Ligand-free copper(I) catalyzed N- and O-arylation of aryl halides

Article abstract of DOI:10.1016/j.tetlet.2007.08.026

A simple and industrially viable protocol for C-N and C-O coupling is reported here. Arylation of phenol, benzylamine and imidazole with aryl bromides is achieved using ligand-free Cu(I) halide salts in low catalytic amount (2.5 mol %).

Full text of DOI:10.1016/j.tetlet.2007.08.026

Tetrahedron Letters 48 (2007) 7366–7370
Ligand-free copper(I) catalyzed N- and O-arylation of aryl halides
Elena Sperotto,a Johannes G. de Vries,b Gerard P. M. van Klinka and Gerard van Kotena,*
aOrganic Chemistry and Catalysis, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
bDSM Research, Life Sciences, Advanced Synthesis and Catalysis, PO Box 18, 6160 MD Geleen, The Netherlands
Received 21 June 2007; revised 3 August 2007; accepted 6 August 2007
Available online 10 August 2007
Abstract—A simple and industrially viable protocol for C–N and C–O coupling is reported here. Arylation of phenol, benzylamine
and imidazole with aryl bromides is achieved using ligand-free Cu(I) halide salts in low catalytic amount (2.5 mol %).
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
acids,9 1,10-phenanthrolines,10 diols11 and other nitro-
gen- and oxygen-containing ligands.7,12
The formation of aryl-nitrogen and aryl-oxygen bonds
via cross-coupling reactions represent a powerful means
for the preparation of various compounds that are of
biological, pharmaceutical and material interest.1 Since
its discovery, the copper-mediated Ullmann coupling
reaction2 is still the straightforward method to form
the requisite carbon–heteroatom bonds. However, the
synthetic scope of this reaction is strongly limited by
the insolubility of copper(I) salts in organic solvents, the
high reaction temperatures required (ꢀ200 °C) and the
sensitivity of the substituted aryl halide to the harsh
reaction conditions applied. Another major drawback
of this protocol is the use of stoichiometric amounts of
copper or copper salts, which results in the production
of large quantities of waste, making this method envi-
ronmentally unfriendly. Milder reactions using trans-
metallating agents, such as triarylbismuth,3 aryllead
triacetates,4 arylboronic acids5 and hypervalent aryl sil-
oxanes,6 have been developed but these alternatives are
limited since the preparation of highly functionalized
substrates usually requires multistep sequences. Impor-
tant developments have been made on the Ullmann-type
coupling reaction, mainly improving the reaction condi-
tions and tolerability of substrates.7 The key seems to be
modification of the catalytic system via addition of a
wide range of additives in order to improve the solubil-
ity of the copper source, allowing in this way, the use of
a catalytic amount of copper and milder reaction condi-
tions. Generally, this goal is reached via in situ forma-
tion of a copper-complex by addition of a suitable,
often bidentate, chelator such as diamines,8 amino
An alternative is the preparation of a chemically well-
defined and soluble copper-complex to be employed in
the reaction.13 Recently, for N-14 and O-15arylation
reactions soluble aminoarenethiolato-copper(I) com-
plexes (CuSAr)16 were used. Different disubstituted
diaryl ethers and arylamines have been synthesized from
aryl bromides, using only 2.5 mol % of the copper(I)
complex.
The aminoarenethiolato-copper catalyzed reactions are
typically carried out under reaction conditions of 6–
16 h at 160 °C, in the presence of 1.1 equiv of inorganic
base.14,15 For mechanistic investigations, tests with cat-
alytic amounts of ligand-free copper halides were under-
taken resulting in remarkably high activities. Motivated
by these results, several tests on O- and N-arylation
reactions with different Cu-halide salts were performed
under conventional heating conditions (Tables 1–3).
This Letter contains these preliminary results describing
the copper(I)-catalyzed arylation reaction of phenol,
benzylamine and imidazole using phenyl iodide and aryl
bromides as arylating agents. To the best of our knowl-
edge, protocols using low catalytic amounts of simple,
cheap and ligand-free copper(I) salts in the Ullmann-
type coupling reaction have not been reported thus far.
2. Results and discussion
Three different Cu(I) halide salts were employed, CuCl,
CuBr17 and CuI, in order to determine the influence of
*
Corresponding author. E-mail: g.vankoten@uu.nl
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.026

E. Sperotto et al. / Tetrahedron Letters 48 (2007) 7366–7370
Table 1. O-Arylation reaction of phenol with aryl halidesa
7367
Y
O
HO
2.5 mol% CuX
+
Cs2CO3 1.1 eq,
NMP 1 mL
160 oC, 16 h
Entry
1
CuX
Aryl halide
Product
Yieldb (%)
Br
O
CuCl
89
I
O
O
O
O
O
2
3
4
5
6
CuCl
CuBr
CuBr
CuI
80c
87c
72
Br
I
Br
I
72
CuI
42
Br
O
7
8
CuBr
CuBr
89c
78c
Br
O
MeO
MeO
O
Br
9
CuI
68d
O
O
Br
Br
a Reaction conditions: aryl halide (5 mmol), phenol (6.5 mmol), Cs2CO3 (5.5 mmol), CuX (2.5 mol %), NMP (1 mL), 160 °C, 16 h, under N2.
b Determined by GC using dihexyl ether as internal standard.
c Isolated yield.
d 3 equiv of phenol and Cs2CO3.
the anion. The solvent (NMP), inorganic base (K2CO3
or Cs2CO3), temperature (160 °C) and time (16 h)
parameters were kept constant to facilitate comparison
with data collected previously by us, employing the
CuSAr copper catalyst.14,15 As shown in Tables 1 and
3, the best substrate for these two examples of C–N
and C–O coupling reactions was bromobenzene, while
in the case of N-arylation with imidazole (Table 2),
the arylating agent iodobenzene gave similar results to
the bromo compound. The use of chlorobenzene as sub-
strate was not investigated since yields in screening tests
were very poor (between 1% and 18%). Moderate to
good results were obtained for the O-arylation of bromo
and iodobenzene, with yields between 42% and 89%,
including an example of tri-substitution of 1,3,5-tri-
bromobenzene with phenol. N-Arylation of imidazole
led to the preparation of the desired products in good
yields (67–79%) while arylation of benzylamine gave
rather poor results (yields between 9% and 50%). As
shown in Table 1, para-substituted phenyl bromides
(entries 7 and 8) were also suitable substrates for the
preparation of substituted diaryl ethers. They show a
positive influence in the case of the N-arylation of
imidazole (Table 2, entries 7 and 8), while in the case
of arylation of benzylamine the presence of a substituent
on the phenyl ring did not bring about any improve-
ment. These data underline the difference not only
between O- and N-nucleophiles in the coupling process,
but also between primary and secondary amines. It
appears that the nature of the halide anion present in
the mixture (derived either from the Cu salt or from
the aryl donor) plays a pivotal role in the reaction since
the best results were achieved in the presence of bromide
anions. A possible explanation could be the presence of
iodide ions stabilizing the Cu atom in its +1 oxidation
state, rendering the species stable and insoluble,18 while

7368
E. Sperotto et al. / Tetrahedron Letters 48 (2007) 7366–7370
Table 2. N-Arylation reaction of imidazole with aryl halidesa
2.5 mol% CuX
HN
Y
+
N
N
N
K2CO3 1.1 eq,
NMP 1 mL
160 oC, 16 h
Entry
1
CuX
Aryl halide
Product
Yieldb (%)
67
Br
N
CuCl
N
N
N
N
N
N
I
2
3
4
5
6
CuCl
CuBr
CuBr
CuI
61c
86c
72
N
N
N
N
N
Br
I
Br
I
70
CuI
72c
Br
N
7
8
CuBr
CuBr
89
91
N
Br
MeO
N
N
MeO
a Reaction conditions: aryl halide (5 mmol), imidazole (6.5 mmol), K2CO3 (5.5 mmol), CuX (2.5 mol %), NMP (1 mL), 160 °C, 16 h, under N2.
b Determined by GC using dihexyl ether as internal standard.
c Isolated yield.
the bromide ion would permit a change in oxidation
state, allowing a possible catalytic cycle. In this regard,
four mechanisms are proposed in the literature that
can be classified into two main categories: those in which
the oxidation state of copper changes throughout the
mechanistic cycle and those in which the oxidation state
remains constant. The four different alternatives involve:
(a) oxidative addition/reductive elimination of ArX on
copper(I); (b) aryl radical intermediates; (c) r-bond
metathesis through a four-centred intermediate and (d)
p-complexation of copper(I) on ArX.7 Therefore, the
positive influence of bromide ions observed in the
above-mentioned reactions seems to corroborate with
mechanism (a) or (b), which presumes a change of the
Cu formal oxidation state during the C–X coupling
reaction. Further investigations regarding mechanistic
aspects of the copper-catalyzed aromatic nucleophilic
substitutions are currently in progress.
sive preparation of external ligands and activated
substrates.
3. Experimental
General procedure for catalytic test reactions: The cata-
lytic tests were performed using standard Schlenk
techniques. In a general procedure, a Schlenk tube
containing N2 was charged with inorganic base
(5.5 mmol) and solid substrate. Liquid reagents (aryl
halide: 5 mmol; amine/phenol: 6.5 mmol) and solvent
(NMP, 1 mL) were then added and finally the copper(I)
salt was added. The reaction was kept under an inert
atmosphere19 and placed in a preheated oil bath at
160 °C for 16 h. Subsequently, the reaction was
allowed to cool to room temperature and quenched by
adding acetonitrile (5 mL) and dihexyl ether (100 ll,
0.425 mmol) as external standard. All samples were ana-
lyzed by gas chromatography. For the etherification
reaction, the reaction mixture was filtered through a
plug of Celite and the solvent removed in vacuo to yield
the crude product, which was purified by silica gel chro-
matography (eluent: hexane). In the case of the amina-
tion reaction, the reaction mixture was washed with
4 M NaOH and the organic layer was dried over
In summary, this Letter describes a simple method for
the preparation of diaryl ethers and N-arylated benzyl-
amines and imidazoles. The catalytic system adopted is
simple and cheap, starting from commercially available
compounds and employing only a catalytic amount
(2.5 mol %) of the Cu(I) halide salt. This protocol avoids
the otherwise time-consuming and sometimes expen-

E. Sperotto et al. / Tetrahedron Letters 48 (2007) 7366–7370
Table 3. N-Arylation reaction of benzylamine with aryl halidesa
7369
H2N
2.5 mol% CuX
Y
+
NH
K2CO3 1.1 eq,
NMP 1 mL
160 oC, 16 h
Entry
1
CuX
Aryl halide
Product
Yieldb (%)
Br
32c
CuCl
NH
NH
NH
NH
NH
NH
I
2
3
4
5
6
7
8
CuCl
CuBr
CuBr
CuI
11
15
10
50
9
Br
I
Br
I
CuI
Br
NH
CuI
35
25
Br
MeO
NH
CuI
MeO
a Reaction conditions: aryl halide (5 mmol), benzylamine (6.5 mmol), K2CO3 (5.5 mmol), CuX (2.5 mol %), NMP (1 mL), 160 °C, 16 h, under N2.
b Determined by GC using dihexyl ether as internal standard.
c Isolated yield.
5. (a) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077;
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MgSO4, filtered and evaporated in vacuo to yield the
crude product, which was purified by silica gel column
chromatography (eluent: EtOAc/hexane).
7. For reviews, see: (a) Lindley, J. Tetrahedron 1984, 40,
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Acknowledgements
We thank DSM, the Ministry of Economic Affairs,
NWO/CW, NRSC-C and Chemspeed Technologies for
the financial support given to the CW/CombiChem
programme.
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