Sequential One-Pot Synthesis of Imidazoles and 2H-Imidazolones from β-Ketoamines, Acylating Agents and Ammonium Acetate

Article abstract of DOI:10.1002/bkcs.11005

An efficient, practical, straight forward, and transition metal-free three-component synthesis of diversely substituted imidazoles and 2H-imidazolones from β-ketoamines, acylating agents, and ammonium acetate has been described herein. This approach invol

Full text of DOI:10.1002/bkcs.11005

Article
DOI: 10.1002/bkcs.11005
BULLETIN OF THE
H. B. Jalani et al.
KOREAN CHEMICAL SOCIETY
Sequential One-Pot Synthesis of Imidazoles and 2H-Imidazolones from
β-Ketoamines, Acylating Agents and Ammonium Acetate
*
Hitesh B. Jalani, Eeda Venkateswararao, Manoj Manickam, and Sang-Hun Jung
College of Pharmacy and Institute of Drug Research and Development, Chungnam National University,
Daejeon 34134, Korea. *E-mail: jungshh@cnu.ac.kr
Received August 11, 2016, Accepted October 11, 2016
An efficient, practical, straight forward, and transition metal-free three-component synthesis of
diversely substituted imidazoles and 2H-imidazolones from β-ketoamines, acylating agents, and
ammonium acetate has been described herein. This approach involves [3+1+1] cyclization through
consecutive formation of three C–N bonds as a sequence of initial amidation of β-ketoamines with
acylating agent, β-iminoketoamide formation with ammonia, and acid catalyzed concomitant cyclode-
hydration to afford the imidazoles and 2H-imidazolones. This methodology has advantages such as
single flask operation, readily available starting materials, mild conditions, broad functional groups
tolerance, and simple work-up procedure.
Keywords: Imidazoles, 2H-Imidazolones, One-pot, β-ketoamines, Cyclodehydration, Acetic acid
Introduction
this regard, we report herein, a one-pot methodology for the
preparation of highly substituted imidazoles from
β-ketoamines (see Appendix S1, Supporting information for
the detailed description on the synthesis of α-ketoamines),
commercially available acid chlorides or acid anhydrides,
and ammonium acetate (Scheme 1). Also 2H-imidazolones
from β-ketoamines (see Appendix S1, Supporting informa-
tion for the detailed description on the synthesis of α-ketoa-
mines), chloroformates, and ammonium acetate as illustrated
in Scheme 1.
Imidazole is one the most familiar heterocyclic scaffold pres-
ent in various biologically interesting natural products1 as
well as pharmaceutical substances.2 Plenty of molecules con-
sist of imidazole backbone have been identified as important
and useful chemical substances such as functionalized
materials,3 precursors to ionic liquids,4 N-heterocyclic
carbenes,5 and molecules emitting white light.6 Therefore,
ample research efforts have been made toward the acquisi-
tion of multi substituted imidazole derivatives and thus vari-
ous synthetic methods have been developed. Common
methods for the synthesis of imidazoles have been developed
using different catalyst promoted preparation,7 multi-
component reactions,8 Van Leusen strategy,9 and solid phase
synthesis.10 Addition to these, rhodium-catalyzed N–H inse-
tion reaction of primary ureas with diazocarbonyls is one of
the useful methods for the synthesis of highly substituted
2H-imidazoles and imidazoles.11 However, there are very
few reports for the synthesis of diversely substituted 2H-
imidazolones.11–13 Having significance application of imid-
azole library,1–6 efficient and straight forward approaches for
the acquisition of highly substituted imidazole from simple
chemical reagents are very important. Four-component one-
pot procedures for the synthesis of imidazoles involving con-
densation of benzil or benzoin with amines, aldehydes, and
ammonia were developed.7,8e However, in these procedures,
aldehydes are unavoidably required as one of the reaction
partners and thereby restrict the functional diversity within
the imidazole scaffold. Since the carboxylic acid derivatives
such as acid chlorides, acid anhydrides, and chloroformates
are apparently more diverse, methods using acid derivatives
for the synthesis of imidazoles would be more important. In
Results and Discussion
In order to devise an efficient and simple protocol, we ini-
tially investigated model reaction of 1-(4-chlorophenyl)-2-
(4-methoxyphenylamino)ethanone (1a) with acetyl chloride
(2a) in the presence of triethylamine in dichloroethane to
afford the β-ketoamide 3a after 2 h. Treatment of 3a with
ammonium acetate in presence of sulfuric acid for 10 h at
reflux temperature showed a new spot on TLC, which was
then isolated and characterized as imidazole 4a (Table 1,
entry 1) with only 18% overall yield. Based on this result,
we developed one-pot sequential procedure without isola-
tion of intermediate 3 (see experimental section for detail
procedure).
For the optimization of this procedure, reaction para-
meters including various bases, acids, solvents, and temper-
ature were examined as shown in Table 1 (entries 2–16).
First, the solvents such as dichloroethane (DCE), acetonitrile
(ACN), tetrahydrofuran (THF), N,N-dimethylformamide
(DMF), and toluene were investigated with triethylamine
and sulfuric acid (Table 1, entries 2–5). Toluene was found
to be the most suitable solvent with 39% yield (Table 1,
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(Table 1, entry 10), sodium carbonate (Table 1, entry 11), and
cesium carbonate (Table 1, entry 12) afforded the highest yield
(58%) of imidazole 4a. Subsequently, the ratio of potassium
carbonate and acetic acid was also investigated to get the max-
imum yield. It was enhanced from 58% to 74% in this reaction
using 1a (1 mmol), potassium carbonate (1.2 mmol), and ace-
tic acid (0.5 mL) refluxing in toluene for 10 h (Table 1, entry
15). It was found to be the best reaction conditions for the syn-
thesis of imidazole 4a.
When reaction was carried out without either base or
acid and both, the desired product was not formed and
starting material were recovered (Table 1, entry 16–18).
This result suggested the requirement of acid for the
cyclization.
With the optimized reaction condition in hand, we turned
our attention toward the scope of various acid chlorides
(2a–2m) for the synthesis of imidazole as given in Table 2.
Diverse alkyl, aryl, or hetero-aryl acid chlorides efficiently
provided the imidazoles with good to excellent yield.
Therefore propionic acid (2b), cyclohexylcarboxylic (2f),
ethyl 4-chloro-4-oxobutanoate (2d), 4-nitrobenzoic (2i),
trans-4-fluorocinnamic (2h), isonicotinic (2l), and
thiophene-2-carboxylic (2m) acid chlorides were employed
Scheme 1. One-pot synthesis of diversely substituted imidazoles
and 2H-imidazolones.
entry 5). After the optimization of solvent, next we concen-
trated to find the best acid in step 2 for cyclization. In order
to make this process applicable for the industrial utilization,
we examined the economical bronsted acids for this reac-
tion. As a result, acetic acid gave the best yield for the for-
mation of 4a with yield 46% (Table 1, entry 7) followed by
sulfuric acid (39%, Table 1, entry 5), and p-toluenesulfonic
acid (32%, entry 6).
Finally various bases were tested to increase the yield of
4a. Use of potassium carbonate (Table 1, entry 13) as com-
pared to trimethylamine (Table 1, entry 7), pyridine (Table 1,
entry 8), 2,6-lutidine (Table 1, entry 9), sodium bicarbonate
Table 1. Screening for the reaction conditions.a
Entry
Base/acid
Base/acidb (mL)
Solvent
T(ꢀC)
Yieldc(%)
1
2
3
4
5
6
7
8
Triethylamine/H2SO4
Triethylamine/H2SO4
Triethylamine/H2SO4
Triethylamine/H2SO4
Triethylamine/H2SO4
Triethylamine/PTS
Triethylamine/AcOH
Pyridine/AcOH
2,6-lutidine/AcOH
NaHCO3/AcOH
Na2CO3/AcOH
Cs2CO3/AcOH
K2CO3/AcOH
1.1/1
1.1/1
1.1/1
1.1/1
1.1/1
1.1/1
1.1/1
1.1/1
1.1/1
1.1/1
1.1/1
1.1/1
1.1/1
1.2/1
1.2/0.5
1.2/0
0/0.5
0/0
DCE
ACN
THF
DMF
83ꢀC
18
20
28
30
39
32
46
50
44
45
51
53
58
59
74
81ꢀC
67ꢀC
120ꢀC
110ꢀC
110ꢀC
110ꢀC
110ꢀC
110ꢀC
110ꢀC
110ꢀC
110ꢀC
110ꢀC
110ꢀC
110ꢀC
110ꢀC
110ꢀC
110ꢀC
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
9
10
11
12
13
14
15
16
17
18
a
K2CO3/AcOH
K2CO3/AcOH
K2CO3/AcOH
K2CO3/AcOH
Trace
Trace
–
K2CO3/AcOH
Reaction conditions: 1a (1 mmol), 2a (1.1 mmol), NH4OAc (5.0 mmol), solvent (2 mL).
Base (eq.) in first step & acid (mL) in the second step.
Isolated yield of 4a.
b
c
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Sequential One-Pot Synthesis of Imidazoles and 2H-Imidazolones from
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Table 2. Synthesis of tri/tetra substituted imidazoles using various acid chlorides.
a
Reaction conditions: 1a (1 mmol), 2a-m (1.1 mmol), NH4OAc (5.0 mmol), solvent (2 mL).
Base (eq.) in first step & acid (mL) in the second step.
Isolated yield of 4a.
b
c
to afford the corresponding imidazole with good yield.
Regarding the electronic effects of benzoyl chloride, it was
observed that electron withdrawing groups present in the
acid chloride gave high yield (p-nitrobenzoyl chloride,
yield 92%, 4i). Electron releasing group containing 4-N,N-
dimethylaminobenzoyl chloride gave moderate yield (48%,
4m). These results proved that the scope of acid chloride
derivatives is very wide. There are limited reports on the
three-component one-pot syntheses of tetra-substituted imi-
dazoles from the readily available starting materials. The
microwave condition14 was applied for synthesis of imidaz-
ole having 4,5-dimethyl group as shown in 4k. However,
the present procedure conveniently provided 4e and 4k
with 56% and 68% yield, respectively.
Next, we explore the substrate scope of various acid
anhydrides (2n–2r) as depicted in the Table 3.
Most of anhydrides were successfully employed for the
synthesis of imidazoles, though anhydride compared to acid
chloride gave relatively lower yield (for example 4a & 4b).
Even highly sterically hindered pivalic anhydride (2p) gave
good yield of the imidazole (4s, 69%). Acid anhydride
incorporating strong electron withdrawing such as trifluoro-
methane group afforded the highest yield (4t, 79%). Sur-
prisingly, the highly hindered β-ketoamine 1h gave fairly
good yield (4p, 53%).
It was revealed that there are very few reports on the
synthesis of 1,4-diaryl-1,3-dihydro-2H-imidazol-2-one.11
Kohn et al.,13 described the reaction of 3-substituted hydan-
toins with 4 equiv of lithium aluminum hydride in THF at
room temperature for 2 days gave moderate yields of 4-
hydroxy-2H-imidazolidinones which on treatment with tri-
fluoroacetic acid undergoes dehydration to give the corre-
sponding 2H-imidazolones. Considering the importance of
1,4-disubstituted-1,3-dihydro-2H-imidazol-2-one from syn-
thesis as well as biological activity point of view, we were
interested in development of the efficient protocol for 2H-
imidazolones using our established reactions. We undetook
the investigation of methyl chloroformate (2s) and phenyl
chloroformate (2t) as acylating agent in this reaction, in
which gave the 2H-imidazolones with good yields as
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Sequential One-Pot Synthesis of Imidazoles and 2H-Imidazolones from
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β-Ketoamines, Acylating agents and Ammonium acetate
KOREAN CHEMICAL SOCIETY
Table 3. Synthesis of tri/tetra substituted imidazoles using various acid anhydrides.
Table 4. Synthesis of di/tri substituted 2H-imidazolones using chloroformates.
depicted in Table 4. Addition to this, the limitation of the
procedure described by Kohn et al. gave 1,4-diaryl-2H-
imidazolones while, present protocol furnished 1,4,5-tri-sub-
stituted-2H-imidazolones, for example, 4y with 71% yield.
This highly substituted product formation has proved our
protocol as a versatile which uses simple reaction conditions.
Based on the above experimental results, the reaction
mechanism could be discribed as shown in Scheme 2.
The first step is the reaction of β-amino-ketone 1 with
acylating agent 2 in the presence of potassium carbonate
affords the β-ketoamide 3. In the next step, imine (5) is
Scheme 2. Plausible reaction mechanism.
which then cyclize to 2H-imidazolones with the removal of
formed by the reaction of ammonium acetate and β-ketoa-
mide. The nucleophilic attack of imine on the amide car-
bonyl results in cyclized product 6 which further undergoes
dehydration under the acidic condition15 and thereby affords
the imidazole. In case of methyl chloroformate, the
β-ketocarbamate will be formed, instead of β-ketoamide in
the first step and its subsequent reaction with ammonium
acetate in presence of acid will give imine intermediate,
alcohol.
Conclusion
In conclusion, a practical type of transition metal-free
sequential one-pot process for the synthesis of diversely
substituted imidazoles and 2H-imidazolones from β-ketoa-
mines, acylating agents, and ammonium acetate was
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Sequential One-Pot Synthesis of Imidazoles and 2H-Imidazolones from
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robust reaction conditions with easily available starting
materials. Being characterized by the diversity (β-amino-
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Acknowledgment. This work was supported by Research
Fund of Chungnam National University.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
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