Visible light-emitting diode light-driven one-pot four component synthesis of poly-functionalized imidazoles under catalyst- And solvent-free conditions

Article abstract of DOI:10.1039/d0nj02527e

Here, we have demonstrated the visible LED light-promoted synthesis of poly functionalized imidazole derivatives by a four component condensation of 1,2-diphenyl 1,2-diketone aromatic aldehydes and ammonium acetate and/or amines in excellent yields. The solvent- and catalyst-free reaction conditions, excellent isolated yields of the products, shorter reaction times, and simple isolation and purification of the products make the present protocol efficient and a green alternative to existing protocols. This journal is

Full text of DOI:10.1039/d0nj02527e

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DOI: 10.1039/D0NJ02527E
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Visible light-emitting diode light-driven one-pot four component
synthesis of poly-functionalized imidazoles under catalyst and
solvent-free conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Geetika Patel,a Ashok Raj Patela and Subhash Banerjee*a
DOI: 10.1039/x0xx00000x
Here, we have demonstrated visible LED light promoted synthesis Synthesis of imidazole was first reported in 1858 by Heinrich
of poly functionalized imidazole derivatives by the four Debus via cyclocondensation of glyoxal, formaldehyde, and
component condensation of 1,2-diphenyl 1,2-diketone, aromatic ammonia.12 Later on, various methods have already reported
aldehydes and ammonium acetate and /or amines in excellent for the synthesis of substituted imidazoles by varying the
yields. The solvent and catalyst-free reaction conditions, excellent functional groups on reactants. Traditionally, imidazole
isolated yields of the products, shorter reaction time, simple derivatives have also been prepared by Ugi reaction and
isolation and purification of products have made the present Davidson cyclization13 or by reaction of imidazolium yelids and
protocol efficient and green alternatives to those of existing lithiated imidazoles.14
protocols.
O
O
S
N
N
H
N
N
H
N
F
F
O
F
N
O
Naturally occurring five-member imidazole scaffolds have a
unique role in heterocyclic chemistry and have their broad
spectrum of applications in the field of biochemistry and
pharmacology.1 Multisubstituted imidazole derivatives have
exhibited wide range of biological activities such as anti-
Pimobendan
lansoprazole
H
N
O
S
H
N
CH3
S
CN
N
N
N
CH3
OCH3
H3CO
CH3
N
N
H
N
H
H3C
Omeprazole
inflammatory, anti-allergic,2 analgesic,3
antibacterial,4
Cimetidine
antitumor,5 and anticancer/antitubercular/antifungal/anti-HIV6
activities. Some well know fundamental parts of human
organism such as purine, histamine, histidine, biotin, Vitamin-
B12 and a component of DNA base have also established by
imidazole nucleus as core scaffold.6 A number of imidazole
based commercially available drugs are present in the market
such as omeprazole,7 pimobendan,8 cimetidine and
iansoprazole9 (Fig 1). Some substituted imidazoles are
admitted as convivial inhibitors of P38 kinase.10 These moieties
also used as fungicides, herbicides and plant growth
regulators.11 Recent advances in green chemistry and
organometallic catalysis has extended the applications of
imidazoles as ionic liquids and N-heterocyclic carbenes. As
consequences, a number of methods for the synthesis of
multi-substituted imidazole derivatives have been developed.
Fig. 1 Structures of few imidazole-based pharmacologically
active molecules.
Recently, 2,4,5-substituted and 1,2,4,5-substituted imidazoles
have been synthesized by multicomponent reaction by the
reactions of 1,2-dicarbonyl compounds, aldehydes, and a
nitrogen source using various catalysts such as Fe3O4–PEG–
Cu,15 K5CoW12O40 3H2O,16 PEG-400,17 DABCO,18 InCl3.3H2O,19
BF3/SiO2,20 Silica-bonded propylpiperazine-N-sulfamic acid
24
(SBPPSA),21 TiCl4-SiO2,22 SiO2/NaHSO4,23 Zr(acac)2, Poly
phosphoric acid impregnated on silica gel (PPA–SiO2),25
26
[Hbim]BF4,
acid
Nano-MgAl2O4,27 Polymer-ZnCl2,28 silica sulfuric
(SSA),29
CAN,30
Yb(OTF)3,31
L-proline,32
K7Na3P2W18Cu4O68,33 H2NaPO4 and Fe3O4/SO3H@zeolite-Y.35
However, use of Lewis acid, costly ionic liquids, and heavy
metal as catalyst, tedious work up process, purification, use of
volatile and hazardous organic solvents limited their practical
applications. Thus, development of novel green synthetic
method for synthesis of poly-substituted imidazole derivatives
is highly desirable.
34
a. aDepartment of Chemistry, Guru Ghasidas Vishwavidyalaya, Koni, Bilaspur, PIN-
495009, Chhattisgarh, India.
Email: ocsb2006@gmail.com
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Recently, visible light driven organic synthesis has been
attracted much attention in the context of green chemistry.36
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Among other, C−H arylation reactions using aryl diazonium (correlated color temperature 6500 K) in a quartz vessel
View Article Online
salts under photochemical conditions has widely been targeting for the synthesis of 1,2,4,5-tetrDaOphI:e10n.y10l-319H/D-i0mNiJd0a25zo27leE
investigated.37-39 Recently, various nitrogen containing (1a). Only N-benzylidenebenzenamine (2a) was isolated in 45%
molecules have been synthesized under visible LED light. For yield along with the other starting materials at room
example, Rueping et al.40 have reported a oxidative three- temperature under solvent-free reaction conditions (entry 1,
component reactions for the direct synthesis of α-amino Table 1). When the power of visible white LED light was
amides and imides from tertiary amines by using increased to 20 W, no significant change in the conversion was
Ir(ppy)2(bpy)PF6 in presence of blue LED via the observed (entry 2, Table 1). However, when the above
functionalization of C(sp3)–H bonds adjacent to nitrogen reaction was performed at 60 oC, the desired product was
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atoms and aerobic oxidation reactions. A visible-light-induced, produced along with the byproduct 2a in 7:3 ratio. The
1
Eosin
Y
catalyzed three-component synthesis of 3- formation of products was confirmed by the H NMR study
arylsulfonylquinoline derivatives through N-propargyl aromatic (entry 3, Table 1). Next, we have screened the reaction at
amines, diaryliodonium salts and sulfur dioxide has been different temperature. It was observed with increasing
reported.41 However, most the reported method involves use temperature conversion as well as proportion of desired
of photocatalysts. Very recently, Park et al.42 have reported product (1a) increased (entry 3-6, Table 1) and maximum
o
two component syntheses of benzimidazoles under visible conversion and yield of 1a was observed at 100 C (entry 5,
light in presence of molecular oxygen (Scheme 1). Wang and Table 1).
his
group43
have
reported
visible-light-promoted
Ir[dF(CF3)ppy]2(dtbbpy)PF6-catalyzed synthesis of 2-substituted Table 1 Optimization of reaction conditionsa
benzimidazoles via amidinyl radicals (Scheme 1). However,
Ph
visible light-promoted multicomponent synthesis of highly
substituted imidazole derivatives has not been reported in the
literature to the best of our knowledge.
N
Ph
O
Conditions
NH4OAc
H
C
O
Ph
Ph
N
Ph
N
Ph
1a
Ph
Ph
H
Ph
O
PhNH2
2a
As a part of our continuous interest in the development of
green synthetic methodologies,44,45 very recently, we have
reported visible LED light promoted aerobic oxidation of
alcohols and amines using CuxFe1-x@RCAC.45 Here, we have
reported one-pot four component synthesis of polysubstituted
imidazole derivatives using white LED (correlated color
temperature 6500 K) under catalyst-and solvent-free reaction
conditions (Scheme 1).
Entry
Conditions
Time
(min.)
Conversi
on (%)
% of 1a:
2a
1.
LED/RT
60
60
60
60
40
45
42
75
0:100
0:100
70:30
80:20
2.
3.
4.
LEDb /RT
LED/60oC
LED/80oC
Previous methods
N
NH2
NH2
O2 /MeOH
O
Ar
LED (7 W)
N
H
Ar
H
5.
6.
LED/100oC
LED/120oC
60
60
95
95
100:0
100:0
Ref. 42
O
LG
Ir[dF(CF3)ppy]2(dtbbpy)PF6
N
N
Ar
7.
8.
9.
Dark/100oC
LED/100oC
LED/100oC
60
30
72
62
0:100
100:0
MTBE, LED (13 W)
N
H
Ar
N
H
Ref. 43
Present method
Ph
90
60
95
65
100:0
100:0
N
N
R
NH2
O
10. LEDb /80oC
Ar
O
O
Ph
Ph
aConditions: Benzil (1.0 mmol), benzaldehyde (1 mmol),
ammonium acetate (1 mmol), aniline (1 mmol), neat
condition, 10 W white LED bulb and 25 ml quartz round
bottom flask. b 20 W LED bulb was used.
Ph
Ph
White LED
Ar
H
R
N
NH4OAc
Ar
N
NH4OAc
Ph
H
o
Interestingly, when model reaction was performed at 100 C
under dark conditions, only 2a was produced (entry 7, Table
1). Thus, LED plays an important role in the formation of
desired 1,2,4,5-tetraphenyl-1H-imidazole (1a). On the other
hand, with decreasing reaction time yield decreased to 62%
(entry 8, Table 1). Thus, a mixture of benzil, benzaldehyde and
Scheme 1 Previous and present method of visible LED light-
promoted synthesis of imidazole derivatives.
Initially, we have tested the MCR of benzil, benzaldehyde and
aniline and ammonium acetate under visible white LED light
2 | J. Name., 2012, 00, 1-3
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aniline and ammonium acetate in (1:1:1:1) under 10 W LED (1a-f, Table 2). Again, both aromatic and benzyl VaiemwiAnreticslewOnelirnee
light at 100 C produced optimized yield (95%) under solvent- participated in this present LED promoted MCRs.
free conditions and was considered as optimized reaction Further, when the reaction was carried out in presence of 2
o
DOI: 10.1039/D0NJ02527E
conditions (entry 5, Table 1).
equivalents of ammonium acetate in absence of amine i.e.
6
Next, using optimized reaction conditions, we have explored when benzil (1.0 mmol), aromatic aldehyde (1 mmol) and
the scope of the methodology for the synthesis ammonium acetate (2 mmol) were heated at 100 oC in
polysubstituted imidazole derivatives. In a simple experimental presence of LED light (10 W) under neat conditions 2-aryl-4,5-
procedure, a mixture of benzil (1.0 mmol), aromatic aldehyde diiphenyl-1H-imidazole derivatives (3a-h) were formed in
(1 mmol), ammonium acetate (1 mmol) and amine (1 mmol) excellent yields (92-98%). The results were summarized in
were heated at 110 C in presence of LED light (10 W) under Table 3.
neat conditions in a 25 ml quartz round bottom flask till
completion of reaction (TLC monitored). After the completion Table 3 Product scope of visible LED-driven synthesis of 2-aryl-
of reaction the reaction mixture was poured into ice-cold ,4,5-diphenyl-1H-imidazolesa
water which results the precipitation of imidazole derivatives.
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o
The precipitate was filtered, dried in oven and recrystallized
from hot ethanol. The pure products were analyzed by their
melting point determination and NMR spectroscopic studies.
Ph
O
N
O
Ph
LED
100 o
Ar
2 NH4OAc
+
+
Ar
H
N
H
C
Ph
O
Ph
Table 2 Product scope of visible LED-driven synthesis of 2-aryl-
1,4,5-triphenyl-1H-imidazolesa
Ph
Ph
Ph
Ph
N
N
N
N
OMe
H
H
Ph
Ph
O
Ph
Ph
O
N
N
3a, M.P: 273-275 oC15
Yield: 98%; Time: 30 min.
3b, M.P: 329 -330 oC15
Yield: 92%; Time: 30 min.
LED
100 o
Ar
RNH2
NH4OAc
+
+
+
Ar
H
C
O
R
Ph
N
Ph
N
Ph
Ph
Me
Br
N
N
Ph
Ph
N
Cl
N
N
Ph
Ph
H
H
N
3c, M.P: 310-312 oC15
Yield: 93%; Time: 30 min.
3d, M.P: 374-375 oC19
Yield: 97%; Time: 30 min.
O2N
1b, M.P: 259-263 oC15
Yield: 92%; Time: 90 min.
1a, M.P: 2180 -220 oC. 19
Yield: 95%; Time: 60 min.
Ph
N
Ph
N
Cl
N
H
N
H
Ph
Ph
Ph
N
Ph
N
OMe
3e, M.P: 330-331 oC15
Yield: 96%; Time: 30min.
3f, M.P: 233-235 oC35
Yield: 94%; Time: 30 min.
N
N
Ph
Ph
MeO
OMe
OMe
Ph
N
Ph
Ph
N
N
Me
1c, M.P: 170-173 oC15
Yield: 85 %; Time: 45 min.
NO2
1d, M.P: 183-184 oC34
N
Ph
H
H
Yield: 93%; Time: 120 min.
Ph
3g, M.P: 389-390 oC19
Yield: 96%; Time: 30 min.
3h, M.P: 240-242 oC.19
Yield: 93%; Time: 30 min.
Ph
N
N
OMe
Cl
N
Ph
N
Ph
aConditions: Benzil (1.0 mmol), benzaldehyde (1 mmol),
ammonium acetate (2 mmol), neat condition, 10 W LED
bulb, 100 oC and 25 ml quartz round bottom flask.
1f, M.P: 159-165 oC19
Yield: 85%; Time: 90 min.
1e, M.P: 159 -168 oC19
Yield: 97%; Time: 100 min.
aConditions: Benzil (1.0 mmol), benzaldehyde (1 mmol),
ammonium acetate (1 mmol), aniline (1 mmol), neat
condition, 10 W LED bulb 100 oC and 25 ml quartz round
bottom flask.
In general all the reactions listed in Table 2 and 3 were very
clean and high. The present visible LED promoted synthetic
route offered several advantages such as (i) metal and other
catalyst-free reaction, (ii) reactions were performed under
neat conditions and no hazardous organic solvents were used,
(iii) shorter reaction time (60 min.) and high percentage of
yields yielding (85-97 %), (iv) no byproduct formation, (v)
simple isolation from water and purification from hot ethanol
A
variety of 2-aryl-1,4,5-triphenyl-1H-imidazoles were
synthesized by taking various aromatic aldehydes and amines
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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21
22
L-proline
8.5-10
h
and thus avoid of tedious work up and purification process.
Thus, the present method is better alternative green protocol
to these of existing protocols.
Finally, a comparison of our present LED promoted method to
those of reported methods15-35 for the synthesis of immidazole
via MCR of benzil, aldehydes, ammonium acetate and amines
has been presented in Table 4. The comparison clearly
demonstrated that present methods are more efficient,
economic and eco-friendly in nature compared to reported
methods.
DOI: 10.1039/D0NJ02527E
K7Na3P2W18Cu4O68 1.5-2 h
33
H2NaPO4
25-40
min.
80-92
85-98
34
35
9
Fe3O4/SO3H@zeoli 20-65
te-Y/ 120 oC
min.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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The present protocol is also effective in large scale synthesis of
2-aryl-,4,5-diphenyl-1H-imidazoles and good yield (82%) of 3a
was obtained after 5 fold scaled-up (5 mmol scale) under the
optimized reaction conditions.
Table 4 Comparison of present method to those of reported
methods for the synthesis of 2-aryl-4,5-diiphenyl-1H-imidazole
derivatives.
Next we have investigated the mechanism of LED light
promoted synthesis of imidazoles by performing few control
experiments as given in Scheme 3. When benzil, benzalehyde,
ammonium acetate and amiline are hated at 100 oC under dark
conditions, N-benzylidenebenzenamine was formed as only
product (Eq. 1, Scheme 2). Further, when imine was heated at
110 oC with benzil and ammonium acetate, no desired product
was formed and staring materials were isolated (Eq. 2, Scheme
2). Interesting, when the above reaction was performed in
presence of LED light desired product was formed in 95%
yields (Eq. 3, Scheme 2). Thus, LED plays a crucial role in the
formation of imidazole (1a). This reaction also proved that
imine is formed as intermediate. Finally, a significant decrease
in yield of 1a was observed when the optimized reaction was
performed in presence of a radical quencher, (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO) (Eq. 4, Scheme 2). This
indicates that the reaction proceeds via radical pathway.
Again, doing reaction in argon atmosphere, the yield of the
product decreased to 40%. Thus, aerial oxygen also plays a
significant role in the process (Eq. 4, Scheme 2).
Entry Catalyst/Conditions
Time
Yield
(%)
Ref.
1
LED/100 oC
30-55
min.
88-98
This
work
2
Fe3O4–PEG–Cu/110
oC
30-55
min.
88-98
15
3
4
K5CoW12O40.3H2O
PEG-400
2-2.5 h
1.5-2 h
80-93
89-96
16
17
5
6
7
8
9
DABCO
12-15 h 92
18
19
20
21
22
InCl3.3H2O
BF3/SiO2
SBPPSA
6-9 h
2 h
47-84
80-96
85-90
60-91
1-2.5 h
2.5 h
PhCHO
+
100 o
C
Ph
O
H
TiCl4.SiO2
(Eq. 1)
(Eq. 2)
C
Ph
NH4OAc
N
Ph
H2O
Ph
Ph
O
O
PhNH2
10
11
SiO2/NaHSO4
Zr(acac)2
120
min
20-40
min.
85-92
87-96
23
24
H
100 o
C
C
Ph
Ph
N
Ph
No reaction
Ph
O
240 min
NH4OAc
12
13
PPA–SiO2
[Hbim]BF4
12-20
min.
87-97
85-95
25
26
Ph
N
Ph
Ph
O
O
H
LED
C
(Eq. 3)
Ph
Ph
N
Ph
N
Ph
2-2.5 h
100 o
C
Ph
NH4OAc
60 min
95%
14
15
Nano-MgAl2O4
Polymer-ZnCl2
15 min
240
89-96
31-96
27
28
Ph
N
PhCHO
LED/100 o
60 min
C
Ph
Ph
O
O
(Eq. 4)
+
NH4OAc
N
Ph
Ph
PhNH2
Conditions
Yield (%)
16
17
18
SSA
4-8 h
3-6 h
3-6 h
59-73
65-85
17-92
29
30
31
18
40
TEMPO (3 equiv.)/Air
Argon
CAN
Scheme 2 Few control experiments to study the mechanism.
Based on the following observation, a plausible mechanism of
visible LED light and heat promoted synthesis of imidazole
derivative (1a) under catalyst and solvent-free conditions has
Yb(OTF)3
4 | J. Name., 2012, 00, 1-3
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been depicted in Scheme 3. The reaction initiated via the
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Notes and references
View Article Online
DOI: 10.1039/D0NJ02527E
formation of imine intermediate (A) by eliminating of water
molecule from benzaldehyde and aniline and decomposition of
ammonium acetate results the formation of acetic acid and
ammonia. The oxygen in air has been photo-excited to
1
L. Zhang, X. M. Peng, G. L. Damu, R. X. Geng and S. H. Zhou,
Med. Res. Rev. 2014, 34, 340–437. (b) D. I. Ma Gee, M.
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Black, J. W.; Durant, G. J.; Emmett, J. C.; Ganellin, C. R.
Nature, 1974, 248, 65–67.
.-
superoxide radical (O2 ),46 which further reacts with ammonia
.
to produce amino radical (NH2 ). It is well known that
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4
5
superoxide radical abstract hydrogen atom from the protic
reagents.47 The formation of NH2 radical was also reported by
the reaction of ammonia and hydroxyl radical.48 The NH2
radical was then added to imine followed by the reaction with
fresh ammonia to form diamine [B]. In the next step,
condensation of diamine with 1,2-benzil followed by
dehydration through the imino intermediate [C] yielded the
desired product 1a.
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A. Verma, S. Joshi, D. Singh Journal of Chemistry Volume
H
Ph
Ph
Ph
O
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2013,
Article
ID
329412,
12
pages
H
H
C
H
NH2
NH2
+ NH3
- NH2
NH2
O
Ph
H
Ph
OH
NH2
http://dx.doi.org/10.1155/2013/329412
C
C
Ph
Ph
Ph
N
Ph
Ph
N
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[A]
H2O
Ph
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N
[B]
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[C]
H
C
Ph
PhNH2 PhCHO
N
Ph
Ph
H2O
NH3
[A]
N
H2O2 + O2
HO2
NH4OAc
LED
AcOH
Ph
Ph
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LED
+e
NH3
O2
[O2]*
[O2]
NH2
Ph
1a
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Scheme 3 Proposed mechanism for the visible LED light
promoted formation of 1,2,4,5-tetraphenyl imidazole (1a).
Conclusions
In summary, we have demonstrated an efficient and
environmentally friendly visible LED light-heat promoted
protocol for the synthesis of 2,4,5-substituted and 1,2,4,5-
substituted imidazoles by the multicomponent condensation
of 1,2-diphenyl 1,2-diphenyl 1,2-diketone, aromatic aldehydes
and ammonium acetate and /or amines in excellent yields. The
present method offered several advantages such as (i) solvent
and catalyst-free reaction conditions, (ii) excellent isolated
yields of the products (85-98%), (iii) shorter reaction time (60
min.), (iv) simple and economic isolation from ice cold water,
(v) purification of products by recrystallization from ethanol
and thus avoiding any volatile and hazardous organic solvents.
Thus, the present visible LED light/heat-promoted
multicomponent synthesis is better green alternatives to those
of existing protocols.
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Acknowledgment
The present study is partly financially supported by CCOST,
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Conflicts of interest
There are no conflicts to declare.
26 S. A. Siddiqui, U. C. Narkhede, S. S. Palimkar, T. Daniel, R. J.
This journal is © The Royal Society of Chemistry 20xx
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New Journal of Chemistry
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DOI: 10.1039/D0NJ02527E
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Graphical Abstract
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Visible light-emitting diode light-driven one-pot four component synthesis of poly-
functionalized imidazoles under catalyst and solvent-free conditions
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Ph
N
R NH2
R
N
ArCHO
O
O
Ph
Ph
Ph
Ph
R
N
NH4OAc
R
NH4OAc
N
Ph
H
• VisibleLED light promoted MCRs
• Metal and acid catalyst-free conditions
• Solvent-freereactions
• Excellent yieldsof products(85-98%)
Visible light-emitting diode light-driven green and sustainable protocol has been demonstrated for the
one-pot four component synthesis of poly-functionalized imidazoles under catalyst and solvent-free
conditions.