ORGANIC
LETTERS
2012
Vol. 14, No. 13
3494–3497
Mild and Rapid Hydroxylation of
Aryl/Heteroaryl Boronic Acids and
Boronate Esters with N-Oxides
Chen Zhu,* Rui Wang, and J. R. Falck*
Division of Chemistry, Department of Biochemistry, University of Texas Southwestern
Medical Center, Dallas, Texas 75390, United States
j.falck@utsouthwestern.edu; chen.zhu@utsouthwestern.edu
Received May 28, 2012
ABSTRACT
Aryl and heteroaryl boronic acids and boronate esters are rapidly, often within minutes, transformed into the corresponding phenols by N-oxides
in an open flask at ambient temperature. This transformation has broad compatibility with a variety of functional groups.
Phenol is a ubiquitous structural unit found in a vast
array of naturalproducts and pharmaceuticals.1 Moreover,
it frequently serves as the key synthetic intermediate for
construction of more complex structures. Consequently,
establishing mild and efficient access to phenols, espe-
cially in the presence of polyfunctional groups, is of great
significance.
Arylboronic acids and related aromatic/heteroaromatic
boronate esters are readily available and have found broad
applications in synthetic chemistry.2 Their transformation
into phenols is typically accomplished through transition-
metal-catalyzed hydroxylationoroxidative hydroxylation,
but it continues to remain an area of active investigation.
For example, Wang et al. and Fu et al. have recently
reported copper-catalyzed hydroxylations of arylboronic
acids at room temperature,3,4 albeit using a stoichiometric
strongbase(KOHorNaOH) (Scheme1(a)). Subsequently,
alternative base-free or palladium-catalyzed conditions
were developed.5 However, these approaches required sev-
eral hours to complete the conversions. The hydroxylation
of arylboronic acids has been achieved without transition
metal catalysis, but this requires strong oxidants such as
hydrogen peroxide and oxone for success (Scheme 1 (b)).6,7
Moreover, the amount of oxidant needed and the reaction
conditions (time, temperature) often must be carefully
controlled to avoid overoxidation of sensitive functionality.
From a practical point of view, nonmetal-mediated pro-
cesses are much preferred in the pharmaceutical industry,
since metal contamination can induce severe concerns and
metal removal can be expensive. Herein, we reveal the first
N-oxide mediated transformation of arylboronic acids to
(5) (a) Inamoto, K.; Nozawa, K.; Yonemoto, M.; Kondo, Y. Chem.
Commun. 2011, 47, 11775. (b) Kaboudin, B.; Abedi, Y.; Yokomatsu, T.
Eur. J. Org. Chem. 2011, 6656. (c) Chowdhury, A. D.; Mobin, S. M.;
Mukherjee, S.; Bhaduri, S.; Lahiri, G. K. Eur. J. Inorg. Chem. 2011,
3232.
(6) (a) Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117. (b)
Simon, J.; Salzbrunn, S.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. J.
Org. Chem. 2001, 66, 633. (c) Travis, B. R.; Ciaramitaro, B. P.; Borhan,
B. Eur. J. Org. Chem. 2002, 3429. (d) Prakash, G. K. S.; Chacko, S.;
Panja, C.; Thomas, T. E.; Gurung, L.; Rasul, G.; Mathew, T.; Olah,
G. A. Adv. Synth. Catal. 2009, 351, 1567.
(7) For other hydroxylations of boronic acids, see: (a) Kianmehr, E.;
Yahyaee, M.; Tabatabai, K. Tetrahedron Lett. 2007, 48, 2713. (b) Hosoi,
K.; Kuriyama, Y.; Inagi, S.; Fuchigami, T. Chem. Commun. 2010, 46,
1284. (c) Zou, Y.-Q.; Chen, J.-R.; Liu, X.-P.; Lu, L.-Q.; Davis, R.-L.;
Jørgensen, K. A.; Xiao, W.-J. Angew. Chem., Int. Ed. 2012, 51, 784.
(1) (a) Tyman, J. H. P. Synthetic and Natural Phenols; Elsevier: New
York, 1996. (b) Rappoport, Z. The Chemistry of Phenols; Wiley-VCH:
Weinheim, 2003.
(2) (a) Diederich, F; Stang, P. J. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 1998. (b) Hall, D. G. Boronic Acids:
Preparation and Applications in Organic Synthesis and Medicine; Wiley-
VCH: Weinheim, 2007. (c) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50,
6722.
(3) Xu, J.; Wang, X.; Shao, C.; Su, D.; Cheng, G.; Hu, Y. Org. Lett.
2010, 12, 1964.
(4) Yang, H.; Li, Y.; Jiang, M.; Wang, J.; Fu, H. Chem.;Eur. J.
2011, 17, 5652.
r
10.1021/ol301463c
Published on Web 06/26/2012
2012 American Chemical Society