A convenient synthesis of 4(5)-(hetero)aryl-1H-imidazoles via microwave-assisted Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2014.09.104

A simple and rapid access to a variety of 4(5)-arylated imidazoles via palladium-catalyzed Suzuki-Miyaura cross-coupling reaction is described. Coupling parameters were screened for efficient C-4 arylation of N-unprotected 4-iodoimidazole with a broad range of boronic acids under microwave irradiation. Twenty-one imidazole derivatives were synthesized in modest to excellent yields in short reaction times.

Full text of DOI:10.1016/j.tetlet.2014.09.104

Tetrahedron Letters 55 (2014) 6347–6350
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convenient synthesis of 4(5)-(hetero)aryl-1H-imidazoles via
microwave-assisted Suzuki–Miyaura cross-coupling reaction
⇑
Sophie Vichier-Guerre, Laurence Dugué, Sylvie Pochet
Unité de Chimie et Biocatalyse, Institut Pasteur, CNRS, UMR3523, 28 rue du Docteur Roux, 75724 Paris Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 July 2014
Revised 19 September 2014
Accepted 23 September 2014
Available online 28 September 2014
A simple and rapid access to a variety of 4(5)-arylated imidazoles via palladium-catalyzed Suzuki–Miya-
ura cross-coupling reaction is described. Coupling parameters were screened for efficient C-4 arylation of
N-unprotected 4-iodoimidazole with a broad range of boronic acids under microwave irradiation.
Twenty-one imidazole derivatives were synthesized in modest to excellent yields in short reaction times.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
4(5)-Arylimidazoles
C-arylation
Microwave assisted synthesis
Suzuki–Miyaura cross-coupling
Boronic acids
The imidazole ring is a privileged motif present in a wide range of
natural products and bioactive molecules. Therefore, this versatile
scaffold has been largely exploited in medicinal chemistry affording
many highly-substituted imidazoles with a broad spectrum of bio-
logical properties, including antifungal, antibacterial and antimalar-
ial agents.1 They are known as potent inhibitors of p38 MAP kinase,2
selective COX-2 inhibitors3 or ALK5 inhibitors.4 4(5)-Aryl-1H-imi-
dazoles have also attracted great interest over the past decades.
These compounds act as powerful reversible inhibitors of b-glucosi-
dase5 potent receptor antagonists6 or inhibitors of indoleamine 2,3-
dioxygenase.7 4-Arylimidazoles can also be regarded as modified
purines in which the imidazole and pyrimidine rings are separated
by a single carbon–carbon bond.8 The inherent flexibility of these
nucleobase mimics provides original ‘dimensional’ probes of
enzyme–coenzyme binding-sites with promising enzymatic and
biological activities. The potential of these flexible nucleobases, such
as the hydrogen bonding capacities of the corresponding nucleo-
sides for DNA or protein recognition9 and their biological proper-
ties10 has recently been illustrated.
Scheme 1. Preparation of target 4(5)-(hetero)aryl-1H-imidazoles (3).
the imidazole ring via cyclo-condensation reactions.12 Despite
being improved using microwave technology,13 these de novo
methods suffer from several drawbacks as the modest yield of
multi-step reaction sequences, the reagent availability, and limited
substrate scope. These are not well adapted to the generation of
libraries of 4-arylimidazoles.14 The other route involves the regio-
selective C-arylation of imidazole. While efficient conditions for
metal-mediated direct C-2 arylation have been developed, to our
knowledge, there is only one report that described direct C-4 ary-
lation of free (NH)-imidazole with a pyrazolo-pyrimidine chloride
via an AlCl3-induced C–C bond forming reaction.15 On the opposite,
As part of our program to develop original small-molecules as
chemical probes, we searched for a rapid and efficient synthetic
access to a wide range of 4(5)-arylated imidazoles. Several syn-
thetic routes to C-arylimidazole derivatives have been reported
in the literature.11 The most general approach, in particular for
the highly substituted imidazoles, consists in the building-up of
⇑
Corresponding author. Tel.: +33 1 4061 3805; fax: +33 1 4568 8404.
E-mail address: spochet@pasteur.fr (S. Pochet).
http://dx.doi.org/10.1016/j.tetlet.2014.09.104
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6348
S. Vichier-Guerre et al. / Tetrahedron Letters 55 (2014) 6347–6350
Table 1
Synthesis of 4(5)-(hetero)aryl-1H-imidazoles (3a–3u)
Entry
Boronic acid
Conditionsa temperature/time
Product
Isolated yield (%)
90
2a
1
A, 110 °C, 2 h
3a
B(OH)2
H3CO
2b
B(OH)2
2
3
4
A, 110 °C, 2 h
A, 120 °C, 1 h
A, 120 °C, 1 h
3b
3c
3d
82
62
53
2c
B(OH)2
2d
B(OH)2
2e
5
6
A, 110 °C, 2 h
A, 120 °C, 1 h
3e
3f
80
46
H3C
HO
B(OH)2
2f
B(OH)2
C2H5O
Br
2g
B(OH)2
7
8
9
A, 120 °C, 1 h
A, 110 °C, 2 h
A, 110 °C, 1 h
3g
3h
3i
67
57b
91
2h
B(OH)2
F
F
2i
B(OH)2
NC
2j
A, 110 °C, 1 h
B, 110 °C, 1 h
0
30
10
11
12
3j
B(OH)2
2k
B(OH)2
A, 110 °C, 2 h
A, 110 °C, 2 h
3k
3l
67
88
O
2l
B(OH)2
O
H3C
2m
B(OH)2
13
14
15
A, 120 °C, 2 h
A, 110 °C, 1 h
A, 110 °C, 2 h
3m
3n
3o
61
67
70
OHC
S
2n
B(OH)2
S
2o
B(OH)2
O
N
2p
A, 110 °C, 2 h
B, 110 °C, 1 h
0
41
16
17
3p
3q
B(OH)2
N
A, 110 °C, 2 h
B, 110 °C, 2 h
0
52
2q
B(OH)2
N
A, 110 °C, 2 h
B, 110 °C, 1 h
0
35
18
19
2r
B(OH)2
3r
3s
H2N
N
2s
B(OH)2
B,110 °C, 2 h
B, 110 °C, 1 h
71
95
N
tBuO
N
2t
B(OH)2
N
20
3t
OtBu
2u
B(OH)2
21
B, 120 °C, 2 h
3u
64
CHO
a
Reagents and conditions: Method A: 1a (1 mmol), boronic acid 2 (2 mmol), CsF (3 mmol), PdCl2(dppf) (0.05 mmol), BnEt3NCl (0.05 mmol), toluene/H2O (1/1, 14 mL/
mmol); Method B: 1a (1 mmol), boronic acid 2 (1.6 mmol), Pd(PPh3)4 (0.08 mmol), DMF/1 M Na2CO3 (5 mL/mmol).
b
3 equiv of 2h has been used with fractional addition.

S. Vichier-Guerre et al. / Tetrahedron Letters 55 (2014) 6347–6350
6349
numerous conditions have been reported for Pd-catalyzed direct
Table 2
Screening of coupling parameters using 4-pyridinyl-boronic acid (2p)a
arylation of N-substituted imidazoles with aryl bromides. Thus,
the introduction of benzyl16 or SEM14 protecting group at N1 posi-
tion allowed the regioselective C-5 arylation with aryl bromides.
The addition of stoichiometric or excess copper(I) salt to the cata-
lytic system, even without ligand or base, was found to change the
site selectivity affording 2-arylated imidazole in good yield.17
These authors have reported occasionally difficult N-debenzylation
into 4(5)-aryl-1H-imidazoles.
Alternatively, 4-arylimidazoles can be conveniently prepared via
Suzuki–Miyaura cross-coupling reaction.18 Bellina et al.17 have
reported a one-step procedure for the preparation of 4(5)-aryl-1H-
imidazoles by PdCl2(dppf)-catalyzed Suzuki–Miyaura reaction
between 4-bromo-1H-imidazole and arylboronic acids under
phase-transfer conditions. However long reaction times are gener-
ally required (up to 48 h) and phenylboronic acids bearing sensitive
groups (such as an aldehyde) were not coupled by this method. To
circumvent this difficulty, Rault and co-workers19 have described
the use of 4(5)-imidazolylboronic acid derivatives in Suzuki–Miya-
ura cross-coupling reactions with different (hetero)aryl halides.
Nevertheless, this reverse methodology required supplementary
steps (THP-protection-deprotection sequence of the imidazole NH
function) and the desired 4(5)-aryl-1H-imidazole derivatives are
obtained in moderate yields (20–59% after reaction-deprotection
sequence).
Catalyst
Base
Solvent
Heating
Yield
PdCl2(dppf)
PdCl2(dppf)
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
CsF/BnEt3Cl
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
CsF/CuI
Toluene/H2O
DME/H2O
DME/EtOH
Toluene /EtOH
Toluene /EtOH
Toluene/EtOH
Toluene/H2O
DMF/H2O
110 °C/5 h
110 °C/0.5 h
90 °C*/2 h
110 °C/7 h
80 °C*/12 h
110 °C/5 h
110 °C/5 h
110 °C/1 h
110 °C/2 h
Trace
nd
4%
nd
nd
nd
trace
41%
nd
DMF/H2O
nd: no coupling product was detected.
a
Reaction conditions: from 1a (1 mmol), see Supplementary data.
Oil bath.
*
Good results were also obtained with 2-(benzo)furanyl and
2-(benzo)thienyl derivatives (2k–2n), as well as with the more hin-
dered 4-(dibenzofuranyl)boronic acid (2o) (Table 1, entry 15), and
the coupling products 3k–3o were isolated in yields ranging from
61% to 88% (entries 11–15). However, in the case of heteroarylboron-
ic acids containing nitrogen such as pyridine, pyrimidine and iso-
quinoline derivatives 2p–2r, no reaction or only traces of products
were detected under the conditions used. Cross-coupling reactions
involving pyridinyl and pyrimidinylboronic acids are notoriously
challenging, as these derivatives are prone to deborylation.23 Taking
4-pyridinylboronic acid (2p) as a model substrate, we evaluated the
effect of different parameters, such as the catalyst, the base and the
solvent, on the coupling yield with iodide 1a (see Supporting infor-
mation for detailed description). Table 2 summarizes the results
obtained following established procedures for Suzuki–Miyaura
reactions involving coupling partners bearing nitrogen.21b,23a,24
Remarkably, the use of Pd(PPh3)4 as catalyst and Na2CO3 as the
base in a mixture of DMF/H2O at 110 °C under microwave irradia-
tion were the best conditions, affording the coupling product 3p in
41% yield. The use of CuI in combination with CsF has been
reported to improve coupling reaction of pyridinylboronic acids.24
However, in our hands no coupling product was detected by LC/
MS.
The best conditions were then applied to other boronic acids
bearing nitrogen (2q–2t) affording in a short reaction time the
desired products 3q–3t in moderate to excellent yields (35–95%).
Interestingly, reaction of 1a with 2-formylphenylboronic acid
(2u) gave compound 3u in good yield (Table 1, entry 21), while
the phase-transfer catalysis conditions did not produce the desired
compounds.17 Similar beneficial effect was observed using 4-cya-
nophenylboronic acid (2j), compound 3j was successfully isolated
(30% yield), while no reaction occurred under previous catalytic
conditions (Table 1, entry 10).
In this context, we were interested in developing a rapid and
efficient synthetic access to a wide range of 4-arylated imidazoles.
To date,20 there are limited examples of 4(5)-heteroarylation of
free (NH)-imidazole21 and to the best of our knowledge, only one
report on microwave-assisted synthesis of C-aryl-imidazoles via
Suzuki–Miyaura cross-coupling reaction.22
Herein we report a one step procedure for the selective Pd-cat-
alyzed C-4 arylation of free (NH)-imidazole with aryl- and hetero-
aryl-boronic acids under microwave conditions (Scheme 1).
Initially we attempted the microwave-assisted Suzuki–Miyaura
cross-coupling reaction between commercially available 4-iodo or
4-bromo-1H-imidazole (1a and 1b, respectively) and 2-naph-
thylboronic acid (2a) under the phase-transfer catalysis conditions
reported by Bellina and co-workers.17 Thus, imidazole halide 1 was
reacted with 2 equiv of 2a in the presence of 2 equiv of CsF, 5 mol %
of PdCl2(dppf) and 5 mol % of BnEt3NCl in a 1/1 mixture of toluene/
water under microwave irradiation at a ceiling temperature of
110 °C. Under these conditions, a total conversion of bromide 1b
was observed after 2 h (monitored by TLC and LC–MS) and the
expected compound 3a was isolated in 90% yield (data not shown)
as compared to 92% of yield after 72 h under classical thermal con-
ditions.17 Iodide 1a was also effective for C-arylation providing
compound 3a in similar yield and short reaction time (Table 1,
entry 1). A similar reactivity of iodide 1a with 3-methoxy-2-naph-
thylboronic acid (2b) was observed, and the coupling product 3b
was isolated in excellent yield (Table 1, entry 2). Also, iodide 1a
was selected as a convenient partner for coupling reactions under
microwave irradiation.
We then explored the scope and limitations of this method with
a range of commercially available boronic acids, including arenes
and heteroarenes presenting different electronic/steric effects and
substitution patterns (functional motifs). As shown in Table 1, the
coupling of iodide 1a with phenylboronic acids substituted in meta
or para position with electron-donating or withdrawing groups pro-
ceeded well within 1 or 2 h affording the coupling products 3c–3i in
yields ranging from 46% to 91% (entries 3–9). It is noteworthy that
coupling of the electron-deficient 2,4-difluorophenylboronic acid
(2i) afforded 3i in excellent yield, while in the case of the strong
electron-withdrawing 4-cyano substituent (2j), no coupling
product was detected, even after prolonged reaction time or higher
temperature (Table 1, entry 10).
The chemical structures of all synthesized compounds were
confirmed by 1H and 13C NMR spectra and mass spectroscopy.
The purity of compounds was checked by analytical HPLC and
found to be >95%.
In conclusion, we have developed and optimized conditions for
Suzuki–Miyaura cross-coupling of 4-iodo-1H-imidazole with a
variety of aryl- and heteroaryl-boronic acids. As anticipated, the
use of microwave irradiation considerably shortened the reaction
times in comparison with conventional heating conditions. More
interestingly, this one-step procedure gave similar or superior
yields of compounds for those previously described. Moreover a
broad range of substrates, including nitrogen-containing heterocy-
cles, sterically hindered or bearing sensitive functional groups (as
aldehyde), was successfully coupled providing the desired prod-
ucts in modest to excellent yields. These original 4-substituted imi-
dazoles constitute valuable starting points for further chemical
diversification into biological tools or as potential therapeutic
agents.

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10. (a) Seley, K. L.; Quirk, S.; Salim, S.; Zhang, L.; Hagos, A. Bioorg. Med. Chem. Lett.
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This work was financially supported by the Direction des Appli-
cations de la Recherche et des Relations Industrielles (DARRI no.
08-183), Institut Pasteur and CNRS. The authors would like to
thank Céline Taglang and Laura Lanoë for technical assistance.
11. Bellina, F.; Cauteruccio, S.; Rossi, R. Tetrahedron 2007, 63, 4571–4624.
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Supplementary data
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Supplementary data (synthetic procedures and NMR spectra for
all compounds) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.104.
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