Highly selective synthesis of 4(5)-aryl-, 2,4(5)-diaryl-, and 4,5-diaryl-1H-imidazoles via Pd-catalyzed direct C-5 arylation of 1-benzyl-1H-imidazole

Article abstract of DOI:10.1016/j.tet.2008.01.051

Highly selective, practical, and efficient protocols for the preparation of 4(5)-aryl-1H-imidazoles 2, 2,4(5)-diaryl-1H-imidazoles 3, and 4,5-diaryl-1H-imidazoles 1 are described. A key step of these protocols is the regioselective synthesis of 5-aryl-1-benzyl-1H-imidazoles 9 by Pd-catalyzed direct C-5 arylation of commercially available 1-benzyl-1H-imidazole (8) with aryl halides. The three-step synthesis of compounds 3 from 8 also involves the Pd-catalyzed and Cu-mediated direct C-2 arylation of imidazoles 9 with aryl halides under base-free and ligandless conditions. On the other hand, the four-step synthesis of imidazoles 1 from 8 also involves the regioselective bromination of compounds 9 and a Suzuki reaction of the resulting 5-aryl-1-benzyl-4-bromo-1H-imidazoles 11 with arylboronic acids 5 under phase-transfer conditions, followed by N-debenzylation.

Full text of DOI:10.1016/j.tet.2008.01.051

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 6060e6072
www.elsevier.com/locate/tet
Highly selective synthesis of 4(5)-aryl-, 2,4(5)-diaryl-,
and 4,5-diaryl-1H-imidazoles via Pd-catalyzed direct
C-5 arylation of 1-benzyl-1H-imidazole
*
Fabio Bellina , Silvia Cauteruccio, Annarita Di Fiore, Chiara Marchetti, Renzo Rossi
*
Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
Received 27 August 2007; received in revised form 15 October 2007; accepted 17 October 2007
Available online 16 January 2008
Abstract
Highly selective, practical, and efficient protocols for the preparation of 4(5)-aryl-1H-imidazoles 2, 2,4(5)-diaryl-1H-imidazoles 3, and 4,5-
diaryl-1H-imidazoles 1 are described. A key step of these protocols is the regioselective synthesis of 5-aryl-1-benzyl-1H-imidazoles 9 by
Pd-catalyzed direct C-5 arylation of commercially available 1-benzyl-1H-imidazole (8) with aryl halides. The three-step synthesis of compounds
3 from 8 also involves the Pd-catalyzed and Cu-mediated direct C-2 arylation of imidazoles 9 with aryl halides under base-free and ligandless
conditions. On the other hand, the four-step synthesis of imidazoles 1 from 8 also involves the regioselective bromination of compounds 9 and
a Suzuki reaction of the resulting 5-aryl-1-benzyl-4-bromo-1H-imidazoles 11 with arylboronic acids 5 under phase-transfer conditions, followed
by N-debenzylation.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Imidazoles; Direct arylation; Regioselectivity; CeH bond activation; Biologically active compounds
1. Introduction
B-Raf,8 5(4)-aryl-4(5)-(3,4,5-trimethoxyphenyl)- and 5-aryl-
1-methyl-4-(3,4,5-trimethoxyphenyl)-1H-imidazoles have
Mono- and di-C-aryl substituted imidazoles are important
compounds because of their significant pharmacological and
biological activities. Monosubstituted 4(5)-aryl-1H-imidazoles,
for example, include compounds with good in vitro antifungal
activity,1 potent inhibitors of b-glucosidase,2 and substances
which exhibit activin receptor like kinase 5 (ALK5) inhibitory
activity,3 and several 4(5)-aryl-2-heteroaryl-1H-imidazoles
have been shown to possess antiinflammatory properties4 as
well as NPY5 receptor antagonist activity.5 On the other hand,
2-alkyl-4(5)-aryl-1H-imidazoles are of interest as potent Naþ
channel blockers6 and several 5(4)-aryl-4(5)-(4-fluorophenyl)-
1H-imidazoles are p38 MAP kinase inhibitors.7 Moreover,
2-tert-butyl-4(5)-(4-fluorophenyl)-5(4)-(4-pyridyl)-1H-imid-
azole has been identified as a submicromolar inhibitor of
been shown to be potent cytotoxic agents able to mimic the ac-
tivity of combretastatin A-4 against the polymerization of tubu-
lin,9 and 2-substituted 4,5-diaryl-1H-imidazoles have been
identified as COX-2 inhibitors10 and as human CB1 receptor in-
verse agonists.11
In light of this significance, mild and efficient methods for
the synthesis of C-aryl substituted imidazoles have been devel-
oped and a variety of synthetic procedures have been particu-
larly devised for the synthesis of 4,5-diaryl-1H-imidazoles 1.12
However, despite the progress, the state-of-the-art for the
synthesis of these compounds remains less than ideal.
Ar2
N
N
N
Ar2
N
H
N
H
N
H
Ar1
Ar1
Ar1
1
2
3
* Corresponding authors. Tel.: þ39 050 2219282; fax: þ39 050 2219260
(F.B.); tel.: þ39 050 2219214; fax: þ39 050 2219260 (R.R.).
E-mail addresses: bellina@dcci.unipi.it (F. Bellina), rossi@dcci.unipi.it
(R. Rossi).
On the other hand, relatively few methods for the synthesis
of 4(5)-aryl-1H-imidazoles 2 and 2,4(5)-diaryl-1H-imidazoles
3 have been reported in the literature and these synthetic
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.051

F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
6061
Ar2
Ar1
protocols suffer from providing modest yields, requiring un-
N
N
Ar2
available and/or expensive reagents and/or affording signifi-
cant amounts of byproducts.13,14 Thus, we thought it right to
develop concise and effective novel approaches for the prepa-
ration of imidazoles 2 and 3, and in the context of our studies
on the synthesis of arylazole derivatives via highly selective
transition metal-catalyzed reactions,15 we discovered that aryl-
imidazoles 2 can be efficiently and selectively prepared by
PdCl2(dppf)-catalyzed SuzukieMiyaura reaction of cheap
and commercially available 4(5)-bromo-1H-imidazole (4)16
with arylboronic acids 5 under phase-transfer conditions
(Scheme 1).16 We also established that N-unprotected com-
pounds 2 are able to undergo highly selective Pd(OAc)2-cata-
lyzed and CuI-mediated direct C-2 arylation with a variety of
activated and inactivated aryl iodides 6 and bromides 7 under
base-free and ligandless conditions to produce 2,4(5)diaryl-
1H-imidazoles 3 in modest to good yields.16
Ar1
N
H
N
H
3
1
Ar2
Ar1
N
N
Bn
12
N
N
Bn
10
Ar2
N
Ar1
Ar1
N
H
2
Br
N
N
N
N
N
Ar1
Ar1
N
Bn
Bn
Bn
8
11
9
Scheme 2.
introduction, several attempts to synthesize these compounds
by direct Pd-catalyzed arylation of free (NH)-imidazole with
aryl iodides proved to be unsuccessful. We then speculated
that, alternatively to the procedure illustrated in Scheme 1,
compounds 2 might be conveniently synthesized by the strat-
egy, outlined in the retrosynthetic analysis shown in Scheme 2,
which involves the direct C-5 arylation of the N-protected
imidazole 8 with aryl halides 6 or 7, followed by deprotection
of the resulting 5-aryl-1-benzyl-1H-imidazoles 9 (Scheme 3).
Ar2I (6) or Ar2Br (7)
Ar1B(OH)2 (5)
Br
N
N
N
Pd(OAc)2, CuI
Ar2
PdCl2(dppf), CsF
DMF, 140 °C (for 6)
DMA, 160 °C (for 7)
(30 - 78 %)
Ar1
N
H
Ar1
N
H
N
H
BnEt3NCl (cat)
MePh / H2O, reflux
(62 – 91 %)
3
4
2
Scheme 1.
In our continuing studies of the Pd-catalyzed intermolecular
direct arylation reactions of heteroarenes with aryl halides17
and their synthetic applications,15aed,f,16 we also turned our at-
tention to the preparation of imidazoles 1 and 3 by approaches
based on the synthesis of 4(5)-aryl-1H-imidazoles 2 via Pd-
catalyzed direct C-5 arylation of free (NH)-imidazole with
aryl iodides, but, to our disappointment, no expected arylation
product was obtained from this reaction using a variety of ex-
perimental conditions.18 However, we were able to develop
novel and convenient approaches to the highly selective synthe-
sis of imidazoles 1e3 in which the key step was the preparation
of 5-aryl-1-benzyl-1H-imidazoles 9 by highly selective Pd-cat-
alyzed direct C-5 arylation of commercially available 1-benzyl-
1H-imidazole (8) with a variety of activated and deactivated
aryl iodides and bromides. The approach to compounds 3 also
involved the Pd-catalyzed and Cu-mediated direct C-2 arylation
of imidazoles 9 with aryl iodides 6 or aryl bromides 7 under
base-free and ligandless conditions. Herein, we describe the
results of these synthetic studies. Scheme 2 outlines the retro-
synthetic sequences for the preparation of compounds 1e3. It
is worth mentioning that the results of the synthesis of diaryl-
imidazoles 3 from 8 proved to be competitive with those of
the two-step procedure summarized in Scheme 1 in which
4(5)-bromoimidazole 4 was used as the starting material.
N
N
N
Bn
9
N
N
N-debenzylation
Pd(OAc)2, ligand
base, solvent, Δ
Ar1-X
+
Ar1
N
H
Ar1
Bn
8
6: X = I
2
7: X = Br
Scheme 3.
No reports on the direct C-5 arylation of 8 have been
reported to date. Thus, at the onset of this study we investi-
gated the Pd-catalyzed arylation of this imidazole derivative
with two typical unactivated aryl halides, 4-anisyl iodide
(6a) and 4-anisyl bromide (7a). In particular, we evaluated
the effect of a number of parameters such as the nature of
the halogen of the aryl halide, the base and solvent on the
chemical yield, and the selective formation of the required
C-5 arylated imidazole 9a. In fact, two possible regioisomers,
i.e., the C-2 and C-4 arylated derivatives 13a and 14a, respec-
tively, might also be obtained.
Ar1
N
N
N
N
Ar1
Bn
Bn
13a : Ar1 = 4-MeOC6H4
14a : Ar1 = 4-MeOC6H4
2. Results and discussion
As regards the ligand to be employed in this reaction, we
thought it right to use tris(2-furylphosphine) since in a recent
study involving the Pd-catalyzed C-5 arylation of 1-methyl-
1H-imidazole with aryl halides,19 we found that its use allows
the preparation of 5-aryl-1-methyl-1H-imidazoles not contam-
inated by byproducts derived from arylearyl scrambling
2.1. Synthesis of 4(5)-aryl-1H-imidazoles
Our first goal was the efficient and selective preparation of
4(5)-aryl-1H-imidazoles 2. However, as mentioned in the

6062
F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
Table 1
Screening of the reaction conditions for the selective C-5 arylation of 8 with
aryl halides 6a and 7a
Compound 15a was presumably derived from a Pd-cata-
lyzed Ullmann-type reductive coupling of 6a21 and imidazole
10a was very likely derived from Pd-catalyzed C-2 arylation
of 9a. Unsatisfactory chemical yields and a lower C-5 selectiv-
ity were also observed when the base (entries 2 and 3, Table 1)
and solvent (entries 4 and 5, Table 1) were changed. Moreover,
no reaction was observed when 8 was reacted with 6a in tolu-
ene in the presence of K2CO3 or CsOAc as the base (entries 6
and 7, respectively, Table 1). However, pleasingly, we found
that the reaction of 8 with 2 equiv of bromide 7a in DMF at
140 ꢀC in the presence of 2 equiv of K2CO3 occurred in a satis-
factory yield and with complete C-5 selectivity (entry 8, Table
1).23 Interestingly, the crude reaction mixture proved to contain
only the expected imidazole 9a along with ca. 20% of 10a and
a small amount of biphenyl 15a. By contrast, the use of toluene
as the solvent resulted in a diminished yield and 93% C-5
selectivity (entry 11, Table 1), and unsatisfactory results were
also obtained when 8 was reacted with 7a in DMF in the pres-
ence of Cs2CO3 (entry 9, Table 1) as well as when the reaction
of 8 with 7a was performed in dry DMF or toluene in the pres-
ence of KF (entries 10 and 12, respectively, Table 1).
Having successfully demonstrated the viability of the
Pd(OAc)2/P(2-furyl)3-catalyzed C-5 arylation of 8 with the de-
activated aryl bromide 7a in DMF in the presence of K2CO3 as
the base, we then applied the reaction conditions of entry 8 of
Table 1 to the synthesis of a number of 5-aryl-1-benzyl-1H-
imidazoles 9 from 8 and electron-neutral and electron-deficient
aryl bromides 7 (Table 2). We found that these arylations
showed good to excellent regioselectivity, and occurred in sat-
isfactory to good yields. A satisfactory yield of the required
4(5)-aryl-1H-imidazole was also obtained in the Pd-catalyzed
reaction of 8 with strongly deactivated bromide 7g (entry 7,
Table 2). We supposed that, analogously to the Pd-catalyzed
direct arylations of 1-aryl-1H-imidazoles (Ref. 15a) and
N
N
Pd(OAc)2
+
4-MeOC6H4-X
P(2-furyl)3
base, solvent
48 h, Δ
Ar1
N
N
Bn
9a : Ar1 = 4-MeOC6H4
Bn
6a : X = I
8
7a : X = Br
Entrya
X
Base
Solvent
Yield of 9ab (%)
C5-selectivityc
1
I
CsF
DMF
DMF
DMF
40
46
40
44
37
d
d
58d
51
13
34
11
96
95
88
88
77
2
I
Cs2CO3
K2CO3
CsF
3
I
4
I
Toluene
Toluene
Toluene
Toluene
DMF
5
I
Cs2CO3
K2CO3
CsOAc
K2CO3
Cs2CO3
KF
6
I
d
7
I
d
100
85
93
93
90
8
Br
Br
Br
Br
Br
9
DMF
DMF
10
11
12
a
K2CO3
KF
Toluene
Toluene
The reactions were run for 48 h with 1 mmol of 8, 2 mmol of 6a or 7a,
5 mol % Pd(OAc)2, and 10 mol % P(2-furyl)3 in 5 mL of solvent at 140 ꢀC
(DMF) or at 110 ꢀC (toluene) in the presence of 2 equiv of a base.
b
The values are referred to GLC yields (naphthalene or biphenyl were used
as internal standards). Unless otherwise reported, the values of the conversion
were less then 90%.
c
The C-5 selectivity was expressed as the 9a/(9aþ13aþ14a) GLC molar
ratio.
d
Isolated yield. The conversion was quantitative.
reactions involving the ligand and aryl halides.20 On the other
hand, as regards the electrophiles to be employed in the aryla-
tion reactions, which we used as a test case, we thought it right
to use aryl bromide 7a in addition to aryl iodide 6a since aryl
bromides are cheaper even though less reactive than the corre-
sponding iodides in some Pd-catalyzed reactions.21 Moreover,
it has been reported that catalyst poisoning occurs in
Pd-catalyzed direct intramolecular arylation reactions with
aryl iodides due to the accumulation of iodide in the reaction
media.22
As shown in Table 1, the first experiment was run by react-
ing imidazole 8 with iodide 6a under experimental conditions
very similar to those used for the selective C-5 arylation of
1-aryl-1H-imidazoles.15a In particular, 8 was reacted with
2 equiv of 6a in DMF at 140 ꢀC for 48 h in the presence of
5 mol % Pd(OAc)2, 10 mol % P(2-furyl)3, and 2 equiv of
CsF (entry 1, Table 1). After this period of time, the observed
C-5 selectivity was 96%, but the GLC yield of 9a was only
40%. Moreover, GLC and GCeMS analyses showed that the
crude reaction mixture was contaminated by significant
amount of 4,40-dimethoxybiphenyl (15a) and 4% of the 2,5-di-
aryl-1H-imidazole 10a.15f
Table 2
Pd-catalyzed regioselective synthesis of 5-aryl-1-benzyl-1H-imidazoles 9
N
N
Pd(OAc)2, P(2-furyl)3
K2CO3, DMF, 140 °C
Ar1Br
+
Ar1
N
Bn
N
Bn
8
7
9
Entrya Ar1Br
Ar1
Reaction Product
time (h)
C5-selectivityc
7
9
Yieldb (%)
1
2
3
4
5
6
7
8
9
7a 4-MeOC6H4
7b C6H5
48
27
43
66
65
64
9a 58
9b 73
9c 72
9d 43
9e 45
9f 49
9g 60
9h 66
9i 57
100
100
100
100
99
7c 2-Naphthyl
7d 4-ClC6H4
7e 4-CF3C6H4
7f 4-MeC6H4
99
7g 3,4,5-(MeO)3C6H2 70
7h 6-MeO-2-naphthyl 88
100
100
94
7i 5-Pyrimidyl
87
a
The reactions were run with 1 mmol of 8, 2 mmol of 7, 5 mol % Pd(OAc)2,
OMe
N
and 10 mol % P(2-furyl)3 in 5 mL of DMF at 140 ꢀC in the presence of 2 equiv
of K2CO3. After the reaction times reported in the table, the reactions were
complete.
Ar2
Ar1
N
Bn
b
The values are referred to isolated yields.
The C-5 selectivity is expressed as 9/(9þ13þ14) GLC molar ratio.
MeO
10a : Ar1 = Ar2 = 4-MeOC6H4
15a
c

F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
6063
Table 3
N-Debenzylation of 5-aryl-1-benzyl-1H-imidazoles 9 by Pd-catalyzed transfer
hydrogenation
Table 4
Synthesis of 1-benzyl-2,5-diaryl-1H-imidazoles 10 by Pd-catalyzed and
Cu-mediated direct C-2 arylation of 1-benzylimidazoles 9 with aryl iodides
6 or aryl bromides 7
N
N
N
Method A or B
N
N
Pd(OAc)2, CuI
Ar2-X
Ar2
Ar1
Ar1
N
H
+
DMF, 140 °C (for 6)
or DMA, 160 °C (for 7)
Bn
Ar1
Ar1
N
Bn
N
Bn
9
2
9
6: X = I
7: X = Br
10
Entry
Substrate
Methoda
Reaction
timeb (h)
Product
9
Ar1
2
Yieldb (%)
Entrya 4(5)-Aryl-
1-benzylimidazole
Aryl halide
6 or 7 Ar2
Reaction Product
time (h)
1
2
3d
4
5
6
7
a
9a
9c
9b
9d
9b
9f
4-MeOC6H4
2-Naphthyl
C6H5
A
48
36
144
22
10
2
2a
2c
2b
2b
2b
2d
2e
97
57
Ac
Ae
A
9
Ar1
10 Yield
(%)
57
4-ClC6H4
C6H5
(93)f
99
1
2
3
4
5
6
9a 4-MeOC6H4 6b
9b C6H5 6a
9a 4-MeOC6H4 6a
C6H5
68
139
168
65
10b 56
B
4-MeOC6H4
4-MeOC6H4
2-Naphthyl
10c 88
10a 21
10d 59
10e 65
10f 21
4-MeC6H4
5-Pyrimidyl
B
97
97
9i
B
2
9b C6H5
7c
7j
Method A: 10% Pd/C, 10 equiv of HCOONH4, MeOH, reflux. Method B:
9f
9i
4-MeC6H4
4-(EtOOC)C6H4 140
4-MeC6H4 168
20% Pd(OH)2/C, 15 equiv of HCOONH4, MeOH, reflux.
b
Unless otherwise reported, the reactions were complete after the reported
5-Pyrimidyl 7f
a
The reactions were run using 1 mmol of 9 and 2 mmol of 6 in 5 mL of
DMF at 140 ꢀC or 2 mmol of 7 in 5 mL of DMA at 160 ꢀC in the presence
of 5 mol % Pd(OAc)2 and 2 equiv of CuI.
reaction times.
c
Additional 10 equiv of HCOONH4 were added after 18 h.
A 90% conversion was observed after 144 h.
Aliquots of additional 10 equiv of HCOONH4 were added after 24 and
d
e
48 h.
f
GLC yield.
performed by conversion of compounds 9 into 1-benzyl-2,5-
diaryl-1H-imidazoles 10 followed by catalytic N-debenzyla-
tion. In particular, compounds 10 were prepared by reaction
of 9 with 2 equiv of aryl halides 6 or 7 in the presence of
5 mol % Pd(OAc)2 and 2 equiv of CuI under base-free and
ligandless conditions (Table 4), using a protocol similar to
that we recently developed for the selective direct C-2 aryla-
tion of a variety of azoles.15e,f These convenient experimental
conditions allowed us to avoid the Pd-catalyzed reduction of
aryl halides, which can occur when these electrophiles are
reacted in the presence of a Pd(II) derivative and an inorganic
base in dry DMF at 120e150 ꢀC.26
As shown in Table 4, the reactions involving aryl iodides 6
were performed in DMF at 140 ꢀC, but, as expected, those
involving aryl bromides 7 required more severe reaction con-
ditions and thus were run in DMA at 160 ꢀC. Notably, a pro-
longed reaction time was required for all of these reactions,
which, nevertheless, occurred with complete C-2 selectivity.
Interestingly, the required imidazoles 10bee were obtained
in satisfactory to good yields (entries 1, 2, 4, and 5, Table 4)
but, unexpectedly, compounds 10a and 10f were both isolated
in 21% yields (entries 3 and 6, respectively, Table 4).
We next turned to the preparation of 2,4(5)-diaryl-1H-imid-
azoles 3 by N-debenzylation of 10. Table 5 summarizes the re-
sults obtained in the deprotection of compounds 10bee (entries
1e4). In particular, the clean and efficient debenzylation of 10b
and 10c was performed according to method A, i.e., by refluxing
these compounds in methanol in the presence of a catalytic
amount of 10% Pd/C and 10 equiv of ammonium formate (en-
tries 1 and 2, respectively, Table 5). In contrast, 3c was obtained
from 10e in a satisfactory yield using Pearlman’s catalyst and
ammonium formate as the hydrogen source in refluxing meth-
anol (method B) (entry 3, Table 5). This protocol, however,
proved to be unsuitable to convert 10d into 3d (entry 4, Table
5). Nevertheless, 3d, which we recently synthesized in 41%
1-methyl-1H-imidazole (Ref. 23), a mechanism involving an
electrophilic aromatic substitution has to be considered as the
most probable for the direct C-5 arylations of compound 8.
Next, we established the feasibility of N-deprotecting
compounds 9 by a procedure reported in the literature for the
efficient debenzylation of several N-benzylamine derivatives,24a
1-benzyl-2-methyl-1H-imidazole24b and 2-amino-1-(5-amino-
1-benzyl-1H-imidazol-4-yl)ethanone
bis(hydrochloride).24c
Thus, a suspension of a compound 9 and an equal weight of
10% Pd/C in methanol was treated with a large molar excess of
anhydrous ammonium formate and the mixture was refluxed
for 22e144 h. Entries 1e4 of Table 3 summarize the results
obtained in the debenzylation of 9ae9d according to this proce-
dure (method A). Compound 2a was so obtained in 97% yield
after reactionwith 10 equivof ammonium formate for 48 h (entry
1, Table 3). However, as shown in entries 2 and 3 of this table, the
N-debenzylation of 9c and 9b required the use of overall 20 and
30 equiv of ammonium formate, respectively, and in these cases
10 equiv of the hydrogen transfer reagent were added to the reac-
tion mixtures every 18e24 h.24d It is worth noting that use of
method A for the deprotection of 9d (entry 4, Table 3) occurred
with hydrodehalogenation of the CeCl bondofthis imidazole de-
rivative producing 2b as the sole reaction product in 93% GLC
yield. Notably, reaction times shorter than those of entries 1e4
characterized the N-debenzylation reactions of 9b, 9f, and 9i,
which were performed using 15 equiv of ammonium formate in
refluxing methanol in the presence of catalytic amounts of Pearl-
man’s reagent (method B)25 (entries 5, 6, and 7, Table 3).
2.2. Synthesis of 2,4(5)-diaryl-1H-imidazoles
According to the retrosynthetic analysis shown in Scheme
2, the synthesis of 2,4(5)-diaryl-1H-imidazoles
3 was

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F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
Table 5
N-Debenzylation of 1-benzyl-2,5-diaryl-1H-imidazoles 7
Table 6
Synthesis of 1-benzyl-4,5-diaryl-1H-imidazoles 12 by Pd-catalyzed Suzukie
Miyaura reaction between 4-bromoimidazoles 11 and arylboronic acids 5
N
N
Method A, B or C
Ar2
Ar2
Br
Ar2
N
N
N
N
Ar1
Ar1
N
N
H
PdCl2(dppf), Et3BnNCl
Ar2-B(OH)2
+
Bn
10
CsF, toluene / H2O, Δ
Ar1
Ar1
3
Bn
Bn
5
11
12
Entry Reagent
Methoda Reaction Product
time (h)
Entrya Reagents
Product
10 Ar1
Ar2
3
Yieldb (%)
11 Ar1
5
Ar2
12 Yield (%)
1
2
3
4
5
10b 4-MeOC6H4 C6H5
A
A
B
B
C
24
69
3
3a 86
3b 99
3c 68
3d dc
3d (80)
10c C6H5
10e 4-MeC6H4 4-(EtOOC)C6H4
4-MeOC6H4
1
2
3
4
11a 4-MeOC6H4 5b C6H5
11c 2-Naphthyl 5c 3,4,5-(MeO)3C6H2
12a 99
12b 92
10d C6H5
10d C6H5
2-Naphthyl
2-Naphthyl
70
70
11c 2-Naphthyl 5d Benzo[d][1,3]dioxol-5-yl 12c 93
11d 4-CF3C6H4 5a 4-MeOC6H4 12d 67
a
a
Method A: 10% Pd/C, 10 equiv of HCOONH4, MeOH, reflux. Method B:
20% Pd(OH)2/C, 15 equiv of HCOONH4, MeOH, reflux. Method C: 20%
Pd(OH)2/C, H2 (1 atm), MeOH, reflux.
The reactions were run using 1 mmol of 11 and 2 equiv of 5 in 14 mL of
a 1:1 mixture of toluene and water at 110 ꢀC (oil bath) for 24 h, in the presence
of 5 mol % PdCl2(dppf), 5 mol % Et3BnNCl, and 3 equiv of CsF.
b
Isolated chemical yields. The value in parenthesis is referred to a GLC
yield.
c
of the corresponding imidazoles 9aec, 9e, and 9h, respec-
tively, with a very small molar excess of NBS in MeCN at
room temperature.
Compound 10d was quantitatively recovered from the reaction mixture.
overall yield from bromide 4 according to the two-step reaction
sequence illustrated in Scheme 1,16 could be obtained in 80%
GLC yield by debenzylation of 10d with H2 at atmospheric
pressure (balloon) and Pd(OH)2/C in refluxing methanol
(method C) (entry 5, Table 5). It should also be noted that the
prolonged time of this reaction (70 h) caused the formation of
a significant amount of byproduct, which, on the basis of its
EIMS spectrum, presumably corresponded to 4(5)-dihydro-
naphthyl-2-phenyl-1H-imidazole.
The first attempts to perform the C-4 arylation of some
typical bromoimidazoles 11 involved a Suzuki-type reaction
of these bromides with 1.5 equiv of arylboronic acids 5 in
a mixture of water and DMF at 100 ꢀC in the presence of
5 mol % Pd(OAc)2, 10 mol % t-Bu3P$HBF4, and 9 equiv of
Na2CO3.7a However, the required 1-benzyl-4,5-diaryl-1H-
imidazoles 12 were obtained in low to moderate yields.7a
Moreover, the crude reaction mixtures proved to contain sig-
nificant amounts of compounds 9 derived from a reductive de-
halogenation of bromoimidazoles 11. However, we were
pleased to find that when compounds 11 were reacted with
2 equiv of 5 in a 1:1 mixture of toluene and water at 110 ꢀC
for 24 h in the presence of 5 mol % PdCl2(dppf), 5 mol %
BnEt3NCl, and 3 equiv of CsF, 1-benzyl-4,5-diarylimidazoles
12 were obtained in good to excellent yields. Table 6 summa-
rizes the results obtained in the preparation of 12aed.
Finally, cleavage of the N-benzyl protecting group of 12a
by treatment with 10% Pd/C and 10 equiv of ammonium
2.3. Synthesis of 4,5-diaryl-1H-imidazoles
The route followed to prepare 4,5-diaryl-1H-imidazoles 1
according to the retrosynthetic strategy illustrated in Scheme 2
isaconvergentfour-step sequencethatrelies ontheregioselective
synthesis of 4-bromoimidazoles 11 by bromination of com-
pounds 9 and a Pd-catalyzed SuzukieMiyaura reaction between
compounds 11 and arylboronic acids 5, followed by N-debenzyl-
ation of the resulting 1-benzyl-4,5-diaryl-1H-imidazoles 12.
It should be noted that this synthetic protocol is significantly
different from those previously reported in the literature,7a
some of which involve the preparation of compounds 1 via
multi-step sequences based on the construction of the imid-
azole ring from commercially unavailable starting reagents.27
As shown in Scheme 4, compounds 11aee were obtained
chemically and isomerically pure in 64e80% yield by reaction
Table 7
N-Debenzylation of 1-benzyl-2,5-diaryl-1H-imidazoles 12
Ar2
Ar2
N
N
N
Method A, B or C
Ar1
Ar1
N
H
Bn
12
1
Entry Reagent
Ar1
Methoda Reaction Product
time (h)
9
Ar2
1
Yield
(%)
Br
N
N
N
N
NBS (1.05 equiv)
MeCN, rt, 1 - 2 h
Ar1
Ar1
11
1
2
12a 4-MeOC6H4 C6H5
12b 2-Naphthyl 3,4,5-(MeO)3C6H2
A
3
d
1a 99
1b db
Bn
Bn
A, B
or C
9
Ar1
11 Yield (%)
9
3
4
12c 2-Naphthyl Benzo[d][1,3]dioxol-5-yl C
12d 4-CF3C6H4 4-MeOC6H4
69
66
1c 46c
1d 99
80
80
70
79
a
b
c
e
h
4-MeOC6H4
C6H5
2-naphthyl
4-CF3C6H4
a
C
b
a
Method A: 10% Pd/C, 10 equiv of HCOONH4, MeOH, reflux. Method B:
c
20% Pd(OH)2/C, 15 equiv of HCOONH4, MeOH, reflux. Method C: 20%
Pd(OH)2/C, H2 (1 atm), MeOH, reflux.
d
64
6-MeO-2-naphthyl
e
b
Compound 12b was quantitatively recovered from the reaction mixture.
The reaction occurred in 60% GLC conversion.
c
Scheme 4.

F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
6065
formate in refluxing methanol (method A) gave 4,5-diaryl-1H-
imidazole 1a in 99% yield (entry 1, Table 7).
the Pd-catalyzed and Cu-mediated C-2 arylation of 5-aryl-1-
benzyl-1H-imidazoles 9.
Unfortunately, attempts at removal of the benzyl group of
12b according to this method as well as by treatment of 12b
with 20% Pd(OH)2/C and 15 equiv of ammonium formate in
refluxing methanol (method B) or by reaction with H2
(1 atm) in the presence of 20% Pd(OH)2/C (method C) were
uniformly unsuccessful and 12b was quantitatively recovered
from the reaction mixtures (entry 2, Table 7). Nevertheless,
method C proved to be suitable to convert 12c and 12d into
the required 4,5-diaryl-1H-imidazoles, 1c and 1d, in 46 and
99% yield, respectively (entries 3 and 4, respectively, Table 7).
4. Experimental
4.1. General
Melting points are uncorrected. Merck precoated 60 F254
aluminum silica gel sheets were used for TLC analyses. GLC
analyses were performed on a Dani GC 1000 instrument with
a PTV injector, which was equipped with a Dani DDS 1000
data station. Two types of capillary columns were used: an All-
tech AT-5 bonded FSOT column (30 mꢁ0.25 mm i.d.) and an
Alltech AT-35 bonded FSOT column (30 mꢁ0.25 mm i.d.).
Purifications by MPLC on silica gel (Aldrich silica gel Merk
Grade 9385, particle size 0.040e0.063 mm) were performed
3. Conclusions
In this study, we have demonstrated that the benzyl group
of commercially available 1-benzyl-1H-imidazole (8) has
two important roles. Firstly, it allows the highly regioselective
Pd-catalyzed direct C-5 arylation of the imidazole ring of 8
with both electron-neutral and electron-poor aryl bromides.
Secondly, it can be selectively removed from 5-aryl-1-benzyl-
1H-imidazoles 9 allowing the two-step synthesis of 4(5)-
aryl-1H-imidazoles 2 from 8.16 This result is of particular
interest since all attempts to prepare compounds 2 by Pd-cata-
lyzed direct C-5 arylation of (NH)-free imidazole with aryl ha-
lides have been unsuccessful so far. This practical and
versatile method does not require the use of expensive or sen-
sitive reagents and affords overall yields comparable or not
much lower than those obtained by the one-step procedure
that involves a Suzuki-type reaction of 4(5)-bromo-1H-imid-
azole (4) with arylboronic acids 5.16 Furthermore, compounds
9 prepared from 8 as precursors to imidazoles 2 have been
shown to be useful starting materials for the regioselective
synthesis of 2,4(5)-diaryl-1H-imidazoles 3 and 4,5-diaryl-
1H-imidazoles 1. Notably, the three-step protocol developed
for the synthesis of compounds 3 from 8, which involves the
Pd-catalyzed and Cu-mediated C-2 arylation of imidazoles 9
with both aryl iodides or bromides of any electronic properties
under base-free and ligandless conditions, exhibits good func-
tional group tolerance and high regioselectivity. Moreover, its
overall yields have proven similar to those obtained by the
procedure that allows the two-step preparation of 3 via Pd-cat-
alyzed direct C-2 arylation of imidazoles 2.16 Finally, we have
developed a four-step approach for the highly regioselective
synthesis of 4,5-diarylimidazoles 1, which represents the first
effective and versatile procedure reported so far in the litera-
ture for the preparation of this biologically important class
of heterocycles in which Pd-catalyzed reactions are used as
key steps for the functionalization of the imidazole ring.7a,28
Unfortunately, this approach, which is potentially useful for
the highly regioselective synthesis of a series of imidazoles
1 bearing various substituents on their aryl rings, suffers
from the occasionally difficult N-debenzylation of 1-benzyl-
4,5-diaryl-1H-imidazoles 12 either by Pd-catalyzed transfer
hydrogenation or catalytic hydrogenolysis with H2. Studies
aimed to overcome this difficulty are in progress. At present,
our attention is also turned to elucidate the mechanism of
on a Buchi B-680 system using a Knauer K-2400 differential
¨
refractometer as detector. Electron impact mass spectra were
measured at 70 eV by GLCeMS. GLCeMS analyses were
performed using an Agilent 6890 Network GC system inter-
faced with an Agilent 5973 Network mass selective detector.
NMR spectra were recorded on a Varian Gemini 200 MHz
spectrometer and a Varian Gemini 300 MHz spectrometer
with TMS as the internal reference. All reactions were per-
formed in flame-dried glassware under a positive atmosphere
of argon by standard syringe, cannula, and septa techniques.
1-Benzyl-1H-imidazole (8), aryl iodides 6, aryl bromides 7,
P(2-furyl)3, Pd(OAc)2, CuI, PdCl2(dppf), 10% Pd/C (Merck),
and 20% Pd(OH)2/C (Aldrich) were commercially available.
The following compounds were prepared according to the liter-
ature: 2-(2-naphthyl)-4(5)-phenyl-1H-imidazole (3d)16 and
1-benzyl-2-(4-methoxyphenyl)-1H-imidazole (13a).15f
4.2. Procedure for the screening of the reaction conditions
for the Pd-catalyzed C-5 arylation of 1-benzyl-1H-imidazole
(8) with 4-anisyl iodide (6a) or 4-anisyl bromide (7a)
A mixture of compound 8 (1.0 mmol), Pd(OAc)2 (11.2 mg,
0.05 mmol), P(2-furyl)3 (23.3 mg, 0.1 mmol), 4-methoxy-
phenyl iodide 6a or bromide 7a (2.0 mmol), and a base
(2.0 mmol) in toluene or DMF (5 mL) was stirred under argon
for 48 h at the temperature reported in Table 1. After being
cooled to room temperature, the crude reaction mixture was di-
luted with CH2Cl2, naphthalene or biphenyl was added as inter-
nal standard and the resulting mixture was analyzed by GLC
and GCeMS. Table 1 summarizes the results of this screening.
4.3. General procedure for the Pd-catalyzed C-5 arylation
of 1-benzyl-1H-imidazole (8) with aryl bromides 7
To a flame-dried reaction vessel equipped with a silicon
rubber, a reflux condenser and a magnetic stirrer were added
compound 8 (1.0 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol),
P(2-furyl)3 (23.3 mg, 0.1 mmol), an aryl bromide 7 (2.0 mmol),
if a solid, and K2CO3 (0.28 g, 2.0 mmol). The reaction vessel
was evacuated, and back-filled with argon, and this sequence
was repeated twice. DMF (5 mL) and an aryl bromide 7, if

6066
F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
a liquid, were then added successively under a stream of argon
by syringe at room temperature. The resulting mixture was
stirred under argon at 140 ꢀC for the period of time reported
in Table 2. The completion of the reaction and the composition
of the reaction mixture were established on the basis of GLC
and GLCeMS analyses of a sample of the reaction mixture
treated with a saturated NH4Cl solution and extracted with
AcOEt. After being cooled to room temperature, the reaction
mixture was diluted with AcOEt (25 mL), poured into a satu-
rated aqueous NH4Cl solution (100 mL), and extracted with
AcOEt (4ꢁ25 mL). The organic extract was washed with brine
(2ꢁ20 mL), dried, and concentrated under reduced pressure.
The residue was purified by MPLC on silica gel. This procedure
was employed to prepare compounds 9aei (Table 2). GLC anal-
ysis showed that these compounds had chemical purity higher
than 98%.
4.3.4. 1-Benzyl-5-(4-chlorophenyl)-1H-imidazole (9d)
The crude reaction product obtained in entry 4 of Table 2
by Pd-catalyzed reaction of 8 with bromide 7d was purified
by MPLC on silica gel with a mixture of CH2Cl2 and methanol
(98:2) as eluent to give 9d (0.11 g, 43%) as a yellow solid. Mp
79e81 ꢀC. EIMS, m/z 270 (23), 269 (12), 268 (68), 91 (100),
1
65 (10). H NMR (300 MHz, CDCl3) d 7.60 (s, 1H), 7.30 (m,
5H), 7.20 (m, 2H), 7.15 (s, 1H), 7.00 (m, 2H), 5.14 (s, 2H). 13
C
NMR (75.5 MHz, CDCl3) d 139.0, 136.5, 134.2, 130.1, 129.0
(2C), 128.9 (2C), 128.6, 128.2, 128.1 (2C), 126.6 (2C), 123.6,
48.8. Anal. Calcd for C16H13ClN2: C, 71.51; H, 4.87. Found:
C, 71.39; H, 4.80.
4.3.5. 1-Benzyl-5-[(4-trifluoromethyl)phenyl]-1H-
imidazole (9e)
The crude reaction product obtained in entry 5 of Table 2 by
Pd-catalyzed reaction of 8 with bromide 7e was purified by
MPLC on silica gel with a mixture of CH2Cl2 and methanol
(98:2) as eluent to give 9e (0.13 g, 45%) as a yellow solid. Mp
61e63 ꢀC. EIMS, m/z 303 (11), 302 (55), 92 (8), 91 (100), 65
(8). 1H NMR (200 MHz, CDCl3) d 7.63 (m, 2H), 7.59 (s, 1H),
7.36 (m, 5H), 7.22 (s, 1H), 7.01 (m, 2H), 5.18 (s, 2H). 13C
NMR (50.3 MHz, CDCl3) d 139.6, 136.4, 133.4, 132.1, 129.4,
129.1 (2C), 128.9 (2C), 128.2 (2C), 126.5 (2C), 126.0, 125.7,
125.6, 49.0. Anal. Calcd for C17H13F3N2: C, 67.54; H, 4.33.
Found: C, 67.45; H, 4.24.
4.3.1. 1-Benzyl-5-(4-methoxyphenyl)-1H-imidazole (9a)
The crude reaction product obtained in entry 1 of Table 1 by
Pd-catalyzed reaction of 8 with bromide 7a was purified by
MPLC on silica gel with a mixture of CH2Cl2 and methanol
(98:2) as eluent to give 9a (0.13 g, 58%) as a pale yellow solid.
Mp 79e81 ꢀC. EIMS, m/z 265 (20), 264 (100), 173 (29), 119
(17), 91 (61). 1H NMR (300 MHz, CDCl3) d 7.55 (s, 1H), 7.28
(m, 3H), 7.19 (m, 2H), 7.08 (s, 1H), 7.01 (m, 2H), 6.88 (m,
2H), 5.11 (s, 2H), 3.81 (s, 3H). 13C NMR (75.5 MHz, CDCl3)
d 159.5, 138.2, 133.1, 130.3 (2C), 128.8 (2C), 127.8 (2C),
127.7, 126.6 (2C), 121.9, 114.0, 55.2, 48.5. Anal. Calcd for
C17H16N2O: C, 77.25; H, 6.10. Found: C, 77.14; H, 6.03.
4.3.6. 1-Benzyl-5-(4-tolyl)-1H-imidazole (9f)
The crude reaction product obtained in entry 6 of Table 2 by
Pd-catalyzed reaction of 8 with bromide 7f was purified by
MPLC on silica gel with a mixture of CH2Cl2 and methanol
(98:2) as eluent to give 9f (0.12 g, 49%) as a yellow solid. Mp
89e90 ꢀC. EIMS, m/z 249 (15), 248 (77), 103 (6), 92 (8), 91
4.3.2. 1-Benzyl-5-phenyl-1H-imidazole (9b)
The crude reaction product obtained in entry 2 of Table 2 by
Pd-catalyzed reaction of 8 with bromide 7b was purified by
MPLC on silica gel with a mixture of CH2Cl2 and methanol
(97:3) as eluent to give 9b (0.17 g, 73%) as a pale yellow solid.
Mp 112 ꢀC. EIMS, m/z 235 (18), 234 (95), 92 (8), 91 (100), 65
(11). 1H NMR (300 MHz, CDCl3) d 7.58 (s, 1H), 7.33 (m, 8H),
7.15 (s, 1H), 7.01 (m, 2H), 5.15 (s, 2H). 13C NMR (75.5 MHz,
CDCl3) d 138.7, 136.8, 129.8, 128.94 (2C), 128.92 (2C), 128.7
(2C), 128.3, 128.1, 127.9, 126.7 (2C), 119.1, 48.8. The spectral
properties of this compound were in agreement with those pre-
viously reported.29
1
(100). H NMR (200 MHz, CDCl3) d 7.59 (s, 1H), 7.29 (m,
3H), 7.17 (m, 4H), 7.12 (s, 1H), 7.01 (m, 2H), 5.14 (s, 2H),
2.36 (s, 3H). 13C NMR (50.3 MHz, CDCl3) d 138.3, 138.1,
136.8, 133.5, 129.4 (2C), 128.9 (2C), 128.8 (2C), 127.9,
127.7, 126.7 (2C), 126.6, 48.7, 21.2. Anal. Calcd for
C17H16N2: C, 82.22; H, 6.49. Found: C, 82.10; H, 6.36.
4.3.7. 1-Benzyl-5-(3,4,5-trimethoxyphenyl)-1H-imidazole (9g)
The crude reaction product obtained in entry 7 of Table 2 by
Pd-catalyzed reaction of 8 with bromide 7g was purified by
MPLC on silica gel with a mixture of CH2Cl2 and methanol
(97:3) as eluent to give 9g (0.19 g, 60%) as an orange oil.
EIMS, m/z 325 (21), 324 (100), 310 (9), 309 (47), 91 (65). 1H
NMR (200 MHz, CDCl3) d 7.64 (s, 1H), 7.32 (m, 3H), 7.14 (s,
1H), 7.05 (m, 2H), 6.41 (s, 2H), 5.18 (s, 2H), 3.84 (s, 3H),
3.65 (s, 6H). 13C NMR (50.3 MHz, CDCl3) d 153.2 (2C),
138.7, 138.0, 137.3, 133.5, 129.0 (2C), 127.9, 126.3 (2C),
126.0, 124.9, 106.2 (2C), 60.9, 55.9 (2C), 48.7. Anal. Calcd
for C19H20N2O3: C, 70.35; H, 6.21. Found: C, 70.27; H, 6.18.
4.3.3. 1-Benzyl-5-(2-naphthyl)-1H-imidazole (9c)
The crude reaction product obtained in entry 3 of Table 2 by
Pd-catalyzed reaction of 8 with bromide 7c was purified by
MPLC on silica gel with a mixture of CH2Cl2 and methanol
(98:2) as eluent to give 9c (0.14 g, 72%) as a pale yellow solid.
Mp 158e160 ꢀC. EIMS, m/z 285 (22), 284 (100), 139 (19), 91
1
(58). H NMR (300 MHz, CDCl3) d 7.83 (d, J¼8.79 Hz, 2H),
7.73 (m, 2H), 7.64 (s, 1H), 7.49 (m, 2H), 7.41 (dd, J¼8.79 and
1.96 Hz, 1H), 7.29 (m, 4H), 7.05 (m, 2H), 5.21 (s, 2H). 13C
NMR (75.5 MHz, CDCl3) d 138.9, 136.8, 133.2, 132.7, 128.9
(2C), 128.6, 128.4, 128.04 (2C), 128.02, 127.8, 127.7, 127.0,
126.7 (2C), 126.65, 126.57, 126.47, 48.9. Anal. Calcd for
C20H16N2: C, 84.48; H, 5.67. Found: C, 84.36; H, 5.43.
4.3.8. 1-Benzyl-5-(6-methoxy-2-naphthyl)-1H-
imidazole (9h)
The crude reaction product obtained in entry 8 of Table 2
by Pd-catalyzed reaction of 8 with bromide 7h was purified

F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
6067
by MPLC on silica gel with a mixture of CH2Cl2 and methanol
(96:4) as eluent to give 9h (0.21 g, 66%) as a pale brown solid.
Mp 123e125 ꢀC. EIMS, m/z 315 (24), 314 (100), 223 (46),
Pd-catalyzed SuzukieMiyaura reaction of 4(5)-bromo-1H-im-
idazole (4) with 4-methoxyphenylboronic acid.16
1
169 (32), 91 (36). H NMR (200 MHz, CDCl3) d 7.67 (m,
4.4.2. 4(5)-Phenyl-1H-imidazole (2b)
4H), 7.33 (m, 4H), 7.19 (m, 2H), 7.12 (s, 1H), 7.04 (m, 2H),
5.19 (s, 2H), 3.92 (s, 3H). 13C NMR (50.3 MHz, CDCl3)
d 158.2, 138.7, 136.9, 134.0, 129.5, 128.9 (2C), 128.6,
128.3, 127.9, 127.8, 127.2, 127.1, 126.7, 126.7 (2C), 126.0,
124.7, 119.4, 105.6, 55.3, 48.8. Anal. Calcd for C21H18N2O:
C, 80.83; H, 5.77. Found: C, 80.76; H, 5.60.
The crude reaction mixture obtained by N-debenzylation of
1-benzylimidazole 9b (entry 3, Table 3) was worked up using
the general procedure reported for this method to give 2b
1
(82 mg, 57%) as a colorless solid. Mp 131e132 ꢀC. The H
and 13C NMR data of this compound were in good agreement
with those of an authentic sample of 2b prepared by Pd-cata-
lyzed SuzukieMiyaura reaction of 4(5)-bromo-1H-imidazole
(4) with phenylboronic acid.16 Compound 2b was also obtained
in 99% yield by Pd-catalyzed N-debenzylation of 9b according
to method B (entry 5, Table 3) (see below).
4.3.9. 5-(1-Benzyl-1H-imidazol-5-yl)pyrimidine (9i)
The crude reaction product obtained in entry 9 of Table 2
by Pd-catalyzed reaction of 8 with bromide 7i was purified
by MPLC on silica gel with a mixture of CH2Cl2 and methanol
(93:7) as eluent, followed by recrystallization from CH2Cl2
and Et2O, to give 9i (0.13 g, 57%) as a pale yellow solid.
Mp 143e144 ꢀC. EIMS, m/z 237 (8), 236 (51), 92 (8), 91
4.4.3. 4(5)-(2-Naphthyl)-1H-imidazole (2c)
The crude reaction product obtained by N-debenzylation
of 1-benzylimidazole 9c (entry 2, Table 3) was purified by
MPLC on silica gel with a mixture of CH2Cl2 and methanol
(95:5) as eluent to give 2c (0.110 g, 57%) as a brown solid.
Mp 165e166 ꢀC. The 1H and 13C NMR data of this compound
were in good agreement with those of an authentic sample of
2c prepared by Pd-catalyzed SuzukieMiyaura reaction of
4(5)-bromo-1H-imidazole (4) with 2-naphthylboronic acid.16
1
(100), 65 (10). H NMR (300 MHz, CDCl3) d 9.15 (s, 1H),
8.63 (s, 2H), 7.81 (s, 1H), 7.31 (m, 4H), 6.99 (m, 2H), 5.21
(s, 2H). 13C NMR (75.5 MHz, CDCl3) d 157.9, 155.9 (2C),
140.5, 135.5, 130.3, 129.3 (2C), 128.5, 126.4 (2C), 126.0,
124.4, 49.3. Anal. Calcd for C14H12N4: C, 71.17; H, 5.12.
Found: C, 71.06; H, 5.09.
4.4. General procedure for the Pd-catalyzed N-debenzylation
of 5-aryl-1-benzyl-1H-imidazoles 9 with 10% Pd/C (method A)
4.5. General procedure for the Pd-catalyzed N-debenzylation
of 5-aryl-1-benzyl-1H-imidazoles 9 with 20% Pd(OH)2/C
(method B)
This method was used for the selective N-debenzylation
reaction of 9aec (entries 1e3, Table 3). To a stirred suspension
of 5-aryl-1-benzyl-1H-imidazole 9 (1 mmol) and an equal
weight of 10% Pd/C in methanol (8 mL), anhydrous ammonium
formate (0.63 g, 10 mmol) was added in a single portion under
argon. The resulting mixture was stirred under reflux and the re-
action was monitored by GLC. The reaction for 9a was complete
after 48 h (entry 1, Table 3) and that involving 9c, which required
the addition of a second aliquot of ammonium formate (0.63 g,
10 mmol) after 18 h, was complete after 36 h (entry 2, Table
3). However, N-debenzylation of 9b according to this method
proved to be much more difficult. In fact, it involved the use of
a very large molar excess of ammonium formate (1.89 g,
30 mmol), which was added in three portions after every 24 h
(entry 3, Table 3). After completion of the reaction, the reac-
tion mixture was cooled at room temperature and the catalyst
was removed by filtration through a Celite pad, which was
thenwashedwithmethanol.Thecombinedfiltrateswereconcen-
trated under reduced pressure to give the required 4(5)-aryl-1H-
imidazole 2.
To a stirred suspension of 5-aryl-1-benzyl-1H-imidazole 9
(1 mmol) and 20% Pd(OH)2/C (Aldrich) (0.2 g) in methanol
(70 mL), anhydrous ammonium formate (0.95 g, 15 mmol)
was added in a single portion under argon. The resulting
mixture was stirred under reflux for the period of time reported
in Table 3. After completion of the reaction, the reaction mix-
ture was cooled at room temperature and the catalyst was
removed by filtration through a Celite pad, which was then
washed with methanol. The combined filtrates were concen-
trated under reduced pressure and the residue was dissolved
in AcOEt (50 mL) and washed with a 10% NH4OH solution.
The aqueous phase was extracted with AcOEt (3ꢁ15 mL)
and the organic extract was washed with brine (2ꢁ30 mL)
and then concentrated under reduced pressure to give the
required 4(5)-aryl-1H-imidazole 2. This method was used
for the selective N-debenzylation of 9b, 9f, and 9i (entries 5,
6, and 7, respectively, Table 3).
4.5.1. 4(5)-(4-Tolyl)-1H-imidazole (2d)
The crude reaction mixture obtained by N-debenzylation of
1-benzylimidazole 9f (entry 5, Table 3) was worked up using
the general procedure reported for this method to give 2d
(0.153 g, 97%) as a colorless solid. Mp 106e107 ꢀC (lit.13a
mp 112e114 ꢀC). EIMS, m/z 159 (12), 158 (100), 157 (32),
139 (27), 103 (12). 1H NMR (200 MHz, CDCl3) d 11.39 (br s,
1H), 7.59 (m, 3H), 7.29 (br s, 1H), 7.15 (m, 2H), 2.32 (s, 3H).
13C NMR (50.3 MHz, CDCl3) d 138.0, 136.8, 135.4, 129.9,
4.4.1. 4(5)-(4-Methoxyphenyl)-1H-imidazole (2a)
The crude reaction product obtained by N-debenzylation of
1-benzylimidazole 9a (entry 1, Table 3) was worked up using
the general procedure reported for this method to give 2a
(0.168 g, 97%) as a yellow solid. Mp 113e115 ꢀC. The H
and 13C NMR data of this compound were in good agreement
with those of an authentic sample of 2a prepared by
1

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F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
129.5 (2C), 124.9 (2C), 115.7, 21.1. Anal. Calcd for C10H10N2:
C, 75.92; H, 6.37. Found: C, 75.83; H, 6.11.
(2C), 55.3, 48.4. Anal. Calcd for C23H20N2O: C, 81.15; H,
5.92. Found: C, 81.03; H, 5.77.
4.6.2. 1-Benzyl-2-(4-methoxyphenyl)-5-phenyl-1H-
imidazole (10c)
4.5.2. 5-(1H-Imidazol-5-yl)pyrimidine (2e)
The crude reaction mixture obtained by N-debenzylation of
1-benzylimidazole 9i (entry 7, Table 3) was purified by MPLC
on silica gel with a mixture of CH2Cl2 and methanol (90:10)
as eluent to give 2e (0.14 g, 97%) as a colorless solid. Mp
210e213 ꢀC. EIMS, m/z 148 (21), 147 (76), 146 (100), 120
The crude reaction product obtained in entry 2 of Table 4 by
Pd-catalyzed and Cu-mediated reaction of 9b with iodide 6awas
purified by MPLC on silica gel with a mixture of CH2Cl2 and
methanol (99:1) as eluent to give 10c (0.30 g, 88%) as a pale yel-
low solid. Mp 134e136 ꢀC. EIMS, m/z 341 (11), 340 (43), 250
(18), 249 (100), 119 (7). 1H NMR (300 MHz, CDCl3) d 7.49 (m,
1
(27), 92 (41). H NMR (200 MHz, CD3OD) d 9.15 (s, 2H),
9.01 (s, 1H), 8.55 (br s, NH), 7.88 (s, 1H), 7.80 (s, 1H). 13C
NMR (50.3 MHz, CD3OD) d 170.5, 157.0, 154.0 (2C), 138.6,
129.9, 116.9. Anal. Calcd for C7H6N4: C, 57.53; H, 4.14. Found:
C, 58.03; H, 4.23.
2H), 7.26 (m, 9H), 6.87 (m, 4H), 5.25 (s, 2H), 3.80 (s, 3H). 13
C
NMR (75.5 MHz, CDCl3) d 160.1, 149.4, 137.9, 134.8, 130.4,
130.2 (2C), 128.9 (2C), 128.7 (2C), 128.6 (2C), 128.0, 127.9,
127.4, 125.9 (2C), 123.5, 113.9 (2C), 55.3, 48.5. Anal. Calcd
for C23H20N2O: C, 81.15; H, 5.92. Found: C, 81.07; H, 5.88.
4.6. General procedure for the Pd- and Cu-mediated C-2
arylation of 5-aryl-1-benzyl-1H-imidazoles 9 with aryl
halides 6 or 7
4.6.3. 1-Benzyl-2,5-di(4-methoxyphenyl)-1H-
imidazole (10a)
The crude reaction product obtained in entry 3 of Table 4 by
Pd-catalyzed and Cu-mediated reaction of 9a with iodide 6a
was purified by MPLC on silica gel with a mixture of toluene
and AcOEt (30:70þ0.1% Et3N) as eluent to give 10a (78 mg,
21%) as a brown solid. Mp 125e127 ꢀC. EIMS, m/z 371 (10),
To a flame-dried reaction vessel equipped with a silicon rub-
ber, a reflux condenser, and a magnetic stirrer were added com-
pound 9 (1.0 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), and CuI
(0.38 g, 2.0 mmol). The reaction vessel was evacuated and
back-filled with argon and this sequence was repeated twice.
A deaerated solution of an aryl iodide 6 (2.0 mmol) in DMF
(5 mL) was then added by syringe under a stream of argon
and the resulting mixture was stirred under argon at 140 ꢀC
for the period of time reported in Table 4. When an aryl bro-
mide 7 (2.0 mmol) was used as the electrophile, the C-2 aryla-
tion reaction was performed in DMA (5 mL) at 160 ꢀC for the
period of time reported in Table 4. The completion of the reac-
tion was established on the basis of TLC, GLC, and GLCeMS
analyses of a sample of the reaction mixture treated with a sat-
urated NH4Cl solution basified with a few drops of NH4OH.
After being cooled to room temperature, the reaction mixture
was diluted with AcOEt (30 mL), poured into a saturated aque-
ous NH4Cl solution (100 mL), which was basified with a few
drops of NH4OH, stirred in the open air for 0.5 h, and then
extracted with AcOEt (5ꢁ25 mL). The organic extract was
washed with brine (2ꢁ20 mL), dried, and concentrated under
reduced pressure and the residue was purified by MPLC on
silica gel. This procedure was used to prepare 1-benzyl-2,5-di-
aryl-1H-imidazoles 10aef (entries 1e6, Table 4).
1
370 (39), 280 (20), 279 (100), 119 (11). H NMR (200 MHz,
CDCl3) d 7.56 (m, 6H), 6.85 (m, 6H), 5.21 (s, 2H), 3.80 (s, 3H),
3.78 (s, 3H). 13C NMR (50.3 MHz, CDCl3) d 160.0, 159.5,
148.9, 138.0, 134.5, 130.4 (2C), 130.1 (2C), 128.8 (2C), 127.6,
127.4, 125.9 (2C), 123.6, 122.7, 114.0 (2C), 113.9 (2C), 55.3
(2C), 48.3. Anal. Calcd for C24H22N2O2: C, 77.81; H, 5.99.
Found: C, 78.04; H, 5.81.
4.6.4. 1-Benzyl-2-(2-naphthyl)-5-phenyl-1H-imidazole (10d)
The crude reaction product obtained in entry 4 of Table 4 by
Pd-catalyzed and Cu-mediated reaction of 9b with bromide 7c
was purified by MPLC on silica gel with a mixture of toluene
and AcOEt (70:30þ0.1% Et3N) as eluent to give 10d (0.21 g,
59%) as a red solid. Mp 155e157 ꢀC. EIMS, m/z 361 (16), 360
(56), 270 (21), 269 (100), 139 (18). 1H NMR (200 MHz,
CDCl3) d 7.99 (s, 1H), 7.76 (m, 5H), 7.47 (m, 2H), 7.34 (s, 5H),
7.24 (m, 3H), 6.88 (m, 2H), 5.35 (s, 2H). 13C NMR (50.3 MHz,
CDCl3) d 149.2, 137.7, 135.4, 133.2, 132.9, 130.0, 129.0 (2C),
128.8 (2C), 128.7 (2C), 128.4, 128.3 (2C), 128.2, 128.0, 127.6,
127.5, 126.7, 126.4, 126.3, 125.9 (2C), 48.7. Anal. Calcd for
C26H20N2: C, 86.60; H, 5.59. Found: C, 86.43; H, 5.43.
4.6.1. 1-Benzyl-5-(4-methoxyphenyl)-2-phenyl-1H-
imidazole (10b)
4.6.5. 1-Benzyl-2-[(4-ethoxycarbonyl)]phenyl-2-(4-tolyl)-
1H-imidazole (10e)
The crude reaction product obtained in entry 1 of Table 4 by
Pd-catalyzed and Cu-mediated reaction of 9awith iodide 6b was
purified by MPLC on silica gel with a mixture of CH2Cl2 and
methanol (98:2) as eluent to give 10b (0.19 g, 56%) as a yellow
solid. Mp 107e109 ꢀC. EIMS, m/z 341 (14), 340 (53), 281 (11),
The crude reaction product obtained in entry 5 of Table 4 by
Pd-catalyzed and Cu-mediated reaction of 9f with bromide 7j
was purified by MPLC on silica gel with a mixture of toluene
and AcOEt (70:30þ0.1% Et3N) as eluent to give 10e (0.26 g,
65%) as a pink solid. Mp 115e117 ꢀC. EIMS, m/z 397 (29),
1
249 (100), 207 (88). H NMR (300 MHz, CDCl3) d 7.56 (m,
1
2H), 7.35 (m, 3H), 7.23 (m, 4H), 7.19 (m, 2H), 6.84 (m, 4H),
5.24 (s, 2H), 3.79 (s, 3H). 13C NMR (75.5 MHz, CDCl3)
d 159.6, 148.9, 137.9, 134.8, 131.1, 130.5 (2C), 128.7 (4C),
128.5 (2C), 128.7, 127.4, 125.9 (2C), 122.45, 119.1, 114.0
396 (100), 306 (18), 305 (82), 277 (11). H NMR (200 MHz,
CDCl3) d 8.02 (m, 2H), 7.66 (m, 2H), 7.22 (m, 7H), 7.12 (s,
1H), 6.86 (m, 2H), 5.29 (s, 2H), 4.37 (q, J¼7.0 Hz, 2H), 2.34
(s, 3H), 1.38 (t, J¼7.0 Hz, 3H). 13C NMR (50.3 MHz, CDCl3)

F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
6069
d 166.2, 147.9, 138.3, 137.5, 136.0, 135.1, 130.4, 129.7 (2C),
129.4 (2C), 129.0 (2C), 128.9 (2C), 128.4 (2C), 127.6, 126.8,
126.0, 125.7 (2C), 61.1, 48.6, 21.2, 14.3. Anal. Calcd for
C26H24N2O2: C, 78.76; H, 6.10. Found: C, 78.65; H, 5.98.
4.7.3. Ethyl 4-(5-p-tolyl-1H-imidazol-2-yl)benzoate (3c)
The crude reaction product obtained by N-debenzylation of
1-benzylimidazole 10e according to method B (entry 3, Table
5) was purified by MPLC on silica gel with a mixture of tol-
uene and AcOEt (80:20þ0.1% Et3N) as eluent to give 3c
(0.21 g, 68%) as a colorless solid. Mp 197e198 ꢀC. EIMS,
m/z 307 (22), 306 (100), 278 (37), 261 (9), 233 (9). 1H
NMR (200 MHz, DMSO-d6) d 8.11 (m, 4H), 7.79 (m, 3H),
7.22 (m, 2H), 4.34 (q, 2H, J¼7 Hz), 2.32 (s, 3H), 1.35 (t,
3H, 7 Hz). 13C NMR (50.3 MHz, CDCl3) d 165.4, 144.5,
141.9, 135.4, 134.6, 131.6, 129.6 (2C), 129.0 (2C), 128.8,
124.7 (2C), 124.4 (2C), 114.8, 60.7, 20.7, 14.1. Anal. Calcd
for C19H18N2O2: C, 74.49; H, 5.92. Found: C, 75.10; H, 6.03.
4.6.6. 5-(1-Benzyl-2-p-tolyl-1H-imidazol-5-yl)-
pyrimidine (10f)
The crude reaction product obtained in entry 6 of Table 4
by Pd-catalyzed and Cu-mediated reaction of 9i with bromide
7f was purified by MPLC on silica gel with a mixture of
CH2Cl2 and methanol (97:3) as eluent to give 10f (68 mg,
21%) as a pink solid. Mp 162e164 ꢀC. EIMS, m/z 327 (14),
1
326 (58), 235 (21), 207 (7), 91 (100). H NMR (200 MHz,
CDCl3) d 9.09 (s, 1H), 8.61 (s, 2H), 7.49 (m, 2H), 7.39
(s, 1H), 7.24 (m, 5H), 6.86 (m, 2H), 5.27 (s, 2H), 2.37 (s,
3H). 13C NMR (50.3 MHz, CDCl3) d 157.7, 155.8 (2C),
151.9, 139.5, 136.7, 130.1, 129.5 (2C), 129.2 (2C), 128.7
(2C), 128.1, 127.2, 125.6 (2C), 125.1, 123.6, 48.9, 21.3. Anal.
Calcd for C21H18N4: C, 77.28; H, 5.56. Found: C, 77.16; H,
5.49.
4.8. Hydrogenolysis of compound 10d using 20% Pd(OH)2/C
(method C)
A mixture of 10d (91 mg, 0.336 mmol) and 20% Pd(OH)2/C
(66 mg) in methanol (25 mL) was hydrogenated under an atmo-
spheric pressure of hydrogen using a balloon with vigorous stir-
ring for 70 h under reflux (entry 5, Table 5). The mixture was
filtered through Celite and the filtrate was concentrated under
reduced pressure to give a yellow solid residue. TLC, GLC,
and GLCeMS analyses showed that it consisted of 2-(2-naph-
thyl)-4(5)-phenyl-1H-imidazole (3d) contaminated by ca.
20% of a byproduct, which presumably corresponded to 4(5)-di-
hydronaphthyl-2-phenyl-1H-imidazole. The EIMS data for 3d
were: m/z 271 (21), 270 (100), 269 (20), 207 (10), 139 (10).
This compound, which was obtained in 80% GLC yield, had
GLC retention time and EIMS spectrum identical to those of
an authentic sample of 3d prepared according to the reaction
sequence illustrated in Scheme 1.16
4.7. General methods for the N-debenzylation of 1-benzyl-
2,5-diaryl-1H-imidazoles 10
Compounds 10b and 10c were converted into the correspond-
ing 2,4(5)diaryl-1H-imidazoles 3a and 3b, respectively, accord-
ing to the procedure (method A) used to prepare imidazoles
2aec from 5-aryl-1-benzyl-1H-imidazoles 9aec. On the other
hand, the N-debenzylation reaction of compounds 10d and
10e was performed using the same procedure (method B) em-
ployed for the preparation of imidazoles 2b, 2d, and 2e. How-
ever, method B proved to be unsuitable for the preparation of
3d from 10d. Table 5 summarizes the results obtained in the
deprotection of 1-benzyl-2,5-diaryl-1H-imidazoles 10bed.
4.9. General procedure for the synthesis of 5-aryl-1-benzyl-4-
bromo-1H-imidazoles 11
4.7.1. 4(5)-(4-Methoxyphenyl)-2-phenyl-1H-imidazole (3a)
The crude reaction mixture obtained from the N-debenzyl-
ation of 10b according to method A (entry 1, Table 5) was
worked up according to the general procedure reported for
this method to give 3a (0.22 g, 86%) as a pale pink solid.
Mp 170e174 ꢀC. EIMS, m/z 251 (18), 250 (100), 236 (9),
To a stirred suspension of 5-aryl-1-benzyl-1H-imidazole 9
(1 mmol) in anhydrous MeCN (4 mL) was added a solution of
freshly recrystallized NBS (0.19 g, 1.05 mmol) in anhydrous
MeCN (2 mL) under argon. The resulting solution was stirred
at room temperature and the reaction was monitored by GLC
and GCeMS. After completion of the reaction (1e2 h), the
reaction mixture was diluted with CH2Cl2 and the solvents
were eliminated at reduced pressure. The crude reaction mixture
was purified by MPLC. This procedure was used to prepare
bromoimidazoles 11aee. GLC analyses showed that these com-
pounds had chemical purity higher than 98%.
1
235 (50), 207 (12). H NMR (300 MHz, CDCl3) d 8.37 (br
s, 1H, NH), 7.86 (m, 2H), 7.65 (m, 2H), 7.30 (m, 3H), 7.22
(s, 1H), 6.89 (m, 2H), 3.80 (s, 3H). 13C NMR (50.3 MHz,
CDCl3) d 158.9, 146.8, 138.6, 129.8, 128.8 (2C), 128.78,
126.4 (2C), 125.5 (2C), 125.0, 116.6, 114.2 (2C), 55.3. The
spectral properties of this compound were in agreement with
those previously reported.30
4.9.1. 1-Benzyl-4-bromo-5-(4-methoxyphenyl)-1H-
imidazole (11a)
4.7.2. 2-(4-Methoxyphenyl)-4(5)-phenyl-1H-imidazole (3b)
The crude reaction product obtained by N-debenzylation of
1-benzylimidazole 10c according to method A (entry 1, Table
5) was worked up according to the general procedure reported
for this method to give 3b (0.247 g, 99%) as pale yellow solid.
Mp 125e127 ꢀC. The physical and spectral properties of this
compound were in good agreement with those previously
reported.15f
The crude reaction product obtained by reaction of NBS with
5-arylimidazole9awaspurifiedbyMPLConsilicagelwithamix-
ture of toluene and AcOEt (80:20) as eluent to give 11a (0.25 g,
80%) as an orange oil. EIMS, m/z 345 (16), 344 (82), 343 (17),
342 (85), 91 (100). 1H NMR (300 MHz, CDCl3) d 7.47 (s, 1H),
7.28 (m, 3H), 7.19 (m, 2H), 6.98 (m, 2H), 6.93 (m, 2H), 5.00 (s,
2H), 3.82 (s, 3H). 13C NMR (75.4 MHz, CDCl3) d 160.0, 136.7,

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F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
135.9, 131.6 (2C), 130.1, 128.9 (2C), 128.2, 126.9 (2C), 120.1,
114.9, 114.2 (2C), 55.3, 49.7. Anal. Calcd for C17H15BrN2O: C,
59.49; H, 4.41. Found: C, 59.72; H, 4.69.
123.0, 119.5, 115.1, 105.7, 55.4, 49.9. Anal. Calcd for
C21H17BrN2O: C, 64.13; H, 4.36. Found: C, 64.61; H, 4.47.
4.10. General procedure for the synthesis of 4,5-diaryl-1-
benzyl-1H-imidazoles 12aed
4.9.2. 1-Benzyl-4-bromo-5-phenyl-1H-imidazole (11b)
The crude reaction product obtained by reaction of NBS with
5-arylimidazole 9b was purified by MPLC on silica gel with
a mixture of toluene and AcOEt (80:20) as eluent to give 11b
(0.27 g, 80%) as a yellow solid. Mp 115e118 ꢀC. EIMS, m/z
A deaerated mixture of 5-aryl-1-benzyl-4-bromo-1H-imid-
azole 11 (1.0 mmol), arylboronic acid 5 (2.0 mmol), CsF
(0.456 g, 3.0 mmol), PdCl2(dppf) (0.041 g, 0.05 mmol), and
BnEt3NCl (0.011 g, 0.05 mmol) in toluene (7 mL) and water
(7 mL) was refluxed under argon. After completion of the
reaction (24 h), the mixture was cooled to room temperature
and partitioned between water and AcOEt, and the organic
extract was washed with brine, dried, and concentrated under
reduced pressure. The residue was purified by MPLC on silica
gel to provide the desired product. This procedure was used to
prepare compounds 12a, 12b, 12c, and 12d.
1
315 (10), 314 (52), 313 (10), 312 (54), 91 (100). H NMR
(300 MHz, CDCl3) d 7.50 (s, 1H), 7.40 (m, 3H), 7.29 (m, 5H),
6.97 (m, 2H), 5.04 (s, 2H). 13C NMR (75.4 MHz, CDCl3)
d 137.0, 135.8, 130.3 (2C), 128.9 (2C), 128.89, 128.7 (2C),
128.2, 128.1, 127.0 (2C), 119.1, 115.0, 49.9. Anal. Calcd for
C16H13BrN2: C, 61.36; H, 4.18. Found: C, 60.98; H, 4.23.
4.9.3. 1-Benzyl-4-bromo-5-(naphthalen-2-yl)-1H-
imidazole (11c)
4.10.1. 1-Benzyl-5-(4-methoxyphenyl)-4-phenyl-1H-
imidazole (12a)
The crude reaction product obtained by reaction of NBS with
5-arylimidazole 9c was purified by MPLC on silica gel with
a mixture of toluene and AcOEt (70:30) as eluent to give 11c
(0.25 g, 70%) as a colorless solid. Mp 123e126 ꢀC (CH2Cl2).
EIMS, m/z 365 (11), 364 (51), 363 (12), 362 (52), 91 (100).
1H NMR (300 MHz, CDCl3) d 7.89 (s, 1H), 7.86 (s, 1H), 7.77
(m, 2H), 7.53 (m, 3H), 7.38 (dd, 1H, J¼2.1 and 8.7 Hz), 7.29
(m, 3H), 7.00 (m, 2H), 5.09 (s, 2H). 13C NMR (75.4 MHz,
CDCl3) d 137.8, 137.1, 135.8, 133.1, 133.0, 130.0, 128.9 (2C),
128.4, 128.3, 128.2, 127.8, 127.3, 127.0 (2C), 126.9, 126.6,
125.4, 115.3, 50.0. Anal. Calcd for C20H15BrN2: C, 66.13; H,
4.16. Found: C, 66.37; H, 4.34.
The crude reaction product obtained by reaction of bromo-
imidazole 11a with phenylboronic acid 5b was purified by
MPLC on silica gel with a mixture of toluene and AcOEt
(30:70) as eluent to give 12a (0.34 g, 99%) as a pale orange
solid. Mp 144e147 ꢀC. EIMS, m/z 341 (26), 340 (100), 249
1
(19), 119 (20), 91 (32). H NMR (300 MHz, CDCl3) d 7.71
(s, 1H), 7.52 (m, 2H), 7.19 (m, 8H), 6.99 (m, 2H), 6.89 (m,
2H), 4.96 (s, 2H), 3.83 (s, 3H). 13C NMR (75.4 MHz,
CDCl3) d 159.9, 137.9, 136.8, 136.6, 134.4, 132.2 (2C),
128.8 (2C), 128.1 (2C), 127.9, 126.9 (2C), 126.4 (2C),
126.3, 126.0, 122.3, 114.4 (2C), 55.2, 48.7. Anal. Calcd for
C23H20N2O: C, 81.15; H, 5.92. Found: C, 81.63; H, 6.01.
4.9.4. 1-Benzyl-4-bromo-5-(4-(trifluoromethyl)phenyl)-1H-
imidazole (11d)
4.10.2. 1-Benzyl-5-(naphthalen-2-yl)-4-(3,4,5-
The crude reaction product obtained by reaction of NBS with
5-arylimidazole 9e was purified by MPLC on silica gel with
a mixture of CH2Cl2 and methanol (98:2) as eluent to give
11d (0.30 g, 79%) as a yellow oil. EIMS, m/z 383 (9), 382
(48), 381 (10), 380 (50), 91 (100). 1H NMR (200 MHz,
CDCl3) d 7.65 (m, 2H), 7.59 (s, 1H), 7.43 (m, 2H), 7.31 (m,
3H), 6.99 (m, 2H), 5.09 (s, 2H). 13C NMR (50.3 MHz, CDCl3)
d 137.9, 135.3, 131.8, 131.2, 130.6 (2C), 129.1 (2C), 128.5
(2C), 128.2, 128.0, 126.9 (2C), 126.6, 126.1, 126.0, 125.7 (q,
1C, J¼3.8 Hz), 115.7, 50.2. Anal. Calcd for C17H12BrF3N2:
C, 53.56; H, 3.17. Found: C, 53.85; H, 3.26.
trimethoxyphenyl)-1H-imidazole (12b)
The crude reaction product obtained by reaction of bromo-
imidazole 11c with 3,4,5-trimethoxyphenylboronic acid 5c was
purified by MPLC on silica gel with a mixture of CH2Cl2 and meth-
anol (98:2) as eluent to give 12b (0.42 g, 92%) as an orange solid.
Mp 134e135 ꢀC. EIMS, m/z 451 (32), 450 (100), 436 (22), 435
1
(73), 91 (65). H NMR (300 MHz, CDCl3) d 7.87 (s, 1H), 7.84
(s, 1H), 7.73 (m, 3H), 7.52 (m, 2H), 7.29 (m, 4H), 6.97 (m, 2H),
6.78 (s, 2H), 5.02 (s, 2H), 3.77 (s, 3H), 3.48 (s, 6H). 13C NMR
(75.4 MHz, CDCl3) d 152.9, 138.2, 137.0, 136.6, 136.5, 133.2,
133.0, 130.6, 129.8, 128.9, 128.8 (2C), 128.4, 128.0 (2C), 127.9,
127.7, 126.96, 126.93 (2C), 126.8, 126.6, 126.0, 103.3 (2C),
60.8, 55.6 (2C), 48.9. Anal. Calcd for C29H26N2O3: C, 77.13; H,
5.82. Found: C, 77.54; H, 5.75.
4.9.5. 1-Benzyl-4-bromo-5-(6-methoxynaphthalen-2-yl)-1H-
imidazole (11e)
The crude reaction product obtained by reaction of NBS with
5-arylimidazole 9h was purified by MPLC on silica gel with
a mixture of CH2Cl2 and methanol (99:1) as eluent to give 11e
(0.25 g, 64%) as a yellow oil. EIMS, m/z 395 (23), 394 (94),
4.10.3. 4-(Benzo[d][1,3]dioxol-5-yl)-1-benzyl-5-
(naphthalen-2-yl)-1H-imidazole (12c)
The crude reaction product obtained by reaction of bromo-
imidazole 11c with benzo[d][1,3]dioxol-5-ylboronic acid 5d
was purified by MPLC on silica gel with a mixture of toluene
and AcOEt (50:50þ0.1% Et3N) as eluent to give 12c (0.38 g,
93%) as a colorless solid. Mp 83e85 ꢀC. EIMS, m/z 405 (31),
1
393 (24), 392 (100), 91 (86). H NMR (200 MHz, CDCl3)
d 7.89 (s, 1H), 7.71 (m, 3H), 7.55 (s, 1H), 7.31 (m, 4H), 7.17
(m, 2H), 6.99 (m, 2H), 5.07 (s, 2H), 3.93 (s, 3H). 13C NMR
(50.3 MHz, CDCl3) d 158.5, 136.9, 135.9, 134.5, 129.8, 129.7,
128.9 (2C), 128.5, 128.2, 127.9, 127.2, 127.0 (2C), 125.4,
1
404 (100), 313 (13), 255 (15), 91 (25). H NMR (200 MHz,

F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
6071
CDCl3) d 7.83 (m, 2H), 7.71 (m, 3H), 7.51 (m, 2H), 7.27 (m,
4H), 6.98 (m, 4H), 6.61 (d, 1H, J¼8 Hz), 5.84 (s, 2H), 4.98 (s,
2H). 13C NMR (50.3 MHz, CDCl3) d 147.4, 146.2, 138.3,
137.1, 136.6, 133.3, 133.1, 130.3 (2C), 128.8 (2C), 128.7,
128.4, 128.2, 128.0, 127.9, 127.0 (2C), 126.8, 126.5, 126.0,
120.4 (2C), 108.2, 107.4, 100.7, 48.9. Anal. Calcd for
C27H20N2O2: C, 80.18; H, 4.98. Found: C, 80.67; H, 5.06.
108.3, 108.0, 101.0. Anal. Calcd for C20H14N2O2: C, 76.42; H,
4.49. Found: C, 77.01; H, 4.52.
4.11.3. 4-(4-Methoxyphenyl)-5-(4-(trifluoromethyl)phenyl)-
1H-imidazole (1d)
Colorless solid (0.32 g, 99%). Mp 59e62 ꢀC. EIMS, m/z 319
(19), 318 (100), 317 (27), 303 (19), 205 (10). 1H NMR
(200 MHz, DMSO-d6) d 7.77 (s, 1H), 7.59 (m, 4H), 7.32 (m,
2H), 6.93 (m, 2H), 3.80 (s, 3H). 13C NMR (50.3 MHz, CDCl3)
d 161.2, 139.1, 136.8 (2C), 130.8 (2C), 130.0, 129.4, 128.9
(2C), 128.5, 128.4, 126.3 (q, J¼4.22 Hz), 125.3, 115.4 (2C),
55.8. Anal. Calcd for C17H13F3N2O: C, 64.15; H, 4.12. Found:
C, 64.76; H, 4.32.
4.10.4. 1-Benzyl-4-(4-methoxyphenyl)-5-(4-(trifluoromethyl)-
phenyl)-1H-imidazole (12d)
The crude reaction product obtained by reaction of bromo-
imidazole 11d with 4-methoxyphenylboronic acid 5a was
purified by MPLC on silica gel with a mixture of CH2Cl2 and
methanol (98:2) as eluent to give 12d (0.27 g, 67%) as a pale
brown oil. EIMS, m/z 409 (27), 408 (100), 317 (12), 119 (12),
Acknowledgements
1
91 (45). H NMR (200 MHz, CDCl3) d 7.68 (s, 1H), 7.60 (m,
2H), 7.33 (m, 7H), 6.95 (m, 2H), 6.77 (m, 2H), 4.98 (s, 2H),
3.76 (s, 3H). 13C NMR (50.3 MHz, CDCl3) d 158.6, 137.8,
137.6, 136.2, 134.6, 131.3 (2C), 128.9 (2C), 128.1 (2C), 126.8
(2C), 126.6 (2C), 126.3, 126.1, 126.0, 125.8, 114.1, 113.8
(2C), 55.2, 49.0. Anal. Calcd for C24H19F3N2O: C, 70.58; H,
4.69. Found: C, 71.03; H, 4.81.
This work was financially supported by the University of
Pisa.
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4,5-diaryl-1H-imidazoles 12
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1
251 (24), 250 (100), 249 (36), 235 (20), 206 (14). H NMR
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(200 MHz, DMSO-d6) d 12.4 (br s, 1H), 7.78 (s, 1H), 7.51 (m,
2H), 7.42 (m, 5H), 6.97 (m, 2H), 3.80 (s, 3H). 13C NMR
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The crude reaction product obtained by N-debenzylation of
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6072
F. Bellina et al. / Tetrahedron 64 (2008) 6060e6072
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