A practical oxone - Mediated, high-throughput, solution-phase synthesis of benzimidazoles from 1,2-phenylenediamines and aldehydes and its application to preparative scale synthesis

Article abstract of DOI:10.1055/s-2003-40888

Addition of oxone to a mixture of a 1,2-phenylenediamine and an aldehyde in wet DMF at room temperature results in rapid formation of benzimidazoles under very mild conditions. The reaction is applicable to a wide range of substrates including aliphatic,

Full text of DOI:10.1055/s-2003-40888

PAPER
1683
A Practical Oxone®–Mediated, High-Throughput, Solution-Phase Synthesis
of Benzimidazoles from 1,2-Phenylenediamines and Aldehydes and its Appli-
cation to Preparative Scale Synthesis
O
xone®–Med
i
iate
d
S
e
ynthesis of
r
B
enzimi
r
dazole
s
efrom 1,2-Phenyle
L
nediamines and
.
A
ldehydes Beaulieu,* Bruno Haché, Elisabeth von Moos
Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard Street, Laval (Québec) H7S 2G5, Canada
Fax +1(450)6828434; E-mail: pbeaulieu@lav.boehringer-ingelheim.com
Received 31 March 2003
While many strategies are available for benzimidazole
Abstract: Addition of oxone® to a mixture of a 1,2-phenylenedi-
synthesis,4 the most popular approaches generally involve
amine and an aldehyde in wet DMF at room temperature results in
condensation–dehydration of 1,2-phenylenediamines 1
with carboxylic acids (or equivalents), or condensation
rapid formation of benzimidazoles under very mild conditions. The
reaction is applicable to a wide range of substrates including ali-
phatic, aromatic and heteroaromatic aldehydes, and is not signifi- with aldehydes under oxidative conditions (Scheme 1).
cantly affected by steric or electronic effects. In most cases, crude
The use of carboxylic acids or equivalents (nitriles, ami-
products are isolated in good to excellent yields (59–95%) and ho-
dates, orthoesters) is usually performed under strongly
mogeneities (86–99%) by simple precipitation or extraction from
acidic3a,b or harsh dehydrating conditions that often re-
the reaction mixture and do not require additional purification. Lim-
quire high temperatures3d,5c or the use of agents such as
itations to the scope of this methodology were encountered in cases
phosphorus anhydrides.5 The reaction can also be per-
formed stepwise via intermediate amides 2. While exten-
sive structural diversity is available commercially in the
case of carboxylic acids, availability of nitriles, amidates
and ortho esters is much more limited. In the case of alde-
hydes, good structural diversity is also accessible from
commercial sources. In this case, the reaction proceeds
through a benzimidazoline 3, which requires an oxidative
step for conversion to the corresponding benzimidazole 4
as shown in Scheme 1. While this oxidation can proceed
spontaneously by disproportionation, this can lead to the
occurrence of side-products.3g,6 Other oxidative methods
require the use of nitrobenzene or DMF at elevated tem-
peratures,7 metal ions,5a,8 organic oxidants such as quino-
nes,9 tetracyanoethylene,10 and benzofuroxan,11 or
inorganic sulfites under heating.6b,12 Iodine can also be
used for the oxidative step but can lead to side reaction
when performed in the presence of aromatic rings prone to
electrophilic attack.13 While many published methods are
effective, several are not conveniently performed in a
high-throughput fashion. The main limitations arise from
the use of high temperatures (often >150 °C), long reac-
tion times, toxic solvents, and the use of strongly acidic
conditions that may be detrimental to some sensitive sub-
strates. The use of metal ions (e.g. Fe, Cu), in addition to
environmental concerns, often requires de-complexation
of the metal from the product benzimidazole with the help
of obnoxious reagents such as H2S.5a,8 The use of organic
oxidants, while practical for solid-phase chemistry, usual-
ly requires an additional separation–purification step to
remove reduced by-products which limits their usefulness
when performed in solution.
where aldehydes were sensitive to oxone® under the acidic reaction
conditions. The features of this methodology make it particularly
well suited for the high-throughput, solution-phase synthesis of
benzimidazole libraries. The low cost and simplicity of this proce-
dure makes it equally attractive for preparative-scale syntheses
where safety and environmental issues are of greater concern.
Key words: benzimidazoles, heterocycles, aldehydes, amines, ox-
one, combinatorial chemistry
Interest in benzimidazole-containing structures stems
from their widespread occurrence in molecules that dis-
play a plethora of useful biological properties. Substituted
benzimidazole derivatives have found commercial appli-
cation in veterinarian medicine as anthelmintic agents and
in such diverse human therapeutic areas as antiulcers, an-
tihypertensives, antivirals, antifungals, anticancers and
antihistaminics to name just a few.1 In light of the affinity
they display towards a variety of enzymes and protein re-
ceptors, medicinal chemists would certainly qualify them
as ‘privileged sub-structures’ for drug design.2
The advent of high-throughput screening technologies has
impacted significantly on the methodologies that are used
for the synthesis of medicinal compounds. The implemen-
tation in the laboratory of high-throughput synthetic tech-
niques to increase the number of molecules generated by
chemists is now a prerequisite to competitive advantage in
the field. The parallel synthesis of benzimidazole libraries
is a good example of this trend and several publications
describing methodologies for this application, both in so-
lution phase and on solid supports, have appeared in the
literature.3
In setting out to develop a new methodology to prepare
poly-substituted benzimidazole libraries, several criteria
were defined in advance: applicability to high-throughput
synthesis in solution phase, short reaction times, mild con-
ditions, broad scope, clean reactions requiring minimal or
Synthesis 2003, No. 11, Print: 05 08 2003.
Art Id.1437-210X,E;2003,0,11,1683,1692,ftx,en;M00803SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1684
P. L. Beaulieu et al.
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Table 1 1,2-Phenylenediamine Starting Materials 1
Starting material R2NH2
Yield (%) Yield (%)
98
100
99
99
98
70
95
5
6
7
8
98
Scheme 1
substrates, ease of recovery of products and ability to pro-
mote a reaction between organic substrates and an inor-
ganic reagent (oxone®: 2 KHSO5·KHSO4·K2SO4).14 We
found that ‘wet’ DMF (DMF–H2O, 30:1) satisfied all of
the above criteria: diamine 5 and 2-pyridinecarboxalde-
hyde (1.1 equiv) were dissolved in a 30:1 mixture of
DMF–H2O (ca. 1.5 mL on a mmol scale) and oxone® (0.65
equiv; the reagent provides two moles of oxidizing agent)
was added. After stirring the light suspension for 30 min-
utes at room temperature, HPLC analysis indicated com-
plete conversion to the desired benzimidazole (Table 2,
entry 1). The reaction mixture, which still had the appear-
ance of a very light suspension, was diluted with 20 vol-
umes of water, causing precipitation of the product, which
was collected by filtration, washed with water and dried.
The yield of crude product was 85% and it had >99% ho-
mogeneity as shown by reversed-phase HPLC. Encour-
aged by this initial result, we set out to examine the scope
and limitations of this procedure.
no purification, ease of isolation and environmental
friendliness. After screening a set of potential oxidizing
agents, we discovered that oxone®14 effects a clean conver-
sion of 1,2-phenylenediamines 1 and aldehydes to the de-
sired benzimidazoles 4 as shown in Scheme 2.
Scheme 2
The transformation proceeded under very mild conditions
and satisfied all of our previously set criteria. In particu-
lar, crude products were isolated in good to excellent
yields (59–95%) by simple filtration of a precipitate or ex-
traction with an organic solvent. The homogeneity (as de-
termined by reversed-phase HPLC) of the crude products
was generally > 86% which is satisfactory for direct bio-
logical testing or further structural elaboration. In several
instances, isolated crude products gave satisfactory CHN
elemental analyses. This paper describes the scope and
limitations we encountered in the development of this
methodology.
As can be seen from the results in Table 2, the methodol-
ogy is applicable to a wide range of substrates. In all cases,
crude benzimidazoles of >86% homogeneity, as deter-
mined by RP-HPLC, were isolated by simple filtration of
a precipitate resulting from dilution of the reaction mix-
ture with aqueous K2CO3. When the product remained in
solution or as an oil, it was isolated by extraction with
EtOAc. Crude products were recovered in 59–95% yield.
Phenylenediamines containing electron-rich alkylaryl (6),
hindered tertiary alkyl (7) or aromatic N-substituents (8)
performed equally well. The diversity laid out in our se-
lection of aldehydes (Table 2) further reinforces the scope
of this methodology. Aromatic as well as heteroaromatic
aldehydes can be used. Some nitrogen and sulfur contain-
ing heterocycles (entries 1, 4 and 14) were not affected by
the oxidizing power of oxone®, and electron-rich aldehydes
(entries 9 and 10) were also well tolerated. Functionalities
such as carboxylic acid (entry 2) and phenolic hydroxyl
groups (entry 3) do not require protection. Interestingly,
the literature describes very limited examples of benzimi-
dazole syntheses from aliphatic aldehydes.3c,12a As can be
1,2-Phenylenediamine starting materials 1 were obtained
either from commercial sources or prepared in two steps
from 2-chloro- or 2-fluoronitroarenes via an SNAr reac-
tion followed by reduction of the nitro group by catalytic
hydrogenolysis15 as shown in Table 1.
Phenylenediamine 5 and 2-pyridinecarboxaldehyde were
used as substrates for the initial optimization of the reac-
tion conditions (Table 2, entry 1). In selecting an appro-
priate solvent for the transformation, several factors were
taken into consideration: inertness towards oxidizing
agents, adequate solubilizing capacity for a diverse set of
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Oxone®–Mediated Synthesis of Benzimidazoles from 1,2-Phenylenediamines and Aldehydes
1685
Table 2 Preparation of Benzimidazoles
In general, reactions are complete in less than 2 hours, ex-
tending to overnight in the case of hindered substrates (en-
tries 9 and 11) or less electrophilic aldehydes (entries 9,
10 and 13). The longer reaction time required in the case
of 4-cyanobenzaldehyde (entry 8) is quite surprising when
compared to another electron-deficient substrate, 4-ni-
trobenzaldehyde (entry 7), which reacted much faster,
however, both the yield and purity of the isolated product
remained very high.
En- Starting material
try
R3CHO
Reac- Yielda Homo-
tion
time
(h)
(crude) geneityb
(%)
(crude)
(%)
1
2
1
85
>99
Nevertheless, some limitations were encountered in the
development of this methodology and they are summa-
rized in Table 3. In most cases, unsuccessful reactions
could be traced to the aldehyde component and its incom-
patibility towards oxone®. For example , -unsaturated al-
dehydes (in entries 1 and 2 of Table 3) and indole 3-
carboxaldehyde gave complex reaction mixtures. In the
case of hindered aldehydes (e.g. pivalaldehyde), 4-(di-
methylamino)benzaldehyde and some heterocyclic alde-
0.5
66
98
3 6
4 6
1
1
84
73
>99
>99
hydes
(e.g.
2-thiazolylcarboxaldehyde,
2-
pyrrolecarboxaldehyde) an unusual side reaction led to
the formation of 2H-benzimidazoles such as 9 (entry 1 in
Table 3 and Scheme 3). The occurrence of benzimidazole
9 can be rationalized from initial oxone®-promoted Bayer–
Villiger oxidation of the aldehyde to give the correspond-
ing formate ester 10. This in turn formylates the phe-
nylenediamine to produce intermediate formamide 11 and
the reduced aldehyde (in some cases, the presence of the
alcohol–phenol was confirmed by mass spectral analysis
of the reaction mixture).14c,16 Under the acidic conditions
of the reaction, formamide 11 undergoes rapid ring clo-
sure to 2-hydroxybenzamidine 12 followed by dehydra-
tion to benzimidazole 9. This process is comparable to the
well-known formation of 2H-benzimidazoles from 1,2-
phenylenediamines and orthoformates.3a,b,17
5 6
6 6
7
2
80
83
79
96
>99
99
0.5
2.5
8 7
9 7
18
19
89
70
97
92
10 7
11 7
5
95
59
86
97
Table 3 Limitations of this Methodology
22
Entry
1
Diamine
Aldehydes
Comments
5
Aldehydes
unstable to
oxone
or
7
12
1.5
89
97
Side reaction:
(2H-benz-
imidazole)
13 8
14 8
20
86
88
96
96
1.5
15 8
1.5
68
94
2
8
Complex
reaction
mixture
a Yield of crude material obtained after dilution of reaction mixture
with 20 volumes of aq K2CO3and collection of the precipitate by fil-
tration or extraction with EtOAc.
b Reversed-phase HPLC homogeneity of the crude products.
Indole:
self-
condensation
seen from entries 5, 6 and 15 in Table 2, aliphatic alde-
hydes are good substrates for the oxone®-mediated proce-
dure.
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1686
P. L. Beaulieu et al.
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Scheme 3
Table 4 Extension of the Methodology to the Preparation of N-H-
Benzimidazoles
Extension of this methodology to the preparation of N-H-
benzimidazoles required some minor adjustments to the
general operating procedure. As shown in Scheme 4,
when 4-hydroxybenzaldehyde and 4,5-dimethyl-1,2-phe-
nylenediamine 13 were reacted with oxone® under stan-
dard conditions,
a
2:1 mixture of the desired
benzimidazole 14 and diimine 15 was obtained.18 To min-
imize formation of diimine 15, the aldehyde was added
slowly over 1 h (as a solution in DMF using a syringe
pump) to a mixture of phenylenediamine and oxone®. The
observed ratio of desired benzimidazole 14 to diimine 15
improved to 14:1, providing a simple solution for the ex-
tension of the methodology to this class of products
(Table 4). Table 4 illustrates that formation of the diimine
side product 15 can be maintained under 10%. Despite the
presence of this contaminant, the desired benzimidazole
14 was isolated in reasonable yield and purity using the
standard isolation protocol (precipitation or extraction).
Entry RCHO
HPLC
ratio
14:15
Reaction Yield 14 % Homo-
timea
(h)
(crude)b geneity
(%)
HPLC
(crude)
1
2
3
14:1
9:1
3
82
85
55
87
90
0.5
0.25
15:1
>99
a Reaction time following addition of the aldehyde over 1 h using a
syringe pump.
b Yield of crude material obtained after dilution of the reaction mix-
ture with 20 volumes of water and collection of the precipitate by fil-
tration or extraction with EtOAc.
The oxone®-mediated synthesis of benzimidazoles present-
ed here also shows great potential as a method of choice
for large-scale synthesis of these heterocycles under safe
and environmentally sound conditions. To demonstrate
this potential, the reaction shown in entry 1 of Table 2 was
scaled-up to provide multi-gram quantities of the corre-
sponding benzimidazole (72% yield, > 99% HPLC homo-
geneity, see Experimental section).19
Finally, as another potential extension of this methodolo-
gy, we attempted to prepare benzoxazoles from ortho-
aminophenols and aldehydes. Most methods capable of
carrying out this transformation involve the use of metals.
Scheme 4
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Oxone®–Mediated Synthesis of Benzimidazoles from 1,2-Phenylenediamines and Aldehydes
1687
0.1% TFA over 11 min). Mps are uncorrected and due to the amor-
phous nature of isolated solids, are reported only in cases where rea-
sonably-well defined melting ranges were observed.
However, a recent report describes a two-step process in
which 2-aminophenols are first condensed with aldehydes
to form a benzoxazoline intermediate 16 which undergoes
oxidative conversion to a benzoxazole 17 with DDQ in an
organic solvent.20a A redox system consisting of chromi-
um(II) chloride and Mn0 has also been reported to convert
ortho-nitrophenols directly into benzoxazoles.20b As
shown in Scheme 5, attempts to oxidize intermediate 16
with oxone® in wet DMF resulted in hydrolysis back to the
starting materials and none of the desired benzoxazole 17
was formed. We suspect the acidic conditions associated
with our procedure are not compatible with the hydrolyti-
cally sensitive aminal 16. Running the reaction under ba-
sic conditions (in the presence of K2CO3) did not resolve
the problem.
1,2-Phenylenediamines from 2-Chloronitroarenes or 2-Fluoro-
nitroarenes and Amines; Ethyl 4-(tert-Butylamino)-3-nitro-
benzoate and Ethyl 3-Amino-4-(tert-butylamino)benzoate (7);
General Procedure
Ethyl 4-chloro-3-nitrobenzoate (5.00 g, 21.8 mmol) was dissolved
in DMSO (20 mL) and tert-butylamine (9.2 mL, 87 mmol, 4 equiv)
was added dropwise. The reaction mixture was stirred 6 h at 70 °C
after which RP-HPLC analysis indicated completion of the reaction.
H2O (150 mL) was added and the resulting yellow precipitate was
collected by filtration, washed with H2O and dried under vacuum to
give the desired nitroarene intermediate.
Yield: 5.75 g (98% yield); > 99% homogeneity by RP-HPLC; crys-
talline yellow solid; mp 124–125 °C.
1H NMR (DMSO-d6): = 8.58 (d, J = 2.2 Hz, 1 H), 8.49 (s, 1 H),
7.92 (dd, J = 9.2, 2.0 Hz, 1 H), 7.33 (d, J = 9.2 Hz, 1 H), 4.27 (q,
J = 7.1 Hz, 2 H), 1.47 (s, 9 H), 1.30 (t, J = 7.1 Hz, 3 H).
13C NMR (DMSO-d6): = 164.3, 146.7, 135.2, 131.1, 128.7, 116.3,
115.9, 60.6, 52.2, 28.9, 14.2.
HRMS (FAB+): m/z calcd for C13H18N2O4, 266.1267; found,
266.1270.
The nitroarene derivative from above (5.16 g, 19.4 mmol) was dis-
solved in MeOH (100 mL) and hydrogenated (1 atm H2 gas) over
20% Pd(OH)2 on charcoal (400 mg) for 24 h. The solution was fil-
tered through a glass fiber filter and volatiles removed under re-
duced pressure to give a dark purple–blue oil that was purified by
flash chromatography (silica gel; EtOAc–hexanes, 1:3→2:3) to
give compound 7.
Scheme 5
Yield: 3.24 g (70% yield); >97% homogeneity by RP-HPLC; brown
semi-solid.
In summary, we have developed an efficient methodology
for the preparation of substituted benzimidazoles from
1,2-phenylenediamines and aldehydes, which makes use
of a mild oxone®-mediated oxidative process. The meth-
odology is applicable to a wide variety of aldehyde sub-
strates (aliphatic, aromatic and heteroaromatic) and
delivers crude products in good yield, excellent homoge-
neity and often analytically pure form, after simple isola-
tion by precipitation or extraction. Reaction conditions are
well adapted to the high-throughput, solution-phase syn-
thesis of benzimidazole libraries. In addition, the method-
ology can be easily scaled-up to produce large amounts of
product under safe and environmentally-friendly condi-
tions.
1H NMR (DMSO-d6): = 7.20 (s, 1 H), 7.19 (dd, J = 9.0, 2.0 Hz, 1
H), 6.72 (d, J = 8.6 Hz, 1 H), 4.75 (br s, 2 H), 4.49 (br s, 1 H), 4.18
(q, J = 7.0 Hz, 2 H), 1.36 (s, 9 H), 1.26 (t, J = 7.0 Hz, 3 H).
13C NMR (DMSO-d6): = 166.3, 139.3, 135.2, 120.3, 116.9, 115.1,
111.3, 59.4, 50.6, 29.3, 14.4.
HRMS (FAB+): m/z calcd for C13H20N2O2, 236.1525; found
236.1530.
Ethyl 4-(Cyclohexylamino)-3-nitrobenzoate and Ethyl 3-Ami-
no-4-(Cyclohexylamino)benzoate (5)
The nitroarene intermediate was obtained from ethyl 4-chloro-3-ni-
trobenzoate and cyclohexylamine (2.1 equiv).
Yield: 98%; 1.48 mole scale; >97% homogeneity by RP-HPLC;
crystalline yellow solid; mp 82.5–83.5 °C.
1H NMR (DMSO-d6): = 8.61 (d, J = 2.0 Hz, 1 H), 8.28 (d, J = 7.8
Hz, 1 H), 7.95 (dd, J = 9.3, 2.0 Hz, 1 H), 7.22 (d, J = 9.1 Hz, 1 H),
4.29 (q, J = 7.1 Hz, 2 H), 3.72 (m, 1 H), 2.00–1.92 (m, 2 H), 1.75–
1.65 (m, 2 H), 1.65–1.56 (m, 1H), 1.48–1.38 (m, 4 H), 1.31 (t, J =
7.1 Hz, 3 H), 1.30–1.22 (m, 1 H).
13C NMR (DMSO-d6): = 164.3, 146.5, 135.7, 130.2, 128.5, 116.0,
115.1, 60.6, 50.6, 31.7, 24.9, 24.0, 14.2.
Reagents and solvents (HPLC grade) were from commercial sourc-
es and were used as received. All reactions were carried out under
open atmosphere with no precautions taken to exclude ambient
1
moisture. H and 13C NMR spectra were recorded on a 400 MHz
Bruker Avance-400 and are calibrated to the solvent chemical shift.
Low-resolution mass spectra were obtained on a Micromass Plat-
form LCZ model ZMD 4000 in electrospray mode. High-resolution
mass spectra were obtained on a Micromass AutoSpec instrument
in FAB ionization mode, using an NBA matrix. HPLC chromato-
grams were recorded on a Waters Alliance 2690 equipped with a
Waters 2487 dual wavelength UV-absorbance detector set at 220/
254 nm. Separations were performed on a YMC CombiScreen
ODS-AQ 300 reversed-phase column (50 × 4.6 mm I.D., particle
size S-5 M, 120 Å, 0 to 50% or 5 to 100% MeCN + 0.1% TFA in
MS (ES+): m/z = 293 (MH+). Anal. Calcd for C15H20N2O4: C, 61.63;
H, 6.90; N, 9.58. Found: C, 62.02; 6.99; N, 9.67.
Hydrogenolysis of the nitro group following the model procedure
gave compound 5 as an amorphous dark purple solid that was used
without further purification.
Yield: 99%; >98% homogeneity by RP-HPLC; mp 98–105 °C.
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P. L. Beaulieu et al.
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1H NMR (DMSO-d6): = 7.18 (dd, J = 8.1, 2.0 Hz, 1 H), 7.16 (m,
1 H), 6.45 (d, J = 8.3 Hz, 1 H), 4.89 (br d, J = 6.6 Hz, 1 H), 4.79 (br
s, 2 H), 4.17 (q, J = 7.1 Hz, 2 H), 1.95 (br d, J = 10.3 Hz, 2 H), 1.73
(br dt, J = 13.2, 3.4 Hz, 2 H), 1.62 (br dt, J = 12.7, 3.4 Hz, 1 H),
1.42–1.28 (m, 2 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.22–1.10 (m, 3 H).
13C NMR (DMSO-d6): = 166.3, 139.4, 133.8, 120.7, 116.4, 114.5,
108.1, 59.3, 50.6, 39.5, 32.5, 25.5, 24.6, 14.4.
Hydrogenolysis of the nitro group following the model procedure
gave compound 8, which was used without further purification.
Yield: 95%; 96% homogeneity by RP-HPLC; dark semi-solid.
1H NMR (DMSO-d6): = 7.10–7.03 (m, 3 H), 6.99 (br s, J = 1.6 Hz,
1 H), 6.89 (d, J = 8.2 Hz, 2 H, part of AB), 6.80 (br d, J = 8.0 Hz, 1
H), 5.14 (br s, 1 H), 2.23 (s, 3 H).
13C NMR (DMSO-d6): = 140.7, 139.3, 133.3, 129.5, 129.0, 121.3
(q), 118.0, 116.6, 113.2, 113.1, 110.7, 20.3.
HRMS (FAB+): m/z calcd for C15H22N2O2, 262.1681; found,
262.1683.
HRMS (FAB+): m/z calcd for C14H13F3N2, 266.1031; found,
266.1041.
Anal. Calcd for C15H22N2O2: C, 68.67; H, 8.45; N, 10.68. Found: C,
69.02; 8.57; N, 10.33.
Oxone®-Mediated Preparation of Benzimidazoles from 1,2-
Phenylenediamines and Aldehydes; Ethyl 1-Cyclohexyl-2-pyri-
din-2-yl-1H-benzimidazole-5-carboxylate (Entry 1, Table 2);
General Procedure
N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-nitroaniline and N-[2-(3,4-
Dimethoxyphenyl)ethyl]benzene-1,2-diamine (6)
From 2-fluoronitrobenzene and 3,4-dimethoxyphenethylamine (1.1
equiv) and diisopropylethylamine (1.4 equiv as an acid scavenger),
the nitroarene intermediate was obtained after 16 h at 70 °C.
Diamine 5 (0.500 g, 1.91 mmol, 1 equiv) was dissolved in DMF (3
mL) and distilled H2O (0.1 mL) was added. 2-Pyridinecarboxalde-
hyde (0.20 mL, 2.1 mmol, 1.1 equiv) was added followed by oxone®
(0.762 g, 1.24 mmol, 0.65 equiv). The mixture was stirred for 1 h at
r.t. after which HPLC analysis indicated complete reaction. The re-
action mixture was added dropwise with vigorous stirring into a
mixture of K2CO3 (1 M; 2.5 mL) and H2O (60 mL). In cases where
the product precipitated as a free flowing solid, it was collected by
filtration, washed with H2O and dried. In cases where gummy ma-
terial precipitated (as in this example) the product was extracted
into EtOAc (40 mL), the organic phase was washed with H2O, brine
and dried (MgSO4). Evaporation of the solvent gave a reddish
brown solid that was dried under vacuum (0.567 g, 85% yield,
> 99% homogeneity). The material was identical to that prepared on
a larger scale (see below).
Yield: quantitative; >98% homogeneity; crystalline orange solid;
mp 134–134.5 °C.
1H NMR (DMSO-d6): = 8.08 (br t, J = 6.2 Hz, 1 H), 8.04 (dd,
J = 8.6, 1.4 Hz, 1 H), 7.56–7.50 (m, 1 H), 7.09 (d, J = 8.6 Hz, 1 H),
6.92 (d, J = 1.6 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.80 (dd, J = 8.2,
1.8 Hz, 1 H), 6.70–6.64 (m, 1 H), 3.75 (s, 3 H), 3.71 (s, 3 H), 3.56
(q, J = 5.9 Hz, 2 H), 2.88 (t, J = 7.0 Hz, 2 H).
13C NMR (DMSO-d6): = 148.7, 147.4, 145.1, 136.7, 131.2, 130.9,
126.2, 120.7, 115.3, 114.6, 112.7, 112.0, 55.5, 55.4, 43.9, 34.0.
MS (ES+): m/z = 267 (MH+).
Anal. Calcd for C16H18N2O4: C, 63.57; H, 6.00; N, 9.27. Found: C,
63.37; 6.04; N, 9.28.
Hydrogenolysis of the nitro group following the model procedure
gave compound 6 that was used without further purification.
Preparative Scale Synthesis of Ethyl 1-Cyclohexyl-2-pyridin-2-
yl-1H-benzimidazole-5-carboxylate (Entry 1, Table 2)
The procedure described above on 1 mmol scale was scaled up to
prepare multi-gram quantities of benzimidazoles. The following
procedure is representative. Diamine 5 (26.70 g, 101.7 mmol) was
dissolved in DMF (160 mL) and H2O (5.3 mL) was added. 2-Pyridi-
necarboxaldehyde (10.65 mL, 112 mmol) was added dropwise fol-
lowed by oxone® (40.67 g, 66 mmol) in one portion. HPLC analysis
indicated complete reaction after stirring for 30 min at r.t.. The re-
action mixture was added slowly with vigorous stirring to H2O (1
L) and K2CO3 (1 M; 110 mL) was added in small portions (caution:
foaming). The precipitated solid was extracted into EtOAc (500
mL) and the extract washed successively with H2O (2 ×) and brine.
After drying (MgSO4), the solvent was evaporated under reduced
pressure to give a black residue. Trituration (hexane–tert-butyl me-
thyl ether 9:1; 200 mL), filtration and drying under vacuum gave the
desired benzimidazole product.
Yield: 98%; 96% homogeneity by RP-HPLC; dark purple semi-sol-
id.
1H NMR (DMSO-d6): = 6.90–6.85 (m, 2 H), 6.79 (dd, J = 8.0, 1.6
Hz, 1 H), 6.58–6.46 (m, 3 H), 6.42 (dt, J = 7.1, 1.6 Hz, 1 H), 4.41
(br m, 1 H), 3.75 (s, 3 H), 3.71 (s, 3 H), 3.21 (t, J = 7.2 Hz, 2 H),
2.81 (t, J = 7.2 Hz, 2 H).
13C NMR (DMSO-d6): = 148.7, 147.2, 135.8, 135.1, 132.5, 120.5,
117.7, 116.9, 114.2, 112.7, 112.0, 110.0, 55.6, 55.4, 45.3, 34.5.
HRMS (FAB+): m/z calcd for C16H20N2O2, 272.1525; found,
272.1527.
N-(4-Methylphenyl)-2-nitro-4-(trifluoromethyl)aniline and N1-
(4-Methylphenyl)-4-(trifluoromethyl)benzene-1,2-diamine (8)
From 4-fluoro-3-nitrobenzotrifluoride and para-toluidine (1.05
equiv) and diisopropylethylamine (1.05 equiv as an acid scaven-
ger), the nitroarene intermediate was obtained after 16 h at 70 °C.
Yield: 25.80 g (72% yield); >99% homogeneity; grayish brown sol-
id; mp 130–132 °C.
1H NMR (DMSO-d6): = 8.78 (br d, J = 4.1 Hz, 1 H), 8.31 (d,
J = 1.2 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.05 (dd, J = 7.6, 1.6 Hz,
1 H), 8.02 (d, J = 8.6 Hz, 1 H), 7.89 (dd, J = 8.6, 1.4 Hz, 1 H), 7.58
(ddd, J = 7.4, 4.9, 1.0 Hz, 1 H), 5.34 (tt, J = 12.4, 3.6 Hz, 1 H), 4.35
(q, J = 7.0 Hz, 2 H), 2.28 (m, 2 H), 1.97 (m, 2 H), 1.87 (m, 2 H),
1.68 (m, 1 H), 1.47–1.30 (m, 3 H), 1.37 (t, J = 7.0 Hz, 3 H).
13C NMR (DMSO-d6): = 166.1, 152.3, 149.8, 149.0, 142.4, 137.7,
137.5, 125.6, 124.6, 123.7, 123.4, 121.4, 113.5, 60.5, 56.7, 30.5,
25.6, 24.5, 14.2.
Yield: 98%; >99% homogeneity by RP-HPLC; crystalline orange
solid; mp 113.5–114 °C.
1H NMR (DMSO-d6): = 8.35 (br d, J = 1.0 Hz, 1 H), 7.72 (dd,
J = 9.0, 2.0 Hz, 1 H), 7.29 (d, J = 8.2 Hz, 2 H, part of AB), 7.24 (d,
J = 8.4 Hz, 2 H, part of AB), 7.13 (t, J = 4.5 Hz, 1 H), 2.34 (s, 3 H).
13C NMR (DMSO-d6): = 145.2, 135.9, 135.3, 131.7, 131.6, 131.5,
130.2, 125.4, 124.0, 123.9, 117.4, 116.8 (q), 20.6.
MS (ES–): m/z = 295 (M – H).
MS(ES–): m/z = 350 (M – H).
Anal. Calcd for C14H11F3N2O2: C, 56.76; H, 3.74; N, 9.46. Found:
C, 57.11; 3.57; N, 9.44.
Anal. Calcd for C21H23N3O2: C, 72.02; H, 6.68; N, 11.88. Found: C,
71.75; 6.57; N, 11.76.
Synthesis 2003, No. 11, 1683–1692 © Thieme Stuttgart · New York

PAPER
Oxone®–Mediated Synthesis of Benzimidazoles from 1,2-Phenylenediamines and Aldehydes
1689
3-{1-[2-(3,4-Dimethoxyphenyl)ethyl]-1H-benzimidazol-2-
yl}benzoic Acid (Entry 2, Table 2)
From diamine 6 and 3-carboxybenzaldehyde, the product was iso-
lated by extraction.
Yield: 80%; 96% homogeneity; dark oil that solidified on standing.
1H NMR (DMSO-d6): = 7.55 (d, J = 7.2 Hz, 1 H), 7.53 (d, J = 7.0
Hz, 1 H), 7.22–7.11 (m, 2 H), 6.78 (d, J = 8.0 Hz, 1 H), 6.51 (br s,
1 H), 6.47 (dd, J = 8.0, 1.6 Hz, 1 H), 4.39 (t, J = 6.3 Hz, 2 H), 3.67
(s, 3 H), 3.58 (s, 3 H), 2.94 (t, J = 6.1 Hz, 2 H), 2.36–2.29 (m, 1 H),
1.75–1.60 (m, 3 H), 1.55–1.40 (m, 4 H), 1.24–1.17 (m, 3 H).
Yield: 66% yield; 98% homogeneity; amorphous light-beige solid;
mp 167–172 °C.
1H NMR (DMSO-d6): = 13.17 (br s, 1 H), 8.03 (m, 2 H), 7.76 (t,
J = 7.8 Hz, 2 H), 7.69 (d, J = 7.6 Hz, 1 H), 7.59 (t, J = 7.8 Hz, 1 H),
7.34 (t, J = 7.3 Hz, 1 H), 7.28 (t, J = 7.4 Hz, 1 H), 6.62 (d, J = 8.0
Hz, 1 H), 6.31 (d, J = 1.2 Hz, 1 H), 6.25 (dd, J = 8.0, 1.4 Hz, 1 H),
4.53 (t, J = 6.3 Hz, 2 H), 3.65 (s, 3 H), 3.46 (s, 3 H), 2.90 (t, J = 7.2
Hz, 2 H).
13C NMR (DMSO-d6): = 159.0, 148.7, 147.6, 142.3, 134.3, 130.7,
121.4, 121.2, 120.8, 118.4, 112.5, 111.9, 110.2, 55.6, 55.2, 44.5,
35.0, 34.7, 31.5, 25.7, 25.5.
HRMS (FAB+): m/z calcd for C23H29N2O2, 365.2229; found,
365.2244.
13C NMR (DMSO-d6): = 166.8, 152.5, 148.5, 147.6, 142.6, 135.4,
133.1, 131.0, 130.6, 130.0, 129.8, 129.7, 128.7, 122.6, 122.1, 120.4,
119.2, 112.0, 111.5, 111.3, 55.3, 55.0, 45.9, 34.4.
1-[2-(3,4-Dimethoxyphenyl)ethyl]-2-isopropyl-1H-benzimida-
zole (Entry 6, Table 2)
From diamine 6 and isobutyraldehyde, the product was isolated by
extraction.
HRMS (FAB+): m/z calcd for C24H33N2O4, 403.1658; found,
403.1662.
Yield: 83%; >99% homogeneity; as a dark oil.
1H NMR (DMSO-d6): = 7.59 (d, J = 8.1 Hz, 1 H), 7.56 (d, J = 8.3
Hz, 1 H), 7.22 (t, J = 7.5 Hz, 1 H), 7.18 (t, J = 7.6 Hz, 1 H), 6.79 (d,
J = 8.3 Hz, 1 H), 6.55 (br d, J = 6.4 Hz, 1 H), 6.53 (br s, 1 H), 4.41
(t, J = 6.6 Hz, 2 H), 3.68 (s, 3 H), 3.58 (s, 3 H), 2.95 (t, J = 6.6 Hz,
2 H), 2.91 (m, 1 H), 1.13 (d, J = 6.6 Hz, 6 H).
4-{1-[2-(3,4-Dimethoxyphenyl)ethyl]-1H-benzimidazol-2-yl}-
phenol (Entry 3, Table 2).
From diamine 6 and 4-hydroxybenzaldehyde, the product was iso-
lated by precipitation.
Yield: 84% yield; > 99% homogeneity; amorphous dark-beige sol-
id; mp 238–242 °C.
13C NMR (DMSO-d6): = 159.8, 158.7, 147.6, 134.2, 130.4, 122.0,
121.8, 120.9, 118.0, 112.6, 112.0, 110.7, 55.6, 55.3, 44.6, 34.6,
25.5, 21.5.
1H NMR (DMSO-d6): = 9.87 (s, 1 H), 7.65 (d, J = 7.8 Hz, 1 H),
7.61 (d, J = 7.6 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.25 (t, J = 7.0
Hz, 1 H), 7.21 (t, J = 7.4 Hz, 1 H), 6.86 (d, J = 8.2 Hz, 2 H), 6.71 (d,
J = 8.0 Hz, 1 H), 6.43 (s, 1 H), 6.40 (d, J = 8.0 Hz, 1 H), 4.44 (t,
J = 6.8 Hz, 2 H), 3.67 (s, 3 H), 3.56 (s, 3 H), 2.90 (t, J = 8.0 Hz, 2
H).
13C NMR (DMSO-d6): = 158.5, 153.6, 148.6, 147.5, 142.5, 135.4,
130.5, 130.1, 121.9, 121.7, 121.0, 120.4, 118.7, 115.2, 112.2, 111.8,
110,8, 55.5, 55.1, 45.7, 34.4.
HRMS (FAB+): m/z calcd for C20H25N2O2, 325.1916; found,
325.1928.
Ethyl 1-tert-Butyl-2-(4-nitrophenyl)-1H-benzimidazole-5-car-
boxylate (Entry 7, Table 2)
From diamine 7 and 4-nitrobenzaldehyde, the product was isolated
by precipitation.
Yield: 79%; 99% homogeneity; amorphous light-gray solid; mp
135–140 °C.
MS (ES+): m/z = 375 (MH+).
Anal. Calcd for C23H22N2O3: C, 73.78; H, 5.92; N, 7.48. Found: C,
73.55; 6.07; N, 7.40.
1H NMR (DMSO-d6): = 8.32 (d, J = 8.6 Hz, 2 H), 8.24 (s, 1 H),
8.07 (d, J = 8.8 Hz, 1 H), 7.91 (d, J = 8.6 Hz, 2 H), 4.34 (q, J = 7.1
Hz, 2 H), 1.58 (s, 9 H), 1.35 (t, J = 7.0 Hz, 3 H).
2-{1-[2-(3,4-Dimethoxyphenyl)ethyl]-1H-benzimidazol-2-yl}-
quinoline (Entry 4, Table 2)
From diamine 6 and quinoline-2-carboxaldehyde, the product was
isolated by precipitation.
13C NMR (DMSO-d6): = 166.0, 153.1, 147.8, 142.6, 141.8, 138.0,
131.3, 123.6, 123.0, 122.8, 121.0, 115.3, 60.6, 59.6, 30.7, 14.2.
HRMS (FAB+): m/z calcd for C20H22N3O4, 368.1610; found,
368.1608.
Yield: 73% yield; > 99% homogeneity; as an amorphous dark-beige
solid; mp 132–133 °C.
Ethyl 1-tert-Butyl-2-(4-cyanophenyl)-1H-benzimidazole-5-car-
boxylate (Entry 8, Table 2)
From diamine 7 and 4-cyanobenzaldehyde, the product was isolated
by precipitation.
1H NMR (DMSO-d6): = 8.46 (d, J = 8.6 Hz, 1 H), 8.29 (d, J = 8.6
Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.87
(t, J = 7.2 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1
H), 7.70 (t, J = 7.4 Hz, 1 H), 7.37 (t, J = 7.4 Hz, 1 H), 7.31 (t, J = 7.4
Hz, 1 H), 6.68 (d, J = 8.0 Hz, 1 H), 6.59 (br s, 1 H), 6.55 (br d,
J = 8.0 Hz, 1 H), 5.24 (t, J = 6.8 Hz, 2 H), 3.65 (s, 3 H), 3.47 (s, 3
H), 3.07 (t, J = 6.6 Hz, 2 H).
13C NMR (DMSO-d6): = 150.1, 149.3, 148.5, 147.4, 146.5, 142.1,
136.8, 136.4, 130.5, 130.2, 128.9, 128.0, 127.5, 127.3, 123.5, 122.5,
121.5, 120.6, 119.7, 112.4, 111.8, 111.1, 55.5, 54.9, 46.4, 35.4.
Yield: 89%; 97% homogeneity; amorphous beige solid; mp 287–
292 °C.
1H NMR (DMSO-d6): = 8.23 (s, 1 H), 8.06 (d, J = 8.8 Hz, 1 H),
7.97 (d, J = 8.2 Hz, 2 H), 7.91 (dd, J = 8.8, 1.4 Hz, 1 H), 7.82 (d,
J = 8.2 Hz, 2 H), 4.35 (q, J = 7.0 Hz, 2 H), 1.56 (s, 9 H), 1.35 (t,
J = 7.0 Hz, 3 H).
13C NMR (DMSO-d6): = 166.0, 153.5, 142.6, 140.1, 138.0, 131.7,
130.8, 123.6, 123.0, 121.0, 118.5, 115.3, 112.0, 60.6, 59.6, 30.7,
14.3.
HRMS (FAB+): m/z calcd for C26H23N3O2, 409.1790; found,
409.1797.
Anal. Calcd for C26H23N3O2: C, 76.26; H, 5.66; N, 10.26. Found: C,
75.82; 5.70; N, 10.13.
MS (ES+): m/z = 348 (MH+).
Anal. Calcd for C21H21N3O2: C, 72.60; H, 6.09; N, 12.10. Found: C,
72.76; 5.85; N, 12.07.
2-Cyclohexyl-1-[2-(3,4-dimethoxyphenyl)ethyl]-1H-benzimida-
zole (Entry 5, Table 2)
From diamine 6 and cyclohexanecarboxaldehyde, the product was
isolated by extraction.
Synthesis 2003, No. 11, 1683–1692 © Thieme Stuttgart · New York

1690
P. L. Beaulieu et al.
PAPER
Ethyl 1-tert-Butyl-2-(3,4-dimethoxyphenyl)-1H-benzimidazole-
5-carboxylate (Entry 9, Table 2)
Anal. Calcd for C21H14BrF3N2: C, 58.49; H, 3.27; N, 6.50. Found:
C, 58.43; 3.02; N, 6.30.
From diamine 7 and 3,4-dimethoxybenzaldehyde, the product was
isolated by precipitation.
N-{4-[1-(4-Methylphenyl)-5-(trifluoromethyl)-1H-benzimida-
zol-2-yl]phenyl}acetamide (Entry 13, Table 2)
From diamine 8 and 4-acetamidobenzaldehyde, the product was
isolated by precipitation.
Yield: 70%; 92% homogeneity; amorphous brown solid; mp 74–
80 °C.
1H NMR (DMSO-d6): = 8.19 (s, 1 H), 8.00 (d, J = 8.8 Hz, 1 H),
7.86 (d, J = 8.8 Hz, 1 H), 7.14 (s, 1 H), 7.04 (m, 2 H), 4.34 (q,
J = 7.0 Hz, 2 H), 3.83 (s, 3 H), 3.78 (s, 3 H), 1.58 (s, 9 H), 1.35 (t,
J = 7.0 Hz, 3 H).
13C NMR (DMSO-d6): = 166.2, 155.3, 149.4, 147.8, 142.4, 138.0,
127.3, 123.2, 122.5, 122.4, 120.7, 115.1, 113.5, 110.7, 60.5, 59.4,
55.7, 55.5, 30.6, 14.3.
Yield: 86% yield; 96% homogeneity; beige-pink amorphous solid;
broad, undefined melting range.
1H NMR (DMSO-d6): = 10.13 (s, 1 H), 8.13 (s, H), 7.61–7.55 (m,
3 H), 7.47 (d, J = 8.6 Hz, 2 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.36 (s, 1
H), 7.33 (d, J = 8.2 Hz, 2 H), 2.42 (s, 3 H), 2.05 (s, 3 H).
13C NMR (DMSO-d6): = 168.7, 154.0, 141.8, 140.8, 139.4, 138.9,
133.3, 130.6, 129.9, 127.3, 123.3, 123.2, 119.7, 118.4, 116.4, 116.3,
111.5, 24.1, 20.8.
HRMS (FAB+): m/z calcd for C22H27N2O4, 383.1971; found,
383.1968.
HRMS (FAB+): m/z calcd for C23H19F3N3O, 410.1480; found,
Ethyl 2-(1,3-Benzodioxol-5-yl)-1-tert-butyl-1H-benzimidazole-
5-carboxylate (Entry 10, Table 2)
410.1481.
From diamine 7 and piperonal, the product was isolated by precipi-
tation.
1-(4-Methylphenyl)-2-(2-thienyl)-5-(trifluoromethyl)-1H-benz-
imidazole (Entry 14, Table 2)
From diamine 8 and 2-thiophenecarboxaldehyde, the product was
isolated by precipitation.
Yield: 95%; 86% homogeneity; brown semi-solid.
1H NMR (DMSO-d6): = 8.19 (m, 1 H), 7.99 (d, J = 8.8 Hz, 1 H),
7.86 (dd, J = 8.8, 1.4 Hz, 1 H), 7.15 (s, 1 H), 7.00 (s, 2 H), 6.12 (br
s, 2 H), 4.34 (q, J = 7.0 Hz, 2 H), 1.58 (s, 9 H), 1.35 (t, J = 7.0 Hz,
3 H).
13C NMR (DMSO-d6): = 166.1, 154.8, 147.9, 146.6, 142.4, 137.9,
128.5, 123.8, 123.2, 122.6, 120.7, 115.0, 110.3, 107.6, 101.4, 60.5,
59.4, 30.6, 14.2.
Yield: 88% yield; 96% homogeneity; amorphous light-beige solid;
mp 139–145 °C.
1H NMR (DMSO-d6): = 8.12 (s, 1 H), 7.61 (dd, J = 5.1, 2.9 Hz, 1
H), 7.55 (d, J = 8.6 Hz, 1 H), 7.51–7.46 (m, 3 H), 7.43 (d, J = 8.2
Hz, 2 H), 7.29–7.23 (m, 2 H), 2.47 (s, 3 H).
13C NMR (DMSO-d6): = 150.3, 141.8, 139.6, 139.4, 133.0, 130.9,
130.2, 127.9, 127.7, 127.6, 127.1, 119.8, 119.7, 116.4, 116.3, 111.4,
20.9.
HRMS (FAB+): m/z calcd for C21H23N2O4, 367.1658; found,
367.1659.
HRMS (FAB+): m/z calcd for C19H14F3N2S, 359.0830; found,
Ethyl 1-tert-Butyl-2-(3-chloro-1-methyl-1H-indol-2-yl)-1H-
benzimidazole-5-carboxylate (Entry 11, Table 2)
From diamine 7 and 3-chloro-1-methyl-2-indolecarboxaldehyde,
the product was isolated by precipitation.
359.0843.
2-Isobutyl-1-(4-methylphenyl)-5-(trifluoromethyl)-1H-benzim-
idazole (Entry 15, Table 2)
From diamine 8 and isovaleraldehyde, the product was isolated by
extraction.
Yield: 59% yield; 97% homogeneity; amorphous dark-beige solid;
mp 182–185 °C.
Yield: 68% yield; 94% homogeneity; amorphous light-beige solid;
mp 103–107 °C.
1H NMR (DMSO-d6): = 8.03 (s, 1 H), 7.53–7.40 (m, 5 H), 7.24 (d,
J = 8.4 Hz, 1 H), 2.65 (d, J = 7.2 Hz, 2 H), 2.45 (s, 3 H), 2.09 (m, 1
H), 0.86 (d, J = 6.7 Hz, 6 H).
1H NMR (DMSO-d6): = 8.34 (s, 1 H), 8.15 (d, J = 8.6 Hz, 1 H),
7.97 (d, J = 8.8 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.60 (d, J = 7.8
Hz, 1 H), 7.40 (t, J = 7.2 Hz, 1 H), 7.27 (t, J = 7.4 Hz, 1 H), 4.37 (q,
J = 7.0 Hz, 2 H), 3.61 (s, 3 H), 1.60 (s, 9 H), 1.36 (t, J = 7.0 Hz, 3
H).
13C NMR (DMSO-d6): = 165.9, 143.1, 142.8, 137.7, 135.2, 128.8,
124.0, 123.9, 123.6, 123.5, 121.7, 121.0, 117.8, 115.5, 111.0, 105.4,
60.7, 59.8, 31.3, 29.2, 14.2.
13C NMR (DMSO-d6): = 156.8, 141.8, 139.1, 138.5, 132.3, 130.7,
127.2, 119.1, 119.0, 116.0, 115.9, 110.9, 35.9, 26.9, 22.3, 20.8.
MS (ES+): m/z = 333 (MH+).
HRMS (FAB+): m/z calcd for C23H25ClN3O2, 410.1635; found,
410.1628.
Anal. Calcd for C19H19F3N2: C, 68.66; H, 5.76; N, 8.43. Found: C,
68.96; 5.69; N, 8.10.
2-(4-Bromophenyl)-1-(4-methylphenyl)-5-(trifluoromethyl)-
1H-benzimidazole (Entry 12, Table 2)
From diamine 8 and 4-bromobenzaldehyde, the product was isolat-
ed by precipitation.
Ethyl 1-Cyclohexyl-1H-benzimidazole-5-carboxylate (9)
The reaction of diamine 5 with thiazole-2-carboxaldehyde gave
compound 9 as the main product (81% according to RP-HPLC)
which was isolated as the trifluoroacetic acid salt by preparative
RP-HPLC.
Yield: 89% yield; 97% homogeneity; amorphous light-beige solid;
mp 134–138 °C.
1H NMR (DMSO-d6): = 8.17 (s, 1 H), 7.66–7.58 (m, 3 H), 7.49 (d,
J = 8.4 Hz, 2 H), 7.44–7.35 (m, 5 H), 2.42 (s, 3 H).
13C NMR (DMSO-d6): = 153.2, 141.9, 139.4, 139.0, 133.0, 131.5,
131.1, 130.7, 128.4, 127.2, 123.8, 123.5, 120.1, 116.8, 116.7, 111.7,
20.7.
Yield: 77% yield; > 99% homogeneity.
1H NMR (DMSO-d6): = 9.21 (s, 1 H), 8.33 (s, 1 H), 8.06–8.01 (m,
2 H), 4.60 (tt, J = 11.7, 3.8 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 2.17–
2.08 (br m, 2 H), 1.95–1.80 (m, 4 H), 1.73 (br d, J = 9.3 Hz, 1 H),
1.52 (br q, J = 13.2 Hz, 2 H), 1.36 (t, J = 7.1 Hz, 3 H), 1.29 (qt,
J = 13.0. 4.8, 1 H).
MS (ES+): m/z = 431, 433 (MH+).
13C NMR (DMSO-d6): = 165.6, 143.1, 136.7, 135.0, 125.8, 124.7,
118.7, 112.6, 61.0, 55.8, 32.2, 24.9, 24.7, 14.2.
Synthesis 2003, No. 11, 1683–1692 © Thieme Stuttgart · New York

PAPER
Oxone®–Mediated Synthesis of Benzimidazoles from 1,2-Phenylenediamines and Aldehydes
1691
HRMS (FAB+): m/z calcd for C16H20N2O2, 272.1525; found,
272.1529.
References
(1) (a) Spasov, A. A.; Yozhitsa, I. N.; Bugaeva, L. I.;
Anisimova, V. A. Pharm. Chem. J. 1999, 33, 232.
N-Unsubstituted Benzimidazoles; 4-(5,6-Dimethyl-1H-benzimi-
dazol-2-yl)phenol (Entry 1, Table 4); General Procedure
The following procedure is representative. 4,5-Dimethyl-1,2-phe-
nylenediamine (13) (0.226 g, 1.66 mmol) was dissolved in DMF (2
mL) and H2O (0.05 mL) was added, followed by oxone® (0.663 g,
1.08 mmol, 0.65 equiv). A solution of 4-hydroxybenzaldehyde
(0.213 g, 1.75 mmol, 1.05 equiv) in DMF (1 mL) was added drop-
wise over 1 h (syringe pump) to the stirred reaction mixture. After
completion, stirring was continued for an additional 3 h at which
point RP-HPLC analysis indicated completion of the reaction. The
reaction mixture was added dropwise with stirring to H2O (60 mL)
and the pH was adjusted to 7 by addition of solid K2CO3. The result-
ing amorphous orange-beige precipitate was collected by filtration,
washed with H2O and dried.
(b) Preston, P. N. Chem. Heterocycl. Compd. 1980, 40, 531.
(2) (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D.
F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D.
J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.;
Hirshfield, J. J. Med. Chem. 1988, 31, 2235. (b) Mason, J.
S.; Morize, I.; Menard, P. R.; Cheney, D. L.; Hulme, C.;
Labaudiniere, R. F. J. Med. Chem. 1999, 42, 3251.
(3) See for example: (a) Chi, Y.-C.; Sun, C.-M. Synlett 2000,
591. (b) Huang, W.; Scarborough, R. M. Tetrahedron Lett.
1999, 40, 2665. (c) Wu, Z.; Rea, P.; Wickham, G.
Tetrahedron Lett. 2000, 41, 9871. (d) Thomas, J. B.; Fall,
M. J.; Cooper, J. B.; Burgess, J. P.; Carroll, F. I. Tetrahedron
Lett. 1997, 38, 5099. (e) Phillips, G. B.; Wei, G. P.
Tetrahedron Lett. 1996, 37, 4887. (f) Sun, Q.; Yan, B.
Bioorg. Med. Chem. Lett. 1998, 8, 361. (g) Smith, J. M.;
Krchák, V. Tetrahedron Lett. 1999, 40, 7633. (h) Mayer, J.
P.; Lewis, G. S.; McGee, C.; Bankaitis-Davis, D.
Tetrahedron Lett. 1998, 39, 6655.
Yield: 0.323 g (82%); 87% homogeneity by RP-HPLC; mp
>300 °C.
1H NMR (DMSO-d6): = 10.15 (br s, 1 H), 7.98 (d, J = 8.6 Hz, 2
H), 7.37 (s, 2 H), 6.95 (d, J = 8.4 Hz, 2 H), 2.33 (s, 6 H).
13C NMR (DMSO-d6): = 159.9, 150.0, 135.2, 131.7, 128.6, 118.7,
115.9, 114.2, 20.0.
(4) Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43,
1893.
HRMS (FAB+): m/z calcd for C15H15N2O, 239.1184; found,
239.1178.
(5) (a) White, A. W.; Almassy, R.; Calvert, A. H.; Curtin, N. J.;
Griffin, R. J.; Hostomsky, Z.; Maegley, K.; Newell, D. R.;
Srinivasan, S.; Golding, B. T. J. Med. Chem. 2000, 43,
4084. (b) Hendrickson, J. B.; Hussoin, M. S. J. Org. Chem.
1987, 52, 4137. (c) Dunwell, D. W.; Evans, D.; Smith, C. E.;
Williamson, W. R. N. J. Med. Chem. 1975, 18, 692.
(d) Güngör, T.; Fouquet, A.; Teulon, J.-M.; Provost, D.;
Cazes, M.; Cloarec, A. J. Med. Chem. 1992, 35, 4455.
(e) Barni, E.; Savarino, P. J. Heterocycl. Chem. 1979, 16,
1583.
4-(5,6-Dimethyl-1H-benzimidazol-2-yl)benzonitrile (Entry 2,
Table 4)
From 4,5-dimethyl-1,2-phenylenediamine (13) and 4-cyanobenz-
aldehyde, the product was isolated by precipitation.
Yield: 85%; 90% homogeneity; amorphous cream-colored solid;
mp 216–225 °C (decomp).
1H NMR (DMSO-d6): = 8.29 (d, J = 8.4 Hz, 2 H), 8.02 (d, J = 8.4
(6) (a) Smith, J. G.; Ho, I. Tetrahedron Lett. 1971, 38, 3541.
(b) Jonas, R.; Klockow, M.; Lues, I.; Prücher, H.; Schliep, H.
J.; Wurziger, H. Eur. J. Med. Chem. 1993, 28, 129.
(7) (a) Blettner, C. G.; König, W. A.; Rühter, G.; Stenzel, W.;
Schotten, T. Synlett 1999, 307. (b) Sun, Q.; Gatto, B.; Yu,
C.; Liu, A.; Liu, L. F.; LaVoie, E. J. J. Med. Chem. 1995, 38,
3638. (c) Ben-Alloum, A.; Bakkas, S.; Soufiaoui, M.
Tetrahedron Lett. 1998, 39, 4481. (d) Satz, A. L.; Bruice, T.
C. Bioorg. Med. Chem. Lett. 1999, 9, 3261. (e) Rangarajan,
M.; Kim, J. S.; Sim, S.-P.; Liu, A.; Liu, L. R.; LaVoie, E. J.
Bioorg. Med. Chem. 2000, 8, 2591. (f) Black, D. St.C.;
Kumar, N.; Wong, L. C. H. Synthesis 1986, 474.
(8) (a) Denny, W. A.; Rewcastle, G. W.; Baguley, B. C. J. Med.
Chem. 1990, 33, 814. (b) Dang, Q.; Brown, B. S.; Erion, M.
D. Tetrahedron Lett. 2000, 41, 6559. (c) Singh, M. P.;
Sasmal, S.; Lu, W.; Chatterjee, M. N. Synthesis 2000, 1380.
(d) Gravatt, G. L.; Baguley, B. C.; Wilson, W. R.; Denny, W.
A. J. Med. Chem. 1994, 37, 4338.
Hz, 2 H), 7.43 (s, 2 H), 2.34 (s, 6 H).
13C NMR (DMSO-d6): = 148.2, 137.4, 133.8, 132.9, 132.0, 126.8,
118.6, 115.2, 111.7, 20.0.
HRMS (FAB+): m/z calcd for C16H14N3, 248.1188; found,
248.1196.
2-(4-Bromophenyl)-5,6-dimethyl-1H-benzimidazole (Entry 3,
Table 4)
From 4,5-dimethyl-1,2-phenylenediamine 13 and 4-bromobenz-
aldehyde, the product was isolated by precipitation.
Yield: 55% yield; >99% homogeneity; amorphous beige-orange
solid; mp >300 °C.
1H NMR (DMSO-d6): = 8.09 (d, J = 8.4 Hz, 2 H), 7.92 (d, J = 8.4
Hz, 2 H), 7.55 (s, 2 H), 2.39 (s, 6 H).
13C NMR (DMSO-d6): = 147.6, 134.4, 132.5, 129.1, 125.7, 124.6,
114.1, 19.9 (one resonance overlap).
(9) (a) Vanden Eynde, J. J.; Delfosse, F.; Lor, P.; Van
Haverbeke, Y. Tetrahedron 1995, 51, 5813. (b)Hopkins, K.
T.; Wilson, W. D.; Bender, B. C.; McCurdy, D. R.; Hall, J.
E.; Tidwell, R. R.; Kumar, A.; Bajic, M.; Boykin, D. W. J.
Med. Chem. 1998, 41, 3872. (c) Lombardy, R. L.; Tanious,
F. A.; Ramachandran, K.; Tidwell, R. R.; Wilson, W. D. J.
Med. Chem. 1996, 39, 1452.
HRMS (FAB+): calcd for C15H14BrN2: 301.0340. Found: 301.0333.
Acknowledgements
We are very grateful to Mr. Michael Little for analytical support and
Mr. James Gillard for some preliminary experiments. We would
also like to acknowledge useful comments from referees.
(10) Chikashita, H.; Nishida, S.; Miyazaki, M.; Morita, Y.; Itoh,
K. Bull Chem. Soc. Jpn. 1987, 60, 737.
(11) Pätzold, F.; Zeuner, F.; Heyer, T. h.; Niclas, H.-J. Synth.
Commun. 1992, 22, 281.
Synthesis 2003, No. 11, 1683–1692 © Thieme Stuttgart · New York

1692
P. L. Beaulieu et al.
PAPER
(12) (a) Ridley, H. F.; Spickett, R. G. W.; Timmis, G. M. J.
Heterocycl. Chem. 1965, 2, 453. (b) Göker, H.; Kus, C.;
Boykin, D. W.; Yildiz, S.; Altanlar, N. Bioorg. Med. Chem.
2002, 10, 2589.
(13) Yukawa, H.; Nagatani, T.; Torisawa, Y.; Okaichi, Y.; Tada,
N.; Furuta, T.; Minamikawa, J.-I.; Nishi, T. Bioorg. Med.
Chem. Lett. 1997, 7, 1267.
literature, but usually involves organic peracids as oxidant.
See for example: (a) Yeager, G. W.; Schissel, D. N.
Synthesis 1991, 63. (b) Krow, G. R. Org. React. 1993, 43,
251. (c) Occurrence of an oxone®-promoted Baeyer–
Villiger process has been proposed in the literature: Wu,
X.-Y.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792;
see also earlier reference (Ref. 14c).
(14) (a) Narsaiah, A. V. Synlett 2002, 1178. (b) For other uses of
oxone® in organic synthesis, see for example: Lee, K.-J.;
You, H.-W. Synlett 2001, 105; and references cited therein.
(c) After submission of this manuscript, Borhan et al.
reported on the use of oxone® for the oxidation of aldehydes
to carboxylic acids: Travis, B. R.; Sivakumar, M.; Hollist, G.
O.; Borhan, B. Org. Lett. 2003, 5, 1031; it appears that
formation of benzimidazoles under the present reaction
conditions is faster than oxidation of the aldehyde substrate
to the corresponding carboxylic acid. It is possible however
that this latter pathway can become competitive for less
reactive substrates and account for some of the lower yields.
(15) For an alternative reduction of nitro groups with stannous
chloride, see for example: Bellamy, F. D.; Ou, K.
Tetrahedron Lett. 1984, 25, 839.
(17) DMF alone or its dimethyl acetal can also promote
conversion of 1,2-phenylenediamines to 2H-benz-
imidazoles, but this usually requires elevated temperatures
and is not suspected to occur under the present oxone®-
promoted reaction conditions: Mataka, S.; Shimojyo, Y.;
Hashimoto, I.; Tashiro, M. Liebigs Ann. 1995, 10, 1823.
(18) The ratio of 14 to 15 did not vary significantly upon
prolonged reaction times indicating that under the reaction
conditions, equilibration of the diamine 15 to benzamidine 3
and eventually to product 14 did not occur.
(19) It is very likely that the quenched reaction mixtures still
retain some oxidizing potential and should be disposed of
appropriately to avoid hazardous decompositions. It has
been reported for example that oxone® will lose active
oxygen slowly under alkaline conditions, see: (a) Kennedy,
R. J.; Stock, A. M. J. Org. Chem. 1960, 25, 1901. (b) Ball,
D. L.; Edwards, J. O. J. Am. Chem. Soc. 1956, 78, 1125.
(20) (a) Chang, J.; Zhao, K.; Pan, S. Tetrahedron Lett. 2002, 43,
951; and references cited therein. (b) Hari, A.; Karan, C.;
Rodrigues, W. C.; Miller, B. L. J. Org. Chem. 2001, 66, 991.
(16) The formation of an intermediate formate ester from the
starting aldehyde through a Baeyer–Villiger oxidation is
inferred from detection of the corresponding alcohol.
Precedent for this kind of process can be found in the
Synthesis 2003, No. 11, 1683–1692 © Thieme Stuttgart · New York