One-pot synthesis of new, biologically active 3,5-disubstituted-1,2,4- oxadiazoles

Article abstract of DOI:10.1080/00397910903370717

New chiral 3,5-disubstituted-1,2,4-oxadiazoles have been prepared via an efficient one-pot procedure by the condensation of new chiral amidoximes derived from amino acids with aldehydes. This method is applicable to both aliphatic and aromatic aldehydes,

Full text of DOI:10.1080/00397910903370717

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One-Pot Synthesis of New, Biologically
Active 3,5-Disubstituted-1,2,4-
oxadiazoles
Najeh Tka a & Béchir Ben Hassine a
a Laboratoire de Synthèse Organique Asymétrique et Catalyse
Homogène, Faculté des Sciences de Monastir, Monastir, Tunisia
Version of record first published: 04 Oct 2010
To cite this article: Najeh Tka & Béchir Ben Hassine (2010): One-Pot Synthesis of New, Biologically
Active 3,5-Disubstituted-1,2,4-oxadiazoles, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 40:21, 3168-3176
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Synthetic Communications1, 40: 3168–3176, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903370717
ONE-POT SYNTHESIS OF NEW, BIOLOGICALLY ACTIVE
3,5-DISUBSTITUTED-1,2,4-OXADIAZOLES
´
Najeh Tka and Bechir Ben Hassine
`
Laboratoire de Synthese Organique Asymetrique et Catalyse Homogene,
Faculte des Sciences de Monastir, Monastir, Tunisia
´
`
´
New chiral 3,5-disubstituted-1,2,4-oxadiazoles have been prepared via an efficient one-pot
procedure by the condensation of new chiral amidoximes derived from amino acids with
aldehydes. This method is applicable to both aliphatic and aromatic aldehydes, leading
easily to the corresponding pure oxadiazoles in excellent yields. These new compounds were
tested for their antibacterial and antifungal activities using microdilution tests against some
strains of bacteria and fungi, and they showed excellent antibacterial activity.
Keywords: Aldehydes; amidoximes; amino acids; antibacterial and antifungal activities; 1,2,4-oxadiazoles
INTRODUCTION
Thanks to its increased hydrolytic and metabolic stability, the oxadiazole
nucleus is a well-studied pharmacophoric scaffold. 1,2,4-Oxadiazole rings occur
widely in biologically active synthetic compounds and are often used in drug
discovery as hydrolysis-resisting bioisosteric replacements for ester or amide func-
tionalities.[1,2] Numerous 1,2,4-oxadiazoles have been suggested as potential agonists
for cortical muscarinic,[3] benzodiazepine,[4] and 5-HT1D (5-hydroxytryptamine)
receptors.[5] Moreover, they have shown activity as anti-inflammatory agents[6]
and antirhinoviral agents.[7]
The most common routes to 1,2,4-oxadiazoles couple amidoxime with
activated carboxylic acid derivatives,[8–10] active esters,[11] and carboxylic acids in
the presence of coupling reagents.[12,13] Other new and broadly explored methods
couple amidoxime with aldehydes. To date, only two reports have been published.
The first procedure includes a condensation of arylamidoxime with butyralde-
hyde,[14] followed by oxidation using MnO2 in CH2Cl2 or sodium hypochlorite in
tetrahydrofuran (THF)=H2O. This reaction is time-consuming and takes between
5 and 8 days to be complete. The second example is a microwave-assisted reaction[15]
between arylaldehydes and arylamidoximes prepared from the corresponding nitriles
under microwave irradiation. This method gives 3,5-disubstituted-1,2,4-oxadiazoles
Received August 4, 2009.
Address correspondence to Bechir Ben Hassine, Laboratoire de Synthese Organique Asymetrique
´
et Catalyse Homogene (01 UR 1201), Faculte des Sciences de Monastir, Avenue de l’Environnement,
`
´
`
5019, Monastir, Tunisie. E-mail: bechirbenhassine@yahoo.fr
´
3168

3,5-DISUBSTITUTED-1,2,4-OXADIAZOLES
3169
in good yields within a short reaction time. However, it does not seem to be suitable
for aliphatic aldehydes boiling at a low temperature or irradiated at 150 ꢀC. As far
as we know, no general method has been reported for the preparation of 1,2,4-
oxadiazoles coupling amidoxime with aliphatic and aromatic aldehydes. Therefore,
this method needs further study.
Herein, we report a general and efficient method for the synthesis of new
3,5-disubstituted-1,2,4-oxadiazoles by condensing chiral amidoximes derived
from amino acids with both aliphatic or aromatic aldehydes. Some biologic tests
have been conducted to evaluate the antibacterial and antifungal activities of our
new compounds.
RESULTS AND DISCUSSION
The synthetic route to the targeted oxadiazoles 3a–g is outlined in Scheme 1.
The chiral 1-benzenesulfonylpyrrolidin-2-carboxamidoxime 1 was successfully pre-
pared from the corresponding optically pure 2-(S)-1-benzenesulfonylpyrrolidin-2-
carbonitrile[16] by a simple treatment with 1 equivalent of hydroxylamine
hydrochloride and 2 equivalents of triethylamine overnight at room temperature.
The condensation of amidoxime 2 with aliphatic and aromatic aldehydes in toluene
for 3 h affords the chiral 5-alkyl-3-(10-benzenesulfonylpyrrolidin-20-yl)-1,2,4-
oxadiazoles 3a–g in good chemical yields. The results are summarized in Table 1.
The synthetic route to target oxadiazoles 6h–k is outlined in Scheme 2.
Optically pure N-methyl-N-phenylsulfonyl-2-aminonitriles 4 have been successfully
prepared by our team[16] from the corresponding commercially available amino acids
(L)-alanine and (L)-isoleucine. The treatment of this compound with 1.2 equivalents
of hydroxylamine hydrochloride and 2.5 equivalents of triethylamine in refluxing
ethanol over 1 day led to the corresponding amidoximes 5 with moderate yields.
The condensation of amidoximes 5 with the para-formaldehyde or benzaldehyde
in toluene during 4 h gave the chiral 5-alkyl-3-(N-methyl-N-phenylsulfonyl-1-
aminoalkyl)-1,2,4-oxadiazoles 6h–l with chemical yields ranging from 69 to 74%.
As part of our work on the synthesis of new heterocyclic compounds from amino
acids,[17,18] we investigated chiral amidoximes derived from proline, alanine, and
isoleucine to cyclize with aldehydes to afford new 3,5-disubstituted-1,2,4-oxadiazoles.
The addition of hydroxylamine to aminonitriles 1 and 4 gives initially the
corresponding amidoxime. This reaction proved to be easy with cyclic nitrile 1
and gave the corresponding amidoxime 2 in quantitative yield at room temperature
Scheme 1. Synthesis of chiral 5-alkyl-3-(10-benzenesulfonylpyrrolidin-20-yl)-1,2,4-oxadiazoles 3a–g from
proline. a, R ¼ H; b, R ¼ Me; c, R ¼ Ph; d, R ¼ p-Ph-Me; e, R ¼ p-Ph-OMe; f, R ¼ o-Ph-Cl; and g,
R ¼ o-Ph-CN.

3170
N. TKA AND B. BEN HASSINE
Table 1. Synthesis of chiral 3,5-disubstituted-1,2,4-oxadiazoles 3a–g and 6h–k from the corresponding
amino acids
a
Amino acids
Oxadiazole
R
Yield (%)
Mp (ꢀC)
[a]D
Proline
Proline
Proline
Proline
Proline
Proline
Proline
Alanine
Alanine
Isoleucine
Isoleucine
3a
3b
3c
3d
3e
3f
H
Me
91
87
84
86
90
88
60
74
71
69
70
93–95
—
ꢁ65.5
ꢁ50.0
ꢁ47.4
ꢁ40.4
ꢁ45.4
ꢁ60.6
ꢁ55.5
ꢁ42.4
ꢁ59.4
ꢁ70.6
ꢁ52.5
pH
114–116
99–101
107–109
—
p-MeC6H5
p-OMeC6H5
o-Cl C6H5
o-CNC6H5
pH
3g
6h
6i
119–121
126–128
—
H
pH
6j
6k
—
139–141
H
ac ¼ 0.0033, CHCl3.
using an aprotic solvent. However, it did not work with the acyclic nitriles 4 under
the same conditions. Even after prolonging the time of reaction and heating, the
reaction did not provide the desired products with encouraging yields. The reaction
gave better results by refluxing the acyclic nitriles 4 derived from alanine and
isoleucine for 24 h in ethanol as solvent. Chemical yields of the reaction were 54
and 62%, respectively.
The condensation of amidoximes 2 and 5 with aliphatic or aromatic aldehydes
in refluxing toluene gave the corresponding 1,2,4-oxadiazoles. Mechanistically, it is
reasonable to assume that first the amidoxime is condensed with aldehyde to form
in situ the imine derivative 7. Then this intermediate is cyclized to the
4,5-dihydro-1,2,4-oxadiazole derivative 8, which is finally oxidized under the reac-
tion conditions to produce 1,2,4-oxadiazole (Scheme 3).
Pure 3,5-disubstituted-1,2,4-oxadiazoles were easily prepared in excellent yields
from the corresponding amidoximes. In all cases, the conversion of the amidoxime
derived from proline was complete within 3 h. Nevertheless, it takes more time
and is less efficient with amidoximes derived from alanine and isoleucine.
We have observed that the best chemical yields of oxadiazoles prepared from
proline 3a–f were obtained with aromatic aldehydes possessing electron-donating
groups. However, the presence of an electron-attracting group on the aromatic ring
decreases the reactivity of the aldehyde, and the corresponding oxadiazole was
obtained in poor yield (Table 1, entry 3g). On the other hand, we observed that
Scheme 2. Synthesis of chiral 5-alkyl-3-(N-methyl-N-phenylsulfonyl-1-aminoalkyl)-1,2,4-oxadiazoles 6h–k
from the corresponding amino acids: h, R0 ¼ Me, R ¼ H; i, R0 ¼ Me, R ¼ Ph; j, R0 ¼ Sec-Bu, R ¼ H; and k,
R0 ¼ Sec-Bu, R ¼ Ph.

3,5-DISUBSTITUTED-1,2,4-OXADIAZOLES
3171
Scheme 3. Proposed mechanism for the formation of 1,2,4-oxadiazole.
the reaction gave chiral 1,2,4-oxadiazoles in good yields when using toluene as sol-
vent. When benzene is used, the reaction takes place more slowly and less efficiently.
Chiral 3,5-disubstituted-1,2,4-oxadiazoles 3a–g and 6h–k were prepared start-
ing from optically pure 2-aminonitriles.[16] Partial racemization of initial asymmetric
carbon might occur after a possible elimination of the proton by the use of strong
bases or by heating. Optical purity of obtained compounds was confirmed by chiral
high-performance liquid chromatography (HPLC). According to the HPLC studies,
new chiral 3,5-disubstituted-1,2,4-oxadiazoles were formed without a significant
racemization (see the experimental section).
Antibacterial activities of some 3,5-disubstituted-1,2,4-oxadiazoles were
studied along with an antibacterial drug named levofloxacin. The obtained minimum
inhibitory concentrations values (MIC) of the tested standard and compounds are
shown in Table 2. The results revealed all compounds to be very effective at low
concentrations and show better activity than levofloxacin.
Table 2 shows also the antifungal activities of reported 1,2,4-oxadiazoles in
comparison with the antifungal amphotericin B. Based on the obtained values, the
synthesized compounds show moderate antifungal activities. In all cases, the MICs
of the active compounds are greater than the standard antibiotic. Exceptionally,
compound 4e was found to show better antifungal activity against C. albicans.
MIC values were determined by a microtiter plate dilution method as described
by Ferreira et al.[19] The inoculum of the bacteria and yeasts were prepared from
12-h broth cultures, and suspensions were adjusted to 0.5 McFarland standard
Table 2. Antibacterial and antifungal activities of 1,2,4-oxadiazoles (MIC, mg mLꢁ1
)
Organism
Bacteria
MIC 3a MIC 3b MIC 3e MIC 3f MIC 6h Amphotericin B Levofloxacin
K. pneumonie (clinical isolated)
0.12
0.25
0.25
0.25
0.25
0.12
0.5
0.12
0.06
0.25
0.25
0.25
0.25
0.25
0.25
0.12
0.12
0.25
0.25
nd
nd
nd
nd
0.3
S. aureus ATCC 27950
E. faecalis ATCC 29212
E. coli ATCC 25922
0.61
1.22
0.3
0.12
Yeasts
C. parapsilosis ATCC 22019 5 45 0.25
0.25
0.12
0.25
0.25
0.25
0.12
0.03
0.25
0.25
0.25
0.25
0.12
0.25
0.25
0.25
0.25
0.05
0.05
0.05
0.05
nd
nd
nd
nd
C. kreusei ATCC 6258 2.5 45
C. albicans ATCC 90028
C. glabrata ATCC 90030
0.25
0.12
0.25
Notes. Levofloxacin: controlled antibiotic; amphotericin B: controlled antifungal. MIC: minimum
inhibitory concentration, given as mg mLꢁ1. Nd: not determined.

3172
N. TKA AND B. BEN HASSINE
turbidity. The plate was covered with a sterile plate sealer and then incubated for
18 h at 37 ꢀC.
In summary, a convenient one-pot method for the preparation of novel,
biologically active chiral 3,5-disubstituted-1,2,4-oxadiazoles has been developed
using chiral amidoxime, derived from inexpensive and readily available amino acids.
The reaction gave oxadiazoles in good yields and proved to be applicable to
both aliphatic and aromatic aldehydes. The synthesized compounds were screened
for their antibacterial and antifungal activities against a spectrum of microbial
organisms. These studies proved that all compounds showed excellent antibacterial
activity.
EXPERIMENTAL
General Procedure for the Preparation of
3,5-Disubstituted-1,2,4-oxadiazoles
The chiral amidoxime (5 mmol) was dissolved in 200 mL of dry toluene, and then
aldehyde (5.5 mmol) was added with a small quantity of paratoluenesulfonic acid
(PTSA) as a catalyst. The mixture was refluxed for 3–4 h with azeotropic water removal
until the amidoxime was consumed (as monitored by thin-layer chromatography,
TLC). After cooling to room temperature, the solution was washed with water
(25 mL). After separation, the aqueous layer was extracted with chloroform
(3 ꢂ 50mL). The combined organic extracts were dried over MgSO4, filtered,
and concentrated in vacuo, and the residue obtained was purified by column
chromatography on silica gel (10% ethyl acetate=90% cyclohexane) to give the
3,5-disubstituted-1,2,4-oxadiazole, which was recrystallized from hexane=chloroform
(7:3).
5-Hydro-3-(1’-benzenesulfonylpyrrolidin-2’-yl)-1,2,4-oxadiazoles 3a
Yield 91%; mp 93–95 ꢀC; [a]D ꢁ65.5 (c 0.33%, CHCl3); ee > 99.5% [HPLC
analysis using a Chirobiotic V column, 4.6 mm ꢂ 250 mm, under the following con-
ditions: heptane=isopropanol (93:7) as mobile phase, rt, k 254 nm, flow rate 0.6 mL=
min, retention time 19.66 min]; IR (cmꢁ1): n ¼ ¼ 1600; nNꢁO ¼ 908;
CN
nCꢁO ¼ 1221;1H NMR (300 MHz, CDCl3): d 1.78 (m, 1H), 2.04 (m, 3H), 3.38 (m,
1H), 3.57 (m, 1H), 4.95 (m, 1H), 7.50 (m, 3H), 7.76 (m, 1H), 8.57 (s, 1H); 13C
NMR (75 MHz, CDCl3): d 24.71, 32.31, 49.29, 54.83, 127.85, 129.75, 133.29,
137.98, 165.39, 170.64; MS=EI m=z ¼ 279.5 (Mþ.). Anal. calcd. for C12H13N3O3S
(279.32): C, 51.60; H, 4.99; N, 15.04. Found: C, 51.64; H, 5.02; N, 15.08.
5-Methyl-3-(1’-benzenesulfonylpyrrolidin-2’-yl)-1,2,4-oxadiazoles 3b
Yield 87%; [a]D ꢁ50.0 (c 0.33%, CHCl3); ee > 99.5% [HPLC analysis using a
Chirobiotic V column, 4.6 mm ꢂ 250 mm, under the following conditions: heptane=
isopropanol (93:7) as mobile phase, rt, k 254 nm, flow rate 0.6 mL=min, retention
time 22.95 min]; IR (cmꢁ1): nC¼N ¼ 1604; nNꢁO ¼ 912; nCꢁO ¼ 1230;1H NMR
(300 MHz, CDCl3): d 1.81 (m, 1H), 2.11 (m, 3H), 2.50 (s, 3H), 3.45 (m, 1H), 3.64

3,5-DISUBSTITUTED-1,2,4-OXADIAZOLES
3173
(m, 1H), 4.90 (dd, 1H, J ¼ 6.9 Hz, J ¼ 2.7 Hz), 7.58 (m, 3H), 7.81 (m, 1H); 13C NMR
(75 MHz, CDCl3): d 12.71, 24.66, 32.42, 49.30, 54.93, 127.87, 129.39, 133.15, 138.07,
171.22, 177.26. Anal. calcd. for C13H15N3O3S (293.35): C, 53.23; H, 5.15; N, 14.32.
Found: C, 53.31; H, 5.19; N, 14.38.
5-Phenyl-3-(1’-benzenesulfonylpyrrolidin-2’-yl)-1,2,4-oxadiazoles 3c
Yield 84%; mp 114–116 ꢀC; [a]D ꢁ47.4 (c 0.33%, CHCl3); IR (cmꢁ1):
nC¼N ¼ 1602; nNꢁO ¼ 918; nCꢁO ¼ 1222;1H NMR (300 MHz, CDCl3): d 1.91 (m,
1H), 2.22 (m, 3H), 3.55 (m, 1H), 3.70 (m, 1H), 5.04 (dd, 1H, J ¼ 6.9 Hz, J ¼ 2.7 Hz),
7.61 (m, 6H), 7.86 (m, 2H), 8.06 (m, 2H); 13C NMR (75 MHz, CDCl3): d 24.36,
32.18, 48.87, 54.78, 127.51, 128.16, 128.96, 129.07, 132.76, 132.86, 133.19, 137.53,
170.92, 176.52.
5-p-Tolyl-3-(1’-benzenesulfonylpyrrolidin-2’-yl)-1,2,4-oxadiazoles 3d
Yield 86%; mp 99–101 ꢀC; [a]D ꢁ40.4 (c 0.33%, CHCl3); ee > 99.5% [HPLC
analysis using a Chirobiotic V column, 4.6 mm ꢂ 250 mm, under the following con-
ditions: heptane=isopropanol (93:7) as mobile phase, rt, k 254 nm, flow rate 0.6 mL=
min, retention time: 24.19 min]; IR (cmꢁ1): nC¼N ¼ 1605; nNꢁO ¼ 910;
nCꢁO ¼ 1220;1H NMR (300 MHz, CDCl3): d 1.84 (m, 1H), 2.19 (m, 3H), 3.49 (m,
1H), 3.66 (m, 1H), 3.90 (s, 1H), 5.01 (dd, 1H, J ¼ 6.9 Hz, J ¼ 2.7 Hz), 6.98 (m,
2H), 7.45 (m, 3H), 7.84 (m, 2H), 7.99 (m, 2H); 13C NMR (75 MHz, CDCl3), d
24.22, 32.53, 49.08, 51.84, 54.67, 127.33, 128.02, 128.84, 129.14, 132.45, 132.99,
133.04, 138.13, 171.02, 176.47. Anal. calcd. for C19H19N3O3S (369.45): C, 61.77;
H, 5.18; N, 11.37. Found: C, 61.81; H, 5.22; N, 11.42.
5-(4-Methoxyphenyl)-3-(1’-benzenesulfonyl-pyrrolidin-2’-yl)-
1,2,4-oxadiazoles 3e
Yield 90%; mp 107–109 ꢀC; [a]D ꢁ45.4 (c 0.33%, CHCl3); IR (cmꢁ1):
nC¼N ¼ 1597; nNꢁO ¼ 931; nCꢁO ¼ 1234;1H NMR (300 MHz, CDCl3): d 1.81 (m,
1H), 2.05 (m, 3H), 3.42 (m, 1H), 3.58 (m, 1H), 3.80 (s, 1H), 4.95 (dd, 1H, J ¼ 6.9 Hz,
J ¼ 2.7 Hz), 6.91 (m, 2H), 7.37 (m, 3H), 7.76 (m, 2H), 7.90 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 24.69, 32.49, 49.21, 55.17, 55.92 114.79, 116.94, 127.85,
129.29, 130.41, 132.68, 133.08, 138.29, 171.62, 176.17. Anal. calcd. for C19H19N3O4S
(385.44): C, 59.21; H, 4.97; N, 10.90. Found: C, 59.27; H, 5.02; N, 10.93.
5-(2-Chlorophenyl)-3-(1’-benzenesulfonylpyrrolidin-2’-yl)-
1,2,4-oxadiazoles 3f
Yield 88%; [a]D ꢁ60.6 (c 0.33%, CHCl3); ee > 99.5% [HPLC analysis using a
Chirobiotic V column, 4.6 mm ꢂ 250 mm, under the following conditions: heptane=
isopropanol (93:7) as mobile phase, rt, k 254 nm, flow rate 0.6 mL=min, retention
time: 25.84 min]; IR (cmꢁ1); nC¼N ¼ 1603; nNꢁO ¼ 917; nCꢁO ¼ 1219;1H NMR
(300 MHz, CDCl3): d 1.86 (m, 1H), 2.17 (m, 3H), 3.44 (m, 1H), 3.62 (m, 1H), 5.04
(dd, 1H, J ¼ 6.9 Hz, J ¼ 2.7 Hz), 7.43 (m, 6H), 7.82 (m, 2H), 7.91 (m, 1H); 13C

3174
N. TKA AND B. BEN HASSINE
NMR (75 MHz, CDCl3): d 24.65, 32.48, 49.20, 55.10, 123.47, 127.73, 129.47, 131.77,
132.32, 133.77, 133.91, 138.11, 171.45, 174.82.
5-(2-Cyanophenyl)-3-(1’-benzenesulfonylpyrrolidin-2’-yl)-
1,2,4-oxadiazoles 3g
Yield 60%; mp 119–121 ꢀC; [a]D ꢁ55.5 (c 0.33%, CHCl3); IR (cmꢁ1):
nC¼N ¼ 1605; nNꢁO ¼ 913; nCꢁO ¼ 1232;1H NMR (300 MHz, CDCl3): d 1.81 (m,
1H), 2.23 (m, 3H), 3.49 (m, 1H), 3.66 (m, 1H), 5.01 (dd, 1H, J ¼ 6.9 Hz, J ¼ 2.7 Hz),
7.55 (m, 6H), 7.75 (m, 2H), 7.84 (m, 1H); 13C NMR (75 MHz, CDCl3): d 24.29,
32.33, 49.07, 55.18, 118.85, 127.42, 128.72, 129.06, 129.17, 132.75, 133.26, 133.22,
137.42, 171.12, 176.37. Anal. calcd. for C19H16 N4O3S (380.43): C, 59.99; H, 4.24;
N, 14.73. Found: C, 60.07; H, 4.29; N, 14.78.
5-Hydro-3-(N-methyl-N-
phenylsulfonyl-1-aminoethyl)-1,2,4-oxadiazoles 6h
Yield 74%; mp 126–128 ꢀC; [a]D ꢁ42.4 (c 0.33%, CHCl3); IR (cmꢁ1):
nC¼N ¼ 1609; nNꢁO ¼ 911; nCꢁO ¼ 1221;1H NMR (300 MHz, CDCl3): d 0.76 (d,
3H, J ¼ 6.9 Hz), 2.56 (s, 3H), 4.40 (q, 1H), 7.38 (m, 3H), 7.65 (m, 2H), 8.67 (s,
1H); 13C NMR (75 MHz, CDCl3): d 12.18, 29.10, 53.32, 127.32, 129.72, 133.28,
139.75, 152.19, 176.36. Anal. calcd. for C11H13N3O3S (267.31): C, 49.43; H, 4.90;
N, 15.72. Found: C, 49.49; H, 4.99; N, 15.73.
5-Phenyl-3-(N-methyl-N-
phenylsulfonyl-1-aminoethyl)-1,2,4-oxadiazoles 6i
Yield 71%; [a]D ꢁ59.4 (c 0.33%, CHCl3); ee > 99.5% [HPLC analysis using a
Chirobiotic V column, 4.6 mm ꢂ 250 mm, under the following conditions: heptane=
isopropanol (93:7) as mobile phase, rt, k 254 nm, flow rate 0.6 mL=min, retention
time: 26.45 min]; IR (cmꢁ1); nC¼N ¼ 1601; nNꢁO ¼ 921; nCꢁO ¼ 1241;1H NMR
(300 MHz, CDCl3): d 0.84 (d, 3H, J ¼ 6.3 Hz), 2.61 (s, 3H), 4.34 (q, 1H), 7.65 (m,
6H), 7.94 (m, 2H), 8.16 (m, 2H); 13C NMR (75 MHz, CDCl3): d 13.25, 30.11,
54.12, 127.57, 128.16, 129.84, 132.76, 133.45, 137.53, 139.85, 152.14, 171.12, 177.06.
5-Hydro-3-(N-methyl-N-phenylsulfonyl-1-amino-2-
methylbutyl)-1,2,4-oxadiazoles 6j
Yield 69%; [a]D ꢁ70.6 (c 0.33%, CHCl3); ee > 99.5% [HPLC analysis using a
Chirobiotic V column, 4.6 mm ꢂ 250 mm, under the following conditions: heptane=
isopropanol (93:7) as mobile phase, rt k 254 nm, flow rate 0.6 mL=min, retention
time: 21.41min]; IR (cmꢁ1); nC¼N ¼ 1611; nNꢁO ¼ 915; nCꢁO ¼ 1225;1H NMR
(300 MHz, CDCl3): d 0.81 (t, 3H), 0.92 (d, 3H, J ¼ 6.6 Hz), 1.21 (m, 1H), 1.96 (m,
1H), 2.87 (s, 3H), 4.02 (d, 1H, J ¼ 11.7 Hz), 7.53 (m, 3H), 7.59 (m, 2H), 8.71 (s,
1H); 13C NMR (75 MHz, CDCl3): d 11.14, 15.94, 25.03, 30.10, 32.72, 63.80,
127.46, 129.44, 133.15, 139.91, 171.78, 177.48. MS=EI m=z ¼ 309.5 (Mþ.). Anal.

3,5-DISUBSTITUTED-1,2,4-OXADIAZOLES
3175
calcd. for C14H19N3O3S (309.39): C, 54.35; H, 6.19; N, 13.58. Found: C, 54.39; H,
6.23; N, 13.63.
5-Phenyl-3-(N-methyl-N-phenylsulfonyl-1-amino-2-
methylbutyl)-1,2,4-oxadiazoles 6k
Yield 70%; mp 139–141 ꢀC; [a]D ꢁ52.5 (c 0.33%, CHCl3); IR (cmꢁ1):
nC¼N ¼ 1600; nNꢁO ¼ 927; nCꢁO ¼ 1230;1H NMR (300 MHz, CDCl3): d 0.91
(t, 3H), 1.12 (d, 3H, J ¼ 6.7 Hz), 1.29 (m, 1H), 2.05 (m, 1H), 3.11 (s, 3H), 4.18
(d, 1H, J ¼ 11.1 Hz), 7.71 (m, 6H), 7.91 (m, 2H), 8.16 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 12.58, 17.24, 26.82, 31.44 33.72, 62.14, 127.36, 129.22, 134.54,
139.52, 170.12, 177.24.
ACKNOWLEDGMENTS
The authors thank Dr. Gwilherm Evano from the University of Versailles,
´ ´
France, for his help and the DGRSRT (Direction Generale de la Recherche
´
Scientifique et de la Renovation Technologique) of the Tunisian Ministry of Higher
Education and Scientific Research and Technology for the financial support of this
research work.
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