Bimetallic Cu-Mn B spinel oxide catalyzed oxidative synthesis of 1,2-disubstituted benzimidazoles from benzyl bromides

Article abstract of DOI:10.1039/c8nj05504a

Cu-Mn B (a heterogeneous catalyst) catalyzed synthesis of 1-benzyl-2-phenyl-1H-benzo[d]imidazoles is reported. In this reaction, 2-phenyl-1H-benzo[d]imidazoles are found to be the side products. The reported protocol is simple and highly efficient, tolerates a wide variety of substrates and the products were formed in good to excellent yield.

Full text of DOI:10.1039/c8nj05504a

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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DOI: 10.1039/C8NJ05504A
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Bimetallic Cu-Mn B spinel oxide catalyzed oxidative synthesis of
1,2-disubstituted benzimidazoles from benzyl bromides
Received 00th January 20xx,
Accepted 00th January 20xx
Rohit Sharma,a# Firdoos Ahmad Sofi,a# Preeti Rana,a `Prasad V. Bharatama*
DOI: 10.1039/x0xx00000x
www.rsc.org/
condensation of o-phenylenediamine with aldehyde,15 C-H
amination reaction of
Cu-Mn B, (a heterogeneous catalyst) catalyzed synthesis of 1-
benzyl-2-phenyl-1H-benzo[d]imidazolesis reported. In this
reaction, 2-phenyl-1H-benzo[d]imidazoles are found to be the side
products. Reported protocol is simple, highly efficient, tolerates
wide variety of substrates and products were formed in good to
excellent yield.
N,N´-diphenyl formamidine,16 coupling
reaction between N-benzyl-2-iodoaniline and benzamide,17 reaction
of 2-nitroaniline with benzyl bromide and aldehyde18 and
acceptorless dehydrogenative coupling of tertiary amines and
arylamines.19 But, all these reported methods suffer from various
drawbacks, such as the use of harsh reaction conditions, low
substrate scope, lower yields and longer reaction times. Based on
these reports, we started working towards the synthesis of 1,2-
disubsituted benzimidazoles by using bimetallic Cu-Mn catalyst
available with us. Cu-Mn B catalyst is prepared by using literature
reported method.20 This catalyst has been used in various organic
transformations which involves Chan-Lam type of coupling reaction
for C-N bond formation,21 Husigen cyclo addition reaction,20
regioselective halogenations of phenols and N-heterocycles,22
synthesis of imidazopyridine scaffold,23 synthesis of amides24 and in
nitrogen insertion reaction for the synthesis of quinazolinones.25
Inspired from previous literature reports and our ongoing interest
for the synthesis of N-heterocycles,24, 25 we started working towards
exploring catalytic application of Cu-Mn spinel oxide for the
synthesis of N-heterocycles.
The 1,2-disubstituted benzimidazoles are privileged
scaffold present in various natural and medicinally important
compounds. This type of scaffold is also present in various
types of marketed drugs as well.1-4 These are one of the most
important N-heterocycles in terms of drug discovery
perspective.5-7 The therapeutic application of these compounds
are reported in hypertension,8 obesity,9 HIV,7 HSV-110 and
influenza.11 Thus, the development of efficient methods for
the synthesis of 1,2-disubstituted benzimidazole scaffold is of
utmost importance in organic synthesis.
Figure 2. Cu-Mn B catalyzed synthesis of 1-benzyl-2-phenyl-1H-
benzo[d]imidazole and 2-phenyl-1H-benzo[d]imidazole.
Figure 1. Previous methods and our approach.
Initial attempt was to utilize Cu-Mn B catalyst for the synthesis
of 1-benzyl-2-phenyl-1H-benzo[d]imidazole. After getting insight
from literature for the synthesis of 1-benzyl-2-phenyl-1H-
benzo[d]imidazole, it was found suitable to utilize o-
Phenylenediamine and benzyl bromide as starting material. Firstly,
model reaction was conducted using Cu-Mn B as catalyst, in the
presence of ligand L-proline, DMSO and K2CO3 under reflux
conditions for 12 h, but we were able to isolate desired product in
25 % yield with the formation of 2-phenyl-1H-benzo[d]imidazole 4a
as well in 40 % yield. Further reaction was conducted without using
Various methods were reported in literature for the synthesis of
but only a few methods were reported
for the synthesis of 1,2-disubstituted benzimidazoles, these include
12-14
benzimidazole scaffold,
a.Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research. S.A.S Nagar-Mohali-160062
# These authors contributed equally
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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ligand. To our surprise, the desired product 3a was formed in 68 %
yield and 2-phenyl-1H-benzo[d]imidazole 4a was formed in 20 %.
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DOI: 10.1039/C8NJ05504A
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Table 1. Solvent and catalyst optimization studiesa
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Entry
1.
2.
Catalyst(% (w/w)
CuCl2(10)
CuCl2 (10)
CuO (10)
Cu(OAc)2(10)
Cu-Mn B (10)
Cu-Mn B (20)
Cu-Mn B (10)
CuO (10)
Temp. (ºC) Base(equiv)
Time (h) Solvent
Ligand(equiv) %Yielda(3a/4a)
110
110
110
110
110
110
110
110
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K3PO4 (3)
12
12
12
12
12
12
12
12
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
None
0
L-proline (20)
None
None
None
None
0
3.
Trace
(15:40)
(68:20)
66:18
(25:40)
trace
4.
5.b
6
7.
8.
L-proline (20)
None
9.
110
110
110
110
90
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
12
12
12
12
12
12
DMSO
DMSO
Toluene
DMSO
Water
DMF
None
None
None
None
None
None
Cu(OTf)2
0
10.c
11.c
12.d
13
Cu-Mn B (10)
Cu-Mn B (10)
Cu-Mn B (10)
Cu-Mn B (10)
Cu-Mn B (10)
50:10
0:50
50:50
0:10
14.
110
10:40
Reagents and conditions: o-phenylenediamine 1a (1 equiv.), benzyl bromide 2a (2 equiv.), Cu-Mn B (10% w/w), K2CO3 (2.5 equiv.), DMSO
(3mL); aisolated yield; boptimized reaction condition; c under N2 atmosphere; d under O2 atmosphere
The separation of the two products in column chromatography
has been found to be easy because of their distinguishable Rf
Apart from that, strong electron withdrawing group, such as 5-
values. In this reaction selectivity for 3a was achieved by 77 %. nitro OPD (Figure 3 entry, 3h and 3i) was also tried in this reaction.
Further screening of the catalytic reaction was done by using The reaction works well with all types of substituted OPDs giving
various solvents such as toluene, DMF and water but none of them corresponding product in good yields. In case of electron
found to be efficient for this transformation. We also tried Cu (I) withdrawing groups in OPDs (Figure 3 entry 3h, 3i, 3j, 3k and 3p ),
and Cu (II) catalyst for this transformation but none of them found yields are lesser in comparison in electron donating groups (Figure 4
suitable. Cu-Mn B was found to be suitable catalyst for this entry 3l, 3m and 3n).
transformation. This might be due to distinct Cu-Mn B phase as
Benzyl bromide bearing substituents in meta position (Figure 3,
shown in previous literature reports based on PXRD.24 Also, in case entry 3c, 3f and 3i) gave slightly lower yield in comparison to para
of Cu-Mn B, as revealed in XPS analysis, these metals exit in substituents (Figure 3, entry 3b, 3d, 3e, 3g, 3k, 3n and 3o). Also, in
multiple oxidation states (Cu+2, Mn+2, Mn+3 and Mn+4) in bimetallic case of OPD bearing disubstituted 4,5-dichlorobenzene-1,2-diamine
Cu-Mn catalyst. Having optimized reaction conditions in hand, next (Figure 3 entry 3p) reaction works well giving corresponding
we tried to explore substrate scope of reaction for various product in good yield. No particular electronic effect was seen in
substituted benzyl bromides, reaction works well with all the synthesis of 2-aryl benzimidazole.
substituted benzyl bromides bearing electron withdrawing (Figure 3
entry, 3d, 3e and 3f) as well as electron donating group (Figure 3
entry, 3b, 3c and 3g)
Yields in case of electron withdrawing groups (Figure 3 entry 3d,
3e and 3f) in benzyl bromides are slightly higher in comparison to
electron donating groups (Figure 3 entry, 3b, 3c and 3g). Also, we
tried various substituted OPDs (o-Phenylenediamine) bearing
electron withdrawing (Figure 3 entry 3h, 3i, 3j, 3k and 3p ) and
electron donating groups (Figure 3 entry 3l, 3m and 3n) as well as
di- substituted OPDs (Figure 3 entry 3o and 3p).
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Reagents and conditions: OPD 1a (1 equiv.), benzyl bromide 2a (2 equiv.), Cu-Mn B (10 %w/w), K2CO3 (3 equiv.), DMSO (3 mL), 110 C, 12 h
Figure 3. Substrate scope of reaction by using substituted OPD and benzyl bromides.
A plausible mechanism of reaction can be proposed (Figure 4), 4a along a similar pathway. Formation of compound 3a from the
which involves initial Ullmann type of coupling between OPD and preformed 4a is also possible in the same catalytic condition as
benzyl bromide leading to the formation of the doubly N-alkylated evidenced by the control experiment.
intermediate I. Oxidation of benzylic carbon in intermediate I leads
to the generation of iminic intermediate II. Subsequently,
cyclization happens due to the nucleophilic attack of benzylic
nitrogen at the iminic carbon centre, leading to the formation of
intermediate III. Additional oxidation step leads to the formation of
final product 3a. Mono substituted benzimidazole, intermediate IV
also may be formed in the initial step, yielding 2-aryl benzimidazole
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Figure 4: Plausible mechanism for the generation of title compounds
Next, we tried to check the recyclability of catalyst. The catalyst
was recovered by filtration after every reaction and reused for four
successive reactions for the synthesis of 2-Aryl-N benzyl
benzimidazole 3a without loss of significant activity. The % yields
over 4 cycles were 68, 65, 60 and 55 %. The reduction in the yields
during recycling process may be attributed to the limitations in the
catalyst recovery. Further, in order to know the surface morphology
of catalyst and size of Cu-Mn B nanoparticles, Scanning electron
microscopy analysis shows that surface morphology of the catalyst
remains same before and after four cycles of reaction also size of
nanoparticles remains same.
In summary, we have developed an efficient method for the
synthesis of 1,2-disubstituted benzimidazoles using bimetallic
catalyst in one pot. Further, reaction has wide substrate scope,
various functional groups are well tolerated and catalyst can be
reused up to four cycles. The side product 2-aryl benzimidazole
also can be isolated, though in small yields.
(a)
Acknowledgements
The authors thank Mrs. Parveen Sharma from CSIR-IIIM, Jammu
for technical support. RS thanks to DST-SERB, New Delhi for the
award of Postdoctoral research fellowship (file no.
PDF/2017/000232).
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