Studies on [2?+?3] cycloaddition reaction of nitrile oxides to linear dipolarophiles bearing multiple double bonds

Article abstract of DOI:10.1007/s00706-016-1797-4

Abstract: Site selectivity, regioselectivity, and stereoselectivity of [2?+?3] cycloaddition of benzonitrile oxides to polyunsaturated esters were examined. Site selectivity was correlated with electron charges of unsaturated carbon atoms. Structure of the products has been established by an extensive application of ¹H and ¹³C NMR spectroscopy and electrospray ionization mass spectrometry. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-016-1797-4

Monatsh Chem
DOI 10.1007/s00706-016-1797-4
ORIGINAL PAPER
Studies on [2 + 3] cycloaddition reaction of nitrile oxides to linear
dipolarophiles bearing multiple double bonds
Mirosław Gucma1 W. Marek Gołe˛biewski1
Alicja Katarzyna Michalczyk1
•
•
Received: 26 April 2016 / Accepted: 5 June 2016
Ó Springer-Verlag Wien 2016
Abstract Site selectivity, regioselectivity, and stereose-
lectivity of [2 ? 3] cycloaddition of benzonitrile oxides to
polyunsaturated esters were examined. Site selectivity was
correlated with electron charges of unsaturated carbon
atoms. Structure of the products has been established by an
the synthesis of several pharmaceuticals [2] and natural
product [3]. The easy cleavage of their weak hetero N–O
bond affords several synthetically important compounds,
such as b-hydroxy ketones, b-hydroxy esters, a,b-unsatu-
rated carbonyl compounds, or iminoketones [4]. The nitrile
oxides can be formed either by Huisgen method from
aldoximes by chlorination and base-induced dehydrochlo-
rination [1] or by dehydration of primary nitro compounds
by phenyl isocyanates [5] (Mukayama method) or ethyl
chloroformate (Shimizu method) [6].
1
extensive application of H and 13C NMR spectroscopy
and electrospray ionization mass spectrometry.
Graphical abstract
A key feature of the cycloaddition is the cis-stereospeci-
ficity—from E-alkenes 4,5-anti isomers are produced and
fromZ-alkenes4,5-syn productsare obtained[4]. Reactionsof
monosubstituted and 1,1-disubstituted alkenes furnish
regioselectively 5-substituted 2-isoxazolines while 1,2-dis-
ubstituted olefins usually afford mixtures of regio- and
stereoisomers. These problems were treated by two approa-
ches. Inthe first methoda substratecontrol was applied, where
opticallyactivereagents,muchmoreoftendipolarophilesthan
dipoles were used. One variant of this method was based on
the use of chiral auxiliaries temporarily linked usually by an
ester or amide bond to the dipolarophiles [7–9]. The second
more effective method relied on chiral metal catalysts or
organocatalysts. Shortage of reports on metal assisted 1,3-
dipolarcycloadditionsofnitrileoxideswasdue tointerference
of catalyst with generation of these dipoles and formation of
unreactive complexes [10].
Keywords Alkenes Á Polyunsaturated esters Á
Site selectivity Á NMR spectroscopy Á Mass spectroscopy
Introduction
The [2 ? 3] cycloaddition of nitrile oxides to alkenes is the
most convenient method for the preparation of 2-isoxazo-
lines [1]. These heterocycles are valuable intermediates in
Cycloaddition of nitrile oxides to polyunsaturated alkenes
was examined to a limited extent and concerned mostly a
conjugated 1,3-diene system. In cycloaddition of benzoni-
trile oxide to 2-alkoxy-1,3-butadienes only the unsubstituted
vinyl group participated in the reactions while in case of
phenylglyoxylonitrile oxide both double bonds reacted [11].
This result indicated the dominance of steric effect over the
electronic one in the first case, where more sterically
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-016-1797-4) contains supplementary
material, which is available to authorized users.
& W. Marek Gołe˛biewski
golebiewski@ipo.waw.pl
1
Institute of Industrial Organic Chemistry, Annopol 6, 3-236
Warsaw, Poland
123

M. Gucma et al.
demanding dipole did not interact with the activated double
bond. 2-Highly substituted diastereoisomerically pure buta-
and 4, to the unconjugated diene 6, to the allene 18, to the
conjugated triene of acetylcholecalciferol (vitamin D3, 12),
to the unconjugated triene 8 (cis-neridiol acetate) and to the
alkene–alkyne acetate 10 as well as cycloaddition of 4-(2-
propyl)benzonitrile oxide (13b) to the latter dipolarophile.
These reactions are presented in Schemes 3, 4 and 5. The
spectroscopic data for the cycloadducts are presented in the
experimental section.
diene derivative underwent
a
chemoselective and
regioselective nitrile oxide cycloaddition to provide isoxa-
zoline system en route to carbon skeleton of myriaporone
[12]. 1,3-Dipolar cycloaddition of nitrile oxides to
1-phenylsulfonyl-1,3-dienes occurred in a regioselective
manner at 1,1-substituted double bond [13]. Tricarbonyl[(1-
4-g)-2-methoxy-5-methyl-enecyclohexa-1,3-diene]iron
underwent 1,3-dipolar cycloaddition reaction regio-, stereo-,
and chemoselectively at its exocyclic double bond [14].
In reactions of nitrile oxides with dimethyl 7-(diphenyl-
methylene)bicyclo[2.2.1]hept-2-ene-5,6-dicarboxylate only
disubstituted norbornene double bond participated [15].
Similarly in lately examined by us cycloadditions of aryl
nitrile oxides to norbornenes substituted with an acrylate-
derived moiety only adducts to norbornene system were
formed with good site and exo selectivity [16].
Reaction of the dipole 13a and the diene 3 gave a 1:1
mixture of cycloadducts 14 and 15 to the C2–C3 double
bond (30 %) and a cycloadduct 16 to the C4–C5 bond
(23 %), separated by
a
column chromatography
1
(Scheme 3). In the H NMR spectrum of compound 14 a
diagnostic proton H5 was a doublet of doublets at
5.40 ppm, showing a vicinal coupling with H4 (doublet at
4.25 ppm, J = 6.9 Hz) and with the olefinic proton H6
(ddq, J = 7.8, 1.5, 15.0 Hz), part of the E-propenyl side
chain; H5 was also correlated in the 2D NMR HSQC
spectrum with C5 (87.25 ppm). In the other regioisomer 15
the diagnostic H5 (d, J = 4.5 Hz) correlated in the 2D
NMR HSQC spectrum with C5 (84.70 ppm) showed only
vicinal coupling with H4 (dd at 4.25 ppm, J = 4.5,
9.0 Hz). In the third adduct 16 an acrylic side chain was
attached at C5. H5 was an apparent triplet of doublets at
4.94 ppm, because of similar vicinal couplings with H4
(dq, J = 5.3, 6.3 Hz) and with H7 (dd, J = 5.3, 15.6 Hz).
Reaction with the phenyl diene 4 showed on the other
hand a good site- and regioselectivity and only one adduct
17 to the C2–C3 bond was observed. It was a phenyl analog
of the cycloadduct 14, and its structure was similarly
established by analysis of NMR spectra.
We have described recently [2 ? 3] cycloaddition
reaction of nitrile oxides to cyclohexenes [17], medium
ring cycloalkenes [18], crotonamides and cinnamides [19],
as well as to a,b-unsaturated esters [20].
Studies on synthesis of cholecalciferol (vitamin D3)
analogs directed towards optimization of biological activity
were carried out [21, 22].
Herein we present results of our research concerning site
selectivity, regioselectivity, and stereochemistry of 1,3-
dipolar cycloaddition reaction of two benzonitrile oxides to
conjugated and unconjugated dienes, an allene, to conju-
gated and unconjugated trienes, and to an alkene–alkyne.
Structure of the products has been established by an
1
application of H and 13C NMR spectroscopy and elec-
A high selectivity towards cycloaddition to the terminal
double bond was found in case of the allenyl ester 18,
1
which gave only one ester 19. H NMR spectrum showed
trospray ionization mass spectrometry. Some of the
obtained products showed moderate fungicidal activities.
only one olefinic proton of H6 at 6.62 ppm and 2H singlet
of H4 at 3.93 ppm. In the other possible cycloadducts, two
alkenyl protons are expected and one or zero H4. This
corollary was confirmed by 13C NMR spectrum where C4
gave a high field signal at 32.71 ppm and C5 absorbed at a
very low field (167.2 ppm).
Results and discussion
Synthesis of the dipolarophiles
(2E,4E)-2,4-Dienoic acids 2a, 2b were obtained by the
Knoevenagel condensation [27] of the corresponding
aldehydes with malonic acid. Esters 3, 4, and 6 were pre-
pared by acidic esterification (Scheme 1). Acetates 8, 10,
and 12 were prepared by reaction with acetic acid in the
presence of N,N0-dicyclohexylcarbodiimide (DCC) and
4-dimethylaminopyridine (DMAP). Ester 18 was pur-
chased from Aldrich (Scheme 2).
Cycloaddition to the unconjugated diene 6 occurred
mainly to the a,b-unsaturated ester moiety affording
regioisomeric products 20 and 21 in 3:2 ratio and 50 %
overall yield (Scheme 4). Unexpectedly, an addition of
methanol components occurred to the C6–C7 double bond,
originating presumably from the methyl ester group. No
olefinic protons were observed and another quaternary
methoxy group was identified in the 1H and 13C NMR
spectra of both esters. A similar side reaction was observed
by us before [17]. 2D NMR HMBC spectra of 20 and 21
showed correlation peaks between OC12H3 at 3.16 ppm and
C9 at 74.4 ppm. A diagnostic correlation was also observed
in 2D HMBC spectrum of compound 20 between H4 at 3.67
Structural analysis of the cycloadducts
We have examined [2 ? 3] cycloaddition of 4-(trifluo-
romethyl)benzonitrile oxide (13a) to conjugated dienes 3
123

Studies on [2 ? 3] cycloaddition reaction of nitrile oxides to linear dipolarophiles bearing…
Scheme 1
H
C O
CO2CH3
H
CO2
H
R
H
R
H
R
CH3OH
Py
+ (HO2C)2CH2
H+
2
H
3 4
,
1
H
H
1 2a 3
1 2b 4
-
3C
3C
,
R = CH3 ,
-
,
CO2
H
R = Ph
H
3C
H
3C
H
H
3C
3C
CO2CH3
H
H
H
H
H
CH3OH
H
(CH2)2
(CH2)2
6
5
3C12
3C
H
H
3C
H
3C
H
H
H
H
H
H
3C
10
6
CH3
CH3
OH
7
1
AcOH
DCC, DMAP
H
3C
(CH2)2
(CH2)2
(CH2)2
(CH2)2
AcO
8
7
H
H
stereoselection in 1,3-dipolar cycloadditions of benzonitrile
oxides to terminal alkenes bearing an allylic stereocenters
[24]. In the absence of hydrogen bonding the major
diastereoisomers had always 5,6-anti relative configuration
like that of compound 23 at Scheme 4.
Scheme 2
H
H
8
7
CH3
AcOH
CH3
OH
CH3
3
10
OCOCH3
CH3
5
DCC, DMAP
10
9
1
23
Reaction of both benzonitrile oxides 13a, 13b with the
alkene–alkyne acetate 10 yielded mixtures of major
monoadducts to the double bond 25, 26 and minor bisad-
ducts 27 and 28 (Scheme 5). Comparison of product
amounts demonstrates that a double bond is seven times
more reactive than the triple bond in reaction of dipole 13a
and in case of the dipole 13b with an electron-donating
substituent this ratio of reactivities is greater than 9.
Regiochemistry of the second addition to alkyne system
was as expected from FMO considerations where oxygen
atom of the dipole tends to attack the more-substituted
carbon atom [24]. It was confirmed by 2D ROESY NMR
spectra where proximity of aryl H2’’/H6’’ protons
(7.85 ppm) and H6a (2.67 ppm) for compound 27 and
proximity of H2’’/H6’’ protons (7.61 ppm) and H6a
(2.66 ppm) for compound 28 were found. These correla-
tions were not possible in the other regioisomer.
25
19
14
AcOH
10
16
H
H
H
H
DCC, DMAP
H
H
8
5
7
11
12
1
HO
CH3COO
and C3 at 155.6 ppm which was missing in the spectrum of
regioisomer 21. A minor product 22 was formed by
cycloaddition to the C6–C7 double bond. Regiochemistry of
the cycloaddition leading to 22 and the major adduct 20 can
be explained by Frontier Molecular Orbital (FMO) consid-
erations. Reactions of the alkenes with electron-donating
substituents and moderately electron-withdrawing sub-
stituents (such as an ester group) are controlled by
LUMOdipol–HOMOalkene (DE = 8.28 eV) interaction since
LUMOalkene–HOMOdipol energy gap (DE = 9.87 eV) is
higher. Bond formation occurs between atoms of the larger
orbital coefficients and leads to isoxazolines with the oxygen
atom next to the more-substituted carbon atom [23].
Finally cycloaddition of 4-(trifluoromethyl)benzonitrile
oxide (13a) to acetylcalciferol acetate (12) afforded a
mixture of 5,8-syn 29 and 5,8-anti 30 adducts to the most
easily excessible exocyclic double bond with the expected
regiochemistry
(Scheme 5).
Structures
of
both
diastereoisomers were proposed based on 1H NMR spectra.
In the syn-adduct 29, the diagnostic H4 was a pair of
geminally coupled protons (3.42, 3.31 ppm, J = 16.5 Hz),
while in the anti-adduct 30 H4 were a two proton singlet at
3.36 ppm. In a preferred pseudo diequatorial conformation
of the acetate substituent and C4–C5 bond H4 chemical
shifts can be differentiated by interaction with C6–C13
diene system.
Cycloaddition to cis-neridiol acetate (8) afforded an
unseparable mixture of anti 23 and syn 24 adducts to the
most exposed terminal double bond in 40:35 ratio
(Scheme 4). Regiochemistry of the reaction results from
FMO factors. Anti configuration was proposed to the major
isomer 23 based on literature data concerning
123

M. Gucma et al.
Scheme 3
O
N
6
H
H
CO2CH3
CH3
H
H
H
O
CO2CH3
O
8
O
7
N
N
6
N
5
5
H
H
4
H
6
+
+
CH2Cl2
CH3
CO2CH3
+
8
3
H
H
H
9
H
CH3
10
16
15
R
14
13a
R = CF3
CF3
CF3
CF3
13b
R = i-Pr
H
Ph
7
H
O
N
5
H
CH2Cl2
13a
4
+
8
CO2CH3
H
2'
17
CF3
H
6
8
H
O
N
CO2CH2Ph
5
C
CH2Cl2
13a
+
Ph
CO2CH2
18
2'
19
CF3
Scheme 4
15
13
6
CO2CH3
14
10
O
5
O
O
11
10
CO2CH3
N
N
N
10
5
5
7
OCH3
12
8
H
11
12
H
CH2Cl2
7
OCH3
13
6 + 13a
H
CO2CH3
11
2'
2'
+
2'
15
+
21
22
20
CF3
CF3
CF3
H
H
O
18
7
O
17
15
H
H
H
H
N
N
5
CH2Cl2
13
10
8 + 13a
OCOCH3
OCOCH3
19
2'
+
24
23
CF3
CF3
Rationalization of the observed site selectivity
Generally the greater was the amount of negative charges
at both carbon atoms of the unsaturated bond, the higher was
the reactivity of the cycloaddition reaction. The total charges
for the diene 6 at C6–C7 of -0.289 correspond to the for-
mation of 50 % of the products 22 and 21, while the C2–C3
Table 1 gives electron charges at the alkenyl (alkynyl)
carbon atoms of the dipolarophiles 3, 4, 6, 8, 10, 18, and
the observed site selectivity in the cycloaddition reaction.
123

Studies on [2 ? 3] cycloaddition reaction of nitrile oxides to linear dipolarophiles bearing…
Table 1 Electron charges at the alkenyl carbon atoms of the dipolarophiles 3, 4, 6, 8, 10, 12, 18 and site selectivity in the cycloaddition reaction
Dipolarophile/C atom C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
Site selectivity
3
–
–
–
-0.201 -0.039 -0.176 -0.111
-0.197 -0.041 -0.161 -0.075
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
4
C2/C3
C2/C3
6
-0.228 -0.008
–
–
–
–
–
-0.185 -0.104
-0.173 -0.108
-0.160 -0.210
8
-0.18 -0.182
–
-0.174 -0.107 C1/C2
10
12
18
–
–
–
–
–
-0.111 -0.175
–
–
–
–
C6/C7
C4/C7
C3/C4
–
-0.067 -0.075
–
–
-0.220 -0.102 -0.164 -0.064
-0.158 -0.066 -0.171
–
–
–
–
bond with total -0.236 gave rise to only 10 % of the product
22. For the alkene–alkyne 10 the total charges at C6–C7 bond
of -0.37 corresponded to 52.5 % (and 56 % for the other
dipole) of cycloadducts, and to the C3–C4 bond with the total
electron charges of -0.286 only 7.5 % (and 6 %) of
cycloaddition took place. In case of trienes 8 and 12 exclu-
sively an addition to the terminal double bonds with the
highest electron densities was observed. This direction of the
reaction was favored also by steric factors. The latter effects
were decisive in case of compound 4 where in spite of similar
electron densities at both double bonds the reaction showed
good site selectivity. It could be explained by steric interac-
tions of the phenyl substituent and a more difficult approach
of the dipole to the double bond of the dipolarophile.
fungi: Alternaria alternata, Botrytis cinerea, Fusarium
culmorum, Phytophthora cactorum, and Rhizoctonia solani
was examined. Generally only a moderate potency was
found, particularly against P. cactorum and R. solani.
Diene 4 was the most active from the dipolarophiles dis-
playing a higher potency against F. culmorum and P.
cactorum than the reference compound chlorothalonil.
From the cycloadducts tested compounds 14–16 were the
most active (Table 2).
Conclusions
High regio- and site selectivity of 1,3-dipolar cycloaddition
reaction of 4-(trifluoromethyl)benzonitrile oxide to the
conjugated dienyl ester 4, to the allenyl ester 18, to the
conjugated 12 and the unconjugated trienic ester 8 were
observed. A correlation of double bond reactivity with
electron charges was found. Steric effects were also
Biological activity of the products
Fungicidal inhibitory activities of dipolarophiles 3–12 and
cycloadducts 14–30 against the following phytopathogenic
123

M. Gucma et al.
Table 2 Fungicidal inhibitory activities of compounds 3, 4, 8, 10, 12, 14, 15, 16, 17, 19, 23, 24, 25, 26, 27, 28, 29, 30 at 200 lg/cm3
Compound
A. a.a
B. c.
F. c.
P. c.
Rh. s.
3
16.0
–
14.8
12.0
0
22.0
40.0
22.0
20.0
6.0
29.0
68.0
0
30.0
27.0
17.0
0
4
8
–
10
17.4
14.0
38.0
–
22.2
14.8
17.0
40.0
40.0
0
42.2
12.9
44.0
–
12
38.0
49.0
51.0
67.0
0
14
33.0
33.0
33.0
16.0
0
15
16
44.0
–
56.0
0
17
19
21.7
–
17.8
10.0
37.8
35.6
0
11.1
0
0
23 ? 24
22.0
13.3
24.4
0
0
25
39.1
41.3
0
11.1
0
52.0
46.0
0
26
27
3.2
35.4
6.4
12.9
61.0
28
20.0
0
29.7
6.3
16.0
0
66.0
0
29
30
Chlorothalonilb
0
0
0
0
–
80.0
38.0
88.0
Percentage of linear growth inhibition
a
A. a. Alternaria alternata, B. c. Botrytis cinerea, F. c. Fusarium culmorum, P. c. Phytophthora cactorum, Rh. s. Rhizoctonia solani
b
Reference compound
important. The addition to the exocyclic and terminal
some alpha carbon atoms were sometimes not observed
because of strong 19F–13C coupling. In order to further
characterize these compounds, 19F spectra were recorded. EI
mass spectra were run on an AMD M-40 instrument, elec-
trospray ionization-mass spectra (ESI–MS) on a LCT
(Micromass) apparatus. Flash chromatography was carried
out using silica gel S 230–400 mesh (Merck) and hexanes-
ethyl acetate mixtures as eluents. Hydroximinoyl acid
chlorides were prepared from the corresponding aryl alde-
hyde oximes and NCS in DMF [25]. Calculations of electron
charges on alkenyl carbon atoms, molecular modeling and
substrate HOMO/LUMO energies were calculated with the
Hyperchem 7.5 program using semiempirical AM1 method
[26]. Elemental analyses (C, H) were conducted using the
Elemental Analyser Vario EL III, their results were found to
be in good agreement ( 0.3 %) with the calculated values.
alkene group was strongly favored. A much higher reac-
tivity of the alkene than alkyne function was found
(addition to the compound 10). All diastereoisomeric
1
products were fully characterized by H and 13C NMR 1D
and some by 2D spectroscopy. Some dipolarophiles and
adducts showed a moderate fungistatic activity. Further
research is in progress to analyze the biological potency of
the new products, and to improve regioselectivity of the
cycloaddition reaction.
Experimental
Reagent grade chemicals were used without further purifi-
cation unless otherwise noted. Spectra were obtained as
1
follows: IR spectra on JASCO FTIR-420 spectrometer, H
Methyl (2E,4E)-hexa-2,4-dienoate (3)
NMR spectra and 13C NMR spectra on Varian 500 UNITY
plus-500 and Varian 300 UNITY plus 300 spectrometers in
deuterated chloroform using TMS as internal standard. 2D
HSQC (heteronuclear single quantum coherence) and 2D
ROESY (rotating frame nuclear Overhauser effect spec-
troscopy) analyses were carried out on a Bruker AVANCE
III 500 MHz spectrometer. Chemical shifts are given in ppm
(d) relative to tetramethylsilane (TMS) as an internal stan-
dard, coupling constants are reported in Hz. In 13C NMR
spectra, signals of fluorine-substituted carbon atoms and
A brown liquid (yield: 25 %) was obtained by the
Knoevenagel condensation [27] of 2-(2E)-but-2-enal with
malonic acid followed by acidic esterification. It was
identical to the published ester [28].
Methyl (2E,4E)-5-phenylpenta-2,4-dienoate (4)
A yellowish wax (yield: 35 %) was obtained by the
Knoevenagel condensation [27] of trans cinnamaldehyde
with malonic acid followed by acidic esterification. Iden-
tical to the published ester [29].
123

Studies on [2 ? 3] cycloaddition reaction of nitrile oxides to linear dipolarophiles bearing…
Methyl (2E)-3,7-dimethylocta-2,6-dienoate (6)
A greenish liquid, yield: 75 %. Identical to the published
ester [30].
Methyl 5-[(1E)-prop-1-en-1-yl]-3-[4-(trifluoromethyl)
phenyl]-4,5-dihydro-1,2-oxazole-4-carboxylate
(14, C15H14F3NO3)
A brownish liquid, yield: 15 %; 1H NMR (CDCl3,
300 MHz): d = 7.81 (d, J = 8.5 Hz, 2H, H2’, H6’), 7.65
(d, J = 8.5 Hz, 2H, H3’, H5’), 5.90 (dqd, J = 15.0, 6.6,
1.5 Hz, 1H, H7), 5.60 (ddq, J = 15.0, 7.8, 1.5 Hz, 1H, H6),
5.40 (dd, J = 7.8, 6.9 Hz, 1H, H5), 4.25 (d, J = 6.9 Hz, 1H,
H4), 3.74 (s, 3H, H3CO), 1.78 (dd, J = 6.6, 1.5 Hz, 3H, H8)
ppm; 13C NMR (CDCl3, 125.8 MHz): d = 169.4 (C9),
152.8 (C3), 132.1 (C7), 131.8 (q, J = 32.8 Hz, C4’), 131.2
(C1’), 127.1 (C6), 127.0 (C2’, C6’), 125.7 (q, J = 3.8 Hz,
C3’, C5’), 123.8 (q, J = 272.4 Hz, F3C), 87.3 (C5), 58.6
(C4), 53.2 (C10), 17.7 (C8) ppm; MS (EI): m/z = 313 (M?,
55), 294 ([M - F]?, 30), 145 (C6H5CF3, 100).
(6E)-3,7,11-Trimethyldodeca-1,6,10-trien-3-yl propanoate
(8)
N,N-Dicyclohexylcarbodiimide (DCC, 8 mmol in dry
CH2Cl2) was added with stirring at room temperature to
a solution of acetic acid (6 mmol), alcohol 7 (6 mmol) and
4-(dimethylamino)pyridine (1.8 mmol) in a mixture of dry
dichloromethane/acetonitrile (5 cm3, 1:1) under dry argon.
Stirring was continued for 24 h. The reaction mixture was
filtered and the filter paper was washed with dichloro-
methane. The solution was washed with water, dilute HCl,
water, aqueous solution of sodium bicarbonate, and finally
several times with water. The solution was dried (MgSO4)
and the product obtained after evaporation of the solvent
was purified by flash chromatography on silica gel
affording the expected ester 8 as a yellowish wax (50 %)
[31].
Methyl 4-[(1E)-prop-1-en-1-yl]-3-[4-(trifluoromethyl)
phenyl]-4,5-dihydro-1,2-oxazole-5-carboxylate
(15, C15H14F3NO3)
A brownish liquid, yield: 15 %; 1H NMR (CDCl3,
500 MHz): d = 7.83 (d, J = 8.0 Hz, 2H, H2’, H6’), 7.64
(d, J = 8.0 Hz, 2H, H3’, H5’), 5.81 (dq, J = 16.0, 6.5 Hz,
1H, H9), 5.55 (ddd, J = 16.0, 9.0, 1.5 Hz, 1H, H8), 4.90
(d, J = 4.5 Hz, 1H, H5), 4.51 (dd, J = 9.0, 4.5 Hz, 1H,
H4), 3.82 (s, 3H, H7), 1.71 (dd, J = 6.5, 1.5 Hz, 3H, H10)
ppm; 13C NMR (CDCl3, 125.8 MHz): d = 131.9 (C9),
127.7 (C2’, C6’), 126.2 (C8), 125.6 (C3’, C5’), 84.7 (C5),
55.0 (C4), 53.0 (C7), 18.0 (C10) ppm; MS (EI): m/z = 313
(M?, 23), 294 ([M - F]?, 35), 212 (80), 127 (90), 111
(100), 69 (83).
2-Methylhept-6-en-3-yn-2-yl acetate (10, C10H14O2)
It was prepared in the same way as ester 8; a brownish
liquid, yield: 50 %. 1H NMR (CDCl3, 300 MHz): d = 5.80
(ddt, J = 17.0, 10.2, 5.1 Hz, 1H, H6), 5.35 (dq, J = 17.0,
1.8 Hz. 1H, H7a), 5.11 (dq, J = 10.2, 1.8 Hz, 1H, H7b),
2.99 (dt, J = 5.1, 1.8 Hz, 2H, H5), 2.02 (s, 3H, H10), 1.66
(s, 6H, H1, H8) ppm; 13C NMR (CDCl3, 75.5 MHz):
d = 169.5 (C9), 132.2 (C6), 116.1 (C7), 83.9 (C3), 80.0
(C4), 72.4 (C2), 29.2 (C8), 28.9 (C1), 22.9 (C5), 22.0 (C10)
ppm.
Methyl
(2E)-3-[5-methyl-3-[4-(trifluoromethyl)phenyl]-
Cholecalciferol acetate (12)
It was prepared in the same way as ester 8; a brownish
4,5-dihydro-1,2-oxazol-4-yl]prop-2-enoate
(16, C15H14F3NO3)
1
liquid, yield 40 %. H NMR, 13C NMR identical to the
A brownish liquid, yield: 23 %; 1H NMR (CDCl3,
300 MHz): d = 7.77 (d, J = 8.7 Hz, 2H, H2’, H6’), 7.67
(d, J = 8.7 Hz, 2H, H3’, H5’), 6.91 (dd, J = 15.6, 5.3 Hz,
1H, H7), 6.14 (dd, J = 15.6, 1.5, 1H, H8), 4.94 (app. td,
J = 5.3, 1.5 Hz, 1H, H5), 3.74 (s, 3H, H10), 3.56 (qd,
J = 6.3, 5.3 Hz, 1H, H4), 1.39 (d, J = 6.3 Hz, 3H, H6)
ppm; 13C NMR (CDCl3, 125.8 MHz): d = 166.3 (C9),
159.2 (C3), 143.6 (C7), 132.0 (q, J = 32.8 Hz, C4’), 131.7
(C1’), 127.3 (C2’, C6’), 125.9 (q, J = 3.8 Hz, C3’, C5’),
123.9 (q, J = 272.0 Hz, F3C), 122.2 (C8), 86.9 (C5), 51.9
(C10), 47.8 (C4), 17.4 (C6) ppm; MS (EI): m/z = 313
(M?, 75), 294 ([M - F]?, 30), 254 (45), 226 (50), 198
(87), 173 (88), 145 (C6H4CF3, 100), 126 (30), 111 (75), 95
(35), 67 (45).
published data [32].
Cycloaddition reaction of dipolarophiles 3, 4, 6, 8, 10, 12,
and 18 with benzonitrile oxides. A general procedure for
preparation of esters 14–30
4-(Trifluoromethyl)benzonitrile oxide was generated as
follows: a solution of 0.25 g of the corresponding
chlorobenzaldoxime (1.12 mmol) in dry dichloromethane
was passed through an Amberlyst-21 column and added
dropwise over 30 min to the solution of a dipolarophile in
dry dichloromethane, and the solution was stirred overnight
at room temperature. Water was added, organic layer was
separated and the aqueous one extracted with dichloro-
methane. The combined organic layers were dried
(MgSO4) and the product was purified by flash column
chromatography. Chlorobenzaldoximes were prepared
from the corresponding aryl aldehyde oximes and N-
chlorosuccinimide (NCS) in N,N-dimethylformamide
(DMF) [21, 22].
Methyl 5-[(E)-2-phenylethenyl]-3-[4-(trifluoromethyl)
phenyl]-4,5-dihydro-1,2-oxazole-4-carboxylate
(17, C20H16F3NO3)
ꢀ
A brown liquid, yield: 35 %; IR (KBr): m = 3460, 2970,
2930, 2850, 1739, 1650, 1620, 1599, 1580, 1497, 1440,
123

M. Gucma et al.
1410, 1330, 1257, 1150, 1120, 1112, 1072, 1018, 968, 920,
870, 846, 830, 750, 695 cm-1 1H NMR (CDCl3,
H15), 3.16 (s, 3H, H12), 1.8–1.5 (m, 6H, H6, H7, H8), 1.46
(s, 3H, H13), 1.14 (s, 3H), 1.13 (s, 3H) ppm; 13C NMR
(CDCl3, 125.8 MHz): d = 168.3 (C14), 153.4 (C3), 132.9
(C1’), 131.6 (q, J = 32.7 Hz C4’), 126.6 (C2’, C6’), 125.6
(q, J = 3.9 Hz, C3’, C5’), 91.1 (C5), 74.4 (C9), 52.7
(C12), 50.9 (C15), 41.9 (C4), 40.2 (C8), 37.6 (C6), 24.9
(C10), 24.8 (C11), 20.4 (C13), 18.0 (C7) ppm.
;
200 MHz): d = 7.85 (dm, J = 8.1 Hz, 2H, H2’, H6’),
7.67 (dm, J = 8.1 Hz, 2H, H3’, H5’), 7.43–7.27 (m, 5H),
6.77 (d, J = 15.8 Hz, 1H, H7), 6.26 (dd, J = 15.8, 7.5 Hz,
1H, H6), 5.64 (ddd, J = 7.5, 6.5, 1.0 Hz, 1H, H5), 4.39 (d,
J = 7.5 Hz, 1H, H4), 3.76 (s, 3H, H9) ppm; 13C NMR
(CDCl3, 125.8 MHz): d = 169.1 (C8), 152.9 (C3), 135.4
(C1’’), 134.4 (C7), 132.1 (C1’), 131.9 (q, J = 32.7 Hz,
C4’), 128.7 (C2’, C6’), 128.6 (C3’’, C5’’), 127.2 (C4’’),
126.9 (C2’’, C6’’), 125.8 (q, J = 3.9 Hz, C3’, C5’), 124.7
(C6), 123.8 (q, J = 272.2 Hz, F3C), 87.0 (C5), 58.9 (C4),
53.3 (C9) ppm; 19F NMR (CDCl3, 471 MHz): d = -63.33
(s, 3F, F3CAr) ppm; MS (EI): m/z = 374 ([M - H]?, 3),
356 ([M - F]?, 25), 316 ([M - O=COCH3]?, 52), 212
(22), 144 (63), 145 (C6H4CF3, 56), 129 (100), 115 27), 104
(48), 77 (C6H5, 18); MS (ESI): m/z = 376 ([M?H]?).
Methyl (2E)-5-[5,5-dimethyl-3-[4-(trifluoromethyl)
phenyl]-4,5-dihydro-1,2-oxazol-4-yl]-3-methylpent-2-eno-
ate (22, C20H26F3NO4)
A brown liquid, yield: 10 %; 1H NMR (CDCl3, 500 MHz):
d = 7.76 (d, J = 8.3 Hz, 2H, H2’, H6’), 7.67 (d,
J = 8.3 Hz, 2H, H3’, H5’), 5.59 (q, J = 1.0 Hz, 1H,
H12), 3.67 (s, 3H, H14), 3.17 (dd, J = 8.0, 3.5 Hz, 1H,
H4), 2.17 (s, 3H, H11), 2.16–2.08 (m, 2H, H9), 1.86–1.78
(m, 2H, H8), 1.53 (s, 3H, H6), 1.37 (s, 3H, H7) ppm; 13C
NMR (CDCl3, 125.8 MHz): d = 166.8 (C=O), 159.5 (C3),
158.2 (C10), 131.9 (q, J = 32.7 Hz, C4’), 130.8 (C1’),
127.3 (C2’, C6’), 126.2 (q, J = 3.8 Hz, C3’, C5’), 124.1
(q, J = 272.1 Hz, F3C), 116.3 (C12), 87.6 (C5), 53.4 (C4),
51.2 (C14), 38.2 (C9), 28.7 (C8), 25.8 (C6), 20.9 (C7) ppm.
Benzyl (2E)-[3-[4-(trifluoromethyl)phenyl]-1,2-oxazol-
5(4H)-ylidene]ethanoate (19, C19H14F3NO3)
A brown liquid, yield: 50 %; 1H NMR (CDCl3, 300 MHz):
d = 7.90 (dd, J = 8.2, 0.6 Hz, 2H, H2’, H6’), 7.69 (d,
J = 8.2 Hz, 2H, H3’, H5’), 7.37 (m, 5H), 6.62 (s, 1H, H6),
5.22 (s, 2H, H8), 3.93 (s, 2H, H4) ppm; 13C NMR (CDCl3,
75.5 MHz): d = 167.2 (C5), 166.1 (C7), 161.4 (C3), 135.0
(C1’’), 132.3 (C1’), 131.7 (q, J = 32.5 Hz, C4’), 128.6
(C3’’, C5’’), 128.6 (C4’’), 128.4 (C2’’, C6’’), 127.1 (C2’,
C6’), 125.8 (q, J = 3.8 Hz, C3’, C5’), 123.8 (q,
J = 270.7 Hz, F3C), 101.6 (C6), 67.5 (C8), 32.7 (C4)
ppm; MS (ESI): m/z = 361 (M?, 20), 360 ([M - H]?, 95),
189 (70), 145 (20).
(5,6)-Anti (5Z)-6,10-dimethyl-2-[3-[4-(trifluoromethyl)
phenyl]-4,5-dihydro-1,2-oxazol-5-yl]undeca-5,9-dien-2-yl
acetate (23) and (5,6)-syn (5Z)-6,10-dimethyl-2-[3-[4-(tri-
fluoromethyl)phenyl]-4,5-dihydro-1,2-oxazol-5-yl]undeca-
5,9-dien-2-yl acetate (24)
ꢀ
IR (neat): m = 2970, 2929, 2860, 1735, 1620, 1600, 1450,
1410, 1326, 1248, 1169, 1129, 1070, 1016, 916, 843,
770 cm-1; MS (ESI): m/z = 474 ([M ? Na]?, 100), 178
(12); HRMS (ESI): m/z calcd for C25H32F3NO3Na
474.2232, found 474.2217.
Methyl 3-[4-(trifluoromethyl)phenyl]-5-(4-methoxy-4-
methylpentyl)-5-methyl-4,5-dihydro-1,2-oxazole-4-car-
boxylate (20, C20H26F3NO4)
1
23 (C25H32F3NO3): A brown liquid, yield: 40 %; H NMR
(CDCl3, 200 MHz): d = 7.79 (d, J = 8.4 Hz, 2H, H2’,
H6’), 7.67 (d, J = 8.4 Hz, 2H, H3’, H5’), 5.28 (dd,
J = 10.0, 9.0 Hz, 1H, H5), 5.16–5.08 (m, 2H, H9, H13),
3.34 (d, J = 10.0 Hz, 1H, H4a), 3.33 (d, J = 9.0 Hz, 1H,
H4b), 2.20–1.80 (m, 8H, H7, H8, H11, H12), 2.02 (s, 3H,
H20), 1.69 (s, 9H, H17, H16, H15), 1.41 (s, 3H, H18) ppm;
13C NMR (CDCl3, 125.8 MHz): d = 170.0 (C19), 155.4
(C3), 136.0 (C10), 132.8 (q, J = 1.0 Hz, C1’), 131.9
(C14), 131.7 (C4’), 126.9 (C2’, C6’), 125.7 (q, J = 3.9 Hz,
C3’, C5’), 124.2 (C9), 124.1 (C13), 123.8 (q,
J = 272.16 Hz, F3C), 84.2 (C6), 84.7 (C5), 35.6 (C7), 35.5
(C4), 31.9 (C11), 25.7 (C12), 23.4 (C16), 22.2, 22.1, 21.9,
18.5 (C20), 17.7 (C15) ppm.
A brown liquid, yield: 30 %; 1H NMR (CDCl3, 500 MHz):
d = 7.77 (d, J = 8.0 Hz, 2H, H2’, H6’), 7.66 (d,
J = 8.0 Hz, 2H, H3’, H5’), 3.67 (s, 1H, H4), 3.68 (s, 3H,
H15), 3.16 (s, 3H, H12), 1.82 (m, 2H, H6), 1.58–1.42 (m,
4H, H7, H8), 1.48 (s, 3H, H13), 1.14 (s, 3H), 1.13 (s, 3H)
ppm; 13C NMR (CDCl3, 125.8 MHz): d = 170.5 (C14),
155.6 (C3), 133.2 (d, J = 1.3 Hz, C1’), 131.6 (q,
J = 32.6 Hz, C4’), 127.0 (C2’, C6’), 125.7 (q,
J = 3.8 Hz, C3’, C5’), 123.8 (q, J = 271.4 Hz, CF3),
87.8 (C5), 74.4 (C9), 60.4 (C4), 51.9 (C15), 49.1 (C12),
40.0 (C8), 39.0 (C6), 24.9 (C10), 24.8 (C11), 24.8 (C13),
18.0 (C7) ppm.
1
24 (C25H32F3NO3): A brown liquid, yield: 35 %; H NMR
Methyl 3-[4-(trifluoromethyl)phenyl]-4-(4-methoxy-4-
methylpentyl)-4-methyl-4,5-dihydro-1,2-oxazole-5-car-
boxylate (21, C20H26F3NO4)
A brown liquid, yield: 20 %; 1H NMR (CDCl3, 500 MHz):
d = 7.71 (d, J = 8.3 Hz, 2H, H2’, H6’), 7.65 (d,
J = 8.3 Hz, 2H, H3’, H5’), 4.13 (s, 1H, H5), 3.72 (s, 3H,
(CDCl3, 200 MHz): d = 7.79 (d, J = 8.4 Hz, 2H, H2’,
H6’), 7.67 (d, J = 8.4 Hz, 2H, H3’, H5’), 5.25 (dd,
J = 11.0, 8.8 Hz, 1H, H5), 5.11 (m, 2H, H9, H13), 3.32 (d,
J = 11.0 Hz, 1H, H4a), 3.27 (d, J = 8.8 Hz, H4b),
2.20–1.80 (m, 8H, H7, H8, H11, H12), 2.01 (s, 3H, H20),
123

Studies on [2 ? 3] cycloaddition reaction of nitrile oxides to linear dipolarophiles bearing…
1.62 (s, 9H, H17, H16, H15), 1.52 (s, 3H, H18) ppm; 13C
NMR (CDCl3, 125.8 MHz): d = 170.3 (C19), 155.1 (C3),
136.0 (C10), 132.8 (q, J = 1.3 Hz, C1’), 131.9 (C14),
131.7 (C4’), 126.9 (C2’, C6’), 125.7 (q, J = 3.9 Hz, C3’,
C5’), 124.1 (C9), 124.1 (C13), 123.8 (q, J = 272.2 Hz,
F3C), 84.3 (C6), 84.0 (C5), 35.6 (C7), 34.2 (C4), 31.9
(C11), 26.5 (C12), 23.4 (C16), 22.2, 22.1, 22.0, 19.8 (C20),
17.7 (C15) ppm.
1H, H4b), 2.67 (dd, J = 17.0, 4.5 Hz, H6a), 2.57 (dd,
J = 17.0, 6.5 Hz, H6b), 1.95 (s, 3H, H11), 1.59 (s, 3H),
1.58 (s, 3H) ppm; 13C NMR (CDCl3, 125.8 MHz):
d = 169.3 (C10), 156.7 (C8), 142.1 (C3), 142.0 (C14),
132.8 (q, J = 32.8 Hz, C4’), 131.3 (q, J = 32.7 Hz, C4’’),
128.7 (C1’), 128.7 (C1’’), 126.3 (C2’, C6’, C2’’, C6’’),
125.6 (m, C3’, C5’, C3’’, C5’’), 123.9 (q, J = 272.4 Hz,
F3CAr’), 123.7 (q, J = 272.4 Hz, F3C-Ar’’), 108.7 (C7),
84.5 (C5), 78.1 (C9), 50.7 (C4), 29.1 (C12), 29.0 (C13),
21.9 (C6), 21.1 (C11) ppm; MS (ESI): m/z = 563
([M ? Na]?, 100); HRMS (ESI): m/z calcd for C26H22F6-
N2O4Na 563.1381, found 563.1375.
2-Methyl-5-[3-[4-(trifluoromethyl)phenyl]-4,5-dihydro-
1,2-oxazol-5-yl]pent-3-yn-2-yl acetate
(25, C18H18F3NO3)
A brown liquid, yield: 45 %; 1H NMR (CDCl3, 300 MHz):
d = 7.82 (d, J = 8.1 Hz, 2H, H2’, H6’), 7.66 (d,
J = 8.1 Hz, 2H, H3’, H5’), 4.95 (dddd, J = 10.2, 6.9,
6.5, 4.8 Hz, 1H, H5), 3.47 (dd, J = 16.9, 10.2 Hz, 1H,
H4a), 3.38 (dd, J = 16.9, 6.9 Hz, 1H, H4b), 2.68 (dd,
J = 16.8, 4.8 Hz, H6a), 2.68 (dd, J = 16.8, 6.5 Hz, H6b),
1.91 (s, 3H, H11), 1.58 (s, 3H), 1.54 (s, 3H) ppm; 13C NMR
(CDCl3, 75.5 MHz): d = 169.2 (C10), 155.4 (C3), 132.9
(C1’), 131.5 (q, J = 32.4 Hz, 1C, C4’), 126.9 (C2’, C6’),
125.3 (q, J = 3.9 Hz, C3’, C5’), 123.8 (q, J = 272.3 Hz,
F3C), 83.9 (C7), 79.2 (C5), 78.8 (C8), 71.8 (C9), 38.7 (C4),
28.9 (C12, C13), 25.0 (C6), 21.7 (C11) ppm; MS (ESI): m/
z = 376 ([M ? Na]?, 100); HRMS (ESI): m/z calcd for
C18H18F3NO3Na 376.1136, found 376.1127.
2-[3-[4-(Propan-2-yl)phenyl]-4-[3-[4-(propan-2-yl)phe-
nyl-4,5-dihydro-1,2-oxazol-5-yl]methyl]-1,2-oxazol-5-
yl]propan-2-yl acetate (28, C30H36N2O4)
A brown liquid, yield: 12 %; 1H NMR (CDCl3, 300 MHz):
d = 7.87 (d, J = 8.2 Hz, 2H, H2’, H6’), 7.61 (d,
J = 8.0 Hz, 2H, H2’’, H6’’), 7.27 (d, J = 8.2 Hz, 2H,
H3’, H5’), 7.25 (d, J = 8.0 Hz, 2H, H3’, H5’), 4.26 (dddd,
J = 7.2, 6.6, 4.8, 4.2 Hz, 1H, H5), 3.08 (dd, J = 13.2,
4.2 Hz, 1H, H4a), 2.97–2.87 (m, 2H, 2x HC(CH3)2), 2.90
(dd, J = 13.2, 6.6 Hz, 1H, H4b), 2.66 (dd, J = 16.7,
4.8 Hz, H6a), 2.50 (dd, J = 16.7, 7.2 Hz, H6b), 1.96 (s,
3H, H11), 1.58 (s, 6H, H12, H13), 1.31–1.22 (m, 12H, 2x
(H3C)2CH) ppm; 13C NMR (CDCl3, 125.8 MHz):
d = 169.3 (C10), 157.5 (C8), 152.1 (C3), 149.6 (C14),
135.9, 129.9, 128.6, 127.8 (C4’), 126.8 (C3’), 126.6 (C5’),
125.8 (C2’, C6’), 126.4, 108.3 (C7), 84.1 (C5), 78.6, 77.6
(C9), 72.0, 50.6 (C4), 34.3, 33.9, 29.7, 29.7, 29.1 (CH3),
29.0 (CH3), 23.9 (CH3), 23.9 (CH3), 23.8 (CH3), 23.7
(CH3), 22.0 ppm; MS (ESI): m/z = 489 ([M?H]?, 35),
488 ([M]?, 55), 450 (83), 448 (83), 389 (55), 388 (100).
2-Methyl-5-[3-[4-(propan-2-yl)phenyl]-4,5-dihydro-1,2-
oxazol-5-yl]pent-3-yn-2-yl acetate (26, C18H18F3NO3)
A brown liquid, yield: 50 %; 1H NMR (CDCl3, 300 MHz):
d = 7.62 (d, J = 8.2 Hz, 2H, H2’, H6’), 7.26 (d,
J = 8.2 Hz, 2H, H3’, H5’), 4.86 (dddd, J = 9.9, 7.1, 6.6,
4.7 Hz, 1H, H5), 3.44 (dd, J = 16.9, 9.9 Hz, 1H, H4a),
3.31 (dd, J = 16.9, 6.6 Hz, 1H, H4b), 2.92 (septet,
J = 6.9 Hz, 1H, H-C(CH3)2), 2.64 (dd, J = 16.7, 4.7 Hz,
H6a), 2.55 (dd, J = 16.7, 7.1 Hz, H6b), 1.92 (s, 3H, H11),
1.59 (s, 3H), 1.56 (s, 3H), 1.25 (d, J = 6.9 Hz, 6H,
(H3C)2CH) ppm; 13C NMR (CDCl3, 75.5 MHz):
d = 169.2 (C10), 156.2 (C3), 151.0 (C4’), 126.9 (C1’),
126.7 (C5’, C3’), 126.6 (C2’, C6’), 83.6 (C7), 79.2 (C8),
78.5 (C5), 71.9 (C9), 39.3 (C4), 33.9 (CMe2), 29.0, 28.9,
25.0 (C6), 23.7 (Me2C), 21.8 (C11) ppm; MS (ESI): m/
z = 350 ([M ? Na]?, 100); HRMS (ESI): calcd for
C18H18F3NO3Na 350.1732, found 350.1723.
(5R, 6Z, 8S)-6-[2[(4E, 7aR)-7a-methyl-1-[(2R)-6-methyl-
heptan-2-yl]-octahydro-1H-inden-4-ylidene)-3-[trifluo-
romethyl)phenyl]-1-oxa-2-azaspiro[4, 5]dec-2-8-yl acetate
(29) and (5S, 6Z, 8S)-6-[2[(4E, 7aR)-7a-methyl-1-[(2R)-6-
methylheptan-2-yl]-octahydro-1H-inden-4-ylidene)-3-[tri-
fluoromethyl)phenyl]-1-oxa-2-azaspiro[4, 5]dec-2-8-yl acetate
(30)
29 (C37H50F3NO3): A yellowish semisolid, yield: 24 %; 1H
NMR (CDCl3, 500 MHz): d = 7.78 (d, J = 8.5 Hz, 2H,
H2’, H6’), 7.66 (d, J = 8.5 Hz, 2H, H3’, H5’), 6.28 (d,
J = 11.6 Hz, 1H, H12), 6.19 (d, J = 11.6, 1H, H11), 5.02
(quint, J = 4.0 Hz, 1H, H8), 3.42 (d, J = 16.5 Hz, H4a),
3.31 (d, J = 16.5 Hz, H4b), 2.76 (dd, J = 12.5, 4.0 Hz,
1H, H17a), 2.62 (dd, J = 12.5, 4.0 Hz, 1H, H9a), 2.49
(dm, J = 12.5 Hz, 1H, H9b), 2.27–2.21 (m, 2H, H17b,
H21), 2.06 (s, 3H, H3CC=O), 2.06–2.01 (m, 2H), 2.03–1.94
(m, 2H), 1.89–1.83 (m, 2H), 1.79–1.72 (m, 1H), 1.69–1.62
(m, 1H), 1.54–1.49 (m, 2H), 1.33–1.29 (m, 5H), 1.16–1.10
(m, 3H), 0.90–0.82 (m, 2H), 0.89 (s, 3H, H3C), 0.90–0.82
(m, 9H, 3 CH3) ppm; 13C NMR (CDCl3, 125.8 MHz):
2-[3-[4-(Trifluoromethyl)phenyl]-4-([[3-[4-(trifluo-
romethyl)phenyl]-4,5-dihydro-1,2-oxazol-5-yl]methyl)-1,2-
oxazol-5-yl]propan-2-yl acetate (27, C26H22F6N2O4)
A brown liquid, yield: 15 %; 1H NMR (CDCl3, 500 MHz):
d = 8.06 (d, J = 8.0 Hz, 2H, H2’, H6’), 7.85 (d,
J = 8.0 Hz, 2H, H2’’, H6’’), 7.68 (d, J = 8.0 Hz, 2H,
H3’’, H5’’), 7.69 (d, J = 8.0 Hz, 2H, H3’, H5’), 4.28
(dddd, J = 11.3, 6.5, 4.5, 4.0 Hz, 1H, H5), 3.12 (dd,
J = 13.3, 4.0 Hz, 1H, H4a), 2.73 (dd, J = 13.3, 11.3 Hz,
123

M. Gucma et al.
d = 170.9 (C30), 154.7 (C3), 145.3 (C6), 139.5 (C13),
133.4, 130.9, 129.5, 126.7 (C2’, C6’), 125.7 (q,
J = 3.9 Hz, C3’, C5’), 123.8, 122.1, 119.2, 116.0, 90.4
(C5), 69.5 (C8), 56.6 (C13, H3CC=O), 46.0 (C4), 40.4,
40.3, 39.5, 36.1, 33.4, 29.7, 28.3, 28.2 (CH3), 27.6, 27.3,
23.9, 23.6, 22.8 (CH3), 22.5, 22.2, 21.4 (CH3), 18.8 (CH3)
ppm.
expressed as the percentage of fungi linear growth inhibi-
tion compared to that of the control.
Acknowledgments This work was supported in part by the Polish
Ministry of Science and Higher Education (Research Grant NR EMC:
0150 084 31), which is gratefully acknowledged.
30 (C37H50F3NO3): A yellowish semisolid, yield: 29 %; 1H
NMR (CDCl3, 500 MHz): d = 7.77 (d, J = 8.0 Hz, 2H,
H2’, H6’), 7.65 (d, J = 8.0 Hz, 2H, H3’, H5’), 6.37 (d,
J = 11.6 Hz, H11), 6.25 (d, J = 11.6, H12), 4.89 (ddd,
J = 11.0, 9.0, 4.5 Hz, 1H, H8), 3.36 (s, 2H, H4), 2.79 (dm,
J = 11.0 Hz, 1H, H7a), 2.72 (dd, J = 13.8, 3.3 Hz, 1H,
H9a), 2.33–2.28 (m, 2H, H9b, H7b), 2.17 (s, 3H, H3C),
2.20–2.10 (m, 2H), 2.06 (s, 3H, H31), 2.04–1.96 (m, 3H),
1.84–1.81 (m, 1H), 1.66–1.51 (m, 4H), 1.37–1.24 (m, 3H),
1.17–1.04 (m, 2H), 0.98–0.85 (m, 5H), 1.70–1.45 (m, 1H,
H10), 0.92 (d, J = 6.5 Hz, 3H, H23), 0.87 (d, J = 6.5 Hz,
3H, H28), 0.86 (d, J = 6.5 Hz, 3H, H29), 0.57 (s, 3H,
H3C) ppm; 13C NMR (CDCl3, 125.8 MHz): d = 170.4
(C30), 154.7 (C3), 145.7 (C6), 139.5 (C13), 133.4 (q,
J = 1.1 Hz, C1’), 131.0, 129.2, 126.7 (C2’, C6’), 125.7 (q,
J = 3.6 Hz, C3’, C5’), 123.7 (C11), 116.1 (C12), 90.4
(C5), 71.4 (C8), 56.7, 56.0, 46.0 (C4), 45.4, 41.6, 40.5,
39.5, 36.1, 34.8, 29.7, 28.2, 28.0, 27.6, 23.9, 23.6, 23.0,
22.6, 21.3, 18.9 ppm.
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