Base-Promoted Cycloisomerization for the Synthesis of Oxazoles and Imidazoles

Article abstract of DOI:10.1002/ejoc.201801351

Treatment of propargylamides or propargylamidines with cesium carbonate in DMSO results in the formation of the corresponding oxazoles or imidazoles in good yields. A large variety of substrates with various functional groups are tolerated. DFT study on a model substrate reveals that the reactions proceed via a sequence involving allene formation, intramolecular cyclization, and double-bond isomerization.

Full text of DOI:10.1002/ejoc.201801351

A Journal of
Accepted Article
Title: Base-promoted cycloisomerization for the synthesis of oxazoles
and imidazoles
Authors: Lidan Zhang, Ke Xiao, Yan Qiao, Xin Li, Chuanjun Song, and
Junbiao Chang
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801351
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801351
Supported by

10.1002/ejoc.201801351
European Journal of Organic Chemistry
FULL PAPER
Base-promoted cycloisomerization for the synthesis of oxazoles
and imidazoles
Lidan Zhang,a Ke Xiao,a Yan Qiao,b Xin Li,a Chuanjun Song,*, a and Junbiao Chang*, a, c
O
Abstract: A cesium carbonate promoted, transition metal and
halogen-free 5-exo-dig type cyclization reaction for the synthesis of
oxazoles and imidazoles has been developed.
S
R1
N
N
N
O
O
Me
N
HO
O
N
N
N
+
N
N
R2
H
Me
R3
N
SMe
O
Introduction
N
N
2
3
R1
R
R
=
=
=
=
=
H
-
A,
gesashidine
O
R1
R1
R2
R2
R
H
3
=
,R3
=
CO2
,
,
O
A,
B,
dragmacidonamine
dragmacidonamine
-
Substituted oxazoles, imidazoles and related heterocycles are
important structural motifs present in many bioactive natural
products[1,2] (Figure 1) and pharmaceuticals[3] that display
antitumor, antiviral, antifungal, antibacterial, and antiproliferative
activities. They also serve as useful synthetic intermediates and
=
CO2
O
telomestatin
Figure 1. Examples of natural products that incorporate oxazoles and
imidazoles
ligands in organic synthesis.[4] Therefore, development of Results and Discussion
efficient strategies toward the synthesis of these heterocyclic
compounds from easily available starting materials is an active
research area.[5,6] Among these, the transition metal catalyzed
cycloisomerization of propargylamides and propargylamidines
has emerged as a popular method in recent years to access the
corresponding oxazoles and imidazoles.[7,8] However, the
majority of these methods face drawbacks such as harsh
reaction conditions, limited substrate scope, and poor functional
group tolerance. Also, removal of trace amount of toxic metal
catalysts from the desired products (often used as ligands) is
difficult. Recently, we have become interested in the base-
mediated cyclization reaction for the synthesis of structurally
interesting heterocyclic compounds.[9] Herein, we report an
efficient, general, and environmentally benign protocol for the
synthesis of oxazoles and imidazoles via cesium carbonate
Optimization of reaction conditions was carried out with
propargyl benzamide 1a and the results were collected in Table
1. The reaction was complete within two hours in the presence
o
of 2 equiv of sodium hydride at 100 C in DMSO. However, the
desired product 2a was isolated in 30% yield only (entry 1). The
product yield could be improved to 80% when potassium tert-
butoxide was applied (entry 2). No reaction occurred in the
presence of organic bases (entries 3, 4) or weak inorganic base
(entry 5). The reaction was sluggish in the presence of
potassium carbonate, and 2a was obtained in 21% isolated yield
after 2 hours, together with large amount of the unreacted
starting material recovered (entry 6). However, delightfully, the
reaction proceeded efficiently and cleanly when cesium
carbonate was used, and 2a was isolated in 89% yield (entry 7).
Therefore, we chose cesium carbonate as the base for further
optimization. Solvent screening indicated that polar solvent
favored product formation. 2a was isolated in 80% and 66%
yields, respectively, in acetonitrile and DMF (entries 10, 11),
while no reaction occurred in THF, 1,4-dioxane, toluene, or DCE
(entries 8, 9, 12, 13). Next, the base-to-substrate ratio and
reaction temperature were briefly explored (entries 14‒17), and
the best result remained by employing 2 equiv of cesium
carbonate in DMSO at 100 oC.
promoted
cycloisomerization
of
propargylamides
and
propargylamidines. To the best of our knowledge, these
represent the first examples of base-mediated cyclization of
propargylamidines for the assembly of imidazoles. [10]
Table 1. Optimization of reaction conditions for the base promoted synthesis
of oxazole 2a
[a]
Lidan Zhang, Ke Xiao, Xin Li, and Prof. Dr. Chuanjun Song
College of Chemistry and Molecular Engineering, Zhengzhou
University,
O
O
base/solvent
2 h
Zhengzhou 450001, P. R. China
E-mail: chjsong@zzu.edu.cn
Dr. Yan Qiao
Pathophysiology Department, Basic Medical College of Zhengzhou
University,
Zhengzhou 450001, China
N
N
H
[b]
[c]
2a
1a
Prof. Dr. Junbiao Chang
entry
base (equiv)
solvent
temp. (oC)
isolated
yield
Collaborative Innovation Center of New Drug Research and Safety
Evaluation, Henan Province,
Zhengzhou 450001, P. R. China
E-mail: changjunbiao@zzu.edu.cn
1
2
NaH (2.0)
DMSO
DMSO
100
100
30%
80%
KOtBu (2.0)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801351
European Journal of Organic Chemistry
FULL PAPER
a
a
a
3
NMM (2.0)
DMSO
DMSO
DMSO
DMSO
DMSO
THF
100
100
100
100
100
100
100
100
100
100
100
100
100
90
‒
‒
‒
Table 2. Substrate scope
R3
4
DBU (2.0)
Cs2CO
equiv)
3 (2
DMSO, 100 oC
R3
R2
5
NaHCO3 (2.0)
K2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (1.0)
Cs2CO3 (3.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
X
X
6
21% b
R1
R1
N
R2
=
NH)
O,
N
(X
H
-
7
89%
-
w
2a
w
1a
a
8
‒
a
O
O
O
9
1,4-dioxane
CH3CN
DMF
‒
O
N
N
N
Ph
10
11
12
13
14
15
16
17
80%
66%
N
MeO
F
2b
2c
2d
2a
81%
85%
90%
89%
,
,
,
,
a
toluene
DCE
‒
Br
O
O
O
O
F
3C
a
‒
N
N
N
N
Cl
NC
DMSO
DMSO
DMSO
DMSO
75%
85%
75%
88%
2f
2g
2h
45%
,
2e
,
85%
68%
82%
,
,
O
O
O
O
N
N
N
N
Ph
110
O
S
2j
74%
,
2k
,
2l
2i
61%
88%
,
97%
,
[a] No reaction. [b] incomplete reaction.
Ph
O
O
O
O
Ph
Ph
Ph
N
N
N
N
Ph
Ph
Ph
With the optimized reaction conditions in hand, the reaction
scope of various propargylamides and propargylamidines were
investigated, and the results were collected in Table 2. A series
of unsubstituted aryl propargylamides (R1 = Ar, R2 = R3 = H) with
either a para-, ortho-, or meta-substituted phenyl ring (1b-h)
reacted smoothly to give the corresponding oxazolines 2b-h in
moderate to good isolated yields. Under the reaction conditions,
naphthalenyl, as well as heteroaryl substituted oxazolines 2i-k
could also be obtained. Delightfully, the base-sensitive α,β-
unsaturated propargylamide 1l proceeded cleanly to give 2l
eventlessly. Further explorations indicated that internal (1m), α-
substituted (1n), and doubly substituted aryl acetylenic amide
moieties (1q-s) could all cyclize as expected to provide the
desired products (2m, n, q-s). The cyclization of aliphatic
propargylamides (1o, p) also proceeded efficiently, resulting in
the formation of 2o and 2p, respectively. Inspired by the results,
we then explored the cyclization reaction of propargylamidines
1t-w, which could be successfully conducted under the reaction
conditions to yield imidazoles 2t-w in good isolated yields.
Finally, bisamides 1x and 1y could also be persuaded to cyclize,
providing bisoxazolines 2x and 2y in 72% and 75% isolated
yields, respectively (Scheme 1).
2p
82%
2n
2o
80%
,
,
2m
83%
88%
,
,
Ph
Ph
Ph
O
O
O
Ph
N
N
Ph
N
Ph
Ph
2q
85%
2r
2s
53%
,
,
65%
,
Ph
N
N
N
N
N
H
N
N
N
H
Ph
Ph
H
H
F
3C
2t
85%
,
2v
,
2w
73%
,
2u
68%
75%
,
O
H
N
Cs2CO3
N
O
N
N
H
oC
DMSO,100
72%
O
O
2x
1x
N
O
Cs2CO3
O
N
NH
O
O
oC
DMSO,100
75%
HN
2y
1y
Scheme 1. Synthesis of bisoxazolines 2x and 2y
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10.1002/ejoc.201801351
European Journal of Organic Chemistry
FULL PAPER
Experimental Details. Melting points were determined on a hot-stage
apparatus and were uncorrected. Infrared spectra were obtained using
an FT-IR spectrometer. 1H and 13C NMR spectra were obtained on a 400
MHz spectrometer. High-resolution mass spectra were recorded on a Q-
TOF mass spectrometer. Flash column chromatography was performed
over silica gel 200―300 mesh.
Two possible mechanisms were proposed for the base-mediated
oxazoline formation. The first (mechanism A) involves a 5-exo-
dig cyclization via direct nucleophilic attack of the triple bond by
the deprotonated amide, followed by isomerization of the formed
exocyclic double bond. In the second mechanism (mechanism
B), rearrangement of acetylene occurs first to give an allenic
intermediate, which is then attacked by the amide moiety. In the
present work, a DFT study on the transformation of compound
1d to 2d was performed, as no theoretical calculations on this
kind of reaction have been carried out previously. According to
the calculated results, mechanism A consists of three reaction
steps, including deprotonation of the NH group, intramolecular
cyclization and double bond isomerization. As shown in Figure 2,
the first reaction step is a barrier-less process, and the second
reaction step is rate-determining with free energy barrier of 21.3
kcal/mol. The isomerization of the carbon-carbon double bond in
m2A to the thermodynamically more stable product 2d is
believed to be an easy process and thus was not considered in
the calculation. Mechanism B consists of five reaction steps,
including two consecutive proton transfer processes giving rise
to the allenic intermediate m2B, NH- deprotonation followed by
intramolecular cyclization and proton transfer to form the final
product. The intramolecular cyclization is rate-determining with
the highest free energy barrier of 18.6 kcal/mol. In comparison,
the free energy barrier of mechanism B is 2.7 kcal/mol lower
than that of mechanism A, indicating that mechanism B is more
energetically favorable.
General procedure for the preparation oxazoles and imidazoles 2a-
2y. A mixture of propargylamides/propargylamidines 1a-1y (1.0 mmol),
Cs2CO3 (2.0 mmol), and DMSO (5 mL) was stirred at 100 °C for 2 h and
cooled. Water (2 mL) was added. The resulting mixture was extracted
with ethyl acetate (3 × 20 mL). The combined organic extracts were
washed with brine (30 mL), then dried (Na2SO4), filtered and evaporated
in vacuo. The residue was purified by column chromatography on silica
gel (petroleum ether/EtOAc) to afford oxazoles and imidazoles 2a-2y.
5-Methyl-2-phenyloxazole (2a)[7f]: The title compound was prepared
according to the general produce by stirring a mixture of 1a (80 mg, 0.5
mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC for 2 h.
The crude product was purified by column chromatography on silica gel
(12% EtOAc in petroleum ether) to afford 2a (71 mg, 89% yield) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ = 8.00 (dd, J = 8.2, 2.0 Hz,
2H ), 7.46–7.38 (m, 3H), 6.83 (q, J = 1.3 Hz, 1H), 2.38 (d, J = 1.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ = 160.7, 148.9, 129.9, 128.7, 127.8, 125.9,
124.2, 11.1 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C10H10NO
160.0757, found 160.0764.
5-Methyl-2-(p-tolyl)oxazole (2b)[7f]: The title compound was prepared
according to the general produce by stirring a mixture of 1b (87 mg, 0.5
mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC for 2 h.
The crude product was purified by column chromatography on silica gel
(10% EtOAc in petroleum ether) to afford 2b (70 mg, 81% yield) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ = 7.88 (d, J = 8.0 Hz, 2H),
7.23 (d, J = 8.0 Hz, 2H), 6.80 (q, J = 1.2 Hz, 1H), 2.38 (s, 3H), 2.37 (d, J
= 1.2 Hz, 3H) ppm; 13C NMR (100MHz, CDCl3) δ = 160.9, 148.5, 140.0,
129.4, 125.9, 125.1, 124.0, 21.5, 11.0 ppm; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C11H12NO 174.0913, found 174.0916.
Cs
Cs
H
:
O
O
O
∆
G
O
N
(kcal/mol)
•
H
H
H
O
F
NH
F
O
NH
17.0
O
ts1A
NH
H
O
10.4
NH
7.9
O
F
ts1B
F
m1B
6.3
N
6.0
m1'B
ts2B
F
O
3.9
m2B
NH
F
H
O
1d
-2.9
2-(4'-Methoxyphenyl)-5-methyloxazole (2c)[7f]: The title compound was
prepared according to the general produce by stirring a mixture of 1c (95
mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC
for 2 h. The crude product was purified by column chromatography on
silica gel (10% EtOAc in petroleum ether) to afford 2c (80 mg, 85% yield)
as a colorless oil: 1H NMR (400 MHz,CDCl3) δ = 7.93 (d, J = 8.9 Hz, 2H),
6.95 (d, J = 8.9 Hz, 2H), 6.78 (q, J = 1.2 Hz, 3H), 3.85 (s, 3H), 2.37 (d, J
= 1.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 160.9, 160.8, 148.2,
127.5, 123.9, 120.7, 114.1, 55.4, 11.0 ppm; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C11H12NO2 190.0863, found 190.0864.
N
0.3
ts4B
-4.3
m2A
H
m1A
F
O
F
-12.2
O
NH
-14.2
m4B
N
O
ts3B
N
H
-18.0
-18.3
H
O
F
m3B
F
m2'B
F
N
-32.9
2d
-32.9
O
O
N
H
N
2d
H
F
O
O
N
N
F
F
F
F
Figure 2. The free energy profile for the two possible reaction mechanisms on
the transformation of 1d to 2d
Conclusions
2-(4'-Fluorophenyl)-5-methyloxazole (2d): The title compound was
prepared according to the general produce by stirring a mixture of 1d (89
mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC
for 2 h. The crude product was purified by column chromatography on
silica gel (12% EtOAc in petroleum ether) to afford 2d (80 mg, 90% yield)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ = 7.99–7.96 (m, 2H),
7.14–7.10 (m, 2H), 6.81 (q, J = 1.3 Hz, 1H), 2.38 (d, J = 1.3 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ = 163.7 (d, JF-C = 248.6 Hz ), 159.9, 148.9,
128.0 (d, JF-C = 8.5 Hz), 124.2, 124.2, 115.9 (d, JF-C = 21.9 Hz), 11.0 ppm;
IR (neat) νmax/cm−1 1625, 1562, 1405, 1370, 1274, 1030; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C10H9FNO 178.0663, found 178.0668.
In summary, we have developed an efficient and practical
approach toward the synthesis of oxazoles and imidazoles via
Cs2CO3-mediated cycloisomerization of propargylamides and
propargylamidines. A large variety of substrates with various
functional groups are tolerated. Moreover, the reaction does not
require the aid of halogen or transition metal catalyst, and is thus
environmentally friendly.
Experimental Section
2-(4'-Chlorophenyl)-5-methyloxazole (2e): The title compound was
prepared according to the general produce by stirring a mixture of 1e (97
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10.1002/ejoc.201801351
European Journal of Organic Chemistry
FULL PAPER
mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC
for 2 h. The crude product was purified by column chromatography on
silica gel (10% EtOAc in petroleum ether) to afford 2e (79 mg, 82% yield)
as a white solid: mp 36–37 oC; 1H NMR (400 MHz,CDCl3) δ = 7.92 (d, J =
8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 6.83 (q, J = 1.2 Hz, 1H), 2.38 (d, J =
1.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 159.8, 149.2, 135.9,
129.0, 127.2, 126.3, 124.4, 11.1 ppm; IR (neat) νmax/cm−1 1635, 1582,
1408, 1380, 1278, 1090; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C10H935ClNO 194.0367, found 194.0371.
silica gel (8% EtOAc in petroleum ether) to afford 2j (55 mg, 74% yield)
as an orange oil: 1H NMR (400 MHz, CDCl3) δ = 7.51 (dd, J = 1.7, 0.8 Hz,
1H), 6.93 (dd, J = 3.4, 0.8 Hz, 1H), 6.80 (q, J = 1.2 Hz, 1H), 6.51–6.49 (m,
1H), 2.36 (d, J = 1.2 Hz, 3H) ppm; 13C NMR (100MHz, CDCl3) δ = 153.6,
148.5, 143.9, 143.2, 124.0, 111.7, 110.4, 10.9 ppm; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C8H8NO2 150.0550, found 150.0548.
5-Methyl-2-(thiophen-2'-yl)oxazole (2k)[7b]: The title compound was
prepared according to the general produce by stirring a mixture of 1k (83
mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC
for 2 h. The crude product was purified by column chromatography on
silica gel (10% EtOAc in petroleum ether) to afford 2k (50 mg, 61% yield)
as an orange oil: 1H NMR (400 MHz, CDCl3) δ = 7.60 (dd, J = 3.7, 1.2
Hz ,1H), 7.36 (dd, J = 5.1, 1.2 Hz ,1H), 7.09–7.07 (m, 1H), 6.77 (q, J =
1.2 Hz, 1H), 2.36 (d, J = 1.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
= 156.9, 148.4, 130.5, 127.8, 127.5, 126.8, 124.1, 11.0 ppm; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C8H8NOS 166.0321, found 166.0334.
4-(5'-Methyloxazol-2'-yl)benzonitrile (2f): The title compound was
prepared according to the general produce by stirring a mixture of 1f (92
mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC
for 2 h. The crude product was purified by column chromatography on
silica gel (12% EtOAc in petroleum ether) to afford 2f (78 mg, 85% yield)
as a white solid: mp 90–91 oC; 1H NMR (400 MHz, CDCl3) δ = 8.09 (d, J
= 8.5 Hz, 2H), 7.73 (d, J = 8.5 Hz, 2H), 6.92 (q, J = 1.2 Hz, 1H), 2.43 (d, J
= 1.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 158.8, 150.4, 132.6,
131.5, 126.3, 125.1, 118.5, 113.1, 11.2 ppm; IR (neat) νmax/cm−1 2227,
1599, 1449, 1408, 1346, 1260, 1125; HRMS (ESI-TOF) m/z [M + H]+
calcd for C11H9N2O 185.0709, found 185.0718.
(E)-5-Methyl-2-styryloxazole (2l)[7f]: The title compound was prepared
according to the general produce by stirring a mixture of 1l (93 mg, 0.5
mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC for 2 h.
The crude product was purified by column chromatography on silica gel
(10% EtOAc in petroleum ether) to afford 2l (81 mg, 88% yield) as an
2-(2'-Bromophenyl)-5-methyloxazole (2g)[7i]: The title compound was
prepared according to the general produce by stirring a mixture of 1g
(119 mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2.0 mL) at
1
orange oil: H NMR (400 MHz, CDCl3) δ = 7.53–7.50 (m, 2H), 7.44–7.35
(m, 3H), 7.31 (tt, J = 7.1, 1.4 Hz, 1H), 6.90 (d, J = 16.4 Hz, 1H), 6.79 (q, J
= 1.2 Hz, 1H), 2.36 (d, J = 1.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ = 160.6, 148.6, 135.7, 134.7, 128.9, 128.8, 127.0, 124.4, 114.2, 11.1
ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C12H12NO 186.0913, found
186.0915.
100 oC for
2 h. The crude product was purified by column
chromatography on silica gel (16% EtOAc in petroleum ether) to afford
1
2g (81 mg, 68% yield) as a colorless oil: H NMR (400 MHz, CDCl3) δ =
7.90 (dd, J = 7.8, 1.8 Hz, 1H), 7.70 (dd, J = 8.0, 1.2 Hz, 1H), 7.39 (td, J =
7.5, 1.2 Hz , 1H), 7.28–7.24 (m, 1H), 6.93 (q, J = 1.2 Hz, 1H), 2.41 (d, J =
1.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 159.0, 149.4, 134.5,
130.9, 130.8, 128.6, 127.3, 124.2, 120.8, 11.1 ppm; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C10H979BrNO 237.9862, found 237.9857.
5-Benzyl-2-phenyloxazole (2m)[7d]: The title compound was prepared
according to the general produce by stirring a mixture of 1m (118 mg, 0.5
mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC for 2 h.
The crude product was purified by column chromatography on silica gel
(10% EtOAc in petroleum ether) to afford 2m (103 mg, 88% yield) as an
5-Methyl-2-[3'-(trifluoromethyl)phenyl]oxazole (2h)[11]
:
The title
1
compound was prepared according to the general produce by stirring a
mixture of 1h (114 mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and
DMSO (2 mL) at 100 oC for 2 h. The crude product was purified by
column chromatography on silica gel (14% EtOAc in petroleum ether) to
afford 2h (51 mg, 45% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ = 8.27 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.57 (t,
J = 7.8 Hz, 1H) 6.88 (q, J = 1.2 Hz, 1H), 2.42 (d, J = 1.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ = 159.3, 149.7, 131.3 (q, JF-C = 32.5 Hz),
129.3, 129.0 (q, JF-C = 1.4 Hz), 128.5, 126.3 (q, JF-C = 3.6 Hz), 124.6,
123.8 (q, JF-C = 270.7 Hz) , 122.8 (q, JF-C = 4.0 Hz), 11.1 ppm; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C11H9F3NO 228.0631, found 228.0631.
orange oil: H NMR (400 MHz, CDCl3) δ = 8.00–7.98 (m, 2H), 7.44–7.39
(m, 3H), 7.35–7.24 (m, 5H), 6.86 (t, J = 1.1 Hz, 1H), 4.06 (s, 2H) ppm;
13C NMR (100 MHz, CDCl3) δ = 161.3, 151.4, 136.7, 130.1, 128.7, 128.7,
128.7, 127.7, 127.0, 126.1, 124.9, 32.2 ppm; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C16H14NO 236.1070, found 236.1074.
5-Methyl-2,4-diphenyloxazole (2n)[12]
:
The title compound was
prepared according to the general produce by stirring a mixture of 1n
(118 mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at
100 oC for
2 h. The crude product was purified by column
chromatography on silica gel (20% EtOAc in petroleum ether) to afford
2n (98 mg, 83% yield) as a white solid: mp 72–73 oC; 1H NMR (400 MHz,
CDCl3) δ = 8.12–8.09 (m, 2H), 7.77–7.75 (m, 2H), 7.50–7.42 (m, 5H),
7.36–7.32 (m, 1H), 2.26 (s, 3H) ppm; 13C NMR (100MHz, CDCl3) δ =
159.4, 144.0, 136.0, 132.4, 130.0, 128.7, 128.6, 127.7, 127.3, 126.8,
126.2, 12.1 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14NO
236.1070, found 236.1075.
5-Methyl-2-(naphthalen-2'-yl)oxazole (2i): The title compound was
prepared according to the general produce by stirring a mixture of 1i (105
mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC
for 2 h. The crude product was purified by column chromatography on
silica gel (10% EtOAc in petroleum ether) to afford 2i (101 mg, 97% yield)
as a white solid: mp 102–103 oC; 1H NMR (400 MHz, CDCl3) δ = 8.49 (s,
1H), 8.11 (dd, J = 8.6, 1.8 Hz, 1H), 7.94–7.83 (m, 3H), 7.54–7.50 (m, 2H),
6.89 (q, J = 1.2 Hz, 1H), 2.44 (d, J = 1.2 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ = 160.9, 149.1, 133.9, 133.1, 128.6, 128.6, 127.9, 127.0,
126.7, 125.6, 125.1, 124.4, 123.2, 11.2 ppm; IR (neat) νmax/cm−1 1599,
1508, 1439, 1368, 1260, 1111; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C14H12NO 210.0913, found 210.0918.
2,5-dimethyl-4-phenyloxazole (2o)[13]
:
The title compound was
prepared according to the general produce by stirring a mixture of 1o (87
mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC
for 2 h. The crude product was purified by column chromatography on
silica gel (13% EtOAc in petroleum ether) to afford 2o (69 mg, 80% yield)
as an orange oil: 1H NMR (400 MHz, CDCl3) δ = 7.64–7.61 (m, 2H), 7.40
(t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 2.47 (s, 3H), 2.44 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ = 159.1, 143.3, 134.3, 132.5, 128.6, 127.0,
126.5, 13.8, 11.8 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C11H12NO 174.0913, found 174.0917.
2-(Furan-2'-yl)-5-methyloxazole (2j)[7f]
:
The title compound was
prepared according to the general produce by stirring a mixture of 1j (75
mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100oC
for 2 h. The crude product was purified by column chromatography on
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10.1002/ejoc.201801351
European Journal of Organic Chemistry
FULL PAPER
2-Benzyl-5-methyl-4-phenyloxazole (2p): The title compound was
prepared according to the general produce by stirring a mixture of 1p
(125 mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at
4-Methyl-2-(p-tolyl)-1H-imidazole (2u)[16]
prepared according to the general procedure by stirring a mixture of 1u
:
The title compound was
(86 mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at
100 oC for
2
h. The crude product was purified by column
100 oC for
2
h. The crude product was purified by column
chromatography on silica gel (10% EtOAc in petroleum ether) to afford
2p (102 mg, 82% yield) as an orange oil : 1H NMR (400 MHz, CDCl3), δ =
7.65 (dd, J = 8.5, 1.5 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.36–7.30 (m, 6H),
4.12 (s, 2H), 2.48 (s, 3H) ppm; 13C NMR (100MHz, CDCl3) δ = 160.6,
144.0, 135.8, 134.5, 132.4, 128.8, 128.7, 128.6, 127.1, 127.0, 126.7,
34.7, 11.9 ppm; IR (neat) νmax/cm−1 1585, 1571, 1448, 1287, 1163, 1014,
1111; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H16NO 250.1226,
found 250.1226.
chromatography on silica gel (40% EtOAc in petroleum ether) to afford
o
imidazole 2u (65 mg, 75% yield) as a yellow solid: mp 210–211 C [lit[16]
mp 214 °C]; 1H NMR (400 MHz, DMSO) δ = 7.78 (d, J = 8.2 Hz, 2H),
7.21 (d, J = 8.2 Hz, 2H), 6.68 (s, 1H), 2.31 (s, 3H), 2.19 (s, 3H) ppm; 13
,
C
NMR (100 MHz, DMSO) δ = 145.3, 137.3, 129.6, 128.8, 124.9, 21.3, 12.4
ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C11H13N2 173.1073, found
173.1075.
4-Methyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazole (2v): The title
compound was prepared according to the general procedure by stirring a
mixture of 1v (113 mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and
DMSO (2 mL) at 100 oC for 2 h. The crude product was purified by
column chromatography on silica gel (30% EtOAc in petroleum ether) to
afford imidazole 2v (77 mg, 68% yield) as a white solid: mp 211–212 oC;
1H NMR (400 MHz, DMSO) δ = 12.51 (s, 1H), 8.09 (d, J = 8.2 Hz, 2H),
7.77 (d, J = 8.2 Hz, 2H), 6.90 (s, 1H), 2.22 (s, 3H) ppm; 13C NMR (100
5-(Cyclopropylmethyl)-2,4-diphenyloxazole (2q): The title compound
was prepared according to the general produce by stirring a mixture of
1q (138 mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL)
at 100 oC for
2 h. The crude product was purified by column
chromatography on silica gel (15% EtOAc in petroleum ether) to afford
2q (117 mg, 85% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ =
8.11 (dd, J = 8.1, 1.9 Hz, 2H), 7.74 (dd, J = 8.5, 1.5 Hz, 2H), 7.50–7.42
(m, 5H), 7.36–7.32 (m, 1H), 2.91 (d, J = 6.6 Hz, 2H), 1.19–1.15 (m, 1H),
0.61–0.56 (m, 2H), 0.35–0.31 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
δ = 159.6, 147.5, 136.0, 132.4, 130.0, 128.7, 128.6, 127.8, 127.5, 127.1,
126.2, 30.4, 9.8, 4.5 ppm; IR (neat) νmax/cm−1 1596, 1494, 1448, 1338,
1259, 1156; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H18NO 276.1383,
found 276.1385.
MHz, DMSO) δ = 143.7, 135.0, 127.9 (q, JF-C = 31.7 Hz), 126.1 (q, JF-C
=
4.0 Hz), 125.2, 124.32 (q, JF-C = 270.1 Hz), 14.49; IR (neat) νmax/cm−1
1605, 1536, 1444, 1322, 1248, 1095; HRMS (ESI-TOF) m/z [M + H]+
calcd for C11H10F3N2 227.0791, found 227.0790.
4-Benzyl-2-phenyl-1H-imidazole (2w)[8a]: The title compound was
prepared according to the general procedure by stirring a mixture of 1w
(117 mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at
100 oC for 2 h. The crude product was purified by column
chromatography on silica gel (30% EtOAc in petroleum ether) to afford
imidazole 2w (85 mg, 73% yield) as a yellow solid: mp 170–171 oC ; 1H
NMR (400 MHz, DMSO) δ = 7.90 (d, J = 7.1 Hz, 2H), 7.41 (d, J = 7.7 Hz,
2H), 7.32–7.28 (m, 5H), 7.22–7.16 (m, 1H), 6.86 (s, 1H), 3.90 (s, 2H)
ppm; 13C NMR (100 MHz, DMSO) δ = 145.6, 140.9, 131.3, 129.1, 129.0,
128.7, 128.2, 126.4, 125.1, 33.5 ppm; HRMS (ESI-TOF) m/z [M + H]+
calcd for C11H15N2 235.1230, found 235.1230.
5-Benzyl-2,4-diphenyloxazole (2r)[14]: The title compound was prepared
according to the general produce by stirring a mixture of 1r (156 mg, 0.5
mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC for 2 h.
The crude product was purified by column chromatography on silica gel
(15% EtOAc in petroleum ether) to afford 2r (101 mg, 65% yield) as an
1
orange oil: H NMR (400 MHz, CDCl3) δ = 8.10–8.08 (m, 2H), 7.77–7.74
(m, 2H), 7.48–7.42 (m, 5H), 7.38–7.27 (m, 6H), 4.43 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ = 160.2, 145.6, 137.3, 137.3, 132.1, 130.2, 128.8,
128.7, 128.3, 127.7, 127.6, 127.1, 126.8, 126.3, 32.0; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C22H18NO 312.1383, found 312.1383.
5,5'-Dimethyl-2,2'-bioxazole (2x): The title compound was prepared
according to the general produce by stirring a mixture of 1t (82 mg, 0.5
mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC for 2 h.
The crude product was purified by column chromatography on silica gel
(10% EtOAc in petroleum ether) to afford 2x (59 mg, 72% yield) as a
white solid: mp 100–101 oC; 1H NMR (400 MHz, CDCl3) δ = 6.91 (q, J =
1.2 Hz, 2H), 2.41 (d, J = 1.2 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ
= 150.7, 150.5, 124.8, 11.0 ppm; IR (neat) νmax/cm−1 1600, 1473, 1442,
1288, 1132, 1008; HRMS (ESI-TOF) m/z [M + H]+ calcd for C8H9N2O2
165.0659, found 165.0669.
5-Benzyl-4-cyclohexyl-2-phenyloxazole (2s)[14]: The title compound
was prepared according to the general produce by stirring a mixture of 1s
(159 mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at
100 oC for
2 h. The crude product was purified by column
chromatography on silica gel (18% EtOAc in petroleum ether) to afford
2s (84 mg, 53% yield) as a white solid: mp 94–96 oC; 1H NMR (400 MHz,
CDCl3) δ = 7.99–7.97 (m, 2H), 7.41–7.31 (m, 5H), 7.26–7.24 (m, 3H),
4.07 (s, 2H), 2.57 (tt, J = 11.8, 3.6 Hz, 1H), 1.88–1.68 (m, 7H), 1.36–1.33
(m, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 159.8, 144.0, 142.2, 138.0,
129.7, 128.6, 128.5, 128.3, 128.0, 126.6, 126.1, 35.7, 32.4, 31.2, 26.6,
25.9 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H24NO 318.1852,
found 318.1851.
1,4-Bis(5'-methyloxazol-2'-yl)benzene (2y)[7b]: The title compound was
prepared according to the general produce by stirring a mixture of 1y
(120 mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at
4-Methyl-2-phenyl-1H-imidazole (2t)[15]: The title compound was
prepared according to the general produce by stirring a mixture of 1t (79
mg, 0.5 mmol), Cs2CO3 (326 mg, 1.0 mmol), and DMSO (2 mL) at 100 oC
for 2 h. The crude product was purified by column chromatography on
silica gel (30% EtOAc in petroleum ether) to afford imidazole 2t (67 mg,
85% yield) as a yellow solid: mp 184–185 oC [lit[15], mp 180.5–181.6 °C];
1H NMR (400 MHz, DMSO) δ = 7.89 (d, J = 7.1 Hz, 2H), 7.42 (t, J = 7.6
Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 6.83 (s, 1H), 2.20 (s, 3H) ppm; 13C NMR
(100 MHz, DMSO) δ = 145.1, 131.4, 129.1, 128.0, 124.9, 12.4 ppm;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C10H11N2 159.0917, found
159.0922.
100 oC for
2 h. The crude product was purified by column
chromatography on silica gel (10% EtOAc in petroleum ether) to afford
2y (90 mg, 75% yield) as a white solid: mp 174–175 oC [ lit[7b], mp 170
oC ]; 1H NMR (400 MHz, CDCl3) δ = 8.05 (s, 4H), 6.85 (q, J = 1.2 Hz, 2H),
2.39 (d, J = 1.2 Hz, 6H) ppm; 13C NMR (100MHz, CDCl3) δ = 160.1,
149.3, 128.7, 126.2, 124.6, 11.1 ppm; HRMS (ESI-TOF) m/z [M + H]+
calcd for C14H13N2O2 241.0972, found 241.0972.
Acknowledgements
We are grateful to the NSFC (#81330075) for financial support.
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10.1002/ejoc.201801351
European Journal of Organic Chemistry
FULL PAPER
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Keywords: oxazoles • imidazoles • cyclization • alkynes •
transition metal free
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10.1002/ejoc.201801351
European Journal of Organic Chemistry
FULL PAPER
Heterocycle synthesis
Lidan Zhang,a Ke Xiao,a Yan Qiao,b Xin
Li,a Chuanjun Song,*, a and Junbiao
Chang*, a, c
R3
Cs2CO3
R3
R2
X
DMSO, 100 oC
X
Text for Table of Contents
Page No. – Page No.
R1
N
Base-promoted cycloisomerization for
the synthesis of oxazoles and
imidazoles
R1
N
R2
=
NH)
O,
(X
H
Treatment of propargylamides or propargylamidines with cesium carbonate in DMSO results in the formation of the
corresponding oxazoles or imidazoles in good yields. A large variety of substrates with various functional groups are
tolerated. DFT study on a model substrate reveals that the reactions proceed via a sequence involving allene formation,
intramolecular cyclization, and double-bond isomerization.
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