Synthesis of oxazoles from enamides via phenyliodine diacetate-mediated intramolecular oxidative cyclization

Article abstract of DOI:10.1021/jo302073e

A group of functionalized oxazoles were synthesized in moderate to good yields from enamides via phenyliodine diacetate (PIDA)-mediated intramolecular cyclization. The main advantageous features of the present method include its broad substrate scope and the heavy-metal-free characteristic of the oxidative carbon-oxygen bond formation process.

Full text of DOI:10.1021/jo302073e

Article
pubs.acs.org/joc
Synthesis of Oxazoles from Enamides via Phenyliodine Diacetate-
Mediated Intramolecular Oxidative Cyclization
Yunhui Zheng, Xuming Li, Chengfeng Ren, Daisy Zhang-Negrerie, Yunfei Du,* and Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, China
S
* Supporting Information
ABSTRACT: A group of functionalized oxazoles were synthesized in
moderate to good yields from enamides via phenyliodine diacetate (PIDA)-
mediated intramolecular cyclization. The main advantageous features of the
present method include its broad substrate scope and the heavy-metal-free
characteristic of the oxidative carbon−oxygen bond formation process.
INTRODUCTION
■
Presented in many biologically active natural products and
pharmaceutical agents, the oxazole skeleton is an important
heterocyclic motif.1 For example, both bengazole A2 (a potent
antifungal marine natural product) and oxaprozin3 (a non-
steroidal anti-inflammatory drug) possess an oxazole subunit in
their chemical structure (Figure 1). Accordingly, there exists a
Figure 2. General strategies for the synthesis of oxazoles from enamide
derivatives.
Figure 1. Representative oxazoles in natural products and
pharmaceutical agents.
achieved in a low yield (Figure 2, path d).8 Moreover, it was
found that 5-(subsituted amino)oxazole compounds could be
formed from the reaction of an enamide compound, i.e., 2-
acylamino-3,3-dihaloacrylonitrile, with amines.9 The analogous
5-(subsituted mercapto)oxazole compounds could also be
prepared from 2-acylamino-3,3-bis(substituted mecapto)-
acrylonitrile10 and polarized ketene dithioacetals11 in the
presence of silver compounds (Ag2O, Ag2CO3 or AgOAc)
(Figure 2, path e). Buchward et al12 have reported a two-step,
one-pot preparation of oxazoles from vinyl halides and primary
amides, which consists of the formation of an enamide
intermediate through copper-catalyzed amidation of vinyl
halides, followed by iodine-mediated intramolecular cyclization
and elimination of HI under basic conditions (Figure 2, path f).
Most recently, a copper(II)-catalyzed oxidative cyclization of
enamides to 2,5-disubstituted oxazoles via vinylic C−H bond
functionalization has also been described by the same group as
the complement of the previous work.13 Stahl and co-workers14
large and versatile selection of methods for the synthesis of this
important class of compounds.4 Among them, annulation of
enamide derivatives provides a convenient access to oxazole
compounds through intramolecular carbon−oxygen bond
formation. For examples, β-alkoxy-β-ketoenamides can undergo
a TFA-mediated cyclization to afford 5-acetyloxazole derivatives
(Figure 2, path a).5 Glorius and co-workers6 have developed a
copper-catalyzed preparation of 2,5-disubstituted oxazoles from
primary amides reacting with 1,2-dihalogenated olefins, which
involves the formation of a halogen-substituted enamide
intermediate (Figure 2, path b). A similar enamide substrate,
i.e., an N-acyl-β-halodehydroaminobutyric acid derivative, can
also cyclize to oxazole-4-carboxylate via a base-mediated
dehalogenation reaction (Figure 2, path c).7 However, the
electron-withdrawing carbonyl substituent in the enamide
substrates seems to be indispensable. In 1948, Cornforth
reported the formation of oxazoles from enamide derivatives,
such that upon treatment of α-hexanoylamino-β-ethylthioa-
crylic acid with mercuric chloride, 2-amyloxazole could be
Received: September 21, 2012
Published: October 29, 2012
© 2012 American Chemical Society
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reported the process of a series of enamide compounds,
prepared via Ru-catalyzed anti-Markovnikov hydroamidation of
alkynes, being converted to 3-nonsubstituted oxazoles via
copper(II)-mediated oxidative cyclization.
intramolecuar C−O bond formation is favored over aromatic
C−N bond formation in the presence of hypervalent
iodine(III)-reagent.
Considering that the yield obtained for 2a was fairly low, 1a
was used as a model substrate to further optimize the reaction
parameters. By changing the solvent to DCE and keeping the
temperature at reflux, the product yield was improved.
However, the yield was still far from satisfactory because of
the formation of other unidentified byproducts. The use of the
less potent PIDA diminished the formation of the byproducts,
which led to a slight improvement of the product yield. Another
hypervalent iodine(III) reagent, i.e., PhIO, was also studied
but was found ineffective for this conversion. Our further study
was focused on improving the yield by the introduction of some
additive, such as BF3·Et2O or TFA, which have been well-
known for their ability to active the hypervalent iodine(III)
reagent.25 The result showed that when 1a was subjected to
PIDA in the presence of 1.0 equiv of BF3·Et2O, the desired
product 2a could be obtained in a yield of 54%. Increasing the
dosage of BF3·Et2O to 2.0 equiv furnished oxazole 2a in an
excellent yield of 90%. However, a lower yield was observed
when the amount of BF3·Et2O was further increased to 3.0
equiv. TFA was also investigated but was found not as effective
as BF3·Et2O. Further solvent screening shows that no other
solvent, including toluene, acetonitrile, TFE or ethyl acetate, is
superior to DCE.
In recent decades, hypervalent iodine(III) regents have
received considerable attention due to their attractive character-
istics, such as ready availability, nontoxicity, environmental
benignity, while displaying similar reactivities as the heavy metal
congeners, such as Hg(II), Tl(III), and Pb(IV) in many
oxidative organic transformation.15 Their unique properties
offer promising applications in facilitating metal-free oxidative
reactions, as they have shown to efficiently take the place of the
highly toxic heavy metals as oxidants. Various N-containing
heterocylces have been accessed by using hypervalent iodine-
(III) oxidants to realize the oxidative C−N,16 N−N,17 N−S18
or even C−C19 bond formation. In our laboratory, we have
successfully realized the construction of indole,16b,19c,20
azirine,21 and 2-trifluoromethyl oxazole22 from the reaction of
enamine derivatives with hypervalent iodine reagent. As a
continuation of our work, we report herein the efficient
syntheses of a series of variously functionalized oxazoles from
the reactions of enamides with phenyliodine diacetate.23
RESULTS AND DISCUSSION
■
In our previous work, the enamine substrate 1 was successfully
converted to the N-arylated indole framework 2 through a
phenyliodine bis(trifluoroacetate) (PIFA)-mediated intramo-
lecular oxidative cyclization (Scheme 1, eq 1).16b This method
Under the optimal reaction conditions (Table 1, entry 7), the
generality of the method was investigated. The enamides 1b−d,
Table 1. Optimization of Iodine(III)-Mediated Annulation
of Enamides
Scheme 1. Proposed Route to Access Indole-2-carboxylic
Acid Esters Based on the Previously Reported PIFA-
Mediated Synthesis of Indole-3-carboxylic Acid Ester
a
additive
(equiv)
time
(h)
yield
b
entry oxidant
solvent
T (°C)
(%)
1
2
3
4
5
6
7
PIFA
PIFA
none
none
DCM
DCE
DCE
DCE
reflux
reflux
reflux
reflux
reflux
reflux
reflux
1
1
1
1
1
1
1
7
13
15
0
PIDA none
PhIO none
PIDA BF3·Et2O (1.0) DCE
PIFA BF3·Et2O (1.0) DCE
PIDA BF3·Et2O
54
31
90
DCE
was found to be very useful for the synthesis of N-substituted
indole compounds bearing a cyano or ethoxycarbonyl group at
3-position. Considering that indole-2-carboxylic acid ester is
also a class of biologically important compounds,24 we became
interested in investigating whether the readily available enamide
substrate, i.e., (Z)-methyl 2-acetamido-3-phenylacrylate (1a),
could also undergo the similar hypervalent iodine-mediated
oxidative C−N bond formation to conceivably give the indole-
2-carboxylic acid esters (2a′) (Scheme 1, eq 2). To our
surprise, no reaction occurred when enamide 1a was subjected
to the identical conditions for the cyclization of enamine 1, but
some reaction did take place after the reaction temperature was
raised to reflux. But unfortunately, no desired indole product
was formed, except for the oxazole 2a obtained in a very low
yield. The structure of this unexpected oxazole compound was
firmly established by X-ray crystal analysis (see Supporting
Information for details). This result clearly indicates that when
there is no substitution at the β-position of enamide 1a, the
(2.0)
8
9
PIDA BF3·Et2O (3.0) DCE
PIDA CF3CO2H
(3.0)
reflux
reflux
1
1
70
27
DCE
10
11
12
13
PIDA BF3·Et2O (2.0) toluene
PIDA BF3·Et2O (2.0) CH3CN
PIDA BF3·Et2O (2.0) TFE
PIDA BF3·Et2O (2.0) EtOAc
85
12
4
trace
21
reflux
reflux
reflux
3
37
1
49
a
Reaction conditions: 1a (0.5 mmol), oxidant (0.65 mmol) in solvent
(5 mL). Isolated yields.
b
analogues of 1a that bear an ester group, were further studied
since they are readily available through the reactions of
substituted benzaldehyde with glycine derivatives. Each of the
substrates, containing either an electron-deficient or electron-
rich substituent on the benzene ring, was converted to the
corresponding oxazoles 2b−d in good to excellent yields.
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a
Table 2. Synthesis of Oxazoles via PIDA-Mediated Annulation of Enamides 1
a
b
c
General conditions: 1 (1.0 equiv), BF3·Et2O (2.0 equiv), PIDA (1.3 equiv) in DCE under reflux. Isolated yields. Ar1 herein refers to 4-
d
chlorophenyl group. Ar2 herein refers to 3,4-dimethoxyphenyl group.
Furthermore, different ester group such as benzoyloxycarbonyl
group was also applicable to the method.
which renders the synthesis of the oxazole compounds bearing
a carbonyl group at the 5-position.
Further study (Table 2) shows that the acetyl group in the
substrate can be changed into a long-chained acyl group or
bulky aroyl group, which makes this method applicable to the
synthesis of various 2-alkyl and 2-aryl oxazoles. When the β-aryl
group in the substrate was replaced by an alkyl group, the
corresponding enamide 1j also afforded the desired oxazole 2j,
but in a much lower yield. The successful conversion of 1k to
2k implies that the ester group in the substrate can also be
replaced with a carbonyl ketone moiety. Furthermore, the
electron-withdrawing carbonyl substitution at the α-position in
the enamide substrate can also be switched to the β-position,
The result of our further study (Table 3) shows that the α-
ester group in the enamide substrate is not indispensable for
the reaction to occur. Under the reaction conditions, both Z
and E isomers of enamide 1o were converted to the cyclized
oxazole 2o in almost the same yield, which indicates that the
configuration of the substrate has little influence on the
outcome of yield. For α-aryl enamides 1p−r, the cyclization
occurs smoothly to afford the desired 4-aryloxazole 2p−r in
good yields. The method can be further applied to the
preparation of 4,5-diphenyloxazole 2s. For enamides 1t and 1u,
bearing no substitution at either the α- or β-position of the
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synthesize other oxaprozin analogues such as 6b and 6c, which
can bear various substituents on the two phenyl rings.
A possible mechanistic pathway for this iodine(III)-mediated
cyclization of enamide is shown in Scheme 3. First, the iodo
intermediate B was formed from the reaction of the enamide
substrate A with PIDA by losing one molecule of AcOH. Then
the imine intermediate B is isomerized into the enamide C.
When substituent R2 represents an electron-withdrawing
substituent, such as a carbonyl group, nucleophilic addition of
the carbonyl oxygen atom to the sp2 carbon bonded to the
hypervalent iodine in D1 occurred, forming five-membered
intermediate E1. Subsequent reductive elimination of PhI and
AcOH provided product F. Alternatively, when substituent R2
is not electron-withdrawing and represents a methyl group or
hydrogen atom, intermediate D2 may undergo intramolecular
cyclization to give the six-membered intermediate E2. Finally,
the reductive elimination of PhI from E2 realized the oxidative
C−O bond formation to furnish the title oxazole compound F
(Scheme 3).
Table 3. Further Synthesis of Variously Functionalized
Oxazoles
a
CONCLUSION
■
In summary, we have developed a new hypervalent iodine(III)-
mediated synthesis of highly functionalized oxazoles starting
from the readily available enamides. Differing from the
traditional transition-metal participated heterofunctionalization
of C−H bonds, this approach realizes the synthesis of variously
functionalized oxazoles through oxidative carbon−oxygen bond
formation free of the catalytic transition metals.
EXPERIMENTAL SECTION
■
General Information. 1H and 13C NMR spectra were recorded on
a 400 MHz instrument (100 MHz for 13C NMR) at 25 °C. Chemical
shift values were given in ppm and referred to the internal standard
TMS set as 0.00 ppm. The peak patterns are indicated as follows: s,
singlet; d, doublet; t, triplet; q, quadruplet; qui, quintuplet; m,
multiplet; and dd, doublet of doublets. The coupling constants, J, are
reported in hertz (Hz). Low-resolution mass spectrometry (ESI) was
performed on an ion-trap spectrometer. High resolution mass spectra
(HRMS) were obtained on a Q-TOF microspectrometer. Melting
points were determined with a national micromelting point apparatus
without corrections. TLC plates were visualized by exposure to
ultraviolet light. Toluene, THF, DCM and DCE were dried by CaH2
before use. Other reagents and solvents were purchased at reagent
grade and used without further purification. All reactions were
performed in standard glassware, heated at 70 °C for 3 h before use.
Flash column chromatography was performed over silica gel 200−300
mesh, and the eluent was a mixture of petroleum ether (PE) and ethyl
acetate (EtOAc).
General Procedures for the Preparation of Substrates.
1. General Procedure for the Preparation of 1a−e and 1g−i.
Adapted from a previously reported procedure with some
modifications.28 To a suspension of N-acylglycine (50 mmol), sodium
acetate (50 mmol), and acetic anhydride (30 mL) was added the
aromatic aldehyde (50 mmol). The reaction mixture was stirred at
room temperature for 1 h and then heated to 80 °C. After 12 h, the
reaction mixture was cooled down to room temperature, mixed with
water (0.5 L) and stirred at room temperature for 1 h. The insoluble
material was separated by filtration. The alcohol (20 mL) solution of
the insoluble material (10 mol) and triethylamine (2 mL) was heated
under reflux for 3 h. The solvent was evaporated, and the residue was
suspended in water and extracted with EtOAc (4 × 30 mL). The
combined organic layer was washed with brine, dried over anhydrous
Na2SO4 and then concentrated by a rotary evaporator. The crude
product was purified by flash column chromatography (EtOAc/PE) to
give the desired compounds.
a
b
General conditions: see Table 2. Isolated yields.
enamide substrates, the reaction affords the desired 4-
nonsubstituted or 5-nonsubstituted oxazoles respectively. But
2u was obtained in a relatively low yield because of the
formation of more byproducts.
One application of this hypervalent iodine(III)-mediated
synthesis of oxazole is to synthesize oxaprozin (6a). Adopting
the known method,26 the required enamide substrate 4a can be
prepared from the readily available ketone 3a in 77% yield.
Subjecting 4a to our optimized cyclization conditions
conveniently furnished the oxazole intermediate 5a, which
undergoes the known basic hydrolysis27 to afford oxaprozin in
excellent yield (Scheme 2). This approach can be utilized to
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Scheme 2. Synthesis of Oxaprozin Analogues via PIDA-Mediated Cyclization
(Z)-Methyl 2-benzamido-3-phenylacrylate (1g).30 Yield: 50%,
3.52 g, white solid, mp 126−127 °C; H NMR (400 MHz, CDCl3)
Scheme 3. Proposed Mechanistic Pathway
1
δ 7.86 (d, J = 7.4 Hz, 2H), 7.77 (br s, 1H), 7.56 (t, J = 7.4 Hz, 1H),
7.52−7.43 (m, 5H), 7.33 (m, 3H), 3.86 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.9, 133.8, 133.5, 132.2, 132.1, 129.7, 129.5, 128.7, 128.6,
127.5, 124.4, 52.7; One carbon was missing due to overlapping.
(Z)-Methyl 2-(4-chlorobenzamido)-3-phenylacrylate (1h). Yield:
55%, 4.33 g, white solid, mp 174−175 °C; 1H NMR (400 MHz,
CDCl3) δ 7.84 (br s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 7.0 Hz,
3H), 7.41 (d, J = 8.4 Hz, 2H), 7.32 (m, 3H), 3.83 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.8, 165.0, 138.4, 133.6, 132.8, 131.7, 129.7,
129.6, 129.0, 128.9, 128.6, 124.3, 52.8; HRMS (ESI) m/z calcd for
+
C17H14Cl35NNaO3 [M + Na+] 338.0554, found 338.0555.
(Z)-Methyl 2-(3,4-dimethoxybenzamido)-3-phenylacrylate (1i).
Yield: 67%, 5.71 g, white solid, mp 110−111 °C; 1H NMR (400
MHz, CDCl3) δ 7.83 (s, 1H), 7.53−7.45 (m, 3H), 7.45−7.38 (m, 2H),
7.32 (m, 3H), 6.88 (dd, J = 8.3, 3.1 Hz, 1H), 3.92 (s, 3H), 3.89 (s,
3H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 165.4,
152.3, 149.0, 133.8, 131.7, 129.7, 129.4, 128.6, 125.9, 124.8, 120.4,
110.9, 110.3, 56.0, 55.9, 52.7; HRMS (ESI) m/z calcd for
+
C19H19NNaO5 [M + Na+] 364.1155, found 364.1155.
2. General Procedure for the Preparation of 1f. Adapted from a
previously reported procedure with some modifications.31 To a
suspension of 2-heptanamidoacetic acid (6 mmol) in THF (30 mL)
was added dicyclohexylcarbodiimide (8 mmol). The reaction mixture
was stirred at room temperature overnight and then filtered and
concentrated on a rotary evaporator. The crude product was purified
by flash column chromatography (EtOAc/PE). Then the product was
added to the suspension of sodium acetate (5 mmol), acetic anhydride
(3 mL) and aromatic aldehyde (5 mmol). The reaction mixture was
stirred at room temperature for 1 h and then heated to 80 °C. After 12
h, the reaction mixture was cooled down to room temperature, mixed
with water (50 mL) and stirred at room temperature for 1 h. The
insoluble material was separated by filtration. The methanol (10 mL)
solution of the insoluble material (5 mmol) and triethylamine (1 mL)
was heated under reflux for 3 h. The solvent was evaporated, and the
residue was suspended in water and extracted with EtOAc (4 × 30
mL). The combined organic layer was washed with brine, dried over
anhydrous Na2SO4 and then concentrated by a rotary evaporator. The
crude product was purified by flash column chromatography (EtOAc/
PE) to give the desired compound.
(Z)-Methyl 2-acetamido-3-phenylacrylate (1a). Yield: 56%, 6.77 g,
white solid, mp 124−125 °C; 1H NMR (400 MHz, CDCl3) δ 7.46 (d,
J = 6.0 Hz, 2H), 7.42−7.29 (m, 4H), 7.02 (br s, 1H), 3.85 (s, 3H),
2.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.0, 165.8, 133.7,
132.4, 129.7, 129.5, 128.6, 124.4, 52.7, 23.3; HRMS (ESI) m/z calcd
+
for C12H13NNaO3 [M + Na+] 242.0788, found 242.0791.
(Z)-Methyl 2-acetamido-3-(4-chlorophenyl)acrylate (1b).29 Yield:
52%, 6.58 g, white solid, mp 169−170 °C; 1H NMR (400 MHz,
CDCl3) δ 7.45−7.29 (m, 5H), 7.10 (s, 1H), 3.85 (s, 3H), 2.13 (s, 3H).
(Z)-Methyl 2-acetamido-3-(4-fluorophenyl)acrylate (1c).29 Yield:
62%, 7.34 g, white solid, mp 144−145 °C; 1H NMR (400 MHz,
CDCl3) δ 7.42 (m, 3H), 7.06 (m, 3H), 3.85 (s, 3H), 2.13 (s, 3H).
(Z)-Methyl 2-acetamido-3-(4-methoxyphenyl)acrylate (1d).
Yield: 24%, 3.26 g, white solid, mp 135−136 °C; 1H NMR (400
MHz, CDCl3) δ 7.45−7.41 (m, 3H), 6.98 (s, 1H), 6.89 (d, J = 8.3 Hz,
2H), 3.83 (s, 6H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
169.6, 166.1, 160.5, 133.4, 131.8, 126.1, 122.3, 114.0, 55.3, 52.4, 23.1;
+
HRMS (ESI) m/z calcd for C13H15NNaO4 [M + Na+] 272.0893,
found 272.0898.
(Z)-Benzyl 2-acetamido-3-phenylacrylate (1e). Yield: 53%, 4.21 g,
1
(Z)-Methyl 2-heptanamido-3-phenylacrylate (1f). Yield: 44%, 764
white solid, mp 116−118 °C; H NMR (400 MHz, CDCl3) δ 7.45−
1
7.30 (m, 11H), 7.14 (br s, 1H), 5.26 (s, 2H), 2.08 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 169.0, 165.2, 135.6, 133.7, 132.6, 129.7, 129.5,
128.6, 128.6, 128.4, 128.4, 124.4, 67.5, 23.4; HRMS (ESI) m/z calcd
mg, white solid, mp 73−74 °C; H NMR (400 MHz, CDCl3) δ 7.44
(d, J = 6.2 Hz, 2H), 7.32 (d, J = 5.9 Hz, 4H), 7.23 (br s, 1H), 3.81 (s,
3H), 2.30 (t, J = 7.3 Hz, 2H), 1.74−1.56 (m, 2H), 1.29 (br s, 6H),
0.88 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.0, 165.8,
+
for C18H17NNaO3 [M + Na+] 318.1101, found 318.1106.
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133.8, 132.0, 129.6, 129.3, 128.5, 124.5, 52.6, 36.6, 31.5, 28.9, 25.3,
N-(1,2-Diphenylvinyl)acetamide (1s).38 Yield: 57%, 410 mg, white
solid (minor/major = 1:1.9); H NMR (400 MHz, CDCl3) minor
1
+
22.5, 14.0; HRMS (ESI) m/z calcd for C17H24NO3 [M + H+]
isomer δ 7.59−7.27 (m, 10H), 6.63 (s, 1H), 6.52 (s, 1H), 1.72 (s, 3H);
major isomer δ 7.59−7.27 (m, 6H), 7.07−7.05 (m, 3H), 6.93−6.91
(m, 2H), 6.74 (s, 1H), 2.08 (s, 3H).
290.1751, found 290.1754.
3. General Procedure for the Preparation of 1j, 1k, 1l,m, 1n, 1o,
1p−s, 1t and 1u. The desired substrates 1j,32 1k,33 1l,m,34 1n,35 1o,34
1p−s,26b 1t,36 and 1u26b were prepared according to the literature
procedures. The ratio of the minor and major isomers of the enamide
(E)-N-Styrylacetamide (1t).39 Yield: 44%, 480 mg, light yellow
1
solid, mp 111−112 °C; H NMR (400 MHz, CDCl3) δ 7.51 (dd, J =
1
was determined from the H NMR spectral data.
14.6, 10.9 Hz, 1H), 7.30 (m, 5H), 7.18 (t, J = 6.8 Hz, 1H), 6.08 (d, J =
14.6 Hz, 1H), 2.11 (s, 3H).
(Z)-Methyl 2-acetamidobut-2-enoate (1j).32 Yield: 30%, 610 mg,
white solid, mp 59−60 °C; 1H NMR (400 MHz, CDCl3) δ 6.94 (br s,
1H), 6.82 (q, J = 7.2 Hz, 1H), 3.77 (s, 3H), 2.13 (s, 3H), 1.78 (d, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.2, 165.1, 134.3,
125.9, 52.4, 23.4, 14.8.
N-(1-Phenylvinyl)acetamide (1u).26b Yield: 68%, 1.17 g, white
1
solid, mp 93−94 °C; H NMR (400 MHz, DMSO-d6) δ 9.33 (br s,
1H), 7.48−7.30 (m, 5H), 5.62 (s, 1H), 4.98 (s, 1H), 2.01 (s, 3H).
4. General Procedure for the Preparation of 4a−4c. The desired
substrates 4a−4c were prepared according to the literature
procedures.26
(Z)-N-(3-Oxo-1,3-diphenylprop-1-en-2-yl)acetamide (1k).37 Yield:
1
70%, 910 mg, white solid, mp 184−187 °C; H NMR (400 MHz,
Methyl 4-((1,2-diphenylvinyl)amino)-4-oxobutanoate (4a). Yield:
77%, 761 mg, white solid (minor/major = 1:1.2); 1H NMR (400 MHz,
DMSO-d6) minor isomer δ 9.65 (s, 1H), 7.56 (d, J = 7.6 Hz, 2H), 7.51
(d, J = 7.2 Hz, 2H), 7.43−7.27 (m, 6H), 6.73 (s, 1H), 3.60 (s, 3H),
2.72−2.51 (m, 4H); major isomer δ 9.40 (s, 1H), 7.34−7.21 (m, 5H),
7.18 (s, 1H), 7.07 (t, J = 7.2 Hz, 2H), 6.98 (t, J = 7.2 Hz, 1H), 6.84 (d,
J = 7.6 Hz, 2H), 3.60 (s, 3H), 2.72−2.51 (s, 4H); 13C NMR (100
MHz, DMSO-d6) mixture δ 173.3, 173.3, 170.9, 170.8, 139.3, 137.2,
137.1, 136.5, 136.5, 134.9, 129.8, 129.3, 129.0, 128.9, 128.8, 128.7,
128.4, 128.3, 127.7, 126.2, 126.1, 123.1, 51.8, 31.3, 30.5, 29.1, 29.0;
Three carbons were missing due to overlapping; HRMS (ESI) m/z
CDCl3) δ 7.86 (d, J = 7.6 Hz, 2H), 7.63−7.32 (m, 9H), 6.68 (s, 1H),
2.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.5, 168.6, 136.9,
133.8, 133.1, 132.5, 130.4, 129.7, 129.4, 129.3, 128.9, 128.3, 23.2.
(Z)-N-(4-Oxo-4-phenylbut-2-en-2-yl)acetamide (1l).34 Yield: 43%,
1
874 mg, white solid, mp 98−99 °C; H NMR (400 MHz, CDCl3)
δ12.81 (br s, 1H), 7.91 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H),
7.46 (t, J = 7.2 Hz, 2H), 6.04 (s, 1H), 2.52 (s, 3H), 2.23 (s, 3H).
(Z)-N-(4-Oxopent-2-en-2-yl)acetamide (1m).34 Yield: 54%, 761
mg, light yellow solid, mp 43−44 °C; 1H NMR (400 MHz, CDCl3) δ
12.32 (br s, 1H), 5.33 (s, 1H), 2.37 (s, 3H), 2.15 (s, 3H), 2.14 (s, 3H).
(Z)-Methyl 3-acetamidobut-2-enoate (1n).35 Yield: 54%, 730 mg,
white solid, mp 42−43 °C; 1H NMR (400 MHz, CDCl3) δ 11.10 (br
s, 1H), 4.91 (s, 1H), 3.70 (s, 3H), 2.38 (s, 3H), 2.15 (s, 3H).
(Z)-N-(1-Phenylprop-1-en-2-yl)acetamide (Z-1o).38 Yield: 70%,
1.30 g, light yellow solid, mp 87−89 °C; 1H NMR (400 MHz,
CDCl3) δ 7.69−7.28 (m, 3H), 7.10−7.24 (m, 3H), 5.71 (s, 1H), 2.30
(s, 3H), 1.99 (m, 3H).
+
calcd for C19H20NO3 [M + H+] 310.1438, found 310.1441.
Methyl 4-((1-(4-fluorophenyl)-2-phenylvinyl)amino)-4-oxobuta-
noate (4b). Yield: 68%, 650 mg, white solid (minor/major = 1:1.2);
1H NMR (400 MHz, DMSO-d6) minor isomer δ 9.44 (s, 1H), 7.31−
7.06 (m, 8H), 6.85 (d, J = 7.2 Hz, 2H), 3.60 (s, 3H), 2.60−2.53 (m,
4H); major isomer δ 9.69 (s, 1H), 7.54 (d, J = 7.2 Hz, 2H), 7.36 (t, J =
7.6 Hz, 2H), 7.31−7.06 (m, 4H), 7.03 (d, J = 7.2 Hz, 1H), 6.69 (s,
1H), 3.60 (s, 3H), 2.62−2.56 (m, 4H); 13C NMR (100 MHz, DMSO-
d6) mixture δ 173.3, 173.2, 170.9, 163.6, 161.2, 137.0, 135.8, 135.6,
135.2 (d, JC−F = 234.9 Hz), 134.6 (d, JC−F = 237.8 Hz), 132.0 (d, JC−F
= 8.3 Hz), 129.3, 129.1, 128.8, 128.5, 128.1 (d, JC−F = 8.1 Hz), 127.7,
126.3, 123.0, 117.0, 115.8 (d, JC−F = 21.2 Hz), 115.5 (d, JC−F = 21.3
Hz), 51.8, 31.3, 30.4, 29.0, 28.9; Three carbons were missing due to
overlapping; HRMS (ESI) m/z calcd for C19H18FNNaO3+ [M + Na+]
350.1163, found 350.1165.
(E)-N-(1-Phenylprop-1-en-2-yl)acetamide (E-1o).38 Yield: 10%,
1
186 mg, white solid, mp 62−63 °C; H NMR (400 MHz, DMSO-
d6) δ 9.14 (s, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.22−7.12 (m, 3H), 7.08
(br s, 1H), 1.98 (s, 3H), 1.97 (s, 3H).
N-(1-(p-Tolyl)prop-1-en-1-yl)acetamide (1p). Yield: 62%, 1.21 g,
white solid (minor/major = 1:1.9); 1H NMR (400 MHz, CDCl3)
minor isomer δ 7.30 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.71
(br s, 1H), 5.99 (q, J = 6.8 Hz, 1H), 2.35 (s, 3H), 1.82 (d, J = 6.8 Hz,
3H), 1.78 (s, 3H); major isomer δ 7.24 (d, J = 8.0 Hz, 2H), 7.09 (d, J
= 7.8 Hz, 2H), 6.95 (br s, 1H), 5.88 (q, J = 6.8 Hz, 1H), 2.31 (s, 3H),
2.12 (s, 3H), 1.72 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
minor isomer δ 173.5, 138.1, 135.7, 129.4, 128.1, 125.2, 121.2, 21.1,
20.5, 13.6; major isomer δ 168.4, 137.4, 135.3, 134.0, 129.1, 125.4,
120.2, 23.3, 21.1, 14.0; HRMS (ESI) m/z calcd for C12H15NNaO+ [M
+ Na+] 212.1046, found 212.1047.
Methyl 4-((1-(2,5-dimethoxyphenyl)-2-(3-(trifluoromethyl)-
phenyl)vinyl)amino)-4-oxobutanoate (4c). Yield: 61%, 936 mg,
1
white solid (minor/major = 1:2.3); H NMR (400 MHz, DMSO-d6)
minor isomer δ 9.63 (s, 1H), 7.77−7.78 (m, 2H), 7.55 (d, J = 4.4 Hz,
2H), 7.05−6.92 (m, 1H), 6.87 (m, 2H), 6.52 (s, 1H), 3.73 (s, 3H),
3.72 (s, 3H), 3.57 (s, 3H), 2.51 (s, 4H); major isomer 9.42 (s, 1H),
7.47 (s, 1H), 7.33−7.30 (m, 2H), 7.14 (d, J = 6.0 Hz, 1H), 7.05−6.92
(m, 3H), 6.67 (d, J = 2.8 Hz, 1H), 3.64 (s, 3H), 3.60 (s, 3H), 3.57 (s,
3H), 2.51 (s, 4H); 13C NMR (100 MHz, DMSO-d6) mixture δ 173.3,
173.2, 170.9, 170.1, 153.9, 153.5, 151.8, 151.7, 138.9, 138.0, 135.6,
134.2, 132.8, 132.3, 129.6, 129.3, 129.4 (q, JC−F = 31.3 Hz), 129.1 (q,
N-(1-(4-Bromophenyl)prop-1-en-1-yl)acetamide (1q). Yield: 56%,
1
867 mg, white solid (minor/major = 1:15.2); H NMR (400 MHz,
DMSO-d6) minor isomer δ 8.73 (br s, 1H), 7.56 (d, J = 8.9 Hz, 2H),
7.40 (d, J = 8.0 Hz, 2H), 6.20 (q, J = 6.8 Hz, 1H), 2.08 (s, 3H), 1.40
(d, J = 6.8 Hz, 3H); major isomer δ 9.17 (s, 1H), 7.49 (d, J = 8.5 Hz,
2H), 7.31 (d, J = 8.5 Hz, 2H), 5.93 (q, J = 6.8 Hz, 1H), 2.00 (s, 3H),
1.66 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) major
isomer δ 168.5, 138.1, 134.4, 131.5, 127.6, 120.7, 120.5, 23.1, 14.2. The
13C NMR data of the minor isomer was not collected due to its low
concentration; HRMS (ESI) m/z calcd for C11H12Br79NNaO+ [M +
Na+] 275.9994, found 275.9997.
JC−F = 30.4 Hz), 126.1, 125.3 (q, JC−F = 243.8 Hz), 124.6 (q, JC−F
=
270.9 Hz), 124.2 (q, JC−F = 4.0 Hz), 123.5, 122.2 (q, JC−F = 3.5 Hz),
116.9, 115.7, 115.5, 114.4, 114.1 (q, JC−F = 4.1 Hz), 113.7, 113.5 (q,
JC−F = 3.5 Hz), 56.7, 56.3, 56.0, 55.9, 51.8, 51.7, 31.4, 30.5, 29.0, 28.9;
One carbon was missing due to overlapping; HRMS (ESI) m/z calcd
+
for C22H22F3NNaO5 [M + Na+] 460.1342, found 460.1343.
5. General Procedure for the Synthesis of Oxazole Derivatives.
To a solution of the enamide (2.0 mmol) in dried DCE (20 mL) was
added BF3·Et2O (4.0 mmol). The reaction mixture was heated to
reflux, and then PIDA (2.6 mmol) was added in one portion rapidly.
After stirring under reflux for 0.5−3 h, the reaction mixture was cooled
down to rt, quenched with saturated aqueous NaHCO3, and then
extracted with DCM. The combined organic layer was washed with
brine, dried over anhydrous Na2SO4 and concentrated by the rotary
evaporator. The crude product was purified by flash column
chromatography (EA/PE) to give the desired compounds.
N-(1-(3,4-Dimethoxyphenyl)prop-1-en-1-yl)acetamide (1r). Yield:
46%, 1.12 g, white solid (minor/major = 1:13.9); 1H NMR (400 MHz,
DMSO-d6) minor isomer δ 8.63 (s, 1H), 7.02 (s, 1H), 6.90 (s, 1H),
6.85 (s, 1H), 6.05 (q, J = 6.8 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 2.00
(s, 3H), 1.73 (d, J = 6.8 Hz, 3H); major isomer δ 9.03 (s, 1H), 6.95 (s,
1H), 6.88 (s, 2H), 5.83 (q, J = 6.8 Hz, 1H), 3.76 (s, 3H), 3.74 (s, 3H),
2.00 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, DMSO-
d6) major isomer δ 168.1, 148.9, 148.8, 134.8, 131.8, 118.0, 117.9,
111.9, 109.4, 56.0, 55.9, 23.2, 14.3. The 13C NMR data of the minor
isomer was not collected due to its low concentration; HRMS (ESI)
Methyl 2-methyl-5-phenyloxazole-4-carboxylate (2a). Yield: 90%,
+
1
m/z calcd for C13H18NO3 [M + H+] 236.1281, found 236.1284.
446 mg, white solid, mp 76−77 °C; H NMR (400 MHz, CDCl3) δ
10358
dx.doi.org/10.1021/jo302073e | J. Org. Chem. 2012, 77, 10353−10361

The Journal of Organic Chemistry
Article
8.07 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 6.8 Hz, 3H), 3.94 (s, 3H), 2.56
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.6, 159.8, 155.4, 130.2,
128.4, 128.2, 127.0, 126.6, 52.2, 13.8; HRMS (ESI) m/z calcd for
(2,4-Dimethyloxazol-5-yl)(phenyl)methanone (2l). Yield: 86%,
260 mg, colorless oil; H NMR (400 MHz, CDCl3) δ 7.97 (d, J =
1
7.6 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.2 Hz, 2H), 2.55 (s,
3H), 2.49 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.4, 162.6,
147.7, 145.0, 137.1, 132.6, 129.1, 128.3, 14.2, 14.0; HRMS (ESI) m/z
+
C12H11NNaO3 [M + Na+] 240.0631, found 240.0632.
Methyl 5-(4-chlorophenyl)-2-methyloxazole-4-carboxylate (2b).
1
+
calcd for C12H11NNaO2 [M + Na+] 224.0682, found 224.0685.
Yield: 90%, 445 mg, white solid, mp 110−111 °C; H NMR (400
MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H),
3.94 (s, 3H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5,
159.9, 154.3, 136.2, 129.4, 128.7, 126.9, 125.4, 52.3, 13.8; HRMS
1-(2,4-Dimethyloxazol-5-yl)ethanone (2m). Yield: 55%, 160 mg,
1
white solid, mp 58−60 °C; H NMR (400 MHz, CDCl3) δ 2.51 (s,
3H), 2.46 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
187.3, 162.3, 145.5, 145.0, 27.4, 14.2, 13.5; HRMS (ESI) m/z calcd for
+
(ESI) m/z calcd for C12H10ClNNaO3 [M + Na+] 274.0241, found
+
C7H9NNaO2 [M + Na+] 162.0525, found 162.0526.
274.0243.
Methyl 5-(4-fluorophenyl)-2-methyloxazole-4-carboxylate (2c).
Methyl 2,4-dimethyloxazole-5-carboxylate (2n). Yield: 88%, 436
1
1
Yield: 74%, 365 mg, white solid, mp 100−101 °C; H NMR (400
mg, white solid, mp 45−48 °C; H NMR (400 MHz, CDCl3) δ 3.91
(s, 3H), 2.50 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
163.1, 159.0, 146.1, 137.3, 51.8, 14.1, 13.1; HRMS (ESI) m/z calcd for
MHz, CDCl3) δ 8.11 (dd, J = 8.4, 5.2 Hz, 2H), 7.16 (t, J = 8.4 Hz,
1H), 3.94 (s, 3H), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
164.9, 162.4, 161.2 (d, JC−F = 287.9 Hz), 154.6, 130.4 (d, JC−F = 8.4
Hz), 126.3, 123.2, 115.6 (d, JC−F = 21.8 Hz), 52.2, 13.7; HRMS (ESI)
m/z calcd for C12H10FNNaO3+ [M + Na+] 258.0537, found 258.0542.
Methyl 5-(4-methoxyphenyl)-2-methyloxazole-4-carboxylate
(2d). Yield: 85%, 250 mg, white solid, mp 59−60 °C; 1H NMR
(400 MHz, CDCl3) δ 8.06 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.4 Hz,
2H), 3.93 (s, 3H), 3.87 (s, 3H), 2.54 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.7, 161.1, 159.1, 155.7, 129.9, 125.2, 119.5, 113.8, 55.3,
+
C7H9NNaO3 [M + Na+] 178.0475, found 178.0478.
2,4-Dimethyl-5-phenyloxazole (2o).42 Yield: 50% (Z-1o), 94 mg,
1
48%(E-1o), 91 mg, white solid, mp 48−50 °C; H NMR (400 MHz,
CDCl3) δ 7.57 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.29 (t, J =
7.6 Hz, 1H), 2.48 (s, 3H), 2.38 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ 159.3, 145.1, 131.6, 129.3, 128.7, 127.3, 125.1, 13.9, 13.2.
2,5-Dimethyl-4-(p-tolyl)oxazole (2p). Yield: 82%, 406 mg, white
1
solid, mp 42−44 °C; H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.2
+
52.1, 13.7; HRMS (ESI) m/z calcd for C13H13NNaO4 [M + Na+]
Hz, 2H), 7.21 (d, J = 7.2 Hz, 2H), 2.47 (s, 3H), 2.45 (s, 3H), 2.37 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 142.9, 136.7, 134.3,
129.6, 129.2, 126.4, 21.2, 13.8, 11.7; HRMS (ESI) m/z calcd for
C12H13NNaO+ [M + Na+] 210.0889, found 210.0894.
270.0737, found 270.0741.
Benzyl 2-methyl-5-phenyloxazole-4-carboxylate (2e).40 Yield:
78%, 230 mg, light yellow solid, mp 69−70 °C; 1H NMR (400
MHz, CDCl3) 8.04−7.92 (m, 2H), 7.42 (m, 5H), 7.37−7.29 (m, 3H),
5.39 (s, 2H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.0,
159.9, 155.6, 135.7, 130.1, 128.6, 128.5, 128.35, 128.3, 127.0, 126.7,
66.8, 13.8.
4-(4-Bromophenyl)-2,5-dimethyloxazole (2q). Yield: 82%, 243 mg,
1
light yellow solid, mp 46−47 °C; H NMR (400 MHz, CDCl3) δ
7.56−7.45 (m, 4H), 2.47 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.3, 143.7, 133.4, 131.7, 131.4, 128.0, 121.0, 13.8, 11.8;
HRMS (ESI) m/z calcd for C11H10BrNNaO+ [M + Na+] 273.9838,
found 273.9838.
Methyl 2-hexyl-5-phenyloxazole-4-carboxylate (2f). Yield: 81%,
1
233 mg, white solid, mp 32−33 °C; H NMR (400 MHz, CDCl3) δ
8.07 (dd, J = 8.0, 1.6 Hz, 2H), 7.42−7.50 (m, 3H), 3.93 (s, 3H), 2.85
(t, J = 7.6 Hz, 2H), 1.89−1.77 (m, 2H), 1.42−1.37 (m, 2H), 1.35−
1.27 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 163.5, 162.7, 155.2, 130.1, 128.4, 128.2, 127.1, 126.4, 52.2, 31.3, 28.8,
28.1, 27.0, 22.5, 14.0; HRMS (ESI) m/z calcd for C17H21NNaO3+ [M
+ Na+] 310.1414, found 310.1417.
4-(3,4-Dimethoxyphenyl)-2,5-dimethyloxazole (2r). Yield: 71%,
1
211 mg, white solid, mp 63−65 °C; H NMR (400 MHz, CDCl3) δ
7.23 (d, J = 1.6 Hz, 1H), 7.10 (dd, J = 8.0, 1.6 Hz, 1H), 6.90 (d, J = 8.4
Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H), 2.47 (s, 3H), 2.46 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 159.0, 149.1, 148.2, 142.6, 134.1, 125.4,
118.9, 111.2, 110.0, 55.9, 55.9, 13.8, 11.7; HRMS (ESI) m/z calcd for
Methyl 2,5-diphenyloxazole-4-carboxylate (2g).41 Yield: 83%, 245
mg, white solid, mp 74−75 °C; 1H NMR (400 MHz, CDCl3) δ 8.18−
8.13 (m, 4H), 7.55−7.44 (m, 6H), 3.99 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.7, 159.8, 155.3, 131.1, 130.4, 128.8, 128.5, 128.4,
1287.0, 127.0, 126.9, 126.3, 52.4.
+
C13H15NNaO3 [M + Na+] 256.0944, found 256.0947.
2-Methyl-4,5-diphenyloxazole (2s). Yield: 70%, 205 mg, colorless
oil; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 6.8 Hz, 2H), 7.58 (d, J
= 6.8 Hz, 2H), 7.40−7.27 (m, 6H), 2.56 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 160.2, 145.3, 135.2, 132.5, 129.1, 128.6, 128.6, 128.4,
128.0, 127.9, 126.5, 14.0; HRMS (ESI) m/z calcd for C16H13NNaO+
[M + Na+] 258.0889, found 258.0890.
Methyl 2-(4-chlorophenyl)-5-phenyloxazole-4-carboxylate
(2h).41 Yield: 89%, 266 mg, white solid, mp 122−124 °C; H NMR
1
(400 MHz, CDCl3) δ 8.17−8.05 (m, 4H), 7.46−7.51 (m, 5H), 3.98 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 162.5, 158.9, 155.5, 137.4,
130.5, 129.2, 128.5, 128.4, 128.1, 128.0, 126.8, 124.8, 52.4.
2-Methyl-5-phenyloxazole (2t).42 Yield: 56%, 166 mg, light yellow
1
solid, mp 43−45 °C; H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.6
Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.22 (s,
1H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.1, 151.2,
128.9, 128.3, 128.1, 124.0, 121.7, 14.0.
Methyl 2-(3,4-dimethoxyphenyl)-5-phenyloxazole-4-carboxylate
(2i). Yield: 84%, 251 mg, white solid, mp 131−132 °C; 1H NMR (400
MHz, CDCl3) δ 8.12 (d, J = 6.8 Hz, 2H), 7.74 (dd, J = 8.4, 1.6 Hz,
1H), 7.66 (d, J = 1.6 Hz, 1H), 7.56−7.43 (m, 3H), 6.96 (d, J = 8.4 Hz,
1H), 4.05−3.92 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 162.7,
159.9, 155.0, 151.7, 149.2, 130.3, 128.4, 127.8, 127.1, 120.3, 119.1,
111.0, 109.6, 56.2, 56.0, 52.4; One carbon was missing due to
2-Methyl-4-phenyloxazole (2u).43 Yield: 30%, 148 mg, yellow
1
solid, mp 40−42 °C; H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H),
7.71 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.2 Hz,
1H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 140.7,
133.2, 131.2, 128.7, 127.9, 125.4, 13.9.
+
overlapping; HRMS (ESI) m/z calcd for C19H17NNaO5 [M + Na+]
Methyl 3-(4,5-diphenyloxazol-2-yl)propanoate (5a).3b Yield: 73%,
362.0999, found 362.1004.
1
101 mg, white solid, mp 58−60 °C; H NMR (400 MHz, CDCl3) δ
Methyl 2,5-dimethyloxazole-4-carboxylate (2j). Yield: 37%, 110
1
7.63−7.65 (m, 2H), 7.57 (dd, J = 8.0, 1.6 Hz, 2H), 7.31−7.39 (m,
6H), 3.74 (s, 3H), 3.22 (t, J = 7.2 Hz, 2H), 2.94 (t, J = 7.2 Hz, 2H).
Methyl 3-(4-(4-fluorophenyl)-5-phenyloxazol-2-yl)propanoate
(5b). Yield: 87%, 281 mg, colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.60 (dd, J = 8.4, 5.2 Hz, 2H), 7.57−7.50 (m, 2H), 7.41−
7.28 (m, 3H), 7.05 (t, J = 8.4 Hz, 2H), 3.73 (s, 3H), 3.18 (t, J = 7.6
Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
mg, white solid, mp 44−46 °C; H NMR (400 MHz, CDCl3) δ 3.90
(s, 3H), 2.59 (s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
162.8, 159.4, 156.2, 127.2, 51.8, 13.7, 11.8; HRMS (ESI) m/z calcd for
+
C7H9NNaO3 [M + Na+] 178.0475, found 178.0480.
(2-Methyl-5-phenyloxazol-4-yl)(phenyl)methanone (2k). Yield:
1
76%, 198 mg, colorless oil; H NMR (400 MHz, CDCl3) δ 8.05 (d,
J = 7.6 Hz, 2H), 7.98−7.41(m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.48−
7.38 (m, 5H), 2.58 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 188.9,
159.1, 154.7, 137.5, 133.8, 133.0, 130.3, 130.1, 128.5, 128.2, 127.7,
172.4, 162.6 (d, JC−F = 245.9 Hz), 161.8, 145.3, 134.2, 129.7 (d, JC−F
=
8.1 Hz), 128.8, 128.7, 128.6, 126.5, 115.6 (d, JC−F = 21.4 Hz), 51.9,
30.9, 23.5; One carbon was missing due to overlapping; HRMS (ESI)
m/z calcd for C19H16FNNaO3+ [M + Na+] 348.1006, found 348.1009.
+
127.4, 13.9; HRMS (ESI) m/z calcd for C17H13NNaO2 [M + Na+]
286.0838, found 286.0843.
10359
dx.doi.org/10.1021/jo302073e | J. Org. Chem. 2012, 77, 10353−10361

The Journal of Organic Chemistry
Article
Methyl 3-(4-(2,5-dimethoxyphenyl)-5-(3-(trifluoromethyl)-
phenyl)oxazol-2-yl)propanoate (5c). Yield: 72%, 591 mg, white
solid, mp 95−96 °C; H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H),
̀
(2) For selected examples, see: (a) Adamczeski, M.; Quinoa, E.;
̃
Crews, P. J. Am. Chem. Soc. 1988, 110, 1598. (b) Rodríguez, J.; Nieto,
R. M.; Crews, P. J. Nat. Prod. 1993, 56, 2034. (c) Rudi, A.; Kashman,
Y.; Benayahu, Y.; Schleyer, M. J. Nat. Prod. 1994, 57, 829. (d) Mulder,
R. J.; Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1999, 64, 4995.
(e) Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, M.; Ley, S. V.
Angew. Chem., Int. Ed. 2006, 45, 6714. (f) Mulder, R. J.; Shafer, C. M.;
Dalisay, D. S.; Molinski, T. F. Bioorg. Med. Chem. Lett. 2009, 19, 2928.
(g) Chandrasekhar, S.; Sudhakar, A. Org. Lett. 2010, 12, 236.
(3) For selected examples, see: (a) Brown, K.; Cavalla, J. F.; Green,
D.; Wilson, A. B. Nature 1968, 219, 164. (b) Kotani, E.; Kobayashi, S.;
Adrachi, M.; Tsujioka, T.; Nakamura, K.; Tobinaga, S. Chem. Pharm.
Bull. 1989, 37, 606. (c) Yoshida, F.; Topliss, J. G. J. Med. Chem. 2000,
43, 2575. (d) Seidler, J.; McGovern, S. L.; Doman, T. N.; Shoichet, B.
K. J. Med. Chem. 2003, 46, 4477.
1
7.58 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz,
1H), 7.09 (d, J = 3.2 Hz, 1H), 6.95 (dd, J = 9.2, 3.2 Hz, 1H), 6.87 (d, J
= 9.2 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.52 (s, 3H), 3.23 (t, J = 7.6
Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
172.4, 161.9, 153.8, 150.9, 145.1, 132.7, 130.6 (q, JC−F = 32.0 Hz),
130.1, 128.6, 128.2, 124.1 (q, JC−F = 3.3 Hz), 124.0 (q, JC−F = 270.7
Hz), 122.1 (q, JC−F = 3.9 Hz), 121.9, 116.3, 115.8, 112.3, 55.8, 55.5,
+
51.9, 30.8, 23.6; HRMS (ESI) m/z calcd for C22H20F3NNaO5 [M +
Na+] 458.1186, found 458.1191.
6. General Procedure for the Synthesis of 6a−c. Adapted from a
previously reported procedure with some modifications.27 To a
solution of esters (0.75 mmol) in methanol (2 mL) was added 1 M
NaOH (8 mL). The mixture was stirred at 50 °C for 0.5−2.5 h. After
cooling to room temperature, the reaction mixture was diluted with 1
M HCl (15 mL), and the products were separated by filtration.
3-(4,5-Diphenyloxazol-2-yl)propanoic acid (6a).3b Yield: 90%, 76
mg, white solid, mp 160−161 °C; 1H NMR (400 MHz, CDCl3) δ 9.48
(br s, 1H), 7.63−7.35 (m, 10H), 3.26−3.00 (m, 4H).
(4) For selected methods to oxazoles, see: (a) Turchi, I. J.; Dewar, M.
J. S. Chem. Rev. 1975, 75, 389. (b) Wipf, P.; Miller, C. P. J. Org. Chem.
1993, 58, 3604. (c) Coqueron, Pierre-Yves; Didier, C.; Ciufolini, M. A.
Angew. Chem., Int. Ed. 2003, 42, 1411. (d) Jiang, H.; Huang, H.; Cao,
H.; Qi, C. Org. Lett. 2010, 12, 5561. (e) Wan, C.; Zhang, J.; Wang, S.;
Fan, J.; Wang, Z. Org. Lett. 2010, 12, 2338. (f) Wan, C.; Gao, L.;
Wang, Q.; Zhang, J.; Wang, Z. Org. Lett. 2010, 12, 3902. (g) Wu, J.;
Chen, W.; Hu, M.; Zou, H.; Yu, Y. Org. Lett. 2010, 12, 616. (h) Zeng,
X.; Ye, K.; Lu, M.; Juan Chua, P.; Tan, B.; Zhong, G. Org. Lett. 2010,
3-(4-(4-Fluorophenyl)-5-phenyloxazol-2-yl)propanoic acid (6b).
1
Yield: 93%, 216 mg, white solid, mp 161−162 °C; H NMR (400
MHz, CDCl3) δ 7.59 (dd, J = 8.4, 5.6 Hz, 2H), 7.53 (d, J = 7.2 Hz,
2H), 7.33−7.38 (m, 3H), 7.05 (t, J = 8.8 Hz, 2H), 3.19 (t, J = 7.2 Hz,
2H), 2.96 (t, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 176.8,
162.7 (d, JC−F = 246.2 Hz), 162.0, 145.5, 134.0, 129.8 (d, JC−F = 8.1
Hz), 128.7, 128.7, 128.6, 128.2, 126.5, 115.6 (d, JC−F = 21.5 Hz), 30.9,
́
12, 2414. (i) Cano, I.; Alvarez, E.; Carmen Nicasio, M.; Perez, P. J. J.
́
Am. Chem. Soc. 2011, 133, 191. (j) He, W.; Li, C.; Zhang, L. J. Am.
Chem. Soc. 2011, 133, 8482. (k) Davies, P. W.; Cremonesi, A.;
Dumitrescu, L. Angew. Chem., Int. Ed. 2011, 58, 8931. (l) Ritson, D. J.;
Spiteri, C.; Moses, J. E. J. Org. Chem. 2011, 76, 3519. (m) Zhang, J.;
Coqueron, Pierre-Yves; Ciufolini, M. A. Heterocycles 2011, 82, 949.
(n) Xie, J.; Jiang, H.; Cheng, Y.; Zhu, C. Chem. Commun. 2012, 48,
979.
+
23.2; HRMS (ESI) m/z calcd for C18H14FNNaO3 [M + Na+]
334.0850, found 334.0851.
3-(4-(2,5-Dimethoxyphenyl)-5-(3-(trifluoromethyl)phenyl)oxazol-
2-yl)propanoic acid (6c). Yield: 95%, 300 mg, white solid, mp 138−
139 °C; 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.59 (d, J = 7.8
Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.09 (d, J =
2.8 Hz, 1H), 6.95 (dd, J = 9.0, 2.8 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H),
3.79 (s, 3H), 3.52 (s, 3H), 3.24 (t, J = 7.2 Hz, 2H), 2.97 (t, J = 7.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 176.3, 162.2, 153.7, 151.0,
145.3, 132.4, 130.7 (q, JC−F = 31.9 Hz), 129.9, 128.6, 128.3, 123.9 (q,
JC−F = 270.8 Hz), 124.3 (q, JC−F = 3.5 Hz), 122.1 (q, JC−F = 3.7 Hz),
121.3, 116.2, 116.0, 112.4, 55.8, 55.5, 30.9, 23.3; HRMS (ESI) m/z
(5) (a) Lechel, T.; Lentz, D.; Reissig, H. -U. Chem.Eur. J. 2009, 15,
5432. (b) Lechel, T.; Gerhard, M.; Trawny, D.; Brusilowskij, B.;
Schefzig, L.; Zimmer, R.; Rabe, J. P.; Lentz, D.; Schalley, C. A.; Reissig,
H. -U. Chem.Eur. J. 2011, 17, 7480.
(6) Schuh, K.; Glorius, F. Synthesis 2007, 15, 2297.
(7) For selected examples, see: (a) Shin, C.; Sato, Y.; Sugiyama, H.;
Nanjo, K.; Yoshimura. J. Bull. Chem. Soc. Jpn. 1977, 50, 1788. (b) Das,
J.; Reid, J. A.; Kronenthal, D. R.; Singh, J.; Pansegrau, P. D.; Mueller,
R. H. Tetrahedron Lett. 1992, 33, 7835. (c) Ferreira, P. M. T.;
Castanheira, E. M. S.; Monteiro, L. S.; Pereira, G.; Vilaca̧ , H.
Tetrahedron 2010, 66, 8672.
(8) Cornforth, J. W.; Huang, H. T. J. Chem. Soc. 1948, 1964.
(9) Matsumura, K.; Miyashita, O.; Saraie, T.; Hashimoto, N. Chem.
Pharm. Bull. 1976, 24, 924.
(10) Matsumura, K.; Miyashita, O.; Shimadzu, H.; Hashimoto, N.
Chem. Pharm. Bull. 1976, 24, 948.
+
calcd for C21H18F3NNaO5 [M+ Na+] 444.1029, found 444.1033.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectral data for all compounds and X-ray structural data of 2a
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org
AUTHOR INFORMATION
(11) Misra, N. C.; Ila, H. J. Org. Chem. 2010, 75, 5195.
■
(12) Martin, R.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 5521.
(13) Cheung, C.; Buchwald, S. L. J. Org. Chem. 2012, 77, 7526.
(14) Wendlandt, A. E.; Stahl, S. S. Org. Biomol. Chem. 2012, 10, 3866.
(15) For selected examples, see: (a) Stang, P. J. J. Org. Chem. 2003,
68, 2997. (b) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656.
(c) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (d) Kita,
Y.; Dohi, T. Chem. Commun. 2009, 45, 2073. (e) Uyanik, M.; Ishihara,
K. Chem. Commun. 2009, 45, 2086.
(16) For selected examples, see: (a) Correa, A.; Tellitu, I.;
Domínguez, E.; SanMartin, R. J. Org. Chem. 2006, 71, 8316. (b) Du,
Y.; Liu, R.; Linn, G.; Zhao, K. Org. Lett. 2006, 8, 5919. (c) Ciufolini,
M. A.; Braun, N. A.; Canesi, S.; Ousmer, M.; Chang, J.; Chai, D.
Synthesis 2007, 3759. (d) Malamidou-Xenikaki, E.; Spyroudis, S.;
Tsanakopoulou, M.; Hadjipavlou-Litina, D. J. Org. Chem. 2009, 74,
7315. (e) Liang, H.; Ciufolini, M. A. Tetrahedron 2010, 66, 5884.
(f) Lovick, H. M.; Michael, F. E. J. Am. Chem. Soc. 2010, 132, 1249.
(g) Cho, S.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133, 5996.
(h) Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J. Angew.
Chem., Int. Ed. 2011, 50, 8605. (i) Kim, H.; Cho, S.; Chang, S. Org.
Corresponding Author
*E-mail: duyunfeier@tju.edu.cn; kangzhao@tju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the National Natural Science Foundation of
China (#21072148) for financial support.
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