A rapid access to substituted oxazoles via PIFA-mediated oxidative cyclization of enamides

Article abstract of DOI:10.1016/j.tet.2017.01.027

A facile and rapid access to multi-substituted oxazoles has been achieved under mild reaction conditions in a short reaction time. Reaction of enamides 1 with [bis(trifluoroacetoxy)iodo]benzene (PIFA) in trifluoroethanol (TFE) at room temperature for 15?min afforded the desired oxazoles 2 in moderate to excellent yields (58–98%). A wide range of functional group tolerance has been observed for these transformations.

Full text of DOI:10.1016/j.tet.2017.01.027

Tetrahedron xxx (2017) 1e8
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A rapid access to substituted oxazoles via PIFA-mediated oxidative
cyclization of enamides
Midori Kamiya, Motohiro Sonoda, Shinji Tanimori*
Department of Applied Biosciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuencho, Nakaku, Sakai, Osaka,
599-8531, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and rapid access to multi-substituted oxazoles has been achieved under mild reaction conditions
in a short reaction time. Reaction of enamides 1 with [bis(trifluoroacetoxy)iodo]benzene (PIFA) in tri-
fluoroethanol (TFE) at room temperature for 15 min afforded the desired oxazoles 2 in moderate to
excellent yields (58e98%). A wide range of functional group tolerance has been observed for these
transformations.
Received 2 December 2016
Received in revised form
7 January 2017
Accepted 10 January 2017
Available online xxx
© 2017 Elsevier Ltd. All rights reserved.
Keywords:
Oxazole
Hypervalent iodine
Enamide
Oxidative cyclization
PIFA
1. Introduction
with other reagents17 and oxidation of oxazolines.18 However, these
methodologies suffer from some disadvantages, such as the
Oxazoles are one of the valuable scaffolds existing in a wide
variety of biologically active compounds, such like pharmaceuticals
and agrochemicals (Fig. 1).1 Therefore, various synthetic methods
have been developed for the synthesis of oxazoles with diverse
substituents,2 which include the method based on Van Leusen
oxazole synthesis,3 cyclyzation of enamide by hypervalent iodine
reagent PhI(OTf)2 generated in situ,4 phenyliodine diacetate
(PIDA),5 NBS,6 and catalytic copper(II) with oxidant,7 synthesis
from amides and amines with ketones through a CeN and CeO
bond forming ring closure,8 annulation of alkynes, nitriles, and O-
atoms,9 cyclization of acetylenic amides,10 ring expansion of keto
aziridines,11 a [2 þ 2 þ 1] annulation of a terminal alkyne,12 t-
BuOOH/I2-mediated domino oxidative cyclization from alkenes and
amines,13 an iodine-catalyzed tandem oxidative cyclization from
requirement of Brønsted acid catalysts, transition-metal catalysts,
Lewis acid reagents, or previously prepared substrates, which limit
the overall functional group tolerance of the transformation. As
indicated above, oxidative cyclyzation of enamide to oxazole under
metal-free condition have been reported by employing hypervalent
iodine and NBS.4e6,16 This approach without the use of toxic tran-
sition metal would be more environmentally benign process.
However these processes require excess Lewis acid, longer reaction
time, and higher temperature. In this report, we disclose the suc-
cessful PIFA-mediated rapid and highly efficient access to
substituted oxazoles with broad substrate scope by the use of tri-
fluoroethanol (TFE) as solvent (Fig. 2).
2. Results and discussion
aldehydes and b
eaminoketones,14 the cyclization of propargyl al-
cohols and amides by p-toluenesulfonic acid (PTSA) and Zn(OTf)2,15
I2-catalyzed CeO bond formation and dehydrogenation with TBHP
The optimization studies were carried out with enamide 1a as
model substrate (Table 1). Reaction of 1a derived from benzamide
and acetylacetone (see supporting informations) with PIFA (1.1
equiv) in acetonerile at room temperature for 26 h afforded the
desired oxazole 2a in 14% yield (entry 1). Another solvents (CH2Cl2,
(ClCH2)2, and EtOH) with the use of PIFA resulted in the unsatis-
factory yields (entries 2e4, 11e27%). To our delight, the yield was
dramatically grown up to 91% isolated yield by changing the solvent
from b
-acylamino ketones.16 Traditional methods for synthesizing
oxazoles have also been composed of the CeC coupling of oxazoles
* Corresponding author.
E-mail address: tanimori@bioinfo.osakafu-u.ac.jp (S. Tanimori).
http://dx.doi.org/10.1016/j.tet.2017.01.027
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2
M. Kamiya et al. / Tetrahedron xxx (2017) 1e8
1k, which resulted in complete recovery of starting material. The
reason was temporary assumed as follows. Coordination of PIFA to
the amide oxygen in 1k would be inhibited due to the decrease of
electron density of amide oxygen by the strong electron-
withdrawing nature of trifluoromethyl group (see Fig. 2).
A one-pot process without the isolation of enamide intermedi-
ate has been achieved by using 2-methylbenzamide and acetyla-
cetone as the starting materials (Scheme 1). A reaction of both
starting materials in the presence of acid catalyst afforded enamide
1e, after removal of the solvent in vacuo, the residue was directly
subjected to the optimal conditions to provide target oxazole 2e in
63% isolated yield.
Fig. 1. A natural product and drugs with oxazole structures.
A plausible mechanism for the formation of oxazoles 2 from
enamides 1 mediated by PIFA is shown in Fig. 3. At first, the iodo
intermediate I was formed from the reaction of the enamide sub-
strate 1 with PIFA by losing one molecule of trifluoroacetic acid and
concomitant E/Z-isomerization. The E/Z-isomerization would occur
easily due to the release of intramolecular hydrogen bond between
NH hydrogen and ketone oxygen atom. Then, nucleophilic addition
of the carbonyl oxygen atom to the sp2 carbon occurred, forming
five-membered carbocation II with the release of PhI and CF3COꢀ2 .
Subsequent deprotonation provided product 2 by the action of
CF3COꢀ2 . The effect of fluorous solvent (TFE) in the reaction has not
been unclear at present. Presumably, TFE would accelerate the E/Z-
isomerization and deprotonation step (II / 2) by coordination of
carbonyl group. The activation of PIFA by coordination, which
would enhance the electrophilicity of iodine (III) center, and also
enhancing the solubility of reagents would also probable.19
Finally, to demonstrate the utility of this reaction, the interme-
diate for a potential antitumor agent20 has been synthesized
smoothly in 3 steps via the cyclization of enamide 1q from
commercially available starting materials in good yield (Scheme 2).
Reaction of ethyl (2-fluorobenzoyl)acetate with ammonium ace-
tate20 followed by acetyl chloride afforded enamide 1r in 63% yield
(2 steps). The cyclization of enamide 1q to oxazole 2q has been
accomplished under the standard conditions in 84% yield. Previous
synthesis from the same starting materials under the presence of
Fig. 2. Transition-metal-free synthesis of oxazoles.
Table 1
Optimization studies for the transformation of enamide 1a to oxazole 2a.a
Entry
Oxidant (equiv.)
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
PIFA (1.1)
PIFA (1.1)
PIFA (1.1)
PIFA (1.1)
PIFA (1.1)
PIDA (1.1)
e
MeCN
CH2Cl2
ClCH2CH2Cl
EtOH
TFE
TFE
26
28
24
24
0.25
20
0.25
14b
11c
27c
22c
HDNIB
([hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]benzene)
afforded oxazole 2q in only 20% yield.19
91b (93%)b,d
81b
0
TFE
3. Conclusion
TFE ¼ trifleoroethanol, PIDA ¼ phenyliodine (III) diacetate, PIFA ¼ phenyliodine (III)
bis (trifluoroacetate).
In conclusions, we have demonstrated a rapid and efficient ac-
cess to substituted oxazoles from readily available starting mate-
rials (typically, amides and 1,3-dicarbonyl compounds). The success
rely on the modification of previous method (Fig. 2) by just
replacing the solvent to trifluoroethanol, which resulted in higher
yields (up to 98% isolated yields), milder reaction conditions (room
temperature (standard conditions)), shorter reaction time (15 min
(standard conditions)), and broad substrate scope (15 examples)
avoiding the use of additives such like Lewis acid and base. Further
studies directed toward the application of this method to the
synthesis of other biologically active compounds and heterocyclic
compounds are now under way and will be reported in due course.
a
Reaction conditions: enamide (1a; 0.25 mmol, 1 equiv.) and PIFA or PIDA (1.1
equiv.) in TFE at room temperature.
b
Isolated yield.
GC yield.
c
d
Result with 1.0 g of starting material and 1.3 equiv. of PIFA.
to trifluoroethanol (TFE) (entry 5). Iodobenzene diacetate (PIDA)
also afforded a good yield of product (entry 6). A reaction without
the use of oxidant did not take place (entry 7). A gram-scale
transformation also provided oxazole 2a in a comparable yield
(93%, entry 5 in parenthesis).
Next, we carried out the cyclization of several enamides under
the optimized conditions to elucidate the scope of the reaction
(Table 2). Regarding the R2 and R3 substitutions, alkyls (2b and 2c),
aromatic (2d), and ester (2l and 2o) accept the transformation to
provide the corresponding oxazoles in moderate to excellent yields.
Substitutions at the aromatic ring did not influence the reactivity in
spite of the electronic nature and positions (2e, 2f, 2g, 2h and 2i).
Displacement of benzene ring to alkyls (2j, 2l, and 2m) including a
sterically hindered (2n) and heteroaromatic ones (2p) did not in-
fluence the reactivity to afford desired substituted oxazoles in
excellent yields except for trifluoromethyl-substituted substrate
4. Experimental section
4.1. General
Unless stated otherwise, reactions were monitored by thin layer
chromatography (TLC) on silica gel plates (60 F254), visualizing
with ultraviolet light or iodine spray. Column chromatography was
performed on silica gel (60e120 mesh) using hexane and ethyl
acetate. 1H and 13C NMR spectra were determined in CDCl3 solution
using 400 and 100 MHz spectrometers, respectively. Proton
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M. Kamiya et al. / Tetrahedron xxx (2017) 1e8
3
Table 2
Synthesis of diversely substituted oxazoles.a3
Scheme 1. One-pot synthesis of oxazole 2e.
Scheme 2. Formal synthesis of antitumor agent.
Fig. 3. Plausible mechanism for the formation of oxazole from enamide.
the internal standard and expressed in parts per million. Spin
multiplicities are given as s (singlet), d (doublet), t (triplet), and m
chemical shifts (
d) are relative to tetramethylsilane (TMS,
d
¼ 0.0) as
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M. Kamiya et al. / Tetrahedron xxx (2017) 1e8
(multiplet) as well as b (broad). Coupling constants (J) are given in
hertz. Infrared spectra were recorded on an FT-IR spectrometer.
Melting points were determined by using a Büchi melting point B-
540 apparatus and are uncorrected. MS spectra were obtained on a
mass spectrometer. HRMS was determined using JEOL JNM-AX 500
mass spectrometer.
silica gel column chromatography (hexane:EtOAc ¼ 8:1) and
recrystallization with EtOAc provided 1d (0.37 g, 41%) as a pale
yellow needle crystal; Rf 0.4 (hexane:EtOAc ¼ 8:1); mp 109 ꢁC (lit.23
108e110 ꢁC); 1H NMR (400 MHz, CDCl3)
d
¼ 13.85 (br. s, 1H), 8.11
(dd, J ¼ 7.1, 1.2 Hz, 2H), 7.96 (dd, J ¼ 7.1, 1.5 Hz, 2H), 7.66e7.50 (m,
4H), 7.47 (dd, J ¼ 7.6, 7.1 Hz, 2H), 6.18 (s, 1H), 2.68 (s, 3H) ppm; 13
C
NMR (100 MHz, CDCl3)
d
¼ 191.8, 166.2, 158.2, 138.7, 133.7, 132.6,
4.2. General procedures for the synthesis of enamides (1a-n and
1p)21
132.4, 128.9 (2C), 128.6 (2C), 128.0 (2C), 127.7 (2C), 102.5, 22.7 ppm.
4.2.5. 3-Methyl-N-((Z)-1-methyl-3-oxobut-1-enyl)benzamide (1e)
Following the general procedure, m-toluamide (0.65 g,
4.8 mmol), acetylacetone (0.39 g, 3.9 mmol), and p-TsOH (40.0 mg,
0.2 mmol) was stirred in toluene (12 ml) for 6 h. Purification by
silica gel column chromatography (hexane:EtOAc ¼ 7:1) provided
1e (0.64 g, 77%) as a pale yellow solid; Rf 0.31 (hexane:EtOAc ¼ 7:1);
mp 67e68 ꢁC; IR (KBr): 3054, 1962, 1689, 1638, 1592, 1481, 1261,
p-Toluenesulfonic acid (4e20 mol%) was added to a stirred so-
lution of amide (1.0 equiv) and diketone (0.8e6.3 equiv) in solvent
and the mixture was stirred for a period of time at reflux temper-
ature. After that the mixture was allowed to cool to room tem-
perature. The mixture was washed with saturated aqueous NaHCO3
and water, dried over Na2SO4 and solvent was evaporated in vacuo.
The residue was purified by silica gel column chromatography or
recrystallization to afford pure substituted enamides 1.
1169, 811, 731 cmꢀ1; 1H NMR (400 MHz, CDCl3)
7.88e7.78 (m, 2H), 7.43e7.34 (m, 2H), 5.46 (s, 1H), 2.53 (s, 3H), 2.44
(s, 3H) 2.20 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 13.33 (br. s, 1H),
d
¼ 199.9,166.2,
4.2.1. N-((Z)-1-Methyl-3-oxobut-1-enyl)benzamide (1a)22
156.0, 138.7, 133.6, 133.3, 128.7, 128.6, 124.8, 106.0, 30.4, 22.0,
21.4 ppm; HRMS (FAB): m/z [MþH]þ calcd for C13H16O2N: 218.1181,
found: 218.1160.
Following the general procedure, benzamide (1.5 g, 12.5 mmol),
acetylacetone (1.0 g, 10 mmol), and p-TsOH (0.12 g, 0.63 mmol) was
stirred in toluene (20 ml) for 6 h. Purification by recrystallization
with chloroform provided 1a (1.1 g, 54%) as a pale yellow solid; Rf
0.47 (hexane:EtOAc ¼ 5:1); mp 81e82 ꢁC (lit.22 82e83 ꢁC); 1H NMR
4.2.6. 2-Methoxy-N-((Z)-1-methyl-3-oxo-3-phenylpropenyl)
benzamide (1f)
Following the general procedure, o-methoxybenzamide (0.20 g,
1.3 mmol), 1-phenyl-1,3-butanedione (0.21 g, 1.32 mmol), and p-
TsOH (18.0 mg, 0.07 mmol) was stirred in toluene (2.5 ml) for 6 h.
(400 MHz, CDCl3)
d
¼ 13.40 (br. s, 1H), 8.09e7.95 (m, 2H), 7.61e7.45
(m, 3H), 5.47 (s, 1H), 2.54 (s, 3H), 2.21 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3)
d
¼ 200.0, 166.0, 156.1, 133.6, 132.6, 128.8 (2C),
127.9 (2C), 106.1, 30.4, 22.0 ppm.
Purification
by
silica
gel
column
chromatography
(hexane:EtOAc ¼ 5:1) provided 1f (0.16 g, 40%) as a pale yellow oil;
4.2.2. N-((Z)-1-Ethyl-3-oxopent-1-enyl)benzamide (1b)
Rf 0.4 (hexane:EtOAc ¼ 5:1); IR (NaCl): 3457, 3069,1925,1677,1628,
Following the general procedure, benzamide (0.61 g, 5.0 mmol),
3,5-heptanedione (0.51 g, 4.0 mmol), and p-TsOH (50.6 mg,
0.27 mmol) was stirred in toluene (9 ml) for 7.5 h. Purification by
silica gel column chromatography (hexane:EtOAc ¼ 15:1) provided
1590, 1475, 1023, 760 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
¼ 13.50
(br. s, 1H), 8.08 (dd, J ¼ 7.8, 2.0 Hz, 1H), 7.99e7.92 (m, 2H), 7.55e7.42
(m, 4H), 7.09e7.01 (m, 2H), 6.12 (s, 1H), 4.17 (s, 3H), 2.67 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 190.2,165.4,157.9,156.3,139.2,
1b (0.63 g, 68%) as
a
pale yellow solid; Rf 0.36
133.8, 132.4, 132.0, 128.4 (2C), 127.6 (2C), 122.0, 120.8, 111.4, 103.2,
55.6, 24.0 ppm; HRMS (FAB): m/z [MþH]þ calcd for C18H18O3N:
296.1287, found: 296.1289.
(hexane:EtOAc ¼ 15:1); mp 33e35 ꢁC; IR (KBr): 3741, 2971, 1692,
1643, 1601, 1479, 1150, 703 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
¼ 13.34 (br. s, 1H), 8.05 (dd, 2H, J ¼ 6.8, 2.0 Hz), 7.59e7.46 (m, 3H),
5.52 (s, 1H), 2.96 (q, J ¼ 7.3 Hz, 2H), 2.50 (q, J ¼ 7.3 Hz, 2H), 1.24 (t,
4.2.7. 2-Bromo-N-((Z)-1-ethyl-3-oxopent-1-enyl)benzamide (1g)
Following the general procedure, o-Bromobenzamide (0.52 g,
2.6 mmol), 3,5-heptanedione (0.27 g, 2.1 mmol), and p-TsOH
(30.0 mg, 0.16 mmol) was stirred in toluene (2.5 ml) for 6 h. Puri-
fication by silica gel column chromatography (hexane:EtOAc ¼ 8:1)
J ¼ 7.3 Hz, 3H), 1.15 (t, J ¼ 7.3 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3)
d
¼ 203.7, 165.4, 161.0, 133.8, 132.4, 128.8 (2C), 127.9 (2C),
103.7, 36.5, 27.5, 12.7, 8.7 ppm; HRMS (FAB): m/z [MþH]þ calcd for
C
14H18O2N: 232.1337, found: 232.1333.
provided 1g (0.36 g, 56%) as
a pale yellow oil; Rf 0.34
4.2.3. N-((Z)-1-isopropyl-4-methyl-3-oxopent-1-enyl)benzamide
(1c)
Following the general procedure, benzamide (0.60 g, 5.0 mmol),
2,6-dimethyl-3,5-heptanedione (0.63 g, 4.0 mmol), and p-TsOH
(49.5 mg, 0.26 mmol) was stirred in toluene (13 ml) for 24 h. Pu-
(hexane:EtOAc ¼ 8:1); IR (NaCl): 2976, 1819, 1706, 1593, 1483, 1244,
1119, 1032, 823, 742 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
¼ 12.64 (br.
s, 1H), 7.63 (d, J ¼ 8.0 Hz, 1H), 7.54 (dd, J ¼ 7.6, 1.2 Hz, 1H), 7.39 (dt,
J ¼ 7.6, 1.2 Hz, 1H), 7.31 (dt, J ¼ 8.0, 1.7 Hz, 1H), 5.51 (s, 1H), 2.95 (q,
J ¼ 7.3 Hz, 2H), 2.47 (q, J ¼ 7.3 Hz, 2H), 1.26 (t, J ¼ 7.3 Hz, 3H), 1.08 (t,
rification
by
silica
gel
column
chromatography
J ¼ 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 203.4, 166.2,
(hexane:EtOAc ¼ 17:1) provided 1c (0.34 g, 32%) as a yellow oil; Rf
159.7, 137.6, 133.8, 131.6, 128.8, 127.6, 119.8, 104.2, 36.5, 27.4, 12.6,
8.3 ppm; HRMS (FAB): m/z [MþH]þ calcd for C14H17O2N79Br:
310.0443, C14H17O2N81Br: 312.0422, found: 310.0459, 312.0422.
0.4 (hexane:EtOAc ¼ 17:1); IR (NaCl): 2970, 1599, 1475, 1247, 1139,
1067, 915, 814, 707 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
¼ 13.41 (br. s,
1H), 8.06 (d, J ¼ 6.8 Hz, 2H), 7.56e7.49 (m, 3H), 5.65 (s, 1H), 4.12
(sep, J ¼ 6.8 Hz,1H), 2.67 (sep, J ¼ 6.8 Hz,1H),1.24 (d, J ¼ 6.8 Hz, 6H),
4.2.8. 3-Cyano-N-((Z)-1-methyl-3-oxobut-1-enyl)benzamide (1h)
Following the general procedure, 3-cyanobenzamide (0.22 g,
1.50 mmol), acetylacetone (0.44 g, 4.41 mmol), and p-TsOH
(15.0 mg, 0.08 mmol) was stirred in toluene (5 ml) for 5.5 h. Puri-
fication by recrystallization with EtOH provided 1h (0.25 g, 72%) as
a pale brown needle crystal; Rf 0.3 (hexane:EtOAc ¼ 3:1); mp
178e180 ꢁC; IR (KBr): 3067, 2231, 1688, 1635, 1594, 1477, 1260, 1166,
1.16 (d, J ¼ 7.1 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 207.2,
166.7,165.5,134.2,132.3,128.8 (2C),127.9 (2C),100.0, 41.3, 29.6, 21.5
(2C), 19.0 (2C) ppm; HRMS (FAB): m/z [MþH]þ calcd for C16H22O2N:
260.1650, found: 260.1668.
4.2.4. N-((Z)-Methyl-3-oxo-3-phenylpropenyl)benzamide (1d)23
Following the general procedure, benzamide (0.52 g, 4.3 mmol),
1-phenyl-1,3-butanedione (0.55 g, 3.4 mmol), and p-TsOH (60.0 mg,
0.32 mmol) was stirred in toluene (8 ml) for 6.5 h. Purification by
793, 738 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
¼ 13.50 (br. s, 1H), 8.31
(s, 1H), 8.23 (d, J ¼ 8.0 Hz, 1H), 7.85 (d, J ¼ 7.6 Hz, 1H), 7.65 (t,
J ¼ 7.8 Hz, 1H), 5.54 (s, 1H), 2.53 (s, 3H), 2.23 (s, 3H) ppm; 13C NMR
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M. Kamiya et al. / Tetrahedron xxx (2017) 1e8
5
(100 MHz, CDCl3)
d
¼ 200.5, 163.7, 155.4, 135.5, 135.0, 132.0, 131.5,
4.2.13. 2,2-Dimethyl-N-((Z)-1-methyl-3-oxobut-1-enyl)
propionamide (1n)
129.8, 117.8, 113.4, 106.9, 30.5, 21.8 ppm; HRMS (FAB): m/z [MþH]þ
calcd for C13H13O2N2: 229.0977, found: 229.0947.
Following the general procedure, pivalamide (1.0 g, 9.9 mmol),
acetylacetone (4.95 g, 49.4 mmol), and p-TsOH (211.0 mg, 1.1 mmol)
was stirred in toluene (25 ml) for 16.5 h. Purification by silica gel
column chromatography (hexane:EtOAc ¼ 15:1) provided 1n
(1.38 g, 76%) as a pale yellow oil; Rf 0.32 (hexane:EtOAc ¼ 15:1); IR
4.2.9. N-((Z)-1-Ethyl-3-oxopent-1-enyl)-4-nitrobenzamide (1i)
Following the general procedure, 4-nitrobenzamide (1.66 g,
10.0 mmol), 3,5-heptanedione (1.0 g, 8.0 mmol), and p-TsOH
(151.2 mg, 0.8 mmol) was stirred in xylene (12 ml) for 18.5 h. Pu-
(NaCl): 3700, 2968, 1709, 1644, 1595, 1482, 1260, 1134 cmꢀ1 1H
;
NMR (400 MHz, CDCl3)
d
¼ 12.64 (br. s,1H), 5.36 (s,1H), 2.39 (s, 3H),
2.15 (s, 3H), 1.29 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3)
178.7, 156.1, 105.5, 40.4, 30.3, 27.3 (3C), 22.0 ppm.
d
¼ 199.6,
rification
by
silica
gel
column
chromatography
(hexane:EtOAc ¼ 7:1) and recrystallization with EtOH provided 1i
(0.85 g, 39%) as
a pale yellow needle crystal; Rf 0.42
(hexane:EtOAc ¼ 7:1); mp 107e110 ꢁC; IR (KBr): 3442, 2977, 1695,
4.2.14. N-((Z)-1-Methyl-3-oxobut-1-enyl)nicotinamide (1p)
1643, 1614, 1478, 1344, 1241, 1148, 1102, 846, 712 cmꢀ1 1H NMR
;
Following the general procedure, nicotinamide (0.5 g,
4.1 mmol), acetylacetone (2.1 g, 20.5 mmol), and p-TsOH (160.0 mg,
0.82 mmol) was stirred in xylene (20 ml) for 23 h. Purification by
silica gel column chromatography (hexane:EtOAc ¼ 1:2) provided
1p (0.54 g, 64%) as a yellow solid; Rf 0.4 (hexane:EtOAc ¼ 1:2); mp
93e94 ꢁC; IR (KBr): 3050, 1691, 1639, 1603, 1483, 1267, 1195, 1101,
(400 MHz, CDCl3)
d
¼ 13.53 (br. s, 1H), 8.36 (d, J ¼ 8.8 Hz, 2H), 8.21
(d, J ¼ 8.8 Hz, 2H), 5.59 (s, 1H), 2.96 (q, J ¼ 7.4 Hz, 2H), 2.54 (q,
J ¼ 7.4 Hz, 2H),1.25 (t, J ¼ 7.4 Hz, 3H),1.16 (t, J ¼ 7.4 Hz, 3H) ppm; 13
C
NMR (100 MHz, CDCl3)
d
¼ 204.2, 163.3, 160.3, 150.0, 139.4, 129.0
(2C), 124.0 (2C), 104.6, 36.6, 27.3, 12.5, 8.5 ppm; HRMS (FAB): m/z
[MþH]þ calcd for C14H17O4N2: 277.1188, found: 277.1145.
1018, 973, 729 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
¼ 13.48 (br. s, 1H),
9.27 (s, 1H), 8.81 (d, J ¼ 4.8 Hz, 1H), 8.30 (ddd, J ¼ 8.2, 2.0, 1.7 Hz,
1H), 7.46 (dd, J ¼ 8.2, 4.8 Hz, 1H), 5.53 (s, 1H), 2.54 (s, 3H), 2.22 (s,
4.2.10. N-((Z)-1-Methyl-3-oxo-3-phenylpropenyl)acetamide (1j)24
Following the general procedure, acetamide (0.29 g, 4.9 mmol),
1-phenyl-1,3-butanedione (0.77 g, 4.7 mmol), and p-TsOH (50.0 mg,
0.3 mmol) was stirred in toluene (9 ml) for 24 h. Purification by
silica gel column chromatography (hexane:EtOAc ¼ 4:1) provided
1j (0.60 g, 73%) as a pale orange solid; Rf 0.38 (hexane:EtOAc ¼ 4:1);
3H) ppm; 13C NMR (100 MHz, CDCl3)
149.5, 135.2, 129.3, 123.5, 106.7, 30.5, 21.8 ppm; HRMS (FAB): m/z
[MþH]þ calcd for C11H13O2N2: 205.0977, found: 205.0972.
d
¼ 200.4, 164.2, 155.4, 152.9,
4.3. Synthesis of (Z)-methyl 3-(benzamido)acrylate (1o).25
mp 96e98 ꢁC (lit.24 98e99 ꢁC); 1H NMR (400 MHz, CDCl3)
d
¼ 12.82
Benzoquinone (1.8 g, 16.6 mmol, 1.6 equiv) p-toluenesulfonic
acid (1.0 g, 5.3 mmol, 0.5 equiv), palladium (II) acetate (0.2 g,
0.9 mmol, 10 mol%), molecular sieves (1.5 g, 4 Å) was added to a
stirred solution of benzamide (1.2 g, 10.0 mmol, 1.0 equiv) in
toluene (50 ml) and the mixture was stirred for 1 min at room
temperature under open air; then to this mixture were added
methyl acrylate (9.9 g, 115 mmol, 11.5 equiv), and the mixture was
stirred for 25 h at room temperature under open air. The reaction
mixture was then filtered (Celite). The mixture was washed with
water (ꢂ2), dried over Na2SO4, and solvent was evaporated in
vacuo. The residue was purified by silica gel column chromatog-
raphy (hexane:EtOAc ¼ 8:1) to afford pure substituted 1o (1.1 g,
52%) as a white solid; Rf 0.37 (hexane:EtOAc ¼ 8:1); mp 70 ꢁC (lit.25
(br. s, 1H), 7.90 (d, J ¼ 7.3 Hz, 2H), 7.54 (t, J ¼ 7.3 Hz, 1H), 7.46 (t,
J ¼ 7.3 Hz, 2H), 6.05 (s, 1H), 2.52 (s, 3H), 2.23 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3)
d
¼ 191.4, 169.9, 157.5, 138.6, 132.4, 128.5 (2C),
127.6 (2C), 101.5, 25.5, 22.5 ppm.
4.2.11. (Z)-3-Hexanoylaminobut-2-enoic acid methyl ester (1l)
Following the general procedure, hexanamide (0.1 g,
0.87 mmol), methyl acetoacetate (0.1 g, 0.87 mmol), and p-TsOH
(16.5 mg, 0.09 mmol) was stirred in toluene (2 ml) for 20 h. Puri-
fication
by
silica
gel
column
chromatography
(hexane:EtOAc ¼ 17:1) provided 1l (0.13 g, 67%) as a pale yellow oil;
Rf 0.6 (hexane:EtOAc ¼ 5:1); IR (NaCl): 3236, 2954,1719,1676,1632,
73e74 ꢁC); 1H NMR (400 MHz, CDCl3)
d
¼ 11.49 (br. d, J ¼ 7.6 Hz,
1259,1151, 808, 730 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
¼ 11.11 (br. s,
1H), 7.96 (d, J ¼ 7.8 Hz, 2H), 7.76 (dd, J ¼ 10.8, 8.8 Hz, 1H), 7.60 (t,
1H), 4.90 (s, 1H), 3.70 (s, 3H), 2.39 (s, 3H), 2.35 (t, J ¼ 7.6 Hz, 2H),
J ¼ 7.6 Hz, 1H), 7.51 (t, J ¼ 7.6 Hz, 2H), 5.28 (d, J ¼ 8.8 Hz, 1H), 3.78 (s,
1.75e1.61 (m, 2H), 1.40e1.28 (m, 4H), 0.90 (t, J ¼ 6.8 Hz, 3H) ppm;
3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 170.0, 164.5, 138.9, 132.9,
13C NMR (100 MHz, CDCl3)
d
¼ 172.2, 169.6, 155.4, 95.8, 51.0, 38.3,
31.2, 24.8, 22.3, 22.0, 13.9 ppm; HRMS (FAB): m/z [MþH]þ calcd for
132.1, 128.9 (2C), 127.7 (2C), 96.7, 51.4 ppm.
C
11H20O3N: 214.1443, found: 214.1436.
4.4. General procedures for the synthesis of oxazoles 2a-q
4.2.12. Cyclohexanecarboxylic acid ((Z)-1-methyl-3-oxobut-1-enyl)
amide (1m)
Following the general procedure, cyclohexanecarboxamide
(0.40 g, 3.1 mmol), acetylacetone (1.95 g, 19.5 mmol), and p-TsOH
(74.2 mg, 0.39 mmol) was stirred in toluene (15 ml) for 24 h. Pu-
PIFA (1.1e1.3 equiv) was added to a stirred solution of enamides
1 (1.0 equiv) in TFE and the mixture was stirred for 15 min at room
temperature. The reaction was quenched with saturated aqueous
NaHCO3 and the mixture diluted with EtOAc and extracted with
EtOAc. The organic layers were washed with water and brine and
dried over Na2SO4, and the solvent was evaporated in vacuo. The
residue was purified by silica gel column chromatography to afford
pure substituted oxazoles 2.
rification
by
silica
gel
column
chromatography
(hexane:EtOAc ¼ 12:1) provided 1m (0.54 g, 83%) as a pale yellow
solid; Rf 0.41 (hexane:EtOAc ¼ 12:1); mp 34e36 ꢁC; IR (KBr): 2933,
2855, 1701, 1596, 1478, 1441, 1262, 1159, 809 cmꢀ1 1H NMR
;
(400 MHz, CDCl3)
d
¼ 12.41 (br. s, 1H), 5.33 (s, 1H), 2.38 (d,
4.4.1. 1-(4-Methyl-2-phenyloxazol-5-yl)ethanone (2a)6
Following the general procedure, enamide 1a (1.0 g, 4.9 mmol)
and PIFA (2.8 g, 6.4 mmol) in TFE (37.0 ml) was stirred for 15 min.
J ¼ 0.7 Hz, 3H), 2.26 (tt, J ¼ 11.6, 3.4 Hz, 1H), 2.14 (s, 3H), 1.96 (d,
J ¼ 13.2 Hz, 2H), 1.85e1.76 (m, 2H), 1.69 (d, J ¼ 11.0 Hz, 1H), 1.47 (dq,
J ¼ 12.0, 2.9 Hz, 2H), 1.38e1.16 (m, 3H) ppm; 13C NMR (100 MHz,
Purification
by
silica
gel
column
chromatography
CDCl3)
d
¼ 199.6, 175.1, 155.9, 105.3, 46.9, 30.3, 29.3 (2C), 25.6, 25.5
(hexane:EtOAc ¼ 5:1) provided 2a (0.92 g, 93%) as a white solid; Rf
(2C), 21.9 ppm; HRMS (FAB): m/z [MþH]þ calcd for C12H20O2N:
0.32 (hexane:EtOAc ¼ 5:1); mp 66e67 ꢁC (lit.6 61e63 ꢁC); 1H NMR
210.1494, found: 210.1469.
(400 MHz, CDCl3)
d
¼ 8.12 (d, J ¼ 7.6 Hz, 2H), 7.60e7.46 (m, 3H), 2.58
Please cite this article in press as: Kamiya M, et al., A rapid access to substituted oxazoles via PIFA-mediated oxidative cyclization of enamides,
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6
M. Kamiya et al. / Tetrahedron xxx (2017) 1e8
(s, 3H), 2.57 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
146.3, 145.1, 131.6, 128.9 (2C), 127.1 (2C), 126.3, 27.5, 13.8 ppm.
d
¼ 187.6,161.4,
7.14e7.03 (m, 2H), 4.00 (s, 3H), 2.68 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3)
132.7,131.0,129.6 (2C),128.2 (2C),120.8,115.3,111.9, 55.9,14.3 ppm;
HRMS (FAB): m/z [MþH]þ calcd for C18H16O3N: 294.1130, found:
294.1129.
d
¼ 182.2, 160.7, 158.1, 148.9, 144.5, 137.2, 133.0,
4.4.2. 1-(4-Ethyl-2-phenyl-oxazol-5-yl)propan-1-one (2b)
Following the general procedure, enamide 1b (54.9 mg,
0.24 mmol) and PIFA (112.3 mg, 0.26 mmol) in TFE (3.0 ml) was
sterred for 15 min. Purification by silica gel column chromatog-
raphy (hexane:EtOAc ¼ 17:1) provided 2b (46.1 mg, 85%) as a white
solid; Rf 0.35 (hexane:EtOAc ¼ 15:1); mp 33 ꢁC; IR (KBr): 2975,
1677, 1583, 1539, 1455, 1373, 1269, 1134, 1092, 1008, 931, 786,
4.4.7. 1-[2-(2-Bromophenyl)-4-ethyloxazol-5-yl]propan-1-one (2g)
Following the general procedure, enamide 1g (0.25 g,
0.80 mmol) and PIFA (0.41 g, 0.96 mmol) in TFE (3.7 ml) was stirred
for 25 min. Purification by silica gel column chromatography
(hexane:EtOAc ¼ 10:1) provided 2g as a pale brown solid (0.22 g,
90%); Rf 0.36 (hexane:EtOAc ¼ 10:1); mp 44e46 ꢁC; IR (KBr): 2975,
697 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
¼ 8.12 (dd, J ¼ 2.0, 7.8 Hz,
2H), 7.55e7.46 (m, 3H), 2.99 (q, J ¼ 7.6 Hz, 2H), 2.95 (q, J ¼ 7.3 Hz,
2H), 1.31 (t, J ¼ 7.6 Hz, 3H), 1.24 (t, J ¼ 7.3 Hz, 3H) ppm; 13C NMR
1675, 1573, 1441, 1375, 933, 735, cmꢀ1 1H NMR (400 MHz, CDCl3)
;
(100 MHz, CDCl3)
d
¼ 190.9, 161.2, 151.5, 144.1, 131.4, 128.9 (2C),
d
¼ 8.08 (dd, J ¼ 7.6, 1.2 Hz, 1H), 7.74 (d, J ¼ 8.0 Hz, 1H), 7.44 (t,
127.1 (2C),126.6, 33.0, 20.9,12.7, 7.5 ppm; HRMS (FAB): m/z [MþH]þ
J ¼ 7.6 Hz, 1H), 7.40e7.31 (m, 1H), 3.00 (q, J ¼ 7.6 Hz, 2H), 2.97 (q,
calcd for C14H16O2N: 230.1181, found: 230.1167.
J ¼ 7.3 Hz, 2H),1.32 (t, J ¼ 7.6 Hz, 3H),1.23 (t, J ¼ 7.3 Hz, 3H) ppm; 13
C
NMR (100 MHz, CDCl3)
d
¼ 191.3, 159.8, 150.8, 144.3, 134.7, 132.0
4.4.3. 1-(4-Isopropyl-2-phenyl-oxazol-5-yl)-2-methyl-propan-1-
one (2c)
Following the general procedure, enamide 1c (0.26 g, 1.0 mmol)
and PIFA (0.49 g, 1.1 mmol) in TFE (3.7 ml) was sterred for 15 min.
(2C), 127.5 (2C), 121.2, 33.2, 20.8, 12.7, 7.5 ppm; HRMS (FAB): m/z
[MþH]þ calcd for C14H15O2N79Br: 308.0286, C14H15O2N81Br:
310.0266, found: 308.0290, 310.0290.
Purification
by
silica
gel
column
chromatography
4.4.8. 3-(5-Acetyl-4-methyloxazol-2-yl)benzonitrile (2h)
(hexane:EtOAc ¼ 18:1) provided 2c as a white solid (0.22 g, 85%); Rf
0.30 (hexane:EtOAc ¼ 18:1); mp 55 ꢁC; IR (KBr): 2971, 1669, 1568,
1458, 1365, 1278, 1085, 966, 693 cmꢀ1; 1H NMR (400 MHz, CDCl3):
Following the general procedure, enamide 1h (45.1 mg,
0.20 mmol) and PIFA (93.3 mg, 0.22 mmol) in TFE (1.4 ml) was
stirred for 15 min. Purification by silica gel column chromatography
(hexane:EtOAc ¼ 2:1) provided 2h as a white solid (37.3 mg, 83%);
Rf 0.35 (hexane:EtOAc ¼ 2:1); mp 164e165 ꢁC; IR (KBr): 3071, 2228,
d
¼ 8.13 (dd, J ¼ 7.8, 2.0 Hz, 2H), 7.54e7.46 (m, 3H), 3.70 (sep,
J ¼ 6.8 Hz, 1H), 3.42 (sep, J ¼ 6.8 Hz, 1H), 1.31 (d, J ¼ 6.8 Hz, 6H), 1.26
(d, J ¼ 6.8 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 194.5, 161.2,
1680, 1579, 1384, 1296, 1133, 945, 634 cmꢀ1 1H NMR (400 MHz,
;
156.5, 142.6, 131.3, 128.8 (2C), 127.1 (2C), 126.8, 37.5, 26.3, 21.2 (2C),
18.3 (2C) ppm; HRMS (FAB): m/z [MþH]þ calcd for C16H20O2N:
258.1494, found: 258.1555.
CDCl3)
d
¼ 8.40 (s, 1H), 8.35 (d, J ¼ 8.0 Hz, 1H), 7.81 (d, J ¼ 8.0 Hz,
1H), 7.65 (t, J ¼ 8.0 Hz, 1H), 2.59 (s, 3H), 2.58 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3)
d
¼ 187.4, 158.9, 146.3, 145.5, 134.5, 130.9, 130.5,
130.0, 127.7, 117.7, 113.5, 27.6, 13.7 ppm; HRMS (FAB): m/z [MþH]þ
4.4.4. (4-Methyl-2-phenyl-oxazol-5-yl)phenyl-methanone (2d)
Following the general procedure, enamide 1d (51.6 mg,
0.19 mmol) and PIFA (92.0 mg, 0.21 mmol) in TFE (3.0 ml) was
sterred for 15 min. Purification by silica gel column chromatog-
raphy (hexane:EtOAc ¼ 8:1) provided 2d as a white solid (50.1 mg,
98%); Rf 0.40 (hexane:EtOAc ¼ 8:1); mp 87e89 ꢁC (lit.6 62e64 ꢁC);
calcd for C13H11O2N2: 227.0821, found: 227.0797.
4.4.9. 1-[4-Ethyl-2-(4-nitrophenyl)oxazol-5-yl]propan-1-one (2i)
Following the general procedure, enamide 1i (0.30 g, 1.08 mmol)
and PIFA (0.51 g, 1.19 mmol) in TFE (3.5 ml) was sterred for 15 min.
Purification
by
silica
gel
column
chromatography
1H NMR (400 MHz, CDCl3)
d
¼ 8.16e8.00 (m, 4H), 7.70e7.45 (m,
(hexane:EtOAc ¼ 7:1) provided 2i as a pale yellow solid (0.27 g,
92%); Rf 0.39 (hexane:EtOAc ¼ 7:1); mp 108e109 ꢁC; IR (KBr): 2983,
1677,1577, 1518,1339,1092, 932, 858, 714 cmꢀ1; 1H NMR (400 MHz,
6H), 2.63 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 182.7, 161.8,
149.2, 144.8, 137.3, 132.8, 131.7, 129.3 (2C), 129.0 (2C), 128.5 (2C),
127.2 (2C), 126.3, 14.3 ppm.
CDCl3)
d
¼ 8.36 (d, J ¼ 8.7 Hz, 2H), 8.30 (d, J ¼ 8.7 Hz, 2H), 3.01 (q,
J ¼ 7.6 Hz, 2H), 2.98 (q, J ¼ 7.3 Hz, 2H), 1.32 (t, J ¼ 7.6 Hz, 3H), 1.25 (t,
4.4.5. 1-(4-Methyl-2-(m-tolyl)oxazol-5-yl)ethanone (2e)
J ¼ 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 190.8, 158.8,
Following the general procedure, enamide 1e (0.18 g,
0.85 mmol) and PIFA (0.40 g, 0.94 mmol) in TFE (3.5 ml) was stirred
for 15 min. Purification by silica gel column chromatography
(hexane:EtOAc ¼ 8:1) provided 2e as a white solid (0.17 g, 93%); Rf
0.35 (hexane:EtOAc ¼ 8:1); mp 73e76 ꢁC; IR (KBr): 2925, 1673,
151.7, 149.3, 144.9, 132.0, 127.9 (2C), 124.2 (2C), 33.2, 20.8, 12.6,
7.4 ppm; HRMS (FAB): m/z [MþH]þ calcd for C14H15O4N2: 275.1032,
found: 275.1002.
4.4.10. (2,4-Dimethyloxazol-5-yl)phenylmethanone (2j)
1585, 1468, 1382, 1266, 1100, 945, 730, 635 cmꢀ1
;
1H NMR
Following the general procedure, enamide 1j (54.2 mg,
0.27 mmol) and PIFA (150.8 mg, 0.35 mmol) in TFE (1.8 ml) was
stirred for 15 min. Purification by silica gel column chromatography
(hexane:EtOAc ¼ 3:2) provided 2j as a yellow oil (49.1 mg, 91%); Rf
0.39 (hexane:EtOAc ¼ 3:2); IR (NaCl): 2927, 1646, 1591, 1553, 1349,
(400 MHz, CDCl3)
d
¼ 7.94 (s, 1H), 7.90 (d, J ¼ 7.6 Hz, 1H), 7.42e7.31
(m, 2H), 2.57 (2s, 6H), 2.44 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 187.6, 161.6, 146.2, 145.0, 138.8, 132.5, 128.9, 127.7, 126.1, 124.3,
27.5, 21.3, 13.7 ppm; HRMS (FAB): m/z [MþH]þ calcd for C13H14O2N:
216.1024, found: 216.1003.
1177, 913, 721 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
¼ 7.89 (d,
J ¼ 7.6 Hz, 2H), 7.52 (t, J ¼ 7.6 Hz, 1H), 7.43 (dd, J ¼ 8.0, 7.6 Hz, 2H),
4.4.6. [2-(2-Methoxyphenyl)-4-methyloxazol-5-yl]
phenylmethanone (2f)
2.48 (s, 3H), 2.41 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 182.7,
162.7, 147.9, 145.1, 137.2, 132.7, 129.2 (2C), 128.4 (2C), 14.3, 14.1 ppm.
Following the general procedure, enamide 1f (51.7 mg,
0.18 mmol) and PIFA (80.1 mg, 0.19 mmol) in TFE (1.4 ml) was
stirred for 15 min. Purification by silica gel column chromatography
(hexane:EtOAc ¼ 3:1) provided 2f as a white solid (47.8 mg, 93%); Rf
0.36 (hexane:EtOAc ¼ 3:1); mp 86e88 ꢁC; IR (KBr): 1632, 1560,
4.4.11. 4-Methyl-2-pentyloxazole-5-carboxylic acid methyl ester
(2l)
Following the general procedure, enamide 1l (48.8 mg,
0.23 mmol) and PIFA (130.7 mg, 0.30 mmol) in TFE (2.0 ml) was
stirred for 15 min. Purification by silica gel column chromatography
(hexane:EtOAc ¼ 8:1) provided 2l as a pale blue oil (30.2 mg, 62%);
1520, 1465, 1383, 1182, 1015, 911, 720 cmꢀ1 1H NMR (400 MHz,
;
CDCl3)
d
¼ 8.29e8.19 (m, 2H), 8.16e8.06 (m, 1H), 7.68e7.46 (m, 4H),
Please cite this article in press as: Kamiya M, et al., A rapid access to substituted oxazoles via PIFA-mediated oxidative cyclization of enamides,
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M. Kamiya et al. / Tetrahedron xxx (2017) 1e8
7
Rf 0.35 (hexane:EtOAc ¼ 8:1); IR (NaCl): 2956, 1725, 1616, 1553,
1442, 1389, 1344, 1279, 1194, 1148, 1106, 768 cmꢀ1 1H NMR
(400 MHz, CDCl3)
¼ 3.91 (s, 3H), 2.77 (t, J ¼ 7.6 Hz, 2H), 2.45 (s,
3H), 1.79 (quin, J ¼ 7.6 Hz, 2H), 1.40e1.30 (m, 4H), 0.90 (t, J ¼ 6.8 Hz,
and the mixture was stirred for 6 h at reflux temperature. After that
the mixture was allowed to cool to room temperature, and solvent
was evaporated in vacuo. The residue was dissolved in TFE (3 ml)
and added to a solution of PIFA (266.0 mg, 0.61 mmol, 1.3 equiv.),
and the mixture was stirred for 15 min at room temperature. The
reaction was quenched with saturated aqueous NaHCO3 and the
mixture diluted with EtOAc and extracted with EtOAc. The organic
layers were washed with water and brine and dried over Na2SO4,
and the solvent was evaporated in vacuo. The residue was purified
by silica gel column chromatography (hexane:EtOAc ¼ 5:1) to
afford pure substituted oxazole 2e (63.9 mg, 63%).
;
d
3H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 166.8, 159.2, 146.2, 137.1,
51.9, 31.3, 28.3, 26.6, 22.2, 13.9, 13.3 ppm; HRMS (FAB): m/z [MþH]þ
calcd for C11H18O3N: 212.1287, found: 212.1263.
4.4.12. 1-(2-Cyclohexyl-4-methyloxazol-5-yl)ethanone (2m)
Following the general procedure, enamide 1m (49.5 mg,
0.24 mmol) and PIFA (139.3 mg, 0.32 mmol) in TFE (2.0 ml) was
sterred for 15 min. Purification by silica gel column chromatog-
raphy (hexane:EtOAc ¼ 8:1) provided 2m as a yellow solid
(40.2 mg, 82%); Rf 0.34 (hexane:EtOAc ¼ 8:1); mp 38e39 ꢁC; IR
(NaCl): 2932, 2857, 1681, 1592, 1540, 1386, 1362, 1132, 1081, 951,
4.6. Formal synthesis of antitumor agent (Scheme 2)
4.6.1. (Z)-3-Acetylamino-3-(2-fluorophenyl)acrylic acid ethyl ester
(1q)
635 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
¼ 2.81 (tt, J ¼ 11.6, 3.6 Hz,
1H), 2.47 (s, 3H), 2.45 (s, 3H), 2.07 (d, J ¼ 12.8 Hz, 2H), 1.89e1.79 (m,
Ammonium acetate (1.73 g, 2.24 mmol, 4.0 equiv.) was added to
2H), 1.73 (d, J ¼ 12.0 Hz, 1H), 1.67e1.53 (m, 2H), 1.45e1.23 (m, 3H)
a
stirred solution of ethyl (2-fluorobenzoyl)acetate (1.18 g,
ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 187.6, 169.0, 144.9 (2C), 37.6,
5.60 mmol, 1.0 equiv.) in MeOH (10 ml) and the mixture was stirred
for 19 h at reflux temperature. After that the solvent was evapo-
rated in vacuo and the redidure was dissolved with EtOAc. The
solution was washed with water (x 2) and brine and dried over
Na2SO4, and the solvent was evaporated in vacuo. The residue was
purified by silica gel column chromatography (hexane:EtOAc ¼ 8:1)
to afford pure substituted enamine as a yellow oil (1.16 g, quant.) Rf
0.28 (hexane:EtOAc ¼ 8:1), which was used directly in the next
step.
30.4 (2C), 27.4, 25.6, 25.5 (2C), 13.6 ppm; HRMS (FAB): m/z [MþH]þ
calcd for C12H18O2N: 208.1338, found: 208.1356.
4.4.13. 1-(2-tert-Butyl-4-methyloxazol-5-yl)ethanone (2n)
Following the general procedure, enamide 1n (53.5 mg,
0.29 mmol) and PIFA (163.2 mg, 0.38 mmol) in TFE (2.0 ml) was
stirred for 15 min. Purification by silica gel column chromatography
(hexane:EtOAc ¼ 6:1) provided 2n as a yellow solid (44.9 mg, 85%);
Rf 0.35 (hexane:EtOAc ¼ 6:1); mp 44 ꢁC; IR (KBr): 2977, 1678, 1591,
Pyridine (0.38 g, 4.8 mmol, 10.0 equiv.) was added to a stirred
solution of enamine (0.10 g, 0.48 mmol,1.0 equiv.) in benzene (3 ml)
and the solution was cooled to 0 ꢁC. Acetyl chloride (0.28 g,
3.58 mmol, 7.5 equiv.) was added dropwise, and the mixture was
stirred for 48 h at 0 ꢁC under an atmosphere of nitrogen. Then,
acetyl chloride (0.84 g, 10.7 mmol, 22.5 equiv) was dropwise to
complete reaction. The reaction was quenched with brine, extrac-
ted with CHCl3 (x 3) and dried over Na2SO4, and the solvent was
evaporated in vacuo. The residue was purified by silica gel column
chromatography (hexane:EtOAc ¼ 5:1) to afford pure substituted
1536, 1381, 1364, 1290, 1266, 1124, 951, 636 cmꢀ1 1H NMR
;
(400 MHz, CDCl3)
d
¼ 2.48 (s, 3H), 2.46 (s, 3H), 1.42 (s, 9H) ppm; 13
C
NMR (100 MHz, CDCl3)
d
¼ 187.7, 172.0, 145.0, 144.8, 33.9, 28.4 (3C),
27.4, 13.6 ppm; HRMS (FAB): m/z [MþH]þ calcd for C10H16O2N:
182.1181, found: 182.1167.
4.4.14. Methyl 2-phenyloxazole-5-carboxylate (2o)
Following the general procedure, enamide 1o (50.8 mg,
0.25 mmol) and PIFA (118.2 mg, 0.27 mmol) in TFE (3.0 ml) was
stirred for 7 h. Purification by silica gel column chromatography
(hexane:EtOAc ¼ 10:1) provided 2o as a white needle crystal
(29.0 mg, 58%); Rf 0.27 (hexane:EtOAc ¼ 10:1); mp 88e90 ꢁC (lit.6
enamide 1q as
(hexane:EtOAc ¼ 5:1); IR (NaCl): 3280, 2983,1724,1676,1630,1488,
1294, 1079, 1033, 763 cmꢀ1 1H NMR (400 MHz, CDCl3)
a pale yellow oil (76.8 mg, 63%); Rf 0.28
;
d
¼ 10.92
85e87 ꢁC); 1H NMR (400 MHz, CDCl3)
d
¼ 8.15 (dd, J ¼ 7.3, 1.5 Hz,
(br. s, 1H) 7.42e7.32 (m, 1H), 7.28 (ddd, J ¼ 7.6, 7.4, 1.7 Hz, 1H), 7.15
(dt, J ¼ 7.6, 1.2 Hz, 1H), 7.03 (ddd, J ¼ 10.6, 8.5, 1.2 Hz, 1H), 5.15 (s,
1H), 4.23 (q, J ¼ 7.1 Hz, 2H), 2.15 (s, 3H), 1.32 (t, J ¼ 7.1 Hz, 3H) ppm;
2H), 7.86 (s, 1H), 7.58e7.47 (m, 3H), 3.95 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3)
d
¼ 164.3, 158.2, 142.0, 135.5, 131.6, 128.9 (2C),
127.2 (2C), 126.3, 52.2 ppm.
13C NMR (100 MHz, CDCl3)
d
¼ 168.6, 167.8, 159.4 (d, JCF ¼ 247.8 Hz),
149.2, 130.9 (d, JCF ¼ 8.2 Hz), 129.0 (d, JCF ¼ 2.5 Hz), 124.3 (d,
JCF ¼ 14.0 Hz), 123.9 (d, JCF ¼ 3.3 Hz), 115.1 (d, JCF ¼ 21.4 Hz), 100.7,
60.4, 24.6, 14.2 ppm; HRMS (FAB): m/z [MþH]þ calcd for
4.4.15. 1-(4-Methyl-2-pyridin-3-yl-oxazol-5-yl)-ethanone (2p)
PIFA (245.7 mg, 0.57 mmol) was added to a stirred solution of
enamide 1p (50.5 mg, 0.25 mmol) in TFE (4.0 ml) and the mixture
was stirred for 4 h at room temperature. The reaction mixture was
evaporated in vacuo. The residue was purified by silica gel column
chromatography (hexane:EtOAc ¼ 1:3) to afford substituted oxa-
C
13H15O3NF: 252.1036, found: 252.1092.
4.6.2. 4-(2-Fluorophenyl)-2-methyloxazole-5-carboxylic acid ethyl
ester (2q)
zole 2p as
a
pale yellow solid (37.7 mg, 75%); Rf 0.41
PIFA (109.5 mg, 0.26 mmol, 1.3 equiv) was added to a stirred
solution of enamide 1q (49.2 mg, 0.20 mmol,1.0 equiv) in TFE (2 ml)
and the mixture was stirred for 30 min at room temperature. The
reaction was quenched with saturated aqueous NaHCO3 and the
mixture diluted with EtOAc and extracted with EtOAc. The organic
layers were washed with water and brine and dried over Na2SO4,
and the solvent was evaporated in vacuo. The residue was purified
by silica gel column chromatography (hexane:EtOAc ¼ 4:1) to
afford pure substituted oxazole 2q as a pale brown oil (41.1 mg,
84%); Rf 0.33 (hexane:EtOAc ¼ 4:1); IR (NaCl): 2979, 1726, 1567,
1491, 1378, 1256, 1130, 1020, 763 cmꢀ1; 1H NMR (400 MHz, CDCl3)
(hexane:EtOAc ¼ 1:3); mp 93e95 ꢁC; IR (KBr): 3527, 3475, 1669,
1595, 1416, 1595, 1071, 914, 781, 641 cmꢀ1 1H NMR (400 MHz,
;
CDCl3)
d
¼ 9.34 (d, J ¼ 1.2 Hz, 1H), 8.76 (dd, J ¼ 4.9, 1.5 Hz, 1H), 8.38
(dt, J ¼ 8.0, 2.0 Hz, 1H), 7.46 (dd, J ¼ 8.0, 4.9 Hz, 1H), 2.58 (2s, 6H)
ppm; 13C NMR (100 MHz, CDCl3)
d
¼ 187.4, 159.0, 152.1, 148.2, 146.2,
145.4, 134.2, 123.7, 122.7, 27.5, 13.7 ppm; HRMS (FAB): m/z [MþH]þ
calcd for C11H11O2N2: 203.0820, found: 203.0791.
4.5. One-pot method for the synthesis of oxazole 2e (Scheme 1)
p-Toluenesulfonic acid (5.5 mg, 0.03 mmol, 5.0 mol%) was added
to a stirred solution of m-toluamide (63.6 mg, 0.47 mmol,1.0 equiv.)
and acetylacetone (47.2 mg, 0.47 mmol, 1.0 equiv) in toluene (2 mL)
d
¼ 7.49 (ddd, J ¼ 7.6, 7.3, 1.9 Hz, 1H), 7.40e7.30 (m, 1H), 7.15 (t,
J ¼ 7.6 Hz, 1H), 7.07 (dd, J ¼ 9.1, 7.6 Hz, 1H), 4.24 (q, J ¼ 7.1 Hz, 2H),
2.53 (s, 3H), 1.19 (t, J ¼ 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
Please cite this article in press as: Kamiya M, et al., A rapid access to substituted oxazoles via PIFA-mediated oxidative cyclization of enamides,
Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.01.027

8
M. Kamiya et al. / Tetrahedron xxx (2017) 1e8
6. Panda N, Mothkuri R. New J Chem. 2014;38:5727e5735.
d
¼ 163.5, 160.0 (d, JCF ¼ 250.2 Hz), 157.9, 140.8, 138.4, 131.2 (d,
7. Cheung CW, Buchwald SL. J Org Chem. 2012;77:7526e7537.
8. (a) Zhang M, Huang L, Huang H, Li X, Wu W, Jiang H. Org Lett. 2014;16:
5906e5909;
(b) Wang C, Zhang J, Wang S, Fan J, Wang Z. Org Lett. 2010;12:2338e2341;
(c) Bai Y, Chen W, Chen Y, Huang H, Xiao F, Deng G-J. RSC Adv. 2015;5:
8002e8005.
JCF ¼ 3.3 Hz), 131.1 (d, JCF ¼ 3.3 Hz), 123.8 (d, JCF ¼ 4.2 Hz), 119.2 (d,
JCF ¼ 14.0 Hz), 115.6 (d, JCF ¼ 21.4 Hz), 61.3, 14.2, 13.9 ppm; HRMS
(FAB): m/z [MþH]þ calcd for C13H13O3NF: 250.0879, found:
250.0878.
9. (a) Saito A, Taniguchi A, Kambara Y, Hanzawa Y. Org Lett. 2013;15:2672e2675;
(b) Rassadin VA, Boyarskiy VP, Kukushkin VY. Org Lett. 2015;17:3502e3505.
10. (a) Senadi GC, Hu W-P, Hsiao J-S, Vandavasi JK, Chen C-Y, Wang J-J. Org Lett.
2012;14:4478e4481;
Acknowledgments
This work was financially supported by JSPS KAKENHI Grant
Number 25410051.
(b) Peng H, Akhmedov NG, Liang Y-F, Jiao N, Shi X. J Am Chem Soc. 2015;137:
8912e8915.
11. (a) Samimi HA, Mohammadi S. Synlett. 2013;24:223e225;
(b) Samimi HS, Dadvar F. Synthesis. 2015;47:1899e1904.
12. He W, Li C, Zhang L. J Am Chem Soc. 2011;133:8482e8485.
13. Jiang H, Huang H, Cao H, Qi C. Org Lett. 2010;12:5561e5563.
14. Wan C, Gao L, Wang Q, Zhang J, Wang Z. Org Lett. 2010;12:3902e9305.
15. (a) Pan Y-M, Zheng F-J, Lin H-X, Zhan Z-P. J Org Chem. 2009;74:3148e3151;
(b) Kumar MP, Liu R-S. J Org Chem. 2006;71:4951e4955.
16. Gao W-C, Hu F, Huo Y-M, Chang H-H, Li X, Wei W-L. Org Lett. 2015;17:
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Please cite this article in press as: Kamiya M, et al., A rapid access to substituted oxazoles via PIFA-mediated oxidative cyclization of enamides,
Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.01.027