Microwave-induced one-pot synthesis of 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-butan-2-ones under solvent free conditions

Article abstract of DOI:10.1016/j.tetlet.2007.06.116

The synthesis of 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-butan-2-ones (5a-l) from methyl levulinate (4) and arylamidoximes (1a-l) is described. The reaction was carried out in a microwave oven without any solvent in much shorter time and in yields comparable wi

Full text of DOI:10.1016/j.tetlet.2007.06.116

Tetrahedron Letters 48 (2007) 6195–6198
Microwave-induced one-pot synthesis of
4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-butan-2-ones
under solvent free conditions
b
a
a
´
Jucleiton Jose R. de Freitas, Juliano Carlo R. de Freitas, Ladjane P. da Silva,
Joao R. de Freitas Filho,a,b, Gisele Y. V. Kimura and Rajendra M. Srivastava
a
a,
*
*
˜
aDepartamento de Quı´mica Fundamental, Universidade Federal de Pernambuco, 50.740-540 Recife, PE, Brazil
b
ˆ
Unidade Academica de Garanhuns, Universidade Federal Rural de Pernambuco, Recife, PE, Brazil
Received 25 May 2007; revised 19 June 2007; accepted 21 June 2007
Available online 24 June 2007
Abstract—The synthesis of 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-butan-2-ones (5a–l) from methyl levulinate (4) and arylamidoximes (1a–
l) is described. The reaction was carried out in a microwave oven without any solvent in much shorter time and in yields comparable
with conventional heating.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
In general, O-acylamidoximes are cyclodehydrated
either by heat or by bases to generate 1,2,4-oxadiaz-
oles.12 In 2001, a publication appeared describing such
cyclization by employing tetrabutylammonium fluoride
(TBAF) as an activator.13 1,2,4-Oxadiazoles can also
be obtained by the reaction of amidoximes and a car-
boxylic acid in the presence of a coupling reagent, like
dicyclohexylcarbodiimide (DCC), diisopropylcarbo-
diimide (DIC), and 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide (EDC).14
1,2,4-Oxadiazoles owe their significance primarily due to
their wide range of biological activities, which have been
well documented in four surveys.1–4 During the last two
decades, these heteroaryl compounds have been
receiving considerable attention in the drug discovery
programs with reported muscarinic agonist, benzodiaze-
pine receptor agonist, 5HT agonist, and antirhinoviral
activities.5a–e 1,2,4-Oxadiazoles are bioisosteres for
esters and amides and the replacement of these groups
with the heterocyclic ring makes them resistant to
enzyme-catalyzed hydrolysis and improves their biolog-
ical activities.5c,6,7 The bioisosteres just mentioned above
have also been utilized for planning the preparation of
dipeptidomimetics.8 Our own group has been involved
in testing 1,2,4-oxadiazoles against inflammation and
found several of them possessing antiinflammatory
properties.9a–d Besides, N-methylpyridinium salts having
a perfluoroalkylated 1,2,4-oxadiazoles have been pre-
pared by Italian researchers and considered to be a
new family of salts as prospective fluorous solvents.10
Lately, Pibiri et al. synthesized and characterized a series
of alkyl-1,2,4-oxadiazolylpyridinium salts and classified
them as ionic liquids.11
In the framework of our ongoing research, we needed 4-
[3-(aryl)-1,2,4-oxadiazol-5-yl]-butan-2-ones, which we
prepared by using an appropriate benzamidoxime or
arylamidoxime and levulinic acid in the presence of
DCC in methylene chloride to get O-acyl intermediates,
which were cyclized to 1,2,4-oxadiazoles following the
known procedure.9a This way, eight oxadiazoles 5a–
e,g,i,l were prepared although it took much longer reac-
tion time and needed more work-up for acquiring the
final products. While this work was in progress, we came
across a recent report where carboxylic acid esters, ami-
doximes and potassium carbonate were refluxed in tolu-
ene for 6–12 h to obtain 1,2,4-oxadiazoles in moderate
to excellent yields.15 At this point, it occurred to us to
try to discern a procedure, which could reduce the
reaction time drastically. Apparently, microwave irradi-
ation appeared to be the first option. We did attempt
the microwave-accelerated preparation using methyl
*
Corresponding authors. Tel.: +55 81 2126 8440x5015; fax: +55 81
2126 8442 (R.M.S.); tel.: +55 81 34530258 (J.R.F.F.); e-mail
addresses: joaoveronice@yahoo.com.br; rms_indu@yahoo.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.116

6196
J. J. R. de Freitas et al. / Tetrahedron Letters 48 (2007) 6195–6198
O
levulinate, amidoxime, and potassium carbonate under
solventless conditions and indeed succeeded in synthe-
sizing 12 1,2,4-oxadiazoles 5a–l in 5–10 min.16
OCH3
K2CO3
+
1a-l
+
O
4
Ar
Microwave
radiation
C
Table 1 shows the comparison of eight conventionally
prepared oxadiazoles 5a–e,g,i,l with the ones obtained
by microwave procedure. The extensive diminution in
reaction time in the latter method in conjunction with
a very simple work-up and relatively high yields con-
vinced us to communicate this environmentally benign
synthesis of 1,2,4-oxadiazoles containing a carbonyl
function in its C-5 side chain (Scheme 1).
NH2
O
O
N
O
..
Path "B"
Path "A"
OCH3
OCH3
O
O
7
6
CH3O-
O
O
H
C
1a-l
+
C
3a-l
5a-l
3a-l
H2O
The mechanism of formation of 1,2,4-oxadiazoles from
amidoximes and an acid employing DCC as a carbonyl
group activator is straight forward. The first step is the
intermediate 3 production followed by thermal cyclode-
hydration to generate 5.9a However, the formation of 5
by microwave-mediated process is quite different. In
fact, there are two equally probable mechanisms: In
8
Scheme 2. Two possible paths for the formation of 5 from 4 and 1 in
the presence of K2CO3.
path ‘A’ the base may abstract a proton from 1 to create
an anion at the oxygen atom, which attacks the carbonyl
carbon of 4 to furnish an unstable tetrahedral species 6
with subsequent loss of methanol to give 3. This latter
product ejects water to yield 5. In path ‘B’, the alpha
proton from 4 is extracted by the base to give 7, which
loses a methoxide anion to produce ketene 8. This reac-
tive ketene gets condensed with amidoxime to provide 3,
which expels a water molecule on heating to form the
final heterocycle 5. In both cases, methanol is produced
and is quickly removed by evaporation, which drives the
reaction to completion. Lately, acyl ketene formation
from a b-keto ester under thermal condition has been
reported.17 Although, the esters in the present work
are different, but we feel that ketene formation under ba-
sic condition should be favored. The reviewer suggested
that the pKa value of a b-keto ester reported earlier17
will be very different compared to the pKa value of the
substrate described in this letter. This suggestion is gen-
uine and we appreciate the referee’s advice. Certainly,
more work can be pursued to ascertain the mechanism
of formation of these oxadiazoles involving the ketene
formation. At this moment, it is not possible to confirm
whether both mechanisms are operating or only one of
them is responsible to give the desired products 5a–l.
Both mechanisms are depicted is Scheme 2.
Table 1. Comparison of conventional heating and microwave irradi-
ation on reaction of 1a–l with 2 and 4
Entry
Conventional
method
Microwave method
Compounds
Time
(h)
Yielda
(%)
Time
(min)
Yielda
(%)
Rfb
5a
5b
5c
5d
5e
5f
18
18
18
18
18
—
18
—
18
—
—
18
87
90
89
92
85
—
89
—
75
—
—
86
10
10
10
10
8
8
8
5
5
93
90
90
93
89
85
91
86
88
85
85
89
0.70
0.79
0.78
0.75
0.81
0.69
0.83
0.70
0.67
0.64
0.64
0.67
5g
5h
5i
5j
8
8
8
5k
5l
a Isolated yields.
b Determined in 9:1, CH2Cl2/EtOAc.
O
OH
Ar
1a-e, g, i, l
+
The experimental procedures for the syntheses of both
types are described,18 while other properties are fur-
nished in the reference section.19
NH2
O
2
O
C
N
O
Method"A"
Ar
NH2
OH
O
3a-e, g, i, l
C
N
In conclusion, we have discovered a practical and rapid
procedure for the microwave-accelerated synthesis of
1,2,4-oxadiazoles from methyl levulinate and arylami-
doximes in the presence of potassium carbonate without
using any solvent. This method furnishes the products
very quickly, simplifies the work-up and is environmen-
tally benign. Besides, two possible mechanisms of
formation of these heterocycles are suggested.
Method "B" - Microwave
(5-10min)
Ar
C
N
1
N
CH3
O
O
OCH3
O
K2CO3
+
5a-e, g, i, l (from method "A")
O
4
5a-l (from method "B")
Ar
g: p-BrPh
a: Ph
2''
6''
3''
h: m-NO Ph
b: o-tolyl
c: m-tolyl
d: p-tolyl
e: p-ClPh
f: m-BrPh
2
1''
Ar =
i: p-NO Ph
2
4''
j: o-CH OPh
3
5''
k : m-CH OPh
3
Acknowledgements
l: p-CH OPh
3
We thank the Conselho Nacional de Desenvolvimento
Scheme 1. Synthesis of 1,2,4-oxadiazoles employing conventional as
well as microwave radiation techniques.
´
´
Cientıfico e Tecnologico (CNPq) for providing financial

J. J. R. de Freitas et al. / Tetrahedron Letters 48 (2007) 6195–6198
6197
stirred in a 150 mL round-bottom flask under nitrogen
atmosphere. Dicyclohexylcarbodiimide (DCC) (27.0
mmol) was added to it and the stirring continued for 3 h
at rt to give O-levulinylarylamidoximes (3a–e,g,i,l). Fil-
tration to remove DCU and solvent evaporation left an
oil, which was heated in an oil bath at 78 °C for 18 h. After
the reaction, the impure product was chromatographed
over a silica gel column employing n-hexane–ethyl acetate
(9:1) as an eluent. The fractions containg the right Rf
values of the compound were combined and the sol-
vent was evaporated to get chromatographically pure
4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-butan-2-ones (5a–e,g,i,l).
Microwave method: A mixture of methyl levulinate 4
(1.0 mmol), appropriate arylamidoximes 1a–l (1.58 mmol)
and K2CO3 (0.85 mmol) was well triturated and placed in
a small glass test tube followed by irradiation in a
domestic microwave oven (100% potency, 650 W) for
10 min and then cooled. After the reaction, the compound
was chromatographed over a silica gel column and eluted
with n-hexane–ethyl acetate (9:1). The fractions containing
the desired compound were combined and the solvent
evaporated to get chromatographically pure 4-[3-(aryl)-
1,2,4-oxadiazol-5-yl]-butan-2-ones (5a–l).
support. One of us (J.J.R.F.) is thankful to Programa
´
Institucional de Bolsas de Iniciac¸ao Cientıfica (PIBIC)/
˜
CNPq.
References and notes
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R.; Mack, R. A. J. Org. Chem. 1996, 61, 3228–3229; (b)
Chen, C.; Senanayake, C. H.; Bill, T. J.; Larsen, R. D.;
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3738–3741; (c) Diana, G. D.; Volkots, D. L.; Nitz, T. J.;
Bailey, T. R.; Long, M. A.; Niranjan, V.; Aldous, S.;
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Street, L. J.; Baker, R.; Book, T.; Kneen, C. O.; MacLeod,
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Herbert, R. H.; Freedman, S. B.; Harley, E. A. J. Med.
Chem. 1990, 33, 2690–2697.
6. Andersen, K. E.; Lundt, B. F.; Joergensen, A. S.;
Branstrup, C. Eur. J. Med. Chem. 1996, 31, 417–425.
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23–49.
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L.; luthanan, K. J. Med. Chem. 1999, 42, 4331–4342.
9. (a) Miranda Bezerra, N. M.; De Oliveira, S. P.; Srivastava,
R. M.; da Silva, J. R. Fa´rmaco 2005, 60, 955–960; (b)
Srivastava, R. M.; Seabra, G. M. J. Braz. Chem. Soc.
1997, 8, 397–405; (c) Afiatpour, P.; Srivastava, R. M.; de
Oliveira, M. L.; Barreiro, E. J. Braz. J. Med. Biol. Res.
1994, 27, 1403–1406; (d) Antunes, R.; Srivastava, R. M.
Heterocycl. Commun. 1996, 2, 247–250.
10. Pibiri, I.; Pace, A.; Buscemi, S.; Vivona, N.; Malpezzi, L.
Heterocycles 2006, 68, 307–321.
11. Pibiri, I.; Pace, A.; Piccionello, A. P.; Pierroˆ, P.; Buscemi,
S. Heterocycles 2006, 68, 2653–2661.
12. Shiou, S.; Shine, H. J. J. Heterocycl. Chem. 1989, 26, 125–
128.
13. Gangloff, A. R.; Litvak, J.; Shelton, E. J.; Sperandio, D.;
Wang, V. R.; Rice, K. D. Tetrahedron Lett. 2001, 42,
1441–1443, and references quoted in the article.
14. Katritzky, A. R.; Shestopalov, A. A.; Suzuki, K. ARKI-
VOK 2005, 7, 36–55, and references cited therein.
15. Amarasinghe, K. K. D.; Maier, M. B.; Srivastava, A.;
Gray, J. L. Tetrahedron Lett. 2006, 47, 3629–3631.
16. Microwave reactions were performed in a domestic
microwave oven, SANYO, model EM-300B (220 V;
650 W/2450 MHz). The precise heating area in the oven
was located, and the experiments were repeated at least a
couple of times. Therefore, we feel confident that these
experiments can be repeated by any chemist.
17. Du, W.; Truong, Q.; Qi, H.; Guo, Y.; Chobanion, H. R.;
Hagmann, W. H.; Hale, J. J. Tetrahedron Lett. 2007, 48,
2231–2235.
18. Synthesis of 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-butan-2-ones
(5a–e,g,i,l).Conventional method: A mixture of levulinic
acid 2 (28.0 mmol) and appropriate arylamidoxime 1a, g,
i, l (27.0 mmol) in dry dichloromethane (50 mL) was
19. Compound 4-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-2-one
(5a): Pale yellow oil, yield 93%. IR (KBr): 1720; 1590;
1570; 1360; 1160; 720 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 8.07–8.02 (m, 2H, H-20 and H-60, Ph-H), 7.50–7.43 (m,
3H, H-30, H-40 and H-50, Ph-H), 3.23–3.18 (ddd, 2H,
J = 1.5 Hz, J = 6.7 Hz, J = 14.3 Hz, H-6 and H-60), 3.09–
3.04 (ddd, 2H, J = 1.5 Hz, J = 6.6 Hz, J = 14.7 Hz, H-7
and H-70), 2.26 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d 205.6 (C-8); 179.2 (C-3); 170 (C-5); 131.5 (C-100); 129.5
(C-300 and C-500); 129.1 (C-400); 127.7 (C-200 and C-600); 39.6
(C-6); 30.25 (C-7); 21.1 (CH3). Anal. Calcd for
C12H12O2N2: C, 66.66; H, 5.55; N, 12.95. Found: C,
66.51; H, 5.62; N, 12.74.
Compound 4-(3-o-tolyl-1,2,4-oxadiazol-5-yl)-butan-2-one
(5b): Pale yellow oil, yield 90%. IR (KBr): 1710; 1590;
1565; 1360; 1335; 1160; 740 cmꢀ1 1H NMR (300 MHz,
.
CDCl3): d 7.92 (d, J = 7.2 Hz, 1H, Ph-H), 7.38–7.25 (m,
3H, Ph-H), 3.20 (t, 2H, J = 6.96 Hz, H-6 and H-60), 3.04
(t, 2H, J = 6.78 Hz, H-7 and H-70),2.59 (s, 3H, Ph–CH3),
2.22 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d 205.7
(C-8); 178.1 (C-3); 169.1 (C-5); 138.5 (C-100); 131.7 (C-300);
126.4 (C-500); 130.8 (C-200); 130.3 (C-400); 126.4 (C-600); 39.5
(C-7); 30.25 (C-6); 20.9 (CH3); 14.5 (Ph–CH3). Anal.
Calcd for C13H14O2N2: C, 67.81; H, 6.13; N, 12.17.
Found: C, 67.83; H, 6.49; N, 12.06.
Compound 4-(3-m-tolyl-1,2,4-oxadiazol-5-yl)-butan-2-one
(5c): Pale yellow oil, yield 89%. IR (KBr): 1720; 1595;
1575; 1350; 1150; 745 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 7.82–7.79 (m, 2H, Ph-H), 7.32–7.23 (m, 2H, Ph-H), 3.15
(dd, 2H, J = 1.3 Hz, J = 7.5 Hz, H-6 and H-60), 3.00 (d,
2H, J = 6.78 Hz, H-7 and H-70), 2.35 (s, 3H, Ph–CH3),
2.18 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d 205.7
(C-8); 179.2 (C-3); 1.68.6 (C-5); 138.9 (C-100); 129 (C-200);
129.3 (C-500); 128.8 (C-400); 132.2 (C-300); 124.8 (C-600); 39.5
(C-7); 30.0 (C-6); 21.6 (CH3); 14.1 (Ph–CH3). Anal. Calcd
for C13H14O2N2.1/2H2O: C, 65.24; H, 6.27; N, 11.71.
Found: C, 65.83; H, 6.03; N, 11.61.
Compound 4-(3-p-tolyl-1,2,4-oxadiazol-5-yl)-butan-2-one
(5d): Pale yellow oil, yield 92%. IR (KBr): 1720; 1590;
1565; 1350; 1120; 740 cm1. 1H NMR (300 MHz, CDCl3): d
7.94 (d, J = 8.1 Hz, 2H, H-200 and H-600), 7.27 (d,
J = 7.8 Hz, 2H, H-300 and H-500), 3.18 (dt, 2H, J =
1.3 Hz, J 8.1 Hz, H-6 and H-60), 3.05 (dt, 2H, J =
1.3 Hz, J = 8.1 Hz, H-7 and H-70), 2.39 (s, 3H, Ph–
CH3), 2.24 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d
205.7 (C-8); 179.0 (C-3); 168.5 (C-5); 141.8 (C-100); 129.8

6198
J. J. R. de Freitas et al. / Tetrahedron Letters 48 (2007) 6195–6198
(C-400); 127.6 (C-300 and C-500); 124.3 (C-200 and C-600); 39.6
(C-6); 30.2 (C-7); 21.9 (CH3); 21.0 (Ph–CH3). Anal. Calcd
for C13H14O2N2: C, 67.83; H, 6.13; N, 12.17. Found: C,
67.65; H, 6.16; N, 11.93.
Compound 4-(3-p-nitrophenyl-1,2,4-oxadiazol-5-yl)-butan-
2-one (5i): Crystals from chloroform/cyclohexane, mp:
73–74 °C, yield 88%. IR (KBr): 1700; 1580; 1540; 1360;
1
1160; 740 cmꢀ1. H NMR (300 MHz, CDCl3): d 7.99 (d,
Compound
4-(3-p-chlorophenyl-1,2,4-oxadiazol-5-yl)-
2H, J = 8.4 Hz, H-200 and H-600, Ph–H), 7.44 (d,
J = 8.4 Hz, 2H, H-300 and H-500), 3.20 (dt, 2H,
J = 1.3 Hz, J = 8.1 Hz, H-6 and H-60), 3.06 (dt, 2H,
J = 1.3 Hz, J = 6.8 Hz, H-7 and H-70), 2.25 (s, 3H, CH3).
13C NMR (75 MHz, CDCl3): d 205.6 (C-8); 179.4 (C-3);
167.8 (C-5); 137.6 (C-100); 129.5 (C-400); 129.0 (C-300 and C-
500); 125.7 (C-200 and C-600); 39.5 (C-7); 30.2 (C-6); 21.0
(Ph–CH3). Anal. Calcd for C12H11O4N3: C, 55.17; H, 4.24;
N, 16.09. Found: C, 55.22; H, 4.65; N, 15.93.
butan2-one (5e): Crystals from chloroform/cyclohexane,
mp: 74–75 °C yield 89%. IR (KBr): 1740; 1580; 1540; 1360;
1160; 740 cm1. 1H NMR (300 MHz, CDCl3): d 7.99 (d,
2H, J = 8.4 Hz, H-200 and H-600), 7.44 (d, J = 8.4 Hz, 2H,
H-300 and H-500), 3.20 (dt, 2H, J = 1.3 Hz, J = 8.1 Hz, H-6
and H-60), 3.06 (dt, 2H, J = 1.3 Hz, J = 6.8 Hz, H-7 and
H-70), 2.25 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d
205.6 (C-8); 179.4 (C-3); 167.8 (C-5); 137.6 (C-100); 129.5
(C-400); 129.0 (C-300 and C-500); 125.7 (C-200 and C-600); 39.5
(C-7); 30.2 (C-6); 21.0(CH3). Anal. Calcd for
C12H11O2N2Cl: C, 57.49; H, 4.39; N, 11,17. Found: C,
57.45; H, 4.52; N, 11.05.
Compound 4-(3-o-metoxyphenyl-1,2,4-oxadiazol-5-yl)-butan-
2-one (5j): Pale yellow oil, yield 85%. IR (KBr): 1711;
1601; 1493; 1346; 1252; 757 cmꢀ1 1H NMR (300 MHz,
.
CDCl3):
d
7.94
(dd,
1H,
J = 2.1 Hz,
J =
Compound 4-(3-m-bromophenyl-1,2,4-oxadiazol-5-yl)-butan-
2-one (5f): Semisolid, yield 85%. IR (KBr): 1718; 1589;
1558; 1350; 720 cmꢀ1. 1H NMR (300 MHz, CDCl3): d 8.17
(t, J = 1.5 Hz, 1H, Ph), 7.94 (d, J = 4.8 Hz, 1H, Ph), 7.60
(d, J = 6.3 Hz, 1H, Ph), 3.17 (dt, J = 1.5 Hz, J = 6.9 Hz,
H-6 and H-60), 3.06 (dt, J = 1.5 Hz, J = 6.3 Hz, H-7 and
H-70), 2.26 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d
205.6 (C-8); 179.5 (C-3); 167.8 (C-5); 132.4 (C-100); 129.2
(C-300); 131.2 (C-500); 126.2 (C-60); 129.0 (C-200); 125.7 (C-
400); 39.5 (C-7); 30.1 (C-6); 21.0 (Ph–CH3). Anal. Calcd for
C12H11O2N2Br: C, 48.84; H, 3.76; N, 9.49. Found: C,
49.20; H, 3.66; N, 9.24.
7.5 Hz, Ph–H), 7.46 (dt, 1H, J = 1.8 Hz, J = 14.1 Hz,
Ph–H), 7.05 (dt, 2H, J = 1.8 Hz, J = 14.1 Hz, Ph–H), 3.96
(s, 3H, OCH3), 3.21 (dt, 2H, J = 1.5 Hz, J = 8.7 Hz, H-6
and H-60), 3.07 (dt, 2H, J = 1.5 Hz, J = 6.9 Hz, H-7 and
H-70), 2.25 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d
205.7 (C-8); 178.9 (C-3); 168.3 (C-5); 125.1 (C-100); 162.2
(C-200); 129.3 (C-400); 119.6 (C-500); 114.5 (C-300); 128.2 (C-
600); 39.6 (C-7); 30.2 (C-6); 21.6 (CH3O); 21.0 (CH3). Anal.
Calcd for C13H14O3N2: C, 63.40; H, 5.73; N, 11.38.
Found: C, 63.31; H, 5.77; N, 11.12.
Compound
butan-2-one (5k): Semisolid, yield 85%. IR (KBr): 1717;
1572; 1468; 1348; 1045; 762 cmꢀ1 1H NMR (300 MHz,
4-(3-m-metoxyphenyl-1,2,4-oxadiazol-5-yl)-
Compound
4-(3-p-bromophenyl-1,2,4-oxadiazol-5-yl)-
.
butan-2-one (5g): Crystals from chloroform/cyclohexane,
mp: 84–84.5 °C, yield 91%. IR (KBr): 1700; 1585; 1540;
1360; 1180; 760 cmꢀ1. 1H NMR (300 MHz, CDCl3): d 7.84
(d, J = 8.6 Hz, 2H, Ph–H), 7.53 (d, J = 8.6 Hz, 2H, Ph–
H), 3.94 (dt, 2H, J = 1.3 Hz, J = 6.96 Hz, H-6 and H-60),
3.02 (dt, 2H, J = 1.3 Hz, J = 6.38 Hz, H-7 and H-70), 2.20
(s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d 205.6 (C-8);
179.5 (C-3); 167.8 (C-5); 132.4 (C-100); 129.2 (C-300 and
C-500); 129.0 (C-200 and C-600); 125.7 (C-400); 39.5 (C-7); 30.1
(C-6); 21.0 (Ph–CH3). Anal. Calcd for C12H11O2N2Br: C,
48.84; H, 3.76; N, 9.49. Found: C, 48.29; H, 3.65; N, 9.12.
Compound 4-(3-m-nitrophenyl-1,2,4-oxadiazol-5-yl)-butan-
2-one (5h): Semisolid, yield 86%. IR(KBr): 1707; 1572;
1352; 1167; 723 cmꢀ1. 1H NMR (300 MHz, CDCl3): d 8.90
(t, 1H, J = 1.5 Hz, J = 3.6 Hz, Ph–H), 8.37 (t, 2H, J =
1.8 Hz, J = 10.2 Hz, Ph–H), 7.67 (t, 1H, J = 0.6 Hz,
J = 8.4 Hz, Ph–H), 3.23 (dt, 2H, J = 1.8 Hz, J = 12 Hz,
H-6 and H-60), 3.06 (dt, 2H, J = 1.5 Hz, J = 13.2 Hz, H-7
and H-70), 2.25 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d 205.6 (C-8); 179.4 (C-3); 167.8 (C-5); 137.6 (C-100); 129.5
(C-400); 132.2 (C-300); 129.9 (C-500); 125.7 (C-200); 124.2 (C-
600); 39.5 (C-7); 30.2 (C-6); 21.0 (CH3). Anal. Calcd for
C12H11O4N3: C, 55.17; H, 4.24; N, 16.09. Found: C, 55.10;
H, 4.13; N, 15.94.
CDCl3): d 7.64 (dt, 2H, J = 1.5 Hz, J = 7.8 Hz, Ph–H),
7.36 (dt, 1H, J = 0.9 Hz, J = 8.4 Hz, Ph–H), 3.85 (s, 3H,
OCH3), 3.20 (dt, 2H, J = 1.5 Hz, J = 12.9 Hz, H-6 and H-
60), 3.06 (dt, 2H, J = 1.5 Hz, J = 13.2 Hz, H-7 and H-70),
2.24 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d 205.7
(C-8); 178.9 (C-3); 168.3 (C-5); 162.2 (C-300); 129.3 (C-100);
119.6 (C-400); 114.5 (C-200); 130.2 (C-50); 121.5 (C-600); 39.6
(C-7); 30.2 (C-6); 21.6 (CH3O); 21.0 (CH3). Anal. Calcd
for C13H14O3N2: C, 63.40; H, 5.73; N, 11.38. Found: C,
63.12; H, 5.81; N, 11.10.
Compound 4-(3-p-metoxyphenyl-1,2,4-oxadiazol-5-yl)-butan-
2-one (5l): Semisolid, yield 89%. IR (KBr): 1707; 1591;
1450; 1358; 1060; 750 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 7.98 (d, J = 9.0 Hz, 2H, H-200 and H-600, Ph–H), 6.96 (d,
J = 8.8 Hz, 2H, H-300 and H-500, Ph–H), 3.84 (s, 3H,
OCH3), 3.19 (dt, 2H, J = 1.5 Hz, J = 8.2 Hz, H-6 and H-
60), 3.04 (dt, 2H, J = 1.5 Hz, J = 8.1 Hz, H-7 and H-70),
2.24 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): d 205.7
(C-8); 178.9 (C-3); 168.3 (C-5); 162.2 (C-400); 129.3 (C-100);
119.6 (C-200 and C-600); 114.5 (C-300 and C-500); 39.6 (C-7);
30.2 (C-6); 21.6 (CH3O); 21.0 (CH3). Anal. Calcd for
C13H14O3N2: C, 63.40; H, 5.73; N, 11.38. Found: C, 63.75;
H, 5.68; N, 11.58.