Intermolecular and selective synthesis of 2,4,5-trisubstituted oxazoles by a gold-catalyzed formal [3+2] cycloaddition

Article abstract of DOI:10.1002/anie.201103563

Oxazole new world: A gold-catalyzed intermolecular reaction of pyridine-N-aminides with ynamides can be used to prepare trisubstituted 1,3-oxazoles with a variety of functional groups. This formal [3+2] cycloaddition employs robust conjugated N-ylides as

Full text of DOI:10.1002/anie.201103563

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
under http://dx.doi.org/10.1002/anie.201103563.
Angew. Chem. Int. Ed. 2011, 50, 8931 –8935
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8931

Communications
pared by intramolecular cyclization[18] or elaboration around
an oxazole core.[19]
The novel reactivity of the aminide as a potentially
controllable N-acyl nitrene equivalent to form oxazoles was
studied (Table 1). No product was observed in the absence of
Table 1: Reaction optimization survey.[a]
Entry Catalyst
1a [equiv] Solvent
T [8C] 3aa (2a)
[%][b]
1
2
3
4
5
6
7
8
–
1.1
1.1
ClCH2CH2Cl 70
ClCH2CH2Cl 70
0 (>95)
Scheme 2. Ynamide scope for the gold-catalyzed oxazole cycloaddi-
tion.[a] [a] Reaction conditions: 1a (1.5 equiv), 2(a–i) (1.0 equiv), and
[Au-I] (5 mol%) in toluene (0.1m) were reacted at 908C. Reactions
were monitored by TLC and stopped after the time shown in
parentheses. Yields refer to isolated product after column chromatog-
raphy. Ns=2-nitrobenzenesulfonyl, TBS=tert-butyldimethylsilyl,
THP=tetrahydropyranyl.
para-TsOH
0 (>95)
53 (47)
37 (57)
59 (34)
40 (57)
79 (6)
65 (22)
95 (0)
61 (14)
0 (94)
[Ph3PAuSbF6][c] 1.1
ClCH2CH2Cl 70
ClCH2CH2Cl 70
ClCH2CH2Cl 70
ClCH2CH2Cl 70
ClCH2CH2Cl 70
ClCH2CH2Cl 70
[Ph3PAuNTf2]
AuBr3
Na[AuCl4]
[Au-I]
1.1
1.1
1.1
1.5
2
1.5
1.5
1.5
1.5
1.5
[Au-I]
9
[Au-I]
CH3C6H5
CH3C6H5
CH3C6H5
CH3C6H5
90
90
90
110
10
11
12
13
[Ph3PAuOTf][c]
were well tolerated on the ynamide p system in our studies
(3af–3ai). Acid-labile functionality survives the process
unscathed (3ag). The 4-oxazolidinone-1,3-oxazole 3ah was
formed in good yield despite the potential for ring expansion
of the cyclopropane. The reactions of terminal ynamides
afforded complex mixtures. The more labile nosyl protecting
group on the nitrogen atom of the ynamide was also
explored.[22] A 2-nitrobenzenesulfonamide, which is geomet-
rically capable of an intramolecular redox reaction between
the nitro group and the gold-activated p system,[23] was
employed to test the intermolecular reaction, and the desired
oxazole 3ai was formed in good yield.
The regiochemical outcome of this transformation is
consistent with a proposed mechanistic overview in which
nucleophilic attack by the aminide occurs adjacent to the
nitrogen of a gold-activated ynamide F/F’ to give adduct G
(Scheme 3).[4c,5,24] Cyclization to J/J’ can be viewed after
elimination of pyridine as either a 4p electrocyclization of the
extensively delocalized gold-stabilized carbocation I or a
capture of the electrophilic carbon center in carbenoid I’ by
the acyl oxygen,[25] with both routes assisted by the heter-
oatom substituent. However, to account for the lack of
–
–
–
0 (>95)
3 (86)
ortho-xylene 140
[a] Reaction conditions: 1a (as shown), 2a (0.1 mmol, 1 equiv), catalyst
(5 mol%), solvent (0.1m), 24 h. [b] Yields and ratios calculated by
1H NMR spectroscopy against a known quantity of an internal standard.
[c] Prepared in situ by adding equimolar quantities of [Ph3PAuCl] and the
appropriate AgI salt. [Au-I]= dichloro(pyridine-2-carboxylato)gold(III),
Ts =toluene-4-sulfonyl.
a gold catalyst at 708C, either with or without Brønsted acid
(Table 1, entries 1 and 2). Cationic gold(I) complexes and
gold tribromide (Table 1, entries 3–5) were similarly effective
to [Au-I], though sodium tetrachloroaurate was slightly less
active (Table 1, entry 6). The use of 1.5 equivalents of 1a saw
improved conversion, though a further increase was not
beneficial (Scheme 1 vs. Table 1, entries 7 and 8). Switching to
a less polar solvent at higher temperature resulted in nearly
quantitative formation of the desired product using robust air-
stable [Au-I] (Table 1, entry 9) with a less clean reaction
observed using a cationic gold species (Table 1, entry 10).
Even at significantly higher temperatures thermal reactions
saw only trace amounts of oxazole identified (Table 1,
entries 11–13).
ꢀ
competing 1,2-insertion reactions, C O bond formation must
be fast, and likely commences with developing carbocationic
A range of functionalized ynamides were treated with
aminide 1a under the optimized reaction conditions
(Scheme 2).[20] Benzyl, aryl, and alkyl substituents at the
nitrogen atom were all well-tolerated, as was a tethered silyl
ether (3aa–3ac). Oxazole 3ad was prepared in good yield,
given the propensity of N-allyl ynamides to undergo a thermal
Claisen rearrangement.[21] Excellent chemoselectivity for the
ynamide p system occurred in the presence of an alkene (3ad)
or even an alkyne (3ae).
Though developing gold carbenoids are commonly
observed to undergo facile 1,2-insertion reactions into
[1–5]
ꢀ
ꢀ
adjacent C H and strained C C bonds,
alkyl substituents
Scheme 3. Proposed mechanism for the formation of 1,3-oxazoles.
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ꢀ
character (G!H!J) prior to the complete N N bond
Ynamides with conjugated p systems reacted predictably
in the oxazole synthesis: oxazolidinone-derived enynamide 4
underwent cycloaddition to the 5-vinyl oxazole 5 [Eq. (3)],
and the conjugated diynamide 6 reacted cleanly at the
p system directly connected to nitrogen atom to give the
5-alkynyloxazole 7 in high yield [Eq. (4)].
fission. Elimination of the gold-catalyst from J then yields
oxazole 3.
An alternative mechanism involving the formation of a
gold nitrene and an initial chelotropic reaction with the
ynamide was ruled out, as a regioisomeric oxazole would be
expected.[26] Furthermore, no reaction was seen when com-
plexes established in atom-transfer processes, [Rh2(OAc)4],
[Cu(CN)4]BF4, or AgOTf, were used.
Alongside continued variation of the ynamide, the
reaction scope was evaluated with respect to the aminide to
vary the 2-substituent in the product oxazoles (Scheme 4). An
Preliminary studies indicate that the reaction is not
limited to ynamides. 4-Ethoxyoxazole 9 was successfully
prepared from ynol ether 8 under the standard reaction
conditions [Eq. (5)]. However, ynol ether 10 gave the a,b,g,d-
unsaturated ethylimidate 11 [Eq. (6)] in keeping with the
gold-catalyzed nitrene transfer to alkyl-substituted yna-
mides[5] and oxidation of alkyl-substituted ynol ethers.[4c]
The additional allylic activation of the adjacent methylene
ꢀ
group sees 1,2-insertion supplant C O bond formation.
Scheme 4. Scope for the gold-catalyzed oxazole cycloaddition.[a]
[a] Reaction conditions: 1(b–g) (1.5 equiv), 2(a–l) (1.0 equiv) and [Au-I]
(5 mol%) in toluene (0.1m) were reacted at 908C. Reactions were
monitored by TLC and stopped after the time shown in parentheses.
Yields refer to isolated product after column chromatography. [b] Con-
taminated with <5% of the 5-vinyloxazole from HBr elimination.
TBDPS=tert-butyldiphenylsilyl.
In summary, a regioselective gold-catalyzed intermolecu-
lar [3 + 2] cycloaddition across electronically biased p systems
is reported. The preparatively straightforward synthesis of
highly substituted and functionalized 1,3-oxazoles employs
conjugated N-ylides as robust and chemoselective N-nucleo-
philic N-acyl nitrene/1,3-N,O-dipole equivalents. Strikingly,
the reaction is highly chemoselective, and the desired path-
way proceeds in preference to several other available
processes. Further study into the reactions of ylides with
ortho-bromobenzene group is readily incorporated allowing
for future modification (3bb and 3bj). Remarkably, a primary
alkyl bromide is also tolerated under these conditions (3bk).
Straightforward access to a bis-heteroaryl axis is demon-
strated by the incorporation of a furyl unit (3cb and 3cg). The
same process can be used to prepare valuable 2-vinyl oxazoles
(3da–3eb),[27] including polyunsaturated systems 3ed and
3ee. Aliphatic substituents can also be introduced at the 2-
position as shown with nosylated compound 3 fi. Heteroatom
incorporation at the 2-position was readily achieved using
methoxycarbonyl aminide, with excellent yields even with an
N-allyl ynamide (3ga, 3gd, and 3ge).
ꢀ
electrophilically activated C C p systems is ongoing.
Received: May 24, 2011
Revised: July 4, 2011
Published online: July 26, 2011
Angew. Chem. Int. Ed. 2011, 50, 8931 –8935
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8933

Communications
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[12] CCDC 819432 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.ca-
m.ac.uk/datarequest/cif.
Keywords: 1,3-oxazoles · cycloaddition · gold ·
homogeneous catalysis · ynamides
.
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