Angewandte
Chemie
DOI: 10.1002/anie.200802464
Amide Synthesis
Heterogeneously Catalyzed Efficient Oxygenation of Primary Amines
to Amides by a Supported Ruthenium Hydroxide Catalyst**
Jung Won Kim, Kazuya Yamaguchi, and Noritaka Mizuno*
Dedicated to the Catalysis Society of Japan on the occasion of its 50th Anniversary
Amides are a very important class of compounds in chemistry
and biology that have been used as intermediates in peptide
and protein synthesis, intensifiers of perfume, anti-block
3) the use of water as a solvent, 4) applicability to various
kinds of substrates, and 5) heterogeneous catalysis, allowing
facile catalyst/product separation and reusability of the
Ru(OH) /Al O catalyst.
[1]
reagents, color pigments for inks, detergents, and lubricants.
x
2
3
Traditionally, amides have been synthesized by the reaction of
activated carboxylic acid derivatives, such as acid chlorides,
Initially, various metal hydroxide catalysts were prepared
and applied to the transformation of benzylamine to benza-
mide in water using air as a sole oxidant (Table 1). The
Ru(OH) /Al O catalyst showed the highest catalytic activity
[2]
anhydrides, and esters with amines including ammonia or by
[
2]
the acid-catalyzed rearrangements of ketoximes. However,
these traditional methods often produce vast amounts of toxic
chemical by-products. Therefore, the development of efficient
procedures for the synthesis of amides that avoid the wasteful
use of stoichiometric reagents and/or acidic and basic media is
highly desirable and still a great challenge in modern organic
x
2
3
and selectivity for the transformation of benzylamine to
benzamide (Table 1, entries 1–9). Various ruthenium catalysts
were also applied to the desired oxidation. Ru(OH) /Al O
x
2
3
again showed the highest catalytic activity and selectivity
(Table 1, entries 1, 10–18). The catalyst precursor
[
3]
[4]
synthesis.
RuCl ·nH O showed lower catalytic activity than the
3
2
In general, it is very difficult to oxygenate the a-
Ru(OH) /Al O catalyst and gave a mixture of benzamide,
x 2 3
methylene groups of amines to the corresponding
benzonitrile, benzaldehyde, and benzoic acid (Table 1,
entry 14). Complexes such as [Ru (CO) ], [RuCl (PPh ) ],
[
4,5]
amides.
For example, the stoichiometric oxidant RuO4
3
12
2
3 3
(
generated by the reaction of RuO with NaIO ) has been
[{RuCl (p-cymene)} ], and [Ru(acac) ] were similarly inef-
2 2 3
2
4
[
5]
used alongside the protection of NH groups. To date, to our
fective (Table 1, entries 15–18). Heterogeneous ruthenium
catalysts, such as Ru/C (Ru metal on activated carbon),
2
knowledge, no efficient catalytic oxygenation of amines to
produce amides have been reported. Herein, we report the
oxygenation of primary amines to primary amides by
molecular oxygen (from air) in water, in the presence of an
easily prepared, supported ruthenium hydroxide catalyst,
3
+
[8]
RuHAP (Ru -exchanged hydroxyapatite), and anhydrous
RuO2 (bulk oxide) did not show high catalytic activity
(Table 1, entries 11–13). Pretreatment of the catalyst with
base significantly increased the activity (Table 1, entry 1 cf.
entry 10), as a result of the generation of the active ruthenium
[
6]
Ru(OH) /Al O . This catalytic oxygenation has the follow-
x
2
3
ing significant advantages from the standpoint of green
hydroxide species on the surface of the Al O3 support.
2
[
7]
chemistry: 1) high atom efficiency and no production of
toxic waste materials (theoretically, only water is formed as a
by-product). Eq. (1)], 2) the use of air as the sole oxidant,
Benzamide was not formed in the absence of any catalyst
(Table 1, entry 21), in the presence of just Al O (Table 1,
2
3
entry 19) or with Al O pretreated with an aqueous NaOH
2
3
solution (Table 1, entry 20).
The scope of the Ru(OH) /Al O -catalyzed transforma-
x
2
3
tions of amines to amides was examined (Table 2). The
transformation of benzylamines, which contain electron-
donating as well as electron-withdrawing substituents, pro-
ceeded efficiently to give the corresponding benzamides in
high yields (Table 2, entries 1–6). In the transformations of
methoxybenzylamines, the lower reaction rate of o-methox-
ybenzylamine relative to m- and p-analogues indicates a steric
effect (Table 2, entry 5 cf. entries 3 and 4). This fact suggests
the coordination of substrates to the metal center on the
Ru(OH) /Al O catalyst and that the transformation proceeds
[
*] J. W. Kim, Dr. K. Yamaguchi, Prof. Dr. N. Mizuno
Department of Applied Chemistry, School of Engineering
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
Fax: (+81)-3-5841-7220
E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp
x
2
3
through intramolecular attack by the ruthenium hydroxide
species on the coordinated (activated) substrates. A similar
steric effect was evident for the Ru(OH) /Al O -catalyzed
[
**] This work was supported in part by the Core Research for
Evolutional Science and Technology (CREST) program of the Japan
Science and Technology Agency (JST) and a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture, Science,
Sports and Technology of Japan.
x
2
3
[6c]
hydration of nitriles.
Furthermore, non-activated linear,
branched, and cyclic aliphatic amines were converted into the
corresponding aliphatic amides in high yields (Table 2,
entries 7–10). Nicotinamide was obtained from picolylamine
Angew. Chem. Int. Ed. 2008, 47, 9249 –9251
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9249