Supercritical methanol as solvent and carbon source in the catalytic conversion of 1,2-diaminobenzenes and 2-nitroanilines to benzimidazoles

Article abstract of DOI:10.1039/c5gc01040c

Benzimidazoles and N-methylbenzimidazoles were synthesized by simply heating 1,2-diaminobenzenes in supercritical methanol over copper-doped porous metal oxides. These catalysts were derived from synthetic hydrotalcites that only contain earth-abundant starting materials. The carbon equivalents needed for the construction of the benzimidazole core originated from the solvent itself, which is known to undergo reforming to hydrogen and carbon monoxide through the formation of a formaldehyde intermediate. A variety of 1,2-diaminobenzenes were converted to the corresponding mixtures of benzimidazoles and N-methylated analogues in good yields. Interestingly, the more challenging, but readily available 2-nitroanilines, which require an additional reduction step prior to cyclization, could also be successfully converted to benzimidazoles in high selectivity. Furthermore, various other alcohols were applied besides methanol, to obtain 2-alkyl- and 1,2-dialkylbenzimidazoles. Preliminary mechanistic insights into the origins of N-alkylation as well as the reactivity of the nitro derivatives are discussed.

Full text of DOI:10.1039/c5gc01040c

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Supercritical methanol as solvent and carbon source in the catalytic
conversion of 1,2-diaminobenzenes and 2-nitroanilines to
benzimidazoles
Received 00th January 20xx,
Accepted 00th January 20xx
Zhuohua Sun a, Giovanni Bottaria and Katalin Barta*a
DOI: 10.1039/x0xx00000x
Benzimidazoles and N-methylbenzimidazoles were synthesized by simply heating 1,2-diaminobenzenes in supercritical
methanol over copper-doped porous metal oxides. These catalysts were derived from synthetic hydrotalcites that only
contain earth-abundant starting materials. The carbon equivalents needed for the construction of the benzimidazole core
originated from the solvent itself, which is known to undergo reforming to hydrogen and carbon monoxide through the
formation of formaldehyde intermediate. A variety of 1,2-diaminobenzenes were converted to the corresponding mixtures
of benzimidazoles and N-methylated analogues in good yields. Interestingly, the more challenging, but readily available 2-
nitroanilines, which require an additional reduction step prior to cyclization, could also be successfully converted to
benzimidazoles in high selectivity. Furthermore, various other alcohols were applied besides methanol, to obtain 2-alkyl-
and 1,2-dialkylbenzimidazoles. Preliminary mechanistic insights into the origins of N-alkylation as well as the reactivity of
the nitro derivatives are discussed.
www.rsc.org/
synthesis of benzimidazole consists of heating 1,2-
diaminobenzene in concentrated formic acid.8 Many of the
classical methods suffer from low atom economy and
Introduction
Benzimidazole and its derivatives are frequently targeted in
medicinal chemistry research due to their prominent biological
activity.1,2 Several pharmaceutically active structures,
containing the benzimidazole core, have been found to exhibit
significant activity against viruses such as HIV,3 herpes (HSV-1)4
or influenza.5 Furthermore, Esomeprazole (Figure 1) has been
one of the top selling drugs against peptic ulcers and gastro
esophageal reflux in the last decade, while Telmisartan
(Micardis), containing a 1,2-disubstituted benzimidazole, is a
popular antihypertensive.6
formation of stoichiometric amounts of waste due to substrate
leaving groups or additives.7 Recent reports focused on
improving reaction conditions using aldehydes as substrates
and an appropriate oxidizing agent. For example, an inorganic
iodine catalyst in the presence of hydrogen peroxide afforded
high benzimidazole yields from 1,2-diaminobenzenes and
aldehydes at room temperature.9 Microwave-assisted
methodologies have also reduced reaction times.10 In all the
strategies detailed above, the availability of the coupling
partner to o-phenylenediamine may present further
limitations.
Alcohols are readily available starting materials that will
become accessible by fermentation11 or catalytic conversion of
renewable lignocellulose.12 Therefore the development of
catalytic methodologies for the synthesis of benzimidazoles
directly from alcohols is desired. Recent approaches involve
the classical or photochemical oxidation or dehydrogenation of
the alcohol to obtain the more reactive aldehyde, which
subsequently reacts with the diamine to form the desired
benzimidazole ring. For example, one-pot benzimidazole
synthesis was carried out using bifunctional supported gold
and palladium catalysts under oxygen pressure.13 The use of an
iron phthalocyanine catalyst was also reported, which afforded
Figure 1. Commercial drugs containing a benzimidazole core unit.
Classical methods for benzimidazole synthesis involve the
coupling of o-phenylenediamines with acids, acid chlorides or
anhydrides (Scheme 1a), usually requiring strongly acidic
conditions.2,7 For example, a standard procedure for the
a
variety of 2-substituted benzimidazoles from 1,2-
diaminobenzenes.14 Elegant approaches using TiO215and Pt-
TiO216,17 allowed for the photocatalytic (λ>300 nm) coupling of
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hydrogenation steps were transferred from the solvent itself,
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26
which in part underwent reforming to syDnOgIa:s1.0.1039/C5GC01040C
We have devised a related concept for the synthesis of
benzimidazoles using copper doped porous metal oxides in
methanol, whereby in situ formed formaldehyde,27 the
primary product of methanol dehydrogenation would serve as
source of useful carbon equivalents for the construction of the
benzimidazole core upon reaction with 1,2-diaminobenzenes
(scheme 1c). Moreover, the hydrogen produced under these
reaction conditions would allow for accomplishing an
additional reduction step starting from more readily available
2-nitroanilines with no other reagents needed.
Herein, we report the development of such a new, additive-
free method for the preparation of benzimidazoles from
various 1,2-diaminobenzenes as well as 2-nitroanilines simply
by heating these starting materials in scMeOH that acts both
as solvent and reactant, in presence of copper-doped porous
metal oxides (Cu-PMOs). The methodology is extended to the
use of different neat n-alcohols, which offer a route to 1,2-
dialkylbenzimidazoles in good yields.
Experimental section
Catalyst preparation
The HTC (hydrotalcite) catalyst precursors were prepared by a
coprecipitation method, according to literature.24,29 In a typical
procedure, a solution containing AlCl3·6H2O (12.07 g, 0.05
mol), Cu(NO3)2·2.5H2O (6.98 g, 0.03 mol) and MgCl2·6H2O
(24.40 g, 0.12 mol) in deionized water (0.2 L) was added to a
solution containing Na2CO3 (5.30 g, 0.05 mol) in water (0.3 L)
at 60oC under vigorous stirring. The pH was kept between 9
and 10 by addition of small portions of a 1M solution of NaOH.
The mixture was vigorously stirred at 60oC for 72 h. After
cooling to room temperature, the light blue solid was filtered
and resuspended in a 2M solution of Na2CO3 (0.3 L) and stirred
overnight at 40oC. The catalyst precursor was filtered and
washed with deionized water. After drying the solid for 6 h at
100oC, an hydrotalcite precursor (HTC) was obtained. The
corresponding copper-porous metal oxide (Cu-PMO) was
obtained after calcining this material at 460oC for 24 h in air.
Other doped catalysts were prepared according to the same
procedure, replacing a defined amount of Mg2+ and/or Al3+
with Zn2+ , Ni2+ and Ru3+.
Scheme 1. Comparison of existing methods and methods developed in this paper for
the synthesis of benzimidazoles from 1,2-diaminobenzenes as well as 2-nitroanilines. a)
classical methods b) catalytic acceptorless dehydrogenative coupling c) the use of
copper doped porous metal oxides for the transfer of useful carbon equivalents from
methanol.
o-arylenediamines with a variety of alcohols. This catalytic
systems could be also successfully applied to 2-nitroaniline
substrates that are in-situ reduced to 1,2-diaminobenzenes.15,
17
Acceptorless dehydrogenative coupling (Scheme 1b and 1c) 18
has emerged as an attractive strategy for a variety of processes
starting from alcohols during which only hydrogen gas and
innocuous water molecules are eliminated. Through
acceptorless dehydrogenative condensation, important N-
heterocycles
(cyclic
amines,
lactames,
pyrroles,
benzimidazoles, etc.) can be accessed in a clean and highly
atom-economic manner.19,20,21 In 2014, Kempe and coworkers
reported a robust catalytic system for the synthesis of
benzimidazoles and quinoxalines from aromatic 1,2-diamines
Catalytic reactions
22
using a wide range of alcohols and diols.
The reported
In a typical experiment, the substrate (1 mmol) was placed in a
Swagelok stainless steel microreactor (10 mL) and dissolved in
methanol (3 mL). The appropriate amount of catalyst (50 mg)
was added the reactor was sealed and placed in a pre-heated
aluminum block at the desired temperature. After the
indicated reaction time, the microreactor was cooled-down in
an ice-water bath and the liquid sample was separated by
filtration. Samples were analysed by GC-MS-FID (Hewlett
Packard 5890) equipped with a Restek RTX-1701 capillary
iridium catalyst capable of acceptorless dehydrogenation, is
highly active at very low catalyst loadings (0.04-1.4%), and
requires the addition of base and diglyme solvent (scheme 1b).
Homogeneous ruthenium catalysts are also known to afford a
number of benzimidazoles, but only in the presence of an
olefin sacrificial acceptor and catalytic amounts of acid.23
The use of copper doped porous metal oxides (Cu-PMO) for
the depolymerization of organosolv lignin24 and lignocellulosic
biomass25 in supercritical methanol was introduced by Ford
and co-workers. In this unique catalyst system, the reductive
equivalents needed for depolymerization and various
o
o
column (40 C keep for 5 minutes, then increased to 280 C
o
with a rate of 10 C/min and keep for 5 minutes). Isolated
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products were purified by column chromatography (silica gel, subsequently 1a and 1b were isolated by column
View Article Online
DOI: 10.1039/C5GC01040C
eluent dichloromethane/hexane/methanol).
chromatography and unambiguously characterized.
Small amounts of N-methylbenzene-1,2-diamine 1c were also
detected in the product mixture (see mechanistic
Recycling tests
After a typical catalytic run (1 mmol 1,2-diaminobenzene, 100 considerations). Decreasing the reaction temperature to 250
mg Cu-PMO, 3 mL methanol, 250 °C, 6h), the catalyst was °C, conversion was 69% and a 2/1 ratio between 1a and 1b
separated from the reaction solution by centrifugation and was found. When the reaction time was prolonged to 3h and
subsequent decantation, additionally washed with methanol 6h higher substrate conversion of 80% and 100% respectively
(2×10 mL), then with acetone (1×10 mL), and dried overnight and lower 1a/1b ratio (1.7/1 and 0.8/1) were seen. Little or no
at room temperature prior to the next run.
product was formed at 220 °C and 150 °C within 2 hours (table
1, entry 5 and 6).
Next, the catalyst to substrate ratio was varied by gradually
increasing substrate amount from 0.6 to 2 mmol at constant
catalyst loading (50 mg) and methanol volume (3 mL). These
results are summarized in table S2 and figure S2. At low
substrate to catalyst ratio (cca 5:1), full conversion was
achieved in 3h and comparable amounts of 1a and 1b were
observed. At higher concentration of o-phenylenediamine, the
substrate was partially converted (e.g. 53% conversion when
using 2 mmol substrate, 7 mol% Cu to substrate, table S2,
entry 5). In all cases, 1a was the major product and the 1a/1b
ratio ranged between 1.3 and 1.9. Thus it can be concluded
that lower temperatures and higher substrate concentration
favor benzimidazole 1a, over its methylated analogue 1b. N-
methyl-o-phenylenediamine could also be detected in the
product mixture up to 13% yield and its formation was favored
at high substrate concentration (see mechanistic
considerations).
Results and discussion
Benzimidazole formation from o-phenylendiamine
Scheme 2. Formation of benzimidazole and N-methylbenzimidazole from 1,2-
diaminobenzene in scMeOH by using copper doped porous metal oxides.
Table 1. Optimization of reaction conditions for the conversion of 1,2-diaminobenzene
to benzimidazole derivatives in methanol using Cu-PMO catalyst. a
Selectivity %b
Time Conversion
(h)
Entry
T (oC)
(%)b
1a (%)
1b (%)
1c (%)
1
2
3
4
5
6
280
250
250
250
220
150
2
2
3
6
2
2
100
69
80
100
16
0
43
41
46
43
13
0
57
21
27
56
1
0
7
7
1
2
0
Table 2. Screening of different PMO compositions for the conversion of 1,2-
diaminobenzene to benzimidazoles derivatives.a
Selectivity %.b%
Conversionb
Catalyst
0
(%)
Not
identified
1a (%)
1b (%)
1c (%)
a. Reaction conditions: 1,2-diaminobenzene (1 mmol), Cu-PMO (50mg), methanol
(3ml). b. Determined by GC analysis.
Cu-PMO
Cu-Ni-PMO
Cu-Zn-PMO
80
62
92
46
45
50
27
9
7
5
3
0
1
4
We started our investigations identifying the products formed
upon heating 1,2-diaminobenzenes in supercritical methanol
in the presence of a Cu-PMO. This catalyst composition,
prepared by calcination of the corresponding hydrotalcite
35
a. Reaction conditions: 1,2-diaminobenzene (1 mmol), catalyst (50 mg) ,
methanol (3 ml), 250 oC, 3h. b. Determined by GC analysis.
o
precursor at 460 C, was previously used in our laboratory for
the hydrogenation of substrates derived from renewables.27,28
The advantages of using hydrotalcite derived copper-doped
Mg-Al mixed oxides in the above-mentioned transformation
are: a) the use of readily available and inexpensive metal
precursors, b) modular synthesis allowing for introduction of
other metal dopants, c) porous amorphous structure with
optimal distribution of the active metals.
The characterization of all porous metal oxides prepared is
shown in the supporting information (see composition
described in table S1). The reaction using 1 mmol 1,2-
diaminobenzene and 50 mg Cu-PMO catalyst at 280 °C for 2 h
(table 1, entry 1) afforded full substrate conversion. The two
main reaction products were identified as benzimidazole 1a
and N-methylbenzimidazole 1b, formed in almost equimolar
ratio (Scheme 2). GC-MS and GC-FID analysis using authentic
standards confirmed formation of these desired products, and
The advantage of hydrotalcites is their modular synthesis as
subtle changes in catalyst composition are expected to have an
influence on catalytic activity. 29 As shown in table 2, two new
catalyst compositions were prepared (see also table S1),
additionally introducing 5 % of Ni2+ or Zn2+ metal dopants,
which did have an influence on both catalyst activity and
product selectivity. With Cu-Ni-PMO 62% conversion was seen
(table 2, entry 2) however 1a selectivity improved compared to
the reactions with Cu-PMO. An opposite effect was found with
Cu-Zn-PMO, which was the most active among the catalysts
tested, and afforded the highest selectivity to benzimidazole
1a (50% at 92% substrate conversion, table 2, entry 3), but a
lower 1a/1b ratio (1.4, compared to 1.7 with Cu-PMO and 5.0
with Cu-Ni-PMO). The amount of unidentified products when
the zinc-doped composition was used was 4%, which is more
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than in the other cases where these amounts were practically the lowest substrate conversion (38%, table 3, eVnietwryAr1tic)lewOhnliinlee
DOI: 10.1039/C5GC01040C
insignificant.
the nickel-doped catalyst showed a moderate 46% conversion
and a 1a/1b ratio of 20/1. Especially when small amounts of Zn
(1/3 with respect to Cu) were introduced, the substrate was
fully converted after 6 hours with 82% selectivity to 1a (table
3, entry 3). Higher Zn loadings (Cu-Zn10-PMO , with 1/2 Zn to
Cu ratio) did not improve the catalyst activity (table 3, entry 4).
Surprisingly, even by introducing ruthenium noble metal in the
composition the catalyst activity did not perform as good as
the Cu-Zn-PMO catalyst; however, a good 69% conversion and
10/1 ratio between 1a and 1b was obtained (table 3, entry 5).
For comparison, a reaction was also performed with Cu-PMO
at longer reaction time (20h, table 3, entry 6) in order to
ensure full conversion and direct comparison with Cu-Zn-PMO
in terms of 1a selectivity. Indeed, a 79% selectivity to 1a was
obtained, close to that obtained by Cu-Zn-PMO.
Formation of benzimidazoles directly from 2-nitroaniline
Scheme 3. One-pot synthesis of benzimidazole derivatives from 2-nitroaniline.
Table 3. Synthesis of benzimidazoles 1a and 1b using 2-nitroaniline substrate.a
Selectivity %b
Conversion
Entry
Catalyst
(%)b
1a
1b
Other products
(%)
(%)
(%)c
In summary, all PMO catalysts prepared were suitable to carry
out the conversion of 2-nitroaniline to benzimidazole in
methanol. Among these, significant differences were
observed: the performance of Cu-PMO and Cu-Ni-PMO was
comparable but considerably lower than the Ru- and Zn-doped
PMO catalysts. The same trend was observed in the conversion
of 1,2-diaminobenzene, but in this case, the differences were
more pronounced.
In addition, figure S2 shows the product formation profile
during 5 hours using Cu-Zn-PMO. The conversion increased
linearly during the first 3 hours (92% conversion), with no
significant changes in the composition of the product mixture.
Kinetic fitting of the obtained data points, revealed a rate
constant of approximately k=0.5 h-1 for the benzimidazole 1a
formation (see supporting information, figure S3) and a
pseudo-first order regime due to supposed excess of
formaldehyde generated.
1
2
3
Cu-PMO
Cu-Ni-PMO
Cu-Zn-PMO
38
46
30
41
82
4
2
4
3
7
100
11
Cu-Zn10-
PMO
4
25
16
2
2
5
6d
Cu-Ru-PMO
Cu-PMO
69
60
79
6
3
5
100
16
a. Reaction conditions: catalyst (50 mg), 2-nitroaniline (1 mmol), methanol (3 ml),
250 oC, 6h. b. Determined by GC-FID. c. Other products mainly include 1-
(methoxymethyl)-benzimidazole. d Reaction time was 20h.
Compared to phenylenediamines, 2-nitroanilines are more
readily available substrates. Generally, 2-nitroanilines are
reduced to 1,2-diaminobenzenes with zerovalent metals (Fe,
Sn, Zn) and diluted mineral acids.30 Direct catalytic methods
that allow for conversion of 2-nitroanilines to benzimidazoles
involve the reduction of the nitro functionality first, followed
by cyclization. A number of such systems, mainly using
aldehydes and acids as coupling partners are known. 31,32,33,34
However, the one-pot direct coupling of alcohols with 2-
nitroanilines to benzimidazoles has only been accomplished by
using photocatalysts,15, 17, 18 and to the best of our knowledge,
the present study represents the first example.
It has been previously shown that copper nanoparticles are
active in reduction of nitro-aromatics.35 Since during methanol
reforming both Cu(0) nanoparticles and hydrogen gas are
generated in our system,27 we anticipated that Cu-PMO in
scCH3OH will be uniquely suited for the reduction of 2-
nitroanilines. The Cu-PMO catalyst is expected to a) promote
the formation of hydrogen gas via methanol reforming, b)
reduce the nitro group by the in situ formed Cu(0) species and
c) provide carbon equivalents for the construction of the
benzimidazole scaffold.
Substrate scope
This new method could be successfully extended to a variety
of 1,2-diaminobenzenes and 2-nitroanilines with various
substituents on the aromatic ring. The reactions were carried
out at 250 °C for a reaction time ensuring full substrate
conversion. The main products were isolated by column
chromatography. It was already discussed that 1,2-
diaminobenzene affords an approximately 1:1 mixture of 1a
and 1b. A good 78% combined isolated yield was obtained
(table 4, entry 1). Using 1,2-diamino-4-methoxybenzene
resulted in a similar outcome (76% combined yield, table 4,
entry 2). Interestingly, a methyl group in the 4 position favored
the formation of the simple benzimidazole (60%, table 4, entry
3) while the analogous t-butyl substrate favored N-
methylbenzimidazole (64%, table 4, entry 4). An interesting
case is offered by substrate 3,3’-diaminobenzidine, containing
a diphenyl backbone and two possible reactive sites (table 4,
entry 5). In this case the progress of the reaction was
monitored by TLC due to the high molecular weights of the
products. Three different products were detected and isolated
by chromatography. The major product 5c was isolated in a
good 51% yield while lower yields of two N-methylated
Indeed, the PMO catalysts showed moderate to excellent
activity (38% to full conversion in 6 hours) depending on the
metal dopant (see table 3) in the direct conversion of 2-
nitroanilines to benzimidazoles. More interestingly, the
reaction was shown highly selective towards the formation of
benzimidazole 1a (see table 3). The Cu-PMO catalyst afforded
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benzimidazoles were obtained (15% of the bis-N-methylated substrates were more reactive. A deactivating effect was
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5a and 8% of the mono-N-methylated 5b, both present as observed for
a
4-chloro-1,2-diaminobenzene,
DOI: 10.1039/C5GC0w10h4i0cCh
couple of structural isomers). A diaminopyridine backbone preferentially underwent methylation of the NH2 groups
afforded valuable imidazo-pyridine compounds, although a affording only little benzimidazole yields (table 4, entry 7),
lower yield could be attributed to less basic NH2 groups (table moreover, dehalogenation also took place.
4, entry 6). A longer reaction time (15h) did not afford higher Several 2-nitroanilines were also employed to give higher
substrate conversion. Electronic effects derived from yields of unsubstituted benzimidazoles, and most substrates
substituents in the aromatic ring largely influenced the were fully converted in only 3h in presence of the more
reactivity of 1,2-diaminobenzenes. More electron-rich reactive Cu-Zn-PMO catalyst. When using 2-nitroaniline, 68%
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DOI: 10.1039/C5GC01040C
Table 4. Scope of methodology in the formation of benzimidazoles and N-methylbenzimidazoles using Cu-PMO and Cu-Zn-PMO compositions.
Selectivityc (yield)d (%)
Time
(h)
Entrya
Substrate
Conversion (%)c
a
b
1
2
3
6
6
6
100
100
100
1a, 56c (42)d
1b, 44 (36)
2a, 51 (42)
3a, 70 (60)
2b, 49 (34)
3b, 28 (21)
4
6
100
4a, 8
4b, 76 (64)
5
15
100
5a (15)
5b (8)
5c (51)
6
7
6
6
40
6a (4)
6b, (22)
100
42
16
24
8b
9b
6
3
3
100
100
100
8a, 82 (68)
9a, 80 (73)
10a, 80 (73)
8b, 11
9b, 13
10b
10b, 12
11b
3
100
11a, 78 (61)
11b, 7
12b
13b
6
100
86
12a, 90 (80)
13a, (7)
12b, 3
12
13b, (5)
a. Reaction conditions: substrate (1 mmol), Cu-PMO (50 mg), methanol (3ml), 250 oC. b. Reaction conditions: substrate (1 mmol), Cu-Zn-PMO (50 mg), methanol (3ml),
250 oC c. Determined by GC-FID. d. Isolated yields after chromatography.
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Table 5. Synthesis of 2-alkyl- and 1,2-dialkylbenzimidazoles by using different alcohols.
View Article Online
DOI: 10.1039/C5GC01040C
Entrya
Alcohol
Ethanol
Time (h)
6
substrate
Yield (%)c
1
1,2-diaminobenzene
14a
14a
37
14b
14b
38
16
2
3
Ethanol
19
15
2-nitroaniline
77
1-propanol
1,2-diaminobenzene
15a
15a
66
15b
15b
23
27
4
5
1-propanol
1-butanol
19
15
2-nitroaniline
62
1,2-diaminobenzene
16a
44
16b
24
6
1-pentanol
15
15
1,2-diaminobenzene
1,2-diaminobenzene
17a
18a
50
17b
18b
45
7b
Benzyl alcohol
26
26
a) Reaction conditions: substrate (1 mmol), alcohol (3 ml), Cu-PMO (50 mg), 250 oC. Full substrate conversion. b) Reaction conditions: 1,2-diaminobenzene (1 mmol),
benzyl alcohol (1 mmol), Cu-PMO (50 mg), toluene (3ml), 250 oC. 80% conversion. c) Isolated yields by column chromatography.
benzimidazole yield was achieved. In contrast to the 1,2- products may be further functionalized by C-H activation.36
diaminobenzenes, alkyl substituents and electron-donating - Metal-catalyzed alkylation,37 arylation,38 acylation39 and
OMe group in the aromatic ring of 2-nitroanilines did not annulation reactions40 are known to proceed at this position
influence to a large extent the product selectivity. Selectivity with excellent chemoselectivity. Nonetheless, we extended the
to N-methyl benzimidazoles 8b-12b ranged from 3% to 13%. scope of our methodology established with methanol, to the
Very good isolated yields of benzimidazoles 8a-12a were use of other n-alcohols to form 2-alkylbenzimidazole products,
obtained (68-80%) and are shown in table 4 (entry 8-12). The since supported copper catalysts41 and copper hydrotalcites
presence of a halogen led to significant catalyst deactivation, are known to generally promote dehydrogenation of a variety
and only small amounts of benzimidazole products (12% of alcohols to the corresponding aldehydes. 42, 43 Reaction of
combined yield, table 4, entry 13) were obtained.
1,2-diaminobenzenes in ethanol gave results very similar to
Table 4 shows that benzimidazoles unsubstituted in the 2 those observed in methanol (75% combined yield with a 1:1
position can be readily prepared in methanol solvent from product ratio, table 5, entry 1). The 2-nitroaniline in ethanol
both 1,2-diaminobenzenes as well as 2-nitroanilines in good afforded higher yield of compound 14a (77%) and smaller
yields. In order to achieve variations in the 2 position, fraction of 14b (16%, table 5, entry 2). When the reaction was
frequently related to a specific biological activity, these carried out in 1-propanol, a good isolated yield of 2-
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ethylbenzimidazole was obtained from 1,2-diaminobenzene while a small Mg and Al loss was observed in the analysis of
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(66%, table 5, entry 3), and this amount was similar when 2- the liquid sample after reaction with theDCOuI:-P10M.1O039c/aCt5aGlyCs0t.1040C
nitroaniline was used (62%, table 5, entry 4). 2-
Mechanistic considerations
alkylbenzimidazoles were isolated as main products when 1-
butanol and 1-pentanol was coupled with 1,2-diaminobenzene
(table 5, entry 5 and 6). The corresponding 2,3-dialkylated
products were also isolated in moderate yields (24% and 45%).
A reaction between 1,2-diaminobenzene and benzyl alcohol
was performed in toluene affording almost full diamine
conversion, but low 2-phenylbenzimidazole yield (26%, table 5,
entry 7). Interestingly, an equal amount (26%) of benzylated
starting material was isolated accounting for a competition
between the hydrogenation of the imine intermediate with the
cyclization process.
Based on previous reports16,17,35, 36, 44 a preliminary mechanistic
description can be proposed involving methanol
dehydrogenation,
imine
formation/cyclization
and
dehydrogenation. The Cu-PMO catalysts have multiple roles,
catalyzing
methanol
reforming
which
leads
to
formaldehyde12,27 that likely represents a key intermediate.45
Excess of formaldehyde with 1,2-diaminobenzene has been
elsewhere
shown
to
give
the
expected
N-
methylbenzimidazole.10 In addition, we have independently
verified the formation of benzimidazole with formaldehyde in
presence of a Cu-PMO catalyst.
Recycling tests and catalyst stability
The more activated 1,2-diaminobenzene substrates may react
with one or two molecules of formaldehyde (present in excess
in the reaction medium) to give imine intermediates. Related
imines with benzyl alcohol have been detected by Ghosh et al.
at room temperature.47 However, the imines shown on
Scheme 4 will be difficult to isolate, as they should undergo
rapid cyclization or hydrogenation. In fact, hydrogenation of
the imine bond is plausible and would account for the
formation of larger amounts of 1c (scheme 4, green arrow).
Compound 1a can be originated from cyclization of the mono-
imine intermediate, 1,3-hydrogen shift and dehydrogenation
of the corresponding benzimidazoline intermediate (scheme 4,
blue arrows) analogously to previously proposed pathways.35
The process should be further driven by the aromatization to
the corresponding benzimidazole product, which would be
aided by the catalyst. Related dehydrogenation of the CH-NH
bond to imines and nitriles with alumina-supported Cu
nanoparticles is known. 46
Figure 2. Catalyst recycling experiments. Conditions: 1,2-diaminobenzene (1
mmol), Cu-PMO (100 mg), methanol (3 ml), 250 oC, 6h.
Recycling experiments were conducted at 250 oC with 1,2-
diaminobenzene (1 mmol and Cu-PMO (0.1 g) for 6 h (see
figure 2). The catalyst was recovered at the end of each run,
washed with methanol and acetone, and reused after drying.
The catalyst showed excellent selectivity to benzimidazole and
1-methylbenzimidazole (>80%) for 6 cycles and after the 7th
cycle still a good 75% combined selectivity was observed. The
catalyst has proven considerable stability after converting
more than 0.5 g 1,2-diaminobenzene in relatively harsh
conditions.
Scheme 4. Proposed reaction network for the formation of 1a, 1b and 1c from 1,2-
Interestingly, a variation in selectivity to benzimidazole 1a is
visible between the first and the second cycle (45% vs 20%
selectivity) while the relative product distribution is constant
for the subsequent cycles. This trend is very likely related to
the initial low concentration of active Cu0 species, and which
are formed in situ during the first cycle from CuO present in
the catalyst.27
diaminobenzene (solid arrows indicate the main pathways).
Under comparable reaction conditions (see table S3 in the
supporting information), the Cu-Zn-PMO showed almost no
leaching of the metals incorporated in the catalyst structure
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Scheme 5. Cyclization of N-methyl-o-phenylendiamine (top) and direct methylation of
benzimidazole (bottom) in scMeOH and in presence of Cu-PMO.
on different compositions differing in the Zn loVaiedwinAgrticslehOonulinlde
shed light on the promoting effect of this dopant towards the
DOI: 10.1039/C5GC01040C
nitro group reduction.
N-methylbenzimidazole 1b can be obtained through several
possible pathways (scheme 4, solid red arrows). Compounds 1c
can be a precursor of 1b, which can be obtained by reaction of
1c with formaldehyde, H shift and dehydrogenation. We have
verified that compound 1c is indeed converted into 1b in high
84% yield in 3h at 250 °C (scheme 5, top). This observation is
also in agreement with the relatively low amount of 1c in the
product mixtures (1-7%, see table 1). A second, less likely
possibility is the formation of a diimine intermediate followed
Conclusions
A variety of benzimidazole derivatives have been successfully
synthesized in supercritical methanol by means of inexpensive
copper catalysts, that are derived from earth abundant
materials, whose structure and catalytic properties are easily
tunable. The solvent serves as source of in-situ formed
formaldehyde, thus useful carbon for the construction of the
benzimidazole core through the acceptorless dehydrogenative
condensation strategy. 1,2-diaminobenzenes could be
converted with moderate to excellent combined yields of
benzimidazoles and N-methylbenzimidazoles. Moreover, more
readily available 2-nitroanilines could also be used to yield
benzimidazoles in even higher selectivity. The described
methodology displays a number of advantages: a) neat
methanol is both solvent and reactant and can be replaced by
other n-alcohols in order to access targeted benzimidazoles or
2-alkylbenzimidazoles, b) no additives other than the solvent
(oxidants, bases or acids) are needed, c) catalysts consist of
readily available, inexpensive metals and d) only water and
hydrogen are generated as by-products. Future efforts focus
on the synthesis of valuable N- and O-heterocyclic compounds
and developing more active dehydrogenation catalysts that
can operate at milder reaction conditions.
by reduction to
a
monoimine and subsequent
cyclization/dehydrogenation to the desired product 1b. A third
way to generate 1b is the methylation of benzimidazole 1a,
nevertheless low conversion and product yield (~10% with
both Cu-PMO and Cu-Zn-PMO, scheme 5, bottom) were
obtained using benzimidazole 1a as starting material in
scMeOH, also according to the expected lower reactivity of the
aromatic substrate 1a.
Scheme 6. Proposed pathways network for the formation of 1a and 1b from 2-
nitroaniline.
Regarding the reactivity of 2-nitroanilines in the presence of
Cu-PMO catalysts in scMeOH, we performed test reactions
using 2-nitrotoluene in order to gain insight into the outcome
of nitro group reduction. The reaction proceeded with full
conversion to N,2-dimethylaniline (57%) and N,N,2-
trimethylaniline (43%) after 6h with Cu-PMO. Under the same
experimental conditions, conversion was only 38% with 2-
nitroaniline as substrate (table 3, entry 1). While the reduction
of aromatic nitro compounds is already known to proceed in
presence of copper catalysts,36 to the best of our knowledge
no data are available on the copper-mediated cyclization of o-
nitroanilines to benzimidazoles directly from alcohols.
Methods employing semiconductor photocatalytic systems are
known to perform the mentioned one-pot process.15, 17, 18
Based on thus far available experimental data and previous
reports, our preliminary proposed mechanism comprises
several steps, summarized in scheme 6. The high selectivity to
benzimidazole 1a hints at direct cyclization of already at the
hydroxylamine stage. The formed product might undergo
subsequent dehydration (scheme 6). In contrast, reduction to
1,2-diaminobenzene, would instead lead to a mixture of 1a
and 1b (as shown in table 1) as previously established. The
competing hydrogenation of the N=CH2 bond does not take
place to a large extent and the small amount of 1b in these
runs seems to coincide in most cases (see table 4) with slow
methylation of 1a (see scheme 5 and 6).
Acknowledgements
We are grateful for financial support from the China
Scholarship Council (grant number 201406060027) and from
European Commission for an Intra-european Marie Curie
fellowship (grant 622724 - Asymm.Fe.SusCat).
Notes and references
1
L. B. Townsend and G. R. Revankar, Chem. Rev., 1970, 70, 389–
438.
2
M. Alamgir, D. St. C. Black and N. Kumar, in Bioactive
Heterocycles III, ed. M. Khan, Springer Berlin Heidelberg, 2007,
vol. 9, pp. 87–118.
3
4
A. R. Porcari, R. V. Devivar, L. S. Kucera, J. C. Drach and L. B.
Townsend, J. Med. Chem., 1998, 2623, 1252–1262.
M. T. Migawa, J. Girardet, J. A. Walker, G. W. Koszalka, S. D.
Chamberlain, J. C. Drach and L. B. Townsend, J. Med. Chem.,
1998, 2623, 1242–1251.
5
6
B. Soni, PharmaTutor, 2014, 2, 110–118.
L. C. R. Carvalho, E. Fernandes and M. M. B. Marques, Chem. Eur.
J., 2011, 17, 12544–12555.
7
a) D. A. Horton, G. T. Bourne and M. L. Smythe, Chem.
Rev. 2003, 103, 893-930. b) S. S. Panda, R. Malik and S. C. Jain,
Curr. Org. Chem., 2012, 16, 1905-1919.
Another interesting point relates to the presence of dopants in
the PMO compositions. In this regard, more extended studies
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Please do not adjust margins
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Page 11 of 11
ARTICLE
Journal Name
8
9
E. C. Wagner and W. H. Millett, Org. Synth. 1939, 19, 12-12.
C. Zhu and Y. Wei, ChemSusChem, 2011, 4, 1082–1086.
30 a) F.Cavani, F.Trifiró and A.Vaccari, Catal. Today, 1991, 11, 173-
View Article Online
DOI: 10.1039/C5GC01040C
301. b) S. Nishimura, A. Takagaki, K. Ebitani, Green Chem., 2013,
15, 2026–2042.
10 a) S. M. Landge and B. Török, Catal. Lett., 2008, 122, 338–343; b)
Z. Mao, Z. Wang, J. Li, X. Song and Y. Luo, Synth. Commun., 2010,
40, 1963-1977.; c) G. Navarrete-Vazquez, H. Moreno-Diaz, S.
31 R. A. Smiley, Phenylene- and Toluenediamines, John Wiley &
Sons, Inc., New York, 2000
Estrada-Soto, M. Torres-Piedra, I. Leon-Rivera, H. Tlahuext, O. 32 D. S. VanVliet, P. Gillespie and J. J. Scicinski, Tetrahedron Lett.,
Munoz-Muniz and H. Torres-Gomez, Synth. Commun., 2007, 37,
2815-2825; d) G. V. Reddy, V. V. V. N. S. R. Rao, B. Narsaiah and
P. S. Rao, Synth. Commun., 2002, 32, 2467-2476.
2005, 46, 6741–6743.
33 E. J. Hanan, B. K. Chan, A. A. Estrada, D. G. Shore and J. P.
Lyssikatos, Synlett, 2010, 18, 2759–2764.
11 R. Arora, S. Behera and S. Kumar, Recent Adv. Bioenergy Res.,
2014, 3, 149–155. B) H. H. Khoo, Renew. Sustain. Energy Rev.,
2015, 46, 100–119
34 T. B. Nguyen, J. L. Bescont, L. Ermolenko and A. A. Mourabit,
Org. Lett, 2013, 15, 6218–6221.
35 N. A. Weires, J. Boster, J. Magolan, Eur. J. Org. Chem., 2012, 33,
12 a) K. Barta, P. C. Ford, Acc. Chem. Res., 2014, 47, 1503–1512. b)
A. Dutta, M. Talmadge, J. Hensley, M. Worley, D. Dudgeon, D.
Barton, P. Groenendijk, D. Ferrari, B. Stears, E. Searcy, C. Wright
and J. R. Hess, Environ. Prog. Sustainable Energy, 2012, 31, 182-
190.
6508–6512.
36 a) A. Saha and B. Ranu, J. Org. Chem., 2008, 73, 6867–6870. b) R.
Kaur, C. Giordano, M. Gradzielski and S. K. Mehta, Chem. Asian
J., 2014, 9, 189–198. c) H. Feng, Y. Li, S. Lin, E. V Van der Eycken
and G. Song, Sustain. Chem. Process., 2014, 2, 14.
13 V. R. Ruiz, A. Corma and M. J. Sabater, Tetrahedron, 2010, 66,
730–735.
37 J. C. Lewis, R. G. Bergman and J. A. Ellman, Acc. Chem. Res.,
2008, 41, 1013–1025.
14 M. Bala, P. K. Verma, U. Sharma, N. Kumar and B. Singh, Green
Chem., 2013, 15, 1687–1693.
38 a) V. Ritleng, C. Sirlin and M. Pfeffer, Chem Rev., 2002, 102,
1731–1769. b) K. L. Tan, S. Park, J. A. Ellman and R. G. Bergman,
J. Org. Chem., 2004, 69, 7329-7335. c) K. L. Tan, R. G. Bergman
and J. A. Ellman, J. Am. Chem. Soc., 2002, 124, 13964-13965.
15 H. Wang, R. E. Partch and Y. Li, J. Org. Chem., 1997, 62, 5222-
5225.
16 Y. Shiraishi, Y. Sugano, S. Tanaka and T. Hirai, Angew. Chem. Int.
Ed. Engl., 2010, 49, 1656–1660.
39 S. Pivsa-Art, T. Satoh, Y. Kawamura, M. Miura and M. Nomura,
Bull. Chem. Soc. Jpn., 1998, 71, 467–473.
17 K. Selvam and M. Swaminathan, Tetrahedron Lett., 2011, 52,
40 a) N. Chatani, T. Fukuyama, F. Kakiuchi and S. Murai, J. Am.
Chem. Soc., 1996, 118, 493-494. b) E. J. Moore, W. R. Pretzer, T.
J. O’Connell, J. Harris, L. LaBounty, L. Chou and S. S.Grimmer, J.
Am. Chem. Soc., 1992, 114, 5888-5890.
3386–3392.
18 M. Annadhasan, K. Selvam and M. Swaminathan, Synth.
Commun., 2012, 42, 1500–1508.
19 a) C. Gunanathan, D. Milstein, Science, 2013, 341, 1229712. b) G.
E. Dobereiner, R. H. Crabtree, Chem. Rev., 2010, 110, 681–703.
41 K. L. Tan, R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc.,
2001, 123, 2685-2686.
20 S. Michlik and R. Kempe, Nat. Chem., 2013, 5, 140–144.
42 L. Zhang, Y. Zhang, Y. Deng and F. Shi, Catal. Sci. Technol., 2015,
DOI: 10.1039/c5cy00316d.
21 D. Forberg, J. Obenauf, M. Friedrich, S. Hühne, W. Mader, G.
Motzc, R. Kempe, Catal. Sci. Technol., 2014, 4, 4188–4192.
43 T. Mitsudome, Y. Mikami, K. Ebata, T. Mizugaki, K. Jitsukawa
and K. Kaneda, Chem. Commun., 2008, 39, 4804–4806.
22 D. Pingen and D. Vogt, Catal. Sci. Technol., 2014, 4, 47–52
44 J. Bain, P. Cho and A. Voutchkova-Kostal, Green Chem., 2015, 17,
23 T. Hille, T. Irrgang and R. Kempe, Chem. Eur. J., 2014, 20, 5569–
2271–2280.
5572.
45 P. Ghosh and A. Mandal, Catal. Commun., 2011, 12, 744–747.
24 A. J. Blacker, M. M. Farah, M. I. Hall, S. P. Marsden, O. Saidi and
J. M. J. Williams, Org. Lett., 2009, 11, 2039-2042.
46 M. B. Boucher, M. D. Marcinkowski, M. L. Liriano, C. J. Murphy,
E. A. Lewis, A. D. Jewell, M. F. G. Mattera, G. Kyriakou, M.
Flytzani-Stephanopoulos and E. C. H. Sykes, ACS Nano, 2013, 7,
6181–6187.
25 K. Barta, T. D. Matson, M. L. Fettig, S. L. Scott, A. V. Iretskii and P.
C. Ford, Green Chem., 2010, 12, 1640–1647.
26 T. D. Matson, K. Barta, A. V Iretskii and P. C. Ford, J. Am. Chem.
Soc., 2011, 133, 14090–14097.
47 D. Damodara, R. Arundhathi and P. R. Likhar, Adv. Synth. Catal.,
2014, 356, 189–198.
27 G. S. Macala, T. D. Matson, C. L. Johnson, R. S. Lewis, A. V.
Iretskii and P. C. Ford, ChemSusChem, 2009, 2, 215–217.
28 A. J. Kumalaputri, G. Bottari, P. M. Erne, H. J. Heeres and K.
Barta, ChemSusChem, 2014, 7, 2266–2275.
29 W.Yin, R.H. Wenderbosch, G. Bottari, K.K. Krawzcyk, K. Barta
and H.J. Heeres, Appl. Catal. B: Environ., 2015, 166-167, 56-65.
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