Nitroacetic Esters in the Regioselective Synthesis of Isoxazole-3,5-dicarboxylic Acid Derivatives

Article abstract of DOI:10.1021/acs.joc.9b02427

An efficient and high-yielding strategy to prepare "unsymmetrical" 4-aryl-isoxazol-3,5-dicarboxylic acid derivatives from nitroacetic esters and aromatic aldehydes has been developed. The strategy is based on the isolation and usage of the previously missed intermediate of the Dornow reaction - 5-hydroxy-6-oxo-4-aryl-6H-1,2-oxazine-3-carboxylates. In addition, the mechanism of the Dornow reaction was partially revised.

Full text of DOI:10.1021/acs.joc.9b02427

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Article
Nitroacetic esters in the regioselective synthesis
of isoxazole-3,5-dicarboxylic acids derivatives
Alexander Yu. Smirnov, Elvira R Zaitseva, Olga A. Belozerova, Roman S Alekseyev,
Nadezhda S Baleeva, Marina B Zagudaylova, Andrey A. Mikhaylov, and Mikhail S Baranov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02427 • Publication Date (Web): 08 Nov 2019
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Nitroacetic esters in the regioselective synthesis of isoxazole-3,5-
dicarboxylic acids derivatives
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Alexander Yu. Smirnov,† Elvira R. Zaitseva,†,§ Olga A. Belozerova,† Roman S. Alekseyev,& Nadezhda
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S. Baleeva,† Marina B. Zagudaylova,† Andrey A. Mikhaylov,† and Mikhail S. Baranov*,†,‡
† Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia
§ D. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Sq., Moscow 125047, Russia
& Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow 119991, Russia
‡ Pirogov Russian National Research Medical University, Ostrovitianov 1, Moscow 117997, Russia
*E-mail: baranovmikes@gmail.com
ABSTRACT: An efficient and high-yielding strategy to prepare “unsymmetrical” 4-aryl-isoxazol-3,5-dicarboxylic acids derivatives from
nitroacetic esters and aromatic aldehydes has been developed. The strategy is based on the isolation and usage of the previously missed
intermediate of the Dornow reaction - 5-hydroxy-6-oxo-4-aryl-6H-1,2-oxazine-3-carboxylates. In addition the mechanism of Dornow reac-
tion was partially revised.
carboxylate salts 2 (Scheme 1).8 However, the synthetic pro-
INTRODUCTION
cedures proposed in that work were characterized by rather
The development of new synthetic approaches with the use of
low yields. Moreover, the suggested mechanism contradicted
the simple and cheap reagents leading to densely functional-
our later observations and the possible role of these com-
ized heterocyclic scaffolds is highly aimed by the modern
pounds in the conversion of nitroacetic esters into isoxazole
organic chemistry. Among such reagents, nitroacetic esters
derivatives was not discussed.
should be emphasized. Their condensation with esters of acet-
ylene mono-1 and dicarboxylic acids,2 acrylic derivatives,3 and
other unsaturated compounds4 is well known and leads to the
formation of isoxazole and isoxazoline rings. Another example
of these esters reaction is condensation with aromatic alde-
hydes, which leads to the formation of derivatives of isoxa-
zole-3,5-dicarboxylic acids. This process is so-called as Dor-
now reaction and dates back to the 50s of the last century.5
Application of the reaction up to date was sporadic since the
proposed conditions often give a mixture of isoxazole-3,5-
dicarboxylic acid esters 1 and their mono or diamides.5,6
What’s more the usage of esters 1 in the synthesis of "unsym-
metrical" derivatives of isoxazole dicarboxilic acid was lim-
ited due to the similar reactivity of two ester groups (Scheme
1). To the best of our knowledge, no protocol is still known
which could afford regioselective formation of such isoxazoles
with different substitution pattern of carboxylic moieties at the
positions 3 and 5. Development of a selective protocol would
provide huge application possibilities for drug discovery and
medicinal chemistry.7
Scheme 1. Condensation of nitroacetic esters with aromatic
aldehydes
In the present work, we optimized the protocol of compounds
2 synthesis, revised the Dornow reaction mechanism (regard-
ing intermediacy of oxazinones 2) and demonstrated synthetic
potential of these substances in the regioselective synthesis of
“unsymmetrical” mono and diamides of isoxazole-3,5-
dicarboxylic acids.
In our previous communication, we observed that condensa-
tion of aromatic aldehydes with nitroacetic esters can also
generate
5-hydroxy-6-oxo-4-aryl-6H-1,2-oxazine-3-
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aliphatic aldehydes, which transformed into the complex mix-
tures.
RESULTS AND DISCUSSION
During the optimization of the condensation reaction condi-
tions (Table 1, SI Part 1), we showed that the highest yields of
the compounds 2 are achieved in highly polar, but aprotic me-
dia (e.g. acetonitrile). It was shown that the presence of ter-
tiary amines (DIPEA, Et3N) instead of diethylamine, which
was used in our previous communication,8 leads to a signifi-
cant deceleration of the reaction. Meanwhile the presence of
less sterically hindered secondary (as well as primary) amines
leads to the uncontrolled formation of amides (data is not
shown in table 1).
Scheme 2. Scope of the reaction of nitroacetic esters with
aromatic aldehydes
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Table 1. Examining the reaction conditions of nitroacetic
esters condensationa
Yield
of 2a
45%b
15%b
Yield
of 1a
Solvent
Time
Temp.
iPrOH
CHCl3
THF
7 d
7 d
25 oC
25 oC
25 oC
25 oC
25 oC
80 oC
80 oC
~50%c
~35%c,d
7 d
11%b
~5%c
63%b
~5%c
~10%c
89%b
~25%c,d
~30%c,d
~5%c
dioxane
CH3CN
iPrOH
CH3CN
7 d
2 d
12 h
12 h
~80%c
74%b
CH3CN 2d at 25oC + 3h at 80 oC
~5%c
aReaction conditions: 2 mmol of benzaldehyde, 4.4 mmol of iso-
propyl nitroacetate and 5 mmol of Et2NH were mixed in the cor-
b
c
1
responding solvent (see SI). Isolated yield. Determined by H
NMR for the reaction mixtures. dResidual unreacted starting mate-
rials remained.
Surprisingly, we found that the temperature mode also affects
the ratio of products 1 and 2. Thus, while instant reflux of the
reaction mixture leads to the almost exclusive formation of
ester 1, the combination of the introductory period at room
temperature of two days and subsequent short heating gave a
product 2 in the highest yield (Table 1).
aPredominant formation of ester 1, the yields were determined by
1H NMR for the reaction mixtures.
The ease of formation of oxazinones 2 inspired us to reconsid-
er the mechanism of the Dornow reaction. Based on the litera-
ture data, isoxazole formation starts from 3,5-dinitroglutaric
esters I cyclization into isoxazoline N-oxides II (Scheme 3).
The intermediacy of compounds II was confirmed in previous
studies5,6 and their isolation was also possible.9 However, in-
formation about the following steps was contradictory. The
mostly appeared in literature mechanism involves water elimi-
nation directly from the isoxazolines II, which occurs after
deprotonation and migration of the double bond (Scheme 3,
We successfully transferred the developed technique on a se-
ries of aldehydes having various electronic and sterical proper-
ties along with three simple nitroacetic esters (Scheme 2). In
most cases resulting diethylammonium salts 2 could be easily
separated from the reaction mixture by crystallization. After-
wards, the treatment with hydrochloric acid, converted all of
these salts into hydroxy derivatives 3-5. The main limitations
that were revealed were the usage of aldehydes with EWG, in
which case mainly the esters 1 were formed and the usage of
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Path C). However, in some works, the possible formation of
The structure of compounds 2, having carbonyl groups already
2
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oximes III (Scheme 3, Path B) was also discussed. This pro-
cess also occurs after deprotonation, but at a different position
of the isoxazoline cycle.6c,10 Our results suggest that both of
these processes actually take place. Thus, the predominant
formation of esters 1 in the case of aldehydes with electron-
withdrawing substituents (Scheme 2, bottom) can be explained
by the increased acidity of the proton at the position 4, which
is necessary for the passage of the reaction along the path C.
At the same time, formation of oxazolinones 2 (as well as re-
lated diaryl compounds in other publications11), confirms the
formation of oximes III.
differentiated, has brought us to a successful idea of synthesis
of monoamides simply by treatment of these oxazinones with
primary and secondary amines (Table 2).
We found that interaction of oxazinones 3 and 4 with amines
was always accompanied with the formation of symmetric
diamides in the case of methyl and ethyl esters (in one case it
was isolated and fully characterized see SI, compound 6a*).
The problem can be avoided by the use of the isopropyl deriv-
atives.
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During the optimization (Table 2), we showed that this reac-
tion takes place only in the presence of double excess of amine
and requires heating. Excess of amine in some cases could be
replaced by combination of 1 equivalent of amine and excess
of DIPEA, but this approach was not universal (not applicable
for e.g. primary amines). Finally the best results were achieved
upon heating in chloroform with 2 equivalents of correspond-
ing amine.
Scheme 3. Processes occurred during the interaction of
nitroacetic esters and aromatic aldehydes
Table 2. Examining the reaction of oxazinones with amines
at various conditions
Solvent
Amine
Temp Timeb Yiel
da
iPrOH
iPrOH
iPrOH
EtOH
pyrrolidine (1.2 equiv)
pyrrolidine (1.2 equiv)
pyrrolidine (2 equiv)
pyrrolidine (2 equiv)
pyrrolidine (2 equiv)
pyrrolidine (2 equiv)
pyrrolidine (2 equiv)
pyrrolidine (2 equiv)
24 h
24 h
5 h
0%c
0%c
25°C
70°C
70°C
70°C
70°C
70°C
70°C
70°C
70°C
71%
61%
66%
68%
65%
84%
80%
5 h
CH3CN
dioxane
THF
8 h
6 h
6 h
CHCl3
CHCl3
12 h
12 h
cyclohexylamine (2
equiv)
CHCl3
CHCl3
pyrrolidine (1 equiv),
DIPEA (1.2 equiv)
12 h
12 h
90%
9%c
70°C
70°C
The cyclization of oximes III into five- or six-membered rings
(Pathways A and B) can be highly sensitive to the medium
properties, that explains the different ratios of products 1 and 2
in various solvents. The revealed dependence on the tempera-
ture mode can be associated with the aldehyde remained in the
mixture (SI Part 2). The aldehyde may affect the properties of
the medium and/or can prevent the formation of anion in posi-
tion 5 and stimulate the process to proceed along the path C.
The heating is probably necessary for E/Z isomerization of
oxime III.
cyclohexylamine (1
equiv), DIPEA (1.2
equiv)
aIsolated yield. Full conversion time, unless otherwise indicated.
b
cStarting materials remain unreacted.
Apparently, this transformation (which is somewhat close to
path B, because it includes the oxime IV formation) also oc-
curred in many other previously described examples of nitroa-
cetic esters condensation with aldehydes in the presence of
various amines,5,6 simultaneously with the reaction by path-
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aAccompanied with diamide formation. bUnidentified by-products
ways B and C. This fact well explains the previously observed
simultaneous formation of esters 1 and mono and diamides of
isoxazole-3,5-dicarboxylic acids with the predominant for-
mation of monoamides at position 3. Therefore, isolation of
products 2 is the previously “missed link” which allows to
control the selectivity of the process.
formation. сStarting materials remain.
The yield of the reaction decreases dramatically when amines
with the bulky substituents were used (e.g. no reaction with
diisopropyl or dicyclohexylamine). We also found that the
reaction conditions are not applicable for anilines and thiols.
An increase of temperature (e.g. boiling in DMF or dioxane)
did not allow the corresponding derivatives to be obtained.
According to the optimized procedure, we synthesized few
amides 6 and 7, bearing methyl and ethyl esters, with moder-
ate yield and a library of more than five dozens of mono-
amides 8 in a good yields (Scheme 4). The exclusive for-
mation of the amide in position 5 was confirmed by the single
crystal X-Ray analysis (SI Part 5, compound 8ce).
9
Facing this obstacle, an indirect approach was developed.
Thus, we showed that the proposed oxazinones can be con-
verted to the corresponding isoxazole-5-carboxylic acids on
the example of compounds 5c (Scheme 5). Surprisingly, the
action of alkali (as well as carbonates or hydrocarbonates) led
to the formation of a complex mixture, but after the treatment
with acid, the necessary isoxazole-5-carboxylic acid 9 was
formed. This product can be easily used in the synthesis of
monoamides that were inaccessible by the above-mentioned
general approach by HBTU or acyl chloride-mediated conden-
sations (Scheme 5).
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Scheme 4. Scope of the oxazinones 3-5 reaction with
amines
Scheme 5. Formation of izoxazole-5-carboxilic acid 9 and cor-
responding monoamides 10 and 11
To fully establish a library of compounds, which the described
method could provide, “unsymmetrical” diamides were syn-
thesized from monoamides 8cb and 11 via intermediate for-
mation of acid at position 3 (Scheme 6).
Scheme 6. Synthesis of diamides
The scale-up experiments were also conducted. The yields of
condensation and isoxazole formation even slightly increase
upon increase of scale (Scheme 7).
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5 ml of acetonitrile. Resulted solution was stirred for 48 h at
Scheme 7. Scale-up experiments
room temperature and then additionally heated in oil bath at
80°C for 3 h. All volatiles were removed in vacuo, 6-7 ml of
corresponding alcohol was added and the mixture was re-
fluxed until the complete solid dissolution (1-5 min). Resulted
solution was cooled to -20°C and stored for 8 h at this temper-
ature. The precipitated diethylammonium salt was filtered and
washed with a cold (0°C) alcohol (1-2 ml, twice), washed with
2 ml of ether and dried in vacuo. To obtain neutral hydroxyox-
azines the corresponding salt (2 mmol) was dissolved in 50 ml
of CHCl3 and washed 3 times with 20 ml of 3% aq. HCl. Or-
ganic layer was dried with anhydrous Na2SO4 and evaporated.
For all presented compounds this procedure allowed to obtain
a pure product. Anyway, if it is necessary, 5-hydroxy-6-oxo-4-
aryl-6H-1,2-oxazine-3-carboxylates could be purified by col-
umn chromatography using CHCl3 – EtOH mixture as eluent
(~20:1, v:v).
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CONCLUSIONS
Thus, in the present work, we showed that 5-hydroxy-6-oxo-4-
aryl-6H-1,2-oxazine-3-carboxylates 2 are one of the interme-
diates of the Dornow reaction – the process of nitroacetic es-
ters condensation with aldehydes, which leads to the formation
of isoxazole-3,5-dicarboxylic acids derivatives. The possible
simultaneous formation of various intermediates in this reac-
tion explains the formation of complex mixtures, observed by
authors of the previous works. Contrary, the proposed in this
work technique of oxazinones 2 isolation allows to precede the
process selectively. Based on the utilization of these oxazi-
nones a general and high-yielding protocol for regioselective
3-(isopropoxycarbonyl)-6-oxo-4-phenyl-6H-1,2-oxazin-5-
olate diethylammonium salt (2a). 1H NMR (700 MHz,
CDCl3): δ 0.91 - 1.01 (m, 12 H), 2.22 (q, J=7.1 Hz, 4 H), 4.86
(spt, J=6.3 Hz, 1 H), 7.26 - 7.29 (m, 2 H), 7.29 - 7.33 (m, 1 H),
7.34 - 7.38 (m, 2 H), 9.12 (br. s., 2 H); 13C{1H} NMR (176
MHz, CDCl3): δ 11.8, 21.2, 43.0, 70.0, 110.8, 127.7, 130.0,
128.6, 134.6, 154.5, 156.7, 162.6, 170.2. The 1H and 13C spec-
tra are identical to the previously reported in the literature.8
diisopropyl 4-phenylisoxazole-3,5-dicarboxylate (1a). White
1
solid, m.p. 77-78°C. H NMR (700 MHz, DMSO-d6): d 1.12
(d, J=6.3 Hz, 6 H), 1.14 (d, J=6.1 Hz, 6 H), 4.99 - 5.10 (m, 2
H), 7.37 - 7.48 (m, 5 H); 13C{1H} NMR (176 MHz, DMSO-
d6): d 21.1 (2 C), 70.2 (2 C), 124.3, 127.0, 127.5, 128.5,
130.0, 155.3, 155.8, 156.8, 158.1; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C17H20NO5 318.1336; Found 318.1338.
formation
of
“unsymmetrical”
4-aryl-isoxazol-3,5-
dicarboxylic acids derivatives is developed and a library of
60+ 3,5-substituted isoxazoledicarboxylates was synthesized.
EXPERIMENTAL SECTION
methyl
5-hydroxy-6-oxo-4-phenyl-6H-1,2-oxazine-3-
General Comments. Commercially available reagents were
used without additional purification. Isopropyl nitroacetate
was synthesized according the literature procedure.12 E. Merck
Kieselgel 60 was used for column chromatography. Thin layer
chromatography (TLC) was performed on silica gel 60 F254
glass-backed plates (MERCK). Visualization was effected by
UV light (254 or 312 nm) and staining with KMnO4.
carboxylate (3a). Yield 410 mg (83%), white solid, m.p. 148-
1
149°C; H NMR (700 MHz, CDCl3): d 3.74 (s, 3H), 7.32 -
7.40 (m, 2H), 7.42 - 7.50 (m, 3H); 13C{1H} NMR (176 MHz,
CDCl3): d 53.5, 116.2, 128.5, 128.7, 129.7, 144.1, 153.0,
161.4, 163.6; HRMS (ESI-TOF) m/z: [M-H]- Calcd for
C12H8NO5 246.0408; Found 246.0405.
methyl
5-hydroxy-4-(4-methoxyphenyl)-6-oxo-6H-1,2-
NMR spectra were recorded on a 700 MHz Bruker Avance
III NMR at 303 K and Bruker Fourier 300. Chemical shifts are
oxazine-3-carboxylate (3c). Yield 405mg (73%), white solid,
1
m.p. 105-107°C; H NMR (700 MHz, DMSO-d6): d 3.67 (s,
1
reported relative to residue peaks of CDCl3 (7.27 ppm for H
3H), 3.79 (s, 3H), 7.00 (d, J=9.0 Hz, 2H), 7.24 (d, J=9.0 Hz,
2H); 13C{1H} NMR (75 MHz, DMSO-d6): d 53.4, 55.2, 113.9,
114.9, 121.7, 130.1, 146.4, 153.1, 159.5, 162.0, 162.7; HRMS
(ESI-TOF) m/z: [M-H]-. C13H10NO6 Calcd for 276.0514;
Found 276.0511.
and 77.0 ppm for 13C) or DMSO-d6 (2.51 ppm for 1H and 39.5
ppm for 13C). Melting points were measured on a SMP 30
apparatus without correction. High-resolution mass spectra
(HRMS) spectra were recorded on a Bruker micrOTOF II
instrument using electrospray ionization (ESI). The measure-
ments were done in a positive ion mode (interface capillary
voltage – 4500 V) or in a negative ion mode (3200 V); mass
range from m/z 50 to m/z 3000; external or internal calibration
was done with ESI Tuning Mix, Agilent. A syringe injection
was used for solutions in acetonitrile, methanol, or water (flow
rate 3 mL/min). Nitrogen was applied as a dry gas; interface
temperature was set at 180°C.
methyl 4-(2-fluorophenyl)-5-hydroxy-6-oxo-6H-1,2-oxazine-
3-carboxylate (3f). Yield 339 mg (64%), white solid, m.p.
1
107-109°C; H NMR (700 MHz, CDCl3): d 3.83 (s, 3H), 7.18
(t, J=9.1 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.42 (t, J=7.3 Hz,
1H), 7.48 (q, J=6.7 Hz, 1H); 13C{1H} NMR (176 MHz,
CDCl3): d 53.5, 111.3, 115.7 (d, J=21.4 Hz), 116.6 (d, J=15.4
Hz), 124.4 (d, J=3.3 Hz), 130.7 (d, J=2.3 Hz), 131.8 (d, J=8.4
Hz), 145.2, 151.5, 159.4 (d, J=248.6 Hz), 161.1, 163.3; HRMS
(ESI-TOF) m/z: [M-H]- Calcd for C12H7FNO5 264.0314;
Found 264.0312.
General procedure for synthesis of 5-hydroxy-6-oxo-4-
aryl-6H-1,2-oxazine-3-carboxylates. 2 mmol (1 equiv) of
arylaldehyde, 4.4 mmol (2.2 equiv) of nitroacetic ester and
365 mg (5 mmol, 2.5 equiv) of diethylamine were dissolved in
methyl 5-hydroxy-6-oxo-4-(thiophen-2-yl)-6H-1,2-oxazine-
3-carboxylate (3i). Yield 334 mg (66%), white solid, m.p.
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2H), 7.12 (d, J=8.5 Hz, 2H), 9.74 (br. s., 1H), 12.20 (br. s.,
165°C with decomposition; H NMR (700 MHz, CDCl3): d
3.91 (s, 3H), 7.15 (t, J=4.4 Hz, 1H), 7.33 (d, J=3.3 Hz, 1H),
7.59 (d, J=4.8 Hz, 1H); 13C{1H} NMR (176 MHz, CDCl3): d
53.8, 109.9, 127.5, 128.4, 129.8, 130.2, 142.6, 152.3, 161.6,
163.3; HRMS (ESI-TOF) m/z: [M-H]- Calcd for C10H6NO5S
251.9972; Found 251.9969.
1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 20.9, 70.8, 79.2,
115.2, 115.3, 120.1, 130.2, 146.2, 153.8, 158.0, 161.0, 162.8;
HRMS (ESI-TOF) m/z: [M-H]- Calcd for C14H12NO6
290.0670; Found 290.0666.
isopropyl
4-(4-(dimethylamino)phenyl)-5-hydroxy-6-oxo-
6H-1,2-oxazine-3-carboxylate (5e). Yield 288 mg (45%), or-
methyl
5-hydroxy-4-(3-methoxyphenyl)-6-oxo-6H-1,2-
oxazine-3-carboxylate (3j). Yield 398 mg (72%), white solid,
m.p. 96-97°C; H NMR (700 MHz, CDCl3): d 3.76 (s, 3H),
3.83 (s, 3H), 6.90 - 6.94 (m, 2H), 6.98 (dd, J=8.2, 1.6 Hz, 1H),
7.37 (t, J=7.9 Hz, 1H); 13C{1H} NMR (176 MHz, CDCl3): d
53.6, 55.4, 114.4, 115.4, 115.9, 120.7, 129.8, 129.9, 144.4,
153.1, 159.8, 161.5, 163.9; HRMS (ESI-TOF) m/z: [M-H]-
Calcd for C13H10NO6 276.0514; Found 276.0509.
5-hydroxy-6-oxo-4-phenyl-6H-1,2-oxazine-3-
carboxylate (4a). Yield 376 mg (72%), white solid, m.p. 117-
118°C; H NMR (700 MHz, DMSO-d6): d 0.95 (t, J=7.1 Hz,
3H), 4.07 (q, J=7.2 Hz, 2H), 7.27 - 7.33 (m, 2H), 7.38 - 7.47
(m, 3H); 13C{1H} NMR (75 MHz, CDCl3): d 13.6, 63.2, 116.0,
128.5, 128.8, 129.8, 143.7, 153.3, 160.8, 163.8; HRMS (ESI-
TOF) m/z: [M-H]- Calcd for C13H10NO5 260.0564; Found
260.0566.
5-hydroxy-4-(4-methoxyphenyl)-6-oxo-6H-1,2-
oxazine-3-carboxylate (4c). Yield 535 mg (78%), white solid,
m.p. 103-105°C; H NMR (700 MHz, DMSO-d6): d 1.01 (t,
J=7.1 Hz, 3H), 3.78 (s, 3H), 4.11 (q, J=7.1 Hz, 2H), 7.00 (d,
J=8.6 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H); 13C{1H} NMR (75
MHz, CDCl3): d 13.7, 55.3, 63.2, 114.2, 115.8, 120.4, 130.0,
143.4, 153.5, 160.6, 161.0, 163.8; HRMS (ESI-TOF) m/z: [M-
H]- Calcd for C14H12NO6 290.0670; Found 290.0668.
1
ange solid, m.p. 130-132°C with decomposition; H NMR
1
(700 MHz, DMSO-d6): d 1.07 (d, J=6.3 Hz, 6H), 2.93 (s, 6H),
4.92 (spt, J=6.2 Hz, 1H), 6.75 (d, J=8.9 Hz, 2H), 7.15 (d,
J=8.9 Hz, 2H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.0,
70.7, 111.5, 115.5, 116.5, 129.6, 145.7, 150.4, 153.9, 161.2,
162.9; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H19N2O5
319.1288; Found 319.1286.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ethyl
isopropyl
4-(2-fluorophenyl)-5-hydroxy-6-oxo-6H-1,2-
oxazine-3-carboxylate (5f). Yield 516 mg (88%), white solid,
1
1
m.p. 133-134°C; H NMR (700 MHz, DMSO-d6): d 1.00 (br.
s., 6H), 4.87 (spt, J=6.2 Hz, 1H), 7.25 - 7.31 (m, 2H), 7.35 (td,
J=7.5, 1.6 Hz, 1H), 7.46 - 7.50 (m, 1H); 13C{1H} NMR (176
MHz, DMSO-d6): d 20.8, 70.7, 109.6, 115.5 (d, J=21.6 Hz),
117.9 (d, J=16.4 Hz), 124.5 (s, J=3.0 Hz), 131.1 - 131.2 (m, 2
C), 148.0, 152.3, 159.2 (d, J=246.6 Hz), 160.3, 162.3; HRMS
(ESI-TOF) m/z: [M-H]- Calcd for C14H11FNO5 292.0627;
Found 292.0621.
ethyl
1
isopropyl 5-hydroxy-6-oxo-4-(3-(trifluoromethyl)phenyl)-
6H-1,2-oxazine-3-carboxylate (5g). Yield 384 mg (56%),
white solid, m.p. 158-160°C; 1H NMR (700 MHz, DMSO-d6):
d 0.97 (d, J=6.3 Hz, 6H), 4.85 (spt, J=6.2 Hz, 1H), 7.63 (d,
J=7.7 Hz, 1H), 7.65 (s, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.79 (d,
J=7.7 Hz, 1H); 13C{1H} NMR (176 MHz, DMSO-d6): d 20.7,
70.8, 113.6, 123.9 (q, 272.2 Hz), 125.3 (q, J=3.5 Hz), 125.5
(q, J=3.7 Hz), 129.2 (q, J=31.9 Hz), 129.6, 131.5, 133.2,
147.6, 152.5, 160.5, 162.6; HRMS (ESI-TOF) m/z: [M-H]-
Calcd for C15H11F3NO5 342.0595; Found 342.0605.
isopropyl
5-hydroxy-6-oxo-4-phenyl-6H-1,2-oxazine-3-
carboxylate (5a). Yield 425 mg (86%), white solid, m.p. 133-
135°C; H NMR (700 MHz, DMSO-d6): d 0.97 (d, J=6.3 Hz,
1
6H), 4.85 (spt, J=6.3 Hz, 1H), 7.28 - 7.32 (m, 2H), 7.39 - 7.47
(m, 3H); 13C{1H} NMR (75 MHz, DMSO-d6): d 20.78, 70.78,
115.04, 128.35, 128.78, 128.83, 129.98, 146.78, 153.28,
160.74, 162.72; HRMS (ESI-TOF) m/z: [M-H]- Calcd for
C12H8NO5 246.0408; Found 246.0405.
isopropyl 5-hydroxy-4-(4-isopropylphenyl)-6-oxo-6H-1,2-
oxazine-3-carboxylate (5b). Yield 361 mg (57%), white solid,
m.p. 128-130°C; H NMR (700 MHz, DMSO-d6): d 0.94 (d,
J=6.3 Hz, 6H), 1.20 (d, J=7.0 Hz, 6H), 2.91 (spt, J=6.9 Hz,
1H), 4.85 (spt, J=6.2 Hz, 1H), 7.22 (d, J=8.2 Hz, 2H), 7.32 (d,
J=8.2 Hz, 2H); 13C{1H} NMR (75 MHz, DMSO-d6): d 20.7,
23.8, 33.3, 70.7, 115.1, 126.3, 127.4, 128.8, 146.6, 149.3,
153.5, 160.8, 162.7; HRMS (ESI-TOF) m/z: [M-H]- Calcd for
C17H18NO5 316.1190; Found 316.1188.
5-hydroxy-4-(4-methoxyphenyl)-6-oxo-6H-1,2-
oxazine-3-carboxylate (5c). Yield 506 mg (83%), white solid,
m.p. 120-122°C; H NMR (700 MHz, DMSO-d6): d 1.03 (d,
J=6.3 Hz, 6H), 3.78 (s, 3H), 4.89 (spt, J=6.2 Hz, 1H), 7.00 (d,
J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H); 13C NMR{1H} (75
MHz, DMSO-d6): d 20.9, 55.3, 70.8, 113.8, 114.8, 121.9,
130.3, 146.6, 153.5, 159.6, 160.9, 162.8; HRMS (ESI-TOF)
m/z: [M-H]- Calcd for C15H14NO6 304.0826; Found 304.0834.
isopropyl
5-hydroxy-4-(naphthalen-1-yl)-6-oxo-6H-1,2-
oxazine-3-carboxylate (5h) .Yield 566 mg (87%), white solid,
1
m.p. 148-150°C; H NMR (700 MHz, DMSO-d6): d 0.44 (d,
J=6.3 Hz, 3H), 0.70 (d, J=6.3 Hz, 3H), 4.57 (spt, J=6.2 Hz,
1H), 7.37 (dd, J=7.0, 0.9 Hz, 1H), 7.50 - 7.53 (m, 1H), 7.53 -
7.58 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.96 - 8.01 (m, 2H);
13C{1H} NMR (75 MHz, DMSO-d6): d 20.1, 20.6, 70.2, 113.9,
125.3, 125.8, 126.3, 126.5, 127.1, 128.0, 128.1, 129.1, 130.9,
133.0, 148.0, 153.6, 160.4, 162.6; HRMS (ESI-TOF) m/z: [M-
H]- Calcd for C18H14NO5 324.0877; Found 324.0882.
1
isopropyl
5-hydroxy-6-oxo-4-(thiophen-2-yl)-6H-1,2-
oxazine-3-carboxylate (5i). Yield 371 mg (66%), green solid,
1
m.p. 128-130°C; H NMR (700 MHz, DMSO-d6): d 1.14 (d,
isopropyl
J=6.3 Hz, 6H), 5.03 (spt, J=6.2 Hz, 1H), 7.11 - 7.13 (m, 1H),
7.13 - 7.16 (m, 1H), 7.75 (dd, J=5.1, 1.0 Hz, 1H); 13C{1H}
NMR (75 MHz, DMSO-d6): d 21.0, 71.2, 108.2, 127.0, 128.5,
129.1, 129.8, 146.7, 152.5, 161.1, 162.3; HRMS (ESI-TOF)
m/z: [M-H]- Calcd for C12H10NO5S 280.0285; Found
280.0285.
1
isopropyl
4-(2-chlorophenyl)-5-hydroxy-6-oxo-6H-1,2-
oxazine-3-carboxylate (5k). Yield 216 mg (35%), white solid,
1
isopropyl
5-hydroxy-4-(4-hydroxyphenyl)-6-oxo-6H-1,2-
oxazine-3-carboxylate (5d). Yield 495 mg (85%), white solid,
m.p. 180-181°C; H NMR (700 MHz, DMSO-d6): d 1.03 (d,
J=6.3 Hz, 6H), 4.89 (spt, J=6.2 Hz, 1H), 6.81 (d, J=8.6 Hz,
m.p. 170-171°C; H NMR (700 MHz, DMSO-d6): d 0.91 (d,
J=6.3 Hz, 3 H), 1.00 (d, J=6.3 Hz, 3 H), 4.83 (spt, J=6.2 Hz, 1
H), 7.35 (d, J=7.6 Hz, 1 H), 7.41 (t, J=7.5 Hz, 1 H), 7.43 - 7.47
(m, 1 H), 7.55 (d, J=7.8 Hz, 1 H); 13C{1H} NMR (176 MHz,
1
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The Journal of Organic Chemistry
methyl 5-(benzylcarbamoyl)-4-(4-methoxyphenyl)isoxazole-
DMSO-d6): d 20.6, 20.7, 70.5, 113.3, 127.1, 129.1, 129.4,
2
3
4
3-carboxylate (6cd). Yield 53 mg (73%), white solid, m.p. 68-
69°C; 1H NMR (700 MHz, DMSO-d6): d 3.79 (s, 3H), 3.82 (s,
3H), 4.40 (d, J=6.1 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 7.25 (d,
J=7.6 Hz, 3H), 7.31 (d, J=7.1 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H),
9.49 (t, J=6.1 Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d
42.3, 52.9, 55.1, 113.2, 118.6, 121.0, 127.0, 127.4, 128.3,
131.5, 138.4, 154.9, 155.8, 159.4, 159.6, 159.9; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C20H19N2O5 367.1288; Found
367.1290.
130.6, 131.2, 132.7, 147.6, 152.1, 160.0, 162.4; HRMS (ESI-
TOF) m/z: [M-H]- Calcd for C14H11ClNO5 308.0331; Found
308.0328.
5
6
7
isopropyl
4-(2-bromophenyl)-5-hydroxy-6-oxo-6H-1,2-
oxazine-3-carboxylate (5l). Yield 311 mg (44%), white solid,
m.p. 164-166°C; H NMR (700 MHz, DMSO-d6): d 0.90 (d,
1
J=6.3 Hz, 3 H), 0.99 (d, J=6.1 Hz, 3 H), 4.83 (spt, J=6.2 Hz, 1
H), 7.33 (dd, J=7.5, 1.6 Hz, 1 H), 7.36 (td, J=7.8, 1.7 Hz, 1 H),
7.45 (td, J=7.5, 1.1 Hz, 1 H), 7.71 (dd, J=8.0, 1.0 Hz, 1 H);
13C{1H} NMR (176 MHz, DMSO-d6): d 20.6, 20.7, 70.5,
115.1, 123.1, 127.6, 130.7, 131.3, 131.5, 132.2, 147.3, 152.1,
159.9, 162.5; HRMS (ESI-TOF) m/z: [M-H]- Calcd for
C14H11BrNO5 351.9826; Found 351.9828.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
methyl
4-(4-methoxyphenyl)-5-(morpholine-4-
carbonyl)isoxazole-3-carboxylate (6ce). Yield 38 mg (51%),
white solid, m.p. 137-139°C; 1H NMR (700 MHz, DMSO-d6):
d 3.11 (dd, J=16.8, 4.5 Hz, 4H), 3.48 - 3.53 (m, 2H), 3.53 -
3.58 (m, 2H), 3.80 (s, 3H), 3.85 (s, 3H), 7.03 (d, J=8.6 Hz,
2H), 7.31 (d, J=8.6 Hz, 2H); 13C{1H} NMR (176 MHz,
DMSO-d6): d 42.1, 46.4, 52.9, 55.2, 65.5, 65.6, 114.0, 118.2,
119.0, 130.7, 153.5, 156.6, 159.5, 159.7, 160.2; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C17H19N2O6 347.1238; Found
347.1239.
isopropyl 4-(2,3-dichlorophenyl)-5-hydroxy-6-oxo-6H-1,2-
oxazine-3-carboxylate (5m). Yield 206 mg (30%), white solid,
1
m.p. 161-162°C; H NMR (700 MHz, DMSO-d6): d 0.90 (d,
J=6.1 Hz, 3 H), 1.02 (d, J=6.3 Hz, 3 H), 4.84 (spt, J=6.2 Hz, 1
H), 7.32 (dd, J=7.6, 1.5 Hz, 1 H), 7.43 (t, J=7.9 Hz, 1 H), 7.69
(dd, J=8.1, 1.4 Hz, 1 H); 13C{1H} NMR (176 MHz, DMSO-
d6): d 20.6, 20.8, 70.5, 112.9, 128.3, 129.8, 130.8, 131.1,
131.8, 132.1, 147.8, 151.5, 159.9, 162.4; HRMS (ESI-TOF)
m/z: [M-H]- Calcd for C14H10Cl2NO5 341.9942; Found
341.9940.
General procedure of synthesis of isoxazole-3,5-bis-
carboxylic acid amides. 0.2 mmol (1 equiv) of corresponding
oxazinone and 0.4 mmol (2 equiv) of amine were dissolved in
0.5 ml of CHCl3. Resulted solution was stirred for 12 h in oil
bath at 70°C. All volatiles were removed in vacuo and the
residue was purified by column chromatography using CHCl3
– EtOH mixture as eluent (100:1, v:v for all compounds ex-
cept 8da-8de when 20:1, v:v mixture was used).
ethyl
5-(morpholine-4-carbonyl)-4-phenylisoxazole-3-
carboxylate (7ae). Yield 56 mg (85%), white solid, m.p. 88-
1
90°C; H NMR (700 MHz, DMSO-d6): d 1.20 (t, J=7.1 Hz,
3H), 3.05 (t, J=4.3 Hz, 2H), 3.12 - 3.17 (m, 2H), 3.46 - 3.51
(m, 2H), 3.53 - 3.56 (m, 2H), 4.31 (q, J=7.1 Hz, 2H), 7.33 -
7.41 (m, 2H), 7.43 - 7.52 (m, 3H); 13C{1H} NMR (75 MHz,
DMSO-d6): d 13.7, 42.2, 46.5, 62.1, 65.5, 65.6, 119.3, 126.4,
128.5, 129.0, 129.5, 153.8, 156.5, 158.9, 160.7; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C17H19N2O5 331.1288; Found
331.1288.
isopropyl
5-(methylcarbamoyl)-4-phenylisoxazole-3-
carboxylate (8aa). Yield 48 mg (84%), white solid, m.p. 150-
152°C; H NMR (700 MHz, DMSO-d6): d 1.13 (d, J=6.3 Hz,
1
methyl 4-(4-methoxyphenyl)-5-(methylcarbamoyl)isoxazole-
3-carboxylate (6ca). Yield 29 mg (50%), white solid, m.p.
120-122°C; 1H NMR (700 MHz, CDCl3): d 2.95 (d, J=4.8 Hz,
3H), 3.86 (s, 3H), 3.90 (s, 3H), 6.35 (br. s., 1H), 6.98 (m, 2H),
7.38 (m, 2H); 13C{1H} NMR (75 MHz, DMSO-d6): d 25.8,
52.9, 55.1, 113.2, 118.6, 120.8, 131.5, 154.9, 156.1, 159.4,
159.7, 159.8; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H15N2O5 291.0975; Found 291.0976.
6H), 2.73 (d, J=4.6 Hz, 3H), 5.06 (dt, J=12.4, 6.2 Hz, 1H),
7.34 - 7.47 (m, 5H), 8.92 (d, J=4.5 Hz, 1H); 13C{1H} NMR
(75 MHz, DMSO-d6): d 21.1, 25.8, 70.2, 120.9, 127.1, 127.7,
128.3, 130.0, 155.7, 155.9, 158.6, 160.0; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C15H17N2O4 289.1183; Found
289.1182.
isopropyl 4-phenyl-5-(pyrrolidine-1-carbonyl)isoxazole-3-
carboxylate (8ab). Yield 47 mg (72%), colorless oil; 1H NMR
(700 MHz, DMSO-d6): d 1.18 (d, J=6.3 Hz, 6H), 1.69 - 1.83
(m, 4H), 3.23 (t, J=6.7 Hz, 2H), 3.41 (t, J=6.9 Hz, 2H), 5.1
(spt, J=6.2 Hz, 1H), 7.35 - 7.43 (m, 2H), 7.45 - 7.47 (m, 3H);
13C{1H} NMR (75 MHz, DMSO-d6): d 21.1, 23.4, 25.2, 45.9,
47.0, 70.2, 119.3, 126.8, 128.2, 128.6, 129.4, 154.5, 155.6,
158.6, 161.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C18H21N2O4 329.1496; Found 329.1495.
4-(4-methoxyphenyl)-N3,N5-dimethylisoxazole-3,5-
dicarboxamide (6a*). Yield 16 mg (28%), white solid, m.p.
118-120°C; 1H NMR (700 MHz, CDCl3): d 2.92 (d, J=5.0 Hz,
3H), 2.95 (d, J=5.0 Hz, 3H), 3.85 (s, 3H), 6.22 (br. s., 1H),
6.64 (br. s., 1H), 6.98 (m, 2H), 7.42 (m, 2H); 13C{1H} NMR
(75 MHz, DMSO-d6): d 25.9 (2 C), 55.2, 113.4, 119.1, 119.4,
131.1, 156.6, 158.3, 158.7, 159.3, 159.5; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C14H16N3O4 290.1135; Found
290.1128.
isopropyl
5-(cyclohexylcarbamoyl)-4-phenylisoxazole-3-
methyl
4-(4-methoxyphenyl)-5-(pyrrolidine-1-
carboxylate (8ac). Yield 57 mg (80%), white solid, m.p. 90-
91°C; 1H NMR (700 MHz, DMSO-d6): d 1.05 - 1.12 (m, 1H),
1.14 (d, J=6.3 Hz, 6H), 1.20 - 1.31 (m, 4H), 1.55 (d, J=12.8
Hz, 1H), 1.66 (dd, J=9.4, 3.3 Hz, 2H), 1.73 (d, J=9.2 Hz, 2H),
3.59 - 3.72 (m, 1H), 5.07 (spt, J=6.3 Hz, 1H), 7.36 - 7.42 (m,
5H), 8.74 (d, J=8.0 Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-
d6): d 21.1, 24.6, 25.0, 31.8, 48.3, 70.2, 120.4, 127.1, 127.8,
128.4, 129.9, 154.8, 155.4, 158.6, 160.7; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C20H25N2O4 357.1809; Found
357.1806.
carbonyl)isoxazole-3-carboxylate (6cb). Yield 14 mg (21%),
white solid, m.p. 114-115°C; 1H NMR (700 MHz, DMSO-d6):
d 1.71 - 1.81 (m, 4H), 3.18 (t, J=6.7 Hz, 2H), 3.42 (t, J=6.9
Hz, 2H), 3.79 (s, 3H), 3.84 (s, 3H), 6.98 (d, J=8.8 Hz, 2H),
7.33 (d, J=8.6 Hz, 2H); 13C{1H} NMR (75 MHz, DMSO-d6): d
23.4, 25.2, 45.9, 46.9, 52.9, 55.1, 113.7, 118.5, 119.0, 130.6,
153.8, 155.8, 159.5, 159.7, 161.4; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C17H19N2O5 331.1288; Found 331.1292.
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2
3
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5
6
7
8
isopropyl
5-(benzylcarbamoyl)-4-phenylisoxazole-3-
TOF) m/z: [M+H]+ Calcd for C24H27N2O4 407.1965; Found
407.1963.
carboxylate (8ad). Yield 65 mg (89%), white solid, m.p. 136-
1
isopropyl
4-(4-isopropylphenyl)-5-(morpholine-4-
137°C; H NMR (700 MHz, DMSO-d6): d 1.14 (d, J=6.3 Hz,
carbonyl)isoxazole-3-carboxylate (8be). Yield 75 mg (97%),
white solid, m.p. 121-122°C; 1H NMR (700 MHz, DMSO-d6):
d 1.21 (d, J=6.3 Hz, 6H), 1.22 (d, J=6.9 Hz, 6H), 2.94 (dt,
J=13.8, 6.9 Hz, 1H), 3.03 - 3.09 (m, 2H), 3.13 - 3.19 (m, 2H),
3.47 - 3.52 (m, 2H), 3.52 - 3.57 (m, 2H), 5.12 (spt, J=6.3 Hz,
1H), 7.29 (m, 2H), 7.34 (m, 2H); 13C{1H} NMR (75 MHz,
DMSO-d6): d 21.2, 23.8, 33.2, 42.2, 46.5, 65.5, 65.6, 70.2,
119.2, 123.8, 126.4, 129.4, 149.4, 154.1, 156.6, 158.5; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C21H27N2O5 387.1914;
Found 387.1911.
6H), 4.40 (d, J=6.1 Hz, 2H), 5.07 (spt, J=6.2 Hz, 1H), 7.22 -
7.27 (m, 3H), 7.31 (t, J=7.5 Hz, 2H), 7.36 - 7.42 (m, 5H), 9.53
(t, J=6.0 Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.1,
42.3, 70.2, 121.1, 127.0, 127.0, 127.4, 127.7, 128.3, 128.4,
130.0, 138.4, 155.6, 158.5, 160.0; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C21H21N2O4 365.1496; Found 365.1496.
isopropyl 5-(morpholine-4-carbonyl)-4-phenylisoxazole-3-
carboxylate (8ae). Yield 67 mg (97%), colorless oil; 1H NMR
(700 MHz, DMSO-d6): d 1.20 (d, J=6.3 Hz, 6H), 3.06 (t, J=4.2
Hz, 2H), 3.12 - 3.18 (m, 2H), 3.45 - 3.52 (m, 2H), 3.52 - 3.57
(m, 2H), 5.13 (spt, J=6.2 Hz, 1H), 7.35 - 7.40 (m, 2H), 7.44 -
7.49 (m, 3H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.2,
42.2, 46.5, 65.5, 65.6, 70.3, 119.2, 126.5, 128.5, 128.9, 129.4,
154.1, 156.5, 158.5, 160.6; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C18H21N2O5 345.1445; Found 345.1443.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
isopropyl
4-(4-methoxyphenyl)-5-
(methylcarbamoyl)isoxazole-3-carboxylate (8ca). Yield 54 mg
(85%), white solid, m.p. 91-93°C; 1H NMR (700 MHz,
DMSO-d6): d 1.18 (d, J=6.3 Hz, 6H), 2.73 (d, J=4.8 Hz, 3H),
3.79 (s, 3H), 5.09 (dt, J=12.4, 6.2 Hz, 1H), 6.96 (d, J=8.8 Hz,
2H), 7.32 (d, J=8.8 Hz, 2H), 8.87 (d, J=4.3 Hz, 1H); 13C{1H}
NMR (75 MHz, DMSO-d6): d 21.2, 25.8, 55.2, 70.2, 113.2,
118.9, 120.6, 131.4, 155.7, 156.1, 158.8, 159.4, 159.7; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C16H19N2O5 319.1288;
Found 319.1289.
isopropyl
4-(4-isopropylphenyl)-5-
(methylcarbamoyl)isoxazole-3-carboxylate (8ba). Yield 63 mg
(96%), white solid, m.p. 101-102°C; H NMR (700 MHz,
1
DMSO-d6): d 1.13 (d, J=6.3 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H),
2.73 (d, J=4.6 Hz, 3H), 2.93 (quin, J=6.8 Hz, 1H), 5.06 (quin,
J=6.2 Hz, 1H), 7.27 (m, 2H), 7.30 (m, 2H), 8.92 (d, J=5.0 Hz,
1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.1, 23.8, 25.8,
33.3, 70.2, 120.8, 124.4, 125.6, 130.0, 148.6, 155.8, 156.0,
158.7, 159.8; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C18H23N2O4 331.1652; Found 331.1653.
isopropyl
4-(4-methoxyphenyl)-5-(pyrrolidine-1-
carbonyl)isoxazole-3-carboxylate (8cb). Yield 53 mg (74%),
1
white solid, m.p. 87-89°C; H NMR (700 MHz, DMSO-d6): d
1.22 (d, J=6.3 Hz, 6H), 1.71 - 1.77 (m, 2H), 1.77 - 1.82 (m,
2H), 3.21 (t, J=6.6 Hz, 2H), 3.42 (t, J=6.9 Hz, 2H), 3.79 (s,
3H), 5.13 (spt, J=6.2 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 7.32 (d,
J=8.9 Hz, 2H); 13C{1H} NMR (176 MHz, DMSO-d6): d 21.2,
23.4, 25.2, 45.9, 46.9, 55.1, 70.2, 113.7, 118.6, 118.9, 130.7,
154.4, 155.8, 158.7, 159.5, 161.2; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C19H23N2O5 359.1601; Found 359.1605.
isopropyl
4-(4-isopropylphenyl)-5-(pyrrolidine-1-
carbonyl)isoxazole-3-carboxylate (8bb). Yield 64 mg (86%),
white solid, m.p. 89-90°C; H NMR (700 MHz, DMSO-d6): d
1
1.19 (d, J=6.3 Hz, 6H) 1.22 (d, J=6.9 Hz, 6H) 1.72 - 1.82 (m,
4H) 2.92 (spt, J=6.9 Hz, 1H) 3.25 (t, J=6.7 Hz, 2H) 3.42 (t,
J=6.9 Hz, 2H) 5.11 (spt, J=6.2 Hz, 1H) 7.24 - 7.34 (m, 4H);
13C{1H} NMR (75 MHz, DMSO-d6): d 21.2, 23.5, 23.8, 25.3,
33.2, 46.0, 47.1, 70.3, 119.3, 124.1, 126.2, 129.4, 149.0,
154.6, 155.7, 158.7, 161.4; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C21H27N2O4 371.1965; Found 371.1966.
isopropyl
5-(cyclohexylcarbamoyl)-4-(4-
methoxyphenyl)isoxazole-3-carboxylate (8cc). Yield 52 mg
1
(68%), white solid, m.p. 124-126°C; H NMR (700 MHz,
DMSO-d6): d 1.04 - 1.15 (m, 1H), 1.18 (d, J=6.3 Hz, 6H), 1.20
- 1.32 (m, 4H), 1.55 (d, J=12.8 Hz, 1H), 1.67 (dd, J=9.3, 3.3
Hz, 2H), 1.69 - 1.78 (m, 2H), 3.62 - 3.72 (m, 1H), 3.79 (s,
3H), 5.09 (spt, J=6.2 Hz, 1H), 6.90 - 7.00 (m, 2H), 7.28 - 7.37
(m, 2H), 8.70 (d, J=7.8 Hz, 1H); 13C{1H} NMR (176 MHz,
DMSO-d6): d 21.2, 24.6, 25.0, 31.8, 48.3, 55.2, 70.2, 113.3,
118.9, 120.1, 131.3, 155.0, 155.4, 158.8, 159.4, 160.3; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C21H27N2O5 387.1914;
Found 387.1919.
isopropyl
5-(cyclohexylcarbamoyl)-4-(4-
isopropylphenyl)isoxazole-3-carboxylate (8bc). Yield 76 mg
(95%), viscous oil; H NMR (700 MHz, DMSO-d6): d 1.10
1
(dd, J=12.1, 2.8 Hz, 1H), 1.14 (d, J=6.1 Hz, 6H), 1.22 (d,
J=6.9 Hz, 6H), 1.23 - 1.29 (m, 4H), 1.51 - 1.57 (m, 1H), 1.61 -
1.67 (m, 2H), 1.70 - 1.76 (m, 2H), 2.93 (spt, J=6.9 Hz, 1H),
3.62 - 3.70 (m, 1H), 5.07 (spt, J=6.2 Hz, 1H), 7.27 (m, 2H),
7.30 (m, 2H), 8.69 (d, J=8.0 Hz, 1H); 13C{1H} NMR (75 MHz,
DMSO-d6): d 21.1, 23.8, 24.5, 25.0, 31.8, 33.3, 48.2, 70.2,
120.4, 124.4, 125.7, 129.8, 148.7, 154.8, 155.5, 158.7, 160.4;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H31N2O4
399.2278; Found 399.2276.
isopropyl
5-(benzylcarbamoyl)-4-(4-
methoxyphenyl)isoxazole-3-carboxylate (8cd). Yield 73 mg
(93%), white solid, m.p. 91-93°C; 1H NMR (700 MHz,
DMSO-d6): d 1.18 (d, J=6.3 Hz, 6H), 3.79 (s, 3H), 4.40 (d,
J=6.1 Hz, 2H), 5.09 (spt, J=6.3 Hz, 1H), 6.93 - 6.96 (m, 2H),
7.23 - 7.27 (m, 3H), 7.29 - 7.34 (m, 4H), 9.46 (t, J=6.1 Hz,
1H); 13C{1H} NMR (176 MHz, DMSO-d6): d 21.15, 42.28,
55.12, 70.18, 113.18, 118.76, 120.70, 126.94, 127.31, 128.26,
131.34, 138.38, 155.61, 155.74, 158.68, 159.41, 159.69;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H23N2O5
395.1601; Found 395.1604.
isopropyl
5-(benzylcarbamoyl)-4-(4-
isopropylphenyl)isoxazole-3-carboxylate (8bd). Yield 74 mg
(91%), white solid, m.p. 64-66°C; 1H NMR (700 MHz,
DMSO-d6): d 1.14 (d, J=6.1 Hz, 6H), 1.22 (d, J=7.0 Hz, 6H),
2.92 (spt, J=6.9 Hz, 1H), 4.40 (d, J=6.1 Hz, 2H), 5.07 (spt,
J=6.2 Hz, 1H), 7.22 - 7.28 (m, 5H), 7.28 - 7.34 (m, 4H), 9.50
(t, J=6.0 Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.1,
23.8, 33.3, 42.3, 70.2, 121.0, 124.3, 125.7, 127.0, 127.4,
128.3, 130.0, 138.4, 148.7, 155.7, 158.6, 159.8; HRMS (ESI-
isopropyl
4-(4-methoxyphenyl)-5-(morpholine-4-
carbonyl)isoxazole-3-carboxylate (8ce). Yield 68 mg (91%),
white solid, m.p. 129-130°C; 1H NMR (700 MHz, DMSO-d6):
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158.8, 159.4, 159.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C17H21N2O6 349.1394; Found 349.1392.
d 1.22 (d, J=6.3 Hz, 6H), 3.12 (d, J=4.8 Hz, 2H), 3.15 (d,
2
3
4
5
6
7
J=4.8 Hz, 2H), 3.51 (t, J=4.2 Hz, 2H), 3.55 (t, J=4.3 Hz, 2H),
3.80 (s, 3H), 5.14 (spt, J=6.3 Hz, 1H), 7.01-7.04 (m, 2H),
7.28-7.32 (m, 2H); 13C{1H} NMR (75 MHz, DMSO-d6): d
21.3, 42.1, 46.5, 55.3, 65.7, 70.2, 113.9, 118.3, 118.9, 130.8,
154.1, 156.7, 158.6, 159.7, 160.1; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C19H23N2O6 375.1551; Found 375.1554.
isopropyl
5-((4-hydroxybutyl)carbamoyl)-4-(4-
methoxyphenyl)isoxazole-3-carboxylate (8ck). Yield 67 mg
(89%), yellow oil; 1H NMR (700 MHz, DMSO-d6): d 1.18 (d,
J=6.3 Hz, 6H), 1.36 - 1.42 (m, 2H), 1.49 (quin, J=7.3 Hz, 2H),
3.15 - 3.22 (m, 2H), 3.34 - 3.41 (m, 2H), 3.79 (s, 3H), 4.37 (t,
J=5.1 Hz, 1H), 5.09 (quin, J=6.3 Hz, 1H), 6.96 (d, J=8.8 Hz,
2H), 7.32 (d, J=8.8 Hz, 2H), 8.90 (t, J=5.7 Hz, 1H); 13C{1H}
NMR (75 MHz, DMSO-d6): d 21.2, 25.4, 29.8, 55.2, 60.3,
70.2, 113.2, 118.9, 120.4, 131.4, 155.6, 155.6, 158.8, 159.4,
160.0; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H25N2O6
377.1707; Found 377.1704.
isopropyl
5-(dimethylcarbamoyl)-4-(4-
8
9
methoxyphenyl)isoxazole-3-carboxylate (8cf). Yield 57 mg
(86%), colorless oil; H NMR (700 MHz, DMSO-d6): d 1.22
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(d, J=6.3 Hz, 6H), 2.74 (s, 3H), 2.94 (s, 3H), 3.79 (s, 3H), 5.14
(quin, J=6.3 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.8
Hz, 2H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.3, 34.5,
37.2, 55.2, 70.2, 113.9, 118.5, 130.6, 154.2, 158.0, 158.7,
159.6, 160.9; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C17H21N2O5 333.1445; Found 333.1443.
isopropyl
4-(4-hydroxyphenyl)-5-
(methylcarbamoyl)isoxazole-3-carboxylate (8da). Yield 23 mg
1
(38%), yellow solid, m.p. 168-170°C; H NMR (700 MHz,
isopropyl
5-(diethylcarbamoyl)-4-(4-
DMSO-d6): d 1.18 (d, J=6.3 Hz, 6H), 2.74 (d, J=4.8 Hz, 3H),
5.10 (spt, J=6.2 Hz, 1H), 6.78 (m, 2H), 7.21 (m, 2H), 8.83 (d,
J=4.6 Hz, 1H), 9.63 (s, 1H); 13C{1H} NMR (75 MHz, DMSO-
d6): d 21.2, 25.8, 70.2, 114.6, 117.0, 120.8, 131.3, 155.8,
156.2, 157.7, 158.9, 159.4; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C15H17N2O5 305.1132; Found 305.1132.
methoxyphenyl)isoxazole-3-carboxylate (8cg). Yield 26 mg
(36%), white solid, m.p. 80-81°C; 1H NMR (700 MHz,
CDCl3): d 1.01 (t, J=7.1 Hz, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.33
(d, J=6.1 Hz, 6H), 3.12 (q, J=7.2 Hz, 2H), 3.49 (q, J=7.0 Hz,
2H), 3.83 (s, 3H), 5.26 (spt, J=6.3 Hz, 1H), 6.92 (m, J=8.8 Hz,
2H), 7.37 (m, J=8.8 Hz, 2H); 13C{1H} NMR (75 MHz,
DMSO-d6): d 12.2, 13.9, 21.2, 42.4, 55.1, 70.2, 113.8, 117.6,
118.3, 130.4, 154.0, 157.6, 158.7, 159.6, 161.3; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C19H25N2O5 361.1758; Found
361.1761.
isopropyl
4-(4-hydroxyphenyl)-5-(pyrrolidine-1-
carbonyl)isoxazole-3-carboxylate (8db). Yield 58 mg (85%),
white solid, m.p. 173-175°C; 1H NMR (700 MHz, DMSO-d6):
d 1.22 (d, J=6.3 Hz, 6H), 1.70 - 1.75 (m, 2H), 1.75 - 1.81 (m,
2H), 3.16 (t, J=6.7 Hz, 2H), 3.42 (t, J=7.0 Hz, 2H), 5.13 (spt,
J=6.3 Hz, 1H), 6.80 (m, 2H), 7.18 (m, 2H), 9.70 (s, 1H);
13C{1H} NMR (75 MHz, DMSO-d6): d 21.2, 23.5, 25.3, 45.9,
47.0, 70.3, 115.2, 116.8, 119.1, 130.6, 154.5, 156.0, 157.9,
158.9, 161.0; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C18H21N2O5 345.1445; Found 345.1443.
isopropyl
4-(4-methoxyphenyl)-5-(piperidine-1-
carbonyl)isoxazole-3-carboxylate (8ch). Yield 50 mg (67%),
white solid, m.p. 98-99°C; H NMR (700 MHz, DMSO-d6): d
1
1.05 - 1.12 (m, 2H), 1.23 (d, J=6.3 Hz, 6H), 1.44 (d, J=4.2 Hz,
2H), 1.49 (d, J=4.8 Hz, 2H), 3.05 - 3.12 (m, 2H), 3.52 (t, J=5.4
Hz, 2H), 3.79 (s, 3H), 5.14 (quin, J=6.3 Hz, 1H), 7.01 (d,
J=8.6 Hz, 2H), 7.30 (d, J=8.6 Hz, 2H); 13C{1H} NMR (75
MHz, DMSO-d6): d 21.2, 23.5, 24.9, 25.6, 42.3, 47.0, 55.2,
70.2, 113.9, 118.1, 118.4, 130.6, 154.0, 156.4, 158.7, 159.6,
161.0; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H25N2O5
373.1758; Found 373.1754.
isopropyl
5-(cyclohexylcarbamoyl)-4-(4-
hydroxyphenyl)isoxazole-3-carboxylate (8dc). Yield 31 mg
1
(42%), yellow solid, m.p. 157-159°C; H NMR (700 MHz,
DMSO-d6): d 1.07 - 1.12 (m, 1H), 1.18 (d, J=6.3 Hz, 6H), 1.23
- 1.27 (m, 4H), 1.55 (d, J=12.6 Hz, 1H), 1.66 (dd, J=8.2, 4.2
Hz, 2H), 1.69 - 1.76 (m, 2H), 3.61 - 3.72 (m, 1H), 5.10 (spt,
J=6.3 Hz, 1H), 6.78 (m, 2H), 7.20 (m, 2H), 8.62 (d, J=8.0 Hz,
1H), 9.64 (br. s., 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d
21.2, 24.5, 25.0, 31.8, 48.2, 70.2, 114.7, 117.0, 120.2, 131.2,
155.1, 155.5, 157.7, 159.0, 160.1; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C20H25N2O5 373.1758; Found 373.1759.
isopropyl
4-(4-methoxyphenyl)-5-((pyridin-2-
ylmethyl)carbamoyl)isoxazole-3-carboxylate (8ci). Yield 62
mg (79%), white solid, m.p. 143-145°C; H NMR (700 MHz,
1
DMSO-d6): d 1.18 (d, J=6.3 Hz, 6H), 3.78 (s, 3H), 4.51 (d,
J=6.0 Hz, 2H), 5.10 (quin, J=6.2 Hz, 1H), 6.95 (d, J=8.8 Hz,
2H), 7.25 - 7.29 (m, 2H), 7.35 (d, J=8.8 Hz, 2H), 7.74 (td,
J=7.7, 1.8 Hz, 1H), 8.47 - 8.50 (m, 1H), 9.43 (t, J=5.8 Hz,
1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.2, 44.2, 55.2,
70.2, 113.2, 118.7, 121.0, 121.1, 122.3, 131.5, 136.8, 148.9,
155.7, 155.9, 157.3, 158.7, 159.5, 159.5; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C21H22N3O5 396.1554; Found
396.1550.
isopropyl
5-(benzylcarbamoyl)-4-(4-
hydroxyphenyl)isoxazole-3-carboxylate (8dd).Yield 59 mg
1
(77%), white solid, m.p. 169-170°C; H NMR (700 MHz,
DMSO-d6): d 1.18 (d, J=6.3 Hz, 6H), 4.40 (d, J=6.1 Hz, 2H),
5.09 (spt, J=6.3 Hz, 1H), 6.76 (m, 2H), 7.20 (m, 2H), 7.22 -
7.27 (m, 3H), 7.28 - 7.34 (m, 2H), 9.42 (t, J=6.0 Hz, 1H), 9.63
(s, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.2, 42.3,
70.2, 114.6, 117.0, 121.0, 127.0, 127.3, 128.3, 131.3, 138.5,
155.8, 155.9, 157.8, 158.9, 159.5; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C21H21N2O5 381.1445; Found 381.1441.
isopropyl
5-((2-hydroxyethyl)carbamoyl)-4-(4-
methoxyphenyl)isoxazole-3-carboxylate (8cj). Yield 49 mg
(70%), yellow oil; 1H NMR (700 MHz, DMSO-d6): d 1.18 (d,
J=6.3 Hz, 6H), 3.27 (q, J=6.1 Hz, 2H), 3.47 (q, J=6.0 Hz, 2H),
3.79 (s, 3H), 4.71 (t, J=5.6 Hz, 1H), 5.09 (quin, J=6.3 Hz, 1H),
6.96 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 8.82 (t, J=5.4
Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.2, 41.7,
55.2, 59.2, 70.2, 113.2, 118.9, 120.6, 131.4, 155.7, 155.8,
isopropyl
4-(4-hydroxyphenyl)-5-(morpholine-4-
carbonyl)isoxazole-3-carboxylate (8de). Yield 23 mg (32%),
white solid, m.p. 203-204°C; 1H NMR (700 MHz, DMSO-d6):
d 1.22 (d, J=6.3 Hz, 6H), 3.05 - 3.15 (m, 4H), 3.47 - 3.57 (m,
2H), 5.14 (spt, J=6.2 Hz, 1H), 6.82-6.85 (m, 2H), 7.15-7.19
(m, 2H), 9.76 (s, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d
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21.3, 42.1, 46.5, 65.5, 65.6, 70.2, 115.4, 116.5, 119.1, 130.7,
Hz, 6H), 2.73 (d, J=4.8 Hz, 3H), 5.06 (spt, J=6.2 Hz, 1H),
154.1, 156.8, 158.1, 158.7, 159.8; HRMS (ESI-TOF) m/z:
7.22 - 7.28 (m, 2H), 7.46 - 7.50 (m, 2H), 9.04 (q, J=4.5 Hz,
1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.1, 25.8, 70.2,
114.8 (d, J=6.7 Hz), 115.1, 115.5 (d, J=14.9 Hz), 123.9 (d,
J=3.0 Hz), 130. 9 (d, J=8.2 Hz), 132.4 (d, J=2.2 Hz), 155.4,
155.7, 159.4 (d, J=245.9 Hz), 158.1, 160.8; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C15H16FN2O4 307.1089; Found
307.1086.
[M+H]+ Calcd for C18H21N2O6 361.1394; Found 361.1392.
isopropyl
4-(4-(dimethylamino)phenyl)-5-
(methylcarbamoyl)isoxazole-3-carboxylate (8ea). Yield 51 mg
1
(77%), orange solid, m.p. 122-124°C; H NMR (700 MHz,
DMSO-d6): d 1.21 (d, J=6.3 Hz, 6H), 2.73 (d, J=4.8 Hz, 3H),
2.93 (s, 6H), 5.11 (spt, J=6.2 Hz, 1H), 6.71 (d, J=8.8 Hz, 2H),
7.22 (d, J=8.8 Hz, 2H), 8.79 (d, J=4.5 Hz, 1H); 13C{1H} NMR
(75 MHz, DMSO-d6): d 21.3, 25.8, 39.9, 70.3, 111.3, 113.4,
120.8, 130.7, 155.8, 156.4, 159.0, 159.2; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C17H22N3O4 332.1605; Found
332.1605.
isopropyl
4-(2-fluorophenyl)-5-(pyrrolidine-1-
9
carbonyl)isoxazole-3-carboxylate (8fb). Yield 69 mg (99%),
colorless oil; 1H NMR (700 MHz, DMSO-d6): d 1.15 (d, J=6.3
Hz, 6H), 1.80 - 1.84 (m, 4H), 3.38 - 3.44 (m, 4H), 5.10 (spt,
J=6.2 Hz, 1H), 7.27 (td, J=7.5, 0.9 Hz, 1H), 7.29 - 7.33 (m,
1H), 7.46 (td, J=7.6, 1.6 Hz, 1H), 7.48 - 7.52 (m, 1H); 13C{1H}
NMR (75 MHz, DMSO-d6): d 21.1, 23.4, 25.5, 46.2, 47.2,
70.3, 114.0, 115.1 - 115.6, (m, 2C), 124.4 (d, J=3.7 Hz), 131.2
(d, J=8.2 Hz), 131. 8 (d, J=2.2 Hz), 155.0 (d, J=8.2 Hz), 157.
7 (d, J=245.9 Hz), 158.2, 162.4; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C18H20FN2O4 347.1402; Found 347.1397.
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isopropyl
4-(4-(dimethylamino)phenyl)-5-(pyrrolidine-1-
carbonyl)isoxazole-3-carboxylate (8eb). Yield 73 mg (98%),
orange solid, m.p. 98-100°C; 1H NMR (700 MHz, DMSO-d6):
d 1.25 (d, J=6.3 Hz, 6H), 1.69 - 1.76 (m, 2H), 1.76 - 1.82 (m,
2H), 2.93 (s, 6H), 3.15 (t, J=6.7 Hz, 2H), 3.43 (t, J=7.0 Hz,
2H), 5.15 (spt, J=6.2 Hz, 1H), 6.74 (d, J=8.8 Hz, 2H), 7.18 (d,
J=8.8 Hz, 2H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.3,
23.5, 25.3, 45.9, 46.9, 70.3, 111.7, 113.1, 119.1, 129.8, 150.4,
154.5, 156.3, 159.2, 160.5; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C20H26N3O4 372.1918; Found 372.1914.
isopropyl
5-(cyclohexylcarbamoyl)-4-(2-
fluorophenyl)isoxazole-3-carboxylate (8fc). Yield 60 mg
1
(80%), white solid, m.p. 121-122°C; H NMR (700 MHz,
DMSO-d6): d 1.09 (dt, J=12.4, 3.3 Hz, 1H), 1.13 (d, J=6.3 Hz,
6H), 1.20 - 1.33 (m, 4H), 1.56 (dd, J=9.8, 3.2 Hz, 1H), 1.65 -
1.77 (m, 4H), 3.62 - 3.69 (m, 1H), 5.07 (spt, J=6.2 Hz, 1H),
7.22 - 7.29 (m, 2H), 7.44 - 7.50 (m, 2H), 8.90 (d, J=7.9 Hz,
1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.1, 24.7, 25.0,
31.8, 48.4, 70.2, 114.6, 115.0 (d, J=20.9 Hz), 115.5 (d, J=14.9
Hz), 123.9 (d, J=3.7 Hz), 130.9 (d, J=8.2 Hz), 132.2 (d, J=1.5
Hz), 154.3, 155.6, 159.4 (d, J=245.1 Hz), 158.2, 161.3; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C20H24FN2O4 375.1715;
Found 375.1711.
isopropyl
5-(cyclohexylcarbamoyl)-4-(4-
(dimethylamino)phenyl)isoxazole-3-carboxylate (8ec). Yield
1
38 mg (48%), orange solid, m.p. 129-130°C; H NMR (700
MHz, DMSO-d6): d 1.11 (dd, J=12.6, 3.5 Hz, 1H), 1.21 (d,
J=6.3 Hz, 6H), 1.23 - 1.29 (m, 4H), 1.55 (dd, J=13.6, 3.9 Hz,
1H), 1.63 - 1.70 (m, 2H), 1.71 - 1.79 (m, 2H), 2.93 (s, 6H),
3.64 - 3.72 (m, 1H), 5.12 (quin, J=6.3 Hz, 1H), 6.72 (d, J=8.9
Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 8.62 (d, J=7.7 Hz, 1H);
13C{1H} NMR (75 MHz, DMSO-d6): d 21.3, 24.5, 25.0, 31.8,
39.9, 48.2, 70.3, 111.4, 113.4, 120.3, 130.5, 150.3, 155.3,
155.5, 159.3, 159.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H30N3O4 400.2231; Found 400.2230.
isopropyl 5-(benzylcarbamoyl)-4-(2-fluorophenyl)isoxazole-
3-carboxylate (8fd). Yield 72 mg (94%), white solid, m.p.
1
143-145°C; H NMR (700 MHz, DMSO-d6): d 1.13 (d, J=6.3
Hz, 6H), 4.40 (d, J=6.1 Hz, 2H), 5.07 (spt, J=6.2 Hz, 1H),
7.22 - 7.28 (m, 5H), 7.29 - 7.34 (m, 2H), 7.45 - 7.51 (m, 2H),
9.66 (t, J=6.0 Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d
21.0, 42.3, 70.2, 114.9, 115.0 (d, J=13.0 Hz), 115.4 (d, J=15.4
Hz), 123.8 (d, J=3.3 Hz), 127.0, 127.3, 128.3, 130.9 (d, J=8.4
Hz), 132.3 (d, J=2.0 Hz), 138.3, 155.1, 155.7, 158.0, 159.4 (d,
J=245.6 Hz), 160.8; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C21H20FN2O4 383.1402; Found 383.1400.
isopropyl
5-(benzylcarbamoyl)-4-(4-
(dimethylamino)phenyl)isoxazole-3-carboxylate (8ed). Yield
1
57 mg (70%), orange solid, m.p. 93-95°C; H NMR (700
MHz, DMSO-d6): d 1.21 (d, J=6.3 Hz, 6H), 2.93 (s, 6H), 4.41
(d, J=6.1 Hz, 2H), 5.12 (spt, J=6.3 Hz, 1H), 6.70 (d, J=8.8 Hz,
2H), 7.20 - 7.27 (m, 5H), 7.31 (t, J=7.5 Hz, 2H), 9.38 (t, J=6.0
Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.3, 39.9,
42.3, 70.3, 111.3, 113.3, 121.1, 127.0, 127.4, 128.3, 130.7,
138.5, 150.3, 155.8, 156.1, 159.0, 159.2; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C23H26N3O4 408.1918; Found
408.1914.
isopropyl
4-(2-fluorophenyl)-5-(morpholine-4-
carbonyl)isoxazole-3-carboxylate (8fe). Yield 72 mg (99%),
colorless oil; 1H NMR (700 MHz, DMSO-d6): d 1.17 (d, J=6.3
Hz, 6H), 3.25 (br. s., 4H), 3.55 (d, J=3.3 Hz, 4H), 5.11 (spt,
J=6.2 Hz, 1H), 7.29 - 7.37 (m, 2H), 7.44 (td, J=7.6, 1.6 Hz,
1H), 7.51 - 7.56 (m, 1H); 13C{1H} NMR (75 MHz, DMSO-d6):
d 21.1, 42.2, 46.6, 65.6, 65.8, 70.3, 113.5, 114.7 (d, J=14.9
Hz), 115.6 (d, J=20.9 Hz), 124.7 (d, J=3.7 Hz), 131.4 - 131.7
(m), 154.6, 156.0, 159.3 (d, J=246.6 Hz), 158.1, 161.5; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C18H20FN2O5 363.1351;
Found 363.1350.
isopropyl
4-(4-(dimethylamino)phenyl)-5-(morpholine-4-
carbonyl)isoxazole-3-carboxylate (8ee). Yield 61 mg (79%),
1
orange oil; H NMR (700 MHz, DMSO-d6): d 1.25 (d, J=6.3
Hz, 6H), 2.94 (s, 6H), 3.11 (s, 4H), 3.52 (t, J=4.5 Hz, 2H),
3.56 (t, J=4.5 Hz, 2H), 5.15 (spt, J=6.2 Hz, 1H), 6.77 (d, J=8.8
Hz, 2H), 7.16 (d, J=8.6 Hz, 2H); 13C{1H} NMR (75 MHz,
DMSO-d6): d 21.3, 39.8, 42.1, 46.5, 65.5, 65.6, 70.2, 111.8,
112.8, 119.3, 129.9, 150.5, 154.1, 157.0, 159.0, 159.3; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C20H26N3O5 388.1867;
Found 388.1864.
isopropyl
5-(methylcarbamoyl)-4-(3-
(trifluoromethyl)phenyl)isoxazole-3-carboxylate (8ga). Yield
1
52 mg (73%), white solid, m.p. 129-131°C; H NMR (700
isopropyl 4-(2-fluorophenyl)-5-(methylcarbamoyl)isoxazole-
3-carboxylate (8fa). Yield 50 mg (82%), white solid, m.p.
MHz, DMSO-d6): d 1.10 (d, J=6.3 Hz, 6H), 2.73 (d, J=4.8 Hz,
3H), 5.04 (spt, J=6.3 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.71 (d,
1
134-136°C; H NMR (700 MHz, DMSO-d6): d 1.12 (d, J=6.3
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J=7.8 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.82 (s, 1H), 9.02 (d,
7.57 (m, 2H), 7.99 (m, 2H), 8.98 (d, J=4.6 Hz, 1H); 13C{1H}
NMR (75 MHz, DMSO-d6): d 20.4, 20.8, 25.7, 69.6, 119.3,
124.9, 125.1, 125.6, 125.8, 126.4, 128.2, 128.3, 128.6, 131.9,
132.8, 155.5, 156.6, 158.0, 161.1; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C19H19N2O4 339.1339; Found 339.1337.
J=4.6 Hz, 1H); 13C{1H} NMR (176 MHz, DMSO-d6): d 21.0,
25.7, 70.0, 120.0, 123.9 (q, J=190.1 Hz), 124.8 - 125.0 (m),
127.0 (q, J=4.0 Hz), 128.3 (q, J=31.8 Hz), 128.5, 128.7, 134.4,
155.4, 155.5, 158.1, 160.3; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C16H16F3N2O4 357.1057; Found 357.1059.
isopropyl
4-(naphthalen-1-yl)-5-(pyrrolidine-1-
isopropyl
5-(pyrrolidine-1-carbonyl)-4-(3-
carbonyl)isoxazole-3-carboxylate (8hb). Yield 72 mg (95%),
1
(trifluoromethyl)phenyl)isoxazole-3-carboxylate (8gb). Yield
white solid, m.p. 93-94°C; H NMR (700 MHz, DMSO-d6): d
1
0.65 (d, J=5.1 Hz, 3H), 0.83 (d, J=5.1 Hz, 3H), 1.67-1.83 (m,
4H), 3.28 - 3.35 (m, 3H), 3.51 (br. s., 1H), 4.79 (spt, J=6.2 Hz,
1H), 7.46 - 7.51 (m, 2H), 7.51 - 7.57 (m, 3H), 8.01 (t, J=8.7
Hz, 2H); 13C{1H} NMR (75 MHz, DMSO-d6): d 20.4, 20.9,
23.3, 25.4, 46.1, 47.2, 69.6, 118.3, 124.7, 125.1, 125.2, 126.0,
126.6, 128.3, 129.0, 131.7, 132.9, 155.2, 155.8, 158.0, 162.6;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H23N2O4
379.1652; Found 379.1653.
31 mg (39%), viscous oil; H NMR (700 MHz, DMSO-d6): d
9
1.14 (d, J=6.3 Hz, 6H), 1.78 - 1.84 (m, 4H), 3.39 - 3.44 (m,
4H), 5.09 (spt, J=6.2, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.72 (d,
J=7.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.83 (s, 1H); 13C{1H}
NMR (176 MHz, DMSO-d6): d 21.0, 23.3, 25.4, 46.2, 47.2,
70.1, 119.1, 124.0 (q, J=272.4 Hz), 125.1 (q, J=3.3 Hz), 126.5
(d, J=4.0 Hz), 128.5, 128.7 (q, J=31.8 Hz), 129.0, 133.9,
154.5, 155.1, 158.1, 162.1; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C19H20F3N2O4 397.1370; Found 397.1370.
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isopropyl
5-(cyclohexylcarbamoyl)-4-(naphthalen-1-
isopropyl
5-(cyclohexylcarbamoyl)-4-(3-
yl)isoxazole-3-carboxylate (8hc). Yield 62 mg (77%), white
1
(trifluoromethyl)phenyl)isoxazole-3-carboxylate (8gc). Yield
solid, m.p. 146-148°C; H NMR (700 MHz, DMSO-d6): d
1
58 mg (68%), white solid, m.p. 120-122°C; H NMR (700
0.66 (d, J=6.1 Hz, 3H), 0.80 (d, J=6.1 Hz, 3H), 1.01 - 1.10 (m,
1H), 1.13 - 1.21 (m, J=12.5, 12.5, 12.4, 3.3, 3.3 Hz, 2H), 1.24
- 1.29 (m, 2H), 1.48 - 1.54 (m, 1H), 1.59 (d, J=6.9 Hz, 2H),
1.65 (d, J=12.0 Hz, 2H), 3.52 - 3.60 (m, 1H), 4.79 (spt, J=6.2
Hz, 1H), 7.42 - 7.50 (m, 3H), 7.50 - 7.57 (m, 2H), 8.00 (dd,
J=8.2, 5.1 Hz, 2H), 8.72 (d, J=8.0 Hz, 1H); 13C{1H} NMR (75
MHz, DMSO-d6): d 20.5, 20.8, 24.5, 25.0, 31.8, 48.2, 69.6,
119.1, 124.8, 125.1, 125.5, 125.9, 126.4, 128.2, 128.3, 128.7,
131.8, 132.9, 154.3, 156.4, 158.0, 161.5; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C24H27N2O4 407.1965; Found
407.1960.
MHz, DMSO-d6): d 1.04 - 1.10 (m, 1H), 1.11 (d, J=6.3 Hz,
6H), 1.19 - 1.34 (m, 4H), 1.55 (d, J=13.0 Hz, 1H), 1.67 (d,
J=13.0 Hz, 2H), 1.72 (d, J=10.3 Hz, 2H), 3.61 - 3.69 (m, 1H),
5.05 (spt, J=6.2 Hz, 1H), 7.64 (t, J=7.7 Hz, 1H), 7.70 (d, J=7.6
Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.81 (s, 1H), 8.89 (d, J=8.0
Hz, 1H); 13C{1H} NMR (176 MHz, DMSO-d6): d 21.0, 24.6,
24.9, 31.7, 48.3, 70.1, 119.7, 124.9 (q, J=272.4 Hz), 124.9 -
125.0 (m), 126.7 - 126.9 (m), 128.3 (q, J=31.8 Hz) 128.6,
128.7, 134.3, 154.4, 155.1, 158.1, 161.0; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C21H24F3N2O4 425.1683; Found
425.1682.
isopropyl
5-(benzylcarbamoyl)-4-(naphthalen-1-
yl)isoxazole-3-carboxylate (8hd). Yield 65 mg (79%), white
isopropyl
5-(benzylcarbamoyl)-4-(3-
1
(trifluoromethyl)phenyl)isoxazole-3-carboxylate (8gd) Yield
solid, m.p. 158-160°C; H NMR (700 MHz, DMSO-d6): d
1
0.66 (d, J=6.1 Hz, 3H), 0.80 (d, J=6.1 Hz, 3H), 4.33 (d, J=6.3
Hz, 2H), 4.79 (spt, J=6.2 Hz, 1H), 7.17 (d, J=7.2 Hz, 2H),
7.19 - 7.23 (m, 1H), 7.24 - 7.29 (m, 2H), 7.45 (d, J=3.6 Hz,
2H), 7.48 (dd, J=7.0, 1.0 Hz, 1H), 7.51 - 7.56 (m, 2H), 8.00
(dd, J=8.0, 5.1 Hz, 2H), 9.54 (t, J=6.1 Hz, 1H); 13C{1H} NMR
(75 MHz, DMSO-d6): d 21.2, 42.3, 70.3, 114.6, 117.0, 121.0,
127.0, 127.3, 128.3, 131.4, 138.5, 155.8, 155.9, 157.8, 158.9,
159.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H23N2O4
415.1652; Found 415.1654.
79 mg (92%), white solid, m.p. 126-128°C; H NMR (700
MHz, DMSO-d6): d 1.10 (d, J=6.1 Hz, 6H), 4.40 (d, J=6.1 Hz,
2H), 5.05 (spt, J=6.2 Hz, 1H), 7.21 - 7.28 (m, 3H), 7.30 (t,
J=7.4 Hz, 2H), 7.63 (t, J=7.8 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H),
7.77 (d, J=7.9 Hz, 1H), 7.82 (s, 1H), 9.63 (t, J=6.0 Hz, 1H);
13C{1H} NMR (176 MHz, DMSO-d6): d 21.0, 42.3, 70.1,
120.3, 124.1 (q, J=272.0 Hz), 125.0 (q, J=3.7 Hz), 126.9 (d,
J=4.0 Hz), 127.0, 127.3, 128.3, 128.6, 128.7, 134.4, 138.3,
155.3, 155.4, 158.0, 160.4; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C22H20F3N2O4 433.1370; Found 433.1367.
isopropyl
5-(morpholine-4-carbonyl)-4-(naphthalen-1-
yl)isoxazole-3-carboxylate (8he). Yield 78 mg (99%), white
isopropyl
5-(morpholine-4-carbonyl)-4-(3-
1
solid, m.p. 95-97°C; H NMR (700 MHz, DMSO-d6): d 0.72
(trifluoromethyl)phenyl)isoxazole-3-carboxylate (8ge). Yield
76 mg (92%), white solid, m.p. 94-95°C; 1H NMR (700 MHz,
DMSO-d6): d 1.17 (d, J=6.3 Hz, 6H), 3.16 (br. s., 2H), 3.26
(br. s., 2H), 3.49 (br. s., 2H), 3.54 (br. s., 2H), 5.11 (spt, J=6.2
Hz, 1H), 7.69 - 7.73 (m, 2H), 7.81 - 7.85 (m, 2H); 13C{1H}
NMR (176 MHz, DMSO-d6): d 21.1, 42.2, 46.5, 65.5, 65.8,
70.2, 118.4, 123.9 (q, J=272.1 Hz), 125.5 (q, J=3.5 Hz), 126.4
- 126.5 (m), 128.0, 129.0 (q, J=31.8 Hz), 129.5, 133.8, 154.0,
156.1, 158.0, 161.2; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C19H20F3N2O5 413.1319; Found 413.1314.
(d, J=5.5 Hz, 3H), 0.88 (d, J=5.5 Hz, 3H), 2.88 (br. s., 1H),
2.99 (br. s., 1H), 3.22 (br. s., 1H), 3.32 (br. s., 3H), 3.40 (br. s.,
1H), 3.43 (br. s., 1H), 4.80 - 4.87 (spt, J=6.3, 1H), 7.48 (d,
J=6.3 Hz, 1H), 7.49 - 7.53 (m, 1H), 7.55 - 7.61 (m, 3H), 8.02
(d, J=7.9 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H); 13C{1H} NMR (75
MHz, DMSO-d6): d 20.5, 20.9, 42.1, 46.5, 65.5, 65.7, 69.7,
117.6, 124.3, 124.5, 125.2, 126.2, 126.7, 128.4, 129.3, 131.5,
132.9, 155.4, 156.2, 157.9, 161.7; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C22H23N2O5 395.1601; Found 395.1598.
isopropyl 5-(methylcarbamoyl)-4-(thiophen-2-yl)isoxazole-
3-carboxylate (8ia). Yield 46 mg (78%), white solid, m.p.
isopropyl
5-(methylcarbamoyl)-4-(naphthalen-1-
yl)isoxazole-3-carboxylate (8ha). Yield 51 mg (75%), white
1
1
123-125°C; H NMR (700 MHz, DMSO-d6): d 1.23 (d, J=6.3
solid, m.p. 160-162°C; H NMR (700 MHz, DMSO-d6): d
Hz, 6H), 2.76 (d, J=4.6 Hz, 3H), 5.15 (spt, J=6.3 Hz, 1H),
7.12 (dd, J=5.1, 3.6 Hz, 1H), 7.31 (dd, J=3.6, 1.2 Hz, 1H),
0.64 (d, J=6.3 Hz, 3H), 0.79 (d, J=6.3 Hz, 3H), 2.68 (d, J=4.8
Hz, 3H), 4.77 (spt, J=6.2 Hz, 1H), 7.41 - 7.48 (m, 3H), 7.50 -
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7.69 (dd, J=5.1, 1.2 Hz, 1H), 8.99 (d, J=4.2 Hz, 1H); 13C{1H}
DMSO-d6): d 21.3, 55.1, 69.6, 112.9, 116.9, 121.1, 131.3,
NMR (75 MHz, DMSO-d6): d 21.2, 25.9, 70.7, 113.8, 125.9,
126.9, 128.4, 130.2, 155.5, 155.8, 158.7, 160.1; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C13H15N2O4S 295.0747; Found
295.0746.
155.0, 158.7, 159.3, 159.9, 165.9; HRMS (ESI-TOF) m/z: [M-
H]- Calcd for C15H14NO6 304.0827; Found 304.0828.
isopropyl
5-((2-methoxy-2-oxoethyl)carbamoyl)-4-(4-
methoxyphenyl)isoxazole-3-carboxylate (10). 31 mg (0.1
mmol) of 9 was dissolved in 10 ml of CH3CN, then 49 mg
(0.13 mmol) of HBTU, 17.5 mg (0.14 mmol) of methyl
glycinate hydrochloride and 39 mg (0.3 mmol) of DIPEA were
added and the resulted mixture was stirred for 24 h. Then the
solution was evaporated to one quarter of the original volume,
100 ml of EtOAc was added, the resulted organic solution was
washed with 30 ml of water, 35 ml of 3% HCl, 30 ml of water,
2 times with 35 ml of saturated aqueous NaHCO3, 30 ml of
water and 3 times with 30 ml of brine. Organic layer was dried
over anhydrous Na2SO4, all volatiles were removed in vacuo.
The residue was purified with column chromatography using
CHCl3 – EtOH mixture as eluent (20:1, v:v). Yield 31 mg
isopropyl
5-(pyrrolidine-1-carbonyl)-4-(thiophen-2-
yl)isoxazole-3-carboxylate (8ib). Yield 53 mg (80%), colorless
oil; 1H NMR (700 MHz, DMSO-d6): d 1.27 (d, J=6.3 Hz, 6H),
1.76 - 1.81 (m, 2H), 1.81 - 1.86 (m, 2H), 3.25 (t, J=6.6 Hz,
2H), 3.46 (t, J=6.9 Hz, 2H), 5.19 (spt, J=6.2 Hz, 1H), 7.15 (dd,
J=5.1, 3.6 Hz, 1H), 7.31 (dd, J=3.6, 1.2 Hz, 1H), 7.71 (dd,
J=5.1, 1.1 Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d
21.3, 23.5, 25.3, 46.1, 47.0, 70.7, 112.5, 125.8, 127.5, 128.6,
129.7, 154.1, 155.4, 158.6, 161.6; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C16H19N2O4S 335.1060; Found 335.1059.
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
isopropyl
5-(cyclohexylcarbamoyl)-4-(thiophen-2-
yl)isoxazole-3-carboxylate (8ic). Yield 46 mg (64%), white
1
1
(83%), colorless oil; H NMR (700 MHz, DMSO-d6): d 1.18
solid, m.p. 102-103°C; H NMR (700 MHz, DMSO-d6): d
(d, J=6.3 Hz, 6H), 3.64 (s, 3H), 3.79 (s, 3H), 3.98 (d, J=5.7
Hz, 2H), 5.10 (spt, J=6.2 Hz, 1H), 6.96 (d, J=8.6 Hz, 2H),
7.34 (d, J=8.8 Hz, 2H), 9.37 (t, J=5.8 Hz, 1H); 13C{1H} NMR
(75 MHz, DMSO-d6): d 21.2, 40.7, 51.9, 55.2, 70.3, 113.2,
118.6, 121.5, 131.5, 155.8, 156.0, 158.6, 158.8, 159.5, 169.4;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H21N2O7
377.1343; Found 377.1342.
1.08 - 1.16 (m, 1H), 1.24 (d, J=6.1 Hz, 6H), 1.27 (t, J=10.4
Hz, 4H), 1.56 (d, J=12.2 Hz, 1H), 1.64 - 1.73 (m, 2H), 1.73 -
1.81 (m, 2H), 3.66 - 3.74 (m, 1H), 5.07 - 5.21 (m, J=6.4, 6.3,
6.3, 6.3, 6.3, 6.3 Hz, 1H), 7.12 (dd, J=5.1, 3.6 Hz, 1H), 7.30
(dd, J=3.6, 1.2 Hz, 1H), 7.69 (dd, J=5.1, 1.0 Hz, 1H), 8.86 (d,
J=7.9 Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.2,
24.5, 25.0, 31.8, 48.4, 70.7, 113.2, 126.0, 127.0, 128.4, 130.0,
154.8, 155.2, 158.7, 160.9; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C18H23N2O4S 363.1373; Found 363.1368.
isopropyl
4-(4-methoxyphenyl)-5-
(phenylcarbamoyl)isoxazole-3-carboxylate (11). 152 mg (0.5
mmol) of 9 was dissolved in 30 ml of CH2Cl2, then 190 mg
(1.5 mmol) of oxalyl chloride and one drop of DMF were add-
ed. Resulted solution was stirred at RT for 3 h, and then all
volatiles were removed in vacuo. Residue was dissolved in 30
ml of CH2Cl2, 70 mg of aniline (0.75 mmol) and 129 mg (1
mmol) of DIPEA were added and resulted mixture was stirred
for 18 h. 200 ml of EtOAc was added, resulted organic solu-
tion was washed with 40 ml of water, 50 ml of 3% HCl, 40 ml
of water, 2 times with 50 ml of saturated aqueous NaHCO3, 40
ml of water and 3 times with 40 ml of brine. Organic layer was
dried over anhydrous Na2SO4, all volatiles were removed in
vacuo. The residue was purified with column chromatography
using hexane – EtOAc mixture as eluent (3:1, v:v). Yield 141
mg (74%), viscous oil; 1H NMR (700 MHz, DMSO-d6): d 1.20
(d, J=6.3 Hz, 6H), 3.80 (s, 3H), 5.12 (spt, J=6.3, 1H), 6.99 (d,
J=8.6 Hz, 2H), 7.15 (t, J=7.4 Hz, 1H), 7.33 - 7.42 (m, 4H),
7.69 (d, J=8.0 Hz, 2H), 10.86 (s, 1H); 13C{1H} NMR (75
MHz, DMSO-d6): d 21.2, 55.2, 70.4, 113.3, 118.7, 120.5,
121.4, 124.7, 128.8, 131.3, 137.7, 154.2, 155.7, 158.7, 159.5,
159.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H21N2O5
381.1445; Found 381.1444.
4-(4-methoxyphenyl)-5-(pyrrolidine-1-carbonyl)isoxazole-3-
carboxylic acid (12). 358 mg (1 mmol) of 8cb was dissolved
in 10 ml of iPrOH, then solution of 160 mg (4 mmol) of
NaOH in 10 ml of water was added. Resulted mixture was
stirred for 18 h. All volatiles were removed in vacuo, the resi-
due was dissolved in 20 ml of water. 1 ml of conc. aqueous
HCl was added and the resulted solution was extracted 3 times
with 75 ml of EtOAc. Combined organic layers were washed 3
times with 15 ml of brine, dried over anhydrous Na2SO4 and
then all volatiles were removed in vacuo. Resulted white solid
was washed with 5 ml of Et2O and dried in vacuo. Yield 265
isopropyl 5-(benzylcarbamoyl)-4-(thiophen-2-yl)isoxazole-
3-carboxylate (8id). Yield 63 mg (85%), white solid, m.p.
1
128-130°C; H NMR (700 MHz, DMSO-d6): d 1.23 (d, J=6.3
Hz, 6H), 4.43 (d, J=6.0 Hz, 2H), 5.15 (spt, J=6.2 Hz, 1H),
7.11 (dd, J=5.1, 3.7 Hz, 1H), 7.23 - 7.29 (m, 3H), 7.30 (dd,
J=3.6, 1.2 Hz, 1H), 7.32 (t, J=7.5 Hz, 2H), 7.70 (dd, J=5.1, 1.1
Hz, 1H), 9.59 (t, J=6.0 Hz, 1H); 13C{1H} NMR (75 MHz,
DMSO-d6): d 21.2, 42.4, 70.7, 114.1, 125.9, 127.0, 127.1,
127.4, 128.4, 128.5, 130.3, 138.3, 155.6, 158.6, 160.1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C19H19N2O4S 371.1060;
Found 371.1059.
isopropyl
5-(morpholine-4-carbonyl)-4-(thiophen-2-
yl)isoxazole-3-carboxylate (8ie). Yield 65 mg (93%), colorless
oil; 1H NMR (700 MHz, DMSO-d6): d 1.27 (d, J=6.3 Hz, 6H),
3.21 (t, J=4.3 Hz, 2H), 3.25 (t, J=4.4 Hz, 2H), 3.59 (dd,
J=16.1, 4.9 Hz, 4H), 5.19 (spt, J=6.3 Hz, 1H), 7.17 (dd, J=5.1,
3.7 Hz, 1H), 7.29 (dd, J=3.6, 1.2 Hz, 1H), 7.73 (dd, J=5.1, 1.1
Hz, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 21.3, 42.2,
46.5, 65.5, 65.8, 70.6, 112.6, 125.4, 127.7, 128.7, 129.8,
153.8, 156.3, 158.4, 160.6; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C16H19N2O5S 351.1009; Found 351.1008.
3-(isopropoxycarbonyl)-4-(4-methoxyphenyl)isoxazole-5-
carboxylic acid (9). 305 mg (1 mmol) of 5c was dissolved in
mixture of 30 ml of water and 30 ml of iPrOH, then 4.5 ml of
conc. aq. HCl was added. Resulted mixture was refluxed for 4
h on a hot plate magnetic stirrer and cooled to room tempera-
ture. All volatiles were removed in vacuo and the residue was
purified with column chromatography using CHCl3 – EtOH
mixture as eluent (9:1, v:v). Yield 199 mg (59%), colorless
1
viscous oil; H NMR (700 MHz, DMSO-d6): d 1.17 (d, J=6.3
Hz, 6H), 3.76 (s, 3H), 5.06 (spt, J=6.2 Hz, 1H), 6.89 (d, J=8.8
Hz, 2H), 7.31 (d, J=8.8 Hz, 2H); 13C{1H} NMR (75 MHz,
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4-(4-methoxyphenyl)-5-(phenylcarbamoyl)isoxazole-3-
mg (84%), white solid, m.p. 260°C with decomposition; Major
2
3
1
carboxylic acid (15). 76 mg (0.2 mmol) of 11 was dissolved in
the mixture of 1 ml of water and 1 ml of iPrOH. 32 mg (0.8
mmol) of NaOH was added and the resulted mixture was
stirred for 1 h. Then 20 ml of water was added and the solution
was acidified to pH=1 with 3% HCl. Mixture was extracted 3
times with 50 ml of EtOAc, combined organic layers were
washed 3 times with 30 ml of brine, dried over Na2SO4. All
volatiles were removed in vacuo. Yield 59 mg (87%), color-
form (~75%): H NMR (700 MHz, DMSO-d6), d ppm: 1.84 -
1.93 (m, 4H), 3.40 (t, J=6.4 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H),
3.76 (s, 3H), 6.97 (d, J=9.0 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H);
Minor form (~25%): 1H NMR (700 MHz, DMSO-d6): d 1.59 -
1.70 (m, 4H), 3.08 (t, J=6.7 Hz, 2H), 3.23 (t, J=7.0 Hz, 2H),
3.74 (s, 3H), 6.93 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H);
13C{1H} NMR (both forms) (176 MHz, DMSO-d6): d 23.5,
23.8, 25.0, 25.3, 44.9, 45.1, 46.2, 46.7, 55.1, 114.0, 114.3,
118.9, 123.0, 123.4, 124.2, 128.3, 128.4, 158.2, 158.7, 159.2,
159.4, 159.7, 161.1, 161.3, 161.4, 161.8, 162.2; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C16H17N2O5 317.1132; Found
317.1136.
4
5
6
7
8
9
1
less oil; Major form: H NMR (700 MHz, DMSO-d6): d 3.78
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(s, 3H), 6.95 - 7.03 (m, 2H), 7.15 (t, J=7.4 Hz, 1H), 7.32 - 7.41
(m, 3H), 7.66 - 7.72 (m, 3H), 10.83 (br. s., 1H); 13C{1H} NMR
(75 MHz, DMSO-d6): d 55.2, 114.0, 114.2, 119.2, 119.8,
119.9, 123.9, 124.4, 128.7, 128.9, 138.1, 158.3, 160.4, 161.8;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H15N2O5
339.0975; Found 339.0977.
4-(4-methoxyphenyl)-N-phenyl-5-(pyrrolidine-1-
carbonyl)isoxazole-3-carboxamide (13). 32 mg (0.1 mmol) of
12 was dissolved in 10 ml of CH2Cl2, then 38 mg (0.3 mmol)
of oxalyl chloride and one drop of DMF were added. Resulted
solution was stirred at RT for 3 h, and then all volatiles were
removed in vacuo. Residue was dissolved in 10 ml of CH2Cl2,
14 mg of aniline (0.15 mmol) and 148 mg (1.15 mmol) of
DIPEA were added and resulted mixture was stirred for 18 h.
100 ml of EtOAc was added, resulted organic solution was
washed with 30 ml of water, 35 ml of 3% HCl, 30 ml of water,
2 times with 35 ml of saturated aqueous NaHCO3, 30 ml of
water and 3 times with 30 ml of brine. Organic layer was dried
over anhydrous Na2SO4, all volatiles were removed in vacuo.
Residue was washed with 5 ml of Et2O and dried in vacuo.
4-(4-methoxyphenyl)-N-phenyl-3-(pyrrolidine-1-
carbonyl)isoxazole-5-carboxamide (16). 34 mg (0.1 mmol) of
15 was dissolved in 10 ml of CH2Cl2, and then 38 mg (0.3
mmol) of oxalyl chloride and one drop of DMF were added.
Resulted solution was stirred at RT for 3 h, and then all vola-
tiles were removed in vacuo. Residue was dissolved in 10 ml
of CH2Cl2, 53 mg (0.75 mmol) of pyrrolidine and 26 mg (0.2
mmol) of DIPEA were added and resulted mixture was stirred
for 18 h. 100 ml of EtOAc was added, resulted organic solu-
tion was washed with 20 ml of water, 30 ml of 3% HCl, 20 ml
of water, 2 times with 30 ml of saturated aqueous NaHCO3, 20
ml of water and 3 times with 30 ml of brine. Organic layer was
dried over anhydrous Na2SO4, all volatiles were removed in
vacuo. The residue was purified with column chromatography
using hexane – EtOAc mixture as eluent (3:2, v:v). Yield 30
1
Yield mg (92%), white solid, m.p. 198-199°C; H NMR (700
MHz, DMSO-d6): d 1.73 - 1.86 (m, 4H), 3.24 (t, J=6.7 Hz,
2H), 3.47 (t, J=6.9 Hz, 2H), 3.76 (s, 3H), 6.99 (d, J=9.0 Hz,
2H), 7.15 (t, J=7.4 Hz, 1H), 7.33 - 7.41 (m, 4H), 7.68 (d, J=7.6
Hz, 2H), 11.00 (s, 1H); 13C{1H} NMR (176 MHz, DMSO-d6):
d 23.5, 25.2, 45.9, 47.0, 55.1, 114.2, 117.6, 118.8, 120.0,
124.6, 128.9, 129.9, 137.9, 156.3, 157.5, 157.6, 159.5, 159.9;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H22N3O4
392.1605; Found 392.1604.
1
mg (77%), white solid, m.p. = 188-190°C; H NMR (700
MHz, DMSO-d6): d 1.75 - 1.81 (m, 2H), 1.81 - 1.85 (m, 2H),
3.27 - 3.29 (m, 2H), 3.44 (t, J=7.1 Hz, 2H), 3.78 (s, 3H), 6.99
(d, J=8.8 Hz, 2H), 7.15 (t, J=7.3 Hz, 1H), 7.36 (t, J=7.9 Hz,
2H), 7.42 (d, J=8.8 Hz, 2H), 7.71 (d, J=7.8 Hz, 2H), 10.88 (s,
1H); 13C{1H} NMR (75 MHz, DMSO-d6): d 23.8, 25.3, 45.6,
47.7, 55.2, 113.9, 118.8, 119.7, 120.5, 124.7, 128.8, 130.5,
137.8, 154.7, 157.9, 158.1, 159.1, 159.5; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C22H22N3O4 392.1605; Found
392.1610.
methyl
(4-(4-methoxyphenyl)-5-(pyrrolidine-1-
carbonyl)isoxazole-3-carbonyl)glycinate (14). 32 mg (0.1
mmol) of 12 was dissolved in 10 ml of CH3CN, then 49 mg
(0.13 mmol) of HBTU, 17.5 mg (0.14 mmol) of methyl
glycinate hydrochloride and 39 mg (0.3 mmol) of DIPEA were
added and the resulted mixture was stirred for 24 h. Then the
solution was evaporated to one quarter of the original volume,
100 ml of EtOAc was added, the resulted organic solution was
washed with 30 ml of water, 35 ml of 3% HCl, 30 ml of water,
2 times with 35 ml of saturated aqueous NaHCO3, 30 ml of
water and 3 times with 30 ml of brine. Organic layer was dried
over anhydrous Na2SO4, all volatiles were removed in vacuo.
The residue was purified with column chromatography using
CHCl3 – EtOH mixture as eluent (20:1, v:v). Yield 34 mg
(89%), colorless oil; 1H NMR (700 MHz, DMSO-d6): d 1.72 -
1.84 (m, 4H), 3.19 (t, J=6.7 Hz, 2H), 3.45 (t, J=7.0 Hz, 2H),
3.67 (s, 3H), 3.78 (s, 3H), 4.02 (d, J=6.1 Hz, 2H), 6.97 (d,
J=8.8 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H), 9.39 (t, J=5.9 Hz, 1H);
13C{1H} NMR (176 MHz, DMSO-d6): d 23.5, 25.2, 40.9, 45.9,
47.0, 51.9, 55.2, 113.9, 117.7, 118.7, 130.1, 156.4, 156.5,
159.4, 159.6, 160.1, 169.4; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C19H22N3O6 388.1503; Found 388.1504.
methyl
(4-(4-methoxyphenyl)-5-
(phenylcarbamoyl)isoxazole-3-carbonyl)glycinate (17). 34 mg
(0.1 mmol) of 15 was dissolved in 10 ml of CH3CN, then 49
mg (0.13 mmol) of HBTU, 17.5 mg (0.14 mmol) of methyl
glycinate hydrochloride and 39 mg (0.3 mmol) of DIPEA were
added and the resulted mixture was stirred for 24 h. Then the
solution was evaporated to one quarter of the original volume,
100 ml of EtOAc was added, the resulted organic solution was
washed with 20 ml of water, 30 ml of 3% HCl, 20 ml of water,
2 times with 30 ml of saturated aqueous NaHCO3, 20 ml of
water and 3 times with 30 ml of brine. Organic layer was dried
over anhydrous Na2SO4, all volatiles were removed in vacuo.
The residue was purified with column chromatography using
CHCl3 - EtOH mixture as eluent (20:1, v:v). Yield 27 mg
1
(66%), white solid, m.p. = 69-71°C; H NMR (700 MHz,
DMSO-d6): d 3.67 (s, 3H), 3.78 (s, 3H), 4.03 (d, J=6.1 Hz,
2H), 6.95 (m, J=8.8 Hz, 2H), 7.15 (t, J=7.3 Hz, 1H), 7.36 (t,
J=7.8 Hz, 2H), 7.44 (m, J=8.8 Hz, 2H), 7.70 (d, J=8.0 Hz,
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Page 14 of 15
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2
3
4
5
6
7
8
2H), 9.41 (t, J=5.9 Hz, 1H), 10.87 (s, 1H); 13C{1H} NMR (75
MHz, DMSO-d6): d 40.9, 52.0, 55.2, 113.5, 118.7, 120.4,
120.5, 124.7, 128.8, 131.1, 137.7, 154.7, 157.8, 158.5, 159.4,
159.5, 169.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C21H20N3O6 410.1347; Found 410.1352.
(2) (a) Yavari, I.; Moradi, L. A synthesis of isoxazoles through
the reaction of activated acetylenes and alkyl 2-nitroethanoates
in the presence of triphenylphosphine Tetrahedron Letters.
2006, 47, 1627. (b) Yavari, I.; Piltan, M.; Moradi, L. Synthesis
of pyrrolo[2,1-a]isoquinolines from activated acetylenes, ben-
zoylnitromethanes, and isoquinoline Tetrahedron. 2009, 65,
2067.
Gram-scale
synthesis.
isopropyl
5-hydroxy-4-(4-
methoxyphenyl)-6-oxo-6H-1,2-oxazine-3-carboxylate (5c). P-
Anisaldehyde (6.8 g, 50 mmol), isopropyl nitroacetate (16.2 g,
110 mmol) and diethylamine (9.1 g, 125 mmol) were dis-
solved in 130 ml of acetonitrile. Resulted solution was stirred
for 48 h at room temperature and then additionally heated at
80°C for 3 h. All volatiles were removed in vacuo, 160 ml of
isopropanol was added and the mixture was refluxed until the
complete solid dissolution (5 min). Resulted solution was
cooled to -20°C and stored for 2 h at this temperature. The
precipitated diethylammonium salt was filtered and washed
with a cold (0°C) alcohol (20 ml, twice), washed with 20 ml of
ether and dried in vacuo. The diethylammonium salt was dis-
solved in 500 ml of CHCl3 and washed 3 times with 200 ml of
3% aq. HCl. Organic layer was dried with anhydrous Na2SO4
and evaporated to obtain pure 5c. Yield 13.0 g (85%).
(3) Trogu, E.; De-Sarlo, F.; Machetti, F. Michael Additions
versus Cycloaddition Condensations with Ethyl Nitroacetate
and Electron‐Deficient Olefins. Chem. Eur. J. 2009, 15, 7940.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) Cecchi, L.; De-Sarlo, F.; Machetti, F. Synthesis of 4,5‐
Dihydroisoxazoles by Condensation of Primary Nitro Com-
pounds with Alkenes by Using a Copper/Base Catalytic Sys-
tem. Chem. Eur. J. 2008, 14, 7903.
(5) (a) Dornow, A.; Wiehler, G. Über die Umsetzung von Al-
dehyden mit Nitroessigester†. Über aliphatische Nitroverb-
indungen; III. Justus Liebigs Ann. Chem. 1952, 578, 113. (b)
Dornow, A.; Frese, A. Über einige Umsetzungen von Ni-
troessigester. Über aliphatische Nitroverbindungen V. Justus
Liebigs Ann. Chem. 1953, 581, 211. (c) Dornow, A.; Frese, A.
Über einige Anlagerungs‐ und Kondensationsreaktionen des
Nitroessigsäureäthylesters. Über aliphatische Nitroverb-
indungen IV. Justus Liebigs Ann. Chem. 1952, 578, 122.
isopropyl
4-(4-methoxyphenyl)-5-(pyrrolidine-1-
carbonyl)isoxazole-3-carboxylate (8cb). Oxazinone 5c (3.05
g, 10 mmol) and pyrrolidine (1.4 g, 20 mmol) were dissolved
in 25 ml of CHCl3. Resulted solution was stirred for 12 h at
70°C. All volatiles were removed in vacuo and the residue was
purified by column chromatography using CHCl3 – EtOH
mixture as eluent (100:1, v:v). Yield 2.8 g (78%).
(6) (а) Chen, K.; Chen, Y.; Chuang, C. Ethyl α‐
Nitrocinnamates in the Synthesis of Highly Functionalized
Isoxazoles. Eur. J. Org. Chem. 2010, 5292. (b) Zen, S.;
Umezawa, S. Synthetic Studies of the Derivatives of Nitroace-
tic Acid. II. The Synthesis of Isoxazolecarboxylic Acids from
α,β-Unsaturated α-Nitroesters. Bull. Chem. Soc. Jpn. 1963, 36,
1146. (с) Zen, S.; Koyama, Masao. Synthesis of 4-Substituted
Isoxazole-3,5-dicarboxylic Acids from 2-Substituted-1,3-
dinitroglutarates and the Reaction Mechanism therefrom. Bull.
Chem. Soc. Jpn. 1971, 44, 2882. (d) Chen, K.; Chen, Y.;
Chuang, C. Ethyl α‐Nitrocinnamates in the Synthesis of High-
ly Functionalized Isoxazoles. Eur. J. Org. Chem. 2010, 5292.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Reaction optimization, X-ray crystallography data, NMR spec-
tra (PDF) and CIF file.
AUTHOR INFORMATION
Corresponding Author
(7) (a) Zhu, J.; Mo, J.; Lin, H.; Chen, Y.; Sun, H. The recent
progress of isoxazole in medicinal chemistry, Bioorg. Med.
Chem. 2018, 26, 3065. (b) Baruchello, R.; Simoni, D.; Gri-
solia, G.; Barbato, G.; Marchetti, P.; Rondanin, R.; Mangiola,
S.; Giannini, G.; Brunetti, T.; Aloatti, D.; Gallo, G.; Ciacci,
A.; Vesci, L.; Castorina, M.; Milazzo, F.; Cervoni, M.L.; Gug-
lielmi, M.B.; Barbarino, M.; Foderà, R.; Pisano, C.; Cabri, W.
Novel 3,4-Isoxazolediamides as Potent Inhibitors of Chaper-
one Heat Shock Protein 90. J. Med. Chem. 2011, 5424, 8592.
(c) Sun, J.; Lin, C,; Qin, X.; Dong, X.; Tu, Z.; Tang, F.; Chen,
C.; Zhang, J. Synthesis and biological evaluation of 3,5-
disubstituted-4-alkynylisoxozales as a novel class of HSP90
inhibitors. Bioorg. Med. Chem. Lett., 2015, 16, 3129.
*E-mail: baranovmikes@gmail.com.
Author Contributions
The manuscript was written through contributions of all au-
thors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors gratefully acknowledge support from the Russian
Foundation for Basic Research Grant 18-03-00094-a.
REFERENCES
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droisoxazoles by a one-pot cascade reaction Tetrahedron,
2017, 73, 331. (b) Zhu, C.; Sun, X.; Deng, X.; Zheng. J.; Tang,
2
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