Angewandte
Chemie
DOI: 10.1002/anie.201108540
Synthetic Methods
Synthesis of Aryl(di)azinyl Ketones through Copper- and Iron-
catalyzed Oxidation of the Methylene Group of Aryl(di)azinyl-
methanes**
Johan De Houwer, Kourosch Abbaspour Tehrani, and Bert U. W. Maes*
Aryl(di)azinyl ketones are very useful intermediates in the
synthesis of pharmaceuticals, such as antihistamines, anti-
malarials, antiarrhythmic agents, b2-adrenergic agonists, and
anticancer therapeutics.[1] The oxidation of aryl(di)azinyl-
methanes is an attractive approach to synthesize these
Scheme 1. Initial reaction that revealed the oxidation method. Condi-
tions: Cu(OAc)2·H2O (15 mol%), AcOH (5 equiv), DMSO, O2, 1008C,
24 h.
compounds. Classical conditions for this transformation
often apply (more than) stoichiometric quantities of hazard-
ous oxidants, such as potassium permanganate and selenium
dioxide.[2] In the context of the current drive for a more
sustainable society, in which waste minimization and atom
economy are of utmost importance, the development of
sustainable and inexpensive oxidation protocols is highly
desirable. A lot of effort has already been made in rendering
oxidative processes catalytic by utilizing transition metals in
combination with cheaper oxidants, such as peroxides and
molecular oxygen.[3,4] Also, the use of nonmetal-based
catalysts has been investigated over the last decade.[5] How-
ever, some of these protocols suffer from poor selectivity and
require harsh reaction conditions, expensive catalysts, or the
use of a large excess of less sustainable oxidants, such as
peroxides. Herein, we report a transition metal catalyzed
oxidation of aryl(di)azinylmethanes by using cheap and
readily available base metals (Cu and Fe) as catalysts in
combination with O2, the most sustainable oxidant avail-
able.[6]
Recently, our research group has reported a Cu-catalyzed
intramolecular C-H amination of N-phenylpyridin-2-amine
for the synthesis of the pyrido[1,2-a]benzimidazole skele-
ton.[7] Surprisingly, in an attempt to synthesize pyrido[1,2-
a]indole (2) starting from 2-benzylpyridine (1a) that was
based on this method, a mixture of phenyl(pyridin-2-yl)me-
thanol (3a) and phenyl(pyridin-2-yl)methanone (4a) was
obtained instead (Scheme 1).
This unexpected result prompted us to optimize the
reaction conditions for the benzylic oxidation of 1a. 10 mol%
of Cu(OAc)2·H2O is the optimal catalyst loading (Table 1,
entries 1–3). Omitting the Cu catalyst gave only traces of the
desired product (Table 1, entry 4), thus showing the necessity
of the catalyst. Next we turned our attention to the source of
Cu; Cu halide salts gave faster reactions than the other Cu
sources that were assessed (Table 1, entries 5–10). The differ-
ence between the CuI and CuII salts was negligible, which
suggests that the reaction proceeds via a CuII species and that
the CuI salts are oxidized in situ. The appearance of the
typical green-blue color of CuII at the beginning of the
reaction supports this hypothesis. It should be highlighted that
even Cu metal can be used to promote the oxidation (Table 1,
entry 6). To test whether Cu or impurities of other metals that
are present are responsible for the catalysis, a very pure
sample of CuI (99.999%) was tested; this gave essentially the
same result as with 98% grade CuI (Table 1, entry 11). CuI
(98%) was chosen as the ideal catalyst precursor based on
a combination of a fast conversion of the substrate and the
best price/mol ratio of all of the tested copper halides. From
the solvents that were tested, DMSO gave the fastest reaction
(Table 1, entries 12–14) and was, therefore, selected for the
rest of the optimization study. Finally the influence of the
additive was investigated. Lowering the amount of acetic acid
from five to only one equivalent led to a much slower
reaction, whereas the ketone/alcohol ratio (selectivity)
improved (compare Table 1, entries 10 and 15). A control
experiment without additive revealed that the use of an acid
additive is vital for the oxidation process (Table 1, entry 16).
When pivalic acid was used, a similar result was obtained
(Table 1, entry 17). With benzoic acid and trifluoroacetic acid,
better kinetics were achieved, however, there was also
a substantial decrease in selectivity (Table 1, entries 18–19).
The use of a Lewis acid (AlCl3) gave a conversion of over
90%, but a slower reaction (Table 1, entry 20). The bases
DBU and CsOAc gave low conversions or only traces of the
desired product (Table 1, entries 21–22). From an economic
and a selectivity point of view, one equivalent of acetic acid
proved to be optimal. Utilizing these optimized conditions,
phenyl(pyridin-2-yl)methanone (2a) was isolated in 80%
yield, starting from 1a (Table 2, entry 1). When the reaction
[*] J. De Houwer, Prof. Dr. K. Abbaspour Tehrani,
Prof. Dr. B. U. W. Maes
Organic Synthesis, Department of Chemistry, University of Antwerp
Groenenborgerlaan 171, 2020 Antwerp (Belgium)
E-mail: bert.maes@ua.ac.be
[**] This work was supported by the Institute for the Promotion of
Innovation by Science and Technology in Flanders (IWT-Flanders),
the University of Antwerp (BOF), and the Hercules Foundation.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 2745 –2748
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2745
De Houwer, Johan
