Efficient and highly regioselective direct C-2 arylation of azoles, including free (NH)-imidazole, -benzimidazole and -indole, with aryl halides

Article abstract of DOI:10.1016/j.tet.2006.12.068

The Pd- and Cu-mediated reaction of a large variety of π-electron sufficient heteroarenes, which include free (NH)-imidazoles, -benzimidazole and -indole, with aryl iodides under ligandless and base-free conditions provides regioselectively the required 2-arylheterocycle derivatives in high yields. 2-Aryl-1-phenyl-1H-imidazoles can also be prepared by a one-pot domino HALEX and Pd- and Cu-mediated arylation reactions of 1-phenyl-1H-imidazole with activated and unactivated aryl bromides under base-free and ligandless conditions. The protocol for the synthesis of 2-arylazoles involving the use of aryl iodides has been found to be suitable for the efficient preparation of three bioactive compounds and a key intermediate in the synthesis of a heparanase inhibitor.

Full text of DOI:10.1016/j.tet.2006.12.068

Tetrahedron 63 (2007) 1970–1980
Efficient and highly regioselective direct C-2 arylation of azoles,
including free (NH)-imidazole, -benzimidazole and -indole,
with aryl halides
*
Fabio Bellina, Chiara Calandri, Silvia Cauteruccio and Renzo Rossi
*
Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
Received 10 October 2006; revised 13 December 2006; accepted 21 December 2006
Available online 27 December 2006
Abstract—The Pd- and Cu-mediated reaction of a large variety of p-electron sufficient heteroarenes, which include free (NH)-imidazoles,
-benzimidazole and -indole, with aryl iodides under ligandless and base-free conditions provides regioselectively the required 2-arylhetero-
cycle derivatives in high yields. 2-Aryl-1-phenyl-1H-imidazoles can also be prepared by a one-pot domino HALEX and Pd- and Cu-mediated
arylation reactions of 1-phenyl-1H-imidazole with activated and unactivated aryl bromides under base-free and ligandless conditions. The
protocol for the synthesis of 2-arylazoles involving the use of aryl iodides has been found to be suitable for the efficient preparation of three
bioactive compounds and a key intermediate in the synthesis of a heparanase inhibitor.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
reaction sequences. Other useful methods for the synthesis
of 2-arylazole derivatives are based on the construction of
the heteroaryl–aryl bond at the 2-position of these heterocy-
cles by Pd-catalyzed cross-coupling reactions between aryl
halides or pseudohalides and 2-azolyl organometallics or be-
tween arylmetals and 2-haloazoles.21–24 However, these pro-
cedures, in which the coupling partners are both activated,
often involve several steps for preactivation of the coupling
partners. Thus, this methodology is time-consuming and
economically inefficient as it requires the installation and
subsequent disposal of stoichiometric amounts of activating
agents.
2-Arylazoles represent privileged structural motifs fre-
quently found in molecules that elicit important biological
responses. In fact, 2-aryl-1H-indole derivatives include
antiprotozoal agents,1 gonadotropin releasing hormone an-
tagonists,2 anti-estrogens,3 h5-HT2A receptor antagonists4
and compounds that exhibit anti-inflammatory5 or cytotoxic
activity.6 On the other hand, some 2-arylbenzothiazole
derivatives have been shown to possess potent inhibitory
activity against human cancer cell lines7 and some 2-aryl-
1H-benzimidazoles have been reported to possess inotropic
activity due at least in part to their Ca2+-sensitizing effect.8
Other 2-arylazoles containing two heteroatoms such as
some 2-aryl-1H-imidazoles have been described as antago-
nists of the cannabinoid CB1 receptor,9 selective COX-2
inhibitors,10 cytotoxic agents against a variety of cancer
cell lines11 or as neuropeptide Y5 antagonists.12 Finally, sev-
eral 2-arylbenzoxazoles have been shown to be heparanase
inhibitors13 and some 2-arylthiazoles have been reported
to be hepatotoxic agents.14
A very attractive, convenient and practical alternative to
these synthetic approaches involves the intermolecular
azolyl–aryl bond formation by transition metal-mediated
C-2 arylation of azoles 1 with aryl halides or pseudohalides
2 in the presence of a suitable ligand and an inorganic base
(Scheme 1).25 This methodology, which addresses issues of
synthetic efficiency and reaction processing, in the case of
the regioselective Pd-catalyzed C-2 arylation reactions
of 1-methyl-1H-imidazole25a and 1-aryl-1H-imidazoles11
with aryl halides, also requires the use 2 equiv of CuI as
additive.
The biological activities of these azoles have made them
popular synthetic targets. Numerous synthetic methods,
however, involve the construction of the azole ring by het-
eroannulation processes,7b,8,12,14a,15–20 which frequently re-
quire the preparation of the starting materials by multi-step
Y
Z
Y
Z
cat, base, ligand
solvent
Ar
+
Ar–X
3
1
2
Keywords: Azoles; Direct arylation; Regioselectivity; Biologically active
compounds; C–H bond activation.
* Corresponding authors. Tel.: +39 050 2219282/14; fax: +39 050 2219260;
e-mail addresses: bellina@dcci.unipi.it; rossi@dcci.unipi.it
(Y = CH, N; Z = NMe, NAr, NH, NAc, NMs, NBn, NSEM);
(Y = N; Z = O); (Y = N; Z = S); (X = Br, I, OTf)
Scheme 1.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.068

F. Bellina et al. / Tetrahedron 63 (2007) 1970–1980
1971
In the course of our studies into the synthesis and evaluation
of the biological properties of vicinal diaryl substituted five-
membered heterocycle derivatives11,26 we recently devel-
oped a regioselective and efficient procedure to prepare
1,2-diaryl-1H-imidazoles through direct C-2 arylation of
1-aryl-1H-imidazoles with aryl halides in the presence of
CuI and CsF and catalytic Pd(OAc)2 in DMF at 140 ꢀC under
ligandless conditions.11a Next, we examined more deeply the
reaction conditions under which to perform the direct C-2
arylation of 1-aryl-1H-imidazoles and other azoles and in
a preliminary communication we reported that a variety of
p-electron sufficient heteroarenes that included thiazole,
oxazole, 1-aryl-1H-imidazoles, 1-methyl-1H-imidazole as
well as free (NH)-imidazole, -benzimidazole and -indole
can undergo effective and highly regioselective Pd- and
Cu-mediated C-2 arylation with aryl iodides under base-
free and ligandless conditions.27 In this paper, we wish to
disclose the full details and scope of this unprecedented
and convenient methodology, which allows the use of
substrates containing base-sensitive groups, such as the NH
groups of imidazole, benzimidazole and indole, without their
prior protection. Moreover, we describe the successful use of
activated or unactivated aryl bromides in the synthesis of 2-
aryl-1-phenyl-1H-imidazoles by one-pot domino HALEX28
and Pd- and Cu-mediated arylation reactions of 1-phenyl-
1H-imidazole (4a) under base-free and ligandless conditions.
Finally, wereporttheapplicationsofournovelprotocolforthe
direct C-2 arylation of azoles to the preparation of the imid-
azole derivative 5, which is a selective COX-2 inhibitor,20d
2-(4-aminophenyl)-1H-benzimidazole (6a), which is a key
intermediate in the synthesis of a heparanase inhibitor29 and
some compounds with antimicrobial activities30 and
biologically active 2-arylbenzothiazoles 6b and 6c.
Compound 6b is a potent topoisomerase II inhibitor17b and
6c (CJM 126) is able to elicit biphasic growth inhibitory
effects against a panel of estrogen receptor-positive and
oestrogen receptor-negative human mammary cancer cell
lines in vitro.7c
2. Results and discussion
We initiated the study by examining the reaction of 4a with
2 equiv of 4-iodoanisole (7a) in DMF at 140 ꢀC in the pres-
ence of 5 mol % Pd(OAc)2 and 2 equiv of CuI and found that
after 26 h the reaction was complete and had cleanly and re-
gioselectively furnished the required 2-aryl-1H-imidazole
8a in 70% isolated yield (Table 1, entry 1). Interestingly,
this yield was significantly higher than that we previously
obtained in a similar reaction performed in the presence of
2 equiv of CsF.11a It is also worth mentioning that the crude
reaction mixture did not contain the biaryl derivative derived
from homocoupling of 7a or the triaryl derivative that would
have resulted from the C-2 and C-5 arylations of 4a. In
contrast, these byproducts contaminated the crude reaction
mixture obtained from the Pd- and Cu-mediated reaction of
4a with 7a, which was performed in the presence of CsF.11a
Next, we examined the possible influence of some reaction
parameters on the outcome of this C-2 arylation and found
that when the amount of CuI was reduced from 2 equiv to
0.5 equiv the reaction time was much longer (126 h) and
that compound8awas obtained in a lower yield (49%). More-
over, weobservedthatnoreaction occurred usingtoluene, xy-
lene, dioxane, diglyme or DMSO as solvent in place of DMF.
In contrast, the use of a solvent such as DMF, DMA or DMPU
possessing mildly basic characteristics proved to be neces-
sary. However, DMF proved to be the solvent of choice.
Me
R
N
N
N
N
The good result obtained in the preparation of 8a from 4a
and 7a using the experimental conditions reported in entry
1 of Table 1 prompted us to extend the procedure used in
this entry to the synthesis of other 1,2-diaryl-1H-imidazoles.
Entries 2–5 of Table 1 summarize the good results obtained
in the regioselective preparation of compounds 8b–d and 5
using these experimental conditions.
Cl
Ar1
4a : R = H; Ar1 = Ph
5
N
SO2Me
Ar2
Y
6a : Y = NH; Ar2 = 4-H2NC6H4
6b : Y = S; Ar2 = 3,4-Cl2C6H3
6c : Y = S; Ar2 = 4-H2NC6H4
We also investigated the use of aryl bromides 9 in the Pd- and
Cu-mediated C-2 arylation of 4a under base-free and
Table 1. Pd- and Cu-mediated C-2 arylation of 1-aryl-1H-imidazoles 4 with aryl iodides 7
R
N
R
N
N
Ar2
Pd(OAc)2 (5 mol %), CuI (2.0 equiv)
+
Ar2–I
N
DMF, 140 °C, 25–69 h
Ar1
4a–d
Ar1
8a–d and 5
7a–c
Entry
Reagents
Reaction timea
(h)
Product
Isolated yieldb
(%)
4
R
Ar1
7
Ar2
8 or 5
1
2
3
4
5
4a
4a
4b
4c
H
H
H
H
Me
Ph
Ph
7a
7b
7a
7a
7c
4-MeOC6H4
Ph
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
26
69
48
25
48
8a
8b
8c
8d
5
70 (62)
76 (55)
66 (38)
84 (67)
78 (62)
4-MeOC6H4
4-MeSO2C6H4
4-MeSO2C6H4
4dc
a
The reactions were complete after the reaction times indicated.
The values in parenthesis are referred to the isolated yields obtained in the corresponding reactions performed in the presence of 2 equiv of CsF (Ref. 11a).
This compound was not regioisomerically pure. It was contaminated by ca. 20% of 5-methyl-1-[(4-methylsulfonyl)phenyl]-1H-imidazole (4e).
b
c

1972
F. Bellina et al. / Tetrahedron 63 (2007) 1970–1980
ligandless conditions, but, in a test involving the reaction of
4a with 2 equiv of bromobenzene (9a) in DMF at 140 ꢀC,
1,2-diphenyl-1H-imidazole (8b) was obtained in only 41%
GLC yield after 161 h (Table 2, entry 1). A similar modest
GLC yield was obtained when the reaction between 4a
and 4-bromobenzotrifluoride (9b) was carried out using
analogous experimental conditions (Table 2, entry 2).
imidazole (10d), thiazole (10e), oxazole (10f), benzothiazole
(11a) and free (NH)-benzimidazole (11b).
Tables 3 and 4 summarize the results obtained in the highly
regioselective Pd- and Cu-mediated C-2 arylation reactions
of these heterocycles with unactivated, activated and deacti-
vated aryl iodides 7 under base-free and ligandless condi-
tions. Notably, the reactions occurred in high yields and
were very clean. In fact, the crude reaction mixtures obtained
from azoles 10 and iodides 7 contained no regioisomers of
the required 2-arylheteroarenes 1232 and, in the case of
free (NH)-imidazole (10c) and -benzimidazole (11b) were
also free of N-aryl derivatives.
Nevertheless, we found that the results of the reaction of 4a
with 9a could be improved by addition of 4 equiv of NaI to
the reagents. In fact, compound 8b was so obtained in 47%
isolated yield after 165 h at 140 ꢀC (Table 2, entry 3). A fur-
ther improvement of the yield of 8b was obtained using KI in
place of NaI. In fact, under these conditions 8b was obtained
in 57% yield (Table 2, entry 4). Interestingly, these experi-
mental conditions allowed us to prepare 8e in 72% yield
from 4a and the activated aryl bromide 9b (Table 2, entry
5), but they proved to be unsuitable for the C-2 arylation
of 4a with the deactivated aryl bromide 9c (Table 2, entry
6). It should also be noted that, despite their very long
reaction times and the unexpected presence in the final
reaction mixtures of significant amounts of aryl iodides
7 corresponding to the aryl bromides used as reagents, the
reactions, which provided compounds 8b and 8e were not
complete.
N
Y
N
Y
R
10a : Y = NMe; R = H
10b : Y = NBn; R = H
10c : Y = NH; R = H
10d : Y = NH; R = Ph
10e : Y = S; R = H
10f : Y = O; R = H
11a : Y = S
11b : Y = NH
Table 3. Synthesis of 2-arylazoles 12 by C-2 arylation of azoles 10
N
N
Ar2
Pd(OAc)2 (5 mol %), CuI (2.0 equiv)
DMF, 140 °C
+
Ar2–I
Iodides 7 most likely derived from an HALEX reaction be-
tween NaI or KI and aryl bromides 9 and compounds 8b and
8e were likely formed, at least in part, by C-2 arylation reac-
tions involving iodides 7. On the other hand, the result that
the arylation reactions were not complete could be explained
taking into account that the presence of a large molar excess
of iodide anions reduces the electrophilicity of the aryl-
palladium halide species31 undergoing transmetallation with
the 1-phenyl-1H-imidazol-2-ylcopper species, which pre-
sumably are intermediates of the catalytic cycle of these
arylations.
Y
10
Y
12
R
R
7
Entrya,b
Reagents
Ar2
Reaction Product Isolated
timea
(h)
yieldb
(%)
10
R
Y
7
12
1
2
10a
10b
10c
10c
10c
10c
10c
H
H
H
H
H
H
H
NMe 7a 4-MeOC6H4 48
NBn 7a 4-MeOC6H4 48
NH 7a 4-MeOC6H4 48
NH 7a 4-MeOC6H4 52
12a
12b
12c
12c
12d
12e
12f
12g
12h
12i
99
87
53
84
89
84
47
47
84
23
74
3
4c
5
NH 7b Ph
48
6
7
8
NH 7d 4-CF3C6H4 48
NH 7e 2-MeC6H4 48
10d Ph NH 7a 4-MeOC6H4 72
Next, the protocol developed for the Pd- and Cu-mediated
synthesis of compounds 8 from 1-aryl-1H-imidazoles 4 and
aryl iodides 7 was investigated for the regioselective C-2
arylation of several other p-electron sufficient heteroarenes
that included 1-methyl-1H-imidazole (10a), 1-benzyl-1H-
imidazole (10b), free (NH)-imidazole (10c), 5-phenyl-1H-
9
10
10e
10f
10f
H
H
H
S
O
O
7a 4-MeOC6H4 48
7a 4-MeOC6H4 48
7a 4-MeOC6H4 74
11d
12i
a
Unless otherwise reported the reactions were run using 1 mmol of 10 and
2 mmol of iodides 7 in 5 mL of DMF at 140 ꢀC.
The conversion of all reactions reported was quantitative.
This reaction was run using 2 mmol of 10c and 1 mmol of 7a.
This reaction was run using 3 mmol of 10f and 1 mmol of 7a.
b
c
d
Table 2. C-2 arylation of 1-phenyl-1H-imidazole (4a) with aryl bromides 9
R
R
N
N
Ar2
Pd(OAc)2 (5 mol %), CuX (2.0 equiv)
MI (4 equiv), DMF, 140 °C
Table 4. Synthesis of 2-arylbenzoazoles 6 by C-2 arylation of compounds
11
+
Ar2–Br
N
N
Ph
4a : R = H
Ph
8 : R = H
N
Y
N
Y
Pd(OAc)2 (5 mol %), CuI (2.0 equiv)
DMF, 140 °C
Ar2
+ Ar2–I
9
Entrya
Aryl bromide
Ar2
MI
Reaction Product Isolated
11
Entrya
7
6
timea (h)
yieldb (%)
9
8
Reagents
Ar2
Reaction Product Isolated
yield (%)
time (h)
1
2
3
4
5
6
9a Ph
—
—
161
115
8b
8e
8b
8b
8e
—
(41)
(35)
47
57
72
11
Y
7
6
9b 4-CF3C6H4
9a Ph
9a Ph
9b 4-CF3C6H4
9c 4-MeOC6H4 KI
NaI 165
KI
KI
1
2
3
4
11a
11a
S
S
7f 4-NO2C6H4 115
7g 3,4-Cl2C6H3 48
6d
6b
6e
6f
85
87
81
89
164
166
166
11b NH 7a 4-MeOC6H4
11b NH 7f 4-NO2C6H4
48
96
—
a
a
The reactions were run using 1 mmol of 4a and 2 mmol of aryl bromides 9.
The values in parenthesis are referred to GLC yield (naphthalene was used
as internal standard).
The reactions were run using 1 mmol of 11 and 2 mmol of iodides 7 in
5 mL of DMF. After the period of time reported here the conversion of
the reactions was quantitative.
b

F. Bellina et al. / Tetrahedron 63 (2007) 1970–1980
1973
On the other hand, the use of ligandless conditions pre-
vented the formation of byproducts that might derive
from scrambling of the aryl moieties of iodides 7 with the
organic group of the ligands, which had been found in the
crude reaction mixtures obtained from the Pd-catalyzed
arylation of 1-aryl-1H-imidazoles 4 in the presence of
triarylphosphines.26c
Scheme 3 summarizes the results obtained in this prelimi-
nary investigation.
OMe
N
Y
+
I
4a : Y = NPh
10c : Y = NH
10e : Y = S
7a
It should also be noted that in entries 4 and 11 of Table 3,
where a molar excess of imidazole (10c) and oxazole (11),
respectively, was reacted with aryl iodide 7a, the required
2-arylazoles were obtained in yields significantly higher
than those of the same reactions performed using a molar ex-
cess of 7a (Table 3, entries 3 and 10, respectively). However,
despite these good results, we preferred to perform the other
arylation reactions reported in Tables 3 and 4 using a molar
excess of aryl iodides 7 since the purification of the reaction
mixtures and isolation of the required chemically pure 2-
arylazoles proved to be easier by using these experimental
conditions.
10 % Pd/C (5 mol %)
CuI (2 equiv)
DMF, 140 °C
N
Y
OMe
(144 h; 90 %)
8a : Y = NPh
12c : Y = NH (68 h; 41 %)
12h : Y = S
(48 h; 62 %)
Scheme 3.
Thus, the reaction of 4a with 2 equiv of 7a in DMF at 140 ꢀC
for 144 h in the presence of 10% Pd/C (5 mol %) and CuI
(2 equiv) gave 8a in a yield (90%) higher than that obtained
using Pd(OAc)2 in place of Pd/C (Table 1, entry 1). However,
the yields of compounds 12c and 12h (41 and 62%, respec-
tively), which were prepared using Pd/C as the catalyst
proved to be lower than those obtained in the analogous
reactions performed under homogeneous conditions (Table
3, entries 4 and 9, respectively).
It is also worth noting that compound 6b, which was ob-
tained in 87% yield by arylation of 11a with 7g (Table 4,
entry 2), is a topoisomerase II inhibitor.17b On the other
hand, compounds 6d and 6f, which were prepared in 85
and 89% yield, respectively, by arylation of 11a and 11b
with 7f (Table 4, entries 1 and 4, respectively), could be
selectively reduced by using zinc dust and hydrazinium
monoformate33 to give the biologically active derivatives
6c7c and6a29,30 in67and90%yield, respectively(Scheme2).
Recently, compound 6c has been used to prepare a rhenium
complex that enters MCF-7 breast cancer cell lines and the
analogous radioactive 99mTc complex that produces fast
blood and soft tissue clearance when administered to healthy
mice.34 Compounds 6a and 6c were so prepared since they
could not be synthesized by Pd- and Cu-mediated direct aryl-
ation of benzimidazole (11b) and benzothiazole (11a),
respectively, with4-iodoaniline. Infact, thesereactions,which
provided black reaction mixtures, did not produce significant
amounts of the required 2-(4-aminophenyl)benzoazoles.
Finally, it appeared to be of interest to investigate the pos-
sibility of using our novel protocol for the Pd- and Cu-
mediated C-2 arylation of azoles with aryl iodides under
base-free and ligandless conditions also for the selective
C-2 arylation of free (NH)-indole (13a). In fact, even though
all results that we had obtained for the arylation reactions of
1,3-azoles using this protocol might indicate that the pres-
ence and participation of a basic pyridine-like nitrogen
atom was required in the heteroarenes, which were used as
substrates for the arylation reaction, we speculated that
the presence of a pyridine-like nitrogen atom might be
unnecessary provided that the arylation reaction was per-
formed in a solvent such as DMF or DMA with mildly basic
characteristics.36
N
NO2
Y
6d : Y = S
6f : Y = NH
13a : R = H
13b : R = Bn
Zn, H2N–NH2
HCOOH, MeOH, rt
13c : R = 4-MeOC6H4
13d : R = SO2C6H4
13e : R = Me
N
R
N
NH2
Y
6c : Y = S
(67 %)
6a : Y = NH (90 %)
As we had hoped for, we found that 13a is able to react with
iodide 7a in DMF at 140 ꢀC in the presence of 5 mol %
Pd(OAc)2 and 2 equiv of CuI to give 2-aryl-1H-indole 14a
in 35% isolated yield (Table 5, entry 1). Interestingly,
when the reaction between 2 equiv of 7a and 13a was per-
formed in DMA at 160 ꢀC, instead of in DMA at 140 ꢀC,
compound 14a was obtained in 54% isolated yield (Table 5,
entry 2).
Scheme 2.
We also performed a preliminary study aimed at evaluating
the possibility of using Pd/C in place of Pd(OAc)2 in the
regioselective Pd- and Cu-mediated C-2-arylation of azoles
4a, 10c and 10e. In fact, Pd/C is an inexpensive heteroge-
neous catalyst, which can be removed by filtration at the
end of the reaction and, thus, does not contaminate the
reaction product. Moreover, it can be recycled for another
reaction.35
However, this compound was isolated in only 10% yield
from the Pd- and Cu-mediated reaction of 2 equiv of 13a
with 7a (Table 5, entry 3). On the other hand, the Pd- and

1974
F. Bellina et al. / Tetrahedron 63 (2007) 1970–1980
Table 5. Pd- and Cu-mediated C-2 arylation of free (NH)-indole (13a)
free (NH)-indole and its 1-substituted derivatives under
these experimental conditions and that acidic conditions
promote the oligomerization of indole.37
Pd(OAc)2 (5 mol %), CuI (2.0 equiv)
+ Ar2–I
Ar2
DMF, 140 °C or DMA, 160 °C
N
H
N
H
14
13a
7
Finally, regarding the mechanism of the arylation reactions
of the azoles used in this paper as substrates, we propose
that it involves, as we recently reported,11a the formation
of an organocopper(I) derivative followed by a transmetalla-
tion reaction with an arylpalladium(II) halide species and
a reductive elimination. On the other hand, coordination
of heterocycles 4, 10 and 11 to CuI to form p-complexes
might significantly lower the pKa of their C–H bonds at
position 2 and facilitate their conversion into C–Cu
bonds.38 However, at present, a reaction mechanism involv-
ing the presence of organopalladium(II) and organopalla-
dium(IV) species and organocopper(I) derivatives cannot
be excluded.39
Entrya
Reagents
Ar2
Solvent Reaction
temperature
(ꢀC)
Product Isolated
yield
7
14
(%)
1
7a 4-MeOC6H4 DMF
7a 4-MeOC6H4 DMA
7a 4-MeOC6H4 DMA
7b Ph DMA
7d 4-CF3C6H4 DMA
140
160
160
160
160
14a
14a
14a
14b
14c
35
53
10
29
33
2
3b
4
5
a
Unless otherwise reported the reactions were run using 1 mmol of 13a and
2 mmol of iodides 7 in 5 mL of DMF or DMA for 48 h.
The reaction was run using a 2/1 molar ratio between 13a and 7a.
b
Studies on further applications of our direct arylation proto-
col for the synthesis of compounds of interest in medicinal
chemistry are in progress.
Cu-mediated reaction of 13a with 2 equiv of iodides 7b and
7d in DMA at 160 ꢀC gave compounds 14b and 14c in 29
and 33% yield, respectively (Table 5, entries 4 and 5, respec-
tively). Unfortunately, the protocolusedtoprepare2-aryl-1H-
indoles 14a–d proved to be unsuitable for the arylation of
1-benzyl-1H-indole (13b), 1-(4-methoxyphenyl)-1H-indole
(13c), 1-(benzensulfonyl)-1H-indole (13d) and 1-methyl-
1H-indole (13e). In fact, the required 2-aryl-1-substituted-
1H-indoles were obtained in very low yields.
4. Experimental
4.1. General
Melting points are uncorrected. Merck precoated 60 F254
aluminium 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 Alltech AT-1 bonded FSOT column (30 mꢁ
0.25 mm i.d.) and an Alltech AT-35 bonded FSOT column
(30 mꢁ0.25 mm i.d.). Purifications by MPLC on silica gel
(Merck silica gel 60, particle size 0.015–0.040 mm) were
3. Conclusions
We have disclosed an efficient and reliable general method
for the direct and highly regioselective C-2 arylation of
azoles with aryl iodides, which does not produce byproducts
and thus allow to obtain the required 2-arylazoles in high
purity. The unprecedented reaction conditions of this new
procedure, which do not involve the use of a base, can also
be employed for the arylation of substrates containing
base-sensitive groups such as the NH groups in imidazole,
benzimidazole and indole, without their prior protection.
This new arylation protocol, which is suitable for medicinal
chemistry where a wide diversity of products is desired, has
been applied for the preparation of a large variety of 2-aryl-
azoles that include three biologically active compounds and
a key intermediate of a heparanase inhibitor and some anti-
microbial products. Moreover, we have developed a one-pot
domino procedure for the synthesis of 2-aryl-1-phenyl-1H-
imidazoles from 1-phenyl-1H-imidazole and activated or
unactivated aryl bromides.
€
performed 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 GLC/MS. GLC/
MS analyses were performed using an Agilent 6890 Network
GC system interfaced 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 performed in flame dried glassware under
a positive atmosphere of argon by standard syringe, cannula
and septa techniques. 1-Phenyl-1H-imidazole (4a), 4-iodo-
anisole (7a), iodobenzene (7b), 1-chloro-4-iodobenzene
(7c), 4-iodobenzotrifluoride (7d), 2-iodotoluene (7e), 1-
iodo-4-nitrobenzene (7f), 1,2-dichloro-4-iodobenzene (7g),
bromobenzene (9a), 4-bromobenzotrifluoride (9b), 4-bromo-
anisole (9c), 1-methyl-1H-imidazole (10a), 1-benzyl-1H-
imidazole (10b), imidazole (10c), 4(5)-phenyl-1H-imidazole
(10d), thiazole (10e), oxazole (10f), benzothiazole (11a),
benzimidazole (11b) and indole (13a) were commercially
available. The following compounds were prepared accord-
ing to the literature: 1-(4-methoxyphenyl)-1H-imidazole
(4b),11a 1-[(4-methylsulfonyl)phenyl]-1H-imidazole (4c),11a
4-methyl-1-[(4-methylsulfonyl)phenyl]-1H-imidazole(4d),11a
1-benzyl-1H-indole (13b),40 1-(4-methoxyphenyl)-1H-
indole (13c)41 and 1-phenylsulfonyl-1H-indole (13d).42
Compound 4d, which was contaminated by ca. 20% of
5-methyl-1-[(4-methylsulfonyl)phenyl]-1H-imidazole (4e),
The results presented in this paper also indicate that the Pd-
and Cu-mediated arylation, under base-free and ligandless
conditions, may involve also heterocycles that do not contain
a basic pyridine-like nitrogen atom, provided that this reac-
tion is performed in a solvent with mildly basic characteris-
tics. Nevertheless, the Pd- and Cu-mediated C-2 arylation
of free (NH)-indole with aryl iodides under base-free and
ligandless conditions provides 2-aryl-1H-indoles in modest
yields. In our opinion, this result can be rationalized taking
into account that a significant lowering of the pH of the
reaction mixture, due to the development of iodidric acid,
is produced in the Pd- and Cu-mediated C-2 arylation of

F. Bellina et al. / Tetrahedron 63 (2007) 1970–1980
1975
was used without any further purification in a subsequent
Pd- and Cu-mediated arylation reaction with iodide 7c.
as a colourless solid. Mp 78–79 ꢀC (lit.11a mp 77–79 ꢀC).
EIMS, m/z 221 (14), 220 (90), 219 (100), 193 (12), 90
(11). H NMR (300 MHz, CDCl3) d 7.43 (m, 5H), 7.33 (d,
1
4.2. General procedure for the Pd- and Cu-mediated C-2
arylation of 1-aryl-1H-imidazoles 4a–d, azoles 10a–f and
benzoazoles 11a,b with aryl iodides 7
J¼1.3 Hz, 1H), 7.27 (m, 5H), 7.19 (d, J¼1.3 Hz, 1H). 13C
NMR (75.5 MHz, CDCl3) d 146.2, 138.0, 129.7 (2C),
129.5, 129.1, 128.8 (2C), 128.6, 128.4 (2C), 127.5, 125.9
(2C), 122.9. The physical and spectral properties of this
compound were in good agreement with those reported for
8b prepared by Pd- and Cu-mediated reaction of 4a with
7b in DMF at 140 ꢀC in the presence of CsF under ligandless
conditions.11a
Compound 4, 10 or 11 (1.0 mmol), Pd(OAc)2 (11.2 mg,
0.05 mmol), CuI (0.38 g, 2.0 mmol) and (if a solid) aryl
iodide 7 (2.0 mmol) were placed in the reaction vessel under
a stream of argon. The reactionvessel equipped with a silicon
septum, a reflux condenser and a magnetic stirrer was evac-
uated and back-filled with argon, and this sequence was re-
peated twice. Deaerated DMF (5 mL) and (if a liquid) the
aryl iodide 7 (2.0 mmol) were then added successively by
syringe under a stream of argon. The resulting mixture was
stirred at 140 ꢀC under argon for the period of time reported
in Tables 1, 3 and 4. The degree of completion of the reaction
was evaluated by GLC and GLC/MS analyses of a sample of
the crude reaction mixture. After being cooled to room tem-
perature the reaction mixture was diluted with AcOEt and
poured into a saturated aqueous NH4Cl solution and the re-
sulting mixture was stirred in the open air for 0.5 h and then
extracted with AcOEt. The organic extract was washed with
water, dried, filtered trough Celite and the filtrate was con-
centrated under reduced pressure. The residue was purified
by MPLC on silica gel and the chromatographic fraction
containing the required compound were collected and con-
centrated under reduced pressure. This procedure was em-
ployed to prepare compounds 8a–d and 5 (Table 1, entries
1–5), 2-arylazoles 12a–i (Table 2, entries 1–11) and 2-
arylbenzoazoles 6d, 6b and 6e (Table 4, entries 1–3). GLC
analysis showed that all these compounds had chemical
purity higher than 98%. However, the crude reaction product
obtained in entry 4 of Table 4 was purified by recrystal-
lization. Compound 6f, which was so obtained had 92%
chemical purity.
4.2.3. 1,2-Bis(4-methoxyphenyl)-1H-imidazole (8c). The
crude reaction product obtained in entry 3 of Table 1 by
Pd- and Cu-mediated reaction of 4b with 7a was purified
by MPLC on silica gel with a mixture of CH2Cl2 and
MeOH (98:2) as eluent and subsequent treatment with
3-(mercaptopropyl)-functionalized silica gel to give 8c
(0.19 g, 66%) as a colourless solid. Mp 107–109 ꢀC (lit.11a
mp 107–109 ꢀC). EIMS, m/z 281 (18), 280 (100), 279
(33), 265 (20), 147 (17). 1H NMR (300 MHz, CDCl3)
d 7.39 (d, J¼8.3 Hz, 2H), 7.28 (br s, 1H), 7.16 (m, 2H),
7.09 (br s, 1H), 6.92 (m, 2H), 6.81 (d, J¼8.3 Hz, 2H), 3.85
(s, 3H), 3.79 (s, 3H). 13C NMR (75.5 MHz, CDCl3)
d 160.4, 159.7, 146.3, 131.0, 130.1 (2C), 127.2 (2C),
126.0, 122.8, 121.0, 114.7 (2C), 113.9 (2C), 55.6, 55.3.
The physical and spectral properties of this compound
were in good agreement with those reported for 8c prepared
by Pd- and Cu-mediated reaction of 4b with 7a in DMF
at 140 ꢀC in the presence of CsF under ligandless
conditions.11a
4.2.4. 2-(4-Methoxyphenyl)-1-[(4-methylsulfonyl)-
phenyl]-1H-imidazole (8d). The crude reaction product ob-
tained in entry 4 of Table 1 by Pd- and Cu-mediated reaction
of 4c with 7a was purified by MPLC on silica gel with a mix-
ture of CH2Cl2 and MeOH (98:2) as eluent and subsequent
treatment with 3-(mercaptopropyl)-functionalized silica
gel to give 8d (0.28 g, 84%) as a colourless solid. Mp
154–156 ꢀC (lit.11a mp 154–155 ꢀC). EIMS, m/z 329 (22),
328 (100), 327 (57), 248 (28), 148 (86). 1H NMR
(300 MHz, CDCl3) d 7.98 (m, 2H), 7.42 (m, 2H), 7.29 (m,
3H), 7.18 (s, 1H), 6.82 (m, 2H), 3.80 (s, 3H), 3.09 (s, 3H).
13C NMR (75.5 MHz, CDCl3) d 160.4, 146.8, 142.8,
140.0, 130.4 (2C), 129.0 (3C), 126.4 (2C), 121.9, 121.4,
114.1 (2C), 55.3, 44.4. The physical and spectral properties
of this compound were in good agreement with those re-
ported for 8d prepared by Pd- and Cu-mediated reaction of
4c with 7a in DMF at 140 ꢀC in the presence of CsF under
ligandless conditions.11a
4.2.1. 2-(4-Methoxyphenyl)-1-phenyl-1H-imidazole (8a).
The crude reaction product obtained in entry 1 of Table 1
by Pd- and Cu-mediated reaction of 4a with 7a was purified
by MPLC on silica gel with a mixture of AcOEt and toluene
(50:50+0.1% Et3N) as eluent and subsequent treatment with
3-(mercaptopropyl)-functionalized silica gel to give 8a
(0.17 g, 70%) as a pale yellow solid. Mp 125–127 ꢀC
(lit.11a mp 125–127 ꢀC). EIMS, m/z 251 (17), 250 (100),
1
249 (70), 235 (13), 206 (26). H NMR (300 MHz, CDCl3)
d 7.43 (m, 3H), 7.37 (m, 2H), 7.30 (br s, 1H), 7.24 (m,
2H), 7.14 (br s, 1H), 6.80 (m, 2H), 3.78 (s, 3H). 13C NMR
(75.5 MHz, CDCl3) d 160.3, 146.1, 138.1, 130.2 (2C),
129.7 (2C), 128.6, 127.0, 125.8 (2C), 122.5, 121.3, 113.6
(2C), 55.2. The physical and spectral properties of this com-
pound were in good agreement with those reported for 8a
prepared by Pd- and Cu-mediated reaction of 4a with 7a in
DMF at 140 ꢀC in the presence of CsF under ligandless
conditions.11a
4.2.5. 4-Methyl-2-(4-chlorophenyl)-1-[(4-methylsulfo-
nyl)phenyl]-1H-imidazole (5). The crude reaction product
obtained in entry 4 of Table 1 by Pd- and Cu-mediated reac-
tion of 4d with 7c was purified by MPLC on silica gel with
a mixture of CH2Cl2 and MeOH (98:2) as eluent and sub-
sequent treatment with 3-(mercaptopropyl)-functionalized
silica gel to give 8d (0.27 g, 78%) as a colourless solid.
Mp 60–61 ꢀC (lit.11a mp 60 ꢀC). EIMS, m/z 348 (38), 347
4.2.2. 1,2-Diphenyl-1H-imidazole (8b). The crude reaction
product obtained in entry 2 of Table 1 by Pd- and Cu-medi-
ated reaction of 4a with 7b was purified by MPLC on silica
gel with a mixture of AcOEt and toluene (50:50+0.1% Et3N)
as eluent and subsequent treatment with 3-(mercapto-
propyl)-functionalized silica gel to give 8b (0.17 g, 76%)
1
(33), 346 (100), 345 (38), 226 (21). H NMR (300 MHz,
CDCl3) d 7.97 (m, 2H), 7.38 (m, 2H), 7.31 (m, 2H), 7.27
(m, 2H), 6.94 (s, 1H), 3.09 (s, 3H), 2.33 (s, 3H). 13C NMR
(75.5 MHz, CDCl3) d 144.9, 142.4, 140.1, 138.9, 135.4,

1976
F. Bellina et al. / Tetrahedron 63 (2007) 1970–1980
130.1 (2C), 129.1 (2C), 128.9 (2C), 127.6, 126.1 (2C), 119.1,
44.4, 13.4. The physical and spectral properties of this
compound were in good agreement with those reported for
5 prepared by Pd- and Cu-mediated reaction of 4d with 7a
in DMF at 140 ꢀC in the presence of CsF under ligandless
conditions.11a
4.2.10. 2-[(4-Trifluoromethyl)phenyl]-1H-imidazole
(12e). The crude reaction product obtained in entry 6 of
Table 3 by Pd- and Cu-mediated reaction of 10c with 7d
was purified by MPLC on silica gel with a mixture of
CH2Cl2 and MeOH (95:5) as eluent to give 12e (0.18 g,
84%) as a colourless solid. Mp 219–221 ꢀC (lit.40 mp
248 ꢀC). EIMS, m/z 213 (11), 212 (100), 193 (9), 185 (33),
1
4.2.6. 2-(4-Methoxyphenyl)-1-methyl-1H-imidazole
(12a). The crude reaction product obtained in entry 1 of
Table 3 by Pd- and Cu-mediated reaction of 10a with 7a
was purified by MPLC on silica gel with a mixture of
CH2Cl2 and MeOH (96:4) as eluent and subsequent treat-
ment with 3-(mercaptopropyl)-functionalized silica gel to
give 12a (0.19 g, 99%) as a yellow oil. EIMS, m/z 188
158 (13). H NMR (300 MHz, CD3OD) d 8.03 (m, 2H),
7.74 (m, 2H), 7.20 (s, 2H). 13C NMR (75.5 MHz, CD3OD)
d 146.5, 135.0, 131.3 (d, JC–F¼32 Hz), 126.9, (q, JC–F
¼
3.6 Hz, 2C), 126.8 (2C), 124.8. Anal. Calcd for
C10F3H6N2: C, 56.88; H, 2.86. Found: C, 56.69; H, 3.10.
4.2.11. 2-(2-Methylphenyl)-1H-imidazole (12f). The crude
reaction product obtained in entry 7 of Table 3 by Pd- and
Cu-mediated reaction of 10c with 7e was purified by
MPLC on silica gel with a mixture of CH2Cl2 and MeOH
(96:4) as eluent to give 12f (75 mg, 47%) as a colourless
solid. Mp 138–139 ꢀC (lit.45 mp 136 ꢀC). EIMS, m/z 159
(11), 158 (96), 157 (100), 130 (17), 103 (7). 1H NMR
(300 MHz, CDCl3) d 7.38 (d, J¼7.5 Hz, 1H), 7.21 (m,
2H), 7.10 (t, J¼7.5 Hz, 1H), 6.91 (m, 2H), 2.36 (s, 3H).
13C NMR (75.5 MHz, CDCl3) d 147.0, 136.5, 130.9,
130.5, 129.2, 128.6 (2C), 125.7, 122.3, 20.6. Anal. Calcd
for C10H10N2: C, 75.92; H, 6.37: Found: C, 75.86; H, 6.23.
1
(100), 187 (93), 173 (16), 172 (22), 145 (17). H NMR
(300 MHz, CDCl3) d 7.55 (m, 2H), 7.08 (d, J¼1.0 Hz,
1H), 6.97 (m, 2H), 6.92 (d, J¼1.0 Hz, 1H), 3.83 (s, 3H),
3.69 (s, 3H). 13C NMR (75.5 MHz, CDCl3) d 159.9, 147.8,
130.0 (2C), 128.1, 123.2, 122.0, 113.9 (2C), 55.3, 34.4.
The spectroscopic data of this compound were in agreement
with those previously reported.43
4.2.7. 1-Benzyl-2-(4-methoxyphenyl)-1H-imidazole
(12b). The crude reaction product obtained in entry 2 of
Table 3 by Pd- and Cu-mediated reaction of 10b with 7a
was purified by MPLC on silica gel with a mixture of
CH2Cl2 and MeOH (97:3) as eluent and subsequent treat-
ment with 3-(mercaptopropyl)-functionalized silica gel to
give 12b (0.23 g, 87%) as a pale orange oil. EIMS, m/z
4.2.12. 2-(4-Methoxyphenyl)-5-phenyl-1H-imidazole
(12g). The crude reaction product obtained in entry 8 of
Table 3 by Pd- and Cu-mediated reaction of 10d with 7a was
purified by MPLC on silica gel with a mixture of CH2Cl2 and
MeOH (99:1) as eluent to give 12g (0.12 g, 47%) as a yellow
solid. Mp 160–162 ꢀC. EIMS, m/z 251 (19), 250 (100), 235
1
265 (19), 264 (98), 174 (12), 173 (100), 91 (34). H NMR
(300 MHz, CDCl3) d 7.46 (m, 2H), 7.30 (m, 3H), 7.14 (d,
J¼1.2 Hz, 1H), 7.06 (m, 2H), 6.90 (m, 3H), 5.16 (s, 2H),
3.77 (s, 3H). 13C NMR (75.5 MHz, CDCl3) d 160.0, 148.1,
137.1, 130.1 (2C), 128.9 (2C), 128.7 (2C), 127.8, 126.5
(2C), 114.0 (2C), 55.2, 50.3. Anal. Calcd for C17H16N2O:
C, 77.25; H, 6.10. Found: C, 77.31; H, 6.03.
1
(41), 207 (13), 89 (8). H NMR (300 MHz, CDCl3) d 7.77
(m, 2H), 7.71 (d, J¼6.9 Hz, 2H), 7.37–7.20 (m, 4H), 6.85
(m, 2H), 3.78 (s, 3H). 13C NMR (75.5 MHz, CDCl3)
d 160.1, 147.4, 138.8, 132.7, 128.7 (2C), 126.9 (3C), 124.9
(2C), 123.0, 116.9, 114.2 (2C), 55.3. Anal. Calcd for
C16H14N2O: C, 76.78; H, 5.64. Found: C, 76.69; H, 5.60.
4.2.8. 2-(4-Methoxyphenyl)-1H-imidazole (12c). The
crude reaction product obtained in entry 4 of Table 3 by
Pd- and Cu-mediated reaction of 10c with 7a was purified
by MPLC on silica gel with a mixture of CH2Cl2 and
MeOH (95:5) as eluent to give 12c (0.15 g, 84%) as a colour-
less solid. Mp 152–153 ꢀC (lit.43 mp 160–161 ꢀC). EIMS,
4.2.13. 2-(4-Methoxyphenyl)thiazole (12h). The crude re-
action product obtained in entry 9 of Table 3 by Pd- and Cu-
mediated reaction of 10e with 7a was purified by MPLC on
silica gel with a mixture of hexane and AcOEt (80:20) as elu-
ent to give 12h (0.16 g, 84%) as a pale yellow oil. EIMS, m/z
1
m/z 175 (11), 174 (100), 159 (46), 147 (7), 131 (29). H
1
NMR (300 MHz, acetone-d6) d 9.04 (br s, 1H), 7.92 (m,
2H), 7.10 (s, 2H), 6.97 (m, 2H), 3.81 (s, 3H). 13C NMR
(75.5 MHz, acetone-d6) d 160.8, 147.3, 127.5 (2C), 124.9,
123.6, 115.0, 55.7. Anal. Calcd for C10H10N2: C, 68.95; H,
5.79. Found: C, 68.87; H, 5.64. The spectral data of this com-
pound were in agreement with those previously reported.43
192 (12), 191 (100), 176 (43), 148 (15), 58 (21). H NMR
(300 MHz, CDCl3) d 7.89 (m, 2H), 7.79 (d, J¼3.2 Hz, 1H),
7.23 (d, J¼3.2 Hz, 1H), 6.93 (m, 2H), 3.82 (s, 3H). 13C
NMR (75.5 MHz, CDCl3) d 168.4, 161.2, 143.5, 128.2 (2C),
126.7, 118.0, 114.4 (2C), 55.5. The spectral data of this com-
pound were in agreement with those previously reported.43
4.2.9. 2-Phenyl-1H-imidazole (12d). The crude reaction
product obtained in entry 5 of Table 3 by Pd- and Cu-medi-
ated reaction of 10c with 7b was purified by MPLC on silica
gel with a mixture of CH2Cl2 and MeOH (95:5) as eluent to
give 12d (0.13 g, 89%) as a pale yellow solid. Mp 141–
143 ꢀC (lit.44 mp 140–142 ꢀC). EIMS, m/z 145 (10), 144
(100), 117 (41), 90 (17), 77 (8). 1H NMR (300 MHz,
CD3OD) d 7.86 (m, 2H), 7.41 (m, 3H), 7.13 (m, 2H). 13C
NMR (75.5 MHz, CD3OD) d 148.1, 131.5, 129.9 (2C),
129.7 (2C), 126.4 (2C), 123.8. The spectral properties of
this compound were in agreement with those of commer-
cially available 12d.
4.2.14. 2-(4-Methoxyphenyl)oxazole (12i). The crude reac-
tion product obtained in entry 11 of Table 3 by Pd- and Cu-
mediated reaction of 10f with 7a was purified by MPLC on
silica gel with a mixture of hexane and AcOEt (80:20) as
eluent to give 12i (0.13 g, 74%) as a pale yellow oil.
EIMS, m/z 176 (11), 175 (100), 132 (25), 120 (21), 91
1
(16). H NMR (300 MHz, CDCl3) d 7.98 (m, 2H), 7.65 (d,
J¼0.7 Hz, 1H), 7.19 (d, J¼0.7 Hz, 1H), 6.97 (m, 2H), 3.85
(s, 3H). 13C NMR (75.5 MHz, CDCl3) d 162.1, 161.4,
138.0, 128.1, 128.0 (2C), 120.3, 114.2 (2C), 55.4. The
spectral data of this compound were in agreement with those
previously reported.42

F. Bellina et al. / Tetrahedron 63 (2007) 1970–1980
1977
4.2.15. 2-(4-Nitrophenyl)benzothiazole (6d). The crude re-
action product obtained in entry 1 of Table 4 by Pd- and Cu-
mediated reaction of 11a with 7f was purified by MPLC on
silica gel with a mixture of toluene and petroleum ether
(70:30+0.1% Et3N) as eluent and subsequent treatment
with 3-(mercaptopropyl)-functionalized silica gel to give
6d (0.22 g, 85%) as a pale yellow solid. Mp 226–228 ꢀC
(lit.46 mp 228–230 ꢀC). EIMS, m/z 257 (16), 256 (100),
iodide (4.0 mmol) were placed in the reaction vessel under
a stream of argon. The reaction vessel, which was fitted
with a silicon septum, a reflux condenser and a magnetic stir-
rer, was evacuated and back-filled with argon, and the se-
quence was repeated twice. Deaerated DMF (5 mL) and an
aryl bromide 9 (2.0 mmol) were then added successively
by syringe under a stream of argon. The resulting mixture
was stirred at 140 ꢀC under argon for the period of time re-
ported in Table 2. The degree of completion of the reaction
was evaluated by GLC and GLC/MS analysis of a sample of
the crude reaction mixture after treatment with a saturated
aqueous NH4Cl solution. After being cooled to room tem-
perature the reaction mixture was worked up using the
same procedure employed for the Pd- and Cu-mediated C-
2 arylation reactions of compounds 4a–d, 10a–f and 11a,b
with aryl iodides 7. This procedure was used to prepare com-
pounds 8b and 8e in 57 and 72% yield, respectively (Table 2,
entries 4 and 5). It should be noted that, at least in the case of
the reaction of 4a with bromobenzene (9b), a higher yield of
8b was obtained when KI was used in place of NaI (compare
entries 3 and 4 of Table 2). However, this procedure proved
to be unsuitable for the C-2 arylation of 4a with 4-bromo-
anisole (9c) (Table 2, entry 6).
1
226 (12), 210 (37), 209 (37). H NMR (300 MHz, CDCl3)
d 8.35 (m, 2H), 8.26 (m, 2H), 8.13 (d, J¼7.8 Hz, 1H), 7.96
(m, 1H), 7.54 (m, 1H), 7.48 (m, 1H). 13C NMR (75.5 MHz,
CDCl3) d 154.1, 149.0, 139.2, 135.5, 128.3 (2C), 126.9,
126.2, 124.3 (2C), 123.9, 121.8 (2C). Anal. Calcd for
C13H8N2O2S: C, 60.93; H, 3.14. Found: C, 60.83; H, 3.07.
4.2.16. 2-(3,4-Dichlorophenyl)benzothiazole (6b). The
crude reaction product obtained in entry 2 of Table 4 by
Pd- and Cu-mediated reaction of 11a with 7g was purified
by MPLC on silica gel with a mixture of toluene and petro-
leum ether (20:80) as eluent and subsequent treatment with
3-(mercaptopropyl)-functionalized silica gel to give 6b
(0.24 g, 87%) as a colourless solid. Mp 115–116 ꢀC (lit.46
mp 117–118 ꢀC). EIMS, m/z 283 (14), 282 (11), 281 (67),
280 (20), 279 (100). 1H NMR (200 MHz, acetone-d6)
d 8.27 (d, J¼1.8 Hz, 1H), 8.12 (m, 1H), 8.05 (m, 2H), 7.74
(d, J¼8.4 Hz, 1H), 7.53 (m, 2H). 13C NMR (50.3 MHz,
C6D6) d 164.9, 154.6, 135.6, 135.0, 133.9, 133.7, 131.0,
129.3, 126.8, 126.6, 125.8, 124.0, 121.8. The 1H NMR
data of this compound were in agreement with those previ-
ously reported.17b
4.3.1. 1-Phenyl-2[(4-trifluoromethyl)phenyl]-1H-imid-
azole (8e). The crude reaction product obtained in entry 5
of Table 2 by Pd- and Cu-mediated reaction of 4a with 4-
bromobenzotrifluoride (9b) in the presence of KI was puri-
fied by MPLC on silica gel with a mixture of AcOEt and
toluene (50:50+0.1% Et3N) and subsequent treatment with
3-(mercaptopropyl)-functionalized silica gel to give 8e
(0.21 g, 72%) as a pale yellow solid. Mp 85–87 ꢀC (lit.11a
mp 85–87 ꢀC). EIMS, m/z 289 (15), 288 (92), 287 (100),
4.2.17. 2-(4-Methoxyphenyl)-1H-benzimidazole (6e). The
crude reaction product obtained in entry 3 of Table 4 by Pd-
and Cu-mediated reaction of 11b with 7a was purified by
MPLC on silica gel with a mixture of CH2Cl2 and MeOH
(96:4) as eluent to give 6e (0.18 g, 81%) as a pale yellow
solid. Mp 215–217 ꢀC (lit.47 mp 224–229 ꢀC). EIMS, m/z
1
269 (6), 261 (22). H NMR (300 MHz, CDCl3) d 7.53 (m,
4H), 7.46 (m, 3H), 7.32 (br s, 1H), 7.22 (m, 3H). 13C
NMR (75.5 MHz, CDCl3) d 145.0, 138.0, 133.1, 130.4,
129.8 (2C), 128.9 (2C), 128.7 (2C), 125.9 (2C), 125.2
(2C), 124.0, 123.7. The spectral properties of this com-
pound, which had chemical purity higher than 98%, were
in agreement with those previously reported.11a
1
225 (16), 224 (100), 209 (37), 181 (28), 90 (4). H NMR
(300 MHz, DMSO-d6) d 8.14 (m, 2H), 7.57 (m, 2H), 7.19
(m, 2H), 7.12 (m, 2H), 3.85 (s, 3H). 13C NMR (75.5 MHz,
CDCl3) d 160.5, 151.3, 127.9 (4C), 122.7, 121.7 (2C),
114.3 (4C), 55.2. Anal. Calcd for C14H12N2O: C, 77.98; H,
5.39. Found: C, 77.85; H, 5.24.
4.4. Preparation of 2-(4-aminophenyl)benzothiazole
(6c) by selective reduction of 2-(4-nitrophenyl)-
benzothiazole (6d)
4.2.18. 2-(4-Nitrophenyl)-1H-benzimidazole (6f). The
crude reaction product obtained in entry 4 of Table 4 by
Pd- and Cu-mediated reaction of 11b with 7f was purified
by recrystallization from Et2O and EtOH to give 6f
(0.21 g, 89%) as a pale yellow solid. Mp 306–308 ꢀC
(lit.48 mp 297–299). EIMS, m/z 240 (15), 239 (100), 209
A suspension of compound 6d (128 mg, 0.5 mmol) and
zinc dust (65.4 mg, 1.0 mmol) in methanol (1 mL) was
stirred at room temperature under argon atmosphere with
hydrazinium monoformate (0.2 mL), which was prepared
by neutralizing slowly equal molar amounts of hydrazine hy-
drate and 85% formic acid in an ice water bath, with constant
stirring. After 44 h at room temperature, the reaction, which
initially was exothermic and effervescent, was complete.
The reaction mixture was filtered through Celite and the
filtrate was concentrated under reduced pressure. The solid
residue was recrystallized from EtOH and water to give 6c
(76 mg, 67%) as a colourless solid. Mp 151–153 ꢀC (lit.49
155–157 ꢀC). EIMS, m/z 228 (6), 227 (16), 226 (100), 113
(6), 108 (8). 1H NMR (200 MHz, CDCl3) d 8.00 (d,
J¼7.8 Hz, 1H), 7.89 (m, 2H), 7.84 (d, J¼8.1 Hz, 1H), 7.44
(t, J¼6.9 Hz, 1H), 7.31 (t, J¼6.9 Hz, 1H), 6.72 (m, 2H),
3.83 (br s, 2H). 13C NMR (50.3 MHz, CDCl3) d 168.5,
154.2, 149.3, 134.5, 129.2 (2C), 126.1, 124.5, 123.9,
1
(11), 193 (50), 192 (26). H NMR (300 MHz, DMSO-d6)
d 8.41 (m, 4H), 7.67 (m, 2H), 7.28 (m, 2H). 13C NMR
(50.3 MHz, DMSO-d6) d 148.9, 147.7, 143.8, 136.0,
135.2, 127.3 (2C), 124.2 (2C), 123.5, 122.2, 119.4, 111.7.
GLC analysis showed that 6f had chemical purity higher
than 92%.
4.3. Procedure for the preparation of 2-aryl-1-phenyl-
1H-imidazoles 8 from 1-phenyl-1H-imidazole (4a) and
aryl bromides 9
Compound 4a (144 mg, 1.0 mmol), Pd(OAc)2 (11.2 mg,
0.05 mmol), CuI (0.38 g, 2.0 mmol), sodium or potassium

1978
F. Bellina et al. / Tetrahedron 63 (2007) 1970–1980
1
122.5, 121.4, 114.8 (2C). The H NMR data of this chemi-
cally pure compound were in agreement with those previ-
ously reported.50
(60:40) as eluent to give 14a (120 mg, 53%) as a pale yellow
solid. Mp 224–227 ꢀC (lit.53 mp 228–230 ꢀC). EIMS, m/z
224 (16), 223 (100), 209 (11), 181 (22), 152 (10). 1H
NMR (300 MHz, DMSO-d6) d 11.43 (s, 1H), 7.80 (m,
2H), 7.49 (d, J¼7.8 Hz, 1H), 7.38 (d, J¼7.8 Hz, 1H), 7.03
(m, 4H), 6.76 (d, J¼1.7 Hz, 1H), 3.80 (s, 3H). 13C NMR
(75.5 MHz, DMSO-d6) d 158.7, 137.7, 136.8, 128.8, 126.3
(2C), 124.8, 121.0, 119.6, 119.1, 114.3 (2C), 111.0, 97.2,
55.1. The spectral data of this compound, which had chem-
ical purity higher than 98%, were in agreement with those
previously reported.52
4.5. Preparation of 2-(4-aminophenyl)-1H-benzimid-
azole (6a) by selective reduction of 2-(4-nitrophenyl)-
1H-benzimidazole (6f)
Compound 6f (239 mg, 1.0 mmol) was reduced to 6a
(188 mg, 90%) using the same procedure employed for the
preparation of 6c from 6d. Compound 6a, which was recrys-
tallized from MeOH and water, was a pale yellow solid. Mp
240–241 ꢀC (lit.51a mp 243–244 ꢀC). EIMS, m/z 210 (15),
4.7.2. 2-Phenyl-1H-indole (14b). The crude reaction prod-
uct obtained in entry 4 of Table 5 by Pd- and Cu-mediated
reaction of 13a with 7b was purified by MPLC on silica
gel with a mixture of toluene and hexane (60:40) as eluent
to give 14b (56 mg, 29%) as a colourless solid. Mp 186–
188 ꢀC (lit.54 mp 188–189 ꢀC). EIMS, m/z 194 (15), 193
(100), 192 (13), 165 (19), 97 (7). 1H NMR (300 MHz,
CDCl3) d 8.30 (br s, 1H), 7.65–7.61 (m, 3H), 7.37 (m,
4H), 7.16 (m, 2H), 6.82 (s, 1H). 13C NMR (75.5 MHz,
CDCl3) d 137.9, 136.8, 132.4, 129.3, 129.0 (2C), 127.7,
125.1 (2C), 122.3, 120.7, 120.2, 110.9, 100.0. GLC analysis
showed that 14b had chemical purity higher than 98%. Its
spectral properties were in agreement with those previously
reported.55
1
209 (100), 208 (15) 181 (6), 104 (9). H NMR (300 MHz,
CD3OD) d 8.51 (br s, 2H), 7.83 (m, 2H), 7.57 (m, 2H),
7.28 (m, 2H), 6.79 (m, 2H). 13C NMR (50.3 MHz,
CD3OD) d 153.6, 153.3, 137.5 (2C), 129.7 (2C), 124.5
(2C), 115.9, 115.6 (2C), 114.8 (2C). The H NMR data of
this chemically pure compound were in agreement with
1
those previously reported.51b
4.6. General procedure for the Pd/C–CuI mediated C-2
arylation of azoles 4a, 10d and 10f with aryl iodide 7a
A Schlenk-type glass reactor equipped with a silicon sep-
tum, a reflux condenser and a magnetic stirrer was evacuated
and refilled with argon. The reactor was then charged with
an azole (1.0 mmol), 10% Pd/C (53.2 mg, 5 mol%), CuI
(0.38 g, 2.0 mmol), aryl iodide 7a (468 mg, 2.0 mmol) under
a stream of argon. Deaerated DMF (5 mL) was then added
by syringe and the resulting mixture was stirred at 140 ꢀC
under argon for the period of time reported in Scheme 3. Re-
action progress was monitored by GLC. After being cooled
to room temperature the reaction mixture was worked using
the protocol described in Section 4.2. This procedure was
employed to prepare 8a in 90% yield from 4a, 12d in 41%
yield from 10d and 12i in 62% yield from 10f (Scheme 3).
The chemical purity of compounds 8a, 12d and 12i was
higher than 98%. Their physical and spectral properties
were in good agreement with those of the same compounds
prepared by Pd(OAc)2–CuI mediated arylation reactions.
4.7.3. 2-[(4-Trifluoromethyl)-phenyl]-1H-indole (14c).
The crude reaction product obtained in entry 5 of Table 5
by Pd- and Cu-mediated reaction of 13a with 7d was purified
by MPLC on silica gel with a mixture of toluene and hexane
(30:70) as eluent to give 14c (86 mg, 33%) as a colourless
solid. Mp 192–194 ꢀC. EIMS, m/z 262 (17), 261 (100),
1
260 (4), 233 (5), 165 (7). H NMR (300 MHz, acetone-d6)
d 7.93 (d, J¼7.8 Hz, 2H), 7.63 (d, J¼7.8 Hz, 2H), 7.47 (d,
J¼7.8 Hz, 1H), 7.31 (d, J¼8.7 Hz, 1H), 7.02 (t, J¼6.9 Hz,
1H), 6.924 (s, 1H), 6.921 (t, J¼6.9 Hz, 1H). 13C NMR
(75.5 MHz, acetone-d6) d 137.3, 135.9, 135.6, 128.2 (q,
JC–F¼42 Hz), 125.3 (q, JC–F¼3.9 Hz, 2C), 124.8 (2C),
123.9 (q, JC–F¼226 Hz), 122.1, 120.1, 119.4, 110.84,
110,78, 100.5. Anal. Calcd for C15H10F3N: C, 68.96; H,
3.86. Found: C, 68.83; H, 3.91. GLC analysis showed that
14c had chemical purity higher than 98%.
4.7. General procedure for the Pd(OAc)2–CuI-mediated
synthesis of 2-aryl-1H-indoles 14
Indole (13a) (0.12 g, 1.0 mmol), Pd(OAc)2 (11.2 mg,
0.05 mmol), CuI (0.38 g, 2.0 mmol) and an aryl iodide 7
(2.0 mmol) were placed in the reaction vessel under a stream
of argon. The reaction vessel equipped with a silicon septum,
a reflux condenser and a magnetic stirrer was evacuated and
back-filled with argon, and this sequence was repeated
twice. Deaerated DMA (5 mL) was added by syringe under
a stream of argon and the mixture was stirred at 160 ꢀC for
48 h. It was then cooled to room temperature and worked
up using the protocol reported in Section 4.2. The crude
reaction product was purified by MPLC on silica gel. This
procedure was employed to prepare 2-aryl-1H-indoles
14a–c (entries 2–5, Table 5).
Acknowledgements
This work was financially supported by the University of
Pisa.
References and notes
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