Synthesis of 3,4-diaryl-5-carboxy-4,5-dihydroisoxazole 2-oxides as valuable synthons for anticancer molecules

Article abstract of DOI:10.1016/j.tet.2017.10.016

The convenient regioselective scalable synthesis of 3,4-diaryl-5-carboxy-4,5-dihydroisoxazole 2-oxides was developed based on a condensation of simple starting materials (arylbenzaldehydes, arylnitromethanes, and ethoxycarbonylmethylpyridinium bromide) un

Full text of DOI:10.1016/j.tet.2017.10.016

Accepted Manuscript
Synthesis of 3,4-diaryl-5-carboxy-4,5-dihydroisoxazole 2-oxides as valuable synthons
for anticancer molecules
Natalia B. Chernysheva, Anna S. Maksimenko, Fedor A. Andreyanov, Victor P. Kislyi,
Yuri A. Strelenko, Victor N. Khrustalev, Marina N. Semenova, Victor V. Semenov
PII:
S0040-4020(17)31031-1
10.1016/j.tet.2017.10.016
TET 29019
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 May 2017
Revised Date: 24 September 2017
Accepted Date: 9 October 2017
Please cite this article as: Chernysheva NB, Maksimenko AS, Andreyanov FA, Kislyi VP, Strelenko YA,
Khrustalev VN, Semenova MN, Semenov VV, Synthesis of 3,4-diaryl-5-carboxy-4,5-dihydroisoxazole
2-oxides as valuable synthons for anticancer molecules, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.10.016.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

1
ACCEPTED MANUSCRIPT
Graphical Abstract

2
ACCEPTED MANUSCRIPT
Synthesis of 3,4-diaryl-5-carboxy-4,5-dihydroisoxazole 2-oxides as valuable synthons for
anticancer molecules
a
a
a
a
Natalia B. Chernysheva, Anna S. Maksimenko, Fedor A. Andreyanov, Victor P. Kislyi, Yuri A.
a
b,c
d
a,
Strelenko, Victor N. Khrustalev, Marina N. Semenova, Victor V. Semenov *
a
N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian
Federation
b
Faculty of Science, RUDN University, 6 Miklukho-Maklay Street, 117198 Moscow, Russian
Federation
c
A. N. Nesmeyanov Institute of Organoelement Compounds RAS, 28 Vavilov Street, 119991 Moscow,
Russian Federation
d
N. K. Koltzov Institute of Developmental Biology RAS, 26 Vavilov Street, 119334 Moscow, Russian
Federation
∗
Corresponding author.
Victor V. Semenov.
Mailing address: N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991
Moscow, Russian Federation.
Phone: +7 916 620 9584
Fax: +7 499 135 5328
E-mail address: vs@zelinsky.ru
∗
Corresponding author.
E-mail address: vs@zelinsky.ru (Victor V. Semenov)

3
ACCEPTED MANUSCRIPT
Abstract
The convenient regioselective scalable synthesis of 3,4-diaryl-5-carboxy-4,5-dihydroisoxazole
-oxides was developed based on a condensation of simple starting materials (arylbenzaldehydes,
2
arylnitromethanes, and ethoxycarbonylmethylpyridinium bromide) under mild conditions. The
obtained synthons can be applied for the synthesis of 3,4-diarylisoxazole derivatives capable of
suppressing malignant growth.
Keywords:
3
3
,4-Diarylisoxazoles
,4-Diarylisoxazoline oxides
Carbonylmethylpyridinium
Anticancer synthons
1
. Introduction
Isoxazoles and isoxazolines exhibit a broad range of biological effects, including antiviral,
1
2
,3
4–8
anti-inflammatory, and anticancer activities.
Fig. 1. Chemical route to anticancer combretastatin A-4 (CA4) analogs with 3,4-diarylisoxazole
fragments. A Inhibitor of tubulin polymerization. B Hsp90 inhibitor.
o-Diarylazoles can be considered as cis-restricted analogues of combretastatin A-4 (CA4, Fig.
1
), a highly potent natural cytostatic originally isolated from the bark of African willow tree
9
Combretum caffrum. To avoid cis-trans isomerization that causes activity decrease, diverse N-
containing rings have been introduced to replace the ethene linker, resulting in compounds with

4
ACCEPTED MANUSCRIPT
1
0
antiproliferative antitubulin effects comparable with those of CA4. Among them, 5-unsubstituted
diaryl-o-isoxazole A (Fig. 1) effectively inhibited both cancer cell growth and in vitro tubulin
5
,7
polymerization. Polyoxygenated 3,4-diarylisoxazoles with 5-carboxamide groups (e.g., B, Fig. 1)
were reported to inhibit Hsp90, a chaperone protein that assists folding of various proteins including
8
those implicated in malignancy.
Several synthetic strategies for diarylisoxazolines and diarylisoxazoles have been reported. Due
to the challenges in regioselective functionalization, currently available synthetic routes for 3,4-
diarylisoxazoline N-oxides as well as for 3,4-diarylisoxazoles are rather scarce. The known methods
require expensive and commercially inaccessible reagents and catalysts, give low yields, and are
1
1
practically not scalable. Considering the literature evidence, the present study was aimed to the
development of an efficient, inexpensive, and scalable procedure for regioselective synthesis of 3,4-
diaryl-isoxazoline N-oxides 5-carboxylates (C, Fig. 1) from available materials under mild conditions.
1
2–14
The ability of isoxazolines to rearrange readily to the respective isoxazoles
use in the preparation of molecules with potential anticancer activity.
allows for their further
2
. Results and discussion
Recently it was shown that arylmethylidene nitro acetic esters 1 reacted with ethoxycarbonyl
methylpyridinium bromide 2 in the presence of Et N to afford 4-aryl-isoxazole-3,5-dicarboxylates 3 in
3
1
5
high yields (Scheme 1).
Scheme 1. Synthesis of diethyl 4-(aryl)isoxazole-3,5-dicarboxylates 3.

5
ACCEPTED MANUSCRIPT
A reproduction of this reaction using 3-(3,4,5-trimethoxyphenyl)-2-nitropropene derivative of 1
showed a formation of intermediate isoxazoline oxide 4a (Scheme 2). Notably, isoxazole 3a was the
only product at the reaction temperature of 20–60 °C, whereas at 10 °C both 3a and 4a were found in
1
the reaction mixture. Isoxazoline N-oxide 4a was separated, and its structure was confirmed by H-
NMR-, MS-, and X-ray analyses (Fig. 2). This result led to a proposal that 3,4-diaryl-5-
ethoxycarbonyl-4,5-dihydroisoxazole 2-oxides 8 could be obtained selectively by the reaction of
diarylnitrostilbenes 7 with pyridinium salt 2. Corresponding starting nitrostilbenes 7a–j were easily
1
6,17
synthesized by condensation of phenylnitromethanes 5 with aldehydes 6.
formed as single products under the mild conditions at different temperatures and reaction times: 20
C, 100–200 h, or 60 °C, 4–5 h. Importantly, the starting pyridinium bromide 2 and nitrostilbenes 7 can
be readily obtained in an amount of 10–20 g, affording isoxazolines 8 in multi-gram scale. The
Isoxazolines 8a–j were
°
1
13
structures of 8 were proved by H-, C-NMR-, and MS-analyses.
Scheme 2. Synthesis of 3,4-diaryl-5-ethoxycarbonyl-4,5-dihydroisoxazole 2-oxides 8.

6
ACCEPTED MANUSCRIPT
The rearrangement of 3,4-diarylisoxazoline oxides to isoxazoles is well documented in the
1
2–14
literature.
As an example, we selected a procedure in water solution of 2% NaOH at room
1
2
temperature for the rearrangement of 8a (Scheme 3).
Scheme 3. Rearrangement of 3,4-diarylisoxazoline oxide 8a to the respective isoxazole 10a.
4
-(4-Chlorophenyl)-5-(ethoxycarbonyl)-3-(4-methoxyphenyl)-4,5-dihydroisoxazole 2-oxide (8a) was
quantitatively hydrolysed to the corresponding 3,4-diaryl-4,5-dihydroisoxazole 2-oxide (9a) in acidic
medium. Then 9a was rearranged in alkaline medium with simultaneous decarboxylation directly to
unsubstituted isoxazole 10a at 20 °C (200 h) or 60 °C (6 h). 10a was easily separated in alkaline media
in good yield over two steps (67%).
Isoxazoline N-oxide 4a was characterized by single-crystal X-ray diffraction study. The structure
is shown in Figure 2 along with the atomic numbering schemes. The geometrical parameters for 4a are
available in the Supplementary Data. The central isoxazoline ring adopted an envelope conformation,
with the C5 carbon atom deviating from the mean plane passed through the other atoms of the ring by
0
.222(2) Å. The 4-phenyl and 5-ethoxy carbonyl substituents were located in gauche (trans)
configuration (-127.86(10)°). Thus, the crystal of 4a consisted of enantiomeric pairs with the
4RS,5RS)-relative configuration of the asymmetric centers. The 3-carboxylate fragment lay within the
(
basal plane of the isoxazoline ring (the dihedral angle is 4.16(7)°). The ethoxy group of the 3-
carboxylate substituent had gauche conformation relative to the carbonyl group (the C6─O4─C7─C8
torsion angle is -78.47(14)°), while the ethoxy group of the 5-carboxylate substituent was trans
arranged to the carbonyl group (the C18─O9─C19─C20 torsion angle is 174.99(10)°). The 3- and 5-
methoxy groups in 4-(3,4,5-trimethoxyphenyl) substituent were coplanar to the plane of the benzene
ring (the C10─C11─O5─C15 and C14─C13─O7─C17 torsion angles are -3.31(17) and 0.23(17)°,
respectively), whereas the 4-methoxy group in 4-(3,4,5-trimethoxyphenyl) substituent was rotated
relative to the benzene plane (the C11─C12─O6─C16 torsion angle is 83.78(13)°).

7
ACCEPTED MANUSCRIPT
Fig. 2. Molecular structure of 3,5-bis(ethoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)-4,5-
dihydroisoxazole 2-oxide 4a (50% ellipsoids).
3
. Conclusions
The regioselective synthesis of 3,4-diaryl-isoxazoline N-oxide-5-carboxylates 8 was designed
based on a condensation of arylbenzaldehydes and arylnitromethanes followed by interaction with
ethoxycarbonylmethylpyridinium bromide and intramolecular cyclization. The reaction required
readily available and inexpensive starting materials, proceeded under mild conditions, and could be
reproduced on multi-gram scale. The ability of isoxazolines 8 to rearrange readily to the respective 5-
carbalkoxy-3,4-diarylisoxazoles and 5-unsubstituted 3,4-diarylisoxazoles allows for their potential
application in synthesis of possible anticancer drugs. Transformation of isoxazolines 8 to 3,4-
diarylisoxazoles depending on reaction conditions and different substituents will be published later.
4
. Experimental section
4
.1. General methods

8
ACCEPTED MANUSCRIPT
1
Melting points were measured on a Boetius melting point apparatus and were uncorrected. H
1
3
NMR and C NMR spectra were recorded on a Bruker DRX-500 instrument [working frequencies of
1
13
5
00.13 MHz ( H) and 125.76 MHz ( C)]. Chemical shifts were stated in parts per million (ppm) and
referenced to the appropriate NMR solvent peaks. Spin-spin coupling constants (J) were reported in
Hertz (Hz). NMR spectra (Supporting Information) were prepared using an original software designed
at N. D. Zelinsky Institute of Organic Chemistry RAS (Moscow, Russian Federation)
(http://nmr.ioc.ac.ru:8080/SDF2PDF.kl1). IR spectra nave been measured by Bruker AlphaT
instrument. Low resolution mass spectra (m/z) were recorded on a Finnigan MAT/INCOS 50 mass
spectrometer at 70 eV using direct probe injection. High resolution mass spectra (HRMS) were
measured on a Bruker maXis and micrOTOF II instruments using electrospray ionization (ESI).
Elemental analysis was performed on the automated Perkin-Elmer 2400 CHN microanalyzer. Flash
chromatography was carried out on silica gel (Acros, 0.035–0.070 mm, 60 Å). TLC was performed on
Merck 60 F254 plates. Solvents, benzaldehydes, and ethyl bromoacetate were purchased from Acros
Organics (Belgium) at the highest commercial quality and used as received. 4,7-Dimethoxy-2H-1,3-
1
8
benzodioxole-5-carbaldehyde was synthesized from apiol, isolated from parsley seed extract.
1
9
Phenylnitromethanes 5 were synthesized by modified procedure (see below).
4
.2. General experimental procedure for the synthesis of compounds 3a and 4a
2
0
A mixture of ethyl 2-nitro-3-(3,4,5-trimethoxyphenyl)propenoate (0.362 g, 1.16 mmol),
ethoxycarbonylmethylpyridinium bromide (0.430 g, 1.75 mmol), acetonitrile (10 mL), and
triethylamine (0.352 g, 3.5 mmol) was stirred at 10 °C for 45 h, then acidified with 10% aqueous HCl
(pH 1–2). The reaction mixture was evaporated and dissolved in methylene chloride (50 mL); the
solution was washed with water (4 × 20 mL), filtered and dried using cotton wool. All volatiles were
removed in vacuo. The resulting oil (0.3 g) was passed through silica gel column eluted with
benzene/ethyl acetate mixtures (19:1 to 9:1) to give diethyl 4-(3,4,5-trimethoxyphenyl)isoxazole-3,5-
dicarboxylate 3a (0.026 g, 6%) and 3,5-bis-(ethoxycarbonyl)-4-(3,4,5-trimethoxyphenyl)-4, 5-
dihydroisoxazole 2-oxide 4a (0.081 g, 18%).
4
.2.1. Diethyl 4-(3,4,5-trimethoxyphenyl)isoxazole-3, 5-dicarboxylate (3a)
White crystals; 0.026 g (6%); mp 115–117 °C; R = 0.5 (benzene/ethyl acetate = 9:1); H NMR
1
f
(
500 MHz, CDCl3) δ 6.62 (2H, s, H-2′,6′), 4.31–4.38 (4H, m, OCH ), 3.90 (3H, s, OMe), 3.85 (6H, s,
2

9
ACCEPTED MANUSCRIPT
1
3
OMe), 1.30 (6H, t, J = 7.0 Hz, Me); C NMR (500 MHz, CDCl
3
) δ 13.6 (2C), 55.9(2C), 60.0,
6
1.9+62.0, 107.9 (2C), 121.9, 124.3, 137.8, 152.1(2C), 155.5, 155.8, 156.5, 158.6. νmax (KBr) 1733
-1
(
COO), 1336 (Ar), 1246 (OEt), 1228 (MeOPh) cm ; EIMS m/z 379 [M]+ (100), 362 (4), 306 (21), 233
18). Anal. Calcd for C18 : C, 56.99; H, 5.58; N, 3.69. Found: C, 57.13; H, 5.48; N, 3.71.
(
H21NO
8
4
.2.2. 3,5-Bis-(ethoxycarbonyl)-4-(3, 4, 5-trimethoxyphenyl)-4, 5-dihydroisoxazole 2-oxide (4a)
1
Yellow crystals; 0.081 g (18%); mp 168–170 °C; R
NMR (500 MHz, CDCl 6.50 (2H, s, H-2′,6′), 4.93 (1H, d, J = 3.0 Hz, H-4), 4.78 (1H, d, J = 3.0 Hz,
H-5), 4.32–4.37 (2H, m, OCH ), 4.20–4.27 (2H, m, OCH ), 3.86 (6H, s, OMe), 3.84 (3H, s, OMe), 1.35
f
= 0.35 (benzene/ethyl acetate = 9:1); H
3
) δ
2
2
1
3
(
3H, t, J = 7.0 Hz, Me), 1.22 (3H, t, J = 7.0 Hz, Me); C NMR (500 MHz, CDCl )
δ
14.1, 14.3, 52.4,
3
5
1
6.3 (2C), 60.4, 61.7, 62.3, 78.3, 105.0 (2C), 109.9, 134.3, 137.7, 153.6 (2C), 158.1, 168.3. νmax (KBr)
-1
760 (5-COO), 1732 (3-COO), 1627 (Ar) cm ; EIMS m/z 397 [M]+ (100), 379 (4), 295 (30), 264
(
63). Anal. Calcd for C H NO : C, 54.40; H, 5.83; N, 3.52. Found: C, 54.49; H, 5.97; N, 3.42.
18 23 9
4
.3. Methoxyphenylnitromethane (5a)
Solid sodium perborate tetrahydrate (55.4 g, 0.36 mol) was added by small portions during 40
min to a stirred solution of p-methoxybenzaldehyde oxime (9 g, 60 mmol) in glacial acetic acid (300
mL) at 60 °C. Reaction mixture was stirred at 60 °C for 4–5 h and stored overnight at room
temperature. The cooled reaction mixture was poured into ice water (350 mL) and extracted with
methylene chloride (2 × 100 mL followed by 1 × 50 mL). Combined extracts were washed with water
(2 × 100 mL), 1 N aqueous solution of NaOH (2 × 100 mL), and water until pH 7, then filtered and
dried using cotton wool. The solvent was removed in vacuo to afford 4-methoxyphenylnitromethane 5a
1
as a yellow oil (4.83 g, 44% yield); H NMR (300 MHz, CDCl )
δ
7.38 (2H, d, J = 8.5 Hz, H-2,6), 6.94
3
(
2H, d, J = 8.5 Hz, H-3,5), 5.38 (2H, s, CH ), 3.82 (3H, s, OMe) (corresponds to published NMR
2
2
1
spectra of 5a ). During this procedure anisic acid and 4-methoxy-2-nitrophenol as byproducts were
separated from combined washing solutions (water and 1 N NaOH). Dark red alkaline solution was
acidified with concentrated aqueous HCl to pH 2 and extracted with methylene chloride (3 × 50 mL).
The methylene chloride extract was washed with water until neutral pH, and dried by filtration through
cotton wool. The solvent was removed in vacuo and the residue (2.14 g) was treated with benzene.
White crystals were filtered and washed with benzene and petroleum ether on the filter to obtain 0.92 g
2
2
(
10%) of anisic acid as white crystals; mp 181–183 °C (lit. mp 182–185 °C); EIMS m/z 152 [M]+
(100), 136 (93). The benzene washings were partially evaporated and passed through a silica gel

1
0
ACCEPTED MANUSCRIPT
column eluted with toluene to afford 4-methoxy-2-nitrophenol as bright orange crystals (0.30 g, 6%
2
2
1
yield); mp 80–81 °C (lit. mp 78–80 °C); H NMR (500 MHz, CDCl )
δ
10.35 (1H, s, OH), 7.59 (1H,
3
d, J = 3.0 Hz, H-3), 7.21 (1H, dd, J = 9.0 Hz, J = 3.0 Hz, H-5), 7.09 (1H, d, J = 9.0 Hz, H-6), 3.33 (3H,
1
3
3
s, OMe); C NMR (500 MHz, CDCl ) δ 152.6, 150.1, 127.3, 120.9, 105.7, 60.0; EIMS m/z 169 [M]+
(92), 154 (5), 124 (12), 15 (100).
1
9
4
.4. Phenylnitromethane (5b)
Synthesized by the same procedure; 48% yield.
1
6,17
4
.5. General experimental procedure for the synthesis of 1,2-diaryl-1-nitroethylenes 7
A mixture of phenylnitromethane 5 (12 mmol), aldehyde 6 (13 mmol), MeOH (4 mL),
MeNH ⋅HCl (0.10 g), and NаHCO (0.04 g) was stirred at room temperature for 120–200 h (TLC
2
3
control) or at 60 °C for 4–6 h. Methanol was evaporated and methylene chloride (70 mL) was added to
the mixture. The solution was washed with water (3 × 20 mL), dried by filtration through cotton wool,
then the solvent was removed and the residue was triturated with minimal amount of MeOH.
Nitroethylene crystals were filtered, washed with methanol and dried in vacuo.
4
.5.1. 2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1-nitroethylene (7a)
Yellow crystals; 1.1 g (63%); mp 121–123 °C; R = 0.35 (benzene); H NMR (500 MHz,
1
f
CDCl3) δ 8.12 (1H, s, CH=), 7.21–7.26 (4H, m, H-2′,6′; H-2′′,6′′), 7.06 (2H, d, J = 8.5 Hz, H-3′′,5′′),
1
3
7
1
1
.00 (2H, d, J = 8.5 Hz, H-3′,5′), 3.87 (3H, s, OMe); C NMR (500 MHz, CDCl )
δ
55.2, 114.6 (2C),
3
21.9, 128.8 (2C), 130.3, 132.0, 132.4 (2C), 132.9 (2C), 135.3, 149.8, 160.3; νmax (KBr) 1607 (C=C),
-1
2 s 2
523 (vas NO ), 1318 (v NO ), 1251 (PhOMe) cm ; EIMS m/z 289 [M]+ (12), 243 (88), 228 (13), 185
(
100). Anal. Calcd for C H ClNO : C, 62.19; H, 4.17; N, 4.83. Found: C, 62.25; H, 4.37; N, 4.52.
15 12 3
4
.5.2. 1-(4-Methoxyphenyl)-1-nitro-2-(4-nitrophenyl)ethylene (7b)
Yellow crystals; 2.02 g (56%); mp 133–135 °C; R = 0.46 (benzene); H NMR (500 MHz,
1
f
CDCl3) δ 8.13 (1H, s, CH=), 8.09 (2H, d, J = 9.0 Hz, H-3′′,5′′), 7.30 (2H, d, J = 9.0 Hz, H-2′′,6′′), 7.23
1
3
(
2H. d, J = 9.0 Hz, H-2′,6′), 7.00 (2H, d, J = 9.0 Hz, H-3′,5′), 3.89 (3H, s, OMe); C NMR (500 MHz,
CDCl3) δ 55.2, 114.6 (2C), 121.2, 123.5 (2C), 131.57, 131.6 (2C), 132.1 (2C), 138.2, 147.7, 152.0,
1
60.6; νmax (KBr) 1608 (C=C), 1540 (v NO ), 1517 (v NO ), 1344 (v NO ), 1324 (v NO ), 1256
as 2 as 2 s 2 s 2

1
1
ACCEPTED MANUSCRIPT
-1
(
PhOMe) cm ; EIMS m/z 300 [M]+ (11), 254 (100), 208 (12), 165 (40). Anal. Calcd for C H N O :
15 12 2 5
C, 60.00; H, 4.03; N, 9.33. Found: C, 60.10; H, 4.13; N, 9.42.
4
.5.3. 2-(3-Methoxyphenyl)-1-(4-methoxyphenyl)-1-nitroethylene (7c)
Yellow crystals; 1.62 g (57%); mp 93–95 °C; R = 0.48 (benzene); H NMR (500 MHz,
1
f
6
DMSO-d ) δ 8.23 (1H, s, CH=), 7.33 (2H, d, J = 8.5 Hz, H-2′,6′), 7.23 (1H, t, J = 8.0 Hz, H-5′′), 7.08
(2H, d, J = 8.5 Hz, H-3′,5′), 6.94 (1H, dd, J = 8.0 Hz, J = 2.5 Hz, H-6′′), 6.84 (1H, d, J = 8.0 Hz, H-4′′),
1
3
6
5
.73 (1H, brs, H-2′′), 3.84 (3H, s, OMe′), 3.63 (3H, s, OMe′′); C NMR (500 MHz, CDCl
3
) δ 55.2,
5.7, 115.0 (2C), 116.0, 117.2, 122.8, 124.2, 130.2, 132.5, 132.9 (2C), 134.6, 149.9, 159.4, 160.8; νmax
-1
(
KBr) 1611 (C=C), 1576(Ar), 1512 (v NO ), 1317 (v NO ), 1273 (PhOMe) cm ; EIMS m/z 285 [M]+
as 2 s 2
(
80), 239 (100), 224 (33), 209 (12). Anal. Calcd for C H NO : C, 67.36; H, 5.30; N, 4.91. Found: C,
16 15 4
6
7.45; H, 5.42; N, 4.76.
4
.5.4. 2-(3,5-Dimethoxyphenyl)-1-(4-methoxyphenyl)-1-nitroethylene (7d)
Yellow crystals; 2.77 g (73%); mp 132–134 °C; R = 0.44 (benzene); H NMR (500 MHz,
1
f
CDCl3) δ 8.12 (1H, s, CH=), 7.28 (2H, d, J = 9.0 Hz, H-2′,6′), 7.02 (2H, d, J = 9.0 Hz, H-3′,5′), 6.43
(1H, t, J = 2.5 Hz, H-4′′), 6.29 (2H, d, J = 2.5 Hz, H-2′′,6′′), 3.89 (3H, s, OMe′), 3.58 (6H, s, OMe′′);
1
3
C NMR (500 MHz, CDCl3) δ 55.4 (2C), 55.7, 103.2, 109.4 (2C), 115.0 (2C), 122.83, 132.5 (2C),
1
33.3, 134.7, 150.0, 160.5 (2C), 160.8; νmax (KBr) 1592 (C=C), 1509 (v NO ), 1315 (v NO ), 1296
as
2
s
2
-1
(
PhOMe) cm ; EIMS m/z 315 [M]+ (29), 269 (100), 254 (28), 239 (21). Anal. Calcd for C17
5
H17NO : C,
6
4.75; H, 5.43; N, 4.44. Found: C, 64.61; H, 5.39; N, 4.58.
4
.5.5. 1-(4-Methoxyphenyl)-1-nitro-2-(3,4,5-trimethoxyphenyl)ethylene (7e)
23
1
Yellow crystals; 1.85 g (45%); mp 136–138 °C (lit. mp 137 °C); R = 0.48 (benzene); H
f
NMR (500 MHz, CDCl3) δ 8.14 (1H, s, CH=), 7.29 (2H, d, J = 8.5 Hz, H-2′,6′), 7.02 (2H, d, J = 8.5
13
Hz, H-3′,5′), 6.4 (2H, s, H-2′′,6′′), 3.86 (3H, s, OMe′), 3.84 (3H, s, OMe′′), 3.61 (6H, s, OMe′′); C
NMR (500 MHz, CDCl3) 55.4, 55.5 (2C), 60.2, 109.0 (2C), 114.8 (2C), 122.7, 126.4, 132.3 (2C),
34.7, 139.8, 148.3, 152.6 (2C), 160.5; νmax (KBr) 1579 (C=C), 1514 (v NO ), 1501(Ar), 1312 (v
δ
1
as
2
s
-1
2
NO ), 1252 (PhOMe) cm ; EIMS m/z 345 [M]+ (38), 299 (100), 269 (21), 253 (22). Anal. Calcd for
C H NO : C, 62.60; H, 5.55; N 4.06. Found: C, 62.40; H, 5.41; N, 4.26.
1
8
19
6
4
.5.6. 1-(4-Methoxyphenyl)-1-nitro-2-(2-thienyl)ethylene (7f)

1
2
ACCEPTED MANUSCRIPT
1
Yellow crystals; 2.46 g (63%); mp 145–147 °C; R
CDCl3) 8.48 (1H, s, CH=), 7.39 (1H, d, J = 5.0 Hz, H-5′′), 7.36 (1H, d, J = 3.5 Hz, H-3′′), 7.28 (2H,
d, J = 8.5 Hz, H-2′,6′), 7.06 (2H, d, J = 8.5 Hz, H-3′,5′), 7.01 (1H, t, J = 4.5 Hz, H-4′′), 3.91 (3H, s,
f
= 0.53 (benzene); H NMR (500 MHz,
δ
1
3
OMe); C NMR (500 MHz, CDCl )
δ
55.3, 115.0 (2C), 121.6, 127.8, 129.6, 132.6 (2C), 134.9, 135.1,
3
1
1
37.9, 146.0, 160.9; νmax (KBr) 1636, 1603 (C=C), 1515 (v NO ), 1496 (PhOMe), 1301 (v NO ),
as
2
s
2
-1
245 (PhOMe) cm ; EIMS m/z 261 [M]+ (42), 215 (100), 200 (40), 184 (33), 171 (68). Anal. Calcd for
C H NO S: C, 59.76; H, 4.24; N, 5.36. Found: C, 59.88; H, 4.32; N, 5.76.
1
3
11
3
4
.5.7. 1-(4-Methoxyphenyl)-1-nitro-2-(1-methylpyrazol-4-yl)ethylene (7g)
1
Yellow crystals; 1.37 g (44%); mp 151–153 °C; R = 0.20 (benzene); H NMR (500 Hz, CDCl )
f
3
δ
3
3
8.15 (1H, s, CH=), 7.25 (2H, d, J = 8.5 Hz, H-2′,6′), 7.14 (1H, s, H-3′′), 7.04 (2H, d, J = 8.5 Hz, H-
1
3
′,5′), 6.98 (1H, s, H-5′′), 3.92 (3H, s, OMe), 3.82 (3H, s, N-Me); C NMR (500 MHz, CDCl )
δ
3
8.75, 55.2, 114.0, 114.7 (2C), 123.1, 127.6, 131.6 (2C), 134.0, 140.0, 145.3, 160.2; νmax (KBr) 1645
-1
(
C=C), 1548 (vas NO
2
), 1487 (PhOMe), 1312 (v
s 2
NO ), 1273 (PhOMe) cm ; EIMS m/z 259 [M]+ (45),
2
6
13 (100), 198 (21), 170 (13). Anal. Calcd for C H N O : C, 60.23; H, 5.05; N, 16.21. Found: C,
1
3
13
3
3
0.43; H, 5.15; N, 16.42.
4
.5.8. 2-(4-Methoxyphenyl)-1-nitro-1-phenylethylene (7h)
2
4
1
Yellow crystals; 1.4 g (34%); mp 147–149 °C (lit. mp 152–153 °C); R = 0.15 (benzene); H
f
NMR (500 MHz, CDCl3)
δ
8.25 (1H, s, CH=); 7.54 (3H, m, H-2′,4′,6′), 7.37 (2H, m, H-3′,5′), 7.06
(2H, d, J = 9.0 Hz, H-2′′,6′′), 6.78 (2H, d, J = 9.0 Hz, H-3′′,5′′), 3.80 (3H, s, OMe).
4
.5.9. 2-(3,4,5-Trimethoxyphenyl)-1-nitro-1-phenylethylene (7i)
25
1
Yellow crystals; 2.57 g (68%); mp 148–150 °C (lit. mp 147 °C); R = 0.31 (benzene); H
f
NMR (500 MHz, CDCl
3
)
δ
8.19 (1H, s, CH=); 7.53 (3H, m, H-2′,4′,6′), 7.39 (2H, m, H-3′,5′), 6.36
(2H, s, H-2′′,6′′), 3.85 (3H, s, 4′′-OMe), 3.57 (6H, s, 3′′,5′′-OMe).
4
.5.10. 2-(2,5-Dimethoxy-3,4-methylenedioxyphenyl)-1-nitro-1-phenylethylene (7j)
1
Dark orange crystals; 2.01 g (76%); mp 142–144 °C; R
DMSO-d
OCH O), 5.84 (1H, s, H-6′′), 3.98 (3H, s, OMe), 3.18 (3H, s, OMe); C NMR (500 MHz, DMSO-d
f
= 0.42 (benzene); H NMR (500 MHz,
6
) δ 8.44 (1H, s, CH=); 7.45–7.60 (3H, m H-2′,4′,6′), 7.36–7.42 (2H, m, H-3′,5′), 6.08 (2H, s,
1
3
2
6
)

1
3
ACCEPTED MANUSCRIPT
δ
147.8, 139.9, 138.6, 138.5, 138.2, 131.1, 130.7 (2C), 129.9, 129.4 (2C), 128.6, 116.0, 108.2, 102.7,
-1
6
0.6, 55.3; νmax (KBr) 1643 (C=C), 1596 (v NO ), 1305 (v NO ), 1069 (Ar) cm ; HRMS
as 2 s 2
(
ESI/QTOF) m/z: [M+H]+ Calcd for C H NO 330.0972; Found 330.0975; [M + NH ]+ Calcd for
1
7
16
6
4
C
17
H
19
N
2
O
6
347.1238; Found 347.1235. Anal. Calcd for C17
H15NO
6
: C, 62.00; H, 4.59; N, 4.25.
Found: C, 62.21; H, 4.44; N, 4.38.
4
.6. General experimental procedure for the synthesis of 3,4-diaryl-5-ethoxycarbonyl-4,5-
dihydroisoxazole 2-oxides 8
A mixture of the corresponding nitroethylene (5 mmol), ethoxycarbonylmethylpyridinium
2
6
bromide (7.5 mmol), and triethylamine (15 mmol) in dry acetonitrile (40 mL) was stirred at 60 °C for
–5 h (TLC control). Acetonitrile was removed in vacuo, and then methylene chloride (150 mL) was
4
added. The methylene chloride extract was washed with water, 5% aqueous HCl, water until pH 7, and
dried by filtration through cotton wool. Methylene chloride was removed in vacuo and the residue was
triturated in ethanol. The collected crystals were washed with ethanol and dried in air to obtain a 4,5-
dihydroisoxazole 2-oxides 8. When crystallization was unavailable, 4,5-dihydroisoxazole 2-oxides 8
were isolated by column chromatography. For each compound, the appropriate conditions are
specified.
4
.6.1. 4-(4-Chlorophenyl)-5-(ethoxycarbonyl)-3-(4-methoxyphenyl)-4,5-dihydroisoxazole 2-oxide (8a)
1
Off-white solid; 0.8 g (73%); mp 96–98 °C; R
f
= 0.51 (benzene/ethyl acetate = 9:1); H NMR
(500 MHz, CDCl
3
)
δ
7.78 (2H, d, J = 9.0 Hz, H-2′,6′), 7.35 (2H, d, J = 8.5 Hz, H-3′′,5′′'), 7.28 (2H, d, J
=
8.5 Hz, H-2′′,6′′), 6.87 (2H, d, J = 9.0 Hz, H-3′,5′), 5.03 (1H, d, J = 2.5 Hz, H-4), 4.76 (1H, d, J = 2.5
1
3
Hz, H-5), 4.33–4.36 (2H, m, OCH ), 3.79 (3H, s, OMe), 1.34 (3H, t, J = 7.0 Hz, Me); C NMR (500
2
MHz, CDCl3)
δ
169.0, 160.5, 136.9, 134.6, 129.8 (2C), 128.6 (2C), 128.4 (2C), 117.6, 114.4 (2C),
1
1
14.1, 78.4, 62.6, 55.4, 53.9, 14.1; νmax (KBr) 1764 (COO), 1614 (N=O), 1516 (PhOMe), 1262 (OEt),
-1
5
202 (Ar) cm ; EIMS m/z 375 [M]+ (4), 243 (16), 165 (38), 29 (100). Anal. Calcd for C19H18ClNO :
C, 60.72; H, 4.83; N, 3.73. Found: C, 60.60; H, 4.92; N, 3.55.
4
.6.2. 5-(Ethoxycarbonyl)-3-(4-methoxyphenyl)-4-(4-nitrophenyl)-4,5-dihydroisoxazole 2-oxide (8b)
Room temperature, 24 h, column chromatography (benzene/ethyl acetate 19:1; 9:1); off-white
1
solid; 0.62 g (53%); mp 126–128 °C; R = 0.44 (benzene/ethyl acetate = 9:1); H NMR (500 MHz,
f
3
CDCl ) δ 8.24 (2H, d, J = 8.5 Hz, H-3′′,5′′), 7.75 (2H, d, J = 9.0 Hz, H-2′,6′), 7.55 (2H, d, J = 8.5 Hz,

1
4
ACCEPTED MANUSCRIPT
H-2′′,6′′), 6.88 (2H, d, J = 9.0 Hz, H-3′,5′), 5.19 (1H, d, J = 2.5 Hz, H-4), 4.78 (1H, d, J = 2.5 Hz, H-5),
1
3
4
1
1
1
, 35 (2H, m, OCH ), 3.80 (3H, s, OMe), 1.36 (3H, t, J = 7.0 Hz, Me); C NMR (500 MHz, CDCl )δ
2 3
4.6, 54.4, 55.8, 63.4, 78.2, 114.0 (2C), 115.0 (2C), 117.6, 128.75 (2C), 128.82 (2C), 145.9, 148.5,
61.2, 169.1; νmax (KBr) 1763 (COO), 1618 (N=O), 1519 (v NO ), 1348 (v NO ), 1516 (PhOMe),
as
2
s
2
-1
262 (OEt), 1185(Ar) cm ; EIMS m/z 386 [M]+ (29), 328 (23), 313 (25), 254 (69), 29 (100). Anal.
Calcd for C H N O : C, 59.07; H, 4.70; N, 7.25. Found: C, 59.37; H, 4.90; N, 7.38.
1
9
18
2
7
4
.6.3. 5-(Ethoxycarbonyl)-4-(3-methoxyphenyl)-3-(4-methoxyphenyl)-4,5-dihydroisoxazole 2-oxide (8c)
1
White solid; 2.02 g (69%); mp 119–121 °C; R = 0.51 (benzene/ethyl acetate = 9:1); H NMR
f
(500 MHz, CDCl3)
δ
7.82 (2H, d, J = 9.0 Hz, H-2′,6′), 7.28 (1H, t, J = 8.0 Hz, H-5′′), 6.92 (1H, d, J =
7
2
.5 Hz, H-6′′), 6.84–6.88 (4H, m, H-3′,5′+H-2′′+H-4′′), 4.99 (1H, d, J = 2.5 Hz, H-4), 4.80 (1H, d, J =
1
3
.5 Hz, H-5), 4.32 (2H, m, OCH
14.2, 55.2, 55.7, 55.8, 62.6, 78.3, 114.8 (2C), 115.0, 115.4, 116.2, 120.3, 129.8, 130.0,
30.3 (2C), 131.2, 161.1, 161.4, 171.3, νmax (KBr) 1747 (COO), 1605 (N=O), 1261 (OEt), 1167 (Ar)
2
), 3.78 (6H, s, OMe), 1.34 (3H, t, J = 7.0 Hz, Me); C NMR (500
3
MHz, CDCl ) δ
1
-1
cm ; EIMS m/z 371 [M]+ (28), 313 (23), 239 (100), 224 (20). Anal. Calcd for C H NO : C, 64.68; H,
2
0
21
6
5
.70; N, 3.77. Found: C, 64.72; H, 5.61; N, 3.52.
4
.6.4. 4-(3,5-Dimethoxyphenyl)-5-(ethoxycarbonyl)-3-(4-methoxyphenyl)-4,5-dihydroisoxazole 2-oxide
(8d)
1
Off-white solid; 1.28 g (64%); mp 105–107 °C; R = 0.37 (benzene/ethyl acetate = 9:1); H
f
NMR (500 MHz, CDCl3)
2H, d, J = 2.0 Hz, H-2′′,6′′), 6.39 (1H, t, J = 2.0 Hz, H-4′′), 4.94 (1H, d, J = 3.0 Hz, H-4), 4.79 (1H, t,
J = 3.0 Hz, H-5), 4.32 (2H, m, OCH ), 3.79 (3H, s, OMe′), 3.76 (6H, s, OMe′′), 1.34 (3H, t, J = 7.0 Hz,
δ 7.83 (2H, d, J = 7.0 Hz, H-2′,6′), 6.87 (2H, d, J = 7.0 Hz, H-3′,5′), 6.46
(
2
1
3
Me); C NMR (500 MHz, CDCl )
δ
169.2, 161.7 (2C-ipso), 160.4, 140.8, 128.4 (2C), 118.0, 114.33,
3
1
14.25 (2C), 105.3 (2C), 100.1, 78.4, 62.5, 55.5, 55.3 (2C), 54.7, 14.1; νmax (KBr) 1749 (COO), 1613
-
1
(
N=O), 1515 (PhOMe), 1256 (OEt), 1194 (Ar) cm ; EIMS m/z 401 [M]+ (100), 343 (13), 284 (71),
2
69 (25). Anal. Calcd for C H NO : C, 62.84; H, 5.78; N, 3.49. Found: C, 62.64; H, 5.68; N, 3.60.
21 23 7
4
.6.5. 5-(Ethoxycarbonyl)-3-(4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-4,5-dihydroisoxazole 2-
oxide (8e)
Off-white solid; 1.39 g (64%); mp 155–157 °C; R
NMR (500 MHz, CDCl 7.83 (2H, d, J = 9.0 Hz, H-2′,6′), 6.89 (2H, d, J = 9.0 Hz, H-3′,5′), 6.53
1
f
= 0.20 (benzene/ethyl acetate = 9:1); H
3
) δ

1
5
ACCEPTED MANUSCRIPT
2
(2H, s, H-2′′,6′′), 4.90 (1H, d, J = 3.0 Hz, H-4), 4.80 (1H, d, J = 3.0 Hz, H-5), 4.34 (2H, m, OCH ),
1
3
3
1
6
.83 (9H, s, OMe), 3.81 (3H, s, OMe), 1.35 (3H, t, J = 7.0 Hz, Me); C NMR (500 MHz, CDCl ) δ
3
69.3, 160.5, 154.1 (2C-ipso), 138.1, 134.0, 128.5 (2C), 117.9, 114.4, 114.3 (2C), 104.0 (2C), 78.6,
2.6, 60.8, 56.3 (2C), 55.4, 54.9, 14.1; νmax (KBr) 1751 (COO), 1614 (N=O), 1516 (PhOMe), 1258
-1
(
8
OEt), 1127 (Ar) cm ; EIMS m/z 431 [M]+ (46), 373 (15), 299 (100). Anal. Calcd for C22H25NO : C,
6
1.25; H, 5.84; N, 3.25. Found: C, 61.44; H, 5.62; N, 3.51.
4
.6.6. 5-(Ethoxycarbonyl)-3-(4-methoxyphenyl)-4-( 2-thienyl)-4,5-dihydroisoxazole 2-oxide (8f)
Column chromatography (benzene/ethyl acetate 19:1); white solid; 0.934 g (36%), mp 132–134
1
°
C; R
f
= 0.51 (benzene/ethyl acetate = 9:1); H NMR (500 MHz, CDCl
3
)
δ
7.86 (2H, d, J = 9.0 Hz, H-
2
′,6′), 7.27 (1H, d, J = 5.0 Hz, H-5′′), 7.05 (1H, br d, J = 3.5 Hz, H-3′′), 6.96 (1H, dd, J = 5.0 Hz, 3.6
Hz, H-4′′), 6.90 (1H, d, J = 9.0 Hz, H-3′,5′), 5.35 (1H, d, J = 2.5 Hz, H-4), 4.88 (1H, d, J = 2.5 Hz, H-
1
3
5
δ
5
), 4.33 (2H, m, OCH ), 3.81 (3H, s, OMe), 1.34 (3H, t, J = 7.0 Hz, Me); C NMR (500 MHz, CDCl )
2
3
168.8, 160.5, 140.5, 128.4 (2C), 127.6, 126.3, 126.2, 117.6, 114.4, 114.3 (2C), 114.1, 78.7, 62.6,
-
1
5.4, 49.6, 14.1; νmax (KBr) 1753 (COO), 1613 (N=O), 1517 (PhOMe), 1267 (OEt) 1193 (Ar) cm ;
S: C, 58.78; H, 4.93; N,
EIMS m/z 347 [M]+ (63), 229 (21), 215 (100). Anal. Calcd for C17H17NO
5
4
.03. Found: C, 58.92; H, 4.81; N, 4.13.
4
.6.7. 5-(Ethoxycarbonyl)-3-(4-methoxyphenyl)-4-(1-methyl-1H-pyrazol-3-yl)-4,5-dihydroisoxazole 2-
oxide (8g)
Column chromatography (benzene/ethyl acetate 4:1; 1:1); gray solid; 0.89 g (64%); mp 92–93
1
°
C; R
f
= 0.31 (benzene/ethyl acetate = 9:1); H NMR (500 MHz, CDCl
3
) δ 7.84 (2H, d, J = 9.0 Hz, H-
2
′,6′), 7.51 (1H, s, H-3′′), 7.33 (1H, s, H-5′′), 6.90 (2H, d, J = 9.0 Hz, H-3′,5′), 5.04 (1H, d, J = 2.5 Hz,
H-4), 4.77 (1H, d, J = 2.5 Hz, H-5), 4.31 (2H, m, OCH ), 3.86 (3H, s, OMe), 3.81 (3H, s, N-Me), 1.33
2
1
3
(
3H, t, J = 7.0 Hz, Me); C NMR (500 MHz, CDCl )
δ
169.1, 160.5, 137.7, 128.6, 128.5 (2C), 118.9,
3
1
17.6, 114.3 (2C), 114.3, 78.9, 62.5, 62.5, 55.4, 45.2, 39.2, 29.7, 14.1; νmax (KBr) 1753 (COO), 1619
-
1
(
N=O), 1514 (PhOMe), 1261 (OEt), 1182 (Ar) cm ; EIMS m/z 345 [M]+ (33), 287 (29), 213 (100),
1
98 (21). Anal. Calcd for C H N O : C, 59.12; H, 5.55; N, 12.17. Found: C, 59.32; H, 5.61; N, 12.37.
17 19 3 5
4
.6.8. 5-(Ethoxycarbonyl)-4-(4-methoxyphenyl)-3-phenyl-4,5-dihydroisoxazole 2-oxide (8h)
1
White solid; 0.65 g (38%); mp 99–101 °C; R = 0.50 (benzene/ethyl acetate = 9:1); H NMR
f
(500 MHz, DMSO-d6) δ 7.9 (2H, d, J = 7.5 Hz, H-2′,6′), 7.45 (3H, m, H-3′,4′,5′), 7.30 (2H, d, J = 8.5

1
6
ACCEPTED MANUSCRIPT
Hz, H-2′′,6′′), 6.95 (2H, d, J = 8.5 Hz, H-3′′,5′′), 5.35 (1H, d, J = 2.5 Hz, H-4), 5.07 (1H, d, J = 2.5 Hz,
1
3
H-5), 4.25 (2H, q, J = 7.0 Hz, OCH ), 3.75 (3H, s, OMe), 1.28 (3H, t, J = 7.0 Hz, Me); C NMR (500
2
MHz, DMSO-d6)
δ
168.8, 159.1, 130.6, 129.6, 128.8 (2C), 128.5 (2C), 126.6 (2C), 125.3, 115.1, 114.7
(2C), 78.0, 61.8, 55.2, 52.1, 14.0; νmax (KBr) 1760 (COO), 1612 (N=O), 1512 (Ar), 1257 (OEt), 1203
-1
(
Ar) cm ; HRMS (ESI/QTOF) m/z: [M + Na]+ Calcd for C19
5
H19NO Na 364.1155; Found 364.1150;
[
M + K]+ Calcd for C H NO K 380.0895; Found 380.0892. Anal.Calcd for C H NO : C, 66.85; H,
1
9
19
5
19 19
5
5
.61; N, 4.10. Found: C, 66.60; H, 5.55; N, 4.42.
4
.6.9. 5-(Ethoxycarbonyl)-3-phenyl-4-(3,4,5-trimethoxyphenyl)-4,5-dihydroisoxazole 2-oxide (8i)
1
White solid; 2.29 g (57%); mp 129–131 °C; R
500 MHz, DMSO-d
H-2′′,6′′), 5.38 (1H, d, J = 2.5 Hz, H-4), 5.19 (1H, d, J = 2.5 Hz, H-5), 4.27 (2H, m, OCH
f
= 0.38 (benzene/ethyl acetate = 9:1); H NMR
(
6
) δ 7.93 (2H, d, J = 8.0 Hz, H-2′,6′), 7.46–7.37 (3H, m, H-3′,4′,5′), 6.70 (2H, s,
2
6
), 3.74 (6H,
168.7,
1
3
s, OMe), 3.63 (3H, s, OMe), 1.29 (3H, t, J = 7.0 Hz, Me); C NMR (500 MHz, DMSO-d
)
δ
1
5
53.4 (2C), 137.3, 134.4, 129.7, 128.8 (2C), 126.6 (2C), 125.4, 115.0, 104.6 (2C), 77.7, 61.8, 60.0,
-1
6.0 (2C), 53.0, 14.0; νmax (KBr) 1741 (COO), 1613 (N=O), 1463 (Ar), 1239 (OEt), 1130 (Ar)cm ;
402.1547; Found 402.1543. Anal. Calcd for
C H NO : C, 62.84; H, 5.78; N, 3.49. Found: C, 62.61; H, 5.70; N, 3.61.
HRMS (ESI/QTOF) m/z: [M + H]+ Calcd for C21H24NO
7
2
1
23
7
4
.6.10. 4-(2,5-Dimethoxy-3,4-methylenedioxyphenyl)-5-(ethoxycarbonyl)-3-phenyl-4,5-
dihydroisoxazole 2-oxide (8j)
White solid; 1.16 g (56%); mp 129–132 °C; R = 0.46 (benzene/ethyl acetate = 9:1); H NMR
1
f
(
500 MHz, DMSO-d
J = 7.5 Hz, H-4′), 6.50 (1H, s, H-6′′), 6.03 (2H, s, OCH
J = 3.5 Hz, H-5), 4.25 (2H, m, OCH ), 3.83 (3H, s, OMe), 3.73 (3H, s, OMe), 1.27 (3H, t, J = 7.0 Hz,
6
)
δ
7.84 (2H, d, J = 7.5 Hz, H-2′,6′), 7.43 (2H, t, J = 7.5 Hz, H-3′,5′); 7.37 (1H, t,
2
O), 5.44 (1H, d, J = 3.5 Hz, H-4), 5.08 (1H, d,
2
1
3
Me); C NMR (500 MHz, DMSO-d )
δ
169.1, 139.3, 139.3, 137.1, 136.0, 129.9, 129.2 (2C), 126.7
6
(2C), 125.9, 123.9, 114.7, 108.0, 102.5, 77.5, 62.1, 60.6, 57.2, 48.8, 14.3; νmax (KBr) 1763 (COO),
-1
1
618 (N=O), 1509 (Ar), 1214 (OEt), 1066 (Ar) cm ; HRMS (ESI/QTOF) m/z: [M + K]+ Calcd for
C H NO K 454.0899; Found 454.0893. Anal. Calcd for C H NO : C, 60.72; H, 5.10; N, 3.37.
2
1
22
8
21 21
8
Found: C, 60.58; H, 5.15; N, 3.48.
4
.7. 5-Carboxy-4-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydroisoxazole 2-oxide (9a)

1
7
ACCEPTED MANUSCRIPT
A solution of compound 8a (0.546 g, 1.5 mmol) in dioxane (15 mL) and aqueous HCl (9%, 3
mL) was heated at ~ 60 °C for 5 h, then kept overnight at room temperature. Dioxane was evaporated
in vacuo and the residue was extracted with ethyl acetate (3 × 25 mL). The extracts were washed with
water, brine, dried with anhydrous sodium sulfate. The solvent was removed in vacuo to afford 9a as
f
white solid (0.512 g, 98% yield); mp 116–119 °C; R = 0.31 (benzene/methanol/acetic acid = 45:8:4);
1
H NMR (500 MHz, DMSO-d6) δ 13.75 (1H, br s, COOH), 7.85 (2H, d, J = 9.0 Hz, H-2′,6′), 7.45 (2H,
d, J = 8.5 Hz, H-3′′,5′′), 7.39 (2H, d, J = 8.5 Hz, H-2′′,6′′), 6.97 (2H, d, J = 9.0 Hz, H-3′,5′), 5.39 (1H,
1
3
d, J = 2.5 Hz, H-4), 4.99 (1H, d, J = 2.5 Hz, H-5), 3.75 (3H, s, OMe); C NMR (500 MHz, DMSO-d )
6
δ
173.3, 1159.9, 138.0, 132.7, 129.2 (2C), 129.1 (2C), 128.2 (2C), 117.4, 114.3 (2C), 114.0, 77.4,
-1
5
5.2, 51.9; νmax (KBr) 1752 (COO), 1609 (N=O), 1510 (PhOMe), 1260 (OEt), 1170 (Ar) cm ; EIMS
m/z 347 [M]+(17), 316 (17), 303 (16), 135 (100). Anal. Calcd for C H ClNO : C, 58.72; H, 4.06; N,
1
7
14
5
4
.03. Found: C, 58.65; H, 4.16; N, 4.25.
4
.8. 4-(4-Chlorophenyl)-3-(4-methoxyphenyl)isoxazole (10a)
A mixture of acid 9a (1 mmol, 0.348 g), 2% ethanolic NaOH solution (7 mL), and water (3 mL)
was stirred at 60 °C for 6 h, then ethanol was removed in vacuo. The residue was suspended in
methylene chloride (100 mL), aqueous alkaline layer was separated, and the methylene chloride extract
was washed with water (2 × 20 mL). The methylene chloride solution was dried by filtration through
cotton wool and evaporated in vacuo to afford 4-(4-chlorophenyl)-3-(4-methoxyphenyl)isoxazole (10a)
1
as white crystals (0.19 g, 67% yield); mp 89–91°C; R
500 MHz, CDCl
′′,6′′), 7.19 (2H, d, J = 8.5 Hz, H-3′′,5′′), 6.90 (2H, d, J = 9.0 Hz, H-3′,5′), 3.83 (3H, s, OMe); C
NMR (500 MHz, CDCl3) 160.8, 159.7, 156.2, 134.0, 130.1 (2C), 130.0 (2C), 129.0 (2C), 127.7,
20.4, 119.6, 114.2 (2C), 55.3; νmax (KBr) 1610, 1524, 1438, 1251, 1181 cm ; EIMS m/z 285
M]+(100), 257 (29), 242 (46). Anal. Calcd for C H ClNO : C, 67.26; H, 4.23; N, 4.90. Found: C,
f
= 0.62 (benzene/ethyl acetate = 9:1); H NMR
(
3
) δ 8.48 (1H, s, H-5), 7.41 (2H, d, J = 9.0 Hz, H-2′,6′), 7.33 (2H, d, J = 8.5 Hz, H-
1
3
2
δ
-1
1
[
1
6
12
2
6
7.42; H, 4.31; N, 4.72.
4
.8. X-ray crystal structure determination
α
Data were collected using a Bruker APEX-II CCD diffractometer (λ(MoK )-radiation, graphite
2
7
monochromator, ω and φ scanning mode) and corrected for absorption using the SADABS program
(
For the details, see Table S1, Supplementary data). The crystal structure of 4a was determined by
2
direct methods and refined by a full-matrix least squares technique on F with anisotropic displacement

1
8
ACCEPTED MANUSCRIPT
parameters for non-hydrogen atoms. The hydrogen atoms in both compounds were placed in calculated
positions and refined within the riding model with fixed isotropic displacement parameters (U (H) =
iso
1
3
.5Ueq(C) for the CH -groups and 1.2Ueq(C) for the other groups). All calculations were carried out
2
8
using the SHELXTL program. Crystallographic data for 4a have been deposited with the Cambridge
Crystallographic Data Center. CCDC 1535083 (4a) contains supplementary crystallographic data for
this paper. These data can be obtained free of charge from the Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk or
www.ccdc.cam.ac.uk).
Appendix A. Supplementary Data
Supplementary data related to this article can be found at ..... These data include X-ray data for 4a
(PDF).
Acknowledgements
This work was carried out with the financial support of the Ministry of Education and Science
of the Russian Federation (Agreement number 02.a03.21.0008) and the Russian Foundation for Basic
Research (Grant No. 16-03-00648 dated of February 15, 2016).
References
1
. Srivastava S, Bajpai LK, Batra S, Bhaduri AP, Maikhuri JP, Gupta G, Dhar JD. Bioorg Med Chem.
999;7:2607–2613.
1
2
3
4
. Dadiboyena S, Nefzi A. Eur J Med Chem. 2010;45:4697-4707.
. Perrone MG, Scilimati A, Simone L, Vitale P. Curr Med Chem. 2010;17:3769–3805.
. Simoni D, Grisolia G, Giannini G, Roberti M, Rondanin R, Piccagli L, Baruchello R, Rossi M,
Romagnoli R, Invidiata FP, Grimaudo S, Jung MK, Hamel E, Gebbia N, Crosta L, Abbadessa V,
Di Cristina A, Dusonchet L, Meli M, Tolomeo M. J Med Chem. 2005;48:723–736.
. Kaffy J, Pontikis R, Carrez D, Croisy A, Monneret C, Florent JC. Bioorg Med Chem.
5
6
2
006;14:4067–4077 and citations herein.
. Sun, L.; Borella, C.; Li, H.; Jiang, J.; Chen, S.; Koya, K.; Inoue, T.; Du, Z.; Foley, K.; Wu, Y.;
Zhang, M.; Ying, W. WIPO Patent WO 2006/089177, 2006.

1
9
ACCEPTED MANUSCRIPT
7
8
. Sun CM, Lin LG, Yu HJ, Cheng CY, Tsai YC, Chu CW, Din YH, Chau YP, Don MJ. Bioorg Med
Chem Lett. 2007;17:1078–1081.
. (a) Drysdale MJ, Dymock BW, Finch H, Webb P, Mcdonald E, James KE, Cheung KM, Mathews
TP. WIPO Patent WO WO2004072051, 2004;
(b) Brough PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, Cheung K-MJ, Collins
I, Davies NGM, Drysdale MJ, Dymock B, Eccles SA, Finch H, Fink A, Hayes A, Howes R,
Hubbard RE, James K, Jordan AM, Lockie A, Martins V, Massey A, Matthews TP, McDonald E,
Northfield CJ, Pearl LH, Prodromou C, Ray S, Raynaud FI, Roughley SD, Sharp SY, Surgenor A,
Walmsley DL, Webb P, Wood M, Workman P, Wright L. J Med Chem. 2008;51:196–218;
(
c) Zhang C, Wang X, Liu H, Zhang M, Geng M, Sun L, Shen A, Zhang A. Eur J Med Chem.
017;125:315–326.
. Pettit GR, Singh SB, Hamel E, Lin CM, Alberts DS, Garcia-Kendall D. Experientia. 1989;45:209–
11.
2
9
2
1
1
0. Mikstacka R, Stefanski T, Rózanski J. Cell Mol Biol Lett. 2013;18:368–397 and citations herein.
1. (a) Caramella P, Albini E, Bandiera T, Corsico Coda A, Grunanger P, Albini FM. Tetrahedron.
1
983;39:689–699;
(
b) Kim HJ, Lee JH, Olmstead MM, Kurth MJ. J Org Chem. 1992;57:6513–6519;
c) Grecian S, Fokin VV. Angew Chem Int Ed. 2008;47:8285–8287;
d) Brahma S, Ray JK. J Heterocyclic Chem. 2008;45:311–317;
(
(
(
(
(
e) Schmitt DC, Lam L, Johnson JS. Org Lett. 2011;13:5136–5139;
f) Dissanayake AA, Odom AL. Tetrahedron. 2012;68:807–812;
g) Jia Q, Benjamin PMS, Huang J, Du Z, Zheng X, Zhang K, Conney AH, Wang J. Synlett.
2
013;24:79–84.
1
1
1
2. Kohler EP. J Am Chem Soc. 1924;46:1733–1747.
3. Kohler EP, Darling SF. J Am Chem Soc. 1930;52:1174–1181.
4. (a) Worrall DE. J Am Chem Soc. 1938;60:2841–2844;
(
(
(
b) Shechter H, Conrad F. J Am Chem Soc. 1954;76:2716–2720;
c) Zen S, Koyama M. B Chem Soc Jpn. 1971;44:2882;
d) Johnson CR, Lockard JP, Kennedy ER. J Org Chem. 1980;45:264–271.
1
1
5. Chen KP, Chen Y-J, Chuang C-P. Eur J Org Chem. 2010:5292–5300.
6. Rorig K. J Org Chem. 1950;15:391–395.

2
0
ACCEPTED MANUSCRIPT
1
1
7. Ishmaeva EA, Vereshchagina YaA, Chachkov DV, Vasil’eva OS, Ostroglyadov ES, Nikonorov
AA, Litvinov IA, Krivolapov DB, Alimova AZ, Berestovitskaya VM. Russ J Gen Chem.
2
012;82:911–920.
8. Semenov VV, Kiselyov AS, Titov IY, Sagamanova IK, Ikizalp NN, Chernysheva NB, Tsyganov
DV, Konyushkin LD, Firgang SI, Semenov RV, Karmanova IB, Raihstat MM, Semenova MN. J
Nat Prod. 2010;73:1796–1802.
1
2
2
2
2
9. Olah GA, Ramaiah P, Lee C-S, Prakash GK. Synlett. 1992;337–339.
0. Lehnert W. Synthesis. 1976:827–829.
1. Walvoord RR, Kozlowski MC. J Org Chem. 2013;78:8859–8864.
2. www.sigmaaldrich.com/catalog.
3. Lettré H, Fernholz H. Hoppe-Seyler's Z Physiol Chem. 1943;278:175–200.
DOI:10.1515/bchm2.1943.278.1-6.175.
2
2
2
4. Madhu G, Namboothiri INN. Tetrahedron. 2007;63:11973–11983.
5. Heatley F, Cox MK, Jones A, Jacques B. J Chem Soc Perkin Trans 2. 1976:510–512.
6. Malkov AV, Pernazza D, Bell M, Bella M, Massa A, Teply F, Meghani P, Kocovsky P. J Org
Chem. 2003;68:4727–4742.
2
2
7. Sheldrick, G. M. SADABS v. 2.03, Bruker/Siemens Area Detector Absorption Correction Program,
Bruker AXS: Madison, Wisconsin, USA; 2003.
8. Sheldrick GM. Acta Crystallogr C Struct Chem. 2015;71(Pt 1):3–8.

ACCEPTED MANUSCRIPT
Highlights
•
•
•
•
A synthesis of 3,4-diaryl-5-carboxy-4,5-dihydroisoxazole 2-oxides is designed.
Reaction route includes condensation of arylbenzaldehydes and arylnitromethanes.
The targeted molecules are able to rearrange easily to respective diarylisoxazoles.
The synthesized compounds are of value for anticancer drug development.