Synthesis of new 1,2,4- and 1,3,4-oxadiazole derivatives as potential nonpeptide angiotensin II receptor antagonists

Article abstract of DOI:10.1080/00397910500447066

The synthesis of new 1,2,4- and 1,3,4-oxadiazole derivatives as potential nonpeptide angiotensin II receptor antagonists is described. The quinoxalinone systems used as the "northern moiety" in these compounds were alkylated through a liquid/liquid phase-

Full text of DOI:10.1080/00397910500447066

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Synthesis of New 1,2,4‐ and 1,3,4‐Oxadiazole
Derivatives as Potential Nonpeptide
Angiotensin II Receptor Antagonists
Emerson Meyer a , Antonio C. Joussef b & Luciana de B. P. de Souza b
a Departamento de Química Orgânica e Inorgânica , Universidade Federal do
Ceará , Fortaleza, Brazil
b Departamento de Química , Universidade Federal de Santa Catarina ,
Florianópolis, Brazil
Published online: 16 Aug 2006.
To cite this article: Emerson Meyer , Antonio C. Joussef & Luciana de B. P. de Souza (2006) Synthesis of
New 1,2,4‐ and 1,3,4‐Oxadiazole Derivatives as Potential Nonpeptide Angiotensin II Receptor Antagonists,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
36:6, 729-741, DOI: 10.1080/00397910500447066
To link to this article: http://dx.doi.org/10.1080/00397910500447066
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Synthetic Communicationsw, 36: 729–741, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500447066
Synthesis of New 1,2,4- and 1,3,4-Oxadiazole
Derivatives as Potential Nonpeptide
Angiotensin II Receptor Antagonists
Emerson Meyer
´ ˆ
Departamento de Quımica Organica e Inorganica, Universidade Federal
ˆ
´
do Ceara, Fortaleza, Brazil
Antonio C. Joussef and Luciana de B. P. de Souza
´
Departamento de Quımica, Universidade Federal de Santa Catarina,
´
Florianopolis, Brazil
Abstract: The synthesis of new 1,2,4- and 1,3,4-oxadiazole derivatives as potential
nonpeptide angiotensin II receptor antagonists is described. The quinoxalinone
systems used as the “northern moiety” in these compounds were alkylated through a
liquid/liquid phase-transfer catalysis protocol, with good yields and high nitrogen-
to oxygen-alkylated product (N/O) ratios.
Keywords: Alkylation, oxadiazoles, PTC, tetrazoles
INTRODUCTION
The renin–angiotensin system (RAS) is known to play a crucial role in cardio-
vascular regulation and the maintenance of blood pressure. Angiotensin II
(AII) is the active hormone of the RAS, mediating a variety of physiological
functions through stimulation of specific receptors on the cell surface, which
can be blocked by selective receptor antagonists.[1,2]
The discovery by Du Pont of the first orally active, nonpeptide, AII
receptor antagonist DuP 753 (Losartan) opened an exciting new phase of
Received in the USA September 16, 2005
Address correspondence to Emerson Meyer, Departamento de Quımica Organica e
ˆ ´
Inorganica, Universidade Federal do Ceara, Fortaleza, CE, Brazil. E-mail: meyere33@
´
ˆ
yahoo.com.br
729

730
E. Meyer, A. C. Joussef, and L. de B. P. de Souza
research to investigate AT1-selective agents for the treatment of hypertension.
Since then, a plethora of other AII antagonists have been reported.[3–5]
Recently we have described the synthesis of new potential nonpeptide
angiotensin II receptor antagonists containing heterocyclic spacers, particu-
larly 1,2,4- and 1,3,4-oxadiazole derivatives.[6,7] In the present study, we
have undertaken the synthesis of a number of new AII receptor antagonist
analogues in which the disubstituted oxadiazole moiety has been retained
while modifications have been made to the so-called “northern moiety” (1–3)
and in the acidic group (4) attached to the heterocyclic spacer (Figure 1).
RESULTS AND DISCUSSION
In the synthesis of the target molecules 1a, 1b, 2a, and 2b the key step consists
of the alkylation of the 3-alkylquinoxalinones 5 and 10 with the benzylic
bromides 8 and 9 (Scheme 1). However, it is well known that alkylation of
quinoxalinones[8–10] and related heterocycles[11] commonly affords a
mixture of the N- and O-alkylated products as a result of their ambident
anionic character.
Most of the conventionally used methods for the alkylation of quinoxali-
nones involve strong bases, and consequently dry solvents and an inert atmos-
phere. Even so, unacceptable lack of regioselectivity is usually found. With
this in mind, we started a search for more convenient and efficient method-
ologies, focusing enhancement of N-regioselectivity, for the alkylation of qui-
noxalinones. Our first attempt was based on Rutar and Kikelj’s report
describing the regioselective N-alkylation of benzoxazines, under solid/
liquid phase-transfer catalysis.[12] As a model reaction, we performed the
alkylation of the 3-methyl-1H-quinoxalin-2-one (5) with benzyl bromide
(Scheme 2).
In the presence of K2CO3 and a catalytic amount of TEBAB (benzyl-
triethylammonium bromide) (20 mol%) in hot CH3CN we obtained, after
6 h, 79% of the alkylated derivatives (6 and 7) in a ratio of 73 : 27, favoring
the desired N-alkylated product (6) (Table 1, entry 1). In fact, this ratio is
somewhat poorer than that obtained using NaH or K2CO3 in DMF, although
the overall yield is similar.[9,10] To further develop this methodology, we
Figure 1. New AII receptor antagonist analogues.

1,2,4- and 1,3,4-Oxadiazole Derivatives
731
Scheme 1.
carried out the same reaction in a liquid/liquid two-phase system (CH2Cl2/
H2O), at room temperature with TBAB (tetrabutylammonium bromide)
(20 mol%) as the phase-transfer catalyst and NaOH as the base. Although
the overall yield of the alkylated derivatives was only slightly better (81%
isolated yield, after 12 h), the N/O ratio obtained was significantly higher.
(83 : 17 after chromatographic separation) (Table 1, entry 2). Based on this
encouraging result, we examined the performance of other “quats,” such as
TBPB (tetrabutylphosphonium bromide), TBAHS (tetrabutylammonium
hydrogensulphate), TBBC (benzyltributylammonium chloride), and TEBAB
regarding their N/O regioselectivities.
Surprisingly, all “quats” showed similar N/O ratios (about 83 : 17 deter-
mined by GC), and, as expected, no reaction was observed in the absence of
quaternary salt. In all cases the parent quinoxalinone was not detected in
the organic phase. (Control experiments were carried out to ensure that the
product distribution was not influenced by further equilibration under the
reaction conditions.) On considering the solubility of the quinoxalinone 5 in
aqueous alkali, we can suggest that an extraction-type mechanism is
operating; that is, the deprotonation of 5 takes place in the aqueous phase
and then the anion is extracted into the organic phase.[13]
By virtue of the simplicity of the PTC protocol, we elected this method-
ology for the synthesis of the target molecules 1a, 1b, 2a, and 2b, as shown in
Scheme 1.
Scheme 2.

732
E. Meyer, A. C. Joussef, and L. de B. P. de Souza
Table 1. Reaction conditions for the alkylation of 5
Entry
Conditions
6a
7a
1
2
K2CO3/TEBAB (20 mol%) CH3CN 608C (6 h)
NaOH/TBAB (20 mol%) CH2Cl2/H2O 258C (12 h)
73
83
27
17
aDescribes the relative ratio of the isolated products.
The alkylation of the quinoxalinones 5 and 10[14] with the halides 8 and
9[6] was performed at room temperature in a biphasic system (CH2Cl2/H2O)
with TBAB as the phase-transfer catalyst (20 mol%). After 12 h, TLC
indicated the completion of the reaction.
The yields and regioselectivities were in the same range as those observed
in the model reaction (Table 2). The regioisomers were easily separated by
flash chromatography (except in the case of the quinoxalinone 10, entries 2
and 4, where the Rf values of the halides 8 and 9 and the O-alkylated
products 11d and 12d are too close). In the 13C NMR spectra of 11a, 11b,
12a, and 12b the benzylic signal at ca. d 45 ppm was consistent with N-
rather than O-alkylation (in this case the benzylic signal is observed at ca. d
70 ppm). Furthermore, these assignments were confirmed by NOESY
(Nuclear Overhauser Effect Spectroscopy) experiments, based on cross
peaks connecting the N-benzylic methylene group protons and the proton at
the C-8 position of the quinoxalinone ring. The hydrolysis of the N-
alkylated products 11a, 11b, 12a, and 12b with NaOH in MeOH/THF/
H2O, followed by acidic workup, afforded the target compounds 1a, 1b, 2a,
and 2b, respectively, in excellent yields (Table 2).
The synthesis of the valsartan[15] analogue 3 was effected following the
route outlined in Scheme 3. Alkylation of L-valine methyl ester with the
halide 8[6] was carried out using 4-(dimethylamino)pyridine (DMAP) and a
catalytic amount of KI. The secondary amine 13 was acylated with valeryl
chloride to furnish 14. Finally, 14 was converted to the diacid 3 by ester hydroly-
sis with NaOH in MeOH/H2O followed by acidic workup in 70% yield.
The synthetic strategy for the construction of the tetrazole derivative 4 is
shown in Scheme 4. 4-Methylphenyl amidoxime (15)[6] was acylated with
Table 2. Yields for alkylation and hydrolysis reactions
N-alkylated
O-alkylated
Acid/yield
(%)
Entry Halide Quinoxalinone product/yield (%) product/yield (%)
1
2
3
4
8
8
9
9
5
10
5
11a/76
11b/68
12a/69
12b/66
11c/16
11d/Not isolated
12c/12
1a/93
1b/93
2a/93
2b/91
10
12d/Not isolated

1,2,4- and 1,3,4-Oxadiazole Derivatives
733
Scheme 3.
2-cyanobenzoic acid[16] in the presence of DCC/DMAP to furnish 16 in 85%
yield. Upon treatment with a catalytic amount of TBAF[17] the O-acylamidox-
ime 16 underwent cyclization to the 1,2,4-oxadiazole 17 with a 73% yield. The
methyl group of 17 was brominated with N-bromosuccinimide (NBS) in the
presence of benzoyl peroxide to furnish 18, which through the reaction with
ethyl 2-methyl-4-oxo-l,4-dihydroquinoline-6-carboxylate[18] in the presence
of K2CO3 in CH3CN gave the O-alkylated product 19 as the only regioisomer.
Finally, 19 was converted to the tetrazole 4 through the reaction with tributyl-
tin azide and the subsequent ester hydrolysis, in 68% overall yield.
CONCLUSIONS
In summary, we describe a new, easy to perform, and efficient procedure,
based on phas-transfer catalysis, for the alkylation of quinoxalinones. This
mild, less hazardous methodology seems to be a good alternative to the
commonly applied NaH/DMF system, furnishing comparable N/O ratios.
Additionally, we report the synthesis of new 1,2,4- and 1,3,4-oxadiazole
derivatives as potential nonpeptide angiotensin II receptor antagonists.
Scheme 4.

734
E. Meyer, A. C. Joussef, and L. de B. P. de Souza
These compounds are currently under pharmacological evaluation, and the
results will be published elsewhere.
EXPERIMENTAL
General
´
Melting points were measured using a Kofler hot-stage apparatus (Microquı-
mica APF-301) and are uncorrected. Each analytical sample was homo-
geneous as confirmed by TLC performed on silica gel (Kieselgel 60 F
254-Merck) plates, which were visualized with UV light. Flash chromato-
1
graphy was performed with Merck silica gel 60 (230–400 mesh). H NMR
spectra were recorded on a Bruker AW-200 (200-MHz) instrument, with tetra-
methylsilane (TMS) as the internal standard, and 13C NMR spectra were
recorded on a Bruker (50.3-MHz) spectrometer. Elemental analyses were
within +0.4% of theoretical values and were determined on a Perkin-Elmer
2400 instrument. Quinoxalinones 5 and 10 were prepared according to litera-
ture procedures.[11,15]
General Procedure for the Alkylation of Quinoxalinones
A solution of NaOH (1.1 mmol) in H2O (1 mL) was added to a solution of qui-
noxalinone (1.0 mmol), benzylic halide (1.1 mmol), and TBAB (0.2 mmol) in
CH2Cl2 (10 mL). The biphasic mixture was agitated with a vibromixer at room
temperature for 12 h. The organic layer was separated, and the aqueous phase
was extracted twice with 10 mL portions of CH2Cl2. The combined organic
extracts were washed with brine (2 ꢀ 10 mL) and dried (MgSO4). The
solvent was removed under vacuum, and the residue was flash chromato-
graphed on SiO2 using hexane/EtOAc (7 : 3 changing on a gradient to 1 : 1
for 11a, 11c, 12a, and 12c or 4 : 1 changing on a gradient to 4 : 3 for 11b
and 12b) as eluents.
Methyl 2-f5-[4-(3-methyl-2-oxo-1H-quinoxalin-1-ylmethyl)phenyl]-1,3,4-
oxadiazol-2-ylgbenzoate (11a). White powder; yield: 76%; mp 191–1928C.
1H NMR (CDCl3): d ¼ 2.68 (s, 3 H), 3.82 (s, 3 H), 5.57 (s, 2 H), 7.21–8.06
(m, 12 H). 13C NMR (CDCl3): d ¼ 22.17, 46.16, 53.25, 114.69, 123.75,
124.11, 124.41, 127.98, 128.17, 130.25, 130.49, 130.91, 131.99, 132.25,
132.86, 133.43, 139.92, 155.68, 158.91, 164.45, 165.06, 167.64. Anal.
calcd. for C26H20N4O4: C, 69.02; H, 4.46; N, 12.38. Found: C, 68.81; H,
4.47; N, 12.49.
Methyl 2-f5-[4-(3-methylquinoxalin-2-yloxymethyl)phenyl]-1,3,4-oxadiazol-
1
2-ylgbenzoate (11c). White powder; yield: 16%; mp 149–1518C. H NMR

1,2,4- and 1,3,4-Oxadiazole Derivatives
735
(CDCl3): d ¼ 2.72 (s, 3 H), 3.84 (s, 3 H), 5.65 (s, 2 H), 7.58–8.15 (m, 12 H).
13C NMR (CDCl3): d ¼ 21.08, 53.38, 67.89, 124.03, 124.30, 127.33,
127.43, 127.75, 128.73, 129.02, 129.66, 130.63, 131.04, 132.10, 132.35,
139.40, 140.28, 141.36, 148.54, 156.32, 164.59, 165.43, 167.89. Anal.
calcd. for C26H20N4O4: C, 69.02; H, 4.46; N, 12.38. Found: C, 68.91; H,
4.45; N, 12.13.
Methyl 2-f3-[4-(3-methyl-2-oxo-1H-quinoxalin-1-ylmethyl)phenyl]-1,2,4-
oxadiazol-5-ylgbenzoate (12a). White powder; yield: 69%; mp 160–1638C.
1H NMR (CDCl3): d ¼ 2.68 (s, 3 H), 3.84 (s, 3 H), 5.57 (s, 2 H), 7.19–8.13
(m, 12 H). 13C NMR (CDCl3); d ¼ 22.20, 46.23, 53.32, 114.78, 124.33,
124.48, 126.77, 127.92, 128.60, 130.18, 130.29, 130.69, 132.05, 132.52,
132.83, 132.93, 133.44, 139.22, 155.72, 158.94, 167.71, 168.67, 175.98.
Anal. calcd. for C26H20N4O4: C, 69.02; H, 4.46; N, 12.38. Found: C, 69.30;
H, 4.54; N, 12.64.
Methyl 2-f3-[4-(3-methylquinoxalin-2-yloxymethyl)phenyl]-1,2,4-oxadiazol-
1
5-ylg benzoate (12c). White powder; yield: 12%; mp 150–1538C. H NMR
(CDCl3): d ¼ 2.72 (s, 3 H), 3.87 (s, 3 H), 5.64 (s, 2 H), 7.55–8.22
(m, 12 H). 13C NMR (CDC13): d ¼ 21.09, 53.47, 68.11, 124.68, 127.09,
127.24, 127.46, 128.34, 128.72, 128.86, 129.60, 130.43, 130.82, 132.17,
132.62, 133.01, 139.37, 140.33, 140.64, 148.63, 156.42, 167.92, 169.03,
176.09. Anal. calcd. for C26H20N4O4: C, 69.02; H, 4.46; N, 12.38. Found:
C, 68.72; H, 4.46; N, 12.44.
Methyl 2-f5-(4-(3-butyl-2-oxo-1H-quinoxalin-1-ylmetlhyl)phenyl]-1,3,4-
oxadiazol-2-ylgbenzoate (11b). White powder; yield: 68%; mp 125–
1268C. 1H NMR (CDCI3): d ¼ 1.00 (t, J ¼ 7.2 Hz, 3 H), 1.45–1.56
(m, 2 H), 1.74–1.87 (m, 2 H), 3.02 (t, J ¼ 7.3 Hz, 2 H), 3.81 (s, 3 H), 5.57
(s, 2 H), 7.16–8.06 (m, 12 H). 13C NMR (CDCl3): d ¼ 13.85, 22.60, 28.78,
33.91, 45.50, 52.59, 113.95, 123.05, 123.46, 123.69, 127.35, 127.50,
129.52, 129.75, 129.85, 130.27, 131.35, 131.61, 132.03, 132.87, 139.37,
154.77, 161.26, 163.81, 164.44, 167.01. Anal calcd. for C29H26N4O4: C,
70.43; H, 5.30; N, 11.33. Found: C, 70.33; H, 5.23; N, 11.63.
Methyl 2-f3-[4-(3-butyl-2-oxo-1H-quinoxalin-1-ylmethyl)phenyl]-1,2,4-
oxadiazol-5-ylgbenzoate (12b). White powder; yield: 66%; mp 139–
1418C. 1H NMR (CDCl3): d ¼ 1.00 (t, J ¼ 7.2 Hz, 3 H), 1.42–1.57
(m, 2 H), 1.76–1.91 (m, 2 H), 3.03 (t, J ¼ 7.4 Hz, 2 H), 3.85 (s, 3 H),
5,57 (s, 2 H), 7.18–8.13 (m, 12 H). 13C NMR (CDC13): d ¼ 14.64,
23.41, 29.59, 34.74, 46.37, 53.46, 114.82, 124.38, 124.56, 124.66,
126.90, 128.02, 128.75, 130.22, 130.46, 130.82, 132.18, 132.64, 132.91,
132.97, 133.68, 139.41, 155.60, 162.11, 167.89, 168.84, 176.11. Anal.
calcd. for C29H26N4O4: C, 70.43; H, 5.30; N, 11.33. Found: C, 70.56;
H, 5.29; N, 11.64.

736
E. Meyer, A. C. Joussef, and L. de B. P. de Souza
General Procedure for the Preparation of Carboxylic Acids 1a, 1b,
2a, and 2b
A solution of the ester (11a, 11b, 12a, 12b) (0.50 mmol), NaOH (1.50 mmol)
in MeOH (10 mL), THF (5 mL), and H2O (2 mL) was stirred at rt for 24 h.
The solvents were evaporated, and the residue was dissolved in H2O
(10 mL). The solution was acidified with aqueous HCl until pH 4, and the
resulting precipitate was collected by filtration, washed with H2O, and dried
under vacuum.
2-f5-[4-(3-Methyl-2-oxo-1H-quinoxalin-1-ylmethyl)phenyl]-1,3,4-oxadiazol-
1
2-ylgbenzoic acid (1a). White solid; yield: 93%; mp 204–2078C (dec). H
NMR (DMSO-d6): d ¼ 2.52 (s, 3 H), 5.57 (s, 2 H), 7.28–7.96 (m, 12 H).
13C NMR (DMSO-d6): d ¼ 21.38, 44.81, 114.89, 122.55, 122.74, 123.59,
126.95, 127.77, 128.96, 129.38, 129.69, 130.02, 130.21, 131.52, 132.19,
132.31, 136.63, 139.96, 154.64, 158.05, 163.84, 164.68, 168.41. Anal calcd.
.
for C25H18N4O4 1.5H2O: C, 64.51; H, 4.55; N, 12.04. Found: C, 64.34; H,
4.35; N, 11.94.
2-f5-[4-(3-Butyl-2-oxo-1H-quinoxalin-1-ylmethyl)phenyl]-1,3,4-oxadiazol-
1
2-ylgbenzoic acid (1b). White solid; yield: 93%; mp 220–2238C. H NMR
(DMSO-d6): d ¼ 0.94 (t, J ¼ 7.2 Hz, 3 H), 1.31–1.50 (m, 2 H), 1.62–1.86
(m, 2 H), 2.89 (t, J ¼ 7.8 Hz, 2 H), 5.60 (s, 2 H), 7.36–7.99 (m, 12 H). 13C
NMR (DMSO-d6): d ¼ 13.91, 22.10, 28.15, 33.17, 44.81, 114.85, 122.33,
123.04, 123.61, 127.01, 127.86, 129.18, 129.73, 130.47, 131.80, 131.98,
132.31, 132.76, 140.28, 154.32, 160.65, 163.80, 164.04, 167.65. Anal.
calcd. for C28H24N4O4: C, 69.99; H, 5.03; N, 11.66. Found: C, 70.01; H,
4.97; N, 11.80.
2-f3-[4-(3-Methyl-2-oxo-1H-quinoxalin-1-ylmethyl)phenyl]-1,2,4-oxadiazol-
1
5-ylgbenzoic acid (2a). White solid; yield: 93%; mp . 1818C (gradual). H
NMR (DMSO-d6): d ¼ 2.52 (s, 3 H), 5.59 (s, 2 H), 7.29–8.04 (m, 12 H).
13C NMR (DMSO-d6): d ¼ 21.39, 44.88, 114.88, 123.58, 123.82, 125.27,
127.55, 127.76, 129.00, 129.67, 129.89, 130.46, 131.89, 132.24, 132.35,
132.46, 133.06, 139.72, 154.65, 158.06 167.42, 167.61, 176.15. Anal. calcd.
for C25H18N4O4: C, 68.49; H, 4.14; N, 12.78. Found: C, 68.50; H, 4.14; N,
13.01.
2-f3-[4-(3-Butyl-2-oxo-1H-quinoxalin-1-ylmethyl)phenyl]-1,2,4-oxadiazol-
1
5-ylgbenzoic acid (2b). White solid; yield: 91%; mp . 1568C (gradual). H
NMR (DMSO-d6): d ¼ 0.95 (t, J ¼ 7.2 Hz, 3 H), 1.38–1.49 (m, 2 H), 1.68–
1.83 (m, 2 H), 2.91 (t, J ¼ 7.3 Hz, 2 H), 5.60 (s, 2 H), 7.30–8.04 (m, 12 H).
13C NMR (DMSO-d6): d ¼ 13.90, 22.10, 28.17, 33.17, 44.85, 114.90,
123.58, 123.77, 125.64, 127.47, 127.64, 129.15, 129.50, 129.72, 131.69,
132.02, 132.31, 138.33, 139.43, 154.33, 160.63, 167.23, 168.33, 177.54.

1,2,4- and 1,3,4-Oxadiazole Derivatives
737
Anal. calcd. for C28H24N4O4: C, 69.99; H, 5.03; N, 11.66. Found: C, 69.79; H,
4.95; N, 11.86.
Methyl (S)-2-f[4-[5-(2-carbomethoxyphenyl)-1,3,4-oxadiazol-2-yl]phenyl]
methylg amino-3-methylbutanoate (13). Triethylamine (0.49 mL, 3.54 mmol)
was added to a suspension of L-valine methyl ester hydrochloride (593 mg,
3.54 mmol) in dry CH3CN (10 mL) under Ar at 258C. A solution of methyl
2-[5-(4-bromomethylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (8) (455 mg,
1.22 mmol) in CH2Cl2 (10 mL) was added to the resulting milky suspension,
followed by 4-(dimethylamino)pyridine (50 mg, 0.41 mmol) and some
crystals of KI. After being stirred at rt for 36 h, the mixture was concentrated
under vacuum. The residue was partitioned between CH2Cl2 (20 mL) and
water (10 mL). The aqueous layer was extracted with CH2Cl2 (2 ꢀ 10 mL);
the combined organic layers were washed with brine (3 ꢀ 10 mL) and dried
(MgSO4). After solvent removal, the crude product was purified by column
chromatography on silica gel, eluting with hexane–EtOAc (4 : 1) to give 13
(320 mg, 62%) as a viscous colorless oil.
1H NMR (CDCl3/CC14): 0.96 (d, J ¼ 6.7 Hz, 6 H), 1.88 (s, 1 H),
1.92 (septet, J ¼ 6.7 Hz, 1 H), 2.99 (d, J ¼ 6.0 Hz, 1 H), 3.63
(d, J ¼ 13.8 Hz, 1 H), 3.74 (s, 3 H), 3.84 (s, 3 H), 3.93 (d, J ¼ 13.8 Hz, 1 H),
7.48–8.04 (m, 8 H). 13C NMR (CDCl3/CCl4): d ¼ 19.22, 20.03, 32.38,
52.19, 52.79, 53.41, 67.24, 123.08, 124.38, 127.57, 128.13, 129.51, 130.63,
131.03, 132.06, 132.35, 145.12, 164.44, 165.72, 168.03, 176.31. Anal.
calcd. for C23H25N3O5: C, 65.24; H, 5.95; N, 9.92. Found: C, 65.09; H,
5.95; N, 9.76.
Methyl (S)-2-f[4-[5-(2-carbomethoxyphenyl)-1,3,4-oxadiazol-2-yl]phenyl]
methylg pentanoylamino-3-methylbutanoate (14). Valeryl chloride
(0.19 mL, 1.63 mmol) was added dropwise to a solution of the amine 13
(300 mg, 0.71 mmol) in dry pyridine (5 mL) under N2 at 08C. The reaction
mixture was then allowed to warm to room temperature and stirred
overnight. The reaction was quenched by pouring into H2O (15 mL) and
then extracted with EtOAc (3 ꢀ 10 mL). The combined organic extracts
were washed successively with H2O (3 ꢀ 10 mL), aqueous HCl (5%,
3 ꢀ 5 mL), saturated aqueous NaHCO3 (3 ꢀ 10 mL), and brine
(3 ꢀ 10 mL). The organic phase was dried (MgSO4), and the solvent was
removed under vacuum. Chromatography of the residue on silica gel using
hexane/EtOAc (4 : 1 ! 7 : 3) as the eluent gave the title compound 14
(316 mg, 88%) as a colorless oil. 1H NMR analysis of 14 revealed a
complex mixture of conformers and/or topomers at room temperature.
1H NMR (DMSO-d6, 1008C): d ¼ 0.92–0.98 (m, 6 H), 1.07 (d,
J ¼ 6.5 Hz, 3 H), 1.37–1.47 (m, 2 H), 1.64–1.71 (m, 2 H), 2.37–2.54
(m, 3 H), 3.58 (s, 3 H), 3.91 (s, 3 H), 4.52–4.95 (m, 3 H), 7.52–8.11
(m, 8 H). Anal. calcd. for C28H33N3O6: C, 66.26; H, 6.55; N, 8.28. Found:
C, 66.11; H, 6.32; N, 8.26.

738
E. Meyer, A. C. Joussef, and L. de B. P. de Souza
(S)-2-f[4-[5-(2-Carboxyphenyl)-1,3,4-oxadiazol-2-yl]phenyl]methylgpentanoyl
amino-3-methylbutanoic acid (3). A solution of NaOH (47 mg, 1.17 mmol)
in H2O (2 mL) was added to a solution of the diester 14 (200 mg,
0.39 mmol) in MeOH (10 mL), and the resulting mixture was heated at
508C for 18 h. After cooling, the solvent was evaporated under vacuum, and
the residue was taken up with H2O (10 mL) and acidified with aqueous HCl
to pH 4. The resulting precipitate was collected by filtration, washed with
H2O, and dried under vacuum to afford 3 (132 mg, 70%) as a colorless crystal-
line solid.
Mp 99–1028C. IR (KBr): 2962, 2872, 1724, 1612, 1266 cm21. 1H NMR
analysis of 3 revealed a complex mixture of conformers and/or topomers at
room temperature.
1H NMR (DMSO-d6, 1008C): d ¼ 0.89–1.08 (m, 9 H), 1.28–1.47
(m, 2 H), 1.53–1.59 (m, 2 H), 2.29–2.53 (m, 3 H), 4.47 (brs, 1 H), 4.77
.
(s, 2 H), 7.53–8.06 (m, 8 H). Anal. calcd. for C26H29N3O6 H2O: C, 62.76;
H, 6.28; N, 8.44. Found: C, 62.63; H, 5.97; N, 8.33.
(O-2-Cyanobenzoyl)-4-methylphenyl amidoxime (16). A mixture of
4-methylphenyl amidoxime (15) (1.50 g, 10.0 mmol), 2-cyanobenzoic acid
(1.40 g, 9.52 mmol), DCC (2.06 g, 10.0 mmol), and DMAP (116 mg,
0.95 mmol) in dry THF (60 mL) was stirred at room temperature for 12 h
under N2. The DCU was filtered off and washed with THF. The filtrate was
evaporated and the residue was recrystallized twice from acetone/H2O to
furnish the title compound 16 (2.26 g, 85%) as a white solid. Mp 135–
1378C. IR (KBr): 3322, 2932, 2854, 2228, 1742, 1614, 1262 cm21
NMR (CDCl3): d ¼ 2.40 (s, 3 H), 5.71 (brs, 2 H), 7.23–8.41 (m, 8 H).
.
1H
2-[3-(4-Methylphenyl)-1,2,4-oxadiazol-5-yl]benzonitrile (17). TBAF (1 M
in THF, 0.72 mL, 0.72 mmol) was added dropwise to a solution of 16
(2.00 g, 7.16 mmol) in THF (50 mL), under N2. The reaction mixture was
stirred at room temperature for 48 h and then poured into EtOAc (60 mL).
The organic phase was washed with H2O (3 ꢀ 20 mL) and brine
(3 ꢀ 20 mL) and then dried (MgSO4). The solvent was evaporated under
vacuum, and the residue was crystallized from acetone/H2O to afford the
product 17 (1.37 g, 73%) as a white solid.
Mp 165–1678C. IR (KBr): 2922, 2226, 1594, 1362, 780 cm21. 1H NMR
(CDCl3): d ¼ 2.44 (s, 3 H), 7.30–8.36 (m, 8 H). 13C NMR (CDCl3):
d ¼ 22.32, 112.44, 117.47, 124.20, 126.79, 128.33, 130.35, 130.77, 133.12,
133.73, 135.91, 142.63, 169.95, 173.08. Anal. calcd. for C16H11N3O: C,
73.55; H, 4.24; N, 16.08. Found: C, 73.28; H, 4.13; N, 16.02.
2-[3-(4-Bromomethylphenyl)-1,2,4-oxadiazol-5-yl]benzonitrile (18).
A
mixture of 17 (1.00 g, 3.83 mmol), NBS (681 mg, 3.83 mmol), and benzoyl
peroxide (92 mg, 0.38 mmol) in CCl4 (25 mL) was refluxed for 4 h. After
cooling to room temperature, the solvent was removed under vacuum, and

1,2,4- and 1,3,4-Oxadiazole Derivatives
739
the residue was taken up with CH2Cl2 (30 mL). The organic phase was washed
with 0.5 N aqueous NaOH (3 ꢀ 20 mL) and brine (3 ꢀ 20 mL) and then dried
(MgSO4). The solvent was evaporated to give 755 mg (58%, 89% purity) of
1
crude 18 as a white powder, suitable for use without further purification. H
NMR (CDCl3): d ¼ 4.55 (s, 2 H), 7.53–8.36 (m, 8 H).
Ethyl 4-f4-[5-(2-cyanophenyl)-1,2,4-oxadiazol-3-yl]benzyloxyg-2-methyl-
quinoline carboxylate (19). A mixture of 18 (306 mg, 0.90 mmol), ethyl
2-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (200 mg, 0.86 mmol),
and powdered K2CO3 (297 mg, 2.15 mmol) in anhydrous CH3CN (10 mL)
was heated under reflux for 5 h under Ar. After being allowed to cool to
room temperature, the reaction mixture was poured into H2O, and the
resulting precipitate was filtered off, washed with H2O, and recrystallized
from EtOH to afford 19 (327 mg, 77%) as a white powder.
1
Mp 210–2138C. H NMR (CDCl3): d ¼ 1.44 (t, J ¼ 7.1 Hz, 3 H), 2.71
(s, 3 H), 4.45 (q, J ¼ 7.1 Hz, 2 H), 5.42 (s, 2 H), 6.74 (s, 1 H), 7.65–8.37
(m, 10 H), 8.98 (s, 1 H). 13C NMR (CDCl3): d ¼ 15.06, 26.83, 61.87, 70.47,
103.06, 112.40, 117.42, 119.85, 125.62, 126.50, 127.10, 127.54, 128.34,
128.86, 129.01, 130.31, 130.74, 133.27, 133.75, 135.91, 139.67, 151.53,
162.49, 163.30, 167.04, 169.48. Anal. calcd. for C29H22N4O4: C, 71.01; H,
4.52; N, 11.42. Found: C, 71.27; H, 4.48; N, 11.78.
2-Methyl-4-f4-(5-(2H(1H)-tetrazol-5-yl)phenyl]-1,2,4-oxadiazol-3-yl]
benzyloxy]quinoline-6-carboxylicacid(4).Compound19 (250 mg, 0.51 mmol)
was added to a solution of Bu3SnN3 (0.49 mL, 1.78 mmol) in anhydrous toluene
(10 mL), under Ar. After stirring at reflux for 72 h, the solvent was removed
under vacuum, and the residue was taken up in EtOH (10 mL). To the resulting
suspension a solution of NaOH (300 mg, 7.50 mmol) in H2O (5mL) was added,
and the mixture was kept at 608C for 24 h. The solvents were removed under
vacuum, the residue was taken up in H2O (10mL) and heptane (10 mL), and
the resultant biphasic mixture was stirred overnight. The aqueous phase was
separated and acidified to pH 3 with aqueous HCl. The resulting precipitate was
filtered off, washed with H2O and heptane, and then dried under vacuum to
furnish 4 (174 mg, 68%) as an off-white solid.
Mp . 2508C. IR (KBr): 3385, 1651, 1603, 1354 cm21. 1H NMR (DMSO-
d6): d ¼ 2.63 (s, 3 H), 5.51 (s, 2 H), 7.16 (s, 1 H), 7.74–8.18 (m, 10 H), 8.74
(s, 1 H). Anal. calcd. for C27H19N7O4: C, 64.15; H, 3.79; N, 19.40. Found:
C, 63.81; H, 3.97; N, 19.08.
ACKNOWLEDGMENTS
The authors are indebted to CNPq and FUNCAP for financial support of this
work.

740
E. Meyer, A. C. Joussef, and L. de B. P. de Souza
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