NMR studies on [2+3] cycloaddition of nitrile oxides to cyclohexene derivatives

Article abstract of DOI:10.1016/j.molstruc.2013.12.035

Site selectivity, regioselectivity and stereoselectivity of [2+3] cycloaddition of 4-trifluoromethylbenzonitrile oxide to cyclohexene carboxylates substituted with alkenyl functions were examined. Site selectivity was correlated with electron charges of alkenyl carbon atoms. Structure of the products has been established by an extensive application of 2D ¹H and ¹³C NMR spectroscopy and electrospray ionization mass spectrometry.

Full text of DOI:10.1016/j.molstruc.2013.12.035

Journal of Molecular Structure 1060 (2014) 223–232
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
NMR studies on [2+3] cycloaddition of nitrile oxides to cyclohexene
derivatives
⇑
Mirosław Gucma, W. Marek Gołe˛biewski , Alicja K. Michalczyk
Institute of Industrial Organic Chemistry, Annopol 6, 3-236 Warsaw, Poland
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
[2+3] Cycloaddition of nitrile oxides to conjugated ester substituted with 2-propenyl group occurs with a
complete site selectivity and regioselectivity.
ꢀ
Site selectivity and regioselectivity of
the [2+3] cycloaddition reaction was
established by 2D NMR spectroscopy.
Outstanding effect of carbohydrate-
ytterbium triflate catalysts on
selectivity of the reaction was
demonstrated.
ꢀ
ꢀ
ꢀ
Influence of alkene electron densities
on cycloaddition to cyclohexene
derivatives was found.
Complete 1H and 13C NMR
characterization of 3a,4,5,6,7,7a-
hexahydro-1,2-benzoxazoles was
achieved.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 October 2013
Received in revised form 5 December 2013
Accepted 5 December 2013
Available online 22 December 2013
Site selectivity, regioselectivity and stereoselectivity of [2+3] cycloaddition of 4-trifluoromethylbenzonit-
rile oxide to cyclohexene carboxylates substituted with alkenyl functions were examined. Site selectivity
was correlated with electron charges of alkenyl carbon atoms. Structure of the products has been estab-
lished by an extensive application of 2D 1H and 13C NMR spectroscopy and electrospray ionization mass
spectrometry.
Ó 2013 Elsevier B.V. All rights reserved.
Keywords:
[2+3] Dipolar cycloaddition
Cyclohexenes
Site selectivity
2D NMR
1. Introduction
The nitrile oxides can be formed either by Huisgen method from
aldoximes by chlorination and base-induced dehydrochlorination
[2+3] Cycloaddition of nitrile oxides to alkenes is the most con-
venient method for the preparation of 2-isoxazolines [1] which can
be easily reduced to several synthetically important compounds
[1] or by dehydration of primary nitro compounds by phenyl isocy-
anates [3] (Mukayama method) or ethyl chloroformate (Shimizu
method) [4].
such as b-hydroxy ketones, b-hydroxy esters,
bonyl compounds or iminoketones [2].
a
,b-unsaturated car-
Reactions of monosubstituted and 1,1-disubstituted alkenes are
very regioselective favoring strongly 5-substituted 2-isoxazolines.
On the other hand 1,2-disubstituted olefins usually afford mixtures
of regio- and stereoisomers. Two methods have been used to solve
these problems. One approach was
application of optically active reagents, much more often of
a substrate control, an
⇑
Corresponding author. Tel.: +48 22 81112311; fax: +48 22 8110799.
E-mail address: golebiewski@ipo.waw.pl (W.M. Gołe˛biewski).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.12.035

224
M. Gucma et al. / Journal of Molecular Structure 1060 (2014) 223–232
dipolarophiles than dipoles. One variant of this method was the
use of chiral auxiliaries temporarily linked usually by an ester or
amide bond to the dipolarophiles [5]. The second more effective
approach relied on chiral metal reagents and catalysts. Shortage
of reports on metal assisted 1,3-dipolar cycloadditions of nitrile
oxides was due to interference of catalyst with generation of these
dipoles and formation of unreactive complexes [6]. First asymmet-
ric metal-catalyzed [2+3] cycloaddition reactions of nitrile oxides
2. Experimental
2.1. Materials and physical measurements
Reagent-grade chemicals were used without further purifica-
tion unless otherwise noted. Acids 1, 7 and aldehydes 10, 16 were
purchased from Aldrich. Hydroximinoyl acid chlorides were pre-
pared from the corresponding aryl aldehyde oximes and N-chloro-
succinimide (NCS) in N,N-dimethylformamide (DMF) [18].
to c-substituted allylic alcohols were carried out with diethylzinc
as a catalyst, and (R,R)-diisopropyl tartrate as the chiral auxiliary
[7]. An expedient approach to achieve an excellent regio- and
enantioselectivity was a modification of the dipolarophile by
attaching an achiral template of pyrazolidinone type and use of a
bulky chiral Lewis acid obtained from magnesium iodide and bis-
oxazoline derivative. [8] The diastereoselectivity of the thermal
and magnesium-mediated cycloaddition of substituted nitrile oxi-
des with chiral homoallylic alcohols, where anti product was fa-
vored, was explored using density functional theory [9].
Other catalytic systems applied involved acrylamides bearing
chiral auxiliary of oxazolidinone and imidazolidinone type and a
chiral complex comprising ytterbium triflate and 2,6-bis[4-(S)-iso-
propyl-2-oxazolidin-2-yl]pyridine (PyBOX) ligand. [10]. Excellent
enantioselectivities with moderate to good regioselectivities were
achieved in cycloaddition reaction of aryl nitrile oxides and croton-
amides with complexes of carbohydrates with Yb(OTf)3, TiCl4,
Mg(OTf)2, and CsF as well as with (ꢁ)-sparteine-Yb(OTf)3 system.
High enantiomeric excess and high regioselectivity were observed
for cinnamides in reactions mediated by Yb(OTf)3 complexes with
carbohydrates, R-BINOL, and (ꢁ)-sparteine [11]. Asymmetric cyclo-
addition reactions of nitrile oxides catalyzed by chiral binaphthyl-
diimine-Ni(II) complexes displayed high regioselectivity and
moderate to high enantioselectivity. Molecular modeling using
PM3 calculations were carried out to gain insight into the mecha-
nisms of the asymmetric induction [12].
Site-selectivity of nitrile oxides cycloaddition to polyunsatu-
rated alkenes was examined in several laboratories. In cycloaddition
of benzonitrile oxide to 2-alkoxy-1,3-butadienes only the unsubsti-
tuted vinyl group participated in the reactions while in case of phe-
nylglyoxylonitrile oxide both double bonds reacted [13]. This result
indicated the dominance of steric effect over the electronic one in
the first case, where more sterically demanding dipole did not inter-
act with the activated double bond. In reactions of nitrile oxides
with dimethyl 7-(diphenylmethylene)bicyclo[2.2.1]hept-2-ene-
5,6-dicarboxylate only disubstitured norbornene double bond part-
cipated [14]. Similarly in recently examined 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 [15].
[2+3] Cycloaddition of nitrile oxides to some cycloalkenes was
examined before. Cycloadditions to cyclobutene, cyclopentene,
and to 2,5-dihydrofuran derivatives were described in the review
literature [2]. Cycloaddition reaction of nitrile oxides derived from
aromatic aldoximes to unsubstituted cycloalkenes (cyclopentene,
cyclohexene, cycloheptene and cyclooctene) provided only
cis-fused cycloadducts [16]. The cycloaddition of different nitrile
oxides to (R)-(+)-limonene, proceeded regioselectively and not
stereospecifically at the extracyclic double bond, to form (5R/S)-
isoxazolines [17].
Spectra were recorded as follows: IR spectra on a JASCO FTIR-
420 spectrometer, 1H, 13C NMR, COSY (correlation spectroscopy),
HSQC (heteronuclear single quantum coherence), HMBC (hetero-
nuclear multiple bond correlation) and NOESY (nuclear Overhauser
effect spectroscopy) analyses on a Varian 500 UNITY plus-500 and
a Varian VNMRS 600 spectrometers in deuterated chloroform or
acetone. The 1H NMR spectra were recorded using single-pulse se-
quence and spectral width (SW) ca. 7000 Hz, 30° pulse width
(pw = 2.3 ms), an acquisition time (at) of ca. 3.2 s and 22 k complex
points. The FIDs were processed with zero filling. The 13C spectra
were obtained using a spectral range of ca. 38000 Hz, 30° pulse
width (4.2 ms), an acquisition time of ca. 1.2 s and a relaxation de-
lay of 1.0 s and collecting 48 k complex points. Chemical shifts are
given in ppm (d) relative to tetramethylsilane (TMS) as an internal
standard, coupling constants are reported in Hz. The 2D g-COSY
and NOESY spectra were run using spectral width (ca. 6500 Hz)
in both dimensions, at = 0.25 s, 2–4 (COSY) and 4–8 (NOESY) tran-
sients per 256 increments, relaxation delay d1 = 1.0 s. Prior to Fou-
rier transormation (FT) the data were processed using squared
sinebell (COSY) and gaussian (NOESY) multiple function. In case
of the NOESY experiments mixing time ca. 500–700 ms was cho-
sen. The echo-antiecho phase-sensitive, gradient selected 1H/13
C
HSQC correlation were obtained with an acquisition time (at) of
0.25 s, spectral window of 6500 Hz (F2) and 24,000 Hz (F1),
2 ꢂ 512 increments in the 13C dimension, a d1 = 1.0 s relaxation
delay and 2 transients per t1 increment. Experiments were opti-
mized for 1J(CAH) = 140 Hz. The data were zero-filled to 2048
points and processed using cosine-squared window function in
both dimensions prior to Fourier transformation. The proton and
carbon 90° pulse lengths were 6.9 and 12.5 ms, respectively. The
1HA13N HMBC experiments with PFG coherence selection using
two PFG pulses were recorded with the following parameters: an
acquisition time (at) 0.25 s, spectral windows of 6500 Hz (F2)
and 24,000 Hz (F1); 2 ꢂ 256 increments in the 13C dimension, 8
transients per increment and relaxation delay 1.5 s. This kind of
experiment was optimized for nJ(CAH) = 8.0 Hz. The proton and
carbon 90° pulse lengths were 6.9 and 12.5 ms, respectively. The
1HA15N HMBC experiments with PFG coherence selection using
two PFG pulses were recorded with the following parameters: an
acquisition time (at) 0.25 s, spectral windows of 6500 Hz (F2)
and 12,000 Hz (F1); 2 ꢂ 256 increments in the 15N dimension,
16–32 transients per increment and relaxation delay 1.5 s, opti-
mized for nJ(NAH) = 5.0 Hz. The proton and nitrogen 90° pulse
lengths were 7.2 and 30.0 ms, respectively.
EI mass spectra were run on an AMD M-40 instrument, electro-
spray ionization-mass spectra (ESI-MS) 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. Calculations of electron charges on alkenyl carbon atoms
and substrate HOMO/LUMO energies were calculated with the
Hyperchem 7.5 program using semiempirical AM1 method.
Herein we present results of our research concerning site selec-
tivity, regioselectivity and stereoselectivity of 1,3-dipolar cycload-
dition of 4-trifluoromethylbenzonitrile oxide to cyclohexene
carboxylates and to cyclohexenes functionalized with alkenyl and
alkenoate substituents. Structure of the products has been estab-
lished by an extensive application of 2D 1H and 13C NMR spectros-
copy and electrospray ionization mass spectrometry. Some of the
obtained products showed fungicidal activities.
2.2. Syntheses of dipolarophiles
Esters 3a,b and 7 were prepared from the corresponding acids
by esterification [19].

M. Gucma et al. / Journal of Molecular Structure 1060 (2014) 223–232
225
2.2.1. Methyl cyclohex-1-ene-1-carboxylate (3a)
J = 21.3 Hz, 2H, H2C@C), 2.36 (m, 1H, H6eq), 2.32 (m, 1H, H8eq),
2.20 (m, 2H, H7, H8ax), 2.18 (m, 1H, H6ax), 1.93 (m, 1H, H9eq),
1.76 (s, 3H, H12), 1.53 (m, 1H, H9ax) ppm; 13C NMR (CDCl3,
50.3 MHz): d 173.3 (C@O), 149.8 (C3), 148.9 (C4), 139.5 (C5),
134.6 (C10), 114.3 (C2), 109.2 (C11), 40.6 (C7), 31.9 (C6), 26.9
(C9), 24.5 (C8), 20.8 (CH3, C12); HR ESI MS calcd for C12H15O2:
191.1072, found: 191.1069.
It was obtained as a straw-colored oil, yield 60%. 1H NMR
(CDCl3, 200 MHz) d 6.99 (m, 1H, H3), 3.73 (s, 3H, H3CO), 2.22 (m,
4H, H7, H4), 1.63 (m, 4H, H6, H5) ppm.
2.2.2. -Menthyl cyclohex-1-ene-1-carboxylate (3b)
L
N,N0-dicyclohexylcarbodiimide (DCC) (1.72 g, 8.34 mmol in dry
CH2Cl2) was added with stirring at room temperature to a solution
(b) Ester 18 was obtained from the acid 17 [19] as a yellowish
oil, yield 65%; 1H NMR (CDCl3, 500 MHz): d 7.31 (d, J = 15.8 Hz,
1H, H3), 6.19 (m, 1H, H5), 5.77 (d, J = 15.8 Hz, 1H, H2), 4.74 (dm,
J = 16.5 Hz, 2H, H2C@C), 3.75 (s, 3H), 2.34 (m, 1H, H6eq), 2.30 (m,
1H, H8eq), 2.17 (m, 3H, H7, H8ax, H6ax), 1.93 (m, 1H, H9eq),
1.75 (s, 3H, H12), 1.53 (m, 1H, H9ax) ppm.
of cyclohex-1-ene-1-carboxylic acid (0.793 g, 6.3 mmol),
(1.04 g, 6.7 mmol) and 4-dimethyloaminopyridine (0.196 g,
1.6 mmol) in mixture of dry dichloromethane/acetonitrile
L-menthol
a
(5 mL, 1:1) under dry argon. Stirring was continued for 24 h. The
reaction mixture was filtered and the filter paper was washed with
dichloromethane. 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 menthyl ester
3b as a yellowish wax (55%), mp. 29–30 °C. 1H NMR (CDCl3,
600 MHz) d 6.95 (m, 1H, H3), 4.73 (td, J = 10.9; 4.3 Hz, 1H, H70),
2.26 (m, 2H, H7), 2.18 (m, 2H, H4), 2.03 (dm, J = 12.0 Hz, 1H,
H60eq), 1.89 (septuplet d, J = 7.0; 2.7 Hz, 1H, H70), 1.68 (m, 2H,
H30eq, H40eq), 1.65 (m, 2H, H40ax, H5), 1.60 (m, 2H, H4ax, H5ax),
1.51 (m, 1H, H50), 1.42 (m, H20), 1.08 (m, 1H, H30ax), 0.98 (m, 1H,
H60ax), 0.90 (d, J = 6.6 Hz, 3H, H100), 0.90 (d, J = 7.1 Hz, 3H, H80),
0.87 (m, 1H, H40ax), 0.77 (d, J = 6.9 Hz, H90) ppm; 13C (from HSQC,
CDCl3, 150 MHz): d 139.0 (C3), 131.3 (C2), 74.2 (C8), 47.2 (C9), 40.9
(C13), 34.3 (C11), 31.4 (C12), 26.4 (C14), 25.7 (C4), 24.2 (C7), 23.5
(C30), 22.2 (C6), 22.1 (C5), 21.5 (C10), 20.7 (C8), 16.7 (C9) ppm. HR
ESI MS calcd. for C17H28O2Na: 287.1987, found: 287.1974.
2.3. Cycloaddition reaction of dipolarophiles 3a, 3b, 7, 12, 18 with 4-
trifluoromethylbenzonitrile oxide (4). A general procedure for
preparation of 5, 6, 8, 9, 13–15, 19–22
4-Trifluoromethylbenzonitrile oxide (4) was generated as fol-
lows:
a solution of the corresponding chloroxime (0.25 g,
1.12 mmol) in dry dichloromethane was passed through an
Amberlyst-21 column and added dropwise over 30 min to the solu-
tion of a dipolarophile in dry dichloromethane, and the solution
was stirred overnight at room temperature. Water was added, or-
ganic layer was separated and the aqueous one extracted with
dichloromethane. The combined organic layers were dried
(MgSO4) and the product was purified by flash column
chromatography.
2.3.1. Methyl 3-[4-(trifluoromethyl)phenyl]-3a,4,5,6,7,7a-hexahydro-
1,2-benzoxazole-7a-carboxylate (arylACO2Me cis) (5a)
2.2.3. Methyl cyclohex-3-ene-1-carboxylate (7)
It was obtained as a gray-green oil, yield: 20%; IR (KBr): 3447,
2960, 2850, 1740, 1625, 1440, 1410, 1325, 1275, 1280, 1250,
It was prepared [19] as a yellowish oil, yield 60%; 1H NMR
(CDCl3, 200 MHz) d 5.68 (m, 2H, H4, H5), 3.69 (s, 3H, H3CO), 2.57
(m, 1H, H2), 2.25 (m, 2H), 2.08 (m, 3H), 1.68 (m, 1H) ppm
1175, 1129, 1105, 1068, 1015, 910, 845, 780, 675 cmꢁ1 1H, 13C
;
NMR see Tables 4 and 5; ESI-MS m/z 350 (M++Na).
2.2.4. Methyl (2E)-3-(cyclohex-3-en-1-yl)prop-2-enoate (12)
2.3.2. Methyl 3-[4-(trifluoromethyl)phenyl]-3a,4,5,6,7,7a-hexahydro-
1,2-benzoxazole-7a-carboxylate (arylACO2Me trans) (6a)
(a) (2E)-3-(cyclohex-3-en-1-yl)prop-2-enoic acid (11) was ob-
tained by the Knoevenagel condensation [20] of aldehyde 10 with
malonic acid as a yellowish solid mp. 39–41 °C, yield 90%; IR (KBr):
3420, 3170, 3040, 2960, 2840, 2720, 2700, 2630, 2595, 2510, 2380,
1689, 1642, 1450, 1421, 1315, 1287, 1250, 1228, 1140, 1105, 1040,
It was obtained as a white crystalline material, mp. 104–106 °C,
yield 20%. 1H, 13C NMR see Tables 4 and 5; 15N HMBC NMR (CDCl3,
600 MHz): d ꢁ11.1 (s, N2) ppm; 19F NMR (CDCl3, 470 MHz): d
ꢁ63.01 (s, CF3) ppm; ESI MS m/z 350 (M++Na); HR ESI MS calcd
for C16H16O3NF3Na: 350.0980, found: 350.0984.
980, 948, 915, 860, 750, 720, 695, 656 cmꢁ1 1H NMR (CDCl3,
;
200 MHz): d 11.30 (s, 1H, OH), 7.11 (dd, J = 15.7; 6.9 Hz, 1H, H3),
5.84 (dd, J = 15.7; 1.3 Hz, 1H, H2), 5.70 (m, 2H, H6, H7), 2.45 (m,
1H, H4), 2.10 (m, 3H), 1.98 (m, 1H), 1.85 (m, 1H), 1.48 (m, 1H)
ppm; HR ESI MS calcd. for C9H11O2: 151.0759, found: 151.0763.
(b) Ester 12 was obtained from the acid 11 as a yellow oil, yield
60%; 1H NMR (CDCl3, 500 MHz) d 6.98 (dd, J = 15.8; 7.1 Hz, 1H, H3),
5.83 (dd, J = 15.8; 1.4 Hz, 1H, H2), 5.69 (m, 2H, H6, H7), 3.73 (s, 3H,
H3CO), 2.45 (m, 1H, H4), 2.16 (m, 1H, H9eq), 2.10 (m, 2H), 1.92 (m,
1H, H5ax), 1.83 (m, 1H, H9eq), 1.47 (m, 1H, H9ax) ppm; 13C (from
HSQC, CDCl3, 150 MHz): d 153.9 (C3), 127.5 (C6), 125.3 (C7), 118.8
(C2), 51.2 (H3COAC@O), 36.4 (C4), 30.1 (C9), 27.5 (C5), 24.4 (C8)
ppm.
2.3.3. L-Menthyl 3-(4-trifluoromethylophenyl)-3a,4,5,6,7,7a-
hexahydro-1,2-benzoxazole-7a-carboxylates (5b, 6b)
This were obtained as a grey wax, yield 25%; IR (KBr): 2928,
2860, 1725, 1620, 1456, 1410, 1360, 1324, 1280, 1247, 1169,
1131, 1069, 1050, 1015, 960, 880, 846, 770, 740, 600 cmꢁ1 1H,
;
13C NMR see Tables 4 and 5; 5b 15N NMR (from 15NA1H HMBC, ace-
tone, 600 MHz): d ꢁ8.3 (s, N2) ppm. 6b 15N NMR (from 15NA1H
Table 1
Cycloaddition reactions of the dipole 4 to the dipolarofiles 3a, 3b.
2.2.5. Methyl (2E)-3-[(4S)-4-(prop-1-en-2-yl)cyclohex-1-en-1-
No
Lewis acid
Ligand
Dipolarofile
Yield%
Products%
yl]prop-2-enoate (18)
5a
6a
5b
6b
(a)
(2E)-3-[(4S)-4-(prop-1-en-2-yl)cyclohex-1-en-1-yl]prop-2-
1
2
3
4
5
6
Yb(OTf)3
Yb(OTf)3
–
Yb(OTf)3
Yb(OTf)3
–
Aa
3a
3a
3a
3b
3b
3b
20
15
35
18
25
20
0
2
48
–
–
100
98
52
–
–
–
–
–
–
55
58
52
–
–
–
45
42
48
enoic acid (17) was obtained by the Knoevenagel condensation of
aldehyde 16 with malonic acid [20] as a brown solid, yield 25%;
IR (KBr): 3430, 3180, 3050, 2946, 2900, 2840, 2720, 2640, 2595,
2500, 2410, 2300, 1679, 1650, 1637, 1617, 1415, 1360, 1310,
R-(+)-Bb
–
Rac-B
–
–
–
1280, 1140, 1105, 1005, 985, 950, 890, 835, 800, 720, 653 cmꢁ1
;
1H NMR (CDCl3, 600 MHz): d 10.5 (s, 1H, OH), 7.39 (d, J = 15.6 Hz,
1H, H3), 6.25 (m, 1H, H5), 5.78 (d, J = 15.6 Hz, 1H, H2), 4.75 (d,
a
A (+)-(4,6-benzylidene)methyl-
B 1,10-bi-2-naphthol.
a-D-glucopyranoside, Fig. 1.
b

226
M. Gucma et al. / Journal of Molecular Structure 1060 (2014) 223–232
J = 3.8 Hz, C30, C50), 124.5 (q, J = 272.0 Hz, CF3), 80.8 (C5), 51.5
(OCH3), 43.7 (C4), 38.1 (C7), 28.0 (C6), 26.3 (C9), 25.0 (C8) ppm.
Table 2
Cycloaddition reactions of the dipole 4 to the dipolarofile 12.
No.
Catalyst
Yield%
Products%
2.3.6. Methyl 4-(cyclohex-3-en-1-yl)-3-[4-(trifluoromethyl)phenyl]-
4,5-dihydro-1,2-oxazole-5-carboxylates (13a, 13b)
13a
13b
14a
14b
15a
15b
1
2
3
Yb(OTf)3-Aa
Yb(OTf)3-Cb
–
60
70
60
1
14
37
1
16
38
51.3
70
9.5
43.7
0
9.5
1.5
0
2.5
1.5
0
2.5
This were obtained as a celadon oil; IR (KBr): 3030, 2960, 2920,
2850, 1762, 1740, 1640, 1618, 1438, 1412, 1328, 1320, 1280, 1240,
1209, 1160, 1121, 1067, 1014, 925, 880, 847, 775, 658, 640,
a
(+)-(4,6-Benzylidene)methyl-
a
-
D-glucopyranoside, Fig. 1.
595 cmꢁ1 1H, 13C NMR see Tables 6 and 7; EI MS m/z 353
;
b
1,2:3,4-di-O-isopropylidene-a-D-galactopyranose.
(M++H), 334 [(M+ꢁF)+H], 294 [(M+AO@CAOCH3) + H], 214 [(M+-
C6H9O@CAOCH3) + H], 145 (F3CAC6H4), 81 [(C6H9) + H], 80 (C6H9).
Table 3
Cycloaddition reactions of the dipole 4 to the dipolarofile 18.
2.3.7. Methyl 5-(cyclohex-3-en-1-yl)-3-[4-(trifluoromethyl)phenyl]-
4,5-dihydro-1,2-oxazole-4-carboxylates (14a, 14b)
No.
Catalyst
Yield%
Products%
This were obtained as a yellow oil, 1H, 13C NMR see Tables 6 and
7; (14a) 15N NMR (CDCl3, 600 MHz): d ꢁ3.94 (s, N2) ppm; (14b)
15N NMR (CDCl3, 600 MHz): d ꢁ3.95 (s, N2) ppm; 19F NMR (CDCl3,
471 MHz): d ꢁ63.34 (s, F3CAr) ppm; HR ESI MS calcd for C18H18O3-
NF3Na: 376.1136, found: 376.1148.
19a
19b
20ab
21
22
1
2
Yb(OTf)3-Aa
–
93
96
42
47
44
37
7
5
1
2
6
9
a
(+)-(4,6-Benzylidene)methyl-a-D-glucopyranoside, Fig. 1.
2.3.8. Methyl (2E)-3-[3-(4-trifluoromethylphenyl)-3a,4,5,6,7,7a-
hexahydro-1,2-benzoxazol-6-yl]prop-2-enoate (15a) and methyl
(2E)-3-[3-(4trifluoromethylphenyl)-3a,4,5,6,7,7a-hexahydro-1,2-
benzoxazol-5-yl]prop-2-enoate (15b)
HMBC, acetone, 600 MHz): d ꢁ8.0 (s, N2) ppm; HR ESI MS calcd for
25H32O3NF3Na: 474.2232, found: 474.2216.
C
This were obtained as a brown oil, yield 6%; (15a) 1H NMR
(CDCl3, 500 MHz): d 7.78 (m, 2H), 7.67 (m, 2H), 6.93 (dm,
J = 16.0 Hz, 1H), 5.84 (dd, J = 16.0; 1.5 Hz, 1H), 4.62 (m, 1H), 3.75
(m, 3H), 2.47 (m, 1H), 2.17 (m, 1H), 2.04 (m, 1H), 1.90 (m, 1H),
2.3.4. Methyl 3-[4-(trifluoromethyl)phenyl]-3a,4,5,6,7,7a-hexahydro-
1,2-benzoxazole-6-carboxylate (8)
It was obtained as a green oil, yield 10%; 1H NMR (acetone-d6,
600 MHz) d 8.00 (d, J = 8.3 Hz, 2H, H50, H30), 7.81 (d, J = 8.3 Hz,
2H, H60, H20), 4.65 (m, 1H, H5), 3.68 (s, 3H, H3CO), 3.57 (m, 1H,
H4), 2.57 (m, 1H, H7), 2.45 (m, H6eq), 2.19 (m, H9eq), 2.03 (m,
H6ax), 1.95 (H8eq), 1.47 (m, H8ax), 1.25 (m, H9ax) ppm; 13C
NMR (from HSQC, acetone-d6, 150 MHz) d 131.1 (q, J = 32.8 Hz,
C40), 129.1 (C10), 128.0 (C20, C60), 126.4 (q, J = 3.8 Hz, C30, C50),
124.5 (q, J = 272.0 Hz, CF3), 81.4 (C5), 51.6 (OCH3), 43.5 (C4), 38.0
(C7), 28.0 (C6), 26.3 (C9), 25.6 (C8) ppm.
1.76 (m, 1H); (15b) 1H NMR (CDCl3, 500 MHz):
d 7.83 (d,
J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 6.85 (dd, J = 16.0; 7.0 Hz,
1H), 5.79 (dd, J = 16.0; 1.5 Hz, 1H), 4.54 (m, 1H), 3.71 (m, 3H),
2.47 (m, 1H), 2.17 (m, 1H), 2.04 (m, 1H), 1.90 (m, 1H), 1.76 (m,
1H); HR ESI MS calcd. for C18H18O3NF3Na: 376.1136, found:
376.1126.
2.3.9. Methyl (2E)-3-[(4S)-4-{5-methyl-3-[4-
2.3.5. Methyl 3-[4-(trifluoromethyl)phenyl]-3a,4,5,6,7,7a-hexahydro-
1,2-benzoxazole-5-carboxylate (9)
(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazol-5-yl}cyclohex-1-en-
1-yl)prop-2-enoates (19a, 19b)
It was obtained as a green oil, yield 10%; 1H NMR (acetone-d6,
600 MHz) d 8.18 (d, J = 8.3 Hz, 2H, H50, H30), 7.93 (d, J = 8.3 Hz,
2H, H60, H20), 4.51 (m, 1H, H5), 3.61 (s, 3H, H3CO), 3.65 (m, 1H,
H4), 2.57 (m, 1H, H8), 2.31 (m, 1H, H9eq), 2.20 (m, 1H, H6eq),
2.00 (m, 1H, H7eq), 1.87 (m, 1H, H9ax), 1.60 (m, 1H, H6ax), 1.21
(m, 1H, H7ax) ppm; 13C NMR (from HSQC, acetone-d6, 150 MHz)
d 131.1 (q, J = 32.8 Hz, C40), 129.1 (C10), 128.0 (C20, C60), 126.4 (q,
This were obtained as a yellowish wax, mp. 138–139 °C, yield
93%; IR (KBr): 3420, 2960, 2929, 2850, 1708, 1634, 1620, 1600,
1439, 1412, 1328, 1275, 1169, 1140, 1120, 1071, 1040, 975, 933,
842, 802, 780, 600 cmꢁ1; 19a: 1H NMR (CDCl3, 600 MHz) d 7.73
(d, J = 8.2 Hz, 2H, H60, H20), 7.65 (d, J = 8.2 Hz, 2H, H50, H30), 7.30
(dd, J = 15.8; 3.4 Hz, 1H, H13), 6.17 (m, 1H, H9), 5.78 (d,
J = 15.8 Hz, 1H, H14), 3.75 (s, 3H, H3CO), 3.26 (d, J = 16.8 Hz, 1H,
Table 4
1H NMR signals d of 5a, 6a (600 MHz, CDCl3), and 5b, 6b (acetone d6) (J in Hz).
H
5a
6a
5b
6b
4
3.58 (dd, 12.7, 6.2)
2.10 (dm, 15.0), 1.79 (m)
1.61 (dm, 12.7), 1.45 (dt, 13.5, 3.8)
1.73 (dm, 13.9), 1.25 (m)
1.25 (m), 1.13 (m)
8.12 (d, 8.2)
7.74 (d, 8.2)
7.74 (d, 8.2)
3.88 (dd, 9.7, 7.3)
2.34 (dt, 15.1, 3.6), 1.89 (ddd, 15.1, 12.5, 5.3)
1.72 (m), 1.55 (m)
1.66 (m), 1.34 (m)
2.10 (m), 1.26 (m)
7.81 (d, 8.2)
7.65 (d, 8.2)
7.65 (d, 8.2)
4.05 (dd, 10.9, 4.4)
2.23 (m), 1.94 (m)
1.73 (m), 1.48 (m)
1.66 (m), 1.38 (m)
2.23 (m), 1.22 (m)
8.06 (d, 8.2)
7.82 (d, 8.2)
7.82 (d, 8.2)
8.06 (d, 8.2)
4.65 (td, 10.9, 4.4)
1.42 (m)
1.66 (m), 1.05 (m)
1.66 (m), 0.89 (m)
1.48 (m)
1.86 (m), 1.02 (m)
1.80 (m)
0.63 (d, 7.1)
0.87 (d, 6.7)
0.87 (m)
3.97 (dd, 9.9, 7.1)
2.28 (m), 1.98 (m)
1.73 (m), 1.48 (m)
1.66 (m), 1.38 (m)
2.28 (m), 1.22 (m)
8.02 (d, 8.2)
7.82 (d, 8.2)
7.82 (d, 8.2)
8.02 (d, 8.2)
4.63 (td, 10.9, 4.4)
1.42 (m)
1.66 (m), 1.07 (m)
1.66 (m), 0.89 (m),
1.48 (m)
1.91 (m), 0.99 (m)
1.85 (m)
0.57 (d, 6.9)
0. 79 (d, 6.9)
0.77 (d, 6.9)
6eq, 6ax
7eq, 7ax
8eq, 8ax
9eq, 9ax
20
30
50
60
8.12 (d, 8.2)
3.71 (s)
7.81 (d, 8.2)
3.74 (s)
OCH3/100
200
300
400
500
600
700
800
900
1000
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–

M. Gucma et al. / Journal of Molecular Structure 1060 (2014) 223–232
227
Table 5
13C NMR signals d of b (50.3 MHz, CDCl3), 6a (125 MHz, CDCl3), and 5b, 6b (acetone d6) (J 13C-F in Hz).
C
5a
6a
5b
6b
3
4
159.0
51.9
162.2
46.3
163.3
46.8
163.0
47.3
5
87.6
88.0
88.8
88.9
6
30.8
27.6
28.2
28.0
7
20.1
19.5
20.6
20.5
8
23.4
20.7
21.7
21.6
9
26.6
26.0
26.9
27.0
OAC@O/10
173.5
131.1
128.2
126.1 (q, 3.6)
132.0 (q, 27.5)
126.1 (q, 3.6)
128.2
52.4
–
–
–
–
–
–
–
–
–
174.1
131.9
127.4
125.8 (q, 3.4)
132.0 (q, 27.5)
125.8 (q, 3.4)
127.4
53.0
–
–
–
–
–
–
–
–
172.8
133.7
128.4
126.7 (q, 2.8)
132.0 (q, 26.9)
126.7 (q, 2.8)
128.4
76.0
47.8
23.8
34.9
32.1
41.3
26.8
16.2
20.9
22.2
125.1 (q, 271)
173.4
133.8
128.4
126.7 (q, 2.8)
132.0 (q, 26.9)
126.7 (q, 2.8)
128.4
76.1
47.8
23.9
34.9
32.1
41.2
26.7
16.2
20.9
22.3
125.1 (q, 271)
10
20
30
40
50
60
100/OCH3
200
300
400
500
600
700
800
900
1000
CF3
–
–
123.7 (q, 272)
Table 6
1H NMR signals d of 13a,b (CDCl3, 500 MHz) and 14a,b (600 MHz) (J in Hz).
H
13a
13b
14a
14b
4
5
4.00 (dd, 4.0; 3.5)
5.00 (d, 4.0)
3.81 (s)
4.05 (dd, 4.0; 3.5)
5.02 (d, 4.0)
3.82 (s)
4.27 (d, 6.7)
4.89 (dd, 6.7, 6.7)
3.73 (s)
4.27 (d, 6.7)
4.86 (dd, 6.8, 6.7)
3.73 (s)
OCH3
6
2.06 (m)
2.13 (m)
1.95 (m)
1.95 (m)
7eq, 7ax
8
2.16 (m), 1.99 (m)
5.66 (m)
2.13 (m), 1.99 (m)
5.66 (m)
2.14 (m), 1.86 (m)
5.69 (m)
2.21 (m), 1.95 (m)
5.69 (m)
9
5.63 (m)
5.63 (m)
5.69 (m)
5.69 (m)
10eq, 10ax
11eq, 11ax
20
30
50
60
2.06 (m), 1.90 (m)
1.82 (m), 1.72 (m)
7.82 (d, 8.5)
7.68 (d, 8.5)
7.68 (d, 8.5)
7.82 (d, 8.5)
2.06 (m), 1.90 (m)
1.82 (m), 1.49 (m)
7.82 (d, 8.5)
7.68 (d, 8.5)
7.68 (d, 8.5)
7.82 (d, 8.5)
2.14 (m), 2.08 (m)
1.79 (m), 1.44 (m)
7.81 (d, 8.3)
7.66 (d, 8.3)
7.66 (d, 8.3)
7.81 (d, 8.3)
2.12 (m), 2.10 (m)
1.95 (m), 1.44 (m)
7.81 (d, 8.3)
7.66 (d, 8.3)
7.66 (d, 8.3)
7.81 (d, 8.3)
Table 7
13C NMR signals d of 13a,b (150.8 MHz, CDCl3) and 14a, b (125 MHz, CDCl3) (J 13C-F in Hz).
C
13a
13b
14a
14b
3 (C@N)
157.1
157.1
152.7
152.6
4
56.9
57.4
56.0
55.9
5
80.3
80.0
90.5
90.1
OCH3
C@O
6
53.0
171.2
34.2
53.0
171.1
33.9
53.1
170.0
38.2
53.1
169.9
38.2
7
29.8
25.0
26.7
26.7
8
125.3
125.3
124.7
124.7
9
126.8
127.3
125.2
125.2
10
11
10
25.0
25.4
127.5
127.7
125.9 (q, 3.9)
125.9 (q, 3.9)
127.7
131.9 (q, 30.5)
123.7 (q, 259.9)
27.3
25.7
127.5
127.6
125.9 (q, 3.9)
125.9 (q, 3.9)
127.6
131.9 (q, 30.5)
123.7 (q, 259.9)
24.4
23.9
127.5
126.9
125.7 (q, 4.1)
125.7 (q, 4.1)
126.9
131.8 (q, 32.7)
123.7 (q, 271.2)
24.5
23.9
127.5
126.9
125.8 (q, 4.1)
125.8 (q, 4.1)
126.9
131.8 (q, 32.7)
123.7 (q, 271.2)
20
30
50
60
40
CF3
H4a), 2.98 (d, J = 16.8 Hz, 1H, H4b), 2.43 (m, 1H, H8eq), 2.36 (m, 1H,
H11eq), 2.18 (m, 1H, H11ax), 2.04 (m, 2H, H8ax, H12eq), 1.97 (m,
1H, H7), 1.47 (s, 3H, H6, H3C), 1.44 (m, 1H, H12ax) ppm; 13C
NMR (CDCl3, 125.6 MHz) d 167.8 (C@O), 154.6 (C3), 147.1 (C13),
136.9 (C9), 134.9 (C10), 133.6 (C10), 131.4 (q, J = 32.0 Hz, C40),
126.6 (C60, C20), 125.6 (q, J = 3.8 Hz, C30, C50), 123.8 (q,

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M. Gucma et al. / Journal of Molecular Structure 1060 (2014) 223–232
J = 272.0 Hz, CF3), 115.2 (C14), 89.9 (C5), 51.5 (H3CO), 43.0 (C4),
42.3 (C7), 27.8 (C8), 24.8 (C11), 23.8 (C6), 23.3 (C12) ppm; 19F
NMR (CDCl3, 471 MHz): d ꢁ63.23 (s, F3C) ppm; 15N NMR (CDCl3,
600 MHz): d ꢁ8.71 (s, N2) ppm; 19b: 1H NMR (CDCl3, 600 MHz)
d 7.73 (d, J = 8.2 Hz, 2H, H60, H20), 7.65 (d, J = 8.2 Hz, 2H, H50,
H30), 7.30 (dd, J = 15.8; 3.4 Hz, 1H, H13), 6,17 (m, 1H, H9), 5.78
(d, J = 15.8 Hz, 1H, H14), 3.74 (s, 3H, H3CO), 3.25 (d, J = 16.8 Hz,
1H, H4a), 3.00 (d, J = 16.8 Hz, 1H, H4b), 2.40 (m, 1H, H8eq), 2.36
(m, H11eq), 2.18 (m, H11ax), 2.08 (m, 1H, H8ax), 2.04 (m,
H12eq), 1.96 (m, 1H, H7), 1.45 (s, 3H, H6, H3C), 1.34 (m, 1H,
H12ax) ppm; 13C NMR (CDCl3, 125.6 MHz) d 167.8 (C@O), 154.7
(C3), 147.1 (C13), 136.8 (C9), 134.8 (C10), 133.4 (C10), 131.4 (q,
J = 32.0 Hz, C40), 126.6 (C60, C20), 125.5 (q, J = 3.8 Hz, C30, C50),
123.8 (q, J = 272.0 Hz, ArACF3), 115.0 (C14), 90.3 (C5), 51.4
(H3CO), 42.5 (C4), 42.2 (C7), 27.6 (C8), 24.4 (C11), 23.4 (C6), 23.1
(C12) ppm; 15N NMR (CDCl3, 600 MHz): d ꢁ8.72 (s, N2) ppm; HR
ESI MS calcd for C21H22O3NF3Na: 416.1450, found: 416.1465.
2H, H200, H600), 7.65 (d, J = 8.5 Hz, 2H, H30, H50), 7.65 (d, J = 8.0 Hz,
2H, H300, H500), 5.90 (m, 1H, H9), 5.36 (d, J = 6.3 Hz, 1H, H14), 4.28
(d, J = 6.3 Hz, 1H, H13), 3.74 (s, 3H, H3CO), 3.23 (d, J = 16.8 Hz,
1H, H4a), 2.93 (d, J = 16.8 Hz, 1H, H4b), 2.30 (m, 2H), 2.17 (m,
2H), 1.74 (m, 2H), 1.57 (s, 3H, CH3C), 1.38 (m, 1H) ppm; HR ESI
MS calcd for C29H26O4N2F6Na: 603.1694, found: 603.1696.
2.3.12. Methyl (2E)-3-[(4S)-4-(2-methoxypropan-2-yl)cyclohex-1-en-
1-yl]prop-2-enoate (22)
It was obtained as a celadon oil, yield: 12%; IR (neat): 2970,
2947, 2830, 1719, 1632, 1623, 1615, 1460, 1434, 1380, 1364,
1308, 1285, 1270, 1167, 1079, 1050, 1020, 982, 925, 860, 823,
; d 7.31 (d,
802, 740, 660 cmꢁ1 1H NMR (CDCl3, 500 MHz)
J = 15.8 Hz, 1H, H3), 6.18 (m, 1H, H5), 5.77 (d, J = 15.8 Hz, 1H,
H2), 3.74 (s, 3H, H3COAC@O), 3.19 (s, 3H, H3COC), 2.31 (dm,
J = 13.2 Hz, 1H, H9eq), 2.26 (dt, J = 13.5; 5.0 Hz, 1H, H6eq), 2.12
(m, 1H, H9ax), 2.04 (m, 1H, H6ax), 1.95 (m, 1H, H8eq), 1.73 (m,
1H, H7), 1.26 (m, 1H, H8ax), 1.14 (s, 3H, H11, H3CC), 1.12 (s, 3H,
H12, H3CC) ppm; 13C NMR (CDCl3, 126 MHz) d 168.3 (C@O),
147.9 (C3), 138.9 (C5), 135.1 (C4), 114.8 (C2), 76.5 (C10), 51.7 (H3-
COAC@O), 49.1 (H3COC), 42.1 (C7), 28.3 (C6), 25.4 (C9), 23.4 (C8),
22.3 (C11, H3CC), 22.2 (C12, H3CC) ppm. ESI MS m/z 261 (M++Na);
EI MS m/z 239 (M++H), 206 [M+A(H3CO)AH], 73 [(H3C)2ACOCH3].
2.3.10. Methyl 3-(4-trifluoromethylphenyl)-5-[4-(prop-1-en-2-
yl)cyclohex-1-en-1-yl]-4,5-dihydro-1,2-oxazole-4-carboxylates
(20a,b)
This were obtained as a celadon mush, yield 7%; 1H NMR (CDCl3,
500 MHz): d 7.82 (d, J = 8.5 Hz, 2H, H20, H60), 7.66 (d, J = 8.5 Hz, 2H,
H30, H50), 5.90 (m, 1H, H7), 5.36 (d, J = 6.5 Hz, 1H, H5), 4.73 (dm,
J = 17.0 Hz, 2H, H13), 4.30 (d, J = 6.5 Hz, 1H, H4), 3.74 (s, 3H,
H3CO), 2.18 (m, 2H, H8eq, 11eq), 2.06 (m, 2H, H9ax, 11ax), 1.87
(m, 1H, H8ax), 1.73 (s, 3H, H3CAC@C), 1.68 (m, 1H, H10eq), 1.54
(m,1H, H10ax) ppm; ESI MS m/z 393 (M+).
2.4. Fungicidal testing
The compounds were screened for fungicidal activity in vitro.
The tests were carried out for Fusarium culmorum (F. c.), Phytoph-
thora cactorum (P. c.), Rhizoctonia solani (R. s.), and Botrytis cinerea
(B. c.), and involved determination of mycelial growth retardation
in potato glucose agar (PGA). Stock solutions of test chemicals in
acetone were added to agar medium to give a concentration of
200 mg/L and dispersed into Petri dishes. Four discs containing
the test fungus were placed at intervals on the surface of the solid-
ified agar and the dishes were then inoculated for 4–8 days
depending on the growth rate of the control samples, after which
fungal growth was compared with that in untreated control sam-
ples. The fungicidal activity was expressed as the percentage of
fungi linear growth inhibition compared to that of the control.
2.3.11. Methyl 4-[(4S)-4-(3-{4-trifluoromethylphenyl}-5-methyl-4,5-
dihydro-1,2-oxazol-5-yl)cyclohex-1-en-1-yl]-3-(4-trifluoromethyl-
phenyl)-4,5-dihydro-1,2-oxazole-5-carboxylates (21)
This were obtained as an oil, yield: 3%; 1H NMR (CDCl3,
500 MHz) d 7.81 (d, J = 8.5 Hz, 2H, H20, H60), 7.81 (d, J = 8.0 Hz,
Scheme 1. Cycloaddition of dipole 4 to dipolarophiles 3a,b. i MeOH, H+, ii DCC,
DMAP, iii 3a, CH2Cl2, Yb(OTf)3-ligand A (Fig. 1) or Yb(OTf)3-ligand B or without the
catalyst, iv 3b, CH2Cl2, Yb(OTf)3-rac ligand B or without the catalyst.
Scheme 2. Cycloaddition of the dipole 4 to the dipolarophiles 12. i 4, CH2Cl2, ii
CH2(CO2H)2, Py, morpholine, iii MeOH, H+, iv 4, CH2Cl2, Yb(OTf)3-ligand A (Fig. 1) or
Yb(OTf)3-ligand C or without the catalyst.

M. Gucma et al. / Journal of Molecular Structure 1060 (2014) 223–232
229
Scheme 3. Cycloaddition of the dipole 4 to the dipolarophile 18. i CH2(CO2H)2, Py, morpholine, ii MeOH, H+, and iii 4, CH2Cl2, Yb(OTf)3-ligand A or without the catalyst.
Fig. 1. Chiral ligands used in nitrile oxide cycloaddition reactions.
Fig. 3. Partial electron charges on atoms of interest involved in reaction of 18 and 4.
7, and to cyclohexenes functionalized with alkenoate and alkenyl
substituents 12 and 18. The compounds described in this work
are presented in Schemes 1–3 and Figs. 1–3. Cycloaddition product
and catalysts applied are displayed in Tables 1–3. 1H NMR chemi-
cal shifts and multiplicities of adducts 5a,b; 6a,b and 13a,b; 14a,b
are shown, respectively, in Tables 4 and 6. 13C NMR chemical shifts
of adducts 5a,b; 6a,b and 13a,b; 14a,b are shown, respectively, in
Tables 5 and 7. The spectroscopic data for the other products were
presented in the experimental section.
Cycloaddition of 4-trifluoromethylbenzonitrile oxide (4) to es-
ter 3a without a catalyst afforded a mixture in 1:1.1 ratio of diaste-
reoisomers 5a and 6a separated by column chromatography as the
only regioisomers (Table 1). Diastereoselectivity of the reaction
was dramatically improved after application of catalysts. The chiral
ligands used in these studies are displayed in Fig. 1. Use of com-
plexes of ytterbium triflate-(+)-(4,6-benzylidene)methyl-a-D-
glucopyranoside (A) and ytterbium triflate-R-BINOL (B) furnished
ester 6a as the only product in the first case, and a 98:2 mixture
of 6a, 5a. We have applied before these and other catalytic systems
to mediate the cycloaddition reaction of aryl nitrile oxides and cro-
tonamides and cinnamides [11]. No hydrogen atom was observed
on C5 in both isomers 5a, 6a which would occur in the other regioi-
somers as proved by the HSQC spectra. This result can be rational-
ized by steric factors and dominant orbital control.
Fig. 2. Selected COSYs, NOEs and HMBC for adducts 5b, 14, 19b and 22.
3. Results and discussion
3.1. Structural analysis of the cycloadducts
Reactions of the alkenes with electron-donating substituents
and moderately electron-withdrawing substituents (as an ester
group) are controlled by LUMOdipol–HOMOalkene (DE = 8.67 eV)
We have examined [2+3] cycloaddition of 4-(trifluoro-
methyl)benzonitrile oxide (4) to cyclohexene carboxylates 3a, 3b,

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M. Gucma et al. / Journal of Molecular Structure 1060 (2014) 223–232
interaction since LUMOalkene–HOMOdipol energy gap (
D
E = 9.98) is
mediated by ytterbium triflate-(+)-(4,6-benzylidene)methyl-a-D-
higher [21]. Bond formation between atoms of the larger orbital
coefficients leads to the 5-substituted fused isoxazolines [22].
Mass spectrometry showed molecular weight of 327 m.u. for
both isomers and HR ESI MS confirmed the composition C16H16F3-
NO3Na. Configuration of 5a with a cis relationship of the carbonyl-
methoxy and aryl group, and 6a with a trans relationship of these
groups was established from analysis of the NMR spectra. In 1H
NMR of 6a the diagnostic proton 9eq showed a large chemical shift
at 2.10 ppm and in isomer 5a this proton absorbed at 1.25 ppm.
This difference can be explained by the deshielding effect of the
proximal aromatic ring in 6a isomer.
glucopyranoside was highly regio- and site-selective and afforded
only 19a,b pair. Formation of the major products 19a,b, epimers
at C5, by cycloaddition to the propenyl side chain was proved by
presence of the geminally coupled H4 protons of isoxazoline as
doublets at 3.25, 3.26 and 2.98, 3.00 ppm with a large coupling
constant of 16.8 Hz. There was no hydrogen atoms at C5
(90.1 ppm) expected in the other regioisomer as shown by 2D
HSQC NMR spectrum. An unsaturated conjugated ester moiety
was preserved as witnessed by presence of the E-olefin (doublets
at 7.30 and 5.78 ppm with coupling constant of 15.8 Hz in 1H
NMR spectrum as well as signals at 147.1 and 115.2 ppm in 13C
NMR spectrum, and cyclohexene double bond (multiplet at
6.17 ppm of H9 and peaks at 136.9 and 134.9 pm in 13C NMR spec-
trum). Correlation in the 2D NMR NOESY spectrum in 19b epimer
between H4b and C5ACH3 protons and a correlation in 19a isomer
between H4a and H7 proton at 1.96 ppm allowed to establish the
structure of two diastereoisomers. High resolution electrospray
mass spectrometry exhibited the quasi-molecular formula as C21-
H22O3NF3Na for the products.
The minor diastereoisomeric products 20a,b differing in relative
orientation of H5 and propenyl substituent were formed in ca 7%
yield by cycloaddition to the conjugated exocyclic double bond.
1H NMR spectrum showed vicinally coupled H4 and H5 protons
of 2-isoxazoline moiety as doublets at, respectively, 5.37 and
4.30 ppm with a coupling constant of 6.8 Hz, and a cyclohexene
fragment with an exocyclic propenyl group. Structures with posi-
tion of the ester function at C4 of isoxazoline ring was proposed
based on the observed larger values of H4,5 coupling constant
(J > 4 Hz) and the larger difference of chemical shifts in 4-esters
Cycloaddition of the L-menthyl ester 3b afforded cis-fused dia-
stereoisomers 5b, 6b in 1.4:1 ratio. In both isomers close position
of H4 and aromatic protons H20, H60 was found. Structure 5b was
assigned to the major isomer based on position at the lower field
of H4 proton slightly more deshielded by the carbonyl group than
the respective proton of 6b, as indicated by molecular modelling.
Cycloaddition of the unconjugated ester 7 afforded unseparable
mixture of cis-fused regioisomers 8 and 9 in 7:3 ratio in a low 20%
yield. On the other hand reaction of the conjugated, activated ester
3a gave in the same conditions cycloadducts 5a, 6a in 35% yield
(Table 1). The structure 8 was ascribed to the major isomer because
of position at the lower field of the diagnostic H5 proton at
4.65 ppm (deshielded by b-methoxycarbonyl group) than H5 in
the other regioisomer 9 (4.51 ppm). This direction of addition
was favored by the orbital factors. The reaction is LUMO-dipole
controlled and oxygen atom of the dipole tends to attack the dipol-
arophile atom closer to the substitution position.
Cycloaddition to the dipolarophile 12 without any catalyst
afforded a mixture of regioisomeric major adducts to the exocyclic
double bond 13a,b (75%) and 14a,b (19%) as well as a mixture of
minor adducts to the cyclohexene ring, 15a,b (5%) in an overall
60% yield (Table 2). An application of the catalyst (ytterbium tri-
and amides (
respective values were J > 4 Hz and (
D
d > 1 ppm) than in 5-esters and amides, where
d < 1 ppm [11].
D
The second minor products were bis-adducts 21 (a mixture of
four unseparable diastereoisomers) showing similar regioselectiv-
ity of the dipole addition to both exocyclic double bonds as found
in the compounds 19a,b and 20. High resolution electrospray mass
spectrometry exhibited the quasi-molecular formula as C29H26O4-
N2F6Na for the products.
flate
and
1,2:3,4-di-O-isopropylidene-a-D-galactopyranose)
(Fig. 1, ligand C) reversed the regioselectivity and favored forma-
tion of isomer 14a (70%); isomers 13a (14%) and 13b (16%) were
also present. The other catalyst (ytterbium triflate-(+)-(4,6-benzyl-
idene)methyl-
a
-
D
-glucopyranoside, ligand A) showed very good
A quite unexpected product was a methoxy ester 22. 1H NMR
spectrum displayed a methyl cyclohexene acrylate fragment as in
the dipolarophile, two aliphatic singlet methyl groups at 1.12
and 1.14 ppm, and an extra methoxy group at 3.19 ppm. 13C
NMR spectrum contained only four olefinic carbon atoms at
147.9, 138.9, 135.1, and 114.8 ppm. EI MS showed the molecular
weight of 238 m.u. and fragmention ions at m/z at 206 correspond-
ing to a loss of methanol, and the parent ion at m/z 73 correspond-
ing to Me2COMe composition. These results indicated that an
addition of methanol to the very reactive exocyclic propenyl dou-
ble group took place. This conclusion was confirmed by the pres-
ence of a new quaternary carbon atom at 76.5 ppm showing in
HMBC spectrum correlations with OCH3 group protons at 3.19,
H8, and CH3AC10 protons. The only source of the methoxy group
could be the ester function.
stereochemistry. The main products were regioisomers 14a,b
(95%); the minor isomers 13a,b and 15a,b were formed with,
respectively, only 2% and 3% yields.
A complete assignment of 1H and 13C NMR spectra of 13a,b and
14a,b adducts based on analysis of 1D and 2D 1H and 13C NMR
spectra (COSY, HSQC and HMBC) is presented in Tables 6 and 7.
In both pairs trans relationship of H5AH4 protons reflects E config-
uration of the dipolarophile 12 preserved in the cycloaddition reac-
tion. Regiochemistry shown for 13a,b/14a,b was proven by
observation of a strong correlation in the HMBC spectrum of
14a,b between H5 and C7 and 1H NMR spectrum. In diastereoiso-
meric pair 14a,b (47:53 mixture) the diagnostic proton H5 was a
doublet of doublets at, respectively, 4.89 and 4.86 ppm coupled
to the adjacent H4 and H6 protons. In diastereoisomeric pair
13a,b the diagnostic proton H5 was a doublet at respectively,
5.00 and 5.02 ppm coupled only to the H4 proton. An analysis of
the COSY spectrum enabled also assignment of all signals of the
cyclohexene moiety. Configuration of 14b was ascribed to the
more populated isomer because of the position of H7eq proton at
a slightly lower field in result of deshielding effect of the adjacent
ester group.
Table 8 gives the positions of the nitrogen N-2 atom in isoxaz-
oline-2 derivatives. The found values lie in the range characteristic
for isoxazolines-2 described in the literature [23]. The most nega-
tive values of d ꢁ11.1 ppm occurred for systems with just one
hydrogen in the isoxazoline-2 ring at C4 in adduct 6a. Less negative
Reaction of the nitrile oxide 4 with the dipolarophile 18 affor-
ded mainly diastereoisomeric adducts to the exocyclic propenyl
group 19a,b in 80% yield (Table 3). The minor products were
formed by cycloaddition to the conjugated exocyclic double bond
– 20a,b (5%), reaction mixture contained also products 21 of a dou-
ble cycloaddition, and an unexpected side product 22. Reaction
Table 8
a
15N NMR signals d (600 MHz, CDCl3) of 6, 14, 19.
N
2
6a
14a
14b
19a
19b
ꢁ11.1
ꢁ3.93
ꢁ3.95
ꢁ8.71
ꢁ8.72
a
Obtained from 2D 15NA1H HMBC correlations.

M. Gucma et al. / Journal of Molecular Structure 1060 (2014) 223–232
231
Table 9
Electron charges at the alkenyl carbon atoms of the dipolarophiles 3a,b, 12, 18, and regioselectivity in the cycloaddition reaction.
Dipolarophile/C atom
C2
C3
C10
C11
C4/C6
C5/C7
Site selectivity
Regioselectivity
Reg. 4
Reg. 5
3a
3b
12
18
ꢁ0.14
ꢁ0.14
ꢁ0.20
ꢁ0.21
ꢁ0.08
ꢁ0.08
ꢁ0.06
ꢁ0.03
–
–
–
–
–
–
–
–
–
–
C2/C3
C2/C3
C2/C3
C10/C11
1
1.1
1a
1
1.4b
4
ꢁ0.17
ꢁ0.16
ꢁ0.11
ꢁ0.22
ꢁ0.11
ꢁ0.11
0
100
a
Regioisomer 5b.
Regioisomer 6b.
b
values are found for a system where there are two hydrogens on
one carbon atom, as in compounds 19a,b. The least negative values
d = ꢁ3.93 ppm, and d = ꢁ3.95 ppm were observed in the com-
pounds with hydrogens at the adjacent carbon atoms C4 and C5
in compounds 14a and 14b.
spatial structure showed no potency. One can see very clearly the
impact of the spatial structure on the fungicidal activity. This sup-
ports the value of testing pure isomers (see Table 10).
The dipolarofiles have also been screened, as well as the side
product 22. Particularly active was the acid 11 which showed fun-
gicide activity comparable with that of the commercial fungicide
chlorothalonil.
3.2. Rationalization of the observed site selectivity and regioselectivity
Table 9 gives electron charges at the alkenyl carbon atoms of
the dipolarophiles 3a,b, 12, 18, and the observed regioselectivity
in the cycloaddition reaction.
4. Conclusions
High regio- and site selectivity of 1,3-dipolar cycloaddition
reaction of 4-trifluoromethylbenzonitrile oxide to trienic ester 18
was observed. A correlation of double bond reactivity with electron
charges was found. The addition to the exocyclic propene group
was strongly favored. Cycloaddition to the ester 12 occurred with
a good site selectivity to the conjugated double bond. Both selec-
tivities were influenced by application of the catalysts. With ytter-
For compound 18 a linear dependence of the reactivity on elec-
tron charges at the alkenyl carbon atoms can be observed (Fig. 3).
The greater was the amount of negative charges of both carbon
atoms of the double bond, the higher was the reactivity of the
cycloaddition reaction. The most negative C10AC11 bond is the
most reactive. The total charges at C10AC11 of ꢁ0.33 correspond
to the formation of 96% of the products 19a,b. The C2AC3 bond
with total ꢁ0.24 is less reactive because it gave rise to only 6% of
the product 20a,b. The C4AC-5 bond (charges of ꢁ0.22) showed
no reactivity in the reaction of cycloaddition. With diminishing
bond electron charges decreased regioselectivity of the reaction
from triene 18 to mono alkenes 3a,b. An exception was compound
12 where the cyclohexenyl bond showed lower reactivity than the
exocyclic one in spite of higher electron density. It could be ratio-
nalized by the steric effects and a more difficult approach of the di-
pole to the hindered internal double bond of the dipolarophile.
bium triflate-1,2:3,4-di-O-isopropylidene-a-D-galactopyranose the
regioselectivity was reversed to 30:70 and site selectivity im-
proved – no addition to the isolated double bond was found. With
the other catalyst (ytterbium triflate-(+)-(4,6-benzylidene)methyl-
a-D-glucopyranoside) this trend was magnified and mainly regio-
isomer-4 was formed (95:2) with site selectivity strongly biased
towards conjugate addition (97:3). Use of ytterbium triflate-(+)-
(4,6-benzylidene)methyl-a-D-glucopyranoside complex resulted
in 100% regio- and diastereoselectivity and furnished ester 6a as
the only product. These data demonstrate a high importance of
the catalyzed cycloadddition reactions.
All diastereoisomeric products were fully characterized by 1H
and 13C NMR 1D and 2D spectroscopy. Some dipolarophiles and ad-
ducts showed good fungistatic activity. Further research is in pro-
gress to analyze the biological potency of the new products, to
improve regioselectivity of the cycloaddition reaction and to ex-
plain formation of the side-product.
3.3. Biological activity of the products
A pair of diastereoisomers 14a, 14b showed a much higher
activity then the other regioisomeric pair 13a, 13b. A nearly pure
13a is more active than the sum (13a + 13b), which implies that
the diastereoisomer 13b is less active. Diastereoisomer 5a shows
some activity while the diastereoisomer 6a of somewhat different
Acknowledgement
Table 10
This work was supported in part by the Polish Ministry of Sci-
ence and Higher Education Research (Grant No. N209 003 638),
which is gratefully acknowledged.
Fungicidal inhibitory activitiesa of compounds 5, 6, 11, 12, 13, 14, 18, 22 at 200 mg/L.
Compound
B. c.b
F. c.
P. c.
Rh. s.
5a
6a
38.0
0.0
16.0
0.0
0.0
0.0
0.0
0.0
Appendix A. Supplementary material
5b + 6b
0.0
0.0
0.0
0.0
11
12
13a
13a + 13b
14a + 14b
18
50.0
34.0
42.0
28.9
74.0
26.7
73.4
80
18.0
14.0
4.0
100
10.3
2.6
100
36.0
38.0
0.0
64.0
64.0
46.7
88
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2013.
12.035.
0.0
0.0
44.0
38.0
44.0
38
41.0
60.0
2.4
22
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Chlorothalonilc
61
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