Highly efficient and eco-friendly protocol to functionalized imidazoles via ring-opening of α-nitro epoxides

Article abstract of DOI:10.1039/c5ra07770b

A simple and direct synthesis of functionalized imidazoles from α-nitro-epoxides and amidines was developed. This reaction could proceed smoothly in a highly efficient and eco-friendly manner in moderate to excellent yields. A plausible mechanism has also

Full text of DOI:10.1039/c5ra07770b

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DOI: 10.1039/C5RA07770B
Journal Name
RSCPublishing
COMMUNICATION
Highly Efficient and Ecoꢀfriendly Protocol to
Functionalized Imidazoles via RingꢀOpening of αꢀNitro
Epoxides
Cite this: DOI: 10.1039/x0xx00000x
Xiao Guo,‡Jiaan Shao,‡HuanLiu,Binhui Chen, Wenteng Chen, Yongping Yu*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
challenging to find a more attractive protocol to prepare
polysubstituted imidazoles with various substituents from
simple, readily available building blocks.
A simple and direct synthesis of functionalized imidazoles
from αꢀnitroꢀepoxides and amidines was developed. This
reaction could proceed smoothly in a highly efficient and ecoꢀ
friendly manner in moderate to excellent yields. A plausible
mechanism has also been proposed.
Nitroepoxides9 are an interesting class of compounds with
unique chemical reactivities. Exploited as potentially synthons
with two vicinal electrophilic centers, nitroepoxides are
Imidazoles, an important class of
Nꢀcontaining heteroaromatic particularly attractive intermediates and building blocks in
compounds, are frequently found in various pharmacologically organic synthesis.10
active compounds and natural products.1 Among them,
In view of the special properties of nitroepoxides, we envisioned
functionalized imidazoles are privileged core structures used in that this synthon could be employed for the synthesis of
medicinal chemistry because of their excellent biological polysubstituted imidazoles by simply treated with amidines. An
effects, such as antitumor, antifungal, antibacterial, antiviral, attractive feature of this protocol is that two molecules could be
antiinflammatory and antiarthritic activities.2 In addition, the directly assembled into the desired compounds without any
utility is also found as fluorescence, agricultural products, dyes transition metal catalysts.
and chemsensing.3
In light of the importance of imidazoles, a great deal of
Initially, 2ꢀmethylꢀ2ꢀnitroꢀ3ꢀphenyloxirane, 1.5 equiv. of
formamidine acetate and 1.5 equiv. of K2CO3 were selected as
attention has been given to their organic synthesis. A number of
model reagents to optimize the reaction conditions (Table 1). It
classical methods were established, involving threeꢀcomponent
was pleased to see that the reaction afforded the desired
cyclocondensation of a 1,2ꢀdiketone, αꢀhydroxyketone or αꢀ
ketomonoxime with an aldehyde and ammonium acetate,4
imidazole 3a in 36% yield (Table 1, entry 1). Gratifyingly, the
yield was notably increased when more equivalents (2 equiv.) of
metalꢀcatalyzed arylations of prepared imidazole rings,5 reaction of
aryl cyanides with α,αꢀdilithioarylnitromethanes,6 cyclization of
K2CO3 were added into the reaction mixture (Table 1, entry 2).
αꢀhaloketones with amidines,7 cyclization of nitroolefins with
However, it did not give a significant change (Table 1, entry 3)
amidines.8 Despitethese strategies have been greatly improved to be
while continuously increasing the amount of base (3 equiv.).
highly valuable for the construction of imidazoles, it is still
Further, other inorganic bases (Na2CO3, Cs2CO3, NaOH and
NaOMe) and organic bases (Et3N and DBU) were also tested for
the reaction. It was revealed that NaOMe was the most efficient
Zhejiang Province Key Laboratory of AntiꢀCancer Drug Research,
one (Table 1, entries 4ꢀ9). In order to improve the conversion of
College of Pharmaceutical Science, Zhejiang University, 866 Yuhangtang
this reaction, other conditions were also evaluated. Optimization
Road, Zijin Campus, Hangzhou 310058, China. Eꢀmail: yyu@zju.edu.cn.
‡ Xiao Guo and Jiaan Shao contributed equally to this work.
of solvent demonstrated that MeOH (Table 1, entry 9) was
superior to other aprotic and protic solvents (Table 1, entries 10ꢀ
† Electronic Supplementary Information (ESI) available: Experimental
17). Replacing MeOH with other solvents caused either a
procedures, characterization and spectra data of the final products. For
decrease in the yield (Table 1, entries 10ꢀ15 and 17) or failure to
ESI see DOI: 10.1039/c000000x/
obtain the corresponding products (Table 1, entry 16).
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DOI: 10.1039/C5RA07770B
Table 2 Scope of the cyclization reaction of 1 and 2a,b
Furthermore, temperature screening showed that room
temperature (25 °C) was optimal to obtain the maximum yield of
the product (Table 1, entries 18ꢀ20). On the basis of the above
studies, the optimal reactivity was obtained in MeOH at 25 °C
when 2.0 eqiuv. of NaOMe was employed (Table 1, entry 9).
Table 1 Optimization of reaction conditionsa
Entry
Base
(equiv.)
Solvent
T
(oC)
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
Conver
sionb (%)
36
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20c
K2CO3(1.5)
K2CO3(2)
K2CO3(3)
Na2CO3(2)
Cs2CO3(2)
NaOH(2)
Et3N(2)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
85
85
70
75
21
61
68
DBU(2)
NaOMe(2)
NaOMe(2)
NaOMe(2)
NaOMe(2)
NaOMe(2)
NaOMe(2)
NaOMe(2)
NaOMe(2)
NaOMe(2)
NaOMe(2)
NaOMe(2)
NaOMe(2)
95(91) c.
81
IPA
DMF
67
83
35
trace
trace
n.r.
32
27
95
CH3CN
THF
Dioxane
Toluene
H2O
MeOH
MeOH
MeOH
25
50
a Reaction conditions: mixtures of amidines (0.75 mmol, 1.5 equiv.) ,
base (1.0 mmol, 2.0 equiv.) and 3 mL of solvent was stirred at 25 oC
for 0.5h, and then nitroepoxide (0.5 mmol, 1.0 equiv.) was added, 25
oC,8h. b Isolated yield.
92
a
Reaction conditions: mixtures of amidines (0.15 mmol), base
o
(0.2 mmol) and 3 mL of solvent was stirred at 25 C for 0.5h,
and then nitroepoxide (0.1 mmol) was added, 25 C,8h. b The
o
conversion rate was determined by HPLC, based on the
disappearance of the starting nitroepoxide (1a). c Isolated yields.
The most successful entry is highlighted in bold.
higher yield than that with electronꢀwithdrawing groups (3q
versus 3p). Interestingly, the reaction could tolerate when R3
group was
a hetero aryl motif (Table 2, 3s). Notably,
imidazo[1,2ꢀa]pyridine scaffolds could also be constructed when
pyridinꢀ2ꢀamine was introduced via this reaction process (Table 2,
With the optimized reaction conditions in hand, the scope was
examined by coupling a range of nitroepoxides and amidines. As
shown in Table 2, the groups at the R1 and R2 positions of
nitroepoxides 1, either aryl or alkyl substitution, worked well
with amidines. It was also found that at the R1 position,
nitroepoxide bearing an orthoꢀbrominephenyl group afforded the
product 3e in lower yield than the metaꢀ or paraꢀbrominephenyl
substituted nitroepoxides (Table 2, 3f and 3d). Both aryl and
alkyl substitutions at the R3 position were found compatible in
3t
, 3u). The structures of the functionalized imidazoles
1
synthesized in the study were characterized from H NMR, 13C
NMR spectroscopies and HRMS analysis.
On the basis of the above experimental results, the following
possible mechanism for this reaction was proposed (Scheme 1).
In the case of base and amidines 2, the nitroepoxide 1 would
undergo a ring opening to give the intermediate II, which
continued undergoing an intramolecular nucleophilic addition
and elimination of one molecule of H2O to afford the final
this reaction. However,
a lower yield was given when
arylsubstitutions were present (3o versus 3m and 3n). Moreover,
as shown in Table 2, aryl substituents bearing electronꢀdonating
groups at the R3 position afforded the desired imidazoles in a
product 3.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA07770B
Scheme 1 Proposed Mechanism for the Tandem Reaction
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In summary, we have developed a new and mild strategy to
prepare functionalized imidazoles. This novel reaction can be
realized via a domino process involving a ringꢀopening of αꢀ
nitro epoxides and an intramolecular nucleophilic addition from
easily available αꢀnitroꢀepoxides and amidines or their analogues.
Operational simplicity, mild reaction conditions, and facile
substituent variation are all notable aspects of this methodology.
This makes it a highly practical approach in the medicinal chemistry.
4
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Acknowledgment
This project was supported from the National Natural Science
Foundation of China (No. 81273356 and 81473074), National
Science & Technology Major Projects for “Major New Drugs
Innovation and Development” of China (2014ZX09304002ꢀ
007) , Program for Zhejiang Leading Team of S&T Innovation,
and Arthritis & Chronic Pain Research Institute, USA, to Y.Y.,
and the China Postdoctoral Science Foundation Funded Project
(2014M550331), National Natural Science Foundation of China
(No. 81402778) and the Fundamental Research Funds for the
Central Universities (No. 2015QNA7029) to W.C.
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