An unexpected transformation by reduction of isoxazolines

Article abstract of DOI:10.1016/j.crci.2012.06.001

Aromatic nitrile oxides undergo regio- and stereo-specific 1,3-dipolar cycloaddition reactions with racemic 5-hydroxy-4-methyl-1,5-dihydropyrrol-2-one derivatives 1. In each case, a single product 3 results from an anti approach to the hydroxyl group, the

Full text of DOI:10.1016/j.crci.2012.06.001

C. R. Chimie 15 (2012) 653–657
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Full paper/Memoire
An unexpected transformation by reduction of isoxazolines
*
Naoufel Ben Hamadi , Moncef Msaddek
Laboratory of Synthesis Heterocyclic and Natural Substances, Department of Chemistry, Faculty of Sciences of Monastir, Boulevard of Environment,
5000 Monastir, Tunisia
A R T I C L E I N F O
Article history:
A B S T R A C T
Received 8 April 2012
Accepted after revision 4 June 2012
Aromatic nitrile oxides undergo regio- and stereo-specific 1,3-dipolar cycloaddition
Available online 12 July 2012
reactions with racemic 5-hydroxy-4-methyl-1,5-dihydropyrrol-2-one derivatives 1. In
each case, a single product 3 results from an anti approach to the hydroxyl group, the
oxygen of the 1,3-dipole being attached to C-5 of pyrrolidinones. A detailed study of a
procedure for the selective reduction of D2-isoxazolines to the corresponding vinylogous
Keywords:
1,3-dipolar cycloaddition
Isoxazolines
amide derivatives is reported.
Regioselectivity
´
ß 2012 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Stereo-selectivity
Vinylogous amide
1. Introduction
cycloaddition of aromatic nitrile oxides with chiral 5-
hydroxy-4-methyl-1,5-dihydropyrrol-2-one derivatives.
Over the years, nitrile oxides have become important
building blocks in organic synthesis. The nitrile oxides-
olefin 1,3-dipolar cycloaddition is a powerful reaction in
that it can create as many as two new contiguous
stereogenic centres in a single step [1]. In general, a
reductive ring opening of D2-isoxazolines can result in
either complete reduction to an amino alcohol or N–O
2. Results and discussion
The synthetic route to the targeted D2-isoxazolines
3ae-be is outlined in Scheme 2. The 1,3-dipolar
cycloaddition of 5-hydroxy-4-methyl-1,5-dihydropyr-
rol-2-ones 1a-b with aromatic nitrile oxides 2c-e at
110 8C in toluene solution for 2h, compound 3ae-be was
obtained (Scheme 1).
bond reduction/hydrolysis to
b-hydroxy ketones through
hydroxyimine intermediates [2]. We envisioned that a
judicious choice of reducing agent other than the reported
catalytic hydrogenolysis [3] to give the vinylogous amide
derivatives allowing the synthesis of many products of
potential interest [4]. Based on an evaluation of the nitrile
oxides cycloaddition, it was felt that the stereochemistry of
these new centers could be controlled if the reaction
system were properly designed. As a continuation of our
effort to utilize heterocyclic compounds as dipolarophiles
in 1,3-dipolar cycloaddition reactions [5], we report the
The 1,3-dipolar cycloaddition of arylnitrile oxides is, in
each case, regiospecific. The chemical shifts of C-6a (13
C
NMR) are in excellent agreement with those usually
obtained when this quaternary carbon is attached to
oxygen atom. The syn or anti stereochemistry of this
cycloaddition product was determined from a NOESY
spectrum. The trans relationship between protons 3a-H
and 6-H was deduced from absence of an NOE effect. The
complete anti-selectivity observed in reactions with 5-
hydroxy-4-methyl-1,5-dihydropyrrol-2-ones, electrostat-
ic repulsion should account for the observed results.
Moreover, syn orientation of the oxygen-containing
pyrrolidinones to the oxygen atom of nitrile oxide leads
to greater repulsion in the transition state (Scheme 2) [6].
* Corresponding author.
E-mail address: bh_naoufel@yahoo.fr (N. Ben Hamadi).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.06.001

654
N. Ben Hamadi, M. Msaddek / C. R. Chimie 15 (2012) 653–657
Ar2
C
N
OH
OH
OH
N
Me
H
Cl
1
Me
H
O
Et3N, toluene
6
5
4
6a
3a
Ar1
Ar1
2
N
N
3
H
Ar2
O
O
2c-e
anti-3
1a-b
a : Ar1 = Ph
b : Ar1 = p-C6H4-OCH3
c : Ar2 = Ph
3ac : Ar1 = Ph, Ar2 = Ph
d : Ar2 = p-C6H4-CH3
e : Ar2 = p-C6H4-OCH3
3ad : Ar1 = Ph, Ar2 = p-C6H4-CH3
3ae : Ar1 = Ph, Ar2 = p-C6H4-OCH3
3bc : Ar1 = p-C6H4-OCH3, Ar2 = Ph
3bd : Ar1 = p-C6H4-OCH3, Ar2 = p-C6H4-CH3
3be : Ar1 = p-C6H4-OCH3, Ar2 = p-C6H4-OCH3
Scheme 1.
A similar mode of addition has been reported earlier for
hydride [12], sodium in ethanol, hydrogenation over
nickel, palladium, or platinum oxide [13], and Mo(CO)6
[14]. Reduction of 3 to the vinylogous amide derivatives 4
was achieved cleanly and in high yield by using Fe/NH4Cl
in the presence of water [15] (Scheme 3).
1H NMR, 13C NMR, IR, HRMS, and elemental analyses
characterized all the synthesized vinylogous amide deri-
vatives 4. 1H NMR of 4bc showed one doublet at 0.72 ppm
the reaction of 5-alkoxy-2(5H)-furanone with aromatic
nitrile oxides [7] as well as by other dipoles [8]; it is mainly
determined by HOMO, LUMO interactions [9].
The D2-isoxazolines 3ac-be proved unexpectedly resis-
tant to reduction by a variety of reducing agents, including
zinc-acetic acid system [10], sodium borohydride with
either NiCl2.6H2O or CoCl2.6H2O [11], lithium aluminium
OH
Me
H
Ar2
C
N
O
N
Ar1
+
O
electrostatic
repulsion
Ar2
C
N
O
Me
Me
O
OH
N
O
OH
H
N
Ar1
N
H
Ar1
Ar2
C
O
TS-syn-3
TS-anti-3
OH
OH
Me
H
Me
H
O
O
N
N
Ar1
N
N
Ar1
H
Ar2
O
H
Ar2
O
syn-3
anti-3
Scheme 2.

N. Ben Hamadi, M. Msaddek / C. R. Chimie 15 (2012) 653–657
655
O
OH
H
Me
H
Me
O
Fe/NH4Cl
N
Ar1
N
N
Ar1
EtOH/H2O, 80°C
Ar2
H
Ar2
O
O
NH2
4ac-be
3ac-be
4ac : Ar1 = Ph, Ar2 = Ph
4ad : Ar1 = Ph, Ar2 = p-C6H4-CH3
4ae : Ar1 = Ph, Ar2 = p-C6H4-OCH3
4bc : Ar1 = p-C6H4-OCH3, Ar2 = Ph
4bd : Ar1 = p-C6H4-OCH3, Ar2 = p-C6H4-CH3
4be : Ar1 = p-C6H4-OCH3, Ar2 = p-C6H4-OCH3
Scheme 3.
H
O
OH
O
O
OH
Me
Me
Me
H
H
Me
O
H
HO
Fe/NH4Cl
EtOH/H2O, 80°C
-H2O
Ar1
N
Ar1
N
Ar1
N
N
HN
N
Ar1
Ar2
Ar2
H
H
H
Ar2
O
Ar2
O
O
NH2
NH
4ac-be
3''ac-be
3'ac-be
3ac-be
Scheme 4.
corresponding to three methyl protons and showed
multiplet at 3.62–3.67 for one proton attached at carbon
C-2, three protons correspond to –OCH3 group. Two
doublet at 7.00 and 7.21 ppm are due to the AA0BB0 system
corresponding to aromatic protons. The two N–H groups
appeared as a broad singulet at 7.39 and 8.22 ppm. The
formation of the product was further confirmed by correct
elemental analyses. The appearance of the two N–H signals
at different chemical shifts would be expected, since one of
them will be intramolecularly H-bonded to the adjacent
The methyl group increases the dipolarophilic reactivity of
the pyrrolidinones, as well as their regioselectivity. Finally,
the electrostatic repulsion between oxygen-containing
pyrrolidinones and the oxygen atom of nitrile oxide are the
main reasons for the observed anti-selectivity. These
heterocycles were reduced to unexpected vinylogous
amide derivatives using iron and ammonium chloride.
4. Experimental details
C
O. Also, the
Z
configuration was deduced from
Infrared spectra were recorded on a Perkin-Elmer IR-
197 spectrophotometer in KBr discs. NMR spectra were
obtained with a Bruker AC 300 spectrometer operating at
300 MHz for 1H and at 75.64 MHz for 13C using TMS as the
internal standard. Elemental analysis was performed with
a Perkin-Elmer 240B microanalyzer. High-resolution mass
spectra (HRMS) were recorded on a Waters Micromass GCT
instrument. The melting points, thermal transitions, and
mesomorphic textures were determined using an Olympus
BX50 microscope equipped with a Mettler Toledo FP-82
hot-stage and a PM-30 exposure control unit. All the
reagents were obtained from commercial sources and used
without further purification. 5-hydroxy-4-methyl-1,5-
dihydropyrrol-2-ones 1a-b were obtained by the reduction
of citraconimide derivatives with NaBH4 [16]. The aromat-
ic nitrile oxides 2c-e were prepared according to published
procedures [17]. The organic solvents were of commercial
grade quality and all were dried by traditional methods. In
observation of an NOE effect between ortho-aromatic
protons and the methyl protons at C4.
The plausible mechanism for the formation of iso-
xazolines 4 is given in Scheme 4. The back-donation from a
p
d filled orbital of Fe to the lumo p* of isoxazoles, which
should facilitate the N–O bond cleavage give the
intermediate 30. The dehydration of the intermediate 30
leads to the formation of intermediate 300. The final product
of the cycloaddition 4 is obtained by isomerization of
intermediate 300.
3. Conclusion
In conclusion, our studies have revealed that the 1,3-
dipolar cycloaddition of aromatic nitrile oxides with
various electron deficient olefins gives bicyclic D2
-
isoxazolines with complete regio- and stereo-selectivity.

656
N. Ben Hamadi, M. Msaddek / C. R. Chimie 15 (2012) 653–657
general, all the compounds were purified by column
chromatography on silica gel (60–120 mesh), and crystal-
lization from analytical grade solvents. The purity of the
sample was checked by thin-layer chromatography (Merck
Kieselgel 60F254).
(s, 1H, 3a–H), 5.56 (d, 1H, OH, J = 7.5 Hz), 6.94 (d, 1H, 6-H,
J = 7.5 Hz), 7.02 (d, 2H) and 7.83 (d, 2H): AA0BB0 part.
J = 9 Hz, 7.21–7.58 (m, 5H, Harom). 13C{1H}NMR (DMSO)
d:
19.02, 55.70, 59.50, 87.83, 91.71, 114.38–161.18, 154.38,
167.65. Elemental analysis: C19H18N2O4 requires C, 67.44;
H, 5.36; N, 8.28%; Found: C, 67.50; H, 5.41; N, 8.33%.
4.1. General procedure for the addition of aromatic nitrile
oxides to 5-hydroxy-1,5-dihydropyrrol-2-one derivatives
4.1.5. (3aR*,6R*,6aS*)-6-exo-hydroxy-5-(4-methoxyphenyl)-
6a-methyl-3-(4-methylphenyl)-3a,5,6,6a-tetrahydro-4H-
pyrrolo[3,4-d]isoxazole-4-one 3bd
A
solution of dipolarophiles 1a-b (1 mmol) and
chloroximes 2c-e (1.1 mmol) in toluene (10 mL), was
stirred at 110 8C. To this solution, trimethylamine (0.2 mL),
dissolved in toluene (10 mL), was added dropwise. The
precipitated triethylammonium chloride was removed by
filtration and the filtrate was concentrated in vacuo, and
chromatography (SiO2; ethyl acetate/petroleum ether, 2:1)
to afford compounds 3ac-be.
Yield (212 mg, 60%), white solid. M.p = 169–170 8C. IR
(KBr)
1H-NMR (DMSO)
y
max/cmꢀ1: 1643 (C N); 1744 (C O); 3300 (OH).
d
: 1.45 (s, 3H, CH3), 2.37 (s, 3H, CH3),
3.77 (s, 3H, OCH3), 4.67 (s, 1H, 3a-H), 5.47 (d, 1H, OH,
J = 7.8 Hz), 6.91 (d, 1H, 6-H, J = 7.8 Hz), 6.96 (d, 2H) and
7.41 (d, 2H): AA’BB’ part. J = 9 Hz, 7.29 (d, 2H) and 7.80
(d, 2H): AA0BB0 part. J = 7.8 Hz. 13C{1H}NMR (DMSO)
d:
19.06, 21.36, 55.61, 59.15, 88.15, 92.04, 114.11–157.67,
154.76, 167.40. Elemental analysis: C20H20N2O4 requires
C, 68.17; H, 5.72; N, 7.95%; Found: C, 68.30; H, 5.67;
N, 7.79%.
4.1.1. (3aR*,6R*,6aS*)-6-exo-hydroxy-6a-methyl-3,5-
diphenyl-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazole-
4-one 3ac
Yield (214 mg, 70%), white solid. M.p = 224–225 8C. IR
(KBr)
NMR (DMSO)
(d, 1H, OH, J = 7.8 Hz), 6.49 (d, 1H, 6-H, J = 7.8 Hz), 7.23–
7.81 (m, 10H, Harom). 13C{1H}NMR (DMSO)
: 19.12, 61.04,
89.35, 91.09, 122.90–137.00, 153.97, 169.01. Elemental
analysis: C18H16N2O3 requires C, 70.12; H, 5.23; N, 9.09%;
Found: C, 70.15; H, 5.35; N, 8.99%.
y
max/cmꢀ1: 1640 (C N); 1740 (C O); 3300 (OH). 1H-
4.1.6. (3aR*,6R*,6aS*)-6-exo-hydroxy-3,5-di(4-
methoxyphenyl)-6a-methyl-3a,5,6,6a-tetrahydro-4H-
pyrrolo[3,4-d]isoxazole-4-one 3be
d
: 1.62 (s, 3H, CH3), 4.11 (s, 1H, 3a–H), 4.61
d
Yield (144 mg, 40%), white solid. M.p = 181–182 8C. IR
(KBr)
1H-NMR (DMSO)
y
max/cmꢀ1: 1638 (C N); 1733 (C O); 3300 (OH).
d
: 1.67 (s, 3H, CH3), 3,74 (s, 3H, OCH3),
3.82 (s, 3H, OCH3), 4.14 (s, 1H, 3a-H), 5.40 (d, 1H, OH,
J = 7.8 Hz), 7.15 (d, 1H, 4-H, J = 7.8 Hz), 6.92 (d, 2H) and
7.36 (d, 2H): AA0BB0 part. J = 9 Hz, 7.06 (d, 2H) and 7.66
(d, 2H): AA0BB0 part. J = 8.7 Hz. 13C{1H}NMR (DMSO)
20.31, 55.62, 55.74, 60.36, 84.77, 89.69, 114.36–161.28,
157.79, 170.23. Elemental analysis: C20H20N2O5 requires
C, 65.21; H, 5.47; N, 7.60%; Found: C, 65.33; H, 5.45; N,
7.75%.
4.1.2. (3aR*,6R*,6aS*)-6-exo-hydroxy-6a-methyl-3-(4-
methylphenyl)-5-phenyl-3a,5,6,6a-tetrahydro-4H-
pyrrolo[3,4-d]isoxazole-4-one 3ad
d:
Yield (256 mg, 80%), white solid. M.p = 191–192 8C. IR
(KBr)
NMR (DMSO)
y
max/cmꢀ1: 1635 (C N); 1735 (C O); 3300 (OH). 1H-
d
: 1.66 (s, 3H, CH3), 2.52 (s, 3H, CH3), 4.19 (s,
1H, 3a-H), 4.53 (d, 1H, OH, J = 7.5 Hz), 6.61 (d, 1H, 6-H,
J = 7.5 Hz), 7.36–7.80 (m, 9H, Harom). 13C{1H}NMR (DMSO)
4.2. General procedure for reduction of isoxazolines
d: 19.20, 21.01, 60.02, 89.40, 90.93, 123.45–140.89, 154.31,
168.59. Elemental analysis: C19H18N2O3 requires C, 70.79;
H, 5.63; N, 8.69%; Found: C, 70.75; H, 5.56; N, 8.54%.
To
a
100 mL round-bottomed flask isoxazoline
(1 mmol), and NH4Cl (3 mmol) in ethanol and water
(1:1, 10 mL) was added Fe powder (3 mmol). The mixture
was heated to 80 8C and was allowed to stir at this
temperature for 3 h. The EtOH was removed under reduced
pressure and the reaction mixture was extracted with
dichlorometane (3 ꢁ 50 mL). The organic solution was
dried over Na2SO4, evaporated and chromatography (SiO2;
ethyl acetate/petroleum ether, 3:1) to afford compounds
4ac-be.
4.1.3. (3aR*,6R*,6aS*)-6-exo-hydroxy-3-(4-methoxyphenyl)-
6a-methyl-5-phenyl-3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-
d]isoxazole-4-one 3ae
Yield (236 mg, 70%), white solid. M.p = 202–203 8C. IR
(KBr)
NMR (DMSO)
y
max/cmꢀ1: 1630 (C N); 1740 (C O); 3300 (OH). 1H-
d
: 1.69 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 4.18
(s, 1H, 3a-H), 4.56 (d, 1H, OH, J = 7.5 Hz), 6.53 (d, 1H, 6-H,
J = 7.5 Hz), 7.07–7.69 (m, 9H, Harom). 13C{1H}NMR (DMSO)
d
:
20.24, 55.74, 60.26, 84.45, 89.02, 114.98–161.31,
4.2.1. (Z)-3-(amino(phenyl)methylene)-4-methyl-1-
phenylpyrrolidine-2,5-dione 4ac
156.28, 170.45. Elemental analysis: C19H18N2O4 requires
C, 67.44; H, 5.36; N, 8.28; Found: C, 67.55; H, 5.45; N,
8.31%.
Yield (284 mg, 85%), white solid. M.p = 196–197 8C. IR
(KBr)
(NH2).1H-NMR (DMSO)
J = 7.2 Hz, 1H), 7.42 (br s, 1H), 7.47 to 7.65 (m, 10H), 8.35
(br s, 1H), 13C{1H}NMR (DMSO)
: 16.6, 38.2, 93.3, 127.4,
y
max/cmꢀ1
:
1732 (C O); 1735 (C O); 3330
d: 0.82 (d, J = 7.2 Hz, 3H), 3.74 (q,
4.1.4. (3aR*,6R*,6aS*)-6-exo-hydroxy-5-(4-methoxyphenyl)-
6a-methyl-3-phenyl-3a,5,6,6a tetrahydro-4H-pyrrolo[3,4-
d]isoxazole-4-one 3bc
d
127.8, 127.9, 129.0, 129.1, 130.2, 133.2, 136.2, 157.9, 170.6,
177.9. HRMS (M+H)+ requires 309.1233 found 309.1239.
Elemental analysis: C18H16N2O2 requires C, 73.95; H, 5.52;
N, 9.58; found C 73.85, H 5.66, N 9.61%.
Yield (276 mg, 90%), white solid. M.p = 178–179 8C. IR
(KBr)
NMR (DMSO)
y
max/cmꢀ1: 1635 (C N); 1737 (C O); 3300 (OH). 1H-
d
: 1.44 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 4.70

N. Ben Hamadi, M. Msaddek / C. R. Chimie 15 (2012) 653–657
657
4.2.2. (Z)-3-(amino(p-tolyl)methylene)-4-methyl-1-
4.2.6. (Z)-3-(amino(4-methoxyphenyl)methylene)-1-(4-
phenylpyrrolidine-2,5-dione 4ad
methoxyphenyl)-4-methylpyrrolidine-2,5-dione 4be
Yield (245 mg, 80%), white solid. M.p = 182–183 8C. IR
Yield (264 mg, 75%), white solid. M.p = 199–200 8C. IR
(KBr)
max/cmꢀ1: 1730 (C O); 1733 (C O); 3330 (NH2), 1H
NMR (CDCl3) : 0.88 (d, J = 7.2 Hz, 3H), 3.49 (q, J = 7.2 Hz,
1H), 3.76 (s, 3H), 3.80 (s, 3H), 4.73 (br s, 1H), 6.90 (J = 8.7 Hz,
2H), 7.11 (J = 8.7 Hz; 2H), 7.23 (J = 9.0 Hz, 2H), 7.37
(J = 9.0 Hz, 2H), 8.39 (br s, 1H). 13C{1H}NMR (CDCl3)
d:
17.0, 39.0, 55.8, 55.9, 95.4, 114.7, 114.8, 125.6, 127.8,
128.2, 128.8, 156.7, 159.4, 161.4, 171.9, 179.0. HRMS
(M+H)+ requires 369.1444 found 369.1440. Elemental
analysis: C20H20N2O4 requires C, 68.17; H, 5.72; N, 7.95;
found C 68.13, H 5.66, N 7.88%.
(KBr)
NMR (CDCl3)
J = 7.2 Hz, 1H), 3.83 (s, 3H), 7.43 (br s, 1H), 6.94 to 7,55 (m,
8H), 8.35 (br s, 1H). 13C{1H}NMR (CDCl3)
: 17.1, 39.0, 95.4,
y
max/cmꢀ1: 1730 (C O); 1736 (C O); 3330 (NH2).1H
y
d
: 0.83 (d, J = 7.2 Hz, 3H), 1.65 (s, 3H), 3.57 (q,
d
d
114.6, 125.6, 127.3, 128.1, 128.9, 129.6, 155.2, 156.7, 159.3,
161.5, 171.8, 179.1. HRMS (M+H)+ requires 323.1390 found
323.1396. Elemental analysis: C19H18N2O2 requires C, C,
74.49; H, 5.92; N, 9.14; found C 75.63, H 5.87, N 9.09%.
4.2.3. (Z)-3-(amino(4-methoxyphenyl)methylene)-4-
methyl-1-phenylpyrrolidine-2,5-dione 4ae
Yield (241 mg, 75%), white solid. M.p = 169–170 8C, IR
References
(KBr)
NMR (DMSO)
y
max/cmꢀ1: 1735 (C O); 1740 (C O); 3330 (NH2), 1H
d
: 0.72 (d, J = 7.2 Hz, 3H), 2.50 (s, 3H), 3.61 (q,
[1] (a) K.H. Robert, R.S. Becky, J. Org. Chem. 55 (1990) 4603;
ˇ
´
´
J = 7.2 Hz, 1H), 3.79 (s, 3H), 7.01 (J = 8.7 Hz, 2H), 7.21
(J = 8.7 Hz; 2H), 7.44 (br s, 1H), 7.53 to 7,56 (m, 5H), 8.19 (br
(b) L’. Fisera, L. Jaroskova, I. Matejkova, H. Heimgartner, Heterocycles 40
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[4] F. Mark, G.A.D. Yonghong, J.K. Charles, P. Damon, R.D. Jeffrey, Bioorg.
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[5] (a) N. Ben Hamadi, M. Msaddek, Heterocycl. Commun. 12 (2006) 457;
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[6] S.H. Schroeter, R. Appel, R. Brammer, G.O. Schenck, Justus Liebigs Ann.
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s, 1H). 13C{1H}NMR (DMSO)
d: 16.5, 38.1, 55.7, 93.4, 114.2,
125.8, 127.8, 128.6, 129.1, 130.2, 136.2, 157.6, 158.8, 170.9,
178.1. HRMS (M+H)+ requires 339.1339 found 339.1342.
Elemental analysis: C19H18N2O3 requires C, 70.79; H, 5.63;
N, 8.69; found C 70.71, H 5.58, N 8.55%.
4.2.4. (Z)-3-(amino(phenyl)methylene)-1-(4-
methoxyphenyl)-4-methylpyrrolidine-2,5-dione 4bc
Yield (306 mg, 95%), white solid. M.p = 174–175 8C. IR
(KBr)
NMR (CDCl3)
y
max/cmꢀ1: 1729 (C O); 1738 (C O); 3330 (NH2). 1H
ˇ
[7] (a) L’. Fisera, P. Oravec, Collect. Czech. Chem. Commun. 52 (1987) 1315;
d
: 0.72 (d, J = 7.2 Hz, 3H), 3.62 (q, J = 7.2 Hz,
(b) B. De Lange, B.L. Feringa, Tetrahedron Lett. (1988) 5317;
ˇ
¨
(c) L’. Fisera, P. Oravec, G. Roman, Monatschefte fur Chemie 122 (1991)
165.
1H), 3.79 (s, 3H), 7.00 (J = 9.0 Hz, 2H), 7.21 (J = 9.0 Hz, 2H),
7.39 (br s, 1H), 7.51 to 7,59 (m, 5H), 8.22 (br s, 1H).
13C{1H}NMR (CDCl3)
d: 16.6, 38.1, 55.7, 93.4, 114.2, 125.8,
127.8, 128.6, 129.1, 130.1, 136.3, 157.6, 158.8, 170.9, 178.1.
HRMS (M+H)+ requires 339.1339 found 339.1331. Elemen-
tal analysis: C19H18N2O3 requires C, 70.79; H, 5.63; N, 8.69;
found C 70.82, H 5.59, N 8.75%.
´
`
´
[8] R.J.L. Garcıa, A. Fraile, G. Gonzalez, M.R. Martın, F.R. Clemente, G.R. Ruth,
J. Org. Chem. 68 (2003) 6534, and references therein.
[9] R. Huisgen, in: A. Padwa (Ed.), 1,3-Dipolar Cycloaddition Chemistry, vol.
1. Wiley, New York, 1984, 1.
[10] P.M. Wovkulich, M.R. Uskokovic, Tetrahedron 41 (1985) 3455.
[11] (a) M. Annunziata, F. Cinquini, A. Cozzi, R.A. Gilardi, J. Chem. Soc. Perkin
Trans. 1 (1985) 2289;
(b) K. Amstrong, W. Collington, G. Knight, A. Naylor, S. Warren, J. Chem.
Soc. Perkin Trans. 1 (1993) 1433.
[12] (a) R. Huisgen, H. Hauck, R. Grashey, H.H. Seidl, Chem. Ber. 102 (1969)
736;
(b) W. Oppolzer, M. Petrzilka, J. Am. Chem. Soc. 98 (1976) 6722.
[13] (a) T. Koizumi, H. Hirai, E. Yoshii, J. Org. Chem. 47 (1982) 4004;
(b) H. Lida, K. Kasahara, C. Kibayashi, J. Am. Chem. Soc. 108 (1986) 4647.
[14] (a) K.T. Geoffrey, T. William, Org. Lett. 4 (2002) 4101;
(b) P.G. Baraldi, A. Barco, S. Benetti, S. Manfredini, D. Simoni, Synthesis
(1987) 276;
4.2.5. (Z)-3-(amino(p-tolyl)methylene)-1-(4-
methoxyphenyl)-4-methylpyrrolidine-2,5-dione 4bd
Yield (235 mg, 70%), white solid. M.p = 166–167 8C, IR
(KBr)
NMR (CDCl3)
J = 7.2 Hz, 1H), 3.83 (s, 3H), 4.75 (br s, 1H), 6.97 to 7,52 (m,
8H), 8.41 (br s, 1H). 13C{1H}NMR (CDCl3)
: 17.0, 39.0, 55.8,
y
max/cmꢀ1: 1737 (C O); 1737 (C O); 3330 (NH2). 1H
d
: 0.84 (d, J = 7.2 Hz, 3H), 1.62 (s, 3H), 3.58 (q,
d
(c) S.-M. Paek, H. Yun, N.-J. Kim, J.-W. Jung, D.-J. Chang, S. Lee, J. Yoo, H.-
J. Park, Y.-G. Suh, J. Org. Chem. 74 (2009) 554.
95.4, 114.7, 125.6, 127.2, 128.2, 128.8, 129.6, 155.1, 156.8,
159.4, 161.4, 171.9, 179.1. HRMS (M+H)+ requires
[15] (a) J. Dahong, C Yuanwei, J. Org. Chem. 73 (2008) 9181;
(b) K. Ieva, L. Ringaile, B. Algirdas, C. Inga, Synlett. 23 (2012) 381.
[16] M. Nobuyuki, N. Toshiki, H. Masaomi, I. Kazuhiro, B. Junichiro, Y.
Hidemi, T. Kunihiko, J. Chem. Soc. Perkin Trans. 1 (2002) 707.
[17] M. Christl, R. Huisgen, Chem. Ber. 106 (1973) 3345.
353.1495
20H20N2O3 requires C, 71.41; H, 5.99; N, 8.33; found C
71.53, H 5.89, N 8.37%.
found
353.1490.
Elemental
analysis:
C