Synthesis of Functionalized Imidazolium Salts via Iodine-Mediated Annulations of Enamines

Article abstract of DOI:10.1021/acs.orglett.9b00541

A novel annulation reaction of two enamine molecules with iodine under basic conditions to form 4-functionalized imidazolium salts has been established. In this reaction, iodine acts as both an iodinating reagent and a Lewis acid catalyst. Features of this synthetic method include facilitative preparation of substrates, no use of transition metals, mild reaction conditions, simplicity of operation, and gram scale synthesis.

Full text of DOI:10.1021/acs.orglett.9b00541

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Functionalized Imidazolium Salts via Iodine-Mediated
Annulations of Enamines
Biao Xia, Wenjun Chen, Qiongli Zhao, Wenquan Yu,* and Junbiao Chang*
College of Chemistry and Molecular Engineering; Collaborative Innovation Center of New Drug Research and Safety Evaluation,
Henan Province; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China
S
* Supporting Information
ABSTRACT: A novel annulation reaction of two enamine molecules with
iodine under basic conditions to form 4-functionalized imidazolium salts has
been established. In this reaction, iodine acts as both an iodinating reagent
and a Lewis acid catalyst. Features of this synthetic method include facilitative
preparation of substrates, no use of transition metals, mild reaction
conditions, simplicity of operation, and gram scale synthesis.
a
midazolium salts are ionic liquids (IL)1 that have been well
Table 1. Optimization of Reaction Conditions
I
investigated and are valuable precursors for the preparation of
N-heterocyclic carbenes (NHC).2 They enjoy a wide range of
applications as liquid crystals,3 pharmaceuticals,1c,4 and motifs
of functional materials.4c,5 To date, the construction of the
heterocyclic framework of imidazolium salts uses N-quaterniza-
tion of preformed imidazoles,6 and Arduengo-type cyclization
and variations of this reaction.6a,7 In 2011, Polyakova and co-
workers reported a modular approach to the synthesis of N,N′-
b
entry
base
solvent
temp
rt
time
yield
54%
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
K2HPO4
K3PO4
LiOH
NaOH
NaHCO3
NaOAc
tBuOK
LiHMDS
DBU
DCE
DCE
DCE
toluene
CH2Cl2
CHCl3
CCl4
DMSO
MeOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
8 h
4 h
4 h
4 h
4 h
8 h
6 h
1 h
1 h
4 h
4 h
4 h
4 h
1 h
4 h
6 h
8 h
2 h
1 h
4 h
4 h
50 °C
84 °C
50 °C
40 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
73%
34%
69%
36%
54%
65%
0%
di-tert-alkyl imidazolium salts from but-3-yn-2-yl methanesulfo-
nates or N-tert-alkyl aldonitrones. In 2013, Basle and Mauduit
8
́
devised a multicomponent cyclization reaction for the assembly
of unsymmetrical imidazolium salts from sterically congested
amines.9 In 2015, the Zhu group implemented the synthesis of
1,3,4,5-tetrasubstituted imidazolium compounds from prop-
argylamines and isonitriles in the presence of multiple combined
catalysts.10 In 2017, Su and Liu developed a gold-catalyzed [2 +
2+1] annulation reaction of aryldiazo nitriles and imines to
prepare all aryl-substituted imidazolium salts.11 Despite these
elegant methods, however, novel and simple synthetic pathways
to access imidazolium frameworks are still in demand.
9
0%
22%
10
11
12
13
14
15
16
17
18
19
c
86% (82%)
55%
31%
trace
0%
23%
20%
Over the past decades, enamines have been shown to play an
important role in organocatalysis12 and have also been used
extensively for the synthesis of diverse heterocyclic com-
pounds13 including indoles,14 pyridines,15 pyrroles,16 pyra-
zoles,17 and imidazoles.18 However, to the best of our
knowledge, annulation reactions of enamines to form
imidazolium skeletons have never been investigated. In this
paper, we demonstrate such a reaction for the synthesis of 4-
functionalized 1H-imidazol-3-ium salts from readily accessible
enamines, a reaction promoted by molecular iodine under basic
conditions.
DCE
DCE
DCE
DCE
trace
0%
82%
d
20
e
K2HPO4
K2HPO4
21
79%
a
Optimal reaction conditions (entry 11): 1a (0.5 mmol), I2 (0.65
b
mmol), K2HPO4 (1.5 mmol), DCE (10 mL), 50 °C. Isolated yields.
c
d
Yield of gram-scale reaction (6 mmol). 1.5 equiv of I2 was used.
With 1.5 equiv of TEMPO.
e
The required enamine substrates can be readily obtained by
the condensation of aliphatic amines with β-keto esters. In the
presence of a base such as K2CO3, the I2-mediated annulation of
two enamine molecules (1a) forms 2,5-diphenyl-1H-imidazol-3-
ium iodide salt (2a) in 1,2-dichloroethane (DCE) at 50 °C, the
optimal reaction temperature (Table 1, entry 2). Solvent
Received: February 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00541
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 1. Scope of R Group
Scheme 2. Scope of R1 and R2 Groups
a
Reaction conditions: 1 (0.5 mmol), I2 (0.65 mmol), K2HPO4 (1.5
b
mmol), DCE (10 mL), 50 °C (isolated yields are given). K2CO3 was
used as base.
a
Reaction conditions: 1 (0.5 mmol), I2 (0.65 mmol), K2HPO4 (1.5
b
mmol), DCE (10 mL), 50 °C (isolated yields are given). Reaction
c
was performed at −20 °C. Reaction was performed at room
screening (entries 2, 4−9) shows that DCE is the ideal solvent
for this transformation. Further screening of a series of inorganic
and organic bases (entries 10−19) reveals that K2HPO4 is the
best base (entry 11). Upon changing the base from K2CO3 to
K2HPO4, the reaction also proceeds well at room temperature,
but overall the yields are slightly decreased when exploring the
substrate scope. Thus, 50 °C was chosen as the optimal
temperature. The present reaction requires at least 1.3 equiv of
iodine, and additional iodine fails to improve the yield of the
product (entry 20). In addition, the product 2a can be
successfully synthesized on a gram scale (entry 11). In the
presence of TEMPO, a free radical scavenger, the reaction was
not affected significantly (entry 21), which ruled out a radical
mechanism.
d
temperature. K2CO3 was used as base.
In an examination of the scope and generality of the reaction
(Scheme 1), various 3-aryl enamines were subjected to the
above optimal annulation conditions. Iodine-mediated cycliza-
tion of these substrates afforded the expected 4-carboxylic ester-
substituted imidazolium salts in moderate to excellent yields
(2a−2l, 34−92%). The structure of the imidazolium iodide salt
(2f) was confirmed by X-ray crystallography.19 This reaction is
compatible with both electron-donating groups (EDGs) and
electron-withdrawing groups (EWGs) on the phenyl ring (R).
Generally, incorporation of EDGs favors this transformation
(2b, 2i−2j vs 2d−2h). The exception is the methoxy substrate,
B
DOI: 10.1021/acs.orglett.9b00541
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Control experiments were performed to investigate the
mechanism of the formation of the imidazolium entity. The
iodide intermediate 3aa could be isolated because of its
relatively superior stability. Treatment of this iodide with a
catalytic amount of iodine afforded the corresponding
imidazolium salt (2aa) successfully (Scheme 3). On the basis
Scheme 3. Synthesis of Imidazolium Salt 2aa via Isolated
Iodide 3aa
of these experimental results and our previous works,22
a
tentative mechanism is proposed for this reaction (Scheme 4).
With the reaction leading to product 2a as an example, iodine-
mediated oxidative iodination of enamine 1a under basic
conditions generates two iodides, A and B.22 Then nucleophilic
substitution of iodide A by the enamine nitrogen of compound B
produces C, deprotonation of which forms an intermediate D,
which furnishes compound E upon imine-enamine tautomeriza-
tion. Subsequently, I2-catalyzed intramolecular aza-Michael
addition of E leads to the 2,3-dihydro-1H-imidazole (G).
Finally, I2-catalyzed rearrangement of G produces the
imidazolium framework (2a) and an enolate H. Upon workup
with aqueous solution, H is converted to the acetate ester (I).23
In this transformation, molecular iodine plays a dual role: as an
oxidant in the first step oxidative iodination, and then as a Lewis
acid24 in aza-Michael addition (E → F) and arrangement (F →
G) steps, respectively.
Scheme 4. Proposed Mechanism
For the first time, we have established a novel synthetic
process for the construction of the imidazolium framework via
I2-promoted annulations of enamines in the presence of base.
Under mild reaction conditions, cyclization of readily accessible
enamine substrates affords a variety of 4-functionalized
imidazolium iodide salts. In this transformation, iodine behaves
as both iodinating reagent and Lewis acid catalyst. This
transition-metal-free synthetic process is operationally simple
and can be conveniently conducted on a gram scale.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00541.
Experimental details, characterization data, NMR spectra
of isolated compounds (PDF)
Accession Codes
CCDC 1895252 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
which afforded product 2c20 in a decreased yield with
unidentified byproducts. The reaction of an o-tolyl enamine
resulted in complicated product mixtures,21 which probably
arose from the steric hindrance of the ortho-methyl group. The
presence of a methoxy or a cyano substituent significantly
decreases the yield of the product (2c, 2h). This methodology is
also successful with pyridyl and thiophenyl substituted
substrates (2k−2l) but fails with an enamine bearing an alkyl
group at R position (2m).
In light of these encouraging results, we further explored the
substrate scope of enamines bearing various R1 or R2 groups
(Scheme 2). Under the optimal reaction conditions, imidazo-
lium salts bearing a variety of 4-functional groups (CO-R2)
(2n−2ab) are synthesized smoothly from the corresponding
substrates in satisfactory yields. Replacement of the N-methyl
group with an ethyl or benzyl group (R1) also leads to the
desired product (2ac−2ad20). However, in the cases of
enamines 1ae−1af, no expected products were formed due to
the steric hindrance of the N-isopropyl and phenyl moieties.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wenquan_yu@zzu.edu.cn.
*E-mail: changjunbiao@zzu.edu.cn.
ORCID
Wenquan Yu: 0000-0002-3711-0006
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 81773570 and U1804283), the Young Backbone
Teachers Fund of Zhengzhou University (No.
C
DOI: 10.1021/acs.orglett.9b00541
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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