Three-Component [2+2+1] Gold(I)-Catalyzed Oxidative Generation of Fully Substituted 1,3-Oxazoles Involving Internal Alkynes

Article abstract of DOI:10.1002/adsc.201900097

Three-component [2+2+1] gold(I)-catalyzed reaction of internal alkynes (alkynyl esters or -ketones), nitriles, and 2-chloropyridine N-oxide led to a wide range of fully substituted 1,3-oxazoles (32 examples; up to 92% isolated yields). Nitrile R³

Full text of DOI:10.1002/adsc.201900097

Title: Three component [2+2+1] Gold(I)-catalyzed Oxidative Generation
of Fully Substituted 1,3-Oxazoles Involving Internal Alkynes
Authors: Vadim Kukushkin, Dmitry Dar'in, and Alexey Dubovtsev
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900097
Link to VoR: http://dx.doi.org/10.1002/adsc.201900097

10.1002/adsc.201900097
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Three-Component [2+2+1] Gold(I)-Catalyzed Oxidative
Generation of Fully Substituted 1,3-Oxazoles Involving Internal
Alkynes
Alexey Yu. Dubovtsev,* Dmitry V. Dar’in, Vadim Yu. Kukushkin*
Saint Petersburg State University, Universitetskaya Nab. 7/9, 199034 Saint Petersburg, Russian Federation
E-mails: a.dubovtsev@spbu.ru (A.Yu.D.), v.kukushkin@spbu.ru (V.Yu.K.)
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Three-component [2+2+1] gold(I)-catalyzed thiocyanate (R3 = SPr). The advantages of the developed
reaction of internal alkynes (alkynyl esters or -ketones), method include mild reaction conditions, high functional-
nitriles, and 2-chloropyridine N-oxide led to a wide range of group tolerance, broad range of substituents R1/R3 along
fully substituted 1,3-oxazoles (32 examples; up to 92% with a possibility of easy modification of COR2 or the
isolated yields). Nitrile R3CN species, employed in the amino group when R1 = NH2.
reaction as both reactants and solvents, comprise
conventional nitriles (R3 = Alk, Ar) and also push-pull
Keywords: Homogeneous catalysis; Heterocycles;
systems such as cyanamides (R3 = NH2 and NAlk2) and the
Oxidation, Gold catalysts; Synthetic methods
increasing attention as these species are widespread
Introduction
in natural objects and, furthermore, numerous
synthetic oxazoles exhibit some useful biological
Today, homogeneous catalysis involving gold(I)
activity modes.[7] Hence, the development of new
species comprises one of the most effective methods
effective synthetic strategies for assembly of highly
for the activation of alkynes leading to a substantial
substituted 1,3-oxazole framework is quite desirable.
diversity of follow-up chemical transformations.[1] In
Some [2+2+1] methodologies using alkynes for the
particular, Au-catalyzed reactions of acetylenes are
synthesis of 1,3-oxazoles have recently been
successfully utilized in the synthesis of various carbo-
developed.[8] Zhang et al. reported an intermolecular
and heterocyclic structures, including natural
AuI-catalyzed reaction that proceeds via gold α-oxo
compounds.[2] Intermolecular transformations of
carbene intermediate to grant 2,5-disubstituted 1,3-
alkynes that utilize gold α-oxo carbenes generated in
oxazoles (for alternative AuI-catalyzed synthesis see
situ are of special interest due to the possibility of a
ref.[9]) from terminal alkynes, nitriles, and 8-
facile growth of the molecular complexity using
methylquinoline N-oxide; the latter serves as an
relatively small building blocks.[3] Although the
oxygen donor.[10] Some of us extended this strategy to
reactions of α-oxo carbenes derived from terminal
such specific nitriles as cyanamides and employed
alkynes are studied rather actively,[4] only a few
these species for the (terminal alkyne)-based MsOH-
examples of relevant transformations of internal
supported synthesis of 2-amino-1,3-oxazoles; these
alkynes are known[5] and, moreover, these examples
heterocyclic systems are difficult to obtain by other
are limited to the usage of highly reactive internal
methods.[11] These two Au-catalyzed reactions were
ynamides,[5b,c] or electron-deficient alkynes.[5d]
unsuccessful for relevant transformations of internal
Internal and terminal alkynes possess the same
alkynes thereby not allowing the synthesis of fully
CC group, but in many instances, their reactivities
substituted oxazoles.
are different. This is because some reactions with
Herein we report our observations on the gold-
terminal alkynes proceed via intermediate generation
catalyzed oxidation of internal alkynes for generation
of acetylide and this is not feasible for internal
of 2,4,5-trisubstituted 1,3-oxazoles.
alkynes. On the other hand, different steric/electronic
properties of the two types of alkynes also affect an
outcome of the reaction. The lower reactivity and
Results and Discussion
reduced regioselectivity[5d,6] of internal alkynes
compared with terminal species is a weak point of the
vast majority of gold-catalyzed syntheses and
therefore application of internal alkynes as substrates
form further transformations is challenging.
In order to develop a useful approach to the synthesis
of 2,4,5-trisubstituted 1,3-oxazoles, we have
attempted to apply internal alkynes seemingly
unreactive toward the heterocyclization. We found
that diphenylacetylene 1, taken as a suitable model,
under the Zhang reaction conditions [8-
In the context of the current work, it is noteworthy
that 1,3-oxazole derivatives have attracted an
1
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10.1002/adsc.201900097
Advanced Synthesis & Catalysis
methylquinoline N-oxide (1.3 equiv), Ph3PAuNTf2 (5
mol %), MeCN, 60 °C, 2h] delivered only 1,2-
diphenylethane-1,2-dione 2 (87% relatively to the N-
oxide) (Scheme 1, a) as a result of the diketonization.
The usage of internal ynamide 3 (Scheme 1, b) also
led to the diketonization of the alkyne moiety and α-
keto imide 4 was obtained in almost quantitative
(96%) yield. Gold(I)-catalyzed diketonization of
diarylalkynes and internal ynamides with either N-
oxides or sulfoxides has been previously reported.[12]
In these cases, the performed experiments do not
prove the generation of gold α-oxo carbene
intermediates.[12a] Our attempts to employ mono- and
dialkyl-substituted internal acetylenes in the
heterocyclization also failed, probably because of
facile side reactions, e.g. 1,2-CH insertions.[5a]
oxides.[5a,11,14] However, the usage of 1 equiv. of
MsOH leads to a significant reduction of the yield
(Entry 7).
Because of the electron-deficiency of the substrate,
we expected the reduced ability of propiolate 5 for
coordination with Ph3PAu+ species that prompted us
to employ the powerful σ-donating NHC ligand,
namely
IPr[15]
(1,3-bis(2,6-diisopropylphenyl)-
imidazol-2-ylidene). Indeed, the replacement of
Ph3PAuNTf2
IPrAuCl/AgNTf2 (a molar ratio 1:1) allowed the
by
the catalytic system
Table 1. Optimization of the reaction conditions.a)
Owing the availability of alkynyl esters and
because the electron withdrawing ester group can
contribute to the increase of the electrophilicity[13] of
the gold α-oxo carbene, we examined ethyl 3-
phenylpropiolate 5 as the acetylene component of the
reaction featuring the structure-directing group. We
found that target ethyl 2-methyl-5-phenyloxazole-4-
carboxylate 6 can be initially obtained in 50% yield
(before the optimization; see later) as a result of the
heterocyclization (Scheme 1, c).
We began optimizing the reaction conditions
(Table 1) by testing several N-oxides 7a–e as sources
of O atom in the nucleophilic oxygenation. The best
results were obtained using electron-deficient N-
oxides 7e,f (Entries 5,6) and one of them, 2-
chloropyridine N-oxide 7e, was chosen for further
study. The introduction of acid additives to prevent
poisoning of the catalyst is one of the most common
methods for increasing the efficiency of gold-
catalyzed nucleophilic oxygenation of alkynes by N-
Entry Catalyst
N-
Temp Time Yield
oxide (°C)
(h)
(%)b)
50
1
Ph3PAuNTf2
60
60
60
60
60
60
60
60
60
60
60
80
80
80
RT
80
80
80
80
2
7a
7b
7c
7d
7e
7f
2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgOTf
AgOTf
2
15
3
2
40
4
2
30
5
2
62
6
2
57
45c)
7
2
7e
7e
7e
7e
7e
7e
8
2
74
9
2
76
10
11
12
13
14
15
16
17
18
2
–
TfOH
2
–
IPrAuCl/AgOTf
6
82
88d)
71e)
51
58f)
23g)
38h)
IPrAuCl/AgOTf 7e
6
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
IPrAuCl/AgOTf
6
7e
7e
7e
7e
7e
7e
72
6
6
6
19
6
33i)
a)
b)
All reactions were carried out at a 0.2 mmol scale (0.4 M). Isolated
yield. c) MsOH (1 equiv.) was used. d) 1.1 equiv. of 7e was used. e) 2 equiv.
f)
g)
of 7e was used. 3 mol % of IPrAuCl/AgOTf was used. 10 equiv. of
MeCN was used, PhCl was taken as a solvent. h) 10 equiv. of MeCN was
i)
Scheme 1. Initial attempts of heterocyclization of internal
used, DCE was used as a solvent. 10 equiv. of MeCN was used, THF
alkynes.
was used as a solvent.
2
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10.1002/adsc.201900097
Advanced Synthesis & Catalysis
Table 2. Reactivity screenings for nitrile substrates 10.a),b)
increase of the yield to 74%. Replacing AgNTf2 in
the catalytic system with AgOTf increased the yield
by only 2% (Entry 9). The catalytic role of gold in
this heterocyclization was confirmed by the inability
of either AgOTf or TfOH alone to catalyze this
reaction (Entries 10,11). The yield was further
improved to 82% by increasing of both temperature
(from 60 to 80 °C) and the reaction time (from 2 to 6
h) (Entry 12). Although under these conditions the
complete alkyne conversion was achieved, but by-
product derived from over-oxidation 8 (Table 1) was
formed (16% isolated yield). A decrease in the
amount of the N-oxide (1.3 to 1.1 equiv; reducing the
amount to 1.0 gave a slightly poorer yield) leads to an
increase in the proportion of oxazole 6 (88%) and, on
the contrary, increasing the amount of the N-oxide to
2 equiv. leads to an increase in the proportion of by-
product 8 (28%) (Entries 13,14). The reaction at
20 °C was much slower and the oxazole yield
obtained after 72 h was somewhat lower (51%).
Using lower catalyst loading (3 mol %) also leads to
a significant reduction in the efficiency of the
reaction (Entry 16). Unfortunately, our attempts to
use solvents other than acetonitrile as the reaction
medium (PhCl, DCE, or THF) were less successful
even with a 10-fold excess of MeCN (Entries 17–19).
Summarizing, the best results were obtained with 1.1
equiv of 2-chloropyridine N-oxide and 5 mol % of
IPrAuCl/AgOTf in MeCN (as both the reactant and
solvent[16]) at 80 °C for 6 h.
With the optimal conditions at hand, the reaction
scope was then examined. First, a range of nitriles
was tested using ethyl and methyl 3-phenylpropiolate
taken as the alkyne component (Table 2). Nitriles
with various saturated aliphatic (primary, secondary,
tertiary, cyclic) substituents reacted to grant
corresponding oxazoles 11a–h in good yields (58–
91%). The reaction is tolerant to functional
substituents (MeO, CO2Et, Cl), however, in the case
of less reactive electron-deficient nitriles, the yield of
the oxazoles decreases and the over-oxidation of
alkynes to tricarbonyl compounds becomes prevalent.
Thus, when γ-chlorobutyronitrile was employed, a
ratio of oxazole 11h and by-product 8 was 3:2, and
when trichloroacetonitrile was tested, 8 was the only
reaction product (84% yield relative to the N-oxide).
Conducting the reactions under water-free conditions
does not affect the ratio between the heterocyclization
and over-oxidation products. The reaction also
worked well with unsaturated and aromatic nitriles.
These results encouraged us to study a specific push-
pull class of RCN species, namely cyanamides, as
solvents and reactants. To our delight 2-amino-1,3-
oxazoles 11m–p were obtained in acceptable yields
including compounds featuring such azaheterocyclic
fragments as piperidine and morpholine or even the
unprotected NH2-group. The solid state structure of 2-
a)
b)
All reactions were carried out at a 0.2 mmol scale (0.4 M). Isolated
yield. c) Ph3AuNTf2 10 mol %, 16 h.
Figure 1. ORTEP drawing of compound 11p (CCDC
1891862)
displacement ellipsoids.
showing
50%
probability
amplitude
amino-1,3-oxazole
11p
studied
by
X-ray
crystallography (Figure 1).[17] In addition, another
type of push-pull nitriles, propyl thiocyanate, can also
be used in the heterocyclization and 2-propylthio-
substituted oxazole 11q was obtained in 37% yield
using larger (10 mol %) catalyst loading. Although
the yield of the reaction involving the thiocyanate is
moderate, this gold(I)-catalyzed heterocyclization can
still be considered as successful taking into account
the high affinity of gold centers to sulfur[18] that
3
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10.1002/adsc.201900097
Advanced Synthesis & Catalysis
usually leads to poisoning of gold-containing
catalysts.[19] In addition, number of synthetic
approaches toward 2-thio- substituted 4-acyl-1,3-
oxazoles is quite limited.[20]
To further determine the substrate scope, several
alkynes were tested using acetonitrile as the reaction
partner (Table 3). The yield of the oxazoles bearing
electron-withdrawing groups (NO2, CN, F), as a rule,
is significantly higher in comparison with products
featuring electron-donating (Me, OMe) fragments in
the aromatic substituent; a significant amount of
over-oxidation products was detected in the latter
case. A good yield was also obtained in the case of
the ortho-substituted substrate (13g). This reaction
also permitted the use of heteroaryl- and alkyl 3-
substituted propiolates or even unsubstituted methyl
propiolate, and good to moderate yields were
achieved (13h,i,j). Our reaction conditions could also
be applied for the heterocyclization of alkynyl ketone
(such as 1,3-diphenylprop-2-yn-1-one) as a substrate
in the synthesis of 4-benzoyl-substituted oxazoles
(13k,l). 4-Phenylbut-3-yn-2-one (12m) under the
reaction conditions is converted to isomeric oxazoles
13m and 13m’ (overall yield 62%; Scheme 2). For
Scheme 2. Synthesis of isomeric oxazoles 13m and 13m’.
the
asymmetrically
substituted
alkynones
PhCOС≡СC6H4R-4 (R = OMe, NO2), the formation
of two isomeric aroyloxazoles is also possible.
However, in the latter two cases the prevailing
process is over-oxidation and the total yield of the
corresponding oxazole does not exceed 10%.
A plausible mechanism of the heterocyclization is
given on Scheme 3. First, coordination of the π-acidic
cationic gold fragment to the triple bond gives an
Scheme 3. A plausible mechanism for generation of 6, 8,
11, and 13.
alkyne complex (A). The formed gold-bound alkyne
intermediate undergoes nucleophilic oxygenation by
a pyridine N-oxide via an addition–elimination
process. It is believed that the availability of the IPr
ligand that—as a representative of diaminocarbenes
exhibits superior donor properties[21]—provides only
moderate electrophilic activation of the CC triple
bond.
Table 3. Reactivity screenings for alkyne substrates 12.a),b)
Next, the nucleophilic attack by nitrile 10 on the
reactive gold carbene intermediate B affords the
intermediate C cyclizing, finally, to oxazoles 6, 11,
and 13 with regeneration of the catalyst. The
formation of by-product 8 is likely due to the
interaction between gold oxo-carbene B with another
molecule of N-oxide followed by the hydration of
tricarbonyl D; a similar rhodium-catalyzed synthesis
of 1,2,3-tricarbonyl compounds from diazo species
has been previously described.[22]
The difference in the reactivity of internal alkynes
3 and 5 and alkynyl ethers (or ketones) is probably
due to the stabilizing effect of the electron-
withdrawing ester (or ketone) substituents at the α-
oxo carbene intermediate that makes the carbene-
involving reaction preferable.
Conclusions
a)
b)
All reactions were carried out at a 0.2 mmol scale (0.4 M). Isolated
yield.
4
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10.1002/adsc.201900097
Advanced Synthesis & Catalysis
IPrAuCl (6.2 mg, 10.0 μmol, 5 mol %) and AgOTf (2.6 mg,
10.0 μmol, 5 mol %) were added to the solution of alkyne
5 or 9 (0.2 mmol) and 2-chloropyridine N-oxide (28.5 mg,
0.22 mmol, 1.1 equiv) in nitrile species 10 (1.0 mL). The
resulting mixture was stirred at 80 °C for 6 h or overnight.
After cooling, the solvent was then removed in vacuo. The
residue was purified by silica gel chromatography eluting
with Hexane/EtOAc (gradient from 8:1 to pure EtOAc) to
afford target oxazoles 6, 11, 13.
In summary, motivated by the wish to enhance very
low reactivity (or even its absence) of internal
alkynes in the reactions involving gold α-oxo
carbenes and to employ these alkynes for the
synthesis of 1,3-oxazoles, we have developed a facile
method for direct preparations of a diverse range of
fully-substituted oxazoles from alkynyl esters (or
ketones), various nitrile systems, and 2-
chloropyridine N-oxide – the latter was taken as an
oxygen donor. In addition to conventional nitriles,
push-pull nitriles such as cyanamides and
thiocyanates can also be used as both reagents and
solvents. The advantages of our method include mild
reaction conditions and a wide scope of obtained
oxazoles bearing multiple useful functionalities and,
e.g. the possibility of introducing unsubstituted NH2
group at 2nd position of the heterocycles allows the
possibility of significant modification the prepared
oxazoles.[23] Moreover, the presence of ester- or
ketone substituent at 4th position of the oxazole ring
opens up additional possibilities for alteration of the
prepared oxazoles via reduction[24] or by hydrolysis–
decarboxylation followed by CH-functionalization.[25]
Further studies of the mechanism of the observed
reaction and efforts to develop the utility in a variety
of synthetic applications of the transformations of
gold α-oxo carbenes are ongoing in our group.
Ethyl 2-methyl-5-phenyloxazole-4-carboxylate (6)[26]
was obtained from ethyl 3-phenylpropiolate (5) (34.8 mg,
0.2 mmol) and acetonitrile as a colorless solid (40.7 mg,
88%); mp 64.5–65.5 °C (hexane/ethyl acetate); Rf 0.35
1
(hexane/ethyl acetate 2:1); H NMR (400 MHz, CDCl3) δ
8.03–8.00 (m, 2H, Ph), 7.46–7.38 (m, 3H, Ph), 4.39 (q, J =
7.1 Hz, 2H, CH2), 2.53 (s, 3H, Me), 1.37 (t, J = 7.1 Hz, 3H,
MeCH2); 13C NMR (100 MHz, CDCl3) δ 162.2, 159.9,
155.3, 130.2, 128.4, 128.3, 127.1, 126.9, 61.3, 14.4, 13.9;
+
HRMS (ESI): m/z [M + Na]+ calcd. for C13H13NNaO3 :
254.0788; found: 254.0791.
Ethyl 2,2-dihydroxy-3-oxo-3-phenylpropanoate (8)[27]
was obtained from ethyl 3-phenylpropiolate (5) (34.8 mg,
0.2 mmol) and 2,2,2-trichloroacetonitrile as a yellowish oil
(18.2 mg, 75% relative to the N-oxide); Rf 0.40
(hexane/ethyl acetate 2:1); hydrate form:keto form =
1
84:16; H NMR for hydrate form (400 MHz, CDCl3) δ
8.09–8.06 (m, 2H, Ph), 7.62 (t, J = 7.4 Hz, 1H, Ph), 7.49–
7.45 (m, 2H, Ph), 5.35 (br. s, 2H, 2OH), 4.21 (q, J = 7.1 Hz,
2H, CH2), 1.08 (t, J = 7.1 Hz, 3H, Me); 13C NMR for
hydrate form ( (100 MHz, CDCl3) δ 191.7, 170.0, 134.8,
131.5, 130.3, 128.9, 91.8, 63.3, 13.8; HRMS for keto form
+
(ESI): m/z [M + Na]+ calcd. for C11H10NaO4 : 229.0471;
found: 229.0482.
Methyl
2-methyl-5-phenyloxazole-4-carboxylate
Experimental Section
(11a)[28] was obtained from methyl 3-phenylpropiolate (9)
(32.0 mg, 0.2 mmol) and acetonitrile as a colorless solid
(36.9 mg, 85%); mp 76.0–77.0 °C (hexane/ethyl acetate);
Initial attempts of heterocyclization of internal alkynes;
synthesis and characterization of diketo compounds 2,
4
1
Rf 0.25 (hexane/ethyl acetate 2:1); H NMR (400 MHz,
CDCl3) δ 8.06–8.03 (m, 2H, Ph), 7.47–7.40 (m, 3H, Ph),
3.92 (s, 3H, MeO), 2.54 (s, 3H, Me); 13C NMR (100 MHz,
CDCl3) δ 162.7, 159.9, 155.5, 130.3, 128.5, 128.3, 127.1,
126.7, 52.3, 13.9; HRMS (ESI): m/z [M + Na]+ calcd. for
Ph3PAuNTf2 (9.2 mg, 12.5 μmol, 5 mol %) was added to
the solution of diphenylacetylene 1 or N-methyl-2-oxo-2-
+
phenyl-N-tosylacetamide
3
(250 μmol) and 8-
C12H11NNaO3 : 240.0631; found: 240.0643.
methylquinoline N-oxide (51.7 mg, 325 μmol, 1.3 equiv)
in acetonitrile (1.0 mL). The resulting mixture was stirred
at 60 °C for 2 h. After cooling, the solvent was then
removed in vacuo. The residue was purified by silica gel
chromatography eluting with Hexane/EtOAc (gradient
from 12:1 to 4:1) to afford diketo compounds 2, 4.
Ethyl 2-ethyl-5-phenyloxazole-4-carboxylate (11b)[26]
was obtained from ethyl 3-phenylpropiolate (5) (34.8 mg,
0.2 mmol) and propionitrile as a colorless solid (44.6 mg,
91%); mp 36–37 °C (hexane/ethyl acetate); Rf 0.30
1
(hexane/ethyl acetate 4:1); H NMR (400 MHz, CDCl3) δ
8.04–8.01 (m, 2H, Ph), 7.48–7.41 (m, 3H, Ph), 4.41 (q, J =
7.1 Hz, 2H, CH2O), 2.89 (q, J = 7.6 Hz, 2H, CH2), 1.40 (t,
J = 7.6 Hz, 3H, MeCH2), 1.39 (t, J = 7.1 Hz, 3H,
MeCH2O); 13C NMR (100 MHz, CDCl3) δ 164.3, 162.4,
155.2, 130.2, 128.4 (×2), 127.4, 126.9, 61.4, 21.8, 14.4,
1,2-Diphenylethane-1,2-dione (2)[12a]: yellow solid (29.7
mg, 87% relative to the N-oxide); mp 94.5–95.5 °C
(hexane/ethyl acetate); Rf 0.30 (hexane/ethyl acetate 12:1);
1H NMR (400 MHz, CDCl3) δ 7.99–7.97 (m, 4H, Ar), 7.66
(t, J = 7.4 Hz, 2H, Ar), 7.51 (t, J = 7.8 Hz, 4H, Ar); 13C
NMR (100 MHz, CDCl3) δ 194.7, 135.0, 133.2, 130.0,
11.4; HRMS (ESI): m/z [M
+
Na]+ calcd. for
+
C14H15NNaO3 : 268.0944; found: 268.0949.
129.2; HRMS (ESI): m/z [M
+
Na]+ calcd. for
+
C14H10NaO2 : 233.0573; found: 233.0578.
Ethyl
2-isopropyl-5-phenyloxazole-4-carboxylate
(11c)[29] was obtained from ethyl 3-phenylpropiolate (5)
(34.8 mg, 0.2 mmol) and isobutyronitrile as a colorless
solid (36.8 mg, 71%); mp 41.0–42.0 °C (hexane/ethyl
N-methyl-2-oxo-2-phenyl-N-tosylacetamide
(4)[12b]
:
colorless solid (49.5 mg, 96% relative to the N-oxide); mp
106.5–108.5 °C (hexane/ethyl acetate); Rf 0.35
1
acetate); Rf 0.40 (hexane/ethyl acetate 4:1); H NMR (400
1
(hexane/ethyl acetate 4:1); H NMR (400 MHz, CDCl3) δ
MHz, CDCl3) δ 8.02–7.99 (m, 2H, Ph), 7.47–7.40 (m, 3H,
Ph), 4.40 (q, J = 7.1 Hz, 2H, CH2), 3.20 (hept, J = 7.0 Hz,
1H, CH), 1.42 (s, 3H, Me), 1.40 (s, 3H, Me), 1.38 (t, J =
7.1 Hz, 3H, MeCH2); 13C NMR (100 MHz, CDCl3) δ 167.3,
162.5, 154.9, 130.1, 128.5, 128.4, 127.5, 126.8, 61.4, 28.6,
20.5, 14.4; HRMS (ESI): m/z [2M + Na]+ calcd. for
7.94 (d, J = 7.0 Hz, 2H, Ar), 7.89 (d, J = 8.4 Hz, 2H, Ar),
7.65 (t, J = 7.5 Hz, 1H, Ar), 7.53 (t, J = 7.7 Hz, 2H, Ar),
7.40 (d, J = 8.1 Hz, 2H, Ar), 3.24 (s, 3H, MeN), 2.47 (s,
3H, Me); 13C NMR (100 MHz, CDCl3) δ 188.2, 167.4,
146.0, 134.6, 133.6, 133.0, 130.3, 129.8, 129.0, 128.6, 30.9,
+
21.9; HRMS (ESI): m/z [M
+
Na]+ calcd. for
C30H34N2NaO6 : 541.2309; found: 541.2303.
C16H15NNaO4S+: 340.0614; found: 340.0609.
Ethyl
2-(tert-butyl)-5-phenyloxazole-4-carboxylate
General procedure for the gold(I)-catalyzed synthesis
of oxazoles 6, 11, 13 and tricarbonyl compound 8
(11d) was obtained from ethyl 3-phenylpropiolate (5) (34.8
mg, 0.2 mmol) and pivalonitrile as a colorless solid (31.7
mg, 58%); mp 82.0–83.0 °C (hexane/ethyl acetate); Rf 0.45
1
(hexane/ethyl acetate 4:1); H NMR (400 MHz, CDCl3) δ
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900097
Advanced Synthesis & Catalysis
8.00–7.96 (m, 2H, Ph), 7.48–7.40 (m, 3H, Ph), 4.40 (q, J =
7.1 Hz, 2H, CH2), 1.46 (s, 9H, 3Me), 1.37 (t, J = 7.1 Hz,
3H, MeCH2); 13C NMR (100 MHz, CDCl3) δ 169.7, 162.6,
154.8, 130.1, 128.5, 128.4, 127.6, 126.8, 61.4, 34.0, 28.6,
8.19–8.15 (m, 2H, Ph), 8.12–8.09 (m, 2H, Ph), 7.53–7.45
(m, 6H, Ph), 4.46 (q, J = 7.1 Hz, 2H, CH2), 1.43 (t, J = 7.1
Hz, 3H, Me); 13C NMR (100 MHz, CDCl3) δ 162.4, 160.0,
155.2, 131.2, 130.4, 128.9, 128.7, 128.5, 128.46, 127.3,
127.0, 126.6, 61.6, 14.4; HRMS (ESI): m/z [M + H]+ calcd.
14.4; HRMS (ESI): m/z [2M
+
Na]+ calcd. for
+
+
C32H38N2NaO6 : 569.2622; found: 569.2646.
for C18H16NO3 : 294.1125; found: 294.1125.
Ethyl
2-cyclopropyl-5-phenyloxazole-4-carboxylate
Ethyl 5-phenyl-2-(4-tolyl)oxazole-4-carboxylate (11k)[31]
was obtained from ethyl 3-phenylpropiolate (5) (34.8 mg,
0.2 mmol) and 4-methylbenzonitrile (500 mg) as a
colorless solid (32.6 mg, 53%); mp 84.0–85.0 °C
(hexane/ethyl acetate); Rf 0.50 (hexane/ethyl acetate 4:1);
1H NMR (400 MHz, CDCl3) δ 8.12–8.10 (m, 2H, Ar), 8.05
(d, J = 8.3 Hz, 2H, Ar), 7.52–8.44 (m, 3H, Ar), 7.29 (d, J =
8.0 Hz, 2H, Ar), 4.46 (q, J = 7.1 Hz, 2H, CH2), 2.42 (s, 3H,
Me), 1.42 (t, J = 7.1 Hz, 3H, MeCH2); 13C NMR (100
MHz, CDCl3) δ 162.5, 160.2, 154.9, 141.6, 130.3, 129.7,
128.7, 128.5, 128.4, 127.4, 127.0, 123.8, 61.6, 21.7, 14.4;
(11e) was obtained from ethyl 3-phenylpropiolate (5) (34.8
mg, 0.2 mmol) and cyclopropanecarbonitrile as a colorless
solid (42.2 mg, 82%); mp 70.0–71.0 °C (hexane/ethyl
1
acetate); Rf 0.40 (hexane/ethyl acetate 2:1); H NMR (400
MHz, CDCl3) δ 7.98–7.94 (m, 2H, Ph), 7.45–7.38 (m, 3H,
Ph), 4.39 (q, J = 7.1 Hz, 2H, OCH2), 2.16 (tt, J = 8.4, 5.0
Hz, 1H, CH), 1.37 (t, J = 7.1 Hz, 3H, Me), 1.20–1.13 (m,
2H, CH2), 1.12–1.06 (m, 2H, CH2); 13C NMR (100 MHz,
CDCl3) δ 164.4, 162.3, 154.4, 130.0, 128.4, 128.3, 127.3,
127.1, 61.3, 14.4, 9.0, 8.5; HRMS (ESI): m/z [M + H]+
+
+
calcd. for C15H16NO3 : 258.1125; found: 258.1132.
HRMS (ESI): m/z [M + H]+ calcd. for C19H18NO3 :
308.1281; found: 308.1281.
Ethyl
2-(2-methoxyethyl)-5-phenyloxazole-4-
carboxylate (11f) was obtained from ethyl 3-
phenylpropiolate (5) (34.8 mg, 0.2 mmol) and 3-
methoxypropanenitrile as a colorless oil (40.2 mg, 73%);
Ethyl 5-phenyl-2-(3-(trifluoromethyl)phenyl)oxazole-4-
carboxylate (11l) was obtained from ethyl 3-
phenylpropiolate (5) (34.8 mg, 0.2 mmol) and 3-
(trifluoromethyl)benzonitrile as a yellow solid (39.0 mg,
54%); mp 83.5–84.5 °C (hexane/ethyl acetate); Rf 0.20
1
Rf 0.35 (hexane/ethyl acetate 1:1); H NMR (400 MHz,
CDCl3) δ 8.03–8.00 (m, 2H, Ph), 7.48–7.41 (m, 3H, Ph),
4.40 (q, J = 7.1 Hz, 2H, CH2O), 3.83 (t, J = 6.7 Hz, 2H,
CH2), 3.38 (s, 3H, MeO), 3.13 (t, J = 6.7 Hz, 2H, CH2),
1.38 (t, J = 7.1 Hz, 3H, MeCH2); 13C NMR (100 MHz,
CDCl3) δ 162.3, 160.9, 155.5, 130.2, 128.5, 128.4, 127.2,
127.1, 69.3, 61.4, 58.9, 29.0, 14.4; HRMS (ESI): m/z [M +
1
(hexane/ethyl acetate 8:1); H NMR (400 MHz, CDCl3) δ
8.42 (s, 1H, Ar), 8.35 (d, J = 7.8 Hz, 1H, Ar), 8.12–8.09
(m, 2H, Ar), 7.75 (d, J = 7.8 Hz, 1H, Ar), 7.63 (t, J = 7.9
Hz, 1H, Ar), 7.55–7.47 (m, 3H, Ar), 4.47 (q, J = 7.1 Hz,
2H, CH2), 1.43 (t, J = 7.1 Hz, 3H, Me); 13C NMR (100
MHz, CDCl3) δ 162.2, 158.5, 155.8, 131.7 (q, JF = 33.0 Hz,
C), 130.7, 130.1, 129.6, 128.8, 128.7, 128.6, 127.6 (q, JF =
3.7 Hz, CH), 127.4, 126.9, 123.9 (q, JF = 3.9 Hz, CH),
123.8 (q, JF = 272.5 Hz, CF3), 61.8, 14.4; HRMS (ESI):
Na]+ calcd. for C15H17NNaO4 : 298.1050; found: 298.1061.
+
Methyl
2-(2-ethoxy-2-oxoethyl)-5-phenyloxazole-4-
carboxylate (11g) was obtained from methyl 3-
phenylpropiolate (9) (32.0 mg, 0.2 mmol) and ethyl 2-
cyanoacetate as a colorless solid (31.8 mg, 55%); mp 50.5–
51.5 °C (hexane/ethyl acetate); Rf 0.35 (hexane/ethyl
+
m/z [M + Na]+ calcd. for C19H14F3NNaO3 : 384.0818;
found: 384.0809.
1
acetate 3:2); H NMR (400 MHz, CDCl3) δ 8.08–8.05 (m,
Methyl
2-(dimethylamino)-5-phenyloxazole-4-
2H, Ph), 7.50–7.43 (m, 3H, Ph), 4.23 (q, J = 7.2 Hz, 2H,
CH2Me), 3.94 (s, 5H, OMe+CH2), 1.28 (t, J = 7.2 Hz, 3H,
Me); 13C NMR (100 MHz, CDCl3) δ 167.0, 162.5, 156.5,
156.0, 130.6, 128.6, 128.5, 127.0, 126.8, 62.1, 52.4, 34.7,
carboxylate (11m) was obtained from methyl 3-
phenylpropiolate (9) (32.0 mg, 0.2 mmol) and N,N-
dimethylcyanamide as a colorless solid (31.0 mg, 63%);
mp 95.5–97.0 °C (hexane/ethyl acetate); Rf 0.30
14.2; HRMS (ESI): m/z [M + H]+ calcd. for C15H16NO5 :
(hexane/ethyl acetate 3:2); H NMR (400 MHz, CDCl3) δ
+
1
290.1023; found: 290.1027.
7.98–7.95 (m, 2H, Ph), 7.42 (t, J = 7.4 Hz, 2H, Ph), 7.35 (t,
J = 7.3 Hz, 1H, Ph), 3.90 (s, 3H, MeO), 3.14 (s, 6H, 2Me);
13C NMR (100 MHz, CDCl3) δ 163.4, 160.2, 149.6, 129.1,
128.4, 127.8, 127.5, 127.1, 52.3, 38.0; HRMS (ESI): m/z
Ethyl
2-(3-chloropropyl)-5-phenyloxazole-4-
carboxylate (11h) was obtained from ethyl 3-
phenylpropiolate (5) (34.8 mg, 0.2 mmol) and 4-
chlorobutanenitrile as a colorless oil (34.1 mg, 58%); Rf
0.40 (hexane/ethyl acetate 2:1); 1H NMR (400 MHz,
CDCl3) δ 8.02–7.99 (m, 2H, Ph), 7.48–7.41 (m, 3H, Ph),
4.40 (q, J = 7.1 Hz, 2H, OCH2), 3.66 (t, J = 6.3 Hz, 2H,
CH2Cl), 3.04 (t, J = 7.4 Hz, 2H, CH2), 2.32 (p, J = 6.6 Hz,
2H, CH2CH2Cl), 1.38 (t, J = 7.1 Hz, 3H, OCH2Me); 13C
NMR (100 MHz, CDCl3) δ 162.2, 161.9, 155.4, 130.3,
128.47, 128.46, 127.13, 127.06, 61.5, 43.9, 29.7, 25.5,
[M + H]+ calcd. for C13H15N2O3 : 247.1077; found:
+
247.1084.
Ethyl 5-phenyl-2-(piperidin-1-yl)oxazole-4-carboxylate
(11n) was obtained from ethyl 3-phenylpropiolate (5) (34.8
mg, 0.2 mmol) and piperidine-1-carbonitrile as a yellowish
1
oil (27.6 mg, 46%); Rf 0.45 (hexane/ethyl acetate 3:2); H
NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.1 Hz, 2H, Ph),
7.40 (t, J = 7.4 Hz, 2H, Ph), 7.34 (t, J = 7.3 Hz, 1H, Ph),
4.38 (q, J = 7.1 Hz, 2H, CH2), 3.57–3.55 (m, 4H, 2CH2),
1.64 (s, 6H, 3CH2), 1.37 (t, J = 7.1 Hz, 3H, Me); 13C NMR
(100 MHz, CDCl3) δ 163.0, 159.7, 149.0, 129.0, 128.3,
128.0, 127.7, 127.2, 61.2, 46.7, 25.2, 24.0, 14.4; HRMS
14.4; HRMS (ESI): m/z [M
C15H16ClNNaO3 : 316.0711; found: 316.0725.
+
Na]+ calcd. for
+
Ethyl 5-phenyl-2-vinyloxazole-4-carboxylate (11i) was
obtained from ethyl 3-phenylpropiolate (5) (34.8 mg, 0.2
mmol) and acrylonitrile as a colorless oil (25.8 mg, 53%);
+
(ESI): m/z [M + Na]+ calcd. for C34H40N4NaO6 : 623.2840;
found: 623.2866.
1
Rf 0.40 (hexane/ethyl acetate 2:1); H NMR (400 MHz,
CDCl3) δ 8.08–8.05 (m, 2H, Ph), 7.49–7.42 (m, 3H, Ph),
6.67 (dd, J = 17.7, 11.2 Hz, 1H, CH=), 6.30 (dd, J = 17.7,
0.8 Hz, 1H, CH=), 5.74 (dd, J = 11.3, 0.8 Hz, 1H, CH=),
4.42 (q, J = 7.1 Hz, 2H, CH2), 1.39 (t, J = 7.1 Hz, 3H, Me);
13C NMR (100 MHz, CDCl3) δ 162.2, 158.9, 155.0, 130.5,
128.6, 128.5, 128.0, 127.0, 123.7, 122.9, 61.5, 14.4;
Methyl
2-morpholino-5-phenyloxazole-4-carboxylate
(11o) was obtained from methyl 3-phenylpropiolate (9)
(32.0 mg, 0.2 mmol) and morpholine-4-carbonitrile as a
colorless solid (23.1 mg, 40%); mp 74.0–75.0 °C
(hexane/ethyl acetate); Rf 0.20 (hexane/ethyl acetate 1:1);
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.1 Hz, 2H, Ph),
7.45 (t, J = 7.3 Hz, 2H, Ph), 7.39 (t, J = 7.3 Hz, 1H, Ph),
3.93 (s, 3H, Me), 3.82 (t, J = 4.8 Hz, 4H, 2CH2), 3.62 (t, J
= 4.8 Hz, 4H, 2CH2); 13C NMR (100 MHz, CDCl3) δ 163.1,
159.2, 150.0, 129.4, 128.4, 127.7, 127.5, 126.7, 66.2, 52.3,
HRMS (ESI): m/z [M + Na]+ calcd. for C14H13NNaO3 :
+
266.0788; found: 266.0797.
Ethyl 2,5-diphenyloxazole-4-carboxylate (11j)[30] was
obtained from ethyl 3-phenylpropiolate (5) (34.8 mg, 0.2
mmol) and benzonitrile as a colorless solid (38.7 mg,
66%); mp 85.0–86.0 °C (hexane/ethyl acetate); Rf 0.45
+
45.9; HRMS (ESI): m/z [M + H]+ calcd. for C15H17N2O4 :
289.1183; found: 289.1189.
1
(hexane/ethyl acetate 4:1); H NMR (400 MHz, CDCl3) δ
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900097
Advanced Synthesis & Catalysis
Ethyl 2-amino-5-phenyloxazole-4-carboxylate (11p) was
obtained from ethyl 3-phenylpropiolate (5) (34.8 mg, 0.2
mmol) and cyanamide (500 mg) as a colorless solid (41.8
mg, 90%); mp 157.0–158.0 °C (hexane/ethyl acetate); Rf
0.35 (hexane/ethyl acetate 1:2); 1H NMR (400 MHz,
CDCl3) δ 7.98–7.95 (m, 2H, Ph), 7.44–7.35 (m, 3H, Ph),
5.57 (s, 2H, NH2), 4.36 (q, J = 7.2 Hz, 2H, CH2), 1.37 (t, J
= 7.1 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3) δ 162.6,
158.7, 149.7, 129.4, 128.4, 127.8, 127.4, 126.3, 61.2, 14.4;
(12e) (39.8 mg, 0.2 mmol) and acetonitrile as a colorless
solid (41.0 mg, 80%); mp 102.5–103.5 °C (hexane/ethyl
1
acetate); Rf 0.20 (hexane/ethyl acetate 1:1); H NMR (400
MHz, CDCl3) δ 8.21 (d, J = 8.7 Hz, 2H, Ar), 7.72 (d, J =
8.6 Hz, 2H, Ar), 4.41 (q, J = 7.1 Hz, 2H, OCH2), 2.56 (s,
3H, Me), 1.39 (t, J = 7.1 Hz, 3H, OCH2Me); 13C NMR
(100 MHz, CDCl3) δ 161.9, 161.0, 152.9, 132.2, 131.1,
129.1, 128.6, 118.4, 113.4, 61.8, 14.4, 14.0; HRMS (ESI):
+
m/z [M + Na]+ calcd. for C14H12N2NaO3 : 279.0740; found:
+
HRMS (ESI): m/z [M + Na]+ calcd. for C12H12N2NaO3 :
279.0748.
255.0740; found: 255.0740.
Methyl
5-(4-fluorophenyl)-2-methyloxazole-4-
Ethyl
5-phenyl-2-(propylthio)oxazole-4-carboxylate
carboxylate (13f) was obtained from methyl 3-(4-
fluorophenyl)propiolate (12f) (35.6 mg, 0.2 mmol) and
acetonitrile as a colorless solid (32.9 mg, 70%); mp 100.5–
101.5 °C (hexane/ethyl acetate); Rf 0.20 (hexane/ethyl
(11q) was obtained from ethyl 3-phenylpropiolate (5) (34.8
mg, 0.2 mmol) and 1-thiocyanatopropane as a colorless oil
(21.6 mg, 37%); Rf 0.30 (hexane/ethyl acetate 8:1); H
1
1
NMR (400 MHz, CDCl3) δ 8.00–7.95 (m, 2H, Ph), 7.49–
7.40 (m, 3H, Ph), 4.39 (q, J = 7.1 Hz, 2H, OCH2Me), 3.24
(t, J = 7.2 Hz, 2H, CH2S), 1.82 (h, J = 7.3 Hz, 2H,
MeCH2CH2), 1.37 (t, J = 7.1 Hz, 3H, OCH2Me), 1.06 (t, J
= 7.4 Hz, 3H, Me); 13C NMR (100 MHz, CDCl3) δ 162.0,
159.9, 156.5, 130.2, 128.4, 128.33, 128.29, 127.0, 61.5,
34.6, 23.0, 14.3, 13.3; HRMS (ESI): m/z [M + H]+ calcd.
for C15H18NO3S+: 292.1002; found: 292.1002.
acetate 2:1); H NMR (400 MHz, CDCl3) δ 8.11–8.06 (m,
2H, Ar), 7.16–7.11 (m, 2H, Ar), 3.92 (s, 3H, OMe), 2.54 (s,
3H, Me); 13C NMR (100 MHz, CDCl3) δ 163.8 (d, JF =
251.9 Hz, CF), 162.7, 159.8, 154.7, 130.5 (d, JF = 8.5 Hz,
CH), 126.4, 123.3 (d, JF = 3.4 Hz, C), 115.7 (d, JF = 21.9
Hz, CH), 52.4, 13.9; HRMS (ESI): m/z [M + Na]+ calcd.
+
for C12H10FNNaO3 : 258.0537; found: 258.0537.
Ethyl
5-(2-fluorophenyl)-2-methyloxazole-4-
Methyl 2-methyl-5-(4-tolyl)oxazole-4-carboxylate (13a)
was obtained from methyl 3-(4-tolyl)propiolate (12a) (34.8
mg, 0.2 mmol) and acetonitrile as a colorless solid (24.5
mg, 53%); mp 81.0–82.0 °C (hexane/ethyl acetate); Rf 0.30
carboxylate (13g) was obtained from ethyl 3-(2-
fluorophenyl)propiolate (12g) (38.4 mg, 0.2 mmol) and
acetonitrile as a colorless oil (36.9 mg, 74%); Rf 0.30
1
(hexane/ethyl acetate 2:1); H NMR (400 MHz, CDCl3) δ
1
(hexane/ethyl acetate 3:2); H NMR (400 MHz, CDCl3) δ
7.64–7.60 (m, 1H, Ar), 7.47–7.42 (m, 1H, Ar), 7.22 (t, J =
8.1 Hz, 1H, Ar), 7.16 (d, J = 9.8 Hz, 1H, Ar), 4.32 (q, J =
7.1 Hz, 2H, OCH2), 2.55 (s, 3H, Me), 1.29 (t, J = 7.2 Hz,
3H, OCH2Me); 13C NMR (100 MHz, CDCl3) δ 161.6,
161.3, 160.0 (d, JF = 253.4 Hz, CF), 150.0, 132.2 (d, JF =
8.5 Hz, CH), 131.4 (d, JF = 1.8 Hz, CH), 129.6, 123.9 (d,
JF = 3.7 Hz, CH), 116.1 (d, JF = 21.4 Hz, CH), 116.0 (d, JF
= 13.9 Hz, C), 61.3, 14.2, 14.0; HRMS (ESI): m/z [M +
7.95 (d, J = 8.3 Hz, 2H, Ar), 7.25 (d, J = 8.0 Hz, 2H, Ar),
3.91 (s, 3H, OMe), 2.53 (s, 3H, Me), 2.39 (s, 3H, Me); 13C
NMR (100 MHz, CDCl3) δ 162.7, 159.6, 155.9, 140.6,
129.2, 128.2, 126.1, 124.3, 52.2, 21.6, 13.9; HRMS (ESI):
+
m/z [M + Na]+ calcd. for C13H13NNaO3 : 254.0788; found:
254.0797.
Na]+ calcd. for C13H12FNNaO3 : 272.0693; found:
+
Ethyl
5-(4-methoxyphenyl)-2-methyloxazole-4-
272.0702.
carboxylate (13b) was obtained from ethyl 3-(4-
methoxyphenyl)propiolate (12b) (40.8 mg, 0.2 mmol) and
acetonitrile as a colorless solid (31.9 mg, 61%); mp 62.0–
63.0 °C (hexane/ethyl acetate); Rf 0.30 (hexane/ethyl
acetate 3:2); 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.9
Hz, 2H, Ar), 6.96 (d, J = 9.0 Hz, 2H, Ar), 4.40 (q, J = 7.1
Hz, 2H, OCH2), 3.85 (s, 3H, OMe), 2.53 (s, 3H, Me), 1.39
(t, J = 7.1 Hz, 3H, OCH2Me); 13C NMR (100 MHz,
CDCl3) δ 162.5, 161.1, 159.3, 155.7, 130.1, 125.7, 119.8,
113.9, 61.3, 55.5, 14.5, 13.9; HRMS (ESI): m/z [M + H]+
Ethyl 2-methyl-5-(thiophen-2-yl)oxazole-4-carboxylate
(13h)[26] was obtained from ethyl 3-(thiophen-2-
yl)propiolate (12h) (36.0 mg, 0.2 mmol) and acetonitrile as
a colorless solid (34.6 mg, 73%); mp 72.0–73.0 °C
(hexane/ethyl acetate); Rf 0.30 (hexane/ethyl acetate 2:1);
1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 4.9 Hz, 1H, Ar),
7.49 (d, J = 6.1 Hz, 1H, Ar), 7.14–7.12 (m, 1H, Ar), 4.44
(q, J = 7.2 Hz, 2H, CH2), 2.53 (s, 3H, Me), 1.43 (t, J = 7.1
Hz, 3H, MeCH2); 13C NMR (100 MHz, CDCl3) δ 162.2,
159.2, 151.3, 129.9, 129.3, 128.6, 127.8, 125.1, 61.4, 14.5,
+
calcd. for C14H16NO4 : 262.1074; found: 262.1065.
13.9; HRMS (ESI): m/z [M
+
Na]+ calcd. for
Methyl
2-methyl-5-(4-
methyl 3-(4-
C11H11NNaO3S+: 260.0352; found: 260.0355.
(trifluoromethoxy)phenyl)oxazole-4-carboxylate (13c)
was
obtained
from
(trifluoromethoxy)phenyl)propiolate (12c) (48.8 mg, 0.2
mmol) and acetonitrile as a colorless solid (40.4 mg, 67%);
mp 41.0–42.0 °C (hexane/ethyl acetate); Rf 0.25
Ethyl 5-hexyl-2-methyloxazole-4-carboxylate (13i) was
obtained from ethyl non-2-ynoate (12i) (36.5 mg, 0.2
mmol) and acetonitrile as a colorless oil (35.0 mg, 69%);
1
1
(hexane/ethyl acetate 3:2); H NMR (400 MHz, CDCl3) δ
Rf 0.35 (hexane/ethyl acetate 2:1); H NMR (400 MHz,
8.14 (d, J = 9.0 Hz, 2H, Ar), 7.29 (d, J = 8.0 Hz, 2H, Ar),
3.93 (s, 3H, OMe), 2.55 (s, 3H, Me); 13C NMR (100 MHz,
CDCl3) δ 162.6, 160.2, 154.2, 150.4, 130.0, 127.1, 125.6,
120.7, 120.5 (q, JF = 258.2 Hz, CF3), 52.5, 13.9; HRMS
CDCl3) δ 4.34 (q, J = 7.2 Hz, 2H, OCH2), 2.98–2.94 (m,
2H, CH2), 2.42 (s, 3H, Me), 1.64 (p, J = 7.6 Hz, 2H, CH2),
1.36 (t, J = 7.1 Hz, 3H, OCH2Me), 1.32–1.23 (m, 6H,
3CH2), 0.87–0.84 (m, 3H, Me); 13C NMR (100 MHz,
CDCl3) δ 162.5, 160.2, 159.5, 127.1, 60.8, 31.5, 28.9, 27.8,
26.0, 22.6, 14.5, 14.1, 13.8; HRMS (ESI): m/z [M + Na]+
(ESI): m/z [M + Na]+ calcd. for C13H10F3NNaO4 :
+
324.0463; found: 324.0454.
+
calcd. for C13H21NNaO3 : 262.1414; found: 262.1405.
Methyl
2-methyl-5-(4-nitrophenyl)oxazole-4-
carboxylate (13d) was obtained from methyl 3-(4-
nitrophenyl)propiolate (12d) (41.0 mg, 0.2 mmol) and
acetonitrile as a colorless solid (48.2 mg, 92%); mp 139.0–
140.0 °C (hexane/ethyl acetate); Rf 0.20 (hexane/ethyl
Methyl 2-methyloxazole-4-carboxylate (13j)[32] was
obtained from methyl propiolate (12j) (16.8 mg, 0.2 mmol)
and acetonitrile as a colorless solid (15.2 mg, 54%); mp
58.5–59.5 °C (hexane/ethyl acetate); Rf 0.25 (hexane/ethyl
1
1
acetate 1:1); H NMR (400 MHz, CDCl3) δ 8.32–8.26 (m,
acetate 2:1); H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H,
4H, Ar), 3.94 (s, 3H, MeO), 2.58 (s, 3H, Me); 13C NMR
(100 MHz, CDCl3) δ 162.3, 161.3, 152.7, 148.3, 132.7,
129.1, 128.9, 123.7, 52.7, 14.0; HRMS (ESI): m/z [M +
Ar), 3.88 (s, 3H, MeO), 2.49 (s, 3H, Me); 13C NMR (100
MHz, CDCl3) δ 162.5, 161.8, 143.9, 133.3, 52.2, 13.9;
+
HRMS (ESI): m/z [M + Na]+ calcd. for C6H7NNaO3 :
Na]+ calcd. for C12H10N2NaO5 : 285.0482; found:
164.0318; found: 164.0317.
+
285.0481.
(2-Methyl-5-phenyloxazol-4-yl)(phenyl)methanone
(13k)[28] was obtained from 1,3-diphenylprop-2-yn-1-one
(12k) (41.2 mg, 0.2 mmol) and acetonitrile as a yellowish
Ethyl 5-(4-cyanophenyl)-2-methyloxazole-4-carboxylate
(13e) was obtained from ethyl 3-(4-cyanophenyl)propiolate
7
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10.1002/adsc.201900097
Advanced Synthesis & Catalysis
1
oil (30.0 mg, 57%); Rf 0.25 (hexane/ethyl acetate 8:1); H
NMR (400 MHz, CDCl3) δ 8.07–8.05 (m, 2H, Ph), 7.98–
7.93 (m, 2H, Ph), 7.55 (t, J = 7.4 Hz, 1H, Ph), 7.49–7.39
(m, 5H, Ph), 2.59 (s, 3H, Me); 13C NMR (100 MHz,
CDCl3) δ 189.0, 159.2, 154.8, 137.7, 134.0, 133.0, 130.4,
130.2, 128.6, 128.3, 127.8, 127.5, 14.0; HRMS (ESI): m/z
14, 5382-5391; e) B. Alcaide, P. Almendros, J. M.
Alonso, Molecules 2011, 16, 7815-7843.
[3] a) D. B. Huple, S. Ghorpade, R. S. Liu, Adv. Synth.
Catal. 2016, 358, 1348-1367; b) Z. Zheng, Z. Wang, Y.
Wang, L. Zhang, Chem. Soc. Rev. 2016, 45, 4448-
4458; c) L. Zhang, Acc. Chem. Res. 2014, 47, 877-888;
d) H. S. Yeom, S. Shin, Acc. Chem. Res. 2014, 47, 966-
977; e) J. Xiao, X. Li, Angew. Chem. Int. Ed. 2011, 50,
7226-7236; f) J. Schießl, P. M. Stein, J. Stirn, K. Emler,
M. Rudolph, F. Rominger, A. S. K. Hashmi, Adv. Synth.
Catal. 2019, 361, 725-738.
+
[M + Na]+ calcd. for C17H13NNaO2 : 286.0838; found:
254.0843.
(2-(Diethylamino)-5-phenyloxazol-4-
yl)(phenyl)methanone (13l) was obtained from 1,3-
diphenylprop-2-yn-1-one (12k) (41.2 mg, 0.2 mmol) and
N,N-diethylcyanamide as a yellow oil (34.6 mg, 54%); Rf
0.25 (hexane/ethyl acetate 8:1); 1H NMR (400 MHz,
CDCl3) δ 8.15–8.12 (m, 2H, Ph), 7.82–7.79 (m, 2H, Ph),
7.51 (t, J = 7.4 Hz, 1H, Ph), 7.40 (t, J = 7.5 Hz, 2H, Ph),
7.34 (t, J = 7.3 Hz, 2H, Ph), 7.30–7.26 (m, 1H, Ph), 3.55 (q,
J = 7.2 Hz, 4H, 2CH2), 1.28 (t, J = 7.1 Hz, 6H, 2Me); 13C
NMR (100 MHz, CDCl3) δ 189.5, 158.9, 148.2, 137.9,
134.5, 132.8, 130.6, 128.6, 128.4, 128.35, 128.1, 126.8,
43.0, 13.6; HRMS (ESI): m/z [M + Na]+ calcd. for
[4] a) E. P. A. Talbot, M. Richardson, J. M. McKenna, F.
D. Toste, Adv. Synth. Catal. 2014, 356, 687-691; b)
G. Wu, R. Zheng, J. Nelson, L. Zhang, Adv. Synth.
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+
C20H20N2NaO2 : 343.1417; found: 343.1425.
(2,5-Dimethyloxazol-4-yl)(phenyl)methanone (13m) was
obtained from 4-phenylbut-3-yn-2-one (12m) (28.8 mg,
0.2 mmol) and acetonitrile as a colorless solid (14.9 mg,
37%); mp 55.0–57.0 °C (hexane/ethyl acetate); Rf 0.45
1
(hexane/ethyl acetate 4:1); H NMR (400 MHz, CDCl3) δ
8.18 (d, J = 6.9 Hz, 2H, Ph), 7.55 (t, J = 7.3 Hz, 1H, Ph),
7.47 (t, J = 7.5 Hz, 2H, Ph), 2.63 (s, 3H, Me) 2.48 (s, 3H,
Me); 13C NMR (100 MHz, CDCl3) δ 188.4, 158.4, 157.1,
137.8, 134.6, 132.7, 130.2, 128.3, 13.9, 12.7; HRMS (ESI):
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+
m/z [M + H]+ calcd. for C12H12NO2 : 202.0868; found:
202.0871.
1-(2-Methyl-5-phenyloxazol-4-yl)ethan-1-one (13m′)[33]
was obtained from 4-phenylbut-3-yn-2-one (12m) (28.8
mg, 0.2 mmol) and acetonitrile as a colorless solid (10.0
mg, 25%); mp 78.5–79.5 °C (hexane/ethyl acetate); Rf 0.35
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1
(hexane/ethyl acetate 4:1); H NMR (400 MHz, CDCl3) δ
8.16-8.12 (m, 2H, Ph), 7.48-7.41 (m, 3H, Ph), 2.61 (s, 3H,
Me) 2.55 (s, 3H, Me); 13C NMR (100 MHz, CDCl3) δ
194.4, 158.9, 153.4, 134.5, 130.5, 128.5, 128.1, 127.4, 29.2,
13.9; HRMS (ESI): m/z [M
+
Na]+ calcd. for
+
C12H11NNaO2 : 224.0687; found: 224.0688.
Acknowledgements
A.Yu.D. thanks the Russian Science Foundation for support of
these studies (grant 18-73-00026). We are much obliged to the
Center for Magnetic Resonance, Center for Chemical Analysis
and Material Research (both belonging to Saint Petersburg State
University) for physicochemical measurements.
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Three component [2+2+1] Gold(I)-catalyzed
Oxidative Generation of Fully Substituted 1,3-
Oxazoles Involving Internal Alkynes
Adv. Synth. Catal. Year, Volume, Page – Page
Alexey Yu. Dubovtsev,* Dmitry V. Dar’in,
Vadim Yu. Kukushkin*
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