Regioselective formation of 2,5-disubstituted oxazoles via copper(I)-catalyzed cycloaddition of acyl azides and 1-alkynes

Article abstract of DOI:10.1021/ja109732s

The reaction of 1-alkynes with acyl azides in the presence of [Tpm ^*,BrCu(NCMe)]BF₄ [Tpm^*,Br = tris(3,5-dimethyl-4-bromopyrazolyl)methane] as the catalyst provides 2,5-oxazoles in moderate to high yields. This is a novel transformation of the CuAAC type that constitutes a significant variation of the commonly observed [3 + 2] cycloaddition reaction to yield 1,2,3-triazoles.

Full text of DOI:10.1021/ja109732s

Published on Web 12/20/2010
Regioselective Formation of 2,5-Disubstituted Oxazoles Via
Copper(I)-Catalyzed Cycloaddition of Acyl Azides and 1-Alkynes
†
‡
,§
Israel Cano, Eleuterio Alvarez, M. Carmen Nicasio,* and Pedro J. Pe´rez*,†
´
Laboratorio de Cata´lisis Homoge´nea, Departamento de Qu´ımica y Ciencias de los Materiales, Unidad Asociada al
CSIC, Centro de InVestigacio´n en Qu´ımica Sostenible (CIQSO), Campus de El Carmen s/n, UniVersidad de HuelVa,
21007-HuelVa, Spain, Instituto de InVestigaciones Qu´ımicas, CSIC-UniVersidad de SeVilla, AVenida de Americo
Vespucio 49, 41092-SeVilla, Spain and Departamento de Qu´ımica Inorga´nica, UniVersidad de SeVilla,
Aptdo 1203, 41071-SeVilla, Spain
Received August 16, 2010; E-mail: mnicasio@us.es; perez@dqcm.uhu.es
Scheme 1. (top) Catalytic Formation of Oxazoles from Direct
Abstract: The reaction of 1-alkynes with acyl azides in the
presence of [Tpm*,BrCu(NCMe)]BF4 [Tpm*,Br ) tris(3,5-dimethyl-
4-bromopyrazolyl)methane] as the catalyst provides 2,5-oxazoles
in moderate to high yields. This is a novel transformation of the
CuAAC type that constitutes a significant variation of the com-
monlyobserved[3+2]cycloadditionreactiontoyield1,2,3-triazoles.
Reaction of Phenylacetylene and Benzoyl Azides; (bottom) X-ray
Structures of Oxazoles 3b (left) and 4a (right)
The copper-catalyzed azide-alkyne cycloaddition (CuAAC)
reaction constitutes one of the most interesting examples of click
chemistry.1 Since its discovery,2 the CuAAC methodology has
become a powerful tool with growing applications in different areas
such as polymer and material sciences, bioconjugation, and
medicinal chemistry.3 We recently developed a catalytic system
for this transformation based on a well-defined and stable Cu(I)
complex, [Tpm*,BrCu(NCMe)]BF4 [Tpm*,Br ) tris(3,5-dimethyl-4-
bromopyrazolyl)methane], that efficiently promotes the formation
of N-sulfonyl-1,2,3-triazoles from sulfonyl azides and 1-alkynes
under mild conditions (eq 1).4
were obtained in a 10:1 ratio and showed all resonances in the
8.2-7.2 ppm region in the H NMR spectrum. However, neither
1
the carbonyl resonance nor the ν(CO) band were observed in the
13C NMR and FTIR spectra, respectively. Therefore, the expected
formation of the N-benzoyl-1,2,3-triazole seemed to have failed
following this route. A second experiment carried out using
p-Me(C6H4)CON3 as the azide led to the same observations: two
compounds 3b and 4b (along with the corresponding amide derived
from that azide) lacking the characteristic spectroscopic data typical
of the expected triazoles were isolated. In order to ascertain the
nature of the new compounds obtained, single crystals of 3b and
4a were grown, and their structures were unambiguously confirmed
by X-ray diffraction analysis.7 To our surprise, they were identified
as the oxazoles shown in Scheme 1, and the NMR data were in
complete agreement with those formulations.7
The oxazole heterocycle is an important structural motif in many
natural products, drugs, and biologically active compounds.8 Two
types of strategies are commonly used to prepare substituted oxazole
derivatives: (1) synthesis of acyclic precursors and their subsequent
cyclization9 and (2) functionalization of the parent oxazole ring.10
Recently, a metal-catalyzed cyclization of propargylic alcohols with
amides for the synthesis of oxazoles has been developed.11 In a
very recent contribution, p-toluenesulfonic acid has been shown to
catalyze a tandem propargylation/cycloisomerization reaction.12
Although reliable and high-yielding, some of these reactions require
harsh conditions that are incompatible with sensitive functional
groups. In this context, protocols based on metal-catalyzed reactions
under mild conditions are desirable. While the reaction of acyl
Encouraged by these results, we decided to expand the scope of
this reaction using acyl azides, as the formation of the corresponding
N-benzoyl-1,2,3-triazoles by the [3 + 2] azide-alkyne cycloaddition
has remained elusive to date.5 Under the protocol used for the
synthesis of N-sulfonyltriazoles,4 phenylacetylene (1a; 1.2 mmol)
and benzoyl azide (2a; 1.0 mmol) were reacted in chloroform at
40 °C in the presence of catalytic amounts (5 mol %) of
[Tpm*,BrCu(NCMe)]BF4.6 The azide was consumed after 24 h, as
inferred from FTIR spectroscopy of the reaction mixture, from
which three compounds were identified. One of them was benza-
mide, PhCONH2 (29% NMR yield),7 which resulted from decom-
position of the initial azide. The other two compounds, 3a and 4a,
† Universidad de Huelva.
‡ CSIC, Instituto de Investigaciones Qu´ımicas.
§ Universidad de Sevilla.
9
10.1021/ja109732s  2011 American Chemical Society
J. AM. CHEM. SOC. 2011, 133, 191–193 191

C O M M U N I C A T I O N S
Table 1. Screening Conditions for Tpm*,BrCu(I)-Catalyzed
Table 2. Scope of the Reactiona
Formation of Oxazolesa
entry
solvent
temp (°C)
conv. (%)b
(3a + 4a)/5ab
1
2
3
4
CHCl3
CHCl3
CHCl3
THF
MeOH
CHCl3
40
60
25
40
40
40
>95
>95
14
93
<2
<2
3:1
1.2:1c
>99:1
1.2:1
-
5
entry
R1
R2
3
yield (%)b
4
yield (%)b c
,
6d
-
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
p-MeC6H4
p-MeC6H4
p-MeC6H4
Ph
p-MeC6H4
p-MeOC6H4 3c
p-NO2C6H4
Ph
p-MeC6H4
3a
3b
60
77
82
14
61
56
63
43
52
49
46
59
18d
17d
24d
41
38
36
18d
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
6
4
<2
<2
6
5
6
<2
<2
7
a Reactions were performed with phenylacetylene (1.2 mmol),
benzoyl azide (1.0 mmol), and catalyst (0.05 mmol) in solvent (1 mL)
for 24 h. b Determined by 1H NMR analysis of the crude mixture using
an internal standard. c Reaction time ) 12 h. d CuI was used as the
catalyst precursor.
3d
3e
3f
p-MeOC6H4 3g
azides and alkynes has been investigated previously,13 it is worth
pointing out that, to the best of our knowledge, the formation of
an oxazole ring from a CuAAC reaction as reported herein has no
precedent in the literature.14
p-MeOC6H4 p-MeOC6H4 3h
9
p-BrC6H4
3-thienyl
3-thienyl
3-thienyl
1-propyl
1-butyl
cyclopropyl
Ph
p-MeC6H4
p-MeOC6H4 3i
Ph
p-MeC6H4
p-MeOC6H4 3l
Ph
Ph
p-MeOC6H4 3o
2-thienyl
2-thienyl
10
11
12
13
14
15
16
17
18
19
3j
3k
4
<2
<2
<2
4
<2
<2
<2
3
3m
3n
After this seminal experiment, we decided to investigate the
reaction conditions in order to improve the selectivity (Table 1)
using 1a and 2a as the reactants. We found that temperature exerted
an important influence on the efficiency of oxazole formation. The
selectivity (for oxazoles vs benzamide) provided at 40 °C decreased
markedly as the temperature was raised to 60 °C (entry 2). However,
full selectivity for the formation of oxazoles was observed at room
temperature, although with low conversion (entry 3). Solvents other
than chloroform did not improve the yield (entries 4 and 5). Finally,
it is also worth mentioning that when CuI was employed as the
catalyst precursor, no reaction was observed, indicating a crucial
role of the Tpm*,Br ligand (i.e., the Tpm*,BrCu core) in this
transformation. This is in agreement with the previously proposed
accelerating effect of ligands in click reactions.15
Under the optimal conditions based on the use of chloroform as
the solvent and 40 °C as the reaction temperature, we examined
the scope with regard to the azide and alkyne components (Table
2). An array of 2,5-disubstituted oxazoles (3a-s) were prepared
in moderate to good yields (43-82%) with the appearance of
trisubstituted oxazoles (4a-s) incorporating two molecules of the
initial alkynes as minor byproducts. The RCONH2 amides and/or
unreacted starting azides completed the mass balance. In all cases,
only the 2,5-disubstituted oxazoles were observed, with no evidence
of the formation of the 2,4-disubstituted isomers, indicating
complete control of the regioselectivity. As the data in Table 2
show, the nature of the substituents on the benzoyl azides affects
the efficiency of the reaction: electron-rich azides led to higher
yields of oxazoles 3 than those with electron-withdrawing groups
on the phenyl rings (Table 2, entries 1-4). The use of arylacetylenes
provided the oxazoles in similar yields with little influence of the
electronic effect of the substituents.
3p
3q
3r
3s
p-MeOC6H4 2-thienyl
cyclopropyl 2-thienyl
a Reactions were performed with phenylacetylene (1.2 mmol),
benzoyl azide (1.0 mmol) and catalyst (0.05 mmol) in CHCl3 (1 mL) for
24 h at 40 °C. b Isolated yield based on azide (average of two runs).
The remaining initial azide was converted into RCONH2 and/or
recovered unreacted. c Yields of <2% for compounds 4 correspond to
products that could not be isolated because of the extremely low
conversion. d Reaction was performed at 60 °C.
of internal alkynes and the regioselective formation of 2,5-
disubstituted oxazoles could be a consequence of the formation of
copper acetylide as the first step of the reaction, followed by a [3
+ 2] cycloaddition reaction with the azide (Scheme 2), in a manner
similar to the well-known mechanism for the formation of
N-substituted-1,2,3-triazoles.5,17-21 However, in our case, the
conversion of the copper triazolyl intermediate A into the corre-
sponding triazole does not take place. Presumably, intermediate A
could be transformed into the copper ketenimide species D through
species B or C.5,19,21 Protonation of the ketenimide would trigger
Scheme 2. Plausible Mechanism for the Formation of Oxazoles
from 1-Alkynes and Acyl Azides
However, when alkylacetylenes were employed, the yields
decreased (entries 13-15 and 19), a feature also observed in several
CuAAC reactions leading to triazoles.16 Heteroaromatic substituents
were also tolerated in both the alkyne (entries 10-12) and the azide
(entries 16-19). Alkynes of the type XCH2Ct CH (X ) Cl, OH)
or Me3SiCt CH did not afford the desired oxazoles. Overall, the
scope of this new reaction seems to be quite broad, although the
development of future more active catalysts is needed to improve
the yields for the less reactive substrates.
We also found that only terminal alkynes undergo this process.
In addition, experiments carried out with Ph-Ct C-Ct C-Ph (a
plausible precursor of 4a) as the reactant failed. Thus, the formation
of the trisubstituted oxazoles 4 should proceed along the reaction
path that leads to disubstituted derivatives 3. The lack of reactivity
9
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a rearrangement and cyclization of the organic fragment to give F
(two resonance forms shown in Scheme 2) in a manner that is
similar but not identical to that previously proposed by Gevorgyan
and co-workers for the formation of pyrroles.22 A 1,2-hydrogen
shift23 would afford G, from which 3a would be formed with the
concomitant release of the catalyst. The origin of the trisubstituted
oxazoles would be explained by proton loss from intermediate G
followed by coupling with a copper acetylide.
In conclusion, we have found a novel route for the catalytic and
regioselective synthesis of 2,5-disubstituted oxazoles from simple
reactants such as 1-alkynes and acyl azides using a copper(I) catalyst
precursor. Work aimed at the development of more active and
selective catalysts and of a more complete understanding of the
mechanism of this transformation is currently underway.
Acknowledgment. This work is dedicated to Prof. Jose´ Bar-
luenga on the occasion of his retirement. This research was finan-
cially supported by MEC (Proyecto CTQ2008-00042/BQU, Con-
solider Ingenio 2010, Grant CSD2006-003) and the Junta de
Andaluc´ıa (Proyecto P07-FQM-02745). I.C. thanks MEC for a
research fellowship. We gratefully acknowledge Prof. Antonio
Echavarren for helpful discussions. Dr. Ana Caballero and Dr.
Toma´s R. Belderrain are thanked for assistance with GC-MS and
NMR studies.
Supporting Information Available: Detailed experimental proce-
dures, analytical and spectroscopic data, and crystallographic data for
3b and 4a (CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
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