PIFA-Mediated Oxidative Cyclization Reactions of α-Acyl Acrylamides: A Synthetic Route to Substituted Isoxazol-3(2 H)-ones

Article abstract of DOI:10.1055/s-0037-1609318

An intramolecular cyclization of various α-acyl β-amino acrylamides in the presence of PIFA and TFA is described. This transformation features mild reaction conditions, simple execution, high chemo selectivity, and metal catalyst-free oxidation, and thereby, provides not only an alternative protocol for the construction of N-O bond, but also an efficient and straightforward synthesis of substituted isoxazol-3(2 H)-ones from readily available α-acyl acrylamides.

Full text of DOI:10.1055/s-0037-1609318

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
en
J. Yuan et al.
Paper
Synthesis
PIFA-Mediated Oxidative Cyclization Reactions of α-Acyl Acryl-
amides: A Synthetic Route to Substituted Isoxazol-3(2H)-ones
Jingwen Yuana,b
Chitturi Bhujanga Raoa
Qian Zhanga
R1
O
O
O
O
N
R1
PIFA/TFA, CH2Cl2, r.t.
R2
N
R2
H
Rui Zhang*a
Yongjiu Lianga
Ning Zhanga
H
NHMe
Metal-free oxidation
N–O bond formation
Chemoselectivity
H
O
R1 = aryl
R2 = aryl, alkyl
12 examples
up to 73% yield
Dewen Dong*a
a Key Laboratory of Synthetic Rubber, Changchun Institute of
Applied Chemistry, Chinese Academy of Sciences, Changchun
130022, P. R. China
ariel@ciac.ac.cn
dwdong@ciac.ac.cn
b University of Chinese Academy of Sciences, Beijing 100049,
P. R. China
Received: 04.12.2017
Accepted after revision: 16.01.2018
Published online: 21.02.2018
the synthesis of isoxazol-3(2H)-ones, especially those with
wide applicability to achieve more elaborate and flexible
substitution patterns, still remains a significant challenge
for organic chemists.
DOI: 10.1055/s-0037-1609318; Art ID: ss-2017-h0778-op
Abstract An intramolecular cyclization of various α-acyl β-amino
acrylamides in the presence of PIFA and TFA is described. This transfor-
mation features mild reaction conditions, simple execution, high chemo-
selectivity, and metal catalyst-free oxidation, and thereby, provides not
only an alternative protocol for the construction of N–O bond, but also
an efficient and straightforward synthesis of substituted isoxazol-3(2H)-
ones from readily available α-acyl acrylamides.
OAc
O
OAc
AcO
O
NH
N
O
O
O
OAc
HN
N
O
O
N
H
Key words acrylamides, cyclization, heterocycles, hypervalent iodine
reagents, N–O bond formation, isoxazol-3(2H)-ones
agonists of the human
5-HT receptors
plant growth
stimulator
fibrinolysis
inhibitor
Figure 1 Selected isoxazol-3(2H)-ones with bioactivities
Isoxazol-3(2H)-ones and their benzo-/hetero-fused an-
alogues constitute the core structural motifs in some natu-
rally occurring and artificial compounds along with diverse
bio-, physio-, and pharmacological activities (Figure 1).1,2 In
addition, the functionalized isoxazol-3(2H)-ones are widely
used in organic chemistry, agrochemistry, and material
chemistry.3 So far, a variety of synthetic approaches to such
heterocycles are already available based on either the mod-
ification of the pre-constructed heterocyclic skeleton or the
direct heterocyclization from appropriate open chain pre-
cursors. Among these methods, the most common and no-
table one involves the cyclocondensation reactions of 1,3-
dielectrophiles with hydroxylamine.4 Recently, Han and co-
workers reported a novel synthesis of isoxazol-3(2H)-ones
from alkynyl aldehydes and nitrosobenzenes via a highly
regioselective umpolung strategy.5 Most recently, we devel-
oped an alternative protocol for accessing isoxazol-3(2H)-
ones via copper-nitrene triggered annulation of α-acyl cin-
namides.6 This intramolecular cyclization represents one of
the few examples for a straightforward synthesis of isoxaz-
ol-3(2H)-one through an N–O bond formation.7 Neverthe-
less, the development of novel and efficient approach for
Over the past decades, hypervalent iodine reagents have
emerged as a very important type of oxidants in organic
transformations for their low toxicity, chemoselective oxi-
dizing ability, and the mild reaction conditions required.8,9
In the early 1990s, Kikugawa and co-workers found that N-
acyl nitrenium ions could be generated by the oxidation of
amides with phenyliodine(III) bis(trifluoroacetate) (PIFA).10
Later on, it was demonstrated that the nitrenium ions stabi-
lized by the electron-donating effect of a proper neighbor-
ing group (alkoxy, aryl, or nitrogen) were useful synthetic
intermediates to construct N–C, N–S, or N–N linkage
(Scheme 1a).11–13
In our previous work, we investigated the reaction be-
haviors of a variety of functionalized amides in the pres-
ence of different hypervalent iodine reagents, and achieved
efficient synthesis of substituted pyrrolin-4-ones (Scheme
1b),14 benzo[d]thiazoles,15 isothiazol-3(2H)-ones,16 spiro-
fused pyrazolin-5-one N-oxides,17 spiro-fused dihydrofu-
ran-3(2H)-ones,18 and 2,5-dihydrofurans.19 During these
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

B
J. Yuan et al.
Paper
Synthesis
diacetate (PIDA) and iodosobenzene (PhIO), were employed
(entries 3 and 4). Notably, the addition of trifluoroacetic
acid (TFA) indeed promoted the reactions of 1a, as seen by
the shortened reaction times (entries 5–8). Further experi-
ments revealed that TFA was the most effective additive
among the tested ones (entries 6, 9, and 10). Actually, TFA
was frequently used in various PIFA-mediated organic
transformations.13,21 The solvent screening disclosed that
the employment of toluene or acetonitrile resulted in lower
yields of 2a (entries 11 and 12), and no desired product was
formed in THF as monitored by TLC (entry 13). The higher
reaction temperature could shorten the reaction time, but
the yield of 2a was somewhat lowered (entry 14). There-
fore, the optimal reaction conditions were obtained when
1a was treated with PIFA (1.5 equiv) and TFA (1.0 equiv) in
dichloromethane at room temperature for 6 hours, whereby
the yield of 2a reached 71% (entry 6).
(a) Tellitu's work13a
O
O
R1
PIFA/TFA
N
N
R1
H
N
CH2Cl2, r.t.
NHR
R
(b) Our previous work14
O
O
O
O
R1
R1HN
PIFA/TFA
N
H
NHR1
R2
N
NHR
R2
R2
CH2Cl2, r.t.
R
(c) This work
R1
O
O
O
N
R1
PIFA/TFA
R2
N
R2
O
H
CH2Cl2, r.t.
H
NHMe
H
O
Next, we examined the influence of different enamine
moiety of α-acyl acrylamides on their oxidative reactions
under the above optimal reaction conditions (Table 2). As a
comparison, the reaction of 3a was rather sluggish even
though the reaction time was increased to 12 hours, which
furnished 2a in moderate yield along with recovery of some
starting material (Table 2, entry 2). In stark contrast, the re-
Scheme 1 PIFA-mediated oxidative cyclization reactions
inter- or intramolecular reactions, the construction of C–C,
C–N, C–O, N–S, or N–N bond had been established. Obvi-
ously, these results reveal that there exists a chemoselective
C–O and C–N bond formation during the oxidation of am-
ides. In this context, we prepared a series of functionalized
acrylamides from β-oxo amides, and envisaged that under
appropriate conditions the oxidation of the newly synthe-
sized acrylamides might generate heteroatom-centered in-
termediates and lead to cyclization. After a series of detailed
investigation, we developed a novel and efficient synthesis
of substituted isoxazol-3(2H)-ones through a chemoselec-
tive intramolecular N–O bond formation (Scheme 1c).
According to our previously reported procedure,20 a se-
ries of α-acyl acrylamides were prepared from commercial-
ly available β-oxo amides in good yields, but the prepara-
tion of N-methoxy-α-acyl acrylamide was not successful.
The reaction of α-acyl acrylamide 1a with PIFA (1.0 equiv)
was initially attempted in dichloromethane at room tem-
perature. The reaction proceeded sluggishly, as indicated by
TLC, and furnished one main product after workup and pu-
rification of the resulting mixture by silica column chroma-
tography (Table 1, entry 1). The product was characterized
as 2-(4-chlorophenyl)-5-methyl-3-oxo-2,3-dihydroisoxaz-
ole-4-carbaldehyde (2a) on the base of its spectral and ana-
lytical data.
Table 1 Optimization of the Reaction Conditionsa
Cl
O
O
H
O
oxidant
additive
N
Cl
H
N
H
O
O
NHMe
2a
1a
Entry Oxidant
(equiv)
Additive
(equiv)
Solvent
Time
(h)
Yield
(%)b
1
2
PIFA (1.0)
–
–
–
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
MeCN
THF
24
15
15
15
3
32 (53)
PIFA (1.5)
PIDA (1.5)
PhIO (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (2.0)
PIFA (2.0)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
62
3
NRc
NRc
64
4
5
TFA (3.0)
6
TFA (1.0)
TFA (1.0)
6
71
7
4
65
8
TFA (0.5)
5
63
9
BF3·OEt2(1.0)
CF3CH2OH (1.0)
TFA (1.0)
12
6
44 (15)
60
10
11
12
13
14
The optimizations of various reaction parameters, in-
cluding hypervalent iodines, additives, solvents, and tem-
peratures, were then investigated, and some results are
summarized in Table 1. It was observed that the yield of 2a
was significantly improved by increasing the loading
amount of PIFA to 1.5 equivalents, though it still required
15.0 hours to complete the reaction (Table 1, entry 2). How-
ever, no reaction occurred as indicated by TLC when other
hypervalent iodine(III) reagents, such as phenyliodine(III)
7
58
TFA (1.0)
6
53
TFA (1.0)
12
1.5
0 (84)
67d
TFA (1.0)
CH2Cl2
a Reagents and conditions: 1a (1.0 mmol), solvent (10.0 mL), r.t.
b Isolated yield of 2a (data in parentheses for the recovery of 1a).
c No reaction.
d Under reflux.
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J. Yuan et al.
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Synthesis
action of 4a resulted in a complex mixture, and no desired
product 2a was observed (entry 3). In the case of 5a, an in-
separable mixture was formed though 2a could be detected
1
by H NMR spectroscopy (entry 4). Thus, it seems that the
α-acyl acrylamides with secondary enamine group are
more favorable to the oxidative cyclization reaction.
Figure 2 ORTEP drawing of 2e
Table 2 Effect of Enamine Group of α-Acyl Acrylamides on Their
Cyclization Reactionsa
demonstrated that amides could be easily oxidized to N-
acyl nitrenium ions by hypervalent iodine reagent, and only
those stabilized by proper neighboring groups (e.g., non-
activated and moderately deactivated or activated N-aryl
rings) could exhibit sufficiently long life to undergo subse-
quent organic reactions, as disclosed by other research-
ers.10–13,22
Cl
O
O
H
O
PIFA/TFA
N
Cl
H
N
CH2Cl2, r.t.
H
O
O
R'
2a
1a, 3a–5a
Entry
Acrylamide
R′
Time (h)
Yield (%)b
Interestingly, the reaction of 1c with PIFA (1.5 equiv)
and TFA (1.0 equiv) in dichloromethane at room tempera-
ture furnished a major product rather than 2c by prolong-
ing the reaction time from 1 to 4 hours. The product was
characterized as N-(2-hydroxy-4-methylphenyl)-2-[(me-
thylamino)methylene]-3-oxobutanamide (6c) on the basis
of its spectral and analytical data (Scheme 2).23,24 Notably,
6c was also obtained in 62% yield within 0.5 hour by per-
forming the above reaction under reflux. Clearly, in the case
of 1c, the synthesis of either thermodynamic product 6c or
1
2
3
4
1a
3a
4a
5a
NHMe
NHPh
NMe2
NH2
6
71
12
4
52 (24)c
0
4
mixtured
a Reagents and conditions: acrylamide (1.0 mmol), PIFA (1.5 mmol), TFA
(1.0 mmol), CH2Cl2 (10.0 mL), r.t.
b Isolated yield of 2a.
c The data in parentheses for the recovery of 3a.
d Product 2a could be detected by 1H NMR spectroscopy.
With the optimal reaction conditions in hand, the scope
and limitation of the PIFA-mediated oxidative transforma-
tion were then investigated. A range of reactions of α-acyl
acrylamides 1 were carried out in the presence of PIFA and
TFA in dichloromethane at room temperature, and some of
the results are summarized in Table 3.
Table 3 Synthesis of Isoxazol-3(2H)-ones 2 from α-Acyl Acrylamides 1a
R2
O
O
O
R1
PIFA/TFA
N
R1
R2
N
H
H
CH2Cl2, r.t.
H
NHMe
O
O
It was observed that the reactions of α-acyl acrylamides
1b–f bearing varied N-arylamide groups (CONHR1) pro-
ceeded smoothly to afford the corresponding isoxazol-
3(2H)-ones 2b–f in moderate to good yields (Table 3, entries
2–6). However, no reaction occurred when 1g with a strong
electron-withdrawing nitro group on its phenyl ring was
employed (entry 7), whereas the reaction of 1h with an N-
alkylamide group failed to give the desired product 2h, only
leading to a complex mixture (entry 8). The versatility of
this isoxazol-3(2H)-one synthesis was further evaluated by
performing α-acyl acrylamides 1i–n bearing other alkyl- or
arylacyl groups (R2CO) under the identical conditions to af-
ford the corresponding isoxazol-3(2H)-ones 2i–n in fairly
good yields (entries 9–14). The products 2 were character-
ized by their spectral and analytical data, and the structure
of 2e was elucidated by X-ray diffraction analysis as shown
in Figure 2 (for details, see the Supporting Information).
Thus, we have established a protocol for the operation-
ally simple and efficient construction of N–O bond in a che-
moselective manner, which provided a straightforward syn-
thetic route to substituted isoxazol-3(2H)-ones from func-
tionalized acrylamides 1. These obtained results further
1
2
Entry
1
R1
R2
Me
Time (h)
2
Yield (%)b
1
2
1a
4-ClC6H4
Ph
6
3
2a
71
1b
1c
1d
1e
1f
Me
2b
2c
2d
2e
2f
59
3
4-MeC6H4
4-BrC6H4
2-ClC6H4
3-ClC6H4
4-NO2C6H4
Me
Me
1
51
4
Me
6
73
5
Me
12
12
12
12
5
56
6
Me
54
7
1g
1h
1i
Me
2g
2h
2i
NRc
mixture
70
8
Me
9
4-ClC6H4
4-ClC6H4
Ph
n-Pr
10
11
12
13
14
1j
Ph
6
2j
68
1k
1l
Ph
2
2k
2l
62
Ph
4-MeC6H4
4-ClC6H4
4-MeOC6H4
2
63
1m
1n
Ph
2
2m
2n
62
Ph
2
67
a Reagents and conditions: 1 (1.0 mmol), PIFA (1.5 mmol), TFA (1.0 mmol),
CH2Cl2 (10.0 mL), r.t.
b Isolated yields.
c No reaction.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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J. Yuan et al.
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Synthesis
kinetic product 2c could be controlled by simply changing
the reaction conditions. On the contrary, the reaction of 1a
under reflux still delivered 2a as the predominant product
and only trace amount of the corresponding phenol 6a was
detected even though the reaction time was prolonged to
24 hours. For the α-acyl acrylamides 1o–q decorated with
strongly electron-donating o-methoxy, p-methoxy or di-
methyl groups R on their N-aryl rings, the reactions pro-
ceeded smoothly to afford exclusively the corresponding N-
aryl hydroxylated products 6o–q in moderate yields
(Scheme 2). When the reaction of 1p was performed in the
presence of PIFA without TFA at room temperature, it fur-
nished the hydroxylated product 6p in 57% yield after 6.0
hours. Attempts to synthesize the corresponding isoxazol-
3(2H)-ones 2o,p from 1o,p by varying the reaction condi-
tions were fruitless. These results reveal that the electronic
effect of amide motifs of α-acyl acrylamides 1 is of crucial
importance for their transformation mediated by PIFA.
On the basis of all the obtained results, a mechanism for
the metal-free oxidative reaction of α-acyl acrylamides 1 is
proposed as depicted in Scheme 3. In the presence of TFA,
α-acyl acrylamide 1 reacts with PIFA to generate an electro-
philic species A,10–13 which might be represented by several
resonance structures including N-acyl nitrenium ion A-1
and phenonium ions A-2 and A-3.11b,22a,25 The stability of
these resonance forms depends on the electronic effect of
the amide motifs. Under acidic conditions, an intramolecu-
lar cyclization of N-acyl nitrenium ion B, keto-enol tautom-
er of A-1, bearing non-activated and moderately activated
or deactivated N-aryl rings (1a–f and 1i–n) takes place in a
chemoseletive manner to afford the intermediate C,13 which
undergoes hydrolysis during workup to give isoxazol-
3(2H)-one 2. Considering of the formation of intermediate
B, it is not hard to understand that no desired product 2a
was formed from 4a. On the other hand, the positive charge
of intermediate A bearing strong activated N-aryl rings (1o–
q) can be delocalized preferentially on the para (A-2) and
OH
O
H
O
O
O
PIFA (1.5 equiv)/TFA (1.0 equiv)
CH2Cl2, r.t., 0.5–4.0 h
N
N
R
H
R
H
NHMe
1
H
NHMe
6
Cl
OMe
Me
Me
Me
OH
O
O
O
O
N
N
N
H
N
H
H
H
OH
OH
OH
OMe
6p (64%, 1.0 h)
6q (60%,1.0 h)
6c (63%, 4.0 h )
6o ( 67%, 0.5 h)
Scheme 2 N-Aryl hydroxylation of α-acyl acrylamides 1
OH
O
H
O
O
H
O
R2
R2
N
N
H
H
R
R
NHMe
NHMe
6 (para)
1
TFA
PhI
TFA
PIFA
H2O
O
O
O
H
O
+
O
O
O
O
+
CF3
R2
N
R2
R2
N
N
H
R
R
R
NHMe
A-2
A-1
H
NHMe
H
NHMe
D
O
CF3
O
O
OH
O
O
H
O
+
O
R
+
N
R2
R2
N
R2
N
H
R
R
Me
H
N
NHMe
A-3
B
H
NHMe
E
H+
– H+
H2O
TFA
HO
O
H
O
O
N
O
N
R
R
H2O
R
R2
O
Me
R2
R2
N
H
O
MeNH2
NHMe 6 (ortho)
2
H
N
C
H
O
Scheme 3 Proposed mechanism for the oxidative reaction of α-acyl acrylamides 1 with PIFA/TFA
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

E
J. Yuan et al.
Paper
Synthesis
ortho (A-3) positions of the aromatic rings and trapped by a
trifluoroacetate anion to form intermediate D or E,11b,23 fol-
lowed by hydrolysis to give the hydroxylated product 6.
In summary, we have described herein an intramolecu-
lar cyclization of α-acyl acrylamides 1 in the presence of
PIFA and TFA. This transformation features mild reaction
conditions, simple execution, high chemoselectivity, and
metal catalyst-free oxidation, and thereby, provides an al-
ternative protocol not only for the construction of N–O
bond, but also for the efficient and straightforward synthe-
sis of substituted isoxazol-3(2H)-ones. Further studies on
the mechanism involved in the reactions and the utilization
and extension of the scope of the protocol are currently un-
derway in our laboratory.
IR (KBr): 3101, 3069, 2862, 2792, 1689, 1682, 1616, 1590, 1495, 1486,
1422, 1384, 1359, 771, 689 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.70 (s, 3 H), 7.29 (t, J = 7.5 Hz, 1 H),
7.47 (t, J = 7.8 Hz, 2 H), 7.70 (d, J = 7.8 Hz, 2 H), 9.95 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 185.1, 174.0, 161.6, 135.7, 129.3,
126.6, 117.4, 110.6, 13.7.
HRMS (ESI): m/z [M + Na]+ calcd for C11H9NO3Na: 226.0475; found:
226.0501.
5-Methyl-3-oxo-2-(p-tolyl)-2,3-dihydroisoxazole-4-carbaldehyde
(2c)
White solid (111 mg, 51%); mp 62–63 °C.
IR (KBr): 3088, 3034, 2924, 2862, 2788, 1692, 1614, 1581, 1512, 1422,
1383, 1363, 808 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 2.34 (s, 3 H), 2.67 (s, 3 H), 7.34 (d,
J = 8.0 Hz, 2 H), 7.53 (d, J = 8.0 Hz, 2 H), 9.78 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 185.2, 173.8, 161.7, 136.9, 133.2,
129.8, 118.3, 110.5, 21.0, 13.7.
HRMS (ESI): m/z [M + Na]+ calcd for C12H11NO3Na: 240.0631; found:
240.0659.
All reagents were purchased from commercial sources and used with-
out treatment, unless otherwise indicated. 1H NMR and 13C NMR
spectra were recorded at 25 °C at 300 MHz (or 400 MHz) and 100
MHz (or 75 MHz), respectively, with TMS as internal standard. IR
spectra (KBr) were recorded on FTIR-spectrophotometer in the range
of 400–4000 cm–1. High-resolution mass spectra (ESI-TOF-Q/HRMS)
were recorded on a Bruker micrOTOF-Q II mass spectrometer. Melting
points were determined on a TECH X-4 micro-melting point appara-
tus. All reactions were monitored by TLC with GF254 silica gel-coated
plates. Chromatography was carried out on flash silica gel (300–400
mesh).
2-(4-Bromophenyl)-5-methyl-3-oxo-2,3-dihydroisoxazole-4-car-
baldehyde (2d)
Pale yellow solid (206 mg, 73%); mp 71–72 °C.
IR (KBr): 3098, 3069, 3040, 2858, 2752, 1719, 1665, 1631, 1580, 1493,
1425, 1403, 1365, 827, 763 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.69 (s, 3 H), 7.58 (d, J = 9.2 Hz, 2 H),
7.61 (d, J = 9.2 Hz, 2 H), 9.93 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 184.9, 174.2, 161.5, 134.8, 132.4,
The preparation of α-acyl acrylamides 1a–q and 3a are described in
the Supporting Information.
119.6, 118.5, 110.6, 13.7.
Isoxazol-3(2H)-ones 2; General Procedure
HRMS (ESI): m/z [M + Na]+ calcd for C11H8BrNO3Na: 303.9580; found:
303.9597.
To a well-stirred solution of PIFA (645 mg, 1.5 mmol) and TFA (0.076
mL, 1.0 mmol) in CH2Cl2 (10 mL) was added α-acyl acrylamide 1 (1.0
mmol) at r.t. The reaction mixture was kept at r.t. under stirring until
the completion of the reaction as indicated by TLC. The resulting mix-
ture was poured into brine (50 mL) and extracted with CH2Cl2 (3 × 20
mL). The combined organic phases were washed with H2O, dried (an-
hyd MgSO4), filtered, and evaporated in vacuo. The residue was puri-
fied by column chromatography on silica gel with PE/EtOAc as the
eluent to give the desired product 2 (Table 3).
2-(2-Chlorophenyl)-5-methyl-3-oxo-2,3-dihydroisoxazole-4-car-
baldehyde (2e)
White solid (133 mg, 56%); mp 76–77 °C.
IR (KBr): 3076, 2931, 2858, 2754, 1706, 1692, 1611, 1593, 1474, 1416,
1381, 771, 747 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.67 (s, 3 H), 7.39–7.59 (m, 4 H), 9.94
(s, 1 H).
2-(4-Chlorophenyl)-5-methyl-3-oxo-2,3-dihydroisoxazole-4-car-
baldehyde (2a)
13C NMR (100 MHz, CDCl3): δ = 185.2, 176.8, 164.9, 133.8, 132.4,
132.1, 131.0, 130.8, 127.8, 109.5, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C11H8ClNO3Na: 260.0085; found:
260.0105.
Pale yellow solid (169 mg, 71%); mp 78–79 °C. The reaction of sub-
strate 3a (315 mg, 1.0 mmol) under identical conditions gave 2a in
52% yield.
IR (KBr): 3115, 3094, 3044, 2925, 2865, 2763, 1713, 1656, 1628, 1591,
1493, 1424, 1406, 1369, 816, 760 cm–1
.
X-ray Crystal Data26
1H NMR (300 MHz, CDCl3): δ = 2.69 (s, 3 H), 7.43 (d, J = 8.7 Hz, 2 H),
7.66 (d, J = 8.7 Hz, 2 H), 9.93 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 184.9, 174.2, 161.6, 134.3, 131.9,
C11H8ClNO3, white crystal, M = 237.64, triclinic, P-1, a =6.8948(8) Å, b
= 7.2403(9) Å, c = 10.7983(13) Å, α = 90.885(2)°, β = 102.147(2)°, γ =
94.426(2)°, V = 525.14(11) Å3, Z = 7, T = 273 K, F000 = 244.0, F000’ =
244.41, R = 0.0509 (1706), wR2 = 0.1598 (2088).
129.4, 118.4, 110.6, 13.7.
HRMS (ESI): m/z [M + Na]+ calcd for C11H8ClNO3Na: 260.0085; found:
260.0118.
2-(3-Chlorophenyl)-5-methyl-3-oxo-2,3-dihydroisoxazole-4-car-
baldehyde (2f)
Pale yellow solid (128 mg, 54%); mp 63–64 °C.
5-Methyl-3-oxo-2-phenyl-2,3-dihydroisoxazole-4-carbaldehyde
(2b)
IR (KBr): 3105, 3081, 2925, 2864, 2737, 1694, 1614, 1593, 1482, 1433,
1381, 786, 736, 711 cm–1
.
Light red solid (120 mg, 59%); mp 66–68 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

F
J. Yuan et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 2.71 (s, 3 H), 7.25 (d, J = 7.8 Hz, 1 H),
7.39 (t, J = 8.1 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.72 (t, J = 1.8 Hz, 1 H),
9.93 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 184.5, 169.5, 162.7, 145.3, 135.8,
129.7, 129.3, 128.8, 126.5, 122.2, 117.4, 108.2, 21.9.
HRMS (ESI): m/z [M + Na]+ calcd for C17H13NO3Na: 302.0788; found:
302.0802.
13C NMR (100 MHz, CDCl3): δ = 184.8, 174.4, 161.6, 136.7, 135.1,
130.4, 126.3, 116.8, 114.7, 110.6, 13.7.
HRMS (ESI): m/z [M + Na]+ calcd for C11H8ClNO3Na: 260.0085; found:
260.0108.
5-(4-Chlorophenyl)-3-oxo-2-phenyl-2,3-dihydroisoxazole-4-car-
baldehyde (2m)
Yellow solid (186 mg, 62%); mp 136–138 °C.
2-(4-Chlorophenyl)-3-oxo-5-propyl-2,3-dihydroisoxazole-4-car-
baldehyde (2i)
IR (KBr): 3092, 3069, 2860, 1699, 1683, 1582, 1552, 1495, 1371, 832,
746, 707 cm–1
.
White solid (186 mg, 70%); mp 62–63 °C.
1H NMR (300 MHz, CDCl3): δ = 7.33 (t, J = 7.5 Hz, 1 H), 7.51 (t, J = 7.5
Hz, 2 H), 7.57 (d, J = 8.7 Hz, 2 H), 7.80 (d, J = 7.8 Hz, 2 H), 8.30 (d, J = 8.7
Hz, 2 H), 10.05 (s, 1 H).
IR (KBr): 3106, 3084, 2961, 2863, 2813, 2770, 1697, 1683, 1610, 1590,
1489, 1439, 1367, 825, 749 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.06 (t, J = 7.6 Hz, 3 H), 1.77–1.87 (m, 2
H), 3.04 (t, J = 7.6 Hz, 2 H), 7.43 (d, J = 9.2 Hz, 2 H), 7.66 (d, J = 9.2 Hz, 2
H), 9.92 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 184.6, 167.8, 162.5, 140.6, 135.6,
130.1, 129.4, 126.9, 123.4, 117.6, 108.9.
HRMS (ESI): m/z [M + Na]+ calcd for C16H10ClNO3Na: 322.0241; found:
322.0239.
13C NMR (100 MHz, CDCl3): δ = 184.8, 177.8, 161.7, 134.3, 131.8,
129.4, 118.3, 110.0, 29.3, 20.0, 13.6.
HRMS (ESI): m/z [M + Na]+ calcd for C13H12ClNO3Na: 288.0398; found:
288.0424.
5-(4-Methoxyphenyl)-3-oxo-2-phenyl-2,3-dihydroisoxazole-4-
carbaldehyde (2n)
Pale yellow solid (197 mg, 67%); mp 147–149 °C.
2-(4-Chlorophenyl)-3-oxo-5-phenyl-2,3-dihydroisoxazole-4-car-
baldehyde (2j)
IR (KBr): 3068, 3017, 2980, 2951, 2924, 2853, 1712, 1698, 1687, 1608,
1595, 1584, 1575, 1548, 1507, 1495, 1368, 841, 747, 687 cm–1
.
Yellow solid (204 mg, 68%); mp 111–113 °C.
1H NMR (300 MHz, CDCl3): δ = 3.93 (s, 3 H), 7.07 (d, J = 8.7 Hz, 2 H),
7.30 (t, J = 7.5 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 2 H), 7.80 (d, J = 8.1 Hz, 2 H),
8.37 (d, J = 8.7 Hz, 2 H), 10.03 (s, 1 H).
IR (KBr): 3105, 3065, 2862, 2770, 1700, 1687, 1598, 1582, 1562, 1492,
1451, 822, 760, 739, 684 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.47 (d, J = 9.0 Hz, 2 H), 7.60 (t, J = 7.2
Hz, 2 H), 7.70 (t, J = 7.5 Hz, 1 H), 7.78 (d, J = 9.0 Hz, 2 H), 8.25–8.28 (m,
2 H), 10.05 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 184.6, 169.0, 164.3, 163.1, 135.8, 131.0,
129.3, 126.4, 117.3, 114.4, 107.2, 55.6.
HRMS (ESI): m/z [M + Na]+ calcd for C17H13NO4Na: 318.0737; found:
318.0742.
13C NMR (100 MHz, CDCl3): δ = 184.2, 169.6, 162.3, 134.2, 132.0,
129.5, 129.3, 129.1, 128.8, 124.8, 118.4, 108.7.
HRMS (ESI): m/z [M + Na]+ calcd for C16H10ClNO3Na: 322.0241; found:
Phenols 6; General Procedure
322.0256.
To a well-stirred solution of PIFA (645 mg, 1.5 mmol) and TFA (0.076
mL, 1.0 mmol) in CH2Cl2 (10 mL) was added the required α-acyl acryl-
amide 1c,o–q (1.0 mmol) at r.t. The reaction mixture was kept at r.t.
under stirring until the completion of the reaction as indicated by
TLC. The resulting mixture was poured into brine (50 mL), neutralized
with sat. aq NaHCO3, and extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic phases were washed with H2O, dried (anhyd MgSO4),
filtered, and evaporated in vacuo. The residue was purified by flash
column chromatography on silica gel with PE/EtOAc as the eluent to
give the desired product 6.
3-Oxo-2,5-diphenyl-2,3-dihydroisoxazole-4-carbaldehyde (2k)
Yellow solid (164 mg, 62%); mp 93–94 °C.
IR (KBr): 3059, 2862, 2775, 1696, 1684, 1592, 1583, 1564, 1496, 755,
738, 683 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.38 (t, J = 7.6 Hz, 1 H), 7.57 (t, J =
7.6 Hz, 2 H), 7.67 (t, J = 7.2 Hz, 2 H), 7.77 (d, J = 7.2 Hz, 1 H), 7.82–7.84
(m, 2 H), 8.22–8.24 (m, 2 H), 9.87 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 184.4, 169.3, 162.4, 135.7, 134.0,
129.3, 129.0, 128.8, 126.7, 124.9, 117.4, 108.8.
N-(2-Hydroxy-4-methylphenyl)-2-[(methylamino)methylene]-3-
oxobutanamide (6c)
HRMS (ESI): m/z [M + Na]+ calcd for C16H11NO3Na: 288.0631; found:
Pale yellow solid (156 mg, 63%); mp 173–174 °C.
288.0646.
IR (KBr): 3277, 3192, 3060, 3037, 2943, 2920, 1654, 1626, 1610, 1600,
3-Oxo-2-phenyl-5-(p-tolyl)-2,3-dihydroisoxazole-4-carbaldehyde
1561, 1525, 1399, 1382, 1290, 885, 830, 811 cm–1
.
(2l)
1H NMR (300 MHz, CDCl3): δ = 2.28 (s, 3 H), 2.34 (s, 3 H), 3.22 (d, J =
5.1 Hz, 3 H), 6.66 (d, J = 7.8 Hz, 1 H), 6.83 (s, 1 H), 6.87 (d, J = 7.8 Hz, 1
H), 7.80 (d, J = 13.5 Hz, 1 H), 9.65 (s, 1 H), 10.24 (br s, 1 H), 12.12 (s, 1
H).
13C NMR (100 MHz, DMSO-d6): δ = 194.8, 167.3, 163.3, 146.9, 132.3,
125.5, 120.5, 119.8, 115.8, 101.3, 36.5, 26.6, 21.1.
Pale yellow solid (176 mg, 63%); mp 92–93 °C.
IR (KBr): 3076, 3037, 2914, 2861, 2772, 1695, 1681, 1609, 1587, 1555,
1508, 1496, 1461, 1372, 830, 745, 686 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.48 (s, 3 H), 7.31 (t, J = 7.5 Hz, 1 H),
7.39 (d, J = 8.1 Hz, 2 H), 7.50 (t, J = 7.8 Hz, 2 H), 7.81 (d, J = 7.8 Hz, 2 H),
8.20 (d, J = 8.4 Hz, 2 H), 10.05 (s, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C13H16N2O3Na: 271.1053; found:
271.1072.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

G
J. Yuan et al.
Paper
Synthesis
N-(2-Hydroxy-4-methoxyphenyl)-2-[(methylamino)methylene]-
3-oxobutanamide (6o)
Pannecouque, C.; De Clercq, E.; Cushman, M. J. Med. Chem. 2006,
49, 5316. (c) Dhanya, R.-P.; Sidique, S.; Sheffler, D. J.; Nickols, H.
H.; Herath, A.; Yang, L.; Dahl, R.; Ardecky, R.; Semenova, S.;
Markou, A.; Conn, P. J.; Cosford, N. D. P. J. Med. Chem. 2011, 54,
342.
Pale yellow solid (177 mg, 67%); mp 163–164 °C.
IR (KBr): 3300, 3191, 3140, 3060, 3001, 2935, 2835, 1657, 1613, 1598,
1521, 1464, 1421, 1381, 1287, 889, 830, 798 cm–1
.
(2) (a) Jensen, A. A.; Plath, N.; Pedersen, M. H. F.; Isberg, V.; Krall, J.;
Wellendorph, P.; Stensbol, T. B.; Gloriam, D. E.; Krogsgaard-
Larsen, P.; Frolund, B. J. Med. Chem. 2013, 56, 1211. (b) Cheng, L.;
Pettersen, D.; Ohlsson, B.; Schell, P.; Karle, M.; Evertsson, E.;
Pahlén, S.; Jonforsen, M.; Plowright, A. T.; Boström, J.; Fex, T.;
Thelin, A.; Hilgendorf, C.; Xue, Y.; Wahlund, G.; Lindberg, W.;
Larsson, L.-O.; Gustafsson, D. ACS Med. Chem. Lett. 2014, 5, 538.
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1974 (b) Nakamura, K.; Nakamura, S. Eur. Patent Application
220746, 1987. (c) Pajouhesh, H.; Hosseini-Meresht, M.;
Pajouhesh, S. H.; Curry, K. Tetrahedron: Asymmetry 2000, 11,
4955. (d) Cullen, M. D.; Deng, B.-L.; Hartman, T. L.; Watson, K.
M.; Buckheit, R. W. Jr.; Pannecouque, C.; De Clercq, E.; Cushman,
M. J. Med. Chem. 2007, 50, 4854. (e) Cullen, M. D.; Sarkar, T.;
Hamel, E.; Hartman, T. L.; Watson, K. M.; Buckheit, R. W. Jr.;
Pannecouque, C.; De Clercqd, E.; Cushman, M. Bioorg. Med.
Chem. Lett. 2008, 18, 469.
1H NMR (300 MHz, CDCl3): δ = 2.34 (s, 3 H), 3.22 (d, J = 5.1 Hz, 3 H),
3.77 (s, 3 H), 6.43 (dd, J = 8.7, 2.7 Hz, 1 H), 6.57 (d, J = 2.7 Hz, 1 H), 6.89
(d, J = 8.7 Hz, 1 H), 7.80 (d, J = 13.5 Hz, 1 H), 9.88 (s, 1 H), 10.23 (br s, 1
H), 12.09 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 194.8, 167.1, 163.3, 155.7, 148.3,
121.5, 121.4, 103.8, 101.9, 101.3, 55.4, 36.5, 26.6.
HRMS (ESI): m/z [M + Na]+ calcd for C13H16N2O4Na: 287.1002; found:
287.1021.
N-(2-Hydroxy-4,6-dimethylphenyl)-2-[(methylamino)methy-
lene]-3-oxobutanamide (6p)
Pale yellow solid (168 mg, 64%); mp 182–183 °C.
IR (KBr): 3229, 3007, 2968, 2940, 2920, 2855, 1659, 1614, 1556, 1538,
1468, 1380, 1293, 886, 797, 727 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.26 (s, 3 H), 2.32 (s, 3 H), 2.35 (s, 3 H),
3.23 (d, J = 5.1 Hz, 3 H), 6.59 (s, 1 H), 6.71 (s, 1 H), 7.82 (d, J = 13.5 Hz,
1 H), 9.15 (s, 1 H), 10.29 (br s, 1 H), 12.00 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 195.6, 168.0, 163.6, 151.0, 135.5,
132.9, 122.7, 122.3, 116.2, 100.5, 36.7, 26.5, 21.0, 19.0.
(4) (a) Sugai, S.; Sato, K.; Ueda, T.; Kataoka, K.; Tomita, K. Heterocy-
cles 1983, 20, 1123. (b) Noriaki, K.; Takamitsu, Y.; Kazuo, S.;
Toyokuni, H.; Soji, S. Chem. Pharm. Bull. 2000, 48, 509. (c) Flores,
A. F. C.; Zanatta, N.; Rosa, A.; Brondani, S.; Martins, M. A. P. Tet-
rahedron Lett. 2002, 43, 5005. (d) Clark, A. J.; Patel, D.;
Broadhurst, M. J. Tetrahedron Lett. 2003, 44, 7763.
HRMS (ESI): m/z [M + Na]+ calcd for C14H18N2O3Na: 285.1210; found:
285.1228.
(5) Han, R.; Qi, J.; Gu, J.; Ma, D.; Xie, X.; She, X. ACS Catal. 2013, 3,
2705.
(6) Yu, M.; Zhang, Q.; Li, G.; Yuan, J.; Zhang, N.; Zhang, R.; Liang, Y.;
Dong, D. Adv. Synth. Catal. 2016, 358, 410.
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2013, 11, 542.
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102, 2523. (b) Stang, P. J. J. Org. Chem. 2003, 68, 2997.
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43, 901. (g) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116,
3328.
N-(5-Chloro-4-hydroxy-2-methoxyphenyl)-2-[(methylami-
no)methylene]-3-oxobutanamide (6q)
Pale yellow solid (179 mg, 60%); mp 191–193 °C.
IR (KBr): 3245, 3187, 3154, 3062, 2941, 2918, 1650, 1615, 1598, 1572,
1535, 1465, 1447, 1409, 1378, 1290, 887, 810 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.31 (s, 3 H), 3.18 (d, J = 5.1 Hz, 3 H),
3.89 (s, 3 H), 5.48 (br s, 1 H), 6.59 (s, 1 H), 7.79 (d, J = 13.2 Hz, 1 H),
8.40 (s, 1 H), 10.67 (br s, 1 H), 11.97 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 195.0, 167.1, 163.4, 148.7, 148.5,
121.7, 120.8, 110.0, 101.1, 100.7, 56.4, 35.6, 26.5.
HRMS (ESI): m/z [M + Na]+ calcd for C13H15ClN2O4Na: 321.0613;
(9) (a) Kita, Y.; Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.;
Eichhorn, J. J. Org. Chem. 1996, 61, 5857. (b) Wardrop, D. J.;
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Zhao, K. Org. Lett. 2006, 8, 5919. (d) Uyanik, M.; Ishihara, K.
Chem. Commun. 2009, 2086. (e) Sun, Y.; Fan, R. Chem. Commun.
2010, 46, 6834. (f) Wei, H.-L.; Piou, T.; Dufour, J.; Neuville, L.;
Zhu, J. Org. Lett. 2011, 13, 2244. (g) Dohi, T.; Takenaga, N.; Nakae,
T.; Toyoda, Y.; Yamasaki, M.; Shiro, M.; Fujioka, H.; Maruyama,
A.; Kita, Y. J. Am. Chem. Soc. 2013, 135, 4558. (h) Yoshimura, A.;
Nguyen, K. C.; Klasen, S. C.; Saito, A.; Nemykin, V. N.; Zhdankin,
V. V. Chem. Commun. 2015, 51, 7835. (i) Izquierdo, S.; Essafi, S.;
Del Rosal, I.; Vidossich, P.; Pleixats, R.; Vallribera, A.; Ujaque, G.;
Lledos, A.; Shafir, A. J. Am. Chem. Soc. 2016, 138, 12747.
(j) Zhang, B.; Zhang, X.; Hu, B.; Sun, D.; Wang, S.; Zhang-Negre-
rie, D.; Du, Y. Org. Lett. 2017, 19, 902.
found: 321.0629.
Funding Information
Financial support of this research by the National Natural Science
Foundation of China (21502185 and 21542006) is greatly acknowl-
edged.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609318.
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(10) Kikugawa, Y.; Kawase, M. Chem. Lett. 1990, 581.
(11) (a) Wardrop, D. J.; Zhang, W. Org. Lett. 2001, 3, 2353. (b) Itoh, N.;
Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. J. Org. Chem. 2002, 67,
7424. (c) Kikugawa, Y.; Nagashima, A.; Sakamoto, T.; Miyazawa,
E.; Shiiya, M. J. Org. Chem. 2003, 68, 6739.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

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