Divergent synthesis of polysubstituted isoxazoles, isoxazoline N-oxides, and dihydroisoxazoles by a one-pot cascade reaction

Article abstract of DOI:10.1016/j.tet.2016.12.005

An efficient one-pot synthesis of a new class of 3,4,5-trisubstituted isoxazoline N-oxides/isoxazoles and dihydroisoxazoles is developed by a green approach from aromatic and aliphatic aldehydes by controlling the reaction conditions. Aldehydes were reacted with ethyl nitroacetate in the presence of DABCO as a catalyst under ultrasonication. In aromatic aldehydes, isoxazoline N-oxides were obtained exclusively when the reaction was carried out at 40 °C, but raising the temperature to 80 °C isoxazoles were formed selectively. Aliphatic aldehydes, on the other hand, gave a mixture of isoxazoline N-oxides and dihydroisoxazoles where the ratio of these depended on the bulk of the aliphatic chain on the aldehyde. This is the first method for the synthesis of aliphatic 4-substituted-3,5-bis(ethoxycarbonyl)-isoxazoline N-oxides and 4-substituted-3,5-bis(ethoxycarbonyl)-dihydroisoxazoles with good to excellent yields.

Full text of DOI:10.1016/j.tet.2016.12.005

Accepted Manuscript
Divergent synthesis of polysubstituted isoxazoles, isoxazoline N-oxides, and
dihydroisoxazoles by a one-pot cascade reaction
Abdul Rouf, Ertan Şahin, Cihangir Tanyeli
PII:
S0040-4020(16)31273-X
10.1016/j.tet.2016.12.005
TET 28297
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 August 2016
Revised Date: 24 November 2016
Accepted Date: 6 December 2016
Please cite this article as: Rouf A, Şahin E, Tanyeli C, Divergent synthesis of polysubstituted isoxazoles,
isoxazoline N-oxides, and dihydroisoxazoles by a one-pot cascade reaction, Tetrahedron (2017), doi:
10.1016/j.tet.2016.12.005.
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Divergent Synthesis of Polysubstituted Isoxazoles, Isoxazoline N-oxides, and
Dihydroisoxazoles by a One-pot Cascade Reaction
Abdul Rouf,a Ertan Şahinb and Cihangir Tanyelic*
aPresent address: Department of Chemistry, University of Florida, Gainesville, Florida, United States
bDepartment of Chemistry, Atatürk University, 25240 Erzurum-Turkey
cDepartment of Chemistry, Middle East Technical University, 06800 Ankara-Turkey
tanyeli@metu.edu.tr

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Divergent Synthesis of Polysubstituted Isoxazoles, Isoxazoline N-oxides, and
Dihydroisoxazoles by a One-pot Cascade Reaction
Abdul Rouf,a Ertan Şahinb and Cihangir Tanyelic*
aPresent address: Department of Chemistry, University of Florida, Gainesville, Florida, United States
bDepartment of Chemistry, Atatürk University, 25240 Erzurum-Turkey
cDepartment of Chemistry, Middle East Technical University, 06800 Ankara-Turkey
*E-mail: tanyeli@metu.edu.tr

1
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Tetrahedron
journal homepage: www.elsevier.com
Divergent Synthesis of Polysubstituted Isoxazoles, Isoxazoline N-oxides, and
Dihydroisoxazoles by a One-pot Cascade Reaction
Abdul Rouf,a Ertan Şahinb and Cihangir Tanyelic*
aPresent address: Department of Chemistry, University of Florida, Gainesville, Florida, United States
bDepartment of Chemistry, Atatürk University, 25240 Erzurum-Turkey
cDepartment of Chemistry, Middle East Technical University, 06800 Ankara-Turkey
*E-mail: tanyeli@metu.edu.tr
ARTICLE INFO
Article history:
2009 Elsevier Ltd. All rights reserved.
Received
Received in revised form
ABSTRACT
An efficient one-pot synthesis of a new class of 3,4,5-trisubstituted isoxazoline N-oxides/
isoxazoles and dihydroisoxazoles is developed by a green approach from aromatic and aliphatic
aldehydes by controlling the reaction conditions. Aldehydes were reacted with ethyl nitroacetate
in the presence of DABCO as a catalyst under ultrasonication. In aromatic aldehydes,
isoxazoline N-oxides were obtained exclusively when the reaction was carried out at 40 °C, but
raising the temperature to 80 °C isoxazoles were formed selectively. Aliphatic aldehydes, on the
other hand, gave a mixture of isoxazoline N-oxides and dihydroisoxazoles where the ratio of
these depended on the bulk of the aliphatic chain on the aldehyde. This is the first method for the
synthesis of aliphatic 4-substituted-3,5-bis(ethoxycarbonyl)-isoxazoline N-oxides and 4-
substituted-3,5-bis(ethoxycarbonyl)-dihydroisoxazoles with good to excellent yields.
Accepted
Available online
Keywords:
Isoxazoline N-oxides
Isoxazoles
Dihydroisoxazoles
Cascade Reaction
Ethyl nitroacetate
1. Introduction
respectively, both requiring harsh reaction conditions.12,17
Consequently, there is significant demand to develop a novel
practical route targeting one-pot cascade synthesis of isoxazoline
N-oxides, isoxazoles and dihydroisoxazoles.
Functionalized isoxazoline N-oxides (cyclic five-membered
nitronates)/isoxazoles and dihydroisoxazoles, are versatile
heterocycles and occupy a significant position in organic
chemistry because of their existence in a wide range of bioactive
synthetic compounds and natural products.1,2 They also act as
precursors for the construction of complex compounds,3 like β-
hydroxy-ketones,4 γ-amino-alcohols,5 α,β-unsaturated oximes,6
and β-hydroxy-nitriles.7
To the best of our knowledge, there is yet no practical and
simple method for the synthesis of isoxazoline N-oxides,
isoxazoles, and dihydroisoxazoles. In addition, there is no
method in the literature for the synthesis of aliphatic 4-
substituted-3,5-bis(ethoxycarbonyl)-isoxazoline N-oxides and 4-
substituted-3,5-bis(ethoxycarbonyl)-dihydroisoxazoles and this is
the first method for their synthesis in good to excellent yields. In
the present article, we report a simple and green method for the
Several methods have been adopted for the synthesis of these
heterocycles, such as, a) the synthesis of isoxazoline N-oxide
derivatives,8 by asymmetric synthesis,9 reaction of ethyl
nitroacetate with α-bromo enones,10 condensation of α-nitro-
esters with aldehydes catalyzed by zinc complexes of amino
acids,11 [3+2] cycloaddition12, b) isoxazoles by cycloaddition
reactions, under thermal conditions, etc,13-16 and c) little-known
dihydroisoxazoles mostly from isoxazoline N-oxides in presence
of trimethylphosphite.17
synthesis of
a series of polysubstituted isoxazoline N-
oxides/isoxazoles, and dihydroisoxazoles, in a single divergent
step just by controlling the reaction conditions.
2. Results and discussion
However, these routes usually suffer from a variety of
limitations, such as toxic and expensive reagents, use of harmful
organic solvents, anhydrous conditions and cumbersome reaction
steps; therefore, an efficient and simple synthetic route to these
heterocycles is of great interest. Additionally, dihydroisoxazoles
and isoxazoles were synthesized from isoxazoline N-oxides by
reduction in the presence of trimethylphosphite P(OMe)3 at reflux
and heating at 160 °C under microwave irradiation in DMF,
The strategy started by reacting ethyl nitroacetate and
benzaldehyde in presence of 20 mol % DABCO as the catalyst.
The reaction was sluggish (4 d) and we were able to isolate the
corresponding isoxazoline N-oxide product in only 20% yield
using toluene at room temperature (entry 1, Table 1). The effects
of solvent, base and temperature were investigated to establish
the optimal working conditions. Of the screened solvents, THF

2
Tetrahedron
proved to be the best organic solvent (entries 1–9), but was still
insensitive towards the electronic nature of aldehydes,
ACCEPTED MANUSCRIPT
inefficient (yields ≤ 40%; time = 4 d). However, we steadily
observed remarkable increments in chemical yields in neat
nitroaromatics being the exception with slightly lower yields
(entries 8–10).
condition,
ionic
liquid
1-butyl-3-methylimidazolium
tetrafluoroborate (BMIMBF4), and water (50%, 52%, 58% yields,
respectively; entries 10–12) with 24 h reaction time. Among
these, we decided to use water as the solvent for this
transformation (cascade reactions when performed in green
solvents, like water, offer more impact and advantages in the
process18). Moreover, we applied ultrasonication to overcome the
inhomogeneity problems we faced while using water as solvent
(entries 13–18). Gratifyingly, all afforded 2a as the sole product
in reasonable yields (55–78%). Remarkably, 20 mol % use of
DABCO gave the best yield of 78% (entry 13).
Table 2.Varying aromatic aldehydesa
Product
Entry
Aldehyde
R
(% Yield)b
2a (78)
2b (84)
2c (86)
2d (82)
2e (80)
2f (85)
2g (88)
2h (65)
2i (72)
1
1a
1b
1c
1d
1e
1f
Ph
Table 1. Screening of conditions in the synthesis of
isoxazoline N-oxidesa
2
2-Me-C6H4
2,6-Me-C6H3
2-OMe-C6H4
3-OMe-C6H4
4-OMe-C6H4
2,4,6-(MeO)3-C6H2
2-NO2-C6H4
3-NO2-C6H4
4-NO2-C6H4
2-Cl-C6H4
3
4
5
6
7
1g
1h
1i
Time
(days)
Entry
Solvent
Base
Yield (%)b
8
1
Toluene
Hexane
THF
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DBU
4
4
4
4
4
4
4
4
4
1
1
1
1
1
1
1
1
1
20
15
40
20
20
30
30
17
15
50
52
58
78
67
55
60
55
65
9
2
10
11
12
13
14
15
16
17
18
19
20
1j
2j (69)
2k (85)
2l (84)
3
1k
1l
4
Methanol
Ethanol
DCM
3-Cl-C6H4
5
1m
1n
1o
1p
1q
1r
4-Cl-C6H4
2m (85)
2n (86)
2o (84)
2p (85)
2q (82)
2r (92)
2s (90)
2t (89)
6
2,6-Cl2-C6H3
2-Br-C6H4
7
Chloroform
DMF
8
4-Br-C6H4
9
DMSO
Neat
4-F-C6H4
10
11
12
13c
14c
15c
16c
17c
18c
CH2-C6H5
BMIMBF4
Water
Water
Water
Water
Water
Water
Water
1s
1t
2-Thienyl
3-Thienyl
aReaction conditions. 1a–t (1.0 mmol), ethyl nitroacetate (1.68
mmol), base (20 mol %), H2O (2 mL), 40 °C, 24 h. Yield of
isolated product.
b
Triethylamine
Piperidine
Pyrrolidine
K2CO3
When aliphatic aldehydes (1u–z) were subjected to above
optimized reaction conditions, the product formation varied with
the length of the aliphatic chain used. With lower aliphatic chain
incorporating aldehydes, isoxazoline N-oxides were the minor
products (Entries 1–3, Table 3), while, the major products of the
reaction of aldehydes 1u–w and the only product of the
aldehydes 1x–z were determined to have a dihydroisoxazole
structure. These products were easily differentiated by comparing
the proton NMR coupling constants (J) of the ring protons. It was
2.5 Hz for the ring protons of isoxazoline N-oxides and 5.5 Hz
for those of dihydroisoxazoles.
aReaction conditions. 1a (1.0 mmol), ethyl nitroacetate (1.68
b
mmol), base (20 mol %), H2O (2 mL), rt. Yield of isolated
products. cUltrasonication was employed at 40 °C. Time in days
With the optimized reaction conditions in hand, the scope of
this DABCO catalyzed one-pot cascade reaction was examined
further by varying the aldehydes. All the reactions were
conducted in H2O at 40 °C by ultrasonication for 24 h. The
results are summarized in Table 2. It was observed that the
isoxazoline N-oxides were formed exclusively at ultrasonication
at 40 °C in good yields through double condensation of ethyl
nitroacetate with the aldehyde. Most of the cyclization products
were obtained in moderate to excellent yields (65–92%; entries
1–20, Table 2). It was clearly observed that the yields are fairly

3
Table 3. Employing aliphatic aldehydesa
ACCEPTED MANUSCRIPT
O
N
O
O
N
O
O
O
O
O
DABCO (20 mol %)
O
OEt
EtO
OEt
R
OEt
R
H
EtO
R
H2O, ultrasonication,
40 °C, 24 h
NO2
1u-z
isoxazoline-N-oxides
2u-w
dihydroisoxazoles
3u-w
ethyl nitroacetate
Yield of
2u–z (%)
13
Yield of
Total yield
(%)b
Entry Aldehyde
R
3u
64
74
76
-
–z (%)
1
2
3
4
5
6
1u
1v
1w
1x
1y
1z
Ethyl
77
88
90
90
94
94
n-Propyl
n-Butyl
14
14
90
94
94
Scheme 1. Proposed mechanism for the isoxazoline N-oxides
and isoxazoles
iso-Butyl
n-Pentyl
n-Octyl
The structures of heterocyclic products were further supported
by NMR spectroscopy and X-ray crystallography (Figure 1).
-
-
aReaction conditions. 1u–z (1.0 mmol), ethyl nitroacetate
b
(1.68 mmol), base (20 mol %), H2O (2 mL), 40 °C, 24 h. Yield
of isolated products.
We were also interested in the consequences of higher
temperatures for this reaction. To this end, we heated up several
reactions to higher temperatures of 60 °C or more and were
surprised by the formation of further dehydrated aromatic
isoxazoles instead of isoxazoline N-oxides (Table 4).
Table 4. Formation of isoxazolesa
Figure 1. X-Ray crystal structure of 2k
3. Conclusions
Entry
Aldehyde
Ar
Product yield (%)b
In conclusion, we have developed an efficient, green and one-
pot method for the synthesis of a new class of isoxazoline N-
oxides, isoxazoles and dihydroisoxazoles by reacting alkyl/aryl
aldehydes with ethyl nitroacetate in presence of base (DABCO)
in good yields. The formation of these heterocycles was
successfully and selectively achieved by controlling the reaction
temperature. Isoxazoline N-oxides were exclusively obtained
under ultrasonication at 40 °C; however, when the same reaction
was carried out at 80 °C, only isoxazoles were obtained. The
present methodology targeting the synthesis of these heterocyclic
compounds is highly advantageous (e.g., short reaction time, use
of water as the solvent, catalytic process with high yields and
mild temperatures) and we expect will show potential in
heterocyclic and natural product chemistry in the future.
1
2
3
4
1h
1j
2-NO2-C6H4
4-NO2-C6H4
3-Cl-C6H4
4h (86)
4j (90)
4l (85)
4m (89)
1l
1m
4-Cl-C6H4
aReaction conditions. 1h–m (1.0 mmol), ethyl nitroacetate
(1.68 mmol), base (20 mol %), H2O (2 mL), 80 °C, 24 h. Yield
of isolated products.
b
These results suggest that the stringent control of reaction
products can be achieved by just controlling the operative
temperatures. This reaction proceeded faster particularly with
aromatic aldehydes carrying electron withdrawing substituents.
By a time-dependent TLC and NMR analysis of this aromatizing
reaction, we observed that isoxazoline N-oxides were first formed
which then presumably slowly underwent dehydration to form
isoxazoles (Scheme 1). The present methodology can thus be
efficiently used for the synthesis of diverse isoxazole
heterocycles just by controlling the reaction temperatures.
4. Experimental
4.1. General Information
All the reagents and solvents used were purchased from
commercial suppliers (Aldrich Chemicals) and used without
further purification unless otherwise noted. 1H NMR and 13C
NMR spectra were recorded on a 400 MHz spectrophotometer
using CDCl3 as the solvent. Chemical shift values are reported in
ppm taking tetramethylsilane as the internal standard, and J
values are given in hertz. Spin multiplicities are reported as
following: s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet). HRMS data were acquired on a time of flight (TOF)
mass spectrometer. IR spectra of all new compounds were
obtained by an IR spectrometer. X-ray diffraction structure
analysis was done for 2k. All the reactions were performed in
distilled water in the ultrasonic bath at 40–80 °C. Flash column
chromatography (FCC) was performed by using glass columns
with a flash grade silica gel (230–400 mesh). Reactions were
We presume that the mechanism accounting for the formation
of products involve a base-promoted nitroaldol reaction of
aldehyde and ethyl nitroacetate as the first step. The nitroaldol
product then undergoes dehydration to yield α,β-unsaturated
nitroolefin 5. The attack of the second active methelene
compound to this reactive Michael acceptor form the
intermediate conjugate adduct 6, which cyclizes through the
attack of nitronate oxygen atom to the other nitro-group-bearing
α-carbon, thereby eliminating NO2 to form the desired
isoxazoline N-oxides.8g At higher temperatures, however, these
isoxazoline N-oxides transform into more stable aromatic
isoxazoles by dehydration (Scheme 1).

4
Tetrahedron
ACCEPTED MANUSCRIPT
1
monitored by thin layer chromatography (TLC) using precoated
1761, 1692, 1630, 1217, 1407, 1373, 1233, 1198 cm-1. H NMR
(400 MHz, CDCl3) δ 7.12 – 6.89 (m, 3H), 5.48 (d, J = 5.5 Hz,
1H), 4.85 (d, J = 5.5 Hz, 1H), 4.29 – 4.25 (m, 2H), 4.16 – 4.06
(m, 2H), 2.40 (s, 3H), 2.26 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H), 1.00
(t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.9, 157.0,
136.4, 135.5, 132.8, 130.0, 127.9, 127.4, 107.6, 75.7, 61.6, 60.9,
46.0, 19.6, 18.1, 13.0, 12.6. HRMS (ESI) calcd. For
C17H21NNaO6 [M + Na]+ 358.1267, found 358.1276.
silica gel plates, visualized by UV light. Melting points were
determined on Buchi B-542 apparatus by an open capillary
method and are uncorrected.
4.2. Experimental procedure
4.2.1. General procedure for the synthesis of isoxazoline N-
oxides (2a-z) and dihydroisoxazoles (3u–w)
4.3.4.
3,5-Bis(ethoxycarbonyl)-4-(2-methoxyphenyl)-4,5-
1,4-Diazabicyclo[2.2.2]octane (DABCO) (20 mol %) was
added to a mixture of aldehyde (1.0 mmol, 1.0 eq.) and ethyl
nitroacetate (1.68 mmol, 2.0 eq. ) at 0 °C dissolved in water (2
mL). The reaction mixture was stirred for 5 min at 0 °C and then
ultrasonicated for 24 h at 40 °C. After the completion of the
reaction as indicated by TLC, the reaction was quenched with
ethyl acetate (3 × 6 mL). The combined organic extract was
washed with water (2 × 5 mL) and 5% HCl (1 × 3 mL), dried
over anhydrous MgSO4 and concentrated in vacuo. The residue
was loaded on to a silica gel column and eluted with hexane:
ethyl acetate to afford isoxazoline N-oxides 2a–z, and
dihydroisoxazoles 3u–w.
dihydroisoxazole 2-oxide (2d): (Isolated yield 82% as yellow
solid). Mp = 98–100 °C. Purified by column chromatography on
silica gel, Rf (20% ethyl acetate/hexane) 0.93. IR (neat) 2960,
2923, 1745, 1736, 1636, 1493, 1462, 1221, 1008 cm-1. H NMR
1
(400 MHz, CDCl3) δ 7.25 (dd, J = 8.0, 1.6 Hz, 1H), 7.07 (dd, J =
8.0, 1.6 Hz, 1H), 6.91 – 6.81 (m, 2H), 5.07 (d, J = 4.0 Hz, 1H),
4.80 (d, J = 4.0 Hz, 1H), 4.30 – 4.20 (m, 2H), 4.20 – 4.06 (m,
2H), 3.80 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H), 1.07 (t, J = 7.5 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 167.8, 158.4, 156.6, 130.3,
128.3, 120.4, 111.0, 77.6, 62.4, 61.9, 56.0, 47.9, 14.2, 13.7.
HRMS (ESI) calcd. for C16H19NNaO7 [M + Na]+ 360.1059, found
360.1053.
4.2.2. General procedure for the synthesis of isoxazoles (4h, 4j, 4l
4.3.5.
3,5-Bis(ethoxycarbonyl)-4-(3-methoxyphenyl)-4,5-
and 4m)
dihydroisoxazole 2-oxide (2e): (Isolated yield 80% as brown
viscous oil). Purified by column chromatography on silica gel, Rf
(20% ethyl acetate/hexane) 0.94. IR (neat) 2980, 1732, 1652,
1490, 1378, 1222, 1017, 753 cm-1. 1H NMR (400 MHz, CDCl3) δ
7.26 (m, 1H), 6.89 – 6.73 (m, 3H), 4.85 (d, J = 3.0 Hz, 1H), 4.74
(d, J = 3.0 Hz, 1H), 4.31 – 4.18 (m, 2H), 4.18 – 4.06 (m, 2H),
3.75 (s, 3H), 1.30 (t, J = 7.5 Hz, 3H), 1.10 (t, J = 7.5 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 168.0, 160.4, 158.1, 139.4, 130.6,
119.0, 113.8, 112.9, 108.5, 78.6, 62.6, 62.2, 55.7, 53.0, 14.3,
14.1. HRMS (ESI) calcd. for C16H19NNaO7 [M + Na]+ 360.1059,
found 360.1051.
1,4-Diazabicyclo[2.2.2]octane (DABCO) (20 mol %) was
added to a mixture of aldehyde (1.0 mmol, 1.0 eq.) and ethyl
nitroacetate (1.68 mmol, 2.0 eq. ) at 0 °C dissolved in water (2
mL). The reaction mixture was stirred for 5 min at 0 °C and then
ultrasonicated for 24 h at 80 °C. After the completion of the
reaction as indicated by TLC, the reaction was quenched with
ethyl acetate (3 × 6 mL). The combined organic extract was
washed with water (2 × 5 mL) and 5% HCl (1 × 3 mL), dried
over anhydrous MgSO4 and concentrated in vacuo. The residue
was loaded on to a silica gel column and eluted with hexane:
ethyl acetate to afford isoxazoles 4h, 4j, 4l, and 4m.
4.3.6.
3,5-Bis(ethoxycarbonyl)-4-(4-methoxyphenyl)-4,5-
dihydroisoxazole 2-oxide (2f): (Isolated yield 85% as yellow
viscous oil). Purified by column chromatography on silica gel, Rf
(20% ethyl acetate/hexane) 0.90. IR (neat) 2976, 1748, 1732,
4.3. Experimental characterization data for products
4.3.1. 3,5-Bis(ethoxycarbonyl)-4-phenyl-4,5-dihydroisoxazole
2-oxide (2a): (Isolated yield 78% as yellow solid). Mp = 75–76
°C. [Lit.14c Mp = 74 °C]. Purified by column chromatography on
silica gel, Rf (20% ethyl acetate/hexane) 0.95. IR (neat) 2962,
1
1634, 1207, 1005, 734 cm-1. H NMR (400 MHz, CDCl3) δ 7.18
(d, J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 4.83 (d, J = 3.0 Hz,
1H), 4.72 (d, J = 3.0 Hz, 1H), 4.25 (dd, J = 7.5, 2.0 Hz, 2H), 4.12
(dd, J = 7.5, 4.5 Hz, 2H), 3.74 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H),
1.11 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.9,
158.9, 157.2, 129.0, 127.2, 113.3, 107.9, 77.8, 61.5, 60.9, 54.6,
50.9, 12.9. HRMS (ESI) calcd. for C16H19NNaO7 [M + Na]+
360.1059, found 360.1092.
1745, 1725, 1632, 1432, 1207, 1176, 1007, 737 cm-1. H NMR
1
(400 MHz, CDCl3) δ 7.39 – 7.21 (m, 5H), 4.86 (d, J = 3.0 Hz,
1H), 4.77 (d, J = 3.0 Hz, 1H), 4.33 – 4.20 (m, 2H), 4.20 – 4.05
(m, 2H), 1.34 – 1.23 (t, J = 7.5 Hz, 3H), 1.10 (t, J = 7.5 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 168.2, 158.1, 138.0, 129.3, 128.6,
127.1, 109.0, 78.8, 62.6, 62.1, 52.7, 14.2, 13.5. HRMS (ESI)
calcd. for C15H17NNaO6 [M + Na]+ 330.0954, found 330.0984.
4.3.7.
3,5-Bis(ethoxycarbonyl)-4-(2,4,6-trimethoxyphenyl)-
4,5-dihydroisoxazole 2-oxide (2g): (Isolated yield 88%. As
colorless crystalline solid). Mp = 150–152 °C. [Lit.14c Mp = 150
°C]. Purified by column chromatography on silica gel, Rf (20%
ethyl acetate/hexane) 0.75. IR (neat) 2961, 1763, 1730, 1652,
4.3.2. 3,5-Bis(ethoxycarbonyl)-4-(o-tolyl)-4,5-dihydroisoxazole
2-oxide (2b): (Isolated yield 84% as yellow solid). Mp = 117–
120 °C. Purified by column chromatography on silica gel, Rf
(20% ethyl acetate/hexane) 0.95. IR (neat) 2980, 1755, 1729,
1622, 1217, 1202, 1037, 752 cm-1. 1H NMR (400 MHz, CDCl3) δ
7.25 – 7.05 (m, 4H), 5.06 (d, J = 3.0 Hz, 1H), 4.75 (d, J = 3.0 Hz,
1H), 4.35 – 4.23 (m, 2H), 4.11 (dd, J = 7.5, 1.3 Hz, 2H), 2.40 (s,
3H), 1.29 (d, J = 7.5 Hz, 3H), 1.08 (t, J = 7.5 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 168.4, 158.3, 136.3, 135.3, 130.9, 128.5,
127.3, 126.0, 109.1, 78.5, 62.4, 61.6, 48.5, 19.3, 13.9, 13.2.
HRMS (ESI) calcd. for C16H19NNaO6 [M + Na]+ 344.1110, found
344.1131.
1
1594, 1508, 1235, 1122, 1003, 792 cm-1. H NMR (400 MHz,
CDCl3) δ 6.43 (s, 2H), 4.86 (d, J = 3.0 Hz, 1H), 4.71 (d, J = 3.0
Hz, 1H), 4.36 – 4.24 (m, 2H), 4.23 – 4.12 (m, 2H), 3.80 (dd, J =
12.5, 7.5 Hz, 9H), 1.31 (t, J = 7.5 Hz, 3H), 1.15 (t, J = 7.5 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 167.8, 157.6, 152.9, 137.3,
132.5, 107.9, 103.0, 77.8, 61.7, 61.1, 59.8, 55.3, 52.0, 13.1, 13.0.
HRMS (ESI) calcd. for C18H23NNaO9 [M + Na]+ 420.1271, found
420.1265.
4.3.8.
3,5-Bis(ethoxycarbonyl)-4-(2-nitrophenyl)-4,5-
dihydroisoxazole 2-oxide (2h): (Isolated yield 65% as yellow
oil). Purified by column chromatography on silica gel, Rf (20%
ethyl acetate/hexane) 0.90. IR (neat) 2972, 1735, 1723, 1643,
1245, 1105, 7564 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.99 (dd, J
= 8.5, 1.5 Hz, 1H), 7.65 – 7.58 (m, 1H), 7.54 – 7.44 (m, 1H),
4.3.3.
4-(2,6-Dimethylphenyl)-3,5-bis(ethoxycarbonyl)-4,5-
dihydroisoxazole 2-oxide (2c): (Isolated yield 86% as yellow
solid).Mp = 110–111 °C. Purified by column chromatography on
silica gel, Rf (20% ethyl acetate/hexane) 0.95. IR (neat) 2982,

5
7.38 (dd, J = 8.0, 1.5 Hz, 1H), 5.55 (d, J = 3.0 Hz, 1H), 4.88 (d, J
= 3.0 Hz, 1H), 4.33 – 4.30 (m, 2H), 4.13 – 4.10 (m, 2H), 1.31 (t,
J = 7.5 Hz, 3H), 1.05 (t, J = 7.5 Hz, 3H).13C NMR (101 MHz,
CDCl3) δ 165.3, 155.1, 145.5, 131.9, 130.1, 127.1, 125.8, 123.4,
105.8, 76.3, 60.5, 60.0, 45.1, 11.6, 11.4. HRMS (ESI) calcd. for
C15H16N2NaO8 [M + Na]+ 375.0804, found 375.0831.
1.28 (t, J = 7.5 Hz, 3H), 1.12 (t, J = 7.5 Hz, 3H). 13C NMR (101
ACCEPTED MANUSCRIPT
MHz, CDCl3) δ 166.1, 156.1, 134.6, 132.7, 127.7, 126.3, 106.8,
76.7, 61.0, 60.3, 50.3, 11.9. HRMS (ESI) calcd. for
C15H1635ClNNaO6 [M + Na]+ 364.0564, found 364.0586.
4.3.14. 4-(2,6-Dichlorophenyl)-3,5-bis(ethoxycarbonyl)-4,5-
dihydroisoxazole 2-oxide (2n): (Isolated yield 86% as colorless
solid). Mp = 70–72 °C. Purified by column chromatography on
silica gel, Rf (20% ethyl acetate/hexane) 0.93. IR (neat) 2982,
4.3.9.
3,5-Bis(ethoxycarbonyl)-4-(3-nitrophenyl)-4,5-
dihydroisoxazole 2-oxide (2i): (Isolated yield 72% as yellow
solid). Mp = 79–81 °C. [Lit.14c Mp = 81 °C]. Purified by column
chromatography on silica gel, Rf (20% ethyl acetate/hexane)
0.84. IR (neat) 3383, 2990, 1738, 1702, 1636, 1526, 1348, 1206,
1760, 1730, 1619, 1436, 1216, 1014, 767 cm-1. H NMR (400
1
MHz, CDCl3) δ 7.43 – 7.25 (m, 2H), 7.23 – 7.12 (m, 1H), 5.94
(d, J = 7.0 Hz, 1H), 5.01 (d, J = 7.0 Hz, 1H), 4.36 – 4.17 (m, 2H),
4.16 – 3.96 (m, 2H), 1.37 – 1.22 (t, J = 7.5 Hz, 3H), 1.01 (t, J =
7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.0, 157.1, 135.3,
134.4, 131.0, 129.2, 128.0, 106.3, 74.1, 61.9, 60.9, 47.5, 13.0,
12.5. HRMS (ESI) calcd. for C15H1535Cl2NNaO6 [M + Na]+
398.0174, found 398.0194.
1
1049, 888 cm-1. H NMR (400 MHz, CDCl3) δ 8.26 – 8.13 (m,
2H), 7.64 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 4.93 (d, J
= 3.0 Hz, 1H), 4.89 (d, J = 3.0 Hz, 1H), 4.33 – 4.24 (m, 2H),
4.17- 4.14 (m, 2H), 1.30 (t, J = 7.5 Hz, 3H), 1.13 (t, J = 7.5 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 166.1, 156.2, 147.1, 138.5,
131.4, 128.8, 122.1, 120.9, 106.5, 76.6, 61.8, 60.3, 51.1, 12.8,
12.4. HRMS (ESI) calcd. for C15H16N2NaO8 [M + Na]+ 375.0804,
found 375.0808.
4.3.15.
4-(2-Bromophenyl)-3,5-bis(ethoxycarbonyl)-4,5-
dihydroisoxazole 2-oxide (2o): (Isolated yield 84% as yellow
solid). Mp = 72–74 °C. Purified by column chromatography on
silica gel, Rf (20% ethyl acetate/hexane) 0.91. IR (neat) 2981,
4.3.10.
3,5-Bis(ethoxycarbonyl)-4-(4-nitrophenyl)-4,5-
1
dihydroisoxazole 2-oxide (2j): (Isolated yield 69% as yellow
solid). Mp = 97–98 °C. [Lit.14c Mp = 98 °C]. Purified by column
chromatography on silica gel, Rf (20% ethyl acetate/hexane)
0.85. IR (neat) 2981, 1754, 1742, 1623, 1257, 1105, 845 cm-1. 1H
NMR (400 MHz, CDCl3) δ 8.27 – 8.18 (m, 2H), 7.53 – 7.41 (m,
2H), 4.92 (d, J = 3.0 Hz, 1H), 4.85 (d, J = 3.0 Hz, 1H), 4.30 –
4.27 (m, 2H), 4.16 – 4.13 (m, 2H), 1.29 (t, J = 6.0 Hz, 3H), 1.13
(t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.8, 157.1,
150.9, 149.3, 142.1, 126.9, 122.7, 85.9, 61.0, 54.3, 12.2. HRMS
(ESI) calcd. for C15H16N2NaO8 [M + Na]+ 375.0804, found
375.0817.
2928, 1754, 1732, 1625, 1203, 1016, 752 cm-1. H NMR (400
MHz, CDCl3) δ 7.58 (dd, J = 8.0, 1.5 Hz, 1H), 7.36 – 7.26 (m,
1H), 7.21 – 7.13 (m, 2H), 5.38 (d, J = 3.5 Hz, 1H), 4.78 (d, J =
3.5 Hz, 1H), 4.29 – 4.26 (m, 2H), 4.14 – 4.11 (m, 2H), 1.29 (t, J
= 7.5 Hz, 3H), 1.09 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 165.8, 156.1, 134.9, 131.5, 128.5, 126.6, 121.2, 106.7,
76.3, 60.8, 60.2, 49.7, 11.9, 11.7. HRMS (ESI) calcd. for
C15H1679BrNNaO6 [M + Na]+ 408.0059, found 408.0071.
4.3.16.
4-(4-Bromophenyl)-3,5-bis(ethoxycarbonyl)-4,5-
dihydroisoxazole 2-oxide (2p): (Isolated yield 85% as yellow
solid). Mp = 93–95 °C. Purified by column chromatography on
silica gel, Rf (20% ethyl acetate/hexane) 0.92. IR (neat) 2974,
4.3.11.
4-(2-Chlorophenyl)-3,5-bis(ethoxycarbonyl)-4,5-
1
dihydroisoxazole 2-oxide (2k): (Isolated yield 85% as colorless
crystalline solid). Mp = 109–111 °C. Purified by column
chromatography on silica gel, Rf (20% ethyl acetate/hexane)
0.93. IR (neat) 2982, 2930, 1754, 1731, 1652, 1205, 1016, 753
2928, 1724, 1617, 1225, 1009, 737 cm-1. H NMR (400 MHz,
CDCl3) δ 7.50 – 7.43 (m, 2H), 7.17 – 7.09 (m, 2H), 4.81 (d, J =
3.0 Hz, 1H), 4.75 (d, J = 3.0 Hz, 1H), 4.27 (dd, J = 7.5, 2.0 Hz,
2H), 4.13 (dd, J = 7.5, 3.0 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H), 1.12
(t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 168.0, 158.1,
137.1, 132.5, 128.8, 122.9, 78.6, 62.8, 61.9, 52.2, 14.2. HRMS
(ESI) calcd. for C15H1679BrNNaO6 [M + Na]+ 408.0059, found
408.0093.
1
cm-1. H NMR (400 MHz, CDCl3) δ 7.43 – 7.33 (m, 1H), 7.29 –
7.18 (m, 3H), 5.36 (d, J = 3.5 Hz, 1H), 4.79 (d, J = 3.5 Hz, 1H),
4.28 (m, 2H), 4.15 – 4.05 (m, 2H), 1.29 (t, J = 7.5 Hz, 3H), 1.12
– 1.01 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.4,
156.9, 134.1, 131.9, 129.3, 129.1, 127.4, 126.1, 107.1, 77.1, 61.7,
61.1, 48.6, 13.0, 12.6. HRMS (ESI) calcd. for C15H1635ClNNaO6
[M + Na]+ 364.0564, found 364.0594.
4.3.17.
3,5-Bis(ethoxycarbonyl)-4-(4-fluorophenyl)-4,5-
dihydroisoxazole 2-oxide (2q): (Isolated yield 82% as yellow
semi-solid). Purified by column chromatography on silica gel, Rf
(20% ethyl acetate/hexane) 0.91. IR: 2980, 2925, 1720, 1637,
4.3.12.
4-(3-Chlorophenyl)-3,5-bis(ethoxycarbonyl)-4,5-
1456, 1205, 1019, 732 cm-1. H NMR (400 MHz, CDCl3) δ 7.51
1
dihydroisoxazole 2-oxide (2l): (Isolated yield 84% as colorless
semi-solid). Purified by column chromatography on silica gel, Rf
(20% ethyl acetate/hexane) 0.90. IR (neat) 2968, 1750, 1745,
– 7.41 (m, 1H), 7.28 – 7.21 (m, 2H), 7.11 – 6.97 (m, 2H), 4.83 (d,
J = 3.0 Hz, 1H), 4.77 (d, J = 3.0 Hz, 1H), 4.27 – 4.25 (m, 2H),
4.21 – 4.04 (m, 2H), 1.28 (t, J = 7.5 Hz, 3H), 1.12 (t, J = 7.5 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 167.0, 161.6 (d, J = 245.0
Hz), 156.7, 131.8, 127.6 (d, J = 7.8 Hz), 115.2 (d, J = 22.0 Hz),
107.6, 77.5, 61.8, 61.0, 50.8, 12.9, 12.7. HRMS (ESI) calcd. for
C15H16FNNaO6 [M + Na]+ 348.0859, found 348.0831.
1
1622, 1307, 1267, 754 cm-1. H NMR (400 MHz, CDCl3) δ 7.66
(dd, J = 6.0, 3.5 Hz, 1H), 7.47 (dd, J = 6.0, 3.5 Hz, 1H), 7.27 (dd,
J = 5.0, 2.0 Hz, 2H), 4.84 (d, J = 3.0 Hz, 1H), 4.75 (d, J = 3.0 Hz,
1H), 4.29 – 2.36 (m, 2H), 4.20 – 4.07 (m, 2H), 1.29 (t, J = 7.5
Hz, 3H), 1.13 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
166.8, 156.4, 138.2, 133.6, 129.3, 127.1, 125.9, 123.5, 98.3, 76.9,
61.2, 60.7, 50.6, 12.7, 12.2. HRMS (ESI) calcd. for
C15H1635ClNNaO6 [M + Na]+ 364.0564, found 364.0596.
4.3.18. 4-Benzyl-3,5-bis(ethoxycarbonyl)-4,5-dihydroisoxazole
2-oxide (2r): (Isolated yield 92% as yellow viscous oil). Purified
by column chromatography on silica gel, Rf (20% ethyl
acetate/hexane) 0.92. IR: 2923, 2852, 1727, 1647, 1446, 1193,
4.3.13.
4-(4-Chlorophenyl)-3,5-bis(ethoxycarbonyl)-4,5-
1094, 700 cm-1. H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 8.0,
1
dihydroisoxazole 2-oxide (2m): (Isolated yield 85% as colorless
solid). Mp = 98–99 °C. [Lit.14c Mp = 98 °C]. Purified by column
chromatography on silica gel, Rf (20% ethyl acetate/hexane)
0.92. IR (neat) 2979, 1752, 1742, 1644, 1178, 1105, 834 cm-1. 1H
NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.5 Hz, 2H), 7.21 (d, J =
9.0 Hz, 2H), 4.82 (d, J = 3.0 Hz, 1H), 4.76 (d, J = 3.0 Hz, 1H),
4.27 (dd, J = 7.5, 2.0 Hz, 2H), 4.13 (dd, J = 7.5, 4.0 Hz, 2H),
6.5 Hz, 2H), 7.22 (dd, J = 6.5, 4.0 Hz, 1H), 7.15 (t, J = 7.0 Hz,
2H), 4.66 (d, J = 2.5 Hz, 1H), 4.33 – 4.21 (m, 2H), 4.16 – 4.05
(m, 2H), 3.98 – 3.96 (m, 1H), 3.24 (dd, J = 14.0, 4.5 Hz, 1H),
2.90 (dd, J = 14.0, 9.5 Hz, 1H), 1.32 – 1.25 (m, 3H), 1.19 – 1.12
(m, 3H). 13C NMR (101 MHz, CDCl3) δ 168.3, 158.5, 135.8,
129.0, 127.0, 109.5, 75.2, 62.4, 61.9, 49.0, 37.1, 14.1, 13.9.

6
Tetrahedron
HRMS (ESI) calcd. for C16H19NNaO6 [M + Na]+ 344.1110,
5.5 Hz, 1H), 4.38 – 4.24 (m, 2H), 4.20 – 4.17 (m, 2H), 3.72 –
ACCEPTED MANUSCRIPT
found 344.1143.
3.52 (m, 1H), 1.88 – 1.74 (m, 1H), 1.62 – 1.46 (m, 1H), 1.29 –
1.27 (m, 8H), 0.90 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 167.2, 157.5, 151.2, 82.3, 59.7, 49.4, 30.5, 17.5, 11.9,
11.0. HRMS (ESI) calcd. for C12H19NNaO5 [M + Na]+ 280.1161,
found 280.1159.
4.3.19.
3,5-Bis(ethoxycarbonyl)-4-(thiophen-2-yl)-4,5-
dihydroisoxazole 2-oxide (2s): (Isolated yield 90% as black
solid). Mp = 95–96 °C. Purified by column chromatography on
silica gel, Rf (20% ethyl acetate/hexane) 0.93. IR: 3107, 2962,
1758, 1730, 1625, 1402, 1218, 1015, 753 cm-1. H NMR (400
4.3.25. 4-Butyl-3,5-bis(ethoxycarbonyl)-4,5-dihydroisoxazole
2-oxide (2w): (Isolated yield 14% as yellow oil). Purified by
column chromatography on silica gel, Rf (20% ethyl
acetate/hexane) 0.93. IR (neat) 2959, 2934, 1731, 1633, 1231,
1
MHz, CDCl3) δ 7.30 – 7.16 (m, 1H), 7.01 (d, J = 3.5 Hz, 1H),
6.93 (dd, J = 11.0, 7.0 Hz, 1H), 5.17 – 5.06 (d, J = 3.0 Hz, 1H),
4.93 (d, J = 3.0 Hz, 1H), 4.36 – 4.04 (m, 4H), 1.36 – 1.24 (m,
3H), 1.22 – 1.09 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 166.7,
156.9, 138.7, 126.5, 125.0, 107.4, 77.9, 61.8, 61.1, 47.5, 13.1,
12.9. HRMS (ESI) calcd. for C13H15NNaO6S [M + Na]+
336.0518, found 336.0548.
1014, 856 cm-1. H NMR (400 MHz, CDCl3) δ 4.67 (d, J = 3.0
1
Hz, 1H), 4.34 – 4.16 (m, 4H), 3.65 – 3.55 (m, 1H), 1.87 – 1.77
(m, 1H), 1.70 (dd, J = 9.0, 5.5 Hz, 1H), 1.36 – 1.22 (m, 10H),
0.90 – 0.83 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 168.1, 157.3,
108.2, 75.0, 61.5, 61.1, 46.4, 30.6, 26.8, 21.1, 13.4, 12.6. HRMS
(ESI) calcd. for C13H21NNaO6 [M + Na]+ 310.1267, found
310.1297.
4.3.20.
3,5-Bis(ethoxycarbonyl)-4-(thiophen-3-yl)-4,5-
dihydroisoxazole 2-oxide (2t): (Isolated yield 89% as black
solid). Mp = 58–60 °C. Purified by column chromatography on
silica gel, Rf (20% ethyl acetate/hexane) 0.91. IR (neat) 3092,
4.3.26.
Diethyl
4-butyl-4,5-dihydroisoxazole-3,5-
2985, 2907, 1751, 1726, 1624, 1211, 1015, 750 cm-1. H NMR
dicarboxylate (3w): (Isolated yield 76% as yellow oil). Purified
by column chromatography on silica gel, Rf (20% ethyl
acetate/hexane) 0.93. IR (neat) 2959, 2932, 1720, 1377, 1206,
1110, 1017, 770 cm-1. 1H NMR (400 MHz, CDCl3) δ 4.78 (d, J =
5.5 Hz, 1H), 4.28 (dd, J = 7.5, 3.5 Hz, 2H), 4.18 (dd, J = 7.5, 2.5
Hz, 2H), 3.68 – 3.59 (m, 1H), 1.83 (m, 1H), 1.57 – 1.54 (m, 1H),
1.32 – 1.21 (m, 10H), 0.88 – 0.83 (m, 3H). 13C NMR (101 MHz,
CDCl3) δ 168.0, 158.5, 152.3, 83.6, 60.8, 50.8, 29.7, 26.9, 20.7,
13.4, 12.8. HRMS (ESI) calcd. for C13H21NNaO5 [M + Na]+
294.1317, found 294.1339.
1
(400 MHz, CDCl3) δ 7.31 (dd, J = 5.0, 3.0 Hz, 1H), 7.24 – 7.16
(m, 1H), 7.02 (dd, J = 5.0, 1.5 Hz, 1H), 4.92 (d, J = 3.0 Hz, 1H),
4.88 (d, J = 3.0 Hz, 1H), 4.26 (d, J = 7.5 Hz, 2H), 4.16 (dd, J =
11.5, 7.5 Hz, 2H), 1.28 (t, J = 7.5 Hz, 3H), 1.15 (t, J = 7.5 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 168.1, 158.1, 137.7, 127.5,
125.9, 123.0, 108.6, 78.2, 62.7, 62.1, 47.9, 14.1, 14.0. HRMS
(ESI) calcd. for C13H15NNaO6S [M + Na]+ 336.0518, found
336.0526.
4.3.21. 3,5-Bis(ethoxycarbonyl)-4-ethyl-4,5-dihydroisoxazole
2-oxide (2u): (Isolated yield 13% as yellow oil). Purified by
column chromatography on silica gel, Rf (20% ethyl
acetate/hexane) 0.94. IR (neat) 3412, 2980, 2941, 1720, 1651,
4.3.27. 3,5-Bis(ethoxycarbonyl)-4-isobutyl-4,5-dihydroisoxazole
2-oxide (2x): (Isolated yield 90% as yellow oil). Purified by
column chromatography on silica gel, Rf (20% ethyl
acetate/hexane) 0.94. IR (neat) 3413, 2960, 2873, 1720, 1230,
1562, 1233, 1013 cm-1. H NMR (400 MHz, CDCl3) δ 4.67 (d, J
1
1
= 3.0 Hz, 1H), 4.32 – 4.21 (m, 4H), 3.61 – 3.55 (m, 1H), 1.91 –
1.87 (m, 1H), 1.81 – 1.69 (m, 1H), 1.35 – 1.20 (m, 6H), 1.05 –
0.93 (t, J = 6.5 Hz 3H). 13C NMR (101 MHz, CDCl3) δ 167.7,
157.6, 108.9, 74.6, 61.3, 60.7, 48.0, 24.0, 12.9, 9.1. HRMS (ESI)
calcd. for C11H17NNaO6 [M + Na]+ 282.0954, found 282.0968.
1015 cm-1. H NMR (400 MHz, CDCl3) δ 4.67 (d, J = 2.5 Hz,
1H), 4.33 – 4.15 (m, 4H), 3.69 – 3.60 (m, 1H), 1.71 (d, J = 7.0
Hz, 1H), 1.66 – 1.60 (m, 2H), 1.26 (dt, J = 9.5, 7.5 Hz, 6H), 0.93
(t, J = 7.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 168.7, 158.6,
109.4, 76.2, 62.4, 61.9, 46.0, 40.6, 25.5, 23.3, 21.1, 14.0. HRMS
(ESI) calcd. for C13H21NNaO6 [M + Na]+ 310.1267, found
310.1295.
4.3.22. Diethyl 4-ethyl-4,5-dihydroisoxazole-3,5-dicarboxylate
(3u): (Isolated yield 64% as yellow oil). Purified by column
chromatography on silica gel, Rf (20% ethyl acetate/hexane)
0.95. IR (neat) 2962, 2878, 1719, 1258, 1225, 1207, 1015, 793
4.3.28. 3,5-Bis(ethoxycarbonyl)-4-pentyl-4,5-dihydroisoxazole
2-oxide (2y): (Isolated yield 94% as yellow oil). Purified by
column chromatography on silica gel, Rf (20% ethyl
acetate/hexane) 0.95. IR (neat) 2956, 2927, 1239, 1112, 917 cm-1.
1H NMR (400 MHz, CDCl3) δ 4.79 (d, J = 5.5 Hz, 1H), 4.33 –
4.23 (m, 2H), 4.23 – 4.12 (m, 2H), 3.65 – 3.62 (m, 1H), 1.88 –
1.76 (m, 1H), 1.56 – 1.53 (m, 1H), 1.34 – 1.22 (m, 12H), 0.84 –
0.82 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 169.2, 159.9, 153.6,
84.5, 62.2, 62.0, 51.6, 31.1, 30.9, 26.0, 22.3, 14.0, 13.9. HRMS
(ESI) calcd. for C14H23NNaO6 [M + Na]+ 324.1423, found
324.1439.
cm-1. H NMR (400 MHz, CDCl3) δ 4.79 (d, J = 5.5 Hz, 1H),
1
4.41 – 4.24 (m, 2H), 4.24 – 4.10 (m, 2H), 3.70 – 3.56 (m, 1H),
1.98 – 1.75 (m, 1H), 1.73 – 1.58 (m, 1H), 1.39 – 1.15 (m, 6H),
0.92 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 168.3,
158.9, 152.4, 83.1, 61.1, 51.9, 23.1, 13.2, 9.5. HRMS (ESI)
calcd. for C11H17NNaO5 [M + Na]+ 266.1004, found 266.1026.
4.3.23. 3,5-Bis(ethoxycarbonyl)-4-propyl-4,5-dihydroisoxazole
2-oxide (2v): (Isolated yield 14% as yellow oil). Purified by
column chromatography on silica gel, Rf (20% ethyl
acetate/hexane) 0.94. IR (neat) 3411, 2965, 2938, 2876, 1724,
1654, 1375, 1228, 1013 cm-1. 1H NMR (400 MHz, CDCl3) δ 4.67
(d, J = 2.5 Hz, 1H), 4.36 – 4.14 (m, 4H), 3.64 – 3.62 (m, 1H),
1.86 – 1.75 (m, 1H), 1.70 – 1.68 (m, 1H), 1.43 – 1.40 (m, 2H),
1.26 (dt, J = 11.5, 7.1 Hz, 6H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 167.8, 159.0, 103.5, 74.9, 62.9, 61.6, 61.2,
46.5, 32.8, 24.9, 13.1, 12.2. HRMS (ESI) calcd. for
C12H19NNaO6 [M + Na]+ 296.1110, found 296.1138.
4.3.29. 3,5-Bis(ethoxycarbonyl)-4-octyl-4,5-dihydroisoxazole
2-oxide (2z): (Isolated yield 94% as pale yellow oil). Purified by
column chromatography on silica gel, Rf (20% ethyl
acetate/hexane) 0.95. IR (neat) 3413, 2925, 2855, 1725, 1627,
1465, 1191, 1111, 859 cm-1. H NMR (400 MHz, CDCl3) δ 4.67
1
(d, J = 2.5 Hz, 1H), 4.32 – 4.17 (m, 4H), 3.65 – 3.57 (m, 1H),
1.87 – 1.77 (m, 1H), 1.75 – 1.65 (m, 1H), 1.27 – 1.34 (m, 18H),
0.81 – 0.79 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 168.8, 158.6,
108.9, 76.0, 62.4, 62.0, 47.7, 31.8, 29.3, 29.1, 29.0, 25.8, 22.6,
14.0.HRMS (ESI) calcd. for C17H29NNaO6 [M + Na]+ 366.1893,
found 366.1921.
4.3.24.
Diethyl
4-propyl-4,5-dihydroisoxazole-3,5-
dicarboxylate (3v): (Isolated yield 74% as yellow oil). Purified
by column chromatography on silica gel, Rf (20% ethyl
acetate/hexane) 0.94. IR (neat) 3421, 2976, 2928, 1734, 1634,
1217, 1105 1006 cm-1. 1H NMR (400 MHz, CDCl3) δ 4.78 (d, J =
4.3.30. Diethyl 4-(2-nitrophenyl)isoxazole-3,5-dicarboxylate
(4h): (Isolated yield 86% as colorless solid). Mp. 71–73 °C.

7
C. D.; Klotz, K.-N. Bioorg. Med. Chem. 1998, 6, 401–408; (f)
Purified by column chromatography on silica gel, Rf (20% ethyl
acetate/hexane) 0.92. IR (neat) 2986, 2968, 1727, 1522, 1345,
ACCEPTED MANUSCRIPT
1197, 1020, 851, 792 cm-1. H NMR (400 MHz, CDCl3) δ 8.20
Ko, D.-H.; Maponya, M. F.; Khalil, M. A.; Oriaku, E. T.; You, Z.;
Lee, J. Med. Chem. Res. 1998, 8, 313–324.
1
3. (a) Righi, P.; Marotta, E.; Landuzzi, A.; Rosini, G. J. Am. Chem.
Soc. 1996, 118, 9446–9447; (b) Righi, P.; Marotta, E.; Landuzzi
A.; Rosini, Chem.–Eur. J. 1998, 4, 2501–2512; (c) Sommermann,
T.; Kim, B. G.; Peters, E.-M.; Linker T. Chem. Commun. 2004,
2624–2625; (d) Nishiuchi, M.; Sato, H.; Umemoto N.; Murakami,
S. Chem. Lett. 2008, 37, 146–147; (e) Smirnov, V. O.;
Sidorenkov, A. S.; Khomutova, Y. A.; Ioffe, S. L.; Tartakovsky,
V. A. Eur. J. Org. Chem. 2009, 3066–3074.
(dd, J = 8.5, 1.5 Hz, 1H), 7.62 (ddd, J = 9.5, 8.0, 1.5 Hz, 2H),
7.33 (dd, J = 7.5, 1.5 Hz, 1H), 4.33 – 4.08 (m, 4H), 1.19 – 1.16
(m, 6H). 13C NMR (101 MHz, CDCl3) δ 156.6, 154.7, 153.8,
152.6, 145.7, 130.9, 130.5, 128.0, 122.6, 121.4, 120.7, 60.4, 60.4,
11.6, 11.6. HRMS (ESI) calcd. for C15H14N2NaO7 [M + Na]+
357.0699, found 357.0722.
4. (a) Kozikowski, A. P.; Stein, P. D. J. Am. Chem. Soc. 1982, 104,
4023–4024; (b) Bode, J. W.; Carreira, E. M. Org. Lett. 2001, 3,
1587–1590.
5. (a) Kozikowski, A. P.; Chen, Y. Y. J. Org. Chem. 1981, 46, 5248–
5255; (b) Muller, I.; Jager, V. Tetrahedron Lett. 1982, 23, 4777–
4780.
6. (a) Jager, V.; Grund, H. Angew. Chem., Int. Ed. Engl. 1976, 15,
50–58; (b) Lee, S. Y.; Lee, B. S.; Lee, C.-W.; Oh, D. Y. J. Org.
Chem. 2000, 65, 256–257.
7. (a) Moersch, G. W.; Wittle, E. L.; Neuklis, W. A. J. Org. Chem.
1967, 32, 1387–1390; (b) Yashiro, A.; Nishida, Y.; Kobayashi, K.;
Ohno, M. Synlett 2000, 361–362.
4.3.31. Diethyl 4-(4-nitrophenyl)isoxazole-3,5-dicarboxylate
(4j): (Isolated yield 90% as colorless crystals). Mp = 110–113
°C. [Lit.14d Mp
=
112–113 °C]. Purified by column
chromatography on silica gel, Rf (20% ethyl acetate/hexane)
0.92. IR (neat) 2980, 2924, 1720, 1602, 1415, 1107, 1009 cm-1.
1H NMR (400 MHz, CDCl3) δ 8.25 – 8.23 (m, 2H), 7.55 – 7.44
(m, 2H), 4.44 – 4.17 (m, 4H), 1.41 – 1.13 (m, 6H). 13C NMR (101
MHz, CDCl3) δ 158.8, 157.2, 155.9, 154.8, 133.6, 131.3, 130.1,
123.7, 123.0, 62.8, 13.9. HRMS (ESI) calcd. C15H14N2NaO7 [M +
Na]+ 357.0699, found 357.0758.
8. (a) Kunetsky, R. A.; Dilman, A. D.; Ioffe, S. L.; Struchkova, M. I.;
Strelenko, Y. A.; Tartakovsky. V. A. Org. Lett. 2003, 5, 4907–
4909; (b) Johnson, C. R.; Lockard, J. P.; Kennedy, E. R. J. Org.
Chem. 1980, 45, 264–271; (c) Shechter, H.; Conrad, F. J. Am.
Chem. Soc. 1954, 76, 2716-2720; (d) An, J.; Lu, L-Q.; Yang, Q-
Q.; Wang, T.; Xiao, W-J. Org. Lett. 2013, 15, 542–545; (e)
Bianchi, L.; Ghelfi, F.; Giorgi, G.; Maccagno, M.; Petrillo, G.;
Spinelli, D.; Stenta, M.; Tavani, C. Eur. J. Org. Chem. 2013,
6298–6309; (f) Zhong, C.; Gautam, N. L. S.; Petersen, J. L.;
Akhmedov, N. G.; Shi, X. Chem. Eur. J. 2010, 16, 8605–8609; (g)
Kaji, E.; Zen, S.; Chem. Pharm. Bull. 1980, 28, 479–486; (h)
Zhong, C.; Gautam, L. N. S.; Wang, D.; Akhmedov, N. G.;
Petersen, J. L.; Shi, X. Tetrahedron 2011, 67, 4402–4411; (i)
Zhou, R.; Duan, C.; Yang, C.; He, Z. Chem. Asian J. 2014, 9,
1183–1189; (j) Harada, K.; Kaji, E.; Sasaki, K.; Zen, S.
Heterocycles 1996, 42, 289–304; (k) Harada, K.; Sasaki, K.; Kaji,
E.; Zen, S. Heterocycles 1993, 36, 449–454.
9. (a) Kano, T.; Yamamoto, A.; Song S.; Maruoka, K. Chem.
Commun. 2011, 47, 4358–4360; (b) Shi, Z.; Tan, B.; Leong, W.
W. Y.; Zeng, X.; Lu, M.; Zhong, G. Org. Let. 2010, 12, 5402–
5405; (c) Jiang, H.; Elsner, P.; Jensen, K. L.; Falcicchio, A.;
Marcos, V.; Jørgensen, K. A. Angew. Chem., Int. Ed. Engl. 2009,
48, 6844–6848; (d) Zhu, C-Y.; Deng, X-M.; Sun, X-L.; Zheng, J-
C.; Tang, Y. Chem. Commun. 2008, 738–740.
4.3.32. Diethyl 4-(3-chlorophenyl)isoxazole-3,5-dicarboxylate
(4l): (Isolated yield 85% as dark red viscous liquid). Purified by
column chromatography on silica gel, Rf (20% ethyl
acetate/hexane) 0.95. IR (neat) 2982, 2956, 1725, 1512, 1365,
1137, 1025, 853, 732 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.38 –
7.32 (m, 1H), 7.32 – 7.23 (m, 2H), 7.19 – 7.16 (m, 1H), 4.29 -–
4.25 (m, 4H), 1.24 – 1.22 (m, 6H). 13C NMR (101 MHz, CDCl3)
δ 158.9, 157.4, 156.1, 155.1, 133.6, 130.2, 129.1, 129.1, 128.7,
128.3, 62.5, 13.9, 13.8. HRMS (ESI) calcd. C15H1435ClNNaO5 [M
+ Na]+ 346.0458, found 346.0492.
4.3.33. Diethyl 4-(4-chlorophenyl)isoxazole-3,5-dicarboxylate
(4m): (Isolated yield 89% as colorless crystals). Mp = 72–74 °C.
[Lit.14d Mp = 75–76 °C]. Purified by column chromatography on
silica gel, Rf (20% ethyl acetate/hexane) 0.95. IR (neat) 2985,
1
2924, 1725, 1494, 1315, 1178, 1012, 835, 792 cm-1. H NMR
(400 MHz, CDCl3) δ 7.41 – 7.30 (m, 2H), 7.28 – 7.21 (m, 2H),
4.35 – 4.18 (m, 4H), 1.31 – 1.13 (m, 6H). 13C NMR (101 MHz,
CDCl3) δ 157.3, 155.4, 154.6, 153.6, 133.6, 129.8, 126.3, 123.7,
122.8, 61.1, 12.1. HRMS (ESI) calcd. C15H1435ClNNaO5 [M +
Na]+ 346.0458, found 346.0463.
10. Galli, C.; Marotta, E.; Righi, P.; Rosini G. J. Org. Chem. 1995, 60,
6624-6626.
11. Chatterjee, A.; Jha, S. C.; Joshi. N. N. Tetrahedron Lett. 2002, 43,
5287–5289.
5. Acknowledgements
12. (a) Duan, H.; Sun, X.; Liao, W.; Petersen, J. L.; Shi, X. Org. Lett.
2008, 10, 4113–4116; (b) Perez, V.; Rabasso, N.; Fadel, A. Eur. J.
Org. Chem. 2016, 320–324.
Dr. Abdul Rouf thanks the Scientific and Technological
Research Council of Turkey (TUBITAK) for the financial
support. We thank Dr. Murat Işik for his valuable suggestions
and Dilşad Susam for helping to prepare SI.
13. (a) Vieira, A. A.; Bryk, F. R.; Conte, G.; Bortoluzzi, A. J.;
Gallardo, H. Tetrahedron Lett. 2009, 50, 905–908; (b) Katritzky,
A. R.; Wang, M.; Zhang, S.; Voronkov, M. V. J. Org. Chem.
2001, 66, 6787–6791; (c) Shen, D. M.; Shu, M.; Chapman, K. T.
Org. Lett. 2000, 2, 2789-2792; (d) Shankar, B. B.; Yang, D. Y.;
Girton, S.; Ganguly, A. K. Tetrahedron Lett. 1998, 39, 2447–
2448; (e) Freeman, F.; Chen, T.; Van der Linden, J. B. Synthesis
1997, 861–862; (f) Chen, S.; Ren, J.; Wang, Z. Tetrahedron 2009,
65, 9146–9151; (g) Best, W. M.; Ghisalberti, E. L.; Powell, M. J.
Chem. Research, 1998, 388–389.
Supplementary data
Copies of 1H and 13C NMR spectra and X-Ray (CCDC
1438429) is available at http://dx.doi.org/xxxx.
References
14. (a) Cuadrado, P.; González-Nogal, A. M.; Valero. R. Tetrahedron
2002, 58, 4975–4980; (b) Waldo, J. P.; Larock, R. C. Org. Lett.
2005, 7, 5203–5205; (c) Melot, J-M.; Texier-Boullet, F.; Foucaud,
A. Synthesis 1988, 558–560; (d) Chen, K-Po.; Chen, Y-J.;
Chuang, C-P. Eur. J. Org. Chem. 2010, 5292–5300.
15. (a) He, Y.; Lin, N.-H. Synthesis 1994, 9, 989–992; (b) Nitz, T. J.;
Volkots, D. L.; Aldous, D. J.; Oglesby, R. C. J. Org. Chem. 1994,
59, 5828–5832.
16. Machetti, F.; Cecchi, L.; Trogu, E.; Sarlo, F. De. Eur. J. Org.
Chem. 2007, 435–4359.
17. (a) Marotta, E.; Micheloni, L. M.; Scardovi, N.; Righi, P. Org.
Lett. 2001, 3, 727–729; (b) Rosini, G.; Marotta, E.; Righi, P.;
Seerden, J.-P. J. Org. Chem. 1991, 56, 6258–6260.
1. Marsini, M. A.; Huang, Y.; Water, R. W. V. D.; Pettus, T. R. R.
Org. Lett. 2007, 9, 3229–3232.
2. (a) Kang, Y. K.; Shin, K. J.; Yoo, K. H.; Seo, K. J.; Hong, C. Y.;
Lee, C.-S.; Park, S. Y.; Kim, D. J.; Park, S. W. Bioorg. Med.
Chem. Lett. 2000, 10, 95–99; (b) Talley, J. J.; Brown, D. L.;
Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J. L.;
Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.;
Zweifel, B. S.; Seibert, K. J. Med. Chem. 2000, 43, 775–777; (c)
Frølund, B.; Jørgensen, A. T.; Tagmose, L.; Stensbøl, T. B.;
Vestergaard, H. T.; Engblom, C.; Kristiansen, U.; Sanchez, C.;
Krogsgaard-Larsen, P.; Liljefors, T. J. Med. Chem. 2002, 45,
2454–2468; (d) Giovannoni, M. P.; Vergelli, C.; Ghelardini, C.;
Galeotti, N.; Bartolini, A.; Dal Piaz, V. J. Med. Chem. 2003, 46,
1055–1059; (e) Conti, P.; Dallanoce, C.; Amici, M. D.; Micheli,
18. Li, C-J.; Trost, B. M. Proc. Natl Acad. Sci. USA. 2008, 36, 13197–
13202.