A novel domino strategy for forming poly-substituted quaternary imidazoles through a Cs2CO3-promoted aryl migration process

Article abstract of DOI:10.1039/c3ob40666k

A new domino strategy for the synthesis of highly functionalized quaternary imidazole derivatives via [3 + 2] heterocyclization, involving aryl migration and ring-opening of oxirane, has been developed. This domino reaction enables the successful assembly of three new sigma bonds including two C-N bonds in a simple operation. Features of this strategy include the mild conditions, convenient operation, and short reaction periods (15-20 min). The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40666k

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A novel domino strategy for forming poly-substituted
quaternary imidazoles through a Cs2CO3-promoted aryl
migration process†
Cite this: Org. Biomol. Chem., 2013, 11,
3603
Received 4th April 2013,
Accepted 16th April 2013
Hai-Wei Xu, Wei Fan, Meng-Yuan Li, Bo Jiang,* Shu-Liang Wang and Shu-Jiang Tu*
DOI: 10.1039/c3ob40666k
www.rsc.org/obc
A new domino strategy for the synthesis of highly functionalized some examples including dispacamides, mauritiamine, and
quaternary imidazole derivatives via [3 + 2] heterocyclization, rhopaladins display potent antihistamine, antifouling, and
involving aryl migration and ring-opening of oxirane, has been antibacterial activity, respectively.7 In addition, a variety of syn-
developed. This domino reaction enables the successful assembly thetic 4,4-disubstituted imidazoles have found therapeutic
of three new sigma bonds including two C–N bonds in a simple applications in drugs such as the well established phenytoin,8
operation. Features of this strategy include the mild conditions, for the treatment of different types of epileptic seizures, and
convenient operation, and short reaction periods (15–20 min).
nilutamide,9 a non-steroidal orally active anti-androgen used
in the therapy of metastatic prostate cancer (Fig. 1). Because of
their unique biological and pharmacological characteristics,
some modern methodologies for the formation of 4,4-disubsti-
tuted imidazoles have been developed. Most of them involve
cyclization of salicylamide,10 3-hydroxyaminobutan-2-one,11 or
2-aminoacetamides12 and various other total syntheses.13
Despite the limited construction of 4,4-disubstituted imid-
azoles, an exploration of a versatile strategy for the direct for-
mation of quaternary imidazole frameworks would be highly
favorable.
The functional quaternary imidazoles, being synthetically
intriguing structural features in a myriad of compounds, can
serve as “privileged structures” in many biologically important
molecules and pharmacological substances.1 They have also
been found in natural alkaloids, such as calcaridine A,2 hydanto-
cidin,3 kottamides A–D,4 and an indole marine alkaloid
from the tunicate Dendrodoa grossularia5 (Fig. 1), some of
which exhibit nonselective herbicidal activity.6 Additionally,
The pursuit of highly efficient synthetic strategies continues
to demand an enormous effort aimed at atom-economic synth-
eses, environmental aspects and remarkable selective control
for constructing natural products or natural-like structures.14
Domino reactions, being one of the most effective methods to
improve synthetic efficiency, can implement reaction cascades
and generate the structural diversity of quaternary stereo-
centers found in natural products and biologically important
molecules by simultaneous formation of three or more bonds
from simple substrates.15 Obviously, such transformations can
help to avoid the tedious steps of protection and deprotection
of functional groups and isolation of intermediates, thereby
minimizing the generation of waste and rendering the trans-
formations green.16 In recent years, considerable effort has
been devoted to the development of various domino reactions
towards the formation of heterocycles.17 However, the utiliz-
ation of domino reactions selectively yielding quaternary imi-
dazoles through aryl migration, to the best of our knowledge,
has not been well documented so far.
Fig. 1 Some bioactive quaternary imidazoles.
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou,
211116, P. R. China. E-mail: jiangchem@jsnu.edu.cn, laotu@jsnu.edu.cn;
Fax: +0086-516-83500065; Tel: +0086-516-83500065
Recently, our group developed a series of unique domino
reactions for the construction of useful functionalized
complex molecules of chemical and pharmaceutical
†Electronic supplementary information (ESI) available. CCDC 932135. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob40666k
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Gratifyingly, the reaction promoted by Cs2CO3 worked well in
ethylene glycol at an increased temperature of 120 °C, which
afforded the corresponding product, 3a, in 81% yield (Table 1,
entry 9). A further increase in reaction temperature failed to
improve the yield of the desired product 3a (Table 1, entry 10).
Subsequently, the same reaction was investigated under classi-
cal heating (CH) conditions at 120 °C for 180 min, providing
the desired product 3a in 80% yield (Table 1, entry 11).
Scheme 1 The synthesis of polysubstituted quaternary imidazoles.
importance.18 As a result of our continuous effort on these
domino processes, herein, we would like to disclose another
new Cs2CO3 promoted domino reaction of aryl amidines 1
with 1,3-diaryl-2,3-epoxypropan-1-ones 219 in ethylene glycol
yielding poly-substituted quaternary imidazoles (Scheme 1).
The unique characteristics of the presented reaction demon-
strate the formation of a quaternary imidazole skeleton with
the concomitant achievement of poly-functionalization resid-
ing at different sites of the imidazole unit. This is readily
achieved in a domino fashion involving an aryl migration and
ring-opening of oxirane, forming up to three sigma bonds in a
one-pot operation from common and inexpensive starting
materials (Scheme 1). This observation is very useful in
organic chemistry.
An initial reaction using 4-chlorobenzimidamide (1a) and a
preformed 1,3-diaryl-2,3-epoxypropan-1-one (2a) as simple
model substrates in ethylene glycol was investigated to establish
the feasibility of the strategy and to screen the reaction con-
ditions (Table 1). Different bases such as Et3N, NaOEt, NaOH,
K2CO3, and Cs2CO3 were explored. The results are listed in
Table 1. The reaction scarcely proceeded to provide the expected
product 3a in the presence of EtONa or Et3N at 100 °C under
microwave heating. A low yield (31%) of product 3a was
observed using NaOH as a base promoter. The identical reac-
tion promoted by K2CO3 at 100 °C generated a slightly higher
yield of 3a (52%). Cs2CO3 as a mild base gave the expected qua-
ternary imidazole 3a in 74% yield (Table 1, entry 5). Sub-
sequently, different solvents were screened, and it was found
that the reaction proceeded more efficiently in ethylene glycol
than that in CH3CN, EtOH, or DMF (Table 1, entries 3–7).
With the above optimized conditions in hand, we then pro-
ceeded to explore the substrate diversity of this Cs2CO3 pro-
moted domino reaction of aryl amidines 1 and 1,3-diaryl-2,3-
epoxypropan-1-ones 2.21 The results are presented in Table 2.
At the beginning, we studied the 1,3-diaryl-2,3-epoxypropan-1-
one substrate scope. 4-Chlorobenzimidamide 1a was used as a
model substrate (Table 2, entries 1–3), and the results indi-
cated that the substituents residing in different positions on
the aromatic ring of 2 were all successfully engaged in the reac-
tion and readily transformed into the corresponding quatern-
ary imidazoles 3a–3g in 76–87% yields. The bulky
o-chlorosubstituted epoxypropan-1-ones 2c, 2d, 2f and 2g were
suitable for these domino reactions. As an extension of the
above study, we devised a variety of aryl amidines 1 to react
with 2 to investigate the possibility of this transformation. The
substituents on the aromatic ring of the aryl amidines 1 did
not hamper the reaction process. Reactions of bromo- (1b),
methyl- (1d), or methoxy-substituted (1e and 1f) aryl amidines
1 with 1,3-diaryl-2,3-epoxypropan-1-ones 2 all worked well to
provide the desired quaternary imidazoles in moderate to good
yields with short reaction times. Moreover, pyridin-3-yl and
pyridin-4-yl amidines were also converted into the correspond-
ing pyridin-3-yl and pyridin-4-yl substituted quaternary imid-
azoles 3v–3x in 67–74% isolated yields. The tolerance of
different functionalities, such as chloride and bromide in this
protocol provides the opportunity for further chemical mani-
pulations of the products. It is worth mentioning that the proto-
col provides a unique pathway for the generation of 4,4-
disubstituted imidazoles with concomitant achievement of C2-
arylation, C4-bisfunctionalization, and C5-hydroxylation in a
one-pot operation, which are normally difficult to prepare by
other methods. Moreover, it gives a new example of a hetero-
cyclization involving aryl migration process in an economical
and atom-efficient fashion, providing a valuable strategy to dis-
cover new bioactive compounds.
Table 1 Optimization of reaction conditions
In all cases, the reaction proceeded at a very fast speed and
can be finished within 15–20 minutes. The reaction process is
environmentally friendly because water is nearly the sole by-
product. In most cases, the products precipitated out after the
reaction mixture was poured into cold water. The structural
Entry
Base (equiv.)
Solvent
T/°C
Time
Yield/%
1
2
3
4
5
6
7
8
Et3N
EtONa
NaOH
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
EtOH
CH3CN
DMF
Ethylene glycol
Ethylene glycol
Ethylene glycol
100
100
100
100
100
100
100
100
120
130
120
15 min
15 min
15 min
15 min
15 min
20 min
15 min
20 min
15 min
15 min
3.0 ha
Trace
Trace
31
52
74
69
32
12
81
1
elucidation of the products was determined from their IR, H
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NMR, 13C NMR, and HRMS spectra. The structure of com-
pound 3h was unequivocally confirmed by X-ray analysis
(Fig. 2). During these processes, up to three sigma bonds were
formed accompanied by the cleavage of the three C–O bonds
of 1,3-diaryl-2,3-epoxypropan-1-one.
9
10
11
79
80
On the basis of experimental results, a reasonable reaction
mechanism for this domino reaction is postulated in Scheme 2.
a Conventional heating.
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Table 2 The domino synthesis of compounds 3a
Entry
1
2
3
Timeb Yieldc/% Entry
2
3
Timeb Yieldc/%
15
20
16
18
81%
86%
82%
85%
13
14
15
16
16
17
15
16
74%
72%
81%
82%
2
3
4
5
6
7
8
17
19
20
20
87%
81%
70%
67%
17
18
19
20
18
15
16
18
85%
76%
83%
84%
9
18
16
18
18
74%
81%
76%
85%
21
22
23
24
20
15
16
15
64%
67%
72%
74%
10
11
12
a Reagents and conditions: 120 °C, Cs2CO3, ethylene glycol (1.5 mL), microwave heating. b Time (min). c Isolated yield.
Firstly, the nucleophilic addition between 1,3-diaryl-2,3-
epoxypropan-1-ones 2 and aryl amidines 1 occurs, leading
Conclusion
to intermediate A. An aryl migration/ring-opening of oxirane In conclusion, we have developed a new and metal-free [3 + 2]
followed to yield the amide intermediate B. Intermediate B heterocyclization of 1,3-diaryl-2,3-epoxypropan-1-ones, that led
then undergoes H-transfer, dehydration and intramolecular to the efficient construction of a quaternary imidazole skeleton
cyclization to afford the imidazolidone E, which converts with high regioselectivity. This reaction process involves a
into the final quaternary imidazole through a tautomerism nucleophilic addition/aryl migration/ring-opening of oxirane/
process.
cyclization sequence. Undoubtedly, this domino strategy
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Acknowledgements
We are grateful for financial support from the National Science
Foundation of China (21072163, 21232004, 21272095, and
21102124), PAPD of Jiangsu Higher Education Institutions, the
NSF of Jiangsu Education Committee (11KJB150016), Jiangsu
Science and Technology Support Program (No. BE2011045),
the Qing Lan Project (12QLG006), and Science Research Foun-
dation of Jiangsu Normal Univ (Nos. 10XLR20, 11XLA05).
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cally,
(3-(4-chlorophenyl)oxiran-2-yl)(phenyl)methanone
(2a, 1 mmol, 0.258 g, 1.0 equiv.) was introduced in a 10 mL
Initiator™ reaction vial, 4-chlorobenzimidamide (1a,
1.0 mmol, 0.154 g, 1.0 equiv.) and Cs2CO3 (1.0 mmol,
0.326 g, 1.0 equiv.) as well as ethylene glycol (1.5 mL) were
then successively added. Subsequently, the reaction vial
was closed and then pre-stirred for 20 seconds. The
mixture was irradiated (Time: 15 min, Temperature:
120 °C; Absorption Level: High; Fixed Hold Time) until
TLC (petroleum ether–acetone 3 : 1) revealed that conver-
sion of the starting material 2a was complete. The reaction
mixture was then cooled to room temperature and then
diluted with cold water (20 mL). The solid product was col-
lected by Büchner filtration and was purified by recrystalli-
zation from 60% ethanol to afford the desired pure
imidazoles 3a as a white solid (mp: 253–254 °C).
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