Highly regioselective synthesis of 2,4,5-(hetero)aryl substituted oxazoles by intermolecular [3+2]-cycloaddition of unsymmetrical internal alkynes

Article abstract of DOI:10.1039/c3cc45410j

A robust N-nucleophilic 1,3-N,O-dipole equivalent reacts with unsymmetrical internal alkynes under gold catalysis. Conjugation from a remote nitrogen lone pair enables and controls this convergent and highly regioselective process.

Full text of DOI:10.1039/c3cc45410j

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Highly regioselective synthesis of 2,4,5-(hetero)aryl
substituted oxazoles by intermolecular [3+2]-
cycloaddition of unsymmetrical internal alkynes†
Cite this: Chem. Commun., 2013,
49, 8617
Received 17th July 2013,
Accepted 8th August 2013
Elli Chatzopoulou and Paul W. Davies*
DOI: 10.1039/c3cc45410j
www.rsc.org/chemcomm
A robust N-nucleophilic 1,3-N,O-dipole equivalent reacts with substitution patterns are important across areas including bio-
unsymmetrical internal alkynes under gold catalysis. Conjugation active natural products and pharmaceuticals,7 agrochemicals,8
from a remote nitrogen lone pair enables and controls this con- organic dyes,9 ligands for catalysis,10 and polymers11 yet can be
vergent and highly regioselective process.
difficult to prepare in a convergent fashion.12
Intermolecular addition to an unsymmetrical internal alkyne
Cycloaddition reactions of a 1,3-dipole with an alkyne are attractive represents a considerable regioselectivity and reactivity challenge
and widely applied in heteroaromatic synthesis1 but are not gen- with no examples of intermolecular nitrene addition on to an
erally realised for the preparation of 1,3-oxazoles due to the internal alkyne by p-acid mediated atom-transfer processes.13,14
competing rearrangement and insertion chemistry of the required With the heteroatom in the ynamide series dictating regio-
1,3-N,O-dipole, acyl nitrene A/A0 (Fig. 1).2 Alternative strategies that selectivity,6,15 we were interested to see whether a nitrogen posi-
achieve this transformation and avoid direct use of acyl-nitrenes tioned more remotely from the reactive site could exert similar
would therefore be attractive: recently several oxazole-forming reac- influence in internal alkynes and commenced our study using
tions of alkynes have been disclosed, including a triazole fragmen- 3-indolyl-alkynes 1 (Scheme 1). Electrophilic activation of the
tation strategy using N-acyl azides,3 and oxidative formal [2+2+1] alkyne by a p-acid16 should see intermolecular nucleophilic attack
3-component reactions of terminal4 and internal alkynes.5 We by the aminide 2 directed proximal to the indole if the contri-
reported a synthesis of 4-amido-/4-alkoxy-oxazoles from ynamides/ bution by overlap with the nitrogen lone pair is regio-determining
ynol ethers in a formal [3+2]-cycloaddition strategy.6 Gold activation (represented as B0). C–O bond formation may proceed via 4-p
of the ynamide triggers a process in which pyridine-N-aminides 2 electrocyclization with developing cationic character as the N–N
react as dipolar cycloaddition-selective acyl nitrene equivalents.
We were keen to investigate whether this intriguing reactivity aromatization of E would afford the oxazole 3.
bond elongates to eliminate pyridine (C–D–E).6,17 Deaurative
profile could be accessed in reactions with unsymmetrical inter-
In the presence of a Au(III) precatalyst, the free indole derivative
nal alkynes (Fig. 1). 2,4,5-Trisubstituted oxazoles with all-carbon 1a afforded oxazole 3aa in low yield with significant starting
material remaining (Table 1, entry 1). The additional unsaturation
at the developing C-4 position did not alter the reaction pathway.
Fig. 1 Oxazoles by [3+2]-cycloaddition across alkynes.
School of Chemistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT,
UK. E-mail: p.w.davies@bham.ac.uk; Tel: +44 (0)121 4144408
† Electronic supplementary information (ESI) available: Synthetic procedures,
optimisation survey, characterisation data and spectra. Detailed structural assign-
ment of 7. NMR comparison charts for oxazole products. CCDC 950268. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
Scheme 1 Proposed mechanism for [3+2] intermolecular cycloaddition.
Chem. Commun., 2013, 49, 8617--8619 8617
c3cc45410j
c
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Table 1 Reaction study screening
alkyne (3ea–3ga). The use of substrates bearing alkyl substituents
such as n-butyl on the alkyne was generally unsuccessful and
resulted in complex mixtures, unlike the ynamide series.6 This is
likely due to hydride shift from an alkyl group adjacent to the
organogold centre competing with C–O bond formation.14,15
However, a useful yield of 3ia was observed with a cyclopropyl
substituent. Despite the additional steric encumbrance that an
o-bromo substituent presents around the internal alkyne, 3ja was
formed in good yield. Functionalised benzenes and heteroaryl
groups are readily introduced at the 2-position on use of the
appropriate ylide 2. The convergency of this approach allows for
the formation of isomeric oxazoles with complete regiocontrol
through choice of ylide and alkyne (e.g. 3ja vs. 3ab, 3ha vs. 3ad,
Entry Catalyst
2a C (M) Solvent
T (1C) 3aaa (%)
1
2
3
4
5
6
7
8
Au-I
Au-II/AgSbF6
—
I
I
I
I
I
I
I
I
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
Toluene
90
12
m-Xylene 120
m-Xylene 120
m-Xylene 120
m-Xylene 120
m-Xylene 120
m-Xylene 120
m-Xylene 120
m-Xylene 120
m-Xylene 120
m-Xylene 120
m-Xylene 120
73 (64b)
0
TfOH
AgSbF6
Au-II
Au-III
Au-IIIe
Au-III
Au-III
Au-III
Au-III
0c
25
61
78d
48
Table 2 Scope of intermolecular cycloaddition of 3-indolyl alkynesa
9
II
21
18
75
50
10
11
12
III 0.2
IV 0.2
V
0.2
a
b
Isolated yields after flash chromatography. 2a (1.0 equiv.).
c
Immediate degradation of the starting material at 5 mol% loading.
Average yield across 3 runs. 1 mol% catalyst loading. Crystal struc-
d
e
ture of oxazole 3aa with ellipsoids drawn at the 50% probability level.‡
Only the 4-(3-indolyl)oxazole regioisomer was observed. N-Deacti-
vated indoles 1 (R = SO2Me, CO2Me; R1 = Ph) were unreactive. A
study into the reaction conditions (see ESI† for details) established
that good conversion and yields could be obtained using a more
electrophilic cationic gold(I) species stabilised by a phosphite
ligand at elevated temperature and higher concentration in
m-xylene (Table 1, entry 2). No conversion was observed in the
absence of any catalyst, with degradation seen in the presence of a
Brønsted acid (entries 3 and 4). Both AgSbF6 and the gold chloride
complex Au-II catalyse the reaction (entries 5 and 6) yet are more
effective in combination (entry 2). The preformed cationic gold
species Au-III18 gave similar results to the species generated in situ
(entry 7 vs. 2), even maintaining a reasonable yield at 1 mol%
loading (entry 8).
The yield was not improved with higher loadings of 2a though a
1 : 1 stoichiometry of ylide : alkyne remained effective (entry 2).
Several ylide derivatives 2a(I–V)19 were prepared to test the impact
of the acyl-nitrene delivery moiety. With the exception of 3-bromo-
pyridine derivative 2aIV, the ylides were generally less reactive or
stable than unsubstituted 2aI (entries 9–12).
As substituted (3-indolyl)-oxazole motifs are of interest as
natural product derivatives,20 functional organic chromophores21
and medicinal compounds;22 the formation of varied polysubsti-
tuted 4-(3-indolyl)oxazoles was explored (Table 2). Under the same
conditions (entry 2, Table 1), N-alkyl, -allyl and -benzyl substitu-
ents are all tolerated on the indole though were less reactive
(3aa–3ca and 3fa). The regioselectivity was not diminished by the
presence of electron-rich benzene or heteroaryl groups on the
a
Reaction conditions: 1(a–l) (1.0 equiv.), 2(a–f) (1.5 equiv.), Au-IV
(5 mol%), m-xylene (0.2 M). Isolated yields after flash chromatography.
b
B90% purity.
c
8618 Chem. Commun., 2013, 49, 8617--8619
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used in all calculations. The final R1 was 0.0525 (I > 2s(I)) and wR(F2)
was 0.1537 (all data).
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Substituted benzene derivatives were examined to probe the
importance of remote activation of the alkyne by a conjugated
nitrogen lone pair (Scheme 2). Whilst p-N,N-dialkyl systems
4(a–c) afforded the desired oxazoles 5(a–c)a as single regioisomers
in good to moderate yield, neither the m-aniline derivative 4d or a
p-anisole derivative 4e underwent reaction. An N-unsubstituted
analogue afforded complex mixtures. The reactivity trend corre-
lates across all the systems tested with the ability of the hetero-
atom lone pair to donate electron density onto the alkyne.23
The remarkable distinction between the activating effects of
amino vs. alkoxy groups on this cycloaddition was further exam-
ined: despite competition between two nominally activating
groups and an absence of steric bias about the alkyne, 6 reacted
to give oxazole 7 in high yield as a single regioisomer (Scheme 3).
In conclusion, a convergent and efficient synthesis of poly-
aromatic 2,4,5-trisubsituted oxazoles has been developed from
readily prepared starting materials. The reaction shows pyridine-
N-aminides can be employed as acyl nitrene equivalents for
selective formal [3+2]-cycloaddition onto electron-rich internal
alkynes under gold-catalysis. A remote conjugated nitrogen lone
pair exerts superb regiochemical control over this intermolecular
process. Further investigations into the mechanism and applica-
tion of this formal [3+2]-cycloaddition strategy are on-going.
The authors thank Dr Louise Male (University of Birmingham)
for X-ray crystallography and the University of Birmingham for
financial support. The facilities used in this research were part
supported through Birmingham Science City AM2 by Advantage
West Midlands and the European Regional Development Fund.
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tion onto the alkyne–gold complex B: the greater ability of nitrogen
over oxygen to donate electron density (represented as B0 Scheme 1),
appears key in the observed reactivity to render the LUMO of B
sufficiently accessible. p-Aniline is therefore predicted to be less
activating than 3-indolyl due to the greater disruption of aromatic
character represented through the charged resonance forms in the
former (analogous to B0) resulting in longer reaction times.
Notes and references
‡ CCDC 950268. Crystal data for 3aa: C23H16N2O, M = 336.38, mono-
clinic, a = 12.0222(2) Å, b = 7.2396 (1) Å, c = 20.9825(3) Å, b = 106.482(1),
U
= T = 120(2) K, space group P21/c, Z = 4,
1751.19(5) Å3,
11 907 reflections measured, 3042 unique (Rint = 0.0655) which were
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 8617--8619 8619