temperature.16 However, the potential of this method is limited
by the fact that arylglyoxals, save phenylglyoxal hydrate, are
commercially unavailable; moreover, this approach involves the
formation of significant amounts of byproducts consisting of
TABLE 1. Synthesis of 4(5)-Aryl-1H-imidazoles 1 via
Pd-Catalyzed Reaction of 4(5)-Bromo-1H-imidazole (7) with
Arylboronic Acids 8a
1
Ar -B(OH)2
Product
-aroyl-4(5)-aryl-1H-imidazoles.16
yieldb
(%)
2
reaction
time (h)
entry
1c
8
Ar1
1
8a
8b
8a
8b
8c
8d
8e
8f
C6H5
4-ClC6H4
C6H5
4-ClC6H4
4-MeOC6H4
4-AcC6H4
91
139
65
48
66
72
72
72
72
72
1a
1b
1a
1b
1c
1d
1e
1f
66
62
66
82
91
83
90
76
86
0
c
2
3
4
5
6
7
8
9
2-naphthyl
In our continuing studies of the synthesis of arylazole
17
2,5-(MeO)2C6H3
benzo[d][1,3]-dioxol-5-yl
2-(CHO)C6H4
derivatives, we were interested in the development of concise
and efficient novel approaches for preparation of monosubsti-
tuted 4(5)-aryl-1H-imidazoles 1 and disubstituted 2,4(5)-diaryl-
8g
8h
1g
1h
10
a
Unless otherwise noted, the reactions were run with 1 mmol of 7, 2
1
H-imidazoles 2 from cheap, commercially available starting
mmol of 8, 5 mol % of PdCl2(dppf), 5 mol % of BnEt3NCl, and 3 equiv of
CsF in 14 mL of a 1:1 mixture of toluene and water at 110 °C (oil bath
temperature). b Isolated yields. c This reaction was run with 5 mol % of
PdCl2(PPh3)2.
materials. Herein, we report an efficient and general entry to
imidazoles 1, which utilizes a Pd-catalyzed Suzuki-Miyaura-
type reaction between commercially available 4(5)-bromo-1H-
imidazole (7) and arylboronic acids 8 under phase-transfer
1
8,19
conditions.
Moreover, we describe the successful use of
phenylboronic acid (8a), which was performed according to a
procedure previously employed to prepare 4 from iodide 3 and
activated and unactivated aryl bromides and iodides in the
synthesis of 2,4(5)-diaryl-1H-imidazoles 2 by Pd-catalyzed and
Cu-mediated direct C-2-arylation of N-unprotected compounds
3
-thienylboronic acid, that is, in DMF at 80 °C for 24 h in the
presence of 5 mol % of Pd(PPh3)4 and 2 equiv of aqueous Na2-
1
under base-free and ligandless conditions. It should be noted
11
CO3, afforded only traces of the required 4(5)-phenyl-1H-
that we had previously employed similar reaction conditions
for the efficient and highly regioselective direct C-2-arylation
of a large variety of azoles, which included 1-aryl-1H-
imidazoles, 1-methyl- and 1-benzyl-1H-imidazole, thiazole,
oxazole, benzothiazole, and free (NH)-imidazole, -benzimida-
imidazole (1a). With this in mind, we thought it right to try a
Suzuki-type coupling under phase-transfer conditions according
to a procedure similar to that we previously employed for the
selective C-4-arylation of 3,4-dichloro-2(5H)-furanone with
19a
arylboronic acids. We were then pleased to find that, when 7
1
7a,c,20
zole, and -indole.
was reacted with 2 equiv of phenylboronic acid (8a) in a 1:1
mixture of toluene and water for 91 h at 110 °C in the presence
of 5 mol % of PdCl2(PPh3)2, 5 mol % of benzyltriethylammo-
nium chloride, and 3 equiv of CsF, the required 4(5)-phenyl-
Our initial investigations were focused to the preparation of
imidazoles 1 by direct C-5-arylation of free (NH)-imidazole with
aryl iodides in DMF at 140 °C in the presence of 2 equiv of a
base such as Cs2CO3 or KOAc and a catalyst system consisting
of 5 mol % of Pd(OAc)2 and 10 mol % of tris(2-furyl)phosphine
or 20 mol % of PPh3, but, to our disappointment, no expected
arylation product was obtained.
1
H-imidazole 1a was obtained in 66% yield (entry 1, Table 1).
Moreover, a very similar reaction of 7 with 4-chlorophenylbo-
ronic acid (8b) for 139 h at 110 °C gave 1b in 62% yield (entry
2
, Table 1). Unfortunately, this protocol proved to be ac-
Searching for an alternative synthetic route, we speculated
that imidazoles 1 might be conveniently prepared by a Suzuki-
Miyaura reaction between N-unprotected bromoimidazole 7 and
arylboronic acids 8. However, a model reaction of 7 with
companied by an undesirable side reaction due to the aryl-
aryl interchange between palladium- and phosphine-bound
21
phenyl groups, which, in the case of the synthesis of 1b, led
to small amounts of the phenyl coupling product 1a. Neverthe-
less, this side reaction did not occur when PdCl2(dppf) was used
as the catalyst precursor in place of PdCl2(PPh3)2. Furthermore,
the use of PdCl2(dppf) for the preparation of 1a and 1b caused
higher yields and a significant reduction in the reaction time
(
16) Zuliani, V.; Cocconcelli, G.; Fantini, M.; Ghiron, C.; Rivara, M. J.
Org. Chem. 2007, 72, 4551.
17) (a) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R. Tetrahedron
007, 63, 1970. (b) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R.
(
2
Eur. J. Org. Chem. 2007, 2147. (c) Bellina, F.; Cauteruccio, S. Rossi, R.
Eur. J. Org. Chem. 2006, 1379. (d) Bellina, F.; Cauteruccio, S.; Mannina,
L.; Rossi, R.; Viel, S. Eur. J. Org. Chem. 2006, 693. (e) Bellina, F.; Rossi,
R. Tetrahedron 2006, 62, 7213. (f) Bellina, F.; Cauteruccio, S.; Mannina,
L.; Rossi, R.; Viel, S. J. Org. Chem. 2005, 70, 3997.
(
compare entries 3 and 4 with entries 1 and 2, respectively,
Table 1).
Having successfully demonstrated the viability of the PdCl2-
(dppf)-catalyzed arylation of 7 with boronic acids 8a and 8b,
we then tested the scope and limitation of this reaction by
applying the reaction conditions of entries 3 and 4 of Table 1
to the synthesis of compounds 1 from 7 and commercially
available boronic acids 8c-h. The reactions involving 8c-g
proved to be clean and, as shown in Table 1, gave the required
imidazole derivatives in high yields (entries 5-9). Nevertheless,
the Pd-catalyzed reaction of 7 with 2-formylboronic acid (8h)
did not produce the required imidazole 1h. On the contrary, a
(18) For recent reviews on the Suzuki-Miyaura reactions, see: (a)
Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419. (b) Miyaura, N. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., de Meijere, A.,
Eds.; Wiley-VCH: New York, 2004; Chapter 2. (c) Miyaura, N Top. Curr.
Chem. 2002, 219, 11.
(
19) For examples of Pd-catalyzed Suzuki-Miyaura reactions performed
under phase-transfer conditions, see: (a) Bellina, F.; Anselmi, C.; Martina,
F.; Rossi, R. Eur. J. Org. Chem. 2003, 2290. (b) Zhang, J.; Blazecka, P.
G.; Belmont, D.; Davidson, J. G. Org. Lett. 2002, 4, 4559.
(20) For selected examples of Pd-catalyzed C-arylations of free (NH)-
azoles with aryl halides, see: (a) Akita, Y.; Itagaki, Y.; Takizawa, S.; Ohta,
A. Chem. Pharm. Bull. 1989, 37, 1477 (indole). (b) Rieth, R. D.; Mankad,
N. P.; Calimano, E.; Sadighi, J. P. Org. Lett. 2004, 6, 3981 (pyrrole). (c)
Ref 17a (imidazole, benzimidazole, indole). (d) Ref 17c (imidazole,
benzimidazole, indole). (d) Wang, X.; Gribkov, D. V.; Sames, D. J. Org.
Chem. 2007, 72, 1476 (indole derivatives, pyrrole).
(21) (a) Morita, D. K.; Stille, J. K.; Norton, J. R. J. Am. Chem. Soc.
1995, 117, 8576. (b) O’Keefe, D. F.; Dannock, M. C.; Marcuccio, S. M.
Tetrahedron Lett. 1992, 33, 6679. (c) Kong, K.-C.; Cheng, C.-H. J. Am.
Chem. Soc. 1991, 113, 6313.
8
544 J. Org. Chem., Vol. 72, No. 22, 2007