The catalytic intermolecular orthoarylation of phenols

Article abstract of DOI:10.1002/anie.200390037

The use of Wilkinson's catalyst with diisopropylphosphinite ligands acting as cocatalysts allows the catalytic orthoarylation of phenols [Eq. (1)], a process that relies on a C-H activation of a phenol that has been incorporated into the cocatalyst by transesterification.

Full text of DOI:10.1002/anie.200390037

Communications
Direct Aryl Halide Phenol Coupling
interested to see whether catalytic transesterification of
phenols and their subsequent CꢀH activation by orthometa-
The Catalytic Intermolecular Orthoarylation of
Phenols**
lation could be used to realize the intermolecular orthoar-
ylation of these substrates (Scheme 1), a process that, to the
best of our knowledge, has not been previously reported. Such
a process could allow the synthesis of a wide range of
Robin B. Bedford,* Simon J. Coles,
Michael B. Hursthouse, and Michael E. Limmert
[
8]
selectively 2-arylated phenols.
The substrates used in optimization studies were 4-
bromoacetophenone and the bulky phenol 2,4-di-tert-butyl-
phenol, since phosphorus donors that incorporate this aryl
oxide residue have been found to undergo particularly facile
The biaryl subunit is an important structural motif that is
found in a wide range of compounds such as natural products,
polymers, liquid crystals, and ligands for homogeneous
transition-metal catalysts.[1] One class of reaction that pro-
vides particular challenges for the catalytic chemist is the
synthesis of orthoarylated phenols. Currently the most
commonly used catalytic routes to these compounds employ
Suzuki or Stille coupling reactions.[ These require the
introduction and subsequent loss of stoichiometric amounts
of either boronic acid/ester or organotin functions. Therefore
the ability to couple an aryl halide directly with a phenol
[
9]
orthometalation reactions. Initial experiments focused on
the use of either 1) palladium catalysts formed in situ from
dipalladium tris(dibenzylideneacetone) with the ligands
tris(2,4-di-tert-butylphenyl)phosphite (1), (2,4-di-tert-butyl-
phenyl) diphenyl phosphinite (2), or (2,4-di-tert-butylphenyl)
diisopropyl phosphinite (3a) acting as cocatalysts, or
2) preformed palladacyclic catalysts containing these li-
2]
[
9b,c]
gands.
In all cases we observed either no reaction or the
oxidative coupling of the phenol to give 2,2’,4,4’-tetra-tert-
butylbiphenol (4).
(
Scheme 1) without the need for a sacrificial electrophilic
boron or tin fragment would be highly desirable from both
synthetic and atom-economic points of view.
By contrast when Wilkinson©s catalyst is employed with an
appropriate cocatalyst, then the reaction proceeds as shown in
Scheme 1 to give the orthoarylated phenol, 2,4-di-tert-butyl-6-
4
’-acetylphenyl phenol (5a). The molecular structure of this
[
10]
new phenol was determined and is shown in Figure 1. The
choice of cocatalyst is important; the reaction works with the
bulky triarylphosphite ligand 1, but a large excess (3.5 equiv-
alents) of aryl bromide is required otherwise the major
product formed is again the homocoupled biphenol 4. The
triarylphosphinite ligand 2 also functions as a cocatalyst and
does not require such a large excess of aryl bromide, but when
it is replaced by the aryl dialkylphosphinite 3a then the
reaction is far more efficient and higher yields of the product
are obtained. In principle any OAr functional group can be
incorporated into the phosphinite cocatalyst, but for ease of
product identification and purification we usually employed
phosphinites that contain the substrate phenol. The data from
the catalytic studies with Wilkinson©s catalyst and the aryl
dialkylphosphinite ligands acting as cocatalysts are summar-
ized in Table 1.
Scheme 1. The catalytic orthoarylation of phenols.
The transition-metal-catalyzed ortho-selective arylation
of phenols has been limited to a few examples of intra-
molecular couplings of aryl halides that are tethered to the
phenolic substrates,[ and the reactions of aryl halides with 1-
naphthol or 2-aryl-substituted phenols.[ In all cases the
reactions proceed via the formation of stable five- or six-
membered metallacycles. Simple phenols avoid orthometala-
tion reactions with late transition metals as this would give
3]
4]
[
5]
unfavorably strained, four-membered metallacycles. How-
ever when aryloxide groups are incorporated into phosphorus
donors such as phosphites, P(OAr)3, or phosphinites,
PR (OAr), then facile orthometalation can occur to give
As can be seen from Table 1, entries 1±6, good to excellent
conversions to the 2-arylated phenols are obtained regardless
of whether the aryl bromide used is activated, nonactivated,
or deactivated with respect to oxidative addition. The
2
low-strain, five-membered metallacyles. Lewis exploited this
phenomenon when he demonstrated that ruthenium triaryl-
phophite complexes catalyze the ortho-specific deuteration
and ethylation of phenol.[ These catalytic processes rely on
the reversible in situ transesterification of catalytic amounts
of triaylphosphite ligands with the substrate phenols. We were
6,7]
[*] Dr. R. B. Bedford, Dr. M. E. Limmert
School of Chemistry
University of Exeter
Exeter, EX4 4Q D (UK)
Fax: (þ44)1392-263-434
E-mail: r.bedford@ex.ac.uk
Dr. S. J. Coles, Prof. M. B. Hursthouse
EPSRC National Crystallography Service
University of Southampton (UK)
[**] We gratefully acknowledge the EPSRC for funding.
Figure 1. Molecular structure of compound 5a.
1
12
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Chemie
Table 1: Catalytic orthoarylation of phenols.[a]
Entry
Phenol
Aryl
halide
Phosphinite
cocatalyst
Product (yield [%])[b]
1
1
1
2
(R ¼tBu)
5a: R ¼tBu (96)
1
1
(R ¼H)
5b: R ¼H (96)
1
1
3
4
(R ¼tBu)
5c: R ¼tBu (86)
1
1
(R ¼H)
5d: R ¼H (79)
1
5
6
(R ¼tBu)
1
(R ¼H)
1
1
5
5
e: R ¼tBu (81)
6e: R ¼tBu (6)
1
1
1
f: R ¼H (84)
6 f: R ¼H (8)
7e: R ¼tBu (5)
7
5 f (100)
8
9
1
1
1
5g (25)[c]
5h (15)
5i (68)
0
1
2
5j (53)
5k (21)[c]
1
3
5
m (71)
8 (23)
[
(
a] Reaction conditions: Phenol (1.0 mmol), aryl halide (1.5 mmol), Cs CO (1.7 mmol), [RhCl(PPh ) ] (0.05 mmol), PR (OAr) (0.15 mmol), toluene
10 mL), reflux, N , 18 h. [b] Yield of isolated product. [c] Estimated by H NMR spectroscopy.
2
2 3 3 3 2
1
reaction also proceeds smoothly when the sterically hindered
aryl bromide 2-bromo-para-xylene is employed (Table 1,
entry 7). Even aryl chlorides can be used as substrates
introduced 2-aryl group occurs. Such multiple arylation
reactions have been observed before.
[
4]
It is not necessary to have a bulky tert-butyl group in the 2-
positon of the phenol for the reaction to proceed; the
incorporation of progressively smaller groups such as isopro-
pyl and ethyl still gives good yields of the products (Table 1,
entries 10 and 11). Activity was even seen with 2-methylphe-
nol (Table 1, entry 12), however in this case the yield was
somewhat lower. No activity is observed with unsubstituted
phenol. The reduction in catalytic activity with decreasing
steric bulk implies that the rate-determining step is probably
the orthometalation of the phosphinite ligand. To accelerate
this process and thus facilitate the use of phenol as a substrate
(
Table 1, entries 8 and 9), although much lower yields of
coupled products result. In all cases where the phenol
substrate is unsubstituted at the 4-position only orthoaryla-
tion occurs; a simple electrophilic reaction of these substrates
should also lead to the formation of paraarylated products.
This demonstrates that the reaction is indeed ortho-selective,
which in turn implies that the CꢀH activation of the phenol
occurs after it has been incorporated into the phosphinite
cocatalyst. In certain cases the reaction does not stop at the
simple 2-arylated products and arylation of the previously
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113

Communications
(0.550 g, 1.70 mmol) in toluene (10 mL) were heated at reflux under
N2 for 18 h, cooled and quenched with HCl (aq) (2m, 5 mL). The
mixture was extracted with CH Cl (3 î 25 mL), dried (MgSO ),
2
2
4
filtered, and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography (silica, CHCl /hexane
3
1
:1) to give 5a as a colorless solid (0.313 g, 96%).
Received: September 2, 2002 [Z50087]
[
1] a) S. P. Stanforth, Tetrahedron 1998, 54, 263 ± 303; b) G. Bring-
mann, R. Walter, R. Weirich, Angew. Chem. 1990, 102, 1006;
Angew. Chem. Int. Ed. Engl. 1990, 29, 977 ± 991.
[
2] For recent examples see: a) M. A. Zhuravel, S. T. Nguyen,
Tetrahedron Lett. 2001, 42, 7925 ± 7928; b) R. Kranich, K. Eis, O.
Geis, S. M¸hle, J. W. Bats, H.-G. Schmalz, Chem. Eur. J. 2000, 6,
2874 ± 2894; c) K. B. Simonsen, K. V. Gothelf, K. A. J˘rgensen,
J. Org. Chem. 1998, 63, 7536 ± 7538; d) D. E. Zembower, H.
Zhang, J. Org. Chem. 1998, 63, 9300 ± 9305; e) S. Yonezawa, T.
Komurasaki, K. Kawada, T. Tsuri, M. Fuji, A. Kugimiya, N.
Haga, S. Mitsumori, M. Inagaki, T. Nakatani, Y. Tamura, S.
Takechi, T. Taishi, M. Ohtani, J. Org. Chem. 1998, 63, 5831 ± 5837.
3] a) D. D. Hennings, S. Iwasa, V. H. Rawal, J. Org. Chem. 1997, 62,
2 ± 3; b) D. D. Hennings, S. Iwasa, V. H. Rawal, Tetrahedron Lett.
1997, 38, 6379 ± 6382.
Scheme 2. Plausible reaction mechanism.
we investigated the application of the bulkier phosphinite
[
cocatalyst PtBu (OPh) (3b), formed by reaction of PtBu Cl
2
2
with sodium phenoxide. In this case a number of products
resulted that proved very difficult to separate. However it was
[4] a) T. Satoh, Y. Kawamura, M. Miura, M. Nomura, Angew. Chem.
1997, 109, 1820 ± 1822; Angew. Chem. Int. Ed. Engl. 1997, 36,
1
possible to determine by H NMR spectroscopy that roughly
1
740 ± 1742; b) T. Satoh, J. Inoh, Y. Kawamura, Y. Kawamura,
M. Miura, M. Nomura, Bull. Chem. Soc. Jpn. 1998, 71, 2239 ±
246.
one third of the 4-bromoanisole used was incorporated into
coupled products.
2
It is not necessary to have an alkyl group in the 2-position
to facilitate the coupling reaction; 1-naphthol can also be used
as a substrate (Table 1, entry 13). In this case a small amount
of a second, 2,8-diarylated product (8), is observed. Presum-
ably the 8-arylation occurs after the 2-arylation as there is no
evidence for the formation of 8-arylated naphthol. It is
possible that the 8-arylation does not proceed through the
orthometalation of a phosphinite intermediate since 1-naph-
thol itself has been shown to undergo 8-arylation in the
presence of a palladium catalyst.[
[
5] Miura and co-workers have demonstrated the 1-arylation of 2-
naphthols. This pattern of reactivity presumably results from the
high susceptibility of the 1-position to electrophilic attack rather
than the formation of a highly strained four-membered pallada-
cycle. See references [4].
[
[
[
6] L. N. Lewis, Inorg. Chem. 1985, 24, 4433 ± 4435.
7] L. N. Lewis, J. F. Smith, J. Am. Chem. Soc. 1986, 108, 2728 ± 2735.
8] Very recently Yamaguchi and co-workers reported the gallium-
catalyzed orthoalkynylation of phenols with haloalkynes: K.
Kobayashi, M. Arisawa, M. Yamaguchi, J. Am. Chem. Soc. 2002,
124, 8528 ± 8529.
4]
[
9] a) R. B. Bedford, S. Castillon, P. A. Chaloner, C. Claver, E.
Fernandez, P. B. Hitchcock, A. Ruiz, Organometallics 1996, 15,
A plausible mechanism for the new reaction is given in
Scheme 2, in which the phosphinite cocatalyst coordinates to
and orthometalates at a rhodium(iii) center formed previously
by oxidative addition of the aryl halide. However, it is
possible that the orthometalation step precedes the oxidative
3990 ± 3997; b) D. A. Albisson, R. B. Bedford, S. E. Lawrence,
P. N. Scully, Chem. Commun. 1998, 2095 ± 2096; c) R. B. Bed-
ford, S. L. Welch, Chem. Commun. 2001, 129 ± 130; d) R. B.
Bedford, S. L. Hazelwood, Organometallics 2002, 21, 2599 ±
2600.
I
addition and occurs at a Rh center. Either way, subsequent
reductive elimination of the orthometalated ligand and the
aryl group leads to the reformation of the active catalyst and
the liberation of a new 2-arylated aryl dialkylphosphinite
ligand. This ligand then undergoes catalytic transesterifica-
tion with the starting phenol to regenerate the cocatalyst and
liberate the 2-arylated phenol product.
[10] CCDC-192419 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (þ 44)1223-336-033; or deposit
@
ccdc.cam.ac.uk).
In summary, we have demonstrated for the first time the
catalytic intermolecular ortho-selective arylation of phenols.
We are currently examining the scope of this reaction with a
range of phenols and related substrates and a variety of
coupling partners.
Experimental Section
Typical catalytic procedure: Synthesis of 5a: [RhCl(PPh ) ] (0.046 g,
3
3
0
.05 mmol), 3a (0.048 g, 0.15 mmol), 4-bromoacetophenone (0.300 g,
1
.50 mmol), 2,4-di-tert-butylphenol (0.206 g, 1.00 mmol), and Cs CO
2
3
1
14
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