Electrochemical Synthesis of Benzimidazoles via Dehydrogenative Cyclization of Amidines

Article abstract of DOI:10.1002/cssc.202100254

The development of efficient and sustainable methodologies for the synthesis of N-heterocycles is a constant focus of organic synthesis. Herein an electrochemical method is reported for the synthesis of benzimidazoles through dehydrogenative cyclization of easily available N-aryl amidines. The reactions were conducted under simple constant current conditions in an undivided cell without need for catalysts, chemical oxidants, or additives, and produced H₂ as the only theoretical byproduct.

Full text of DOI:10.1002/cssc.202100254

Communications
doi.org/10.1002/cssc.202100254
ChemSusChem
Electrochemical Synthesis of Benzimidazoles via
Dehydrogenative Cyclization of Amidines
Huai-Bo Zhao,[a, b] Jin-Liang Zhuang,*[a] and Hai-Chao Xu*[b]
driven CÀ N bond forming reactions[9] and have reported
The development of efficient and sustainable methodologies
for the synthesis of N-heterocycles is a constant focus of organic
synthesis. Herein an electrochemical method is reported for the
synthesis of benzimidazoles through dehydrogenative cycliza-
tion of easily available N-aryl amidines. The reactions were
conducted under simple constant current conditions in an
undivided cell without need for catalysts, chemical oxidants, or
additives, and produced H2 as the only theoretical byproduct.
electrochemical cyclization of elaborated amidines for the
synthesis of polycyclic heterocycles (Scheme 1c).[9f] The reac-
tions of simple N-aryl amines without the urea moiety are more
difficult because of potential overoxidation of the products.
Herein we report the successful synthesis of benzimidazoles
through electrochemical cyclization of N-aryl amidines
(Scheme 1d). These electromically driven reactions require no
metal catalysts, chemical oxidants, or additives.
We began our study by optimizing the electrolysis con-
ditions for the cyclization of amidine 1 (Table 1), which was
prepared in one step from N-methylaniline and 2-fluorobenzo-
nitrile (see the Supporting Information). For operational con-
venience, the reactions were conducted under constant current
conditions in a simple undivided cell (a three-necked round-
bottomed flask) equipped with a reticulated vitreous carbon
(RVC) anode and a Pt plate cathode. A screening of reaction
conditions revealed that the electrolysis of 1 in a mixed solvent
of THF/MeOH (5:1) at reflux with a constant current of 10 mA
without any acidic or basic additives afforded the desired
benzimidazole 2 in 65% yield (entry 1). The use of MeOH
(entry 2) or hexafluoroisopropanol (HFIP)/MeOH (5:1) (entry 3)
as solvent resulted in a diminished yield of 52% or no product
Benzimidazole is a ubiquitous structural motif in bioactive
compounds and functional materials.[1] While these heterocycles
are commonly prepared from ortho-functionalized anilines,[2]
the intramolecular CÀ H/NÀ H cross-coupling of N-aryl amidines
represents an attractive strategy that minimizes substrate
prefunctionalization.[3] In this context, Brasche and Buchwald
reported in early 2008 Cu-catalyzed cyclizations of N-aryl
amidines under acidic conditions with O2 as the terminal
oxidant (Scheme 1a).[3a] They found that an ortho-substituent
(R“) on the Ar2 group is essential for the reactions of
functionalized amidines, which limits the scope of these
catalytic reactions. At almost the same time, a similar aerobic
transformation was reported by Shi and co-workers employing
Pd-catalysis in the presence of a stoichiometric amount of
Cu(OAc)2 (Scheme 1b).[3b]
An ideal approach to achieve dehydrogenative cross-
coupling reactions is through H2 evolution without need for
metal catalysts and sacrificial chemical oxidants.[4] Such an
approach reduces environmental impact and safety concerns
for the synthetic process, especially in large-scale production.[5,6]
Organic electrochemistry is an enabling synthetic tool to
achieve oxidant-free dehydrogenative transformations through
H2 evolution and has been applied to CÀ H/NÀ H cross-
coupling.[7,8] We have been interested in electrochemically
[a] Dr. H.-B. Zhao, Dr. J.-L. Zhuang
School of Chemistry and Materials Science
Key Lab for Functional Materials Chemistry of Guizhou Province
Guizhou Normal University
116 Baoshan Road North, Guiyang 550001 (P. R. China)
E-mail: jlzhuang@xmu.edu.cn
[b] Dr. H.-B. Zhao, Prof. Dr. H.-C. Xu
Key Laboratory of Chemical Biology of Fujian Province
College of Chemistry and Chemical Engineering
Xiamen University
Xiamen 361005 (P. R. China)
E-mail: haichao.xu@xmu.edu.cn
Homepage: Web: http://hcxu.xmu.edu.cn
Scheme 1. Synthesis of benzimidazoles through oxidative cyclization of
amidines. (a) Cu-catalyzed aerobic cyclization of amidines. (b) Pd-catalyzed
aerobic cyclization of amidines. (c) Electrochemical cyclization of elaborated
amidines. (d) This work: electrochemical cyclization of simple amidines.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cssc.202100254
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an ortho substituent at Ar2 generally afforded lower yields (7 vs.
Table 1. Optimization of reaction conditions.[a]
3; 8 vs. 2). A likely explanation was that the ortho-substituent
reduced conjugation of the Ar2 group with the benzimidazole
ring system and thus increased the oxidation potential of the
product, diminishing its oxidative decomposition. The N-phenyl
group substituted at the meta position with OMe (9), F (10) and
CN (11) were tolerated but afforded a mixture of regioisomers.
The Ar2 group could be phenyl rings substituted at the ortho
position with Cl (12), Br (13), CF3 (14), or Me (15), the meta
position with OMe (16), Cl (17), or CF3 (18), or the para position
with Me (19) or Cl (20). Disubstituted phenyl rings (21–25) and
a pyridyl group (26) were also tolerated.
Entry
Deviation from standard conditions
Yield[b] [%]
1
2
3
4
5
6
7
none
65
52
0
52
50
55
65
MeOH as solvent
HFIP/MeOH (5:1) as solvent
c(1)=0.05 m
I=15 mA
Et4NPF6 (2.0 equiv.)
Et4NPF6 (3.0 equiv.)
We have recently shown that methyl benzoheterocycles
underwent site-selective electrochemical benzylic oxidation in
MeOH to generate dimethylacetals.[10] Hence, N-3,5-dimeth-
ylphenyl amidines were subjected to electrolysis MeOH to
afford benzimidazoles 27–32 via dehydrogenative cyclization
and selective oxidation of the Me group at position 6 to a
dimethylacetal group (Scheme 3). No product derived from the
oxidation of the Me group at C4 was observed. Although THF
was helpful for the cyclization step, these challenging multistep
reactions were conducted without THF because the Me
oxidation benefits from pure MeOH as solvent. The sequential
cyclization and site-selective Me oxidation provided access to
functionalized benzimidazoles that were difficult to obtain with
existing methods. Benzimidazole 33 bearing an electron-with-
drawing pyridyl group at position 2 failed to undergo methyl
oxidation because of competitive solvent oxidation.
[a] Reaction conditions: RVC anode (1 cm×1 cm×1.2 cm), Pt cathode
(1 cm×1 cm), 1 (0.3 mmol), solvent (9 mL). [b] Isolated yield.
at all. Other variations such as increasing the concentration of 1
to 0.05 m (entry 4), the electric current to 15 mA (entry 5), or
the amount of electrolyte to 2 or 3 equiv. (entries 6 and 7) all
failed to further boost the yield of 2.
We then investigated the substrate scope of the electro-
chemical cyclization reactions of amidines (Scheme 2). The N-
phenyl ring (Ar1) could be substituted at the para position with
Me (3 and 7), F (4) or Cl (5). The introduction of a MeO (6) group
at this position resulted in a low yield of 14% probably due to
overoxidation of the electron-rich product. Substates without
Cyclic voltammetry studies revealed that benzimidazole 8
(Ep/2 =1.29 V vs. saturated calomel electrode, SCE) was oxidized
at higher potential than amidine 34 (Ep/2 =1.51 V vs. SCE) with a
~
~
potential gap ( E) of only 0.22 V (Scheme 4a). E is expected to
decrease with more electron-rich pairs of amidine and the
corresponding benzimidazole product, explaining the low yield
caused by electron-donating substituents (e.g., 6).
Scheme 2. Scope of benzimidazole synthesis. Reaction conditions: amidine
(0.3 mmol), Et4NPF6 (0.3 mmol), THF/MeOH (5:1, 9 mL), reflux, 3.9–4.3 h (4.9–
5.3 F molÀ 1). All yields are isolated yields.
Scheme 3. Scope of benzimidazole synthesis via sequential cyclization and
Me oxidation. Reaction conditions: amidine (0.2 mmol), Et4NPF6 (0.1 mmol),
MeOH (9 mL), reflux, 4.5–5.9 h (8.5–11.0 FmolÀ 1). All yields are isolated yields.
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radical 39.[11] The site selectivity for the deprotonation arises
from the distribution of more positive charge at C6 than C4.[10]
This electron-rich C-radical 39 is oxidized on the anode to
carbocation 40, which is trapped with MeOH to generate ether
41. Since the oxidation potential of 41 is expected to be close
to that of 37,[12] it undergoes another 2e-oxidation and reaction
with MeOH to generate dimethylacetal 27. This compound is
more difficult to oxidize than 36 because of the electron-
withdrawing property of the acetal group and thus does not
react further.
In summary, we have developed an electrochemical method
for the synthesis of benzimidazoles through dehydrogenative
cyclization of easily available N-aryl amidines. The tandem
cyclization/Me oxidation affords functionalized benzimidazoles
bearing a useful dimethylacetal group. The electrochemical
synthesis of benzimidazoles require no catalysts, oxidants, or
additives, providing a sustainable access to this importance
class of N-heterocycles.
Acknowledgements
Financial support of this research from NSFC (No. 21861013,
21971213), Guizhou Provincial Science and Technology Founda-
tion (No. 20185769), and Fundamental Research Funds for the
Central Universities.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: amidine · CÀ H functionalization · electrochemical
synthesis · oxidation · radical cyclization
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Manuscript received: February 2, 2021
Revised manuscript received: February 12, 2021
Accepted manuscript online: February 19, 2021
Version of record online: February 24, 2021
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