Oxidative Cyclization of β-Aminoacrylamides Mediated by PhIO: Chemoselective Synthesis of Isoxazoles and 2 H-Azirines

Article abstract of DOI:10.1021/acs.joc.8b02132

Cyclization of a variety of β-aminoacrylamides in the presence of iodosobenzene (PhIO) is described. This process features mild reaction conditions, simple execution, and high chemoselectivity and thereby provides an efficient protocol for the divergent s

Full text of DOI:10.1021/acs.joc.8b02132

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Article
Oxidative Cyclization of #-Aminoacrylamides Mediated by
PhIO: Chemoselective Synthesis of Isoxazoles and 2H-Azirines
Chaoran Li, Jingwen Yuan, Qian Zhang, Chitturi Bhujanga Rao,
Rui Zhang, Yanning Zhao, Bicheng Deng, and Dewen Dong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02132 • Publication Date (Web): 16 Nov 2018
Downloaded from http://pubs.acs.org on November 18, 2018
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The Journal of Organic Chemistry
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Oxidative Cyclization of β-Aminoacrylamides Mediated by
PhIO: Chemoselective Synthesis of Isoxazoles and 2H-Azirines
Chaoran Li,a,b Jingwen Yuan,b Qian Zhang,b Chitturi Bhujanga Rao,b Rui Zhang,b Yanning Zhao,a,*
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Bicheng Deng,a,b Dewen Dong a,b
*
a Key Laboratory of Preparation and Application of Environmental Friendly Materials of the Ministry
of Education, Jilin Normal University, Changchun 130103, China
b CAS Key Laboratory of High-Performance Synthetic Rubber and its Composite Materials,
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
E-mail: yanningzhao@jlnu.edu.cn; dwdong@ciac.ac.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract
Cyclization of a variety of β-amino acrylamides in the presence of iodosobenzene (PhIO) is
described. This process features mild reaction conditions, simple execution and high chemoselectivity,
and thereby provides an efficient protocol for the divergent synthesis of substituted isoxazoles and
2H-azirines via switchable N-O and N-C bond formation controlled by simply varying the
β-substituent R3 of the readily available substrates.
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Introduction
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Five-membered aza-heterocycles, such as isoxazoles and pyrazoles, have attracted significant
research for their presence in numerous natural products and designed molecules along with diverse
bioactivities,1,2 and found widespread applications in organic synthesis,3 medicinal chemistry,4 and
agrochemistry.5 Thus, the development of convenient, efficient, and in particular environmentally
benign synthetic approaches to construct N-C and N-X (X = N, O, S) bonds has emerged as a
continuing focus in synthetic chemistry.6,7 In this context, the functionalization of various amides
mediated by hypervalent iodine reagents represents one of the most straightforward and fascinating
protocols to access various nitrogen-containing compounds.8,9
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In the early 1990s, Kikugawa et al discovered that N-acyl nitrenium ions could be generated by
the oxidation of amides with phenyliodine(III)-bis(trifluoroacetate) (PIFA), and demonstrated their
potential in electrophilic aromatic substitution to create N-C linkage.10 In 2006, Tellitu et al
successfully achieved the synthesis of indazolones via PIFA-mediated intramolecular N-N bond
formation of anthranilamides (Scheme 1a)11. Most recently, Anand et al reported the synthesis of
benzisoxazoles, instead of indazolones, via phenyliodine (III) diacetate (PIDA)-mediated
intramolecular N-O bond formation of 2-amino- benzohydrazides (Scheme 1b).12
During the course of our studies on the reactions of various functionalized β-oxo amides
mediated by hypervalent iodine reagents, we developed efficient synthesis of isothiazol-3(2H)-ones, 13
spiro-fused pyrazolin-5-one N-oxides,14 2,5-dihydrofurans15 and spiro-fused dihydrofuran-3(2H)-
ones,16 respectively, in which N-S, N-N or C-O bond is formed. In contrast to Tellitu’s work,11 we
noted that treatment of different β-aminoacrylamides with PIFA delivered pyrrolin-4-ones17 and
isoxazol-3(2H)-ones18 via N-C and N-O bond formation, respectively, and the product with N-N bond
formation was not even detected within these reactions (Scheme 1c). Clearly, it is only small variation
on the chemical structures of substrates that caused the significant influence on their oxidative reaction
orientation and selectivity.
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Scheme 1. Hypervalent Iodine Reagent-Mediated Cyclizations.
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In connection with our previous work and following with our research on the synthesis of highly
valuable heterocycles from β-oxo amide derivatives, we investigated the reaction behaviors of
α-acyl-β-aminoacrylamides towards different hypervalent iodine (III) reagents. As a result, we
developed an efficient divergent synthesis of substituted isoxazoles and 2H-azirines from α-acyl-
β-amino acrylamides mediated by PhIO via switchable N-O bond and N-C bond formation depending
on the nature of β-substituent R3 of the readily available substrates (Scheme 1d). Herein, we wish to
report our experimental results and present a proposed mechanism involved in the oxidative
cyclization reactions.
Results and Discussion
According to our reported procedure,19 a series of β-aminoacrylamides 1 were prepared from
commercially available β-oxo amides. From these substrates, α-acetyl-β-amino-N-phenyl acrylamide
1a was selected as the model compound for the subsequent investigation in the presence of different
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hypervalent iodine reagents. The reaction of 1a and PIFA (1.5 equiv) was first attempted in the
presence of trifluoroacetic acid (TFA, 1.0 equiv) in dichloromethane (DCM) at room temperature. As
indicated by TLC, the reaction took place, but it finally formed an inseparable mixture (Table 1, entry
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1
1). From the H NMR spectra of the mixture, some characteristic signals of isoxazol-3(2H)-one 2a
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could be observed (see Supporting Information), which is consistent with our previous reported
results.18 To our delight, treatment of 1a with PIDA, a less potent oxidant than PIFA, in the presence
of TFA (1.0 equiv) in DCM at room temperature furnished a main product, which was characterized as
1-[5-(phenylamino) isoxazol-4-yl]ethan-1-one 3a on the basis of its spectral and analytical data (Table
1, entry 2). Similarly, the reaction of 1a with PIDA and acetic acid (AcOH) also generated 3a (Table 1,
entry 3). The structure of 3a was further elucidated by X-ray diffraction analysis (see supporting
information). Indeed, the similar phenomenon wherein PIFA and PIDA exhibited different reaction
behaviors was found by Li and coworkers in the oxidative reactions of enamines,20 and this might
originate from their different oxidativities.
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Table 1. Reaction of 1a under Different Conditions.a
Entry
1
Oxidant
(equiv)
Additive
(equiv)
Solvent
CH2Cl2
Time
(h)
Yieldb
(%)
PIFA (1.5)
TFA (1.0)
12.0
mixture
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3
PIDA (1.5)
PIDA (1.5)
TFA (1.0)
CH2Cl2
CH2Cl2
12.0
12.0
45(26)
51(18)
AcOH (1.0)
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PhIO (2.0)
PhIO (2.0)
AcOH (1.0)
AcOH (1.0)
AcOH (2.0)
CH2Cl2
CH2Cl2
CH2Cl2
12.0
1.3
57(15)
68
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PhIO (2.0)
PhIO (2.0)
PhIO (2.0)
PIDA (2.0)
PhIO (2.0)
PhIO (2.0)
PhIO (2.0)
TFA (2.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
1.6
64
8
CF3CH2OH (2.0)
3.0
59
.
9
BF3 OEt2 (2.0)
1.0
mixture
73
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1.0
—
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AcOH (2.0)
AcOH (2.0)
AcOH (2.0)
12.0
12.0
12.0
18(66)
26(52)
42(38)
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toluene
a Reagents and conditions: 1a (1.0 mmol), solvent (10.0 mL), rt. b The data in parentheses for the
recovery of 1a.
An extensive optimization of various reaction parameters, including hypervalent iodines,
additives, and solvents, was then investigated, and some results are summarized in Table 1. It was
observed that the yield of 3a was slightly improved when PhIO was employed (entry 4), and the
conversion of 1a was accelerated by increase of PhIO to 2.0 equivalents (entries 5 and 6). These
results reveal that the oxidativity of hypervalent iodine reagents and their loading dosages have
significant influences on the reaction of acrylamide 1a.18 Further experiments demonstrate that acetic
acid is more effective than other tested additives (entries 5-9). Considering that PIDA could be
generated from PhIO in the presence of AcOH in DCM at room temperature,20 we conducted a
reaction of 1a with PIDA (2.0 equiv), which afforded 3a in 73% yield (entry 10). The solvent
screening revealed that the reaction of 1a and PhIO could take place in acetonitrile, THF or toluene,
but the conversion of 1a was slow and the yield of 3a was quite lower (entries 11-13).
Table 2. Synthesis of Isoxazoles 3 from β-Aminoacrylamides 1.a
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a Reagents and conditions: 1 (1.0 mmol), PhIO (2.0 mmol), AcOH (2.0 mmol), DCM (10.0 mL), rt;
The data in parentheses: yield and reaction time.
With the optimal reaction conditions in hand, the scope and limitations of the PhIO-mediated
oxidative transformation were then explored. Thus, a series of β-aminoacrylamides 1 were treated with
PhIO (2.0 equiv) and AcOH (2.0 equiv) in DCM at room temperature, and some of the results are
summarized in Table 2. It was found that the reactions of 1b-j bearing varied electron-donating/
electron-withdrawing N-aryl, N-alkyl and N-benzylamide group R1 proceeded smoothly and furnished
the corresponding isoxazoles 3b-j in moderate to good yields. The versatility of this isoxazole
synthesis was further evaluated by performing β-amino acryl amides 1k-p bearing varied alkyl, aryl or
amino groups R2 under the identical conditions to afford the corresponding isoxazoles 3k-p in good
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yields. Therefore, we developed a protocol for the operationally simple and efficient construction of
N-O bond in a chemoselective manner, which also provided a straightforward synthesis of substituted
isoxazoles of type 3 from functionalized acrylamides 1.
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Table 3. Synthesis of 2H-azirines 4 from β-Aminoacrylamides 1.a
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Reagents and conditions: 1 (1.0 mmol), PhIO (2.0 mmol), AcOH (2.0 mmol), DCM (10.0 mL), rt.
b The data in parentheses: yield for 4 and reaction time.
Notably, when acrylamide 1q bearing a β-methyl substituent R3 was subjected to the identical
conditions as described for 3a in entry 6, Table 1, the reaction proceeded smoothly to give a major
product, which was characterized as 2-acetyl-N-(4-methoxyphenyl)-3-methyl-2H-azirine-2-
carboxamide 4q, instead of the corresponding isoxazole 3q, on the basis of its spectral and analytical
data (Table 3). Comparison of the 13C NMR spectra between 4q and 3b let us establish the structure of
4q without difficulty (see supporting information). In the 13C NMR spectra of 3b, a characteristic peak
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however, the peak at this region disappears, and a new peak appears at 45 ppm which is easily
assigned to the signal of C(sp3)-2 of 2H-azirine ring.21,22
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In the same fashion, acrylamides 1r-w decorated by varied alkyl and aryl groups R3 at β-position
were exclusively converted into the corresponding fully substituted 2H-azirines 4r-w in moderate to
fairly good yields (Table 3). These results indicated that the nature of β-substituent R3 is of crucial
importance for the transformation of acrylamides 1 mediated by PhIO. Namely, the chemoselective
synthesis of isoxazoles 3 or 2H-azirines 4 can be switched by simply varying the β-substituent of
α-acyl-β-aminoacrylamides 1. Actually, 2H-azirines are highly strained and reactive three-membered
aza-heterocycles, and extensively studied for their presence in some natural products and their utility
as versatile intermediates for the synthesis of other aza-heterocycles.23,24
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Consequently, we selected 4s as a model compound and subjected it to thermolysis conditions, i.e.
in xylene under reflux in the N2 atmosphere. The reaction proceeded smoothly as indicated by TLC
results and furnished two products, which were characterized as isomeric isoxazoles 3s and 5s on the
basis of their spectral and analytical data (Scheme 2).21 Obviously, 3s and 5s were formed through
chemoselective rearrangement of 2H-azirine 4s,25,26 and the selectivity might be attributed to the
different reactivity of O-atom in a ketone or an amide group.27 This finding provided an alternative
protocol for the synthesis of fully substituted isoxazoles of type 3 and 5.
Scheme 2. Thermolysis of 2H-azirine 4s
On the basis of all the obtained results, a mechanism for the metal-free oxidative reaction of
α-acyl-β-aminoacrylamides 1 is proposed as illustrated in Scheme 3. The transformation is initiated
from the nucleophilic addition of acetic acid to idosobenzene to form a tricoordinated iodine species,
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i.e. PIDA.20 Acrylamide 1 reacts with the in-situ generated PIDA to give an intermediate A-1,21 which
can also be represented by its resonance structures, carbanion A-2 and enolate ion A-3.27,28 For both
electronic and steric effects, carbanion A-2 is a favorable form when R3 is alkyl or aryl group, wherein
carbanion is particularly stabilized by the adjacent electron-withdrawing carbonyl groups and iminium
moiety, and undergoes a cyclization to afford intermediate B along with the release of phenyl iodide
and acetate anion.21 The deprotonation of B by acetate anion produces the title 2H-azirine 4. While R3
is H, the formation of planar conjugated enolate ion A-3 is viable not only for the small size of R3 but
also for the ease of charge delocalization. The subsequent cyclization of A-3 takes place to form
intermediate C, which is deprotonated to give the product isoxazole 3.
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Scheme 3. Plausible Mechanism for the Reaction of β-Amino acrylamides 1.
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Conclusions
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In summary, we developed a facile and efficient divergent synthesis of isoxazoles and
2H-azirines by oxidative cyclization of a variety of β-amino acrylamides in the presence of
iodosobenzene (PhIO), wherein N-O or N-C bond formation is controlled by simply varying the
β-substituent of the readily available substrates. The mild reaction conditions, simplicity of execution,
high chemoselectivity, and synthetic potential of the products make this novel protocol very attractive.
Further work on the reaction mechanism, the scope expansion and the utility of this metal catalyst-free
protocol are currently underway in our laboratory.
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Experimental Section
General Experimental
All reagents were purchased from commercial sources and used without treatment unless
otherwise indicated. 1H NMR and 13C NMR spectra were recorded at 25 oC 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
were recorded on a LTQ-Orbitrap mass spectrometer using ESI mode. Melting points were determined
on a micro-melting point apparatus, and uncorrected.
Preparation and analytical data of β-aminoacrylamides 1
General procedure A for the preparation of 1a-o: 19 To a well-stirred solution of α-acyl-β-
dimethyaminoacrylamide (5.0 mmol) in ethanol (15.0 mL) was added NH4OAc (0.96 g, 12.5 mmol) at
room temperature. Then the reaction mixture was heated and stirred under reflux until the completion
of the reaction as indicated by TLC. The resulting mixture was poured into saturated aqueous NaCl
(100.0 mL). The precipitated solid was collected by filtration, washed with water (3 × 20.0 mL), and
dried in vacuo to give compound 1.
β-Aminoacrylamides 1a-f are known compounds. They were prepared and their analytical data
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1
(for H NMR spectra, see supporting Information) are in good agreement with those reported in the
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literature.19
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2-(Aminomethylene)-3-oxo-N-phenylbutanamide (1a). Prepared from 2-[(dimethylamino)
methylene]-3-oxo-N-phenylbutanamide (1.16 g, 5.0 mmol) via general procedure A. Compound 1a
was obtained as a white solid (0.92 g, 90%).
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2-(Aminomethylene)-3-oxo-N-(p-tolyl)butanamide (1b). Prepared from 2-[(dimethylamino)
methylene]-3-oxo-N-(p-tolyl)butanamide (1.23 g, 5.0 mmol) via general procedure A. Compound 1a
was obtained as a white solid (0.95 g, 87%).
2-(Aminomethylene)-N-(4-methoxyphenyl)-3-oxobutanamide (1c). Prepared from 2-[(dimethyl-
amino)methylene]-N-(4-methoxyphenyl)-3-oxobutanamide (1.31 g, 5.0 mmol) via general procedure
A. Compound 1a was obtained as a white solid (1.06 g, 91%).
2-(Aminomethylene)-N-(2-methoxyphenyl)-3-oxobutanamide (1d). Prepared from 2-[(dimethyl-
amino)methylene]-N-(2-methoxyphenyl)-3-oxobutanamide (1.31 g, 5.0 mmol) via general procedure
A. Compound 1a was obtained as a white solid (1.04 g, 89%).
2-(Aminomethylene)-N-(4-chlorophenyl)-3-oxobutanamide (1e). Prepared from N-(4-chloro-
phenyl)-2-[(dimethylamino)methylene]-3-oxobutanamide (1.33 g, 5.0 mmol) via general procedure A.
Compound 1a was obtained as a white solid (1.05 g, 88%).
2-(Aminomethylene)-N-(2-chloro-6-methoxyphenyl)-3-oxobutanamide (1f). Prepared from N-(2-
chloro-6-methoxyphenyl)-2-[(dimethylamino)methylene]-3-oxobutanamide (1.48 g, 5.0 mmol) via
general procedure A. Compound 1a was obtained as a white solid (1.15 g, 86%).
2-(Aminomethylene)-N-(2-chlorophenyl)-3-oxobutanamide (1g). Prepared from N-(2-chloro
phenyl)-2-[(dimethylamino)methylene]-3-oxobutanamide (1.33 g, 5.0 mmol) via general procedure A.
o
Compound 1g was obtained as a white solid (1.11 g, 93%). mp 183-184 C; 1H NMR (300 MHz,
CDCl3): δ 12.08 (s, 1H), 10.20 (bs, 1H), 8.39 (d, J = 8.1 Hz, 1H), 7.98-8.05 (m, 1H), 7.39 (d, J = 8.1
Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 6.98-7.03 (m, 1H), 5.94 (bs, 1H), 2.34 (s, 3H); 13C {1H} NMR (100
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MHz, DMSO-d6): δ 195.4, 166.6, 161.0, 135.5, 128.6, 126.9, 123.1, 121.6, 121.1, 100.7, 25.6; IR
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3
4
5
(KBr): ν = 3204, 2958, 1642, 1618, 1454, 1401, 755 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for
C11H12ClN2O2 239.0582; Found 239.0578.
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2-(Aminomethylene)-3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide (1h). Prepared from 2-
[(dimethylamino)methylene]-3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide (1.50 g, 5.0 mmol) via
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general procedure A. Compound 1h was obtained as a white solid (1.20 g, 88%). mp 189-190 C; 1H
NMR (300 MHz, CDCl3): δ 11.94 (s, 1H), 10.25 (bs, 1H), 7.99-8.07 (m, 1H), 7.73 (d, J = 8.7 Hz, 2H),
7.55 (d, J = 8.7 Hz, 2H), 5.89 (bs, 1H), 2.34 (s, 3H); C {1H} NMR (100 MHz, DMSO-d6): δ 195.7,
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166.8, 161.2, 141.9, 125.5, 124.0 (q, 1JCF = 270), 122.3 (q, 2JCF = 30), 118.8, 100.5, 25.6; IR (KBr): ν =
3332, 3239, 2943, 1638, 1619, 1455, 1403, 776 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for
C12H12F3N2O2 273.0845; Found 273.0839.
2-(Aminomethylene)-N-butyl-3-oxobutanamide (1i). Prepared from N-butyl-2-[(dimethylamino)
methylene]-3-oxobutanamide (1.06 g, 5.0 mmol) via general procedure A. Compound 1i was obtained
as a yellowish solid (0.78 g, 85%). mp 37-38 oC; 1H NMR (300 MHz, CDCl3): δ 10.28 (s, 1H), 9.52 (s,
1H), 7.85-7.93 (m, 1H), 5.81 (s, 1H), 3.26-3.32 (m, 2H), 2.24 (s, 3H), 1.48-1.58 (m, 2H), 1.32-1.44 (m,
2H), 0.92 (t, J = 7.2 Hz, 3H); C {1H} NMR (75 MHz, CDCl3): δ 196.0, 169.1, 158.7, 103.5, 38.1,
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31.5, 26.0, 20.2, 13.7; IR (KBr): ν = 3334, 2960, 2932, 1639, 1613, 1454, 1399, 740 cm-1. HRMS (ESI)
m/z: [M + H]+ Calcd for C9H17N2O2 185.1279; Found 185.1272.
2-(Aminomethylene)-N-benzyl-3-oxobutanamide (1j). Prepared from N-benzyl-2-[(dimethylamino)
methylene]-3-oxobutanamide (1.23 g, 5.0 mmol) via general procedure A. Compound 1j was obtained
as a white solid (0.98 g, 90%). mp 94-95 C; 1H NMR (300 MHz, DMSO-d6): δ 9.90-9.94 (m, 2H),
o
8.45 (bs, 1H), 7.99-8.07 (m, 1H), 7.20-7.34 (m, 5H), 4.39(d, J = 6.0 Hz, 2H), 2.18 (s, 3H); C {1H}
13
NMR (100 MHz, DMSO-d6): δ 194.8, 168.2, 160.1, 139.4, 127.8, 126.7, 126.2, 100.8, 40.8, 25.5; IR
(KBr): ν = 3313, 3239, 2955, 1639, 1541, 1497, 1453, 1396 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd
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for C12H15N2O2 219.1128; Found 219.1125.
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2-(Aminomethylene)-N-(4-chlorophenyl)-3-oxohexanamide (1k). Prepared from N-(4-chloro
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phenyl)-2-[(dimethylamino)methylene]-3-oxohexanamide (1.47 g, 5.0 mmol) via general procedure A.
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Compound 1k was obtained as a white solid (1.21 g, 91%). mp 150-151 C; H NMR (300 MHz,
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CDCl3): δ 11.87 (s, 1H), 10.26 (bs, 1H), 8.01-8.08 (m, 1H), 7.55-7.60 (m, 2H), 7.27-7.30 (m, 2H),
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5.87 (bs, 1H), 2.58 (t, J = 7.2 Hz, 2H), 1.65-1.77 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); C {1H} NMR
(100 MHz, CDCl3): δ 199.0, 167.7, 158.6, 137.1, 128.8, 128.4, 121.8, 103.1, 39.6, 19.2, 14.0; IR
(KBr): ν = 3327, 3191, 2962, 1643, 1614, 1536, 1454, 1400, 829 cm-1. HRMS (ESI) m/z: [M + H]+
Calcd for C13H16ClN2O2 267.0895; Found 267.0885.
3-Amino-2-benzoyl-N-hexylacrylamide (1l). Prepared from 2-benzoyl-3-(dimethylamino)-N-
hexylacrylamide (1.51g, 5.0 mmol) via general procedure A. Compound 1l was obtained as a
yellowish solid (1.18 g, 86%). mp 48-49 oC; 1H NMR (300 MHz, CDCl3): δ 10.27 (s, 1H), 9.51 (s, 1H),
7.54-7.61 (m, 1H), 7.40-7.45 (m, 5H), 5.72 (s, 1H), 3.32-3.38 (m, 2H), 1.55-1.64 (m, 2H), 1.31-1.42
(m, 6H), 0.88 (t, J = 6.6 Hz, 3H); C {1H} NMR (75 MHz, CDCl3): δ 196.2, 169.1, 162.2, 140.5,
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130.1, 128.2, 128.1, 102.9, 38.5, 31.5, 29.5, 26.8, 22.5, 14.0; IR (KBr): ν = 3304, 2952, 1639, 1613,
1454, 1399, 740 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C16H23N2O2 275.1754; Found 275.1743.
3-Amino-2-benzoyl-N-phenylacrylamide (1m). Prepared from 2-benzoyl-3-(dimethylamino)-
N-phenylacrylamide (1.47 g, 5.0 mmol) via general procedure A. Compound 1m was obtained as a
white solid (1.18 g, 89%). mp 150-152 C; 1H NMR (300 MHz, CDCl3): δ 11.65 (s, 1H), 10.24 (bs,
o
1H), 7.63-7.72 (m, 3H), 7.40-7.51 (m, 5H), 7.34 (t, J = 7.8 Hz, 2H), 7.09 (t, J = 7.2 Hz, 1H), 5.89 (bs,
1H); 13C {1H} NMR (100 MHz, CDCl3): δ 196.4, 167.5, 162.8, 140.2, 138.2, 130.4, 128.8, 128.3,
128.1, 123.8, 120.8, 102.9; IR (KBr): ν = 3368, 3223, 2973, 1648, 1536, 1444, 1371, 1319 cm-1.
HRMS (ESI) m/z: [M + H]+ Calcd for C16H15N2O2 267.1128; Found 267.1125.
3-Amino-2-benzoyl-N-(4-chlorophenyl)acrylamide (1n). Prepared from 2-benzoyl-N-(4-chloro
phenyl)-3-(dimethylamino)acrylamide (1.64 g, 5.0 mmol) via general procedure A. Compound 1n was
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obtained as a white solid (1.41 g, 94%). mp 146-148 oC; 1H NMR (400 MHz, CDCl3): δ 11.71 (s, 1H),
10.20 (bs, 1H), 7.67-7.73 (m, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.41-7.50 (m, 5H), 7.29 (d, J = 8.8 Hz,
2H), 5.87 (bs, 1H); 13C {1H} NMR (100 MHz, CDCl3): δ 196.4, 167.4, 162.8, 140.0, 136.9, 130.5,
128.8, 128.5, 128.4, 128.1, 121.8, 102.9; IR (KBr): ν = 3337, 3412, 2964, 1647, 1596, 1533, 1492,
1401, 833 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C16H14ClN2O2 301.0738; Found 301.0729.
3-Amino-2-(4-methylbenzoyl)-N-phenylacrylamide (1o). Prepared from 3-(dimethylamino)-2-(4-
methylbenzoyl)-N-phenylacrylamide (1.54 g, 5.0 mmol) via general procedure A. Compound 1o was
obtained as a white solid (1.23 g, 88%). mp 137-138 oC; 1H NMR (300 MHz, CDCl3): δ 11.67 (s, 1H),
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10.17 (bs, 1H), 7.63-7.74 (m, 3H), 7.30-7.41 (m, 4H), 7.23 (d, J = 7.8 Hz, 2H), 7.08 (t, J = 7.5 Hz, 1H),
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5.86 (bs, 1H), 2.41 (s, 3H); C {1H} NMR (100 MHz, CDCl3): δ 196.4, 167.6, 162.6, 140.9, 138.2,
137.4, 128.9, 128.8, 128.4, 123.7, 120.8, 102.9, 21.4; IR (KBr): ν = 3340, 3231, 2955, 1648, 1579,
1535, 1443, 753 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C17H17N2O2 281.1285; Found 281.1277.
General procedure B for the preparation of 2-(Aminomethylene)-N1,N3-diphenylmalonamide
1p: To a well-stirred solution of 2-[(dimethylamino)methylene]-N1,N3-diphenylmalonamide (1.55 g,
5.0 mmol) in ethanol (15.0 mL) was added aqueous ammonia (aq. 25%, 1.0 mL, 12.5 mmol) at room
temperature. The reaction mixture was kept at room temperature under stirring until the completion of
the reaction as indicated by TLC. The resulting mixture was poured into saturated aqueous NaCl
(100.0 mL). The precipitated solid was collected by filtration, washed with water (3 × 20.0 mL), and
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dried in vacuo to give 1p as a white solid (0.84 g, 60％). mp 162-163 C; H NMR (300 MHz,
DMSO-d6): δ 11.42 (s, 1H), 9.66 (s, 1H), 9.27-9.33 (m, 1H), 8.21 (bs, 1H), 7.87-7.95 (m, 1H), 7.56 (t,
J = 7.2 Hz, 4H), 7.26-7.32 (m, 4H), 6.98-7.05(m, 2H); 13C {1H} NMR (100 MHz, DMSO-d6): δ 168.4,
166.7, 154.6, 139.0, 138.5, 128.3, 127.9, 122.3, 122.0, 120.1, 118.7, 92.8; IR (KBr): ν = 3335, 1655,
1639, 1611, 1453, 1404, 787 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C16H16N3O2 282.1237;
Found 282.1234.
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General procedure C for the preparation of 1q-w:29 To a well-stirred solution of enaminone
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(10.0 mmol) and aryl isocyanate (10.0 mmol) in CH2Cl2 (20.0 mL) was added Ni(acac)2 (0.15 g, 0.6
mmol) at room temperature. Then the reaction mixture was heated and stirred under reflux until the
completion of the reaction as indicated by TLC. The resulting mixture was poured into saturated
aqueous NaCl (100.0 mL) and extracted with CH2Cl2 (3 × 30.0 mL). The combined organic phase was
washed with water, dried over anhydrous MgSO4, filtered, and evaporated in vacuo. The residue was
purified by column chromatography on silica gel using EtOAc-petroleum as the eluent to give
compound 1.
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2-Acetyl-3-amino-N-(p-tolyl)but-2-enamide (1q). Prepared from 4-aminopent-3-en-2-one (0.99 g,
10.0 mmol) and 4-methylphenyl isocyanate (1.34 g, 10.0 mmol) via general procedure C. The crude
product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 5:1) to
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give 1q as a yellowish solid (1.16 g, 50%). mp 155-157 C; H NMR (300 MHz, DMSO-d6): δ 10.19
(d, J = 4.8 Hz, 1H), 9.98 (s, 1H), 7.90 (d, J = 4.5 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.1 Hz,
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2H), 2.24 (s, 3H), 2.00 (s, 3H)，1.95 (s, 3H); C {1H} NMR (100 MHz, DMSO-d6): δ 191.5, 167.6,
161.6, 136.7, 131.4, 128.4, 118.6, 108.0, 27.1, 19.9, 19.4; IR (KBr): ν = 3314, 2963, 1667, 1635, 1602,
1448, 1401, 813 cm-1. HRMS (ESI) m/z: [M + Na]+ Calcd for C13H16N2O2Na 255.1104; Found
255.1100.
2-Acetyl-3-amino-N-(4-methoxyphenyl)but-2-enamide (1r). Prepared from 4-aminopent-3-en-2-
one (0.99 g, 10.0 mmol) and 4-methoxyphenyl isocyanate (1.51 g, 10.0 mmol) via general procedure C.
The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate =
5:1) to give 1r as a yellowish solid (1.27 g, 51%). mp 174-176 oC; 1H NMR (400 MHz, DMSO-d6): δ
10.18 (d, J = 4.4 Hz, 1H), 9.91 (s, 1H), 7.86 (d, J = 3.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 6.86 (d, J =
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8.4 Hz, 2H), 3.71 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H); C {1H} NMR (100 MHz, DMSO-d6): δ 191.5,
167.3, 161.5, 154.7, 132.4, 120.1, 113.2, 108.0, 54.6, 27.1, 19.4; IR (KBr): ν = 3186, 3135, 2954, 1659,
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1639, 1614, 1509, 1412, 777 cm-1. HRMS (ESI) m/z: [M + Na]+ Calcd for C13H16N2O3Na 271.1053;
Found 271.1046.
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2-Acetyl-3-amino-N-(4-chlorophenyl)but-2-enamide (1s). Prepared from 4-aminopent-3-en-2-one
(0.99 g, 10.0 mmol) and 4-chlorophenyl isocyanate (1.55 g, 10.0 mmol) via general procedure C. The
crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 5:1)
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to give 1s as a yellowish solid (1.24 g, 49%). mp 179-180 oC; 1H NMR (300 MHz, DMSO-d6): δ 10.22
(s, 2H), 7.98 (d, J = 4.5 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 2.00 (s, 3H), 1.95
(s, 3H); 13C {1H} NMR (75 MHz, DMSO-d6): δ 191.5, 168.0, 162.0, 138.2, 128.0, 126.1, 120.1, 107.7,
27.3, 19.5; IR (KBr): ν = 3234, 3131, 2960, 1659, 1639, 1611, 1454, 1401, 776 cm-1. HRMS (ESI) m/z:
[M + Na]+ Calcd for C12H13ClN2O2Na 275.0558; Found 275.0553.
3-Amino-2-propionyl-N-(p-tolyl)pent-2-enamide (1t). Prepared from 5-aminohept-4-en-3-one
(1.27 g, 10.0 mmol) and 4-methylphenyl isocyanate (1.34 g, 10.0 mmol) via general procedure C. The
crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 4:1)
to give 1t as a white solid (1.38 g, 53%). mp 182-183 oC; 1H NMR (300 MHz, DMSO-d6): δ 10.18 (d,
J = 4.5 Hz, 1H), 10.05 (s, 1H), 7.75 (d, J = 4.5 Hz, 1H), 7.54(d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz,
2H), 2.33 (q, J = 7.2 Hz, 2H), 2.24 (s, 3H), 2.19 (t, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H), 0.95 (t, J
= 7.5 Hz, 3H); 13C {1H} NMR (75 MHz, DMSO-d6): δ 195.0, 167.6, 165.9, 136.8, 131.5, 128.5, 118.6,
107.2, 31.5, 26.3, 20.0, 12.5, 8.8; IR (KBr): ν = 3334, 3101, 2970, 2932, 1632, 1615, 1464, 1398, 747
cm-1. HRMS (ESI) m/z: [M + Na]+ Calcd for C15H20N2O2Na 283.1417; Found 283.1408.
3-Amino-N-(4-chlorophenyl)-2-propionylpent-2-enamide (1u). Prepared from 5-aminohept-4-en-
3-one (1.27 g, 10.0 mmol) and 4-chlorophenyl isocyanate (1.55 g, 10.0 mmol) via general procedure C.
The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate =
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5:1) to give 1u as a white solid (1.40 g, 50%). mp 187-189 C; H NMR (300 MHz, DMSO-d6): δ
10.30 (s, 1H), 10.21 (d, J = 4.5 Hz, 1H), 7.81 (d, J = 4.8 Hz, 1H), 7.70 (d, J = 9.0 Hz, 2H), 7.35 (d, J =
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8.7 Hz, 2H), 2.32 (q, J = 7.5 Hz, 2H), 2.20 (q, J = 7.5 Hz, 2H), 1.11 (t, J = 7.5 Hz, 3H), 0.95 (t, J = 7.5
Hz, 3H); 13C {1H} NMR (75 MHz, DMSO-d6): δ 194.9, 168.0, 166.2, 138.2, 128.1, 126.2, 120.0,
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106.9, 31.6, 26.3, 12.5, 8.8; IR (KBr): ν = 3238, 2953, 2932, 1656, 1603, 1494, 1389, 693 cm-1.
HRMS (ESI) m/z: [M + Na]+ Calcd for C14H17ClN2O2Na 303.0871; Found 303.0865.
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3-Amino-2-benzoyl-N-(4-chlorophenyl)but-2-enamide (1v). Prepared from 3-amino-1-phenylbut-2
-en-1-one (1.61 g, 10.0 mmol) and 4-chlorophenyl isocyanate (1.55 g, 10.0 mmol) via general
procedure C. The crude product was purified by column chromatography (silica gel, petroleum
ether/ethyl acetate = 4:1) to give 1v as a yellowish solid (1.51 g, 48%). mp 167-168 oC; 1H NMR (300
MHz, DMSO-d6): δ 10.54 (s, 1H), 9.96 (s, 1H), 8.37 (s, 1H), 7.47-7.50 (m, 2H), 7.38 (d, J = 9.0 Hz,
2H), 7.20-7.28 (m, 5H), 2.09 (s, 3H); 13C {1H} NMR (75 MHz, CDCl3): δ 198.1, 168.7, 167.4, 143.2,
137.3, 131.9, 128.8, 128.7, 128.5, 128.3, 121.8, 102.2, 25.6; IR (KBr): ν = 3337, 2852, 1659, 1639,
1614, 1455, 1407, 786 cm-1. HRMS (ESI) m/z: [M + Na]+ Calcd for C17H15ClN2O2Na 337.0714;
Found 337.0704.
3-Amino-2-benzoyl-N-(4-chlorophenyl)-3-phenylacrylamide (1w). Prepared from 3-Amino-1,3-
diphenylprop-2-en-1-one (2.23 g, 10.0 mmol) and 4-chlorophenyl isocyanate (1.55 g, 10.0 mmol) via
general procedure C. The crude product was purified by column chromatography (silica gel, petroleum
ether/ethyl acetate = 5:1) to give 1w as a yellowish solid (1.77 g, 47%). mp 154-156 oC; 1H NMR (300
MHz, DMSO-d6): δ 11.87 (s, 1H), 10.44 (s, 1H), 8.09 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H),
7.51-7.58 (m, 4H), 7.37-7.48 (m, 5H), 7.30-7.34 (m, 2H), 6.45 (s, 1H); 13C {1H} NMR (75 MHz,
CDCl3): δ 199.0, 170.6, 167.1, 142.8, 138.3, 137.2, 130.7, 130.7, 128.9, 128.9, 128.8, 128.4, 128.3,
127.5, 121.6, 102.4; IR (KBr): ν = 3331, 3335, 1639, 1615, 1526, 1454, 696 cm-1. HRMS (ESI) m/z:
[M + Na]+ Calcd for C22H17ClN2O2Na 399.0871; Found 399.0860.
Preparation and analytical data of products 3 and 4
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General procedure D: To a well-stirred solution of PhIO (0.44 g, 2.0 mmol) and AcOH (0.12 g,
2.0 mmol) in CH2Cl2 (10.0 mL) was added β-aminoacrylamide 1 (1.0 mmol) at room temperature. The
reaction mixture was kept at room temperature under stirring until the completion of the reaction as
indicated by TLC. The resulting mixture was poured into saturated aqueous NaCl (100.0 mL) and
extracted with CH2Cl2 (3 × 20.0 mL). The combined organic phase was washed with water (3 × 20.0
mL), dried over anhydrous MgSO4, filtered, and evaporated in vacuo. The residue was purified by
column chromatography on silica gel using EtOAc-petroleum as the eluent to give product 3 or 4.
1-[5-(Phenylamino)isoxazol-4-yl]ethanone (3a). Prepared from 1a (0.20 g, 1.0 mmol) via general
procedure D. The crude product was purified by flash column chromatography (silica gel, petroleum
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ether/ethyl acetate = 7:1) to give 3a as a white solid (0.15 g, 76%). mp 99-100 °C; 1H NMR (400 MHz,
CDCl3): δ 9.98 (s, 1H), 8.36 (s, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.17 (t, J = 7.2
Hz, 1H), 2.40 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 191.3, 166.6, 149.2, 136.4, 129.5, 124.6,
119.0, 97.9, 27.2; IR (KBr): ν = 3237, 3071, 2921, 1647, 1611, 1579, 1541, 1460, 1242, cm-1. HRMS
(ESI) m/z: [M + H]+ Calcd for C11H11N2O2 203.0815; Found 203.0809.
X-ray Crystal Data for 3a: white crystal, M = 202.21, orthorhombic, P212121, a = 6.5102(6) Å, b
= 10.6554(10) Å, c = 14.2094(13) Å, α = 90.00°, β = 90.00°, γ = 90.00°, V = 985.69(16) Å3, Z = 4, T =
273.15 K, F000 = 424.0, F000’ = 424.19, R = 0.0447(1708), wR2 = 0.1099(1993). CCDC deposition
number: 1834343. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Center, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 (0)1223 762911; or deposit@ccdc.cam.ac.uk).
1-[5-(p-Tolylamino)isoxazol-4-yl]ethanone (3b). Prepared from 1b (0.22 g, 1.0 mmol) via general
procedure D. The crude product was purified by flash column chromatography (silica gel, petroleum
ether/ethyl acetate = 6:1) to give 3b as a yellowish solid (0.11 g, 51%). mp 132-134 °C; 1H NMR (300
MHz, CDCl3): δ 9.91 (s, 1H), 8.34 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 2.39 (s,
3H), 2.35 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 191.2, 166.6, 149.2, 134.4, 133.9, 130.0,
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119.1, 97.7, 27.1, 20.8; IR (KBr): ν = 3229, 3102, 2926, 1654, 1601, 1565, 1558, 1467, 1246, 812 cm-1.
HRMS (ESI) m/z: [M + H]+ Calcd for C12H13N2O2 217.0972; Found 217.0964.
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1-[5-[(4-Methoxyphenyl)amino]isoxazol-4-yl)ethanone (3c). Prepared from 1c (0.23 g, 1.0 mmol)
via general procedure D. The crude product was purified by flash column chromatography (silica gel,
petroleum ether/ethyl acetate = 7:1) to give 3c as a yellowish solid (0.18 g, 79%). mp 167-168 °C; 1H
NMR (300 MHz, CDCl3): δ 9.83 (s, 1H), 8.33 (s, 1H), 7.37 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz,
2H), 3.81 (s, 3H), 2.39 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ191.1, 166.6, 156.8, 149.3, 129.5,
121.0, 114.6, 97.5, 55.5, 27.1; IR (KBr): ν = 3237, 3134, 2924, 1659, 1614, 1591, 1562, 1462, 1393,
1263, 822 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C12H13N2O3 233.0921; Found 233.0916.
1-{5-[(2-Methoxyphenyl)amino]isoxazol-4-yl}ethanone (3d). Prepared from 1d (0.23 g, 1.0 mmol)
via general procedure D. The crude product was purified by flash column chromatography (silica gel,
petroleum ether/ethyl acetate = 7:1) to give 3d as a yellowish solid (0.18 g, 78%). mp 105-106 °C; 1H
NMR (400 MHz, CDCl3): δ 10.47 (s, 1H), 8.36 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 8.0 Hz,
1H), 7.01 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 3.97 (s, 3H), 2.41 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3): δ 191.0, 166.4, 149.3, 148.1, 126.4, 124.5, 121.1, 118.1, 110.5, 98.4, 56.0, 27.2; IR
(KBr): ν = 3267, 3025, 2942, 1651, 1613, 1585, 1550, 1498, 1463, 1254, 750 cm-1. HRMS (ESI) m/z:
[M + H]+ Calcd for C12H13N2O3 233.0921; Found 233.0912.
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1-{5-[(4-Chlorophenyl)amino]isoxazol-4-yl}ethanone (3e). Prepared from 1e (0.24 g, 1.0 mmol)
via general procedure D. The crude product was purified by flash column chromatography (silica gel,
petroleum ether/ethyl acetate = 6:1) to give 3e as a yellowish solid (0.14 g, 57%). mp 171-172 °C; 1H
NMR (300 MHz, CDCl3): δ 9.99 (s, 1H), 8.37 (s, 1H), 7.34-7.42 (m, 4H), 2.41 (s, 3H); 13C {1H} NMR
(100 MHz, CDCl3): δ 191.5, 166.4, 149.2, 135.1, 129.9, 129.6, 120.3, 98.1, 27.3; IR (KBr): ν = 3238,
3193, 1656, 1605, 1568, 1538, 1433, 1392, 1244, 825 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for
C11H10ClN2O2 237.0425; Found 237.0420.
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1-{5-[(5-Chloro-2-methoxyphenyl)amino]isoxazol-4-yl}ethanone (3f). Prepared from 1f (0.27 g,
1.0 mmol) via general procedure D. The crude product was purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate = 7:1) to give 3f as a yellowish solid (0.21 g, 77%). mp
128-129 °C; 1H NMR (300 MHz, CDCl3): δ 10.47 (s, 1H), 8.38 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.06
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(dd, J1 = 2.4 Hz, J2 = 8.7 Hz,1H), 6.86 (d, J = 8.7 Hz, 1H), 3.97 (s, 3H), 2.42 (s, 3H); C {1H} NMR
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(75 MHz, CDCl3): δ 191.2, 166.0, 149.2, 146.5, 127.3, 126.2, 123.8, 117.9, 111.3, 98.6, 56.3, 27.2; IR
(KBr): ν = 3261, 3062, 2954, 1652, 1618, 1582, 1551, 1497, 1255, 853, 727 cm-1. HRMS (ESI) m/z:
[M + H]+ Calcd for C12H12ClN2O3 267.0531; Found 267.0525.
1-{5-[(2-Chlorophenyl)amino]isoxazol-4-yl}ethanone (3g). Prepared from 1g (0.24 g, 1.0 mmol)
via general procedure D. The crude product was purified by flash column chromatography (silica gel,
petroleum ether/ethyl acetate = 7:1) to give 3g as a yellowish solid (0.17 g, 70%). mp 116-117 °C; 1H
NMR (300 MHz, CDCl3): δ 10.65 (s, 1H), 8.41 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 7.8 Hz,
1H), 7.34 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 2.44 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3):
δ 191.5, 166.3, 149.2, 133.9, 129.8, 128.0, 124.9, 122.9, 119.2, 98.8, 27.3; IR (KBr): ν = 3103, 3059,
2922, 1649, 1611, 1571, 1545, 1455, 1379, 1247, 736 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for
C11H10ClN2O2 237.0425; Found 237.0419.
1-{5-{[4-(Trifluoromethyl)phenyl]amino}isoxazol-4-yl}ethanone (3h). Prepared from 1h (0.27 g,
1.0 mmol) via general procedure D. The crude product was purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate = 7:1) to give 3h as a yellowish solid (0.21 g, 76%). mp
154-155 °C; 1H NMR (300 MHz, CDCl3): δ 10.16 (s, 1H), 8.40 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.57
13
(d, J = 8.7 Hz, 2H), 2.43 (s, 3H); C {1H} NMR (100 MHz, CDCl3): δ 191.8, 166.3, 149.2, 139.5,
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126.9, 126.4 (q, JCF = 33), 124.0 (q, JCF = 270), 118.6, 98.5, 27.4; IR (KBr): ν = 3238, 3170, 1658,
1618, 1594, 1542, 1333, 1248, 1115, 836 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C12H10F3N2O2
271.0689; Found 271.0685.
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1-[5-(Butylamino)isoxazol-4-yl]ethanone (3i). Prepared from 1i (0.18 g, 1.0 mmol) via general
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2
procedure D. The crude product was purified by flash column chromatography (silica gel, petroleum
ether/ethyl acetate = 10:1) to give 3i as a yellowish solid (0.13 g, 71%). mp 53-54 °C; 1H NMR (300
MHz, CDCl3): δ 8.22 (s, 1H), 7.74 (s, 1H), 3.46 (q, J = 6.9 Hz, 2H), 2.30 (s, 3H), 1.57-1.69 (m, 2H),
1.34-1.46 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (75 MHz, CDCl3): δ 190.7, 169.6, 149.9,
96.4, 42.3, 31.7, 27.0, 19.8, 13.6; IR (KBr): ν = 3202, 2906, 2854, 1656, 1589, 1433, 1247, 815 cm-1.
HRMS (ESI) m/z: [M + H]+ Calcd for C9H15N2O2 183.1128; Found 183.1135.
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1-[5-(Benzylamino)isoxazol-4-yl]ethanone (3j). Prepared from 1j (0.22 g, 1.0 mmol) via general
procedure D. The crude product was purified by flash column chromatography (silica gel, petroleum
ether/ethyl acetate = 7:1) to give 3j as a white solid (0.17 g, 77%). mp 84-85 °C; 1H NMR (300 MHz,
DMSO-d6): δ 8.25 (s, 1H), 8.05 (s, 1H), 7.30-7.39 (m, 5H), 4.64 (d, J = 6.3 Hz, 2H), 2.31 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3): δ 190.7, 169.4, 149.9, 136.5, 128.8, 128.0, 127.5, 96.6, 46.4, 26.9; IR
(KBr): ν = 3313, 3031, 2959, 1647, 1594, 1548, 1435, 1169, 952, 738 cm-1. HRMS (ESI) m/z: [M +
H]+ Calcd for C12H13N2O2 217.0972; Found 217.0970.
1-{5-[(4-Chlorophenyl)amino]isoxazol-4-yl}butan-1-one (3k). Prepared from 1k (0.27 g, 1.0
mmol) via general procedure D. The crude product was purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate = 7:1) to give 3k as a yellowish solid (0.20 g, 76%). mp
132-133 °C; 1H NMR (300 MHz, CDCl3): δ 10.08 (s, 1H), 8.38 (s, 1H), 7.33-7.42 (m, 4H), 2.67 (t, J =
7.2 Hz, 2H), 1.69-1.81 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 194.6,
166.5, 148.8, 135.2, 129.7, 129.6, 120.1, 97.7, 41.8, 18.0, 13.8; IR (KBr): ν = 3244, 2972, 1644, 1613,
1575, 1546, 1434, 1213, 1163, 821 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C13H14ClN2O2
265.0738; Found 265.0733.
[5-(Hexylamino)isoxazol-4-yl](phenyl)methanone (3l). Prepared from 1l (0.27 g, 1.0 mmol) via
general procedure D. The crude product was purified by flash column chromatography (silica gel,
petroleum ether/ethyl acetate = 11:1) to give 3l as a white solid (0.20 g, 74%). mp 73-74 °C; 1H NMR
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(300 MHz, CDCl3): δ 8.31 (s, 1H), 8.18 (s, 1H), 7.71-7.74 (m, 2H), 7.46-7.58 (m, 3H), 3.53 (q, J = 6.9
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Hz, 2H), 1.66-1.76 (m, 2H), 1.22-1.44 (m, 6H), 0.90 (t, J = 6.6 Hz, 3H); C {1H} NMR (75 MHz,
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CDCl3): δ 187.3, 171.1, 150.5, 139.0, 131.7, 128.6, 127.7, 95.1, 42.6, 31.3, 29.6, 26.3, 22.5, 14.0; IR
(KBr): ν = 3280, 2918, 1648, 1592, 1547, 1446, 899, 744 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for
C16H21N2O2 273.1598; Found 273.1622.
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Phenyl[5-(phenylamino)isoxazol-4-yl]methanone (3m). Prepared from 1m (0.27 g, 1.0 mmol) via
general procedure D. The crude product was purified by flash column chromatography (silica gel,
petroleum ether/ethyl acetate = 7:1) to give 3m as a yellowish solid (0.20 g, 74%). mp 191-193°C; 1H
NMR (300 MHz, CDCl3): 10.45 (s, 1H), 8.46 (s, 1H), 7.78-7.81 (m, 2H), 7.51-7.63 (m, 5H), 7.43 (t,
13
J = 8.4 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H); C {1H} NMR (100 MHz, CDCl3): 187.9, 168.2, 150.0,
138.7, 136.5, 132.2, 129.6, 128.8, 127.9, 124.9, 119.3, 96.8; IR (KBr): ν = 3234, 3064, 1629, 1600,
1570, 1541, 1445, 1263, 1133, 899, 738 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C16H13N2O2
265.0972; Found 265.0987.
{5-[(4-Chlorophenyl)amino]isoxazol-4-yl}(phenyl)methanone (3n). Prepared from 1n (0.30 g, 1.0
mmol) via general procedure D. The crude product was purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate = 7:1) to give 3n as a yellowish solid (0.17 g, 58%). mp
1
156-158 °C; H NMR (300 MHz, CDCl3): 10.46 (s, 1H), 8.47 (s, 1H), 7.79 (d, J = 7.2 Hz, 2H),
7.46-7.61 (m, 5H), 7.38 (d, J = 9.0 Hz, 2H); 13C {1H} NMR (100 MHz, CDCl3):  188.0, 168.0, 150.0,
138.5, 135.1, 132.4, 130.1, 129.7, 128.9, 127.9, 120.5, 96.9; IR (KBr): ν = 3278, 3153, 1651, 1622,
1584, 1556, 1461, 1248, 835, 738 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C16H12ClN2O2 299.0582;
Found 299.0578.
[5-(Phenylamino)isoxazol-4-yl](p-tolyl)methanone (3o). Prepared from 1o (0.28 g, 1.0 mmol) via
general procedure D. The crude product was purified by flash column chromatography (silica gel,
petroleum ether/ethyl acetate = 7:1) to give 3o as a yellowish solid (0.18 g, 65%). mp 142-143 °C; 1H
NMR (300 MHz, CDCl3): 10.46 (s, 1H), 8.47 (s, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 7.8 Hz,
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2H), 7.42 (t, J = 7.5 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 2.45 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3): 187.6, 168.1, 149.9, 142.9, 136.5, 135.9, 129.5, 129.4, 128.0, 124.7, 119.2,
96.6, 21.5; IR (KBr): ν = 3237, 3050, 1638, 1601, 1581, 1541, 1500, 1458, 1264, 1133, 905 cm-1.
HRMS (ESI) m/z: [M + H]+ Calcd for C17H15N2O2 279.1128; Found 279.1126.
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N-Phenyl-5-(phenylamino)isoxazole-4-carboxamide (3p). Prepared from 1p (0.28 g, 1.0 mmol)
via general procedure D. The crude product was purified by flash column chromatography (silica gel,
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petroleum ether/ethyl acetate = 7:1) to give 3p as an orange solid (0.15 g, 53%). mp 130-131 °C; H
NMR (300 MHz, CDCl3):  9.76 (s, 1H), 8.32 (s, 1H), 7.46-7.55 (m, 3H), 7.43 (s, 1H), 7.32-7.41 (m,
5H), 7.11-7.21 (m, 2H); 13C {1H} NMR (100 MHz, CDCl3):  167.3, 161.5, 146.9, 137.1, 136.9, 129.5,
129.1, 124.9, 124.0, 121.0, 118.5, 89.5; IR (KBr): ν = 3351, 3294, 1659, 1632, 1597, 1531, 1445, 1314,
1247, 750 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C16H14N3O2 280.1081; Found 280.1070.
2-Acetyl-3-methyl-N-(p-tolyl)-2H-azirine-2-carboxamide (4q). Prepared from 1q (0.23 g, 1.0
mmol) via general procedure D. The crude product was purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate = 4:1) to give 4q as a yellowish solid (0.15 g, 63%). mp
102-104 °C; 1H NMR (300 MHz, CDCl3):10.59 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz,
2H), 2.65 (s, 3H), 2.31 (s, 3H), 1.95 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): 207.2, 164.5, 155.0,
135.1, 134.1, 129.4, 120.1, 45.4, 27.9, 20.8, 11.7; IR (KBr): ν = 3238, 3193, 2920, 1656, 1605, 1592,
1568, 1471, 1392, 1241, 825 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C13H15N2O2 231.1128;
Found 231.1123.
2-Acetyl-N-(4-methoxyphenyl)-3-methyl-2H-azirine-2-carboxamide (4r). Prepared from 1r (0.25
g, 1.0 mmol) via general procedure D. The crude product was purified by flash column
chromatography (silica gel, petroleum ether/ethyl acetate = 4:1) to give 4r as a yellowish solid (0.15 g,
62%). mp 78-79 °C; 1H NMR (300 MHz, CDCl3): δ 10.56 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 6.86 (d, J
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= 9.0 Hz, 2H), 3.79 (s, 3H), 2.65 (s, 3H), 1.95 (s, 3H); C {1H} NMR (100 MHz, CDCl3): δ 207.2,
164.4, 156.4, 155.0, 130.8, 121.6, 114.0, 55.4, 45.3, 27.8, 11.6; IR (KBr): ν = 3272, 3224, 2973, 1692,
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1660, 1554, 1511, 1366, 1258, 1175, 837 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C13H15N2O3
247.1077; Found 247.1069.
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2-Acetyl-N-(4-chlorophenyl)-3-methyl-2H-azirine-2-carboxamide (4s). Prepared from 1s (0.25 g,
1.0 mmol) via general procedure D. The crude product was purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate = 4:1) to give 4s as a yellowish solid (0.17 g, 68%). mp
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127-128 °C; H NMR (300 MHz, CDCl3): 10.76 (s, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 9.0
Hz, 2H), 2.66 (s, 3H), 1.95 (s, 3H); C {1H} NMR (100 MHz, CDCl3):  207.2, 164.8, 154.7, 136.2,
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129.4, 128.9, 121.3, 45.3, 27.8, 11.6; IR (KBr): ν = 3248, 3215, 1691, 1594, 1547, 1494, 1401, 1281,
1173, 826 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C12H12ClN2O2 251.0582; Found 251.0572.
3-Ethyl-2-propionyl-N-(p-tolyl)-2H-azirine-2-carboxamide (4t). Prepared from 1t (0.26 g, 1.0
mmol) via general procedure D. The crude product was purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate = 9:1) to give 4t as a yellowish solid (0.17 g, 64%). mp
89-91 °C; 1H NMR (300 MHz, CDCl3): s, 1Hd, J = 8.4 Hz, 2Hd, J = 8.4 Hz,
2H6-3.02 (m, 2H), 2.33-2.44 (m, 2H), 2.31 (s, 3H), 1.81-1.94 (m, 1H), 1.43 (t, J = 7.5 Hz, 3H),
1.03 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (75 MHz, CDCl3): 209.7, 164.8, 157.8, 135.1, 133.9, 129.4,
120.0, 45.6, 32.9, 20.8, 19.9, 8.9, 7.2; IR (KBr): ν = 3263, 2940, 2925, 1692, 1604, 1553, 1405, 1318,
820 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C15H19N2O2 259.1441; Found 259.1458.
N-(4-Chlorophenyl)-3-ethyl-2-propionyl-2H-azirine-2-carboxamide (4u). Prepared from 1u (0.28
g, 1.0 mmol) via general procedure D. The crude product was purified by flash column
chromatography (silica gel, petroleum ether/ethyl acetate = 10:1) to give 4u as a white solid (0.19 g,
67%). mp 117-119 °C; 1H NMR (300 MHz, CDCl3): 10.90 (s, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.28 (d,
J = 8.7 Hz, 2H), 2.87-3.02 (m, 2H), 2.29-2.43 (m, 1H), 1.80-1.94 (m, 1H), 1.44 (t, J = 7.5 Hz, 3H),
1.04 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (75 MHz, CDCl3): 209.8, 165.1, 157.6, 136.3, 129.2, 128.9,
121.2, 45.5, 32.9, 19.9, 9.0, 7.1; IR (KBr): ν = 3280, 2938, 2897, 1689, 1622, 1561, 1435, 1324, 832
cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for C14H16ClN2O2 279.0895; Found 279.0909.
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2-Benzoyl-N-(4-chlorophenyl)-3-methyl-2H-azirine-2-carboxamide (4v). Prepared from 1v (0.31
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g, 1.0 mmol) via general procedure D. The crude product was purified by flash column
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chromatography (silica gel, petroleum ether/ethyl acetate = 7:1) to give 4v as a yellowish solid (0.18 g,
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58%). mp 120-122 °C; H NMR (300 MHz, CDCl3):  10.32 (s, 1H), 7.67 (d, J = 7.2 Hz, 2H),
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7.51-7.59 (m, 3H), 7.40-7.45 (m, 2H), 7.30 (d, J = 8.7 Hz, 2H), 2.56 (s, 3H); 13C {1H} NMR (75 MHz,
CDCl3): 200.6, 165.3, 157.0, 136.3, 136.2, 132.7, 129.5, 129.1, 128.5, 128.4, 121.3, 44.9, 12.3; IR
(KBr): ν = 3241, 2790, 1647, 1573, 1552, 1498, 1394, 1235, 819, 741 cm-1. HRMS (ESI) m/z: [M +
H]+ Calcd for C17H14ClN2O2 313.0738; Found 313.0743.
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2-Benzoyl-N-(4-chlorophenyl)-3-phenyl-2H-azirine-2-carboxamide (4w). Prepared from 1w (0.38
g, 1.0 mmol) via general procedure D. The crude product was purified by flash column
chromatography (silica gel, petroleum ether/ethyl acetate = 10:1) to give 4w as a yellowish solid (0.21
1
g, 56%). mp 134-136 °C; H NMR (300 MHz, CDCl3):  10.09 (s, 1H), 7.90-7.93 (m, 2H), 7.76-7.79
(m, 2H), 7.65-7.70 (m, 1H), 7.55-7.61 (m, 4H), 7.50 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.8 Hz 2H),
7.28-7.32 (m, 2H); 13C {1H} NMR (75 MHz, CDCl3): 199.9, 165.1, 156.5, 136.2, 135.7, 134.8,
132.9, 131.0, 129.6, 129.5, 129.0, 128.7, 128.4, 121.2, 120.6, 45.5; IR (KBr): ν = 3226, 2927, 1663,
1597, 1536, 1493, 1401, 1246, 824, 725, 693 cm-1. HRMS (ESI) m/z: [M + H]+ Calcd for
C22H16ClN2O2 375.0895; Found 375.0887.
Preparation and analytical data of products 3s and 5s
General procedure E: The solution of 4s (0.25 g, 1.0 mmol) in xylene (5.0 mL) was heated to
reflux under stirring in N2 atmosphere until the completion of the reaction as indicated by TLC. The
resulting mixture was poured into saturated aqueous NaCl (30.0 mL) and extracted with CH2Cl2 (3 ×
15.0 mL). The combined organic phase was washed with water (3 × 20.0 mL), dried over anhydrous
MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography (silica
gel, petroleum ether/ethyl acetate = 10:1) to give products 3s and 5s.
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1-{5-[(4-Chlorophenyl)amino]-3-methylisoxazol-4-yl}ethanone (3s). Prepared from 4s (0.25 g,
1.0 mmol) via general procedure E. The crude product was purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate = 7:1) to give 3s as a yellowish solid (0.06 g, 23%). mp 109-
111 °C; 1H NMR (300 MHz, CDCl3): 9.49 (s, 1H), 7.28-7.35 (m, 4H), 2.47 (d, J = 5.7 Hz, 6H); 13C
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{1H} NMR (75 MHz, CDCl3): 193.0, 155.1, 149.7, 136.1, 129.5, 128.6, 119.4, 115.6, 25.7, 13.8; IR
(KBr): ν = 3247, 3028, 2922, 1694, 1595, 1551, 1489, 1436, 1245, 748 cm-1. HRMS (ESI) m/z: [M +
H]+ Calcd for C12H12ClN2O2 251.0582; Found 251.0569.
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N-(4-Chlorophenyl)-3,5-dimethylisoxazole-4-carboxamide (5s). Prepared from 4s (0.25 g, 1.0
mmol) via general procedure E. The crude product was purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate = 10:1) to give 5s as a yellowish solid (0.17 g, 66%). mp 128-
129 °C; 1H NMR (300 MHz, CDCl3): 8.71 (s, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H),
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2.64 (s, 3H), 2.44 (s, 3H); C {1H} NMR (75 MHz, DMSO-d6):  159.6, 158.0, 152.9, 137.1, 128.3,
127.9, 126.7, 121.3, 12.8, 10.9; IR (KBr): ν = 3224, 2928, 1646, 1615, 1571, 1438, 1231, 784 cm-1.
HRMS (ESI) m/z: [M + H]+ Calcd for C12H12ClN2O2 251.0582; Found 251.0565.
Associated Content
Author Information
Corresponding Author
E-mail: yanningzhao@jlnu.edu.cn; dwdong@ciac.ac.cn.
Note
The authors declare no competing financial interest.
Supporting Information
The supporting Information is available free of charge on the ACS Publication website at
DOI:10.1021/acs.joc.XXXXXXXX.
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X-ray crystallographic data (CIF file) of 3a. H and C NMR spectra copies of compounds 1-5
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(PDF).
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Acknowledgement
9
Financial support of this research by the National Natural Science Foundation of China
(21502185 and 21542006) and the Department of Science and Technology of Jilin Province
(20170203005SF) is greatly acknowledged. C. B. Rao thanks the award of CAS President's
International Fellowship for Postdoctoral Researchers (2016PT021), and R. Zhang thanks the support
of Youth Innovation Promotion Association CAS (2018261).
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