Electrochemical synthesis of 1,2,4,5-tetrasubstituted imidazoles from enamines and benzylamines

Article abstract of DOI:10.1039/d1ob00942g

An electrochemical method for synthesizing 1,2,4,5-tetrasubstituted imidazoles was developed under undivided electrolytic conditions. This synthesis was specifically realized based on electrochemical C(sp³)-H aminationviaenamines and amines. Readily available starting materials were used, avoiding the use of both transition metals and oxidants. The practicability of the method lies in its broad substrate adaptability and in its ability to provide a simple green pathway for synthesizing GABA_Areceptor analogs.

Full text of DOI:10.1039/d1ob00942g

Organic &
Biomolecular Chemistry
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Electrochemical synthesis of 1,2,4,5-
tetrasubstituted imidazoles from enamines and
benzylamines†
Cite this: Org. Biomol. Chem., 2021,
19, 6682
Wenxing Wang, Shuo Zhang, Guang Shi and Zhiwei Chen
*
An electrochemical method for synthesizing 1,2,4,5-tetrasubstituted imidazoles was developed under
undivided electrolytic conditions. This synthesis was specifically realized based on electrochemical
C(sp3)–H amination via enamines and amines. Readily available starting materials were used, avoiding the
use of both transition metals and oxidants. The practicability of the method lies in its broad substrate
adaptability and in its ability to provide a simple green pathway for synthesizing GABAA receptor analogs.
Received 14th May 2021,
Accepted 9th July 2021
DOI: 10.1039/d1ob00942g
rsc.li/obc
ventional methods, the reaction conditions included transition
metals, equivalent bases, or dangerous oxidizing agents,
Introduction
Imidazole is an important heterocyclic compound, and exists which have detrimental features.
in many natural products and drugs (Fig. 1). Examples of imid-
Our group has been committed to conducting research on
azole with a substituent group attached to the nitrogen atom β-enamine esters.12 As a simple and easily available substrate,
have been found to display anti-virus,1 anti-inflammatory,2 it has multiple reaction sites, which provide a novel method
anticancer,3 and antifungal activities as well as other pharma- for the construction of heterocycles. In 2021, our team
cological effects.4 Furthermore, imidazole is also used as an reported examples of an electrochemical oxidative cyclization
environmentally friendly ionic solvent and carbene ligand.5,6
to synthesize polysubstituted pyrroles from enamines
Traditional methods for synthesizing imidazole derivatives (Scheme 1c).13 There have, however, been few reports of elec-
include the Bredereck synthesis, van Leusen reaction and trochemically performed intermolecular reactions involving
Debus–Radziszewski reaction.7 However, most of the existing β-enamine esters, and the apparent difficulty in achieving such
methods show poor regioselectivity, give only 4,5-bisarylimida- intermolecular reactions might be due to competitive intra-
zoles, and many of these reaction conditions require the use of molecular oxygenation cyclization. In the current work, we
a strong base or high temperature or produce environmentally developed a set of efficient electrochemical syntheses of tetra-
unfriendly byproducts. Currently, transition-metal-catalyzed substituted imidazoles from β-enamine esters and amines
methods are more commonly used to synthesize imidazole (Scheme 1d).
derivatives. However, relatively few metal-free syntheses of
imidazoles have been reported.8 C(sp3)–H amination reactions
have provided a new way to synthesize 1,2,4,5-tetrasubstituted
imidazole.9 In 2014, Devendra K. Agrawal and co-workers
reported a concise route involving copper-mediated oxidative
C–H functionalizations to synthesize highly substituted imid-
azoles from benzylamine and Enamine ester (Scheme 1a).10 In
2019, Xia and co-workers reported reacting two enamine mole-
cules with iodine under basic conditions to form 4-functiona-
lized imidazolium salts (Scheme 1b).11 Substitution in the con-
Collaborative Innovation Center of Yangtze River Delta Region Green
Pharmaceuticals, Zhejiang University of Technology, College of Pharmaceutical
Sciences, Zhejiang University of Technology, Chao Wang Road 18th, 310014
Hangzhou, China. E-mail: chenzhiwei@zjut.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00942g
Fig. 1 Examples of useful imidazole-containing molecules.
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Table 1 Optimization of reaction conditionsa
Entry
Variation from standard conditions
Yieldb (%)
1
2
3
4
5
6
7
8
None
80
71
63
72
34
44
37
22
0
Graphite as anode
Graphite as cathode
Ni foam as cathode
nBu4NI instead of KI
NH4I instead of KI
NaI instead of KI
NH4Br instead of KI
No KI
9
10
11
12
13
14
15
16
17
18
19
10 mol% KI instead of 1 equiv. KI
MeCN instead of DMSO
DMAc instead of DMSO
DMF instead of DMSO
MeOH instead of DMSO
15 mA instead of 10 mA
5 mA instead of 10 mA
Under air
67
56
46
50
Trace
75
69
77
76
0
Scheme 1 Syntheses of various multi-substituted imidazoles including
those of our previous work and current work.
No nBu4NBF4
Results and discussion
No electricity
a Reaction conditions: 1a (0.5 mmol, 95.5 mg), 2a (1.5 mmol, 160 mg),
Initially, methyl (Z)-3-(phenylamino)but-2-enoate 1a and ben-
zylamine 2a were selected as the model substrates to optimize KI (0.5 mmol, 83 mg), nBu4NBF4 (0.03 M), dimethyl sulfoxide (DMSO,
5 mL) in an undivided cell with a platinum plate anode (20 mm ×
the electrolysis conditions. The desired product 1,2,4,5-tetra-
substituted imidazole 3aa was obtained in 80% yield in an
15 mm) and a platinum plate cathode (20 mm × 15 mm), constant
current = 10.0 mA, argon, rt, 10 h. Isolated yields. b Isolated yields after
undivided cell containing two platinum electrodes. The best column chromatography.
condition was found to be that employing KI (1 eq.) and
nBu4NBF4 (0.03 M) in DMSO at room temperature under a con-
stant current of 10 mA under argon conditions for 10 h
(Table 1, entry 1). A series of control experiments validated the
necessity of each reaction condition. Replacing the platinum
electrode with a graphite electrode or nickel foam was associ-
ated with a decrease in the efficiency of the transformation
(Table 1, entries 2–4). Including KI was found to be essential
for the reaction (Table 1, entry 9), while other electrolytes such
as TBAI, NH4I, NH4Br and NaI showed poor performances
(Table 1, entries 5–8). Not including KI resulted in no for-
mation of target product. When the amount of KI included
was changed to 10 mol%, the yield decreased to 67% (Table 1,
entry 10), demonstrating that the halide ion might act as a
redox agent to promote the formation of products. When other
solvents such as DMF, DMAc or MeOH were used instead of
DMSO, a low or trace yield of 3aa was observed (Table 1,
entries 11–14). Either increasing or lowering the current was
associated with a lower yield of the final product (Table 1,
entries 15 and 16). Meanwhile, the reaction showed little sensi-
tivity to oxygen and could be run under atmospheric con-
ditions (Table 1, entry 17). Finally, no product was found when
there was no electricity (Table 1, entry 19), indicating the
crucial nature of including electricity.
Scheme 2 Benzylamine scope. Reaction conditions: 1a (0.5 mmol,
After establishing the optimal reaction conditions, the
adaptability of the substrate was also investigated. As shown in
Scheme 2, various kinds of benzylamines were examined, and
all of them gave the corresponding products in good yields.
95.5 mg), 2a–2k (1.5 mmol, 160 mg), KI (0.5 mmol, 83 mg), nBu4NBF4
(0.03 M), dimethyl sulfoxide (DMSO, 5 mL) in an undivided cell with a
platinum plate anode (20 mm × 15 mm) and a platinum plate cathode
(20 mm × 15 mm), constant current = 10.0 mA, argon, rt, 10 h. Isolated
Both the electron-donating groups (EDGs) and electron-with- yields.
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drawing groups (EWGs) on the benzylamine were compatible electron-withdrawing groups in the same position were slightly
with the reaction, but the yield of benzylamine with electron- higher than those resulting from the use of electron-donating
withdrawing substituents (3ab, 3ad, 3af) was better than that groups. The highest yield of 81% was obtained when a thick
with electron-donating substituents (3ac, 3ae, 3ag). When a ring was on N. The substrate with the strong electron-withdraw-
polysubstituted benzylamine was used as a substrate, the yield ing group NO2 on the N-phenylene ring (3pa) was tested but
of the corresponding product (3ah) was 73%. In addition, unfortunately did not react. We went on to test some other non-
furan-2-ylmethanamine (3ai) and thiophen-2-ylmethanamine aromatic substituents on N. Happily, under the standard con-
(3aj) were smoothly synthesized in 74% and 69% yields, ditions of the reaction, even if the substituent on the N was a
respectively. However, for aliphatic amines with long chains, non-aromatic group such as nbutyl (3ga), cyclohexyl (3ha), or
no target product was obtained. This meant that the weak C–H benzyl (3ia), corresponding multisubstituted imidazoles con-
bond adjacent to the amino group was essential for the taining COOR2 were successfully synthesized in the medium.
smooth progress of the reaction.
Also, the replacement of methyl ester with ethyl or tert-butyl
In addition, a range of alkenamine substrates was investi- ester did not result in a significant decrease in the reaction
gated (Scheme 3). First, we examined the effect of the substitu- yield (3ja, 3ka). When the R group was a benzene ring (3la),
ent group on the benzene ring on the reaction, the substituted only a 37% yield of the intended target was obtained; and a by-
groups of halogen, methyl were chosen, including the benzene product was obtained, namely an indole resulting from an oxi-
ring substituted at the o-position (3ea), the m-position (3da) and dative cyclization of the substrate.14 When R was an ethyl group
the p-position (3ba, 3ca). The results showed that these were (3ma) or isopropyl group (3na), the corresponding polysubsti-
good substrates for the reaction, and the yields were in the tuted imidazole was still obtained in good yield (72%, 73%).
range 65%–76%. The yields of the alkenamine compounds with When use of methylenimine ketone (3oa) was involved in the
substituents attached to the para-position were higher than for reaction, a product yield of 64% was still obtained.
those with substituents attached to the ortho-position. This
Amino acids have also been tested due to their low costs
difference was attributed to the para-position not being involved and easy availability. In particular, the same product 3aa was
in steric clashes. And the yields resulting from the use of the obtained in 27% yield when using the amino acid 2-amino-2-
phenylacetic acid instead of benzylamine (Scheme 4a). The
ability to use an amino acid improved the applicability of the
reaction. The general synthesis of enamine compounds was
achieved by carrying out dehydration condensations of 1,3-
dicarbonyl compounds with amines. To make the reaction
substrate and operation simpler, we also performed a one-pot
tandem reaction with methyl acetoacetate and benzylamine as
substrates under standard conditions; this reaction did not
yield the target product, but rather a polysubstituted oxazole.
Based on the preparation of enamine requiring acid catalysis,
we conducted a simple screening of acids and temperature. A
37% yield was achieved by adding trifluoromethanesulfonic
acid and adjusting the temperature to 60 °C (Scheme 4b).
Finally, to understand the mechanism of the reaction, we
performed the control experiments shown in Scheme 5. The
addition of 2 equiv. of 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO), 2,6-di-tert-butyl-4-methylphenol (BHT), and 1,1-
diphenylethylene (1,1-DPE) to the reaction solution under
standard reaction conditions gave 72%, 53%, and 74% yields,
Scheme 3 Enamine scope. a Reaction conditions: 1b–1k (0.5 mmol,
95.5 mg), 2a (1.5 mmol, 160 mg), KI (0.5 mmol, 83 mg), nBu4NBF4 (0.03
M), dimethyl sulfoxide (DMSO, 5 mL) in an undivided cell with a platinum
plate anode (20 mm × 15 mm) and a platinum plate cathode (20 mm ×
15 mm), constant current = 10.0 mA, argon, rt, 10 h. b Isolated yields.
Scheme 4 One-pot tandem reaction method.
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Scheme 7 Gram-scale and synthetic applications.
display great potency as a specific allosteric modulator of the
GABAA receptor.16 Using the scheme reported herein, a gram-
scale reaction of enaminyl esters and benzylamine was carried
out at 5 mmol scale (Scheme 7), and the CH3 analogue of the
above bioactive molecule was obtained in 62% yield when the
current was increased to 25 mA and the reaction time was
extended to 45 h, demonstrating the potential utility of the
reaction.
Scheme 5 Control experiments.
respectively, which indicated that the main step of the reaction
did not involve a free radical mechanism. When molecular
iodine was employed as an oxidant, the desired product was
obtained with a yield of 23%. These results suggested that
in situ-electrogenerated molecular iodine is the active species
in the reaction. The intermediates were not separated under
standard conditions, but the possible intermediates as well as
the hydrolysis products of the intermediates were captured by
performing high-resolution mass spectrometry. The intermedi-
ate structure was found to not be in the form of an enamine,
but in the form of an imine. Finally, control experiments on
enaminates under standard conditions unfortunately did not
capture the possible intermediates, which may have been due
to the instability of the iodine intermediates.
Conclusions
In summary, we have developed a green and facile electro-
chemical approach for synthesizing 1,2,4,5-tetrasubstituted
imidazoles. Notably, the synthetic method exhibited a wide
functional group tolerance, and did so without the use of an
external oxidant or transition-metal catalyst. The reaction
could be scaled up to a 5 mmol scale and was successfully
used to construct a GABAA receptor analogue. The electro-
chemical reaction of enamines is being further investigated in
our laboratory.
Based on the experimental results and previous reports,10,15
a possible reaction pathway for the formation of 3aa was
proposed (Scheme 6). Initially, according to this proposal,
molecular iodine was generated in situ on the anode, and this
iodine reacted with β-enamine esters 1a to generate the iodi-
nated intermediate A. Then, the intermediate B was obtained
as a result of nucleophilic substitution of benzylamine.
Subsequently, the electrochemical oxidation of B generated C,
and C underwent intramolecular cyclization to form intermedi-
ate D. Finally, according to the proposed mechanism, the
target product was formed as a result of deprotonation and
electrochemical oxidation.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We gratefully acknowledge the Provincial Planning Project of
Zhejiang Provincial Science and Technology Department
(LGF19B060005) for financial support.
The bioactive molecule ethyl 2-(4-bromophenyl)-1-(2,4-
dichlorophenyl)-1H-imidazolecarboxylate has been shown to
Notes and references
1 A. Verma, S. Joshi and D. Singh, J. Chem., 2013, 2013,
1–12.
2 Y. Yu, R. M. Huff and R. M. Weier, J. Med. Chem., 2000, 43,
3168–3185.
3 (a) J. Dietrich, V. Gokhale and X. D. Wang, Bioorg. Med.
Chem., 2010, 18, 292–304; (b) R. Guda, G. Kumar and
R. Korra, J. Photochem. Photobiol., B, 2017, 176, 69–80;
(c) A. Ramesh, A. Singh and G. Srikanth,
MedChemCommun, 2014, 5, 1751.
4 (a) B. Narasimhan, D. Sharma and P. Kumar, Med. Chem.
Res., 2011, 20, 1119–1140; (b) Y. Fang, R. Yuan, W. Ge,
Scheme 6 Plausible mechanism.
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et al., Res. Chem. Intermed., 2017, 43, 4413–4421;
Organic & Biomolecular Chemistry
9 (a) Z. Yang, J. Zhang, L. Hu, et al., J. Org. Chem., 2020, 85,
5952–5958; (b) L. Zeng, J. Li, J. Gao, et al., Green Chem.,
2020, 22, 3416–3420; (c) P. Qian, Z. Zhou, K. Hu, et al., Org.
Lett., 2019, 21, 6403–6407; (d) P. Qian, Z. Yan, Z. Zhou,
et al., J. Org. Chem., 2019, 84, 3148–3157; (e) P. Qian,
Z. Yan, Z. Zhou, et al., Org. Lett., 2018, 20, 6359–6363.
(c) P. Molina, A. Tarraga and F. Oton, Org. Biomol. Chem.,
2012, 10, 1711–1724; (d) G. Sharma, A. Ramesh, A. Singh,
et
al.,
MedChemCommun,
2014,
5,
1751–1760;
(e) M. Antolini, A. Bozzoli, C. Ghiron, et al., Bioorg. Med.
Chem. Lett., 1999, 9, 1023–1028; (f) J. Choi, M. Plummer,
J. Starr, et al., J. Med. Chem., 2012, 55, 852–870; (g) B. Lagu, 10 A. Pandya and D. Agrawal, Tetrahedron Lett., 2014, 55,
K. A. Fluge and E. Tozzo, ACS Med. Chem. Lett., 2018, 9,
935–940.
1835–1838.
11 B. Xia, W. Chen, Q. Zhao, et al., Org. Lett., 2019, 21, 2583–
5 Y. F. Tao, Green Chem., 2016, 18, 1240.
2587.
6 K. Kureja, J. Zinke, C. Bruhn, et al., Chem. Commun., 2019, 12 (a) F. Peng, J. Liu, L. Li, et al., Eur. J. Org. Chem., 2018, 666–
55, 9705–9708.
672; (b) Z. W. Chen, L. Zheng and J. Liu, Eur. J. Org. Chem.,
2019, 3051–3060; (c) J. Liu, G. Shi and Z. W. Chen,
ChemistrySelect, 2020, 5, 5615–5620; (d) Z. W. Chen,
Z. R. Dai, Z. Zhu, et al., Tetrahedron Lett., 2017, 58, 1258–
1261; (e) Z. W. Chen, H. Chen, X. F. Yang, et al., Synlett,
2017, 28, 463–1466.
7 (a) H. Debus, Ueber die einwirkung des ammoniaks auf
glyoxal, Ann. Chem. Pharm., 1858, 107, 199–208;
(b) B. Radziszewski, Ueber die constitution des lophins
und verwandter. Verbindungen, Ber. Dtsch. Chem. Ges.,
1882, 15, 1493–1496.
8 (a) J. Xie, Y. Huang and H. Song, Org. Lett., 2017, 19, 6056– 13 Z. W. Chen, G. Shi, W. Tang, et al., Eur. J. Org. Chem., 2021,
6059; (b) J. Jayram and V. Jeena, Green Chem., 2017, 19, 951–955.
5841–5845; (c) M. Wang, L. H. Li and J. M. Lu, Green Chem., 14 S. Tang, X. Gao and A. W. Lei, Chem. Commun., 2017, 53,
2017, 19, 5172–5177; S. Shi, K. Xu and C. Jiang, J. Org. 3354–3356.
Chem., 2018, 83, 14791–14796; (d) A. Kumar, Z. H. Li and 15 (a) C. Wan, J. Zhang and S. Wang, Org. Lett., 2010, 12,
S. K. Sharma, Org. Lett., 2013, 15, 1874–1877; (e) M. Garzon,
E. M. Arce and R. J. Reddy, Adv. Synth. Catal., 2017, 359,
2338–2341; (b) G. Yuan, Z. Zhu, X. Gao, et al., RSC Adv.,
2014, 4, 24300–24303.
1837–1843; (f) F. Xu, S. A. Shule and D. A. Watson, Angew. 16 B. Asproni, G. Talani, F. Busonero, et al., J. Med. Chem.,
Chem., Int. Ed., 2018, 57, 12081–12085.
2005, 48, 2638–2645.
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