Iron-Catalyzed Synthesis of 2H-Imidazoles from Oxime Acetates and Vinyl Azides under Redox-Neutral Conditions

Article abstract of DOI:10.1021/acs.orglett.7b00203

A novel and versatile method for the synthesis of 2H-imidazoles via iron-catalyzed [3 + 2] annulation from readily available oxime acetates with vinyl azides has been developed. This denitrogenative process involved N-O/N-N bond cleavages and two C-N bond formations to furnish 2,4-substituted 2H-imidazoles. This protocol was performed under mild reaction conditions and needed no additives or ligands. Furthermore, this is a green reaction involving oxime acetate as internal oxidant, acetic acid, and nitrogen as byproducts.

Full text of DOI:10.1021/acs.orglett.7b00203

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Synthesis of 2H‑Imidazoles from Oxime Acetates and
Vinyl Azides under Redox-Neutral Conditions
Zhongzhi Zhu, Xiaodong Tang, Jianxiao Li, Xianwei Li, Wanqing Wu, Guohua Deng,*
and Huanfeng Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A novel and versatile method for the synthesis of 2H-imidazoles via
iron-catalyzed [3 + 2] annulation from readily available oxime acetates with vinyl
azides has been developed. This denitrogenative process involved N−O/N−N
bond cleavages and two C−N bond formations to furnish 2,4-substituted 2H-
imidazoles. This protocol was performed under mild reaction conditions and
needed no additives or ligands. Furthermore, this is a green reaction involving
oxime acetate as internal oxidant, acetic acid, and nitrogen as byproducts.
Scheme 1. Synthesis of Substituted 2H-Imidazoles
n the past decades, transition-metal-catalyzed oxidative
Icoupling has attracted much attention and provided an
ideal synthetic mode for the formation of C−C and C−X
bonds.1 Among the numerous catalysts explored in this field,
noble metal catalysts including Pd, Rh, Ir, and Ru are often
employed. However, due to the cost, toxicity, and sustainability,
the first-row transition metals, especially abundant metals such
as copper2 and iron,3 have increasingly attracted the attention
of chemists. In this regard, iron, which is one of the most
abundant, inexpensive, and environmentally friendly metals on
the earth, has shown high reactivity and great potential in
replacing precious metal catalysts for organic synthesis.
2H-Imidazoles are important motifs found in a broad
spectrum of biologically active natural products4 as well as in
organic synthesis.5 They could be used as chiral auxiliaries for
organic synthesis reactions6a,b and for detection of a diradical
intermediate.6c Despite their good synthetic utility, the
synthesis of functionalized 2H-imidazoles is rarely reported.
Classical methods for their synthesis involve Weiss’ protocols in
which a series of 4,5-diphenyl-2H-imidazoles were structured
from benzil, ketone, and ammonium acetate (Scheme 1, Figure
1a).7a The certain issues of this system are limited substrate
scope and the use of large amounts of acid. After that, only two
examples for the synthesis of 2H-imidazoles were reported.
Chiba et al. employed KI as catalyst to synthesize this skeleton
by electrolytic oxidation of ketones in ammoniacal methanol
(Figure 1b).7b Thereafter, Auricchio’s group reported an
alternative approach to nitrogen heterocycles by the cleavage
of the azirine ring with poor selectivity and low yield (Figure
1c).7c However, the preparation of some practical and sensitive
2H-imidazoles is one of the continuing challenges among
general preparative methods. Thus, the development of efficient
transformations that exhibited mild conditions and good
functional group tolerance for the synthesis of 2H-imidazoles
is highly desirable.
In addition, considering the requirement of green and
sustainable chemistry, using green oxidants such as O2 or
8
internal oxidant9 will increase the value of the transformation
very well. Oximes and their derivatives are a kind of internal
oxidant that can be easily prepared by the reaction of ketone,
hydroxylamine hydrochloride, and acetic anhydride. Originating
from our continuous studies on oximes and oxime acetates as
substrate and oxidant,10 herein we present an iron-catalyzed
synthesis of polysubstituted 2H-imidazoles from oxime acetates
and vinyl azides (Scheme 1d).
At the outset, we used acetophenone oxime acetate (1a) and
(1-azidovinyl)benzene (2a) as model substrates to screen iron
salts and solvents under air atmosphere (Table 1). The desired
product could be obtained in 72% GC yield when we used
Fe(OAc)2 (5 mol %) as catalyst in CH3CN at 80 °C under air
(entry 1). Various iron catalysts were examined, but they did
not show apparent positive effects to this transformation
Received: January 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00203
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a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Oxime Acetates
b
entry
cat.
solvent
temp (°C)
yield (%)
1
Fe(OAc)2
FeSO4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DMSO
DCE
80
80
80
80
80
80
80
80
80
70
90
100
90
90
90
90
90
72
46
2
3
FeF3
24
4
FeCl3
25
5
FeBr3
trace
24
6
FeBr2
7
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
Fe(OAc)2
21
8
11
9
81
10
11
12
DCE
62
c
DCE
94 (90)
DCE
68
91
0
d
13
DCE
14
DCE
e
15
Zn(OTf)2
AgOAc
DCE
0
e
16
DCE
0
e
17
Pd(OAc)2
DCE
0
a
Reaction conditions: unless otherwise noted, all reactions were
performed with 1a (0.3 mmol), 2a (0.36 mmol), and catalyst (5 mol
b
%) in solvent (2.0 mL) for 6 h. Yields and conversions analyzed by
a
Reactions were performed with 1 (0.3 mmol), 2a (0.36 mmol), and
Fe(OAc)2 (5 mol %) in DCE (2 mL) at 90 °C for 6 h. Isolated yields.
c
GC/MS and dodecane as internal standard are based on 1a. Isolated
yields. Under N2 atmosphere. Lewis acids (5 mol %).
d
e
a
Scheme 3. Substrate Scope of Vinyl Azides
(entries 2−6). Next, different solvents such as toluene, DMSO,
and DCE were investigated, and DCE was found to be the
optimal solvent (entries 7−9). Further examination of the
temperature showed that 90 °C proved to be the best, affording
3aa in 94% GC yield and 90% isolated yield (entries 10−12).
Moreover, we found that N2 atmosphere had no significant
effect on the reaction (entry 13), and no reaction occurred in
the absence of Fe(OAc)2 catalyst (entry 14). In addition, Lewis
acids such as Zn(OTf)2, AgOAc, and Pd(OAc)2 could not
catalyze this transformation (entries 15−17).
Based on the optimization study, the substrate scope of
oxime acetates was investigated (Scheme 2). Generally, this
reaction proceeded smoothly and gave the desired products 3
in moderate to good yields (56−90%, Scheme 2). The
acetophenone oxime acetates with group 4-NO2 and 4-CF3
were compatible with this conversion and the desired products
were isolated in a slightly low yield (3aj, 3ak). Notably, the
steric hindrance had little effect on the reaction (3ah and 3am,
3aa and 3an, 3ag, 3al, and 3ao). Moreover, oxime acetates
derived from other aromatic ketones such as propiophenone,
benzophenone, 3,4-dihydronaphthalen-1(2H)-one and 6,7,8,9-
tetrahydro-5H-benzo[7]annulen-5-one could be accessed
through this route to generate the annulation products 3aq−
at in good yields. In addition, the heteroarene oxime acetates
were compatible with this transformation (3au−aw). When 1-
acetylnaphthalene oxime acetate was used as the substrate, 3ax
could be isolated in 61% yield. Furthermore, the aliphatic oxime
acetate also could be transformed into the desired product in
moderate yields (3ay−bc).
a
Reactions were performed with 1 (0.3 mmol), 2a (0.36 mmol), and
Fe(OAc)2 (5 mol %) in DCE (2 mL) at 90 °C for 6 h. Isolated yields.
Next, we sought to investigate the scope of the vinyl azides
(Scheme 3). In general, the azidovinylbenzenes with various
functional groups, including methyl, tert-butyl, chloro, bromo,
ester groups, were reacted under the optimal reaction
conditions, and moderate to excellent yields of the desired
products were obtained (3bc−bh). Satisfactorily, with strong
electron-withdrawing substituents (−NO2, −CF3) on the
aromatic ring, the transformation proceeded smoothly to afford
the desired products (3bi,bj). We also found that substitution
at the ortho-, meta-, or para-position of the aromatic ring had a
B
DOI: 10.1021/acs.orglett.7b00203
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Letter
slight impact (3bk−bn). Moreover, naphthalene vinyl azide was
also compatible in this reaction, affording the desired product
3bo in 65% yield. In addition, the aliphatic vinyl azide was also
compatible in this transformation and afforded the desired
product (3bp) in 68% yield.
A gram-scale reaction of 1ab was carried out on a 10 mmol
scale under the standard reaction conditions, providing 1.82 g
of the desired product 3ab in 78% isolated yield (Scheme 4).
Similar results were obtained when oxime acetate 1as was used
under the standard conditions, and the desired 3as was
achieved in 73% yield.
radical scavenger TEMPO, BHT, and 1,1-diphenylethylene to
our standard reaction. We found that this conversion was not
inhibited completely, but the yield of product 3aa was reduced
significantly (eq 3).
On the basis of previous reports and our preliminary results,
a tentative mechanism for the iron-catalyzed [3 + 2] annulation
of oxime acetates with vinyl azides is proposed in Scheme 7.
Scheme 7. Proposed Mechanism
Scheme 4. Large-Scale Synthesis of 3
To demonstrate the practical utility of this novel method,
further transformations of 3 are illustrated in Scheme 5.
Scheme 5. Further Transformations of 3
First, imine anion intermediate A was produced via reduction of
1a by an Fe(II) species with a two-step, single electron-transfer
process.12f,k Next, a nucleophilic attack may occur between
anion intermediate A and 2H-azirine 4a12b,g−j or Michael
addition−elimination of the A to the vinyl azides2a,12d,e to form
the intermediate B. Then, intermediate C was formed via
intramolecular cyclization of intermediate B.12a Finally,
oxidative dehydrogenation of C by Fe(III) species gave the
product 3 (path a). There was an alternative approach that
intermediate B was first oxidized by Fe(III) to form the imine
radical intermediate D, which cyclized to intermediate E.
Finally, the product 3 was obtained via sequential oxidation/
deprotonation process (path b).
Compound 3 could be effectively oxidized to 6a and 6b with
acetic acid peroxide.11 In addition, compound 3 also could be
restored to 7 with lithium aluminum hydride smoothly in good
yields (7a−d).
To gain more insight into the reaction mechanism, several
experiments were performed in Scheme 6. First, the aryl-2H-
In summary, an efficient and external-oxidant-free iron-
catalyzed [3 + 2] annulation of oxime acetates with vinyl azides
has been developed, providing rapid access to a series of
functionalized 2H-imidazoles. The reaction involves N−O/N−
N bond cleavages and two new C−N bond formations. The
advantages of this protocol include low-cost catalyst, facile
conditions, easy handling, and high atom economy. Various
2,2,5-trisubstituted 2H-imidazoles were formed in good yields.
Further studies to explore asymmetric synthesis and new
transformations of oxime acetates are in progress in our
laboratory.
Scheme 6. Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00203.
azirine 4a, which was considered to be a possible intermediate
generated from aryl vinyl azides, was reacted with 1 under the
optimal conditions, 3aa and 3ah could be obtained in high
yields, and we also detected trace amount of 3ab, which came
from the self-coupling of 4a (eq 1). Moreover, treatment of 2a
with isolable imines 5 under the standard conditions in the
absence of 1ar afforded 3ar in 84% yield. This result indicated
that the generation of imine or imine intermediates was
involved in this transformation. Thereafter, we added 5 equiv of
Experimental procedures, condition screening table,
characterization data, and copies of NMR spectra for
all products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ghdeng@scut.edu.cn.
C
DOI: 10.1021/acs.orglett.7b00203
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
F. V.; Slivo, C.; Swahn, B.-M.; Olsson, L.-L.; Johansson, P.; Eketjall, S.;
Falting, J. J. Med. Chem. 2012, 55, 9297.
̈
̈
*E-mail: jianghf@scut.edu.cn.
ORCID
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Huanfeng Jiang: 0000-0002-4355-0294
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Key Research and Development
Program of China (2016YFA0602900), the National Natural
Science Foundation of China (21420102003), and the
Fundamental Research Funds for the Central Universities
(2015ZY001) for financial support.
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