Rhodium(NHC)-catalyzed O -arylation of aryl bromides

Article abstract of DOI:10.1021/ol200603c

Chemical equations presented. The first example of the rhodium-catalyzed O-arylation of aryl bromides is reported. While the right combination of rhodium species and N-heterocyclic carbene (NHC) offered an effective catalytic system enabling the arylation to proceed, the choice of NHC was determined to be most important. The developed O-arylation protocol has a wide range of substrate scope, high functional group tolerance, and flexibility allowing a complementary route to either N- or O-arylation depending on the choice of NHC.

Full text of DOI:10.1021/ol200603c

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2368–2371
Rhodium(NHC)-Catalyzed O-Arylation of
Aryl Bromides
Hyun Jin Kim, Min Kim, and Sukbok Chang*
Department of Chemistry and Molecular-Level Interface Research Center,
Korea Advanced Institute of Science & Technology (KAIST), Daejeon 305-701, Korea
sbchang@kaist.ac.kr
Received March 7, 2011
ABSTRACT
The first example of the rhodium-catalyzed O-arylation of aryl bromides is reported. While the right combination of rhodium species and
N-heterocyclic carbene (NHC) offered an effective catalytic system enabling the arylation to proceed, the choice of NHC was determined to be most
important. The developed O-arylation protocol has a wide range of substrate scope, high functional group tolerance, and flexibility allowing a
complementary route to either N- or O-arylation depending on the choice of NHC.
A variety of natural products and synthetic intermedi-
ates contain a biaryl ether linkage in their structures.1
Therefore, intensive efforts have been devoted to develop-
ing more efficient and practical routes to prepare the biaryl
ether bond starting from simple precursors. A conven-
tional procedure used to provide the ether linkage is the
Ullmann type reaction,2 which has been widely utilized in
organic synthesis and other areas. Although the protocol
offers O-arylated products in good yields, there are several
limitations such as high reaction temperatures and the
requirement of stoichiometric amounts of a copper species.
This aspect has led to the development of more useful
catalytic procedures by key contributions from the
Buchwald3 and Hartwig groups.4
catalytic activity in the O-arylation.5 Diamine or other
types of compounds6 have also been utilized as highly
efficient ligands in combination with a copper species for
efficient reactions. Heterogenized systems of copper cata-
lysts have also been introduced for the O-arylation.7 On
the other hand, sterically bulky phosphines were revealed
to be crucial for achieving high activity in the Pd-catalyzed
ether bond formation.3b In addition, some promising
protocols of metal-free O-arylation have been reported in
recent years.8
Despite the above mentioned significant progress,
there is still room for further improvement especially
with respect to substrate scope, functional group com-
patibility, or synthetic utility. Recently, we have de-
monstrated that the unique catalytic activity of rho-
dium species can be obtained by a combination of
suitable N-heterocyclic carbene (NHC) ligands in the
CꢀC or CꢀN bond formation.9 In our continuing
efforts to develop more efficient and practical metal-
catalyzed organic transformations,10 we report herein
The success of the catalytic protocols can be attributed
to the right combination of metal precursors and suitable
ligands. For instance, copper species in the presence of
amino acids are shown to exhibit dramatically improved
(1) (a) Saywer, J. S. Tetrahedron 2000, 56, 5045. (b) Boger, D. L.;
Miyazaki, S.; Kim, S. H.; Wu, J. H.; Castle, S. L.; Loiseleur, O.; Jin, Q. J.
Am. Chem. Soc. 1999, 121, 10004.
(2) (a) Lindley, J. Tetrahedron 1984, 40, 1433. (b) Frlan, R.; Kikelj, D.
Synthesis 2006, 2271. (c) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
(d) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954. (e)
Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(3) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 10333. (b) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe,
J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369.
(4) (a) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109.
(b) Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413.
(5) (a) Cai, Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45, 1276.
(b) Cai, Q.; Ma, D. Org. Lett. 2003, 5, 3799.
(6) (a) Cristau, H.-J.; Cellier, P. P.; Hamada, S.; Spindler, J.-F.;
Taillefer, M. Org. Lett. 2004, 6, 913. (b) Ouali, A.; Spindler, J.-F.;
Cristau, H.-J.; Taillefer, M. Adv. Synth. Catal. 2009, 348, 499.
(7) (a) Benyahya, S.; Monnier, F.; Wong Chi Man, M.; Bied, C.;
Ouzzani, F.; Taillefer, M. Green Chem. 2009, 11, 1121. (b) Sreedhar, B.;
Arundhathi, R.; Reddy, P. L.; Kantam, M. L. J. Org. Chem. 1996, 61,
1133.
(8) (a) Yuan, Y.; Thome, I.; Kim, S. H.; Chen, D.; Beyer, A.;
Bonnamour, J.; Zuidema, E.; Chang, S.; Bolm, C. Adv. Synth. Catal.
2010, 352, 2892. (b) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99. (c)
Bates, R. B.; Janda, K. D. J. Org. Chem. 1982, 47, 4374.
r
10.1021/ol200603c
Published on Web 04/06/2011
2011 American Chemical Society

the first example of the Rh(NHC)-catalyzed O-aryla-
tion of aryl bromides.
ligand alone was ineffective (entry 3), the combined use of
NHC and phosphine ligands did not furnish more enhanced
results (entry 4) compared to the conditions using the ICy
NHC ligand alone (entry 2).
Not surprisingly, the type of employed rhodium pre-
cursors was highly important for an efficient O-arylation
as seen in entry 5. A prolonged reaction time increased the
product yield (entry 6). Using Rh2(OAc)4 as a metal
precursor, various NHCs were subsequently screened to
reveal that, as anticipated, N-substituents of the imidazo-
lium skeleton significantly influenced the efficiency. For
instance, the introduction of bulkier N-substituents such as
It-Bu or IAd resulted in an inhibition of the reaction
(entries 7 and 8, respectively). In addition, the use of IMes
in combination with Rh2(OAc)4, one of our successful
systems utilized in the CꢀC bond formation,9b was also
ineffective (entry 9).
Interestingly, an NHC ligand (Cy2-bimy) derived from
benzimidazolium salts was determined to be more effective
than the corresponding imidazolyl derivative (compare
entries 10 and 6). It should be noted that the benzimida-
zolium salts are readily prepared as a stable solid in one
step starting from the corresponding benzimidazoles.11a
Considering the fact that NHCs derived from benzimida-
zolium salts have rarely been utilized in transitions metal
catalysis,11 the present result would provide important
insight for further investigations of NHCs in other reac-
tions. While a monomeric Rh-NHC species12 obtained
from the use of [RhCl(cod)]2 instead of Rh2(OAc)4 in
combination with the Cy2-bimy ligand provided only a
moderate yield (entry 11), another NHC derived from an
iPr2-benzimidazolium skeleton was more promising (e.g.,
entry 12).13
Table 1. Optimization of the Reaction Conditionsa
entry
catalytic systems
Rh2(OAc)4
t (h)
yield (%)b
1
24
12
12
12
24
24
24
24
24
24
24
24
24
0
50
0
2
Rh2(OAc)4 þ ICy HBF4
3
3
Rh2(OAc)4 þ PCy3
4
Rh2(OAc)4 þ ICy HBF4 þ PCy3
55
0
3
5
RhCl3 þ ICy HBF4
3
6
Rh2(OAc)4 þ ICy HBF4
70
0
3
7
Rh2(OAc)4 þ It-Bu HCl
3
8
Rh2(OAc)4 þ IAd HCl
0
3
9
Rh2(OAc)4 þ IMes HCl
0
3
10
11
12
13c
Rh2(OAc)4 þ Cy2-bimy HPF6
95
40
66
95
3
[RhCl(cod)]2 þ Cy2-bimy HPF6
3
[RhCl(cod)]2 þ iPr2-bimy HBr
3
Rh2(OAc)4 þ Cy2-bimy HPF6 þ
3
AgPF6
14c
15d
[RhCl(cod)]2 þ iPr2-bimy HBr þ
24
24
95
93
3
AgSbF6
Rh(cod)(iPr2-bimy)Br þ AgSbF6
a Conditions: 1 (0.2 mmol), 2 (0.3 mmol), rhodium catalyst
(10 mol %), NHC ligand (2 equiv to Rh), t-BuONa (2 equiv to 1),
and toluene (0.2 mL). b 1H NMR yield (internal standard: 1,1,2,
2-tetrachloroethane). c Rhodium catalyst (3 mol %), NHC ligand
(10 mol %), AgPF6 (10 mol %). d 5 mol % of Rh-NHC and 10 mol %
of Ag salt were employed.
Using bromobenzene (1a) and 4-methoxyphenol (2a) as
coupling partners, optimization of the intermolecular
O-arylation procedure was first investigated (Table 1).
While the reaction was completely ineffective uisng only
the Rh2(OAc)4 catalyst (10 mol %) in the absence of ligands
(entry 1), the addition of certain NHC ligands provided
much improved results. For instance, an NHC ligand
derived from N,N-dicyclohexylimidazolium accelerated the
O-arylation reaction to afford (4-methoxyphenyl)-phenyl
ether (3a) in 50% NMR yield (entry 2). While a phosphine
Figure 1. Crystallographic structure of Rh(cod)(iPr2-bimy)Br.
It was observed that cationic Rh species generated in situ
by the addition of a silver species into the reaction mixture
was highly active,14 giving excellent product yields even
(9) (a) Kim, M.; Lee, J.; Lee, H.-Y.; Chang, S. Adv. Synth. Catal.
2009, 351, 1807. (b) Kim, M.; Kwak, J.; Chang, S. Angew. Chem., Int. Ed.
2009, 48, 8935. (c) Kim, M.; Chang, S. Org. Lett. 2010, 12, 1640. (d)
Kwak, J.; Kim, M.; Chang, S. J. Am. Chem. Soc. 2011, 133, 3780.
(10) (a) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev. 2004,
33, 302. (b) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008,
130, 9254. (c) Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc.
2008, 130, 16158. (d) Hwang, S. J.; Kim, H. J.; Chang, S. Org. Lett. 2009,
11, 4588. (e) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem.,
Int. Ed. 2009, 48, 9127. (f) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S.
Angew. Chem., Int. Ed. 2010, 49, 9899. (g) Kim, S. H.; Chang, S. Org.
Lett. 2010, 12, 1868. (h) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132,
10272.
(11) (a) Huynh, H. V.; Han, Y.; Ho, J. H. H.; Tan, G. K. Organo-
metallics 2006, 25, 3267. (b) Gung, B. W.; Bailey, L. N.; Craft, D. T.;
Barnes, C. L.; Kirschbaum, K. Organometallics 2010, 29, 3450.
(12) The structure of isolated Rh(cod)(NHC) complexes has been
€
characterized: (a) Turkmen, H.; Pape, T.; Hahn, F. E.; C-etinkaya, B.
Eur. J. Inorg. Chem. 2008, 5418. (b) Li, J.; Stewart, I. C.; Grubbs, R. H.
Organometallics 2010, 29, 3765.
(13) Gaillard, S.; Nun, P.; Slawin, A. M. Z.; Nolan, S. P. Organome-
tallics 2010, 29, 5402.
Org. Lett., Vol. 13, No. 9, 2011
2369

14). A stable neutral complex of Rh(cod)(iPr2-bimy)Br
was isolated, and its structure was unambiguously char-
acterized (Figure 1). As expected, the catalytic activity of
the isolated Rh-NHC species was observed to be as high as
the neutral precursor if it was converted to the correspond-
ing cationic species (entries 14 and 15).
Table 2. O-Arylation of Aryl Bromides with Various Phenolsa,b
Under the optimized conditions using Rh2(OAc)4-(Cy2-
bimy) as a catalyst, a range of substrates was employed in
the O-arylation reaction (Table 2). Electronic variation on
aryl bromides did not much influence the reaction effi-
ciency (entries 2ꢀ5). When 4-bromochlorobenzene was
employed, a selective O-arylation took place preferentially
at the aryl-Br bond in good yield (entry 5). When 4-methyl-
chlorobenzene was examined, a poor product yield of 3b
was obtained under the identical conditions (entry 6). Not
only 4-bromobiphenyl but also 2-naphtyl bromide were
readily reacted with 4-methoxyphenol to afford polyaryl
and fused aromatic ether compounds (entries 7 and 8,
respectively).
On the other hand, it was observed that electronic
variation on the phenol counterpart was more sensitive
to the reaction efficiency. For instance, whereas the reac-
tionofphenols bearingelectron-richsubstituentssmoothly
produced an ether linkage, electron-deficient phenols un-
derwent the arylation with lower efficiency (compare en-
tries 9 and 10). Notably, O-arylation of heteroaryl bromides
proceeded without difficulty. For example, 2-bromothia-
zole and 2-bromopyridine were readily reacted with phenols
to furnish the desired ethers in synthetically acceptable
yields (entries 12 and 13, respectively). Since the reaction
conditions require a strong base (t-BuONa) in more than
stoichiometric amounts, several functional groups were
found to be incompatible. For instance, poor reactivity
was observed in the reaction of 4-bromobenzonitrile with
p-methoxyphenol with the recovery of the unchanged phe-
nol being more than 90% (entry 14).
Scheme 1. Optimization of New Standard Reaction Conditions
a Conditions: 1 (0.2 mmol), 2 (0.3 mmol), Rh2(OAc)4 (3 mol %), Cy2-
bimy HPF6 (10 mol %), AgPF6 (10 mol %), t-BuONa (2 equiv to 1), and
3
toluene (0.2 mL) at 100 °C for 24 h. b Isolated yield. c 1H NMR yield.
In order to overcome the poor functional group toler-
ance observed under the above conditions, we tried to
replace t-BuONa with milder bases (Scheme 1). After
extensive screenings, we found that the use of Cs2CO3 in
with less amounts of a Rh2(OAc)4 precursor (3 mol %,
entry 13). Likewise, the use of an in situ generated mono-
meric cationic Rh-NHC species, Rh(cod)(iPr2-bimy)/PF6,
significantly improved the reaction efficiency when com-
pared to the corresponding neutral catalyst (entries 12 and
(14) Fructos, M. R.; de Fremont, P.; Nolan, S. P.; Diaz-Requejo,
M. M.; Perez, P. J. Organometallics 2006, 25, 2237.
2370
Org. Lett., Vol. 13, No. 9, 2011

a cosolvent of toluene and triethylamine (1:1)15 afforded a
comparable result when compared to that using t-BuONa
(compare the new standard conditions of Scheme 1 and
entry 1 of Table 2).15 Interestingly, a pregenerated Rh-
NHC species, Rh(cod)(iPr2-bimy)Br, was more effective
for the reaction than the in situ generation procedure
adding a Rh precursor and NHC ligand separately. This
result may be ascribed to a postulate that the formation of
a Rh-NHC complex is less efficient under the new condi-
tions using a milder base.
benzyl alcohol was readily arylated to give the desired
benzyl phenyl ether (3p) in an acceptable yield (entry 4).
However, simple aliphatic alcohols did not undergo ether-
ification under the present conditions. When 1,4-dibromo-
benzene was reacted with a phenol, a double O-arylation
took place leading to a symmetric diaryl ether (3r) in
moderate yield (entry 6).
In line with our recent report,9c it was demonstrated
that a suitable choice of NHC ligands can lead to chemo-
selective O- or N-arylation under otherwise similar Rh-
catalyzed conditions (Scheme 2). A facile O-arylation of
4-bromochlorobenzene with 4-methoxyphenol was achieved
by the action of a Rh-(iPr2-bimy) catalyst to give an aryl
ether (3e) in good yield. Subsequent N-aryltion at the
arylꢀCl bond of 3e proceeded smoothly using a Rh-(IiPr)
system, which was previously shown to be effective for the
N-arylation reaction reported by us.9c
Table 3. O-Arylation Using Cs2CO3 as a Mild Basea,b
Scheme 2. Tandem CꢀO and CꢀN Bond Formations
In conclusion, we have presented the first example of a
Rh(NHC)-catalyzed O-arylation reaction. A suitable
choice of both rhodium species and NHC ligands was
crucialfor achieving high catalytic activity. A wide range in
substrate scope and high functional group tolerance were
observed using the developed O-arylation procedure.
a Conditions: 1 (0.2 mmol), 2 (0.3 mmol), Rh(cod)(iPr2-bimy)Br
(5 mol %), AgSbF6 (10 mol %), Cs2CO3 (2 equiv to 1), toluene
(0.2 mL), and Et3N (0.2 mL) at 100 °C for 24 h. b Isolated yield. c See
the Supporting Information for details.
Under the newly developed conditions, the substrate
scope was next examined especially with regard to func-
tional group tolerance (Table 3). To our delight, it was
observed that a wide range of labile organic groups were
compatible under the new reaction protocol.
Indeed, sensitive functional groups such as an ester,
acetyl, or cyano moiety were completely intact (entries 1,
2, and 3, respectively), which were not tolerated under the
former conditions using t-BuONa as a base. It is noted that
Acknowledgment. This work was supported by the
National Research Foundation (Star Faculty Program,
KRF-2008-C00024) and MIRC (NRF-2010-0001957).
We acknowledge the Korea Basic Science Institute for
the mass analysis and crystal analysis. We also thank Mr.
Kyungseok Jeong for advice on crystal structure analysis.
Supporting Information Available. Experimental details,
and 1H and 13C NMR spectra of new compounds, and CIF
file of Rh(cod)(iPr2-bimy)Br. This material is available free
of charge via the Internet at http://pubs.acs.org.
(15) This set of conditions was previously employed by Buchwald et
al. in the Pd-catalyzed CꢀO coupling reaction: Vorogushin, A. V.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 8146.
Org. Lett., Vol. 13, No. 9, 2011
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