Application of N-Acylbenzotriazoles in the Synthesis of 5-Substituted 2-Ethoxy-1,3,4-oxadiazoles as Building Blocks toward 3,5-Disubstituted 1,3,4-Oxadiazol-2(3H)-ones

Article abstract of DOI:10.1021/acs.joc.7b01863

5-Substituted-2-ethoxy-1,3,4-oxadiazoles were conveniently prepared through a one-pot sequential N-acylation/dehydrative cyclization between ethyl carbazate and N-acylbenzotriazoles in the presence of Ph₃P-I₂ as a dehydrating agent. Subsequent treatment with a stoichiometric amount of alkyl halides (X = Cl, Br, I) enables a rapid access to a variety of 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-ones in good to excellent yields.

Full text of DOI:10.1021/acs.joc.7b01863

Note
pubs.acs.org/joc
Application of N‑Acylbenzotriazoles in the Synthesis of 5‑Substituted
2‑Ethoxy-1,3,4-oxadiazoles as Building Blocks toward 3,5-
Disubstituted 1,3,4-Oxadiazol-2(3H)‑ones
Sirawit Wet-osot,†,‡ Wong Phakhodee,†,§ and Mookda Pattarawarapan*,†,§
†Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, ‡Graduate School, and §Center
of Excellence in Materials Science and Technology, Chiang Mai University, Chiang Mai 50200, Thailand
S
* Supporting Information
ABSTRACT: 5-Substituted-2-ethoxy-1,3,4-oxadiazoles were
conveniently prepared through a one-pot sequential N-
acylation/dehydrative cyclization between ethyl carbazate and
N-acylbenzotriazoles in the presence of Ph3P−I2 as a
dehydrating agent. Subsequent treatment with a stoichiometric
amount of alkyl halides (X = Cl, Br, I) enables a rapid access to
a variety of 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-ones in
good to excellent yields.
ecently, there has been a growing interest in the synthesis
and application of 2,5-disubstituted 1,3,4-oxadiazoles.1
Owing to their unique characteristics, including a broad range
of biological activities2 as well as excellent electron-transporting
properties,3 1,3,4-oxadiazoles are promising candidates in drug
discovery, agrochemicals, and material development.
reaction times, and requirement of linear assembly of reactants
using multistep synthesis. Convergent approach toward the
synthesis of 1,3,4-oxadiazol-2(3H)-one derivatives with the
flexibility to incorporate various substituent groups at both 3-
and 5-positions is thus highly desirable.
In this regard, we have developed a convenient one-pot two-
step method for constructing ethoxy-substituted 1,3,4-oxadia-
zoles coupled with their conversion toward 3,5-disubstituted
1,3,4-oxadiazol-2(3H)-ones (Scheme 1).
R
Among the derivatives, 5-substituted 2-alkoxy-1,3,4-oxadia-
zole has received less attention4 despite the fact that
compounds possessing this structural motif have been shown
to exhibit kinase inhibition (I)5 as well as antifungal (II)4d and
antibacterial (III)4d activities (Figure 1). Interestingly, it can
also be used as a building block toward other valuable products
such as 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-ones.6 The
representative examples of bioactive oxadiazolones are IV
(openers of large-conductance Ca2+-activated potassium (Maxi-
K) channels),7 V (selective inhibitor of monoamine oxidase
type B),8 VI (potent human recombinant fatty acid amide
hydrolase inhibitor),9 and VII (effective agent at stimulating
neural stem cell maturation).10
According to Scheme 1, a number of methods have been
introduced for the synthesis of 3,5-disubstituted 1,3,4-
oxadiazol-2(3H)-ones. The selected examples include (i) N-
alkylation of alkoxy-substituted 1,3,4-oxadiazoles;6b,c (ii) N-
alkylation of 1,3,4-oxadiazole-2-(3H)-ones using alkyl halide-
s7,8a,11 or alcohol;12 (iii) decarboxylative cyclization of N-
acylhydrazine-1,2-dicarboxylates derived from Mitsunobu re-
agents;13 (iv) oxidative cyclization and rearrangement of alkyl
carbazates and aldehydes;14 (v) palladium-catalyzed oxidative
carbonylation of hydrazides;15 (vi) one-pot reaction of
acylhydrazines, carbon disulfide, propylene oxide, and organic
halides under refluxing in water;16 (vii) cyclization of N-
substituted acylhydrazines using phosgene;17 and (viii) 1,3-
dipolar cycloaddition of nitrile imine and carbon dioxide.18
Nevertheless, the existing procedures still involve the use of
hazardous or expensive reagents, harsh conditions, long
Based on our previous experiences involving the synthetic
application of N-acylbenzotriazoles and phosphine-mediated
reactions,19 it was envisaged that a one-pot procedure through
N-acylation of ethyl carbazate with N-acylbenzotriazoles 1,
followed by Ph3P−I2-mediated dehydrative cyclization, should
directly give rise to ethoxy-substituted 1,3,4-oxadiazoles 2. 3,5-
Disubstituted 1,3,4-oxadiazol-2(3H)-ones 3 could then be
obtained through N-alkylation of 2 with inexpensive and
readily available alkyl halides. It is important to note that unlike
the previously described method requiring multistep prepara-
tion of the starting oxadiazoles and ineffective thermal
alkylation with excess alkyl iodides,13,14 we have devised an
improved protocol under milder conditions using stoichio-
metric amount of alkyl halides (X = Cl, Br, I).
We set out to explore the one-pot procedure toward 2 using
ethyl carbazate and N-benzoylbenzotriazole as the model
substrates. Although the synthesis of acylhydrazines from N-
acylbenzotriazoles has previously been reported in THF
without any base or additives at room temperature,20 we
decided to perform the first acylation step in dichloromethane
in favor to the subsequent cyclization mediated by the Ph3P−I2
system. Unfortunately, it was found that ethyl 2-benzoylhy-
drazine-1-carboxylate was afforded in low amount when ethyl
Received: July 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b01863
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Note
Figure 1. Examples of bioactive compounds containing a 1,3,4-oxadiazole or 1,3,4-oxadiazol-2(3H)-one unit.
Scheme 1. Previously Reported Methods and Our Approach toward 3,5-Disubstituted 1,3,4-Oxadiazolones
carbazate was treated with N-benzoylbenzotriazole in the
absence of base, even under ultrasonic irradiation (see Table
S1). In the presence of triethylamine, N-acylation proceeded
smoothly within 30 min. However, no oxadiazole formation
was observed after subsequent treatment with Ph3P−I2,
suggesting some interference of the remaining species from
the first step. To our delight, when using potassium carbonate
with the addition of a catalytic amount of DMAP (10 mol %),
the time for the N-acylation step was reduced to ca. 10 min.
Subsequent treatment with Ph3P−I2 and Et3N then gave rise to
the desired product 2a in 86% yield within 5 min stirring at
room temperature.
Without necessity to further optimize the reaction
conditions, we then focus on the synthesis of 2 through a
one-pot sequential acylation−dehydrative cyclization between
ethyl carbazate with N-acylbenzotriazoles (1). As summarized
in Scheme 2, oxadiazoles 2 were afforded in good to excellent
yields within 5 min cyclization. The developed conditions were
found to be compatible with substrates containing electron-
donating as well as electron-withdrawing groups such as p-
OMe, p-Cl, p-Br, p-I, m-NMe2, or m-NO2, though the presence
of a strong electron-withdrawing p-NO2 group lowered the
yield of product 2e. Substrates bearing a sterically hindered o-I,
o-OMe, or o-NPh group reacted smoothly to give good yields
of 2f−2h. Additionally, other oxadiazoles having biphenyl (2k),
naphthyl (2l), alkyl (2m), conjugated (2n), reactive hydroxy
(2o), and heterocyclic (2p) functionalities could be prepared in
satisfactory yields.
With a series of 2 in hand, the N-alkylation conditions
toward the synthesis of 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-
ones 3 were optimized. Based on the previous studies,
conversions of 2 into 3 require prolonged heating with an
excess of alkyl halide at high temperatures (160−250 °C).6b,c
To obtain the best conditions, we decided to carry out the
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DOI: 10.1021/acs.joc.7b01863
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Scheme 2. Synthesis of 5-Substituted 2-Ethoxy-1,3,4-oxadiazoles 2
reaction in a pressure tube under heating in a preset oil bath. By
simply heating 2a with benzyl chloride (1.2 equiv) in DMF at
180 °C for 30 min, a complex mixture was obtained. Lowering
the temperature to 120 °C gave no conversion. However, N-
alkylation in the presence of Et3N (1.2 equiv) and a catalytic
amount of KI (10 mol %) rapidly provided the desired
oxadiazolone product 3a in 85% yield within 5 min (Scheme
3).
The reaction was also found to proceed smoothly with other
primary benzylic halides containing electron-withdrawing,
electron-donating, as well as vinyl groups (see compounds
3b−3d). In the synthesis of 3d and 3e, the presence of a
polymerizable styryl group could be tolerated. The substrates
bearing electron-withdrawing or electron-donating groups
reacted with benzyl chloride to afford the products 3f and 3g
in satisfactory yields. It should be noted that, using the method
in route iv (Scheme 1), the direct thermal rearrangement of the
in situ generated 5-(4-nitrophenyl)-1,3,4-oxadiazoles bearing
−OMe or −OBn groups only gave a decomposed mixture
without the desired oxadiazolones.14
With the success in the synthesis of N-benzyl derivatives,
substrate scope was further extended to other types of alkyl
halides. Compared to primary benzyl halides, methyl iodide and
isobutyl bromide were less effective, giving products 3h and 3i,
respectively, in lower yields. Whereas the desired product 3j
could be obtained in moderate yield using secondary allylic
halide, an attempt to use secondary benzylic halides such as (1-
bromoethyl)benzene failed to give the desired product. Instead,
the de-ethylated product, 5-phenyl-1,3,4-oxadiazole-2-(3H)-one
(4), and the product derived from O- to N-ethyl migration (5)
were obtained in 40 and 45%, respectively. It was initially
believed that competing β-elimination of the halide substrate
may liberate HBr to catalyze the de-ethylation process,6d
whereas the ethyl migration should be feasible in the absence of
an alkyl halide. However, 1H NMR analysis of the crude
products revealed no trace of styrene byproduct but the
presence of 1-phenylethanol along with its corresponding
formate ester derived from thermal reaction of (1-bromoethyl)-
benzene with DMF (see Figure S1 in the Supporting
Information).21 Thus, the mechanism underlying the formation
of 4 and 5 remains unclear and requires further investigation.
It should be noted that the synthesis of 2 and 3 could be
carried out in gram scale without complication, except that
longer times are required for the reaction to complete. Starting
with N-benzoylbenzotriazole (5.00 g, 22.2 mmol) and ethyl
carbazate (2.54 g, 24.4 mmol), compound 2a was obtained in
84% yield (3.55 g) after ca. 1 h. Conversion of 2a into 3d, 3l,
and 3m using 1.00 g (5.26 mmol) of 2a and the corresponding
chlorides (6.312 mmol) for each reaction also gave high yields
of the products after 15 min stirring at 120 °C in a pressure
tube (Scheme 3).
To gain a mechanistic insight, control experiments were
further carried out. When 2a was subjected to the above-
described conditions in the absence of an alkyl halide, only the
thermal rearrangement product 5 was formed in 37% without
detectable de-ethylated product 4 (Scheme 4a). Whereas
treatment of 5 with benzyl chloride led to no conversion to
3a, 4 underwent rapid benzylation to give 3a in high yield
(Scheme 4b,c). These results suggested that 5 is not the
reactive species. Although the formation of 3 through 4 is
possible, it is highly unlikely that 4 is the key intermediate as it
was not generally observed even in the absence of alkyl halide.
Thus, the plausible mechanism for the Ph3P−I2-mediated
formation of 2 and its conversion into 3 is shown in Scheme 5.
N-Acylation of ethyl carbazate with N-acylbenzotriazole
provides the corresponding hydrazide, which undergoes
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Note
Scheme 3. Synthesis of 3,5-Disubstituted 1,3,4-Oxadiazol-2(3H)-ones 3
substitution of 2 with R2X, followed by de-ethylation of the O-
ethyl group with halide ions or possibly with triethylamine.
In summary, we have developed a convenient one-pot
approach for the preparation of 5-substituted 2-ethoxy-1,3,4-
oxadiazoles directly from N-acylbenzotriazoles. The reaction
proceeded rapidly under mild conditions with functional group
tolerance. These compounds served as versatile building blocks
toward a variety of 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-
ones, which may be difficult to obtain with previously reported
procedures.
Scheme 4. Control Experiments
EXPERIMENTAL SECTION
■
General Information. All reagents were purchased from Sigma-
Aldrich Co., USA, and used without further purification. N-
Acylbenzotriazoles were synthesized according to our reported
procedure.19a,d The acylation step was performed in an ultrasonic
bath equipped with thermostat operating at 37 kHz (Elmasonic
S30(H), Germany). The reaction was monitored by thin-layer
chromatography carried out on silica gel plates (60F254, MERCK,
Germany) and visualized under UV light (254 nm). Melting points
were determined using Mettler Toledo DSC equipment at a heating
phosphorylation with phosphonium iodide before cyclization to
give 2. N-Alkylation of 2 could proceed via nucleophilic
D
DOI: 10.1021/acs.joc.7b01863
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Note
Scheme 5. Plausible Mechanism for the Formation of 2 and 3
rate of 6 °C/min and are uncorrected. NMR spectra were determined
2-Ethoxy-5-(2-methoxyphenyl)-1,3,4-oxadiazole (2g): colorless
oil (0.0954 g, 80% yield); Rf 0.32 (10% EtOAc/hexanes); H NMR
1
1
using a Bruker AVANCE (400 MHz for H). Chemical shifts were
reported in parts per million (ppm, δ) downfield from TMS. High-
resolution mass spectra (HRMS) were recorded using the LC-DAD-
ESI-MS/MS system that consisted of a Waters Alliance 2695 LC-DAD
and a Q-TOF 2 (quadrupole mass filter-time-of-flight) mass
spectrometer with a Z-spray ES source.
(400 MHz, CDCl3) δ 7.80 (dd, J = 7.6, 1.6 Hz, 1H), 7.44 (td, J = 8.4,
1.6 Hz, 1H), 7.02 (t, J = 8.4 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 4.59 (q,
J = 7.2 Hz, 2H), 3.92 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 165.8, 159.3, 157.7, 132.7, 130.0, 120.8, 113.4,
111.9, 69.1, 56.0, 14.4; TOF-HRMS calcd for C11H13N2O3 (M + H)+
221.0926, found 221.0932.
General Procedure for the Synthesis of 5-Substituted 2-
Ethoxy-1,3,4-oxadiazoles 2. A mixture of N-acylbenzotriazole 1
(0.54 mmol), ethyl carbazate (0.59 mmol), DMAP (6.6 mg, 0.054
mmol), and K2CO3 (0.0895 g, 0.648 mmol) in dry CH2Cl2 (2 mL)
was sonicated in an ultrasonic bath for 10 min or until complete amide
bond formation based on TLC. I2 (0.2056 g, 0.81 mmol) and Ph3P
(0.2125 g, 0.81 mmol) were then added to the solution at 0 °C with
stirring. After that, the mixture was treated with Et3N (0.164 g, 1.62
mmol) and stirred at room temperature for 5 min. The crude mixture
was concentrated under reduced pressure and then purified by column
chromatography using 5−20% ethyl acetate in hexane.
2-(5-Ethoxy-1,3,4-oxadiazol-2-yl)-N-phenylaniline (2h): colorless
1
oil (0.1142 g, 75% yield); Rf 0.53 (15% EtOAc/hexanes); H NMR
(400 MHz, CDCl3) δ 9.16 (s, 1H), 7.68 (dd, J = 8.0, 1.6 Hz, 1H),
7.34−7.21 (m, 6H), 7.06 (t, J = 7.2 Hz, 1H), 6.79 (t, J = 8.0 Hz, 1H),
4.57 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 164.7, 160.7, 144.1, 140.8, 131.8, 129.3, 127.7, 123.5,
122.2, 117.8, 113.9, 107.7, 69.3, 14.3; TOF-HRMS calcd for
C16H16N3O2 (M + H)+ 282.1243, found 282.1247.
3-(5-Ethoxy-1,3,4-oxadiazol-2-yl)-N,N-dimethylaniline (2i): yellow
solid (0.1150 g, 91% yield); mp 91−92 °C; Rf 0.34 (20% EtOAc/
2-Ethoxy-5-phenyl-1,3,4-oxadiazole (2a):6a white solid (0.0886 g,
86% yield); mp 119−120 °C; Rf 0.32 (10% EtOAc/hexanes); 1H
NMR (400 MHz, CDCl3) δ 7.94−7.91 (m, 2H), 7.48−7.43 (m, 3H),
4.60 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 165.8, 160.6, 131.3, 129.0, 126.2, 124.2, 69.3, 14.4.
2-Ethoxy-5-(4-methoxyphenyl)-1,3,4-oxadiazole (2b):22 white
solid (0.1073 g, 90% yield); mp 81−83 °C; Rf 0.31 (10% EtOAc/
1
hexanes); H NMR (400 MHz, CDCl3) δ 7.30−7.22 (m, 3H), 6.80
(ddd, J = 8.2, 2.8, 1.2 Hz, 1H), 4.58 (q, J = 7.2 Hz, 1H), 2.97 (s, 6H),
1.50 (t, J = 7.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.5,
161.1, 150.5, 129.5, 124.6, 115.0, 113.9, 109.2, 69.0, 40.3, 14.3; TOF-
HRMS calcd for C12H16N3O2 (M + H)+ 234.1243, found 234.1243.
2-Ethoxy-5-(3-nitrophenyl)-1,3,4-oxadiazole (2j):24 white solid
(0.0995 g, 78% yield); mp 84−85 °C; Rf 0.30 (15% EtOAc/hexanes);
1H NMR (400 MHz, CDCl3) δ 8.67 (t, J = 2.0 Hz, 1H), 8.29 (ddd, J =
8.0, 2.4, 1.2 Hz, 1H), 8.22 (dt, J = 8.0, 1.2 Hz, 1H), 7.66 (t, J = 8.0 Hz,
1H), 4.60 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H).
1
hexanes); H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 9.0 Hz, 2H),
6.92 (d, J = 9.0 Hz, 2H), 4.54 (q, J = 7.2 Hz, 1H), 3.80 (s, 3H), 1.47 (t,
J = 7.2 Hz, 2H).
2-(4-Chlorophenyl)-5-ethoxy-1,3,4-oxadiazole (2c):23 white solid
(0.1071 g, 88% yield); mp 111−113 °C; Rf 0.33 (20% EtOAc/
2-([1,1′-Biphenyl]-4-yl)-5-ethoxy-1,3,4-oxadiazole (2k): white
solid (0.1426 g, 99% yield); mp 115−117 °C; Rf 0.41 (20% EtOAc/
1
1
hexanes); H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.6 Hz, 2H),
hexanes); H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.8 Hz, 2H),
7.43 (d, J = 8.6 Hz, 2H), 4.60 (q, J = 7.2 Hz, 2H), 1.51 (t, J = 7.2 Hz,
3H).
2-(4-Bromophenyl)-5-ethoxy-1,3,4-oxadiazole (2d): white solid
7.64 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.44−7.33 (m, 3H),
4.57 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 165.6, 160.2, 143.7, 139.7, 128.9, 128.0, 127.4, 127.0,
126.4, 122.8, 69.2, 14.3; TOF-HRMS calcd for C16H15N2O2 (M + H)+
267.1134, found 267.1136.
(0.1296 g, 89% yield); mp 125−126 °C; Rf 0.39 (20% EtOAc/
1
hexanes); H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 2H),
2-Ethoxy-5-(naphthalen-2-yl)-1,3,4-oxadiazole (2l):4a white solid
(0.0990 g, 76% yield); mp 95−96 °C; Rf 0.32 (15% EtOAc/hexanes);
1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.03 (dd, J = 8.8, 1.6 Hz,
1H), 7.91−7.84 (m, 3H), 7.57−7.52 (m, 2H), 4.63 (q, J = 7.2 Hz,
2H), 1.54 (t, J = 7.2 Hz, 3H).
7.58 (d, J = 8.8 Hz, 2H), 4.59 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 159.8, 132.3, 127.5,
125.8, 123.1, 69.5, 14.4; TOF-HRMS calcd for C10H1079BrN2O2 (M +
H)+ 268.9926, found 268.9923; calcd for C10H1081BrN2O2 (M + H)+
270.9906, found 270.9901.
2-Ethoxy-5-(4-nitrophenyl)-1,3,4-oxadiazole (2e):23 white solid
(0.0805 g, 63% yield); mp 156−157 °C; Rf 0.30 (15% EtOAc/
2-Ethoxy-5-(naphthalen-1-ylmethyl)-1,3,4-oxadiazole (2m):
liquid (0.1157 g, 84% yield); Rf 0.34 (20% EtOAc/hexanes); 1H
NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 8.0
Hz, 1H), 7.83−7.79 (m, 1H), 7.57−7.42 (m, 4H), 4.49 (s, 2H), 4.45
(d, J = 7.2 Hz, 1H), 1.39 (t, J = 7.2 Hz, 2H); 13C{1H} NMR (100
MHz, CDCl3) 165.9, 161.0, 133.9, 131.7, 129.9, 128.8, 128.6, 127.7,
126.7, 126.1, 125.5, 123.5, 68.9, 30.0, 14.3; TOF-HRMS calcd for
C15H15N2O2 (M + H)+ 255.1134, found 255.1139.
1
hexanes); H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.8 Hz, 2H),
8.12 (d, J = 8.8 Hz, 2H), 4.65 (q, J = 7.2 Hz, 2H), 1.54 (t, J = 7.2 Hz,
3H).
2-Ethoxy-5-(2-iodophenyl)-1,3,4-oxadiazole (2f): white solid
(0.1388 g, 81% yield); mp 52−53 °C; Rf 0.30 (10% EtOAc/hexanes);
1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 7.6, 1.6 Hz, 1H), 7.69
(dd, J = 7.6, 1.6 Hz, 1H), 7.41 (td, J = 7.6, 1.6 Hz, 1H), 7.13 (td, J =
7.6, 1.6 Hz, 1H), 4.59 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 165.9, 159.9, 141.2, 132.1,132.0,
130.9, 129.2, 128.2, 93.7, 69.4, 14.4; TOF-HRMS calcd for
C10H10IN2O2 (M + H)+ 316.9787, found 316.9784.
2-Ethoxy-5-styryl-1,3,4-oxadiazole (2n): white solid (0.0926 g,
1
79% yield); mp 57−59 °C; Rf 0.42 (20% EtOAc/hexanes); H NMR
(400 MHz, CDCl3) δ 7.50−7.48 (m, 2H), 7.40−7.31 (m, 4H), 6.87
(d, J = 16.4 Hz, 1H), 4.58 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 165.2, 160.5, 137.3, 134.9, 129.8,
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129.1, 127.4, 110.3, 69.3, 14.4; TOF-HRMS calcd for C12H13N2O2 (M
+ H)+ 217.0977, found 217.0971.
(m, 6H), 7.02−6.96 (m, 2H), 4.97 (s, 2H), 3.89 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 157.8, 153.6, 152.2, 135.2, 132.9, 129.4,
128.8, 128.2, 120.6, 112.8, 111.9, 55.9, 49.7; TOF-HRMS calcd for
C16H15N2O3 (M + H)+ 283.1083, found 283.1085.
4-(5-Ethoxy-1,3,4-oxadiazol-2-yl)phenol (2o): white solid (0.0749
1
g, 67% yield); mp 201−202 °C; Rf 0.30 (40% EtOAc/hexanes); H
3-Methyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3h):25 white solid
(0.0543 g, 75% yield); mp 105−106 °C; Rf 0.31 (10% EtOAc/
NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8
Hz, 2H), 4.51 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 165.2, 161.0, 160.2, 128.0, 116.0, 69.2,
14.3; TOF-HRMS calcd for C10H10N2NaO3 (M + Na)+ 229.0589,
found 229.0585.
1
hexanes); H NMR (400 MHz, CDCl3) δ 7.81−7.78 (m, 2H), 7.50−
7.41 (m, 3H), 3.47 (s, 3H).
3-Isobutyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3i):26 liquid
(0.0476 g, 53% yield); Rf 0.54 (10% EtOAc/hexanes); 1H NMR
(400 MHz, CDCl3) δ 7.84 (dd, J = 8.0, 1.6 Hz, 2H), 7.52−7.43 (m,
3H), 3.60 (d, J = 6.8 Hz, 2H), 2.21 (m, 1H), 0.99 (d, J = 6.8 Hz, 6H).
3-(Cyclohex-2-en-1-yl)-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3j):
liquid (0.0608 g, 61% yield); Rf 0.54 (10% EtOAc/hexanes); 1H
NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 2H), 7.50−7.42 (m,
3H), 6.05−6.02 (m, 1H), 5.67−5.64 (m, 1H), 4.80−4.74 (m, 1H),
2.11−1.91 (m, 4H), 1.81−1.64 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 153.3, 153.2, 132.4, 131.4, 128.9, 125.7, 125.1, 124.1, 52.1,
28.0, 24.3, 20.3; TOF-HRMS calcd for C14H15N2O2 (M + H)+
243.1134, found 243.1141.
2-Ethoxy-5-(pyridin-3-yl)-1,3,4-oxadiazole (2p): liquid (0.0871 g,
84% yield); Rf 0.30 (30% EtOAc/hexanes); 1H NMR (400 MHz,
CDCl3) δ 9.04 (s, 1H), 8.62 (d, J = 4.8 Hz, 1H), 8.12 (dd, J = 8.0, 2.0
Hz, 1H), 7.35−7.31 (m, 1H), 4.53 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 158.2, 151.8,
146.9, 133.1, 123.6, 120.5, 69.5, 14.2; TOF-HRMS calcd for
C9H10N3O2 (M + H)+ 192.0773, found 192.0776.
General Procedure for the Synthesis of 3,5-Disubstituted
1,3,4-Oxadiazol-2(3H)-ones 3. In a 9 mL Ace pressure tube,
oxadiazole 2 (0.41 mmol), alkyl halide (0.49 mmol), Et3N (0.0496 g,
0.49 mmol), KI (6.8 mg, 0.041 mmol) and DMF (1 mL) were added
before the mixture was placed in a preset oil bath at 120 °C. After
being stirred for 5 min, the crude mixture was purified by column
chromatography using 5−15% ethyl acetate in hexane.
3-(2-Methylbenzyl)-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3l):
white solid (1.2723 g, 91% yield); mp = 94−96 °C; Rf 0.41 (10%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 8.4, 1.6
Hz, 2H), 7.51−7.41 (m, 2H), 7.37−7.35 (m, 1H), 7.28−7.20 (m, 3H),
4.97 (s, 2H), 2.47 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.6,
153.4, 136.7, 133.0, 131.6, 130.7, 129.5, 128.9, 128.6, 126.4, 125.7,
123.9, 47.5, 19.4; TOF-HRMS calcd for C16H15N2O2 (M + H)+
267.1134, found 267.1137.
3-(Naphthalen-1-ylmethyl)-5-phenyl-1,3,4-oxadiazol-2(3H)-one
(3m): yellow solid (1.3382 g, 84% yield); mp = 119−121 °C; Rf 0.42
(15% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ δ 8.29 (d, J =
8.8 Hz, 1H), 7.88 (t, J = 8.0 Hz, 2H), 7.78−7.75 (m, 2H), 7.65−7.60
(m, 2H), 7.56−7.47 (m, 2H), 7.43−7.36 (m, 3H), 5.38 (s, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 153.5, 153.4, 133.9, 131.5, 131.3,
3-Benzyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3a):25 white solid
(0.0878 g, 85% yield); mp 112−115 °C; Rf 0.47 (10% EtOAc/hexanes
1
2 developed); H NMR (400 MHz, CDCl3 δ 7.85−7.80 (m, 2H),
7.49−7.31 (m, 8H), 4.95 (s, 2H).
3-(4-Bromobenzyl)-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3b):
white solid (0.1247 g, 92% yield); mp 118−120 °C; Rf 0.50 (20%
1
EtOAc/hexanes 2 developed); H NMR (400 MHz, CDCl3) δ 7.81
(dd, J = 8.4, 1.2 Hz, 2H), 7.52−7.42 (m, 5H), 7.29 (d, J = 8.4 Hz, 2H),
4.90 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.6, 153.5, 133.9,
132.1, 131.7, 130.1, 129.0, 125.8, 123.7, 122.6, 49.2; TOF-HRMS calcd
for C15H1279BrN2O2 (M + H)+ 331.0082, found 331.0089; calcd for
C15H1281BrN2O2 (M + H)+ 333.0062, found 333.0054.
130.5, 129.5, 128.9, 128.2, 127.0, 126.1, 125.7, 125.4, 123.8, 123.4,
47.7; TOF-HRMS calcd for C19H15N2O2 (M + H)+ 303.1134, found
303.1132.
3-(3-Methoxybenzyl)-5-phenyl-1,3,4-oxadiazol-2(3H)-one (3c):
white solid (0.1052 g, 91% yield); mp 78−80 °C; Rf 0.41 (10%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.2 Hz,
2H), 7.52−7.43 (m, 3H), 7.31−7.24 (m, 3H), 7.17 (d, J = 7.2 Hz,
1H), 4.94 (s, 2H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
153.6, 153.3, 138.6, 134.9, 131.5, 129.2, 129.0, 128.9, 128.8, 125.7,
125.4, 123.9, 49.8, 21.4; TOF-HRMS calcd for C16H15N2O3 (M + H)+
283.1083, found 283.1078.
5-Phenyl-1,3,4-oxadiazol-2(3H)-one (4):27 yellow solid (0.0265 g,
40% yield); mp 133−135 °C; Rf 0.30 (20% EtOAc/hexanes); 1H
NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.46−7.35 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 155.6, 155.1, 131.5, 128.9,
125.6, 123.9.
3-Ethyl-5-phenyl-1,3,4-oxadiazol-2(3H)-one (5):13 liquid (0.0352
5-Phenyl-3-(4-vinylbenzyl)-1,3,4-oxadiazol-2(3H)-one (3d): white
1
solid (0.1027 g, 90% yield); mp 124−125 °C; Rf 0.47 (10% EtOAc/
g, 45% yield); Rf 0.45 (10% EtOAc/hexanes); H NMR (400 MHz,
1
hexanes); H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 8.4, 1.6 Hz,
CDCl3) δ 7.83 (d, J = 8.4 Hz, 3H), 7.51−7.43 (m, 3H), 3.85 (d, J = 7.2
Hz, 2H), 1.40 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 153.5, 153.3, 145.4, 131.6, 129.1, 125.7, 124.1, 41.2, 13.6.
2H), 7.51−7.36 (m, 7H), 6.70 (dd, J = 17.6, 10.8 Hz, 1H), 5.75 (dd, J
= 17.6, 0.8 Hz, 1H), 5.26 (dd, J = 10.8, 0.8 Hz, 1H), 4.94 (s, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 153.7, 153.5, 137.9, 136.3, 134.5,
131.7, 129.0, 128.7, 126.8, 125.8, 123.9, 114.6, 49.6; TOF-HRMS calcd
ASSOCIATED CONTENT
for C17H15N2O2 (M + H)+ 279.1134, found 279.1131.
■
5-(4-Chlorophenyl)-3-(4-vinylbenzyl)-1,3,4-oxadiazol-2(3H)-one
(3e): white solid (0.1100 g, 86% yield); mp 126−128 °C; Rf 0.45 (10%
EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz,
2H), 7.43−7.36 (m, 6H), 6.70 (dd, J = 17.6, 10.8 Hz, 1H), 5.75 (d, J =
17.6 Hz, 1H), 5.26 (d, J = 10.8 Hz, 1H), 4.92 (s, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 153.4, 152.7, 137.95, 137.89, 136.3, 134.3, 129.4,
128.7, 127.1, 126.8, 122.4, 114.7, 49.7; TOF-HRMS calcd for
C17H1435ClN2O2 (M + H)+ 313.0744, found 313.0761; calcd for
C17H1437ClN2O2 (M + H)+ 315.0714, found 315.0712.
3-Benzyl-5-(4-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one (3f): yellow
solid (0.0901 g, 74% yield); mp 153−155 °C; Rf 0.30 (10% EtOAc/
hexanes 2 developed); 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 9.2
Hz, 2H), 8.00 (d, J = 9.2 Hz, 2H), 7.44−7.33 (m, 5H), 4.98 (s, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 153.1, 151.5, 149.4, 134.5, 129.4,
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01863.
Copies of 1H NMR of all products and 13C NMR spectra
for new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mookdap55@gmail.com. Fax: (+) 66-53-892277.
ORCID
129.1, 128.7, 128.5, 126.6, 124.4, 50.2; TOF-HRMS calcd for
C15H12N3O4 (M + H) 298.0828, found 298.0834.
3-Benzyl-5-(2-methoxyphenyl)-1,3,4-oxadiazol-2(3H)-one (3g):
liquid (0.0994 g, 86% yield); Rf 0.41 (10% EtOAc/hexanes); 1H
NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 7.8, 1.6 Hz, 1H), 7.46−7.29
Wong Phakhodee: 0000-0002-5489-9555
Mookda Pattarawarapan: 0000-0002-7484-122X
+
Notes
The authors declare no competing financial interest.
F
DOI: 10.1021/acs.joc.7b01863
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(18) Guo, C.-X.; Zhang, W.-Z.; Zhang, N.; Lu, X.-B. J. Org. Chem.
2017, 82, 7637.
ACKNOWLEDGMENTS
■
Financial support from the Center of Excellence for Innovation
in Chemistry (PERCH-CIC), Office of the Higher Education
Commission, Ministry of Education, Thailand, and Center of
Excellence in Materials Science and Technology under the
administration of Materials Science Research Center, Faculty of
Science, Chiang Mai University is gratefully acknowledged.
Special appreciation to Chulabhorn Research Institute (CRI),
Thailand, for the ESI-MS analysis.
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DOI: 10.1021/acs.joc.7b01863
J. Org. Chem. XXXX, XXX, XXX−XXX