.
Angewandte
Communications
DOI: 10.1002/anie.201200750
Aerobic Oxidation
Room-Temperature Copper-Catalyzed Oxidation of Electron-
Deficient Arenes and Heteroarenes Using Air**
Qiang Liu, Pan Wu, Yuhong Yang, Ziqi Zeng, Jie Liu, Hong Yi, and Aiwen Lei*
Although transition-metal-catalyzed direct functionalization
From a synthetic point of view, copper-catalyzed oxidative
À
À
of C H bonds has emerged as a powerful method to construct
hydroxylation of C H bonds is an elegant approach but also
[1]
À
À
new C C and C heteroatom bonds, oxidative functionali-
a challenging method to develop. Towards this target, Yu and
co-workers, reported that stoichiometric amounts of Cu-
(OAc)2 mediated ortho-selective hydroxylation of 2-phenyl-
pyridines employing O2 (1 atm) as the oxidant and proceeding
through an acetoxylation/hydroxylation sequence at 1308C.[9]
Moreover, a serial of copper-catalyzed aerobic oxidative
À
zation of C H bonds under mild conditions (at room temper-
ature and using air as the oxidant) still remains a very
challenging field.[2] In particular, the synthesis of phenols by
direct oxidation of arenes with O2 as the oxidant is still
regarded as one of the main challenges for catalysis, and is
rarely reported.[3] A groundbreaking method reported by
Fujiwara and co-workers used Pd(OAc)2 as the catalyst to
convert benzene into phenol with molecular oxygen; how-
ever, this method gave low yields (2–3%) and used extremely
forcing reaction conditions (15 atm O2, 15 atm CO, 1808C).[4]
Recently, Yu and Zhang reported a novel Pd-catalyzed direct
ortho hydroxylation of potassium benzoates in the presence of
O2 (1 atm) as the oxidant.[5] However, several drawbacks still
remain including the high catalyst loading (10 mol% of
Pd(OAc)2) and high temperature (1158C). Thus, it is still
necessary to develop a powerful synthetic method for the
[10]
[11]
[12]
À
À
À
C N, C C, and C S couplings of electron-deficient
arenes and heteroarenes have been achieved. Inspired by
these reports and by the efficiency of copper-containing
oxidizing enzymes in nature, we have developed a copper-
catalyzed “oxygenase-type” oxidation of arenes and hetero-
arenes at room temperature in the presence of air (1 atm) as
the oxidant, thus accomplishing the oxygen-atom transfer
from O2 in the air onto the substrates (Scheme 1). To the best
À
of our knowledge, most copper-catalyzed aerobic C H
oxidation reactions are oxidase-type reactions,[2a] and there
are very few examples of oxygenase-type reactions.[13]
À
oxidative hydroxylation of C H bonds under mild reaction
conditions.
Recent advances in the broad array of copper-catalyzed
À
aerobic oxidative C H functionalizations highlight the poten-
tial to achieve the oxidative hydroxylation of arenes utilizing
copper catalysts.[1e,2a] Additionally, copper is the metal
element of choice for many biological oxidation metabo-
lisms.[6] Examples include copper-containing oxidases, which
combine the oxidation of substrates and the reduction of O2 to
H2O or H2O2, and oxygenases, which mediate oxygen-atom
transfer onto the substrates.[7] These enzymes are widely
distributed in plant and animal tissues; one example is
tyrosinase, which performs copper-catalyzed hydroxylation
of aromatic compounds with O2 under mild conditions.[8]
Scheme 1. Copper-catalyzed “oxygenase-type” oxidation of arenes and
heteroarenes.
For the optimization study, we focused our attention on
the oxidation of benzothiazole 1a by sequential oxidative
hydroxylation and keto–enol tautomerization (Table 1). The
use of 5 mol% of CuCl2 and 1.2 equivalents of NaOtBu in
DMF under air (balloon) at 258C gave the best result for the
aerobic oxidation of heteroarenes (Table 1, entry 1). More
satisfactory yields (80%) were obtained by increasing the
copper catalyst loading to 15 mol% and the amount of base to
1.5 equivalents. Other reaction parameters also had an impact
on the efficiency of this reaction (Table 1) . Among the bases
we tested, the use of NaOtBu provided the best yield of 2a
(Table 1, entries 1–3). Better results were achieved when the
reaction was performed in polar solvents rather than nonpolar
solvents, such as DCE and toluene (Table 1, entries 4–7).
Changing the copper salts also influenced the result (Table 1,
entries 8–11). Notably, the use of CuCl gave similar results to
CuCl2 but within a shorter reaction time (20 min), thus
demonstrating that both CuI and CuII catalyst precursors were
able to facilitate this transformation (Table 1, entry 10).
Consequently, it is possible that the conversion between
CuII and CuI species might occur during this reaction process.
The ligand effects were also examined and it was found that
the reaction was slightly inhibited by all the tested N- and O-
[*] Q. Liu,[+] P. Wu,[+] Y. Yang, Z. Zeng, J. Liu, H. Yi, Prof. A. Lei
The College of Chemistry and Molecular Sciences, Wuhan University
430072, Wuhan, Hubei (P.R. China)
E-mail: aiwenlei@whu.edu.cn
Prof. A. Lei
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
730000, Lanzhou (P.R. China)
[+] These authors contributed equally to this work.
[**] This work was supported by the Program for Changjiang Scholars
and Innovative Research Team in University (IRT1030) and National
Natural Science Foundation of China (20972118 and 20832003). We
also thank Dr. Andrew Crawford for his help in revising this
manuscript.
Supporting information for this article is available on the WWW
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 4666 –4670