DOI: 10.1002/anie.201103563
Synthetic Methods
Intermolecular and Selective Synthesis of 2,4,5-Trisubstituted Oxazoles
by a Gold-Catalyzed Formal [3 + 2] Cycloaddition**
Paul W. Davies,* Alex Cremonesi, and Lidia Dumitrescu
The generation and subsequent evolution of metal-stabilized
ꢀ
carbocation/carbenoid reactivity patterns from C C p sy-
stems is central to p-acid catalysis.[1] Following the formation
of a-oxo/imido organogold species by intramolecular atom-
transfer processes onto alkynes,[2,3] such intermediates
[Eq. (1), B–D, Ts = toluene-4-sulfonyl] have very recently
been accessed by intermolecular attack of an O- or N-
nucleophilic oxidant[4] or nitrene equivalent[5] to an electro-
philically activated p system [Eq. (1), A!B]. The intermedi-
ates are quenched by the reaction with a functionality
contained within the alkyne starting material (at R or
R1),[4,5] a [3 + 3] sigmatropic rearrangement at B,[6] or by
further reaction with a nucleophilic oxidant[4c,7] or nitrile[8] in
the absence of faster intramolecular processes. Though
elimination of the delivery system [Eq. (1), B!C/D] may
not proceed as a distinct step,[4] the overall reactivity patterns
observed are reminiscent of electrophilic a-oxo-metal carbe-
Conjugated N-ylides were selected to achieve the
required two-center reactivity. While robust pyridine-N-
ꢀ
ꢀ =
aminides, such as 1a (Y Z = N C O), are established as
1,3-C,N dipoles incorporating the pyridine group,[10] an
alternate reactivity as an N-nucleophilic 1,3-N,O-dipole
equivalent would emerge under the proposed catalytic
regime. Gratifyingly, aminide 1a reacted with ynamide 2a in
the presence of the dichloro(pyridine-2-carboxylato)gold(III)
precatalyst[11] ([Au-I]) to afford the cycloaddition product
oxazole 3aa as a single regioisomer alongside recovered
starting material (Scheme 1). Single-crystal X-ray diffraction
confirmed the structure of 3aa and hence the regioselectivity
of the intermolecular cycloaddition.[12]
ꢀ
noids (C/D), and thus allow C C triple bonds to be perceived
of as simpler and direct alternatives to extensively used
a-oxo-diazo compounds.
However, the introduction of functionality adjacent to the
electrophilic organogold center in such processes offers wider
opportunity for the design of efficient transformations. We
questioned whether the intermolecular nucleophilic attack on
A, which initiates the organometallic intermediate, could
simultaneously install the means to quench it [Eq. (2)]. The
resulting gold-catalyzed intermolecular cycloaddition across
the p system would, as far as we are aware, be unprece-
dented.[9]
Scheme 1. a) Formal cycloaddition of ynamide 2a with the robust 1,3-
N,O-dipole equivalent 1a. b) Crystal structure of 3aa; hydrogen atoms
omitted for clarity. Bn=benzyl, brsm=based on recovered starting
material, Ms=methanesulfonyl.
ꢀ
Though [3 + 2] cycloadditions across C C p systems are
widely employed for the preparation of other heterocycles,
their application toward 1,3-oxazoles is extremely limited.[13]
This is seemingly due to poor chemoselectivity in the
formation and application of the required 1,3-N,O-dipole
equivalent, acyl nitrenes, for instance by thermal or photo-
chemical decomposition of acyl azides in the presence of
alkynes.[14,15] A copper-catalyzed cycloaddition–fragmenta-
tion–cyclization cascade affords 2,5-disubstituted oxazoles
from terminal alkynes and acyl azides.[16] Similarly convergent
one-step or one-pot methods to prepare functionalized 1,3-
oxazoles are rare,[8] and often require the use of highly
reactive species with consequent structural limitations.[17]
Instead, these important motifs for bioactive molecules,
ligand frameworks, and materials are most commonly pre-
[*] Dr. P. W. Davies, A. Cremonesi, Dr. L. Dumitrescu
School of Chemistry, University of Birmingham
Edgbaston, B15 2TT, Birmingham (UK)
E-mail: p.w.davies@bham.ac.uk
[**] Financial support from the University of Birmingham is gratefully
acknowledged. We thank Johnson Matthey plc for a generous loan
of metal salts. Instrumentation used for this research was in part
supported by Birmingham Science City AM2 with support from
AWM and ERDF.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 8931 –8935
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8931