Synthesis of isomeric 2,3,5-trisubstituted perhydropyrrolo[3,4-d]- isoxazole-4,6-diones via 1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.1002/jhet.395

(Chemical Equation Presented) A series of isoxazolidine derivates (isomeric 2,3,5-trisubstitutedperhydropyrrolo[3,4-d]isoxazole-4,6-diones) used as anti-inflammatory, immunosuppressive, antibacterial agent, and inhibitor for some enzymes were synthesized. These compounds were prepared by 1,3-dipolar cycloaddition of N-methyl maleimide and N-phenyl maleimide with nitrones. Diastereomeric products obtained in this reaction were separated by column chromatography and recrystallized. All compounds synthesized were characterized by elemental analysis and spectroscopic methods (¹H NMR, ¹³C NMR, and FTIR).

Full text of DOI:10.1002/jhet.395

954
Synthesis of Isomeric 2,3,5-Trisubstituted Perhydropyrrolo[3,4-d]-
isoxazole-4,6-diones via 1,3-Dipolar Cycloaddition Reactions
Vol 47
¨
Hamdi Ozkan and Yilmaz Yildirir*
Department of Chemistry, Arts and Sciences Faculty, Gazi University, Ankara, Turkey
*E-mail: yildirir@gazi.edu.tr
Received June 22, 2009
DOI 10.1002/jhet.395
Published online 21 June 2010 in Wiley InterScience (www.interscience.wiley.com).
A series of isoxazolidine derivates (isomeric 2,3,5-trisubstitutedperhydropyrrolo[3,4-d]isoxazole-4,6-
diones) used as anti-inflammatory, immunosuppressive, antibacterial agent, and inhibitor for some
enzymes were synthesized. These compounds were prepared by 1,3-dipolar cycloaddition of N-methyl
maleimide and N-phenyl maleimide with nitrones. Diastereomeric products obtained in this reaction
were separated by column chromatography and recrystallized. All compounds synthesized were charac-
terized by elemental analysis and spectroscopic methods (1H NMR, 13C NMR, and FTIR).
J. Heterocyclic Chem., 47, 954 (2010).
INTRODUCTION
ularly alkaloids [20] amino acids and amino sugars.
Among a plethora of functional groups, the nitrone func-
tionality has etched a place of distinction in organic syn-
thesis. Remarkable regio-, stereo-, face-, and chemose-
lectivity along with efficient incorporation of multiple
stereocenters have made nitrone cycloaddition reactions
an attractive and efficient key step in the synthesis of a
great many natural products of biological interest. In
recent years, focus has been shifted toward asymmetric
nitrone cycloaddition reactions; enantioselective [21],
catalytic enantioselective [22], and diastereoselective
[23] synthetic methodologies, as well as metal-assisted
stereocontrol [24] have been reported. Isoxazolidines
have been found to exhibit antimicrobial activity [25–
28] and have been used as enzyme inhibitors [29–31].
Isoxazolidine nucleoside analogues, in which a furanose
ring has been replaced by an N,O-heterocyclic system,
are a particularly interesting group of compounds due to
their potential antiviral activity [32–36]. Isoxazolidines
have also been used as useful building blocks in the
synthesis of various natural and unnatural compounds,
including alkaloids, biologically active b-aminoacids,
b-lactams, amino sugars, and simple 1,3-aminoalcohols
owing to the facile cleavage of the NAO bond [37–39].
1,3-Dipolar cycloaddition reactions have been used
for the synthesis of heterocyclic compounds [1]. High
stereospecificity/stereoselectivity associated with these
reactions make them synthetically important [2–5]. It
has been found that 1,3-dipolar cycloaddition reactions
proceed through a concerted mechanism [6]. The
nitrone-olefin 1,3-dipolar cycloaddition reaction is inter-
esting, as it can create as many as three new contiguous
stereogenic centers in a single step [7,8]. Both inter and
intramolecular nitrone–alkene cycloaddition reactions
have received attention because they are useful methods
for the formation of heterocycles of biological interest
[9–12].
Isoxazolidines, the products of 1,3-dipolar cycloaddi-
tion reactions [13–20] between nitrones and alkenes, are
saturated, five membered heterocycles containing adja-
cent nitrogen and oxygen atoms. As a result of the labile
nature of the NAO bond under mildly reducing condi-
tions, isoxazolidines have long been regarded as impor-
tant synthetic intermediates and have been extensively
utilized as 1,3-amino alcohol in a similar way to a wide
variety of natural products and related molecules, partic-
C
V
2010 HeteroCorporation

July 2010
Synthesis of Isomeric 2,3,5-Trisubstituted Perhydropyrrolo[3,4-d]isoxazole-4,6-diones via 1,3-
Dipolar Cycloaddition Reactions
955
Scheme 1. i: K2CO3, CH2Cl2, MgSO4, reflux. 2a: R ¼ 2-thiophenyl;
2b: R ¼ 5-methyl-2-thiophenyl; 2c: R ¼ 3-methyl-2-thiophenyl; 2d:
R ¼ 4-phenyl-2-thiophenyl; 2e: 5-phenyl-2-thiophenyl; 2f: R ¼ 4-
methylsulfanylbenzyl; 2g: R ¼ 2-furanyl; 2h: R ¼ 5-methyl-2-furanyl;
2i: 1H-pyrrole-2-yl; 2j: R ¼ 1-methyl-1-H-indole-3-yl.
ing to the formation of structurally diverse and highly
functionalized nitrogen-containing compounds. Studies
on both inter- and intramolecular nitrone to alkene dipo-
lar cycloadditions have received much interest from a
stereochemical point of view, as up to three new stereo-
genic centers can be created in the isoxazolidines
depending on the structural features of the starting mate-
rials. Despite the known existence of acyclic nitrones as
mixtures of (E)- and (Z)-isomers, or as single isomer in
the case of cyclic analogues, the diastereoselectivity of
cycloaddition depends also on the structures of the
alkene dipolarophiles. In most cases, cycloadducts were
formed in a predictable stereocontrolled manner due to
steric and electronic effects [42].
A review of the literature revealed that no more reports
have been published on the synthesis of sulphur contain-
ing isomeric 2,3,5-trisubstitutedperhydropyrrolo[3,4-d]
isoxazole-4,6-diones. The aim of this work is to synthe-
sis a new type of isoxazolidine derivatives and charac-
terizes their structures by using spectroscopic techniques
In this study, a diastereomeric couple of two isoxazo-
lidines was produced by 1,3 dipolar cycloaddition reac-
tion of nitrons to alkenes, and the 1,3 dipolar cycloaddi-
tion reactions of substituted-N-methyl nitrons with
N-methyl and N-phenyl maleimide were investigated
(Schemes 1 and 2).
1
such as H NMR, 13C NMR.
1
RESULTS AND DISCUSSION
The evaluation of H NMR spectra of cis-isomers of
isoxazolidines exhibited that Ha protons have chemical
shifting between 4 and 5 ppm giving doublet peak with
a coupling constant (J ꢀ 7 Hz); chemical shift value of
Hb protons 3–4 ppm and doublet’s doublet peak J ¼
8/7 Hz; Hc chemical shifting 3–4 ppm and doublet peak
with J ¼ 8.5 Hz.Cis-isomers of isoxazolidines have
greater coupling constant of Hb-Hc protons (J ¼ 6–8
Hz) than trans-isomers (J ¼ 2–5 Hz). Hc proton gives a
double peak approximately at 3.8–4.0 ppm for cis- iso-
mers but a broad singlet peak at 4.3–4.5 ppm for trans
isomers. It was observed that cis-isomers were obtained
in higher yield than trans-isomers in the reaction of
N-methyl-C-substituted nitrons with N-methyl maleimi-
de.The peak multiplicity due to the spin spin coupling
The 1,3-dipolar cycloaddition reactions between nitro-
nes and an alkene is an extremely powerful synthetic
method for the creation of complex heterocyclic struc-
tures. Best regarded as a concerted but asynchronous
[4p þ 2 p] suprafacial process, the reaction allows up to
three contiguous carbon stereocentres to be created in a
single step. In a manner analogous to the famous [4p þ
2p] cycloaddition reactions first noted by Diels and
Alder [40], nitrone–alkene cycloadditions can occur
with the nitrone and alkene approaching each other. The
reaction results in two possible products an endo- or
exo- fashion; the two possible transition states giving
rise to two diastereomeric products [41].
The 1,3-dipolar cycloaddition of nitrones to alkenes
has been the most efficient approach used for the con-
struction of isoxazolidines because the stereochemistry
of the reaction is predictable, and the mechanism has
been established. A wide range of acyclic and cyclic
nitrones has been reacted with substituted alkenes lead-
1
of Ha and Hb protons are clearly seen from H NMR
spectra of the trans addition products. On the other
hand, the spin spin coupling between Hb and Hc protons
could not be seen. The peak belonging to Hc proton,
appeared as a wide singlet. This situation is well
Scheme 2. ii: Benzene, reflux, 4a: R ¼ 2-thiophenyl, R1 ¼ Me; 4b: R ¼ 5-methyl-2-thiophenyl, R1 ¼ Me; 4c: R ¼ 3-methyl-2-thiophenyl, R1
¼
Me; 4d: R ¼ 4-phenyl-2-thiophenyl, R1 ¼ Me; 4e: R ¼ 5-phenyl-2-thiophenyl, R1 ¼ Me; 4f: R ¼ 4-methylsulfanylphenyl, R1 ¼ Me; 4g: R ¼
2-furanyl, R1 ¼ Me; 4h: R ¼ 5-methyl-2-furanyl, R1 ¼ Me; 4i: R ¼ 1H-pyrrole-2-yl, R1 ¼ Me; 4j: R ¼ 1-methyl-1-H-indole-3-yl, R1 ¼ Me; 4k:
R ¼ 2-thiophenyl, R1 ¼ Ph; 4l: R ¼ 5-methyl-2-thiophenyl, R1 ¼ Ph; 4m: R ¼ 3-methyl-2-thiophenyl, R1 ¼ Ph; 4n: R ¼ 4-phenyl-2-thiophenyl,
R1 ¼ Ph; 4o: R ¼ 5-phenyl-2-thiophenyl, R1 ¼ Ph; 4p: R ¼ 4-methylsulfanylphenyl, R1 ¼ Ph; 4q: R ¼ 2-furanyl, R1 ¼ Ph; 4r: R ¼ 5-methyl-2-
furanyl, R1 ¼ Ph.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
H. Ozkan and Y. Yildirir
956
Vol 47
d, ppm): 2.5 (s, 3H, CH3), 3.1 (s, 3H, CH3), 3.8 (dd, 1H, Hb,
J ꢃ 8.4/7.5 Hz), 4.2 (d, 1H, Hc, J ꢃ 8.8 Hz), 5.0 (d, 1H, Ha,
J ꢃ 7.2 Hz), 7.0–7.4 (m, 3H, ArAH), 13C NMR (in CDCl3, d,
ppm): 25, 43, 54, 71.35, 77, 127.0–127.9 (3C), 136, 173, 176.
Anal. Calcd. For C11H12N2O3S: C 52.37; H, 4.79; N, 11.10; S,
12.71. Found: C, 51.93; H, 4.73; N, 10.96; S, 12.58.
Trans-4a. Yield: 35%, mp 168–169ꢁC. IR (cmꢂ1): 1700 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.5 (s, 3H, CH3), 3.1
(s, 3H, CH3), 3.8 (d,1H, Hb, J ꢃ 7.2 Hz), 4.8 (very broad, 1H,
Hc), 5.0 (d, 1H, Ha, J ꢃ 7 Hz), 7.0–7.4 (m, 3H, ArAH); 13C
NMR (in CDCl3, d, ppm): 24, 41, 56, 72, 76, 127.0–128.2
(3C), 135, 174, 175. Anal. Calcd. For C11H12N2O3S: C 52,37;
H, 4,79; N, 11,10; S, 12,71. Found: C, 52,06; H, 4,72; N,
11,04; S, 12,30.
adjusted with the literatures. Because of the free rotation
of NAC single bond, the proton in the methyl group
and the Hc proton are sterically push each other. The
electronic circle of Hc proton is consistently changed.
Therefore, the peak due to Hc proton and methyl pro-
tons bonded to N atom on the isoxazolidine ring caused
to occur a wide peak. The Ortep diagrams obtained
from X-Ray analyzes of isoxazolidines (for example,
cis-4c compound [43] and cis-4e compound [44]) it
exhibited that Ha, Hb, and Hc protons are at the same
side of the plane.The 13C NMR spectra of the trans
addition products showed that some singlet’s carbons
did not appear. However, the other data (such as X-Ray
analyses of these compounds) confirm the proposed
structures.
2,5-Dimethyl-3-(5-methyl-thiophen-2-yl)-tetrahydro-pyr-
rolo[3,4-d]isoxazole-4,6-dione
cis-4b.
Cis-4b. Yield:
64%, mp 121–122ꢁC. IR (cmꢂ1): 1707 s (C¼¼O); H NMR: (in
CDCl3, d, ppm): 2.4 (s, 3H, CH3), 2.7 (s, 3H, CH3), 3.0 (s,
3H, CH3), 3.7 (dd, 1H, Hb, J ꢃ 8.3/7.7 Hz), 4.1 (d, 1H, Hc, J
ꢃ 8.8 Hz), 4.9 (d, 1H, Ha, J ꢃ 7.3 Hz), 6.6–6.9 (dd, 2H,
ArAH); 13C NMR (in CDCl3, d, ppm): 15, 25, 42, 54, 71.35,
77, 126–142 (4C), 174, 176. Anal. Calcd. For C12H14N2O3S:
C 54.12; H, 5.30; N, 10.52; S, 12.04. Found: C, 54.90; H,
5.33; N, 10.04; S, 11.64.
1
EXPERIMENTAL
All melting points were determined by an Electrothermal
9100 apparatus and are uncorrected. 1H NMR and 13C NMR
spectra were recorded on a Bruker 400 (400 MHz) NMR spec-
trometer. Samples were prepared in CDCl3 and DMSO-d6 with
TMS as internal standard. Chemical shifts are given in ppm
and coupling constant are given in Hz. Microanalyses were
performed on a LECO-932 CHNS-O element analyzer. FTIR
spectra were recorded on a Mattson 1000 spectrometer as KBr
pellets. Column chromatography was carried out on Merck
Kieselgel (particle size 0.063–0.200 mm) and solvents were
distilled before use. N-Methylhydroxylamine hydrochloride,
N-methylmaleimide, N-phenylmaleimide and substituted alde-
hydes, and other chemicals were obtained from Sigma–
Aldrich.
General procedure for the synthesis of substituted nitro-
nes (2a–j). Substituted aldehydes (10 mmol) were added to a
solution of N-methylhydroxylamine hydrochloride (1.65 g, 20
mmol) in CH2Cl2 (50 mL). K2CO3 (3.03 g, 22 mmol) and
MgSO4 (0.60 g, 5 mmol) were added and the mixture refluxed
for 12 h, and the reaction was monitored by TLC. The reaction
mixture was filtered and solvent was evaporated. Then, column
chromatography of the residue (n-hexane/ethyl acetate 1:1)
gave nitrone (compound 2). The crude product was recrystal-
lized from CH2Cl2/n-hexane [45].
General procedure for the synthesis of substituted 2,5-
dimethy tetrahydro-pyrrolo[3,4-d]isoxazole-4,6-dione, (exem-
plified by cis-4a, trans-4a). A mixture of N-methyl-C-(thio-
phene-2-yl) nitrone 2a (3 mmol, 0,429 g) and N-methylmalei-
mide 3a (3.3 mmol, 0.370 g) was dissolved in 50 mL ben-
zene. The reacting mixture was refluxed for 6–12 h. During
this time, the reaction was monitored by TLC. Then, the sol-
vent was evaporated. The products were separated by column
chromatography [46]. The mixture of ethylacetate and petro-
leum ether was used as an eluent. The cis- and trans-isomers
were recrystallized separately from CHCl3/n-hexane mixture.
Spectroscopic and analytical data of new compounds are given
below.
2,5-Dimethyl-3-(3-methyl-thiophen-2-yl)-tetrahydro-pyr-
rolo[3,4-d]isoxazole-4,6-dione, cis-4c, trans-4c.
Cis-
4c. Yield: 61%, mp 130–132ꢁC IR (cmꢂ1): 1704 s (C¼¼O); H
NMR: (in CDCl3, d, ppm): 2.3 (s, 3H, CH3), 2.7 (s, 3H, CH3),
3.0 (s, 3H, CH3), 3.6–3.8 (dd, 1H, Hb, J ꢃ 8.7/7.5 Hz), 4.2 (t,
1H, Hc, J ꢃ 8.8 Hz), 4.9–5.0 (d, 1H, Ha, J ꢃ 7.3 Hz), 6.8–7.2
(dd, 2H, ArAH, J ꢃ 5.05); 13C NMR (in CDCl3, d, ppm): 14,
25, 43, 53, 70, 77, 126–137 (4C), 174, 176. Anal. Calcd. For
C12H14N2O3S: C 54.12; H, 5.30; N, 10.52; S, 12.04. Found: C,
53.71; H, 5.21; N, 10.39; S, 12.03.
1
Trans-4c. Yield: 30%, mp 137–138ꢁC IR (cmꢂ1): 1714 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.3 (s, 3H, CH3), 2.4
(s, 3H, CH3), 3.1 (s, 3H, CH3), 3.6–3.8 (dd,1H, Hb J ꢃ 7.2
Hz), 4.5–4.8 (very broad, 1H, Hc), 4.8–5.0 (d, 1H, Ha, J ꢃ 6
Hz),, 6.5–6.9(dd, 2H, ArAH, J ꢃ 5.05 ); 13C NMR (in CDCl3,
d, ppm): 15, 25, 39, 57, 67, 72, 75, 125–142 (4C), 173, 176.
Anal. Calcd. For C12H14N2O3S: C 54.12; H, 5.30; N, 10.52; S,
12.04. Found: C, 53.81; H, 5.38; N, 10.78; S, 12.02.
2,5-Dimethyl-3-(4-phenyl-thiophen-2-yl)-tetrahydro-pyr-
rolo[3,4-d]isoxazole-4,6-dione, cis-4d, trans-4d.
Cis-
4d. Yield: 65%, mp 146–148ꢁC IR (cmꢂ1): 1716 s (C¼¼O); H
NMR: (in CDCl3, d, ppm): 2.7 (s, 3H, CH3), 3.1 (s, 3H, CH3),
3.7–3.8 (dd, 1H, Hb, J ꢃ 8.4/7.7 Hz), 4.2 (d, 1H, Hc, J ꢃ 8.8
Hz), 4.9–5.0 (d, 1H, Ha, J ꢃ 7.3 Hz), 7.3–7.6 (m, 7H, ArAH);
13C NMR (in CDCl3, d, ppm): 25, 43, 54, 71, 77, 122–143 (8C),
173, 176.15. Anal. Calcd. For C17H16N2O3S: C 62.18; H, 4.91;
N, 8.53; S, 9.76. Found: C, 62.75; H, 4.88; N, 8.24; S, 10.01.
1
Trans-4d. Yield: 32%, mp 158–160ꢁC IR (cmꢂ1): 1700 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.5 (s, 3H, CH3), 3.1
(s, 3H, CH3), 3.7–3.8 (d, 1H, Hb, J ꢃ 7.2 Hz), 4.8 (very
broad, 1H, Hc ), 4.9–5.0 (d, 1H, Ha, J ꢃ 7.1 Hz), 7.3–7.7 (m,
7H, ArAH); 13C NMR (in CDCl3, d, ppm): 25, 39, 57, 67, 75,
119–142 (8C), 175, 176. Anal. Calcd. For C17H16N2O3S: C
62.18; H, 4.91; N, 8.53; S, 9.76. Found: C, 39.17; H, 3.05; N,
5.32; S, 5.68.
2,5-Dimethyl-3-(thiophen-2-yl)-tetrahydro-pyrrolo[3,4-d]iso-
xazole-4,6-dione, cis-4a, trans-4a. Cis-4a. Yield: 63%, mp
149–150ꢁC. IR (cmꢂ1): 1714 s (C¼¼O); 1H NMR: (in CDCl3,
2,5-Dimethyl-3-(5-phenyl-thiophen-2-yl)-tetrahydro-pyr-
rolo[3,4-d]isoxazole-4,6-dione, cis-4e, trans-4e.
Cis-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
Synthesis of Isomeric 2,3,5-Trisubstituted Perhydropyrrolo[3,4-d]isoxazole-4,6-diones via 1,3-
Dipolar Cycloaddition Reactions
957
4e. Yield: 60%, mp 180–181ꢁC IR (cmꢂ1): 1704 s (C¼¼O); H
NMR: (in CDCl3, d, ppm): 2.8 (s, 3H, CH3), 3.1 (s, 3H, CH3),
3.7–3.8 (dd, 1H, Hb, J ꢃ 8.4/7.7 Hz), 4.1– 4.2 (d, 1H, Hc, J
ꢃ 8.8 Hz), 4.9–5.0 (d, 1H, Ha, J ꢃ 7.3 Hz), 7.2–7.6 (m, 7H,
ArAH); 13C NMR (in CDCl3, d, ppm): 25, 43, 54, 71, 77,
123–128 (4C),134–135 (3C), 172, 175. Anal. Calcd. For
C17H16N2O3S: C 62.18; H, 4.91; N, 8.53; S, 9.76. Found: C,
60.94; H, 5.22; N, 8.59; S, 9.17.
Trans-4e. Yield: 33%, mp 126–128ꢁC IR (cmꢂ1): 1700 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.5 (s, 3H, CH3), 3.1
(s, 3H, CH3), 3.8 (d, 1H, Hb, J ꢃ 7.2 Hz), 4.6–4.8 (very
broad, 1H, Hc ), 4.9.5.0 (d, 1H, Ha, J ꢃ 7.2 Hz), 6.8–7.7 (m,
7H, ArAH); 13C NMR (in CDCl3, d, ppm): 25, 75, 122–133
(5C). Anal. Calcd. For C17H16N2O3S: C 62.18; H, 4.91; N,
8.53; S, 9.76. Found: C, 62.52; H, 5.06; N, 8.56; S, 9.55.
2,5-Dimethyl-3-(4-methylsulfanyl-phenyl)-tetrahydro-pyrrolo[3,
1
(very broad, 1H, Hc ), 4.9–5.0 (d, 1H, Ha, J ꢃ 7.4 Hz), 5.98–
6.25 (m, 2H, ArAH); 13C NMR (in CDCl3, d, ppm): 13, 25,
53, 75, 106, 111. Anal. Calcd. For C12H14N2O4: C 57.59; H,
5.64; N, 11.19. Found: C, 58.08; H, 5.46; N, 11.21.
2,5-Dimethyl-3-(1-methyl-1H-pyrrol-2-yl)-tetrahydro-pyrrolo[3,
4-d]isoxazole-4,6-dione, cis-4i, trans-4i.
Cis-4i. Yield: 62%,
mp 179–180ꢁC IR (cmꢂ1): 1703 s (C¼¼O); 1H NMR: (in
CDCl3, d, ppm): 2.7 (s, 3H, CH3), 2.9–3.0 (s, 3H, CH3), 3.7
(s, 3H, CH3), 3.7–3.8 (dd, 1H, Hb, J ꢃ 7.8 Hz), 3.9 (d, 1H,
Hc, J ꢃ 8.6 Hz), 4.9 (d, 1H, Ha, J ꢃ 7.3 Hz), 6.2–7.5 (m, 3H,
ArAH); 13C NMR (in CDCl3, d, ppm): 25, 34, 43, 53, 69, 76,
110–125 (4C), 174, 176. Anal. Calcd. For C12H15N3O3: C
57.82; H, 6.07; N, 16.86. Found: C, 58.28; H, 5.96; N, 17.01.
Trans-4i. Yield: 29%, mp 145–146ꢁC IR (cmꢂ1): 1705 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.5 (s, 3H, CH3), 3.1
(s, 3H, CH3), 3.7 (s, 3H, CH3), 3.7–3.8 (d, 1H, Hb, J ꢃ 7 Hz),
4.6 (very broad, 1H, Hc ), 4.9–5.0 (d, 1H, Ha, J ꢃ 7.5 Hz),
6.0–6.7 (m, 3H, ArAH); 13C NMR (in CDCl3, d, ppm): 25, 37
43, 54, 71, 77, 135–150 (4C), 175, 176. Anal. Calcd. For
C12H15N3O3: C 57.82; H, 6.07; N, 16.86. Found: C, 57.72; H,
6.09; N, 17.09.
4-d]isoxazole-4,6-dione, cis-4f, trans-4f.
Cis-4f. Yield: 62%,
mp 140–141ꢁC IR (cmꢂ1): 1718 s (C¼¼O); 1H NMR: (in
CDCl3, d, ppm): 2.5 (s, 3H, CH3), 2.7 (s, 3H, CH3), 3.1 (s,
3H, CH3), 3.7–3.8 (dd, 1H, Hb, J ꢃ 8.4/7.4 Hz), 3.8 (d, 1H,
Hc, J ꢃ 8.6 Hz), 4.9 (d, 1H, Ha, J ꢃ 7.2 Hz), 7.1–7.3 (dd,
4H, ArAH, J ꢃ 8 Hz); 13C NMR (in CDCl3, d, ppm): 15, 25,
42.8, 54.6, 75, 76.75, 127–128 (2C), 134–135 (3C), 174, 176.
Anal. Calcd. For C14H16N2O3S: C 57.52; H, 5.52; N, 9.58; S,
10.97. Found: C, 60.79; H, 7.26; N, 8.15; S, 9.29.
2,5-Dimethyl-3-(1-methyl-1H-indol-3-yl)-tetrahydro-pyrrolo[3,4-
d]isoxazole-4,6-dione, cis-4j, trans-4j. Cis-4j. Yield: 60%, mp
198–200ꢁC IR (cmꢂ1): 1703 s (C¼¼O); 1H NMR: (in CDCl3,
d, ppm): 2.7 (s, 3H, CH3), 3.0 (s, 3H, CH3), 3.8 (s, 3H, CH3),
3.6–3.7 (dd, 1H, Hb, J ꢃ 8.0/7.7 Hz), 4.1–4.2 (d, 1H, Hc, J ꢃ
8.6 Hz), 4.9–5.0 (d, 1H, Ha, J ꢃ 7.3 Hz), 6.9–7.0 (s,1H), 7.1–
7.6 (m, 4H, ArAH); 13C NMR (in CDCl3, d, ppm): 25, 33, 43,
54, 70, 76, 106, 109–127 (6C), 173, 176. Anal. Calcd. For
C16H17N3O3: C 64.20; H, 5.72; N, 14.04. Found: C, 63.67; H,
5.79; N, 14.17.
Trans-4j. Yield: 32%, mp 131–133ꢁC IR (cmꢂ1): 1704 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.5 (s, 3H, CH3), 3.1
(s, 3H, CH3), 3.9 (s, 3H, CH3), 3.7–3.8 (d, 1H, Hb, J ꢃ 7 Hz),
4.8 (very broad, 1H, Hc ), 4.9–5.0 (d, 1H, Ha, J ꢃ 7.1 Hz),
6.9–7.0 (s,1H), 7.1–7.8 (m, 4H, ArAH); 13C NMR (in CDCl3,
d, ppm): 24, 25, 30, 32, 56, 76, 108, 109–128 (6C). Anal.
Calcd. For C16H17N3O3: C 64.20; H, 5.72; N, 14.04. Found:
C, 65.21; H, 5.34; N, 14.50.
Trans-4f. Yield: 32%, mp 148–150ꢁC IR (cmꢂ1): 1696 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.4–2.8 (6H, 2CH3),
3.1 (s, 3H, CH3), 3.6–3.8 (d, 1H, Hb, J ꢃ 7.2 Hz), 4.6–4.8
(very broad, 1H, Hc ), 4.9.5.0 (d, 1H, Ha, J ꢃ 7.2 Hz), 7.2–
7.7.4 (m, 4H, ArAH); 13C NMR (in CDCl3, d, ppm): 17, 26,
43, 54, 71, 77, 122–143 (5C), 161, 176. Anal. Calcd. For
C14H16N2O3S: C 57.52; H, 5.52; N, 9.58; S, 10.97. Found: C,
57.91; H, 6.63; N, 9.43; S, 10.73
2,5-Dimethyl-3-(furan-2-yl)-tetrahydro-pyrrolo[3,4-d]isoxa-
zole-4,6-dione, cis-4g, trans-4g.
Cis-4g. Yield: 52%, mp
143–144ꢁC IR (cmꢂ1): 1717 s (C¼¼O); 1H NMR: (in CDCl3,
d, ppm): 2.7 (s, 3H, CH3), 3.1 (s, 3H, CH3), 3.7–3.8 (dd, 1H,
Hb, J ꢃ 8.1/7.8 Hz), 3.9 (d, 1H, Hc, J ꢃ 8.5 Hz), 4.9 (d, 1H,
Ha, J ꢃ 7.3 Hz), 6.2–7.5 (m, 3H, ArAH); 13C NMR (in
CDCl3, d, ppm): 25, 40, 44, 50, 69, 76, 110–147 (4C), 174,
176. Anal. Calcd. For C11H12N2O4: C 55.93; H, 5.12; N,
11.86. Found: C, 58.02; H, 5.47; N, 12.03.
2-Methyl-5-phenyl-3-(thiophen-2-yl)-tetrahydro-pyrrolo[3,4-
d]isoxazole-4,6-dione, cis-4k. Cis-4k. Yield: 43%, mp 154–
156ꢁC IR (cmꢂ1): 1711 s (C¼¼O); 1H NMR: (in CDCl3, d,
ppm): 2.8 (s, 3H, CH3), 3.8–3.9 (dd, 1H, Hb, J ꢃ 8.3/8.0 Hz),
4.4 (d, 1H, Hc, J ꢃ 8.8 Hz), 5.0–5.1 (d, 1H, Ha, J ꢃ 7.5 Hz),
7.0–7.5 (m, 8H, ArAH); 13C NMR (in CDCl3, d, ppm): 43,
55, 72, 77, 112–136 (8C), 173, 176. Anal. Calcd. For
C16H14N2O3S: C 61.13; H, 4.49; N, 8.91; S, 10.20. Found: C,
62.42; H, 4.49; N, 8.92; S, 10.17.
Trans-4g. Yield: 40%, mp 150–152ꢁC IR (cmꢂ1): 1704 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.4 (s, 3H, CH3), 3.1
(s, 3H, CH3), 3.7 (d, 1H, Hb, J ꢃ 7.3 Hz), 4.6 (very broad,
1H, Hc ), 4.9 (d, 1H, Ha, J ꢃ 7.4 Hz), 6.3–7.5 (m, 3H,
ArAH); 13C NMR (in CDCl3, d, ppm): 25, 40, 54, 71, 77,
135–150 (4C), 173, 176. Anal. Calcd. For C11H12N2O4: C
55.93; H, 5.12; N, 11.86. Found: C, 55.77; H, 4.75; N, 11.65.
2,5-Dimethyl-3-(5-methylfuran-2-yl)-tetrahydro-pyrrolo[3,4-
d]isoxazole-4,6-dione, cis-4h, trans-3h. Cis-4h. Yield: 64%,
mp 150–151ꢁC IR (cmꢂ1): 1702 s (C¼¼O); 1H NMR: (in
CDCl3, d, ppm): 2.3 (s, 3H, CH3), 2.7 (s, 3H, CH3), 3.1 (s,
3H, CH3), 3.7–3.8 (dd, 1H, Hb, J ꢃ 8.2/7.7 Hz), 3.9 (d, 1H,
Hc, J ꢃ 8.6 Hz), 4.9 (d, 1H, Ha, J ꢃ 7.3 Hz), 5.9–6.2 (dd,
2H, ArAH); 13C NMR (in CDCl3, d, ppm): 13, 25, 39, 54, 69,
76, 110–153 (4C), 175, 176. Anal. Calcd. For C12H14N2O4: C
57.59; H, 5.64; N, 11.19. Found: C, 57.37; H, 5.59; N, 11.25.
Trans-4h. Yield: 33%, mp 154–155ꢁC IR (cmꢂ1): 1701 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.3 (s, 3H, CH3), 2.4
(s, 3H, CH3), 3.1 (s, 3H, CH3), 3.8 (d, 1H, Hb, J ꢃ 7 Hz), 4.5
2-Methyl-5-phenyl-3-(5-methylthiophen-2-yl)-tetrahydro-pyr-
rolo[3,4-d]isoxazole-4,6-dione, cis-4l, trans-4l. Cis-4l. Yield:
1
41%, mp 139–141ꢁC IR (cmꢂ1): 1722 s (C¼¼O); H NMR: (in
CDCl3, d, ppm): 2.5 (s, 3H, CH3), 2.7 (s, 3H, CH3) 3.7–3.8
(dd, 1H, Hb, J ꢃ 8.5/7.7 Hz), 4.2 (d, 1H, Hc, J ꢃ 8.8 Hz),
5.0–5.1 (d, 1H, Ha, J ꢃ 7.5 Hz), 6.6–7.5 (m, 7H, ArAH); 13C
NMR (in CDCl3, d, ppm): 16, 43, 54, 72, 77, 126–142 (8C),
173, 176. Anal. Calcd. For C17H16N2O3S: C 62.18; H, 4.91;
N, 8.53; S, 9.76. Found: C, 61.96; H, 4.86; N, 8.72; S, 9.55.
Trans-4l. Yield: 47%, mp 152–155ꢁC IR (cmꢂ1): 1718 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.4 (s, 3H, CH3), 2.6
(s, 3H, CH3), 3.8–3.9 (d, 1H, Hb, J ꢃ 7,2 Hz), 4.8–4.9 (very
broad, 1H, Hc), 5.0–5.1 (d, 1H, Ha, J ꢃ 7.1 Hz), 6.6–7.6 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
H. Ozkan and Y. Yildirir
958
Vol 47
8H, ArAH); 13C NMR (in CDCl3, d, ppm): 15, 39, 53, 71, 77,
125–142 (8C), 175.0, 175.46. Anal. Calcd. For C17H16N2O3S:
C 62.18; H, 4.91; N, 8.53; S, 9.76. Found: C, 61.91; H, 4.90;
N, 8.41; S, 10.16.
64.39; H, 5.12; N, 7.90; S, 9.05. Found: C, 64.43; H, 5.14; N,
7.75; S, 8.87.
Trans-4p. Yield: 42%, mp 184–185ꢁC IR (cmꢂ1): 1718 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.0–3.0 (6H, 2CH3),
3.8–3.9 (d, 1H, Hb, J ꢃ 7.5 Hz), 4.8 (broad, 1H, Hc), 5.0–5.1
(d, 1H, Ha, J ꢃ 7.4 Hz), 7.2–7.6 (m, 9H, ArAH); 13C NMR
(in CDCl3, d, ppm): 15, 75, 126–139 (6C). Anal. Calcd. For
C19H18N2O3S: C 64.39; H, 5.12; N, 7.90; S, 9.05. Found: C,
64.43; H, 5.50; N, 8.07; S, 7.67.
2-Methyl-5-phenyl-3-(3-methylthiophen-2-yl)-tetrahydro-pyrrolo
[3,4-d]isoxazole-4,6-dione, cis-4m, trans-4m.
Cis-4m. Yield:
1
40%, mp 108–109ꢁC IR (cmꢂ1): 1722 s (C¼¼O); H NMR: (in
CDCl3, d, ppm): 2.5 (s, 3H, CH3), 2.8 (s, 3H, CH3) 3.8–3.9
(dd, 1H, Hb, J ꢃ 8.5/7.9 Hz), 4.2–4.4 (d, 1H, Hc, J ꢃ 8.9 Hz),
5.0–5.1 (d, 1H, Ha, J ꢃ 7.5 Hz), 6.8–7.6 (m, 7H, ArAH); 13C
NMR (in CDCl3, d, ppm): 14, 43, 53, 70, 77, 125–137 (8C),
171, 175. Anal. Calcd. For C17H16N2O3S: C 62.18; H, 4.91; N,
8.53; S, 9.76. Found: C, 62.63; H, 5.15; N, 8.65; S, 9.46.
Trans-4m. Yield: 46%, mp 144–145ꢁC IR (cmꢂ1): 1718 s
(C¼¼O); 1H NMR: (in CDCl3, d, ppm): 2.4 (s, 3H, CH3), 2.6
(s, 3H, CH3), 3.8–3.9 (d, 1H, Hb J ꢃ 7 Hz), 5.0–5.1 (very
broad, 1H, Hc), 5.1–5.2 (d, 1H, Ha, J ꢃ 7.1 Hz), 6.8–7.6 (m,
7H, ArAH); 13C NMR (in CDCl3, d, ppm): 14, 44, 54, 67, 77,
126–144 (8C), 175, 177. Anal. Calcd. For C17H16N2O3S: C
62.18; H, 4.91; N, 8.53; S, 9.76. Found: C, 61.91; H, 4.90; N,
8.41; S, 10.16
2-Methyl-5-phenyl-3-(furan-2-yl)-tetrahydro-pyrrolo[3,4-
d]isoxazole-4,6-dione, cis-4q.
Cis-4q. Yield: 40%, mp
101–103ꢁC IR (cmꢂ1): 1710 s (C¼¼O); 1H NMR: (in CDCl3,
d, ppm): 2.7 (s, 3H, CH3), 3.8–3.9 (dd, 1H, Hb, J ꢃ 8.5/7.7
Hz), 4.0–4.1 (d, 1H, Hc, J ꢃ 8.7 Hz), 5.0–5.1 (d, 1H, Ha, J ꢃ
7.5 Hz), 6.3–7.6 (m, 8H, ArAH); 13C NMR (in CDCl3, d,
ppm): 43, 53, 71, 77, 110–147 (7C), 172, 175. Anal. Calcd.
For C16H14N2O4: C 64.42; H, 4.73; N, 9.39 Found: C, 56.33;
H, 5.02; N, 12.10.
2-Methyl-5-phenyl-3-(5-methylfuran-2-yl)-tetrahydro-pyrrolo
[3,4-d]isoxazole-4,6-dione, cis-4r.
Cis-4r. Yield: 42%, mp
137–140ꢁC IR (cmꢂ1): 1701 s (C¼¼O); 1H NMR: (in CDCl3,
d, ppm): 2.4 (s, 3H, CH3), 2.7 (s, 3H, CH3), 3.8–3.9 (dd, 1H,
Hb, J ꢃ 8.5/7.7 Hz), 3.9–4.0 (d, 1H, Hc, J ꢃ 8.7 Hz), 5.1–5.2
(d, 1H, Ha, J ꢃ 7.5 Hz), 6.3–7.6 (m, 7H, ArAH); 13C NMR
(in CDCl3, d, ppm): 14, 43, 50, 53, 77, 111–147 (8C), 155,
176. Anal. Calcd. For C17H16N2O4: C 65.38; H, 5.16; N, 8.97.
Found: C, 68.07; H, 5.19; N, 9.14.
2-Methyl-5-phenyl-3-(4-phenylthiophen-2-yl)-tetrahydro-
pyrrolo[3,4-d]isoxazole-4,6-dione, cis-4n, trans-4n.
Cis-
4n. Yield: 41%, mp 145–146ꢁC IR (cmꢂ1): 1723 s (C¼¼O); H
NMR: (in CDCl3, d, ppm): 2.8–2.9 (s, 3H, CH3) 3.7–3.8 (dd,
1H, Hb, J ꢃ 8.7/7.7 Hz), 4.3 (d, 1H, Hc, J ꢃ 8.8 Hz), 5.0–5.1
(d, 1H, Ha, J ꢃ 7.5 Hz), 7.2–7.6 (m, 12H, ArAH); 13C NMR
(in CDCl3, d, ppm): 43, 55, 72, 77, 122–143 (12C), 173, 176.
Anal. Calcd. For C22H18N2O3S: C 67.67; H, 4.65; N, 7.17; S,
8.21. Found: C, 67.83; H, 4.68; N, 7.11; S, 7.92.
1
Acknowledgment. The authors are grateful to Gazi University
(BAP Project Number: FEF 05/2006-46).
Trans-4n. Yield: 44%, mp 134–138ꢁC IR (cmꢂ1): 1710 s
1
(C¼¼O); H NMR: (in CDCl3, d, ppm): 2.6 (s, 3H, CH3), 3.8–
3.9 (d, 1H, Hb J ꢃ 7.3 Hz), 4.9–5.0 (very broad, 1H, Hc),
5.1–5.2 (d, 1H, Ha, J ꢃ 7.1 Hz), 6.8–7.6 (m, 7H, ArAH); 13C
NMR (in CDCl3, d, ppm): 49, 76, 120–142 (11C), 175. Anal.
Calcd. For C22H18N2O3S: C 67.67; H, 4.65; N, 7.17; S, 8.21.
Found: C, 67.23; H, 4.67; N, 6.99; S, 7.36.
REFERENCES AND NOTES
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4o. Yield: 43%, mp 166–167ꢁC IR (cmꢂ1): 1717 s (C¼¼O); H
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1
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NMR: (in CDCl3, d, ppm): 2.5 (s, 3H, CH3), 2.7 (s, 3H, CH3),
3.8–3.9 (dd, 1H, Hb, J ꢃ 7.3/7.4 Hz), 3.9–4.0 (d, 1H, Hc, J ꢃ
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1
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis of Isomeric 2,3,5-Trisubstituted Perhydropyrrolo[3,4-d]isoxazole-4,6-diones via 1,3-
Dipolar Cycloaddition Reactions
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet