Enantioselective 1,3-dipolar cycloaddition reactions using chiral lanthanide catalysts

Article abstract of DOI:10.1002/jhet.5570450620

(Chemical Equation Presented) Regio- and stereoselective 1,3-dipolar cycloaddition of nitrile oxides to internal 2-pentenols, α,β- unsaturated esters and amides catalyzed by R-(+) BINOL-lanthanide complexes affords corresponding 3-aryl-2-isoxazolines with

Full text of DOI:10.1002/jhet.5570450620

Nov-Dec 2008
1687
Enantioselective 1,3-Dipolar Cycloaddition Reactions Using Chiral
Lanthanide Catalysts
W. Marek Goꢀꢁbiewski* and Mirosꢀaw Gucma
Institute of Industrial Organic Chemistry, 03-236 Warsaw, Poland
golebiewski@ipo.waw.pl
Received May 21, 2008
O
R
1
O
R
-
-
N
R-(+) BINOL Yb(OTf)3
N
R
R
1
+
R
R
1
C
N O
2
R
2
2
R
R
ee up to 89%
Regio- and stereoselective 1,3-dipolar cycloaddition of nitrile oxides to internal 2-pentenols, ꢀ,ꢁ-
unsaturated esters and amides catalyzed by R-(+) BINOL-lanthanide complexes affords corresponding 3-
aryl-2-isoxazolines with enantioselectivities up to 89% ee.
J. Heterocyclic Chem., 45, 1687 (2008).
INTRODUCTION
derivative, which allowed to achieve high regio- and
stereoselectivity [13].
We have just reported application of chiral lanthanide -
(-)-sparteine complexes as catalysts in 1,3-dipolar
cycloaddition of nitrile oxides to unsaturated alcohols,
where enantioselectivities up to 68% were obtained. [1]
This work is an extention of the previous research to a
different catalytic system and other dipolarophiles
resulting in a higher enantioselectivity of the reaction.
1,3-Dipolar cycloaddition of nitrile oxides to alkenes is
the most convenient method of preparation of useful
building blocks - 2-isoxazolines [2]. They can be easily
reduced to several synthetically important chain
compounds such as ꢁ-hydroxy ketones, ꢁ-hydroxy esters,
ꢀ,ꢁ-unsaturated carbonyl compounds or iminoketones [3].
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. Therefore synthetic application of 1,3-
dipolar cycloaddition remained for a long time rather
limited.
The second more promising approach relied on chiral
metal reagents and catalysts. Shortage of reports on metal
assisted 1,3-dipolar cycloadditions of nitrile oxides is due
to interference of catalyst with generation of these dipoles
and formation of unreactive complexes [14]. The other
difficulty is ascribed to relatively low-lying HOMO
energies of nitrile oxides as compared to nitrones [15].
Ukaji and Inomata performed first asymmetric metal-
catalyzed 1,3-dipolar cycloaddition reaction of nitrile
oxides to ꢂ-substituted allylic alcohols with diethylzinc as
a catalyst, and (R,R)-diisopropyl tartrate as the chiral
auxiliary [16]. Later they used N-sulfonylated (S,S)-2,3-
diaminosuccinate derivative as a chiral information [17].
Sibi modified a dipolarophile - crotonamide by attaching
an achiral template of pyrazolidinone type and used a
bulky chiral Lewis acid obtained from magnesium iodide
and bisoxazoline derivative achieving excellent regio- and
enantioselectivity [18a]. This approach was extended to
the reaction with ꢀ,ꢁ-disubstituted acryimides [18b]. Faita
and Quadrelli applied
a polymer supported chiral
Two methods have been used to solve these problems.
One approach was an application of optically active
reagents, much more often of dipolarophiles than dipoles
[4].
oxazolidin-2-one- magnesium catalyst [19].
Lanthanide catalysts are also an attractive solution [20].
Large lanthanide complexes, particularly triflate
derivatives, are mild Lewis acids [21]. In contrast to many
other Lewis acids lanthanide triflates are not deactivated
by basic nitrogen-containing compounds and their
stability in the presence of water enables repeated use
even in an organic-aqueous environment [22].
Lanthanides were successfully applied in the asymmetric
1,3-dipolar cycloaddition of nitrones and alkenes by two
groups. Jørgensen et al. applied chiral complex of
ytterbium triflate with 2,6-bis[4-(S)-isopropyl-2-oxazol-
idin-2-yl]pyridine (PyBOX) in cycloaddition to
One variant of this method was the use of chiral
auxiliaries temporarily linked usually by an ester or amide
bond to the dipolarophiles. Literature examples of ester
type groups were camphor [5] and menthol derivatives
[6]. As chiral amide derivatives were applied inter alia
Rebeck benzoxazole derivative [7], oxazoline derivatives
[8], oxazolidin-2-ones [9], imidazolidin-2-ones [10],
derivatives of proline benzyl ester [11], and as the most
effective Oppolzer’s camphorsultam [12] and its borane

1688
W. M. Goꢀꢁbiewski and M. Gucma
Vol 45
N-alkenoyloxazolidinones with enantioselectivities of up
to 73% [23]. Kobayashi et al. used a heterochiral catalyst
comprising ytterbium triflate, (S)-binaphthol (S-BINOL)
and chiral amine N-methyl-bis[(R)-1-phenylethyl]amine
((R)-MNEA) achieving enantioselectivities of up to 96%
[24]. Yamamoto et al. have just published asymmetric
1,3-dipolar cycloaddition of benzonitrile oxides to
acrylamides bearing chiral auxiliary of oxazolidinone and
imidazolidinone type and a chiral complex comprising
magnesium salt or ytterbium triflate as well as PyBOX
ligand in equimolar amounts [25]. The best
enantioselectivity was achieved at low temperature of -78
°C with magnesium bromide/ PyBOX system.
Unexpectedly in some cases higher enantioselectivities
were observed at room temperatures than at 0 °C.
Control of regio- and enantioselectivity of nitrile oxides
1,3-dipolar cycloaddition reaction is more difficult to for
steric and quantum-chemical reasons [26, 15], than is the
case for nitrones. Steric interaction between nitrile oxide
and dipolarophile is relatively small, since N atom is
unsubstituted and C atom of the dipole bears only a single
substituent, while in nitrones N atom is substituted and C
atom can be attached to two substituents. This situation
makes planning of new chiral auxiliaries and catalysts
more challenging.
oxides with a set of dipolarophiles in the presence of
lanthanide- BINOL system as a catalyst. BINOL is a
versatile chiral reagent for which application in synthesis
has been recently reviewed [27]. First we studied a reaction
of aryl nitrile oxides with 2-penten-1-ols using racemic
BINOL and different lanthanide triflates, solvents, and
bases to generate nitrile oxides from the corresponding
hydroximinoyl chlorides. A preferred way to obtain the
dipole was passing a hydroximinoyl chloride solution
through a column of Amberlyst 21 [18]. From the several
tested catalyst systems one formed from BINOL and
anhydrous ytterbium triflate was most promising as far as
regioselectivity and yield of the reaction was concerned in
comparison to praseodymium, scandium, and ytterbium
triflate hydrate, similarly as in experiments with sparteine.
In contrast, however, to our previous work [1] the best
results were obtained with small amounts of molar 10-20%
of the catalyst, as compared to equimolar amounts required
by sparteine-lanthanide system to achieve satisfactory yield
and selectivity. An increase in the catalyst proportion
resulted in a better yield and regioselectivity of the reaction
(Table, 1 entry 1 and 4). In case of sparteine-mediated
reaction a reversal of regioselectivity was observed, when
catalyst amount was increased twice [1].
The effect of diethyl ether and dichloromethane on
regiochemistry was most pronounced as compared to the
other solvents, such as acetonitrile, toluene or DMF, and
the regioisomer-4 was favored in both of the components,
solvents. An exception was the reaction run in
dichloromethane, where regioisomer-5 was favored.
RESULTS AND DISCUSSION
In continuation of our efforts to improve regioselectivity
and enantioselectivity of the cycloaddition reaction we
present the results of the reaction of a series of nitrile
Scheme 1
O
N
C
O
CH OH
O
Et
2
N
N
R
R-(+)-BINOL-Yb(OTf)3
HOCH
2
Et
+
+
CH OH
2
Et
1
R
R
3
4
2
R = CF3, Et, iPr, OMe
Table 1
Reactions with BINOL-(R)-Yb(OTf)3 catalyst and different dipoles and 2-penten-1-ols.
Entry
1
R
Solvent
Cat.
Yield
%
41
43
47
64
68
61
27
3:4 ratio
3 ee
%
4 ee
%
1a
2
Z
Z
Z
Z
E
Z
E
Z
CF3
CF3
CF3
CF3
CF3
i-Pr
i-Pr
OMe
Et2O
Et2O
CH2Cl2
Et2O
Et2O
Et2O
CH2Cl2
Et2O
10%
10%
10%
20%
10%
10%
-
1:1.9
1:1.4
1:2
60
30
28
45
70
48
-
18
18
16
68
60
71
-
3
4a
5
1:3
1.4:1
1:2.9
1.7:1
0:100
6
7
8a
10%
49
-
73
a Dipolarophile was added after dipole.

Nov-Dec 2008
Enantioselective 1,3-Dipolar Cycloaddition Reactions Using Chiral Lanthanide Catalysts
1689
Scheme 2
HOCH
2
O
CH OH
2
Et
O
O
R-(+)-BINOL-Yb(OTf)3
N
N
R
CH OH
2
N
R
Et
CH OH
2
Et
R
C N O
Et
+
2
R
Reactions carried out with sparteine-triflate catalyst in
ether were more regioselective than those in
dichloromethane, though yields were lower [1].
Reactions of the alkenes with electron-donating
substituents and moderately electron-withdrawing
substituents (ester group) are controlled by LUMOdipol
–
Reaction of aryl nitryl oxides with Z- and E-2-penten-1-
ol in the presence of chiral R-(+) BINOL-ytterbium
triflate complex was next examined (Scheme 1, Table 1).
The degree of chiral induction depended on addition order
of the components, on dipole substitution pattern, and on
dipolarophile configuration. It was higher when
dipolarophile was added after the dipole (entries 1, 4, 8),
similarly as in experiments mediated by sparteine
complex. Electron-donating substituents in the dipole
facilitated chirality transfer from both the catalytic
systems. Regioisomer-4 was favored for Z-pentenol and
in reaction of 4-methoxybenzonitrile was the only
detected form showing the best enantioselectivity with ee
of 73% (reaction 8). In case of E-2-penten-1-ol (entries 5
and 7) regioisomer-5 was favored and E-2-pentenol
showed higher ee than Z-counterpart.
The idea of metal catalyst application is based on the
preferential coordination of one partner of the reaction,
which results in lowering its Frontier Molecular Orbitals
(FMOs). As a consequence a relevant HOMO-LUMO
energy gap decreases, overlap of FMOs is enhanced and
the catalyzed reaction is accelerated. If both reaction
partners were coordinated resultant lowering of all FMOs
would not be so unequivocal for acceleration of the
cycloaddition, though Kanemasa reported calculations on
interaction of magnesium alkoxide with allyl alcohol and
formonitrile oxide, where FMOs of the dipole were
lowered, and those of the dipolarophile were raised [14].
HOMOalkene interaction since LUMOalkene – HOMOdipol
energy gap is higher [28]. This corresponds to a preferred
coordination of the nitrile oxide to ytterbium, as witnessed
by our observation, that regioselectivities were higher,
when dipole was added before dipolarophile to the
catalyst. Results of the reaction for E-2-pentenol (Table 1,
entry 5) could be rationalized by a proposed Scheme 2,
where E-pentenol is hydrogen-bonded to the BiNOL OH
group. Direction of the asymmetric induction follows
from the geometry of a transient, presumably, octahedral
complex of ytterbium triflate, where the si-face of
pentenols is shielded by hydrogen-bonded solvent
molecule (diethyl ether) – axially twisted BINOL moiety.
As a consequence an attack of nitrile oxide occurs from
the pentenols re-face. The absolute configuration of 4-
ethyl-5-hydroxymethyl-3-(4-trifluoromethyl)phenyl-2-
isoxazoline (Table 1, entry 5) was proposed to be 4R,5R
by comparison of specific optical rotation with that of an
analogous compound [16a].
We examined next application of the chiral lanthanide
catalyst in the enantioselective cycloaddition reaction of aryl
nitrile oxides to electron-deficient dipolarophiles,
unsaturated esters (Scheme 3, Table 2). It was gratifying to
find unexpectedly high ee of 89% for regioisomer 4 (Table
2, entry 5) in a reaction with 10% load of the catalyst.
The examined esters included 2-pentenecarboxylates,
crotonates, and methyl acrylate. Regioselectivity of the
reaction depended on steric demands of the ester function
Scheme 3
O
N
C
1
+
O
CO R
O
R
2
R
N
N
-
-
R-(+) BINOL Yb(OTf)3
1
+
CO R
1
2
CO R
2
5
R
2
R
6
7
2
2
R
R
2
1
2
R = Et, Me, H; R = Et, Me, tBu; R = CF , Cl , iPr, OMe
3
n

1690
W. M. Goꢀꢁbiewski and M. Gucma
Vol 45
Table 2
Reactions with BINOL-(R)-Yb(OTf)3 catalyst and different dipoles and esters
Entry
R
R1
R2
Cat.
Yield
%
6:7 ratio
6 ee
%
-
-
-
7 ee
%
-
-
-
85
89
-
65
77
45
56
1
2
3
4
5
6
7
8
9
10
Et
Me
Et
Et
Me
H
Me
Me
Me
Me
Me
Et
t-Bu
Me
Me
Me
4-CF3
2,3,6-Cl3
4-CF3
4-CF3
4-CF3
4-CF3
4-CF3
2,4-Cl2
4-i-Pr
-
-
70
64
63
49
68
92
51
68
28
91
1:2.1
1:3
a
Yb(OTf)3
10%
10%
10%
10%
10%
10%
10%
1:1.9
1:2.5
1.6:1
100:0
1:100
1:2
6
25
34
-
20
-
Et
Me
Me
Me
1:32
1:14
4-OMe
56
a Without BINOL.
(was excellent in case of t-butyl ester) and character of the
dipole substituents. Reactions with nitrile oxides bearing
electron-withdrawing substituents were less regioselective
than reactions with dipoles bearing electron-donating
substituents (Table 2, entries 9-10). In all cases, apart
from acrylate and methyl crotonate (entries 5 and 6),
regioisomer-4 was favored.
Degree of the chiral induction was related to structure of
the reagents and as opposed to the reactions of pentenols
dipoles bearing electron-withdrawing substituents showed
higher ee than dipoles with electron-donating groups
(entries 9-10). High level of enantioselectivity of the
reaction is more difficult to explain than in the reactions of
pentenols. In the transition state nitrile oxide is probably
coordinated to the axially chiral lanthanide catalyst and the
dipole attacks the re-face of the dipolarophile, similarly as
in case of pentenols affording presumably (4R,5S)-5-
ethyl(methyl)-4-carboxylates.
The effect of the catalyst was most pronounced in case
of amides, which were the next examined dipolarophiles.
Cycloaddition of arylbenzonitrile to electron-deficient
amides such as aromatic amines derivatives 8 and 9 as
well as (S)-4-benzyl-3-((E)-pent-2-enoyl)-oxazolidin-2-
one (11) (Scheme 4) was next examined. Reaction carried
out in the presence of triethyl amine was not efficient
(yield below 10%). Much more success was achieved in
the process performed in the presence of the chiral
catalytic lanthanide
-
(R)-BINOL complex with
compound 11. Dipolarophile with a chiral auxiliary group
was prepared starting from the commercial L-phenyl-
alanine following a described protocol [29,30]. The
aminoacid was esterified with methanolic HCl, then crude
iminoester was acylated with ethyl chloroformate and the
ester group was reduced with calcium borohydride formed
in situ from sodium borohydride and calcium chloride.
The obtained alcohol was cyclised in the presence of
Scheme 4
Cl
Cl
Cl
O
O
N
Et
NH
NO
2
Et
O
NH
9
8
Cl
O
O
O
HN
Et
N
O
R-(+)-BINOL-Yb(OTf)3
E-EtCH=CHCOCl
R
C N O
10
11
2
O
O
O
CO Me
2
O
N
N
N
O
K CO
2
3
Mg (OCH )
3 2
Et
Et
F C
3
F C
3
12
6a
Amides as dipolarophiles in cycloaddition reaction.

Nov-Dec 2008
Enantioselective 1,3-Dipolar Cycloaddition Reactions Using Chiral Lanthanide Catalysts
1691
5: IR (neat) 3410, 2960, 1760, 1618, 1410, 1329, 1240, 1211,
potassium carbonate to oxazolidinone-2 analog 10, which
was then acylated with (E)-2-pentenecarboxylic acid
chloride after conversion to the corresponding lithium
imide to afford N-pentenoyl derivative 11 [31]. The
suggested transition state of the cycloaddition reaction
with nitrile oxide involves coordination of the bidentate
ligand, oxazolidinone-2, which is more favored, than
coordination of the dipole, as established for reactions
with participation of nitrones [32]. This coordination is
accompanied by substitution of one triflate group, which
occurs readily due to kinetic lability of lanthanide-X
bonds and easy exchange of ligands [20]. Because re-face
approach of the dipole is hindered by a proximate chiral
ꢀ-benzyl group preferential attack of nitrile oxide follows
from the more exposed upper si-face of the dipolarophile
olefinic bond resulting in formation of 5-isoxazolidine
amide 12 with 4R,5R, S-benzyl configuration of the major
diastereoisomer. The chiral auxiliary was removed with
methanolic magnesium methoxide affording chiral
isoxazolidine ester with ee 77% [33].
1
1167, 1124, 1071, 1027, 893, 850, 626 cm-1; H NMR (CDCl3,
200 MHz ꢁ 7.81 (d, J = 8.6 Hz, 2 H, H-5’, H-3’), 7.66 (d, J = 8.6
Hz, 2 H, H-2’, H-6’), 4.94 (d, J = 4.1 Hz, 1 H, H-5), 3.94
(quintuplet, J = 4.1 Hz, 1 H, H-4), 3.82 (s, 3 H, CH3O), 1.77 (m,
J = 7.3 Hz, 2 H), 1.00 (t, J = 7.3 Hz, 3 H). Anal. Calcd. for
C14H14F3NO3: C, 55.82, H, 4.68. Found: C, 55.73, H, 4.69.
Regioisomer-4: IR (neat) 3430, 2969, 1744, 1620, 1440, 1412,
1
1325, 1169, 1128, 1071, 1020, 930, 845, 600 cm-1; H NMR
(CDCl3, 200 MHz) ꢁ 7.82 (d, J = 8.6 Hz, 2 H, H-3’, H-5’), 7.68
(d, J = 8.6 Hz, 2 H, H-2’, H-6’), 4.96 (q, J = 6.3 Hz, 1 H, H-5),
4.15 (d, J = 6.3 Hz, 1 H, H-4), 3.73 (s, 3 H, CH3O), 1.79 (m, 2
H), 1.04 (t, J = 7.3 Hz, 3 H). Anal. Calcd. for C14H14F3NO3: C,
55.82; H, 4.68. Found: C, 55.74; H, 4.40.
Methyl 3-(2,3,6-trichlorophenyl)-4-methyl-4,5-dihydrois-
oxazole-5-carboxylate (6c) and methyl 3-(2,3,6-trichloro-
phenyl)-5-methyl-4,5-dihydroisoxazole-4-carboxylate
Isomer–5: IR (neat) 2955, 1746, 1570, 1437, 1393, 1300, 1210,
(7c).
1
1179, 1100, 1021, 890, 817 cm-1; H NMR (CDCl3, 200 MHz) ꢁ
7.48 (d, J = 8.7 Hz, 1 H, H-4'), 7.33 (d, J = 8.7 Hz, 1 H, H-5'),
4.84 (d, J = 6.6 Hz, 1 H, H–5), 4.15 (d, J = 6.6 Hz, 1 H, H-4),
3.86 (s, 3 H, CH3O), 1.33 (d, J = 6.6 Hz, 3 H). Anal. Calcd. for
C13H12Cl3NO3: C, 46.39; H, 3.59. Found: C, 46.10; H, 3.44.
Isomer–4: IR (neat) 2940, 1743, 1560, 1440, 1400, 1210, 1190,
110, 1022, 920, 820, 780, 730 cm-1; 1H NMR (CDCl3, 200 MHz)
ꢁ 7.49 (d, J = 8.7 Hz, 1 H, H-4'), 7.34 (d, J = 8.7 Hz, 1 H, H-5'),
5.36 (quintuplet J = 6.7 Hz, 1 H, H-5), 4,15 (d, J = 6.7 Hz, 1 H,
H-4), 3.64 (s, 3 H, CH3O), 1.55 (d, J = 6.7 Hz, 3 H). Anal.
Calcd. for C13H12Cl3NO3: C, 46.39; H, 3.59. Found: C, 46.22; H,
3.51.
Ethyl 3-(4-trifluoromethylphenyl)-4,5-dihydroisoxazole 5-
carboxylate (7d) [35]. This compound was obtained as an oil;
IR (neat) 3040, 2998, 2840, 1741, 1331, 1224, 1164, 841 cm-1;
1H nmr (CDCl3, 200 MHz): ꢁ 7.79 (d, J = 8.5 Hz, 2H, H-3', H-
5'), 7.67 (d, J = 8.5 Hz, 2H, H-2', H-6'), 5.22 (dd, J = 11.0; 8.5
Hz, 1H, H-5), 4.28 (q, J = 7.0 Hz, 2H, CH2), 3.67 (d, J = 8.5 Hz,
1H, H-4a), 3.65 (d, J = 11.0 Hz, 1H, H-4b), 1.33 (t, J = 7.0 Hz,
3H, CH3).
tert-Butyl 3-(4-trifluoromethylphenyl)-4,5-dihydroisoxa-
zole-5-ethyl-4-carboxylate (7e). This compound was obtained
as an oil; IR (neat) 3204, 2904, 1740, 1675, 1600, 1520, 1470,
1326, 1225, 1180, 1131, 1067, 1016, 860, 760, 700, 600 cm-1; 1H
NMR (CDCl3, 200 MHz) ꢁ 7.97 (d, J = 8.4 Hz, 1 H, H-3', H-5'),
7.79 (d, J = 8.4 Hz, 1 H, H-2', H-6'), 5.13 (m, 1 H, H-5), 4.41 (d,
J = 6.4 Hz, 1 H, H-4), 2.17 (s, 9 H, tBu), 1.83 (m, 2 H), 1,12 (m,
3 H). Anal. Calcd. for C17H20F3NO3: C, 59.47; H, 5.87. Found:
C, 59.27; H, 6.12.
EXPERIMENTAL
Reagent grade chemicals were used without further
purification unless otherwise noted. Spectra were obtained as
follows: IR spectra on JASCO FTIR-420 spectrometer, 1H NMR
spectra on Varian 500 UNITY plus-500 and Varian 200 UNITY
plus 200 spectrometers in deuterated chloroform using TMS as
internal standard, EI mass spectra on AMD M-40 spectrometer.
Elemental analyses were performed at Microanalysis Laboratory
of Institute of Organic Chemistry, Polish Academy of Sciences,
Warsaw. Flash-chromatography was carried out using silica gel
S 230-400 mesh (Merck).
Hydroximinoyl acid chlorides were prepared from the
corresponding aryl aldehyde oximes and NCS in DMF [15]. The
corresponding nitrile oxides were generated in situ by
dehydrohalogenation with triethylamine or on Amberlyst A-21
column [7].
[4/5-Ethyl-3-aryl)-4,5-dihydroisoxazol-5/4-yl]methanols
(3/4a,b,c Table 1, entry 1, 6, 8) and methyl 3-(4-trifluoro-
methylphenyl)-4-methyl-4,5-dihydroisoxazole-5-carboxylate (6b)
and its regioisomer (7b) (Table 2, entry 2) have been described
before [1].
General procedure for the cycloaddition reactions. A
mixture of (R)-BINOL (0.10 mmol), Yb(OTf)3 (0.10 mmol) in
dry dichloromethane was stirred at r.t. for 30 min. Dipolarophile
(1 mmol) was added drop-wise followed by a solution of dipole
in the same solvent generated by passing a hydroximinoyl
chloride solution through a column of Amberlyst 21 over 20-30
min. The solution was stirred at r. t. for ca. 19 h, and water was
added to quench the reaction followed by a usual work-up. The
crude product was purified by flash column chromatography on
silica gel and the enantiomeric excess of separated regioisomers
was determined by HPLC analysis (Astec Cyclobond I 2000
RN).
Methyl 3-(2,4-dichlorophenyl)-4-methyl-4,5-dihydroisoxa-
zole-5-carboxylate (6f and methyl 3-(2,4-dichlorophenyl)-5-
methyl-4,5-dihydroisoxazole-4-carboxylate (7f). These
compounds were obtained as oils. Isomer–5: IR (neat) 3050,
2930, 1740, 1619, 1597, 1517, 1469, 1440, 1385, 1350, 1320,
1
1270, 1220, 1184, 925, 860, 824, 749 cm-1; H NMR (CDCl3,
200 MHz) ꢁ 7.40 (m, 3 H, H-6', H-5', H-3'), 4.80 (d, J = 7.1 Hz,
1 H, H-5), 4.02 (quintuplet, J = 7.1 Hz, H-4), 3.85 (s, 3 H,
CH3O), 1.23 (d, J = 7.1 Hz, 3 H). Anal. Calcd. for C13H13Cl2NO3:
C, 51.68; H, 4.34. Found: C, 51.96; H, 4.47. Isomer–4: IR (neat)
2950, 1743, 1620, 1587, 1480, 1440, 1380, 1203, 1103, 1014,
1
900, 822, 800 cm-1; H NMR (CDCl3, 200 MHz) ꢁ 7.54 (d, J =
Methyl 3-(4-trifluoromethylphenyl)-4-ethyl-4,5-dihydrois-
oxazole-5-carboxylate (6a) and methyl 3-(4-trifluoromethyl-
phenyl)-5-ethyl-4,5-dihydroisoxazole-4-carboxylate (7a).
These compounds were obtained as colorless oils. Regioisomer-
8.4 Hz, 1 H, H-6'), 7.44 (d, J = 2.2 Hz, 1 H, H-3'), 7.30 (dd, J =
8.4; 2.2 Hz, 1 H, H-5'), 5.08 (quintuplet, J = 6.8 Hz, 1 H, H-5),
4.46 (d, J = 6.8 Hz, H-4), 3.65 (s, 3 H, CH3O), 1.55 (d, J = 6.8

1692
W. M. Goꢀꢁbiewski and M. Gucma
Vol 45
Hz, 3 H). Anal. Calcd. for C13H13Cl2NO3: C, 51.68; H, 4.34.
Found: C, 51.87; H, 4.22.
oxazolidin-2-one (12) and 4-benzyl-3-[5-ethyl-3-(4-trifluoro-
methyl-phenyl)-4,5-dihydro-isoxazole-4-carbonyl]-oxazolidin-
2-one (13). The reaction was carried out in diethyl ether for 8
days and afforded product in 55% yield as a mixture of oily
regioisomers 5/4 in 3:1 ratio. Regioisomer–5: [ꢂ]D= + 113,5 (c
0.7, acetone); IR (neat) 2931, 1783, 1704, 1392, 1327, 1220,
1170, 1125, 1069, 1020, 900, 846, 704 cm-1; 1H NMR (CDCl3) ꢀ
7.85 (d, J = 8.3 Hz, 2 H, H-6', H-2'), 7.68 (d, J = 8.3 Hz, 2 H, H-
5', H-3'), 7.26 (m, 5 H), 5.98 (dd, J = 10.5; 3.3 Hz, 1 H, H-5),
4.68 (m, 1 H, NCH(CH2)2), 4.31 (m, 2 H, OCH2), 4.00 (m, 1 H,
H-4), 3.31 (m, 1 H, H –12b, ArCH2), 2.84 (m, 1 H, H-12a,
ArCH2), 1.88 (m 2 H), 0.94 (t, J = 7,5 Hz, 3 H); EIMS m/z (%)
446 (M+, 5), 417 (M+ -Et), 242 (CF3C6H4CNOCHCHC2H5, 100),
214 (CF3C6H4CNOCHCH, 50). Anal. Calcd. for C24H26N2O4: C,
61.88; H, 4.74. Found: C, 61.61; H, 4.98. Regioisomer-4: [ꢂ]D=
+ 25.4 (c 0.5, acetone); IR (neat) 3040, 2960, 1779, 1683, 1616,
1598, 1510, 1471, 1440, 1382, 1321, 1278, 1250, 1220, 1178,
1150, 1125, 980, 860, 827, 751, 700, 670 cm-1; 1H NMR
(CDCl3) ꢀ 7.99 (d, J = 8.7 Hz, 2 H, H-6', H-2'), 7.65 (d, J = 8.7
Hz, 2 H, H-5', H-3'), 7.28 (m, 5 H), 5.42 (d, J = 4.2 Hz, 1 H, H-
4), 4.71 (m, 2 H, H-5, H-10), 4.32 (dd, J = 6.8; 4.6 Hz, 1 H, H-
6a -OCH2), 4.19 (dd, J = 6.8; 3.6 Hz, 1 H, H-6b OCH2), 3.30
(dd, J = 13.3; 3.0 Hz, 1 H, H-12a ArCH2), 2.85 (dd, J = 13.3; 9.2
Hz, 1 H, H-12b ArCH2), 1.86 (q, J = 7.4 Hz, 2 H), 1.05 (t, J =
7.4 Hz, 3 H). Anal. Calcd. for C24H26N2O4: C, 61.88; H, 4.74.
Found: C, 61.72; H, 4.93.
Methyl 3-(4-isopropylphenyl)-4,5-dihydroisoxazole-4-methyl-
5-carboxylate (6g) and methyl 3-(4-isopropylphenyl)-4,5-
dihydroisoxazole-5-methyl-4-carboxylate (7g). These
compounds were obtained as oils. Isomer–5: IR (KBr) 2970,
1730, 1617, 1600, 1517, 1466, 1380, 1270, 1214, 1148, 815, 747
cm -1; Isomer–4: IR (KBr) 2961, 1741, 1611, 1514, 1435, 1420,
1
1340, 1310, 1252, 1125, 1100, 1023, 923, 838, 575 cm-1; H
NMR (CDCl3, 200 MHz) ꢀ 7.63 (d, J = 8.5 Hz, 2 H, H–2', H–6'),
7.25 (d, J = 8.5 Hz, 2 H, H–5', H–3'), 5.07 (quintuplet, J = 6.2
Hz, 1 H, H–5), 4.07 (d, J = 6.2 Hz, 1 H, H–4), 3.72 (s, 3 H,
CH3OCO), 2.94 (septuplet, J = 7.0 Hz, 1 H, CH(CH3)2), 1.44 (d,
J = 6.2 Hz, 3 H), 1.25 (d, J =7.0 Hz, 6 H). Anal. Calcd. for
C15H19NO3: C, 68.94, H, 7.33. Found: C, 69.19; H, 7.56.
Methyl 3-(4-methoxyphenyl)-4-methyl-4,5-dihydroisoxa-
zole-5-carboxylate (6h) and methyl 3-(4-methoxyphenyl)-5-
methyl-4,5-dihydroisoxazole-4-carboxylate (7h). These
compounds were obtained as oils. Isomer–5: IR (neat) 2955,
1740, 1606, 1516, 1457, 1350, 1300, 1258, 1210, 1180, 1070,
1
1019, 880, 837, 700 cm -1; H NMR (CDCl3, 200 MHz) ꢀ 7.63
(d, J = 9.1 Hz, 1 H, H- 5', H-3'), 6.92 (d, J = 9.1 Hz, 2 H, H-6',
H-2'), 4.77 (d, J = 3.8 Hz, 1 H, H-5), 4.04 (m, 1 H, H-4), 3.93 (s,
3 H, CH3OCO), 3.80 (s, 3 H, CH3OPh), 1.42 (d, J = 6.5 Hz, 3
H). Isomer–4: 1H NMR (CDCl3, 200 MHz) ꢀ 7.64 (d, J = 6.8 Hz,
2 H, H-2', H-6'), 6.91 (d, J = 6.8 Hz, 2 H, H-5', H-3'), 5.06
(quintuplet, J = 6.2 Hz, 1 H, H-5), 4.06 (d, J = 6.2 Hz, 1 H, H-4),
3.83 (s, 3 H, CH3OCO), 3.71 (s, 3 H, CH3OPh), 1.45 (d, J = 6.2
Hz, 3 H). Anal. Calcd. for C13H15NO4: C, 62.64, H, 6.07. Found:
C, 62.89, H, 6.16.
Removal of chiral auxiliary. Methyl 3-(4-trifluoromethyl-
phenyl)-4-ethyl-4,5-dihydroisoxazole-5-carboxylate (6a) [33].
Methanolic 6% solution of magnesium methoxide (0.1 mL, 0.07
mmol) was added to a solution of amide 12 (0.012 g, 0.027
mmol) in methanol (1.5 mL). The mixture was stirred for 30
min. at r.t., water was added and product was extracted with
CH2Cl2 (4 x 5 mL). The combined organic extracts were washed
with brine, dried and purified by flash-chromatography. Yield
7.4 mg (91%), [ꢂ]D25= + 127.0 (c 0.5, acetone), ee 77%.
(E)-Pent-2-enoic acid (4,6-dichloropyrimidin-2-yl)-amide
(8). This compound was obtained as an oil. IR (neat) 3395,
3220, 3100, 2960, 1694, 1644, 1542, 1500, 1410, 1300, 1250,
1
1210, 1164, 1103, 823, 780 cm-1; H NMR (CDCl3) ꢀ 8.70 (s, 1
H, NH), 7.23 (dt, J = 15.4; 6.1 Hz, 1 H, CH2CH=C), 7.05 (s, 1
H, H-5'), 6.61 (dt, J = 15.4, 1.7 Hz, 1 H, OCCH=C), 2.30 (qd, J
= 7.4; 1.8 Hz, 1 H), 2.33 (qd, J = 6.8; 1.8 Hz, 1 H), 1.14 (d, J =
6.8 Hz, 1 H), 1.10 (d, J = 7.4 Hz, 2 H). ). Anal. Calcd. for
C9H9Cl2N3O: C, 68.94, H, 7.33. Found: C, 69.19; H, 7.56.
(E)-Pent-2-enoic acid (2,6-dichloro-4-nitrophenyl)-amide
(9). This compound was obtained as an oil. IR (KBr) 3233,
3100, 2990, 1672, 1649, 1506, 1390, 1346, 1190, 812, 740 cm -1;
1H NMR (CDCl3) ꢀ 8.26 (s, 2 H, H–3', H-5'), 7.19 (s, 1 H, NH),
7.15 (dt, J = 15.3; 6.2 Hz, 1 H, CH2CH=C), 6.04 (dt, J = 15.3,
1.7 Hz, 1 H, OCCH=C), 2.32 (qd, J = 6.7; 1.7 Hz, 1 H), 2.30
(qd, J = 7.4 Hz, 1 H), 1.14 (t, J = 6.7 Hz, 1 H), 1.10 (t, J = 7.4
Hz, 2 H). Anal. Calcd. for C11H10Cl2N2O3: C, 47.70, H, 3.49.
Found: C, 47.53; H, 3.38.
Acknowledgements. This work was supported in part by the
Polish Ministry of Science and Higher Education Research
(Grant 429E-142/S/07), what is gratefully acknowledged.
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