'One-pot' synthesis of chiral N-protected α-amino acid-derived 1,2,4-oxadiazoles

Article abstract of DOI:10.1055/s-2004-822391

A series of α-amino acid-derived 1,2,4-oxadiazoles have been synthesized via an easy, inexpensive and one-pot protocol. The heterocycles were obtained in good yields and in relatively short reaction times.

Full text of DOI:10.1055/s-2004-822391

PAPER
1589
‘One-Pot’ Synthesis of Chiral N-Protected a-Amino Acid-Derived
1,2,4-Oxadiazoles
‘O
ne-Pot’ Synthes
n
is of
C
hiral
N
t
-
Prote
o
cted 1,2,4-
O
n
xadiazoles io L. Braga,*a Diogo S. Lüdtke,a Eduardo E. Alberto,a Luciano Dornelles,*b Wolmar A. Severo Filho,b
Valeriano A. Corbellini,b Daiane M. Rosa,b Ricardo S. Schwabb
a
Departamento de Química, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS, Brazil
Fax +55(55)2208031; E-mail: albraga@quimica.ufsm.br
b
Departamento de Química e Física, Universidade de Santa Cruz do Sul, 96815-900, Santa Cruz do Sul, RS, Brazil
E-mail: luciano@unisc.br
Received 9 January 2004; revised 26 March 2004
oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl),14a and
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tet-
rafluoroborate (TBTU).20 The O-acylated amidoxime can
be isolated or immediately undergo a cyclodehydration
reaction to form the heterocyclic ring usually by heating
to temperatures higher than 100 °C. Microwave tech-
niques have also been employed in the synthesis of such
heterocycles.21
A recent report of Hernandez22 concerning the synthesis
of 1,2,4-oxadiazole-containing a- and b3-amino acids
starting from Fmoc-protected aspartic acid prompted us to
disclose our results in the preparation of this class of het-
erocycles containing a chiral center.
Abstract: A series of a-amino acid-derived 1,2,4-oxadiazoles have
been synthesized via an easy, inexpensive and one-pot protocol.
The heterocycles were obtained in good yields and in relatively
short reaction times.
Key words: amino acids, oxadiazoles, heterocycles
Oxadiazoles have often been described as bioisosters of
amides and esters.1 Due to the increased hydrolytic2 and
metabolic stability of the oxadiazole ring, improved phar-
macokinetic and in vivo performance are often observed,
which make this heterocycle an important structural motif
to the pharmaceutical industry. As a consequence of these
characteristics, oxadiazoles have impacted numerous
drug discovery programs, including muscarinic agonists,3
benzodiazepine receptor partial agonists,4 dopamine
transporters,5 antirhinovirals,6 growth hormone secreta-
gogues,7 and 5-HT receptor agonists.8 They are also re-
ported as inhibitors of tyrosine kinase,9 baterial and
human DNA topoisomerases,10 and human neutrophil
elastase.11
As part of our growing interest in using a-amino acids as
chiral building blocks in organic synthesis,23 we describe
herein an easy, inexpensive one-pot synthetic route for the
preparation of a set of chiral N-protected a-amino acid-
derived 1,2,4-oxadiazoles.
The synthetic route to afford the 1,2,4-oxadiazoles was
applied on appropriately protected amino acids shown in
Figure 1.
1,2,4-Oxadiazoles have been most commonly synthesized
in solution and on solid support in a two-step process by
reaction of amidoximes and activated carboxylic acid de-
rivatives (Scheme 1).
O
O
H
O
H
H
N
OEt
N
OEt
N
OEt
HO
HO
HO
O
O
Me
O
2
3
1
O
OH
N
O
N
O
R
N
+
O
O
R'
R
H
O
X
R'
N
R
NH2
R'
H
N
OEt
NH2
N
OEt
HO
HO
BnS
O
Scheme 1
O
5
S
4
In the first step, the amidoxime is O-acylated by the acti-
vated carboxylic acid derivative, which can be previously
prepared or in situ activated by several methods including
the use of acid chloride,12 acid fluoride,13 symmetrical an-
hydride,14 active ester,9 ester with sodium ethoxide,15
N,N′-carbonyldiimidazole (CDI),16 acyl palladium com-
plexes,17 dicyclohexylcarbodiimide (DCC),14a,18 2-(di-
methylamino)isopropyl chloride (DIC),19 1-[3-(dimethyl-
amino)propyl]-3-ethylcarbodiimide (EDC),10,12,14a bis(2-
Figure 1
All five amino acids were conveniently protected by treat-
ment with ethyl chloroformate in an aqueous sodium bi-
carbonate solution.24 The amidoximes were prepared
using classic procedures from the corresponding nitriles
by reaction with hydroxylamine in refluxing ethanol.25
Initial studies were performed using the benzonitrile de-
rived amidoxime a and the protected L-phenylalanine de-
rivative 2 (Scheme 2).
SYNTHESIS 2004, No. 10, pp 1589–1594
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x
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0
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Advanced online publication: 26.05.2004
DOI: 10.1055/s-2004-822391; Art ID: M00404SS
© Georg Thieme Verlag Stuttgart · New York
Activation of the carboxylic acid moiety with DCC and
further acylation of the amidoxime in dioxane as solvent

1590
A. L. Braga et al.
PAPER
Table 1 Synthesis of a-Amino Acid-Derived 1,2,4-Oxadiazoles
O
O
H
OH
H
N
Ph
N
N
OEt
DCC, dioxane Ph
OEt
N
N
O
+
O
HO
O
H
DCC, dioxane
100 °C
H
OH
NH2
NH2
O
N
OEt
Ar
O
N
N
OEt
Ph
+
HO
N
Ph
2
a
R
O
Ar
NH2
R
O
a–e
1–5
1a–5e
heat, 100 °C
Compound Ar
R
Time (h) Yield (%)
1a
2a
3a
4a
5a
1b
2b
3b
4b
5b
1c
2c
3c
4c
5c
1d
2d
Ph
Ph
Ph
Ph
Ph
Me
8
9
73
75
76
65
60
65
82
75
80
79
70
70
80
72
73
60
70
64
73
70
71
65
73
60
68
N
N
O
H
Ph
N
OEt
CH2Ph
O
Ph
2a
i-Bu
8
Scheme 2
CH2SCH2Ph
CH2CH2SCH3
Me
8
8
furnished the O-acylamidoxime which was not isolated
and immediately underwent a cyclodehydration reaction
when heating to 100 °C for eight hours, delivering the
1,2,4-oxadiazole derivative 2a in 73% yield after purifica-
tion. It was gratifying that the carbamate protective group
was not affected under these conditions.
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
8
CH2Ph
9
i-Bu
12
12
10
8
CH2SCH2Ph
CH2CH2SCH3
Me
The present reaction has been further extended to a broad-
er range of protected amino acids 1–5 shown in Figure 1
and to a set of aryl-substituted amidoximes a–e. All reac-
tions were carried out in dioxane as solvent and monitored
by TLC and the results are depicted in Table 1.
CH2Ph
8
The reaction was performed using amino acids with lipo-
philic (alanine, phenylalanine and leucine) and sulfurated
(S-benzyl-cysteine and methionine) side chains. The elec-
tronic effect of the substituents at the amidoximes was
also studied. Aryl amidoximes containing electron-donat-
ing groups as methyl and methoxy and electron-with-
drawing groups like chloro and nitro were prepared and
studied in the oxadiazole formation. We could observe
i-Bu
10
8
CH2SCH2Ph
CH2CH2SCH3
Me
8
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-NO2Ph
4-NO2Ph
4-NO2Ph
4-NO2Ph
4-NO2Ph
8
CH2Ph
8
that all the 1,2,4-oxadiazoles were obtained in good yields 3d
i-Bu
8
for the amino acids studied. The nature of the side chain
does not play a significant role in terms of conversion to
4d
CH2SCH2Ph
CH2CH2SCH3
Me
10
10
8
the desired heterocycle, since the results obtained with li-
pophilic and sulfurated side chains were quite similar. It
could also be noted that the substitution pattern at the ar-
omatic ring of the amidoxime does not exert a strong in-
fluence in the heterocycle formation. This is accounted for
by analyzing the results obtained either with electron-do-
nating or electron-withdrawing groups, once a significant
variation in both yield and reaction time was not observed.
5d
1e
2e
3e
4e
5e
CH2Ph
8
i-Bu
8
CH2SCH2Ph
CH2CH2SCH3
8
8
Furthermore, the reaction was also carried out with non-
natural amino acids. The aryl amidoximes a–e were react-
ed with the protected amino acids of R configuration ent-
1–5. The reaction proceeded in a similar way and the het-
erocycles ent-1a–5e were achieved in similar yields
(Scheme 3).
In summary, we have described an easy and one-pot syn-
thesis for several a-amino acids derived 1,2,4-oxadia-
zoles. Their preparation was achieved in good yields and
although a limited number of substituents has been pre-
sented here, it can be extended to many other substrates,
since amino acids are low-cost, easily available starting
materials. The reaction conditions proved to be compati-
ble with the carbamate protective group which can be fur-
ther converted into other functional groups. One of the
most interesting features of the methodology presented
here is that there is not necessity to isolate the acylated
N
O
O
DCC, dioxane
100 °C
H
H
OH
Ar
N
OEt
N
OEt
N
N
+
HO
R
O
R
O
Ar
NH2
ent 1a–5e
58 - 85% yield
a–e
ent 1–5
Scheme 3
Synthesis 2004, No. 10, 1589–1594 © Thieme Stuttgart · New York

PAPER
‘One-Pot’ Synthesis of Chiral N-Protected 1,2,4-Oxadiazoles
1591
Ethyl [(S)-3-Methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)butyl]car-
bamate (3a)
Yield: 76%; oil; Rf = 0.55 (hexane–EtOAc, 70:30).
amidoxime constituting therefore a short and practical
protocol for the formation of such heterocycles.
Studies dealing with the use of these amino acid-derived
heterocycles as a chiral pool for the design of novel cata-
lysts applied in stereoselective transformations are now
underway in our laboratories.
[a]D20 = –46 (c 0.65, CH2Cl2).
IR: 3305, 2929, 1699, 1659 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.06 (d, 2 H, J = 7.8 Hz), 7.4–7.5
(m, 3 H), 5.45 (d, 1 H, J = 8.2 Hz), 5.2–5.3 (m, 1 H), 4.13 (q, 2 H,
J = 7.1 Hz), 1.7–1.9 (m, 3 H), 1.20 (t, 3 H, J = 6.8 Hz), 0.99 (d, 6 H,
J = 6.2 Hz).
Melting Points are uncorrected. 1H and 13C NMR spectra were re-
corded at 200 and 50 MHz respectively with tetramethylsilane as in-
ternal standard. IR spectra were recorded in a range of 4000–600
cm–1 using a Nicolet Magna 550 spectrometer. Column chromatog-
raphy was performed using Merck Silica Gel (230–400 mesh) fol-
lowing the methods described by Still.26 Thin layer chromatography
(TLC) was performed using Merck Silica Gel GF254 (0.25 mm
thickness). For visualization, TLC plates were either placed under
ultraviolet light, or stained with iodine vapor, or acidic vanillin.
Most reactions were monitored by TLC for disappearance of start-
ing material. Dioxane was dried over Na. All other solvents were
used as purchased unless otherwise noted. All amino acids were
protected by conventional procedures.23 Aryl amidoximes a–e were
prepared by classical procedures.24
13C NMR (CDCl3, 50 MHz): d = 179.5, 167.5, 155.7, 130.5, 128.1,
126.8, 126.1, 60.5, 55.0, 34.3, 24.8, 24.0, 13.8.
Anal. Calcd for C16H21N3O3: C, 63.35; H, 6.98; N, 13.85. Found: C,
63.37; H, 6.99; N, 13.91.
Ethyl [(R)-2-(Benzylthio)-1-(3-phenyl-1,2,4-oxadiazol-5-yl)eth-
yl]carbamate (4a)
Yield: 65%; mp 116–118 °C; Rf = 0.48 (hexane–EtOAc, 70:30).
[a]D20 = –25 (c 0.6, CH2Cl2).
IR: 3324, 2926, 1706, 1682 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.06 (d, 2 H, J = 8.8 Hz), 7.46 (d,
2 H, J = 8.6 Hz), 7.2–7.3 (m, 5 H), 5.60 (d, 1 H, J = 7.9 Hz), 5.2–
5.4 (m, 1 H), 4.17 (q, 2 H, J = 7.2 Hz), 3.69 (s, 2 H), 3.03 (d, 2 H,
J = 5.9 Hz), 1.27 (t, 3 H, J = 7.0 Hz).
Synthesis of N-Protected a-Amino Acid-Derived 1,2,4-Oxadi-
azoles; General Procedure
To a 50 mL round-bottomed flask equipped with a reflux condenser,
under an argon atmosphere, N,N¢-dicyclohexylcarbodiimide (2.2
mmol) was added to a solution of the appropriate N-protected ami-
no acid (2 mmol) and the aryl amidoxime (2 mmol) in of dry diox-
ane (20 mL). The reaction mixture was heated under stirring at 100
°C for the time indicated in Table 1. After this time the solvent was
removed under vacuum and the residue purified by flash
chromatography26 (hexane:EtOAc, 70:30).
13C NMR (CDCl3, 50 MHz): d = 177.7, 167.9, 155.6, 136.9, 130.9,
128.5, 128.2, 127.1, 126.8, 126.0, 61.2, 47.9, 35.9, 34.1, 14.1.
Anal. Calcd for C20H21N3O3S: C, 62.64; H, 5.52; N, 10.96. Found:
C, 62.81; H, 5.62; N, 11.02.
Ethyl [(S)-3-(Methylthio)-1-(3-phenyl-1,2,4-oxadiazol-5-yl)pro-
pyl]carbamate (5a)
Yield: 60%; mp 59–61 °C; Rf = 0.41 (hexane–EtOAc, 70:30).
Ethyl [(S)-1-(3-Phenyl-1,2,4-oxadiazol-5-yl)ethyl]carbamate
(1a)
Yield: 73%; mp 77–79 °C; Rf = 0.38 (hexane–EtOAc, 70:30).
[a]D20 = –34 (c 0.65, CH2Cl2).
IR: 3304, 2929, 1682, 1651 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.06 (d, 2 H, J = 7.7 Hz), 7.4–7.5
(m, 3 H), 5.75 (d, 1 H, J = 8.5 Hz), 5.2–5.4 (m, 1 H), 4.17 (q, 2 H,
J = 7.1 Hz), 2.62 (t, 2 H, J = 7.2 Hz), 2.2–2.4 (m, 2 H), 2.12 (s, 3 H),
1.26 (t, 3 H, J = 6.9 Hz).
13C NMR (CDCl3, 50 MHz): d = 178.7, 168.1, 155.8, 131.2, 128.4,
127.3, 126.3, 61.4, 47.8, 33.0, 31.3, 29.6, 15.3, 14.3.
[a]D20 = –64 (c 0.5, CH2Cl2).
IR: 3304, 2936, 1699, 1681 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.05 (d, 2 H, J = 7.6 Hz), 7.4–7.5
(m, 3 H), 6.43 (d, 1 H, J = 7.6 Hz), 5.1–5.3 (m, 1 H), 4.12 (q, 2 H,
J = 7.0 Hz), 1.63 (d, 3 H, J = 7.2 Hz), 1.19 (t, 3 H, J = 6.8 Hz).
13C NMR (CDCl3, 50 MHz): d = 179.7, 167.7, 155.6, 130.8, 128.3,
126.9, 126.1, 60.9, 44.2, 18.9, 14.0.
Anal. Calcd for C15H19N3O3S: C, 56.06; H, 5.96; N, 13.07. Found:
C, 56.12; H, 5.99; N, 13.11.
Anal. Calcd for C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found: C,
59.84; H, 5.66; N, 15.99.
Ethyl {(S)-1-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]eth-
yl}carbamate (1b)
Yield: 65%; mp 91–92 °C; Rf = 0.41 (hexane–EtOAc, 70:30).
[a]D20 = –67 (c 0.6, CH2Cl2).
IR: 3305, 2983, 1685, 1675 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.91 (d, 2 H, J = 8.6 Hz), 7.35 (d,
2 H, J = 8.6 Hz), 6.25 (d, 1 H, J = 7.8 Hz), 5.1–5.2 (m, 1 H), 4.10
(q, 2 H, J = 7.0 Hz), 1.60 (d, 3 H, J = 7.2 Hz), 1.18 (t, 3 H, J = 7.0
Hz).
13C NMR (CDCl3, 50 MHz): d = 179.9, 167.0, 155.5, 136.9, 128.7,
128.3, 124.7, 61.0, 53.2, 19.0, 14.1.
Ethyl [(S)-2-Phenyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]car-
bamate (2a)
Yield: 75%; mp 93–94 °C; Rf = 0.46 (hexane–EtOAc, 70:30).
[a]D20 = +2 (c 0.6, CH2Cl2).
IR: 3313, 2978, 1694, 1679 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.05 (d, 2 H, J = 7.6 Hz), 7.4–7.5
(m, 3 H), 7.2–7.3 (m, 3 H), 7.13 (d, 2 H, J = 7.4 Hz), 5.78 (d, 1 H,
J = 8.0 Hz), 5.4–5.5 (m, 1 H), 4.10 (q, 2 H, J = 7.1 Hz), 3.31 (d, 2
H, J = 5.8 Hz), 1.19 (t, 3 H, J = 6.7 Hz).
13C NMR (CDCl3, 50 MHz): d = 178.5, 168.0, 155.6, 134.9, 131.1,
129.3, 129.1, 128.6, 127.3, 126.3, 61.3, 49.6, 39.5, 14.2.
Anal. Calcd for C13H14ClN3O3: C, 52.80; H, 4.77; N, 14.21. Found:
C, 52.94; H, 4.87; N, 14.36.
Anal. Calcd for C19H19N3O3: C, 67.64; H, 5.68; N, 12.46. Found: C,
67.51; H, 5.65; N, 12.33.
Ethyl {(S)-1-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-2-phe-
nylethyl}carbamate (2b)
Yield: 82%; mp 99–100 °C; Rf = 0.49 (hexane–EtOAc, 70:30).
Synthesis 2004, No. 10, 1589–1594 © Thieme Stuttgart · New York

1592
A. L. Braga et al.
PAPER
[a]D20 = –38 (c 0.55, CH2Cl2).
IR: 3318, 2986, 1694, 1641 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.98 (d, 2 H, J = 8.6 Hz), 7.44 (d,
2 H, J = 8.6 Hz), 7.2–7.3 (m, 3 H), 7.09 (d, 2 H, J = 7.4 Hz), 5.43
(d, 1 H, J = 8.0 Hz), 5.2–5.3 (m, 1 H), 4.13 (q, 2 H, J = 7.1 Hz), 3.31
(d, 2 H, J = 5.9 Hz), 1.23 (t, 3 H, J = 6.6 Hz).
1H NMR (CDCl3, 200 MHz): d = 7.93 (d, 2 H, J = 7.8 Hz), 7.24 (d,
2 H, J = 8.0 Hz), 6.37 (d, 1 H, J = 7.8 Hz), 5.1–5.3 (m, 1 H), 4.11
(q, 2 H, J = 7.0 Hz), 2.37 (s, 3 H), 1.63 (d, 3 H, J = 7.0 Hz), 1.17 (t,
3 H, J = 7.0 Hz).
13C NMR (CDCl3, 50 MHz): d = 179.5, 167.8, 155.6, 141.1, 129.1,
127.0, 123.4, 60.9, 44.2, 21.0, 19.1, 14.1.
Anal. Calcd for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26 Found: C,
60.99; H, 6.14; N, 14.89.
13C NMR (CDCl3, 50 MHz): d = 178.7, 167.0, 155.6, 136.0, 135.0,
128.8, 128.7, 128.3, 128.2, 126.8, 124.6, 61.0, 49.5, 34.5, 14.1.
Anal. Calcd for C19H18ClN3O3: C, 61.38; H, 4.88; N, 11.30. Found:
C, 61.65; H, 4.96; N, 11.48.
Ethyl [(S)-1-(3-p-Tolyl-1,2,4-oxadiazol-5-yl)-2-phenylethyl]car-
bamate (2c)
Yield: 70%; mp 87–89 °C; Rf = 0.53 (hexane–EtOAc, 70:30).
[a]D20 = –32 (c 0.65, CH2Cl2).
IR: 3306, 2980, 1690, 1659 cm–1.
Ethyl {(S)-1-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-meth-
ylbutyl}carbamate (3b)
Yield: 75%; oil; Rf = 0.68 (hexane–EtOAc, 70:30).
[a]D20 = –41 (c 0.6, CH2Cl2).
IR: 3307, 2930, 1697, 1679 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.90 (d, 2 H, J = 8.8 Hz), 7.35 (d,
2 H, J = 8.8 Hz), 5.43 (d, 1 H, J = 8.0 Hz), 5.0–5.2 (m, 1 H), 4.07
(q, 2 H, J = 7.2 Hz), 1.6–1.9 (m, 3 H), 1.16 (t, 3 H, J = 7.2 Hz), 0.92
(d, 6 H, J = 6.4 Hz).
1H NMR (CDCl3, 200 MHz): d = 7.93 (d, 2 H, J = 7.0 Hz), 7.22 (d,
2 H, J = 7.0 Hz), 7.1–7.2 (m, 5 H), 6.04 (d, 1 H, J = 8.6 Hz), 5.3–
5.5 (m, 1 H), 4.05 (q, 2 H, J = 7.2 Hz), 3.28 (d, 2 H, J = 5.8 Hz), 2.35
(s, 3 H), 1.17 (t, 3 H, J = 7.0 Hz).
13C NMR (CDCl3, 50 MHz): d = 178.3, 167.9, 155.6, 141.2, 135.0,
129.1, 128.9, 128.2, 127.1, 126.9, 123.4, 61.1, 49.6, 39.3, 21.2,
14.1.
13C NMR (CDCl3, 50 MHz): d = 180.4, 167.9, 153.7, 137.8, 129.6,
129.2, 125.5, 56.2, 43.5, 35.3, 25.9, 25.1, 14.9.
Anal. Calcd for C20H21N3O3: C, 68.36; H, 6.02; N, 11.96. Found: C,
68.39; H, 6.04; N, 11.99.
Anal. Calcd for C16H20ClN3O3: C, 56.89; H, 5.97; N, 12.44. Found:
C, 56.77; H, 6.03; N, 12.31.
Ethyl [(S)-3-Methyl-1-(3-p-tolyl-1,2,4-oxadiazol-5-yl)butyl]car-
bamate (3c)
Yield: 80%; oil; Rf = 0.60 (hexane–EtOAc, 70:30).
[a]D20 = –39 (c 0.7, CH2Cl2).
IR: 3310, 2934, 1697, 1649 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.94 (d, 2 H, J = 8.0 Hz), 7.23 (d,
2 H, J = 8.0 Hz), 6.55 (d, 1 H, J = 8.8 Hz), 5.1–5.3 (m, 1 H), 4.15
(q, 2 H, J = 6.8 Hz), 2.4 (s, 3 H), 1.5–1.9 (m, 3 H), 1.22 (t, 3 H,
J = 6.4 Hz), 0.95 (d, 6 H, J = 6.2 Hz).
13C NMR (CDCl3, 50 MHz): d = 179.4, 167.6, 155.7, 140.8, 128.9,
126.8, 123.4, 60.6, 46.6, 41.9, 24.2, 24.0, 20.8, 13.9.
Ethyl {(R)-2-(benzylthio)-1-[3-(4-chlorophenyl)-1,2,4-oxadi-
azol-5-yl]ethyl}carbamate (4b)
Yield: 80%; mp 129–130 °C; Rf = 0.45 (hexane–EtOAc, 70:30).
[a]D20 = –29 (c 0.6, CH2Cl2).
IR: 3326, 2977, 1683, 1641 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.00 (d, 2 H, J = 8.6 Hz), 7.44 (d,
2 H, J = 8.6 Hz), 7.2–7.3 (m, 5 H), 5.67 (d, 1 H, J = 8.0 Hz), 5.2–
5.4 (m, 1 H), 4.16 (q, 2 H, J = 7.0 Hz), 3.67 (s, 2 H), 3.01 (d, 2 H,
J = 6.0 Hz), 1.26 (t, 3 H, J = 7.2 Hz).
13C NMR (CDCl3, 50 MHz): d = 178.1, 167.6, 155.6, 137.5, 137.1,
129.1, 128.8, 128.6, 127.4, 124.8, 61.7, 48.3, 36.5, 34.7, 14.4.
Anal. Calcd for C17H23N3O3: C, 64.33; H, 7.30; N, 13.24. Found: C,
64.35; H, 7.33; N, 13.25.
Anal. Calcd for C20H20ClN3O3S: C, 57.48; H, 4.82; N, 10.05.
Found: C, 57.66; H, 4.98; N, 10.12.
Ethyl [(R)-2-(Benzylthio)-1-(3-p-tolyl-1,2,4-oxadiazol-5-yl)eth-
yl]carbamate (4c)
Yield: 72%; mp 124–126 °C; Rf = 0.46 (hexane–EtOAc, 70:30).
[a]D20 = –34 (c 0.5, CH2Cl2).
IR: 3304, 2939, 1692, 1659 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.94 (d, 2 H, J = 8.0 Hz), 7.29 (d,
2 H, J = 8.0 Hz), 7.1–7.2 (m, 5 H), 5.84 (d, 1 H, J = 8.2 Hz), 5.3–
5.4 (m, 1 H), 4.15 (q, 2 H, J = 7.2 Hz), 3.65 (s, 2 H), 3.00 (d, 2 H,
J = 6.0 Hz), 2.39 (s, 3 H), 1.25 (t, 3 H, J = 7.2 Hz).
13C NMR (CDCl3, 50 MHz): d = 177.6, 168.2, 155.6, 141.6, 137.0,
129.4, 128.9, 128.7, 128.5, 127.3, 124.8, 61.5, 48.2, 36.3, 34.5,
21.4, 14.4.
Ethyl {(S)-1-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-(me-
thylthio)propyl}carbamate (5b)
Yield: 79%; oil; Rf = 0.50 (hexane–EtOAc, 70:30).
[a]D20 = –44 (c 0.55, CH2Cl2).
IR: 3304, 2928, 1694, 1651 cm–1
1H NMR (CDCl3, 200 MHz): d = 8.00 (d, 2 H, J = 8.4 Hz), 7.43 (d,
2 H, J = 8.6 Hz), 6.39 (d, 1 H, J = 8.4 Hz), 5.2–5.3 (m, 1 H), 4.17
(q, 2 H, J = 7.2 Hz), 2.62 (t, 2 H, J = 7.0 Hz), 2.2–2.4 (m, 2 H), 2.12
(s, 3 H), 1.26 (t, 3 H, J = 6.8 Hz).
13C NMR (CDCl3, 50 MHz): d = 178.9, 167.0, 155.8, 137.0, 128.7,
128.3, 124.6, 61.2, 47.5, 32.4, 29.5, 15.0, 14.1.
Anal. Calcd for C21H23N3O3S: C, 63.45; H, 5.83; N, 10.57. Found:
C, 63.88; H, 5.96; N, 10.63.
Anal. Calcd for C15H18ClN3O3S: C, 50.63; H, 5.10; N, 11.81.
Found: C, 50.44; H, 4.97; N, 11.52.
Ethyl [(S)-1-(3-p-Tolyl-1,2,4-oxadiazol-5-yl)-3-(methylthio)pro-
pyl]carbamate (5c)
Yield: 73%; oil; Rf = 0.46 (hexane–EtOAc, 70:30).
[a]D20 = –48 (c 0.65, CH2Cl2).
IR: 3305, 2925, 1702, 1669 cm–1.
Ethyl [(S)-1-(3-p-Tolyl-1,2,4-oxadiazol-5-yl)ethyl]carbamate
(1c)
Yield: 70%; mp 88–89 °C; Rf = 0.38 (hexane–EtOAc, 70:30).
[a]D20 = –13 (c 0.6, CH2Cl2).
IR: 3290, 2930, 1715, 1656 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.93 (d, 2 H, J = 8.0 Hz), 7.24 (d,
2 H, J = 8.0 Hz), 6.39 (d, 1 H, J = 8.6 Hz), 5.2–5.3 (m, 1 H), 4.15
Synthesis 2004, No. 10, 1589–1594 © Thieme Stuttgart · New York

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‘One-Pot’ Synthesis of Chiral N-Protected 1,2,4-Oxadiazoles
1593
(q, 2 H, J = 7.0 Hz), 2.62 (t, 2 H, J = 7.0 Hz), 2.38 (s, 3 H), 2.1–2.3
(m, 2 H), 2.09 (s, 3 H), 1.24 (t, 3 H, J = 7.0 Hz).
13C NMR (CDCl3, 50 MHz): d = 178.5, 167.8, 155.8, 141.2, 129.1,
127.0, 123.2, 66.5, 51.0, 29.4, 21.1, 14.9, 14.1.
13C NMR (CDCl3, 50 MHz): d = 177.5, 167.9, 161.8, 155.6, 137.1,
128.9, 128.7, 128.4, 127.1, 118.6, 114.1, 61.4, 55.1, 48.1, 36.2,
34.5, 14.3.
Anal. Calcd for C21H23N3O4S: C, 61.00; H, 5.61; N, 10.16. Found:
C, 60.87; H, 5.49; N, 10.03.
Anal. Calcd for C16H21N3O3S: C, 57.29; H, 6.31; N, 12.53. Found:
C, 57.50; H, 6.46; N, 12.71.
Ethyl {(S)-1-[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl]-3-(me-
thylthio)propyl}carbamate (5d)
Yield: 70%; mp 96–98 °C; Rf = 0.33 (hexane–EtOAc, 70:30).
[a]D20 = –47 (c 0.4, CH2Cl2).
Ethyl {(S)-1-[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl]eth-
yl}carbamate (1d)
Yield: 60%; mp 117–118 °C; Rf = 0.27 (hexane–EtOAc, 70:30).
[a]D20 = –34 (c 0.5, CH2Cl2).
IR: 3302, 2985, 1731, 1691 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.90 (d, 2 H, J = 9.0 Hz), 6.87 (d,
2 H, J = 8.8 Hz), 5.80 (d, 1 H, J = 8.2 Hz), 5.0–5.2 (m, 1 H), 4.06
(q, 2 H, J = 7 .2 Hz), 3.75 (s, 3 H), 1.56 (d, 3 H, J = 7.0 Hz), 1.16 (t,
3 H, J = 6.8 Hz).
IR: 3296, 2932, 1736, 1679 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.00 (d, 2 H, J = 8.6 Hz), 6.97 (d,
2 H, J = 8.6 Hz), 6.21 (d, 1 H, J = 8.6 Hz), 5.2–5.3 (m, 1 H), 4.16
(q, 2 H, J = 7.2 Hz), 3.84 (s, 3 H), 2.63 (t, 2 H, J = 7.0 Hz), 2.2–2.4
(m, 2 H), 2.10 (s, 3 H), 1.25 (t, 3 H, J = 6.8 Hz).
13C NMR (CDCl3, 50 MHz): d = 178.3, 167.6, 161.6, 155.7, 128.7,
118.6, 113.9, 61.1, 55.0, 47.6, 32.7, 29.5, 15.0, 14.2.
13C NMR (CDCl3, 50 MHz): d = 179.4, 167.7, 161.8, 155.6, 128.9,
118.8, 114.0, 61.2, 55.1, 44.4, 19.6, 14.3.
Anal. Calcd for C16H21N3O4S: C, 54.68; H, 6.02; N, 11.96. Found:
C, 54.83; H, 6.26; N, 12.14.
Anal. Calcd for C14H17N3O4: C, 57.72; H, 5.88; N, 14.42. Found: C,
57.94; H, 5.99; N, 14.75.
Ethyl {(S)-1-[3-(4-Nitrophenyl)-1,2,4-oxadiazol-5-yl]ethyl}car-
bamate (1e)
Yield: 71%; mp 113–114 °C; Rf = 0.31 (hexane–EtOAc, 70:30).
[a]D20 = –38 (c 0.7, CH2Cl2).
Ethyl {(S)-1-[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl]-2-phe-
nylethyl}carbamate (2d)
Yield: 70%; mp 95–97 °C; Rf = 0.42 (hexane–EtOAc, 70:30).
[a]D20 = –60 (c 0.7, CH2Cl2).
IR: 3308, 2970, 1686, 1659 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.84 (d, 2 H, J = 8.8 Hz), 6.9–7.1
(m, 5 H), 6.80 (d, 2 H, J = 8.8 Hz), 5.76 (d, 1 H, J = 8.4 Hz), 5.2–
5.3 (m, 1 H), 3.96 (q, 2 H, J = 7.0 Hz), 3.64 (s, 3 H), 3.16 (d, 2 H,
J = 5.6 Hz), 1.04 (t, 3 H, J = 7.0 Hz).
IR (cm-1): 3283, 2930, 1726, 1675 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.0–8.2 (m, 4 H), 6.06 (d, 1 H,
J = 7.8 Hz), 5.1–5.2 (m, 1 H), 4.08 (q, 2 H, J = 7.2 Hz), 1.60 (d, 3
H, J = 7.0 Hz), 1.16 (t, 3 H, J = 7.0 Hz).
13C NMR (CDCl3, 50 MHz): d = 180.7, 166.4, 155.6, 149.2, 132.2,
128.1, 123.7, 61.2, 50.1, 19.2, 14.2.
13C NMR (CDCl3, 50 MHz): d = 178.1, 167.6, 161.7, 155.6, 135.0,
129.0, 128.9, 128.3, 126.9, 118.7, 113.9, 61.1, 55.0, 49.6, 39.3,
14.2.
Anal. Calcd for C13H14N4O5: C, 50.98; H, 4.61; N, 18.29. Found: C,
51.11; H,4.85; N, 18.50.
Ethyl {(S)-1-[3-(4-Nitrophenyl)-1,2,4-oxadiazol-5-yl]-2-phenyl-
ethyl}carbamate (2e)
Yield: 65%; mp 102–104 °C; Rf = 0.45 (hexane–EtOAc, 70:30).
Anal. Calcd for C20H21N3O4: C, 65.38; H, 5.76; N, 11.44. Found: C,
65.12; H, 5.34; N, 11.15.
Ethyl {(S)-1-[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl]-3-me-
thylbutyl}carbamate (3d)
Yield: 64%; oil; Rf = 0.49 (hexane–EtOAc, 70:30).
[a]D20 = –42 (c 0.6, CH2Cl2).
IR: 3305, 2934, 1697, 1659 cm–1.
[a]D20 = –2 (c 0.5, CH2Cl2).
IR: 3305, 2920, 1695, 1659 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.1–8.3 (m, 4 H), 7.1–7.3 (m, 5
H), 6.33 (d, 1 H, J = 7.4 Hz), 5.4–5.5 (m, 1 H), 4.10 (q, 2 H, J = 7.0
Hz), 3.35 (d, 2 H, J = 6.0 Hz), 1.15 (t, 3 H, J = 6.8 Hz).
1H NMR (CDCl3, 200 MHz): d = 7.99 (d, 2 H, J = 8.6 Hz), 6.95 (d,
2 H, J = 8.6 Hz), 6.32 (d, 1 H, J = 8.6 Hz), 5.1–5.2 (m, 1 H), 4.15
(q, 2 H, J = 7.0 Hz), 3.81 (s, 3 H), 1.5–1.9 (m, 3 H), 1.22 (t, 3 H,
J = 6.6 Hz), 0.97 (d, 6 H, J = 6.2 Hz).
13C NMR (CDCl3, 50 MHz): d = 179.3, 167.5, 161.5, 155.8, 128.6,
118.6, 113.5, 60.8, 54.7, 46.7, 42.2, 24.2, 23.1, 14.0.
13C NMR (CDCl3, 50 MHz): d = 179.5, 166.3, 155.5, 149.0, 135.0,
131.9, 128.7, 128.2, 127.9, 126.8, 123.5, 61.0, 53.2, 38.8, 14.0.
Anal. Calcd for C19H18N4O5: C, 59.68; H, 4.74; N, 14.65. Found: C,
59.55; H, 4.53; N, 14.48.
Ethyl {(S)-3-Methyl-1-[3-(4-nitrophenyl)-1,2,4-oxadiazol-5-
yl]butyl}carbamate (3e)
Yield: 73%; oil; Rf = 0.46 (hexane–EtOAc, 70:30).
[a]D20 = –32 (c 0.5, CH2Cl2).
IR: 3305, 2931, 1696, 1654 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.2–8.4 (m, 4 H), 6.28 (d, 1 H,
J = 8.6 Hz), 5.2–5.3 (m, 1 H), 4.15 (q, 2 H, J = 7.2 Hz), 1.6–1.9 (m,
3 H), 1.24 (t, 3 H, J = 6.8 Hz), 0.96 (d, 6 H, J = 6.2 Hz).
13C NMR (CDCl3, 50 MHz): d = 180.6, 166.3, 155.8, 149.0, 133.2,
128.0, 123.6, 61.0, 46.9, 41.9, 24.2, 21.2, 14.1.
Anal. Calcd for C17H23N3O4: C, 61.25; H, 6.95; N, 12.60. Found: C,
61.28; H, 7.01; N, 12.74.
Ethyl {(R)-2-(Benzylthio)-1-[3-(4-methoxyphenyl)-1,2,4-oxadi-
azol-5-yl]ethyl}carbamate (4d)
Yield: 73%; mp 124–126 °C; Rf = 0.34 (hexane–EtOAc, 70:30).
[a]D20 = –22 (c 0.7, CH2Cl2).
IR: 3310, 2929, 1692, 1663 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.98 (d, 2 H, J = 8.8 Hz), 7.2–7.3
(m, 5 H), 6.95 (d, 2 H, J = 8.8 Hz), 5.93 (d, 1 H, J = 8.4 Hz), 5.2–
5.3 (m, 1 H), 4.15 (q, 2 H, J = 7.2 Hz), 3.81 (s, 3 H), 3.66 (s, 2 H),
3.00 (d, 2 H, J = 6.0 Hz), 1.21 (t, 3 H, J = 7.0 Hz).
Anal. Calcd for C16H20N4O5: C, 55.17; H, 5.79; N, 16.08. Found: C,
55.32; H, 5.89; N, 16.20.
Synthesis 2004, No. 10, 1589–1594 © Thieme Stuttgart · New York

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A. L. Braga et al.
PAPER
Ethyl {(R)-2-(Benzylthio)-1-[3-(4-nitrophenyl)-1,2,4-oxadiazol-
5-yl]ethyl}carbamate (4e)
Yield: 60%; oil; Rf = 0.46 (hexane–EtOAc, 70:30).
[a]D20 = –14 (c 0.5, CH2Cl2).
IR: 3305, 2925, 1697, 1659 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.2–8.4 (m, 4 H), 7.2–7.4 (m, 5
H), 5.98 (d, 1 H, J = 8.2 Hz), 5.3–5.4 (m, 1 H), 4.13 (q, 2 H, J = 7.2
Hz), 3.72 (s, 2 H), 3.05 (d, 2 H, J = 6.4 Hz), 1.26 (t, 3 H, J = 7.0 Hz).
13C NMR (CDCl3, 50 MHz): d = 178.8, 166.6, 155.6, 149.2, 136.9,
132.0, 128.7, 128.4, 128.2, 127.2, 123.8, 61.6, 48.2, 36.3, 34.3,
14.3.
C.; Eyermann, D. J.; Lynch, B. A.; MacNeil, I. A.; Ram, M.
K.; van Schravendijk, M. R.; Violette, S.; Sawyer, T. K. J.
Med. Chem. 1999, 42, 4088. (c) Leite, A. C. L.; Vieira, R.
F.; de Faria, A. R.; Wanderley, A. G.; Afiatpour, P.;
Ximenes, E. C. P. A.; Srivastava, R. M.; de Oliveira, C. F.;
Medeiros, M. V.; Antunes, E.; Brondani, D. J. Il Farmaco
2000, 55, 719.
(10) Rudolph, J.; Theis, H.; Hanke, R.; Endermann, R.;
Johannsen, L.; Geschke, F.-U. J. Med. Chem. 2001, 44, 619.
(11) Ohmoto, K.; Yamamoto, T.; Horiuchi, T.; Imanishi, H.;
Odakagi, Y.; Kawabata, K.; Sekioka, T.; Hirota, Y.;
Matsuoka, S.; Nakai, H.; Toda, M. J. Med. Chem. 2000, 43,
4927.
Anal. Calcd for C20H20N4O5S: C, 56.06; H, 4.70; N, 13.08. Found:
C, 56.23; H, 4.89; N, 13.20.
(12) Rice, K. D.; Nuss, J. M. Bioorg. Med. Chem. Lett. 2001, 11,
753.
(13) Sams, C. K.; Lau, J. Tetrahedron Lett. 1999, 40, 9359.
(14) (a) Borg, S.; Estenne-Bouhtou, G.; Luthman, K.; Csöregh, I.;
Hesselink, W.; Hacksell, U. J. Org. Chem. 1995, 60, 3112.
(b) Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.;
Terenius, L.; Luthman, K. J. Med. Chem. 1999, 42, 4331.
(c) Liang, G.-B.; Qian, X. Bioorg. Med. Chem. Lett. 1999, 9,
2101.
(15) Bedford, C. D.; Howd, R. A.; Dailey, O. D.; Miller, A.;
Nolen, H. W.; Kenley, R. A.; Kern, J. R.; Winterle, J. S. J.
Med. Chem. 1986, 29, 2174.
Ethyl {(S)-3-(Methylthio)-1-[3-(4-nitrophenyl)-1,2,4-oxadiazol-
5-yl]propyl}carbamate (5e)
Yield: 68%; oil; Rf = 0.29 (hexane–EtOAc, 70:30).
[a]D20 = –18 (c 0.45, CH2Cl2).
IR: 3305, 2925, 1683, 1649 cm–1.
1H NMR (CDCl3, 200 MHz): d = 8.2–8.4 (m, 4 H), 6.42 (d, 1 H,
J = 8.2 Hz), 5.2–5.4 (m, 1 H), 4.17 (q, 2 H, J = 7.0 Hz), 2.69 (t, 2 H,
J = 7.0 Hz), 2.2–2.4 (m, 2 H), 2.15 (s, 3 H), 1.27 (t, 3 H, J = 7.2 Hz).
(16) (a) Liang, G.-B.; Feng, D. D. Tetrahedron Lett. 1996, 37,
6627. (b) Deegan, T. L.; Nitz, T. J.; Cebzanov, D.; Porco, J.
A. Jr. Bioorg. Med. Chem. Lett. 1999, 9, 209.
(17) Young, J. R.; DeVita, R. J. Tetrahedron Lett. 1998, 39, 3931.
(18) De Melo, S. J.; Sobral, A. D.; de Lima Lopes, H.; Srivastava,
R. M. J. Braz. Chem. Soc. 1998, 9, 465.
13C NMR (CDCl3, 50 MHz): d = 179.7, 166.3, 155.8, 149.0, 132.0,
127.0, 123.7, 61.2, 47.6, 32.3, 29.5, 15.0, 14.1.
Anal. Calcd for C15H18N4O5S: C, 49.17; H, 4.95; N, 15.29. Found:
C, 49.34; H, 4.87; N, 15.16.
(19) Hébert, N.; Hannah, A. L.; Sutton, S. C. Tetrahedron Lett.
1999, 40, 8547.
Acknowledgment
(20) Poulain, R. F.; Tartar, A. L.; Déprez, B. P. Tetrahedron Lett.
2001, 42, 1495.
The authors thank CAPES, CNPq and FAPERGS for financial sup-
port. CAPES is also acknowledged for a Ph.D. fellowship to D.S.L.
(21) (a) Kaboudin, B.; Navace, K. Heterocycles 2003, 60, 2287.
(b) Srivastava, R. M.; Seabra, G. M. J. Braz. Chem. Soc.
1997, 8, 397. (c) Oussaid, B.; Moeini, L.; Martin, B.;
Villemin, D.; Garrigues, B. Synth. Commun. 1995, 25, 1451.
(22) (a) Hamzé, A.; Hernandez, J.-F.; Martinez, J. Tetrahedron
Lett. 2003, 44, 6079. (b) Hamzé, A.; Hernandez, J.-F.;
Fulcrand, P.; Martinez, J. J. Org. Chem. 2003, 68, 7316.
(23) (a) Braga, A. L.; Appelt, H. R.; Schneider, P. H.; Silveira, C.
C.; Wessjohann, L. A. Tetrahedron: Asymmetry 1999, 10,
1733. (b) Braga, A. L.; Appelt, H. R.; Schneider, P. H.;
Rodrigues, O. E. D.; Silveira, C. C.; Wessjohann, L. A.
Tetrahedron 2001, 57, 3291. (c) Braga, A. L.; Appelt, H. R.;
Rodrigues, O. E. D.; Silveira, C. C.; Wessjohann, L. A.;
Schneider, P. H. Tetrahedron 2002, 58, 10413. (d) Braga,
A. L.; Vargas, F.; Andrade, L. H.; Silveira, C. C.
Tetrahedron Lett. 2002, 43, 2335. (e) Braga, A. L.;
Rodrigues, O. E. D.; Paixão, M. W.; Appelt, H. R.; Silveira,
C. C.; Bottega, D. P. Synthesis 2002, 2338. (f) Braga, A. L.;
Silva, S. J. N.; Lüdtke, D. S.; Drekener, R. L.; Silveira, C. C.;
Rocha, J. B. T.; Wessjohann, L. A. Tetrahedron Lett. 2002,
43, 7329. (g) Braga, A. L.; Paixão, M. W.; Lüdtke, D. S.;
Silveira, C. C.; Rodrigues, O. E. D. Org. Lett. 2003, 5, 2635.
(h) Braga, A. L.; Rubim, R. M.; Schrekker, H. S.;
Wessjohann, L. A.; de Bolster, M. W. G.; Zeni, G.; Sehnem,
J. A. Tetrahedron: Asymmetry 2003, 14, 3291.
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Synthesis 2004, No. 10, 1589–1594 © Thieme Stuttgart · New York