Catalytic procedures for multicomponent synthesis of imidazoles: Selectivity control during the competitive formation of tri- and tetrasubstituted imidazoles

Article abstract of DOI:10.1039/c2gc35277j

The catalytic potential of different fluoroboric acid-derived catalyst systems viz. aq HBF₄, solid supported HBF₄, metal tetrafluoroborates (inorganic salts), solid supported metal tetrafluoroborates, and tetrafluoroborate based ionic liquids (organic salts) were investigated for the three component reaction (3-MCR) of 1,2-diketone, aldehyde, and ammonium salts to form 2,4,5-trisubstituted imidazoles and the four component reaction (4-MCR) involving 1,2-diketone, aldehyde, amine and ammonium acetate to form 1,2,4,5-tetrasubstituted imidazoles. The HBF₄-SiO₂ was found to be the stand out catalyst for both the 3-MCR and 4-MCR processes. The next most effective catalysts are LiBF₄ and Zn(BF₄) ₂ to form 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles via the 3-MCR and 4-MCR, respectively. This is the first report on the unaddressed issue of competitive formation of 2,4,5-trisubstituted imidazole during the 4-MCR involving 1,2-diketone, aldehyde, amine and ammonium acetate and highlights the influence of the catalyst systems in controlling the selective formation of tetra substituted imidazole. The metal salt of weak protic acids drive selectivity towards tetra substituted imidazole in the order tetrafluoroborates > perchlorates > triflates. The catalytic potency of tetrafluoroborates was in the order Zn(BF₄)₂ > Co(BF₄)₂ > AgBF₄ ≈ Fe(BF ₄)₂ > NaBF₄ ≈ LiBF₄ ≈ Cu(BF₄)₂. The developed protocols worked well for different diketones, various aryl, heteroaryl, and alkyl aldehydes and in the case of the preparation of 1,2,4,5-tetrasubstituted imidazoles different amines can be used. The effectiveness of different ammonium salts as nitrogen source has been investigated and ammonium acetate is proved to be the best. The HBF₄-SiO₂ is recyclable for five consecutive uses without significant loss of catalytic activity. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2gc35277j

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ARTICLE TYPE
Catalytic procedures for multicomponent synthesis of imidazoles:
selectivity control during the competitive formation of tri- and tetra-
substituted imidazoles
Dinesh Kumar,a Damodara N. Kommi,a Alpesh R. Patela and Asit K. Chakraborti*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The catalytic potential of different fluoroboric acid derived catalyst systems viz; aq HBF4, solid supported
HBF4, metal tetrafluoroborates (inorganic salts), solid supported metal tetrafluoroborates, and
tetraflouroborate based ionic liquids (organic salts) were investigated for three component reaction (3-
10 MCR) of 1,2-diketone, aldehyde, and ammonium salts to form 2,4,5-trisubstituted imidazole and four
component reaction (4-MCR) involving 1,2-diketone, aldehyde, amine and ammonium acetate to form
1,2,4,5-tetrasubstituted imidazole. The HBF4-SiO2 was found to be the stand alone catalyst for both the 3-
MCR and 4-MCR processes. The next effective catalysts are LiBF4 and Zn(BF4)2 to form 2,4,5-
trisubstituted and 1,2,4,5-tetrasubstituted imidazoles via the 3-MCR and 4-MCR, respectively. This is the
15 first report on the unaddressed issue of competitive formation of 2,4,5-trisubstituted imidazole during the
4-MCR involving 1,2-diketone, aldehyde, amine and ammonium acetate and highlights the influence of
the catalyst systems in controlling the selective formation of tetra substituted imidazole. The metal salt of
weak protic acids drive selectivity towards tetra substituted imidazole in the order tetrafluoroborates >
perchlorates > triflates). The catalytic potency of tetrafluoroborates in the order Zn(BF4)2 > Co(BF4)2 >
20 AgBF4 ≈ Fe(BF4)2 > NaBF4 ≈ LiBF4 ≈ Cu(BF4)2. The developed protocols worked well for different
diketones, various aryl, heteroaryl, and alkyl aldehydes and in the case of the preparation of 1,2,4,5-
tetrasubstituted imidazoles different amines can be used. The effectiveness of different ammonium salts
as nitrogen source has been investigated and ammonium acetate is proved to be the best. The HBF4-SiO2
is recyclable for five consecutive uses without significant loss of catalytic activity.
hydroxy/acetoxy/silyloxyketone or 1,2-ketomonoxime with an
aldehyde and ammonium acetate (Route A, Scheme 1) (i) in
HOAc under or under
reflux2-4,6a,6c,7,9,12,13
25 Introduction
Multicomponent reactions (MCRs) enjoy an outstanding status in
organic and medicinal chemistry for high degree of atom
economy and application in the diversity-oriented convergent
synthesis of complex organic molecules from simple and readily
30 available substrates in a single vessel and fulfil some of the
objectives of ideal synthesis.1
The heterocyclic scaffolds comprising of 2,4,5-trisubstituted
and 1,2,4,5-tetrasubstituted imidazoles are present in compounds
possessing versatile pharmacological action such as anti-
35 inflammatory agents,2 CSBP kinase inhibitor,3 anti-bacterial
agents,4 glucagon receptor antagonists,5 p38 MAP kinase
inhibitors,6 modulators of Pgp-mediated multidrug resistance,7
ligands of the Src SH2 protein,8 antitumor agents,9 inhibitors of
mammalian 15-LOX,10 CB1 cannabinoid receptor antagonists,11
40 and inhibitors of B-Raf kinase.12 These have generated interest to
synthetic organic/medicinal chemists to develop synthetic
methodologies for the construction of these heterocyclic scaffolds
and the various strategies are summarised in Scheme 1.
microwave/ultrasonic/classical heating in presence or absence of
50 catalyst14 or under pressure using continuous flow micro reactor
under superheating condition,15 (ii) in the presence of Lewis acid
catalysts (Route B),16 and (iii) Ni-catalysed cyclotrimerisation
(with expulsion of NH3) of aromatic nitriles under pressure (60-
120 psi) and high temperature (180-230 °C) hydrogenation
55 condition for prolonged period (48 h) (Route C, Scheme 1).17
The reported synthesis of 1,2,4,5-trisubstituted imidazoles
involve
reaction
of
a
1,2-diketone,
α-
hydroxy/acetoxy/silyloxyketone or 1,2-ketomonoxime, an
aldehyde, an amine and ammonium acetate (Route D, Scheme 1)
60 carried out by (i) microwave irradiation in the presence of silica
gel/zeolite HY or silica gel-NaHSO4,18 (ii) heating under reflux in
suitable solvents or under neat condition at 140 ºC in the presence
of catalysts.14l,19
The alternative approaches are the reaction of α-bromoketone
65 with substituted amidine10,11 (Route E) for syntheses of 2,4,5-
trisubstituted and 1,2,4,5-tetrasubstituted imidazoles or the
cyclocondensation of N-alkyl-α-acetamidoketone/alcohol with
The 2,4,5-trisubstituted imidazoles are generally synthesized
45 by
the
reaction
of
a
1,2-diketone,
α-
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H
N
Ph
O
O
Ph
Ph
ammonium acetate in HOAc or with ammonium trifluoroacetate
O
H
catalyst
(as solvent) under reflux20 for preparing 1,2,4,5-tetrasubstituted
imidazoles (Route F). Recently synthesis of 1,2,4,5-
tetrasubstituted imidazoles has been achieved from alkenes via a
two-step ketoiodonation/cyclisation strategy (Route G).21 The
2,4,5-risubstituted imidazoles may also be prepared following
multistep process from imidazole-based vicinal bromostannanes
sequentially performing Stille and Suzuki coupling reactions.22
+
NH4OAc
(5 mmol)
Ph
+
neat, 120 °C
N
Ph
Ph
1
2
3
(2.5 mmol)
(2.5 mmol)
Scheme 2. Synthesis of 2,4,5-trisubstituted imidazole 3 via 3-MCR.
5
Initially we realised that as metal salt of a strong protic acid
should be strong Lewis acid, metal triflates could be ideal for the
45 purpose as TfOH is the strongest protic acid (H0 = -14.1)26
However, metal triflates are prone to liberate TfOH27 and
necessitate the use of solvent, excess of reagent, and additives or
sub zero temperature to minimize/avoid side reactions.28
Although HNTf2 is a weaker Brønsted acid than TfOH29 and
50 ligand exchange is usually not observed during organic
transformation performed in the presence of metal triflimides,30
the high cost and lack of commercial availability do not make
metal triflimides popular. The metal perchlorates31 appear to be
the next best effective electrophilic activation agent but often
55 form strong adduct with amines that could be detrimental to the
catalytic efficiency for reactions involving amine.31k The milder
Lewis acid property of metal tetrafluoroborates, as HBF4 is a
weaker Brønsted acid, brought our attention to HBF4 derived
catalyst systems as metal tetrafluoroborates are known to catalyze
60 various organic reactions.32 Hence, the model reaction (Scheme
2) was performed under the catalytic influence of various metal
tetrafluoroborates. The best result was obtained with LiBF4
affording 3 in 90% yield after 20 min. The other metal
tetrafluoroborates gave lesser yields in longer time (table 1) with
65 the relative catalytic potential following the order Cu(BF4)2 >
Fe(BF4)2 ≈ Zn(BF4)2 > Co(BF4)2 ≈ AgBF4 > NaBF4. The use of
tetrafluoroborate containing ionic liquids (ILs) (organic salts of
HBF4) e.g., [bmim][BF4]33 and [NHC][BF4]34 afforded inferior
yields. Poor conversion to 3 was observed in the absence of
70 catalyst (entry 11, table 1).
R1
R2
X
R1
R2
Y
O
H
+
Or
R3
O
O
NH4OAc Route A
R1
R2
Br
O
H
R1
N
HN
Route B
Route C
NH2
R3
+
N
Ar
Ni-cat, H2
R3
R2
N
R1
X
R1
R2
Y
R1
R2
I
Or
R2
O
O
H
NHR4
HN
O
+
+
Route D
R4
Route G
R3
O
Or
N
R3
IBX, I2
DMSO
NH4OAc and
/or R4NH2
R3
R3
R1
R2
N
R2
X = O, OAc, NOH
Y = OH, OTBDMS
N
Route F
Route E
R1
R4
R1
R2
Br
NH4OAc Or
NH4OCOCF3
R1
R2
N
R3
HN
NHR4(H)
+
R3
O
O
O
10
Scheme 1. Synthetic strategies for construction 2,4,5-trisubstituted and
1,2,4,5-tetrasubstituted imidazole scaffolds.
Most of these synthetic methods suffer from one or more
drawbacks, such as laborious and complex work-up and
15 purification procedure, generation of significant amounts of waste
materials, strong acidic conditions, occurrence of side reactions,
low yields, use of expensive and moisture sensitive
reagents/catalysts, special efforts for the preparation of the
starting materials,6a,21,22 the use of auxiliary reagents,2b,3,6a,21 and
Table 1. The 3-MCR of 1, 2, and NH4OAc to form 3 in the presence of
HBF4 derived catalyst systems.a
apparatus/reactor.15,17
These,
necessitates
the
Entry
Catalyst
Time (min)
Yield (%)b,c
20 special
improvement of the tried and tested methodologies for new
catalytic procedure to enrich the medicinal chemists’ toolbox23
for convenient synthesis of 2,4,5-trisubstituted and 1,2,4,5-
tetrasubstituted imidazoles keeping in view the timely need of
25 generating new chemical entities for newer therapeutic
applications.24 We report herein fluoroboric acid derived catalytic
systems for a convenient and effective synthesis of 2,4,5-
trisubstituted and 1,2,4,5-tetrasubstituted imidazoles following 3-
MCR and 4-MCR processes, respectively, addressing the
30 unattended issue on competitive formation of these heterocycles.
75 1
2
3
4
5
80 6
7
8
9
10
85 11
NaBF4
AgBF4
60
60
45
45
45
45
20
45
45
60
300
70
75
85
80
76
80
90
65
58
70
16
Cu(BF4)2
Zn(BF4)2
Co(BF4)2
Fe(BF4)2
LiBF4
[bmim][BF4]
[NHC][BF4]
HBF4 (aq 50 %)
none
aThe mixture of 1 (2.5 mmol), 2 (2.5 mmol, 1 equiv) and NH4OAc (5
mmol, 2 equiv) was heated at 120 ºC (oil bath) in the presence of the
catalyst (10 mol %) under neat condition. bYield of 3 after purification
(crystallisation, aq EtOH). cIR, NMR and APCI-MS.
Results and Discussion
In search for an effective catalyst, we considered the 3-MCR of
benzil (1), benzaldehyde (2), and NH4OAc to form 2,4,5-
triphenylimidazole (3) as the model reaction (Scheme 2). Since
35 the reaction has been anticipated to proceed through electrophilic
activation of the carbonyl substrates, to accelerate the imine
formation with NH4OAc,25 we visualized that a suitable metal
Lewis acid that could function as a more effective electrophilic
activation agent would offer a more convenient way to from the
40 heterocyclic framework.
90
However, the use of HBF4 (aq 50%) gave 3 in 70% yield after
1 h (entry 10, table 1). This encouraged us to investigate whether
the catalytic potency of HBF4 could be enhanced on a solid
surface. There has been increasing awareness on the use of solid
acids and chemical processes on solid surfaces35 and the inherited
95 advantages of heterogonous catalyst system36 for sustainable
chemistry development. These and our interest/experience on the
use of solid supported protic acid as catalyst in various organic
2
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transformations37 prompted us to perform the model reaction
using HBF4 immobilised on various solid supports such as
chromatographic silica gel with different mesh size as well as
neutral, acidic, and basic alumina (table 2). Excellent result was
influence of the solid support (230-400 mesh silica gel) on the
catalytic potential of the metal tetrafluoroborates (table 3).
However, no significant improvement of catalytic efficiency was
observed indicating the fact that the silica surface exhibits some
5
obtained with HBF4 adsorbed on chromatographic silica gel (230- 70 specific effect on HBF4 perhaps in increasing its Brønsted acidity.
400 mesh) (herein referred as HBF4-SiO2) affording 92% yield of
Table 3. Influence of the solid support (230-400 mesh silica gel) on the
3 in 15 min. As a mater of fact, HBF4-SiO238 turned out to be the
catalytic potential of metal tetrafluoroborates for the synthesis of 3 via the
3-MCR of 1, 2, and NH4OAc .a
most efficient catalyst system for this 3-MCR process and even
was superior to the metal tetrafluoroborates.
Entry
Catalyst
Time (min)
Yield (%)b,c
10 Table 2. Catalytic potential of HBF4 adsorbed on various solid surface for
75 1
2
3
4
5
80 6
7
8
9
10
85 11
12
13
14
15
90 16
17
16
19
20
NaBF4
NaBF4-SiO2
NaBF4
NaBF4-SiO2
AgBF4
AgBF4-SiO2
AgBF4
AgBF4-SiO2
Cu(BF4)2
Cu(BF4)2-SiO2
Cu(BF4)2
Cu(BF4)2-SiO2
Zn(BF4)2
Zn(BF4)2-SiO2
Zn(BF4)2
Zn(BF4)2-SiO2
Co(BF4)2
Co(BF4)2-SiO2
Co(BF4)2
Co(BF4)2-SiO2
Fe(BF4)2
Fe(BF4)2-SiO2
Fe(BF4)2
Fe(BF4)2-SiO2
LiBF4
LiBF4-SiO2
LiBF4
60
60
15
15
60
60
15
15
45
45
15
15
45
45
15
15
45
45
15
15
45
45
15
15
20
20
15
15
70
72
22
25
75
81
32
34
72
75
35
38
80
82
35
40
75
75
25
26
80
82
35
35
90
90
78
80
the synthesis of 3 via the 3-MCR of 1, 2, and NH4OAc.a
Entry
Catalyst
Time (min)
Yield (%)b,c
1
2
15 3
4
5
6
7
20 8
9
10
11
12
25 13
14
15
16
17
30 18
19
20
21
22
35 23
24
25
26
27
40 28
29
30
31
32
45 33
34
35
36
37
HBF4-SiO2 (230-400)
HBF4-SiO2 (100-200)
HBF4-SiO2 (100-200)
HBF4-SiO2 (60-120)
HBF4-SiO2 (60-120)
HBF4- acidic Al2O3
HBF4- acidic Al2O3
HBF4- basic Al2O3
HBF4- basic Al2O3
HBF4- neutral Al2O3
SiO2 (230-400)
SiO2 (230-400)
SiO2 (100-200)
SiO2 (100-200)
SiO2 (60-120)
SiO2 (60-120)
Acidic Al2O3
Acidic Al2O3
Basic Al2O3
15
45
15
60
15
30
15
25
15
30
300
15
5 h
15
5 h
15
5 h
15
5 h
15
5 h
15
5 h
15
5 h
15
45
15
60
15
60
15
50
15
30
15
60
15
5 h
92
80
52
78
40
75
41
80
32
37
42
nil
40
nil
38
nil
26
nil
25
nil
26
nil
68
34
66
30
65
22
54
16
53
18
55
16
53
21
58
23
16
95 21
22
23
24
25
Basic Al2O3
Neutral Al2O3
Neutral Al2O3
K10
K10
KSF
100 26
27
28
LiBF4-SiO2
aThe mixture of 1 (2.5 mmol), 2 (2.5 mmol, 1 equiv) and NH4OAc (5
mmol, 2 equiv) was heated at 120 ºC (oil bath) in the presence of different
105 catalyst system (10 mol %) under neat condition. bYield of 3 after
purification (crystallisation, aq EtOH). cIR, NMR and APCI-MS.
KSF
Zeolite type Y
Zeolite type Y
Zeolite K/L
Zeolite K/L
Thus, two different catalyst systems derived from fluoroboric
acid e.g., HBF4–SiO2 and LiBF4 emerged out to be efficient
catalysts to promote the 3-MCR of 1,2-diketone, aldehyde and
Zeolite ZSM 5
Zeolite ZSM 5
Zeolite Na/Fau
Zeolite Na/Fau
Zeolite NH4-Y
Zeolite NH4-Y
Amberlyst 33
Amberlyst 33
none
110 NH4OAc for
a convenient synthesis of 2,4,6-trisubstituted
imidazole. Further studies on the optimisation of various other
reaction parameters such as the amount of the catalyst, reaction
temperature, influence of the solvent and the effect of various
ammonium salts as the nitrogen source.
50 38
39
a
The mixture of 1 (2.5 mmol), 2 (2.5 mmol, 1 equiv) and NH4OAc (5
mmol, 2 equiv) was heated at 120 ºC (oil bath) in the presence of the
catalyst (10 mol %) under neat condition. bYield of 3 after purification
55 (crystallisation, aq EtOH). cIR, NMR and APCI-MS.
115
The use of 2 mol% of HBF4–SiO2 and 10 mol % of LiBF4 was
found to be the optimal amount of the catalyst (table 4) for best
results (afforded 3 in 92 % and 90 % yields after 15 and 20 min,
respectively).
As often the support material itself exhibit catalytic efficiency
for various organic reactions39 we also performed the model
reactions involving 1 (1 equiv), 2 (1 equiv) and 3 (2 equiv)
(Scheme 2) in the presence of solid supports (various silica gel
60 and alumina) and other heterogeneous catalysts e.g., clays,
zeolites, and amberlites (table 2). However, poor yield was
obtained in each case indicating the role of HBF4 in catalyzing
the reaction.
Table 4. Effect of amount of the catalyst during the 3-MCR of 1, 2, and
120 NH4OAc to form 3.a
Entry
mol %
HBF4–SiO2
LiBF4
Time (h) Yield (%)b
Time (h) Yield (%)b
1
2
125 3
nil
2
2
2
2
0.25
0.25
0.25
trace
trace
12
47
92
2
2
2
2
2
2
2
trace
trace
15
20
45
0.25
0.5
1.0
2.0
5
4
5
6
5
As the immobilisation of HBF4 on silica (230-400 mesh)
65 drastically increased its catalytic efficiency we next explored the
93
93
58
72
7.5
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8
9
10
15
0.25
0.25
93
93
0.34
0.34
90
90
Table 7. The effect of various ammonium salts as the nitrogen source on
the 3-MCR to form 3.a
aThe mixture of 1 (2.5 mmol), 2 (2.5 mmol, 1 equiv) and NH4OAc (5
60 EntryNitrogen source
HBF4-SiO2
LiBF4
Time (h) Yield (%)b Time (h) Yield (%)b
mmol, 2 equiv) was heated at 120 ºC (oil bath) under neat condition.
c
5
bYield of 3 after purification (crystallisation, aq EtOH). IR, NMR and
1
2
NH4Cl
NH4F
4
nil
35
41
40
42
nil
52
nil
25
92
55
nil
4
nil
32
40
35
38
nil
52
nil
21
90
48
nil
APCI-MS.
4
4
3
65 4
5
6
7
NH4F·HF
NH4HCO3
(NH4)2CO3
(NH4)2SO4
NH4SCN
NH4ClO4
(NH4)2HPO4
4
4
The effect of the reaction temperature was evaluated next
(table 5). The best operating reaction temperature was found to be
120 °C (oil bath). An increase of the reaction temperature to 150
10 ºC did not show any significant increase of the yield of 3 which,
however, decreased in lowering the reaction temperature to 100,
80, and 50 ºC. No significant amount of 3 was formed in carrying
out the reactions at rt.
4
4
4
4
4
4
4
4
8
70 9
4
4
4
4
10 NH4OAc
11 HCO2NH4
12 (NH4)4[Ce(SO4)4]
0.25
4
0.34
4
4
4
Table 5. The effect of temperature on the 3-MCR of 1, 2, and NH4OAc to
15 form 3.a
aThe mixture of 1 (2.5 mmol), 2 (2.5 mmol, 1 equiv) and 3 (5 mmol, 2
75 equiv) was heated at 120 ºC (oil bath) in the presence of different
ammonium salt (2 equiv) using HBF4-SiO2 (2 mol %) or LiBF4 (10 mol
Entry
Temp (°C)
HBF4–SiO2
LiBF4
Time (h) Yield (%)b
Time (h) Yield (%)b
b
%) under neat condition. Yield of 3 after purification (crystallisation, aq
EtOH). cIR, NMR and APCI-MS).
1
2
rt
50
12
12
trace
32
12
12
trace
30
The generality of HBF4-SiO2 and LiBF4 as catalysts for
80 synthesis of 2,4,5-trisubstituted imidazole is demonstrated
through the treatment of various aryl/heteroaryl/aliphatic
aldehydes with different 1,2-diketone and ammonium acetate
(Table 8). The reactions were monitored by TLC. However, the
progress of the reaction can also be monitored visually. A clear
85 melt is formed after addition of all of the components and after
completion of the reaction (or maximal product formation) the
reaction mixture is converted to a solid mass. Wherein the
reaction mixture solidified, although complete conversion to the
product did not occur, no further progress was observed in
90 prolonging the reaction time.
The promising results obtained in case of 3-MCR synthesis of
2,4,5-trisubstituted imidazoles encouraged to test the developed
protocols for the synthesis of 1,2,4,5-tetrasubstituted imidazoles
via the 4-MCR (Route D, scheme 1) by the reaction of 1 (2.5
95 mmol) with 2 (2.5 mmol, 1 equiv), NH4OAc (2.5 mmol, 1 equiv)
and benzyl amine 4 (2.5 mmol, 1 equiv) to form 1-benzyl-2,4,5-
triphenylimidazole 5 (Scheme 3).
20 3
80
12
12
0.25
0.25
62
76
92
92
12
12
0.34
0.34
55
75
90
90
4
5
6
100
120
150
a The mixture of 1 (2.5 mmol), 2 (2.5 mmol, 1 equiv) and NH4OAc (5
25 mmol, 2 equiv) was heated in the presence of HBF4–SiO2 (2 mol %) and
LiBF4 (10 %) under neat condition. bYield of 3 after purification
(crystallisation, aq EtOH). cIR, NMR and APCI-MS).
To evaluate any beneficial/detrimental effect of solvents on the
HBF4-SiO2 and LiBF4 catalysed 2,4,5-trisubstituted imidazole
30 formation, the reactions (Scheme 2) were performed in
hydrocarbon, halogenated hydrocarbon, ethereal, protic polar and
aprotic polar solvents (Table 6). The yields of 3 decreased
drastically indicating the detrimental effect of the solvents.
Table 6. Solvent effect on the 3-MCR of 1, 2, and NH4OAc to form 3.a
35 EntrySolvent
HBF4-SiO2
LiBF4
Yield (%)b Yield (%)c
5
Yield (%)b Yield (%)c
1
2
3
40 4
5
6
Water
MeOH
EtOH
10
55
48
24
23
25
8
15
20
9
trace
42
38
20
15
12
10
12
15
8
12
53
42
25
31
32
8
28
21
12
9
48
40
25
13
10
6
12
13
5
iPrOH
tBuOH
F3CCH2OH
MeCN
DCM
7
8
45 9
10 THF
11 Dioxane
12 PhMe
DCE
Scheme 3. 4-MCR synthesis of 1-benzyl-2,4,5-triphenylimidazole 5.
6
trace
9
trace
12
10
100 We were delighted with the clean formation of 5 in excellent
yield (90 %) in case of the HBF4–SiO2 catalyzed reaction within
short time intervals (10 min). However, in case of the LiBF4
catalyzed reaction, we noticed the formation of 2,4,6-triphenyl
imidazole 3 as side product (15% yield) in addition to desired 1-
105 benzyl-2,4,5-triphenylimidazole 5 (45 % yield) (entry 20, table
9).
12
aThe mixture of 1 (2.5 mmol), 2 (2.5 mmol, 1 equiv) and NH4OAc (5
50 mmol, 2 equiv) was treated under reflux for 5 h in different solvent (5
mL) in the presence of the HBF4-SiO2 (2 mol %) and LiBF4 (10 mol %).
bYield of 3 after purification (crystallisation, aq EtOH). IR, NMR and
c
APCI-MS).
The effect of the nitrogen source was evaluated in carrying out
55 the reactions by replacing NH4OAc with other ammonium salts
(table 7) and NH4OAc was proved to be the most effective
nitrogen source.
110
4
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Table 8. Synthesis of 2,4,5-trisubstituted imidazoles via the 3-MCR of 1,2-diketone, aldehyde and NH4OAc catalysed by HBF4-SiO2 and LiBF4.a
5 Entry
1,2-Diketone
Aldehyde
Method A
Time (min)
Method B
Time (min)
Yield (%)b,c
Yield (%)b,c
1
2
10 3
4
5
6
7
15 8
9
10
11
12
20 13
14
15
R1 = R2 = Ph
R3 = R4 = R5 = R6 = H
15
22
26
15
17
15
18
25
25
21
40
22
20
20
30
92
90
91
96
95
95
94
92
92
96
81
88
90
90
72
20
20
25
12
15
15
20
30
25
20
60
20
25
20
40
90
88
90
90
92
89
95
90
89
92
85
86
85
88
70
R1 = R2 = Ph
R1 = R2 = R4 = H; R5 = OMe
R1 = R2 = R4 = H; R5 = NMe2
R1 = R2 = R4 = H; R5 = Cl
R3 = Br; R4 = R5 = R6 = H
R3 = NO2; R4 = R5 = R6 = H
R1 = R2 = R4 = H; R5 = CF3
R1 = R2 = R4 = H; R5 = CN
R1 = R2 = R4 = H; R5 = OH
R3 = R5 = R6 = Me; R4 = H
R3 = R4 = R5 = R6 = H
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = 4-OMe-C6H4
R1 = R2 = 4-Cl- C6H4
R1 = R2 = 2-Furyl
R1 = R2 = 2-Thienyl
R1 = R2 = Me
R3 = R4 = R5 = R6 = H
R3 = R4 = R5 = R6 = H
R3 = R4 = R5 = R6 = H
R3 = R4 = R5 = R6 = H
CHO
O
R1 = R2 = Ph
R1 = R2 = Ph
20
24
95
95
22
25
92
90
O
16
17
CHO
S
R1 = R2 = Ph
R1 = R2 = Ph
20
35
97
86
25
30
95
85
CHO
O
25 18
19
N
CHO
CHO
20
21
R1 = R2 = Ph
R1 = R2 = Ph
30
35
90
85
35
30
88
85
CHO
CHO
22
R1 = R2 = Ph
35
84
40
82
30
aMethod A: The mixture of 1,2-diketone (2.5 mmol), aldehyde (2.5 mmol, 1 equiv) and NH4OAc (5 mmol, 2 equiv) was heated at 120 °C (oil bath) in the
presence of HBF4-SiO2 (2 mol%) under neat condition. Method B: The mixture of 1,2-diketone (2.5 mmol), aldehyde (2.5 mmol, 1 equiv) and NH4OAc
(5 mmol, 2 equiv) was heated at 120 °C (oil bath) in the presence of LiBF4 (10 mol%) under neat condition. bThe yield of the desired 2,4,5-trisubstituted
imidazoles obtained after purification (recrystallization, EtOH). cAll compounds were characterized by IR, NMR and MS (APCI).
35
We realised that this is the first report on the competitive
tetrasubstituted imidazole 5 is favoured in case of metal salts of
formation of the tri-substituted imidazole for a multicomponent 50 weak acid (metal tetrafluoroborates) compared to metal salts of
protocol designed for the formation of tetra-substituted imidazole.
stong protic acid (metal triflates; triflic acid). The catalytic
potency for 5:3 selectivity in favour of 5 (tetra substituted
imidazole) follows the order: metal tetrafluoroborate > metal
perchlorates > metal triflates. In case of metal tetrafluoroboares,
40 Therefore, we focussed on this unattended issue on the selectivity
of formation of the tri- and tetra-substitute imidazoles. The
catalytic potential of different metal tetrafluoroborates was
assessed for the selectivity of formation of 5 and 3 (scheme 3, 55 the selectivity towards 5 was observed to be in the order Zn(BF4)2
table 9). While in all cases the competitive formation of 3 was
45 observed, the best selectivity (5:3 = 95:5; overall yield 96%) was
exhibited by Zn(BF4)2 (entry 11, table 9). We also tested the
catalytic potential for the corresponding perchlorates and triflates.
> Co(BF4)2 > AgBF4 ≈ Fe(BF4)2 > NaBF4 ≈ LiBF4 ≈ Cu(BF4)2.
This clearly distinguished the advantage of tetrafluoroborates
compared to the stronger Lewis acids perchlorates and triflates
and justified our rational of choosing the fluoroboric acid derived
The study reveals that in general, the selectivity of formation of 60 catalyst systems in the initial catalyst selection process (table 1).
This journal is © The Royal Society of Chemistry [year]
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38 27 58:42
1
55 2
3
4
5
6
60 7
8
9
10
11
65 12
13
14
17
TfOH
TfOH-SiO2
HClO4 (aq 70 %)60
HClO4-SiO2
p-TsOH
p-TsOH-SiO2 10
MSA
MSA-SiO2
TFA
60
10
74
92
75
90
72
80
75
78
70
74
78
85
72
95
52
65
51 34 60:40
45 23 66:34
66 16 80:20
43 17 72:28
57 13 82:18
48 16 75:25
59 11 84:16
47 15 76:24
52 13 80:20
49 21 70:30
66 12 85:15
Table 9. The catalytic potential of metal tetrafluoroborates, perclhorates,
and triflates for the 5:3 selectivity during the 4-MCR of 1, 2, 4, and
10
60
NH4OAc.a
5 Entry
Catalyst
Time
(min)
Yield (%)
Selectivity
60
10
60
10
Overallb 5c 3c (5:3)d
1
2
3
10 4
5
6
HBF4–SiO2
NaBF4
NaClO4
NaOTf
AgBF4
AgClO4
AgOTf
Cu(BF4)2
Cu(ClO4)2
Cu(OTf)2
Zn(BF4)2
Zn(ClO4)2
Zn(OTf)2
Co(BF4)2
Co(ClO4)2
Co(OTf)2
Fe(BF4)2
Fe(ClO4)2
Fe(OTf)2
LiBF4
10
60
60
60
60
60
60
45
45
45
15
15
15
40
40
40
45
45
45
30
30
30
95
68
65
68
74
78
82
85
88
90
96
85
88
78
80
81
79
82
85
68
65
68
95 00 100:00
45 15 75:25
35 23 60:40
34 28 55:45
56 14 80:20
42 30 58:42
41 33 55:45
54 21 72:28
48 32 60:40
43 39 52:48
89 15 95:05
56 22 72:28
40 40 50:50
58 10 85:15
46 25 65:35
42 28 60:40
54 14 79:21
53 21 72:28
49 27 65:35
45 15 75:25
34 22 60:40
30 25 55:45
TFA-SiO2
H2SO4 (conc) 60
H2SO4-SiO2 10
HBF4 (aq 50 %) 60
HBF4-SiO2
BF3-OEt2
BF3-SiO2
57
8
88:12
10
4 h
2 h
95 00 100:00
30 10 74:26
50 08 85:15
7
8
18
15 9
10
11
12
13
20 14
15
16
17
18
25 19
20
21
22
70 aThe mixture of 1, 2 (2.5 mmol), 4 (2.5, 1 equiv) and NH4OAc (2.5 mmol,
1 equiv) was heated at 120 ºC (oil bath) under solvent free condition in
b
the presence of different catalyst (10 mol %). Yield after crystallisation
c
(aq EtOH) of the isolated crude product. Isolated yield of 5 and 3 after
d
chromatographic purification. Based on the isolated and purified yields
75 of 5 and 3.
To examine whether the catalytic potency (in terms of yield as
well as 5:3 selectivity) of various metal tetrafluoroborates for the
4-MCR of 1, 2, 4, and NH4OAc could imrpoved by
immobilisation on silica gel (230-400 mesh), various metal
80 tetrafluoroborates adsorbed on silica were used as the catalyst
(table 11). However, only marginal improvement was observed in
each case further suggesting that the adsorption on solid support
has greater influence on the protic (Brönsted) acid than the
corresponding metal Lewis acid.
LiClO4
LiOTf
aThe mixture of 1 (2.5 mmol), 2 (2.5 mmol, 1 equiv), 4 (2.5 mmol, 1
30 equiv), and NH4OAc (2.5 mmol, 1 equiv), was heated at 120 ºC (oil bath)
under solvent free condition in the presence of different catalyst (10 mol
b
%). Yield after crystallisation (aq EtOH) of the isolated crude product.
d
cIsolated yield of 5 and 3 after chromatographic purification. Based on
85 Table 11. Comparison of the catalytic potential of metal tetrafluoroborates
as such as well as immobilised on silica gel for the 5:3 selectivity during
the 4-MCR of 1, 2, 4, and NH4OAc.a
the isolated and purified yields of 5 and 3.
35
Various organic and inorganic protic acids were also used as
catalyst for the 4-MCR of 1, 2, 4, and NH4OAc to determine the
5:3 selectivity (table 10). The best yields (90-95%) were obtained
with TfOH, HClO4 and HBF4 adsorbed on silica. However the
selectivity in favour of the tetrsubstituted imidazole 5 was
Entry
Catalyst
Time
(min)
Yield (%)
Selectivity
Overallb 5c 3c (5:3)d
90 1
2
3
4
5
95 6
7
8
9
10
NaBF4
NaBF4-SiO2
AgBF4
AgBF4-SiO2
Cu(BF4)2
Cu(BF4)2-SiO2 45
Zn(BF4)2 15
Zn(BF4)2-SiO2 15
Co(BF4)2 40
Co(BF4)2-SiO2 40
Fe(BF4)2 45
Fe(BF4)2-SiO2 45
60
60
60
60
45
68
70
74
75
85
84
96
98
78
80
79
85
68
76
45 15 75:25
48 12 80:20
56 14 80:20
60 11 85:15
54 21 72:28
60 15 80:20
40 observed with weaker protic acid HBF4 (entry 5, table 10). In
general, significant inprovement in terms of reaction time, yield
and selectivity was observed in using the corresponding protic
acid adsorbed on silica gel (230-400 mesh) but the influence on
the catalytic potential due to adsorbtion on the solid support was
45 more pronounced with inorganic protic acids than that of organic
protic acids (except for TfOH). The non-protic/Lewis acid (e.g.,
BF3·OEt2) acid was less effective although the yield and
selectivity was increased on being adsorbtion on silica.
89
89
5
5
95:05
95:05
58 10 85:15
58 14 80:20
54 14 79:21
59 15 80:20
45 15 75:25
51 14 78:22
100 11
12
13
14
LiBF4
LiBF4-SiO2
30
30
Table 10. The catalytic potential of organic and inorganic Bronsted acids
50 as such as well as immobilised on silica gel for the 5:3 selectivity during
the 4-MCR of 1, 2, 4, and NH4OAc.a
aThe mixture of 1 (2.5 mmol), 2 (2.5 mmol, 1 equiv), 4 (2.5 mmol, 1
105 equiv), and NH4OAc (2.5 mmol, 1 equiv), was heated at 120 ºC (oil bath)
under solvent free condition in the presence of different catalyst system
b
(10 mol %). Yield after crystallisation (aq EtOH) of the isolated crude
Entry
Catalyst
Time
(min)
Yield (%)
Selectivity
product. cIsolated yield of 5 and 3 after chromatographic purification.
dBased on the isolated and purified yields of 5 and 3.
Overallb 5c 3c (5:3)d
110
Thus, identifying the unaddressed issue on the selectivity of
formation of the tri- and tetra-substituted imidazoles during the 4-
MCR of a 1,2-diketone, an aldehyde, an amine and NH4OAc
inspired us to revisit the reported methods (table 12). It was
revealed that all of these reported procedures led to the mixture of
115 5 and 3 during the 4-MCR involving 1, 2, 4, and NH4OAc.
Compared to these reported catalysts the fluoroboric acid derived
catalyst systems HBF4-SiO2 and Zn(BF4)2 afforded the best
results with 5:3 selectivities of 100:0 and 95:5, respectively, and
6
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Table 15. Catalyst recovery and reuse during the preparation of tetra
with 95 and 89% yield, respectively, of the purified 5.
substituted imidazole 5 via the 4-MCR of 1, 2, 4, and NH4OAc a
Table 12. Re-assessment of reported catalyst system for competitive
Scaleb
(mmol)
HBF4-SiO2
Recovered Recovery
(g)
formation of 5 and 3 during the 4-MCR of 1, 2, 4, and NH4OAc.a
Run
Used
(g)
Yield (%)c,d
Entry
Catalyst
Time
Yield (%)
Selectivity
65
(%)
5
(min)
Overallb 5c 3c (5:3)d
1st
50
40
30
20
10
1.0
0.9
90
96
84
74
84
95
95
89
88
85
e
1
2
3
4
10 5
6
FeCl3·6H2O
FeCl3·6H2O
InCl3
86
52
76
72
81
68
96
95
54 21 72:28
30 10 75:25
52 13 82:18
44 21 68:32
63 07 90:10
51 09 85:15
2nd
3rd
4th
0.50
0.25
0.12
0.05
0.48
0.21
0.089
0.042
10f
g
InCl3
10f
70 5th
h
ZrOCl2·8H2O
aThe mixture of 1, 2 (1 equiv with respect to 1), 4 (1 equiv with respect to
1) and NH4OAc (1 equiv with respect to 1) was heated at 120 ºC (oil bath
temp) under solvent free condition in the presence of the HBF4-SiO2 (2
mol%). bThe amount of 1 used for the reaction. cYield of 5 after
75 purification (crystallisation, aq EtOH). dIR, NMR and APCI-MS.
ZrOCl2·8H2O 10f
7
8
Zn(BF4)2
HBF4–SiO2
10
10
89
5
95:05
95 00 100:00
aThe mixture of 1 (2.5 mmol), 2 (2.5 mmol, 1 equiv), 4 (2.5 mmol, 1
15 equiv), and NH4OAc (2.5 mmol, 1 equiv), was treated under different
experimental condition in the presence of the catalyst. bYield after
crystallisation (aq EtOH) of the isolated crude product. cIsolated yield of 5
and 3 after chromatographic purification. dBased on the isolated and
purified yields of 5 and 3. eReaction was performed following the
To assess the effect of various solvents used for the
preparation of HBF4–SiO2 on its catalytic efficiency, aq HBF4
was added to the slurry of SiO2 (230-400 mesh) in various
solvents (table 16). The resultant HBF4–SiO2 (experimental) was
80 used as catalyst for the (i) 3-MCR to form 3 and (ii) the 4-MCR
to form 5 (table 16). No significant variation of the catalytic
activity was observed for HBF4–SiO2 prepared using Et2O, DCE
and EtOAc. Hence for further uses the catalyst was prepared
using EtOAc as it is the preferred solvent based on the solvent
85 selection guide of pharmaceutical industries.40 However, protic
polar solvents (H2O and EtOH) appeared to be less effective for
the purpose perhaps due to lack of removal of the trace amount of
these solvents from the catalyst that would reduce its catalytic
efficiency.
f
20 reported procedure under ref 19c. Reaction was performed using this
g
reported catalyst under solvent free condition at 120 °C. Reaction was
performed following the reported procedure under ref 19f. hReaction was
performed following the reported procedure under ref 19g. eIsolated yield
as reported in the corresponding literature.
25
Thus, for selective formation of the tetra substituted imidazoles
via the 4-MCR of a 1,2-diketone, an aldehyde, an amine and
NH4OAc two new catalyst systems derived from HBF4 have been
identified: HBF4-SiO2 [Method C] and Zn(BF4)2 [Method D].
The application of these two catalyst systems was extended for
30 diversified synthesis of 1,2,4,5-tetrasubstituted imidazole by the
reaction of different aryl/heteroaryl/aliphatic aldehydes with 1,2-
diketone, various amines and NH4OAc (table 13).
90 Table 16. Comparative catalytic behaviour of HBF4-SiO2 prepared using
different organic solvent.
We next investigated the reusability of HBF4–SiO2. The
reaction of 1 (50 mmol) was carried out with (i) 2 (50 mmol, 1
35 equiv) and NH4OAc (100 mmol, 2 equiv) to form the 2,4,5-
trisubstituted imidazole 3 via the 3-MCR and (ii) 2 (50 mmol, 1
equiv), 4 (50 mmol, 1 equiv) and NH4OAc (50 mmol, 1 equiv) to
form the 1,2,4,5-tetrasubstituted imidazole 5 via the 4-MCR at
120 °C in the presence of HBF4–SiO2 (2 mol%) under neat
40 condition. In each case, after completion of the reaction, the
reaction mixture was diluted with EtOH (100 mL) and the
catalyst was separated by filtration. The recovered catalyst was
reactivated by heating at 80 °C for 24 h under vacuum (10 mm
Hg) and reused for consecutive fresh batches of reactions without
45 any significant decrease in product yields (tables 14 and 15).
Entry
Solventa
3-MCR to form 3b
4-MCR to form 5c
Yield (%)d,e
Yield (%)d,e
1
95 2
3
4
5
Et2O
92
92
90
85
70
95
95
95
88
75
DCE
EtOAc
EtOH
H2O
aThe solvent used during the preparation of HBF4-SiO2 (experimental).
100 bThe mixture of 1 (2.5 mmol), 2 (2.5 mmol, 1 equiv) and NH4OAc (5
mmol, 2 equiv) was heated at 120 ºC (oil bath) in the presence of HBF4-
c
SiO2 (2 mol %) under neat condition for 15 min. The mixture of 1 (2.5
mmol), 2 (2.5 mmol, 1 equiv), 4 (2.5 mmol, 1 equiv) and ) and NH4OAc
(2.5 mmol, 1 equiv) was heated at 120 ºC (oil bath) in the presence of
105 HBF4-SiO2 (2 mol %) under neat condition for 10 min. cYield after
purification (crystallisation, aq EtOH). eIR, NMR and APCI-MS.
Table 14. Catalyst recovery and reuse during the preparation of the
trisubstituted imidazole 3 via the 3-MCR of 1, 2, and NH4OAc.a
Run
Scaleb
HBF4-SiO2
Yield (%)c,d
(mmol)
Used
(g)
Recovered Recovery
50
(g)
(%)
1st
50
40
30
20
10
1.0
0.9
90
90
88
75
80
95
95
90
88
84
2nd
3rd
4th
0.50
0.25
0.12
0.05
0.45
0.22
0.09
0.04
110
55 5th
aThe mixture of 1, 2 (1 equiv with respect to 1) and NH4OAc (2 equiv
with respect to 1) was heated at 120 ºC (oil bath temp) under solvent free
b
condition in the presence of the HBF4-SiO2 (2 mol%). The amount of 1
used for the reaction. cYield of 3 after purification (crystallisation, aq
60 EtOH). dIR, NMR and APCI-MS.
This journal is © The Royal Society of Chemistry [year]
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Table 13. Synthesis of 1,2,4,5-trisubstituted imidazoles via the 4-MCR of 1,2-diketone, aldehyde, amine, and NH4OAc catalysed by HBF4-SiO2 and
Zn(BF4)2.a
5 Entry
1,2-Diketone
Aldehyde
Amine
Method C
Time (min)
Method D
Time (min)
Yield (%)b,c
Yield(%)b,c
CHO
NH2
R1
R3
R2
R4
1
10 2
3
4
5
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = H
R3 = R4 = H
R3 = R4 = H
R3 = R4 = H
R3 = R4 = H
R3 = R4 = H
10
15
12
10
20
20
35
95
93
96
96
85
90
82
12
15
16
12
25
20
40
92
90
95
92
88
85
80
R1 = H; R2 = OMe
R1 = H; R2 = Cl
R1 = H; R2 = NO2
R1 = H; R2 = OH
R1 = H; R2 = Cl
6
15 7
R3 = Cl; R4 = H
R1 = H; R2 = NMe2 R3 = OMe; R4 = OH
R1 = R2 = Ph
R1 = R2 = Ph
R3 = R4 = H
R3 = R4 = H
18
25
94
93
20
25
92
90
CHO
CHO
O
8
9
CHO
O
R1 = R2 = Ph
R1 = R2 = Me
R3 = R4 = H
R3 = R4 = H
15
25
96
75
18
35
95
72
O
10
11
R1 = R2 = H
20
O
N
R1 = R2 = Ph
R1 = H; R2 = OMe
30
88
25
85
NH2
12
CHO
NH2
R1
R2
R
13
14
25 15
R1 = R2 = Ph
R1 = R2 = Ph
R1 = R2 = Ph
R1 = H; R2 = Cl
R1 = R2 = H
R1 = R2 = NMe2
R = H
R = Cl
R = OMe
18
20
28
94
95
90
15
20
25
90
92
88
NH2
16
17
R1 = R2 = Ph
R1 = H; R2 = H
20
20
82
80
25
22
80
81
NH2
R1 = R2 = Ph
R1 = H; R2 = Cl
aMethod C:The mixture of 1,2-diketone (2.5 mmol, 1 equiv), aldehyde (2.5 mmol, 1 equiv), amine (2.5 mmol, 1 equiv) and NH4OAc (0.19 g, 2.5 mmol, 1
equiv) was heated at 120 C in the presence of HBF4-SiO2 (2 mol%) under neat condition. Method D:The mixture of 1,2-diketone (2.5 mmol, 1 equiv),
°
°
30 aldehyde (2.5 mmol, 1 equiv), amine (2.5 mmol, 1 equiv) and NH4OAc (0.19 g, 2.5 mmol, 1 equiv) was heated at 120 C in the presence of ZnBF4 (10
mol%) under neat condition. bThe yield of the corresponding 1,2,4,5-tetrasubstituted imidazoles obtained after purification (crystallization, aq EtOH). cAll
compounds were characterized by IR, NMR and MS (APCI).
50 be a preferred choice. The relative catalytic efficiency of the
Bronsted acid catalyst to offer selective formation of the tetra-
Conclusions
substituted imidazole followed the order HBF4 > HClO4 > TfOH.
In case of metal Lewis acids, the metal tetrafluoroborate proved
to be the best suited catalyst for selective formation of the tetra
55 substituted imidazole via the 4-MCR and the relative catalytic
efficiency was in the order tetrafluoroborate> perchlorate>
triflate. For various metal tetrafluoroborate the observed catalytic
Through this study we report conveninet syntheses of tri- and
35 tetra-substituted imidazoles via 3-MCR and 4-MCR processes,
respectively, catalysed by fluoroboic based catalyst systems. The
catalyst systems HBF4-SiO2 (heterogenious) and LiBF4 were
found to be most effective for the preparation of 2,4,5-
trisubstituted imidazoles during the 3-MCR of 1,2-diketone,
40 aldehyde and NH4OAc. Amongst the various ammonium salts
used for the purpose as the nitrogen source best results were
obtained with NH4OAc and justified its universal use for such
transformation. During the 4-MCR involving 1,2-diketone,
aldehyde, amine, and NH4OAc to form 1,2,4,5-tetrasubstituted
45 imidazoles competitive formation of the 2,4,5-trisubstituted
imidazole was found to be a potential problem and an issue not
addressed/attended so far. Proper choice of the catalyst was the
critical aspect in controlling the selectivity for which the catalyst
(metal Lewis acid) derived from a weaker protic acid appeared to
potential was: Zn(BF4)2 > Co(BF4)2 > AgBF4 ≈ Fe(BF4)2
>
NaBF4 ≈ LiBF4 ≈ Cu(BF4)2. Immobilisation on solid support
60 increased the catalytic efficiency which, however, is more
significant/prominent for Bronsted acids (particularly inorganic
protic acids) rather than the metal Lewis acids. The heterogenious
catalyst system HBF4–SiO2 appeared to be the stand alone
catalyst for the synthesis of tri- and tetra-substituted imidazoles
65 via the 3-MCR and 4-MCR, respectively. Amongst the Lewis
acids LiBF4 is most effective for the 3-MCR and Zn(BF4)2 for the
4-MCR to form the tri- and tetra-substituted imidazoles
8
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

General procedure for s
2,4,5 Triphenyl imidazole 4 (Method B)
ynthesis of 2,4,
Page 9 of 12
Green Chemistry
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5 trisubstituted imidazoles.
respectively. The heterogeneous catalyst HBF4–SiO2 can be
recovered and reused for five consecutive times without any
significant loss of its catalytic activity. The new catalytic
procedures for the synthesis of tri- and tetra-substituted
imidazoles fufill the tripple bottmline philosophy of green
chemistry and are imoprtant addition to the tool box of medicinal
chemists.
The mixture of 1 (0.52 g, 2.5 mmol, 1 equiv), 2 (0.25 mL, 2.5 mmol, 1
100 equiv) and NH4OAc (0.39 g, 5 mmol, 2 equiv) were heated at 120 °C
(bath temperature) in the presence of LiBF4 (10 mol%) under neat
condition. After the completion of the reaction (solid mass formation, 20
min), the crude product recrystallized from aq EtOH to afford 3 (0.67 g,
92%) as white solid.16a
85 General procedure for synthesis of 1,2,4,5 tetrasubstituted
imidazoles. 1-Benzyl-2,4,5-triphenyl imidazole 6 (Method C).
The mixture of 1 (0.52 g, 2.5 mmol, 1equiv), 2 (0.25 mL, 2.5 mmol, 1
equiv), NH4OAc (0.19 g, 2.5 mmol, 1 equiv) and 4 (0.27 mL, 2.5 mmol, 1
equiv) were heated at 120 °C (bath temperature) in the presence of HBF4-
180 SiO2 (0.04 g, contains 2 mol% of HBF4) under neat condition. After the
completion of the reaction (solid mass formation, 10 min), the reaction
mixture was diluted with EtOH (10 mL) and passed through a plug of
cotton to separate the catalyst. The cotton plug retaining the catalyst was
5
Notes and references
aDepartment of Medicinal Chemistry, National Institute of
10 Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S.
Nagar 160 062, Punjab, India. E-mail: akchakraborti@niper.ac.in;
akchakraborti@rediffmail.com
‡ Experimental section: The 1H NMR (300 MHz) and 13C NMR (75
MHz) spectra were recorded on a Bruker Advance DPX 300 MHz NMR
15 spectrometer in CDCl3 using TMS as an internal standard. J values are
given in Hz. The IR spectra were recorded either as KBr pellets (for
solids) or neat (for liquids) on a Nicolet Impact 410 FTIR spectrometer.
Mass spectra were recorded on a GCMS- QP 5000 (Shimadzu) [for EI],
and Finnigan MAT-LCQ [for APCI] mass spectrometers. The reactions
20 were monitored by TLC (Merck®, Silica gel 60 F254). Evaporation of
solvents was performed at reduced pressure, using a Bǘchi rotary
evaporator.
washed with EtOH (2
× 2.5 mL). The combined filtrates were
185 concentrated under rotary vacuum evaporation and the crude product
recrystallized from aq EtOH to afford 5 (0.70 g, 95%) as white solid,18a
m.p. 161 °C. IR (KBr): max = 2985, 1600, 1580, 1500, 1480 cm-1.1H
NMR (CDCl3, 400 MHz): δ = 7.65 (d, J = 4.7 Hz, 2 H, ArH), 7.57 (d, 2
H, J = 9.7 Hz, ArH), 6.80-7.39 (m, 16 H, ArH), 5.10 (s, 2 H, PhCH2). MS
190 (APCI) m/z: 373 (MH+). The cotton plug retaining the catalyst was
transferred to a rb flask (10 mL) and dried under rotary vacuum
evaporation whereupon the catalyst came out of the cotton. The catalyst
was activated under vacuum (10 mm Hg) at 100 ºC for 24 h and reused.
The remaining reactions were performed following this general procedure
195 and the physical data (mp, IR, NMR and MS) of all known compounds
were identical with those reported in the literature.
Preparation of fluoroboric acid adsorbed on silica-gel (HBF4-SiO2).
The HBF4-SiO2 was prepared following the procedure first time reported
25 by its inventors.37a A magnetically stirred suspension of silica gel (26.7 g,
230-400 mesh) in EtOAc (75 mL) was treated with 40% aq HBF4 (3.3 g;
8.25 mL, 15 mmol) for 3 h. The mixture was concentrated under rotary
vacuum evaporation and the residue dried under vacuum (10 mm Hg) at
100°C for 72 h to afford HBF4-SiO2 (HBF4: 0.5 mmol g-1) as a free
30 flowing powder.
Representative procedure for preparation of metal tetrafluoroborate
immobilized on silica-gel.
Silica gel (1 g, 230–400 mesh) was added to the solution of LiBF4 (0.1 g,
1.07 mmol) in EtOH (10 mL) and the mixture was stirred magneticall for
35 6 h at room temperature. The mixture was concentrated under rotary
vacuum evaporation and the residue was dried under reduced pressure (10
General procedure for synthesis of 1,2,4,5 tetrasubstituted
imidazoles. 1-Benzyl-2,4,5-triphenyl imidazole 6 (Method D).
The mixture of 1 (0.52 g, 2.5 mmol, 1equiv), 2 (0.25 mL, 2.5 mmol, 1
150 equiv), NH4OAc (0.19 g, 2.5 mmol, 1 equiv) and 4 (0.27 mL, 2.5 mmol, 1
equiv) were heated at 120 °C (bath temperature) in the presence of
Zn(BF4)2 (10 mol%) under neat condition. After the completion of the
reaction (solid mass formation, 12 min), the reaction mixture was diluted
with EtOH (10 mL) and passed through a plug of cotton to separate the
155 catalyst. The cotton plug retaining the catalyst was washed with EtOH (2
× 2.5 mL). The combined filtrates were concentrated under rotary vacuum
evaporation and the crude product recrystallized from aq EtOH to afford
5 (0.70 g, 95%) as white solid.18a
mm Hg) at 100°C for 24
h to afford the SiO2-supported metal
tetrafluoroborate (LiBF4: 10 % w/w or 0.97 mmol g-1) as a free flowing
powder.
Experimental Procedure of Large Scale synthesis of trisubstituted
120 Imidazole and Catalyst Reuse.
40 Procedure for preparation of [NHC][BF4] ionic liquid.34
Caprolactam 1.13 g (10 mmol) was added to 50% aq fluoroboric acid
(1.26 mL, 10 mmol) and the resulrtant soklution was magnetically
stiorred for 30 min at room temperature. The mixture was concentrated
under rotary vacuum evaporation and resudue was dried under vacuum
45 (5–10 mmHg) for 4 h at 90 °C to obtain a light yellow clear liquid.
General procedure for synthesis of 2,4,5 trisubstituted imidazoles.
2,4,5 Triphenyl imidazole 4 (Method A).
To a magnetically stirred mixture of 1 (10.4 g, 50 mmol, 1 equiv), 2 (5.0
mL, 50 mmol, 1 equiv) and NH4OAc (7.8 g, 100 mmol, 2 equiv) was
added HBF4-SiO2 (800 mg, 1 mmol, 2 mol%) and the reaction mixture
was heated at 120 °C. After the completion of reaction (20 min, TLC), the
205 reaction mixture was diluted with EtOH (50 mL), filtered through a plug
of cotton (to separate the catalyst), and the cotton plug was washed with
EtOH (2 × 20 mL). The combined filtrates were concentrated on a rotary
evaporator to afford the crude product. The crude product was
recrystallized from aq EtOH to afford 3 (13.5 g, 95%) as white solid.16a
210 The cotton plug retaining the recovered catalyst was put in a rb flask (20
mL) and dried under rotary vacuum evaporation when the catalyst
separated out from the cotton (720 mg, 90%). The catalyst was activated
by heating under reduced pressure (10 mm Hg) at 80 °C for 24 h. The
reaction was repeated at 40 mmol, 30 mmol, 20 mmol and 10 mmol
215 scales the in presence of the recovered HBF4-SiO2 (0.5 g, 0.25 g, 0.12 g
and 0.05 g, respectively) to afford 2,4,5 triphenyl imidazole 3 in 11.2 g
(95 %), 8.0 g (90 %), 5.2 g (88 %), and 2.5 g (84 %), respectively, as
white solid identical (spectral data) with an authentic sample.
The mixture of 1 (0.52 g, 2.5 mmol, 1 equiv), 2 (0.25 mL, 2.5 mmol, 1
equiv) and NH4OAc (0.39 g, 5 mmol, 2 equiv) was heated at 120 °C (bath
50 temperature) in the presence of HBF4-SiO2 (0.04 g, contains 2 mol% of
HBF4) under neat condition. After the completion of the reaction (solid
mass formation, 15 min), the reaction mixture was diluted with EtOH (10
mL) and passed through a plug of cotton to separate the catalyst. The
cotton plug retaining the catalyst was washed with EtOH (2 × 2.5 mL).
55 The combined filtrates were concentrated under rotary vacuum
evaporation and the crude product recrystallized from aq EtOH to afford
3 (0.67 g, 92%) as white solid,16a m.p. 274 °C. IR (KBr) max = 1216,
1638, 2470, 2993, 3434 cm-1. 1H NMR (CDCl3, 400 MHz): δ = 7.91 (d, J
= 9.5 Hz, 2 H, ArH), 7.59 (d, J = 8.5 Hz, 4 H, ArH), 7.29-7.48 (m, 9 H,
60 ArH). MS (APCI) m/z: 297 (MH+). The cotton plug retaining the catalyst
was transferred to a rb flask (10 mL) and dried under rotary vacuum
evaporation whereupon the catalyst came out of the cotton. The catalyst
was activated under vacuum (10 mm Hg) at 80 ºC for 24 h and reused.
The remaining reactions were performed following this general procedure
65 and the physical data (mp, IR, NMR and MS) of all known compounds
were identical with those reported in the literature.
Representative Experimental Procedure of Large Scale synthesis of
140 Tetrasubstituted Imidazole and Catalyst Reuse.
To a magnetically stirred mixture of 1 (10.4 g, 50 mmol, 1 equiv), 2 (5.0
mL, 50 mmol, 1 equiv), NH4OAc (3.9 g, 50 mmol, 1 equiv) and 4 (5.3 g,
50 mmol, 1 equiv) was added HBF4-SiO2 (800 mg, 1mmol, 2 mol %) and
the reaction mixture was heated at 120 °C. After the completion of
170 reaction (20 min, TLC), the reaction mixture was diluted with EtOH (50
mL), filtered through a plug of cotton (to separate the catalyst), and the
cotton plug was washed with EtOH (2 × 20 mL). The combined filtrates
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 9

Green Chemistry
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were concentrated on a rotary evaporator to afford the crude product. The
as
3
crude product was recrystallized from aq EtOH to afford 5 (18.3 g, 95%)
white solid.18a The cotton plug retaining the recovered catalyst was put in
a rb flask (20 mL) and dried under rotary vacuum evaporation when the
catalyst separated out from the cotton (720 mg, 90%). The catalyst was
activated by heating under reduced pressure (10 mm Hg) at 80 °C for 24 105
h. The reaction was repeated at 40 mmol, 30 mmol, 20 mmol and 10
mmol scales the in presence of the recovered HBF4-SiO2 (0.5 g, 0.25 g,
10 0.12 g and 0.05 g, respectively) to afford 5 in 14.6 g (95 %), 10.3 g (89
%), 6.8 g (88 %), and 3.2 g (85 %), respectively as white solid identical
(spectral data) with an authentic sample.
Laydon, D. E. Griswold, M. C. Chabot-Fletcher, J. J. Breton and J. L.
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W. Abt, M. E. Sorenson, J. M. Smietana, R. F. Hall, R. S. Garigipati,
P. E. Bender, K. F. Erhard, A. J. Krog, G. A. Hofmann, P. L.
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Dancheck, A. J. Forsyth, D. S. Fletcher, B. Frantz, W. A. Hanlon, C,
F. Harper, S. J. Hofsess, M. Kostura, J. Lin, S. Luell, E. A. O’neill,
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Revesz, E. Blum, F. E. D. Padova, T. Buhl, R. Feifel, H. Gram, P.
Hiestand, U. Manning and G. Rucklin, Bioorg. Med. Chem. Lett.
2004, 14, 3595; c) M. Mader, A. De dios, C. Shih, R. Bonjouklian, T.
Li, W. White, B. L. De Uralde, C. Sánchez-Martinez, M. Del Prado,
C. Jaramillo, E. De Diego, L. M. M. Cabrejas, C. Dominguez, C.
Montero, T. Shepherd, R. Dally, J. E. Toth, A. Chatterjee, S. Pleite, J.
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a) M. J. Newman, J. C. Rodarte, K. D. Benbatoul, S. J. Romano, C.
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90
4
5
The physical data (IR, NMR and MS) of new compounds are provided
below.
15 1-(4-Chlorobenzyl)-2-(4-chlorophenyl)-4,5-diphenyl-1H-imidazole
(Table 11, Entry 6) White Solid (1.0 g, 95 % ), m.p. 177-178 °C. IR
(KBr)
= 3420, 3006, 1606, 1483, 1275, 1092, 832, 764 cm-1. 1H 170
6
max
NMR (400 MHz, CDCl3): δ = 7.53-7.58 (m, 4 H ArH), 7.31-7.40 (m, 5 H,
ArH), 7.12-7.24 (m, 7 H, ArH), 6.7 (d, J = 8.4 Hz, 2 H, ArH), 5.04 (s, 3
20 H, PhCH2). 13C NMR (100 MHz, CDCl3): δ = 146.8, 138.4, 135.7, 134.1,
133.4, 130.9, 130.6, 130.2, 130.2, 130.1, 129.2, 129.0, 128.9, 128.5,
128.9, 128.2, 127.3, 126.8, 126.6, 47.7. HRMS (ESI) m/z calcd for 175
C28H20Cl2N2Na+ [M + Na+], 477.0896; Found 477.0894.
1-(4-Methoxy-2-hydroxybenzyl)-2-(4-dimethylaminophenyl)-4,5-
25 diphenyl-1H-imidazole (Table 11, Entry 7) White Solid (0.97 g, 82 % ),
m.p. 271-272 °C. IR (KBr)
= 3430, 2994, 1610, 1396, 1280, 834,
max
776 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.50 (m, 2 H ArH), 7.45(d, J 180
= 8.8 Hz, 2 H, ArH), 7.24 (m, 1 H, ArH), 7.08-7.18 (m, 5 H, ArH), 6.65
(d, J = 7.2 Hz, 2 H, ArH), 6.60 (t, J = 6.3 Hz, 2 H, ArH), 6.54 (d, J = 8.8
30 Hz, 2 H, ArH), 6.12-6.15 (m, 1 H, ArH), 6.12 (s, 2 H, CH2), 3.85 (s, 3 H,
OCH3), 2.88 (s, 6 H, CH3). 13C NMR (100 MHz, CDCl3): δ = 150.6,
148.2, 146.4, 146.2, 131.1, 129.9, 129.5, 128.5, 128.3, 128.0, 126.8, 185
117.0, 116.2, 115.2, 112.5, 112.0, 110.9, 56.0, 47.8, 40.2. HRMS (ESI)
m/z calcd for C31H29N3O2Na+ [M + Na+], 498.2152; Found 498.2164.
35 4-(2-(2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazol-1-
7
yl)ethyl)morpholine (Table 7, Entry 12) White Solid (0.9 g, 88 %), IR
(KBr)
= 3420, 2896, 1625, 1385, 1280, 766 cm-1. 1H NMR (400 140
max
MHz, CDCl3): δ = 7.62-7.66 (m, 2 H, ArH), 7.51-7.53 (m, 2 H, ArH),
7.41-7.48 (m, 5 H, ArH), 7.17-7.21 (m, 2 H, ArH), 7.10 (m, 1 H, ArH),
40 6.98-7.02 (m, 2 H, ArH), 4.00 (t, J = 7.32 Hz, 2 H, CH2), 3.85 (s, 3 H,
OCH3), 3.48 (t, J = 4.60 Hz, 4 H, CH2), 2.23 (t, J = 7.16 Hz, 2 H, CH2),
2.04 (t, J = 4.52 Hz, 4 H, CH2). 13C NMR (100 MHz, CDCl3): δ = 160.1, 120
147.8, 137.5, 134.5, 131.5, 131.0, 130.6, 129.2, 129.1, 128.7, 128.4,
126.8, 126.2, 123.7, 114.0, 66.7, 58.2, 55.4, 53.4, 41.8. HRMS (ESI) m/z
45 calcd for C28H29N3O2Na+ [M + Na+], 462.2152; Found 462.2164.
1-(4-Methoxyphenyl)-2-(4-dimethylaminophenyl)-4,5-diphenyl-1H-
imidazole (Table 11, Entry 15) white solid (1.0 g, 90 %), IR (KBr)
max = 3425, 2982, 1625, 1390, 1282, 847, 745 cm-1. 1H NMR (400 MHz,
CDCl3): δ = 7.60-7.62 (m, 2 H, ArH), 7.33-7.35 (m, 2 H, ArH), 7.12-7.27
50 (m, 8 H, ArH), 6.97-7.70 (m, 2 H, ArH), 6.76-6.80 (m, 2 H, ArH), 6.57-
6.60 (m, 2 H, ArH), 3.79 (s, 3 H, OCH3), 2.94 (s, 6 H, CH3). 13C NMR
(100 MHz, CDCl3): δ = 158.9, 150.0, 147.7, 137.6, 134.8, 131.2, 131.1, 140
130.4, 130.3, 129.8, 129.7, 128.2, 128.0, 127.6, 127.4, 126.3, 118.4,
114.1, 111.5, 55.3, 40.2. HRMS (ESI) m/z calcd for C30H27N3ONa+ [M +
55 Na+], 468.2046; Found 468.2046.
8
9
L. Wang, K. W. Woods, Q. Li, K. J. Barr, R. W. McCroskey, S. M.
Hannick, L. Gherke, R. B. Credo, Y. H. Hui, K. Marsh, R. Warner, J.
Y. Lee, N. Zielinsky- Mozng, D. Frost, S. H. Rosenberg and H. L.
Sham, J. Med. Chem. 2002, 45, 1697.
130 10 D. S. Weinstein, W. Liu, K. Ngu, C. Langevine, D. W. Combs, S.
Zhuang, C. Chen C. S. Madsen, T. W. Harper, J. A. Robl Bioorg.
Med. Chem. Lett. 2007, 17, 5115.
11 J. H. M. Lange, H. H. Van Stuivenberg, H. K. A. C. Coolen, T. J. P.
Adolfs, A. C. McCreary, H. G. Keizer, H. C. Wals, W. Veerman, A.
J. M. Borst, W. de Looff, P. C.Verveer and C. G Kruse, J. Med.
Chem. 2005, 48, 1823.
12 A. K. Takle, M. J. B. Brown, S. Davies, D. K. Dean, G. Francis, A.
Gaiba, A. W. Hird, F. D. King, P. J. Lovell, A. Naylor, A. D. Reith,
J. G. Steadman and D. M. Wilson, Bioorg. Med. Chem. Lett. 2006,
2-(4-Chlorophenyl)-1-cyclohexyl-4,5-diphenyl-1H-imidazole (Table
11, Entry 17) White solid (1.0 g, 80 %), IR (KBr)
= 3746, 3449, 145
16, 378.
max
2925, 1747, 1447, 1366, 1275, 1216, 1091, 750 cm-1. 1H NMR (400 MHz,
CDCl3): δ = 7.54-7.58 (m, 2 H, ArH), 7.39-7.48 (m, 9 H, ArH), 7.06-7.16
60 (m, 3 H, ArH), 3.88-3.95 (m, 1H, cyCH), 1.62-1.85 (m, 4 H, cyCH2),
1.42-1.58 (m, 3 H, cyCH2), 0.99-1.10 (m, 2 H, cyCH2), 0.79 (m, 1 H,
cyCH2). 13C NMR (100 MHz, CDCl3): δ = 146.4, 138.0, 135.0, 134.4, 175
132.3, 132.1, 131.3, 130.9, 129.4, 128.9, 128.7, 128.6, 127.9, 126.6,
126.1, 58.4, 33.6, 26.2, 25.0. HRMS (ESI) m/z calcd for C27H25ClN2H+
65 [M + H+], 413.1779; Found 413.1790.
13 a) J. Wang, R. Mason, D. V. Derveer, K. Feng and X. R. Bu, J. Org.
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1
For reviews, see: a) R. W. Armstrong, A. P. Combs, P. A. Tempest,
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Catalytic procedures for multicomponent
synthesis of imidazoles: selectivity control
during the competitive formation of tri- and
tetra-substituted imidazoles
Dinesh Kumar, Damodara N. Kommi, Alpesh R. Patel
and Asit K. Chakraborti*
H
N
Method A
or
(R)Ar
(R)Ar
O
O
O
H
+
+
Ar(R)
Ar(R)
+
+
NH4OAc
NH4OAc
Method B
N
Ar(R)
(R)Ar
(R)Ar
(R)Ar
(R)Ar
O
O
Method A
or
N
N
H
NH2
+
Ar(R)
Method C
Ar(R)
(R)Ar
O
(R)Ar
Ar(R)
Method A: HBF4-SiO2 (2 mol%), neat, 120 °C, 10 - 35 min
Method B:
LiBF4 (10 mol%), neat, 120 °C, 12 - 40 min
Method C: Zn(BF4)2 (10 mol%), neat, 120 °C, 12 - 35 min
Fluoroboric acid derived catalyst systems for selectivity control
in the multicomponent reactions for synthesis of tri- and tetra-
substituted imidazoles.