Unexpected phenol production from arylboronic acids under palladium-free conditions; Organocatalyzed air oxidation

Article abstract of DOI:10.1021/ol202500z

An intriguing class of quinones that efficiently catalyze the air oxidation (overall hydroxylation) of arylboronic acids to the corresponding phenol is reported. Autocatalysis in the parent system is particularly efficient and leads to rapid, quantitative synthesis of quinones such as 4 from boronic acid 1 at room temperature using air as stoichiometric oxidant. The efficiency results from a balance between two-stage conjugate addition and migration with each step driven by aromatization of a naphthalene fragment.

Full text of DOI:10.1021/ol202500z

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6034–6037
Unexpected Phenol Production from
Arylboronic Acids under Palladium-Free
Conditions; Organocatalyzed Air
Oxidation
Andrew N. Cammidge,* Victoria H. M. Goddard, Christopher P. J. Schubert,
Hemant Gopee, David L. Hughes, and Daniel Gonzalez-Lucas
School of Chemistry, University of East Anglia, Norwich NR4 7TJ, U.K.
a.cammidge@uea.ac.uk
Received September 15, 2011
ABSTRACT
An intriguing class of quinones that efficiently catalyze the air oxidation (overall hydroxylation) of arylboronic acids to the corresponding phenol
is reported. Autocatalysis in the parent system is particularly efficient and leads to rapid, quantitative synthesis of quinones such as 4 from
boronic acid 1 at room temperature using air as stoichiometric oxidant. The efficiency results from a balance between two-stage conjugate
addition and migration with each step driven by aromatization of a naphthalene fragment.
SuzukiÀMiyaura cross-couplings employing boronic
acids as the organometallic component are widely en-
countered.1 Indeed it is reasonable to state that the re-
action is among the most important to be developed
over recent decades. The scope of the reaction is now
broad. Part of the reason for the wide use of the reaction
derives from the use of boronic acids. They are typically
relatively easy to synthesize and have long-term shelf
stability. Reactions generally do not require dry or inert
conditions. To promote transmetalation and rapid cataly-
tic turnover, boronic acids (or their boronate esters) need
tobe activated by reaction withan appropriate nucleophile
to form the boronate complex. Preisolation of these species
is often convenient.2 The conversion of carbonÀboron
bonds into carbonÀoxygen bonds via intramolecular mi-
gration are similarly very important reactions. They are
exemplified by the anti-Markovnikov synthesis of alcohols
from alkenes but extend to many other multistep processes
that first involve other CÀB to CÀC migrations.3 The final
CÀB to CÀO conversion is invariably achieved using
hydrogen peroxide that, under basic conditions, generates
HOOÀ that adds to boron to form the boronate salt. CÀB
to CÀO migration then proceeds with displacement of
hydroxide as leaving group.
As part of a separate program we sought to couple
simple bromobenzenes with alkoxynaphthylboronic acids 1
and 5. The coupling reaction was expected to be relatively
(1) Reviews on the SuzukiÀMiyaura reaction include (a) Miyaura,
N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633. (c) Bellina, F.; Carpita, A.;
Rossi, R. Synthesis 2004, 2419.
(2) Cammidge, A. N.; Goddard, V. H. M.; Gopee, H.; Harrison,
N. L.; Hughes, D. L.; Schubert, C. J.; Sutton, B. M.; Watts, G. L.;
Whitehead, A. J. Org. Lett. 2006, 8, 4071.
(3) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic
Press: London, 1988.
r
10.1021/ol202500z
Published on Web 10/26/2011
2011 American Chemical Society

The key step therefore appears to be the production of
phenol from boronic acid, and the most surprising observa-
tion occurred during model reaction studies. In one model,
designed as a control experiment, the palladium catalyst was
omitted from the reaction. Remarkably, an identical outcome
was observed, and the reaction produced 4in essentially quan-
titative yield in about 1 h at room temperature (Scheme 2).
Scheme 1. Exclusive Formation of Quinones 4 and 6 during
SuzukiÀMiyaura Couplings Employing Alkoxynaphthylboro-
nic Acids 1 and 5 via their Corresponding Naphthols and the
Crystal Structure of 69
Scheme 2. Palladium-Free Conversion of Alkoxynaphthyl-
boronic Acid 1 to Quinone 4
Oxidative hydroxylation of certain alkylboronates is
known to occur via a radical mechanism,10 but this observa-
tion is unexpected for the arylboronic acids under this study
and therefore a separate, unique mechanism must operate.
The generality of the palladium-free phenol production was
therefore investigated further. Simple, electron-rich, and ste-
rically encumbered arylboronic acids were subjected to the
aerobic, basic reaction conditions, but in all cases the reac-
tions failed to yield any more than a trace of the correspond-
ing phenols (Scheme 3). The oxidation reaction therefore ap-
peared to be unique to specific alkoxynaphthylboronic acids.
A careful control experiment was performed whereby oxygen
was rigorously excluded from a reaction carried out in an
NMR tube. In the absence of oxygen the reaction of 1 un-
ambiguously rests at the trihydroxyboronate salt2 state, 9.
Production of the quinone 4(via the naphthol) occurs rapidly
when air is allowed into the reaction (Scheme 3).
straightforward, although it was recognized that the
boronic acid component had significant steric demand.
In fact, SuzukiÀMiyaura coupling under standard con-
ditions4 (Pd, toluene/ethanol/water) gave none of the desired
product. Rather, the highly colored quinones 4 (dark pink)
and 6 (blue) were isolated in high yields (Scheme 1). At first
sight production of 4 and 6 can be easily rationalized. It is
known that metals such as palladium can catalyze the oxida-
tion of boronic acids to alcohols using molecular oxygen,
and phenolic side products are often observed in such
reactions.5 Efficient catalysis of the process by copper has
also been recently reported.6 Oxidative coupling was easy to
verify through independent synthesis of alkoxynaphthol 8.
Subjecting 8 to the reaction conditions (base, air) rapidly
yielded quinone 6, and no other reagents were needed. Such
oxidative couplings often employ metal salts as reagents or
catalysts,7 although aerobic oxidation is also reported.8
Scheme 3. Model Reactions Showing Only Trace Phenol For-
mation from Typical Arylboronic Acids and Demonstration
That Oxygen Drives Naphthol and Quinone Formation for 1
(4) (a) Bahl, A.; Grahn, W.; Stadler, S.; Feiner, F.; Bourhill, G.;
Brauchle, C.; Reisner, A.; Jones, P. G. Angew. Chem., Int. Ed. Engl.
1995, 34, 1485. (b) Andersen, N. G.; Maddaford, S. P.; Keay, B. A.
J. Org. Chem. 1996, 61, 9556.
Org. Lett., Vol. 13, No. 22, 2011
6035

Scheme 4. Mechanism for the Autocatalytic Production of
Quinone 4
Scheme 5. Use of 4 as a General and Versatile Organocatalyst
for Oxidative Hydroxylation of Arylboronic Acids by Aira
Two further observations then led to the final unmask-
ing of the process taking place in these transformations.
(5) (a) Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H.
J. Am. Chem. Soc. 2006, 128, 6829. (b) Chaicharoenwimolkul, L.;
Munmai, A.; Chairam, S.; Tewasekson., U.; Sapudom, S.; Lakliang,
Y.; Somosook, E. Tetrahedron Lett. 2008, 49, 7299. (c) Sakurai, H.;
Tsunoyama, H.; Tsukuda, T. J. Organomet. Chem. 2007, 692, 368. (d)
Yoo, K. S.; Yoon, C. H.; Jung, K. W. J. Am. Chem. Soc. 2006, 128,
16384. (e) Tsunoyama, H.; Sakurai, H.; Ichikuni, N.; Negishi, Y.;
Tsukuda, T. Langmuir 2004, 20, 11293. (f) Jung, Y. C.; Mishra, R. K.;
Yoon, C. H.; Jung, K. W. Org. Lett. 2003, 5, 2231. (g) Lam, P. Y. S.;
Bonne, D.; Vincent, G.; Clark, C. G.; Combs, A. P. Tetrahedron Lett.
2003, 44, 1691. (h) Crawford, C. L.; Barnes, M. J.; Peterson, R. A.;
Wilmarth, W. R.; Hyder, M. L. J. Organomet. Chem. 1999, 581, 194. (i)
Smith, K. A.; Campi, E. M.; Jackson, W. R.; Marcuccio, S.; Naeslund,
C. G. M.; Deacon, G. B. Synlett 1997, 131.
a Inset: conversion of mesitylboronic acid to mesityl alcohol mon-
itored by 1H NMR spectroscopy (Ar-H, left, and Me, right); time = 0
(top), time = 7 days (bottom).
Closer monitoring of the reaction revealed that there is an
induction period (ca. 5À20 min) after which time the
reaction proceeds rapidly tocompletion. Further screening
of conditions revealed that at least 2 equiv of strong base
(barium hydroxide, sodium hydroxide, etc.) was required
for reaction. These observations allowed the mechanism of
the overall reaction to be unraveled, and it was found to
proceed via an autocatalytic pathway, accounting for both
the observed kinetics (induction period) and the substrate
specificity. Scheme 4 describes the mechanism operating.
Trace peroxide produces a low concentration of naphthol
in the mixture. Oxidative phenolic coupling (slow due to
high dilution) gives quinone 4 after further air oxidation.
In the presence of strong base, trihydroxyboronate salt 9
undergoes further deprotonation, and the resulting nu-
cleophile attacks quinone 4 in a conjugate addition driven
by aromatization of one naphthalene fragment. Migration
of the naphthalene unit from boron to oxygen is facile and
(6) Xu, J.; Wang, X.; Shao, C.; Su, D.; Cheng, G.; Hu, Y. Org. Lett.
2010, 12, 1964.
(7) (a) Kral, A.; Laatsch, H. Z. Naturforsch. B 1993, 48, 1401. (b)
Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev.
2002, 102, 1359. (c) Hon, S.-W.; Li, C.-H.; Kuo, J.-H.; Barhate, N. B.;
Liu, Y.-H.; Wang, Y.; Chen, C.-T. Org. Lett. 2001, 3, 869. (d) Nakajima,
M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S. J. Org. Chem. 1999, 64,
2264. (e) Toda, F.; Tanaka, K.; Iwata, S. J. Org. Chem. 1989, 54, 3007. (f)
Corma, A.; Garcia, H. Chem. Rev. 2002, 102, 3837. (g) Sakamoto, T.;
Yonehara, H.; Pac, C. J. Org. Chem. 1997, 62, 3194. (h) Otsuka, T.;
Okamoto, I.; Kotani, E.; Takeya, T. Tetrahedron Lett. 2004, 45,
2643.
(8) Bao, J. B.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant,
E. B.; Rob, A. C.; Whitcomb, M. C.; Yeung, S. M.; Ostrander, R. L.;
Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 3392.
(9) Crystal structure data is deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication number CCDC
838471.
(10) Cadot, C.; Dalko, P. I.; Cossy, J.; Ollivier, C.; Chuard, R.;
Renaud, P. J. Org. Chem. 2002, 67, 7193.
6036
Org. Lett., Vol. 13, No. 22, 2011

favored by aromatization of the second naphthalene frag-
ment of the catalyst. Hydrolysis of the boronate produced
and air oxidation of both products produce more quinone
4 to mediate further boronic acid oxidation.
Autocatalysis in the parent system is particularly efficient
and leads to rapid, quantitativesynthesis of quinones4 and
6. The quinones show wide potential for mediating air
oxidations resulting from a balance between two-stage
conjugate addition and migration (each driven by aroma-
tization of a naphthalene fragment) and efficient air
oxidation under basic conditions to return the quinone
from the resulting bisnaphtholate. Ease of production of
quinones such as 4 and consequent low cost, combined
with potential for straightforward immobilization on solid
supports, make them a potentially important new class of
oganocatalyst for mediating clean air oxidations.
The final verification of the catalytic activity of quinones
such as 4 was achieved by returning to the original model
reactions. For example, mesitylboronic acid produces no
more than a trace of the corresponding phenol product
when treated with concentrated KOH in THF for 7 days
at room temperature (Scheme 3). However, addition of
a catalytic quantity (ca. 5%) of 4 leads to smooth air
oxidation. This and the other reactions were most con-
veniently monitored by NMR spectroscopy (using deuter-
ated THF and KOH in D2O) and gave complete
conversion of the arylboronic acid to the corresponding
phenol in 3À7 days. The reactions stalled after consump-
tion of all available air in the tube and restarted whenit was
opened periodically. The catalyst remained at the end of
the reaction, suggesting robustness and reusability.
Acknowledgment. We thank the EPSRC, The Lever-
hulme Trust, and INTERREG IVA for funding and
EPSRC for access to the Mass Spectrometry (Swansea)
service.
Supporting Information Available. Experimental meth-
ods for 4 and 6 and details of the X-ray structure of 6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary we have discovered a class of organic
quinones that catalyze the air oxidation (overall hydro-
xylation) of arylboronic acids to the corresponding phenols.
Org. Lett., Vol. 13, No. 22, 2011
6037