Synthesis and fungicidal activity of 2-(diphenylmethyl)-3-arylisoxazolidine-5-carboxamides

Article abstract of DOI:10.1007/s00706-015-1568-7

A series of new 2-(diphenylmethyl)-3-arylisoxazolidine-5-carboxamides have been prepared from aldehydes. A key step was an uncatalyzed stereoselective and regioselective 1,3-dipolar cycloaddition reaction of N-benzylidene-N-diphenylmethyl nitrones with et

Full text of DOI:10.1007/s00706-015-1568-7

Monatsh Chem
DOI 10.1007/s00706-015-1568-7
ORIGINAL PAPER
Synthesis and fungicidal activity of 2-(diphenylmethyl)-3-
arylisoxazolidine-5-carboxamides
1
Krzysztof Zelechowski W. Marek Goł e˛ biewski Maria Krawczyk
1
•
1
_
•
Received: 15 June 2015 / Accepted: 29 August 2015
Ó Springer-Verlag Wien 2015
Abstract
A
series of new 2-(diphenylmethyl)-3-
Introduction
arylisoxazolidine-5-carboxamides have been prepared from
aldehydes. A key step was an uncatalyzed stereoselective
and regioselective 1,3-dipolar cycloaddition reaction of N-
benzylidene-N-diphenylmethyl nitrones with ethyl acry-
late. Some of these amides exhibited fungicidal activities
against Fusarium culmorum, Phytophthora cactorum, Al-
ternaria alternata, Rhizoctonia solani, Botrytis cinerea,
and Blumeria graminis.
1,3-Dipolar cycloaddition reaction of nitrones to alkenes is
the most convenient method of preparation of isoxazo-
lidines which can be easily transformed via reductive ring
opening to c-amino alcohols, where configuration of all
carbon atoms is preserved [1]. The obtained c-amino
alcohols are important semi-products in synthesis of b-
amino acids, b-lactam antibiotics, or piperidine and indo-
lizidine alkaloids. Nitrones, on the contrary to most of the
other dipoles, are stable compounds not requiring prepa-
ration in situ, and therefore can be used at room
temperature without an inert atmosphere.
Graphical abstract
Stereospecificity is a striking feature of this reaction
discovered by Huisgen—geometry of the alkene is com-
pletely preserved in the cycloadduct. However, problem
of regio- and stereoselectivity of this transformation
should still be solved. In reaction of nitrones with
monosubstituted alkenes two regioisomeric products can
be formed—5-isoxazolidines with a substituent on the
carbon atom a to the oxygen atom, and 4-isoxazolidines
with a substituent on the carbon atom b to the oxygen
atom, depending on the electronic character of the sub-
stituents. According to the theory of frontier molecular
orbitals (FMO) reactions of the alkenes with electron-
donating substituents are controlled by interactions of
dipole LUMO and dipolarophile HOMO orbitals, which
leads to 5-isoxazolidines. On the other hand reactions of
the alkenes with strongly electron-accepting substituents
are controlled by interactions of dipole HOMO and
dipolarophile LUMO orbitals leading exclusively to
Keywords Cycloaddition Á Nitrones Á Stereoselectivity Á
NMR spectroscopy Á Configuration Á Fungicides
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1568-7) contains supplementary
material, which is available to authorized users.
&
W. Marek Goł e˛ biewski
golebiewski@ipo.waw.pl
4
-isoxazolidines. In case of alkenes with moderately
electron-accepting substituents, similarly as with 1,2-
disubstituted alkenes, formation of mixture of regioiso-
mers is expected [2, 3]. This problem is approached by a
1
Institute of Industrial Organic Chemistry, Annopol 6, 03-236
Warsaw, Poland
123

_
K. Zelechowski et al.
substrate control (choice of both cycloaddition reaction
partners) or by application of the appropriate catalysts.
Stereochemistry of the reaction is another problem,
since products can be formed via endo and exo interme-
diate states on routes which often cannot be easily
predicted, and acyclic nitrones can undergo E/Z isomer-
ization [4–7]. Problem of diastereoselectivity and
enantioselectivity of the cycloaddition reaction was han-
dled by application of chiral nitrones or alkenes or since
A character of the N-substituent was critical in the
planned syntheses of nitrones. We reasoned that a bulky
group, such as diphenylmethyl (DPM), would favor regio-
and stereoselectivity of the cycloaddition reaction. This
corollary was confirmed by our initial experiments where
N-benzyl protective group was used and a complex mixture
of cycloaddition products was obtained. Similarly mixtures
of products were obtained in cycloaddition of C-(3-pyr-
idyl)-N-alkylnitrones (N-Me, benzyl, and DPM protection)
with methyl acrylate and with optically active N-(acry-
loyl)bornane-10,2-sultams [21]. Only in the presence of
Lewis acid one major cis-isomer was obtained in reaction
of the sultam derivative apart from the other cycloadducts.
Another advantage of using DPM N-protection was that it
could be easily removed through NBS oxidation followed
by acidic hydrolysis of the formed hemiaminal [22, 23] or
1
994 by application of chiral catalysts [1, 8, 9].
Isoxazolidine derivatives exhibit a broad spectrum of
biological activities. Isoxazolidine-based nucleoside ana-
logs show a cytotoxic potency [10, 11]. Spiro isoxazolidine
derivatives of a-santonine show anticancer and antiviral
activity [12]. Isoxazolidine-3,5-dione is a hypoglycemic
agent [13]. A literature data analysis of the recent years
concerning synthesis of new plant protection agents indi-
cates that many new active substances were obtained by
combination of the known biologically active compounds,
often of a quite different mechanism of action. Favorable
effect of such a combination can be a synergistic increase
of efficacy of the obtained compound mixtures. An alter-
native approach consists in planning new chemical
compounds containing in one molecule two different tox-
ophors. The obtained new chemical compounds can easier
undergo formulation than a mixture of two compounds
containing each single toxophors, which can differ signif-
icantly in physicochemical properties. Carboxamides are
one of the several known groups of herbicides; many
examples are provided by Pesticide Manual monograph
with Et SiH/TFA leaving the isoxazolidine ring intact [24].
3
Z-geometry was ascribed to the nitrones based on steric
1
consideration and relatively high field position in the H
NMR spectrum of the azomethine proton giving sharp
signals at d = 7.44–7.57 ppm [25]. In case of E-geometry
absorption above 8 ppm is expected. It is well established
that nitrones with the bulky groups possess Z-configuration
with N-aryl (alkyl)—C-aryl groups in a trans relationship
as proved by X-ray crystallography and NOE experiments.
It is also assumed that this configuration is maintained in
the transition state and no Z/E isomerization is taking place
[26].
A key step in the synthesis of the title compounds was
1,3-dipolar cycloaddition reaction of nitrones 5a–5c with
ethyl acrylate functioning also as a solvent. Two new chiral
centers were created in the reaction where two regioiso-
mers and two cis/trans stereoisomers are possible. Analysis
[
14]. Biological activity of simple isoxazolidine derivatives
is also known [15–17]. 2-Alkyl-N-substituted isoxazolidi-
nes show insecticidal, fungicidal, and arachnicidal
properties [18]. In light of a growing plant pathogens
resistance to action of the applied pesticides and increasing
registration hurdles there is a constant demand for new,
more selective plant protection agents. In this work com-
bination in one molecule of isoxazolidine and carboxamide
moiety was planned. Herein, we present results of our
research concerning stereoselective and regioselective 1,3-
dipolar cycloaddition reaction of N-benzylidene-N-
diphenylmethyl nitrones with ethyl acrylate and transfor-
mation of the obtained esters to carboxamides.
1
of the H NMR spectra showed a high selectivity of the
cycloaddition, since only one major crystalline trans 3,5-
disubstituted isoxazolidine was obtained in each case
(Scheme 1). One of the minor trans 3,4-disubstituted
isoxazolidines 8c, formed in about 5:95 proportion, was
isolated by flash chromatography of the mother liquor
obtained after crystallization of the major isomer. Neither
of the two possible cis isomers has been detected.
1
Differences in the H NMR spectra allow for a clear
distinction between the two regioisomers. The 3,5 regioi-
3
somer showed characteristic signals for the C H-C H H -
4
a
b
5
C H unit, i.e., two dd for the methine protons H-3 at
4.55–4.57 ppm and for H5 at 4.29–4.41 ppm, and a mul-
tiplet at 2.90–3.02 ppm as well as a ddd at 2.64–2.66 ppm
derived from non-equivalent diastereotopic protons of the
C-4 methylene group. In contrast, the 3,4 regioisomer
Results and discussion
Chemistry
3
4
5-
Nitrones 5a–5c were prepared starting from benzophenone
by oximation [19], reduction of the oximes with sodium
cyanoborohydride [20], and condensation with arylalde-
hydes 4a–4c.
showed signals characteristic of the system C H-C H-C
H H , i.e., a doublet at 4.51 ppm for the C-3 methine
a
b
proton, a dd at 4.36 and a doublet at 4.30 ppm for the non-
equivalent diastereotopic protons of the C-5 methylene
1
23

Synthesis and fungicidal activity of 2-(diphenylmethyl)-3-arylisoxazolidine-5-carboxamides
Scheme 1
group, and a ddd of the central C-4 methine group at
3
.42 ppm.
The relative location of protons in positions 3 and 5 of
ethyl 2-(diphenylmethyl)-3-arylisoxazolidine-5-carboxy-
lates was determined based on the 2D NMR ROESY
spectrum. This technique allows to find correlations
between the proximate protons, regardless of the number of
bonds separating these atoms. On the basis of this spec-
trum, it can be concluded that the methine protons in
positions 3 and 5 interact with the different protons of the
methylene group, which means that they are located on the
opposite sides of the plane of the isoxazolidine ring, and
that aryl and ester functions are trans. This is illustrated in
the Figs. 1 and 2. Both regioisomers and the corresponding
transition states leading to them are displayed in Scheme 2.
The major 3,5-trans isomer 7X is formed via Z-exo TS.
The minor 3,4-trans isomer 8X is formed via Z-endo TS
destabilized by steric interaction of the ester—DPM
groups. The electronic effects are of minor importance,
since matching between negative charge of terminal oxy-
gen atom of the dipole and positive end of b-carbon atom
of the acrylate would favor regioisomer 8X.
Fig. 1 Selected ROSY spectrum for ester 7a and preferred confor-
mations of esters 7a–7c and 8a–8c
Isoxazolidines exhibit an envelope conformation of the
ring with the O atom placed out-of-plane [27, 28]. In light
of the above results a preferred all-pseudoequatorial con-
formation 7X can be proposed to the major isomers of
esters 7a–7c. The dihedral angles from molecular modeling
between H5/H4 and H3/H4 are close to 0° (19°) and 180°
a
a
(161°), respectively. Thus, the observed coupling constants
7.2 and 8.4 Hz correspond to pseudoaxial positions of the
relevant protons and pseudoequatorial positions of C3-aryl
and C5-ester substituents [29].
The next steps were saponification of the major esters
7a–7c and synthesis of carboxamides 11a–11f and 12a–12i
via the intermediate acid chlorides used to acylate aniline
123

_
K. Zelechowski et al.
Fig. 2 2D NMR ROESY
spectrum of ester 7a
Scheme 2
or piperidine/piperazine/morpholine derivatives. In the
secondary aryl amides 11a–11f a signal broadening was
observed. It could be explained by inversion at the nitrogen
flexible than saturated 6-membered rings [31]. Conforma-
1
tional analysis of the bicyclic isoxazolidines by H NMR
showed two sets of peaks at low temperature spectra of
some compounds, ascribed to the presence of two isomers
interconverting via nitrogen atom inversion (a rate
1
atom taking place on the H NMR time scale [30].
5
-Membered nitrogen heterocyclic rings are much more
1
23

Synthesis and fungicidal activity of 2-(diphenylmethyl)-3-arylisoxazolidine-5-carboxamides
determining step) followed by a low-energy ring flip. The
free energy of activation of the process was measured (ca
obtained amides, compounds with electron-withdrawing
groups (EWG) in the acid moiety and with electron-donating
groups (EDG) in the amine moiety tend to demonstrate the
best fungicidal activity. The highest potency against B.
cinerea (89.9 %) was displayed by the aromatic amide 11a.
This compound with the EDG in the amine part was also
most active against P. cactorum. The best activity against R.
solani was exhibited by heterocyclic amides 12a and 12i
with the EWG in the acid moiety. The most potent fungi-
static activity against B. cinerea was shown also by the same
compounds 12a, 12i, and 11b.
5
5.7 kJ/mol in the temperature range up to 20 °C). For
simple monocyclic 3,5,5-trisubstituted isoxazolidines this
energy was estimated as 50–58 kJ/mol based on NMR
measurements at variable temperatures [32]. Presence of
electronegative substituents increases the nitrogen inver-
sion barrier to the extent, that some invertomers can be
0
separated. For 2-methoxy-N,N -dimethylisoxazolidine-3,3-
dicarboxamide this energy is equal to 88-100 kJ/mol
[
33]. 5-Methyl-2-(2-nitro-1-phenylethoxy)-3,3-dinitro-5-
phenylisoxazolidines exist at room temperature as pairs of
N-invertomers, for which free energy of activation at
3
53 K was measured (75 kJ/mol) [34]. Esters 7a–7c and
Conclusion
1
aliphatic amides 11a–11f show sharp signals in the H
NMR spectrum. This result suggests either a fast inversion
at the nitrogen atom and occurrence of the averaged con-
figuration, or rather a high energy barrier to the inversion
and presence of only one invertomer. Broadening of proton
Several new 3-arylisoxazolidine-5-carboxamides 11a–12i
have been prepared using corresponding nitrones as basic
starting materials. The obtained compounds were character-
1
13
ized by spectroscopic methods (IR, H, and C NMR as well
as MS spectra). NMR methods (including 2D techniques)
allowed to define the detailed stereo- and regioselectivity of
the synthesized compounds. Carboxamides 12a and 12i
showed a moderate antifungal activity against Rhizoctonia
solani and Botrytis cinerea fungal strains. Based on the
obtained results syntheses of new, more potent derivatives
with different N-substituents could be envisaged.
1
signals in H NMR spectrum of the aromatic amides 11a–
1
ered, that N-inversion/ring inversion are taking place on the
1f indicates rather, that DG of N-inversion was so low-
1
H NMR time scale. In the transition state of this process
the isoxazolidine ring is planar and presence of a reso-
nance-stabilized aromatic carbamoyl moiety should lower
the energy of this TS compared to the tertiary amides.
The biological activity
Experimental
The obtained carboxamides were screened for the antifungal
activity against propiconazole as a reference compound
Reagent grade chemicals were used without further
purification unless otherwise noted. Spectra were
recorded as follows: IR spectra on a JASCO FTIR-420
(
Table 1). Analyzing generally moderate activity of the
Table 1 Fungicide activity of
amides against 5 species of
pathogenic fungi (in vitro, on
PDAs and in vivo), % inhibition
of mycelial growth
Comp
Botrytis
cinerea
Fusarium
culmorum
Phytophthora
cactorum
Rhizoctonia
solani
Blumeria
graminis
1000 ppm
2
00 ppm
1
1
1
1
1
1
1
1
1
1
1
1
1a
1b
1c
1e
1f
14.0
57.5
11.9
19.0
38.1
54.5
61.0
33.3
0
0
30
0
72
0
0
37.5
0
89.9
17.8
5.0
0
0
0
0
9.7
0
0
0
12.8
40.7
46.6
3.5
2a
2c
2d
2e
2f
33
50
0
40
0
88.5
0
0
36.0
0
0
0
28.7
45.5
7.6
0
0
–
0
2h
2i
23.1
75
0
9.5
36
74
0
42
100
73
86
16.9
100
a
Propiconazole 100
a
Reference compound
123

_
K. Zelechowski et al.
1
13
spectrometer, H, C NMR, and ROESY spectra on a
Varian 500 UNITY plus-500, and a Varian 200 UNITY
plus-200 spectrometers in deuterated chloroform.
Chemical shifts are given in ppm (d) relative to TMS as
an internal standard, coupling constants are reported in
Hz. EI mass spectra were run on an AMD M-40
instrument, ESI mass spectra on a LCT (Micromass)
apparatus. Flash chromatography was carried out using
silica gel S 230–400 mesh (Merck) using hexane—ethyl
acetate mixtures as an eluent. Molecular Mechanics
calculations were performed with the computer program
Hyperchem 7.5.
Synthesis of ethyl esters of 2-(diphenylmethyl)-3-
arylisoxazolidine-5-carboxylic acid—typical
procedure
Ethyl 2-(diphenylmethyl)-3-phenylisoxazolidine-5-
carboxylate (7a, C25H25NO )
3
3
In a dry 25 cm flask equipped with a magnetic stirrer, reflux
condenser provided with a calcium chloride tube were placed
3
1.92 g 5a (6.7 mmol) and 7.4 cm ethyl acrylate (67 mmol).
The flask was placed in an oil bath heated to 100 °C and
reaction mixture was stirred for 19.5 h. The solution turned
clear yellow during the reaction. After cooling to ambient
temperature the reaction mixture was concentrated under
reduced pressure (water pump) using a short set for distillation.
The resulting pale yellow oil was placed in the refrigerator for
Synthesis of nitrones—typical procedure: N-
Benzylidenediphenylmethanamine, N-oxide (5a)
3
about 2 h. The precipitate was suspended in 20 cm hexane,
3
filtered, and was washed with hexane (2 9 10 cm ). The
3
In a dry 150 cm flask equipped with a calcium chloride
3
precipitate was recrystallized from 40 cm ethanol to afford
tube were placed 1.79 g N-(diphenylmethyl)hydroxy-
3
lamine (9 mmol), 130 cm toluene, and 1.2 g magnesium
1.78 g (69 %) of a colorless solid. m.p.: 116–117 °C;
f
R
= 0.44 (cyclohexane:ethyl acetate 4:1); IR (KBr)
3
sulfate (10 mmol, 1.1 eq). Benzaldehyde (1.4 cm ,
vꢀ = 3063, 3031, 2979, 1729, 1492, 1451, 1279, 1211,
-1 1
1
3.5 mmol, 1.5 eq) was added dropwise to the suspen-
sion. The mixture was stirred at room temperature for
6 h, was filtered and concentrated in vacuo. The solid
743 cm ; H NMR (200 MHz, CDCl ): d = 7.53 (bs, 2H),
3
7.36–7.07 (m, 13H, aryl), 5.12 (bs, 1H), 4.56 (dd, J = 6.9,
8.4 Hz, 1H, H3), 4.34 (dd, J = 4.6, 7.2 Hz, 1H, H5), 4.16 (q,
J = 7.2 Hz, 2H), 2.97 (app. quintet, J = 6.5 Hz, 1H, H4a),
2.66 (ddd, J = 4.4, 8.4, 12.5 Hz, 1H, H4b), 1.22 (t,
2
3
residue was recrystallized from 35 cm methanol to afford
.0 g of a colorless product (77 %). m.p.: 152–153 °C
Ref. [35] 163–165 °C); R = 0.27 (cyclohexane-ethyl
2
1
3
(
J = 7.2 Hz, 3H) ppm;
d = 14.1, 41.4, 61.3, 65.6, 73.8, 127.0, 127.1, 127.2, 127.9,
28.2, 128.2, 128.3, 128.4, 140.8, 141.6, 141.8, 172.2 ppm;
HRMS (ESI): m/z calcd for C H NO Na 410.1732; found:
C NMR (50 MHz, CDCl ):
3
f
acetate 4:1).
1
N-[4-(1-Methylethyl)benzylidene]diphenylmethanamine,
2
5
25
3
N-oxide (5b, C H NO)
2
3 23
4
10.1736.
Ethyl 2-(diphenylmethyl)-3-[4-(1-methylethyl)phenyl]isox-
azolidine-5-carboxylate (7b, C28
Yield: 1.39 g (63 %) of a colorless solid; m.p.: 134–136 °C
(ethanol); R = 0.47 (cyclohexane:ethyl acetate 4:1); IR
(KBr) vꢀ = 3063, 3031, 2960, 2905, 1732, 1453, 1205,
Yield: 1.35 g (81 %) of a colorless product; m.p.: 138–
1
40 °C; R = 0.47 (cyclohexane:ethyl acetate 4:1); IR
f
(
KBr): vꢀ = 3063, 2926, 1555, 1495, 1454, 1325, 1268,
H31NO )
3
-
1 1
167, 1135, 1066, 845, 722 cm ; H NMR (200 MHz,
1
CDCl ): d = 8.20–8.16 (m, 2H), 7.44 (s, 1H), 7.37–7.24
f
3
(
m, 12H), 6.35 (s, 1H), 2.92 (septet, J = 6.8 Hz, 1H), 1.24
1
d, J = 6.8 Hz, 6H) ppm; C NMR (50 MHz, CDCl3):
3
-1 1
(
1159, 1053, 803, 744 cm ; H NMR (200 MHz, CDCl ):
3
d = 23.9, 34.4, 83.6, 126.8, 128.2, 128.7, 128.9, 129.2,
35.1, 137.4, 152.1 ppm; HRMS (ESI): m/z calcd for
C H NONa 352.1677, found 352.1672.
d = 7.08–7.55 (m, 14H, Ar), 5.11 (s, 1H), 4.57 (dd,
J = 6.9, 8.4 Hz, 1H, H3), 4.29 (dd, J = 4.6, 7.0 Hz, 1H,
H5), 4.15 (q, J = 7.2 Hz, 2H), 2.90 (m, 1H, H4a), 2.66
1
2
3 23
(
ddd, J = 4.6, 8.4, 12.9 Hz, 1H, H4b), 1.23 (d, J = 6.8 Hz,
N-[4-(Trifluoromethyl)benzylidene]diphenylmethanamine,
1
H), 1.22 (t, J = 7.2 Hz, 3H) ppm; C NMR (50 MHz,
3
6
N-oxide (5c, C H F NO)
2
1 16 3
CDCl ): d = 14.1, 24.0, 33.8, 41.3, 61.3, 65.4, 73.7, 126.3,
1
3
Yield: 1.57 g (85 %) of a colorless product; m.p.: 150-
27.0, 127.1, 127.2, 127.9, 128.1, 128.3, 137.9, 141.6,
1
53 °C; R = 0.34 (cyclohexane:ethyl acetate 4:1); IR
f
1
41.8, 147.7, 172.3 ppm; HRMS (ESI): m/z calcd for
(
KBr): vꢀ = 3063, 3021, 3000, 2956, 2926, 1605, 1496,
C H NO Na 452.2202, found 452.2198.
28 31
-
463, 1294, 1138, 868, 724 cm ; H NMR (200 MHz,
1
1
3
1
CDCl3): d = 8.36 (d, J = 8.2 Hz, 2H), 7.65 (d,
J = 8.2 Hz, 2H), 7.57 (s, 1H), 7.45–7.30 (m, 10H),
Ethyl 2-(diphenylmethyl)-3-[4-(trifluoromethyl)phenyl]-
isoxazolidine-5-carboxylate (7c, C26 NO ) and
ethyl 2-(diphenylmethyl)-3-[4-(trifluoromethyl)phenyl]-
isoxazolidine-4-carboxylate (8c, C26 NO
Yield: 1.45 g (74 %) of a colorless solid; m.p.: 131–132 °C;
= 0.31 (cyclohexane:ethyl acetate 4:1); IR (KBr)
H
F
24
3
3
1
3
6
.40 (s, 1H) ppm;
d = 84.2, 126.5 (q, J = 3.5 Hz), 129.7, 129.9, 130.5,
31.0, 133.9, 136.8, 138.5 ppm; HRMS (ESI): m/z calcd
for C H F NONa 378.1082, found 378.1073.
C NMR (50 MHz, CD OD):
3
H
24
F
3
)
3
1
R
2
1 16 3
f
1
23

Synthesis and fungicidal activity of 2-(diphenylmethyl)-3-arylisoxazolidine-5-carboxamides
vꢀ = 3031, 2979, 1731, 1454, 1324, 1212, 1158, 1129, 1067,
The solution was concentrated under reduced pressure. The
3
resulting oil was dissolved in 5 cm toluene, cooled in ice-
-
1
1
1
018, 745 cm
;
H
NMR (200 MHz, CDCl3):
d = 7.57–7.09 (m, 14H, Ar), 5.16 (s, 1H), 4.55 (dd,
J = 6.6, 8.5 Hz, 1H, H3), 4.41 (dd, J = 4.6, 7.2 Hz, 1H,
H5), 4.17 (q, J = 7.3 Hz, 2H), 3.02 (app. quintet,
J = 6.8 Hz, 1H, H4a), 2.64 (ddd, J = 4.7, 8.5, 13.0 Hz,
water bath to a temperature of about 0 °C and a solution of
0.057 g 4-methoxyaniline (0.47 mmol, 1.1 eq) in 2 cm
3
3
toluene was added dropwise followed by 0.12 cm triethy-
lamine (0.87 mmol, 2 eq). The mixture was stirred at about
1
3
1
H, H4b), 1.23 (t, J = 7.3 Hz, 3H) ppm; C NMR
0 °C for 30 min, and then at room temperature for 3 h. The
reaction mixture was diluted with 15 cm toluene and
3
(
50 MHz, CDCl ): d = 14.1, 41.4, 61.5, 65.5, 74.4, 76.6,
3
3
washed successively with 10 cm water, 10 cm 5 % HCl,
3
1
25.3 (q, J = 3.9 Hz), 127.1, 127.4, 127.5, 127.8, 128.0,
3
and 10 cm water. The organic phase was dried over sodium
1
28.3, 128.4, 141.0, 141.9, 145.0, 172.0 ppm; HRMS (ESI):
m/z calcd for C H F NO Na 478.1606, found 478.1591.
2
sulfate. After filtration and concentration, the resulting oil
was recrystallized from ethyl acetate:hexane mixture (1:19)
to afford 0.14 g (73 %) of a colorless product. m.p.: 137–
6
24
3
3
The crystallization mother liquor was concentrated to
afford 0.41 g of a yellow oil, 0.14 g of which was
subjected to flash chromatography on silica gel to give
1
3.1 mg of a yellow oil which was identified by H NMR
138 °C; R = 0.23 (cyclohexane: ethyl acetate 4:1); IR
f
2
(KBr) vꢀ = 3375, 3063, 3031, 3000, 2937, 1675, 1523, 1453,
-1 1
1231, 1039, 833, 751 cm ; H NMR (200 MHz, CDCl ):
spectrum as the other regioisomer, ethyl 2-(diphenyl-
methyl)-3-[4-(trifluoromethyl)phenyl]isoxazolidine-4-car-
3
d = 7.78 (bs, 1H, NH), 7.46–6.80 (m, 19H, Ar), 4.93 (bs,
1H), 4.65 (t, J = 8.1 Hz, 1H, H3), 4.35 (m, 1H, H5), 3.79 (s,
13
boxylate (8c). The overall yield was 4 %; R = 0.38
f
1
cyclohexane:ethyl acetate 4:1); H NMR (200 MHz,
(
3H), 3.01 (m, 1H, H4a), 2.93–2.81 (m, 1H, H4b) ppm;
C
CDCl ): d = 7.54–7.07 (m, 14H, Ar), 5.16 (s, 1H), 4.51
NMR (50 MHz, CDCl ): d = 41.0, 55.7, 65.2, 114.2, 121.3,
3
3
(
d, J = 5.1 Hz, 1H, H3), 4.36 (dd, J = 6.8, 8.4 Hz, 1H,
H5a), 4.30 (d, J = 8.4 Hz, 1H, H5b), 4.21 (q, J = 7.2 Hz,
H), 3.42 (ddd, J = 5.1, 6.8, 8.4 Hz, 1H, H4), 1.26 (t,
127.6, 127.8, 127.9, 128.7, 128.9, 129.0, 130.4, 140.5,
156.6 ppm; HRMS (ESI): m/z calcd for C H N O Na
0 28 2 3
3
2
487.1998, found 487.2011.
1
3
J = 7.2 Hz, 3H) ppm; C NMR (50 MHz, CDCl3):
d = 14.4, 58.0, 61.8, 68.7, 69.6, 72.8, 125.5 (q,
J = 3.7 Hz), 127.5, 127.6, 127.8, 128.0, 128.4, 128.6,
N-(4-Chlorophenyl)-2-(diphenylmethyl)-3-phenylisoxazo-
lidine-5-carboxamide (11b, C29 25ClN
Yield: 0.13 g of a colorless product (64 %); m.p.:
95–196 °C (ethyl acetate:hexane 1:13); R = 0.39 (cyclo-
H
O )
2 2
1
28.6, 141.0, 141.6, 146.3, 172.3.
1
f
Hydrolysis of ethyl 2-(diphenylmethyl)-3-
arylisoxazolidine-5-carboxylates—typical procedure
hexane:ethyl acetate 4:1); IR (KBr) vꢀ = 3364, 3063, 3031,
-1 1
2916, 1683, 1590, 1519, 1401, 1027, 829, 745 cm ; H
NMR (200 MHz, CDCl ): d = 7.88 (bs, NH), 7.45–7.22 (m,
3
2
-(Diphenylmethyl)-3-phenylisoxazolidine-5-carboxylic
19H, Ar), 4.91 (bs, 1H), 4.64 (t, J = 8.2 Hz, 1H, H3), 4.38
acid (9a)
To a suspension of 1.39 g ethyl 2-(diphenylmethyl)-3-
(m, 1H, H5), 3.02 (m, 1H, H4a), 2.94–2.81 (m, 1H, H4b)
1
3
ppm; C NMR (50 MHz, CDCl ): d = 40.6, 65.0, 72.3,
3
phenylisoxazolidine-5-carboxylate (7a, 3.6 mmol) in
7
120.8, 127.4, 127.6, 127.7, 128.5, 128.7, 128.8, 129.3, 135.6,
3
.2 cm ethanol was added 17.6 g of 2 % sodium hydrox-
140.3, 141.8, 170.4 ppm; HRMS (ESI): m/z calcd for
ide. The mixture was heated under reflux with stirring for
3
h. After cooling 5 cm of 2 N hydrochloric acid was
C H25ClN O Na 491.1502, found 491.1518.
29 2 2
3
added and the mixture was extracted with dichloromethane
3
3 9 30 cm ). The organic phase was dried over sodium
2-(Diphenylmethyl)-N-(4-methoxyphenyl)-3-[4-(1-
methylethyl)phenyl]isoxazolidine-5-carboxamide
(
sulfate. After filtration and concentration, the precipitate
was recrystallized from dichloromethane-hexane (1:6) to
afford 1.19 g of the product (92 %).
(11c, C33
Yield: 0.12 g (62 %) of a colorless product; m.p.:
80–81 °C (toluene-hexane); R = 0.26 (cyclohexane:ethyl
acetate 4:1); IR (KBr) vꢀ = 3354, 3063, 3031, 2960, 1672,
H N O )
34 2 3
f
-
1 1
Synthesis of amides 11a–11f, 12a–12i—typical
procedure
1512, 1453, 1413, 1248, 1032, 832, 746 cm ; H NMR
(200 MHz, CDCl ): d = 7.77 (bs, NH), 7.45–6.79 (m,
9H, Ar), 4.95 (bs, 1H), 4.65 (t, J = 8.0 Hz, 1H, H5), 4.29
(bs, 1H, H3), 3.78 (s, 3H), 3.01–2.80 (m, 3H), 1.26 (d,
3
1
2
-(Diphenylmethyl)-N-(4-methoxyphenyl)-3-phenylisoxa-
1
3
zolidine-5-carboxamide (11a, C H N O )
3
J = 6.8 Hz, 6H) ppm; C NMR (50 MHz, CDCl ):
3
0 28 2 3
To a solution of 0.15 g 2-(diphenylmethyl)-3-phenylisoxa-
3
zolidine-5-carboxylic acid (0.42 mmol) in 5 cm toluene
d = 24.2, 27.1, 34.0, 55.6, 64.9, 72.1, 114.1, 121.4,
126.7, 127.7, 127.8, 128.8, 128.9, 130.4, 140.5, 148.5,
3
was added dropwise 62 cm thionyl chloride (0.85 mmol,
156.6, 170.3 ppm; HRMS (ESI): m/z calcd for C33
O Na 529.2467, found 529.2471.
3
H N
34 2-
2
eq). The mixture was stirred at room temperature for 18 h.
123

_
K. Zelechowski et al.
-1 1
2853, 1639, 1492, 1453, 1254, 1228, 1016, 747 cm ; H
N-(4-Chlorophenyl)-2-(diphenylmethyl)-3-[4-(1-
methylethyl)phenyl]isoxazolidine-5-carboxamide
NMR (200 MHz, CDCl ): d = 7.54–7.11 (m, 15H, Ar), 5.01
3
(
11d, C H ClN O )
2 2
(s, 1H), 4.68 (t, J = 7.9 Hz, 1H, H5), 4.52 (dd, J = 1.6,
7.8 Hz, 1H, H3), 3.79–3.65 (m, 2H), 3.25–3.00 (m, 3H), 2.46
(ddd, J = 2.2, 8.5, 13.0 Hz, 1H, H4b), 1.62–1.17 (m, 6H)
3
2
31
Yield: 0.12 g (67 %) of a colorless product; m.p.:
1
34–135 °C (ethyl acetate:hexane 1:30); R = 0.45 (cy-
f
1
3
clohexane:ethyl acetate 4:1); IR (KBr) vꢀ = 3378, 3063,
ppm; C NMR (50 MHz, CDCl ): d = 24.5, 25.3, 25.7,
3
-1 1
021, 2958, 1692, 1516, 1400, 831, 747 cm ; H NMR
3
36.8, 43.6, 46.6, 66.3, 74.2, 76.5, 126.8, 126.9, 127.0, 127.6,
127.8, 128.2, 128.3, 128.5, 128.8, 142.2, 142.6, 142.8,
168.2 ppm; HRMS (ESI): m/z calcd for C H N O Na
(
200 MHz, CDCl ): d = 7.86 (bs, NH), 7.45–7.17 (m,
3
1
1
8H, Ar), 4.93 (bs, 1H), 4.65 (t, J = 8.1 Hz, 1H), 4.32 (bs,
1
H), 2.98–2.81 (m, 3H), 1.26 (d, J = 6.8 Hz, 6H) ppm;
2
8 30 2 2
3
C
449.2205, found 449.2185.
2-(Diphenylmethyl)-3-phenyl-5-isoxazolidinyl]-
4-morpholinyl)methanone (12b, C H N O )
NMR (50 MHz, CDCl ): d = 24.0, 33.8, 40.6, 64.8, 72.0,
1
3
[
20.8, 126.6, 127.5, 127.6, 127.7, 128.7, 128.8, 128.8,
(
2
7 28 2 3
1
29.3, 135.6, 140.3, 148.38 ppm; HRMS (ESI): m/z calcd
Yield: 0.14 g (84 %) of a colorless product; m.p.:
for C H ClN O Na 533.1972, found 533.1993.
3
2
31
2 2
1
52–153 °C (ethyl acetate:hexane 1:25); R = 0.31 (cy-
f
2
-(Diphenylmethyl)-N-(4-methoxyphenyl)-3-[4-(trifluo-
romethyl)phenyl]isoxazolidine-5-carboxamide
11e, C H F N O )
clohexane:ethyl acetate 1:1); IR (KBr) vꢀ = 3063, 3031,
-1 1
2926, 2863, 1642, 1454, 1232, 1113, 1027, 749 cm ; H
(
NMR (200 MHz, CDCl ): d = 7.53–7.14 (m, 15H, Ar),
3
1
27
3
2
3
3
Yield: 0.12 g (66 %) of a colorless product; m.p.:
4.99 (s, 1H), 4.64 (t, J = 7.8 Hz, 1H, H5), 4.56 (bd,
J = 6.8 Hz, 1H, H3), 3.82–3.68 (m, 2H), 3.64–3.52 (m,
1H), 3.40–3.24 (m, 3H), 3.18 (t, J = 4.8 Hz, 2H), 2.69
(app. quintet, J = 5.4 Hz, 1H), 2.51 (ddd, J = 2.0, 8.7,
1
58–160 °C (ethyl acetate:hexane 1:10); R = 0.15 (cy-
f
clohexane:ethyl acetate 4:1); IR (KBr) vꢀ = 3360, 3063,
3
1
000, 2937, 2386, 1675, 1529, 1413, 1325, 1247, 1158,
-
1
1
123, 1067, 828, 746 cm ; H NMR (200 MHz, CDCl ):
13
13.1 Hz, 1H, H4b) ppm; C NMR (50 MHz, CDCl3):
3
d = 7.77 (bs, NH), 7.59 (d, J = 7.8 Hz, 1H), 7.45–7.15
d = 36.1, 42.6, 45.8, 66.1, 66.2, 74.0, 76.2, 126.6, 127.0,
127.6, 127.8, 128.3, 128.4, 128.7, 141.8, 142.1, 142.4,
168.5 ppm; HRMS (ESI): m/z calcd for C H N O Na
(
m, 14H, Ar), 6.82 (d, J = 9.0 Hz, 2H), 4.92 (bs, 1H), 4.65
(
t, J = 8.0 Hz, 1H, H5), 4.45 (m, 1H, H3), 3.79 (s, 3H),
3
2
7 28 2 3
1
3
.16–3.09 (m, 1H, H4a), 2.91–2.79 (m, 1H, H4b) ppm;
C
451.1998, found 451.1999.
NMR (50 MHz, CDCl ): d = 40.6, 55.7, 65.0, 73.1, 75.9,
3
Ethyl 4-[[2-(diphenylmethyl)-3-phenyl-5-isoxazolidinyl]-
1
14.2, 121.3, 125.6 (q, J = 5.7 Hz), 127.6, 128.0, 128.0,
carbonyl]piperazine-1-carboxylate (12c, C H N O )
0 33 3 4
3
1
28.3, 129.0, 129.1, 130.3, 140.6, 156.6, 169.7 ppm;
Yield: 0.16 g (77 %) of a colorless product; m.p.:
HRMS (ESI): m/z calcd for C H F N O Na 555.1871,
31 27 3 2 3
1
61–162 °C (ethyl acetate:hexane 1:20); R = 0.26 (cy-
f
found 555.1891.
clohexane:ethyl acetate 1:1); IR (KBr) vꢀ = 3063, 3021,
2979, 2926, 1707, 1640, 1452, 1288, 1227, 1092,
N-(4-Chlorophenyl)-2-(diphenylmethyl)-3-[4-(trifluo-
romethyl)phenyl]isoxazolidine-5-carboxamide
-
1
1
748 cm ; H NMR (200 MHz, CDCl ): d = 7.53–7.10
3
(
11f, C H ClF N O )
3 2 2
(m, 15H, Ar), 4.97 (s, 1H), 4.64 (t, J = 7.8 Hz, 1H, H5),
4.56 (bd, J = 7.6 Hz, 1H, H3), 4.12 (q, J = 7.1 Hz, 2H),
3.90–3.55 (m, 3H), 3.31–3.26 (m, 2H), 3.18–2.89 (m, 3H),
2.51 (ddd, J = 1.6, 8.7, 13.1 Hz, 1H, H4b), 2.22–2.13 (m,
3
0
24
Yield: 0.14 g (70 %) of a colorless product; m.p.:
1
58–159 °C (ethyl acetate:hexane 1:15); R = 0.36 (cy-
f
clohexane:ethyl acetate 4:1); IR (KBr) vꢀ = 3376, 3063,
1
3
3
1
031, 2926, 2368, 1690, 1594, 1528, 1493, 1384, 1326,
1 1
170, 1124, 1069, 1017, 815 cm ; H NMR (200 MHz,
1H), 1.25 (t, J = 7.1 Hz, 3H) ppm; C NMR (50 MHz,
-
CDCl ): d = 14.8, 36.2, 42.3, 43.4, 45.3, 61.7, 66.2, 74.3,
3
CDCl ): d = 7.85 (bs, NH), 7.61–7.17 (m, 18H, Ar), 4.91
76.5, 126.8, 127.2, 127.7, 127.9, 128.4, 128.6, 128.9,
141.9, 142.3, 142.6, 155.5, 168.8 ppm; HRMS (ESI): m/z
calcd for C H N O Na 522.2369, found 522.2387.
3
(
s, 1H), 4.62 (t, J = 8.0 Hz, 1H, H5), 4.52 (dd, J = 1.3,
7
1
6
1
.9 Hz, 1H, H3), 3.17–3.11 (m, 1H, H4a), 2.92–2.80 (m,
1
3
0 33 3 4
3
H, H4b) ppm; C NMR (50 MHz, CDCl ): d = 40.1,
3
[
2-(Diphenylmethyl)-3-[4-(1-methylethyl)phenyl]-5-isoxa-
4.8, 120.7, 125.5 (q, J = 3.5 Hz), 127.4, 127.8, 127.9,
zolidinyl](1-piperidinyl)methanone (12d, C H N O )
3
1 36 2 2
28.0, 128.9, 129.0, 129.4, 135.4 ppm; HRMS (ESI): m/z
Yield: 0.14 g (78 %) of a colorless product; m.p.:
63–164 °C (ethyl acetate:hexane 1:10); R = 0.22 (cy-
calcd for C H ClF N O Na 559.1376, found 559.1375.
3 2 2
3
0
24
1
f
[
2-(Diphenylmethyl)-3-phenyl-5-isoxazolidinyl]-
clohexane:ethyl acetate 4:1); IR (KBr) vꢀ = 3063, 3031,
-1 1
2931, 2852, 1640, 1452, 1384, 1229, 747 cm ; H NMR
(
1-piperidinyl)methanone (12a, C H N O )
2
8 30 2 2
Yield: 0.13 g (81 %) of a colorless product; m.p.:
69–170 °C (ethyl acetate:hexane 1:13); R = 0.22 (cyclo-
(200 MHz, CDCl ): d = 7.53–7.42 (m, 4H, Ar), 7.33–7.12
(m, 10H, Ar), 5.00 (s, 1H), 4.69 (t, J = 8.0 Hz, 1H, H5),
3
1
f
hexane:ethyl acetate 4:1); IR (KBr) vꢀ = 3063, 3031, 2931,
4.49 (bd, J = 8.0 Hz, 1H, H3), 3.76–3.62 (m, 2H),
1
23

Synthesis and fungicidal activity of 2-(diphenylmethyl)-3-arylisoxazolidine-5-carboxamides
3
.22–3.00 (m, 3H), 2.88 (sept., J = 6.8 Hz, 1H), 2.48 (ddd,
2852, 1641, 1453, 1329, 1230, 1123, 1070, 1018, 850,
-
1 1
749 cm ; H NMR (200 MHz, CDCl ): d = 7.58–7.46 (m,
J = 2.2, 8.6, 13.0 Hz, 1H, H4b), 1.40–1.36 (m, 4H), 1.24
3
1
3
d, J = 6.8 Hz, 6H), 1.17 (m, 2H) ppm; C NMR
(
6H), 7.40 (dd, J = 1.7, 7.6 Hz, 2H), 7–32–7.12 (m, 6H, Ar),
5.03 (s, 1H), 4.66 (t, J = 7.8 Hz, 1H, H5), 4.50 (bd,
J = 7.4 Hz, 1H, H3), 3.85–3.66 (m, 2H), 3.26–3.00 (m, 3H),
2.42 (ddd, J = 2.3, 8.4, 13.0 Hz, 1H, H4b), 1.41–1.17 (m,
(
50 MHz, CDCl ): d = 24.0, 24.4, 25.1, 25.6, 33.7, 36.2,
3
4
3.4, 46.4, 65.9, 74.0, 126.4, 126.7, 127.3, 127.7, 128.0,
1
28.1, 128.6, 139.6, 142.0, 142.6, 147.4, 168.1 ppm;
1
3
HRMS (ESI): m/z calcd for C H N O Na 491.2674,
3
6H) ppm; C NMR (50 MHz, CDCl ): d = 24.3, 25.1, 25.5,
1
36
2
2
3
found 491.2674.
36.9, 43.5, 46.4, 66.0, 74.2, 76.3, 125.2 (q, J = 3.6 Hz),
126.8, 127.1, 127.6, 127.8, 128.2, 128.7, 141.6, 142.4, 146.5,
[
2-(Diphenylmethyl)-3-[4-(1-methylethyl)phenyl]-5-isoxa-
167.7 ppm; HRMS (ESI): m/z calcd for C H F N O Na
29 29 3 2 2
zolidinyl](4-morpholinyl)methanone (12e, C H N O )
3
517.2079, found 517.2080.
2-(Diphenylmethyl)-3-[4-(trifluoromethyl)phenyl]-5-
isoxazolidinyl](4-morpholinyl)methanone
(12h, C28
Yield: 0.12 g (71 %) of a colorless product; m.p.: 164–
65 °C (ethyl acetate:hexane 1:25); R = 0.24 (cyclohex-
3
0
34
2
Yield: 0.12 g (70 %) of a colorless product; m.p.: 154–
[
1
3
7
55 °C (ethyl acetate:hexane 1:20); IR (KBr) vꢀ = 3063,
031, 2964, 2863, 1640, 1454, 1274, 1232, 1113, 1027,
-
1
1
H F N O )
27 3 2 3
47 cm ; H NMR (200 MHz, CDCl ): d = 7.50–7.42
3
(
m, 4H, Ar), 7.32–7.14 (m, 10H, Ar), 4.97 (s, 1H), 4.65 (t,
1
f
J = 8.0 Hz, 1H, H5), 4.52 (bd, J = 8.0 Hz, 1H, H3),
ane:ethyl acetate 4:1); IR (KBr) vꢀ = 3063, 3021, 2905,
3
3
2
.81–3.69 (m, 2H), 3.65–3.52 (m, 1H), 3.39–3.27 (m, 3H),
.24–3.16 (m, 2H), 2.89 (septet, J = 6.9 Hz, 1H),
.74–2.63 (m, 1H), 2.52 (ddd, J = 1.7, 8.6, 13.0 Hz, 1H,
2
7
859, 1639, 1455, 1329, 1232, 1113, 1069, 1018, 850,
-
1
1
50 cm ; H NMR (200 MHz, CDCl ): d = 7.59–7.48
3
1
3
(m, 6H), 7.40 (dd, J = 1.7, 8.0 Hz, 2H), 7.35–7.13 (m, 6H,
Ar), 5.00 (s, 1H), 4.66 (t, J = 8.0 Hz, 1H, H5), 4.60 (d,
J = 7.0 Hz, 1H, H3), 3.88–3.70 (m, 2H), 3.64–3.53 (m,
H4b), 1.24 (d, J = 7.0 Hz, 6H) ppm; C NMR (50 MHz,
CDCl ): d = 24.2, 33.9, 36.0, 42.8, 46.0, 66.1, 66.4, 74.2,
3
7
6.5, 126.6, 126.8, 127.1, 127.7, 127.8, 128.0, 128.4,
1
1
H), 3.40–3.25 (m, 3H), 3.19–3.15 (m, 2H), 2.75–2.64 (m,
1
28.9, 139.6, 142.0, 142.6, 147.7, 168.8 ppm; HRMS
H, H4a), 2.46 (ddd, J = 2.1, 8.5, 13.1 Hz, 1H, H4b) ppm;
(
ESI): m/z calcd for C H N O Na 493.2467, found
30 34 2 3
13
C NMR (50 MHz, CDCl ): d = 36.6, 42.9, 46.1, 66.1,
3
4
93.2465.
66.4, 74.4, 76.4, 125.5 (q, J = 3.6 Hz), 127.2, 127.3, 127.6
(
q, J = 32.0 Hz), 127.7, 127.8, 128.5, 129.0, 141.6, 142.4,
Ethyl 4-[[2-(diphenylmethyl)-3-[4-(1-methylethyl)phenyl]-
-isoxazolidinyl]carbonyl]piperazine-1-carboxylate
12f, C H N O )
1
46.5, 168.4 ppm; HRMS (ESI): m/z calcd for C H F
28 27 3-
5
N O Na 519.1871, found 519.1852.
2
3
(
3
3 39 3 4
Yield: 0.15 g (75 %) of a colorless product; m.p.: 158–
Ethyl 4-[[2-(diphenylmethyl)-3-[4-(trifluoromethyl)-
phenyl]-5-isoxazolidinyl]carbonyl]piperazine-1-
carboxylate (12i, C H N O F )
1
59 °C (ethyl acetate:hexane 1:13); R = 0.33 (cyclohex-
f
ane:ethyl acetate 1:1); IR (KBr) vꢀ = 3063, 3031, 2961,
3
1 32 3 4 3
-
1
1
1
694, 1641, 1436, 1242, 998, 748 cm
200 MHz, CDCl3): d = 7.52–7.42 (m, 4H, Ar),
.33–7.13 (m, 10H, Ar), 4.96 (s, 1H), 4.65 (t,
J = 8.0 Hz, 1H, H5), 4.52 (bd, J = 7.4 Hz, 1H, H3),
.11 (q, J = 7.1 Hz, 2H), 3.90–3.54 (m, 3H), 3.31–3.24
m, 2H), 3.17–3.00 (m, 2H), 3.00–2.82 (m, 2H), 2.52 (ddd,
J = 1.4, 8.5, 13.1 Hz, 1H, H4b), 2.22–2.12 (m, 1H), 1.25
;
H NMR
Yield: 0.14 g (69 %) of a colorless product; m.p.: 183–
(
184 °C (ethyl acetate:hexane 1:9); R = 0.4 (cyclohex-
f
7
ane:ethyl acetate 1:1); IR (KBr) vꢀ = 3031, 3973, 2989,
-1 1
905, 1688, 1653, 1430, 1325, 1228, 1116, 747 cm ; H
2
4
NMR (200 MHz, CDCl ): d = 7.55–7.17 (m, 14H, Ar),
3
(
4
3
2
.99 (s, 1H), 4.66–4.59 (m, 2H), 4.12 (q, J = 7.2 Hz, 2H),
.99–3.73 (m, 2H), 3.62–3.55 (m, 1H), 3.35–2.90 (m, 5H),
.47 (ddd, J = 1.9, 8.5, 13.1 Hz, 1H), 2.23–2.14 (m, 1H),
1
3
(
t, J = 7.1 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H) ppm;
C
1
3
NMR (50 MHz, CDCl ): d = 14.8, 24.2, 33.9, 35.9, 42.3,
3
1.25 (t, J = 7.2 Hz, 3H) ppm; C NMR (50 MHz,
4
1
1
3.1, 43.4, 45.3, 61.7, 66.0, 74.3, 76.5, 126.6, 126.8, 127.1,
27.7, 127.8, 128.0, 128.4, 128.9, 139.5, 142.0, 142.7,
47.7, 155.5, 168.8 ppm; HRMS (ESI): m/z calcd for
CDCl ): d = 14.8, 36.6, 42.4, 43.3, 45.3, 61.7, 66.1,
3
74.4, 76.4, 125.5 (q, J = 4.2 Hz), 127.2, 127.7, 127.8,
127.9, 128.5, 129.0, 141.6, 142.4, 146.4, 155.5, 168.5 ppm;
C H N O Na 564.2838, found 564.2838.
3
3
39
3
4
HRMS (ESI): m/z calcd for C H F N O Na 590.2243,
31 32 3 3 4
found 590.2227.
Fungicidal testing
In vitro test
[
2-(Diphenylmethyl)-3-[4-(trifluoromethyl)phenyl]-5-isox-
azolidinyl](1-piperidinyl)methanone
12g, C H F N O )
(
2
9 29 3 2 2
Yield: 0.13 g (75 %) of a colorless product; m.p.: 174–
1
75 °C (ethyl acetate:hexane 1:12); R = 0.22 (cyclohex-
The compounds were screened in vitro for antifungal
activity against the following five plant pathogens:
f
ane:ethyl acetate 4:1); IR (KBr) vꢀ = 3063, 3031, 2932,
123

_
K. Zelechowski et al.
Fusarium culmorum Sacc., Phytophthora cactorum
Schroek, Alternaria alternata Keissl.(Fr.), Rhizoctonia
solani Kuhn, and Botrytis cinerea Pers. Ex Fr.
control was calculated according to the Abbot formula
[36].
Acknowledgments This work was supported in part by the Polish
Ministry of Science and Higher Education (Grant No. 429/E-142/S/
The test involved determination of mycelial growth
retardation in potato glucose agar (PGA; Difco). Stock
2
011), which is gratefully acknowledged.
3
solutions of test chemicals in acetone (2 cm ) were added
3
to agar medium to give a concentration of 200 mg/cm and
dispersed into sterile Petri dishes. Plates were inoculated
within 24 h after they were poured. Four discs (5 mm
diameter) were cut from the margins of actively growing
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