An electrochemical oxidative multicomponent cascade annulation of ketones and amines used to produce imidazoles

Article abstract of DOI:10.1039/d0gc00375a

An electrochemical dehydrogenative [2 + 2 + 1] annulation used for the synthesis of imidazoles has been developed under undivided electrolytic conditions. In an undivided cell, aryl ketones and amines can smoothly participate in this transformation to furnish a variety of substituted imidazoles. The reaction avoids the use of both transition-metal catalysts and peroxide reagents, which makes it more sustainable and renewable.

Full text of DOI:10.1039/d0gc00375a

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An electrochemical oxidative multicomponent
cascade annulation of ketones and amines used
to produce imidazoles†
Cite this: DOI: 10.1039/d0gc00375a
Received 30th January 2020,
Accepted 30th March 2020
Liang Zeng,‡a Jing Li,‡a Jun Gao,a Xunhai Huang,a Wei Wang,a Xiaohui Zheng,a
*
a,b Ganpeng Li,a Shengyong Zhanga and Yonghui He*a
DOI: 10.1039/d0gc00375a
Lijun Gu,
rsc.li/greenchem
An electrochemical dehydrogenative [2 + 2 + 1] annulation used which generally require the preparation of an intermediate
for the synthesis of imidazoles has been developed under undi- that subsequently undergoes the desired cyclization reaction.
vided electrolytic conditions. In an undivided cell, aryl ketones and Despite the significance of these developments, expensive and
amines can smoothly participate in this transformation to furnish a toxic metals, chemical oxidants and non-commercially avail-
variety of substituted imidazoles. The reaction avoids the use of able starting materials are always required in these reactions,
both transition-metal catalysts and peroxide reagents, which leading to difficulties in the purification of the target products
makes it more sustainable and renewable.
from a mass of undesired products and metal residues.25–27 In
addition, the synthesis of imidazole products bearing alkene,
alkyne or α-amino acid ester substituents via a convergent
route has not been achieved to date. Therefore, a green
method for the preparation of imidazole derivatives with wide
applicability is a necessary yet challenging task.
Electricity initiated organic transformations are emerging
as uniquely powerful tools for the construction of new chemi-
cal bonds in organic synthesis due to their environmentally
The expedient synthesis of substituted aromatic heterocycles
from inexpensive and readily available starting materials via
the generation of several bonds in a single process is a major
challenge in modern organic chemistry.1 For this purpose,
multicomponent cascade reactions are considered to be an
ideal tool.2–7 These reactions represent a class of ideal organic
reactions because they empower efficiency, elegance, and
novelty.8 However, the development of cascade reactions used
to construct aromatic heterocycles remains a daunting task for
synthetic chemists.9,10 Many natural products, biologically
important molecules and pharmaceuticals contain an imid-
azole core (Scheme 1). Substituted imidazoles have a wide
range of applications in organic synthesis acting as organic
catalysts, carbene ligands and ionic solvents as well as in other
fields of chemistry and agriculture.11–18 The pursuit of a
general and efficient synthesis of imidazoles that controls the
introduction of the substituents in a highly regioselective
fashion has been of continued interest to synthetic organic
chemists.19–21 Therefore, a number of routes leading to substi-
tuted imidazoles have been described in the literature.22–24
Traditional methods for the synthesis of imidazole derivatives
include the Debus–Radziszewski and Bredereck syntheses,
benign
nature,
sustainability
and
mild
operating
conditions.28–38 Using electrons as mass-free reagents, the use
of a stoichiometric amount of chemical oxidant can be
avoided, thereby eliminating the production of waste. The
electrochemical intermolecular oxidative cyclization reaction
has emerged as a powerful transformation that allows the
rapid assembly of complex ring systems in an atom- and step-
economic manner.39–45 Over the last few years, many appli-
cations of the electrochemical intermolecular oxidative cycliza-
tion reaction toward the construction of various heterocycles,
such as pyrazines, pyrroles, imidazo[1,2-a]pyridines, etc. have
been reported.46–50 However, an electrochemical oxidative mul-
ticomponent cascade cyclization reactions used for the con-
struction of imidazole derivatives has not been reported to
date. Herein, we report the successful development of an
electrochemical dehydrogenative [2 + 2 + 1] annulation used
aKey Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs
Commission & Ministry of Education, Yunnan Minzu University, Kunming, Yunnan,
650500, China. E-mail: gulijun2005@126.com, hee_csu@126.com
bKey Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Guizhou University, Guiyang 550025, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0gc00375a
‡These authors contributed equally.
Scheme 1 Examples of useful imidazole-containing molecules.
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Table 1 Optimization of the reaction conditionsa
Scheme 2 The electrochemical synthesis of imidazole derivatives.
for the synthesis of imidazoles. Advantageously, this process
proceeds in a metal- and external oxidant-free fashion to
provide a variety of functionalized imidazoles (Scheme 2).
We began our study by optimizing the reaction conditions
for the intermolecular cascade cyclization of acetophenone 1a,
benzylamine 2a and butan-1-amine 3a (Table 1). The setup for
constant current electrolysis consisted of an undivided cell (a
three-necked round-bottomed flask) equipped with a Pt plate
anode and Pt plate cathode. The reaction was conducted using
1 equiv. of 2a and 3a at room temperature in the presence of
20 mol% LiClO4 and 50 mol% NH4I. When the reaction was
carried out in MeCN under 9 mA constant current in the undi-
vided cell, the [2 + 2 + 1] annulation product 4aa was obtained
in 85% yield. A shorter reaction time was insufficient to effec-
tively form the product 4aa (entry 2). Changing the electrolyte
from LiClO4 to nBu4NBF4 or nBu4NPF6 resulted in a reduced
product yield (entries 3 and 4). Both increasing or decreasing
the current afforded the final product in lower yield (entries
5–8). As for the reaction solvent, DMSO, H2O and EtOH exhibi-
ted lower product yields when compared with MeCN (entries
9–11). When used HI or I2 instead of NH4I, the reaction pro-
ceeded with poor reactivity (entries 12 and 13). Replacing NH4I
with NH4Br, NaI, the products were obtained in 33%, 47%
respectively (entries 14 and 15). However NH4Cl did not give
Entry
Variation from the standard conditions
Yieldb (%)
1
2
3
4
5
6
7
8
None
8 h instead of 10 h
85
62
72
78
43
71
66
61
nBu4NBF4 instead of LiClO4
nBu4NPF6 instead of LiClO4
3 mA instead of 9 mA
7 mA instead of 9 mA
11 mA instead of 9 mA
15 mA instead of 9 mA
DMSO instead of MeCN
H2O instead of MeCN
EtOH instead of MeCN
HI instead of NH4I
9
69
10
11
12
13
14
15
16
17
18
19
20
21c
n.d.
Trace
61
59
33
47
n.d.
80
75
55
I2 instead of NH4I
NH4Br instead of NH4I
NaI instead of NH4I
NH4Cl instead of NH4I
Air instead of Ar
60 °C instead of R.T.
C(+)|C(−) instead of Pt(+)|Pt(−)
No current
n.d.
74
Large-scale reaction
a Reaction conditions: Pt plate anode (15 mm × 15 mm × 0.2 mm), Pt
plate cathode (15 mm × 15 mm × 0.2 mm), constant current = 9 mA, 1a
(0.5 mmol), 2a (0.5 mmol), 3a (0.75 mmol), NH4I (0.25 mmol), LiClO4
(0.1 M), MeCN (10 mL), Ar, room temperature, undivided cell.
b Isolated yield. c For details, see ESI.†
the desired product (entry 16). In addition, this reaction could the reaction, furnishing the imidazole product in 62% yield
also be carried out under an air atmosphere under electrolytic (Table 2, entry 8). Interestingly, a heterocyclic aromatic ketone
conditions (entry 17). Moreover, increasing the reaction temp- gave the desired product (4aj) in 75% yield (Table 2, entry 9).
erature to 60 °C gave the annulation product in 75% yield Finally, 1,2-diphenylethanone reacts with benzylamine to
(entry 18). Replacing the Pt plate with a glassy carbon electrode furnish the desired product in good yield (Table 2, entry 10).
led to poor reaction efficiency (entry 19). Finally, the control Unfortunately, aliphatic ketones did not participate in the
experiment indicated that electricity was essential for the reaction.
transformation (entry 20). The scalability of the reaction was
Subsequently, we examined the generality of the electro-
demonstrated by the facile preparation of 1.03 g of product 4aa chemical dehydrogenative annulation with respect the amine
(entry 21). Therefore, this protocol can be used as a practical starting materials (2 and 3) (Table 3). The substituents on the
method to synthesize the precursors of some important bio- phenyl ring of the benzylamines studied had no obvious influ-
active molecules.
ence on the reaction and the expected imidazole products were
With the best conditions in hand, the scope of the electro- produced in good to high yield. In addition, a variety of func-
lytic [2 + 2 + 1] cyclization protocol was investigated in regard tional groups were tolerated and the reaction was not affected
the scope of the aryl ketone starting material (Table 2). A by alkyl, ether and halides groups (4ba–4ea). A heteroaryl
variety of aryl ketones with p-substituted electron-donating or amine was used in the reaction and gave the desired product
electron-withdrawing groups on the aromatic ring led to the (4fa) in good yield. It is noteworthy that propan-1-amine was
desired products in good yield. It is particularly noteworthy also tolerated in the reaction (4ga). Gratifyingly, an amino acid
that functional groups such as Me, MeO, F and CN were well- ester was compatible in the cascade reaction, which gave
tolerated in the reaction (Table 2, entries 1–4). Aryl ketones product (4ha). Alkenyl- and alkynyl-substituted amines also
possessing an ortho or para chlorine substituent gave their displayed good activity in this electrochemical intermolecular
corresponding products in acceptable yield (Table 2, entries 5 annulation reaction (4ia and 4ja).
and 6), thereby facilitating additional modification at the halo-
To gain an insight into the reaction mechanism, several
genated positions. Notably, a poly-substituted aryl ketone gave control reactions were conducted. First, when the reaction of
the desired product (4ah) in good yield (Table 2, entry 7). A α-iodo ketone 1a′ with 2a and 3a was carried out under the
substrate bearing a naphthyl group was successfully applied in standard reaction conditions, the desired product was
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Table 2 Scope of aryl ketone (1) used in the reactiona
Table 3 Scope of amines 2 and 3 used in the reactiona
Entry
1
Substrates 1
Products 3
Yieldb (%)
81
2
3
4
5
6
76
69
65
71
70
a Reaction conditions: Pt plate anode (15 mm × 15 mm × 0.2 mm), Pt
plate cathode (15 mm × 15 mm × 0.2 mm), constant current = 9 mA, 1a
(0.5 mmol), 2a (0.5 mmol), 3a (0.75 mmol), NH4I (0.25 mmol), LiClO4
(0.1 M), MeCN (10 mL), Ar, room temperature, undivided cell.
b Isolated yield.
obtained in 91%. This result indicated that compound 1a′ may
be involved in the process. Second, when the reaction of 1a
with 2a and 3a was carried out in the presence of a stoichio-
metric amount of iodine as an oxidant, no desired product
was obtained at room temperature. Third, the replacement of
NH4I with I2 gave the desired product in 59% (Table 1, entry
13), which is lower than that of the model reaction (Table 1,
entry 1). The results indicated that the oxidation of C to D with
I2 may be involved in this process, but they are not the main
pathways of this electrochemical dehydrogenative annulations
process. Fourth, the reaction was suppressed in the presence
of 1.0 equiv. of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO),
suggesting that a radical process may be involved in the trans-
formation. In addition, cyclic voltammetric (CV) experiments
were also performed to investigate the reaction process
(Fig. S1†). In the NH4I case (Fig. S1,† curve c), an obvious oxi-
dation peak occurred at 0.55 V vs. Ag/AgCl (SCE), which was
due to the electro-oxidation of I− ions. The results suggested
that the electrochemical oxidation of I− ions at an anode was a
main process.
7
8
76
62
9
75
77
10
Based on the literature and the observations mentioned
above,35,42,51–53 a plausible mechanism was proposed and
shown in Scheme 3. Initially, iodide was oxidized into an
iodine radical, which reacted with 1a to afford α-iodo ketone
1a′. Nucleophilic attack of the amine to the C–I bond formed
α-amino ketone A. At the same time condensation of α-amino
a Reaction conditions: Pt plate anode (15 mm × 15 mm × 0.2 mm), Pt
plate cathode (15 mm × 15 mm × 0.2 mm), constant current = 9 mA, 1a
(0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol), NH4I (0.25 mmol), LiClO4
(0.1 M), MeCN (10 mL), Ar, room temperature, undivided cell.
b Isolated yield.
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alternative pathway was the condensation of α-iodo ketone 1a′
with benzylamine delivering imine B and nucleophilic attack
of 1-aminobutane to the C–I bond to produce intermediate C.
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D would give the desired aromatization product 4aa via an oxi-
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In summary, we have successfully developed an efficient
electrochemical intermolecular oxidative cyclization reaction
used for the synthesis of polysubstituted imidazoles. Our
electrochemical synthetic method is compatible with a wide
range of aryl ketones and amines. Notably, this methodology
has been achieved without the use of an external oxidant or
transition-metal catalyst, and the scalability of the reaction is
also beneficial for industrial production.
Conflicts of interest
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Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (21662045, 11547233), Applied
Basic Research Project of Yunnan (2016FB019, 2016FB149)
and Opening Foundation of the Key Laboratory of Green
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