COMMUNICATION
Unconventional oxazole formation from isocyanidesw
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Aurelie dos Santos, Laurent El Kaım,* Laurence Grimaud* and Caroline Ronsseray
Received (in Cambridge, UK) 6th March 2009, Accepted 7th May 2009
First published as an Advance Article on the web 20th May 2009
DOI: 10.1039/b904699b
The coupling of an acyl chloride with an isocyanide affords
2,5-disubstituted oxazoles under mild basic conditions instead of
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4,5-disubstituted derivatives when using Schollkopf conditions
2,6-lutidine was finally selected and added at the beginning of
the Nef reaction to give 3a in a 60% isolated yield. Its
structure was confirmed by an alternative preparation of the
same compound from 1-azidoacetophenone and p-chlorobenzoyl
(butyllithium); this reaction constitutes a remarkable example of
a base-induced chemoselective process in isocyanide chemistry.
chloride.7 The analysis of these results in light of the Schollkopf
¨
reaction shows that the change of base leads to a completely
different reaction path. Strong bases afford 4,5-disubstituted
oxazoles, whereas 2,6-lutidine gives 2,5-disubstituted regioisomers
(Scheme 3).
Over the last twenty years, a large number of compounds
bearing an oxazole nucleus have been isolated from diverse
marine sources, as well as from the fermentation broth
of numerous bacteria.1 Besides the biological relevance of
these compounds, the interest in oxazoles is mostly associated
with the moderate stabilization of their aromatic ring and
their consequent use as synthetic intermediates towards
other heterocyclic families or aliphatic compounds.2 The
traditional preparation of oxazoles by the dehydration of
a-acylaminocarbonyls (Robinson–Gabriel type reactions)3
has, following the pioneering studies of the groups of Van
Various isocyanides 1 and acyl chlorides 2 were treated
under these optimized conditions to form oxazoles 3 in
moderate to good yields (Table 1). Both aromatic and aliphatic
acyl chlorides participated in this new coupling. Considering
the isocyanide component, the reaction is compatible with the
presence of heteroaromatic rings, such as pyridyl (Table 1,
entries 8–10) and furyl (Table 1, entries 11–12). With a pyridyl-
substituted isocyanide, the basic nature of the pyridyl allowed
the formation of the new oxazole without any additional
base, but in a moderate 32% yield. However, the addition of
2,6-lutidine raised the yield to 62%. Allylic isocyanides may
also be used in this reaction, though with slightly lower yields
(Table 1, entry 13). Unfortunately, aliphatic isocyanides
treated with benzoyl chloride (Table 1, entry 15) failed to give
any oxazole using 2,6-lutidine or stronger bases, such as DBU.
We were rather puzzled by the possible mechanism of this
reaction. A careful look at the literature revealed that a similar
synthesis of an oxazole ring was observed after basic treatment
of a Nef adduct derived from isocyanoacetate (Scheme 4).8
However, the regioselectivity of the process is opposite to the
one we observed. In our case, the mechanism might be related
to the oxazole formations reported by Zhu et al.9
Leusen4 and Schollkopf,5 been greatly enriched by strategies
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using isocyanides (Scheme 1).
When considering the Schollkopf reaction, though the
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isocyanide moiety increases the acidity of the vicinal proton,
strong bases such as n-BuLi or LDA are still needed to
perform the deprotonation of the alkyl and benzyl isocyanide
and the subsequent attack on the acyl chloride. Following our
previous studies concerning the Nef reaction (a-addition of
acyl chlorides to isocyanides giving acyl imidoyl chlorides),6
we presumed that a terminal acyl group might alter the acidity
of the compound. This would, in turn, allow electrophilic
additions under smoother conditions and lead to an overall
three-component extension of the Schollkopf synthesis
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(Scheme 2).
Nitrilium ylides are the most likely intermediates in
this oxazole formation from Nef adducts. Indeed [3 + 2]-
cycloadditions have already been observed by the basic treat-
ment of Nef adducts with dipolarophiles.10 In the case of
oxazoles, an electrocyclization of a nitrilium ylide intermediate
may be the key step. However, if such a process is easy to
imagine, with the formation of oxazoles from isocyanoacetates,
the direct cyclization of nitrilium ylide A to 3 is less obvious
The first trials with diazonium salts were quite deceiving,
since when an equimolar mixture of p-chlorobenzylisocyanide
and benzoyl chloride was heated in toluene at 60 1C, and then
a stoichiometric amount of triethylamine and p-nitrophenyl
diazonium tetrafluoroborate was added, none of the expected
triazole could be isolated. More interestingly, traces of a new
oxazole were observed, which just retained the structural
elements present in the Nef adduct. We then performed blank
assays by heating the Nef adduct with various bases; in all
cases, the corresponding 2,5-disubstituted oxazole, 3a, was
isolated (Scheme 3). In the light of the known reversibility
of the Nef reaction in the presence of nucleophilic bases,6a,b
Laboratoire Chimie et Proce´de´s, UMR 7652, Ecole Nationale
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Superieure des Techniques Avancees, 32 Bd Victor, 75015 Paris,
France. E-mail: laurent.elkaim@ensta.fr, laurence.grimaud@ensta.fr;
Fax: +33 145528322; Tel: +33 145525537
w Electronic supplementary information (ESI) available: Further
experimental procedures and characterisation data. See DOI:
10.1039/b904699b
Scheme 1 Oxazole formation from isocyanides.
Chem. Commun., 2009, 3907–3909 | 3907
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This journal is The Royal Society of Chemistry 2009