Sodium hypochlorite-mediated synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from hydrazides and aldehydes

Article abstract of DOI:10.1007/s10593-020-02669-6

[Figure not available: see fulltext.] A simple and convenient method for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles has been developed. Structurally divergent symmetrical and unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles can be obtained in moderate to high yields via NaOCl-mediated oxidative cyclization of N-acylhydrazones, generated in situ from aliphatic and aromatic hydrazides and aldehydes.

Full text of DOI:10.1007/s10593-020-02669-6

DOI 10.1007/s10593-020-02669-6
Chemistry of Heterocyclic Compounds 2020, 56(3), 371–376
Sodium hypochlorite-mediated synthesis of 2,5-disubstituted
1,3,4-oxadiazoles from hydrazides and aldehydes
Karuna Raman Paidi1, Murali Krishna Kolli1,
Eeda Koti Reddy2, Venkata Ramana Pedakotla1*
1 Sri Krishnadevaraya University,
Ananthapur, Andhra Pradesh 515003, India; e-mail: ramanpk4u@gmail.com
2 Vignan's Foundation for Science, Technology and Research
(Deemed to be University),
Guntur–Tenali Rd., Vadlamudi, Andhra Pradesh 522213, India
e-mail: ekr.chem@gmail.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(3), 371–376
Submitted August 17, 2019
Accepted after revision December 23, 2019
A simple and convenient method for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles has been developed. Structurally divergent sym-
metrical and unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles can be obtained in moderate to high yields via NaOCl-mediated oxida-
tive cyclization of N-acylhydrazones, generated in situ from aliphatic and aromatic hydrazides and aldehydes.
Keywords: N-acylhydrazone, aldehyde, hydrazide, oxadiazole, sodium hypochlorite, oxidative cyclization.
Functionalized nitrogen- and oxygen-containing hetero-
cycles frequently demonstrate biological activity.1 For
example, compounds containing 1,3,4-oxadiazole motif
possess anti-inflammatory,2 antimicrobial,3 antidiabetic,4
analgesic,5 antioxidant,6 antibacterial,7 antifungal,8 anti-
viral,9 anticancer,10 antihypertensive,11 antimalarial,12 anti-
tubercular,13 and hypoglycemic14 activities (Fig. 1). Several
1,3,4-oxadiazole derivatives act as inhibitors of HIV
integrase15 as well as prevent angiogenesis16 and platelet
aggregation.17 Compounds with 1,3,4-oxadiazole fragment
are also successfully applied in agricultural18 and materials
chemistry.19 Some 1,3,4-oxadiazole derivatives with unique
optoelectronic properties are utilized in energy-efficient
organic molecular devices.20 Hence, compounds with 1,3,4-
oxadiazole fragment have attracted significant interest
among synthetic and medicinal chemists leading to
extensive efforts to develop new synthetic protocols for the
preparation of 2,5-disubstituted 1,3,4-oxadiazoles.
Me
Me
N
N
N
MeO
O
N
O
S
O
N
N
N
N
OMe
NH
O
N
O
OH
Zibotentan
Nesapidil
(anticancer agent)
(antihypertensive agent)
O
O
H2N
NO2
O
N
N
Furamizole
(antibiotic)
O
F
Me
OH
N
N
N
Initially, 2,5-disubstituted 1,3,4-oxadiazoles were synthe-
sized by the cyclodehydration of 1,2-diacylhydrazines
using dehydrating agents TsCl/DIPEA,21 SOCl2, P2O5, and
H
H
Me
N
N
O
N
Me Me
Raltegravir
(antiHIV agent)
O
O
22
POCl3 under mild reaction conditions and propyl-
phosphonic anhydride (T3P)23 under high temperature
conditions. In addition, cyclodehydration reactions under
mild conditions were performed applying XtalFluor-E,24
Figure 1. Biologically active molecules containing 1,3,4-oxa-
diazole fragment.
0009-3122/20/56(3)-0371©2020 Springer Science+Business Media, LLC
371

Chemistry of Heterocyclic Compounds 2020, 56(3), 371–376
2-chloro-1,3-dimethylimidazolinium chloride,25 PPh3/CCl4,
Scheme 1
PPh3/CBr4, or PPh3/I2,26 and Burgess reagent.27 Recently,
Patel and coworkers reported the synthesis of 2,5-disub-
stituted 1,3,4-oxadiazoles via Cu-catalyzed C–H functio-
nalization of N-acylhydrazones.28 Gao and Wei performed
cyclization of hydrazides using Bu4NI as catalyst and
t-BuOOH as oxidant.29 The same group developed a
synthetic protocol for obtaining 2,5-disubstituted 1,3,4-
oxadiazoles via t-BuOI-promoted oxidative cyclization of
N-acylhydrazones.30 Subsequently, Chang's and Patel's
groups described the importance of I2-mediated oxidative
C–O bond formation for the synthesis of 1,3,4-oxadiazoles
from N-acylhydrazones.31 Dobrotă and coworkers reported
oxidative cyclization of N-acylhydrazones using Dess–
Martin periodinane.32 Shang and coworkers demonstrated
metal-free synthesis of 2,5-disubstituted 1,3,4-oxadiazoles
via oxidative dehydrogenation of N'-(arylmethyl)hydrazides
and N-(arylmethyl)hydrazones using PhI(OAc)2.33 In 2017,
Ding's group reported Fe(III)/TEMPO-catalyzed oxidative
cyclization of N-acylhydrazones.34 Several approaches for
green synthesis of 2,5-disubstituted 1,3,4-oxadiazoles have
been developed, for example, application of catalytic
amounts of (NH4)2Ce(NO3)6 in PEG 40035 or electrolysis at
room temperature using LiClO4 in MeCN as electrolyte.36
In addition, other transition metal-free oxidants, for
example, DDQ37 and trichloroisocyanuric acid,38 have been
also utilized for the synthesis of 2,5-disubstituted 1,3,4-
oxadiazoles. However, many of these compounds are
highly toxic and harmful to the environment. Thus, it is
necessary to find new reagents, which are nontoxic and
eco-friendly and can efficiently promote the construction of
2,5-disubstituted 1,3,4-oxadiazole ring under mild
conditions.
oxidation. Application of 5 equiv of NaOCl allowed to
obtain 2,5-disubstituted 1,3,4-oxadiazole 3b in 87% yield.
Higher temperature (50°C) did not significantly increase
the yield of product 3b. The optimized reaction conditions
include refluxing of hydrazide 1a and aldehyde 2b in t-BuOH
to afford intermediate N-acylhydrazones (completion of the
reaction was confirmed by TLC) followed by addition of
5 equiv of 10–12% aqueous NaOCl and stirring at room
temperature for 45 min (Table 1).
With the optimized reaction conditions in hand, 2,5-di-
substituted 1,3,4-oxadiazoles 3a–x were synthesized using
aliphatic and aromatic hydrazides 1a–i and aldehydes 2a–o.
Hydrazides and aldehydes with both electron-donating and
electron-withdrawing groups were tolerated, and the
desired 2,5-disubstituted 1,3,4-oxadiazoles were success-
fully obtained in moderate to high yields (50–93%)
(Scheme 2).
Table 1. Optimization of the oxidative cyclization conditions*
Herein, we report NaOCl-mediated one-pot synthesis of
2,5-disubstituted 1,3,4-oxadiazoles from hydrazides and
aldehydes via oxidative cyclization. NaOCl is com-
mercially available, cheap, and non hazardous oxidizing
reagent. Previously, it has been used for oxidation of
secondary alcohols to ketones,39 chlorination of N-trityl-
proline methyl ester,40 and synthesis of α,β-diketones from
β-ketoaldehydes41 and isomeric benzoxazoles from
o-hydroxyaryl ketimines.42 In 2000, Yavolovsky and
coworkers reported NaOCl-mediated transformation of
1,2,5-thiadiazole or 1,2,5-selenadiazole N-oxides into the
respective 1,2,5-oxadiazoles.43
Recently, we discovered that NaOCl is able to promote
oxidative cyclization of N-acylhydrazone, derived from
benzohydrazide (1a) and benzaldehyde (2a), to afford
2,5-disubstituted 1,3,4-oxadiazole 3a (Scheme 1). In this
work, interaction of hydrazide 1a and isobutyraldehyde
(2b) was selected as a model reaction and optimization of
the reaction conditions for the oxidative cyclization of
N-acylhydrazone 4 was performed. Among the tested
solvents and reagents, t-BuOH in combination with NaOCl
at ambient temperature provided the highest yield of
product 3b, whereas MeOH and EtOH underwent
oxidation and therefore decreased the overall concentration
of NaOCl. Hence, solvent has a major impact on the
cyclization step, as tertiary alcohols are resistant to
Solvent
MeCN
MeOH
MeOH
EtOH
Reagent
NaClO4
NaClO4
NaClO4
NaClO4
NaClO2
NaClO2
NaClO2
NaClO2
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
Amount, equiv Time, h Yield, %
2
2
3
2
2
4
2
3
2
3
4
5
5
2
2
_
Traces
Traces
Traces
Traces
10
2
1
MeCN
EtOH
1
1
i-PrOH
t-BuOH
MeOH
EtOH
1
25
1
30
1
35
0.75
0.75
0.75
0.5
40
i-PrOH
t-BuOH
t-BuOH**
60
87
85
* Amounts of reactants: benzohydrazide (1a) (136 mg, 1 mmol), isobutyr-
aldehyde (2b) (0.1 ml, 1 mmol), solvent (5 ml).
** Reaction was conducted at 50°C.
372

Chemistry of Heterocyclic Compounds 2020, 56(3), 371–376
Scheme 2
In conclusion, we have demonstrated a simple and
Synthesis of 2,5-disubstituted 1,3,4-oxadiazoles 3a–x
(General method). Aldehyde 2a–o (1 mmol) was added to a
solution of hydrazide 1a–i (1 mmol) in t-BuOH (5 ml), and
the reaction mixture was refluxed for 2–3 h. After
completion of the reaction, the mixture was cooled to 0°C
and 10–12% aq NaOCl (5 ml, 5 mmol) was added
dropwise. The reaction mixture was stirred at room tempe-
rature for 1–2 h. After completion of the reaction, solvent
was evaporated under reduced pressure. The obtained
residue was dissolved in EtOAc (20 ml) and washed with
brine (2×10 ml). The organic layer was dried over
anhydrous Na2SO4. Crude product was purified by column
chromatography (SiO2, gradient elution with EtOAc –
petroleum ether, 3:7–2:3).
efficient one-pot synthesis of 2,5-disubstituted 1,3,4-oxa-
diazoles from aromatic and aliphatic hydrazides and
aldehydes via NaOCl-mediated oxidative cyclization of the
in situ formed N-acylhydrazones under mild reaction
conditions. The main advantages of the developed synthetic
method are broad substrate scope, functional group
tolerance, and moderate to high yields of products.
Experimental
1H and 13C NMR spectra (400 and 100 MHz, respec-
tively) were recorded on a Bruker Avance 500 spectrometer at
room temperature in CDCl3 (compounds 3a–h,k–o,q–t,v)
or DMSO-d6 (compounds 3i,j,p,u,w,x) using TMS as
internal standard. HRMS analyses were performed on a
JEOL GC MATE II instrument (EI, 70 eV). Melting points
were measured on a micro melting point apparatus and are
uncorrected. Progress of the formation of N-acylhydrazones
was monitored by TLC on Merck precoated silica gel 60
F254 plates using CHCl3–MeOH, 9:1, as eluent (visualiza-
tion with UV light).
2,5-Diphenyl-1,3,4-oxadiazole (3a). Yield 205 mg
(93%), white solid, mp 138°C (mp 137–138°C32). 1H NMR
spectrum, δ, ppm: 8.15–8.13 (4H, m, H Ph); 8.12–7.55
(6H, m, H Ph). 13C NMR spectrum, δ, ppm: 163.5; 130.7;
128.0; 125.9; 122.9. Found, m/z: 222.0901 [M]+. C14H10N2O.
Calculated, m/z: 222.0885.
2-Phenyl-5-(propan-2-yl)-1,3,4-oxadiazole (3b). Yield
1
All solvents and reagents were purchased from Aldrich
and Avra.
164 mg (87%), white solid, mp 132–133°C. H NMR
spectrum, δ, ppm (J, Hz): 8.06–8.03 (2H, m, H-2,6); 7.54–
373

Chemistry of Heterocyclic Compounds 2020, 56(3), 371–376
7.47 (3H, m, H-3,4,5); 3.31–3.24 (1H, m, CH(CH3)2); 1.46
126.7; 126.0; 120.8; 79.8; 49.1; 45.1; 35.6; 35.0; 31.0;
28.5; 20.7. Found, m/z: 370.6106 [M–1]+. C21H29N3O3.
Calculated, m/z: 370.4733.
(6H, d, J = 6.8, CH(CH3)2). 13C NMR spectrum, δ, ppm: 170.8;
164.6; 131.4; 128.9; 126.7; 124.2; 26.4; 20.0. Found, m/z:
188.7157 [M]+. C11H12N2O. Calculated, m/z: 188.2258.
2-(4-Nitrophenyl)-5-(propan-2-yl)-1,3,4-oxadiazole (3c).
2-(4-tert-Butylphenyl)-5-(2-phenylethyl)-1,3,4-oxadiazole
(3i). Yield 267 mg (87%), off-white solid, mp 115–117°C.
1H NMR spectrum, δ, ppm: 7.97–7.95 (2H, m, H-2,6); 7.55–
7.53 (2H, m, H-3,5); 7.41–7.34 (3H, m, H Ph); 7.32–7.27
(2H, m, H Ph); 3.27–3.25 (2H, m, CH2CH2Ph); 3.25–3.20
(2H, m, CH2CH2Ph); 1.38 (9H, s, C(CH3)3). 13C NMR
spectrum, δ, ppm: 155.2; 150.7; 139.6; 137.9; 130.0; 128.7;
128.3; 126.6; 125.5; 121.1; 35.0; 32.7; 31.3; 27.4. Found, m/z:
306.4124 [M]+. C20H22N2O. Calculated, m/z: 306.4015.
2-[5-(2-Phenylethyl)-1,3,4-oxadiazol-2-yl]phenol (3j).
1
Yield 210 mg (90%), brown solid, mp 150–152°C. H NMR
spectrum, δ, ppm (J, Hz): 8.38–8.35 (2H, m, H-2,6); 8.26–
8.23 (2H, m, H-3,5); 3.35–3.28 (1H, m, CH(CH3)2); 1.49
(6H, d, J = 6.8, CH(CH3)2). 13C NMR spectrum, δ, ppm:
172.0; 162.9; 149.4; 129.7; 127.7; 124.3; 26.5; 20.0.
Found, m/z: 233.2843 [M]+. C11H11N3O3. Calculated, m/z:
233.2233.
2-(2-Phenylethyl)-5-(propan-2-yl)-1,3,4-oxadiazole
(3d).
1
Yield 200 mg (92%), light-brown solid, mp 125–127°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.33–7.27 (2H, m,
H-2,6 Ph); 7.25–7.20 (3H, m, H-3,4,5 Ph); 3.17–3.09 (5H, m,
CH2CH2Ph, CH(CH3)2); 1.35 (6H, d, J = 6.8, CH(CH3)2).
13C NMR spectrum, δ, ppm: 170.9; 166.0; 139.5; 128.6;
128.2; 126.5; 32.6; 27.2; 26.2; 19.8. Found, m/z: 216.2824
[M]+. C13H16N2O. Calculated, m/z: 216.2789.
Yield 228 mg (85%), brown solid, mp 133–136°C. H NMR
spectrum, δ, ppm (J, Hz): 10.22 (1H, s, OH); 7.73 (1H, dd,
J = 7.8, J = 1.2, H-3); 7.48–7.44 (1H, m, H-5); 7.33–7.29
(4H, m, H Ph); 7.23–7.20 (1H, m, H Ph); 7.09 (1H, d,
J = 8.4, H-6); 7.02 (1H, t, J = 7.6, H-4); 3.27 (2H, t, J = 7.6,
CH2CH2Ph); 3.11 (2H, t, J = 7.6, CH2CH2Ph). 13C NMR
spectrum, δ, ppm: 165.9; 163.9; 157.7; 140.2; 133.7; 128.7;
126.8; 120.2; 117.5; 109.9; 32.0; 26.8. Found, m/z:
266.2898 [M]+. C16H14N2O2. Calculated, m/z: 266.2946.
2-(Biphenyl-4-yl)-5-phenyl-1,3,4-oxadiazole (3k). Yield
225 mg (76%), white solid, mp 115–117°C (mp 164–
tert-Butyl 3-[5-(propan-2-yl)-1,3,4-oxadiazol-2-yl]pyrro-
lidine-1-carboxylate (3e). Yield 250 mg (88%), colorless
1
liquid, bp 102–104°C. H NMR spectrum, δ, ppm (J, Hz):
3.84–3.79 (1H, m) and 3.62–3.60 (3H, m, 2NCH2); 3.48–
3.45 (1H, m, NCH2CH); 3.31–3.20 (1H, m, CH(CH3)2);
2.40–2.30 (2H, m, NCH2CH2); 1.46 (9H, s, C(CH3)3); 1.38
(6H, d, J = 7.2, CH(CH3)2). 13C NMR spectrum, δ, ppm:
171.3; 166.4; 154.2; 79.8; 49.0; 45.0; 34.8; 28.4; 26.3;
20.6; 19.9. Found, m/z: 281.2482 [M]+. C14H23N3O3.
Calculated, m/z: 281.3507.
1
166°C31b). H NMR spectrum, δ, ppm (J, Hz): 8.23–8.17
(5H, m, H Ph); 7.77 (2H, d, J = 8.0, H Ar); 7.67 (2H, d,
J = 8.0, H Ar); 7.57–7.40 (5H, m, H Ph). 13C NMR
spectrum, δ, ppm: 164.6; 164.5; 144.5; 139.8; 131.7; 129.1;
128.9; 128.1; 127.7; 127.4; 127.2; 126.9; 124.0; 122.7.
Found, m/z: 298.1206 [M]+. C20H14N2O. Calculated, m/z:
298.3805.
tert-Butyl 3-[5-(3-bromophenyl)-1,3,4-oxadiazol-2-yl]-
pyrrolidine-1-carboxylate (3f). Yield 350 mg (90%),
colorless liquid (rotamers observed by 1H NMR). 1H NMR
spectrum, δ, ppm: 8.30–8.26 (2H, m, H Ar); 7.83–7.81
(1H, m, H Ar); 7.70–7.66 (1H, m, H Ar); 3.98–3.35 (1H,
m) and 3.80–3.62 (3H, m, 2NCH2); 3.59–3.45 (1H, m,
NCH2CH); 2.50–2.35 (2H, m, NCH2CH2); 1.49 (9H, s,
C(CH3)3). 13C NMR spectrum, δ, ppm: 155.2; 150.7; 139.6;
128.7; 128.3; 126.9; 126.6; 126.0; 125.4; 121.1; 65.2; 34.6;
32.7; 31.1. Found, m/z: 394.2876 [M]+. C17H20BrN3O3.
Calculated, m/z: 394.2630.
2-(4-Methoxyphenyl)-5-phenyl-1,3,4-oxadiazole (3l).
Yield 226 mg (90%), white solid, mp 150°C (mp 148–
1
149°C32). H NMR spectrum, δ, ppm (J, Hz): 8.17–8.11
(2H, m, H Ph); 8.09–8.06 (2H, m, H Ar); 7.58–7.53 (3H,
m, H Ph); 7.04–7.02 (2H, m, H Ar); 3.89 (3H, s, CH3).
13C NMR spectrum, δ, ppm: 163.4; 163.0; 161.3; 130.4;
127.9; 127.6; 125.7; 123.0; 115.3; 113.4; 54.4. Found, m/z:
252.0921 [M]+. C15H12N2O2. Calculated, m/z: 252.0902.
2-(4-Fluorophenyl)-5-phenyl-1,3,4-oxadiazole (3m).
Yield 218 mg (91%), white solid, mp 151°C (mp 151–
1
152 C43). H NMR spectrum, δ, ppm (J, Hz): 8.28–8.22
tert-Butyl 3-[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]pyrro-
lidine-1-carboxylate (3g). Yield 270 mg (85%), brown
(2H, m, H Ar); 8.15–8.11 (2H, d, J = 8.6, H Ar); 7.56–7.51
(5H, m, H Ph). 13C NMR spectrum, δ, ppm: 164.9; 163.9;
138.1; 132.0; 129.6; 129.3; 128.3; 127.1; 123.9; 122.5.
Found, m/z: 240.1782 [M]+. C14H9FN2O. Calculated, m/z:
240.1796.
1
solid, mp 125–127°C. H NMR spectrum, δ, ppm (J, Hz):
8.83 (2H, d, J = 6.0, H-2,6); 7.91 (2H, d, J = 5.9, H-3,5);
3.95–3.87 (1H, m) and 3.78–3.65 (3H, m, 2NCH2); 3.60–
3.46 (1H, m, NCH2CH); 2.50–2.35 (2H, m, NCH2CH2);
1.48 (9H, s, C(CH3)3). 13C NMR spectrum, δ, ppm: 167.6;
163.3; 154.4; 150.7; 130.9; 120.4; 80.0; 49.1; 45.0; 34.8;
29.9; 28.5. Found, m/z: 315.2327 [M]+. C16H20N4O3.
Calculated, m/z: 315.2550.
2-(4-Bromophenyl)-5-phenyl-1,3,4-oxadiazole (3n). Yield
270 mg (90%), white solid, mp 161°C (mp 164–168°C32).
1H NMR spectrum, δ, ppm: 8.12−8.10 (2H, m, H Ar);
8.05−8.02 (2H, m, H Ar); 7.59−7.55 (5H, m, H Ph).
13C NMR spectrum, δ, ppm: 166.7; 165.7; 138.3; 131.4;
129.5; 129.4; 127.1; 126.6; 123.7; 122.4. Found, m/z:
300.0283 [M]+. C14H9ClN2ON. Calculated, m/z: 299.9898.
4-[5-(2-Methylphenyl)-1,3,4-oxadiazol-2-yl]benzonitrile
(3o). Yield 195 mg (75%), brown solid, mp 120–122°C.
1H NMR spectrum, δ, ppm (J, Hz): 8.26 (2H, dd, J = 9.2,
J = 2.4, H-2,6); 8.05–8.02 (1H, m, H-6'); 7.84 (2H, dd,
J = 9.2, J = 2.4, H-3,5); 7.50–7.24 (3H, m, H-3',4',5'); 2.64
tert-Butyl 3-[5-(4-tert-butylphenyl)-1,3,4-oxadiazol-2-yl]-
pyrrolidine-1-carboxylate (3h). Yield 305 mg (82%),
1
yellow solid, mp 120–123°C. H NMR spectrum, δ, ppm
(J, Hz): 7.95 (2H, d, J = 8.4, H-2,6); 7.51 (2H, d, J = 8.4,
H-3,5); 3.95–3.87 (1H, m) and 3.78–3.65 (3H, m, 2NCH2);
3.60–3.46 (1H, m, NCH2CH); 2.54–2.37 (2H, m,
NCH2CH2); 1.47 (9H, s, OC(CH3)3); 1.37 (9H, s, C(CH3)3).
13C NMR spectrum, δ, ppm: 166.2; 165.2; 155.4; 154.3;
374

Chemistry of Heterocyclic Compounds 2020, 56(3), 371–376
(3H, s, CH3). 13C NMR spectrum, δ, ppm: 165.5; 162.7;
138.6; 132.8; 131.9; 131.2; 129.0; 127.7; 127.2; 126.2;
125.6; 122.3; 115.0; 22.0. Found, m/z: 261.2854 [M]+.
C16H11N3O. Calculated, m/z: 261.2780.
7.90 (3H, m, H Ar); 7.68–7.56 (2H, m, H Ar); 7.44–7.30
(3H, m, H Ar). 13C NMR spectrum, δ, ppm: 165.0; 163.4;
132.0; 131.9; 131.3; 130.0; 129.8; 129.1; 128.3; 128.1;
127.0; 124.8; 123.8; 123.5. Found, m/z: 290.2568 [M]+.
C16H10N4O2. Calculated, m/z: 290.2762.
2-(3,5-Dimethoxyphenyl)-5-(3-iodophenyl)-1,3,4-oxa-
diazole (3p). Yield 282 mg (70%), white solid, mp 129–
131°C. 1H NMR spectrum, δ, ppm: 8.37 (1H, s, H Ar); 8.08–
8.01 (2H, m, H Ar); 7.57–7.43 (2H, m, H Ar); 7.33–6.99
(2H, m, H Ar); 3.89 (6H, s, 2OCH3). 13C NMR spectrum,
δ, ppm: 163.2; 163.1; 153.9; 147.7; 141.0; 135.0; 132.0;
126.3; 125.8; 125.4; 121.4; 118.2; 116.9; 96.0; 61.3; 56.5.
Found, m/z: 408.2230 [M]+. C16H13IN2O3. Calculated, m/z:
408.1905.
N,N-Dimethyl-5-phenylethyl-1,3,4-oxadiazol-2-amine
(3w). Yield 109 mg (50%), brown liquid. 1H NMR spectrum,
δ, ppm (J, Hz): 7.31–7.17 (5H, m, H Ph); 2.98–2.97 (2H,
m, CH2CH2Ph ); 2.93 (6H, s, N(CH3)2); 2.81–2.80 (2H, m,
CH2CH2Ph). 13C NMR spectrum, δ, ppm: 165.0; 160.0;
140.5; 128.8; 128.6; 126.7; 38.2; 32.1; 26.9. Found, m/z:
217.2564 [M]+. C12H15N3O. Calculated, m/z: 217.2670.
2,4-Dichloro-6-(5-phenyl-1,3,4-oxadiazol-2-yl)phenol
(3x). Yield 190 mg (62%), brown solid, mp 130–133°C.
1H NMR spectrum, δ, ppm (J, Hz): 10.84 (1H, br. s, OH);
8.16 (2H, d, J = 8.0, H-2,6); 7.78 (1H, d, J = 3.6, H-5');
7.65–7.55 (4H, m, H-3,4,5,3'). 13C NMR spectrum, δ, ppm:
163.9; 162.6; 152.2; 133.3; 132.5; 129.1; 127.1; 125.0;
124.7; 123.1; 122.6; 109.9. Found, m/z: 307.1010 [M]+.
C14H8Cl2N2O2. Calculated, m/z: 307.1315.
tert-Butyl {[5-(4-tert-butylphenyl)-1,3,4-oxadiazol-2-yl]-
methyl}carbamate (3q). Yield 232 mg (70%), brown
1
liquid. H NMR spectrum, δ, ppm (J, Hz): 7.96 (2H, d,
J = 8.4, H-2,6); 7.51 (2H, d, J = 8.4, H-3,5); 5.41 (1H, s,
NH); 4.64 (2H, d, J = 5.2, CH2); 1.47 (9H, s, OC(CH3)3);
1.31 (9H, s, C(CH3)3). 13C NMR spectrum, δ, ppm: 175.5;
165.4; 163.7; 155.5; 126.8; 125.7; 120.7; 80.6; 35.9; 35.1;
31.1; 28.3. Found, m/z: 330.7551 [M]+. C18H25N3O3.
Calculated, m/z: 330.4094.
1
Supplementary information file containing H and 13C
tert-Butyl {[5-(propan-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-
carbamate (3r). Yield 174 mg (72%), colorless liquid.
1H NMR spectrum, δ, ppm (J, Hz): 5.34 (1H, s, NH); 4.53
(2H, d, J = 5.6, CH2); 3.21–3.14 (1H, m, CH(CH3)2); 1.46
(9H, s, C(CH3)3); 1.38 (6H, d, J = 6.8, CH(CH3)2).
13C NMR spectrum, δ, ppm: 171.6; 163.9; 155.5; 80.5;
35.8; 28.2; 26.3; 19.9. Found, m/z: 241.2492 [M]+.
C11H19N3O3. Calculated, m/z: 241.2869.
NMR spectra of the synthesized compounds is available at
the journal website at http://link.springer.com/journal/10593.
The authors thank University of Hyderabad for NMR
spectroscopic analyses. Karuna Raman Paidi, Murali
Krishna Kolli, and Venkata Ramana Pedakotla acknowledge
Department of chemistry, Sri Krishnadevaraya University
for laboratory facilities.
tert-Butyl {[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-
carbamate (3s). Yield 180 mg (65%), gray solid, mp 128–
References
1
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130°C. H NMR spectrum, δ, ppm (J, Hz): 8.84–8.83 (2H,
m, H Py); 7.92–7.91 (2H, m, H Py); 5.28 (1H, s, NH); 4.69
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1
mp 139–142°C. H NMR spectrum, δ, ppm (J, Hz): 8.12
(2H, d, J = 8.4, H-2,6); 7.74 (2H, d, J = 8.0, H-3,5); 7.66–
7.64 (2H, m, H-2',6'); 7.50–7.45 (2H, m, H-3',5'); 7.43–
7.40 (1H, m, H-4'); 5.27 (1H, s, NH); 4.67 (2H, d, J = 4.0,
CH2); 1.50 (9H, s, C(CH3)3). 13C NMR spectrum, δ, ppm:
165.2; 163.8; 155.4; 144.6; 139.7; 129.0; 128.2; 127.7;
127.4; 127.1; 122.4; 80.7; 36.0; 28.3. Found, m/z: 351.3054
[M]+. C20H21N3O3. Calculated, m/z: 351.3990.
[5-([1,1'-Biphenyl]-4-yl)-1,3,4-oxadiazol-2-yl]methan-
amine (3u). Yield 125 mg (50%), gray solid, mp 140–143°C.
1H NMR spectrum, δ, ppm: 8.10–8.08 (2H, m, H-2,6); 7.94–
7.92 (2H, m, H-3,5); 7.79–7.74 (2H, m, H-2',6'); 7.53–7.45
(3H, m, H-3',4',5'); 3.99 (2H, s, CH2). 13C NMR spectrum,
δ, ppm: 168.5; 164.2; 143.7; 139.2; 129.6; 128.8; 128.0;
127.5; 127.1; 122.9; 37.1. Found, m/z: 251.2976 [M]+.
C15H13N3O. Calculated, m/z: 251.2832.
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