Synthesis of 1,2,4-Oxadiazoles by Tandem Reaction of Nitroalkenes with Arenes and Nitriles in the Superacid TfOH

Article abstract of DOI:10.1021/acs.joc.9b00812

The tandem reaction of nitroalkenes with arenes and nitriles in the superacid CF₃SO₃H (TfOH) results in the formation of 1,2,4-oxadiazole derivatives in yields up to 96%. This reaction proceeds via the consequent interaction of arenes and nitriles, as nucleophiles, with intermediate cationic species derived by the protonation of nitroalkenes in TfOH. This is novel and general synthesis of 1,2,4-oxadiazoles, which are very important compounds for medicinal chemistry.

Full text of DOI:10.1021/acs.joc.9b00812

Note
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Synthesis of 1,2,4-Oxadiazoles by Tandem Reaction of Nitroalkenes
with Arenes and Nitriles in the Superacid TfOH
Andrei A. Golushko,† Olesya V. Khoroshilova,‡ and Aleksander V. Vasilyev*,†,§
†Department of Organic Chemistry, Institute of Chemistry, Saint Petersburg State University, Universitetskaya nab., 7/9, Saint
Petersburg 199034, Russia
‡Center for X-ray Diffraction Studies, Research Park, Saint Petersburg State University, Universitetskiy pr., 26, Saint Petersburg,
Petrodvoretz 198504, Russia
§Department of Chemistry, Saint Petersburg State Forest Technical University, Institutsky per., 5, Saint Petersburg 194021, Russia
S
* Supporting Information
ABSTRACT: The tandem reaction of nitroalkenes with arenes and
nitriles in the superacid CF3SO3H (TfOH) results in the formation
of 1,2,4-oxadiazole derivatives in yields up to 96%. This reaction
proceeds via the consequent interaction of arenes and nitriles, as
nucleophiles, with intermediate cationic species derived by the
protonation of nitroalkenes in TfOH. This is novel and general synthesis of 1,2,4-oxadiazoles, which are very important
compounds for medicinal chemistry.
Scheme 1. Main Current Methods for the Synthesis of 1,2,4-
Oxadiazoles
INTRODUCTION
■
a
1,2,4-Oxadiazoles are important heterocyclic compounds due
to their various kinds of biological activity. Several reviews on
the syntheisis of 1,2,4-oxadiazole derivatives and study of their
properties have been recently published.1−11 In medicinal
chemistry oxadiazoles are considered as bioisosteric analogues
of ester or amide groups.12 1,2,4-Oxadiazole ring is found in
many drugs. For instance, Butalamine is a coronary vasodilator
and local anesthetic,13 Libexin is a cough suppressant,14 and
Ataluren is used for the treatment of fibrosis (Figure 1).15
Nowadays, further progress in the synthesis of oxadiazole
derivatives and studies on their properties are actual goals in
chemistry, biology, and medicine.
a
From literature data.
acid CF3SO3H (triflic acid, TfOH) affording the correspond-
ing oximes of 3,3,3-trihalogeno-1,2-diarylpropan-1-ones II
(Scheme 2).30 This reaction proceeds through the series of
cationic intermediates A−E; some of them, A, C, E, were
caught by NMR in TfOH to prove the reaction mechanism. In
this reaction two arene molecules (π-nucleophiles) react
consequently with cations A and then C leading to oximes
II.30 One of the key intermediates of this transformation is
cation C, which was specially generated at low temperature
−40 °C in TfOH and studied by means of NMR.30 These
species are stable under these conditions and react very slowly
with second arene molecule at −40 °C in TfOH with the
formation of structures D and then cations E.
Figure 1. Examples of drugs containing 1,2,4-oxadiazole structure.
There are two main methods for the construction of 1,2,4-
oxadiazole ring. The first one is O-acylation of amidoximes by
carboxylic acids or their derivatives followed by cascade
cyclization-dehydration leading to target oxadiazoles (see data
in reviews3,6,9,11 and recent papers on similar procedures16−24
)
The main idea of the present study was to generate cations
C from various nitroalkenes 1 under their reactions with arenes
in TfOH and subject these species to consequent interaction
with nitriles, as n-nucleophiles. In this case, one may expect an
(amidoxime route in Scheme 1). Another approach is based on
the [3 + 2] cycloaddition of nitriles with nitrile oxides25 or silyl
nitronates26 (Scheme 1 and data in reviews6,9,11). One more
method is based on the transformations of aldoximes.2,5,6,27
On the basis of our studies on electrophilic activation of
organic compounds,28,29 we recently described reactions of
3,3,3-trihalogeno-1-nitropropenes I with arenes in the super-
Received: March 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00812
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Scheme 2. Reactions of CHaI3-Nitroethylenes I with Arenes in TfOH Leading to Oximes II
a
Data from ref 30.
a
Scheme 3. Main Idea of the Present Work
a
Tandem reaction of arenes and nitriles with cations generated from nitroalkenes 1 in the superacid TfOH.
intermediate formation of species F and, then, compound G,
which may finally lead to 1,2,4-oxadiazole 2 (Scheme 3).
Thus, the main goal of this work was a study of tandem
reaction of nitroalkenes with arenes and nitriles under the
superelectrophilic activation conditions in TfOH.
Scheme 5. Reactions of Nitroalkene 1a with Various Arenes
and Acetonitrile in TfOH Leading to Oxadiazoles 2f−2n
RESULTS AND DISCUSSION
We started with checking reactions of CCl3-nitroethylene 1a
with benzene and various nitriles in TfOH (Scheme 4). The
■
Scheme 4. Reactions of Nitroalkene 1a with Benzene and
Various Nitriles in TfOH Leading to Oxadiazoles 2a−2e
reaction was performed in a one-pot, two-step procedure. First,
nitroalkene 1a was added to a mixture of benzene (1.5 equiv)
with TfOH and CH2Cl2 at −40 °C to generate species C
during 1.5 h (see Schemes 2 and 3). It is critical for this step to
keep temperatire at −40 °C, since at higher temperature
cations C undergo consequent transformations.30 Then, the
superacidic solution was quenched (for 10 min) with an excess
of a nitrile or with a mixture of nitrile and pyridine (the last
one was used to neutralize TfOH) and cooled to ca. −30 to
−20 °C. Indeed, this method afforded the series of oxadiazoles
2a−2e (Scheme 4). It should be specially mentioned that
addition of pyridine is crucial for quenching of superacidic
solutions of cations C with benzonitrile and cyclopropylnitrile,
since these particular nitriles are easily cyclized into the
corresponding 1,3,5-triazines in TfOH. Addition of pyridine
decreases significantly the amount of triazine byproducts.
Then, the reaction scope with various arenes (1.5 equiv) was
studied using 1a and acetonitrile, which gave oxadiazoles 2f−
2n in yields up to 94% (Scheme 5). Besides benzene, other
arenes, toluene, xylenes (dimethylbenzene), pseudocumene
(1,2,4-trimethylbenzene), anisole (methoxybenzene), veratrole
(1,2-dimethoxybenzene), and even sterically hindered sub-
strates mesitylene (1,3,5-trimethylbenzene) and durene
(1,2,4,5-tetramethylbenzene), were successfully involved in
this reaction (Scheme 5). Note that the presence of the
trichloromethyl substituent in oxadiazoles 2a−2n provides
opportunities for further structural modification of these
molecules by transformation of CCl3 group into, for instance,
the carboxylic one and many others.
Apart from compound 1a, different nitrostyrenes 1b−1f
took part in the reaction affording oxadiazoles 2o−2zb in good
yields, up to 96% (Scheme 6). In general, the yields of
oxadiazoles 2o−2zb, prepared from aryl substituted nitro-
ethylenes 1b−1f (Scheme 6), are higher compared to the
yields of oxadiazoles 2a−2n, obtained from CCl3-substituted
nitroethylene 1a (Schemes 4 and 5). It could be explained by
higher stability of intermediate diaryl substituted cations C (R
B
DOI: 10.1021/acs.joc.9b00812
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
minimization. Additional crystallographic information is available in
the Supporting Information.
Scheme 6. Reactions of Nitrostyrenes 1b−1f with Arenes
and Nitriles in TfOH Leading to Oxadiazoles 2o−2zb
Starting nitroalkenes were synthesized according to the literature
procedures for 1a33 and for 1b−1f.34
General Procedure for the Synthesis of 1,2,4-Oxadiazoles 2.
Nitroalkene 1 (0.16 mmol) was added to a mixture of TfOH (0.7
mL), CH2Cl2 (0.3 mL), and arene (0.24 mmol) at −40 °C. After it
was stirred at −40 °C for 1.5 h, the reaction mixture was poured at
once into nitrile (5 mL; in case of benzonitrile and cyclo-
propanecarbonitrile −2.00 mmol solution in 5 mL of CH2Cl2 and
pyridine, 50 mg) cooled to −30 °C. The resulting solution was heated
to −20 °C and stirred at this temperature for 10 min, then quenched
with water (10 mL) and extracted with CHCl3 (3 × 10 mL). The
combined organic phases were washed three times with water (20
mL), then dried with Na2SO4. Solvent was evaporated under the
reduced pressure. In some cases, reaction products were additionally
purified by preparative TLC on silica gel with elution by petroleum
ether−ethyl acetate mixtures (v/v) (see an eluent mixture for each
compound below).
Large Scale Procedure for the Synthesis of Oxadiazole 2a.
A solution of nitroalkene 1a (1.6 mmol) in CH2Cl2 (0.5 mL) was
dropwise added to a mixture of TfOH (3 mL), CH2Cl2 (1 mL), and
arene (2.4 mmol) at −40 °C. After it was stirred at −40 °C for 2 h,
the reaction mixture was poured at once into acetonitrile (20 mL)
cooled to −30 °C. The resulting solution was heated to room
temperature, then quenched with water (10 mL) and extracted with
CHCl3 (3 × 20 mL). The combined organic phases were washed with
saturated aqueous solution of NaHCO3 (20 mL) and three times with
water (20 mL), then dried with Na2SO4. Solvent was evaporated
under the reduced pressure; purification was performed by column
chromatography with a mixture of petroleum ether (40−70)−ethyl
acetate, 9:1 (v/v). Yield 192 mg (41%).
5-Methyl-3-(2,2,2-trichloro-1-phenylethyl)-1,2,4-oxadiazole
(2a). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), benzene
(19 mg, 0.24 mmol), and acetonitrile (5 mL). Yield 30 mg (65%).
1
Transparent oil. H NMR, δ, ppm: 2.63 s (3H), 5.31 s (1H), 7.37−
7.41 m (3H), 7.76−7.79 m (2H). 13C{1H} NMR, δ, ppm: 12.6, 63.1,
98.8, 128.4, 129.4, 131.5, 133.2, 167.7, 176.8. IR (KBr, cm−1): 1580
(CN). HRMS (ESI-time-of-flight (TOF)) m/z: [M + H]+ Calcd
for C11H10Cl3N2O 290.9854; Found 290.9858.
= Ar′ in Scheme 3) and, therefore, higher selectivity of
reactions of these species.
Structures of compounds 2i, 2n, 2o, and 2x were
additionally confirmed by X-ray analysis data (see Supporting
Information).
5-Ethyl-3-(2,2,2-trichloro-1-phenylethyl)-1,2,4-oxadiazole
(2b). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), benzene
(19 mg, 0.24 mmol), and propionitrile (5 mL). Yield 18 mg (38%).
Transparent oil. Purification by preparative TLC with mixture of
CONCLUSION
■
1
We have developed a novel synthesis of 1,2,4-oxadiazoles
based on the tandem reaction of nitroalkenes with arenes and
nitriles in the superacid TfOH. This reaction is a general
method for the synthesis of 1,2,4-oxadiazole derivatives. The
method is tolerant to various substituents in starting
compounds (nitroalkenes, arenes, and nitriles), at least, to
groups, which are stable under superacidic solvation.
petroleum ether−ethyl acetate, 9:1. H NMR, δ, ppm: 1.41 t (3H, J
7.6 Hz), 2.95 q (2H, J 7.6 Hz), 5.32 s (1H), 7.34−7.50 m (3H),
7.75−7.82 m (2H). 13C{1H} NMR, δ, ppm: 10.8, 20.5, 63.3, 98.9,
128.4, 129.3, 131.6, 133.2, 167.5, 180.9. IR (KBr, cm−1): 1578 (C
N). HRMS (ESI-TOF) m/z: [M + Ag]+ Calcd for C12H11Cl3N2OAg
410.8997; Found 410.8982.
5-Chloromethyl-3-(2,2,2-trichloro-1-phenylethyl)-1,2,4-oxa-
diazole (2c). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol),
benzene (19 mg, 0.24 mmol), and chloroacetonitrile (5 mL).
Transparent oil. 1H NMR, δ, ppm: 4.72 s (2H), 5.37 s (1H),
7.39−7.42 m (3H), 7.76−7.78 m (2H). 13C{1H} NMR, δ, ppm: 33.4,
63.1, 98.6, 128.5, 129.5, 131.5, 132.8, 168.2, 174.6. IR (KBr, cm−1):
1585 (CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C11H8Cl4N2ONa 348.9254; Found 348.9250.
EXPERIMENTAL SECTION
■
The NMR spectra of solutions of compounds in CDCl3 were
recorded at 400, 376, and 100 MHz for 1H, 19F, and 13C NMR
spectra, respectively, at 23 °C. The hydrogen residual signals of
1
CDCl3 (δ 7.26 ppm) for H NMR spectra and the carbon signals of
CDCl3 (δ 77.0 ppm) for 13C NMR were used as references. 19F NMR
were indirectly referred to the signal of CFCl3 (δ 0.0 ppm). IR spectra
of compounds were taken in KBr. High-resolution mass spectrometry
(HRMS) was performed in electrospray ionization (ESI) mode. The
preparative reactions were monitored by thin-layer chromatography
(TLC) performed on silica gel plates using UV light for detection.
Preparative TLC was performed on silica gel 5−40 μm.
X-ray Diffraction Study. A suitable crystal was selected and
studied on the diffractometer. The crystal was kept at 100(2) K
during data collection. With Olex2,31 the structure was solved with
the ShelXS32 structure solution program using Direct Methods and
refined with the ShelXL refinement package using Least Squares
5-Cyclopropyl-3-(2,2,2-trichloro-1-phenylethyl)-1,2,4-oxa-
diazole (2d). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol),
benzene (19 mg, 0.24 mmol), and cyclopropanecarbonitrile (172 mg,
2.56 mmol). Yield 18 mg (35%). Transparent oil. Purification by
preparative TLC with a mixture of petroleum ether−ethyl acetate, 9:1.
1H NMR, δ, ppm: 1.23−1.28 m (4H), 2.20−2.27 m (1H), 5.26 s
(1H), 7.37−7.40 m (3H), 7.76−7.78 m (2H). 13C{1H} NMR, δ,
ppm: 8.0, 10.58, 10.60, 63.2, 99.0, 128.3, 129.3, 131.6, 133.2, 167.5,
181.7. IR (KBr, cm−1): 1581(CN). HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C13H11Cl3N2ONa 338.9830; Found 338.9830.
3-(2,2,2-Trichloro-1-phenylethyl)-5-phenyl-1,2,4-oxadiazole
(2e). Obtained from the nitroalkene 1a (30 mg, 0.16 mmol), benzene
C
DOI: 10.1021/acs.joc.9b00812
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(19 mg, 0.24 mmol), and benzonitrile (230 mg, 2.24 mmol). Yield 16
mg (28%). Transparent oil. Purification by preparative TLC with
mixture of petroleum ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 5.41
s (1H), 7.40−7.41 m (3H), 7.52−7.56 m (2H), 7.59−7.63 m (1H),
7.85−7.88 m (2H), 8.16−8.19 m (2H). 13C{1H} NMR, δ, ppm: 63.3,
99.0, 124.1, 128.4, 128.4, 129.3, 129.4, 131.7, 133.2, 133.2, 168.3,
175.9. IR (KBr, cm−1): 1562 (CN). HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C16H12Cl3N2O 353.0010; Found 353.0007.
3-(2,2,2-Trichloro-1-(4-methylphenyl)ethyl)-5-methyl-1,2,4-
oxadiazole (2f). Obtained from the nitroalkene 1a (30 mg, 0.16
mmol), toluene (22 mg, 0.24 mmol), and acetonitrile (5 mL). Yield
25 mg (53%). Transparent oil. Purification by preparative TLC with
mixture of petroleum ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 2.36
s (3H), 2.62 s (3H), 5.28 s (1H), 7.20 d (2H, J 7.95 Hz), 7.64−7.66
m (2H). 13C{1H} NMR, δ, ppm: 12.6, 21.3, 62.9, 99.1, 129.1, 130.3,
131.4, 139.4, 167.8, 176.8. IR (KBr, cm−1): 1585 (CN). HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C12H11Cl3N2ONa 326.9830;
Found 326.9830.
acetonitrile (5 mL). Yield 19 mg (34%). Reddish solid, mp 139−140
°C. Purification by preparative TLC with mixture of petroleum
1
ether−ethyl acetate, 9:1. H NMR, δ, ppm: 2.07 s (CH3), 2.16 s
(CH3), 2.31 s (CH3), 2.48 s (CH3), 2.59 s (CH3), 6.04 s (1H), 7.05 s
(1H). 13C{1H} NMR, δ, ppm: 12.4, 18.3, 19.1, 20.9, 21.8, 60.1, 98.9,
132.1, 133.3, 134.45, 134.51, 135.9, 136.1, 168.8, 176.3. IR (KBr):
1588 cm−1 (CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C15H17Cl3N2ONa 369.0299; Found 369.0299.
3-(2,2,2-Trichloro-1-(4-methoxyphenyl)ethyl)-5-methyl-
1,2,4-oxadiazole (2m). Obtained from the nitroalkene 1a (30 mg,
0.16 mmol), methoxybenzene (25 mg, 0.24 mmol), and acetonitrile
(5 mL). Yield 17 mg (33%). Transparent oil. Purification by
preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1.
1H NMR, δ, ppm: 2.63 s (3H), 3.81 s (3H), 5.25 s (1H), 6.88−6.92
m (2H), 7.67−7.70 m (2H). 113C{1H} NMR, δ, ppm: 12.6, 55.4, 62.5,
99.3, 113.8, 125.2, 132.8, 160.4, 167.8, 176.8. IR (KBr, cm−1): 1588
(CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C12H11Cl3N2O2Na 342.9779; Found 342.9775.
3-(2,2,2-Trichloro-1-(3,4-dimethylphenyl)ethyl)-5-methyl-
1,2,4-oxadiazole (2g). Obtained from the nitroalkene 1a (30 mg,
0.16 mmol), 1,2-dimethylbenzene (25 mg, 0.24 mmol), and
3-(2,2,2-Trichloro-1-(2,5-dimethoxylphenyl)ethyl)-5-meth-
yl-1,2,4-oxadiazole (2n). Obtained from the nitroalkene 1a (30 mg,
0.16 mmol), 1,2-dimethoxybenzene (33 mg, 0.24 mmol), and
acetonitrile (5 mL). Yield 19 mg (34%). Yellowish solid, mp 144−
146 °C. Purification by preparative TLC with mixture of petroleum
ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 2.63 s (3H), 3.88 s (3H),
3.90 s (3H), 5.24 s (1H), 6.86 d (1H, J 8.4 Hz), 7.28 dd (1H, J 8.4,
2.2 Hz), 7.34 d (1H, J 2.2 Hz). 13C{1H} NMR, δ, ppm: 12.6, 56.0,
56.2, 62.8, 99.2, 110.7, 114.6, 124.4, 125.4, 148.6, 145.0, 167.8, 176.7.
IR (KBr, cm−1): 1578 (CN). HRMS (ESI-TOF) m/z: [M + Ag]+
Calcd for C13H13Cl3N2O3Ag 456.9057; Found 456.9037.
5-Methyl-3-(diphenylmethyl)-1,2,4-oxadiazole (2o). Ob-
tained from the β-nitrostyrene 1b (30 mg, 0.2 mmol), benzene (16
mg, 0.2 mmol), and acetonitrile (5 mL). Yield 19 mg (34%).
Colorless solid, mp 75−76 °C. Purification by preparative TLC with
mixture of petroleum ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 2.57
s (3H), 5.60 s (1H), 7.24−7.38 m (10H). 13C{1H} NMR, δ, ppm:
12.6, 48.8, 127.4, 128.8, 128.9, 139.7, 171.8, 176.8. IR (KBr, cm−1):
1586 (CN). HRMS (ESI-TOF) m/z: [M + Ag]+ Calcd for
C16H14N2OAg 357.0161; Found 357.0152.
3-(Diphenylmethyl)-5-phenyl-1,2,4-oxadiazole (2p). Ob-
tained from the β-nitrostyrene 1b (30 mg, 0.2 mmol), benzene (16
mg, 0.2 mmol), and benzonitrile (200 mg, 2.0 mmol). Yield 50 mg
(79%). Transparent oil. 1H NMR, δ, ppm: 5.72 s (1H), 7.28−7.31 m
(2H), 7.35−7.39 m (4H), 7.44−7.45 m (4H), 7.49−7.53 m (2H),
7.56−7.60 m (1H), 8.15−8.17 m (2H). 13C{1H} NMR, δ, ppm: 49.0,
124.4, 127.3, 128.3, 128.7, 129.0, 129.1, 132.8, 139.9, 172.4, 175.9. IR
(KBr, cm−1): 1561. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C21H16N2ONa 335.1155; Found 335.1162.
1
acetonitrile (5 mL). Yield 48 mg (94%). Transparent oil. H NMR,
δ, ppm: 2.27 s (3H), 2.29 s (3H), 2.63 s (3H), 5.26 s (1H), 7.14−
7.17 m (1H), 7.50−7.51 m (2H). 13C{1H} NMR, δ, ppm: 12.6, 19.7,
20.0, 63.0, 99.0, 128.8, 129.7, 130.6, 132.5, 136.7, 138.0, 167.8, 176.7.
IR (KBr, cm−1): 1585 (CN). HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C13H13Cl3N2ONa 340.9986; Found 340.9987.
3-(2,2,2-Trichloro-1-(2,4-dimethylphenyl)ethyl)-5-methyl-
1,2,4-oxadiazole (2h). Obtained from the nitroalkene 1a (30 mg,
0.16 mmol), 1,3-dimethylbenzene (25 mg, 0.24 mmol), and
1
acetonitrile (5 mL). Yield 45 mg (88%). Yellowish oil. H NMR, δ,
ppm: 2.32 s (3H), 2.54 s (3H), 2.60 s (3H), 5.67 s (1H), 7.06−7.08
m (2H), 8.02−8.05 m (1H). 13C{1H} NMR, δ, ppm: 12.6, 20.7, 21.2,
57.2, 99.6, 126.9, 129.3, 130.3, 131.8, 138.0, 139.1, 168.0, 176.7. IR
(KBr, cm−1): 1585 (CN). HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C13H13Cl3N2ONa 340.9986; Found 340.9990.
3-(2,2,2-Trichloro-1-(2,5-dimethylphenyl)ethyl)-5-methyl-
1,2,4-oxadiazole (2i). Obtained from the nitroalkene 1a (30 mg,
0.16 mmol), 1,4-dimethylbenzene (25 mg, 0.24 mmol), and
acetonitrile (5 mL). Yield 30 mg (59%). Colorless solid, mp 97−97
°C. Purification by preparative TLC with mixture of petroleum
ether−ethyl acetate, 9:1. 1H NMR, δ, ppm: 2.35 s (3H), 2.54 s (3H),
2.61 s (3H), 5.69 s (1H), 7.04−7.15 m (2H), 7.92 s (1H). 13C{1H}
NMR, δ, ppm: 12.6, 20.3, 21.3, 57.5, 99.4, 130.0, 130.8, 130.9, 132.0,
135.0, 135.7, 167.9, 176.7. IR (KBr, cm−1): 1582 (CN). HRMS
(ESI-TOF) m/z: [M + Ag]+ Calcd for C13H13Cl3N2OAg 424.9153;
Found 424.9139.
3-(2,2,2-Trichloro-1-(2,4,5-trimethylphenyl)ethyl)-5-methyl-
1,2,4-oxadiazole (2j). Obtained from the nitroalkene 1a (30 mg,
0.16 mmol), 1,2,4-trimethylbenzene (28 mg, 0.24 mmol), and
5-Cyclopropyl-3-(diphenylmethyl)-1,2,4-oxadiazole (2q).
Obtained from the β-nitrostyrene 1b (30 mg, 0.2 mmol), benzene
(16 mg, 0.2 mmol), and cyclopropanecarbonitrile (135 mg, 2.0
mmol). Yield 41 mg (74%). Transparent oil. 1H NMR, δ, ppm: 1.17−
1.24 m (4H), 2.17−2.23 m (1H), 5.56 s (1H), 7.24−7.28 m (2H),
7.31−7.35 m (8H). 13C{1H} NMR, δ, ppm: 8.0, 10.2, 48.9, 127.3,
128.7, 128.9, 139.9, 171.6, 181.6. IR (KBr, cm−1): 1581. HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C18H16N2ONa 299.1155; Found
299.1160.
1
acetonitrile (5 mL). Yield 49 mg (92%). Transparent oil. H NMR,
δ, ppm: 2.23 s (3H), 2.26 s (3H), 2.52 s (3H), 2.61 s (3H), 5.65 s
(1H), 7.02 s (1H), 7.86 s (1H). 13C{1H} NMR, δ, ppm: 12.6, 19.5,
19.7, 20.1, 57.4, 99.6, 129.5, 131.3, 132.3, 134.3, 135.3, 137.8, 168.0,
176.6. IR (KBr, cm−1): 1586 (CN). HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C14H15Cl3N2ONa 355.0143; Found 355.0146.
5-Methyl-3-(2,2,2-trichloro-1-(2,4,6-trimethylphenyl)ethyl)-
1,2,4-oxadiazole (2k). Obtained from the nitroalkene 1a (30 mg,
0.16 mmol), 1,3,5-trimethylbenzene (28 mg, 0.24 mmol), and
acetonitrile (5 mL). Yield 22 mg (42%). Yellowish oil. Purification
by preparative TLC with mixture of petroleum ether−ethyl acetate,
9:1. 1H NMR, δ, ppm: 2.18 s (3H), 2.27 s (3H), 2.58 s (3H), 2.60 s
(3H), 5.83 s (1H), 6.85 s (1H), 6.97 s (1H). 13C{1H} NMR, δ, ppm:
12.4, 21.0, 22.1, 22.8, 60.0, 98.8, 129.1, 130.1, 132.1, 138.3, 138.9,
139.9, 168.2, 176.3. IR (KBr): 1588 cm−1 (CN). HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C14H16Cl3N2O 333.0323; Found
333.0320.
3-((2,5-Dimethylphenyl)phenylmethyl)-5-methyl-1,2,4-oxa-
diazole (2r). Obtained from the β-nitrostyrene 1b (30 mg, 0.2
mmol), p-xylene (22 mg, 0.2 mmol), and acetonitrile (5 mL). Yield 52
1
mg (93%). Yellow solid, mp 102−104 °C. H NMR (CDCl3, 400
MHz) δ, ppm: 7.35−7.31 (m, 2H), 7.28−7.27 (m, 1H), 7.25−7.24
(m, 1H), 7.10−7.06 (m, 2H), 7.02−7.00 (m, 1H), 5.76 (s, 1H), 2.58
(s, 3H), 2.28 (s, 6H). 13C{1H} NMR (CDCl3, 101 MHz) δ, ppm:
176.6, 171.9, 139.1, 137.4, 135.6, 133.2, 130.6, 129.3, 128.9, 128.6,
128.1, 127.1, 45.3, 21.2, 19.3, 12.5. IR (KBr, cm−1): 1586 (CN).
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H19N2O 279.1492;
Found 279.1501.
5-Methyl-3-(2,2,2-trichloro-1-(2,3,5,6-tetramethylphenyl)-
ethyl)-1,2,4-oxadiazole (2l). Obtained from the nitroalkene 1a (30
mg, 0.16 mmol), 1,2,4,5-tetramethylbenzene (25 mg, 0.19 mmol), and
3-((3,4-Dimethylphenyl)-phenylmethyl)-5-phenyl-1,2,4-ox-
adiazole (2s). Obtained from the β-nitrostyrene 1b (30 mg, 0.2
mmol), o-xylene (22 mg, 0.2 mmol), and benzonitrile (200 mg, 2.0
D
DOI: 10.1021/acs.joc.9b00812
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
1
mmol). Yield 47 mg (69%). Yellowish oil. H NMR, δ, ppm: 2.26 s
(6H), 5.66 s (1H), 7.12−7.20 m (3H), 7.27−7.30 m (1H), 7.34−7.38
m (2H), 7.43−7.45 m (2H), 7.49−7.53 m (2H), 7.56−7.60 m (1H).
13C{1H} NMR, δ, ppm: 19.5, 20.0, 48.7, 124.5, 126.4, 127.2, 128.3,
acetonitrile (5 mL). Yield 46 mg (90%). Yellowish oil. H NMR, δ,
ppm: 2.25 s (3H), 2.27 s (3H), 2.59 s (3H), 5.70 s (1H), 6.99−7.01
m (2H), 7.08 d (1H, J 7.5 Hz), 7.16−7.18 m (2H), 7.27−7.30 m
(2H). 13C{1H} NMR, δ, ppm: 12.6, 19.4, 21.3, 44.8, 128.4, 128.9,
129.2, 130.4, 130.9, 133.19, 133.21, 135.9, 137.0, 137.8, 171.7, 176.9.
IR (KBr, cm−1): 1587 (CN). HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C18H18ClN2O 313.1101; Found 313.1102.
128.7, 129.0, 129.1, 130.0, 130.2, 132.7, 135.7, 136.9, 137.3, 140.1,
172.6, 175.8. IR (KBr, cm−1): 1562. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C23H21N2O 341.1649; Found 341.1656.
3-((4-Bromophenyl)phenylmethyl)-5-methyl-1,2,4-oxadia-
zole (2za). Obtained from the p-bromo-β-nitrostyrene 1f (30 mg,
0.13 mmol), bezene (15 mg, 0.2 mmol), and acetonitrile (5 mL).
Yield 42 mg (93%). Yellowish oil. 1H NMR, δ, ppm: 2.58 s (3H), 5.44
s (1H), 7.20−7.22 m (2H), 7.27−7.35 m (5H), 7.44−7.46 m (2H).
13C{1H} NMR, δ, ppm: 12.6, 48.2, 121.5, 127.6, 128.8, 128.9, 130.7,
5-Methyl-3-((4-methylphenyl)phenylmethyl)-1,2,4-oxadia-
zole (2t). Obtained from the p-methyl-β-nitrostyrene 1c (30 mg, 0.18
mmol), benzene (22 mg, 0.28 mmol), and acetonitrile (5 mL). Yield
1
39 mg (81%). Yellowish oil. H NMR, δ, ppm: 2.34 s (3H), 2.57 s
(3H), 5.57 s (1H), 7.15 d (2H, J 7.9), 7.24 d (2H, J 8.1 Hz), 7.26−
7.36 m (5H). 13C{1H} NMR, δ, ppm: 12.6, 21.1, 48.4, 127.3, 128.7,
128.78, 128.84, 129.4, 136.7, 137.0, 139.9, 172.0, 176.7. IR (KBr,
cm−1): 1587 (CN). HRMS (ESI-TOF) m/z: [M + Ag]+ Calcd for
C17H16N2OAg 371.0320; Found 371.0308.
131.9, 138.8, 139.2, 171.4, 177.0. IR (KBr, cm−1): 1585 (CN).
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H14BrN2O
329.0294; Found 329.0284.
3-((4-Bromophenyl)-(2,5-dimethylphenyl)methyl)-5-meth-
yl-1,2,4-oxadiazole (2zb). Obtained from the p-bromo-β-nitro-
styrene 1f (30 mg, 0.13 mmol), p-xylene (21 mg, 0.2 mmol), and
3-((2,5-Dimethylphenyl)-(4-methylphenyl)methyl)-5-meth-
yl-1,2,4-oxadiazole (2u). Obtained from the p-methyl-β-nitro-
styrene 1c (30 mg, 0.18 mmol), p-xylene (29 mg, 0.28 mmol), and
1
1
acetonitrile (5 mL). Yield 45 mg (96%). Yellowish oil. H NMR, δ,
acetonitrile (5 mL). Yield 34 mg (64%). Yellowish oil. H NMR, δ,
ppm: 2.25 s (3H), 2.27 s (3H), 2.60 s (3H), 5.68 s (1H), 7.00 d (2H,
J 10.1 Hz) 7.07−7.12 m (3H), 7.44 d (2H, J 8.44 Hz). 13C{1H}
NMR, δ, ppm: 12.6, 19.4, 21.3, 44.9, 121.3, 128.5, 129.2, 130.8, 130.9,
131.8, 133.2, 135.9, 137.0, 138.3, 171.6, 176.9. IR (KBr, cm−1): 1586
(CN). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H18BrN2O
357.0610; Found 357.0597.
ppm: 2.26 s (3H), 2.28 s (3H), 2.33 s (3H), 2.58 s (3H), 5.70 s (1H),
6.98−7.01 m (1H), 7.03−7.08 m (2H), 7.13 s (4H). 13C{1H} NMR,
δ, ppm: 12.6, 19.4, 21.2, 21.3, 45.1, 128.1, 128.9, 129.3, 129.4, 130.7,
133.2, 135.7, 136.1, 136.8, 137.7, 172.2, 176.7. IR (KBr, cm−1): 1587
(CN). HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C19H20N2ONa 315.1458; Found 315.1468.
3-((4-Methylphenyl)phenylmethyl)-5-phenyl-1,2,4-oxadia-
zole (2v). Obtained from the p-methyl-β-nitrostyrene 1c (30 mg,
0.18 mmol), benzene (22 mg, 0.28 mmol), and benzonitrile (98 mg,
0.93 mmol). Yield 19 mg (32%). Transparent oil. Purification by
preparative TLC with mixture of petroleum ether−ethyl acetate, 9:1.
1H NMR, δ, ppm: 2.33 s (3H), 5.65 s (1H), 7.15 d (2H, J 8.0 Hz),
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00812.
■
S
1H, 13C NMR and IR spectra of compounds (PDF)
X-ray data (CIF)
X-ray data (CIF)
X-ray data (CIF)
X-ray data (CIF)
7.28−7.35 m (5H), 7.39−7.41 m (2H), 7.48−7.52 m (2H), 7.55−
7.59 m (1H), 8.12−8.15 m (2H). 13C{1H} NMR, δ, ppm: 21.2, 48.7,
124.5, 127.3, 128.4, 128.7, 128.9, 129.0, 129.1, 129.5, 132.8, 136.9,
137.0, 140.1, 172.6, 175.9. IR (KBr, cm−1): 1561. HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C22H18N2ONa 349.1312; Found 349.1318.
3-((4-Fluorolphenyl)phenylmethyl)-5-methyl-1,2,4-oxadia-
zole (2w). Obtained from the p-fluoro-β-nitrostyrene 1d (30 mg,
0.18 mmol), benzene (21 mg, 0.27 mmol), and acetonitrile (5 mL).
AUTHOR INFORMATION
Corresponding Author
*E-mail: aleksvasil@mail.ru, a.vasilyev@spbu.ru
ORCID
Aleksander V. Vasilyev: 0000-0003-3628-1492
Notes
■
1
Yield 37 mg (77%). Transparent oil. H NMR, δ, ppm: 2.58 s (3H),
5.57 s (1H), 6.96−7.06 m (2H), 7.27−7.36 m (7H). 13C{1H} NMR,
δ, ppm: 12.6, 48.0, 115.9 d (J 21.5 Hz), 127.5, 128.8, 128.9, 130.5 d (J
8.0 Hz), 135.5 d (J 3.4 Hz), 139.6, 162.1 d (J 247.1 Hz), 171.7, 176.9.
19F NMR, δ, ppm: −115.39 s. IR (KBr, cm−1): 1587 (CN). HRMS
(ESI-TOF) m/z: [M + Ag]+ Calcd for C16H13FN2OAg 375.0070;
Found 375.0070.
The authors declare no competing financial interest.
CCDC 1888351 (2i), CCDC 1894770 (2n), CCDC 1894769
(2o), and CCDC 1894768 (2x) contain the supplementary
crystallographic data, which can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: (internat.) + 44-1223-336-
033; E-mail: deposit@ccdc.cam.ac.uk.
3-((4-Fluorophenyl)-(2,5-dimethylphenyl)methyl)-5-meth-
yl-1,2,4-oxadiazole (2x). Obtained from the p-fluoro-β-nitrostyrene
1d (30 mg, 0.18 mmol), p-xylene (29 mg, 0.27 mmol), and
acetonitrile (5 mL). Yield 48 mg (90%). Colorless solid, mp 93−94
1
°C. H NMR, δ, ppm: 2.26 s (3H), 2.28 s (3H), 2.59 s (3H), 5.22 s
(1H), 6.99−7.03 m (4H), 7.08 d (1H, J 8.1 Hz), 7.19−7.23 m (2H).
13C{1H} NMR, δ, ppm: 12.6, 19.3, 21.3, 44.7, 115.5 d (J 21.5 Hz),
128.3, 129.2, 130.6 d (J 8.1 Hz), 130.8, 133.2, 134.9 d (J 3.2 Hz),
135.8, 137.3, 162.0 d (J 245.9 Hz) 171.9, 176.9. 19F NMR, δ, ppm:
−115.5 s. IR (KBr, cm−1): 1588 (CN). HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C18H17FN2ONa 319.1203; Found 319.1217.
3-((4-Chlorophenyl)phenylmethyl)-5-methyl-1,2,4-oxadia-
zole (2y). Obtained from the p-chloro-β-nitrostyrene 1e (30 mg, 0.16
mmol), benzene (19 mg, 0.25 mmol), and acetonitrile (5 mL). Yield
ACKNOWLEDGMENTS
■
This work was supported by Russian Scientific Foundation
(Grant No. 18-13-00008). Spectral studies were performed at
Center for Magnetic Resonance, Center for Chemical Analysis
and Materials Research, and Research Center for X-ray
Diffraction Studies of Saint Petersburg State University, Saint
Petersburg, Russia. A.A.G. thanks O. Brunko for support of this
work.
1
45 mg (96%). Yellowish oil. H NMR, δ, ppm: 2.58 s (3H), 5.56 s
(1H), 7.27−7.30 m (5H), 7.31−7.32 m (3H), 7.33−7.34 m (1H).
13C{1H} NMR, δ, ppm: 12.6, 48.1, 127.6, 128.8, 128.87, 128.90,
130.3, 133.3, 138.2, 139.3, 171.5, 177.0. IR (KBr, cm−1): 1587 (C
N). HRMS (ESI-TOF) m/z: [M + Ag]+ Calcd for C16H13ClN2O
390.9766; Found 390.9762.
REFERENCES
■
3-((4-Chlorophenyl)-(2,5-dimethylphenyl)methyl)-5-meth-
yl-1,2,4-oxadiazole (2z). Obtained from the p-chloro-β-nitrostyrene
1e (30 mg, 0.16 mmol), p-xylene (26 mg, 0.25 mmol), and
(1) Vivona, N.; Buscemi, S. An Assay for 1,2,4- and 1,2,5-
Oxadiazoles. Heterocycles 1995, 41, 2095−2116.
E
DOI: 10.1021/acs.joc.9b00812
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(2) Hemming, K. Recent developments in the synthesis, chemistry
and applications of the fully unsaturated 1,2,4-oxadiazoles. J. Chem.
Res. 2001, 2001 (6), 209−216.
(23) Zarei, M. A mild and efficient one-pot preparation of 1,2,4-
oxadiazoles from nitriles and carboxylic acids using Vilsmeier reagent.
Chemistry Select 2018, 3, 11273−11276.
(24) Augustine, J. K.; Hegde, S. G.; Alagarsamy, P.; et al. PTSA-
ZnCl2: an efficient catalyst for the synthesis of 1,2,4-oxadiazoles from
amidoximes and organic nitriles. J. Org. Chem. 2009, 74, 5640−5643.
(25) Nishiwaki, N.; Kobiro, K.; Hirao, S.; Sawayama, J.; Saigo, K.;
Ise, Y.; Okajima, Y.; Ariga, M. Inverse electron-demand 1,3-dipolar
cycloaddition of nitrile oxide with common nitriles leading to
functionalized 1,2,4-oxadiazoles. Org. Biomol. Chem. 2011, 9, 6750−
6754.
(3) Kayukova, L. A. Synthesis of 1,2,4-Oxadiazoles (a review).
Pharm. Chem. J. 2005, 39, 539−547.
(4) Sui Xiong, C.; Drewe, J.; Kasibhatla, S. A Chemical Genetics
Approach for the Discovery of Appotosis Inducers: From Phenotypic
Cell Based HTS Assay and Structure-Activity Relationship studies, to
Identification if Potential Anticancer Agents and Molecular Targets.
Curr. Med. Chem. 2006, 13, 2627−2644.
(5) Hemming, K. 1.2.4-Oxadiazoles. Comprehensive Heterocyclic
Chemistry III. 2008, 5, 243−314.
(6) Pace, A.; Pierro, P. The new era of 1,2,4-oxadiazoles. Org.
Biomol. Chem. 2009, 7, 4337−4348.
(7) Bokach, N. A.; Kuznetsov, M. L.; Kukushkin, V. Y. 1.3-Dipolar
cycloaddition of nitrone-type dipoles to uncomplexed and metal-
bound substrates bearing the CN triple bond. Coord. Chem. Rev. 2011,
255, 2946−2967.
(8) Bora, R. O.; Dar, B.; Pradhan, V.; Farooqui, M. 1,2,4-
Oxadiazoles: Synthesis and Biological Applications. Mini-Rev. Med.
Chem. 2014, 14, 355−369.
(9) Pace, A.; Buscemi, S.; Piccionello, A. P.; Pibiri, I. Chapter Three:
Recent Advances in the Chemistry of 1,2,4-oxadiazoles. Adv.
Heterocycl. Chem. 2015, 116, 85−136.
(26) Nikodemiak, P.; Koert, U. Metal-Catalysed Synthesisof
Functionalized 1,2,4-Oxadiazoles from Silyl Nitronates and Nitriles.
Adv. Synth. Catal. 2017, 359, 1708−1716.
(27) Yoshimura, A.; Nguyen, K. C.; Klasen, S. C.; Saito, A.;
Nemykin, V. N.; Zhdankin, V. N. Preparation, structure, and versatile
reactivity of pseudocyclic benziodoxole triflate, new hypervalent
iodine reagent. Chem. Commun. 2015, 51, 7835−7838.
(28) Vasilyev, A. V. Electrophilic activation of acetylene in Brønsted
superacids. Reactions of vinyl type cations. Russ. Chem. Rev. 2013, 82,
187−204.
(29) Kazakova, A. N.; Vasilyev, A. V. Trifluoromethanesulfonic acid
in organic synthesis. Russ. J. Org. Chem. 2017, 53, 485−509.
(30) Golushko, A. A.; Sandzhieva, M. A.; Ivanov, A. Yu.; Boyarskaya,
I. A.; Khoroshilova, O. A.; Barkov, A. Yu.; Vasilyev, A. V. Reactions of
3,3,3-trihalogeno-1-nitropropenes with arenes in the superacid
CF3SO3H: synthesis of (Z)-3,3,3-trihalogeno-1,2-diarylpropan-1-one
oximes and study on the reaction mechanism. J. Org. Chem. 2018, 83,
10142−10157.
(10) Aghazadeh Tabrizi, M.; Baraldi, P. G.; Borea, P. A.; et al.
Medicinal Chemistry, Pharmacology, and Potential Therapeutic
Benefits of Cannabinoid CB2 Receptor Agonists. Chem. Rev. 2016,
116, 519−560.
(31) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A.
K.; Puschmann, H. OLEX2: a complete structure solution, refinement
and analysis program. J. Appl. Crystallogr. 2009, 42, 339−341.
(32) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr.,
Sect. A: Found. Crystallogr. 2008, 64, 112−122.
(11) Piccionello, A. P.; Pace, A.; Buscemi, S. Rearrangements of
1,2,4-oxadiazole: “one ring to rule them all. Chem. Heterocycl. Compd.
2017, 53, 936−947.
(12) Bostrom, J.; Hogner, A.; Llinas, A.; Wellner, E.; Plowright, A. T.
Oxadiazoles in Medicinal Chemistry. J. Med. Chem. 2012, 55, 1817−
1830.
(33) Shechter, H.; Ley, D. E.; Roberson, E. B., Jr. Nitroalkanes from
Conjugated Nitroalkenes by Reduction with Complex Hydrides. J.
Am. Chem. Soc. 1956, 78, 4984−4991.
(13) Palazzo, G.; Corsi, G. Arzneim.-Forsch. 1962, 12, 545−549.
(14) Coupar, I. M.; Hedges, A.; Metcalfe, H. L.; Turner, P. Effect of
aminophenylline, butalamine and imolamine on human isolated
smooth muscle. J. Pharm. Pharmacol. 1969, 21, 474−475.
(15) Jones, A. M.; Helm, J. M. Emerging Treatments in Cyclic
Fibrosis. Drugs 2009, 69, 1903−1910.
(16) de Oliveira, V. N. M.; dos Santos, F. G.; Ferreira, V. P. G.;
Araujo, H. M.; do O Pessoa, C.; Nicolete, R.; de Oliveira, R. N.
Focused microwave irradiation-assisted synthesis of N-cyclohexyl
derivatives with antitumor activity. Synth. Commun. 2018, 48, 2522−
2532.
(34) Balachandra, B.; Shanmugam, S.; Muneeswaran, T.;
Ramakritinan, M. Iodine catalyzed one-pot synthesis of highly
substituted N-methyl pyrroles via [3 + 2] annulation and their in
vitroevaluation as antibacterial agents. RSC Adv. 2015, 5, 64781−
64789.
(17) Zarei, M. A Mild and Efficient One-Pot Preparation of 1,2,4-
Oxadiazoles from Nitriles and Carboxylic Acids Using Vilsmeier
Reagent. ChemistrySelect. 2018, 3, 11273−11276.
(18) Li, E.; Wang, M.; Wang, Z.; Yu, W.; Chang, J. NBS-mediated
practical cyclization of N-acyl amidines to 1,2,4-oxadiazoles via
oxidative N−O bond formation. Tetrahedron 2018, 74, 4613−4618.
(19) Pankrat’eva, V. E.; Sharonova, T. V.; Tarasenko, M. V.; Baikov,
S. V.; Kofanov, E. R. One-Pot Synthesis of 3,5-Disubstituted 1,2,4-
Oxadiazoles Using Catalytic System NaOH-DMSO. Russ. J. Org.
Chem. 2018, 54, 1250−1255.
(20) Sharonova, T.; Pankrat'eva, V.; Savko, P.; Baykov, S.; Shetnev,
A. Facile room-temperature assembly of the 1,2,4-oxadiazole core
from readily available amidoximes and carboxylic anids. Tetrahedron
Lett. 2018, 59, 2824−2827.
(21) Baykov, S.; Sharonova, T.; Shetnev, A.; Rozhkov, S.; Kalinin, S.;
Smirnov, A. V. The first one-pot ambient-temperature synthesis of
1,2,4-oxadiazoles from amidoximes and carboxylic esters. Tetrahedron
2017, 73, 945−951.
(22) Tarasenko, M.; Duderin, N.; Sharonova, T.; Baykov, S.;
Shetnev, A.; Smirnov, A. Room-temperature synthesis of pharmaceuti-
cally important carboxylic acids bearing the 1,2,4-oxadiazole moiety.
Tetrahedron Lett. 2017, 58, 3672−3677.
F
DOI: 10.1021/acs.joc.9b00812
J. Org. Chem. XXXX, XXX, XXX−XXX