Synthetic approaches to sterically hindered N-arylimidazoles through copper-catalyzed coupling reactions

Article abstract of DOI:10.1002/ejoc.200400453

Optimization studies allowed the efficient synthesis of a simple structural motif based on meta-bis(1-imidazolyl)benzenes 1 through copper-catalyzed coupling of 1,3-diiodobenzene and imidazole under mild reaction conditions. This protocol was then used to prepare a representative sterically hindered N-arylimidazole 2a, the most common structural motif among N-heterocyclic carbenes (NHC). Having optimized the main variables governing Cu^I-catalyzed imidazole N-arylation, the first Ullmann-type synthesis of N-mesitylimidazole (2a) is reported. Moreover, the coupling between boronic acids as the aryl donor partners and either imidazole or benzimidazole was examined; in all cases the reactions proceeded in very low yield. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400453

FULL PAPER
Synthetic Approaches to Sterically Hindered N-Arylimidazoles through
Copper-Catalyzed Coupling Reactions
Ermitas Alcalde,*[a] Immaculada Dinarès,*[a] Sandra Rodríguez,[a] and
Cristina Garcia de Miguel[a]
Keywords: Arylation / Benzimidazole / Imidazole / N-Heterocyclic carbenes / Ullman-type condensation
Optimization studies allowed the efficient synthesis of a sim-
ple structural motif based on meta-bis(1-imidazolyl)benzenes
1 through copper-catalyzed coupling of 1,3-diiodobenzene
and imidazole under mild reaction conditions. This protocol
was then used to prepare a representative sterically hindered
N-arylimidazole 2a, the most common structural motif among
N-heterocyclic carbenes (NHC). Having optimized the main
variables governing CuI-catalyzed imidazole N-arylation, the
first Ullmann-type synthesis of N-mesitylimidazole (2a) is re-
ported. Moreover, the coupling between boronic acids as the
aryl donor partners and either imidazole or benzimidazole
was examined; in all cases the reactions proceeded in very
low yield.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
imidazolylidenes, the largest class of N-heterocyclic carb-
enes (NHCs).[4] As part of our ongoing research on imida-
zolium quaternary salts as the main structural motifs within
dicationic imidazoliophanes,[5a] and especially dicationic
open-chain systems,[5b] we pursued the synthesis of more or
less sterically hindered N-arylimidazoles: bis(imidazole) 1
and N-arylimidazoles 2a–d.
Introduction
A variety of coupling protocols for copper-mediated C(a-
ryl)–N bond formation, especially the application of
Ullmann-type condensations to the N-arylation of nitrogen
heterocycles, have led to practical synthesis of sterically un-
hindered N-arylimidazoles together with other azoles and
indoles. Among the synthetic routes available, the common
“aryl donor” partners of imidazole are either aryl halides
or arylboronic acids, and the aryl groups are sterically un-
hindered moieties.[1] To the best of our knowledge, only two
reports include several ortho-substituted Ar–I(Br)[2a] or ar-
ylboronic acids,[3] while no report deals with di-ortho-sub-
stituted aryl derivatives, such as 2-iodo-1,3,5-trimethylben-
zene or 2,4,6-trimethylphenylboronic acid. Buchwald et al.
have made advances in the development of Ullmann-type
methodology, and N-arylation of NH-heteroaromatic com-
pounds yields unhindered N-arylazoles,[2b] e.g. N-arylimida-
zoles, and more or less hindered N-arylindoles,[2a] together
with N-arylpyrroles and N-arylpyrazoles.[2c] Moreover, Cri-
stau et al. have examined the copper-catalyzed N-arylation
of azoles.[2d,2e] As for the coupling of arylboronic acids with
imidazoles,[1] the latest development is a catalytic reaction
in dry MeOH in the presence of a simple copper salt, such
as CuCl or CuI.[3]
We examined the use of these protocols in the synthesis
of simple targeted N-arylimidazole subunits, and we now
report a mild protocol for an Ullmann-type condensation
that allows the synthesis of bis(imidazole) 1, the simple
structural motif based on meta-bis(1-imidazolyl)benzenes,
in excellent yield.[6] More importantly, having optimized the
relevant variables governing Cu-catalyzed N-arylation of
imidazole, the first Ullmann-type synthesis of the sterically
hindered 1-mesitylimidazole (2a) was accomplished in 50%
isolated yield after chromatographic purification.
In parallel, N-arylimidazoles are found in a broad array
of imidazolium quaternary salts used as key precursors to
[a] Laboratori de Química Orgànica, Facultat de Farmàcia, Uni-
versitat de Barcelona,
Av. Joan XXIII s/n, 08028-Barcelona, Spain
Fax: (internat.) + 34-934024539
E-mail: ealcalde@ub.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2005, 1637–1643
DOI: 10.1002/ejoc.200400453
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E. Alcalde, I. Dinarès, S. Rodríguez, C. Garcia de Miguel
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Scheme 1.
Results and Discussion
Cu-catalyzed N-arylation of imidazole (3) was first ad-
dressed, in order to prepare 1,3-bis-(1-imidazolyl)benzene
(1). We examined the coupling of imidazole (3) and 1,3-
diiodobenzene under standard Buchwald N-arylation con-
ditions:[2b,7] 5mol-% of air-stable CuI in combination with
20% of ligand, 1 m in 1,4-dioxane (Scheme 1). Since the aryl
halide is disubstituted, the mol-% of CuI and the ligand
were doubled; the selected ligands were the racemic trans-
1,2-cyclohexanediamine (A)[2b] together with N,NЈ-di-
methylethylenediamine (B), which have been used in the N-
arylation of indoles.[2a]
Initially, K2CO3 was used as the base, but only monosub-
stituted derivative 4 was isolated (Table 1, entry 1). When
the base was changed to Cs2CO3, the yield was improved
to 80% for bis(imidazole) 1. When coupling was carried out
in a sealed tube at 95 °C, the yield was improved to 95%
(entry 4), whereas in the presence of ligand B practically no
reaction was observed. This approach works well for scale-
up purposes because no chromatographic separations were
required to obtain good yields (entry 6).
Scheme 2.
As a starting point, we assayed conditions similar to
those used to prepare the meta-bis(N-imidazolyl)benzene
(1), but no reaction was observed since the C-aryl donor is
2-iodo-1,3,5-trimethylbenzene. Other conditions were then
examined by raising the reaction temperature and by chang-
ing the catalyst, solvent (1,4-dioxane, toluene, DME, DMF)
and ligand (see Supporting Information). At 170 °C, in
DMF with 10 mol-% of CuI and 40 mol-% of ligand B, the
reaction progressed to afford the N-mesitylimidazole (2a) in
26% yield (see Table 2, entry 1). With a reaction time of
48 h, the yield reached 50% after chromatographic purifica-
tion (entry 2), and this isolated yield was maintained when
the reaction was scaled up to 10 mmol.
Table 2. Selected results in the preparation of 1-mesitylimidazole
(2a), in the presence of Cs2CO3 as a base.[a]
Table 1. Reactions of imidazole (3) with 1,3-diiodobenzene.[a]
Entry
L
Base
T [°C]
Yield [%][b]
1
4
1
2
3
4
A
A
A
A
B
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
110
110
5[c]
80
79
34
15
15
5
110[d]
95[e]
95[e]
95[e]
Entry
L
Solvent
T [°C]
Time [h] Yield [%]
95
[b]
5
–
10[c]
8
6[f]
A
89[g]
1
B
B
B
A
B
B
DMF
DMF
DMF
DMF
DMF
DMF
170
170
170
170
170
170
24
48
48
48
48
48
26
50
47
37
38
54
2
3[c]
4
[a] All reactions 0.5 m in 1,4-dioxane with respect to 1,3-diiodo-
benzene unless otherwise noted. [b] Isolated yield after chromato-
graphic purification. [c] Calculated by 1H NMR from treated reac-
tion mixture. [d] 48 h. [e] Sealed tube. [f] Scale up to 5 mmol.
[g] 76% yield from first crystallization of reaction mixture in hex-
ane/Me2CO.
5[d]
6[e]
[a] All reactions 1 m with respect to 2-iodo-1,3,5-trimethylbenzene
unless otherwise noted. [b] Isolated yield after chromatographic pu-
rification. [c] With 5 mol-% CuI and 20 mol-% L. [d] 0.5 m. [e] 2 m.
We next examined the utility of this modified Cu-cata-
lyzed N-arylation procedure for the preparation of sterically
hindered N-arylimidazoles (Scheme 2).
Similar results were observed when the standard percent-
For N-mesitylimidazole (2a), only three experimental ages,[7] 5 mol-% of CuI and 20 mol-% of ligand, were used
procedures are described in the literature, excluding patents. (entry 3), whereas the use of ligand A reduced the yield (en-
The classical multicomponent imidazole synthesis has been try 4). Although the optimal initial concentration of the
applied starting from mesitylammonium salt[8] or from mes- starting materials with respect to 2-iodo-1,3,5-trimethylben-
itylamine;[4c,9] yields range from 17% to 43%.[10]
zene showed that the coupling was most efficient at 2 m (en-
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Sterically Hindered N-Arylimidazoles through Cu-Catalyzed Coupling Reactions
FULL PAPER
try 6), when the reaction was scaled up to 10 mmol, the lene.[4c] By exploiting the modified protocol applied to 1,3-
yield was decreased by 25%, and the formation of mesity- iodobenzene (see Table 1, entry 4), no reaction was ob-
lene was observed.
served, whereas by forcing the conditions, 1-(2-naphthyl)-
As for the base,[1] a mild Ullmann-type condensation 1H-imidazole (2c) was obtained in good yield (Table 3); fol-
procedure has recently been applied to the synthesis of sec- lowing our protocol, the yield was 26% higher than that
ondary arylamines through the use of CuI and CsOAc in previously reported.[4c] In contrast, 1-(1-naphthyl)-1H-imi-
the absence of ligand.[11] Thus, Cs2CO3 was replaced by dazole (2d) was obtained in 57% isolated yield, whereas
CsOAc, and the results are compiled in Table S2 (see Sup- yields of 85% have been reported.[4c]
porting Information). The first run gave N-mesitylimida-
An alternative protocol for C–N bond formation involves
zole (2a) in 33% yield and the workup was very simple. In the reactions of arylboronic acids with NH-azoles using
addition, the coupling was subjected to the same conditions stoichiometric or catalytic amounts of a copper source; the
as reported,[11] and the yield was decreased to 12% (see Chan–Evans–Lam modified Ullmann condensation ap-
Supporting Information).
pears to be an efficient N-arylation method for azoles in-
The best reaction conditions for the preparation of 2a cluding imidazole (3).[1] For reasons of brevity, unproduc-
were then applied to other N-arylazoles such as 2b–d tive experiments related with the application of the Chan–
(Scheme 2, Table 3 and Supporting Information). Coupling Evans–Lam modified Ullmann condensation, both stoi-
of imidazole (3) with the sterically congested 2-iodo-1,3- chiometric and catalytic CuII protocols,[12] are omitted (see
diisopropylbenzene was clearly less efficient, and when we Supporting Information). Coupling with the sterically hin-
scaled up the reaction to 10 mmol, the yield was main- dered 2,4,6-trimethylphenylboronic acid was then examined
tained; curiously, at higher temperatures, the yield de- under a variety of reaction conditions, and the best experi-
creased. The best way to prepare 2b is by the two-step ment gave N-mesitylimidazole (2a) in very low yield as
modified classical imidazole synthesis starting from 2,6-di- shown in Scheme 3 (method A). Other arylboronic acids
isopropylaniline.[9]
were also used, including simple phenylboronic and 1-naph-
thylboronic acids (see Supporting Information).
Table 3. Selected results for reactions of aryl halides with imidazole
(3).[a]
Scheme 3. Reagents and conditions: Method A = Ar-B(OH)2
(2 mmol), Cu(OAc)2 (1.1 mmol), Py (2.2 mmol), 3 (1 mmol), dry
CH2Cl2, air, 25 °C, 48 h; Method B = Ar-B(OH)2 (1 mmol), CuI
(0.05 mmol), 3 (1.2 mmol), dry MeOH, air, reflux, 6 h.
Concurrently with our work, Yu et al.[3] reported that a
simple copper salt catalyzed the coupling of imidazole with
arylboronic acids in MeOH, but this recent coupling proto-
col has not yet been extended to the preparation of 1-mes-
itylimidazole (2a), even though 2,4,6-trimethylphenylbo-
ronic acid is currently commercially available. We attempted
to apply this new protocol to the coupling between 2,4,6-
trimethylphenylboronic acid and imidazole (3) (Scheme 3,
method B).
By following the same experimental procedure,[3] and
with CuCl (5 mol-%), the coupling reaction afforded an 8%
yield of the desired 1-mesitylimidazole (2a, entry 1,
Table 4), whereas with CuI (5 mol-%) the average yield was
9% (entries 2 and 3, Table 4). Other variables such as sol-
vent and mol-% of the catalyst were examined, and neither
product formation nor any trace of 2a were observed (see
[a] All reactions were carried out in DMF unless otherwise noted.
[b] Isolated yield. [c] With 5 mol-% CuI and 20 mol-% ligand A.
[d] In 1,4-dioxane.
On the other hand, the Ullmann-type condensation Supporting Information). For 2d and 2e, the coupling yields
should work very well with unhindered aryl halides under were lower than those reported.[3] Consequently, these pro-
standard coupling conditions;[1,2] by using this one-step tocols were not further investigated.
route, 1-(2-naphthyl)-1H-imidazole (2c) has recently been
Since potassium aryltrifluoroborate salts are another
prepared in 54% isolated yield from 2-bromonaphtha- source of arylboron,[1,13,14] the reaction of imidazole (3)
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E. Alcalde, I. Dinarès, S. Rodríguez, C. Garcia de Miguel
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Scheme 4. Reagents and conditions: Method A = Ph-BF3 K+ (2 mmol), Cu(OAc)2 (1.1 mmol), Py (2.2 mmol), 3 (1 mmol), dry CH2Cl2,
–
–
air, 25 °C, 48 h; Method B = Ar-BF3 K+ (1 mmol), CuI (0.05 mmol), 3 (1.2 mmol), dry MeOH, air, reflux, 3 h.
Table 4. Selected results in the reactions of arylboronic acids and N-Arylation of Benzimidazole
imidazole (3).
Given the results for 1H-imidazole (3), N-arylation of
5,6-dimethyl-1H-benzimidazole (5)[15a] was examined. To
date, coupling protocols for copper-mediated C(aryl)–N
bond formation when benzimidazoles are the nucleophilic
reaction partner have received little attention.[1] For aryl ha-
lides as the aryl donor, Buchwald et al. have introduced a
general Ullmann-type synthesis of unhindered N-arylazo-
les[1,2b] and unhindered 1-(3,5-dimethylphenyl)-1H-benzimi-
dazole, for example, has been obtained in 91% yield.[15b]
Accordingly, several experiments involving the Cu-cata-
lyzed coupling between 2-iodo-1,3,5-trimethylbenzene and
5,6-dimethyl-1H-benzimidazole (5) were carried out, under
the best reaction conditions found for preparation of 2a,
with changes in the concentration or the reaction tempera-
ture (see Table S5 in Supporting Information). Surprisingly,
none of these experiments generated N-mesityl-5,6-dimeth-
ylbenzimidazole (6a), thus necessitating other experimental
conditions beyond the scope of the present study. It is clear
that the general conditions should be adapted for each sub-
strate type.
When ArB(OH)2 is the aryl donor,[1] this copper-cata-
lyzed C(aryl)–N bond formation has many drawbacks,
which, in particular cases, have been resolved.[3,12] To the
best of our knowledge, there are two protocols for the syn-
thesis of N-arylated benzimidazoles[12] and imidazoles[3]
[a] Isolated yield.
that merit attention due to their efficiency; unhindered N-
arylazoles have been obtained in respectable yields.
with unhindered potassium aryltrifluoroborate salts was
Accordingly, coupling of unhindered ArB reagents[1,13]
then examined (Scheme 4). Potassium phenyltrifluorobor- and 5,6-dimethyl-1H-benzimidazole (5) was examined by
ate gave no trace of 2e, whereas potassium 4-methylphen- using the stoichiometric CuII method[12a] and the catalytic
yltrifluoroborate generated the unhindered N-arylimidazole CuI method[3] (Scheme 5). When ArB(OH)2 was the aryl
2f in very low yield (4 %). This is the first example of N- donor, method A[12a] gave the unhindered N-arylbenzimida-
–
arylation of azoles by ArBF3 K+ salts.
zole 6f in 64% yield, whereas by using method B,[3] the yield
Scheme 5. Reagents and conditions: Method A = Ar-B(OH)2 (2 mmol), Cu(OAc)2 (1.1 mmol), Py (2.2 mmol), 5 (1 mmol), dry CH2Cl2,
air, room temperature, 48 h; Method B = Ar-BXn (1 mmol), CuI (0.05 mmol), 5 (1.2 mmol), dry methanol, air, reflux, 3 h; Method C =
–
Ar-BF3 K+ (1.1 mmol), Cu(OAc)2 (1.1 mmol), Py (2.2 mmol), 5 (1 mmol), dry 1,4-dioxane, air, room temperature, 24 h.
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Sterically Hindered N-Arylimidazoles through Cu-Catalyzed Coupling Reactions
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1,3-Bis(1-imidazolyl)benzene (1): 1H NMR (300 MHz, CDCl3): δ =
7.91 (br.s, 2 H), 7.61 (t, 1 H, J = 8 z), 7.42 (s, 1 H), 7.41 (d, 2 H,
J = 8 z), 7.33 (br.s, 2 H), 7.24 (br.s, 2 H) ppm. 13C NMR
(75.4 MHz, CDCl3): δ = 138.6, 135.4, 131.4, 131.0, 120.1, 118.0,
114.5 ppm. EI-MS: m/z (%): 210 (100) [M+]. M.p. 136–137 °C. The
NMR spectroscopic data are in accordance with those reported.[6]
1-(3-Iodophenyl)-1H-imidazole (4): Colorless foam. 1H NMR
(300 MHz, CDCl3): δ = 7.84 (br.s, 1 H), 7.75 (br.s, 1 H), 7.70 (d, 1
H), 7.36 (d, 1 H), 7.26 (br.s, 1 H), 7.23–7.17 (m, 2 H) ppm. 13C
NMR (50.3 MHz, CDCl3): δ = 138.1, 136.3, 135.3, 131.1, 130.6,
130.2, 120.5, 117.9, 94.6 ppm. EI-MS: m/z (%): 270 (100) [M+].
C9H7IN2•0.5Me2CO (299.11): calcd. C 42.16, H 3.37, N 9.37;
found C 42.43, H 3.16, N 9.08.
was reduced to 37%. Alternatively, the coupling of the cor-
–
responding ArBF3 K+ salt and benzimidazole 5 (method C)
produced 6f, albeit in low yields.[14]
Conclusions
The Ullmann-type condensation between 1,3-diodoben-
zene and imidazole (3) under mild reaction conditions af-
forded simple meta-bis(1-imidazolyl)benzene (1) in excellent
yield, and application of this Cu-catalyzed N-arylation pro-
tocol to the synthesis of basic sterically hindered N-arylimi-
dazoles was examined. We identified the optimal conditions
for the coupling of 2-iodo-1,3,5-trimethylbenzene and imi-
dazole (3), and the best experiment gave N-mesitylimida-
zole (2a) in 50% yield, although the reaction temperature
is high. As an alternative route, the coupling of 2,4,6-tri-
methylphenylboronic acid with imidazole (3) was also ex-
amined, and after a trial of a variety of conditions, the best
experiment gave 2a in very low yield, confirming the ca-
pricious nature of the reaction with arylboronic acids as
aryl donor partners. From these optimization studies for
Typical Procedure for N-Arylation of Imidazole: An oven-dried re-
sealable tube was back-filled with argon and charged with aryl ha-
lide (1 mmol), imidazole 3 (0.082 g, 1.2 mmol), CuI (0.019 g,
0.1 mmol), dry DMF (1 mL), N,NЈ-dimethylethylenediamine
(0.041 mL, 0.4 mmol) and Cs2CO3 (0.684 g, 2.1 mmol) under a
stream of argon. The tube was sealed with a Teflon valve and the
reaction mixture was stirred magnetically at 170 °C for 48 h. The
resulting suspension was cooled to room temperature, and Cl2CH2
(20 mL) and NH4OH (20 mL) were added. The separate layers
were washed, combined organic layers were dried, and solvent was
the synthesis of topical and useful imidazole units 1, 2a, 2c removed. The residue was purified by flash chromatography
(EtOAc) to afford pure product.
and 2d we conclude that the method of choice is Ullmann-
type condensation with aryl halides as aryl donors and CuI
as the catalyst, whereas the best option to prepare 1-(2,6-
diisopropylphenyl)-imidazole (2b) is a recently reported
two-step modified classical imidazole synthesis. Efforts are
currently being directed toward the use of these imidazole
1-(2,4,6-Trimethylphenyl)-1H-imidazole (2a): The product was ob-
tained as a colorless crystalline solid (0.095 g, 50% yield). 1H NMR
(200 MHz, CDCl3): δ = 7.44 (s, 1 H), 7.24 (s, 1 H), 6.97 (s, 2 H),
6.90 (s, 1 H), 2.34 (s, 3 H), 1.99 (s, 6 H) ppm. M.p. 116–117 °C. The
NMR spectroscopic data are in accordance with those reported.[4c]
building blocks for the construction of molecular scaffolds 1-(2,6-Diisopropylphenyl)-1H-imidazole (2b): The product was ob-
tained as colorless needles (0.044 g, 19% yield). 1H NMR
(200 MHz, CDCl3): δ = 7.51 (br.s, 1 H), 7.45 (t, 1 H), 7.27 (d, 2
ranging from dicationic and polycationic systems to their
metal complexes.
H), 7.24 (s, 1 H), 6.95 (br.s, 1 H), 2.39 (m, 1 H), 1.13 (d, 6 H) ppm.
M.p. 122–123 °C. The NMR[4c] data and m.p.[9] are in accordance
with those reported.
Experimental Section
1-(2-Naphthyl)-1H-imidazole (2c): The product was obtained as a
white solid (0.156 g, 80% yield). H NMR (200 MHz, CDCl3): δ =
General Remarks: All reactions were carried out in glassware that
had been oven-dried and cooled under a stream of argon. Commer-
1
8.00–7.83 (m, 5 H), 7.78 (s, 1 H), 7.59–7.51 (m, 3 H), 7.42 (br.s, 1
cially available reagents were used without further purification. 1-
H), 7.27 (s, 1 H) ppm. M.p. 122–123 °C. The NMR spectroscopic
Iodo-2,6-diisopropylbenzene was synthesized according to litera-
data and m.p. are in accordance with those reported.[4c]
ture procedure.[11] All materials were weighed in air. All yields re-
ported in Tables 1–6 refer to isolated yields (average of two runs)
1-(1-Naphthyl)-1H-imidazole (2d): The product was obtained as a
1
white solid (0.112 g, 57% yield). H NMR (200 MHz, CDCl3): δ =
7.98–7.94 (m, 2 H), 7.78 (s, 1 H), 7.61–7.44 (m, 5 H), 7.31–7.27
(m, 2 H) ppm. M.p. 72 °C. The NMR spectroscopic data are in
accordance with those reported.[4c]
of compounds estimated to be pure as determined by 1H NMR
and TLC. The new compounds 4 and 6f were further characterized
by elemental analysis. Compounds described in the literature were
characterized by comparison of their 1H NMR spectra to pre-
viously reported data.
Preparation of 1-(2,4,6-Trimethylphenyl)imidazole (2a) from 2,4,6-
Trimethylphenylboronic Acid. Method A: An oven-dried two-necked
round-bottomed 50 mL flask containing a magnetic stirrer bar
was charged with 2,4,6-trimethylphenylboronic acid (0.695 g,
4.24 mmol), anhydrous Cu(OAc)2 (0.423 g, 2.33 mmol), pyridine
(0.375 mL, 4.66 mmol) and CH2Cl2 (10 mL). After five minutes,
imidazole (0.144 g, 2.12 mmol) was added and the reaction mixture
was stirred under air at room temperature for 48 h. MeOH/NH3
(6 mL) was added, the solution was evaporated, and the residue
was filtered through a 1×1 cm pad of silica gel and eluted with
EtOAc. Purification by flash chromatography on alumina
(3×15 cm; CH2Cl2) provided N-(2,4,6-trimethylphenyl)imidazole
(2a, 0.016 g, 4% yield).
1,3-Bis(1-imidazolyl)benzene (1): An oven-dried resealable tube was
back-filled with argon and charged with imidazole 3 (0.163 g,
2.4 mmol), CuI (0.019 g, 0.1 mmol), Cs2CO3 (1.368 g, 4.2 mmol),
1,3-diiodobenzene (0.330 g, 1 mmol), racemic trans-1,2-cyclohexa-
nediamine (0.048 mL, 0.4 mmol) and 2 mL of dry 1,4-dioxane un-
der a stream of argon. The reaction tube was quickly sealed and
the contents were stirred at 95 °C for 24 h. The cooled reaction
mixture was diluted with EtOAc, filtered through a plug of silica
gel and eluted with additional EtOAc saturated with NH3. The
filtrate was concentrated, and the resulting residue was purified by
column chromatography [hexane/EtOAc (1:1); EtOAc/NH3;
EtOAc/MeOH (9:1)] to provide 1-(3-iodophenyl)-1H-imidazole (4,
0.014 g, 5% yield) and bis(1-imidazolyl)benzene (1, 0.200 g, 95%
yield).
Method B: An oven-dried round-bottomed 50 mL flask containing
a magnetic stirrer bar was charged with 2,4,6-trimethylphenylbo-
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E. Alcalde, I. Dinarès, S. Rodríguez, C. Garcia de Miguel
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ronic acid (0.164 g, 1 mmol), CuI (0.009 g, 0.05 mmol), and dry
(project BQU2002–0347). Additional support was provided by the
MeOH (5 mL). After five minutes, imidazole (0.082 g, 1.2 mmol) Comissionat per a Universitats i Recerca de la Generalitat de Cata-
was added and the reaction mixture was stirred under air at reflux
for 6 h. The solvent was evaporated, and NH4OH solution (10%,
5 mL) and EtOAc (5 mL) were added. The organic layer was
washed with water and dried, and the solvent was removed. Purifi-
cation by flash chromatography on silica (1×15 cm; EtOAc) pro-
vided N-(2,4,6-trimethylphenyl)imidazole (2a, 0.017 g, 9% yield).
lunya (grant 2001SGR00082). S. R. thanks the Departament d’U-
niversitats, Recerca i Societat de l’Informació (DURSI) de la Gene-
ralitat de Catalunya for an F. I. fellowship. C. G. thanks DGI,
MEC (Spain) for an F.P.I. fellowship.
[1] For a review of the state of the art in modern synthetic meth-
ods for copper-mediated C–(aryl)–heteroatom bond formation,
see: S. V. Ley, A. W. Thomas, Angew. Chem. 2003, Angew.
Chem. Int. Ed. 2003, 42, 5400–5449.
[2] a) J. C. Antilla, A. Klapars, S. L. Buchwald, J. Am. Chem. Soc.
2002, 124, 11684–11688, and references cited therein. b) A.
Klapars, J. C. Antilla, X. Huang, S. L. Buchwald, J. Am. Chem.
Soc. 2001, 123, 7727–7729; c) J. C. Antilla, J. M. Baskin, T. E.
Barder, S. L. Buchwald, J. Org. Chem. 2004, 69, 5578–5587; d)
H.-J. Cristau, P. P. Cellier, J.-F. Spindler, M. Taillefer, Eur. J.
Org. Chem. 2004, 695–709; e) H.-J. Cristau, P. P. Cellier, J.-F.
Spindler, M. Taillefer, Chem. Eur. J. 2004, 10, 5607–5622.
[3] J.-B. Lan, L. Chen, X.-Q. Yu, J.-S. You, R.-G. Xie, Chem. Com-
mun. 2004, 188–189 and references cited therein.
5,6-Dimethyl-1-(4-methylphenyl)-1H-benzimidazole (6f). Method A:
An oven-dried two-necked round-bottomed 50 mL flask containing
a magnetic stirrer bar was charged with 4-methylphenylboronic
acid (0.272 g, 2 mmol), anhydrous Cu(OAc)2 (0.200 g, 1.1 mmol),
pyridine (0.18 mL, 2.2 mmol) and CH2Cl2 (4 mL). After five min-
utes, 5,6-dimethylbenzimidazole (5, 0.146 g, 1 mmol) was added
and the reaction mixture was stirred under air at room temperature
for 48 h. MeOH/NH3 (3 mL) was added, the solution was evapo-
rated, and the residue was filtered through a 1×1 cm pad of silica
gel and eluted with EtOAc. Purification by flash chromatography
on silica gel (2×15 cm; EtOAc) provided 5,6-dimethyl-1-(4-meth-
ylphenyl)benzimidazole (6f, 0.151 g, 64% yield).
[4] For recent reviews on NHC, see: a) W. A. Herrmann, Angew.
Chem. 2002, Angew. Chem. Int. Ed. 2002, 41, 1290–1309; b)
M. C. Perry, K. Burgess, Tetrahedron: Asymmetry 2003, 14,
951–961. For some examples on chiral NHC ligands for the
development of new asymmetric catalysts, see: c) M. C. Perry,
X. Cui, M. T. Powell, D.-R. Hou, J. H. Reibenspies, K. Burgess,
J. Am. Chem. Soc. 2003, 125, 113–123. For calix[4]arene-sup-
ported NHC ligands, see: d) F. Markus, G. Mass, J. Schatz,
Eur. J. Org. Chem. 2004, 607–613.
[5] a) E. Alcalde, N. Mesquida, M. Vilaseca, Rapid Commun. Mass
Spectrom. 2000, 14, 1443–1447 and references cited therein. b)
E. Alcalde, N. Mesquida, M. Alemany, C. Alvarez-Rúa, S.
García-Granda, P. Pacheco, L. Pérez-García, Eur. J. Org.
Chem. 2002, 1221–1231 and references cited therein.
Method B: An oven-dried round-bottomed 50 mL flask containing
a magnetic stirrer bar was charged with 4-methylphenylboronic
acid (0.136 g, 1 mmol) or potassium 4-methylphenyltrifluoroborate
(0.198 g, 1 mmol), CuI (0.009 g, 0.05 mmol) and dry MeOH
(4 mL). After five minutes, 5,6-dimethylbenzimidazole (5, 0.175 g,
1.2 mmol) was added and the reaction mixture was stirred under air
at reflux for 3 h. The solvent was evaporated, and NH4OH solution
(10%, 5 mL) and EtOAc (5 mL) were added. The organic layer
was washed with water and dried, and the solvent was removed.
Purification by flash chromatography on silica (1×15 cm; EtOAc)
provided 5,6-dimethyl-1-(4-methylphenyl)benzimidazole (6f; see
Scheme 5).
Method C: An oven-dried two-necked round-bottomed 50 mL flask
containing a magnetic stirrer bar was charged with potassium 4-
methylphenyltrifluoroborate (0.217 g, 1.1 mmol), anhydrous
Cu(OAc)2 (0.200 g, 1.1 mmol), pyridine (0.18 mL, 2.2 mmol) and
dry 1,4-dioxane (4 mL). After five minutes, 5,6-dimethylbenzimida-
zole (5, 0.146 g, 1 mmol) was added and the reaction mixture was
stirred under air at room temperature for 24 h. MeOH/NH3 (6 mL)
was added, the solution was evaporated, and the residue was fil-
tered through a 1×1 cm pad of silica gel and eluted with EtOAc.
Purification by preparative chromatography on a silica gel plate
with EtOAc/CHCl3 (75:25) as the eluent provided 5,6-dimethyl-1-
(4-methylphenyl)benzimidazole (6f, 0.013 g, 6% yield).
5,6-Dimethyl-1-(4-methylphenyl)-1H-benzimidazole (6f): 1H NMR
(400 MHz, CDCl3): δ = 8.00 (s,1 H), 7.65 (s, 1 H), 7.39–7.34
(AAЈBBЈ syst., 4 H), 7.27 (s, 1 H), 2.45 (s, 3 H), 2.39 (s, 3 H), 2.35
(s, 3 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 142.3, 141.7,
138.2, 134.0, 133.2, 132.6, 132.0, 130.7, 124.1, 120.6, 110.8, 21.3,
20.8, 20.5 ppm. M.p. 96–97 °C. EI-MS: m/z (%): 236 (100) [M+].
C16H16N2 (236.31): calcd. C 81.32, H 6.82, N 11.85; found C 81.16,
H 6.98, N 11.67.
[6] Concomitant with our work, an Ullmann-type condensation
procedure was also applied to prepare bis(imidazole) 1: V. C.
Vargas, R. J. Rubio, T. K. Hollis, M. E. Salcido, Org. Lett.
2003, 5, 4847–4849.
[7] For the coupling of imidazole (3) with 5-iodo-1,3-dimethylben-
zene reported by Buchwald et al.,[2b] the reaction was carried
out in the presence of 5 mol-% of air-stable CuI in combination
either with 10 mol-% of 1,10-phenanthroline or, as the Sup-
porting Information indicates, 20% of racemic trans-1,2-cyclo-
hexanediamine (A), 1 m in 1,4-dioxane. On the other hand,
Burgess et al.[4c] have pointed out that 1,10-phenanthroline can
be difficult to separate from the N-arylimidazole product.
[8] M. G. Gardiner, W. A. Herrmann, C.-P. Reisinger; J. Schwarz,
M. Spiegler, J. Organomet. Chem. 1999, 572, 239–247.
[9] Concurrent with our work, Zang et al. reported a convenient
modified two-step procedure for the classical synthesis of imi-
dazoles and its applicability to the preparation of sterically hin-
dered N-arylimidazoles; for example 1-mesityl-1H-imidazole
(2a, 43%) and 1-(2,6-diisopropylphenyl)-1H-imidazole (2b,
45%): J. Liu, J. Chen, J. Zhao, Y. Zhao, L. Li, H. Zhang, Syn-
thesis 2003, 2661–2666 and references cited therein.
[10] In our hands, following the protocols described by Herrmann
et al.[8] and Burgess et al.,[4c] N-mesitylimidazole 2a was ob-
tained in ca. 15% isolated yield whereas the modified two-step
procedure recently reported by Liu et al.[9] worked very well
(43% yield).
Supporting Information Available (see also footnote on the first
page of this article): Tables S2 and S5. Complete Tables 2, 3 and 4.
Experimental procedures not detailed in the printed manuscript
and attempted preparation of N-arylazoles from arylboronic acids
(Schemes 6 and 7).
[11] K. Okano, H. Tokuyama, T. Fukuyama, Org. Lett. 2003, 5,
4987–4990.
[12] a) Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters,
D. M. T. Chan, A. Combs, Tetrahedron Lett. 1998, 39, 2941–
2944; b) J. P. Collman, M. Zhong, Org. Lett. 2000, 2, 1233–
1236.
[13] For a review on potassium trifluoro(organo)borates, see: S.
Darses, J.-P. Genet, Eur. J. Org. Chem. 2003, 4313–4327. For a
Acknowledgments
This research was supported by the Dirección General de Investiga-
ción (DGI), Ministerio de Ciencia y Tecnología (MCyT), Spain
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Eur. J. Org. Chem. 2005, 1637–1643

Sterically Hindered N-Arylimidazoles through Cu-Catalyzed Coupling Reactions
FULL PAPER
ligand- and base-free CuII-catalyzed C–N bond-formation
[15] a) For 1H NMR spectral simplification, 5,6-dimethyl-1H-
benzimidazole (5) was used instead of 1H-benzimidazole. b)
Cu-catalyzed coupling of 5-iodo-1,3-dimethylbenzene with 1H-
benzimidazole was reported to proceed in 91% yield.[2b,c]
[16] B. S. Jensen, L. Teuber, D. Strobaek, P. Christophersen, S. P.
Olesen, PCT Int. Appl. 2000, WO 0069823A120001123.
Received: June 30, 2004
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method for the coupling of either ArB(OH)2 or ArBF3 K+ with
amines, anilines as well as pyrrole,[14] see: T. D. Quach, R. A.
Batey, Org. Lett. 2003, 5, 4397–4440 and references cited
therein.
[14] In general, N-arylation of primary and secondary amines and
anilines with PhB(OH)2 gave slightly greater yields than
PhBF3 K+.[13]
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