One pot synthesis of 1,2,4,5-tetrasubstituted-imidazoles catalyzed by trityl chloride in neutral media

Article abstract of DOI:10.1039/c4ra10589c

Trityl chloride (TrCl or Ph₃CCl) efficiently catalyzes the one-pot multi-component condensation of benzil with aldehydes, primary amines and ammonium acetate under neutral and solvent-free conditions to give 1,2,4,5-tetrasubstituted imidazoles in high to excellent yields and in short reaction times. Mechanistically, it is attractive that trityl chloride promotes the reaction by in situ generation of trityl carbocation (Ph₃C⁺).

Full text of DOI:10.1039/c4ra10589c

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One pot synthesis of 1,2,4,5-tetrasubstituted-imidazoles catalyzed by
trityl chloride in neutral media
Ahmad Reza Moosavi-Zare,*a Zhila Asgari,b Abdolkarim Zare,*cMohammad Ali Zolfigol,*bMohsen
Shekouhyd
5
Received (in XXX, XXX) XthXXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
Trityl chloride (TrCl or Ph3CCl) efficiently catalyzes the oneꢀpot multiꢀcomponent condensation of benzil with aldehydes, primary
amines and ammonium acetate under neutral and solventꢀfree conditions to give 1,2,4,5ꢀtetrasubstituted imidazoles in high to excellent
yields and in short reaction times. Mechanistically, it is attractive that trityl chloride by in situ generation of trityl carbocation (Ph3C+)
10 promotes the reaction.
Multiꢀcomponent reactions (MCR) play an important role in
combinatorial chemistry because of their capability to synthesize
target molecules with atomic economy and high efficiency, by
15 reaction of three or more reactants in one step. Furthermore, these
reactions increase synthetic efficacy and simplicity with respect
to the conventional organic transformations.1
aldehydes, primary amines and ammonium acetate, for the first
time (Scheme 1).
Cl
HO
N
HO
N
55
N
N
N
RO
N
N
N
N
NH
O
N
NH
Imidazole derivatives are one of the most important classes of
nitrogenꢀcontaining fiveꢀmembers heterocycles. For example,
20 they are an essential component of various biological and
pharmaceutical molecules, including histidine, histamine, biotin,
losartan, olmesartan, eprosartan, miconazole, ketoconazole,
clotrimazole and trifenagrel.2 Some pharmaceutical compounds,
based on imidazol moiety, are displayed in Figure 1. Moreover,
25 imidazole derivatives are used as green solvents in form of ionic
liquids,3 and as Nꢀheterocyclic carbenes in organometallic
chemistry.4 1,2,4,5ꢀTetrasubstituted imidazoles are an important
class of imidazoles which are prepared via the oneꢀpot multiꢀ
component condensation of benzil with aldehydes, primary
30 amines and ammonium acetate using acidic catalysts.5 Although
several catalysts for this transformation are known, development
of newer catalysts with high novelty which can promote the
reaction attract attention for their difference with the others, and
effectiveness.
35 Currently, development of organocatalysts has attracted much
attention in organic synthesis, especially from green chemistry
point of view.6 These catalysts have some advantages compared
with acidic catalysts or precious metal, such as commercial
availability, low cost, relative nonꢀtoxicity, air stability, need to
40 simple reaction conditions, and ability to promote a chemical
reaction via different activation modes.7,8 Considering the high
importance of organocatalysts, recently, we have applied a
neutral and attractive kind of these catalysts namely triarylmethyl
chlorides (Ar3CCl) to promote the preparation of 12ꢀarylꢀ
45 8,9,10,12ꢀtetrahydrobenzo[a]ꢀxanthenꢀ11ꢀones,7
Losartan
Olmesartan
S
Cl
60
N
Cl
O
HOOC
N
N
N
N
O
O
O
N
COOH
Eprosartan
Ketoconazole
65
70
75
Cl
NMe2
N
Cl
Cl
O
N
N
O
NH
N
N
Cl
Cl
Miconazole
Clotrimazole
Trifenagrel
Figure 1. The structure of losartan, olmesartan, eprosartan,
miconazole, ketoconazole, clotrimazole and trifenagrel as drugs.
80
Scheme 1. The preparation of 1,2,4,5ꢀtetrasubstituted imidazoles.
To optimize the reaction conditions, as a model reaction, the
85 condensation of benzil (1 mmol) with benzaldehyde (1 mmol),
aniline (1 mmol) and ammonium acetate (1 mmol) was studied in
the presence of different molar ratios of trityl chloride at range of
50ꢀ100 °C under solventꢀfree conditions; the respective results
are summarized in Table 1. As Table 1 indicates, the best results
90 were obtained when the reaction was performed using 10 mol %
of the organocatalyst at 90 ºC. To confirm that heat can not
bis(indolyl)methanes,9 1ꢀamidoalkylꢀ2ꢀnaphthols10 and Nꢀ
sulfonyl imines.11 In the mentioned investigations, we have used
Ar3CCl to catalyze the two and threeꢀcomponent reactions.
However, in the presented work, we employ trityl chloride (TrCl
50 or Ph3CCl) as a homogeneous organocatalyst to promote a oneꢀ
pot fourꢀcomponent reaction, i.e. the condensation of benzil with
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thermodynamically promote the reaction in the absence of
catalyst; the model reaction was examined at 90 ºC under
In a plaucible mechanism which is supported by the literature
(Scheme 2),2,5,22 at first, aldehyde is activated by Ph3C+ generated
catalystꢀfree conditions. In these conditions, the desired product 25 from Ph3CCl; consequently, two resonance forms of the activated
was obtained in trace yield after 120 min. This observation
clearly showed that heat can not promote the reaction without
catalyst; thus, presence of catalyst (e.g. TrCl) is essential for the
aldehyde (I and II) can produce.1a,1e,10 The activated aldehyde
react with amine to give iminium intermediate III. Afterward, III
reacts with ammonia (resulted from ammonium acetate) to afford
IV, and this intermediate reacts with trityl alcohol (Ph3COH) to
30 provide V and Ph3CCl. In the next step, intermediate VI produces
by nucleophilic attack of the nitrogens of V to the carbonyl
groups of benzil. Finally, 1,2,4,5ꢀtetrasubstituted imidazole is
synthesized by removing two molecules of H2O from VI.
O
5
reaction.
Table 1. Effect of the catalyst amount and temperature on the reaction
between benzil, benzaldehyde, aniline and ammonium acetate.
Mol% of TrCl
Temp. (°C)
Time (min)
Yielda (%)
7
90
50
30
30
61
37
10
+
Ph3CCl
10
10
10
80
90
100
30
30
30
64
79
79
35
H
H
H
10 aIsolated yield.
Cl
O
O
After optimization of the reaction conditions, the efficiency and
scope of the organocatalyst was evaluated by the reaction of
benzil with various arylaldehydes, different primary amines and
ammonium acetate using 10 mol% of TrCl at 90 ºC; the
15 corresponding results are summarized in Table 2. As it can be
seen in Table 2, all reactions proceeded efficiently to afford the
desired 1,2,4,5ꢀtetrasubstituted imidazoles in high yields and in
short reaction times. Thus, TrCl was efficient to catalyze the oneꢀ
pot fourꢀcomponent reaction.
H
N
I
II
H
40
N
H
+
H
N
Cl
H
H
H
HO
III
O
H
H
20 Table 2. The synthesis of 1,2,4,5ꢀtetrasubstituted imidazoles using TrCl
(10 mol %) under solventꢀfree conditions at 90°C.
N
H
45
50
55
60
65
Time (min)/
Yielda (%)
M.p. (°C)
Entry
Ar
R
Found/Reported.
H
+ Ph3COH
- H2O
H
C
H
N
N
N
H
Ph3CCl
+
218ꢀ220/
218ꢀ2215a
156ꢀ158/
156ꢀ1595a
165ꢀ167/
165ꢀ1685a
188ꢀ190/
189ꢀ1914b
146ꢀ147/
145ꢀ1474b
H
1a
1b
1c
C6H5
C6H5
C6H5
30/79
32/80
35/76
H
H
Cl
H
N
H
V
IV
C6H5CH2
C6H5CH2
O
4ꢀCH3ꢀC6H4
O
H
1d
1f
4ꢀClꢀC6H4
3ꢀNO2ꢀC6H4
4ꢀNO2ꢀC6H4
4ꢀClꢀC6H4
4ꢀCH3ꢀC6H4
4ꢀCH3ꢀC6H4
20/81
60/78
30/81
H
C
N
N
H
H
H
H
C
IV
N
O
N
H
H
O
O
214ꢀ217/
215ꢀ2174b
O
1g
158ꢀ160/
161ꢀ1634b
197ꢀ200/
198ꢀ2014b
193ꢀ195/
194ꢀ1964b
131ꢀ133/
130ꢀ1325a
148ꢀ150/
148ꢀ1515a
134ꢀ137/
135ꢀ1385a
158ꢀ160/
158ꢀ1615a
280ꢀ283/
282ꢀ2845a
1h
1i
4ꢀClꢀC6H4
4ꢀClꢀC6H4
4ꢀCH3ꢀC6H4
C6H5CH2
4ꢀFꢀC6H4
30/79
20/78
60/75
H
- 2 H2O
N
N
H
C
1j
4ꢀCH3ꢀC6H4
N
N
H
H
3ꢀCH3Oꢀ
C6H4
OH
1k
C6H5CH2
40/75
OH
VI
1l
1m
1n
1o
4ꢀClꢀC6H4
C6H5
C6H5CH2
C6H5CH2
C6H5
30/79
35/78
45/75
35/81
Scheme 2.The proposed mechanism for the synthesis of 1,2,4,5ꢀ
tetrasubstitutedimidazoles using trityl chloride.
4ꢀOHꢀC6H4
4ꢀCH3Oꢀ
C6H4
70 To confirm the generation of I and II as resonance structures of
the activated aldehyde, benzaldehyde was treated with trityl
chloride at room temperature, and IR, H NMR, and UV spectra
1
4ꢀOHꢀC6H4
of the mixture was run;2,5 the obtained results include:
IR (nujol): νmax (cmꢀ1) of the carbonyl group of benzaldehyde
75 (1705) was decreased to 1697 in the mixture of benzaldehyde and
trityl chloride (Fig. S1).
197ꢀ200/
1p
4ꢀCNꢀC6H4
4ꢀCH3ꢀC6H4
30/82
198ꢀ2014b
232ꢀ234/
233ꢀ2355a
198ꢀ200/
199ꢀ2024b
198ꢀ200/
198ꢀ2014b
1q
1r
1s
4ꢀOHꢀC6H4
2ꢀThienyl
2ꢀThienyl
4ꢀCH3ꢀC6H4
4ꢀCH3ꢀC6H4
4ꢀOHꢀC6H4
35/82
20/78
3/92
1H NMR (300 MHz, CDCl3): chemical shift (ppm) of the HC=O
of benzaldehyde (9.78) was increased to 10.04 in the mixture of
PhCHO and TrCl (Fig. S2).
aIsolated yield.
80 UV: maximum absorption of benzaldehyde and trityl chloride
2
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were 240 and 222 nm, respectively. However, λmax of the mixture
of PhCHO and TrCl was observed in 245 nm (Fig. S3).
These observations showed that aldehyde in the presence of trityl
chloride give resonance forms I and II.
ammonium acetate at 90 ºC in solventꢀfree conditions to furnish
1,2,4,5ꢀtetrasubstituted imidazoles. The promising points for the
presented catalytic process include generality, efficacy, high
35 yield, simplicity, cleaner reaction profile, relatively short reaction
times and good agreement with the green chemistry protocols.12
5
Although TrOH produced during the reaction; but it can not
catalyze the reaction like TrCl. To confirm this point, we tested
the model reaction in the presence of TrOH as catalyst in which
the product yield was only 23% after 50 min. This result verified
that TrOH is changed to TrCl during the reaction.
Acknowledgements
The authors gratefully acknowledge support of this work by the
Research Affairs Office of BuꢀAli Sina University (Grant number
40 32ꢀ1716 entitled development of chemical methods, reagents and
molecules), University of Sayyed Jamaleddin Asadabadi, Payeme
Noor University, and Center of Excellence in Development of
Environmentally Friendly Methods for Chemical Synthesis
(CEDEFMCS), for providing support to this work.
45
10 Thus, the mecanism is confirmed by the above observations
besides the literature.2,5,22
Catalytic application of other trityl sources such as
monomethoxytrityl chloride (Ph2(pꢀMeOC6H4)CCl, MMTCl),
dimethoxytrityl
chloride
(Ph(pꢀMeOC6H4)2CCl)
and
15 triphenylmethanol (TrOH) on the model reaction, was also
investigated under solventꢀfree conditions at 90 ºC. The results
are shown in Figure 2. As Figure 2 indicates, higher yield and
shorter reaction time were obtained using trityl chloride.
Furthermore, turn over numbers (TON) and turn over frequencies
20 (TOF) on the effectiveness of these catalysts for the synthesis of
the imidazoles were calculated (Fig. 2). The TON and TOF
values showed that TrCl is more efficient than MMTCl, DMTCl
and TrOH.
Notes and references
aDepartment of Chemistry, University of SayyedJamaleddinAsadabadi,
Asadabad, 6541835583, Iran; E-mail:moosavizare@yahoo.com
bFaculty of Chemistry, Bu-Ali Sina University, Hamedan, 6517838683,
50 Iran
cDepartment of Chemistry, Payame Noor University, PO Box 19395-
3697, Tehran, Iran
dDepartment of Chemistry, College of Science, Shiraz University, 71454,
Shiraz, Iran
55 † Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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2
3
4
5
25 Figure 2. Catalytic activity of different triarylmethyl sources (10 mol%)
on the reaction between benzil (1 mmol), benzaldehyde (1 mmol), aniline
(1 mmol) and ammonium acetate (1 mmol) at 90 °C.
Conclusions
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In summary, we have applied TrCl as a neutral and homogenous
30 organocatalyst for the oneꢀpot fourꢀcomponent reaction of
aldehydes with amines (aliphatic or aromatic), benzil and
8
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This journal is © The Royal Society of Chemistry [year]
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Hasaninejad, F. Panahi, Synthesis, 2008, 617.
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12 General procedure for the synthesis of 1,2,4,5ꢀtetrasubstituted
imidazoles: A mixture of compounds consisting of benzil (1 mmol),
aldehyde (1 mmol), primary amine (1 mmol), ammonium acetate (1
mmol) and TrCl (10 mol%) in a 10 mL roundꢀbottomed flask
connected to a reflux condenser, was stirred in an oilꢀbath (90 °C).
After completion of the reaction, as monitored by TLC, the reaction
mixture was cooled to room temperature, and then petroleum ether (5
ml) was added to the crude reaction mixture, and filtered to separate
the catalyst which will be recycled for other reactions. Then, the pure
product was obtained by recrystallization of the reaction mixture in
ethanol (90 %) or ethyl acetate.
5
10
15
4
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Graphical Abstract
One pot synthesis of 1,2,4,5-tetrasubstituted-imidazoles catalyzed
by trityl chloride in neutral media
Ahmad Reza Moosavi-Zare,* Zhila Asgari, Abdolkarim Zare,* Mohammad Ali Zolfigol,*
Mohsen Shekouhy