Metal-free, acid-promoted synthesis of imidazole derivatives via a multicomponent reaction

Article abstract of DOI:10.1021/ol402892z

An expedient and metal-free synthetic route has been developed for the construction of tri- and tetrasubstituted imidazole derivatives via acid promoted multicomponent reaction methodology. The reaction proceeded smoothly with a range of functionalities to produce the imidazole scaffolds in good to excellent yields.

Full text of DOI:10.1021/ol402892z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Metal-Free, Acid-Promoted Synthesis
of Imidazole Derivatives via a
Multicomponent Reaction
Chung-Yu Chen,§ Wan-Ping Hu,‡ Pi-Cheng Yan,† Gopal Chandru Senadi,† and
Jeh-Jeng Wang*,†
Departments of Medicinal and Applied Chemistry, Biotechnology, and Pharmacy,
Kaohsiung Medical University, Kaohsiung, Taiwan
jjwang@kmu.edu.tw
Received October 8, 2013
ABSTRACT
An expedient and metal-free synthetic route has been developed for the construction of tri- and tetrasubstituted imidazole derivatives via acid
promoted multicomponent reaction methodology. The reaction proceeded smoothly with a range of functionalities to produce the imidazole
scaffolds in good to excellent yields.
Diversified imidazole scaffolds are a vital class of hetero-
cycles because of their abundance in natural products1 and
broad use in the field of medicinal chemistry.2 In particu-
lar, they are well-known for their anticancer,3 antifungal,4
and antibacterialactivities.5 On the other hand, highly sub-
stituted imidazoles derivatives possess good photophysical
properties, which result in their potential in material
chemistry application such as organic electroluminescent
devices (OLED).6 In addition, imidazole derivatives were
utilized as ligands in the metal catalyzed reaction7 and also
as fluorescent probes.8 Based on the above facts, a variety
of synthetic routes have been devised for the synthesis of
imidazole analogues.9
In general, 2,4,5-trisubstituted imidazoles were synthe-
sized by the reaction of 1,2-diketone or keto-monoxime or
† Department of Medicinal and Applied Chemistry.
‡ Department of Biotechnology.
§ Department of Pharmacy
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r
10.1021/ol402892z
XXXX American Chemical Society

Table 1. Optimization of Reaction Conditions to Synthesize
Compound 4aa,b
Scheme 1. Synthesis of Imidazole Derivatives with Various
Methodologies
entry
[O]
solvent
additive
t/°C yield
140
1
KMnO4 DMSO NH4OAc/ZnO/PivOH
À
2
CAN
DMP
PIFA
PIDA
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
DMSO NH4OAc/ZnO/PivOH
DMSO NH4OAc/ZnO/PivOH
DMSO NH4OAc/ZnO/PivOH
DMSO NH4OAc/ZnO/PivOH
DMSO NH4OAc/ZnO/PivOH
DMSO NH4OAc/ZnO/PivOH
DMSO NH4OAc/ZnI2/PivOH
140 trace
140 88%
140 76%
140 67%
140 71%
140 84%
140 43%
3
4
5
6
7c
8c
9c
DMSO NH4OAc/ZnBr2/PivOH 140 27%
DMSO NH4OAc/ZnCl2/PivOH 140 31%
10c
11c
12c
13c
14c
15c
16c
17c
18c
19c
20c
21c
R-hydroxy/acetoxy/silyloxy-ketone as shown in Scheme 1.
Moreover, some other reactions were performed with
or without using the catalysts under pressure with
superheating conditions (Method A, Scheme 1).10 Apart
from these synthetic methods, Lewis acid catalyzed
addition reactions with amidines (Method B)11 and
Ni-catalyzed cyclotrimerization (with expulsion of
NH3) of aromatic nitriles under drastic reaction condi-
tions for a prolonged period were also reported in the
literature (Method C) .12
DMSO NH4OAc/PivOH
DMSO NH4OH/PivOH
DMSO NH4OAc/AcOH
DMSO NH4OAc/TFA
DMSO NH4OAc/TsOH
DMSO NH4OAc/none
140 83%
140 65%
140 32%
140 73%
140 49%
140
À
DMF
NH4OAc/PivOH
NH4OAc/PivOH
NH4OAc/PivOH
NH4OAc/PivOH
140 33%
MeCN
PhCl
140
140
140
À
À
À
CHCl3
DMSO NH4OAc/PivOH
DMSO NH4OAc/PivOH
100 61%
140 65%
140 25%
However, most of these methods suffer from one or
more limitations such as harsh reaction conditions, un-
satisfactory product yields, tedious isolation procedures,
and expensive and detrimental metal precursors, which
limit their use under the aspect of environmentally benign
processes. Therefore, development of mild, economical,
and complementary approaches for 2,4,5-trisubstituted
and 1,2,4,5-tetrasubstituted imidazole derivatives is still
highly desired due to their extreme significance.
Herein, we report our studies to develop a new approach
toward the synthesis of substituted imidazole derivatives
using an internal alkyne, aldehyde, and aniline in one
pot via pivalic acid promoted benzil formation followed
by cyclocondensation of amidines through a multicom-
ponent strategy. The synthetic method has anadvantage of
22c,d none
23c,e
none
H2O
NH4OAc/PivOH
a Reactions were performed with 1a (1.0 mmol), oxidant (1.0 mmol),
additive NH4OAc (4.0 mmol), ZnO (1.0 mmol), PivOH (1.0 mmol),
solvent (DMSO/H2O = 1:1) at 140 °C for 12 h. b Isolated yield.
c Prolonged reaction time 24 h. d Without H2O. e Without DMSO.
affording an imidazole core with high structural diversity
and excellent reaction yields.
In the search for effective conditions, the reaction was
carried out with diphenylacetylene (1a), benzaldehyde (2a)
with various oxidants, additives, solvents, and tempera-
tures to form 2,4,5-triphenylimidazole 4a as summarized
in Table 1. The reaction of 1awith a stoichiometric amount
of DMP (Dess-Martin periodinane), KMnO4, and CAN
in the presence of NH4OAc/ZnO/PivOH as an additive
in DMSO solvent was carried out at 140 °C, following our
previous reported conditions13 (Table1, entries 1À3). The
use of DMP afforded the required product 4a in 88% yield
(entry 3), whereas KMnO4 and ceric (IV) ammonium
nitrate (CAN) did not produce the desired product
(entries 1À2). Subsequently, by changing the oxidant to
PIFAandPIDA, the requiredproduct was produced albeit
in low yields (entries 4À5). Surprisingly, the desired pro-
duct 4a was obtained in the absence of oxidant (entry 6).
From the optimistic result of entry 6, we further pro-
longed the reaction time to 24 h, which then produced
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B
Org. Lett., Vol. XX, No. XX, XXXX

Figure 2. The four components were the series of imidazole
derivatives. Reactions were performed with 1 (1.0 mmol), 2
(1.0 mmol), 3 (1.0 mmol), PivOH (1.0 mmol), and NH4OAc
(4.0 mmol) in the presence of a solvent mixture (DMSO/H2O = 1:1)
at 140 °C for 24À48 h. Isolated yields provided.
Figure 1. The three components were the series of imidazole
derivatives. Reactions were performed with 1 (1.0 mmol), 2
(1.0 mmol), NH4OAc (4.0 mmol), and PivOH (1.0 mmol) in the
presence of a solvent mixture (DMSO/H2O = 1:1) at 140 °C for
24À40 h. Isolated yields provided.
with the yield of 80% and 83% respectively, and these
molecules will provide a convenient access for metal-
catalyzed cross-coupling reactions. Heterocyclic aldehyde
(furan-2-carbaldehyde) was well tolerated under similar
reaction conditions to obtain the compound 4i in 83%
yield. An electron-donating group at the ortho-, meta-, and
para-position of aromatic ring B was also tolerated with
an 82À88% yield (4jÀ4l). Aliphatic aldehydes were also
found to be the best reaction components to be used for
the synthesis of compounds 4fÀ4h in 68À74% yields.
In particular, the ring B bearing the 3,4,5-trimethoxy
group also proceeded smoothly to afford the desired
products 4oÀ4p in good yields. These products were made
with this strategy, because the structureÀactivity relation-
ship of Combretastatin A4 indicates that the presence
of the 3,4,5-trimethoxy group on ring B is fundamental
for antitubulin and anticancer activity.14
With the success of a three component reaction in hand,
we further extended our methodology for the construction
of various substituted imidazole scaffolds by utilizing four
component reactions. We initiated the feasibility of four
component reaction to construct imidazole derivatives;
under identical reaction conditions (Table 1, entry 11) with
a stoichiometric ratio of aniline derivatives as the fourth
component, to our delight, the reaction underwent smooth
conversion to obtain the desired compounds in good to
excellent yields (Figure 2, 5aÀr). Regardless of the electronic
2,4,5-triphenylimidazole 4a in 84% yield (entry 7). We
assumed that the additive ZnO played a crucial role in the
reaction. Based on the above reason, we have performed
the reaction with various zinc salts, and results show
no product formation (entries 8À10). To our delight, the
bestresultwas obtainedin the absence of ZnO toaffordthe
compound 4a in 83% yield (entry 11). Furthermore, the
ammonia source was investigated by replacing NH4OAc
withNH4OH, buttheyield of product4ais not satisfactory
(65%, entry 12). With a different acid such as AcOH, TFA
(trifluoroacetic acid), TsOH (p-toluenesulfonic acid),
or without an acid as an additive, the yields were unsatis-
factory compared with PivOH (entries 11, 13À16). The
feasibility of the reaction was investigated with various
solvents (entries 17À20), and it was found that reaction
in a dual solvent system (DMSO/H2O = 1:1) produced
the desired target in excellent yield (entry 11). Finally, the
reaction was performed without H2O or DMSO, but
there was a decrease in yield of 4a (entries 22À23).
Therefore, the conditions described in entry 11 (4 equiv
of NH4OAc in DMSO and H2O with PivOH) were
found to be optimal.
With the optimized conditions in hand, we have studied
the scope and limitations with various alkyl and aryl
aldehydes and internal alkynes. In Figure 1, the one-pot
approach to synthesize a wide range of imidazole deriva-
tives with various substituents was performed, including
electron-withdrawing and -donating functional groups on
the aromatic moieties 4aÀ4p. It is remarkable that the aryl
chloride and bromide were compatible substrates 4bÀ4c
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Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Synthesis of Dimer Derivative of Imidazolea,b
Scheme 3. Control Experiments
a Reaction was performed with 6 (1.0 mmol), 2a (2.0 mmol), and
NH4OAc (6.0 mmol) in the presence of PivOH (2.0 mmol), in a solvent
mixture (DMSO/H2O = 1:1) at 140 °C for 48 h. b Isolated yield.
effect of the substituents on the aromatic rings and
nature of aldehydes (2), the construction of the scaffold
progressed well to obtain the desired molecules 5aÀ5r in
65À88% yield.
In particular, the D ring bearing an aliphatic group also
proceeded smoothly to obtain the corresponding imida-
zole product (5r). The MCR reaction was quite general,
asanelectron-donating or -withdrawinggroup or aliphatic
substitutent on R1, R2, and R3 was tolerated. Moreover,
the structures of 4h, 5c, and 5q were confirmed unambigu-
ously with the help of ORTEP diagram (Supporting
Information (SI), Figure S2).
Scheme 4. Plausible Reaction Mechanism for the Acid-Pro-
moted Construction of Imidazole
Next, we were curious to know whether diynes undergo
this type of reaction because the resulting product would
generate imidazole moieties which may find application in
medicinal chemistry and OLED devices15 (Scheme 2).
Accordingly, 1,4-bis(phenylethynyl)benzene 6 was carried
out with 2 equiv of benzaldehyde under an established
procedure. Interestingly, 1-(2,5-diphenyl-1H-imidazol-4-
yl)-4-(2,4-diphenyl-1H-imidazol-5-yl) benzene (7) was ob-
tained in 55% yield.
To gain insight into the reaction mechanism, we carried
out a few control experiments as shown in Scheme 3.
For detailed explanation (Supporting Information (SI),
Scheme S1, page S19).
were screened with fluorescence emission and UV absorp-
tion, and compound 5p18,20b showed the best results com-
pared with the other analogues. This promising molecule 5p
could be a potential candidate for photodynamic therapy
(PDT) of skin cancer19 and organic electroluminescent
devices.6,20
Based on our observations and previous literature,13,16
a plausible mechanism is outlined in Scheme 4. In the
presence of pivalic acid and DMSO the alkynes will be
oxidized to generate the intermediate 8a. Meanwhile, the
aldehyde 2a will react with two molecules of ammonium
acetate to give the intermediate A (Path A, Scheme 4).17
Yet, 2a reacts with one molecule of ammonium acetate and
aniline to produce the intermediate B (Path B). Both
intermediates will undergo a cyclocondensation reaction
with 8a to give the desired products 4a and 5a, respectively.
In summary, we have described a simple, efficient, and
eco-friendly methodology for the synthesis of imidazole
analogues from various internal alkynes, aldehydes, and
anilines by a pivalic acid mediated multicomponent reac-
tion. The ambient conditions, easy work-up procedure, and
excellent product yields make this methodology an alter-
native approach to replace the conventional transition metal
catalyzed processes. Moreover, the synthesized compounds
Acknowledgment. We thank the National Science
Council of the Republic of China for financial support.
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of 1H and 13
C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX