Copper- or iron-catalyzed arylation of phenols from respectively aryl chlorides and aryl iodides

Article abstract of DOI:10.1002/chem.200800436

The utility of diketone-1 was checked, which was first introduced for bimetallic Fe-Cu catalysts, in copper-catalyzed arylation of phenols from aryl chlorides. A systematic study was first undertaken by choosing 3,5-dimethylphenol as a model substrate. The first blank test was undertaken with PhCl and the dieketone-1/[Cu(acac)₂] system. The second blank test was performed without copper and showed as expected that the arylation from PhCl did not proceed at all with a catalytic system only based on iron. A protocol permitting the arylation of 3,5-dimethylphenol with chlorobenzene in excellent yield. The system diketone-1//[Cu(acac)₂] efficiently promotes cross-coupling reactions between phenols and chlorobenzene or aryl chlorides, which are deactivated by electron-donating substituents. The results indicate that an efficient global method for arylation of phenols from aromatic chlorides can be discovered.

Full text of DOI:10.1002/chem.200800436

COMMUNICATION
DOI: 10.1002/chem.200800436
Copper- or Iron-Catalyzed Arylation ofPhenols rfom respectively Aryl
Chlorides and Aryl Iodides
Ning Xia and Marc Taillefer*[a]
The diaryl ether structure is found in numerous important
organic compounds in the pharmaceutical and polymer in-
dustries.[1] The common synthesis of diaryl ethers usually re-
quires the reaction of phenols with aryl halides in the pres-
ence of a catalyst containing a transition metal. It has been
Scheme 1. 1/Fe/Cu/-catalyzed arylation of dimethylphenol with PhCl.[6a]
reported that Pd-catalyzed methods can function in this
role, but their high costs and elaborate ligands are draw-
backs when compared with copper-mediated reactions.[2,3]
Indeed, in recent years much workhas contributed to im-
proving the traditional Ullmann ether synthesis, which re-
quires stoichiometric quantities of copper and harsh condi-
tions. In spite of great advances in the use of copper cata-
lysts associated with specific ligands,[4] the aryl chlorides are
still problematic substrates. To our knowledge there are
very few examples available involving them in copper-cata-
lyzed arylation with phenols.[3b,c] Thus a convenient and gen-
eral method for arylation from aryl chlorides should be of
great interest to industrial production and laboratory re-
search due to their low cost and ready availability.[5] Recent-
ly we presented an original example of cooperative bimetal-
lic Fe–Cu catalysis affording O-, N-, or C-arylation of
ly here, is the iron-catalyzed arylation of phenols from aryl
iodides.[7]
A systematic study was first undertaken by choosing 3,5-
dimethylphenol as a model substrate (synthesis of 2 f,
Table 1). Our first test allowed us to checkthe result pre-
sented in Scheme 1, because we observed that under quite
similar conditions the arylation of dimethylphenol from
chlorobenzene was indeed possible even in the presence of
a lower quantity (10%) of iron catalyst (Table 1, entry 1).
The first blank test was undertaken with PhCl and the dike-
tone-1/[Cu(acac)2] system (Table 1, entry 2). The result was
G
Table 1. 1/Cu-catalyzed O-arylation of 3,5-dimethylphenol from aryl hal-
ides.
nucleo
philes from aryl bromides.[6] In this workwe observed
G
that the efficiency of the catalytic system was dramatically
increased by the addition of 2,2,6,6-tetramethyl-3,5-heptane-
dione (1) as ligand, thus allowing, for example, arylation of
phenols from non-activated chlorobenzene (Scheme 1).[6a]
These initial results encouraged us to carefully investigate
this system. We now report the first general method for
copper-catalyzed arylation of phenols from aryl chlorides.[7]
An additional finding of this study, touched upon only brief-
Fe
Cu
X
Solvent
Yield [%][a]
1
2
3
4
5
6
7
8
9
FeCl3
[Cu
[Cu
[Cu
N
Cl
Cl
Br
Cl
Br
I
Cl
Cl
Cl
Cl
Cl
Cl
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
40
60
95[b]
0
FeCl3
FeCl3
FeCl3
18
85,97[c]
18
[a] N. Xia, Dr. M. Taillefer
CuBr
CuBr
CuI
CuBr2
CuBr
CuBr
Institut Charles Gerhardt Montpellier, CNRS UMR 5253
Architectures MolØculaires et MatØriaux NanostrucuturØs
Ecole Nationale SupØrieure de Chimie de Montpellier
8 rue de l’Ecole Normale
34296 Montpellier Cedex 5 (France)
Fax : (+33)467-144-319
64
57
10
11
12
57
43[d]
91[e]
E-mail: marc.taillefer@enscm.fr
[a] GC yield yields determined with 1,3-dimethoxybenzene as the inter-
nal standard. [b] Reaction temperature: 708C. [c] Reaction time: 24 h.
[d] 0.4 equiv of ligand. [e] Reaction time: 36 h.
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
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Table 2. Ligand 1/Cu-catalyzed O-arylation of phenols from aryl chlor-
ides.
surprising, because in absence of iron salt, diaryl ether 2 f
was obtained in a very acceptable yield (60%). Another in-
dication of the efficiency of this system was that the reaction
using bromobenzene allowed us to obtain ether 2 f quantita-
tively at a remarkably low temperature (708C, Table 1,
entry 3). The second blanktest was performed without
copper and showed as expected that the arylation from
PhCl did not proceed at all with a catalytic system only
based on iron (Table 1, entry 4). However, when we tested
the bromobenzene under the same conditions as previously,
we were intrigued by the formation of a modest but signifi-
cant amount of ether 2 f (18%; Table 1, entry 5). Finally, we
selected iodobenzene, which is a more powerful electrophile,
with which we obtained the coupling product in 85% yield
(see below). We then continued our study and by a system-
atic variation of parameters we were able to establish a pro-
tocol permitting the arylation of 3,5-dimethylphenol with
chlorobenzene in excellent yield (entry 12). Among the sol-
vents, bases, and copper sources tested (Table 1, entries 7–
12), DMF, caesium carbonate, and copper bromide were
found to be the best combination.
R1
H
H
H
H
H
R2
Product
Yield [%][a]
1
2
3
4
5
H
2a
2b
2c
2d
2e
81
80
91
87
40
4-Me
4-OMe
4-tBu
F
6
7
H
3,5-Me2
3,5-Me2
2f
82
91
4-Me
2g
8
9
4-Me
4-MeO
4-Me
2h
2h
99
53
4-MeO
Next we explored the breadth of application of this new
method. Thus the system diketone-1/[Cu(acac)2] efficiently
A
10
11
12
13
4-MeO
4-MeCO
4-NO2
4-CN
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
2i
2j
2k
2l
81
95
88
90
promotes cross-coupling reactions between phenols and
chlorobenzene or aryl chlorides, which are deactivated by
electron-donating substituents. We have thus isolated several
different diaryl ethers 2a–i using unreactive substrates such
as chlorobenzene, 4-chlorotoluene, and even 4-chloroanisole
(Table 2, entries 1–10). That the O-nucleophile can also be
varied considerably is attested to by the following examples
that all undergo efficient coupling under our conditions: p-
toluene, p-methoxyphenol, p-fluorophenol, p-tertiobutylphe-
nol, 3,5 dimethylphenol, and phenol itself. In most cases
when the reactions were carried out with Cs2CO3 as the
base, excellent isolated yields were obtained at 1358C, a re-
markably low temperature relative to those required in the
classic stoichiometric Ullmann arylation of phenol with aryl
chlorides. In the presence of more reactive aryl chlorides
substituted by electron-withdrawing groups (CH3CO, CN or
NO2) our catalytic system also gave excellent yields of
biaryl ethers (Table 2, entries 11–13). However here, particu-
larly for NO2, the catalyst proved unnecessary and cross-
coupling proceeds in high yield by nucleophilic aromatic
substitution.[8]
We believe that these results indicate that we have discov-
ered an efficient global method for arylation of phenols
from aromatic chlorides. The stronger donor character of b-
diketone 1 compared to acac probably facilitates oxidative
addition of the chlorobenzene to copper.[9] This may also be
the key to the successful arylation of dimethylphenol from
phenyl iodide catalyzed by iron (Table 1, entry 6). We con-
firmed the efficiency of the ligand 1/iron combination as a
catalyst by conducting screening tests with phenyl iodine or
with iodobenzenes bearing electron-donating substituents
(Scheme 2). Thus very good isolated yields of diaryl ethers
were obtained from un- or deactivated aryl iodides, (iodo-
benzene, 4-iodotoluene, or 4-iodoanisole) with phenol, 4-flu-
[a] Yield of isolated product.
Scheme 2. Ligand 1/Fe-catalyzed arylation of phenols from aryl iodides
(isolated yields in brackets).[7]
orophenol, or 3.5-dimethylphenol. The reaction also takes
place quantitatively with electron-withdrawing groups on
the aryl iodides (R=NO2, CN, or CH3CO), but here good
yields with the same substrates are obtained under SNAr
conditions. Although the aryl iodides are much less chal-
lenging than the chlorides, this catalytic system is very inter-
À
esting because it constitutes the first report of C O coupling
catalyzed by iron.[7,10]
A final example shows the advantage of complementary
use of copper and iron in this catalyst system: using both
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Chem. Eur. J. 2008, 14, 6037 – 6039

Coupling Reactions
COMMUNICATION
metals with ligand 1 enables a chemoselective one-pot syn-
thesis of an unsymmetrical polyether as demonstrated by
the preparation of oligomer 3 in 80% isolated yield
(Scheme 3). Such compounds, which are otherwise difficult
[1] a) A. V. Rama Rao, M. K. Gurjar, L. Reddy, A. S. Rao, Chem. Rev.
1995, 95, 2135; b) The Pesticide Manual, 10th ed. (Ed.: C. Tomlin),
British Crop Protection Council, Farnham, 1994.
[2] a) C. H. Burgos, T. E. Barder, X. Huang, S. L. Buchwald, Angew.
Chem. 2006, 118, 4427; Angew. Chem. Int. Ed. 2006, 45, 4321; b) G.
Mann, C. Incarvito, A. L. Rheigold, J. F. Hartwig, J. Am. Chem. Soc.
1999, 121, 3224; c) S. Harkal, K. Kumar, D. Michalik, A. Zapf, R.
Jackstell, F. Rataboul, T. Riemeier, A. Monsees, M. Beller, Tetrahe-
dron Lett. 2005, 46, 3227.
[3] a) K. Kunz, U. Scholz, D. Ganzer, Synlett 2003, 15, 2428; b) I. P. Be-
letskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004, 248, 2337; c) F.
Monnier, M. Taillefer, Angew. Chem. 2008, 120, 3140; Angew.
Chem. Int. Ed. 2008, 47, 3096.
[4] a) B. H. Lipshutz, J. B. Unger, B. R. Taft, Org. Lett. 2007, 9, 1089;
b) A. Ouali, J.-F. Spindler, A. Jutand, M. Taillefer, Adv. Synth. Cat.
2007, 349, 1906; c) A. Ouali, J.-F. Spindler, H.-J. Cristau, M. Taille-
fer, Adv. Synth. Cat. 2006, 348, 499; d) A. Ouali, R. Laurent, A.-M.
Caminade, J.-P. Majoral, M. Taillefer, J. Am. Chem. Soc. 2006, 128,
15990; e) Y. Jin, J. Liu, Y. Yin, H. Fu, Y. Jiang, Y. Zhao, Synlett
2006, 1564; f) Q. Cai, B. Zou, D. Ma, Angew. Chem. 2006, 118, 1298;
Angew. Chem. Int. Ed. 2006, 45, 1276; g) H.-J. Cristau, P. P. Cellier,
S. Hamada, J.-F. Spindler, M. Taillefer, Org. Lett. 2004, 6, 913; h) D.
Ma, Q. Cai, Org. Lett. 2003, 5, 3799; i) E. Buck, Z. J. Song, D.
Tschaen, P. G. Dormer, R. P. Volante, P. J. Reider, Org. Lett. 2002, 4,
1623; j) J. Hassan, M. SØvignon, C. Gozzi, E. Schultz, M. Lemaire,
Chem. Rev. 2002, 102, 1359; k) R. K. Gujadhur, C. G. Bates, D. Ven-
kataraman, Org. Lett. 2001, 3, 4315; l) A. V. Kalinin, J. F. Bower, P.
Riebel, V. Snieckus, J. Org. Chem. 1999, 64, 2986; m) J.-F. Marcoux,
S. Doye, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 10539.
[5] a) K. Weissermel, H. J. Arpe, Industry Organic Chemistry, Wiley-
VCH, Weinheim (Germany), 1997, p. 349.
[6] a) M. Taillefer, N. Xia, A. Ouali, US 2006 60/818,334 and PCT 2007/
001836; b) M. Taillefer, N. Xia, A. Ouali, Angew. Chem. 2007, 119,
952; Angew. Chem. Int. Ed. 2007, 46, 934.
[7] Patented results: N. Xia, M. Taillefer, 2007 US patent 60996830.
[8] a) Under similar conditions 4-fluoronitrobenzene reacts more quick-
ly than 4-chloronitrobenzene; b) Related results are known although
often following from the use of more activated substrates or metal
(Pd)-catalyzed systems: B. Smith, J. March, Marchꢀs Advanced Or-
ganic Chemistry: Reactions, Mechanisms, and Structure, 6th ed.,
Wiley, New York, 2007, p. 853, and references therein.
Scheme 3. In situ chemoselective 1/Fe- and 1/Cu-catalyzed synthesis of a
polyarylether. a) Conditions as in Scheme 2; b) in situ addition of CuBr
and of the 3,5-dimethylphenol; conditions as in Table 2.
to synthesize selectively, are important target molecules for
the life sciences.[11]
In summary, we have checked the utility of diketone 1,
which was first introduced for bimetallic Fe–Cu catalysts,[6a]
in copper-catalyzed arylation of phenols from aryl chlorides.
This reaction—of considerable economic importance—pro-
vides a challenge to which we supply the first satisfying solu-
tion. Commercial availability, low cost, and low toxicity of
the copper system makes it very competitive to existing Pd-
based protocols. Moreover, our method is easily adaptable
to an industrial scale for which financial and environmental
factors are of greater importance.[6a,7] Finally, we have also
shown the efficiency of catalysts employing diketone 1 using
iron alone as the metal and its use with both metals to
afford a clean entry into the regioselective synthesis of un-
symmetrical aromatic polyethers.
Experimental Section
[9] M. Fabre, J. Jaud, M. Hliwa, J.-P. Launay, J. Bonvoisin, Inorg. Chem.
2006, 45, 9332.
[10] Very recently the group of Prof. Carsten Bolm obtained similar re-
sults in the case of phenyl iodide or of aryl iodides deactivated by
electron-donating substituents (O. Bistri, A. Correa, C. Bolm,
Angew. Chem. 2008, 120, 596; Angew. Chem. Int. Ed. 2008, 47, 586).
In the case of aromatic iodides activated by electron-withdrawing
substituents we found under our conditions that the presence of the
catalytic system Fe/diketone 1 was not necessary to obtain excellent
isolated yields of 2j, 2k, and 2l.
For synthesis and characterization data of 2 and 3 and a general proce-
dure for the catalytic reactions, see the Supporting Information.
Acknowledgements
The authors are grateful to the CNRS and the region of Languedoc
Roussillon for Ph.D. grant and financial support.
[11] L. L. J. Winneroski, Y. Xu, J. S. York, patent 2005 WO 05/
037763 A1.
Keywords: aryl chlorides · aryl iodides · copper · coupling
reactions · iron
Received: December 7, 2007
Published online: May 21, 2008
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