Synthesis of 2-(Trifluoromethyl)oxazoles from β-monosubstituted enamines via PhI(OCOCF3)2-Mediated trifluoroacetoxylation and cyclization

Article abstract of DOI:10.1021/jo202070h

Treatment of β-monosubstituted enamines with phenyliodine bis(trifluoroacetate) (PIFA) was found to give a variety of 4,5-disubstituted 2-(trifluoromethyl)oxazoles. This approach allows the incorporation of the trifluoromethyl moiety in PIFA into the fina

Full text of DOI:10.1021/jo202070h

Note
pubs.acs.org/joc
Synthesis of 2-(Trifluoromethyl)oxazoles from β-Monosubstituted
Enamines via PhI(OCOCF3)2-Mediated Trifluoroacetoxylation and
Cyclization
Feifei Zhao, Xin Liu, Rui Qi, Daisy Zhang-Negrerie, Jianhui Huang, Yunfei Du,* and Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, China
S
* Supporting Information
ABSTRACT: Treatment of β-monosubstituted enamines with phenyliodine
bis(trifluoroacetate) (PIFA) was found to give a variety of 4,5-disubstituted
2-(trifluoromethyl)oxazoles. This approach allows the incorporation of the
trifluoromethyl moiety in PIFA into the final products, which presumably
takes place via the oxidative β-trifluoroacetoxylation of the enamine
substrates followed by subsequent intramolecular cyclization.
n the last two decades, hypervalent iodine(III) reagents,
especially phenyliodine bis(trifluoroacetate) (PIFA) and
iodo moieties of PIDA are incorporated into the final product
via β-iodination and N-arylation respectively (Figure 1, type
2).7b It has also been recognized that one acetate group of
PIDA can be installed onto the β-position of an enamine
compound, possibly through reductive elimination of iodoben-
zene6 or nucleophilic substitution by the acetate anion8 (Figure
1, type 3). However, to our knowledge, reports on the
integration of the trifluoroacetate moiety of PIFA into an
enamine substrate in the literature are scarce, if any. Herein, we
report a novel formation of 2-(trifluoromethyl)oxazole
derivatives9−11 from reactions of β-monosubstituted enamines
with PIFA, in which PIFA serves as a fluorinating reagent for
the introduction of the trifluoromethyl moiety, a biologically
important functional group.12
I
phenyliodine diacetate (PIDA), have been vastly used in
many useful organic transformations.1 Among them, reactions
of hypervalent iodine(III) reagents with enamine compounds
have been thoroughly investigated.2 Various heterocyclic
compounds such as pyrroles,3 indoles,4 and azirines5 can be
obtained by such reactions, depending on the substitution
pattern of the enamine substrates and the type of the
iodine(III) reagents used. In all cases, PIFA and PIDA are
converted into trifluoroacetate and acetate respectively, with
the release of the recyclable iodobenzene, after the oxidative
process (Figure 1, type 1).6 In a few reactions of enamines with
During the course of our study on the reaction of enamines
with hypervalent iodine(III) reagents,4,5a,7c we found that the β-
monosubstituted enamine 1a, bearing a terminal ethoxycar-
bonyl group, upon treatment with PIDA, gave no expected
azirine compounds.5a The replacement of PIDA with the more
potent PIFA led us accidentally to discover that an interesting
heterocyclic compound 2a13 was formed in the process. The
structure of this 2-(trifluoromethyl)oxazole 2a was undoubtedly
established by X-ray crystal analysis (see Supporting
Information for details).
Enamine 1a was used as the model substrate for the
optimization of reaction conditions, and the results are
summarized in Table 1. It was found that the reaction yield
was significantly improved and the reaction time shortened
when the amount of PIFA was increased from 1.0 equiv to 1.2
equiv and the reaction temperature was increased from room
temperature to 45 °C (Table 1, entries 1−2). However, even
higher temperature, such as at reflux, reduced the yield of the
desired product due to the formation of a complex mixture of
byproducts (Table 1, entry 3). Data in Table 1 (entries 4−7)
Figure 1. General reaction types of enamine compounds with PIFA
and PIDA.
PIDA, the phenyliodine moiety in PIDA can be incorporated
into the final products.7 For example, upon treatment of 4-
phenylaminocoumarin with PIDA, both the phenyl and the
Received: October 5, 2011
Published: November 8, 2011
© 2011 American Chemical Society
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Note
a
Table 1. Optimization of the Reaction Conditions
b
entry
PIFA equiv
solvent
[1a] (M)
T (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
1.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
0.1
rt
45
3
35
52
30
66
73
0.1
1
0.1
reflux
45
0.5
1.5
1.5
2
0.05
0.04
0.02
0.2
45
c
45
80
45
1
40
73
d
8
0.02
0.02
0.02
0.02
0.02
0.02
0.02
45
2
e
c
9
45
2
75
10
11
12
13
14
45
2
trace
68
64
15
0
f
TFE
45
2
toluene
EtOAc
DMF
45
2
45
2
45
2
a
b
c
All reactions were carried out by adding PIFA to a solution of 1a in dry solvent unless specifically mentioned. Isolated yields. Average of three
d
e
f
runs. Enamine 1a was added portionwise to a solution containing PIFA. 4 Å molecular sieves were added. TFE herein refers to 2,2,2-
trifluoroethanol.
show that the concentration of substrate 1a in the solvent can
greatly influence the outcome of the reaction. Specifically, when
the reaction mixture was diluted to 0.02 M, the yield was
dramatically increased to 80%, while at 0.2 M, the yield was
only 40%. We also found that addition of the enamine 1a in a
portionwise manner to a solution of PIFA in dry solvent at low
concentration, as opposed to one portion, does not greatly
affect the reaction yield (Table 1, entry 8). An attempt to
further increase the yield by including molecular sieves for the
purpose of absorbing the water generated during the reaction
course was not successful (Table 1, entry 9). Furthermore, the
presence of a Lewis or Brønsted acid such as CuSO4, BF3·Et2O,
or TFA somehow reduced the yield in a series of experiments
carried out between −20 °C and room temperature (not
shown). Finally, our solvent study shows that none of the
solvents including TFE, toluene, EtOAc, CH3CN, or DMF is
superior to DCE. Data (Table 1, entries 10−14) show that
yields were reduced by around 15% with TFE and toluene as
solvent, but tanked to only 15%, trace, and absolutely nothing
in the other three solvents.
Under the best conditions (Table 1, entry 6), we explored
the scope and limitations14 of the newly developed method by
using various β-monosubstituted enamines5a,9 bearing a
terminal carbonyl functionality. Results show that (i) the
presence of either electron-donating or electron-withdrawing
substituents in the α-phenyl ring of enamine 1a does not
influence the reaction to any significant extent as the desired
oxazoles were all obtained in fairly good yields (Table 2, entries
2−5); (ii) the α-phenyl ring in 1a is not indispensable for the
reaction and can be replaced by an alkyl substituent such as
methyl, benzyl, or cyclohexenylmethyl group (Table 2, entries
6−8); (iii) the β-carboxylic ester groups can be replaced by an
acyl group (Table 2, entries 9−16). A variety of 4-alkyl-5-aroyl-
2-(trifluoromethyl)oxazoles were obtained with the 4-tert-
butyloxazole 2m being prepared in the most satisfying yield
of 90%. 4-Phenyl-5-pivaloyloxazole 2n was also obtained from
α-phenyl-β-pivaloyl enamine 1n, the regioisomer of 1m in a
parallel fashion. Oxazoles 2o and 2p were obtained (Table 2,
entries 15−16), albeit in much lower yields due to the
formation of a complex mixture of unidentified byproducts
from α-aryl-β-aroyl enamines 1o and 1p.
A proposed mechanistic pathway is shown in Scheme 1.
Initially, the reaction of β-monosubstituted enamines 1 with
PIFA gives the β-iodo iminium salt A, which is expected to be a
stable intermediate owing to the existence of an internal H-
bond.7c Next, the generated trifluoroacetate anion, although a
relatively weak base, nucleophilically attacks the sp3 carbon
center in A to give intermediate B,15 with the leaving group
dissociating into an iodobenzene molecule and a trifluoroace-
tate anion. After the proton transfer from the iminium center to
the carbonyl oxygen of the trifluoroacetate moiety, an
intramolecular attack on the electron-positive carbonyl group
by the N of the amino group occurs in C and leads to D.
Finally, upon protonation of the generated hydroxyl group by
the ammonium proton in D, the aromatization is realized and
gives the heterocyclic oxazoles 2 via the elimination of one H2O
molecule from E. The proposed reaction mechanism is
consistent with the observation that the presence of a Lewis
or Brønsted acid is disadvantageous to the reaction, as Lewis or
Brønsted acids will understandably reduce the nucleophilicity of
the enamine or compete with PIFA as an additional electrophile
during the first nucleophilic substitution step between the
enamine and PIFA.
The β-trifluoroacetoxylated enamine intermediate C in the
mechanistic pathway was not detected in the reaction process.
In order to further probe into the reaction mechanism, we
studied, under identical reaction conditions, the reaction of the
enamine substrates with PIDA,16 which bears the more
nucleophilic acetate groups. To our pleasant surprise, the
corresponding β-acetoxylated enamines 3a and 3b could both
be separated as stable compounds, albeit in lower yields of 44%
and 40% respectively. Further treatment of enamines 3a and 3b
with AcOH under reflux in DCE gave respectively 2-
methyloxazoles 4a and 4b in excellent yields via intramolecular
condensation (Scheme 2). These results imply that the reaction
of enamine compound 1 with PIFA also adopts the similar
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Note
a
Table 2. Synthesis of 2-(Trifluoromethyl)oxazoles via PhI(OCOCF3)2-Mediated Trifluoroacetoxylation and Cyclization
a
b
c
Optimal conditions: 1 (1.0 equiv), PIFA (1.2 equiv) in DCE stirred at 45 °C. Isolated yield. Ar herein refers to 4-chlorophenyl.
processes of β-trifluoroacetoxylation and condensation, con-
sistent with the proposed mechanism. The only difference is
that the corresponding β-trifluoroacetoxylated enamine C, due
to the presence of the electron-withdrawing trifluoromethyl
group, is too reactive and undergoes simultaneous condensa-
tion, while the β-acetoxylated enamines 3 are stable enough to
be separated, even though relatively harsh conditions were
needed for the cyclization step.
CONCLUSION
■
In conclusion, we have discovered a new approach to the
synthesis of a variety of 2-(trifluoromethyl)oxazoles from
reactions of β-monosubstituted enamines with PIFA. The key
features of this method are the incorporation of the
trifluoromethyl moiety in PIFA into the final product and the
formation of a heterocyclic oxazole ring. The presence of both
the oxazole ring as well as the trifluoromethyl group renders
this class of compounds important for their promising
applications in pharmaceutical research.
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Note
Procedure for the Synthesis of Methyl 2-Methyl-4-phenyl-
oxazole-5-carboxylate (4a) and (2,4-Dimethyloxazol-5-yl)-
(phenyl)methanone (4b). To a solution of the β-acetoxylated
enamines 3a or 3b (0.5 mmol) in dry DCE (10 mL) was added AcOH
(2.5 mmol, 0.14 mL) at reflux. Then the reaction mixture was kept at
the same temperature for 10 h. TLC was used to indicate the reaction
process. When the reaction was completed, the solvent was
evaporated, and the residue was passed through a silica gel column
to give the corresponding desired product 4a or 4b.
Scheme 1. Proposed Mechanistic Pathway
Ethyl 3-Amino-4-cyclohexenylbut-2-enoate (1h). 1h was
purified by silica gel chromatography (EtOAc/PE = 5/95). Rf = 0.5
1
(EtOAc/PE = 20/80). Yield 2.237 g, 46% as colorless oil. H NMR
(400 MHz, CDCl3) δ 7.85 (br s, 1H, NH2), 5.60 (s, 1H, CH), 4.76 (br
s, 1H, NH2), 4.55 (s, 1H, CH), 4.11 (q, J = 7.0 Hz, 2H, CH2) 2.75 (s,
2H, CH2), 2.04−2.03 (m, 2H, CH2), 1.90−1.89 (m, 2H, CH2), 1.62−
1.55 (m, 4H, CH2), 1.26 (t, J = 7.0 Hz, 3H, CH3). 13C NMR (100
MHz, CDCl3) δ 170.3, 161.1, 133.7, 126.2, 84.3, 58.5, 45.2, 27.4, 25.3,
22.7, 22.1, 14.6. HRMS (ESI) m/z calcd for C12H20NO2 [M + H+]
+
Scheme 2. Further Probe into the Reaction Mechanism
210.1489, found 210.1493.
3-Amino-1-(2-iodophenyl)but-2-en-1-one (1k). 1k was puri-
fied by silica gel chromatography (EtOAc/PE = 10/90). Rf = 0.3
(EtOAc/PE = 20/80). Overall yield (2 steps) 3.070 g, 38% as a yellow
1
solid, mp 130−131 °C. H NMR (400 MHz, CDCl3) δ 10.00 (br s,
1H, NH2), 7.85 (d, J = 7.5 Hz, 1H, Harom), 7.34−7.27 (m, 2H, Harom),
7.04−7.00 (m, 1H, Harom), 5.81 (br s, 1H, NH2), 5.24 (s, 1H, CH),
2.00 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 184.4, 147.2,
144.9, 142.2, 140.1, 132.5, 128.8, 128.3, 91.8, 13.6. HRMS (ESI) m/z
calcd for C10H11INO+ [M + H+] 287.9880, found 287.9883.
3-Amino-1-(3-(trifluoromethyl)phenyl)but-2-en-1-one (1l).
1l was purified by silica gel chromatography (EtOAc/PE = 10/90).
Rf = 0.4 (EtOAc/PE = 40/60). Overall yield (2 steps) 1.151 g, 39% as
a yellow solid, mp 130−131 °C. 1H NMR (400 MHz, CDCl3) δ 10.27
(br s, 1H, NH2), 8.13 (s, 1H, Harom), 8.04 (d, J = 8.0 Hz, 1H, Harom),
7.68 (d, J = 8.0 Hz, 1H, Harom), 7.52 (t, J = 8.0 Hz, 1H, Harom), 5.71 (s,
1H, CH), 5.71 (br s, 1H, NH2), 2.07 (s, 3H, CH3). 13C NMR (100
MHz, CDCl3) δ 187.3, 164.4, 140.9, 130.6 (q, JF−C = 32 Hz), 130.3,
128.8, 127.2 (q, JF−C =3 Hz), 124.1 (q, JF−C = 271 Hz), 124.0 (q, JF−C
= 3 Hz), 91.9, 22.7. HRMS (ESI) m/z calcd for C11H11F3NO+ [M +
H+] 230.0787, found 230.0788.
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out at 45 °C
without precaution of air and stirred magnetically. H, 13C and 19F
1
NMR spectra were recorded on a 400 MHz spectrometer at 25 °C.
Chemical shift values (ppm) are calibrated according to the internal
standard of TMS set as 0.00 ppm. The peak patterns are indicated as
follows: br s, broad singlet; s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet and dd, doublet of doublets. The coupling constants J are
reported in hertz (Hz). High resolution mass spectrometry (HRMS)
was recorded on a Q-TOF microspectrometer. Melting points were
determined with a national micromelting point apparatus without
correction. Organic solutions were concentrated by rotary evaporation
under vacuum. TLC plates were visualized by exposure to ultraviolet
light. Toluene was dried over CaH2 before use. EtOH was dried over
CaO and then distilled before use. 1,2-Dichloroethane was dried over
CaH2 and distilled before use. Other reagents were purchased as
reagent grade and used without further purification. All reactions were
performed under nitrogen atmosphere in standard glassware, heated at
70 °C for 3 h before use. Flash column chromatography was
performed over silica gel (100−200 mesh) and eluents were a mixture
of EtOAc and petroleum ether (PE).
1-Amino-4,4-dimethyl-1-phenylpent-1-en-3-one (1n). 1n
was purified by silica gel chromatography (EtOAc/PE = 10/90). Rf
= 0.5 (EtOAc/PE = 30/70). Yield 2.678 g, 55% as a white solid, mp
1
62−63 °C. H NMR (400 MHz, CDCl3) δ 10.00 (br s, 1H, NH2),
7.55 (d, J = 8.0 Hz, 2H, Harom), 7.43−7.41 (m, 3H, Harom), 5.62 (s, 1H,
CH), 5.40 (br s, 1H, NH2), 1.20 (s, 9H, CH3). 13C NMR (100 MHz,
CDCl3) δ 206.1, 161.7, 138.1, 130.4, 128.9, 126.3, 90.7, 42.3, 27.7.
HRMS (ESI) m/z calcd for C13H18NO+ [M + H+] 204.1383, found
204.1386.
The β-ester group substituted enamines 1a−1f,4b,5a,17,18,20 1g−1h,21
the β-carbonyl group substituted enamines 1i−1p,5a,19,20 and PIFA22
were prepared according to the literature. PIFA was recrystallized and
dried in vacuum before use.
General Procedure for the Synthesis of 2-(Trifluoromethyl)-
oxazoles (2a−p). To a solution of enamine 1 (1.0 mmol) in dry
DCE (50 mL) was added PhI(OCOCF3)2 (0.516 g, 1.2 mmol) in one
portion at 45 °C. Then the reaction mixture was kept at the same
temperature for 1.5−3 h. TLC was used to indicate the reaction
process. When the reaction was completed, the solvent was
evaporated, and the residue was passed through a silica gel column
to give the desired product 2.
Procedure for the Synthesis of Methyl 2-Acetoxy-3-amino-
3-phenylacrylate (3a) and 3-Amino-1-oxo-1-phenylbut-2-en-2-
yl Acetate (3b). To a solution of enamine 1 (2.0 mmol) in dry DCE
(4 mL) was added PhI(OAc)2 (0.837 g, 2.6 mmol) in one portion at
room temperature. Then the reaction mixture was kept at the same
temperature for 1 h. TLC was used to indicate the reaction process.
When the reaction was completed, the reaction mixture was quenched
with saturated aqueous NaHCO3 (10 mL) and extracted with DCM
(10 mL × 3). The organic layers were combined and dried over
Na2SO4. The solvent was evaporated, and the residue was passed
through a silica gel column to give the desired product.
Methyl 4-Phenyl-2-(trifluoromethyl)oxazole-5-carboxylate
(2a). 2a was purified by silica gel chromatography (EtOAc/PE = 1/
99). Rf = 0.6 (EtOAc/PE = 5/95). Yield 0.217 g, 80% as a white solid,
1
mp 47−48 °C. H NMR (400 MHz, CDCl3) δ 8.11−8.08 (m, 2H,
H
arom), 7.48−7.46 (m, 3H, Harom), 3.97 (s, 3H, CH3). 13C NMR (100
MHz, CDCl3) δ 157.9, 150.7 (q, JF−C = 45 Hz), 146.9, 137.8, 130.5,
129.4, 128.5, 128.4, 116.0 (q, JF−C = 270 Hz), 52.8. 19F NMR (377
MHz, CDCl3+) δ −66.08 to −66.12 (m, 3F). HRMS (EI) m/z calcd for
C12H9F3NO3 [M + H+] 272.0529, found 272.0532.
Methyl 4-p-Tolyl-2-(trifluoromethyl)oxazole-5-carboxylate
(2b). 2b was purified by silica gel chromatography (EtOAc/PE =
1/99). Rf = 0.5 (EtOAc/PE = 5/95). Yield 0.231 g, 81% as a light-
yellow solid, mp 89−90 °C. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J
= 8.0 Hz, 2H, Harom), 7.27 (d, J = 8.0 Hz, 2H, Harom), 3.95 (s, 3H,
CH3), 2.40 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 158.0, 150.6
(q, JF−C = 45 Hz), 147.0, 140.9, 137.5, 129.3, 129.1, 125.7, 116.1 (q,
J
F−C = 270 Hz), 52.6, 21.4. 19F NMR (377 MHz, CDCl3) δ −66.12 to
−66.15 (m, 3F). HRMS (EI) m/z calcd for C13H11F3NO3+ [M + H+]
286.0686, found 286.0689.
Methyl 4-(2-Methoxyphenyl)-2-(trifluoromethyl)oxazole-5-
carboxylate (2c). 2c was purified by silica gel chromatography
(EtOAc/PE = 1/99). Rf = 0.4 (EtOAc/PE = 5/95). Yield 0.205 g, 68%
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Note
as a light yellow solid, mp 48−49 °C. 1H NMR (400 MHz, CDCl3) δ
7.50 (dd, J = 7.5, 1.6 Hz, 1H, Harom), 7.47−7.43 (m, 1H, Harom), 7.06
(t, J = 7.5 Hz, 1H, Harom), 7.00 (d, J = 7.5 Hz, 1H, Harom), 3.87 (s, 3H,
CH3), 3.80 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ: 157.8,
157.2, 150.7 (q, JF−C = 47 Hz), 142.7, 149.9, 131.6, 130.9, 120.5, 117.9
(q, JF−C = 270 Hz), 114.8, 111.1, 55.5, 52.5. 19F NMR (377 MHz,
CDCl3) δ −65.85 to −65.87 (m, 3F). HRMS (EI) m/z calcd for
8.10−8.07 (m, 2H, Harom), 7.25−7.20 (m, 2H, Harom), 2.63 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3) δ 180.4, 166.1 (d, JF−C = 255
Hz), 149.8 (q, JF−C = 44 Hz), 147.4, 145.7, 132.2, 132.1, 116.2 (q, JF−C
= 270 Hz), 116.0 (d, JF−C = 220 Hz), 13.8. 19F NMR (377 MHz,
CDCl3) δ −66.01 to −66.07 (m, 3F), −103.36- −103.43 (m, 1F).
HRMS (EI) m/z calcd for C12H8F4NO2 [M + H+] 274.0486, found
+
274.0487.
C13H11F3NO4 [M + H+] 302.0635, found 302.0636.
+
(2-Iodophenyl)(4-methyl-2-(trifluoromethyl)oxazol-5-yl)-
methanone (2k). 2k was purified by silica gel chromatography
(EtOAc/PE = 1/99). Rf = 0.5 (EtOAc/PE = 5/95). Yield 0.171 g, 45%
as light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.5 Hz,
1H, Harom), 7.50 (t, J = 7.5 Hz, 1H, Harom), 7.39 (d, J = 7.5 Hz, 1H,
Methyl 4-(4-Bromophenyl)-2-(trifluoromethyl)oxazole-5-
carboxylate (2d). 2d was purified by silica gel chromatography
(EtOAc/PE = 1/99). Rf = 0.6 (EtOAc/PE = 5/95). Yield 0.233 g, 67%
1
as a ligh-yellow solid, mp 74−75 °C. H NMR (400 MHz, CDCl3) δ
H
arom), 7.25 (t, J = 7.5 Hz, 1H, Harom), 2.43 (s, 3H, CH3). 13C NMR
8.02 (d, J = 8.5 Hz, 2H, Harom), 7.60 (d, J = 8.5 Hz, 2H, Harom), 3.98 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3) δ 157.8, 150.7 (q, JF−C = 45
Hz), 145.8, 137.9, 131.7, 130.9, 127.4, 125.2, 116.0 (q, JF−C = 270 Hz),
52.9. 19F NMR (377 MHz, CDCl3) δ −66.12 (m, 3F). HRMS (EI) m/
(100 MHz, CDCl3) δ 184.4, 151.1, 150.6, 146.3 (q, JF−C = 44 Hz),
147.2, 140.1, 132.5, 128.8, 128.4, 116.0 (q, JF−C = 270 Hz), 91.8, 13.6.
19F NMR (377 MHz, CDCl3) δ −66.03 (s, 3F). HRMS (EI) m/z calcd
z calcd for C12H879BrF3NO3 [M + H+] 349.9634, found 349.9637.
+
for C12H8F3INO2 [M + H+] 381.9546, found 381.9547.
+
Methyl 4-(4-Chlorophenyl)-2-(trifluoromethyl)oxazole-5-
carboxylate (2e). 2e was purified by silica gel chromatography
(EtOAc/PE = 1/99). Rf = 0.5 (EtOAc/PE = 5/95). Yield 0.195 g, 64%
as a light-yellow solid, mp 73−74 °C. 1H NMR (400 MHz, CDCl3) δ
8.10 (d, J = 8.5 Hz, 2H, Harom), 7.43 (d, J = 8.5 Hz, 2H, Harom), 3.98 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3) δ 157.8, 150.7 (q, JF−C = 45
Hz), 145.7, 137.9, 136.7, 130.7, 128.7, 126.9, 116.0 (q, JF−C = 270 Hz),
52.8. 19F NMR (377 MHz, CDCl3) δ −66.19 (s, 3F). HRMS (EI) m/z
( 4 - M e t h y l - 2 - ( t r i f l u o r o m e t h y l ) o x a z o l - 5 - y l ) ( 3 -
(trifluoromethyl)phenyl)methanone (2l). 2l was purified by silica
gel chromatography (EtOAc/PE = 1/99). Rf = 0.6 (EtOAc/PE = 5/
1
95). Yield 0.184 g, 57% as yellow oil. H NMR (400 MHz, CDCl3) δ
8.29 (s, 1H, Harom), 8.22 (d, J = 8.0 Hz, 1H, Harom), 7.91 (d, J = 8.0 Hz,
1H, Harom), 7.71 (t, J = 8.0 Hz, 1H, Harom), 2.65 (s, 3H, CH3). 13C
NMR (100 MHz, CDCl3) δ 180.7, 150.1 (q, JF−C = 46 Hz), 148.1,
145.4, 136.5, 132.4, 131.5 (q, JF−C = 33 Hz), 130.0 (q, JF−C = 4 Hz),
129.4, 126.3 (q, JF−C = 4 Hz), 123.5 (q, JF−C = 271 Hz), 116.1 (q, JF−C
= 271 Hz), 13.9. 19F NMR (377 MHz, CDCl3) δ −63.09 (s, 3F),
calcd for C12H835ClF3NO3 [M + H+] 306.0139, found 306.0142.
+
Benzyl 4-Methyl-2-(trifluoromethyl)oxazole-5-carboxylate
(2f). 2f was purified by silica gel chromatography (EtOAc/PE = 1/
99). Rf = 0.5 (EtOAc/PE = 5/95). Yield 0.166 g, 58% as yellow oil. 1H
NMR (400 MHz, CDCl3) δ 7.45−7.42 (m, 2H, Harom), 7.41−7.35 (m,
3H, Harom), 5.39 (s, 2H, CH2), 2.53 (s, 3H, CH3). 13C NMR (100
MHz, CDCl3) δ 157.4, 150.7 (q, JF−C = 44 Hz), 146.2, 139.3, 134.8,
128.79, 128.76, 128.6, 116.0 (q, JF−C = 270 Hz), 67.5, 13.2. 19F NMR
(CDCl3, 377 MHz) δ −66.14 (m, 3F). HRMS (EI) m/z calcd for
−66.14 (s, 3F). HRMS (EI) m/z calcd for C13H8F6NO2 [M + H+]
+
324.0454, found 324.0454.
(4-tert-Butyl-2-(trifluoromethyl)oxazol-5-yl)(phenyl)-
methanone (2m). 2m was purified by silica gel chromatography
(EtOAc/PE = 1/99). Rf = 0.7 (EtOAc/PE = 5/95). Yield 0.267 g, 90%
1
as a white solid, mp 40−41 °C. H NMR (400 MHz, CDCl3) δ 7.86
(d, J = 7.5 Hz, 2H, Harom), 7.65 (t, J = 7.5 Hz, 1H, Harom), 7.53 (t, J =
7.5 Hz, 2H, Harom), 1.43 (s, 9H, CH3). 13C NMR (100 MHz, CDCl3)
δ 183.8, 156.4, 148.4 (q, JF−C = 44 Hz), 144.5, 136.7, 133.8, 129.6,
128.7, 116.3 (q, JF−C = 269 Hz), 33.2, 28.9. 19F NMR (377 MHz,
C13H11F3NO3 [M + H+] 286.0686, found 286.0687.
+
Ethyl 4-Benzyl-2-(trifluoromethyl)oxazole-5-carboxylate
(2g). 2g was purified by silica gel chromatography (EtOAc/PE = 1/
99). Rf = 0.5 (EtOAc/PE = 5/95). Yield 0.144 g, 48% as colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.35−7.28 (m, 4H, Harom), 7.25−7.21
+
CDCl3) δ −65.73 (s, 3F). HRMS (ESI) m/z calcd for C15H15F3NO2
[M + H+] 298.1049, found 298.1044.
2,2-Dimethyl-1-(4-phenyl-2-(trifluoromethyl)oxazol-5-yl)-
propan-1-one (2n). 2n was purified by silica gel chromatography
(EtOAc/PE = 1/99). Rf = 0.8 (EtOAc/PE = 5/95). Yield 0.214 g, 72%
as a white solid, mp 29−30 °C. 1H NMR (400 MHz, CDCl3) δ 8.06−
8.03 (m, 2H, Harom), 7.46 (t, J = 4.0 Hz, 3H, Harom), 1.38 (s, 9H, CH3).
13C NMR (100 MHz, CDCl3) δ 195.0, 149.1 (q, JF−C = 47 Hz), 146.8,
(m, 1H, Harom), 4.44 (q, J = 7.0 Hz, 2H, CH2), 4.27 (s, 2H, CH2), 1.42
(t, J = 7.0 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 157.5, 150.9
(q, JF−C = 44 Hz), 148.1, 139.2, 136.9, 128.9, 128.7, 127.0, 116.0 (q,
JF−C = 271 Hz), 62.1, 32.9, 14.2. 19F NMR (377 MHz, CDCl3) δ
−66.00 (s, 3F). HRMS (ESI) m/z calcd for C14H13F3NO3+ [M + H+]
300.0842, found 300.0845.
144.1, 130.5, 129.5, 129.1, 128.3, 116.2 (q, JF−C = 270 Hz), 44.6, 26.3.
Ethyl 4-(Cyclohexenylmethyl)-2-(trifluoromethyl)oxazole-5-
carboxylate (2h). 2h was purified by silica gel chromatography
(EtOAc/PE = 1/99). Rf = 0.6 (EtOAc/PE = 5/95). Yield 0.182 g, 60%
as colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.51 (s, 1H, CH), 4.43
(q, J = 7.0 Hz, 2H, CH2), 3.56 (s, 2H, CH2), 2.01−2.00 (m, 2H, CH2).
1.97−1.95 (m, 2H, CH2), 1.65−1.59 (m, 2H, CH2), 1.57−1.51 (m,
2H, CH2), 1.42 (t, J = 7.0 Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3) δ 157.5, 150.7 (q, JF−C = 44 Hz), 147.7, 139.7, 133.3, 124.5,
116.2 (q, JF−C = 270 Hz), 61.9, 35.1, 28.3, 25.2, 22.7, 22.0, 14.1. 19F
NMR (377 MHz, CDCl3) δ −66.00 (m, 3F). HRMS (ESI) m/z calcd
19F NMR (377 MHz, CDCl3) δ −66.06 (m, 3F). HRMS (EI) m/z
calcd for C15H15F3NO2 [M + H+] 298.1048, found 298.1047.
+
Phenyl(4-phenyl-2-(trifluoromethyl)oxazol-5-yl)methanone
(2o). 2o was purified by silica gel chromatography (EtOAc/PE = 1/
99). Rf = 0.5 (EtOAc/PE = 5/95). Yield 0.133 g, 42% as a white solid,
1
mp 70−71 °C. H NMR (400 MHz, CDCl3) δ 7.99−7.97 (m, 2H,
H
arom), 7.90 (d, J = 7.5 Hz, 2H, Harom), 7.62 (t, J = 7.5 Hz, 1H, Harom),
7.48 (t, J = 7.5 Hz, 2H, Harom), 7.43−7.41 (m, 3H, Harom). 13C NMR
(100 MHz, CDCl3) δ 182.8, 150.3 (q, JF−C = 47 Hz), 146.6, 144.5,
for C14H17F3NO3 [M + H+] 304.1155, found 304.1158.
+
136.2, 133.9, 130.5, 129.7, 129.2, 128.9, 128.7, 128.5, 116.3 (q, JF−C
=
270 Hz). 19F NMR (377 MHz, CDCl3) δ −65.87 (m, 3F). HRMS
(4-Methyl-2-(trifluoromethyl)oxazol-5-yl)(phenyl)-
methanone (2i). 2i was purified by silica gel chromatography
(EtOAc/PE = 1/99). Rf = 0.5 (EtOAc/PE = 5/95). Yield 0.156 g, 61%
(ESI) m/z calcd for C17H11F3NO2 [M + H+] 318.0736, found
+
318.0740.
1
as a white solid, mp 41−42 °C. H NMR (400 MHz, CDCl3) δ 8.01
(4-Chlorophenyl)(4-(4-chlorophenyl)-2-(trifluoromethyl)-
oxazol-5-yl)methanone (2p). 2p was purified by silica gel
chromatography (EtOAc/PE = 1/99). Rf = 0.6 (EtOAc/PE = 5/95).
(d, J = 7.0 Hz, 2H, Harom), 7.66 (t, J = 7.0 Hz, 1H, Harom), 7.55 (t, J =
7.0 Hz, 2H, Harom), 2.62 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3)
δ 182.2, 149.8 (q, JF−C = 47 Hz), 147.1, 145.9, 136.0, 133.7, 129.4,
128.7, 116.3 (q, JF−C = 270 Hz), 13.9. 19F NMR (377 MHz, CDCl3) δ
1
Yield 0.178 g, 46% as a white solid, mp 86−87 °C. H NMR (400
MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 2H, Harom), 7.88 (d, J = 8.5 Hz,
2H, Harom), 7.50 (t, J = 8.5 Hz, 2H, Harom), 7.42 (d, J = 8.5 Hz, 2H,
+
−66.01 to −66.02 (m, 3F). HRMS (EI) m/z calcd for C12H9F3NO2
arom). 13C NMR (100 MHz, CDCl3) δ 181.2, 150.2 (q, JF−C = 44
[M + H+] 256.0580, found 256.0585.
H
Hz), 146.1, 144.3, 140.7, 137.0, 134.4, 131.0, 130.6, 129.2, 128.8,
(4-Fluorophenyl)(4-methyl-2-(trifluoromethyl)oxazol-5-yl)-
methanone (2j). 2j was purified by silica gel chromatography
(EtOAc/PE = 1/99). Rf = 0.6 (EtOAc/PE = 5/95). Yield 0.139 g, 51%
as a light-yellow solid, mp 42−43 °C. 1H NMR (400 MHz, CDCl3) δ
127.2, 116.1 (q, JF−C = 271 Hz). 19F NMR (377 MHz, CDCl3) δ
+
−65.93 (s, 3F). HRMS (EI) m/z calcd for C17H935Cl2F3NO2 [M +
H+] 385.9957, found 385.9961.
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The Journal of Organic Chemistry
Note
Methyl 2-Acetoxy-3-amino-3-phenylacrylate (3a). 3a was
purified by silica gel chromatography (TEA/EtOAc/PE = 1/10/90).
Rf = 0.3 (EtOAc/PE = 20/80). Yield 0.226 g, 40% as a white solid, mp
69−71 °C. 1H NMR (400 MHz, CDCl3) δ 7.44−7.40 (m, 5H, Harom),
3.75 (s, 3H, CH3), 1.92 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ
170.6, 166.1, 152.9, 135.0, 129.7, 128.5, 127.5, 112.1, 51.2, 20.3.
ketones mediated by PIDA and BF3·Et2O, see: Wang, J.; Liu, S.; Yu,
W. Synlett 2009, 2529.
(4) (a) For the synthesis of N-substituted indoles from N-
substituted 2-aryl-3-amino-2-alkenenitriles and 2-aryl-3-amino-2-alke-
necarboxylates via PIFA-mediated oxidative C−N bond formation,
see: Du, Y.; Liu, R.; Linn, G.; Zhao, K. Org. Lett. 2006, 8, 5919. (b)
For the synthesis of indoles from N-arylenamines via PIDA-mediated
oxidative C−C bond formation, see: Yu, W.; Du, Y.; Zhao, K. Org.
Lett. 2009, 11, 2417.
(5) For examples describing the conversion of β-substituted
enamines into 2H-azirines via PIDA-mediated oxidation, see: (a) Li,
X.; Du, Y.; Liang, Z.; Li, X.; Pan, Y.; Zhao, K. Org. Lett. 2009, 11, 2643.
(b) Shimada, N.; Ashburn, B. O.; Basak, A. K.; Bow, W. F.; Vicic, D.
A.; Tius, M. A. Chem. Commun. 2010, 46, 3774.
HRMS (ESI) m/z calcd for C12H14NO4 [M + H+] 236.0813, found
+
236.0815.
3-Amino-1-oxo-1-phenylbut-2-en-2-yl acetate (3b). 3b was
purified by silica gel chromatography (TEA/EtOAc/PE = 1/15/85). Rf
= 0.2 (EtOAc/PE = 30/70). Yield 0.193 g, 44% as a white solid, mp
1
110−112 °C. H NMR (400 MHz, CDCl3) δ 7.61−7.59 (m, 2H,
H
arom), 7.39−7.34 (m, 3H, Harom), 1.96 (s, 3H, CH3), 1.95 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3) δ188.54, 170.56, 155.78, 139.50,
130.07, 127.84, 127.37, 123.21, 20.52, 18.39. HRMS (ESI) m/z calcd
for C12H13NO3Na+ [M +Na+] 242.0788, found 242.0782.
(6) Dohi, T.; Kita, Y. Chem. Commun. 2009, 2073.
(7) For selected examples, see: (a) Papoutsis, I.; Spyroudis, S.;
Varvoglis, A. Tetrahedron Lett. 1996, 37, 913. (b) Papoutsis, I.;
Spyroudis, S.; Varvoglis, A. J. Heterocycl. Chem. 1996, 33, 579.
(c) Chen, Y.; Ju, T.; Wang, J.; Yu, W.; Du, Y.; Zhao, K. Synlett 2010,
231.
Methyl 2-Methyl-4-phenyloxazole-5-carboxylate (4a). 4a
was purified by silica gel chromatography (PE). Rf = 0.2 (EtOAc/PE
= 5/95). Yield 0.103 g, 95% as a white solid, mp 53−54 °C. 1H NMR
(400 MHz, CDCl3) δ 8.05−8.03 (m, 2H, Harom), 7.46−7.42 (m, 3H,
H
arom), 3.91 (s, 3H, CH3), 2.57 (s, 3H, CH3). 13C NMR (100 MHz,
(8) Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K.
J. Am. Chem. Soc. 2005, 127, 12244.
CDCl3) δ 162.99, 158.88, 147.19, 136.17, 130.17, 129.62, 129.20,
+
128.14, 52.11, 14.17. HRMS (ESI) m/z calcd for C12H12NO3 [M +
(9) For selected formation of substituted 2-(trifluoromethyl)
oxazoles, see: (a) Cunico, F. R.; Kuan, P. C. Tetrahedron Lett. 1990,
31, 1945. (b) Nicolaou, K. C.; Hughes, R.; Pfefferkorn, J. A.;
Barluenga, S. Chem. - Eur. J. 2001, 7, 4296. (c) Pavlik, W. J.; St. Martin,
H.; Lambert, A. K.; Lowell, A. J.; Tsefrikas, M. V.; Eddins, K. C.;
Kebede, N. J. Heterocycl. Chem. 2005, 42, 273. (d) Lechel, T.; Lentz,
D.; Reissig, H. U. Chem. Eur. J. 2009, 15, 5432 and the references
cited therein.
(10) For selected examples describing the formation of oxazoles
utilizing hypervalent iodine(III) reagents, see: (a) Varma, R. S.;
Kumar, D. J. Heterocycl. Chem. 1998, 35, 1533. (b) Chen, J. M.; Wu, L.
L.; Huang, X. Chin. Chem. Lett. 2004, 15, 143. (c) Lee, J. E.; Koh, H.
Y.; Seo, S. H.; Baek, Y. Y.; Rhim, H.; Cho, Y. S.; Choo, H.; Pae, A. N.
Bioorg. Med. Chem. Lett. 2010, 20, 4219.
H+] 218.0812, found 218.0810.
(2,4-Dimethyloxazol-5-yl)(phenyl)methanone (4b). 4b was
purified by silica gel chromatography (PE). Rf1= 0.5 (EtOAc/PE =
30/70). Yield 0.090 g, 90% as a colorless oil. H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 7.5 Hz, 2H, Harom), 7.59 (t, J = 7.5 Hz, 1H,
H
arom), 7.49 (t, J = 7.5 Hz, 2 H, Harom), 2.55 (s, 3H, CH3), 2.49 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3) δ 182.64, 162.74, 147.80, 145.13,
137.24, 132.72, 129.20, 128.39, 14.28, 14.07. HRMS (ESI) m/z calcd
for C12H12NO2 [M + H+] 202.0863, found 202.0861.
+
ASSOCIATED CONTENT
* Supporting Information
■
S
Spectral data for all new compounds; X-ray structural data of
2a. This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) For a recent report on the formation of isoxazoles using PIFA,
see: Jawalekar, A. M.; Reubsaet, E.; Rutjes, F. P. J. T.; van Delft, F. L.
Chem. Commun. 2011, 47, 3198.
(12) For selected examples describing the importance of the
AUTHOR INFORMATION
Corresponding Author
*E-mail: duyunfeier@tju.edu.cn; combinology@yahoo.com
trifluoromethylated compounds, see: (a) Muller, K.; Faeh, C.;
■
̈
Diederich, F. Science 2007, 317, 1881. (b) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) Nie, J.;
Guo, H. C.; Cahard, D.; Ma, J. A. Chem. Rev. 2011, 111, 455.
(13) For a study that describes the reaction of 1a with PIDA in the
presence of BF3·Et2O that gives polysubstituted pyrrole product, see
ref 3c.
ACKNOWLEDGMENTS
■
Y.D. gratefully acknowledges the National Natural Science
Foundation of China (20802048, 21072148) for financial
support. R.Q. thanks the National Undergraduate Innovative
Test Program.
(14) (a) All the reactions studied involve acyclic β-enamino ester or
β-enaminone substrates. However, when cyclic β-enaminone 5 was
subjected to the identical conditions, no desired 2-(trifluoromethyl)
oxazole product was obtained but instead, a complex mixture.
Unfortunately, it was also found that β-cyano enamine 6 and β-nitro
enamine 7 failed to form any desired oxazole products in either case.
(b) For the preparation of enamine 5, see: Baraldi, P. G.; Simoni, D.;
Manfredini, S. Synthesis 1983, 902. For the preparation of enamine 6,
see ref 5a. For the preparation of enamine 7, see: (c) Bowman, R. K.;
Johnson, J. S. J. Org. Chem. 2004, 69, 8537. (d) Seko, S.; Komoto, I. J.
Chem. Soc., Perkin Trans. 1 1998, 2975 .
REFERENCES
■
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Note
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