Application of chiral ligands: Carbohydrates, nucleoside-lanthanides and other Lewis acid complexes to control regio- and stereoselectivity of the dipolar cycloaddition reactions of nitrile oxides and esters

Article abstract of DOI:10.1039/c4ra15975f

Chiral Lewis acid mediated 1,3-dipolar cycloaddition reactions of 4-trifluoromethylbenzonitrile oxide to methyl crotonate as well to β-substituted acrylates and (Z)-pent-2-en-1-yl esters were examined. Excellent enantioselectivities with moderate to good regioselectivities were achieved for crotonates with complexes of BiBr₃ with (+)-(4,6-benzylidene)methyl-α-d-glucopyranoside C, with the l-ascorbic acid I-FeCl₃ system, and with lipase Candida antarctica. High enantiomeric excess was observed for isopropyl ester and benzyl ester. The outstanding ee values were achieved for acrylates with β-t-butyl, cyclohexyl, and 1,3-benzodioxol-5-yl groups in cycloadditions catalyzed by C-Yb(OTf)₃ and the (+)-2-hydroxy-3-pinanone N-TiCl₄ system. High enantioselectivities were found in reactions of (Z)-pent-2-en-1-yl esters mediated by complexes N-Mg(OTf)₂ and N-TiCl₄.

Full text of DOI:10.1039/c4ra15975f

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PAPER
Application of chiral ligands: carbohydrates,
nucleoside-lanthanides and other Lewis acid
complexes to control regio- and stereoselectivity
of the dipolar cycloaddition reactions of nitrile
oxides and esters†
Cite this: RSC Adv., 2015, 5, 13112
*
Mirosław Gucma, W. Marek Gołebiewski and Maria Krawczyk
˛
Chiral Lewis acid mediated 1,3-dipolar cycloaddition reactions of 4-trifluoromethylbenzonitrile oxide to
methyl crotonate as well to b-substituted acrylates and (Z)-pent-2-en-1-yl esters were examined.
Excellent enantioselectivities with moderate to good regioselectivities were achieved for crotonates with
complexes of BiBr3 with (+)-(4,6-benzylidene)methyl-a-D-glucopyranoside C, with the L-ascorbic acid I–
FeCl3 system, and with lipase Candida antarctica. High enantiomeric excess was observed for isopropyl
ester and benzyl ester. The outstanding ee values were achieved for acrylates with b-t-butyl, cyclohexyl,
and 1,3-benzodioxol-5-yl groups in cycloadditions catalyzed by C–Yb(OTf)3 and the (+)-2-hydroxy-3-
pinanone N–TiCl4 system. High enantioselectivities were found in reactions of (Z)-pent-2-en-1-yl esters
mediated by complexes N–Mg(OTf)2 and N–TiCl4.
Received 8th December 2014
Accepted 16th January 2015
DOI: 10.1039/c4ra15975f
www.rsc.org/advances
reagents,4 chiral auxiliaries,5–7 chiral metal catalysts,8–10 or
organocatalysts.11,12
Introduction
Imines derived from (+)- and (ꢀ)-2-hydroxy-3-pinanone
We have reported recently the application of chiral Lewis acids
as catalysts in the 1,3-dipolar cycloaddition reaction of aryl
nitrile oxides and secondary a- or b-substituted acrylamides.
Excellent enantioselectivities with moderate to good regiose-
lectivities were achieved for crotonamides with complexes of
carbohydrates with Yb(OTf)3, TiCl4, Mg(OTf)2, and CsF as well
as with the (ꢀ)-sparteine–Yb(OTf)3 system. High enantiomeric
excess and high regioselectivity were observed for cinnamides
in reactions mediated by Yb(OTf)3 complexes with carbohy-
drate, R-BINOL, and (ꢀ)-sparteine.1
were used as chiral auxiliaries in enantioselective
syntheses of anabasine, a naturally occurring nicotinic
acetylcholine receptor ligand,13 and in syntheses of
1,3-Dipolar cycloaddition of nitrile oxides to alkenes is the
most synthetically useful method of preparation of 2-isoxazo-
lines2 which can be easily reduced to several synthetically
important compounds such as b-hydroxy ketones, b-hydroxy
esters, a,b-unsaturated carbonyl compounds or iminoketones.3
Reactions of monosubstituted and 1,1-disubstituted alkenes
furnish regioselectively 5-substituted 4,5-dihydroisoxazoles
while 1,2-disubstituted olens usually afford mixtures of regio-
and stereoisomers.
To control regio- and stereoselectivity of the reaction several
approaches were used such as application of optically active
Institute of Industrial Organic Chemistry, Annopol 6, 03-236 Warsaw, Poland. E-mail:
golebiewski@ipo.waw.pl; Fax: +48 22 811 0799; Tel: +48 22 811 1231
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra15975f
Fig. 1 Chiral ligands used in nitrile oxides 1,3-dipolar cycloaddition
reactions.
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Table 1 Enantioselective 4-trifluoromethylbenzonitrile oxide cycloaddition reactions to crotonate 3a
Chiral catalysta
Yieldb (%)
Rs 5a/6a
% ee 5a
% ee 6a
c
Entry
d
1
2
A–Yb(OTf)3
90
67
65
28
80
73
52
96
27
69
56
90
35
72
45
88
38
54
59
24
39
18
15
18
24
42
41
30
19
30
31
45
44
31
37
47
27
87
79
73
67
56
90
36
62/38
40/60
89/11
45/55
70/30
72/28
82/18
84/16
73/27
82/18
63/37
75/25
76/24
62/38
76/24
71/29
67/37
69/31
55/45
82/18
65/35
17/83
76/24
17/83
46/54
50/50
65/35
61/39
70/30
64/36
53/47
64/36
50/50
66/34
79/21
77/23
68/32
48/52
55/45
63/37
46/54
82/18
97/3
99.8
7.6
8.0
1.4
5.6
70
B–Yb(OTf)3
C–Yb(OTf)3
C–Yb(OTf)3
G–Yb(OTf)3
H–Yb(OTf)3
M–Yb(OTf)3
N–Yb(OTf)3
J–Yb(OTf)3
K–Yb(OTf)3
O–Yb(OTf)3
I–Yb(OTf)3
F–Yb(OTf)3
L–Yb(OTf)3
D
D–Yb(OTf)3
P–Yb(OTf)3
E–Yb(OTf)3
C–Ag(OTf)
C–Cu(OTf)2
C–Hf(OTf)4
C–AuBr3
3
4d
5
10.8
14.0
14.4
5.0
18.8
34.4
10.4
3.4
18.2
0.1
3.0
4.2
1.8
1.4
1.4
0
1.4
1.4
0.8
3.0
0.1
0.2
50
0.1
0.6
0.2
19.2
6.2
99.9
2.8
—
0.6
0.1
0.4
2.0
0.8
0.2
0.1
1.2
0.2
0.2
0.4
0.6
0.02
8.8
2.4
1.2
1.4
0.2
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43d
44
0.2
6.0
13.2
0.4
23.6
12.0
10.0
2.4
2.4
0.8
1.0
C–PdCl2
C–BiBr3
C–FeCl3
—
C–LiClO4
C–CsF
55.8
73.2
3.4
—
19.4
35.8
22.8
9.2
43.6
18.6
8.6
C–Mg(OTf)2
C–Co(CH3COO)2$4H2O
C–(40%)Yb(ClO4)3/(60%)H2O
I–Fe2O3
I–Fe3O4
I–Yb2O3
I–TiCl4
I–CsF
I–FeCl3
N–YbF3
N–TiCl4
N–LiClO4
7.6
8.0
10.0
84.4
10.0
47.0
10.4
10.2
7.0
N–Fe2O3
Lipase “Candida antarctica”
Lipase “Candida antarctica”
Lipase “Candida rugosa”
98.8
11.2
37/63
a
R-BINOL-A, S-BINOL-B, (+)-(4,6-benzylidene)methyl-a-D-glucopyranoside-C, 1,2:3,4-di-O-isopropylidene-a-D-galactopyranose-D, quinine diethyl
phosphate-E, L-gulonic acid g-lactone-F, cytidine-G, inosine-H, L-ascorbic acid-I, L-(+)-arabinose-J, R-(+)-glycidol-K, (ꢀ)-menthol-L, (ꢀ)-a-santonin-
b
c
M, (+)-2-hydroxy-3-pinanone-N, cholesteryl acetate-O, L-tyrosine-P. Isolated yield of esters 5a and 6a. Regioisomer 5a/regioisomer 6a.
Reaction in Et2O.
d
(S)-glutamic acid receptors.14 (+)-2-Hydroxy-3-pinanone in an ionic liquid were used in 1,3-dipolar cycloaddition reac-
derivatives were used to prepare imino-triphenylphosphine tions under microwave irradiation.18
ligands in palladium-catalyzed asymmetric Diels–Alder
Immobilized lipase B from Candida antarctica was applied in
enantioselective hydrolyses and amminolyses of diethyl-3-
reactions.15
Copper(II) sulfate–sodium ascorbate system (generating hydroxyglutarate and dimethyl-3-hydroxyglutarate.19
Cu(I)) catalyzed azide–alkyne cycloaddition reactions.16
Candida rugosa lipase immobilized on calix[4]arene carbox-
Mixtures of ascorbate and copper reacted as oxidizing agent, ylic acid-graed magnetic nanoparticles was highly active both
catalyzing the formation of reactive hydroxyl radicals via Fenton in the enantioselective hydrolysis of racemic naproxen and
reaction.17 Ascorbic acid based ionic liquid and a copper catalyst p-nitrophenylpalmitate methyl esters.20
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A combination of an achiral pyrazolidinone ligand and obtained with catalytic systems comprising (+)-2-hydroxy-3-
chiral Lewis acids was applied to successfully relay stereo- pinanone (ligand N); its inuence on regioselectivity depen-
chemical information from the chiral ligand to the reaction ded on the type of LA used. This catalyst affords a large
center in enantioselective Diels–Alder cycloadditions.21 increase of yield (96%) (Table 1, reaction no. 8) compared to
Similarly, rare earth-chiral phosphate complexes were in the reaction without a catalyst (42%, reaction no. 26).
some cases highly effective in the presence of achiral addi- Applying this ligand with different LA (Table 1, reactions no.
tives in the asymmetric hetero-Diels–Alder reaction of alde- 8, 38–41) one can see changes of all the parameters specied
hydes with the Danishefsky's diene.22
in this table. Good yields were also obtained for the systems
In quest of controlling stereochemistry and regiochemistry involving Yb(OTf)3 and carbohydrates C and D as ligands.
of nitrile oxides 1,3-dipolar cycloaddition reaction to a,b- Catalytic systems comprising this ligands and other LA
unsaturated esters, we have examined new catalytic systems, described in the literature to complex different other ligands
comprising chiral ligands (Fig. 1, Table 1), as well as inorganic were also tested.25 Those examined systems included
and organic salts of metals belonging to several groups of combination of C with AuBr3, AgOTf, PdCl2, Cu(OTf)2,
elements, especially lanthanides.
Hf(OTf)4, FeCl3, CsF, Mg(OTf)2 and additionally undescribed
in the literature salts such as LiClO4 and BiBr3. The best
enantioselectivity was obtained with R-BINOL–Yb(OTf)3
(Table 1, reaction no. 1), carbohydrate C–BiBr3 system for
both regioisomers (Table 1, reaction no. 24), with L-ascorbic
acid I–FeCl3 system (Table 1, reaction no. 37), and with lipase
Candida antarctica for regioisomer 5a. It is the rst report of a
highly efficient application of this enzyme to catalyze enan-
tioselective 1,3-dipolar cycloaddition reaction. Immobilized
lipases were used before in enantioselective hydrolyses and
amminolyses of esters (vide supra). Combination of the
carbohydrate C–Yb(OTf)3 afforded good enantioselectivity (ee
of 70%) for one of the regioisomers (Table 1, reaction no. 3).
Satisfactory effect was also obtained for quinine diethyl
phosphate (ligand E) and ytterbium triate as LA (Table 1,
reaction no. 18).
Results and discussion
We have applied rst 1,3-dipolar cycloaddition reaction of 4-
triuoromethylbenzonitrile oxide to methyl crotonate 5a as a
model ester to test the efficiency of all used catalytic systems.
The results yields, regioselectivity, and enantioselectivity of the
obtained 2-isoxazolines are presented in the Table 1.
In the cycloaddition reaction of nitrile oxide to methyl
crotonate catalytic systems were used, which on one hand
were tested and selected as the most efficient in the cyclo-
addition to the aromatic amides,1 and on the other hand the
systems affecting stereochemistry and regiochemistry, which
have been proved to be effective for the other dipolar-
ophiles.23,24 Forty four different catalytic systems consisting
of Lewis acids (LA) and chiral ligands were used (Table 1).
Different ligands of the same LA as well as different LA for the
same chiral ligands were applied. The best yields were
In another approach to control the above cycloaddition
reaction mixed catalytic systems involving LA-ligand-1 (1 eq.) –
ligand-2 (2 eq.) were examined (Table 2). The source of chirality
Table 2 Results of 4-trifluoromethylbenzonitrile oxide cycloaddition reactions to crotonate 3a in the presence of Yb(OTf)3 and chiral and achiral
ligands
Entry
Ligands-1 1 eq.
Ligands-2 2 eq.
Yielda (%)
Rsb 5a/6a
% ee reg. 5a
% ee reg. 6a
1
2
3
4
5
(A + B)
(A + B)
A
A
A
K
L
45
43
5
39
47
28/72
82/18
50/50
33/67
62/38
30.0
14.8
—
5.8
7.6
0.6
1.6
85.0
1.4
P(C6H5)3
DMAP
Aniline
6.0
6
A
74
64/36
41.4
33.4
7
8
A
A
25
87
55/45
45/55
63.6
14.4
13.4
4.0
9
A
A
73
69
57/43
62/38
11.8
8.4
0.6
1.2
10
a
Isolated yield of esters 5a and 6a. b Regioisomer 5a/regioisomer 6a.
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was either ligand-1 or ligand-2; as ligand-1 chiral or racemic was also obtained for 1,3-benzodioxol-5-yl group (Table 3,
BINOL (ligand A + B) was used. It was expected that increased reaction no. 30). N-Decyl substituent was much more effec-
steric demands of such a mixed catalyst would create a chiral tive than methyl group in this respect (cf. entries 8 and 2).
sphere where an approach of the dipol to one side of the bound Interactions of the catalytic complex with amide and alcohol
dipolarophile will be preferred. The best enantioselectivity was type dipolarophiles were described in one of our previous
achieved for a combination of BINOL A with voluminous tri- papers.26
phenyl phosphine (Table 2, reaction no. 3, ee ¼ 85%) and with
N-cyclohexyl-N,N-dimethylamine (Table 2, reaction no. 7, ee ¼ process, which is most pronounced for t-butyl (Table 3, reaction
63.6%). no. 14), 2-furanyl (Table 3, reaction no. 28) and for 1,3-
Having selected the most efficient catalytic systems in the benzodioxol-5-yl group (Table 3, reaction no. 30).
model cycloaddition to methyl crotonate the next step was to Results of cycloadditions to (Z)-pent-2-en-1-yl esters are
The same steric factors favour also regioselectivity of the
analyze inuence of dipolarophile structure on stereo- presented (Table 4). High enantioselectivity was achieved for
selectivity of the reaction. An effect of the ester type and three different catalytic systems, better on average enantiose-
character of the double bond substituent was analyzed. The lectivity than one observed in case of E-esters. In all these
best enantioselectivity was observed for isopropyl ester experiments higher enantioselectivities were found for
(Table 3, reaction no. 6), benzyl ester (Table 3, reaction no. regioisomers 5 than for regioisomers 4. Such a difference of
24), where excellent ee values were noticed for both enantioselectivities between regioisomers 4 and 5 has been also
regioisomers, phenyl ester (Table 3, no. 26), and pyrrolidine- recorded before (Scheme 2).27
2,5-dione-1-yl ester (Table 3, reaction no. 22). These results
Analyzing values of electron charges on double bond carbon
indicate a benecial effect of a bulky ester function. Simi- atoms of the dipolarophiles some regularities can be noticed
larly, voluminous olenic substituents contribute to between charges and yields as well as regiochemistry of the
increase enantioselectivity of the reaction. The outstanding cycloaddition reaction (Table 5). The smaller is a difference
ee values were achieved for t-butyl and cyclohexyl groups between values of charges on C-2 and C-3 carbon atoms in the
(Table 3, reactions no., respectively, 15 and 17). Good result dipolarophile, the greater is yield of the reaction.
Table 3 Enantioselective 4-trifluoromethylbenzonitrile oxide cycloaddition reactions to esters 3b–p
Entry
5/6
R1
R2
Catalyst
Yielda (%)
Rsb 5/6
% ee reg. 5
% ee reg. 6
1
2
3
4
5
6
7
8
b
b
c
Me
Me
Me
Me
Me
Me
n-Decyl
n-Decyl
n-Decyl
Me
Me
i-Pr
i-Pr
t-Bu
t-Bu
Cyclohexyl
Cyclohexyl
Me
Me
Me
Me
Me
Me
Me
Et
Et
n-Octyl
n-Octyl
i-Pr
i-Pr
Et
Et
Et
Menthyl
Menthyl
Me
Me
Me
Me
Me
—
92.6
31.0
2.0
59
80
34
19
30
15
84
90
75
27
70
49
75
37
17
33
50
40
27
70
40
40
27
70
39
65
67
71/29
63/37
5050
—
1.4
—
12.5
—
96.8
—
30.0
34.0
20.0
22.0
—
1.8
—
55.2
—
99.0
1.0
—
30.0
—
79.6
—
93.2
—
17.0
—
2.0
—
—
2.6
—
1.0
—
0.8
—
64.6
34.0
10.0
8.0
—
13.0
—
99.0
—
30.6
3.0
—
30.0
—
4.2
—
100
—
83.2
—
—
—
85.0
D–Yb(OTf)3
—
E–Yb(OTf)3
—
E–Yb(OTf)3
—
E–Yb(OTf)3
D–Yb(OTf)3
—
Yb(OTf)3
—
C–Yb(OTf)3
—
C–Yb(OTf)3
—
N–TiCl4
(A + B)–Yb(OTf)3
—
E–Yb(OTf)3
—
C–Yb(OTf)3
—
N–TiCl4
—
N–La(OTf)3
—
D–Yb(OTf)3
—
c
70/30
40/60
70/30
50/50
71/29
65/35
60/40
75/25
77/23
66/34
88/12
30/70
60/40
25/75
50/50
69/31
70/30
70/30
85/15
60/40
65/35
50/50
81/19
97/3
d
d
e
e
e
f
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
f
g
g
h
h
i
i
j
k
k
l
Me
3-Pinanon-2-yl
3-Methyloxetan-3-methyl
3-Methyloxetane-3-methyl
Pyrrolidine-2,5-dione-1-yl
l
Pyrrolidine-2,5-dione-1-yl
m
m
n
n
o
o
p
p
Benzyl
Benzyl
Phenyl
Phenyl
Me
Me
Me
Me
Me
Me
Furan-2-yl
Furan-2-yl
1,3-Benzodioxol-5-yl
1,3-Benzodioxol-5-yl
95/5
25/75
7/93
C–Yb(OTf)3
54.8
a
Isolated yield of esters 5 and 6. b Regioisomer 5/regioisomer 6.
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Table 4 Enantioselective 4-trifluoromethylbenzonitrile oxide cycloaddition reactions to Z-pent-2-en-1-yl esters 7a and 7b
Entry
8/9
R3
Catalyst
Yielda (%)
Rsb 8/9
% ee reg. 8a, 8b
% ee reg. 9a, 9b
1
2
3
4
5
6
a
a
b
b
b
b
Me
Me
CH2OMe
CH2OMe
CH2OMe
CH2OMe
—
N–TiCl4
—
N–TiCl4
N–Mg(OTf)2
C–Yb(OTf)3
40
32
45
37
34
70
68/32
82/18
65/35
81/19
20/80
28/72
—
64.6
—
25.8
16.0
32.0
—
97.2
—
99
99
44
a
Isolated yield of esters 8 and 9. b Regioisomer 8/regioisomer 9.
Scheme 1 Nitrile oxide cycloaddition reaction to esters 3a–p.
The value of charges on C-2 is also essential, since for the
relatively small absolute values with the comparable difference
of C-2/C-3 charges, the reaction yield is higher than in cases
with a larger absolute value of the charge on C-2 (compare
values for the dipolarophiles pairs 3e and 3f, 3d–k and 3a–i).
The difference between the sums of C-2 and C-3 electron
charges and sums of H-2 and H-3 electron charges is also
important; the smaller is the difference, the better is
Scheme 2 Nitrile oxide cycloaddition reaction to esters 7a and 7b.
Table 5 Electron charges at the alkenyl carbon atoms of the dipolarophiles 3a–p and regioselectivity of the cycloadducts 5/6 (Scheme 1)
Regioselectivity
Dipolarophile 3
C2
C3
H2
H3
Yield (%)
Reg.-5
Reg.-6
a
b
d
e
ꢀ0.210
ꢀ0.210
ꢀ0.207
ꢀ0.213
ꢀ0.207
ꢀ0.205
ꢀ0.206
ꢀ0.205
ꢀ0.212
ꢀ0.207
ꢀ0.214
ꢀ0.179
ꢀ0.195
ꢀ0.068
ꢀ0.070
ꢀ0.071
ꢀ0.064
ꢀ0.073
ꢀ0.065
ꢀ0.060
ꢀ0.065
ꢀ0.065
ꢀ0.070
ꢀ0.064
ꢀ0.017
ꢀ0.030
0.154
0.154
0.155
0.154
0.153
0.155
0.155
0.155
0.156
0.155
0.157
0.159
0.157
0.145
0.144
0.143
0.146
0.144
0.146
0.146
0.146
0.148
0.144
0.146
0.169
0.148
42
93
80
19
84
75
70
75
30
70
40
70
65
50
71
40
50
60
77
88
60
69
60
50
97
25
50
29
60
50
40
23
12
40
31
40
50
3
f
g
h
i
k
m
n
o
p
75
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Table
6
Fungicidal inhibitory activitiesa of compounds 3–9 at
200 mg Lꢀ1
Compound
B. c.b
F. c.
P. c.
R. s.
3c
3e
0
0
16.0
22.0
24.0
20.0
16.0
29.0
45.8
16.7
20.8
19.4
19.4
80.6
0
0
0
6.0
0
Scheme 3 Proposed mechanism of chiral induction with TiCl4–N 3f
18.8
43.8
18.0
32.0
25.0
3.8
11.5
20.0
0
75.0
8.0
52.0
26.9
36.0
0
16.3
10.0
5.0
100
0
54.0
18.0
17.0
68.0
31.0
0
10.3
48.0
38.0
100
34.0
34.0
36.2
60.0
38.0
24.0
37.9
28.0
0
system.
3j
3k
3l
5b
5c
5e
5g
regiochemistry (compare e.g. data for the dipolarophiles pair
3n and 3o).
0
8.7
1.8
0.7
100
0
0
0
0
6.5
6.5
6.5
1.8
0
The observed enantioselectivity of the reaction leading to 4-
carboalkoxy derivatives could be tentatively explained by 5h
3l + 5l
5m
5o
6b
6d
binding of the esters to the chiral catalytic complex, such as
presented at Scheme 3, of titanium tetrachloride with (+)-3-
hydroxy-2-pinanone (N), followed by a preferential attack of
nitrile oxide from the lower si-face of the alkene opposite to the
20.0
37.5
25.8
3.2
geminal dimethyl bridge affording isoxazolines of 4R,5S 6g
6i
6k
6l
6p
4.0
38.4
0
44.0
40.0
80.0
0
conguration. This direction of enantioselectivity was found
also for complexes of ligand N with ytterbium triate and
lithium perchlorate, as well as for complexes of Yb(OTf)3 with
carbohydrate C, R-BINOL, tyrosine, cytidine, and L-menthol.
47.8
22.6
0
16.0
38.0
9a
28.2
61.0
48.0
88.0
The absolute conguration of the cycloadducts was established Chlorothalonilc
based on comparison of literature data for the similar
a
Percentage of linear growth inhibition. b B. c. – Botrytis cinerea, F. c. –
Fusarium culmorum, P. c. – Phytophtora cactorum, R. s. – Rhizoctonia
solani. c Reference compound.
compounds.28
The opposite chirality indicated by opposite elution order
of enantiomers of the same compound from the chiral
column and opposite sign of optical rotation was observed
for the catalytic systems of (+)-(4,6-benzylidene)methyl-a-D-
glucopyranoside (carbohydrate C) with BiBr3, PdCl2, LiClO4,
CsF, Mg(OTf)2, CsF, Yb(OTf)3, complexes of L-ascorbic acid (I)
with CsF, FeCl3, and reaction mediated by lipase Candida
antarctica. In this case the observed enantioselectivity could
be explained e.g. by a preferred attack of the nitrile oxide
from upper re-face of the dipolarophile opposite to the ligand
alpha-1,2-substituents affording isoxazolines of 4S,5R
conguration (Scheme 4).
The obtained esters have been screened for the biological
activity. Inhibition of the linear growth of fungi being pests of
important cultivated plants is displayed in Table 6. Good
fungicidal activity was found for esters 3l and 5l containing
several carbonyl groups. Moderate biological potency was
noticed for 5b, 5d and 5o, 6k products with four- and ve-
membered rings containing oxygen atom. Cycloadducts
exhibit higher fungicidal activity than starting dipolarophiles
(compare pairs 3l, 5l; 3e, 5e; 3k, 6k).
Conclusion
We have applied new chiral Lewis acids to study 1,3-dipolar
cycloaddition reaction of aryl nitrile oxides and crotonates as
well as substituted acrylates mediated by chiral complexes of
carbohydrates C, D, F, I, J, A, nucleosides G and H as well as
natural products derivatives with inorganic and organic salts of
metals belonging to several groups of elements, especially
lanthanides, achieving high enantioselectivity and regiose-
lectivity for some systems. Depending on the type of catalytic
system 4R,5S or 4S,5R-trisubstituted isoxazolines can be
obtained. We are continuing research to diminish amount of
chiral Lewis acid from equimolar to catalytic quantities.
Experimental
Reagent grade chemicals were used without further purication
unless otherwise noted. Hydroximinoyl acid chlorides were
prepared from the corresponding aryl aldehyde oximes and NCS
in DMF.29,30 The corresponding nitrile oxides were generated in
situ by dehydrohalogenation of hydroximinoyl acid chlorides
with triethylamine or on Amberlyst A-21 column.27
Spectra were obtained as follows: IR spectra on JASCO FTIR-
420 spectrometer, 1H, 13C NMR on a Varian 200 UNITY plus-200
and a Varian 500 UNITY plus-500, COSY (correlation spectros-
copy), HSQC (heteronuclear single quantum coherence), HMBC
(heteronuclear multiple bond correlation) and NOESY (nuclear
Overhauser effect spectroscopy) analyses on a Varian 500 UNITY
Scheme 4 Proposed mechanism of chiral induction with BiBr3–C
system.
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plus-500 and a Varian VNMRS 600 spectrometers in deuterated acetate as a mobile phase. The expected esters 3 were obtained
chloroform using TMS as internal standard, ESI and HR ESI as yellowish waxes (40–80%).
mass spectra on Micromass LCT spectrometer. Flash-
Octyl (2E)-but-2-enoate (3c).37 A brownish oil (55%). 1H NMR
chromatography was carried out using silica gel S 230-400 (200 MHz, CDCl3): d 6.97 (dq, J ¼ 15.5; 8.4 Hz, 1H, H3C–HC]C–),
mesh (Merck). Elemental analyses were performed at Micro- 5.84 (dq, J ¼ 15.5; 1.8 Hz, 1H, –C]CH–C]O), 4.11 (t, J ¼ 6.6 Hz,
analysis Laboratory of Institute of Organic Chemistry, Polish 2H, –O–CH2–, H-5), 1.88 (dd, J ¼ 6.8; 1.8 Hz, 3H, H3C–CH]CH–,
Academy of Sciences, Warsaw. The electron charges were H-4), 1.63 (m, 2H), 1.28 (m, 10H), 0.88 (t, J ¼ 6.6 Hz, 3H,
calculated using the computer program Hyperchem 7.5. Enan- H3C–CH2). EI-MS m/z (% intensity) 199 (M+ + H, 5), 183 (M+ ꢀ CH3,
tioselectivity of reactions was determined by HPLC analysis (AD- 2), 155 (M+ ꢀ C3H7, 2), 141 (M+ ꢀ C4H9, 3), 127 (M+ ꢀ C5H11, 3), 87
H chiral column).
(H3C–CH]CH–C]O–O + 1H, 80), 69 (H3C–CH]CH–C]O, 100),
41 (H3C–CH]CH, 70).
Propan-2-yl(2E)-but-2-enoate (3d).38 A brownish oil (73%). IR
(lm, cmꢀ1): 2981, 2960, 2880, 1719, 1660, 1470, 1440, 1375,
1308, 1298, 1278, 1191, 1150, 1110, 1003, 965, 901, 840, 750,
690. 1H NMR (500 MHz, CDCl3): d 6.94 (dq, J ¼ 15.0; 7.0 Hz, 1H,
H3C–HC]C–C]O), 5.82 (dq, J ¼ 15.0; 2.0 Hz, 1H, –C]CH–C]
O), 5.05 (sept, J ¼ 6.3 Hz, 1H, H3C–CH–CH3), 1.87 (dd, J ¼ 6.8;
1.5 Hz, 3H, H3C–HC]C), 1.25 (d, J ¼ 6.8 Hz, 6H, (H3C)2CH).
Ethyl tridec-(2E)-2-enoate (3e).39 NaH 60% (1.5 mmol) of THF
was added dropwise with stirring at 0 ꢂC over 10 min to the
solution of diisopropyl (ethoxycarbonylmethyl)phosphonate (1
Syntheses of dipolarophiles 3a, 3b, 3c, 3d, 3f, 3g, 3h, 3i, 3j, 3k,
3l, 3m, 3n, 3o and 3p
Acids 2g, 2h, 2i, 2n, 2o, 2p were prepared in the Knoevenagel
condensation with malonic acid from the corresponding
aldehyde.31
(2E)-4-Methylpent-2-enoic acid (2g).32 A brownish oil (85%).
1H NMR (500 MHz, CDCl3): d 10.99 (s, 1H, –OH), 7.07 (dd, J ¼
15.5; 7.5 Hz, 1H, HC]C–C]O), 5.78 (dd, J ¼ 15.5; 1.5 Hz, 1H,
–C]CH–C]O), 2.49 (m, J ¼ 7.0; 1.5 Hz, 1H, H–C(CH3)2), 1.08
(d, J ¼ 7.0 Hz, 6H, 2ꢁ H3C–CH).
ꢂ
mmol) in anhydrous Et2O and the solution was stirred at 0 C
(2E)-4,4-Dimethylpent-2-enoic acid (2h).33 A brownish oil
ꢂ
and then at rt for 60 min. The solution was cooled to ꢀ15 C
1
(60%). H NMR (200 MHz, CDCl3): d 7.08 (d, J ¼ 15.8 Hz, 1H,
and an aldehyde 1 (1 mmol) solution in anhydrous THF was
added dropwise with stirring over 20–30 min and then the
solution was stirred at rt for 24 h under anhydrous argon. The
solution was washed with water, dilute NH4Cl aqueous solu-
tion, several times with water and was dried (MgSO4). The
product obtained aer evaporation of the solvent was puried
by ash chromatography on silica gel using mixtures of
hexane–ethyl acetate as a mobile phase. The expected ester 3e
was obtained as a yellowish wax (65%). 1H NMR (200 MHz,
CDCl3): d 6.97 (dt, J ¼ 15.6; 7.0 Hz, 1H, –H2C–HC]C), 5.81 (dt,
J ¼ 15.6; 1.4 Hz, 1H, –C]CH–C]O), 4.18 (t, J ¼ 7.2 Hz, 2H, O]
C–O–CH2, H-14), 2.19 (m, 2H, –H2C–HC]C), 1.43 (m, 16H,
–H2C–CH2), 0.88 (t, J ¼ 6.6 Hz, 3H, H3C–CH2). EI-MS m/z
(% intensity) 241 (M+ + H, 10), 226 (M+ ꢀ CH3, 4), 213 ((M+ ꢀ
C2H5) + 1H, 5), 156 (M+ ꢀ C6H13, 5), 142 (M+ ꢀ C7H15, 5), 128
(M+ ꢀ C8H17, 5), 114 (M+ ꢀ C9H19, 10), 101 ((M+ ꢀ C10H21 + 1H,
50), 86 (H3C–CH]CH–C]O–O, 30), 69 (H3C–CH]CH–C]O,
45), 41 (H3C–CH]CH, 100).
–HC]C–C]O), 5.75 (d, J ¼ 15.8 Hz, 1H, –C]CH–C]O), 1.08
(s, 9H, 3ꢁ H3C–C).
(2E)-3-Cyclohexylprop-2-enoic acid (2i).34 A brownish oil
(85%). IR (KBr, cmꢀ1): 2921, 1690, 1645, 1460, 1418, 1313, 1280,
1233, 1225, 1175, 1140, 995, 950, 880, 850, 780, 727, 696, 595,
535. 1H NMR (200 MHz, CDCl3): d 11.26 (s, 1H, –OH), 7.04 (dd,
J ¼ 16.0; 6.8 Hz, 1H, –HC]C–C]O), 5.77 (dd, J ¼ 16.0; 1.4 Hz,
1H, –C]CH–C]O), 2.11 (m, 1H, HCCH2), 1.73 (m, 5H), 1.24
(m, 5H). 13C NMR (50.3 MHz, CDCl3): d (ppm) ¼ 172.99 (H3CO–
C]O), 157.34 (CH), 118.51 (CH), 40.69 (1C, C-10), 31.69 (2C,
C-20, C-60), 26.06 (2C, C-30, C-50), 25.83 (C-40).
(2E)-3-(Furan-2-yl)prop-2-enoic acid (2o).35 A brownish oil
(50%). IR (KBr, cmꢀ1): 3420, 3200, 3150, 3080, 2995, 2927, 2840,
2815, 2700, 2595, 2530, 2480, 2280, 1700, 1670, 1627, 1560, 1480,
1415, 1390, 1312, 1271, 1230, 1193, 1070, 1022, 976, 950, 940, 925,
880, 860, 840, 756, 665. 1H NMR (500 MHz, CDCl3): d 10.83 (s, 1H,
–OH), 7.53 (d, J ¼ 15.6 Hz, 1H, –HC]C–C]O), 7.52 (d, J ¼ 4.3 Hz,
1H, H-20), 6.67 (d, J ¼ 8.5 Hz, 1H, H-50), 6.49 (td, J ¼ 8.5: 4.3 Hz,
1H, H-40), 6.32 (d, J ¼ 15.6 Hz, 1H, –C]CH–C]O).
Menthyl (2E)-but-2-enoate (3f).40 A brownish oil (45%). IR
(neat, cmꢀ1): 2955, 2880, 1718, 1659, 1447, 1370, 1307, 1290,
1
1187, 1101, 1040, 1016, 1000, 960, 920, 840, 760, 734, 690. H
General procedure for synthesis of esters 3c, 3f, 3j, 3k, 3l36
NMR (500 MHz, CDCl3): d 6.95 (dq, J ¼ 15.5; 6.8 Hz, 1H, H3C–
N,N0-Dicyclohexylcarbodiimide (DCC) (14 mmol) in anhydrous HC]C–), 5.83 (dq, J ¼ 15.5; 1.8 Hz, 1H, –C]CH–C]O), 4.72
CH2Cl2 was added with stirring at room temperature to a (td, J ¼ 11.0; 4.5 Hz, 1H, H-10), 2.01 (m, 1H, H-6eq0), 1.88 (m, 1H,
solution of carboxylic acid (10 mmol), alcohol (10 mmol) and 4- H-80), 1.87 (dd, J ¼ 6.8; 2.0 Hz, 3H, H3C–CH]CH), 1.68 (m, 2H,
dimethyloaminopyridine (6.5 mmol) in a mixture of anhydrous H-4eq0, H-3eq0), 1.50 (m, 1H, H-50), 1.40 (m, 1H, H-20), 1.1 (m,
dichloromethane–acetonitrile (5 mL, 1 : 1) under anhydrous 1H, H-3ax0), 0.95 (m, 1H, H-6ax0), 0.90 (d, J ¼ 6.5 Hz, 3H, H3C–
argon. Stirring was continued for 24 h. The reaction mixture was CH), 0.89 (d, J ¼ 7.0 Hz, 3H, H3C–CH), 0.85 (m, 1H, H-4ax0), 0.76
ltered and the lter paper was washed with dichloromethane. (d, J ¼ 7.5 Hz, 3H, H3C–C]C). 13C NMR (from HSQC, 150 MHz,
The solution was washed with water, dilute HCl, water, aqueous CDCl3): d 143.0 (C-3), 122.5 (C-2), 73 (C-10), 42 (C-20), 41 (C-60), 34
solution of sodium bicarbonate, and nally several times with (C-40), 31.5 (C-50), 26.2 (C-80), 23.5 (C-30).
water. The solution was dried (Na2SO4) and the product
Methyl (2E)-3-cyclohexylprop-2-enoate (3i).41 A brownish oil
1
obtained aer evaporation of the solvent was puried by ash (70%). H NMR (500 MHz, CDCl3): d 6.92 (dd, J ¼ 16.0; 6.5 Hz,
chromatography on silica gel using mixtures of hexane–ethyl 1H, –HC]C–C]O), 5.77 (dd, J ¼ 16.0; 1.5 Hz, 1H, C]CH–C]O),
13118 | RSC Adv., 2015, 5, 13112–13124
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3.83 (s, 3H, H3C–O–C]O), 2.25 (m, 1H, HCCH2), 1.87 (m, 4H), 718. H NMR (200 MHz, CDCl3): d 7.59 (d, J ¼ 16.0 Hz, 1H, Ar-
1.79 (m, 1H, H-4a0), 1.41 (m, 2H), 1.32 (m, 1H), 1.28 (m, 2H). 13C HC]C–C]O), 7.02 (d, J ¼ 1.8 Hz, H-30), 7.00 (dd, J ¼ 7.8; 1.8 Hz,
NMR (125.9 MHz, CDCl3): d (ppm) ¼ 167.43 (H3C–O–C]O), 1H, H-50), 6.80 (d, J ¼ 7.8 Hz, 1H, H-60), 6.26 (d, J ¼ 16.0 Hz, 1H,
154.48 (CH), 118.42 (CH), 51.26 (H3C–O), 40.35 (1C, C-10), 31.62 –C]CH–C]O), 6.00 (s, 2H, OCH2O), 3.78 (s, 3H, H3C–O–C]O).
(2C, C-20, C-60), 25.85 (2C, C-30, C-50), 25.62 (C-40).
2,6,6-Trimethyl-3-oxobicyclo [3.1.1] hept-2-yl (2E) but-2-
enoate (3j). A brownish oil (65%). IR (KBr, cmꢀ1): 2925, 2880,
General procedure for the cycloaddition reactions
1720, 1650, 1470, 1442, 1405, 1370, 1308, 1295, 1266, 1186, 1150, A mixture of a chiral ligand-1 (1.0 mmol) and a Lewis acid (1.0
1100, 1080, 1053, 998, 970, 855, 833, 753, 690 cmꢀ1. 1H NMR (600 mmol) in anhydrous dichloromethane was stirred at rt for
MHz, CDCl3): d 6.86 (dq, J ¼ 15.5; 8.6 Hz, 1H, H3C–CH]C), 5.75 60 min. Chiral ligand-2 (2.0 mmol) in anhydrous dichloro-
(dq, J ¼ 15.5; 1.8 Hz, 1H, C]CH–C]O), 2.97 (t, J ¼ 6.3 Hz, 1H, C– methane was stirred at rt for 60 min. A solution of 4-tri-
HC–C), 2.77 (dd, J ¼ 18.9; 2.4 Hz, 1H, H-7a), 2.65 (dt, J ¼ 18.9; 3.2 uoromethylbenzonitrile oxide was added dropwise over 20
Hz, 1H, H-7b), 2.40 (m, 1H, H-10a), 2.12 (m, 1H, H-8), 1.83 (dd, J min to the solution of esters 3, 7 in anhydrous dichloro-
¼ 6.8; 1.6 Hz, 3H, H3C–CH]C), 1.61 (s, 3H, CH3), 1.57 (m, 1H, H- methane, and the solution was stirred overnight at room
10b), 1.35 (s, 3H, –CH3), 0.86 (s, 3H, –CH3). 13C NMR (from temperature. Water was added, organic layer was separated and
HMBC, 150.8 MHz, CDCl3)]: d 206.72 (C–C]O–C), 165.10 (O]C– the aqueous one extracted with dichloromethane. The
CH]C), 144.92 (H3C–CH]C), 123.13 (O]CCH]C), 86.15 ([O– combined organic layers were dried (MgSO4) and the product
C–C]O(CH3)]), 49.06 (C–CH–C), 43.30 (C-7), 38.29 (C-8), 27.77 (C- obtained aer evaporation of the solvent was puried by ash
10), 27.39 (H3C), 22.53 (H3C), 21.29 (H3C), 17.87 (H3C). HR ESI- chromatography on silica gel using mixtures of hexane–ethyl
MS calcd for: C14H20O3Na ¼ 259.1310. Found ¼ 259.1310.
acetate as a mobile phase.
(3-Methyloxetan-3-yl)methyl (2E)-but-2-enoate (3k).42
A
Methyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-5-
1
brownish oil (40%). H NMR (200 MHz, CDCl3): d 7.03 (dq, J ¼ methyl-4-carboxylate (5a). A yellow oil (yield in Table 2). [a]D25
15.5; 6.7 Hz, 1H, H3C–HC]C), 5.89 (dq, J ¼ 15.5; 1.8 Hz, 1H, ¼ ꢀ150.0 (c 0.2 in acetone) [99.8% ee, (R, S) rich]. 1H NMR (200
–C]CH–C]O), 4.55 (d, J ¼ 6.0 Hz, 2H, –O–CH2–C-anti), 4.40 (d, MHz, CDCl3): d 7.82 (d, J ¼ 8.6 Hz, 2H, H-50, H-30), 7.65 (d, J ¼ 8.6
J ¼ 6.0 Hz, 2H, –O–CH2–C-syn), 4.21 (s, 2H, –O–CH2–, H-5), 1.90 Hz, 2H, H-60, H-20), 5.15 (quintet, J ¼ 6.3 Hz, 1H, H-5), 4.11 (dq,
(dd, J ¼ 6.8; 1.6 Hz, 3H, H3C–CH]CH–), 1.35 (s, 3H, H3C–C, H- J ¼ 6.3 Hz, H-4), 3.73 (s, 3H, CH3O), 1.49 (d, J ¼ 6.3 Hz, 3H, CH3–
9). 13C NMR (50 MHz, CDCl3): d 166.68 (–O–C]O), 145.53 (C-3, CH). Anal. calcd for C13H12F3NO3: C 54.4: H 4.2. Found: C 54.4;
H3C–HC]C), 122.44 (C-2, C]CH–C]O), 79.78 (C-7), 79.79 (C- H 4.0%.
8), 68.48 (OCH2), 39.34 (C-6), 21.39 (C-9), 18.20 (C-4).
Methyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-4-
2,5-Dioxopyrrolidin-1-yl (2E)-but-2-enoate (3l).43
A
white methyl-5-carboxylate (6a).48 A yellow oil; 1H NMR (200 MHz,
semisolid (55%). 1H NMR (500 MHz, CDCl3): d 7.28 (dm, J ¼ 15.8 CDCl3): d 7.97 (d, J ¼ 8.1 Hz, 2H, H-50, H-30), 7.68 (d, J ¼ 8.1 Hz,
Hz, 1H, H3C–HC]C), 6.05 (dq, J ¼ 15.8; 1.5 Hz, 1H, –C]CH– 2H, H-60, H-20), 4.84 (d, J ¼ 4.2 Hz, 1H, H-5), 4.02 (dq, J ¼ 7.3; 4.2
C]O), 2.84 (s, 4H, H-40, H-50), 2.00 (dd, J ¼ 6.5; 2.0 Hz, 3H, H3C– Hz, H-4), 3.81 (s, 3H, CH3O–), 1.43 (d, J ¼ 7.3 Hz, 3H, CH3–CH).
CH]CH).
Ethyl
3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-5-
Benzyl (2E)-but-2-enoate (3m).44 A brownish oil (35%). 1H methyl-4-carboxylate (5b). A yellow oil (yield in Table 3). IR
NMR (200 MHz, CDCl3): d 7.35–6.85 (m, 6H, H-20, H-30, H-40, H- (KBr, cmꢀ1): 2980, 2932, 1737, 1619, 1600, 1560, 1448, 1412,
50, H-60 and H3C–CH]C), 5.95 (dm, J ¼ 15.0 Hz, 1H, O]CHC] 1350, 1326, 1300, 1160, 1127, 1070, 1027, 933, 900, 847, 780. 1H
C), 5.13 (d, J ¼ 5.6 Hz, 2H, Ar-CH2OC]O), 1.79 (dd, J ¼ 6.8; 1.8 NMR (CDCl3, 300 MHz): d 7.99–7.60 (m, 4H, H-30, H-50, H-20, H-
Hz, 3H, H3C–CH]C).
60), 5.16 (m, J ¼ 6.3; 6.6 Hz, 1H, H-5), 4.19 (qd, J ¼ 7.2; 1.5 Hz,
Phenyl (2E)-but-2-enoate (3n).45 A gray oil (35%). 1H NMR 2H, OCH2CH3), 4.09 (d, J ¼ 6.3 Hz, 1H, H-4), 1.50 (d, J ¼ 6.3 Hz,
(200 MHz, CDCl3): d 7.26–7.05 (m, 6H, H-20, H-30, H-40, H-50, H-60 3H, H3C–CH), 1.19 (t, J ¼ 7.2 Hz, 3H, O–CH2–CH3). EI-MS m/z (%
and H3C–CH]C), 5.95 (m, 1H, O]CHC]C), 1.85 (m, 3H, H3C– intensity) 301 (M+, 18), 282 (M+ ꢀ F, 19), 228 (M+ ꢀ C]
CH]C).
OOCH2CH3, 16), 214 (M+ ꢀ C]OOCH2CH3CH3, 45), 187 (F3-
Methyl (2E)-3-(furan-2-yl)prop-2-enoate (3o).46 A brownish oil CC6H4CNO, 12), 145 (F3CC6H4, 32), 69 (CF3, 15), 43 (100). Anal.
(35%). IR (oil, cmꢀ1): 3420, 3550, 3120, 3160, 3000, 2951, 2920, calcd for C14H14F3NO3: C 55.8: H 4.7. Found: C 55.6; H 4.8%.
2840, 1714, 1642, 1559, 1480, 1435, 1390, 1308, 1280, 1260, 1215,
Ethyl
3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-4-
1166, 1075, 1040, 1018, 973, 930, 884, 870, 840, 750, 682. 1H NMR methyl-5-carboxylate (6b). A yellow oil; IR (KBr, cmꢀ1): 2960,
(500 MHz, CDCl3): d 7.47 (d, J ¼ 1.5 Hz, 1H, H-50), 7.43 (d, J ¼ 15.5 2925, 1738, 1615, 1598, 1525, 1463, 1405, 1380, 1325, 1260,
Hz, 1H, –HC]C–C]O), 6.60 (d, J ¼ 3.5 Hz, 1H, H-30), 6.45 (dd, 1200, 1170, 1127, 1070, 1040, 900, 847. 1H NMR (CDCl3, 300
J ¼ 3.5; 1.5 Hz, 1H, H-40), 6.31 (d, J ¼ 15.5 Hz, 1H, –C]CH–C] MHz): d 7.99–7.60 (m, 4H, H-30, H-50, H-20, H-60), 4.82 (d, J ¼ 4.2
O), 3.77 (s, 3H, H3C–O–C]O). 13C NMR (50.3 MHz, CDCl3): Hz, 1H, H-5), 4.28 (q, J ¼ 7.1 Hz, 2H, O–CH2CH3), 4.02 (dq, J ¼
d 167.6 (H3C–O–C]O), 151.0, 144.9, 131.4, 115.6, 115.0, 112.4, 7.2; 4.2 Hz, 1H, H-4), 1.43 (d, J ¼ 7.2 Hz, 3H, H3C–CH), 1.32 (t,
51.8.
Methyl (2E)-3-(1,3-benzodioxol-5-yl)prop-2-enoate (3p).47
J ¼ 497.1 Hz, 3H, OCH2CH3). EI-MS m/z (% intensity) 301 (M+,
12), 282 (M+ ꢀ F, 14), 228 (M C]OOCH2CH3, 100), 214 (M+ ꢀ
A
greyish semisolid (87%). IR (lm, cmꢀ1): 3430, 3040, 2960, 2900, C]OOCH2CH3CH3, 12), 187 (F3CC6H4CNO, 30), 145 (F3CC6H4,
2840, 2800, 1703, 1625, 1600, 1497, 1455, 1448, 1360, 1310, 32), 69 (CF3, 8). Anal. calcd for C14H14F3NO3: C 55.8: H 4.7.
1255, 1201, 1174, 1130, 1102, 1037, 1004, 925, 860, 825, 727, Found: C 55.9; H 4.9%.
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OOCH2CH3C10H21, 10), 145 (F3CC6H4, 10), 69 (CF3, 12). Found: C,
64.7; H, 7.5. Calcd for C23H32F3NO3: C 64.6, H 7.55%.
Octyl
3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-5-
methyl-4-carboxylate (5c). A yellow oil; 1H NMR (200 MHz,
CDCl3): d 7.83 (d, J ¼ 8.2 Hz, 2H, H-20, H-60), 7.65 (d, J ¼ 8.2 Hz,
2H, H-30, H-50), 5.15 (quintet, J ¼ 6.4 Hz, 1H, H-5), 4.11 (t, J ¼ 6.4
Hz, 2H, OCH2CH2), 4.10 (d, J ¼ 6.4 Hz, 1H, H-4), 1.50 (d, J ¼ 6.4
Hz, 3H, H3C–CH), 1.59–1.10 (m, 12H), 0.88 (t, J ¼ 6.6 Hz, 3H,
H3C–CH2). 13C NMR (125.90 MHz, CDCl3): d 169.01 (–O–C]O),
152.87 (1C, C-3), 132.44 (1C, C-10), 131.79 (q, J ¼ 32.8 Hz, 1C, C-
40), 127.11 (2C, C-60, C-20), 125.65 (q, J ¼ 3.8 Hz, 2C, C-50, C-30),
123.8 (q, 1C, J ¼ 272 Hz, F3C-Ar), 82.82 (1C, C-5), 66.33 (1C, O]
C–OCH2CH2), 59.80 (C-4), 31.74, 29.09, 29.04, 28.37, 25.69,
22.58, 20.73, 14.04. HR-ESI-MS calcd for: C20H26O3NF3Na ¼
408.1762. Found ¼ 408.1778.
Menthyl 5-methyl-3-[4-(triuoromethyl)phenyl]-4,5-dihydro-
isoxazole-4-carboxylate (diastereoisomers A and B) (5f). A
yellow wax; A/B ¼ 60/40. A: 1H NMR (200 MHz, CDCl3): d 7.80 (d,
J ¼ 8.2 Hz, 2H, H-20, H-60), 7.65 (d, J ¼ 8.2 Hz, 2H, H-30, H-50),
5.07 (m, 1H, H-5), 4.62 (m, 1H, J ¼ 10.9 Hz, H-100), 4.11 (d, J ¼ 7.2
Hz, 1H, H-4), 2.00–1.80 (m, 1H, H-6eq00), 1.66–1.39 (m, 3H, H-
4eq00, H-3eq00, H-700), 1.53 (d, J ¼ 6.4 Hz, 3H, H-6, H3C), 1.5–1.35
(m, 1H, H-200), 1.38–1.17 (m, 1H, H-500), 1.10–0.70 (m, 3H, H-
4ax00, H-3ax00, H-6ax00), 0.88 (d, J ¼ 6.2 Hz, 3H, H-1000, H3C), 0.64
(d, J ¼ 6.8 Hz, 3H, H-800, H3C), 0.44 (d, J ¼ 7.0 Hz, 3H, H-900, H3C).
13C NMR from HMBC (150.3 MHz, CDCl3): d 168.46 (H3CO–C]
O), 153.03 (C-3), 132.52 (C-40), 131.74 (1C, C-1), 127.05 (2C, C-60,
C-20), 125.49 (2C, C-50, C-30), 83.01 (C-5), 76.37 (C-100), 60.55 (C-4),
46.68 (C-200), 40.43 (C-600), 33.98 (C-400), 31.35 (C-500), 25.78 (C-700),
20.41 (C-1000), 15.53 (C-900).
Octyl
3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-4-
methyl-5-carboxylate (6c). A yellow oil; 1H NMR (CDCl3, 200
MHz): d 7.84–7.63 (m, 4H, H-30, H-50, H-20, H-60), 4.82 (d, J ¼ 4.4
Hz, 1H, H-5), 4.19 (t, J ¼ 6.7 Hz, 2H, O–CH2CH2), 4.00 (dd, J ¼
7.1; 4.4 Hz, 1H, H-4), 1.43 (d, J ¼ 7.1 Hz, 3H, H3C–CH), 1.59–1.10
(m, 12H, CH2–CH2–CH2), 0.87 (t, J ¼ 6.6 Hz, 3H, H3C–CH2). EI-
MS m/z (% intensity) 385 (M+, 5), 370 (M+ ꢀ CH3, 12), 328 (M+ ꢀ
C4H9, 3), 286 (M+ ꢀ C7H15, 2), 228 (M+ ꢀ C]OOC8H17, 100), 214
(M+ ꢀ C]OOC8H17CH3, 50), 187 (F3CC6H4CNO, 20), 145
(F3CC6H4, 40), 69 (CF3, 45). Found: C, 62.1; H, 6.7. Calcd for
B: 1H NMR (200 MHz, CDCl3): d 7.80 (d, J ¼ 8.2 Hz, 2H, H-20,
H-60), 7.65 (d, J ¼ 8.2 Hz, 2H, H-30, H-50), 5.10 (m, 1H, H-5), 4.66
(m, H-100), 4.09 (d, J ¼ 6.0 Hz, 1H, H-4), 2.00–1.80 (m, 1H, H-
6eq00), 1.66–1.39 (m, 3H, H-4eq00, H-3eq00, H-700), 1.50 (d, J ¼ 6.4
Hz, 3H, H-6), 1.5–1.35 (m, 1H, H-200), 1.38–1.17 (m, 1H, H-500),
1.10–0.70 (m, 3H, H-4ax00, H-3ax00, H-6ax00), 0.84 (d, 3H, H-1000,
H3C), 0.78 (d, J ¼ 7.2 Hz, 3H, H-800, H3C), 0.64 (d, J ¼ 6.8 Hz, 3H,
H-900, H3C). 13C NMR (from HMBC, 150.3 MHz, CDCl3): d 168.46
(H3C–O–C]O), 153.03 (C-3), 132.52 (C-40), 131.74 (C-1), 127.05
(2C, C-60, C-20), 125.49 (2C, C-50, C-30), 82.71 (C-5), 76 (C-100),
60.06 (C-4), 46.68 (C-200), 40.43 (C-600), 33.98 (C-400), 31.35 (C-500),
25.78 (C-700), 20.41 (C-1000), 15.53 (C-900). HR-ESI-MS m/z calcd
for: C22H28F3NO3Na ¼ 434.1919. Found ¼ 434.1903.
C
20H26F3NO3: C 62.3, H 4.5%.
Isopropyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-
5-methyl-4-carboxylate (5d). A yellow oil; 1H NMR (200 MHz,
CDCl3): d 7.82 (d, J ¼ 8.1 Hz, 2H, H-50, H-30), 7.65 (d, J ¼ 8.1 Hz,
2H, H-60, H-20), 5.12 (m, 1H, H-5), 5.07 [m, 1H, O–CH–(CH3)2],
4.06 (d, J ¼ 6.6 Hz, 1H, H-4), 1.50 (d, J ¼ 6.6 Hz, 3H, CH3–CH),
1.18 (d, J ¼ 6.2 Hz, 3H), 1.15 (d, J ¼ 5.8 Hz, 3H). EI-MS m/z 315
(M+), 296 (M+ ꢀ F), 214 (M+ ꢀ CH3C]OOCH3 + H), 145
(F3CC6H4), 43 (–HC(CH3)2). Found: C, 57.3; H, 5.0. Calcd for
Menthyl 4-methyl-3-(4-triuoromethylphenyl)-4,5-dihydro-
isoxazole-5-carboxylate (diastereoisomers C and D) (6f). (C +
D): a yellow wax; IR (KBr, cmꢀ1): 2958, 2920, 2860, 1732, 1620,
1598, 1560, 1456, 1415, 1360, 1326, 1245, 1171, 1130, 1071,
1013, 932, 846, 780. C: 1H NMR (200 MHz, CDCl3): d 7.81 (d, J ¼
8.2 Hz, 2H, H-20, H-60), 7.67 (d, J ¼ 8.2 Hz, 2H, H-30, H-50), 4.79
(m, 1H, H-5), 4.78 (m, 1H, H-100), 3.96 (m, 1H, H-4), 1.66–0.40 (m,
H-4a00, H-3a00, H-800, H-6, H3C–, H-500, H-200, H-4b00, H-3b00, H-6b00,
H-700, H3C–, H-1000, H3C–, H-900, H3C).
C
15H16F3NO3: C 57.1, H 5.1%.
Isopropyl 3 (4-triuoromethylphenyl)-4,5-dihydroisoxazole-
4-methyl-5-carboxylate (6d). A yellow oil; 1H NMR (200 MHz,
CDCl3): d 7.82 (d, J ¼ 8.0 Hz, 2H, H-50, H-30), 7.68 (d, J ¼ 8.0 Hz,
2H, H-60, H-20), 5.09 [m, 1H, O–CH–(CH3)2], 4.78 (d, J ¼ 4.6 Hz,
1H, H-5), 4.00 (m, 1H, H-4), 1.52–1.16 (m, 9H). HR EI-MS calcd
for: C15H16F3NO3 ¼ 315.1082. Found ¼ 315.1082.
D: 1H NMR (200 MHz, CDCl3): 7.81 (d, J ¼ 8.2 Hz, 2H, H-20, H-
60), 7.67 (d, J ¼ 8.2 Hz, 2H, H-30, H-50), 4.81 (m, 1H, H-5), 4.63 (m,
1H, H-100), 3.92 (m, 1H, H-4), 1.66–0.40 (m, H-4a00, H-3a00, H-800,
H-6, H3C–, H-500, H-200, H-4b00, H-3b00, H-6b00, H-700, H3C–, H-1000,
H3C–, H-900, H3C). Found: C, 64.5; H, 6.7. Calcd for
Ethyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-5-decyl-
4-carboxylate (5e). A yellow oil; 1H NMR (200 MHz, CDCl3): d 7.82
(d, J ¼ 8.1 Hz, 2H, H-20, H-60), 7.65 (d, J ¼ 8.1 Hz, H, H-30, H-50),
4.99 (dt, J ¼ 6.6; 6.4 Hz, 1H, H-5), 4.18 (q, J ¼ 7.3 Hz, 2H, O–
CH2CH3), 4.13 (d, J ¼ 6.6 Hz, 1H, H-4), 1.90–1.10 (m, 14H), 0.88
(m, 6H, 2ꢁ H3C–CH2). EI-MS m/z (% intensity) 427 (M+, 5), 408
(M+ ꢀ 1F, 7), 354 (M+ ꢀ C]OOCH2CH3, 12), 286 (M+ ꢀ C10H21,
100), 214 (M+ ꢀ C]OOCH2CH3C10H21, 7), 187 (F3CC6H4CNO, 10),
145 (F3CC6H4, 8), 69 (CF3, 10). Found: C, 64.35; H, 7.4. Calcd for
C23H32F3NO3: C 64.6, H 7.55%.
C
22H28F3NO3: C 64.2, H 6.85%.
Methyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-5-
isopropyl-4-carboxylate (5g). A grey oil; IR (neat, cmꢀ1): 2964,
2930, 2860, 1743, 1619, 1598, 1560, 1470, 1437, 1412, 1395,
1340, 1326, 1170, 1128, 1071, 1016, 941, 860, 845, 770. 1H NMR
(200 MHz, CDCl3): d 7.82 (d, J ¼ 8.3 Hz, 2H, H-20, H-60), 7.65 (d,
J ¼ 8.3 Hz, 2H, H-30, H-50), 4.78 (dd, J ¼ 7.0; 6.6 Hz, 1H, H-5),
4.22 (d, J ¼ 7.0 Hz, 1H, H-4), 3.73 (s, 3H, H3C–O–C]O), 1.99
(septet, 1H, HC(CH3)2), 1.03 (d, J ¼ 6.9 Hz, 3H, (H3C)2CH), 1.0
(d, J ¼ 7.0 Hz, 3H, (H3C)2CH). EI-MS m/z (% intensity) 315 (M+,
20), 296 (M+ ꢀ F, 14), 212 (M+ ꢀ HC(CH3)2C]OOCH3, 100), 145
(F3CC6H4, 40), 59 (H3COC]O, 38), 43 (H–C(CH3)3, 67). Found:
C, 57.0; H, 5.3. Calcd for C15H16F3NO3: C 57.15, H 5.1%.
Ethyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-4-decyl-
5-carboxylate (6e). A yellow oil; 1H NMR (200 MHz, CDCl3): d 7.80
(d, J ¼ 8.4 Hz, 2H, H-20, H-60), 7.68 (d, J ¼ 8.4 Hz, H, H-30, H-50),
4.91 (d, J ¼ 3.8 Hz, 1H, H-5), 4.26 (q, J ¼ 7.2 Hz, 2H, O–CH2CH2),
3.93 (dt, J ¼ 7.4; 3.8 Hz, 1H, H-4), 1.80–1.10 (m, 14H, CH2–CH2–
CH2), 0.87 (m, 6H, 2ꢁ H3C–CH2). EI-MS m/z (% intensity) 427 (M+,
5), 408 (M+ ꢀ F, 5), 354 (M+ ꢀ C]OOCH2CH3, 100), 214 (M+ ꢀ C]
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6.5 Hz, 1H, H-5), 4.03 (d, J ¼ 6.5 Hz, 1H, H-4), 2.96 (m, 1H, H-13),
2.81–2.32 (m, 1H, H-9a, H-9b), 2.26–2.20 (m, 2H, H-10b, H-12a),
2.09–2.06 (m, 1H, H-10b), 1.50 (s, 3H, H3C), 1.65–1.20 (m, 9H, H-
12b, H-13, H-6, H3C–CH, H-16, H3C), 0.83 (s, 3H, H-15, H3C).
B: 1H NMR (500 MHz, CDCl3): d 7.79 (d, J ¼ 8.5 Hz, 2H, H-60,
H-20), 7.65 (d, J ¼ 8.5 Hz, 2H, H-50, H-30), 5.16 (d, J ¼ 6.5 Hz, 1H,
H-5), 4.05 (d, J ¼ 6.5 Hz, 1H, H-4), 2.8 (t, J ¼ 6.0 Hz, 1H, H-13),
2.81–2.32 (m, 2H, H-9a, H-9b), 2.26–2.20 (m, 2H, H-12a, H-10a),
2.03–2.00 (m, 1H, H-10b), 1.54 (s, 3H, H3C), 1.65–1.20 (m, 9H, H-
12b, H-13, H-6, H3C–CH, H-15, H3C), 0.81 (s, 3H, H-16, H3C).
(A + B) HR-ESI-MS calcd for: C22H24O4NF3Na ¼ 446.1555.
Found ¼ 446.1548.
isopropyl-5-carboxylate (6g). A yellow oil, IR (neat, cmꢀ1):
2963, 2930, 2852, 1760, 1744, 1619, 1600, 1560, 1466, 1430,
1412, 1370, 1326, 1170, 1129, 1070, 1017, 900, 883, 853, 770,
700. 1H NMR (CDCl3, 200 MHz): d 7.81 (d, J ¼ 8.3 Hz, 2H, H-20,
H-60), 7.67 (d, J ¼ 8.3 Hz, 2H, H-30, H-50), 4.98 (d, J ¼ 3.9 Hz, 1H,
H-5), 3.94 (t, J ¼ 3.9 Hz, 1H, H-4), 3.82 (s, 3H, H3C–OC]O), 2.19
(dm, J ¼ 7.0 Hz, 1H, HC(CH3)2), 1.09 (d, J ¼ 7.0 Hz, 3H,
(H3C)2CH), 0.79 (d, J ¼ 6.8 Hz, 3H, (H3C)2CH). EI-MS m/z 315 (%
intensity) (M+, 12), 296 (M+ ꢀ F, 14), 214 (M+ ꢀ HC(CH3)2C]
OOCH3 + H, 100), 145 (F3CC6H4, 30), 69 (F3C, 7). Found: C,
56.95; H, 4.95. Calcd for C15H16F3NO3: C 57.15, H 5.1%.
(+)-3-Pinanon-2-yl 4-methyl-3-(4-(triuoromethylphenyl)-4,5-
dihydroisoxazole-5 carboxylate) (diastereoisomers C and D)
(6j). A yellow oil; C: 1H NMR (500 MHz, CDCl3): d 7.78 (d, J ¼ 8.5
Hz, 2H, H-60, H-20), 7.68 (d, J ¼ 8.5 Hz, 2H, H-50, H-30), 4.72 (d,
J ¼ 4.5 Hz, 1H, H-5), 3.89 (d, J ¼ 4.5 Hz, 1H, H-4), 2.89 (t, J ¼ 6.0
Hz, 1H, H-13), 2.81–2.75 (m, 1H, H-9a, H-9b), 2.72–2.65 (m, 2H,
H-12a, H-10a), 2.15 (m, 1H, H-10b), 1.64 (s, 3H, H3C), 1.58–1.20
(m, 9H, H-12b, H-13, H-6, H3C–CH, H-15, H3C), 0.88 (s, 3H, H-
16, H3C) ppm.
Methyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-5-
(tert-butyl)-4-carboxylate (5h). A yellow oil; IR (neat, cmꢀ1):
2960, 2860, 1743, 1619, 1600, 1560, 1475, 1437, 1412, 1369,
1
1326, 1169, 1128, 1072, 1017, 943, 870, 845, 770, 695, 602. H
NMR (200 MHz, CDCl3): d 7.81 (d, J ¼ 8.2 Hz, 2H, H-20, H-60),
7.65 (d, J ¼ 8.2 Hz, 2H, H-30, H-50), 4.70 (d, J ¼ 7.2 Hz, 1H, H-5),
4.25 (d, J ¼ 7.2 Hz, 1H, H-4), 3.73 (s, 3H, H3C–O–C]O), 0.99 (s,
9H, (H3C)3C). EI-MS m/z (% intensity) 329 (M+, 18), 310 (M+ ꢀ F,
15), 213 (M+ ꢀ C(CH3)3C]OOCH3, 42), 212 (M+ ꢀ HC(CH3)3C]
OOCH3, 42), 187 (F3CC6H4CNO, 12), 145 (F3CC6H4, 15), 69 (F3C,
8), 57 (C(CH3)3, 100). Found: C, 58.65; H, 5.7. Calcd for
D: 1H NMR (500 MHz, CDCl3): d 7.78 (d, J ¼ 8.5 Hz, 2H, H-60,
H-20), 7.68 (d, J ¼ 8.5 Hz, 2H, H-50, H-30), 4.72 (d, J ¼ 4.5 Hz, 1H,
H-5), 3.96 (d, J ¼ 4.5 Hz, 1H, H-4), 2.81 (t, J ¼ 6.0 Hz, 1H, H-13),
2.81–2.32 (m, 1H, H-9a, H-9b), 2.26–2.10 (m, 2H, H-10a, H-12a),
2.02 (m, 1H, H-10), 1.65 (s, 3H, H3C), 1.59–1.20 (m, 9H), 0.87 (s,
3H, H-15, H3C).
C
16H18F3NO3: C 58.35, H 5.5%.
Methyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-4-
(tert-butyl)-5-carboxylate (6h). A yellow oil; IR (neat, cmꢀ1): 2926,
2852, 1741, 1618, 1600, 1550, 1468, 1430, 1411, 1380, 1325, 1170,
1
(C + D) HR-ESI-MS calcd for: C22H24O4NF3Na ¼ 446.1555.
1130, 1069, 1016, 880, 847, 770, 700, 630. H NMR (200 MHz,
CDCl3): d 7.80–7.60 (m, 4H, H-20, H-60, H-30, H-50), 5.07 (d, J ¼ 2.9
Hz, 1H, H-5), 3.76 (d, J ¼ 2.9 Hz, 1H, H-4), 3.81 (s, 3H, H3C–O–
C]O), 0.93 (s, 9H, (H3C)3C). EI-MS m/z (% intensity) 329 (M+,
10), 310 (M+ ꢀ F, 12), 214 (M+ ꢀ C(CH3)3C]OOCH3 + H, 100),
145 (F3CC6H4, 20), 69 (F3C, 5), 57 (C(CH3)3, 72). Found: C, 58.4;
H, 5.6. Calcd for C16H18F3NO3: C 58.35, H 5.5%.
Found ¼ 446.1558.
(3-Methyloxetan-3-yl)-methyl 3-(4-triuoromethylphenyl)-4,5-
dihydroisoxazole-5-methyl-4-carboxylate (5k). A green oil; 1H
NMR (200 MHz, CDCl3): d 7.82 (d, J ¼ 8.1 Hz, 2H, H-20, H-60), 7.66
(d, J ¼ 8.1 Hz, 2H, H-30, H-50), 5.20 (dq, J ¼ 6.5; 6.1 Hz, 1H, H-5),
4.29 (d, J ¼ 2.2 Hz, 2H, H-9), 4.27 (d, J ¼ 2.2 Hz, 2H, H-10), 4.21 (s,
2H, –O–CH2C), 4.17 (d, J ¼ 6.1 Hz, 1H, H-4), 1.50 (d, J ¼ 6.5 Hz,
3H, H3C–CH), 1.15 (s, 3H, H3C–C). 13C NMR (125.9 MHz, CDCl3):
d 168.86 (O–C]O), 152.59 (1C, C-3), 132.37 (1C, C-40), 124.79 (1C,
C-10), 127.12 (2C, C-60, C-20), 125.76 (q, J ¼ 3.8 Hz, 2C, C-50, C-30),
82.71 (1C, C-5), 79.13 (C-9), 79.09 (C-10), 70.25 (1C, –C–CH2–O),
59.52 (1C, C-4), 39.06 (1C, C-8, –C–), 20.76 (1C, H3C–C, C-11),
20.74 (1C, C-9, H3C–CH–). HR ESI-MS calcd for: C17H18O4NF3-
Na ¼ 380.1086. Found ¼ 380.1082.
Methyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-5-
cyclohexyl-4-carboxylate (5i). A yellow oil; IR (neat, cmꢀ1):
2930, 2856, 1743, 1620, 1596, 1560, 1520, 1451, 1435, 1411,
1324, 1260, 1175, 1129, 1070, 1017, 1000, 938, 895, 860, 846,
770, 690. 1H NMR (200 MHz, CDCl3): d 7.81 (d, J ¼ 8.2 Hz, 2H, H-
20, H-60), 7.65 (d, J ¼ 8.2 Hz, 2H, H-30, H-50), 4.78 (dd, J ¼ 6.7; 6.6
Hz, 1H, H-5), 4.25 (d, J ¼ 6.5 Hz, 1H, H-4), 3.72 (s, 3H, H3C–O–
C]O), 1.89–1.60 (m), 1.35–1.00 (m). EI-MS m/z (% intensity) 355
(M+, 23), 336 (M+ ꢀ F, 18), 314 (100), 272 (M+ ꢀ C6H11, 20), 213
(M+ ꢀ C6H11C]OOCH3, 35), 145 (F3CC6H4, 25), 83 (C6H11, 60).
HR EI-MS calcd for: C18H20F3NO3 ¼ 355.1395. Found ¼
355.1391.
(3-Methyloxetan-3-yl)-methyl 3-(4-triuoromethylphenyl)-4,5-
dihydroisoxazole-4-methyl-5-carboxylate (6k). A yellow oil; 1H
NMR (200 MHz, CDCl3): d 7.81 (d, J ¼ 8.2 Hz, 2H, H-20, H-60), 7.68
(d, J ¼ 8.2 Hz, 2H, H-30, H-50), 4.87 (d, J ¼ 4.1 Hz, 1H, H-5), 4.55–
4.15 (m, 4H, H-9, H-10), 4.31 (s, 2H, OCH2C), 4.05 (dd, J ¼ 7.2; 4.1
Hz, 1H, H-4), 1.44 (d, J ¼ 7.2 Hz, 3H, H3C–CH), 1.34 (s, 3H, H3C–
C). EI-MS m/z (% intensity) 358 (M+ + H, 2), 338 (M+ ꢀ F, 15), 228
(100), 157 (M+ ꢀ (CH2OCH2CCH3)CH2OC]O, 25), 145 (F3CC6H4,
35), 72 (H2COCH2CCH3 + H, 85). Found: C, 57.2; H, 4.35. Calcd
for C17H15F3NO4: C 57.15, H 4.25%.
Methyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-4-
cyclohexyl-5-carboxylate (6i). A yellow oil; 1H NMR (200 MHz,
CDCl3): d 7.80 (d, J ¼ 8.4 Hz, 2H, H-20, H-60), 7.67 (d, J ¼ 8.4 Hz,
2H, H-30, H-50), 5.02 (d, J ¼ 3.8 Hz, 1H, H-5), 3.91 (dd, J ¼ 3.8; 3.4
Hz, 1H, H-4), 3.80 (s, 3H, H3CO–C]O), 1.73 (m), 1.45–0.90 (m).
Found: C, 60.7; H, 5.8. Calcd for C18H20F3NO3: C 60.85, H 5.65%.
(+)-3-Pinanon-2-yl 5-methyl-3-(4-(triuoromethylphenyl)-4,5-
dihydroisoxazole-4-carboxylate) (diastereoisomers A and B)
Pyrrolidine-2,5-dione-1-yl
3-(4-triuoromethylphenyl)-4,5-
dihydroisoxazole-5-methyl-4-carboxylate (5l). A yellow oil; 1H
NMR (200 MHz, CDCl3): d 7.97–7.64 (m, 4H, H-20, H-60, H-30, H-
50), 5.23 (dq, J ¼ 7.0; 6.5 Hz, 1H, H-5), 4.39 (d, J ¼ 6.5 Hz, 1H, H-
1
(5j). A grey oil; A: H NMR (500 MHz, CDCl3): d 7.81 (d, J ¼ 8.5
Hz, 2H, H-60, H-20), 7.68 (d, J ¼ 8.5 Hz, 2H, H-50, H-30), 5.07 (d, J ¼
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4), 2.84 (m, 4H), 1.61 (d, J ¼ 7.0 Hz, 3H, H3C–CH). Found: C, CH]CH–O), 110.18 (C-8, C]CH–CH]CH–O), 80.61 (C-5),
51.7; H, 3.7. Calcd for C16H13F3N2O5: C 51.9, H 3.55%. 57.01 (C-4), 53.53 (H3CO–C]O). HR ESI-MS calcd for: C16H12
-
Pyrrolidine-2,5-dione-1-yl
3-(4-triuoromethylphenyl)-4,5- F3NO4Na ¼ 362.0616, Found ¼ 362.0610.
dihydroisoxazole-4-methyl-5-carboxylate (6l). A yellow oil; 1H
Methyl 4-(2-furyl)-3-(4-(triuoromethylphenyl)-4,5-dihydro-
1
NMR (200 MHz, CDCl3): d 7.82 (d, J ¼ 8.2 Hz, 2H, H-20, H-60), isoxazole-5-carboxylate) (6o). A yellow oil; H NMR (300 MHz,
7.67 (d, J ¼ 8.2 Hz, 2H, H-30, H-50), 4.99 (d, J ¼ 4.1 Hz, 1H, H-5), CDCl3): d 8.3–7.6 (m, 4H, H-20, H-60, H-30, H-50), 7.5–7.3 (m, 1H,
4.27 (dq, J ¼ 7.0; 4.1 Hz, 1H, H-4), 2.10–1.00 (m, 4H), 1.36 (d, J ¼ H-9), 6.54 (dm, J ¼ 3.3 Hz, 1H, H-7), 6.42 (dd, J ¼ 3.3; 1.9 Hz, 1H,
7.0 Hz, 3H, H3C–CH). EI-MS m/z (% intensity) 363 (M+, 2), 344 H-8), 5.67 (d, J ¼ 2.4 Hz, 1H, H-5), 5.51 (d, J ¼ 2.4 Hz, 1H, H-4),
(M+ ꢀ F, 2), 212 (M+ ꢀ H(CH3)C]OOCH2C6H5, 5), 145 3.76 (s, 3H, H3C–O–C]O). HR-EI-MS calcd for: C16H12F3NO4 ¼
(F3CC6H4, 50), 91 (H2CC6H5, 30), 83 (100). Found: C, 52.2; H, 339.0718. Found ¼ 339.0686.
3.8. Calcd for C16H13F3N2O5: C 51.9, H 3.55%.
Methyl 5-(1,3-benzodioxolyl)-3-(4-triuoromethylphenyl)-4,5-
1
Benzyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-5- dihydroisoxazole-4-carboxylate (5p). A yellow oil; H NMR (200
methyl-4-carboxylate (5m). A yellow oil; [a]2D5 ¼ ꢀ115.0 (c 0.45 MHz, CDCl3): d 7.74 (d, J ¼ 8.1 Hz, 2H, H-20, H-60), 7.56 (d, J ¼ 8.1
in acetone [93.2% ee, (R, S) rich]). IR (KBr, cmꢀ1): 3435, 2970, Hz, 2H, H-30, H-50), 6.79 (d, J ¼ 9.6. Hz, 1H, H-500), 6.78 (d, J ¼ 9.6
2930, 1738, 1619, 1599, 1499, 1456, 1412, 1377, 1327, 1169, Hz, 1H, H-600), 6.71 (s, 1H, H-300), 5.97 (m, 2H, H-700), 5.94 (m, 1H,
1128, 1071, 1014, 938, 909, 853, 756, 701. H NMR (200 MHz, H-5), 4.98 (s, 1H, H-4), 3.85 (s, 3H, H3CO–C]O). 13C NMR (50.3
1
CDCl3): d 7.72 (d, J ¼ 8.2 Hz, 2H, H-20, H-60), 7.55 (d, J ¼ 8.2 Hz, MHz, CDCl3): d 170.06 (H3CO–C]O), 157.15 (C-3), 148.15 (C-200),
2H, H-30, H-50), 7.27 (m, 2H, H-200, H-600), 7.14 (m, 3H, H-300, H-400, 147.87 (C-100), 132.75 (C-10), 131.93 (C-400), 131.50 (m, C-40), 127.78
H-500), 5.14 (m, 3H, ArCH2O and H-5), 4.12 (d, J ¼ 6.6 Hz, 1H, H- (C-60, C-20), 125.60 (m, 2C, C-50, C-30), 121.00 (C-600), 109.08 (C-500),
4), 1.49 (d, J ¼ 6.4 Hz, 3H, H3C–CH). EI-MS m/z (% intensity) 363 107.50 (C-300), 101.41 (C-700), 86.75 (C-5), 57.57 (C-4), 53.10
(M+, 23), 344 (M+ ꢀ F, 18), 212 (M+ ꢀ H(CH3)C]OOCH2C6H5, (H3CO–C]O). Found: C, 58.2; H, 3.5. Calcd for C19H14F3NO5: C
12), 145 (F3CC6H4, 15), 91 (H2CC6H5, 100). Found: C, 62.5; H, 58.0, H 3.6%.
4.1. Calcd for C19H16F3NO3: C 62.8, H 3.9%.
Methyl 4-(1,3-benzodioxolyl)-3-(4-triuoromethylphenyl)-4,5-
1
Benzyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-4- dihydroisoxazole-5-carboxylate (6p). A yellow oil; H NMR (200
methyl-5-carboxylate (6m). A yellow oil; 1H NMR (200 MHz, MHz, CDCl3): d 7.84 (d, J ¼ 8.2 Hz, 2H, H-20, H-60), 7.65 (d, J ¼ 8.2
CDCl3): d 7.81–7.53 (m, 5H) and 7.30–7.09 (m, 4H), 5.23 (s, 2H, Hz, 2H, H-30, H-50), 6.80 (m, 3H, H-300, H-500, H-600), 5.95 (m, 2H,
ArCH2–O), 4.85 (d, J ¼ 4.4 Hz, 1H, H-5), 3.96 (dq, J ¼ 7.2; 4.4 Hz, H-700), 5.94 (d, J ¼ 6.9 Hz, 1H, H-5), 4.46 (d, J ¼ 6.9 Hz, 1H, H-4),
1H, H-4), 1.41 (d, J ¼ 7.2 Hz, 3H, H3C–CH). Found: C, 62.7; H, 3.77 (s, 3H, H3CO–C]O). 13C NMR (50.3 MHz, CDCl3): d 169.41
3.8. Calcd for C19H16F3NO3: C 62.8, H 3.9%.
(H3CO–C]O), 152.83 (C-3), 148.51 (C-200), 148.31 (C-100), 132.92
Phenyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-5- (C-10), 132.2 (q, J ¼ 32.4 Hz, 1C, C-40), 127.43 (2C, C-60, C-20),
methyl-4-carboxylate (5n). A yellow oil; 1H NMR (200 MHz, 125.94 (q, J ¼ 3.6 Hz, 2C, C-50, C-30), 123.9 (q, J ¼ 272.3 Hz, Ar-
CDCl3): d 7.94–6.91 (m, 10H, H-20, H-30, H-40, H-50, H-60, H-200, H- CF3), 119.59 (C-600), 108.70 (C-500), 106.09 (C-300), 101.59 (C-700),
300, H-400, H-500, H-600), 5.33 (dm, J ¼ 6.4 Hz, 1H, H-5), 4.33 (d, J ¼ 87.66 (C-5), 61.30 (C-4), 53.48 (H3CO–C]O). HR ESI-MS calcd
6.4 Hz, 1H, H-4), 1.59 (d, J ¼ 6.4 Hz, 3H, H3C–CH). HR-EI-MS for: C19H14F3NO5Na ¼ 416.0722, found ¼ 416.0739.
calcd for: C18H14F3NO3 ¼ 349.0926. Found ¼ 349.0944.
(2Z)-Pent-2-en-1-yl acetate (7a).49 A yellow oil (35%). 1H NMR
Phenyl 3-(4-triuoromethylphenyl)-4,5-dihydroisoxazole-4- (200 MHz, CDCl3): d 5.71–5.42 (m, 2H, H3CCH2HC]CH), 5.88
methyl-5-carboxylate (6n). A yellow oil; 1H NMR (300 MHz, (dq, J ¼ 15.4; 1.7 Hz, 1H, O]CHC]C), 4.44 (d, J ¼ 6.6 Hz, 2H,
CDCl3): d 7.94–6.90 (m, 9H, aryl), 5.06 (d, J ¼ 4.3 Hz, 1H, H-5), OCH2CH]C), 2.10 (qd, J ¼ 7.3; 2.4 Hz, 2H, H3CCH2–CH]C),
4.17 (dq, J ¼ 7.2; 4.3 Hz, 1H, H-4), 1.51 (d, J ¼ 7.2 Hz, 3H, 2.04 (s, 3H, H3C–C]O), 0.99 (t, J ¼ 7.3 Hz, 3H, H3C–CH2).
H3C–CH). EI-MS m/z (% intensity) 349 (M+, 15), 330 (M+ ꢀ F, 10),
(2Z)-Pent-2-en-1-yl methoxyacetate (7b). A yellow oil (35%).
1H NMR (CDCl3, 200 MHz): d 5.80–5.20 (m, 2H, H2C–CH]CH–
273 (M+ ꢀ C6H5 + H, 5), 256 (M+ ꢀ C6H5O, 35), 228 (M+
ꢀ
C6H5OC]O, 100), 212 (M+ ꢀ H(CH3)OC]OC6H5, 20), 145 CH2), 4.72 (d, J ¼ 6.6 Hz, 2H, O]C–O–CH2–HC]C), 4.04 (s, 2H,
(F3CC6H4, 70). Found: C, 62.25; H, 4.2. Calcd for C18H14F3NO3: C OCH2–C]O), 3.45 (s, 3H, H3CO), 2.13 (m, J ¼ 7.5 Hz, 2H, C]
61.9, H 4.05%.
CH–CH2–CH3), 1.00 (t, J ¼ 7.5 Hz, 3H, H3CCH2). Found: C, 60.9;
Methyl 5-(2-furanyl)-3-(4-(triuoromethylphenyl)-4,5-dihy- H, 9.15. Calcd for C8H14O3: C 60.7, H 8.9%.
droisoxazole-4-carboxylate) (5o). A yellow oil; IR (KBr, cmꢀ1):
[5-Ethyl-3-(4-(triuoromethylphenyl)-4,5-dihydroisoxazol-4-
3440, 3130, 3010, 2970, 2840, 1745, 1620, 1600, 1560, 1500, yl)]methyl acetate (8a). A greenish oil; IR (KBr, cmꢀ1): 3436,
1437, 1413, 1326, 1300, 1250, 1220, 1170, 1160, 1131, 1070, 2964, 1746, 1635, 1619, 1450, 1400, 1385, 1337, 1324, 1238,
1014, 997, 921, 848, 830, 754. 1H NMR (200 MHz, CDCl3): d 7.89 1167, 1127, 1075, 1050, 980, 920, 937, 846, 775. H NMR (200
1
(d, J ¼ 8.2 Hz, 2H, H-20, H-60), 7.68 (d, J ¼ 8.2 Hz, 2H, H-30, H-50), MHz, CDCl3): d 7.90 (d, J ¼ 8.3 Hz, 2H, H-60, H-20), 7.68 (d, J ¼ 8.3
7.42 (dd, J ¼ 1.8; 0.6 Hz, 1H, H-9), 6.48 (dd, J ¼ 3.2; 0.6 Hz, 1H, Hz, 2H, H-50, H-30), 4.55 (dt, J ¼ 8.4; 6.4 Hz, 1H, H-5), 4.23 (dd,
H-7), 6.38 (dd, J ¼ 3.2; 1.8 Hz, 1H, H-8), 6.03 (d, J ¼ 6.4 Hz, 1H, J ¼ 11.9; 4.6 Hz, 1H, HC–HaC–OC]O), 4.20 (dd, J ¼ 11.9; 7.3 Hz,
H-5), 4.80 (d, J ¼ 6.4 Hz, 1H, H-4), 3.75 (s, 3H, H3CO–C]O). 13
C
1H, –HC–HbC–OC]O), 3.79 (ddd, J ¼ 8.4; 7.3; 4.6 Hz, 1H, H-4),
NMR (50.3 MHz, CDCl3): d 168.97 (H3CO–C]O), 152.92 (C-3), 2.00 (s, 3H, H3C–C]O), 1.92 (m, 2H, HC–CH2CH3), 1.16 (t, J ¼
150.04 (C-6, OC]CH), 143.97 (C-9), 132.15 (q, J ¼ 33.0 Hz, C- 7.4 Hz, 3H, H3C–CH2). EI-MS m/z (% intensity) 339 (M+ + H + Na,
40), 131.99 (C-10), 127.55 (2C, C-60, C-20), 125.94 (q, J ¼ 4.0 Hz, 2C, 20), 314 (M+ ꢀ 1H, 5), 296 (M+ ꢀ F, 5), 213 (M+ ꢀ CH3C]
C-50, C-30), 124.0 (q, J ¼ 272.3 Hz, Ar-CF3), 110.93 (C-7, C]CH– OOCH2C2H5, 10), 187 (F3CC6H4CNO, 85), 173 (100), 145
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(F3CC6H4, 45). Found: C, 54.5; H, 4.2. Calcd for C15H14F3NO4: C days depending on the growth rate of the control samples, aer
54.7, H 4.3%. which fungal growth was compared with that in untreated
[4-Ethyl-3-(4-(triuoromethylphenyl)-4,5-dihydroisoxazol-5- control samples. The fungicidal activity was expressed as the
yl)]methyl acetate (9a). A yellow oil; IR (KBr, cmꢀ1): 2972, 2940, percentage of fungi linear growth inhibition compared to that
2860, 1745, 1620, 1595, 1563, 1520, 1460, 1411, 1360, 1326, of the control.
1236, 1169, 1128, 1069, 1040, 1015, 920, 848, 778. 1H
NMR (CDCl3, 200 MHz): d 7.80 (d, J ¼ 8.3 Hz, 2H, H-20, H-60),
Acknowledgements
7.68 (d, J ¼ 8.3 Hz, 2H, H-30, H-50), 4.83 (ddd, J ¼ 9.1; 7.7; 4.2 Hz,
1H, H-5), 4.59 (dd, J ¼ 12.0; 4.2 Hz, 1H, H-6a), 4.42 (dd, J ¼ 12.0; This work was supported in part by the Polish Ministry of
7.7 Hz, 1H, H-6b), 3.66 (dt, J ¼ 9.1; 5.6 Hz, 1H, H-4), 2.15 (s, 3H, Science and Higher Education Research (Grant 410/E-142/S/
H3CC]O), 1.68 (m, 2H, H-7, CH–CH2–CH3), 0.92 (t, J ¼ 7.5 Hz, 2013), what is gratefully acknowledged. The authors thank Dr
3H, H-8, CH2–CH3). EI-MS m/z (% intensity) 316 (M+ + H, 2), 296 Łukasz Gorecki, Department of Bioorganic Chemistry, Faculty
´
(M+ ꢀ 1F, 10), 213 (M+ ꢀ CH3C]OOCH2C2H5, 50), 198 (100), of Chemistry, Wrocław University of Technology, Poland for a
187 (F3CC6H4CNO, 8), 145 (F3CC6H4, 32). Found: C, 54.55; H, generous sample of quinine diphosphate.
4.15. Calcd for C15H14F3NO4: C 54.7, H 4.3%.
[4-Ethyl-3-(4-triuoromethylphenyl)-4,5-dihydroisoxazol-5-
References
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CDCl3): d 8.10–7.66 (m, 4H, H-20, H-60, H-30, H-50), 4.23–3.20
(m, 4H, H-5, H-6a, H-6b, H-4), 4.01 (s, 2H, O]C–CH2–O), 3.35 (s,
3H, H3C–OC), 1.65 (m, 2H, H-7, CH–CH2CH3), 0.97 (t, J ¼ 7.2 Hz,
3H, H-8). Found: C, 53.4; H, 4.6. Calcd for C16H16F3NO5: C 53.5,
H 4.5%.
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