A Heterogeneous Gold(I)-Catalyzed [2 + 2 + 1] Annulation of Terminal Alkynes, Nitriles, and Oxygen Atoms Leading to 2,5-Disubstituted Oxazoles

Article abstract of DOI:10.1021/acs.joc.7b00386

The first heterogeneous gold(I)-catalyzed [2 + 2 + 1] annulation of terminal alkynes, nitriles, and oxygen atoms has been achieved by using an MCM-41-immobilized phosphine-gold(I) complex as catalyst and 8-methylquinoline N-oxide as oxidant under mild conditions, yielding a variety of 2,5-disubstituted oxazoles in good to excellent yields with broad substrate scope. The new heterogeneous gold(I) catalyst can easily be recovered by simple filtration of the reaction solution and recycled for at least eight times without significant loss of activity.

Full text of DOI:10.1021/acs.joc.7b00386

Article
pubs.acs.org/joc
A Heterogeneous Gold(I)-Catalyzed [2 + 2 + 1] Annulation of
Terminal Alkynes, Nitriles, and Oxygen Atoms Leading to 2,5-
Disubstituted Oxazoles
Weisen Yang,†,‡ Rongli Zhang,† Feiyan Yi,† and Mingzhong Cai*,†
†Key Laboratory of Functional Small Organic Molecule, Ministry of Education and College of Chemistry & Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P. R. China
‡College of Ecology and Resources Engineering, Wuyi University, Wuyishan City 354300, P. R. China
S
* Supporting Information
ABSTRACT: The first heterogeneous gold(I)-catalyzed [2 + 2 + 1]
annulation of terminal alkynes, nitriles, and oxygen atoms has been
achieved by using an MCM-41-immobilized phosphine−gold(I)
complex as catalyst and 8-methylquinoline N-oxide as oxidant under
mild conditions, yielding a variety of 2,5-disubstituted oxazoles in good
to excellent yields with broad substrate scope. The new heterogeneous
gold(I) catalyst can easily be recovered by simple filtration of the
reaction solution and recycled for at least eight times without significant
loss of activity.
Scheme 1. Homogeneous Gold(I)-Catalyzed Synthesis of
Oxazoles
INTRODUCTION
■
Oxazoles with their 2 and 5 positions substituted with aryl or
alkyl groups are privileged scaffolds found in many pharmaco-
logically active synthetic molecules and natural products, which
exhibit numerous significant biological activities and unique
properties.1 These oxazoles are also important synthetic
intermediates in organic synthesis.2 Subsequently, a variety of
methods have been developed to form oxazoles, such as metal/
halogen-promoted intramolecular cyclization of acyclic pre-
cursors,3 transition-metal-catalyzed bimolecular annulation,4
oxidation of oxazolines,5 the C−C coupling of prefunctional-
ized oxazoles with various organometallic reagents,6 and other
elegant protocols recently reported.7 However, most of these
methods suffer from some drawbacks such as low atom
efficiency, inaccessible starting materials, limited substrate
scope and the use of stoichiometric amounts of sometimes
toxic transition metal catalysts or oxidants. Hence, development
of a more eco-friendly procedure for the synthesis of oxazole
derivatives under mild conditions from readily available starting
materials still represents a continuing challenge.
Homogeneous gold catalysis is among innovative projects of
modern organic synthesis, and Au(I) or Au(III) complexes
have evolved as mild Lewis acid catalysts for organic
transformations requiring the activation of π bonds in the
past two decades.8 Recently, gold(I) or gold(III)-catalyzed [3 +
2] cycloaddition9 and intramolecular cyclization of propargylic
amides10 for the synthesis of oxazole derivatives under mild
conditions have attracted considerable interest. The gold(I)-
catalyzed one-pot heterocyclization of terminal alkynes with
nitriles or cyanamides in the presence of an oxygen-delivering
oxidant has provided a simple and efficient approach to 2,5-
disubstituted oxazoles (Scheme 1a and 1b).11 Li et al. described
a gold(I)-catalyzed tandem reaction of amide−aldehyde−
alkyne coupling and cyclization leading to 2,4,5-trisubstituted
oxazoles (Scheme 1c).12 Very recently, Park and co-workers
Received: February 26, 2017
© XXXX American Chemical Society
A
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reported a gold(I)-catalyzed annulation of α-diazo oxime ethers
and nitriles, providing an alternative method for the synthesis of
2,4,5-trisubstituted oxazoles (Scheme 1d).13
Scheme 3. Synthesis of the MCM-41−PPh3−AuNTf2
Complex
Although these gold-catalyzed syntheses of oxazole deriva-
tives are highly efficient, industrial applications of these
homogeneous gold complexes remain a challenge because
they are quite expensive, not recyclable, and difficult to separate
from the product, which is a particularly significant drawback
for their application in the pharmaceutical industry. Immobi-
lization of homogeneous catalysts on various porous materials
with high surface areas is usually the method of choice because
the supported catalysts can be easily recovered by a simple
filtration process after reactions.14 The discovery of meso-
porous MCM-41 materials has provided a new possible
candidate for an ideal support to immobilize homogeneous
catalysts and given an enormous stimulus to research in
heterogeneous transition-metal catalysis.15 The hexagonally
ordered MCM-41 material possesses large and uniform pore
size, ultrahigh surface area, big pore volume, and rich silanol
groups in the inner walls.16 To date, some functionalized
MCM-41-supported palladium,17 rhodium,18 molybdenum,19
gold,20 and copper21 complexes have been successfully used as
potentially green and sustainable catalysts in organic reactions.
Recently, we reported the carbonylative cross-coupling
reactions of aryl iodides with organostannanes,17d arylboronic
acids,17e and triarylbismuths17f catalyzed by immobilization of
palladium in MCM-41 and the C−N and C−S bond formation
reactions catalyzed by immobilization of copper in MCM-4121
with facile separation and recyclability of the catalysts.
However, to the best of our knowledge, no example of a
heterogeneous gold-catalyzed synthesis of oxazoles has been
reported until now. In continuing our efforts to develop
efficient heterogeneous transition-metal catalysts for organic
synthesis,17d−f,21 herein we report the first synthesis of an
MCM-41-immobilized phosphine gold(I) complex [MCM-41−
PPh3−AuNTf2] and its successful application to the [2 + 2 + 1]
annulation of terminal alkynes, nitriles, and oxygen atoms from
an oxidant leading to 2,5-disubstituted oxazoles (Scheme 2).
°C for 24 h, followed by the silylation with Me3SiCl in toluene
at room temperature for 24 h to afford triphenylphosphine-
functionalized MCM-41 (MCM-41−PPh3). The latter was
subsequently treated with Me2SAuCl and AgNTf2 in dichloro-
methane (DCM) at room temperature to generate the MCM-
41-immobilized phosphine gold(I) complex [MCM-41−PPh3−
AuNTf2] as a gray powder, and the gold content of the complex
was found to be 0.25 mmol g−1 according to the ICP-AES
measurements. The MCM-41−PPh3−AuNTf2 complex was
characterized by small-angle X-ray powder diffraction (XRD)
[Figure S1] and energy-dispersive X-ray spectroscopy (EDS)
[Figure S2] [see Supporting Information].
The MCM-41−PPh3−AuNTf2 complex was then used as
catalyst for the [2 + 2 + 1] annulation of terminal alkynes,
nitriles, and oxygen atoms from an oxidant. Initial experiments
with phenylacetylene (1a) and acetonitrile (2a) as both the
reacting partner and the solvent were performed to optimize
the reaction conditions, and the results are summarized in
Table 1. At first, different N-oxides as oxidants were tested at 60
°C in the presence of 5 mol % MCM-41−PPh3−AuNTf2
complex (entries 1−6). Among the oxidants examined, pyridine
N-oxide (A), 3,5-dichloropyridine N-oxide (B), 2,6-dibromo-
pyridine N-oxide (C), and 2,4-dichloropyridine N-oxide (D)
afforded a low to moderate yield (entries 1−4), both quinoline
N-oxides (E and F) gave good results and 8-methylquinoline
N-oxide (E) was the best choice (entries 5 and 6). When a
homogeneous gold(I) complex was used as catalyst, the desired
product 3a was isolated in 92% yield (entry 7), indicating that
the catalytic activity of MCM-41−PPh3−AuNTf2 complex was
comparable to that of Ph3PAuNTf2. The special catalytic role of
gold(I) in this annulation was demonstrated by the inability of
AgNTf2 and HNTf2 to catalyze this reaction (entries 8 and 9).
In order to examine the effect of the support on the reaction,
we prepared a magnetic nanoparticle-immobilized phosphine
gold(I) complex (Fe3O4@SiO2−PPh3−AuNTf2) by using a
silica-coated Fe3O4 (Fe3O4@SiO2) as the support instead of
MCM-41 according to the procedure summarized in Scheme 3.
However, when Fe3O4@SiO2−PPh3−AuNTf2 was used as the
catalyst, only a trace of the desired product 3a was formed
(entry 10). The effect of the linker on the reaction was also
examined by replacing 1-(4-(diphenylphosphino)phenyl)-3-(3-
(triethoxysilyl)propyl)urea with a commercially available
(EtO)3Si(CH2)2PPh2 in the procedure outlined in Scheme 3
to prepare another MCM-41-immobilized phosphine gold(I)
complex [MCM-41−PPh2−AuNTf2]. The MCM-41−PPh2−
Scheme 2. Heterogeneous Gold(I)-Catalyzed Synthesis of
2,5-Disubstituted Oxazoles from Terminal Alkynes and
Nitriles
The new heterogeneous gold(I) catalyst exhibits high catalytic
activity in the reaction under mild reaction conditions and can
easily be recovered from the reaction mixture by a simple
filtration of the reaction solution, and its catalytic efficiency
remains unaltered even after recycling eight times.
RESULTS AND DISCUSSION
■
The MCM-41-immobilized phosphine gold(I) complex
[MCM-41−PPh3−AuNTf2] was synthesized according to the
procedure summarized in Scheme 3. First, the mesoporous
material MCM-41 reacted with 1-(4-(diphenylphosphino)-
phenyl)-3-(3-(triethoxysilyl)propyl)urea22 in toluene at 100
B
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a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst (mol %)
oxidant
temp (°C)
time (h)
yield (%)
1
MCM-41−PPh3−AuNTf2 (5)
MCM-41−PPh3−AuNTf2 (5)
MCM-41−PPh3−AuNTf2 (5)
MCM-41−PPh3−AuNTf2 (5)
MCM-41−PPh3−AuNTf2 (5)
MCM-41−PPh3−AuNTf2 (5)
Ph3PAuNTf2 (5)
A
B
C
D
E
F
E
E
E
E
E
E
E
E
E
E
E
60
60
60
60
60
60
60
60
60
60
60
25
40
80
60
60
60
8
49
51
15
57
2
8
3
8
4
8
c
5
8
91
6
8
77
92
0
7
4
8
AgNTf2 (5)
24
24
24
12
24
24
8
9
HNTf2 (5)
0
10
11
12
13
14
15
16
17
Fe3O4@SiO2−PPh3−AuNTf2(5)
MCM-41−PPh2−AuNTf2 (5)
MCM-41−PPh3−AuNTf2 (5)
MCM-41−PPh3−AuNTf2 (5)
MCM-41−PPh3−AuNTf2 (5)
MCM-41−PPh3−AuNTf2 (2.5)
MCM-41−PPh3−AuNTf2 (1.0)
MCM-41−PPh3−AuNTf2 (10)
trace
58
0
11
85
d
24
48
79
42
3
90
a
b
c
Reaction conditions: 1a (0.3 mmol), oxidant (1.3 equiv) in MeCN (3 mL) under air. Isolated yield. TON and TOF was 18.2 and 2.3 h−1,
d
respectively. TON and TOF was 31.6 and 1.3 h−1, respectively.
AuNTf2 complex could afford a moderate yield of 3a (entry
11). The effect of temperature on the model reaction was also
investigated (Table 1, entries 5 and 12−14). The reaction did
not work at room temperature, the reaction at 60 °C gave the
best result, and other temperatures were substantially less
effective. Reducing the amount of the catalyst to 2.5 mol %
resulted in a lower yield, and a long reaction time was required
(entry 15). When the amount of the catalyst was further
decreased to 1.0 mol %, the reaction proceeded slowly and the
desired product 3a was isolated in only 42% yield after 48 h
(entry 16). Increasing the amount of the catalyst could shorten
the reaction time but did not improve the yield (entry 17).
Thus, the optimized conditions for this transformation are the
MCM-41−PPh3−AuNTf2 (5 mol %), and 8-methylquinoline
N-oxide (1.3 equiv) in acetonitrile as both the reacting partner
and the solvent at 60 °C under air for 8 h (Table 1, entry 5).
With this promising result in hand, we started to investigate
the scope of this heterogeneous gold(I)-catalyzed [2 + 2 + 1]
annulation reaction under the optimized conditions, and the
results are summarized in Table 2. First, various terminal
alkynes were examined by using acetonitrile as the nitrile
source. As shown in Table 2, a wide range of terminal
arylacetylenes having different electronic and steric natures
were allowed to react with acetonitrile. The electron-rich
substituted phenylacetylenes 1b−e gave the desired products
3b−e in good to excellent yields. In contrast, the electron-
deficient substituted phenylacetylenes 1f and 1g showed
slightly lower reactivity and afforded the corresponding
oxazoles 3f and 3g in 74 and 73% yield, respectively. A
disubstituted phenylacetylene 1h and a biphenylacetylene 1i
proved to be also good alkyne substrates and could react with
acetonitrile effectively to give the desired products 3h and 3i in
good yields. The reactions of sterically congested arylacetylenes
such as 2-methylphenylacetylene 1j and 2-chlorophenylacety-
lene 1k were still serviceable even if ortho substitution did
decrease the reaction yields due to steric hindrance. The bulky
1-naphthylacetylene could give the desired oxazole 3l in 72%
yield. It is noteworthy that 1,4-diethynylbenzene 1m was
selectively converted to an acetylene-containing oxazole 3m in
74% yield, which can be further functionalized. In addition to
arylacetylenes, aliphatic terminal alkynes such as 1-hexyne 1n,
5-chloro-1-pentyne 1o, and 5-phenyl-1-pentyne 1p underwent
the annulation with acetonitrile smoothly to afford the
corresponding products 3n−p in 71−88% yields. Cyclo-
alkylacetylenes 1q and 1r were also suitable alkyne substrates
and gave the desired oxazoles 3q and 3r in 76 and 84% yield,
respectively. Interestingly, alkylacetylenes bearing a free
carboxylic acid moiety or an acid-labile THP group 1s and 1t
could react with acetonitrile effectively to furnish the expected
oxazoles 3s and 3t in high yields. The scope of alkyne
substrates can be expanded to heteroarylacetylenes. For
example, the reaction of 3-ethynylthiophene 1u with acetoni-
trile gave the desired oxazole 3u in 78% yield. However, with
propargyl alcohols and their derivatives as alkyne substrates, a
complex mixture was formed due to the presence of
intramolecular trapping of the α-oxo gold carbene intermedi-
ates as a major side reaction.23 Similarly, propargyl amides and
propargyl bromide were not good alkyne substrates.
This annulation reaction also permitted the use of other
nitriles as both the reacting partner and the solvent. For
example, isobutyronitrile 2b could react with phenylacetylene
1a and cyclopropylacetylene 1q smoothly to afford the desired
oxazoles 3v and 3w in high yields. Phenylacetonitrile 2c
underwent the annulation with phenylacetylene 1a effectively
to give the expected oxazole 3x in 75% yield. Besides these
three aliphatic nitriles, aromatic nitriles such as benzonitrile 2d
and 4-methylbenzonitrile 2e were also good nitrile sources, and
reactions with aryl- or alkylacetylenes proceeded smoothly,
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Table 2. Heterogeneous Gold(I)-Catalyzed Annulation of Terminal Alkynes and Nitriles Leading to 2,5-Disubstituted
a b
,
Oxazoles
a
b
c
Reaction conditions: 1 (0.3 mmol), E (1.3 equiv) in R1-CN (3 mL) at 60 °C under air for 8 h. Isolated yield. For 24 h.
affording functionalized oxazoles 3y−3b′ in good yields. In
addition, a heterocyclic nitrile such as thiophene-2-carbonitrile
2f also proved to be a suitable nitrile source, and the reaction
with 1d afforded the expected product 3c′ in a moderate yield.
Only when nitriles were used both as reagent and the reaction
solvent did the annulation reaction proceed smoothly because
nitriles could react with the gold carbene intermediate rapidly
enough that some side reactions would be largely suppressed.
So, when an expensive or not readily available nitrile was used
as the substrate, the reaction must be carried out by using at
least 3.0 equiv of the nitrile under solvent-free conditions;
however, the solvent-free conditions were not suitable for
heterogeneous catalysis. The present method provides a quite
general, simple, and practical route for the synthesis of a variety
of 2,5-disubstituted oxazoles from commercially available
alkynes and nitriles. A range of functional groups were easily
tolerated, including a free carboxylic acid moiety, an acid-labile
THP group, an alkyl chloride, a cyclopropyl group, bulky 1-
naphthyl and tert-butyl groups, thienyl, and aryl groups having
different electronic and steric natures.
was allowed to react further. In this case, no significant increase
in conversion was observed, indicating that leached gold species
from the catalyst (if any) are not responsible for the observed
activity. It was also confirmed by ICP-AES analysis that no gold
species could be detected in the filtrate. These results show that
the gold(I) complex remains on the support at elevated
temperatures during the reaction and the observed catalysis was
intrinsically heterogeneous.
A plausible mechanism for heterogeneous gold(I)-catalyzed
[2 + 2 + 1] annulation reaction of alkynes 1 and nitriles 2 with
8-methylquinoline N-oxide is illustrated in Scheme 4.25 First,
coordination of the MCM-41−PPh3−AuNTf2 complex to the
C−C triple bond in terminal alkyne 1 gives an MCM-41-
anchored phosphine−Au alkyne complex (A). The latter
undergoes the reaction with an oxygen-delivering oxidant to
produce an MCM-41-anchored phosphine-gold carbene
intermediate (B) via an addition−elimination process. Then
the nucleophilic attack by nitrile 2 on the gold carbene
intermediate B affords the intermediate C. Finally, intermediate
C can undergo the intramolecular cyclization to give the desired
oxazole 3 and regenerate the MCM-41−PPh3−AuNTf2
complex.
To verify whether the observed catalysis was due to the
heterogeneous catalyst MCM-41−PPh3−AuNTf2 or to a
leached gold species in solution, we performed the hot filtration
test.24 For this, the reaction of phenylacetylene with acetonitrile
was carried out until a conversion of 30%. Then the catalyst was
removed from the solution at 60 °C by filtration, and the filtrate
For the practical application of a heterogeneous precious
metal catalyst system, its ease of separation, stability, and
reusability are important factors. The MCM-41−PPh3−AuNTf2
can be easily separated and recovered by a simple filtration of
D
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recovered by filtration of the reaction solution, and recycled for
at least eight times without significant loss of activity.
Scheme 4. Proposed Catalytic Cycle
EXPERIMENTAL SECTION
■
General Methods. All chemicals were reagent grade and used as
purchased. The mesoporous MCM-4116 and 1-(4-(diphenylphos-
phino)phenyl)-3-(3-(triethoxysilyl)propyl)urea22 were prepared ac-
cording to the literature methods. The silica-coated Fe3O4 (Fe3O4@
SiO2) was prepared according to our previous procedure.26 The
products were purified by flash chromatography on silica gel. A
mixture of EtOAc and light petroleum ether was generally used as
eluent. All products were characterized by comparison of their spectra
and physical data with those of authentic samples. IR spectra were
recorded on an FT-IR spectrometer. H and 13C NMR spectra were
1
recorded at 400 or 100 MHz with CDCl3 as the solvent and TMS as
an internal standard. Chemical shifts are reported in δ (ppm) relative
to TMS. HRMS spectra were recorded on a Q-Tof spectrometer with
micromass MS software using electrospray ionization (ESI). Melting
points are uncorrected. Gold content was determined with inductively
coupled plasma atom emission spectrometry (ICP-AES). X-ray
diffraction (XRD) measurements were carried out at room temper-
ature using an X-ray powder diffractmeter. X-ray energy-dispersive
spectroscopy (EDS) was performed using a microscope.
Preparation of MCM-41−PPh3−AuNTf2 and MCM-41−PPh2−
AuNTf2 Complexes. 1-(4-(Diphenylphosphino)phenyl)-3-(3-
(triethoxysilyl)propyl)urea (0.525 g, 1 mmol) was added to a
suspension of 2.0 g of the MCM-41 in 100 mL of dry toluene. The
mixture was stirred at 100 °C for 24 h under Ar. Then the solid was
filtered, washed with CHCl3 (2 × 20 mL), and dried in vacuum at 150
°C for 5 h. The dried white solid was then soaked in a solution of 2.5 g
of Me3SiCl in 80 mL of dry toluene at room temperature under
stirring for 24 h. The solid product was filtered, washed with acetone
(3 × 20 mL), and dried in vacuum at 120 °C for 5 h to obtain 2.367 g
of hybrid material MCM-41-PPh3. The phosphine content was found
to be 0.36 mmol g−1 by elemental analysis.
the reaction solution. We next examined the recycling of the
catalyst by using the annulation reaction of phenylacetylene 1a
with acetonitrile. After carrying out the reaction, the catalyst
was recovered by simple filtration and washed with ethyl
acetate and diethyl ether. After being air-dried, it can be reused
directly without further purification. The recovered gold
catalyst was used in the next run, and almost consistent
activity was observed for eight consecutive cycles (Figure 1). In
In a small Schlenk tube, 1.00 g of the above-functionalized MCM-41
(MCM-41−PPh3) was mixed with Me2SAuCl (83 mg, 0.28 mmol) in
30 mL of dry CH2Cl2. The mixture was stirred at room temperature
for 8 h under an argon atmosphere. The precipitate was filtered off,
washed with CH2Cl2, and then treated with AgNTf2 (107 mg, 0.28
mmol) in CH2Cl2 (30 mL) at room temperature for 0.5 h. The solid
product was filtered, washed with NH3·H2O (2 × 10 mL), distilled
water, and EtOH, and dried under vacuum to give 1.039 g of a gray-
gold complex (MCM-41−PPh3−AuNTf2). The gold content was
found to be 0.25 mmol g−1 by ICP-AES.
Figure 1. Recycle of the MCM-41−PPh3−AuNTf2 catalyst.
The MCM-41−PPh2−AuNTf2 complex was prepared by using
(EtO)3Si(CH2)2PPh2 (0.377 g, 1 mmol) as the starting material in the
same manner, the gold content was found to be 0.27 mmol g−1 by
ICP-AES.
addition, the Au leaching in the supported catalyst was also
determined by ICP-AES analysis. The gold content of the
catalyst was found to be 0.24 mmol g−1 after eight consecutive
runs, indicating that only 4% of gold had been lost from the
MCM-41 support.
Preparation of Fe3O4@SiO2−PPh3−AuNTf2 Complex. To a
suspension of 0.75 g of Fe3O4@SiO2 in 30 mL of dry toluene was
added a solution of 1-(4-(diphenylphosphino)phenyl)-3-(3-
(triethoxysilyl)propyl)urea (0.263g, 0.5 mmol) in 10 mL of dry
toluene. The mixture was stirred at 110 °C under argon atmosphere
for 24 h. Then the resulting material was magnetically separated,
washed repeatedly with toluene and CH2Cl2 to remove any
unanchored species, and dried at 100 °C under vacuum for 5 h to
afford 0.89 g of the triphenylphosphine-functionalized Fe3O4@SiO2
(Fe3O4@SiO2−PPh3) as brown nanoparticles. The phosphine content
was found to be 0.28 mmol g−1 by elemental analysis.
In a small Schlenk tube, 0.5 g of Fe3O4@SiO2−PPh3 was mixed with
Me2SAuCl (42 mg, 0.14 mmol) in 15 mL of dry CH2Cl2. The mixture
was stirred at room temperature for 8 h under an argon atmosphere.
The solid material was magnetically separated, washed with CH2Cl2,
and then treated with AgNTf2 (53 mg, 0.14 mmol) in CH2Cl2 (15
mL) at room temperature for 0.5 h. The solid product was
magnetically separated, washed with NH3·H2O (2 × 10 mL), distilled
water, and EtOH, and dried under vacuum to give 0.519 g of Fe3O4@
CONCLUSIONS
■
We have developed an efficient intermolecular reaction of α-
oxo gold carbenes generated via heterogeneous gold(I)-
catalyzed alkyne oxidation with nitriles leading to a variety of
2,5-disubstituted oxazoles in mostly good to excellent yields.
This heterogeneous [2 + 2 + 1] annulation has many attractive
features, such as (1) the substrate scope is broad, and a wide
range of alkynes and nitriles are allowed, (2) the reaction
conditions are exceptionally mild, (3) the reaction is tolerant of
a range of functional groups including a free carboxylic acid
moiety and an acid-labile THP group, and (4) this
heterogeneous gold(I) catalyst can easily be prepared via a
simple procedure from commercially readily available reagents,
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SiO2−PPh3−AuNTf2 as brown nanoparticles. The gold content was
found to be 0.21 mmol g−1 by ICP-AES.
143.8, 140.8, 137.7, 128.4, 127.3, 126.9, 126.8, 124.3, 121.9, 28.6, 15.6,
14.1. HRMS calcd for C18H17NO+ [M+]: 263.1310, found 263.1322.
2-Methyl-5-(2-methylphenyl)oxazole (3j).11a Light yellow oil (31.7
mg, 61%). IR (neat): 2927, 1648, 1585, 1557, 1142, 1092, 762 cm−1.
1H NMR (400 MHz, CDCl3): δ 7.69−7.63 (m, 1H), 7.30−7.22 (m,
3H), 7.10 (s, 1H), 2.54 (s, 3H), 2.46 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 160.7, 150.5, 134.7, 131.1, 128.1, 127.5, 126.6, 126.1, 124.8,
21.8, 14.0.
General Procedure for the Heterogeneous Gold-Catalyzed
Oxazole Formation. 8-Methylquinoline N-oxide (E, 62 mg, 0.39
mmol) and MCM-41−PPh3−AuNTf2 (60 mg, 0.015 mmol) were
added to a solution of a terminal alkyne 1 (0.3 mmol) in nitrile 2 (3
mL) at 60 °C. The reaction mixture was stirred at 60 °C for 8−24 h.
After being cooled to room temperature, the catalyst was separated by
a simple filtration of the reaction solution, washed with ethyl acetate (2
× 5 mL) and diethyl ether (2 × 5 mL), and reused in the next run.
The filtrate was concentrated under reduced pressure, and the residue
was purified by chromatography on silica gel (eluent: light petroleum
ether/ethyl acetate = 5:1) to afford the oxazole product 3.
2-Methyl-5-phenyloxazole (3a).27 Light yellow solid (43.4 mg,
91%). Mp 58−59 °C. IR (KBr): 2925, 1696, 1558, 1451, 942, 766, 690
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.64−7.57 (m, 2H), 7.40 (t, J =
7.6 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.20 (s, 1H), 2.53 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 161.0, 151.1, 128.8, 128.2, 128.1, 123.9,
121.9, 14.1.
5-(2-Chlorophenyl)-2-methyloxazole (3k). Brown oil (36.6 mg,
1
63%). IR (neat): 2924, 1645, 1575, 1448, 1061, 934, 760 cm−1. H
NMR (400 MHz, CDCl3): δ 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (s,
1H), 7.47−7.44 (m, 1H), 7.36−7.30 (m, 1H), 7.26−7.20 (m, 1H),
2.54 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.0, 147.7, 134.3,
130.6, 130.4, 128.6, 127.5, 127.1, 127.0, 14.0. HRMS calcd for
C10H8ClNO+ [M+]: 193.0294, found 193.0296.
2-Methyl-5-(naphthalen-1-yl)oxazole (3l). Red brown oil (45.2
mg, 72%). IR (neat): 2923, 1639, 1592, 1578, 1345, 1083, 825, 746
cm−1. 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J = 8.0 Hz, 1H), 7.90−
7.83 (m, 2H), 7.70 (d, J = 7.6 Hz, 1H), 7.57−7.47 (m, 3H), 7.29 (s,
1H), 2.59 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.3, 150.2,
133.9, 130.1, 129.3, 128.7, 126.9, 126.2, 126.1, 125.6, 125.3, 125.2,
124.9, 14.1. HRMS calcd for C14H11NO+ [M+]: 209.0841, found
209.0840.
2-Methyl-5-(4-methylphenyl)oxazole (3b).27 Light yellow solid
(46.2 mg, 89%). Mp 57−58 °C. IR (KBr): 2923, 1646, 1596, 1554,
1060, 956, 824, 817 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.49 (d, J =
8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.14 (s, 1H), 2.51 (s, 3H), 2.37
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.6, 151.3, 138.1, 129.5,
125.5, 123.9, 121.2, 21.3, 14.0.
5-(4-Ethynylphenyl)-2-methyloxazole (3m). Light yellow solid
(40.7 mg, 74%). Mp 119−120 °C. IR (KBr): 3291, 2926, 2127,
1
1593, 1578, 1059, 949, 743 cm−1. H NMR (400 MHz, CDCl3): δ
5-(4-Butylphenyl)-2-methyloxazole (3c). Light yellow oil (55.5 mg,
1
86%). IR (neat): 2927, 1651, 1597, 1548, 1063, 954, 826 cm−1. H
7.57−7.54 (m, 2H), 7.53−7.50 (m, 2H), 7.23 (s, 1H), 3.14 (s, 1H),
2.53 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.5, 150.4, 132.6,
128.4, 123.7, 122.9, 121.7, 83.3, 78.3, 14.1. HRMS calcd for C12H9NO+
[M+]: 183.0684, found 183.0678.
NMR (400 MHz, CDCl3): δ 7.50 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4
Hz, 2H), 7.14 (s, 1H), 2.61 (t, J = 7.8 Hz, 2H), 2.50 (s, 3H), 1.65−
1.55 (m, 2H), 1.41−1.30 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 160.7, 151.4, 143.1, 128.9, 125.7, 123.9, 121.2,
35.4, 33.5, 22.3, 14.0, 13.9. HRMS calcd for C14H17NO+ [M+]:
215.1310, found 215.1314.
5-Butyl-2-methyloxazole (3n). Light yellow oil (29.6 mg, 71%). IR
(neat): 2954, 1579, 1445, 1222, 1118, 750 cm−1. 1H NMR (400 MHz,
CDCl3): δ 6.57 (s, 1H), 2.59 (t, J = 7.6 Hz, 2H), 2.40 (s, 3H), 1.64−
1.56 (m, 2H), 1.41−1.32 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 160.1, 152.7, 121.8, 29.7, 25.2, 22.1, 13.9, 13.7.
HRMS calcd for C8H13NO+ [M+]: 139.0997, found 139.0989.
5-(3-Chloropropyl)-2-methyloxazole (3o). Light yellow oil (39.3
5-(4-Methoxyphenyl)-2-methyloxazole (3d).27 Light yellow solid
(52.2 mg, 92%). Mp 89−90 °C. IR (KBr): 2962, 2837, 1585, 1506,
1028, 832, 814, 750 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J =
8.8 Hz, 2H), 7.06 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.49
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.3, 159.6, 151.1, 125.5,
121.1, 120.3, 114.3, 55.3, 14.0.
1
mg, 82%). IR (neat): 2956, 1578, 1446, 1223, 1120, 749 cm−1. H
NMR (400 MHz, CDCl3): δ 6.65 (s, 1H), 3.57 (t, J = 6.4 Hz, 2H),
2.79 (t, J = 7.2 Hz, 2H), 2.41 (s, 3H), 2.13−2.03 (m, 2H). 13C NMR
(100 MHz, CDCl3): δ 160.6, 150.7, 122.8, 43.7, 30.5, 22.7, 13.9.
C7H10ClNO+ [M+]: 159.0451, found 159.0455.
2-Methyl-5-(3-methylphenyl)oxazole (3e).27 Light yellow oil (42.6
mg, 82%). IR (neat): 2925, 1643, 1587, 1546, 1083, 946, 816, 760
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.45−7.38 (m, 2H), 7.32−7.26
(m, 1H), 7.18 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 2.52 (s, 3H), 2.39 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 160.9, 151.3, 138.5, 128.9,
128.8, 128.1, 124.6, 121.8, 121.1, 21.4, 14.0.
2-Methyl-5-(3-phenylpropyl)oxazole (3p). Light yellow oil (53.1
mg, 88%). IR (neat): 2926, 1693, 1577, 1447, 1364, 1121, 751, 698
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.31−7.26 (m, 2H), 7.22−7.14
(m, 3H), 6.59 (s, 1H), 2.67 (t, J = 7.6 Hz, 2H), 2.61 (t, J = 7.4 Hz,
2H), 2.40 (s, 3H), 2.00−1.91 (m, 2H). 13C NMR (100 MHz, CDCl3):
δ 160.2, 152.2, 141.5, 128.5, 128.4, 126.0, 122.2, 35.1, 29.2, 24.9, 13.9.
HRMS calcd for C13H15NO+ [M+]: 201.1154, found 201.1159.
5-Cyclopropyl-2-methyloxazole (3q). Light yellow oil (28.1 mg,
5-(4-Chlorophenyl)-2-methyloxazole (3f).27 Light yellow solid
(43.0 mg, 74%). Mp 84−85 °C. IR (KBr): 2924, 1641, 1599, 1442,
1
1059, 941, 812 cm−1. H NMR (400 MHz, CDCl3): δ 7.56−7.51 (m,
2H), 7.41−7.34 (m, 2H), 7.19 (s, 1H), 2.52 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 161.3, 150.2, 133.9, 129.1, 126.7, 125.2, 122.3, 14.0.
5-(4-Bromophenyl)-2-methyloxazole (3g).27 Light yellow solid
(52.1 mg, 73%). Mp 82−83 °C. IR (KBr): 2922, 1664, 1574, 1550,
1360, 1077, 948, 817 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J
= 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.21 (s, 1H), 2.52 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 161.3, 150.2, 132.0, 127.1, 125.4, 122.4,
121.9, 14.1.
1
76%). IR (neat): 2972, 2359, 1614, 1569, 976, 750 cm−1. H NMR
(400 MHz, CDCl3): δ 6.55 (s, 1H), 2.38 (s, 3H), 1.86−1.79 (m, 1H),
0.91−0.76 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 159.7, 149.7,
121.0, 14.2, 13.9, 6.2. HRMS calcd for C7H9NO+ [M+]: 123.0684,
found 123.0691.
5-Cyclohexyl-2-methyloxazole (3r).11a Light yellow oil (41.6 mg,
1
84%). IR (neat): 2930, 2361, 1579, 1450, 1219, 754 cm−1. H NMR
5-(3-Chloro-4-methylphenyl)-2-methyloxazole (3h). Light yellow
oil (48.6 mg, 78%). IR (neat): 2923, 1639, 1579, 1472, 1063, 931, 822
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 1.6 Hz, 1H), 7.40−
7.35 (m, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 2.52 (s, 3H), 2.39
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 161.2, 150.0, 135.9, 135.0,
131.4, 127.4, 124.5, 122.2, 122.1, 19.9, 14.1. HRMS calcd for
C11H10ClNO+ [M+]: 207.0451, found 207.0446.
5-(4′-Ethylbiphenyl-4-yl)-2-methyloxazole (3i). White solid (66.4
mg, 84%). Mp 160−162 °C. IR (KBr): 2926, 1661, 1594, 1548, 1365,
1059, 942, 821 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.8
Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.28 (d, J
= 8.4 Hz, 2H), 7.22 (s, 1H), 2.69 (q, J = 7.6 Hz, 2H), 2.53 (s, 3H),
1.27 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 161.1, 151.0,
(400 MHz, CDCl3): δ 6.54 (s, 1H), 2.65−2.54 (m, 1H), 2.39 (s, 3H),
2.02−1.95 (m, 2H), 1.81−1.67 (m, 3H), 1.42−1.29 (m, 5H). 13C
NMR (100 MHz, CDCl3): δ 159.8, 157.1, 120.2, 35.2, 31.1, 26.0, 25.7,
13.9.
5-(2-Methyloxazol-5-yl)pentanoic Acid (3s).11a Light yellow solid
(45.6 mg, 83%). Mp 76−77 °C. IR (KBr): 3115, 2942, 2358, 1696,
1262, 751 cm−1. 1H NMR (400 MHz, CDCl3): δ 10.06 (br, 1H), 6.64
(s, 1H), 2.66−2.58 (m, 2H), 2.42 (s, 3H), 2.41−2.35 (m, 2H), 1.75−
1.66 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 177.6, 160.6, 152.2,
121.4, 33.8, 27.0, 25.2, 24.2, 13.7.
2-Methyl-5-[2-(tetrahydropyran-2-yloxy)ethyl]oxazole (3t).11a
Red brown oil (50.7 mg, 80%). IR (neat): 2942, 2873, 1579, 1384,
1
1123, 1035 cm−1. H NMR (400 MHz, CDCl3): δ 6.68 (s, 1H), 4.62
F
DOI: 10.1021/acs.joc.7b00386
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(t, J = 3.4 Hz, 1H), 4.00−3.91 (m, 1H), 3.85−3.74 (m, 1H), 3.70−
3.59 (m, 1H), 3.55−3.44 (m, 1H), 2.92 (t, J = 6.8 Hz, 2H), 2.41 (s,
3H), 1.85−1.76 (m, 1H), 1.74−1.66 (m, 1H), 1.61−1.47 (m, 4H). 13C
NMR (100 MHz, CDCl3): δ 160.4, 149.7, 123.1, 98.7, 64.9, 62.2, 30.5,
26.5, 25.4, 19.4, 13.9.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mzcai@jxnu.edu.cn.
ORCID
Mingzhong Cai: 0000-0002-1056-2846
Notes
The authors declare no competing financial interest.
■
2-Methyl-5-(thiophen-3-yl)oxazole (3u). Light yellow oil (38.7 mg,
1
78%). IR (neat): 2928, 2875, 1583, 1495, 1387, 1126, 1027 cm−1. H
NMR (400 MHz, CDCl3): δ 7.47−7.44 (m, 1H), 7.38−7.34 (m, 1H),
7.28−7.24 (m, 1H), 7.04 (s, 1H), 2.50 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 160.4, 148.0, 129.4, 126.7, 124.4, 121.4, 120.0, 14.0. HRMS
calcd for C8H7NOS+ [M+]: 165.0248, found 165.0253.
ACKNOWLEDGMENTS
2-Isopropyl-5-phenyloxazole (3v).27 Light yellow oil (50.1 mg,
■
1
89%). IR (neat): 2974, 1569, 1456, 1276, 748, 699 cm−1. H NMR
We thank the National Natural Science Foundation of China
(no. 21462021), the Natural Science Foundation of Jiangxi
Province of China (no. 20161BAB203086), and Key
Laboratory of Functional Small Organic Molecule, Ministry
of Education (no. KLFS-KF-201409) for financial support.
(400 MHz, CDCl3): δ 7.61 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.6 Hz,
2H), 7.29 (t, J = 7.4 Hz, 1H), 7.21 (s, 1H), 3.20−3.09 (m, 1H), 1.40
(d, J = 7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 168.7, 150.7,
128.8, 128.4, 128.1, 124.0, 121.6, 28.6, 20.5.
5-Cyclopropyl-2-isopropyloxazole (3w).11a Light yellow oil (39.1
mg, 86%). IR (neat): 2973, 2359, 1612, 1569, 976, 750 cm−1. 1H NMR
(400 MHz, CDCl3): δ 6.55 (s, 1H), 3.05−2.95 (m, 1H), 1.88−1.78
(m, 1H), 1.31 (d, J = 7.2 Hz, 6H), 0.92−0.88 (m, 2H), 0.77−0.70 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 167.4, 153.7, 120.7, 28.4, 20.4,
6.3, 6.2.
REFERENCES
■
(1) (a) Wipf, P. Chem. Rev. 1995, 95, 2115. (b) Hamada, Y.; Shioiri,
T. Chem. Rev. 2005, 105, 4441. (c) Jin, Z. Nat. Prod. Rep. 2013, 30,
869. (d) Heng, S.; Gryncel, K. R.; Kantrowitz, E. R. Bioorg. Med. Chem.
2009, 17, 3916. (e) Davyt, D.; Serra, G. Mar. Drugs 2010, 8, 2755.
(f) Walsh, C. T.; Malcolmson, S. J.; Young, T. S. ACS Chem. Biol.
2012, 7, 429. (g) Wilson, Z. E.; Fenner, S.; Ley, S. V. Angew. Chem.,
Int. Ed. 2015, 54, 1284.
(2) (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Clapham, B.;
Sutherland, A. J. J. Org. Chem. 2001, 66, 9033. (c) Chatani, N.;
Fukuyama, T.; Tatamidani, H.; Kakiuchi, F.; Murai, S. J. Org. Chem.
2000, 65, 4039. (d) Gissibl, A.; Finn, M. G.; Reiser, O. Org. Lett. 2005,
7, 2325.
(3) For selected examples, see: (a) Merkul, E.; Muller, T. J. J. Chem.
Commun. 2006, 4817. (b) Pan, Y.; Zheng, F.; Lin, H.; Zhan, Z. J. Org.
Chem. 2009, 74, 3148. (c) Zheng, Y.; Li, X.; Ren, C.; Zhang-Negrerie,
D.; Du, Y.; Zhao, K. J. Org. Chem. 2012, 77, 10353. (d) Cheung, C.
W.; Buchwald, S. L. J. Org. Chem. 2012, 77, 7526. (e) Wang, Y.-F.;
Chen, H.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134, 11980.
(f) Senadi, G. C.; Hu, W.-P.; Hsiao, J.-S.; Vandavasi, J.-K.; Chen, C.-Y.;
Wang, J.-J. Org. Lett. 2012, 14, 4478. (g) Hu, Y.; Yi, R.; Wang, C.; Xin,
X.; Wu, F.; Wan, B. J. Org. Chem. 2014, 79, 3052.
(4) For selected examples, see: (a) Cano, I.; Alvarez, E.; Nicasio, M.
C.; Perez, P. J. J. Am. Chem. Soc. 2011, 133, 191. (b) Wan, C.; Zhang,
J.; Wang, S.; Fan, J.; Wang, Z. Org. Lett. 2010, 12, 2338. (c) Shi, B.;
Blake, A. J.; Lewis, W.; Campbell, I. B.; Judkins, B. D.; Moody, C. J. J.
Org. Chem. 2010, 75, 152. (d) Li, X.; Huang, L.; Chen, H.; Wu, W.;
Huang, H.; Jiang, H. Chem. Sci. 2012, 3, 3463. (e) Odabachian, Y.;
Tong, S.; Wang, Q.; Wang, M.; Zhu, J. Angew. Chem., Int. Ed. 2013, 52,
10878. (f) Xu, Z.; Zhang, C.; Jiao, N. Angew. Chem., Int. Ed. 2012, 51,
11367. (g) Zheng, J.; Zhang, M.; Huang, L.; Hu, X.; Wu, W.; Huang,
H.; Jiang, H. Chem. Commun. 2014, 50, 3609. (h) Zhang, L.; Zhao, X.
Org. Lett. 2015, 17, 184.
(5) For selected examples, see: (a) Meyers, A. I.; Tavares, F. X. J. Org.
Chem. 1996, 61, 8207. (b) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.;
Williams, D. R. Org. Lett. 2000, 2, 1165. (c) Williams, D. R.; Lowder,
P. D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron Lett. 1997, 38, 331.
(d) Wang, Y.; Li, Z.; Huang, Y.; Tang, C.; Wu, X.; Xu, J.; Yao, H.
Tetrahedron 2011, 67, 7406. (e) Huang, Y.; Ni, L.; Gan, F.; He, Y.; Xu,
J.; Wu, X.; Yao, H. Tetrahedron 2011, 67, 2066. (f) Li, X.; Li, C.; Yin,
B.; Liu, P.; Li, J.; Shi, Z.; Li, C. Chem. - Asian J. 2013, 8, 1408.
(6) (a) Alberico, D.; Scott, M. K.; Lautens, M. Chem. Rev. 2007, 107,
174. (b) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2006,
8, 2495. (c) Lee, K.; Counceller, C. M.; Stambuli, J. P. Org. Lett. 2009,
11, 1457. (d) Williams, D. R.; Fu, L. F. Org. Lett. 2010, 12, 808.
(e) Zhang, M. L.; Zhang, S. H.; Liu, M. C.; Cheng, J. Chem. Commun.
2011, 47, 11522. (f) Shen, X.-B.; Zhang, Y.; Chen, W.-X.; Xiao, Z.-K.;
Hu, T.-T.; Shao, L.-X. Org. Lett. 2014, 16, 1984.
2-Benzyl-5-phenyloxazole (3x).27 Light yellow solid (52.9 mg,
75%). Mp 50−52 °C. IR (KBr): 2925, 2359, 1565, 1453, 1106, 751,
697 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.62−7.57 (m, 2H), 7.43−
7.24 (m, 9H), 4.18 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 162.6,
151.5, 135.5, 128.8, 128.7, 128.3, 128.2, 128.1, 127.1, 124.1, 122.0,
34.8.
2,5-Diphenyloxazole (3y).27 White solid (47.8 mg, 72%). Mp 74−
1
75 °C. IR (KBr): 2361, 1446, 1276, 1135, 762, 687 cm−1. H NMR
(400 MHz, CDCl3): δ 8.11 (dd, J = 7.4, 1.8 Hz, 2H), 7.74−7.71 (m,
2H), 7.51−7.41 (m, 6H), 7.34 (t, J = 7.4 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 161.2, 151.3, 130.3, 128.9, 128.8, 128.5, 128.1, 127.5,
126.3, 124.2, 123.5.
5-Butyl-2-phenyloxazole (3z). Light yellow oil (50.1 mg, 83%). IR
1
(neat): 3028, 2926, 1597, 1454, 1120, 750, 712 cm−1. H NMR (400
MHz, CDCl3): δ 8.00 (d, J = 7.2 Hz, 2H), 7.48−7.38 (m, 3H), 6.83 (s,
1H), 2.72 (t, J = 7.4 Hz, 2H), 1.73−1.64 (m, 2H), 1.48−1.38 (m, 2H),
0.96 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 160.6, 153.3,
129.8, 128.7, 127.9, 126.0, 123.6, 29.8, 25.4, 22.2, 13.7. HRMS calcd
for C13H15NO+ [M+]: 201.1154, found 201.1146.
5-tert-Butyl-2-phenyloxazole (3a′). Light yellow oil (37.4 mg,
1
62%). IR (neat): 2967, 2359, 1576, 1314, 955, 753 cm−1. H NMR
(400 MHz, CDCl3): δ 8.01 (dd, J = 8.0, 1.6 Hz, 2H), 7.46−7.38 (m,
3H), 6.79 (s, 1H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3): δ
161.0, 160.4, 129.9, 128.7, 128.0, 126.0, 121.0, 31.6, 28.8. HRMS calcd
for C13H15NO+ [M+]: 201.1154, found 201.1152.
2-(4-Methylphenyl)-5-phenyloxazole (3b′). White solid (49.4 mg,
70%). Mp 72−73 °C. IR (KBr): 2360, 1598, 1448, 1274, 1137, 764,
1
690 cm−1. H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.4 Hz, 2H),
7.74−7.67 (m, 2H), 7.46−7.39 (m, 3H), 7.35−7.23 (m, 3H), 2.40 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 161.4, 150.9, 140.7, 129.6,
128.9, 128.3, 128.1, 126.3, 124.8, 124.2, 123.4, 21.6. HRMS calcd for
C16H13NO+ [M+]: 235.0997, found 235.0992.
5-(4-Methoxyphenyl)-2-(thiophen-2-yl)oxazole (3c′).28 Light yel-
low solid (40.2 mg, 52%). Mp 91−92 °C. IR (KBr): 2965, 1574, 1503,
1496, 1025, 834, 817, 749 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.70
(dd, J = 3.6, 1.2 Hz, 1H), 7.62 (dd, J = 6.8, 2.0 Hz, 2H), 7.43−7.39 (m,
1H), 7.26 (s, 1H), 7.14−7.09 (m, 1H), 6.96 (dd, J = 6.8, 2.0 Hz, 2H),
3.84 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.9, 156.8, 150.9,
130.2, 128.0, 127.9, 127.3, 125.7, 121.8, 120.6, 114.4, 55.4.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00386.
(7) (a) Graham, T. H. Org. Lett. 2010, 12, 3614. (b) Saito, A.;
Taniguchi, A.; Kambara, Y.; Hanzawa, Y. Org. Lett. 2013, 15, 2672.
(c) Selvi, T.; Srinivasan, K. Chem. Commun. 2014, 50, 10845.
1
Copies of H and 13C NMR spectra for the products
(PDF)
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DOI: 10.1021/acs.joc.7b00386
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(d) Wang, B.; Chen, Y.; Zhou, L.; Wang, J.; Tung, C.-H.; Xu, Z. J. Org.
Chem. 2015, 80, 12718. (e) Zeng, T.-T.; Xuan, J.; Ding, W.; Wang, K.;
Lu, L.-Q.; Xiao, W.-J. Org. Lett. 2015, 17, 4070. (f) Chatterjee, T.;
Cho, J. Y.; Cho, E. J. J. Org. Chem. 2016, 81, 6995.
(8) For selected recent reviews of gold catalysis, see: (a) Gorin, D. J.;
Toste, F. D. Nature 2007, 446, 395. (b) Hashmi, A. S. K. Chem. Rev.
2007, 107, 3180. (c) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem.
Rev. 2008, 108, 3351. (d) Wegner, H. A.; Auzias, M. Angew. Chem., Int.
Ed. 2011, 50, 8236. (e) Corma, A.; Leyva-Perez, A.; Sabater, M. J.
Chem. Rev. 2011, 111, 1657. (f) Obradors, C.; Echavarren, A. M. Acc.
Chem. Res. 2014, 47, 902. (g) Dorel, R.; Echavarren, A. M. Chem. Rev.
2015, 115, 9028. (h) Huple, D. B.; Ghorpade, S.; Liu, R.-S. Adv. Synth.
Catal. 2016, 358, 1348.
2014, 395, 349. (d) Zhao, H.; He, W.; Wei, L.; Cai, M. Catal. Sci.
Technol. 2016, 6, 1488.
(22) Lindner, E.; Salesch, T.; Brugger, S.; Hoehn, F.; Wegner, P.;
Mayer, H. A. J. Organomet. Chem. 2002, 641, 165.
(23) (a) Ye, L.; He, W.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550.
(b) Ye, L.; He, W.; Zhang, L. Angew. Chem., Int. Ed. 2011, 50, 3236.
(24) Lempers, H. E. B.; Sheldon, R. A. J. Catal. 1998, 175, 62.
(25) (a) Li, G.; Zhang, L. Angew. Chem., Int. Ed. 2007, 46, 5156.
(b) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132,
3258. (c) Lu, B.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 14070.
(26) Yang, W.; Wei, L.; Yi, F.; Cai, M. Catal. Sci. Technol. 2016, 6,
4554.
(27) Ibata, T.; Sato, R. Bull. Chem. Soc. Jpn. 1979, 52, 3597.
(28) Pulici, M.; Quartieri, F.; Felder, E. R. J. Comb. Chem. 2005, 7,
463.
(9) (a) Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Angew. Chem.,
Int. Ed. 2011, 50, 8931. (b) Luo, Y.; Ji, K.; Li, Y.; Zhang, L. J. Am.
Chem. Soc. 2012, 134, 17412. (c) Chen, M.; Sun, N.; Chen, H.; Liu, Y.
Chem. Commun. 2016, 52, 6324.
(10) (a) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org.
Lett. 2004, 6, 4391. (b) Weyrauch, J. P.; Hashmi, A. S. K.; Schuster, A.;
Hengst, T.; Schetter, S.; Littmann, A.; Rudolph, M.; Hamzic, M.;
Visus, J.; Rominger, F.; Frey, W.; Bats, J. W. Chem. - Eur. J. 2010, 16,
956. (c) Hashmi, A. S. K.; Blanco Jaimes, M. C.; Schuster, A. M.;
Rominger, F. J. Org. Chem. 2012, 77, 6394. (d) Peng, H.; Akhmedov,
N. G.; Liang, Y.-F.; Jiao, N.; Shi, X. J. Am. Chem. Soc. 2015, 137, 8912.
(11) (a) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133, 8482.
(b) Rassadin, V. A.; Boyarskiy, V. P.; Kukushkin, V. Y. Org. Lett. 2015,
17, 3502.
(12) Querard, P.; Girard, S. A.; Uhlig, N.; Li, C.-J. Chem. Sci. 2015, 6,
7332.
(13) Loy, N. S. Y.; Choi, S.; Kim, S.; Park, C.-M. Chem. Commun.
2016, 52, 7336.
(14) (a) Cole-Hamilton, D. J. Science 2003, 299, 1702. (b) Akiyama,
R.; Kobayashi, S. Chem. Rev. 2009, 109, 594. (c) Climent, M. J.;
Corma, A.; Iborra, S. Chem. Rev. 2011, 111, 1072. (d) Molnar, A.
Chem. Rev. 2011, 111, 2251. (e) Yoon, M.; Srirambalaji, R.; Kim, K.
Chem. Rev. 2012, 112, 1196.
(15) (a) Kresge, C. T.; Leonowicz, M. E.; Roth, W. J.; Vartuli, J. C.;
Beck, J. S. Nature 1992, 359, 710. (b) Maschmeyer, T.; Rey, F.; Sankar,
G.; Thomas, J. M. Nature 1995, 378, 159. (c) Zhou, W.; Thomas, J.
M.; Shephard, D. S.; Johnson, B. F. G.; Ozkaya, D.; Maschmeyer, T.;
Bell, R. G.; Ge, Q. Science 1998, 280, 705. (d) Taguchi, A.; Schuth, F.
Microporous Mesoporous Mater. 2005, 77, 1. (e) Martin- Aranda, R. M.;
Cejka, J. Top. Catal. 2010, 53, 141.
(16) Beck, J. S.; Vartuli, J. C.; Roth, W. J.; Leonowicz, M. E.; Kresge,
C. T.; Schmitt, K. D.; Chu, C. T.-W.; Olson, D. H.; Sheppard, E. W.;
McCullen, S. B.; Higgins, J. B.; Schlenker, J. L. J. Am. Chem. Soc. 1992,
114, 10834.
(17) For selected examples, see: (a) Mehnert, P. C.; Weaver, D. W.;
Ying, J. Y. J. Am. Chem. Soc. 1998, 120, 12289. (b) Mukhopadhyay, K.;
Sarkar, B. R.; Chaudhari, R. V. J. Am. Chem. Soc. 2002, 124, 9692.
(c) Baleizao, C.; Corma, A.; Garcia, H.; Leyva, A. J. Org. Chem. 2004,
69, 439. (d) Cai, M.; Zheng, G.; Ding, G. Green Chem. 2009, 11, 1687.
(e) Cai, M.; Peng, J.; Hao, W.; Ding, G. Green Chem. 2011, 13, 190.
(f) Hao, W.; Liu, H.; Yin, L.; Cai, M. J. Org. Chem. 2016, 81, 4244.
(18) Shyu, S.-G.; Cheng, S.-W.; Tzou, D.-L. Chem. Commun. 1999,
2337.
(19) (a) Jia, M.; Seifert, A.; Thiel, W. R. Chem. Mater. 2003, 15, 2174.
(b) Nunes, C. D.; Valente, A. A.; Pillinger, M.; Fernandes, A. C.;
Romao, C. C.; Rocha, J.; Goncalves, I. S. J. Mater. Chem. 2002, 12,
1735.
(20) (a) Gonzalez-Arellano, C.; Corma, A.; Iglesias, M.; Sanchez, F.
Adv. Synth. Catal. 2004, 346, 1758. (b) Corma, A.; Gutierrez-Puebla,
E.; Iglesias, M.; Monge, A.; Perez-Ferreras, S.; Sanchez, F. Adv. Synth.
Catal. 2006, 348, 1899. (c) Villaverde, G.; Corma, A.; Iglesias, M.;
Sanchez, F. ACS Catal. 2012, 2, 399.
(21) (a) Xiao, R.; Zhao, H.; Cai, M. Tetrahedron 2013, 69, 5444.
(b) Zhao, H.; He, W.; Yao, R.; Cai, M. Adv. Synth. Catal. 2014, 356,
3092. (c) Cai, M.; Yao, R.; Chen, L.; Zhao, H. J. Mol. Catal. A: Chem.
H
DOI: 10.1021/acs.joc.7b00386
J. Org. Chem. XXXX, XXX, XXX−XXX