Mild oxidative cyclization of sydnone-benzoylhydrazone with lead oxide to 2,5-disubstituted-1,3,4-oxadiazole-sydnone hybrid derivatives

Article abstract of DOI:10.1002/jhet.21

The mild oxidation of sydnone-benzoylhydrazone hybrids with lead oxide in acetic acid/dichloromethane solution inducted their intramolecular cyclization to provide the corresponding 2,5-disubstituted-1,3,4-oxidiazole derivatives. The sydnone moiety has be

Full text of DOI:10.1002/jhet.21

January 2009
Mild Oxidative Cyclization of Sydnone-Benzoylhydrazone with
Lead Oxide to 2,5-Disubstituted-1,3,4-Oxadiazole–Sydnone
Hybrid Derivatives
111
Kuo-Chen Chiang,a,b Fung Fuh Wong,c* Chih-Hao Hung,c Yu-Ying Huang,c
Po-Wei Chang,c Yang-Ming Liao,d and Shao-Kai Linb
aDepartment of Resources Engineering, National Cheng Kung University,
Tainan, Taiwan 70101, Republic of China
bSustainable Environment Research Center, National Cheng Kung University,
Tainan City, Taiwan 709, Republic of China
cGraduate Institute of Pharmaceutical Chemistry, China Medical University,
Taichung, Taiwan 40402, Republic of China
dDepartment of Chemistry, National Cheng Kung University,
Tainan, Taiwan 70101, Republic of China
*E-mail: ffwong@mail.cmu.edu.tw
Received May 2, 2008
DOI 10.1002/jhet.21
Published online 6 February 2009 in Wiley InterScience (www.interscience.wiley.com).
The mild oxidation of sydnone-benzoylhydrazone hybrids with lead oxide in acetic acid/dichlorome-
thane solution inducted their intramolecular cyclization to provide the corresponding 2,5-disubstituted-
1,3,4-oxidiazole derivatives. The sydnone moiety has been efficient preserved for the future work in the
mild oxidation.
J. Heterocyclic Chem., 46, 111 (2009).
INTRODUCTION
chloramine T [21]. The azines were used as oxidative
cyclization precursors. Herein, we report the aldehyde
N-acylhydrazone containing sydnone moiety with lead
oxide reagent, at 40ꢀC for 2 h to afford 2,5-disubsti-
tuted-1,3,4-oxadiazole–sydnone hybrids in 51–63%. In
this mild oxidative cyclization, the sydnone moiety is
able to be successful preserved without decomposition.
Sydnones attract attention due to their wildly useful
properties, including biological and pharmaceutical
usage [1], synthetic application [2], photochromic prop-
erties [3], and preparation of electroluminescent materi-
als [4]. Sydones, also considered as the masked hydra-
zines, can react with HCl for de-masking for the further
formation of heterocycles [5].
1,3,4-Oxadiazoles have been reported to be biologi-
cally versatile compounds displaying a variety of biolog-
ical effects, which include anti-inflammatory [6], anti-
fungal [7], antiparasitic [8], and antimicrobial activities
[9]. In addition, they have been used as bioisosteres on
the carboxamide moiety [10]. The most common syn-
thetic approach to 1,3,4-oxidiazoles involves cyclodehy-
dration of 1,2-diacylhydrazines. Typically, the reaction
is carried out by using thionyl chloride [11], phospho-
rous oxychloride [12], phosphorous pentoxide [13], tri-
phenylphosphine [14], or trifluoromethane–sulfonic an-
hydride as the dehydrating agent [15].
RESULTS AND DISCUSSION
The synthetic pathway of the 2,5-disubstituted-1,3,4-
oxadiazole–sydnone hybrid derivatives (7–10) was
depicted in Scheme 1. Following by the published pro-
cedure [2,22], the sydnone compounds were easily con-
verted to the 3-aryl-4-formyl-sydnone derivatives 1a–1d
in a solution of POCl3 and DMF by the Schmidt reac-
tion. And benzoyl chloride reacted with hydrazine
monohydrate to generate benzoylhydrazones 2a–2d.
Then various 3-aryl-4-formyl-sydnone derivatives 1a–1d
(p-R1 ¼ H, Me, OMe, and OEt) were mixed with ben-
zoylhydrazones 2a–2d (p-R2 ¼ H, Me, Cl, and sydnone)
and stirred for 2.0–6.0 h in an EtOH solution to achieve
the elimination and give the corresponding products 3–6
in good yields (74–86%, see Table 1) [23].
Another alternative route to 1,3,4-oxadiazoles by oxi-
dative cyclization from the corresponding aldehyde N-
acylhydrazones proceeds with lead tetraacetate [16],
lead oxide [17], potassium permanganate [18], electro-
chemical methods [19], iodobenzene diacetate [20], or
C
V
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K.-C. Chiang, F. F. Wong, C.-H. Hung, Y.-Y. Huang, P.-W. Chang, Y.-M. Liao, and S.-K. Lin
Vol 46
Scheme 1. The synthetical route of 2,5-disubstituted-1,3,4-oxadiazole–
sydnone hybrid derivatives.
Scheme 2. The proposed mechanism of the oxidative cyclization.
Aldehyde N-acylhydrazones 3–6 were performed the
oxidative–cyclization by using fresh KMnO4 in acetic
acid/dichloromethane solution. The low isolable oxida-
tive–cyclization products were provided because of the
further oxidation formation and the damage of sydnone
ring by KMnO4. In the controllable and improvable
experiment, the commercially available reagent lead ox-
ide (PbO2) was selected for the mild oxidative–cycliza-
tion agent [17,24]. When the aldehyde N-acylhydrazones
3–6 were oxidized with 2.5 equiv of lead oxide (PbO2),
the 2,5-disubstituted-1,3,4-oxadiazole–sydnone hybrid
derivatives 7–10 were formed in 50–63% yields. The
long range of the substitution effects on R1 (H, Me,
OMe, and OEt) and R2 (H, Me, Cl, and sydnone) posi-
tions are not clearly a function of the isolated yield and
the results are shown in Table 1.
Because of the electron radical can be stabilized by the
strong electronegativity of oxygen atom, the electron
radical migrates from nitrogen to oxygen atom to form
the radical intermediate 13. The intermediate 13 under-
goes the further oxidative cyclization to yield 2,5-disub-
stituted-1,3,4-oxadiazole–sydnone hybrid 14 [23].
In conclusion, we have developed a mild and efficient
oxidative–cyclization method for the synthesis of 2,5-
disubstituted-1,3,4-oxadiazole–sydnone hybrid deriva-
tives. Using this mild radical cyclization, the sydnone
ring was successfully preserved to provide 1,3,4-oxadia-
zole–sydnone hybrids in the core molecular.
EXPERIMENTAL
The proposed oxidative–cyclization mechanism is
shown in the Scheme 2. The aldehyde N-acylhydrazone
11 can be oxidized by lead oxide (PbO2) to trap the
hydrogen and afford the hydrazonyl radical 12 [17].
General procedure. Analytical thin-layer chromatography
was performed on precoated plates (silica gel 60 F-254), pur-
chased from Merck Inc. Purification by gravity column chro-
matography was carried out by use of Merck Reagents Silica
Gel 60 (particle size 0.063–0.200 mm, 70–230 mesh ASTM).
Infrared (IR) spectra were measured on a Bomem Michelson
Series FT-IR spectrometer. The wave numbers reported are
referenced to the polystyrene 1601 cmꢁ1 absorption. Absorp-
tion intensities are recorded by the following abbreviations: s,
strong; m, medium; w, weak. Proton NMR spectra were
obtained on a Bruker-300 (400 MHz) spectrometer by use of
CDCl3 and d6-DMSO as solvent. Carbon-13 NMR spectra
were obtained on a Varian a Bruker-300 (100 MHz) spectrom-
eter by used of CDCl3 as solvent. Carbon-13 chemical shifts
are referenced to the center of the CDCl3 triplet (d 77.0 ppm).
Multiplicities are recorded by the following abbreviations: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; J, cou-
pling constant (hertz). Elemental analyses were carried out on
a Heraeus CHN–O RAPID element analyzer. Mass spectra
were measured on a VG Platform II GC-MS Instruments. FAB
mass and High-resolution mass spectra were obtained by
Table 1
The yields of aldehyde N-acylhydrazones 3–6 and
2,5-disubstituted-1,3,4-oxadiazole–sydnone hybrid derivatives 7–10.
Entry
Compounds Yield Compounds Yield
3–6
R1
H
R2
(%)
7–10
(%)
H
Me
Cl
Sydnone
H
Me
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
80
86
77
84
83
83
75
87
82
85
75
89
82
84
74
89
7a
7b
7c
7d
8a
8b
8c
8d
9a
57
57
50
51
59
58
51
53
61
60
53
58
63
62
53
57
Me
Cl
Sydnone
H
Me
OMe
OEt
9b
9c
means of a Finnigan/Thermo Quest MAT 95XL mass
spectrometer.
Cl
Sydnone
H
Me
9d
10a
10b
10c
10d
Standard procedure for the substitution reaction. To a
solution of 3-aryl-4-formyl-sydnone derivatives (1a–1d, 0.38 g,
2.00 mmol, 1.0 equiv) and benzoylhydrazones (2a–2d, 0.27 g,
2.00 mmol, 1.6 equiv) in EtOH (10 mL) was stirred and
Cl
Sydnone
added
one
drop
of
aqueous
H2SO4
solution.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009
Mild Oxidative Cyclization of Sydnone-Benzoylhydrazone with Lead Oxide
to 2,5-Disubstituted-1,3,4-Oxadiazole–Sydnone Hybrid Derivatives
113
The reaction mixture was stirred at room temperature for 2.0 h.
After the reaction was completed, the resultant precipitate
was filtrated, washed with cold EtOH (20 mL ꢂ 2), and
dried in vacuum oven. The residue was purified by recrys-
tallization from EtOAc to give pure aldehyde N-acylhydra-
zones 3–6 as white powder in 74–86% yields.
(DMSO-d6, 300 MHz) d 3.88 (s, 3H, OCH3), 7.12–7.72 (m, 9
H), 8.03 (s, 1 H), 11.56 (s, 1 H, NH); 13C NMR (DMSO-d6,
75 MHz) d 56.8, 106.2, 121.2, 121.7, 127.7, 129.3, 130.5,
130.6, 133.7, 134.8, 142.3, 162.8, 164.0; IR (KBr) 3334 (s,
NH), 1755 (m, C¼¼O), 1704 m cmꢁ1; FABMS m/z (relative in-
tensity) 339 (M þ 1, 68), 338 (Mþ, 6).
3-Phenyl-4-formylsydnone benzoylhydrazone (3a). Mp (re-
crystallized from EtOAc) 196–198ꢀC; 1H NMR (DMSO-d6,
300 MHz) d 7.40–7.82 (m, 10 H), 8.11 (s, 1 H), 11.69 (s, 1 H,
NH); 13C NMR (DMSO-d6, 75 MHz) d 106.1, 125.9, 127.7,
128.7, 130.3, 132.1, 133.2, 133.4, 134.5, 142.1, 162.9, 164.3; IR
(KBr) 3370 (s, NH), 1755 (m, C¼¼O), 1695 m cmꢁ1; FABMS m/z
(relative intensity) 309 (M þ 1, 59), 308 (Mþ, 15).
3-(p-Methoxyphenyl)-4-formylsydnone p-methylbenzoyl-
hydrazone (5b). Mp (recrystallized from EtOAc) 178–180ꢀC;
1H NMR (DMSO-d6, 300 MHz) d 2.34 (s, 3H, CH3), 3.88 (s,
3H, OCH3), 7.25–7.79 (m, 8 H), 8.02 (s, 1 H), 11.66 (s, 1 H,
NH); 13C NMR (DMSO-d6, 75 MHz) d 21.1, 56.7, 106.4, 121.3,
121.8, 127.7, 129.1, 130.3, 131.8, 133.8, 134.5, 142.1, 162.7,
164.0; IR (KBr) 3332 (s, NH), 1748 (m, C¼¼O), 1701 m cmꢁ1
;
3-Phenyl-4-formylsydnone p-methylbenzoylhydrazone (3b).
Mp (recrystallized from EtOAc) 197–199ꢀC; 1H NMR
(DMSO-d6, 300 MHz) d 2.21 (s, 3H, CH3), 7.12–7.72 (m, 9
H), 8.03 (s, 1 H), 11.56 (s, 1 H, NH); 13C NMR (DMSO-d6,
75 MHz) d 21.2, 106.2, 125.9, 127.5, 127.7, 129.2, 130.3,
132.8, 133.4, 134.3, 142.2, 162.8, 164.1; IR (KBr) 3338 (s,
NH), 1754 (m, C¼¼O), 1692 m cmꢁ1; FABMS m/z (relative in-
tensity) 323 (M þ 1, 74), 322 (Mþ, 35).
FABMS m/z (relative intensity) 353 (M þ 1, 21), 352 (Mþ, 2).
3-(p-Methoxyphenyl)-4-formylsydnone p-chlorolbenzoyl-
hydrazone (5c). Mp (recrystallized from EtOAc) 191–193ꢀC;
1H NMR (DMSO-d6, 300 MHz) d 3.87 (s, 3H, OCH3), 7.03–
7.70 (m, 8 H), 7.90 (s, 1 H), 11.52 (s, 1 H, NH); 13C NMR
(DMSO-d6, 75 MHz) d 56.6, 106.1, 121.1, 121.2, 127.4,
129.2, 130.1, 130.5, 132.9, 134.5, 142.0, 161.7, 163.8; IR
(KBr) 3361 (s, NH), 1755 (m, C¼¼O), 1699 m cmꢁ1; FABMS
m/z (relative intensity) 373 (M þ 1, 62), 372 (Mþ, 13).
3-Phenyl-4-formylsydnone p-chlorolbenzoylhydrazone (3c).
1
Mp (recrystallized from EtOAc) 200–202ꢀC; H NMR (DMSO-
3-(p-Methoxyphenyl)-4-formylsydnone 4-(sydnon-3-yl)ben-
zoylhydrazone (5d). Mp (recrystallized from MeOH) 204–
d6, 300 MHz) d 7.10–7.80 (m, 9 H), 7.86 (s, 1 H), 11.68 (s, 1
H, NH); 13C NMR (DMSO-d6, 75 MHz) d 106.0, 125.3, 125.8,
127.1, 128.5, 130.2, 132.1, 133.2, 133.5, 142.3, 161.8, 163.9; IR
1
206ꢀC; H NMR (DMSO-d6, 300 MHz) d 3.87 (s, 3H, OCH3),
7.24–8.15 (m, 10 H, ArH þ sydnone), 11.92 (s, 1 H, NH); IR
(KBr) 3092 (s, NH), 1746 (m, C¼¼O), 1683 m cmꢁ1; FABMS
m/z (relative intensity) 423 (M þ 1, 6), 422 (Mþ, 1).
(KBr) 3364 (s, NH), 1755 (m, C¼¼O), 1689 m cmꢁ1
.
3-Phenyl-4-formylsydnone 4-(sydnon-3-yl)benzoylhydrazone
(3d). Mp (recrystallized from MeOH) 183–185ꢀC; 1H NMR
(DMSO-d6, 300 MHz) d 7.05–8.68 (m, 11 H, ArH þ syd-
none), 12.35 (s, 1 H, NH); IR (KBr) 3091 (s, NH), 1745 (m,
C¼¼O), 1681 m cmꢁ1; FABMS m/z (relative intensity) 393
(M þ 1, 3), 392 (Mþ, 24).
3-(p-Ethoxyphenyl)-4-formylsydnone benzoyl-hydrazone
(6a). Mp (recrystallized from EtOAc) 192–194ꢀC; 1H NMR
(DMSO-d6, 300 MHz) d 1.37 (t, 3 H, J ¼ 7.0 Hz, CH3), 4.15
(q, 2 H, J ¼ 7.0 Hz, CH2), 7.20–7.83 (m, 9 H), 8.15 (s, 1 H),
11.70 (s, 1 H, NH); 13C NMR (DMSO-d6, 75 MHz) d 14.7,
64.2, 106.2, 125.8, 127.5, 127.7, 128.7, 129.1, 132.2, 133.2,
134.9, 142.3, 161.5, 163.0; IR (KBr) 3352 (s, NH), 1749 (m,
C¼¼O), 1698 m cmꢁþ1; FABMS m/z (relative intensity) 353
(M þ 1, 21), 352 (M , 3).
3-(p-Methylphenyl)-4-formylsydnone benzoylhydrazone
(4a). Mp (recrystallized from EtOAc) 191–193ꢀC; 1H NMR
(DMSO-d6, 300 MHz) d 2.46 (s, 3H, CH3), 7.25–7.75 (m, 9 H),
8.11 (s, 1 H), 11.66 (s, 1 H, NH); 13C NMR (DMSO-d6, 75
MHz) d 21.1, 106.1, 125.7, 127.3, 127.7, 129.0, 129.3, 130.3,
131.1, 134.5, 143.2, 162.8, 164.7; IR (KBr) 3352 (s, NH), 1758
3-(p-Ethoxyphenyl)-4-formylsydnone p-methylbenzoyl-
hydrazone (6b). Mp (recrystallized from EtOAc) 189–191ꢀC;
1H NMR (DMSO-d6, 300 MHz) d 1.33 (t, 3 H, J ¼ 7.0 Hz,
CH3), 2.44 (s, 3H, CH3), 4.13 (q, 2 H, J ¼ 7.0 Hz, CH2),
7.20–7.78 (m, 9 H), 8.15 (s, 1 H), 11.65 (s, 1 H, NH); 13C
NMR (DMSO-d6, 75 MHz) d 14.7, 21.2, 64.2, 106.1, 125.8,
127.4, 127.7, 128.7, 129.2, 130.2, 133.2, 134.6, 142.3, 164.0;
(m, C¼¼O), 1692 m cmꢁ1
.
3-(p-Methylphenyl)-4-formylsydnone p-methylbenzoylhydra-
zone (4b). Mp (recrystallized from EtOAc) 197–199ꢀC; 1H
NMR (DMSO-d6, 300 MHz) d 2.20 (s, 3H, CH3), 2.46 (s, 3H,
CH3), 7.25–7.75 (m, 8 H), 8.16 (s, 1 H), 11.67 (s, 1 H, NH);
13C NMR (DMSO-d6, 75 MHz) d 21.0, 21.2, 106.3, 126.2,
127.3, 127.9, 129.8, 130.4, 132.6,134.5, 142.6, 162.5, 164.0;
IR (KBr) 3358 (s, NH), 1740 (m, C¼¼O), 1695 m cmꢁ1
;
FABMS m/z (relative intensity) 367 (M þ 1, 19), 366 (Mþ, 4).
3-(p-Ethoxyphenyl)-4-formylsydnone p-chlorolbenzoyl-
hydrazone (6c). Mp (recrystallized from EtOAc) 195–197ꢀC;
1H NMR (DMSO-d6, 300 MHz) d 1.36 (t, 3 H, J ¼ 7.0 Hz,
CH3), 4.13 (q, 2 H, J ¼ 7.0 Hz, CH2), 7.13–7.80 (m, 8 H),
7.91 (s, 1 H), 11.66 (s, 1 H, NH); 13C NMR (DMSO-d6, 75
MHz) d 14.6, 64.1, 105.8, 125.5, 127.2, 127.7, 128.8, 129.4,
132.2, 133.0, 134.6, 142.1, 160.8, 162.9; IR (KBr) 3350 (s,
NH), 1745 (m, C¼¼O), 1699 m cmꢁ1; FABMS m/z (relative in-
tensity) 387 (M þ 1, 51), 386 (Mþ, 3).
IR (KBr) 3345 (s, NH), 1752 (m, C¼¼O), 1695 m cmꢁ1
.
3-(p-Methylphenyl)-4-formylsydnone p-chlorolbenzoylhydra-
zone (4c). Mp (recrystallized from EtOAc) 201–203ꢀC; 1H
NMR (DMSO-d6, 300 MHz) d 2.43 (s, 3H, CH3), 7.28–7.90
(m, 8 H), 7.98 (s, 1 H), 11.63 (s, 1 H, NH); 13C NMR
(DMSO-d6, 75 MHz) d 21.0, 106.0, 125.1, 127.0, 127.4,
128.8, 129.1, 130.2, 130.9, 134.2, 143.1, 162.4, 164.1; IR
(KBr) 3359 (s, NH), 1752 (m, C¼¼O), 1695 m cmꢁ1
.
4-(sydnon-3-yl)ben-
3-(p-Methylphenyl)-4-formylsydnone
3-(p-Ethoxyphenyl)-4-formylsydnone 4-(sydnon-3-yl)ben-
zoylhydrazone (6d). Mp (recrystallized from MeOH) 178–
180ꢀC; 1H NMR (DMSO-d6, 300 MHz) d 1.37 (t, 3 H, J ¼
6.9 Hz, CH3), 4.14 (q, 2 H, J ¼ 6.9 Hz, CH2), 7.21–8.16 (m,
10 H, ArH þ sydnone), 11.93 (s, 1 H, NH); IR (KBr) 3094 (s,
NH), 1749 (m, C¼¼O), 1677 m cm–1; FABMS m/z (relative in-
tensity) 437 (M þ 1, 6), 436 (Mþ, 4).
zoylhydrazone (4d). Mp (recrystallized from MeOH) 210–
212ꢀC; 1H NMR (DMSO-d6, 300 MHz) d 2.43 (s, 3H, CH3),
7.39–8.15 (m, 10 H, ArH þ sydnone), 11.93 (s, 1 H, NH); IR
(KBr) 3095 (s, NH), 1751 (m, C¼¼O), 1679 m cmꢁ1
(5a). Mp (recrystallized from EtOAc) 183–185ꢀC; 1H NMR
.
3-(p-Methoxyphenyl)-4-formylsydnone benzoyl-hydrazone
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Vol 46
Standard procedure for the oxidative–cyclization.
3-(p-Methylphenyl)-4-[5-(p-chlorophenyl)-1,3,4-oxadiazol-
Aldehyde N-acylhydrazones 3–6 (0.31 g, 1.00 mmol, 1.0
equiv) was dissolved in glacial acetic acid/dichloromethane (1/
1, 15 mL). Lead oxide (PbO2, 0.60 g, 2.50 mmol, 2.5 equiv)
was added to the reaction mixture and stirred at 35–40ꢀC for
1.5–6 h. After the reaction was completed, the reaction mix-
ture was filtrated to remove the lead oxide residue and washed
with cold dichloromethane (10 mL ꢂ 3). The filtrate was
washed and extracted with saturated NaHCO3 aqueous solution
(20 mL ꢂ 2) to remove the residue glacial acetic acid. The
combined organic layer was dried with MgSO4 (s) and concen-
trated under reduced pressure. The residue was purified by
recrystallization from dichloromethane to give pure 2,5-disub-
stituted-1,3,4-oxidiazole–sydnone hybrid derivatives 7–10 as a
white powder in 50–63% yields.
3-Phenyl-4-(5-phenyl-1,3,4-oxadiazol-2-yl)sydnone (7a).
Mp (recrystallized from CH2Cl2) 177–179ꢀC; 1H NMR
(DMSO-d6, 300 MHz) d 7.51–7.96 (m, 10 H); 13C NMR
(DMSO-d6, 75 MHz) d 97.6, 120.6, 126.0, 126.5, 129.7,
129.9, 132.5, 133.0, 134.5, 154.1, 163.1, 163.9; IR (KBr) 1749
m cmꢁ1; FABMS m/z (relative intensity) 307 (M þ 1, 77),
306 (Mþ, 9); Anal. Calcd for C16H10N4O3: C, 62.74; H, 3.72;
N, 18.30. Found: C, 62.51; H, 3.35; N, 18.04.
2-yl]sydnone (8c). Mp (recrystallized from CH2Cl2) 202–
205ꢀC; 1H NMR (DMSO-d6, 300 MHz) d 2.42 (s, 3H, CH3),
7.43–7.99 (m, 9 H); IR (KBr) 1749 m cmꢁ1; FABMS m/z (rel-
ative intensity) 357 (M þ 1, 51), 356 (Mþ, 16); Anal. Calcd
for C17H11N4O3Cl: C, 57.55; H, 3.10; N, 15.80. Found: C,
57.33; H, 3.07; N, 15.72.
4-[5-(4-Sydnon-3-yl-phenyl)-1,3,4-oxadiazol-2-yl]-3-(4-
methylphenyl)sydnone (8d). Mp (recrystallized from CH2Cl2)
215–217ꢀC; 1H NMR (DMSO-d6, 300 MHz) d 2.45 (s, 3H,
CH3), 7.52 (d, 2 H, J ¼ 8.2 Hz), 7.79 (d, 2 H, J ¼ 8.2 Hz),
7.88 (s, 1 H), 8.01 (d, 2 H, J ¼ 8.6 Hz), 8.14 (d, 2 H, J ¼ 8.6
Hz); IR (KBr) 1753 m cmꢁ1; FABMS m/z (relative intensity)
397 (M þ 1, 64), 396 (Mþ, 11); Anal. Calcd for C18H10N6O5:
C, 56.43; H, 2.97; N, 20.79. Found: C, 56.18; H, 3.24; N,
20.96.
3-p-Methoxyphenyl-4-(5-phenyl-1,3,4-oxadiazol-2-yl)-sydnone
(9a). Mp (recrystallized from CH2Cl2) 224–226ꢀC; 1H NMR
(DMSO-d6, 300 MHz) d 3.89 (s, 3H, OCH3), 7.25–7.78 (m, 9
H); 13C NMR (DMSO-d6, 75 MHz) d 56.6, 97.4, 122.3, 125.9,
126.3, 129.1, 130.2, 132.1, 133.6, 134.7, 154.8, 162.2, 164.0;
IR (KBr) 1748 m cmꢁ1; FABMS m/z (relative intensity) 337
(M þ 1, 37), 336 (Mþ, 4); Anal. Calcd for C17H12N4O4: C,
60.71; H, 3.57; N, 16.67. Found: C, 60.87; H, 3.67; N, 16.54.
3-(p-Methoxyphenyl)-4-[5-(p-methylphenyl)-1,3,4-oxadiazol-
2-yl]sydnone (9b). Mp (recrystallized from CH2Cl2) 188–
190ꢀC; 1H NMR (DMSO-d6, 300 MHz) d 2.38 (s, 3H, CH3),
3.87 (s, 3H, OCH3), 7.19–7.88 (m, 8 H); IR (KBr) 1755 m
cm–1; FABMS m/z (relative intensity) 350 (M þ 1, 28), 349
(Mþ, 8); Anal. Calcd for C18H13N4O4: C, 61.71; H, 3.71; N,
16.00. Found: C, 61.52; H, 3.54; N, 15.86.
3-Phenyl-4-[5-(p-methylphenyl)-1,3,4-oxadiazol-2-yl]-sydnone
(7b). Mp (recrystallized from CH2Cl2) 205–207ꢀC; 1H NMR
(DMSO-d6, 300 MHz) d 2.42 (s, 3H, CH3), 7.34–7.94 (m, 9 H);
13C NMR (DMSO-d6, 75 MHz) d 21.2, 106.2, 125.9, 127.5,
127.7, 129.2, 130.3, 132.8, 133.4, 134.3, 142.2, 162.8, 164.1; IR
(KBr) 1743 m cmꢁ1; FABMS m/z (relative intensity) 321 (M þ
1, 48), 320 (Mþ, 14); Anal. Calcd for C17H12N4O3: C, 63.75; H,
3.75; N, 17.50. Found: C, 63.91; H, 3.87; N, 17.81.
3-Phenyl-4-[5-(p-chlorophenyl)-1,3,4-oxadiazol-2-yl]sydnone
(7c). Mp (recrystallized from CH2Cl2) 187–189ꢀC; 1H NMR
(DMSO-d6, 300 MHz) d 7.43–7.99 (m, 9 H); 13C NMR
(DMSO-d6, 75 MHz) d 97.4, 121.3, 126.2,128.4, 129.5, 132.0,
3-(p-Methoxyphenyl)-4-[5-(p-chlorophenyl)-1,3,4-oxadiazol-
2-yl]sydnone (9c). Mp (recrystallized from CH2Cl2) 203–
1
205ꢀC; H NMR (DMSO-d6, 300 MHz) d 3.88 (s, 3H, OCH3),
7.25–7.75 (m, 8 H); IR (KBr) 1744 m cmꢁ1; FABMS m/z (rel-
ative intensity) 372 (M þ 1, 31), 371 (Mþ, 9); Anal. Calcd for
C17H11N4O4Cl: C, 55.06; H, 2.97; N, 15.11. Found: C, 54.94;
H, 2.81; N, 14.89.
133.1, 136.5, 154.5, 162.9, 164.0; IR (KBr) 1755 m cmꢁ1
;
Anal. Calcd for C16H9N4O3Cl: C, 56.38; H, 2.64; N, 16.45.
Found: C, 56.63; H, 2.41; N, 16.64.
3-Phenyl-4-[5-(p-chlorophenyl)-1,3,4-oxadiazol-2-yl]-syd-
none (7c). Mp (recrystallized from CH2Cl2) 187–189ꢀC; 1H
NMR (DMSO-d6, 300 MHz) d 7.43–7.99 (m, 9 H); 13C NMR
(DMSO-d6, 75 MHz) d 97.4, 121.3, 126.2,128.4, 129.5, 132.0,
4-[5-(4-Sydnon-3-yl-phenyl)-1,3,4-oxadiazol-2-yl]-3-(4-
methoxyphenyl)sydnone (9d). Mp (recrystallized from CH2Cl2)
225–227ꢀC; 1H NMR (DMSO-d6, 300 MHz) d 3.86 (s, 3H,
OCH3), 7.35 (d, 2 H, J ¼ 8.2 Hz), 7.82 (d, 2 H, J ¼ 8.2 Hz),
7.88 (s, 1 H), 8.03 (d, 2 H, J ¼ 8.5 Hz), 8.13 (d, 2 H, J ¼ 8.5
Hz); IR (KBr) 1749 m cmꢁ1; FABMS m/z (relative intensity)
421 (M þ 1, 3), 420 (Mþ, 1); Anal. Calcd for C19H12N6O6: C,
53.77; H, 2.83; N, 22.64. Found: C, 53.97; H, 2.96; N, 22.81.
3-p-Ethoxyphenyl-4-(5-phenyl-1,3,4-oxadiazol-2-yl)sydnone
(9a). Mp (recrystallized from CH2Cl2) 187–189ꢀC; 1H NMR
(DMSO-d6, 300 MHz) d 1.38 (t, 3 H, J ¼ 6.9 Hz, CH3), 4.16
(q, 2 H, J ¼ 6.9 Hz, CH2), 7.18–7.84 (m, 9 H); 13C NMR
(DMSO-d6, 75 MHz) d 14.6, 64.2, 97.5, 115.3, 122.7, 126.5,
126.8, 127.5, 129.7, 132.5, 154.2, 161.7, 163.1, 164.0; IR
(KBr) 1751 m cmꢁ1; FABMS m/z (relative intensity) 351
(M þ 1, 49), 350 (Mþ, 4); Anal. Calcd for C18H14N4O4: C,
61.71; H, 4.00; N, 16.00. Found: C, 61.58; H, 4.10; N, 15.89.
3-(p-Ethoxyphenyl)-4-[5-(p-methylphenyl)-1,3,4-oxadiazol-
2-yl]sydnone (10b). Mp (recrystallized from CH2Cl2) 204–
206ꢀC; 1H NMR (DMSO-d6, 300 MHz) d 1.38 (t, 3 H, J ¼
6.9 Hz, CH3), 2.43 (s, 3H, CH3), 4.19 (q, 2 H, J ¼ 6.9 Hz,
CH2), 7.22 (d, 2 H, J ¼ 9.0 Hz), 7.36 (d, 2 H, J ¼ 8.1 Hz),
7.64 (d, 2 H, J ¼ 8.1 Hz), 7.82 (d, 2 H, J ¼ 9.0 Hz); 13C
133.1, 136.5, 154.5, 162.9, 164.0; IR (KBr) 1755 m cmꢁ1
;
Anal. Calcd for C16H9N4O3Cl: C, 56.38; H, 2.64; N, 16.45.
Found: C, 56.62; H, 2.41; N, 16.64.
3-p-Methylphenyl-4-(5-phenyl-1,3,4-oxadiazol-2-yl)sydnone
(8a). Mp (recrystallized from CH2Cl2) 204–206ꢀC; 1H NMR
(DMSO-d6, 300 MHz) d 2.43 (s, 3H, CH3), 7.41–7.78 (m, 9
H); 13C NMR (DMSO-d6, 75 MHz) d 21.2, 97.5, 122.6, 125.8,
126.7, 129.3, 129.9, 132.1, 133.5, 134.6, 154.5, 162.8, 163.6;
IR (KBr) 1752 m cmꢁ1; FABMS m/z (relative intensity) 321
(M þ 1, 45), 320 (Mþ, 13); Anal. Calcd for C17H12N4O3: C,
63.75; H, 3.75; N, 17.50. Found: C, 63.68; H, 3.42; N, 17.86.
3-p-Methylphenyl-4-(5-phenyl-1,3,4-oxadiazol-2-yl)sydnone
(8a). Mp (recrystallized from CH2Cl2) 204–206ꢀC; 1H NMR
(DMSO-d6, 300 MHz) d 2.43 (s, 3H, CH3), 7.41–7.78 (m, 9
H); 13C NMR (DMSO-d6, 75 MHz) d 21.2, 97.5, 122.6, 125.8,
126.7, 129.3, 129.9, 132.1, 133.5, 134.6, 154.5, 162.8, 163.6;
IR (KBr) 1752 m cmꢁ1; FABMS m/z (relative intensity) 321
(M þ 1, 45), 320 (Mþ, 13); Anal. Calcd for C17H12N4O3: C,
63.75; H, 3.75; N, 17.50. Found: C, 63.68; H, 3.42; N, 17.86.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009
Mild Oxidative Cyclization of Sydnone-Benzoylhydrazone with Lead Oxide
to 2,5-Disubstituted-1,3,4-Oxadiazole–Sydnone Hybrid Derivatives
115
F. F.; Lin, C.-M.; Chen, W.-Y.; Yeh, M.-Y. Heteroatom Chem 2006, 17,
160.
NMR (DMSO-d6, 75 MHz) d 14.6, 21.3, 64.2, 97.5, 115.2,
120.0, 126.5, 126.8, 127.5, 130.2, 142.8, 153.9, 161.7, 163.2,
164.0; IR (KBr) 1751 m cmꢁ1; FABMS m/z (relative intensity)
365 (M þ 1, 91), 364 (Mþ, 7); Anal. Calcd for C19H16N4O4:
C, 62.64; H, 4.40; N, 15.37. Found: C, 62.19; H, 4.08; N,
15.01.
3-(p-Ethoxyphenyl)-4-[5-(p-chlorophenyl)-1,3,4-oxadiazol-
2-yl]sydnone (10c). Mp (recrystallized from CH2Cl2) 190–
192ꢀC; 1H NMR (DMSO-d6, 300 MHz) d 1.39 (t, 3 H, J ¼
7.0 Hz, CH3), 4.17 (q, 2 H, J ¼ 7.0 Hz, CH2), 7.21–7.89 (m,
8 H); 13C NMR (DMSO-d6, 75 MHz) d 14.7, 64.3, 97.6,
114.8, 122.9, 125.9, 127.0, 127.8, 130.0, 132.1, 154.4, 161.5,
163.2, 164.1; IR (KBr) 1749 m cmꢁ1; FABMS m/z (relative
intensity) 385 (M þ 1, 11), 384 (Mþ, 3); Anal. Calcd for
C18H13N4O4Cl: C, 56.17; H, 3.38; N, 15.43. Found: C, 56.54;
H, 3.68; N, 15.94.
4-[5-(4-Sydnon-3-yl-phenyl)-1,3,4-oxadiazol-2-yl]-3-(4-
ethoxyphenyl)sydnone (10d). Mp (recrystallized from CH2Cl2)
178–181ꢀC; 1H NMR (DMSO-d6, 300 MHz) d 1.38 (t, 3 H,
J ¼ 7.0 Hz, CH3), 4.16 (q, 2 H, J ¼ 7.0 Hz, CH2), 7.25 (d, 2
H, J ¼ 8.2 Hz), 7.85 (d, 2 H, J ¼ 8.2 Hz), 7.88 (s, 1 H), 8.03
(d, 2 H, J ¼ 8.5 Hz), 8.16 (d, 2 H, J ¼ 8.5 Hz); IR (KBr)
1746 m cmꢁ1; FABMS m/z (relative intensity) 437 (M þ 1,
28), 436 (Mþ, 13); Anal. Calcd for C20H16N6O6: C, 55.05; H,
3.67; N, 19.27. Found: C, 55.37; H, 3.84; N, 19.47.
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Acknowledgment. This work was supported by the National
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet