Cycloaddition of acyclic nitrones with phenyl isocyanate: Synthesis and ring-opening reactions of 1,2,4-oxadiazolidin-5-ones

Article abstract of DOI:10.1080/00397910500501466

The cycloaddition of nitrones with unsubstituted or electron-donating substituents on the C-phenyl 1a,c,f with phenyl isocyanate proceeds smoothly for a short time with high yields to give the corresponding 1,2,4-oxadiazolidinone 2, and 1b,d,e with electron-withdrawing substituents gave the corresponding oxadiazolidinone in moderate yields after prolonged heating. Oxadiazolidinones 2a,c,f undergo diethylamine-induced fragmentation for a short time to give the corresponding Schiff bases, and oxadiazolidinones 2b,d,e remain unchanged in these conditions. Prolonged heating of 2d,e in the presence of diethylamine led to complex mixtures. In the case of 2b the corresponding amidine was the main product of the reaction. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500501466

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Cycloaddition of Acyclic Nitrones with Phenyl
Isocyanate: Synthesis and Ring‐Opening
Reactions of 1,2,4‐Oxadiazolidin‐5‐ones
Necdet Coşkun a & Aydın Parlar a
a Department of Chemistry , Uludağ University , Görükle Bursa, Turkey
Published online: 16 Aug 2006.
To cite this article: Necdet Coşkun & Aydın Parlar (2006) Cycloaddition of Acyclic Nitrones with Phenyl
Isocyanate: Synthesis and Ring‐Opening Reactions of 1,2,4‐Oxadiazolidin‐5‐ones, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:8, 997-1004, DOI:
10.1080/00397910500501466
To link to this article: http://dx.doi.org/10.1080/00397910500501466
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Synthetic Communicationsw, 36: 997–1004, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500501466
Cycloaddition of Acyclic Nitrones with
Phenyl Isocyanate: Synthesis and
Ring-Opening Reactions of 1,2,4-
Oxadiazolidin-5-ones
Necdet Cos¸kun and Aydın Parlar
˘
¨ ¨
Department of Chemistry, Uludag University, Gorukle Bursa, Turkey
Abstract: The cycloaddition of nitrones with unsubstituted or electron-donating sub-
stituents on the C-phenyl 1a,c,f with phenyl isocyanate proceeds smoothly for a
short time with high yields to give the corresponding 1,2,4-oxadiazolidinone 2, and
1b,d,e with electron-withdrawing substituents gave the corresponding oxadiazolidi-
none in moderate yields after prolonged heating. Oxadiazolidinones 2a,c,f undergo
diethylamine-induced fragmentation for a short time to give the corresponding
Schiff bases, and oxadiazolidinones 2b,d,e remain unchanged in these conditions.
Prolonged heating of 2d,e in the presence of diethylamine led to complex mixtures.
In the case of 2b the corresponding amidine was the main product of the reaction.
Keywords: Acyclic nitrone, 1,3-dipolar cycloaddition, 1,2,4-oxadiazolidin-5-one, sec-
amine induced fragmentation of 1,2,4-Oxadiazolidin-5-ones, Substituent effect
INTRODUCTION
The nitrones are well-known 1,3-dipoles in thermal cycloadditions reactions
with multiple bond systems to provide various heterocyclic five-membered
ring systems.[1] The cycloadducts of di- and triarylimidazoline 3-oxides[2]
with a variety of dipolarophiles[3] give bicyclic compounds with potentially
interesting biological activity. (A series of tetrahydroimidazo compounds
including tetrahydroimidazooxadiazolones were tested for their anticancer
Received in the U.K. April 9, 2005
Address correspondence to Necdet Cos¸kun, Department of Chemistry, Uludag
¨ ¨
University, 16059, Gorukle Bursa, Turkey. E-mail: coskun@uludag.edu.tr
˘
997

998
N. Cos¸kun and A. Parlar
activity and found to be quite active at 1025 molar concentrations). However,
they are a source of new heterocyclic compounds via interesting ring-opening
reactions.[4] The reaction of imidazoline 3-oxides with aryl isocyanates was
shown to proceed regio- and diastereoselectively. Although it is generally
accepted that most 1,3-dipolar cycloadditions are concerted reactions, we
have also supposed the two-step reaction involving a zwitterionic intermediate
as an alternative to the concerted mechanism.[3a,b] Unfortunately we were
unable to isolate any intermediate supporting the two-step mechanism. Inter-
esting reactions of these adducts at different conditions, especially the double
cis elimination they undergo in the presence of dialkylamines, were
reported.[4a,b]
We report herein the synthesis and ring-opening reactions of 1,2,4-oxa-
diazolidin-5-ones. The effect of substituents at C-phenyl on the rate and
yield of cycloaddition of nitrones 1 with phenyl isocyanate was demonstrated
for the first time. Compounds 2a–f were shown to undergo retro cycloaddition
reactions when heated under vacuum. Compounds 2a,c,f undergo easy cis
elimination in the presence of secondary amines, and compounds 2b,d,e
remain unchanged.
Nitrones 1a,c,f were refluxed in acetonitrile for a short time with a
threefold excess of phenyl isocyanate to give oxadiazolidinones 2a,c,f in
high yields, and nitrones 1b,d,e,g convert slowly to the corresponding oxadia-
zolidinones 2b,d,e,g in moderate yields (see Scheme 1 and Table 1).
The structures of 1,2,4-oxadiazolidinones 2a,c,f were deduced from their
IR and 1H and 13C NMR spectra. Compound 2c is known in the literature,[5]
and has had its melting point reported. IR (KBr) spectra of adducts 2a,c,f show
a nC¼O in the range 1744–1754 cm21. Characteristic singlets near 5.70 corre-
spond to the C-3 methine proton, and the benzylic CH2 appears as an AB
system at 4.28 (JAB ¼ 11.9). The benzylic carbon and the C-3 have signals
near d 62 and 81 ppm respectively in their 13C NMR spectra. This is in
good agreement with the data reported in the literature.[6] Compounds 2a–f
underwent a retro cycloaddition reaction when heated under vacuum. The
formed nitrones were isolated and compared with authentic samples (see
Table 1). Compounds 2a,c,f were refluxed in acetonitrile for 18 h but no con-
version to any nitrone or other product was observed. The same compounds
Scheme 1. Reagents: 1–3 (a) R ¼ 3,4-(MeO)2C6H3, R1 ¼ H; (b) R ¼ 2-NO2C6H4,
R1 ¼ H; (c) R ¼ Ph, R1 ¼ Ph; (d) R ¼ 2-NO2C6H4, R1 ¼ 2,3-(MeO)2C6H3; (e)
R ¼ 2-NO2C6H4, R1 ¼ Ph; (f) R ¼ 2,3-(MeO)2C6H3, R1 ¼ Ph; (g) R ¼ 3-NO2C6H4,
R1 ¼ Ph.

Cycloaddition of Acyclic Nitrones
999
Table 1. Synthesis of oxadiazolidinones 2 and their thermal retrocycloadditions
Retro cycloaddition
Yield
Compound (%)
Time Temp. Time
(8C)
Yield
(min) Product (%)
mp
nC¼O (h)
2a
2b
2c
2d
2e
2f
83
52
91
41
43
96
62
oil
1759 3.5
1774 24
170
190
160
190
190
160
10
6
1a
1b
1c
1d
1e
1f
42
33a
53
128–129
124–1256
141–142
139–140
120–122
decomposesb
1744
1.5
5
1759 24
1744 24
6
42
27
6
10
1754
3
57
2 g
aAll nitrones obtained were recrystallized and compared with authentic samples.
bThe yield of the formed compound was deduced from the recovered yield of 1 g.
Attempts to isolate the compound by means of TLC led to its decomposition. The
product was seen to form slowly as in the cases of other nitrones with electron-with-
drawing substituents.
were treated with diethyl amine in refluxing acetonitrile to give the corre-
sponding benzylidenaniline and a second product, which is probably benzal-
dimine, within 3 h. (In the case of 2c the same conversion with
triethylamine completes within 24 h). The mixture was acidified and
extracted with chloroform. After drying the solvent and filtering and evapor-
ating the residue, it was proved to be benzaldehyde by comparing its IR
spectrum with a standard sample. The acidic fraction was basified and
extracted. The product remaining in the chloroform extract was aniline.
Compounds 2b,d,e have nC¼O in the range 1744–1774 cm21. Character-
istic singlets near 6.70 corresponding to C-3 linked hydrogen are at higher
frequency than the corresponding 2c,f. This indicated it to be eclipsed with
the nitrogen’s lone pair at position 2. The molecular modeling studies
revealed this. The benzylic CH2 appears as an AB system near 4.44 ppm.
The benzylic carbon signal appears near d 62, and the signal for C-3 is
77 ppm. (In the case of 2e the signal for C-3 is not seen, probably because
of to coincidence with the CDCl3 triplet). Compounds 2b,d,e did not
undergo cis elimination with diethylamine when refluxed in acetonitrile for
3 h. However, the resulting mixtures after l6 h of reflux did not contain the
corresponding Schiff bases. Corresponding amidine was isolated and charac-
terized in the case of 2b.
Nitrone 1c was stirred in acetonitrile with a threefold excess of
phenyl isocyanate at room temperature for 24 h, and the main product was
N,O-diphenylcarbamoyl-N-benzylhydroxylamine 3 (Scheme 2). The same
product was isolated in 8% yield from the reaction of 1c at the conditions
in Scheme 1.

1000
N. Cos¸kun and A. Parlar
Scheme 2.
The formation of compound 3 may be rationalized by assuming the
formation of an intermediate A (see Scheme 2), the hydrolysis of which
gives compound B, which in turn reacts with second mole of phenyl isocya-
nate to give 3. Compound 3 was obtained by the reaction of N-benzylhydrox-
ylamine hydrochloride with 2 mol of phenyl isocyanate in THF at room
temperature.
An inspection of the energy-minimized conformations of 2a,c,f showed
that benzylic protons and the oxygen lone pair are suitable for cis elimination
with diethyl amine in the trans invertomers (see Figure 1). The trans inverto-
mers of 2a,c,f are more stable than the cis invertomers. There is a slight differ-
ence between the energies of trans and cis invertomers in the cases of
2-nitrophenyl-substituted oxadiazolidinones 2b,d,e. Trans 2b is slightly
more stable than cis 2b, however, in this invertomer the methyl protons and
the oxygen lone pair as well as the C-3 hydrogen and oxygen lone pair are
equally suitably positioned for cis elimination. Cis invertomer is the more
stable in the case of 2d, and there the C-3 hydrogen is in a more appropriate
position for cis elimination to give the corresponding amidine than the
benzylic protons. Therefore, in this case the ring opening leading to
amidine formation should predominate. Cis invertomer 2e is more stable
than the trans one, and in this invertomer the C-3 hydrogen and oxygen
lone pair are again in the same side of the heterocyclic ring, whereas the
benzylic protons are in the sterically crowded side and could not undergo
cis elimination. Thus, 2-nitrophenyl-substituted oxadiazolidinones 2b,d,e
underwent cis elimination through the C-3 hydrogen and ring oxygen lone
pair.
The probable mechanism for the fragmentation of oxadiazolidinones 2
leading to imines is depicted in Scheme 3. The cis elimination through
Figure 1. Cis and trans invertomers of oxadiazolidinone 2c.

Cycloaddition of Acyclic Nitrones
1001
Scheme 3.
transition state A induced by diethylamine produce intermediate B, which
fragments to give the corresponding aldimine, benzalaniline, and carbon
dioxide. To the best of our knowledge this type of fragmentation has not
been reported so far and could serve as an useful tool for the determination
of the more stable invertomer of 1-benzyl or alkyl substituted-1,2,4-
oxadiazolidinones.
EXPERIMENTAL
Melting points were taken on an Electrothermal digital melting-point
apparatus. Infrared spectra were recorded on a Mattson 1000 FTIR. NMR
spectra were recorded on a Bruker Dpx 400-MHz spectrometer. Visualization
was effected with UV light. Freshly prepared nitrones[7] were used after
recrystallization from ether–petroleem ether. The elemental analyses were
performed on a EuroEA 3000 CHNS analyser. MM2 energy minimizations
were performed using Chem3D Ultra 6.
Benzyl(methyl)-3,4-diphenyl-[1,2,4]oxadiazolidin-5-ones 2, General
Procedure
Phenyl isocyanate (3 mmol) dissolved in acetonitrile (2 mL) was added to a
solution of nitrone 1 (1 mmol) in acetonitrile (13 mL), and the reaction
mixture was refluxed for the specified time (see Table 1). The solvent was
evaporated, and the product crystallized from ethanol.
Data
2-Methyl-3-(3,4-dimethoxyphenyl)-4-phenyl-[1,2,4]oxadiazolidin-5-one
1
2a. From nitrone 1a. IR nC¼O 1759 cm21. H NMR (CDCl3) d 2.76 (3H, s),
3.76 (3H, s), 3.79 (3H, s), 5.43 (1H, s), 6.73 (1H, d, J ¼ 8.6), 6.84 (2H, m),
7.06 (1H, m), 7.21 (4H, m). 13C NMR (CDCl3) d 45.62; 56.32; 56.36;
86.38; 110.18; 111.32; 120.98; 121.94; 125.99; 127.61; 129.51; 136.5;

1002
N. Cos¸kun and A. Parlar
150.06; 150.82; 155.2. Anal. calcd. for C17H18N2O4 (314.34) C, 64.96; H,
5.77; N, 8.91. Found C, 64.77; H, 5.80; N, 8.90.
2-Methyl-3-(2-nitrophenyl)-4-phenyl-[1,2,4]oxadiazolidin-5-one 2b. From
1
nitrone 1b. IR (KBr) nC¼O 1774 cm21; H NMR (CDCl3) d 3.06 (3H, s),
6.66 (1H, s), 7.12 (1H, t, J ¼ 7.4), 7.31 (3H, m), 7.41 (2H, m), 7.58 (2H,
m) 8.11 (1H, d, J ¼ 7.6). 13C NMR (CDCl3) d 47.57; 79.77; 118.87;
125.52; 126.72; 127.76; 130.03; 130.91; 132.15; 134.56; 137.04; 148.56;
155.30. Anal. calcd. for C15H13N3O4 (299.28) C, 60.20; H, 4.38; N, 14.04.
Found C, 60.14; H, 4.49; N, 13.90.
2-Benzyl-3,4-diphenyl-[1,2,4]oxadiazolidin-5-one 2c. From nitrone 1c. IR
(KBr) nC¼O 1744 cm21
;
1H NMR (CDCl3) d 4.28 (2H, AB system,
JAB ¼ 11.9), 5.72 (1H, s), 7.04–7.33 (15H, m). 13C NMR (CDCl3) d 62.79;
81.39; 120.58; 125.59; 127.28; 128.98; 129.29; 129.43; 129.62; 130.03;
130.13; 134.12; 136.17; 136.71; 155.21. Anal. calcd for C21H18N2O2
(330.38) C, 76.34; H, 5.49; N, 8.48. Found C, 76.30; H, 5.49; N, 8.47.
2-(2,3-Dimethoxybenzyl-)-3-(2-nitrophenyl)-4-phenyl-[1,2,4]oxadiazoli-
din-5-one 2d. From nitrone 1d. IR (KBr) nC¼O1759 cm21; 1H NMR (CDCl3)
d 3.61 (3H, s), 3.77 (3H, s), 4.44 (2H, AB system, JAB ¼ 13.7), 6.72 (1H, m),
6.96 (2H, m), 7.03 (1H, m), 7.18 (5H, m), 7.31 (1H, d, J ¼ 8.0), 7.47 (2H, m),
8.03 (1H, d, J ¼ 8.0). 13C NMR (CDCl3) d56.25; 57.90; 61.42; 77.19; 113.75;
118.94; 124.23; 124.64; 125.13; 126.45; 127.35; 127.82; 129.60; 130.58;
132.78; 134.26; 136.59; 148.35; 148.74; 153.29; 155.59. Anal. calcd. for
C23H21N3O6 (435.43) C, 63.44; H, 4.86; N, 9.65. Found C, 63.35; H, 4.95;
N, 9.50.
2-Benzyl-3-(2-nitrophenyl)-4-phenyl-[1,2,4]oxadiazolidin-5-one 2e. From
1
nitrone 1e. IR (KBr) nC¼O 1744 cm21; H NMR (CDCl3) d 4.35 (2H, AB
system, JAB ¼ 13.7), 6.87 (1H, s), 7.07 (1H, m), 7.21 (8H, m), 7.35 (4H, m),
7.48 (2H, m), 8.07 (1H, d, J ¼ 7.5). 13C NMR (CDCl3) d 64.32; 118.87;
121.55; 125.46; 126.58; 127.92; 128.91; 129.12; 129.54; 129.81; 130.82;
132.43; 133.88; 134.48; 136.54; 148.64; 155.33. Anal. calcd. for C21H17N3O4
(375.38) C, 67.19; H, 4.56; N, 11.19. Found C, 67.15; H, 4.56; N, 11.05.
2-Benzyl-3-(2,3-dimethoxyphenyl)-4-phenyl-[1,2,4]oxadiazolidin-5-one
1
2f. H NMR (CDCl3) d 3.51 (3H, s), 3.77 (3H, s), 4.31 (2H, AB system,
JAB ¼ 13.00), 6.29 (1H, s), 6.82 (2H, m), 6.94 (1H, t, J ¼ 8.00), 7.08 (1H,
t, J ¼ 8.00), 7.18–7.48 (9H, m). Anal. calcd. for C23H22N2O4 (390.43) C,
70.75; H, 5.68; N, 7.17. Found C, 70.57; H, 5.84; N, 7.03.
Retro Cycloaddition of Compounds 2, General Procedure
Compound 2 (0.1mmol) was placed in a glass sample vial and heated in a
vacuum oven, then left to cool at room temperature. The compounds were
isolated by means of preparative TLC. The identities of the obtained

Cycloaddition of Acyclic Nitrones
1003
compounds were determined by comparing their melting points as well as their
IR spectra with those of authentic samples (see Table 1 for experimental details).
Reaction of 2 with Secondary Amines, General Procedure
Diethylamine (8 mL) was added to a solution of 2 (0.3 mmol) in acetonitrile
(13 mL), and the mixture was refluxed at stirring for 3 to 16 h. The solvent
was evaporated, and the residue subjected to preparative TLC. In the cases
of 2a,c,f the products of the reactions were the corresponding Schiff bases.
They were detected by comparing them with authentic sample as well as
hydrolyzing them to the corresponding amine and aldehydes.
Data
N-Methyl-2-nitro-N0-phenyl-benzamidine, from the reaction of 2d. Yield
70%. Mp 131–1328C; IR (KBr) nNH 3251 cm21; nC¼N 1621 cm21 1H NMR
(CDCl3) d 1.53 (1H, brs), 2.96 (3H, s), 6.61 (1H, m), 6.87 (1H, m), 6.97
(2H, m), 7.43 (3H, m), 7.92 (1H, m). Anal. calcd. for C14H13N3O2 (255.27)
C, 65.87; H, 5.13; N, 16.46. Found C, 65.80; H, 5.20; N, 16.50.
N,O-Diphenylcarbamoyl-N-Benzylhydroxylamine 3. Phenyl isocyanate
(1 mmol) was added to the solution of nitrone 1c (1 mmol) in THF (10 mL)
and the mixture was stirred at room temperature for 24 h. The solvent was
evaporated, and the product was dissolved in ethanol and left to crystallize
at room temperature. The compound melts at 1698C with decomposition. IR
1
(KBr) nNH 3277 cm21; nC¼O 1774 and nC¼N 1642 cm21; H NMR (CDCl3)
d 4.82 (2H, s), 7.05 (2H, m), 7.14 (2H, m), 7.19–7.31 (7H, m), 7.39 (4H,
m), 7.49 (1H, s). 13C NMR (CDCl3) d 56.31; 119.89; 120.56; 125.02;
125.37; 128.93; 129.32; 129.48; 129.54; 129.98; 135.04; 136.16; 137.22;
151.34; 155.60. Anal. calcd. for C21H19N3O3 (361.39) C, 69.79; H, 5.30; N,
11.63. Found C, 69.22; H, 5.41; N, 11.04.
ACKNOWLEDGMENT
˘
The financial support of Uludag University Research Fund is gratefully
acknowledged (Project 2001/2).
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