Overriding ortho-para selectivity via a traceless directing group relay strategy: The meta-selective arylation of phenols

Article abstract of DOI:10.1021/ja500457s

The direct functionalization of phenols at the ortho and para position is generally facilitated by the electron-donating nature of the hydroxyl group. Accessing meta-functionalized phenols from the parent phenols, on the other hand, generally requires lengthy synthetic sequences. Here, we report the first methodology for the one-pot direct meta-selective arylation of phenols. This methodology is based on a traceless directing group relay strategy. In this process carbon dioxide is used as a transient directing group which facilitates a palladium catalyzed arylation meta to the phenol hydroxyl group with iodoarenes. This transformation proceeds with complete meta-selectivity and is compatible with a variety of functional groups both in the phenol and in the iodoarene coupling partner.

Full text of DOI:10.1021/ja500457s

Communication
pubs.acs.org/JACS
Overriding Ortho−Para Selectivity via a Traceless Directing Group
Relay Strategy: The Meta-Selective Arylation of Phenols
Junfei Luo, Sara Preciado, and Igor Larrosa*
School of Biological and Chemical Sciences, Queen Mary University of London, Joseph Priestley Building, Mile End Road, E1 4NS,
London, U.K.
S
* Supporting Information
Scheme 1. Strategies for Regioselective C−H
Functionalization of Phenols
ABSTRACT: The direct functionalization of phenols at
the ortho and para position is generally facilitated by the
electron-donating nature of the hydroxyl group. Accessing
meta-functionalized phenols from the parent phenols, on
the other hand, generally requires lengthy synthetic
sequences. Here, we report the first methodology for the
one-pot direct meta-selective arylation of phenols. This
methodology is based on a traceless directing group relay
strategy. In this process carbon dioxide is used as a
transient directing group which facilitates a palladium
catalyzed arylation meta to the phenol hydroxyl group with
iodoarenes. This transformation proceeds with complete
meta-selectivity and is compatible with a variety of
functional groups both in the phenol and in the iodoarene
coupling partner.
henols are important structural motifs found in natural
Pproducts, pharmaceuticals, and polymers, as well as
common versatile building blocks for synthesis.1 Thus, methods
for the efficient synthesis of phenols selectively functionalized
at specific ring positions are of high interest. Due to the well-
known ortho/para directing ability of the electron-donating
hydroxyl group, a great many methodologies for the ortho- and
para-functionalization of phenols have been reported and are
commonly exploited (Scheme 1a).1,2 However, this same
strong directing effect prevents the selective direct functional-
ization of phenols at the meta position. Consequently, over the
past decade, a variety of indirect methodologies have been
developed based on the oxidation of substituted cyclo-
hexanones,3 cycloaddition reactions,4 or the late installation
of the OH functionality.5 Given the wide availability of cheap
phenol starting materials, the development of a methodology
capable of using those building blocks to directly produce meta-
functionalized phenols would be highly desirable. Ideally, such
methodology would proceed in one step and be operationally
simple and scalable. To date, only a handful of methodologies
able to perform a direct meta-functionalization of substituted
benzenes have been reported but none allow for the direct
meta-selective functionalization of phenols.6,7 A recent ground-
breaking report by Yu and co-workers described a strategy for
the meta-olefination8 and arylation9 of phenols that involves
the installation at the hydroxyl of an innovatively designed
moiety containing a strategically positioned nitrile group able to
coordinate a Pd catalyst and therefore direct the functionaliza-
tion at the meta-position (Scheme 1b). However, this approach
requires five independent synthetic operations/purifications.
Herein we report the first strategy allowing the direct selective
meta-arylation of phenols.10 Our methodology uses CO2 as a
traceless relay directing group in order to facilitate direct meta-
arylation of phenols in a single synthetic operation. This
versatile process is easily scalable and allows fast access to meta-
arylphenols, important structural motifs contained in bio-
logically active compounds, natural products, and organic
electronic materials.
We hypothesized that the meta-functionalization of phenols
may be accessible via a traceless directing group relay strategy
(Scheme 1c). We envisioned that, instead of transforming the
hydroxyl group into a meta-directing group, we could use it to
direct the ortho-installation of a secondary removable directing
group. This second group would then facilitate an ortho-
arylation (meta to the hydroxyl group) and, when cleaved,
reveal the desired meta-arylated phenol. Further, we envisaged
that by carefully selecting this traceless relay directing group,11
it should be possible to carry out this transformation in a single
synthetic operation. Based on the well-known reactivity of
phenols toward ortho-carboxylation with CO2 (i.e., Kolbe−
Schmitt reaction),12 recent work on the transition-metal-
Received: January 15, 2014
Published: March 11, 2014
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
catalyzed decarboxylation of benzoic acids,13,14 and the
suitability of carboxylic acids to act as directing groups to
mediate ortho-C−H arylations,15 we anticipated that CO2H
would be an ideal traceless directing group candidate for testing
our hypothesis (Scheme 1c).
Scheme 2. Scope of the Meta-Arylation of Phenol (1a) with
Iodoarenes
a
We started our investigation by exploring the reactivity of
salicylic acid (2a) with iodoarene 5a toward the tandem
arylation/decarboxylation process (Table 1). Examination of
Table 1. Optimization of the Tandem Arylation/
a
Decarboxylation of Salicylic Acid 2a
b
entry
Pd cat.
additive
T (°C)
yield
a
Pd(OAc)2
−
−
−
−
−
−
130
130
130
120
150
150
150
29%
26%
59%
48%
70%
83%
92%
b
c
Pd(PPh3)4
PEPPSI-IPr
PEPPSI-IPr
PEPPSI-IPr
PEPPSI-IPr
PEPPSI-IPr
d
e
c
f
c
g
K2CO3 (0.5 equiv)
a
Reactions were carried out with 2a (1.0 equiv), 5a (3.0 equiv), Pd cat.
b
(2 mol %), Ag2CO3 (1.0 equiv) in AcOH (1.0 M) for 16 h. Yields
were calculated by H NMR analysis using an internal standard. 0.5
c
1
a
b
Yields are of pure isolated product. para-Iodobenzyl alcohol was
equiv of Ag2CO3 was used.
used as starting material.
reaction conditions previously developed for a different class of
benzoic acids led to formation of the desired meta-arylated
product 4aa in 29% yield (Table 1, entry a).11k The source of
the Pd catalyst (Table 1, entries a−c) proved crucial, with
PEPPSI-IPr16 leading to the best yields. The temperature of the
reaction and the addition of K2CO3 as an additive were also
found to improve the performance of the system, leading to the
formation of 4aa in 92% yield (Table 1, entries d−g).
(for example, p-OMe 4ab and p-NO2 4ai were obtained in 63%
and 54% isolated yield, respectively). The reaction conditions
are compatible with Cl and Br, which are convenient handles
for further functionalization (4ad, 4ae, and 4an). Interestingly,
aldehyde functionality (4ag), despite its sensitivity to oxidation,
is also compatible with the reaction without requiring the use of
protecting groups. On the other hand, when para-iodobenzyl
alcohol was used as the coupling partner, an in situ acetylation
occurred leading to the acetyl ester 4ah. Ortho-substituents at
the iodoarene are not tolerated, suggesting a sterically crowded
intermediate is being formed during the coupling. Finally,
heteroarenes such as iodoindole and iodopyridine can be used
as coupling partners leading to the corresponding meta-
heteroarylphenol products 4am and 4an.
We then explored the applicability of this novel strategy for
phenol meta-arylation to ortho and meta substituted phenol
starting materials 1b−o (Scheme 3). Gratifyingly, a wide variety
of substituted phenols smoothly underwent meta-arylation
without any modification to the standard conditions developed.
On the other hand, a number of substituted phenols were
found to afford higher yields if 4 mol % of the Pd catalyst were
added in two batches (2 mol % each) during the reaction,
indicating that for some substrates catalyst decomposition can
be a problem. In this case there was no advantage using
PEPPSI-IPr over the cheaper Pd(OAc)2. Moderately electron-
donating substituents at C3 led to good yields of meta-arylation
(4ba, 4ca, and 4da). On the other hand, the more electron-
donating MeO group afforded a low yield of the desired
product 4ea, due to fast protodecarboxylation of the salicylic
acid intermediate. This side reaction could be prevented by
using a CF3O group instead which allowed the arylation to
proceed in good yield (4fa). Electron-withdrawing groups at
Having developed suitable conditions for the arylation/
decarboxylation tandem process we studied the development of
a compatible carboxylation reaction, in order to access the
desired one-pot meta-arylation process. Whereas the Kolbe−
Schmitt carboxylation would traditionally require the synthesis
and isolation of the sodium or potassium phenoxide from
phenol prior to reaction with CO2, we investigated the in situ
deprotonation and carboxylation of phenol (1a) in order to
develop a truly operationally simple process. After extensive
optimization we found that treating 1a with KOH under 25 atm
of CO2 at 190 °C for 2 h, followed by addition of the iodoarene
5a, the Pd catalyst, Ag2CO3, and AcOH, and further reaction at
130 °C for 16 h allowed the selective direct meta-arylation of
1a to 4aa in 65% isolated yield after column chromatography
(Scheme 2, 4aa). This represents an average of 87% for each of
the three steps in the carboxylation/arylation/decarboxylation
overall sequence. The process is completely selective for the
meta position, with no arylation in ortho or para being
detected.17 Further, unlike most direct arylations of mono-
substituted arenes, the reaction is completely selective for
mono- versus bis-arylation.10
Gratifyingly, our traceless directing group relay meta-
arylation of phenol 1a is very general (Scheme 2), with both
electron-donating and -withdrawing groups being well tolerated
in para and meta positions of the iodoarene coupling partner
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Journal of the American Chemical Society
Communication
materials, it allows streamlined access to molecules that would
otherwise require many more steps for their synthesis. For
example, the synthesis of γ-secretase inhibitor 6 (Scheme 4),
Scheme 3. Scope of the Meta-Arylation of Phenols (1b−p)
a
with Iodoarene 5a
Scheme 4. Fast and Efficient Synthesis of γ-Secretase
Inhibitor 6
under study for treatment of Alzheimer’s disease, was
accomplished in only three steps from 3-bromophenol (1h),
with the key meta-arylation step forming 4ho in 64% isolated
yield. A subsequent O-arylation19 and α-alkylation20 afforded 6,
with 41% overall yield after only three steps. The previous
synthesis of 6 required eight separate reaction steps and
purifications starting from 1,3-dibromo-5-fluorobenzene (8),
with 6% overall yield.21
In order to better understand the present transformation we
stopped and analyzed the reaction of 1a after the carboxylation
step (Scheme 5). Contrary to our initial hypothesis,
Scheme 5. Mechanistic Investigation
a
b
Yields are of pure isolated product. 4 mol % Pd(OAc)2, added in
two batches, was used instead of PEPPSI-IPr, and the reaction was
c
1
stirred for 40 h. Yield determined by H NMR analysis using an
internal standard.
C3, including Cl and Br, were also compatible with the reaction
(4ga and 4ha), but the strongly electron-withdrawing NO2
group led to no reaction, by preventing the initial carboxylation
step. A variety of substituents at C2 were also tolerated,
affording the corresponding meta-arylated phenols in good
yields (4ja−oa). As was the case with phenol (1a), in all cases
the arylation reaction was completely selective for the meta
position, with no other arylation products being observed.18 On
the other hand, substitution at C4 of the phenol was found
incompatible with the arylation step: para-fluorophenol
afforded arylation product 4pa in only 11% yield, whereas
para-methylphenol led to no coupling (both underwent
carboxylation in 50% and 61% yield, respectively). Similarly
to the lack of tolerance for ortho-substituted iodoarenes, this
result confirms that steric hindrance next to the reacting C−H
bond is deleterious, suggesting a highly sterically encumbered
intermediate is being formed in the reaction.
This methodology is easily scalable. Applying our standard
conditions, without any modification to the meta-arylation of
1b with 5a in a 5.0 mmol (1.2 g) scale of the iodoarene,
afforded the corresponding biaryl 4ba in 70% isolated yield
(0.73 g, 3.5 mmol).
Because this methodology provides easy access to meta-
arylphenols from cheap and readily available phenol starting
carboxylation of 1a was found to proceed at both the ortho
and para position leading to a 48:23 mixture of acids 2a and
2a′. We then tested 2a and 2a′, separately, in the tandem
arylation/decarboxylation process. Interestingly, both hydrox-
ybenzoic acids afforded the meta-arylation product 4aa,
indicating the CO2H group is able to direct the arylation
meta to OH, and the resulting biaryl protodecarboxylates
regardless of the regiochemistry of the initial carboxylation.
This regioconvergence results in a more robust process,
consistent with the complete meta-regioselectivity of arylation
observed in all reactions. The ortho-arylation step is consistent
with a Pd(II/IV) process as initially proposed by Daugulis,
where the role of the Ag(I) salt would be as an iodide
scavenger.15a Finally, the decarboxylation step of the electron-
rich hindered intermediates 3 is likely mediated by Pd(II) as
previously demonstrated for 2,6-disubstituted benzoic acids.11k
In conclusion, we report the first example of a one-pot direct
meta-functionalization of phenols. This process is based on a
strategy that involves the use of CO2 as a traceless directing
group. Upon carboxylation, the hydroxyl group relays the
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Journal of the American Chemical Society
Communication
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that affords meta-arylphenol products and leaves no trace of the
participation of CO2 in the overall process. This transformation
is completely regioselective, and compatible with a variety of
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traceless directing group strategy will be applicable to the
development of other useful one-pot meta-functionalization
processes.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
́ ́
131, 7502. (c) García-Rubia, A.; Urones, B.; Gomez Arrayas, R.;
Carretero, J. C. Chem.Eur. J. 2010, 16, 9676. (d) Robbins, D. W.;
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dez-Ibanez, M. A.; Gomez Arrayas, R.;
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(e) García-Rubia, A.; Fernan
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AUTHOR INFORMATION
Corresponding Author
i.larrosa@qmul.ac.uk
■
́
́ ́ ́ ́
Fernandez-Ibanez, M. A.; Gomez Arrayas, R.; Carretero, J. C. Angew.
̃
Chem., Int. Ed. 2011, 50, 10927. (g) Huang, C.; Chattopadhyay, B.;
Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 12406. (h) Richter, H.;
Notes
Beckendorf, S.; Mancheno, O. G. Adv. Synth. Catal. 2011, 353, 295.
̃
The authors declare no competing financial interest.
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Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem.
Soc. 2011, 133, 7222. (k) Cornella, J.; Righi, M.; Larrosa, I. Angew.
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the European Research Council for
a Starting Grant (to I.L.), the China Scholarship Council and
Queen Mary University of London for a studentship (to J.L.),
the Marie Curie Foundation for an Intra-European Fellowship
(to S.P.), and the EPSRC National Mass Spectrometry Service
(Swansea).
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