Regiocontrolled synthesis of 1,2-diaryl-1H-imidazoles by palladium- and copper-mediated direct coupling of 1-aryl-1H-imidazoles with aryl halides under ligandless conditions

Article abstract of DOI:10.1002/ejoc.200500636

A large variety of 1,2-diaryl-1H-imidazoles, including a selective COX-2 inhibitor, have been regioselectively synthesised in moderate to high yields by direct coupling of 1-aryl-1H-imidazoles with aryl iodides or bromides in DMF in the presence of CsF an

Full text of DOI:10.1002/ejoc.200500636

FULL PAPER
DOI: 10.1002/ejoc.200500636
Regiocontrolled Synthesis of 1,2-Diaryl-1H-imidazoles by Palladium- and
Copper-Mediated Direct Coupling of 1-Aryl-1H-imidazoles with Aryl Halides
under Ligandless Conditions
Fabio Bellina,*[a] Silvia Cauteruccio,[a] Luisa Mannina,[b,c] Renzo Rossi,*[a] and
Stéphane Viel[c,d]
Keywords: C–C coupling / Synthetic methods / Regioselectivity / Palladium / Copper
A large variety of 1,2-diaryl-1H-imidazoles, including a se-
species and a reductive elimination, is proposed. New one-
lective COX-2 inhibitor, have been regioselectively synthe- step procedures for the synthesis of 1,2,5-triaryl-1H-imid-
sised in moderate to high yields by direct coupling of 1-aryl-
1H-imidazoles with aryl iodides or bromides in DMF in the
presence of CsF and catalytic amounts of Pd(OAc)2 under
ligandless conditions. A possible mechanism for this new
highly regioselective C-2 arylation reaction, involving the
azoles, based on palladium- and copper-mediated arylation
of 1-aryl-1H-imidazoles, have also been developed. Interest-
ingly, some imidazole derivatives prepared in this study have
been found to exhibit significant cytotoxic activity against
some human tumour cell lines.
formation of an organocopper(
transmetallation reaction with an arylpalladium(II) halide
I
) derivatives followed by a
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
pound 2m, which was recently prepared in 31% yield by
CuI-mediated N-arylation of 3b with 4-nitrophenyl iodide
(4h).[8f]
Introduction
Imidazoles possessing two aryl substituents appear fre-
quently in molecules that elicit important biological re-
sponses. Thus, some 1,5-diaryl-1H-imidazoles 1 (Figure 1)
include substances that act as selective inhibitors of cyclo-
oxygenase-2 (COX-2)[1] and are cytotoxic against a variety
of human cancer cell lines.[2] On the other hand, some 1,2-
diaryl-1H-imidazoles 2 have been reported to be antago-
nists of the cannabinoid CB1 receptor[3,4] or to be able to
inhibit COX-2 selectively.[5,6,7] The biological activities of
compounds 1 and 2 have made them popular synthetic tar-
gets, and numerous methods for the synthesis of these het-
erocycles have been developed.[8,9] These synthetic methods,
however, involve the construction of the imidazole ring by
multi-step reaction sequences and, before our studies, no
simple and straightforward synthesis of compounds 1 and
2 had been described, with the exception of that of com-
We have recently been directing attention to the regiose-
lective synthesis of these heterocycles by transition metal-
mediated direct C-arylation of readily available 1-aryl-1H-
imidazoles 3[10] and have found that a variety of compounds
1 (R1 = H) can be regioselectively synthesised, generally in
moderate yields, through direct coupling of the correspond-
ing 1-substituted derivatives with aryl halides 4 in DMF at
140 °C in the presence of CsF as the base and a catalyst
precursor consisting of a mixture of Pd(OAc)2 and AsPh3
(Scheme 1).[2]
The obtained data supported a reaction mechanism in-
volving electrophilic attack of an arylpalladium(ii) halide
species onto the most electron-rich position in the imid-
azole ring of a given compound 3 (see Figure 4 below).[2]
Moreover, it was found that, among the imidazoles synthe-
sised in this study, compounds 1b, 1c, 1d and 3b were char-
acterised by significant cytotoxicity against human tumour
cell lines, 1b being the most potent compound [MG-MID
log GI50 = –7.09].[2]
These results stimulated our interest in developing a sim-
ple, efficient and general method for the regioselective syn-
thesis of 1,2-diaryl-1H-imidazoles 2, involving the transi-
tion metal-mediated direct C-2 arylation of compounds 3
with aryl halides 4, and in evaluating the cytotoxic activities
of some imidazole derivatives prepared in this way. On the
other hand, Miura and co-workers[11] had previously syn-
thesised 1-methyl-2-phenyl-1H-imidazole (7) in modest
[a] Dipartimento di Chimica e Chimica Industriale, University of
Pisa,
Via Risorgimento 35, 56126 Pisa, Italy
Fax: +39-0502219260
E-mail: bellina@dcci.unipi.it, rossi@dcci.unipi.it
[b] Dipartimento S.T.A.A.M., Universiy of Molise,
86100 Campobasso, Italy
[c] Istituto di Metodologie Chimiche, CNR,
via Salaria Km 29.300, 00016 Monterotondo Stazione, Roma,
Italy
[d] University of Provence, Jeune Equipe Traces, Centre de Saint-
Jerome,
Case 511, 13397 Marseille Cedex, France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2006, 693–703
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
693

F. Bellina, S. Cauteruccio, L. Mannina, R. Rossi, S. Viel
FULL PAPER
Figure 1. Chemical structures of compounds 1–4.
Figure 2. Chemical structures of compounds 6–9, 10a, 11.
Scheme 1.[2] Reagents and conditions: a) 4 (2.0 equiv.), Pd(OAc)2
(5 mol-%), AsPh3 (10 mol-%), CsF (2.0 equiv.), DMF, 140 °C, 17–
161 h, 9–61%.
In this paper we report the results of our study[14] of the
Pd- and Cu-mediated C-2 arylation of 1-aryl-1H-imidazoles
3 with aryl halides 4 and disclose an efficient procedure
yield by Pd- and Cu-mediated treatment of 1-methyl-1H- for the highly regioselective synthesis of various diaryl-1H-
imidazole (6, Figure 2) with iodide 4a, but we were aware imidazoles 2, involving significant modifications, in terms
of the fact that, under suitable experimental conditions, 6 of Pd catalyst precursor and the base, of the experimental
and thiazole (8) can undergo efficient Pd- and Cu-mediated conditions used by Miura and co-workers for the synthesis
arylation at C-2 with iodobenzoate immobilized on an in- of 7 from 6[11] and by Kondo and co-workers[12] and Mori
soluble polymer support 9[12] or iodide 4b,[13] respectively.
and co-workers[13] for the C-2 arylation of 6 and 8. More-
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Eur. J. Org. Chem. 2006, 693–703

Regiocontrolled Synthesis of 1,2-Diaryl-1H-imidazoles
FULL PAPER
over, we also describe new one-step procedures for the prep- Pd(OAc)2 and PPh3, which produces 1e as the major prod-
aration of some 1,2,5-triaryl-1H-imidazoles 5 obtained as uct.[2] Compounds 1a and 2a were presumably derived from
by-products in the Pd- and Cu-mediated synthesis of some arylation reactions between 3a and iodide 4a, produced by
compounds 2.[15] Finally, we report data that indicate that an unexpected exchange reaction involving PPh3 and 4b.
some imidazoles prepared in this study exhibit an indisput-
able cytotoxicity against human tumour cell lines.
In a search for a more selective and efficient procedure
for the synthesis of 2e we carefully examined the influence
on the reaction of a number of variables, such as the
amount of Pd, the Pd ligand, the 3a/CuI molar ratio and
the base (Table 1).
Results and Discussion
We thus found that CuI, even in the absence of Pd-
We initiated the study on the synthesis of compounds 2 (OAc)2, is able to promote the C-2 arylation of 3a with
by performing the reaction between 3a and 4b under the complete regioselectivity. However, the yields were generally
experimental conditions used by Miura and co-workers for low (Table 1, Entries 2, 3 and 11). Moreover, we observed
the synthesis of 6.[11] Thus, 3a was treated with 2 equiv. of that the use of arylated ligands (e.g., PPh3 or AsPh3) gave
4b, 2 equiv. of CuI and 2 equiv. of Cs2CO3 in DMF at rise to by-products originating from the scrambling of the
140 °C for 48 h in the presence of 10 mol-% Pd(OAc)2 and organic groups of the ligands with the aryl moiety of 4b
20 mol-% PPh3 (Table 1, Entry 1). This reaction took place (Table 1, Entries 1–3 and 5), but the use of ligands that did
with 87% conversion and furnished a complex reaction not contain aryl groups did not allow us to improve the
mixture containing triarylated imidazole 5e as the major yield of the reaction significantly (Table 1, Entries 4 and 6).
product, diaryl imidazole 1e,[2] significant amounts of 1a Nevertheless, we found that, under ligandless conditions,
and 2a and (4-methoxyphenyl)diphenylphosphane (11), in catalytic amounts of Pd(OAc)2 promote the regioselective
addition to the required diaryl imidazole 2e,[2] which was C-2 arylation of compound 3a in the presence of 2 equiv.
obtained in 9% GLC yield. It should be noted that com- of CuI and 2 equiv. of Cs2CO3 or CsF (Table 1, Entries 7
pounds 1a, 2e, 5e, 10a and 11 were also by-products of the and 8). Moreover, the use of CsF as the base allowed us to
reaction between 3a and 4b in the presence of Cs2CO3 as obtain homogeneous reaction mixtures, higher yields and
the base and a catalyst precursor consisting of a mixture of more reproducible results. Finally, we found that when the
Table 1. Screening reaction conditions for the selective C–2 arylation of 3a with iodide 4b.
Entry[a]
Pd(OAc)2
(mol-%)
CuI
(equiv.)
Ligand
(mol-%)
Base
GLC conversion
2e:1e:5e
GLC molar ratio
Yield of
of 3a[b]
2e[b,c]
1
2
3
4
5
6
7
8
9
10
–
–
10
10
10
10
10
10
5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.5
2.0
2.0
PPh3 (20)
PPh3 (65)
PPh3 (20)
P(OEt)3 (20)
AsPh3 (20)
P(tBu)3 (20)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsF
88
65
85
87
88
90
100
97
40
100
44
15:8:77
100:0:0
100:0:0
68:24:8
44:25:31
24:18:58
44:12:44
54:6:40
35:65:0
81:1:18
100:0:0
9[d]
19[d]
30[d]
20
30[d]
21
–
–
–
–
–
42
50 (41)
11
(62)
26
CsF
CsF
CsF
10
11
–
[a] The reactions were performed with 1 mmol of 3a, 2 equiv. of 4b, 2 equiv. of base in 5 mL of DMF at 140 °C for 48 h. [b] Determined
by GLC analysis with use of an internal standard (naphthalene). [c] The values in parenthesis indicate isolated yields. [d] The crude
reaction mixture also contained significant amounts of 1,2- and 1,5-diphenyl-1H-imidazole 2a and 1a, respectively.
Eur. J. Org. Chem. 2006, 693–703
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695

F. Bellina, S. Cauteruccio, L. Mannina, R. Rossi, S. Viel
FULL PAPER
amount of Pd(OAc)2 was reduced from 10 mol-% to 5 mol-
% the reaction occurred with higher regioselectivity and in
better chemical yield (compare Entries 8 and 10 of Table 1).
In contrast, unsatisfactory results were obtained when we
reduced the amount of CuI from 2.0 to 0.5 equiv.; in this
case, in fact, the prevalent formation of the regioisomeric
1,5-diaryl-1H-imidazole 1e was observed (compare En-
tries 8 and 9 of Table 1).
After this initial screening, which had demonstrated the
viability of the Pd- and Cu-mediated selective C-2 arylation
of 3a with 4b, we tested the scope and limitations of this
reaction by applying the reaction conditions of Entry 10 of
Table 1 to the synthesis of 1,2-diaryl-1H-imidazoles 2 from
1-aryl-1H-imidazoles 3a–g and aryl halides 4a–f.
Compounds 3a–d were prepared as previously re-
ported,[2] whilst 3e was synthesised by the method described
in 1999 by Buchwald et al.[10i] [i.e., by treatment of 2-bro-
monaphthalene (4f) with 1.5 equiv. of imidazole (12) in xy-
lenes at 110 °C in the presence of Cs2CO3, 1,10-phenan-
Scheme 3. Reaction conditions: a) NaH (1.03 equiv.), DMF, 0–
20 °C, 2 h, then 4g (1.03 equiv.), DMF, room temp., 24 h (for 3f)
or 50 °C, 67 h (for 3g), 75% for 3f, 78% for 3g.
throline and catalytic amounts of trans-trans-dibenzylidene- 2 equiv. of CuI and 2 equiv. of CsF provided reaction mix-
acetone (dba) and (CuOTf)2·toluene (Scheme 2)].
tures in which 1,5-diaryl-1H-imidazoles 1a–j were either
present only in very small amounts or completely absent.
However, significant amounts of 1,2,5-triaryl-1H-imid-
azoles 5a, 5b, 5c, 5d and 5e contaminated the reaction mix-
tures obtained in Entries 1, 11, 10, 2 and 9, respectively, of
Table 2. Compounds 5a and 5e were isolated in 26% and
16% yields, respectively, from the reaction mixtures of En-
tries 1 and 9 of Table 2. On the other hand, compound 5d
was identified by comparison of its GLC retention time and
EI-MS spectrum with those of an authentic sample of this
substance obtained as a by-product in the Pd-catalysed C–
5 arylation of 3a with 4c.[2]
Interestingly, compound 2k, a selective COX-2 inhibi-
tor,[5] could be prepared in 62% yield from 3f and 4e by the
established procedure (Table 2, Entry 12), so this synthesis
of 2k competes favourably with those reported in the litera-
ture for the preparation of this and similar compounds,[5]
which provide the required substances by multi-step se-
quences and in lower overall yields.[5]
Scheme 2. Reaction conditions: a) 12 (1.5 equiv.), (CuOTf)2·toluene
(5 mol-%), dba (5 mol-%), 1,10-phenanthroline (1.0 equiv.),
Cs2CO3 (1.1 equiv.), xylenes, 110 °C, 71 h, 61%.
The structural assignments of compounds 2a–l, 5a and
1
5e (Figure 3) were achieved with the aid of their H and
On the other hand, compounds 3f and 3g were synthe- 13C NMR spectra and by a combination of 2D NMR tech-
sised by treatment of 13 and 14, respectively, with NaH in niques including 1H–13C Heteronuclear Multiple Bond
DMF, followed by treatment with fluoride 4g (Scheme 3). Correlation (HMBC) and 1H–13C Heteronuclear Single
Nevertheless, 3f prepared in this way was not regiochem- Quantum Coherence (HSQC). On the other hand, the
ically pure: in fact, GLC, EI-MS and NMR analyses structures of 1,5-diaryl-1H-imidazoles 1e and 1f, which
showed that the reaction illustrated in Scheme 3 furnished were by-products of the reactions corresponding to En-
a 75:25 mixture of 3f and 5-methyl-1-[(4-methylsulfonyl)- tries 9 and 3 of Table 2, were established by comparison of
phenyl]-1H-imidazole (3h). We then used this mixture in a the GLC retention times and EI-MS spectra of these imid-
subsequent Pd- and Cu-mediated arylation reaction with azoles with those of authentic samples obtained by direct
iodide 4e.
Pd-catalysed coupling of the corresponding 1-aryl-1H-imid-
Table 2 summarises the results of the reactions per- azoles 3 with the appropriate aryl halides 4 in DMF at
formed to prepare 1,2-diaryl-1H-imidazoles 2a–l. As illu- 140 °C by the procedure we developed recently.[2] Finally,
strated in this Table, the established procedure allowed us the structural assignments of 5b and 5c, which we had pre-
to obtain compounds 2a–k in moderate to high yields and liminarily made on the basis of EI-MS spectra of these
with high or complete selectivity (Table 2, Entries 1–7 and compounds, were confirmed by comparison of their EI-MS
9–12). In particular, as regards the selectivity, all of the re- data and GLC retention time with those of authentic sam-
actions performed in the presence of 5 mol-% Pd(OAc)2, ples of 5b and 5c prepared as previously reported[2] by treat-
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Regiocontrolled Synthesis of 1,2-Diaryl-1H-imidazoles
Table 2. Pd- and Cu-mediated synthesis of 1,2-diaryl-1H-imidazoles 2 from 1-aryl-1H-imidazoles 3 and aryl halides 4.
FULL PAPER
Reagents
3
Reaction
time (h)
Products
2:1:5 GLC molar ra-
tio
Isolated
yield (%)
Entry[a]
R1
R2
Ar1
4
Ar2
X
2
1
2
3
4
5
6
7
8
9
3a
3a
3c
3d
3d
3b
3e
3g
3a
3c
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
C6H5
C6H5
4a
4c
4d
4d
4b
4f
4d
4b
4b
4b
4b
4e
C6H5
4-CF3C6H4
I
I
I
I
I
Br
I
I
I
I
65
64
24
20
20
43
42
19
48
20
48
26
63:0:37
72:0:28
96:4:0
100:0:0
100:0:0
100:0:0
100:0:0
–
81:1:18
87:0:13
86:0:14
90:0:10
2a
2d
2f
2g
2h
2i
2j
2l
2e
2c
2b
2k
55[b]
64
59
79
67
57
57
94
62[c]
38
4-MeOC6H4
4-MeSO2C6H4
4-MeSO2C6H4
3,4,5-(MeO)3C6H2
2-naphthyl
4-MeSO2C6H4
C6H5
4-MeOC6H4
3,4,5-(MeO)3C6H2
MeSO2C6H4
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
4-MeOC6H4
2-naphthyl
3,4,5-(MeO)3C6H2
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
10
11
12
3b
H
Me
I
I
52
62
3f[d]
[a] The reactions were run with 1 mmol of a particular compound 3, 2 equiv. of a given compound 4, 5 mol-% Pd(OAc)2, 2 equiv. of CuI
and 2 equiv. of CsF in DMF at 140 °C until the conversions were quantitative. [b] MPLC of the crude reaction mixture on silica gel after
conventional workup also allowed isolation of 5a in 26% yield. [c] MPLC of the crude reaction mixture on silica gel after conventional
workup also allowed isolation of 5e in 16% yield. [d] Used as a 75:25 mixture with 5-methyl-1-[(4-methylsulfonyl)phenyl]-1H-imidazole
(3h).
ment of 3 equiv. of 4b with 3b and 3c, respectively, in DMF
at 140 °C for 114 h in the presence of 10 mol-% Pd-
(OAc)2, 20 mol-% P(tBu)3, 3 equiv. of CuI, and 3 equiv. of
CsF (Scheme 4). We then used a similar procedure to pre-
pare 5e in 32% yield from 3a and 4b (Scheme 4).
Scheme 4. Reaction conditions: a) 4b (2.0 equiv.), Pd(OAc)2
(10 mol-%), Cs2CO3 (2.0 equiv.), CuI (2.0 equiv.), DMF, 140 °C,
66 h, 32%. b) 4b (3.0 equiv.), Pd(OAc)2 (10 mol-%), P(tBu)3
–
(20 mol-%) (for 3b), [P(tBu)3H]+BF4 (20 mol-%) (for 3c), CsF
(3.0 equiv.), CuI (3.0 equiv.), DMF, 140 °C, 114–281 h, 21% (for
5b), 36% (for 5c).
Figure 3. Chemical structures of compounds 5a–e.
Finally, we found that compound 5e, which we had iso-
lated in 16% yield as a by-product of the Pd- and Cu-medi- imidazoles 2, even though the presence of these last com-
ated reaction between 3a and 4b (Table 2, Entry 9), could pounds has rarely been observed in the crude final reaction
also be prepared in 57% GLC yield by treatment of 2e with mixtures from the Pd- and Cu-mediated reactions. On the
2 equiv. of 4b in DMF at 140 °C in the presence of 5 mol- other hand, the results of the reactions summarised in
%
Pd(OAc)2, 2 equiv. of CuI and 2 equiv. of CsF Scheme 5 show that the rate of a Pd- and Cu-mediated aryl-
(Scheme 5). On the other hand, 5e could also be obtained ation of a typical 1,5-diaryl-1H-imidazole is higher than
in 74% GLC yield from the reaction between 2e and that of a Pd- and Cu-mediated reaction involving the corre-
2 equiv. of 4b in DMF at 140 °C for 46 h in the presence of sponding 1,2-diaryl-1H-imidazole.
5 mol-% Pd(OAc)2, 2 equiv. of CuI and 2 equiv. of CsF,
It should also be noted that the success of the selective
which took place with quantitative conversion (Scheme 5).
C-2 arylation of compounds 3 strongly depended on the
These results suggest that 1,2,5-trisubstituted 1H-imid- amount of CuI used. In fact, when the amount of CuI was
azoles 5, which were present in several crude reaction mix- reduced from 2.0 equiv. to 0.5 equiv., the regioselectivity of
tures obtained from the Pd- and Cu-mediated arylation re- the arylation reaction switched from C-2 to C-5 (compare
actions of 1-aryl-1H-imidazoles 3, are very probably mainly Entries 8 and 9, Table 1). Moreover, we had previously ob-
formed by Pd- and Cu-mediated arylation of 1,5-diaryl-1H- served that treatment of 3b with 2.0 equiv. of 4b in DMF
Eur. J. Org. Chem. 2006, 693–703
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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697

F. Bellina, S. Cauteruccio, L. Mannina, R. Rossi, S. Viel
FULL PAPER
Scheme 5. a) 4b (2.0 equiv.), Pd(OAc)2 (5 mol-%), CsF (2.0 equiv.), CuI (2.0 equiv.), DMF, 140 °C, 113 h, 57% (GLC). b) 4b (2.0 equiv.),
Pd(OAc)2 (5 mol-%), CsF (2.0 equiv.), CuI (2.0 equiv.), DMF, 140 °C, 46 h, 74% (GLC).
at 140 °C in the presence of 10 mol-% Pd(OAc)2 and of the aryl halides 4. Nevertheless, at present it seems diffi-
2 equiv. of Cs2CO3 provided a mixture of 1b and 2b in a cult, on the basis of this mechanism, to explain the com-
87:13 molar ratio.[2]
plete C-2 regioselectivity of the Pd- and Cu-mediated aryl-
The mechanisms we propose for the Pd- and Cu-medi- ation of 2-aryl-1H-imidazoles 3 characterised by a strongly
ated C-2 arylation and the Pd-catalysed C-5 regioselective electron-rich group at N-1.
arylation of 1-aryl-1H-imidazoles 3 are shown in Figure 4.
We also believe that the fact that the palladium- and cop-
In particular, we suppose that, in the presence of a base, 1- per-mediated arylation reaction of compounds 3 occurs in
aryl-1H-imidazoles 3 exist in equilibrium with the corre- the absence of ligands such as triarylphosphanes or AsPh3
sponding organocopper(i) derivatives B.[16] This hypothesis can be explained by allowing for the fact that imidazoles
is partly supported by literature data concerning the ability 3 probably represent the ligands of the palladium species
of CuI salts to metallate acidic C–H bonds and, in particu- involved in this reaction.
lar, the C-2 position of imidazoles 3.[17] Compounds B
It is also interesting to note that, according to the mecha-
might then undergo transmetallation with the arylpalladi- nisms reported in Figure 4, the C-2 arylation of compounds
um(ii) halide species A, which derive from the oxidative ad- 3 should involve the use of catalytic amounts of CuI. In
dition of aryl halides 4 to the Pd0 species generated in situ. fact, this salt, which is initially consumed to form the spe-
Finally, subsequent deprotonation and reductive elimi- cies B, is regenerated in the steps of the reaction that corre-
nation might give the required 1,2-diaryl-1H-imidazoles 2. spond to the conversion of this organocopper species into
On the other hand, we suppose that, when the Pd-catalysed the transmetallation derivative. Nevertheless, as shown by
arylation reaction of 3 is carried out in the presence of cata- comparison of Entries 8 and 9 of Table 1, the C-2 arylation
lytic amounts of CuI salts, which are not sufficient to allow reaction requires the use of a large molar excess of CuI,
the formation of significant amounts of salts B from imid- which appears to be necessary in order to cause the forma-
azoles 3, the arylation occur prevalently at C-5 and presum- tion of significant amounts of B and suitable reaction rates.
ably involves a base-promoted electrophilic attack of com-
On the other hand, we believe that the C-2 arylation of
plex A onto C-5 of the imidazole ring. This position has been 3a with 4b, which we carried out in DMF at 140 °C in the
reported[18] to be more reactive than C-4 or C-2 in electro- presence of a Pd-free system consisting of 2 equiv. of CuI
philic substitution reactions when neutral imidazole interme- and 2 equiv. of Cs2CO3 or CsF (Table 1, Entries 2, 3, and
diates are involved. The hypothesis that two competitive 8), can be regarded as a nucleophilic aromatic substitution
mechanisms may operate is also supported by the fact that assisted by CuI and the base, which proceeds through one
a higher C-2 selectivity was observed when the amount of of the two alternative oxidative addition/reductive elimi-
Pd(OAc)2 was lowered. Complex A should not be involved nation pathways recently proposed by Cristeau et al.[10b] for
in the rate-determining step of the C-2 arylation path, but Cu-catalysed nucleophilic substitution with aromatic ha-
rather involved in that of the C-5 arylation reaction.
The proposed mechanism for the palladium- and copper-
lides.
Finally, it is worth mentioning that 1,2-diaryl-1H-imid-
mediated C-2 arylation of compounds 3 is also supported azoles 2b, 2c and 2f and 1,2,5-triaryl-1H-imidazole 5b were
by the observed dependence of the reaction time on elec- evaluated over a 5-log dose range in the NCI’s in vitro hu-
tronic effects. In fact, for compounds 3 characterised by a man disease-oriented tumour cell line screening panel, con-
strongly electron-withdrawing group such as 4-Me- sisting of 60 human tumour cell lines. Compounds 2b, 2c
SO2C6H4, which should enhance the kinetic acidity of the and 2f were found to be moderately cytotoxic, but 2b, which
2-H proton, these were shorter (19–26 h) than those found had cytotoxicity (MG–MID log GI50 = –5.45) lower than
for 1-aryl-1H-imidazoles containing a strongly electron-rich that of the corresponding 1,5-diaryl-1H-imidazole 1b (MG–
group such as 3,4,5-(MeO)3C6H2 at N-1 (43–48 h). In con- MID log GI50 = –6.64)[2] was, however, significantly active
trast, the yields did not appear to be affected by the nature against the COLO205, HCC-2998, HCT-116, HCT-15,
698
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FULL PAPER
Figure 4. Mechanisms for the Pd- and Cu-mediated C-2 arylation and the Pd-catalysed C-5 arylation of 1-aryl-1H-imidazoles 3.
HT29, KM12 and SW-620 colon cancer cell lines (MG- that 1,2,5-triaryl-1H-imidazoles can be synthesized by Pd-
MID log GI50 = –6.33) and the MDA-MB-435 breast can- and Cu-mediated arylation either of 1,2-diaryl-1H-imid-
cer line (log GI50 = –6.95) of the NCI. On the other hand, azoles at their C-5 positions or of 1,5-diaryl-1H-imidazoles
5b was highly active only against the MOLT-4 leukemia cell at their C-2 positions.
line (log GI50 = –7.88; log TGI –7.36) and 2c was also very
It is proposed that the highly regioselective C-2 arylation
active against this leukemia cell line (log GI50 Ͻ –8.00) and of 1-aryl-1H-imidazoles proceeds by a mechanism involving
the human SR leukemia cell line (log GI50 = –7.78).
the formation of an organocopper(i) derivative, followed by
a transmetallation with an arylpalladium(ii) halide species
and by a reductive elimination.
Conclusions
It is also worth noting that some imidazole derivatives
synthesised in this study have been found to be significantly
cytotoxic against some human tumour cell lines.
Studies on the application of this highly regioselective C-
2 arylation of 1-aryl-1H-imidazoles to the synthesis of hu-
man CB1 receptor antagonists related to SR141716[3,19] and
constituted of suitably substituted 1,2-diaryl-1H-imidazole-
4-carboxamide derivatives with methyl, bromo or cyano
groups at their C-5 positions are in progress.
In this study we have demonstrated that a large variety
of 1,2-diaryl-1H-imidazoles, including a selective COX-2 in-
hibitor, can be efficiently and selectively synthesised by di-
rect Pd- and Cu-mediated C-arylation of readily available
1-aryl-1H-imidazoles with aryl iodides or bromides. This
simple and practical preparation method, which involves
the use of experimental conditions very different from those
previously employed for the C-2 arylation of 1-methyl-1H-
imidazole,[11–13] compares favourably with those previously
described in the literature, which are based on the construc-
tion of the imidazole ring,[9] and allows the preparation of
1,2-diaryl-1H-imidazoles containing electron-donating and/
or electron-withdrawing substituents on the aryl groups
Experimental Section
1-(2-Naphthyl)-1H-imidazole (3e): Imidazole (12, 0.61 g, 9.0 mmol),
linked at their N-1 and C-2 positions. We have also shown 1,10-phenanthroline (1.08 g, 6.0 mmol), trans,trans-dibenzylidene-
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acetone (703 mg, 0.30 mmol), Cs2CO3 (2.15 g, 6.60 mmol), cop-
per(i) trifluoromethanesulfonate toluene complex (156 mg,
0.30 mmol) and 2-bromonaphthalene (4f, 1.24 g, 6.0 mmol) were
placed in a flame-dried reaction vessel fitted with a silicon septum.
The reaction vessel was evacuated and back-filled with argon in a
sequence that was repeated twice. Xylenes (1.2 mL) were then
added under a stream of argon and the resulting mixture was
stirred under argon at 110 °C for 71 h. It was then cooled to room
temperature, diluted with AcOEt (25 mL), poured into a saturated
aqueous NaCl solution (30 mL) and extracted with AcOEt
(4×20 mL). The organic extract was washed with brine (10 mL), 4,5-Dichloro-1-[(4-methylsulfonyl)phenyl]-1H-imidazole (3g): The
dried and concentrated under reduced pressure. The residue was
purified by MPLC on silica gel with a mixture of CH2Cl2 and
methanol (96:4) as eluent to give 3e (0.71 g, 61%) as a pale yellow
crude product obtained from the reaction carried out at 50 °C for
67 h between 4g (1.39 g, 8.0 mmol) and a DMF solution of the
sodium salt prepared from 4,5-dichloro-1H-imidazole (14, 1.07 g,
solid: m.p. 120–121 °C (ref.[20] 121–122 °C). 1H NMR (200 MHz, 7.8 mmol) by the procedure used for the synthesis of a mixture of
CDCl3): δ = 7.98 (br.s, 2 H), 7.93–7.85 (m, 2 H), 7.81 (d, J =
3f and 3h was purified by MPLC on silica gel with a mixture of
CH2Cl2 and methanol (97:3) as eluent to give 3g (1.77 g, 78%) as
2.2 Hz, 1 H), 7.61–7.49 (m, 3 H), 7.26 (s, 1 H), 7.40 (br.s, 1 H) ppm.
13C NMR (50.3 MHz, CDCl3): δ = 135.7, 133.4, 132.0, 130.4, a pale yellow solid: m.p. 150–151 °C. 1H NMR (200 MHz, CDCl3):
130.0, 127.7 (2 C), 127.3, 126.4 (2 C), 126.4 (2 C), 120.1, 119.0,
δ = 8.15 (m, 2 H), 7.64 (m, 2 H), 7.63 (s, 1 H), 3.14 (s, 3 H) ppm.
118.0 ppm. IR (KBr disk): ν = 3094, 1599, 1492, 1308, 1058, 814,
13C NMR (50.3 MHz, CDCl3): δ = 141.3, 138.7, 134.3, 129.2 (2
˜
759 cm–1. EI–MS: m/z (%) = 195 (15) [M + 1]+, 194 (100) [M]+, 193
(8), 167 (45), 154 (14), 140 (29), 127 (22). The spectral properties of
this compound were in satisfactory agreement with those pre-
viously reported.[20]
C), 128.6, 126.0 (2 C), 113.7, 44.4 ppm. IR (KBr disk): ν = 3121,
˜
1594, 1500, 1307, 1148, 949 cm–1. EI-MS: m/z (%) = 292 (69) [M +
1]+, 290 (100) [M], 213 (18), 211 (28), 176 (20), 150 (13), 108 (21).
C10H8Cl2N2O2S (291.16): calcd. C 41.25, H 2.77; found C 41.13,
H 2.55.
4-Methyl-1-[(4-methylsulfonyl)phenyl]-1H-imidazole (3f) and 5-
Methyl-1-[(4-methylsulfonyl)phenyl]-1H-imidazole (3h): A suspen-
sion of NaH in mineral oil (60%, 0.40 g, 10.0 mmol) was washed
with pentane (3 mL) and the resultant solid was suspended in
DMF (5 mL) and treated under argon with a solution of 4(5)-
methyl-1H-imidazole (13, 0.80 g, 9.80 mmol) in DMF (5 mL). The
mixture was stirred for 20 min at room temperature and a solution
of 1-fluoro-4-(methylsulfonyl)benzene (4g, 1.74 g, 10.0 mmol) in
DMF (5 mL) was then added over 4 min. The resulting mixture
was stirred at room temperature for 24 h and was then poured into
an ice-cooled aqueous NH4Cl solution (30 mL) and extracted with
AcOEt (4×25 mL). The organic extract was washed with water
(2×5 mL), dried and concentrated under reduced pressure. GLC,
GLC/EI-MS and NMR analyses of the residue showed the pres-
ence of two regioisomeric compounds, 3f and 3h, in a 75:25 molar
ratio. The residue was purified by MPLC on silica gel with a mix-
ture of CH2Cl2 and methanol (97:3) as eluent to give a mixture of
3f and 3h in a 75:25 molar ratio (1.73 g, 75%) as a colourless solid:
General Procedure for the Pd- and Cu-Mediated Synthesis of 1,2-
Diaryl-1H-imidazoles 5 from Compounds 3 and Aryl Halides 4: The
appropriate compound
3
(1.0 mmol), Pd(OAc)2 (11.2 mg,
0.05 mmol), CuI (0.38 g, 2.0 mmol), CsF (0.30 g, 2.0 mmol) and (if
a solid) the aryl iodide or bromide 4 (2.0 mmol) were placed in a
flame-dried reaction vessel. The reaction vessel was fitted with a
silicon septum and then evacuated and back-filled with argon in a
sequence that was repeated twice. DMF (5 mL) and (if a liquid)
the aryl iodide or bromide (2.0 mmol) were then added successively
by syringe at room temperature under a stream of argon. The re-
sulting mixture was stirred at 140 °C under argon for the period of
time given in Table 2. The degree of completion of the reaction and
the composition of the reaction mixture were established by GLC
and GLC-MS analyses of a sample of the crude reaction mixture
after it had been treated with a saturated aqueous NH4Cl solution
and extracted with AcOEt. After being cooled to room tempera-
ture, the reaction mixture was diluted with AcOEt (35 mL) and
poured into a saturated aqueous NH4Cl solution (75 mL), and the
resulting mixture was stirred in the open air for 0.5 h and then
extracted with AcOEt (4×50 mL). The organic extract was washed
with water (2×5 mL), dried and concentrated under reduced pres-
sure and the residue was purified by MPLC on silica gel. The chro-
matographic fractions containing the required compound were col-
lected and concentrated. A CH2Cl2 solution of the residue was then
stirred for 2 h at room temp. with 3-(mercapto)propyl-function-
alised silica gel (0.50 g, loading 1.2 mmolg–1), which was used as a
metal scavenger. The resulting heterogeneous mixture was filtered
through Celite®, concentrated and analysed. This procedure was
employed to prepare 1,2-diaryl-1H-imidazoles 2a–l (Table 2, En-
tries 1–12).
1
m.p. 110–116 °C. H NMR (600 MHz, CDCl3): (for 3f): δ = 8.04
(m, 2 H, 3Ј-H and 5Ј-H), 7.92 (br.s, 1 H, 2-H), 7.56 (m, 2 H, 2Ј-H
and 6Ј-H), 7.08 (br.s, 1 H, 5-H), 3.07 (s, 3 H, SO2Me), 2.29 (s, 3
H, C-Me) ppm. 13C NMR (150 MHz, CDCl3): (for 7f): δ = 141.4
(C-1Ј), 140.6 (C-4), 138.7 (C-4Ј), 134.4 (C-2), 129.6 (C-3Ј and C-
5Ј), 120.9 (C-2Ј and C-6Ј), 113.9 (C-5), 44.6 (SO2Me), 13.6 (C-
Me) ppm. No NOE cross-peaks between the methyl group at C-4
and the 2Ј-H and 6Ј-H protons could be observed. 1H NMR
(600 MHz, CDCl3): (for 3h): δ = 8.09 (m, 2 H, 3Ј-H and 5Ј-H),
7.66 (br.s, 1 H, 2-H), 7.52 (m, 2 H, 2Ј-H and 6Ј-H), 6.96 (br.s, 1
H, 4-H), 3.10 (s, 3 H, SO2Me), 2.22 (s, 3 H, C-Me) ppm. 13C NMR
(150 MHz, CDCl3): (for 3h): δ = 141.0 (C-1Ј), 140.3 (C-4Ј), 136.7
(C-2), 129.2 (C-3Ј and C-5Ј), 128.3 (C-4), 127.7 (C-5), 126.0 (C-2Ј
and C-6Ј), 44.5 (SO2Me), 10.0 (C-Me) ppm. A NOE cross-peak
between the methyl group at C-5 and the 2Ј-H and 6Ј-H protons
1,2-Diphenyl-1H-imidazole (2a): The crude reaction product ob-
tained in Entry 1 of Table 2 from a Pd- and Cu-mediated reaction
between 3a and 4a was purified by MPLC on silica gel with a
mixture of AcOEt and toluene (50:50 + 0.1% Et3N) as eluent and
could be observed. IR (KBr disk): ν = 3020, 1600, 1514, 1306,
˜
1152, 965, 781 cm–1. EI-MS: m/z (%) (for 3f) = 237 (15), 236 (100),
235 (35), 157 (29), 130 (21), 116 (13), 103 (7). EI-MS: m/z (%) (for subsequent treatment with 3-(mercapto)propyl-functionalised silica
3h) = 237 (14) [M + 1]+, 236 (100) [M]+, 235 (28), 157 (21), 130
(20), 116 (9), 103 (6). C11H12N2O2S (236.29): calcd. C 55.91, H
5.12; found C 55.87, H 5.08.
gel to give 5a (0.12 g, 55%) as a colourless solid: m.p. 77–79 °C
1
(ref.[21] 80–81 °C). H NMR (600 MHz, CDCl3): δ = 7.44 (m, 2 H,
3Ј-H and 5Ј-H), 7.43 (m, 3 H, 3ЈЈ-H, 5ЈЈ-H and 4ЈЈ-H), 7.33 (d, J
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Regiocontrolled Synthesis of 1,2-Diaryl-1H-imidazoles
FULL PAPER
= 1.3 Hz, 1 H, 4-H), 7.30 (m, 1 H, 4Ј-H), 7.27 (m, 2 H, 2Ј-H and 341 (21) [M + 1]+, 340 (100) [M]+, 339 (28), 309 (10), 295 (5), 267
6Ј-H), 7.24 (m, 2 H, 2ЈЈ-H and 6ЈЈ-H), 7.19 (d, J = 1.3 Hz, 1 H, 5- (7), 211 (4). C19H20N2O4 (340.38): calcd. C 67.02, H 5.92; found:
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 146.3 (C-2), 138.0 (C-
1ЈЈ), 129.7 (C-3ЈЈ and C-5ЈЈ), 129.5 (C-1Ј), 129.1 (C-4Ј), 128.8 (C-
3Ј and C-5Ј), 128.6 (C-4ЈЈ), 128.4 (C-2Ј and C-6Ј), 127.5 (C-4Ј),
C 66.84, H 5.80.
125.9 (C-2ЈЈ and C-6ЈЈ), 122.9 (C-5) ppm. IR (KBr disk): ν = 1596,
˜
1497, 1416, 1303, 1136, 1065, 744 cm–1. EI-MS: m/z 221 (14) [M +
1]+, 220 (90) [M]+, 219 (100), 193 (12), 165 (6), 90 (11), 77 (18). The
NMR spectroscopic data of this compound were in satisfactory
agreement with those previously reported.[15c]
1-[(4-Methylsulfonyl)phenyl]-2-(3,4,5-trimethoxyphenyl)-1H-imid-
azole (2g): The crude reaction product obtained in Entry 4 of
Table 2 from a Pd- and Cu-mediated reaction between 3d and 4d
was purified by MPLC on silica gel with a mixture of CH2Cl2 and
methanol (98:2) as eluent and subsequent treatment with 3-(mer-
capto)propyl-functionalised silica gel to give 2g (0.31 g, 79%) as a
2-(4-Methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-imidazole (2b):
The crude reaction product obtained in Entry 11 of Table 2 from a
Pd- and Cu-mediated reaction between 3b and 4b was purified by
MPLC on silica gel with a mixture of CH2Cl2 and methanol (96:4)
as eluent and subsequent treatment with 3-(mercapto)propyl-func-
tionalised silica gel to give 2b (0.18 g, 52%) as a light brown liquid.
1H NMR (600 MHz, CDCl3): δ = 7.36 (m, 2 H, 2Ј-H and 6Ј-H),
7.20 (d, J = 1.2 Hz, 1 H, 4-H), 7.11 (d, J = 1.2 Hz, 1 H, 5-H), 6.79
(m, 2 H, 3Ј-H and 5Ј-H), 6.42 (s, 2 H, 2ЈЈ-H and 6ЈЈ-H), 3.87 (s, 3
H, OMec), 3.78 (s, 3 H, OMea), 3.72 (s, 6 H, OMeb) ppm. 13C
NMR (150 MHz, CDCl3): δ = 159.7 (C-4Ј), 153.6 (C-3ЈЈ and C-
5ЈЈ), 146.5 (C-2), 137.8 (C-4ЈЈ), 134.2 (C-1ЈЈ), 129.8 (C-2Ј and C-
6Ј), 128.3 (C-4), 122.6 (C-1Ј), 122.4 (C-5), 113.6 (C-3Ј and C-5Ј),
103.6 (C-2ЈЈ and C-6ЈЈ), 61.0 (OMec), 56.2 (2×OMeb), 55.2
1
light brown solid: m.p. 68–70 °C. H NMR (600 MHz, CDCl3): δ
= 8.02 (m, 2 H, 3ЈЈ-H and 5ЈЈ-H), 7.47 (m, 2 H, 2ЈЈ-H and 6ЈЈ-H),
7.31 (s, 1 H, 4-H), 7.20 (s, 1 H, 5-H), 6.57 (s, 2 H, 2Ј-H and 6Ј-H),
3.84 (s, 3 H, OMea), 3.64 (s, 6 H, OMeb), 3.08 (s, 3 H,
SO2Me) ppm. 13C NMR (150 MHz, CDCl3): δ = 153.2 (C-3Ј and
C-5Ј), 146.7 (C-2), 142.9 (C-1ЈЈ), 140.4 (C-4ЈЈ), 139.1 (C-4Ј), 129.1
(C-4), 129.0 (C-3ЈЈ and C-5ЈЈ), 126.7 (C-2ЈЈ and C-6ЈЈ), 124.1 (C-
1Ј), 122.5 (C-5), 61.0 (OMea), 56.0 (2×OMeb), 44.0 (SO2Me) ppm.
IR (KBr disk): ν = 2902, 1588, 1497, 1459, 1421, 841 cm–1. EI-MS:
˜
m/z (%) = 389 (23) [M + 1]+, 388 (100) [M]+, 387 (28), 374 (9), 373
(44), 180 (7), 179 (6). C19H20N2O5S (388.45): calcd. C 58.75, H
5.19; found: C 59.07, H 5.03.
(OMe ) ppm. IR (neat): ν = 2939, 1609, 1597, 1506, 1254, 1127,
˜
a
835 cm–1. EI-MS: m/z (%) = 341 (21) [M + 1]+, 340 (100) [M]+, 325
(22), 298 (12), 282 (5), 255 (10), 147 (18). C19H20N2O4 (340.38):
calcd. C 67.04, H 5.92; found: C 66.87, H 5.83.
The characterization of all the other 1,2-diaryl-1H-imidazoles pre-
pared in this study can be found in the Supporting Information.
1,2,5-Tris(4-methoxyphenyl)-1H-imidazole (5c): 1-(4-Methoxy-
phenyl)-1H-imidazole (3c, 174 mg, 1.0 mmol), Pd(OAc)2 (22.4 mg,
0.1 mmol), tri-tert-butylphosphonium tetrafluoroborate (58 mg,
0.2 mmol), CuI (571 mg, 3.0 mmol), and CsF (456 mg, 3.0 mmol)
were placed in a flame-dried reaction vessel, which was fitted with
a silicon septum and evacuated and back-filled with argon in a
sequence that was repeated twice. A solution of 4b (702 mg,
3.0 mmol) in DMF (5 mL) was added by syringe at room tempera-
ture under a stream of argon. The resulting mixture was heated
at 140 °C under argon with stirring and was maintained at this
1-(4-Methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-1H-imidazole (2f):
The crude reaction product obtained in Entry 3 of Table 2 from a
Pd- and Cu-mediated reaction between 3c and 4d was purified by
MPLC on silica gel with a mixture of CH2Cl2 and methanol (96:4)
as eluent and subsequent treatment with 3-(mercapto)propyl-func-
tionalised silica gel to give 2f (0.20 g, 59%) as a light brown liquid.
1H NMR (600 MHz, CDCl3): δ = 7.30 (br.s, 1 H, 4-H), 7.21 (m, 2
H, 2ЈЈ-H and 6ЈЈ-H), 7.10 (br.s, 1 H, 5-H), 6.96 (m, 2 H, 3ЈЈ-H and
5ЈЈ-H), 6.69 (s, 2 H, 2Ј-H and 6Ј-H), 3.84 (s, 3 H, OMec), 3.83 (s, temperature for 281 h. GLC and GLC-MS analyses of a sample of
3 H, OMea), 3.65 (s, 6 H, OMeb) ppm. 13C NMR (150 MHz,
CDCl3): δ = 159.7 (C-4ЈЈ), 152.9 (C-3Ј and C-5Ј), 146.2 (C-2), 138.6
(C-4Ј), 131.2 (C-1ЈЈ), 127.5 (C-2ЈЈ and C-6ЈЈ), 127.3 (C-4), 124.2 (C-
1Ј), 123.2 (C-5), 114.7 (C-3ЈЈ and C-5ЈЈ), 105.9 (C-2Ј and C-6Ј),
the reaction mixture, which was treated with a saturated aqueous
NH4Cl solution and extracted with AcOEt, showed the presence
of compounds 5c, 2c, 4b and 4,4Ј-(dimethoxy)biphenyl (10a). Since
the degree of conversion of the reaction had not significantly in-
creased after further stirring for 3 h, the reaction mixture was co-
oled to room temperature, diluted with AcOEt (50 mL) and poured
60.9 (OMe ), 55.9 (2×OMe ), 55.7 (OMe ) ppm. IR (neat): ν =
˜
a
b
c
2936, 1606, 1586, 1514, 1248, 1125, 838 cm–1. EI-MS: m/z (%) =
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F. Bellina, S. Cauteruccio, L. Mannina, R. Rossi, S. Viel
FULL PAPER
into a saturated aqueous NH4Cl solution (30 mL). The resulting
mixture was stirred in the open air for 0.5 h and extracted with
AcOEt (4×35 mL). The organic extract was washed with brine
(2×7 mL), dried and concentrated under reduced pressure, and the
residue was purified by MPLC on silica gel with a mixture of
CH2Cl2 and methanol (98:2) as eluent to give 5c (139 mg, 36%) as
a pale brown solid. This solid was then purified with 3-(mercapto)
propyl-functionalised silica gel as a metal scavenger by the same
procedure as had been used to purify compounds 2. m.p. 56–58 °C.
1H NMR (600 MHz, CDCl3): δ = 7.46 (m, 2 H, 2ЈЈЈ-H and 6ЈЈЈ-
H), 7.40 (s, 1 H, 4-H), 7.06 (m, 2 H, 2ЈЈ-H and 6ЈЈ-H), 7.02 (m, 2
H, 2Ј-H and 6Ј-H), 6.90 (m, 2 H, 3ЈЈ-H and 5ЈЈ-H), 6.85 (m, 2 H,
3ЈЈЈ-H and 5ЈЈЈ-H), 6.81 (m, 2 H, 3Ј-H and 5Ј-H), 3.89 (s, 3 H,
OMeb), 3.84 (s, 3 H, OMec), 3.78 (s, 3 H, OMea) ppm. 13C NMR
(150 MHz, CDCl3): δ = 161.8 (C-4ЈЈЈ), 160.6 (C-4ЈЈ), 160.3 (C-4Ј),
145.0 (C-2), 135.5 (C-5), 131.2 (C-2ЈЈЈ and C-6ЈЈЈ), 130.7 (C-2Ј and
C-6Ј), 129.2 (C-2ЈЈ and C-6ЈЈ), 126.7 (C-1ЈЈ), 118.7 (C-1Ј), 118.3 (C-
4), 115.8 (C-1ЈЈЈ), 115.2 (C-3ЈЈ and C-5ЈЈ), 114.6 (C-3ЈЈЈ and C-
5ЈЈЈ), 114.3 (C-3Ј and C-5Ј), 55.6 (OMec), 55.5 (OMeb), 55.3
disk): ν = 1608, 1498, 1250, 1174, 1030, 832, 772 cm–1. EI-MS:
˜
m/z (%) = 357 (26) [M + 1]+, 356 (100) [M]+, 355 (25), 342 (8), 341
(30), 208 (6), 177 (10). C23H20N2O2 (356.42): calcd. C 77.51, H
5.66; found: C 77.39, H 5.57.
Method B: 2-[(4-Methoxy)phenyl]-1-phenyl-1H-imidazole (2e,
146 mg, 0.58 mmol), Pd(OAc)2 (6.5 mg, 2.9×10–4 mol), CuI
(223 mg, 1.17 mmol) and CsF (178 mg, 1.17 mmol) were place in a
flame-dried reaction vessel, which was fitted with a silicon septum
and then evacuated and back-filled with argon in a sequence that
was repeated twice. A solution of 4b (274 mg, 1.17 mmol) in DMF
(5 mL) was then added by syringe at room temperature under a
stream of argon and the resulting mixture was stirred at 140 °C
under argon and was maintained at this temperature for 113 h. It
was then cooled to room temperature and worked up by the same
procedure as used in Method A. A GLC analysis of the resulting
crude reaction mixture showed that it contained compound 5e in
57% GLC yield.
(OMe ) ppm. IR (KBr disk): ν = 1610, 1513, 1249, 1176, 1027, 833,
˜
a
801 cm–1. EI-MS: m/z (%) = 386 (100) [M]+, 371 (26), 341 (5), 281
(9), 238 (4), 226 (5), 207 (15). C24H22N2O3 (386.45): calcd. C 74.59,
H 5.74; found: C 74.82, H 5.81.
Method C: 5-[(4-Methoxy)phenyl]-1-phenyl-1H-imidazole (1e,[2]
146 mg, 0.58 mmol), Pd(OAc)2 (6.5 mg, 2.9×10–4 mol), CuI
(223 mg, 1.17 mmol) and CsF (178 mg, 1.17 mmol) were placed in
a flame-dried reaction vessel, which was fitted with a silicon septum
and then evacuated and back-filled with argon in a sequence that
was repeated twice. A solution of 4b (274 mg, 1.17 mmol) in DMF
(5 mL) was then added by syringe at room temperature under a
stream of argon and the resulting mixture was stirred at 140 °C
under argon with stirring and maintained at this temperature for
46 h. The resulting yellow solution was then cooled to room tem-
perature and worked up by the same procedure as used in
Method A. A GLC analysis of the resulting crude reaction mixture
showed that it contained compound 5e in 74% GLC yield.
2,5-Bis(4-methoxyphenyl)-1-phenyl-1H-imidazole (5e): This com-
pound was synthesised by three different procedures (Methods A,
B and C).
Method A: Compounds 3a (144 mg, 1.0 mmol) and 4b (468 mg,
2.0 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), CuI (381 mg, 2.0 mmol)
and Cs2CO3 (652 mg, 2.0 mmol) were placed in a flame-dried reac-
tion vessel, which was fitted with a silicon septum and then evacu-
ated and back-filled with argon in a sequence that was repeated
twice. DMF (5 mL) was then added by syringe at room temperature
under a stream of argon and the resulting mixture was heated to
140 °C under argon with stirring and maintained at this tempera-
ture for 66 h. It was then cooled to room temperature, diluted with
AcOEt (75 mL) and poured into a saturated aqueous NH4Cl solu-
tion (35 mL). The resulting mixture was stirred in the open air for
0.5 h and extracted with AcOEt (4×60 mL). The organic extract
was washed with brine (2×10 mL), dried and concentrated under
reduced pressure. The residue was purified by MPLC on silica gel
with a mixture of AcOEt and toluene (50:50 + 0.1% Et3N) as elu-
ent to give 5e (114 mg, 32%) as a pale yellow solid: m.p. 176–
178 °C. 1H NMR (600 MHz, CDCl3): δ = 7.42 (m, 1 H, 4ЈЈ-H),
7.38 (m, 2 H, 3ЈЈ-H and 5ЈЈ-H), 7.36 (br.s, 1 H, 4-H), 7.34 (d, J =
8.6 Hz, 2 H, 2ЈЈЈ-H and 6ЈЈЈ-H), 7.11 (m, 2 H, 2ЈЈ-H and 6ЈЈ-H),
6.99 (d, J = 8.4 Hz, 2 H, 2Ј-H and 6Ј-H), 6.79 (d, J = 8.6 Hz, 2 H,
3ЈЈЈ-H and 5ЈЈЈ-H), 6.76 (d, J = 8.4 Hz, 2 H, 3Ј-H and 5Ј-H), 3.78
(s, 3 H, OMeb), 3.77 (s, 3 H, OMea) ppm. 13C NMR (150 MHz,
CDCl3): δ = 160.5 (C-4ЈЈЈ), 159.5 (C-4Ј), 144.6 (C-2), 136.2 (C-1ЈЈ),
135.4 (C-5), 130.7 (C-4ЈЈ), 130.6 (C-2ЈЈЈ and C-6ЈЈЈ), 130.3 (C-3ЈЈ
and C-5ЈЈ), 130.2 (C-2Ј and C-6Ј), 128.0 (C-2ЈЈ and C-6ЈЈ), 123.6
(C-4), 120.8 (C-1Ј), 120.1 (C-1ЈЈЈ), 113.96 (C-3ЈЈЈ and C-5ЈЈЈ),
113.95 (C-3Ј and C-5Ј), 55.3 (OMeb), 55.2 (OMea) ppm. IR (KBr
Supporting Information Available: Experimental procedures and
characterization for compounds 2c, 2d, 2e, 2h, 2i, 2j, 2k and 2l and
physical and spectroscopic data for compounds 5a and 5d. This
material is available free of charge via the Internet (see footnote on
the first page of this article).
Acknowledgments
We thank the Ministero dellЈIstruzione, dellЈUniversità e della
Ricerca (MIUR) and the University of Pisa for financial support.
We are also grateful to Mr. Piergiorgio Vergamini for recording IR
spectra.
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Received: August 19, 2005
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Eur. J. Org. Chem. 2006, 693–703
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www.eurjoc.org
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