A Highly Efficient Heterogeneous Copper-Catalyzed Oxidative Cyclization of Benzylamines and 1,3-Dicarbonyl Compounds to Give Trisubstituted Oxazoles

Article abstract of DOI:10.1055/s-0037-1610710

The heterogeneous copper-catalyzed cascade oxidative cyclization between benzylamines and 1,3-dicarbonyl compounds was achieved by using the 3-(2-aminoethylamino)propyl-functionalized MCM-41-immobilized copper(II) complex [MCM-41-2N-Cu(OAc) ₂ ] as catalyst and t -BuOOH (TBHP) as oxidant, with iodine as additive, under mild conditions, yielding a wide variety of 2,4,5-trisubstituted oxazoles in mostly good to excellent yields. This heterogeneous copper catalyst can be facilely prepared via a simple two-step procedure from readily available and inexpensive reagents and exhibits a slightly higher activity than Cu(OAc) ₂. MCM-41-2N-Cu(OAc) ₂ is also easy to recover and can be recycled up to eight times with almost consistent activity. The reaction is the first example of heterogeneous copper-catalyzed intermolecular cyclization for the construction of polysubstituted oxazoles.

Full text of DOI:10.1055/s-0037-1610710

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
L. Wei et al.
Paper
Synthesis
A Highly Efficient Heterogeneous Copper-Catalyzed Oxidative
Cyclization of Benzylamines and 1,3-Dicarbonyl Compounds To
Give Trisubstituted Oxazoles
Li Weia
Shengyong You*b
Yuxin Tuoa
Mingzhong Cai*a
O
R2
MCM-41-2N-Cu(OAc)2
O
O
(10 mol%)
N
R1
Ar
NH2
+
0
0
0
0-0
0
0
2-
1
0
5
6-2
8
4
6
R1
R2
TBHP, I2, DMF, 80 °C
O
Ar
a Key Laboratory of Functional Small Organic Molecules, Ministry
of Education and College of Chemistry & Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P. R. of China
mzcai@jxnu.edu.cn
31 examples
up to 95% yield
Recyclable copper catalyst!
b Institute of Applied Chemistry, Jiangxi Academy of Sciences,
Nanchang 330029, P. R. of China
OSiMe3
O
H
N
ysygood1981@163.com
Si
NH2
MCM-41-2N-Cu(OAc)2
=
O
OMe
Cu(OAc)2
Received: 24.02.2019
Accepted after revision: 02.04.2019
Published online: 02.05.2019
oxazolines,6 and cross-coupling between prefunctionalized
oxazoles and various organometallic reagents.7 However,
these methods often have limitations, such as the need for
harsh conditions, tedious synthetic procedures, and inac-
cessible starting materials. In recent years, reactions cata-
lyzed by transition metals such as gold,8 palladium,9 rhodi-
um,10 and ruthenium11 have provided alternative routes to
oxazoles, since they have overcome most of the disadvan-
tages of the classical synthetic approaches; however, the
use of expensive metal catalysts limits their utility. There-
fore, the development of inexpensive metal-catalyzed con-
struction of oxazole derivatives from readily available start-
ing materials under mild conditions still represents a chal-
lenge.
DOI: 10.1055/s-0037-1610710; Art ID: ss-2019-h0123-op
Abstract The heterogeneous copper-catalyzed cascade oxidative cy-
clization between benzylamines and 1,3-dicarbonyl compounds was
achieved by using the 3-(2-aminoethylamino)propyl-functionalized
MCM-41-immobilized copper(II) complex [MCM-41-2N-Cu(OAc)2] as
catalyst and t-BuOOH (TBHP) as oxidant, with iodine as additive, under
mild conditions, yielding a wide variety of 2,4,5-trisubstituted oxazoles
in mostly good to excellent yields. This heterogeneous copper catalyst
can be facilely prepared via a simple two-step procedure from readily
available and inexpensive reagents and exhibits a slightly higher activity
than Cu(OAc)2. MCM-41-2N-Cu(OAc)2 is also easy to recover and can be
recycled up to eight times with almost consistent activity. The reaction
is the first example of heterogeneous copper-catalyzed intermolecular
cyclization for the construction of polysubstituted oxazoles.
Among the various transition metals, copper is particu-
larly important in organic synthesis because of its low price
and toxicity as well as its environmentally friendly features.
Consequently, there are many reports on copper-catalyzed
oxidative C–H bond activation12 and C–N bond formation
reactions.13 Recently, copper-catalyzed or -mediated inter-
molecular cyclization reactions have provided attractive al-
ternative methods for the synthesis of polysubstituted ox-
azoles owing to their high efficiency, the low price of the
copper catalysts, the mild reaction conditions, and the
ready availability of starting materials.14 However, in all
cases, homogeneous copper salts with high loadings (typi-
cally 0.1–1.5 equiv) were used to achieve high conversion,
and they are difficult to separate from the reaction product
and cannot be recycled. Moreover, homogeneous catalysis
might result in copper contamination of the desired prod-
uct due to the formation of complexes between the oxaz-
oles and the copper salts, thereby limiting the application
of such catalytic systems in the construction of drug mole-
cules, which should not contain any residual metal. Immo-
Key words copper, 2,4,5-trisubstituted oxazole, oxidative cyclization,
heterogeneous catalysis, cascade reaction
The oxazole ring is a privileged five-membered hetero-
cyclic motif found in many bioactive natural products, syn-
thetic molecules, and pharmaceuticals.1 In particular, 2,5-
disubstituted and 2,4,5-trisubstituted oxazoles exhibit di-
verse and significant biological activities such as antibacte-
rial, anticancer, antifungal, anti-inflammatory, and antiviral
properties.2 Additionally, oxazoles are frequently used as
useful building blocks in the synthesis of natural products,
pharmaceuticals, functional materials, and ligand frame-
works.3 As a result, the development of efficient synthetic
routes to multisubstituted oxazoles is of great importance
and various synthetic methodologies have been developed
to construct these important frameworks.4 Classical meth-
ods for the synthesis of oxazole derivatives include intra-
molecular cyclization of acyclic precursors,5 oxidation of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

B
L. Wei et al.
Paper
Synthesis
bilization of the existing copper catalysts on various solid
supports appears to be an attractive solution to these prob-
lems of environmental and economic concern in chemical
and pharmaceutical industries; employing heterogeneous
catalysts could give rise to facile separation, recovery, and
recyclability of the copper catalysts, thus minimizing both
copper contamination of the target product and waste de-
rived from reaction workup.15 In recent years, supported
copper complexes have been successfully applied in car-
bon–carbon16 and carbon–heteroatom17 bond-formation
reactions. However, to the best of our knowledge, heteroge-
neous copper-catalyzed intermolecular cyclization for the
construction of oxazole derivatives has not been explored
until now.
2.17f The condensation of mesoporous MCM-4118a with [3-
(2-aminoethylamino)propyl]trimethoxysilane in toluene
under reflux for 24 h, followed by silylation with Me3SiCl in
toluene at room temperature for 24 hours gave the 3-(2-
aminoethylamino)propyl-functionalized MCM-41 material
(MCM-41-2N). The latter was then reacted with various
copper salts in DMF at room temperature for 12 hours to af-
ford a series of the MCM-41-2N-CuXn complexes as pale
green powders.
OH
1. (MeO)3Si(CH2)3NH(CH2)2NH2
OH
toluene, 100 °C, 24 h
OH
2. Me3SiCl, rt, 24 h
The hexagonally ordered mesoporous MCM-41 material
has recently emerged as a powerful support for the immo-
bilization of homogeneous metal catalysts owing to its out-
standing advantages such as ultrahigh surface area, large
and defined pore size, big pore volume, and the existence of
rich silanol groups in the inner walls, in comparison with
other solid supports.18 To date, MCM-41-anchored transi-
tion-metal complexes, including catalytic systems based on
Pd,19 Rh,20 Mo,21 Au,22 and Cu,16c,d,17f–h have been successful-
ly employed in many organic reactions as highly efficient
and recyclable catalysts. Considering our continued interest
in the development of economical and eco-friendly syn-
thetic routes for organic transformations,17f–h,19d–f,22e herein
we report a heterogeneous copper-catalyzed cascade oxida-
tive cyclization between benzylamines and 1,3-dicarbonyl
compounds leading to 2,4,5-trisubstituted oxazoles by us-
MCM-41
OSiMe3
CuXn
O
Si
OMe
N
H
NH2
DMF, rt, 12 h
O
MCM-41-2N
OSiMe3
O
H
N
Si
NH2
O
OMe
CuXn
MCM-41-2N-CuCl [A], CuXn = CuCl
MCM-41-2N-CuBr [B], CuXn = CuBr
MCM-41-2N-CuI [C], CuXn = CuI
MCM-41-2N-CuCl2 [D], CuXn = CuCl2
MCM-41-2N-CuBr2 [E], CuXn = CuBr2
MCM-41-2N-Cu(OAc)2 [F], CuXn = Cu(OAc)2
ing
the
3-(2-aminoethylamino)propyl-functionalized
MCM-41-immobilized copper(II) complex [MCM-41-2N-
Cu(OAc)2] as catalyst and t-BuOOH (TBHP) as oxidant with
iodine as additive (Scheme 1).
Scheme 2 Preparation of the MCM-41-2N-CuXn complexes
In our initial screening experiments, the cascade oxida-
tive cyclization between benzylamine (1a) and ethyl aceto-
acetate (2a) was chosen as the model reaction to determine
the optimal reaction conditions, and the results are sum-
marized in Table 1. Firstly, various heterogeneous copper
complexes A–F was examined by using a t-BuOOH (TBHP)
solution in n-hexane as oxidant with iodine as additive at
80 °C in MeCN as solvent (entries 1–6). It was found that all
the heterogeneous copper catalysts tested could catalyze
the model reaction in moderate yields, but MCM-41-2N-
Cu(OAc)2 gave the best result (entry 6). The reaction afford-
ed the desired product 3a in a low yield of 15% in the ab-
sence of any copper catalyst (entry 7). Also, the reaction
proceeded inefficiently without molecular iodine as addi-
tive, thereby providing the desired 3a in a poor yield of 10%
(entry 8). When other oxidants such as (t-BuO)2, air, and
oxygen were employed instead of TBHP, low yields of 11–
30% were observed; therefore the use of TBHP solution in n-
hexane as oxidant was the best choice (entries 6 and 9–11).
Subsequently, the effect of solvents on the model reaction
was checked and a significant solvent effect was observed.
O
R2
O
O
MCM-41-2N-Cu(OAc)2
(10 mol%)
N
R1
Ar
NH2
+
R1
R2
O
TBHP, I2, DMF, 80 °C
Ar
1
2
3
OSiMe3
O
Si
O
H
N
MCM-41-2N-Cu(OAc)2
=
NH2
Cu(OAc)2
OMe
Scheme 1 Heterogeneous copper-catalyzed synthesis of polysubsti-
tuted oxazoles
A series of 3-(2-aminoethylamino)propyl-functional-
ized MCM-41-immobilized copper(I) or copper(II) com-
plexes [MCM-41-2N-CuXn] was easily prepared via a two-
step procedure from commercially readily available and in-
expensive[3-(2-aminoethylamino)propyl]trimethoxysilane
according to our previous procedure, as shown in Scheme
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

C
L. Wei et al.
Paper
Synthesis
Replacement of MeCN with THF or ethanol resulted in low
yields (entries 12 and 13), whereas the use of DMF as sol-
vent afforded 3a in 81% yield (entry 14), while toluene and
dioxane were ineffective (entries 15 and 16). Thus, DMF
was found to be the most suitable solvent for this transfor-
mation. Lowering the reaction temperature to 30 °C led to a
lower reaction rate and a lower yield was observed (entry
17). Finally, the amount of the catalyst was also screened.
Reducing the amount of the catalyst to 5 mol% led to a de-
creased yield and required a longer reaction time (entry
18). Increasing the amount of the catalyst to 20 mol% could
shorten the reaction time, but did not enhance the yield
significantly (entry 19). When 10 mol% of Cu(OAc)2 was
used as catalyst, the desired oxazole was also isolated in
77% yield (entry 20), indicating that the MCM-41-2N-
Cu(OAc)2 complex exhibited a slightly higher catalytic ac-
tivity than homogeneous Cu(OAc)2. Therefore, the optimal
reaction conditions were the use of MCM-41-2N-Cu(OAc)2
(10 mol%) as catalyst, a TBHP solution in n-hexane (2 equiv)
as oxidant, molecular iodine (1.2 equiv) as additive, and
DMF as solvent, at 80 °C for 6 hours (entry 14).
With the optimized reaction conditions in hand, we
started to investigate the scope of this heterogeneous cop-
per-catalyzed intermolecular oxidative cyclization reaction.
First, a series of 1,3-dicarbonyl compounds were examined
by using benzylamine (1a) as the substrate. As shown in
Scheme 3, the reactions of a range of 1,3-dicarbonyl com-
pounds 2a–m with benzylamine (1a) afforded the corre-
sponding 2,4,5-trisubstituted oxazoles in good to excellent
yields. For example, the reaction of various acetoacetates
2a–d with 1a proceeded smoothly to give the desired prod-
ucts 3a–d in 80–89% yield. Other -keto esters bearing dif-
ferent alkyl or aryl substituents 2e–h, regardless of the ste-
ric and electronic effects of the substituent, could furnish
the corresponding oxazoles 3e–h in 87–95% yield. It is note-
worthy that CF3-substituted -keto ester 2i was compatible
with the standard conditions and afforded the CF3-substi-
tuted oxazole 3i in 64% yield. In addition, 4-methoxymeth-
yl-substituted methyl acetoacetate 2j was also a suitable
substrate and provided the expected product 3j in 86%
yield. When the reaction substrates were changed from -
keto esters to -diketones (2k and 2l), the reaction also
worked well, giving the expected products 3k and 3l in high
yields. However, -keto amide 2m displayed a lower reac-
tivity than the -keto esters or -diketones and produced
the target product 3m in a lower yield of 43%.
Under the optimized conditions, we next examined the
scope of benzylamine derivatives 1 by using ethyl acetoace-
tate 2a as the substrate; the results are listed in Scheme 4.
The reactions of para- or meta-substituted benzylamines
1b–g with 2a provided the corresponding products 3n–s in
56–82% yield. The electron-rich benzylamines showed a
lower reactivity than the electron-deficient ones. For in-
stance, 4-methoxybenzylamine 1b furnished the desired 3n
in only 56% yield. The sterically hindered ortho-substituted
benzylamines 1h–j also displayed a relatively lower reactiv-
ity and produced the expected products 3t–v in 59–71%
yield. In addition, bulky (naphthalen-1-yl)methanamine 1k
also gave the desired oxazole 3w in moderate yield. Nota-
bly, heteroaryl-substituted methanamines 1l–n were com-
patible with the standard conditions and afforded the 2-he-
teroaryl-substituted oxazoles 3x–z in moderate to good
yields. The reactions of substituted benzylamines 1d and 1g
with -diketones also worked well to give the desired prod-
ucts 3a′ and 3b′ in good yields. Under the optimized reac-
tion conditions, substituted benzylamines or heterocyclic
amines were allowed to react with various -keto esters,
providing the corresponding products 3c′–e′ in 69–91%
yield. We also performed the reaction of butylamine with
2a, but the desired product was not detected, which may
Table 1 Optimization of the Reaction Conditionsa
O
OEt
O
O
copper catalyst
Ph
NH2
+
N
Me
Me
OEt
oxidant, solvent, I2, 80 °C
O
Ph
1a
2a
3a
Entry
Copper catalyst (mol%) Oxidant
Solvent
Yield (%)b
1
2
A (10)
B (10)
C (10)
D (10)
E (10)
F (10)
–
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
(t-BuO)2
air
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
45
49
50
44
46
58
15
10
30
11
12
28
40
81
0
3
4
5
6
7
8c
F (10)
F (10)
F (10)
F (10)
F (10)
F (10)
F (10)
F (10)
F (10)
F (10)
F (5)
9
10
11
12
13
14
15
16
17d
18e
19f
20
O2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
EtOH
DMF
toluene
dioxane
DMF
0
54
64
82
77
DMF
F (20)
Cu(OAc)2 (10)
DMF
DMF
a Reaction conditions: 1a (1.0 mmol, addition in two portions), 2a (0.5
mmol), oxidant (1.0 mmol), I2 (0.6 mmol), solvent (3 mL), 80 °C, 6 h.
b Isolated yield.
c Without I2 as additive.
d Reaction was conducted at 30 °C for 24 h.
e For 16 h.
f For 4 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

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L. Wei et al.
Paper
Synthesis
O
R2
O
R2
MCM-41-2N-Cu(OAc)2
(10 mol%)
O
O
MCM-41-2N-Cu(OAc)2
(10 mol%)
O
O
N
R1
NH2
Ph
+
R1
R2
N
R1
Ar
NH2
+
R1
O
R2
TBHP, I2, DMF, 80 °C
O
TBHP, I2, DMF, 80 °C
Ph
O
1a
Ar
2a–m
1
2
3a–m
3n–e′
O
O
Me
O
O
O
O
OEt
O
OMe
OCH2Ph
Me
OEt
Me
OEt
Me
OEt
N
Me
Me
Me
N
N
O
N
N
N
N
Me
Me
Me
O
O
O
O
O
MeO
F
O
Me
Ph
Ph
Ph
3p, 79%
Ph
3o, 67%
3n, 56%
3a, 81%
3b, 87%
3c, 89%
O
3d, 80%
O
O
O
O
O
OEt
O
OMe
Me
OEt
OEt
Me
Me
Me
OEt
OEt
OEt
Me
N
O
N
N
O
Br
N
N
N
N
n-Pr
Me
Me
O
Ph
Cl
F3C
O
Me
O
O
O
3q, 82%
O
Ph
3r, 75%
O
Ph
3s, 76%
Ph
Ph
3e, 88%
3f, 95%
3g, 87%
O
3h, 88%
O
O
OEt
OEt
O
OEt
OEt
OMe
O
F
Me
Cl
Ph
OMe
N
N
N
N
N
Me
Me
Me
O
N
N
O
CF3
O
Me
Ph
OMe
O
O
F
3t, 69%
3v, 59%
O
O
3k, 80%
3u, 71%
O
Ph
Ph
Ph
O
Ph
O
3i, 64%
3j, 86%
3l, 79%
OEt
OEt
Me
OEt
H
O
N
O
N
N
N
Ph
Me
Me
O
O
N
O
S
Me
3w, 56%
3x, 76%
3y, 74%
O
O
O
O
Ph
3m, 43%
OEt
Ph
Ph
Me
N
N
N
Scheme 3 Heterogeneous copper-catalyzed oxidative cyclization be-
tween benzylamine and various 1,3-dicarbonyl compounds. Reagents
and conditions: 1a (1.0 mmol, addition in two portions), 2 (0.5 mmol),
TBHP (1.0 mmol), I2 (0.6 mmol), MCM-41-2N-Cu(OAc)2 (10 mol%),
DMF (3 mL), 80 °C, 6 h; isolated yields.
Br
Me
Me
O
O
O
N
F
3z, 58%
3a′, 78%
3b′, 80%
O
O
O
OEt
OMe
Me
OEt
N
N
O
N
n-Pr
n-Pr
O
O
imply that it is necessary for a weak C–H bond to be adja-
cent to the amino group for this reaction. The present
method provides a quite general, simple, and practical
route for the synthesis of a variety of 2,4,5-trisubstituted
oxazoles from readily available benzylamine derivatives
and -keto esters or -diketones. A range of functional
groups were easily tolerated, including methyl, methoxy,
fluoro, chloro, bromo, trifluoromethyl, bulky 1-naphthyl
and tert-butyl groups, furyl, thienyl, and pyridinyl groups.
To verify whether the MCM-41-2N-Cu(OAc)2 catalyst is
actually functioning in a heterogeneous manner, or wheth-
er the observed catalysis is due to a leached copper species
in solution, the heterogeneity of MCM-41-2N-Cu(OAc)2 was
checked by the hot filtration experiment.23 For this, the oxi-
dative cyclization reaction of benzylamine (1a) with ethyl
acetoacetate (2a) was conducted until an approximately
40% conversion of 2a. Then MCM-41-2N-Cu(OAc)2 was re-
moved from the solution by filtration at 80 °C and the re-
sulting catalyst-free filtrate was allowed to stir at 80 °C for
another 5 hours. It was found that no increase in the con-
version of ethyl acetoacetate 2a was observed, indicating
that the soluble Cu species leached from MCM-41-2N-
Cu(OAc)2 (if any) are not responsible for the observed activ-
O
Cl
S
Me
3e′, 69%
3d′, 71%
3c′, 91%
Scheme 4 Heterogeneous copper-catalyzed oxidative cyclization be-
tween various benzylamines and -keto esters or -diketones. Reagents
and conditions: 1 (1.0 mmol, addition in two portions), 2 (0.5 mmol),
TBHP (1.0 mmol), I2 (0.6 mmol), MCM-41-2N-Cu(OAc)2 (10 mol%),
DMF (3 mL), 80 °C, 6 h; isolated yields.
ity. It was also confirmed by ICP-AES analysis on the filtrate
that no detectable copper species was found (below 0.2
ppm), which indicates negligible copper leaching. These re-
sults indicate that the copper(II) complex remains on the
support at elevated temperature during the oxidative cy-
clization reaction and MCM-41-2N-Cu(OAc)2 is actually
functioning in a heterogeneous manner.
A plausible mechanism for the heterogeneous cop-
per(II)-catalyzed oxidative cyclization reaction between
benzylamine (1a) and ethyl acetoacetate (2a) is shown in
Scheme 5. First, ethyl acetoacetate (2a) reacts with iodine in
the presence of TBHP to give ethyl 2-iodoacetoacetate,24
which undergoes a nucleophilic substitution reaction with
benzylamine 1a to form intermediate A. The latter can be
further oxidized by TBHP to produce imine intermediate B.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

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Synthesis
Me
O
O
O
I2
Ph
O
+ HI
NH2
+
Ph
N
TBHP
Me
OEt
H
OEt
1a
2a
Ph
H
A
O
HN
TBHP
MCM-41
Me
O
O
Me
EtO
O
[O]
O
N
N
N
Ph
H
E
Cu
OEt
OAc
AcO
B
OEt
HOAc
N
Me
MCM-41
MCM-41
O
Ph
3a
Ph
N
Ph
N
N
N
N
Cu
Cu
O
N
O
AcO
OAc
EtO
AcO
EtO
Me
Me
O
C
O
D
OAc
Scheme 5 Plausible mechanism for the heterogeneous copper(II)-catalyzed synthesis of oxazole derivatives
Subsequent coordination of the imine intermediate B with
MCM-41-2N-Cu(OAc)2 provides an MCM-41-anchored
Schiff base copper(II) complex intermediate C, which un-
dergoes an intramolecular cyclization via an oxygen atom
attacking the C=N double bond to give an MCM-41-an-
chored amino copper(II) complex intermediate D along
with release of an acetate anion. Subsequently, the protono-
lysis of the N–Cu bond in intermediate D with HOAc affords
intermediate E and regenerates the MCM-41-2N-Cu(OAc)2
to complete the catalytic cycle. Finally, intermediate E un-
dergoes further oxidation to furnish the target product 3a.
From an economic and environmental point of view, the
recovery and recycling of a catalyst is a major sustainability
concern for a transition-metal-catalyzed organic reaction.
The recyclability of MCM-41-2N-Cu(OAc)2 was then inves-
tigated by using the cyclization reaction of benzylamine
(1a) with methyl 4-methyl-3-oxopentanoate (2f) (Figure 1).
After completion of the first reaction cycle, the reaction
mixture was diluted with ethyl acetate and filtered. The
washing of the resulting solid with acetone followed by
drying at 60 °C under vacuum allowed the easy recovery of
MCM-41-2N-Cu(OAc)2. As shown in Figure 1, the recovered
catalyst could be reused at least seven times with a slight
decrease in the catalytic activity. In addition, the copper
content of the recovered catalyst after the eighth reaction
run was found to be 0.57 mmol·g–1 by ICP-AES analysis, in-
dicating negligible copper leaching. The high catalytic activ-
ity and stability of the MCM-41-2N-Cu(OAc)2 catalyst may
be mainly due to the efficient active site isolation and the
optimal dispersion of the active sites on the inner channel
walls of MCM-41 with ultrahigh surface area as well as to
the relatively strong coordination action between the 2-
aminoethylamino bidentate ligand and the copper center
anchored on the support.
Figure 1 Recycling of the MCM-41-2N-Cu(OAc)2 catalyst
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

F
L. Wei et al.
Paper
Synthesis
In conclusion, we have developed a facile and efficient
heterogeneous copper(II)-catalyzed tandem oxidative cy-
clization between benzylamines and 1,3-dicarbonyl com-
pounds for the construction of polysubstituted oxazoles,
which are found in a variety of drug-relevant natural and
synthetic compounds. In contrast to the traditional synthet-
ic route to oxazoles, this heterogeneous tandem oxidative
cyclization strategy has some attractive features, such as:
(a) the starting materials are readily available, and a wide
range of benzylamine derivatives and 1,3-dicarbonyl com-
pounds can be used; (b) a wide variety of 2,4,5-trisubstitut-
ed oxazoles can be obtained in mostly good to excellent
yields; (c) the reaction conditions are mild; and (d) the
MCM-41-2N-Cu(OAc)2 catalyst can be easily prepared via a
simple two-step procedure from readily available and inex-
pensive reagents and recovered from the reaction mixture
by filtration, and recycled up to eight times with almost
consistent activity. Thus, the present method is an attrac-
tive alternative to construct polysubstituted oxazoles.
materials in the same manner; the copper content was determined to
be 0.51 mmol·g–1, 0.49 mmol·g–1, 0.53 mmol·g–1, 0.57 mmol·g–1, and
0.61 mmol·g–1, respectively.
Oxazoles 3; General Procedure
To a solution of benzylamine 1 (0.7 mmol) in DMF (3 mL) were suc-
cessively added I2 (0.6 mmol), 1,3-dicarbonyl compound 2 (0.5
mmol), MCM-41-2N-Cu(OAc)2 (86 mg, 0.05 mmol), and TBHP (1
mmol). After the reaction mixture had been stirred for 3 h at 80 °C,
another portion of benzylamine 1 (0.3 mmol) was added to the reac-
tion mixture and the mixture was stirred at 80 °C for another 3 h. Af-
ter being cooled to r.t., the mixture was diluted with EtOAc (15 mL)
and filtered. The MCM-41-2N-Cu(OAc)2 complex was washed with
acetone (2 × 5 mL), followed by drying at 60 °C under vacuum for 2 h,
and reused in the next run. The filtrate was washed with water (2 ×
10 mL) and dried over MgSO4. Then the organic phase was concen-
trated in vacuum and the residue was purified by column chromatog-
raphy (silica gel, light PE/EtOAc = 2:1 to 10:1) to afford the desired
product 3.
Ethyl 5-Methyl-2-phenyloxazole-4-carboxylate (3a)25
Yield: 93.6 mg (81%); pale yellow solid; mp 47–48 °C.
1H NMR (400 MHz, CDCl3):  = 8.10–8.03 (m, 2 H), 7.50–7.42 (m, 3 H),
4.43 (q, J = 7.2 Hz, 2 H), 2.71 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.5, 159.7, 156.1, 130.7, 128.8,
All reagents were obtained from commercial sources and used as re-
ceived without further purification. All solvents were dried and dis-
tilled prior to use. The products were purified by flash column chro-
matography on silica gel. A mixture of light petroleum ether and ethyl
acetate was generally employed as eluent. 1H NMR and 13C NMR spec-
tra were recorded on a Bruker Avance 400 NMR spectrometer (400
MHz or 100 MHz, respectively) by using CDCl3 as solvent and with
TMS as internal reference. Melting points were determined on a Bei-
jing Tech Instrument Co., LTD X-6 melting point apparatus and are
uncorrected. Copper content was determined on a Jarrell-Ash 1100
ICP. HRMS spectra were obtained on an AGILENT 6520 Accurate-Mass
QTOF LC/MS spectrometer in the electrospray mode (ES). Mesoporous
material MCM-41 was easily prepared according to a literature meth-
od.18a
128.7, 126.6, 126.5, 61.0, 14.4, 12.2.
Methyl 5-Methyl-2-phenyloxazole-4-carboxylate (3b)4c
Yield: 94.5 mg (87%); pale yellow solid; mp 87–88 °C.
1H NMR (400 MHz, CDCl3):  = 8.11–8.04 (m, 2 H), 7.52–7.41 (m, 3 H),
3.95 (s, 3 H), 2.72 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.9, 159.7, 156.4, 130.8, 128.8,
128.5, 126.6, 126.1, 52.0, 12.1.
tert-Butyl 5-Methyl-2-phenyloxazole-4-carboxylate (3c)14b
Yield: 115.4 mg (89%); pale yellow solid; mp 72–73 °C.
1H NMR (400 MHz, CDCl3):  = 8.03–7.96 (m, 2 H), 7.41–7.34 (m, 3 H),
2.59 (s, 3 H), 1.55 (s, 9 H).
MCM-41-2N-Cu(OAc)2 (F)17f
A mixture of MCM-41 (2.22 g) and [3-(2-aminoethylamino)pro-
pyl]trimethoxysilane (1.561 g) in anhyd toluene (160 mL) was stirred
at 100 °C under argon for 24 h. The product was filtered and washed
with CHCl3 (30 mL) and dried under vacuum at 150 °C for 5 h. The
dried solid product was then soaked in a solution of Me3SiCl (3.8 g) in
anhyd toluene (120 mL) at 25 °C with stirring under argon for 24 h.
Then the product was filtered, washed with acetone (3 × 20 mL), and
dried under vacuum at 100 °C for 5 h to provide modified material
MCM-41-2N (3.521 g). The nitrogen content was determined to be
1.86 mmol/g by elemental analysis.
13C NMR (100 MHz, CDCl3):  = 161.7, 159.5, 155.1, 130.6, 129.9,
128.7, 126.7, 126.5, 28.3, 28.0, 12.4.
Benzyl 5-Methyl-2-phenyloxazole-4-carboxylate (3d)26
Yield: 117.3 mg (80%); pale yellow solid; mp 91–93 °C.
1H NMR (400 MHz, CDCl3):  = 8.09–8.04 (m, 2 H), 7.49–7.33 (m, 8 H),
5.41 (s, 2 H), 2.68 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.3, 159.8, 156.4, 135.9, 130.8,
128.8, 128.7, 128.6, 128.4, 128.3, 126.6, 66.6, 12.3.
In a Schlenk tube, MCM-41-2N (2.0 g) was mixed with Cu(OAc)2
(0.236 g, 1.3 mmol) in anhyd DMF (30 mL). The reaction mixture was
stirred at r.t. for 12 h under an argon atmosphere. The solid product
was filtered by suction, washed with DMF and acetone, and dried at
60 °C under vacuum for 6 h, to afford the pale blue copper complex
[MCM-41-2N-Cu(OAc)2] (2.135 g). The copper content was deter-
mined to be 0.58 mmol/g by ICP-AES analysis.
Ethyl 2-Phenyl-5-propyloxazole-4-carboxylate (3e)14b
Yield: 114.1 mg (88%); pale yellow solid; mp 52–54 °C.
1H NMR (400 MHz, CDCl3):  = 8.11–8.04 (m, 2 H), 7.50–7.41 (m, 3 H),
4.43 (q, J = 7.2 Hz, 2 H), 3.09 (t, J = 7.4 Hz, 2 H), 1.85–1.76 (m, 2 H),
1.42 (t, J = 7.2 Hz, 3 H), 1.02 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.5, 159.9, 159.7, 130.7, 128.7,
128.6, 126.7, 126.6, 61.0, 28.0, 21.4, 14.4, 13.7.
The other heterogeneous copper catalysts MCM-41-2N-CuCl (A),
MCM-41-2N-CuBr (B), MCM-41-2N-CuI (C), MCM-41-2N-CuCl2 (D),
and MCM-41-2N-CuBr2 (E) were also prepared by using MCM-41-2N
(2.0 g) and the corresponding copper salts (1.3 mmol) as the starting
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

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L. Wei et al.
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Synthesis
Methyl 5-Isopropyl-2-phenyloxazole-4-carboxylate (3f)14b
5-Methyl-N,2-diphenyloxazole-4-carboxamide (3m)14b
Yield: 116.5 mg (95%); pale yellow solid; mp 67–68 °C.
Yield: 59.8 mg (43%); pale yellow solid; mp 90–91 °C.
1H NMR (400 MHz, CDCl3):  = 8.11–8.05 (m, 2 H), 7.50–7.43 (m, 3 H),
3.95 (s, 3 H), 3.90–3.82 (m, 1 H), 1.37 (d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3):  = 164.4, 162.9, 159.4, 130.7, 128.8,
1H NMR (400 MHz, CDCl3):  = 8.88 (s, 1 H), 8.09–8.02 (m, 2 H), 7.72
(d, J = 8.0 Hz, 2 H), 7.61–7.45 (m, 3 H), 7.38 (t, J = 8.0 Hz, 2 H), 7.14 (t,
J = 7.6 Hz, 1 H), 2.78 (s, 3 H).
128.7, 126.7, 126.6, 52.0, 26.2, 20.7.
13C NMR (100 MHz, CDCl3):  = 160.0, 158.6, 153.8, 137.8, 130.8,
130.4, 129.0, 128.9, 126.7, 126.4, 124.3, 119.7, 12.0.
Ethyl 5-(tert-Butyl)-2-phenyloxazole-4-carboxylate (3g)14b
Ethyl2-(4-Methoxyphenyl)-5-methyloxazole-4-carboxylate(3n)14b
Yield: 118.9 mg (87%); pale yellow solid; mp 75–77 °C.
Yield: 73.2 mg (56%); pale yellow solid; mp 78–79 °C.
1H NMR (400 MHz, CDCl3):  = 8.09–8.02 (m, 2 H), 7.49–7.41 (m, 3 H),
4.43 (q, J = 7.2 Hz, 2 H), 1.52 (s, 9 H), 1.44 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 165.6, 162.5, 157.8, 130.6, 128.8,
1H NMR (400 MHz, CDCl3):  = 8.01 (d, J = 8.8 Hz, 2 H), 6.96 (d, J = 8.8
Hz, 2 H), 4.42 (q, J = 7.2 Hz, 2 H), 3.86 (s, 3 H), 2.69 (s, 3 H), 1.42 (t, J =
7.0 Hz, 3 H).
128.7, 126.7, 126.5, 61.2, 33.5, 28.2, 14.3.
13C NMR (100 MHz, CDCl3):  = 162.6, 161.6, 159.8, 155.6, 128.8,
Ethyl 2,5-Diphenyloxazole-4-carboxylate (3h)27
128.3, 119.4, 114.1, 61.0, 55.4, 14.4, 12.2.
Yield: 129.1 mg (88%); pale yellow solid; mp 85–86 °C.
1H NMR (400 MHz, CDCl3):  = 8.14–8.02 (m, 4 H), 7.51–7.38 (m, 6 H),
4.38 (q, J = 7.2 Hz, 2 H), 1.34 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.3, 159.8, 155.1, 131.1, 130.3,
130.0, 128.8, 128.6, 128.4, 127.2, 126.9, 126.4, 61.5, 14.3.
Ethyl 2-(4-Methylphenyl)-5-methyloxazole-4-carboxylate (3o)14b
Yield: 82.2 mg (67%); pale yellow solid; mp 67–69 °C.
1H NMR (400 MHz, CDCl3):  = 7.96 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 8.0
Hz, 2 H), 4.42 (q, J = 7.2 Hz, 2 H), 2.70 (s, 3 H), 2.40 (s, 3 H), 1.42 (t, J =
7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.6, 159.9, 155.9, 141.1, 129.4,
128.7, 128.6, 126.6, 61.0, 21.5, 14.4, 12.2.
Ethyl 2-Phenyl-5-(trifluoromethyl)oxazole-4-carboxylate (3i)
Yield: 91.3 mg (64%); pale yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.18–8.14 (m, 2 H), 7.59–7.47 (m, 3 H),
4.47 (q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.0 Hz, 3 H).
Ethyl 2-(4-Fluorophenyl)-5-methyloxazole-4-carboxylate (3p)14b
Yield: 98.4 mg (79%); pale yellow solid; mp 70–71 °C.
1H NMR (400 MHz, CDCl3):  = 8.09–8.04 (m, 2 H), 7.14 (t, J = 8.6 Hz, 2
H), 4.43 (q, J = 7.2 Hz, 2 H), 2.70 (s, 3 H), 1.42 (t, J = 7.2 Hz, 3 H).
3
13C NMR (100 MHz, CDCl3):  = 162.7, 156.1, 139.9 (q, JC-F = 2.8 Hz),
2
1
136.7 (q, JC-F = 40.8 Hz), 132.4, 129.1, 128.8, 127.5, 119.8 (q, JC-F
=
268.0 Hz), 62.5, 14.0.
HRMS (ESI): m/z [M]+ calcd for C13H10F3NO3: 285.0613; found:
285.0618.
13C NMR (100 MHz, CDCl3):  = 164.3 (d, 1JC-F = 250.1 Hz), 162.4, 158.8,
156.2, 128.7 (d, 3JC-F = 8.6 Hz), 123.0 (d, 4JC-F = 3.2 Hz), 115.9 (d, 2JC-F
=
22.0 Hz), 61.1, 14.4, 12.2.
Methyl 5-(Methoxymethyl)-2-phenyloxazole-4-carboxylate (3j)
Ethyl 2-(4-Chlorophenyl)-5-methyloxazole-4-carboxylate (3q)14b
Yield: 106.3 mg (86%); pale yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.15–8.11 (m, 2 H), 7.51–7.43 (m, 3 H),
4.88 (s, 2 H), 3.98 (s, 3 H), 3.47 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.2, 161.4, 154.2, 131.3, 131.1,
128.8, 127.0, 126.2, 63.6, 58.7, 52.3.
HRMS (ESI): m/z [M]+ calcd for C13H13NO4: 247.0845; found:
Yield: 108.9 mg (82%); pale yellow solid; mp 80–81 °C.
1H NMR (400 MHz, CDCl3):  = 8.01 (d, J = 8.4 Hz, 2 H), 7.43 (d, J = 8.4
Hz, 2 H), 4.43 (q, J = 7.2 Hz, 2 H), 2.71 (s, 3 H), 1.42 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.3, 158.7, 156.3, 136.9, 129.1,
128.9, 127.9, 125.1, 61.1, 14.4, 12.2.
247.0838.
Ethyl 5-Methyl-2-[4-(trifluoromethyl)phenyl]-oxazole-4-carbox-
ylate (3r)
1-(5-Methyl-2-phenyloxazol-4-yl)ethanone (3k)25
Yield: 112.2 mg (75%); pale yellow solid; mp 48–49 °C.
1H NMR (400 MHz, CDCl3):  = 8.19 (d, J = 8.4 Hz, 2 H), 7.72 (d, J = 8.4
Hz, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 2.73 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H).
Yield: 80.5 mg (80%); pale yellow solid; mp 78–79 °C.
1H NMR (400 MHz, CDCl3):  = 8.06–8.01 (m, 2 H), 7.50–7.43 (m, 3 H),
2.69 (s, 3 H), 2.60 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 195.3, 158.6, 154.5, 135.8, 130.6,
2
13C NMR (100 MHz, CDCl3):  = 162.1, 158.2, 156.8, 132.3 (q, JC-F
=
=
3
1
32.5 Hz), 129.7, 129.3, 126.8, 125.8 (q, JC-F = 3.7 Hz), 123.7 (q, JC-F
128.8, 126.9, 126.4, 28.0, 12.4.
270.6 Hz), 61.2, 14.4, 12.3.
HRMS (ESI): m/z [M]+ calcd for C14H12F3NO3: 299.0769; found:
299.0766.
(2,5-Diphenyloxazol-4-yl)(phenyl)methanone (3l)28
Yield: 128.5 mg (79%); pale yellow solid; mp 79–81 °C.
1H NMR (400 MHz, CDCl3):  = 8.20–7.96 (m, 6 H), 7.60–7.46 (m, 9 H).
Ethyl 2-(3-Bromophenyl)-5-methyloxazole-4-carboxylate (3s)
13C NMR (100 MHz, CDCl3):  = 188.8, 159.1, 154.6, 137.1, 133.4,
131.3, 130.6, 130.2, 129.9, 129.0, 128.5, 128.2, 127.9, 127.8, 127.2,
126.8.
Yield: 117.8 mg (76%); pale yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.24 (s, 1 H), 8.00 (d, J = 7.6 Hz, 1 H),
7.58 (d, J = 8.0 Hz, 1 H), 7.33 (t, J = 8.0 Hz, 1 H), 4.43 (q, J = 7.2 Hz, 2 H),
2.72 (s, 3 H), 1.43 (t, J = 7.0 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

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Synthesis
13C NMR (100 MHz, CDCl3):  = 162.3, 158.2, 156.6, 133.6, 130.3,
HRMS (ESI): m/z [M]+ calcd for C11H11NO3S: 237.0460; found:
129.5, 129.1, 128.4, 125.1, 122.9, 61.2, 14.4, 12.3.
237.0455.
HRMS (ESI): m/z [M]+ calcd for C13H12BrNO3: 309.0001; found:
309.0005.
Ethyl 5-Methyl-2-(pyridin-2-yl)oxazole-4-carboxylate (3z)
Yield: 67.3 mg (58%); brown solid; mp 81–82 °C.
Ethyl 2-(2-Chlorophenyl)-5-methyloxazole-4-carboxylate (3t)14b
1H NMR (400 MHz, CDCl3):  = 8.72 (d, J = 4.8 Hz, 1 H), 8.24 (d, J = 8.0
Hz, 1 H), 7.83–7.79 (m, 1 H), 7.39–7.35 (m, 1 H), 4.43 (q, J = 7.2 Hz, 2
H), 2.76 (s, 3 H), 1.42 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.5, 162.2, 158.3, 149.9, 145.4,
137.0, 128.8, 125.0, 122.5, 61.1, 14.4, 12.4.
Yield: 91.7 mg (69%); pale yellow solid; mp 65–66 °C.
1H NMR (400 MHz, CDCl3):  = 8.02–7.97 (m, 1 H), 7.51–7.47 (m, 1 H),
7.41–7.32 (m, 2 H), 4.42 (q, J = 7.2 Hz, 2 H), 2.73 (s, 3 H), 1.42 (t, J = 7.0
Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.3, 157.8, 156.7, 132.7, 131.5,
HRMS (ESI): m/z [M]+ calcd for C12H12N2O3: 232.0848; found:
131.4, 131.0, 128.7, 126.8, 125.8, 61.0, 14.4, 12.3.
232.0851.
Ethyl 2-(2-Methoxyphenyl)-5-methyloxazole-4-carboxylate (3u)
[2-(4-Fluorophenyl)-5-phenyloxazol-4-yl]phenylmethanone (3a′)
Yield: 92.8 mg (71%); pale yellow oil.
Yield: 133.9 mg (78%); pale yellow solid; mp 88–90 °C.
1H NMR (400 MHz, CDCl3):  = 7.96–7.92 (m, 1 H), 7.46–7.40 (m, 1 H),
7.05–6.97 (m, 2 H), 4.41 (q, J = 7.2 Hz, 2 H), 3.94 (s, 3 H), 2.71 (s, 3 H),
1.42 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.6, 162.5, 158.3, 157.7, 155.9,
132.1, 130.6, 120.5, 115.8, 111.7, 60.9, 55.9, 14.4, 12.2.
1H NMR (400 MHz, CDCl3):  = 8.11–8.05 (m, 4 H), 7.98–7.93 (m, 2 H),
7.51 (t, J = 7.4 Hz, 1 H), 7.42–7.35 (m, 5 H), 7.11 (t, J = 8.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 188.7, 164.4 (d, 1JC-F = 250.7 Hz), 158.2,
154.6, 137.4, 135.0, 133.1, 130.6, 130.3, 129.8, 129.0 (d, 3JC-F = 8.7 Hz),
128.6, 128.2, 127.8, 127.3, 116.2 (d, 2JC-F = 22.0 Hz).
HRMS (ESI): m/z [M]+ calcd for C14H15NO4: 261.1001; found:
HRMS (ESI): m/z [M]+ calcd for C22H14FNO2: 343.1009; found:
261.0997.
343.1016.
Ethyl 2-(2,6-Difluorophenyl)-5-methyloxazole-4-carboxylate (3v)
1-[2-(3-Bromophenyl)-5-methyloxazol-4-yl]ethanone (3b′)
Yield: 78.8 mg (59%); pale yellow oil.
Yield: 112.1 mg (80%); pale yellow solid; mp 93–94 °C.
1H NMR (400 MHz, CDCl3):  = 7.48–7.40 (m, 1 H), 7.05–7.00 (m, 2 H),
4.42 (q, J = 7.2 Hz, 2 H), 2.73 (s, 3 H), 1.42 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  = 8.17 (t, J = 1.6 Hz, 1 H), 7.95 (d, J = 7.6
Hz, 1 H), 7.60–7.56 (m, 1 H), 7.33 (t, J = 8.0 Hz, 1 H), 2.69 (s, 3 H), 2.59
(s, 3 H).
13C NMR (100 MHz, CDCl3):  = 195.1, 157.1, 154.8, 135.9, 133.5,
130.4, 129.3, 128.7, 124.8, 122.9, 27.9, 12.4.
13C NMR (100 MHz, CDCl3):  = 162.1, 160.9 (d, 1JC-F = 256.0 Hz), 157.2,
3
2
150.9, 132.4 (t, JC-F = 10.3 Hz), 128.9, 112.1 (d, JC-F = 20.5 Hz), 112.1
(dd, 2JC-F = 20.0 Hz, 4JC-F = 5.1 Hz), 61.1, 14.4, 12.1.
HRMS (ESI): m/z [M]+ calcd for C13H11F2NO3: 267.0707; found:
HRMS (ESI): m/z [M]+ calcd for C12H10BrNO2: 278.9895; found:
267.0705.
278.9893.
Ethyl 5-Methyl-2-(naphthalene-1-yl)oxazole-4-carboxylate (3w)25
Methyl 2-(4-Chlorophenyl)-5-isopropyloxazole-4-carboxylate (3c′)
Yield: 78.7 mg (56%); pale yellow solid; mp 80–82 °C.
Yield: 127.3 mg (91%); pale yellow solid; mp 87–88 °C.
1H NMR (400 MHz, CDCl3):  = 9.19 (d, J = 8.4 Hz, 1 H), 8.21–8.18 (m, 1
H), 7.98–7.86 (m, 2 H), 7.69–7.50 (m, 3 H), 4.45 (q, J = 7.2 Hz, 2 H),
2.77 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  = 8.03–8.00 (m, 2 H), 7.45–7.42 (m, 2 H),
3.95 (s, 3 H), 3.91–3.81 (m, 1 H), 1.37 (d, J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3):  = 164.7, 162.7, 158.5, 136.9, 129.1,
13C NMR (100 MHz, CDCl3):  = 162.6, 159.5, 156.0, 133.8, 131.6,
127.9, 126.7, 125.2, 52.1, 26.2, 20.7.
130.1, 128.5, 128.2, 127.8, 126.4, 126.1, 124.8, 123.2, 61.0, 14.5, 12.3.
HRMS (ESI): m/z [M]+ calcd for C14H14ClNO3: 279.0662; found:
279.0657.
Ethyl 2-(Furan-2-yl)-5-methyloxazole-4-carboxylate (3x)25
Ethyl 2-(Furan-2-yl)-5-propyloxazole-4-carboxylate (3d′)14b
Yield: 84.1 mg (76%); pale yellow solid; mp 74–75 °C.
1H NMR (400 MHz, CDCl3):  = 7.58–7.56 (m, 1 H), 7.10 (d, J = 3.6 Hz, 1
H), 6.55–6.53 (m, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 2.70 (s, 3 H), 1.41 (t, J =
7.2 Hz, 3 H).
Yield: 88.5 mg (71%); pale yellow solid; mp 77–78 °C.
1H NMR (400 MHz, CDCl3):  = 7.57–7.55 (m, 1 H), 7.10 (d, J = 3.6 Hz, 1
H), 6.55–6.52 (m, 1 H), 4.41 (q, J = 7.2 Hz, 2 H), 3.08 (t, J = 7.6 Hz, 2 H),
1.84–1.75 (m, 2 H), 1.41 (t, J = 7.2 Hz, 3 H), 1.01 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.2, 155.7, 152.3, 144.6, 142.0,
128.5, 112.3, 111.9, 61.0, 14.3, 12.0.
13C NMR (100 MHz, CDCl3):  = 162.2, 159.5, 152.4, 144.6, 142.2,
128.3, 112.3, 111.9, 61.0, 27.9, 21.3, 14.4, 13.7.
Ethyl 5-Methyl-2-(thiophen-2-yl)oxazole-4-carboxylate (3y)
Yield: 87.8 mg (74%); pale yellow solid; mp 71–72 °C.
Ethyl 5-Propyl-2-(thiophen-2-yl)oxazole-4-carboxylate (3e′)
1H NMR (400 MHz, CDCl3):  = 7.74–7.71 (m, 1 H), 7.46–7.43 (m, 1 H),
7.11 (t, J = 4.2 Hz, 1 H), 4.42 (q, J = 7.2 Hz, 2 H), 2.69 (s, 3 H), 1.42 (t, J =
7.2 Hz, 3 H).
Yield: 91.5 mg (69%); pale yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.67–7.63 (m, 1 H), 7.39–7.35 (m, 1 H),
7.04 (t, J = 4.2 Hz, 1 H), 4.34 (q, J = 7.2 Hz, 2 H), 2.99 (t, J = 7.4 Hz, 2 H),
1.75–1.65 (m, 2 H), 1.34 (t, J = 7.0 Hz, 3 H), 0.94 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.3, 155.9, 155.7, 128.9, 128.8,
128.7, 128.5, 127.9, 61.1, 14.4, 12.1.
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13C NMR (100 MHz, CDCl3):  = 162.2, 159.5, 155.9, 129.0, 128.8,
128.5, 128.4, 127.9, 61.0, 27.9, 21.3, 14.3, 13.7.
HRMS (ESI): m/z [M+] calcd for C13H15NO3S: 265.0773; found:
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265.0776.
Funding Information
We thank the National Natural Science Foundation of China (No.
21462021), the Natural Science Foundation of Jiangxi Province (No.
20161BAB203086), and the Ministry of Education (Key Laboratory of
Functional Small Organic Molecules, No. KLFS-KF-201704) for finan-
cial support.
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