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Amide Coupling
COMMUNICATION
The formation of zirconium carboxylates would lead to ef-
ficient leaving group activation (Scheme 4c). Early transi-
tion metals like zirconium have relatively labile ligands that
can easily undergo ligand substitution in solution. The for-
mation of metal–oxygen bonds is favoured for zirconium,
but zirconium–amine complexes can also form. Wilson and
Weingarten[39] put forth the possibility that their titanium-
mediated amidation reaction proceeds through a ligand ex-
change of the original complex with carboxylic acids and
amines. They argue that, if this is the case, more sterically
demanding substrates would probably result in lower yields.
That trend also exists for the zirconium-catalysed system de-
scribed herein, but this tendency is well known for most cat-
alytic systems and the argument is not conclusive. It is also
possible that a mechanism in which two or more zirconium
ions interact to form a catalytic complex is at work, in anal-
ogy to the amidation mechanism for titanium(IV) butoxide
at 1458C suggested by Shteinberg et al.[51] Future work will
shed more light upon the mechanism of the ZrCl4-catalysed
amide coupling of carboxylic acids and amines, and mecha-
nistic investigations are currently being pursued.
To conclude, despite the fact that the formation of amides
is one of the most performed reactions in the production of
fine chemicals and pharmaceuticals, very few efficient cata-
lytic amidation processes of non-activated carboxylic acids
have been reported up to now.[52] Furthermore, none of the
existing methods allow full conservation of the enantiomeric
purity of the process going from a chiral starting materials
to the products. Herein, we have presented a novel, mild,
versatile, effective and environmentally benign protocol for
direct amidation by using catalytic amounts of inexpensive
zirconium(IV) chloride. This simple and high-yielding
method tolerates a wide range of functionalities, including
acid labile groups, and is suitable for the amidation of both
simple and more complex starting materials, such as indo-
methacin. The method conserves the enantiomeric purity of
the starting materials and is suitable for larger scale synthe-
ses, which indicates its usability in research laboratories, as
well as in industrial applications.
Scheme 3. Gram-scale preparation of amide 3c.
after filtration of the reaction mixture through a silica pad
(Scheme 3). Moreover, the use of a reaction setup in which
phenyl acetic acid (1a) and benzyl amine (2a) were heated
at reflux in THF (708C) in a dry round-bottomed flask
equipped with a condenser, under otherwise identical condi-
tions to those presented in Table 2, resulted in an 89% iso-
lated yield of amide 3a. The latter example, which was per-
formed on a 40 mmol scale, demonstrates that the catalytic
amidation reaction can productively be performed by using
conventional laboratory equipment. In comparison to other
published gram-scale methods, this zirconium-catalysed ami-
dation protocol has the advantage of being milder, less
toxic, and more compatible with different common solvents.
For instance, the boric acid catalysed system requires
a higher reaction temperature, and results in racemisation of
the chiral starting material when such compounds are em-
ployed.[48] Furthermore, the toxicity of boric acid is signifi-
cantly higher than that of ZrCl4.[49]
There are several possible mechanisms by which the zirco-
nium-catalysed amidation reaction could proceed. Earlier
studies on Lewis acid catalysed amidations[31,41] suggest that
the mechanism might proceed through a route similar to
that of the catalytic amidation of esters, as proposed by, for
example, Bonora et al.[50] With this view in mind, the activa-
tion of the carboxylic acid can be envisioned as carbonyl co-
ordination to zirconium in a classic Lewis acidic fashion
(Scheme 4a). In light of the recent study by Whiting et al.,
the possibility of hydrogen-bonded dimeric carboxylic acid
species cannot be ruled out.[8] Another possibility is simulta-
neous activation of both the carbonyl and the leaving group,
as depicted in Scheme 4b. In both cases, the acid becomes
electropositive enough for subsequent attack by the amine.
Acknowledgements
We are grateful for financial support from the Swedish Research Council,
the Carl Trygger Foundation and the K & A Wallenberg Foundation.
Keywords: amides
·
amines
·
carboxylic acids
·
homogeneous catalysis · zirconium
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Scheme 4. Possible zirconium-mediated activation modes of carboxylic
acids in analogy with the proposed mechanism for the titanium-catalysed
amidation reactions of esters (X=hydrogen-bond accepting ligand/
atom). a) Direct Lewis acid activation by carbonyl activation. b) Simulta-
neous Lewis acid activation of the carbonyl and leaving-group activation
by intramolecular hydrogen bonding. c) Leaving-group activation by for-
mation of zirconium carboxylates.
Chem. Eur. J. 2012, 18, 3822 – 3826
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3825