Facile Synthesis of Polysubstituted Imidazoles through CBr4-Mediated Tandem Cyclization of Amidines with 1,3-Dicarbonyl Compounds or Ketones

Article abstract of DOI:10.1002/ejoc.201601428

Polysubstituted imidazoles were synthesized in a facile metal-free CBr₄-mediated tandem cyclization of amidine with 1,3-dicarbonyl compounds or ketones. The desired products were obtained in moderate to good yields by using simple operation tec

Full text of DOI:10.1002/ejoc.201601428

A Journal of
Accepted Article
Title: Facile Synthesis of Polysubstituted Imidazoles via CBr4 Mediated
Tandem Cyclization of Amidine with 1,3-Dicarbonyl or Ketone
Authors: Xiaoqiang Zhou, Haojie Ma, Chong Shi, Yixin Zhang, Xingxing
Liu, and Guosheng Huang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601428
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10.1002/ejoc.201601428
European Journal of Organic Chemistry
COMMUNICATION
Facile Synthesis of Polysubstituted Imidazoles via CBr4 Mediated
Tandem Cyclization of Amidine with 1,3-Dicarbonyl or Ketone
Xiaoqiang Zhou, Haojie Ma, Chong Shi, Yixin Zhang, XingXing Liu and Guosheng Huang*
Abstract: A facile approach to synthesize polysubstituted imidazoles
via CBr4 mediated tandem cyclization of amidine with 1,3-dicarbonyl
or ketone is described. This metal-free cascade reaction employed
CBr4 as promoter and was carried out with a simple operation under
mild conditions.
metal-free methods for the construction of N-heterocycles,16
herein, we describe facile approach to synthesize
polysubstituted imidazoles via CBr4 mediated tandem cyclization
a
of amidine with 1,3-dicarbonyl or ketone.
As one of the most valuable N-heterocyclic compounds,
imidazoles have been found in many natural products1 and
pharmaceutical compounds.2 The importance of this heterocyclic
structure motivated an intensive research for the development of
new and efficient synthetic strategies.3-6 Transition metal-
catalyzed cycloaddition of amidines has been widely used for
rapidly constructing these compounds.7 In recent years, a series
of methods which catalyzed by copper or iron have been
developed by the group of Neuville,8 Chen,9 and Li10 (Scheme 1).
However, in order to satisfy the low threshold residual tolerance
of metals for pharmaceuticals, complicated purifying procedures
and high cost have to be paid out for removing trace amounts of
residual metal from pharmaceutical precursors such as
polysubstituted imidazoles. From this point, developing metal-free
strategies for the synthesis of imidazole cores is still important.
In 2015, metal-free I2 catalyzed synthesis of substituted
imidazoles from vinyl azides and benzylamines has been reported
by Yan’s group.5 This procedure required highly energetic reagent
iodine and over stoichiometric amounts of peroxide oxidants
TBHP. α-Halogenated ketones or 1,3-dicarbonyls and their
derivatives are versatile synthetic blocks for building complex
molecules in organic chemistry. By virtue of simple operation and
fewer steps, preparing these α-halogenated products in situ has
been highlighted for the construction of heterocycles.11-12 As an
efficient catalyst, carbon tetrabromide has been found to show
good reactivity for the formation of C−C bond in cross-
dehydrogenative coupling (CDC) reactions and double-oxidative
dehydrogenative (DOD) reactions by Huo’s group.13 Recently,
Huo’s group developed an efficient CBr4–mediated oxidative C−N
bond formation reaction to construct complex imidazo[1,2-
a]pyridines and imidazo[1,2-a]pyrimidines.14 During our
preparation of this manuscript, Jaenicke and co-workers reported
an in-situ α-bromination strategy which employed CBrCl3 as
promoter for the formation of imidazo[1,2-a]pyridines.15 As part of
our continuing work in the development of new and efficient
Scheme 1. Synthesis of imidazole from amidine.
To initiate our study, the reaction conditions were screened for
the formation of tetrasubstituted imidazoles by taking ethyl 3-
oxobutanoate (1a) and N-phenylbenzamidine (2a) as model
substrates (Table 1). Various brominating reagents were first
examined. In a typical procedure, a mixture of 1a (0.2 mmol, 1
equiv), 2a (1 equiv), and halogenating reagents (1.0 equiv) in 2
mL of acetonitrile was stirred under air at 70 °C. The desired
product ethyl 4-methyl-1,2-diphenyl-1H-imidazole-5-carboxylate
3aa was detected when NBS, CBrCl3 and CBr4 were employed in
this reaction, respectively (Table 1, entries 1-5). And the desired
3aa was isolated in 41% yield by the use of 1.0 equiv of CBr4.
Although NBS, a highly energetic reagent, could give a higher
yield (44%). To make this transformation milder, CBr4 was
selected to screen the reaction conditions. Increasing the amount
of CBr4 could not improve the yields (Table 1, entry 6).
Subsequently, the yield was enhanced obviously by increasing
the dosage of amidine 2a moderately (Table 1, entries 7-8), while
no better result was observed when the loading of amidine 2a was
increased to 3.0 equiv (Table 1, entry 9). The use of other solvents
Xiaoqiang Zhou, Haojie Ma, Chong Shi, Yixin Zhang, XingXing Liu and
Prof. Guosheng Huang
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of
Nonferrous Metal Chemistry and Resources Utilization of Gansu Province,
Department of Chemistry, Lanzhou University.
Lanzhou, 730000, China.
E-mail: hgs@lzu.edu.cn
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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10.1002/ejoc.201601428
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COMMUNICATION
such as DCE (17 %) and MeOH (40 %), instead of CH3CN, was
found to be less effective (Table 1, entries 10-11). Finally, the
optimized reaction conditions were obtained as follows: 1.0 equiv
of CBr4 was mixed with 1.0 equiv 1a and 2.0 equiv 2a in CH3CN
at 70 °C under air (Table 1, entry 8).
4h, as the proposed intermediate, was used to react with
amidines 2a under standard conditions without CBr4, the desired
imidazole 3ha was obtained in high yield (Scheme 4, a).
Furthermore, this α-brominated intermediate 4d was also isolated
from the reaction of 1d and 2a under standard conditions by
carrying out this reaction at room temperature (Scheme 4, b).
These results validated α-brominated product is the intermediate
of this conversion. In addition, the reaction of 1a and 2a was
conducted in the presence of 2.0 equiv of TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy) under optimized conditions, and no
obvious inhibition was observed (Scheme 4, c). This result
suggested that no radical process was involved in this CBr4
mediated C−H bond amination reaction.
Table 1. Optimization of the reaction conditions [a]
Entry
1
Hal/equiv
TBAB(1.0)
NBS (1.0)
CBrCl3(1.0)
CBr4 (1.0)
CCl4(1.0)
CBr4(2.0)
CBr4(1.0)
CBr4(1.0)
CBr4(1.0)
CBr4(1.0)
CBr4(1.0)
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
Yield [b](%)
0
2
44
trace
41
0
3
4
5
6
39
57
82
83
17
40
7 [c]
8 [d]
9 [e]
10 [d]
11 [d]
MeOH
[a] Conditions: 1a (0.2 mmol), 2a (0.2 mmol), solvent (2 mL), under 70 °C,
overnight and monitored by TLC. [b] Isolated yields. [c] 2a (1.5 equiv, 0.3 mmol).
[d] 2a (2.0 equiv, 0.4 mmol). [e] 2a (3.0 equiv, 0.6 mmol).
With the optimized reaction conditions in hand, the scope and
generality to different amidines were investigated and the results
are summarized in Scheme 2. First, a series of amidines derived
from anilines with electron-donating or withdrawing groups were
examined using optimized conditions. All these amidines could
react with ethyl 3-oxobutanoate 1a smoothly and the desired
tetrasubstituted imidazoles could be obtained efficiently in good
yields. The yields remained relatively stable with the nature of the
different groups in the aromatic ring of anilines (3aa-3aj). Then,
various amidines derived from benzonitriles with electron-
donating or withdrawing groups were carried out in standard
conditions. Except of methoxyl (3an), all other substrates can give
the desired products in moderate to good yields (3ak-3am, 3ao-
3as).
This metal-free oxidative C−N bond formation strategy was
further expanded to a range of β-keto esters, 1,3-diones or
ketones substrates 1 (Scheme 3). Polysubstituted imidazoles
could be obtained smoothly. β-Keto esters with different
substituents could provide the corresponding products in good
yields (3aa-3da), while 1,3-diones and ketones gave moderate
results (3ea-3ia).
Scheme 2. Scope of amidines.
12-15
On the basis of the previous literature reports
and the
above results, the possible mechanism for this transformation is
proposed, as illustrated in Scheme 5. Firstly, intermediate A, the
isomerization of 1a, reacts with CBr4 to give α-brominated
intermediate B. Then the nucleophilic substitution of 2a with B
provides imine intermediate C. Subsequently, intramolecular
To gain mechanistic insights into this transformation, some
control experiments were carried out. Firstly, α-brominated ketone
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European Journal of Organic Chemistry
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nucleophilic addition of
aromatization process affords the final imidazole derivative 3aa.
C
and the connected oxidative
In conclusion, we have demonstrated a facile metal-free
approach to synthesize polysubstituted imidazoles via CBr4
mediated tandem cyclization of amidine with 1,3-dicarbonyl or
ketone. CBr4 was employed to promote this in situ α-C–H
bromination process. Simple operation with inexpensive reagents
and mild reaction conditions make this efficient protocol practical.
Experimental Section
A test tube equipped with a magnetic stir bar was charged with ketones 1
(0.2 mmol), amidines 2 (0.4 mmol), CBr4 (66.4 mg, 0.2 mmol), and CH3CN
(2 mL). Then the reaction mixture was stirred at 70 °C (oil bath
temperature) under air. After completion of the reaction (monitored by
TLC), the reaction mixture was concentrated in vacuo, and the residues
were purified by column chromatography, eluting with petroleum
ether/EtOAc to afford the desired imidazoles 3.
Keywords: amidine • amination • bromination • imidazoles •
metal-free
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Entry for the Table of Contents (Please choose one layout)
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Xiaoqiang Zhou, Haojie Ma, Chong Shi,
Yixin Zhang, XingXing Liu and
Guosheng Huang*
Page No. – Page No.
Facile Synthesis of Polysubstituted
Imidazoles via CBr4 Mediated
Tandem Cyclization of Amidine with
1,3-Dicarbonyl or Ketone
A facile metal-free approach to synthesize polysubstituted imidazoles via CBr4
mediated tandem cyclization of amidine with 1,3-dicarbonyl or ketone is described,
affording desired products in moderate to good yields with a simple operation under
mild conditions.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.