Microwave-assisted synthesis of polysubstituted benzimidazoles by heterogeneous Pd-catalyzed oxidative C-H activation of tertiary amines

Article abstract of DOI:10.1002/ejoc.201101001

Tertiary amines can be used in place of aldehydes and carboxylic derivatives as partners in the synthesis of benzimidazoles. Dehydrogenative amine activation under heterogeneous catalysis was developed for the direct transformation of tertiary amines into benzimidazoles. Good yields and efficient recovery and recycling of the catalyst are some of the advantages of this new methodology, which shows that a simple alkene is used as the overall oxidative agent. Enhanced reaction rates were observed by using focused microwave heating.

Full text of DOI:10.1002/ejoc.201101001

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101001
Microwave-Assisted Synthesis of Polysubstituted Benzimidazoles by
Heterogeneous Pd-Catalyzed Oxidative C–H Activation of Tertiary Amines
Lidia De Luca[a] and Andrea Porcheddu*[a]
Keywords: C-H activation / Nitrogen heterocycles / Hydrogen transfer / Heterogeneous catalysis / Microwave chemistry
Tertiary amines can be used in place of aldehydes and carb-
oxylic derivatives as partners in the synthesis of benzimid-
azoles. Dehydrogenative amine activation under hetero-
geneous catalysis was developed for the direct transforma-
tion of tertiary amines into benzimidazoles. Good yields and
efficient recovery and recycling of the catalyst are some of
the advantages of this new methodology, which shows that
a simple alkene is used as the overall oxidative agent. En-
hanced reaction rates were observed by using focused micro-
wave heating.
vation of tertiary amines followed by oxidative cyclization
with 1,2-phenylenediamine in the presence of a hydrogen
acceptor (Scheme 1).[13]
Introduction
The selective conversion of an amine into a carbonyl
compound is a natural biological process[1] that still remains
a critical challenge in organic synthesis.[2] It would be very
interesting to achieve this goal by promoting new sustain-
able procedures that replace the use of strong stoichiometric
oxidative agents.[3] Recently, it was found that amines bear-
ing α and β hydrogen atoms adjacent to a nitrogen atom
could become promising substrates, as they are readily de-
hydrogenated[4] by transition-metal catalysts to generate
imines.[5] Most of the existing examples of amine activation
are based on the use of iridium and iridium pincer com-
plexes.[6] However, several recent examples outlining the use
of Os, Rh, Ru, and Pd homogeneous catalysts supporting a
variety of different ligands have been reported.[7] Neverthe-
less, despite the impressive multitude of active and selec-
tively soluble catalysts[8] developed to date for C–H acti-
vation,[9] often they are not attractive for industrial applica-
tion owing to stringent requirements for removal of residual
metal from exit streams. In this context, C–H activation
through heterogeneous catalysis represents a fundamental
improvement.[10]
Scheme 1. Preparation of benzimidazole derivatives by “auto-
transfer hydrogenation”.
With this hypothesis in mind, the reaction between o-
phenylenediamine and triethylamine was chosen as a model
to verify our assumption and to find the best reaction con-
ditions (Table 1). o-Phenylenediamine (1a, 1 mmol) was
treated with a nearly stoichiometric amount of triethyl-
amine (2a, 1.1 mmol) in dry toluene using Pd/C (10 wt.-%,
5 mol-%) under microwave dielectric heating at 170 °C for
1.5 h in the presence of an alkene as the hydrogen acceptor
(2.2 mmol).[14] 2-Methylbenzoimidazole (3a) was formed in
almost quantitative isolated yield (Table 1, Entries 1–3).
In order to have a better insight to this reaction, various
parameters were screened. Amongst different alkenes, cro-
tonitrile was chosen as the most suitable (and cheap) hydro-
gen acceptor owing to the volatility of this alkene and its
corresponding reduced product. The solvent plays a signifi-
cant role in terms of isolated yield, as toluene gave the best
results (Table 1, Entry 3), whereas the yield decreased in
other more-polar solvents as THF, MeOH, and 1,4-dioxane
(Table 1, Entries 4–6). Under solvent-free conditions,
(Table 1, Entry 7) a sudden increase in pressure was ob-
served with a risk of explosion (“thermal runaway”).[15] In-
Results and Discussion
Following our interest in the application of Pd/C as a
heterogeneous catalyst for microwave-assisted reactions,[11]
we report herein the synthesis of benzimidazoles[12] under
heterogeneous catalysis based on the one-pot C–H acti-
[a] Università degli Studi di Sassari, Dipartimento di Chimica
Via Vienna 2, 07100 Sassari, Italy
Fax: +39-079-229559
E-mail: anpo@uniss.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101001.
Eur. J. Org. Chem. 2011, 5791–5795
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5791

L. De Luca, A. Porcheddu
SHORT COMMUNICATION
Table 1. Optimization of the reaction conditions.[a]
Scheme 2. The model reaction between 1,2-phelylenediamine and
triethylamine carried out without “hydrogen acceptor”.
Entry
H2
acceptor
Solvent[
toluene
T
[°C]
Pd loading
[mmol-%]
t
[h]
Yield[b]
[%]
1
2
3
4
5
6
7
8
1-hexene
1-dodecene toluene
crotonitrile toluene
170
170
170
170
170
170
170
170
150
190
170
170
170
170
170
170
5
5
5
5
5
5
5
5
5
5
3
2
1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
93
93
93
89
84
65
–
With a more clear picture of the reaction parameters, the
scope and limitations were investigated with respect to the
synthesis of a variety of polysubstituted benzimidazoles.
Some of the most representative results are summarized in
Table 2. We were pleased to find that 1,2-diaminobenzenes
bearing both electron-donating and electron-withdrawing
substituents were converted into the corresponding benz-
imidazoles derivatives 3a–u in good to high yields.[17] It is
also noteworthy that the reaction tolerated a wide range of
functionality on the aryl partner, including carbonyl, ester,
fluoro, and cyano substituents, which are ready for ad-
ditional transformations towards more complex benzimid-
azoles. In general, with o-phenylenediamines bearing an
electron-withdrawing group (Table 2, Entries 2–6), the
yields of the corresponding benzimidazoles decreased even
after prolonged reaction times. 4-Nitro-o-phenylenediamine
crotonitrile
THF
crotonitrile MeOH
crotonitrile dioxane[c]
crotonitrile
neat[d]
crotonitrile toluene
crotonitrile toluene
crotonitrile toluene
crotonitrile toluene
crotonitrile toluene
crotonitrile toluene
crotonitrile toluene
crotonitrile toluene
crotonitrile toluene
1.5 93[e]
9
1.5
1.5
1.5
1.5
1.5
63
92
93
89
80
10
11
12
13
14
15
16
3
1.5 39[f]
[g]
–
1.5
–
3
2.0 40[h]
[a] Unless otherwise specified, the reaction conditions were: o-
phenylenediamine (1.0 mmol), triethylamine (1.1 mmol), Pd/C
(10 wt.-), alkene (2.2 mmol), dry solvent (2.5 mL), under N2.
[b] Isolated yield. [c] 1,4-Dioxane. [d] Under solvent-free condi-
tions, a sudden increase in pressure was observed with risk of ex-
plosion (“thermal runaway”). [e] Reaction performed using a 3:1
molar ratio of triethylamine/1,2-phenylenediamine. [f] Reaction
performed using palladium black in place of Pd/C. [g] Reaction
performed in the absence of any palladium catalyst (control experi-
ment). [h] Reaction carried out in a preheated oil bath.
Table 2. Synthesis of benzimidazoles from ortho-phenylenediamines
and tertiary amines.
creasing the amount of tertiary amine had no effect on
either the yield or the reaction rate (Table 1, Entry 8). Tem-
perature significantly affected the reaction, as working at
temperatures below 160 °C gave incomplete conversion
(Table 1, Entry 9). At 170 °C, the best conversion and reac-
tion rate were achieved, whereas a further increase in tem-
perature did not give any appreciable improvements
(Table 1, Entry 10). Regarding the amount of catalyst re-
quired (Table 1, Entries 11–13), 3 mol-% Pd/C was suf-
ficient to catalyze the reaction, whereas 1 mol-% had a det-
rimental effect on the yield of the product (Table 1, Entry
11 vs. 13). The use of palladium black was significantly less
effective than palladium on charcoal (Table 1, Entry 14).
The same model reaction done with several soluble palla-
dium catalysts gave poor results in terms of yields of 3a
[e.g., Pd(PPh3)4, 18%; PdCl2(PPh3)2, 21%; Pd(AcO)2,
29%]. Control experiments indicated that no reaction oc-
curred in the absence of any palladium catalyst (Table 1,
Entry 15), whereas without the hydrogen acceptor a mix-
ture of products was formed and diamine 4a was the most
abundant component (Scheme 2).
Entry
R
R1
R2
R3
3a–u
(% yield)[b]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Pr
Pr
Bu
pentyl
pentyl
Ph
heptyl
heptyl
Bu
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CN
F
NO2
PhCO
CO2Me
Me
Me
PhCO
H
F
Me
Me
CO2Me
Me
H
H
H
H
H
H
H
Me
H
H
3a (93)
3b (77)
3c (79)
3d (31)
3e (71)
3f (81)
3g (94)
3h (95)
3i (67)
3j (90)
3k (81)
3l (89)
3m (87)
3n (73)
3o (78)
3p (83)
3q (65)
3r (56)
3s (83)
3t (89)
3u (85)
9
10
11
12
13
14
15
16
17
18
19
20
21
H
Me
Me
H
Me
H
Me
H
H
Me
Me
CO2Me
H
H
Me
Me
Ph
In order to compare microwave irradiation with conven-
tional thermal heating, the model reaction was reproduced
in a sealed microwave vial immersed into an oil bath pre-
heated at 170 °C. After 2 h, the conversion was low (40%)
and the process went to completion only within 12 h
(Table 1, Entry 16).[16]
Me
Me
H
H
H
H
[a] Reaction conditions: o-arylenediamine (1 mmol), tertiary amine
(1.1 mmol), Pd/C (10 wt.-%, 3.0 mol-%), dry toluene (2.5 mL),
170 °C, 1.5 h. [b] Yield of isolated products after column
chromatography.
5792
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Eur. J. Org. Chem. 2011, 5791–5795

Microwave-Assisted Synthesis of Polysubstituted Benzimidazoles
Scheme 3. Proposed mechanism for the Pd/C-catalyzed oxidative synthesis of 2-substituted benzimidazoles.
was not entirely consumed in the oxidative cyclization and geneous process. The heterogeneous nature of the catalyst
afforded 6-nitro-1H-benzoimidazole (3d; Table 2, Entry 4) was also confirmed by the Rebeck–Collman three-phase
in low yield together with a mixture of unidentified byprod- tests.[24]
ucts. 3,4-Diaminobenzophenone gave acceptable yields of
The initial step seems to be the insertion of palladium
2-substituted benzimidazole 3e (Table 2, Entry 5). For all into a carbon–hydrogen bond adjacent to the nitrogen,
the remaining combinations of arylenediamine with various leading to a highly active intermediate complex of an imin-
tertiary amines, the desired benzimidazole was isolated in ium ion. The proposed catalytic cycle (Scheme 3) involves
good yields as the major product (Table 2, Entries 9–18).
the removal of a hydride[25] from tertiary amine 2 by a metal
In order to increase the molecular diversity on the benz- catalyst to form (putative) oxidized species 6 (an iminium
imidazole ring,[18] a set of N-substituted phenylenediamines cation),[26] which undergoes a transamination reaction with
was treated with trialkylamines (Table 2, Entries 19–21).[19] o-phenylenediamine (1) to generate intermediate imine 7,
We were also very pleased to observe that the palladium- with generation of 1 mol equivalent of H2. Subsequent for-
catalyzed oxidative cyclization on all these compounds led mation of dihydrobenzazole 8 and oxidation in the presence
to the isolation of N-substituted benzimidazoles 3s–u in of a hydrogen acceptor generates desired heterocycle 3 with
good yields. These last experiments (Table 2, Entries 19–21) regeneration of the Pd catalyst and formal overall transfer
suggest that the method should be quite general for the of two hydrogen molecules to crotonitrile.
preparation of N-substituted benzimidazoles.
In order to drive this protocol towards greater economic
Conclusions
and environmental efficiency, the possibility of recycling the
catalyst was also taken into account. Thus, the recovery and
reusability of the Pd/C catalyst was investigated for the re-
action between o-phenylenediamine and NEt3 in toluene at
170 °C (Table 3).[20] The results presented in Table 3 show
that the catalyst retained its high catalytic activity up to
five consecutive repeated cycles and could be completely
recycled.
In summary we have reported a simple, convenient, and
efficient method for the preparation of benzimidazole deriv-
atives based on the Pd/C-catalyzed C–H activation of terti-
ary amines. This method not only affords the products in
good yields but also avoids the problems associated with
catalyst cost, handling, safety, and pollution. Enhanced re-
action rates were observed by using focused microwave
heating.
Table 3. Recycling test for Pd/C-catalyzed oxidative synthesis of 2-
methyl-1H-benzo[d]imidazole.
Cycle[a]
Yield [%][b]
1
2
3
4
5
Experimental Section
93
91
92
91
92
General Method for the Synthesis of Benzimidazoles: A mixture of
the appropriate o-phenylenediamine (1.0 mmol, 1.0 equiv.), fresh
distilled tertiary amine (1.1 mmol, 1.1 equiv.), crotonitrile
(2.2 mmol, 2.2 equiv.), and 10% Pd/C (0.032g, 0.03 mmol, 3.0 mol-
% compared to o-dianiline) in dry toluene (2.5 mL) was charged
into a 10-mL microwave tube under a nitrogen atmosphere, and
the reaction mixture was irradiated (starting output power: 300 W)
whilst stirring at 170 °C for 1.5 h. After cooling, the solvent was
removed in vacuo, and the organic residue was redissolved in THF.
The palladium catalyst was collected by filtration and washed with
dry THF (3ϫ5 mL). The solvent was removed in vacuo, and the
[a] Reaction conditions: o-phenylenediamine (1 mmol), NEt3
(1.1 mmol), Pd/C (10 wt.-%, 3.0 mol-%), toluene (2.5 mL), 170 °C,
1.5 h. [b] Yield of isolated product.
To ascertain the heterogeneous character of the catalyti-
cally active species in this process, further leaching studies
were performed.[21] Both “Sheldon’s hot-filtration test”[22]
and atomic absorption spectroscopy analysis (ICP-MS) of
the filtrate detected no significant quantities[23] of leached
Pd in solution, suggesting that the reaction is a hetero- crude product was easily purified by column chromatography (hex-
Eur. J. Org. Chem. 2011, 5791–5795
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5793

L. De Luca, A. Porcheddu
SHORT COMMUNICATION
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ane/ethyl acetate) to afford the corresponding benzimidazole. The
identity of the final product was confirmed by satisfactory MS and
1H and 13C NMR spectroscopy.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, characterization data, and
NMR spectra of all compounds.
Acknowledgments
We are grateful for the financial support of the Regione Autonoma
della Sardegna (“Sintesi e caratterizzazione delle proprietà chim-
iche e degli effetti neuromodulatori sul SNC di una libreria di do-
natori di nitrossido derivati dall’acido di Piloty”). We also thank
Prof. Maurizio Taddei for invaluable help in the preparation of this
manuscript.
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the filtrate part.
Less than 2 ppm of leached Pd existed in the filtrate after cata-
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Received: July 9, 2011
[17] The crude products were purified by filtration through a short
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[20] After each run, the catalyst was easily separated by filtration,
washed thoroughly with dry THF, and dried under vacuum to
Published Online: September 6, 2011
Eur. J. Org. Chem. 2011, 5791–5795
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5795