Base-free anaerobic Cu(II) catalysed aryl-nitrogen bond formations

Article abstract of DOI:10.1016/j.tetlet.2004.08.094

The Cu(II) catalysed coupling of arylboronic acids with imidazole can be performed at ambient temperature without the need for base or dioxygen. The presence of water however is essential for the reaction to proceed.

Full text of DOI:10.1016/j.tetlet.2004.08.094

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7659–7662
Base-free anaerobic Cu(II) catalysed aryl-nitrogen bond formations
Sander S. van Berkel,a Adri van den Hoogenband,b Jan Willem Terpstra,b Moniek Tromp,c
Piet W. N. M. van Leeuwena and Gino P. F. van Strijdoncka,*
aUniversity of Amsterdam, Institute of Molecular Chemistry, Nieuwe Achtergracht 166, 1018 WVAmsterdam, Netherlands
bSolvay Pharmaceuticals, Weesp, Netherlands
cUtrecht University, Debye Institute, Department of Inorganic Chemistry and Catalysis, Utrecht, Netherlands
Received 30 June 2004; revised 13 August 2004; accepted 17 August 2004
Abstract—The coupling of arylboronic acids with imidazole in the presence of binuclear bis-l-hydroxy copper(II) complexes is
reported. The reactions can be performed in air as well as under nitrogen atmosphere. Reactions are carried out at ambient tem-
perature without the need for base. The presence of water is essential for the reaction to proceed. Ligand effects on the yield and
selectivity are reported.
Ó 2004 Elsevier Ltd. All rights reserved.
The formation of aryl–aryl bonds and aryl–heteroatom
bonds are among the most important transformations
in organic synthesis. Copper is the most ancient metal
used for the coupling of aryl halides to form biaryls,1
but in the last decade palladium has gained widespread
interest.1–6 In many cases palladium complexes are more
active and selective than copper complexes. Reactions
such as the N-arylation of imidazole, however, generally
proceed only when a copper catalyst is used. Because of
the lowcost of copper in comparison to palladium, the
use of copper in industrial processes is preferred.7 Cop-
per-catalysed aryl-nitrogen bond formations are typi-
cally performed under Ullmann-type conditions.8–11
Several procedures using copper(I) based catalysts have
been reported.12–14 Typically, these reactions require ele-
vated temperatures and have to be performed under
nitrogen atmosphere. Recent developments have shown
that the use of stoichiometric quantities of Cu(OAc)2 re-
sults in an efficient coupling of amines and arylboronic
acids under mild reaction conditions.15–19 Collman20
demonstrated that dimeric copper(II) complexes
(10mol%) give moderate to good yields (40–70%) in
C–N coupling reactions. Water can be used as a solvent,
but in most of the methods described, water is excluded
from the reaction mixture to avoid hydrolysis of the
boronic acid.21 Recently it was shown that simple cop-
per salts in protic solvents can efficiently couple aryl-
boronic acids with imidazole.22 All the procedures
described in the literature are performed under dioxygen
atmosphere and often in the presence of a base. Dioxy-
gen is proposed to play an important role as oxi-
dant,19,20,23 whereas the base is used to activate the
boronic acid for transmetallation. The mechanisms pro-
posed for Cu(II) catalysed reactions are as yet only rea-
sonable guesses, because none of the intermediates have
been isolated or characterised.
As part of our quest for mild catalysts for Caryl–N bond
formation and the elucidation of the reaction mecha-
nism we here report on the novel aerobic and anaerobic
coupling of phenylboronic acid and imidazole in the
absence of base, using catalytic amounts of a copper
catalyst (5mol%) (Scheme 1). The reactions were per-
formed under ambient reaction conditions (air atmos-
phere and 20°C) producing moderate to good yields
depending on the ligand employed.24
H
N
[Cu(OH)(Ligand)] Cl
2
3
2
+
N
Keywords: C–N coupling; Catalysts; Cu(II) complexes; Solvent effects;
Ligand design.
N
(5 mol%)
B(OH)
N
2
4
2
1
*
Corresponding author. Tel.: +31 24 3652189; fax: +31 20 5256422;
e-mail: gino@science.uva.nl
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.094

7660
S. S. van Berkel et al. / Tetrahedron Letters 45 (2004) 7659–7662
Our first efforts were directed towards the investigation
of solvent effects on the phenylation of imidazole, using
[Cu(OH)TMEDA]2Cl2 as a catalyst. After 20h, no con-
version was obtained in anhydrous CH3CN, CH2Cl2 or
NMP (N-methylpyrrolidone). This can only partly be
explained by the poor solubility of the catalyst and/
or products in these solvents. In water, in which the
catalyst is completely dissolved, a 7% yield (GC) was
obtained. Also significant amounts of benzene (ꢀ7%)
and phenol (<2%) were formed. A mixture of NMP
and H2O (1:1 v/v), however, afforded a yield of 56% of
the cross coupled product with high selectivity (less than
5% benzene and no phenol was observed). No signifi-
cant amounts of homo-coupled biphenyl were observed.
an amino alcohol ligand, resulted in a lowyield (10%
after 20h). Changing to an aromatic 2,2-bipyridine lig-
and 3f resulted in a decrease of the yield (68%) after a
prolonged reaction time (5days). Using more electron-
donating ligands, for example, 4,4-dimethoxy-bipyridine
3c and 4,4-dimethyl-bipyridine (3d) also resulted in a
decrease of the yield to, respectively, 44% (5days) and
32% (4days). Reactions performed with dimer com-
plexes possessing the more rigid phenanthroline ligands
(3g and h) showed an increase in yield. The 4,7-dichloro-
phenthroline complex 3h afforded phenylimidazole in
77% yield after 4days. Notably, the neocuproine
complex 3g even gave full conversion after 4days.
The phenylation of imidazole catalysed by complex 3d
was performed at higher temperatures. An increase of
the reaction temperature to 60°C raised the yield from
32% to only 39%. At even higher temperatures, no sig-
nificant amount of product was formed, which is prob-
ably due to catalyst decomposition. With the increase
in temperature, there was also an increase in benzene
formation.
To examine the effect of ligands on the catalyst perform-
ance, binuclear Cu(II) complexes 3a–h were synthesised
bearing several nitrogen-based bidentate ligands21,25,26
and tested in the arylation reaction. The results obtained
using only 5mol% of 3a–h in the arylation of imidazole
are summarised in Table 1. Reactions performed with
the TMEDA–dimer complex 3a gave excellent yields
(99% after 72h). Increasing the amount of catalyst 3a
from 5mol% to 7.5mol% resulted in a yield of 89% after
only 48h. Reactions performed with catalyst 3b bearing
Most reported Cu(II) catalysed arylations of aza-com-
pounds employ a base, thereby limiting the scope of
Table 1. The effect of different ligands on coupling of PhB(OH)2 and imidazolea
Entry
Ligand
Time
Yield 4b (%)
1
3a
20h
72h
56
99
N
N
HO
O
N
2
3
3b
3c
20h
5d
10
44
O
N
N
4
3d
4d
32
N
N
5
6
3e
3f
5d
5d
24
68
N
N
Cl
Cl
N
N
N
7
8
3g
3h
4d
4d
99
77
N
Cl
Cl
N
N
a Reaction conditions: 5mol% of Cu(II) dimer (3a–h), imidazole (68mg, 1.0mmol), PhB(OH)2 (121mg, 1.0mmol) in NMP/H2O (1:1 v/v, 5mL), 20°C
in an air atmosphere.
b Determined by GC analysis using dihexyl ether as an internal standard.

S. S. van Berkel et al. / Tetrahedron Letters 45 (2004) 7659–7662
7661
the reaction to substrates, which contain base-stable
functionalities. The method described here does not re-
quire the presence of a base. In our search for efficient
methods for the arylation of imidazole, however, we
studied the effect of pH on the catalyst performance.
To this end different buffered solutions were used in
the phenylation of imidazole using 5mol% of catalyst
3a. At pH4 and 6 (citrate buffer) no product was
observed. At pH8 (tricine buffer) no product formation
was observed either, probably due to the interference
of tricine with the copper complex. The use of a
HCO3À/CO32À/KOH buffer (pH10), yielded only 14%
of coupled product after 20h at room temperature.
Reactions performed in the presence of 2.5 equiv (with
respect to phenylboronic acid) of NaOH or 1equiv of
K2CO3 yielded only traces of product (4% and less than
1%, respectively). The use of 1equiv of NaOAc under
the same conditions resulted in a somewhat higher yield
of 10% after 20h, still significantly lower than the results
obtained in the absence of a base (56%).
is followed by coordination of imidazole and subsequent
oxidation with dioxygen to a transient Cu(III) species.
After reductive elimination of the product, a Cu(I) spe-
cies is formed. This Cu(I) intermediate is then oxidised
to the starting dimeric Cu(II) complex, again by dioxy-
gen. Our results, however, suggest that the first step of
the reaction involves imidazole. Furthermore, dioxygen
is not required as an oxidant under the conditions em-
ployed here. Studies to gain further insight into the
mechanism of this important reaction are in progress.
The implications of these results for the mechanism,
together with spectroscopic studies, will be discussed
elsewhere.27
In conclusion, we have developed a novel, mild method
for the N-arylation of imidazole. We have demonstrated
that this reaction can be selectively performed in an
NMP/H2O mixture, at ambient temperature and atmos-
phere, using catalytic amounts of the cheap and com-
mercially available [Cu(OH)TMEDA]2Cl2 dimer as the
catalyst. The presence of an NMP/H2O mixture in-
creases the yield considerably, whereas addition of base
and the presence of dioxygen are not needed. Moreover,
our results suggest that the first step of the reaction
involves imidazole coordination.
To investigate the role of dioxygen in our system, we
performed reactions with complex 3d under pure dioxy-
gen atmosphere, resulting in a similar yield as was
obtained under an ambient atmosphere. To our surprise,
reaction under nitrogen atmosphere resulted in the same
yield as obtained in the presence of dioxygen.
References and notes
Our mild method proved useful for the coupling of imi-
dazole with a range of different arylboronic acids. The
highest yield (75%) was obtained with an electron with-
drawing CF3 substituent at the meta position of the
boronic acid. The meta nitro analogue, however, only
resulted in a 21% yield. Introduction of an electron
releasing methoxy group at the para position resulted
in a similar yield of 19%. The presence of a substituent
at the ortho position decreased the yield dramatically.
Obviously the steric hindrance caused by these substitu-
ents slows down the reaction considerably. Naphthyl-
boronic acid was coupled to imidazole in 21% yield.
Under the conditions employed, attempted use of
heteroaryl boronic acids such as benzofuranboronic acid
resulted in C–C coupling rather than C–N coupling.
1. Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382–2384.
2. Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
131–209.
3. Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046–
2067.
4. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805–818.
´
5. Mann, G.; Hartwig, J. F.; Driver, M. S.; Fernandez-Rivas,
C. J. Am. Chem. Soc. 1998, 120, 827–828.
6. Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.;
Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415–3418.
7. Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359–1469.
8. Lindley, J. Tetrahedron 1984, 40, 1433–1456.
9. Bacon, R. G. R.; Hill, H. A. O. J. Chem. Soc. 1964, 1097–
1107.
´
10. Fanta, P. E. Synthesis 1974, 1, 9–21.
11. Sainsbury, M. Tetrahedron 1980, 36, 3327–3359.
12. Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett. 2001, 3, 4315–4317.
13. Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793–
796.
The use of phenylboronic acid in the absence of imidaz-
ole results in a fast C–C homocoupling, forming biphen-
yl. A stoichiometric reaction of the Cu(II) dimer and
phenylboronic acid, followed by the addition of imidaz-
ole did not result in C–N product formation, while
the reverse addition sequence (first imidazole and then
phenylboronic acid) resulted in selective formation of
the C–N coupled product. We therefore concluded that
the Cu complex reacts rapidly with imidazole in the
selectivity-determining step, followed by reaction with
the boronic acid. Experiments with increasing amounts
of imidazole or phenylimidazole product added to the
reaction mixture resulted in a decrease of the reaction
rate. This suggests inhibition of the reaction by excess
imidazole and/or phenylimidazole.
14. Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 11684–11688.
15. Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters,
M. P. Tetrahedron Lett. 1998, 39, 2933–2936.
16. Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M.
Y.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000,
122, 7600–7601.
17. Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077–
2079.
18. Yu, S.; Saenz, J.; Srirangam, J. K. J. Org. Chem. 2002, 67,
1699–1702.
19. Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, G. C.;
Combs, A. P. Tetrahedron Lett. 2003, 44, 1691–1694.
20. Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S. J.
Org. Chem. 2001, 66, 7892–7897.
Collman proposed a mechanism for Cu(II) catalysed C–
N bond formation in which the binuclear Cu(II) first re-
acts with phenylboronic acid. This transmetallation step

7662
S. S. van Berkel et al. / Tetrahedron Letters 45 (2004) 7659–7662
21. Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J. Org.
Chem. 2001, 66, 1528–1531.
22. Lan, J.-B.; Chen, L.; Yu, X.-Q.; You, J.-S.; Xie, R.-G.
Chem. Commun. 2004, 2, 188–189.
23. Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236.
24. Typical experimental conditions: To the appropriate
amount of Cu catalyst 3 in 5mL of solvent was added
imidazole 2 (68mg, 1mmol) and arylboronic acid 1
(1mmol). Dihexyl ether (115lL, 0.5mmol) was added as
an internal standard. Unless otherwise stated no base was
added and the reactions were carried out in an air
atmosphere. The reaction mixture was stirred according
to the given reaction times. Product formation was
determined by GC and GC–MS. Samples (0.05mL) were
taken from the reaction mixture at regular time intervals.
CH2Cl2 and a saturated solution of NH4Cl were added to
the sample. After separation of the layers, the organic
layer was filtered through a plug of MgSO4. The retention
time of the products (phenylimidazole 4, biphenyl, phenol
and benzene) were confirmed by comparison with authen-
tic samples.
25. Mitchell, T. P.; Bernard, W. H.; Wasson, J. R. Acta Cryst.
1970, 26, 2096–2101.
26. Ferraro, J. R.; Walker, W. R. Inorg. Chem. 1965, 4, 1382–
1386.
27. Tromp, M. PhD Thesis, University of Utrecht, 2004.