidazole analogs 4a−f (series I) and 5a−f (series II)
a Method A: using 0.01 equiv FeCl3 in MeCN at 90 °C with continuous O2 bubbling; Method B: using 0.03 equiv FeCl3 in DMF at 120 °C
with continuous O2 bubbling.
b Yields reported for isolated products, purified after silica gel flash chromatography and conversion to the HCl salts.
Towards our targeted objective of preparing Hoechst benzimidazole derivatives by following a 2-step approach
33258 analogs, we further applied the FeCl3-method to (Scheme 2), comprising of: (a) PCC-mediated preparation
the preparation of bi-benzimidazole compounds 12−15 in of the benzimidazole-5-carboxaldehydes 8−11, and (b)
high overall yields from the respective hydroxymethyl- their coupling with 4-(4-methylpiperazinyl)-1,2-phe-
Table 2 Preparation of benzimidazole analogs 6a−e (series III) and 7a−d (series IV).
a Method A: using 0.01 equiv FeCl3 in MeCN at 90 °C with continuous O2 bubbling; Method B: using 0.03 equiv FeCl3 in DMF at 120 °C
with continuous O2 bubbling.
b Yields reported for isolated products, purified after silica gel flash chromatography and conversion to the HCl salts.
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Synthetic Utility of Catalytic Fe(III)/Fe(II) Redox Cycling Towards Fused Heterocycles
1383
N
H3C
N
CH3
N
N
N
N
N
N
(b)
(a)
(a)
(a)
N
N
H
6e
7a
N
N
N
OHC
OHC
H3C
12
13
H
N
H
8
N
N
N
(b)
N
N
OCH3
N
H
H3C
H
H
9
OCH3
N
N
N
N
(b)
N
N
N
7c
N
N
OHC
N
H
N
N
H
14
15
H3C
H
N
10
N
N
H3C
CH3
N
N
N
(b)
(a)
N
N
H
7d
OHC
NO2
H3C
H
H
11
NO2
Reagents: a) PCC/CH2Cl2; b) 0.03 equiv. FeCl3/O2/DMF.
Preparation of 2,5’-bi(benzimidazole) analogs related to Hoechst 33258
Scheme 2
nylenediamine in DMF, using the Fe(III)/Fe(II) redox cy- oxidant with the diamine and aldehyde substrates with re-
cling with O2 exposure a second time. The procedure dox-sensitive substituents, such as hydroxymethyl, nitro-
using FeCl3 therefore compares better to the frequently pyrrole, and the tertiary amine groups (N-
employed PPA-mediated and nitrobenzene methods that methylpiperazine, dimethylanilino); (2) minimal loss in
often fail,20 or afford lower yields,12e towards the prepara- product yields due to metal ion complexation to benzimi-
tion of such 2,5’-bi-benzimidazole assemblies. It is evi- dazole products, despite the presence of suspected
dent that the FeCl3 method, owing to its simplicity and chelating units such as 2’-imidazole and 2’-pyridine (com-
versatility, offers a more expeditious route to the develop- pare 5a−e, 6b, 12 and 17); (3) relative ease of isolation of
ment of Hoechst 33258 analogs derived from differently products in purified forms free of contamination due to
substituted benzimidazole and imidazopyridine subunits.
transition metal ions (column chromatography); and (4)
the environmental friendliness due to the use of catalytic
amounts of Fe(III) and polar solvents. Considering the
mechanistic similarities between the oxidative cycliza-
tion of Schiff’s base intermediates from diamines and al-
dehydes to that for o-aminophenols,23 the Fe(III)/Fe(II)-
redox cycling method should be equally applicable to the
preparation of benzoxazole and related classes of fused
heterocycles. It would also be interesting to explore the
amenability of this methodology towards solid-phase syn-
thesis of diversified sets of analogous benzimidazole and
imidazopyridine derivatives.28 In terms of specific appli-
cation of this mild redox cycling approach to benzimida-
zole derivatives, several analogs of Hoechst 33258 with a
varying arrangement of the bis-benzimidazole units have
been prepared. Data from our ongoing investigations of
their fluorescence properties and DNA binding character-
istics will be reported in due course.
Finally, we have extended this synthetic method for the
preparation of additional extended bis-benzimidazole and
imidazopyridine derivatives 16−20, using commercially
available substrates, as depicted in Scheme 3. These com-
pounds are also particularly interesting for the study of
their photochemical properties, such as prototropic equi-
libria in the excited state and fluorescence emissions asso-
ciated with the benzimidazole and imidazopyridine ring
systems,21 including their potential utility in the develop-
ment of novel symmetrical Hoechst 33258 analogs as nu-
cleic acid binding probes.22
In summary, the catalytic redox cycling approach based
on Fe(III)/Fe(II) couple and molecular O2 as co-oxidant
serves well in providing a high-yielding and convenient
access to 30 different benzimidazole and imidazopyridine
derivatives, 4a−f, 5a−f, 6a−e, 7a−d, 12−20, in a much
more straightforward manner than from previously re-
ported methods. Some particularly noteworthy features of
the application of this procedure have emerged from the
wide range of benzimidazole and imidazopyridine prod-
ucts prepared as part of this work: (1) compatibility of an
Melting points, uncorrected, were recorded on a Electrothermal
capillary melting point apparatus. All solvents and reagents were
obtained from Aldrich Chemical Co. All the diamines and aldehyde
compounds were obtained from Aldrich or Lancaster Inc. Literature
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1384
M. P. Singh et al.
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N
N
NH2
NH2
(a)
N
H
N
H
H3C
CH3
84 %
H3C
16
17
N
NH2
NH2
(b)
OCH3
OCH3
N
78 %
N
H
N
N
N
(b)
N
N
N
H
92 %
18
NH2
NH2
N
N
(a)
N
N
H
N
H
86 %
19
20
(c)
N
N
H2N
H2N
NH2
NH2
82 %
N
H
N
H
N
N
Reagents and conditions: (a) 1,4-Ph(CHO)2/FeCl3/O2/DMF, 120 °C; (b) 4-MeOPhCHO/ FeCl3/O2/DMF, 120 °C; (c) 4-Pyridine-CHO/FeCl3/
O2/DMF, 120 °C
Additional bis-benzimidazole and imidazopyridine analogs 16−20 prepared using Method B
Scheme 3
methods were followed for the preparation of 4-(4-methyl-1-piper-
azinyl)-1,2-benzenediamine (1),12b-e 3,4-diaminobenzyl alcohol,19
2-imidazolecarboxaldehyde,18 1-methyl-4-nitro-2-pyrrolecarboxal-
dehyde,24 and 4-acetamido-3-nitrobenzaldehyde.25 Anhydrous
CH3CN and DMF were distilled from BaO prior to use according to
analysis. Removal of the solvent and silica gel flash chromatogra-
phy (gradient elution from EtOAc to a 1:1 EtOAc/MeOH solvent
mixture) gave the benzimidazole analogs in the indicated yields
with spectral data consistent with the assigned structures for the
products. Hydrochloride salts were prepared by treatment with
methanolic HCl, evaporation followed by crystallization from
EtOH/Et2O.
1
standard practices. The H- and 13C NMR spectra were obtained
1
with a Bruker AMX-300 or AVANCE-500 spectrometers. All H
chemical shifts (in ppm) are reported relative to TMS as internal
standard for solutions in DMSO-d6, CDCl3 and CD3OD. In cases
where D2O was used, the residual HOD signal was taken as the ref-
erence. All 13C chemical shifts are relative to the solvent signals
when DMSO-d6 or CD3OD were used, and to the signal from trace
amounts of MeOH added as a solute when using D2O solutions. For
Method B: To a stirred solution of the diamine (3.2 mmol) in DMF
(15 mL) was added a solution of the aldehyde (3 mmol) in DMF,
and the solution was stirred for 1 h at 80 °C. Solid FeCl3∑6H2O
(24 mg, 0.09 mmol, 0.03 molar equiv) was then added and the mix-
ture stirred at 120 °C with continuous O2 bubbling through the so-
lution for 10 h. The progress of the reaction was monitored by TLC
analysis of the aliquots. DMF was removed by evaporation and
products isolated in pure form by silica gel flash chromatography
(gradient elution from EtOAc to 1:1 EtOAc/MeOH solvent mix-
ture). Hydrochloride salts were prepared by treatment with methan-
olic HCl, evaporation followed by crystallization EtOH/Et2O.
1
assignment of the H and 13C signals, the use of abbreviations Ar,
Bzi, Im, Py, and Pyr is made for relating to the aryl, benzimidazole,
imidazole, pyrrole, and pyridine units, respectively. 13C data in-
cludes the designations s (singlet), d (doublet), t (triplet), and q
(quartet) determined from the standard APT (attached proton test)
experiments. High resolution mass spectra (EI and FAB) were re-
corded using high voltage (70 eV) on a VG Analytical 70VSE mass
spectrometer.
In order to simplify the presentation of analytical and spectroscopic
data, the benzimidazole and related analogs prepared in this study
are grouped into series I-VI. Series I consists of the benzimidazole
analogs 4a−f obtained from the coupling of 4-(4-methyl-1-piperazi-
nyl)-1,2-benzenediamine12c (1) with electron-rich benzaldehyde de-
rivatives. Series II comprises additional analogs 5a−f derived from
the same diamine and electron-deficient benzaldehyde substrates.
Series III contains the benzimidazole products 6a−e obtained from
N-methyl-2-imidazolecarboxaldehyde and different diamines. Se-
ries IV comprises analogs 7a−d prepared from heterocyclic alde-
hydes and 3,4-diaminobenzyl alcohol.19 Series V and VI correspond
to extended 2,5'-bi(benzimidazole) derivatives and imidazopyridine
analogs as described below. The spectral data for the series I (4a−f)
and series II (5a−f) products are collectively presented in Tables 3
and 4, respectively.
Oxidative Coupling of ortho-Diamines with Aromatic and Het-
eroaromatic Aldehydes; General Procedure
Method A: To a stirred solution of the diamine (3.2 mmol) in MeCN
(25 mL) was added a solution of the aldehyde (3 mmol) in MeCN,
and the solution was stirred for 1 h at 90 °C. The mixture was then
evaporated to dryness and the resulting Schiff's base resuspended in
MeCN (30 mL), and solid FeCl3∑6H2O (9 mg, 0.03 mmol, 0.01 mo-
lar equiv) was added. The mixture was stirred for 90 °C with con-
tinuous O2 bubbling through the solution for 5−8 h, depending on
the course of completion of the reaction as monitored by TLC and
NMR analysis of the aliquots, drawn periodically and filtered
through a short silica gel bed to remove iron salts to enable NMR
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Synthetic Utility of Catalytic Fe(III)/Fe(II) Redox Cycling Towards Fused Heterocycles
1385
Series I (4a−f) (Table 3)
2-(4-Hydroxyphenyl)-5-(4-methyl-1-piperazinyl)-1H-benzimi-
dazole (4a)
Prepared from 4-hydroxybenzaldehyde and 4-(4-methyl-1-piper-
azinyl)-1,2-benzenediamine using Method A, and isolated as the
hydrochloride salt after purification (92% yield); mp 228−230 °C
(dec).
2-(4-Acetamidophenyl)-5-(4-methyl-1-piperazinyl)-1H-benz-
imidazole (4f)
Prepared from 4-acetamidobenzaldehyde and 4-(4-methyl-1-piper-
azinyl)-1,2-benzenediamine using Method A, and isolated as the
hydrochloride salt after purification (92% yield); mp 180−182 °C.
Series II (5a−f) (Table 4)
5-(4-Methyl-1-piperazinyl)-2-(4-nitrophenyl)-1H-benzimid-
azole (5a)
Prepared from 4-nitrobenzaldehyde and 4-(4-methyl-1-piperazi-
nyl)-1,2-benzenediamine using Method B, and isolated as the hy-
drochloride salt after purification (82% yield); mp >300 °C.
2-(4-Methoxyphenyl)-5-(4-methyl-1-piperazinyl)-1H-benzimi-
dazole (4b)
Prepared from 4-methoxybenzaldehyde and 4-(4-methyl-1-piper-
azinyl)-1,2-benzenediamine using Method A, and isolated as the
hydrochloride salt after purification (94% yield); mp 193−195 °C.
5-(4-Methyl-1-piperazinyl)-2-(3-nitrophenyl)-1H-benzimid-
azole (5b)
Prepared from 3-nitrobenzaldehyde and 4-(4-methyl-1-piperazi-
nyl)-1,2-benzenediamine using Method B, and isolated as the hy-
drochloride salt after purification (84% yield); mp >300 °C.
2-(3,4-Dimethoxyphenyl)-5-(4-methyl-1-piperazinyl)-1H-benz-
imidazole (4c)
Prepared from 3,4-dimethoxybenzaldehyde and 4-(4-methyl-1-pip-
erazinyl)-1,2-benzenediamine using Method A, and isolated as the
hydrochloride salt after purification (86% yield); mp 226−230 °C.
2-(4-Cyanophenyl)-5-(4-methyl-1-piperazinyl)-1H-benzimid-
azole (5c)
Prepared from 4-cyanobenzaldehyde and 4-(4-methyl-1-piperazi-
nyl)-1,2-benzenediamine using Method B, and isolated as the hy-
drochloride salt after purification (85% yield); mp 212−215 °C.
2-(4-Methylphenyl)-5-(4-methyl-1-piperazinyl)-1H-benzimid-
azole (4d)
Prepared from 4-methylbenzaldehyde and 4-(4-methyl-1-piperazi-
nyl)-1,2-benzenediamine using Method A, and isolated as the hy-
drochloride salt after purification (90% yield); mp 245−248 °C.
2-(3-Cyanophenyl)-5-(4-methyl-1-piperazinyl)-1H-benzimid-
azole (5d)
Prepared from 3-cyanobenzaldehyde and 4-(4-methyl-1-piperazi-
nyl)-1,2-benzenediamine using Method B, and isolated as the hy-
drochloride salt after purification (82% yield); mp 296−299 °C.
2-(4-Dimethylaminophenyl)-5-(4-methyl-1-piperazinyl)-1H-
benzimidazole (4e)
Prepared from 4-(dimethylamino)benzaldehyde and 4-(4-methyl-1-
piperazinyl)-1,2-benzenediamine using Method A, and isolated
as the hydrochloride salt after purification (94% yield); mp 289−
293 °C.
Table 3 Spectral Data for Series I (4a–f) Analogs
Compound
EI-HRMS
1H NMR (solvent, 300 MHz), d, J (Hz)
13C NMR (solvent, 75 MHz), d
4a
calcd for C18H20N4O 308.1637
found 308.1638 (M , 100%),
238.0972 (M - C4H8N; 45%),
237.0903 (M - C4H9N; 43%)
(D2O): 7.42 (d, 2 H, J = 9), 7.32 (d, 1 H, (D2O, 318 K): 163.2 (s), 150.7 (s), 149.3 (s),
+
J = 8.7), 7.02 (d, 1 H, J = 8.7), 6.85 (s,
1 H), 6.69 (d, 2 H, J = 9), 3.59-3.70 (m, 119.1 (d), 116.4 (d), 114.7 (s), 101.5 (d),
4 H), 3.08 (m, 4 H), 2.94 (s, 3 H) 55.8 (t), 49.2 (t), 45.7 (q)
133.9 (s), 131.1 (d), 127.3 (s), 119.8 (d),
4b
4c
4d
calcd for C19H22N4O 322.1793
found 322.1799 (M , 100%),
252.1134 (M - C4H8N; 17%),
251.1058 (M - C4H9N; 19%)
(DMSO-d6): 11.2 (s, 1 H, D2O exch., NH), (D2O): 164.8 (s), 150.6 (s), 148.2 (s), 133.5
8.40 (d, 2 H, J = 9), 7.68 (d, 1 H, J = 8.5), (s), 130.2 (d), 126.9 (s), 119.7 (d), 117.1 (d),
7.33 (d, 1 H, J = 8.5), 7.29 (d, 2 H, J = 9), 116.1 (d), 114.7 (s), 101.2 (d), 58.0 (q), 55.6
7.19 (s, 1 H), 3.86 (s, 3 H), 3.50 (m, 4 H), (t), 49.1 (t), 45.4 (q)
3.10 (m, 4 H), 2.80 (s, 3 H)
+
calcd for C20H24N4O2 352.1899
(D2O): 6.99 (d, 1 H, J = 8.5), 6.85 (d, 1 H, (D2O): 154.3 (s), 150.8 (s), 150.5 (s), 148.2
+
found 352.1893 (M , 100%),
J = 8.3), 6.75 (d, 1 H, J = 8.5), 6.57 (s,
(s), 133.6 (s), 126.9 (s), 122.6 (d), 119.8 (d),
282.1236 (M - C4H8N; 38%),
281.1161 (M - C4H9N; 43%)
1 H), 6.48 (s, 1 H), 6.40 (d, 1 H, J = 8.3), 116.0 (d), 114.7 (s), 113.8 (d), 109.5 (d),
3.59-3.73 (m, 4 H), 3.45 (s, 3 H), 3.39 (s, 100.8 (d), 58.3 (q), 58.1 (q), 55.6 (t), 49.1
3 H), 2.98-3.18 (m, 4 H), 2.94 (s, 3 H)
(DMSO-d6): 11.03 (s, 1 H, D2O exch.,
(t), 45.4 (q)
calcd for C19H22N4 306.1844
found 306.1843 (M+, 100%),
236.1190 (M - C4H8N; 38%),
235.1116 (M - C4H9N; 41%)
(D2O): 150.7 (s), 148.4 (s), 133.7 (s), 127.3
NH), 8.26 (d, 2 H, J = 8.8), 7.71 (d, 1 H, (s), 119.2 (d), 116.2 (s), 115.9 (d), 114.6 (s),
J = 8.5), 7.53 (d, 2 H, J = 8.8), 7.35 (dd, 110.2 (d), 109.3 (d), 101.0 (d), 55.7 (t), 49.4
1 H, J = 8.5, 1.5), 7.20 (d, 1 H, J = 1.5),
3.60-3.71 (m, 4 H), 3.19 (m, 4 H), 2.81 (s,
3 H), 2.44 (s, 3 H)
(t), 45.2 (q), 24.8 (q)
4e
4f
calcd for C20H25N5 335.2109
found 335.2107 (M+, 100%),
265.1465 (M - C4H8N; 36%),
264.1394 (M - C4H9N; 32%)
(D2O): 7.13 (d, 1 H, J = 8.7), 6.93 (d, 1 H, J (D2O): 153.9 (s), 150.2 (s), 150.0 (s), 133.9
= 8.7), 6.91 (d, 2 H, J = 9), 6.80 (s, 1 H),
6.15 (d, 2 H, J = 9), 3.59-3.70 (m, 4 H),
(s), 130.1 (d), 127.7 (s), 119.0 (d), 115.7 (d),
113.9 (d), 109.4 (s), 101.7 (d), 55.8 (t), 49.6
2.98-3.17 (m, 4 H), 2.93 (s, 3 H), 2.25 (s, (t), 45.4 (q), 41.8 (q)
6 H)
calcd for C20H23N5O 349.1902
found 349.1904 (M+, 100%),
279.1240 (M - C4H8N; 28%),
278.1170 (M - C4H9N; 18%)
(D2O): 7.20 (d, 1 H, J = 8.5), 7.12 (d, 2 H, J (D2O): 174.1 (s), 151.0 (s), 148.2 (s), 144.3
= 9), 7.00 (2 d, 3 H), 6.83 (s, 1 H), 3.60-
3.74 (m, 4 H), 3.2 (m, 4 H), 3.01 (s, 3 H), 120.1 (d), 118.0 (s), 116.5 (d), 101.3 (d),
2.95 (s, 3 H) 55.8 (t), 49.3 (t), 45.6 (q), 26.0 (q)
(s), 134.0 (s), 129.8 (d), 127.3 (s), 121.4 (d),
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Table 4 Spectral Data for Series II (5a–f) Analogs
Compound
EI-HRMS data
1H NMR (300 MHz), d, J (Hz)
13C NMR (solvent, 75 MHz), d
5a
calcd for C18H19N5O2 337.1538
found 337.1539 (M+, 58%),
266.0802 (M - C4H9N; 16%)
(D2O): 8.23 (d, 2 H, J = 9), 7.95 (d, 2 H, J = (D2O): 151.8 (s), 151.4 (s), 148.3 (s), 135.8
9), 7.58 (d, 1 H, J = 8.7), 7.26 (d, 1 H, J = (s), 130.6 (d), 129.2 (s), 128.2 (s), 127.3 (d),
8.7), 7.14 (s, 1 H), 3.66-3.90 (m, 4 H),
121.4 (d), 117.5 (d), 102.3 (d), 55.6 (t), 49.5
(t), 45.8 (q)
3.13-3.32 (m, 4 H), 2.97 (s, 3 H)
5b
calcd for C18H19N5O2 337.1538
found 337.1537 (M+, 48%),
267.0879 (M - C4H8N; 12%),
266.0809 (M - C4H9N; 18%)
(D2O): 8.61 (s, 1 H), 8.30 (d, 1 H, J = 8.5), (D2O, 318 K): 151.8 (s), 151.2 (s), 149.8 (s,
8.21 (d, 1 H, J = 8.5), 7.77 (t, 1 H, J = 8.5), C), 135.9 (d), 135.3 (s), 134.3 (d), 130.3
7.56 (d, 1 H, J = 8.7), 7.22 (d, 1 H, J = 8.7), (d), 129.0 (s), 126.6 (s), 124.9 (d), 121.6
7.16 (s, 1 H), 3.58-3.88 (m, 4 H), 3.15-
(d), 117.7 (d), 102.7 (d), 55.9 (t), 49.7 (t),
45.7 (q)
3.32 (m, 4 H), 2.97 (s, 3 H)
5c
calcd for C17H19N5 317.1640
found 317.1637 (M+, 100%),
247.0974 (M - C4H8N; 23%),
246.0905 (M - C4H9N; 37%)
(D2O): 7.69 (d, 4 H), 7.48 (d, 1 H, J = 8.7), (D2O): 151.5 (s), 147.4 (s), 136.0 (d), 134.7
7.19 (d, 1 H, J = 8.7), 7.00 (s, 1 H), 3.72- (s), 129.5 (d), 128.2 (s), 128.0 (s), 121.4 (d),
3.81 (m, 4 H), 3.2 (m, 4 H), 2.98 (s, 3 H)
120.4 (s), 117.4 (s), 117.2 (d), 101.7 (d),
55.5 (t), 49.1 (t), 45.7 (q)
5d
calcd for C17H19N5 317.1640
found 317.1642 (M+, 100%),
247.0983 (M - C4H8N; 34%),
246.0918 (M - C4H9N; 61%)
(D2O): 8.15 (m, 2 H), 7.95 (d, 1 H, J = 8.5), (D2O): 151.1 (s), 147.2 (s), 136.2 (s), 134.8
7.77 (t, 1 H, J = 8.5), 7.60 (d, 1 H, J = 8.7), (s), 131.8 (d), 130.7 (d), 129.7 (s), 127.6
7.27 (d, 1 H, J = 8.7), 7.22 (s, 1 H), 3.73 (m, (d), 126.2 (s), 121.1 (d), 119.8 (s), 117.6
4 H), 3.25 (m, 4 H), 2.95 (s, 3 H)
(d), 115.6 (d), 102.1 (d), 55.3 (t), 49.3 (t),
45.4 (q)
5e
5f
calcd for C19H20N4O2 336.1586
found 336.1577 (M+, 100%)
(D2O): 7.50 (s, 2 H), 7.36 (s, 2 H), 7.20 (d, (D2O, 318 K): 170.2 (s), 151.6 (s), 147.5 (s),
1 H, J = 8.7), 6.93 (d, 1 H, J = 8.7), 6.72 (s, 135.8 (s), 134.7 (s), 133.1 (d), 128.8 (d),
1 H), 3.75 (m, 4 H), 3.05 (m, 4 H), 2.88 (s, 127.9 (s), 127.3 (s), 121.1 (d), 117.3 (d),
3 H)
101.4 (d), 55.8 (t), 49.0 (t), 45.7 (q)
calcd for C20H23N6O3+ (MH+)
395.1823
found 395.1828
(DMSO-d6): 10.96 (s, 1 H), 10.71 (s, 1 H, (DMSO-d6, 318 K): 173.7 (s), 150.9 (s),
exch), 8.78 (s, 1 H), 8.53 (d, 1 H, J = 8.7), 150.7 (s), 147.8 (s), 143.8 (s), 133.7 (s),
7.87 (d, 1 H, J = 8.7), 7.61 (d, 1 H, J = 8.7), 130.1 (d), 129.2 (d), 126.4 (s), 123.1 (d),
7.17 (d, 1 H, J = 8.7), 7.14 (s, 1 H), 3.62- 122.3 (s), 119.6 (d), 115.7 (d), 102.6 (d),
3.76 (m, 4 H), 3.18 (m, 4 H), 2.89 (s, 3 H), 55.6 (t), 49.1 (t), 45.7 (q), 26.2 (q)
2.16 (s, 3 H)
2-(4-Carboxyphenyl)-5-(4-methyl-1-piperazinyl)-1H-benzimi-
dazole (5e)
Prepared from 4-formylbenzoic acid and 4-(4-methyl-1-piperazi-
nyl)-1,2-benzenediamine using Method B, and isolated as the hy-
drochloride salt after purification (78% yield); mp 278−280 °C.
EI-HRMS: m/z calcd for C16H20N6 296.1749, found 296.1749 (M+,
100%), 226.1137 (M − C4H8N; 31%), 225.1059 (M − C4H9N;
26%).
5-Methyl-2-(1-methyl-2-imidazolyl)-1H-benzimidazole (6b)
Prepared from 1-methyl-2-imidazolecarboxaldehyde and 3,4-di-
aminotoluene using Method A; yield: 96%; mp 180−182 °C;
1H NMR (300 MHz, DMSO-d6): δ = 12.80 (s, D2O exch., 1 H, NH),
7.54 (d, 1 H, J = 8.6 Hz, Bzi-CH), 7.26 (s, 1 H, Im-CH), 7.28 (s, 1
H, Bzi-CH), 7.11 (s, 1 H, Im-CH), 7.02 (d, 1 H, J = 8.6 Hz, Bzi-
CH), 4.16 (s, 3 H, NCH3), 2.41 (s, 3 H, CH3).
2-(4-Acetamido-3-nitrophenyl)-5-(4-methyl-1-piperazinyl)-1H-
benzimidazole (5f)
Prepared from 4-acetamido-3-nitrobenzaldehyde25 and 4-(4-meth-
yl-1-piperazinyl)-1,2-benzenediamine using Method
B (84%
yield); >300 °C.
Series III (6a−f). 2-(1-Methyl-2-imidazolyl)-substituted Benz-
imidazole Analogs
2-(1-Methyl-2-imidazolyl)-5-(4-methyl-1-piperazinyl)-1H-ben-
zimidazole (6a)
Prepared from N-methyl-2-imidazolecarboxaldehyde and 4-(4-me-
thyl-1-piperazinyl)-1,2-benzenediamine using Method B, and iso-
lated as the hydrochloride salt after purification ; yield: 86%; mp
219−221 °C.
1H NMR (300 MHz, D2O): δ = 7.67 (d, 1 H, J = 8.7 Hz, Bzi-CH),
7.58 (s, 2 H, Im-CH), 7.28 (s, 1 H, Bzi-CH), 7.23 (d, 1 H, J = 8.7
Hz, Bzi-CH), 4.08 (s, 3 H, Im-NCH3), 3.75 (m, 4 H, CH2), 3.22 (m,
4 H, CH2), 2.96 (s, 3 H, NCH3).
13C NMR (75 MHz, DMSO-d6, 318 K): δ = 144.5 (s, C), 143.0 (s,
C), 138.7 (s, C), 136.2 (s, C), 132.3 (s, C), 129.8 (d, CH), 127.4 (d,
CH), 122.2 (d, CH), 118.1 (d, CH), 110.1 (d, CH), 38.0 (q, CH3),
24.8 (q, CH3).
EI-HRMS: m/z calcd for C12H12N4 212.1063, found 212.1057 (M+,
100%).
2-(1-Methyl-2-imidazolyl)-1H-benzimidazole-5-carboxylic
Acid (6c)
Prepared from 1-methyl-2-imidazolecarboxaldehyde and 3,4-di-
aminobenzoic acid using Method B; yield: 75%; mp 265−268 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.82 (s, D2O exch., 1 H, NH),
8.18 (s, 1 H, Bzi-CH), 7.84 (d, 1 H, J = 8.7 Hz, Bzi-CH), 7.65 (d, 1
H, J = 8.7 Hz, Bzi-CH), 7.49 (s, 1 H, Im-CH), 7.20 (s, 1 H, Im-CH),
4.19 (s, 3 H, NCH3).
13C NMR (75 MHz, D2O, 318 K): δ = 149.7 (s, C), 138.9 (s, C),
137.2 (s, C), 135.6 (s, C), 135.2 (s, C), 128.9 (d, CH), 124.1 (d, CH),
120.6 (d, CH), 118.5 (d, CH), 103.7 (d, CH), 55.4 (t, CH2), 50.3 (t,
CH2), 45.4 (q, CH3), 38.8 (q, CH3).
Synthesis 2000, No. 10, 1380–1390 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthetic Utility of Catalytic Fe(III)/Fe(II) Redox Cycling Towards Fused Heterocycles
1387
1H NMR (300 MHz, CD3OD): δ = 8.20 (s, 1 H, Bzi-CH), 7.88 (d, 1
H, J = 8.4 Hz, Bzi-CH), 7.49 (d, 1 H, J = 8.4 Hz, Bzi-CH), 7.22 (s,
1 H, Im-CH), 7.06 (s, 1 H, Im-CH).
13C NMR (75 MHz, DMSO-d6, 318 K): δ = 170.2 (s, C), 148.2 (s,
C), 143.2 (s, C), 138.9 (s, C), 131.3 (d, CH), 130.8 (s, C), 129.5 (d,
CH), 128.1 (d, CH), 127.6 (s, C), 122.1 (d, CH), 199.6 (d, CH), 37.8
(q, CH3).
1H NMR (300 MHz, DMSO-d6): δ = 12.7 (s, D2O exch., 1 H, NH),
8.91 (d, 1 H, J = 4.8 Hz, Pyr-CH), 8.18 (d, 1 H, J = 6.8 Hz, Pyr-CH),
7.95 (m, 1 H, Pyr-CH), 7.62 (d, 1 H, J = 8.5 Hz, Bzi-CH), 7.48 (d,
1 H, J = 8.5 Hz, Bzi-CH), 7.34 (s, 1 H, Bzi-CH), 7.21 (dd, 1 H,
J = 7.0, 4.8 Hz, Pyr-CH), 5.18 (t, exch, 1 H, OH), 4.58 (d, 2 H,
J = 5.6 Hz, CH2).
13C NMR (75 MHz, DMSO-d6, 318 K): δ = 153.8 (s, C), 152.3 (s,
C), 148.9 (s, C), 144.4 (d, CH), 137.6 (s, C), 136.5 (s, C), 128.4 (d,
CH), 125.2 (d, CH), 124.2 (d, CH), 122.8 (d, CH), 121.2 (d, CH),
112.7 (d, CH), 62.8 (t, CH2).
FAB-HRMS: m/z calcd for C12H11N4O2+ (M + H+) 243.0885, found
243.0888.
Methyl 2-(1-Methyl-2-imidazolyl)-1H-benzimidazole-5-carbox-
ylate (6d)
Prepared from 1-methyl-2-imidazolecarboxaldehyde and methyl
3,4-diaminobenzoate using Method B; yield: 83%; mp 195 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.78 (s, D2O exch., 1 H, NH),
8.19 (s, 1 H, Bzi-CH), 7.85 (d, 1 H, J = 8.6 Hz, Bzi-CH), 7.69 (d, 1
H, J = 8.6 Hz, Bzi-CH), 7.46 (s, 1 H, Im-CH), 7.17 (s, 1 H, Im-CH),
4.19 (s, 3 H, NCH3), 3.87 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6, 318 K): δ = 171.1 (s, C), 147.2 (s,
C), 141.5 (s, C), 140.3 (s, C), 130.6 (d, CH), 129.5 (s, C), 129.1 (d,
CH), 127.7 (d, CH), 127.3 (s, C), 120.8 (d, CH), 118.8 (d, CH), 52.6
(q, CH3), 38.0 (q, CH3).
FAB-HRMS: m/z calcd for C13H12N3O+ (M + H+) 226.0980, found
226.0979.
5-(Hydroxymethyl)-2-(4-pyridinyl)-1H-benzimidazole (7c)
Prepared from 4-pyridinecarboxaldehyde and 3,4-diaminobenzyl
alcohol using Method B; yield: 92%; mp 80−83 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.75 (s, D2O exch., 1 H, NH),
8.72 (d, 2 H, J = 6.2 Hz, Pyr-CH), 8.07 (d, 2 H, J = 6.2 Hz, Pyr-CH),
7.71 (d, 1 H, J = 8.7 Hz, Bzi-CH), 7.52 (s, 1 H, Bzi-CH), 7.26 (d, 1
H, J = 8.7 Hz, Bzi-CH), 5.21 (t, exch, 1 H, OH), 4.60 (d, 2 H, J = 5.6
Hz, CH2).
13C NMR (75 MHz, DMSO-d6, 318 K): δ = 151.0 (s, C), 148.0 (s,
C), 144.1 (d, CH), 141.3 (s, C), 137.2 (s, C), 136.8 (s, C), 125.6 (d,
CH), 122.5 (d, CH), 121.4 (d, CH), 113.1 (d, CH), 62.6 (t, CH2);
FAB-HRMS: m/z calcd for C13H12N3O+ (M + H+) 226.0980, found
226.0984.
EI-HRMS: m/z calcd for C13H12N4O2 256.0961, found 256.0956
(M+, 100%), 225.0777 (34%), 197.0816 (21%).
5-(Hydroxymethyl)-2-(1-methyl-2-imidazolyl)-1H-benzimid-
azole (6e)
Prepared from 1-methyl-2-imidazolecarboxaldehyde and 3,4-di-
5-(Hydroxymethyl)-2-(1-methyl-4-nitro-2-pyrrolyl)-1H-benz-
imidazole (7d)
aminobenzyl alcohol19 using Method A; yield: 90%; mp 156 °C.
Prepared from 1-methyl-3-nitro-2-pyrrolecarboxaldehyde24 and
3,4-diaminobenzyl alcohol using Method B; yield: 94%; mp 253
°C.
1H NMR (300 MHz, DMSO-d6): δ = 12.89 (s, D2O exch., 1 H, NH),
7.59 (d, 1 H, J = 8.7 Hz, Bzi-CH), 7.46 (s, 1 H, Bzi-CH), 7.41 (s, 1
H, Im-CH), 7.20 (d, 1 H, J = 8.7 Hz, Bzi-CH), 7.12 (s, 1 H, Im-CH),
5.17 (t, exch, 1 H, J = 5 Hz, OH), 4.58 (d, 2 H, J = 5 Hz, CH2), 4.18
(s, 3 H, NCH3).
13C NMR (75 MHz, CD3OD, 310 K): δ = 147.1 (s, C), 145.9 (s, C),
140.5 (s, C), 139.0 (s, C), 136.1 (s, C), 131.0 (d, CH), 127.8 (d, CH),
124.3 (d, CH), 120.5 (d, CH), 112.9 (d, CH), 66.2 (t, CH2), 37.9 (q,
CH3).
1H NMR (300 MHz, DMSO-d6): δ = 12.68 (s, D2O exch., 1 H, NH),
8.24 (d, 1 H, J = 1.5 Hz, Py-CH), 7.59 (d, 1 H, J = 8.7 Hz, Bzi-CH),
7.51 (d, 1 H, J = 1.5 Hz, Py-CH), 7.45 (s, 1 H, Bzi-CH), 7.40 (d, 1
H, J = 8.7 Hz, Bzi-CH), 5.14 (t, exch, 1 H, OH), 4.59 (d, 2 H, J = 6
Hz, CH2), 4.17 (s, 3 H, NCH3).
13C NMR (75 MHz, DMSO-d6, 318 K): δ = 144.2 (s, C), 143.1 (s,
C), 137.3 (s, C), 135.0 (s, C), 133.4 (s, C), 127.7 (d, CH), 124.6 (s,
C), 121.7 (d, CH), 117.7 (d, CH), 109.7 (d, CH), 106.0 (d, CH), 63.3
(t, CH2), 38.0 (q, CH3).
EI-HRMS: m/z calcd for C12H12N4O 228.1012, found 228.1013
(M+, 100%), 211.0985 (38%).
Series IV (7a−d): 5-(Hydroxymethyl)-2-(aryl)benzimidazole
Analogs
5-(Hydroxymethyl)-2-(4-methoxyphenyl)-1H-benzimidazole
EI-HRMS: m/z calcd for C13H12N4O3 272.0910, found 272.0911
(M+, 100%), 226.0965 (21%), 225.0909 (37%), 196.0880 (12%).
(7a)
Pyridinum Chlorochromate Oxidation of Alcohols 6e, 7a−d to
Aldehydes 8−11
The following compounds 8−11 were prepared using pyridinum
chlorochromate for oxidation of the corresponding hydroxymethyl-
benzimidazole derivatives from above, according to previously re-
ported procedures.12b-d
Prepared from 4-methoxybenzaldehyde and 3,4-diaminobenzyl al-
cohol using Method A; yield: 91%; mp 224−226 °C (Lit.26 mp 221−
222 °C).
1H NMR (300 MHz, DMSO-d6): δ = 12.55 (s, D2O exch., 1 H, NH),
7.92 (d, 2 H, J = 9 Hz, Ar-CH), 7.50 (d, 1 H, J = 8.7 Hz, Bzi-CH),
7.43 (s, 1 H, Bzi-CH), 7.11 (d, 1 H, J = 8.7 Hz, Bzi-CH), 6.94 (d, 2
H, J = 9 Hz, Ar-CH), 5.15 (t, exch, 1 H, OH), 4.57 (d, 2 H, J = 6 Hz,
CH2), 3.81 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6, 318 K): δ = 162.8 (s, C), 144.4 (s,
C), 143.0 (s, C), 136.8 (s, C), 132.8 (s, C), 128.2 (d, CH), 121.2 (d,
CH), 116.8 (d, CH), 115.1 (d, CH), 114.2 (s, C), 108.8 (d, CH), 63.6
(t, CH2), 56.8 (q, CH3).
2-(1-Methyl-2-imidazolyl)-1H-benzimidazole-5-carboxalde-
hyde (8)
This compound was obtained from 6e in 78% yield after silica gel
flash chromatography (2:1 MeOH/EtOAc eluent); mp 180−183 °C.
1H NMR (300 MHz, CDCl3): δ = 10.05 (s, 1 H, CHO), 8.10 (s, 1 H,
Bzi-CH), 7.82 (d, 1 H, J = 8.6 Hz, Bzi-CH), 7.62 (d, 1 H, J = 8.6 Hz,
Bzi-CH), 7.29 (s, 1 H, Im-CH), 7.20 (s, 1 H, Im-CH), 4.38 (s, 3 H,
NCH3);
EI-HRMS: m/z calcd for C15H14N2O2 254.1056, found 254.1048
(M+, 100%), 239.0808 (M − CH3, 27%), 212.0861 (M − C2H3O,
42%).
FAB-HRMS: m/z calcd for C12H11N4O+ (M+H+) 227.0933, found
227.0940.
5-(Hydroxymethyl)-2-(2-pyridinyl)-1H-benzimidazole (7b)
Prepared from 2-pyridinecarboxaldehyde and 3,4-diaminobenzyl
alcohol using Method B; yield: 82%; mp 123−125 °C.
2-(4-Methoxyphenyl)-1H-benzimidazole-5-carboxaldehyde (9)
Prepared from 7a in 82% yield after silica gel flash chromatography
(EtOAc eluent); mp 174−176 °C.
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M. P. Singh et al.
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1H NMR (300 MHz, CDCl3): δ = 9.94 (s, 1 H, CHO), 8.20 (d, 2 H,
J = 8.7 Hz, Ar-CH), 7.92 (s, 1 H, Bzi-CH), 7.76 (d, 1 H, J = 8.5 Hz,
Bzi-CH), 7.48 (d, 1 H, J = 8.5 Hz, Bzi-CH), 7.17 (d, 2 H, J = 8.7 Hz,
Ar-CH), 3.83 (s, 3 H, OCH3).
EI-HRMS: m/z calcd for C13H9N3O 223.0788, found 223.0779 (M+,
100%), 218.0538 (M − CH3, 31%), 180.0605 (M − C2H3O, 22%).
H, J = 1.5 Hz, Bzi'-CH), 6.96 (dd, 1 H, J = 8.5, 1.5 Hz, Bzi'-CH),
3.27 (m, 4 H, CH2), 2.73 (m, 4 H, CH2), 2.41 (s, 3 H, NCH3).
EI-HRMS: m/z calcd for C24H23N7 409.2015, found 409.2013 (M+,
100%), 339.1416 (38%), 338.1318 (30%), 325 (51%).
2-(1-Methyl-4-nitro-2-pyrrolyl)-5-[5-(4-methyl-1-piperazinyl)-
1H-benzimidazol-2-yl]-1H-benzimidazole (15)
2-(4-Pyridinyl)-1H-benzimidazole-5-carboxaldehyde (10)
This compound was obtained from 7c in 69% yield after silica gel
flash chromatography (MeOH eluent); mp 157−159 °C.
1H NMR (300 MHz, CDCl3): δ = 9.84 (s, 1 H, CHO), 8.87 (d, 2 H,
J = 6.2 Hz, Pyr-CH), 8.37 (d, 2 H, J = 6.2 Hz, Pyr-CH), 7.90 (s, 1
H, Bzi-CH), 7.78 (d, 1 H, J = 8.4 Hz, Bzi-CH), 7.47 (d, 1 H, J = 8.4
Hz, Bzi-CH).
This compound was obtained from the reaction of diamine 1 with
11 according to Method B; yield: 85%; mp 235−238 °C.
1H NMR (500 MHz, DMSO-d6): δ = 12.61 (s, exch, 1 H, NH), 8.33
(s, 1 H, Py-CH), 8.24 (s, 1 H, Bzi-CH), 8.03 (d, 1 H, J = 8.4 Hz, Bzi-
CH), 7.68 (d, 1 H, J = 8.4 Hz, Bzi-CH), 7.58 (s, 1 H, Py-CH), 7.43
(d, 1 H, J = 8.7 Hz, Bzi'-CH), 6.99 (s, 1 H, Bzi'-CH), 6.92 (d, 1 H,
J = 8.7 Hz, Bzi'-CH), 4.21 (s, 3 H, Py-NCH3), 3.11 (m, 4 H, CH2),
2.51 (m, 4 H, CH2), 2.28 (s, 3 H, NCH3).
FAB-HRMS: m/z calcd for C13H10N3O+ (M + H+) 224.0853, found
224.0848.
FAB-HRMS: m/z calcd for C24H25N8O2+ (M + H+) 457.2101, found
457.2097.
2-(1-Methyl-4-nitro-2-pyrrolyl)-1H-benzimidazole-5-carboxal-
dehyde (11)
Prepared from 7d in 91% yield after silica gel flash chromatography
(4:1 MeOH/EtOAc eluent); mp 303 °C.
1H NMR (300 MHz, CDCl3): δ = 9.67 (s, 1 H, CHO), 7.74 (s, 1 H,
Bzi-CH), 7.47 (d, 1 H, J = 1.2 Hz, Py-CH), 7.43 (d, 1 H, J = 8.4 Hz,
Bzi-CH), 7.39 (d, 1 H, J = 8.4 Hz, Bzi-CH), 7.22 (d, 1 H, J = 1.2 Hz,
Py-CH), 4.12 (s, 3 H, NCH3).
Series VI (16−20): Extended Bis-benzimidazole and Imidazopy-
ridine Derivatives
2,2’-(1,4-Phenylenebis)(5-methyl-1H-benzimidazole) (16)
Prepared from 1,4-benzenedicarboxaldehyde and 2 molar equiv of
3,4-diaminotoluene using Method B; yield: 84%; mp 176−178 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.86 (s, exch, 1 H, NH), 8.30
(s, 4 H, Ar-CH), 7.50 (d, 2 H, J = 8.4 Hz, Bzi-CH), 7.39 (s, 2 H, Bzi-
CH), 7.06 (d, 2 H, J = 8.4 Hz, Bzi-CH), 2.43 (s, 6 H, CH3).
13C NMR (75 MHz, HCl salt in D2O): δ = 145.6 (s, C), 143.9 (s, C),
136.8 (s, C), 132.2 (s, C), 123.1 (d, CH), 119.0 (d, CH), 117.3 (d,
CH), 113.6 (s, C), 111.0 (d, CH), 24.6 (q, CH3).
EI-HRMS: m/z calcd for C13H10N4O3 270.0758, found 270.0753
(M+, 100%), 223.1137 (51%).
Series V (12−15): 2,5’-Bis-1H-benzimidazole Analogs of
Hoechst 33258
FAB-HRMS: m/z calcd for C22H19N4+ (M + H+) 339.1611, found
339.1596.
2-(1-Methyl-2-imidazolyl)-5-[5-(4-methyl-1-piperazinyl)-1H-
benzimidazol-2-yl]-1H-benzimidazole (12)
Prepared from diamine 1 and compound 8 using Method B and iso-
lated as the HCl salt; yield: 82%; mp 184−187 °C.
2-(4-Methoxyphenyl)imidazo[4,5-b]pyridine (17)
Prepared from 4-methoxybenzaldehyde and 2,3-diaminopyridine
using Method B; yield: 78%; mp 235−237 °C. (Lit.27 mp 230−232
°C for free base).
1H NMR (300 MHz, DMSO-d6): δ = 12.26 (s, D2O exch., 1 H, NH),
8.29 (d, 1 H, J = 4.5 Hz, Pyr-CH), 8.17 (d, 2 H, J = 9 Hz, Ar-CH),
7.95 (d, 1 H, J = 7.2 Hz, Pyr-CH), 7.21 (dd, 1 H, J = 7.2, 4.5 Hz,
Pyr-CH), 7.13 (d, 2 H, Ar-CH), 3.84 (s, 3 H, CH3);
1H NMR (500 MHz, CD3OD): δ = 8.34 (d, 1 H, J = 1.5 Hz, Bzi-
CH), 8.02 (dd, 1 H, J = 8.7, 1.5 Hz, Bzi-CH), 7.78 (d, 1 H, J = 8.7
Hz, Bzi-CH), 7.53 (d, 1 H, J = 8.5 Hz, Bzi'-CH), 7.35 (s, 1 H, Im-
CH), 7.20 (s, 1 H, Im-CH), 7.16 (d, 1 H, J = 1.5 Hz, Bzi'-CH), 7.07
(dd, 1 H, J = 8.5, 1.5 Hz, Bzi'-CH), 4.23 (s, 3 H, Im-NCH3), 3.25 (m,
4H, CH2), 2.69 (m, 4H, CH2), 2.39 (s, 3H, N-CH3).
EI-HRMS: m/z calcd for C23H24N8 412.2124, found 412.2125 (M+,
100%), 359.1889 (54%), 342.1516 (30%), 341.1388 (28%), 318
(44%), 274 (28%).
13C NMR (75 MHz, HCl salt in D2O): δ = 161.2 (d, CH), 155.2 (d,
CH), 154.1 (s, C), 148.2 (s, C), 132.2 (s, C), 130.9 (s, C), 125.8 (d,
CH), 119.2 (d, CH), 117.8 (d, CH), 117.1 (s, C), 55.3 (q, CH3).
2-(4-Methoxyphenyl)-5-[5-(4-methyl-1-piperazinyl)-1H-benz-
imidazol-2-yl]-1H-benzimidazole (13)
EI-HRMS: m/z calcd for C13H11N3O 225.0903, found 225.0907
(M+, 100%), 210.0667 (M-CH3, 36%), 182.0720 (M-C2H3O, 29%).
This compound was obtained from diamine 1 and compound 9 us-
ing Method B; yield: 76%; mp 248−250 °C.
2-(4-Methoxyphenyl)imidazo[4,5-c]pyridine (18)
Prepared from 4-methoxybenzaldehyde and 3,4-diaminopyridine
using Method B; yield: 92%; mp 265−268 °C. (Lit.27 mp 271−273
°C).
1H NMR (300 MHz, CDCl3): δ = 8.81 (s, 1 H, Pyr-CH), 8.21 (d, 1
H, J = 7.2 Hz, Pyr-CH), 8.03 (d, 2 H, J = 8.5 Hz, Ar-CH), 7.56 (d,
1 H, J = 7.2 Hz, Pyr-CH), 6.98 (d, 2 H, J = 8.5 Hz, Ar-CH), 3.83 (s,
3 H, CH3).
1H NMR (500 MHz, CD3OD). δ = 8.23 (d, 1 H, J = 1.3 Hz, Bzi-
CH), 7.96 (d, 2 H, J = 8.8 Hz, Ar-CH), 7.93 (dd, 1 H, J = 8.7, 1.3
Hz, Bzi-CH), 7.65 (d, 1 H, J = 8.7 Hz, Bzi-CH), 7.48 (d, 1 H, J = 8.5
Hz, Bzi'-CH), 7.11 (d, 1 H, J = 1.5 Hz, Bzi'-CH), 7.02 (dd, 1 H,
J = 8.5, 1.5 Hz, Bzi'-CH), 6.98 (d, 2 H, J = 8.8 Hz, Ar-CH), 3.18 (m,
4 H, CH2), 2.53 (m, 4 H, CH2), 2.32 (s, 3 H, NCH3).
EI-HRMS: m/z calcd for C26H26N6O 438.2168, found 438.2172
13C NMR (75 MHz, HCl salt in D2O): δ = 161.4 (s, C), 157.7 (s, C),
145.9 (s, C), 136.5 (s, C), 132.6 (d, CH), 129.5 (d, CH), 128.2 (d,
CH), 116.9 (s, C), 113.6 (d, CH), 110.5 (d, CH), 55.2 (q, CH3).
FAB-HRMS: m/z calcd for C13H12N3O+ (M + H+) 226.0971, found
226.0973.
(M+, 100%), 368.1562 (28%), 365.1440 (26%), 352 (48%).
5-[5-(4-Methyl-1-piperazinyl)-1H-benzimidazol-2-yl]-2-(4-py-
ridinyl)-1H-benzimidazole (14)
Prepared from diamine 1 and the aldehyde derivative 10, using
Method B; yield: 78%; mp 276−280 °C.
1H NMR (500 MHz, CD3OD): δ = 8.76 (d, 2 H, J = 6.2 Hz, Pyr-
CH), 8.30 (d, 1 H, J = 1.5 Hz, Bzi-CH), 8.16 (d, 2 H, J = 6.2 Hz,
Pyr-CH), 8.01 (dd, 1 H, J = 8.7, 1.5 Hz, Bzi-CH), 7.72 (d, 1 H,
J = 8.7 Hz, Bzi-CH), 7.49 (d, 1 H, J = 8.5 Hz, Bzi'-CH), 7.12 (d, 1
2,2’-(1,4-Phenylenebis)imidazo[4,5-c]pyridine (19)
Prepared from 1,4-benzenedicarboxaldehyde and 2 molar equiv of
3,4-diaminopyridine using Method B; yield: 86%; mp 228−230 °C.
Synthesis 2000, No. 10, 1380–1390 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthetic Utility of Catalytic Fe(III)/Fe(II) Redox Cycling Towards Fused Heterocycles
1389
1H NMR (300 MHz, DMSO-d6): δ = 12.48 (s, D2O exch., 1 H, NH),
8.99 (s, 2 H, Pyr-CH), 8.34 (d, 2 H, J = 7.6 Hz, Pyr-CH), 8.26 (s, 4
H, Ar-CH), 7.66 (d, 2 H, J = 7.6 Hz, Pyr-CH).
13C NMR (75 MHz, HCl salt in D2O): δ = 157.4 (s, C), 145.6 (s, C),
136.2 (s, C), 132.9 (d, CH), 129.8 (d, CH), 117.1 (d, CH), 110.7 (d,
CH), 112.9 (s, C).
(a) Lakowicz, J. R.; Gryczynski, I.; Schrader, M.; Engelhardt,
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FAB-HRMS: m/z calcd for C18H13N6 (M + H+) 312.1193, found
+
(b) Teng, M.-K.; Usman, N.; Frederick, C.A.; Wang, A. H.-J.
Nucleic Acids Res. 1988, 16, 2671.
313.1186.
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5,5’-Bis[2-(4-pyridinyl)-1H-benzimidazole] (20)
Prepared from 2 molar equiv of 4-pyridinecarboxaldehyde relative
to 3,3'-diaminobenzidine using Method B; yield: 91%; mp >300 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.21 (s, D2O exch., 1 H, NH),
8.78 (d, 4 H, J = 6 Hz, Pyr-CH), 8.14 (d, 4 H, J = 6 Hz, Pyr-CH),
7.75−7.88 (m, 4 H, Bzi-CH), 7.63 (s, 2 H, Bzi-CH).
13C NMR (75 MHz, HCl salt in D2O): δ = 148.6 (s, C), 147.5 (s, C),
142.9 (d. CH), 136.7 (s, C), 132.7 (s, C), 126.5 (s, C), 120.7 (d, CH),
119.1 (d, CH), 115.8 (d, CH), 112.6 (d, CH).
(e) Abu-Daya, A.; Brown, P. M.; Fox, K. R. Nucleic Acids
Res. 1995, 17, 3385.
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Clegg, R. M. Biochemistry 1990, 29, 9029.
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27, 1619.
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Biochemistry 1996, 35, 13745.
FAB-HRMS: m/z calcd for C24H17N6 (M + H+) 389.1518, found
+
389.1510.
(b) Lombardy, R. L.; Tanious, F. A.; Ramachandran, K.;
Tidwell, R. R.; Wilson, W. D. J. Med. Chem. 1996, 39, 1452.
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Acknowledgement
The authors wish to acknowledge financial and infrastructure sup-
port from the University of Saskatchewan. This research program is
supported through grant support (to MPS) from the Natural Sci-
ences and Engineering Research Council (NSERC) of Canada, the
Health Services and Utilization Research Commission (HSURC) of
Saskatchewan, and the Canadian Foundation for Innovation (CFI).
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Article Identifier:
1437-210X,E;2000,0,10,1380,1390,ftx,en;M05500SS.pdf
Synthesis 2000, No. 10, 1380–1390 ISSN 0039-7881 © Thieme Stuttgart · New York